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DESIGW AND SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS WITH SULPHUR AND
NITROGEN CONTAINING HETEROCYCLES AND RELATED COMPOUNDS
RESUME
T H E S I S SUBMITTED FOR THE DEGREE OF
Mottor of PliUogopIip IN
C H E M I S T R Y
BY
MUJEEBUR RAHMAN V. P
DEPARTMENT OF CHEMISTRY FACULTY OF SCIENCE
ALIGARH MUSLIM UNIVERSITY ALIGARH (INDIA)
2002
RESUME
The thesis describes the work related to synthesis, structure elucidation
stereochemistry and biological assay (anticancer and antimicrobial screening)
grouped in three parts Wdti six chapters as long alkyl chain substituted-j'-
tr iazolo-thiadiazepines, long alkyl chain substi tuted-benzopyrano-^-tr iazolo-
thiadiazepines, long alkyl chain substi tuted-^-triazolo-thiadiazoles, 2-aryl-3-
7V-long alkyl chain substi tuted-thiazolidin-4-ones/thiazan-4-one, 2-aryl-2-
methyi-3-A^-long alkyl chain- •substituted-thiazolidin-4-one and biological
screening: study for anticancer and antimicrobial activity.
The techniques used for structure elucidation are 'H-NMR, '^C-NMR,
APT,NOE, 2DNMR (COSY, HETCOR) including DCI-MS, IR and FTIR.
PART ONE
l,2,4-TRIAZOLOf3,4-b|fl,3,4]THIADIAZEPINES/THIDIAZOLES
CHAPTER I. Long alkyl chain substituted-s-Triazolo-Thiadiazepines
4-Amino-5-mercapto- l ,2 ,4- t r iazoles and their A^-bridged heterocyclic
derivatives have received much attention during recent years on account of
their wide spectrum biological potentialities. The 1,2,4-triazole nucleus has
been incorporated into a wide variety of therapeutically interesting drugs
including Hi/H2-Histamine receptor blockers, cholinesterase active agents,
CNS stimulants, antianxiety agents and sedatives. Also 1,3,4-thiadiazepine
derivatives are associated with a varied range of biological activities such as
anticancer, anti-HIV, anticholinergic, antidepressant, anaesthetic, calcium
antagonist choleretics and ACE inhibitory activity. Prompted by these
observations and as part of our continuing programme in the search of
biologically active compounds with sulphur and ni t rogen containing
heterocycles, we have undertaken the synthesis of two novel compounds,
2-(4-chlorophenyl)-4-[2-(4-chlorophenyl)ethenyl]-7-(9-decenyl)-2,3-dihydro
-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine (4) and 2,4-bis(4-chlorophenyl)-7-
(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine (7) by the
reaction of 4-amino-3-(9-decenyl)-5-mercapto- l ,2 ,4- t r iazole (1) with ( i ) l ,5-
bis(4-chlorophenyl)pent- l ,4-dien-3-one (2) and (ii) 4 ,4 ' -dichlorochalcone (5)
.In each of the above synthesis, a Michael adduct of (2)/(5) and the s-triazole
(1) were also obtained. The reaction of (1) with l ,3 -b is (2- th ienyl )propen- l -
one (8) furnished only the Michael adduct (9) as the sole product . (Scheme 1)
The structures of these compounds were established on the basis of
spectral studies such as IR, DCI-MS, EI-MS, 'H-NMR, and '^C-NMR spectra.
LOT > K " ^ H H Y
(4) CI
(7)
(N X D u
o
dj c <u N C u JD b -C -o
^ — X JJ 3 c
.2 -CS <D KI N
I I S t ' aj -o T:
o
X C « <u c
c
•v
o o e
W •a c ra
vo
PO
<D c
J
i t 1 § D. iJ 2 ^ ~ o o
>>o • — -
m c o
-C
:5 W t/1 15 fo
w
K U CZ)
c <u a . o
c D
CHAPTER II. Long alkyl chain substituted-Benzopyrano-s-Triazolo-Thiadiazepines
As part of our programme in search of biologically active compounds and in
continuation of the work described in previous chapter, we extended our work on the
reaction of the ^-triazole (1) with exocyclic a;y^unsaturated enone systems and
synthesised two novel compounds, 2,3-bis(4-chlorophenyl)-ll-(9-decenyl)-2a,3-
dihydro[l]benzopyrano[3,4-e]-2,2a-dihydro-l,2t4-triazolo[3,4-b][l,3,4]thiadiazep-
ine (12) and 2,3-bis(phenyl)-ll-(9-decenyl)-2a,3-dihydro[l]benzopyrano[3,4-e}-
2,2a-dihydro-l,2,4-triaz olo[3,4-b][l,3,4]thiadiazepine (15) by the reaction of the i--
triazole (1) with £'-3-(4-chlorobenzylidene)-4'-chloro flavanone (10) and E-3-
benzyiidene flavanone (13) in dry benzene using j:?-TsOH as catalyst. An adduct, 2-
(4-chIorophenyl)-3-[3-(9-decenyl)-4-amino-5-(4-chlorobenzylthio)-l,2,4-triazolyl]-
2,3-dihydro-4-benzopyrone (11) in the former and 2-(phenyl)-3-[3-(9-decenyl)-4-
amino-5-(benzylthio)-l,2,4-triazolyl]-2,3-dihydro-4-benzopyrone (14) in the latter
was also obtained in good yields(Scheme 2).
(11), (14)
( 1 1 ) , ( 1 2 ) : R = R ' = C I
( 1 4 ) , ( 1 5 ) : R = R ' = H
( 1 2 ) , ( 1 5 )
The structures of these compounds were confirmed by IR, DCI-MS, 'H-NMR.
'^C-NMR, COSY and HETCOR spectral studies. The configurations at the three
stereogenic centres C-2, C-3 and C-l '" in compounds (11) and (14) were established
on the basis of the inspection of models and the values of coupling constants.
N N
SH +
O H
(10) R = R' = C1 (13) R = R' = H
Molar ratio (1:1) Diy benzene Reflux 38/32 h
(11) R = R' = C1 (14) R = R' = H
(12) R = R' = C1 (15) R = R' = H
SCHEME 2
6
CHAPTER HI. Long alkvl chain substituted-5-Triazolo-Thiadiazoles
1,2,4-Triazole and its derivat ives have been found to play vital role in
medic ine , agricul ture and industry. The fused r ing sys tems such as
5- t r iazolo[3 ,4-b] [ l ,3 ,4] th iad iazoles have varied range of b io logica l activities
as ant ibacter ia l , ant i fungal , antiinflammatory, antihypertensive, analgesic and
an the lmin t ic agents. These findings have tempted us to under take this
p rob lem on the synthesis of three new compounds, (i) 2-(4-methoxyphenyl)-
5-(9-decenyl)-2,3-dihydro-l,2,4-tnazolo[3,4-b] [l,3,4]thiadiazole (17) (ii) 2-
(4-chlorophenyl)-5-(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thia-
diazole (19) and (in) 2-(2-thienyl)-5-(9-decenyl)-2,3-dihydro-l,2,4-
triazolo[3,4-b][l,3,4]thiadiazole (21) f rom (i) p - a n i s a l d e h y d e ^ (ii)
/7-chlorobenzaldehyde and (iii) th iophen-2-a ldehyde respec t ive ly using
4-amino-3- (9-decenyl ) -5 -mercap to- l ,2 ,4 - t r i azo le (1) in the presence of a
catalyt ic amount of / j -TsOH. In each react ion, the co r re spond ing Schi f f bases
(16), (18), and (20) have also been obtained. The react ion of fu r fu ra ldehyde
with the t r iazole (1) yielded only the Schif f base (22) ( S c h e m e 3).
The structure of these compounds were es tabl ished on the basis of
spectral s tudies of IR, DCI-MS, ' H - N M R and '^C-NMR spectra .
N N
jl '1
I NH2 (1)
-CHO O - CHO
N N
I N = C H -
(16) R = 0CH3 ( 1 8 ) R = C1
N — N
( 2 0 ) X = S
( 2 2 ) X = O
+
N N
\ H N -
Q ( 1 7 ) R = 0 C H 3
( 1 9 ) R = CI
( 2 1 ) X = S
SCHEME 3
PART TWO
2,3-DISUBSTITUTEDTHIAZOLIDIN-4-ONES/THIAZAN-4-QNES
CHAPTER IV. 2-Arvl-3-iV-Long alkvl chain substituted-Thiazolidin-4-ones/Thiazan-4-one,
The interest in substituted thiazolidin-4-ones and thiazan-4-ones in
particular for medical application is increasing strongly. The thiazolidin-4-
ones, their derivatives and analogues have been found to exhibit usually high
in vitro activity against Mycobacterium tuberculosis, highly potent and
selective anti-Platelet Activating Factor activity and broad spectrum activity
against various diseases. Because 4-thiazolidinones substi tuted in the
2-posit ion were proven to be biologically very potent and selective and in
anticipation that by incorporating a long chain alkyl thioether moiety to
thiazolidin-4-one ring, the biological activity may be enhanced due to
lipophilization of the resulting molecule, we have under taken this problem. It
consists of the synthesis of the following four novel compounds , (i) 2-(3-
nitrophenyl)-3-[ll-(carboxymethylthio)undecanamido]thiazolidin-4-one (26),
(ii) 2-(3-nitrophenyl)-5-(methyl)-3-(10-undecenamido)thiazolidin-4-one (27)
and 2-(3-nitrophenyl)-5-(methyl)-3-[ll-{(l-carboxy)ethylthio}undecan-
amidoJthiazolidin-4-one (28), (Hi) 2-(3-nitrophenyl)-3-[ll-(2-carboxyethyl-
thio)undecanamido]tltiazan-4-one (30) f rom m-ni trobenzaldehyde-10-
undecenohydrazone (24) using mercaptoacetic acid in (i), 2-mercapto-
propionic acid in (ii) and 3-mercaptopropionic acid in (iii) in dry benzene. An
adduct, (25) in the former and (29) in the latter was also obtained in good
yields. (Scheme 1)
The compounds (24), (25) and (29) were found to exist in to be in its
two forms, synperiplanar (major) and antiperiplanar (minor) as represented
in F ig . 1. The s tructure and s tereochemistry of these compounds were
es tabl ished on the basis of IR, DCI-MS, 'H-NMR, '^C-NMR, NOE
experiments,COS Y and HETCOR spectral studies.
synperiplanar
H H
/ He ( 2 4 ) R = — C H = < ; ^
HZ
( 2 5 ) R = — ( C H 2 ) 2 — S — C F ^ - C O O H
( 2 9 ) R = — ( C H 2 ) 2 — S — C H J — C H 2 - C O O H
H R'
NO2
(26) R=
(27) R =
(28) R= -
-(CH2)2—S— CF^-COOH R' = H
— C H = < ( Hz
(CH2)2—S—CH-COOH
CH3
R = CH3
R = CH3
10
o z
O
(N JC
- I X' X , 5= 3 <U JJ i | i u § " c ^ fi I ^ ^ "o
.2 — S d « S O I-E iS ^ o I E
f s i O I ^ o u
i u
(N
I X C/i C/i 00 XXX
o fO
^
0 a c s -^ .o
1 s s s e C/5
S faJ I U c/D
11
CHAPTER V. 2-ArvI-2-Methvl-3-7V-Long alkyl chain substituted-Thiazolidin-4-one
As part of our programme in search of biologically active compounds with
sulphur and nitrogen containing heterocycles and in continuation of the above
mentioned work, we have undertaken this problem on the synthesis of 2-(4-
chlorophenyl-2-methyl-3-[l l-(carboxymethyl/2-carboxyethylthio)undecanamido]thi-
azolidin-4-ones/thiazan-4-one from /7-chloroacetophenone-10-undeceno-hydrazone
(31) using (i) mercaptoacetic acid and (ii) 3-mercapto propionic acid. An adduct,
(32) in the former and (35) as the sole product in the latter was also obtained
in good yields. (Scheme 1)
The structures of these compounds were established by IR, DCI-MS.
'H-NMR, '^C-NMR, NOE experiments, COSY and HETCOR spectral studies. Here
again the compounds (31), (32) and (35) were found to exist in its two forms,
synperiplanar (major) and antiperiplanar (minor) as represented in Fig. 2
( 3 2 ) R = — ( C H 2 ) 2 — S — C H 2 - C O O H
( 3 5 ) R = — ( C H 2 ) 2 - S - C H 2 - C H 2 - C 0 0 H
Fig. 2
12
O I
O::
to fO
. oo ^ <N
X
§ C g ^
.9 6 "tS
W S w W u CAJ
fO
o X
IT)
r<
01 c
- E O O
O ^
oi n: a:
fO
PART THREE
SCREENING FOR BIOLOGICAL ACTIVITY
CHAPTER VI. Study for Anticancer and Antimicrobial Activities
(A) A N T I C A N C E R A C T I V I T Y
The compounds (I) , (4), (7), (9), (12), (16), (17), (20), (21), (22), (24),
(26), (27), (30), (31) and (32) have been evaluated for ant icancer activity first
in the 3-cell lines of three types of human cancers: breast (MCF7), Lung
(NCI-H460) and CNS (SF-268) at one concentration as the one dose primary
anticancer assay. Out of the sixteen compounds screened, only one
compound, (27) was found to be active. This compound was then screened for
cytotoxic activity at five different concentrations against 60 cell lines of nine
types of human cancers: leukaemia, lung, colon, CNS, melanoma, ovarian,
renal, prostate and breast. This compound showed anticancer activity only at
higher concentration, Ix 10"^. Noteworthy results was obtained in the case of
non-small lung cancer, melanoma and renal where the reduct ion in growth is
75, 74 and 70 and 77% respectively .
(B) A N T I M I C R O B I A L ACTIVITY
A total of 10 compounds were tested against two Gram +ve bacteria
{Staphylococcus aureus, Bacillus subtilis) and two Gram -ve bacteria {Escherichia
coli, Pseudomonas aeruginosa) and a yeast, Candida albicans. Varying level of anti-
microbial activity was detected against one or more test organisms. Solvent control
(DMSO) showed non-significant inhibition to test microorganisms. Antimicrobial
activity against Gram -ve bacteria was deduced in all compounds. However such
activity could be detected only in four compounds against Gram +ve bacteria. The
14
compounds (25), (26), (30) and (31) demonstrated activity against both Gram +ve
and Gram -ve bacteria.
The compounds exhibited antimicrobial activity in the concentration range
200 ng to 500 fig/100 |il. Two compounds, (30) and (31) also demonstrated
antifungal (anticandidal) activity. Overall broad spectrum antimicrobial activity
i.e. active against Gram +ve and Gram -ve was deduced in (25), (26), (30) and (31).
These compounds may be directly explored in the preparation of topical antiinfective
agents. However, further exploration requires detailed study on exact MIC values and
least toxicity to host cell and system.
DESIGN AND SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS WITH SULPHUR AND
NITROGEN CONTAINING HETEROCYCLES AND RELATED COMPOUNDS
T H E S I S SUBMITTED FOR THE DEGREE OF
B o t t o r o f $ l ) i l Q ^ o p t ) p
IN
C H E M I S T R Y
BY
MUJEEBUR RAHMAN V. P
DEPARTMENT OF C H E M I S T R Y F A C U L T Y OF S C I E N C E
A L I G A R H MUSLIM U N I V E R S I T Y ALIGARH (INDIA)
2002
THESIS
DEPARTMENT OF CHEMISTRY A L I G A R H M U S L I M U N I V E R S I T Y
A L I O A R H — 2 0 2 0 0 2
P H O N E S Int. 3 1 7 3 1 8
Certtticate
I certify that the work presented in this thesis entitled "Design and
synthesis of biologically active compounds with sulphur and nitrogen
containing heterocycles and related compounds" has been carried out by
Mr. Mujeebur Rahman V.P. under my supervision. It is original in nature
and has not been submitted for any other degree.
(Prof. W.H. Ansari)
I bow my head with all humility and reverence to the Almighty
for the completion of this task.
Words fail to express my indebtedness that I owe to my erudite
research guide, Prof. Wajid Husain Ansari, who inspired to take up
this task. I will cherish throughout my life the valuable suggestions,
constructive criticism and unending support that 1 received from him
throughout the course of this study.
I wish to place on record the kind help received from Prof.
Shafiullah and Prof. M. Ilyas, who as Chairmen of the Department
provided all the necessary facilities for undertaking this research
problem. It is my privilege to have the guidance of Late Prof. M.S.
Ahmad, who as my teacher was generous enough in showing me the
right path. I would like to thank all the faculty members of the
department, specially, Dr. A. Rauf for their constant support and
encouragement.
I M!ish to express my veneration to Prof. G. Lemiere, University
of AntM'erp (RUCA), Belgium, who as our collaborator carried out the
spectral studies of our compounds. Dr. S.K. Raza and Dr.V.V. Singh,
Defence Research Development Organization, Gwalior, India are also
acknowledged deeply for their kind cooperation in providing some
spectra. The help received from National Cancer Institute, Maryland,
Bethesda, USA in carrying out the anticancer activity of our
compounds is also truly acknowledged. I wish to express my
benevolence to Dr. I. Ahmad, Department of Agricultural
Microbiology, Faculty of Agricultural Studies, A.M.U., Aligarh, India
for his help in the determination of antimicrobial properties of some
novel compounds.
/ M'ish to record my debt of gratitude to many people who directly
or indirectly extended their support and encouragement especially my
lab colleagues, Sayeed Mukhtar and S.P. Singh for their all out help
and manifold cooperation throughout the course of this work.
I would like to express my profound sense of gratitude and
felicitation to Mr. K. Alavi, Mr. Naushad, Mr L.K. Peter and Mustafa
Kausar for all the help received from them.
I find no words to express my feelings for my dear parents whose
blessings and prayers was always a source of inspiration to me. I will
always cherish the valuable advice of my Late father-in-law. Last but
not the least 1 thank my wife without whose magnanimous support
nothing could have been done and my son Waquid vt'ho waited patiently
and stayed without me for days. I also thank my all family members for
their concern and suggestions at various stages.
J
(Mujeebur Rahman V.P.)
CONTENTS
Synthesis, Structure Elucidation and Biological Screening
CHAPTERS Contents Pages
General Introduction (i-ii)
PART ONE: l,2,4-TRIAZOLO[3,4-b][l,3,4]THIADIAZEPINES/ 1-164 THIADIAZOLES
THEORETICAL 1-19
CHAPTER I : Long alkyl chain substituted-5-Triazolo-Thiadiazepines 20-68
DISCUSSION 20-58
EXPERIMENTAL 59-68
CHAPTER II: Long alkyl chain substituted-Benzopyrano-^-Triazolo- 69-115 Thiadiazepines
DISCUSSION 69-107
EXPERIMENTAL 108-115
CHAPTER III: Long alkyl chain substituted-5-Triazolo-Thiadiazoles 116-164
DISCUSSION 116-148
EXPERIMENTAL 149-156
REFERENCES 157-164
PART TWO : 2,3-DISUBSTITUTED THIAZ0LIDIN-4-0NES/ 165-286 THIAZAN-4-0NES
THEORETICAL 165-178
CHAPTER IV : 2-Aryl-3-A^-Long alkyl chain substituted-Thiazolidin- 179-243 4-ones/Thiazan-4-one
DISCUSSION 179-232
EXPERIMENTAL 233-243
CHAPTER V: 2-Aryl-2-Methyl-3-A^-Long alkyl chain substituted- 244-286 Thiazolidin-4-one
DISCUSSION 244-270
EXPERIMENTAL 271-276
REFERENCES 277-286
PART THREE: SCREENING FOR BIOLOGICAL ACTIVITY 287-300
CHAPTER VI : Study for Anticancer and Antimicrobial Activities 287-299
(A) ANTICANCER ACTIVITY 287-295
(B) ANTIMICROBIAL ACTIVITY 296-298
REFERENCES 299
CONCLUSION 300
LIST OF PUBLICATIONS 301
GENERAL INTRODUCTION
Heterocyclic compounds are very widely distributed in nature and are
essential to life as they play a vital role in the metabol ism of all living cells.
Thus, for example, the fol lowing are heterocyclic compounds: the pyrimidine
and purine bases of the genetic material DNA; the essential amino acids
proline, histidine and tryptophan; the vitamins and coenzyme precursors
thiamine, r iboflavine, pyridoxine, folic acid and biotin; the B12 and E families
of vitamin; the photosynthesizing pigment chlorophyll ; the oxygen
transport ing pigment hemoglobin, and its breakdown products the bile
pigments; the hormones kinetin, heteroauxin, serotonin and histamine,
together with most of the sugars. There are a vast number of
pharmacological ly active heterocyclic compounds, many of which are in
regular clinical use. Some of these are natural products , for example
antibiotics such as penicillin and cephalosporin, alkaloids such as vinblastine,
ellipticine, morphine and reserpine, and cardiac glycosides such as those of
digitalis. However, the large majori ty are synthetic heterocycl ics which have
found widespread use, for example as anticancer agents, analeptics,
analgesics, hypnotics and vasopressor modif iers , and as pesticides,
insecticides, weedkillers and rodenticides.
There is also a large number of synthetic heterocycl ic compounds with
other important practical applications, as dyestuffs , copolymers , solvents,
photographic sensitizers and developers, as ant ioxidants and vulcanization
accelerators in the rubber industry, and many are valuable intermediates in
synthesis.
The broad spectrum of biological activities associated with these
compounds and the multiplicity of action displayed by certain individual
members make them one of most interesting class of compounds . The current
research in organic chemistry and closely allied branches of biology is
characterized by extensive investigation of physiologically active compounds
encountered in the plant and animal world. The search for these active
constituents which control the biological process of various systems have
acted as a powerful st imulus to the further development of the chemistry of
heterocyclic compounds. Synthesising any useful organic compound is easier
than to isolate the same from natural resources. Therefore , in recent years
much effor t are being applied by chemists in synthesising such organic
compounds which possess high degree of biological activities. Innumerable
heterocyclic compounds have been prepared across the world for better
therapeutics, part icularly the compounds having hetero atoms such as O, S
and N.
A study on the inf luence of structure on activity shows that sometimes
a minor change in heterocyclic nuclei enhances the pharmacological profi le
many folds than its parent nuclei. The search for new eff ic ient and safe nuclei
lead to an improvement in the existing drugs by increasing their potency,
duration of action and decreasing side effects as well as creating new
biologically active agents by molecular modificat ion.
The successful application of heterocyclic compounds in these and
many other ways, and their appeal as materials in applied chemistry and in
more and fundamental and theoretical studies ensures virtually limitless
series of structurally novel heterocyclic compounds with wide range of
physical, chemical and biological properties.
Keeping in view of the importance of heterocyclic compounds , we
have undertaken this problem on 'Design and Synthesis of Biologically
Active Compounds with Sulphur and Nitrogen Containing Heterocycles ' -
A H
1,2,4-TRIAZ0L0[3,4- b]ll,3,4J THIADIAZEPINES/THIADIAZOLES
I jy "'J »I ^^
J J, J a U J J r .
THEORETICAL
Thiadiazepines and thiadiazoles are two important classes of
biologically active seven and five membered heterocycles containing one
sulfur and two nitrogen atoms. The isomeric structures are also possible for
thiadiazepine and thiadiazole rings depending upon the relat ive posit ions of
the three heteroatoms and the degree of oxidation of the ring systems.
Thiadiazepines and thiadiazoles having sulfur and ni t rogen atoms at 1,3,4-
posit ions are called 1,3,4-thiadiazepines and 1,3,4-thiadiazoles (I and II) .
N N
R^ III
N N
R' "N-/
N
R •R'
V R^
4 N - N 3
II
R'
N N
•N
N:
IV R'
R = Alkyl/Aryl/Heterocyclic r ' = Alkyl/Aryl/Heterocyclic
R^ R^ = H/Alkyl/Aryl
R'
N N
\ H N -
VI
R'
l ,2 ,4-Triazolo[3,4-b][ l ,3 ,4] thiadiazepine/ thiadiazole ( I I I / IV) are the
fused rings system of 1,2,4-triazole with l ,3 ,4- th iadiazepine/ l ,3 ,4- th iadiazole
and their dihydro derivatives are represented by the s t ructures (V) and (VI)
respectively.
2
1,3,4-Thiadiazepine derivatives are associated witli a varied range of
biological activities such as antimicrobial'"^, anticancer^, he rb i c ida^ ' ^ anti-
viral^, anti-HIV'®"'"', anticholinergic'^, antidepressant'^"'^, anaes thet ic '^
cholere t ics '^ calcium antagonist '^ and A C E inhibitory'^ activity. They have
also gained industrial imiportance as charge generators for
electrophotographic photoconductors^"®-'' and photoreceptors^^^
The 5-Triazoio-thiadiazole derivatives have been extensively studied in
the recent past. Numerous reports are available in the literature which
highlight their chemistry and use. l ,2 ,4-Tr iazolo[3 ,4-b][ l ,3 ,4] th iadiazole
derivatives have been found to be associated with diverse biological activities
such as antibacteriaP'"^^ antifungaP'"^^'^^"^®, anti-inflammatory^"''^'"^-',
anthelmintic^'•^^ ana lges ic" , antihypertensive^^-^^'"''', herbicidal' '" and
pesticidal activity'^'.
Several methods are reported for the synthesis of 1,2,4-triazolo[3,4-
b][ l ,3 ,4] thiadiazepines and l ,2 ,4~tr iazolo[3,4-b][ l ,3 ,4] thiadiazoles .
l , 2 ,4 -Tr iazo lo f3 ,4 -b] f l , 3^4] th iad iazep ines
The substituted and unsubst i tu ted-4-amino-3-mercapto- l ,2 ,4- t r iazoles
on cyclocondensat ion with ^./^-unsaturated ketones in presence of acidic or
basic catalyst yield 6 ,8-disubst i tu ted- l ,2 ,4- t r iazolo[3 ,4-b][ l ,3 ,4] th iadia-
zepines.
N.N. Koles et al.''^" have reported the s tereoselect ive addition of
4-amino-3-mercapto- l ,2 ,4- t r iazole with acetylenic ketone to give the Michael
adduct (VII) which on cyclocondensation with D M F yielded 6,8-diphenyl-
1,2,4-triazolo [3,4-bJ [1,3,4] thiadiazepines (VIII). Similar reaction of the
4-amino-3 -mercap to - l , 2 ,4 - t r i azo le with 4-n i t rocha lcone a f fo rded only the
Michae l adduct (IX) and all a t tempts fai led to undergo cyclocondensation'*^' ' .
N N
I NH2
O N N Ph
Ph SH
O2N.
NO2 0
N N
I NH2
0
•Ph
IX
N N
VIII Ph
J.E. Glo tova et a l / ^ have shown that the pheny l subs t i tu ted acetyl inic
ke tone with 4 -amino-3 -mercap to - l , 2 ,4 - t r i azo le in acet ic acid g ives6 ,8-d iphe-
nylsubs t i tu ted- l ,2 ,4- t r iazolo[3 ,4- -b] [ l ,3 ,4] th iad iazepine (X ) whi le unsubst i -
tu tedacety l in ic ke tone yieldsonly the Michael adduct (XI).
N N
N ^SH
O
'Ph
AcOH
NH2
AcOH
0
Ph
N N O
NH^ XI
-Ph
N N
I N
Recent ly , U.V.Laddi et al."^'' have synthes ised 3-subs t i tu ted-6 ,8-
d iphenyl -d ihydro- l ,2 ,4 - t r i azo lo [3 ,4 -b] [ l ,3 ,4 ] th iad iazep ine (XII) by the
cyc locondensa t ion of 3 - subs t i tu ted-4-amino-5-mercap to- l ,2 ,4 - t r i azo les with
cha lcone in presence of catalytic amount of acetic acid.
N N N N O
+ R"
I NH2
Ph AcOH^
MeOH
R = Ph PI
=N-0-(CH2)n-
=N-0-(CH2)n-
R' N ' I
N
Ph
Ph
XII
B. Kal luraya et al.'*''^ reported that the ace ty len ic ke tones on
condensa t ion with 3 - subs t i tu ted-4 -amino-5-mercap to - l ,2 ,4 - t r i azo les in
ethanol f irst gave the Michael adduct , l - a ry l -3 - (5 -n i t ro -2- th ieny l ) -3 - [3 -
sus t i tu ted-4-amino-5-mercap to- l ,2 ,4 - t r i azo le (XIII) wh ich on fur ther
t rea tment wi th conc. H2SO4 yielded 6 -a ry l -8 - (5 -n i t ro -2- th ieny l ) - l ,2 ,4 - t r i azo lo
[3 ,4 -b] [ l ,3 ,4 ] th iad iazep ines (XIV).
NO-
N N
Ph'
XIV
Ph
O
N N
/^N-^SH ^ I
NH2
EtOH, A
r
N N
N' EtOH/conc. H2SO4
Ph'
O C-
X I I I
N02
R = H, CH3, C2H5, C3H7, Phenyl, jPtolyloxymethyl
In a similar reaction'*''®''', a - b r o m o c h a l c o n e on condensa t ion with
3 - subs t i tu ted-4-amino-5-mercap to- l ,2 ,4 - t r i azo les us ing sodium acetate as
catalyst a f fo rded the Michael adducts (XVa-d) which on cycl i sa t ion furnished
the cor responding t r iazolo- thiadiazepines (XVIa-d).
Ar'
Br N N
,Ar + NaOAc / EtOH.
0 R / ^ N - - S H
N H ,
N N
A
•N-^S -HBr
Ar XVI a d
a: Ar = Phenyl Ar' = 2-Nitrothienyl b: Ar = Phenyl Ar' = /?-anisyl c: Ar = p-chiorophenyl, Ar' =p-Tolyl. d: Ar= Phenyl
N N
A r -
N N H , O X- Ar'
Br
XVa-d
i-H20
N
R' I
N
\ O h Br
Ar'
When 3-ary l -2-bromo-1 - [4- (n i t ro-2- th ienyl ) ]propen-1 -one condensed
with 3 - subs t i tu ted-4-amino-5-mercap to - l ,2 ,4 - t r i azo les , the produc t obtained
was 3-subs t i tu ted-7-a ry l idene-6- (4-n i t ro -2- th ienyl ) - l ,2 ,4 - t r i azo lo[3 ,4-b]
[l,3,4]thiadiazines'*'*'^ (XVII) instead of the expec ted t r iazo lo- th iad iazepines .
NO2 N- -N
R' ' N ^ SH I
NH2 NaOAc/EtOH, A
N-
R" "N I
N
-N N-
R'
Ar
'N' I N,
• N
O2N Ar = Phenyl,/?- anisyl, p-chlorophenyl, /p-methylphenyl XVll
^CH-Ar
O2N
They'*'''' have also synthesised novel 3-subs t i tu ted-6- (3-ary l
sydnony l ) -8 -a ry l - l ,2 ,4 - t r i azo lo [3 ,4 -b ] [ l ,3 ,4 ] th iad iazep ines ( X V I I I ) by
reac t ing 2 -b romo- l - (3 - a ry l sydnony l ) -3 - a ry l -2 -p ropen - l -one wi th 3-subst i -
tu t ed -4 -amino-5-mercap to - l ,2 ,4 - t r i azo les in ethanol in p resence of sodium
acetate.
N - • N
R ' "N SH
N H , O O
Ar = Ph, Ph-0CH3 R = CH3_ Ph, o-cresyloxymethyl,
p-cresyloxymethyl R'= H, CH3, OCH3.
N -
N - N E t O H , N a O A c 0 N / K , ^ Ar
R' 0
O
•N' /
• N
O,® N.
XVIII ^R'
G.J. Reddy et al.'^^ have synthesised 7 - (2 ' -hydroxybenzo ly l ) -3 -phenyl -
l ,2 ,4 - t r i azo lo [3 ,4 -b ] [ l ,3 ,4 ] th iad iazep ines (XIX) by the react ion of
3 - f o r m y l c h r o m o n e s with 3 -pheny l -4 -amino-5 -mercap to - l , 2 ,4 - t r i azo le s in
presence o fBu4N^HS04~ catalyst .
N N
P h - ^ N ^ S H O H C
N H ,
r ' = H, Me, CI, Br, R^ = H, Me
XIX
A.M. El -Sayed et al.'^^ have repor ted the synthes is of 3-( t r i f luro-
methyl ) -6-amino-7 ,8-d isubs t i tu ted-1 ,2 ,4- t r iazo lo[3 ,4-b] [ 1 ,3 ,4] th iadiazepines
(XX) by the react ion of 4 -amino-5 -mercap to - (3 - t r i f l u rome thy l ) - l , 2 ,4 - t r i azo le
with yl id ine malononi t r i les .
N N N C 33 IM N
F3C Y SH ^ NHj
, 1
R' F r- "N F3C I N
R = H, Ph, 4-CIC6H4, 4-NO2C6H4,2-Pyrrolyl, HjN 2-Pyridyl
R^ = CN, C02Et
R"
X X
The react ion of 3 - subs t i tu ted -4 -amino-5-mercap to - l ,2 ,4 - t r i azo les with
2 ,4 -pen tand ione yielded 3-subs t i tu ted-6 ,8-d imethyl - l ,2 ,4- t r iazolo[3 ,4-
b][13,4] th iadiazepines ( X X l / ' - ' ^
N N H" R
R = 3-Me,3-Me, 4-Me, 4-NO2, 4 - C l , 2—Br, Me
; "Me
XXI
N i z a m u d d i n et al.^ have prepared some 3 -a ry loxyme thy l -8 -n i t ro - l , 2 , 4 -
t r i azo lo[3 ,4 -b] [ l ,3 ,4 ]benzoth iad iazep ines ( X X I I I ) as po ten t herb ic ida l agent
by the cycl isa t ion of 5 -a ry loxymethy l -4 - (2 -ch loro-5-n i t robenzy l ideneamine) -
3 -mercap to - l , 2 ,4 - t r i azo le s (XXI I ) with pyridine.
NO. N N
OCH2- + OHC-'N SH
I NH2 CI'
O MeOH
R N N
-OCH2- -^SH CI
N = C H
XXII
R
Pyridine
NO2
R = 2 - C 1 , 4 -C i ,2 ,4-Ci2 . 2-CH3, 4 - C H 3
N N
-OCH2
/ V
xxni
s 3
NO2
B Prabhuswami et al have synthesised s- tr iazolo th iadiazepino-
quinol ines (XXIV) by the condensat ion of ch loroformyl quinol ines with
3 - subs t i t u t ed -4 -amino -5 -mercap to - l , 2 ,4 - tnazo l e s The base catalysed faci le
in t ramolecular rearrangement of (XXIV) yielded 5- t r iazolothiadiazino-
qumol ines (XXV) by the rearrangement involving N - N bond scission
CHO N N
NH,
XXIV XXV
R = H Mc CI R' = Me Ph X = C1
A Brukstus et al ^ have shown that the cyc locondensa t ion ol
pyr imidine carboxaldehyde with benz imidazole th iones gave benzimidazo
[2 , l -b ]pyr imido[5 ,4 - f ] [ l , 3 ,4 ] th i ad iazep ine ( X X V I ) and 5H-benz imidazo
[ 2 ' , r 2 ,3 ] [ l ,3 ] th iaz ino[6 ,5 -d]pyr imid ine (XXVII )
MeS. ^ N .
N,
CI
H
^CHO H2N' Q
NaOAc
MeS^ N. ^ S
N;
Ci :N
XIII
-N. .N
OH CI
XXVIl
A.Kakeh i et al.^' have carried out the react ion of unsymmetr ica l ly
subst i tu ted 1-pyr id in ioamidates (XXVIIIa-e) wi th d imethylace ty lene
d icarboxyla te ( D M A D ) which a f fo rded the corresponding d imethyl -2-ary l -6-
me thy l -5aH-pyr ido [ l , 2 -d ] [ l , 3 ,4 ] th i ad iazep in -4 ,5 -d ica rboxy la t e s (XXIXa-e)
along wi th the rearranged produc ts (XXXa-e) in minor amount . Similar
react ion of l - (2 -methy lqu ino l ino)amida tes (XXVIII f ,g ) wi th D M A D gave
only d ime thy l -2 -a ry l -5a -methy l -5aH- l ,3 ,4 - thad iazep ino [4,5-a] quinol ine-
4 ,5-d icarboxyla tes (XXXm,n)^'.
COjMe CHCI3, 50-60°C
COiMe 8h
R', R2 = (CH=CH)2-
R4 = Me
r ' = R'' = H, R = Me CHCI3, 50° - 60°C 4h
Me COjMe
Ar XXIX a - e
R '
COjMe
Ar
'Me
COOMe COOMe
n : Ar = 2-thienyl
XXX a - e COiMe
R' R^ Ar
Me H H Ph
Me H H ;?-MeC6H4
Me H H p- M e O C e H
Me H H P-CIC6H4
Me H H 2- th ienyl
H Me Ph
H Me 2- th ienyl
a
b
c
d
e
f
H
H
H
H
H
-(CH=CH2)-
-(CH=CH2)-
1 0
J Bolos et al have reported the multistep asymmetr ic synthesis of
(3R,rS)-3-[ l ( -carboxy-3-phenylpropyl)amino]-4-oxo-2,3 ,4 ,5- te t rahydropyrrolo-
[2 , ] -b ] [ ] ,3 ,4 ] th iad iazep ine-5-ace t ic acid (XXXIId ) , a potent A C E inhibition
active agent f rom A/^-carbobenzoxy-L-senne through a sequence involving
pyrrole th iocyanat ion, fo l lowed by the reduct ive c leavage of the th iocyanate
group, and cyclisat ion of the result ing halo-thiol m the key synthet ic steps
Thus ( /^ ) -2- [ (benzyloxycarbonyl )amino] -3- iodo- / / - (2 - th iocyana to- l -pyr ro ly l )
p ropanamide (XXXI) (prepared f rom A^-carbo-benzoxy-L-serine) , on
reduct ive t reatment with NaBH4 afforded ( /^ ) -3- [ (benzyloxycarbonyl )amino]-
2 .3 ,4 ,5- te t rahydropyr ro lo[2 , l -b] [1 .3 ,4] th iad iazepin-4-one ( X X X I I )
NHZ HO. ^
HO i) DDC/N-H^drovs'succinimidc ^COOH ^ ^
») N-NH2
N
Z N H ^ \ / N H
o I
Z N H — - NH
O
XXXI
Thiadiazepin-4-one (XXXII ) on t reatment with e thy lb romoace ta t e in
the presence of sodiumethoxide af forded ( X X X I I a ) wh ich on hydrolyt ic
c leavage with lodo tnmethy l s i l ane (ISiMes) a f fo rded ( X X X I I b ) Alkylat ion of
( X X X I I b ) with racemic e thy l -2-bromo-4-phenylbu tanoa te gave ( X X X I I c )
which on hydrolysis a f forded the target molecule ( X X X I I d )
1 1
Z N H '
/ N ' I BrCHzCOOEt
N H NaOEt *
o
(XXXII)
. N
0 COOEt
(XXXIIb)
ZNH
/ ^ N - ^
V S o C O O E t
(XXXIIa)
i) IS iMe j
ii) M e O H
R = Et R = H
(XXXIId)
Recently, V.A. Bakulev and co-worker s . " have reported the first
synthesis of some novel bis t r iazolo[ l ,3 ,6] thiadiazepine derivatives by the
base catalysed condensation of aromatic and al iphatic 1,2-diamine with
5-chloro- l ,2 ,3- th iadiazoles via a multistep process which is thought to
involve two Dimroth rearrangements and subsequent loss of hydrogen-
sulphide by intramolecular nucleophilic subst i tut ion. Thus, when
5-chlorothiadiazole ester (2 equiv) on reaction with 1,2-phenylenediamine
( l equ iv ) in presence of EtsN undergo Dimroth rear rangement to yield a
mixture of 5-( l ,2 ,3- t r iazol -5-ylsul fanyl) - l ,2 ,3- th iadiazoles (XXXIIIa-e) and
novel b is t r iazolo[ l ,5-b;5 ' , r - f ] [ l ,3 ,6] thiadiazepine derivatives (XXXIVa,d-e).
Prolonged heating of the reaction mixture gave (XXXIVa,d-e ) as the pure
products. Saponificat ion of (XXXIVa,d-e) gave the diacid (XXXIVf) which
on decarboxylat ion by heating to melt at 180 °C gave the bistriazolo
[ l ,3 ,6] thiadiazepine (XXXIVg)
1 2
N // \ • ci
H2N
H2N' Q EtjN, EtOH Reflux
a: r ' = R^ = COjEt b: r ' = R = CONH2 c: r ' = R^ = CONHMe d: r ' = CONH2, R^ = C02Et e; R ' = CONHMe, R^ = C02Et
N -
J \ NH
. N H ,
N -
N // w R2 ,NH2
XXXIII a-e
N -
N '/ \ N SH
,NH2
N W / N-N N-
XXXIV a, d-e
n - n n - n 180 °C
iNaOH, thenHCl ^ (Saponification)
COOH COOH
N , \\ I
(Decarboxylation) N - N N - n '
/ ' ^ \
XXXIV g XXXIV f
l ,2 ,4-TriazoIof3 ,4-b][ l ,3 ,41thiadiazoles .
3,6-Disubsti tuted-2,3-dihydro-l ,2,4-tr iazolo[3,4-b][l ,3,4]thiadiazoles
can be conveniently synthesised by reacting 3-substi tuted-4-amino-5-
mercapto-l ,2,4-tr iazoles with aldehydes in presence of an acid catalyst like p-
TsOH, HCl etc.
S. Sangeetha et al.^^'^^ have prepared a number of 3-substituted-6-
(2 ' ,4 ' -dialkoxy-5-alkyl)phenyl-5,6-dihydro-l ,2,4-tr iazolo[3,4-b][l ,3,4]thiadi-
azoles (XXXV) by the reaction of 4-amino-3-phenyl substi tuted-5-mercapto-
1 3
1,2,4-tr iazoles with 2 ,4-d ia lkoxy-5-a lky lbenza ldehydes in presence of
/ j - T s O H as catalyst .
N- -N
NHz
OHC-
R O'
R'
OR /j-TsOH
Benzene R
R = 2-Me.C6H4, 2—OH.C6H4,2—CLC6H4 r ' = Et, Pr R^ R = Me, Et
XXXV
S. Hai jan et al^^^'^^ have synthesised var ious 3 ,6-disubs t i tu ted-2 ,3-
d ihydro - l , 2 ,4 - t r i azo lo [3 ,4 -b ] [ l , 3 ,4 ] th iadiazoies ( X X X V I ) by the react ion of
3-ary lsubs t i tu ted-4-amino-5-mercapto-1 ,2 ,4- t r iazo les wi th d i f fe ren t a ldehydes
in the presence of catalytic amount of HCl.
N- -N N-
Ar I NH2
+ R—CHO HCl
SH Ar
-N
HN—( R
XXXVI
Ar = 4-NO2.C6H4, 3-NO2.C6H4, 2—CLC6H4, 2-MeO ,2-Furfuryl, CH3.CH=CH
R = 4-MeO.C6H4, 4-Me2N.C6H4, 4—CLCeH,, 2—OH.C6H4, 3-MeO.C6H4, C6H5-CH=CH
A number of 5 ,6 -d ihydro-6- (subs t i tu ted-phenyl ) -5- (2 ,3-epoxypropyl ) -
3 -methy l - l , 2 ,4 - t r i azo lo [3 ,4 -b ] [ l , 3 ,4 ] th iad iazo les^^ ' (XXXVI) have been
prepared by first condens ing 3 -methy l subs t i tu ted-4-amino-5-mercap to-1 ,2 ,4 -
t r iazo leswi th var ious subst i tuted aromat ic a ldehydes in b e n z e n e using Dean
Stark appara tus in presence of /7-TsOH as catalyst f o l l owed by alkylat ion
with l - ch lo ro -2 ,3 -epoxypropane in ace tone and K2CO3
1 4
N N + R—CHO
- CH3 SH NH,
p-TsOH
Benzene
N N
HN-R
K2CO3 C H 2 - C H - C H 2 C I
O N N
C H s '
H2C-CH —CH2
0
A-n-N-
R XXXVII
R = 4-MeO.C6H4, 3,4—(MeO)2.C6H3. 4—CLC6H4, 3, 4—(OCH20).C6H3
In a s imilar react ion, they have also prepared some 2-subs t i tu ted
phenyl -3- (3-a lky l /a ry l ) -5 ,6 -d ihydro-1 .2 ,4 - t r i azo lo[3 ,4 -b] [ l ,3 ,4 ] th iad iazo l -6-
y l indoles (XXXVIII ) by the condensat ion of 2 -a ry l indo le -3 -a ldehydes with
3-subs t i tu ted-4-amino-5-mecapto-1 .2 .4- t r iazo les in p resence of /?-TsOH as
catalyst .
N N
C H 3 ' SH
NH2
Q H
D M F
N N
C H / ^S
H N -
Q
Q 'N'
R = CH3, C2H5, C3H7, CfiHj, CH2.C6H5, 2 - M e CeHj , 4 - M e O . C 6 H 4
r ' = CH3, CI
XXXVIIl
G. A. E l - S a r a r ° has syn thes i sed s o m e 3 - ( 2 - b e n z o f u r a n y l ) - 5 , 6 -
d i h y d r o - 6 - s u b s t i t u t e d - l , 2 , 4 - t r i a z o l o [ 3 , 4 - b ] [ l , 3 , 4 ] t h i a d i a z o l e s ( X X X I X ) by
r e a c t i n g 4 - a m i n o - 3 - ( 2 - b e n z o f u r a n y l ) - 5 - m e r c a p t o - 1 , 2 , 4 - t r i a z o l e wi th
1 5
d i f f e r e n t a l d e h y d e s such as jO-anisaldehyde, s a l i c y l a l d e h y d e , /?-chloro-
b e n z a l d e h y d e and 2 - t h i o p h e n a l d e h y d e in p r e s e n c e of p y r i d i n e as ca ta lys t .
Q N N
+ R - C H O P i p e r i d e n e ^ ^ ^ |
N N
I NH,
a b s . E t O H S H
H N -
X X X I X
R = 2 - O H . C 6 H 5 , 4 - M e O . C 6 H 4 , 4—CI .C6H4, 2 — t h i o p h e n y l
Z.Wang et al.^'^ have carried out the s te reose lec t ive synthes is of a
number of new chiral 3 ,6 -d ia ry l -5 ,6 -d ihydro t r i azo lo [3 ,4 -b] [ l ,3 ,4 ] th iadiazoles
( X L ) by the Mannich react ion of 3 -a ry l -4 -amino-5 -mercap to - l , 2 ,4 - t r i azo le s
with var ious alkyl or aryla ldehydes in the presence of cata lyt ic amount of
L-(+)- tar tar ic acid.
N- -N
^ r + R—CHO L-(+)-Tartaric acid
C H 3 ^ Y S H
NH2 H "R HN
H XL
Ar = 2-MeO.C6H4, 4-MeO.C6H4 R = C H = C H - C H 3 , 2 - M E O . C 6 H 4 , CGHJ, 2 - O H . C 6 H 4 , 4 - O H . C 6 H 4 ,
4-NO2.C6H4, 4-Me2N.C6H4, 4-CI.C6H4
In a s imilar react ion, they have prepared 3 - (3 -pyr idy l ) -6 - (pheny l /
2 - fu ry l ) subs t i tu ted - l ,2 ,4 - t r i azoIo [3 ,4 -b ] [ l ,3 ,4 ] th iad iazoIes 5 4 ( X L I ) by
reac t ing 3 - (3 -pyr idy l ) -4 -amino-5-mercap to - l ,2 ,4 - t r i azo le wi th benza ldehyde
or 2 - f u r f u r a l d e h y d e in the presence of L-(+)- tar tar ic acid . But , in this case,
the absolu te conf igura t ion was not detected.
1 6
CPJO L-(+) -Tartaric acid N N
R = C6H5, ^ O O XLI
R. Gupta et al .^^have also synthesised a series of novel 7/9-subst i tuted-
4 - (3 -a lky l / a ry l ) -5 ,6 -d ihydro- l ,2 ,4 - t r i azo lo [3 ,4 -b ] [ l , 3 ,4 ] th iad ia zol-6-yl) te t ra-
zo lo [ l , 5 -a ]qu ino l ines ( X L I I ) by the condensa t ion of 7 ,9-disubs t i tu ted-4-
fo rmyl t e t r azo lo [ l , 5 -a ]qu ino l ines with 3 -subs t i tu ted-4-amino-3-n ie rcap to-
1,2,4-tr iazoles under mic rowave irradiat ion us ing basic a lumina as solid
support .
N N
R^n-^sh Q NH2 r
C H O
' N I
fiv/A
R = CH3, C2H5, C3H7, CH2.C6H5, 4-OMe.C6H4, 2-Me.C6H4, 4-OMe.C6H4 1 1 N = N
R' = H, CH3, OCH3
R = H, CH3
M. Kidwai et al.^^ have shown that the react ion of 4 -amino-5 -mercap to -
3- (4 ' -methylquinol iny l -2 ' -oxymethyl ) / ( te t razo ly l -1 ' -methy l ) -1 ,2 ,4 - t r i azo les
with benza ldehyde in D M F under mic rowave i r radia t ion y ie lded the
cor responding 3 - subs t i t u t ed -6 -pheny l -5 ,6 -d ihydro - l , 2 ,4 - t r i azo lo [3 ,4 -b ] [ l , 3 ,4 ]
th iadiazoles ( X L I I I ) .
N N
R-^n-^sh
N- -N
+ R — C H O [iv/A DMF" K
NH2 \
HN
R = C6H5, O 0 N ' "OCHr
n . n XLIII R
N - C H 2 -
1 7
The react ion of 3 -subs t i tu ted-4-an i l ino-5-mercapto- l ,2 ,4 - t r iazo les with
oo-bromoacetophenones yielded 4-an i l ino-5-phenacylmercap to-3- th iophe-
noxyme thy l - l , 2 ,4 - t r i a zo l e s which on brominat ion fo l lowed by cyciisat ion
a f fo rded 3-subs t i tu ted-5-phenyl -6-benzoylsubs t i tu ted- l ,2 ,4 - t r i azo lo[3 ,4-b]
[ 1 ,3 ,4 ] th i ad iazo l id ines" (XLIV) .
N N
N I
P h N H SH
O II
BrCH-C-I R2
Ri jxvM DMr'
N N I I
N
P h N H
Br j AcOH UV-iig)it
N N
N \
P h N
N N
,Q R
EtOH
Pyridine
N
P h N H S I
BrC
0
XLIV
R = CjHj 0 CHj, 4-CH3 CaH) OCH2,4-CLC6H4 SCH,. 2.4-CI2 C6H3OCH2 C f i H j SCH2, 4-CH3 C a R , SCH2, 4-CLC6H4 SCH2
R= H, CI, CH3 R = H, 4-CLC6H4S, 4-CLC6H4O, CfiHj
N.D. Heinde l et al.^^ have reported the synthesis of 3 ,6-disubs t i tu ted-
l ,2 ,4- t r iazo lo[3 ,4-b] [1 .3 ,4] th iad iazoles (XLV) by the condensa t ion of 1,2,4-
t r iazoles wi th c innamaldehyde in ethanol. Dur ing this reac t ion , the format ion
of 3 -R-8-a ry l - l , 2 ,4 - t r i azo lo [3 ,4 -b ] [ l , 3 ,4 ] th iad iazep ines in mino r amount was
also observed .
N- -N
R^n-^sh +
^SH NH2
R = H , AJkyl, Aryl
Ph EtOH
XLV
1 8
R. Gupta et al.^"' have prepared several 3-alkyl /aryl-6-(2-chloro-2-
subst i tu ted-phenylethenyl)-5 ,6-dihydro- l ,2 ,4- t r iazolo[3,4-b][ l ,3 ,4] thiadiazo-
les ( X L V I ) by the condensation of 3-subst i tuted-4-amino-5-mercapto-1,2,4-
triazoles with /7-chlorocinnamaldehyde in benzene conta in ing catalytic
quantity of p - T s O H using Dean Stark apparatus.
N - - N
SH
)3-TSOH
E t O H
N H .
X L V I
R = CH3, C2H5, C3H7, CH2.C6H5,4-OMe.C6H4, 2-Me.C6H5 R, = CI, Br. OMe
Z. Y. Zhang and co-workers^^ have shown that the react ion of 4-amino-
3-( l - jC-chlorophenyl-5-methyl- l ,2 ,3- t r iazol-4-yl) -5-mercapto- l ,2 ,4- t r iazole
with p-chlorobenzaldehyde/benzaldehyde in presence of catalytic amount of
p - T s O H in ethanol afforded 4-benzyl ideneamino-3- ( l -p-chlorophenyl -5-
methyl- l ,2 ,3- t r iazol-4-yl- ) - l ,2 ,4- t r iazol-5- thiones ( X L V I I ) instead of the
cyclised product .
N - - N H
N N H
N - ^ N A , . O H C ^ p-TsOH
EtOH
N N
( X N = C H -N " ^ C H 3
N C H 3
O
Q R = H, CI
X L V I I
CI
CI
B. Kalluraya et a l . " have reported the condensat ion of 5-nitro-2-
(diacetoxymethyl) thiophene with 3-substi tuted 4-amino-5-mercapto-1 ,2 ,4-
triazole yielded the corresponding Sch i f f ' s base ( X L V I I I )
N NH
~ I ^ S NH2
R = H, Aikyl Ph, Ph.0CH2, Ph-CHj
EtOH
1 9
N-
R
-NH
N = CH
XLVIII
-NO2
Similar condensat ion of 3 -subs t i tu ted-4-amino-5-mercap to-1 ,2 ,4 -
t r iazoles with 5 - (2 ,4 -d ich lo ropheny l ) -2 - fu r fu ra ldehyde y ie lded 3 -subs t i tu ted-
4 - [5 - (2 ,4 -d i ch lo ropheny l ) -2 - fu r fu ry l iden^^ ( X L I X )
N N H
^ N ^ , + O H C -
I ^ N H .
Q cv
CI EtOH
N N H
A N -C I ^
N = C H -
XLIX
O cr
CI
R=HAlkyl
brl
Long alkyl chain substituted-s- Triazolo- Th iadiazepin es
O J
2 0
DISCUSSION
SUMMARY
The M'ork described in this chapter includes the reaction of 3-(9-decenyl)-4-
amino-5-mercapto-1,2,4-triazole (1) with:
i) l,5-Bis(4-chlorophenyl)pent-l,4-dien-3-one (2) which afforded an
adduct, 1,5-bis(4-chlorophenyl)-5-[3-(9-decenyl)-4-amino-5-thio-1,2,4-
triazolyljpent-]-en-3-one (3) and a novel compound, 2-(4-
chlorophenyl)-4-[2-(4-chlorophenyl)ethenyl]-7-(9-decenyl)-2,3-dihydro-
1,2,4-triazolo [3,4-b][1,3,4]thiadiazepine (4).
ii) 4,4'-Dichlorochalcone (5) which yielded an adduct, 1,3-bis(4-chloro-
phenyl)-3-[3-(9'decenyl)-4-amino-5-thio-1,2.4-triazolyl]propan-l-one (6)
and a novel compound, 2,4-bis(4-chlorophenyl)-7-(9-decenyl)-2.3-
dihydro-1,2,4-lriazolo[3A-b][l,3,4]thiadiazepine (7).
Hi) 1,3-Bis(2-thienyl)propen-l-one (8) which furnished an adduct. f3-his(2-
thienyl)-3-f3-(9-decenyl)-4-amino-5-lhio-J,2.4-lriazolyljpropan-I-one (9)
as the sole product.
INTRODUCTION
4-Amino-5-mercapto- l ,2 ,4- t r iazoles and their /V-bridged heterocyclic
derivatives have received much attention during recent years on account of
their wide spectrum biological potentialities as anthelmintic^' ',
antihypertensive^^ antitubercular''^'', antibacterial"' ' . ant i fungal" ' ,
antiinflammatory''®, anti-HIV^', antiviral^^ inhibition of cholinesterase ' ' ' .
analgesic^'' and anticonvuisant^^'^^. The 1,2,4-triazole nucleus has been
incorporated into a wide variety of therapeutically interest ing drugs' ' '
including Hi/H2-Histamine receptor blockers, cholinesterase active agents,
CNS stimulants, antianxiety agents and sedatives. Also 1,3,4-thiadiazepine
derivatives are associated with a varied range of biological activities such as
2 1
antimicrobial '"^, anticancer^, herbicidal^"^, antiviral^, anti-HIV'*^"''',
ant icholinergic"^ antidepressant'^"'^, anaes thet ic '^ calcium antagonist '^
choleretics'® and ACE inhibitory'^ activity. Prompted by these observations
and as part of our continuing programme in the search of biological ly active
compounds with sulphur and nitrogen containing heterocycles , we have
undertaken this problem. It consists of the reaction of 3-(9-decenyl) -4-amino-
5-mercapto- l ,2 ,4- t r iazole (1) with ( i ) l ,5 -b is (4-chlorophenyl )pent - l ,4-d ien-3-
one (2) which afforded an adduct, l ,5-bis(4-chlorophenyl)-5-[3-(9-decenyl)-
4-amino-5- th io- l ,2 .4- t r iazoly l ]pent - l -en-3-one (3) and a novel compound, 2-
(4-chlorophenyl)-4-[2-(4-chlorophenyl)ethenyl]-7-(9-decenyl)-2,3-dihydro-
l ,2 ,4- t r iazolo[3,4-b][ l ,3 ,4] thiadiazepine (4). (ii) 4 ,4 ' -d ichlorochalcone (5)
which yielded an adduct, l ,3-bis(4-chlorophenyl)-3-[3-(9-decenyl)-4-amino-
5- th io- l ,2 ,4- t r iazoly l ]propan- l -one (6) and a novel compound, 2,4-bis(4-
chlorophenyl) -7-(9-decenyl) -2 ,3-dihydro- l ,2 ,4- t r iazolo[3 ,4-b][ l ,3 ,4] th iadia-
zepine (7) and (iii) l ,3-bis(2- thienyI)propen- l -one (8) which furnished an
adduct, l ,3-bis(2- thienyl)-3-[3-(9-decenyl)-4-amino-5- thio- l ,2 ,4- t r iazolyl]
p ropan- l -one (9) as the sole product.
Structural assignment and biological assay are discussed. Screening
results of the compounds (4), (7) and (9) are summar ised for anticancer
activity against 3-cell lines of three types of human cancers : lung, breast and
CNS. Screening results of the compounds (4) and (7) are also summarised for
antimicrobial activity against four bacteria, Escherichia coli, Bacillus
subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and one fungi
Candida albicans (details in chapter 6).
2 2
(1)
Hz
(3)
2 3
2' 4' 6 8 io'
(8)
(9)
2 4
R E S U L T S A N D DISCUSSION
The syntheses of compounds (3), (4); (6), (7) and (9) have been
performed by the reaction between a triazole (1) and <3r,;^-unsaturated
carbonyl compounds. The triazole, 3-(9-decenyl)-4-amino-5-mercapto-1,2,4-
triazole FTZ (1) was first prepared following the method adopted by Peng-
Fei Xu et al.^^ by fusing 10-undecenoic acid with thiocarbohydrazide (molar
ratio, 1:1) at 170 °C, as white crystalline needles in 85 % yield. It was then
treated with (i) l ,5-bis(4-chlorophenyl)pent-l ,4-dien-3-one (2) (ii) 4.4'-
dichlorochalcone (5) and (iii) l ,3-bis(2-thienyl)propen-l-one (8) (molar ratio,
1:1) in dry benzene in presence of /?-TsOH. (Scheme 1). The products on
chromatography over a silica gel column using pet. ether-EtOAc (8:2 v/v) as
eluent yielded compounds FBCA (3) and FBCB (4) in (i), F T Z X 4 A (6) and
F T Z X 4 B (7) in (ii) and FTCA (9) in (iii). The reaction of the triazole with
l ,3-bis(2-thienyl)propen-l-one (8) didn't yield the desired product, triazolo-
thiadiazepine, but yielded only the adduct (9) as the sole product.
2 5
2. •a c TO
ro X! 3
!=:
c (U N c <u x>
T 3 ^
o d X 3 (D
<D c 0 1 ^ c u '-3
I
I S 1 ^
o N ^ C —' U ^ JD
2 -a td
o d B
c Q.
_r C o
>1
cx I 0 1
ra Hi
I I s i s s o o. _o O "c3 ^ o " S o V CJ C/3 •3 ^
iri -T T /
S
X u C/)
2 6
3-(9-Decenyl)-4-amino-5-mercapto-l,2,4-triazole F T Z (1)
The outl ine of its synthesis is as fol lows:
. r „ Vr II S
1 7 0 ° C , 1 . 5 h ( O H 10-Undecenoic acid ^
' -H2O
h o ) I NH2
-H20
N N I I i l
I
NH2
FTZ (1)
H N — N H
( > P h n HN I
NH2
Structure Elucidat ion of FTZ (1)
It was a whi te crystal l ine solid, m.p. 82 °C. The s t ruc ture of F T Z was
fu l ly es tabl ished by IR, DCI-MS, ' H - N M R and ' ^ C - N M R spectra . IR-
spec t rum (KBr) gave character is t ic peaks at 3250, 3100 ( N H ), 2900(CH)
2350 (SH) , 1640 (C=C), and 1610 (C=N) cm"'. The D C I - M S spec t rum of the
sample F T Z showed a [M+1]"^ signal at m/z 255 c o n f i r m i n g its molecular
weight 254 which corresponds with the ion [C12H22N4S] . Th i s is equal to the
sum of the molecular weights of 10-undecenoic acid (184) and th iocarbo-
hydraz ide (106) minus two molecules of water. This sugges ted the format ion
of 5- tr iazole r ing by the condensat ion of t h i o c a r b o h y d r a z i d e with
2 7
10-undecenoic acid. It also showed two prominent f ragment ion peaks at
m/z 130 [(M+O-CgHn]^- and m/z 143 [M-CgHu]^ due to the (5- and y-
cleavage to the triazole ring on the long alkyl side chain.
All the signals in 'H-NMR and '^C-NMR spectra (acetone-c/g) (Fig. l a
and l b ) have been assigned to specific H- and C-atoms (Table 1) f rom their
typical chemical shift values, multiplicity and relative integrations. The
' H - N M R spectrum showed a weak broad singlet at 5 12.25 and a sharp
intense singlet at 5 5.18 which were attributed to the thiol and amino
protons. The two double doublets at 5 4.90 (J=10.26, 2.20, He) and 6 4.98
(J=17.21, 2.20, Hz) coupled with each other and with the ad jacent methine
proton were assigned to the two terminal o lefmic protons. HE -10 ' and H ^ - I O '
respectively. The signals appeared as triplet double doublet at 5 5.81 (J=6.78.
10.26, 17.03) were due to the coupling of the methine proton ( - C H = , H - 9 ' )
with the protons at H-8' and HE-10', HZ-10'. Also in '^C-NMR spectrum, the
characterist ic signals appeared at 5 153.34 and 5 168.26 were assigned to the
triazole ring carbons at C-3 and C-5. The other signals were at tr ibuted to the
9-decenyl side chain carbons.
On the basis of above facts, F T Z was characterized as 3-(9-decenyl)-4-
amino-5-mercapto-l,2,4-triazole (1).
FTZ (1)
2 8
J
3
< :
2 9
L •-'tfV »o •> I b W « M > « O C V N «
c f u f f i x i et < > W > > « « * MJ I O « O I tJ • >*
— < • • © «
C tf <D E i n c PC < « x — 4 o »- a . 4. h- z C itl ® £ s:«* oc 3 > — < — o - o e
4. z a u — • c o o « o > o
ao \ t oo 5 t
O o D w C 0
s o w e .
C2. C
E
J w — « i p I
« - «
e Q . Q .
• PJ fO « c
I I I M C O t o e i i «or> . I
a . •> » « •H o a
CM W «g •H .
UJ
W)
3 0
Table 1. 'H-NMR and ^^C-NMR spectra] data of FTZ (1),
H-nr 5(ppm) Integ-ration
Multi-plicity
J (Hz) C-nr S(ppm)
SH 12.25 IH brs 3 153.34
NH, 5.18 2H s 5 168.26
] ' 2.73 2H t ] ' 25.40
2' 1.75 2H br p J « 7.46 2' 26.68
3'-7' 1.33 5x2H br s 3'-7' 29.40-30.20
8' 2.03 2H m 8' 34.40
9' 5.81 IH tdd J9',8' 6.78, Jq' he 10.26. 9' 139.82
J9',Hz 17.03 114.61 HH-IO' 4.90 IH dd JHE,9' 10.26, JHL, Hz 2.20 10' 114.61
Hz-10' 4.98 IH dd JHZ„9' 17.21, JHE, Hz 2.20
l,5-Bis(4-chlorophenyl)-5-[3-(9-decenyl)-4'amino-5-thio-l,2,4-triazolyl]
pent-l-en-3-one FBCA (3) and 2-(4-chlorophenyl)-4-[2-(4-chlorophenyl)
ethenyl]-7-(9-decenyl)]-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine
FBCB (4). [Reaction of the ^-triazole (1) with l ,5-bis(4-chlorophenyl)
pent-l,4-dien-3-one (2)J,
A solution of the 5-triazole (1) and l ,5-bis(4-chIorophenyl)penl-1.4-
dien-3-one (2) (molar ratio, 1:1) in dry benzene was ref luxed with stirring for
32 h in presence of a catalytic amount of /7-TsOH. The products on usual
work up and column chromatography (silica gel, pet. e ther-EtOAc, 8:2 v/v)
yielded a colourless solid FBCA (3) (38%) and a yellow solid, FBCB (4) in
47.5% yield. The reaction sequence is as follows.
3 1
N N CI
FTZ (1) i) p-TsOH /dry benzene Reflux 32 h
N N
CI
Q
N ^ S '
NH2
N N N N
CI
FBCA (3)
Structure Eluc idat ion of F B C A (3)
It was a colour less glassy f lakes, m.p. 84 °C. The s t ruc ture of F B C A
was es tabl i shed by DCI-MS, ' H - N M R and '^C-NMR spectra . The DCI -MS
spec t rum (Fig. 2a) of FBCA showed a set of [M+I]"^ peaks at m/z
557/559/561 showing its molecular weight 556 /558 /560 [C29H34N40C1^S],
which is equal to the sum of the molecular weights of ^- t r iazole (1) (254) and
the d ienone (2) (302). This indicated that an addi t ion p roduc t has been
formed by the nucleophi l ic addi t ion of the thiol g roup to the enone func t ion
of the d ienone (2) and showing that the one ene g roup r ema ins intact . The
prominen t f r agment ion peaks were observed at m/z 255 [ (M+l ) -C i iH80S2]^
as the base peak and at m/z 303/305/307 [(M+1)-C,2H22N4S]^ fo rmed by the
3 2
I f t i l - wlOv-'lli ' U I HL i
t ' TDH '-i -TCMD = r - ' T i f " " r T r c
~fi 'kPi OLD »C<C> ' < Ci ' " L AI< " T;; ' I,,:, ' ~F-I I ~ C' I ON "CILFI "1 " "J'CI "''iCt ~ dCi 'X^Ci
llll I I I'" 1 1 1—'—I" 'I" "I'—I—1—r— 'fct '--Ti "-LI -'nc- •--C' ' T i '•.aft 'Aft ""'Pi ' " f i AC<fi <11 a AOO ii'-tci
• SI.' M A J .1 1 ^ .111 _ V «-R, 1 * 6 546 556 '5?^ 5£S . • '7- ' 553
1 62S
'-L' IT- .N 21 1: Y = N /IP S JIRI/GN =0X100 I NNV= 3325?S2 ~I~LE PPR A
1 'J 1 0 0 A 1 - ^ ^ FIN w - 00 5 306 an W W 4 N RF. W A < 02 00 'j^Ui-R c. 30 I 0 0 C- i 307 0 0 R 3
GO C C 10 302 0 0 1 5 55? 00 35 4 00 i. P 257. 01' 10 C FJ 3GZ OC 73 T n ft N N 1 ^ W 1/ I 00 ?
W 5 y £ U C J- ZO": N 0 1 / T V
t h V A =
1 ::5 ''' oc c r - tl 7 fi
V \ k
^C1 3Z5c. 5
''•fZS'' I • ?£3C"-
iP L
'^CC'L'ISI~ION PR.RAIIETER "' .E'LE
MASS "X'IMGES 7'.' 70C JislTFflPiiTTnw Tjwrc TYP- nr DiiM MdN 1-'-.
Fig. 2a
3 3
re t ro-Michael addit ion of F B C A , in addit ion to other peaks at m/z 165, 143
and m/z 130 as shown in Chart 1.
CH..
[M +1] m/z 557/559/561( 35.4 / 19.6/3.4)
retro-Michael addition
< m/z 255 (100.0) m/z 303/305/307 {12,3IAim3)
N N H
P-cieavage
N ^ S H I
NHj m/z 143(9.2)
N N
i [[ ^ N ^ S H
NH2 m/z 130(15.7)
CHART 1 m/z 165 /167 (28.8/9.2)
' H - N M R and '^C-NMR spectra (Fig. 2b and 2c) showed the s ignals as
assigned (Table 2). ' H - N M R spect rum showed a sharp singlet for amino
protons at 6 5.21. The signals cor responding to the methy lene p ro tons at C-4
appeared as two double doublets at 5 3.47 (J=17.25, 5.50, H-4up) and S 3.97
(J=17.25, 9.31, H-4dn). The signal for the meth ine proton at C-5 appeared as a
double doublet at 5 6.43 (J=9.31, 5.50, H-5) . The signals for the t rans-olef in ic
protons at 5 6.90 (J=16.33, H-2) and 5 7.67 (J=16.33, H-1) indica ted that the
Michael addit ion of thiol has occurred to only one ca rbon-ca rbon double bond
of the dienone (2). It was fur ther conf i rmed by the ' ^C-NMR spec t rum which
3 4
} :
X!
Dio
} :
J
3 5
Q . Q .
W o o i / i i - m o •• ee. a i«) E « « i > < « « ( r i u « > ^ »» U o fi o I H - O •
C O E < >t UJ ^
or - r c s.
•» c tf oi . . -n — ^ n O ' - O C i-H o 9 z le o . £ . • - >,-a w ccj o
o ©• X'W «<» SM-OiA « • ) 0 0 . 0 3 E V > « f « . o « 0 o o ** t
** ui^ C t e c A N o v £ 0 > ( L C — fSiCL — • O CL Z} •]
B T - c e u o > c - j < c «
o <N
• t V •« cn
) O) M « O •
36
fO < u CO u. o « Si •a
u U <u D. Ci s
B a. a icT
u c 1 U
N »
i i -t; s .Si S a
Tj- Tj- OO NO <N on in O NO o Tf NO NO o NO (N (N <N
m on <n vr> «n in Tf- 1—H '—1 ro
in
o
o d cn 1 o on (n
>n o <w rf
u-) o< cn
vo
in oo a\ n
(n o<
m (N —< fn in cs 1
ro 00 on
+ 2 ^
o m m
c .
O in in
in (N ^ i> CO —'
a.
m o<
in (N
d
0 O
(N
m (tl 00 V) rn no no no m r—(
— <N fs « 1—> 1—> 1—5 •—5
w a:
On (N (N
u X
(N (N
On CNl (N
N 3: a n: I—!
on" O
in in CO 00
OS ro 00
in S £ ^
<
<
On ro 00
<
13 Td -O -a -o V -o
i u
•o c c5
z a
fs 0)
3 «
h
c « »-( iM
s A a to"
T) ! ^
in NO o m
r-on o On r-no
m vo o (n
o r-' »n (n o o o
00 o on
00 on (S in
no C<) o fs| on rt t^ rt K t^ r-
u C 1 «
in D.
rj- -o T— ^ fS rn 00
W Kl X X
z o on
cn t i r-f ro" I I
^ ^ ^ ^
3 7
exhibited peaks for the saturated carbon-carbon bond at 5 57.69 (C-5) and
5 45.05 (C-4) and the carbonyl carbon 5 196.04 (C-3). It also showed the
signals corresponding to the ^./^-unsaturated olefenic carbons at 5 127.64
(C-2) and 6 142.08 (C-1), in addition to the usual peaks of i '-triazole moiety
and 9-decenyl side chain carbons as shown in Table 2.
On the basis of the above facts, the structure of compound FBCA was
conf i rmed as 1,5-bis(4-chlorophenyl)-5-[3-(9-decenyl)-4-amino-5-thio-1,2.4-
triazolyljpent-l-en-3-one (3).
FBCA (3)
Structure Elucidation of FBCB (4)
It was a yellow globular shaped crystalline solid, m.p 161 °C. The
structure of FBCB has been established by DCI-MS, 'H-NMR and '^C-NMR
spectra. The DCI-MS spectrum of the sample FBCB (Fig. 3a) showed a set of
[M+l]"^ peaks as the base peak at m/z 539/541/543^ showing its molecular
weight 538/540/542 [C29H32N4SCI2] which is equal to the molecular weight
of (3) (556) minus one molecule of water. This indicated the formation of the
thiadiazepine ring by the intramolecular cyclocondensat ion between the NH2
and CO groups of (3). The formation of the molecular ion as the base peak
indicated the stability of the molecule. The peak at m/z 415/417/419
3 8
1 H M " . - 1 ' ' 4 1 1 - • ' 1 . - > « .M
I 1 f t l i OL. 1 f, S I U I H L :
-L4 CCRN 'TTi r""rT ' r r "" "=r-i
r
\
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1 —;—^ ••—!—••I'-r-i' — r - ^ ; f-ci i 'i;. ^fiPi 21S 225 23S
—.—i ^ — I — — — r — -f- 'Ti -u' <r-,fi • < r. 1'f' •'-f' <ar-
" II ; I, .liil, ! -•"-T —r—I—-I ;• -I I 1 —; [ ; ; ] 1 ] 1 \ ! • 1 i i '•iin ' 511 '' .r-i ''""Pi "" ri ^ur 2JL' 24" 35C' 266 322 3?6 4£'£'
i Hi i I I v I III <11 !i;i
.iiiiiii •'fl J "J 0 dACj -1 " l" ^ " f-l J M L" SK" 52? 528 54?
-i_ .il '"CAN iC ST = ij u .irk;r.T)= 0X10 0 « w w 0^2560 - J ">•[_£ FI'CP
10? 0 0 0 - 30 C 00 - M 0 0 6 . 542 15 n f •7 7Cl 01 V 53t GO lO 2 543
l2? 0 0 Q W V k. n n 30 £ M n w w i nn * V • 0 544 240 0 P < -Kfl-W V w fl u V V w 540 Ci 45 1 2^:5 n n 3 304 0 0 Ic: 541 (1 fl w w 1
28 ? 1 6 . ?
Q
^T/iPT = TDTP.L
240 0 302 0 jj^c; n 505 i •-7Q ' fi
1 rwri = "c;
12i 21s
- g72
•^'•"•J AA
iPi.
^CC'UISniON PARftflElLR 1
M;iC5 Pii|WG£;5 ?C'-?OC' ' TL.GRftTIC.' TIrtES
TYPr nc" CllN Miliv Ti-'c; Fig. 3a
3 9
[(M+O-CgHij]"^ was arised by /7-cleavage of the long alkyl chain to the
t r iazole ring. The peaks at m/z 302/304/306 [(M+l)-C,2H2iN3S]^ and an
another peak at m/z 240 [ (M+O-CiyHj jNCla]^ arised by the c leavage of 1-7
and 3-4 bonds are the diagnost ic peaks for the t r iazolo- th iadiazepine ring
system as shown in Chart 2.
CH7
N N H
\
6 Q
N N
^ N f S s McLaffe r ty rear rangement 3 ^ 6
XI Q "a
m/z 539/541/543 (100.0/75.7/18.7)
m/z 415 /417 /419 (7.6/5 8)
N N
m/z 240(25.1) n ^ o /
P-cleavage
m/z 302 /304/306 (30.6/16.5/4 .2)
H
^ S H N N H
miz 128 (5 9) N ^ S H H
m/z 115 (6.3)
N N
X X H ^ N - ^ S H
H
m/z 102 (9.3)
C H A R T 2
'H -NMR and '^C-NMR signals (Fig. 3b and 3c) were assigned to individual
H-and C-atoms (Table 3) from their typical chemical shift values, multiplicity,
relative integrations and by the comparison with the spectra of (3) (Table 2). The
signal corresponding to NH2 protons at 5 5.12 of (3) has disappeared in the
'H-NMR spectrum of FBCB, showing that NH2 group was involved in
4 0
3
h n I ^
WD
3 3 j j :
4 1
/
ID
Q . Q .
E C
c> V I v>
C C - O f v c w >,
fA u o r ot ^ Oia> — o UJ ft) 4-»
>>-c — • -UJ o o « j f n -H T. — in o 4 » - - x t ;
or - c o 6 u <r V — p
UJ X «>
a . O — O t/ e V
c r> «
x; in « c «o -
V O O O UJ ^ 1- <
- ^ e ,
C CW > Q. _
c — 0 " 0 UJ o >
o o o
t: N «) -J
v> V — C _ I C c <5 O <I — «
CJ - in CM in •> m u> rj CM r» in "C cn cn CM ^ - o in as CM in Ol CO CM tn CO rv- eo <0 O <st <o 00 ui op «r <o W eo e> n <M en m U) m CO in lO cn CO tn rv o in cn cn in 10 m eo CM w lO ^
CM CM n r«. M rg CM rj «D C0 <0 fv 10 in 10 lO cn B «0 tn TT 10 (O in ^ ee o CO
r "
tn in ^ <0 N. «> •-4 fM cn CM cn in ^ (0 «> CM CM in 03 at «e ^ o ^ „ CSJ tn 10 ^ o o cn o ^ us - V r. GO fn iO Op CM n n (0 10 m in cn «o cn w> <0 10 10 CM o to rv cn in in cn o tn <n e
C. te \n tn in tn n N e wa in IT O et in n (C (0 CM o o CI cn eo in in tn o o ^ o o o o e in *r n <0 cn CM cv CM cn P- tn <n CM <v CM r>. CM CM CM fv w **
> o o O e\ lO ^ Q s> Q « in o cn _ «6 CM <n <n «> *0 tn «e in lO ^
w « €9 CSJ (0 0t o fs. o in in CM •> in (O CM cn CNi o eo eo CO cn CM n cn CM ^ 10 CM o in o cn '-I oi o O if <0 <e e <0 «c rs. in •n to CM in *M e (O o V, in ir (n •o rv «0 eo M in tn tn o o so tM o UJ rw O 09 «B <S( *) in CO 0» o O o *r en CM CO 10 fs. in cn w> c CD in tn 0) eo in 10 10 CM in cn a: r- 40 <0 (O CO <0 in m o o o <0 in cn 10 c 9> CO rs. in cn CI eo *y U. O o O O n n « CO CO CM in CO <n tn cn tn cn CM <M CM CM CJ
(M N
X O in CD e cn 10 eo Wi o CM 10 CO <9 CM cn eo O) o Csl cn IT 40 2 in tM CM CM CM CM CM rM cn cn tn cn tn n cn tn tn •c ry rr
CO " T
I c
4 2
E a. o. lO
NO ON ( N 00 CM On r - NO »—1 NO
i r i CO ON v n NO d i n CO
NO CO CM l O l > m CM CM
o 'Cl-O m o <N ON (N
ON
o cn 1—I ON
CM oo On ON
XI- CO t—( CM CO
la C
c3 ON (Ti CN) rn 00
O OS - -
+
03 U CO b 0 C3 «5
•o
u O)
a. PS 1
u
•o c «
Z I
fo O)
CS H
N
>o ON 00 On
00 <M (N o. c D •o •o
1—1 CNT >—J fO ro irf r- 00 00 CO CO irf r- ^ rt
NO NO -o T3 D. ' — '
d 3 U a
3 cs —^ CM ro m <N CM 1—> 1—1 1—J I—J 1—1
On O
o\ I—> r i (N
On <N (N
O E
» io ON
(N <N O
ON w I
ON (N (N
N a:
ON o
ON l-l a:
. i 3 '.ii
T3 •T3 -a t3 -a T3 T3 T3 13 T3 13
a « rc ^ X X X y — (N (N K n: X CnI —< <N
E Cu a to'
r--o <N in <N (N (N CO 00
ON On (N O O 00 00
00 On rn ro r^ <N >r>
vo r--I <N
u a c. -a m (N (N
I rs) CO
o o ^ td PC "t
5o ON ffi nc <;
4 3
the formation of the ring. The absence of NH2 protons signal (§ 5.12) in
' H - N M R spectrum and CO signal (5 196.04) in '^C-NMR spectrum of F B C B
confirmed the formation of thiadiazepine ring. The format ion of the ring has
also been supported by the shifts of two diastereotopic hydrogens to higher
fields, f rom 5 3.47 (Hup-4) to 5 3.07 and from 5 3.97 (Hdn-4) to 6 3.52 and also
of the methine proton from 5 6.43 (H-5) to 5 5.22. The exocycl ic t rans-olefinic
protons signals appeared as doublets at 6 7.27 (J=16.48, H - l " ) and 5 7.66
(J=16.48, H-2"). In '^C-NMR spectrum, in place of CO signal at 6 196.04
(C-3), a signal appeared at higher field at 5 143.16 (C-4) in the formation of
ring. The other thiadiazepine carbons appeared at 5 53.59 (C-2) and 5 36.92
(C-3). The exocyclic olefinic carbon signals appeared at 6 126.76 (C-1") and
5 140.69 (C-2"). The terminal o lefmic carbons appeared at 5 139.81 (C-9')
and 5 114.59 (C-10').
Based on the above discussion, compound F B C B was characterised as
2-(4-chlorophenyl)-4-[2-(4-chlorophenyl)ethenyl]-7-(9-decenyl)]-2,3-dihydro
-1,2,4-triazolo[S,4-b][ 1,3,4]thiadiazepine (4).
4 4
l,3-Bis(4-cltlorophenyl)-3-[3-(9-decenyl)-4-amino-5-tltio-l,2,4-triazolylJpro-
pan-l-one FTZX4A (6) and 2,4-bis(4-chlorophenyl)-7-(9-decenyl)-2,3-
dihydro-l,2,4-triazolo[3,4-b]ll,3,4]thiadiazepine, FTZX4B (7) [Reaction of
the 5-triazole (1) with 4 ,4 ' -dichlorochalcone (5)]
A solut ion of the ^-tr iazole (1) and 4 ,4 ' -d ichIorocha lcone (5) (molar
ratio. 1:1) in dry benzene was re f luxed with st i rr ing for 26 h in presence of a
catalytic amount o f p - T s O H . . The products on ch romatography over silica gel
column using pet. e ther -EtOAc (8:2 v/v) as an eluent a f fo rded two
compounds , a colourless oily liquid FTZX4A (6) (37%) and a yel low
cry stall ine solid FTZX4B (7) (51.9%). The reaction sequence is as fol lows:
N N
FTZ (1)
N N
CI
Q
I NH2
o
(5)
(i) p-TsOH/dry benzene Reflux 26 h
N N
Q
FrZX4A (6) FTZX4B (7)
4 5
Structure Elucidat ion of FTZX4A ( 6)
It was a colour less oily liquid. The s tructure of FTZX4A has been
es tabl ished by FTIR, EI -MS and ' H - N M R spectra. FTIR spect rum gave
character is t ic bands at 3178.55, 3074.26 (NH2), 2927.0 (CH) , 1689.17 ( C = 0 ) ,
1639.66 ( C - N ) and 1590.04 (C=C) cm"'. In EI -MS spec t rum, the molecular
ion peak was absent , but two prominent peaks, one at m/z 254 [ (M+I) -
C i s H n O C b ] ^ ' and another at m/z 277/279/281 [(M+1)-C,2H,4N4S]^
cor respond ing with the tr iazole f ragment and 4 ,4 ' -d ich lo rocha lcone f ragment
ions, appeared possibly by the re t ro-Michael addi t ion of (6) The
f ragmenta t ion pat tern is shown in Chart 3.
CHo.
N N
NH. m/z 531/533 (absent)
retro-Michael addition
N N
I
. NH, m/z 254 (89.0)
t N N
N" ^SH I
NH2
m/z 143 (28.3)
H
m/z 277/279/281 (16.0/9.2) P-cleavage m/z 255 (21.2)
N N Cl-
I SH
o -c=o
NH2
m/z 130 (67.8)
m/z 139/141 (100.0/37.8)
CHART 3
4 6
The 'H-NMR (acetone-cf^) signals were assigned to individual
hydrogen atoms (Table 4) on the basis of typical 5-values , multiplicity,
relative integrations and by comparison with the spectral data of (1) (Table 1)
and the previously established compound (3) (Table 2). The spectrum showed
no signal corresponding to thiol proton at 5 12.25 and in place additional
signals appeared due to the addition of the SH group to a,y5-unsaturated
funct ion of chalcone forming an adduct. A double doublet at 5 6.40 (J=9.08,
5.58) was assigned to H-3 and the two double doublets at 6 3.60 (J=17.10,
5.58) and 5 4.20 (J=17.10, 9.08) were attributed to the two diastereotopic
protons, Hup-2 and Hdn-2. The aromatic protons signals appeared as A2B2
pattern at 5 7.20 (d, J=8.55) and 6 7.42 (d, J=8.55) for one benzene ring and
at S 7.84 (d, J=8.42) and 6 7.70 (d, J=8.42) for another benzene ring. The
other signals were assigned to the 9-decenyl side chain protons.
Based on the above evidence, FTZX4A was character ised as 1,3-bis
(4-chlorophenyl)-3-[3-(9-decenyl)-4-amino-5-thio-l ,2,4-triazolylJpropan-l-
one (6).
' S ^ N
FTZX4A (6)
4 7
Table 4. 'H-NMR spectral data of FTZX4A (6).
H-ni 6(ppm) Integra-tion
Multi-plicity J (Hz)
N H , 5.14 2 H s
3 6.40 I H dd J3.2dn 9.08, J3.2UP 5.58
2up 3.60 I H dd J2up.2dn 17.10, J2UP.3 5.58
2dii 4.20 I H dd J2up,2dn 17.10, J2dn. 3 9.08
1" 2.68 2 H t J,..2" 7.46
1.64 2 H br p J « 7.33 1 1 H "711 J - / 1.23 5x2H br s
8" 1
1.98 2 H m
! 9" 1 5.70 i 1 I H tdd 1
J9..8.. 6.71. V „ r , 10.22. J9". Hz 17.08 |
1 Ht-10" 4.88 I H dd .IHC 9" 10.22. Jn, , , 1 .2 .28 ;
1H/-IO" 4.97 i ! i I H dd J„,,9" 17.08. 2.28 '
Ar-2.6 7.20 2 H d JAr-2.6. Ar-3,5 8 . 5 5
1 1 Ar-3.5 7.42 2 H d JAr-2.6, Ar-3.5 8 . 5 5
Ar'-2.6 7.84 2 H d JAr'-2.6,Ar'-3.5 8 . 4 2
Ar'-3,5 7.70 2 H d JAr'-2.6, Ar'-3.5 8 . 4 2
Structure Elucidation of FTZX^B (7)
It was a pale yellow globule shaped crystalline solid, m.p 148 °C. The
structure of FTZX4B has been fully established by DCI-MS. 'H-NMR and
'^C-NMR spectra. The DCI-MS spectrum displayed a set of peaks
corresponding to [M+l]"^ as the base peak at m/z 513/515/517 showing its
molecular weight to be 512/514/516 [C27H30N4SCI2] which is equal to the
molecular weight of (6) (530) minus one molecule of water. This
4 8
indicated that tlie format ion of thiadiazepine ring has occurred by the
in t ramolecular cyclocondensat ion of (6). Moreover , the appearance of the
molecular ion peak as the base peak highl ighted the stabil i ty of the molecule .
A set of peaks at m/z 276/278/280 and an another peak at m/z 240 arised by
the c leavage of 3-4 and 1-7 bonds are the diagnost ic peaks for the tr iazolo-
th iadiazepine r ing system. The other f ragment ion peaks at m/z 102, 115, and
m/z 128 were obta ined f rom the ion m/z 240 by the c leavage on the long alkyl
side chain at a , P and y-posit ions to the tr iazole ring as shown in chart 4
N N a-cledvaae
N ^ S H H
m/7 102 (9 0)
H
N N
H
m/z 1 1 5 ( 7 9)
C H ,
N N
"CI
[M+H] m/z 513/515 /517 (100 0/72 1/18 3)
1 -7 and 3-4 -bond clca\ due
N- "SH H
m/z 240 (28 6)
y-cleavage
N N
H
m/z 128 (5.1)
CHART 4
m/z 276/278/280 (54 3/27 8/6 8)
Cl- - C = N O m/z 138/140 (5.9)
The ' H - N M R and '^C-NMR signals (Fig.4a and 4b) we re assigned to
individual H- and C-a toms (Table 5) on the basis of chemica l shif t values,
mult ipl ic i ty , re la t ive integrat ions and by compar ing the spectra l data with that
of (6) (Table 4). The absence of N H j pro tons signal (at 5 5 .14) in the
4 9
CL Q .
a
laD
} ^ J M
5 0
« M
w O E * « » > , « > 9 L> O « U
' C
3 Q. <
..com Vi i - w i X 0 0 « » C C 01 . QC oi«> — <n O'-Q c UJ m^a 3 t ^ - - o • - - CO ( u j 0 « 0 €>kn z r ^ o M 6 & ) x i t p « ^ c • «o au 3 iw eie> c a:<oE</)« f>.o«Oo • CL U J ^ C l a C A N «
C £ O > & . i - ^ M O , . o k 0 CM v^JK « «• « ^ e r - o o u J O ^ c ^ ^ C v U Z 3 U —NCOU O 4 <J D.O. O <-« SJIUO. U X .U. k > a o o Q
U J l f ) CSJ ^ «7
v> V <») rs.
rs. ^ in *> «s (M
rf
5 1
pa tT X
H ta 0 05 B
•V "a •4-1 a a O.
PJ S z 1 u m •a c a
Z I
X
\r) o
es H
E a a.
I. e I U
N
-M =
00
d
ON
00 o (N (N d.
On rW
13
ON O MD >n
q iri (N 00 m
cn
r-
rs
ON
r-
00 o (N o
CN i> ro
(N —
«
o Tt d
O-l (N
CO CO CO 1 ON •T) NO o (N 00 NO CO
n <N a< o< ON ro 1—' rN <N (N (N CO
(N I
CO CO o\ — +
<N T—H
N S OS
(N d
w E
00 r--
oc ON
o <N (N N X
tS X
<N
O Osl <N N X
C<l r-'
On ON
00 oo : M3 vo 00 00
i i o
oi <N o,' r^
< < <
-o T3 X) TZi 'X2 T3 T3 T3 -o -o -o
1 e J s n
^ u
s a a to rn
k. c a 3 m
0-) CN
X (N
ON 00 CN
X (N
00
(N X
o\ (N
X (N
O o — (N
X
OS r- ON 00
w X
c 13 en CNl ^ (N I
rn 00
ON
Kl X
I
d ON ^
>!Ih rC K ^ (N CS (N <N
ON '—1 NO — NO Tt IT) 00 t^ K
^^ NO in fo" (N I 1
5 2
' H - N M R spectrum of FTZX4B and shifts of 5 values of the two
diastereotopic methylene hydrogens to higher fields from 5 3.60 (Hup-2) and
S 4.20 (Hdn-2) to 5 3.27 and 5 3.66 respectively and also of the methine
proton from 6 6.40 (H-3) to 5 5.27 indicated the format ion of 1,3,4-
thiadiazepine ring. This was also supported by '^C-NMR spectrum. The signal
corresponding to CO group did not appear and in place other signals
corresponding to thiadiazepine ring carbons appeared which were assigned as
5 143.05 (C-4), 38.42 (C-3), 53.72 (C-2) and 170.18 (C-9a). In addition, the
signals corresponding to the 9-decenyl side chain and the 1,2,4-triazole ring
carbons appeared as shown in T a b l e 5.
Based on the above spectral evidence, compound FTZX4B was
characterised as 2,4-bis(4-chlorophenyl)-7-(9-decenyl)--2,3-dihydro-l,2,4-
triazolo[3,4-b][1,3,4]thiadiazepine (7).
FTZX4B (7)
5 3
l,3-Bis(2-thienyl)-3-[3-(9-decenyl)-4-amino-5-thio-l,2,4-triazolyl]propan-l-
one F T C A (9) [Reaction of the s - tr iazoie (1) wi th l ,3 -b i s (2- th ienyl )
p r o p e n - l - o n e (8)]*
*[This react ion fai led to yield the desired produc t 2,4-bis(2-thienyl)-7-(9-
decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-bJ[l,3,4Jthiadiazepine].
A solut ion of 5-tr iazole (1) and l , 3 -b i s (2 - t h i eny l )p ropen - l -one (8)
(molar ratio, 1:1) in dry benzene was re f luxed wi th s t i r r ing for 30 h in
presence of catalyt ic amount of /7-TsOH. TLC examina t ion of the reaction
mixture revealed only a single spot. The react ion was con t inued for further
10 h, but no other spot developed. The products on pur i f ica t ion by column
chromatography a f fo rded F T C A (9) as the sole produc t as a pale yel low oily
l iquid in 68 .6% yield.
N N
11 I I
NH2
(1)
"SH I I w
o
N N
(8)
i) /7-TSOH /dry benzene Reflux 30 h
F T C A (9)
5 4
Structure Elucidation of F T C A (9)
It was a pale yel low oily liquid. The structure of F T C A has been ful ly
es tabl ished by DCI-MS, ' H - N M R and '^C-NMR spectra . The DCI-MS
spectrum showed [M+l]"^ peak at m/z 475 showing its molecu la r weight to be
474 [C23H30N4OS3] which is equal to the sum of the molecu la r weights of (1)
(254) and l ,3 -b is (2- th ienyI )propen- I -one (8) (220). This sugges ted that an
adduct of (8) and (1) has been fo rmed by the nuc leophi l ic addi t ion (1,4) of
SH group to or.y^-unsaturated carbonyl funct ion. The m o d e of f ragmenta t ion
of the adduct FTCA is shown in Chart 5.
CH2v
N N
i 1 I
NH2
[M+1] m/z 475 (12.5)
/ O
H
r N N
A
# N N
NH2
m/z 255 (67.1)
P-cleavage H
N N W ^SH I
NH2
m/z 143 (3.7)
^SH NH2
m/z 130 (5.7)
retro-Michael addition
// // w
o m/z 221 (100.0)
// 3
O
m/z 111 (32.0)
CHARTS
S 5
The signals in 'H-NMR and '^C-NMR spectra (Fig. 5a and 5b) have
been assigned to specific H- and C-atoms (Table. 6) f rom the chemical shift
values, multiplicity, relative integrations and by comparing with the spectral
data of a previously established structure of compound (6) (Table 4). The
absence of the thiol proton signal at 6 12.25 and <2,y9-unsaturated protons
signals at 6 7.48 and 5 7.93 of the substrate (8) (experimental) and appearance
of the diastereotopic proton signals at 5 3.82 (Hup-2) and 5 4.25 (Hdn-2) is the
clear evidence for the formation of the adduct. The signal of the methine
proton (H-3) appeared as a double doublet at 5 6.79 (J=9.01, 5.80) due to the
coupling with the two diastereotopic protons (Hup-2) and (Hd„-2). The structure
was further confirmed by '^C-NMR spectrum. The disappearance of the signals
corresponding to the a , (3-unsaturated carbons, C-2 (5 121.36) and C-3
(5 140.95) of (8) (see experimental) and the appearance of the signals of the
same positions at higher fields, 5 44.25 (C-3) and 5 54.03 (C-2) indicated the
formation of adduct. The carbon signals have been assigned as 6 189.06
(C-1). 5 152.51 (C-3') and 5 167.48 (C-5'). The signals of 9-decenyl side chain
and the aromatic ring carbons appeared as usual.
Based on the above spectral facts, the structure of the compound FTCA
was established as \,3-bis(2-thienyl)-3-[3-(9-decenyl)-4-amino-5-thio-],2,4-
triozolylJ propan- J -one (9).
^ - - - - «
>i s o s ^ i f
5 6
to • 1- V N z *» n o *>—• lA • ' v ttj wfs . c e
o o « « o o i H ' o o c o) . — ^ w i o « j i n
o- c tt^ae^Eo*' (J a> n wo^ •• (n — tov — t/) O V- O. • •» Ck.UJ N «> C t- X C lU yc 9
c r u i • « r « * • w w c
s a . 4 0 « « 0 . o £ & . 0 4 a c D « u . o " - O O h-00(0 l-> -o
O O (0 ^ t > ® ®
. €0 ® rv MS «) .
^ ^ CO r o o o o «> VI a .
CSi « «> ® «) M •
91 <0 « in u) I M ^ ^ o o ® tt ® (A in in to
• e T - Q . f . a J o
e •
. W)
V o wt e
5 7
e a. o.
« c « : u j . e.— J £ I . i •) e
o M « v> e V o « M «• . • « e e « N C e « > ««
C « oi «. w a : ^ o«»» — - ^ c i o - - O c £ UJ • ^ © • i V CL H . . • > . ' e M C < n O t n w « O M « v> -< r ^ i r t e w C M T i m • < « < » o a o 3 i t jcw^v
« T O « e U O ^^ E « V —Wt — O. - U J ^ C I O ^ D N * * ' UJ X V —NA. ^ i. x: « M « « » « • -
w O ) C - i s c Z « 3 U — V > « 0 U O
o o o o t -
3 l i
Xi in
t - fe
X M <M M
a . <o le o c _ _ -
>
5 8
a o. w to'
o d
00
NO 00 1 ON o CO >n o <r> OO o OO •vO m o (N) ON (N r-" NO fN 00 NO Tf" 00 >n NO >o vd ON Tf cn »—( (N
<N (N cn >—1
vo
c o u
0\ ^
U H b o «
T3
u a O) a,
0! S ^ u
•a c «
a
vo i i C3 H
I. c
m (N
N M
3 .a
Sf.2 C
s a o.
r^ In — (N r^ 00 ON +
2 ^
o 00 >ri
o CO >n
a
o On
Q. 3
Tt Tj-ON ON
O On'
c •T3 <N
C
ci 3 (S
r--Tt rs|
«
On P
N
CN
E
(N r-MD
00 r Ov
ON rs) <N N X
w K
<N (N
ON H
X w X
CN
w X
(N (N (N CN CN CN 00 (N (N rW —' rn —'
(TT o en" O r.
00 oo" 00 CTT 00 iri ))
lO II m II 11 11 II II )
II )
II II 1—) II 1—)
-o T3 -d T3 13 l-H Id 13 T3 -O 13 13 -a TS 13 13 "O 13
r-H ON cN r- (N
00 rW Tt (N —;
00 00 r-} o (N to
1—I I—i
00 ON ON rt-' r t
vo M CO Tf o m ON (N O CN ON r- oo r- K
s
cn o . 3 (N -a CN ^ CN 0-) 00 ON
U X
K1 in f? I
rt I >o I ^ ^ ^ ^ ^ ^
5 9
EXPERIMENTAL
Reagent and solvents were of commercial grade and were used without
further purification, 10-undecenoic acid was also of commercial grade (Fluka,
AG, Switzerland). All melting points were determined on a Koff le r hot-plate
apparatus and are uncorrected. IR spectra were determined on a Perkin-Elmer
621 spectrophotometer in KBr-pellets. FTIR were recorded on Perkin-Elmer
spectrophotometer RXj and wave numbers (v^ax ) were recorded in cm"'. 'H-
NMR and '^C-NMR spectra were recorded in Bruker Ac 300, Brucker DRX
300 and Varian Unity 400 in acetone-^/^ and DMSO-t/^ with TMS as the
internal standard. The abbreviations s, d, t, m, dd. ddd, br p, dt denote singlet,
doublet, triplet, multiplet, double doublet, triple doublet, broad pentet and
double triplet. ' X - N M R were recorded on a Varian unity 75 and 100
spectrometers. ElMS were recorded on V.G. Micromas model ZAB-IF
apparatus at 70 ev ionization voltage. DCI-MS spectra were recorded with a
Ribermag RIO-IOB quadrupole mass spectrometer, using ammonia as reagent
gas. Thin layer chromatography (TLC) was carried out on 0.25 mm layer
plates with silica gel G (Merck). Spots were visualised on exposure to iodine
vapour using iodine chamber. The column chromatography was performed on
silica gel [Merck. (60-120) mesh] using 25-30 g. per g of material to be
separated and purified. Dry solvents were prepared according to standard
procedures. The organic solvents used were of LR grade and were distilled
before use. The abbreviation used pet. ether for petroleum ether and EtOAc
for ethyl acetate,
6 0
4-Amino -3-(9-decenyl)-5-mercapto-l,2,4-triazole FTZ (1)
A mixture of 10-undecenoic acid (6.0 g, 0.0325 mol) and thiocarbo-
hydrazide (3.456 g, 0.0325 mol) taken in a 100 ml round bot tom flask was
fused by heating at 170 °C on an oil bath for 1V2 h, moni tor ing the progress
of the reaction (TLC, silica gel G, pet .ether-EtOAc, 8:2 v/v) which revealed
the formation of a single spot corresponding to the product . The reaction
mixture was then extracted with ethyl acetate, washed successively with
water (3x50 ml), 5% NaHCOs solution (2x50 ml), again with water (3x50
ml) and finally dried over anhydrous Na2S04. The solvent was removed under
reduced pressure and the solid residue thus obtained was crystall ised from
EtOAc-benzene as white crystalline needles, 7.078 g (85.6%), m.p. 82 °C,
R, 0.63 (pet. ether-EtOAc, 8:2 v/v)
Spectral data of FTZ (1)
IR (KBr): v 3250, 3100 (NHj) , 2900 (CH), 2350 (SH), 1630 (C=N), 1610
(C=C), 1550, 1470, 1410, 1370, 1280, 1230, 940, 890, 720 cm"'.
'H-NMR (400 MHz, ace tone-^) : 5h 12.25 ( I H , SH), 5.18 (2H, s, NH2), 2.73
( 2 H , t , J = 7 . 5 1 , H - 1 ' ) , 1 . 7 5 ( 2 H , b r p , J ~ 7 . 4 6 , H - 2 ' ) , 1 . 3 3 (LOH, b r s, H - 3 ' - 7 ' ) ,
2 . 0 3 ( 2 H , m , H - 8 ' ) , 5 . 8 1 ( I H , t d d , J = 6 . 7 8 , 1 0 . 2 6 , 1 7 . 0 3 H - 9 ' ) , 4 . 9 0 ( I H , d d ,
J = 1 0 . 2 6 , 2 . 2 0 , H E - 1 0 ' ) , 4 . 9 8 ( I H , d d , J = 1 7 . 2 1 , 2 . 2 0 , H z - 1 0 ' ) .
'^C-NMR (100 MHz, acetone-^/g): 5c 153.34 (C-3), 5 168.26 (C-5), 25.40
(C-1'), 26.68 (C-2'), 29.40-30.20 (C-3'-7'), 34.40 (C-8') , 139.82 (C-9'), 114.61
(C-10').
6 1
DCI-MS (NH3);; m/z (%) 254 ( M \ 7.1), 255 [ ( M + l ^ , 100.0], 256 (25.3), 257
(9.6), 143 (9.2), 144 (3.6), 130 (17.3), 131 (3.1).
l,5-Bis(4-chlorophenyl)pent-l,4-dien-3-one (2)
It was prepared following a literature procedure^^'^ by condensing
acetone with p-chlorobenzaldehyde (molar ratio, 1:2) in the presence of 2.5
equivalents of sodium hydroxide. To a solution of /?-chlorobenzaldehyde
(604 mg, 4.310 mmol) dissolved in ethanol (20 ml) was added acetone (250
mg, 2.155 mmol) dropwise keeping the solution in an ice bath. To this was
added sodium hydroxide solution (431 mg, 5.38 mmol) drop wise with
stirring for 2 h. until a yel low precipitate was formed. It was then worked up.
The ye l low solid thus obtained was recrystallised f rom benzene to give (2)
as bright yel low crystalline flakes, 710 mg (72.0%), m.p 176 °C, Rf 0.72
(pet. e ther-EtOAc, 8:2 v/v).
Spectra l data of (2)
' H - N M R (400 MHz, acetone-rfg): 5h 7.28 (2x lH , d, J=16.0, H-2/H-4), 7.70
( 2 x l H , d, J=16.0, H- l /H-5) , 7.73 (4H, d, J=8.50, 2xAr-2,6) , 7.45 (4H, d,
J=8.50, 2xAr-3,5) .
4,4'-Dicholrochalcone (5)
It was prepared following a published but sl ightly modified
procedure^^® by condensing j?-chloroacetophenone with p-chlorobenzyl idene
diacetate (both prepared according to reported procedure)^^^ in equimolar
ratio in the presence of 2.5 equivalents of sodium hydroxide . A mixture of
p-chiorobenzyl idene diacetate (6.5 g, 0.0268 mol) dissolved in (21 ml)
ethanol and p-chloroacetophenone (4.13 g, 0.0268 mol) was kept on an ice
bath in a 500 ml flask. To this, sodium hydroxide (2.65g, 0.0671 mol) was
6 2
added drop wise with stirring. After complete addition, the reaction mixture
was fur ther stirred for 3 h, diluted with 300 ml of ice cold water and was then
kept in the refr igerator overnight. The precipitate formed was filtered and
washed successively with water to make it neutral. It was then washed with
10 ml of cold alcohol. The yellow solid thus obtained was recrystal l ised from
acetone-benzene to give (9) as light yellow crystalline needles, 6.29 g (85%),
m.p. 156 °C, Rf 0.72 (pet. ether-benzene, 1:1 v/v)
l,3-Bis(2-thienyl)propen-l-one (8)
It was prepared following a literature procedure^^'' by condensing
thiophen-2-aldehyde (prepared from thiophene according to reported
procedure^^'') with 2-acetylthiophene in equimolar ratio, in the presence of 2.5
equivalents of sodium hydroxide. A mixture of th iophen-2-a ldehyde (500 mg,
3.96 mmol) dissolved in (20 ml) ethanol and 2-acetyl thiophene (554 mg, 3.96
mmol) was kept on an ice bath in a 500 ml flask. To this sodium hydroxide
(396 mg, 9.9 mmol) was added dropwise with stirring. It was stirred further
4 h and then worked up as above. The yellow solid thus obtained was
recrystal l ised (acetone-benzene) to give (8) as light yel low crystal l ine needles,
765 mg (78%), m.p 89 °C, Rf 0.63 (pet .ether-EtOAc, 8:2 v/v).
Spectral data of (8)
' H - N M R ( 400 MHz, acetone-dfi): 5h 7.48 ( IH , d, J=15.41, H-2) , 7.93 ( IH,
d, J=15.41, H-3), 7.67 ( IH , d, J=5.04, Ar-3), 7.60 ( I H , d, J=4.73, Ar'-3), 7.27
( IH , d, J=3.51, Ar-4), 7.17 ( IH, d, J=3.67, Ar'-4), 8.11 ( I H , d, J=3.82, Ar-5) ,
7.91 ( IH , d, J=3.67, Ar'-5).
6 3
' ^C -NMR (100 MHz, acetone-dtf): 5c 181.80 (C-1), 121.36 (C-2), 140.95
(C-3). 146.68 (Ar-C-2), 136.58 (Ar-C-5), 133.06 (Ar'-C-5), 129.34-134.25
(Ar-C-3, Ar '-C-3, Ar-C-4, Ar'-C-4).
DCI-MS (NH3): m/z (%) 221 (100.0), 222 (20.4), 220 (14.0), 191 (3.7). 137
(3.8). I l l (7.2).
l,5-Bis(4-cltlorophenyl)-5-[3-(9-decenyl)-4-amino-5-thio-l,2,4-triazolyl]
pent-l-en-3-one FBCA (3) and 2-(4-chlorophenyl)-4-[2-(4-chlorophenyl)
ethenyl]-7-(9-decenyl)]-2,3-dihydro-l,2,4-tnazolo[3,4-b][l,3,4]thiadiazepine
FBCB (4). [Reaction of the 5-triazole (1) with l ,5-bis(4-
chiorophenyl)pent- l ,4-dien-3-one (2)]
A mixture of the ^-triazole (1) (50 mg, 1.96 mmol) and 1.5-bis(4-
chlorophenyl)pent- l ,4-dien-3-one (2) (590 mg, 1.96 mmol) in dry benzene
(20 ml) was refluxed for 33 h in presence of yC-TsOH (5 mg). The TLC
examination of the reaction mixture revealed the presence of two spots of
equal intensity. It was worked up and subjected to column chromatography
(silica gel, pet. ether-EtOAc, 8:2 v/v) which afforded FBCA (3) as glassy
flakes. 416 mg (38.2%), m.p 84 °C, Rf 0.71, pet. e ther-EtOAc (8:2 v/v).
Further elution of the column using pet. ether-EtOAc (6:4 v/v) followed b>
crystallisation (benzene-acetone) afforded FBCB (4) as yel low crystalline
globules, 460 mg (47.5%), m.p 161 °C, Rf0 .30 (pet. e ther-EtOAc, 8:2 v/v).
Spectral data of FBCA (3)
'H-NMR (400 MHz, acetone-^/g): 5h 5.21 (2H, s, NHj), 6.43 ( IH , dd, J=9.31.
5.50, H-5), 3.47 ( IH , dd, J=I7 .25 , 5.50, H-4up), 3.97 ( I H , dd, J=I7 .25 , 9.31,
H-4dn), 6.90 ( IH , d, J=I6 .33 , H-2), 7.67 ( IH, d, J= 16.33, H - I ) , 2.73 (2H, t,
J=7.48, H- l " ) , 1.70 (2H, br p, J~7.36, H-2"), 1.25 (lOH, br s, H-3"-7") , 2.00
64
( 2 H , m , H - 8 " ) , 5 . 8 0 ( I H , t d d , J = 6 . 7 1 , 1 0 . 2 2 , 1 7 . 0 9 , H - 9 " ) 4 . 9 0 ( I H , d d ,
J = 1 0 . 2 2 , 2 . 2 9 , H E - 1 0 " ) 4 . 9 8 ( I H , d d , J = 1 7 . 0 9 , 2 . 2 9 , H Z - 1 0 " ) , 7 . 3 6 ( I H , d,
J = 8 . 5 4 , H - A r - 2 , 6 ) , 7 . 4 6 ( I H , d , J = 8 . 5 4 , H - A r - 3 , 5 ) , 7 . 7 2 ( I H , d , J = 8 . 3 9 , H -
A r ' - 2 , 6 ) , 7 . 4 9 ( 2 H , d , J = 8 . 3 9 , H - A r ' - 3 , 5 ) .
'^C-NMR (100 MHz, acetone-rf^): 5c 57.69 (C-5), 45.05 (C-4), 196.04 (C-3),
127.64 (C-2), 142.08 (C-1), 152.46 (C-3'), 167.62 (C-5'), 25.21 (C-1"), 26.70
(C-2"), 29.20-30.40 (C-3"-7"), 45.05 (C-8"), 139.35 (C-9"), 114.64 (C-10"),
139.85 (Ar-C-1), 129.29 (Ar-C-2,6), 129.99 (Ar-C-3,5), 134.59 (Ar-C-4),
134.04 (Ar ' -C- l ) , 130.81 (Ar'-C-2,6), 130.09 (Ar'-C-3,5), 136.63 (Ar'-C-4)
DCI-MS (NHs): m/z (%): 557[(M+1)^ 35.4], 558 (10.3), 559 (19.6), 560
(8.7), 561 (7.8), 301 (5.1), 302 (15.5), 303 (73.3), 304 (22.9), 305 (47.0), 306
(10.4), 307 (8.3), 267 (5.5), 254 (20.8), 255 (100.0), 256 (17.6), 257 (6.6),
204 (4.3), 165 (28.8), 167 (9.2), 143 (9.2), 137 (4.8), 130 (15.7), 101 (4.1),
102 (11.0).
Spectral data of F B C B (4)
'H-NMR (400 MHz, acetone-rfg): 5h 3.07 ( I H , dd, J=13.73, 11.75, H-3„p),
3.52 ( I H , dd, J=13.73, 4.89, H-3dn), 5.22 ( IH, dd, J=11.75, 4.89, H-2), 7.27
( IH , d, J=16.48, H-1"), 7.66 ( IH , d, J=16.48, H-2"), 2.83 (2H, t, J=7.47, H-
1'), 1.79 (2H, br p, J~7.44, H-2') , 1.29 (lOH, br s, H-3'-7 ') , 2.00 (2H, m, H-
8'), 5.78 ( I H , tdd, J= 6.7,10.22, 17.09, H-9') , 4.88 ( IH , dd, J=10.22, 2.29, HE-
10'), 4.96 ( I H , dd, J=17.09, 2.29, Hz-10'), 7.42 (2H, d, J=8.54, H-Ar-2,6) ,
7.49 (2H, d, J=8.54, H-Ar-3,5), 7.76 (2H, d, J=8.39, H-Ar '-2,6) , 7.57 (2H, d,
J=8.39, H-Ar'-3,5).
^^C-NMR (100 MHz, acetone-dg): 8c 171.27 (C-9a), 155.84 (C-7), 143.16
(C-4), 36.92 (C-3), 53.59 (C-2), 126.76 (C-1"), 140.69 (C-2"), 25.51 (C-T),
6 5
27.36 (C-2'), 29.20-30.40 (C-3'-7'), 34.42 (C-8'), 139.81 (C-9'), 114.59 (C-
10'), 142.37 (Ar-C-1), 129.47 (Ar-C-2,6), 129.61 (Ar-C-3,5) ,135.23 (Ar-C-4),
134.32 (Ar ' -C- l ) , 130.39 (Ar'-C-2,6), 129.95 (Ar ' -C-3,5) , 136.12 (Ar'-C-4).
DCI-MS (NH3): m/z (%): 538 ( M \ 10.2), 539 [ (M+1)^ 100.0], 540 (45.1),
541 (75.7), 542 (28.9), 543 (18.7), 544 (5.9), 415 (7.6), 416 (5.9), 417 (5.8),
300 (16.5), 301 (5.9), 302 (30.6), 303 (8.5), 304 (16.5), 255 (6.8), 240 (25.1),
128 (5.9), 1 15 (6.3), 102 (9.3).
l,3-Bis(4-chlorophenyl)-3-[3-(9-decenyl)-4-amino-5-thio-l,2,4-tnazolyl]pro -
pan-l-one FTZX4A (6) and 2,4-bis(4-chlorophenyl)-7-(9-decenyl)-2,3-
dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine, FTZX4B (7) [Reaction of
the 5-triazole (1) with 4,4'-dichlorochaIcone (5)]
To a solution of ^-triazole (1) (500 mg, 1.96 mmol ) in dry benzene (20
ml) was added 4,4'-diclilorochalcone (5) (540 mg, 1.96 mmol) and refluxed
for 28 h in presence of /?-TsOH (5 mg). The progress of the reaction was
monitored by TLC (silica gel G, pet .ether-EtOAc, 8:2 v/v) which showed the
presence of two new spots, labelled as FTZX4A (6) and FTZX4B (7). The
solvent was removed under reduced pressure and the residue left was
dissolved in ethyl acetate, washed with water and the organic phase was dried
over anhydrous Na2S04 The products on column chromatography over silica
gel using pet. ether-EtOAc, (8:2 v/v) as eluent y ie lded FTZX4A (6) as
colourless oily liquid, 384 mg (37.0%), Rf 0.63 (pet. e ther-EtOAc, 8:2 v/v).
Further elution of the column using pet. e ther-EtOAc (4:6 v/v) as eluent
yielded FTZX4B (7) as a yellow solid which was recrystal l ised f rom benzene
as pale yellow crystalline globules, 540 mg (51.9%), m.p 148 °C, Rf 0.32
(pet. e the r -E tOAc, 8:2 v/v)
6 6
S p e c t r a l da ta of FTZX^A (6)
FTIR (Neat): v ^^^ 3178.55, 3074.26 (NH2), 2927.0 (CH) , 1689.17 (C=0),
1639.66 (C=N) , 1590.04 (C=C) , 1571.40, 1491.79, 1426.78, 1402.11,
1360.60, 1308.68, 1260.38, 1205.25, 1174.16, 1091.68, 1014.26, 991.38,
961.79, 910.10, 827.98, 783.54, 723.97, 629.04, 531.33, 462 .77 cm"'
^H-NMR ( 300 MHz, acetone-flfg): 5h 5.14 (2H, s, NH2), 6 .40 ( I H , dd,
J = 9 . 0 8 , 5 . 5 8 , H - 3 ) , 3 . 6 0 ( I H , d d , J - 1 7 . 1 0 , 5 . 5 8 , H-2„P) , 4 . 2 0 ( I H , d d , J = 1 7 . 1 0 ,
9 . 0 8 , H-2DN), 2 . 6 8 ( 2 H , t , J = 7 . 4 6 , H - 1 " ) , 1 . 6 4 ( 2 H , b r p , J ~ 7 . 3 3 , H - 2 " ) , 1 .23
(LOH, b r s , H - 3 " - 7 " ) , 1 . 9 8 ( 2 H , m , H - 8 " ) , 5 . 7 0 ( I H , t d d , J = 6 . 2 8 , 1 0 . 2 2 , 1 7 . 0 8 ,
H - 9 " ) , 4 . 8 8 ( I H , d d , J = 1 0 . 2 2 , 2 . 2 8 , H E - 1 0 " ) , 4 . 9 7 ( I H , d d , J = 1 7 . 0 8 , 2 . 2 8 , HZ-
1 0 " ) , 7 . 2 0 ( 2 H , d d , J = 8 . 5 5 , H - A r - 2 , 6 ) , 7 . 4 2 ( 2 H , d d , J = 8 . 5 5 , H - A r - 3 , 5 ) , 7 . 8 4
( 2 H , d d , J = 8 . 4 2 , H - A r - 2 , 6 ) , 7 . 7 0 ( 2 H , d d , J = 8 . 4 2 , H - A r ' - 3 , 5 ) .
E I - M S : m / z ( % ) 2 7 7 ( 1 6 . 0 ) , 2 7 8 ( 4 . 2 ) , 2 7 9 ( 9 . 2 ) , 2 8 0 ( 3 . 1 ) , 2 7 6 ( 1 3 . 3 ) , 2 7 5
( 1 0 . 0 ) , 2 5 5 ( 2 1 . 2 ) , 2 5 6 ( 7 . 0 ) , 2 5 7 ( 3 . 1 ) , 2 4 2 ( 2 6 . 0 ) , 2 4 3 ( 8 . 9 ) , 2 2 1 ( 8 . 0 ) , 2 0 0
( 7 . 2 ) , 1 9 6 ( 1 4 . 0 ) , 1 5 7 ( 1 0 . 0 ) , 1 4 3 ( 2 8 . 3 ) , 130 ( 6 7 . 8 ) , 1 2 8 ( 2 4 . 0 ) , 130 ( 6 7 . 8 ) ,
128 ( 2 4 . 0 ) , 1 0 3 ( 4 . 8 ) , 8 3 ( 9 . 0 ) .
S p e c t r a l da ta of FTZX4B (7)
' H - N M R ( 4 0 0 M H z , acetone-^/<5): 5 h 3 . 2 7 ( I H , d d , J = 1 3 . 9 1 , 12.08, H-3,p),
3 . 6 6 ( I H , d d , J = 1 3 . 9 1 , 4 . 7 6 , H-3DN), 5 . 2 7 ( I H , d d , J = 1 2 . 0 8 , 4 . 7 6 , H - 2 ) , 2 . 8 9
( 2 H , t , J = 7 . 5 1 , H - 1 ' ) , 1 . 8 2 ( 2 H , b r p , J ~ 7 . 4 6 , H - 2 ' ) , 1 . 2 9 ( L O H , b r s , H - 3 ' - 7 ' ) ,
2 . 0 0 ( 2 H , m , H - 8 ' ) , 5 . 7 9 ( I H , t d d , J = 6 . 7 8 , 1 0 . 2 9 , 1 7 . 2 1 , H - 9 ' ) , 4 . 8 9 ( I H , d d ,
J = 1 0 . 2 6 , 2 . 2 0 , H E - 1 0 ' ) , 4 . 9 7 ( I H , d d , J = 1 7 . 2 1 , 2 . 2 0 , H z - 1 0 ' ) , 8 . 1 9 ( 2 H , d,
J = 8 . 7 9 , H - A r ' - 2 , 6 ) , 7 . 6 1 ( 2 H , d , J = 8 . 7 9 , H - A r ' - 3 , 5 ) , 7 . 4 1 ( 2 H , d , J = 8 . 6 1 , H -
A r " - 2 , 6 ) , 7 . 5 6 ( 2 H , d, J = 8 . 6 1 , H - A r " - 3 , 5 ) .
6 7
' ^C -NMR (100 MHz, acetone-rfe): 6c 156.09 (C-9), 170.18 (C-7), 143.05 (C-
4), 38.42 (C-3), 53.72 (C-2), 25.55 (C-T), 27.36 (C-2'), 29.20-30.40 (C-3'-7'),
34.42 (C-8'), 139.83 (C-9'), 114.63 (C-10'), 130.44 (C-Ar '-2,6) , 129.67 (C-
Ar'-3. 5), 130.03 (C-Ar"-2,6), 129.39 (C-Ar"-3,5), 142.31 (C-Ar"-1), 134.24
(C-Ar ' - l ) , 138.81 (C-Ar'-4), 134.39 (C-Ar"-4).
D C I - M S (NH3): m/z (%) 512 ( M ^ 6.2), 513 [ ( M + l ) ^ 100.0], 514 (40.7), 515
(72.1), 516 (25.2), 517 (18.2), 518 (5.4), 273 (3.9), 274 (23.7). 275 (7.4). 276
(54.3), 277 (12.6), 278 (27.8), 279 (6.7), 280 (6.8), 238 (3.9). 239 (3.7). 240
(28.6), 241 (7.4), 242 (5.7), 128 (5.1), 1 15 (7.9), 1 17 (5.1), 102 (9.0), 93
(6.4).
l,3-Bis(2-thienyl)-3-l3-(9-decenyl)-4-amino-5-thio-l,2,4-triazolyl]propan-l-
one FTCA (9) [Reaction of the s-triazole (1) with l ,3-bis(2-thienyl)
propen- l -one (8)]*
*[This reaction failed to yield the desired product 2,4-bis(2-thienyl)-7-(9-
decenyl)-2,3-dihydro-l ,2,4-triazolo[3,4-b] [1,3,4]thiadiazepine].
A mixture of the 1,2,4-triazole (1) (500 mg, 1.96 mmol) and l ,3-bis(2-
th ienyl )propen- l -one (20) (432 mg, 1.96 mmol) in dry benzene (20 ml) was
ref luxed for 28 h in presence of catalytic amount of p - T s O H (5 mg). The
reaction mixture on TLC examination (silica gel G, pet .e ther-EtOAc, 8:2 v/v)
showed the presence of only one spot even by prolonging the reaction. The
products on column chromatography (silica gel, pet. e ther-EtOAc, 8:2 v/v)
afforded FTCA aa pale yellow oily liquid, 640 mg (68.6%), Rt 0.69 (pet.
ether-EtOAc, 8:2 v/v).
6 8
Spectral data of FTCA (9)
^H-NMR (400 MHz, acetone-^/^): 5h 5.21 (2H, s, NH2), 6 .79 ( I H , dd, J=9.01,
5 . 8 0 , H - 3 ) , 3 . 8 2 ( I H , d d , J = 1 6 . 9 4 , 5 . 8 0 , H - 2 ) , 4 . 2 5 ( I H , d d , J = 1 6 . 9 4 , 9 . 0 1 , H -
2) , 2 . 7 1 ( I H , t, J = 7 . 4 7 , H - L " ) , 1 . 6 8 ( 2 H , b r p , J ~ 7 . 3 2 , H - 2 " ) , 1 . 2 8 (LOH, b r s,
H - 3 " - 7 " ) , 2 . 0 2 ( 2 H , m , H - 8 " ) , 5 . 8 1 ( I H , t d d , J - 6 . 7 2 , 1 0 . 2 3 , 1 7 . 0 9 , H - 9 " ) , 4 . 9 1
( I H , d d , J = 1 0 . 2 2 , 2 . 2 9 . H E - 1 0 " ) , 4 . 9 9 ( I H , d d , J = 1 7 . 2 4 , 2 . 2 9 , H ^ - I O " ) , 7 . 9 0
( I H , d d , J = 4 . 8 9 , 1 . 2 2 , H - A r ' - 5 ) , 7 . 2 4 ( I H , d d , J = 4 . 8 8 , 3 . 8 1 H - A r ' - 3 ) . 8 . 0 3
( I H , d d , J = 3 . 8 1 . 1 . 2 2 , H - A r ' - 3 ) 7 . 2 2 ( I H , d d , J = 3 . 5 1 , 1 . 2 2 . H - A r - 5 ) 6 . 9 7 ( I H .
d d , J = 5 . 0 3 , 3 . 5 1 , H - A r - 4 ) , 7 . 3 6 ( I H , d d , J = 5 . 0 3 , 1 . 2 2 , H - A r - 3 ) .
'^C-NMR (100 MHz, acetone-rf^): 5c 152.51 (C-3'), 167.48 (C-5'), 54.03 (C-3).
44.25 (C-2), 189.06 (C-1), 25.18 (C- l" ) , 26.6 (C-2"), 29.20-30.40 (C-3"-7"),
34.45 (C-8"), 139.89 (C-9") 114.64 (C-10"), 126.30-144.78 (Ar + Ar') .
D C I - M S (NH3): m/z (%) 475 ( M ^ 12.5), 476 (4.4), 254 (6.8), 255 (67.1), 256
(11.9). 257 (4.1), 220 (11.5), 221 (100.0), 222 (15.3), 223 (1 1.3), 137 (3.6), 130
(5.7). I l l (32.0).
1,11 11
Long alkyl chain substituted-Benzopyrano-s-Triazolo-Thiadiazepines
6 9
DISCUSSION
SUMMARY
The work included in this chapter deals with the reaction of 4-amino-3-(9-
decenyl)-5-mercapto-l,2,4-triazole (1 ) with :
i) E-3-(4-Chlorobenzylidene)-4'-chloroflavanone (10) which yielded an
adduct, 2-(4-chlorophenyl)-3-[4-amino-2-(9-decenyl)-5-(4-chlorobenzyl-
thio)-! ,2,4-triazolyl]-2,3-dihydro-4-benzopyrone (11) and a novel
compoundj2,3-bis(4-chlorophenyl)-1 l-(9-decenyl)-2a, 3-dihydro[l]benzo-
pyranof3,4-e]-2,2a-dihydro-l,2,4-triazolo[3,4-b][1,3.4Jthiadiazepine (12).
ii) E-3-Benzylidene flavanone (13) which afforded an adduct 2-(phenyl)-3-
[4-amino-3-(9-decenyl)-5-(benzylthio)-1,2,4-triazolyl]-2.3-dihydr0'4-hen-
zopyrone (14) and an analogous new compound, 2.3-bis(phenyl)-J I-(9-
decenyl)-2a,3-dihydro[I]benzopyrano[3,4-e]-2.2a-dihydro-l.2.4-lriazuh)
[3,4-b][},3.4]thiadiazepine (15)
I N T R O D U C T I O N
As part of our programme in search of biologically active compounds
with sulphur and nitrogen containing heterocycles, we have synthesised two
novel compounds, 2-(4-chlorophenyl)-4-[2-(4-chlorophenyl)ethenyl]-7-(9-
decenyl)-2 ,3-dihydro- l ,2 ,4- t r iazolo[3,4-b][ l ,3 ,4] thiadiazepine (4) and 2.4-
bis(4-chlorophenyl)-7-(9-decenyl)-2,3-dihydro-l ,2 ,4-tr iazolo[3.4-bJ[1.3.4]thi-
adiazepine (7) by the reaction of 3-(9-decenyl)-4-amino-5-mercapto-1,2,4-
triazole (1) with l ,5-bis(4-chlorophenyl)pent- l ,4-dien-3-one and 4,4'-
dichlorochalcone (described in Chapter 1). In continuation of the above
mentioned work, we extended our work on the reaction with exocyclic
^./^-unsaturated enone systems and synthesised two novel compounds, (i) 2,3-
bis(4-chlorophenyl)- l l - (9-decenyl) -2a ,3-dihydro[ l ]benzopyrano[3,4-e]-2 ,2a-
7 0
dihydro-l ,2 ,4- t r iazolo[3,4-b][ l ,3 ,4] thiadiazepine (12) and (ii) 2,3-bis(phenyl)
-1 l - (9-decenyl)-2a,3-dihydro[ l ]benzopyrano[3,4-e]-2 ,2a-dihydro- l ,2 ,4- t r iaz-
olo[3,4-b][ l ,3 ,4] thiadiazepine (15) by the reaction of 4-amino-3-(9-decenyl)-
5-mercapto- l ,2 ,4- t r iazole (1) with (i) £ '-3-(4-chlorobenzylidene)-4 '-chloro-
f lavanone (10) and (ii) £-3-benzyl idene f lavanone (13) in dry benzene using
p - T s O H as catalyst. An adduct, 2-(4-chIorophenyI)-3-[3-(9-decenyl)-4-amino-
5-(4-chlorobenzyl thio)- l ,2 ,4- t r iazolyl]-2,3-dihydro-4-benzopyrone (11) in the
former and 2-(phenyi)-3-[3-(9-decenyl)-4-amino-5-(benzylthio)-1,2,4-
tr iazolyl]-2,3-dihydro-4-benzopyrone (14) in the latter was also obtained in
good yields. £'-3-Benzylidene flavanones have been prepared by the reported
procedure^^ and their stereochemistry discussed.
3-Benzyl idene flavanones, often formed as co-products during the
preparat ion of flavanones or chalcones^° have structural similarities with
natural homo isoflavonoids, Eucomin and Eucomol isolated f rom Eucomis
bicolor (Liliaceae)^' and they have been the focuss of attention for their
methods of preparation and stereochemical implications during the past few
years^^. Although the reactions of various substi tuted/unsubsti tuted
benzyl idene f lavanones with 2-aminobenzenethiols to form the corresponding
1,5-benzothiazepine have been described^^'^'', no report on the reaction of
benzyl idene f lavanones with 4-amino-5-mercapto- l ,2 ,4- t r iazoles has
appeared in the literature.
Structural assignment, stereochemistry and biological assay are
discussed. Screening results of the compound (12) is summarised for
anticancer activity against 3-cell lines of three types of human cancers: lung,
breast and CNS (details in Chapter 6).
7 1
4 .R '
O H
(10) , (13)
(11), (14)
(12) , (15)
(10) , (11) , ( 1 2 ) : R = R ' = CI
(13) , (14) , ( 1 5 ) : R = R ' = H
7 2
R E S U L T S A N D D I S C U S S I O N
£-3-Benzyl idene flavanones, AF2 (10) and AFj (13) were first prepared
fol lowing the literature procedure '^ and their structures alongwith the
stereochemistry determined by IR, 'H-NMR and '^C-NMR spectra. IR spectra
(KBr) showed characterist ic bands corresponding to ( C = 0 ) , (C=C, phenyl)
and (C-O-C). The ' H - N M R and '^C-NMR spectral signals were assigned on
the basis of chemical shif t values, coupling constants and by comparison with
the spectral data reported in the literature^^. The absorpt ion of the vinyl
proton (H-y^ (H-1'") at very low field, 5 8.09/8.03 indicated that it is due to
deshielding effect arising from the diamagnetic anisotropy of the carbonyl
group (being in close proximity) which is consistent with the trans
configuration^^ (£ - fo rm) (H cis and Ph trans to the carbonyl group) (in the
cis isomer, the vinyl proton appears at 5 6.65^^). Thus, benzylidene
f lavanones here exhibit ^-conf igurat ion. The conf igura t ion at C-2 was
decided by the inspection of models. Models showed that ^ -S-benzyl idene
f lavanones adopt strainless stable conformation only, when the 2-Ph is axial
and 2-H equatorial as the 2-Ph equatorial in another possible conformer
nearly overlaps with ^ - P - P h causing severe non-bonded interaction. Such an
interaction is not present in the former conformer. It is well known that in
cyclohexanes and other related compounds, a large group normal ly adopts the
equatorial position to avoid 1,3-diaxial interaction. However , in our case,
there are no such axial groups to interact with an axial 2-Ph group. The
preferred conformat ion of £'-3 benzylidene f lavanones (10a and 13a) would
therefore, be (10b and 13b).
7 3
lOa. R=R' = C1 13a. R = R' = H
10b. R=R' = C1 13b. R=R' = H
The title compounds FF2C (12) and FTZX5 (15) were then synthesised
by ref luxing 4-amino-3-(9-decenyl)-5-mercapto- l ,2 ,4- t r iazole FTZ (1) with
£ '-3-(4-chIorobenzylidene)-4 '-chloroflavanone AF2 (10) and £-3-benzyl idene
f lavanone AFi (13) in dry benzene using />-TsOH as catalyst. In above
reaction, a Michael adduct FF2A (11)/ FFjA (14) was also obtained in good
yields (Scheme 2)
7 4
o .OH
+ OHC-,CH3 o -R
O molar ratio (1:3) EtOH/KOH
O H
N N
^SH
NH2
(1)
(10) R = R' = C1 (13) R = R' = H
Molar ratio (1:1) Dry benzene Reflux 38/32 h
(11) R = R' = C1 (14) R = R' = H
N N
(12) R = R ' - C 1 (15) R = R' = H
SCHEME 2
7 5
2,3-Bis(4-chlorophenyl)-ll-(9-decenyl)-2a,3-dihydroll]benzopyrano[3,4-e]-
2,2a-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine FF2C (12) alongwith
the adduct, 2-(4-chlorophenyl)-3-[4-amino-3-(9-decenyl)-5-(4-chlorobenzyl-
thio)-l,2,4-triazolyl]-2,3-dihydro-4-benzopyrone FF2A (11). [Reaction of the
5-triazole FTZ (1) with £'-3-(4-chlorobenzyIidene)-4'-chloroflavanone AF2 (10)]
A solut ion of the 1,2,4-triazole (1) and £ ' -3- (4-chlorobenzyl idene)-4 ' -
ch lo ro f lavanone (10) (molar ratio, 1:1) in dry benzene was re f luxed for 38 h
in the presence of a catalyt ic amount o f /7 -TsOH, moni to r ing the progress of
the react ion by TLC. The react ion mixture revealed the p resence of two spots,
labelled as FF2A (11) and FF2C (12). The res idue left a f te r usual work up
was chromatographed over a silica gel column using pet. e ther -EtOAc, (7:3
v/v) as eluent . Elut ion first y ie lded a colourless glassy f lakes , FF2A (40.5%).
Further e lut ion of the column using pet. e ther -EtOAc, (1:1 v/v) y ie lded a pale
yel low solid, FF2C which was recrystal l ised (pe t . e the r -E tOAc) as white
crystal l ine needles in 44 .72% yield.
N N
N H 2
F T Z (1) Dry benzene//?-TsOH AF2(10) Reflux 38h
F F 2 A ( 1 1 ) F F 2 C ( 1 2 )
7 6
Structure Eluc idat ion of FF7A (11)
It was a colourless glassy flakes, m.p 93 °C. The structure of FF2A has
been established by DCI-MS, 'H-NMR, and '^C-NMR spectra. The DCI-MS
spectrum (Fig. 6a) displayed a set of [M+1]"^ peaks at m/z 635/637/639
showing its molecular weight 634/636/638 [C34H36N4O2SCI2], which is equal
to the sum of the molecular weights of the 1,2,4-triazole (1) (254) and £-3-(4-
ch]orobenzylidene)-4 ' -chloroflavanone (10) (380). This suggested that FF2A
is an adduct of the two compounds. The retro-Michael addit ion fragment ion
peaks were observed at m/z 255 [(M+l)-C22Hi4Cl202]^ as the base peak and
at m/z 381/383/385 [(M+l)-Ci2H22N4S]^. The retro-Diels Alder f ragment ions
were formed at m/z 121 and m/z 259/261/263. The f ragment ion peaks at m/z
130 and 143 were arised by the cleavage on the long alkyl side chain at and
/-posit ionsto the triazole ring as shown in Chart 6.
All the signals in 'H-NMR and '^C-NMR spectra (Fig. 6b and 6c) were
assigned to individual H and C-atoms (Table 7) on the basis of 5 values,
mult ipl ici ty and by comparison with the previously established structures of
similar adducts. The absence of vinylic proton (H- l ' " ) signal at 5 8.03 and
thiol proton signal at 5 12.25 and the appearance of new signals at 5 5.65 as
doublet for H - l ' " and 5 6.42 also as doublet for H-2 in the ' H - N M R spectrum
of FF2A suggested the addition of thiol group to C=C double bond of the
enone systems of £-3-benzyl idene flavanone. This is also supported by the
shifts of the vinylic carbons at 5 138.28 (C- l" ' ) and 133.28 (C-3) to higher
fields 5 60.01 and 5 79.04. The other 'H- and '^C-NMR signals were found
almost identical to that of £'-3-benzylidene f lavanone and tr iazole moieties.
• - . M
7 7
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7 8
E a. a.
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7 9
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a e 3 o O *T r«. e o o a . o w « < n e •«/>
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« « > 0 0 » ) « 4 - « » X O O » » C C o . . . I . tt ^ et«r> ^ C O ' - O C XI
« w « k j s r — t o o . u OJn o o « K > " 0 . . - > , " o » - c n O V C e «><>) «) " Q •) v> « X ' - i n o V 10 i (/) w > » 3 — < « • 0 0 0 . 0 3 « er = Q f ' D o c u ) * ) * r 0 « > 0 0 - - € V O C •• 3 < X V C W L . U ^ S ^ ' O l - V C — ( o o CL • ** tai^ c i a A N v * *
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m (N r-00
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rsi CN
00
m
o o Ov
ON O r- m d ' — '
o cn 1 VO vn 1—1 o oo VO 00 d cn in CN ON ^ 00 VO in VO cK CNl
(N (N CN
<N (T) as ' r t ' ^ m v 0 l > 0 0 0 0 ~ r-
<N m oo ON
i-, < + <
On O
C N
OS ON (N <N oi
in (N
>n 00 00 ON r-(N VO r j CO o I 00 00 H - 00
>—> <ri oo' >—> 1—> H-J
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r f in m ON , \ (N oo CO ,—1 .—1 od 00 00 00 rn rsT fW -o" r-" oo 1—> 1—> i—> 1—> 1—1
o -
00
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tu X
VO
w X N X
rvf ON o rsi
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= a:
3 '.a S a T3 73 -O -O "O -a T3 -a -o XI Xi
T3 s ^ •o T3 -a td
5 2
0) «
H
s a a
to (N m (N r- •—I (N vq ^ IJO in VO
m m VO cs VO I O VO (N 00 00 (N o
V O C<-)
^ ^ ON oo 00 On ON (N
I. a b o <
CN m in VO t^ 00 . _ , LU N tH CN ^ 5N I DH
CH
8 1
CI
N N o O
NH2
CI' Q -O' Q m/z 635 / 637/639(5.4/4.1) [M+1]
retro-Michael addition
-Km
N N
N- "SH
NH2
m/z 143(6.0)
m/z 255 (100.0)
P-cleavage H
N N • i 1]
^ N - ^ S H NH2
m/z 130 (9.4)
m/z 381/383/385 (22.6/14.7/3.2)
retro-Diels Alder fission
m/z 121 (12.4)
m/z 259/261/263 (14.3/6.8)
CHART 6
The large coupl ing constants of C-2 and C-3 pro tons of f l avanone
moiety (JH-2»H-3 11-14) conf i rmed that the two ad jacen t hydrogen a toms are in
axial disposi t ion. This showed that the proton of thiol g roup has been added
s tereoselect ively to C-3 of C=C bond f rom the axial s ide. A plausible
explanat ion may be of fe red for this s tereoselect ivi ty . The addi t ion of thiol
group of (1) to the exocycl ic a,y^-unsaturated carbonyl sys tem of E-3-{4-
chlorobenzyl idene) -4 ' -ch lorof lavanone (10) fo l lowing nuc leoph i l i c path '^
( S c h e m e 3) leads to the fo rmat ion of a s tereoselect ive t rans adduct probably
8 2
by in t ramolecular proton t ransfer of the 1,4-addition moie ty f rom the axial
side at C-3, assuming the bigger group adopts equatorial pos i t ion . Thus, the
conf igura t ions , of all the three s tereocentres (C-2, C-3 and C - l ' " ) could be
settled f rom the coupl ing constants of protons at C-2, 6 6.42 ( I H , d,
J2ax,3axl l . l4) , C-3, 5 4.37 ( I H , dd, J3ax,23x11-14, J3ax ,1'" 2 .75) and C - l ' " , 5
5 . 6 5 ( 1 H , d, J r . . 3 a x 2 . 7 5 ) .
N N
I I
I
NH;, F T Z (1)
N N
AF2(10)
FFjA (11) S C H E M E 3
8 3
Based on the above spectral evidence, s tereostructure of FF2A was
formulated as 2-(4-chlorophenyl)-3-[S-(9-decenyl)-4-amino-5-(4-chloro-
benzylthio)-!,2,4-triazolyl]-2,3-dihydro-4-benzopyrone (11).
CI
0 1 N N Ha (ft
1 U' , 1 4 ? ^ (ft
1 ^ ' 5 4' 3I
FF2A (11)
„ Hz
Structure Elucidat ion of FF^C (12)
It was a white needle shaped crystalline solid, m.p 182 °C. The
structure of FFjC has been established by DCI-MS, ' H - N M R and '^C-NMR
spectra. The DCI-MS spectrum (Fig. 7a) showed a set of [M+1]"^ peaks as the
base peak at m/z 617/619/621 confirming its molecular weight 616/618/620
[ C 3 4 H 3 4 N 4 O S C I 2 ] which is equal to the molecular weight of (11)
(634/636/638) minus one molecule of water. This indicated that
cyclocondensat ion has occurred between the amino group of t r iazole moiety
and carbonyl group of benzopyrone moiety forming th iadiazepine ring. The
peak at m/z 492/494 was obtained by the cleavage on 9-decenyl side chain at
the y^-position to the 5-triazole ring. The peaks at m/z 380/382/384 [(M+1)-
C,2H2iN3S]^ and at m/z 240 [M-C25HigN4SCl2]^ are the diagnost ic f ragment
ion peaks arised by the cleavage of 3-4 and 1-7 bonds of thiadiazepine ring
as shown in Chart 7.
8 4
' tlM" = 1 -!'-. 1 f-.!-' "--l M M . M
!- vjiu-^yti J 1 — ' . TCi I Mi_ J ^-r". , .
' — ' ^
•TTi r" ' rr^'f LV • ' CMCi = il
I
c- = ri>4ii T:Drt'CTi=r-ivi Pf' 1 ficiv-
T—,—,—I—I—,—,—,—I—,—J—r- ^—;—,— (—^— r--,—p—,—r—1— 1—1—I—1—1—f—1—]—r— • » p i < P i C i •< u > 1 ' - • f l ' 1 d i i < ( l i f l 1 ' C i 1 "^ 'C i Q C i ' j p i c t P i ' - ' ' ' f t " p r i a c / A a o q o
T J , j ; J , , ; ; ; J ; , , J ,
••"'fl '••CiCi -^''iCH Ofift - < -Vfi -Cii '-I'u Ci '-l^lll APiC- J. 1 ir d'kt^ iizlO
/ I
\ r i
'11!, Hill
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7S -C - r — : ] 1 r
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7b ££'S 1
66P b i s 1
62S I '
CPAW 1 n PT = 0 41 = nv< nn w r % A w w 10 OX = ?4?56S
TTTI_F FF2C n n K fi 351 0 L •i 0 0 5 A 00 22 4
1 GO 7 5 3P~ n fi w
1 A t,17 0 0 lOO Ci . V 622 00 7 w-
240 00 A 3S3 0 0 A 0 0 c;n w S
372 00 f T 0 0 z A 0 0 B2 360 OS - K A A n n
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C FART TO
1?? 240 365
= 1 Fhin =
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3271'-^ 21312 3417"
- " M
£P A
'ACQUISITION Fi^.R^.fiETER T^il'Lt
ranges -C 70C INTEGR' TIC'N TIIES TYPr'nr PIIM Jfiw TP-
Fig. 7a
8 5
[M+1 ]m/z 61 lie 19/621 (100.0/82.9/22.4)
1-7 and 3-4 cleavage m/z 492/494 (5.4/4.8)
iWz 240 (4.3)
m/z 380/382/384 (23 4/14 2/4 4)
CHART 7
All the signals in ' H - N M R and '^C-NMR spectra (Fig. 7b and 7c) have
been ass igned (Table 8) on the basis of 5 and J va lues and also by
compar ison with the spectra of ( l l ) ( T a b l e 7). The absence of signals
cor responding to amino protons at 5 5.22 and carbonyl g roup at 6 189.69 in
the spectra of FF2C and in place, the appearance of C-4 signal at higher
f ields, 5 156.24 (C-8b) in ' ^C-NMR spectrum is s trongly in agreement with
the fo rmat ion of a thiadiazepine ring by the cyclocondensation of NH2 group with
the carbonyl group. The chemical shifts of H- and C-atoms generally go to higher
fields in the formation of the ring. The same trend was observed in this case also.
The shifts of C-2 and C-3 protons to higher fields from 5 6.42 to 5 5.90 and from
6 4.37 to 5 4.14 in the 'H-NMR spectrum and also from 6 79.04 to 6 76.98 and 6
55.08 to 5 45.22 in '^C-NMR spectrum showed that these positions are
8 6
J E CL Q .
- C S , }
1 ^
J O
1
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t f o V o
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a c - t n o c : V • « > o o : -D o e v T
t u X « ^ X « M
c r - a z • 9 o — O . G d O . O
— f L, iW V
_ t/)C) O 1Q- 93 w o .
O O
C c O) - l-O-O c £ 3 Z * - «s Q. c (n o o — OV) » W CM
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3
^ L
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10 o < I CO CO (c <0 en I ^ tn w <n cn «
• ^ t o 1
1 in lo r^ iC fv I
\ » r i o « •
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8 8
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H
B a. A to
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oo •o ON cn o r-I 00 —I OQ MS 1—)
CC r-" —i t--
'—i r-p
On 00 00
lO 00 00
On rn 00 r-o
ro 00
00 1—5 SD r - ' 1—5
r- SO_ t o 1—5
NO >—5
« 1—5
(N ON OO
O S l O wo (N OO
Csl
o o O (N <N
On OO O N m
(N
ro I ON
w-i Tj-' oo'
kJ 0-) (N (N fS cn oo
< + O n — <
On O
(N (N O
ON ON (M C-l oi <N
tu d: N X
U K U J X
(N C N
U J X
N
ON o
. i >> "3 .a
•o "O "O "O "O T3 "O "O t3 -O 2 -o -o ^ T3 T3
a es X t i i X X X X X ' X X ' ^ X X X X ^
s a a to m o i> CN o ^ ^ rt v ON —; 00 t^ ^ lO
O N r - ; - ^ c N o r ^ o o o N in CN —< c^ lo
o U-N K
I
Tt- r-
u C M
00 t^ NO in m cs c^ 1
o o < 1—( 1 — ( I
I 1 J LU
N 00 ON HC ffi
8 9
involved in ring formation. Also the shift of carbonyl group f rom 5 189.69 to
6 156.24 confirmed that intramolecular cyclocondensat ion has occurred
between the NH2 group of triazole and > C = 0 group of pyrone forming
thiadiazepine ring. The other signals corresponding to tr iazole and
benzopyrone moieties appeared as in (11).
On the basis of above spectral evidence, FF2C was character ised as
2,3-bis(4-chlorophenyl)-l l-(9-decenyl)-2a,3-dihydro[l]benzopyrano[3,4-e]-
2, 2a-dihydro-l, 2,4-triazolo[3,4-b][ 1,3,4]thiadiazepine (12).
FF2C (12)
Mechanism of the formation of FF,A (11) and FF^C (12)
The reaction occurred via nucleophilic attack of thiol group to the
vinyl carbon of 3-benzylidene flavanone which resulted in the format ion of
Michael adduct (11). This was followed by int ramolecular dehydrat ive
cyclocondensat ion between the amino group and the carbonyl group forming
the cyclised product, thiadiazepine (12) (Scheme 4).
9 0
N N N N
H" transfer
N N
H^ transfer
H' FF2A (11)
N- N N
-CI
FF2C (12)
SCHEME 4
9 1
2,3-Bis(phenyl)-ll-(9-decenyl)-2a,3-dihydro[l]benzopyrano[3,4-e]-l,2,4-
triazolo-2,2a-dihydro[3,4-b][l,3,4]ihiadiazepine FTZXg (15) along with the
adduct, 2-(phenyl)-3-[4-amino-3-(9-decenyl)-5-(benzylthio)-l,2,4-triazolyl]-
2,3-dihydro-4-benzopyrone FFjA (14) [Reaction of the s - t r iazo ie (1) with
E-3-ben2yl idene f lavanone (13)]
A solut ion of 1,2,4-triazole (1) and ^ - S - b e n z y l i d e n e f l avanone (13)
(molar ratio, 1:1) in dry benzene was re f luxed for 35 h in presence of a
catalyt ic amount of / )-TsOH. The products on pur i f i ca t ion by column
chromatography (sil ica gel, pet. e ther-EtOAc, 8:2 v/v) a f f o r d e d F F , A (14)
(39 .10%) as pale yel low oily liquid. Further e lut ion of the c o l u m n (pet. ether-
EtOAc. 7:3 v/v) gave white solid mass which on recrys ta l l i sa t ion (benzene-
acetone) a f fo rded FTZX5 (15) as white crystal l ine needles in 46 .36% yield.
N N
'SH
NH2
F T Z (1) O (13)
(i) /7-TsOH/dry benzene Reflux 35 h
FF,A(14) FTZX5 (15)
9 2
Structure Elucidat ion of FFjiA (14)
It was a pale yellow oily liquid. The structure of F F i A has been
established by FTIR, EI-MS and 'H-NMR spectra. The FTIR spectrum
displayed characteristic signals at 3402.9 (NH), 2927.0 (CH), 1694.5 (C=0) ,
1630.8 (C=C), 1607.2 (C=N), 1578.0 (phenyl) and 1495.1 (C-S) cm"'.
EI-MS spectrum of F F i A showed a [M+l]"" peak at m/z 567 confirming its
molecular weight 566 [C35 H38N4O2S], which is equal to the sum of the
molecular weights of the 5-triazole (1) (254) and £-3-benzyl idene f lavanone
(13) (312). This indicated the Michael addition of thiol group to the
or,/?-unsaturated exocyclic system of £-3-benzyl idene f lavanone. The
fragmentat ion pattern was found to be similar to that of FF2A (11). The
characterist ic retro-Michael addition fragment ion peaks were observed at
m/z 313 [M-C25H2oN4S]^ and m/z 255 [M-CnHj iN jS ] " . It also showed the
retro-Diels Alder fragment ions at m/z 191 and m/z 121 in addition to the
common ion peaks as in (11) at m/z 255,143 and 130 as shown in Chart 8.
The 'H-NMR signals (Fig. 8) have been assigned (Table 9) to
individual hydrogen atoms by comparing with the spectra of a previously
described compound (11) (Table 7). The absence of signals corresponding to
thiol proton at 6 12.25 of the triazole and the vinyl proton of the £ -3 -
benzyl idene f lavanone at 5 8.09 and appearance of this proton as doublet at
higher f ield 5 5.52 confirmed the addition of thiol group to a,/?-unsaturated
exocyclic system of £'-3-benzylidene f lavanone. As in (11), the large coupling
constants of protons at C-2 and C-3 positions (12,3 11.40) revealed that the
hydrogen atoms are oriented at the axial disposition. In addit ion, the signals
9 3
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9 4
corresponding to i^-S-benzylidene f lavanone and tr iazole moiet ies also
appeared as shown in Table 9.
CH..
r ~
N N
1! 1 I
NH2 m/z 255 (100.0)
N N H
P-cieavage
I
NH2
m/z 143(10.6)
N N I 11 ^ N - ^ S H
NH2 m/z 130(12.5)
m/z567( 7.2)[ M+V
retro-Michael addition
m/z 3 13 (18.4)
retro-Diels Alder fission
O
m/z 121 (13.3) m/z 193 (12.2)
CHART 8
9 5
Table 9: 'H-NMR spectral data of FF ,A (14)
H-nr 6(ppm) Integ-ration
Multi-plicity
J (Hz)
NH2 5.02 2H s
1"' 5.52 IH d J,... 3 1.80
2 6.38 IH d J2,3 11.40
3 4.38 IH dd h a 11-40,13.9 1-80
5 7.38 IH dd J5,6 7.80, J w 1-65
6 6.95 IH dd J6,7 7.80, J6 5 7.50
7 7.55 IH dd J7,e7.50J7 8 7.20
8 7.16 IH dd Jg,7 7.20, J8 6 1.09
1" 2.76 2H t J i " , 2 " 7 . 2 0
2" 1.73 2H br p J « 7 . 1 8
3"-7" 1.22 5x2H br s
8" 1.99 2H m
9" 5.79 IH tdd J9..8.. 6.68, J9",he 10.20. Jg-.Hz 17.06
He-10" 4.92 IH dd J h e , 9 " 10.20, Jhe. h z 2.29
Hz-10" 4.95 IH dd J h z , 9 " 17.06, J h z , . i e 2.29
Ar'+Ar" 7.17-7.29 2x5H m
Based on the above spectral evidence, F F , A was character ised as, 2-
(phenyl)-3-[4-amino-3-(9-decenyl)-5-(benzylthio)-l,2,4-triazolyl]-2J-dihydro
-4-benzopyrone (14).
9 6
Structure Elucidation of FTZX^dS)
It was a needle shaped white crystalline solid, m.p 167 °C. The
structure of FTZXg has been fully established by IR, DCI-MS, 'H-NMR,
'^C-NMR and further by COSY and HETCOR spectra. IR spectrum displayed
characterist ic absorption bands at 2900 (CH), 1630 (C=C), 1600 (phenyl),
1580 ( C - N ) and 1450 (S-C) cm"'. The DCI-MS spectrum displayed a [M+1]"
peak as the base peak at m/z 549 showing its molecular weight 548
[C34H36N4OS], which is equal to the molecular weight of (14) (566) minus
one molecule of water, indicating the formation of thiadiazepine ring by the
intramolecular cyclocondensat ion between the NH2 and > C = 0 groups of (14).
A less intense peak at m/z 424 [M-CgHp]"^' was obtained by the y9-cleavage
on the 9-decenyl side chain to the triazole ring. The peaks at m/z 310 [m/z
424-C2|H,6N0]^ and m/z 115 [m/z 424-C3H5N3S]^-, arised by the cleavage of
1-7 and 3-4-bonds are the diagnostic peaks of the thiadiazepine r ing obtained
by f ragment ing the ions at m/z 424. The retro-Diels Alder f ragment ion peaks
were observed at m/z 191 and m/z 121 as shown in Chart 9.
All the signals in 'H-NMR and '^C-NMR spectra (Fig. 9a and 9b) were
assigned to individual H and C atoms (Tables 10a and 10b) on the basis of
chemical shifts , multiplicity, relative integrations and by compar ison with the
spectra of a previously established compound FF2C (12) (Table 8). The
absence of the signals corresponding to NH2 protons at 5 5.02 and carbonyl
carbon at 5 189.69 in the 'H- and '^C-NMR spectra and the appearance of C-4
signal at higher field 5 156.09 indicated that the intramolecular
cyclocondensat ion between the two groups has occurred, forming the
thiadiazepine ring. The shifts of C-2 and C-3 protons of pyrone ring to higher
9 7
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Table 10b: ^^C-NMR and HETCOR data of FTZXj (15)
C-nr 5(ppm) HETCOR
13a 164.43
11 157.47'
8b 156.09'
8a 119.03 H-8
8 125.88 H-7
7 122.40 H-6
6 136.00 H-5
5 118.59
4a 144.45 H-3
3 77.47
2a 45.36 H-2
2 60.35
r 25.45 H - r
2' 27.67 H-2'
y-7 29.20-30.40 H-3' - T
8' 34.46 H-8'
9' 139.93
10' 114.64
Ar'-l 136.46
Ar'-2,6 130.11 H-Ar'-2,6
Ar'-3,5 128.72 H-Ar'-3,5
Ar'-4 129.85 H-Ar'-4
Ar" 126.72-128.86 Ar"
' Assignment may be interchanged
i n i
f ields f rom 6 6.38 to 5 5.83 and f rom 5 4.38 to 6 4 .07 in the 'H -NMR
spect rum conf i rmed the format ion of the ring. The other s ignals appeared as
in the adduct (14). Also in '^C-NMR spectrum, the s ignals appeared were
ass igned as 5 157.47 (C-11), 156.09 (C-8b), 77.47 (C-3), 45 .36 (C-2a) , 60.35
(C-2) and 164.43 (C-13a) in addit ion to the signals of a romat ic carbons and
9-decenyl s ide chain as shown in Table 10b.
H \
N N N N
^ ^ ^ ^ P-cleavage^ N ^ .
[ M + l f m / z 549 (100.0) m/z 494 (8.7)
1-7 and 3-4 bond cleavage
H \
N N
H ^SH
m/z 115 (16.0) m/z 310 (11.8)
retro-Diels Alder fission
m/z 121 (5.5)
m/z 193 (6.0)
CHART 9
1 0 2
The ass ignments of ' H - N M R and '^C-NMR signals (Tables 10a and
10b) and the coupl ing of the protons were fur ther con f i rmed by a ' H - ' H
COSY and a H E T C O R spectra. In ' H - ' H C O S Y spec t rum (Fig. 9c), the
double doublet at 5 7.06 (J=8.16, 8.42, H-7) showed two cross peaks each
with a double doublet at 8 7.41 ( J - 8 . 4 2 , 8.24, H-6) and 5 8.16 (J=8.16, 1.65,
H-8) indicat ing the coupl ing of H-7 proton wi th both H-6 and H-8 protons.
Similar ly, the signal at 5 7.41 (H-6) showed two cross peak mult iple ts at
5 7.06 (H-7) and 5 6.54 (J=8.42, 1.10, H-5) , indicat ing the coupl ing of H-6
proton with both H-5 and H-7 protons . The double doublet at 5 4 .07 (J=5.86.
1.10. H-2a) showed a cross peak with the signals at 5 5.83. 5.87 (H-3. H-2),
indicat ing the coupling between them. The signals for the terminal olefenic
methylene protons appeared as two double double ts at 5 4 .90 (J= 10.26. 2.20,
HE-10') and 5 4.98 (J=17.22, 2.20, H^-10') which were found to be coupled
with each other and also with the ad jacen t meth ine p ro ton at 6 5.80. The
signals appeared as triplet double doublet at 5 5.80 (J=6.70 , 10.26, 17.22)
were due to the coupl ing of the methine proton (CH-, H-9 ' ) with the protons
at H-8' and HE-10', H^-IO'. In addit ion, COSY spect rum also showed the cross
peaks cor responding to the other s ignals of 9-decenyl side chain and aromatic
protons (Table 10a).
In H E T C O R spectrum (Fig . 9d , T a b l e 10b) the ' H - N M R signal at
5h 8.16 (H-8) is correlated to 6c 125.88 (C-8) , 5h 7.06 (H-7) to 8c 122.40
(C-7), 8h 7.41 (H-6) to 8c 136.0 (C-6), 8h 6 .54 (H-5) to 8c 118.59 (C-5), 8h
5.83 (H-3) to 8c 77.47 (C-3) and 8h 5.87 (H-2) to 8c 60.35 (C-2) . In addition,
it also showed the cross correlat ion peaks of 9-decenyl s ide chain and the
aromat ic rings.
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On the basis of the above discussion, F T Z X 5 was characterised as 2,3-
bis(phenyl)-l l-(9-decenyl)-2a, 3-dihydro[ 1 JbenzopyranofS, 4-e]-2,2a-dihydro
-1,2,4-triazolo[3,4-b][ 1,3,4]thiadiazepine (15)
F T Z X 5 (15)
1 0 8
EXPERIMENTAL
4-Amino-3-(9-decenyl)-5-mercapto-l,2,4-triazole (1) was prepared
following a literature procedure and spectral studies performed as described in
Chapter 1.
E-3-(4-Chlorobenzylidene)-4'-chloroflavanone AF2 (10).
It was prepared according to a published procedure^^ To a mixture of
2-hydroxyacetophenone (2.0 g, 0.0147 mol) and jf?-chlorobenzaldehyde (6.0 g,
0.0441 mol), a warm solution (45 °C) of KOH (15%) in aqueous-methanol
(1:1) was gradually added with stirring. A clear solution resulted in after the
addition of 23 ml of this solution. Turbidity was removed by adding 1 ml of
methanol on cooling to room temperature. The reaction mixture was then kept
s toppered for 4 days with occasional shaking. The solid mass appeared was
filtered and washed with excess of water fol lowed by 10 ml of alcohol. It was
then recrystal l ised from chloroform-acetone to give AF2 (10) as yellow
crystall ine needles, 3.40 g (61%), m.p. 224-226 °C, Rf 0.66 (pet. ether-
benzene, 8:2 v/v).
Spectral data of AF7 (10)
IR (KBr): v^ax 2850 (C-H), 1665 ( > C = 0 ) , 1605, 1550 (C=C, phenyl) , 1130,
( C - O - C ) , 1095, 1080, 1005, 950, 905, 875, 845, 805, 740 cm"'.
' H - N M R (400 MHz, CDCI3): 6h 6.52 ( IH, s, H-2), 8.03 ( I H , s, H-1'"), 7.85
( IH , dd, J = 7.93, 1.68, H-5), 6.98 ( IH, ddd, J= 7.93, 7.17, 168, H-6), 7.43
( IH , ddd, , J= 7.17, 8.39, 1.68, H-7), 6.95 ( IH , dd, J = 8.39, 1.68, H-8), 7.24-
7.48 (8H, br m, H-Ar '+H-Ar") .
1 0 9
'^C-NMR (CDCI3, 75 MHz,): 5c 76.86 (C-2), 133.28 (C-3), 182.08 (C-4),
138.28 (C-1'"), 122.65 (C-4a), 127.64 (C-Ar-5), 122.10 (C-Ar-6), 136.33 (C-
Ar-7), 118.58 (C-Ar-8), 121.92 (C-8a), 129.16 (C-Ar'-2,6), 131.05 (C-Ar'-
3,5), 128.93 (C-Ar"-2,6), 129.21 (C-Ar"-3,5), 132.37 (C-Ar '-4) , 132.25 (C-
Ar"-4), 136.30 (C-Ar ' - l ) , 134.86 (C-Ar"-1).
E-3-Benzylidene flavanone AFJ (13)
To a mixture of 2-hydroxyacetophenone (5.0 g, 0.0367 mol) and
benzaldehyde (11.70 g, 0.1103 mol), a warm solution (45 °C) of KOH (15%)
in aqueous-methanol (1:1) was gradually added with stirring. A clear solution
resulted in after the addition of 44 ml of this solution. On cooling to room
temperature the reaction mixture became turbid and 1.5 ml of methanol was
added to remove the turbidity. The reaction mixture was then kept at room
temperature. After Ca 3-4 h, an oily liquid began to deposit at the bottom and
the reaction mixture gradually turned into dark green. The reaction mixture
was then kept stoppered for 5 days with occasional shaking. The progress of
reaction was closely monitored by TLC (silica gel G, pet. ether-benzene, 8:2
v/v). The liquid that separated was changed into a semi solid mass, which
showed a mixture of three components (TLC). The reaction mixture was then
extracted with ethyl acetate, washed successively with water to make the
solution neutral and dried over anhydrous sodium sulphate overnight. The
solvent was then distilled off under reduced pressure. The product obtained
was separated and purified by column chromatography (silica gel, pet. ether-
benzene, 8:2 v/v) to give a greenish yellow mass which on crystallisation
(pet. ether-chloroform) yielded £'-3-benzylidene f lavanone (13), 8.0 g (67%),
m.p 104-106 °C, Rf 0.73 (pet. ether-benzene, 8:2 v/v).The other two
1 1 0
components, corresponding to chalcone and flavanone were also obtained in
very low yields on further elution of the column.
Spectral data of AFj (13)
IR (KBr): Vn,ax 2900 (C-H), 1710 (>C=0) , 1625, 1590 (C=C, phenyl), 1110
( C - O - C ) , 1005, 940, 860, 805, 720 cm-'.
'H-NMR (400 MHz, CDCI3,):5h 6.65 ( IH, s, H-2), 8.09 ( IH , s, H-1'"), 7.92
( IH. dd, J = 8.24, 1.83, H-Ar-5), 6.95 ( IH, ddd, J=8.24, 7.14, 1.10, H-Ar-6).
7.47 ( IH, ddd, J=7.14, 7.33, 1.83, H-Ar-7), 6.92 ( IH, dd, J=7.33, 1.10. H-Ar-
8), 7.02-7.43 (lOH, br m, H-Ar' + H-Ar").
'^C-NMR (100 MHz, CDCI3): 5c 77.69 (C-2), 133.28 (C-3). 182.65 (C-4).
l21.63(C-4a), 126.17 (C-Ar-5), 121.75 (C-Ar-6), 136.05 (C-Ar-7), 118.65 (C-
Ar-8). 158.97 (C-8a), 139.32 (C-1'"), 128.63 (C-Ar'-2,6) 129.94 (C-Ar'-3.5),
127.64 (C-Ar"-2,6), 128.85 (C-Ar"-3,5), 129.70 (C-Ar'-4), 128.63 (C-Ar"-4),
138.18 (C-Ar ' - l ) , 134.17 (C-Ar"-1).
2,3-Bis(4-chlorophenyl)-ll-(9-decenyl)-2a,3-dihydro[l]benzopyrano[3,4-e]-
2,2a-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine FF2C (12) alongwith
the adduct, 2~(4-chlorophenyl)-3-[4-amino-3-(9-decenyl)-S-(4-chlorobenzyl-
thio)-l,2,4-triazolyl]-2,3-dihydro-4-benzopyrone FF2A (11). [Reaction of
the 5-triazole (1) with £'-3-(4-chlorobenzylidene)-4'-chloroflavanone (10))
A mixture of ^-triazole (1) (500 mg, 1.96 mmol) and £-3-(4-chloro-
benzylidene)-4'-chloroflavanone (10) (744 mg, 1.96 mmol) in dry benzene
(20 ml) containing catalytic amount of/7-TsOH (5 mg) was ref luxed for 38 h, %
monitoring the progress of the reaction by TLC (silica gel G, pet. ether-
EtOAc, 8:2 v/v). After completion, the reaction mixture on TLC examination
showed two spots, labelled as FF2A (11) (upper) and FF2C (12) (lower)
I l l
which on usual work up and column chromatography (si l ica gel, pet. ether-
EtOAc, 8:2 v/v) afforded F F j A (11) as glassy flakes, 504 mg. (40.5%), m.p.
93 °C, Rf 0.65 (pet. ether-EtOAc, 8:2 v/v). Further elut ion of the column
using pet . ether-EtOAc, (6:4 v/v) as eluent yielded a white solid mass which
on crystal l isat ion (benzene-EtOAc) afforded FF2C (12) as whi te crystalline
needles, 530 mg (44.72%), m.p. 182 °C, RfO.29 (pet. e ther -EtOAc, 6:4 v/v).
Spectral data of FF7A (11)
IR (KBr): 2900 (C-H), 1630, 1600 (C=C, phenyl) , 1580 (C=N), 1560,
1500, 1490, 1450 (S-C), 1420, 1340, 1270, 1200, 1 140, 1 1 10, 1050, 990, 900,
850, 750 cm"'
'H-NMR (400 MHz, acetone-Jg): 5h 5.22 (2H,s, NH2), 5.65 ( I H , d, J=2.75,
H-1'") , 4.37 ( IH , dd, J=10.98, 2.75, H-3), 6.42 ( IH , d, J=10.98, H-2), 7.22
( IH , dd, J=8.39, 1.07, H-8), 7.67 ( IH, ddd, J=8.85, 8.39, 1.68, H-7), 7.06
( IH, ddd, J=8.24, 8.85, 1.07, H-6), 7.51 ( I H , dd, J=8.24, 1.68, H-5), 7.28 -
7.36 (2x4H, m, Ar+Ar') , 2.84 (2H, t, J=7.48, H-1"), 1.83 (2H, br p, J~ 7.43,
H-2"), 1.26 (lOH, br s, H-3'-7'), 2.01 (2H, m, H-8"), 5.81 ( I H , tdd, J=6.71,
10.22, 17.09, H-9"), 4.91 ( IH, dd, J=10.22, 2.29, 10"-HE), 4.99 ( I H , dd,
J=17.09, 2.29, Hz-lO").
'^C-NMR (100 MHz, ncetone-ds): 5c 153.73 (C-3'), 168.72 (C-5') , 25.31
(C-1"), 26.54 (C-2"), 29.20-30.40 (C-3"-7"), 34.44 (C-8") , 139.85 (C-9"),
114.65 (C-10"), 60.01 (C-1"'), 55.08 (C-3), 79.04 (C-2) , 160.10_ (C-8a),
119.00 (C-8), 137.84 (C-7), 122.76 (C-6), 127.46 (C-5), 121.74 (C-4a),
189.69 (C-4), 137.39 (C-Ar"-1), 130.89 (C-Ar"-2,6) , 129.13 (C-Ar"-3,5),
134.66 (C-Ar"-4) , 136.05 (C-Ar ' - l ) , 129.57 (C-Ar'-2,6), 128.85 (C-Ar'-3,5),
134.45 (C-Ar '-4) .
1 1 2
DCI-MS (NHj) : m/z (%) 635 (5.4), 636 (2.5), 637 (4.1), 638 (2.4), 380 (8.4),
381 (22.6), 382 (10.3), 383 (14.7), 384 (4.3), 301 (4.5), 295 (13.4), 254 (5.0),
255 (100.0), 256 (17.6), 257 (26.6), 258 (5.1), 259 (14.3), 261 (6.8), 225
(6.0), 189 (5.0), 149 (4.7), 143 (6.0), 130 (9.4), 121 (12.4), 94 (4.8).
Spectral data of FF^C (12)
' H - N M R (400 MHz, acetone-«f^); 5h 5.90 ( IH, d, 1.07, H-3), 4.14 ( IH, dd,
J=6.41, 1.07, H-2a), 5.92 ( IH, d, J=6.41, H-2), 8.15 ( IH , dd, J=7.94, 1.68, H-
8), 7.10 ( IH, ddd, J=8.85, 7.94, 1.07, H-7), 6.62 ( IH, dd, J=8.39, 1.07, H-5),
5.92 ( IH, d, J=6.4L H-2), 7.17 (2H, d, J=8.69, H-Ar-2,6), 7.50 (H-Ar'-2,6),
7.28-7.29 (4H, m, H-Ar'-3,5, H-Ar'-3,5), 2.76 (2H, t, J=7.48, H-1'), 1.45 (2H,
br p, J~7.47,H-2'), 1.23 (lOH, br s, H-3'-7'), 2.00 (2H, m, H-8'), 5.79 ( IH,
tdd, J=6.71,10.22, 17.09 H-9'), 4.89 ( IH, dd, J=10.22, 2.29, HE-IO'), 4.97
( IH, J=17.09, 2.29, Hz-10').
' ^C-NMR (100 MHz, acetone-^/^): 5h 157.07 (C-11), 156.24 (C-8b), 118.94
(C-8a), 126.02 (C-8), 122.82 (C-7), 136.30 (C-6), 118.56 (C-5), 144.17
(C-4a), 76.98 (C-3), 45.22 (C-2a), 59.39 (C-2), 160.83 (C-13a), 138.63 (C-
Ar-1), 131. 77 (C-Ar-2,6), 128.75a (C-Ar-3,5), 135.42 (C-Ar-4), 134.41 (C-
Ar ' - l ) , 129.61 (C-Ar'-2,6), 128.59 (C-Ar'-3,5), 135.29 (C-Ar'-4), 25.48 (C-1'),
27.81 (C-2'), 29.20-30.40 (C-3'-7'), 34.46 (C-8'), 139.89 (C-9'), 114.63
(C-10').
D C I - M S (NHs): m/z (%) 616[M^ 5.4], 617 (100.0), 618 (50.8), 619 (82.5),
620 (38.2), 621 (22.4), 622 (7.6), 583 (2.6), 585 (2.8), 492 (5.4), 494 (3.8),
378 (7.1), 380 (23.4), 381 (8.1), 382 (14.2), 383 (4.3), 240 (4.3), 199 (3.8),
149 (3.8).
1 1 3
2,3-Bis(phenyl)-ll-(9-decenyl)-2a,3-dihydro[lJbenzopyrano[3,4-e]-2,2a-
dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazepine FTZXg (15) alongwith the
adduct, 2-(phenyl)-3-[3-(9-decenyl)-4-amino-S-(benzylthio)-l,2,4-triazolyl]-
2,3-dihydro-4-benzopyrone FF,A (14) [Reaction of the s-triazole (1) with
E-3-benzyIidene flavanone (13)]
A mixture of the 5-triazole (1) (500 mg, 1.96 mmol) and £ -3 -
benzylidene f lavanone (13) (610 mg, 1.96 mmol) in dry benzene (20 ml) was
ref luxed with stirring on an oil bath at 80 °C using a Dean Stark apparatus for
35 h in presence of a catalytic amount of jtP-TsOH (5 mg). TLC examination
(silica gel G, pet. e ther-EtOAc, 8:2 v/v) of the reaction mixture revealed the
presence of two spots, labelled as FFjA (14) (upper) and FTZX5 (15) (lower).
The solvent was distilled off in vacuum and the residue thus obtained was
dissolved in EtOAc, washed several times with water and the organic phase
dried over anhydrous Na2S04. The solvent was removed under reduced
pressure and the residue left was chromatographed over a silica gel column
using pet. e ther-EtOAc (8: 2 v/v) as eluent which a f forded FF ,A (14) as an
oily liquid, 434 mg (39.10%), Rf 0.66 (pet. ether-EtOAc, 8:2 v/v). Further
elution of the column (pet. ether-EtOAc, 7:3 v/v) yielded FTZXg (14) as a
white solid compound which on recrystallisation (EtOAc-benzene) as white
crystall ine needles, 498 mg (46.36%), m .p . l67 °C, R, 0.31 (pet. ether-EtOAc,
8:2 v/v)
Spectral data of FFj A (14)
FTIR (KBr): v^ax 3402.9, 3068.2 ( N H 2 ) , 3032.9, 2927.0, 2853.9(CH),
2362.6, 1694.5(C=0) , 1630.8 (C=C), 1607.2 (C=N), 1578.1(phenyl) , 1495.1,
1460.5, 1420.1, 1357.6, 1296.0, 1210.7 cm-'
1 1 4
' H - N M R (300 MHz, acetone-f/g): 5h 5.02 (2H, s, NH2), 5 .52 ( I H , d, J=1.80,
H-1'") , 6 .38 ( I H , d, J=11.40, H-2), 4.38 ( IH , dd, J=1 1.40, 1.80, H-3) , 7.16
( IH , dd, J=7.50, 1.09, H-8), 7.55 ( I H , ddd, J=7.50, 7.20, 1.65, H-7) , 6.95
( IH , dd, J=7.80, 7.20, H-6) , 7.38 ( l H , d d , 7.80,1.65, H-5) , 2 .76 (2H, t, J=7.20,
H-1 ' ) , 1.73 (2H, br p, J=7.18, H-2") , 1.22 ( lOH, brs, H-3" -7" ) , 1.99 (2H, m,
H-8") , 5 .79 ( I H , tdd, J=, 6.68, 10.20, 17.06 H-9") , 4 .92 ( I H , d, J=10.20, He-
10"), 4.95 ( I H , d, J=17.06, H^-IO"), 7.17- 7.29 ( lOH, m, 2xAr) .
E I - M S (NH3): m/z (%) 567 [(M+1), 7.2], 568 (3.1), 312 (6.7) , 313 (18.4),
314 (4.5), 254 (6.3), 255 (100.0), 256 (19.8), 191 (12.2) , 192 (5.8), 193
(12.2), 143 (10.6), 144 (2.9), 130 (12.5), 131 (4.1), 121 (13.3) , 122 (3.7)
Spectral data of F T Z X S (15)
' H - N M R (400 MHz, acetone-rf^): 5 h 5.83 ( I H , d, J= poor ly resolved, H-3) ,
4.07 ( I H , dd, J=5.86, 1.10, H-2a) , 5.87 ( IH , d, J=poor ly reso lved , H-2) , 8.16
( I H , dd, J=8.16 , 1.65, H-8) , 7.06 ( I H , dd, J=8.16, 8.42, 1.29, H-7) , 7.41 ( I H ,
dd, J=8 .42 , 8.24, 1.65, H-6) , 6.54 ( I H , dd, J=8.24, 1.10, H-5) , 7.48 (2H, d,
J=7.88, H-Ar ' -2 ,6) , 7.14 (2H, dd, J=7.88, 7.32, H-Ar ' -3 ,5 ) , 7.26 ( I H , d,
J=7.32, H-Ar ' -4) , 7.19-7.24 (5H, m, H-Ar") , 2.76 (2H, t, J=7 .47 , H-1 ' ) , 1.45
(2H, br p, J~7.37, H-2') , 1.24 ( lOH, brs, H-3 '-7 ' ) , 2.01 (2H, m, H-8 ' ) , 5.80
( I H , tdd, J=17.22, 10.25, 6.78, H-9') , 4.90 ( I H , dd, J=10 .25 , 2 .20, HE-10'),
4.98 ( I H , dd, J=17.22, 2.20, Hz-lO') .
'^C-NMR (100 MHz, acetone-^/^): 5c 157.47 (C-11) , 156.09 (C-8b) , 119.03
(C-8a) , 125.88 (C-8), 122.40 (C-7), 136.00 (C-6) , 118.59 (C-5) , 144.45
(C-4a) , 77.47 (C-3), 45.36 (C-2a), 60.35 (C-2) , 164.43 (C-13a) , 136.46
( C - A r ' - l ) , 130.11 (C-Ar ' -2 ,6) , 129.85 (C-Ar '-4) , 126.72-128.86 (C-Ar"-1 , C-
Ar"-2,6 , C-Ar"-3 ,5 , C-Ar"-4) .
1 1 5
D C I - M S (NH3): m/z (%) 549 [(M+1), 100.0], 550 (50.0), 551 (17.9), 424
(8.7), 425 (6.9), 310 (11.8), 312 (38.8), 313 (14.3), 314 (8.7), 208 (5.0), 191
(4.6), 193 (6.0), 121 (5.5), 115 (6.0), 91 (12.8).
b l . f'jL Via )
Hii .
Long alkyl chain substituted-s- Triazolo- Th iadiazoles
1 1 6
DISCUSSION
SUMMARY
The work described in this chapter includes the reaction of 4-amino-3-(9-
decenyl)-5-mercapto-l,2,4-triazole (1) with:
(i) p-Anisaldehyde which yielded 4-(N-4-methoxybenzylidene amino)-3-(9-
decenyl)-5-mercapto-J,2,4-triazole (16) and 2'(4-methoxyphenyl)-5-(9-
decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazole (17)
(ii) p-Chlorobenzaldehyde which afforded 4-(N-4-chlorobenzylidene amino)-
3-(9-decenyl)-5-mercapto-l,2,4-triazole (18) and 2-(4-chlorophenyl)-5-
(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadiazole (19).
(Hi) Thiophen-2-aldehyde which furnished 4-(N-2-thienylidene amino)-3-{9-
decenyl)'5-mercapto-l,2,4-triazole (20) and 2-(2-thienyl)-5-(9-decenyl)-
2.3-dihydro-l,2,4-triazolo[3,4-b][l,3,4] thiadiazole (21).
(iv) Furfur aldehyde which gave 4-(N-2-furfurylidene amino)-3-(9-decenyl)-5-
mercapto-1,2,4'lriazole (22) as the sole product
INTRODUCTION
1,2,4-Triazole and its derivatives have been found to play vital role in
medicine, agriculture and industry^^"^^. The fused ring systems such as
i-- tr iazolo[3,4-b][l ,3,4]thiadiazoles have varied range of biological activities
as antibacterial^'•^^ antifungaP^'^®, a n t i i n f l a m m a t o r y ^ a n t i h y p e r t e n s i v e ^ ^ ' ^ ^
a n a l g e s i c " and anthelmintic^'"^^ agents. The 5-tr iazolo-thiadiazole system can
be viewed as a cyclic analogue of two very important components .
thiosemicarbazide^° and biguanide^' which often display diverse biological
activities probably due to the presence of -N=C-S group responsible for their
activities. Also, the Schiff bases and their complexes prepared by the
condensat ion of various aldehydes and ketones with substi tuted or
1 1 7
unsubsti tuted 1,2,4-triazoles have been found to be potential biologically
active agents^^'^^ as well as substrates for the syntheses of various
heterocycles of medicinal importance^^. These f indings have tempted us to
undertake this problem. It consists of the syntheses of three new compounds,
(i) 2-(4-methoxyphenyl)-5-(9-decenyI)-2,3-dihydro-l ,2 ,4- t r iazolo[3,4-b]
[ l ,3 ,4] thiadiazole (17) (ii) 2-(4-chlorophenyl)-5-(9-decenyl)-2,3-dihydro-
1.2,4-tr iazolol3,4-b][ l ,3 ,4]thiadiazole (19) and (iii) 2-(2-thienyl)-5-(9-
decenyl)-2 ,3-dihydro- l ,2 ,4- t r iazolo[3,4-b][ l ,3 ,4] thiadiazole (21) from (i)
p-anisaldehyde (ii) /?-chlorobenzaldehyde and (iii) th iophen-2-aldehyde
respectively using 4-amino-3-(9-decenyl)-5-mercapto-1.2,4-tr iazole (1) in
the presence of a catalytic amount of p -TsOH. In each reaction, the
corresponding Schiff bases (16), (18), and (20) have also been obtained. The
reaction of fur fura ldehyde with the triazole (1) yielded only the Schiff base
(22). no cyclised product could be isolated due to the decomposi t ion of the
products.
Structural assignment and biological assay are discussed. Screening
results of the compounds (16), (17), (20), (21) and (22) are summarised for
the anticancer activity against 3-cell lines of three types of human cancers:
lung, breast and CNS (details in chapter 6)
(1)
1 1 8
(16) R = 0CH3 ( 1 8 ) R = C1
( 1 7 ) R = 0 C H 3
( 1 9 ) R = C1
( 2 0 ) X - S
( 2 2 ) X = 0
( 2 1 ) X = S
1 1 9
RESULTS AND DISCUSSION
The synthesis of compounds (17), (19) and (21) was carried out by
reacting the triazole (1) (obtained by fusing 10-undecenoic acid with
thiocarbohydrazide) with /?-anisaldehyde, /7-chlorobenzaldehyde and
thiophen-2-aldehyde respectively in dry benzene using p - T s O H as catalyst. It
is believed that the corresponding Schiff base is first formed which undergoes
intramolecular cyclocondensation to give the desired product alongwith the
uncyclised Schiff base in each case (Scheme 4). In the reaction of triazole
with furfural , only the Schiff base could be isolated from the products as on
prolonging the reaction, the product underwent decomposi t ion.
N N
(16) R = 0CH3 (18) R = C1
+ N N
(20) X = S (22) X = 0
(17) R = 0CH3 (19) R = CI
(21) X = S
SCHEME 4
1 2 0
2-(4-Methoxyphenyl)-5-(9-decenyl)-2,3-(iihydro-l,2,4-triazolo[3,4-b][1,3,4]
thiadiazole FTZX' (17) along with the Schiff base, 4-(N-4-
methoxybenzylidene amino)-3-(9-decenyl)-5-mercapto-l,2,4-triazole FTZX
(16) [Reaction of the 5-triazoIe (1) with p-anisaldehyde in presence of
/j-TsOH]
A solution of the 1,2,4-triazole (1) and p-anisaldehyde (molar ratio.
1:1) in dry benzene was refluxed with stirring for 5 h with catalytic amount of
jD-T s OH. T L C examination of the reaction mixture revealed the presence of
two spots, labelled as FTZX (16) and FTZX' (17). The products on column
chromatography (pet. ether-EtOAc, 9:1 v/v) as eluent first afforded a pale
yellow crystalline solid, FTZX (18%) and then a colourless oily liquid.
FTZX' (71%) in yields. The outline of the reaction is as follows:
N N
II II
I
NH2
(1) N N
+ OHC-
FTZX (16)
i p-TsOW dry benzene Reflux 5 h
OCH3
N N
OCH3 \
HN-
FTZX' (17) Q '0CH3
structure Elucidation of FTZX (16)
It was a pale yellow needle shaped crystalline solid, m.p. 66 °C. The
structure of FTZX has been established by IR, DCI-MS, 'H-NMR and '^C-
NMR spectra. The IR spectrum (KBr) exhibited characteristic peaks at 2900
(CH), 2350 (SH), 1630 (C=C), 1600 (C=N), 1580 (phenyl) and 1480 (S-C) cm"'.
iw HflilC: 'lUi ' -VTi'r'.'"" " " r iTi111 " T T I "1K: Tu RI r wuMr . nr~ur u nciTr • i?i ^ ^ i -s7«
)=tlK
121
1 ie!0-'i= 450560 ! I
- 1 1 -s
-1—I- l~l
! HM'':= .-;H.• . K!-.r. XI -..-;. H
1 iV<u->-I
r r ^ / - . ' ' ' N rt J »-<i>4 4
•rUY6 SCfiH 2? I!trlfl=4 TTTrr^^rTry" T = • ^ ^ K ii r K iZ n=A 1 u
' ' ' ' U i I i"i H = '< ••( c; K
I.. . ..,.1 ,1 . . M U . ] . . . .11, mil (••"I I - . J I ; i i . /M KM yw jMM 11M 1/y H ' j i ty 1:1' lyy r^y ^yy iiiy ds y
i 1 1
: t
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li 1 :) ! ! !
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4HH GUYS SCAN 20 SIG'?1A=-4 TTTI F. FT7Y
&T=n;3g B^.CKGL<=(!XlOO 100X= 3S33SS6
? 2 . 0 0 l i s . 0 0 1 ' n fi
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The DCI-MS spectrum of FTZX (Fig. 10 a) showed a [M+1]^ peak at m/z
373 confirming its molecular weight 372 [C20H28N4OS], which is equal to the
sum of the molecular weights of the ^-triazole (1) (254) and /p-anisaldehyde
(136) minus one molecule of water. This indicated the format ion of the Schiff
base by the condensation of/7-anisaldehyde with ^-triazole (1). The prominent
fragment ion peak at m/z 133 (base peak) [(M+l)-Ci2H2iN3S]"'' and a less
intense peak at m/z 240 [(M+l)-C8H8NO]'^ were arised by the exocyciic N-N
bond cleavage. The peak at m/z 206 [m/z 239-SHj'^ and another peak at m/z
115 [m/z 239-C9Hi6]'^' were obtained from the f ragment ion m/z 239 as
shown in Chart 10.
N N II
"SH
N = C H — / ( ^ N — O C H 3 m/z 373 (84.1)[M+1]
exocyciic N —N bond cleavage
N N 11
m/z 206
I 'SH
H
m/z 240 (5.0)
P-cleavage
N N
H
NEC- o -OCH,
m/z 133(100.0)
m/z 115 (26.0)
CHART 10
1 2 3
All the signals in ' H - N M R and '^C-NMR spect ra (Fig . lOb and 10c)
were ass igned to specif ic H- and C- atoms (Table 11a and l i b ) f rom their
typical chemical shif t values, mult ipl ici ty, relat ive in tegra t ions and also by
compar ing with the spectra of F T Z (1). The absence of NHa pro tons at 6 5.18
in ' H - N M R spectrum of F T Z X and appearance of new s ignals at 5 10.16 and
at 5 162.51 for benzyl idene proton and benzyl idene ca rbon conf i rmed the
format ion of the Schif f base. The other signals for p ro tons and carbons
appeared as in F T Z spectra as shown in Table 11a and l i b .
Table l ib : Comparison of the "C-NMR spectral data of FTZX (16) with that of FTZ (1)
FTZX (16) FTZ (1)
C-nr 8(ppm) C-nr 5(ppm)
3 152.85 3 153.34
5 164.22 5 168.26
6 162.51
1' 25 .62 1' 25 .40
2' 26 .73 2' 26 .68
y-T 2 9 . 2 3 - 3 0 . 3 8 y-T 29.40-30.20
8' 34 .43 8' 34 .40
9' 139.85 9' 139.82
10' 114.63 10' 114.61
Ar -1 126.36
A r - 2 , 6 131.24
Ar -3 ,5 115.45
A r - 4 163.73
OCH3 55 .98
L T
1 2 4
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H cu c. to
B I
K
(N
ON
CN N
m C") m r-' »
LU
w X
I—> vo vo r^ vo -» X lij C h C h I
ON m CN N X LU OO oo X ON Os 1—) od od 1 w-l (N r-i'
< < -S
N X < < 1—> 1—I
X} T 3 T 3
-a -o
CN CN (N X (N ffi X (N X (N X
o NO T—1 (N O o 00 ON o
<N D 00 i > cn O 00 ON ON 00 ON RJ (N ro
— (N rn
tu N
00 ON
NO IT) r O
(N m 1 u U < < o
1 2 7
Based on the above evidence, the structure of FTZX was characterised
as 4-(N-4-methoxybenzylidene amino)-3-(9-deceny l)-5-mercapto-1,2,4-
triazole (16).
FTZX (16) OCHi
Structure Elucidation of FTZX' (17)
It was a colourless oily liquid. The consti tution of FTZX' has been
fully established by DCI-MS, 'H-NMR and '^C-NMR spectra. The DCI-MS
spectrum of FTZX' (Fig. 11) showed [M+1]^ peak at m/z 373 as the base
peak corresponding with the molecular formula [C20H28N4OS], indicating thai
the compound FTZX' is different from FTZX (16) in stability but same in
molecular weight. The prominent fragment ion peak at m/z 240 [(M+1)-
CgHyNO]^ and another peak at m/z 133 [(M+l)-C,2H2iN3S]^- were arised by
the cleavage of 3-4 and 1-5 bonds of the thiadiazole ring. The peak at m/z 151
[ M - C i 2 H 2 o N 4 ] ^ obtained by the cleavage of 1-2 and 4-5 bonds of the fused
ring [which was absent in the non-cyclised adduct (16)] is the diagnostic peak
of a ^•-triazolo-thiadiazole ring^^. In addit ion, it also showed the usual
/^-cleavage f ragment ion peak at m/z 115 (Chart 11).
1 2 8
lu 'JuHr : ' -L ' ' -'I"' - - Ti ' r f "vfi r ^ U f J " Z. T I f J J. * 1 J" ' 1- ^ r 'lU" t ' L- Li i
^• t , 0
I • 1
ISi .0
1 'i> O 1 — V - w « * « . . ' . 1 1 . V
I 1 1 HM-- = ^ 'rtxi 1 -- - -n -I ' \ I ' 1 1 ' '-_ 1 , J ,
I I v
- - H
! iGG.- 1 GG 1 ^ 1 >
I u I n L : . . .
-Tfi r""rV-rvf T'
" ^ r r
II <1 <TOhl C- zr! • ' '
^ilr f C'l = M1 .1 1 fiM= " ; c: cr;
r—1 ^ • ; T > — —— ; 1 ^ \ r—I 1 1 r--a 'tifl (fifi ' i n 1 "•'f. ( <5 I afi i < i;;4 < ' C.C> t MA /1 fi
1 1 1
i ' I I
ii, , I _, , , , ^ , 1 1 ^ , , , ^ , , , ^ ^ J , [—, , r—1—•
-.-.fi '••da ••'n - :<i-t ' Cit, -u-iPi ''•i 1 Ci 'idiH "^Cfl
{Mr ny
'I Ml T" ~r -!—'—r - T 1 r -
^-'fi jr-ip j^ia j ^ s a3r. Ada 451; 4£,ri 4og a-ag GLii SCAN 36 STGfiA=5 3 BACKGL'=C'Xi00 lGO%= 3325?52 -TTfr PTTY&TC;
32 n n i w> w
00 1 * A A A -
35 0 0 ~ t 0(1 - " - J A
1 53 n n fi, n r S.O
p T 34< n n 373 00
A rt r .
5 7 inn n
Fig. 11
1 2 9
m/z373 (100.0)[M+H]
1-5 and 3-4 bond cleavage
1-2 and 4-5 bond cleavage
N N
N = C OCH3 H
SH
m/z 133(85.2) m/z240 (42.1)
P-cleavag
H N + N N
i II H
m/z 115(11 .4)
C H A R T 1 1
S = C - O -0CH3
m/z 151 (35.2)
The 'H-NMR and '^C-NMR spectra showed signals as assigned (Table
12). The assignments of all signals to individual H- and C- a toms were made
on the basis of chemical shifts, multiplicity, relative integrations and by a
comparison with the spectral data of the uncyclised Schiff base FTZX (16)
(Tables 11a and l i b ) . The signal corresponding to thiol proton at 6 12.40 of
the Schiff base was found to be absent in the ' H - N M R spectrum of FTZX',
showing that thiol group is involved in the newly formed ring. Also, the
benzylidene proton and carbon signals shifted upfield f rom 6 10.16 to 6 8.60
and f rom 5 162.51 to 5 70.18, confirming the formation of thiadiazole ring. In
addition, both the spectra showed H- and C- signals of aromatic protons,
5-triazole ring and 9-decenyl side chain as shown in Table 12.
Table 12. ^H-NMR and ^^C-NMR spectral data of FTZX' (17)
1 3 0
H-nr 5(ppm) Integ-ration
Multip-licity J (Hz) C-nr 5(ppm)
6 8.60 IH S 3 151.71
NH - 6 70.18
R 2.83 2H t h\T 7.32 7a 164.33
2' 1.75 2H br p J « 7.36 R 25.54
y-T 1.30 5x2H br s 2' 26.65
8' 2.01 2H m y-T 29.22-30.37
9'
10'-HE
5.79
4.90
IH
IH
tdd
dd
J9.HZ 17.09, J9'.HB 10.23, J9',8' 6.72 JHE,9' 10.26, JHE, HZ 2.29
8'
9'
34.45
139.82 I
l O ' - H z 4.97 IH dd W 17.09, JHE, Hz 2.29 10' 114.49
Ar-2,6 7.43 2H d J A r - 2 , 6 , A r - 3 , 5 8 . 8 5 Ar-1 126.70
Ar-3,5 6.97 2H d J A r - 2 , 6 5 A r - 3 , 5 8.85 Ar-2,6 131.04
O C H 3 3.83 3H s Ar-3,5
Ar-4
O C H 3
114.65
161.19
55.67
1 3 1
Based on the above facts, the compound FTZX' was assigned the
structure as 2-(4-methoxyphenyl)-5-(9-decenyl)-2,3-dihydro-l ,2,4-triazolo
[3,4-b][ 1,2,4]thiadiazole (17).
FTZX' (17)
2-(4-Clilorophenyl)-5-(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]
thiadiazole FTZY' (19) along with the Schiff base, 4-(N-4-
chlorobenzylidene amino)-3-(9-decenyl)-5-mercapto-l,2,4-triazole FTZY
(18) [Reaction of the 5-triazole (1) with p-chlorobenzaldehyde in presence of
p-TsOH]
A solution of j-triazole (1) and /?-chlorobenzaldehyde (molar ratio,
1:1) in dry benzene was refluxed with stirring for 12 h in presence of
catalytic quantity of p-TsOH. TLC examination revealed the presence of two
spots, labelled as FTZY (18) and FTZY' (19). The products on column
chromatography (silica gel, pet. ether-EtOAc, 8:2 v/v) as eluent first
furnished a white solid, FTZY which was recrystall ized (benzene-acetone)
as white crystalline needles in 59% yield. Further elution of the column
yielded a colourless oily liquid, FTZY' in 27% yield. The react ion sequence
is as follows.
1 3 2
N- -N
+ OHC-N I
NH2
(1)
^SH o
N- -N
I N :
SH
:CH-
FTZY (18) o
p-TsOH/ dry benzene Reflux 12 h
-CI
-CI +
FTZY' (19)
Structure Eiucidation of FTZY (18)
It was a white needle shaped crystalline solid, m.p. 102 °C. The IR
spectrum (KBr) displayed characteristic absorption bands at 2850 (CH), 2400
(SH), 1640 (C=C), 1620 (C=N), 1570 (phenyl) and 1480 (S-C) cm' ' . The
DCI-MS spectrum showed a set of [M+1]"^ peaks at m/z 377/379 confirming
its molecular weight 376/378 [ C 1 9 H 2 5 N 4 S C I ] which is equal to the sum of the
molecular weights of the 5-triazole (1) (254) and p-chlorobenzaldehyde (140)
minus one molecule of water, suggesting the formation of the Schiff base. All
the signals in the 'H-NMR and '^C-NMR spectra have been assigned to
individual H- and C- atoms (Table 13) by comparing with the spectral data of
a previously established structure of compound (16) (Table 11a and l i b ) . In
'H-NMR spectrum, the absence of NH2 signals at 5 5.18 and appearance of
new signals at 5 10.49 and 5 160.28 for benzyl idene proton and carbon,
conf i rmed the formation of Schiff base. In addition, both the 'H- and '^C-
N M R spectra gave usual signals for the 9-decenyl side chain and A2B2 signals
of /7-chlorophenyl ring as shown in Table 13.
Table 12. ^ H - N M R and ^C-NMR spectral data of FTZX' (17)
1 3 3
H-nr 5(ppm) Integ-ration
Multip-licity J (Hz) C-nr 5(ppm)
SH 12.50 IH brs 3 153.08
6 10.49 IH s 5 163.78
1' 2.84 2H t h ' T 7.32 6 160.28
2' 1.78 2H br p J « 7.46 1' 25.58
y-T 1.31 5x2H br s 2' 26.74
8' 2.01 2H m 3'-7' 29.23-30.39
9' 5.80 IH tdd J9.,8-6.78, J9. he 10.25, J9',Hz 17.03
8' 34.43
j 10'-HE 4.90 IH dd JHE,9'10.25,JHE, Hz 2.38 9' 139.85
1
lO'-Hz 4.98 IH dd JHZ,9' 17.21, JHE, HZ 2.38 10' 114.64
Ar-2,6 7.96 2H d JAr-2,6>Ar-3,5 8-42 Ar-1 132.87
Ar-3,5 7.59 2H d JAr-2,6)Ar-3,5 8.42 Ar-2,6
Ar-3,5
Ar-4
130.82
130.21
138.60
1 3 4
Based on the above discussion, compound FTZY was character ised as 4-
(N-4-chlorobenzylidene amino)-3-(9-decenyl)-5-mercapto-l,2,4-triazole (18).
FTZY (18)
Structure Elucidation of FTZY' (19)
It was a pale yellow oily liquid. The DCI-MS spectrum of FTZY' showed a
set of [M+l]"^ peaks as the base peak at m/z 377/379 confirming its molecular weight
376/378 [C19H25N4SCI]. The fragment ion peaksat m/z 240 [(M+1)-C7H4NC1] ^ and at
m/z 137/139 [(M+O-CuHaiNBS]""' were obtained by the cleavage of 3-4 and 1-5
bonds of the thiadiazole ring. The set of peaks at m/z 155/157 [M-C|2H2oN4]^ was
obtained by the cleavage of 1-2 and 4-5 bonds of the thiadiazole ring as shown in
Chart 12.
N- -N
\ ^ 5 •
HN—
m/z 377/379 (100.0/47.3)
N-
N = C- C1 +
1 ,5 and 3,4 • • bond 1,2 and 4,5-- bond cleavage cleavage
1
- N
A
+
S = C -< -CI
m/z 137/139 (43.7/21.2)
SH H m/z 240 (28.3)
m/z 155/157 (16.4/6.8)
H
N-
P-cleavage
— N
H
A SH
m/z 115 (9.3)
CHART 12
1 3 5
All the signals in the and '^C-NMR spectra have been assigned
(Table 14). The assignments have been made on the basis of chemical shifts,
multiplicity, relative integrations and by comparison with the spectra of the
uncyclised Schiff base FTZY (18) (Table 13). The absence of signal
corresponding to the thiol proton at 5 12.50 and the shif t of benzylidene
proton (H-6) to higher field from 5 10.49 to S 8.84 suggested the formation of
thiadiazole ring. In '^C-NMR spectrum, the benzylidene carbon also shifted to
higher field f rom 5 160.28 to 5 69.23, confirming the format ion of the ring. In
addition, other signals for j:7-chlorophenyl ring and 9-decenyl side chain
appeared as usual as shown in Table 14.
Based on the above spectral evidence, FTZY' was characterised as 2-(4-
chlorophenyl)-5-(9-decenyl)-2,3-dihydro-l, 2,4-triazolo[3,4-b ] [1 ,S,4]thiad-
iazole (19)
FTZY' (19)
Table 12. ^H-NMR and ^^C-NMR spectral data of FTZX' (17)
1 3 6
H-nr 5(ppm) Integ-ration
Multip-licity J (Hz) C-nr 5(ppm)
6 8.84 IH S 3 151.78
r 2.86 2H t J,. 2. 7.33 6 69.23
2' 1.76 2H br p J=«7.35 7a 163.69
y-T 1.31 5x2H br s r 25.56
8' 2.01 2H m 2' 26.62
9' 5.79 IH tdd J9.8.6.72, J9.,HE 10.23, y-T 29.22-30.37
J9.HZ 17.06 10'-HE 4.90 IH dd Jhe,9'10.23,JHE, HZ 2.28 8' 34.42
l O ' - H z 4.97 IH dd W 17.06, JHE, Hz 2.28 9' 139.83
Ar-2,6 7.54 2H d JAr-2,Ar-3,5 8.35 10' 114.51
Ar-3,5 7.37 2H d JAr-2,6?Ar-3,5 8.35 Ar-1 130.12
Ar-2,6 127.25
Ar-3,5 129.14
Ar-4 134.58
1 3 7
2-(2-Thienyl)-5-(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4Jthm^^
azole FT' (21) along with the Schiff base, 4-(N-2-thienylidene amino)-3-(9-
decenyl)-5-mercapto-l,2,4-triazole FT (20) [Reaction of the s-triazole (1)
with thiophen-2-aldehyde]
A solution of the 5-triazole (1) and thiophen-2-aldehyde (molar ratio,
1:1) in dry benzene was ref luxed with stirring for 8 h with catalytic amount of
/?-TsOH. TLC examination of the reaction mixture revealed the formation of a
major and a minor components, labelled as FT (20) and FT' (21). The
products on column chromatography over silica gel using pet. e ther-EtOAc
(9:1 v/v) as eluent yielded a pink crystalline solid, FT (16%) and a colourless
oily liquid FT' (77%). The reaction sequence is as fol lows.
N N
11 II
I
NH2
(1) N N
+ OHC- W
+
/7-TSOH / dry benzene Reflux, 8 h
N N
FT' (21) I
Structure Elucidation of FT (20)
It was a globule shaped pink crystalline solid, m.p. 74 °C. The IR
spectrum (KBr) of the compound displayed characteristic bands at 2800 (CH),
2300 (SH), 1640 (C=N) and 1580 (C=C) cm"'. The DCI-MS spectrum showed
a [M+1]"^ peak as the base peak at m/z 349, showing its molecular weight 348
1 3 8
[C17H24N4S2] which is equal to the sum of the molecu la r weights of the
5-tr iazole (1) (254) and thiophen-2-aldehyde (112) minus one molecule of
water. This indicated the format ion of the Shif f base. The other f ragment ion
peaks were observed at m/z 240 [(M+1)-C5H4NS]^-, m/z 206 [m/z 239-SH] ^
and m/z 115 [m/z 239-C9Hi6]^'^in addition to the peak at m/z 109 [(M+1)-
C,2H2iN3S]^- as shown in Chart 13.
m/z349(100.0)[M+H]
N—N bond cleavage
N N
H
N = C-
SH
m/z 240 (4.3)
m/z 109(5.2)
m/z 206 (8.5) H
P-cleavage
N N
^ N - ^ S H H
m/z 115(11.6)
CHART 13
The ' H - N M R and '^C-NMR spectra (Fig. 12a and 12b) of FT showed
signals as ass igned (Table 15). The absence of the signal for amino proton at
5 5.18 and appearance of a sharp singlet for the benzy l idene proton at 5 10.60
indicated the format ion of Schiff base. In ' ^C-NMR spec t rum a signal for the
benzyl idene carbon at 5 155.88 due to the format ion of C=N bond appeared.
1 3 9
J I e
3
a 1—( ei)
1 4 0
E
a
r bS t L r t
— ^ o
< « 0 O w w . . X O C
•) M V W £ y o o o J t -<n C '^oi^tn >, uj
3 Q. < O
. c c
rf e — I
a — E u V <0 t- >
Q^tn O — O w o — 3 a :
> • 0 • - - - - — c o — e n f f J o t o — in o r v> E w w > eo V o 3 w •ooe»na vOwsOO e
** u u j ^ C « Q ( & N « > « - > X *> C > Q . t - — N i O . C M '-^tuoL-Z} « > • ' » -
— « r - a w > u i o > C - i < V 30 — fN-tOO 00<t Ct CL < > « j « 3 i u a t > > c
0 0 o
« • J (S
W)
K A (n cn I X • • • • o eo « csi •
(n •-« ^ V) < ' <0 <n —• 4
1 o i n c j «> «
. rs, o ^ tn
o o o o o « f » i D f l o « © i n u i < n r ) n w n n < v j c g c s ( w f o < o c n i • 0) m CD U> I
S tf> w m UJ - to TT
** ^ \t> ^ *o f^ <s n
<M CJ «0 « fw ^
m tn «o V 0 V us r -
P^ CM CM tn
n n
in 0 <0 r«. cn ffi
W ^ 0 CM n CM ^
4 n n t r u s r » . t n c M « r r > . « > r > . o e i
0 w w w fp .H f ^ CM en tr> 0 0 CM CM tn CM « W 0 V m in C M « A V « > < H r v r < . ( O e ) C 3 ( e O o o rr an pw m - p^ A ft ts. f CM r - in 0 e •> 00 0 «S| «S( W
V <n (O <n in
0 •> fs. «J cn f n w
10 f ^ « <n
0 a> CO tn CM CM •H
^ 0 0 0 en n f n
^ ^ v lu Wi* w 1 1 i ^^ ^^ wj '
CnCMCMCMCMCMCMCMCMCMCMCMCM
o e j e i *r I
1 4 1
Table 12. ^ H - N M R and ^^C-NMR spectral data of FTZX' (17)
H-nr S(ppm) Integ-ration
Multip-licity J (Hz) C-nr 5(ppm)
SH 12.50 IH brs 3 152.82
6 10.60 IH s 5 163.73
1' 1.19 2H t h 'T 7.33 6 155.88
2' 1.77 2H br p J « 7.45 1' 25.57
y-T 1.32 5x2H br s 2' 26.72
8' 2.02 2H m 3'-7' 29.22-30.38
9' 5.80 IH tdd J9.,8'6.59,, J9.,he 10.26, J9. Hz 17.03
8' 34.41
10'-He 4.90 IH dd JHE,9' 10.26, JHE, HZ 2.38 9' 139.83
lO'-Hz 4.98 IH dd JHZ,9' 17.03, JHE; HZ 2.38 10' 114.61
Ar-3 7.83 IH d J Ar-3) Ar-4 4.94 Ar-1 138.45
Ar-4 7.25 IH dd Jat-S,Ar-4 4 . 9 4 , JAr-4,Ar-5 3 . 6 6 Ar-3 132.53
Ar-5 7.73 IH d JAr-45Ar-5 3 . 6 6 Ar-4
Ar-5
129.12
135.28
1 4 2
support ing the formation of the Schiff base. In addition, both spectra showed
the signals corresponding to 9-decenyl side chain and thiophene ring as
shown in Table 15.
Based on the above facts, compound FT was characterised as 4-(N-2-
thienylidene amino)-3-(9-decenyl)-5-mercapto-l,2,4-triazole (20).
FT (20)
Structure Elucidation of FT' (21)
It was a colourless oily liquid. The DCI-MS spectrum of FT' showed a
[M+l]"" peak as the base peak at m/z 349 confi rming its molecular weight 348
[C17H24N4S2]. The fragment ion peaks at m/z 128 [M-Ci2H2oN4]'^' was arised
by the cleavage of 1-2 and 4-5 bonds of the thiadizole ring. The peaks at m/z
240 [ (M+O-CsHjNS]^ and m/z 109 [(M+1)-C,2H2,N3S]^- were obtained by the
cleavage of 1-5 and 3-4 bonds as shown in Chart 14.
All the signals in the 'H-NMR and '^C-NMR spectra have been
assigned to individual H- and C- atoms (Table 16) by compar ing the spectral
data with the previously established compounds FTZX' (16) and FTZY' (18)
(Tables 12 and 14). Both the spectra fully conf i rmed the formation of the
thiadiazole ring. In 'H-NMR spectrum, the absence of signal for thiol proton
at 5 12.50 and the shift of benzylidene proton signal to up f ield f rom 5 10.60
to S 8.93 indicated the formation of the thiadiazole ring. Also in '^C-NMR
1 4 3
spectrum, the shift of benzylidene carbon signal to higher f ield f rom 5 155.88
to 5 66.37, supported the formation of the ring. Both the spectra also showed
the signals for thiophene ring and 9-decenyl side chain as shown in Table 15.
N N
m/z 349(100.0)[M+1]
] -5 and 3-4 bond cleavage
] -2 and 4-5 bond cleavage
1 . N N
N + H ^SH
fee- II \
m/z 128/129 (8.7/5.5)
m/z 109(13.9)
m/z 206(11.7) H
m/z 240(12.7)
p-cleavage
"N N
^ N ^ S H H
m/z 115(11.1)
CHART 14
On the basis of above spectral evidence, FT' was characterised as
5-(9-decenyl)-2-(2-thienyl)-2,3-dihydro-l, 2,4-tnazolo[3,4-b][ 1,3,4Jthaidia-
zole (19).
FT'(21)
Table 12. ^ H - N M R and ^^C-NMR spectral data of FTZX' (17)
1 4 4
H-nr 5(ppm) Integ-ration
Multip-licity J (Hz) C-nr S(ppm)
6 8.93 IH s 3 151.93
r 2.81 2H t Jr,2' 7.32 6 66.37
2' 1.77 2H br p J « 7.36 7a 163.48
y-T 1.31 5x2H br s 1' 25.53
8' 2.01 2H m 2' 26.58 j
9' 5.80 IH tdd J9.8'6.71, J9.,HH 10.22, J9-,Hz 17.09,
y-T 29.22-30.37
10'-HE 4.90 I H dd W 10.22, Jhe, Hz 2.29 8' 34.46
lO'-Hz 4.97 IH dd JHZ,9' 17.09, JHE, HZ2.29 9' 139.85
Ar-3 7.60 I H d JAr-3»Ar-4 5.19 10' 114.66
Ar-4 7.07 I H dd JAR-3,AR-4 5.19 , JAR-4,AR-5 3-67 Ar-1 135.77
Ar-5 7.39 IH d JAr-45Ar-5 3.67 Ar-3
Ar-4
Ar-5
129.06
127.02
130.08
1 4 5
4-(N-2-furfuryUdene amino)-3-(9-decenyl)-5-mercapto-l,2,4-triazole F F
(22). [Reaction of the 5-triazoIe (1) with furfuraldehyde]*
*[This react ion failed to yield the desired product, 5-(9-decenyl)-2-(2-furyl)-
2,3-dihydro-l, 2,4-triazolo[3,4-b][ 1,3,4] thaidiazole. ]
A solution of the 5-triazole (1) and fur fura ldehyde (molar ratio, 1:1)
was ref luxed in dry benzene containing a catalytic amount of p -TsOH. The
progress of the reaction was monitored by TLC, which revealed the presence
of only one spot labelled as FF. The refluxing continued for fur ther 5 h. but
no progress in the reaction was observed and the solution gradually changed
into dark brown in colour. The products on purif icat ion by column
chromatography (pet. ether-EtOAc, 9:1 v/v) yielded a grey coloured
crystall ine solid, F F as the sole product in 57% yield.
N N + OHC-
'SH
(1) N H ,
N N
(
N = C H -
FF (22)
O
p-TsOH/dry benzene Reflux, 11 h
N N
1 4 6
Structure Elucidation of FF (22)
It was a globular shaped grey crystalline solid, m.p. 98 °C. The
structure of FF has been fully established by IR, DCI-MS, 'H-NMR and
'^C-NMR spectra. The IR spectrum (KBr) showed characteris t ic peaks at
2850 (SH), 1640 ( C - C ) and 1610 (C=N) cm''. The DCI -MS spectrum
displayed [M+1]"^ peak as the base peak at m/z 333 conf i rming its molecular
weight [ C 1 7 H 2 4 N 4 O S ] , which is equal to the sum of the molecular weights of
the 5-triazole (1) (254) and furfura ldehyde (96) minus one molecule of water.
This indicated the formation of the Schiff base. Other prominent f ragment ion
peaks were observed at m/z 240 [(M+1)-C5H4NS]\ m/z 206 [m/z 239-SH]"
and m/z 115 [m/z 239-C9H,6]^; in addition to the peak at m/z 93 [(M+1)-
CnH.iNsS] ' ' - as shown in Chart 15.
N N
'SH N = C H - i )
m/z333(100.0)[M+l] O Exocyclic N —N bond cleavage
m/z 206 (4.8) H^
m/z 240 (4.3)
P-cleavag
N N
m/z 115(14.7)
N ^SH
^EC-O
m/z 93(7.0)
CHART 15
1 4 7
All the signals in 'H- and '^C-NMR spectra have been assigned to
individual H-and C-atoms (Table 17) by comparing the spectra with a
previously established compound FT (20) (Table 15). The absence of NH2
proton signal at 5 5.18 in 'H-NMR spectrum and appearance of new signal at
6 10.35 for CH=N proton confirmed the formation of the Schiff base. This is
also supported by the appearance of carbon signal for C H - N at 5 150.11 in
'^C-NMR spectrum. In addition, both the spectra showed characterist ic peaks
of furan ring and 9-decenyl side chain as shown in Table 17.
Based on the above facts, compound FF was characterised as 4-(N-2-
fwfurylidene amino)-S-(9-decenyl)-5-mercapto-l,2,4-triazole (22).
FF (22)
Table 12. ^H-NMR and ^^C-NMR spectral data of FTZX' (17)
1 4 8
H-nr 5(ppm) Integ-ration
Multip-licity J (Hz) C-nr 5(ppm)
SH 12.52 IH brs 3 153.03
6 10.35 IH s 5 163.62
V 2.79 2H t J,. 2' 7.32 6 150.11
2' 1.77 2H br p J « 7.46 r 25.52
y-T 1.32 5x2H br s 2' 26.61
8' 2.02 2H m y-T 29.22-30.38
9' 5.80 IH tdd J9'8'6.59, J9',HE 10.25, Hz 17.21,
8' 34.42
lO'-H,: 4.90 IH dd JHE ,9' 10.25, JHE, HZ 2.38 9' 139.85
l O ' - H z 4.98 IH dd Jh2,9' 17.21, JHC, HZ 2.38 10' 114.62
Ar-3 7.90 IH d JAr-3>Ar-4 1-83 Ar-1 149.40
Ar-4 6.73 IH dd JAr-3!Ar-4 3.48 , Jam,Ar-5 1-83 Ar-3 148.03
Ar-5 7.24 IH d JAr-45Ar-5 3.48 Ar-4
Ar-5
113.50
118.84
1 4 9
EXPERIMENTAL
4-Amino-3-(9-decenyl)-5-mercapto-l,2,4-triazole FTZ (1):
It was prepared according to the literature method^^ as described in Chapter 1.
2-(4-Methoxyphenyl)r5-(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]
thiadiazole FTZX' (17) along with the Schiff base FTZX (16) [Reaction of
the 5-triazoie (1) with p-anisaldehyde in presence of /7-TsOH]
A solution of i - t r iazole (1) (SOOmg, 1.96 mmol) and jO-anisaldehyde
(266 mg, 1.96 mmol) in dry benzene (20 ml) containing p - T s O H (5mg) as
catalyst was refluxed with stirring on an oil bath at 80 °C for 5 h using an
azeotropic water collector. The progress of the reaction was monitored by
TLC (silica gel G, pet. ether-EtOAc, 8:2 v/v) which revealed the presence of
two spots, one minor (upper) and another major (lower), labelled as FTZX
and FTZX'. The reaction mixture was then concentrated under reduced
pressure, extracted with diethyl ether and washed several t imes with water
until the solution was neutral. The ethereal solution was then kept over
anhydrous Na2S04. The solvent was evaporated under reduced pressure and
the residue left was chromatographed over a silica gel column using
(pet .ether-EtOAc, 9.5:0.5v/v as eluent). Elution of the column first afforded a
yellow solid which on crystallisation from pet .e ther-benzene yielded FTZX
as pale yellow crystalline globules, 130 mg (18.2%), m.p. 66 °C, Rf 0.76 (pet.
e ther-EtOAc, 9:1 v/v). Further elution of the column yielded a colourless oily
liquid which was further purif ied by repeated column chromatography using
pet. ether-diethyl ether (8:2 v/v) as eluent to yield FTZX', 518 mg (71.0%),
Rf 0.42 (pet. ether-EtOAc, 9:1 v/v).
1 5 0
Spectral data ofFTZX (16)
IR (KBr): 2900 (CH str), 2350 (SH), 1630 (C=C) 1600 (C-N) , 1580, 1480
(phenyl), 1500, 1460, 1410, 1290, 1250, 1150, 1000, 950, 820 cm-'.
'H-NMR (400 MHz, acetone-rf^): 6h 12.40 ( IH, br s, SH), 10.16 ( IH, s,
H - 6 ) , 2 . 8 1 ( 2 H , t , J = 7 . 3 3 , H - 1 ' ) , 1 . 7 7 ( 2 H , b r p , J « 7 . 3 1 , H - 2 ' ) , 1 . 3 2 (LOH, b r s,
H - 3 ' - 7 ' ) , 2 . 0 1 ( 2 H , m , H - 8 ' ) , 5 . 8 0 ( I H , t d d , J = 6 . 6 0 , 1 0 . 2 5 , 1 7 . 2 1 , H - 9 ' ) , 4 . 9 0
( I H , d d , J = 1 0 . 2 6 , 2 . 3 9 , H E - 1 0 ' ) , 4 . 9 8 ( I H , d d , J = 1 7 . 2 I ; 2 . 3 9 , H , - 1 0 ' ) , 7 . 8 9
( 2 H , d , J = 8 . 9 8 , H - A r - 2 , 6 ) , 7 . 1 0 ( 2 H , d , J = 8 . 9 8 , H - A r - 3 , 5 ) , 3 . 9 1 ( 3 H , s,
O C H 3 ) .
'^C-NMR (100 MHz, acetone-rf^): 5c 152.85 (C-3), 164.22 (C-5), 162.51
(C-6), 25.62 ( C - r ) , 26.73 (C-2'), 29.23-30.38 (C-3'-7'), 34.43 (C-8'), 139.85
(C-9'), 114.63 (C-10'), 126.36 (C-Ar-1), 131.24 (C-Ar-2,6), 115.45 (C-Ar-
3,5), 163.73 (C-Ar-4).
DCI-MS (NH3): m/z (%) 373 (84.), 374 (28.8), 375 (9.8), 239 (4.9), 240
(5.0), 21 1 (1 1.7), 206 (6.9), 133 (100.0), 13 (12.7), 135(7.6).
Spectral data o f F T Z X ' (17)
^H-NMR (400 MHz, acetone-rfg): 6 h 8 . 6 0 ( I H , s, H - 2 ) , 2 . 8 3 ( 2 H , t, J = 7 . 3 2 ,
H - 1 ' ) , 1 . 7 5 ( 2 H , b r p , J = 7 . 3 6 , H - 2 ' ) , 1 . 3 0 (LOH, b r s, H - 3 ' - 7 ' ) , 2 . 0 1 ( 2 H , m , H -
8 ' ) , 5 . 7 9 ( I H , t d d , J = 6 . 7 2 , 1 7 . 0 9 , 1 0 . 2 3 , H - 9 ' ) , 4 . 9 0 ( I H , d d , J = 1 0 . 2 3 , 2 . 2 9 ,
H E - 1 0 ' ) , 4 . 9 7 ( I H , d d , J = 1 7 . 0 9 , 2 . 2 9 , H , - I O ' ) , 7 . 4 3 ( 2 H , d , J = 8 . 8 5 , H - A r - 2 , 6 ) ,
6 . 9 7 ( 2 H , d, J = 8 . 8 5 , H - A r - 3 , 5 ) , 3 . 8 3 ( 3 H , s, O C H 3 ) .
'^C-NMR (100 MHz, acetone-rf^): 5c 151.71 (C-5), 70.18 (C-2), 164.33
(C-7a), 25.54 (C-1'), 26.65 (C-2'), 29.22-30.37 (C-3'-7'), 34.45 (C-8'), 139.82
(C-9'), 114.49 (C-10'), 126.70 (C-Ar-1), 131.04 (C-Ar-2,6), 114.65 (C-Ar-
3,5), 161.19 (C-Ar-4,) 55.67 ( O C H 3 ) .
1 5 1
DCI-MS (NH3): m/z (%) 372 (100.0), 373 (29.5), 374 (9.7), 341 (5.7), 239
(7.6), 240 (42.1), 241 (6.8), 206 (8.3), 151 (35.2), 152 (5.4), 153 (8.0), 133
(85.2), 134 (11.6), 135 (8.6), 136 (50.2), 137 (5.5), 128 (9.1), 115 (11.4), 80
(8.1).
2-(4-Chlorophenyl)-5-(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]
thiadiazole FTZY'(19) along with the Schiff base FTZY (18) [Reaction of
the 5-triazoIe (1) with p-chlorobenzaldehyde in presence of /7-TsOH]
A solution of the 1,2,4-triazole (1) (500 mg, 1.96 mmol) and /?-chloro-
benzaldehyde (274 mg. 1.96 mmol) in dry benzene (20 mi) containing
catalytic amount o f / ' - T s O H (5mg) was refluxed with stirring on an oil bath at
80°C for 12 h using an azeotropic water collector. The products on usual
work up gave a light yellow coloured oily residue. On examinat ion by TLC
(silica gel G, pet. ether-EtOAc, 8:2 v/v), it was found to be a mixture of two
compounds labelled as FTZY (18) (minor, upper) and FTZY' (19) (major,
lower). The oily residue was then chromatographed over a silica gel column
using pet. ether - EtOAc, 8:2 v/v as eluent. Elution of the column first
furnished a white solid, FTZY' which was crystallized f rom benzene-acetone
as white crystall ine needles, 440 mg (59.1%), m.p. 102 °C, Rf 0.68 (pet.
e ther-EtOAc, 8:2 v/v). Further elution of the column yielded a colourless oily
liquid, FTZY', 203 mg (27.3%), Rf 0.37 (pet. e ther-EtOAc, 8:2 v/v).
Spectral data of FTZY (18)
IR (KBr): 2850 (CH str.), 2400 (SH), 1640 (C=C), 1620 (C=N), 1570, 1480
(phenyl), 1450, 1410, 1320, 1240, 1160, 980, 910, 820, 750 cm"'.
'H-NMR (400 MHz, acetone-rfg): 1250 ( IH, s, SH), 10.49 ( I H , s, H-6), 2.84
(2H, t, J=7.32, H - r ) , 2.84 (2H, br p, J«7.46, H-2'), 1.31 ( lOH, br s, H-3'-7') ,
1 5 2
2 . 0 1 ( 2 H , m , H - 8 ' ) , 5 . 8 0 ( I H , t d d , J = 6 . 7 8 , 1 0 . 2 5 , 1 7 . 0 3 , H - 9 ' ) , 4 . 9 0 ( I H , d d ,
J = 1 0 . 2 5 , 2 . 3 8 , H E - 1 0 ' ) , 4 . 9 8 ( I H , d d , J - 1 7 . 2 1 , 2 . 3 8 , H , - 1 0 ' ) , 7 . 9 6 ( 2 H , d ,
J = 8 . 4 2 , H - A r - 2 , 6 ) , 7 . 5 9 ( 2 H , d , J = 8 . 4 2 , H - A r - 3 , 5 ) .
'^C-NMR (100 MHz, acetone-rf,): 6c 153.08 (C-3), 163.78 (C-5), 160.28 (C-
6), 25.58 ( C - r ) , 26.74 (C-2'), 29.23-30.39 (C-3'-7'), 34.43 (C-8'), 139.85 (C-
9'), 114.64 (C-10'), 132.87 (C-Ar-1), 130.82 (C-Ar-2,6), 130.21 (C-Ar-3,5),
138.60 (C-Ar-4).
DCI-MS (NH3): m/z (%): 3 7 7 ( 1 0 0 . 0 ) , 3 7 8 ( 2 9 . 2 ) , 3 7 9 ( 4 1 . 9 ) , 3 8 0 (1 1 .1) ,
2 3 9 ( 4 . 3 ) , 2 4 0 ( 4 . 1 ) , 2 0 6 ( 1 1 . 6 ) , 1 1 5 ( 3 . 6 ) .
Spectral data of FTZY'(19)
'H-NMR (400 MHz, acetone-^/^): 5h 8.84 (IH, s, H-2), 2.86 (2H, t, J=7.33, H-l'),
1.756 (2H, br p, J= 7.35, H-2'), 1.31 (lOH, br s, H-3'-7'), 2.01 (2H, m, H-8'), 5.80
(IH, tdd, J= 6.72, 10.23,17.06, H-9'), 4.97 (IH, dd, J=17.06, 2.29, H,-10'), 7.54 (2H,
d, J=8.35, H-Ar-2,6), 7.37 (2H, d, J-8.35, H-Ar-3,5).
'^C-NMR (100 MHz, acetone-^): 5c 151.78 (C-5), 69.23 (C-2), 163.69 (C-7a),
25.56 (C-r), 26.62 (C-2'), 29.22-30.37 (C-3'-7'), 34.42 (C-8'), 139.83 (C-9'), 114.51
(C-IC), 130.12 (C-Ar-1), 127.25 (C-Ar-2,6), 129.14 (C-Ar-3,5), 134.58 (C-Ar-4,)
DCI-MS (NH3): m/z (%) 377 (100.0), 378 (29.7), 379 (51.5), 240 (28.3), 241 (5.6),
155 (16.4), 157 (6.8), 137 (43.7), 138 (40.8), 139 (21.2).
1 5 3
2-(2-Thienyl)-5-(9-decenyl)-2,3-dihydro-l,2,4-triazolo[3,4-b][l,3,4]thiadi-
azole FT' (21) along with the Schiff base FT (20) [Reaction of the
s-triazole (1) with thiophen-2-aldehyde]
A mixture of 1,2,4-triazole (1) (500 mg, 1.96 mmol) and thiophen-2-
aldehyde (247 mg, 1.96 mmol) in dry benzene (20 ml) containing catalytic
amount of p -TsOH (5mg) was refluxed with stirring on an oil bath at SO' C for
8 h using an azeotropic water collector. The progress of the reaction was
monitored by TLC (pet. ether-EtOAc, 8:2 v/v), which revealed the formation
of one minor (upper) and another major (lower) spot labelled as FT (20) and
FT ' (21). The products on usual work up and column chromatography (silica
gel, pet. ether-EtOAc, 9:1, v/v) first afforded a pink coloured solid, FT
which was recrystallized from pet.ether-benzene as pink crystalline globules,
115 mg (16.3%), m.p. 74°C, Rf 0.82 (pet. ether-EtOAc, 8:2 v/v). Further
elution of the column using (pet. ether-EtOAc, 8:2 v/v), yielded FT' as a
colourless oily liquid, 548 mg (77.2%), Rf 0.44 (pet. ether-EtOAc, 8:2 v/v).
Spectral data of FT (20)
IR (KBr) :2800 (CH str), 2300 (SH), 1640 (C=C), 1690 (C=N), 1580, 1490
(phenyl), 1420, 1400, 1350, 1270, 1200, 1150,1 100, 1040, 980, 890, 830,
800, 750, 700 cm"'.
'H-NMR (400 MHz, acetone-RF^): 5h 12.50 ( IH, s, SH), 10.60 ( I H , s, H-6),
2 . 7 9 ( 2 H , t , J = 7 . 3 3 , H - 1 ' ) , 1 . 7 7 ( 2 H , b r p , J « 7 . 4 5 , H - 2 ' ) , 1 . 3 2 ( L O H , b r s , H - 3 ' -
7 ' ) , 2 . 0 2 ( 2 H , m , H - 8 ' ) , 5 . 8 0 ( I H , t d d , J = 6 . 5 9 , 1 0 . 2 6 , 1 7 . 0 3 , H - 9 ' ) , 4 . 9 0 ( I H ,
d d , J - 1 0 . 2 6 , 2 . 3 8 , H E - 1 0 ' ) , 4 . 9 8 ( I H , d d , J = 1 7 . 0 3 , 2 . 3 8 , H , - 1 0 ' ) , 7 . 8 3 ( I H , d ,
J = 4 . 9 4 , H - A r - 3 ) , 7 . 2 5 ( I H , d d , J = 4 . 9 4 , 3 . 6 6 , H - A r - 4 ) , 7 . 7 3 ( I H , d , J = 3 . 6 6 , H -
Ar-5).
1 5 4
'^C-NMR (100 MHz, acetone-cffi): 5c 152.82 (C-3), 163.73 (C-5), 155.88
(C-6), 25.57 ( C - r ) , 26.72 (C-2'), 29.22-30.38 (C-3'-7'), 34.41 (C-8'), 139.83
(C-9'), 114.61 (C-IC) , 138.45 (C-Ar-1), 132.53 (C-Ar-3), 129.12 (C-Ar-4),
135.28 (C-Ar-5).
D C I - M S (NHj) : m/z (%) 349 (100.0), 350 (26.2), 351 (13.2), 240 (4.3), 206
(8.5), 128 (6.7), 115 (11.6).
Spectral data of FT'(21)
• H - N M R (400 MHz, acetone-rf^): 5h 8.93 ( IH, s, H-2), 2.81 (2H, t, J=7.32,
H-1'), 1.77 (2H, br p, J= 7.36, H-2'), 1.31 (lOH, br s, H-3'-7') , 2.01 (2H, m,
H-8'), 5.80 ( IH, tdd, J=6.71,10.22, 17.09 H-9'), 4.90(1H, dd, J= 10.22, 2.29,
HE-10'), 4.97 ( IH, dd, J=17.09, 2.29, H,-10'), 7.60 ( IH, d, J=5.19, H-Ar-3),
7.07 ( IH, dd, 1=5.19,3.67, H-Ar-4) 7.39 ( IH, d, J=5.19, H-Ar-5).
' ' C - N M R (100 MHz, acetone-^/,): 6c 151.93 (C-5), 66.37 (C-2), 163.48 (C-
7a). 25.53 (C-1'), 26.58 (C-2'), 29.22-30.37 (C-3'-7'), 34.46 (C-8'), 139.85 (C-
9'), 114.66 (C-10'), 135.77 (C-Ar-1), 129.06 (C-Ar-3), 127.02 (C-Ar-4),
130.08 (C-Ar-5)
DCI -MS (NH3): m/z (%) 349 (100.0), 350 (25.4), 351(12.5), 334 (7.8), 239
(4.4), 240 (12.7), 206 (11.7), 129 (5.5), 128 (8.7), 1 15 (11.1), 1 12 (9.1), 109
(13.9).
4-(2-N-furfurylidene amino)-3-(9-decenyl)-5-mercapto-l,2,4-triazole, FF
(22). [Reaction of the 5-triazole (1) with furfuraldehyde]
A solution of 1,2,4-triazoIe (1) (500 mg, 1.96 mmol) and
furfuraldehyde (188 mg. 1.96 mmol) in dry benzene (20 ml) containing
catalytic amount of /?-TsOH (5mg) was refluxed with stirring on an oil bath at
80 °C for 6 h using an azeotropic water collector as described above. The
1 5 5
progress of the reaction was monitored by TLC (pet. ether-EtOAc, 8:2 v/v) at
every 15 min. TLC revealed the formation of only one spot, labelled as FF.
So, the refluxing continued for further 5 h to see the development of another
spot but no progress in the reaction was observed and the colour of the
solution gradually changed into dark brown and a black precipitate started
depositing on the sides of the round bottom flask. This may be due to the
decomposition of the furfural moiety in presence of strong acid (p-TsOH).
The reaction was stopped and the colour of the solution was removed by
passing through the activated charcoal. It was worked up as usual and the
brown oily residue thus obtained was chromatographed over a silica gel
column using pet. ether-EtOAc, 9:1, v/v as eluent which furnished a grey
coloured crystalline solid, FF (22). it was recrystallized from pet. ether-
benzene as grey crystalline globules, 371 mg (57.0%), m.p. 98°C, Rf 0.69
(pet. ether-EtOAc, 8:2 v/v).
Spectral data of FF (22)
IR (KBr): 2850 (CH str.), 2250 (SH), 1640 (C=C), 1610 (C=N), 1580, 1490
(phenyl), 1460, 1400, 1320, 1260, 1220, 1150, 1100, 1070, 1020, 980. 820,
750 cm"'.
'H-NMR (400 MHz, acetone-^/^): 5h 12.52 ( IH, s, SH), 10.35 ( IH, s, H-6).
2 . 7 9 ( 2 H , t , J = 7 . 3 2 , H - T ) , 1 . 7 7 ( 2 H , b r p , J « 7 . 4 6 , H - 2 ' ) , 1 . 3 2 (LOH, b r s , H - 3 ' -
T ) , 2 . 0 2 ( 2 H , m , H - 8 ' ) , 5 . 8 0 ( I H , t d d , 1 = 6 . 5 9 , 1 0 . 2 5 , 1 7 . 2 1 , H - 9 ' ) , 4 . 9 0 ( I H ,
d d , J = 1 7 . 2 . 1 , 2 . 3 8 , H E - 1 0 ' ) , 4 . 9 8 ( I H , d d , J = 1 0 . 2 5 , 2 . 3 8 , H ^ - I O ' ) , 7 . 9 0 ( I H , d ,
J = 1 . 8 3 , H - A r - 3 ) , 6 . 7 3 ( I H , d d , J = 3 . 4 8 , 1 . 8 3 , H - A r - 4 ) , 7 . 2 4 ( I H , d , J = 3 . 4 8 , H -
Ar-5).
1 5 6
' ^C-NMR (100 MHz, acetone-rfg): 5c 153.03 (C-3), 163.62 (C-5), 150.11
(C-6), 25.52 ( C - r ) , 26.61 (C-2'), 29.22-30.38 (C-3'-7'), 34.42 (C-8'), 139.85
(C-9'), 114.62 (C-10'), 149.40 (C-Ar-1), 148.03 (C-Ar-3), 113.50 (C-Ar-4),
118.84 (C-Ar-5).
DCI-MS (NHa): m/z (%) 333 (100.0), 334 (23.9), 335(8.3), 240 (3.2), 206
(4.8), 128 (8.4), 115 (14.7), 96 (12.5), 93 (7.0).
1 5 7
REFERENCES
1. M. Kidwai, P. Sapra, P. Misra, R.K. Saxena and M. Singh, Bioorg. and
Med. Chem., 2001, 9(2), 217.
2. M.M. Ghorab, A.M.Sh. El-Sherief, Y.A. Ammarb and S.I. Mohamed,
II. Farmaco., 2000, 55 (5), 354.
3. A. Dandia and A. Kumar, Phosphorous, Sulfur Silicon Relat. Elem.,
1994, 97(1-4), 27.
4. M.A. Hanna, M.N. Khodeir, M.A Mashaly and H.M. El-Shafei,
Phosphorous Sulfur Silicon Relat. Elem., 1993, 82(1-4), 171.
5. M.A. Khalil, O.A.El-Sayed and H.A. El-Shamy, Arch. Pharm., 1993,
326(8), 489.
6. M.A. Khalil and N.S. Habib,y^rc/2. P/zarw., 1990, 323(8), 471.
7. Nizamuddin, M. Gupta, M.H. Khan and M.K. Srivastava, J. Scientific
and Industr. Res., 1999, 58, 538.
8. (a) B. Beat, H. Moser and G. Pissiotasa, Ciba-Geigy Corp., US Patent,
US 4957535 (1990), C07D-513/04 (b) B. Beat, P. Georg and M. Hans,
Eur. Pat. Appl. EP 210137 (CI. C07D513/04).
9. A.M. Abdelal and A.D. Broom, J. Pharm. Sci., 1989, 3(1), 79.
10. G.V. De Lucca, J. Org. Chem., 1998, 63, 475.
11. P.Y. Lam, P.K. Jadhav, C. J. Eyermann, C. N. Hodge, G.V. De. Lucca
and J.D Rodgers, US Patent, US 5 6 1 0 2 9 4 , 1 9 9 7 , Chem. Abstr., 1 9 9 8 ,
1 2 9 , 1 3 6 1 4 8 U .
1 5 8
12. P. K. Jadhav, V. Prabhakar, W. F. Daneker and F. J. Woerner, US
Patent, US 5506355, 1996, Chem. Abstr., 1996, 125, 34038h.
13. P.Y. Lam, P.K. Jadhav, C.J. Eyermann, C.N. Hodge, G.V. De. Lucca
and J.D. Rodgers, PCX Int. AppL, W09419329 (CI. C07D 243/04),
1994, Chem. Abstr., 1995, 123, 286106u.
14. T.H. Simon, H.N. Robin and J.S. Martin, (Glaxo Wellcome Inc.), US
Patent, US 5589474, 1996. (C07D 267/20).
15. D.Giannotti, G. Viti, P. Sabraci, V. Pestellini, and G. Votterra, J. Med.
Chem., 1991, 34(4), 1356.
16. F. Borsini, G. Volterra, A. Lecci, S. Evangelista and A. Mancinelli,
Arzneim. Forsch., 1991, 41(6), 573.
17. M. Yoh-ichi and O. Kazuo, (Taiho Pharmaceutical Co.), US Patent, US
5036065, 1991 (C07D 285/326).
18. B. Raymond and R. Sylvie, US Patent, US 3609168,1971 (C07D 093/00).
19. J. Bolkos, A. Perez-Beroy, S. Gubert, L. Anglada, A. Sacristan and J.
A. Ortiz, Tetrahedron, 1992, 48(43), 9567.
20. (a) M. Kuroda, M. Amano and F. Noboru, Ger. Off en., DE 4028184
(CI. G03 G5/06), 1991, Chem. Abstr., 1992, 116, 31303u (b) M.
Kuroda, M. Amano, F. Noboru, Ger. Offen., DE 4018010 (CI. G03
G5/06), 1990, Chem. Abstr., 1991, 115, 82195x (c) M. Kuroda, N.
Kosho, Japan Patent, JP 0348 854 [9148,854] (CI. G03 G5/06),1991,
Chem. Abstr., 1991, 115, 170893d.
1 5 9
21. (a) R. Gupta, S.Paul, A. K. Gupta, P. L. Kachroo and S. Bani, Indian J.
Chem., 1997, 36B, 707 (b) R. Gupta, S. Paul, A.K. Gupta, and S. Bani,
Indian J. Chem., 1998, 37B, 498.
22. R. H. Udupi, G.V. Suresh, S.R. Setty and A.R. Bhat, J. Indian Chem.
Soc., 2000,77, 302.
23. M. Kidwai, Y. Goel, P. Kumar and K. Kumar, Indian J. Chem., 1997,
36B, 782.
24. J. Mohan, G.S.R. Anjanayelu and P. Verma, Curr. Sci., 1989, 58. 1028.
25. (a) S. Haijan, W. Zhongyi and S. Haoxin, Yingong Huaxue, 1999,
16(5), 53, Chem. Abstr., 2000, 132, 78513h. (b) S. Haijan, W. Zhongyi
and S. Haoxin, Synth. Commun., 1998, 28(21), 3973.
26. Z.Y. Wang, J.P. You and Y.L. Fang, Youji Huaxue, 1999, 19(3), 288,
Chem. Abstr., 1999, 131,199657w.
27. X.W. Sun, C. H. Chu, Z. Y. Zhang, Q. Wang and S.F. Wang, Pol. J.
Chem., 1999, 73(7), 1203.
28. B.S. Holla, G. Richard and S. Shalini, Farmaco., 1998, 53(8-9), 574.
29. Q. Bano, N. Tiwari, S. Giri and Nizamuddin, Indian J. Chem., 1993,
32B, 399.
30. G.A. El-Saraf, Indian J. Chem., 1992, 31B, 167.
31. R.D. Patil and J.S. Biradar, Indian J. Chem., 2000, 39B, 929.
32. R. Gupta, A.K. Gupta and S. Paul, Indian J. Chem., 2000, 39B, 847.
33. Z.K.A. Ei-Samii, S.A. El-Feky, M.I. Jaeda and E. Hassan, Zhonghua
Xaoxue zazhi, 1991,43, 237.
1 6 0
34. R.H. Udupi, G.V. Suresh, S.S Ramachandra and A.R Bhatt, J. Indian
Chem. Soc., 2000, 77(6), 302.
35. S. Sangeetha, R. Gupta and P.L. Kachroo, J. Indian Chem. Soc., 1996,
73 (11), 625.
36. M.I. Husain and V. Kumar, Indian J. Chem., 1992, 31B, 673.
37. V. Srivastava, S. Sen and R. Shekar, Indian J. Chem., 1994, 33B, 344.
38. Z.K.A. El-Samii, M.I. Al-Ashmawi and B.A. El-Fattah, J. Pharm. Sci.,
1987, 28, 395.
39. (a) R. Gupta, S. Sangeetha, M. Vandna and P.L. Kachroo, Indian J.
Chem., 1996, 35B, 621. (b) R. Gupta, S. Sangeetha and P.L. Kachroo,
Indian J. Chem., 1996, 35B, 718.
40. Z. Zhag, L. Zhao, Loming, Li Zhangming and R. Liao, Youji Hauxme,
1994, 14, 74, Chem. Abstr., 1994, 121, 92673.
41. A.K. Dubey and N.K. Sangwan, Indian J. Heterocyclic Chem., 1994,
3(4), 277.
42. (a) N.M. Koles, V.D Orlov, E.K. Slobodina, E.Y. Yureva and S.D.
Korshunov, Khim. Creterotsikl Soedin., 1992, 2, 267, Chem. Abstr.,
1 9 9 2 , 117, 2 3 3 9 9 0 X . (b) M.V.S.R. Prasad and M.S.R. Naidu, J. Indian
Chem. Soc., 1991, 68, 619.
43. T.E. Giotova, A.S. Nakhmanovich, L.S. Romanenko and M.V. Sigalov,
Khim. Geterotsikl. Soedin., 1991, 7, 990, Chem. Abstr., 1992, 116,
1 2 8 8 8 2 V . (b) U.V. Laddi, M.B. Talawar, S.R. Desai, R.S. Bennur and
S.C. Bennur, Indian J. Chem., 2001, 40B, 828.
1 6 1
44. (a) B. Kalluraya, A. D'souza and B.S. Holla, Indian J. Chem., 1994,
33B, 1017. (b) B.S. Holla, K. Sridhara and B. Kalluraya, Indian J.
Chem., 1991, 30B, 672. (c) B. Kalluyraya, A. D'souza and B.S. Holla,
Indian J. Chem., 1995, 34B, 939.
45. G. J. Reddy, G. Sabitha and A.V. Subha Rao, Synth.Commun., 1999,
22, 2273.
46. A.M. El-Sayed and A. Khodairy, Phosphorous Sulfur Silicon Relat.
Elem., 1998, 132, 41.
47. N. Tiwari, K. Singh and Nizamuddin, Indian. J. Heterocyclin Chem.,
1993, 2(3), 195.
48. LA. Shehata, M.A. Moustafa, A. M. Abdelal and A.A. El-Emam,
Orient J. Chem., 1992, 8 (4), 304.
49. B. Prabhu Swami, S.Y. Ambedkar, Synth. Commun., 1999, 29(20), 3487.
50. A. Brukstus, T. Sadauskas and S. Tumkevicius, Khim. Geterotsikl.
Soedin, 1996, 3, 427, Chem. Abstr., 1996, 125, 16791 Ij.
51. A. Kakchi, S. Ito, F. Ishida and Y. Tominaga, J. Org. Chem., 1997, 62,
7788.
52. N. N. Volkova, E.V. Tarasov, W. Dehaen and V.A. Bakulev, Chem.
Commun., 1999, 22, 2273.
53. S. Sangeetha, R. Gupta and P.L. Kachroo, Natl. Acad. Sci. Lett., 1994,
1 7 ( 1 1 - 1 2 ) , 2 2 1 .
54. Z. Wang, Y. Tianpa and Y. Ling Feng, Youji Huaxue, 1999, 19(3), 288,
Chem. Abstr., 1999, 131, 199657w.
1 6 2
55. (a) S.C. Madhukar and V.R. Joshi, Indian J. Chem., 1995, 34B, 54. (b)
ihid., Indian J. Chem., 1995, 34B, 147.
56. N.D. Heindel, J.D. Laskin, D.E. Heck, R.D. Rapp, C.Guillon, and A.M.
Mendel, PCT Int. AppL, WO 0010564 (CI. A61k31/41), Chem. Abstr.,
2000, 132, 180604a.
57. B. Kalluraya and A. D'souza, J. Indian. Chem. Soc., 1995, 72(2), 137.
58. B.S. Holla, B.S. Rao, K. Sridhara and P.M. Akbarali , Farmaco., 2000,
55(5), 338.
59. C. Temple, Chem. Heterocycl. Comp., 1981, 37, 1.
60. S.M. Kudari and S.E. Badiger, Indian J. Heterocycl. Chem., 1999, 9(2), 99.
61. I.F. Paolo, F. Paolo, S. Daniel and S. Franca, Farmaco., 1996, 51(10), 659.
62. B.S. Holla and U.K. Venkatramana, Farmaco., 1992, 4 7 ( 3 ) , 305.
63. W.D. Jackson and J.B. Polya,v4w5/. J. 5c/., 1951, 13, 149.
64. J. Hanglind, Intern. Cong. Chemotherapy proc., Stullgard, 1963, 1, 887.
65. Z.K.A. El-Samii, M.I. Al-Ashmawi and B.A. El-Fattah, J. Pharm. Sci.,
1987, 28, 395.
66. H. Kumar, V. Patel, P.S. Fernandes and K. Avyas, Indian. J. Chem.,
1990, 29B, 135.
67. N. D. Heindel and J. R. Reid, J. Heterocycl. Chem., 1980, 17, 1087 and
references cited therein.
68. Peng-Fei Xu, Xia-Wen Sun, Lin-Mei Zhang and Zi-Yi Zhang, J. Chem.
Res.(s), 1999, 170.
1 6 3
69. (a) W. Davey and J.R. Gwilt, J. Chem. Soc., 1957, 1008. (b) A.I.
Vogel, "A text book of practical organic Chemistry", Longman,
London, edition, 1978, p.776. (c) ibid., 1978, p. 794. (d) ibid., p.
763. (e) ibid., p. 777.
70. (a) H.G. Krishnamurthy, B. Prakash and S. Sathyanayana, Indian J.
Chem., 1989, 28B, 279 (b) M.K. Seikel, M.J. Lounsbury and S. Wang,
J. Org. Chem., 1962, 27, 2952 (c) J.H. Adams, J. Org. Chem., 1967,
32, 3992.
71. P. Bohler and Ch. Tamm, Tetrahedron Lett., 1967, 36, 479.
72. D.D. Keane, K.G. Marathe, W.L O'Sullivan and E. M. Dhilbin, J. Org.
Chem., 1970, 35(7), 2286.
73. M. Upreti, S. Pant, A. Dandia, U.C. Pant, A.K. Goel and G. K. Patnaik,
Indian J. Chem., 1997, 36B, 1185.
74. S. Pant, B.C, Joshi and U. C. Pant, Indian J. Chem., 1993, 23B, 869.
75. M.G. Dhara, U.K. Mallik and A. G. Mallik, Indian J. Chem., 1996,
35B, 1214.
76. Jerry March, Advanced Organic Chemistry, 4"" Ed., Wiley, 1999, 748.
77. C. Martini, W. Marrucci, A. Lucakhini, G. Baigi and O.J. Livi, J.
Pharm. Sci., 1988, 77, 977.
78. A. Da Sattimo, D. Livi, G. Biagi, G. Primofiore and G. Masoni,
Farmaco. Ed. Sci., 1982, 37, 728.
79. T. Krueger, J. Eickmans and D. Hottkamp, J. Imaging Sci., 1991, 35, 59.
80. K.C. Joshi and S. Giri, J. Indian Chem. Soc., 1963, 40, 42.
81. J. Haglind, Chem. Abstr., 1966, 64, 16509.
1 6 4
82. K.C. Joshi, A. Dandia and N. Ahmad, Indian J. Chem., 1989, 28B, 639.
83. B.S. Holla, M.K. Shivananda and P.M. Akbarali, J. Indian Chem. Soc.,
1998, 75, 532.
0 A T ^ l A l i
2,3-DISUBSTITUTED THIAZOLIDIN-4-ONES/THIAZAN-4-ONES
OAni 11 J r ,
1 6 5
THEORETICAL
4-Thiazolidinones and tetrahydro-l,3-thiazin-4-ones (called as 4-
Thiazanones) are two important classes of biologically active five and six
membered sulphur and nitrogen containing heterocyclic compounds with a
carbonyl group in the 4-position (I) and (II).
3 4 0 H N — f
3 4 0 3 HN ^ HN
I III V
0 0 0 3 IJ4 3
h n ^ N hn-2L Ja
1 J 6
1
II IV VI
0 , (2,4-thiazolidine-dione / th iazan-2,4-dione) V B / V I B , X = S, (2-thiono-4-thiazolidinone or rhodanine /2- th iono-4- th iazanone) V C / V I C , X = NR, (2- immo-4-thiazol idinone or pseudoth iohydantom / 2- imino-4- th iazanone) R V D / V I D , X = N - N = C ^ (2-hydrazmo-4- th iazol id inone/2-hydraz ino-4- th iazanone)
Substituents in the 2, 3 and 5-positions may be varied, but the greatest
difference in structures and properties is exerted by the group attached to the
carbon atom in the 2-position (Rj and R2 in formula II I , IV and X in formula
V, VI). Variations in the substituents attached to the nitrogen atom and the
methylene carbon atom are possible for the structures represented by
formulas III , IV, V and VI.
4-Thiazolidinones have been the subject of extensive study in the
recent past. Numerous reports in the form of chemical reviews''^ and review
articles^'"''^ have appeared in the literature which highlight their chemistry and
1 6 6
use, especially syntheses, reactions and biological activity. 4-Thiazolidinone
derivatives have been found to be associated with diverse biological activities
such as bactericidal^"'", fungicidal^"'", insecticidal"" '^, pesticidal''*,
herbicidal '^ ' '^ antitubercular'^"'^, antiinflammatory^""^^ antitumor^'',
antipsychotic^^"^^, antiviral^^"^", anti-convulsant^'"^'*, anthelmintic^^'^^
respiratory activity^^'^^ antidiarrhoeal^^ and antiarthritic^^. A number of
thiazolidinone derivatives has also been found to exhibit highly potent anti-
anti-histaminic'^^"'''', antidiabetic'^^''"', oxygenase inhibitory^^, calcium
antagonist'^^ potassium inhibitory"^', PPAR agonist '", cardioprotect ive ' ' ,
antiischemic activity" ' '^ and as promising agent for treating Alzheimer
disease'^^, cancer^'* and viral diseases like AIDS^^'^"'^"' and hepatitis-B^'.
Although 4-thiazolidinones have established chemistry, there is only
sporadic reports on the anaologous 4-thiazanones. They are also associated
with wide range of biological activities such as treatment of cardiac
arrhythmia''^, tranquilizer^^ anticoagulant^^, treating peptic u lcer '^
antimicrobial^^"^', antiarthritic®^, anti-rheumatic^^, pesticidal activity'"''
immunoregulatory agent^^ and for treating occular inflammation^®.
Several methods for the preparation of 4-thiazolidinones and 4-
thiazanones have been reported in the literature which are based mainly on
the reaction of:
1. a/p-mercaptoalkanoic acids with
(a) Schiff bases
(b) isothiocynates
(c) isocynates
(d) cyanamideS
1 6 7
2. a/p-halo- or a/p-hydroxy alkanoic acids, a , p-unsaturated acids or their
derivatives with
(a) dithiocarbamates
(b) thiocarbamates
(c) thioureas
(d) thiosemicarbazones
(e) alkali thiocynates
a/p-Mercaptoalkanoic acids have been extensively used for the
syntheses of 4-thiazolidinones/4-thiazanones. The substituted and
unsubstituted a/p-mercaptoalkanoic acids react conveniently with Schiff
bases of aromatic or heterocyclic aldehydes or ketones and aliphatic or
aromatic amines in different solvents to give a variety of 2-substituted-4-
thiazolidinones
Rj HS-C-COOH
I R.
Ry C = N - R
R2-
HS—CH-CH2-COOH
H R - N : ^ >
0
R3
S" R4
VII
-H20
0 R A
N ' RK
R /
VIII
R = alkyl, aryl or heterocyclic Rj = H, alkyl, aryl or heterocyclic R2 = alkyl, aryl or heterocyclic R3 = H, alkyl
R4 = H, alkyl
Hydrazones of aldehydes or ketones react with substituted or
unsubstituted a/p-mercaptoalkanoic acids to form 2-substituted or 2,2-
disubstituted 4-thiazolidinones (IX) ' "'®' or 4-thiazanones (X)®'.
1 6 8
R - N H - N = C R,
•Ri
HS-CH-COOH
- H 2 O
R
H S - C H - C H 2 - C O O H
-H2O
R-NH.
R,
R2-
N R,J R2
,0 'N-
S' IX
•R3
o
"s"
X
~R3
R = alkyl, aryl or heterocyclic R2 = alkyl, aryl or heterocyclic
Ri = H, alkyl, aryl or heterocyclic R3 = H, alkyl R4 = H, alkyl
a-Mercaptoacetic acid or p-mercaptopropionic acid reacts with the
aldehyde or ketone in the presence of ammonium salts such as ammonium
carbonate or acetate in inert solvent. The reaction seems to proceed by the
formation of an aldimine or a ketimine intermediate followed by the
cyclisation with a-mercaptoacetic/p-mercaptopropionic acid to form 2,2
disubstituted-4-thiazolidinones (XI)^''^^-^^/4-thiazanones (XII)
HS CHj COOH/NH3 HN-
O
-H20
HS CH2 CH2COOH/NH3
-H2O
Ri ^ S - ^
XI
o
HN R
R, ^S-^ R3
XII
R = Her alkyl Rj-a lkyl or aryl
a-Mercaptoacetamide reacts with the carbonyl function of aldehydes in
the presence of catalytic amounts of p-toluenesulphonic acid or
1 6 9
borontrifluoride ethereate in inert solvent to give 2-substituted-4-
thiazolidinones (XIII) '^ '^^
O H I HS.CH2.CONH2
R - C = 0
H N -
-H2O R-
S"
XIII
R = alkyl, aryl
a-Mercaptothiocarboxylic acids can also be used for the synthesis of 4-
thiazolidinones (XIV) by the reaction with different Schiff bases^°.
.0 HN-
R, R HS.CH^.COSH^
-"2S Ri "S' XIV
R = alkyl or aryl Ri = H or alkyl R2 = alkyl or aryl
A number of spiro-4-thiazolidinones (XV, XVII ) and 4-thiazanones
(XVI, XVII I ) have been prepared by the reaction of cyclic ketones with
a-mercaptoacet ic acid or P-mercaptopropionic acid in presence of ammonium
salts or substituted amines^'"^'*.
HS.CH2.COOH
-(CH2)
o
(NH4)2C03/ R-NH2
HS.(CH2)2.C00H
(NH4)2C03/ R-NH2
XV, XVI: R = H
XVII, XVIII: R = alkyl or aryl
1 7 0
Substituted and unsubstituted a/p-mercaptoalkanoic acids, their esters
react smoothly with the compounds containing activated nitrile groups in the
presence of an equivalent amount of alcoholate to give 4-thiazolidinones
(XIX)^^ or 4-thiazanones (XX)^^
R 4 R 3 C H - C E N -
HS-C-COOR I R2
.0 X I
®0R R4R3CH
Ri
R2
0
H S - C H - C H ; - COOR
®0R
N
RfRjHC^S'
.0 H N -
R4
RI
S" R2
XIX
0
H N ' "
XX
R = Alky],
R3 = H or aryl ,
Ri = H or alkyl, R2 = H or alky! or aryl
R4 = COOEt, CONH2, CN, Pyridyl, Indoyl or Ph
Monforte et al.^^ have synthesized 4-thiazolidinones by reacting
carbodiimides with a-mercaptopropanoic acid. The acid reacts with one of the
two carbodiimidic C=N groups to give 3-substi tuted-2-imino-5-methyl-4-
thiazolidinones (XXI).
c„, H S — C H - C O O H
R - N = C = N - R — -H2O R _ N ' ^s"
R = alkyl or aryl XXI
Substituted 2-imino-4-thiazolidinones (XXII) or 2-imino-4-thiazanones
(XXIII) are obtained in good yields by the reaction of symmetrical and
unsymmetrical thioureas with various substituted and unsubsti tuted a /p -
1 7 1
haloalkanoic acids, their esters, acid chlorides, amides and carbamates. The
reaction proceeds via the intermediate isothiourea which cyclise in the
presence of sodium acetate or pyridine^^''°^
R - N H - C - N H R ,
SH I
R ^ N H - C = N R ,
X - C - C O Y I R3
- H X
O N H
R , N ^s-' 'R2
XXII
X - C H - C H 2 - C O Y
o
- H X , - H Y R i N ^ S '
XXIII
R = alkyl, aryl or heterocycHc R2 = H or alkyl
R] = alkyi, aryl R3= H or alkyl
A number of fused thiazolidin-4-ones (XXIV) or fused thiazan-4-ones
(XXV) have been prepared by the reaction of cyclic thioureas with various
substituted a//?-haloalkalnoic acids and their derivatives^^"^' '®'*"'®'.
X-CH2-C0Y
HN NH
R = H or alky! X = Halo-Y = CI or OR
- H X , - H Y
ACmrf.
N N
X.CH2.CH2.COY
-HX, -HY
X X I V
x(CH2)n>
N N V
X X V
.0
2-Imino-4-oxo-5-thiazolidinoneacetic acid (XXVI) can be conveniently
prepared from dicarboxylic acids'"^. a-Bromosuccinic acid on treatment with
thioureas in the presence of sodium acetate in methanol gives 2-imino-4-oxo-
S-thiazoUdinoneacetic acid.
1 7 2
R N H - C - N H 2 R N = C - N H 2 + H 0 0 C - C - C H , C O O H -I ^
0 Br
- HBr
HN ^ "
XXVI
R = H, alkyl or aryl
Recently, Madhukar S. Chande et have synthesized 3-amino-2
alkyl/arylimino-5-carbethoxymethyl thiazolidin-4-one (XXVII) by the
reaction of diethylbromomalonate (DBM) with 4-arylsubstituted
thiosemicarbazide in ethanol in the presence of pyridine.
H2N
RNH-C-NHNH2+H5C200C"^~CH2COOC2H5 I \
XXVII
R = H or aryl
Thioureas add to the unsaturated carbon-carbon linkage of maleic,
fumaric, citraconic acids, their esters, imides and anhydrides probably by a
Michael type reaction and cyclisation to give a 2-imino-4-oxo-5-
thiazolidineacetic acid (XXVII I ) """"^
n HN
s R N H - C - N H 2 + H O O C - C H = C H ^ O O H ~ = Y 2 0
RN/ X g X ^CHjCOOH
R = H, alkyl
1 7 3
Dimethyl acetylenedicarboxylate (DMAD) reacts readily with
substituted thioureas, thiosemicarbazides and thiosemicarbazones to give 4-
thiazolidinones (XXIX)""
R N H - C - N H R + H3COOC - C = C -COOCH3
R=H, C H 3 , C g H j C H j or C ^ H j
C H C O O C H ,
Dihydro-l,3-thiazin-4-one derivatives (XXX) and (XXXII) are formed
when alkyl propiolates were added to thioureas and dithiocarbamic acids
respect ively"^ In the latter case, it is necessary to cyclize the initial products
(XXXI) with acetic anhydride.
o
R i - C = C — C O O E t -
R2NRCS.NHR2 - E t O H
NHt.CS2H
Ri - alkyl
NR2
Ri ^ S ' ^ N R z
XXX
[ - E t O H
Rr - S ^ S
XXXI
o N H
XXXII
When the thiosemicarbazone of aldehyde or ketone is allowed to react
with substituted or unsubstituted a-haloalkanoic acids, their esters, amides in
the presence of sodium ethoxide or sodium acetate, the product formed is
aldehyde or ketone derivative of 2-hydrazino-4-thiazoiidinone (XXXIII)"^'"^
or 4-thiazanone (XXXIV)"'".
R.NH,CS.NH.N=C .Ri
R2
SH I
R - N H - C = : N - N R2
R = H or aryl R2 = alkyl or aryl
X-CH-COY Ri
- H X , - H Y R2 \
X-CH,-CH,-COY
-HX, - H Y RI
R] = H, alkyl or aryl R3 = H, alkyl or aryl
1 7 4
R. .0 •N-
: N - N
XXXIII
O
HN '
R3
> XXXIV
A number of exonuclear thiazolidin-4-ones (XXXV) have been
prepared by the reaction of thiosemicarbazones of cyclic ketones with
substituted and unsubstituted a-haloalkanoic acids in the presence of sodium
acetate or sodiumethoxide"^"'^".
S R2 ^ II r - H X A A
N - N H - C — N H ~ R I + X - C H - C O Y — ^ ( C H J ) , , J =
Rlx O
N - N Rj
Ri=H,Aiyl, alkyl R2 = H, alkyl, aiyl XXXV
When a,p-unsaturated acyl isothiocynates were reacted with alkyl
amines or aromatic amnes, it gave the corresponding thioureas (XXXVI)
which on intramolecular cyclization under different conditions (BF3, NaOEt
etc.) yielded the l,3-thiazin-4-one^^'- '" (XXXVII)
o
NCS + ^NH nhcs.n;
XXXVI
.R2 -R3
N R7
R3 XXXVII
R = Alkyl, aryl, heterocyclic Ri = H, alkyl, aryl R2 = Alkyl, aryl R3 = H, alkyl, aryl
1 7 5
A.F.S. Ahmad'^'^ et al. have reported that the reaction of cinnamoyl
isothiocyanate with 4-pyridine carbohydrazide yielded N-cinnamoyl triazole
(XXXIX) presumably via the non-isolable thiosemicarbazide (XXXVIII ) .
Base induced cyclization of (XXXIX) resulted in the intramolecular
cycloaddition of thiolate to the cinnamoyl moiety affording triazolo-thiazin-
4-one (XL).
o o
^NCS N
'NH.NHj
HN - N H
P h -
NHo""
O N
(XXXVIII)
N N T N N
HS^^N'
o ,
(XL) (XXXIX)
A number of 2-pyridyl/aryl substituted 4-thiazolidinones (XLI) have
been synthesized by Tanabe et al" ' in 1995 following the method of surrey^^
by condensing a-mercaptoalkanoic acids with aldehydes and primary amines
or with corresponding Schif f s bases in refluxing benzene or toluene with
continuous removal of water being formed and found to exhibit highly potent
and selective anti-Platelet Activating Factor activity both in vitro and in vivo.
Me H Ri I
R — C H = N - M e HS.CH.COOH
0 Me XLI
R = 3-pyridyl, 4-CI.C6H4, 4-N02 C6H4, 4-MeO.C6H4
1 7 6
S.M. Osman and coworkers have prepared some long alkyl chain
substituted thiazoIidin-4-ones and thiazan-4-ones from modified fatty acids as
part of their programme of preparing fatty acid derivatives^^"^^ They^^ have
reported the synthesis of long alkyl chain substituted thiazolidin-4-ones
(XLII) and thiazan-4-ones (XLIII) by reacting 10-oxoundecanoic acid and
12-oxooctadecanoic acid with mercaptoacetic acid and 3-mercaptopropionic
acid in presence of ammonium carbonate and dry benzene.
HS.CH2.COOH
R V o
RI
(NH4)2C03 /benzene
R Ri X "
H N ^ ^ S
O
HS .(CH2)2 .C00H
XLII
R ^ R , H N ^ ^ S
(NH4)2C03 /benzene O'
XLIII R =CH3, CH3(CH2)8,CH3 (CH2),6
Ri = (CH2)g.COOCH3, (CH2)7.C00CH3
Similar reaction of 9,10-dioxooctadecanoic acid with mercaptoacetic
acid or 3-mercaptopropionic acid and ammonium carbonate gave two
isomeric thiazolidin-4-ones (XLIVa) and (XLIVb)^^'^"' or thiazan-4-ones
(XLVa) and (XLVb). 0
R i
HS .CH2 .COOH
O
Ri
O
(NH4)2C03 /benzsne
R - X H N ^ S
W o
XLIVa O
H S . ( C H 2 ) 2 . C 0 0 H
RI
(NH4)2C03 /benzene 0 ' XLVa XLVb
R = C H 3 ( C H 2 ) 7
R i = ( C H 2 ) 7 . C 0 0 C H 3
1 7 7
J. Mustafa and S.M. Osman^^ have reported the preparation of a mixture
of isomeric thiazan-4-ones (XLVIa) and (XLVIb) by reacting a,P-
unsaturated fatty acid, (£')-methyl-4-oxooctadec-2-enoate with 3-
mercaptopropionic acid and ammonium carbonate.
O
R
H
A r , H
R=CH3(CH2),3 RI = COOCH3
HS.(CH2)2.C00H
(NH4)2C03 ^enzene
XLVIb
They have also prepared a mixture of thiazolidinedione (XLVII) and a
thiazole (XLVIII) by heating a solution of (£)-methyl-4-oxooctadec-2-enoate
with thiourea, sodium acetate, and dilute hydrochloric acid under reflux
condition 85
o H
R
H
H2N.CS.NH2
AcONa, EtOH' dil. HCI, reflux
R=CH3(CH2)I3
RI = COOCH3
R.
O
O 7 /
R
+ S NH
O
XLVII
o 7 /
o
S NH
O
XLVIII
W.H. Ansari and co-workers^®"^^ have synthesised two novel
compounds 2-[3-carboxyethylthio-2-(phenyl)ethyl]-2-(4-chlorophenyl)tetra-
hydro-l,3-thiazin-4-one^^ (XLIX) and 2-[2-carboxymethylthio-2-(4-chloro-
1 7 8
phenyl)ethyl]-2-(4-chlorophenyl)thiazolidin-4-one^^''' ' ' (L) as two novel
compounds from 4,4'-dichlorochalcone using 3-mercaptopropionic acid/
mercaptoacetic acid in presence of ammonium carbonate. In 2002, they have
synthesised a new compound, 2-[2,2-bis(4-chlorophenyl)ethyl]-2-(4-Q n
chlorophenyl)thiazolidin-4-one (LI) from 4,4'-dichlorochalcone via 1,3,3-
tris(4-chlorophenyl)propan-l-one using mercaptoacetic acid in presence of
ammonium carbonate in dry benzene. Compounds (L) and (LI) were studied C 7K B B
for cyctotoxic activity ' against 60 cell lines of nine types of human
cancers. Noteworthy results were obtained in the case of melanoma, colon
and renal cancers where in (LI) the reduction in growth was 52, 80 and 91
respectively.
bll — /m
. i ^ J I .
2-Aryl'3-N-Long alkyl chain substituted-Thiazolidin-4-ones/Thiazan'4'One
179
DISCUSSION
S U M M A R Y
The work described in this chapter includes the reaction of
m-nitrobenzaldehyde-10-undecenohydrazone (24) with:
(i) Mercaptoacetic acid in dry benzene which furnished an adduct, m-nitro-
benzaldehyde-1 l-(carboxymethylthio)undecanohydrazone (25) and a
novel compound, 2-(3-nitrophenyl)-3-[ll-(carboxymethylthio)undecana-
mido]thiazolidin-4-one (26).
(ii) 2-Mercaptopropiomc acid in dry benzene which yielded two novel
compounds, 2-(3-nitrophenyl)-5-methyl-2-(10-undecenamido)thiazolidin-4-
one (27) and 2-(3-nitrophenyl)-5-(methyl)-3-[l l~{(l-carboxy)ethylthio}
undecanamido]thiazolidin-4-one (28).
(iii) 3-Mercaptopropionic acid in dry benzene which afforded an adduct,
m-nitrobenzaldehyde-11 -(2-carboxyethylthio)undecanohydrazone (29) and
a novel compound, 2-(3-nitrophenyl)-3-[ll-(2-carboxyethyl-thio)undecan-
amido]thiazan-4-one (30).
The hydrazone (24) as a substrate was prepared from 10-undecenoicacid
by treatment with hydrazine hydrate in the presence of MeOH and acid to give
10-undecenoacid hydrazide (23) which on condensation with m-nitro-
benzaldehyde yielded the hydrazone (24) as yellow globules in 87% yield. It was
found to exist in two stereoisomeric forms as synperiplanar (major) and
antiperiplanar (minor) as are evident from its stereochemical studies.
1 8 0
INTRODUCTION
A survey of literature revealed that in recent years attention has been
focussed on the synthesis of analogs of naturally occurring long alkyl chain
substituted heterocycles'^^""® and the interest in substituted thiazolidin-4-ones
and thiazan-4-ones in particular for medical application is increasing
strongly. The compound, (-) 2-(5-carboxypentyl)-4-thiazolidinone known as
actithiazic acid is an antibiotic which was isolated'^^®'*' from the culture broth
of a strain of streptomyces and found to show highly specific in vitro activity
against Mycobacterium tuberculosis. Another compound, 2-(4-chlorophenyl)-
3-methyl-4-thiazanone-l,l-dioxide, known by the generic name
chlormezanone, is an important pharmaceutical compound and is widely used
as a tranquilizer^^ which is effective in the treatment of anxiety and tension
states. It has also been claimed to be of beneficial in muscle spasm"' and
effective as anticoagulant^^.
CI
Q o,s ' N - M e
O
Actithiazic acid Chlormezanone
During the past few years, several 2-sbustituted thiazolidin-4-ones and
thiazan-4-ones have been synthesized and found to possess anticonvulsant^'*,
antidiarrhoeal^^, antihistaminic'*^''*'', antimicrobial^"'®'^^ oxygenase
inhibitory''^, calcium antagonist'*^ and K" channel inhibitory activity'*^
Recently, a number of 2-pyridyl substituted 4-thiazolidinones has been
synthesized'*' and found to exhibit highly potent and selective anti-Platelet
1 8 1
Activating Factor activity both in vitro and in vivo. Although a large number
of reports''^ are available for the aromatic and heterocyclic substituted
thiazolidin-4-ones and thiazan-4-ones, there is only sporadic reports on long
alky] chain substituted thiazolidin-4-ones and thiazan-4-ones^^'^^ Also a
number of long chain alkyl thioethers have been reported for their
b a c t e r i c i d a l f u n g i c i d a l ' ^ ^ \ tranquilizer'^^, anti-cholestermic'^^
analgesic'^® and antidepressant'^® activities.
As part of our programme in search of biologically active compounds
with sulphur and nitrogen containing heterocycles, we have synthesised 2-[2-
carboxymethylthio-2-(4-chlorophenyl)ethyl]thiazolidin-4-one as a novel
compound^^. Because 4-thiazolidinones substituted in the 2-position were
proven to be biologically very potent and selective"" and in anticipation that
by incorporating a long chain alkylthioether moiety to thiazolidin-4-one ring,
the biological activity may be enhanced due to lipophilization of the resulting
molecule, we have undertaken this problem. It consists of the synthesis of the
following four novel compounds, (i) 2-(3-nitrophenyl)-3-[l l-(carboxy-
methylthio)undecanamido]thiazolidin-4-one (26), (ii) 2-(3-nitrophenyl)-5-
(methyl)-3-(10-undecenamido)thiazolidin-4-one (27) and 2-(3-nitrophenyl)-5-
(methyl)-3-[l l-{(l-carboxy)ethylthio}undecanamido]thiazolidin-4-one (28),
(iii) 2-(3-nitrophenyl)-3-[l l-(2-carboxyethylthio)undecanamido]thiazan-4-
one (30) from m-nitrbenzaldehyde-lO-undecenohydrazone (24) using
mercaptoacetic acid in (i), 2-mercaptopropionic acid in (ii) and
3-mercaptopropionic acid in (iii) in dry benzene. An adduct,
m-nitrobenzaldehyde-ll-(carboxymethylthio)undecanohydrazone (25) in the
former and w-nitrobenzaldehyde-11-(2-carboxyethylthio)undecanohydrazone
(29) in the latter was also obtained in good yields.
1 8 2
The hydrazone (24) as a substrate has been prepared by the reaction of
10-undecenoacid hydrazide (23) with w-nitrobenzaldehyde and its
stereostructure discussed. Structural assignment, stereochemistry and
biological assay are discussed. Screening results of the compounds (24), (26),
(27), (28) and (30) are summarised for cytotoxic activity against 3-cell lines
of three types of human cancers: lung, breast, CNS and then 60 cell lines of
nine types of human cancers: leukaemia, lung, colon, CNS, melanoma,
ovarian, renal, prostate and breast. Screening results of the above compounds
are also summarised for antimicrobial activity against four bacteria,
Escherichia coli. Bacillus subtilis, Staphylococcus aureus, Pseudomonas
aeruginosa and one fungi Candida albicans (details in Chapter 6)
(24)
1 8 3
N02
H CH3
1 8 4
RESULTS AND DISCUSSION
The syntheses of compounds, (25)-(30) have been performed in two
steps (Scheme 1). The hydrazone FB (24) was first prepared following a
published procedure^ by refluxing a solution of 10-undecenoacid hydrazide
(23) in dry benzene with w-nitrobenzaldehyde (molar ratio, 1:1), as yellow
crystalline needles in 87% yield. The hydrazone FB (24) was then reacted
with (i) mercaptoacetic acid, (ii) 2-mercaptopropionic acid and (iii)
3-mercaptopropionic acid (molar ratio, 1:3) in dry benzene. The products on
column chromatography over silica gel using pet. ether-diethyl ether as eluent
yielded compounds FBX,B (25) and FBX,C (26) in (i); F B X 3 A (27) and
F B X 3 B (28) in (ii), and FBX^B (29) and FBX2C (30) in (iii). In the reaction
of (24) with 2-mercaptopropionic acid, it was observed (TLC examination)
that condensation competes addition, yielding (27) as the first product and
then (28). The increased nucleophilicity of the thio group in 2-mercapto-
propionic acid probably facilitates condensation.
1 8 5
( N CN -C
S I X' X . CN 3 1) <U ^ S u S JJ c ^ y
, rn -O
2 d « i o E
I U
I u O O X u u
u u lyi cA ly^ XXX
o t i Ci ^
^ ^ w w
c
u X u C/2
m-Nitrobenzaldehyde-lO-undecenohydrazone FB (24)
The outl ine of its synthesis is as fol lows
1 8 6
O O MeOH/H""
'OH NH2.NH2.H2O ^NH-NH2 (23)
dry benzene Reflux, 5 h
O
N07
s tructura l Elucidation of FB (24)
It was a yellow globule shaped crystalline solid, m.p. 128 °C. The
structure of FB has been fully confirmed by IR, DCI-MS. 'H-NMR, NOE,
'^C-NMR and HETCOR spectra. IR spectrum exhibited characteristic bands at
3100 (N-H), 2950, 2850 (C-H), 1660, 1640 (C=0) , 1580 (phenyl), 1550
(C=N), 1510 (NO2, asym. str) and 1330 (NO2, sym. str) cm"'. The DCI-MS
spectrum showed a [M+l]'^ signal as the base peak at m/z 332 conforming its
molecular weight 331 which corresponded with the molecular formula
[C18H25N3O3]. It is equal to the sum of the molecular weights of (24) (349)
and m-nitrobenzaldehyde (151) minus one molecule of water. This suggested
that the formation of a Schiff base has occurred by the condensation of
10-undecenoacid hydrazide (23) with m-nitrobenzaldehyde.
The 'H-NMR and '^C-NMR spectra (Fig. l a and l b ) dissolved in
acetone-<i^ showed signals as assigned (Table la) . The assignments of all
signals to specific H- and C-atoms have been performed on the basis of
typical 5-values, multiplicity, relative integrations, a HETCOR spectra and
also by comparing the spectra with reference spectra (SDBS) '^ ' of
1 8 7
a . Q
n
a rH WD
5 S O — TJ n
10 ^ ^ i n N u o o t n • • M o £ g
c ^ T> O o o a j a
•O Xt n c €*
ai "Sg
o> O I
0 — zz\ » «
K ? : g i it ^ K £
_ ° S Sr!. . a S c o o t - - ' • H - o c u w ^ o ^ c
a s ; lO - -
« 40 • 3
i D O l — m o r v i - ^ c n o It) m (O —
^ i n tM
188
e a
o (M
O
O ID
_ O 00
O o
r^ o — (\ j — rv PI — f ^ o
a f t i * M C y f u N o j r v ( M r « o i i M — —
1 O ru
o
o t D
o oa
o o ( M
t K
189
Pi O U H W a
/ ir>
I
(N
r--
C M
X
ro 00
c o
X X i X
(N in NO 1 w k. 1 < < < < UJ X X X i
0) C o O) u «
T t
ca ta 0 C5
•a
u 01 a M p: o u H w K TJ B «
1
u
ai
a
C 3 1—1
« H
S o. a
C O
m </-> ' vO • vP
^ ^ l O
rf m in — (N —' (N
v-i N® r- N° oo o o in (N ^ fS
ON R-o " ^ O . ^ in o r o t— Ti- j ;
m o ~ ro
in • (N i Os <N
ON oo o <N NO 00 o (N oo in NO 00 m ON ^ ON r-' ON d ND rr m (N (N
' — '
r- <N cc 1—' (N IT) NO 1 LH
< 1
Urn
< u. < c
Urn
< <
in r-
O in
R- <N X X
(N (N
N a
oo
(N
(N N X ttl a:
(N on tt
Os (N t^ r o ^ ~ T - Si o c ^ K -b b g
(N N I
On O r o o o ON
o o OO r- On — r-- —
r. On o o ON OS O S r ^
II II II II '—) •—1 )
S Q Cl vi
u •M X) •o •a T3 "O -o -o •a •o •o
T 3
I s bJO S 01 e « (N X (N
a <N m
E E a: K X X
s c. a. w to
l i 00 „ N? f- ON .-H in
m c- ^
Tt ^ r o ON • in r m NO ^ • 1 (N 00 00 ND Os (N — rM
O oo On OJ ' — '
<N in 00 00 00
c I
K (N oo
I
ON
o b CN w N V-. i-
K X < < m u-<
N O I k.
<
1 9 0
10-undecenoic acid, 10-undecenamide and w-nitrobenzaldehyde. The 'H-
NMR and '^C-NMR spectra dissolved in acetone-iig showed several double
signals, especially of NH, H-7 and H-2' in the 'H-NMR spectrum and of C-7,
C - r , C-2', C-3', C-2 and C-6 in the '^C-NMR spectrum which indicated that
this molecule is present in two different forms. The two forms were found to
be in the ratio ( -3 :1) as calculated from the integration values of the N-H and
H-2' signals in the 'H-NMR spectrum. This can be thought of about the
geometrical {E/Z) isomers of the C=N bond or stabile conformers around
single bond such as in the CO-NH group. Irradiation of the NH protons (Fig.
Ic) resulted in a NOE-enhancement of H-7 (both signals), showing that the
N-H proton and H-7 (in both forms) are very near to each other. This can only
be the case in ^-isomer. Further, in case of H-2' signals, a NOE enhancement
was observed only for the largest H-2' signal ( -75%) and absolutely no NOE
enhancement was seen for the small H-2' signal ( -25%) (Table la). This
showed that only in the major form, the H-2' protons are near to the NH-
proton. It was therefore, concluded that both forms of m-nitrobenzaldehyde-
10-undecenohydrazone (24) are due to a major synperiplanar CO-NH
conformation (~75%>) and a minor antiperiplanar CO-NH conformation
( -25%) which are in equilibrium with each other as presented in (Fig.l) . An
additional evidence for this conclusion is the fact that in the 'H-NMR
spectrum of this compound dissolved in DMSO-t/g (Table lb) , again two
forms are observed but in a (~ 4:6) ratio. This observation again is an
indication that the two forms are stabile conformers which are in equilibrium
with each other, an equilibrium which is dependent on the polarity of the
solvent.
1 9 1
en
g; •
C O - ; f e' . o «
m 5 I
ig f X u ^ ^ ^ ^ Z V
I s p> o
y , 8 £
U « ti
ti
•> "O u c « c o o
CD « V -M S - " S g s s ' C w U P'
• « I . C • • > — » — t
-i ^ a
UJ • «/ c
> i« « t K
1gi5 8 .5 JS I z 6 «/i 5
iil Q ^ tJ O Q c - s
L '
^ tl t «. o
1 9 2
Table l b : 'H-NMR spectral data of FB (24) in DMSO-t/g
H - n r 5 ( p p m ) Integ-ration
Mult i -plicity
J (Hz)
7 8.09, 8.50 ( -60%, 40%)
IH s
NH 11.41, 11.54 (60%,40%)
IH s
2' 2 . 22 , 2 .64 ( 4 0 % , 6 0 % )
2H t J r j ' 7.30, 7.41
3' 1.60 2H br p J~7.35
4'-8' 1.28 5x2H br s
9' 2.00 2H m
10' 5.76 IH tdd J,o..9' 6.77, J,O',hz10.26, Jio'.Hz 17.22,
HE 4.93 IH dd Jhe,io' 10.26, JHE, HZ 2.01
Hz 5.00 IH dd 1
J H , I O ' 17.22, Jhe, Hz 2.01
Ar-2 8.47 IH dd J - 2.03, 2.02
Ar-4 8.26 IH dd J= 8.23, 2.02
Ar-5 7.72 IH dd J= 8.23, 7.51
Ar-6 8.09 IH d J= 7.51
The assignments of the protonated carbons in (Table l a ) was further
confirmed by HETCOR spectra (Fig. Id). It was found that 5h signals are
correlated with 5c signals at 6h 8.17, 8.46 ( -75%, 25%; H-7) to 5c 140.79,
144.53 ( -75%, 25%; C-7); 6h2.74, 2.33 ( -75%, 25%; H-2') to 6c 33.09, 35.55
( -75%, 25%; C-2'); 6h 1.69 (H-3'), to 5c 25.41, 26.07 ( - 7 5 % , 25%; C-3'); 5h
1.31 (H-4'-8') to 6c 29.41-30.38 (C-4'-8'); 6h2.02 (H-9') to 6c 34.42 (C-9'); 6h
5.78 (H-10') to 5c 139.81 (C-10'), two signals at 5h 4.88 (He-1 1') and 5h 4.96
( H z - l l ' ) to 5 c 114.59 (C-IV). In aromatic region, the signals at 5 h 8.49
1 9 3
O T3
O ru
o U5
O CD
O o
o nj
E o a C\1 u _
o l O
s
y - nn
1 9 4
(H-Ar-2) correlated to 5c 121.80 (C-Ar-2); 6h 8.22 (H-Ar-4) to 5c 124.56
(C-Ar-4); 6h 7.71 (H-Ar-5) to 6c 130.98 (C-Ar-5) and 6h 8.12 (H-Ar-6) to
5c 133.30 (C-Ar-6) as shown in Table la.
On the basis of these spectral evidence, the structure of compound FB
formulated as m-nitrobenzaldehyde-lO-undecenohydrazone (24) was deduced
to be in its two forms, synperiplanar (major) and antiperiplanar (minor) as
represented in Fig. 1
H H 1 I 1 1
i' N
T NO2
1 9 5
m-Nitrobenzaldehyde-ll-(carboxymethylthio)undecanohydrazone FBX,B
(25) and 2-(3-nitrophenyl)-3-[ll-(carboxymethylthio)undecanamido]thia-
zolidin-4-one FBXjC (26) [Reaction of the hydrazone (24) with
mercaptoacetic acid]
A solution of the hydrazone (24) in dry benzene was refluxed with
mercaptoacetic acid (molar ratio, 1:3) for 16 h collecting the generated water
in an azeotropic water collector. The solvent was distilled off under reduced
pressure and the orange oily residue left was chromatographed over a silica
gel column using (pet.ether-diethylether, 1:1 v/v) as eluent which yielded the
two products, FBX,B (25) as crystalline yellow globules (EtOH) in 31.2%
yield and a yellow oily liquid FBXiC (26) in 54% yield respectively.
o N-
FB (24)
HS.CH2.COOH
"NO2 dry benzene, reflux, 16 h
HO'
0 O S N
FBXiB (25)
HO
+
O O N02 0 NH —N S
FBX,C(26)
Structure Elucidat ion of FBX^B (25)
It was a yellow globule shaped crystalline solid, m.p. 120 The
structure of FBXjB has been established by IR, DIC-MS, 'H-NMR and
'^C-NMR spectra. IR spectrum (KBr) showed characteristic bands at 3250
(NH), 3075 (OH), 2900, 2850 (C-H), 1725 (COOH), 1645 (CO), 1610
(phenyl), 1555 (C=N), 1520 (NO2, asym str), 1350 (NO2, sym str) and 1465
( S - C H 2 ) cm' ' . The DIC-MS spectrum showed a [M+1]^ peak at m/z 424
confirming its molecular weight 423 [C20H29N3O5S], which is equal to the
1 9 6
sum of the molecular weights of (24) (331) and mercaptoacetic acid (92)
suggesting that (25) is an adduct of (24) and mercaptoacetic acid. The peak
appeared at m/z 164 [M-C13H23O2S]'' was due to the cleavage of CO-NH
bond. The base peak at m/z 148 [M-Ci3H25N03S]"^ arised by the cleavage of
N-NH bond and other peaks at m/z 134 [M-Ci5H2oN303]^ and at m/z 118 [M-
C i 6 H 2 3 N 3 0 3 ] ^ formed by the cleavage of 8'-9' bond and 9'-10' bond of the long
alkyl chain respectively as shown in Chart 1.
O O
HO' N.
NH " CH m/z 424 [M+I]
NO2
0
HO"
0
W ^ N H 2
m/z 276 (5.2)
O
m/z 134 (58.8)
-CH3
- H
N. NH" ^ C H ' ^ ^N02
m/z 164(11.8)
m/z 118(13.0) "NO2
m/z 148 (100.0)
CHART 1
The signals in 'H-NMR and '^C-NMR spectra dissolved in DMSO-c?^
were assigned to individual H and C atoms (Table 2a) by comparing with the
spectra of (24) (Table la) . The 'H-NMR spectrum dissolved in acetone-ii?^
showed clearly that this compound was formed by the addition of
mercaptoacetic acid to terminal C=C double bond of compound (24) as the
signals for the terminal olefmic protons at 5 4.88 (Hg-l 1') and 5 4.96 (H^-l 1')
1 9 7
B a a
CO
(N f ^ ^ ^
~ o ro ^ Tf o t-- o • w ^ Tt ^ vo
, m
ON
od ON m »N
N? #N oo oo o o o
ON On VO o o 1—1 LY-) f—t r- CO NO
ON o od O o
NO ( N NO O od CO d ( N NJD T—< od I—1 M <r) FS CN CO RO
CNl (N M M
u C I
U
Csl (N
<N m m vo ^ VH ll kH < < < < < <
f 6 CT! S Q c
s ><
(m 0 «
C! -a
u u D.
0! ^
Z 1
u f) TS c c:
Pi
z
C3
a> !q « H
N (N
ro r-ro
»
(N CN
n
r o CO ON 00 oo NO
m —• CN Cv »N
ON m m ON o q o
r - oo od
l—5 II II H->
II
CN 00
ON l>
-3
S a X)
on a T 3 -o
T 3 •a
-a -o
•o -o
(ii) o
C «« I — I
(N (N (N X
(N p: (N (N
s a a
to (N ^ od sp
00 ^
m in ^ O O ^ ^ ^
„ S? CN sP ON ^ - ^
^ (N ^ Tt m 00 in r — ( o C--CS vn m (N o
CN CO od od od
c 1 X ON
I
(N
(N in NO 1 u 1 1 1 r—1 < < < <
1 9 8
in (24) have disappeared and a new pealc corresponding lo the methylene
protons at C- I" of the terminal thioether moiety appeared as a singlet at
5 3.22. The signals for H-10' appeared as a broad pentet nt 5 1.69 (J~7.28)
and for H-11' appeared as a triplet at 5 2.64 (J=7.32). This was further
confirmed by '^C-NMR spectrum which also showed the disappearance of the
signal corresponding to the olefmic carbons at 5114.59 (C-1 1') and 6 139.81
(C-10') in (24) and the appearance of the new signal corresponding to the
methylene carbon of the terminal thioether moiety at 5 33.20. It also showed
a signal for the carboxylic carbon (C-2") at 5 171.47. The 'H-NMR and
'^C-NMR spectra dissolved in DMSO-^/^/acetone-c/^ showed several double
signals indicating that this molecule is also present in two Ibrms. The signals
corresponding to C-1, C- l ' , C-2' in '^C-NMR spectrum and that of NH, H-7
and H-2' in the 'H-NMR spectrum dissolved in in DMSO-f^, the two forms
were found to be in the ratio (--6:4). From the NH, H-7 and 11-2' signals in the
'H-NMR spectrum in acetone-t/^, the two forms were found in the ratio of
( -3:1) as in (24) (Table 2b). This observation again is an indication that the
two forms are stabile conformcrs which are in equilibrium with each other as
shown in Fig. 2, an equilibrium which is dependent on Ihc polarity of the
solvent.
On the basis of the above discussion, the compound FBXiB was
characterized as m-nitrobenzaldehyde-1 l-(carboxymethylthio)undecano-
hydrazone (25) and its two forms deduced are shown in Fig. 2
1 9 9
H H
HO 2
9 anti-periplanar ^ NO2
Fig. 2
Table 2b: ^H-NMR spectral data of FBX,B (25) in acetone-j/e
H-nr 5(ppin) Integ-ration
Multi-plicity
J (Hz)
7 8.18, 8.48 ( -75%, 25%)
IH s
NH 10.29, 10.66 ( -75%, 25%)
IH s
T 2.31, 2.74 ( -25%, 75%)
2H t J2.,3' 7.30, 7.41
y 1.59 2H brp U1.2S
1.31 6x2H brs
10' 1.69 2H brp J=^7.28
i r 2.64 2H t J,,MO'7.32
1" 3.22 2H s
Ar-2 8.51 IH dd J= 1.98, 1.83
Ar-4 8.24 IH dd J=7 .93 , 1.98
Ar-5 7.73 IH dd J= 7.94, 7.93
Ar-6 8.14 IH dd J= 7.94, 1.98
2 0 0
Structure Elucidation of FBXi^C (26)
It was a yellow oily liquid. The structure of FBXjC has been
confirmed by IR, DCI-MS, 'H-NMR, '^C-NMR and COSY spectra. IR
spectrum gave characteristic peaks at 3250 (NH), 3050 (OH), 2900, 2850 (C-
H), 1725 (COOH), 1685 (CON) 1660 (CONH), 1610 (Phenyl), 1525 (NO2
asym. str) 1355 (NO2 sym. str) and 1430 ( S - C H 2 ) cm-'. The DCI-MS
spectrum (Fig. 3a) showed a [M+1]"^ peak at m/z 498 corresponding with the
molecular formula [C22H31N3O6S2] which is equal to the sum of the molecular
weights of compound (25) (423) plus mercaptoacetic acid (92) minus one
molecule of water. This suggested that the formation of thiazolidinone ring
has occurred by the cyclocondensation of (25) with mercaptoacetic acid. The
mode of fragmentation is presented in Chart 2. The peak at m/z 452 was due
to [M-COOH]"'. The other structure revealing fragment ion peak was
observed at m/z 424 [(M+1)-C0CH2S]^ arised by the cleavage of 1-2 and 3-4
bonds is the diagnostic peak of the thiazolidinone ring^^. Two a-cleavage
fragments to the thiazolidinone ring on the long alkyl chain were observed at
m/z 223 [M-C,3H24N03S]^ and m/z 276 [(M+1)-C9H7N203S]^ along with two
y9-cleavage fragments at m/z 240 [(M+l)-Ci3H22 03S]^ and m/z 258 [M-
C9H9N303S]^ The base peak was observed at m/z 210 [(M+l)-Ci3H24N203S]
arised by the cleavage of 2-3 and 3-4 bonds of the ring. The peaks at m/z 231
[M-C8H9N302S]^ and m/z 215 [M-Ci4H26N03S]^ were formed by the cleavage
of V-2' and 2'-3' bonds of the long alkyl chain. It also showed some common
fragment ion peaks to that of (25) at m/z 166, 148, 134 and m/z 118.
• I r • P P V I r
2 0 1
I
L ,
! I
Zti/i .15
;. i J ."• •• ' •• ' .i.) £ .t i lots-'.- t.jiijr-.i •/t-r'-/
I I yo 1 11 -n I i: SI
I i'i'j-ri—r~-r-rr 17'J . fei iCifcti j+i \
I i y y - V V V J t: w K1 -t tf . y
-T—I—I—— r":—:—r- V I !"l I TT-n—r-m-i - -r-1 -1-i v J O . - , > , 1 \ o 1 0 . ij
! ' I ' l l 1 [ r I I !.,T.,| ' I I I J:
I i -I I
I I
t HM -||V5 T; 11 I-
1 . 1 ' '1 y 1 - 1 . " ' i - ' O 'jf H k f
:M ;-iGiiP.= i'i sr=o:5i? BftCKC-i!=0;';iC'0 icic-'.= riJi; J r ? 11 i' f!
i I ! i . I , . ,Ji I ii 1,1 I Jl,Hl..llllllil,ll lllllllllM.lllillll illll,. 70- 63 1(30 116 ISO- IZ'-O 14(? ISO ItC' 176 ISC I' C- 260- 21S 226 2C'6
! I i 1 1 j j I
1 I
V M
!! !1, , ! . . ,1.. !i!lli.. , 1 . • .•11 .1 ^ i j j y i . K i i j . j . . , . . I l l - I J J 111 Ij . i - j - - , . J i i , ; -J , - J . . . . , - . 1
'fAii 250 ' tw- 27C 3!0 Z-jy 340 350 360' 370- 360. 330
N
;r 1 .1 .1 z : r F 6 X , c
"'J '-fUU -i'. O V^C Ii I.. ^ :: Z JJ,) - nil : - '^iiii.'ii
.1 1 Ij r n . 1 F i g . 3 a ^
! : I .
.. I,
-. r .
HO
, H a
o o
HO- NH m/z 276 (72 2)
0 "NH—N S
m/z 498 [M+1]
C 1 1 1 N
Q m/z 210 (100 0)
m/z 148(15 0)
CHART 2
N O z
„ o NHj-N S
NO2
m/z 240 (91 8)
2 0 2
m/z 1 18 (32 2)
c I I I s
Q
m/z 223 (27 2)
NO2
m/z 166 (40 4)
The signals in 'H-NMR and '^C-NMR spectra dissolved in acetone-^^^
(Fig. 3b and 3c) were assigned to individual H-and C-atoms (Table 3). The
assignments were made from their typical chemical shift values, coupling
constants, relative integrations and also by comparing with the spectra of
FBXiB (25) (Table 2a and 2b). The 'H-NMR spectra are strongly in agreement
with the formation of a thiazolidinone ring as the H-7 signal of (25) has shifted
from 5 8.18, 8.48 ( -75%, 25%) to higher field 6 6.04 (H-2 in FBXiC) due to
the disappearance of C=N double bond and the appearance of two
diastereotopic hydrogen atoms of thiazolidinone ring in the form of double
doublets by coupling with H-2 at 5 3.84 (Jjtrans.a 15.87, 1.68, H-5trans) and S
3.75 ( Jsc.s,215.87, 0.92, H-5cis). Also, the '^C-NMR spectrum (acetone-J^)
indicated the formation of a thiazolidinone ring as the C-7 signal of FBX ,A
has shifted from 5 139.99, 143.24 (-60%, 40%) to 6 62.23 (C-2 in FBX,B).
The assignment of signals as depicted in Table 3 and the coupling of the
2 0 3
G a C i
••KSf
1 J 5
XXXVII
-JS
2 0 4
e. Q • a
C C «
r fe
o w
o
o ID
> o • ^
Ka
'J ff I O ^ <
— ^ c c «J r i » o t " • i >. - o 5 w " U U IJ
c n V <3 a
cc O 3 w bi _ IS- Ui < o . — ^
o a «a c Al O O C
- « •J 3 a : I ^ ® «) O r-i - •
0> O- O ( ' r t c .. ' i;
» t< (O ( . L
- i o a a I S A . . a 3 3 rs< 4J a t D C O O l - - - * « < «
o . U U _J CI C
— If) O ro 01 u j r - a> o« o* n r j i n 8
^ ^ u ) <0 r o
O ffi
o o
O fO
WD
r u o CO t o ^ 01 ^
( W O l t O Cj r^ fXi O 1*1— J
O CVi
r - e o o ' o — J X i f o - ^ i o u s r - m o ' o — c v m « 5 » n 4 0 f -< v « 4 n i n i n i n i A m i n t n i n « n t o ( 0 U ] ( 0 ( O i o i o i o
o ( D
—I ft»
«-• 01 o ) «« C9 lO r^
a i 40 n t o rsi ^ o j
i I t ,
g U. (O
U) H W • I ® jl» * — <»» i O • K «-« O) O <J
Ol <0 ^ <n ID "T o cn t o
i
: V r M • T i
J o m
o o fu
o u j
R I
s a a
CO (N ON
(N rsi O r-CN ON
r--00 m cn
O m o m
00 1 cc m (N r--00 ON 00 ,—1 in CNj
<N ON TT ON od O ON ON d >0 m CN m
<N CN r-) ' — '
C I U U
(N (N l O (N ^ (N
^ (N CO Ti-I I I I
< < < <
1 l U
S o <L) u 03
X CO
o R «
" r t
u <u a wj
cc O U •o e «
Di
z I
u
s z a
M u
3 « H
CZ5 o U
ON X 1
I
X s; c ^
u 1
CN CM (N X X X
N ffi
00 iri (N
ON o <N X
l> 00 iri
(N ON
XI >
"o <U d
»
ro m
CN 2 « ::
00 m ON (N ^ CM O N
ON ON
ON O ON — — oo 11 II
O tT ^ ON oo t^
§ "E X i -o xl T3 -D -T3 -o -o -a
CO "O T3 T3 T3
W) o 01 -4- t
a c3 (N
rN (N vo (N (N
E a a
to q
m • r-; 00 cn rn
-a <u KJ ID CI, a
O O O ON ON
m (N (N cn
Tt <N
(N ( (N 00 00
IT)
o- r-
a I
K (N
ON I o ^
(N
(N lO ^ I I I I l - l t H i H < < < <
2 0 6
protons were further confirmed by COSY spectra (Fig. 3d). The broad signal at
5 6.04 (H-2) showed a weak cross peak with two double doublets at 5 3.75
(J=15.87, 0.92, H-5c,s) and at 5 3.84 (J-15.87, 1.68, H-5trans) indicating the
coupling of H-2 proton with both the ring methylene protons at C-5. In contrast
to FB (24) and FBXjB (25), only one form of FBXjC (26) appeared in the
spectra.
Based on the above discussion, compound F B X , C was characterized as
2-(3-Nitrophenyl)-3-[l l-(carboxymethylthio)undecanamido]thiazolidin-4-one.
(26) and is represented as
H 2- . 1 , H , ...
F B X i C ( 2 6 ) ° H H
2-(3-Nitrophenyl)-5-(methyl)-3-(10-undecenamido)thiazolidin-4-one FBX3A
(27) and 2-(3-nitrophenyl)-5-(methyl)-3-[ll-{(l-carboxy)ethylthio}undecan-
amido]thiazolidin-4-one FBX3B (28) [Reaction of the hydrazone (24) with
2-mercaptopropionic acid]
A solution of FB (24) in dry benzene was refluxed with
2-mercaptopropionic acid (molar ratio, 1:3) in dry benzene for 22 h after
which TLC examination revealed the presence of two spots labelled as
FBX3A (27) (upper) and FBX3B (28) (lower). The products on usual work up
and column chromatography yielded two liquid compounds, FBX3A (42.3%)
as colourless oily liquid and FBX3B (34.5%) as a pale yel low oily liquid. The
reaction sequence is as follows:
0 7
V
• •
-
1
B
U 1
—1 I 1 T -—1 I 1 T - 1 1 I I 1 1 1 1 1 ^ t — i — 1 — 1 —
6 Q
iT) a
•a (T)
e a ru a a. ~
V m r (XI 01 o
a S :
« Q <
i a .
T
M t n Pt N (
t o c O t J ^ CNJ O
. If a — a
, » ^ O c «• o o «
" o in a ^ ^ " - - " - .
; 5 S 21 S X i I
^ I u 2 UJ <t «l o . .
as tt
(iJ ID ^ -•
a — rg Q. - U
£«» c ^ « « •
Q C
[ V) u . i n u . c o
o N
NH'' '^CH'
FB (24)
CH3 HS.CH.COOH
"NO2 ''O' benzene, reflux, 22 h
O H \ O x
NH—N' "S
M FBXjA (27) CH3
Structure Elucidation of FBX^A (27)
It was a colourless oily liquid. The structure of FBX3A has been fully
established by DCI-MS, 'H-NMR, and '^C-NMR spectra. The DCI-MS
spectrum (NH3 as a reagent gas) (Fig. 4a) showed [M+1]'^ peak at m/z 420
and a less intense [M+18]"^ peak at m/z 437, confirming its molecular weight
419 [C21H29N304S], which is equal to the sum of the molecular weights of
compound (24) (331) and 2-mercaptopropionic acid (106) minus one
molecule of water. This indicated that the thiazolidinone ring has been
formed by the cyclocondensation of (24) with 2-mercaptopropionic acid but
no addition of 2-mercaptopropionic acid to the terminal C=C double bond of
the 10-undecenoyl side chain has occurred. The characteristic structure
revealing fragment ion peak was observed at m/z 332 [(M+1)-C0CH(CH3)-
S]" arised by the cleavage of 1-2 and 3-4 bonds of the thiazolidinone ring.
The a-cleavage fragment ion peaks to the ring were observed at m/z 237
[(M+l)-CnH2oNO]^ and at m/z 184 [M^-C,oH9N303S]^ the /^-cleavage
fragment ion peaks were observed at m/z 254 [(M+l)-CiiHi90]"^ and at m/z
167 [ ( M + 1 ) - C i o H i ] N 3 0 3 S ] " ^ along with some lower mass ion peaks as shown
in Chart 3,
iij -jDMr. ,:ii"ii:) jrniir^ r Tiriu r o f r t/cor . r.rrL.fu nuir . rwf i c,-,-> Vw.A
209
, i v i f i - t - 51
' ; '-.ON - n iooe .. J — . - - •• . - • • 1 ^ .0 i ' , • j
1 luO%- ir20?2 A i I t s / \ 1 / \ 1 : ioo^-1 t
-j r- I -1-i i 4 C 0 0
1 ' ' ' ' - ' 1 1 ' ' • H i
-, - ' jTV . 0
' . ' s j 1 i 0 Oi "i -1 j
1 Ci'3 1 00 I ' 1 I' 1 ' ' ! • ! ' Hi
• / ^^
irCc.-iCi Ml - J \ J . ) i
—,... , , • ,• T—T—r—t-i—T -1 1 1 1 1 ' 1 1 1 1 I ' 1 1 1 I • I 1 1 1 1 I I 1 J J -i
1 1 - ' • ' \ •
(
1 * VI V- 'JJ L ^ -- ' ^ 1 ' ^ X 1
^ •• • • .
JLHH 'LU -'''. 2CRH 21 '"liLf iT'sxas'
iiori/r.n^ct ' t OiCi 0-5-1'j.'.
11 : II- I I . Ill I I.ilil.lii ilili il.l I III I iiii'ii'
•I il II ililli II 1.1 I.,
II II. .Ill r 1 '• --^i' • - •"V"1 1 1 1 1 ; ; i .i- •••••• . M KM -jy lyy 1 1 M 1 rjM 1 4y i .y 1 1/-w 1 KM 1 wy
'tft d'
lilL k /
1 1 '1 !•••••••••! r"' !"••'••'!••• 'i 1 1"''"; I r" •• f" " •• I r" "" i cvy cvy :'yy -I'ly f.-y .•" y ••y'' '•'y " ly ' r y •'' y
GUYiQ SCAN 2i SIGttf'i-? RT=Q'3C r(/iri<'r-ri=nY^ nn onTi-^i,
M no 1 0 c; ,1 n 1 1 nn Oil
Fig. 4a
210
NOj
NH — N S
m/z420 (M+lf
NHj m/z 183 (3 6)
NHj ^ I-
„ d NO2 NH2-N^S
m/z 184(11 6) m/z 167(60 5) N H '
m/z 332 (8 0)
NH2-N "S
m/z 254 (82 1)
K •CH3
m/z 130 (16 5)
mJz 149 (26 9) +H
Q -co
m/z 209 (3 3)-<-
I I I N m/z 148 (4 1)
NOT O r
CHj
m/z 237 (100 0)
^ ^ NO,
m/z 166 (8 7)
'+H-
m/z 167 (60 5)
CHART 3
All the signals in the 'H-and '^C-NMR spectra dissolved in acetone-fig
(Fig. 4b and 4c) have been assigned to specific H-and C-atoms (Table 4).
The 'H-NMR spectrum is in strong agreement with the formation of a
thaizolidin-4-one ring as the H-7 signal of (24) has shifted from 6 8.17, 8.46
( -75%, 25%) to 5 6.01-6.04 (position 2 in F B X 3 A ) due to the disappearance
of C=N double bond and formation of ring. Also the NH signal has shifted
from 5 10.41, 10.76 ( -75%, 25%) to 5 9.28 due to the ring formation. The
signal for the thaizolidin-4-one ring protons at C-5 appeared at 5 4.04 (IH,
qd, J -6 .86 , 0.91, H-5cis) and 5 4.11 ( IH, qd, J=7.17, 1.53, H-5uans)- Also, in
'^C-NMR spectrum, the C-7 signal of (24) has shifted f rom 8 140.79, 144.53
( -75%, 25%) to 5 61.16. Contrary to FBXjC (26), the FBX3A (27) 'H-NMR
spectrum showed signals for two terminal olefmic protons (=CH2) at 5 4.90
( IH, dd, J=10.23, 2.13 for HE-11') and 5 4.98 ( IH , dd, J=I7.09, 2.13 for
211
J e a.
1 " 3
fci
5
212
6 a
3 3
u
a c a — a S
« i - " ! : o o ^ c «
*-> W t » w
5 t» Cr-OWMO 5 r I« f ? i? r » a 6 o «fi o oo a
H « — t • «<«
_ • • • • • • • • « . . , , , , , . . .
^ i i i y i i i i i i l i i i i i i y i i i i i i i i i i i H
Q V .
213
I o c o ^ a u c:
fS < X M b
0
T5
u u C, W3 PS
z 1 U
-a c c: a S Z
I
S « H
c I U
E ON cn
Ci. nj d o. nj « m X) XI m xi x> CJ O m •o m •o 00 m ON m (N m to NO 00 (N NO O (N O 00 4 oo NO in oo in 00 o in to r—< oi in 00 Tf VO oi ON (N ON <N ON ro ^ in r-H ON ON ON d in ON m H «N (N m m t—1 rn m r—1 (N m (N <N •—1 •—1 1 •—1 '—1 >—1 '—1 1
C/D O
C c3 l-H
on "o
on C Ki
N
0 O 1 I (N m u-1 m lo c l ro
00 J . b ^ ON --
in a m c3 0 i: ' <N r<-i in 1 I I 1 I I I V-l kH l-H VM VH < < < < < < <
ON O
CO
ON o
m
vo 00 r--
00
OS D X u
X u (N
3 .Si S a
' B OX) o <u fl «
U
E
a to
e I W
X u X u
>—i m m rn <N (N
N (N N d X w X
lil OJ w X X 1—) X 1—) b
>—i ri (N oC o OO ON ON m ON
00 (N CNT d L >
—< R- ' (N R - ^ ON" ON" ON m m o NO CN
b b ON O 00
o 00
ON
I > 11 b w X "N X I I I I I I II i—> > 1—5 1—1 1—> 1 — >
-a O CO
X) ^ ^ Id -d t3 T3 -a T3 -o -a -a
FFI K FFI K FFI ^ ^ ^ ^ rn ffi ffi ffi ffi X ffi ffi rl r-c (N (N VO CN
--H Tt Tt O O O —I ON ^ IT) vo 00 ^ O (N —' <N M CM 00
VO NO ^ ON (N
O 00 NO m m ON ON rn r- ON 4 00 00
00 "o
C/2 d cfl C/5 C VI a
M rt on rt ffi E O O i! u o ^ _ ^ „ „ „ ( N C N i n u r i i r i i n Z r ^ r n ^ l - ^ E K <1
ON (N M NO W N vL >-i
E K < < < <
T3 U 00 a X o
<u
<u
cd a o on <D a on (U a cn (U ^
c <u S c
't/3 C/3 <
214
Hz-11') and the signal for olefinic methine proton (=CH-) at C-10' appeared
at 5 5.81 ( IH, tdd, J = 6.72, 10.23, 17.09 H-10') indicating the presence of a
C=C terminal double bond. This strongly suggested that the addition of
2-mercaptopropionic acid to the terminal double bond has not occurred in this
case. Also, in '^C-NMR spectrum, the signals of the o lefmic carbons appeared
at 5c 139.88 (C-10') and 114.63 (C-11') further confirmed that addition has
not occured. It is probably due to the increased nucleophilicity of the thio
group in 2-mercaptopropionic acid which facilitated condensation rather than
addition. Furher in 'H- and '^C-NMR spectra (Fig. 4a and 4b, Table 4), the
signals corresponding to thiazolidinone ring protons/carbons at C-2, C-5, C-
5-CH3 indicated that this compound contained a mixture of isomers with cis
and trans standing methyl and 3-nitrophenyl groups on the thaizolidin-4-one
ring. However, it is not clear which isomer is the major and which one, the
minor.
Based on the above spectral evidence, compound F B X 3 A was
characterized as 2-(3-Nitrophenyl)-5-(methyl)-3-(10-undecenamido)thiazo-
lidin-4-one and is represented as (27)
0 FBX3A (27)
215
Structure Elucidation of FBXjB (28)
It was a pale yellow oily liquid. The structure of F B X 3 B has been fully
established by DCI-MS, 'H-NMR, and '^C-NMR spectra. The DCI-MS
spectrum (Fig. 5a) showed a set of intense [M+1]"^ and a less intense [M+18]"^
peaks at m/z 526 and m/z 543 confirming the molecular weight 525
[C24H35N3O6S2] which is equal to the sum of the molecular weights of
compound F B X 3 A (419) and 2-mercaptopropionic acid (106). This suggested
that compound F B X 3 B was formed by the addition of 2-mercaptopropionic
acid to the terminal C=C double bond of F B X 3 A . The mode of fragmentation
is presented in Chart 4. The peak at m/z 480 [M-COOH]"^ confirmed the
presence of terminal thioether moiety in the compound. The peak at m/z 419
was due to the loss of [M-HSCH(CH3)C00H]^. The peaks observed at m/z
290 [(M+O-CioHgNjOsSJ^and at m/z 237 (base peak) [(M+1)-C,4H28N03S]^
were due to a-cleavage to the ring. The peaks at m/z 271 [M-CioHnN303S]^
and at m/z 254 [(M+l)-Ci4H25 03S]"' due to the y?-cleavage to the ring. The
characteristic peak for thiazolidinone ring was obsereved at m/z 436
[M-C0CH(CH3)S]^ as shown in Chart 4.
All the signals in the 'H-NMR and '^C-NMR spectra dissolved in
acetone-fig (Fig. 5b and 5c) could be easily assigned to specific H- and C-
atoms (Table 5) by comparison with the spectra of F B X 3 A (27) (Table 4).
All the signals in both the spectra were found compatible with that of F B X 3 A
(27) except H2C=CH- signals which didn' t appear here. In 'H-NMR spectrum,
the signals at 6 4.90 (IH, dd, J=10.23, 2.13, HE - IT) and 6 4.98 ( IH, dd,
J=17.09, 2.13, H z - l l ' ) of F B X 3 A disappeared and in place a new peak
corresponding to H-1" of the terminal thioether moiety appeared as a quartet
at 5 3.42 (J=7.02). This strongly supported that compound F B X 3 B has been
216
ii.. • • " [ • • • • I ' " r - r ' - I " ' . , . . . . . , , . , . . , , • 1 " • • ! r " ' ' ••] r — r
• 4(3 25C i'60 270 260 300 3!0 320 330 3'?0 ?50 360 3?P 390
... .. . i., 1. . . Irll. . 1. I -t—I r-~| ,—, r -i-T 1 p-H 1 1 (—I r-^ ; r—1 1 , , ,—t—, 1 r"-1 1 1— 400 410 420 430 440 453 460 4?0 4S? 4?0 500 510 525 530 540 550
'"BKSB SCRH 35 S!6!1P.= 18 RT^l:? SP.CKGD=S :i?''| ionv= t;cijo;-o rTjLF ."f3x35" - • • - . . - . - w ^ . . .
-r-r ; 1 . . , i ! . ; ,1.(11. ,i..ii. ii,i iiii.i, ii.i>i.i(.i.i.ii.i,iiiii.ii<(i(iiiiU
l " " l • I I . . . .1 • j . . . . [ • I iiiiiiil...... <(4((iiii.. I. i..t.tiiiiui. (.(., . III., tiui ,((li....(..i t. l-'T' -l"-;' h . , . . - I . , . . , , , . . , . . , . . . . , . . . . 1 . . • . • . . . . , . . . . , . . . . . . . . 1 ' - | — I " -1
80 ?0 100 110 120 130 140 150 160 170 150 190 200 210 220 230 rr-i
! 1 ; H I . ! : I. I II 1 ,1)!, )!i. •I""!'"''-I •"•"• ,1., t
T"-'—I" iiiii. I,
'-"I" • p i J . j 1 t • i ' V ' . 1 1 1 240 250 260 270 260 2?0 30-5 310 320 33 ^ 349 350 360
- r T I.. I. li, Mil "T ' : ^ I i ' r""""—I——'—;—'—i——•—r 4(30 4ig <135 iidQ 45g d^a <igg jqo cng Rig c^g q^g pao
5'E'X3l! SCAN C'TC-S .7 r(Ari<'r;n=nY< nn <nny= TITLE: FBXIB"
75 QO 16, c; ISO 00 ^ s * w . A . 245 0 0 24 1 524 n n V V — w/ . A g7 ,00 17 2 184 00 17 253 0 0 17 t . 525 n n
W V 22 ij i l l ; 0 0 17 5 1 ? ? 00 20 0 : 254 0 0 32 A 526 u n w w
A 130. nn 20 k 7>ri7 nn V w 37 2 : 0 C' 33 527 0 0 31 u 138. 00 2B ? H s 00 15 ' g . 30B fin i ? 543 CO 31 7 147, .00 22 7 .•t^-xi 00 100 0 41?, 0 0 i 7 2
CO
A ¥ rw
37APT t: i Fwt) = 45 TnTAi_ " 620Oi
76 0 1022764 237.0 . . . . . . . . . ' "^iii?!-!) 254.0 '"5806 2?Q.O 432?I-524 0 inc;fi.q.q
Fig. 5a
?17
1 ,
I/) bJD
218
6 CL CL
i
n r j o
O tri
c N com v o o : o — o i
u o e u j >-i> • - - I C --O — o CO « A « JCfv. e> w^^r-o •«
UlCU u i « Ol t . - f s » a .
•f a : : 3 > — <t — w t s w w o > c « i u j V- u Z 3 U — -r 3 OL < o « 0. Ol. < 31 ajiua. o 3 c-
« a . o o v » > o o c a S
E c a e
— « e c —
o
ei)
1
H o r«. e» . > « n M « ro
« ) n -M rs. n «
- • ^^ f^ a0 n ^ t AM ^^ ^ ^^ « . rf , fc ® ^^ ^^ ^ i o l e
< fs. fx.
I (M
O r* r ) V I •aimtowtciavvitor-^mwto
219
formed by the addition of 2-mercaptopropionic acid to the terminal C=C
double bond of F B X 3 A .
HO Y >- 0 NH2 CH3
m/z 289 (9 2)
+H
m/z 290 (33 1)
m/z 147 (22 7)
m/z 148 (10 3) m/z 237 (100 0)
o K . CH3
m/z 130(20 5)
s NO,
m/z 166(15 5)
CHART 4
This was further confirmed by '^C-NMR spectrum which also showed the
disappearance of the signals corresponding to the terminal C=C double bond
at 6 114.63 ( C - i r ) and 6 139.88 (C-10') of F B X 3 A and the appearance of the
new signals corresponding to the terminal thioether moiety at 6 41.35 (C-1"),
174.33 (COOH) and 5 17.78 ( r ' - C H j ) indicating that the compound F B X 3 B
contains both thiazolidinone and terminal thioether moieties. The signals of
H-2, H-5, 5-CH3 in 'H-NMR spectrum and C-2, C-5, 5-CH3 in '^C-NMR
spectrum (Table 5) again indicated that this compound also contains mixture
of isomers with cis and trans standing methyl and 3-nitrophenyl group on the
thiazolidinone ring as in F B X 3 A .
220
VC I
Oi c o 41 O «
00 rs CO X ca <*-
o a cs TS n « c.
z u
13 s cs
Z I K
Qi
rt H
S o.
CO
c I
U
N X
.JL = .ii § a
§ G cs I—I u
a m XI O O OO M CO ^ '—I ^ ^ m 00
1—I r- ON ON o ^ CO m < fS
(N fN) OO o
o o cn
(N Tf to ON
CO •a T3 o lo <N NO 1—< OO m CO m OO m OO O to ON CO (N CO ^ to
r - r - Tf- fS CM CO CO CO 1—H
C/2 O
C/3 'o
C/5 c
00 C 00 cd C C<1
X 00
"o cd
K b u r - H CN) U 1—N 1 ^ 1 1 - V-c 1 1 m ^ CN ^ 1—1 ( ^ CN < < <
I 1-4
NO I I
ro IT)
ON O
NO r—< t> OO 00
CO to NO NO
ON m I u ly-i 1 w-i 1
I lO
o u-1 I I u
lO
"O Crt o o VI c ra u crt c. CO X I O (N tN
O lAt u o (N 11 1—) >—1 1—1 1—> 1—1
<N O (N O -o (U > 1 1 o s X c/) «
rn K a: « O u 1—1
CO ON fO ON OO ON ON <N
o i rs rv
00 On ON CO o . O O CJV
II od II
00 II
t--II II
1—1 II
>—1 II
"-1 11
1—1
Td -a T3 -o o cr T3 T3 00
Ui 1- T3 cr T3
K ffi ffi K K ffi ffi r^ r^ ^
X
CN (N vo cs cs m K ffi ^ m —I
-a •a -a
•o (U M c C3 CJ VM a>
(U c o
o IZI VH (U a c/l (U s Kl M (U >
0 c 01 £ £ Ofl M tn
s a. a
CO
o o NO NO
ON 00 O CN NO <N 00 NO CO TO LO NO (N >—1 >O (N M NO CO CO CN R-- ON
F—( ON CN 1—1 CNI CO 00 0C5
k. c I
"o
to c fS
I -o ^
t/3 c u u
(N (N lO >/-) u-i X z
ON u 1 CN 1 1 NO t . . J o ^ : CN CO —' ^ ^ < S-H < < <
2 21
On the basis of the above discussion, the deduced structure of F B X 3 B
as 2-(3-nitrophenyl)-5(methyl)-3-[l l-{(l-carboxy)ethylthio}undecanamido]
thiazolidin-4-one (28) is represented as:
H CH3
FBX3B (28)
m-Nitrobenzaldehyde-ll-(2-carboxyethylthio)undecanohydrazone FBXjB
(29) and 2-(3-nitrophenyl)-3-lll-(2-carboxyethylthio)undecanamidoj-
thiazan-4-one FBX2C (30) [Reaction of the hydrazone (24) with
3-mercaptopropionic acid]
A solution of the hydrazone FB (24) in dry benzene was refluxed with
3-mercaptopropionic acid (molar ratio, 1:3) for 26 h, monitoring the reaction
by TLC which showed it to be a mixture of two components, labelled as
FBX2B (29) (major, upper) and FBXjC (30) (minor, lower). The products on
purification By column chromatography (silica gel, pet. ether-diethyl ether.
1:1 v/v) first yielded a yellow solid which on crystallisation (benzene-
acetone) furnished FBXjB (58.0%) as white crystalline globules and then a
yellow oily liquid of FBX2C in (26.0%) yield.
HS . (CH2)2 .C00H 0 0
NO2 dry benzene, ^ H i ^ n H ' reflux, 26 h
F B X j B (29)
NO2
0 O
H O H ^ - W ^ N H — N
0 FBX2C (30)
N O ,
222
Structure Elucidation of FBX7B (29)
It was a white globule shaped crystalline solid, m.p. 98 °C. The
structure of F B X j B has been fully established by IR, DCI-MS, 'H-NMR and
'^C-NMR spectra. IR spectrum (KBr) showed characteristic peaks at 3175
(N-H), 3040 (OH), 2900, 2800 (C-H), 1730 (COOH), 1645 (CONH), 1605
(Phenyl), 1555 (C=N), 1520 (NO2, asym. str.), 1480 (S-CH2), and 1340
(NO2, sym. str.). The DCI-MS spectrum strongly supported the structure
which showed a [M+1]"^ peak at m/z 438 confirming its molecular weight 437
[C21H31N3O5S]. This is equal to the sum of the molecular weights of (24)
(331) and 3-mercaptopropionic acid (106). This indicated that FBX2B is an
adduct of (24) and 3-mercaptopropionic acid. The base peak at m/z 134
[(M+1)-Ci6H23N303]^ and another fragment ion peak at m/z 304
[M-C5H902S]^ were formed by the cleavage of 9'-10' bond of the long alkyl
chain. The peaks at m/z 218 [M-Ci2Hi302S]^ and at m/z 186 [M-C,2H,2N303]"
were obtained by the cleavage of 3'-4' and 5'-6' bonds. It also showed some
fragment ion peaks common to (25) at m/z 164, 166, 148, 118 and 119 as
shown in Chart 5.
o o
m/z 438 [M+
O O
HO'
m/z 134 (23.6) -CH3
m/z 118(37.7)
Q
m/z 218 (76.1)
NH ^ C H C" ^ NO2 I I I N m/z 148
m/z 164(11.8)
CHART 5
2 21
All the signals in the 'H and '^C-NMR spectra have been assigned to
individual H-and C-atoms (Tables 6a and 6b) by comparison with the NMR
spectra of a previously established compound FB (24) (Tables l a and lb ) and
FBX,B (25) (Tables 2a and 2b). The 'H-NMR spectrum dissolved in acetone-
di clearly showed that this compound was formed by the addition of 3-
mercaptopropionic acid to terminal C=C double bond of compound (24) as
the olefmic proton signals of HE- l l ' - and Hz-11' of (24) at 6 4.88 ( IH, dd,
J=10.22, 2.14, HE-11') and 5 4.96 ( IH, dd, J=17.09, 2.14, Hz-11') have
disappeared and in place two additional triplets at 5 2.74 (J=6.87, H-1 ) and 5
2.57 (J=6.87, H-2 ) corresponding to two methylene protons of the thioether
moiety appeared. The triplet at 5 2.55 (J=7.33) was attributed to the
methylene proton at C-11'. Also, in '^C-NMR spectrum (Table 6a), C-11'
signal of (24) has shifted from 5 114.59 to 6 31.00 and an additional peak was
observed at 5 178.50 for the carboxylic carbon at C-3". Here again, the 'H-
NMR and '^C-NMR spectra showed several double signals, the signals
especially of C-7, C-l", C-2' in '^C-NMR spectrum and of NH, H-7 and H-2' in
'H-NMR spectrum. This indicated that FBX2B is also present in two different
forms as synperiplaner and antiperiplanar conformers of CONH bond in a
55/45 ratio in DMS0-g?6 (Table 6a) and 85/15 ratio in acetone- d^ (Table 6b).
Thus, the two forms are the stabile conformers in equilibrium with each other
as in (24) and (25), and is dependent on the polarity of the solvent.
224
s a c. to
CN li (N ^ WO ^ r- " ^ ^ o
UO !>• UO .IT) —' in Tj-c ^ - . rn _
o 00 06
ON (T)
CN I. N 1 0 0 00 ON 00 as m in
0 0 m m m r — 1 <n — I M3 01 >0 06 r- m in 0 00 d 00 cn d (N vo 06 . — 1 m (N Tt- CM m m
(N (N ro (N m H
1 o
Q c
oT fS ea X oa ta 0 « C! -a 13 u u <u
oi S z 1 u
•a a a
Z 1 X
£1 3 H
e U
<N CO
o
'-H — (N m
—' (N m >0 I I I I I I Li Vh i-i < < < < < <
N K
o
m m ro O »
. — I 00 . — 1
00 0 00 0 rsi (N
r-- r\ ON m i n 00 b ON 0 0 00 — r — 1 06 00
11 rNi I I I I I I I I <—> > — 5 )
•S .t; "a S d
D, CO Qi Li Li J2 Li X) TJ TJ T3 -O -O Td
M) 0 -w <<_> C iss
CN (N X (N p: <N E (N <N Dh K K K
s & c.
CO
sO 10 ^ ^
<N ^ cn ^
00 „ X© (N s p
^ m >n pr, in 00 ' I 7 7 fN ^ 06 w ^ w (N w
ON >n ON m (N 00 <N m NO (N 0
(N (N CN 00 00 00
C I K
(N a\ I o (N
(N tn ^ I I I I iH Vi Li < < < <
225
Table 6b: 'H-NMR spectral data of FBXjB (29) in acetone-rf<5
H - n r 5 (ppm) Integ-ration
Multi-plicity
J (Hz)
7 8 .18 , 8 .48 I H s ( - 8 5 % , 15%)
NH 10.30,10.66 I H s ( - 8 5 % , 15%)
2' 2 .31,2.73 2H t J2.3. 7.31, 7.48 ( - 8 5 % , 15%)
3' 1.56 2H br p J«7 .28
4'-9' 1.31 6x2H br s
10' 1.69 2H br p J^7 .25
i r 2.55 2H t JnMO'7.33
1" 2.74 2H t Jr . 2" 6 .87
2" 2.57 2H t J2M" 6.87
C O O H 12.20 IH br s
Ar-2 8.51 IH dd J= 1.99, 1.82
Ar-4 8.24 IH dd J= 8.08, 1.98
Ar-5 7.73 IH dd J= 8.08, 7.94
Ar-6 8.14 IH dd J= 7.94, 1.86
226
On the basis of the above spectral evidence, compound FBX2B which
was characterized as m-nitrobenzaldehyde-1 l-(2-carboxyethylthio)undecano
hydrazone (29) is represented as in Fig. 4
H H
synperiplanar
H H
Structure Elucidation of FBX^C (30)
It was a pale yellow oily liquid. The structure of FBX2C has been fully
established by IR, DCI-MS, 'H-NMR and '^C-NMR spectra. IR spectrum
(Neat) displayed characteristic absorption bands at 3200 (NH), 3050 (OH),
2910, 2840 (CH), 1710 (COOH), 1680 (CON), 1650 (CONH), 1610 (Phenyl),
1525 (NO2, asym. str), 1430 (S-CH2) and 1375 (NO2, sym. str) cm"'. The
DCI-MS spectrum (Fig. 7a) showed a [M+1]^ peak at m/z 526 confirming its
molecular weight 525 [C24H35N3O6S2] which is equal to the sum of the
227
1 ~ J " < n r*~T—r~>"""rrT i~i I''"I
1."ill's - J I
) M M ' . J ' r rt ( J
II 1 7 1 i i i 1 ! i TTTTTTT C 4 , «
- n — t - i — 1 ; 1 I I I - I r T r - ' " ' ' " 'jzz:
1 MM = 1 ^ ^ u < \ ! - _ """ - 1
. 1 i GIJ ^ f i . M u = I j ' u. r kj. 'i = I ^ i ^ V '' • ' S1 w w
..! i.! -H. • • nil! . . . J . . . . . . ^ - J , . ,
,1, , 111 1 1 . I ' , . 1 1 i I ' (
. . i n I 1/1 1 J l ' i t I ' t t \ 1 - 3 1 1 . - . / l i t J • t/i ^ '^Ln ' ^
nil 1 •II
J A ' T y - t "p lA ' ^ 1,'t n i ' i J 0 < JWW 376 ^ ^
: ; ; i i j i i = : T i i i ~ aia aj ij .laA 45|j ujfi} ilyy 51313 51^ 52)3 553 Jjjy 55^ I T 1 I i i IM
rlH T < jii" If r.Ti= IIJ Ci ii
-0 "
1 ~< •J I i r "* I i t 1 "y 0 ley M h V <->
It 1 ' t M 1 1 . -I j ^ 1 < Ll a 1 w I
J j 1 1 l l 'A 1 fi 1 0 0 A J j w 1 a .
_ _ - J J r< ( X 1 / It i J _ V W W J \J w A.
I j II t i V K i 11 - < 1 M i 1 i i H n 11 I j II w 1 v-*
T 111, - ~ 1 It f — t 1 1 S. A ' X H h i A n .t. . k
It J . - 4_ W / w
Fig. 7a
228
molecular weights of FBX2B (437) and 3-mercaptopropionic acid (106) minus
one molecule of water. This indicated that the cyclocondensation has
occurred between FBX2B and 3-mercaptopropionic acid forming thiazanone
ring. The base peak at m/z 341 [M-CgHgNOaS]"^ was resulted by the cleavage
of 2-3 and 5-6 bonds of the thiazanone ring. The fragment ion peak at m/z
438 [(M+1)-C0CH2CH2S]^ arised by the cleavage of the 1-2 and 3-4 bonds, is
the diagnostic peak of a thiazanone ring®" . The fragment ion peaks at m/z 290
[(M+O-CioHgNjOsS]^ and m/z 237 [M-CnHjeNOsS]^ were obtained by the a -
cleavage to the ring. The fragment ion peaks at m/z 273 [M-CioHjoNaOsS]^
and m/z 254 [M-Ci4H2503S]"^ were due to the /^-cleavage to the ring. These
peaks strongly supported the formation of thiazanone ring. In addition to
these, some peaks common to FBX2B appeared at m/z 220, 165, 121 as shown
in Chart 6.
m/z 438 (41 2)
0
m/z 220 (76 1)
m h 148
+2H ^ m/z 150 (15 7) g
C m/z 166 (23 1)
N
CHART 6
m/z 231 a \ 4)
2 29
All the signals in the 'H-NMR and '^C-NMR spectra dissolved in
acetone-<i6 (Fig. 7b and 7c) have been assigned to individual H-and C-atoms
(Table 7) by comparison with the NMR spectra of FBXzB (Tables 6a and 6b).
The 'H-NMR spectrum is in agreement with the formation of a thiazanone ring
as the H-7 signal of FBXzB has shifted to higher field from 5 8.18, 8.48 (85%,
15%) to 5 6.14 (position 2 in FBX2C) due to the disappearance of C=N double
bond signal and also the NH signal has shifted to higher field from 5 10.30,
10.66 (75%, 25%) to 5 9.12, due to the ring formation. It also showed two
additional triplets for two ring methylene protons (-CH2-CH2-S-) at 5 2.94
(J=6.71, H-5) and 5 3.10 (J=6.71, H-6). Also, in '^C-NMR spectrum, the C-7
signal of FBXjB has shifted to higher field from 5 139.97, 143.22 ( -55%.
45%) to 5 66.02 (position C-2 in F B X 2 C ) . It also showed an additional peak at
6 173.14 for the carbonyl carbon at C-4. Here again, in both the NMR spectra,
only one form of FBX2C appeared
Based on the above spectral evidence, compound FBX2C was
characterized as 2-(3-mtrophenyl)-3-[ll-(2-carboxyethylthio)undecanamido]
thiazan-4-one (30).
NO2
FBX2C (30)
In conclusion, it is stated that the course of addition of mercaptoacetic
acid, 2-mercaptopropionic acid and 3-mercaptopropionic acid to terminal
olefinic bond followed anti-Markovnikov's rule which is attributed to the free
radical mechanism^^. The increased nucieophilicity of thio group in
2-mercaptopropionic acid facilitates condensation rather than addition thereby
yielding FBX3A (27) as the first product and then F B X 3 B (28).
230
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231
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232
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233
EXPERIMENTAL
lO-Undecenoicacid hydrazide (23)
It was prepared from 10-undecenoic acid by a well known common
procedure. A mixture of 10-undecenoic acid (10.Og, 0.0542 mol), methanol
(40 ml) and sulphuric acid (1 ml) was refluxed on a water bath for 6 h. To
this was added freshly distilled hydrazine hydrate (4.08g, 0.0813 mol) and
refluxed for further 8 h. The reaction mixture was cooled, concentrated in
vacuum and the solid residue left was extracted with ethylacetate, waslicd
several times with water and the organic phase dried over anhydrous Na^SOj-
The solvent was distilled off under reduced pressure to a white solid residue
which on crystallization from ethanol afforded (23) as white globules, 9.02 g
(84%). m.p.88 °C, Rf 0.76 (benzene-diethyl ether, 6:4 v/v)
IR (KBr): v,,, , 3300 (N-H), 2950, 2850 (C-H), 1630 (C=0) , 1600 (C-C) .
1575, 1530, 1460, 1440, 1380, 1 190, 1160, 910 cm-1.
m-Nitrobenzaldehyde-lO-undecenohydrazone, FB (24)
It was prepared following the literature method®. A solution of 10-
undecenoacid hydrazide (23) (4.0g, 0.0202 mol) and m-nitrobenzaldehyde
(3.052g, 0.0202 mol) in dry benzene (50 ml) was refluxed with stirring on an
oil bath at 80 °C for 5 h, collecting the generated water in a Dean Stark
apparatus. Progress of the reaction was monitored by TLC (silica gel G, pet.
ether-diethyl ether, 6:4 v/v) at every 15 min. TLC examination showed the
disappearance of the spot corresponding to the substrate and the appearance
of a new spot corresponding to the product, labelled as FB (24). The solution
was then cooled, washed several times with water, and the benzene layer was
dried over Na2S04. The solvent was removed under reduced pressure and the
234 yellow solid residue was crystallized from ethanol to yield FB (24) as yellow
crystalline globules, 5.81g (87%), m.p. 128 °C, Rf 0.70 (benzene-diethylether,
6:4 v/v)
IR ( K B r ) : v„ax 3100 (N-H), 2950, 2850 (C-H), 1660, 1640 (C=0) , 1580
(phenyl, C=C), 1550 (C=N), 1510 (NO2, asym str), 1330 (NO2, sym. str),
1420, 1255, 1225, 1150, 1100, 1055, 970, 935, 885 810,790, 715 cm"'
' H - N M R (, 400 MHz, acetone-^/^): 5h 8.17, 8.46 ( - 7 5 % , 25%); IH, s, H-7),
10.41, 10.76 ( -75%, 25%; IH, s, NH), 2.33, 2.74 ( - 2 5 % , 75%; 2H, t, J= 7.32,
7.48, H-2'), 1.69 (2H, br p, J= 7.32, H-3'), 1.31 (5H, br s, H - 4 ' - 8 ' ) , 2.02 (2H,
m, H-9) , 5.78 ( IH, tdd, J=| 6.72,10.22, 17.09 H-IO'), 4.88 ( I H , dd, J=10.22,
2.14. H r - l l ), 4.96 ( IH, dd, J=17.09, 2.14, l l ' -Hz) , 8.49 ( IH , dd, J=1.99, 1.83
Ar-2), 8.22 ( IH, dd, J=7.94, 1.83, Ar-4), 7.71 ( IH, dd, J=7.78, 7.94, Ar-5)
8.12 ( IH , dd, J=7.78, 1.99, Ar-6).
' H - N M R (400 MHz, DMS0-rf<5): 5h 8.09, 8.50 ( - 6 0 % . 40%; IH. s. H - 7 ) .
1 1.41, 11.54 ( -60%, 40%; IH, s, NH), 2.22, 2.64 ( - 4 0 % , 60%; 2H, t, J= 7.30,
7.41, H-2'), 1.60 (2H, br p, J=7.14, H-3'), 1.28 (lOH, br s, H-4'-8'), 2.00 (2H.
td, J=7.14, 6.60, H-9') 5.76 ( IH, tdd, 1=6.77,10.26, 17.22, H-10'), 4.93 ( ]H,
dd, J=10.26, 2.01, HE), 5.00 ( IH, dd, J=17.22, 2.01, Hz), 8.47 ( IH , dd,
J=2.02. 2.03, Ar-2), 8.26 (IH, dd, J=8.23, 2.02, Ar-4), 7.72 ( I H , dd, J=7.51.
8.23, Ar-5), 8.09 ( IH, d, J -7 .51 , Ar-6)
'^C-NMR (100 MHz, acetone-rf^,): 5c 140.79, 144.53 ( - 7 5 % , 25%; C-7),
170.07, 172.12 ( -75%, 25%; C-l ' ) , 33.09, 35.55 ( - 7 5 % , 25%; C-2'), 25.41,
26.07 ( -75%, 25%; C-3'), 29.22-30.38 (C-4'-8'), 34.42 (C-9'), 139.81 (C-10) ,
114.59 (C- l l ' ) , 137.68 (Ar-C-1), 121.80 (Ar-C-2), 149.72 (Ar-C-3), 124.56
(Ar-C-4), 130.98 (Ar-C-5), 133.30 (Ar-C-6).
235
DCI-MS (NH3): m/z 332 [(M+1), 100.0], 333 (48.0), 334 (19.0), 335 (7.0).
316 (6.4), 317 (3.6), 165 (5.0), 149 (4.4), 118 (4.0), 59 (3.8)
m-Nitrobenzaldehyde-ll-(carboxymethylthio)undecanoltydrazone FBXiB
(25) and 2-(3-nitrophenyl)-3-[ll-(carboxymethylthio)undecanamido]thia-
zolidin-4-one FBX,C (26) [Reaction of the hydrazone (24) with
mercaptoacetic acid]
To a solution of the hydrazone (24) (1.20g, 0.0030 mol) in dry benzene
(20 ml) was added mercaptoacetic acid (0.832g, 0.0090 mol) and refluxed
with stirring on an oil bth at 80 °C for 16 h, collecting the generated water
using a Dean Stark apparatus. The products on TLC examination (silicagel G,
benzene-diethyl ether, 6:4 v/v) showed a major (lower) and a minor (upper)
spot labelled as FBXiB (25) and FBXjC (26). The solution was cooled,
washed several times with water to make the solution neutral and the organic
phase dried over anhydrous Na2S04. The solvent was distilled off under
reduced pressure and the orange oily residue left was chromatographed over a
silica gel column using (pet.ether-diethylether, 1:1 v/v). Elution of the
column first furnished a pale yellow solid FBXiB which was recrystallised
from ethanol as crystalline yellow globules, 217 mg (31.2%), m.p 120 °C, Rf
0.43 (benzene-diethyl ether, 6:4 v/v). Further elution of the column yielded
FBXiC as a yellow oily liquid which was further purified by repeated column
chromatography using the same solvent, 810 mg (54%), Rf 0.38 (benzene-
diethyl ether, 6:4 v/v).
236
Spectral data of FBX,B (25)
IR (KBr): v^^a, 3250 (N-H), 3075 (OH), 2900,2850 (C-H), 1725 (COOH),
1645 (CO), 1610 (Phenyl), 1555 (C=N), 1520 (NO2, asym str), 1350 (NO2,
sym str) 1465 (S-CH2), 1400, 1380,1190 cm"'.
^H-NMR (400 MHz, acetone-^/g,): 5h 8.18, 8.48 ( - 7 5 % , 25%; IH, s, H-7),
10.29,10.66 ( -75%, 25%; IH, s, NH), 2.31, 2.74 ( - 2 5 % , 75%; 2H, t, J=7.30,
7.47, H-2 ') , 1.59 (2H, br p, J «7.25, H-3') , 1.31 (12H, br s, H-4 ' -9 ' ) , 1.69 (2H,
br p, J«7.28, H-10'), 2.64 (2H, t, J=7.32, H - l l ' ) , 3.22 (2H, s, H-1") , 8.51
( IH, dd, 1.98, 1.83, Ar-2), 8.24 ( IH, dd, 7.93,1.98, Ar-4), 7.73 ( IH, dd,
J=7.94, 7.93, Ar-5), 8.14 ( IH, dd, J=7.94, 1.98, Ar-6).
' H - N M R (400 MHz, DMSO-^/fi,): 5H 8.07, 8.27 ( - 6 0 % , 40%; IH, s, H-7),
11.39, 11.53 ( -60%, 40%; IH, s, NH), 2.21, 2.62 ( - 4 0 % , 60%; 2H, t, J=7.33,
7.42, H-2') , 1.48 (2H, br p, J=7.37, H-3'), 1.58 (2H, br p J«7.22, H-10') , 1.25
(12H, br s, H-4 ' -9 ' ) , 2.54 (2H, t, J -7 .34 , H - l l ' ) , 3.17 (2H, s, H-1") , 8.45
( IH, dd, J=1.99, 1.83, Ar-2), 8.21 ( IH, dd, J= 8.05, 1.83, Ar-4), 7.70 ( IH, dd,
J=8.05, 7.69, Ar-5), 8.07 ( IH, dd, J -7 .69 , 1.82, Ar-6).
^^C-NMR (lOOMHz, DMSO-rf^,): 5c 139.99, 143.24 ( - 6 0 % , 40%; C-7),
168.95, 174.57 ( -40%, 60%; C - l ' ) , 31.76, 34.12 ( - 6 0 % , 40%; C-2 ') , 24.17
(C-3'), 28.04-28.79 (C-4'-10') 31.67 (C-11'), 171.47 (C-2") , 33.20 ( C - l " ) ,
136.18 (Ar-C-1), 120.51 (Ar-C-2), 148.18 (Ar-C-3), 123.70 (Ar-C-4), 130.30
(Ar-C-5), 132.60 (Ar-C-6)
DCI-MS (NH3): m/z (%): 424 [ ( M + l ) ^ 50.9] 425 (28.6), 426 (10.2), 336
(10.6), 337 (4.2), 275 (3.8), 276 (52), 218 (5.8), 215 (4.3), 163 [ ( M > C , 3
H23O2S, 11.8], 149 (36.7), 150 (10.2), 165 (9.4), 166 (10.0), 167 (4.8), 147
237
(11.0). 148 [ ( M > C , 3 H25 NO3S, 10.0], 149 (36.7), 150 (10.2), 136 (16.6),
137 (5.3), 133 (9.8), 134 [(M+l)-C,5 H20 N3O3, 58.8], ,121 (9.5), 118 [M^-
C,6H23N303, 13.0], 119(6.3) .
Spectral data of FBX^C (26)
IR (Neat): v^ax 3250 (N-H), 3050(OH), 2900,2850 (C-H), 1725 (COOH),
1685 (CON), 1660 (CONH), 1610 (phenyl), 1525 (NO2 asym str), 1355 (NO.,
sym str), 1430 (S-CH2), 1405, 1260, 1165 cm"'
'H-NMR (400 MHz, acetone-c?^,): 5h 6.04 ( IH, s, H-2), 3.84 (IH, dd,
J=15.87, 1.68, H-5 trans), 3.75 ( IH, dd, J=15.87, 0.92, H-5cis) , 2.10 (2H, t,
J -7 .32 , H-2 ' ) , 1.50 (2H, br p, J=7.14, H-3 ' ) , 1.19 (12H, br s, H-4 ' -9 ' ) , 1.59
(2H. brp, J=7.26, H-10 ' ) 2.64 (2H, t, J=7.33, H-11 ' ) , 3.22 ( IH , s. H-1"), 8.34
( IH, dd, J=1.99, 1.98, Ar-2), 8.24 ( IH, dd, J=8.10, 2.23, Ar-2), 7.71 ( IH,
J=8.10, 7.94, Ar-5), 7.95 ( IH, dd, J=7.94, 1.99, Ar-6).
^^C-NMR (100 MHz, acetone-^/^,): 5c 62.23 (C-2), 172.17 (C-4), 34.09(C--5),
171.71 ( C - r ) , 33.09 (C-2') , 25.97 (C-3') , 29.50-30.00 ( C - 4 ' - l l ' ) , 33.80 (C-
1"), 169.67(C-2"), 142.18 (Ar-C-1), 124.76 (Ar-C-2), 149.54 (Ar-C-3),
123.63 (Ar-C-4), 131.01(Ar-C-5), 135.3l(Ar-C-6).
D C I - M S (NH3): m/z (%) 498 [(M+1)^ 14.5], 499 (10.1), 452 [(M^)-C02H,
10.2], 424 [(M+1)^-SCH2C0, 10.4], 425(4.8), 332(9.5), 273(10.4), 274 (7.6),
275(13.6), 276[(M+1)^-C9H7N203S, 72.2], 277 (31.3), 278 (14.0), 258
[(M+1)^-C9H9N303S, 10.0], 239 (7.2), 240 [(M+O^'-CoHssOsS, 91.8], 241
(35.9), 242 (11.8), 230 (10.9), 231 [(M^)-C8H9N302S, 25.4], 232 (16.3), 223
[(M^)-C,3H24N09S, 27.2], 224 (12.2), 210 [(M+1)^-C,3H24N203S, 39.5], 212
(24.0), 213 (13.1) 214 (6.4), 215 [(M>CI3H24N03S, 47.7], 216 (22.2), 217
(8.1), 218 (14.5), 193 (25.0), 194 (12.2), 195 (29.5), 196 (11.3), 176 (11.8),
2 38
178 (12.7), 162 (8.1), 163 (8.2), 164 (8.1), 165 (7.9), 166 (40.4), 148 (15.0),
149 (10.0), 150 (9.0), 151 (15.4), 152 (16.3), 153 (7.5), 134 (42.2), 135
(20.0), 136 (32.2), 137 (19.0), 138 (30.0), 139 (18.1), 1 18 (32.2), 1 19 (9.5),
1 10 (8.2), 81 (13.1), 82 (9.0), 83 (14.5), 87(1 1.8), 89 (10.4), 91 (12.7), 93
(13.6), 94 (29.0), 95 (17.7), 96 (8.4), 97 (8.6), 99 (20.0), 100 (9.5).
2-(3-Nitrophenyl)-5-(meihyl)-3-(10-undecenaniido)thiazolidin-4-one F B X 3 A
(27) and 2-(3-nitrophenyl)-5-(methyl)-3-[ll-{(l-carboxy)ethylthio}undecan-
amidoJthiazolidin-4-one F B X 3 B (28) [Reaction of the hydrazone (24) with
2-mercaptopropionic acid]
To a solution of the hydrazone (24) ( l .Olg , 0.0030 mol) in dry benzene
(20ml) was added 2-mercaptopropionic acid (0 .96Ig, 0.0090 mol) and
refluxed for 22 h as above, monitoring the progress of reaction by TLC (silica
gel G, pet. ether-diethylether, 3:7 v/v) which revealed the presence of two
spots labelled as F B X 3 A (27) (upper) and F B X 3 B (28) (lower) and then
worked up as usual. The product on purification by column chromatography
(silica gel, pet. ether-diethyl ether, 3:7 v/v) as eluent yielded F B X 3 A as a
colourless oily liquid, 536 mg (42.3%), Rf 0.46 (benzene-diethyl ether, 6:4
v/v). Further elution of the column using pet. ether-diethyl ether, 6:4 v/v
afforded F B X 3 B as a pale yellow oily liquid, 528 mg (34.5%), Rf 0.32
(benzene-diethyl ether, 6:4 v/v).
Spectral data of FBX,A (27)
'H-NMR (400 MHz, acetone-ds,): 5H 6.01 ( IH, d, J=0.91, H-2cis), 6.04 ( IH,
d, J=1.53, H-2trans), 4.04 ( IH, qd, J=6.86, 0.91, H-5cis), 4.11 ( IH, qd,
J=7.17, 1.53, H-5trans), 1.59 (3H, d, J=6.86, S-CHacis), 1.61 (3H, d, J=7.17,
5-CH3trans), 9.28 ( IH, s, NH), 2.11 (2H, t, J=7.25, H-2'), 1.50 (2H, br p.
239
J = 7 . 0 5 , H - 3 ' ) , 1 .22 ( 1 2 H , b r s, H - 4 ' - 9 ' ) 5 . 8 1 ( I H , t d d , J = 6 . 7 2 , 1 0 . 2 3 , 1 7 . 0 9 ,
H - 1 0 ' ) , 4 . 9 0 ( J = 1 0 . 2 3 , 2 . 1 3 , H E - 1 1 ' ) , 4 . 9 8 ( I H , d d . J = 1 7 . 0 9 , 2 . 1 3 ) , 8 . 3 4 ( I H ,
d d , J = 1 . 9 9 , 1 .83 , A r - 2 ) , 8 . 2 6 ( I H , d d , J = 8 . 0 9 ; 1 . 9 9 , A r - 4 ) , 7 . 7 3 ( I H , d d ,
J = 8 . 0 9 , 7 . 9 3 , A r - 5 ) , 7 . 9 5 ( I H , d d , J = 7 . 9 3 , 2 . 2 8 , A r - 6 ) .
'^C-NMR (ICQ MHz, acetone-</<j,): 5c 61.16 (Cc-2), 172.83 (C-4), 39.53 (C-
5cis), 39.82 (C-5tran), 19.46 (C-S-CHjcis), 20.60 (C-S-CHstran), 172.23 (C-
r ) , 34.30 {C-T), 25.98 (C-3'), 29.24-30.39 (C-4'-8'), 34.44 (C-9^), 139.88
(C-10'), 114.63 ( C - i r ) , 141.59 (Ar-C-lcis) , 142.41 (Ar-C-l t rans) , 124.84
(Ar-C-2), 149.55 (Ar-C-3), 123.82 (Ar-C-4), 131.05 (Ar-C-5).
DCI-MS (NH3): m/z (%) 420 [ ( M + l ) \ C21H29N3O4S, 82.1], 421 (36.0), 422
(26.9), 437 [(M+18)^ 6.6], 438 (3.7), 387 (9.1), 332 [(M+18)^-C3H40S, 8.7],
313 (9.1), 266 (4.9), 254 [(M+1)^-C,,H ,90, 82.1], 255 (13.6), 256 (4.9), 237
[(M+1)"-ChH2ONO, 100.0], 238 (20.7). 239 (7.8), 218 (4.1), 209 (3.3), 207
(4.5), 184 (11.6), 185 (6.6), 186 (3.3), 165 (7.0), 166 (8.7), 167(60.5), 168
(9.1), 169 (3.3), 147 (21.9), 148 (4.1), 149 (26.9), 150 (5.3), 151 (4.1), 137
(4.5), 130 (16.5), 131 (3.7), 121 (6.2), 116 (4.5), 117 (3.3), 118 (7.8), ] 10
(5.3), 105 (3.3), 107 (4.5), 95 (4.9), 94 (3.3), 93 (6.2), 91 (3.3), 89 (7.4), 87
(7.4), 85 (24.0), 83 (6.2), 82 (3.3), 81 (14.9), 80 (3.7), 76 (31.1), 74 (21.1),
72 (10.3), 71 (4.1).
Spectral data of FBX^B (28)
'H-NMR (400 MHz, acetone-dg): 5h 6.01 ( IH , d, J=0.91, H-2cis), 6.04 (IH,
d, J=1.53, H-2trans), 4.05 ( IH, qd, J=6.86, 0.91, H-5cis), 4.11 ( IH, qd,
J=7.17, 1.53, H-5trans), 1.59 (3H, d, J=6.87, 5-CH3cis), 1.61 (3H, d, J=7.]7 ,
5-CH3trans), 9.28 ( IH, s, NH), 2.11 (2H, t, J=7.25, H-2'), 1.50 (2H, brp,
J~7.09, H-3'), 1.22 (12H, brs, H-4'-9'), 1.59 (2H, brp, J~poorly resolved, H-
240
10'), 2.67 (2H, m, H-11 ' ) , 3.42 ( IH, q, J=7.02, H-1"), 1.60 (3H, d, J=7.02, 1"-
CH3), 8.34 ( IH, dd, J=1.98, 1.83, Ar-2), 8.26 ( IH, dd, J=8.09, 1.99, Ar-4),
7.73 ( IH , dd, J=8.09, 7.93, Ar-5), 7.95 (IH, dd, J -7 .93 , 2.29, Ar-6).
'^C-NMR (100 MHz, DMSO-rf^): 6c 61.16 (C-2), 172.83 (C-4), 39.53 (C-
5cis), 39.83 (C-5trans), 19.46 (C-S-CHscis), 20.61 (C-S-CHjuans), 172.22 (C-
r ) , 34.08 (C-2') , 25.97 (C-3'), 29.24-30.40 (C -4 ' -10 ' ) , 31.91 (C- IT) , 17.78
(C-1"-CH3), 41.35 (C- l") , 174.33 (C-COOH), 141.57 (Ar -C - lc is) , 142.40
(Ar-C-1 trans), 124.85 (Ar-C-2), 149.55 (Ar-C-3), 123.82 (Ar-C-4), 131.06
(Ar-C-5).
DCI-MS (NH3): m/z (%) 525 [ (M+l )^ C24H35N3O6S2, 22.0], 526 (98.6), 527
(31.0), 524 (58.6), 543 [(M+18)", 31.7], 544 (8.9), 541 (8.9), 480 [ ( M >
COOH, 15.0], 471 (9.8), 454 (9.6), 436 (8.2), 419 [ (M+1)^-SCH(CH3)C00H,
17.2], 405 (7.2), 308 [(M^)-(C|2H2302S. 17.2], 290 [(M+l)^-C,oH8N203S,
33.1], 289 (9.2), 288 (10.4), 280 [(M^)-Ci3H2502S, 10.0], 273 [ (Vf)-
C,OHioN303S, 9.6], 271 (9.4), 237 [ ( M ^ C u H j e N O j S , 100.0], 238 (15.8), 239
(10.3), 229 (14.6), 218 (15.8), 207 (37.2), 199 (20.0), 184 (17.9), 180 (18,6),
164 (15.2), 165 (15.0), 166 (15.5), 151 (14.9), 147 (22.7), 138 (28.9), 130
(20.6), 121 (17.9), 108 (15.2), 87 (17.2), 75 (16.5).
m-Nitrobenzaldehyde-ll-(2-carboxyethylthio)undecanohydrazone FBX2B
(29) and 2-(3-nitrophenyl)-3-[ll-(2-carboxyethylthio)undecanamido]-
thiazan-4-one FBXjC (30) [Reaction of the hydrazone (24) with 3-
mercapto propionic acid]
To a solution of the hydrazone FB (24) (1.02g, 0.0030 mol) in dry
benzene (20 ml) was added 3-mercaptopropionic acid (0.961g, 0.009 mol) and
refluxed for 26 h as described above. TLC examination (silica gel, pet.ether-
241
diethyl ether, 6:4 v/v) of the products showed it to be a mixture of two
compounds labelled as FBX2B (29) (major, upper) and FBX2C (30) (minor,
lower). The products on purification by column chromatography (silica gel,
pet. ether-diethyl ether, 1:1 v/v) first yielded a yellow solid which on
crystallisation from (benzene-acetone) furnished FBX2B as white crystalline
globules, 765 mg (58.0%), m.p 98 °C, RfO.46 (benzene-diethyl ether 6:4 v/v).
Further elution of the column using (pet.ether-diethyl ether, 3:7 v/v) yielded
FBX2C as a yellow oily liquid, 412 mg (26.0%),Rf 0.24 (benzene-d ie thy l
ether, 6:4 v/v).
Spectral data of FBX^B (29)
IR (KBr): 3175 (N-H), 3040 (OH), 2900, 2800 (C-H), 1730 ( ^ O H ) ,
1645 ( m N H ) , 1605 (Phenyl), 1555 (C=N), 1520 (NO2 asym str), 1480 (S-
CH2), 1340 (NO2 sym str), 1415, 1380, 1215, 1 1 10, 800 cm"' .
'H-NMR (400 MHz, acetone-t/^): 5h 8.18, 8.48 (~ 85%, 15%; IH, s, H-7),
10.30, 10.66 ( -85%, 15%; IH, s, NH), 2.31, 2.73 ( - 1 5 % , 85%; 2H, t, J=7.48,
7.31, H-2') , 1.56 (2H, brp, J«7.28, H-3') , 1.31 (12H, br s, H-4 '-9 ' ) , 1.69 (2H,
br p, 7.25,H-10'), 2.55 (2H, t, J=7.33, H-11') , 2.74 (2H, t, J=6.87, H-1") ,
2.57 (2H, t, J=6.87, H-2") , 12.20 ( IH, brs, COOH), 8.51 ( IH , dd, J=1.99,
1.82, Ar-2), 8.24 ( IH, dd, J -8 .08 , 1.98, Ar-4), 7.73 ( IH, dd, J=7.94, 7.63, Ar-
5), 8.14 ( IH, dd, J=7.94, 1.98, Ar-6).
'H-NMR (400 MHz, DMSO-rf^.): 5H 8.11, 8.29 ( - 5 5 % , 45%; IH, s, H-7),
1 1.41, 11.55 ( -55%, 45%; IH, s, NH), 2.23, 2.63 ( - 4 5 % , 55%; 2H, t, J=7.34,
H-2') , 1.48 (2H, brp, J^7.33, H-3') , 1.26 (12H, br s, H-4 ' -9 ' ) , 1.59 (2H, br p,
y^7.14, H-10') , 2.47 (2H, t, J=7.14, H-11') , 2.65 (2H, t, J= 6.77, H - l " ) , 2.49
(2H, t, J=6.77, H-2") , 8.47 ( IH, dd, J=1.99, 1.83, Ar-2), 8.23 ( IH , dd, J=
242
8.05, 2.01, Ar-4) 7.72 ( IH, dd, J=7.88, 8.05, Ar-5), 8.08 ( IH, dd, J=7.88,
2.01, Ar-6);
'^C-NMR (100 MHz, DMSO-rfe,): 5c 139.97, 143.22 ( - 5 5 % , 45%; C-7),
168.92, 174.55 ( -45%, 55%; C-1'), 31.75, 34.11 ( -55%, 45%; C-2'), 24.16
(C-3'), 28.40-28.80 (C-4'-10') , 31.00 (C-11'), 34.53 (C-2") , 26.35 (C-1"),
178.50 (C-3") , 136.17 (Ar-C-1), 120.50 (Ar-C-2), 148.18 (Ar-C-3), 123.69
(Ar-C-4), 130.28 (Ar-C-5), 132.61 (Ar-C-6).
D C I - M S (NH3): m/z (%) 438 [ ( M + l ) \ C21H31N3O5S, 63.5], 439 (41.7), 440
(16.5), 366 (8.2), 336 (24.6), 337 (13.0), 304 [ (M>C5H902S , 14.2], 305
(8.0), 218 [ (M>C,2Hi302S, 25.9], 219 (10.0), 220 (7.4), 201 (8.4), 186
[(M^)-C,2Hi2N303, 18.8), 187 (9.0), 163 (8.2), 164 (9.0), 165 (7.8), 166
(10.6). 148 [(M^)-C,5H2oN303, 24.8], 149 (16.4), 150 (15.2), 151 (15.2), 152
(7.8). 133 (23.6), 134 [(M+1)^-C,6H23N303, 100.0], 135 (67.0), 136 (38.7),
137 (16.8), 118 (37.7), 1 19 (18.2), 120 (26.3), 121 (88.3), 122 (35.1), 123
(15.4), 106 (11.4), 107 (1 1.0), 108 (13.6), 109 (7.8), 94 (9.2), 72 (21.0), 73
(9.0).
Spectral data of FBX^C (30)
IR (Neat): v^^, 3200 (NH), 3050 (OH), 2910, 2840 (C-H), 1710 (COOH),
1680 (CON), 1650 (CONH), 1610 (phenyl) ,1525 (NO2 asym. str), 1430 (S-
CH2), 1375,1350 (NO2 sym. str)1230, 1170,1070, 800, 720 cm"'.
'H-NMR (400 MHz, acetone-^/e): 5h 6.14 ( IH, s, H-2), 2.94 (2H, t, J=6.71,
H-5) 3.10 (2H, t, J=6.71, H-6), 9.12 ( IH, s, NH), 2.09 ( IH , t, J=unresolved,
H-2') . 1.58 (2H, br p, J=7.17, H-3 ' ) 1.29 (12H, m, H-4 ' -9 ' ) , 1.60 (2H, br p,
J= unresolved, H-10') , 2.56 (2H, t, J=7.38, H-11') , 2.75 (2H, t, J=7.17, H-1"),
2.58 (2H, t, J=7.17, H-2"), 8.28 ( IH, dd, J=2.14, 1.83, Ar-2), 8.23 ( IH, dd, J=
243
8.09, 2.29, Ar-4), 7.72 (IH, dd, J=8.09, 7.93, Ar-5), 7.90 ( IH, dd, J=7.93,
1.07, Ar-6).
'^C-NMR (100 MHz, acetone-^/g,): 5c 66.02 (C-2), 173.14 (C-4), 37.24 (C-
5), 27.59 (C-6), 172.35 (C-1'), 34.13 (C-2'), 25.97 (C-3'), 29.50-30.20 (C-4'-
11'), 24.53^ (C-1"), 35.25' (C-2"), 169.15 (C-3"), 141.89 (Ar-C-1), 122.94
(Ar-C-2), 149.36 (Ar-C-3), 124.17 (Ar-C-4), 130.76 (Ar-C-5), 134.65 (Ar-C-
6).
DCI-MS (NHj): m/z (%) 526 [ (M+l )^ C24H35N3O6S2, 18.8], 527 (9.3), 438
[(M+1)^-C0(CH2)2S, 41.2], 439 (15.6), 440 (6.0), 420 (10.5), 406 (4.6), 341
[(M^)-C8H7N02S, 100.0], 342 (31.7), 343 (10.2), 290 (13.8), 254 [(M+1)^-
C,4H2503S, 27.0], 255 (9.0), 237 [(M^)-C,4H26N03S, 71.4], 238 (15.1), 239
(9.5), 220 (76.1), 221 (16.5), 166 (25.3), 167 (17.5), 150 (15.7), 138 (1 1.4),
120 (1 1.4), 121 (33.1), 123 (23.8), 118 (9.1), 93 (12.1), 87 (17.2), 89 (14.0),
81 (12.5), 77 (9.3), 72 (15.5).
-w, fmrv^ WA xm
. ml 2-Aryl-2-Methyl-3-N'Long alkyl chain
substituted'Thiazolidin-4-one
244
DISCUSSION
SUMMARY
The work described in this chapter includes the reaction of p-chloroacetophenone-
10-undecenohydrazone (31) with:
(i) Mercaptoacetic acid in dry benzene which furnished an adduct, p-chloro-
acetophenone-1 l-(carboxymethylthio)undecanohydrazone (32) and a new
compound, 2-(4-chlorophenyl)-2-methyl-3-[l ]-(carboxymethylthio)undec-
anamido]thiazolidin-4-one (33) and a byproduct, bis (carboxymethylthio)-4-
chloroacetophenotal (34).
(ii) 3-Mercaptopropionic acid in dry benzene which afforded an adduct, p-chloro-
acetophenone-1 l-(2-carboxyethylthio)undecanohydrazone (35) as the sole product.
The hydrazone (31) was also found to exist in two stereoisomeric forms as syn-periplanar
(major) and anti-periplanar (minor) [as in (24)] as evident from its stereochemical studies.
I N T R O D U C T I O N
As part of our programme in searcii of biologically active compounds with
sulphur and nitrogen containing heterocycles, we have synthesised four novel
compounds, 2-(3-ni t rophenyl)3-[n-(carboxymethy/ethyl thio)undecanamido
thiazolidin-4-ones/thiazan-4-ones (26), (27), (28) and (30) f rom w-nitrobenz-
aldehyde-10-undeceno-hydrazone (described in Chapter 4). In continuation of
the above mentioned work, we have undertaken this problem on the synthesis of
2 - (4-ch lorophenyl -2-methyl -3- [ l l - ( c a r b o x y m e t h y l / 2 - c a r b o x y e t h y l t h i o ) u n d -
e c a n a m i d o ] t h i a z o l i d i n - 4 o n e s / t h i a z a n - 4 - o n e f rom yc-ch lo roace tophenone-
1 0 - u n d e c e n o h y d r a z o n e (31) u s ing m e r c a p t o a c e t i c a c i d / 3 - m e r c a p t o -
p rop ion i c ac id .
245
Structural assignment, stereochemistry and biological assay are
discussed. Screening results of the compounds (31) and (32) are summarised for
cytotoxic activity against 3-cell lines of three types of human cancers: lung,
breast, CNS. Screening results of the above compounds are also summarised for
antimicrobial activity against four bacteria, Escherichia coli, Bacillus subtilis,
Staphylococcus aureus, Pseudomonas aeruginosa and one fungi Candida
albicans (details in Chapter 6)
(31)
246
R E S U L T S A N D D I S C U S S I O N
The synthesis of compounds (32)-(35) has been performed in two steps (Scheme
2). The hydrazone FD (31) was first prepared following a published procedure^ by
refluxing a solution of 10-undecenoicacid hydrazide (23) in dry benzene with j!?-chloro-
acetophenone (molar ratio, 1:1) as white crystalline needles in 83% yield. The hydrazone
(31) was then reacted with (i) mercaptoacetic acid and (ii) 3-mercaptopropiomc acid
(molar ratio, 1:3) in dry benzene. The products on column chromatography over a silica
gel column using pet.ether-diethyl ether as eluent, yielded compounds FDXjA (32),
FDX,B (33) and FDXjC (34) in (i) and FDXjA (35) a sole product in (ii). The failure of
the reaction to yield the cyclised product in (ii) may be attributed to the increased
nucleophilicity of the carbon at C-7 due to the presence of the electron donating methyl
group which retarded the nucleophilic attack by mercapto group at this carbon.
247
X z
m X M e
\ s
+
0 >=0
X o b.
. 00 (N g
(U u N C
IT) m
fS fi
o
'3!
c C/3
O I
"o a, K O O u
0 1 "o
K O O u
I u X u CO ^ E I
tn r^
a S w X u '73
248
p-Chloroacetophenone-lO-undecenohydrazone FD(31)
A solution of 10-undecenohydrazide (23) in dry benzene was refluxed with
;?-chloroacetophenone for 6 h as described in (24). The products on usual work up
followed by crystallization from ethanol furnished FD (31) as white crystalline needles
in 83% yield. The reaction sequence is as follows:
O O MeOH/H
NH2.NH2.H2O ^ N H - N H ,
(23)
dry benzene Reflux, 6 h
Structure Elucidation of FD (31)
It was a needle shaped white crystalline solid, m.p 64 °C. The stereostructure of
FD has been fully confirmed by IR, DCI-MS, 'H-NMR, '^C-NMR, APT and HETCOR
spectra. IR spectrum (KBr) exhibited characteristic absorption bands at 3175 (NH).
2900, 2850 (C-H), 1675, 1650 (CO), 1595 (phenyl) and 1540 (C=N) cm"'. The DCI-MS
spectrum of the compound showed an intense [M+1]"^ signal at m/z 335/337 which is in
consistent with the molecular formula [C19H27N2OCI]. The signals in 'H-NMR and '^C-
NMR spectra (Fig. 8a and 8b), dissolved in DMSO-c/^ could be easily assigned (Tables
8a and 8b) by comparing the spectra with the previously established hydrazone FB (24).
(Table la and lb).
249
E a a
S >
«
I 03 00 M
c
250
e D Q
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o ID
o CD
s : U T)
V
5 ^ . s a o o r *
c — v u • o ^^ O O M « o c
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-Q 00 bx)
o V
o (O
o CO
o o cy
s s a s s s s t i s s s s a a s n K R i S R i R s R R s w s R s
251
6 Q
Q b O a
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1—1 w X w X >—> N
o O ^ (N ' o I/"! 00 00 1—)
(N r-
(N d O
1—) (N r- K < < 00 vd
(N o ~o o Cv CN (N K w N "(N 11 ffi X < < 1—> >—l > — ! 1—> •-5 >—>
WH X) Xl
E I ro —'
X H- l-rH (N CN iri i: X (N LU HC — (N tN
O \D
O Tj-^ 0
O
O I
to i to (N fS
d
ON ri t\ 1-H (N 00 o VO (N 00 in (N d m (N o r- OS OS Tl-ri
d ri ri w-i Tt-" i> K
-
c X 00 1
— r - M fsT fV CO
u K 00 1 d
r — (
w N Z CN ON
d r — ( X < <
2S2
Table 8b: " C - N M R , A P T and H E T C O R spectral data of FD (31) im D M S O - 4
C-nr 8 (ppm) APT H E T C O R correlat ion vt'ith
7-CH3 13.19,13.76 ( -60%, 40%) CH3 H-CH3
7 145.43, 149.35 ( -60%, 40%) C H-7 r 175.13, 169.16 ( -60%, 40%) C 2' 32.25, 33.92 ( -60%, 40%) CH2 H-2' 3' 24.20, 25.07 ( -60%, 40%) CH2 H-3' 4'-8' 28.18-28.87 CH2 H-4'-8' 9' 33.07 CH2 H-9' 10' 138.73 CH H-10' Ar-1 133.66 C Ar-4 137.11 C Ar-2,6 127.51 CH H-Ar-2,6 Ar-3,5 128.25 CH H-Ar-3,5
Table 8c: ' H - N M R spectral data of FD (31) in DMSO-^/^
H-nr 6(ppm) Integ-ration
Multi-plicity
J(Hz)
7-CH3 2.34,2.76(~75%, 25%) 3H s NH 9.37,9.68 ( -75%,25%) IH s 2' 2.28,2.73 ( -25%,75%) 2H t J2'.3' 6.71,7.62 3' 1.66 2H br p J ~ 7.48 4 ' -8 ' 1.31 5x2H br s
9' 2.04 2H m 10' 5.79 IH tdd J,O'H,17.09, J,O'he10.22,
Jjo'.g' 6.72 HE-11' 4.88 IH dd JHJ:, 10' 10.22, JH^, H,2.29
H z - i r 4.95 IH dd JHZ,10'17.09, JH , HE 2.29
Ar-2,6 7.84 2H d JAr-2, 6, Ar-3,5 8.55 Ar-3,5 7.42 2H d JAr-2,6 ,Ar-3,5 8.55
253
All the signals were found comparable with that of (24) except that it showed no signal
corresponding to the benzylidene proton at C-7 and in place a singlet at 5 2.21, 2.24 (~
60%, 40%) for the methyl group protons appeared. In addition, it also showed the
characteristic A2B2 signals for the /?-chlorophenyl ring. As for (24), here again both the
spectra showed several double signals for 7-CH3, C-7, C-l ' , C-2', and C-3' in the '^C-
NMR spectrum and for H-7-CH3, NH and H-2' in the 'H-NMR spectrum, indicating that
this molecule is also present in two different forms. Irradiation of NH-proton (Fig. 8c)
resulted in a NOE-enhancement of both H-8 signals corresponding with the methyl
group in both forms, suggesting that N-H proton and the methyl group in both forms are
very near to each other. This can only be the case in ^'-isomer. Further, only a very weak
enhancement of the H-2' signal is seen, so it could be impossible to make a definitive
conclusion about the conformation of the CO-NH bond. However, it could be assumed
that in analogy to (24), the major form is the synperiplanar conformer and the minor one
is the antiperiplanar conformer. As in (24), the 'H-NMR spectrum of this compound
dissolved in acetone-fig, again two forms were observed in -3 :1 ratio (Table 8c)
indicating that the equilibrium between the stabile conformers in this case also depends
on the polarity of the solvent.
The structure of the compound was further confirmed by HETCOR spectra
(Fig. 8d and 8d') . It showed cross correlation peaks between CH3-7 (60%, 40%)/CH3-7
(60%, 40%), H-2' (60%, 40%)/C-2' (60%, 40%), H-3' (60%,40%)/C-3' (-60%,40%), H-
4'-8'/ C-4'-8', H - 9 ' / C - 9 ' , H - I O ' / C - I O , HE-11', HZ-117C-11', H-Ar-2,6/C-Ar-2,6, and H -
Ar-3,5/C-Ar-3,5 as shown in Table 8b . An APT spectrum (Fig. 8e) further confirmed
the assignments of '^C-NMR signals (Table 8b).
254
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u u 2 a* • m m » ! t i B* • c
o oi o • • fiosifegis X o • • » • ^
s t F ? 2 -
1
i s , i f 11 ! M f j i | 5 t i n M t i s i i l i s s i i j l i i M i O c i i
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258
Based on the above spectral evidence, the compound (31) was characterised as
p-chloroacetophenone-lO-undecenohydrozone and deduced to be its two forms as
synperipianar (major) and antiperiplanar (minor) (Fig. 8)
, H H
NOE NOE
H CH3
Q XI
synperipianar
NOE
(Fig. 8)
259
p-Chloroacetophenone-ll-(carboxymethylthio)undecanohydrazone FDXiA (32), 2-(4-
ch loroph enyl)-2-methyl-3-[ll-(carboxymethylth io) undecan amidojth iazolidm-4-one
FDXjB (33) and bis(carboxymethylthio)-4-chloroacetophenotal FDX,C (34)
[Reaction of the hydrazone (31) with mercaptoacetic acid]
A mixture of the hydrazone (31) and mercaptoacetic acid (molar ratio, 1:3)
dissolved in dry benzene was refluxed with stirring for 24 h and worked up as usual. The
products on column chromatography first afforded a yellow solid which on
crystallisation (EtOAc) gave FDXiA (32) (41.2%) as white amorphous solid . Further
elution of the column yielded a colourless oily liquid FDX,B (33) (33.3%) and then a
pale yellow solid, FDXjC (34) which on crystallization (EtOAc) afforded white
crystalline needles (13.2%).
HS.CH2.C00H dry benzene, HO reflux, 24 h
FD(31) FDX,A (32)
0 0
OH + HO
CHr
0 N H — N S
F D X , B (33)
Structure Elucidation of FDX^A (32)
It was a white amorphous solid, m.p. 68 °C. The structure of FDXjA has been
fully established by IR, DCI-MS, 'H-NMR and '^C-NMR spectra. IR spectrum exhibited
characteristic peaks at 3150 (N-H), 3050 (OH), 2900, 2850 (C-H), 1640 (CONH), 1700 (
( m O H ) , 1590 (phenyl), 1530 (C=N) and 825 cm"'. The DCI-MS spectrum showed a
260
set of [M+1]"^ peaks as the base peak at m/z 427/429 corresponding with the molecular
formula [C21H31N2O3SCI], which is equal to the sum of the molecular weights of (31)
(334/336) and mercaptoacetic acid (92). This suggested that FDXjA is an adduct of (31)
and HS.CH2.COOH. The two prominent fragment ion peaks at m/z 168/170 [(M)-
CnHssOsS]^ and m/z 154/156 [(M+O-CnHjsNOsS]^ were formed by the cleavage of
CO-NH and N-NH bonds respectively .
The 'H-NMR and '^C-NMR signals have been assigned to individual H-and C-
atoms (Table 9a) by comparing with the spectra of a previously established compound
FBXjB (25) (Table 2a). All the signals were found comparable with (25) except that it
showed no signal at 5 8.07, 8.27 (60%, 40%) corresponding to the benzylidene proton at
C-7 in (25) and in place a singlet at 5 2.22, 2.24 (~ 60%, 40%) for the methyl group at
C-7 appeared in (32). In addition, it also showed the characteristic A2B2 signals for the
jD-chlorophenyl ring. As for (25), here again both the spectra showed several double
signals for 7-CH3, C-7, C-1', C-2', and C-3' in the '^C-NMR spectrum and for H-7-CH3,
NH, H-2' in the 'H-NMR spectrum, indicating that this molecule is also present in two
different forms. The two forms were found to be in the ratio -6 :4 in DMS0-<i(5 (Table 9a
) and -3:1 in acetone-c/^ (Table 9b).
Based on the above spectral evidence, the structure of compounnd FDXiA was
characterised as 4-chloroacetophenone-l l-(carboxymethylthio)undecano hydrazone
(32)which is represented in its two forms as in Fig. 9
261
6 Q
r ?
Q to 0 03 cs -o
I. u O) a. iZl P!i §
u
-n c: «
S Z 1 a • • « OS a 3 cs H
S a
to
S3 I U
N K
s .H
^ £ bX) S « .2 -t-t a es
s a, & to'
u CJ
o r-
O
m" OS tri
O
o VO
O r .
O T
VO f^ cn —;
>n as
O
O >0
<N ON r-) in (N CN m
o oo 00 (N 1 t— IT) r—< o in
OS 00 (N 1 OS Tt in ^ (N q VO ^ f - H rn od 00 r - H en m (N m CN
(N <N " — ' ' — '
U I r- —1 <N on
o VO (N
t--l> oo
in m
as VO n
o 00 vd n
o
00 00
rr^ ri 4 ^ VO (H r n
CX t/: Vh u
a
K ffi ffi a X r<-i ^ CN CN VO ffi ffi ffi ffi ffi (N (N <N (N
O
0 1 (N oi (N CN oi
o
VO
O OS o
o s o
VO
O T —' VO
^ CN OS <N O o 00 m OS r-m in (N in in
(N 1— >—1 H (N rn
U (N r<-)
lO cn (S
I Si
in <
262
Table 9b: ^H-NMR spectral data of FDXiA (32) in acetone-rfg
H-nr 5(ppm) Integr-ation
Multip -licity
J (Hz)
7-CH3 2.30,2.34 3H s ( -25%, 75%)
NH 9.37, 9.68 IH s ( -75%, 25%)
2' 2.28,2.71 2H t J2.3'7.33, 7.32
( -25%, 75%) 3' 1.59 2H brp J«7.33
4'-9' 1.30 6x2H brs
10' 1.67 2H brp J»7.38
i r 2.64 2H t JIIMO'7.48
1" 3.22 2H s
Ar-2,6 7.84 2H d JAr-2,6 Ar-3,5 8.55
Ar-3,5 7.42 2H d JAr-3,5 Ar-2,6 8.55
2 38
H CH3
synperiplanar
H CH3
Structure Elucidation of FDX^B (33)
It was a colourless oily liquid. The structure of FDXjB has been fully
confirmed by IR, DCI-MS, "H-NMR, and '^C-NMR spectra. IR spectrum (Neat) gave
characteristic peaks at 3240 (NH), 3050 (OH), 2900, 2850 (C-H), 1700 (COOH), 1685
(CON) 1660 (CONH), 1600 (phenyl), 1420 (S-CH2), 825 and 780 cm"'. The DCI-MS
spectrum showed a set of [M+1]"^ peaks at m/z 501/503, confirming its molecular
weight 500/502 which corresponds with the molecular formula [C23H33N2O4S2CI].
This is equal to the sum of the molecular weights of compound (32) (426) plus
mercaptoacetic acid (92) minus one molecule of water. This suggested that the
formation of thiazolidinone ring has occurred by the cyclocondensation of (32) with
mercaptoacetic acid. The mode of fragmentations is shown in Chart 7, The set of
264
peaks at m/z 456/458 was due to [ (M+1) -C00H] . The diagnostic peak of the
thiazoiidinon ring was observed at m/z 427/429 [ (M+O-COCHjS] arised by the
cleavage of 1-2 and 3-4 bonds. The set of peaks at m/z 212/214 was due to
<2-cleavage (base peak) and an another set of peaks at m/z 229/231 was due to
/^-cleavage on the long alkyl chain to the thiazolidinone ring. It also showed
some common fragment ion peaks to that of (32) at m/z 276, 155, 134 and m/z
118.
nVz 456/548
O O s
HO" " f ^ T ^ N H m/z 275 (12.5)
O
HO"
O
HO'
0
^^-^fo^NH —N S
m/z 501/503 [M+1]
O
H ^ n h
m/z 427/429 (7.2/3.3)
S O m/z 155/157(31.2/13.1) m/z 197/199(13.4/4.1)
cleavage
- N "S w
o ^ m/z 229/231 (12.6/4.9)
- cleavage
m/z 212/214 (100.7/72.3)
CHART?
265
The signals in 'H-NMR and '^C-NMR spectra dissolved in acetone-c/^
have been assigned to individual H-and C-atoms (Table 10). The assignments
were made from their typical chemical shift values, multiplicity, relative
integrations and also by comparing with the spectra of the previously established
compound FBXjC (Tables 2a and 2b). All the signals in both the spectra were
found comparable except the signal for C-2 proton which didn ' t appear here at
5 6.04 and in place a new singlet at 5 1.98 for the methyl proton was observed. It
also showed a sharp singlet at 5 9.02 for the NH proton. Also in '^C-NMR
spectrum a new signal appeared at 6 20.21 for the methyl carbon at C-2. In
addition, both the spectra gave characteristic signals for the aromatic
protons/carbons of the /?-chlorophenyl ring.
Based on the above discussion, compound FDXjB was characterised as 2-
(4-chlorophenyl)-2-(methyl)-3-[l l-(carboxyrnethylthio)undecanamido]thiazo-
lidin-4-one (33).
.CI
FDX,B (33) H H
266
o c o <u u CJ
ro S3 ><
Q
O - i - t re -a
u 0 u a IZl
csj s Z 1 u f)
PS s I
£ a H
S a a CO
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s U
N X
o m d m
I U CN (N
3 .Si S c .
W) S u .M C e« l-H
s c. a
CO 00 ON
U I (N
CN ^ (N (N rn ^ I I I I
>_ u< Uc < < < <
\D m m lO (N m
MD (N <N b LO r-1
r-' OO OO rN n n I I I I
>—> > 1—1 1—) I—)
a t/2 D. -D X) -a -o -a -a
(N X X ^ X X X X X < N ( N \ 0 ( N r M r M ( N ( N
(N o ON ON 00 M OL o in lO O q in (N RO ON (N - - - - (N
o. c 3 -o in 2 (N ro C\ J b ^ ^ ^
vo m fN r<-r I ( t l fcH
- < <
(U <u > <u (D
JO
£ i C <u s d bJ3 t/2 [/3 <
67
Structure Elucidat ion of FDXj^C (34)
It was a white needle shaped crystalline solid. The structure of the compound was
established by IR, DCI-MS, 'H-NMR and '^C-NMR spectra. IR spectrum (KBr)
showed characteristic peaks at 3100 (OH, br), 1720 (COOH) and 1610 (phenyl) cm"'. In
DCI-MS spectrum the molecular ion peak was absent, but it showed a [(M)-
SCH2COOH] peak as the base peak at m/z 229/231 which corresponds with the stabile
fragment ion: HOOC-CH2-S-C^(CH3)-C6H4Cl. 'H-NMR spectrum dissolved in acetone-
de showed a singlet at 5 2.04 for the methyl proton. It also showed two doublets for two
methylene protons each at 5 3.36 (J=15.26, Hup) and 5 3.46 (J=15.26, Hdn). It gave
characteristic A2B2 signals for the p-chlorophenyl ring as doublets at 5 7.75 (J=8.85, Ar-
2,6), and 6 7.40 (J=8.85, Ar-3, 5). '^C-NMR spectrum dissolved in acetone-ii^ showed
the signals at 6c 30.25 (CH3), 61.77 (S-C-S), 34.04 (CHj), 170.80 (COOH), 142.46 (Ar-
C-1), 129.79 (Ar-C-2, 6), 129.28 (Ar-C-3, 5) and 134.03 (Ar-C-4).
Based on the above spectral evidence, compound FDX|C was characterised as
bis (carboxymethylthio)-4-chloroacetophenotal (34).
CI
H H C H j ^ ^ ^ H H HO. J X . . J X OH
O
F D X I C ( 3 4 )
268
p-Chloroacetophenone-ll-(2-carhoxyethylthio)Jundecanohydrazone FDX2A (35)
[Reaction of the hydrazone (31) with 3-mercaptopropionic acid]*
*[The target compound, 2-(4-chlorophenyl)-2-methyI-3-[l l-(2-carboxyethylthio)
undecanamido]thiazan-4-one could not be obtained probably because of increased
nucleophilicity of N=C-CH3 group carbon]
A solution of the hydrazone (31) in dry benzene was refluxed with 3-
mercaptopropionic acid (molar ratio, 1: 3) for 28 h. The products on purification by
column chromatography afforded a pale yellow solid, FDX2A (35) as the sole product
which was recrystallised (benzene-acetone) as white crystalline globules (54.2%).
Structure Elucidation of FDX^A (35)
It was a white globule shaped crystalline solid, m.p 72 °C. The structure of
FDXjA was fully established by IR, DCI-MS, 'H-NMR and '^C-NMR spectra. The IR
spectrum (KBr) gave characteristic peaks at 3175 (NH), 2900, 2850 (CH),
1680 (COOH), 1650 (CONH), 1595 (phenyl), 1540 (C=N) and 1485 (S-CH2) cm''.
The DCI-MS spectrum showed a set of [M+1]"^ peaks as the base peak at m/z 441/443,
confirming its molecular weight 440/442 which corresponds with the molecular formula
[C22H33N2O3SCI]. This is equal to the sum of the molecular weights of (31) (334/336)
and 3-mercaptopropionic acid (106). This indicated that FDX2A is an adduct of (31)
with HS.CH2.CH2.COOH. Other two prominent fragment ion peaks were observed at
m/z 169/170 [(M+1)-C,3H2303S] due to the cleavage of CO-NH bond and m/z 153/155
[(M+l)-Ci3H25N03S,] arised by the cleavage of N-NH bond.
The 'H-NMR and '^C-NMR signals could be easily assigned to individual H-and
C-atoms (Table 11) by comparing the spectra with that of previously established
269
I o
S Q a
(n <
X Q fe O a •M C5 -o
u u O) a
u
•o B «
s « H
e a.
60
L. C I
U
N ffi
W g C «
^ u
a a w to
o
o
VO r-i
O
O
o
CO ON
o Cp vO . o
o VO I
T
lO
On VO
(N O) rn m
r\
(N o4 m
00 r-00 (N 1 o 00 m
OO o 00 >—1 in o CS »—< p CO tn 00 rn 00
•tt 00 1-H rt r- m (N m CN (N m (N T—(
o r i
(N r^ rj- (N < <
in r-T < <
tn u-i I/O tn oo oo
rn (N p r-" »
(N »
r-r-' o
a\ a\ vd
tN <N ~ — (N
X) ^ t
( y - l ^
u — ^ X X X ^ ffi ffi E E E n: CN CS (N <N <N (N
O
o
(N <N
(N CN
O
o
o Tj-
o
o
rn o
(N m (N
-H Tt m (N ON 00 O 00 C--in IT) t-; Tt;
(N (S (N
S I U X
z tr-0 I
cs
(N ro I I
270
compounds FBX2B.(29)^ and FDXiA.(32) (Tables 6a, 6b and 9a, 9b). Both the spectra
revealed the double signals corresponding to synperiplanar and antiperiplanar
conformers around CO-NH bond as in (29) and (32).
Based on the above spectral evidence, the structure of compound FDX2A was
characterised as p-chloroacetophenone-1 l-(2-carboxyethylthio)undecano hydrazon (35)
which is represented as in Fig. 10
synpe r ip l ana r
H CH3
71
EXPERIMENTAL
p-Chloroacetophenone-10-undecenohydrazone (31)
A mixture of 10-undecenoicacid hydrazide (23) (4.00g, 0.0202 mol) and p-
chloroacetophenone (3.122g, 0.0202 mol) dissolved in dry benzene (50 ml) was refluxed
for 6 h as described in (24) and then worked up as usual. The products on crystallization
from ethanol furnished FD (32) as white crystalline needles, 5.624g (83%), m.p. 64 °C,
Rf 0.80 (benzene- diethylether, 6 : 4 v/v)
IR (KBr): 3175 (NH), 2900, 2850 (C-H), 1675, 1650 (CO), 1595 (phenyl,
C=C), 1540 (C=N), 1485, 1420, 1395, 1 180, 1110, 1090, 980, 900, 820 cm"'.
' H - N M R (400 MHz, acetone-^/^,): 8H 2.34, 2.76 ( -75%, 25%; 3H, s, CH;,-?).
9.37, 9.68 ( -75%, 25%; IH, s, NH), 2.28, 2.73 ( - 2 5 % . 75%; 2H, t, J=6.71, 7.62.
H-2'), 1.66 (2H, br p, J^7.48, H-3'), 1.31 (lOH, brs, H-4 '-8 ' ) , 2.04 (2H, m, H-9'),
5.79 ( IH, tdd, J -6 .72 , 17.09, 10.22, H-10') , 4.88 ( IH, dd, J=10.22, 2.29, Hg),
4.95 ( IH, dd, J= 17.09, 2.29, Hz), 7.84 (2H, d, J= 8.55,Ar-2,6), 7.42 (2H, d, J=
8.55, Ar-3,5).
'H-NMR (400 MHz, DMS0-</<5,): 5 H . 2 . 2 1 , 2 . 2 4 ( - 6 0 % , 4 0 % ; 3 H , s, 7-CH3), 10 .29,
10 .39 ( 4 0 % , 6 0 % ; I H , s, N H ) , 2 .31 , 2 . 6 4 ( 4 0 % , 6 0 % ; 2 H , t, J = 7 . 5 1 , 7 . 3 2 , H - 2 ' ) , 1.57
( 2 H , b rp , J - 6 . 9 6 , H - 3 ' ) , 1-28 (LOH, brs , H - 4 ' - 8 ' ) , 2 . 0 0 ( 2 H , td, J = 7 . 1 4 , 6 5 9 , H - 9 ' ) , 5 .76
( I H , ddt , J = 1 7 . 0 3 , 10.25, 6 .59 , H - 1 0 ) , 4 . 9 2 ( I H , dd , J = 1 0 . 2 5 , 2 . 1 4 , H E - 1 1 ' ) , 4 . 9 8 ( I H ,
dd , J - 1 7 . 0 3 , 2 .15 , H z - 1 1 ' ) , 7 .77 ( 2 H , d, J = 8 . 6 0 , A r - 2 , 6 ) , 7 .45 ( 2 H , d, J = 8 . 6 0 , A r - 3 , 5 ) .
'^C-NMR (lOOMHz, DMSO-rfg): 5c 13.19, 13.76 (-60%, 40%; C-7-CH3), 145.43,
149.35 (-60%, 40%; C-7), 175.13, 169.16 (-60%, 40%; C-1'), 32.25, 33.92 (-60%,
272
40%; C-2'), 24.20, 25.07 (-60%, 40%; C-3'), 28.18-28.87(C-4'-8'), 33.07 (C-9'),
138.73 (C-10'), 114.49 (C- l l ' ) , 133.66 (Ar-C-1), 127.51 (Ar-C-2,6), 128.25 (Ar-C-3,5),
137.11 (Ar-C-4).
DCI-MS (NH3): m/z 335/337 [(M+1) 100.0/48.4; CigHjyClNzO], 336 (49.6), 338 (21.8),
339 (7.7), 210 (7.8), 168/170 [(M+l)-CnH,90, 47.7/18.9], 169 (21.3), 171 (6.5), 167
(6.7), 152/154 [M-CnH2oNO, 10.6/7.5] and 153 (6.3).
p-Chloroacetophenone-ll-(carboxymethylthio)undecanohydrazone FDXjA (32), 2-(4-
cltloroplienyl)-2-methyl-3-[ll-(carboxymethylthio)undecanamido]thiazolidin-4-one
FDX,B (33) and bis(carboxymethylthio)-4-chloroacetophenotal FDX,C (34).
[Reaction of the hydrazone (31) with mercaptoacetic acid]
A mixture of the hydrazone (31), (0.782 mg, 0.0085 mol) dissolved in dry
benezene (20 ml) was refluxed with stirring for 24 h and worked up as described in (24).
The products on purification by column chromatography (silica gel, light pet.ether-
diethyl ether, 1:1 v/v) as eluent first afforded a yellow solid, labelled as FDX,A (32)
which on crystallization from EtOAc afforded crystalline globules, 520 mg (41.2%), m.p
68 °C, Rf 0.49 (benezene-diethylether, 6:4 v/v). Further elution of the column using light
pet.ether-diethylether, 3:7 v/v) furnished a colourless oily liquid, labelled as FDXjB (33)
490 mg (33.3%), Rf 0.39 (benzene-diethylether, 6:4 v/v) and then a pale yellow solid
labelled as FDXiB (34) which on crystallization from EtOAc gave white crystalline
needles, 120mg (13.2%), m.p.l04 °C, RfO.33 (benzene-diethylether, 6:4v/v).
273
Spectral data of FDX^A(32)
IR (KBr): v„ax 3150 (NH), 3050 (OH) 2900, 2850 (C-H), 1700 (COOH), 1640
(CONH), 1590 (phenyl), 1530 (C=N), 1480 (S-CH2) 1420, 1395, 1360, 1250,
1180, 1085, 825 cm"'
' H - N M R (400 MHz, acetone-fiTg): 5H 2.30, 2.34 ( - 2 5 % , 75%; 3H, s, CH,-7),
9.37, 9.68 ( - 7 5 % , 25%; IH, s, NH), 2.28, 2.71 ( - 2 5 % , 75%; 2H, t, J - 7.32.
7.33), 1.59 (2H, br p, J«7.33, H-3'), 1.30 (12H, br s, H-4 ' -9 ' ) , 1.67 (2H,br p.
J«7.48,H-10') , 2.64 (2H, t, J= 7.48, H-11') , 3.22 (2H, s, H-1" ) . 7.84 (2H, d, J=
8.55, Ar-2,6), 7.42 (2H, d, J=8.55, Ar-3,5).
' H - N M R (400 MHz, DMSO -RFG): SH 2.22, 2.24 ( - 6 0 % , 40%; 3H, s, CH,-7).
10.29, 10.39 ( - 4 0 % , 60%; IH, s, NH), 2.31, 2.64 ( -40%, 60%, 2H, t, J= 7.17, H-
2'), 1.50 (2H, br p, J «7.63, H-3'), 1.24 (12H, br s, H-4 ' -9 ' ) , 1.58 (2H, br p, J
-6 .87 , H-10 ' ) , 2.55 (2H, t, J =7.17, H - l l ' ) , 3.19 (2H, s, H-1" ) , 7.77 (2H, d, J =
8.55, Ar-2,6), 7.45 (2H, d, J = 8.55, Ar-3,5).
'^C-NMR (100 MHz, DMSO-rf^,): 5c 13.19, 13.76 ( - 6 0 % , 40%, CH3-7), 145.43,
149.36 ( -60%, 40%; C-7), 169.16, 175.13 ( -40%, 60%; C-1') , 32.25, 33.92
( -60%, 40%; C-2 ') 24.19 (C-3'), 28.0-28.80 (C-4'-10') . 31.64 (C-11') , 171.47
(C-2") , 33.19 (C-1") , 133.45 (Ar-C-1), 127.51 (Ar-C-2,6), 137.10 (Ar-C-4),
128.25 (Ar-C-3,5).
DCI-MS (NH3): m/z 427/429 [(M+1); 100.0/57.7 C21H3J CIN2O3S], 428 (72.5), 430
(31.6), 431 (11.3), 276 (11.1), 210 (9.3), 168/170 [(M)-Ci3H2303S, 40.4/18.9], 169
274
(24.0), 171 (10.1), 154/156 [M+1)-C,3H25N03S, 36.7/12.9], 155 (16.5), 152 (15.0), 153
(8.8), 73 (6.9).
Spectral data of FDXiB (33)
IR (Neat): v^^, 3240 (N-H), 3050(OH), 2900, 2850 (C-H), 1700 (COOH), 1660
(CON), 1640 (CONH), 1600 (phenyl), 1430 (S-CH2), 1240, 1160, 870, 780 cm"'
'H-NMR (400 MHz, acetone-cT^,): 5h 1-98 (3H, s, CH3-2), 3.45 ( I H , d, J=15.56,
H-5up), 3.53 ( IH , d, J=15.56, H-5dn), 9.02 ( lH,s , NH), 2.07 (2H, t, J=7.62, H-
2') , 1.49 (2H, br p, J=7.13, H-3') , 1.19 (12H, br s, H-4 ' -9 ' ) , 1.58 (2H, brp,
J=7.24, H-10 ' ) 2.63 (2H, t, J=7.33, H-11 ' ) , 3.22 ( IH , s, H-1"), 7.30 (IH, d.
J=8.53, Ar-2,6), 7.25 ( IH, d, J=8.53, Ar-3,5).
'^C-NMR (100 MHz, acetone-</<5,): 5c 25.21 (2-CH3), 67.19 (C-2), 172.12 (C-
4), 33.87(C-5), 172.48 (C-T) , 34.18 (C-2') , 25.97 (C-3 ' ) , 29.48-30.30 ( C - 4 ' -
11'), 33.77 (C-1"), 169.65(C-2"), 138.13 (Ar-C-1), 128.84 (Ar-C-2,6), 129.36
(Ar-C-3,5), 133.24(Ar-C-4).
D C I - M S (NH3): m/z (%) 501/503[(M+1)\ 12.3/5.7], 456/458[(M+l) -C02H,
11.7/4.8], 427/429[(M+1)-SCH2C0, 7.3/3.3], 273(10.8), 274 (10.2), 275(12.5),
276( 53.5), 277 (21.8), 278 (8.3), 258 ( 6.7), 259 (11.3), 239 (7.2), 240 (31.8),
241 (13.9), 242 (11.8), 230 (10.9), 231 ( 25.4), 232 (16.3), 223 (27.2), 224
(12.2), 210 ( 34.5), 212 (100.0), 213 (47.4) 214 (72.3), 215 ( 33.5), 216 (11.8),
217 (5.7), 218 (14.5), 197(13.4), 199 (4.1), 176 (11.8), 178 (12.7), 162 (8.1),
163 (8.2), 164 (8.1), 165 (7.9), 166 (40.4), 148 (15.0), 149 (10.0), 150 (9.0), 151
(15.4), 152 (16.3), 153 (7.5), 134 (42.2), 135 (20.0), 136 (32.2), 137 (19.0), 138
(12.0), 168 (18.4), 169 (13.0), 171 (8.1), 154 (22.9), 155 (13.5), 152 (17.0).
2 75
S p e c t r a l da ta of FDXi^C (34)
IR (KBr): v^^x 3100 (OH, br), 1720 (COOH), 1610 (phenyl), 1510, 1400, 1300, 1270,
1170, 1140, 1030, 840, 760 cm"'.
'H-NMR (acetone-rffi): 5h 2.04 (3H, s, CH3), 3.36 (2H, d, J = 15.26, H up), 3.46 (2H, d,
J= 15.26, H dn), 7.75 (2H, d, J=8.85, Ar-2,6), 7.40 (2H, d, J=8.85, Ar-3,5).
'^C-NMR (acetone-dg): 5c 30.25 (CH3) 61.77 (S-C-S), 34.04 (CH2), 170.80
(COOH), 142.46 (Ar-C-1), 129.79 (Ar-C-2,6), 129.28 (Ar-C-3,5), 134.03 (Ar-
C-4)
DCI-MS (NH3): m/z 229/231 [M-(SCH2.C00H), 100.0/231.0], 230 (39.8), 232 (14.8),
171 (23.7), 172 (9.2), 173 (9.5), 139 (14.9), 140 (6.0), 141 (6.0), 85 (5.0)
p-Chloroacetophenone-ll-[(2-carboxyethylthio)]undecanohydrazone F D X 2 A ( 3 5 )
[Reaction of the hydrazone (31) with 3-mercaptopropionic acid]
To a solution of the hydrazone (31) (1.0 g, 0.0028 mol) in dry benzene (20 ml)
was added 3-mercaptopropionic acid (0.903 g, 0.0085 mol) and refluxed for 28 h. The
products on usual work up and column chromatography (silica gel, pet. ether-diethyl
ether, 1:1 v/v) followed by crystallization from (benzene-acetone) afforded the sole
product F D X 2 A ( 3 5 ) as white crystalline globules, 705 mg (54.2%), m.p 72 °C , RF 0.48
(benzene-diethylether, 6:4 v/v).
Spectral data of FDX^A (35)
IR (KBr) : v„,ax 3175 (NH), 2900, 2850 (CH), 1680 ( m O H ) , 1650 (CONH), 1595
(Phenyl), 1540 (C=N), 1485 (S-CH2), 1420, 1460, 1400, 1250, 1190, 1110, 1090, and
825 cm-'.
276
'H-NMR (400 MHz, DMSO-^/tf ) : 6h 2.24, 2.27. ( -60%, 40%; 3H, s, 7-CH3),
10.31, 10.40 ( -40%, 60%; IH, s, NH), 2.32, 2.66 ( -40%, 60%; 2H, t, J =7.42, H-
2'), 1.51 (2H, brp, J;^7.12, H-3'), 1.24 (6x2H, br s, H-4'-9 ' ) , 1.59 (2H, br p, J
^7.02, H-10') , 2.48 (2H, t, J=6.96, H-11') , 2.65 (2H, t, J = 6.79, H - l " ) , 2.50 (2H,
t, J=6.79, H-2") , 7.78(2H, d, J=8.55, H-Ar-2, 6), 7.47 (2H, d, J= 8.55, H-2") ,
7.78 (2H, d, J=8.55, H-Ar-2, 6), 7.47 (2H, d, J -8 .55 , H-Ar-3,5);
'^C-NMR (100 MHz, DMSO-^/^,): 5c 13.20, 13.76 ( -60%, 40%; 7-CH3), 145.42,
149.34 ( - 6 0 % , 40%; C-7), 169.14, 175.11 ( -40%, 60%; C-1 ' ) 32.24, 33.92
( -60%, 40%; C-2') , 24.18(C-3'), 28.10-28.78 (C- 4 '-10') . 31.08 ( C - I T ) , 26.34
(C-1"), 34.51(C-2") , 178.47 (C-3") , 133.44 (C-Ar-1). 127.50 (C-Ar-2, 6),
137.08 (C-Ar-3, 5), 128.25 (C-Ar-4).
DCI-MS: m/z (%) 441 (100.0), 443949.7), 169 (18.3), 170 (5.9), 171 (8.9), 153
(16.7), 155 (6.8).
277
REFERENCES
1. F.C. Brown, Chemical Review, 1961, 464.
2. S.P. Singh, S.S. Parmar, K. Raman and V.I. Stenberg, Chemical Review,
1981, 175.
3. K.A. Zolotoreva and L.A. Pugacheva, Voronezh, 1964, 5, Chem. Abstr.,
1966, 65, 18765.
4. G. Danila, Rev. Chim. (Bucharest), 1978, 29, %2Q;Chem. Abstr.,1979,
90, 72086 p.
5. G. Danila, Rev. Chim. (Bucharest), 1978, 29, 1 152; Chem. Abstr., 1979,
90, 152037 p.
6. N.C. Desai, Dipika Dave, M.D. Shah and G.D. Vyas, Indian J. Chem,
2000, 39B, 277.
7. (a) J. Mohan, V.K. Chada, H.S. Chaudhry, B.D. Sharma and H.K.
Pujari , Indian J. Exp. Biol, 1972, 10, 37 (b) H.Y. Hassan, N. El-
Koussi and Z.S. Farghaly, Chem. Pharm. Bull, 1998, 46, 863.
8. S.B. Desai, P.B. Desai, K.R. Dtssa, Asian J. Chem. 1999, 15(2), 363.
9. R.C. Sharma and D. Kumar, J. Indian Chem. Soc., 2000, 77, 492.
10. E. Piscapo, M.V. Diurno, R. Gagliardi and O. Mazzoni, Boll. Soc. Ital.
Biol. Sper.,m9, 65 (9), 853.
11. C.R. Harris and S.A. Turnbull, Can. EntomoL, 1977, 109, 1 109.
12. D 'Si lva and D.J. Themistocles, US Patent, 760629 (1976); Chem.
Abstr., 1977, 86, 29794y.
13. T.Z. Sainai, Acta Phytopathol. Acad Sci. Hung., 1974, 9, 125, Chem.
Abstr., 1975, 83, 23396m.
14. (a) T. Takematsu, M. Furushima and Y. Hasegawa, Japanese Patent,
7243812 (1972), Chem. Abstr., 1973, 79, 143522 p. (b) T. Takematsu,
2 78
K. Yokoyama, K. Ikeda and Y. Hayashi, Japenese Patent, 75121431
(1975); Chem. Abstr., 1976, 84, 26880 w.
1 5 . E.A.S. Lacroix, British Patent, 1 3 9 0 5 5 0 ( 1 9 7 5 ) ; Chem. Abstr., 1 9 7 5 ,
8 3 , 9 2 3 9 5 X .
16. J.M. Cox, J.M. Clongh, N.J. Barnes, D.P.J. Pearson, I.R. Mathews, S.K.
Vohra, S.C. Smith, G. Mitchell and R.A. Barbe, PCT Int. Appl, WO
9533, 719 (1995); Chem. Abstr., 1995, 124, 261022w.
17. M. Takano, M. Enomoto, K. Saito and S. Kizawa, Japanese Patent,
07,304,759 (1995). Chem. Abstr., 1997, 124, 202239z.
18. (a) W.M. McLamore, W.D. Celmer, V.V. Bogert, F.C. Pennington and
l.A. Solomons, J. Am. Chem. Soc., 1952, 74, 2946. (b) W.M.
McLamore, W.D. Celmer, V.V. Bogert, F.C. Pennington, B.A. Sobin
and l.A. Solomons, J. Am. Chem. Soc., 1953, 75, 105. (c) W.M.
McLamore, W.D. Celmer, V.V. Bogert, F.C. Pennington and l.A.
Solomons, J. Am. Chem. Soc., 1953, 75, 109.
19. H. Oza, D. Joshi and H. Parekh, Indian J. Chem., 1998, 37B, 822.
20. K. Raman, B. R. Pandey, J.P. Barthwal and K.P. Bhargava, Res.
Commun. Chem. Path. Pharmacol., 1977, 18, 765.
21. (a) M.M. Hansen, A.R. Harkness, V.V. Khan and M.J. Martinelli, PCT
Int. Appl, W09619466 (1996), Chem. Abstr., 1996, 125, 142717n. (b)
M.M. Hansen, A.R. Harkness, and S.M. Rentzel, Eur. Patent,
EP761656 (1995), Chem. Abstr., 1997, 126, IIIAIOX.
22. A. Kumar, T. Ram, R. Tyagi, B. Goel, E. Bansal and V.K. Srivastava,
Boll. Chem. Farm., 1998, 137(5), 152.
23. T. Previtera, M.G. Vigorita, G. French and C. Zappala, Farmco., 1994,
49(10), 33.
24. M. Kakakami, K. Koya, T. Ykai, N. Tatsuta, A. Ikegawa, K. Ogawa, T.
Shishido and L.B. Chen, J. Med. Chem., 1997, 40(20), 3151.
279
25. M. Chaudhry, S.S. Parmar, S.K. Chaudhry, A.K. Chaturvedi and B.V.
Ramasastry, J. Pharm. Sci., 1976, 65, 443.
26. (a) N.J. Hrib and J.G. Jurcak, J. Med. Chem., 1992, 35(14), 2712.
(b) N.J. Hrib and J.G. Jurcak, US Patent, 5,229,388 (1993), Chem.
Abstr., 1994, 120, 270452f.
27. N.J. Hrib, J.G. Jurcak, D.E. Bregna, K.L. Burgher, H.B. Hartman,
S.Kafka, L.L. Kerman, S. Kongsamat and J.E. Roehr, J. Med. Chem.,
1996, 39(20), 4044.
28. A. Grafe, H. Leibig and G. Dransch. German Patent, 2151229 (1973),
Chem. Abstr., 1993, 79, 9921q.
29. J.L. Krans, J.C. Graciet and M. Gamberono, PCT Int. Appl.
W09734891 (1996), Chem. Abstr., 1997, 127, 307620g.
30. J.C. Graciet, V. Niddam, M. Gamberoni, C. Tarabans, J. Dessolin, M.
Medon, N. Mourier, F. Zonlim and C. Borel, Bioorganic Med. Chem.
Lett., 1996, 6(15), 1775.
31. R. Shyam and I.C. Tiwari, Bull. Chem. Soc. Jpn., 1977, 50, 514.
32. A.K. Dimri and S.S. Parmar, J. Heterocycl. Chem., 1978, 15, 335.
33. S. Nagar, H.H. Singh, J.N. Sinha and S.S. Parmar, J. Med. Chem., 1973,
16, 178.
34. N. Ergene and G. Capan, Farmaco., 1994, 49(6), 449.
35. R. Girandon, French Patent 2,108834 (1972), Chem. Abstr., 1973, 79,
32040K.
36. R. Aries, French Patent 2,186,245 (1974), Chem. Abstr., 1974, 81,
140869n.
37. S.S. Parmar, C.Duivedi, A. Chaudhry and T.K. Gupta, J. Med. Chem.,
1972, 15, 99.
38. M.V. Diurno; O. Mazzoni; A.A. Izzo and A. Bolognese, II farmaco.,
1997, 52, 237.
280
39. M. Missbach, Eur. Pat. Appl. EP 548,017 (CI. 07D417/12), 1993.
40. Y. Natsume, N. Imanishi, H. Koike and S. Morooka, Arzneium-Forsch.,
1994, 44(11), 1208.
41. (a) Y. Tanabe, H. Yamamoto, M. Murakami, K. Yanagi, Y. Kubota, H.
Okumura, Y. Sanemitsu and G. Suzukamo, J. Chem. Soc. Perkin Trans.
I, 1995, 7, 935. (b) Y. Tanabe, Y. Komuro, N. Imanishi, S. Morooka,
M. Enomoto, A. Kojima, Y. Sanemitsu and M. Mizutani, Tethedron.
Lett., 1991, 32, 379.
42. M.V. Diurno, O. Mazzoni, G. Correale and I.G. Monterry, Farmaco.,
1999, 54(9), 579.
43. T. Previtera, M.G. Vigorita, M. Bisila, F. Orsini, F. Benetolla and G.
Bombieri, Eur. J. Med. Chem., 1994, 29(4), 317.
44. Y. Tagami, T. Yamaguchi, J. Kubo, J. Shimozono, K. Yonemuna and
M. Mukai, Japanese Patent, 0 9 0 3 0 6 7 ( 1 9 9 7 ) , Chem. Abstr.. 1 9 9 7 . 1 2 6 ,
1 7 1 5 9 2 U .
45. H. Ueno, T.Oe, I. Snehiro and Nakamura, US Patent, 55941 16 ( 1 9 9 7 ) ,
Chem. Abstr., 1911, 126, 157507p.
46. B. Valleskey, M. Juliana, D.C. Hunder, C.D. John. J.A. Panetta and
W.N. Shaw, Eur. Patent, 587377 (1994), Chem. Abstr., 1994, 121,
35596t.
47. D.A. Walsh and I.M. Uwaydah, US Patent, 5061720 (1991), Chem.
Abstr. 1992, 116, 59362m.
48. T. Kato, T. Ozaki and K. Tamura, J. Med. Chem., 1999, 42, 3134.
49. N.A. Castle, M. Gross and J.S. Mendoz, PCT Int. Appl. WO 99 62891
(C1.C07D277/14), US Appl, 307708 (1999).
50. S.P. Sahoo, C. Santini, J.K. Boilers, K. Julia, J.V. Heck, E. Metzger and
V.K. Lobardo, PCT Int. Appl, WO 0078, 312 (C1.A61K31/421), 2000,
US Appl, PV 139, 953, (1999).
281
51. T. Kato, T. Ozaki, K. Tsuzuki and N. Ohi, Org. Process Res. Dev.,
2001, 5(2), 122.
52. S.K. Chugai, K. Tamura, Y. Suzuki and M. Akima, PCT Int. Appl, WO
96, 19, 210, 1996, Chem. Ahstr., 1996, 125, 142718.
53. T. Kato and T. Ozaki, PCT Int. Appl, WO 95,00,471 (1995), Chem.
Abstr., 1995, 122, 29084j .
54. M.Y. Ebeid, O.A. Fathallah, M.I. El-Zaher, M.M. Kamel, W.A.M.
Abdon and M.M. Anwar, Bull. Fac. Pharm., 1996, 34(2), 125, Chem.
Abstr., 1997, 126, 180829d.
55. P. Chang and M.C. Hung, Zhonghua Yaoxchang Zazhi, 1991, 43(6),
437, Chem. Abstr., 1992, 116 ,128834f
56. K.Daichii, Jpn. kokai, Tokyo koho JP, 8299523 (C1.A61K31/54) 1982,
Chem. Abstr., 1982, 97,1042299
57. T. Kawasaki, D. Immaru, Y. Osaka, T. Tsuchiya and S. Ono, Eur. Pat.
Appl, EP 50003 (CI. C07D279/06), 1982, 9792300b, Chem. Abstr..
1982, 97, 92300b.
58. El.Sayeed, Aboul-Enein and Y. Hassan. Arch. Pharma, 2001, 334(4),
117.
59. R. Sharma, S. Kumar and H.K. Pujari, Indian J. Chem., 1990, 29B, 440.
60. V. Peesapati and G. Rupavani, Indian J. Chem., 1998, 37B, 468.
61. M.A. Salama and S.A. El-Essa, Indian J. Chem., 2001, 40B, 678.
62. M. Missbach, PCT Int. Appl W09514685 (C1.C0.7D, 279/06), 1995,
Chem. Abstr., 1995, 123, 169640c.
63. M. Missbach, PCT Int. Appl W09514687 (C1.C0.7D, 279/06), 1995,
Chem. Abstr. 1995, 123, 169642e.
64. M. Dzurilla, P. Kutschy, D. Koscik, V. Ficeri and R.K. Kraus, Chem.
Pap., 1990, 44(1), 45.
282
65. D J . Anderson and B.E. Loughman, US 4352929, (Cl.544-54, C0 .7D,
279/06), 1982, Chem. Abstr. 1983, 98, 16708w.
66. C.Y.G. Chiou. US Patent, US 5194434 (Cl.514-227, A61K 31/535),
1993, Chem. Abstr., 1993, 118, 198246f.
67. A.K. Padhy, V.L. Nag and C.S. Panda, Indian J. Chem., 1999, 38B(8),
998.
68. M.G. Vigorita, S. Grasso, M. Zappala, R. Ottana, M.T. Monforte, R.
Barbara and A. Trovato, Farmaco., 1994, 49(4), 271.
69. K. Mogilaiah, P. R. Reddy and R.B. Rao, Indian J. Chem., 1999, 38(B),
495.
70. S. B. Kalaiya and A.R. Parikh, J. Indian Chem. Soc., 1987, 64, 172.
71. R.R. Astik, G.B. Joshi and K.A. Thaker, J. Indian. Chem. Soc., 1975.
52, 1071.
72. S.R. Maynard, J. Heterocycl. Chem., 1974, 587.
73. I.V. Smolanka, U.Y. Mignalia and V.I. Staninets, Ukr. Khim zh., 1966,
32(6), 610, Chem. Abstr., 1966, 65, 12199.
74. M. Kidwai, N. Negi and P. Misra, J. Indian. Chem. Soc., 2000, 77, 46.
75. Y. Tanabe, M. Nagoasa and Y. Nishii, Heterocycl, 1995, 41(9), 2033.
76. H. Oza, D. Joshi and H. Parekh, Indian J. Chem., 1998, 37B, 822.
77. R.S. Lodhi, S.D. Srivastava and S.K. Srivastava, Indian J. Chem., 1998,
37B, 899.
78. H.D. Joshi, P.S. Upadhyay and A.J. Baxi, Indian J. Chem., 2000,
39B(12) 967.
79. K. Mogilaiah, R.B. Rao and G.R. Sudhakar, Indian J. Chem., 2001,
40B(4), 336.
80. E. Bansal, J. Ram, S. Sharma, M. Tyagi and A.P. Rani, Indian J. Chem.,
2001, 40B, 307.
283
81. Y. Satyanarayana and A.H. Siddiqui, Indian J. Chem., 1994, 33B, 569.
82. (a) A.R. Surrey, J. Am. Chem. Soc., 1947, 69, 2911 (b) ibid., 1948, 70,
4262 (c) ibid, 1949, 71, 3105, 3354 (d) A.R. Surrey and R.A. Cutler,
ibid., 1954, 578.
83. Nasirullah, F. Ahmad, S.M. Osman and W. Pimlott, J. Am. Oil. Chem.
Soc., 1982, 59, 411.
84. A. Khan, S. Rafat Husain, F. Ahmad, M.S. Siddiqui and W. Pimlott,
Lipids, 1987, 22(8), 578.
85. J. Mustafa, M.S. Ahmad Jr. and S.M. Osman, J. Chem. Res. (S), 1989,
7, 220.
86. F. Khatoon, R. Pachaury and W.H. Ansari, J. Indian Chem. Soc., 1997,
74, 417.
87. (a) S. Mukhtar, V.P.M. Rahman, W.H. Ansari, G. Lemiere, A. De.
Groot and R. Dommisse, Molecules, 1999, 4, 232, (b) S. Mukhtar, Ph.D
thesis, Aligarh Muslim University, 2002.
88. S.P. Singh, W.H. Ansari, G. Lemiere, T. Jonckers and R. Dommisse,
Eur. J. Med Chem., 2002, 37, 63.
89. K. Pilgrim and G.E. Pollard. J. Heterocycl. Chem., 1977, 14, 1029.
90. S. Satsumabayashi, S. Moroki, K. Murata and A. Takahashi, Synthesis,
1977, 881.
91. (a) K.C. Joshi, A. Dandia and N. Ahmed, Indian J. Chem., 1989, 28B,
639 (b) K.C. Joshi, R. Patni and P. Chand, Heterocycles, 1981, 16,
1551.
92. Z. Paryzek and M. Kielczewski, Bull. Acad. Polon. Sci. Ser. Sci. Chim.,
1975, 23, 9.
93. Shafiullah and H. Aligarh, J. Steroid Bio chem., 1980, 13, 467.
94. S. Marzooq, Al-Thebeiti and F. Maher Ei-Zohry, Indian J. Chem., 1998,
37(B), 804.
284
95. G. Satzunger, Leibigs An. Chem., 1963, 665, 150.
96. P. Monforte, G. Fennech, M. Basil, P. Ficarra and A. Silvestro, J.
Meterocycl. Chem.,\919, 16, 341.
97. P.S. Upadhyay, R.N. Vansdadia and A.J. Baxi. Indian J. Chem., 1990,
29B, 793.
98. M.T.M. El-Kiassimy, A.M. Rahman, G.A. El-Sarat and A.K. Mahmad,
Pure. Appl. Sci. Bull, 1992, 8, 1.
99. A.K. Dimri and S.S. Parmar, J. Heterocycl. Chem., 1978. 15, 335.
1 GO. O.A. El-Sayeed and H.Y.Aboue Enein, Arch. Pharm.,2001, 334(4), 117.
101. C. Dwivedi, T.K. Gupta and S.S. Parmar, J. Med. Chem., 1972, 15, 553.
102. V. N. Chaubey and H. Singh. Bull. Chem. Soc. Jpn., 1970, 43, 2233.
103. H.Y. Hasan, N.A. Al-Koussi and Z.S. Farghaly, Chem. Pharm. Bull.,
1998, 46(5), 863.
104. Shamsuzzaman, A. Salim and M. K. Akram, Indian J. Chem., 1999,
38B, 1218.
105. (a) J. Mohan, Anupama, A. Kumar, A. Kumar and D. Khetar, Ind. J.
Heterocycl. Chem., 2000, 9(4), 251 (b) J. Mohan, G.S.R. Anjanayelu
and D. Madan, J. Indian Chem. Soc., 1991, 68, 252.
106. Rampal, R.N. Handa and H.K. Pujari, Indian J. Chem., 1994, 33B, 520.
107. V. Peesapati and G. Rupavani, Indian J. Chem., 1998, 37B, 468.
108. A.F. Minka, Farm. Zh., 1964, 19, 47, Chem. Abstr., 1966, 64, 3514c.
109. S.C. Mahukar, M.P. Aslam, S.B. Ambhaikar, Indian. J. Chem., 2002,
39B, 603.
110. A.N. Arakelian, H. Dunn, L.L. Grieshammer and L.E. Cokman, J. Org.
Chem., 1960, 25, 465.
111. R. Deghengi and G. Daneault, Can. J. Chem., 1960, 38, 1255.
285
112. J.P. Trivedi, S.J. Contractor and I.D. Shah, J. Indian Chem. Soc., 1966,
43, 265.
113. V. Kishore, N.K. Narain, S. Kumar and S.S. Parmar, Pharmacol. Res.
Commun., 1976, 8, 43.
114. (a) H. Nagase, Chem. Pharm. Bull, 1973, 21, 270 (b) ibid., 1973, 21,
279.
115. E.N. Cain and R.N. Warrener, Aust. J. Chem. 1970, 23, 51.
116. (a) N.P. Buu-Hoi and D. Lavit, J. Org. Chem., 1955, 20, 1191 (b) N.P.
Buu-Hoi and D. Lavit, J. Chem. Soc., 1958, 21, 1721 (c) C. N.P. Buu-
Hoi, T.B. Loc and N.D. Xyong, J. Org. Chem., 1958, 21. 1458 (d) N.P.
Buu-Hoi and N.D. Xyong, Bull. Soc. Chem. France, 1958, 21, 758 (e)
N.P. Buu-Hoi, N.D. Xuong and F. Binon, J. Chem. Soc., 1996, 713.
117. (a) V.S. Ingle, A.R. Sawale, R.D. Ingle and R.A. Mani, Indian J.
Chem., 2001, 40B(2), 124. (b) K.C. Joshi, V.N. Pathak and R.K.
Chaturvedi, Pharmazie, 1986, 41, 634.
118. H. Tamiyama, Y. Tanaka and H. Uchida, J. Pharm. Soc. Jpn, 76, 147-
149, 1956.
119. A.H. Siddiqui, K. V. Rao and D. Ramesh, Indian J. Chem., 1989, 28B,
762.
120. Y. Tomita, T. Ohkawara, T.Yamasaki and M. Furukawa, Heterocycles,
1990, 31(12), 2139.
121. A.A. Elagamey and M.A. Sofan, An. Quim, 1990, 86(1), 62, Chem.
Abstr., 1991, 144, 42713n.
122. (a) M. Dzurilla, P. Kutschy, J. Imrich, D. Koscik and R. Kraus, Collect,
Czech. Chem. Comm., 1991, 56(6), 1287, Chem. Abstr., 1991, 115,
9221 IP (b) M. Dzurilla, PI Kutschy, P. Kristian and D. Koscik, Chem.,
Pap., 1990, 44(2), 221.
286
123. H.H. Elghandour Ahmad, M.M. Ramiz Mahmoud, A.S. Ghozlan Said
and R.H. Elmoghayar Mohamad, Leibigs Ann. Chem., 1988, 10, 983.
124. A.F.S. Ahmad, N. Aouf and M. G. Assy, J. Chem. Res. Synop., 1998. 9,
508.
125. (a) J.C. Derrick and H.J. Soleiman, J.Org. Chem., 2000, 65 ,4943 (b) C.
Stepane, C. Pierre, C.J. Louis and T.J. Yves, Chem. Soc., Perkin Trans.
1, 2000, 353 (c) H. Taishan, Y. Qian and W.J. Yikang, J. Org. Chem.,
2001, 66, 853. (d) N. Yutaka, K. Takeshi, Heterocycles, 2000, 52(2),
553 (e) A. Armstrong, P. A. Basanti, L. H. Jones and J. Ahmad, J. Org.
Chem., 2000, 65, 7020 (f) D. Clark, Tetrahedron, 2000, 56(34), 6181
(g) A. Cantin, P. Moya, M. A. Miranda and J. Pir imo Yufera, J. Agr.
Food. Chem., 2000, 48(8), 3682.
126. (a) B.A. Sobin. J. Am. Chem. Soc., 1952, 74, 2947 (b) W.E. Grundy,
A.I. Whitman, E.G. Rdzok, E.J. Rdzok, M.E. Haris and J.C. Sylvester,
Antibiotic and Chemotherapy, 1952, 2, 399.
127. (a) L. Zirngibl, J. Fischer and K. Thicle, Ger. Offen, 2721401, 1977
Chem. Abst., 1978, 88, 89673j (b) H. A. Brandman, J. E. Freudwald,
M. Manowitz, E.J. Nikawitz and F.H. Sharpell Jr., US Patent, 4086278,
1978, Chem. Abstr., 1978 ,89, 108112q.
128. A.F. Hirsch, US Patent 40^621^, 1978, Chem. Abstr., 1978, 89, 108112.
129. V. Lafon and L. Lafon. Ger. Offen. 2715184, 1977, Chem. Abstr., 1978,
88, 50510d.
130. H.H. Ong, V.B. Anderson and J.A. Profitt , Eur. Patent., 2500, 1979,
Chem. Abstr., 1980, 92, 41788.
131. (a) http:/www. aist.go.jp/RIODB/SDS/Perl/img-disp. SDBS No. 482,
CDS-03-213 (b) ibid, SDBS No. 3896, CDS-03-212 (c) ibid, SDBS
No. 1287, CDS-00226.
J i J J J. \\ H H — I
SCREENING FOR BIOLOGICAL ACTIVITY
Hii
Study for Anticancer and Antimicrobial Activities
287
Biological Screening: Study for Anticancer and Antimicrobial
Activities
(A) A n t i c a n c e r activity against mal ignant human t u m o u r cells:
I N T R O D U C T I O N
The compounds are evaluated as one dose primary anticancer assay in 3-cell
line panel consisting of three types of human cancers: breast (MCF7), Lung (NCI-
H460) and CNS (SF-268). In the screening protocol, each cell line is inoculated and
preincubated for 24-28 h on a microtiter plate. Test agents are then added at a single
concentration and the culture incubated for further 48 h. End-point determinations are
made with alamar blue'. Results for each test agent are reported as the percent of
growth of the treated cells when compared to the untreated control cells. Compounds
which reduce the growth of anyone of the cell lines to 32% or less (negative number
indicates cell kill) are then passed on for evaluation in the full panel of 60- cell lines
over a 5 -log dose range^.
In the fiill panel of 60- cell lines, 9 types of human cancers ; leukaemia, lung
cancer, colon cancer, central nervous system, melanoma, ovarian, renal, prostate and
breast are used. These test agents are added in five 10- fold dilutions and a 48 hours
continuous drug exposure protocol is used. Sulforhodamine B (SRB), a protein-
binding dye assay, is used to estimate cell viability or growth. Results are expressed
as log 10 GI50 which is the drug concentration (M) causing a 50% reduction in the net
protein increase in control cells during the drug incubation.
Data Analysis: The calculated Measurement of Effect: Percentage Growth (PG)
The measured effect of the compound on a cell line is currently calculated according
to one or the other of the following two expressions:
288
If (Mean ODtest - Mean ODtzero) ^ 0. then
PG = 100 X (Mean OD,est - Mean ODtzero)/ Mean OD, ero
Where:
Mean ODtzero^ The average optical density measurements of SRB-derived colour
just before exposure of cell to the test compound.
Mean OD,est= The average optical density measurements of SRB-derived colour after
48 hours exposure of cell to the test compound.
Mean ODcri = The average optical density measurements of SRB-derived colour after
48 hours with no exposure of cell to the test compound.
The results as obtained from experimental data are represented in three ways.
(i) The Data Sheet:
The first two columns of the Table describe the subpanei and cell lines
involved. The next two columns list the Mean ODtzero and Mean OCdri: the next five
columns list the Mean ODtest for each five different concentrations. Each concen-
tration is expressed as the logio (molar or ^g/ml). The next five columns list the
calculated PGs for each concentration. The response parameters GI50, TGI, and
LC50 are interpolated values represenfing the concentrations at which the PG is
+50.0. and -50. respectively.
(ii) Dose-Response Curves:
The dose-response curve page of the data package is created by plotting the
PGs against the logio of the corresponding concentration for every cell line. The cell
line curves are grouped by subpanei: Horizontal lines are provided at the PG values
of + 50.0.and -50. The concentrations corresponding to points where the curves cross
these lines are the GI50, TGI, and LC50 respectively,
(iii) The Mean Graphs:
The mean graphs show mean graphs at each of the principal response
parameters: GI50, TGI, and LC50. Bars extending to the right representing sensitivity
of cell lines to the test agent in excess of the average sensitivity of all tested cell lines.
289
Since the bar scale is logarithmic a bar 2 units to the right implies the compound
achieved the response parameters (eg. GI50) for the cell line at the concentration one-
hundredth the mean concentration required over all cell lines, and thus the cell line is
usually sensitive to that compound. Bar extending to the left correspondingly imply
sensitivity less than the mean.
RESULTS AND DISCUSSION
The compounds [FTZ (1), FBCB (4), FTZX4B (7), FTCA (9), FFjC (12),
FZX (16), FTZX' (17), FT (20), FT' (21), FF (22), FB (24), FBX,C (26), FBX3A
(27), FBXjC (30), FD (31), FDXiA (32)] were evaluated as one dose primary
anticancer assay in a three cell line panel and the results are depicted in Table 1. Out
of the sixteen compounds screened, only one compound, F B X 3 A (27) was found to
be active. This compound was then screened for cytotoxic activity^ at five different
concentrations against 60 cell lines of nine types of human cancers: leukaemia, lung,
colon, CNS, melanoma, ovarian, renal, prostate and breast. A 48 h continuous drug
exposure protocol was used and a Suphorhodamine B protein assay was used to
estimate cell viability or growth. Results (Table 3) are expressed as logjoGI50' which
is the drug concentration (M) causing 50% reduction in the net protein increase in
control cells during the drug incubation. This compound showed activity only at
higher concentration. Noteworthy results was obtained for the compound F B X 3 A in
the case of non-small lung cancer, melanoma and renal where the reduction in growth
is 75, 74 and 70 and 77% respectively (Table 3).
290
Table 1. Results of anticancer activity of the compounds against 3-ceiI lines of human cancers
Test Compounds Concentration
Percent growth Test
Compounds Concentration (Breast) MCF7
(Lung) NCI-H460
(CNS) SF-268
Activity
FTZ (1) IxlQ-'M 69 93 95 Inactive
FBCB (4) IxlG'^M 72 98 1 12 Inactive
FTZX4B (7) 1x10"'M 79 99 106 Inactive
FTCA (9) IxlQ-'M 63 99 90 Inactive
FFjC (12) I x l C ' M 52 67 71 Inactive
FTZX(I6) IxlO'^M 49 82 113 Inactive
FTZX' (17) I x l C ' M 84 98 107 Inactive
FT (20) IxlQ-'M 72 96 109 Inactive
FT' (21) IxlG'^M 94 98 114 Inactive
FF (22) IxlQ-'M 82 96 112 Inactive
FB (24) I x l C ' M 59 95 107 Inactive
FBX,C (26) 1x10"'M 53 49 65 Inactive
FBX3A (27) lxlO"'M 14 1 1 Active
FBXjC (30) IxlQ-'M 48 53 75 Inactive
FD (31) 1X10"'M 61 98 114 Inactive
FDX,A (32) 1x10"'M 47 65 98 Inactive
The dose response curves of the compound F B X 3 A (27) treated with
malignant human tumor cell lines has been deciphered in Fig. l a (Table 2).
In F B X 3 A , the highest percentage of retardation of growth was observed in
NCI-H226 of non-small cell lung cancer (75%). Other significant activities
were observed in UACC-62 (74%), SKMEL-28 (70%) of melanoma cancer,
SN12C (72%) and U031 (70%) of renal cancer.
The overall anticancer effect of the compound (27) on all the malignant
human tumour cell lines is illustrated in Fig. lb .
Mean graphs of the compound (27) which facilitate visual scanning of
data for potential patterns of selectivity for particular cell lines with respect
to a selected response parameters are represented in Fig. Ic.
291
Table Z National Cancer Institute Developmental Therapeut ics P r o g r a m In-Vitro Testing Results
NSC: D- 722671 / I Exper iment ID: 0201NS46-28 Test T y p e : 0 8 Units: Molar
Report Date: February 4 , 2 0 0 2 Test Date: January 14, 2 0 0 2 Q N S : M C :
C O M ! : FBX 3A Stain Reagent: SRB Dual-Pass S S P L : OGVG
L o g l O C o n c e n t r a t i o n T i m e Mean O p t i c a l D e n s i t i e s
P a n e l / C e l l L i n e Z e r o C t r l - 8 0 - 7 0 - 6 0 - 5 0 L e u k e m i a
CCRF-CEM 0 2 1 0 0 7 8 4 0 7 7 6 0 . 7 5 7 0 7 8 9 0 6 1 8 H L - 6 0 ( T B ) 0 4 2 4 1 3 5 3 1 3 6 1 1 3 4 1 1 2 5 8 1 6 8 5 K - 5 6 2 0 1 9 6 1 0 7 2 1 0 6 2 1 0 7 9 1 0 9 8 0 7 3 6 MOLT-4 0 2 3 3 1 1 3 6 1 1 1 9 1 1 2 0 1 0 6 3 0 8 3 0 R P M I - 8 2 2 6 0 3 2 8 0 9 3 4 0 9 1 9 0 9 4 3 0 907 0 6 6 3 SR 0 3 4 0 0 7 0 2 0 7 3 2 0 6 6 7 0 6 3 0 0 4 3 0
N o n - S m a l l C e l l Lung C a n c e r A54 9/ATCC 0 1 6 0 0 7 2 5 0 7 7 5 0 7 8 2 0 737 0 6 3 3 EKVX 0 4 8 0 1 374 1 4 2 6 1 4 3 9 1 467 1 3 5 6 HOP-62 0 2 8 5 1 0 3 2 1 164 1 1 8 9 1 2 0 9 1 1 4 3 HOP-92 0 3 6 2 0 9 5 5 0 9 1 5 0 8 9 1 0 892 0 8 1 6 N C I - H 2 2 6 1 1 0 3 1 7 6 9 1 8 1 5 1 874 1 8 2 0 1 7 6 4 N C I - H 2 3 0 5 2 7 1 414 1 5 0 6 1 5 7 0 1 437 1 3 5 0 NCI-H322M 0 7 5 3 1 2 8 6 1 384 1 3 5 8 1 346 1 2 7 3 N C I - H 4 6 0 0 4 2 4 1 5 4 5 1 5 7 9 1 6 6 8 1 567 1 4 2 7 N C I - H 5 2 2 0 6 7 5 1 3 9 6 1 4 8 3 1 4 5 5 1 5 2 5 1 2 2 4
C o l o n C a n c e r COLO 20 5 0 1 3 5 1 2 4 8 1 2 6 6 1 3 2 2 1 192 1 1 6 0 HCC-2998 0 4 5 7 0 7 5 0 0 8 8 3 0 9 1 0 0 8 5 8 0 8 8 1 HCT-116 0 1 1 3 0 6 3 4 0 7 4 7 0 7 8 8 0 7 5 3 0 7 3 4 HCT-15 0 2 0 7 1 0 5 0 1 0 9 2 1 1 0 4 1 0 9 6 0 9 9 0 HT29 0 4 57 1 2 1 5 1 2 4 1 1 244 1 2 2 1 1 1 0 8 K«12 0 4 2 2 1 3 6 0 1 4 3 3 1 382 1 392 1 2 1 1 SW-620 0 2 5 9 1 1 4 3 1 2 8 5 1 3 3 1 1 3 6 8 1 3 3 9
CNS C a n c e r S F - 2 6 8 0 5 8 6 1 1 7 5 1 1 8 3 1 2 9 2 1 2 4 1 1 1 0 8 S F - 2 9 5 0 4 2 1 1 4 1 7 1 4 5 9 1 4 9 8 1 4 6 8 1 2 7 6 S F - 5 3 9 0 5 2 6 1 4 5 1 1 4 6 7 1 524 1 5 0 1 1 4 2 5 SNB-19 0 5 3 0 0 9 6 8 0 9 9 1 1 074 1 1 1 3 1 0 1 8 SNB-75 0 6 7 8 0 8 2 9 0 9 2 3 0 9 5 1 0 9 4 8 0 907 U2SI 0 2 5 3 1 0 9 0 1 144 1 1 1 0 1 0 2 9 1 0 0 2
Me lanoma LOX IMVI 0 3 3 3 1 0 1 0 1 0 7 3 0 914 0 914 0 8 4 0 KALME-3M 0 7 9 2 1 3 9 6 1 4 5 7 1 4 5 4 1 4 0 7 1 359 M14 0 3 7 6 0 9 4 4 1 0 2 9 1 1 1 3 1 0 5 8 0 9 4 5 SK-MEL-2 0 4 8 5 0 9 9 4 1 0 6 1 1 1 4 3 1 115 1 0 4 9 SK-MEL-28 0 7 7 1 1 4 3 3 1 4 1 8 1 4 7 6 1 474 1 4 5 1 SK-MEL-5 0 5 2 6 1 3 4 2 1 4 5 5 1 4 8 1 1 4 7 8 1 2 6 7 UACC-257 0 7 6 1 1 5 2 0 1 5 8 9 1 6 0 3 1 572 1 334 UACC-62 0 7 5 0 2 1 3 5 2 1 8 5 2 2 3 9 2 1 6 5 1 6 0 3
O v a r i a n C a n c e r IGROVl 0 329 0 9 3 1 1 0 1 8 1 0 1 2 0 8 8 8 0 9 4 9 OVCAR-3 0 2 9 3 0 9 4 8 0 9 9 2 0 9 9 5 0 9 6 9 0 8 3 6 OVCAR-4 0 8 0 1 1 5 8 8 1 5 8 5 1 6 8 1 1 5 9 3 1 3 8 4 OVCAR-5 0 3 1 3 0 9 9 8 1 0 6 9 1 0 9 5 1 036 1 0 1 8 OVCAR-B 0 3 7 9 1 0 5 0 1 1 2 0 1 1 4 2 1 1 4 0 1 0 7 8 SK-OV-3 0 1 4 7 0 9 9 4 1 0 2 7 1 0 9 0 1 0 5 5 1 102
R e n a l C a n c e r 7 8 6 - 0 0 2 4 2 1 1 5 9 1 1 9 9 1 2 6 2 1 237 1 1 4 3 A498 1 0 6 8 1 5 8 8 1 6 6 2 1 6 8 9 1 6 5 3 1 547 ACHN 0 3 8 8 1 4 5 0 1 4 6 7 1 4 8 3 1 4 8 8 1 2 8 3 C A K I - 1 0 4 8 0 1 5 6 7 1 6 1 9 1 6 6 8 1 598 1 3 3 0 SN12C 0 4 8 6 1 5 5 2 1 5 9 6 1 624 1 569 1 4 5 1 T K - 1 0 0 7 6 3 1 6 0 8 1 5 9 6 1 6 5 2 1 6 6 3 1 5 2 6 U C - 3 1 0 4 6 7 1 2 6 1 1 3 5 S 1 3 6 6 1 3 2 7 1 0 7 0
P r o s t a t e C a n c e r P C - 3 0 317 1 034 1 0 4 8 1 0 1 4 0 9 6 1 0 8 3 0 D U - 1 4 5 0 274 0 9 7 0 1 0 0 8 1 0 5 6 1 0 0 5 0 964
B r e a s t C a n c e r MCF7 0 5 6 7 1 1 0 7 1 0 8 3 1 2 0 9 1 1 6 1 1 0 6 1 NCI /ADR-RES 0 5 5 3 1 4 7 5 1 5 5 4 1 6 0 7 1 574 1 364 MDA-MP 231/ATCC 0 3 4 9 0 9 9 9 1 0 1 7 0 9 9 7 1 0 6 2 0 884 HS 5 7 s r 0 6 8 0 0 9 3 0 1 0 2 3 1 0 6 2 0 987 0 8 5 3 MDA-MB-435 0 5 1 8 1 8 1 1 1 9 9 7 2 0 3 2 2 0 0 9 1 6 6 1 MDA-N 0 544 1 7 2 1 1 7 8 7 1 S92 1 906 1 6 7 7 B T - 5 4 J 0 8 2 0 1 1 3 8 1 1 9 7 1 1 9 6 1 1 5 1 1 0 7 2 T - 4 7 D 0 2 5 8 0 8 0 0 0 8 6 1 0 8 1 5 0 8 1 5 0 7 0 9
-4 0
0 519 0 2 2 5 0 216 0 3 4 8 0 208
P e r c e n t G r o w t h
194 6 1 3 2 6 3 222 2 7 9 4 0 3 344 3 7 5
1 7 5 3 4 2 2 6 9 2 0 6 196 2 4 8 3 1 6
187 2 5 2 2 3 0 226 1 3 1
0 3 0 6 0 3 4 5 0 367 0 2 3 3 0 210 0 2 7 8
0 202 0 1 7 8 0 3 6 6 0 2 8 3 0 3 7 0 0 364
0 176 0 201 0 3 6 7 0 137 0 2 6 7 0 1 4 1
0 2 6 5 0 1 7 3
0 4 0 3 0 1 5 3 C 314 0 169 0 3 5 2 0 336
- 8 0 - 7 0 - 6 0 - 5 0 - 4 0 G I 5 0 T C I LC50
99 9 5 1 0 1 7 1 12 2 2 7 E - 0 5 > 1 OOE - 0 4 > 1 OOE - 0 4 1 0 1 99 90 136 10 4 8 2 E - 0 5 > 1 OOE - 0 4 >1 OOE - 0 4
99 1 0 1 1 0 3 62 3 1 e O E - C S >1 OOE - 0 4 >1 OOE - 0 4 ° 3 9 8 92 66 - 7 1 6 6 E - 0 5 7 95E - 0 5 >1 OOE - 0 4 98 1 0 1 96 55 3 1 2 6 E - 0 5 >1 OOE 04 >1 OOE - 0 4
lOS 90 80 2b 39 3 4 9 L 06 2 44L 05 >1 OOC 04
109 1 1 0 102 84 6 2 7 2 E - 0 5 >1 OOL - 0 4 >1 OOE 04 106 1 1 3 1 1 0 98 15 3 7 8 E - 0 5 >1 OOE - 0 4 >1 OOE 04 116 1 2 1 124 115 8 3 3 8 E - 0 5 8 62E - 0 5 >1 OOE 04
93 89 89 77 - 3 9 1 7 0 E - 0 5 4 61E - 0 5 >1 OOE 04 107 1 1 6 1 0 8 99 75 1 9 2 E 05 3 7 2 E 0 5 7 21E 05 1 ! 0 1 1 8 1 0 3 93 24 2 3 3 E - 0 5 b 27E 0 5 >1 OOE - 0 4 l i s 1 1 3 111 98 54 2 0 6 E 0 5 4 39E 0 5 9 37E 05 103 1 1 1 102 89 - 1 2 2 4 5 E - 0 5 7 66E - 0 5 >1 OOE - 0 4 112 1 0 8 l i e 76 - 5 4 1 5 8 E 0 5 3 B3E - 0 5 9 2 7 E - 0 5
102 1 0 7 95 92 4 2 9 9 E - 0 5 >1 OOE--04 >1 OOE 04 1 4 5 1 5 5 137 1 4 5 25 3 6 1 E - 0 5 7 l l E - •05 >1 OOE' -04 122 1 2 9 123 119 30 5 9 4 E 0 5 >1 OOE--04 >1 OOE' -04 1 0 5 1 0 6 1 0 5 93 2 8 8 E 0 5 9 8SE-- 0 5 >1 OOE--04 103 104 1 0 1 86 - 5 7 1 7 8 E 0 5 3 98E-- 0 5 3 90E^ - 0 5 108 1 0 2 1 0 3 84 - 4 1 1 8 7 E - 0 5 4 69E 0 5 >1 OOE 04 116 1 2 1 125 122 6 4 2 0 E 0 5 >1 OOE--04 >1 OOL •04
1 0 1 1 2 0 1 1 1 89 50 1 9 0 E 0 5 4 37E 05 >1 OOE 04 104 1 0 8 1 0 5 86 56 1 7 9 E - 0 5 4 04E 05 9 H E 05 102 1 0 8 1 0 5 97 52 2 0 7 E - 0 5 4 48E-•05 9 68E-•05 105 124 1 3 3 111 57 2 32E 0 5 4 60E 05 9 12E 05 163 1 8 1 179 152 67 2 9 3 E - 0 5 4 96E-- 0 5 8 39E-•05 106 1 0 2 93 89 - 4 8 1 9 3 E - 0 5 4 46E-•05 >1 OOE-•04
109 86 86 7 5 46 1 6 1 E - 0 5 4 18E 0 5 >1 OOE-•04 110 1 1 0 102 94 - 6 1 1 9 2 E - 0 5 4 0 2 E - •05 8 44E-•05 115 1 3 0 1 2 0 100 8 2 9 0 E - 0 5 8 37E-•05 >1 OOE-•04 113 1 2 9 124 1 1 1 - 2 4 2 8 2 E - 0 5 6 6 1 E - 0 5 >1 OOE-•04
98 1 0 6 106 1 0 3 - 7 0 2 0 2 E - 0 5 3 9 4 E - 0 5 7 67E-•05 114 1 1 7 117 9 1 - 6 0 1 8 6 E - 0 5 3 9 9 E - 0 5 8 S6E-•05 109 1 1 1 107 76 -D3 1 5 3 E - 0 5 3 4 9 E - 05 8 OOE--05 104 107 102 62 - 7 4 1 2 2 E - 0 5 2 B4E- 0 5 6 62E 05
114 1 1 3 93 1 0 3 - 3 9 2 3 6 E - 0 5 5 3 3 E - 0 5 > 1 OOE--04 107 1 0 7 1 0 3 83 - 3 9 1 8 6 E - 0 5 4 7 7 E - 0 5 >1 OOE- 04 1 0 0 1 1 2 1 0 1 74 - 5 4 1 5 4 E - 0 5 3 7 8 E - 05 9 26E 05 110 114 1 0 5 103 10 2 9 5 E - 0 5 8 1 9 E - 0 5 >1 OOE- 04 110 1 1 4 1 1 3 104 3 3 22E 0 5 9 4 7 t - 0 5 >1 OOL- 04 104 1 1 1 107 1 1 3 26 5 2 5 E - 0 5 >1 OOE- 04 >1 OOE- 04
104 1 1 1 109 9 8 11 2 7 7 E 0 5 1 9 7 E - OS >1 OOE--04 114 1 2 0 1 1 3 92 - 8 4 1 7 4 E - 0 5 3 3 5 E - 0 5 6 4 4 E - 05 102 1 0 3 104 84 - 4 8 1 8 1 E - 0 5 4 3 3 E - 0 5 ' 1 OOE- 04 105 1 0 9 103 78 24 1 8 9 E - 0 5 5 8 6 E - 0 5 >1 OOE- 04 104 1 0 7 102 90 72 1 7 e E - 0 5 3 6 1 E - 05 7 33L--05
99 1 0 5 106 90 - 6 5 1 8 2 E - 0 5 3 8 1 E - 0 5 8 OOE- 05 112 1 1 3 1 0 8 76 - 7 0 1 5 1 E - 0 5 3 3 2 E 0 5 7 3 1 E - 05
102 97 9 0 12 16 1 7 6 E 0 5 6 5 1 E 05 >1 OOL 04 105 1 1 2 1 0 5 99 - 3 7 3 0 F - 0 5 5 36E 0 5 >1 OOt- 04
96 1 1 9 1 1 0 91 - ? 9 2 2 1 E - 0 5 5 nc 0 5 >1 OOE 04 109 1 1 4 1 1 1 88 - 2 7 2 1 4 E - 0 5 5 80E 0 5 >1 oot- 04 103 1 0 0 110 82 - 5 6 1 7 1 E 0 5 3 9 2 E - 0 5 9 O l E - 05 137 1 5 3 1 2 3 69 - 5 4 1 4 3 E - 0 5 3 6 5 E 0 5 9 31E 05 114 1 1 7 1 1 5 88 - 6 7 1 7 6 E - 0 5 3 6 9 E - 0 5 7 72E 05 106 115 116 96 35 ? 2 5 E - 0 5 5 3 9 F 0 5 >1 OOr 04 118 118 104 79 59 1 6 3 E 0 5 3 7 4 L 05 8 6 0 E - 05 111 1 0 3 1 0 3 83 13 -1 9 9 E - 0 5 >1 OOE 04 >1 OOE- 04
29?
Table 3. Anticancer activity of F B X 3 A (27) against 60 cell line at the concentration of
1.0 X 10"^
Type of cancer Cell line Concen-tration
LogioGISO Retardation of Growth (%)
L e u k a e m i a CCRF-CEM 1 0 X 10^ -4 64 _ HL-60 (TB) l O x l O - ' -4 32 -
K-562 -4 80 -
MOLT-4 l O x l Q - ^ -4 78 7 RPMI-8226 1 0x10"^ -4 90 -
SR I Ox 10-* -5 64 39 Non- sma l l cell A549/ATCC - -4 57 -
L u n g cancer EKVX - -4 42 -
HOP-62 1 0 x 1 0 - " -4 47 8 HOP-92 1 Ox ID"' -4 77 39 NC1-H226 1 Ox 10"' -4 72 75 NCI-H23 - -4 63 24 NCI-H322M - -4 69 54 NC1-H460 1 Ox 10^ -4 61 12 NC1-H522 1 Ox 10"^ -4 80 54
Colon cancer COLO 205 -4 52 -
HCC-2998 1 Ox lO"" -4 44 25 HCT-116 I Ox 10"^ -4 23 HCT-15 1 Ox lO-" -4 54 HT29 1 Ox lO"* -4 75 57 KM 12 1 Ox 10"^ -4 73 41 SW-620 - -4 38 -
C N S cance r SF-268 1 Ox 10-* -4 72 50 SF-295 l O x l O - * -4 75 56 SF-539 1 Ox lO-* -4 68 51 SNB-I9 l O x l O - * -4 63 57 SNB-75 I Ox 10-' -4 53 67 U25I 1 Ox lO"' -4 71 48
M e l a n o m a LOX IMVI l O x l O - ' -4 79 46 MALME-3M -4 72 61 M14 - -4 54 8 SK-MEL-2 1 Ox lO-" -4 55 24 SK-MEL-28 1 Ox lO-' -4 69 97 SK-MEL-5 1 Ox lO-* -4 73 60 UACC-257 1 Ox lO-' -4 82 64 UACC-62 1 Ox 10-' -4 91 74
Ovar ian cancer IGROVI 1 Ox 10-* -4 63 39 OVCAR-3 1 Ox 10"' -4 73 39 OVCAR-4 1 Ox 10-* -481 54 OVCAR-5 - -4 53 10 OVCAR-8 1 Ox 10-* -4 49 3 SK-OV-3 1 Ox lO-' -4 28 -
Renal c ance r 786-0 ! 0 x 1 0 - ' -4 56 11 A498 1 0 x 1 0 - ' -4 76 84 ACHN 1 Ox 10-* -4 74 48 CAKI-1 - -4 72 24 SN12C 1 0 x 1 0 - ' -4 75 72 TK-10 l O x l O - " 4 74 65 UO-31 1 Ox lO-' -4 82 70
Pros ta te cance r PC-3 1 Ox lO-* -4 75 16 DU-I45 . -4 64 37
Breas t cance r MCF7 1 Ox 10"' -4 66 29 NCI/ADR-RES - -4 67 27 MDA-MB-231/ATCC -4 77 56 HS 578T 1 Ox 10-' -4 84 54 MDA-MB-435 - -4 75 67 MDA-N -4 65 35 BT-549 1 Ox 10-' -4 79 59 T-47D 1 Ox 10"' -4 52 13
293
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(B) A N T I M I C R O B I A L A C T I V I T Y
INTRODUCTION
The test organism used in the study included Escherichia coli UP2566
(Central Drug Research Institute, Lucknow, India), Bacillus subtilis MTCC-121
(Institute of Microbial Technology, Chandigarh, India) and clinical isolates of
Staphylococcus aureus (IOA-106), Pseudomoms aeruginosa (IOA-110) and
Candida albicans (IOA-109) (Department of Microbiology, J.N. Medical College,
AMU, Aligarh, India).
Culture Media and Inoculum
Sabour and Dextrose (SD), Nutrient broth and agar were obtained from
Hi-Media Pvt. Ltd. (Bombay, India) and were used for Canadida albicans and test
bacteria respectively. Freshly grown microbial cultures at 37° were appropriately
diluted in sterile normal saline solution to obtain a cell suspension of lO^CFU/ml.
Antimicrobial assay
Each synthetic compound was dissolved in DMSO to obtain a stock solution of
different concentrations ranging from 2000 - 5000 ng/ml. The agar well diffusion
method (Perez et. al^) as adopted by Ahmad and Arina'^ was used for our assay.
0.1 ml of the diluted inoculum (10^ CFU/ml) of test organism was spread on
NA/SDA (Nutrient Agar/Sabour and Dextrose Agar) plates. Wells of 8 mm diameter
were punctured into the agar medium and filled with 100 jil of compound, solvent
blank and an antibiotic (chloramphenicol, 100 |ig/ml) to which the test bacteria were
sensitive. Fluconazole at the concentration of 100 i^g/ml was used as the control
against Candida albicans. The plates were incubated for 18 h at 37 °C. Antimicrobial
activity was evaluated by measuring the zone of inhibition against the test organism.
297
RESULTS AND DISCUSSION
A total of 10 compounds were tested against two Gram +ve bacteria
{Staphylococcus aureus, Bacillus subtilis) and two Gram -ve bacteria
{Estcherichia coli, Pseudomonas aeruginosa) and a yeast, Candida albicans. The
varying level of anti-microbial activity was detected against one or more test
organisms.
Antimicrobial activity of test compounds
The results for the antimicrobial study of the tested compounds detected
against the test organisms Escherichia coli, Bacillus subtilis. Staphylococcus aureus,
Pseudomonas aeruginosa and Candida albicans are depicted in Table 4. Solvent
control (DMSO) showed non-significant inhibition to test microorganisms.
Antimicrobial activity against Gram -ve bacteria was deduced in all compounds.
However such activity could be detected only in four compounds against Gram +ve
bacteria. The compounds (25), (26), (30) and (31) demonstrated activity against both
Gram +ve and Gram -ve bacteria.
The compounds exhibited antimicrobial activity in the concentration range
200 \ig to 500 ^g/100 fil. Two compounds, (30) and (31) also demonstrated
antifungal (anticandidal) activity. It was interesting to note that the compound (31)
which is structurally similar to (24) but only differs in substitution, resulted in the
enhanced activity against fungi. However, the compound (24) is devoid of antifungal
activity. Overall broad spectrum antimicrobial activity i.e. active against Gram +ve
and Gram -ve was deduced in (25), (26), (30) and (31). These compounds may be
directly explored in the preparation of topical antiinfective agents. However, further
exploration requires detailed study on exact MIC values and least toxicity to host cell
and system.
298
Table 4. Antimicrobial activity of some compounds by Agar well diffusion
method
Test Compounds
Effective concentration
Hg/well
Antimicrobial activity in terms of zone of inhibition in mm Test
Compounds
Effective concentration
Hg/well SA BS EC PA CA
FB (24) 500 - - 19 - -
FBX,B (25) 500 12 12 10 14 -
FBX.C (26) 250 - 21 13 12 -
FBXjC (30) 200 12 14 10 16 15
FBXjA (27) 500 - - 18 22 -
FD (31) 500 22 12 28 18 18
FDX,A (32) 500 - - 17 21 1 FTZX4B (7) 500 - - 10 12 -
FBX3B (28) 250 - - 14 16 -
FBCB (4) 300 - - 15 18 -
Chloram- 100 |ig/well 25 20 24 30 -
phenicol Fluconozole 100 ^ig/well - - - - 25
SA, Staphylococcus aureus; BS, Bacillus subtilis; EC, Escherichia coli; PA, Pseudomonas
aeruginosa; CA, Candida albicans.
299
REFERENCES
1. G.D. Gray and E. Wickstrom, Biotechniques, 1996, 21, 780.
2. A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, K. Paull, D. Vistica, C. Hose,
J. Langley, P. Cronise and A. Vaigro-wolff, J. Natl, Cancer Inst., 1991, 38, 757.
3. C. Perez, M. Pauli and P. Bazerque, Acta Biologiae et Medicinae Experimentalis,
1990, 15 , 113.
4. Arina Z. Beg and I. Ahmad, World J. Microbiol, and Biotech., 2000, 16, 841.
300
CONCLUSION
The compounds synthesised in total of seventeen reactions and screened for anticancer/antimicrobial activities are as fol lows:
Chapters Compounds Synthesised
Total Chapters Simple Compounds
New Compounds
Total
I 4 2 6
II 2 2 4
III 4 3 7
IV 3 4 7
V 4 1 5
Grand Total 17 12 29
V I - Screening for Anticancer and Antimicrobial Activities:
(A) Anticancer Activity IG
(B) Antimicrobial Activity l 6
The techniques used for evaluation of structure are 'H-NMR, '^C-NMR,
APT, NOE, 2-DNMR (COSY, HETCOR) including DC-MS, IR and FTIR.
301
List of Publications and Presentations
1. Bifunctional derivatives of70,/>'-dichlorochalcone Part II.
Synthesis of a novel compound 2-[2-(carboxymethylthio-2-(4-chloro-
phenyl)ethyl]-2-(4-chlorophenyl)-4-thiazolidinone.
molecules, 4, 232 (1999).
2. Synthesis, stereochemical study and biological activity of some novel
thiazolidinones, 2-aryl substituted 3-[ l l - (carboxymethylthio)undecan-
amido]thiazolidin-4-ones alongwith l l - (carboxymethyl /e thyl th io undec-
anohydrazones from 10-undecenohydrazide.
Tetrahedron (2002) (communicated)
3. Synthesis and biological activity of novel long alkyl chain substituted-5'-
triazolo-thiadiazepines.
Eur. J. Med. Chem. (2002) (communicated)
4. Synthesis and biological activity of novel long alkyl chain substituted-
benzopyrano-i '-triazolo-thiadiazepines.
Tetrahedron Lett. (2002) (communicated)
5. Synthesis and biological activity of novel long alkyl chain substituted-
i--triazolo-thiadiazoles, Indian J. Chem. (2002) (communicated)
6. Synthesis, stereochemical investigation and biological activity of novel
cyclohexanols from chalcones and their stereoselective syn elimination
products, Eur. J. Med. Chem. (2002) (communicated)
7. Flavonol glycosides from Mallotus philippensis (Euphorbiaceae).
{33'''' Annual convention of chemists, Coimbatore, December 26-29, 1996).
8. Synthesis of 2-p-chlorophenyl -2- ( r -phenyl - r - th iapropionic acid ethyl)
tetrahydro-l ,3-thiazin-4-one from chalcone.
{33''' Annual convention of chemists, Coimbatore, December 26-29, 1996).
9. Synthesis and stereochemical study of E-3-benzylidene flavanones and
their thio-adducts.
{39'^ Annual convention of chemists, Nagarjunanagar , December 22-26,
2002).
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