synthesis of some heterocyclic compounds containing
TRANSCRIPT
Al-Azhar University of Gaza
Deanship of Postgraduate Studies and Research Affairs
Faculty of Science - Chemistry Department
Synthesis of Some Heterocyclic Compounds
Containing Nitrogen and/or Sulfur
By
Tahany Abu Emaileq
Supervisors
Dr. Nabeel K. Shorrab Assistant Prof. of Organic Chemistry
Chemistry Department – Faculty of Science
Al Azhar University of Gaza
Prof. Nada M. Abunada Professor of Organic Chemistry
Chemistry Department-Faculty of Applied Sciences
Al-Aqsa University – Gaza
Dr. Omar A. Miqdad Assistant Prof. of Organic Chemistry
Chemistry Department-Faculty of
Applied Sciences
Al-Aqsa University – Gaza
Submitted in Partial Fulfillment of the Requirements for the Degree of Master
of science in Organic Chemistry
Gaza - Palestine
2014
ii
Al-Azhar University -Gaza
Deanship of Graduate Studies & Scientific
Research
Faculty of Science
Chemistry Department
Synthesis of Some Heterocyclic Compounds
Containing Nitrogen and/or Sulfur
A Thesis submitted in partial fulfillment of
requirements for the degree of Master of Science
in organic chemistry
By
Tahany Abu Emaileq
This Thesis was defended successfully on 31 / 3 /2014 and
approved by
Committee of Evaluation
Dr. Nabeel K. Shorrab ……………………...
Prof. Nada M. Abunada ……………………..
Dr. Omar A. Miqdad ……………………...
Dr. Hussein M. Alhendawi ……………………...
Dr. Naser S. El-Abadla ……………………...
iii
Dedication
Please accept our loyalty which is coming from our hearts which is like
Zamzam water that is irrigating every valley and accompanied by a
covenant to be with you until the Day of Judgment . This loyalty if the
people see it they will extend all their hands to it. But I dedicate it to the
persons who are like moons among people. To the soul of Dr. Ali Al-
Louh may Allah bless his soul.
To the white hand which surrounded me with care and gave me love and
kindness.
To the pure soul of my mother and to the man who I proudly carry his
name, my dear father.
To the man who spent his youth behind the bars, my dear brother Anwar
may Allah ease his agony .
To the basil of my life who supplied me with hope, my brothers and my
sisters.
To my life partner
To my family, relatives and professors
To all those who sweeten my life and increase its beauty . To my male
and female colleagues and to all whom I love, I dedicate this effort in
appreciation and gratitude .
iv
Acknowledgment
I am grateful to Allah, who granted me life, the power and courage to
finish this study.
My deepest appreciation and sincere gratitude to my supervisors
especially Prof. Dr. Nada M. Abu-Nada, Dr. Omar A. Miqdad for
suggesting the research problem, their supervision, their great and
continuous help, encouragement and guidance during the research
course.
My gratitude also to Dr. Nabeel Shorrab for his supervision and directing
the research.
I also extend my profound thanks to Alazhar and Alaqsa universities
especially chemistry department for giving me privilege of working
under their supervision and giving me opportunity to complete my
postgraduate studies.
Also my deep thanks to chemistry department in Alaqsa and Alazhar
University.
Finally, I would like to thank overall my friends, and family for their
continuous help.
Tahany Abu Emaileq
v
Contents
Page No.
Chapter One
Introduction 1
1 Amidrazone 1
1.1 Introduction 1
1.2 Methods in the synthesis of amidrazones 2
1.2.1 Interaction of nitriles with hydrazines 2
1.2.1.1 Hydrazine 2
1.2.1.2 Monosubstituted hydrazines 2
1.2.1.3 Disubstituted hydrazines 2
1.2.2 From imidates and their salts 3
1.2.2.1 Monosubstituted hydrazines 3
1.2.3 From hydrazonoyl halides by aminolysis 3
1.2.4 From imidoyl halides with hydrazines or acid hydrazides 4
1.2.5 From other imidic acid derivatives with hydrazines 4
1.2.6 From amides and thioamides 4
1.2.6.1 Amides 4
1.2.6.2 Thioamides 4
1.2.7 Reduction of nitrazones 5
1.2.8 Reduction of formazans and tetrazolium salts 5
1.2.9 From heterocyclic systems 5
1.2.10 From ketimines, acetylenes, and carbodiimides 6
1.3 Reactions of amidrazones 6
1.3.1 Reaction with Grignard reagents 7
1.3.2 Action of nitrous acid on amidrazones 7
1.3.2.1 Monosubstituted amidrazones 7
1.3.3 Condensation of amidrazones with aldehydes or ketones 7
1.3.3.1 Unsubstituted amidrazones 7
vi
1.3.4 Synthesis of 1,2,4-triazines 8
1.3.5 Miscellaneous heterocyclic systems 8
1.3.5.1 Bisoxadiazoles 8
1.3.5.2 Benzimidazole 8
1.3.5.3 Bis(indole)pyrazinone 9
1.3.5.4 Pyrazolo[3,4-d]pyrimidines 10
1.3.5.5 Pyrazolo[1,5-c]pyrimidines 11
1.3.5.6 1,2,4-Triazoles 11
1.3.5.7 1,2,4-Triazines 12
2 Dihydro-1,2,4-triazoles 15
2.1 Introduction 15
2.2 Synthesis of dihydro-1,2,4-triazoles 15
2.2.1 Cyclization reactions of hydrazones 15
2.2.1.1 Cyclocondensation of hydrazones with monocarbonyl compounds 15
2.2.1.1.1 Amidrazones 15
2.2.1.1.2 Hydrazinoheterocycles 17
2.2.1.1.3 Azo heterocycles 18
2.2.1.2 Cyclization of hydrazone derivatives 18
2.2.1.2.1 Cyclization induced by ethoxymethyenemalononitrile and
ethoxymethylene cyanoacetate
18
2.2.1.2.2 Cyclization induced by Isocyanate- and isothiocyanate 19
2.2.1.2.3 Rearrangement of O-acetyl derivatives of 1,2-hydroxylamino-
hydrazones and thiosemicarbazones
19
2.2.2 1,3-Dipolar cycloaddition reactions 20
2.2.2.1 Nitrilimine addition to acyclic C=N bonds 20
2.2.2.1.1 Nitrilimine addition to C=N bonds in hydrazones, imidates and
oximes
20
2.2.2.1.2 Nitrilimine addition to conjugated C=N bonds 22
2.2.2.1.3 Nitrilimine addition to exocyclic C=N bonds 22
vii
2.2.2.2 Nitrilimine addition to cyclic C=N bonds 22
2.2.2.3 Nitrile ylide addition to azo compounds 24
2.2.2.4 Nitrilimine with 1,3-diazaheterocyclic thiones 24
2.2.2.4.1 Nitrilimine with imidazolethiones 25
2.2.2.4.2 Nitrilimine with 1,2,4-triazolethiones 25
2.2.2.4.3 Nitrilimine with pyrimidinethiones 25
2.2.2.4.4 Nitrilimine with 1,2,4-triazine-5(4H)-thiones 26
2.2.2.4.5 Nitrilimine with 1,2,4-triazepinethiones 27
2.2.2.4.6 Nitrilimine with benzimidazolethiones 27
2.2.2.4.7 Nitrilimine with purinethiones 28
2.2.2.4.8 Nitrilimine with quinazolinethiones 28
2.2.2.4.9 Nitrilimine with pyrido[2,3-d]thiouracils 28
2.2.2.4.10 Nitrilimine with pteridinethiones 29
2.2.2.4.11 Nitrilimine with pyrido[3',2':4,5]thieno[2,3-b]pyrimidinethiones 29
2.2.2.4.12 Nitrilimine with cyclohepta[4,5]-thieno[2,3-d]pyrimidinthiones 30
2.2.2.4.13 Nitrilimine with naphtho[2,1-e]pyrido[2,3-c]pyrimidinethiones 30
Chapter two
2 Purpose of the presented work 31
Chapter three
3 Results and discussion 34
3.1 Preparation of starting materials 34
3.1.1 Preparation of α-chloroacetoacetanilide 34
3.1.2 Preparation of hydrazonoyl chlorides 34
3.2 Reaction of hydrazonoyl chlorides with ammonia, methylamine
and 4-chloroaniline
35
3.3 Reaction of amidrazones 3-5 with acyclic and cyclic ketones 36
Chapter four
4 Experimental 43
4.1 General 43
viii
4.2 Materials and reagents 43
4.3 Solvents 43
4.4 Organic preparations 44
4.4.1 Preparation of α-chloroacetoacetanilide 16 44
4.4.1.1 Preparation of N-Aryl-C-phenylaminocarbonylmethano-
hydrazonoyl chlorides 19
44
4.4.2 Preparation of C-acetylmethanohydrazonoyl chlorides 20 45
4.4.3 Preparation of C-ethoxycarbonyl-N-arylmethanohydrazonoyl
chlorides 21
45
4.5 Organic syntheses 46
4.5.1 Synthesis of 2-amino-N-phenyl-2-(2-arylhydrazono)acetamide 3,
2-Oxo-(2-arylhydrazono)propanamide 4 and ethyl 2-amino-2-(2-
arylhydrazono)acetate 5
46
4.5.2 Synthesis of spiro/4,5-dihyro-1,2,4-triazole derivatives 6-8 and
1,2,4-triazole derivatives 22
50
Appendix 66
References 96
English summary 101
Arabic summary 104
ix
List of Figures
Figure Page No.
Figure 1 IR spectrum of compound 3c in KBr disc 65
Figure 2 Ms spectrum of compound 3c 66
Figure 3 1H NMR spectrum of compound 3c in CDCl3 67
Figure 4 13
C NMR spectrum of compound 3c in CDCl3 68
Figure 5 IR spectrum of compound 8a in KBr disc 69
Figure 6 Ms spectrum of compound 8a 70
Figure 7 1H NMR spectrum of compound 8a in DMSO-d6 71
Figure 8 1H NMR spectrum of compound 8a in DMSO-d6 72
Figure 9 1H NMR spectrum of compound 8a in DMSO-d6 73
Figure 10 13
C NMR spectrum of compound 8a in DMSO-d6 74
Figure 11 IR spectrum of compound 8d in KBr disc 75
Figure 12 Ms spectrum of compound 8d 76
Figure 13 1H NMR spectrum of compound 8d in CDCl3 77
Figure 14 1H NMR spectrum of compound 8d in DMSO-d6 78
Figure 15 IR spectrum of compound 6g in KBr disc 79
Figure 16 Ms spectrum of compound 6g 80
Figure 17 1H NMR spectrum of compound 6g in DMSO-d6 81
Figure 18 13
C NMR spectrum of compound 6g in DMSO-d6 82
Figure 19 IR spectrum of compound 6k in KBr disc 83
Figure 20 Ms spectrum of compound 6k 84
Figure 21 1H NMR spectrum of compound 6k in CDCl3 85
Figure 22 1H NMR spectrum of compound 6k in DMSO-d6 86
Figure 23 13
C NMR spectrum of compound 6k in DMSO-d6 87
Figure 24 IR spectrum of compound 6l in KBr disc 88
Figure 25 1H NMR spectrum of compound 6l in CDCl3 89
x
Figure 26 1H NMR spectrum of compound 6l in DMSO-d6 90
Figure 27 IR spectrum of compound 22a in KBr disc 91
Figure 28 1H NMR spectrum of compound 22a in CDCl3 92
Figure 29 1H NMR spectrum of compound 22a in DMSO-d6 93
Figure 30 13
C NMR spectrum of compound 22a in DMSO-d6 94
xi
List of Abbreviations
Abbreviation Full Name
13C NMR Carbon Thirteen Nuclear Magnetic Resonance
1H NMR Proton Nuclear Magnetic Resonance
AcOH Acetic Acid
CDCl3 Deuterated Chloroform
DBN 1,5-diazabicyclo[4,3,0]non-5-ene
DMF N,N-Dimethylformamide
DMSO-d6 Deuterated Dimethylsulfoxide
IR Infra Red
KBr Potassium Bromide
Lit. Literature
m/z Mass/Charge ratio
M+ Molecular ion
MHz Mega Hertz
mp. Melting Point
MS Mass Spectra
N Normal
oC Degree Celsius
TEA Triethylamine
TLC Thin Layer Chromatography
r.t. Room Temperature
CHAPTER ONE
INTRODUCTION
1
1 AMIDRAZONES
1.1 Introduction
Amidrazones are weak monoacid bases characterized by the structural formula 1, where
R, R', R'', R''' and R'''' can be any of a wide variety of atomic or organic moieties. A
particularly well known example of this class of compounds is aminoguanidine 2.
Besides this, the name hydrazidine (1) has been applied to compounds of type 3 which are
also termed as hydrazide-hydrazones or dihydroformazans. Other names which have been
suggested for amidrazones 1 include “amide hydrazones” and “hydrazide imides”. These
names cover, respectively, amidrazones of the types 4 and 5 (R' ≠ H) which are incapable
of tautomerism. Where tautomerism is possible (R' = H) the terms “amide hydrazone” and
“hydrazide imide” (2) cannot strictly be applied, and the term “amidrazone” is used. It is
intended to adhere to the name amidrazone for all compounds of type 1 and furthermore
to employ the nomenclature introduced by Rapoport and Bonner (3) as it is the least
ambiguous. Amidrazone is named after the acid theoretically obtained from it by
hydrolysis (3). Hence, CH3C(=NNH2)NH2 is acetamidrazone, In addition, in compounds
containing N substituents, the nitrogen atoms are numbered (3) as shown in formula 6
which is therefore named N1-phenyl-N
1,N
3,N
3-trimethylpropionamidrazone. Compound 7
is thus a true diamidrazone (oxaldiamidrazone).
2
Amidrazones which were first obtained and described at the end of the last century, are
attracting ever increasing attention (4, 5), since they find application in the manufacture of
heat resistant polymers (6) and photographic materials (7, 8) and are of interest as
complexones (9-12), including those for the synthesis of biologically active complexes
(11). Individual amidrazones themselves have various sorts of biological activity
antibacterial and antifungal (13-15), tuberculostatic (14), sedatives (16), antiviral (17),
and anticancer (18) and are known as antimetabolites (17), herbicides, rodenticides and
nematocides (19, 20).
1.2 Methods in the synthesis of amidrazones
1.2.1 Interaction of nitriles with hydrazines
1.2.1.1 Hydrazine. Nucleophilic attack of hydrazine on a cyanamide can lead to
amidrazone (4) (Scheme 1).
1.2.1.2 Monosubstituted hydrazines. It was also shown that the reaction between
phenylhydrazine and cyanogen can give rise to two products (21) (Scheme 2).
1.2.1.3 Disubstituted hydrazines. Herbicides of the general formula 8 have been
synthesized in a two step processes (22). The first step involves the reaction of the
cyanogen with dimethylhydrazine in hexane at 5 ºC (Scheme 3). The second contains
treatment of the resultant cyanoformamidrazone at higher temperatures with hydrazine in
isopropyl alcohol (Scheme 3).
3
Methylphenylhydrazine and benzonitrile in benzene were condensed in the presence of
sodium to produce N1-methyl-N
1-phenylbenzamidrazone (23) (Scheme 4).
1.2.2 From imidates and their salts
1.2.2.1 Monosubstituted hydrazines. Imidate salts react smoothly in alcohol at room
temperatures with monosubstituted hydrazines. The products are mainly N1-substituted
amidrazones, but in some cases formazans such as dihydroformazan 9, may form in these
reactions. When two parts of substituted hydrazine to one part of imidate are employed,
the corresponding formazans are obtained in good yield (23-26) (Scheme 5).
1.2.3 From hydrazonoyl halides by aminolysis. Halogenations of bezaldehyde
phenylhydrazones with bromine occurs both in the ω-position and in the N-phenyl group.
The ω-brominated product is very reactive and reacts with concentrated aqueous ammonia
4
solutions to give amidrazones (27) (Scheme 6).
1.2.4 From imidoyl halides with substituted hydrazines or acid hydrazides. This
process is base on the reaction of an imidoyl halide with a substituted hydrazine (28). This
reaction can give rise to two products if suitably chosen monosubstituted hydrazines are
used. These products are the N1,N
3- and the N
2,N
3-disubstituted amidrazones (Scheme 7).
1.2.5 From other imidic acid derivatives with hydrazines. N,N’-Disubstituted
amidines react with phenylhdrazine at temperaturs around 100 oC to give N
1,N
3-
disubstituted amidrazones (29) (Scheme 8).
1.2.6 From amides and thioamides
1.2.6.1 Amides. Amides provide a feasible starting point to the synthesis of
amidrazones, either directly or via the imidoyl halide. A typical example of a direct
synthesis is the condensation of an N,N-disubstituted amide with a substituted hydrazine
in the presence of phosphorus oxychloride (8,30-32) (Scheme 9).
5
1.2.6.2 Thioamides. Cyanothioamides react with hydrazines to give amidrazones among
other products (33). Thus various oxalic acid derivatives have been prepared in this way
using NCCSNH2, H2NCSCSNH2, C2H5OOCCSNH2, and HOOCCSNH2 as starting
materials (34) (Scheme 10).
1.2.7 Reduction of nitrazones. Treatment of N-m-nitrophenylacetnitrazone with tin in
hydrochloric acid afforded the reduced N1-(m-aminophenyl)acetamidrazone, however, it
failed to produce any amidrazone (35) (Scheme 11).
1.2.8 Reduction of formazans and tetrazolium salts. The stepwise hydrogenation of
tetrazolium salts and formazans has been studied (36, 37) (Scheme 12). The successful
methods of reduction are (a) hydrogenation using 5% palladium on barium sulfate, (b)
Raney nickel in methanol and (c) the use of sodium dithionite. The reduction process
follows the sequence as outlined in scheme 12.
6
1.2.9 From heterocyclic systems. In addition to the tetrazolium salts, various
heterocyclic systems have been used to prepare amidrazones through interaction with
hydrazines, although the heterocyclic precursors themselves are not always easily
formed. Thus the reaction of 1,3,4-oxathiazoline 3-dioxide in dioxane solution with
hydrazine gives good yields of amidrazones (38) (Scheme 13).
2,6-
Bis(perfluoroalkyl)-1,3,4-oxadiazoles readily underwent nucleophilic attack at a ring
carbon atom to give products of the type 10 (39),
which reacted with ammonia to give
compounds of formula 11 (Scheme 13).
1.2.10 From ketimines, acetylenes, and carbodiimides. Addition of hydrazine to a
ketimine of type 12 produced N3-substituted amidrazones (40) (Scheme 14).
7
1.3 Reactions of amidrazones
1.3.1 Reaction with Grignard reagents. The formyl group of N1-
formylformamidrazones as 13 reacts with phenylmagnesium bromide to afford
benzaldehyde and a small amount of benzhydrol. N3,N
3-Dimethyl-N
1-
formylformamidrazone was found to give only a trace of benzaldehyde on treatment with
the Grignard reagent (41) (Scheme 15).
1.3.2 Action of nitrous acid on amidrazones
1.3.2.1 Monosubstituted amidrazones. Although N1-substituted amidrazones cannot
form imide azides, they nevertheless form 2,5-disubstituted tetrazoles on treatment with
nitrous acid (42) (Scheme 16).
1.3.3 Condensation of amidrazones with aldehydes or ketones
1.3.3.1 Unsubstituted amidrazones. p-Toluamidrazone gave compound 14 on treatment
with benzaldehyde. Aminoguanidine reacts in similar reaction with aldehydes (43)
(Scheme 17). Bladin (44) obtained two products from the reaction of excess benzaldehyde
with an alcoholic solution of N1-phenylcyanoformamidrazone, namely a Schiff base 15
and a triazole 16 (Scheme 18).
8
1.3.4 Synthesis of 1,2,4-triazines. N-Unsubstituted amidrazones condense only with
dicarbonyl compounds to yield 1,2,4-triazines (45) (Scheme 19).
1.3.5. Miscellaneous heterocyclic systems
1.3.5.1 Bisoxadiazoles. The reaction of carbon disulfide with amidrazones produced the
corresponding 5-thioxothiadiazoles (46), whereas the cyclization of the oxalamidrazone at
100 oC in dichloroacetic acid gave the corresponding bisoxadiazolyl (47) (Scheme 20).
1.3.5.2 Benzimidazole. It was reported that 1,1,1-trimethyl-2-benzoylhydrazinium
hydroxide 17 (48) reacted with phenyl isocyanate via salt formation 18, which on
9
extrusion of CO2 produced 19. Heating 19 yielded the corresponding 1H-benzimidazole
20 (48) (Scheme 21).
Aly et al. reported the syntheses of various classes of 1,2,4-triazoles 21 from the reaction
of amidrazones with 2-dicyanomethyleneindane-1,3-dione 22 (49) (Scheme 22).
1.3.5.3 Bis(indole)triazinone. The preparation of unsubstituted indole-amidrazones
turned out to be relatively straightforward (Scheme 23). Beginning from commercially
available 1H-indole 23, in three steps, the desired amidrazone 25 was obtained in good
yield, via formation of indolyl-3-carbonitrile 24 (50-52) (Scheme 23). In the
cyclocondensation reaction, exposure of amidrazone 26 to ketoester 27 (53) in the
presence of MgSO4 in methanol, followed by reflux in DMF, afforded the desired anti-
triazinone product 28 in 68% yield in addition to syn-triazinone 29 as a minor product
(53) (Scheme 24).
10
1.3.5.4 Pyrazolo[3,4-d]pyrimidines. The imidoesters 31 were obtained by coupling 5-
amino1H-pyrazole-4-carbonitriles 30 with triethyl orthoformate (54-58) (Scheme 25).
11
1.3.5.5 Pyrazolo[1,5-c]pyrimidines. The substituted amidrazones react with
triphenylpyrylium to give pyridinium salts which can be converted to carbodimides (59).
In the presence of TEA/AcOH, the reaction takes a different course and bicyclic products
32 are formed (Scheme 26).
1.3.5.6 1,2,4-Triazoles. Amidrazones are considered as precursors for preparing various
triazoles (60-64) (Scheme 27).
1.3.5.7 1,2,4-Triazines. The reaction of the N3-substituted amidrazones with dimethyl
acetylenedicarboxylate 33 in absolute ethanol at the temperature of -10 °C led to the
formation of derivatives of dimethyl α-[(1-arylamino-1-arylmethylidene)hydrazono]-
12
succinates 34 (65, 66). Cyclization of 34 was carried out in methanol solution in the
presence of triethylamine and led to the formation of methyl 2-(5-oxo-3,4-dialkyl-1,4,5,6-
tetrahydro-1,2,4triazine-6-ylidene)acetates 35 as shown in Scheme 28.
Aly et al. (67) have recently reported the synthesis of fused triazines, benzoindazoles,
1,2,4triazepine-6,11-diones and hydrazino-butane-1,4-diones. These products were
obtained in the reaction of amidrazones with π-deficient compounds. As it is outlined in
Scheme 29, amidrazones reacted with two equivalents of 1,4-benzoquinone 36 or 1,4-
naphthoquinone 38 to give, in a few minutes, after chromatographic purification and
recystallization, compounds 37 (66-85%) and 39 (70-86%), respectively (67) (Scheme
29). In a different manner, the reactions of amidrazones with 2,3,5,6-tetrachloro-1,4-
benzoquinone 40 and 2,3-dichloro-1,4-naphthoquinone 42 (Scheme 30) in dry DMF
produced single product for all substituted amidrazones 41 and 43 respectively (Scheme
30). Syntheses of various 4-aryl-5-imino-3-phenyl-1H-naphtho[2,3-f]-1,2,4-triazepine-
6,11-diones 45 are reported by Aly et al. Their successful synthesis depends on the
reaction of amidrazones with 1,4-dioxo-1,4-dihydronaphthalene-2,3dicarbonitrile 44 (68)
(Scheme 31). Various 1,4-diphenyl-2-{2-(1-arylamino-1-phenylmethylidene)hydrazono}-
butane-1,4-diones 47 were obtained by the reaction of amidrazones with 1,4-diphenyl-2-
butyne-1,4-dione 46 in boiling ethanol (69) (Scheme 32).
13
14
2 DIHYDRO-1,2,4-TRIAZOLES (70)
2.1 Introduction
Dihydro-1,2,4-triazoles (triazolines) can be found in three forms as illustrated in scheme
33
2.2 Synthesis of Dihydro-1,2,4-Triazoles
Numerous reactions are known in literature for synthesis of dihydro-1,2,4-triazole rings.
2.2.1 Cyclization Reactions of Hydrazones
2.2.1.1 Cyclocondensation of hydrazones with monocarbonyl compounds
2.2.1.1.1 Amidrazones. The early synthetic methods of amidrazones usually
involved cyclocondensation of unsubstituted amidrazones with aldehyde, ketones or other
one carbon atom sources. Although the products obtained may be either the Schiff base or
dihydro-1,2,4-triazoles (Scheme 34).
15
Also, the unsubstituted diamidrazones and aldehyde or unsubstituted amidrazone and
dialdehydes were reacted and gave bis-4,5-dihydro-1,2,4-triazoles (Scheme 35).
The N1,N
3-diphenylamidrazone reacted with benzaldehyde to give 4,5-dihydro-1,2,4-
triazole, while N2,N
3-disubstituted amidrazone gave only the Schiff base (Scheme 36).
16
Acetophenone and 2-acetylpyridines, as monoketone, reacted with unsubstituted
amidrazones in refluxing ethanol in the presence of catalytic amount of hydrochloric acid
to give 4,5-dihydro-1,2,4-triazoles. Increased concentration of acid causes hydrolysis of
the amidrazones leading to N-acylhydrazones (Scheme 37).
2.2.1.1.2 Hydrazinoheterocycles
Amidrazones, in which the imine moiety is and integral part of a heterocyclic ring system,
react with aldehyde and ketone to form fused ring dihydro-1,2,4-triazoles. Piperidone
hydrazone 48 in the presence of silica gel in refluxing acetone yields the bicyclic dihydro-
1,2,4-triazole (Scheme 38).
Likewise, acylation of pyridazinylhydrazones 49 yields acylated
dihydrotriazolopyridazines 50 (Scheme 39).
17
2.2.1.1.3 Azo Heterocycles
Fused 1,2,4-triazoline rings 53, 54 are reported from the reaction of 2,2'-azopyridine 51
and 2,2'-azoquinoline 52 with diphenyldiazomethane (Scheme 40).
2.2.1.2 Cyclization of hydrazone derivatives
2.2.1.2.1 Cyclization induced by ethoxymethyenemalononitrile and
ethoxymethylene cyanoacetate
Isothiosemicarbazones of aldehydes and ketones 55 have been reported to cyclize with
both ethoxymethylenemalononitrile 56 and ethoxymethylene cyanoacetate 57 to give the
corresponding dihydrotriazolopyrimidines 58 (Scheme 41).
18
2.2.1.2.2 Cyclization induced by Isocyanate- and isothiocyanate
Isothiosemicarbazones 55 and isocyanates bearing phenyl or tert-butyl group are reported
to react at room temperature overnight to yield dihydro-1,2,4-triazoles 56 (Scheme 42).
2.2.1.2.3 Rearrangement of O-acetyl derivatives of 1,2-hydroxylamino-
hydrazones and thiosemicarbazones
Compounds 57 undergo base-catalyzed rearrangement to form 4,5-dihydro-1,2,4-triazoles
(Scheme 43).
19
2.2.2 1,3-Dipolar Cycloaddition Reactions
2.2.2.1 Nitrilimine addition to acyclic C=N bonds
2.2.2.1.1 Nitrilimine addition to C=N bonds in hydrazones, imidates and oximes
Diphenylnitrilimine cycloadded to hydrazones and imidates to yield 4,5-dihydro-1,2,4-
triazoles (Scheme 44). Also, reaction of ketone oxime 58 with nitrilimines in
tetrahydofuran has been studied and found to result in the formation of the unexpected
dihydro-1,2,4-triazole derivatives 59, rather than the cycloaddition products 60 (71, 72)
(Scheme 45).
20
Reaction of diphenylnitrilimine with C-benzoylimines yields 5-benzoyl-4,5-dihydro-
1,2,4-triazoles (Scheme 46).
When the nitrilimines, generated from hydrazonyl chloride and TEA, reacted with
benzaldehydeazine gave stable 4-benzylideneamino-4,5-dihydro-1,2,4-triazoles (Scheme
47).
21
2.2.2.1.2 Nitrilimine addition to conjugated C=N bonds
Nitrilimines add to conjugated C=N bonds to give the corresponding 4,5-dihydro1,2,4-
triazoles. The 1-azabutadienes reacted with nitrilimines to afford the 4,5-dihydro-5-
alkenyl-1,2,4-triazoles (Scheme 48).
2.2.2.1.3 Nitrilimine addition to exocyclic C=N bonds
In the same manner the nitrilimines add to exocyclic C=N bond of compound 61 to give
spirotriazoline adducts 62 (Scheme 49).
2.2.2.2 Nitrilimine addition to cyclic C=N bonds
Nitrilimines add to cyclic C=N bond, which is an integral part of several N-heteroring
systems, and gave several 4,5-annulated 4,5-dihydro-1,2,4-triazoles. Scheme 50 illustrates
some of these reactions.
22
Also, the reaction of 3,4-dihydro-6,7-dimethoxy(diethoxy)isoquinolines or its 1-methyl
and 1-cyanomethyl derivatives 63 with various nitrilimines in tetrahydrofuran were
reported to afford the respective products 64 (73-76) (Scheme 51).
23
2.2.2.3 Nitrile ylide addition to azo compounds
Nitrile ylides are represented by the resonance structures A and B. They are usually
generated in situ in the presence of the dipolarophile.
Diethylazodicarboxylate 65 cycloadds to a variety of nitrile ylides to give 2,5-dihydro-
1,2,4-triazoles (Scheme 52).
2.2.2.4 Nitrilimine with 1,3-diazaheterocyclic thiones
24
Various fused heterocyclic compounds containing dihydro-1,2,4-triazole ring were
synthesized from the reaction of nitrilimines with variety of 1,3-diazoheterocyclic thiones.
2.2.2.4.1 Nitrilimine with imidazolethiones. Reaction of 4,5-diphenyl imidazoline-
2(3H)-thione 66 with nitrilimines having no α-oxo group in chloroform was reported to
give the respective imidazo[2,1-c]-1,2,4-triazole derivatives 67 (77, 78) (Scheme 53).
2.2.2.4.2 Nitrilimine with 1,2,4-triazolethiones. Reaction of 5-phenyl-1,2,4-
triazole-3(2H)-thione 68 with various nitrilimine gave the thiohydrazides 69, which were
converted into 1,2,4-triazolo[3,4-c]-1,2,4-triazoles 70 by treatment with phosphorus
oxychloride (79-81) (Scheme 54).
2.2.2.4.3 Nitrilimine with pyrimidinethiones. Nitrilimines reacted with 6-
substituted-2-thiouracil 71a and 5,6-disubstituted-2-thiouracil 71b were reported to be
regioselective and afforded the respective 1,2,4-triazolopyrimidinone derivatives 72 (76)
(Scheme 55).
25
Reaction of bis-nitrilimine 73 with 2-methylthiouracil 74 afforded 75 (82) (Scheme 56).
2.2.2.4.4 Nitrilimine with 1,2,4-triazine-5(4H)-thiones. Reactions of nitrilimines
with either 3-thioxo-1,2,4-triazin-5(2H)-ones 76 or 3-methylthio-1,2,4-triazin-5(4H)-one
77 were reported to give in both cased the respective 1,2,4-triazolo[4,3-b]-1,2,4-triazin-
7(1H)-ones 78 (83, 84) (Scheme 57).
26
2.2.2.4.5 Nitrilimine with 1,2,4-triazepinethiones. The reaction of nitrilimines with
1,2,4-triazepine-3,5-dithiones 79 was reported to yield the respective 1,2,4-triazolo[4,3-
d]-1,2,4-triazepines 80 (85) (Scheme 58).
2.2.2.4.6 Nitrilimine with benzimidazolethiones. When benzimidazole-2-thiol 81
was refluxed with nitrilimines in chloroform, it afforded the respective 1,2,4-triazolo[4,3-
a]benzimidazoles 82 (78) (Scheme 59).
The reaction of bis-nitrilimine 73 with 2-methylthiobenzimidazole 83 was reported
recently to give 3,3'-bis(1,2,4-triazolobenzimidazole) 84 (86) (Scheme 60).
27
2.2.2.4.7 Nitrilimine with purinethiones. Recently, it has been reported that the
reactions of hydrazonoyl halides (precursors of nitrilimines) with theophylline-8-thione 85
and 8-methylthiotheophylline 86 in refluxing pyridine yielded in both cases 1,3-
disubstituted 1,2,4-triazolo[3,4-f]purine derivatives 87 (87) (Scheme 61).
2.2.2.4.8 Nitrilimine with quinazolinethiones. Reaction of 2-thioxoquinazolin-
4(1H)-one 88 with various nitrilimines in refluxing chloroform yielded 1,2,4-triazolo[4,3-
a]quinazolin-5-one derivatives 89 (88) (Scheme 62).
2.2.2.4.9 Nitrilimine with pyrido[2,3-d]thiouracils. Recently, it was reported that
treatment of pyrido[2,3-d]-2-thiouracil 90 with nitrilimines yielded the corresponding
pyrido[2,3-d]-1,2,4-triazolo[4,3-a]pyrimidin-5-one derivatives 91 (89, 90) (Scheme 63)
28
2.2.2.4.10 Nitrilimine with pteridinethiones. Reaction of 2-thioxopteridine-4(3H)-
one derivatives 92 with nitrilimines in tetrahydrofuran under reflux afforded the
respective 1,2,4-triazolo[3,4-b]pteridine derivatives 93 (91) (Scheme 64).
2.2.2.4.11 Nitrilimine with pyrido[3',2':4,5]thieno[3,2-d]pyrimidinethiones.
Reaction of nitrilimines with 94 in refluxing dioxane gave pyrido[3',2':4,5]thieno[3,2-d]-
1,2,4-triazolo[4,3-a]pyrimidin-5-one 95 (92) (Scheme 65).
29
2.2.2.4.12 Nitrilimine with cyclohepta[4,5]-thieno[2,3-d]pyrimidinthiones.
Recently various functionalized derivatives of 5H-cyclohepta[4,5]-thieno[2,3-d]-1,2,4-
triazolo[4,3-a]pyrimidin-5-one 97 were synthesized via reaction of nitrilimines with
2,3,5,6,7,8,9-heptahydro-2-thioxo-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidine-4-one 96
(93) (Scheme 66).
2.2.2.4.13 Nitrilimine with naphtho[2,1-e]pyrido[2,3-c]pyrimidinethiones.
Naphtho[2',1':5,6]pyrido[2,3-d]pyrimidinethione derivatives 98 reacted with nitrilimines
and yielded the respective fused naphthotriazolopyridopyrimidines 99 (94) (Scheme 67).
CHAPTER TWO
PURPOSES OF THE PRESENTED WORK
31
2 PURPOSE OF THE PRESENTED WORK
One of the amidrazone reactions is condensation reaction of monocarbonyl compounds (4). It
has been reported that N1-monosubstituted amidrazone 1 react with acyclic ketones to give
dihydro-1,2,4-triazoles 2 (95). The used amidrazones were limited (Scheme 1).
The purpose of the presented work is to investigate the reaction of different N1-
monosubstituted and N1,N
3-disubstituted amidrazones 3-5 with several acyclic and cyclic
ketones and benzaldehyde which are expected to afford spiro/4,5-dihydro-1,2,4-triazoles 6-8
(Scheme 2).
Recently, Drutkowski reported that the o-substituted amidrazones 1 at the arylhydrazone
moiety were recovered unchanged when they were reacted with acyclic ketones. The author
attributed this finding to the steric hindrance of the substituent at the ortho position which
decreased its reactivity (95) (Scheme 3).
32
We here aim to investigate whether the steric hindrance is the cause of lowering reactivity of
amidrazones toward the electrophiles or another factor is.
Also, N1-monosubstituted amidrazones were reacted with aldehydes to afford two products,
namely a Schiff base 10 and a triazole 11 (44), or to give triazoles 13 in some cases and Schiff
bases 15 in another (4) (Scheme 4).
33
However, it has been evidenced by spectroscopic data that the reaction of N1-
phenylbenzamidrazone with aldehydes gives rise to 4,5-dihydro-1,2,4-triazoles rather than
Schiff bases (96).
We aim accordingly to investigate whether the Schiff base or 1,2,4-triazole is the product from
the reaction of N1-monosubstituted amidrazones with benzaldehyde (Scheme 5).
CHAPTER THREE
RESULTS AND DISCUSSION
34
3 RESULTS AND DISCUSSION
3.1 Preparation of Starting Materials
3.1.1 Preparation of α-chloroacetoacetanilide
The α-Chloroacetoacetanilide 16 required in this study was prepared from chlorination
reaction of acetoacetanilide by the action of sulfuryl chloride in dry ether according to the
literature method (experimental part) (Scheme 6).
3.1.2 Preparation of hydrazonoyl halides
The hydrazonoyl chlorides 19-21 employed in this study were prepared, according to Japp-
Klingmann reaction, by coupling of the appropriate arenediazonium chloride with α-
chloroacetoacetanilide 16, 3-chloro-2,4-pentanedione 17 and ethyl 2-chloroacetoacetate 18,
respectively (experimental part) (Scheme 7).
35
3.2 Reaction of Hydrazonoyl Halides with Ammonia, Methylamine and 4-
Chloroaniline
Different amidrazone derivatives 3-5 have been synthesized by nucleophilic substitution of
hydrazonoyl chlorides 19-21 with ammonia, methylamine and 4-chloroaniline in dioxane
according to the previously reported method (97) (Scheme 8). The reaction was promoted by
adding one and half molar amount of ammonia or methylamine as bases. It was carried out at a
temperature between 40 and 45 oC, and was completed up to 12 h. However, 4-Chloroaniline
as nucleophile required an additional equimolar amount of triethylamine as base. The
structures of prepared amidrazones 3-5 were confirmed by elemental analyses and
spectroscopic data, thus, the IR spectra exhibit typical stretching bands of C=O of conjugate
anilide, ketone and ester groups at about 1650-1726 cm-1
and NH in the region of 3418-3237
cm-1
. 1H NMR spectra of these amidrazones in CDCl3 show two characteristic signals, one
singlet of NH2 near 4.9-5.0 ppm or at 6.22 ppm in case of 4-chlorophenyl substituted amide
moiety, another singlet of the =NNH group in the region of 6.0-6.3 ppm. In addition the
characteristic singlet signal of the CONH group in compounds containing anilide group was
observed at about 8.6-9.0 ppm and the expected proton signals of the ethyl group at 1.2-1.4
and 4.2-4.4 ppm as triplet and quartet, respectively. 13
C NMR spectra exhibit two
characteristic signals for the C=O group at about 193 for acetyl, 158-160 for ester and anilide
moieties and for the C=N moiety at about 140-143 ppm.
36
3.3 Reaction of N1-monosubstituted and N
1,N
3-disubsituted Amidrazones 3-5 With
Acyclic, Cyclic Ketones and Benzaldehyde
The spiro/4,5-dihydro-1H-1,2,4-triazole derivatives 6-8 were synthesized from the reactions of
amidrazones 3-5 with cyclic and acyclic ketones and benzaldehyde, in the presence of a
catalytic amount of 4-toluenesulfonic acid in dioxane (Scheme 9). Unlike the previously
described method (95) which used the ketone itself as a solvent, dioxane was used because of
its lower toxicity and lower boiling point than that of the used cyclic ketones which facilitate
its evaporation and trituration. The completion of most reactions was achieved in less than 6
hrs and the yields varied between 70 to 75%. The structures of 4,5-dihydrotriazoles 6-8 were
confirmed by elemental analyses and spectroscopic data.
37
38
The proposed mechanism leading to the formation of 4,5-dihydro-1,2,4-triazole derivatives are
outlined in scheme 10.
39
The IR spectra show typical stretching absorption bands of the C=O bond for anilide and
acetyl groups in the region of 1660-1689 cm-1
and for the ester group in the region of 1703-
1729 cm-1
, the NH bond of dihydrotriazole ring resonated in the region of 3337-3399 cm-1
and
the NH bond of anilide moiety in the region of 3229-3296 cm-1
. 1H NMR spectra in CDCl3 or
DMSO-d6 display a characteristic singlet in the region of 4.48-5.56 ppm or 7.21-7.31 ppm
respectively, due to NH proton of triazole ring. Also, the spectra exhibit a characteristic singlet
in the region of 8.5-8.6 ppm in CDCl3 or in the region of 10.0-10.39 ppm in DMSO-d6 due to
NHCO proton. 13
C NMR spectra display characteristic signals of the suggested structures.
Thus, compounds 7a-c exhibit one signal for methyl carbon of the acetyl group at about 24
ppm. The signal of C=O carbon appears at about 190 ppm. Compounds 8a-e exhibit two
characteristic signals of ethyl ester. One appears at about 14 ppm and the other at 62 ppm
corresponding to methyl and methylene carbons, respectively. The ester carbonyl carbon
appears at about 159 ppm. The compounds 6a-l exhibit one characteristic signal of anilide
C=O at 157 ppm. The C5 carbon of 6-8 appears at about 88-90 ppm which is similar to the
reported values of such spiro-carbon lying between two heteroatoms in the five membered
heterocycles (72, 95). The mass spectra of prepared compounds show the correct molecular
ions and the most important fragmentation patterns of molecular ion involve generation of [M-
43]+, [M-57]
+ and [M-15]
+ ions for the compounds containing cyclohexyl, cycloheptyl and
methyl moieties respectively (Scheme 11).
40
N1-substituted amidrazone 9 has been reported to react with benzaldehyde to give either a
mixture of Schiff base 10 with triazole 11 (44), or to give triazoles 13 in some cases and Schiff
bases 15 in another (4) (Scheme 4). In present work, treatment of N1-substituted amidrazones
3b,d and 4a with benzaldehyde in dioxane in the presence of a catalytic amount of 4-
toluenesulfonic acid gave in each case, a single product as shown by TLC and assigned as
1,2,4-triazole derivatives 22a-c respectively (Scheme 12), The Schiff base 23 was not
detected. The structure of Schiff base 23 was excluded on the basis of elemental analyses and
spectroscopic data. As an example, the 1H NMR spectra don't display signal at 8.0-9.0 ppm
corresponding to -N=CH- of Schiff base in CDCl3 (98-100). Furthermore, the structure of 23
also rejected on the basis of the absence of the stretching band of NH bond of =NNH moiety
in their IR spectra. The structures of the triazole compounds were deduced from their
elemental analyses and spectroscopic data. The IR spectra of all compounds display the
characteristic stretching absorption band of the C=O bond of acetyl and anilide moieties in the
region of 1673-1696 cm-1
and of CONH bond of anilide in the region of 3253-3269 cm-1
. The
1H NMR spectra display a characteristic singlet signal at 10.5 ppm due to anilide NHCO.
13C
NMR spectra exhibit a signal at about 155 ppm due to new formed C=N bond. The mass
spectra of all prepared compounds 22a-c displayed the correct molecular ion peaks.
41
42
It has been reported that when the ortho substituted amidrazone of the arylhydrazone moiety
were reacted with ketone, the amidrazones were recovered unreacted. This result attributed to
the decreased reactivity of amidrazones due to the steric hindrance of the ortho substituent (95)
(Scheme 13). Contrary to this finding, in current work, the amidrazone with ortho methyl
substituent 3c reacts with cyclic and acyclic ketones and give the corresponding 4,5-dihydro-
1,2,4-triazole derivatives 6f-h in good yields. We assume that, the reasonable explanation of
these different results could be attributed not only to the steric hindrance, but also to the nature
of the substituent at the arylhydrazone moiety. Hence, the cyano, fluoro and chloro
substituents decrease the nucleophilicity and reactivity of N1 by the withdrawal effect due to -
I and -R effects of the cyano group and -I effect of fluro and chloro substituents, which is more
effective than that of their +R effect, while the ortho methyl group in 3c increases the
nucleophilicity and reactivity of N1 due to its +I effect. Therefore, the amidrazone 3c will be
more reactive toward the electrophiles, aldehydes and ketones.
CHAPTER FOUR
EXPERIMENTAL
43
4 EXPERIMENTAL
4.1 General
NMR spectra were determined in CDCl3 or DMSO-d6 at 300 MHz or 400 MHz (1H NMR)
and at 75 MHz or 100 MHz (13
C NMR) on a Varian Mercury VX 300 NMR or Bruker
spectrometer using TMS as an internal standard. IR spectra were recorded on Shimadzu
FT-IR 8101 PC infrared spectrophotometer. Mass spectra were recorded on a GCMS-
QP1000 EX spectrometer at 70 eV. Elemental analyses were carried out at the Micro
analytical center of Cairo University. Melting points were measured on a Stuart apparatus
and uncorrected.
4.2 Materials and Reagents
Ammonia 7N methanolic solution, 3-chloro-2,4-penanedione, p-toluidine, triethylamine,
ethyl 2-chloroacetoacetate, methylamine 2M methanolic solution, cyclopentanone were
purchased from Sigma Aldrich Company. Conc. hydrochloric acid was obtained from
Chempal Company. Sodium nitrite, acetoacetanilide, p-toluenesulfonic acid were obtained
from Hi Media Company. Aniline, pyridine and benzaldehyde were obtained from Elnaser
Company. Cyclohexanone and acetone were obtained from Fruta Rome Company. p-
chloroaniline was obtained from Carlo Erba Company. Cycloheptanone was obtained from
Acros Company. o-Toluidine was obtained from Merck Company. Butanone, o-anisidine,
were obtained from British Drug Houses (BDH).
4.3 Solvents
Dioxane and tetrahydrofurane were obtained from Merck Company. Absolute ethanol was
obtained from Elnaser Company. Methanol and Dimethylformamide were obtained from
Chempal Company. Heptane was obtained from Sigma Aldrich Company. Chloroform was
obtained from Lobachemie Company. Dry ether was obtained from ELGoumhouria
Company.
44
4.4 Organic Preparations:
4.4.1 Preparation of α-Chloroacetoacetanilide 16
A solution of sulfuryl chloride (39 g, 0.2 mol) in dry ether (50 ml) was added dropwise
over one hour to a cold suspension of acetoacetanilide 24 (50 g, 0.24 mol) in dry ether (300
ml) while stirring at 0 oC. After additional 15 min, the solvent was removed, and the solid
left was recrystallized from aqueous ethanol to give 45.5 g (75 %) of colorless crystals of
α-chloroacetoacetanilide 16, mp. 137 oC [Lit. mp. 138
oC] (101).
4.4.1.1 Preparation of N-Aryl-C-phenylaminocarbonylmethanohydrazo-
noyl Chlorides 19
A solution of α-chloroacetoacetanilide 16 (2.1 g, 0.01 mol) in ethanol (100 ml) was stirred
with sodium acetate trihydrate (1.36 g, 0.01 mol). The mixture was then cooled in an ice
bath to 0-5 oC and treated with cold (0-5
oC) solution of diazonium salt prepared by
diazotizing the appropriate arylamine (0.01 mol) dissolved in 6 M hydrochloric acid (6 ml)
[or in 3 ml conc. HCl] with a solution of sodium nitrite (0.7 g, 0.01 mol) in water (2-3 ml).
The addition of diazonium salt was carried out with rapid stirring over a period of 20 min.
the reaction mixture was kept basic by the addition, when necessary, of more sodium
acetate. When the addition was complete, the mixture was stirred for another 30 min. and
left to stand for 3 h in the refrigerator. The resulting solid was collected by filtration and
washed thoroughly with water. The crude product was crystallized from ethanol or acetic
acid to give 19a-d.
1. N-Phenyl-C-phenylaminocarbonylmethanohydrazonoyl chloride 19a, mp. 162-
3 oC [Lit. mp. 161-2
oC] (102).
2. N-(4-methylphenyl)-C-phenylaminocarbonylmethanohydrazonoyl chloride
19b, mp. 175-6 oC [Lit. mp. 175-6
oC] (102).
3. N-(2-methylphenyl)-C-phenylaminocarbonylmethanohydrazonoyl chloride
19c, mp. 115-6 oC [Lit. mp. 115-6
oC] (102).
45
4. N-(4-chlorophenyl)-C-phenylaminocarbonylmethanohydrazonoyl chloride
19d, mp. 199-200 oC [Lit. mp. 199-200
oC] (102).
4.4.2 Preparation of C-Acetylmethanohydrazonoyl Chlorides 20
General method
To a stirred solution of 3-chloro-2,4-pentanedione 17 (1.34 g, 0.01 mol) in ethanol (100
ml), was added sodium acetate trihydrate (1.36 g, 0.01 mol). After stirring for 15 min. the
mixture was cooled to 0 oC and treated with a cold solution of aryl diazonium chloride,
prepared by diazotizing aryl amine (0.01 mol) dissolved in 3 mL conc. HCl with a solution
of sodium nitrite (0.7 g, 0.01 mol) in water (10 mL). The addition of the diazonium salt
was carried out with rapid stirring over a period of 20 min. The reaction mixture was
stirred for additional 15 min. and left for 3h in refrigerator. The resulting solid was
collected by filtration and washed thoroughly with water. The crude product was
crystallized form ethanol to give the corresponding hydrazonoyl chlorides 20a,b.
1. N-Phenyl-C-acetylmethanohydrazonoyl chloride 20a was obtained in 75% yield,
mp 142 oC [Lit. mp. 143
oC] (103).
2. N-(4-Bromophenyl)-C-acetylmethanohydrazonoyl chloride 20b was obtained in
74% yield, mp. 142 oC [Lit. mp. 142
oC] (104).
4.4.3 Preparation of C-Ethoxycarbonyl-N-arylmethanohydrazonoyl
chlorides 21.
These compounds were prepared by the same procedure described above using ethyl 2-
chloroacetoacetate 18 instead of 3-chloro-2,5-pentanedione 17.
1. N-Phenyl-C-ethoxycarbonylmethanohydrazonoyl chloride 21a 80% yield, mp.
79-80 oC [Lit. mp. 79-80
oC] (105).
2. N-(4-Chlorophenyl)-C-ethoxycarbonylmethanohydrazonyl chloride 21b 76%
yield, mp. 142-3 oC [Lit. mp. 143
oC] (105).
46
4.5 Organic Syntheses:
4.5.1 Synthesis of 2-Amino-N-phenyl-2-(2-arylhydrazono)acetamide 3, 2-Oxo-
(2-arylhydrazono)propanamide 4 and Ethyl 2-Amino-2-(2-
arylhydrazono)acetate 5
To the solution of ammonia (0.02 mol, 2.85 ml of a 7N methanolic solution) was added
dropwise a solution of appropriate hydrazonoyl halides 19-21 (0.01 mol) in 40-50 ml
dioxane. After stirring at 40-50 oC overnight the mixture was poured into 100 ml cold
water. The solid so formed was collected, washed with water, dried and crystallized from
the given solvent.
2-Amino-N-phenyl-2-(2-phenylhydrazono)ethanamide 3a
Pale orange solid, mp. 155-7 oC [Lit. mp. as chloride 161-5
oC] (97), from ethanol, yield
78%; IR: ν cm-1
3468.2, 3373.8, 3338.1, 3250.4 (NH, NH2), 3024.8 (CH Ar’s), 1676.8
(C=O); 1H NMR (CDCl3): δ ppm 4.95 (s, 2H, NH2), 6.09 (s, 1H, NNH), 6.91-7.72 (m,
10H, Ar’s), 9.12 (s, 1H, NH); 13
C NMR (CDCl3): δ ppm 158.74 (C=O), 143.51 (C=N),
144.91, 139.62, 122.78, 119.23, 116.10, 118.28, 128.91, 129.8 (C, CH) MS m/z: 254 (M+,
73), 237 (13), 209 (56), 187 (13), 147 (27), 133 (30), 118 (20), 107 (8), 92 (61), 77 (57), 65
(72), 51 (18); Anal. Calcd. for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. C, 66.20; H, 5.59;
N, 22.00%.
47
2-Amino-N-phenyl-2-[2-(4-methylphenyl)hydrazono]ethanamide 3b
Pale orange solid, mp. 173-5 oC, from ethanol, yield 78%; IR: ν cm
-1 3384.5, 3338.5,
3242.7 (NH’s), 1683.5 (C=O); 1H NMR (CDCl3): δ ppm 2.31 (s, 3H, CH3), 5.01 (s, 2H,
NH2), 6.20 (s, 1H, NNH), 6.91-7.71 (m, 9H, Ar’s), 8.67 (s, 1H, NHCO); 13
C NMR
(CDCl3): δ ppm 158.80 (C=O), 143.42 (C=N), 144.80, 139.51, 128.3 (C), 130.51, 128.91,
122.77, 118.27, 116.11 (CH), 18.12 (CH3); MS m/z: 268 (M+, 9), 251 (18), 132 (12), 106
(68), 93 (100), 77 (92), 65 (34), 51 (36). Anal. Calcd. for C15H16N4O: C, 67.15; H, 6.01; N,
20.88. Found: C, 67.14; H, 6.03; N, 20.91%.
2-Amino-N-phenyl-2-[2-(2-methylphenyl)hydrazono]ethanamide 3c
Pale orange crystals, mp. 173-5 oC, from ethanol, yield 80%; IR: ν cm
-1 3418.2, 3341.0
(NH’s), 3060.4, 3023.8 (CH Ar’s), 1656.5 (C=O); 1H NMR (CDCl3): δ ppm 2.28 (s, 3H,
CH3), 4.93 (s, 2H, NH2), 6.17 (s, 1H, NNH), 6.88-7.67 (m, 9H, Ar’s), 9.07 (s, 1H, NHCO);
13C NMR (CDCl3): δ ppm 158.82 (C=O), 143.48 (C=N), 140.44, 137.14, 122.13, 130.48,
129.16, 127.21, 124.51, 120.81 (C, CH), 17.13 (CH3); MS m/z: 268 (M+, 80), 222 (4),147
(20), 132 (11), 119 (21), 106 (44), 91 (36), 77 (47), 64 (10), 51 (13); Anal. Calcd. for
C15H16N4O: C, 67.15; H, 6.01; N, 20.88. Found: C, 67.20; H, 6.06; N, 20.94%.
48
2-Amino-2-[2-(4-chlorophenyl)hydrazono]-N-phenylethanamide 3d
Pale orange solid, mp. 183-5 oC, from ethanol, yield, 77%; IR: ν cm
-1 3357.6, 3299.6
(NH’s), 3054.6 (CH Ar’s), 1670.0 (C=O); 1H NMR (CDCl3): δ ppm 4.93 (s, 2H, NH2),
6.18 (s, 1H, NNH), 7.01-7.74 (m, 9H, Ar’s), 8.62 (s, 1H, NHCO); MS m/z: 288 (M+, 15),
290 (5), 289 (14), 251 (15), 235 (16), 218 (14), 203 (17), 188 (17), 162 (16), 145 (22), 114
(16), 107 (16), 80 (92), 64 (100); Anal. Calcd. for C14H13ClN4O: C, 58.24; H, 4.54; N,
19.40. Found: C, 58.29; H, 4.68; N, 19.48%.
2-[2-(4-Chlorophenyl)hydrazono]- 2-methylamino-N-phenylethanamide 3e, mp. 108-
10 oC [Lit. mp. 106-8
oC] (95).
2-Oxo-N’-phenylpropanehydrazonamide 4a
Green crystals, mp. 174-176 oC [Lit. mp. 181-2] (97), from ethanol, yield 84%; IR: ν cm
-1
3438.4, 3341.0, 3256.2 (NH’s), 3025.7 (CH aromatic), 1649.8 (C=O); 1H NMR (CDCl3):
δ ppm 2.34 (s, 3H, CH3), 4.92 (s, 2H, NH2), 6.13 (s, 1H, NNH), 7.20-7.53 (m, 5H, CH
Ar’s); MS m/z: 177 (M+, 100), 160 (9), 134 (11), 118 (73), 108 (16), 91 (77), 92 (81), 77
(27), 65 (75), 51 (18); Anal. Calcd. for C9H11N3O: C, 61.00; H, 6.26; N, 23.71. Found: C,
60.97; H, 6.24; N, 23.68%.
49
N’-(4-Bromophenyl)-2-oxopropanehydrazonamide 4b
Pale orange crystals, mp. 120-122 oC, from ethanol-water, yield 79%; IR: ν cm
-1 3425.9,
3321.7, 3237.9 (NH’s), 1683.5 (C=O); 1H NMR (CDCl3): δ ppm 2.35 (s, 3H, CH3), 4.85 (s,
2H, NH2), 6.18 (s, 1H, NNH), 7.11-7.49 (dd, 4H, Ar’s); 1H NMR (CDCl3): δ ppm 193.24
(C=O), 143.60 (C=N), 142.58, 132.71, 119.81, 114.92, 23.71 (CH3); MS m/z: 257 (M++2,
19), 255 (M+, 20), 197 (30), 195 (25), 171 (100), 155 (40), 157 (38), 143 (38), 117 (20), 91
(60), 76 (68), 63 (78); Anal. Calcd. for C9H10BrN3O: C, 42.21; H, 3.94, N, 16.41. Found:
C, 42.16; H, 4.00; N, 16.44%.
Ethyl 2-amino-2-[2-(4-chlorophenyl)hydrazono]ethanoate 5a
Pale orange crystals, mp. 131-4 oC [Lit. mp. as chloride 133-7
oC] (97), from methanol,
yield 78%; IR: ν cm-1
3395.4, 3306.3, 3246.5 (NH’s), 3070.0 (CH Ar’s), 2984.4, 2912.9
(CH sat.), 1726.9 (C=O); 1H NMR (DMSO-d6): δ ppm 1.27 (t, 3H, J = 7.2 Hz, OCH2CH3),
4.26 (q, 2H, J = 7.2 Hz, OCH2CH3), 6.98-7.39 (m, 6H, Ar’s, NH2), 10.62 (s, 1H, NNH);
13C NMR (DMSO-d6): δ ppm 159.51 (C=O), 140.23 (C=N), 129.51 (2CH), 123.09 (C),
116.77 (C), 115.66 (2CH), 62.91 (OCH2CH3), 14.24 (OCH2CH3); MS m/z: 243 (M++2,
22), 241 (M+, 64), 206 (11), 179 (22), 152 (32), 125 (100), 113 (14), 111 (42), 99 (39), 90
(28), 75 (28), 63 (20); Anal. Calcd. for C10H12ClN3O2: C, 49.70; H, 5.00; N, 17.39. Found:
C, 50.00; H, 4.97; N, 17.43%.
50
Ethyl 2-[2-(4-chlorophenyl)hydrazono]-2-methylaminoethanoate 5b, this compound
was used without separation.
Synthesis of ethyl 2-[2-(4-chlorophenyl)hydrazono-2-(4-chlorophenyl)amino]-
ethanoate 5c
The N-(4-chlorophenyl)-C-ethoxycarbonylmethanohydrazonoyl chloride 21c (0.02 mol,
5.22 gm) in ethanol (50 ml) was treated with 4-chloroaniline (0.02 mol, 2.55 gm) and
triethyl amine (0.02 mol, 2.8 ml). The reaction mixture was refluxed for 30 min. After
cooling the mixture was poured into 100 ml water and the solid precipitated was filtered,
washed with water. On crystallization from ethanol, the amidrazone 5c was obtained in
83% yield.
Yellow crystals, mp. 100-103 oC; IR: ν cm
-1 3320.8 (br. NH’s), 3069.1 (CH Ar’s), 2992.5,
2951.9 (CH sat.), 1702.8 (CO); 1H NMR (CDCl3): δ ppm 1.41 (t, 3H, J = 7.2 Hz,
OCH2CH3), 4.42 (q, 2H, J = 7.2 Hz, OCH2CH3), 6.22 (s, 1H, NH), 6.77-7.21 (two dd, 8H,
Ar’s), 8.74 (s, 1H, NNH); 13
C NMR (CDCl3): δ ppm 159.57 (C=O), 156.34 (C=N), 145.15,
144.69, 126.91, 126.82, 129.28, 129.13, 115.25, 115.13 (C, CH), 63.68 (OCH2CH3), 13.98
(OCH2CH3); MS m/z: 344 (M+2+, 18), 352 (M
+, 30), 307 (32), 290 (29), 277 (40), 234
(35), 218 (30), 191 (32), 155 (33), 117 (35), 111 (24), 98 (57), 80 (100), 73 (26), 64 (71),
55 (42); Anal. Calcd. for C16H15Cl2N3O2: C, 54.56; H, 4.29; N, 11.93. Found: C, 54.60; H,
4.28; N, 11.90%.
51
4.5.2 Synthesis of spiro/4,5-dihyro-1,2,4-triazole derivatives 6-8 and
1,2,4-triazole derivatives 22
Method A. To the solution of the amidrazone 3-5 (0.01 mol) in 50 ml dioxane, the required
ketone or benzaldehyde with a catalytic amount of p-toluenesulfonic acid (0.1 gm) were
added. The reaction mixture was refluxed to the completion of the reaction (monitoring the
reaction progress by TLC). The excess of the solvent was evaporated and the residue was
solidified by trituration with methanol of ethanol. The formed solid was filtered and
crystallized from the given solvent.
Method B. A solution of the appropriate hydrazonoyl halides 19-21 (0.01 mol) in 50 ml
dioxane was added dropwise to 3.6 ml of 7N methanolic solution of ammonia (0.025 mol)
or 12.5 ml of 2M methanolic solution of methylamine (0.025 mol). The mixture was stirred
at 40-45 oC overnight then, filtered to remove the formed salt. To the resulting solution, the
required ketone or benzaldehyde (0.02 mol) and a catalytic amount of p-toluenesulfonic
acid (0.1 gm) were added and refluxed until the reaction was complete (monitoring the
reaction progress by TLC). The excess solvent was evaporated and the residue was
triturated with methanol or ethanol, the solid so formed was filtered and crystallized from
the given solvent.
N,1-Diphenyl-1,2,4-triazaspiro[4.6]undec-2-ene-3-carboxamide 6a
Pale orange crystals, mp. 158-161 oC (from ethanol), yield 70%; IR: ν cm
-1 3371.9, 3296.7
(2NH), 3058.5, 3028.6 (CH Ar’s), 2921.7, 2863.9 (CH sat.), 1672.9 (C=O); 1H NMR
(CDCl3): δ ppm 1.39-2.19 (m, 12H, cycloheptane), 5.48 (s, 1H, NH triazole), 7.08-7.65 (m,
10 H, Ar’s), 8.52 (s, 1H, CONH); 13
C NMR (CDCl3): δ ppm 157.39 (C=O), 144.42 (C=N),
52
143.82, 137.24, 129.14, 128.86, 124.58, 123.51, 121.02, 119.76, (C, CH), 89.08 (spiro C),
39.35, 28.06, 22.23 (cycloheptane C’s); MS m/z: 348 (M+, 29), 305 (22), 291 (80), 198
(24), 160 (21), 118 (32), 91 (46), 77 (100), 51 (24); Anal. Calcd. For C21H24N4O: C, 72.39;
H, 6.94; N, 16.08. Found: C, 72.41; H, 7.00; N, 16.00%
N-Phenyl-1-(4-methylphenyl)-1,2,4-triazaspiro[4.5]dec-2-ene-3-carboxamide 6b
Pale green crystals, mp. 180-182 oC (from methanol), yield 75%; IR: ν cm
-1 3383.5, 3242.7
(NH), 3059.5, 3028.6 (CH Ar’s), 2917.7, 2857.0 (CH sat.), 1683.5 (C=O); 1H NMR
(CDCl3): δ ppm 1.34-2.01 (m, 10H, cyclohexane), 2.35 (s, 3H, CH3), 5.51 (s, 1H, NH
triazole), 7.07-7.66 (m, 9H, Ar’s), 8.52 (s, 1H, CONH); 13
C NMR (CDCl3): δ ppm 157.73
(C=O), 144.29 (C=N), 140.61, 138.53, 131.62, 130.06, 129.09, 124.53, 120.86, 117.87 (C,
CH), 89.71 (spiro C), 35.79, 24.81, 23.20 (cyclohexane C’s), 20.14 (CH3 ring); MS m/z:
348 (M+, 21), 333 (15), 305 (13), 298 (25), 199 (71), 171 (29), 139 (54), 119 (96), 91 (79),
77 (100), 65 (88), 51 (75); Anal. Calcd. For C21H24N4O: C, 72.39; H, 6.94; N, 16.08.
Found: C, 72.42; H, 6.98; N, 16.00%
N-Phenyl-1-(4-methylphenyl)-1,2,4-triazaspiro[4.6]undec-2-ene-3-carboxamide 6c
53
Pale greenish yellow, mp. 174-176 oC (from dioxane-methanol), yield 70%; IR: ν cm
-1
3383.5, 3242.7 (2NH), 3058.5, 3028.6 (CH Ar’s), 2985.2, 2917.7, 2857.0 (CH sat.), 1684.1
(C=O); 1H NMR (CDCl3): δ ppm 1.31-2.21 (m, 12H, cycloheptane), 2.33 (s, 3H, CH3),
5.51 (s, 1H, NH triazole), 7.11-7.65 (m, 9H, Ar’s), 8.53 (s, 1H, CONH); 13
C NMR
(CDCl3): δ ppm 157.68 (C=O), 144.31 (C=N), 141.06, 138.60, 131.09, 130.68, 129.12,
124.61, 120.78, 118.01 (C, CH), 90.06 (spiro C), 38.91, 28.22, 22.51 (Cycloheptane C’s),
20.38 (CH3 ring); MS m/z: 362 (M+, 14), 305 (33), 250 (8), 222 (11), 132 (32), 119 (78),
105 (43), 91 (100), 77 (61), 51 (39); Anal. Calcd. For C22H26N4O: C, 72.90; H, 7.23; N,
15.46. Found: C, 72.87; H, 7.20; N, 15.50%
5,5-Dimethyl-N-phenyl-1-(4-methylphenyl)-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide 6d
Yellow crystals, mp. 180-3 oC (from ethanol) yield 70%; IR: ν cm
-1 3383.5, 3242.7 (2NH),
3034.4 (CH Ar’s), 2917.7 (CH sat.), 1683.5 (C=O); 1H NMR (DMSO-d6): δ ppm 1.53 (s,
6H, 2CH3), 2.33 (s, 3H, CH3 ring), 7.11-7.72 (m, 10H, Ar’s, NH triazole), 10.19 (s, 1H,
CONH); 13
C NMR (DMSO-d6): δ ppm 156.79 (C=O), 144.69 (C=N), 141.10, 138.52,
131.08, 130.66, 129.20, 124.53, 121.71, 118.07 (C, CH), 87.32 (5C), 27.38 (CH3), 20.38
(CH3 ring); MS m/z: 308 (M+, 15), 265 (13), 251 (100), 207 (29), 132 (23), 119 (25), 105
(100), 91 (38), 77 (42), 64 (22), 51 (24); Anal. Calcd. For C18H20N4O: C, 70.11; H, 6.54;
N, 18.17. Found: C, 70.13; H, 6.51; N, 18.21%
54
5-Ethyl-5-methyl-N-phenyl-1-(4-methylphenyl)-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide 6e
Pale yellow flakes, mp. 183-5 oC (from ethanol), yield 70%; IR: ν cm
-1 3384.1, 3244.7
(NH), 3030.5 (CH Ar’s), 2924.5 (CH sat.), 1683.6 (C=O); 1H NMR (DMSO-d6): δ ppm
0.95 (br., 3H, CH2CH3), 1.51 (s, 3H, CH3), 1.84 (m, 2H, CH2CH3), 2.34 (s, 3H, CH3 ring),
7.14-7.62 (m, 10H, Ar’s, NH triazole), 10.12 (s, 1H, CONH); 13
C NMR (DMSO-d6): δ
ppm 156.93 (C=O), 144.41 (C=N), 140.92, 138.47, 131.63, 130.10, 129.12, 124.60,
120.81, 117.65 (C, CH), 89.71 (5C), 28.19 (CH2CH3), 21.92 (CH3), 20.28 (CH3 ring), 8.09
(CH2CH3); MS m/z: 322 (M+, 22), 307 (17), 279 (100), 236 (67), 132 (43), 118 (27), 105
(100), 91 (34), 77 (39), 64 (23), 51 (18); Anal. Calcd. For C19H22N4O: C, 70.78; H, 6.88;
N, 17.38. Found: C, 70.83; H, 6.91; N, 17.40%
N-Phenyl-1-(2-methylphenyl)-1,2,4-triazaspiro[4.4]non-2-ene-3-carboxamide 6f
Pale yellow solid, mp. 216-8 oC (from methanol), yield 71%; IR: ν cm
-1 3359.4, 3239.8
(NH’s), 3065.3 (CH Ar’s), 2961.1, 2924.5, 2857.9 (CH sat.), 1664.3 (C=O); 1H NMR
(CDCl3): δ ppm 0.92-2.11 (m, 8H, cyclopentane), 2.29 (s, 3H, CH3), 6.03 (s, 1H, NH
triazole), 6.88-7.66 (m, 9H, Ar’s), 9.19 (s, 1H, NHCO); MS m/z:334 (M+, 38), 306 (17),
55
242 (31), 200 (23), 183 (15), 172 (15), 154 (17), 148 (78), 132 (34), 119 (69), 106 (42), 93
(72), 77 (100), 65 (79), 55 (54); Anal. Calcd. for C20H22N4O: C, 71.83; H, 6.63; N, 16.75.
Found: C, 71.77; H, 6.60; N, 16.71%.
N-Phenyl-1-(2-methylphenyl)-1,2,4-triazaspiro[4.5]dec-2-ene-3-carboxamide 6g
Pale yellow solid, mp. 138-41 oC (from ethanol), yield 75%; IR: ν cm
-1 3376.6, 3229.9
(2NH), 3065.0 (CH Ar’s), 2931.9 (CH sat.), 1664.6 (C=O); 1H NMR (DMSO-d6): δ ppm
0.96-1.95 (m, 10H, cyclohexane), 2.38 (s, 3H, CH3 ring), 7.15-7.78 (m, 10H, Ar’s, NH
triazole), 10.04 (s, 1H, NHCO); 13
C NMR (DMSO-d6): δ ppm 157.51 (C=O), 146.45
(C=N), 142.35, 138.82, 136.19, 131.26, 129.99, 129.06, 126.79, 126.15, 124.12, 120.55 (C,
CH), 88.58 (spiro), 36.25, 25.18, 22.44 (cyclohexane C’s), 19.27 (CH3 ring); MS m/z: 348
(M+, 48), 322 (66), 305 (47), 294 (36), 275 (24), 256 (29), 212 (21), 186 (37), 152 (27),
132 (71), 119 (52), 107 (45), 91 (100), 77 (76), 65 (55); Anal. Calcd. For C21H24N4O: C,
72.39; H, 6.94; N, 16.08. Found: C, 72.41; H, 6.98; N, 16.03%
5,5-Dimethyl-N-phenyl-1-(2-methylphenyl)-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide 6h
56
Pale yellow solid, mp. 180-3 oC (from ethanol), yield 72%; IR: ν cm
-1 3337.9, 3282.6
(2NH), 3066.2, 3023.8 (CH Ar’s), 2943.6, 2855.7 (CH sat.), 1661.8 (C=O); 1H NMR
(DMSO-d6): δ ppm 1.56 (s, 6H, 2CH3), 2.34 (s, 3H, CH3 ring), 7.03-7.82 (m, 10H, Ar’s,
NH triazole), 10.09 (s, 1H, NHCO); 13
C NMR (DMSO-d6): δ ppm 157.32 (C=O), 144.72
(C=N), 143.69, 138.84, 137.62, 131.07, 128.81, 128.17, 126.41, 122.84, 121.50, 118.26 (C,
CH), 88.92 (5C), 25.84 (CH3), 20.09 (CH3 ring); MS m/z: 308 (M+, 14), 293 (13), 265 (34),
251 (10), 235 (13), 218 (15), 194 (12), 164 (15), 147 (18), 119 (28), 106 (81), 91 (73), 80
(96), 77 (100), 69 (99), 55 (59); Anal. Calcd. For C19H22N4O: C, 70.11; H, 6.54; N, 18.17.
Found: C, 70.15; H, 6.57; N, 18.21%
1-(4-Chlorophenyl)-N-phenyl-1,2,4-triazaspiro[4.5]dec-2-ene-3-carboxamide 6i
Pale yellow solid, mp. 230-2 oC (from dioxane-methanol), yield 70%; IR: ν cm
-1 3399.6,
3267.6 (2NH), 3060.7 (CH Ar’s), 2936.7 (CH sat.), 1668.5 (C=O); 1H NMR (DMSO-d6): δ
ppm 1.16-2.13 (m, 10H, cyclohexane), 7.12-7.66 (m, 10H, Ar’s, NH triazole), 8.63 (s, 1H,
CONH); 13
C NMR (DMSO-d6): δ ppm 158.91 (C=O), 144.13 (C=N), 142.36, 139.37,
130.01, 129.72, 124.53, 123.68, 120.93, 117.18 (C, CH), 89.63 (spiro C), 35.34, 24.68,
22.52 (cyclohexane C’s); MS m/z: 370 (M++2, 25), 368 (M
+, 63), 332 (72), 325 (73), 298
(72), 275 (98), 250 (95), 198 (70), 158 (100), 137 (22), 115 (59), 95 (56), 76 (19), 60 (44),
52 (43); Anal. Calcd. For C20H21ClN4O: C, 65.12; H, 5.74; N, 15.19. Found: C, 65.14; H,
5.77; N, 15.22%
57
1-(4-Chlorophenyl)-4-methyl-N-phenyl-1,2,4-triazaspiro[4.5]dec-2-ene-3-carboxamide
6j
Yellow crystals, mp. 202-4 oC (from ethanol-DMF), yield 74%; IR: ν cm
-1 3289.6 (NH),
3065.9 (CH Ar’s), 2955.3, 2877.9 (CH sat.), 1689.7 (C=O); 1H NMR (DMSO-d6): δ ppm
1.15-2.02 (m, 10H, cyclohexane), 2.97 (s, 3H, NCH3), 6.77-7.54 (m, 9H, Ar’s), 10.39 (s,
1H, NHCO); 13
C NMR (DMSO-d6): δ ppm 159.62 (C=O), 144.55 (C=N), 138.45, 130.05,
129.10, 127.92, 124.63, 123.71, 120.96, 115.27 (C, CH), 85.88 (spiro C), 35.31, 24.53,
22.78 (cyclohexane C’s), 29.83 (NCH3); MS m/z: 384 (M++2, 21), 382 (M
+, 51), 341 (36),
339 (100), 214 (19), 174 (15), 152 (13), 130 (23), 111 (27), 91 (28), 77 (49), 55 (38); Anal.
Calcd. For C21H23ClN4O: C, 65.87; H, 6.05; N, 14.63. Found: C, 65.88; H, 6.10; N,
14.66%
1-(4-Chlorophenyl)-5-ethyl-4,5-dimethyl-N-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide 6k
58
Cannarian yellow, mp. 153-6 oC (from ethanol-THF), yield 74%; IR: ν cm
-1 3271.6 (NH),
3087.4 (CH Ar’s), 2971.7, 2930.3 (CH sat.), 1663.3 (C=O); 1H NMR (CDCl3): δ ppm 0.96
(br, 3H, CH2CH3), 1.46 (s, 3H, CH3), 1.92 (m, 2H, CH2CH3), 3.20 (s, 3H, NCH3), 7.12-
7.63 (m, 9H, Ar’s), 8.61 (s, 1H, NHCO); 1
H NMR (DMSO-d6): δ ppm 0.80 (m, 3H,
CH2CH3), 1.45 (s, 3H, CH3), 1.89-1.95 (m, 1H, CH2CH3), 2.12-2.19 (m, 1H, CH2CH3)
3.01 (s, 3H, NCH3), 7.09-7.78 (m, 9H, Ar’s), 10.20 (s, 1H, NHCO); 13
C NMR (DMSO-d6):
δ ppm 157.40 (CO), 144.31 (C=N), 142.31, 138.57, 129.09, 129.01, 124.45, 123.55,
120.85, 117.29 (C, CH), 89.68 (5C), 28.34 (NCH3), 28.20 (CH2CH3), 21.19 (CH3), 8.06
(CH2CH3); MS m/z: 358 (M++2, 5), 356 (M
+, 15), 327 (20), 301 (20), 247 (21), 226 (19),
205 (23), 186 (21), 152 (39), 131 (23), 119 (100), 111 (39), 92 (43), 77 (30), 64 (21), 56
(62); Anal. Calcd. For C19H21ClN4O: C, 63.95; H, 5.93; N, 15.70. Found: C, 63.97; H,
5.91; N, 15.64%
1-(4-Chlorophenyl)-4-methyl-N,5-diphenyl-4,5-dihydro-1H-1,2,4-triazole-3-
carboxamide 6l
Yellow crystals, mp. 123-5 oC (from ethanol), yield 70%; IR: ν cm
-1 3374.8 (NH), 3035.4
(CH Ar’s), 2957.3, 2913.9 (CH sat.), 1676.8 (C=O); 1H NMR (CDCl3): δ ppm 3.08 (s, 3H,
NCH3), 5.89 (s, 1H, 5H triazole), 6.85-7.66 (m, 14H, Ar’s), 8.64 (s, 1H, NHCO); 1
H NMR
(DMSO-d6): δ ppm 2.89 (s, 3H, NCH3), 6.11 (s, 1H, 5H triazole), 6.95-7.80 (m, 14H,
Ar’s), 10.38 (s, 1H, NHCO); 13
C NMR (DMSO-d6): δ ppm 159.72 (CO), 144.56 (C=N),
143.20, 138.45, 130.04, 129.54, 129.16, 128.87, 127.93, 126.97, 124.65, 123.60, 120.98,
115.21 (C, CH), 85.95 (spiro C), 32.03 (NCH3); MS m/z: 392 (M++2, 4), 390 (M
+, 11), 376
(6), 364 (6), 351 (6), 270 (4), 256 (4), 135 (7), 111 (6), 105 (9), 80 (100), 64 (67); Anal.
59
Calcd. For C22H19ClN4O: C, 67.60; H, 4.90; N, 14.33. Found: C, 67.58; H, 4.88; N,
14.35%
1-(1-Phenyl-1,2,4-triazaspiro[4.5]dec-2-en-3-yl)ethanone 7a
Pale yellow crystals, mp.120-122 o
C (from methanol), yield, 70%; IR: ν cm-1
3351.7 (NH),
3063.4, (CH Ar’s), 2931.3 (CH sat.), 1673.9 (C=O), 1592.9 (C=N); 1H NMR (CDCl3): δ
ppm 1.14-1.97 (m, 10H, cyclohexane), 2.49 (s, 3H, CH3), 5.19 (s, 1H, NH), 7.07-7.35 (m,
5H, ArH’s); 13
C NMR (CDCl3): δ ppm 190.92 (C=O), 147.58 (C=N), 142.32, 129.08,
121.79, 118.61 (C, CH), 88.63 (spiro C), 35.53, 24.76, 23.09 (cyclohexane C’s), 24.90
(COCH3); MS m/z: 257 (M+, 16), 228 (9), 214 (100), 202 (18), 134 (52), 118 (15), 91 (37),
77 (49), 65 (86), 55 (70); Anal. Calcd. For C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found:
C, 70.05; H, 7.39; N, 16.37%
1-(1-Phenyl-1,2,4-triazaspiro[4.6]undec-2-en-3-yl)ethanone 7b
Pale yellow crystals, mp. 123-125 oC, [lit. mp. 120-122] (72) (from methanol), yield, 71%;
IR: ν cm-1
3345.8 (NH), 3058.5, 3028.6 (CH Ar’s), 2954.4 (CH sat.), 1681.6 (C=O),
1602.6 (C=N); 1H NMR (DMSO-d6): δ ppm 1.24-2.03 (m, 12H, cycloheptane), 2.58 (s,
3H, CH3), 5.15 (s, 1H, NH), 7.07-7.40 (m, 5H, ArH’s); 13
C NMR (DMSO-d6): δ ppm
60
189.63 (C=O), 147.34 (C=N), 90.76 (spiro C), 142.49, 129.01, 122.50, 118.71 (C, CH),
39.42, 28.10, 22.17 (cycloheptane C’s), 24.81 (COCH3); MS m/z: 214 (M+-57, 2.6), 178
(68), 141 (32), 119 (26), 108 (68) 93 (100), 77 (90), 51 (100); Anal. Calcd. For C16H21N3O;
C, 70 82; H, 7.80; N, 15.49. Found: C, 70.78; H, 7.78; N, 15.61%
1-(1-(4-Bromophenyl)-1,2,4-triazaspiro[4.5]dec-2-en-3-yl)ethanone 7c
Pale orange crystals, mp.160-162 oC [lit. mp. 160-162] (72) (from ethanol), yield, 73%; IR:
ν cm-1
3371.9 (NH), 3036.6 (CH Ar’s), 2944.4, 2847.8 (CH sat.), 1671.9 (C=O), 1586.2
(C=N); 1H NMR (DMSO-d6): δ ppm 1.12-1.99 (m, 10H, cyclohexane), 2.37 (s, 3H, CH3),
7.17-7.42 (m, 5H, Ar’s, NH); 13
C NMR (DMSO-d6): δ ppm 189.73 (C=O), 147.95 (C=N),
141.93, 131.81, 121.53, 115.55 (C, CH), 88.42 (spiro C), 35.54, 24.68, 23.06 (cyclohexane
C’s), 24.90 (CH3); MS m/z: 337 (M++2, 34), 335 (M
+, 34), 308 (15), 306 (16), 294 (100),
292 (98), 280 (25), 278 (26), 250 (12), 213 (13), 171 (18), 157 (24), 125 (15), 90 (23), 76
(12), 63 (10); Anal. Calcd. For C15H18BrN3O: C, 53.60; H, 5.40; N, 12.50. Found: C,
53.59; H, 5.38; N, 12.51%
Ethyl 1-phenyl-1,2,4-triazaspiro[4.5]dec-2-ene-3-carboxylate 8a
61
Yellow crystals, mp. 152-154 oC (from dioxane), yield 75%, IR: ν cm
-1 3370.0 (NH),
3067.2 (CH Ar’s), 2980.4, 2934.1, 2864.7 (CH sat.), 1703.8 (C=O); 1H NMR (CDCl3): δ
ppm 1.07-2.00 (m, 10H, cyclohexane), 1.39 (t, 3H, J = 7.2 Hz, CH3CH2O-), 4.37 (q, 2H, J
= 7.2 Hz, CH3CH2O-), 5.16 (s, 1H, NH), 7.02-7.30 (m, 5H, Ar’s); 1
H NMR (DMSO-d6): δ
ppm 1.10-1.88 (m, 10H, cyclohexane), 1.30 (t, 3H, J = 7.0 Hz, OCH2CH3), 4.27 (q, 2H, J
= 7.2 Hz, OCH2CH3), 6.92-7.61 (m, 6H, Ar’s, NH triazole); 13
C NMR (DMSO-d6): δ ppm
159.39 (C=O), 143.81 (C=N), 142.04 (C), 129.17 (2CH), 121.94 (CH), 119.02 (2CH),
87.46 (spiro C), 61.56 (OCH2CH3), 35.57, 24.94, 22.22 (cyclohexane), 14.56 (OCH2CH3);
MS m/z: 258 (M+-29, 5), 244 (53), 231 (9), 214 (11), 198 (36), 185 (14), 129 (12), 97 (27),
69 (100), 55 (88); Anal. Calcd. For C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C,
66.90; H, 7.38; N, 14.64%
Ethyl 1-(4-chlorophenyl)-1,2,4-triazaspiro[4.5]dec-2-ene-3-carboxylate 8b
Pale yellow solid, mp. 150-2 oC (from ethanol), yield 72%; IR: ν cm
-1 3365.7 (NH), 3083.8
(CH Ar’s), 2983.3, 2875.5 (CH sat.), 1709.6 (C=O); 1H NMR (CDCl3): δ ppm 1.12-1.98
(m, 10H, cyclohexane), 1.41 (t, 3H, J = 7.2 Hz, OCH2CH3), 4.41 (q, 2H, J = 7.2Hz,
OCH2CH3), 5.16 (s, 1H, NH), 7.13-7.34 (dd, 4H, J = 3Hz, Ar’s); 13
C NMR (CDCl3): δ
ppm 159.44 (C=O), 143.81 (C=N), 142.61, 129.11, 121.02, 117.29 (C, CH), 89.68 (spiro
C), 62.26 (OCH2CH3), 35.54, 24.93, 22.51 (Cyclohexane C’s), 14.53 (OCH2CH3); MS
m/z: 323 (M+2, 8), 321 (M
+, 21), 278 (19), 251 (33), 224 (25), 207 (32), 179 (50), 151 (63),
125 (100), 107 (53), 90 (44), 73 (35), 51 (14); Anal. Calcd. For C16H20ClN3O2: C, 59.72;
H, 6.26; N, 13.06. Found: C, 59.70; H, 6.30; N, 13.10%
62
Ethyl 1-(4-chlorophenyl)-5-ethyl-5-methyl-4,5-dihydro-1H-1,2,4-triazole-3-
carboxylate 8c
Pale yellow solid, mp. 153-6 oC (from methanol), yield 70%; IR: ν cm
-1 3356.4 (NH),
3065.7 (CH Ar’s), 2982.4 (CH sat.), 1709.6 (C=O); 1H NMR (CDCl3): δ ppm 0.96 (s, 3H,
CH3), 1.41 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.50 (m, 3H, CH3CH2-), 1.98 (m, 2H, CH3CH2-
), 4.39 (q, 2H, J = 7.2 Hz, OCH2CH3), 5.17 (s, 1H, NH), 7.16-7.43 (dd, 4H, J = 3Hz,
ArH’s); 13
C NMR (CDCl3): δ ppm 159.42 (C=O), 143.83 (C=N), 142.56, 129.03, 120.92,
117.32 (C, CH), 89.67 (C5), 62.31 (OCH2CH3), 28.22 (CH2CH3), 21.21 (CH3), 14.53
(OCH2CH3), 8.10 (CH2CH3); MS m/z: 297 (M++2, 14), 295 (M
+, 41), 280 (32), 251 (35),
206 (58), 179 (50), 152 (69), 125 (100), 111 (50), 90 (50), 73 (59), 64 (35), 51 (13); Anal.
Calcd. For C14H18ClN3O2: C, 56.85; H, 6.13; N, 14.21. Found: C, 56.88; H, 6.11; N,
14.18%
Ethyl 1-(4-chlorophenyl)-4-methyl-5-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-
carboxylate 8d
63
Yellow solid, mp. 108-10 oC (from ethanol), yield 73%; IR: ν cm
-1 3062.4 (CH Ar’s),
2982.3, 2932.2 (CH sat.), 1717.3 (C=O); 1H NMR (CDCl3): δ ppm 1.43 (t, 3H, J = 7.2 Hz,
OCH2CH3), 2.95 (s, 3H, NCH3), 4.39 (q, 2H, J = 7.2 Hz, OCH2CH3), 5.85 (s, 1H, 5H
triazole), 6.85-7.45 (m, 9H, Ar’s); 1
H NMR (DMSO-d6): δ ppm 1.30 (t, 3H, J = 7.0 Hz,
OCH2CH3), 2.84 (s, 3H, NCH3), 4.30 (q, 2H, J = 7.2 Hz, OCH2CH3), 6.11 (s, 1H, 5H
triazole), 6.82-7.53 (m, 9H, Ar’s);
13C NMR (DMSO-d6): δ ppm 158.88 (CO), 142.50
(C=N), 138.51, 131.43, 130.41, 129.93, 128.42, 127.96, 123.95, 115.14 (C, CH), 85.90
(5C), 61.97 (OCH2CH3), 32.61 (NCH3), 14.44 (OCH2CH3); MS m/z: 345 (M++2, 8), 343
(M+, 21), 307 (5), 298 (5), 268 (32), 266 (89), 252 (44), 238 (31), 214 (33), 190 (11), 171
(10), 138 (27), 125 (29), 111 (59), 105 (60), 90 (28), 77 (100), 57 (87); Anal. Calcd. For
C18H18ClN3O2: C, 62.88; H, 5.28; N, 12.22. Found: C, 62.91; H, 5.24; N, 12.26%
Ethyl 1,4-di(4-chlorophenyl)-5-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxylate 8e
Yellow crystals, mp. 113-5 oC (from ethanol), yield 72%; IR: ν cm
-1 3041.2 (CH Ar’s),
2979.4, 2926.4, 2841.6 (CH sat.), 1729.8 (C=O); 1H NMR (CDCl3): δ ppm 1.27 (t, 3H, J =
7.2 Hz, OCH2CH3), 4.28 (q, 2H, J = 7.2Hz, OCH2CH3), 6.27 (s, 1H, 5H triazole), 6.80-
7.40 (m, 13H, Ar’s); 1H NMR (DMSO-d6): δ ppm 1.18 (t, 3H, J = 7.0 Hz, OCH2CH3),
4.23 (q, 2H, J = 7.2 Hz, OCH2CH3), 6.87-7.49 (m, 14H, Ar’s, 5H triazole); 13
C NMR
(DMSO-d6): δ ppm 158.16 (C=O), 141.49, 141.45, 139.59, 139.37, 138.64, 130.45, 130.42,
129.51, 129.28, 128.03, 126.78, 124.45, 115.49 (C=N, C, CH), 85.67 (5C), 62.14
(OCH2CH3), 14.24 (OCH2CH3); MS m/z: 441 (M++1, 20), 439 (M
+-1, 14), 425 (18), 370
(14), 328 (18), 291 (20), 215 (16), 199 (20), 178 (21), 139 (15), 106 (18), 80 (100), 73
64
(13), 64 (83), 51 (27); Anal. Calcd. For C23H19Cl2N3O2: C, 62.74; H, 4.35; N, 9.54. Found:
C, 62.66; H, 4.33; N, 9.49%
N,5-Diphenyl-1-(4-methylphenyl)-1H-1,2,4-triazole-3-carboxamide 22a
Off white crystals, mp. 259-61 oC (from ethanol-DMF), yield 67%; IR: ν cm
-1 3253.3,
(NH), 3071.0, 3071.3 (CH Ar’s), 2970.8 (CH sat.), 1675.8 (C=O); 1H NMR (CDCl3): δ
ppm 2.43 (s, 3H, CH3), 7.17-7.79 (m, 14H, Ar’s), 9.06 (s, 1H, NHCO); 1H NMR (DMSO-
d6): δ ppm 2.39 (s, 3H, CH3), 7.14-7.86 (m, 14H, Ar’s), 10.52 (s, 1H, NHCO); 13
C NMR
(DMSO-d6): δ ppm 157.80 (C=O), 156.78 (C=N), 155.15 (C=N), 139.99, 138.75, 135.48,
130.95, 130.48, 129.34, 129.12, 127.48, 126.25, 124.59, 121.10 (C, CH), 21.22 (CH3); MS
m/z: 354 (M+, 40), 317 (45), 285 (50), 262 (40), 248 (47), 194 (48), 134 (47), 97 (51), 80
(78), 64 (100), 55 (96); Anal. Calcd. For C22H18N4O: C, 74.56; H, 5.12; N, 15.81. Found:
C, 74.54; H, 5.16; N, 15.84%
1-(4-Chlorophenyl)-N,5-diphenyl-1H-1,2,4-triazole-3-carboxamide 22b
65
Off white solid, mp. 262-4 oC (from ethanol-DMF), yield 69%; IR: ν cm
-1 3261.0 (NH),
3078.8 (CH Ar’s), 2893.3 (CH sat.), 1674.8 (C=O); 1H NMR (DMSO-d6): δ ppm 7.14-7.87
(m, 14H, Ar’s), 10.51 (s, 1H, NHCO); 13
C NMR (DMSO-d6): δ ppm 157.89 (C=O),
153.41, 152.63 (2 C=N), 142.31, 139.98, 138.71, 135.45, 131.02, 130.51, 129.22, 129.13.
127.47, 126.31, 123.47, 117.42 (C, CH); MS m/z: 376 (M++2, 24), 374 (M
+, 68), 282 (26),
214 (100), 151 (30), 125 (35), 111 (48), 99 (23), 77 (45), 64 (25), 51 (14); Anal. Calcd. For
C21H15ClN4O: C, 67.29; H, 4.03; N, 14.95. Found: C, 67.33; H, 4.00; N, 15.00%
1-(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)ethanone 22c
White solid, mp. 114-116 oC (from methanol), yield 72%; IR: ν cm
-1 3056.6 (CH Ar’s),
1696.1 (C=O); 1H NMR (CDCl3): δ ppm 2.75 (s, 3H, CH3), 7.27-7.56 (m, 10H, Ar’s); MS
m/z: 263 (M+, 71), 248 (12), 160 (11), 118 (100), 104 (5), 91 (56), 77 (24), 64 9(), 51 (11);
Anal. Calcd. For C16H13N3O: C, 72.99; H, 4.98; N, 15.96. Found: C, 73.10; H, 4.94; N,
16.00%
APPENDIX
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
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91
92
93
94
95
REFERENCES
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ENGLISH SUMMARY
101
SUMMARY
Nucleophilic substitution reaction of hydrazonoyl chlorides 19-21 with ammonia, methyl
amine and 4-chloroaniline gave the corresponding amidrazones 3a-d, 4a,b and 5a,b,
respectively (Scheme 1). Treatment of amidrazones 3-5 with cyclic and acyclic ketones and
benzaldehyde in dioxane in the presence of 4-toluenesulfonic acid as a catalyst at boiling
temperature gave 4,5-dihydro-1,2,4-triazoles 6a-l, 7a-c and 8a-d, respectively (Scheme 2).
Also, amidrazones 3b,d and 4a were reacted with benzaldehyde under the same reaction
conditions and gave 1,2,4-triazoles 22a-c, respectively (Scheme 3). The structures of the
synthesized compounds have been confirmed by the elemental analyses and spectroscopic data
(IR, MS, 1H NMR and
13C NMR).
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الملخص
-4مع الأمونيا و الميثيل أمين و 21-19 الهيدرازونيل كلوريداتل النيوكليوفيليالإحلال لتفاعمعالجة هذه . )1مخطط ( 5a,bو 4a,b و 3a-d أعطى الأميدرازونات المقابلة كلوروأنيلين
راتولوين با حمض جودفي و و البنزالدهيد والغير حلقيةالكيتونات الحلقية مع 3-5 الأميدرازوناتو 6a-l ،7a-cالمقابلة ترايازولات-1،2،4-دايهيدرو-5، 4 شتقاتسلفونيك كعامل مساعد أعطت م
8a-e 3أيضاً، تم مفاعلة الأميدرازونات .)2مخطط ( على التواليb,d 4وa مع البنزالديهايد تحتتراكيب وقد أثبتت ).3مخطط ( 22a-cترايازولات المقابلة -1،2،4نفس ظروف التفاعل لتعطي
وطيف الكتلةالأشعة تحت الحمراء وبيانات طيفبواسطة التحاليل العنصرية المختلفة المخلقة المركبات .13والكربون هيدروجينالنووي المغناطيسي لأنوية ال وأطياف الرنين
1مخطط
105
2خطط م
106
3مخطط
داءـــــــــإه
لكم فيها مع الأيام عهداً يصاحبكم إلى يوم ،زمزم يسقي كل وادي ءلكم منا وفاءً من قلوبنا كما
آه الناس يزهو لمدوا نحوه كل الأيادي ولكني أخص بها أناساً هم الأقمار بين ر وفاءً لو ،عاديالم
.العباد
إلى روح الدكتور الفاضل على اللوح رحمه االله
.إلى روح والدتي الطاهرة ،البيضاء التي أحاطتني بالرعاية وتعهدتني بالحب والحنانإلى اليد
.إلى والدي العزيز ،إلى من أحمل اسمه بكل فخر
.ج االله كربهإلى أخي الغالي أنور فرَّ ،انقضبإلى من أفنوا زهرة شبابهم خلف ال
.إلى رياحين حياتي، ومن أمدوني بشعاع الأمل إلى إخوتي وأخواتي
.إلى شريك حياتي
.إلى أهلي وأقاربي وأساتذتي
.إلى من بهم تحلو الحياة وتزداد جمالاً إلى زميلاتي وزملائي ولكل من أحب
.أهديهم جميعاً هذا الجهد تقديراً وعرفاناً
غ���������������زة -ع���������������ة الأزه���������������ر مجا عمادة الدراسات العليا والبح�ث العلم�ي كلي�����������������������������������ة العل�����������������������������������وم برن�����������امج ماجس�����������تير الكيمي�����������اء
تحضير بعض المركبات غير متجانسة الحلقة المحتوية على
أو الكبريت/ النيتروجين و
إعداد الباحثة
تهاني موسى أبو معيلق
إشراف
نبيل خليل شراب .د
أستاذ مساعد في الكيمياء العضوية
غزة –جامعة الأزهر
ندى محمد هاشم أبو ندى/ الأستاذ الدكتور
أستاذ الكيمياء العضوية
كلية العلوم التطبيقية –قسم الكيمياء
غزة -جامعة الأقصى
عمر عبد الحي عبد الله مقداد/الدكتور
أستاذ الكيمياء العضوية المساعد
كلية العلوم التطبيقية –قسم الكيمياء
غزة -جامعة الأقصى
ت الحصول على درجة الماجستير في الكيمياءقدمت هذه الرسالة استكمالاً لمتطلبا
من كلية العلوم جامعة الأزهر ـ غزة
فلسطين –غزة
2014