chapter 3 dimedone as a versatile precursor for annulated...
TRANSCRIPT
Chapter 3 Quinoline-3-carboxylates/carboxamides…
152
Chapter 3 Dimedone as a versatile precursor for annulated heterocycles: Diversity oriented one-pot multicomponent synthesis and biological evaluation of some novel quinoline-3-carboxylates and 3-carboxamides 3.1 Introduction Dimedone (1) is an alicyclic compound having 1,3-dicarbonyl groups flanked by a
methylene group and exists in a tautomeric trans-enolized form where intramolecular
hydrogen bonding is not possible [1]. The inherent structural features in (1) have
created various reactive centers: C-1, C-2, and to a less extent C-6 in addition to C-3
in or 3-O (Figure 3.1). Such phenomenon attracted much attention for using it as a
synthetic reagent for the characterizations of aldehydes, since its discovery, by the
formation of readily crystalizable derivatives; determination of formaldehyde in
textiles has been done by a colorometric method [2]. Moreover, dimedone is an
excellent precursor for partially hydrogenated fused heterocycles [3], where two of
the carbon-atoms of dimedone are part of the back bone of the formed heterocycles.
Its structural features and its reactivity to form more functionalized derivatives have
led to the construction of a wide range of fused or spiral biheterocycles.
O O
O OH
(1) DimedoneFigure 3.1
Chapter 3 Quinoline-3-carboxylates/carboxamides…
153
3.2 Dimedone annulated three and four membered heterocycles
O
Me
Me
H
N
O
Me
Me
N HR R
+
O
Me
Me
H
O
Me
Me
NR
NMeMe
O
H
(4)
O
Me
Me
R
O
RR=Act-BuOK or
MeONa
R=CHOt-BuOK orMeONa
(5)(6) R=NHAc(7) R=NHCHO
t-BuOKTriton B+
(3) (11) (8) R=NHAc (9) R=NHCHO(10) R=NC
MeMe
O
N
RMe
Me
O
NH
R
hv
hv
MeCN
+
MeMe
OH
N(2) R=H, Me, Ac, CHO CO2CH2CCl3
MeMe
O
N
H
O
Me
Me
cyclohexanet-butanolhv
hv
(12) (13)
(14) (15)
O +H
N
CH3
O
MeMe
N
Ac
(16)Figure 3.2 Dimedone annulated three and four membered heterocycles
Only few examples were reported related to these ring systems. Moreover,
only those fused with three membered ring mainly containing one heteroatom oxygen
were reported. No examples can be found with a four membered ring containing two
heteroatoms. The epoxide ring in such fused ring systems has been formed by the
epoxidation with t-butylhydroperoxide/Triton-B of the respective double bond in (6)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
154
and (7), which were prepared from (2) via the formation of a fused pyrrole ring, as it
will be shown latter, to give (8) and (9), respectively [4]. Treatment of (9) with
MsCl/Py gave isocyanide (10) [4] (Figure 3.2). Compounds (3) and (13) represented
fused four membered heterocycles, that have been formed by the photochemical
irradiation of (2) (R=H) to give (12), via a photo-aza-Claisen rearrangement, in
addition to the four membered ring (13) in a very poor yield. The formation of which
has been explained to take place from (2) via a [2+2] photo adduct followed by a
retro-Mannich fragmentation [5].
3.3 Dimedone annulated five membered heterocycles with one hetero-
atom 3.3.1 Annulation with pyrrole (synthesis of indoles and carbazoles)
There are two main approaches for constructing indole rings from (1). Starting either
with enamines and introducing the two carbons on C-2 and then amination at C-3
followed by cyclization. Photolysis of enamine (2) gave, depending on the substituent
R, a variety of products containing the tetrahydropyrrole ring fused with acyclobutane
and a cyclohexane ring. Thus, irradiation of (2) (R=Me) gave (4) (R =Me) and the
‘‘crossed’’ [2+2] cycloadduct (14) [5]. In contrast, irradiation of the N-acetyl (2)
(R=Ac) resulted in an acyl migration to form (15) as a minor product and azabicyclo
[2.1.1] hexane (16) as a major one [6]. Reinvestigation of the irradiation of (2)
(R=Ac) led to the isolation of (5) in addition to less amounts of (4) and (3), whose
structures were proven by X-ray analysis; (15) was not detected [6]. Similarly,
photolysis of (2) (R=CHO) gave (3-5) whereas 2 (R=CO2CH2CCl3) gave (5) as a
major product. Ring expansion of (5) (R=CHO) and (5) (R=Ac) with or t-BuOK
MeONa gave (11) and (6), respectively [4].
Photo irradiation of 3-allylamino and 3-allyloxy-5,5-dimethylcyclohex-2-en-1-
one (17) and (18) in cyclohexane generated 2-aza and 2-oxabicyclo [2.1.1] hexanes
(19) and (20), respectively [7,8]. Epimerization of (19) (R=Me) with t-BuOK gave
(21). Ring enlargement of (19) in boiling water afforded (22), existed in equilibrium
with its open form, whose reduction with sodium borohydride gave (23) [8, 9]. Photo
irradiation of the ethereal solution of (17) (X=NCOMe) afforded two epimers 19a and
(19b). Similar irradiation of (17) (X=NPh) afforded in addition to the major product
(19) (X=NPh), carbazole (24) as a minor product [8] (Figure 3.3).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
155
O
MeMe X
MeMe
OH
X
hv
cyclohexane MeMe
OH
N
R
t-BuOK
t-BuOH
O
MeMe Me
O
N
hv
cyclohexane
(17) X=NR(18) X=O
(19) X=NR, Ph(20) X=O
(21) R=Me
H
N
COMe
hvEt2O
H2O, boil
CH3
HOMeMe
O
Me O
NH
R
(19a) (22)
O
MeMe
H
N
COMe
19(b)
+
Me
O
N
MeMe
Me
O
N
MeMe
NaBH4
OH-
(23)
O
MeMe X
MeMe
OH
X
hv
(17) (19) X=NPh(major)
Et2ON
O
Me
Me
(24) minor
Figure 3.3 Synthesis of indoles and carbazoles
The indole (25) was obtained by reaction of (1) with amino acetaldehyde in
the presence of p-toluene sulfonic acid to give the enamine intermediate (25), which
subsequently cyclized with hydrochloric acid. An increase in acid concentration led to
the formation of dimers, while less concentrated acid gave no products [10] (Figure
3.4). The condensation of (1) with 2-azido-1,1-diethoxyethane yielded intermediate
(1a), which on subsequent cyclization gave indolone (26) [11] (Figure 3.4).
Functionalization of dimedone at C-2 provided derivatives suitable for
constructing the pyrrole ring. Thus, tetrahydroindole (28) was obtained from 2-
allyldimedone (27) by reaction with benzylamine followed by iodination in the
Chapter 3 Quinoline-3-carboxylates/carboxamides…
156
presence of triethylamine and subsequent deiodination with DBU in toluene [12]
(Figure 3.5).
O
OHMeMe
O
OHMeMe
O
NH
MeMe
O
MeMe
CHO
NH2
PTSA
N3OEt
OEt
Ph3P, THF, heat
EtO OEt
(1) (25)
(1a) (26)
DMSO/heat
or TFA/CH2Cl2
HCl
Figure 3.4 Synthesis of indolone
NH
O
OMe
Me
O
Me
Me
O
Me
Me
BnNH2
C6H6/D
I2/Et3N
NH
Bn
N
BnI
O
Me
MeN
Bn
MeDBU/PhMe
(27)
(28)
Figure 3.5 Synthesis of tetrahydroindole
3.3.2 Annulation with furan (synthesis of benzofurans)
The synthesis of this ring has been mainly based on C-alkylation at C-2 with a
suitable functional group to add the two carbons of the furan ring. Reaction of the
Chapter 3 Quinoline-3-carboxylates/carboxamides…
157
disodium salt of bis(dimedonyl)methane (29) with iodine was reported to give
cyclopropane (32) [13,14]. Later, the structure of (32) was revised to isomeric
dihydrofuran (30) based on its spectral properties. Consequently, cleavage of the
product with alkali was also revised to yield the benzofuran (31) instead of the
formerly reported (33). The formation of (30) rather than (32) may be due to the
greater stability of (1) in the enol rather than in the keto form [15] [Figure 3.6]. The
attempted bromination of (1) with Dess–Martin periodinance (DMP) in the presence
of triethyl ammonium bromide, methanol, and chloroform gave (30). Its formation
was due to the presence of a dimedone-formaldehyde adduct in situ; formaldehyde
resulted from the oxidation of methanol during the reaction [16].
Me
Me
O
ONa
O
O
NaMe
Me
O
O O
O
Me
MeMe
MeO
O
Me
MeO
COOH
I2 NaOH
OO
Me
Me Me
Me O
O
Me
Me
O
HOOC
I2
(29) (30) (31)
(32) (33)
I2
O O
Figure 3.6 Synthesisofbenzofuran
Reaction of (1) with an equimolar amount of 3,4,5,6,7-penta-O-acetyl-1,2-
dideoxy-1-nitrohept-1-enitol in boiling methanol containing acatalytic amount of
triethylamine gave 3,5,6,7-tetrahydro-2-hydroxyimino-3-(penta-acetoxy-alditol-1-yl)
benzofuran-2H-one (34a) as the main product [17]. The furanone oxime (34b) (R=2-
methylindol-3-yl) was obtained by the formation of a Michael adduct from 1 and 2-
methyl-3-(2-nitrovinyl)indole in the presence of sodium methoxide followed by
heterocyclization [18]. The X-ray analysis of (34c) showed a planar five membered
hetero ring with the pyridine ring almost perpendicular to it while the cyclohexane
ring has a sofa conformation [19] (Figure 3.7). A domino process took place upon
reaction of 1 and a nitro-olefin followed by acetylation to give (35) [20] (Figure 3.7).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
158
O
OHMe
MeO
NOH
RHO
Me
Me
RCH=CHNO2
MeOH/Et3N
NO2
CH3
1. Et3N/THF2. Ac2O/Et3N/ DMAP/THF
OMe
Me
OAc
CH3
NH
R=
NH
CH3 , N
(1) (34)
(35)Figure 3.7 Synthesis of benzofuran
OAc
AcO
R1
OAc
R2
OAc
,
a b c
3.4 Dimedone annulated five membered heterocycles with two hetero-
atom
There are various classes of compounds, which can be presented under this heading.
These include the partially hydrogenated benzo five membered heterocycles with
nitrogen, oxygen or sulfur.
O
Me
MeS
Na
O
Me
MeS
RCH=CHCH2Br
DMSOR
O
Me
MeSH
RPTSA
O
Me
MeSAc
O
MeS
R
CH3
Ac2OQuinoline Δ
Quinoline
160°C
(36) (37)
(39) (38)Figure 3.8 Synthesis of partially hydrogenated benzo five membered heterocycles
Chapter 3 Quinoline-3-carboxylates/carboxamides…
159
O
OMe
Me
O
OMe
MeO
Me
Me
O
Me
Me
O
Me
Me
O
Me
Me
1. K2CO3/DMF
2. CS2/DMF
S
S
1. BrCH2CO2Et/ DMF
2. MeI/ DMFS
S Me
CO2Et
S
hv
S
S
SO2Me
NHO
OBn
(1) (40) (41)
(43) (44) (42)
Figure 3.9 Synthesis of partially hydrogenated benzo five membered heterocycles
3.4.1 Annulation with pyrazole (synthesis of indazoles)
Two main approaches were known for the synthesis of this ring from 1; both started
with 2-acyldimedones either through their enehydrazine or eneamine derivatives [21].
2-Acetyldimedone (45) (R=Me) gave, upon reaction with hydrazine, indazolone (47)
(R=Me, R1=H) [22-25]. Indazole (47) (R=H) was obtained from 2-acyldimedone (45)
with primary amines followed by TFA and then hydrazine hydrate [26, 27].
2-Formyldimedone (45) (R=H) with arylhydrazines gave hydrazino
intermediates (46) (R=H, R1=aryl), which were cyclized to indazolone (48) (R=H) on
heating with PPA [28] (Figure 3.10). Similarly, either 2-hydrazinopyridine or 2-
hydrazinobenzimidazole with 2-acetyl dimedone (45) (R=Me) afforded
tetrahydroindazoles (49) and (50), respectively [29, 30]. 2-Hydrazinobenzimidazole
and (45) at room temperature in ethanol gave (46) where as in refluxing 2-propanol in
the presence of HCl (50) was obtained rather than (51) [30] (Figure 3.10). Reaction of
(1) with dimethyl formamide dimethyl acetal (DMFDMA) gave the enaminone (52)
(R=H) [31] whose reaction with hydrazine afforded the tetrahydroindazole (51) [32]
(Figure 3.10).
Phenylhydrazine and benzaldehyde with 1 gave tetrahydro and hexahydro-
indazoles (53) (Ar=Ph) and (54), respectively [33] (Figure 3.10). Dimedone-
phenylhydrazone (55) with aromatic and heterocyclic aldehydes gave 2,3-diaryl-4-
oxo-4,5,6,7-tetrahydroindazoles (56) (R=Ph) whereas dimedone tosylhydrazone gave
3-aryl-4-oxo-4,5,6,7-tetrahydroindazoles 56 (R=H) [34 ,35]. Treatment of diketoester
Chapter 3 Quinoline-3-carboxylates/carboxamides…
160
(57) with hydrazine hydrate gave pyrazolo[4,5-f]indazole (58) [36]. Examples of (49)
were tested as inhibitors against PC-3 cell proliferation and HSP-90 [37].
Me
Me
O
O
CR
OH
Me
Me
O
O
NH
N
H
R1R1NHNH2 Me
Me
O
N
NHN
N
O
R
O
OMe
Me
O
Me
MeN
N
R
R1
1. R1NH2
2. TFA3. NH2NH2
O
OMe
Me
O
Me
Me
R
RCOOHDCCDMAP
NH2NH2t-BuOH/AcOH/heat
NMe
MeO
DMF/DMA
(46) (51)
(47) R1= H, R=Me(48) R1= Ar(49) R1=
(50) R1=
N
HN
N(45)
(1) (52) R=H
O
OMe
Me
O
Me
Me
O
NMe
Me
PhNHNH2
PhNHNH2PhCHO
ArCHO
NN
NPh
ArAr
Ph+
(55) R=Ph, Ts(53) (54)
ArCHO
O
NMe
Me
N
Ar
R
(56) R= H, Ph
O
OMe
O
Me
Me
O OMe
OH
NH2NH2
MeOH/Δ
NHHN
NHNH
Me
Me
O
O
(57) (58)
Figure 3.10 Synthesis of indazoles
Chapter 3 Quinoline-3-carboxylates/carboxamides…
161
Sequential acylation of (1) by the carboxylic acid functionality of protected
aspartic or glutamic acids gave (59), which upon regioselective cycloaddition with
dinucleophile hydrazine gave indazole (60) (R=H) whose deprotection afforded
pseudo aromatic α-aminoacids (61) (R=H) as homochiral amino acids with a
tetrahydro-indazole as a side chain [38]. Fmoc (62) and thiourea (63) as well as the 1-
benzyl derivatives (60a-62a) (R=Bn) were synthesized [38] (Figure 3.11).
OHO
BocHNCO2But
n
OH
BocHNCO2But
n
1. EDC
DMAP,CH2Cl2 O
O
Me Me
n= 1 or 2
(59)
BocHNCO2But
n
O
Me Me
N
N R
BocHNCO2But
O
Me Me
N
N R
TEA or
3M HCl/Dioxan
(60) R=H(60a) R-Bn
(61) R=H(61a) R=Bn
CO2But
O
Me Me
N
N R
HOOCNHFmoc
O
Me Me
N
N R
O
OO
OAc
AcAc
NCSOAc MeCN
H2O
FmocOSuNaHCO3/Dioxan
O
OO
OAc
AcAc
OAc
HN
S
n
n
n
(63)(62) R=H(62a) R=Bn
Figure 3.11 Synthesis of indazoles
3.4.2 Annulation with oxazole (synthesis of benzoxazoles)
BocHNCO2But
nO
Me Me
OH
O
OHMe
Me
+ PhCNO Cu(acac)2
Rh2(OAc)4N2
O
OMe
Me
N
Ph
BocHNCO2But
nO
Me Me
N
O
FmocHNCO2But
nO
Me Me
N
OO NH2OH
1. TEA or HCl/ Dioxan
2. FmocOSu NaHCO3/ Dioxan
(59) (65) (66)
(1) (64)
Figure 3.12 Synthesis of benzoxazoles
Chapter 3 Quinoline-3-carboxylates/carboxamides…
162
1,3-Dipolar cycloaddition of benzonitrile oxide with (1) led to the formation of
tetrahydrobenzoisoxazole (64) [40]. Acyldimedone (59) with hydroxylamine afforded
benzoisoxazole (65). Subsequent protecting group manipulation afforded the N-Fmoc
(66) [38] (Figure 3.12).
3.4.3 Annulation with thiazole (synthesis of benzothiazoles)
Addition of thiourea to (1) gave the isothiourea (67) [41]. In the presence of iodine, or
NBS and traces of benzoyl peroxide, the thiazole (68) was obtained [42, 43]. Also
(68) was obtained from the reaction of thiourea with 2-halodimedone (69). 2-
Aminobenzothiazole (68) and phenacyl bromide or chloroacetic acid afforded
imidazo[2,1-b]benzothiazoles (70) and (71), respectively [43]. Tetrahydrobenzothiazo
les (72) were obtained from 2-bromodimedone (69) (R1=Br) and aroyl
thiosemicarbazides in THF at room temperature [44]. Dehydrative cyclization of 2-
aroylhydrazinobenzothiazole (72) was achieved by heating in PPA at 160 ºC to give
3-aryl-6,6-dimethyl-8-oxo-5,6,7,8-tetrahydro-1,2,4-4H-triazolo[3,4-b]benzothiazole
(73) [44 ] (Figure 3.13).
O
Me
MeS NH2
NH
O
R1
OHMe
Me
H2NCSNH2 H2NCSNH2/I2
or NBS/ (PhCO)2O2 C6H6, D
N
S
MeMe
O
NH2
(67) (1) R1= H(69) R1= Br
(68)
N
S
MeMe
O
NHNHCOArN
S
MeMe
O
N
S
MeMe
O
N
S
MeMe
O
NHCOArNHCSNH2THF
ClCH2CO2HMeOH
PhCOCH2BrEtOH
PPAN
N
O PhN
N
Ar(73) (72) (71) (70)Figure 3.13 Synthesis of benzothiazoles
Chapter 3 Quinoline-3-carboxylates/carboxamides…
163
3.5 Dimedone annulated five membered heterocycles with three hetero-
atom 3.5.1 Annulation with triazole (synthesis of benzotriazoles)
N
HN
N
NH
NMe
Me
Ar
Ar
HNAr
N
O
O
Me
Me
NH
Ar N
HN
N
NH
NMe
Me
Ar
Ph
HNPh
ArNHNH22 PhNHNH2
AcOH
(74) (76)(75)
N
HN
N
OH
NMe
Me
Ar
Ph
(77)
PhNHNH2AcOHLTA
CuCl2EtOH
NN
N
Me
Me
AcO NN
Ar
Ar NN
N
Me
Me
Ph
X
(78) (82) (X= O, NOH)
Me
Me
O
N
HN
PhMe
Me
O
NHN Ph
Me
MeR
NNN
Ar
+
(79) R=O(80) R=NNHAr + ArN=NAr (81)
O
OMe
Me
PhNHNH2
(1) (83)
NaNO2
H+
NOH
(84)
Ac2O
CuCl2EtOH
Figure 3.14 Synthesis of benzotriazoles
Aryldiazonium chlorides and (1) gave 5,5-dimethylcyclohexan-1,2,3-trione-2-
arylhydrazones (74) [45,46] which upon reaction with excess arylhydrazines in
ethanol gave 5,5-dimethylcyclo- qhexane-1,2,3-trione-1,2,3-tris(arylhydrazones) (75).
Reaction of (74) with two equivalents of phenylhydrazine gave the mixed tris-
hydrazones (76), and with one equivalent of phenylhydrazine gave mixed bis-
hydrazone (77) [47, 48]. Oxidation of (75) gave benzo[d]-1,2,3-triazoles 78-80 in
addition to (81) [45]. Both (76) and (77) with an ethanolic solution of cupric chloride
afforded the same (82) (X=O) [47]. This proved that the substituted aniline and not
aniline itself was lost in each case. Phenylhydrazine and (1) gave (83), which with
sodiumnitrite afforded hydrazone oxime (84). Its treatment with acetic anhydride gave
(82) (X=O). The latter with hydroxylamine gave the corresponding oxime (82)
(X=NOH) [49] (Figure 3.14).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
164
3.6 Dimedone annulated six membered heterocycles with one hetero-
atom 3.6.1 Annulation with pyridine (synthesis of quinolines)
Dimedone has been extensively used in the synthesis of partially hydrogenated
quinoline rings. Thus, 1,4,5,6,7,8-hexahydroquinolines (85) were prepared by
Hantzsch-like synthesis starting from (1), aromatic or aliphatic aldehydes and β-
aminocrotonates or β-aminocrotonamide [50-53]. Hexahydroquinolines (85) were also
obtained by ultrasound or microwave(MW) irradiation of a mixture of (1), aromatic
aldehydes and β-aminocrotonates or ethyl acetoacetate in the presence of ammonium
acetate (54-57) or in water in the presence of triethylbenzylammonium (TEBA)
chloride [58, 59]. Quinolines (85) (R=Ar) also can be obtained from the
bis(dimedonyl)methane derivative with β-aminocrotonates or from arylalkylidene
acetoacetate in the presence of aqueous ammonia or ammonium acetate [52].
Condensation of (1) with either the bis-acetonitrile or the enamines of acetylacetone
or benzoylacetone imine in ethanol and paraformaldehyde, acetaldehyde, or
benzaldehyde afforded the respective 3,4-disubstituted hexahydroquinoline
derivatives 85. Benzaldehyde gave good results, but condensation did not take place
with acetaldehyde and benzoylacetone or acetylacetone imines. When
paraformaldehyde was used, bis(dimedonyl)methane was isolated as a byproduct [60].
The Hantzch cyclocondensation of the four components (1), aldehydes,
ketoesters, and ammonium acetate has attracted much attention for the synthesis of
polyhydroquinolines (86). Various catalysts have been used, such as molecular iodine
[61], CAN [62], HY-zeolite [62, 63], bakersyeast [64], Montmorillonite K10 clay in
methanol [65], L-proline in water, or solvent free condition [66], HClO4–ScO2 under
solvent free condition [67], triethybenzylammonium chloride in water [68], scandium
triflate [69], Yb(OTf)3 [70], and ionic liquids under solvent free conditions such as
hexamethylimidazolium tetrafluoroborate {[hmim]BF4}, decylmethylimidazolium
tetrafluoroborate {[dmim]BF4}, hexamethylimidazolium hexafluorophosphate
{[hmim]PF6}, as well as hexamethylimidazolium bromide {[hmim]Br}, where the
former was the optimum one. Aliphatic aldehydes [71, 72] may be used also. X-ray
study of the 4-(3-chlorophenyl) derivative showed that the N containing ring adopted
a boat conformation and the cyclohexane has a half chair conformation [73]. The
corresponding 4-(2-chloro-5-nitrophenyl) derivative has the chloro substituent in a
Chapter 3 Quinoline-3-carboxylates/carboxamides…
165
syn periplanar orientation with respect to the pyridine ring plane with the nitro group
over it [74]. The use of terephthaldehyde or isophthaldehyde as an aldehyde allowed
the presence of two polyhydroquinolines on the benzene ring; the synthesis was
achieved under MW irradiation [75].
Four-component cyclocondensation of (1), aromatic aldehydes, malononitrile,
and ammonium acetate proceeded under MW irradiation in solvent free conditions to
give highly functionalized hexahydroquinolines in excellent yield. The crystal
structure of 2-amino-3-cyano-4-phenyl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydro
quinoline was determined [76]. Oxidation of 245 with chromic acid gave tetrahydro
derivatives (88) [60], that can be also obtained from reaction of (1) with 3-amino 2-
methylacrylaldehyde [77], or 4-(3-indolyl)pyrimidine (87) [78]. Various derivatives
of (86) and (88) were reported for treatment of cardiovascular and cellular
proliferative diseases [79-82] (Figure 3.15).
O
OMe
Me1
R1
H
R2
H2N
RCHOAcONH4
AcONH4[hmim]BF4 orMW/5 Min orHy-Zeolite/MeCN
CO2R1
O Me
ArCHO
NNMe
N
Me
OHCNH2
(87)or
NH
R
R1
R2
O
Me
Me
(85)
NH
Ar
Me
O
Me
Me N
R
R1
R2
O
Me
Me
R1
O
(86) R=OMe, OEt, HNR' (88) R=R1=H
/MeCN
R2=
HN
Figure 3.15 Synthesis of quinolines
3.6.1.1 Synthesis of quinoline-fused with heterocycles
3.6.1.1.1 Synthesis of furo-quinolines
Intramolecular cyclization of the hexahydroquinolines (86) (Ar=2-trifluoromethyl,
nitro, or methoxyphenyl) with N-bromosuccinimide and pyridinium bromide gave
Chapter 3 Quinoline-3-carboxylates/carboxamides…
166
furo quinolines (89) (R1=H) [51] (Figure 3.16). Three-components reaction of an
aldehyde, enamine (93) and tetronic acid (90) in glacial acetic acid under MW
irradiation without a catalyst gave the furoquinolines (89) [83], via the formation of
the arylidene derivative (91) (Figure 3.16).
NH
Me
Me
O
R
OAr
Me NMe
Me
O Ar
O
O
R
NBS
Pyridinium bromide
(86) R= OMe, OEt (89)
Me
Me
O Ar
O
O
ON
RH
(92)
O
O
O
O
O
OArCHO
Ar
+ Me
Me
O
NH
R(90) (91) (93)
Figure 3.16 Synthesis of furo-quinolines
3.6.1.1.2 Synthesis of pyrrolo-quinolines
OH
MeMe
O
PhO
COMe
Me
OHMe
Me
O
O
O
MeMe
OCOPh
O OHC(COMe)2
Ph
OCHCO2H
Ph
O
KOH/EtOH NaOH/EtOH
(1)(94) (96)
Me
Me
O
Me
MeN
NH
Me
Ph
N
HNO
Ph
AcONH4AcOH
NH3/EtOH150-160°C
Me
MeN
HNO
Ph
(97)(95)Figure 3.17 Synthesis of pyrrolo-quinolines
autoclave
Chapter 3 Quinoline-3-carboxylates/carboxamides…
167
Condensation of (1) with 1,1-diacetyl-2-benzoylethylene in ethanol gave the adduct
(94), which upon treatment with ammonium acetate in acetic acid gave pyrrolo[3,4-
c]quinoline (95) [84].
Michael condensation of (1) and trans-β-benzoylacrylic acid afforded butanoic
acid derivative (96) that can be cyclized, with ammonia in an auto clave at 150–160
ºC, to give 7,7-dimethyl-4-phenyl-1,2,6,7,8,8a-hexahydro-pyrrolo[4,3,2-d,e]quinolin-
2-one (97) [85]. (Figure 3.17).
3.6.1.1.3 Synthesis of pyrazolo-quinolines
NH
NNMe
Me
O R1
R
O
OMe
Me
N
NN N
NH2R
CHO
R1
N
R1
RAr
(98) (98a)
O
OMe
Me
Ar
NH
NNR
R1
EtOH/D
(99)
O
OHMe
Me
Ar
NH
NNR
R1
H
N
N
NH2R
R1
(319b)
R2CHOEtOH
(1) (100)
NH
NNMe
Me
O R1
R(102)
R2
NMe
Me
O
NHMe
Me
OPh
N
MeNH
N
R1
R
ArHN
NN
Me
Me
O
O
Ph
CMe3
(104) (103) (101)
OMe
Me
O
NH
NS
Me
OMe
Me
O
O
NHN
NH2NH2NH2
(105) (106)
Figure 3.18 Synthesis of pyrazolo-quinolines
Chapter 3 Quinoline-3-carboxylates/carboxamides…
168
Friedlander condensation of 5-aminopyrazole-4-carboxaldehydes (98) with dimedone
furnished pyrazolo[3,4-b]quinolines (99). Subsequent Vilsmeier Hack formylation
and sequential cyclocondensation with phenylhydrazine gave bis-pyrazolo[3,4-b:4,
3-f]quinolines [86].
Dimedone with arylidene aminopyrazoles (319a) in ethanol gave the
intermediate adduct (100) that spontaneously cyclized to hexahydropyrazolo[3,4-
c]isoquinolines (101). The cyclization of the adduct (100) took place at C-4 only even
for the N-1-unsubstituted arylidene derivatives (98a) [87].
A one-pot cyclocondensation of 5-amino-3-substituted pyrazole derivatives
(98b) with (1) and substituted benzaldehydes in ethanol afforded the tricyclic linear
tetrahydropyrazolo[3,4-b]quinoline derivative (102) rather than the angular isomer
(101) (R1=Me). The same products were obtained under MW irradiation as energy
transfer agent [88-93].
Cyclocondensation of 3-amino-5-methylpyrazole with 2-arylmethylidene-5,5-
dimethylcyclohexane-1,3-diones or 9-aryl-3,3,6,6-tetramethyl-2,3,4,5,6,7,8,9-octahy
dro-1H-xanthene-1,8-diones, in DMF or methanol gave 4-aryl-3,7,7-trimethyl-1,4,
6,7,8,9-hexahydropyrazolo[3,4-b]quinolin-5-ones (102) whose structure was proved
by the X-ray diffraction data [94].
The reaction proceeded through a first Knoevenagel condensation between (1)
and the aldehydes followed by a Michael addition of the aminopyrazole to these
adducts and further cyclization to give the pyrazolo[3,4-b]quinolines. This passway
was preferred rather than starting by the reaction of (1) with the aminopyrazole to
give the eneaminone because the latter failed to react with aldehydes. NOESY
experiments and X-ray analysis were used to conclude the structure of the product
[95]. The nonaromatic carbocyclic ring in 3-(4-methoxyphenyl)-7,7-dimethyl-1,6,7,8-
tetrahydropyrazolo[3,4-b]quinolin-5-one, adopts an envelope conformation. The
molecules are linked by a combination of hydrogen bonds into a chain of
centrosymmetric ring [96]. In both (101) and (102), the two heterocycles were planar
where as the carbocyclic ring adopted envelope conformation. The pyrazoloquinoline
derivatives (103) (R=Ph, R1=t-butyl, R2=H) was similarly prepared but under MW
and its X-ray crystallography confirmed the structure. When formaldehyde units have
incorporated in the reaction, the spiro compound (103) was obtained [97], whereas,
Chapter 3 Quinoline-3-carboxylates/carboxamides…
169
using orthobenzoic acid trimethyl ester as carbon inserting agent instead of formalin,
(104) was obtained whose structure was confirmed by X-ray [98].
The other angular pyrazoloquinoline derivative (106) was obtained by
hydrazinolysis of 2-imino-7,7-dimethy-4-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-2H
-benzopyran-3-carbonitrile (105). The reaction can be preceded by substitution of the
methylsulfanyl group by hydrazine followed by cyclization to give (106) [99] (Figure
3.18).
3.6.1.1.4 Synthesis of quinolino-isoquinolines
Annulation of 3,4-dihydroisoquinolines with either the enamine diketone (108) or the
β-triketones (109) afforded the isoquinolino[1,2-a]quinoline (8-aza-D-homogonanes)
(110) and (111), respectively [100-101] (Figure 3.19).
NR1
R1
R2
Me
Me
O
O
R4
NR3 H
(107)
OO
R4
H
OMe
Me
HCl/PrOH
NR1
R1
R4
X O
Me
Me
R2
(108) (109) X= NR3, R4=H(110) X=O, R4=Me CO2Me, CH2CO2Me
Figure 3.19 Synthesis of quinolino-isoquinolines
3.6.2 Annulation with pyran (Synthesis of benzopyrans)
Reaction of (1) with diketene (111) in the presence of sodium hydroxide in
tetrahydrofuran gave 2-acetoacetyl dimedone (112). Cyclization of which to the
benzopyran-4,5-dione (113) was performed with acid [102].
Acylation of 1 with acid anhydrides (115) in the presence of sodium hydroxide
gave the expected 2-acylderivatives (116) as major products and the pyran derivatives
(114) as the minor ones. The formation of the pyrans (114) have been explained to
proceed by O-acylation of the initially formed (116) followed by an intramolecular
base catalyzed aldol condensation and loss of H2O [103] (Figure 3.20).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
170
O
OMe
Me
O
OHMe
Me
O
OMe
Me
O
OMe
Me
OO
O
Me
O O
R1
RNaOH/THF
H2SO4
(112) (113) R1=H, R=Me(114) R= Et, Pr R1=Me, Et
OO O
R1 R1115NaOH/Δ
(116)
O
OMe
Me
O
R1
O
OMe
MeR1
O
OR1
OH-
OH
R1
-H2O
(111)
Figure 3.20 Synthesis of benzopyrans
3.7 Dimedone annulated six membered heterocycles with two hetero-
atom 3.7.1 Annulation with pyridazine (synthesis of cinnolines)
This ring system can be constructed by introducing the hydrazine moiety on C-1 or C-
2 of dimedone and then heterocyclization with functionalized carbon reagents. Thus,
reaction of 2-arylhydrazono-5,5-dimethyl-cyclohexane-1,3-dione (74), prepared from
reaction of 1 with aryldiazonium chlorides, with Wittig reagents (117) afforded the
respective tetrahydrocinnolinones (119). Alternatively, (119) were synthesized by the
coupling of (120), obtained from reaction of (1) with Wittig reagent (117), with
benzenediazonium chloride followed by boiling in ethanol and piperidine [104]; the
reaction proceeded through the intermediates (118). In contrast, reaction of (1) with
1,1-diacetyl-2-benzoylethylene in the presence of KOH afforded the adduct (121) that
upon treatment with hydrazine hydrate gave the cinnolinone (122) [84] (Figure 3.21).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
171
O
Ph
O
Me
OO
Me
OMe
Me
O
OMe
Me
O
OMe
Me
O
Me
Me
O
Me
Me
O
Ph
O
Me
OO
Me
NHMe
MeNH2
PhCOCH=C(COMe)2
KOH/EtOH
ArHN+ºNCl N
HNAr
(121) (1)
NH2NH2PhP=CHCOR
(117)PhP=CHCOR117Toluene/Δ
R
O
1. ArHN+ºNCl2.EtOH
piperidine/Δ
N NAr
H
OR
(118)(120)
NN
O
Me
Me X
Y
Ar
(119)X,Y= OX= H, Y= Ph
O Me
OO
Me
Me
MeNH
N
Ph
(122)
Figure 3.21 Synthesis of cinnolines
3.7.1 Annulation with pyrimidine (synthesis of quinazolines)
When the enaminone (123) (R= Me) was reacted with sodium hydride in THF under
reflux followed by phenyl isothiocyanate, it afforded a mixture of products among
them the enaminones (123) (R=Ph), (124), (125), and the quinazoline derivative (126)
[105]. Similarly, reaction of (123) (R=Ph) with methyl isothiocyanate under the same
reaction conditions afforded (124-126) with recovery of (123) (R=Ph) [105]. In
contrast, reaction of enaminone (123) (R=Ph) with benzoyl isothiocyanate afforded
the quinazoline (127) as a single product [106] (Figure 3.21).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
172
O
NH
R
Me
Me
O
NH
R
Me
Me
+
S
NH
MeO
NH
R
Me
Me
S
NH
Ph1. NaH/THF/D
2. PhNCS
(123) (R=Me) (124) (125)
O
NMe
Me
+
N
S
Ph
Me
H
O
Me
Me
N
SPh
Me H+
O
NMe
Me N
S
Me
Ph
HH+
NaH
O
NMe
Me N
S
Me
Ph
O
NH
R
Me
Me
O
NMe
Me N
S
Me
Me
HMeCNS
(123) R=Me R=Ph
O
Me
Me N
HNN
S
SMe
Me
MeH
MeCNS
N
N
O S
SMe
MeMe
Me
N
N
O S
Me
MePh
Ph
PhCONCS
(126)(127)Figure 3.22 Synthesis of quinazolines
3.8 Dimedone annulated six membered heterocycles with three hetero
atom 3.8.1 Annulation with thiadiazine (synthesis of benzothiadiazines)
Reaction of 3-substituted-4-amino-5-mercapto(4H)-1,2,4-triazoles (128) with (1)
resulted 6,7,8,9-tetrahydro-3-substituted-1,2,4-triazolo[4,3-b][1,3,4]benzothiadiazin-
9-ones (129) [107-109). The reaction can be achieved also under MW irradiationin
DMF [110]. The bis-triazolo-benzothiadiazine (131) flanked by dihydroxyethyl was
prepared from 1 and (130) [111]. However, reaction of 4-amino-5-(3-chlorobenzo
[b]thien-2-yl)-1,2,4-triazole-3-thiol (132) with 1 in the presence of NaOH, NaOEt,
NaOAc, or NaH in different solvents led to recovery of the starting material, but in
DMF as a high boiling solvent, the unexpected product (133) was obtained (ElAshry,
Chapter 3 Quinoline-3-carboxylates/carboxamides…
173
unpublished results). Dehydrative cyclization of 4-amino-3-mercapto-6-substituted-
1,2,4-triazin(2H)-ones (134) with (1) in DMSO gave 8,8-dimethyl-7,8,9,10-
tetrahydro-3-substituted-1,2,4-triazino[3,4-b][1,3,4]benzothiadiazin-4,10-diones (135)
[112] (Figure 3.23).
O
OMe
Me
O
Me
Me
O
Me
Me
N
N
HN
R
O
H2N
S
NN
NHS
H2NR
NH
SN
N
NH
N
S
NN
R
OR
1
(128)(134)DMSO
(135)(129)
S
Cl N
NN
NH2
SH
(132)
NaHDMF
DMFpiperidine
N
NN
R1
R
NN
N
SH
NH2
NH2
SH(130)
S
N
HN
NN
R1R
N
NN
S
HN
MeMe
Me
Me
O
O
(131)
S
Cl
N
NN
NS
N MeMe(133)
Figure 3.23 Synthesis of benzothiadiazines
3.9 Dimedone annulated seven membered heterocycles 3.9.1 Annulation with diazepine (synthesis of benzodiazepines)
Reaction of hydrazino-cyclohexenone (136) with ethyl benzoylacetate in acetic acid
afforded an equilibrium mixture of the hydrazine form (137) and the enhydrazone
form (138), which upon heating in PPA produced 3-phenyl-1,8,8-trimethyl-
4,5,6,7,8,9-hexahydro-1,2-benzodiazepine-5,6(1H)-dione (139) [113].
Chlorination of 2-benzoyldimedone (140) with oxalyl chloride afforded the 3-
chloro derivative (141), which upon treatment with ethylenediamine gave the
respective hexahydro-1,4-benzodiazepine (142) [114] (Figure 3.24).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
174
O
Me
MeO
Ms
O
Me
MeN
NH2
Me
K2CO3/CH2Cl2
MeNHNH2
PhCOCH2CO2Et
AcOH/rt
O
Me
MeN
NH
Me
Ph
CO2Et
(136) (137)
O
Me
MeN
N
Me
Ph
CO2EtO
Me
Me N N
O
Me
Ph
PPA90-100°C
(138)(139)
O
Me
MeOH
O
Ph
O
Me
MeCl
O
Ph(COCl)2c
O
Me
Me NH
N
Ph
NH2
NH2
(140) (141) (142)
Figure 3.24 Synthesis of benzodiazepines
3.10 Dimedone annulated eight membered heterocycles 3.10.1 Annulation with azocine (synthesis of benzoazocines)
N
R
O
MeMe
BrO
R1
O
R1
N
OMe
Me
O
O
R1
R1
LDEA
ether/THF
(143)
R = H, MeR1= Me
(144)
N
O
O
R1
R1
Et
+N
O
Me
Me
OO
R1R1
(147) (148)
N
O
Me
MeOH
Et
O
O
R1
R1(149)
+
O
O
R1
R1
NH
O
MeMe
(145)
NH
OMe
Me
OR1
O
R1
(146)
+
+
Figure 3.25 Synthesis of benzoazocines
Treatment of the enaminone (143) (R=H) with LDEA in ether-THF afforded the
tetrahydroquinoline (144), the benzazocine (145) (R=H) and a debrominated product
(146) (R=H) [115]. Under similar reaction conditions the N-ethyl (143) (R=Et) gave
Chapter 3 Quinoline-3-carboxylates/carboxamides…
175
the quinoline (147) and pyridocarbazole (148) in addition to the debrominated alcohol
(149) (Figure 3.25).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
176
3.11 Introduction to Quinoline Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and
is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to
light, become yellow and later brown. Quinoline is only slightly soluble in cold water
but dissolves readily in hot water and most organic solvents (Figure 3.26)[116].
N
H
H
H
H
H
H
H
N1
2
3
456
78
NH
Figure 3.26 Structure of quinoline
3.11.1 Quinoline synthesis
Quinoline was first extracted from coal tar in 1834 by Friedlieb Ferdinand Runge
[117]. Various methods for synthesis of quinoline is depicted below (Figure 3.27)
NH2
+ H
O
Glycerol
H2SO4, PhNO2 NQuinoline
(1) Skraup synthesis [118-120]
CH3
NH2
+
O
CH3 CH3
NH
O
CH3
-H2OZnCl2FeCl3, EtOHReflux, 65%
O2 NQuinoline
CH3
CH3
(2) Dobener-Miller ring synthesis [121]
CHO
NH2
+O CH3
o-Amino aryl aldehyde
KOH
aldol type condensation
NQuinoline
C6H5
CH3
(3) Friedlander Synthesis [119]
NH2
+
CH3
O
O CH3
HeatCondensation
NH
O
CH3
CH3
Con. H2SO492% N
Quinoline
CH3
CH3
(4) Combes synthesis [122]
Figure 3.27 Various methods for the synthesis of quinolines
Chapter 3 Quinoline-3-carboxylates/carboxamides…
177
3.12 Pharmacological profiles of Quinolines Quinoline and its derivatives have always attracted both synthetic and biological
chemist because of its diverse chemical and pharmacological properties. Apart from
classical method for the synthesis of quinoline ring available like Skraup, Doebner-
von Miller, Friedländer, Pfitzinger, Conrad-Limpach, Combes syntheses [123].
Various new methods have been developed which employed metallic or
organometellic reagents such as CuCN, LiCl [124]. Ruthenium (III) chloride
RuCl3.nH2O/3PPh3 [125] Ytterbium (III) triflate Yb(OTf)3 [126], Tungsten vinylidene
complex W(CO)5(THF) [127], Boron trifluoride etherate BF3.OEt2 [128,129],
Benzotriazoleiminium salts etc. [130] for the synthesis of quinoline derivatives.
Moreover, the quinoline ring system occurs in various natural products, especially in
alkaloids and is often used for the design of many synthetic compounds with diverse
pharmacological properties. There are number of natural products of quinoline
skeleton used as a medicine or employed as lead molecule for the development newer
and potent molecules (Figure 3.28).
N N
N
N
N N
OH3C
NHO
H
Cl
CH3
(CH2)3
N
O
CH3
(CH2)3
N
CF3
CH3
HONH
N
O
O
N
CH3
OH
OH O
O
OH
NCOOH
O
O
Quinine (150) Chloroquine(151) Primaquine (152) Mefloquine (153)
Simple Quinoline (154) Simple Quinoline (155) Cryptoleptine (156) Dynemicin (157)
Figure 3.28 Biological activities of quinolines and related heterocycles
For example, quinine (150) was isolated as the active ingredient from the bark
of Cinchona trees and has been used for the treatment of malaria. Its structure
determination and SAR studies resulted in discovery of newer antimalarial drugs like
chloroquine (151), primaquine (152), mefloquine (153) [131] etc. Chimanine
Chapter 3 Quinoline-3-carboxylates/carboxamides…
178
alkaloids, simple quinolines (154,155), isolated from the bark of Galipea longiflora
trees of the Rutaceae family are effective against the parasites Leishmania sp., which
are the agents of leishmaniasis [132], Cryptolepine (156) is an indoloquinoline
alkaloid found in the west African climbing shrub Cryptolepis sanguinolenta [133].
Dynemicin A (157) and Streptonigrin (158), naturally occurring members of the class
of antitumor antibiotics [134,135]. The 8-(diethylaminohexylamino)-6-methoxy-4-
methyl quinoline (159) is highly effective against the protozoan parasite Trypanosoma
cruzy, which is the agent of Chagas’ disease [136] and the 2-(2-methylquinolin-4-
ylamino)-Nphenylacetamide (160) is more active than the standard antileishmanial
drug.
3.12.1 Anticancer activity
N
O
O
O
H2NN
H2N
COOH
CH3
OH
O
O
N
CH3
O
HN(CH2)6
N
N
HN
O
Ph
CH3N
N
NN
N
NH
NH2
NH
H2N
N N
CH3
NR2
R1
CH3
R1, R2 = Ethyl, Isopropyl, pyrrolidinyl, piperidinyl
(158) (159) (160) (161)
(162) (163)
N NN
OO
R3
O
R2R1
Cl
O
R1,R2,R3= Benzoate
(164)
N
O2S NR
NN
R = 4(5)-imidazolylmethyl
(165)
N
NHNH
O
H3C
N
O
HN
O
O
ON
O
N
OH
(166)
N
OH
Cl
(167) (168)
N
O
O
O
O
Et
(169)
Figure 3.29 Anticancer activities od quinolines
Chapter 3 Quinoline-3-carboxylates/carboxamides…
179
Quinoline derivatives fused with various heterocycles have displayed potent
anticancer activity targeting differentsites like topoisomerase I, telomerase, farnasyl
transferase, Src tyrosine kinase, protein kinase CK-II etc. Indole fused 10H-
indolo[3,2-b]quinoline bearing bis-dimethylaminoethyl chain have been synthesized
and evaluated for anticancer activity by Vittorio Caprio et al. [137] and compound
(161) was found to be act on telomerase with IC50 of 16µM. Intercalation with double
stranded DNA is important target for cytotoxicity Yuzi Mikata et al. [138] reported
the synthesis of new derivatives of 2-phenyl quinoline having [(2-
aminoethyl)aminomethyl] group and compound (162) showed ability to intercalate
into double stranded DNA. Similarly pyridine fused pyrido[3,2-g] quinoline
derivative (163) showed strong binding to DNA [139].
Various pyrazolo[3,4-b]quinoline ribofuranosides prepared and evaluated by
Ronald Wolin et al. [140] for their ability to inhibit the nucleotide exchange process
on oncogenic Ras gene and compounds (164) was found to be most active in vitro
studies. A series of 3-imidazolymethylaminophenylsulphonyltetrahydroquinoline
designed and synthesized by Charles Z. Ding et al. as FTI (farnesyl transferase
inhibitors) and compound (165) was found to be most active with FTIC50 of 0.13 µM
[141]. Similarly Src Tyrosine Kinase inhibitors having 4-anilino-3-cyanoquinolines
(166) moiety were developed with IC50 of 5.3 µM [142]. Inhibitors of protein kinase
CK-II have been synthesized by Y. Mettey et al. [143] and compound (167) 6-
hydroxy-10-chlorobenzo[c]quinololizinum was found to be most potent inhibitor and
exhibited good selectivity for CK-II with IC50 0.005 µM.
Dalla Via et al. synthesized 1-[4-(3H-pyrrolo[3,2-f]quinolin-9-ylamino)-
phenyl]-ethanone hydrochloride (168) it showed high antiproliferative activity by
forming an intercalative complex with DNA and inhibiting DNA topoisomerase II
and by blocking the cell cycle in G2/M phase [144]. In-vitro antiproliferative activity
8 Baylis–Hillman adducts and their derivatives against a panel of humor tumor cell
lines was studied by Luciana K. Kohn et al. [145] and quinoline–phthalide (169)
derivative exhibited a potent effect on the proliferation of all cell lines. William
Kemnitzer et al. identified novel apoptosis inducer through caspase and cell-based
high-throughput screening assay and compound 1-(4-(1H-imidazol-1-yl)benzoyl)-3-
cyanopyrrolo[1,2-a]quinoline (170) was found to be highly active in human breast
Chapter 3 Quinoline-3-carboxylates/carboxamides…
180
cancer cells T47D, human colon cancer cells HCT116, and hepatocellular carcinoma
cancer cells SNU398 cell lines [146] (Figure 3.29).
3.12.2 Antimycobacterial activity
Various quinoline containing molecules have been synthesized tested for anti-TB
activity all over the world. D. Sriram et al. [147] synthesized 48 novel 6-
nitroquinolone-3-carboxylic acids derivatives and compound (171) having R = (4-
((benzo[d][1,3]dioxol-5-yl)methyll)piperazin-1-yl) was found to be the most active
compound in vitro with MIC of 0.08 and 0.16 μM against MTB and MDR-TB,
respectively. They also extend their work to synthesized various 2-(sub)-3-
fluoro/nitro-5, 12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid and
evaluated for in-vitro against Mycobacterium tuberculosis H37Rv (MTB), multi-drug
resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis
(MC2) (Figure 3.30).
N
N
O N N
N
OH
OO
R
O2N
N
OH
OO
R1
F
SN R
(170) (171) (172) (173) R = CONH(R)2R = CONHN=CHR
Figure 3.30 Antimycobacterial activities of quinolines
Compound (172) bearing R1=2-(3-(diethyl carbamoyl)piperidin-1-yl)-) was
found to be the most active compound with MIC of 0.18 and 0.08 μM against MTB
and MTR-TB [148]. 3D-QSAR analysis has been employed by Rahul Jain and co-
worker to understand the relationship between structure and anti-TB activity. They
developed new 4-(adamantan-1-yl)-2-substituted quinolines derivatives (173) the
most potent analog of the series produced 99% inhibition at 1.00 μg/mL against drug-
sensitive strain, and MIC of 3.125 μg/mL against isoniazid resistant TB strain [149].
3.12.3 Antimicrobial activity
Quinolones [150] is a special structural class of quinoline antimicrobial agents. It is
characterized by 1,4-dihydro-4-oxo-3-pyridine carboxylic acid and a fused benzene
Chapter 3 Quinoline-3-carboxylates/carboxamides…
181
ring moiety. Extensive SAR have been established on this nucleus and resulted in
number of currently marketed synthetic antimicrobial agent like ciprofloxacin (174),
ofloxacin (175) and sparfloxacin (176) etc (Figure 3.31).
N
O
OH
O
N
HNN
O
OH
O
N
N
N
O
OH
O
N
HNO
CH3H3C
F
NH2
F
(174) Ciprofloxacin (175) Ofloxacin (176) Sparfloxacin
N
CH3
NN
O
O2N
(177)
N
CH3
N
N
OH
CH3
N
N
CH3
NH2
(178)
N
F
HN
CH3
O O
NH
CH3
NAr
(179)Figure 3.31 Antimicrobial activities of quinolines
1-aryl/heteroaryl-5 methyl-1, 2, 4-triazolo[4,3-a]quinoline derivatives synthesized
and tested in vitro for their antibacterial activity and compound (177) exhibited MIC
10 µg/ml against salmonella typhae [151]. Shiv P. Singh et al. [152] reported 4-(4-
pyrozolyl)-2-aminopyrimidines and compound (178) showed moderate activity
against C. albicans, A. niger, Salmonella typhae.
V. Jayathirtha Rao et al. [153] reported synthesis of some new multi
substituted quinoline by Baylis–Hillman reaction and screened them against no. of
Gram-positive organisms, viz., Bacillus subtilis, Bacillus sphaericus, and S. aureus,
and three Gram-negative organisms, viz., Chromobacterium violaceum, Klebsiella
aerogenes, and Pseudomonas aeruginosa. Most of compound exerted a wide range of
broad spectrum of antibacterial activity. G. Venkat Reddy et al. reported a series of
novel imidazo fused quinolone carboxamides (179) and evaluated against
antibacterial activity, derivatives exhibit moderate antibacterial activity [154].
A novel 2-amino-4-(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-cabonitrile (180)
was annulated to various fused analogue such as triazole, pyrimidine, pyrazole and
imidazole system by S. A. Abdel-Mohsen [155] and screened in vitro for their
Chapter 3 Quinoline-3-carboxylates/carboxamides…
182
antimicrobial activities against two strains of bacteria and fungi, compound showed
moderate to good activity. A. R. Parikh et al. [156] synthesized isoxazoline and
cyanopyridines bearing 2-chloro-7-methoxyquinoline moiety and screened for
antimicrobial activity against E.coli, S. aureus, A. niger etc. Compound (181) was
most active. Acetamides analogues of 2-chloro-8-methyl quinoline (182) reported to
have antimicrobial activity [157].
3.12.4 Anticonvulsant activity
In recent years various molecular modifications of quinoline derivatives have been
reported with promising anticonvulsant results. Zhe-Shan Quan et al. [158] reported a
series of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivative with anticonvulsant
activity evaluated by the maximal electroshock test (MES) and their neurotoxicities
were measured by the rotarod test. 5-hexyloxy-[1,2,4]triazolo[4,3-a]quinoline (183)
was found to be most potent anticonvulsant, with median effective dose (ED50) of
19.0 mg/kg.
N
OH
NH2N
N
Ar
(180)
N N N
NN N N
O Cl
N NH2
NR
R= p-Br-C6H4
(181)
CH3
NH
R
OH2NO
C6H13
NN
(182) (183)
O
R
NN
R= Benzyloxy
(184)
O
OH
NR1
R2
(185)
NN
C6H4F OH
OH
O
(186) (187)
Figure 3.32 Anticonvulsant activities of quinolines
They extended their work to synthesized a series of 7-alkoxy-4,5-dihydro-
[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one [159] derivatives and compound 7-
benzyloxyl-4,5-dihydro-[1,2,4]thiazolo[4,3-a]quinoline-1(2H)-one (184) was among
the most active with (ED50) of 12.3 mg/kg. Derivatives of 8-substituted quinoline
Chapter 3 Quinoline-3-carboxylates/carboxamides…
183
were synthesized and tested against seizures induced by maximal electro shock
(MES), pentylenetetrazole (scMet) and compound (185) 8-(3'-(4"-phenylpiperazino)-
2'-hydroxypropyloxy)quinoline was potent in both model of seizure [160].
A fused triazole and triazolone derivatives of quinoline-2(1H)-one and their
anticonvulsant activity were reported [161]. Results of the study revealed that triazole,
but not the triazolone showed stronger anticonvulsant effects and compound (186), 5-
(p-fluorophenyl)-4,5–dihydro-1,2,4-triazolo[4,3-a]quinoline, showed the strongest
anticonvulsant effect with (ED50) of 27.4mg/kg and 22.0mg/kg in the anti-MES and
anti-PTZ test, respectively. Kynurenic acid (187) derivatives analogue 4-urea-5,7-
dichlorokynurenic acid were synthesized and subsequently screened in mice for
anticonvulsant activity by Nichols, et al. [162] most of the compound showed
excellent anticonvulsant activity (Figure 3.32).
3.12.5 Antiinflammatory activity
N
OH
NR1
R2R
N NH
NH
CH3
R1
R2
R3
R
O OH
R
O OH
Cl
R = NO2, CH2COOHR = CH3 R = CF3
F
ON
O
OOH
O
NN
O
N
N NN
NHN
S
Ar
(188) (189)
(190)
(191) (192)
(193) (194)(195)
Figure 3.33 Antiinflammatory activities of quinolines
Various 4–hydroxyquinoline derivatives bearing number of heterocyclic rings
derivatives (188) were synthesized and evaluated for their analgesic and anti-
inflammatory activity by Clemence Francois et al. [163] interesting biological results
were obtained in in-vivo study. Similarly some new 8–(phenylmethylene)
tetrahydroquinoline analogue were synthesized and evaluated for anti-inflammatory
Chapter 3 Quinoline-3-carboxylates/carboxamides…
184
activity both in vivo and in vitro. Compound with general structure (189) totally
inhibit both 5–LOX and COX in rat polymorphonuclear leukocytes assay (PMN) at
50µM [164]. Quinoline with acidic function were reported by Yasushi Kohno et al.
[165,166] as novel substituted 1,2,3,4,-tetrahydroquinoline derivatives and evaluated
for disease modifying anti-rheumatic drugs (DMARD). Of these synthesized
compounds (190-192), significantly suppressed the swelling of adjunct arthritic rat
paw at doses less than 25 mg/kg (acute/chronic).
Ability to inhibit the formation of Leukotrienes via the 5–lipoxygenase
enzyme has also been studied as a target for antiinflammatory drugs. Substituted 2–
cyanoquinoline derivatives (193) represent a distinct class of 5-LOX inhibitors and
posses in vitro and in vivo potency comparable or superior to naphthalenic acid
analogue [167]. Li-Jiau Huang et al. [168] reported the synthesis of novel antiplatelet
agents 4–alkoxy derivatives and compound (194) 5–ethyl–4–methoxy–2–phenyl
quinoline was the most potent with an IC50 0.08µM and was about threefold more
active than indomethacin. Various tetrazolo[1,5-a]quinoline derivatives (195)
containing pyrimidine ring were reported to possess dual antiinflammatory and
antibacterial activity [169] (Figure 3.33).
3.12.6 Cardiovascular activity
In an attempt to identify potential cardiovascular agent as Ca channel blocker, cAMP
phosphodiesterase III etc various chemical modification of quinoline derivatives have
attempted with positives results and have come up new lead compounds.
John M. MeCall et al. [170] reported synthesis and SAR study on a series of
7- (trifluoromethyl)-4-aminoquinoline and evaluated their hypotensive activity.
Compound (196) 1-[(4-fluorophenyl) sulphonyl)-4-[4-[(7-(fluoromethyl)-4-quinolinyl]
amino] benzoyl] piperazine. i.e. losulazine selected for clinical development and
shows hypotensive effect in rat, cat and dog. Some new 4-(diphenyl methyl)-α-[(4-
quinolinyloxy]methyl]-1-piperazinethanol derivatives were also exhibit
cardiovascular activity on isolated perfused rat and guinea pig heart and compound
(197) DPI 201-106 showed potent inotropic effect in rat heart [171].
Mannich bases [172] prepared by aminoalkylation of 3H-pyrrolo[3,2-f]
quinoline (198) showed vasorelexation in the presence of β-blocker propanolol. B.
Bahadir et al. [173] designed new alkyl 4-(2-fluoro-3-chloro-5-trifluoromethyl-phenyl)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
185
-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates (199) and 9-(3-chloro-2-fluoro
-5-trifluoromethylphenyl)-6,7-dihydrofuro[3,4-b]quinoline-1,8-dione (200) as a
structurally analogue of 1,4-dihydro pyridines and investigated their calcium
antagonistic activities on isolated rabbit sigmoid colon and compared with Nifedipine.
N
F3C
NH
N
O
NSO2
F
N
O
OH
N
N
Ph
Ph
N
N
N
NH
H3C
H3C
O O
O
R
F
ClF3C
NH
H3C
H3C
OF
ClF3C
O
O N
NN
R1
HN
N
O
NR2(196) (197) (198)
(199) (200)
(201)
(202) (203)
NH
O
O
O
EtN
NH
OR1
NH
NNH
OR1
HN
R4
R3
R2
Figure 3.34 Cardiovasculactivities of quinolines
Various N-(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)
acetamide (201) have been synthesized and their positive inotropic activity was
evaluated by measuring left atrium stroke volume on isolated rabbit heart preparations
and the most potent derivative showed 13.2% increased stroke volume (milrinone
4.7%) at concentration of 3 × 10-5 M in in vitro study [174]. Quinoline having
pyridazinone moiety (202, 203) were designed and their vasodilator activity was
examined on the isolated main pulmonary artery of the rabbit and compounds showed
moderate vasorelaxant activity compared with standard drug Milrinone [175] (Figure
3.34).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
186
3.13 Aim of current work Thus, in view of the literature findings related to quinoline derivatives, we approached
diversity oriented one-pot multicomponent synthesis and biological evaluation of fifty
analogues pertaining to quinoline-3-carboxylate and 3-carboxamide classes, utilizing
dimedone as a building block. Synthesis of quinoline-3-carboxylates and 3-
carboxamides (YUG-201 to YUG-250) were accomplished by one-pot
multicomponent reaction of dimedone, an appropriate 1,3-bifunctional synthon, an
appropriate aldehydes, ammonium acetate and L-proline using ethanol as a solvent.
Small organic molecules like cinchona alkaloids, L-proline, and its derivatives
are readily commercially available catalysts and have been used in various
transformations with excellent yields. Small organic molecules like cinchona
alkaloids, L-proline, and its derivatives are readily commercially available catalysts
and have been used in various transformations with excellent yields [176]. L-Proline
has been found to be very effective in enamine based direct catalytic asymmetric aldol
[177], Mannich [178], Michael [179], Diels–Alder [180], α-amination reactions, and
Knoevenagel type reactions [180,181]. More recently, proline and its derivatives have
been used in multicomponent Biginelli reactions [182] under solvent free conditions.
We, therefore, were interested in exploiting the activity of L-proline in the synthesis
of polyhydroquinoline derivatives through unsymmetric Hantzsch reaction.
The products were characterized by FT-IR, mass spectra, 1H NMR, 13C NMR
and elemental analysis. X-ray diffraction study of representative compound has also
been provided. The newly synthesized compounds are subjected to various biological
activities viz., antimicrobial, antimycobacterial, anticancer and antiviral.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
187
3.14 Reaction Scheme
NH
O
OOO
O
O
OO
YUG 201-220
R1HO
R1
a
Reagents & Conditions: (a) NH4OAc; L-proline; EtOH, Stirring, 30-40 min.
+
NH
O
OOO
O
O
OO
YUG 221-240
R1HO
R1
a+
NH
NH
OOO
O
YUG 241-250
R1HO
R1
a+ HN
O OR2
R2
Code R1 R2 M.F. M.W. M.P. ºC Yield
% Rf1 Rf2
YUG-201 4-OCH3 - C24H31NO4 397 188-190 80 0.55 0.70 YUG-202 4-CH3 - C24H31NO3 381 218-220 78 0.51 0.65 YUG-203 4-F - C23H28FNO3 385 162-164 81 0.61 0.78 YUG-204 4-Cl - C23H28ClNO3 401 128-130 72 0.57 0.72 YUG-205 3-Cl - C23H28ClNO3 401 216-219 78 0.48 0.67 YUG-206 4-Br - C23H28BrNO3 445 86-88 86 0.60 0.74 YUG-207 2-Cl - C23H28ClNO3 401 88-91 76 0.52 0.68 YUG-208 2-Br - C23H28BrNO3 445 168-172 80 0.62 0.79 YUG-209 3,4-OCH3 - C25H33NO5 427 180-183 88 0.50 0.68 YUG-210 2,5-OCH3 - C25H33NO5 427 182-184 77 0.56 0.76 YUG-211 3,4,5-OCH3 - C26H35NO6 457 144-146 79 0.49 0.69
Chapter 3 Quinoline-3-carboxylates/carboxamides…
188
YUG-212 H - C23H29NO3 367 120-123 84 0.47 0.68 YUG-213 2,4-Cl - C23H27Cl2NO3 435 164-166 72 0.52 0.73 YUG-214 2,6-Cl - C23H27Cl2NO3 435 130-132 81 0.50 0.70 YUG-215 3-OH - C23H29NO4 383 170-173 86 0.58 0.74 YUG-216 2-OH - C23H29NO4 383 138-140 75 0.61 0.81 YUG-217 4-NO2 - C23H28N2O5 412 155-157 79 0.56 0.67 YUG-218 3-NO2 - C23H28N2O5 412 158-160 83 0.49 0.65 YUG-219 2-NO2 - C23H28N2O5 412 148-150 77 0.53 0.72 YUG-220 3-Br - C23H28BrNO3 445 161-163 79 0.59 0.78 YUG-221 4-OCH3 - C23H29NO4 383 145-148 85 0.60 0.79 YUG-222 4-CH3 - C23H29NO3 367 150-152 81 0.61 0.82 YUG-223 4-F - C22H19FN4O 371 151-153 77 0.51 0.69 YUG-224 4-Cl - C22H26ClNO3 387 152-154 83 0.64 0.80 YUG-225 3-Cl - C22H26ClNO3 387 181-183 69 0.52 0.66 YUG-226 4-Br - C22H26BrNO3 431 158-161 75 0.56 0.70 YUG-227 2-Cl - C22H26ClNO3 387 167-168 80 0.50 0.68 YUG-228 2-Br - C22H26BrNO3 431 140-143 75 0.55 0.71 YUG-229 3,4-OCH3 - C24H31NO5 413 174-176 88 0.49 0.63 YUG-230 2,5-OCH3 - C24H31NO5 413 119-121 73 0.59 0.73 YUG-231 3,4,5-OCH3 - C25H33NO6 443 214-216 82 0.60 0.79 YUG-232 H - C22H27NO3 353 184-186 85 0.61 0.82 YUG-233 2,4-Cl - C22H25Cl2NO3 421 188-190 88 0.51 0.69 YUG-234 2,6-Cl - C22H25Cl2NO3 421 180-183 79 0.64 0.80 YUG-235 3-OH - C22H27NO4 369 180-182 87 0.52 0.66 YUG-236 2-OH - C22H27NO4 369 188-191 80 0.56 0.70 YUG-237 4-NO2 - C22H26N2O5 398 118-120 83 0.50 0.68 YUG-238 3-NO2 - C22H26N2O5 398 148-151 79 0.55 0.71 YUG-239 2-NO2 - C22H26N2O5 398 140-143 75 0.49 0.63 YUG-240 3-Br - C22H26BrNO3 431 151-153 77 0.51 0.69 YUG-241 4-OCH3 4-F C26H27FN2O3 434 151-153 80 0.51 0.69 YUG-242 4-CH3 4-F C26H27FN2O3 418 145-148 85 0.60 0.79 YUG-243 4-F 4-F C25H24F2N2O2 422 150-152 89 0.61 0.82 YUG-244 4-Cl 4-F C25H24ClFN2O2 438 151-153 77 0.51 0.69 YUG-245 4-NO2 4-F C25H24FN3O4 449 152-154 83 0.64 0.80 YUG-246 4-OCH3 2-F C26H27FN2O3 434 181-183 69 0.52 0.66 YUG-247 4-CH3 2-F C26H27FN2O3 418 158-161 75 0.56 0.70 YUG-248 4-F 2-F C25H24F2N2O2 422 167-168 80 0.50 0.68 YUG-249 4-Cl 2-F C25H24ClFN2O2 438 140-143 75 0.55 0.71 YUG-250 4-NO2 2-F C25H24FN3O4 449 174-176 88 0.49 0.63
TLC Solvent system Rf1: Hexane: Ethyl acetate – 6:4; TLC Solvent system Rf2: Chloroform: Methanol - 9:1.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
189
3.15 Plausible Reaction Mechanism
NH
O R
R2
O
R1
O
R
R1H2N
R2
O
+
O
R1O
R2
O
O
R1O
R2
O
+
NH2
R
O
O
H2O
RCHO
NH4OAc
H2O + AcOH H2O
RCHO
H2O + AcOH
NH4OAc
Step 3
Step 6 L-proline
L-proline
L-prol
ine
L-pro
line
Step 1
Step 2
Step 5 Step 4
(5) (6)
(7) (8)
(1)
(2)
(3)
(4)
(4)
Figure 3.35 Plausible mechanism for formation of polyhydroquinolines
(9)
The mechanism for the newly synthesized Quinolines is probably similar to
mechanism suggested by A. Kumar et al [66]. We propose a mechanism for the L-
proline catalyzed synthesis of polyhydroquinolines (Figure 3.35). As L-proline is
well known to catalyze aldol and Michael reactions, polyhydroquinoline (9) may be
formed either through step 1→step 2→step 3 or through step 4→step 5→step 6. The
role of L-proline comes in steps (1) and (4) where it catalyses the Knoevenagel type
coupling of aldehydes with active methylene compounds and in steps (3) and (6)
where it catalyses the Michael type addition of intermediates (5), (6) and (7), (8) to
give product (9).
.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
190
3.16 Experimental 3.16.1 Materials and Methods
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was routinely checked by TLC on silica gel-G plates of
0.5 mm thickness and spots were located by iodine. IR spectra were recorded
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were
recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe
technique. 1H NMR and 13C NMR were determined in DMSO-d6 solution on a Bruker
Ac 400 MHz spectrometer. Elemental analysis of the all the synthesized compounds
was carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are
in agreements with the structures assigned.
3.16.2 General procedure for the synthesis of ethyl 1,4,5,6,7,8-hexahydro-7,7-
dimethyl-5-oxo-4-(aryl)-2-propylquinoline-3-carboxylate (YUG -201 to 220)
A mixture of the dimedone (0.01 mol), ethyl 3-oxohexanoate (0.01 mol) and an
appropriate aromatic aldehyde (0.01 mol), ammonium acetate (0.01 mol) and L-
proline (0.001 mol) in 8-10 mL of EtOH was stirred for 30 to 40 min. After
completion of the reaction, the reaction mixture was filtered to give the solid products
YUG-201 to 220, which were recrystallized from ethanol.
3.16.2.1 Ethyl 1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-2-
propylquinoline-3-carboxylate (YUG-201)
NH
O CH3
CH3
OO
H3C
H3C
OCH3
a
bc
d
eH H
f g
H
Hh
i
j
k
lm
n n'
o o'
p
Yield: 80%; mp 188-190 ºC; IR (cm-1): 3279 (N-H stretching of pyridine ring), 3088
(C-H stretching of aromatic ring), 2883 (C-H stretching of alkane), 1697 (C=O
stretching of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
cyclohexanone), 1606 (N-H deformation pyridine ring), 1259 (C-O-C- stretching of
Chapter 3 Quinoline-3-carboxylates/carboxamides…
191
ester) 1085 (C-H in plane bending of aromatic ring), 852 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.89 (s, 3H, Ha),
0.93-0.97 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.17-1.20 (t, 3H, Hd), 1.55-1.62 (m, 2H, He),
1.98-2.02 (d, 1H, Hf), 2.13-2.17 (d, 1H, Hg), 2.13-2.17 (d, 1H, Hh), 2.35-2.39 (d, 1H,
Hi), 2.62-2.70 (m, 2H, Hj), 3.69 (s, 1H, Hk), 3.97-4.02 (q, 2H, Hl), 4.84 (s, 1H, Hm),
6.67-6.70 (dd, 2H, Hnn’, J = 9.74 Hz), 7.09-7.11 (dd, 2H, Hoo’, J = 8.68 Hz), 8.77 (s,
1H, Hp); MS: m/z 397; Anal. Calcd. for C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found:
C, 72.49; H, 7.82; N, 3.48%.
3.16.2.2 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propyl-4-p-tolylquinoline
-3-carboxylate (YUG-202)
abc
d
e
f g
h
ij
kl
m
n n'
oNH
O CH3
CH3
OO
H3C
H3C
CH3
H H
m'
Yield: 78%; mp 218-220 ºC; IR (cm-1): 3273 (N-H stretching of pyridine ring), 3088
(C-H stretching of aromatic ring), 2885 (C-H stretching of alkane), 1699 (C=O
stretching of carbonyl group of ester), 1629 (C=O stretching of carbonyl group of
cyclohexanone), 1608 (N-H deformation pyridine ring), 1259 (C-O-C- stretching of
ester) 1085 (C-H in plane bending of aromatic ring), 850 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.89 (s, 3H, Ha),
0.93-0.97 (t, 3H, Hb), 1.05 (s, 3H, Hc), 1.17-1.21 (t, 3H, Hd), 1.56-1.61 (m, 2H, He),
1.97-2.02 (d, 1H, Hf), 2.13-2.17 (d, 1H, Hg), 2.22 (s, 3H, Hh), 2.28-2.40 (m, 2H, Hi),
2.62-2.70 (m, 2H, Hj), 3.97-4.02 (q, 2H, Hk), 4.85 (s, 1H, Hl), 6.93-6.95 (d, 2H, Hmm’,
J = 7.92 Hz), 7.06-7.08 (d, 2H, Hnn’, J = 8.04 Hz), 8.75 (s, 1H, Ho); MS: m/z 381;
Anal. Calcd. for C24H31NO3: C, 75.56; H, 8.19; N, 3.67. Found: C, 75.53; H, 8.15; N,
3.63%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
192
3.16.2.3 Ethyl 4-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propyl-
quinoline-3-carboxylate (YUG-203)
NH
O CH3
CH3
OO
H3C
H3C
F
abc
d
e
H Hf g
H
Hh
i
jkl
mn n'
o
m'
Yield: 81%; mp 162-164 ºC; IR (cm-1): 3273 (N-H stretching of pyridine ring), 3088
(C-H stretching of aromatic ring), 2889 (C-H stretching of alkane), 1703 (C=O
stretching of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
cyclohexanone), 1606 (N-H deformation pyridine ring), 1282 (C-O-C- stretching of
ester) 1084 (C-H in plane bending of aromatic ring), 854 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.86 (s, 3H, Ha),
0.93-0.97 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.14-1.18 (t, 3H, Hd), 1.54-1.64 (m, 2H, He),
1.97-2.01 (d, 1H, Hf), 2.13-2.18 (d, 1H, Hg), 2.27-2.31 (d, 1H, Hh), 2.36-2.40 (d, 1H,
Hi), 2.61-2.74 (m, 2H, Hj), 3.95-4.03 (m, 2H, Hk), 4.88 (s, 1H, Hl), 6.86-6.91 (t, 2H,
Hmm’, J = 8.84 Hz), 7.16-7.20 (dd, 2H, Hnn’, J = 6.56 Hz), 8.88 (s, 1H, Ho); MS: m/z
385; Anal. Calcd. for C23H28FNO3: C, 71.66; H, 7.32; N, 3.63. Found: C, 71.63; H,
7.28; N, 3.60%.
3.16.2.4 Ethyl 4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propylq
-uinoline-3-carboxylate (YUG-204)
NH
O CH3
CH3
OO
H3CH3C
Cl
H Ha
bc
de
f g
hi
jkl
m
HH
mm m
NH
O CH3
CH3
OO
H3CH3C
Cl
1
23
4 5 67
8
9 101112
1314 15
16 17
18
19
4
13'14'
20
n
Yield: 72%; mp 128-130 ºC; IR (cm-1): 3273 (N-H stretching of pyridine ring), 3088
(C-H stretching of aromatic ring), 2872 (C-H stretching of alkane), 1703 (C=O
stretching of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
Chapter 3 Quinoline-3-carboxylates/carboxamides…
193
cyclohexanone), 1606 (N-H deformation pyridine ring), 1282 (C-O-C- stretching of
ester) 1084 (C-H in plane bending of aromatic ring), 842 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.86 (s, 3H, Ha),
0.93-0.97 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.14-1.18 (t, 3H, Hd), 1.57-1.60 (m, 2H, He),
1.97-2.01 (d, 1H, Hf), 2.13-2.18 (d, 1H, Hg), 2.27-2.31 (d, 1H, Hh), 2.36-2.41 (d, 1H,
Hi), 2.65-2.69 (m, 2H, Hj), 3.96-4.01 (q, 2H, Hk), 4.86 (s, 1H, Hl), 7.16 (d, 4H, Hm, J
= 1.00 Hz), 8.92 (s, 1H, Hn); 13C NMR (DMSO-d6) δ ppm: 13.67, 13.95, 21.83, 26.48,
29.16, 32.02, 32.95, 35.61, 50.25, 58.94, 103.08, 109.61, 127.35, 129.11, 130.25,
146.44, 149.33, 149.60, 166.28, 194.05; MS: m/z 401; Anal. Calcd. for C23H28ClNO3:
C, 68.73; H, 7.02; N, 3.48. Found: C, 68.69; H, 7.00; N, 3.44%.
3.16.2.5 Ethyl 4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propylqu-
inoline-3-carboxylate (YUG-205)
NH
O CH3
CH3
OO
H3CH3C
H Ha
bc
de
f g
hi
jkl
nn'
HH
m
NH
O CH3
CH3
OO
H3CH3C 1
23
4 5 67
8
9 101112
13
14 15
1617
18
194 20
Cl Cl
o
p
2122
Yield: 78%; mp 216-219 ºC; IR (cm-1): 3275 (N-H stretching of pyridine ring), 3086
(C-H stretching of aromatic ring), 2872 (C-H stretching of alkane), 1701 (C=O
stretching of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
cyclohexanone), 1608 (N-H deformation pyridine ring), 1280 (C-O-C- stretching of
ester) 1084 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.88 (s, 3H, Ha), 0.94-0.98 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.15-1.19 (t, 3H, Hd), 1.55-
1.65 (m, 2H, He), 1.99-2.03 (d, 1H, Hf), 2.15-2.19 (d, 1H, Hg), 2.30-2.37 (d, 1H, Hh),
2.37-2.41 (d, 1H, Hi), 2.63-2.74 (m, 2H, Hj), 3.94-4.06 (q, 2H, Hk), 4.89 (s, 1H, Hl),
7.07 (d, 2H, Hm, J = 1.88 Hz), 7.11-7.16 (m, 2H, Hnn’), 7.18 (, 1H, Ho), 8.94 (s, 1H,
Hp); 13C NMR (DMSO-d6) δ ppm: 13.64, 13.91, 21.82, 26.46, 29.12, 32.04, 32.97,
36.05, 50.24, 58.99, 102.93, 109.44, 125.36, 125.88, 127.52, 129.10, 132.42, 149.51,
149.76, 149.82, 166.23, 194.09; MS: m/z 401; Anal. Calcd. for C23H28ClNO3: C,
68.73; H, 7.02; N, 3.48. Found: C, 68.68; H, 7.01; N, 3.45%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
194
3.16.2.6 Ethyl 4-(4-bromophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propylqu-
inoline-3-carboxylate (YUG-206)
NH
O CH3
CH3
OO
H3CH3C
Br
H Ha
bc
de
f g
hi
jkl
m
HH
m'n n'
NH
O CH3
CH3
OO
H3CH3C
Br
1
23
4 5 67
8
9 101112
1314 15
16 17
18
19
4
13'14'
20
o
Yield: 86%; mp 86-88 ºC; IR (cm-1): 3275 (N-H stretching of pyridine ring), 3086 (C-
H stretching of aromatic ring), 2872 (C-H stretching of alkane), 1701 (C=O stretching
of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
cyclohexanone), 1608 (N-H deformation pyridine ring), 1280 (C-O-C- stretching of
ester) 1084 (C-H in plane bending of aromatic ring), 842 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.87 (s, 3H, Ha),
0.94-0.97 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.15-1.19 (t, 3H, Hd), 1.56-1.62 (m, 2H, He),
1.98-2.02 (d, 1H, Hf), 2.14-2.18 (d, 1H, Hg), 2.27-2.31 (d, 1H, Hh), 2.36-2.40 (d, 1H,
Hi), 2.64-2.71 (m, 2H, Hj), 3.96-4.02 (q, 2H, Hk), 4.87 (s, 1H, Hl), 7.11-7.14 (m, 2H,
Hmm’), 7.27-7.30 (m, 2H, Hnn’), 8.88 (s, 1H, Ho); 13C NMR (DMSO-d6) δ ppm: 13.66,
13.93, 21.82, 26.51, 29.16, 32.01, 32.99, 35.73, 50.26, 58.94, 103.08, 109.59, 118.63,
129.53, 130.23, 146.87, 149.31, 149.61, 166.30, 194.12; MS: m/z 445; Anal. Calcd.
for C23H28BrNO3: C, 61.89; H, 6.32; N, 3.14. Found: C, 61.85; H, 6.28; N, 3.11%.
3.16.2.7 Ethyl 4-(2-chlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propylqu-
inoline-3-carboxylate (YUG-207)
NH
O CH3
CH3
OO
H3CH3C
Cl
NH
O CH3
CH3
OO
H3CH3C
Cl
H H
H
H
ab
c
d
e
f g
h
i
j
kl
m
nop
q 1
23
4 5 6
7
8
910
1112
1314
15
1617
18
19 20
2122
4
Yield: 76%; mp 88-91 ºC; IR (cm-1): 3290 (N-H stretching of pyridine ring), 3080 (C-
H stretching of aromatic ring), 2870 (C-H stretching of alkane), 1701 (C=O stretching
Chapter 3 Quinoline-3-carboxylates/carboxamides…
195
of carbonyl group of ester), 1645 (C=O stretching of carbonyl group of
cyclohexanone), 1604 (N-H deformation pyridine ring), 1280 (C-O-C- stretching of
ester) 1080 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.87 (s, 3H, Ha), 0.93-0.97 (t, 3H, Hb), 1.03 (s, 3H, Hc), 1.11-1.14 (t, 3H, Hd), 1.53-
1.63 (m, 2H, He), 1.92-1.97 (d, 1H, Hf), 2.11-2.15 (d, 1H, Hg), 2.26-2.30 (d, 1H, Hh),
2.36-2.40 (d, 1H, Hi), 2.51-2.74 (m, 2H, Hj), 3.95-3.97 (q, 2H, Hk), 5.24 (s, 1H, Hl),
7.04-7.09 (m, 1H, Hm), 7.10-7.13 (m, 1H, Hn), 7.16-7.09 (m, 1H, Ho), 7.30-7.32 (m,
1H, Hp), 8.88 (s, 1H, Hp); 13C NMR (DMSO-d6) δ ppm: 13.72, 13.95, 21.73, 26.46,
29.16, 31.84, 32.92, 34.96, 50.33, 58.82, 103.30, 109.41, 126.17, 126.78, 128.79,
131.34, 132.03, 145.08, 148.78, 149.83, 166.47, 193.81; MS: m/z 401; Anal. Calcd.
for C23H28ClNO3: C, 68.73; H, 7.02; N, 3.48. Found: C, 68.68; H, 7.01; N, 3.45%.
3.16.2.8 Ethyl 4-(2-bromophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propylqu-
inoline-3-carboxylate (YUG-208)
NH
O CH3
CH3
OO
H3CH3C
Br
NH
O CH3
CH3
OO
H3CH3C
Br
H H
H
H
ab
c
d
e
f g
h
i
j
kl
m
nop
q 1
23
4 5 6
7
8
910
1112
1314
15
1617
18
19 20
2122
4
Yield: 80%; mp 168-172 ºC; IR (cm-1): 3286 (N-H stretching of pyridine ring), 3074
(C-H stretching of aromatic ring), 2870 (C-H stretching of alkane), 1699 (C=O
stretching of carbonyl group of ester), 1645 (C=O stretching of carbonyl group of
cyclohexanone), 1604 (N-H deformation pyridine ring), 1280 (C-O-C- stretching of
ester) 1078 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.87 (s, 3H, Ha), 0.93-0.97 (t, 3H, Hb), 1.03 (s, 3H, Hc), 1.11-1.15 (t, 3H, Hd), 1.54-
1.64 (m, 2H, He), 1.92-1.96 (d, 1H, Hf), 2.11-2.15 (d, 1H, Hg), 2.26-2.31 (d, 1H, Hh),
2.36-2.41 (d, 1H, Hi), 2.52-2.72 (m, 2H, Hj), 3.97-4.00 (q, 2H, Hk), 5.20 (s, 1H, Hl),
6.92-6.96 (m, 1H, Hm), 7.14-7.18 (m, 1H, Hn), 7.28-7.31 (m, 1H, Ho), 7.35-7.38 (m,
1H, Hp), 8.90 (s, 1H, Hp); 13C NMR (DMSO-d6) δ ppm: 13.72, 14.09, 21.71, 26.54,
29.13, 31.85, 32.89, 37.07, 50.37, 58.78, 103.80, 109.75, 122.37, 126.93, 127.04,
131.27, 132.11, 147.02, 148.47, 149.72, 166.50, 193.80; MS: m/z 445; Anal. Calcd.
for C23H28BrNO3: C, 61.89; H, 6.32; N, 3.14. Found: C, 61.85; H, 6.29; N, 3.10%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
196
3.16.2.9 Ethyl 1,4,5,6,7,8-hexahydro-4-(3,4-dimethoxyphenyl)-7,7-dimethyl-5-oxo-
2-propylquinoline-3-carboxylate (YUG-209)
NH
O CH3
CH3
OO
H3CH3C
O
CH3OH3C
Yield: 88%; mp 180-183 ºC; MS: m/z 427; Anal. Calcd. for C25H33NO5: C, 70.23; H,
7.78; N, 3.28. Found: C, 70.20; H, 7.74; N, 3.24%.
3.16.2.10 Ethyl 1,4,5,6,7,8-hexahydro-4-(2,5-dimethoxyphenyl)-7,7-dimethyl-5-oxo-
2-propylquin- oline-3-carboxylate (YUG-210)
a
bc
d
e
f g
hi
j
kl
m
n
o
pq
NH
O CH3
CH3
OO
H3CH3C
H H
HH
O
OH3C CH3
r
Yield: 77%; mp 182-184 ºC; IR (cm-1): 3279 (N-H stretching of pyridine ring), 3074
(C-H stretching of aromatic ring), 2899 (C-H stretching of alkane), 1699 (C=O
stretching of carbonyl group of ester), 1647 (C=O stretching of carbonyl group of
cyclohexanone), 1597 (N-H deformation pyridine ring), 1280 (C-O-C- stretching of
ester) 1082 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.89 (s, 3H, Ha), 0.92-0.95 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.15-1.19 (t, 3H, Hd), 1.52-
1.59 (m, 2H, He), 1.93-1.97 (d, 1H, Hf), 2.11-2.14 (d, 1H, Hg), 2.24-2.28 (d, 1H, Hh),
2.34-2.38 (d, 1H, Hi), 2.43-2.50 (m, 2H, Hj), 2.73 (s, 3H, Hk), 2.74 (s, 3H, Hl), 3.95-
3.98 (m, 2H, Hm), 5.05 (s, 1H, Hn), 6.56-6.59 (m, 1H, Ho), 6.68-6.70 (d, 1H, Hp, J =
8.88 Hz), 6.74-6.75 (d, 1H, Hq, J = 3.12 Hz), 8.70 (s, 1H, Hr); MS: m/z 427; Anal.
Calcd. for C25H33NO5: C, 70.23; H, 7.78; N, 3.28. Found: C, 70.19; H, 7.75; N, 3.23%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
197
3.16.2.11 Ethyl 1,4,5,6,7,8-hexahydro-4-(3,4,5-trimethoxyphenyl)-7,7-dimethyl-
5-oxo-2-propylqui- noline-3-carboxylate (YUG-211)
NH
O CH3
CH3
OO
H3CH3C
OCH3
OH3C
OH3C
Yield: 79%; mp 144-146 ºC; MS: m/z 457; Anal. Calcd. for C26H35NO6: C, 68.25; H,
7.71; N, 3.06. Found: C, 68.21; H, 7.68; N, 3.02%.
3.16.2.12 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-4-phenyl-2-propylquino-
line-3-carboxylate (YUG-212)
NH
O CH3
CH3
OO
H3CH3C
Yield: 84%; mp 120-123 ºC; MS: m/z 367; Anal. Calcd. for C23H29NO3: C, 75.17; H,
7.95; N, 3.81. Found: C, 75.13; H, 7.91; N, 3.78%.
3.16.2.13 Ethyl 4-(2,4-dichlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-
2-propylquinoline-3-carboxylate (YUG-213)
NH
O CH3
CH3
OO
H3CH3C
Cl
Cl
Yield: 72%; mp 164-166 ºC; MS: m/z 435; Anal. Calcd. for C23H27Cl2NO3: C, 63.31;
H, 6.24; N, 3.21. Found: C, 63.28; H, 6.20; N, 3.17%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
198
3.16.2.14 Ethyl 4-(2,6-dichlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-
2-propylquinoline-3-carboxylate (YUG-214)
NH
O CH3
CH3
OO
H3CH3C
ClCl
Yield: 81%; mp 130-132 ºC; MS: m/z 435; Anal. Calcd. for C23H27Cl2NO3: C, 63.31;
H, 6.24; N, 3.21. Found: C, 63.27; H, 6.21; N, 3.18%.
3.16.2.15 Ethyl 1,4,5,6,7,8-hexahydro-4-(3-hydroxyphenyl)-7,7-dimethyl-5-oxo-2-
propylquinoline-3-carboxylate (YUG-215)
NH
O CH3
CH3H3C
H3C
O O
OH
Yield: 86%; mp 170-173 ºC; MS: m/z 383; Anal. Calcd. for C23H29NO4: C, 72.04; H,
7.62; N, 3.65. Found: C, 72.00; H, 7.58; N, 3.61%.
3.16.2.16 Ethyl 1,4,5,6,7,8-hexahydro-4-(2-hydroxyphenyl)-7,7-dimethyl-5-oxo-2-
propylquinoline-3-carboxylate (YUG-216)
NH
O CH3
CH3H3C
H3C
O OOH
Yield: 75%; mp 138-140 ºC; MS: m/z 383; Anal. Calcd. for C23H29NO4: C, 72.04; H,
7.62; N, 3.65. Found: C, 72.01; H, 7.59; N, 3.60%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
199
3.16.2.17 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-2-
propylquinoline-3-carboxylate (YUG-217)
NH
O CH3
CH3
OO
H3CH3C
H H
H
H
abc
d
e
f g
h
i
jkl
m
n
o
NO2
m'
n'
Yield: 79%; mp 155-157 ºC; IR (cm-1): 3277 (N-H stretching of pyridine ring), 3086
(C-H stretching of aromatic ring), 2872 (C-H stretching of alkane), 1710 (C=O
stretching of carbonyl group of ester), 1647 (C=O stretching of carbonyl group of
cyclohexanone), 1608 (N-H deformation pyridine ring), 1280 (C-O-C- stretching of
ester) 1060 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.84 (s, 3H, Ha), 0.94-0.98 (t, 3H, Hb), 1.04 (s, 3H, Hc), 1.13-1.16 (t, 3H, Hd), 1.57-
1.64 (m, 2H, He), 1.97-2.01 (d, 1H, Hf), 2.15-2.19 (d, 1H, Hg), 2.29-2.33 (d, 1H, Hh),
2.39-2.43 (d, 1H, Hi), 2.67-2.73 (m, 2H, Hj), 3.95-4.00 (q, 2H, Hk), 5.01 (s, 1H, Hl),
7.41-7.43 (dd, 2H, Hmm’, J = 8.76 Hz), 8.03-8.06 (m, 2H, Hnn’, J = 8.76 Hz), 9.07 (s,
1H, Ho); MS: m/z 412; Anal. Calcd. for C23H28N2O5: C, 61.89; H, 6.32; N, 3.14.
Found: C, 61.85; H, 6.28; N, 3.11%.
3.16.2.18 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-(3-nitrophenyl)-5-oxo-2-propyl
quinoline-3-carboxylate (YUG-218)
NH
O CH3
CH3
OO
H3CH3C
NO2
Yield: 83%; mp 158-160 ºC; MS: m/z 412; Anal. Calcd. for C23H28N2O5: C, 61.89; H,
6.32; N, 3.14. Found: C, 61.86; H, 6.29; N, 3.10%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
200
3.16.2.19 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-2-propyl-
quinoline-3-carboxylate (YUG-219)
NH
O CH3
CH3
OO
H3CH3C
NO2
Yield: 77%; mp 148-150 ºC; MS: m/z 412; Anal. Calcd. for C23H28N2O5: C, 61.89; H,
6.32; N, 3.14. Found: C, 61.85; H, 6.28; N, 3.09%.
3.16.2.20 Ethyl 4-(3-bromophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propyl-
quinoline-3-carboxylate (YUG-220)
NH
O CH3
CH3
OO
H3CH3C
Br
Yield: 79%; mp 161-163 ºC; MS: m/z 445; Anal. Calcd. for C23H28BrNO3: C, 61.89;
H, 6.32; N, 3.14. Found: C, 61.85; H, 6.29; N, 3.10%.
3.16.3 General procedure for the synthesis of methyl 1,4,5,6,7,8-hexahydro-2-
isopropyl-7,7-dimethyl-5-oxo-4-(aryl)quinoline-3-carboxylate (YUG -221 to 240)
A mixture of the dimedone (0.01 mol), methyl 4-methyl-3-oxopentanoate (0.01 mol)
and an appropriate aromatic aldehyde (0.01 mol), ammonium acetate (0.01 mol) and
L-proline (0.001 mol) in 8-10 mL of EtOH was stirred for 30 to 40 min. After
completion of the reaction, the reaction mixture was filtered to give the solid products
YUG-221 to 240, which were recrystallized from ethanol.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
201
3.16.3.1 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-4-(4-methoxyphenyl)-7,7-dimethyl
-5-oxoquinoline-3-carboxylate (YUG-221)
NH
OCH3
CH3
OO
H3CH3C
H H
a
bc
de f
g
h
i
jk
lm
n 12
3
5
67
8
9
10
11
1213
14
1516
17 18
19
20214
O
m'
CH3
CH3
l'
NH
OCH3
CH3
OO
H3CH3C
O
CH3
CH3
14'15'
Yield: 85%; mp 145-148 ºC; IR (cm-1): 3282 (N-H stretching of pyridine ring), 3066
(C-H stretching of aromatic ring), 2891 (C-H stretching of alkane), 1695 (C=O
stretching of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
cyclohexanone), 1604 (N-H deformation pyridine ring), 1267 (C-O-C- stretching of
ester) 1070 (C-H in plane bending of aromatic ring), 840 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.85 (s, 3H, Ha),
1.03 (s, 3H, Hb), 1.13-1.15 (d, 3H, Hc), 1.20-1.22 (d, 3H, Hd), 1.97-2.01 (d, 1H, He),
2.15-2.19 (d, 1H, Hf), 2.41-2.42 (d, 1H, Hg), 3.54 (s, 3H, Hh), 3.68 (s, 3H, Hi), 4.08-
4.15 (m, 1H, Hj), 4.84 (s, 1H, Hk), 6.68-6.72 (dd, 2H, Hll’, J = 11.48 Hz), 7.06-7.10
(dd, 2H, Hmm’, J = 11.48 Hz), 8.35 (s, 1H, Hn); 13C NMR (DMSO-d6) δ ppm: 19.38,
19.49, 26.28, 27.14, 29.40, 31.90, 34.85, 48.71, 50.27, 50.51, 54.60, 102.73, 110.15,
112.91, 128.03, 139.70, 149.78, 152.81, 157.17, 167.41, 194.30; MS: m/z 383; Anal.
Calcd. for C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found: C, 72.00; H, 7.58; N, 3.61%.
3.16.3.2 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-5-oxo-4-p-tolylquinoli-
ne-3-carboxylate (YUG-222)
NH
OCH3
CH3
OO
H3CH3C
H H
a
bc
de f
g
h
j k
lm
n
CH3
m'
CH3
l'
i
Chapter 3 Quinoline-3-carboxylates/carboxamides…
202
Yield: 81%; mp 150-152 ºC; IR (cm-1): 3281 (N-H stretching of pyridine ring), 3014
(C-H stretching of aromatic ring), 2872 (C-H stretching of alkane), 1695 (C=O
stretching of carbonyl group of ester), 1649 (C=O stretching of carbonyl group of
cyclohexanone), 1599 (N-H deformation pyridine ring), 1269 (C-O-C- stretching of
ester), 1068 (C-H in plane bending of aromatic ring), 837 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.86 (s, 3H, Ha),
1.01 (s, 3H, Hb), 1.13-1.15 (d, 3H, Hc), 1.20-1.22 (d, 3H, Hd), 1.98-2.02 (d, 1H, He),
2.15-2.19 (d, 1H, Hf), 2.22 (s, 3H, Hg), 2.34 (s, 3H, Hh), 2.41-2.43 (d, 3H, Hi), 4.07-
4.13 (m, 1H, Hj), 4.86 (s, 1H, Hk), 6.94-6.96 (d, 2H, Hll’, J = 7.92 Hz), 7.05-7.07 (d,
2H, Hmm’, J = 8.04 Hz), 8.25 (s, 1H, Hn); MS: m/z 367; Anal. Calcd. for C23H29NO3: C,
75.17; H, 7.95; N, 3.81. Found: C, 75.13; H, 7.91; N, 3.78%.
3.16.3.3 Methyl 4-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-5-
oxoquinoline-3-carboxylate (YUG-223)
NH
OCH3
CH3
OO
H3CH3C
H H
a
bc
de f
g
h
ij
k
l
m1
2
356
7
89
1011
12
1314
15 16
17
18194
F
CH3
l'
NH
OCH3
CH3
OO
H3CH3C
F
CH3
k'
4
12'
13'
Yield: 77%; mp 151-153 ºC; IR (cm-1): 3288 (N-H stretching of pyridine ring), 3078
(C-H stretching of aromatic ring), 2874 (C-H stretching of alkane), 1707 (C=O
stretching of carbonyl group of ester), 1647 (C=O stretching of carbonyl group of
cyclohexanone), 1600 (N-H deformation pyridine ring), 1265 (C-O-C- stretching of
ester), 1068 (C-H in plane bending of aromatic ring), 850 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.84 (s, 3H, Ha),
1.04 (s, 3H, Hb), 1.14-1.16 (d, 3H, Hc), 1.22-1.23 (d, 3H, Hd), 1.99-2.03 (d, 1H, He),
2.16-2.20 (d, 1H, Hf), 2.42-2.43 (d, 2H, Hg), 3.55 (s, 3H, Hh), 4.10-4.17 (m, 1H, Hi),
4.90 (s, 1H, Hj), 6.86-6.92 (m, 2H, Hkk’), 7.15-7.20 (m, 2H, Hll’), 8.36 (s, 1H, Hm); 13C
NMR (DMSO-d6) δ ppm: 19.36, 19.46, 26.22, 27.18, 29.37, 31.89, 35.17, 50.22,
50.53, 102.31, 109.90, 113.99, 128.62, 143.35, 149.92, 153.31, 159.18, 167.19,
194.24; MS: m/z 371; Anal. Calcd. for C22H26FNO3: C, 71.14; H, 7.06; N, 3.77.
Found: C, 71.10; H, 7.02; N, 3.73%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
203
3.16.3.4 Methyl 4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-
5-oxoquinoline-3-carboxylate (YUG-224)
NH
OCH3
CH3
OO
H3CH3C
Cl
CH3
Yield: 83%; mp 152-154 ºC; MS: m/z 387; Anal. Calcd. for C22H26ClNO3: C, 68.12;
H, 6.76; N, 3.61. Found: C, 68.08; H, 6.72; N, 3.57%.
3.16.3.5 Methyl 4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-
5-oxoquinoline-3-carboxylate (YUG-225)
NH
OCH3
CH3
OO
H3CH3C
CH3
Cl
Yield: 69%; mp 181-183 ºC; MS: m/z 387; Anal. Calcd. for C22H26ClNO3: C, 68.12;
H, 6.76; N, 3.61. Found: C, 68.09; H, 6.73; N, 3.58%.
3.16.3.6 Methyl 4-(4-bromophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-
5-oxoquinoline-3-carboxylate (YUG-226)
NH
OCH3
CH3
OO
H3CH3C
H H
a
bc
de f
g
h
ij
k
m
o
Br
CH3
n
l
Yield: 75%; mp 158-160 ºC; IR (cm-1): 3286 (N-H stretching of pyridine ring), 3076
(C-H stretching of aromatic ring), 2874 (C-H stretching of alkane), 1705 (C=O
stretching of carbonyl group of ester), 1647 (C=O stretching of carbonyl group of
Chapter 3 Quinoline-3-carboxylates/carboxamides…
204
cyclohexanone), 1600 (N-H deformation pyridine ring), 1267 (C-O-C- stretching of
ester), 1068 (C-H in plane bending of aromatic ring), 840 (C-H out of plane bending
for 1,4-disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.86 (s, 3H, Ha),
1.04 (s, 3H, Hb), 1.12-1.14 (d, 3H, Hc), 1.18-1.19 (d, 3H, Hd), 1.91-1.95 (d, 1H, He),
2.13-2.17 (d, 1H, Hf), 2.44 (s, 2H, Hg), 3.51 (s, 3H, Hh), 3.91-3.95 (m, 1H, Hi), 5.17 (s,
1H, Hj), 6.93-6.98 (m, 1H, Hk), 7.16-7.20 (m, 1H, Hl), 7.24-7.27 (m, 1H, Hm), 7.36-
7.39 (m, 1H, Hn), 8.35 (s, 1H, Ho); MS: m/z 431; Anal. Calcd. for C22H26BrNO3: C,
61.12; H, 6.06; N, 3.24. Found: C, 61.08; H, 6.02; N, 3.20%.
3.16.3.7 Methyl 4-(2-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-
5-oxoquinoline-3-carboxylate (YUG-227)
NH
OCH3
CH3
OO
H3CH3C
H H
a
bc
de f
g
h
ij
k
m
o1
2
356
7
89
1011
1213
14
15
1617
18 19
20214
CH3
n
NH
OCH3
CH3
OO
H3CH3C
CH3
l
4
Cl Cl
Yield: 80%; mp 167-168 ºC; IR (cm-1): 3284 (N-H stretching of pyridine ring), 3078
(C-H stretching of aromatic ring), 2874 (C-H stretching of alkane), 1707 (C=O
stretching of carbonyl group of ester), 1643 (C=O stretching of carbonyl group of
cyclohexanone), 1597 (N-H deformation pyridine ring), 1269 (C-O-C- stretching of
ester), 1068 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.87 (s, 3H, Ha), 1.04 (s, 3H, Hb), 1.13-1.14 (d, 3H, Hc), 1.18-1.19 (d, 3H, Hd), 1.91-
1.92 (d, 1H, He), 2.13-2.17 (d, 1H, Hf), 2.43-2.44 (d, 2H, Hg), 3.50 (s, 3H, Hh), 3.94-
4.01 (m, 1H, Hi), 5.23 (s, 1H, Hj), 7.01-7.05 (m, 1H, Hk), 7.11-7.15 (m, 1H, Hl), 7.18-
7.20 (m, 1H, Hm), 7.26-7.29 (m, 1H, Hn), 8.34 (s, 1H, Ho); 13C NMR (DMSO-d6) δ
ppm: 19.25, 19.37, 26.31, 27.07, 29.40, 31.78, 35.01, 50.22, 50.34, 102.63, 109.20,
126.41, 126.87, 128.85, 130.89, 131.94, 145.11, 150.26, 152.05, 167.33, 193.79; MS:
m/z 387; Anal. Calcd. for C22H26ClNO3: C, 68.12; H, 6.76; N, 3.61. Found: C, 68.09;
H, 6.73; N, 3.58%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
205
3.16.3.8 Methyl 4-(2-bromophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-5
-oxoquinoline-3-carboxylate (YUG-228)
NH
OCH3
CH3
OO
H3CH3C
H H
a
bc
de f
g
h
ij
k
m
o1
2
3
5
67
8
910
1112
1314
15
16
1718
19 20
214
CH3
n
NH
OCH3
CH3
OO
H3CH3C
CH3
l
Br Br
22
Yield: 75%; mp 140-143 ºC; IR (cm-1): 3288 (N-H stretching of pyridine ring), 3066
(C-H stretching of aromatic ring), 2874 (C-H stretching of alkane), 1710 (C=O
stretching of carbonyl group of ester), 1641 (C=O stretching of carbonyl group of
cyclohexanone), 1604 (N-H deformation pyridine ring), 1265 (C-O-C- stretching of
ester), 1064 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.87 (s, 3H, Ha), 1.05 (s, 3H, Hb), 1.13-1.15 (d, 3H, Hc), 1.18-1.20 (d, 3H, Hd), 1.92-
1.96 (d, 1H, He), 2.11-2.13 (d, 1H, Hf), 2.44 (s, 2H, Hg), 3.52 (s, 3H, Hh), 3.92-3.99
(m, 1H, Hi), 5.19 (s, 1H, Hj), 6.92-6.96 (m, 1H, Hk), 7.15-7.19 (m, 1H, Hl), 7.25-7.28
(m, 1H, Hm), 7.36-7.38 (m, 1H, Hn), 8.31 (s, 1H, Ho); 13C NMR (DMSO-d6) δ ppm:
19.26, 19.36, 26.38, 27.08, 29.36, 31.79, 32.06, 32.60, 50.26, 50.33, 103.16, 109.65,
122.30, 127.08, 127.14, 130.75, 132.11, 147.11, 150.13, 151.73, 167.35, 193.83; MS:
m/z 431; Anal. Calcd. for C22H26BrNO3: C, 61.12; H, 6.06; N, 3.24. Found: C, 61.09;
H, 6.03; N, 3.21%.
3.16.3.9 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-4-(3,4-dimethoxyphenyl)-7,7-
dimethyl-5-oxo-quinoline-3-carboxylate (YUG-229)
a
b
c
de f
g
h
ij
k
m o
n
l
NH
OCH3
CH3
OO
H3CH3C
H H CH3
OCH3
OH3C
p
Yield: 88%; mp 174-176 ºC; IR (cm-1): 3209 (N-H stretching of pyridine ring), 3066
(C-H stretching of aromatic ring), 2874 (C-H stretching of alkane), 1701 (C=O
Chapter 3 Quinoline-3-carboxylates/carboxamides…
206
stretching of carbonyl group of ester), 1643 (C=O stretching of carbonyl group of
cyclohexanone), 1597 (N-H deformation pyridine ring), 1269 (C-O-C- stretching of
ester), 1068 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.86 (s, 3H, Ha), 1.03 (s, 3H, Hb), 1.12-1.14 (d, 3H, Hc), 1.20-1.21 (d, 3H, Hd), 1.98-
2.02 (d, 1H, He), 2.16-2.20 (d, 1H, Hf), 2.42-2.43 (d, 2H, Hg), 3.04 (s, 3H, Hh), 3.67 (s,
3H, Hi), 3.70 (s, 3H, Hj), 4.10-4.14 (m, 1H, Hk), 4.83 (s, 1H, Hl), 6.46-6.66 (m, 1H,
Hm), 6.71-6.73 (d, 1H, Hn, J = 8.28 Hz), 6.74-6.75 (m, 1H, Ho), 8.39 (s, 1H, Hp); MS:
m/z 413; Anal. Calcd. for C24H31NO5: C, 69.71; H, 7.56; N, 3.39. Found: C, 69.68; H,
7.52; N, 3.35%.
3.16.3.10 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-4-(2,5-dimethoxyphenyl)-7,7-
dimethyl-5-oxo-quinoline-3-carboxylate (YUG-230)
NH
OCH3
CH3
OO
H3CH3C
H Ha
bc
de f
g
h
ij
k
m
o1
235
6
78
9
10
1112
13
14
15
16
17 18
19 20
214
CH3
n
l 22
OCH3
OH3C
NH
OCH3
CH3
OO
H3CH3C
CH3
OCH3
OH3C
n'
13
Yield: 73%; mp 119-121 ºC; IR (cm-1): 3211 (N-H stretching of pyridine ring), 3084
(C-H stretching of aromatic ring), 2885 (C-H stretching of alkane), 1724 (C=O
stretching of carbonyl group of ester), 1658 (C=O stretching of carbonyl group of
cyclohexanone), 1597 (N-H deformation pyridine ring), 1267 (C-O-C- stretching of
ester), 1055 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.88 (s, 3H, Ha), 1.03 (s, 3H, Hb), 1.09-1.11 (d, 3H, Hc), 1.14-1.16 (d, 3H, Hd), 1.91-
1.95 (d, 1H, He), 2.09-2.12 (d, 1H, Hf), 2.40-2.43 (d, 2H, Hg), 3.52 (s, 3H, Hh), 3.64 (s,
3H, Hi), 3.69 (s, 3H, Hj), 3.82-3.94 (m, 1H, Hk), 5.03 (s, 1H, Hl), 6.58-6.61 (m, 1H,
Hm), 6.68-6.72 (dd, 2H, Hnn’, J = 8.28 Hz), 8.27 (s, 1H, Ho); 13C NMR (DMSO-d6) δ
ppm: 19.33, 19.52, 26.01, 27.00, 29.59, 31.80, 33.40, 50.33, 54.91, 55.33, 102.12,
107.94, 110.92, 111.21, 116.18, 135.69, 150.67, 151.30, 151.40, 152.56, 167.84,
193.74; MS: m/z 413; Anal. Calcd. for C24H31NO5: C, 69.71; H, 7.56; N, 3.39. Found:
C, 69.68; H, 7.52; N, 3.35%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
207
3.16.3.11 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-4-(3,4,5-trimethoxyphenyl)-
7,7-dimethyl-5-oxoquinoline-3-carboxylate (YUG-231)
NH
OCH3
CH3
OO
H3CH3C
CH3
OCH3
OH3C
OH3C
Yield: 82%; mp 214-216 ºC; MS: m/z 443; Anal. Calcd. for C25H33NO6: C, 67.70; H,
7.50; N, 3.16. Found: C, 67.66; H, 7.46; N, 3.12%.
3.16.3.12 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-5-oxo-4-phenylq-
uinoline-3-carboxylate (YUG-232)
NH
OCH3
CH3
OO
H3CH3C
CH3
Yield: 85%; mp 184-186 ºC; MS: m/z 353; Anal. Calcd. for C22H27NO3: C, 74.76; H,
7.70; N, 3.96. Found: C, 74.72; H, 7.66; N, 3.92%.
3.16.3.13 Methyl 4-(2,4-dichlorophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-
dimethyl-5-oxoquinoline-3-carboxylate (YUG-233)
NH
OCH3
CH3
OO
H3CH3C
CH3
Cl
Cl
Yield: 88%; mp 188-190 ºC; MS: m/z 421; Anal. Calcd. for C22H25Cl2NO3: C, 62.56;
H, 5.97; N, 3.32. Found: C, 62.52; H, 5.93; N, 3.28%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
208
3.16.3.14 Methyl 4-(2,4-dichlorophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-
dimethyl-5-oxoquinoline-3-carboxylate (YUG-234)
NH
OCH3
CH3
OO
H3CH3C
CH3
ClCl
Yield: 79%; mp 180-183 ºC; MS: m/z 421; Anal. Calcd. for C22H25Cl2NO3: C, 62.56;
H, 5.97; N, 3.32. Found: C, 62.50; H, 5.90; N, 3.20%.
3.16.3.15 Methyl 1,4,5,6,7,8-hexahydro-4-(3-hydroxyphenyl)-2-isopropyl-7,7-dimethyl
-5-oxoquinoline-3-carboxylate (YUG-235)
NH
OCH3
CH3
OO
H3CH3C
CH3
OH
Yield: 87%; mp 180-182 ºC; MS: m/z 369; Anal. Calcd. for C22H27NO4: C, 71.52; H,
7.37; N, 3.79. Found: C, 71.48; H, 7.34; N, 3.75%.
3.16.3.16 Methyl 1,4,5,6,7,8-hexahydro-4-(2-hydroxyphenyl)-2-isopropyl-7,7-dimethyl
-5-oxoquinoline-3-carboxylate (YUG-236)
NH
OCH3
CH3
OO
H3CH3C
CH3
OH
Yield: 80%; mp 188-191 ºC; MS: m/z 369; Anal. Calcd. for C22H27NO4: C, 71.52; H,
7.37; N, 3.79. Found: C, 71.47; H, 7.33; N, 3.74%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
209
3.16.3.17 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-4-(4-nitrophenyl)-5-
oxoquinoline-3-carboxylate (YUG-237)
NH
OCH3
CH3
OO
H3CH3C
CH3
NO2
Yield: 83%; mp 118-120 ºC; MS: m/z 398; Anal. Calcd. for C22H26N2O5: C, 66.32; H,
6.58; N, 7.03. Found: C, 66.28; H, 6.56; N, 7.00%.
3.16.3.18 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-4-(3-nitrophenyl)-
5-oxoquinoline-3-carboxylate (YUG-238)
a
bc
de f
g
h
ij
k
m
o
n
l
NH
OCH3
CH3
OO
H3CH3C
CH3
NO2
H H
Yield: 79%; mp 148-151 ºC; IR (cm-1): 3290 (N-H stretching of pyridine ring), 2956
(C-H stretching of aromatic ring), 2877 (C-H stretching of alkane), 1710 (C=O
stretching of carbonyl group of ester), 1647 (C=O stretching of carbonyl group of
cyclohexanone), 1599 (N-H deformation pyridine ring), 1265 (C-O-C- stretching of
ester), 1068 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.81 (s, 3H, Ha), 1.05 (s, 3H, Hb), 1.17-1.19 (d, 3H, Hc), 1.26-1.28 (d, 3H, Hd), 1.99-
2.03 (d, 1H, He), 2.18-2.22 (d, 1H, Hf), 2.45-2.47 (d, 2H, Hg), 3.55 (s, 3H, Hh), 4.15-
4.19 (m, 1H, Hi), 5.02 (s, 1H, Hj), 7.43-7.47 (t, 1H, Hk), 7.60-7.62 (d, 1H, Hl, J = 7.76
Hz), 7.93-7.96 (m, 1H, Hm), 7.99-8.00 (m, 1H, Hn), 8.55 (s, 1H, Ho); MS: m/z 398;
Anal. Calcd. for C22H26N2O5: C, 66.32; H, 6.58; N, 7.03. Found: C, 66.28; H, 6.56; N,
7.00%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
210
3.16.3.19 Methyl 1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-4-(2-nitrophenyl)-
5-oxoquinol ine-3-carboxylate (YUG-239)
a
bc
de f
g
h
ij
k
m
o
nl
NH
OCH3
CH3
OO
H3CH3C
CH3H H
NO2
Yield: 75%; mp 140-143 ºC; IR (cm-1): 3192 (N-H stretching of pyridine ring), 3049
(C-H stretching of aromatic ring), 2874 (C-H stretching of alkane), 1720 (C=O
stretching of carbonyl group of ester), 1641 (C=O stretching of carbonyl group of
cyclohexanone), 1614 (N-H deformation pyridine ring), 1224 (C-O-C- stretching of
ester), 1064 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm:
0.81 (s, 3H, Ha), 1.03 (s, 3H, Hb), 1.16-1.17 (d, 3H, Hc), 1.23-1.24 (d, 3H, Hd), 1.91-
1.95 (d, 1H, He), 2.12-2.15 (d, 1H, Hf), 2.43 (s, 2H, Hg), 3.49 (s, 3H, Hh), 3.95-3.99
(m, 1H, Hi), 5.59 (s, 1H, Hj), 7.23-7.28 (m, 1H, Hk), 7.39-7.41 (dd, 1H, Hl, J = 7.88
Hz), 7.47-7.51 (m, 1H, Hm), 7.64-7.66 (m, 1H, Hn, J = 8.08 Hz), 8.33 (s, 1H, Ho); MS:
m/z 398; Anal. Calcd. for C22H26N2O5: C, 66.32; H, 6.58; N, 7.03. Found: C, 66.27; H,
6.55; N, 6.99%.
3.16.3.20 Methyl 4-(3-bromophenyl)-1,4,5,6,7,8-hexahydro-2-isopropyl-7,7-dimethyl-
5-oxoquinoline-3-carboxylate (YUG-240)
NH
OCH3
CH3
OO
H3CH3C
CH3
Br
Yield: 77%; mp 151-153 ºC; MS: m/z 431; Anal. Calcd. for C22H26BrNO3: C, 61.12;
H, 6.06; N, 3.24. Found: C, 61.09; H, 6.03; N, 3.21%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
211
3.16.4 General procedure for the synthesis of 4-(aryl)-N-(aryl)-1,4,5,6,7,8-
hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxamide (YUG -241 to 250)
A mixture of the dimedone (0.01 mol), N-(aryl)-3-oxobutanamides (0.01 mol) and an
appropriate aromatic aldehyde (0.01 mol), ammonium acetate (0.01 mol) and L-
proline (0.001 mol) in 8-10 mL of EtOH was stirred for 30 to 40 min. After
completion of the reaction, the reaction mixture was filtered to give the solid products
YUG-241 to 250, which were recrystallized from ethanol.
3.16.4.1 N-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-2,7,7-trimethyl
-5-oxoquinoline-3-carboxamide (YUG-241)
a
bcd
e
f
g
h
ij
k
m
lNH
O
CH3
NH
O
O
F
CH3
H3CH3C
h'
i'
j'k'
Yield: 80%; mp 151-153 ºC; IR (cm-1): 3250 (N-H stretching of pyridine ring), 3053
(C-H stretching of aromatic ring), 2872 (C-H stretching of alkane), 1662 (C=O
stretching of carbonyl group of cyclohexanone), 1608 (C=O stretching of carbonyl
group of amide), 1030 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6)
δ ppm: 0.91 (s, 3H, Ha), 1.03 (s, 3H, Hb), 2.06 (s, 3H, Hc), 2.10-2.14 (d, 2H, Hd), 2.30-
2.33 (d, 2H, He), 3.66 (s, 3H, Hf), 4.91 (s, 2H, Hg), 6,67-6.70 (d, 2H, Hhh’, J = 8.60
Hz ), 6.92-6.97 (t, 2H, Hii’), 7.09-7.11 (d, 2H, Hjj’, J = 8.56 Hz), 7.51-7.54 (m, 2H,
Hkk’), 8.55 (s, 1H, Hl), 9.38 (s, 1H, Hm); MS: m/z 434; Anal. Calcd. for C26H27FN2O3:
C, 71.87; H, 6.26; N, 6.45. Found: C, 71.78; H, 6.12; N, 6.32%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
212
3.16.4.2 N-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-p-tolylqui-
noline-3-carboxamide (YUG-242)
a
b
c d
e
fg
h i
j k m
o
n
m'
l
NH
O
CH3
NH
O
CH3
F
H3CH3C
l'
Yield: 85%; mp 145-148 ºC; IR (cm-1): 3282 (N-H stretching of pyridine ring), 3064
(C-H stretching of aromatic ring), 2870 (C-H stretching of alkane), 1666 (C=O
stretching of carbonyl group of cyclohexanone), 1606 (C=O stretching of carbonyl
group of amide), 1010 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6)
δ ppm: 0.90 (s, 3H, Ha), 1.02 (s, 3H, Hb), 1.95-1.97 (d, 2H, Hc), 2.09 (s, 3H, Hd), 2.25
(s, 3H, He), 2.29-2.30 (d, 2H, Hf), 4.91 (s, 2H, Hg), 6,86-6.94 (m, 4H, Hh-k), 7.08-7.10
(d, 2H, Hll’, J = 8.00 Hz), 7.44-7.47 (m, 2H, Hmm’), 8.47 (s, 1H, Hn), 9.11 (s, 1H, Ho);
MS: m/z 418; Anal. Calcd. for C26H27FN2O2: C, 74.62; H, 6.50; N, 6.69. Found: C,
74.56; H, 6.38; N, 6.59%.
3.16.4.3 N,4-bis(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-
3-carboxamide (YUG-243)
NH
O
CH3
NH
O
F
F
H3CH3C
Yield: 89%; mp 150-152 ºC; MS: m/z 422; Anal. Calcd. for C25H24F2N2O2: C, 71.07;
H, 5.73; N, 6.63. Found: C, 70.93; H, 5.55; N, 6.57%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
213
3.16.4.4 4-(4-chlorophenyl)-N-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-
5-oxoquinoline-3-carboxamide (YUG-244)
NH
O
CH3
NH
O
Cl
F
H3CH3C
Yield: 77%; mp 151-153 ºC; MS: m/z 438; Anal. Calcd. for C25H24ClFN2O2: C, 68.41;
H, 5.51; N, 6.38. Found: C, 68.28; H, 5.39; N, 6.27%.
3.16.4.5 N-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-4-(4-nitrophenyl)-
5-oxoquinoline-3-carboxamide (YUG-245)
NH
O
CH3
NH
O
NO2
F
H3CH3C
Yield: 83%; mp 152-154 ºC; MS: m/z 449; Anal. Calcd. for C25H24FN3O4: C, 66.80;
H, 5.38; N, 9.35. Found: C, 66.68; H, 5.25; N, 9.22%.
3.16.4.6 N-(2-fluorophenyl)-1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-2,7,7-trimethyl
-5-oxoquinoline-3-carboxamide (YUG-246)
NH
O
CH3
NH
O
O
H3CH3C
F
H3C
Yield: 69%; mp 181-183 ºC; MS: m/z 434; Anal. Calcd. for C26H27FN2O3: C, 71.87;
H, 6.26; N, 6.45. Found: C, 71.78; H, 6.12; N, 6.32%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
214
3.16.4.7 N-(2-fluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-p-tolylquinol-
ine-3-carboxamide (YUG-247)
NH
O
CH3
NH
O
H3CH3C
F
CH3
Yield: 75%; mp 158-161 ºC; MS: m/z 418; Anal. Calcd. for C26H27FN2O2: C, 74.62;
H, 6.50; N, 6.69. Found: C, 74.56; H, 6.38; N, 6.59%.
3.16.4.8 N-(2-fluorophenyl)-4-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-
oxoquinoline-3-carboxamide (YUG-248)
ab
cd
e f
g
hi
jk
m
l
h'
j'
NH
O
CH3
NH
O
H3CH3C
F
F
g'
Yield: 80%; mp 167-168 ºC; IR (cm-1): 3271 (N-H stretching of pyridine ring), 3063
(C-H stretching of aromatic ring), 2877 (C-H stretching of alkane), 1643 (C=O
stretching of carbonyl group of cyclohexanone), 1602 (C=O stretching of carbonyl
group of amide), 1012 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6)
δ ppm: 0.88 (s, 3H, Ha), 1.02 (s, 3H, Hb), 2.01 (s, 3H, Hc), 2.12-2.14 (d, 2H, Hd), 2.28-
2.33 (d, 2H, He), 4.96 (s, 1H, Hf), 7.01-7.08 (m, 2H, Hgg’), 7.10-7.13 (m, 2H, Hhh’),
7.14-7.18 (m, 1H, Hi), 7.19-7.24 (m, 2H, Hjj’), 7.47-7.51 (m, 1H, Hk), 8.81 (s, 1H, Hl),
9.22 (s, 1H, Hm); MS: m/z 422; Anal. Calcd. for C25H24F2N2O2: C, 71.07; H, 5.73; N,
6.63. Found: C, 70.93; H, 5.55; N, 6.57%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
215
3.16.4.9 N-(2-fluorophenyl)-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-
oxoquinoline-3-carboxamide (YUG-249)
NH
O
CH3
NH
O
H3CH3C
F
Cl
Yield: 75%; mp 140-143 ºC; MS: m/z 438; Anal. Calcd. for C25H24ClFN2O2: C, 68.41;
H, 5.51; N, 6.38. Found: C, 68.28; H, 5.39; N, 6.27%.
3.16.4.10 N-(2-fluorophenyl)-4-(4-nitrophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trim-
ethyl-5-oxoquinoline-3-carboxamide (YUG-250)
NH
O
CH3
NH
O
H3CH3C
F
NO2
Yield: 88%; mp 174-176 ºC; MS: m/z 449; Anal. Calcd. for C25H24FN3O4: C, 66.80;
H, 5.38; N, 9.35. Found: C, 66.68; H, 5.25; N, 9.22%.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
216
3.17 Spectral Discussion 3.17.1 Mass spectral study
Mass spectra were recorded on Shimadzu GC-MS-QP-2010 model using Direct
Injection Probe technique. Systematic fragmentation pattern was observed in mass
spectral analysis. Molecular ion peak was observed in agreement with molecular
weight of respective compound.
3.17.2 IR spectral study
IR spectra were recorded on Shimadzu FT-IR-8400 model using KBr pellet method.
Various functional groups present in molecule were identified by characteristic
frequency obtained for them. For quinoline derivatives YUG-201 to 250,
confirmatory bands for secondary amine and carbonyl groups were observed at 3209-
3290 cm-1 and 1600-1750 cm-1 respectively, which suggested formation of desired
products YUG-301 to 340.
3.17.3 1H NMR spectral study 1H NMR spectra were recorded in DMSO-d6 solution on a Bruker Ac 400 MHz
spectrometer using TMS as an internal standard. Number of protons and their
chemical shifts were found to support the structure of the synthesized compounds. 1H NMR spectra confirmed the structures of quinolines YUG-301 to 340 on
the basis of following signals: a singlet for the methine proton of pyridine ring at
4.70-5.20 δ ppm, a singlet for the proton of secondary amine of pyridine ring at 8.00-
8.60 δ ppm and singlets for amide at 9.11-9.50 δ ppm. The aromatic ring protons and
J value were found to be in accordance with substitution pattern on phenyl ring.
3.17.4 13C NMR spectral study 13C NMR spectra were recorded in DMSO-d6 solution on a Bruker Ac 400 MHz
spectrometer. Number of carbons and their chemical shifts were found to support the
structure of the synthesized compounds. 13C NMR spectra confirmed the structures of
quinolines (YUG-201 to 240) on the basis of following signals: signal for chiral
carbon of pyridine ring was observed at 30-32 δ ppm. Signal for carbonyl carbon of
dimidone was observed at 193-194 δ ppm, indicates the involvement of dimidone in
cyclization process.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
217
3.18 X-Ray Diffraction Study of Quinoline Carboxylates 3.18.1 Single Crystal Analysis of Ethyl 4-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-
7,7- dimethyl-5-oxo-2-propylquinoline-3-carboxylate (YUG 203)
3.18.1.1 Procedure for the development of single crystal
In the present study, the pure, single spot (on TLC) compound was taken in ethanol
and heated with stirring till it dissolved. A small quantity of charcoal was added for
decolorizing. The solution was then heated to boiling and immediately filtered while
hot in corkable 50 ml conical flask using Whatmann filter paper. The flask was
corked and kept for several days. The crystals thus grown by thin film evaporation
technique were isolated and washed with chilled methanol. The functional groups and
proton and carbon framework of Ethyl 4-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-7,7-
dimethyl-5-oxo-2-propylquinoline-3-carboxylate was supported by IR, 1H NMR, 13C
NMR and Mass Spectral studies.
3.18.1.2 Single Crystal X-ray Diffraction and Structure Determination
X-ray single-crystal data was collected using Mo Kα radiation (λ=0.71073 Å)
radiation on a SMART APEX diffractometer equipped with CCD area detector. Data
collection, data reduction and structure solution/refinement were carried out using the
software package of SMART APEX. Table 1 shows the unit cell parameters and other
crystallographic details. All the structures were solved by direct method and refined
in a routine manner. In most of the cases, nonhydrogen atoms were treated
anisotropically. Whenever possible, the hydrogen atoms were located on a difference
Fourier map and refined. In other cases, the hydrogen atoms were geometrically
fixed. CCDC no. 890170 contains the supplementary crystallographic data for this
article. These data can be obtained from www.ccdc.cam.ac.uk/conts/retrieving.html
free of charge (or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or [email protected]).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
218
3.18.1.3 ORTEP diagram of the organic compound with atom numbering scheme
(40% probability factor for the thermal ellipsoids)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
219
3.18.1.4 Crystal data and structure refinement
Table 1
Empirical formula C23H28FNO3
Formula weight 385.46
Temperature 293(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Spacegroup P21/n
Cell dimensions a = 9.7195(16) Å b = 20.699(3) Å c = 10.6850(18) Å β = 96.717(3)º
Volume 2134.9(6) Å3
Z 4
Density(calculated) 1.199 Mg/m 3
Absorption coefficient 0.084 mm -1
F000 824
Crystal size 0.35 x 0.33 x 0.26 mm
Theta range for data collection 2.68º-28.00º
Index ranges -11 ≤ h ≤ 7 -25 ≤ k ≤ 16 -13 ≤ l ≤ 11
Reflections collected 9515
Independent reflections 4152 [R(int) = 0.0361]
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 4152/0/261
Goodness-of-fit on F2 1.165
Final R indices [I>2�(I)] R1 = 0.0720, wR2 = 0.1617
R indices (all data) R1 = 0.0884, wR2 = 0.1692
Largest diff. peak and hole 0.241 and -0.288 e.Å-3
Chapter 3 Quinoline-3-carboxylates/carboxamides…
220
3.18.1.5 Bond length (Å)
Table 2
No. Atom1 Atom2 Length No. Atom1 Atom2 Length 1 O1 C5 1.234(2) 30 C10 C11 1.529(4) 2 O2 C13 1.197(3) 31 C11 H11A 0.970(3) 3 O3 C13 1.345(3) 32 C11 H11B 0.970(3) 4 O3 C14 1.447(3) 33 C11 C12 1.500(5) 5 F1 C21 1.361(4) 34 C12 H12A 0.959(4) 6 N1 H1C 0.86(3) 35 C12 H12B 0.960(5) 7 N1 C1 1.364(3) 36 C12 H12C 0.961(4) 8 N1 C9 1.388(3) 37 C14 H14A 0.970(3) 9 C1 C2 1.498(3) 38 C14 H14B 0.969(3) 10 C1 C6 1.353(3) 39 C14 C15 1.492(4) 11 C2 H2A 0.969(2) 40 C15 H15A 0.959(3) 12 C2 H2B 0.970(2) 41 C15 H15B 0.960(3) 13 C2 C3 1.522(3) 42 C15 H15C 0.960(3) 14 C3 C4 1.528(3) 43 C16 H16A 0.960(3) 15 C3 C16 1.529(3) 44 C16 H16B 0.959(3) 16 C3 C17 1.529(4) 45 C16 H16C 0.960(3) 17 C4 H4A 0.969(2) 46 C17 H17A 0.960(3) 18 C4 H4B 0.971(2) 47 C17 H17B 0.960(3) 19 C4 C5 1.509(3) 48 C17 H17C 0.961(3) 20 C5 C6 1.435(3) 49 C18 C19 1.379(3) 21 C6 C7 1.516(3) 50 C18 C23 1.384(3) 22 C7 H7 0.980(2) 51 C19 H19 0.930(2) 23 C7 C8 1.522(3) 52 C19 C20 1.390(4) 24 C7 C18 1.523(3) 53 C20 H20 0.930(3) 25 C8 C9 1.355(3) 54 C20 C21 1.357(4) 26 C8 C13 1.471(3) 55 C21 C22 1.355(5) 27 C9 C10 1.497(3) 56 C22 H22 0.930(3) 28 C10 H10A 0.970(2) 57 C22 C23 1.385(5) 29 C10 H10B 0.970(3) 58 C23 H23 0.929(3)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
221
3.18.1.6 Bond angles (º)
Table 3
No. Atom1 Atom2 Atom3 Angle No. Atom1 Atom2 Atom3 Angle 1 C13 O3 C14 116.5(2) 43 C8 C9 C10 128.1(2) 2 H1C N1 C1 118(2) 44 C9 C10 H10A 109.4(2) 3 H1C N1 C9 118(2) 45 C9 C10 H10B 109.4(2) 4 C1 N1 C9 122.6(2) 46 C9 C10 C11 111.0(2) 5 N1 C1 C2 116.2(2) 47 H10A C10 H10B 108.0(2) 6 N1 C1 C6 120.0(2) 48 H10A C10 C11 109.4(2) 7 C2 C1 C6 123.8(2) 49 H10B C10 C11 109.5(2) 8 C1 C2 H2A 108.9(2) 50 C10 C11 H11A 108.9(3) 9 C1 C2 H2B 108.8(2) 51 C10 C11 H11B 108.8(3) 10 C1 C2 C3 113.4(2) 52 C10 C11 C12 113.6(3) 11 H2A C2 H2B 107.8(2) 53 H11A C11 H11B 107.7(3) 12 H2A C2 C3 108.9(2) 54 H11A C11 C12 108.8(3) 13 H2B C2 C3 108.9(2) 55 H11B C11 C12 108.9(3) 14 C2 C3 C4 107.5(2) 56 C11 C12 H12A 109.5(4) 15 C2 C3 C16 109.5(2) 57 C11 C12 H12B 109.5(4) 16 C2 C3 C17 110.6(2) 58 C11 C12 H12C 109.5(4) 17 C4 C3 C16 109.7(2) 59 H12A C12 H12B 109.5(4) 18 C4 C3 C17 110.1(2) 60 H12A C12 H12C 109.4(4) 19 C16 C3 C17 109.5(2) 61 H12B C12 H12C 109.4(4) 20 C3 C4 H4A 108.7(2) 62 O2 C13 O3 121.6(2) 21 C3 C4 H4B 108.6(2) 63 O2 C13 C8 127.4(2) 22 C3 C4 C5 114.3(2) 64 O3 C13 C8 111.0(2) 23 H4A C4 H4B 107.6(2) 65 O3 C14 H14A 110.2(2) 24 H4A C4 C5 108.7(2) 66 O3 C14 H14B 110.2(2) 25 H4B C4 C5 108.7(2) 67 O3 C14 C15 107.4(2) 26 O1 C5 C4 119.2(2) 68 H14A C14 H14B 108.5(2) 27 O1 C5 C6 122.1(2) 69 H14A C14 C15 110.2(2) 28 C4 C5 C6 118.7(2) 70 H14B C14 C15 110.3(2) 29 C1 C6 C5 119.3(2) 71 C14 C15 H15A 109.5(3) 30 C1 C6 C7 121.0(2) 72 C14 C15 H15B 109.5(3) 31 C5 C6 C7 119.7(2) 73 C14 C15 H15C 109.4(3) 32 C6 C7 H7 107.5(2) 74 H15A C15 H15B 109.5(3) 33 C6 C7 C8 110.2(2) 75 H15A C15 H15C 109.5(3) 34 C6 C7 C18 109.8(2) 76 H15B C15 H15C 109.4(3) 35 H7 C7 C8 107.6(2) 77 C3 C16 H16A 109.4(2) 36 H7 C7 C18 107.5(2) 78 C3 C16 H16B 109.5(2) 37 C8 C7 C18 113.9(2) 79 C3 C16 H16C 109.5(2) 38 C7 C8 C9 121.2(2) 80 H16A C16 H16B 109.5(3) 39 C7 C8 C13 118.0(2) 81 H16A C16 H16C 109.4(3) 40 C9 C8 C13 120.7(2) 82 H16B C16 H16C 109.4(3) 41 N1 C9 C8 119.3(2) 83 C3 C17 H17A 109.5(3) 42 N1 C9 C10 112.5(2) 84 C3 C17 H17B 109.5(3) 85 C3 C17 H17C 109.4(3) 96 C19 C20 C21 118.4(3) 86 H17A C17 H17B 109.5(3) 97 H20 C20 C21 120.8(3) 87 H17A C17 H17C 109.4(3) 98 F1 C21 C20 118.8(3) 88 H17B C17 H17C 109.5(3) 99 F1 C21 C22 119.1(3) 89 C7 C18 C19 121.5(2) 100 C20 C21 C22 122.1(3) 90 C7 C18 C23 121.0(2) 101 C21 C22 H22 120.5(4) 91 C19 C18 C23 117.4(2) 102 C21 C22 C23 119.0(3) 92 C18 C19 H19 119.1(2) 103 H22 C22 C23 120.5(3) 93 C18 C19 C20 121.8(2) 104 C18 C23 C22 121.3(3) 94 H19 C19 C20 119.2(3) 105 C18 C23 H23 119.3(3) 95 C19 C20 H20 120.8(3) 106 C22 C23 H23 119.4(3)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
222
3.18.1.7 Atomic coordinates and equivalent thermal parameters of the non-
hydrogen atoms
Table 4
No. Label Xfrac + ESD Yfrac + ESD Zfrac + ESD Uequiv 1 O1 -0.14265(17) 0.19322(9) 0.61505(15) 0.0528 2 O2 0.1861(2) 0.45586(9) 0.61399(18) 0.0639 3 O3 0.09487(19) 0.38672(8) 0.46842(14) 0.0505 4 F1 0.3418(2) 0.13292(11) 0.2794(2) 0.1050 5 N1 0.22400(19) 0.29370(9) 0.86433(18) 0.0395 6 H1C 0.269(3) 0.2962(12) 0.938(3) 0.0530 7 C1 0.1288(2) 0.24538(10) 0.84217(18) 0.0318 8 C2 0.1166(2) 0.19985(11) 0.9493(2) 0.0394 9 H2A 0.0634 0.2205 1.0093 0.0470 10 H2B 0.2085 0.1912 0.9918 0.0470 11 C3 0.0479(2) 0.13598(11) 0.9083(2) 0.0397 12 C4 -0.0839(2) 0.15156(11) 0.8210(2) 0.0411 13 H4A -0.1241 0.1115 0.7870 0.0490 14 H4B -0.1502 0.1714 0.8704 0.0490 15 C5 -0.0619(2) 0.19592(11) 0.71299(19) 0.0359 16 C6 0.0499(2) 0.24159(10) 0.72938(18) 0.0317 17 C7 0.0784(2) 0.28447(11) 0.62026(19) 0.0346 18 H7 -0.0113 0.2980 0.5766 0.0420 19 C8 0.1554(2) 0.34507(10) 0.66916(19) 0.0355 20 C9 0.2269(2) 0.34696(10) 0.7858(2) 0.0362 21 C10 0.3065(3) 0.40236(12) 0.8486(2) 0.0460 22 H10A 0.3393 0.4300 0.7850 0.0550 23 H10B 0.3866 0.3860 0.9018 0.0550 24 C11 0.2163(3) 0.44181(15) 0.9284(3) 0.0686 25 H11A 0.1395 0.4601 0.8737 0.0820 26 H11B 0.1781 0.4131 0.9873 0.0820 27 C12 0.2929(5) 0.49546(18) 1.0008(4) 0.1079 28 H12A 0.3643 0.4776 1.0604 0.1620 29 H12B 0.2296 0.5199 1.0447 0.1620 30 H12C 0.3339 0.5233 0.9435 0.1620 31 C13 0.1491(2) 0.40202(12) 0.5863(2) 0.0406 32 C14 0.0867(3) 0.43835(13) 0.3766(2) 0.0598 33 H14A 0.1771 0.4579 0.3745 0.0720 34 H14B 0.0229 0.4714 0.3983 0.0720 35 C15 0.0369(3) 0.40959(17) 0.2514(3) 0.0716 36 H15A 0.1019 0.3777 0.2301 0.1070 37 H15B 0.0284 0.4429 0.1885 0.1070 38 H15C -0.0518 0.3897 0.2551 0.1070 39 C16 0.0105(3) 0.09957(13) 1.0241(2) 0.0577 40 H16A 0.0937 0.0889 1.0777 0.0870 41 H16B -0.0383 0.0607 0.9979 0.0870 42 H16C -0.0473 0.1263 1.0696 0.0870 43 C17 0.1449(3) 0.09451(14) 0.8390(3) 0.0668 44 H17A 0.1660 0.1168 0.7648 0.1000 45 H17B 0.1007 0.0541 0.8154 0.1000 46 H17C 0.2291 0.0866 0.8934 0.1000 47 C18 0.1526(2) 0.24590(11) 0.52702(19) 0.0375 48 C19 0.2786(3) 0.21667(13) 0.5627(2) 0.0495 49 H19 0.3212 0.2225 0.6445 0.0590 50 C20 0.3436(3) 0.17878(14) 0.4797(3) 0.0628 51 H20 0.4285 0.1593 0.5052 0.0750 52 C21 0.2801(4) 0.17085(14) 0.3607(3) 0.0661 53 C22 0.1574(4) 0.19938(17) 0.3204(3) 0.0719
Chapter 3 Quinoline-3-carboxylates/carboxamides…
223
54 H22 0.1168 0.1938 0.2379 0.0860 55 C23 0.0934(3) 0.23695(14) 0.4040(2) 0.0544 56 H23 0.0091 0.2565 0.3770 0.0650
Chapter 3 Quinoline-3-carboxylates/carboxamides…
224
3.18.1.8 Hydrogen-bonding geometry (Å)
Table 5
D-H...A D-H H-A D-A D-H...A Symmetry codes
N3-H3C ...N1 0.860 2.139 2.989 169.83 1/2-x,1.5-y, -z
N1-H2C ...N3 0.769 2.234 2.989 167.31 1/2-x,1.5-y, -z
Note: D-H and H-A distances are essentially standard values and are not derived from
the experiment.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
225
3.18.2 Single Crystal Analysis of Ethyl 1,4,5,6,7,8-hexahydro-4-(2,5-
dimethoxyphenyl)-7,7-dimethyl-5-oxo-2-propylquinoline-3-carboxylate (YUG-210)
3.18.2.1 Procedure for the development of single crystal
In the present study, the pure, single spot (on TLC) compound was taken in ethanol
and heated with stirring till it dissolved. A small quantity of charcoal was added for
decolorizing. The solution was then heated to boiling and immediately filtered while
hot in corkable 50 ml conical flask using Whatmann filter paper. The flask was
corked and kept for several days. The crystals thus grown by thin film evaporation
technique were isolated and washed with chilled methanol. The functional groups and
proton and carbon framework of Ethyl 1,4,5,6,7,8-hexahydro-4-(2,5-
dimethoxyphenyl)-7,7-dimethyl-5-oxo-2-propylquinoline-3-carboxylate was
supported by IR, 1H NMR, 13C NMR and Mass Spectral studies.
3.18.2.2 Single Crystal X-ray Diffraction and Structure Determination
X-ray single-crystal data was collected using Mo Kα radiation (λ=0.71073 Å)
radiation on a SMART APEX diffractometer equipped with CCD area detector. Data
collection, data reduction and structure solution/refinement were carried out using the
software package of SMART APEX. Table 1 shows the unit cell parameters and other
crystallographic details. All the structures were solved by direct method and refined
in a routine manner. In most of the cases, nonhydrogen atoms were treated
anisotropically. Whenever possible, the hydrogen atoms were located on a difference
Fourier map and refined. In other cases, the hydrogen atoms were geometrically
fixed. CCDC no. 890404 contains the supplementary crystallographic data for this
article. These data can be obtained from www.ccdc.cam.ac.uk/conts/retrieving.html
free of charge (or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or [email protected]).
Chapter 3 Quinoline-3-carboxylates/carboxamides…
226
3.18.2.3 ORTEP diagram of the organic compound with atom numbering scheme
(40% probability factor for the thermal ellipsoids)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
227
3.18.2.4 Crystal data and structure refinement
Table 1
Empirical formula C25H33NO5
Formula weight 427.52
Temperature 293(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Spacegroup C2/c
Cell dimensions a = 21.183(4) Å b = 14.331(3) Å c = 15.438(3) Å β = 93.904(3)º
Volume 4675.5(14) Å3
Z 8
Density(calculated) 1.215 Mg/m 3
Absorption coefficient 0.084 mm -1
F000 1840
Crystal size 0.48 x 0.34 x 0.28 mm
Theta range for data collection 2.64º-27.64º
Index ranges -15 ≤ h ≤ 26 -16 ≤ k ≤ 17 -11 ≤ l ≤ 19
Reflections collected 10270
Independent reflections 4275 [R(int) = 0.0220]
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 4275/0/291
Goodness-of-fit on F2 1.031
Final R indices [I>2�(I)] R1 = 0.0502, wR2 = 0.1350
R indices (all data) R1 = 0.0625, wR2 = 0.1446
Extinction coefficient 0.0081(6)
Largest diff. peak and hole 0.230 and -0.203 e.Å-3
Chapter 3 Quinoline-3-carboxylates/carboxamides…
228
3.18.2.5 Bond length (Å)
Table 2
No. Atom1 Atom2 Length No. Atom1 Atom2 Length 1 O1 C5 1.233(2) 34 C11 H11A 0.970(3) 2 O2 C13 1.202(3) 35 C11 H11B 0.970(2) 3 O3 C13 1.328(2) 36 C11 C12 1.513(4) 4 O3 C14 1.452(3) 37 C12 H12A 0.960(4) 5 O4 C20 1.376(2) 38 C12 H12B 0.960(4) 6 O4 C24 1.420(3) 39 C12 H12C 0.961(3) 7 O5 C23 1.370(2) 40 C14 H14A 0.969(3) 8 O5 C25 1.410(3) 41 C14 H14B 0.970(3) 9 N1 H1C 0.87(2) 42 C14 C15 1.453(4) 10 N1 C1 1.358(2) 43 C15 H15A 0.961(4) 11 N1 C9 1.396(2) 44 C15 H15B 0.959(3) 12 C1 C2 1.502(2) 45 C15 H15C 0.960(4) 13 C1 C6 1.358(2) 46 C16 H16A 0.960(2) 14 C2 H2A 0.970(2) 47 C16 H16B 0.961(3) 15 C2 H2B 0.971(2) 48 C16 H16C 0.960(2) 16 C2 C3 1.526(2) 49 C17 H17A 0.960(2) 17 C3 C4 1.529(2) 50 C17 H17B 0.960(2) 18 C3 C16 1.531(3) 51 C17 H17C 0.960(2) 19 C3 C17 1.524(3) 52 C18 C19 1.375(2) 20 C4 H4A 0.970(2) 53 C18 C23 1.405(2) 21 C4 H4B 0.970(2) 54 C19 H19 0.930(2) 22 C4 C5 1.514(2) 55 C19 C20 1.390(3) 23 C5 C6 1.440(2) 56 C20 C21 1.373(3) 24 C6 C7 1.522(2) 57 C21 H21 0.929(2) 25 C7 H7 0.979(1) 58 C21 C22 1.374(3) 26 C7 C8 1.524(2) 59 C22 H22 0.930(2) 27 C7 C18 1.531(2) 60 C22 C23 1.384(3) 28 C8 C9 1.343(2) 61 C24 H24A 0.959(3) 29 C8 C13 1.482(2) 62 C24 H24B 0.960(3) 30 C9 C10 1.505(2) 63 C24 H24C 0.960(3) 31 C10 H10A 0.969(2) 64 C25 H25A 0.960(2) 32 C10 H10B 0.970(2) 65 C25 H25B 0.961(2) 33 C10 C11 1.510(3) 66 C25 H25C 0.960(3)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
229
3.18.2.6 Bond angles (º)
Table 3 No. Atom1 Atom2 Atom3 Angle No. Atom1 Atom2 Atom3 Angle 1 C13 O3 C14 116.2(2) 43 N1 C9 C8 119.9(1) 2 C20 O4 C24 117.4(2) 44 N1 C9 C10 113.0(1) 3 C23 O5 C25 117.4(2) 45 C8 C9 C10 127.1(2) 4 H1C N1 C1 117(1) 46 C9 C10 H10A 109.0(2) 5 H1C N1 C9 119(1) 47 C9 C10 H10B 109.0(2) 6 C1 N1 C9 122.7(1) 48 C9 C10 C11 113.1(2) 7 N1 C1 C2 115.6(1) 49 H10A C10 H10B 107.7(2) 8 N1 C1 C6 120.9(1) 50 H10A C10 C11 109.0(2) 9 C2 C1 C6 123.5(1) 51 H10B C10 C11 108.9(2) 10 C1 C2 H2A 108.9(1) 52 C10 C11 H11A 108.8(2) 11 C1 C2 H2B 109.0(1) 53 C10 C11 H11B 108.9(2) 12 C1 C2 C3 113.0(1) 54 C10 C11 C12 113.5(2) 13 H2A C2 H2B 107.8(2) 55 H11A C11 H11B 107.7(2) 14 H2A C2 C3 109.0(1) 56 H11A C11 C12 108.9(2) 15 H2B C2 C3 109.0(1) 57 H11B C11 C12 108.9(2) 16 C2 C3 C4 106.8(1) 58 C11 C12 H12A 109.4(3) 17 C2 C3 C16 109.3(1) 59 C11 C12 H12B 109.5(3) 18 C2 C3 C17 110.8(2) 60 C11 C12 H12C 109.5(3) 19 C4 C3 C16 109.4(2) 61 H12A C12 H12B 109.5(4) 20 C4 C3 C17 110.2(2) 62 H12A C12 H12C 109.5(4) 21 C16 C3 C17 110.3(2) 63 H12B C12 H12C 109.5(4) 22 C3 C4 H4A 108.5(2) 64 O2 C13 O3 121.9(2) 23 C3 C4 H4B 108.5(2) 65 O2 C13 C8 126.7(2) 24 C3 C4 C5 115.0(1) 66 O3 C13 C8 111.4(2) 25 H4A C4 H4B 107.6(2) 67 O3 C14 H14A 110.2(2) 26 H4A C4 C5 108.5(2) 68 O3 C14 H14B 110.2(2) 27 H4B C4 C5 108.5(2) 69 O3 C14 C15 107.6(2) 28 O1 C5 C4 119.1(1) 70 H14A C14 H14B 108.4(2) 29 O1 C5 C6 122.5(1) 71 H14A C14 C15 110.2(2) 30 C4 C5 C6 118.3(1) 72 H14B C14 C15 110.2(2) 31 C1 C6 C5 119.4(1) 73 C14 C15 H15A 109.5(3) 32 C1 C6 C7 121.6(1) 74 C14 C15 H15B 109.5(3) 33 C5 C6 C7 118.9(1) 75 C14 C15 H15C 109.5(3) 34 C6 C7 H7 106.9(1) 76 H15A C15 H15B 109.5(3) 35 C6 C7 C8 110.8(1) 77 H15A C15 H15C 109.4(3) 36 C6 C7 C18 110.8(1) 78 H15B C15 H15C 109.4(3) 37 H7 C7 C8 107.0(1) 79 C3 C16 H16A 109.5(2) 38 H7 C7 C18 106.9(1) 80 C3 C16 H16B 109.5(2) 39 C8 C7 C18 114.0(1) 81 C3 C16 H16C 109.5(2) 40 C7 C8 C9 122.4(1) 82 H16A C16 H16B 109.5(2) 41 C7 C8 C13 117.7(1) 83 H16A C16 H16C 109.5(2) 42 C9 C8 C13 119.8(1) 84 H16B C16 H16C 109.4(2) 85 C3 C17 H17A 109.5(2) 103 C21 C22 H22 119.3(2) 86 C3 C17 H17B 109.4(2) 104 C21 C22 C23 121.4(2) 87 C3 C17 H17C 109.5(2) 105 H22 C22 C23 119.3(2) 88 H17A C17 H17B 109.5(2) 106 O5 C23 C18 116.8(1) 89 H17A C17 H17C 109.5(2) 107 O5 C23 C22 123.9(2) 90 H17B C17 H17C 109.5(2) 108 C18 C23 C22 119.3(2) 91 C7 C18 C19 119.5(1) 109 O4 C24 H24A 109.5(2) 92 C7 C18 C23 122.3(1) 110 O4 C24 H24B 109.5(2) 93 C19 C18 C23 118.1(1) 111 O4 C24 H24C 109.5(2) 94 C18 C19 H19 118.9(2) 112 H24A C24 H24B 109.4(3) 95 C18 C19 C20 122.2(2) 113 H24A C24 H24C 109.5(3) 96 H19 C19 C20 118.9(2) 114 H24B C24 H24C 109.4(3) 97 O4 C20 C19 115.4(2) 115 O5 C25 H25A 109.5(2)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
230
98 O4 C20 C21 125.6(2) 116 O5 C25 H25B 109.4(2) 99 C19 C20 C21 119.0(2) 117 O5 C25 H25C 109.5(2) 100 C20 C21 H21 120.0(2) 118 H25A C25 H25B 109.4(2) 101 C20 C21 C22 119.9(2) 119 H25A C25 H25C 109.5(2) 102 H21 C21 C22 120.1(2) 120 H25B C25 H25C 109.5(2)
Chapter 3 Quinoline-3-carboxylates/carboxamides…
231
3.18.2.7 Atomic coordinates and equivalent thermal parameters of the non-
hydrogen atoms
Table 4 No. Label Xfrac + ESD Yfrac + ESD Zfrac + ESD Uequiv 1 O1 0.25790(6) 1.10204(7) 0.24643(8) 0.0487 2 O2 0.00282(8) 0.87188(12) 0.12810(16) 0.1069 3 O3 0.03473(6) 1.01742(9) 0.15059(9) 0.0610 4 O4 0.14766(8) 1.27305(10) 0.01456(9) 0.0765 5 O5 0.19466(7) 0.89432(9) 0.02143(8) 0.0611 6 N1 0.19292(6) 0.79152(9) 0.20313(9) 0.0417 7 H1C 0.2032(9) 0.7337(13) 0.2145(11) 0.0470 8 C1 0.23791(7) 0.85756(10) 0.22103(9) 0.0366 9 C2 0.30172(8) 0.82149(11) 0.25374(11) 0.0440 10 H2A 0.3103 0.7640 0.2235 0.0530 11 H2B 0.3009 0.8071 0.3151 0.0530 12 C3 0.35510(8) 0.89068(11) 0.24114(13) 0.0493 13 C4 0.33457(8) 0.98400(12) 0.27816(13) 0.0530 14 H4A 0.3346 0.9783 0.3408 0.0640 15 H4B 0.3657 1.0309 0.2657 0.0640 16 C5 0.27000(8) 1.01795(10) 0.24361(10) 0.0392 17 C6 0.22393(7) 0.94971(10) 0.21276(9) 0.0355 18 C7 0.15943(7) 0.98293(10) 0.17563(9) 0.0369 19 H7 0.1443 1.0286 0.2166 0.0440 20 C8 0.11196(7) 0.90287(11) 0.17068(10) 0.0413 21 C9 0.12937(8) 0.81353(11) 0.18352(10) 0.0427 22 C10 0.08709(9) 0.72905(12) 0.17846(13) 0.0565 23 H10A 0.0453 0.7469 0.1944 0.0680 24 H10B 0.1036 0.6831 0.2202 0.0680 25 C11 0.08150(12) 0.68509(16) 0.08935(16) 0.0812 26 H11A 0.1218 0.6571 0.0779 0.0970 27 H11B 0.0726 0.7336 0.0464 0.0970 28 C12 0.03041(16) 0.6114(2) 0.0790(3) 0.1288 29 H12A 0.0393 0.5625 0.1206 0.1930 30 H12B 0.0294 0.5860 0.0214 0.1930 31 H12C -0.0099 0.6389 0.0885 0.1930 32 C13 0.04462(9) 0.92595(13) 0.14833(13) 0.0547 33 C14 -0.02831(10) 1.04887(17) 0.12143(18) 0.0780 34 H14A -0.0579 1.0345 0.1647 0.0940 35 H14B -0.0424 1.0178 0.0677 0.0940 36 C15 -0.02528(15) 1.1491(2) 0.1080(3) 0.1277 37 H15A -0.0156 1.1796 0.1627 0.1920 38 H15B -0.0653 1.1710 0.0831 0.1920 39 H15C 0.0071 1.1630 0.0694 0.1920 40 C16 0.41543(9) 0.85705(14) 0.29198(17) 0.0701 41 H16A 0.4282 0.7983 0.2690 0.1050 42 H16B 0.4074 0.8497 0.3521 0.1050 43 H16C 0.4485 0.9021 0.2868 0.1050 44 C17 0.36654(11) 0.90107(15) 0.14522(15) 0.0721 45 H17A 0.3999 0.9453 0.1387 0.1080 46 H17B 0.3285 0.9226 0.1142 0.1080 47 H17C 0.3784 0.8418 0.1224 0.1080 48 C18 0.16516(7) 1.03395(11) 0.08940(9) 0.0392 49 C19 0.15356(8) 1.12826(11) 0.08453(11) 0.0450 50 H19 0.1410 1.1591 0.1335 0.0540 51 C20 0.15993(9) 1.17905(13) 0.00889(12) 0.0530 52 C21 0.17771(10) 1.13344(15) -0.06378(12) 0.0608 53 H21 0.1818 1.1663 -0.1150 0.0730
Chapter 3 Quinoline-3-carboxylates/carboxamides…
232
54 C22 0.18940(10) 1.03914(15) -0.06065(12) 0.0591 55 H22 0.2014 1.0088 -0.1102 0.0710 56 C23 0.18377(8) 0.98833(12) 0.01470(10) 0.0465 57 C24 0.15859(14) 1.32894(18) -0.05889(18) 0.0951 58 H24A 0.2008 1.3186 -0.0756 0.1430 59 H24B 0.1535 1.3936 -0.0446 0.1430 60 H24C 0.1288 1.3125 -0.1061 0.1430 61 C25 0.20875(13) 0.84643(17) -0.05466(14) 0.0799 62 H25A 0.1774 0.8610 -0.1005 0.1200 63 H25B 0.2087 0.7804 -0.0439 0.1200 64 H25C 0.2497 0.8652 -0.0713 0.1200
Chapter 3 Quinoline-3-carboxylates/carboxamides…
233
3.18.2.8 Hydrogen-bonding geometry (Å)
Table 5
D-H...A D-H H-A D-A D-H...A Symmetry codes
N1-H1C ...O1 0.872 2.130 2.992 170.38 1/2+x,1/2-y,1/2+z
Note: D-H and H-A distances are essentially standard values and are not derived from
the experiment.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
234
Mass Spectrum of YUG-201
IR Spectrum of YUG-201
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100%T
3275
.24
3211
.59
3086
.21
2958
.90
2933
.83
2906
.82
2874
.03
1697
.41
9 214
58.2
313
83.0
113
03.9
212
82.7
112
55.7
09
1168
.90
1145
.75
1112
.96
1084
.03 10
57.0
310
41.6
097
4.08
852.
56
759.
98
653.
8959
0.24
420.
50
YUG-201
Chapter 3 Quinoline-3-carboxylates/carboxamides…
235
1H NMR Spectrum of YUG-201
Expanded 1H NMR Spectrum of YUG-201
Chapter 3 Quinoline-3-carboxylates/carboxamides…
236
Expanded 1H NMR Spectrum of YUG-201
Expanded 1H NMR Spectrum of YUG-201
Chapter 3 Quinoline-3-carboxylates/carboxamides…
237
Mass Spectrum of YUG-202
IR Spectrum of YUG-202
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100
%T
3273
.31 32
54.0
232
13.5
130
88.1
429
60.8
329
37.6
8 2885
.60
1699
.34
1629
.90
1608
.69
1491
.02
1458
.23 14
38.9
413
81.0
813
05.8
512
82.7
112
11.3
411
93.9
811
68.9
011
43.8
311
11.0
3 1085
.96
1060
.88
1035
.81
850.
6480
6.27
759.
98
653.
89
455.
2242
6.28
YUG-202
Chapter 3 Quinoline-3-carboxylates/carboxamides…
238
1H NMR Spectrum of YUG-202
Expanded 1H NMR Spectrum of YUG-202
Chapter 3 Quinoline-3-carboxylates/carboxamides…
239
Expanded 1H NMR Spectrum of YUG-202
Expanded 1H NMR Spectrum of YUG-202
Chapter 3 Quinoline-3-carboxylates/carboxamides…
240
Mass Spectrum of YUG-203
IR Spectrum of YUG-203
400600800100012001400160018002000240028003200360040001/cm
10
20
30
40
50
60
70
80
90
100%T
3273
.31
3213
.51
3088
.14
2960
.83
2937
.68
2912
.61
2889
.46
2870
.17
1703
.20
1649
.19
1627
.97
1606
.76
1498
.74
1456
.30
1429
.30
1381
.08
1307
.78
1282
.71
1215
.19
1190
.12
1155
.40
1112
.96 10
84.0
310
60.8
810
33.8
897
6.01
885.
3685
4.49
763.
8473
6.83
686.
6865
3.89
YUG-203
Chapter 3 Quinoline-3-carboxylates/carboxamides…
241
1H NMR Spectrum of YUG-203
Expanded 1H NMR Spectrum of YUG-203
Chapter 3 Quinoline-3-carboxylates/carboxamides…
242
Expanded 1H NMR Spectrum of YUG-203
Expanded 1H NMR Spectrum of YUG-203
Chapter 3 Quinoline-3-carboxylates/carboxamides…
243
Mass Spectrum of YUG-204
IR Spectrum of YUG-204
400600800100012001400160018002000240028003200360040001/cm
45
52.5
60
67.5
75
82.5
90
97.5
%T
3273
.31
3257
.88
3213
.51
3088
.14
2960
.83
2872
.10
1703
.20
1649
.19
1629
.90
1608
.69
1491
.02
1456
.30
1381
.08
1307
.78
1282
.71
1211
.34
1192
.05
1168
.90
1145
.75
1112
.96
1084
.03
1060
.88 10
33.8
8
842.
9276
7.69
742.
6267
3.18
453.
2942
8.21
YUG-204
Chapter 3 Quinoline-3-carboxylates/carboxamides…
244
1H NMR Spectrum of YUG-204
Expanded 1H NMR Spectrum of YUG-204
Chapter 3 Quinoline-3-carboxylates/carboxamides…
245
Expanded 1H NMR Spectrum of YUG-204
13C NMR Spectrum of YUG-204
Chapter 3 Quinoline-3-carboxylates/carboxamides…
246
Mass Spectrum of YUG-205
IR Spectrum of YUG-205
400600800100012001400160018002000240028003200360040001/cm
-0
15
30
45
60
75
90
105
%T
3273
.31
3203
.87
3078
.49
2991
.69
2958
.90
2895
.25
2870
.17
2816
.16
1674
.27
1610
.61
1572
.04
1531
.53
1487
.17
1454
.38
1423
.51
1386
.86
1375
.29
1330
.93
1305
.85
1224
.84
1170
.83
1145
.75
1114
.89 10
82.1
0 1058
.96
1012
.66
974.
0888
1.50
798.
5677
3.48
746.
48 717.
5469
2.47
651.
96
408
92
YUG-205
Chapter 3 Quinoline-3-carboxylates/carboxamides…
247
1H NMR Spectrum of YUG-205
Expanded 1H NMR Spectrum of YUG-205
Chapter 3 Quinoline-3-carboxylates/carboxamides…
248
Expanded 1H NMR Spectrum of YUG-205
Expanded 1H NMR Spectrum of YUG-205
Chapter 3 Quinoline-3-carboxylates/carboxamides…
249
13C NMR Spectrum of YUG-205
Mass Spectrum of YUG-206
Chapter 3 Quinoline-3-carboxylates/carboxamides…
250
IR Spectrum of YUG-206
400600800100012001400160018002000240028003200360040001/cm
10
20
30
40
50
60
70
80
90
100%T
3275
.24 32
52.0
932
09.6
630
86.2
129
60.8
328
72.1
028
16.1
6
1701
.27
1649
.19
1608
.69
1489
.10
1458
.23
1381
.08
1305
.85
1280
.78
1211
.34
1145
.75
1112
.96
1084
.03 10
62.8
110
35.8
197
6.01
885.
3684
2.92
767.
6974
2.62
408
92
YUG-206
1H NMR Spectrum of YUG-206
Chapter 3 Quinoline-3-carboxylates/carboxamides…
251
Expanded 1H NMR Spectrum of YUG-206
Expanded 1H NMR Spectrum of YUG-206
Chapter 3 Quinoline-3-carboxylates/carboxamides…
252
Expanded 1H NMR Spectrum of YUG-206
13C NMR Spectrum of YUG-206
Chapter 3 Quinoline-3-carboxylates/carboxamides…
253
Mass Spectrum of YUG-207
IR Spectrum of YUG-207
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100
110%T
3290
.67
3242
.45
3209
.66
3080
.42
2958
.90
2870
.17
1701
.27
1645
.33
1604
.83
1494
.88
1477
.52
1444
.73
1417
.73
1383
.01
1303
.92
1280
.78
1211
.34
1163
.11
1149
.61
1111
.03
1080
.17
1058
.96
974.
08
883.
4383
9.06
738.
76 677.
04
YUG-207
Chapter 3 Quinoline-3-carboxylates/carboxamides…
254
1H NMR Spectrum of YUG-207
Expanded 1H NMR Spectrum of YUG-207
Chapter 3 Quinoline-3-carboxylates/carboxamides…
255
Expanded 1H NMR Spectrum of YUG-207
Expanded 1H NMR Spectrum of YUG-207
Chapter 3 Quinoline-3-carboxylates/carboxamides…
256
13C NMR Spectrum of YUG-207
Mass Spectrum of YUG-208
Chapter 3 Quinoline-3-carboxylates/carboxamides…
257
IR Spectrum of YUG-208
400600800100012001400160018002000240028003200360040001/cm
10
20
30
40
50
60
70
80
90
100%T
3286
.81
3236
.66
3205
.80 31
67.2
230
99.7
130
74.6
329
56.9
728
70.1
7
1699
.34
1604
.83
1566
.25
1477
.52 14
54.3
814
11.9
413
84.9
413
03.9
212
80.7
812
09.4
111
49.6
111
09.1
110
78.2
410
22.3
197
6.01
887.
28
740.
69
663.
53
412
78
YUG-208
1H NMR Spectrum of YUG-208
Chapter 3 Quinoline-3-carboxylates/carboxamides…
258
Expanded 1H NMR Spectrum of YUG-208
Expanded 1H NMR Spectrum of YUG-208
Chapter 3 Quinoline-3-carboxylates/carboxamides…
259
Expanded 1H NMR Spectrum of YUG-208
13C NMR Spectrum of YUG-208
Chapter 3 Quinoline-3-carboxylates/carboxamides…
260
Mass Spectrum of YUG-210
IR Spectrum of YUG-210
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100
%T
3279
.10
3209
.66
3190
.37
3103
.57
2899
.11
2827
.74
1699
.34
1647
.26
1597
.11
1491
.02
1433
.16
1388
.79
1305
.85
1280
.78
1211
.34
1170
.83 11
18.7
510
82.1
010
30.0
297
4.08
927.
7987
7.64
798.
56
729.
1266
3.53
408
92
YUG-210
Chapter 3 Quinoline-3-carboxylates/carboxamides…
261
1H NMR Spectrum of YUG-210
Expanded 1H NMR Spectrum of YUG-210
Chapter 3 Quinoline-3-carboxylates/carboxamides…
262
Mass Spectrum of YUG-217
IR Spectrum of YUG-217
400600800100012001400160018002000240028003200360040001/cm
45
52.5
60
67.5
75
82.5
90
97.5
105
%T
3277
.17
3221
.23
3086
.21
2964
.69
2872
.10
1710
.92
1647
.26
1608
.69
1523
.82
1489
.10
1381
.08
1344
.43
1305
.85
1280
.78
1211
.34
1141
.90
1109
.11
1084
.03
1060
.88
831.
35
736.
83
YUG-217
Chapter 3 Quinoline-3-carboxylates/carboxamides…
263
1H NMR Spectrum of YUG-217
Expanded 1H NMR Spectrum of YUG-217
Chapter 3 Quinoline-3-carboxylates/carboxamides…
264
Expanded 1H NMR Spectrum of YUG-217
Expanded 1H NMR Spectrum of YUG-217
Chapter 3 Quinoline-3-carboxylates/carboxamides…
265
Mass Spectrum of YUG-221
IR Spectrum of YUG-221
400600800100012001400160018002000240028003200360040001/cm
30
37.5
45
52.5
60
67.5
75
82.5
90
97.5
105%T
3282
.95
3209
.66
3066
.92
2953
.12
2891
.39
2833
.52
1695
.49
1604
.83
1506
.46
1485
.24
1465
.95
1437
.02
1384
.94
1361
.79
1340
.57
1305
.85
1267
.27
1228
.70
1215
.19
1186
.26
1168
.90
1151
.54
1128
.39
1070
.53
1035
.81
840.
99
758.
05 678.
97
455.
22
YUG-221
Chapter 3 Quinoline-3-carboxylates/carboxamides…
266
1H NMR Spectrum of YUG-221
Expanded 1H NMR Spectrum of YUG-221
Chapter 3 Quinoline-3-carboxylates/carboxamides…
267
Expanded 1H NMR Spectrum of YUG-221
Expanded 1H NMR Spectrum of YUG-221
Chapter 3 Quinoline-3-carboxylates/carboxamides…
268
Mass Spectrum of YUG-222
IR Spectrum of YUG-222
400600800100012001400160018002000240028003200360040001/cm
-0
10
20
30
40
50
60
70
80
90
100%T
3281
.02
3252
.09
3207
.73
3078
.49
3014
.84
2953
.12
2872
.10
1695
.49
1599
.04
1487
.17
1467
.88
1383
.01
1367
.58
1307
.78
1269
.20
1215
.19
1153
.47
1126
.47
1068
.60
1020
.38
916.
2287
3.78
837.
13
744.
5568
0.89
408
92
YUG-222
Chapter 3 Quinoline-3-carboxylates/carboxamides…
269
1H NMR Spectrum of YUG-222
Expanded 1H NMR Spectrum of YUG-222
Chapter 3 Quinoline-3-carboxylates/carboxamides…
270
Expanded 1H NMR Spectrum of YUG-222
Expanded 1H NMR Spectrum of YUG-222
Chapter 3 Quinoline-3-carboxylates/carboxamides…
271
Mass Spectrum of YUG-223
IR Spectrum of YUG-223
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100
%T
3288
.74
3217
.37
3078
.49
2964
.69
2874
.03
1707
.06
1647
.26
1600
.97
1489
.10
1464
.02
1384
.94
1344
.43
1265
.35
1217
.12
1184
.33
1126
.47
1068
.60
850.
64
765.
77
671.
25
YUG-223
Chapter 3 Quinoline-3-carboxylates/carboxamides…
272
1H NMR Spectrum of YUG-223
Expanded 1H NMR Spectrum of YUG-223
Chapter 3 Quinoline-3-carboxylates/carboxamides…
273
Expanded 1H NMR Spectrum of YUG-223
Expanded 1H NMR Spectrum of YUG-223
Chapter 3 Quinoline-3-carboxylates/carboxamides…
274
13C NMR Spectrum of YUG-223
Mass Spectrum of YUG-226
Chapter 3 Quinoline-3-carboxylates/carboxamides…
275
IR Spectrum of YUG-226
400600800100012001400160018002000240028003200360040001/cm
15
30
45
60
75
90
105
120
%T
3286
.81
3213
.51
3076
.56
2956
.97
2874
.03
1705
.13
1600
.97
1487
.17
1429
.30
1383
.01
1307
.78
1267
.27
1217
.12
1178
.55
1126
.47
1068
.60
1008
.80
914.
2988
1.50
840.
9980
8.20 767.
6973
6.83
680.
89
YUG-226
1H NMR Spectrum of YUG-226
Chapter 3 Quinoline-3-carboxylates/carboxamides…
276
Expanded 1H NMR Spectrum of YUG-226
Expanded 1H NMR Spectrum of YUG-226
Chapter 3 Quinoline-3-carboxylates/carboxamides…
277
Expanded 1H NMR Spectrum of YUG-226
Mass Spectrum of YUG-227
Chapter 3 Quinoline-3-carboxylates/carboxamides…
278
IR Spectrum of YUG-227
400600800100012001400160018002000240028003200360040001/cm
-0
10
20
30
40
50
60
70
80
90
100%T
3284
.88
3207
.73
3078
.49
2958
.90
2874
.03
1707
.06
1643
.41
1597
.11
1489
.10
1467
.88
1427
.37
1384
.94
1344
.43
1311
.64
1269
.20
1217
.12
1166
.97
1155
.40
1124
.54
1068
.60
837.
13
754.
1972
3.33
678.
97 644.
25
YUG-227
1H NMR Spectrum of YUG-227
Chapter 3 Quinoline-3-carboxylates/carboxamides…
279
Expanded 1H NMR Spectrum of YUG-227
Expanded 1H NMR Spectrum of YUG-227
Chapter 3 Quinoline-3-carboxylates/carboxamides…
280
Expanded 1H NMR Spectrum of YUG-227
13C NMR Spectrum of YUG-227
Chapter 3 Quinoline-3-carboxylates/carboxamides…
281
Mass Spectrum of YUG-228
IR Spectrum of YUG-228
400600800100012001400160018002000240028003200360040001/cm
10
20
30
40
50
60
70
80
90
100%T
3400
.62
3288
.74
3066
.92
2953
.12
2874
.03
1710
.92
1641
.48
1604
.83
1492
.95
1467
.88
1427
.37
1384
.94
1346
.36
1319
.35
1265
.35
1217
.12
1161
.19
1134
.18
1064
.74
1020
.38
991.
4494
5.15
833.
28
750.
3367
8.97
YUG-228
Chapter 3 Quinoline-3-carboxylates/carboxamides…
282
1H NMR Spectrum of YUG-228
Expanded 1H NMR Spectrum of YUG-228
Chapter 3 Quinoline-3-carboxylates/carboxamides…
283
Expanded 1H NMR Spectrum of YUG-228
Expanded 1H NMR Spectrum of YUG-228
Chapter 3 Quinoline-3-carboxylates/carboxamides…
284
13C NMR Spectrum of YUG-228
Mass Spectrum of YUG-229
Chapter 3 Quinoline-3-carboxylates/carboxamides…
285
IR Spectrum of YUG-229
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100
%T
3302
.24
3209
.66
3066
.92
2955
.04
2874
.03
2837
.38
1701
.27
2.90
1510
.31
.24
1467
.88
1383
.01
1340
.57
1309
.71
512
17.1
211
70.8
311
39.9
710
68.6
010
22.3
1
813.
9976
7.69
729.
1266
7.39
YUG-229
1H NMR Spectrum of YUG-229
Chapter 3 Quinoline-3-carboxylates/carboxamides…
286
Expanded 1H NMR Spectrum of YUG-229
Expanded 1H NMR Spectrum of YUG-229
Chapter 3 Quinoline-3-carboxylates/carboxamides…
287
Mass Spectrum of YUG-230
IR Spectrum of YUG-230
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100
%T
3279
.10
3250
.16 32
11.5
930
84.2
829
58.9
028
85.6
028
35.4
5
1724
.42
1658
.84
597.
1181
1467
.88
1446
.66
1425
.44
1386
.86
1365
.65
1317
.43
1267
.27
1244
.13
511
74.6
911
55.4
010
84.0
310
55.1
010
24.2
4 922.
0082
3.63
794.
7070
7.90
680.
89
426.
28
YUG-230
Chapter 3 Quinoline-3-carboxylates/carboxamides…
288
1H NMR Spectrum of YUG-230
Expanded 1H NMR Spectrum of YUG-230
Chapter 3 Quinoline-3-carboxylates/carboxamides…
289
Expanded 1H NMR Spectrum of YUG-230
Expanded 1H NMR Spectrum of YUG-230
Chapter 3 Quinoline-3-carboxylates/carboxamides…
290
13C NMR Spectrum of YUG-230
Mass Spectrum of YUG-238
Chapter 3 Quinoline-3-carboxylates/carboxamides…
291
IR Spectrum of YUG-238
400600800100012001400160018002000240028003200360040001/cm
37.5
45
52.5
60
67.5
75
82.5
90
97.5%T
3290
.67
3244
.38
3217
.37
2956
.97
2877
.89
1743
.71
1710
.92
1647
.26
1599
.04
1529
.60
1487
.17
1431
.23
1381
.08
1350
.22
1309
.71
1265
.35
1215
.19
1161
.19
1126
.47
1068
.60
1024
.24
950.
94
848.
71
732.
9770
0.18 62
8.81
503.
4449
5.72
418.
57
YUG-238
1H NMR Spectrum of YUG-238
Chapter 3 Quinoline-3-carboxylates/carboxamides…
292
Expanded 1H NMR Spectrum of YUG-238
Expanded 1H NMR Spectrum of YUG-238
Chapter 3 Quinoline-3-carboxylates/carboxamides…
293
Mass Spectrum of YUG-239
IR Spectrum of YUG-239
400600800100012001400160018002000240028003200360040001/cm
37.5
45
52.5
60
67.5
75
82.5
90
97.5%T
3944
.56
3348
.54
3192
.30
3049
.56
2962
.76
2874
.03
1743
.71
1720
.56
1666
.55
1641
.48
1614
.47
1531
.53
1483
.31
1465
.95
1446
.66
1429
.30
1384
.94
1348
.29
1319
.35
1269
.20
1224
.84
1178
.55
1145
.75
1064
.74
989.
52
908.
50
742.
62
640.
39
YUG-239
Chapter 3 Quinoline-3-carboxylates/carboxamides…
294
1H NMR Spectrum of YUG-239
Expanded 1H NMR Spectrum of YUG-239
Chapter 3 Quinoline-3-carboxylates/carboxamides…
295
Expanded 1H NMR Spectrum of YUG-239
Expanded 1H NMR Spectrum of YUG-239
Chapter 3 Quinoline-3-carboxylates/carboxamides…
296
Mass Spectrum of YUG-241
IR Spectrum of YUG-241
400600800100012001400160018002000240028003200360040001/cm
45
52.5
60
67.5
75
82.5
90
97.5
105
%T
3250
.16
3053
.42
2953
.12 28
72.1
0
1662
.69
1608
.69
1541
.18
1508
.38
1381
.08
1301
.99
1251
.84
1222
.91
1174
.69 10
99.4
610
30.0
2
837.
13
1
TOC
Chapter 3 Quinoline-3-carboxylates/carboxamides…
297
1H NMR Spectrum of YUG-241
Expanded 1H NMR Spectrum of YUG-241
Chapter 3 Quinoline-3-carboxylates/carboxamides…
298
Expanded 1H NMR Spectrum of YUG-241
Mass Spectrum of YUG-242
Chapter 3 Quinoline-3-carboxylates/carboxamides…
299
IR Spectrum of YUG-242
400600800100012001400160018002000240028003200360040001/cm
-10
0
10
20
30
40
50
60
70
80
90
100%T
3282
.95
3064
.99
2955
.04
2870
.17
1666
.55
1606
.76
1537
.32
1506
.46
1485
.24
1381
.08
1367
.58
1323
.21
1222
.91
1143
.83
1010
.73
976.
01
887.
2883
5.21
TOC
1H NMR Spectrum of YUG-242
Chapter 3 Quinoline-3-carboxylates/carboxamides…
300
Expanded 1H NMR Spectrum of YUG-242
Expanded 1H NMR Spectrum of YUG-242
Chapter 3 Quinoline-3-carboxylates/carboxamides…
301
IR Spectrum of YUG-248
IR Spectrum of YUG-248
400600800100012001400160018002000240028003200360040001/cm
20
30
40
50
60
70
80
90
100%T
3271
.38 30
63.0
629
58.9
028
77.8
9
1643
.41
1602
.90 15
29.6
015
04.5
3
1367
.58
1251
.84
1222
.91
1155
.40
1095
.60
1012
.66
887.
2883
5.21
717.
54
TOC
Chapter 3 Quinoline-3-carboxylates/carboxamides…
302
1H NMR Spectrum of YUG-248
Expanded 1H NMR Spectrum of YUG-248
Chapter 3 Quinoline-3-carboxylates/carboxamides…
303
3.19 Biological evaluation 3.19.1 Antimicrobial evaluation
All the synthesized compounds (YUG-201 to YUG-250) were tested for their
antibacterial and antifungal activity (MIC) in vitro by broth dilution method [183-185]
with two Gram-positive bacteria Staphylococcus aureus MTCC-96, Streptococcus
pyogenes MTCC 443, two Gram-negative bacteria Escherichia coli MTCC 442,
Pseudomonas aeruginosa MTCC 441 and three fungal strains Candida albicans
MTCC 227, Aspergillus Niger MTCC 282, Aspergillus clavatus MTCC 1323 taking
ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and greseofulvin as
standard drugs. The standard strains were procured from the Microbial Type Culture
Collection (MTCC) and Gene Bank, Institute of Microbial Technology, Chandigarh,
India.
The minimal inhibitory concentration (MIC) values for all the newly
synthesized compounds, defined as the lowest concentration of the compound
preventing the visible growth, were determined by using microdilution broth method
according to NCCLS standards [183]. Serial dilutions of the test compounds and
reference drugs were prepared in Muellere-Hinton agar. Drugs (10 mg) were
dissolved in dimethylsulfoxide (DMSO, 1 mL). Further progressive dilutions with
melted Muellere-Hinton agar were performed to obtain the required concentrations. In
primary screening 1000 μg mL-1, 500 μg mL-1 and 250 μg mL-1 concentrations of the
synthesized drugs were taken. The active synthesized drugs found in this primary
screening were further tested in a second set of dilution at 200 μg mL-1, 100 μg mL-1,
50 μg mL-1, 25 μg mL-1, 12.5 μg mL-1, and 6.25 μg mL-1 concentration against all
microorganisms. The tubes were inoculated with 108 cfu mL-1 (colony forming
unit/mL) and incubated at 37 ºC for 24 h. The MIC was the lowest concentration of
the tested compound that yields no visible growth (turbidity) on the plate. To ensure
that the solvent had no effect on the bacterial growth, a control was performed with
the test medium supplemented with DMSO at the same dilutions as used in the
experiments and it was observed that DMSO had no effect on the microorganisms in
the concentrations studied.
The results obtained from antimicrobial susceptibility testing are depicted in
Table 1.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
304
Table 1. Antibacterial and antifungal activity of synthesized compounds YUG-
201 to 250 Code Minimal inhibition concentration (µg mL-1 )
Gram-positive Gram-negative Fungal species S.a. S. p. E.c. P.a. C. a. A. n. A.c.
YUG-201 200 100 100 100 250 1000 250 YUG-202 500 500 250 250 250 200 200 YUG-203 500 500 100 250 500 500 >1000 YUG-204 500 500 250 500 500 >1000 1000 YUG-205 250 62.5 250 500 >1000 >1000 >1000 YUG-206 100 200 62.5 125 500 >1000 >1000 YUG-207 250 250 250 500 1000 500 >1000 YUG-208 200 500 62.5 500 1000 500 500 YUG-209 100 200 500 500 250 >1000 >1000 YUG-210 500 500 100 250 250 1000 250 YUG-111 500 62.5 250 250 250 200 200 YUG-212 100 250 100 250 500 500 >1000 YUG-213 500 250 250 500 500 >1000 1000 YUG-214 500 500 250 500 >1000 >1000 >1000 YUG-215 500 100 100 125 500 >1000 1000 YUG-216 200 500 250 500 1000 500 >1000 YUG-217 250 500 62.5 500 1000 500 500 YUG-218 250 500 500 500 250 >1000 >1000 YUG-219 500 500 1000 1000 500 1000 1000 YUG-220 200 100 100 500 500 1000 200 YUG-221 250 250 250 250 500 500 1000 YUG-222 100 500 500 1000 250 500 500 YUG-223 500 100 62.5 100 500 500 >1000 YUG-224 250 500 500 500 200 500 200 YUG-225 500 250 500 500 1000 1000 1000 YUG-226 500 100 500 250 1000 >1000 1000 YUG-227 250 62.5 100 125 250 1000 500 YUG-228 500 250 200 500 500 1000 >1000 YUG-229 100 250 500 1000 1000 >1000 >1000 YUG-230 500 62.5 62.5 100 250 1000 1000 YUG-231 500 500 100 250 500 500 >1000 YUG-232 500 500 250 500 500 >1000 1000 YUG-233 250 62.5 250 500 >1000 >1000 >1000 YUG-234 100 200 62.5 125 500 >1000 >1000 YUG-235 250 250 250 500 1000 500 >1000 YUG-236 200 500 62.5 500 1000 500 500 YUG-237 100 200 500 500 250 >1000 >1000 YUG-238 500 500 100 250 250 1000 250 YUG-239 500 62.5 250 250 250 200 200 YUG-240 100 250 100 250 500 500 >1000 YUG-241 500 500 250 500 500 >1000 1000 YUG-242 250 62.5 250 500 >1000 >1000 >1000 YUG-243 100 200 62.5 125 500 >1000 >1000 YUG-244 250 250 250 500 1000 500 >1000 YUG-245 200 500 62.5 500 1000 500 500 YUG-246 100 200 500 500 250 >1000 >1000 YUG-247 500 500 100 250 250 1000 250 YUG-248 500 62.5 250 250 250 200 200 YUG-249 100 250 100 250 500 500 >1000 YUG-250 500 250 250 500 500 >1000 1000 Ampicillin 250 100 100 100 - - - Chloramphenicol 50 50 50 50 - - -
Chapter 3 Quinoline-3-carboxylates/carboxamides…
305
Ciprofloxacin 50 50 25 25 - - - Norfloxacin 10 10 10 10 - - - Nystatin - - - - 100 100 100 Greseofulvin - - - - 500 100 100
Chapter 3 Quinoline-3-carboxylates/carboxamides…
306
3.19.2 Antimycobacterial, anticancer and antiviral evaluation
Antimycobacterial, anticancer and antiviral screening of all the newly synthesized
compounds YUG-201 to YUG-250 is currently under investigation and results are
awaited.
Chapter 3 Quinoline-3-carboxylates/carboxamides…
307
3.20 References and Notes [1] Xu, C.; Bartley, J. K.; Enache, D. I.; Knight, D. W.; Hutchings, G. J. Synthesis
2005, 2005, 3468.
[2] H, Yan,; Guangpu Shiyanshi 2004, 21(1), 79.
[3] Milan, M.; Viktor, M.; Rudolf, K.; Dusan, I. Current Organic Chemistry8,
695.
[4] Swindell, C. S.; Patel, B. P.; DeSolms, S. J.; Springer, J. P. The Journal of
Organic Chemistry 1987, 52, 2346.
[5] Vogler, B.; Bayer, R.; Meller, M.; Kraus, W.; Schell, F. M. The Journal of
Organic Chemistry 1989, 54, 4165.
[6] Schell, F. M.; Cook, P. M.; Hawkinson, S. W.; Cassady, R. E.; Thiessen, W.
E. The Journal of Organic Chemistry 1979, 44, 1380.
[7] Tamura, Y. Y.; Kita, H. I.; Ikeda, M. Chemical Communication 1971, 12,
1167.
[8] Tamura, Y.; Ishibashi, H.; Hirai, M.; Kita, Y.; Ikeda, M. The Journal of
Organic Chemistry 1975, 40, 2702.
[9] Tamura, Y.; Kita, Y.; Ishibashi, H.; Ikeda, M. Tetrahedron Letters 1972, 13,
1977.
[10] Desai, R. D.; Indian Journal of Chemical Society 1933, 10, 663.
[11] Bellur, E.; Langer, P. Tetrahedron Letters 2006, 47, 2151.
[12] Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M. R. S.; Payret-Arrúa,
M. E. Tetrahedron 1999, 55, 10915.
[13] Radulescu D.; Georgescu, V. Bulletin Society Chimica 1925, 37, 187.
[14] Radulescu D.; Georgescu, V. Bulletin Society Stiinte 1927, 3, 129.
[15] Greeberg, F. H. Journal of Organic Chemistry 1965, 30, 1251.
[16] Salgaonkar, P. D.; Shukla, V. G.; Akamanchi, K. G. Synthetic
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