Chapter 3 Dimedone as a versatile precursor for annulated ...shodhganga.inflibnet.ac.in/bitstream/10603/46059/10/10_chapter 3.pdf · 3.1 Introduction Dimedone (1) is an alicyclic

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


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)


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).


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


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


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).


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


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


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


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


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


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).


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


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


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


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


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,


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).


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).


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).


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,


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).


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


175

the quinoline (147) and pyridocarbazole (148) in addition to the debrominated alcohol

(149) (Figure 3.25).


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


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


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


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


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


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


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


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


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)


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).


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.


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


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.


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).

.


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


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'








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%.


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'








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





193





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





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%.


194

3.16.2.6 Ethyl 4-(4-bromophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-2-propylqu-


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





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-


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


195

of carbonyl group of ester), 1645 (C=O stretching of carbonyl group of






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-


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









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%.


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-propylquinoline-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








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%.


197

3.16.2.11 Ethyl 1,4,5,6,7,8-hexahydro-4-(3,4,5-trimethoxyphenyl)-7,7-dimethyl-

5-oxo-2-propylquinoline-3-carboxylate (YUG-211)

NH

O CH3

CH3

OO

H3CH3C

OCH3

OH3C

OH3C


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


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-


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%.


198

3.16.2.14 Ethyl 4-(2,6-dichlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-dimethyl-5-oxo-


NH

O CH3

CH3

OO

H3CH3C

ClCl


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-


NH

O CH3

CH3H3C

H3C

O O

OH


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-


NH

O CH3

CH3H3C

H3C

O OOH


7.62; N, 3.65. Found: C, 72.01; H, 7.59; N, 3.60%.


199

3.16.2.17 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-2-


NH

O CH3

CH3

OO

H3CH3C

H H

H

H

abc

d

e

f g

h

i

jkl

m

n

o

NO2

m'

n'









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


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%.


200

3.16.2.19 Ethyl 1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-2-propyl-


NH

O CH3

CH3

OO

H3CH3C

NO2


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-


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




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'







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


202





ester), 1068 (C-H in plane bending of aromatic ring), 837 (C-H out of plane bending



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'








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%.


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%.



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-


NH

OCH3

CH3

OO

H3CH3C

H H

a

bc

de f

g

h

ij

k

m

o

Br

CH3

n

l





204





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%.



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





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%.


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







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




206





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







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%.


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


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


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


H, 5.97; N, 3.32. Found: C, 62.52; H, 5.93; N, 3.28%.


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


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


NH

OCH3

CH3

OO

H3CH3C

CH3

OH


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


NH

OCH3

CH3

OO

H3CH3C

CH3

OH


7.37; N, 3.79. Found: C, 71.47; H, 7.33; N, 3.74%.


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


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)-


a

bc

de f

g

h

ij

k

m

o

n

l

NH

OCH3

CH3

OO

H3CH3C

CH3

NO2

H H







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%.


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







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-


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%.


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



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'



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%.


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'





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%.


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


H, 6.26; N, 6.45. Found: C, 71.78; H, 6.12; N, 6.32%.


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


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'





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%.


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


H, 5.38; N, 9.35. Found: C, 66.68; H, 5.25; N, 9.22%.


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.


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]).


218

3.18.1.3 ORTEP diagram of the organic compound with atom numbering scheme

(40% probability factor for the thermal ellipsoids)


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


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)


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)


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


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


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.


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]).


226

3.18.2.3 ORTEP diagram of the organic compound with atom numbering scheme

(40% probability factor for the thermal ellipsoids)


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


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)


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)


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)


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


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


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.


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


235

1H NMR Spectrum of YUG-201

Expanded 1H NMR Spectrum of YUG-201


236




237



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


238




239




240



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


241




242




243



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


244




245


13C NMR Spectrum of YUG-204


246



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


247




248




249




250


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



251




252




253



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


254




255




256




257


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



258




259




260



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


261




262



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


263




264




265



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


266




267




268



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


269




270




271



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


272




273




274




275


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



276




277




278


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



279




280




281



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


282




283




284




285


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



286




287



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


288




289




290




291


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



292




293



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


294




295




296



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


297




298




299


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



300




301



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


302




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.


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 - - -


305

Ciprofloxacin 50 50 25 25 - - - Norfloxacin 10 10 10 10 - - - Nystatin - - - - 100 100 100 Greseofulvin - - - - 500 100 100


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.


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


[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


[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

Communications 2007, 37, 275.

[17] Gomez-Sanchez, A.; Galan, J.; Rico, M.; Bellanato, J. Journal of the Chemical

Society, Perkin Transactions 1 1985, 2695.

[18] Berestovitskaya, M. V.; Vasileva, O. S.; Aleksandrova, S. M. Russian Journal

of Oraganic Chemistry 2001, 37, 1505.

[19] Berestovitskaya, V. M.; Ostroglyadov, E. S.; Litvinov, I. A.; Vasil’eva, O. S.;

Krivolapov, D. B. Russian Journal of General Chemistry 2004, 74, 1394.


308

[20] Ishikawa, T.; Miyahara, T.; Asakura, M.; Higuchi, S.; Miyauchi, Y.; Saito, S.

Organic Letters 2005, 7, 1211.

[21] Chhabra, S. R.; Hothi, B.; Evans, D. J.; White, P. D.; Bycroft, B. W.; Chan, W.

C. Tetrahedron Letters 1998, 39, 1603.

[22] Hamidian, H.; Fozooni, S.; Hassankhani, A.; Mohammadi, S. Z. Molecules

2011, 16, 9041.

[23] Achrem, A. A.; Moiseenkov, A. M.; Andaburskaja, M. B.; Strakov, A. J.

Journal für Praktische Chemie 1972, 314, 31.

[24] Andersonmckay, J.; Savage, G.; Simpson, G. Australian Journal of Chemistry

1996, 49, 163.

[25] Claramunt, R. M.; López, C.; Pérez-Medina, C.; Pinilla, E.; Torres, M. R.;

Elguero, J. Tetrahedron 2006, 62, 11704.

[26] Bycroft, B. W.; Chan, W. C.; Chhabra, S. R.; Hone, N. D. Journal of the

Chemical Society, Chemical Communications 1993, 778.

[27] Kellam, B.; Chan, W. C.; Chhabra, S. R.; Bycroft, B. W. Tetrahedron Letters

1997, 38, 5391.

[28] Nunn, A. J.; Rowell, F. J. Journal of the Chemical Society, Perkin

Transactions 1 1975, 2435.

[29] Strakova, A.; Strakova, I,; Krasnova, A.; Tonkiha, N.; Petrova, M. Latv. Kim.

Z 1994, 124, 738.

[30] Strakov, A. Y.; Petrova, M. V.; Popelis, J.; Krasnova, A. A.; Strakova, N. A.

Chemistry of Heterocyclic Compounds 1996, 32, 221.

[31] Schenone, P.; Mosti, L.; Menozzi, G. Journal of Heterocyclic Chemistry 1982,

19, 1355.

[32] Claramunt, R. M.; López, C.; Pérez-Medina, C.; Pinilla, E.; Torres, M. R.;

Elguero, J. Tetrahedron 2006, 62, 11704.

[33] Strakovs, A.; Tonkikh, N; Strakova, I,; Rizanova, R,; Petrova, M. Material

zinatne Lietiska Kimija, 2001, 24, 167.

[34] Strakova, I.; Strakovs, A.; Petrova, M. Chemistry of Heterocyclic Compounds

2005, 41, 1398.

[35] Strakova, I.; Strakovs, A.; Petrova, M. Chemistry of Heterocyclic Compounds

2005, 41, 1405.


309

[36] Greenhill, J. V.; Chaaban, I.; Steel, P. J. Journal of Heterocyclic Chemistry

1992, 29, 1375.

[37] Huang, K. H.; Eaves, J.; Veal, J.; Barta, T.; Geng, L.; Hinkley, L.; Hanson, G.

PCT Int. Application 2006 264.

[38] Bok, J. H.; Kim, H. J.; Lee, J. W.; Kim, S. K.; Choi, J. K.; Vicens, J.; Kim, J.

S. Tetrahedron Letters 2006, 47, 1237.

[39] Buscemi, S.; Vivona, N. Journal of Heterocyclic Chemistry 1988, 25, 1551.

[40] Akhrem, A. A.; Khripach, V.A.; Lakhvich, F.A. Khimiya Geterotsiklicheskikh

Soedinenii,1974, 901.

[41] J. Pirkl, Czech. Pat., 1982, 82, 229.

[42] Gurdiniece, E.; Vanags, G.; Barkane, V. Khimiya Geterotsiklicheskikh

Soedinenii, 1964, 7, 65.

[43] Ahluwalia V. K.; Rao, J. S. Indian Journal of Chemistry 28B 1989, 81.

[44] Khazi, I. M.; Mahajanshetti, C. S. Monatshefte für Chemie / Chemical

Monthly 1995, 126, 759.

[45] Lefkopoulou, S.; Stephanatou, J.S.; Alexandrou, N.E. Journal of Chemical

Research 1985, 82, 1076.

[46] Ei ashry, E. S. H.; Awad, L. F.; Ibrahim, E. I.; Bdeewy, O. K. Chinese Journal

of Chemistry 2007, 25, 570.

[47] Hamid, H. A.; Mousaad, A.; Sayed, M.; El Ashry, E. S. H. Organic

Preparations and Procedures International 1993, 25, 569.

[48] Ei ashry, E. S. H.; Awad, L. F.; Ibrahim, E. I.; Bdeewy, O. K. Chinese Journal

of Chemistry 2007, 25, 570.

[49] Lefkopoulou, S.; Theodosiou, M.; Stephanidou-Stephanatou, J.; Alexandrou,

N. E. Journal of Heterocyclic Chemistry 1986, 23, 443.

[50] Stankevich, E.I.; Grinshtein, E. E.; Dubur, G.Y. Chemistry of Heterocyclic

Compounds 1966, 6, 583.

[51] Rose, U. Arzneimittel Forschung - Drug Research 1989, 39, 1393.

[52] Sainani, J. B.; Shah, A. C.; Arya, V. P. Indian Journal of Chemistry 33B 1994,

33, 526.

[53] Safak, C.; Dogan, E.; Erol, K. Turkish Journal of Chemistry 2006, 30, 109.

[54] Kumar Ahluwalia, V.; Goyal, B.; Das, U. Journal of Chemical Research,

Synopses 1997, 266.


310

[55] Tu, S. J.; Zho, J. F.; Deng, X.; Cai, P.J.; Wang, H.; Feng, J. C. Youji Huaxue,

2001, 21, 313.

[56] Tu, S. J.; Zho, J. F.; Deng, X.; Cai, P.J.; Wang, H.; Feng, J. C. Youji Huaxue,

2002, 21, 99.

[57] Jiang, H.; Tu, S.-J.; Feng, Y.-J.; Wei, Z.-W.; Zhou, S.-L. Ziran Kexueban,

2006, 24, 60.

[58] Shi, D. Q.; Mou, J.; Zhuang, Q.Y.; Wang, X.S. Jiegou Huaxue, 2005, 24, 696.

[59] Yu, C.-X.; Shi, D.-Q.; Zhuang, O.-Y. Tu, S.-J. Youji Huaxue, 2006, 26, 263.

[60] Grinshtein, E. E.; Stankerich, E.I.; Dubur, G.Y. Khimiya Geterotsiklicheskikh

Soedinenii, 1967, 3, 1118.

[61] Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-F. Tetrahedron Letters 2005, 46,

5771.

[62] Ko, S.; Yao, C.-F. Tetrahedron 2006, 62, 7293.

[63] Das, B.; Ravikanth, B.; Ramu, R.; Vittal Rao, B. Chemical and

Pharmaceutical Bulletin 2006, 54, 1044.

[64] Kumar, A.; Maurya, R. A. Tetrahedron Letters 2007, 48, 3887.

[65] Song, G.; Wang, B.; Wu, X.; Kang, Y.; Yang, L. Synthetic Communications

2005, 35, 2875.

[66] Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946.

[67] Maheswara, M.; Siddaiah, V.; Damu, G. L.; Rao, C. V.; Arkivoc, 2006, ii, 201.

[68] Shi, D.-Q.; Mou, J.; Zhuang, Q.-Y.; Wang, X.-S. Youji Huaxue, 2004, 24,

1569.

[69] Donelson, J. L.; Gibbs, R. A.; De, S. K. Journal of Molecular Catalysis A:

Chemical 2006, 256, 309.

[70] Wang, L.-M.; Sheng, J.; Zhang, L.; Han, J.-W.; Fan, Z.-Y.; Tian, H.; Qian, C.-

T. Tetrahedron 2005, 61, 1539.

[71] Ji, S.-J.; Jiang, Z.-Q.; Lu, J.; Loh, T.-P. Synlett 2004, 2004, 0831.

[72] Du, B.-X.; Li, Y.-L; Wang, X.-S.; Zhang, M.-M.; Shi, D.-Q.; Tu, S.-J. Youji

Huaxue, 2006, 26, 698.

[73] Li, Y.-L.; Du, B.-X.; Wang, X.-S.; Zhang, M.-M.; Zeng, Z.-S. Acta

Crystallographica Section E 2005, 61, o1634.

[74] Linden, A.; Şafak, C.; Aydın, F. Acta Crystallographica Section C 2004, 60,

o711.


311

[75] Tu, S.; Fang, F.; Zhu, S.; Li, T.; Zhang, X.; Zhuang, Q.; Ji, S.; Zhang, Y.

Journal of Heterocyclic Chemistry 2005, 42, 29.

[76] Tu, S.; Zhang, J.; Zhu, X.; Zhang, Y.; Wang, Q.; Xu, J.; Jiang, B.; Jia, R.;

Zhang, J.; Shi, F. Journal of Heterocyclic Chemistry 2006, 43, 985.

[77] Curran, A. C. W. Journal of the Chemical Society, Perkin Transactions 1 1976,

975.

[78] Stupnikova, T. V.; Nuzhnaya, T.V.; Vdovichenko, A.N. Khimiya

Geterotsiklicheskikh Soedinenii 1983, 7, 555.

[79] Ono, M.; Wada, Y.; Sun, L.; Chen, S.; Przewloka, T.; Zhang, S.; Borella, C.;

Koya, K.; Foley, K.; Xia, Z.-Q.; Li, H.; Zhou, D. PCT Int. Appl 2005, 294.

[80] Bischoff, H.; Gielen-Haertwig, H.; Li, V.; Schmeck, C.; Thutewohl, M.;

Vakolopoulos, A.; Weber, O.; Wuttke, M. Ger Offen 2006, 24.

[81] Bischoff, H.; Gielen-Haertwig, H.; Li, V.; Schmeck, C.; Thutewohl, M.;

Vakolopoulos, A.; Weber, O.; Wuttke, M. Ger Offen 2006, 25.

[82] Ramchandani, S.; DeLaRosa, R.N.; Adams, C.L.; Bergnes, G.; Morgans, D. J.;

Trautman, J.K. PCT Int.Appl 2006, 50.

[83] Tu, S.; Zhang, Y.; Jiang, B.; Jia, R.; Zhang, J.; Zhang, J.; Ji, S. Synthesis 2006,

2006, 3874.

[84] Andin, A. N.; Kaminskii, V.A.; Dubovitskii, S.V. Heterocyclic

Communication 2001, 7, 155.

[85] Dubovitskii S. V.; Kaminskii, V.A. Journal of organic chemistry of the USSR

1997, 33, 1048.

[86] Jachak, M. N.; Avhale, A. B.; Medhane, V. J.; Toche, R. B. Journal of

Heterocyclic Chemistry 2006, 43, 1169.

[87] Hennig, L.; Alva-Astudillo, M.; Meusinger, R.; Mann, G. Monatshefte für

Chemie / Chemical Monthly 1993, 124, 893.

[88] Quiroga, J.; Insuasty, B.; Hormaza, A.; Saitz, C.; Jullian, C. Journal of


[89] Cannon, D.; Quesada, A.; Quiroga, J.; Mejía, D.; Insuasty, B.; Abonia, R.;

Cobo, J.; Nogueras, M.; Sánchez, A.; Low, J. N. Acta Crystallographica

Section E 2001, 57, o151.

[90] Xu, J. N.; Tu, S.H.; Jian, H.; Zhang, J.P.; Zhu, X.T.; Wang, Q. Jiegou Huaxue

2005, 24, 209.


312

[91] Hua, G. P.; Xu, J.N.; Tu, S.J.; Wang, Q.; Zhang, J.P.; Zhu, X.T.; Li, T.J.; Zhu,

S.L.; Zhang, X.J. Yuoji Huaxue, 2005, 25, 1610.

[92] Dress, B. E.; Chakravarty, L.; Prestwich, G.D.; Dorman, G. M.; Urge, L.;

Darvas, F.; Rzepecki, P.W.; Ferguson, C.G. PCT Int.Appl 2005, 56PP.

[93] Bremner, W. S.; Organ, M. G. Journal of Combinatorial Chemistry 2006, 9,

14.

[94] Lipson, V.; Shirobokova, M.; Shishkin, O.; Shishkina, S. Russian Journal of


[95] Quiroga, J.; Mejıa, D.; Insuasty, B.; Abonı a, R.; Nogueras, M.; Sánchez, A.;

Cobo, J.; Low, J. N. Tetrahedron 2001, 57, 6947.

[96] Cruz, S.; Quiroga, J.; Torre, J. M. d. l.; Cobo, J.; Low, J. N.; Glidewell, C.

Acta Crystallographica Section C 2006, 62, o525.

[97] Low, J. N.; Cobo, J.; Mera, J.; Quiroga, J.; Glidewell, C. Acta

Crystallographica Section C 2004, 60, o265.

[98] Low, J. N.; Cobo, J.; Mera, J.; Quiroga, J.; Glidewell, C. Acta

Crystallographica Section C 2004, 60, o479.

[99] E. H. Elgemeie, G.; H. Elghandour, A.; M. Elzanate, A.; M. Hussein, A.

Journal of Chemical Research, Synopses 1997, 256.

[100] Gulyakevich, O. V.; Vasileva, O. S.; Aleksandrova, S. M. Russian Journal of

Oraganic Chemistry 1991, 27, 213.

[101] Gulyakevich, O. V.; Mikhal’chuk, A.L.; Akhrem, A.A.; Russ. Russian Journal

of General Chemistry 1994, 64, 1382.

[102] Kato, T.; Yamamoto, Y.; Hozumi, T. Chemical & Pharmaceutical Bulletin,

1973, 21, 1840.

[103] De Buyck, L.; Schamp, N.; Verhé, R. Tetrahedron Letters 1975, 16, 2491.

[104] Aly Nada, A.; Ragab Mohamed, N.; Mohamed Mahran, A.; Wahba Erian, A.

Journal of Chemical Research, Synopses 1997, 236.

[105] Greenhill, J. V.; Hanaee, J.; Steel, P. J. Journal of the Chemical Society,

Perkin Transactions 1 1990, 1869.

[106] Assy M. G.; Abd-EllMotti, F.M. Indian Journal of Chemistry Sec B 1996,

35(B), 608.

[107] Gogoi, P.C.; Kataky, J.C.S. Heterocycles, 1990, 12, 2147.


313

[108] Laddi, U. V.; Talawar, M.B.; Desai, S.R.; Bennur, R.S.; Bennur, S.C. Indian

Journal of Chemistry 2001, 40B, 828.

[109] Talawar, M. B.; Laddi, U.V.; Somannavar, Y.S.; Bennur, R.S.; Bennur, S. C.

Indian Journal of Heterocyclic Chemistry 1995, 4, 297.

[110] Kidwai, M.; Goel, Y.; Kumar, P.; Kumar, K. Indian Journal of Chemistry Sec

B 1997, 36B, 782.

[111] Moustafa, A. H.; Haggam, R. A.; Younes, M. E.; El Ashry, E. S. H.

Nucleosides, Nucleotides and Nucleic Acids 2005, 24, 1885.

[112] Gendy, Z. El.; Morsy, J.M.; Allimony, H.A.; AbdelMonem, W.R.; Abdel-

Rahman, R.M. Pharmazie, 2001, 56, 376.

[113] Yamasaki, T.; Nishida, K.; Okamoto, Y.; Okawara, T.; Furukawa, M.

Heterocycles, 1998, 47, 315.

[114] Egg, H.; Knauseder, H.; Mayr, S.; Schöpf, D. Journal of Heterocyclic

Chemistry 1995, 32, 655.

[115] Iida, H.; Yuasa, Y.; Kibayashi, C. The Journal of Organic Chemistry 1979, 44,

3985.

[116] H:\nw2\Quinoline ‐ Wikipedia, the free encyclopedia html.

[117] "Quinoline". Encyclopedia Britannica. 1911.

[118] Joule, J. A.; Mills, K. Heterocyclic Chemistry: Wiley, 2010.

[119] Joule, J. A.; Mills, K. Heterocyclic Chemistry at a Glance: John Wiley & Sons,

2007.

[120] Manske R.H..; Kulka M.; Organic Reaction 1953, 7, 59.

[121] Song, Z.; Mertzman, M.; Hughes, D. L. Journal of Heterocyclic Chemistry

1993, 30, 17.

[122] Long R.; Schofield K.; Journal of chemical society 1953, 3161.

[123] Journal of the American Pharmaceutical Association 1952, 41, 516.

[124] Swenson, R. E.; Sowin, T. J.; Zhang, H. Q. The Journal of Organic Chemistry

2002, 67, 9182.

[125] Cho, C. S.; Oh, B. H.; Shim, S. C. Journal of Heterocyclic Chemistry 1999, 36,

1175.

[126] Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthesis

1995, 1995, 801.

[127] Sangu, K.; Fuchibe, K.; Akiyama, T. Org Lett 2004, 6, 353.


314

[128] Crousse, B.; Bégué, J.-P.; Bonnet-Delpon, D. Tetrahedron Letters 1998, 39,

5765.

[129] Crousse, B.; Begue, J.-P.; Bonnet-Delpon, D. ChemInform 2000, 31, no.

[130] Katritzky, A. R.; Denisenko, A.; Denisenko, S. N.; Arend, M. Journal of


[131] Beale, J. M.; Block, J. Wilson and Gisvold's Textbook of Organic Medicinal

and Pharmaceutical Chemistry: Lippincott Williams & Wilkins, 2010.

[132] Fournet, A.; Barrios, A. A.; Munoz, V.; Hocquemiller, R.; Cave, A.; Bruneton,

J. Antimicrobial agents and chemotherapy 1993, 37, 859.

[133] Wright, C. W.; Addae-Kyereme, J.; Breen, A. G.; Brown, J. E.; Cox, M. F.;

Croft, S. L.; Gökçek, Y.; Kendrick, H.; Phillips, R. M.; Pollet, P. L. Journal of

Medicinal Chemistry 2001, 44, 3187.

[134] Nicolaou, K. C.; Gross, J. L.; Kerr, M. A. Journal of Heterocyclic Chemistry

1996, 33, 735.

[135] Bringmann, G.; Reichert, Y.; Kane, V. V. Tetrahedron 2004, 60, 3539.

[136] Chiari, E.; Oliveira, A. B.; Prado, M. A.; Alves, R. J.; Galvao, L. M.; Araujo,

F. G. Antimicrobial agents and chemotherapy 1996, 40, 613.

[137] Caprio, V.; Guyen, B.; Opoku-Boahen, Y.; Mann, J.; Gowan, S. M.; Kelland,

L. M.; Read, M. A.; Neidle, S. Bioorganic & medicinal chemistry letters 2000,

10, 2063.

[138] Mikata, Y.; Yokoyama, M.; Ogura, S.; Okura, I.; Kawasaki, M.; Maeda, M.;

Yano, S. Bioorganic & medicinal chemistry letters 1998, 8, 1243.

[139] Sharples, D.; Spengler, G.; Molnar, J.; Antal, Z.; Molnar, A.; Kiss, J. T.;

Szabo, J. A.; Hilgeroth, A.; Gallo, S.; Mahamoud, A.; Barbe, J. European

journal of medicinal chemistry 2005, 40, 195.

[140] McPhail, A. T.; Wolin, R.; Wang, D.; Kelly, J.; Afonso, A.; James, L.;

Kirschmeier, P. Bioorganic and Medicinal Chemistry Letters 1996, 6, 195.

[141] Ding, C. Z.; Hunt, J. T.; Ricca, C.; Manne, V. Bioorganic & Medicinal

Chemistry Letters 2000, 10, 273.

[142] Wang, Y. D.; Miller, K.; Boschelli, D. H.; Ye, F.; Wu, B.; Floyd, M. B.;

Powell, D. W.; Wissner, A.; Weber, J. M.; Boschelli, F. Bioorganic &

Medicinal Chemistry Letters 2000, 10, 2477.


315

[143] Mettey, Y.; Vierfond, J. M.; Baudry, M.; Cochet, C.; Sarrouilhe, D.

Bioorganic & Medicinal Chemistry Letters 1997, 7, 961.

[144] Via, L. D.; Gia, O.; Gasparotto, V.; Ferlin, M. G. European journal of

medicinal chemistry 2008, 43, 429.

[145] Kohn, L. K.; Pavam, C. H.; Veronese, D.; Coelho, F.; De Carvalho, J. E.;

Almeida, W. P. European journal of medicinal chemistry 2006, 41, 738.

[146] Kemnitzer, W.; Kuemmerle, J.; Jiang, S.; Zhang, H. Z.; Sirisoma, N.;

Kasibhatla, S.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X.

Bioorganic & medicinal chemistry letters 2008, 18, 6259.

[147] Senthilkumar, P.; Dinakaran, M.; Yogeeswari, P.; Sriram, D.; China, A.;

Nagaraja, V. European journal of medicinal chemistry 2009, 44, 345.

[148] Dinakaran, M.; Senthilkumar, P.; Yogeeswari, P.; China, A.; Nagaraja, V.;

Sriram, D. Bioorganic & medicinal chemistry letters 2008, 18, 1229.

[149] Nayyar, A.; Monga, V.; Malde, A.; Coutinho, E.; Jain, R. Bioorganic &

Medicinal Chemistry 2007, 15, 626.

[150] Block, J.; Beale, J. M. Wilson & Gisvold's Textbook of Organic Medicinal and

Pharmaceutical Chemistry: Lippincott Williams & Wilkins, 2003.

[151] Sadana, A. K.; Mirza, Y.; Aneja, K. R.; Prakash, O. European journal of


[152] Singh, S.P.; Batra, H.; Naithani, R.; Om, P. Indian Journal of. Heterocyclic

Chemistry 1999, 9, 73.

[153] Narender, P.; Srinivas, U.; Ravinder, M.; Rao, B. A.; Ramesh, C.; Harakishore,

K.; Gangadasu, B.; Murthy, U. S.; Rao, V. J. Bioorganic & medicinal

chemistry 2006, 14, 4600.

[154] Reddy, G. V.; Kanth, S. R.; Maitraie, D.; Narsaiah, B.; Rao, P. S.; Kishore, K.

H.; Murthy, U. S.; Ravi, B.; Kumar, B. A.; Parthasarathy, T. European journal

of medicinal chemistry 2009, 44, 1570.

[155] Abdel-Mohsen, S. A. ChemInform 2005, 36, no.

[156] Khunt, R.C.; Datta, N.J.; Bharmal, F.M.; Mankad, G.P.; Parikh, A.R. Indian

Journal of Heterocyclic Chemistry 2000, 10, 97.

[157] Bharmal, F.M.; Kaneriya, D.J.; Parekh, H.H. Indian Journal of Heterocyclic

Chemistry 2003, 12, 279.


316

[158] Guo, L. J.; Wei, C. X.; Jia, J. H.; Zhao, L. M.; Quan, Z. S. European journal


[159] Jin, H. G.; Sun, X. Y.; Chai, K. Y.; Piao, H. R.; Quan, Z. S. Bioorganic &


[160] Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.;

Leonard, J. T. Biological & pharmaceutical bulletin 2004, 27, 1683.

[161] Guan, L. P.; Jin, Q. H.; Tian, G. R.; Chai, K. Y.; Quan, Z. S. Journal of

pharmacy & pharmaceutical sciences : a publication of the Canadian Society

for Pharmaceutical Sciences, Societe canadienne des sciences

pharmaceutiques 2007, 10, 254.

[162] U.S Patent Documents: 4788188; 5017576.

[163] Clemence, F.; Le Martret, O.; Delevallee, F.; Benzoni, J.; Jouanen, A.;

Jouquey, S.; Mouren, M.; Deraedt, R. J Med Chem 1988, 31, 1453.

[164] Calhoun, W.; Carlson, R. P.; Crossley, R.; Datko, L. J.; Dietrich, S.;

Heatherington, K.; Marshall, L. A.; Meade, P. J.; Opalko, A.; Shepherd, R. G.

J Med Chem 1995, 38, 1473.

[165] Kohno, Y.; Awano, K.; Miyashita, M.; Fujimori, S.; Kuriyama, K.; Sakoe, Y.;

Kudoh, S.; Saito, K.; Kojima, E. Bioorganic & Medicinal Chemistry

Letters 1997, 7, 1515.

[166] Kohno, Y.; Awano, K.; Miyashita, M.; Ishizaki, T.; Kuriyama, K.; Sakoe, Y.;

Kudoh, S.; Saito, K.; Kojima, E. Bioorganic & Medicinal Chemistry

Letters 1997, 7, 1519.

[167] Dube, D.; Blouin, M.; Brideau, C.; Chan, C. C.; Desmarais, S.; Ethier, D.;

Falgueyret, J. P.; Friesen, R. W.; Girard, M.; Girard, Y.; Guay, J.; Riendeau,

D.; Tagari, P.; Young, R. N. Bioorganic & medicinal chemistry letters 1998, 8,

1255.

[168] Ko, T. C.; Hour, M. J.; Lien, J. C.; Teng, C. M.; Lee, K. H.; Kuo, S. C.; Huang,

L. J. Bioorganic & medicinal chemistry letters 2001, 11, 279.

[169] Bekhit, A. A.; El-Sayed, O. A.; Aboulmagd, E.; Park, J. Y. European journal


[170] McCall, J. M.; TenBrink, R. E.; Kamdar, B. V.; Skaletzky, L. L.; Perricone, S.

C.; Piper, R. C.; Delehanty, P. J. J Med Chem 1986, 29, 133.

[171] Sircar, I.; Haleen, S. J.; Burke, S. E.; Barth, H. J Med Chem 1992, 35, 4442.


317

[172] Ferlin, M. G.; Chiarelotto, G.; Antonucci, F.; Caparrotta, L.; Froldi, G.

European journal of medicinal chemistry 2002, 37, 427.

[173] Bulbul, B.; Ozturk, G. S.; Vural, M.; Simsek, R.; Sarioglu, Y.; Linden, A.;

Ulgen, M.; Safak, C. European journal of medicinal chemistry 2009, 44, 2052.

[174] Zhang, C. B.; Cui, X.; Hong, L.; Quan, Z. S.; Piao, H. R. Bioorganic &

medicinal chemistry letters 2008, 18, 4606.

[175] Abouzid, K.; Abdel Hakeem, M.; Khalil, O.; Maklad, Y. Bioorganic &


[176] Chandrasekhar, S.; Reddy, N. R.; Sultana, S. S.; Narsihmulu, C.; Reddy, K. V.

Tetrahedron 2006, 62, 338.

[177] Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Journal of

Molecular Catalysis A: Chemical 2005, 235, 267.

[178] Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A.

Angewandte Chemie International Edition 2002, 41, 1790.

[179] List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. Journal of the American

Chemical Society 2002, 124, 827.

[180] Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angewandte Chemie

2003, 115, 4365.

[181] Oskooie, H. A.; Roomizadeh, E.; Heravi, M. M. Journal of Chemical

Research 2006, 2006, 246.

[182] Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.; Nagaiah, K. ChemInform

2005, 36, no.

[183] National Committee for Clinical and Laboratory Standards, Method for

Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically

Approved Standard, fourth ed. NCCLS, Villanova, Italy, 1997, Document M

100-S7. S100-S157.

[184] D.H. Isenberg, Essential Procedure for Clinical Microbiology, American

Society for Microbiology, Washington, 1998.

[185] Zgoda, J. R.; Porter, J. R. Pharmaceutical Biology 2001, 39, 221.