Chapter-3 - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/45493/9/09...Few synthesis of fused 1,4DHPs with dimedone were summarized in - review 8 and some are discussed below

Unsymmetrical Polyhydroquinolines

Chapter 3 Page 86

Chapter-3 Synthesis of unsymmectrical Polyhydroquinolines

using Dimedone

CH3

CH3

O

O

Dimedone

1. H. S. Sohal, A. Goyal, R. Khare, R. Sharma and S. Kumar, Facile and efficient

one-pot synthesis of polyhydroquinoline derivatives via unsymmetrical

Hantzsch condensation under solvent-free conditions, Current Trends in

Biotechnology and Chemical Research, 2013, 3(1), pp. 12-16.

2. H. S. Sohal, R. Khare, A. Goyal, A. Woolley, K. Singh and R. Sharma, Multi-

component Approach for the Synthesis of Fused Dihydropyridines via

Unsymmetrical Hantzch Condensation Using Glycerol as Green Solvent,

American Journal of Chemistry, 2014, 4(1), pp.29-34.


Chapter 3 Page 87

3.1 Literature Survey

Now a days, Dimedone is used for the synthesis of various fused hetrocyclics1-7. 1,4-

DHPs fused with dimedone, finds application in biological as well as pharmacological

industry. Few synthesis of fused 1,4-DHPs with dimedone were summarized in

review8 and some are discussed below.

Yao et al.9 synthesized highly substituted thiopyrano[3,4-b]pyridin-5(4H)-one,

thiopyrano[3,4-b]quinoline-4,6(3H,5H)-dione, dithiopyrano[3,4-b:4′,3′-e]pyridine-

4,6(1H,3H)-dione and pyrazolo[3,4-b]thiopyrano[4,3-e]pyridin-5(1H)-one by the

reaction of aromatic aldehyde, 2H-thiopyran-3,5(4H,6H)-dione and enamine such as

the derivatives of amine and 1,3-dicarbonyl compounds and 3-methyl-1-phenyl-1H-

pyrazol-5-amine in acetic acid (Scheme 1).

S

O

O+ArCHO

R1 CH3

O O

O

OCH3

CH3

S

O

O

NN NH2

CH3

SNH

S

O Ar O

SNH

NN

O Ar CH3

SNH

O

R1

O

CH3

Ar

SNH

O OAr

CH3

CH3

Scheme 1

Chebanov et al.10 has used dimedone with 5-amino-3-phenylpyrazole and aromatic

aldehydes to synthesize 1,4,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinolin-5-ones,

5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8-ones and 5a-hydroxy-4,5,5a,6,7,8-

hexahydropyrazolo[4,3-c]quinolizin-9-ones. This procedure efficiently produces

pyrazoloquinolinones in the presence of triethylamine base enclosed in a sealed vessel

at 150oC under microwave or conventional heating (Scheme 2). On the other hand,

under sonication same reaction mixture gave Biginelli type reaction and yield


Chapter 3 Page 88

dihydropyrimidine. In the third reaction, pathway leading to pyrazoloquinolizinones

in a ring-opening/closing sequence can be access by switching from triethylamine to a

more nucleophilic base such as sodium ethoxide or potassium tert-butoxide.

NH

N

Ph

CH3

O

Ar

+O

O

R

R

NH

NNH

Ph O

R

R

Ar

NH

NN

O

R

R

Ar

Ph

N

NHN

ArH OH R

R

O

Ph

EtOH, Et3N

MW, 150 oC, 15 min

EtOH, sonication

rt, 30 min

EtOH, t-BuOK

MW, 150 oC, 15 min

Scheme 2

Ghahremanzadeh et al.11 synthesized novel spirooxindole derivatives using MnFe2O4

nanoparticles (5 mol%) as an efficient magnetically heterogeneous catalyst in water

(Scheme 3).

CH3

CH3

O

O

NH

O

O

NHO

O

R

+

NH

O

NH

O

O

CH3

CH3

O

Nano MnFe2O4

H2O2, reflux, 6h

Scheme 3


Chapter 3 Page 89

An unexpected condensation was observed for the three-component reaction of

dimedone, various anilines and isatin leading to the formation of novel 2-

arylpyrrolo[2,3,4-kl]acridin-1(2H)-ones in the ionic liquid [HMIm]HSO412 (Scheme

4).

O

OCH3

CH3 + NH2

NH

O

O

N

N

CH3

CH3

O

NH

O

N

O O

CH3

CH3

CH3

CH3

R

R

R

Scheme 4

Azzam et al.13 reported ZnO as inexpensive, recyclable heterogeneous catalyst for the

synthesis of some novel octahydroquinolindione-3-carboxylic acid ethyl esters using

diethylmalonate, dimedone, ammonium acetate and aromatic aldehydes in water

under reflux (Scheme 5).

H OO

OCH3

CH3O

O

O

O

CH3

CH3NH4OAc

+NH

O

O

O O

CH3

CH3

CH3

RR

ZnO/H 2O

Reflux

Scheme 5

Pd-nanoparticles were also used for the synthesis of polyhydroquinoline from

aromatic aldehydes, dimedone, ethyl acetoacetate or ethyl cyanoacetate and

ammonium acetate (Scheme 6). The same reaction was also observed in the case of


Chapter 3 Page 90

arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones), ethyl acetoacetate, ammonium

acetate and Pd-nanoparticles in one-pot14.

CH3

CH3

O

O

CHOO O

CH3

CH3

CH3

CH3

OH OHNH

O

O

CH3

CH3

CH3

O

CH3

XO

O

CH3X

O

O

CH3

R

R R

PdCl2/Na2CO3

THF, RefluxPdCl2/Na2CO3

THF, RefluxNH4OAc

NH4OAc

+

+Scheme 6

Khan et al.15 reported synthesis of chromeno[3,4-b]quinoline derivatives in good

yields through Michael initiated Ring Closure (MIRC) by employing condensation of

aromatic aldehydes, 3-aminocoumarins and cyclic 1,3-diketones in the presence of

catalytic amount of p-toluenesulfonic (p-TSA) acid in ethanol under reflux condition

(Scheme 7).

H OO

OCH3

CH3

O

NH2

O

X

+ ONH

O

CH3

CH3

O

XRR

p-TSA/ EtOH

80oC, 7-8h

Scheme 7

Glucose sulfonic acid (GSA) was synthesized for the first time and used as an

efficient catalyst (Scheme 8) for the preparation of tetrahydrobenzo[α]xanthens and

tetrahydrobenzo[α]acridines via the reaction of aromatic aldehydes, 2-naphthol (or β-

naphthylamine) and dimedone in water16.

CH3

CH3

O

OO

Ar

H

OH

NH2

O

O

CH3

CH3

Ar

NH

O

CH3

CH3

Ar

GSA, 90oC, H2O

GSA, 90oC, H2O

+

Scheme 8


Chapter 3 Page 91

Paul et al.17 also used dimedone to afford highly decorated indenodihydropyridine and

dihydropyridine derivatives employing a green solvent ethyl-L-lactate and an organo-

catalyst (±)lactic acid (Scheme 9). This procedure was simple, convenient,

environmentally benign and tolerates wide range of functional groups.

O O

NH2

O

Ar

H O

O

CH3

CH3+ +

NH

O

CH3

CH3

O OAr

+- Lactic Acid

Ethyl-L-lactate, 100oC

Scheme 9

Tabatabaeian et al.18 used transition metal homogenous catalyst RuCl3-xH2O for the

synthesis of pyrimido[4,5-b]quinoline derivatives by efficient, convenient and

environmentally benign procedures (Scheme 10). Tabatabaeian et al. also found that

1,4-DHPs fused with dimedone are biologically, pharmacologically and

antibacterially active.

N

N

O

NH2

CH3

CH3

O O

Ar

H

O

O CH3

CH3+ +N

N

NH

CH3

CH3

O O

CH3

CH3

O

Ar

RuCl 3.xH 2O

(3 mol%)

H20, 85oC

Scheme 10 Dimedone condensed with acetophenone, aromatic aldehydes and ammonium acetate

in the presence of a catalytic amount of Co nanoparticles at room temperature under

solvent-free conditions produces C5-unsubstitiuted 1,4-dihydropyridines (Scheme

11).This catalyst is easily separated by magnetic devices and can be reused without

any apparent loss of activity for the reaction. Safari et al.19 observed that spatially-

hindered aldehydes such as 2-methoxy-, 2-fluoro- and 2-chloro-aldehydes are also

suitable for this reaction.


Chapter 3 Page 92

CH3

CH3

O

O O

Ar

H

CH3O

+ +NH

CH3

CH3

O Ar

NH4OAc/ Cobalt-nano particles

Solvent free, r.t., 1-3h

Scheme 11

Thirumurugan et al.20 synthesized 7,7,7′,7′-tetramethyl-4,4′-bis(aryl)-

4,6,7,8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquinolinyl-5,5′-dione derivatives using

cinnamil, dimedone and ammonium acetate (Scheme 12).

CH2CH2

R R

Dimedone

NH4OAc NH

NH

R R OO

CH3

CH3

CH3

CH3

Scheme 12

Sashidhara et al.21 reported a novel series of coumarin–dihydropyridine hybrids that

have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced

bone loss in vivo. A series of other in vitro data strongly suggested that the product

obtained possess most promising bone anabolic agents (Scheme 13).

O

O

O

CH3

O

CH3

O

O

CH3

CH3

O

O

O

CH3

CHO

NH4OAc

+ NH

O

CH3

CH3

O

CH3

CH3

O

O

O

CH3

O O

Scheme 13

Further, dimedone was used by Tu et al.22 for the synthesis of some novel polycyclic-

fused isoxazolo[5,4-b]pyridines derivatives by a multi-component reaction under


Chapter 3 Page 93

microwave irradiation in water (Scheme 14). This procedure excludes the use of any

additional reagent or catalyst22.

N

ONH2

CH3

O

Ar

HO

O

CH3

CH3+ +

NH

NO

Ar CH3O

CH3

CH3H2O

MW

Scheme 14

Dimedone fused 1,4-DHPs are precursor of many drug molecules. Synthesis and

evaluation of biological importance of this class of compounds has attracted

considerable interest of chemists and biologists. As a result, preparation of

polyhydroquinolines have been reported using various catalysts such as trimethylsilyl

chloride (TMSCl)23, ionic liquid24,25, silica supported over perchloric acid (HClO4–

SiO2)26, HY-Zeolite27, montmorillonite K-1028, cerium(IV) ammonium nitrate29,

iron(III) trifluoroacetate30, heteropoly acid31, Sc(OTf)332 and p-TSA33 under varied

reaction conditions like conventional heating34, microwave irradiation and

ultrasounds35,36. These methods have many advantages over other methods and also

minimize most of the difficulties like long reaction time, wastage of chemicals, simple

workup procedures and recyclization of the catalyst. Along with the advantages,

disadvantages with these procedures are also there like, collection and purification of

catalyst, harsh reaction conditions, unsatisfactory yields, use of harmful solvents, etc.

Thus, development of a clean, green and efficient procedure is still required.

Therefore, we have made an attempt to synthesize polyhydroquinolines in one pot and

solvent free conditions (Scheme 15).

O

O

CH3

CH3

OEt

CH3

O

O

R

H O

NH4OAc

+NH

CH3

CH3

R

OEt

OO

CH3

solvent free

reflux, 1 h, 120 oC

Scheme 15


Chapter 3 Page 94

3.2 Synthesis of Ethyl-2,7,7-trimethyl-5-oxo-4-aryl-1,4,5,6,7,8-

hexahydroquinoline-3-carboxylate (5a-5l): 3.2.1 Experimental and Characterization:

General method

In a conical flask, aromatic aldehyde 3 (0.01 mol), dimedone 1 (0.01 mol), ethyl

acetoacetate 4 (0.01 mol) and ammonium acetate 2 (0.02 mol) were mixed and heated

at 120oC for the stipulated period of time. After the completion of the reaction (vide

TLC, Benzene: Ethyl acetate = 90:10), reaction mixture was cooled to room

temperature and added 10 ml EtOH and contents were poured in ice-cold water, when

solid separated out. Solid obtained was filtered, dried and recrystallized from ethanol

to afford compound 5a-5l (table 1).

O

O

CH3

CH3

OEt

CH3

O

O

R

H O

NH4OAc

+NH

CH3

CH3

R

OEt

OO

CH3

solvent free

reflux, 1 h, 120 oC

1

3 a-l

24

5 a-l

Scheme 15

Table 1: Synthesis of Ethyl-2,7,7-trimethyl-5-oxo-4-aryl-1,4,5,6,7,8-hexahydro

quinoline-3-carboxylate (5a-5l):

Entry R

Aldehydes

Yield

(%) Melting point (oC)

% composition Calcd./Found

C H N

5a

90 203-204 74.31

74.23

7.42

7.41

4.13

4.11

5b Cl

92 243-245 67.46

67.43

6.47

6.43

3.75

3.72


Chapter 3 Page 95

5c

Cl

93 208-209 67.46

67.42

6.47

6.46

3.75

3.74

5d NO2

91 240-242 65.61

65.60

6.29

6.25

20.81

20.75

5e

NO2

90 207-209 65.61

65.58

6.29

6.23

20.81

20.80

5f NO2

92 177-179 65.61

65.56

6.29

6.27

20.81

20.81

5g OH

89 232-233 70.96

70.94

7.09

7.07

3.94

3.93

5h OCH3

87 260-261 71.52

71.50

7.37

7.34

3.79

3.77

5i

83 207-209 75.59

75.58

7.45

7.43

3.83

3.81

5j O

88 247-248 69.28

69.25

7.04

7.00

4.25

4.21


Chapter 3 Page 96

5k CH3

92 261-262 74.76

74.74

7.70

7.61

3.96

3.96

5l N

CH3CH3

91 230-232 72.22

72.20

7.91

7.90

7.32

7.30

Spectral data of some selected compounds

Ethyl-2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

(5a):

NH

CH3

CH3

O

O

O

CH3

CH3

FT-IR (KBr, ν, cm-1): 3287 (N-H Str.), 1718 (C=O Str.),

1740 (C=O Str.).

1H NMR (400 MHz, DMSO-d6, δ, ppm): 0.94 (s, 3H,

CH3), 1.07 (s, 3H, CH3), 1.21 (t, 3H, CH3), 2.13–2.29 (m,

4H, 2xCH2), 2.35 (s, 3H, CH3), 4.06 (q, 2H, CH2CH3),

5.07 (s, 1H, CH), 6.64 (br s, 1 H, NH), 7.08–7.33 (m, 5H,

Ar-H).

13C NMR (100 MHz, DMSO-d6,δ, ppm): 194.4, 166.2,

147.4, 145.8, 142.4, 126.7, 126.5, 124.7, 110.7, 104.7,

58.5, 49.5, 35.3, 34.2, 31.3, 28.1, 25.8, 17.9, 12.9.

MS (EI, m/z(%)): 340 (M+1).

Anal. calcd. for C21H25NO3: C, 74.31; H, 7.42; N, 4.13.

Found: C, 74.23; H, 7.41; N, 4.11%.

Yield: 90%

Melting Point: 203–204oC

Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-


Chapter 3 Page 97

carboxylate (5b):

NH

CH3

CH3

O

O

O

CH3

CH3

Cl


1738 (C=O Str.).


CH3), 1.08 (s, 3H, CH3), 1.18 (t, 3H, CH3), 2.12–2.34 (m,

4H, 2xCH2), 2.37 (s, 3H, CH3), 4.04 (q, 2H, CH2CH3),

5.04 (s, 1H, CH), 6.46 (br s, 1 H, NH), 7.15–7.26 (m, 4 H,

Ar-H).


147.2, 144.3, 142.4, 130.3, 128.1, 126.4, 110.4, 104.4,

58.6, 49.4, 40.4, 34.9, 31.3, 28.1, 25.8, 18.0, 12.9.

MS (EI, m/z(%)): 374 (M+1).

Anal. calcd. for C21H24ClNO3: C, 67.46; H, 6.47; N, 3.75.

Found: C, 67.43; H, 6.43; N, 3.72%.

Yield: 92%


Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-

carboxylate (5d):

NH

CH3

CH3

O

O

O

CH3

CH3

NO2

IR (KBr): 3506 (N-H Str.), 1740 (C=O Str.), 1720 (C=O

Str.).


CH3), 1.09 (s, 3H, CH3), 1.21 (t, 3H, CH3), 2.25–2.35 (m,

4H, 2xCH2), 2.43 (s, 3H, CH3), 4.16 (q, 2H, CH2CH3),

5.15 (s, 1H, CH), 6.98 (br s, 1 H, NH) 7.42-8.05 (m, 4H,

Ar-H).


148.1, 146.9, 143.4, 133.5, 127.3, 121.5, 119.9, 109.7,

103.7, 58.7, 49.3, 35.7, 34.2, 31.4, 28.1, 25.7, 18.1, 12.9.

MS (EI, m/z(%)): 385 (M+1).

Anal. calcd. for C21H24N2O5: C, 65.61; H, 6.29; N, 20.81.

Found: C, 65.60; H, 6.25; N, 20.75%.

Yield: 91%

Melting Point: 240– 242oC

Ethyl-4-(3-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-


Chapter 3 Page 98

carboxylate (5f):

NH

CH3

CH3

O

O

O

CH3

CH3

NO2


1719 (C=O Str.).


CH3), 1.07 (s, 3H, CH3), 1.22 (t, 3H, CH3), 2.12–2.41 (m,

7H), 3.69 (q, 2H, CH2CH3), 5.15 (s, 1H, CH), 6.86 (s, 1H,

NH), 7.35-7.98 (m, 4H, Ar-H).


148.1, 146.9, 143.4, 133.5, 127.3, 121.5, 119.9, 109.7,

103.7, 58.7, 49.3, 35.7, 34.5, 31.4, 28.1, 25.7, 18.1, 12.9.

MS (EI, m/z(%)): 385 (M+1).

Anal. calcd. for C21H24N2O5: C, 65.61; H, 6.29; N, 20.81.

Found: C, 65.56; H, 6.27; N, 20.81%.

Yield: 92%


Ethyl-4-(4-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-

carboxylate (5g):

NH

CH3

CH3

O

O

O

CH3

CH3

OH


1718 (C=O Str.).


CH3), 1.08 (s, 3H, CH3), 1.20 (t, 3H, CH3), 2.08–2.18

(m, 3H, CH3), 2.20–2.35 (m, 4H, 2xCH2), 4.07 (q, 2H,

CH2CH3), 4.98 (s, 1H, CH), 5.62 (br s, 1 H, NH), 6.65-

7.16 (m, 4H, Ar-H).

13C NMR (100 MHz, DMSO-d6, δ, ppm): 195.3, 168.4,

156.6, 149.7, 145.3, 140.4, 131.3, 130.1, 115.5, 112.6,

106.2, 60.2, 54.9, 51.7, 41.1, 36.7, 33.4, 27.4, 19.1, 19.1,

15.1.

MS (EI, m/z(%)): 356 (M+1).


Found: C, 70.94; H, 7.07; N, 3.93%.

Yield: 89%


Ethyl-4-(4-methoxyhenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-


Chapter 3 Page 99

carboxylate (5h):

NH

CH3

CH3

O

O

O

CH3

CH3

OCH3


1716 (C=O Str.).


CH3), 1.07 (s, 3H, CH3), 1.21 (t, 3H, CH3), 2.13–2.36

(m, 7H), 2.38 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.06 (q,

2H, CH2CH3), 5.00 (s, 1H, CH), 6.01 (br s, 1 H, NH),

6.74-7.22 (m, 4H, Ar-H).


157.7, 147.7, 143.1, 139.5, 139.5, 128.9, 113.2, 112.4,

106.3, 59.7, 55.1, 50.7, 41.1, 35.6, 32.6, 29.4, 27.1, 19.4,

14.2.

MS (EI, m/z(%)): 370 (M+1).


Found: C, 71.50; H, 7.34; N, 3.77%.

Yield: 87%

Melting Point: 260-261oC

Ethyl-4-styryl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

(5i):

NH

CH3

CH3

O

O

O

CH3

CH3


1719 (C=O Str.).


CH3), 1.12 (s, 3H, CH3), 1.28 (t, 3H, CH3), 2.19–2.33

(m, 4H, 2x CH2), 2.37 (s, 3H, CH3), 4.18 (q, 2H,

CH2CH3), 4.71 (d, 1H, CH), 6.16 (dd, 1H, CH), 6.58 (d,

1H, CH), 6.23 (d, 2H), 7.21–7.32 (m, 5H, Ar-H), 9.03 (br

s, 1 H, NH).


148.1, 147.2, 143.1, 130.8, 126.5, 125.4, 124.9, 121.8,

119.1, 109.5, 108.6, 102.7, 58.5, 54.1, 49.5, 34.7, 32.1,

31.3, 28.3, 25.8, 18.1, 13.1.

MS (EI, m/z(%)): 366 (M+1).


Found: C, 75.58; H, 7.43; N, 3.81%.

Yield: 83%


Ethyl-4-(furan-2-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-


Chapter 3 Page 100

carboxylate (5j):

NH

CH3

CH3

O

O

O

CH3

O

CH3


1717 (C=O Str.).

1H NMR (400 MHz, DMSO-d6, δ, ppm):1.01 (s, 3H,

CH3), 1.10 (s, 3H, CH3), 1.25 (t, 3H, CH3), 2.21–2.28

(m, 3H, CH3), 2.34–2.38 (m, 4H, 2xCH2), 4.13 (q, 2H,

CH2CH3), 5.20 (s, 1H, CH), 5.81 (br s, 1 H, NH), 6.04–

7.19 (m, 3H, Furyl-H).


157.9, 150.5, 144.2, 140.8, 110.1, 104.7, 103.1, 59.8,

36.9, 30.2, 27.5, 21.1, 19.3, 14.2.

MS (EI, m/z(%)): 334 (M+1).


Found: C, 69.25; H, 7.00; N, 4.21%.

Yield: 88%


Ethyl-4-(4-methylphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-

carboxylate (5k):

NH

CH3

CH3

O

O

O

CH3

CH3

CH3


1715 (C=O Str.).


CH3), 1.08 (s, 3H, CH3), 1.21 (t, 3H, CH3), 2.10–2.24

(m, 4H, 2xCH2), 2.26 (s, 3H, CH3), 2.37 (s, 3H, CH3),

4.06 (q, 2H, CH2CH3), 5.03 (s, 1H, CH), 5.96 (s, 1H,

NH), 7.02-7.19 (m, 4H, Ar-H).


157.7, 147.7, 143.1, 139.5, 139.5, 128.9, 113.2, 112.4,

106.3, 59.7, 55.1, 50.7, 41.1, 35.6, 32.6, 29.4, 27.1, 19.4,

14.2.

MS (EI, m/z(%)): 354 (M+1).


Found: C, 74.74; H, 7.61; N, 3.96%.

Yield: 92%



Chapter 3 Page 101

Proposed Mechanism:

Mechanism proposed for the synthesis of polyhydroquinoline (Scheme 16) includes

the addition of 1 and 2 to give 6 with the loss of an acetic acid molecule. Knoevenagal

condensation between 3 and 4 give enone 7. Then Michael addition of 6 to 7 followed

by cyclization generates 9 via 8, which finally undergoes dehydration to yield the

target molecule 5.

CH3

CH3

O

O

+ NH4OAc +R

H O+ OEt

CH3O

O

CH3

CH3

O

NH2

OEt

CH3O

OR

+

1 2 3 4 6 7

CH3

CH3

O

NH2

R

OEt

O

O CH3

..CH3

CH3

O

NH

OEt

CH3

O

OH

HR

CH3

CH3

O

NH

OEt

CH3

OR

8 9 5 a-l

Scheme 16


Chapter 3 Page 102

3.2.2 Results and Discussion

Experimental Discussion:

In a pilot experiment dimedone, benzaldehyde, ammonium acetate and ethyl

acetoacetate were heated to synthesize Ethyl-2,7,7-trimethyl-5-oxo-4-phenyl-

1,4,5,6,7,8-hexahydroquinoline-3-carboxylate under solvent free conditions at

different temperatures. In the course of reaction, 120oC was found to be the optimum

temperature (Table 2, Entry 4) for the smooth progress of the reaction. Decrease in

the temperature, decreases the rate of reaction while increase in temperature resulted

into decomposition (Table 2, Entry 5-6) of the product.

Table 2: Effect of reaction temperature on the synthesis of 5a

S. No. Temperature Yield (%) Time

1 60 72 7

2 80 81 4

3 100 88 3

4 120 90 1

5 140 84 1

6 160 77 1

In this study, aldehydes carrying different electron donating and electron withdrawing

functional groups were employed. The reactions with aldehydes having electron

withdrawing groups were completed in shorter time period as compared to those

carrying electron donating groups. In all the cases, desired products were obtained in

high yield (83-93%) without the formation of any side product.


Chapter 3 Page 103

Spectral Discussion:

Mass Spectral Study:

Mass spectra were recorded on LC-MS Spectrometer Model Q-ToF Micro Waters.

Systematic fragmentation pattern was observed in mass spectral analysis. Molecular

ion peak was observed in agreement with molecular weight of respective compound.

Mass fragmentation pattern for a representative compound of each series is depicted

below.

NH

CH3

CH3

O

O

O

CH3

CH3

ClNH

CH3

CH3

O

O

O

Cl

NH

CH3

CH3

O

O

O

CH3

Cl

NH

CH3

O

O

O

CH3

NH

O

O

CH3

CH3

Cl

NH

CH3

CH3O

O

CH3

Cl

NH

O

OH

O

Cl

NH

CH3

CH3

O

(M+1)

NH

O

NH

NH

CHCH3

CH3

O

O

O

CH

O

O

CH2

CH2m/z = 281 m/z = 239

m/z = 197

m/z = 91

m/z = 329

m/z = 344

m/z = 310

m/z = 252

m/z = 330

m/z = 329

m/z = 374

m/z = 302

m/z = 224 m/z = 210

m/z = 156

.+.+

.+

+

.+

.+

.

.+

.+

.+.+

.+

.+.+

Figure 1: Mass fragmentation of Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5b.


Chapter 3 Page 104

NH

O

CH3

CH3

O O

CH3

CH3

NO2

OH

CH3

O O

CH3

CH3

NH

O

CH3

O O

CH3

CH3

NO2

N

O

O O

CH3

NO2

NH

O CH3

O O

CH3

CH3

NH

O CH3

O

CH3

NH

O

CH3

O O

CH3

CH3

NH

CH3

O

NO2

CH2

O

O

NH

O

CH3

O O

CH3

CH3

NH

OCH2

NH

OCH

N

O

O

CH3

CH

m/z = 170

m/z = 240

m/z = 310

m/z = 297

m/z = 355

m/z = 325m/z = 309

m/z = 283

m/z = 324

m/z = 296

m/z = 239m/z = 189

m/z = 253

m/z = 385(M+1)

.+

.+

.

.

.+

.+

.+

.+

.+

.+

.+

.+

.+

Figure 2: Mass fragmentation of Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydro quinoline-3-carboxylate, 5d.


Chapter 3 Page 105

Figure 3: Mass spectrum of Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5b.

Figure 4: Mass spectrum of Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5d.


Chapter 3 Page 106

IR Spectral Study:

IR spectra were recorded on Perkin-Elmer Spectrum II infra-red spectrophotometer

using KBr pellet method. Various functional groups present in the molecule were

identified by characteristic frequency obtained for them. For Ethyl-2,7,7-trimethyl-5-

oxo-4-aryl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5a-l, confirmatory bands for

carbonyl (C=O) stretching was observed at 1740 cm-1 for ester and 1720 cm-1 for

ketone groups. Another characteristic band for N-H deformation was observed in

3200-3500 cm-1. Peaks for sp3 and sp2 (Aromatic) C-H stretching were observed

around 2900 cm-1 and 3050-3150 cm-1 respectively. Presence of electron withdrawing

and electron donating groups effects the IR values. Obtained IR data suggested the

formation of 1,4-dihydropyridine ring.

1H NMR Study:

1H NMR spectra were recorded in DMSO-d6 solution on a Bruker Avance II 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 confirms the structures of Ethyl-2,7,7-trimethyl-5-oxo-4-aryl-

1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5a-l, on the basis of following signals:

broad singlet for N-H group and C-H group proton was observed at δ 6.50 and δ 5.00

ppm, indicating the presence of 1,4-dihydropyridines ring. The aromatic ring protons

were observed at δ 6.9-8.10 and J value was found to be in accordance with

substitution pattern on phenyl ring.

Table 3: Comparison of 1H NMR values of some selected compounds from 5a-5l.

Entry 1H NMR values δ in ppm

Ar-H N-H C-H CH3 CH3 CH3 CH3 OCH2 2xCH2

5a 7.08-7.33 6.64 5.07 0.94 1.07 1.21 2.35 4.06 2.13-2.29

5b 7.15-7.26 6.46 5.04 0.94 1.08 1.18 2.37 4.04 2.12-2.34

5d 7.42-8.05 6.98 5.15 0.99 1.09 1.21 2.43 4.16 2.25-2.35

5h 6.74-7.22 6.01 5.00 0.94 1.07 1.21 2.38 4.06 2.13–2.36


Chapter 3 Page 107

From the table 3, it is evident that presence of electron donating group shields the

protons, resulting in the lowering of the δ value and electron withdrawing groups de-

shield the protons, resulting in the increase in the δ values.

13C NMR Study:

13C NMR spectra were recorded in DMSO-d6 solution on a Bruker Avance II 100

MHz spectrometer using TMS as an internal standard. Number of carbon atoms and

their chemical shifts were found to support the structure of the synthesized

compounds.

From the spectrum it was observed that two peaks around δ 190-200 and δ 160-170

ppm are for the two carbonyl carbons. The peaks in the aromatic region δ 120-140

ppm showed the presence of aromatic carbon atoms. Further the presence of methyl

carbon was observed around δ 12-40 ppm. Electron withdrawing and electron

donating groups affect the peaks by shifting it towards higher or lower δ values,

respectively.


Chapter 3 Page 108

Figure 5: 1H NMR Spectrum of Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5b.

Figure 6: 1H NMR Spectrum of Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5d.


Chapter 3 Page 109

Figure 7: 13C NMR spectrum of Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5b.

Figure 8: 13C NMR spectrum of Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5d.


Chapter 3 Page 110

3.2.3 Antibacterial Activity

Synthesized compounds 5a-l were screened for their in vitro antibacterial activity

against six bacterial species namely Klubsellia pneumonia (MTCC 3384),

Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 443),

Straphylococcus aureus (MTCC 96), Bacillius subtilis (MTCC 441), Streptoccus

pyrogens (MTCC 442). Amoxicillin was used as the standard drug, as positive control

while the DMSO was used as negative control.

The minimum inhibitory concentrations of the prepared compounds (5a-5l) were

determined by using Serial tube dilution method at the concentration of 128, 64, 32,

16, 8, 4, 2 and 1 μg/ml against above said microorganisms. The bacterial strains

susceptibility to the studied compounds was determined by the appearance of

turbidity after 24 h of incubation at 37oC. The observed MIC values (µg/ml) for the

compounds 5a-5l are given in table 4.

It is evident from Table 4 that the compounds 5f shows most significant activity

against the various strains namely Escherichia coli, Klubsellia pneumonia,

Pseudomonas aeruginosa, Straphylococcus aureus (gram +ve strains), Bacillius

subtilis (gram -ve strains) at MIC of 8 & 4 µg/ml. The compound 5e displayed potent

activity against Klubsellia pneumonia, Pseudomonas aeruginosa and Straphylococcus

aureus with MIC 8 µg/ml. Compound 5h & 5k were found to be most active against

the Escherichia coli, Klubsellia pneumonia strains. From the antimicrobial activity

data Table 4, some analogs of this series were found to have significantly high

potency against the test microorganisms while some of them have comparable

potency as the reference drugs.


Chapter 3 Page 111

Table 4: Minimum inhibition concentrations (µg/ml) of compounds 5a-5l.

Entry Gram (+ve) bacteria Gram (-ve) bacteria

E.

coli

K.

pneumonia

P.

aeruginosa

S.

aureus

B.

subtilis

S.

pyrogens

5a 32 16 64 32 64 16

5b 32 32 64 128 64 16

5c 16 32 64 32 32 32

5d 16 16 32 32 32 32

5e 32 16 16 8 8 32

5f 8 8 8 8 4 64

5g 64 8 8 8 32 32

5h 8 32 32 32 32 16

5i 32 64 16 16 32 32

5j 16 32 64 16 16 64

5k 8 8 64 16 16 32

5l 16 32 32 32 32 8

Amoxicillin 4 4 4 4 4 4


Chapter 3 Page 112

3.3 Synthesis of 2-Amino-4-aryl-3-cyano-7,7-dimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline (5a-5l): 3.3.1 Experimental and characterization General procedure

In a conical flask aromatic aldehyde 2 (0.01 mol), dimedone 1 (0.01 mol),

malononitrile 3 (0.01 mol), ammonium acetate 4 (0.02 mol) and glycerol (10 ml) were

taken and heated at 110oC for stipulated time. After the completion of reaction (vide

TLC, benzene : ethyl acetate = 90:10), reaction mixture was cooled to room

temperature and added 50 ml ice-cold water when solid separated out. Solid was

filtered, dried and recrystalised from ethanol to afford compound 5a-5l table 5.

O

OCH3

CH3

O

R

H

CN

CN

NH4OAc

+NH

CH3

CH3

O

CN

NH2

R

Glycerol

reflux

1

2

34 5

Scheme 17

Table 5: Synthesis of 2-Amino-4-aryl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline (5a-5l)

Entry R

Aldehydes

Yield

(%) Melting point (oC)

% composition Calcd./Found

C H N

5a

92 277–278 73.72

73.61

6.48

6.58

14.33

14.31

5b Cl

90 285-287 65.96

65.87

5.50

5.44

12.83

12.82


Chapter 3 Page 113

5c Cl

91 265-267 65.96

65.95

5.50

5.48

12.83

12.83

5d Br

90 283-284 58.08

58.02

4.84

4.80

11.29

11.25

5e Br

90 292-294 58.08

58.03

4.84

4.81

11.29

11.31

5f F

91 272-273 69.44

69.40

5.83

5.83

13.50

13.49

5g NO2

91 284-286 63.90

63.77

5.32

5.32

16.56

16.48

5h NO2

92 275-276 63.90

63.81

5.32

5.30

16.56

16.51

5i OH

89 270-271 69.90

69.83

6.15

6.13

13.59

13.58

5j OH

90 283-285 69.90

69.77

6.15

6.14

13.59

13.55

5k CH3

89 292-294 74.27

74.19

6.84

6.81

13.68

13.62


Chapter 3 Page 114

5l OCH3

87 290-291 70.58

70.45

6.50

6.41

13.00

13.01

Spectral Data of compounds

2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline

(5a):

NH

CN

NH2CH3

CH3

O

FT-IR (KBr, ν, cm-1): 3436 (N-H Str.), 3324 (N-H Str.),

2197 (CN Str.), 1719 (C=O Str).


CH3), 1.09 (s, 3H, CH3), 2.01–2.37 (m, 4H, 2×CH2),

4.38 (s, 1H, CH), 5.36 (s, 2H, NH2), 7.07–7.29 (m,

5H, Ar-H), 8.94 (s, 1H, NH).


155.3, 143.9, 128.4, 127.8, 126.2, 119.7, 113.5, 59.7,

50.8, 37.0, 36.9, 32.8, 29.5, 27.4.

MS (EI, m/z(%)): 294.3 (M+1).

Anal. Calcd for C18H19N3O: C, 73.72; H, 6.48; N,

14.33. Found: C, 73.61; H, 6.58; N, 14.31%.

Yield: 92%

Melting Point: 277–278°C


Chapter 3 Page 115

2-Amino-4-(4-chlorophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline(5b):

NH

CN

NH2CH3

CH3

O

Cl

FT-IR (KBr, ν, cm-1): 3437 (N-H Str.), 3326 (N-H

Str.), 2188 (CN Str.), 1722 (C=O Str.).


CH3), 1.04 (s, 3H, CH3), 2.02–2.35 (m, 4H, 2×CH2),

4.17 (s, 1H, CH), 5.48 (s, 2H, NH2), 7.08–7.19 (m,

4H, Ar-H), 8.99 (s, 1H, NH).


155.6, 145.5, 128.4, 127.7, 126.6, 120.8, 113.5, 59.3,

51.4, 37.5, 36.7, 32.5, 29.9, 26.8.

MS (EI, m/z(%)): 327.45 (M+1).

Anal. Calcd for C18H18ClN3O: C, 65.96; H, 5.50; N,

12.83. Found:C, 65.87; H, 5.44; N, 12.82%.

Yield: 90%

Melting Point: 285-287°C

2-Amino-4-(3-chlorophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline(5c):

NH

CN

NH2CH3

CH3

O

Cl


2197 (CN Str.), 1720 (C=O Str.).


CH3), 1.09 (s, 3H, CH3), 1.97–2.38 (m, 4H, 2×CH2),

4.34 (s, 1H, CH), 5.39 (s, 2H, NH2), 7.21–7.41 (m,

4H, Ar-H), 8.96 (s, 1H, NH).


155.7, 143.6, 128.5, 127.4, 126.9, 120.8, 113.4, 59.5,

51.4, 37.5, 36.6, 32.7, 29.7, 27.4.

MS (EI, m/z(%)): 327.45 (M+1).

Anal. Calcd for C18H18ClN3O: C, 65.96; H, 5.50; N,

12.83. Found: C, 65.95; H, 5.48; N, 12.83%.

Yield: 91%



Chapter 3 Page 116

2-Amino-4-(4-bromophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline (5d):

NH

CN

NH2CH3

CH3

O

Br


2196 (CN Str.), 1721 (C=O Str.).


CH3), 1.05 (s, 3H, CH3), 2.05–2.35 (m, 4H, 2×CH2),

4.36 (s, 1H, CH), 5.46 (s, 2H, NH2), 7.02–7.27 (m,

4H, ArH), 8.83 (s, 1H, NH).


155.6, 144.5, 128.7, 127.5, 126.5, 119.7, 112.9, 59.7,

50.9, 37.4, 36.5, 32.7, 29.6, 27.4.

MS (EI, m/z(%)): 371.9 (M+1).

Anal. Calcd for C18H18BrN3O: C, 58.08; H, 4.84; N,

11.29. Found: C, 58.02; H, 4.80; N, 11.25%.

Yield: 90%


2-Amino-4-(3-bromophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline (5e):

NH

CN

NH2CH3

CH3

O

Br


2197 (CN Str.), 1722 (C=O Str.).


CH3), 0.98 (s, 3H, CH3), 2.14–2.47 (m, 4H, 2×CH2),

4.36 (s, 1H, CH), 5.37 (s, 2H, NH2), 7.09–7.21 (m,

4H, ArH), 8.90 (s, 1H, NH).


155.5, 144.3, 128.7, 127.4, 126.3, 120.6, 113.5, 59.6,

50.9, 37.4, 36.7, 32.6, 29.3, 27.6.

MS (EI, m/z(%)): 371.9 (M+1).

Anal. Calcd for C18H18BrN3O: C, 58.08; H, 4.84; N,

11.28. Found: C, 58.03; H, 4.81; N, 11.31%.

Yield: 90%



Chapter 3 Page 117

2-Amino-4-(4-fluorophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline (5f):

NH

CN

NH2CH3

CH3

O

F


2184 (CN Str.), 1721 (C=O Str.).


CH3), 1.07 (s, 3H, CH3), 2.11–2.49 (m, 4H, 2×CH2),

4.22 (s, 1H, CH), 5.52 (s, 2H, NH2), 7.16–7.32 (m,

4H, ArH), 8.84 (s, 1H, NH).


155.7, 144.5, 128.3, 127.5, 127.4, 121.6, 113.5, 59.8,

50.8, 37.4, 36.5, 32.4, 30.1, 27.4.

MS (EI, m/z(%)): 312.35 (M+1).

Anal. Calcd for C18H18FN3O: C, 69.44; H, 5.83; N,

13.50. Found: C, 69.40; H, 5.83; N, 13.49%.

Yield: 91%


2-Amino-4-(4-nitrophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline (5g):

NH

CN

NH2CH3

CH3

O

NO2

FT-IR (KBr, ν, cm-1): 3434 (N-H Str.), 3325 (N-H

Str.), 2209 (CN Str.), 1725 (C=O Str.).


CH3), 1.09 (s, 3H, CH3), 2.07–2.49 (m, 4H, 2×CH2),

4.28 (s, 1H, CH), 5.53 (s, 2H, NH2), 7.22–7.37 (m,

4H, ArH), 8.98 (s, 1H, NH).


154.5, 144.6, 128.5, 127.2, 127.2, 121.1, 113.7, 59.7,

51.5, 37.6, 37.2, 33.0, 29.9, 26.9.

MS (EI, m/z(%)): 338 (M+1).

Anal. Calcd for C18H18N4O3: C, 63.90; H, 5.32; N,

16.56. Found: C, 63.77; H, 5.32; N, 16.48%.

Yield: 91%



Chapter 3 Page 118

2-Amino-4-(3-nitrophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline (5h):

NH

CN

NH2CH3

CH3

O

NO2

FT-IR (KBr, ν, cm-1): 3423 (N-H Str.), 3325 (N-H Str),

2196 (CN Str.), 1722 (C=O Str.).


CH3), 1.12 (s, 3H, CH3), 2.20–2.56 (m, 4H, 2×CH2),

4.59 (s, 1H, CH), 4.77 (s, 2H, NH2), 7.48–7.75 (m,

4H, ArH), 8.92 (s, 1H, NH).


155.2, 144.6, 128.5, 127.1, 126.8, 120.6, 112.8, 59.6,

51.1, 37.6, 36.9, 32.8, 30.4, 27.3.

MS (EI, m/z(%)): 338 (M+1).


16.56. Found: C, 63.81; H, 5.30; N, 16.51%.

Yield: 92%


2-Amino-4-(4-hydroxyphenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline(5i):

NH

CN

NH2CH3

CH3

O

OH

FT-IR (KBr, ν, cm-1): 3436 (O-H Str.), 3384 (N-H

Str.), 3326 (N-H Str.), 2196 (CN Str.), 1719 (C=O).


CH3), 1.09 (s, 3H, CH3), 2.11–2.45 (m, 4H,

2×CH2), 4.36 (s, 1H, CH), 5.89 (s, 2H, NH2), 7.07–

7.29 (m, 4H, ArH), 8.78 (s, 1H, NH), 9.76 (s, 1H,

OH).

13C NMR (100 MHz, DMSO-d6, δ, ppm): 194.9,

166.7, 154.7, 144.3, 128.2, 127.6, 126.5, 120.8,

113.4, 59.9, 50.6, 37.5, 36.8, 32.7, 29.7, 26.8.

MS (EI, m/z(%)): 309 (M+1).


13.59. Found: C, 69.83; H, 6.13; N, 13.58%.

Yield: 89%



Chapter 3 Page 119

2-Amino-4-(3-hydroxyphenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline(5j):

NH

CN

NH2CH3

CH3

O

OH

FT-IR (KBr, ν, cm-1): 3429 (O-H Str.), 3383 (N-H Str.),

3337 (N-H Str.), 2202 (N-H Str.), 1717 (C=O Str.).


CH3), 0.99 (s, 3H, CH3), 1.99–2.30 (m, 4H, 2×CH2),

4.29 (s, 1H, CH), 5.47 (s, 2H, NH2), 7.18–7.29 (m,

4H, ArH), 8.88 (s, 1H, NH), 9.81 (s, 1H, OH).


158.0, 143.8, 128.5, 127.7, 126.6, 121.4, 113.5, 59.6,

50.7, 37.4, 36.6, 32.5, 29.8, 26.9.

MS (EI, m/z(%)): 309 (M+1).


13.59. Found: C, 69.77; H, 6.14; N, 13.55%.

Yield: 90%


2-Amino-4-(4-methylphenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline(5k):

NH

CN

NH2CH3

CH3

O

CH3


2213 (CN Str.), 1718 (C=O Str.).


CH3), 1.04 (s, 3H, CH3), 2.04 (s, 3H, CH3), 1.99–

2.36 (m, 4H, 2×CH2), 4.47 (s, 1H, CH), 5.45 (s, 2H,

NH2), 7.02–7.19 (m, 4H, ArH), 8.79 (s, 1H, NH)

ppm;


156.7, 144.5, 128.7, 127.6, 126.3, 121.7, 113.5, 59.9,

50.8, 37.1, 36.2, 32.9, 30.3, 27.2.

MS (EI, m/z(%)): 307 (M+1).

Anal. Calcd for C19H21N3O: C, 74.27; H, 6.84; N,

Yield: 89%



Chapter 3 Page 120

13.68. Found: C, 74.19; H, 6.81; N, 13.62%.

2-Amino-4-(4-methoxylphenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-

hexahydroquinoline(5l):

NH

CN

NH2CH3

CH3

O

OCH3


2209 (CN Str.), 1717 (C=O Str.).


CH3), 1.02 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 2.10–

2.48 (m, 4H, 2×CH2), 4.28 (s, 1H, CH), 5.57 (s, 2H,

NH2), 7.17–7.39 (m, 4H, Ar-H), 8.84 (s, 1H, NH).


156.8, 144.5, 128.7, 127.4, 126.9, 120.8, 114.3, 59.2,

51.3, 37.2, 37.4, 32.7, 29.5, 26.7.

MS (EI, m/z(%)): 323 (M+1).


13.00. Found: C, 70.45; H, 6.41; N, 13.01%.

Yield: 87%



Chapter 3 Page 121

Proposed Mechanism:

Using dimedone the proposed mechanism for the synthesis of fused 1,4-DHPs follow

the sequence of intermediate steps (Scheme 18), addition of 1 and 4 to give 6

followed by the removal of an acetic acid molecule. On the other side Knoevenagal

condensation between 2 and 3 generates 7, which upon Michal addition with 6

produces 8 followed by cyclization to generate 9 which finally rearranges to yield

fused 1,4-dihydropyridines 5 a-l.

CH3

CH3

O

O

+ NH4OAc +R

H O+

CH3

CH3

O

NH2

+

1 2 34 6 7

CN

CN CN

N

R

..CH3

CH3

O

NH

NH

HR

CN

CH3

CH3

O

NH

NH2

R

CN

8 9 5 a-l

CH3

CH3

O

NH2

R

CN

N

Scheme 18


Chapter 3 Page 122

3.3.2 Results and Discussion:

Experimental Discussion:

Condensation of dimedone 1, benzaldehyde 2a, malononitrile 3 and ammonium

acetate 4 were carried out in different solvents like methanol, ethanol, acetonitrile,

glycerol, toluene and chloroform. Glycerol as solvent provides the good results as

compared to other organic solvents (Table 6, Entry 3).

Table 6: Effect of solvent on the percentage yield of compounds 5a

Entry Solvent Yield (%)

1 Methanol 87

2 Ethanol 90

3 Glycerol 92

4 Toluene 60

5 Chloroform 67

6 Acetonitrile 80

Using glycerol, reaction was carried out at different temperatures and it was found

that 110oC is the optimal temperature (Table 7, Entry 4). Decrease in the

temperature, affects the time and yield to the greater extent but rise in temperature

does not affect the yield and reaction time at all (Table 7, Entry 5 & 6).


Chapter 3 Page 123

Table 7: Effect of temperature on the synthesis of compounds 5a

S. No. Temperature (oC) Yielda (%) Time (hr.)

1 80 48 3

2 90 67 3

3 100 81 2

4 110 92 1

5 120 91 1

6 130 89 1

After optimization, reaction of different aldehydes with dimedone, malononitrile and

ammonium acetate were carried out in glycerol. Reactions proceed smoothly with

aldehydes, carrying electron withdrawing groups (nitro) as well as electron donating

(ether, alkyl, halogen) substituent’s (Table 5).


Chapter 3 Page 124

Spectral Discussion:

Mass Spectral Study:

Mass spectras were recorded on LC-MS Spectrometer Model Q-ToF Micro Waters.

Systematic fragmentation pattern was observed in mass spectral analysis. Molecular

ion peak was observed in agreement with molecular weight of respective compound.

Mass fragmentation pattern for a representative compound of each series is depicted

below.

Figure 9: Mass fragmentation pattern of 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5- oxo-1,4,5,6,7,8-hexahydroquinoline 5a.

NH

CH3

CH3

O

CN

NH2

NH

CH3

CH3

O

CN NH

CH3

O

NH

CH3

O

NH2

NH

CN

NHCH3

CH3

O

CH3

CH3

O

CN

NH2

CH3

CH3

O

NH2

NCH3

CN

(M+1)

NH

CH3

O

CH2

O

NH

CH2

CH

CH3

CH3

O

CH2CH3

CH3

O

CH

m/z = 211m/z = 162

m/z = 156

m/z = 279

m/z = 254

m/z = 239m/z = 195

m/z = 194

m/z = 228

m/z = 91 m/z = 137

m/z = 235

m/z = 294

m/z = 276

m/z = 238

m/z = 253

.+ .+

.+

.+.+.+

.+.+

.+

.+.+

.+.++

.+


Chapter 3 Page 125

NH

O

CH3

CH3

CN

NH2

Br

NH

O

CH3

CH3

NH2

N

O

CH3

CH3

CN

Br

NH

O

CH3 NH2

O

CH3

CH3

CN

N

Br

NH

O

NH2

NH

CH3

CN

NH2

NH

O

CH3

CH3

CN

NH2NH

NH2

N

CH2CH3

CH2

N N

CN

N

(M+1) (M+2)

.+

.+ .

+

.+

.+

.+

.+

.+

.+.

+

.+

+

.+

.+

.+

.+

m/z = 91m/z = 131m/z = 171

m/z = 197

m/z = 210 m/z = 209 m/z = 180 m/z = 155

m/z = 225 m/z = 292

m/z = 264

m/z = 253

m/z = 239

m/z = 356

m/z = 267

m/z = 355

m/z = 373 m/z = 374

Figure 10: Mass fragmentation pattern of 2-Amino-4-(4-bromophenyl)-3-cyano-7,7- dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5d.


Chapter 3 Page 126

Figure 11: Mass Spectrum of 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline 5a.

Figure 12: Mass Spectrum of 2-Amino-4-(4-bromophenyl)-3-cyano-7,7-dimethyl-5- oxo-1,4,5,6,7,8-hexahydroquinoline 5d.


Chapter 3 Page 127

IR Spectral Study:

IR spectra were recorded on Perkin-Elmer Spectrum II infra-red spectrophotometer

using KBr pellet method. Various functional groups present in molecule were

identified by characteristic frequency obtained for them. For 2-Amino-4-aryl-3-cyano-

7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5a-l, confirmatory bands for

carbonyl (C=O) stretching was observed at 1720 cm-1. Other characteristic band for

N-H, N-H (free NH2 group) and C≡N deformation were observed at 3200—3500,

3200-3350 and 2100-2250 cm-1. Peaks for sp3 and sp2 (Aromatic) C-H starching were

observed at 2900 cm-1 and 3050-3150 cm-1 respectively. Effect of electron

withdrawing and electron donating groups has also indicated their effect on IR values.

IR data obtained supports the formation of 1,4-dihydropyridine ring.

1H NMR Study:

1H NMR spectra were recorded in DMSO-d6 solution on a Bruker Avance II 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 confirms the structures of 2-Amino-4-aryl-3-cyano-7,7-dimethyl-5-oxo-

1,4,5,6,7,8-hexahydroquinoline 5a-l, on the basis of following signals:

Broad singlet for N-H group and C-H group proton was observed at δ 8.70-9.00 and δ

4.20-4.60 ppm indicates the presence of 1,4-dihydropyridines ring. The aromatic ring

protons were observed at δ 7.00-7.90.

Table 8: Comparison of 1H NMR values of some selected compounds from 5a-5l.

Entry 1H NMR values δ in ppm

Ar-H N-H C-H NH2 CH3 CH3 2xCH2

5a 7.07-7.29 8.94 4.38 5.36 1.02 1.09 2.01-2.37

5d 7.02-7.27 8.83 4.36 5.46 0.97 1.05 2.05-2.35

5g 7.22-7.37 8.98 4.28 5.53 1.07 1.09 2.07-2.49

5k 7.02-7.19 8.79 4.47 5.45 0.97 1.04 1.99-2.36


Chapter 3 Page 128

From table 8, it is clear that presence of electron donating group shields the aromatic

ring and 1,4-DHP rings, resulting into lowering of the δ value and electron

withdrawing groups de-shield the protons resulting into increasing in the δ values and

J value were found to be in accordance with substitution pattern on phenyl ring.

13C NMR Study: 13C NMR spectra were recorded in DMSO-d6 solution on a Bruker Avance II 100

MHz spectrometer using TMS as an internal standard. Number of carbon atoms and

their chemical shifts were found to support the structure of the synthesized

compounds.

From the spectra it was observed that peak for the carbonyl carbon was around δ 190-

200 ppm. The peaks at δ 120-150 ppm showed the presence of aromatic carbon atoms

depending upon the electron donating or withdrawing groups attached to the phenyl

ring. Further the presence of methyl groups was observed around δ 20-40 ppm. Peak

for C≡N was observed around δ 110-125. Presence of electron withdrawing and

electron donating groups affect the peaks towards higher and lower δ values,

respectively.


Chapter 3 Page 129

Figure 13: 1H NMR Spectrum of 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5a.

Figure 14:1H NMR spectrum of 2-Amino-4-(4-bromophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5d.


Chapter 3 Page 130

Figure 15: 13C NMR spectrum of 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5a

Figure 16: 13C NMR spectrum of 2-Amino-4-(4-bromophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5d.


Chapter 3 Page 131

3.3.3 Antibacterial Activity

Synthesized compounds 5a-l were screened for their in vitro antibacterial activity

against six bacterial species namely Klubsellia pneumonia (MTCC 3384),

Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 443),

Straphylococcus aureus (MTCC 96), Bacillius subtilis (MTCC 441), Streptcoccus

pyrogens (MTCC 442). Amoxicillin was used as the standard drug as positive control

while the DMSO was used as negative control.

The minimum inhibitory concentrations of the prepared compounds (5a-5l) were

determined by using Serial tube dilution method at the concentration of 128, 64, 32,

16, 8, 4, 2 and 1 μg/ml against above said microorganisms. The bacterial strains

susceptibility to the studied compounds was determined by the appearance of

turbidity after 24 h of incubation at 37oC. The observed MIC values (µg/ml) for the

compounds 5a-5l are represented in Table 9.

It is concluded from Table 9 that compounds 5(a-l) prohibits the growth of the many

bacterial strains. The compound 5a was found to be most potent against bacterial

strains Klubsellia pneumonia (MIC 4 µg/ml), Straphylococcus aureus, Bacillius

subtilis, Streptoccus pyrogens. 5b also seems to be active against Klubsellia

pneumonia at MIC 8 µg/ml. The 5c & 5d could exhibit significant activity against

Klubsellia pneumonia, Pseudomonas aeruginosa and Escherichia coli strains

respectively. The compound 5f & 5g showed significant activity against the

Escherichia coli, Straphylococcus aureus (MIC 8 & 4 µg/ml)strains while 5h & 5i

displayed activity against strains of Bacillius subtilis and Escherichia coli with MIC 8

µg/ml. Further 5l was also found to be active against the Escherichia coli and

Pseudomonas aeruginosa. Among the screened samples, many compounds emerged

as most active against tested microorganisms and found to be comparable to the

standard drugs (MIC 8 & 4 µg/ml).


Chapter 3 Page 132

Table 9: Minimum inhibition concentrations (µg/ml) of compounds 5a-5j.

Entry Gram (+ve) bacteria Gram (-ve) bacteria

E.

coli

K.

pneumonia

P.

aeruginosa

S.

aureus

B.

subtilis

S.

pyrogens

5a 16 4 64 8 8 8

5b 32 8 128 16 32 16

5c 16 8 8 16 32 16

5d 8 16 32 16 32 16

5e 16 16 32 32 32 32

5f 8 32 32 8 64 32

5g 8 32 32 4 64 64

5h 16 32 16 16 8 128

5i 8 32 32 16 32 64

5j 32 16 64 128 16 32

5k 16 64 32 32 32 32

5l 8 32 8 64 8 8

Amoxicillin 4 4 4 4 4 4


Chapter 3 Page 133

3.4. Reference

1. Quiroga, J.; Acosta, P. A.; Cruz, S.; Abonía, R.; Insuasty, B.; Nogueras,

M.; Cobo, J. Tetrahedron Lett., 2010, 51, 5443.

2. Sato, S.; Naito, Y.; Aoki, K. Carbo. Res., 2007, 342, 913.

3. Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol. Cat. A: Chem., 2007, 269,

53.

4. Kozlov, N. G.; Kadutskii, A. P. Tetrahedron Lett., 2008, 49, 4560.

5. Lai, J. T.; Kuo, P. Y.; Gau, Y. H.; Yang, D. Y. Tetrahedron Lett., 2007,

48, 7796.

6. Majumdar, K.C.; Samanta, S. K. Tetrahedron, 2001, 57, 4955.

7. Prasad, D.; Preetam, A.; Nath, M. Comptes Rendus Chimie, 2013, 16,

1153.

8. Ashry, E. S. H. E.; Awad, L. F.; Kilany, Y. E.; Ibrahim, E. I. Adv. Het.

Chem., 2009, 98, 1.

9. Yao, C. S.; Wang, C. H.; Jiang, B.; Tu, S. J. J. Comb. Chem., 2010, 12,

472.

10. Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.;

Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org. Chem.,

2008, 73, 5110.

11. Ghahremanzadeh, R.; Rashid, Z.; Zarnani, A. H.; Naeimi, H. App. Cat. A:

Gen., 2013, 467, 270.

12. Kefayati, H.; Narchin, F.; Rad-Moghadam, K. Tetrahedron Lett., 2012, 53,

4573.

13. Azzam, S. H. S.; Siddekha, A.; Pasha, M. A. Tetrahedron Lett., 2012, 53,

6306.

14. Saha, M .; Pal, A. K. Tetrahedron Lett., 2011, 52, 4872.

15. Khan, A. T.; Das, D. K. Tetrahedron Lett., 2012, 53, 2345.

16. Wan, Y.; Zhang, X. X.; Wang, C.; Zhao, L.; Chen, L.; Liu, G.; Huang, S.;

Yue, S.; Zhang, W.; Wu, H. Tetrahedron, 2013, 69, 3947.

17. Paul, S.; Das, A. R. Tetrahedron Lett., 2012, 53, 2206.

18. Tabatabaeian, K.; Shojaei, A. F.; Shirini, F.; Hejazi, S. Z.; Rassa, M.;

Chin. Chem. Lett., 2014, 25, 308.

19. Safari, J.; Banitaba, S. H.; Dehghan, S. Chin. J. Catal., 2011, 32, 1850.


Chapter 3 Page 134

20. Thirumurugan, P.; Nandakumar, A.; Muralidharan, D.; Perumal, P. T. J.

Comb. Chem., 2010, 12, 161.

21. Sashidhara, K. V.; Kumar, M.; Khedgikar, V.; Kushwaha, P.; Modukuri,

R. K.; Kumar, A.; Gautam, J.; Singh, D.; Sridhar, B.; Trivedi R. J. Med.

Chem., 2013, 56, 109.

22. Tu, S. J.; Zhang , X. H.; Han, Z. G., Cao, X. D.; Wu, S. S.; Yan, S.;

Hao, W. J.; Zhang, G.; Ma, N. J. Comb. Chem., 2009, 11, 428.

23. Sabitha, G., Reddy, G. S. K., Reddy, C. S., Yadav, J. S. Tetrahedron Lett.,

2003, 44, 4129.

24. Ji, S. J., Jiang, Z. Q., Lu, J., Loa, T. P. Synlett., 2004, 32, 831.

25. Zhang, X. Y.; Li, Y. Z.; Fan, X. S.; Qu, G. R.; Hu, X. Y.; Wang, J. J. Chin.

Chem. Lett., 2006, 17, 150.

26. Maheswara, M.; Siddaiah, V.; Damu, G. L.; Venkata Rao, C. Arkivoc,

2006, 2, 201.

27. Das, B.; Ravikanth, B.; Ramu, R.; VittalRao, B. Chem. Pharm. Bull.,

2006, 54, 1044.

28. Song, G., Wang, B., Wu, X., Kang, Y., Yang, L. Synth. Commun., 2005,

35, 2875.

29. Reddy, C. S., Raghu, M. Chin. Chem. Lett., 2008, 19, 775.

30. Adibi, H.; Samimi, H. A.; Beygzadeh, M. Catal. Commun., 2007, 8, 2119.

31. Heravi, M. M.; Bakhtiri, K.; Javadi, N. M.; Bamoharram, F. F.; Saeedi,

M.; Oskooi, H. A. J. Mol. Catal. A: Chem., 2007, 264, 50.

32. Donelson, J. L.; Gibbs, A.; De, S. K. J. Mol. Catal. A: Chem., 2006, 256,

309.

33. Cherkupally, S. R.; Mekalan, R. Chem. Pharm. Bull., 2008, 56, 1002.

34. Sufirez, M.; Ochoa, E.; Verdecia, Y.; Verdecia, B.; Moran, L.; Martin, N.;

Quinteiro, M.; Seoane, C.; Soto, J. L.; Novoa, H.; Blaton, N.; Peters, O. M.

Tetrahedron, 1999, 55, 875.

35. Li, M.; Zuo, Z.; Wen, L.; Wang, S. J. J. Comb. Chem., 2008, 10, 436.

36. Tu, S. J.; Zhou, J. F.; Deng, X.; Cai, P. J.; Wang, H.; Feng, J. C. Chin. J.

Org. Chem., 2001, 21, 313.

http://pubs.acs.org/action/doSearch?action=search&author=Modukuri%2C+Ram+K.&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Kumar%2C+Abdhesh&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Gautam%2C+Jyoti&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Singh%2C+Divya&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Sridhar%2C+Balasubramaniam&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Tu%2C+S&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Yan%2C+S&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Hao%2C+W&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Hao%2C+W&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Zhang%2C+G&qsSearchArea=author

Documents

Chapter-3 - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/45493/9/09...Few synthesis of fused 1,4DHPs with dimedone were summarized in - review 8 and some are discussed below