regioselective synthesis of novel 2-chloroquinoline derivatives of 1, 4-dihydro pyridines k. rajesh,...

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Research on Chemical Intermediates ISSN 0922-6168Volume 40Number 5 Res Chem Intermed (2014)40:1851-1866DOI 10.1007/s11164-013-1085-4

Regioselective synthesis of novel 2-chloroquinoline derivatives of 1,4-dihydropyridines

K. Rajesh, P. Iniyavan, S. Sarveswari &V. Vijayakumar

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Regioselective synthesis of novel 2-chloroquinolinederivatives of 1,4-dihydropyridines

K. Rajesh • P. Iniyavan • S. Sarveswari •

V. Vijayakumar

Received: 27 November 2012 / Accepted: 25 January 2013 / Published online: 13 February 2013

� Springer Science+Business Media Dordrecht 2013

Abstract Highly regioselective reaction of some substituted 2,4-dichloroquino-

lines with symmetrical 1,4-dihydropyridines, leading to novel quinoline derivatives

of DHPs, has been achieved in the presence of powdered K2CO3, as a mild and

efficient base, at moderate temperature. All the synthesized compounds were

characterized by use of IR, NMR, and mass spectral data.

Keywords Hantzsch reaction � 1,4-DHPs � 2,4-Dichloroquinolines �Regioselectivity

Introduction

Synthesis of the quinoline ring system is of major interest in the chemistry of fused

five and six-membered heterocycles, because it has many applications in

pharmaceuticals [1], and is widely present in alkaloids, therapeutics, and synthetic

analogues with interesting activity [2, 3] functioning as antimalarial [4], antiasth-

matic [5], anti-inflammatory [6], and platelet-derived growth factor receptor

tyrosine kinase (PDGF-RTK)-inhibiting agents [7]. Some quinoline derivatives and

their salts and esters can be used in the prophylaxis or treatment of arthritis,

cardiovascular diseases, diabetes, renal failure, and, particularly, eating disorders

Electronic supplementary material The online version of this article (doi:

10.1007/s11164-013-1085-4) contains supplementary material, which is available to authorized users.

K. Rajesh � P. Iniyavan � S. Sarveswari � V. Vijayakumar (&)

Centre for Organic and Medicinal Chemistry, VIT University, Vellore 632 014, Tamil Nadu, India

e-mail: [email protected]

K. Rajesh

Department of Chemistry, MS Ramaiah Institute of Technology, Bangalore 560054, Karnataka,

India

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Res Chem Intermed (2014) 40:1851–1866

DOI 10.1007/s11164-013-1085-4

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and obesity [8]. 2,4-Disubstituted quinolines with additional substituents at

positions 5 and 8 have anthelmintic properties and are also active against drug-

resistant nematodes [9]. 1,4-Dihydropyridine (1,4-DHP) derivatives are an impor-

tant class of heterocycles, owing to their potential biological activity, and they have

become valuable drugs for heart disease, with useful effects on angina, hypertension

in biological systems, and, particularly, NADH-induced biological redox reactions

[10]. DHPs, for example nifedipine, nitrendipine, and nimodipine, have found

commercial utility as calcium blockers [11, 12]. The presence of ester groups at the

3 and 5-positions on the 1,4-DHP ring is of crucial importance to their

pharmacological effects. As a result, newly synthesized generations of DHPs have

different pharmacological activity, for example anticancer [13], bronchodilating

[14], antidiabetic [15], neurotropic [16], antianginal [17], and other activity [18]. In

addition, several DHPs have anti-platelet aggregator activity [19] and act as

chemical agents in the treatment of Alzheimer’s disease [20] and as a chemo

sensitizer in tumor therapy [21]. With regard to the diversity of quinolines, 2,4-

dichloroquinolines can be key intermediates in the synthesis of 2,4-disubstituted

quinolines by stepwise substitution at the C-4 and C-2 positions, thereby introducing

new C–O bonding between the two heterocyclic nuclei, which leads to a wide range

of new structures either of biological interest or with other interesting properties.

This prompted us to conduct the work reported here, in which one of the chlorine

atoms in 2,4-dichloroquinolines is selectively replaced by 1,4-DHPs, which were

chosen on the basis of our continuous interest both in quinolines [22–29] and in 1,4-

DHPs [30–35], and their applications in medicinal chemistry.

Results and discussion

2,4-Dichloroquinolines 1a–l were synthesized by use of a method reported in the

literature [22]. The melting point, IR, 1H NMR, and mass spectral data of

compounds 1a–l were in accord with literature data (Table 1). To synthesize

molecules with highly functionalized structures, we tried to incorporate quinoline

groups with different substitution and to convert a halogen in the quinoline into a

new heteroatomic molecule, which could result new structures of high pharmaco-

logical importance or other interesting properties; this also provided the opportunity

to study regioselectivity with reference to the 2,4-dichloroquinolines and was also

expected to increase the activity of both the heterocycles chosen. As a consequence

we chose 1,4-dihydropyridines to react with 2,4-dichloroquinolines to yield new

molecular structures.

One-pot three-component reaction of b-keto ester (2 mmol), p-hydroxybenzal-

dehyde (1 mmol), and ammonium acetate (1.1 mmol) in ethanol afforded the

corresponding 1,4-dihydropyridines (1,4-DHPs) 2a (m.p. 228–230 �C) and 2b (m.p.

230–232 �C) in 86 and 83 % yield, respectively [31–34]. Although regioselective

nucleophilic substitution of 2,4-dichloroquinoline by 4-methoxybenzylalcohol in

the presence of sodium hydride [43] is known, it is not cost effective because of use

of the catalyst 15-crown-5, so powdered K2CO3 was used as a mild and efficient

base to achieve regioselective synthesis of 2,4-dichloroquinolines by reaction with

1852 K. Rajesh et al.

123


1,4-DHPs at moderate temperature, yielding 1,4-dihydropyridine derivatives of the

quinolines. We chose synthesized 1,4-dihydropyridines 2a and 2b to react with 2,4-

dichloroquinolines 1a–i, in which one of the chlorine atoms was selectively

replaced to yield new molecular structures of possibly high pharmacological

importance or with other interesting properties. Synthesis of target molecules 3a–land 4a–l was accomplished by stirring a mixture of substituted 2,4-dichloroquin-

oline 1a–i (1 mol), powdered K2CO3 (1.2 mol), and 1,4-DHP (2a or 2b) (1 mol) in

DMF at 70 �C for 48 h (Scheme 1). The results are listed in Table 2. Progress of the

reaction was monitored by TLC. After completion of the reaction, the reaction

mixture was poured into a beaker containing ice-cold water and stirred well; the

separated solid was filtered to dryness and purified by column chromatography on

silica gel (60–120 mesh) with petroleum ether–ethyl acetate 7:3 as mobile phase,

affording the products 3a–j and 4a–j in the pure form (Table 2). Better results were

observed with powdered K2CO3 than with the granular form, because the larger

surface area of the powdered form enables maximum reactivity of 2,4-dichloro-

quinolines with 1,4-DHPs. All the synthesized compounds were characterized by

use of 1H NMR, 13C NMR, and mass spectral data (detailed data are given in the

Experimental section). Compound 3c has been taken as a representative example of

the substituted 1,4-DHP-quinolines and its spectral characterization is described

below (Fig. 1).

Examination of the proton NMR spectrum of 3c reveals a triplet at d 1.26 ppm

with the coupling constant (J) 7.15 Hz which integrates to six protons and is

ascribed to methyl protons at C-10 and 100. A singlet at d 2.38 ppm integrating to

six protons is ascribed to the methyl protons at C-7 and 70. Another singlet at d2.56 ppm integrates to three protons and corresponds to methyl protons on the

quinoline ring at C-210. The quartet at d 4.12 ppm with the coupling constant

Table 1 Synthesis of compounds 1a–l

Compound R1 R2 R3 Yield (%) M.p. (�C)a

1a –H –H –H 48 65–66 (66–67) [36]

1b –CH3 –H –H 56 92–93 (91–93) [36]

1c –H –CH3 –H 51 80 [37]b

1d –H –H –CH3 55 81–82 (81–82) [38]

1e –OCH3 –H –H 57 167 (168) [39]

1f –H –H –OCH3 34 133–134 (134) [39]

1g –F –H –H 46 94–96 (95) [40]

1h –H –Cl –H 50 106–108 (107) [41]

1i –Br –H –H 42 134

1j –F–Cl–H 36 114–116 (114–116) [22]

1k –CH3–H–CH3 52 102–104 (104–106) [38]

1l 2,4-Dichlorobenzo[h]quinoline 40 131 (131) [42]

a Literature melting points are given in brackets, with the references in square bracketsb Although no melting point is available in the literature, synthesis of this compound has been reported

Regioselective synthesis of novel 2-chloroquinoline derivatives 1853

123


(J) 7.15 Hz integrates to four protons and arises from protons at C-9 and 90. The

singlet at d 5.06 ppm integrating to one proton is ascribed to the proton at C-4 and

the broad singlet at d 5.63 ppm integrating to one proton corresponds to the –NH

proton. The aromatic chemical shift values appeared at 6.48 (s, 1 proton at H-16),

7.03 (d, J = 8.0 Hz, 2 protons at C-13 and 130), 7.42 (d, J = 8.0 Hz, 2 protons at

CHO

NH4OAC

O

O O

O

OH

R

R

O O NH

O

O O

O

OH

R

Rethanol

+ H2CCOOH

COOH

POCl3

5h

1 (a-j)

3 (a-j) (R=C2H5)4 (a-j) (R=CH3)

N

Cl

Cl

R1

R3

R2

NH

O O

O

O

O

N

Cl

R

R

R1

R2

R32a (R=C2H5)2b (R=CH3)

NH2

R1

R2

R3

DMFK2CO3

Scheme 1 Synthesis of 2-chloroquinoline-substituted 1,4-dihydropyridines

Table 2 Synthesis of compounds 3a–d, 3f–j and 3I; 4a–e, 4g–i, 4k and 4I

Compound R1 R2 R3 R Yield (%) M.p. (�C)

3a –H –H –H C2H5 71 172

3b –CH3 –H –H C2H5 73 174–176

3c –H –CH3 –H C2H5 67 180–182

3d –H –H –CH3 C2H5 80 172

3f –H –H –OCH3 C2H5 62 178–180

3g –F –H –H C2H5 70 176

3h –H –Cl –H C2H5 74 186–188

3i –Br –H –H C2H5 78 182

3j –F –Cl –H C2H5 67 184–186

3l 2,4-Dichlorobenzo[h]quinoline C2H5 65 198–200

4a –H –H –H CH3 82 220–222

4b –CH3 –H –H CH3 85 196–198

4c –H –CH3 –H CH3 74 210–212

4d –H –H –CH3 CH3 78 190–192

4e –OCH3 –H –H CH3 72 222–224

4g –F –H –H CH3 71 220–222

4h –H –Cl –H CH3 69 198–200

4i –Br –H –H CH3 75 226–228

4k –CH3 –H –CH3 –CH3 61 226–228

4l 2,4-dichlorobenzo[h]quinoline CH3 73 238–240


123


C-12 and 120), 7.66 (s, 1 proton at C-22), 7.84 (d, J = 8.0 Hz, 1 proton at H-20),

8.16 (d, J = 8.0 Hz, 1 proton at H-19). The chemical shift value at d 8.27 ppm

(s, –OH, 1H) of the reactant molecule 2a was not observed in the target molecule 3cand a shift in the –NH peak from d 7.60 to d 5.63 ppm was also observed. The

signal at d 6.48 ppm (s, 1H, H-16), which is the characteristic of the H-3 proton of

quinoline, indicates formation of the target molecule 3c.

Examination of the 13C NMR spectrum of 3c reveals chemical shift values at d14.33 (C-10, 100), 19.62 (C-7, 70), 24.21 (C-210), 39.37 (C-4), 59.84 (C-9, 90),104.04 (C-3, 5), 105.86 (C-16), 120.30 (C-13, 130), 121.87 (C-18), 126.72 (C-19),

129.07 (C-22), 130.02 (C-12, 120), 130.44 (C-20), 135.61 (C-11), 141.75 (C-21),

144.05 (C-2, 6), 145.87 (C-23), 150.47 (C-17), 151.86 (C-14), 165.82 (C-15),

167.50 (C-8, 80). The m/z value of 3c was 521.1 [M ? 1]. The above discussion of

the spectral data clearly reveals the formation of the desired compound 3c. In a

similar way, the other compounds 3a, b, and d–l (except 3e and 3k) and

4a–l (except 4f and 4j) in this series were also characterized by spectral studies; the

data are included either in the Experimental section or as supplementary data.

Use of K2CO3 under mild experimental conditions greatly suppressed the

formation of disubstituted products and constitutional isomers, hence regioselec-

tivity was increased. A similar reaction, that of 4-chlorobenzenethiol with

2,4-dichloroquinoline at room temperature in the presence triethylamine as mild

base also leads to the 4-substituted product rather than the 2-substituted product

[44]. This is further supported by the observation that use of an acid catalyst in

absolute ethanol alone result in regioselectivity at C2 [45]. Reaction of 1b with

sodium azide at a molar ratio of 1:1 in DMF led regioselectively to 4-azido-2-

chloro-6-methylquinoline (5b) [29], which also indicates the selective reactivity at

C4 of 2,4-dichloroquinolines (Scheme 2). Compound 5b was crystallized from

CHCl3 and then subjected to single-crystal X-ray diffraction study (the ORTEP plot

is given in Fig. 2.).

HN

OO

O

O

O

N

Cl

11 13'

12'

13

10'

9'8'

8

9

10

7

7'

6

5

43

2

1

23

22

2120

19

18

15

1617

14

21'CH3

12

Fig. 1 Diethyl 4-(4-(2-chloro-7-methylquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate


123


Kinetic studies reported in the literature also indicate that the chlorine at C4 of

dichloroquinolines is approximately twice as reactive toward nucleophiles as that at

C2, and that predominately an addition–elimination process occurs [46, 47]. From

these results we reach the conclusion that reaction of 2,4-dichloroquinolines and

1,4-DHPs leads to attack on C-4 rather than C-2 under the mild experimental

conditions used.

N

Cl

Cl

H3C

N

Cl

H3C

N

H3C

Cl

N

N+

N-

N N

N

NaN3/DMF

5a

5b

5c

Scheme 2 Synthesis of 4-azido-2-chloro-6-methylquinoline (5b)

Fig. 2 ORTEP plot of 4-azido-2-chloro-6-methylquinoline (5b)


123


Experimental

Solvents and reagents were commercially sourced and used without further

purification. Melting points were recorded on an Elchem microprocessor-based DT

apparatus in open capillary tubes and are uncorrected. IR spectra were obtained on

an Avatar-330 FTIR spectrophotometer (Thermo Nicolet) using KBr pellets; only

noteworthy absorption (reciprocal centimeters) is listed. NMR spectra were

recorded on Bruker 200, 300, and 500-MHz spectrometers with TMS as internal

standard (chemical shifts d in ppm). Mass spectra were obtained by HRMS and LC–

MS with an Agilent 1200 series LC and Micromass zQ spectrometer. TLC was

performed on silica gel preparative plates (S.D. Fine-Chem) and spots were

visualized in an iodine chamber. Column chromatography was performed on silica

gel (60–120 mesh).

General procedure for synthesis of diethyl 4-(4-(2-chloroquinolin-4-

yloxy)phenyl)-2,6-dimethyl-1,4-dihydro pyridine-3,5-dicarboxylate

(3a–j) (except 3e and 3k)

A mixture of substituted 2,4-dichloroquinoline 1a–j (1 mol), powdered K2CO3

(1.2 mol), and diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-

dicarboxylate (2a) (1 mol) in DMF was stirred at 70 �C for 48 h. Progress of the

reaction was monitored by TLC. After completion of reaction, the reaction mixture

was poured into a beaker containing ice cold water and stirred well. The separated

solid was filtered to dryness and purified by column chromatography on silica gel

(60–120 mesh) with pet. ether–ethyl acetate 7:3 as mobile phase, which afforded the

products 3a–j in the pure form.

Diethyl 4-(4-(2-chloroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (3a)

Yield: 71 %. m.p.: 172 �C; IR (KBr, cm-1): 3,348 (–NH stretching), 2,978

(aromatic –CH stretching), 1,696 (–C=O); 1H NMR (200 MHz, CDCl3) dH: 1.25 (t,

J = 6.8 Hz, 6 protons at C-10, 100), 2.38 (s, 6 protons at C-7, 70), 4.15 (q,

J = 6.8 Hz, 4 protons at C-9, 90), 5.06 (s, 1 proton at C-4), 5.62 (bs, 1 proton at

–NH), 6.50 (s, 1 proton at C-16), 7.03 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130),7.41 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.57 (t, J = 7.0 Hz, 1 aryl proton

at C-20), 7.76 (t, J = 7.0 Hz, 1 aryl proton at C-21), 7.98 (d, J = 8.0 Hz, 1 aryl

proton at C-22), 8.30 (d, J = 8.0 Hz, 1 aryl proton at C-19); MS: m/z Calcd. For

C28H27ClN2O5: 506.1; found. 507.0 [M ? 1]; Anal Calcd for C28H27ClN2O5: C

66.33, H 5.37, N 5.53; Found: C 66.15, H 5.43, N 5.41.

Diethyl 4-(4-(2-chloro-6-methylquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine -3,5-dicarboxylate (3b)

Yield: 73 %. m.p.: 174–176 �C; IR (KBr, cm-1): 3,347 (–NH stretching), 2,977

(aromatic –CH stretching), 1,694 (–C=O); 1H NMR (200 MHz, CDCl3) dH: 1.25


123


(t, J = 6.9 Hz, 6 protons at C-10, 100), 2.38 (s, 6 protons at C-7, 70), 2.55 (s, 3

protons at C-200), 4.15 (q, J = 6.9 Hz, 4 protons at C-9, 90), 5.06 (s, 1 proton at

C-4), 5.63 (bs, 1 proton at –NH), 6.47 (s, 1 proton at C-16), 7.02 (d, J = 8.0 Hz, 2

aryl protons at C-13, 130), 7.40 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.58 (d,

J = 9.0 Hz, 1 aryl proton at C-21), 7.87 (d, J = 9.0 Hz, 1 aryl proton at C-22), 8.06

(s, 1 aryl proton at C-19); LC–MS: m/z Calcd. For C29H29ClN2O5: 520.1; found.

521.2 [M ? 1]; Anal Calcd for C29H29ClN2O5: C 66.85, H 5.61, N 5.38; Found: C

67.53, H 5.50, N 5.33.


dihydropyridine-3,5-dicarboxylate (3c)



J = 7.2 Hz, 6 protons at C-10, 100), 2.38 (s, 6 protons at C-7, 70), 2.56 (s, 3 protons

at C-210), 4.12 (q, J = 7.2 Hz, 4 protons at C-9, 90), 5.06 (s, 1 proton at C-4), 5.63

(s, 1 proton at –NH), 6.48 (s, 1 proton at C-16), 7.03 (d, J = 8.0 Hz, 2 aryl protons

at C-13, 130), 7.41 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.66 (s, 1 aryl proton

at C-22), 7.84 (d, J = 8.0 Hz, 1 aryl proton at C-20), 8.16 (d, J = 8.0 Hz, 1 aryl

proton at C-19); 13C NMR (125 MHz, CDCl3) dC: 14.33 (C-10, 100), 19.62 (C-7, 70),24.21 (C-210), 39.37 (C-4), 59.84 (C-9, 90), 104.04 (C-3, 5), 105.86 (C-16), 120.30

(C-13, 130), 121.87 (C-18), 126.72 (C-19), 129.07 (C-22), 130.02 (C-12, 120),130.44 (C-20), 135.61 (C-11), 141.75 (C-21), 144.05 (C-2, 6), 145.87 (C-23),

150.47 (C-17), 151.86 (C-14), 165.82 (C-15), 167.50 (C-8, 80); MS: m/z Calcd. For


66.85, H 5.61, N 5.38; Found: C 66.73, H 5.53, N 5.29.


dihydropyridine-3,5-dicarboxylate (3d)






at C-13, 130), 7.42 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.49 (t, J = 6.0 Hz,

1 aryl proton at C-20), 7.63 (d, J = 6.0 Hz, 1 aryl proton at C-21), 8.12 (d,

J = 8.0 Hz, 1 aryl proton at C-19); HRMS: m/z Calcd. For C29H29ClN2O5:

520.1765; found. 520.1758 [M?].

Diethyl 4-(4-(2-chloro-8-methoxyquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (3f)

Yield: 62 %. m.p.: 178–180 �C; IR (KBr, cm-1): 3,329 (–NH stretching), 2976




123




at C-13, 130), 7.13 (d, J = 8.0 Hz, 1 aryl proton at C-21), 7.41 (d, J = 8.0 Hz, 2 aryl

protons at C-12, 120), 7.49 (t, J = 7.0 Hz, 1 aryl proton at C-20), 7.86 (d,

J = 8.0 Hz, 1 aryl proton at C-19); 13C NMR (125 MHz, CDCl3) dC: 14.32 (C-10,

100), 19.53 (C-7, 70), 39.33 (C-4), 56.02 (C-220), 59.80 (C-9, 90), 103.90 (C-3, 5),

105.50 (C-16), 109.60 (C-21), 113.55 (C-19), 120.33 (C-13,130), 121.57 (C-18),

126.52 (C-20), 130.04 (C-12, 120), 140.37 (C-11), 144.22 (C-2, 6), 146.12 (C-23),

150.50 (C-17), 151.77 (C-14), 154.50 (C-22), 163.53 (C-15), 167.53 (C-8, 80); MS:

m/z Calcd. For C29H29ClN2O6: 536.1; found. 537.1 [M ? 1]; Anal Calcd for

C29H29ClN2O6: C 64.86, H 5.44, N 5.22; Found: C 65.01, H 5.54, N 5.17.

Diethyl 4-(4-(2-chloro-6-quinolines-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (3g)




J = 7.2 Hz, 4 protons at C-9, 90), 5.06 (s, 1 proton at C-4), 5.63 (s, 1 proton at

–NH), 6.52 (s, 1 proton at C-16), 7.02 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130),7.41 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.52 (t, 1 aryl proton at C-21),

7.87–8.02 (m, 2 aryl protons at C-19, 22); 13C NMR (125 MHz, CDCl3) dC: 14.33

(C-10, 100), 19.67 (C-7, 70), 39.41 (C-4), 59.85 (C-9, 90), 104.06 (C-3, 5), 105.18

(C-16), 106.16 (C-19, JC-F2 = 23.75 Hz), 120.30 (C-13, 130), 120.87 (C-21,

JC-F2 = 23.75 Hz), 121.21 (C-18, JC-F

3 = 12.5 Hz), 130.15 (C-12, 120), 130.66

(C-22, JC-F3 = 10 Hz), 143.98 (C-2, 6), 145.62 (C-23), 146.26 (C-11), 150.61

(C-15), 151.53 (C-17), 159.47 (C-14), 162.26 (C-20, JC-F1 = 206.25 Hz), 167.45

(C-8, 80); HRMS: m/z Calcd. For C28H26ClFN2O5: 524.1514; found. 524.1527 [M?].

Diethyl 4-(4-(2,7-dichloroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-dihydro

pyridine-3,5-dicarboxylate (3h)





–NH), 6.48 (s, 1 proton at C-16), 7.01 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130),7.40 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.67 (d, J = 8.0 Hz, 1 aryl proton

at C-20), 7.90 (d, J = 8.0 Hz, 1 aryl proton at C-19), 8.27 (s, 1 aryl proton at C-22);13C NMR (125 MHz, CDCl3) dC: 14.33 (C-10, 100), 19.68 (C-7, 70), 39.42 (C-4),

59.85 (C-9, 90), 104.07 (C-3, 5), 105.36 (C-16), 120.28 (C-13, 130), 121.15 (C-18),

121.28 (C-19), 129.79 (C-20), 130.17 (C-12, 120), 132.00 (C-21), 132.37 (C-22),

143.96 (C-2, 6), 146.32 (C-11), 147.02 (C-23), 151.45 (C-17), 151.63 (C-14),

162.70 (C-15), 167.44 (C-8, 80); MS: m/z Calcd. For C28H26Cl2N2O5: 540.1; found.

541.1 [M ? 1]; Anal Calcd for C28H26Cl2N2O5: C 62.11, H 4.84, N 5.17; Found: C

62.60, H 4.75, N 5.08.


123


Diethyl 4-(4-(6-bromo-2-chloroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (3i)


(aromatic –CH stretching), 1696 (–C=O); 1H NMR (200 MHz, CDCl3) dH: 1.25 (t,



–NH), 6.51 (s, 1 proton at C-16), 7.02 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130),7.41 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.83–7.88 (m, 2 aryl protons at

C-21, 22), 8.46 (s, 1 aryl proton at C-19); HRMS: m/z Calcd. For C28H26BrClN2O5:

584.0714; found. 584.0726 [M?], 586.0699 [M ? 2].

Diethyl 4-(4-(2,7-dichloro-6-fluoroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (3j)





–NH), 6.56 (d, J = 22 Hz, 1 proton at C-16, splitting experienced due to F at C-20),

7.02 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130), 7.42 (d, J = 8.0 Hz, 2 aryl protons

at C-12, 120), 7.59 (d, J = 8.0 Hz, 1 aryl proton at C-22), 7.87-8.07 (m, 1 aryl

proton at C-19); MS: m/z Calcd. For C28H25Cl2FN2O5: 558.1; found. 559.0

[M ? 1]; Anal Calcd for C28H25Cl2FN2O5: C 60.12, H 4.50, N 5.01; Found: C

59.62, H 4.39, N 4.86.

Diethyl 4-(4-(2-chlorobenzo[h]quinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (3l)





–NH), 6.68 (s, 1 proton at C-16), 7.05 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130),7.41 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.69-7.95 (m, 4 aryl protons at

C-20, 210, 2100, 2200), 8.18 (d, J = 8.0 Hz, 1 aryl proton at C-19), 9.19 (d,

J = 8.0 Hz, 1 aryl proton at C-220); 13C NMR (125 MHz, CDCl3) dC: 14.30 (C-10,

100), 19.70 (C-7, 70), 39.43 (C-4), 59.85 (C-9, 90), 104.11 (C-3, 5), 106.39 (C-16),

117.57 (C-18), 120.29 (C-13, 130), 120.73 (C-19), 125.05 (C-220), 127.23 (C-210),127.78 (C-2100), 128.73 (C-2200), 130.07(C-12, 120), 130.28 (C-20), 130.61 (C-22),

134.25 (C-11), 143.97 (C-2, 6), 145.90 (C-23), 147.48 (C-21), 150.41 (C-17),

152.10 (C-14), 163.35 (C-15), 167.49 (C-8, 80); MS: m/z Calcd. For C32H29ClN2O5:

556.1; found. 557.1 [M ? 1]; Anal Calcd for C32H29ClN2O5: C 69.00, H 5.25, N

5.03; Found: C 69.73, H 5.17, N 5.16.


123


General procedure for synthesis of dimethyl 4-(4-(2-chloroquinolin-4-

yloxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

(4a–j) (except 4f and 4j)

A mixture of substituted 2,4-dichloroquinoline 1a–j (1 mol), powdered K2CO3

(1.2 mol), and dimethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-

3,5-dicarboxylate (2b) (1 mol) in DMF was stirred at 70 �C for 48 h. Progress of

the reaction was monitored by TLC. After the completion of reaction, the reaction

mixture was poured into a beaker containing ice cold water and stirred well. The

separated solid was filtered to dryness and purified by column chromatography on

silica gel (60–120 mesh) with pet. ether–ethyl acetate 7:3 as mobile phase, which

afforded the products 4a–j in the pure form.

Dimethyl 4-(4-(2-chloroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (4a)


(aromatic –CH stretching), 1,697 (–C=O); 1H NMR (200 MHz, CDCl3) dH: 2.38 (s,

6 protons at C-7, 70), 3.70 (s, 6 protons at C-9, 90), 5.08 (s, 1 proton at C-4), 5.73 (s,

1 proton at –NH), 6.55 (s, 1 proton at C-16), 7.02 (d, J = 8.0 Hz, 2 aryl protons at

C-13, 130), 7.40 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.57 (t, J = 7.5 Hz, 1

aryl proton at C-20), 7.78 (t, J = 8.0 Hz, 1 aryl proton at C-21), 7.98 (d,

J = 7.5 Hz, 1 aryl proton at C-22), 8.24 (d, J = 8.0 Hz, 1 aryl proton at C-19); 13C

NMR (125 MHz, CDCl3) dC: 19.64 (C-7, 70), 39.01 (C-4), 51.09 (C-9, 90), 103.78

(C-3, 5), 104.83 (C-16), 117.61 (C-18), 120.49 (C-13, 130), 122.04 (C-19), 126.36

(C-20), 128.17 (C-22), 129.69 (C-12, 120), 131.16 (C-21), 144.41 (C-2, 6), 145.65

(C-11), 148.68 (C-23), 151.29 (C-17), 151.86 (C-14), 163.45 (C-15), 167.91 (C-8,

80); HRMS: m/z Calcd. For C26H23ClN2O5: 478.1295; found. 478.1286 [M?].

Dimethyl 4-(4-(2-chloro-6-methylquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (4b)



6 protons at C-7, 70), 2.59 (s, 3 protons at C-200), 3.69 (s, 6 protons at C-9, 90), 5.01

(s, 1 proton at C-4), 5.69 (s, 1 proton at –NH), 6.48 (s, 1 proton at C-16), 7.01 (d,

J = 8.0 Hz, 2 aryl protons at C-13, 130), 7.33 (d, J = 8.0 Hz, 2 aryl protons at C-12,

120), 7.55 (d, J = 8.0 Hz, 1 aryl proton at C-21), 7.84 (d, J = 8.0 Hz, 1 aryl proton

at C-22), 8.01 (s, 1 aryl proton at C-19); HRMS: m/z Calcd. For C27H25ClN2O5:

492.1452; found. 492.1465 [M?].


dihydro pyridine-3,5-dicarboxylate (4c)


(aromatic –CH stretching), 1,695 (–C=O); 1H NMR (200 MHz, CDCl3) dH: 2.38


123


(s, 6 protons at C-7, 70), 2.56 (s, 3 protons at C-210), 3.70 (s, 6 protons at C-9, 90),5.05 (s, 1 proton at C-4), 5.73 (s, 1 proton at –NH), 6.49 (s, 1 proton at C-16), 7.07

(d, J = 6.0 Hz, 2 aryl protons at C-13, 130), 7.40 (d, J = 6.0 Hz, 2 aryl protons at

C-12, 120), 7.66 (s, 1 aryl proton at C-22), 7.82 (d, J = 8.0 Hz, 1 aryl proton at

C-20), 8.17 (d, J = 8.0 Hz, 1 aryl proton at C-19); MS: m/z Calcd. For


65.79, H 5.11, N 5.68; Found: C 66.46, H 4.98, N 5.58.


dihydro pyridine-3,5-dicarboxylate (4d)



6 protons at C-7, 70), 2.57 (s, 3 protons at C-220), 3.70 (s, 6 protons at C-9, 90), 5.08


J = 8.0 Hz, 2 aryl protons at C-13, 130), 7.41 (d, J = 8.0 Hz, 2 aryl protons at C-12,

120), 7.62 (t, J = 8.0 Hz, 1 aryl proton at C-20), 7.85 (d, J = 8.0 Hz, 1 aryl proton

at C-21), 8.22 (d, J = 8.0 Hz, 1 aryl proton at C-19); 13C NMR (125 MHz, CDCl3)

dC: 18.15 (C-220), 19.66 (C-7, 70), 38.98 (C-4), 51.09 (C-9, 90), 103.83 (C-3, 5),

104.75 (C-16), 117.14 (C-18), 119.76 (C-19), 120.47 (C-13, 130), 125.99 (C-20),

129.62 (C-12, 120), 131.31 (C-21), 136.34 (C-22), 144.34 (C-2, 6), 145.42 (C-11),

147.91 (C-17), 150.14 (C-23), 152.09 (C-14), 163.52 (C-15), 167.90 (C-8, 80); MS:

m/z Calcd. For C27H25ClN2O5: 492.1; found. 493.1 [M ? 1]; Anal Calcd for


Dimethyl 4-(4-(2-chloro-6-methoxyquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (4e)



6 protons at C-7, 70), 3.70 (s, 6 protons at C-9, 90), 3.94 (s, 3 protons at C-200), 5.08


J = 8.0 Hz, 2 aryl protons at C-13, 130), 7.39 (d, J = 10 Hz, 2 aryl protons at C-12,

120), 7.51–7.53 (m, 1 aryl proton at C-21), 7.86–7.96 (m, 2 aryl protons at C-19, 22);13C NMR (125 MHz, CDCl3) dC: 19.66 (C-7, 70), 39.02 (C-4), 51.08 (C-9, 90), 55.66

(C-200), 99.94 (C-19), 103.83 (C-3, 5), 105.15 (C-16), 118.54 (C-18), 120.46 (C-13,

130), 121.26 (C-21), 123.51 (C-22), 129.68 (C-12, 120), 144.33 (C-2, 6), 144.53

(C-11), 145.54 (C-23), 148.54 (C-17), 152.00 (C-14), 157.90 (C-20), 162.41 (C-15),

167.89 (C-8, 80); MS: m/z Calcd. For C27H25ClN2O6: 508.1; found. 509.1 [M ? 1];

Anal Calcd for C27H25ClN2O6: C 63.72, H 4.95, N 5.50; Found: C 62.93, H 5.08, N

5.42.


123


Dimethyl 4-(4-(2-chloro-6-fluoroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (4g)





C-13, 130), 7.39 (d, J = 9 Hz, 2 aryl protons at C-12, 120), 7.45-7.50 (m, 1 aryl

proton at C-21), 7.86-8.02 (m, 2 aryl protons at C-19, 22); 13C NMR (125 MHz,

CDCl3) dC: 19.65 (C-7, 70), 39.02 (C-4), 51.10 (C-9, 90), 103.77 (C-3, 5), 105.24

(C-16), 106.16 (C-19, JC-F2 = 23.75 Hz), 120.43 (C-13, 130), 121.07 (C-21, JC-

F2 = 25 Hz), 121.25 (C-18, JC-F

3 = 10 Hz), 129.75 (C-12, 120), 130.66 (C-22, JC-

F3 = 8.75 Hz), 144.40 (C-2, 6), 145.62 (C-23), 145.83 (C-11), 150.60 (C-15),

151.62 (C-17), 159.47 (C-14), 162.20 (C-20, JC-F1 = 190 Hz), 167.89 (C-8, 80); LC–

MS: m/z Calcd. For C26H22ClFN2O5: 496.1; found. 497.0 [M ? 1]; Anal Calcd for

C26H22ClFN2O5: C 62.84, H 4.46, N 5.64; Found: C 63.44, H 4.38, N 5.47.

Dimethyl 4-(4-(2,7-dichloroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (4h)


(aromatic –CH stretching), 1730, 1695 (–C=O); 1H-NMR (200 MHz, CDCl3) dH:

2.39 (s, 6 protons at C-7, 70), 3.70 (s, 6 protons at C-9, 90), 5.08 (s, 1 proton at C-4),

5.72 (bs, 1 proton at –NH), 6.55 (s, 1 proton at C-16), 7.02 (d, J = 8 Hz, 2 aryl

protons at C-13, 130), 7.39 (d, J = 8 Hz, 2 aryl protons at C-12, 120), 7.69 (d,

J = 8 Hz, 1 aryl proton at C-20), 7.92 (d, J = 8 Hz, 1 aryl proton at C-19), 8.26 (s,

1 aryl proton at C-22); HRMS: m/z Calcd. For C26H22Cl2N2O5: 512.0906; found.

512.0914 [M?].

Dimethyl 4-(4-(6-bromo-2-chloroquinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (4i)


(aromatic –CH stretching), 1696 (–C=O); 1H NMR (200 MHz, CDCl3) dH: 2.38 (s,



C-13, 130), 7.43 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.82-7.85 (m, 2 aryl

protons at C-21, 22), 8.36 (s, 1 aryl proton at C-19); 13C NMR (125 MHz, CDCl3)

dC: 19.73 (C-7, 70), 39.09 (C-4), 59.16 (C-9, 90), 103.79 (C-3, 5), 105.37 (C-16),

116.32 (C-18), 120.35 (C-20), 120.43 (C-13, 130), 121.62 (C-19), 124.57 (C-22),

129.80 (C-12, 120), 134.60 (C-21), 144.37 (C-2, 6), 145.90 (C-11), 147.25 (C-23),


C26H22BrClN2O5: 556.0; found. 557.0 [M ? 1], 559 [M ? 3]. Anal Calcd for

C26H22BrClN2O5: C 55.98, H 3.98, N 5.02; Found: C 55.57, H 3.90, N 4.89.


123


Dimethyl 4-(4-(2-chloro-6,8-dimethylquinolin-4-yloxy)phenyl)-2,6-dimethyl-

1,4-dihydro pyridine-3,5-dicarboxylate (4k)



6 protons at C-7, 70), 2.50 (s, 3 protons at C-220), 2.72 (s, 3 protons at C-200), 3.70 (s,

6 protons at C-9, 90), 5.07 (s, 1 proton at C-4), 5.70 (s, 1 proton at –NH), 6.50 (s, 1

proton at C-16), 7.01 (d, J = 8.0 Hz, 2 aryl protons at C-13, 130), 7.36 (d,

J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.45 (s, 1 aryl proton at C-21), 7.90 (s, 1

aryl proton at C-19); 13C NMR (125 MHz, CDCl3) dC: 18.03 (C-220), 19.66 (C-7,

70), 21.65 (C-200), 38.97 (C-4), 51.08 (C-9, 90), 103.84 (C-3, 5), 104.83 (C-16),

116.88 (C-18), 118.62 (C-19), 120.40 (C-13, 130), 129.59 (C-12, 120), 133.48 (C-

21), 135.93 (C-22), 135.96 (C-20), 144.31 (C-2, 6), 145.30 (C-11), 146.48 (C-17),



66.33, H 5.37, N 5.53; Found: C 67.05, H 5.45, N 5.39.

Dimethyl 4-(4-(2-chlorobenzo[h]quinolin-4-yloxy)phenyl)-2,6-dimethyl-1,4-

dihydro pyridine-3,5-dicarboxylate (4l)



6 protons at C-7, 70), 3.70 (s, 6 protons at C-9, 90), 5.08 (s, 1 proton at C-4), 5.73 (bs,


C-13, 130), 7.38 (d, J = 8.0 Hz, 2 aryl protons at C-12, 120), 7.69-7.74 (m, 2 aryl

protons at C-2200, 2100), 7.83–7.90 (m, 2 aryl protons at C-20, 210), 8.16 (d,

J = 8.0 Hz, 1 aryl proton at C-19), 9.18 (d, J = 8.0 Hz, 1 aryl proton at C-220); 13C

NMR (125 MHz, CDCl3) dC: 19.66 (C-7, 70), 39.00 (C-4), 51.10 (C-9, 90), 103.84

(C-3, 5), 106.44 (C-16), 117.62 (C-18), 118.60 (C-19), 120.40 (C-13, 130), 125.02

(C-220), 127.17 (C-210), 127.29 (C-2100), 127.75 (C-2200), 128.73 (C-20), 129.67

(C-12, 120), 130.28 (C-22), 134.25 (C-21), 144.35 (C-2, 6), 145.44 (C-11), 147.50

(C-17), 150.39 (C-23), 152.21 (C-14), 163.22 (C-15), 167.92 (C-8, 80); MS: m/

z Calcd. For C30H25ClN2O5: 528.1; found. 529.1 [M ? 1]; Anal Calcd for


Conclusion

2-Chloroquinoline derivatives of 1,4-dihydropyridines have been synthesized with

high regioselectivity by reaction of 2,4-dichloroquinolines and 1,4-DHPs in

presence of powdered K2CO3 as base, in DMF, at moderate temperature.

Acknowledgments We are grateful for financial support from the Department of Science and

Technology, Government of India (grant no. SR/FTP/CS-108/2006) and VIT University, Vellore, for

providing research facilities.


123


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