Synthesis of some quinolylpyrido[2,3 …shodhganga.inflibnet.ac.in/bitstream/10603/34621/9/09_chapter3.pdf · Synthesis of some quinolylpyrido ... MCR in solvent–free conditions,

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Synthesis of some quinolylpyrido[2,3-b][1,4]benzodiazepinones viaMCR in solvent–free conditions, and their biological studiesThe present chapter describes one–pot synthesis of some new

quinolylpyrido[2,3-b][1,4]benzodiazepinones via the MCR under solvent–free conditions. Biological screening tests for all newly synthesized compounds were also intended for exploring their bioactivity. 3.1 Introduction

Heterocycles that incorporate the seven–member diazepine ring renderinteresting bioactivities. Besides benzene, discussed in the Chapter 2, a fusion of benzodiazepine with other heterocycles also results in potential biological scaffolds.1 In the era of benzodiazepines, thus a much effort has been devoted to fusion of additional heterocyclic rings also. For example, thieno[2,3-b][1,5]benzodiazepine obtained by replacement of benzene ring of clozapine by isosteric thiophene ring. Flumezapine, for example, is more potent than clozapine due to an electron–donating methyl group at thiophene heterocycle.2

Figure 3.1 Clozpine, Flumezapine and Auranthine.Estazolam,3 triazolam,4 and alprazolam, all with triazole ring fused to the

benzodiazepine, which show a remarkable anxiolytic property are among commonly prescribed benzodiazepines. Midazolam with imidazole nucleus has sedative and hypnotic actions, employed in the treatment of insomnia. Flumazenil,5 which represents imidazole ring, is benzodiazepine antagonist, also acting as cognitive enhancer in Alzheimer’s patient.

Pyridobenzodizepines, as the prototypical privileged substructures, possess high biological and pharmacological activities.6 For instance, (-)–auranthine (Fig. 3.1)7 was isolated from Penicillium aurantiogriseum.

Chapter 3 98

Pyridobenzodizepines have been extensively studied as potential agents to modulate activities of the central nervous system and vasopressin V2 receptor.8

Pirenzepine (Fig. 3.2) is the first M1–selective muscarinic receptor antagonist that has been introduced into ulcer therapy, providing safe and unproblematic treatment of gastritis and duodenal and peptic ulcer.9 Other active pyridobenzodiazepines include rispenzepine–a novel antimuscarinic agent and propizepine introduced in the 1970s–a tricyclic antidepressant (TCA) in the treatment of depression.10 Tampramine, despite TCA action, it is selective norepinephrine reuptake inhibitor and has negligible affinity for adrenergic, histaminergic, and muscarinic receptors.11 AF–DX 116 is the inhibitor of cardio (M2) selective muscarinic receptor, which shows in vitro a 10–fold higher affinity for receptors of heart than for those of the cortex (M1).12 Moreover, as clozapine–like analogs; 8-chloro-6-(4’-methyl-l-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine I and 8-methyl-6-(4’-methyl-1-piperaziny1)-11H-pyrido[2,3-b][1,4]benzodiazepine II are active neuroleptics.13

N N

HN

O

N

N

O

N N

HN

O

N

O

NEt2

N NH

NN

N

R

Pirenzepine AF-DX 116

I: R = ClII: R = Me

N NH

Propizepine; R = MeTampramine; R = H

O N

R

Figure 3.2 Medicinally important pyridobenzodiazepine derivatives.Obesity is a serious and chronic medical condition, a major global health

issue. Liu, P. et al.14 discovered pyridobenzodiazepine sulfonamide–based bombesin receptor subtype 3 agonists. o-Phenelynediamine 1 and 2-chloronicotinic acid 2 were widely used in the synthesis. Benzodiazepine 3 after being reduced by borane gave diazepine sulfonamide 5 with sulfonyl chloride. Further, MK–7725 was found a potent, selective bombesin receptor subtype–3 agonist for the treatment of obesity.15

Chapter 3 99

NH2

NH2

R1

R2

N

O

HO

Cl

R3+MW

NH

HN

N

R1

R2

O

R3NH

HN

N

R1

R2

R3

BH3,THF

ClS

Ar

OO Base

NH

HN

N

R1

R2

R3

SOAr

O

NH

HN

N

SOO

OCF3

NO

N

HO

CF3

MK-7725

1 2 3 4

5

Petrova, M. V. et al.16 synthesized pyrido[2,3-b][1,4]benzodiazepins 10 viareaction of enaminone 8, generated from 2,3-diaminopyridine 6 and dimedone 7,with aldehydes 9.

Bai, X. et al.17 described pyrido[2,3-b][1,4]benzodiazepins 13, employing one–pot, Bischler–Napeiralski type cyclization reaction between 2,3-diaminopyridines 11 and various carboxylic acids 12.

Eberlein, W. G. et al.18 described cardioselective muscarinic receptor antagonist AF–DX 116 analogous 19 and screened for their binding affinity to muscarinic receptors located in cardiac M2 and glandular M3 tissue.

Chapter 3 100

Ellman, J. A. et al.19 used silyl linker for the direct loading of aromatic and heteroaromatic rings on to support, giving pyridobenzodiazepines 24.

Ilien, B. et al.20 described fluorescent pirenzepines 28 & 29 as potential bitopic ligands of the human M1 muscarinic receptor. Linkage of the spacers to the pirenzepine moiety produces bioactive molecules.

Liegeois, J. F. et al.21 described pyrido[2,3-b][1,4]benzodiazepins 31 from 3-amino-2-chloropyridine 14 and various 2-nitrobenzoylchloride 30 via three steps procedure. Compounds 31 gives varied pyridobenzodiazepines 32 via a modified Fryer amidine synthesis.

Chapter 3 101

Potikha, L. M. et al.22 reported pyrido[1,2-b][2,4]benzodiazepines 36 by reaction of [2-(bromomethyl)phenyl](4-chlorophenyl)methanones 33 with pyridine-2-amines 34 followed by heating with acid.

Argade, N. P. et al.23 reported total synthesis of Auranthine 39 with pyridobenzodiazepine as parent moiety. Structurally, Auranthine resembles novel microbial metabolite (-)–asperlicin, a potent neuropeptide antagonist.

3.2 Present workPyrido[2,3-b][1,4]benzodiazepinones were synthesized in the present

work, via MCR, combining 2,3-diaminopyridine, 1,3-cyclohexadione or dimedoneand quinoline-3/4-carbaldehydes under solvent–free conditions. The entire products were characterized by mass, elemental analysis, FT–IR, 1H NMR, and 13C NMR spectroscopy.

Chapter 3 102

3.2.1 Experimental3.2.1.1 Synthesis(A) Synthesis of 6-quinolyl-pyrido[2,3-b][1,4]benzodiazepine-7-ones HBC25―34.All title compounds were synthesized via steps below:a) Preparation of quinoline-carbaldehydes 1a‒e.b) Optimization of the reaction conditions.c) Synthesis of 6-quinolylpyrido[2,3-b][1,4]benzodiazepine-7-ones

HBC25―34.a) Preparation of quinoline-carbaldehydes 1a―e.

All quinoline-carbaldehydes 1a–e, except N–allyl-6-methyl–2–quinolone–3–carbaldehydes, 6–methyl–2–phenoxyquinoline–3–carbaldehyde and 7–methyltetrazolo[1,5–a]quinoline–4–carbaldehyde (utilized in Chapter 2), were prepared by the similar procedure described in Chapter 2. Aldehydes 7-chloro–2–phenoxyquinoline–3–carbaldehyde and 8-chlorotetrazolo[1,5–a]quinoline–4–carbaldehyde were derived from 2,7-dichloroquinoline-3-carbaldehyde.b) Optimization of the reaction condition.

The similar optimized reaction condition described in Chapter 2 was used for the synthesis of entire 6-quinolyl-pyrido[2,3-b][1,4]benzodiazepinones. The reaction time was however in the 3—3.5 h range for a few compounds, which was somewhat higher than earlier.c) Synthesis of 6-quinolyl-pyrido[2,3-b][1,4]benzodiazepine-7-ones HBC25―34.General procedure: In a round–bottom flask, a solvent-free equimolar mixture of 2,3-diaminopyridine (0.01 mol, 1.1 g), dione (0.01 mol, 1.4 g dimedone or 1.12 g 1,3-cyclohexanedione) and quinolone-carbaldehyde (0.01 mol, 2.6 g of 6–methyl–2–phenoxyquinoline–3–carbaldehyde or 2.8 g of 7-chloro–2–phenoxyquinoline–3–carbaldehyde or 2.1 g of 7–methyltetrazolo[1,5–a]quinoline–4–carbaldehyde or 2.3 g of 8-chlorotetrazolo[1,5–a]quinoline–4–carbaldehyde or 2.3 g of N–allyl-6-methyl–2–quinolone–3–carbaldehydes) was heated at 120 ℃ till the completion of the reaction as confirmed by the TLC (2.5―3.5 h). The crude products obtained were purified by washing with ethanol and dried at room temperature. Entire products HBC25―34 were received quantitatively with an excellent purity.

Chapter 3 103

N NH2

NH2

HO

O

RR

N NH

HN O

RR

NR2

NN

N

N NH

HN O

RR

NO

N NH

HN O

RR

NO R2

N O

CHO

N

CHOR2

N NN

(i)

(i)(i) 1e

R Me,H

N

CHO

O

R2

R1

R1

R1

R1

1a-b

1c-d

1a: R1 H, R2 Me

1b: R1 Cl, R2 H

1c: R1 H, R2 Me

1d: R1 Cl, R2 H

HBC25-28

HBC29-32HBC33-34

Scheme 3.1 The reagents and conditions (i) 120 ˚C, 2.5―3.5 hTable 3.1 Physical data of 6-quinolyl-pyrido[2,3-b][1,4]benzodiazepin-7-onesHBC25―34.Product R R1 R2 Time (h) Yield (%) M.P. °C aHBC25 Me H Me 2.8 88 296―298HBC26 H H Me 3.1 85 268―270HBC27 Me Cl H 3.0 86 252―254HBC28 H Cl H 3.2 83 246―248HBC29 Me H Me 2.9 89 288―290HBC30 H H Me 2.6 88 272―274HBC31 Me Cl H 3.2 83 230―232HBC32 H Cl H 3.5 76 236―238HBC33 Me – – 2.7 80 242―244HBC34 H – – 3.0 78 278―280 a Uncorrected

Chapter 3 104

(B) Synthesis of 6-quinolyl-5-allylpyrido[2,3-b][1,4]benzodiazepin-7-onesHBC35―44.

N NH

N O

RR

NO R2

Br

HBC25-28

HBC35-38

R1

N NH

N O

RR

NR2

HBC29-32

HBC39-42

NN

N

R1

N NH

N O

RR

NO

HBC33-34

HBC43-44

(i)

Ally bromide

Scheme 3.2 The reagents and conditions (i) K2CO3, DMF, rt, 10―12 h.General procedure: To a stirred solution of HBC25―34 (0.01 mol) in anhydrous potassium carbonate (0.015 mol) suspended in DMF (25 mL), a solution of allyl bromide (0.015 mol) in DMF (5 mL), was added a drop–wise. The reaction mixture was stirred at room temperature till the completion of the reaction as confirmed by the TLC. The resulting mass was then poured into 100 g of ice with constant stirring. The solid residue was filtered, washed well with cold water (3 x 10 mL), dried and purified by recrystallisation from aqueous ethanol. The products HBC35―44 was obtained quantitatively with an excellent purity.Table 3.2 Physical data of 6-quinolyl-5-allylpyrido[2,3-b][1,4]benzodiazepin-7-ones HBC35―44.Product R R1 R2 Yield (%) M.P. °C aHBC35 Me H Me 93 226―228HBC36 H H Me 89 238―240HBC37 Me Cl H 90 198―200HBC38 H Cl H 91 218―220HBC39 Me H Me 94 206―208HBC40 H H Me 87 200―202HBC41 Me Cl H 92 188―190HBC42 H Cl H 90 232―234HBC43 Me – – 93 176―178HBC44 H – – 91 248―250 a Uncorrected

Chapter 3 105

3.2.1.2 Biological screening test methods usedIdentical methods (2.2.1.2) that described under Experimental part in

Chapter 2 were used to screen compounds for their bioactivity [page No. 53]. 3.3. Results and discussion3.3.1 Spectroscopic data

In all compounds HBC25―44, two IR bands appeared in the 2850―3020cm-1and 3210―3510 cm-1 ranges are assigned to ν C―H and ν N―H respectively. A band in the 1631―1660 cm-1 range indicates C=O of carbonyl. Two bands; one in the 1080―1185 cm-1 range and second in the 1310―1395 cm-1 range, are assigned C―O and C―N functionalities respectively.

Figure 3.3 General structural feature of compounds HBC25―44.Two singlet peaks in 1H NMR; one in the δ 1.12―1.21ppm range and

second in the range δ 1.15―1.25 ppm are owing to six protons of two methyl attached to C―9 carbon. Two doublets; one in the δ 5.57―5.98 ppm range with coupling constant, J = 5.2―5.4 Hz, and second in the δ 5.78―6.95 ppm range with J = 4.4―5.2 Hz, can be assigned to NH―5 and CH―6 methine protonsrespectively in HBC25―34. On allylation however, NH―5 proton of HBC25―34 get disappeared, retaining still singlet CH―6 methine proton in the δ 5.93―6.20 ppmrange in HBC35―44, confirming that allylation occur at NH―5 nitrogen. A NH―11proton in HBC35-44 gave a singlet in the δ 8.86―9.92 ppm range.

The 13C NMR of HBC1―24 showed a peak ~δ 194 ppm is assigned to carbonyl carbon. All the aromatic carbons appeared in the δ 107―171 ppm range. DEPT―135 experiments, indicative of a negative peak, which showed peaks in the δ 40―55 ppm range, are due to CH2 carbon. All methyl carbon appeared in the positive δ 15―33 ppm range.

Chapter 3 106

3.3.2 Biological evaluation All biological screening test results were evaluated in comparison with

that of standard drugs listed under biological evaluation (2.3.3)― the results and discussion section of Chapter 2 [Page No. 59].

Table 3.3 displays a spectrum of biological screening test results of the all quinolylpyrido[2,3-b][1,4]benzodiazepinones HBC25-44. As it reveals, a majority of compounds tested have MIC values, against Gram +ve and Gram –ve bacteria,close to that of standard Ampicillin. A few of them have even the value more than this standard. For example, compounds HBC25,26,29,32,34,35,38,39 and HBC43, against Gram +ve Bacillus subtilis bacteria, approaches the standard drug Norfloxacin in activity. Similarly compounds HBC30 and HBC41, against same bacteria, have MICequal to both the standard drugs Chloramphenicol and Ciprofloxacin. Other standard drug covered in the same catagory is Ciprofloxacin, but against Gram +ve Clostridium tetani bacteria for HBC26,27,29,30,35,36,39 and HBC40. Apart from this, some compounds, against same bacteria, are also close to one more stranded drug. For instance, HBC25 and HBC38 have good potency equal to both Chloramphenicol and Ciprofloxacin. Compounds HBC28 and HBC43, against Gram +ve Streptococcus pneumoniae bacteria, show same potency as well. Both non-allylated and allylated products have good antibacterial properties. With a few exceptions, chloro-products, against a broad range of the bacteria, also revealed good antibacterial properties.

Although the antifungal screening test results are poor, compoundsHBC29,30,31 and HBC36, against Candida albicans fungi, with MIC close to standard Griseofulvin drugs exhibiting good antifungal nature.

Of the all tested compounds, only one compound HBC39, against M.tuberculosis H37Rv bacteria, posses remarkable anti-tuberculosis activity with a growth inhibition > 90% (MIC 125 µgmL-1). The test results are shown in Table 3.3.

The ascorbic acid antioxidant activities of all bioactive quinolylpyrido[2,3-b][1,4]benzodiazepinone scaffolds were determined by Benzie and Strain method. The values are expressed in mM per 100 g of sample (equivalent of ascorbic acid) in Table 3.3.

Chapter 3 107

Chapter 3 108

Analyzing antioxidant results, it showed a majority of the compounds with FRAP values in the 211—327 mmol/100 g range showed a moderate to good ferric reducing antioxidant power.

Analyzing the all compounds in terms of the structure that their bioactivity relates, we found quinolylpyrido[2,3-b][1,4]benzodiazepinones that was derived from methyl substituted quinoline-3-carbaldehyde and dimedone (HBC25,29,33,35,39,43), against almost all bacteria, shows good activity. The benzodiazepines derived from N-allylated quinoline-3-carbaldehyde without methyl substitution also possess good antimicrobial activity (HBC34, 44).

3.3.3 CharacterizationHBC25 6-(6-methyl-2-phenoxyquinolin-3-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C30H28N4O2

N

HN

NH

O

N

OM.P. 296―298 oCM.W. (g/mol) 476Element. Anal. C H NCal 75.61 5.92 11.76Obs 75.68 5.95 11.72

1H NMR δ ppm(CDCl3)1.14 (s, 3H, 9–CH3), 1.16 (s, 3H, 9–CH3), 2.17 (s, 2H, 8–H), 2.35 (s, 3H, 15–CH3), 2.66 (d, 1H, J = 16.0 Hz, 10–Ha), 2.79 (d, 1H, J= 16.8 Hz, 10–Hb), 5.89 (d, 1H, J = 5.2 Hz, 5–H), 6.15 (d, 1H, J= 4.8 Hz, 6–H), 6.57–7.54 (m, 12H, Ar–H), 9.01 (s, 1H, 11–H)

13C NMR δ ppm(CDCl3)21.15, 28.54, 32.39, 44.61, 49.96, 52.63, 108.82, 120.91, 121.13, 122.75, 123.47, 125.16, 125.53, 126.61, 126.88, 127.86, 129.69, 129.89, 130.06, 131.62, 131.99, 134.53, 138.53, 143.02, 153.99, 156.44, 159.62, 192.61FT–IR max cm-1

(KBr) 817, 1002, 1138, 1360, 1422, 1572, 1656, 2958, 3155, 3310

Chapter 3 109

HBC26 6-(6-methyl-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C28H24N4O2M.P. 268–270 oCM.W. (g/mol) 448Element. Anal. C H NCal 74.98 5.39 12.49Obs 74.91 5.36 12.521H NMR δ ppm(CDCl3)

2.10 (m, 2H, 3–H), 2.21 (m, 2H, 8–H), 2.37 (s, 3H, 15–CH3), 2.69 (m, 2H, 10–H), 5.80 (d, 1H, J = 5.2 Hz, 5–H), 6.21 (d, 1H, J= 4.8 Hz, 6–H), 6.70–7.64 (m, 12H, Ar–H), 8.92 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

21.15, 32.40, 44.78, 50.02, 52.22, 108.82, 120.91, 121.13, 122.88, 123.57, 125.26, 125.53, 126.61, 126.88, 127.86, 129.69, 129.89, 130.06, 131.62, 131.99, 134.53, 138.80, 143.25, 153.99, 156.44, 160.22, 193.08FT–IR max cm-1(KBr) 790, 1012, 1145, 1358, 1438, 1580, 1645, 2975, 3202

HBC27 6-(7-chloro-2-phenoxyquinolin-3-yl)-9,9-dimethyl-8,9,10,11-tetrahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C29H25ClN4O2N

HNNH

O

N

O

Cl

M.P. 252–254 oCM.W. (g/mol) 496.5Element. Anal. C H NCal 70.08 5.07 11.27Obs 69.00 5.03 11.311H NMR δ ppm(CDCl3)

1.17 (s, 3H, 9–CH3), 1.19 (s, 3H, 9–CH3), 2.22 (s, 2H, 8–CH2), 2.70 (d, 1H, J = 16.0 Hz, 10–Ha), 2.82 (d, 1H, J = 16.8 Hz, 10–Hb), 5.84 (d, 1H, J = 5.2 Hz, 5–H), 6.07 (d, 1H, J = 4.8 Hz, 6–H), 6.62–7.80 (m, 12H, Ar–H), 8.86 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

28.85, 32.32, 44.71, 50.16, 52.85, 108.63, 120.87, 121.25, 122.86, 123.43, 125.34, 125.57, 126.57, 126.67, 127.84, 129.78, 129.98, 130.75, 131.64, 132.21, 134.53, 138.53, 143.02, 153.89, 156.87, 159.54, 193.18FT–IR max cm-1(KBr) 756, 1140, 1336, 1392, 1523, 1631, 2940, 3239, 3315, 3439

Chapter 3 110

HBC28 6-(7-chloro-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C28H24N4O2

N

HN

NH

O

N

O

Cl

M.P. 246–248 oCM.W. (g/mol) 468Element. Anal. C H NCal 69.15 4.51 11.95Obs 96.22 4.48 11.911H NMR δ ppm(CDCl3)

1.90 (m, 2H, 9–CH2), 2.20 (s, 2H, 8–CH2), 2.78 (m, 2H, 10–CH2), 5.75 (d, 1H, J = 5.2 Hz, 5–H), 5.95 (d, 1H, J = 4.8 Hz, 6–H), 6.71–7.75 (m, 12H, Ar–H), 8.90 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

32.40, 44.61, 50.12, 52.77, 108.23, 120.22, 121.55, 122.95, 123.50, 125.02, 125.78, 126.22, 126.85, 127.82, 129.78, 130.18, 130.75, 131.64, 134.22, 134.53, 138.53, 143.02, 153.89, 156.87, 159.68, 193.25FT–IR max cm-1(KBr) 761, 1150, 1345, 1395, 1540, 1631, 2880, 3250, 3325, 3450

HBC29 6-(7-methyltetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C24H23N7ON

HN

NH

O

NN

NNM.P. 288–290 oCM.W. (g/mol) 425Element. Anal. C H NCal 67.75 5.45 23.04Obs 67.70 5.48 23.00

1H NMR δ ppm(CDCl3)1.21 (s, 3H, 9–CH3), 1.25 (s, 3H, 9–CH3), 2.32 (s, 2H, 8– CH2), 2.45 (s, 3H, 15–CH3), 2.79 (d, 1H, J = 16.0 Hz, 10–Ha), 2.85 (d, 1H, J = 16.8 Hz, 10–Hb), 5.98 (d, 1H, J = 5.0 Hz, 5–H), 6.33 (d, 1H, J = 4.4 Hz, 10–H), 6.34–8.36 (m, 7H, Ar–H), 8.88 (s, 1H, 11–H)

13C NMR δ ppm(CDCl3)26.53, 28.88, 32.33, 42.92, 44.61, 54.08, 107.58, 115.02, 116.37, 118.60, 120.70, 121.10, 122.73, 123.30, 130.84, 131.59, 133.55, 134.46, 135.04, 138.45, 139.13, 156.27, 161.14, 192.76FT–IR max cm-1

(KBr) 761, 980, 1175, 1310, 1385, 1580, 1645, 3220, 3340, 3510

Chapter 3 111

HBC30 6-(7-methyltetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C22H19N7OM.P. 272–274 oCM.W. (g/mol) 397Element. Anal. C H NCal 66.49 4.82 24.67Obs 66.55 4.85 24.631H NMR δ ppm(CDCl3)

1.98 (m, 2H, 9–H), 2.28 (m, 2H, 8–H), 2.35 (S, 3–H, 15–CH3), 2.72 (m, 2H, 10–H), 5.64 (d, 1H, J = 5.2 Hz, 5–H), 5.76 (d, 1H, J = 5.0 Hz, 6–H), 6.52–7.34 (m, 7H, Ar–H), 8.94 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

21.02, 22.11, 31.33, 36.62, 58.19, 108.96, 116.14, 120.65, 122.25, 123.15, 123.63, 123.99, 128.05, 129.12, 129.25, 129.83, 136.24, 136.48, 138.41, 139.57, 158.73, 193.01FT–IR max cm-1(KBr) 770, 968, 1160, 1330, 1390, 1595, 1660, 2910, 3225, 3380, 3490

HBC31 6-(8-chlorotetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C23H20ClN7OM.P. 230–232 oCM.W. (g/mol) 445Element. Anal. C H NCal 61.95 4.52 21.99Obs 61.99 4.49 22.031H NMR δ ppm(CDCl3)

1.15 (s, 3H, 9–CH3), 1.18 (s, 3H, 9–CH3), 2.18 (s, 2H, 8–CH2), 2.63 (d, 1H, J = 16.0 Hz, 10–Ha), 2.92 (d, 1H, J = 16.4 Hz, 10–Hb), 5.98 (d, 1H, J = 5.0 Hz, 5–H), 6.02 (d, 1H, J = 5.2 Hz, 6–H), 6.81–7.57 (m, 7H, Ar–H), 9.82 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

28.85, 32.32, 44.71, 44.88, 50.16, 52.85, 106.08, 120.87, 121.25, 122.86, 125.57, 127.84, 128.22, 129.78, 129.98, 130.70, 131.64, 134.53, 138.53, 139.58, 153.89, 159.54, 193.18FT–IR max cm-1(KBr) 761, 980, 1175, 1310, 1385, 1580, 1645, 2917, 3220, 3340, 3510

Chapter 3 112

HBC32 6-(8-chlorotetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C21H16ClN7OM.P. 236–238 oCM.W. (g/mol) 417Element. Anal. C H NCal 60.36 3.86 23.46Obs 60.40 3.83 23.401H NMR δ ppm(CDCl3)

1.18 (s, 2H, 9–H), 2.22 (m, 2H, 8–CH2), 2.80 (m, 2H, 10–H), 5.62 (d, 1H, J = 5.4 Hz, 5–H), 5.95 (d, 1H, J = 5.2 Hz, 6–H), 6.75–7.82 (m, 7H, Ar–H), 9.62 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

44.88, 45.08, 50.25, 52.90, 106.18, 120.77, 121.35, 123.02.125.57, 127.72, 128.28, 129.83, 130.10, 130.65, 131.78, 134.45, 138.85, 139.58, 153.95, 159.22, 193.45FT–IR max cm-1(KBr) 780, 915, 1181, 1330, 1393, 1588, 1638, 2830, 3240, 3340

HBC33 6-(1-allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C27H28N4O2M.P. 242–244 oCM.W. (g/mol) 440Element. Anal. C H NCal 73.61 6.41 12.72Obs 73.50 6.45 12.69

1H NMR δ ppm(CDCl3)

1.12 (s, 3H, 9–CH3), 1.15 (s, 3H, 9–CH3), 2.120 (s, 2H, 8–H), 2.26 (s, 3H, 15–CH3), 2.61 (d, 1H, J = 16.0 Hz, 10–Ha), 2.75 (d, 1H, J = 16.0 Hz, 10–Hb), 4.71 (m, 2H, 22–H), 5.02 (m, 2H, 20–H), 5.57 (d, 1H, J = 5.2 Hz, 5–H), 5.78 (d, 1H, J = 5.2 Hz, 6–H), 5.88 (s, 1H, 21–H), 6.43–7.84 (m, 7H, Ar–H), 8.92 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

20.34, 20.38, 28.24, 28.68, 28.84, 32.31, 44.15, 44.61, 49.97, 54.17, 107.80, 115.18, 119.72, 120.48, 120.99, 123.24, 128.73, 131.51, 131.61, 132.73, 133.72, 133.95, 136.26, 138.52, 156.16, 161.14, 192.74FT–IR max cm-1(KBr) 787, 933, 1116, 1285, 1392, 1444, 1519, 1572, 1607, 1653, 2917, 2975, 3051, 3215, 3368

Chapter 3 113

HBC34 6-(1-allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C25H24N4O2M.P. 278–280 oCM.W. (g/mol) 412Element. Anal. C H NCal 72.80 5.86 13.58Obs 72.69 5.90 13.551H NMR δ ppm(CDCl3)

2.18 (m, 2H, 9–H), 2.21 (m, 2H, 8–H), 2.30 (s, 3H, 15–CH3), 2.68 (m, 2H, 10–H), 4.75 (m, 2H, 22–H), 5.52 (m, 2H, 20–H), 5.52 (d, 1H, J = 5.2 Hz, 5–H), 5.92 (d, 1H, J = 4.8 Hz, 6–H), 6.03 (s, 1H, 21–H), 6.82–7.75 (m, 7H, Ar–H), 9.52 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

20.34, 28.75, 28.95, 32.22, 44.88, 44.98, 50.07, 54.53, 107.65, 115.25, 119.85, 120.77, 121.10, 123.35, 128.73, 131.51, 131.61, 132.73, 133.72, 133.90, 136.53, 138.22, 156.88, 161.22, 192.80FT–IR max cm-1(KBr) 782, 940, 1126, 1278, 1395, 1444, 1580, 1653, 2895, 2975, 3051, 3210HBC35 5-allyl-6-(6-methyl-2-phenoxyquinolin-3-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C33H32N4O2M.P. 226–228 oCM.W. (g/mol) 516Element. Anal. C H NCal 76.72 6.24 10.84Obs 76.65 6.28 10.87


1.12 (s, 3H, 9–CH3), 1.15 (s, 3H, 9–CH3), 2.25 (s, 2H, 8–H), 2.45 (s, 3H, 15–CH3), 2.65 (d, 1H, J = 16.0 Hz, 10–Ha), 2.72 (d, 1H, J = 16.0 Hz, 10–Hb), 3.89 (m, 2H, 22–H), 5.13 (d, 1H, J = 10 Hz, 20–Ha), 5.29 (d, 1H, J = 16.4 Hz, 20–Hb), 5.78 (m, 1H, 21–H), 6.05 (s, 1H, 6–H), 6.70–7.82 (m, 12H, Ar–H), 8.89 (s, 1H, 11–H) 13C NMR δ ppm(CDCl3)

20.35, 28.56, 28.74, 32.68, 44.52, 51.04, 56.51, 56.54, 109.49, 117.36, 120.70, 122.16, 123.01, 123.72, 125.12, 125.45, 126.54, 126.74, 127.62, 130.18, 131.70, 134.54, 136.68, 136.81, 136.87, 140.94, 143.22, 154.38, 156.31, 159.87, 192.50FT–IR max cm-1(KBr) 780, 850, 980, 1085, 1368, 1450, 1588, 1645, 2940, 3210

Chapter 3 114

HBC36 5-allyl-6-(6-methyl-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C31H28N4O2N

HNN

O

N

OM.P. 238–240 oCM.W. (g/mol) 488Element. Anal. C H NCal 76.21 5.78 11.47Obs 76.15 5.82 11.50

1H NMR δ ppm(CDCl3)1.74 (m, 2H, 9–H), 2.10 (m, 2H, 8–H), 2.34 (s, 3H, 15–CH3), 2.62 (m, 2H, 10–H), 3.97 (m, 2H, 22–H), 5.06 (d, 1H, J = 10 Hz, 20–Ha), 5.19 (d, 1H, J = 16.8 Hz, 20–Hb), 5.80 (m, 1H, 21–H), 6.20 (s, 1H, 6–H), 6.67–7.52 (m, 12H, Ar–H), 9.00 (s, 1H, 11–H)

13C NMR δ ppm(CDCl3)22.15, 32.47, 44.40, 50.04, 56.51, 56.54, 109.49, 117.36, 120.68, 122.16, 123.01, 123.72, 124.91, 125.52, 126.56, 126.74, 127.59, 130.05, 131.70, 134.43, 136.68, 136.81, 136.87, 139.94, 142.96, 154.38, 156.11, 159.76, 192.68

FT–IR max cm-1(KBr) 748, 921, 1196, 1329, 1390, 1501, 1530, 1582, 1614, 2923, 3147, 3311

HBC37 5-allyl-6-(7-chloro-2-phenoxyquinolin-3-yl)-9,9-dimethyl-5,6,8,9, 10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C32H29ClN4O2M.P. 198–200 oCM.W. (g/mol) 536Element. Anal. C H NCal 71.57 5.44 10.43Obs 71.52 5.47 10.39

1H NMR δ ppm(CDCl3)1.21 (s, 3H, 9–CH3), 1.28 (s, 3H, 9–CH3), 2.32 (s, 2H, 8–H), 2.75 (d, 1H, J = 16.0 Hz, 10–Ha), 2.85 (d, 1H, J = 16.0 Hz, 10–Hb), 3.50 (m, 2H, 22–H), 5.18 (d, 1H, J = 10 Hz, 20–Ha), 5.31 (d, 1H, J = 16.4 Hz, 20–Hb), 5.75 (m, 1H, 21–H), 6.10 (s, 1H, 6–H), 6.75–7.71 (m, 12H, Ar–H), 8.98 (s, 1H, 11–H)

13C NMR δ ppm(CDCl3)27.99, 28.83, 32.70, 44.52, 51.16, 56.51, 57.14, 109.57, 114.45, 120.73, 122.25, 123.11, 123.72, 125.22, 125.45, 126.43, 126.74, 127.56, 130.18, 131.70, 134.54, 136.68, 136.81, 136.87, 141.04, 143.22, 154.38, 156.31, 159.68, 192.74

FT–IR max cm-1(KBr) 770, 890, 1080, 1140, 1345, 1480, 1545, 1650, 2890, 3080, 3250, 3340

Chapter 3 115

HBC38 5-allyl-6-(7-chloro-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C30H25ClN4O2M.P. 218–220 oCM.W. (g/mol) 508Element. Anal. C H NCal 70.79 4.95 11.01Obs 70.82 4.98 11.051H NMR δ ppm(CDCl3)

1.362.59 (m, 6H, 8, 9 & 10–H), 3.88 (m, 2H, 22–H), 5.15 (d, 1H, J = 10 Hz, 20–Ha), 5.22 (d, 1H, J = 16.8 Hz, 20–Hb), 5.98 (m, 1H, 21–H), 6.15 (s, 1H, 6–H), 6.62–7.45 (m, 12H, Ar–H), 9.05 (s, 1H, 11–H) 13C NMR δ ppm(CDCl3)

32.58, 44.38, 51.26, 56.65, 57.04, 109.70, 117.34, 120.83, 122.21, 123.31, 123.72, 125.22, 125.45, 126.56, 126.74, 127.43, 130.08, 131.81, 134.40, 136.54, 136.68, 136.87, 141.22, 143.31, 154.38, 156.26, 159.68, 193.68FT–IR max cm-1(KBr) 780, 960, 1055, 1178, 1350, 1410, 1560, 1640, 2896, 3250, 3455

HBC39 5-allyl-6-(7-methyltetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C27H27N7ON

HN

N

O

NN

NNM.P. 206–208 oCM.W. (g/mol) 465Element. Anal. C H NCal 69.66 5.85 21.06Obs 69.60 5.88 21.02


1.07 (s, 3H, 9–CH3), 1.12 (s, 3H, 9–CH3), 2.07 (m, 2H, 8–H), 2.34 (s, 3H, 15–CH3), 2.56 (d, 1H, J = 16.0 Hz, 10–Ha), 2.70 (d, 1H, J = 16.0 Hz, 10–Hb), 4.02 (m, 2H, 24–H), 5.08 (d, 1H, J = 10 Hz, 22–Ha), 5.28 (d, 1H, J = 16.4 Hz, 22–Hb), 5.78 (m, 1H, 23–H), 6.06 (s, 1H, 6–H), 6.53–7.38 (m, 7H, Ar–H), 8.86 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

21.15, 27.81, 28.93, 32.45, 44.85, 50.40, 56.77, 58.14, 108.96, 116.14, 117.82, 120.77, 122.09, 122.99, 123.63, 123.83, 127.40, 127.97, 129.12, 129.25, 129.83, 136.24, 136.48, 138.41, 139.57, 158.73, 193.01FT–IR max cm-1(KBr) 766, 1046, 1393, 1469, 1576, 1660, 2890, 2956, 3217, 3480

Chapter 3 116

HBC40 5-allyl-6-(7-methyltetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C25H23N7OM.P. 200–202 oCM.W. (g/mol) 437Element. Anal. C H NCal 68.63 5.30 22.41Obs 68.70 5.35 22.451H NMR δ ppm(CDCl3)

1.25 (m, 2H, 9–H), 2.21 (m, 2H, 8–H), 2.44 (s, 3H, 15–CH3), 2.66 (m, 2H, 10–H), 4.18 (m, 2H, 24–H), 5.22 (d, 1H, J = 10 Hz, 22–Ha), 5.30 (d, 1H, J = 16.4 Hz, 22–Hb), 5.80 (m, 1H, 23–H), 6.02 (s, 1H, 6–H), 6.62–7.75 (m, 7H, Ar–H), 8.98 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

21.25, 32.21, 44.85, 50.48, 56.87, 58.14, 108.82, 116.22, 117.96, 120.63, 122.09, 122.83, 123.77, 124.12, 127.40, 127.97, 129.09, 129.25, 129.83, 136.24, 136.48, 138.57, 139.41, 158.73, 192.91FT–IR max cm-1(KBr) 750, 990, 1080, 1355, 1425, 1588, 1655, 2890, 3150, 3250, 3388

HBC41 5-allyl-6-(8-chlorotetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C26H24ClN7OM.P. 188–190 oCM.W. (g/mol) 485Element. Anal. C H NCal 64.26 4.98 20.18Obs 64.22 5.01 20.221H NMR δ ppm(CDCl3)

1.12 (s, 3H, 9–CH3), 1.18 (s, 3H, 9–CH3), 2.21 (m, 2H, 8–H), 2.65 (d, 1H, J = 16.0 Hz, 10–Ha), 2.78 (d, 1H, J = 16.0 Hz, 10–Hb), 4.12 (m, 2H, 24–H), 5.18 (d, 1H, J = 10 Hz, 22–Ha), 5.32 (d, 1H, J = 16.4 Hz, 22–Hb), 5.80 (m, 1H, 23–H), 6.12 (s, 1H, 6–H), 6.65–7.49 (m, 7H, Ar–H), 9.02 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

27.45, 28.32, 32.28, 44.77, 50.56, 56.83, 58.04, 109.06, 116.22, 117.72, 120.97, 122.19, 122.83, 123.63, 123.97, 127.40, 127.58, 129.12, 129.25, 129.83, 136.29, 136.48, 138.57, 139.48, 158.29, 192.71FT–IR max cm-1(KBr) 810, 978, 1090, 1158, 1345, 1396, 1568, 1660, 2840, 3025, 3180, 3355

Chapter 3 117

HBC42 5-allyl-6-(8-chlorotetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C24H20ClN7OM.P. 232–234 oCM.W. (g/mol) 457Element. Anal. C H NCal 62.95 4.40 21.41Obs 62.89 4.42 21.391H NMR δ ppm(CDCl3)

1.21 (m, 2H, 9–H), 2.05 (m, 2H, 8–H), 2.65 (m, 2H, 10–H), 4.25 (m, 2H, 24–H), 5.28 (d, 1H, J = 10 Hz, 22–Ha), 5.36 (d, 1H, J = 16.4 Hz, 22–Hb), 5.89 (m, 1H, 23–H), 6.07 (s, 1H, 6–H), 6.65–7.82 (m, 7H, Ar–H), 8.89 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

30.54, 42.85, 44.65, 54.28, 107.69, 115.42, 116.81, 118.78, 120.85, 121.67, 122.69, 123.72, 130.35, 131.65, 133.88, 134.66, 135.25, 139.15, 139.65, 156.84, 161.73, 192.59FT–IR max cm-1(KBr) 750, 935, 1150, 1345, 1408, 1590, 1658, 2912, 3150, 3330

HBC435-allyl-6-(1-allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-9,9-dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4] benzodiazepin-7-oneM.F. C30H32N4O2M.P. 176–178 oCM.W. (g/mol) 480Element. Anal. C H NCal 74.97 6.71 11.66Obs 75.05 6.68 11.62


1.11 (s, 3H, 9–CH3), 1.31 (s, 3H, 9–CH3), 2.12 (s, 2H, 8–H), 2.29 (s, 3H, 15–CH3), 2.55 (d, 1H, J = 16.0 Hz, 10a–H), 2.72 (d, 1H, J = 15.6 Hz, 10b–H),4.03 (m, 2H, 22–H), 4.67 (m, 2H, 25–H), 4.96 (m, 4H, 20 & 23–H), 5.73 (m, 2H, 21 & 24–H), 5.93 (s, 1H, 6–H), 6.52–7.24 (m, 7H, Ar–H), 8.89 (s, 1H, 11–H)13C NMR δ ppm(CDCl3)

20.34, 27.93, 28.94, 32.44, 44.15, 44.35, 50.02, 56.40, 57.23, 109.66, 114.93, 116.05, 116.75, 119.77, 120.40, 121.25, 122.16, 123.48, 131.22, 131.37, 132.98, 133.85, 134.72, 135.95, 136.28, 137.13, 140.48, 156.36, 161.22, 192.17FT–IR max cm-1(KBr) 772, 950, 1090, 1278, 1389, 1450, 1526, 1580, 1653, 2918, 3055, 3240

Chapter 3 118

HBC44 5-allyl-6-(1-allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-oneM.F. C28H28N4O2M.P. 248–250 oCM.W. (g/mol) 452Element. Anal. C H NCal 74.31 6.24 12.38Obs 74.39 6.28 12.421H NMR δ ppm(CDCl3)

1.99–2.25 (m, 4H, 8 & 9–CH2), 2.29 (s, 3H, 15–CH3), 2.68 (m, 2H, 10–CH2), 4.03 (m, 2H, 22–H), 4.67 (m, 2H, 25–H), 4.96 (m, 4H, 20 & 23–H), 5.73 (m, 2H, 21 & 24–H), 5.93 (s, 1H, 6–H), 6.52–7.24 (m, 7H, Ar–H), 8.89 (s, 1H, 5–H)13C NMR δ ppm(CDCl3)

20.35, 22.02, 31.08, 36.57, 44.11, 57.72, 110.73, 115.96, 116.88, 119.82, 120.39, 121.01, 122.07, 123.37, 128.65, 131.08, 131.32, 132.98, 133.64, 134.71, 134.88, 135.77, 136.26, 137.14, 140.36, 158.37, 161.28, 192.53FT–IR max cm-1(KBr) 755, 921, 1027, 1147, 1222, 1362, 1466, 1530, 1576, 1642, 1959, 3186, 323, 3373

N NH

HN O

NO

12

3 4 5 67

89

1011

12 1314

151617

1819

Chapter 3 119

1H NMR spectrum of compound HBC25

APT spectrum of compound HBC25

Chapter 3 120

FT–IR spectrum of compound HBC25



N NH

HN O

N

1

2

34 5 6

7

8

91011

12 1314

15

161718

19NN

N

20

21

Chapter 3 121


N NH

HN O

NCl

1

2

34 5 6

7

8

91011

12 1314

15

161718

19

NN

N

20

21

Chapter 3 122




Chapter 3 123

ESI-MS of compound HBC33


N NH

N O

NO

1

2

34 5 6

7

89

1011

12 1314

15

161718

19

2021

22

Chapter 3 124



Chapter 3 125



Chapter 3 126

ESI-MS of compound HBC39


N NH

N O

N

1

2

34 5 6

7

8

91011

12 1314

15

161718

19NN

N

20

21

2223

24

Chapter 3 127



Chapter 3 128

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Synthesis of some quinolylpyrido[2,3 …shodhganga.inflibnet.ac.in/bitstream/10603/34621/9/09_chapter3.pdf · Synthesis of some quinolylpyrido ... MCR in solvent–free conditions,