CHAPTER 5

Synthesis of imidazo pyridine derivatives containing morpholine nucleus

CWPTEliS Imidazo pyridine derivatives containing morphoRne nucleus

5.1. Introduction

Heterocyclic compounds hold a special place among pharmaceutically significant

natural products and synthetic compounds [1, 2]. Nitrogen heterocycles are abundant in

nature and are of great significance to life because their structural subunits exist in many

natural products such as vitamins, hormones, antibiotics, and alkaloids as well as

pharmaceuticals, herbicides and many more compounds. The remarkable ability of

heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely

contributed to their unique value as traditional key elements of numerous drugs. In both

lead identification and lead optimization processes, there is an acute need for new small

organic scaffolds.

Nitrogen bridgehead-fused heterocycles containing an imidazole ring are common

structural motifs in pharmacologically important molecules, with activities spanning a

diverse range of targets. Probably, the most widely used heterocyclic system from this

group is imidazo-[l, 2-a] pyridine which contained in marketed drugs such as Zolpidem

(1) benzodiazepine agonist, Olprinone (2) the PDE 3 inhibitor and Zolimidine(3)

antiulcer drug as well as other experimental molecules [3-5].

1 2 3

The heterocyclic compounds play significant role in developing new

antimicrobial, anticancer, antimalarial, anticonvulsant agents. Recent observations

suggested that, heterocyclic compounds containing nitrogen as heteroatom are very

120

CJfA'PTE'lii Imidazo pyridine derivatives containing morpHoRne nucleus

important class of organic heterocycles, because of their wide application in medicine,

agriculture and technology aspects. Among these, 2-phenylimidazo[l,2-a]pyridine

derivatives are of significant synthetic interest due to their diverse range of biological

activities. Some of them showed pharmacological properties such as anti-

inflammatory[6,7],aromatase- inhibitors[8],antibacterial[9],antifungal[10],antiviral[l 1] and

analgesic[12] activities. They have also been shown to be selective cyclin

dependant kinase inhibitors[13], GABA[14], and benzodiazepine receptor agonists[15],

and brady kinin B2 receptor antagonists[16]. The Mannich reaction [17] is an amino

alkylation of an acidic proton with formaldehyde and any primary or secondary amine.

Many literatures reveal that, enhancement of biological activity was found on inclusion

of mannich base into the parent moiety [18-21]. Literature shows the presence of

morpholine moiety in the compounds is act as the building block in the preparation of

Linezolid (4), an antibiotic [22] and anticancer agent [23].

Azole class of drugs particularly fused imidazoles occupy prominent place in

medicinal chemistry because of their broad spectrum pharmacological activities such as

anti-inflammatory, analgesic, anticancer, antimicrobial, antiviral, pesticidal cytotoxicity

and anti-arrhythmic [19-23] activities. Omeprazole, Mebendazole, Pimobendan, and

Albendazole are well known drugs in the market which contain fused imidazole as active

core moiety.

121

CJfAfPEli^ Imidazo pyridine derivatives containing morpHofine nucleus

The insertion of polar groups in the organic molecules leads to change in the

absorption properties of the compound in the body. Cyclic secondary amines like

morpholine are an important class of compounds due to their biological significance in

the field of medicine and agriculture. Morpholines are the key pharmacophores in various

important drugs and biologically significant molecules. Acylation or alkylation of

morpholine enhances the original biological activity of the parent molecule. A number of

N, O substituted morpholines have been found to possess interesting pharmacological

properties. Many morpholine derivatives display varied activities like anti-bacterial, anti­

viral, analgesic, anti-inflammatory, as local anesthetics and antiviral agents [24].

Morpholine, a six membered heterocyclic ring is hydrophilic in nature and it

changes the properties of the compound to which it is attached. Morpholine has great

industrial importance and a wide range of applications. It is used as solvent, corrosive

inhibitor and fungicide. The morpholine ring also present in the antidepressant drug

Reboxetine, anticonvulsant like Timonium methyl sulphate. It is also present in some

drugs Pheiunetrazine (7) a stimulant, Morazone (5) a nonsteroidal anti-inflammatory drug

and Fenmetramide (6) an antidepressant drug.

F,C

122

CXA'PT^'R.5 Imidazo pyridine derivatives containing morphoCine nuckus

Desai.C and their co-workers reported the synthesis of a series of novel imidazo-

[l,2-a]pyridine derivatives 8(a-m) and studied their antimicrobial activity [24].

8(a-in)

8(a-i) a= 2-OH; b=2,4 (OH),; c= 4-OH-3-NO;, d=2,4 (OH)2-5-N02; e=3-CI; f=3-Cl-4-F;g= 2-Br; h=3-Br;

i=3-Br-2F; j= 2-Br-4N02; k= 2, 3(F)2, L2,4(F)2; m=2, 6(F)2

Said El Kazzouli et al reported the synthesis of 2-phenylimidazo [1, 2-a]

pyridines (9) as a novel class of melatonin receptor ligands [25].

Miguel Angel and their coworkers synthesized 6-substituted 2-(N-

trifluoroacetylamino) imidazo pyridines (10) and the synthesized compounds were

evaluated for antiproliferative activity against a variety of cancer cell lines. Most of

synthesized compounds displayed moderate cytotoxic activity [26].

R

10

Zhicai Wu and their coworkers designed series of 3, 7-diarylsubstituted

imidazopyridines and developed as a new class of KDR kinase inhibitors. A variety of

123

C3{Jl<PPE1iJ Imidazo pyridine derivatives containing morphoCine nuckus

imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were

identified with good aqueous solubility [27].

o

11 12

Sunil G. Sanghani and Kalpesh J. Ganatra prepared a series of mannich bases (13)

by the reaction of 7-methyl-2-(p-methylphenyl)imidazo[l,2-a]pyridine with secondary

amines and p-formaldehyde in methanol and evaluated them for antimicrobial activities

[28].

,NH2

O »•

AlCIo

CI

N

DM F, Reflux

Methanol

HCHO.Sec Amine

XX^^v^ R-.-

R̂

13

Wesley B Trotter synthesized imidazo morpholine derivatives (14&15) and

studied their analgesic activities [29].

124

CKA<PPE<!i5 Imufazo pyridine derivatives containing morpkoRne nucleus

14 15

Masahiko Hayakawa et al synthesized series of imidazo[l,2-a]pyridine

compounds(16), among which the thiazole derivative inhibited tumor cell growth[30].

-N N

\\ ^ X

R NO,

16

R=CI,X=S02,R =Me

Shrikanth Ulloora et al synthesized series of new imidazo [l,2-a]pyridines(17),

among them many compounds exhibited prominent anticonvulsant activity[31].

17

R=p-CIPh,Ph,p-Tosyl,p-F-Ph,Thiophene-2-

125

CWPM^i Imidazo pyridine derivatives containing morpHofine nucleus

Aldo Andreani et al synthesized imidazo [2, l-b]thiazole guanyl hydrazones(18-

19) which shows potent antitumor activities against breast cancer[32].

N NH2

NH

18 19

Caroline Castera-Ducros et al synthesized series of imidazo [1, 2-a] pyridine

derivatives (20) and evaluated them for antileishmanial activity [33].

20

Ar=2-CH3-C6H4,3-CF3-C6H4,4-OCH3-C6H4

Nurit Dahan-Farkas synthesized 6-substituted imidazo[ 1,2-a]pyridines among

them the following two compounds(21-22) show the proteolytic phase of apoptosis [34].

MeO BnO

OMe

OBn

21 22

Kristjan S. Gudmundsson and Brian A. Johns synthesized imidazo [l,2-a]pyridine

derivatives (23) which shows potent activity against herpes viruses [35].

126

CWPT^'R.S Imidazo pyridine derivatives containing morphoCine nuckus

X=a,Br,H;Y=Me,KC 23

Yoshiyuki Sato, Yu Onozaki synthesized a novel class of imidazopyridines (24)

derivatives which shows antitumor activity [36].

OBz

Said El Kazzouli et al synthesized a novel class of 2-phenylimidazo [1,2-

ajpyridines (25) as melatonin receptor ligands [37].

127

CJfjl'PFEliS Imidazo pyridine derivatives containing morpHoCine nucleus

5.2. Present work

Promoted by the above cited biological importance of imidazo pyridine

derivatives, and in continuation of our efforts to explore biologically important new

heterocyclic compounds, in the present investigation, an attempt was made to improve or

modify its properties to get more potent analogues. The present work describes the

synthesis of series of 4-((2-(4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl) methyl)

morpholine derivatives 29(a-o) by the reaction of substituted imidazo [1,2-a] pyridines

derivatives 28(a-o) with morpholine and formaldehyde.

The synthetic strategy involves the following steps:

1. Synthesis of intermediates substituted imidazo [1,2-a] pyridines derivatives as

reported in chapter 2; 28(a-o)

2. Synthesis of series of 4-((2-(4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl)

methyl) morpholine 29(a-o) derivatives.

The schematic representation of imidazopyridine morpholine derivatives is given in

the following Scheme-6.

128

CJfJl'PI^'R.i Imidazo pyridine derivatives containing morpHoCine nucktis

'XX N NH,

26(a-o)

Comp Rl

a

b

c

d

e

f

g

h

i

J k

1

m

n

0

Br

Br

Br

Br

Br

CH,

CH,

CH,

CH,

CH,

H

H

H

H

H

R2

H

H

H

H

H

H

H

H

H

H

OBz

OBz

OBz

OBz

OBz

R

27

R3

CI

CI

Br

NO,

CN

CI

CI

Br

NO,

CN

CI

CI

Br

NO,

CN

R4

CI

H

H

H

H

CI

H

H

H

H

CI

H

H

H

H

Scheme-6

5.2.1. Synthesis of substituted imidazo [1, 2-a] pyridine derivatives 28(a-o)

Substituted imidazo [1, 2-a] pyridine derivatives 28(a-o) have been synthesized

according to the procedure which is described in chapter 2

129

CKA'PTEliS Imidazo pyridine derivatives containing morphoRne nucleus

5.2.2. Synthesis of 4-((2-(4-chlorophenyl) imidazo [1, 2-a] pyridin-3-yl) methyl) morpholine derivatives 29(a-o).

28(a-o)

H

Q HCHO

EtOH/AcOH

85°C

O - ^ 29(a-o)

The structure of compounds 29(a-o) was confirmed by ' H N M R , '"C N M R and

mass spectral studies. In ' H N M R spectrum, compound 29c showed two triplets at 8 2.41

and 3.52 ppm corresponds to four CH2 protons of morpholine ring and a singlet at 5 4.00

ppm due to bridgehead CH2 protons. The aromatic protons of the compound 29c were

appeared between 8 7.43-8.85ppm. The '^CNMR spectrum of compound 29c showed a

signals at 8 66.0 (2C) and 52 (2C) due to four morpholine carbons, a signal at 8 50.0 ppm

corresponds to methylene carbon and other signals are in well agreement with the

assigned structure. Compound 29c displayed a molecular ion peak M* at m/z 452

corresponding to the molecular mass of the compoimd and isotopic peak [M+2] at m/z

454.

130

Cm<PVE1iS Imidazo pyridine derivatives containing morphoCine nucCeus

I o « O » fJ - -I o c ir o -t

iiiljiiiJ !U

SOS • Z - ^

XEt E —

E a a

* - ' 9 « i .

6:f

i f*

899

itl- L 996' L

^ ^

^

' H N M R spectrum for the compound 29c

131

CJd'PTE'R.S Imidazo pyridine derivatives containing morphotine nucleus

m i •--yfV"-. ¥.1 11. ?^ k!-; 5*1 5f«i

m ih!' £*v;it^. Hi . ^ ^ / Eii-':---

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HI til-'"'

c ft,

- 0

«

I

e i

D n

u§

'•'CNMR spectrum for the compound 29c

132

CXMVEfiS Imidazo pyridine derivatives containing morpHoCine nucleus

Opvniynx R*port Sample' 1 Fle.B OesoiptionB

Vial 2 22 IDS Time 19 48-33

Page

Sample Rapoit

Sample 1 Vial 2:22 ID B File B OeecriptionB

3 : DV DatMStor: TIC

5 .0«+ l i

0 . 0 -

1 . 3 7 8 e + 9»ag»: 1 .378«+

, 0 .50 1 .00 l .SO 2 . 0 0 2 . 5 0 PertNumiier Compound Time AreaAbe Area%Total WMth Height Mace Found

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455.2

200.0 400.0

Peak 10 Compound Time Mas* Found 1 1 4 2

Peak ID Compound Tbne Maae Found 2 1,53

1:MS KS+ 2 : ( T i M : 1 .53) 7.3«+007

2 2 6 . 6 2 2 7 . 6

2 2 5 . 7 ^

100-!

50-

600 .0

214.2, .

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200.0 400.0 ./« 6 0 0 . 0

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112 .9 100^

1 50^

\

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2:M8 SS- 2 : ( I x > a : 1 .53)

= ' ° - * ° " 112 .8 lOOj ^

2:M8 B S -1 .3«+005

488 .0

' 97 .4

o ^ v > ' . ^ .4^tvt, . , f—,., M .^^„-,,/, 200.0 400. 0 6 0 0 . 0

50-j 1 9 6 . 0

O J M U ,

418.2 1 9 9 . 9 3 " - ^ I 4 3 0 . 3

5 2 9 . 1 A

400.0 i/z

6 0 0 . 0

Mass spectrum for the compound 29c

133

CJOt'PFE'R.S Imidazo pyridine derivatives containing morphoRne nucleus

B o. a.

s t i r

$00 Z

t»oz

sjpi

'JXO I oqp. 0661

' H N M R spectrum for the compound 29k

134

C!H'A(PVE<S^5 Imufazo pyridine derivatives containing morpHofine nucleus

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"CNMR spectrum for the compound 29k

135

CWPPEliS ImuCazo pyridine derivatives containing morpkoCine nucteus

D«ta f i l «

V i « l Ho.

X n j e c t i o o Date

: D : \ n A T A \ M « . n O \ 8 S 0 1 7 - 1 2 € - n . D

P l - P - 0 3

2 1 / 0 5 / 2 0 1 0

I n j e c t i o n v o l

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Method i n f o : Method i n £ o : a - 1 0 n N KimaiZVS rCW!<ATX:AC8{98:03} NQBZt.B niSASB B- BOr)nSS:ACN(02:98)

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0 0 1 0 0 . 0 l . S 100 0 3 . 2 JOO 0

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14.sa« 3154.3S1

Asea %

0.fi8« 99.314

Mass spectrum for the compound 29k

136

CKA'PPE'K.S Imidazo pyridine derivatives containing morpkoRne nucleus

MASS REPORT SYMOefCINTt LTD

nte O.yaATAWAYl»«S0n-l26-17D

ASCSKm Cl« NH4

xlO'

"*f " 1 P H f M B I — M l — » f

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StmHttmnm OefiMtb

A

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300

ln«lrumantood«:BMS4X}S Analysed Bjr Pagelofl

Mass spectrum for the compound 29k

137

CWPTEIL^ Imidazo pyridine derivatives containing morpHoCine nucleus

5.3. Experimental protocol

5.3.1. Synthesis of substituted imidazo [1,2-a] pyridines derivatives 28(a-o)

General procedure:

An equimolar mixture of substituted-2-aminopyridines 26(a-o) (1 mmol) and

substituted phenacyl bromides 27 (1 mmol) was taken in dry ethanol (10 ml) and the

reaction mixture was refluxed for about 10-12 h at the temperature of 85 °C . Completion

of reaction was checked by TLC. The solvent was distilled off and the content was

poured into crushed ice with uniform stirring. The product separated and filtered, dried

and recrystallized using ethanol. The purification of compound was done by

chromatography on silica gel using ethyl acetate and hexane as an eluent.

6-Bromo-2-(3, 4-dichlorophenyl) imidazo [1, 2-a] pyridine (28a)

m.p.: 155-158°C; ' H - N M R (400MHz, DMSOd*.): 8.88 (s, IH), 8.46 (s, IH), 8.18 (s, IH),

7.94-7.38 (m, 4H, Ar-H); Mol. Formula Ci3H7BrCl2N2

6-Bromo-2-(4-chlorophenyl) imidazo [1, 2-a] pyridine (28b)

m.p.: 168-170°C; ^HNMR (400MHz DMS0d6); 9.18(s, IH), 8.65 (s, IH), 7.99-7.62 (m,

6H, Ar-H); Mol. Formula Ci3H8BrClN2

6-Bromo-2-(4-bromoplienyl) imidazo ]l,2-a] pyridine (28c)

m.p.; 202-204°C; ^HNMR (400MHz DMSO-dg); 9.19 (s, IH), 8.67 (s, IH), 7.91-7.76(m,

6H,Ar-H); Mol. Formula Ci3H8BrClN2

6-Bromo-2-(4-nitrophenyl) imidazo ]1, 2-a] pyridine (28d)

m.p.; 163-165°C; ^HNMR (400MHz DMSO-ds); 9.11 (s, IH), 8.70 (s, IH), 8.17-7.75

(m, 6H, Ar-H); Mol. Formula CnHgBrNsOz

4-(6-Bromoimidazo Jl, 2-a] pyridin-2-yl) benzonitrile (28e)

138

CK^'PT'EliS Imidazo pyridine derivatives containing morphoCine nucleus

m.p.; 175-177°C; ^HNMR(400MHz DMSO-dfc); 9.1 (s, IH), 8.70 (s, IH), 8.37-7.62 (m,

6H, Ar-H), (LCMS): m/z 299 (M+1); Mol. Formula CBHgBrNjOj

2-(3,4-DichlorophenyI)-6-methylimidazo[l,2-a]pyridine(28f)

m.p.; 193-195°C; ^HNMR(400MHzDMSO-d6); 8.85 (s, IH), 8.72 (s, IH), 8.30 (s, IH),

7.98-7.95 (m, 4H, Ar-H), 2.44 (s, 3H); Mol. Formula CMHIOCIJNZ

2-(4-ChIorophenyI)-6-niethylimidazo [1, 2-al pyridine (28g)

m.p.; 188-190°C; ^HNMR (400MHz DMSO-de); 8.77 (s, IH), 8.68 (s, IH), 7.99-7.68

(m, 6H, Ar-H), 2.43(s, 3H). Mol. Formula C14H11CIN2

2-(4-Bromophenyl)-6-methylimidazo [1, 2-a] pyridine (28h)

m.p.; 176-178°C; ^HNMR (400MHz DMSO-ds); 8.743 (s, IH), 8.67 (s, IH), 7.92-7.73

(m, 6H, Ar-H), 2.32 (s, 3H). Mol. Formula CnHnBrNz

2-(4-Nitrophenyl)-6-methylimidazo [1,2-a] pyridine (28i)

m.p.; 191-193°C; ^HNMR (400MHz DMSO-ds); 8.91 (s, IH), 8.73 (s, IH), 8.17-7.81

(m, 6H,Ar-H ), 2.41(s, 3H). Mol. Formula C14H, .Nj O2

4-(6-Methylimidazo [1, 2-a] pyridin-2-yl) benzonitrile (28j)

m.p.; 168-170°C; ^HNMR (400MHz DMSO-dfe); 8.92 (s, IH), 8.73 (s, IH), 8.44-7.77

(m, 6H,Ar-H), 2.42(s, 3H). Mol. Formula CisHnNj

8-(Benzyloxy)-2-(3,4-dichIorophenyl) imidazo [1, 2-a] pyridine (28k)

m.p.; 199-201°C; ^HNMR(400MHzDMSO-d6); 8.84 (s, IH), 8.43-7.27 (m, 10H,Ar-H),

8.33 (s, 1H),5.47 (s, 2H). Mol. Formula CJOHMCIJNZO

8-(Benzyloxy)-2-(4-chlorophenyl) imidazo [1,2-a] pyridine (281)

m.p.; 212-213°C; ^HNMR(400MHz DMSO-ds); 8.83 (s, IH), 8.48-7.34 (m, 12H,Ar-H),

139

CH^'FFE'g^s Imidazo pyridine derivatives containing morpHoCine nucCeus

5.46 (s, 2H). Mol. Formula C20H15CIN2O

8-(Benzyloxy)-2-(4-bromophenyl) imidazo [1,2-a] pyridine (28m)

m.p.; 203-205°C; ^HNMR(400MHz DMSO-de); 8.86 (s, IH), 8.46-7.41(m, 12H,Ar-H),

5.49 (s, 2H). Mol. Formula C2oH,5BrN20

8-(Benzyloxy)-2-(4-nitrophenyl) imidazo [1,2-al pyridine (28n)

m.p.; 177-179°C; ^HNMR (400MHz DMSO-ds); 8.81(s, IH), 8.38-6.9(m, 12H,Ar-H),

5.49 (s, 2H). Mol. Formula C20H15N3O3

4-(8-(Benzyloxy) imidazo [1, 2-a] pyridin-2-yl) benzonitrile (28o)

m.p.; 186-188°C; W M R (400MHz DMSO-de); 8.71 (s, IH), 8.42-7.25 (m, 12H,Ar-H),

, 5.47(s, 2H). Mol. Formula C21H15N3O

5.3.2. Synthesis of substituted 4-((2-phenylimidazo [1, 2-a] pyridin-3- yl) methyl)

morpholine derivatives 29(a-o)

General procedure:

Compounds 28(a-o) (1 mmol), morpholine (1.2mmol), formaldehyde and catalytic

amount of acetic acid was taken in round bottom flask in dry ethanol (8mL) and refluxed for

6-10 hr at 85°C, the progress of the reaction was monitored by TLC. After completion of

reaction, excess of solvent was distilled off and the content was poured into crushed ice

with uniform stirring. The product was separated, filtered, dried and recrystallized using

ethanol. The purification of compound was done by chromatography on silica gel using

a mixture of ethyl acetate and hexane as an eluent.

6-Bromo-2-(3,4-dicIiIorophenyl)-3-(morpholin-4-yImethyl)imidazo[l,2-a]pyridine

(29a)

White solid. Yield- 75 %, m.p. 185-187°C; ' H N M R ( 4 0 0 M H Z DMSO-daSppm): 8.91 (s,

140

CKH^PTEliS Imidazo pyridine derivatives containing morphoCine nucleus

IH), 8.25 (s, IH), 7.93-7.43 (m, 4H,Ar-H), 4.02 (s, 2H), 3.54 (bs, 4H), 2.47 (bs, 4H);

13

CNMR (400MHz D M S O < 8ppm): 145.1, 144.0,136.2, 135.0,133.8, 133.3, 132.5, 132.0,

130.7, 128.8, 127.0, 116.2, 112.1, 66.5, 53.1, 50.5; MS(LCMS):m/z 441[M], 443 (M+2).

Mol. formula; CgHifeBrCbNsO

6-Broino-2-(4-chlorophenyI)-3-(morphoIin-4-yImethyI)iinidazo[l,2-aJpyridine

(29b)

White solid. Yield- 82 %, m.p.l57-159°C; W M R (400MHZ DMS0-d6, 8ppm): 8.84

(s, IH), 7.93-7.42 (m, 6H,Ar-H), 4.01 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^CNMR

(400 MHz DMSO-d6, 8 ppm): 145.0, 144.0, 136.2, 134.3, 135.0, 132.2, 131.3, 129.8,

128.9, 121.3, 66.8, 53.4, 50.3; MS (LCMS): m/z 408 [M+2]; Mol. formula;

CigHnBrCljNjO.

6-Broino-2-(4-bromophenyl)-3-(morpholin-4-yImethyl)iinidazo[l,2-a]pyridine

(29c)

Off white solid, Yield-78 %,m.p.l76-178°C; ^HNMR (400MHz DMSO-dg, 8 ppm):

8.85 (s, IH), 7.86-7.84 (d, 2H), 7.69-7.66 (d, 2H), 7.61-7.59 (d, IH), 7.44-7.41 (d, IH),

4.00 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^C NMR (400MHz DMSO-de. 8 ppm):

145.2, 144.1, 136.2, 135.3, 133.0, 132.4, 129.4, 123.6, 121.3, 66.8, 53.4, 50.6; MS

(LCMS): m/z 451 (M+1), 454 (M+2), Mol. formula; CigHnBrNjO.

6-Bromo-3-(morpholin-4-ylmethyl)-2-(4-nitrophenyl)imidazo[l,2-a]pyridine (29d)

White solid ,Yield- 80 %.m.p.l88-190°C; ^HNMR (400MHz DMSO-de, 8ppm): 8.89 (s,

IH), 8.12 -7.44 (m, 6H, Ar-H), 4.04 (s, 2H), 3.52 (bs, 4H), 2.43 (bs, 4H); ^^C NMR

(400MHz DMSO-d(„ 8ppm): 146, 143, 139, 132, 129, 128, 126, 119, 118, 110, 106,

141

CW^PVE'R^S Imidazo pyridine derivatives containing morpHofine nucEeus

66.7, 52.8, 50.5;MS(LCMS); m/z-416 [M+] Mol.formula;Ci8Hi7BrCl2N403

4-|6-Broino-3-(niorpholin-4-ylmethyl)iniidazo[l,2-a]pyridin-2-yl]beiizonitrile(29e)

White solid,Yield- 74% m.p. 223-225°C; ' H N M R (400MHZ DMSO-de, 8ppm): 8.91 (s,

IH), 8.35-8.33 (m, 6H, Ar-H) 4.07 (s, 2H), 3.53 (bs,4H), 2.45 (bs, 4H); '^C NMR

(400MHz DMSO-dfc. 8 ppm): 145.3, 144.1, 136.6, 135.0, 132.7, 132.5, 132.1, 128.3, 121.4,

116.8, 115.3, 112.4,66.8, 53.2, 50.4; MS(LCMS)-397[M], Mol fomiula; Ci9Hi7BrN40.

2-(3, 4-Dichlorophenyl)-6-methyl-3-(morpholin-4-ylmethyl)imidazo(l,2-

ajpyridine (29f)

Off white solid. Yield- 76 %,m.p. 157-159°C; ^ HNMR (400MHz DMSO-d*, 5ppm):

8.42 (s, IH), 8.28 (s, IH), 7.95- -7.18 (m, 4H), 3.95 (s, 2H), 3.56 (bs, 4H), 2.50 (bs, 4H),

2.35 (s, 3H); '^CNMR (400MHz DMS04. 5ppm): 143, 141, 135, 131.6, 131.1, 130,

128.6, 128.1, 123, 122, 117, 116, 66, 52, 50, 18; MS(LCMS):m/z 376[M].

Mol.formula; C19H19CI2N3O.

2-(4-Chlorophenyl)-6-methyl-3-(morpholin-4-ylmethyl) imidazo[l,2-a]pyridine

(29g)

White solid. Yield- 78% m.p.l39-137°C; ^HNMR (400MHz DMSO-d*. 6ppm): 8.36 (s,

IH), 7.94- 7.15 (m, 6H,Ar-H ) 3.94 (s, IH), 3.53 (bs, 4H), 2.43 (bs, 4H), 2.34 (s, 3H);

^^CNMR (400MHz DMSO-d«. 5 ppm): 143, 142, 139, 132, 130, 129, 128, 123, 121,

117, 116, 67, 53, 21; MS(LCMS)m/z 341[M], Mol formula; C19H20CIN3O.

2-(4-BromophenyI)-6-methyl-3-(iiiorpholiii-4-ylinethyI)imidazo[l^-a]pyridine(29h)

Off white solid. Yield- 76%,m.p. 175-177°C; ^HNMR (400MHz DMSO-d*, 5ppm): 8.37

(s, IH), 7.88- 7.15 (m, 6H,Ar-H), 3.94 (s, IH), 3.53 (bs, 4H), 2.43 (bs, 4H), 2.34 (s.

142

CWPTEli5 Imidazo pyridine derivatives containing morpHofine nucleus

3H); ^^CNMR (400MHz DMSOA 8ppm): 145.2, 144.1, 135.0, 134.3, 133.8, 132.0,

131.9, 129.1, 124.3, 122.1, 66.7, 53.2, 50.5, 24.7; MS (LCMS): m/z 388[M+2], Mol.

Formula; Ci9H2oBrN30.

6-Methyl-3-(morphoIin-4-ylmethyl)-2-(4-mtrophenyl)imidazo[l,2-a]pyridine

(29i)

Pale Yellow solid, Yield-85 % m.p.; 161-163°C; ^HNMR (400MHz DMSOA 8 ppm):

8.41 (s, IH), 8.15-7.19 (m, 6H,Ar-H) 3.98 (s, 2H), 3.32 (bs, 4H), 2.43 (bs, 4H), 2.35 (s,

3H); ^^CNMR (400MHz DMSO-d,, 8ppm): 147.9, 145.4, 144.1, 139.2, 135.0, 134.1,

133.5, 128.4, 124.2, 122.1, 114.6, 66.7, 53.1, 50.4, 24.2; MS (LCMS):m/z 352[M]. Mol

formula C19H20N4O3

4-(6-Methyl-3-(morpholinomethyl) imidazo [1,2-a] pyridin-2-yl) benzonitrile (29j)

Off white solid, Yield- 80%,m.p. 199-203°C; ^HNMR (400MHz DMSO-4, 5 ppm):

8.44 (s, IH), 8.35-7.21 (m, 6H, Ar-H), 4.02 (s, 2H),3.55 (bs, 4H), 2.48 (bs, 4H), 2.36 (s,

3H); ^^CNMR (400MHz DMSO-d«, 5ppm); 145.3, 144.1, 137.3, 135.1, 134.2, 133.6,

132.2, 128.1, 122.2, 115.6, 114.7, 112.2, 66.5, 53.6, 24.4; MS (LCMS): m/z

332[M+]. Mol.formula;C2oH2oN40.

4-((8-(Benzyloxy)-2-(3,4-dichlorophenyl) imidazo [1,2-a] pyridin-3-yl) methyl)

morpholine (29k)

Off white solid,Yield-82 % , m.p. 187-189°C; ^HNMR (400MHz DMSO-d,. 8ppm):

8.22 (s, 2H), 7.92-7.90 (m, 9H, Ar-H),5.33 (s, 2H),3.54 (s, 2H), 3.32 (bs, 4H), 2.44 (bs,

4H); l^CNMR(DMSOd,,8ppm): 147, 140, 139, 136, 135, 31.6, 131.1, 130, 129, 128,

119, 118, 112, 104, 70, 66, 52, 50; MS (LCMS): m/z 468[M+]; Mol. Formula;

143

CWPTEliS Imidazo pyridine derivatives containing morpfioCine nucleus

C25H23CI2N3O2.

4-((8-(Benzyloxy)-2-(4-chIorophenyl) imidazo [1, 2-a] pyridin-3-yI) methyl)

morpholine (291)

Off white solid,Yield-80%,m.p.l78-180°C; ^HNMR (400MHz DMSO-4, 8 ppm): 8.20-

6.8 (m, 12H, Ar-H), 5.32 (s, 2H), 3.95 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^CNMR

(400MHz DMSO4, 8 ppm): 147, 136, 133, 132, 130, 128.9, 128.6, 119, 118, 112, 103,

70, 66, 53, 51; MS(LCMS):m/z 434 (M+1), 436(M+2); Mol formula; C25H24CIN3O2.

4-(8-(Benzyloxy)-2-(4-bromophenyl) imidazo [1,2-a] pyridin-3-yl) methyl)

morpholine (29m)

White solid,Yield-70%, m.p. 224-226°C; ^HNMR (400MHz DMSO-d*, 8ppm): 8.21-6.82

(m, 12H, Ar-H), 5.36 (s, 2H), 3.95 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^CNMR

(400MHz DMSOdft, 8ppm): 145.3, 143.2, 141.6, 137.1, 135.0, 132.2, 132.1, 129.7, 129.0,

127.7, 127.1, 124.2, 123.1, 70.8, 66.4, 53.8, 50.2; MS(LCMS):m/z 478[M+]; Mol.

formula; C25H24BrN302.

4-((8-(Benzyloxy)-2-(4-iiitrophenyI) imidazo [1,2-a] pyridiii-3-yI) methyl)

morpholine (29n)

Light yellow solid, Yield-72%, m.p. 236-238°C; ^HNMR (400MHz DMSO-4, 6ppm):

8.22-6.83 (m, 12H, Ar-H),5.33 (s, 2H), 3.99 (s, 2H), 3.52 (bs, 4H), 2.43 (bs, 4);

^^CNMR (400MHz DMSOd ,̂ 5ppm): 147.6, 145.3, 143.8, 141.3, 139.1, 137.4, 135.0,

129.0, 128.4, 128.7, 127.9, 124.4, 124.0, 70.8, 65.1, 52.9, 50.6; MS(LCMS): m/z

444[M]. Mol. Formula; C25H24N4O4

144

CWPTEliS Imidazo pyridine derivatives containing morpHofine nucleus

4-(8-(BenzyIoxy)-3-(morphoIinomethyl)imidazo[l,2-a]pyridin-2-yl)benzonitrile

(29o)

Off white solid,Yield-76%,m.p. 203-205°C; Yield-79%; ^HNMR (400MHz DMSO-4,

5ppm): 8.34-6.85 (m, 12H, Ar-H), 5.33 (s, 2H), 4.02 (s, 2H), 3.31 (bs, 4H), 2.45 (bs, 4);

'^CNMR (400MHz DMSOd ,̂ 6ppni): 145.5, 143.4, 141.2, 137.3, 132.5, 129.0, 128.2,

127.7, 127.1, 124.0, 71.0, 66.6, 53.4, 50.8; MS (LCMS): m/z-444 [M+2], Mol.

Formula; C26H24N4O2.

145

CJ&KPTEliS Imidazo pyridine derivatives containing morpHoGne nucleus

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