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Ghetiya, Renish M., 2011, “Studies on Heterocyclic compounds of Medicinal

Interest”, thesis PhD, Saurashtra University

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“STUDIES ON HETEROCYCLIC

COMPOUNDS OF MEDICINAL INTEREST”

A THESIS

SUBMITTED TO THE

SAURASHTRA UNIVERSITY

FOR THE DEGREE OF

Doctor of Philosophy IN

THE FACULTY OF SCIENCE (CHEMISTRY)

BY Renish M. Ghetiya

UNDER THE GUIDANCE

OF

Prof. H. S. Joshi DEPARTMENT OF CHEMISTRY

(DST-FUNDED, UGC-SAP SPONSORED),

SAURASHTRA UNIVERSITY

(Re-Accredited Grade B by NAAC, CGPA 2.93),

RAJKOT - 360 005

(GUJARAT) INDIA

MAY-2011

Gram: UNIVERSITY Phone: (R) 0281-2584221 Fax: 0281-2577633 (O) 0281-2578512

SAURASHTRA UNIVERSITY University Road Rajkot - 360 005

Prof. H. S. Joshi Residence: M.Sc., Ph.D., F.I.C.S. B-1, Amidhara Appartment, Professor, 2- Jalaram Plot, Department of Chemistry University Road, Rajkot - 360 005 No. GUJARAT (INDIA) Date: - -2011 Statement under O. Ph. D. 7 of Saurashtra University The work included in the thesis is my own work under the supervision of Prof. H.

S. Joshi and leads to some contribution in chemistry subsidized by a number of

references.

Date: - -2011 (Renish M. Ghetiya) Place: Rajkot This is to certify that the present work submitted for the Ph.D. Degree of

Saurashtra University by Renish M. Ghetiya his own work and leads to advancement in

the knowledge of chemistry. The thesis has been prepared under my supervision.

Date: - -2011 Prof. H. S. Joshi Place : Rajkot Professor Department of Chemistry Saurashtra University

Rajkot-360005

ACKNOWLEDGEMENT

First and foremost, I wish to pay my sincere homage to the Lord Shiva for

making me capable of doing all that I propose, the work leading to my Ph. D. thesis

submission is one of them.

I would like to express my sincere gratitude to my supervisor Prof. H. S. Joshi

for accepting me as his research student and who made this research a success. It is

with Dr. Joshi’s enthusiasm and integral view on research combined with his

willingness to provide quality chemistry and not less that kept me going and I wish to

say thank you sir. Besides being a wonderful Supervisor, Dr. Joshi is as close as family

and a very good friend and I am deeply honored to have wonderful person like him in

my life. I wish to say thank you so much again for all the help you offered over the

years both in and out of my academic life.

I also owe to Dr. P. H. Parsania, Professor and Head, Department of

Chemistry, Prof. Anamik Shah and Dr. Y. T. Naliapara as I have been constantly

benefited with their lofty research methodology and the motivation as well as their

affectionate. I am thankful to the all staff members of the Department of Chemistry

for their relevant support to me. I am also thankful to Mr. Harshadbhai Joshi for

their kind support. I express my grateful tribute to Department of Chemistry,

Saurashtra University for providing me the excellent laboratory facilities for

accomplishing this work. I also thanks to University Grants Commission for finding

me as Meritorious Research Fellow which is really an achievement and helpful task for

me.

From bottom of heart I specially thanks to my senior Dr. Paresh Zalavadiya

for their selfless help, moral support and guidance during my Ph. D. work.

Words are inadequate to thank my most beloved friend and colleagues

Bhavesh Dodiya and Dinesh Kundariya, who was always helping me in all situations.

His constant support, care and moral boost always kept me encouraged in all the

difficult situations. I will never forget his all kind concern, help, best wishes and that

they have done for me. I am really very much thankful to God for giving me such nice

friends.

I would like to take this opportunity to thank those whom I was fortunate to

know, work and form friendship. How could I ever forget Dr. Satish Tala, Dr. Jignesh

Akbari, Dr. Pankaj Kachhadia, Dr. Vijay Ram, Dr. Kapil Dubal and Dr. Kaushik

Joshi by whom I was inspired for my doctoral work. I heartily express special thanks

to Mr. Piyush Vekariya, Dr. Govind Kher and Mr. Gaurang Pandya for their

unlimited help.

I would like to express my deep sense of gratitude and lots of love towards my

dearest friends Dr. Mehul, Dhiru, Ashish, Batuk, GC, Pankaj, Joshi, Kaila, Odich,

Hitesh, Suro, Rakesh, Anil and Abhay.

I am extremely thankful to my research colleagues and friends Purthvi, Mepal,

Hardik, Dr Ravi, Dr. Nayan, Dr. Rahul, Punit, Ravi, Bhavin, Ramani, Hitesh,

Mrunal, Hardev, Ashish, Arun, Jignesh, Pooja, Rizwan, Ritesh, Leena, Mahesh,

Dangar, Naimish, Manisha, Ladwa, Gami, Piyush, Ram, Dipti, Bipin, Vipul, Shah

and Sudhir.

I get this achievement with tremendous support and cooperation of my friends

Sunny, Ghano, Hiren, Krunal, Renish, Anand, Pankaj, Bhuru, Ankola, Dipak,

Jignesh(Dada), Mayur and Dilip thank you so much to be such a wonderful friend and

fill my life with full of joy and stay with me whenever I needed.

Who have given us everything that we possess in this life? The life itself is their

gift to us, so I am at loss of words in which to own my beloved late grandmother and

grandfather, my mother Smt. Vijyaben, my father Shri Mansukhbahi, Bhabhu

Kantaben and Shantaben, my Ada Premjibhai and Kantibhai, my cousin Brothers

Kiritbhai, Anilbhai, Alpeshbhai, Nileshbhai-Anjana Babhi, who ever enlightened my

path and boosting me to go ahead to reach the goal. I am equally thankful to my

dearest sister Manali. However I assured them to be worthy; of whatever they have

done for me. At last I express my feelings to my Mamas Bhanubhai, Rameshbhai, and

Dineshbhai, who always saw me a new vision.

(Renish M. Ghetiya)

CONTENTS

SYNOPSIS……………………………………………………………………………………..1

STUDIES ON HETEROCYCLIC COMPOUNDS OF MEDICINAL INTEREST PART-A : STUDIES ON PYRAZINE DERIVATIVES

1. Introduction……………………………………………………………………………..7

2. Therapeutic Importance………………………………………………………………...8

3. References………………………………………………………………………………15

PART-I : STUDIES ON 2-(PIPERIDIN-4-YLMETHOXY)PYRAZINE DERIVATIVES

1. Introduction……………………………………………………………………………..18

2. Therapeutic Importance…………………………………………………………….......26

Section-I

Synthesis and biological evaluation of Aryl{4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-

yl}oxy)methyl]piperidin-1-yl}methanones

1. Reaction scheme………………………………………………………………………...32

2. Experimental section……………………………………………………………............33

3. Analytical data………………………………………………………………………….37

4. Spectral study…………………………………………………………………………...39

5. Antimicrobial activity…………………………………………………………………...47

Section-II

Synthesis and biological evaluation of Aryl[4-({[5-(2-fluorophenyl)pyrazin-2-

yl]oxy}methyl)piperidin-1-yl]methanones

1. Reaction scheme………………………………………………………………………...50

2. Experimental section……………………………………………………………………51

3. Analytical data………………………………………………………………………….54

4. Spectral study…………………………………………………………………………...56


Section-III

Synthesis and biological evaluation of Aryl[4-({[5-(thiophen-2-yl)pyrazin-2-


1. Reaction scheme………………………………………………………………………...65


3. Analytical data………………………………………………………………………….69

4. Spectral study…………………………………………………………………………...71


Section-IV

Synthesis and biological evaluation of Aryl[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-


1. Reaction scheme………………………………………………………………………...80

2. Experimental section…………………………………………………………………....81

3. Analytical data………………………………………………………………………….84

4. Spectral study…………………………………………………………………………...86


6. References………………………………………………………………………………95

PART-B : STUDIES ON 6-CHLORO-INDOLE DERIVATIVES

1. Introduction……………………………………………………………………………..99


3. References………………………………………………………………………………110

PART-I: STUDIES ON 6-CHLORO-INDOLE-5-CARBOXYLATE DERIVATIVES

1. Introduction……………………………………………………………………………..115


Section-I

Synthesis and biological evaluation of Methyl 6-chloro-3-[(N,N-dialkylamino)(oxo)acetyl]-1-

methyl-1H-indole-5-carboxylates

1. Reaction scheme………………………………………………………………………...123


3. Analytical data………………………………………………………………………….127

4. Spectral study…………………………………………………………………………...129

5. Antimicrobial activity……………………………………………………………….......135

Section-II

Synthesis and biological evaluation of Methyl 1-benzyl-6-chloro-3-[(N,N-

dialkylamino)(oxo)acetyl]-1H-indole-5-carboxylates

1. Reaction scheme………………………………………………………………………...136


3. Analytical data………………………………………………………………………….140

4. Spectral study…………………………………………………………………………...142


6. References………………………………………………………………………………149

PART-II: STUDIES ON 6-CHLORO-INDOLE-3-YL-GLYOXYLAMIDE DERIVATIVES

1. Introduction……………………………………………………………………………..152


Section-I

Synthesis and biological evaluation of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-N-

aryl-1H-indole-5-carboxamides

1. Reaction scheme………………………………………………………………………...160


3. Analytical data………………………………………………………………………….164

4. Spectral study…………………………………………………………………………...166


Section-II

Synthesis and biological evaluation of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-benzyl-N-

aryl-1H-indole-5-carboxamides

1. Reaction scheme………………………………………………………………………...174


3. Analytical data………………………………………………………………………….178

4. Spectral study…………………………………………………………………………...180


6. References………………………………………………………………………………188

List of publication………………………………………………………………………………190

Studies on hetrocyclic…

Synopsis… 1

A comprehensive summary of the work to be incorporated in the thesis entitled

“STUDIES ON HETEROCYCLIC COMPOUNDS OF MEDICINAL INTEREST”

has been described as under.

PART-A: STUDIES ON PYRAZINE DERIVATIVES

PART-B: STUDIES ON 6-CHLORO-INDOLE DERIVATIVES

PART-A: STUDIES ON PYRAZINE DERIVATIVES

The development of our understanding of disease processes and the resulting

discovery of new drugs for their treatment has improved the quality of life throughout the

world. The primary goal of the our research work is to find and develop new chemical

entities (NCEs) which can be used against untreatable diseases, or which have superior

properties when compared to currently available drugs.

Pyrazine nucleus possesses remarkable pharmaceutical importance and biological

activities, some of their derivatives occur as natural products. Many pyrazine derivatives

have displayed diverse pharmacological activities like anti-inflammatory, antitumor,

calcium channel blocker etc. In view of our on going interest in the synthesis of some

new potentially bioactive pyrazine derivatives have been described as under.

PART-I: STUDIES ON 2-(PIPERIDIN-4-YLMETHOXY)PYRAZINE DERIVATIVES

The synthesis of compound 2-(piperidin-4-ylmethoxy)pyrazine derivatives has

been attracted widespread attention due to their diverse pharmacological properties like

anti-inflammatory, antibiotic, antifungal, herbicidal, antitubercular, etc. To approach this

goal, the synthesis of some new 2-(piperidin-4-ylmethoxy)pyrazine derivatives have been

undertaken.

SECTION-I: Synthesis and biological evaluation of Aryl{4-[({5-[3-

(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-1-yl}methanones


Synopsis… 2

N

NO

NO

R

SO

O

CH3

R=Aryl

Type (I)

2-(Piperidin-4-ylmethoxy)pyrazines derivatives of Type (I) have been synthesized

by the condensation of 2-[3-(methylsulfonyl)phenyl]-5-(piperidin-4-ylmethoxy)pyrazine

with various aromatic acid chlorides in the presence of TEA.

SECTION-II: Synthesis and biological evaluation of Aryl[4-({[5-(2-

fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]methanones

N

NO

NO

R

F R=Aryl

Type (II)

2-(Piperidin-4-ylmethoxy)pyrazines derivatives of Type (II) have been

synthesized by the condensation of 2-(2-fluorophenyl)-5-(piperidin-4-ylmethoxy)pyrazine


SECTION-III: Synthesis and biological evaluation of Aryl[4-({[5-(thiophen-2-

yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]methanones

N

NO

NO

RS

R=Aryl

Type (III)

2-(Piperidin-4-ylmethoxy)pyrazines derivatives of Type (III) have been

synthesized by the condensation of 2-(piperidin-4-ylmethoxy)-5-(thiophen-2-yl)pyrazines



Synopsis… 3

SECTION-IV: Synthesis and biological evaluation of Aryl[4-({[5-(1-benzothiophen-

3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]methanones

S

N

NO

NO

R

R=Aryl

Type (IV)

2-(Piperidin-4-ylmethoxy)pyrazines derivatives of Type (IV) have been

synthesized by the condensation of 2-(1-benzothiophen-3-yl)-5-(piperidin-4-

ylmethoxy)pyrazines with various aromatic acid chlorides in the presence of TEA.

PART-B: STUDIES ON 6-CHLORO-INDOLE DERIVATIVES

Heterocyclic compounds bearing 6-chloro-indole ring system are endowed with

variety of biological activities. Our strategy is based on to develop a new bioactive entity

especially with pharmacological activities bearing heterocyclic ring system. Literature

survey reveals that nitrogen containing heterocyclic compounds like 6-chloro-indole have

received considerable attention in medicinal science due to their biological and

pharmacological activities like anticancer, anti-inflammatory, herbicidal, hypnotic,

sedative, antimicrobial, antitubercular, antithyroid and many other therapeutic activities.

PART-I: STUDIES ON 6-CHLORO-INDOLE-5-CARBOXYLATE DERIVATIVES

The discovery of 6-chloro-indole-5-carboxylate derivatives as potent biologically

active agent has led to the exploration of large number of structural variants, containing

6-chloro-indole-5-carboxylate moiety as an invariable ingredient. Its derivative has shown

various biologically activities such as anticancer, anathematic, antimicrobial,

antihistamine, anti-inflammatory, antibacterial etc. In order to develop therapeutically

important compounds, it was consider of interest to synthesize some 6-chloro-indole-5-

carboxylate shown as under.

SECTION-I: Synthesis and biological evaluation of Methyl 6-chloro-3-[(N,N-

dialkylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxylates


Synopsis… 4

N

O

O

CH3

Cl

O

OCH3

R

R=Secondary amine

Type (V)

6-Chloro-indole-5-carboxylate derivatives of Type (V) have been synthesized by

the condensation of methyl 6-chloro-1-methyl-1H-indole-5-carboxylate with oxalyl

chloride and different secondary amine in the presence of DCM.

SECTION-II: Synthesis and biological evaluation of Methyl 1-benzyl-6-chloro-3-[(

N,N-dialkylamino)(oxo)acetyl]-1H-indole-5-carboxylates

N

O

O

Cl

O

OCH3

R

R=Secondary amine

Type (VI)

6-Chloro-indole-5-carboxylate derivatives of Type (VI) have been synthesized by

the condensation of methyl 1-benzyl-6-chloro-1H-indole-5-carboxylate with oxalyl

chloride and different secondary amine in the presence of DCM.

PART-II: STUDIES ON 6-CHLORO-INDOLE-3-YL-GLYOXYLAMIDE

DERIVATIVES

6-Chloro-indole-3-yl-glyoxylamide moieties represent important building blocks

in both natural and synthetic bioactive compounds, which have been shown to possess

diverse therapeutic activities The nature and the position of the substituent on the indole

moiety influence these activities. Molecules containing 6-chloro-indole-3-yl-


Synopsis… 5

glyoxylamide has been shown to have a broad range of important biological activities

including anticancer, antibacterial, antimicrobial, anti-inflammatory, antitubercular etc.

SECTION-I: Synthesis and biological evaluation of 6-Chloro-3-

[(diethylamino)(oxo)acetyl]-1-methyl-N-aryl-1H-indole-5-carboxamides

N

O

O

N

CH3

Cl

O

NHR

CH3 CH3

R=Aryl

Type (VII)

6-Chloro-indole-3-yl-glyoxylamide derivatives of Type (VII) have been

synthesized by the condensation of 6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-

indole-5-carboxylic acid and different aryl amine in the presence of DCC, HOBT and

TEA.

SECTION-II: Synthesis and biological evaluation of 6-Chloro-3-

[(diethylamino)(oxo)acetyl]-1-benzyl-N-aryl-1H-indole-5-carboxamides

N

O

O

N

Cl

O

CH3

NHR

CH3

R=Aryl

Type (VIII)


Synopsis… 6

6-Chloro-indole-3-yl-glyoxylamide derivatives of Type (VIII) have been

synthesized by the condensation of 1-benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-1H-

indole-5-carboxylic acid and different aryl amine in the presence of DCC, HOBT and

TEA.

The constitution of all the synthesized compounds have been characterized by

using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported

by mass spectroscopy. Purity of all the compounds has been checked on thin layer

chromatographic plate and HPLC technique.

All the compounds have been evaluated for their antibacterial activity towards

Gram +ve and Gram -ve bacterial strains and antifungal activity towards Aspergillus

niger at a concentration 40 µg/ml. The biological activities of the synthesized compounds

have been compared with standard drugs.

Studies on heterocyclic…

Pyrazine derivatives… 7

INTRODUCTION

Pyrazine contains two nitrogen atoms in its aromatic ring.1 Pyrazine play an

important role as intermediates for perfumes,2 pharmaceuticals, agricultural chemicals3

and food spices. Especially, amides and sulfonamides of pyrazines have been used on

various topics as anti-tuberculosis, dyes and pigments,4 oral anti diabetics, nutrition

supplement, insecticides and fungicides.

N

N1

23

4

5

6

In general pyrazine is prepared by the catalytic reaction of diamines with dioles in

a vapour phase, dehydrogenation of piperazine or dealkylation of methyl pyrazine.

Pyrazine and their derivatives form an important class of compounds present in several

natural flavors and complex organic molecules, it is also responsible for flavor in

foodstuffs, like cheese, tea coffee, cooked meats nice aroma etc.5

SYNTHETIC ASPECT

Various methods for the preparation of pyrazine derivatives have been cited in

literature, some of them are as under.

1. The pyrazine derivatives have synthesized by direct conversion of α-hydroxy

ketones and α-keto oximes in the presence of a catalytic amount of ceric

ammonium nitrate was reported by A. Shaabani et al.6

O

OH

R

R

NC

NH2NC

NH2+

CAN, AirH2O, rt., 45 min

N

N

NC

NC

R

R

2. B. M. Latha et al.7 have synthesized pyrazine from ethylenediamine on copper

oxide/copper chromite catalysts.

NH2

NH2 NH

NH

2 -2NH3 -3H2N

N



3. Microwave-assisted synthesis of pyrazine derivatives from α-halo ketone in 7%

NH3 solution was given by T. Utsukihara et al.8

OR

1

R2

X

7 % NH3 aqMicrowave

N

N

R1

R2

R2

R1

4. Synthesis of 2-methyl pyrazine from zinc-modified ferrierite (FER) catalysts was

documented by R. Anand et al.9

NH2

NH2

CH3

OH

OH+

NH

NH

CH3

Intermolecular cyclization

deyhdrogenationZno-FER

N

N CH3

5. W. T. Reichle et al.10 have given the synthesis which involve the reaction of

diketones with appropriate diamines, which gave the diazine which readily

oxidized to the pyrazines.

O

O+

NH2

NH2

N

N

N

N

-2H2O -H2

THERAPEUTIC IMPORTANCE

Over recent years there has been an increasing interest in the chemistry of

pyrazine derivatives because of their biological significance.

1. Analgesic11

2. Antiallergic12

3. Antibacterial13

4. Anti-inflammatory14

5. Antiviral15

6. Diuretic16

7. Anticancer17

8. Anti HIV18

9. Anti hypertensive19

10. Cardiovascular20



11. Antioxidant21

12. Antimycobacterial22

L. E. Seitz et al.23 have synthesized and evaluated antimycobacterial activity of

pyrazine derivatives (1). H. Foks et al.24 have synthesized and screened antibacterial

activity of 1H-pyrazolo[3,4-b]pyrazine derivatives.

N

NO

R1

R1 = aryl(1)

Pyrazine derivatives (2) with an allylsulfur moiety have hepatoprotective effects

against toxicants. Effect of 2-AP on hepatic tumorigenesis in association with glutathione

S-transferase (GST) induction was examined in rats exposed to aflatoxin B1 (AFB1) was

given by T. G. Ha et al.25

N

N SCH2

(2)

H. Foks et al.26 have synthesized and checked tuberculostatic activity of 4-

substituted 3,4,5,6-tetrahydro-2H-[1,2']-bis-pyrazine derivatives (3). F. Micheli et al.27

have synthesized pyrido [2,3-b] pyrazine-8-oxide derivatives as selective glycine

antagonist with in vivo activity.

N

N

N

S

Ph

NN

R1

R1 = Ph, CH2Ph, Pyridine

(3)

Synthesis and evaluation of substituted N-phenylpyrazine-2-carboxamides (4) as

herbicides and abiotic elicitors was reported by M. Dolezal et al.28



N

N O

NH

CH3

CH3CH3

R1

R1 = Cl, I, F, CF3(4)

K. Zurbonsen and coworkers29 have studied antiproliferative, differentiating and

apoptotic effects elicited by imidazo[1,2-a]pyrazine derivatives (5). T. Yanai et al.30 have

synthesized novel pyrazine compounds produced from chitin by the activity of the

enzyme from vibrio alginolyticus TK-24.

NN N

R2

R1

R4

R3

R1 = H, Br R2 = Br, NH2, NHCH3, NHCH2CH3 R3 = CN, HR4 = H, Br, CH2OH, CH2OCH3(5)

Pyrazine derivatives (6) tested against human keratinocyte cells stressed UVB

irradiation showed high anti oxidative properties was given by J. Cavalier et al.31

R1 = R2 = R3= OH, OCH3

N

N

NH2

R1

R3

R2

(6)

B. A. Ellsworth et al.32 have studied structure activity relationships for a series of

pyrazine carboxamide (7) as CB1 antagonists. Pharmaceutical properties of the series (7)

were improved via inclusion of hydroxyl containing side chains. This structural

modification sufficiently improved ADME properties of an orally inactive series such that

food intake reduction was achieved in rat feeding models.

N

N

CH3

CH3

O

R1

(7)



J. W. Corbett et al.33 have synthesized indanylpyrazines (8) and reported

corticotrophin releasing factor type-1 receptor antagonists.

N

NR1

NHR

2

R3

NH

NR1 = R3 = CH3, C2H5

R2 = Propyl(8)

N. Sinha et al.34 have synthesized and screened antimycobacterial activity of some

pyrazine derivatives (9). K. Yoshiizumi et al.35 have synthesized and studied structure

activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine based hydroxamic acids

as HB-EGF shedding inhibitors.

N

NO

NNH Ar

O

N(9)

Pyrazin-2-yl-formamide thiosemicarbazones (10) related to their tuberculostatic

activity was reported by A. Olczak et al.36

N

N

NH2

HNN

S

R1

R1 = secondary amine

(10)

The novel structures 5,7-disubstituted 6-amino-5H-pyrrolo[3,2-b]pyrazine-2,3-

dicarbonitriles (11) and their promising protein kinase inhibitors with antiproliferative

activity was given by G. G. Dubinina et al.37



N

N

NNH2

NC

NC

R1

XN

N

N

NNH2

NC

NC

R1

S OO

X = NH, N-CH3, N-CH2Ph, S

(11)

Synthesis and tuberculostatic activity of pyrazinyl substituted derivatives (12) was

reported by H. Foksi et al.38

N

N

N

S

N

R1 R

2

R1 = R2 = secondary amine

(12)

J. Bostrom et al.39 have studied scaffold hopping, synthesis and structure activity

relationships of 5,6-diaryl-pyrazine-2-amide derivatives (13) of CB1 receptor antagonists.

N

N

Cl

Cl

ClO

NHN

(13)

Synthesis and biological activity of 5-aroylpyrazine-2-carboxylic acid derivatives

(14) was given by M. Dolezal et al.40

N

N

R1

O

R2

R1 = CN, CONH2

R2 = H, OH, Cl(14)

M. Dolezal et al.41 have synthesized and reported antimycobacterial evaluation of

substituted pyrazine carboxamide derivatives (15).



N

N

NH

OX

R1

R2

R1 = H, tert-butylR2 = CH3, CF3, F, ClX = H, Cl(15)

J. Krinkova et al.42 have synthesized and evaluated biological activity of 5-alkyl-

6-(arylsulfanyl)pyrazine-2- thioamides derivatives (16).

N

NR1

CSNH2SR

2

R1 = C3H7, C4H9

R2 = CH3, C2H5, C3H7, C4H9, C6H5(16)

C. G. Bonde coworkers43 have synthesized and given preliminary evaluation of

some pyrazine derivatives (17) as antimicrobial agents.

N

N

ONH

ON S

NOR

1(17)

T. Asaki et al.44 have studied structure activity on diphenylpyrazine derivatives

(18) of prostacyclin receptor agonists.

N

N

Ph

Ph NR

1

OO

OH

R1 = ethyl, allyl, cyclopropyl(18)

Synthesis and antiinflammatory activity of methyl substituted imidazo[1,2-

a]pyrazine derivatives (19) was reported by M. G. Rimoli et al.45

NN N

R1

R2 R1 = CH3, CH2COOH, COOH

R2 = H, COOH(19)



Synthesis of two new hybrid metal-organic polymers using flexible pyrazine

crystal structures was given by C. Zhang et al.46 Synthesis and biological evaluation of

pyrido[2,3-b]pyrazine-N-oxide as selective glycine antagonists was reported by A.

Cugola et al.47 J. E. Dowling et al.48 have synthesized of [1,2,4]triazolo[1,5-a]pyrazines

as adenosine A2A receptor antagonists. C. A. Hargreaves and coworkers49 have studied

tetrahydropyrido[2,3-b]pyrazine scaffolds. H. Mukaiyama et al.50 have synthesized and

given C-SRC inhibitory activity of imidazo[1,5-a]pyrazine derivatives as an agent for

treatment of acute ischemic stroke. D. R. Owen et al.51 have studied structure activity

relationships of pyrazine derivatives as a novel non competitive mGluR1 antagonists.

Synthesis and antimycobacterial activity of pyrazine derivatives documented by L. E.

Seitz et al.52 Imidazo[1,2-a]pyrazine shows the bronchodilatory and cyclic nucleotide

phosphodiesterase inhibitory activities was given by T. O. Vitse et al.53

Thus the important role displayed by pyrazine and its derivatives for various

therapeutic and biological activities prompted us to synthesize some pyrazine moiety in

order to achieve compounds having better therapeutic activities summarized in the part as

under.

STUDIES ON PYRAZINE DERIVATIVES

PART-I: STUDIES ON 2-(PIPERIDINE-4-YLMETHOXY)PYRAZINE

DERIVATIVES



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2-(Piperidin-4-ylmethoxy)pyrazine derivatives… 18

INTRODUCTION


activities, some of their derivatives occur as natural products. In view of our ongoing

interest in the synthesis of some new potentially bioactive pyrazine derivatives (1) have

been described as under.

N

NO

N R2

R1

(1)

The synthesis of compound 2-(piperidin-4-ylmethoxy)pyrazine derivatives has

been attracted widespread attention due to their diverse pharmacological properties like

anti-inflammatory, antibiotic, antifungal, herbicidal, antitubercular, etc. To approach this

goal synthesis of some new 2-(piperidin-4-ylmethoxy)pyrazine derivatives have been

undertaken.

SYNTHETIC ASPECT

Various methods of bromination, diazotization, mitsunobu reaction, suzuki cross

coupling and deprotection of pyrazine derivatives have been cited in literature, some of

the methods are as under.

BROMINATION

1. Bromination of 2-amino pyrazine in presence of bromine and pyridine in CHCl3

was given by S. Sevilla et al.1

N

N NH2

N

N NH2

BrBr

CHCl3

Br2, pyridine

2. F. D. Weal et al.2 have synthesized 2-amino-5-bromopyrazine from pyrazine, N-

bromosuccinamide in acetonitrile solution.

N

N NH2

NBS, CH3CNovernight, rt

N

N NH2

Br



3. Pyrazine react with N-bromosuccinamide in DMSO solution to give 3,5 dibromo

pyrazine was reported by B. Jiang et al.3

N

N NH2

NBS, DMSO N

N NH2

BrBr

4. A. M. Stadler et al.4 have synthesized 2-amino-5-bromopyrazine from pyrazine,

N-bromosuccinamide in CH2Cl2 solution.

N

N NH2

NBSN

N NH2

Br

CH2Cl2

5. Bromination of 2-amino pyrazine from pyrazine and brominating agent was given

by T. Itoh et al.5

N

N NH2

N

N NH2

Brbrominating agent +

N

N NH2

BrBr

DIAZOTIAZITION

6. Preparation of 5-bromopyrazin-2-ol from 2-amine-5-bromopyrazin, NaNO2 and

H2SO4 was reported by F. Jing et al.6

N

N NH2

Br H2SO4, NaNO2N

N OH

Br

7. H. Mukaiyama et al.7 have prepared 5-bromopyrazin-2-ol from 2-amine-5-

bromopyrazin, NaNO2 and CH3COOH in dioxane solution.

N

N NH2

BrCH3COOH, NaNO2

N

N OH

Br

dioxane

8. S. Nobuhiro et al.8 have studies diazotization of 2-amine-5-bromopyrazin in

sulphuric acid and sodium nitrate.



N

N NH2

Br H2SO4, NaNO2N

N OH

Br

20 min 5 oC, 40 min 40 oC

9. H2SO4 and sodium nitrate react with 2-aminopyrazine to gave 2-hydroxypyrazine

was given by Y. Jun et al.9

H2SO4, NaNO2

H2O

N

N NH2

Br

Cl

N

N OH

Br

Cl

10. A. E. Erickson et al.10 have synthesized 5-bromopyrazin-2-ol from 2-amine-5-

bromopyrazin, NaNO2 and H2SO4.

H2SO4, NaNO2N

N NH2

N

N OH

MITSUNOBU REACTION

11. Use of sonication for the coupling of sterically hindered substrates in the phenolic

mitsunobu reaction was reported by S. D. Lepore et al.11

OH

OCH3

O+ OH

sonication

DIAD, PPh3

THF, 25 oC, 15 min

O

OCH3

O

12. Organocatalytic mitsunobu reaction of phenol and acid in THF was documented

by T. Y. S. But et al.12

DEAD, PPh3

O

OH

O2N+

OH

PhTHF

O

O

O2N

Ph

13. Di-p-chlorobenzyl azodicarboxylate (DCAD) was introduced as a novel, stable

and solid variety of mitsunobu coupling in CH2Cl2 was given by B. H. Lipshutz et

al.13



OH+

O

OH OCH3

H3CO

DCAD, PPh3

CH2Cl2, rt

O

O OCH3

H3CO

14. Carbon nucleophiles in the mitsunobu reaction, mono- and dialkylation of

bis(2,2,2-trifluoroethyl) malonates was given by J. M. Takacs et al.14

R1

OH +H

COOCH2CF3

COOCH2CF3

H Mitsunobu conditionsR

1

COOCH2CF3

COOCH2CF3

H 15. Second-generation tags for fluorous chemistry exemplified with a new fluorous

mitsunobu reagent and fluorous triphenylphosphine in THF was reported by Q.

Chu et al.15

OH

CN

+

OH

F

N NO(CH2)3O-t-C4F9

O Ot-C4F9O(CH2)3O

F-TPP, THFNC O

F

16. Multipolymer solution-phase organocatalytic mitsunobu reaction of phenol and

acid in THF was reported by A. M. Harned et al.16

OTPP, HO-DEAD

O

OH

O2N+

OH

PhTHF

O

O

O2N

Ph

SUZUKI CROSS COUPLING

17. Microwave-assisted efficient copper-promoted N arylation of amines with

arylboronic acids was given by S. Chen et al.17

NHO + PhB(OH)2Cu(OAc)2, DBU

DMSO, MWONPh

18. Stepwise cross-coupling reactions in pyrazine derivatives was reported by C.

Yang et al.18



N

N

Br

NH2

OCH3

+Pd(PPh3)4

2 M Na2CO3

N

N NH2

OCH3PhPhB(OH)2

19. A novel and versatile entry to asymmetrically substituted pyrazines was reported

by V. P. Mehta et al.19

N

N

X

S

R2

R1

+Pd(PPh3)4, K2CO3PhB(OH)2

N

N

Ph

S

R2

R11,4-dioxan : H2O (1:1)

MW

20. Microwave-assisted synthesis C-C bond formation of pyrazine derivatives was

documented by S. Sevilla et al.1

N

N

Br

NH2

NHR

1

+Pd(dppf)2Cl.DCM

N

N

Ar

NH2

NHR

1

toluene : EtOH (2:1), 90 oCArB(OH)2

21. Palladium imidazolium carbene catalyzed aryl, vinyl and alkyl suzuki-miyaura

cross coupling synthesis was given by M. B. Andrus et al.20

Ar N2+BF4

-+ R

1-B(OH)2

Pd(OAc)2, THF

N N+

i-Pr

i-Pr

i-Pr

i-PrCl- Ar R

1

22. New coupling partners in room temperature suzuki reaction of alkyl bromides

under remarkable mild conditions was reported by J. H. Kirchhoff et al.21

R1

Br+ R2-B(OH)2

5 mol-% Pd(OAc)2, P(tBu)2Me

KOtBu, t-amyl alcoholR

1

R2

23. S. Li et al.22 have synthesized Pd(OAc)2-catalyzed room temperature suzuki cross-

coupling reaction in aqueous media under aerobic conditions.



+ Ar'-B(OH)2

Pd(OAc)2, K2CO3

EtOH : H2O (2:3), 80 oCAr-X Ar Ar'

24. C. Baillie et al.23 have synthesized and given its applications in the suzuki-

miyaura coupling of aryl chlorides in presence of ferrocenyl monophosphine

ligand in dioxane.

+ Ar'-B(OH)2

Pd(OAc)2

K3PO4, dioxane, 95 oCAr-Cl Ar Ar'

Ferrocenyl monophosphine ligand

25. Suzuki-miyaura cross-coupling reaction under ligand free conditions was given by

W. J. Liu et al.24

+ Ar'-B(OH)2

Pd(OAc)2, TBAB, K2CO3

PEG-400, 110 oCAr-X Ar Ar'

26. Phosphine free palladium acetate catalyzed suzuki reaction in water was given by

L. Liu et al.25

+ Ar'-B(OH)2

Pd(OAc)2, Na2CO3

H2O/PEG-2000 (6:7), 50 oCAr-X Ar Ar'

27. A highly active catalyst for suzuki-miyaura cross coupling reactions of heteroaryl

compounds was reported by K. L. Billingsley et al.26

+ HetAr'-B(OH)2

Pd(OAc)2, K3PO4, n-butanol, 100 oCAr-X Ar Ar'

R1

R3

R2 PCy2



28. Y. M. A. Yamada et al.27 have prepared highly active catalyst for the

heterogeneous suzuki-miyaura reaction by assembled complex of palladium and

non-cross-linked amphiphilic polymer.

+ R2-B(OH)2(ArPh2P)2PdCl2R1-X

Na2CO3, H2O, 100 oCR

1R

2

DEPROTECTION

29. B. Li et al.28 have used aqueous phosphoric acid is an effective, environmentally

benign, selective and mild reagent for the deprotection of tert-butyl carbamates.

R

1

N O

OR

2H3PO4

toluene, rtR

1

NHR

2

30. A stereo conservative deprotection method of amino groups was reported by D.

M. Shendage et al.29

NHCH3

NHO

CH3

OO

HCl-MeOHrt, 1 h

NH2CH3

NHO

CH3

31. Selective removal of the tert-butoxycarbonyl group from secondary amines using

zinc bromide as the deprotecting reagent was given by S. C. Nigama et al.30

NO

O ZnBr2, CH2Cl2 NH

32. N. B. Narasimhulu et al.31 have studied deprotection of piperidine derivatives

from tert-butyl piperidine and TFA in chloroform solution.

CF3COOHN

O

OCH2 NHCH2CH2Cl2, rt



33. Reaction of tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate in HCl in

dioxane solution to gave 4-(prop-2-yn-1-yl)piperidine was prepared by N. D.

Waal et al.32

HCl in dioxaneNO

O

CHNH

CH

34. F. Bois et al.33 have studies deprotection of (2S)-2-methylpiperidine from tert-

butyl (2R)-2-methylpiperidine-1-carboxylate, CF3COOH and anisole in

dichloromethane solution.

CF3COOHN

O

O

CH3

NH

CH3

PhOMe, CH2Cl2

REACTION MECHANISM OF MITSUNOBU

Ph3P..

N NEtO2C

CO2Et+ ..

.. N N-

EtO2C

CO2EtPh3P+

..N N

EtO2C

CO2EtPh3P+

H+

R

O+

H

PNPh3

EtO2C

NH

CO2Et

-O

OH

R

O H..

R

O+

Ph3P

+H+

+N N-

EtO2C

CO2EtHN N

EtO2C

CO2EtH

H+

R

O+

Ph3P

-O=PPh3

+O-

OR



REACTION MECHANISM OF DEPROTECTION

O N

OR

HH

+O N

+

OR

H HN H

H

R+ CO2 +

+

REACTION MECHANISM OF SUZUKI COUPLING

Pd(II) R1R2

Pd(0)R2-X

Pd(II) XR2

Pd(II) OtBuR2

NaOtBu

NaX

R1 BY

Y B

-O

tBu

Y

Y

R1

B-

OtBu

Y

Y

ButO

Na+

R1 R2

NaOtBu


2-(Piperidine-4-yl methoxy)pyrazine derivatives have been tested for various

pharmacology activities, which have been summarized as under.

1. Analgesic34

2. Antibacterial35

3. Antifungal36


5. Antiviral38

6. Anticancer39

7. Anti HIV40

A. V. Shindikar et al.41 have designed, synthesize, and in vivo activity tested in

mice against mycobacterium tuberculosis H37Rv of pyrazine derivatives (2). K. J. French

et al.42 have studied cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazine based inhibitors of

human N-myristoyltransferase-1.



N

N

NH

ON

N

F

F

NH2

N

O O

OH

(2)

D. Sriram et al.43 have synthesized pyrazinamide derivatives (3) and reported

antitubercular properties. D. C. Scopes et al.44 have synthesized new k-receptor agonists

based upon a 2-[(alkylamino)methy]piperidine nucleus.

N

N

NH

O

NN

R1

(3)

Synthesis, anticancer, anti-inflammatory and analgesic activity evaluation of

some pyrazine derivatives (4) reported by S. M. Sondhi et al.45 B. S. Huegi et al.46 have

synthesized and reported pharmacological studied of 4,4-disubstituted piperidine

derivative as a potent analgesic properties.

N

NX

N N

S(4)

B. C. Gordon et al.47 have synthesized pharmaceutical composition containing

piperidine derivatives (5) and doccumented their use as modulators of chemokine CCR5

receptors. Synthesis and analgesic activity of some spiro[dibenz[b,f]oxepin]-10,4’-

piperidine] derivatives was reported by H. H. Ong et al.48

NHR

2

R1

N

R3

R4

Het

(5)



Antimycobacterial and H1-antihistaminic activity of 2-substituted piperidine

derivatives (6) was given by R. Weis et al.49 A. Z. Kabdraisova et al.50 have reported

synthesis and biological activity of N-(2-thoxyethyl)piperidine derivatives of anabasin.

Synthesis and biological screening of some piperidine substituted benzimidazoles was

reported by V. Sundari et al.51 A. Seza et al.52 have studied antimicrobial activity of some

piperidine substituted halogenobenzene derivatives.

NCH3

O H

(6)

S. J. Philippe et al.53 have prepared piperidine derivatives (7) and tested antibiotics

activity. Effect of substituents on N-(1-piperidinobenzyl)acetamide and their

antimicrobial activity was reported by N. Raman et al.54 M. Yoshifumi et al.55 have

studied antimicrobial and anti-plaque activity of N’-alkyl-N-(2-aminoethyl)piperidine

against dental plaque bacteria.

NM

R4

R3

YX

R2

R1

(7)

Synthesis and structure activity relationships of 2-phenyl-1-[(pyridinyland

piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols (8) as antifungal agents

was given by F. Giraud et al.56 K. K. Goel et al.57 have synthesized and screened for

antimicrobial activity of piperidin-4-one derivatives. K. Canan et al.58 have synthesized

and tested antimicrobial activity of some nove 2-[4-(substituted piperidin-1-

ylcarbonyl)phenyl]-1H-benzimidazole derivatives.



OH

N

N

N

NR

2N

R1

X

X

X = Cl, F

R2 = H, CH3

R1 = H, BOC

(8)

M. Ishikawa et al.59 have synthesized and given structure activity relationships of

N-aryl-piperidine derivatives (9) as potent (partial) agonists for human histamine H3

receptor. M. Tibor et al.60 have studied histamine H3 receptor antagonists of 1-(4-

Phenoxymethyl) benzyl)piperidines derivatives.

NH

N

NR

1R1 = H, CF3, C(CH3)3, F, NO2, CH(CH3)2, OCH3, NHCH3, N(CH3)2

(9)

G. D. Maynard et al.61 have synthesized and given SAR of 4-(1H-benzimidazole-

2-carbonyl)piperidines (10) with dual histamine H1/tachykinin NK1 receptor antagonist

activity. A. G. Magid et al.62 have synthesized substituted piperidine derivatives as novel

H1-antagonists. V. Claudio et al.63 studied antinociceptive profile of 2,3,6-trisubstituted

piperidine alkaloids.

NO

NN

R3

NO

R1

R2

R1 = 3,4,5-(OCH3)3

R2 = 3,4-(OCH3)2, OCH3, CF3, F, ClR3 = aryl(10)

C. E. Gutteridge et al.64 have studied N-(3-phenylsulfonyl-3-piperidinoyl)-

phenylalanine derivatives (11) as potent, selective VLA-4 antagonists. Study of piperidine

carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally active

adhesion molecule inhibitors investigated by K. Toshihiko et al.65



NHNH

O OOH

H3COOCH3

SO

R1 O

R1 = aryl

(11)

C. G. Barber et al.66 have investigated 1-amino-1-phenyl-3-piperidinylbutanes

(12) CCR5 antagonists for the treatment of HIV. Analgesic and antiinflammatory activity

screening of 6-acyl-3-piperidinomethyl-2(3H)-benzoxazolone derivatives was reported by

E. D. Demir et al.67

S. Imamura et al.68 synthesized and reported biological evaluation of piperidine-4-

carboxamide derivatives (13) as CCR5 antagonists as anti-HIV-1 agents. Synthesis and

biological activity of piperidinoaryl carbamides and their derivatives was reported by V.

M. Gujrati et al.69 W. Tao et al.70 have synthesized diketopiperidine derivatives as HIV

attachment inhibitors and reported, pharmaceutical compositions and use in the treatment

of HIV infection and AIDS.

NR

1

N

O

NR

3

R2

R1 = COCH3, SO2CH3

R2 = H, Cl, CH3, OCH3R3 = H, F(13)

R. H. K. Foster and coworkers71 have studied piperidine derivatives with

morpholine like analgesia activity. Study of (2S)-1-(arylacetyl)-2-

N

NN

N

NHO

FF

(12)



(aminomethyl)piperidine derivatives and highly selective kappa opioid analgesics was

given by V. Vecchietti et al.72 M. Eiichi and coworkers73 have synthesized and reported

antiallergic activity of novel pyrazine derivative. Synthesis and anti mycobacterial

evaluation of some pyrazine-2-carboxylic acid hydrazide derivatives was documented by

A. A. Mohamed et al.74 G. Katarzyna et al.75 have synthesized and screened antibacterial

activity of novel pyrazine derivative obtained from amindoximes. Synthesis and

antibacterial activity of 6-methoxypyrazine-2-carboxylic acid hydrazide derivatives was

reported by G. Katarzyna et al.76 Synthesis and antimicrobial activity of 2,3-(substituted

phenyl)pyrazine dicarboxamide was given by N. S. Rao et al.77 Pyrazine-2-substituted

carboxamide derivatives synthesis, antimicrobial and leuconostoc mesenteroides growth

inhibition activity study investigated by A. H. F. Wahab et al.78 N. B. Patel et al.79 have

synthesized and reported antimicrobial activity of 2-[3-(arylureido)carbonyl]pyrazine

derivatives. A study of 2-piperidino-1-ethanol and its derivatives as antimicrobial

additives to oils was reported by S. A. Gamzaeva et al.80

Looking to the interesting properties of 2-(piperidine-4-ylmethoxy)pyrazine, we

have synthesized some new 2-(piperidine-4-ylmethoxy)pyrazine, which have been

describe as under.

PART-I: STUDIES ON 2-(PIPERIDINE-4-YLMETHOXY)PYRAZINE

DERIVATIVES

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL{4-

[({5-[3-(METHYLSULFONYL)PHENYL]PYRAZIN-2-YL}OXY)

METHYL]PIPERIDIN-1-YL}METHANONES

SECTION-II: SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL[4-

({[5-(2-FLUOROPHENYL)PYRAZIN-2-YL]OXY}METHYL)

PIPERIDIN-1-YL]METHANONES

SECTION-III: SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL[4-

({[5-(THIOPHEN-2-YL)PYRAZIN-2-YL]OXY}METHYL)

PIPERIDIN-1-YL]METHANONES

SECTION-IV: SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL[4-

({[5-(1-BENZOTHIOPHEN-3-YL)PYRAZIN-2-YL]OXY}

METHYL)PIPERIDIN-1-YL]METHANONES



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL{4-[({5-[3-

(METHYLSULFONYL)PHENYL]PYRAZIN-2-YL}OXY)METHYL]PIPERIDIN-

1-YL}METHANONES


activities, some of their derivatives occur as natural products. In view of these findings, it

appeared of interest to synthesize 2-(piperidin-4-ylmethoxy)pyrazines derivatives by the

condensation of 2-[3-(methylsulfonyl)phenyl]-5-(piperidin-4-ylmethoxy)pyrazine with

various aromatic acid chlorides in the presence of TEA, as shown in reaction scheme.

REACTION SCHEME

NBS, DCMN

N NH2

BrNaNO2

N

N OH

BrN

N NH2

CH3SO2Cl

Et3N, DCM

N

N O

Br

SO

O

CH3

NO

O

OHK2CO3

DMF

Pd(PPh3)4, K2CO3

deprotection

HBTU, Et3N, DMF

R-COOH

H2SO4

HCl in dioxane

N

NO

NO

O

SO

O

N

NO

NHS

OO N

NO

NS

OO

R

O

BOH

OHS

O

O

N

NO

NO

Br O





All the synthesized compounds were tested for their antibacterial and antifungal

activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two

Gram-negative bacteria and three fungal strains. The biological activities of the

synthesized compounds have been compared with standard drugs.



EXPERIMENTAL SECTION

Melting points were determined in open capillary tubes and are uncorrected.

Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm

thickness and spots were located by iodine and UV light. IR spectra were recorded on

Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded

on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.

Purity of the synthesized compounds was checked by HPLC Agilent 1100 series.

Elemental analysis of the all the synthesized compounds was carried out on Euro EA

3000 elemental analyzer and the results are in agreements with the structures assigned.

[A] Preparation of 5-Bromopyrazin-2-amine.

To a stirred cooled to 0 oC solution of 2-aminopyrazine (10.0 g, 0.105 mol) in dry

DCM (250 ml), N-bromosuccinamide (18.72 g, 0.105 mol) was added portion wise. The

mixture was stirred at 0 oC for 24 hour. The reaction was monitored on TLC. After

completion of the reaction, saturated aqueous solution of sodium carbonate was added

(200 ml) to quench the reaction. The organic layer was washed with brine and dried over

anhydrous Na2SO4. The solvent was removed in vacuo and the resulting crude product

was purified by column chromatography on silica gel (eluent: 2 : 8 = E.A. : Hexane) to

obtain pure product. Yield: 70 %, mp 133-135 oC.

[B] Preparation of 5-Bromopyrazin-2-ol.

Sodium nitrite (8.9 g, 0.129 mol) was added portion wise with stirring to

concentrated H2SO4 (49 ml) at 0 oC and the mixture was warmed to dissolved the solid.

The mixture was cooled to 5 oC. To this a solution of 5-bromopyrazin-2-amine (15.0 g,

0.086 mol) in concentrated H2SO4 (71 ml) was added slowly. The reaction mixture was

stirred bellow 5 oC for 30 minute and warmed to 40 oC for 2 hour. The reaction mixture

was poured onto crushed ice. The aqueous solution was extracted with ethyl acetate (250

ml x 3) and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the

solid product was obtained. Yield: 50 %, mp 80-82 oC.

[C] Preparation of 5-Bromopyrazin-2-yl methanesulfonate.

To a stirred cooled (ice bath) solution of 5-bromopyrazin-2-ol (5.0 g, 0.028 mol)

in dry DCM (25 ml), TEA (5.85 ml, 0.042 mol) and CH3SO2Cl (2.80 ml, 0.034 mol) was



added dropwise in solution at 0 oC. The reaction mixture was stirred for 2 hour at room

temperature (monitored by TLC), and the solvent was removed in vacuo. The product

was filtered, washed with water and dried to give analytical pure product. Yield: 80 %,

mp 85-87 oC.

[D] Preparation of tert-Butyl 4-{[(5-bromopyrazin-2-yl)oxy]methyl}piperidine-1-

carboxylate.

To a stirred suspension of K2CO3 (3.036 g, 0.022 mol) and 5-bromopyrazin-2-yl

methanesulfonate (3.0 g, 0.011 mol) in dry DMF (30 ml), tert-butyl 4-

(hydroxymethyl)piperidine-1-carboxylate (2.54 g, 0.011 mol) was added. The solution

was heated on a water bath for 2 hour (monitored by TLC). The reaction mixture was

poured onto crushed ice, thus the precipitate obtained, was filtered and washed with water

to give pure product. Yield: 68 %, mp 99-101 oC.

[E] Preparation of tert-Butyl 4-((5-(3-(methylsulfonyl)phenyl)pyrazine-2-

yloxy)methyl)piperidine-1-carboxylate.

A solution of tert-butyl 4-{[(5-bromopyrazin-2-yl)oxy]methyl}piperidine-1-

carboxylate (1.5 g, 0.004 mol) in toluene (20 ml) was stirred at room temperature under

nitrogen atmosphere. The obtained solution was further stirred for 5.0 minute. To this

solution 3-(methylsulfonyl)phenylboronic acid (0.66 g, 0.004 mol), isopropylalcohol (20

ml) was added at room temperature. To this content a solution of K2CO3 (10.0 ml, 0.02

mol) in water was added dropwise under nitrogen atmosphere and stirred for 5.0 minute.

Palladium tetrakistriphenylphosphine (0.231 g, 0.0002 mol) was added in to the above

reaction mixture and the reaction mixture was heated to reflux for 6 hour (monitored by

TLC). The reaction mixture was added in to the water under stirring. The aqueous layer

was extracted with ethylacetate (100 ml × 3), and the combined organic layers were

washed with water followed by brine and dried over anhydrous Na2SO4. The solvent was

evaporated under vacuum to give crude product. The crude product was used in the next

step without further purification.

[F] Preparation of 2-[3-(Methylsulfonyl)phenyl]-5-(piperidin-4-ylmethoxy)

pyrazine.

A mixture of HCl in dioxane (10 ml) and tert-butyl 4-((5-(3-(methylsulfonyl)

phenyl)pyrazine-2-yloxy)methyl)piperidine-1-carboxylate was stirred at room

temperature for overnight (monitored by TLC), and the solvent was removed in vacuo.



Water and ethylacetate was added in to the crude product and stirred well. The organic

layer was separated and the major impurities were removed in the organic layer. The

aqueous layer was basified using sodium hydroxide solution and the product was

extracted with DCM (100 ml × 3). The combined organic layers were washed with water

followed by brine and dried over anhydrous Na2SO4. The solvent was evaporated under

vacuum to give pure product. Yield: 60 %, mp 138-139 oC.

[G] General procedure for the preparation of Aryl{4-[({5-[3-

(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-1-yl}methanones.

To a stirred cooled (ice bath) solution of 2-[3-(methylsulfonyl)phenyl]-5-

(piperidin-4-ylmethoxy)pyrazine (0.2 g, 0.576 mmol) and aryl acid (0.576 mmol) in dry

DMF (3 ml), HBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro

phosphate) (0.262 g, 0.691 mmol) and TEA (0.1 ml, 0.864 mmol) was added at 0 oC. The

reaction mixture was stirred for 10 hour at room temperature (monitored by TLC). The

reaction mixture was poured onto crushed ice, thus the precipitate separated was filtered

and washed with water to give pure product. The physical constants of the products are

recorder in Table-1a.



Table-1a: Physical constants of Aryl{4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-

yl}oxy)methyl]piperidin-1-yl}methanones.

N

NO

NO

R

SO

O

CH3

Sr. No.

Substitution R MF MW Yield (%) Rf value

1a CH3O

C25H27N3O4S

465.56

75 0.53

1b

O

CH3

C25H27N3O4S

465.56 69 0.51

1c NO

C23H24N4O4S

452.52

72 0.42

1d N

O

C23H24N4O4S

452.52

65 0.40

1e

O

OCH3

C25H27N3O5S

481.56

77 0.45

1f

O

C25H27N3O4S

465.56

82 0.47

1g ONH

O

CH3

C26H28N4O5S

508.58

62 0.30

1h O Br

C25H26BrN3O4S

544.46

75 0.39

1i O

NH2

Br

C24H25BrN4O4S

545.44

66 0.35

1j O

Cl

C24H24ClN3O4S

485.98

80 0.41

TLC solvent system:- E.A. : Hexane = 6 : 4



ANALYTICAL DATA

(4-Methylphenyl){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-

1-yl}methanone (1a). mp 160-162 oC; IR (KBr): 3001, 2929, 2846, 1622, 1538, 1461,

1341, 1301, 1149, 1015, 827 cm-1; MS: m/z = 365 [M]+; Anal. Calcd for C25H27N3O4S: C,

64.50; H, 5.85; N, 9.03. Found: C, 64.23; H, 5.76; N, 8.95%.

(2-Methylphenyl){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-

1-yl}methanone (1b). mp 182-184 oC; Purity by HPLC: 89 %; IR (KBr): 3007 (Ar, C-H

str), 2923 (C-H str), 2860 (C-H str), 1627 (amide, C=O str), 1537 (Ar, C=C str), 1463

(Ar, C=C str), 1344 (C-H ban), 1301 (S=O str asym), 1150 (S=O str sym), 1095 (C-N

str), 1010 (C-O-C str), 742 (C-H o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm

1.40-1.47 (m, 2H, 2CH), 1.75-1.78 (d, J=12.64 Hz, 1H, CH), 1.98-2.02 (d, J=13.08 Hz,

1H, CH), 2.11-2.17 (m, 1H, CH), 2.29 (s, 3H, CH3), 2.83-2.97 (m, 1H, CH), 2.98-3.05

(m, 1H, CH), 3.09 (s, 3H, CH3), 3.54-3.57 (d, J=12.40 Hz, 1H, CH), 4.27-4.28 (d, J=6.40

Hz, 2H, CH2), 4.87-4.90 (d, J=12.92 Hz, 1H, CH), 7.21-7.30 (m, 4H, ArH), 8.02-8.05 (m,

2H, ArH), 8.21-8.14 (m, 2H, ArH), 8.31 (s, 1H, ArH), 8.56-8.57 (d, J=1.24 Hz 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 19.70, 30.10, 35.46, 42.10, 44.59, 46.19, 70.16,

120.18, 123.51, 126.84, 128.08, 130.94, 135.78, 138.14, 140.62, 144.29, 152.55, 156.16,

159.28, 170.21; MS: m/z = 366 [M+1]+; Anal. Calcd for C25H27N3O4S: C, 64.50; H, 5.85;

N, 9.03. Found: C, 64.19; H, 5.77; N, 8.93%.

(Pyridin-4-yl){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-1-

yl}methanone (1c). mp 233-235oC; IR (KBr): 3001, 2916, 2869, 1617, 1535, 1449, 1339,

1300, 1148, 1010, 750 cm-1; MS: m/z = 353 [M+1]+; Anal. Calcd for C23H24N4O4S: C,

62.70; H, 5.61; N, 10.27. Found: C, 62.50; H, 5.52; N, 10.15%.

(Pyridin-2-yl){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-1-

yl}methanone (1d). mp 219-221 oC; Purity by HPLC: 92 %; IR (KBr): 3003, 2919, 2867,

1616, 1534, 1463, 1340, 1300, 1148, 1089, 1058 cm-1; 1H NMR (400 MHz, CDCl3): δ

ppm 1.45-1.54 (m, 2H, 2CH), 1.82-1.85 (d, J=12.56 Hz, 1H, CH), 1.98-2.01 (d, J=12.88

Hz, 1H, CH), 2.17-2.18 (m, J=13.48 Hz, 1H, CH), 4.28-4.29 (d, J=6.52 Hz, 2H, CH2),

4.81-4.84 (d, J=13.12 Hz, 1H, CH), 7.33-7.36 (m, 1H, ArH), 7.61-7.63 (d, J=7.76 Hz,

1H, ArH), 7.78-7.82 (m, 1H, ArH), 8.02-8.05 (m, 2H, ArH), 8.11-8.14 (m, 2H, ArH),

8.32-8.33 (d, J=1.28 Hz, 1H, ArH), 8.56-8.57 (d, J=1.4 Hz, 1H, ArH), 8.59-8.60 (d, J=4.2



Hz, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 28.10, 35.92, 42.25, 44.59, 46.17,

70.61, 120.08, 123.61, 126.83, 128.07, 131.74, 135.43, 137.10, 138.16, 140.23, 144.16,

152.15, 156.64, 159.94, 170.94; MS: m/z = 453 [M+1]+; Anal. Calcd for C23H24N4O4S: C,

61.05; H, 5.35; N, 12.38. Found: C, 60.89; H, 5.26; N, 12.25%.

(3-Methoxyphenyl)[{4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2yl}oxy)methyl]

piperidin-1-yl}methanone (1e). mp 173-175 oC; IR (KBr): 3148, 2921, 2861, 1627, 1538,

1460, 1344, 1301, 1150, 1010, 739 cm-1; MS: m/z = 481 [M]+; Anal. Calcd for

C25H27N3O5S: C, 62.71; H, 5.68; N, 9.62. Found: C, 62.48; H, 5.62; N, 9.49%.

1-{4-[({5-[3-(Methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-1-yl}-2-

phenylethanone (1f). mp 149-151 oC; IR (KBr): 3001, 2929, 2846, 1622, 1538, 1461,

1341, 1301, 1149, 1015, 755 cm-1; MS: m/z = 465 [M]+; Anal. Calcd for C25H27N3O4S: C,

64.50; H, 5.85; N, 9.03. Found: C, 64.20; H, 5.80; N, 8.90%.

(N-Phenylacetamide){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]

piperidin-1-yl}methanone (1g). mp 238-240 oC; IR (KBr): 3345, 3015, 2918, 2823, 1610,

1545, 1445, 1355, 1290, 1115, 1020, 825 cm-1; MS: m/z = 508 [M]+; Anal. Calcd for


[4-(Bromomethyl)phenyl]{4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]

piperidin-1-yl}methanone (1h). mp 167-168 oC; IR (KBr): 3023, 2950, 2826, 1595, 1512,

1442, 1332, 1290, 1140, 1032, 840, 612 cm-1; MS: m/z = 555 [M+1]+; Anal. Calcd for

C25H26BrN3O4S: C, 55.64; H, 4.80; N, 8.89. Found: C, 55.44; H, 4.72; N, 8.76%.

(2-Amino-5-bromophenyl){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]

piperidin-1-yl}methanone (1i). mp 190-192 oC; IR (KBr): 3456, 3385, 3037, 2948, 2852,

1610, 1545, 1462, 1322, 1334, 1152, 1028, 620 cm-1; MS: m/z = 546 [M+1]+; Anal. Calcd

for C24H25BrN4O4S: C, 52.85; H, 4.62; N, 10.27. Found: C, 52.62; H, 4.57; N, 10.20%.

(4-Chlorophenyl){4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)methyl]piperidin-

1-yl}methanone (1j). mp 145-147 oC; IR (KBr): 3045, 2941, 2853, 1620, 1541, 1440,

1311, 1260, 1153, 1015, 820, 740 cm-1; MS: m/z = 486 [M+1]+; Anal. Calcd for

C24H24ClN3O4S: C, 59.31; H, 4.98; N, 8.65. Found: C, 59.04; H, 4.90; N, 8.52%.



SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS

IR spectra of compound 1b

IR spectra of compound 1d

5007501000125015001750200025003000350040001/cm

40

50

60

70

80

90

100

110%T

3007

.12

2923

.22

2860

.53

1627

.01

1537

.32

1463

.06

1442

.80

1344

.43

1301

.03

1252

.81

1150

.58

1095

.60

1010

.73

961.

5587

3.78

846.

7877

1.55

742.

62 686.

6856

9.98

522.

73

JP-105 p

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3003

.27

2919

.36

2867

.28

1616

.40 15

34.4

214

63.0

6

1340

.57

1300

.07

1148

.65

1089

.82

1050

.28

964.

44

844.

8580

7.24

752.

2667

8.97

601.

8157

6.74

JP-104

N

NO

NOS

OO

CH3

CH3

N

NO

NO

N

SO

O

CH3



Mass spectrum of compound 1b

Mass spectrum of compound 1d

N

NO

NOS

OO

CH3

CH3

m/z = 465

N

NO

NO

N

SO

O

CH3

m/z = 452



1H NMR spectrum of compound 1b

Expanded spectrum of compound 1b

N

NO

NOS

OO

CH3

CH3




1H NMR spectrum of compound 1d

N

NO

NO

N

SO

O

CH3



Expanded spectrum of compound 1d




13C NMR spectrum of compound 1d


N

NO

NO

N

SO

O

CH3

N

NO

NOS

OO

CH3

CH3



HPLC of compound 1b



HPLC of compound 1d



ANTIMICROBIAL ACTIVITY

Biological evaluation of Aryl{4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-yl}oxy)

methyl]piperidin-1-yl}methanones.

All of the synthesized compounds (1a-j) were tested for their antibacterial and

antifungal activity (MIC) in vitro by broth dilution method38-40 with two Gram-positive

bacteria Staphylococcus aureus MTCC-96 and Streptococcus pyogenes MTCC 442, two

Gram-negative bacteria Escherichia coli MTCC 443 and Pseudomonas aeruginosa

MTCC 1688 and three fungal strains Candida albicans MTCC 227, Aspergillus Niger

MTCC 282 and Aspergillus clavatus MTCC 1323 taking gentamycin, ampicillin,

chloramphenicol, ciprofloxacin, norfloxacin, nystatin and greseofulvin as standard drugs.

The standard strains were procured from the Microbial Type Culture Collection (MTCC),

Institute of Microbial Technology, Chandigarh, India.

The minimal inhibitory concentration (MIC) values for all the newly synthesized

compounds, defined as the lowest concentration of the compound preventing the visible

growth, were determined by using micro dilution broth method according to NCCLS

standards.38

Minimal Inhibition Concentration [MIC]

The main advantage of the Broth Dilution Method for MIC determination lies in

the fact that it can readily be converted to determine the MIC as well. 1. Serial dilutions were prepared in primary and secondary screening.

2. The control tube containing no antibiotic is immediately subcultured (before

inoculation) by spreading a loopful evenly over a quarter of plate of medium

suitable for the growth of the test organism and put for incubation at 37 0C

overnight.

3. The MIC of the control organism is read to check the accuracy of the drug

concentrations.

4. The lowest concentration inhibiting growth of the organism is recorded as the

MIC.

5. The amount of growth from the control tube before incubation (which represents

the original inoculums) is compared.



Methods used for primary and secondary screening

Each synthesized compounds was diluted obtaining 2000 μg mL-1 concentration,

as a stock solution. Inoculum size for test strain was adjusted to 108 cfu (colony forming

unit) per milliliter by comparing the turbidity.

Primary screen: In primary screening 1000 μg mL-1, 500 μg mL-1 and 250 μg mL-1

concentrations of the synthesized compounds were taken. The active synthesized drugs

found in this primary screening were further tested in a second set of dilution against all

microorganisms.

Secondary screen: The compounds found active in primary screening were similarly

diluted to obtain 200 μg mL-1, 100 μg mL-1, 50 μg mL-1, 25 μg mL-1, 12.5 μg mL-1, and

6.250 μg mL-1 concentrations.

Reading Result: The highest dilution showing at least 99 % inhibition zone is taken as

MIC. The result of this is much affected by the size of the inoculums. The test mixture

should contain 108 organism/mL.

The results obtained from antimicrobial susceptibility testing are depicted in

Table 1b.



Table-1b: Antimicrobial activity of Aryl{4-[({5-[3-(methylsulfonyl)phenyl]pyrazin-2-

yl}oxy)methyl]piperidin-1-yl}methanones.

Sr. No.

Antibacterial Activity Antifungal activity

Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria

S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus

1a 200 200 200 250 1000 500 500 1b 250 250 62.5 100 1000 >1000 >1000 1c 500 500 250 250 1000 500 500 1d 500 250 200 125 500 >1000 >1000 1e 62.5 100 250 500 500 500 1000 1f 200 125 100 250 1000 1000 500 1g 125 500 500 200 >1000 1000 1000 1h 250 250 100 100 >1000 >1000 500 1i 200 200 200 125 500 500 >1000 1j 500 200 100 500 1000 500 500

MINIMAL INHIBITION CONCENTRATION

Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa

(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100

Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10

MINIMAL FUNGICIDAL CONCENTRATION

Standard Drugs C.Albicans A.Niger A.Clavatus

(microgramme/ml) Nystatin 100 100 100

Greseofulvin 500 100 100



SECTION-II

SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL[4-({[5-(2-

FLUOROPHENYL)PYRAZIN-2-YL]OXY}METHYL)PIPERIDIN-1-YL]

METHANONES

Many pyrazine derivatives have displayed diverse pharmacological activities. In

view of our on going interest in the synthesis of some new 2-(piperidin-4-

ylmethoxy)pyrazine derivatives we have under taken the synthesis of 2-(2-fluorophenyl)-

5-(piperidin-4-ylmethoxy)pyrazine with various aromatic acid chlorides in the presence

of TEA.

REACTION SCHEME

Pd(PPh3)4, K2CO3

BOH

OH

Ftoluene, IPA

N

NO

NO

O

F

N

NO

NO

Br O +

deprotection HCl in dioxane

N

NO

NH

F

HBTU, Et3N, DMF

R-COOHN

NO

NO

R

F




















[A] Preparation of tert-Butyl 4-{[(5-bromopyrazin-2-yl)oxy]methyl}piperidine-1-

carboxylate.

See, Part-A, Part-1, Section-I Experimental Section [D].

[B] Preparation of tert-Butyl 4-((5-(2-fluorophenyl)pyrazine-2-yloxy)methyl)

piperidine-1-carboxylate.



nitrogen atmosphere. The obtained solution was stirred for further 5.0 minute. To this

solution 2-fluorophenylboronic acid (0.56 g, 0.004 mol) and isopropyl alcohol (20 ml)

was added at room temperature. To this content a solution of K2CO3 (10 ml, 0.02 mol) in

water was added dropwise under nitrogen atmosphere and stirred for 5.0 minute.








[C] Preparation of 2-[2-Fluorophenyl]-5-(piperidin-4-ylmethoxy)pyrazine.

A mixture of HCl in dioxane (10 ml) and tert-butyl 4-((5-(2-fluorophenyl)

pyrazine-2-yloxy)methyl)piperidine-1-carboxylate was stirred at room temperature for



overnight (monitored by TLC), and the solvent was removed in vacuo. Water and

ethylacetate was added in to the crude product and stirred well. The organic layer was

separated and the major impurities were removed in the organic layer. The aqueous layer

was basified using sodium hydroxide solution and the product was extracted with DCM

(100 ml × 3). The combined organic layers were washed with water followed by brine

and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to give

pure product. Yield: 63 %, mp 141-143 oC.

[D] General procedure for the preparation of Aryl{4-[({5-[2-

fluorophenyl]pyrazin-2-yl}oxy)methyl]piperidin-1-yl}methanones.

To a stirred cooled (ice bath) solution of 2-[2-fluorophenyl]-5-(piperidin-4-

ylmethoxy)pyrazine (0.2 g, 0.696 mmol) and aryl acid (0.696 mmol) in dry DMF (3 ml),

HBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate)

(0.316 g, 0.835 mmol) and TEA (0.1 ml, 0.835 mmol) was added at 0 oC. The reaction

mixture was stirred for 10 hour at room temperature (monitored by TLC). The reaction

mixture was poured onto crushed ice, thus the precipitate separated was filtered and

washed with water to give pure product. The physical constants of the products are


[E] Biological evaluation of Aryl[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)

piperidin-1-yl]methanones.

Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,

antimicrobial activity. The MIC values of the test compounds are recorded in Table-2b.



Table-2a: Physical constants of Aryl[4-({[5-(2-fluorophenyl)pyrazin-2-

yl]oxy}methyl)piperidin-1-yl]methanones.

N

NO

NO

R

F Sr. No.


2a CH3O

C24H24FN3O2

405.46

80 0.51

2b

O

CH3

C24H24FN3O2

405.46

68 0.49

2c NO

C22H21FN4O2

392.42 75 0.43

2d N

O

C22H21FN4O2

392.42

71 0.42

2e

O

OCH3

C24H24FN3O3

421.46 79 0.46

2f

O

C24H24FN3O2

405.46

85 0.48

2g ONH

O

CH3

C25H25FN4O3

448.48

60 0.28

2h O Br

C24H23BrFN3O2

484.36 74 0.36

2i O

NH2

Br

C23H22BrFN4O2

485.34

61 0.30

2j O

Cl

C23H21ClFN3O2

425.88

78 0.46




ANALYTICAL DATA

(4-Methylphenyl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2a). mp 148-150 oC; Purity by HPLC: 93 %; IR (KBr): 3060 (Ar, C-H str),

2877 (C-H str), 2850 (C-H str), 1636 (amide, C=O str), 1534 (Ar, C=C str), 1464 (Ar,

C=C str), 1338 (C-H ban), 1167 (str C-F), 1051 (C-N str), 1006 (C-O-C str), 840 (C-H

o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 1.24-1.30 (m, 2H, 2CH), 1.81-1.88

(m, 2H, 2CH), 2.09-2.14 (m, 1H, CH), 2.38 (s, 3H, CH3), 2.85-3.15 (m, 2H, 2CH), 3.86-

3.88 (d, J=13.24 Hz, 1H, CH), 4.24-4.25 (d, J=6.48 Hz, 2H, CH2), 4.76-4.78 (d, J=13.4

Hz, 1H, CH), 7.13-7.16 (m, 2H, ArH), 7.17-7.21 (m, 2H, ArH), 7.28-7.36 (m, 2H, ArH),

7.86-7.91 (m, 2H, ArH), 8.26-8.27 (d, J=1.4 Hz, 1H, ArH), 8.44-8.45 (d, J=1.4 Hz, 1H,

ArH). 13C NMR (100 MHz, CDCl3): δ ppm 21.40, 30.44, 36.02, 42.71, 47.16, 70.35,

115.81, 116.02, 127.02, 127.91, 129.07, 132.72, 133.23, 134.71, 137.10, 139.87, 144.50,

155.23, 159.33; MS: m/z = 405 [M]+; Anal. Calcd for C24H24FN3O2: C, 71.09; H, 5.97; N,

10.36. Found: C, 70.80; H, 5.90; N, 10.21%.

(2-Methylphenyl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2b). mp 128-130 oC; IR (KBr): 3045, 2923, 2860, 1624, 1537, 1464, 1340,

1169, 1055, 1010, 832 cm-1; MS: m/z = 405 [M]+; Anal. Calcd for C24H24FN3O2: C,

71.09; H, 5.97; N, 10.36. Found: C, 70.82; H, 5.92; N, 10.22%.

(Pyridin-4-yl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2c). mp 120-122 oC; IR (KBr): 3010, 2960, 2837, 1642, 1558, 1440, 1330,


67.33; H, 5.39; N, 14.28. Found: C, 67.08; H, 5.30; N, 14.15%.

(Pyridin-2-yl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2d). mp 100-101 oC; IR (KBr): 3017, 2925, 2850, 1610, 1532, 1461, 1328,


67.33; H, 5.39; N, 14.28. Found: C, 67.01; H, 5.32; N, 14.19%.

(3-Methoxyphenyl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2e). mp 90-91 oC; Purity by HPLC: 95 %; IR (KBr): 3063, 2924, 2858,

1627, 1537, 1478, 1340, 1166, 1050, 1012, 750 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm

1.25-1.50 (m, 2H, 2CH), 1.84-1.96 (m, 2H, 2CH), 2.14-2.17 (m, 1H, CH), 2.83-2.89 (m,

1H, CH), 3.02-3.07 (m, 1H, CH), 3.82-3.86 (m, 4H, OCH3,CH), 4.24-4.26 (d, J=6.4 Hz,



2H, CH2), 4.76-4.79 (d, J=13.0 Hz, 1H, CH), 6.94-6.95 (m, 3H, ArH), 7.13-7.19 (m, 2H,

ArH), 7.29-7.36 (m, 1H, ArH), 7.86-7.90 (m, 2H, ArH), 8.26-8.27 (d, J=1.36 Hz, 1H,

ArH), 8.44-8.45 (d, J=1.32 Hz, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 29.32,

34.71, 42.50, 45.77, 54.70, 70.16, 115.72, 115.96, 127.10, 127.80, 129.10, 132.66,

133.33, 134.61, 137.17, 139.89, 144.33, 155.44, 159.30; MS: m/z = 421 [M]+; Anal.

Calcd for C24H24FN3O3: C, 68.74; H, 5.77; N, 10.98. Found: C, 68.53; H, 5.70; N,

10.88%.

1-[4-({[5-(2-Fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]-2-phenylethanone

(2f). mp 97-99 oC; IR (KBr): 3032, 2960, 2860, 1641, 1525, 1470, 1342, 1162, 1010, 823

cm-1; MS: m/z = 405 [M]+; Anal. Calcd for C24H24FN3O2: C, 71.09; H, 5.97; N, 10.36.

Found: C, 70.85; H, 5.90; N, 10.28%.

(N-Phenylacetamide)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2g). mp 162-164 oC; IR (KBr): 3360, 3027, 2956, 2826, 1617, 1536, 1465,

1323, 1163, 1036, 1001, 838 cm-1; MS: m/z = 448 [M]+; Anal. Calcd for C25H25FN4O3: C,

66.95; H, 5.62; N, 12.49. Found: C, 66.73; H, 5.57; N, 12.40%.

[4-(Bromomethyl)phenyl][4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-

yl]methanone (2h). mp 141-142 oC; IR (KBr): 3027, 2956, 2826, 1617, 1536, 1465,


C24H23BrFN3O2: C, 59.51; H, 4.79; N, 8.68. Found: C, 59.18; H, 4.70; N, 8.55%.

(2-Amino-5-bromophenyl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-

yl]methanone (2i). mp 155-157 oC; IR (KBr): 3433, 3350, 3020, 2940, 2843, 1616, 1542,

1450, 1330, 1160, 1018, 631 cm-1; MS: m/z = 486 [M+1]+; Anal. Calcd for

C23H22BrFN4O2: C, 56.92; H, 4.57; N, 11.54. Found: C, 56.69; H, 4.52; N, 11.43%.

(4-Chlorophenyl)[4-({[5-(2-fluorophenyl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (2j). mp 102-104 oC; IR (KBr): 30256, 2929, 2860, 1629, 1554, 1460, 1321,

1170, 1040, 1003, 818 cm-1; MS: m/z = 426 [M+1]+; Anal. Calcd for C23H21ClFN3O2: C,

64.86; H, 4.97; N, 9.87. Found: C, 64.60; H, 4.93; N, 9.78%.




IR spectra of compound 2a

IR spectra of compound 2e

5007501000125015001750200025003000350040001/cm

50

60

70

80

90

100

110

%T

3060

.17

2877

.89

2850

.88

1636

.65

1534

.42

1507

.42

1464

.98 13

38.6

4 1292

.35

1226

.77

1167

.94

1051

.24

1006

.88

914.

2987

3.78

840.

03

714.

6563

9.42

568.

0652

3.69

JP-203D1

5007501000125015001750200025003000350040001/cm

0

20

40

60

80

100

%T

3063

.06

3010

.98

2924

.18

2858

.60

1627

.01

1537

.32

1508

.38

1478

.49

1455

.34

1421

.58

1340

.57 12

95.2

412

27.7

311

66.9

710

50.2

810

12.6

6

874.

7584

0.03

750.

33 710.

7965

3.89

557.

45 516.

9444

2.68

JP-204D

N

NO

NO

CH3

F

N

NO

NO

FOCH3



Mass spectrum of compound 2a

Mass spectrum of compound 2e

N

NO

NO

CH3

Fm/z = 405

N

NO

NO

FOCH3m/z = 421



1H NMR spectrum of compound 2a

Expanded spectrum of compound 2a

N

NO

NO

CH3

F



1H NMR spectrum of compound 2e

Expanded spectrum of compound 2e

N

NO

NO

FOCH3



Expanded spectrum of compound 2e

13C NMR spectrum of compound 2a

N

NO

NO

CH3

F



13C NMR spectrum of compound 2e

N

NO

NO

FOCH3



HPLC of compound 2a



HPLC of compound 2e



Table-2b: Antimicrobial activity of Aryl[4-({[5-(2-fluorophenyl)pyrazin-2-


Sr. No.




2a 200 200 200 250 1000 1000 1000 2b 125 100 100 62.5 250 500 250 2c 250 100 500 500 500 1000 1000 2d 62.5 125 500 500 250 >1000 >1000 2e 100 100 250 250 500 1000 1000 2f 500 250 500 200 250 500 250 2g 125 200 250 250 500 250 500 2h 250 250 200 500 >1000 500 250 2i 500 500 250 200 500 1000 500 2j 100 62.5 125 100 500 >1000 1000











SECTION-III

SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL[4-({[5-(THIOPHEN-

2-YL)PYRAZIN-2-YL]OXY}METHYL)PIPERIDIN-1-YL]METHANONES

Pyrazine derivatives have been attracted widespread attention due to their diverse

pharmacological properties. Looking to this, the synthesis of 2-(piperidin-4-

ylmethoxy)pyrazines derivatives have been under taken by the condensation of 2-

(piperidin-4-ylmethoxy)-5-(thiophen-2-yl)pyrazines with various aromatic acid chlorides

in the presence of TEA.

REACTION SCHEME

Pd(PPh3)4, K2CO3

toluene, IPA

N

NO

NO

Br O +


HBTU, Et3N, DMF

R-COOH

SB

OH

OH N

NO

NO

OS

N

NO

NH

SN

NO

NO

RS





















carboxylate.


[B] Preparation of tert-Butyl 4-((5-(thiophen-2-yl)pyrazine-2-yloxy)methyl)

piperidine-1-carboxylate.




solution thiophen-2-yl-2-boronic acid (0.51 g, 0.004 mol) and isopropylalcohol (20 ml)

was added at room temperature. To this content a solution of K2CO3 (10 ml, 0.02 mol) in

water was added dropwise under nitrogen atmosphere and stirred for 5.0 minute.








[C] Preparation of 2-[Thiophen-2-yl]-5-(piperidin-4-ylmethoxy)pyrazine.

A mixture of HCl in dioxane (10 ml) and tert-butyl 4-((5-(thiophen-2-yl)pyrazine-

2-yloxy)methyl)piperidine-1-carboxylate was stirred at room temperature for overnight



(monitored by TLC), and the solvent was removed in vacuo. Water and ethylacetate was

added in to the crude product and stirred well. The organic layer was separated and the

major impurities were removed in the organic layer. The aqueous layer was basified using

sodium hydroxide solution and the product was extracted with DCM (100 ml × 3), and

the combine organic layers were washed with water followed by brine and dried over

anhydrous Na2SO4. The solvent was evaporated under vacuum to give pure product.

Yield: 58 %, mp 88-90 oC.

[D] General procedure for the preparation of Aryl{4-[({5-[thiophen-2-yl]pyrazin-

2-yl}oxy)methyl]piperidin-1-yl}methanones.

To a stirred cooled (ice bath) solution of 2-[thiophen-2-yl]-5-(piperidin-4-








[E] Biological evaluation of Aryl[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)

piperidin-1-yl]methanones.





Table-3a: Physical constants of Aryl[4-({[5-(thiophen-2-yl)pyrazin-2-


N

NO

NO

RS

Sr. No.


3a CH3O

C22H23N3O2S

393.50

78 0.50

3b

O

CH3

C22H23N3O2S

393.50

84 0.48

3c NO

C20H20N4O2S

380.46 65 0.39

3d N

O

C20H20N4O2S

380.46

67 0.37

3e

O

OCH3

C22H23N3O3S

409.50

70 0.43

3f

O

C22H23N3O2S

393.50

60 0.46

3g ONH

O

CH3

C23H24N4O3S

436.52 64 0.30

3h O Br

C22H22BrN3O2S

472.39 75 0.42

3i O

NH2

Br

C21H21BrN4O2S

473.38

77 0.34

3j O

Cl

C21H20ClN3O2S

413.92

70 0.45

TLC solvent system:- MeOH : CHCl3 = 1 : 9



ANALYTICAL DATA

(4-Methylphenyl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (3a). mp 82-84 oC; IR (KBr): 3032, 2941, 2863, 1636, 1521, 1453, 1339,

1158, 1012, 842 cm-1; MS: m/z = 394 [M+1]+; Anal. Calcd for C22H23N3O2S: C, 67.15;

H, 5.89; N, 10.68. Found: C, 66.91; H, 5.82; N, 10.58%.

(2-Methylphenyl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]


1175, 1017, 740 cm-1; MS: m/z = 393 [M]+; Anal. Calcd for C22H23N3O2S: C, 67.15; H,

5.89; N, 10.68. Found: C, 66.88; H, 5.84; N, 10.59%.

(Pyridin-4-yl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]methanone

(3c). mp 160-162 oC; IR (KBr): 3010, 2925, 28558, 1627, 1545, 1468, 1316, 1170, 1033,

720 cm-1; MS: m/z = 381 [M+1]+; Anal. Calcd for C20H20N4O2S: C, 63.14; H, 5.30; N,

14.73. Found: C, 62.97; H, 5.25; N, 14.61%.

(Pyridin-2-yl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]methanone

(3d). mp 140-142 oC; IR (KBr): 3031, 2958, 2891, 1620, 1542, 1478, 1298, 1150, 1031,

721 cm-1; MS: m/z = 381 [M+1]+; Anal. Calcd for C20H20N4O2S: C, 63.14; H, 5.30; N,

14.73. Found: C, 62.94; H, 5.26; N, 14.63%.

(3-Methoxyphenyl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (3e). mp 102-104 oC; IR (KBr): 3023, 2930, 2861, 1616, 1541, 1460, 1299,


5.66; N, 10.26. Found: C, 64.20; H, 5.59; N, 10.14%.

1-[4-({[5-(Thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]-2-phenylethanone

(3f). mp 95-97 oC; IR (KBr): 3042, 2935, 2860, 1610, 1564, 1488, 1320, 1112, 1007, 737

cm-1; MS: m/z = 393 [M]+; Anal. Calcd for C22H23N3O2S: C, 67.15; H, 5.89; N, 10.68.

Found: C, 66.85; H, 5.81; N, 10.60%.

(N-Phenylacetamide)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (3g). mp 198-200 oC; Purity by HPLC: 90 %; IR (KBr): 3243 (N-H str), 3027

(Ar, C-H str), 2907 (C-H str), 2853 (C-H str), 1688 (amide, C=O str), 1611 (N-H ban),

1523 (Ar, C=C str), 1447 (Ar, C=C str), 1330 (C-H ban), 1166 (C-N str), 1015 (C-O-C



str), 863 (C-H o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 1.25-1.49 (m, 2H,

2CH), 1.83-1.93 (m, 2H, 2CH), 2.11-2.17 (m, 1H, CH), 2.19 (s, 3H, COCH3), 2.80-2.88

(m, 1H, CH), 2.92-3.01 (m, 1H, CH), 3.92-3.95 (d, J=12.48 Hz, 1H, CH), 4.17-4.19 (d,

J=6.4 Hz, 2H, CH), 4.71-4.74 (d, J=12.20 Hz, 1H, CH), 7.41-7.43 (m, 3H, ArH), 7.57-

7.58 (m, 3H, ArH), 7.79-7.80 (m, 1H, ArH), 8.01-8.02 (d, J=1.28 Hz, 1H, ArH), 8.16-

8.17 (d, J=1.28 Hz, 1H, ArH), 8.22 (s, 1H, NH). 13C NMR (100 MHz, CDCl3): δ ppm

24.77, 30.23, 34.29, 41.78, 46.12, 70.36, 115.12, 118.81, 126.21, 127.26, 128.58, 129.66,

132.19, 134.44, 135.38, 137.32, 141.47, 159.18, 165.95, 169.15; MS: m/z = 436 [M]+;

Anal. Calcd for C23H24N4O3S: C, 63.28; H, 5.54; N, 12.83. Found: C, 63.02; H, 5.49; N,

12.73%.

[4-(Bromomethyl)phenyl][4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (3h). mp 87-89 oC; IR (KBr): 3038, 2940, 2853, 1618, 1525, 1450, 1329,

1175, 1017, 840, 635 cm-1; MS: m/z = 473 [M+1]+; Anal. Calcd for C22H22BrN3O2S: C,

55.93; H, 4.69; N, 8.90. Found: C, 55.80; H, 4.61; N, 8.78%.

(2-Amino-5-bromophenyl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-

yl]methanone (3i). mp 135-136 oC; Purity by HPLC: 87 %; IR (KBr): 3483, 3390, 3013,

2943, 2856, 1638, 1609, 1535, 1443, 1329, 1162, 1017, 651 cm-1; 1H NMR (400 MHz,

CDCl3): δ ppm 1.25-1.40 (m, 2H, 2CH), 1.91-1.94 (m, 1H, CH), 2.11-2.14 (m, 1H, CH),

2.49-2.54 (m, 1H, CH), 2.94-2.97 (m, 1H, CH), 3.30-3.37 (m, 1H, CH), 3.68-3.71 (d,

J=12.48 Hz, 1H, CH), 4.23-4.24 (d, J=6.52 Hz, 2H, CH2), 4.54-4.57 (d, J=12.84 Hz, 1H,

CH), 5.30 (s, 2H, NH2), 6.67-6.69 (d, J=8.52 Hz, 1H, ArH), 7.20-7.21 (m, 2H, ArH),

7.41-7.43 (m, 1H, ArH), 7.57-7.58 (m, 1H, ArH), 7.79-7.80 (m, 1H, ArH), 8.01-8.02 (d,

J=1.24 Hz, 1H, ArH), 8.16-8.17 (d, J=1.20 Hz, 1H, ArH). 13C NMR (100 MHz, CDCl3):

δ ppm 30.47, 35.79, 41.70, 46.11, 70.42, 115.17, 120.23, 126.01, 127.23, 128.54, 129.12,

132.30, 134.11, 135.42, 137.78, 141.17, 144.38, 151.41, 159.52, 167.68; MS: m/z = 473

[M]+; Anal. Calcd for C21H21BrN4O2S: C, 53.28; H, 4.47; N, 11.84. Found: C, 52.99; H,

4.40; N, 11.72%.

(4-Chlorophenyl)[4-({[5-(thiophen-2-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]


1165, 1037, 836, 840 cm-1; MS: m/z = 414 [M+1]+; Anal. Calcd for C21H20ClN3O2S: C,

60.94; H, 4.87; N, 10.15. Found: C, 60.69; H, 4.83; N, 10.02%.




IR spectra of compound 3g

IR spectra of compound 3i

5007501000125015001750200025003000350040001/cm

20

40

60

80

100

%T32

43.4

130

28.3

429

35.7

6 2879

.82

2853

.78

1687

.77

1611

.58

1532

.50 14

46.6

6

1330

.93

1275

.95

1166

.97

1110

.07

1015

.56

863.

17

762.

87 706.

9364

4.25

556.

4847

2.58

415.

67

JP-302

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

105

%T

3483

.56

3390

.01

3013

.87

2943

.47

2856

.67 17

76.5

0

1638

.58

1609

.65

1535

.39

1443

.77

1329

.96

1270

.17

1162

.15

1110

.07

1017

.48

987.

5989

4.04

825.

5676

8.66

692.

4765

1.00

590.

24

JP-304

N

NSO

NO

NH2

Br

N

NSO

NO

NHCOCH3



Mass spectrum of compound 3g

Mass spectrum of compound 3i

N

NSO

NO

NHCOCH3

m/z = 436

N

NSO

NO

NH2

Brm/z = 473



1H NMR spectrum of compound 3g

Expanded spectrum of compound 3g

N

NSO

NO

NHCOCH3



Expanded spectrum of compound 3g

1H NMR spectrum of compound 3i

N

NSO

NO

NH2

Br



Expanded spectrum of compound 3i

Expanded spectrum of compound 3i



13C NMR spectrum of compound 3g

13C NMR spectrum of compound 3i

N

NSO

NO

NH2

Br

N

NSO

NO

NHCOCH3



HPLC of compound 3g



HPLC of compound 3i



Table-3b: Antimicrobial activity of Aryl[4-({[5-(thiophen-2-yl)pyrazin-2-


Sr. No.




3a 100 200 200 250 >1000 500 200 3b 62.5 100 125 100 1000 >1000 500 3c 250 250 62.5 100 500 250 200 3d 200 100 125 62.5 200 500 250 3e 125 100 62.5 200 250 200 500 3f 100 62.5 250 250 200 250 500 3g 100 100 100 125 200 >1000 >1000 3h 200 125 250 250 250 1000 1000 3i 250 200 250 200 1000 1000 1000 3j 200 250 125 250 500 250 500











SECTION-IV

SYNTHESIS AND BIOLOGICAL EVALUATION OF ARYL[4-({[5-(1-

BENZOTHIOPHEN-3-YL)PYRAZIN-2-YL]OXY}METHYL)PIPERIDIN-1-

YL]METHANONES

Pyrazine play an important role as intermediates for perfumes, pharmaceuticals,

agricultural chemicals and food spices. In view of these reports, we have synthesize 2-

(piperidin-4-ylmethoxy)pyrazines derivatives by the condensation of 2-(1-benzothiophen-

3-yl)-5-(piperidin-4-ylmethoxy)pyrazines with various aromatic acid chlorides in the

presence of TEA.

REACTION SCHEME

Pd(PPh3)4, K2CO3

toluene, IPAN

NO

NO

Br O +


HBTU, Et3N, DMF

R-COOH

S

B OH

OHN

NO

NO

OS

N

NO

NH

S

N

NO

NO

RS





















carboxylate.


[B] Preparation of tert-Butyl 4-((5-(1-benzothiophen-3-yl)pyrazine-2-

yloxy)methyl) piperidine-1-carboxylate.




solution 1-benzothiophen-3-yl-3-boronic acid (0.712 g, 0.004 mol) and isopropylalcohol

(20 ml) was added at room temperature. To this content a solution of K2CO3 (10 ml, 0.02

mol) in water was added dropwise under nitrogen atmosphere and stirred for 5.0 minute.








[C] Preparation of 2-[1-Benzothiophen-3-yl]-5-(piperidin-4-ylmethoxy)pyrazine.

A mixture of HCl in dioxane (10 ml) and tert-butyl 4-((5-(1-benzothiophen-3-

yl)pyrazine-2-yloxy)methyl)piperidine-1-carboxylate was stirred at room temperature for



overnight (monitored by TLC), and the solvent was removed in vacuo. Water and

ethylacetate was added in to the crude product and stirred well. The organic layer was

separated and the major impurities were removed in the organic layer. The aqueous layer

was basified using sodium hydroxide solution and the product was extracted with DCM

(100 ml × 3). The combine organic layers were washed with water followed by brine and

dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to give pure

product. Yield: 65 %, mp 81-82 oC.

[D] General procedure for the preparation of Aryl{4-[({5-[1-benzothiophen-3-

yl]pyrazin-2-yl}oxy)methyl]piperidin-1-yl}methanones.

To a stirred cooled (ice bath) solution of 2-[1-benzothiophen-3-yl]-5-(piperidin-4-








[E] Biological evaluation of Aryl[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}

methyl)piperidin-1-yl]methanones.





Table-4a: Physical constants of Aryl[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-


S

N

NO

NO

R

Sr. No.


4a CH3O

C26H25N3O2S

443.56

72 0.52

4b

O

CH3

C26H25N3O2S

443.56

70 0.51

4c NO

C24H22N4O2S

430.52 74 0.46

4d N

O

C24H22N4O2S

430.52

66 0.43

4e

O

OCH3

C26H25N3O3S

459.56

80 0.45

4f

O

C26H25N3O2S

443.56

59 0.48

4g ONH

O

CH3

C27H26N4O3S

486.58

62

0.32

4h O Br

C26H24BrN3O2S

522.45 67 0.41

4i O

NH2

Br

C25H23BrN4O2S

523.44 78 0.35

4j O

Cl

C25H22ClN3O2S

463.97

84 0.46

TLC solvent system:- MeOH : CHCl3 = 2 : 8



ANALYTICAL DATA

(4-Methylphenyl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (4a). mp 108-110 oC; IR (KBr): 3039, 2933, 2858, 1618, 1531, 1444, 1329,

1176, 1016, 854, cm-1; MS: m/z = 443 [M]+; Anal. Calcd for C26H25N3O2S: C, 70.40; H,

5.68; N, 9.47. Found: C, 70.11; H, 5.61; N, 9.38%.

(2-Methylphenyl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]



5.68; N, 9.47. Found: C, 70.09; H, 5.60; N, 9.36%

(Pyridin-4-yl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (4c). mp 80-81 oC; Purity by HPLC: 89 %; IR (KBr): 2993 (Ar, C-H str),

2943 (C-H str), 2854 (C-H str), 1688 (amide, C=O str), 1533 (Ar, C=C str), 1465 (Ar,

C=C str), 1336 (C-H ban), 1174 (C-N str), 1008 (C-O-C str), 746 (C-H o.p. ban) cm-1; 1H

NMR (400 MHz, CDCl3): δ ppm 1.25-1.31 (m, 1H, CH), 1.42-1.48 (m, 1H, CH), 1.81-

1.85 (d, J=12.72 Hz, 1H, CH), 1.96-1.99 (d, J=13.24 Hz, 1H, CH), 2.09-2.17 (m, 1H,

CH), 2.82-2.88 (t, J=11.32 Hz, 1H, CH), 3.63-3.65 (d, J=9.72 Hz, 1H, CH), 4.19-4.21

(dd, J=2.12 & 6.36 Hz, 2H, CH2), 4.76-4.79 (d, J=12.48 Hz, 1H, CH), 7.36-7.45 (m, 3H,

ArH), 7.76-7.84 (m, 2H, ArH), 8.01-8.02 (d, J=1.20 Hz, 1H, ArH), 8.16-8.17 (d, J=1.32

Hz, 1H, ArH), 8.68-8.73 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 29.47,

35.74, 42.42, 47.28, 70.48, 118.20, 120.95, 123.30, 124.62, 128.61, 130.20, 135.32,

142.81, 144.30, 148.82, 152.74, 155.64, 159.19, 169.15; MS: m/z = 430 [M]+; Anal.

Calcd for C24H22N4O2S: C, 66.96; H, 5.15; N, 13.01. Found: C, 66.80; H, 5.10; N,

12.92%.

(Pyridin-2-yl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]

methanone (4d). mp 86-87 oC; Purity by HPLC: 88 %; IR (KBr): 3001, 2933, 2908,

1626, 1533, 1465, 1344, 1172, 1010, 748 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 1.25-

1.33 (m, 1H, CH), 1.39-1.53 (m, 1H, CH), 1.77-1.80 (d, J=12.96 Hz, 1H, CH), 1.93-1.97

(d, J=13.52 Hz, 1H, CH), 2.08-2.16 (m, 1H, CH), 2.82-2.89 (m, 1H, CH), 3.09-3.16 (m,

1H, CH), 3.94-3.98 (d, J=13.28 Hz, 1H, CH), 4.18-4.20 (d, J=6.48 Hz, 2H, CH2), 4.78-

4.82 (d, J=13.20 Hz, 1H, CH), 7.36-7.39 (m, 3H, ArH), 7.44-7.48 (m, 1H, ArH), 7.62-

7.69 (m, 1H, ArH), 7.81-7.85 (m, 3H, ArH), 8.01-8.02 (d, J=1.32 Hz, 1H, ArH), 8.16-



8.17 (d, J=1.32 Hz, 1H, ArH), 8.60-8.61 (d, J=4.36 Hz, 1H, ArH). 13C NMR (100 MHz,

CDCl3): δ ppm 29.42, 35.80, 42.23, 47.06, 70.81, 114.67, 118.11, 120.54, 123.74, 124.51,

128.64, 130.20, 132.18, 135.38, 137.54, 142.80, 148.05, 154.15, 159.51, 168.20; MS: m/z

= 430 [M+1]+; Anal. Calcd for C24H22N4O2S: C, 66.96; H, 5.15; N, 13.01. Found: C,

66.69; H, 5.12; N, 12.90%.

(3-Methoxyphenyl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-

yl]methanone (4e). mp 92-94 oC; IR (KBr): 3064, 2924, 2879, 1627, 1556, 1527, 1440,

1327, 1166, 1014, 727 cm-1; MS: m/z = 459 [M]+; Anal. Calcd for C26H25N3O2S: C,

67.95; H, 5.48; N, 9.14. Found: C, 67.66; H, 5.40; N, 9.04%.

1-[4-({[5-(1-Benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]-2-

phenylethanone (4f). mp 76-78 oC; IR (KBr): 3015, 2938, 2871, 1636, 1548, 1421, 1314,


5.68; N, 9.47. Found: C, 70.16; H, 5.63; N, 9.37%.

(N-Phenylacetamide)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-

1-yl]methanone (4g). mp 117-119 oC; IR (KBr): 3347, 3032, 2946, 2821, 1628, 1556,

1443, 1331, 1224, 1157, 1032, 842 cm-1; MS: m/z = 486 [M]+; Anal. Calcd for


[4-(Bromomethyl)phenyl][4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)

piperidin-1-yl]methanone (4h). mp 72-74 oC; IR (KBr): 3048, 2951, 2820, 1636, 1530,


C26H24BrN3O2S: C, 59.77; H, 4.63; N, 8.04. Found: C, 59.49; H, 4.59; N, 7.90%.

(2-Amino-5-bromophenyl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)

piperidin-1-yl]methanone (4i). mp 120-121 oC; IR (KBr): 3433, 3350, 3020, 2940, 2843,

1616, 1542, 1450, 1320, 1330, 1116, 1018, 631 cm-1; MS: m/z = 524 [M+1]+; Anal.

Calcd for C25H23BrN4O2S: C, 57.36; H, 4.43; N, 10.70. Found: C, 57.02; H, 4.39; N,

10.59%.

(4-Chlorophenyl)[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-yl]oxy}methyl)piperidin-1-yl]


1241, 1118, 1019, 821, 670 cm-1; MS: m/z = 465 [M+1]+; Anal. Calcd for

C25H22ClN3O2S: C, 64.72; H, 4.78; N, 9.06. Found: C, 64.50; H, 4.70; N, 8.59%.




IR spectra of compound 4c

IR spectra of compound 4d

5007501000125015001750200025003000350040001/cm

60

70

80

90

100

%T

2993

.62

2943

.47

2854

.74

1622

.19

1533

.46

1465

.95

1440

.87

1336

.71

1288

.49

1249

.91

1174

.69

1116

.82

1066

.67

1047

.38

1008

.80

829.

4274

6.48

711.

7661

9.17

576.

7450

9.22

.43

JP- 502

5007501000125015001750200025003000350040001/cm

20

40

60

80

100

%T

3001

.34

2933

.83

2908

.75

2850

.88

1626

.05

1585

.54

1533

.46

1465

.95

1344

.43

1292

.35

1197

.83

1172

.76

1122

.61 10

93.6

710

49.3

110

10.7

398

7.59

902.

7282

9.42

748.

41 709.

8365

1.96

569.

0250

5.37

464.

86

N

NSO

NO

N

N

NSO

NO

N



Mass spectrum of compound 4d

1H NMR spectrum of compound 4c

N

NSO

NO

N

m/z = 430

N

NSO

NO

N



Expanded spectrum of compound 4c




1H NMR spectrum of compound 4d


N

NSO

NO

N




13C NMR spectrum of compound 4c

N

NSO

NO

N




N

NSO

NO

N



HPLC of compound 4c



HPLC of compound 4d



Table-4b: Antimicrobial activity of Aryl[4-({[5-(1-benzothiophen-3-yl)pyrazin-2-


Sr. No.




4a 100 200 250 500 200 250 500 4b 200 200 250 250 250 1000 1000 4c 500 500 200 62.5 >1000 >1000 >1000 4d 100 125 100 100 >1000 >1000 500 4e 100 250 100 500 500 1000 500 4f 62.5 100 125 100 250 200 200 4g 200 100 125 200 1000 1000 1000 4h 500 250 250 200 500 500 1000 4i 100 125 62.5 100 250 1000 200 4j 250 500 500 250 1000 250 250











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Indole derivatives… 99

INTRODUCTION

Indole (2,3-benzopyrrole, ketole, 1-benzazole; C8H7N) is an aromatic heterocyclic

organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring

fused to a five-membered nitrogen-containing pyrrole ring. The participation of the

nitrogen lone pair electron in the aromatic ring means that indole is not a base, and it does

not behave like a simple amine.

Indole is a solid at room temperature. It can be produced by bacteria as a

degradation product of the amino acid tryptophan. It occurs naturally in human faces and

has an intense facial odor. At very low concentrations, however, it has a flowery smell,

and is a constituent of many flower scents (such as orange blossoms) and perfumes. It

also occurs in coal tar.

NH1

2

345

67

(1)

Indole compounds include the plant hormone Auxin (indolyl-3-acetic acid), the

anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally

occurring hallucinogen dimethyltryptamine.

The name indole is a portmanteau of the words indigo and oleum, since indole

was first isolated by treatment of the indigo dye with oleum. Indole chemistry began to

develop with the study of the dye indigo. Indigo can be converted to isatin and then to

oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.1 In

1869, he proposed a formula for indole.2

Certain indole derivatives were important dyestuffs until the end of the 19th

century. In the 1930, interest in indole intensified when it became known that the indole

nucleus is present in many important alkaloids, as well is in tryptophan and auxins, and it

remains an active area of research today.3

The indole skeleton is one of the most attractive frameworks with a wide range of

biological and pharmacological activities.4 This physiologically important nucleus is

abundantly found in therapeutic agents5,6 as well as in natural products. Many researchers

have described synthesis of indole and its derivatives along with its applications in

literature.7



SYNTHETIC ASPECT

Various methods for the preparation of indole derivatives have been cited in

literature, some of them are as under.

1. B. George8 has reported one-pot microwave assisted synthesis of indole from

phenylhydrazine and pyruvic acid.

NHNH2 O

HOOC

CH3

ZnCl2PCl5 N

H

+

2. N. Sakai et al.9 have synthesized indium-catalyzed cyclization of 2-ethynylanilines

produced various indole derivatives in good yields for substrates having an alkyl

or aryl group on the terminal alkyne.

NH

R3

R1

R2

5 mol -% in Br3

toluene, reflux 5-20 hR

1

NR

3

R2

3. Rhodium (II) perfluorobutyrate-mediated decomposition of vinyl azides

allows rapid access to a variety of complexes of indole was prepared by B.

J. Stokes et al.10

N3

O

OCH3

R1 R

1

NH

O CH3

O

3-5 mol-%

toluene, 60 oC, 16 h

Rh2(OCOC3F7)4

4. Y. Du and coworkers11 have been synthesized various N-arylated and N-alkylated

indoles and pyrrole-fused aromatic compounds by a phenyliodine

bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization.

R3

NHR

1

R2

EWG

R1

NR

3

R2

EWG

1.3 eq. PhI(O2CCF3)2(PIFA)

CH2Cl2, RT, 30 min



5. Microwave-assisted synthesis of indole derivatives in water via

cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by A.

Carpita et al.12,13

NH2

R2

R1 H2O, 200 oC

MW, base/acid saltR

1

NH

R2

6. Synthesis of 2-substituted indoles via palladium-catalyzed domino Heck reaction

with 71 % yield was given by H. Mao et al.14

I

N R1 N

H

R1Pd(OAc)2, PPh3, 120oC

KOBu-t, DMSO

7. D. K. Whelligan and coworkers15 have synthesized two-step aza- and diazaindoles

from chloroamino-N-heterocycles using ethoxyvinylborolane.

NH2

OEtR

1 AcOHR

1

NH

8. One-pot synthesis of indole derivatives from nitroarenes under hydrogenation

condition with supported gold nanoparticles was reported by Y. Yamane et al.16

NO2

R1

NH

R1H2

Au/Fe2O3

9. A mild preparation of substituted indole from simple aromatic precursors using

(trimethylsilyl)diazomethane was reported by L. Zhu et al.17

NHNH2

OTMSCHN2, CS2CO3

MeOH, 60oC



10. E. V. Sadanandan et al.18 have synthesized 4,6,7-trimethoxyindol marine

alkaloids.

OMe

OMeMeO

COOMe

N3

xylenereflux

OMe

OMeMeO N

H

COOMe

11. S. Wagaw et al.19 have reported novel fischer indole synthesis.

NHN

PhPhR

3+

R1

O R2

TsOH.H2O, EtOHreflux

R3

NH

R1

R2

12. G. A. Kraus and coworkers20 have synthesized indole derivatives under

microwave-assisted conditions with high yields in one-pot reaction.

+PPH3

-Br

N R1

tBuoKTHF, 25 oC N

H

R1

13. Gold(III)-catalyzed indole derivatives from 2-alkynylanilines in EtOH annulations

at room temperature in good yields was reported by A. Arcadi et al.21

R1

NH2

R2

4 mol-% NaAuCl4.2H2O

EtOH, rtR

1

NH

R2

14. Copper(II)-catalyzed cyclization of 2-ethynylaniline derivatives to indoles can be

carried out in a MeOH was given by K. Hiroya et al.22

NH

R3

SO2R1

R2 Cu(OCOCF3)2

MeOH, rtR

2

N

SO2R1

R3



15. A. Dobbs et al.23 have synthesized indole derivatives from ortho-

bromonitrobenzenes with various vinyl grignard reagents in THF.

BrNO2

R1

+R

2

R3

MgBrTHF, -40 oC

Br

R1

NH

R2

R3

16. One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-

iodoanilines and aldehydes under mild ligandless conditions in DMF was reported

by Y. Jia et al.24

R1

NH

I

R2

+O

R3

H5 mol-% Pd(OAc)2 R

1

N

R3

R2

DABCO, DMF, 85 oC

17. Suzuki-Miyaura coupling of ortho-gem-dihalovinylanilines with boronic acids, of

a Pd(OAc)2 catalyst in the presence of K3PO4·H2O was doccumented by Y. Q.

Fang et al.25

NH2

R1

R2

Br

Br

+ R1

NH

Ar

R2

Ar-B(OH)2

1-5 mol-% Pd(OAc)2

K3PO4.H2O, toluene, 90 oC

18. V. Sridharan et al.26 have synthesized microwave assisted 2-arylindoles in good

yields.

NHR

1

O ArMW

DMFR

1

NH

Ar

19. Lewis acids catalyzed cyclization of methyl phenyldiazoacetates was reported by

L. Zhou et al.27



N R1

COOCH3

N2

Zn(OTf)2

MDC, rt NH

R1

COOCH3

REACTION MECHANISM

The reaction of phenyl hydrazine with an aldehyde or ketone initially forms

phenylhydrazone which isomerizes to the respective enamine. After protonation, a cyclic

sigmatropic rearrangement occurs producing an imine. The resulting imine forms a cyclic

aminoacetal, which under acid catalysis eliminates NH3, resulting in the energetically

favorable aromatic indole.

NHN

NHNH

NHNH

H

NH2NH

H+

NH2NH2- +N

HNH2

HH

-H+H

+

NH

NH3

HH

+-H+

-NH3NH

Phenylhydrazone Enamine Imine

AminoacetalIndole THERAPEUTIC IMPORTANCE

The indole ring system represents a privileged structure in drug discovery. The

number of bioactive compounds containing this ring system is so vast that the complete

range of their biological activities can be hardly classified.28-30

1. Analgesic31

2. Antiallergic32

3. Antibacterial33

4. Anticonvulsant34

5. Antifungal35

6. Antihistaminic36


8. Antitumor38



9. Antiviral39

10. β-adrenergic40

11. Diuretic41

12. Insecticidal42

13. Anticancer43

14. Anti HIV44

15. Anti hypertensive45


17. Antioxidant47

B. Pelcman et al.48 have synthesized marine sponge pigment fascaplysin (2) from

indole and reported their antimicrobial activity.

NH

N

(2)

M. C. Pirrung et al.49 have synthesized indolylquinones (3) and checked their

activity on the human insulin receptor by demethylasterriquinone B1 (DAQ B1) and its

consequent oral insulin mimetic activity tested in mice by B. Zhang and coworkers.50

DAQ B1 was also subsequently shown to activate the TrkA nerve growth factor receptor

was reported by N. Wilkie and coworkers.51

O

ONH

NH

OH

OH

(3)

Activities of asterriquinones (4) against HIV protease and HIV reverse

transcriptase have been disclosed by A. Fredenhagen et al.52 and K. Ono et al.53 and also

activity against serine proteases given by U. Mocek et al.54



NH

NH

O

O

OO

RR

R = H, CH3(4)

S. Pasquini et al.55 prepared library of 1,5-disubstituted-3-indole-N-

alkylacetamides as CB2 receptor ligands. Some representatives of CB2 agonists are

compounds AM1241, GW405833, JWH-015 and AM630 possess an indole structure

reported by K. Mackie et al.56 and C. Manera et al.57

N

O

I

NO2

N

N

N

O

O

O

Cl Cl

N

O

N

O

I

N

O

O

AM1241 GW405833 JWH-015 AM630

J. B. Blair et al.58 have synthesized fluorinated indole (5) derivatives.

NH

NR

1

R2

R3

R4

R1 = OH, H, F R2 = H, OCH3

R3 = H, F R4 = H, F(5)

P. Diana et al.59 have synthesized 3,5-bis(3’-indolyl)pyrazoles (6) by cyclization

of diketones and hydrazine monohydrate and evaluated their antitumor properties. The

interest in this class of compounds has been stimulated by both their unique chemical

structure and the wide range of biological properties including antiviral, antimicrobial,

and antitumor activity was given by V. M. Dembitsky et al.60



NH

BrN

NH N

H

Br

(6)

H. Sard et al.61 have synthesized psilocybin analogs (7) and discoved a selective

5-HT2C agonist.

NH

OR N

R = H, P(O)(OH)2

(7)

E. J. Glamkowski et al.62 have synthesized 3-(4-acylaminopiperazin-1-

ylalky1)indoles (8) as potential anti hypertensive agents.

NH

N

NNH

R1

O

R1 = aryl

(8)

M. Banerjee et al.63 have synthesized indole derivatives, such as HIV-1

nonnucleoside reverse transcriptase inhibitor. D. C. Cole et al.64 have tested 5-HT

receptor agonists or antagonists. Q. Shi et al.65 and H. D. H. Showalter et al.66 have

synthesized and tested peroxisome proliferator-activated receptor (PPAR) agonists and

protein tyrosine kinase inhibitors. G. Primofiore and coworkers67 and K. L. Lee et al.68

have prepared and tested benzodiazepine receptor (BzR) ligands. Human cytosolic

phospholipase A2R inhibitor and blood coagulation factor Xa inhibitor have also been

presented by H. Matter et al.69

J. Holenz et al.70 prepared medicinal chemistry driven approaches toward novel

and selective serotonin 5-HT6 receptor ligands (9).



N

NR

2R

1

R3

NHSR

4O

O

(9)

Preparation and antibacterial activities of indole containg compounds reported by

Y. Yasuo et al.71 T. Bhawana et al.72 have synthesized and tested antimicrobial activity

of indole derivatives. Synthesis and biological screening of some new indole

derivatives doccumented by D. S. Mehta et al.73 and G. S. Gadaginamath et al.74 Potent

antimicrobial activity of indole derivatives against methicillin-resistant Staphylococcus

aureus investigated by R. A. Al-Qawasmeh et al.75 Regioselective synthesis and

biological evaluation of bis(indolyl)methane derivatives as anti-infective agents given

by M. Damodiran et al.76

Discovery of indole inhibitor of cytosolis phospholipase A2α reported by K. L.

Lee et al.77 Y. Kawashima et al.78 have studied structure activity of indole derivatives

with analgesic and anti-inflammatory activities. Synthesis and anti-inflammatory

activity of heterocyclic indole derivatives reported by R. Preeti et al.79 Amido indole

derivatives used in cannabinoid receptor modulators discovered by H. John et al.80

M. G. Bursavich et al.81 have synthesized indole derivatives and tested for PI3

kinase-α and the mammalian target. Synthesis and evaluation of indole derivatives as

antagonists of Wnt/β-catenin, signaling and CLL cell survival reported by J. Guangyi

et al.82 D. A. James and coworkers83 synthesized conjugated indole-imidazole

derivatives, displaying cytotoxicity against multidrug resistant cancer cell lines. C.

Girolamo et al.84 have synthesized derivatives of the new ring system indole with

potent antitumor and antimicrobial activity. B. Emile et al.85 have synthesized

substituted indole derivatives as new class of antineoplastics agent.



Endogenous substances and marketed drugs with indole substructures

NH

NH2

O

OHNH

NH2

OH

NH

NH

O

O

N

O

O

OH

O Cl N

O

O NN

NH

NS

NH OO

Tryptophan 5 - HT Melatonin

Indometacin OndansetronSumatriptan

NH

NHS

S

Brassinin

Thus the important role displayed by indole and its derivatives for various

therapeutic and biological activities prompted us to synthesize some carboxylate, and

glyoxylamide derivatives bearing indole moiety in order to achieve compounds having

better therapeutic activities described as in the following parts.

STUDIES ON 6-CHLORO-INDOLE DERIVATIVES

PART-I: STUDIES ON 6-CHLORO-INDOLE-5-CARBOXYLATE

DERIVATIVES


DERIVATIVES



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Indole-5-carboxylate derivatives… 115

INTRODUCTION

Indole-3-yl-glyoxylamide derivatives are potent biologically active agent has led

to the exploration of large number of structural variants, containing 6-chloro-indole-5-

carboxylate moiety as an invariable ingredient so the synthesis of these compounds has

become an important target in current years. The diversity, efficiency and rapid access to

small and highly functionalized organic molecules makes this approach of central current

interest in the construction of compounds library and optimization in drug discovery

process.1,2

NH

O

O

N R2R

1

(1)

A new class of indole-3-yl-glyoxylamide derivatives is high affinity agonists at

the benzodiazepine binding site receptors. It has proved a rich source of clinically

effective drugs, particularly anxiolytics, hypnotics and anticonvulsants.

SYNTHETIC ASPECT

Various methods for the preparation of 3-oxoacetamide-1H-indole derivatives and

alkylation of indole have been cited in literature, some of the methods are as under.

ALKYLATION

1. K. T. Potts et al.3 have synthesized 1-methylindole from indole, CH3I and NaNH2 in

diethyl ether solution.

NH

CH3I

NaNH2, Et2O NCH3

2. R. S. Davidson et al.4 have reported N-alkylation of indole using phase transfer

catalyst with ultrasound.



NH

N

C6H5CH2Br

PEG methyl ether

3. Potassium carbonate as a base for the N-alkylation of indole in ionic liquid was

prepared by Y. R. Jorapur et al.5

NH

+ Br Ph[bmim][BF4], CH3CN

K2CO3, 110 oC N

Ph 4. Alkylation of indole from potassium hydroxide, alkyl/aryl halide in acetone was

reported by C. A. Marlic et al.6

NH

NR

1

KOH, R1Xacetone

5. Synthesis of N-alkyl substituted indole in presence of sodium hydride in DMF was

documented by S. Roy et al. 7

NH

N

NC

NaH, DMFBr CN

6. Dual nucleophilic catalysis with DABCO for the N-methylation of indoles was

synthesized by W. Shieh et al.8

NH

R1 DABCO, DMF

MDC, 95 oC NR

1

CH3



7. B. Sebastian et al.9 have synthesized selective Ruthenium-catalyzed N-alkylation of

indole by using alcohol.

NH

R1

+ R2

OH 24 h, toluene N

R1

R2

Shvo, PTSA

GLYOXYLAMIDE

8. The use of (NHC)CuI complex in combination with a N-heterocyclic carbene

precursor as catalyst for the double carbonylation of aryl iodides and secondary

amines solves the problem of using the precious metal Pd and phosphine ligands

was reported by J. Liu et al.10

IR

1+ CO + NH

R2

R2

NHC-Cu-ICS2CO3

R1

O

O

N

R2

R2

9. J. Zhua and coworkers11 have given one-pot synthesis of nitrogen-containing

heteroaryl α-keto amides from heteroaryl halides.

R1

Cl + NNC

O R1

O

ON(1) Base, THF

(2) CH3COOH

10. I. Bennacefa et al.12 have synthesized halogenated N,N-dialkylel-(2-phenyl-1H-

indol-3-yl)glyoxylamide derivatives.

NH

NH

O

O

R1

(1) (COCl)2, THF, 0OC

(2) Amine, THF, 0OC

11. R. Gitto et al.13 have synthesized glyoxylamide derivatives containing N-substituted

isoquinoline nucleus.



N

OCH3

OCH3

R1

OOH

ON

OCH3

OCH3

R1

OR

2

Ocycloalkylamines,HBTU

DMF, TEA, rt

12. One-step synthesis of N-alkyl-2-aryl-2-oxoacetamide derivatives was given by I.

Yavari et al.14

R1

N+

C-

+

CHO

OH

X

OH

XO

O

NHR

2

13. M. Takhi et al.15 have synthesized 3-indolylglyoxamide derivatives.

NH

NH

O

O

Cl

NH

O

O

R1

(COCl)2

THF, 0OCsecondary amine

THF, 0OC

REACTION MECHANISM

NR

..N

+

R

H-

O

Cl O

Cl

N+

R

HO

-

Cl O

Cl

N+

R

H

O

ClO

R1

NHR

2

NR

OCl

O..

NR

OClN

+

O

R2

R1

H-

NR

ON

O

R2

R1




6-Chloro-indole-3-yl-glyoxylamide derivatives have been tested for various

pharmacological activities, which have been summarized as under.

1. Anticancer16

2. Antitumor17

3. Anxiolytic18

4. Anti-HIV19

5. Antiviral20

6. Antimicrobial15

7. Antileishmanial21

8. GABA-A receptor22

9. Antihypertensive23


F. D. Settimo et al.25 have studied anxiolytic effects of N,N-dialkyl-2-phenylindol-

3-ylglyoxylamides (2) by modulation of translocator protein promoting neurosteroid

biosynthesis. M. Gavish et al.26 and P. Casellas et al.27 have synthesized indole-3-

glyoxamide derivatives in a variety of biological processes, including calcium

homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation,

apoptosis induction, and regulation of immune functions. G. Primofiore et al.28 have

synthesized N,N-dialkyl-2-phenylindol-3-ylglyoxylamides a new class of potent and

selective ligands at the peripheral benzodiazepine receptor.

NH

N R2R

1

R3

O

OR4

R5

R1 = R2 = (CH2)2CH3

R3 = NO2, CF3, H, F

R4 = H, NO2, OCH3, F, Cl

R5 = H, Cl, CH3(2)

N. A. Meanwell et al.29 have described the discovery of indole-3-glyoxamide (3)

derivatives as the first small molecule inhibitors of the gp120-CD4 interaction (HIV-1

attachment inhibition) that demonstrate potent antiviral activity in cell culture.30



NH

FO

O

N

N

O

(3)

Antibacterial activities of 3-indolylglyoxamide substituent have been explored in

an effort to improve the spectrum and potency of this class of agents by M. Takhi et al.15

X

N

O

ON N

R1

F

NO

O

R4R

3R2

R1 = H, CN, NO2, OCH3, Br

R2 = H, CH3

R3 = H, CH3

X = CH, N(4)

A series of marine alkaloid 8,9-dihydrocoscinamide, (5) its analogues and

indolylglyoxylamide derivatives have been synthesized and screened for their in vitro

antileishmanial activity profile in promastigote and amastigote models by L. Gupta et al.21

N

O

O

NH

N

R1

R2

R1 = R

2 = CH3 = SO2Ph

(5)

I. Collins et al.31 have synthesized new class of N-(indol-3-ylglyoxylyl)piperidines

(6) are high affinity agonists at the benzodiazepine binding site of human GABA-A

receptor ion-channels, with modest selectivity for receptors containing the α1.



NH

O

O

NO

R1

R1 = OCH2Ph, NHCH2Ph, N(CH3)CH2Ph

(6)

G. Primofiore and coworkers32 have synthesized N-(arylalkyl)indol-3-

ylglyoxylylamides (7) targeted as ligands of the benzodiazepine receptor, as well as

biological evaluation and molecular modeling analysis of the structure activity

relationships reported by them.

NH

R1

O

O

NHR

2

R3

(7)

V. W. Pike et al.33 have evaluated novel N-methyl-2-phenylindol-3-

ylglyoxylamides (8) as a new chemo type of 18 kDa translocator protein-selective ligand

suitable for the development of positron emission tomography radioligands.

NCH3

NO2

O

O

NnPr

nPr

(8)

Preparation of 2-[5-[[(6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl]amino]-1H-

indol-3-yl]-N,N-dimethyl-2-(oxo)acetamide (9) compounds as 5-HT6 receptor modulators

for use in medicaments was reported by M. V. Ramon et al.34



NH

O

O

NCH3 CH3

NHSO

ON

NCl

S

(9) W. Tao and coworkerss35 have evaluated indole to azaindoles leading to the

discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-

yl)ethane-1,2-dione as a antiviral activity in HIV-1 infected subjects. J. Wang and

coworkers36 have modified structure-activity relationship of a small molecule HIV-1

inhibitor targeting the viral envelope glycoprotein gp120. M. Pascal et al.37 have

synthesized N-aryl(indol-3-yl)glyoxamides as antitumor agents.

Literature survey reveals that the compounds bearing glyoxamides moiety possess

potential drug activity. Looking to the diversified biological activities we have

synthesized some glyoxamides derivatives in order to achieving better therapeutic agents.

These studies are described in following section.

PART-I: STUDIES ON 6-CHLORO-INDOLE-5-CARBOXYLATE

DERIVATIVES

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF METHYL 6-

CHLORO-3-[(N,N-DIALKYLAMINO)(OXO)ACETYL]-1-

METHYL-1H-INDOLE-5-CARBOXYLATES.

SECTION-II: SYNTHESIS AND BIOLOGICAL EVALUATION OF METHYL 1-

BENZYL-6-CHLORO-3-[(N,N-DIALKYLAMINO)(OXO)ACETYL]-

1H-INDOLE-5-CARBOXYLATES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF METHYL 6-CHLORO-3-

[(N,N-DIALKYLAMINO)(OXO)ACETYL]-1-METHYL-1H-INDOLE-5-

CARBOXYLATES

Heterocyclic compounds bearing 6-chloro-indole-5-carboxylate ring system are

endowed with variety of biological activities. Our strategy is based on to develop a new

bioactive entity especially with pharmacological activities bearing heterocyclic ring

system. In view of our on going interest in the synthesis of some new 6-chloro-indole-5-

carboxylate derivatives we have undertaken condensation of methyl 6-chloro-1-methyl-

1H-indole-5-carboxylate with oxalyl chloride and different secondary amine in the

presence of DCM.

REACTION SCHEME









NH

O

OCH3

Cl

CH3ICS2CO3, dry DMF N

O

OCH3

ClCH3

(I) (COCl)2, dry DCM(II) Secondary amine N

O

OCH3

Cl

O

O

R

CH3












[A] Preparation of Methyl 6-chloro-1-methyl-1H-indole-5-carboxylate.

To a stirred suspension of CS2CO3 (2.72 g, 0.02 mol) and methyl 6-chloro-1H-

indole-5-carboxylate (2.09 g, 0.01 mol) in dry DMF (10 ml), after 5 minute CH3I (0.62

ml, 0.01 mol) was added dropwise. The resultant solution was stirred for 5 hour at room

temperature, and poured onto crushed ice, the product was isolated and washed with

water and hexane to give pure product. Yield: 95 %, mp 60-61 oC.

[B] General procedure for the preparation of Methyl 6-chloro-3-[(N,N-

dialkylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxylates.

To a stirred cooled (ice bath) solution of methyl 6-chloro-1-methyl-1H-indole-5-

carboxylate (0.5 g, 2.34 mmol) in dry DCM (12 ml), oxalyl chloride (0.95 ml, 11.21

mmol) was added dropwise in solution. The obtained solution was stirred at 0 oC for 30.0

minute and then at 25-30 oC for 1 hour. Dark yellow colored was formed. The solvent

was removed in vacuo, the residue was dissolved in dry DCM (12 ml) then add different

secondary amine (6.72 mmol) dropwise. The reaction mixture was stirred at 0 oC for 30.0

minute and then 25-30 oC for another 30.0 minute (monitored by TLC). The solvent was

removed in vacuo. The product was dissolved in water and extracted with ethylacetate (25

ml × 3). The combined organic layers were washed with water followed by brine and

dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the solid was

triturated with hexane and resulting precipitate was filtered, washed with hexane and

dried to give analytical pure product. The physical constants of the product are recorder in

Table-5a.



[C] Biological evaluation of Methyl 6-chloro-3-[(N,N-dialkylamino)(oxo)acetyl]-1-

methyl-1H-indole-5-carboxylates.





N

O

O

Cl

O

O

R

CH3

CH3

Table-5a: Physical constants of Methyl 6-chloro-3-[(N,N-dialkylamino)(oxo)acetyl]-

1-methyl-1H-indole-5-carboxylates.

Sr. No.


5a NCH3

CH3

C17H19ClN2O4

350.79

82 0.41

5b ON

C17H17ClN2O5

364.78

85 0.35

5c N

C18H19ClN2O4

362.80

90 0.32

5d NN CH3

C18H20ClN3O4

377.82

88 0.34

5e NNCH3

C19H22ClN3O4

391.84

80 0.33

5f NN

C23H22ClN3O4

439.89

79 0.31

5g NCH3

CH3

CH3

CH3

C19H23ClN2O4

378.84

81 0.40

5h N

C17H17ClN2O4

348.78

78 0.38

5i N

CH3

C19H21ClN2O4

376.83 85 0.42

5j

N CH3

C19H21ClN2O4

376.83

84 0.41

TLC solvent system:- MeoH : CHCl3 = 1 : 9



ANALYTICAL DATA

Methyl 6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxylate (5a).

mp 102-104 oC; Purity by HPLC: 96 %; IR (KBr): 3067 (Ar, C-H str), 2983 (C-H str),

2943 (C-H str), 1752 (ketone, C=O str), 1633 (amide, C=O str), 1527 (Ar, C=C str), 1466

(Ar, C=C str), 1365 (C-H ban), 1247 (C-N str), 784 (C-Cl str) cm-1; 1H NMR (300 MHz,

CDCl3): δ ppm 1.96-1.30 (m, 6H, 2CH3), 3.34-3.41 (q, J=7.04 Hz, 2H, CH2), 3.50-3.57

(q, J=7.15 Hz, 2H, CH2), 3.84 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 7.45 (s, 1H, ArH), 7.89

(s, 1H, ArH), 8.84 (s, 1H, ArH). 13C NMR (75 MHz, CDCl3): δ ppm 12.81, 14.47, 33.89,

39.40, 42.43, 52.37, 112.28, 114.08, 120.57, 124.35, 124.93, 125.98, 129.25, 139.12,

140.63, 163.26, 166.48, 166.62, 185.17; MS: m/z = 350 [M]+; Anal. Calcd for

C17H19ClN2O4: C, 58.21; H, 5.46; N, 7.99. Found: C, 57.97; H, 5.40; N, 7.82%.

Methyl 6-chloro-1-methyl-3-[morpholin-4-yl(oxo)acetyl]-1H-indole-5-carboxylate (5b).

mp 110-112 oC; IR (KBr): 3037, 2948, 2910, 1714, 1635, 1520, 1444, 1258, 787 cm-1;

MS: m/z = 364 [M]+; Anal. Calcd for C17H17ClN2O5: C, 55.97; H, 4.70; N, 7.68. Found:

C, 55.65; H, 4.56; N, 7.50%.

Methyl 6-chloro-1-methyl-3-[oxo(piperidin-1-yl)acetyl]-1H-indole-5-carboxylate (5c).

mp 140-141oC; IR (KBr): 3116, 2979, 2942, 1729, 1708, 1627, 1528, 1442, 1254, 774

cm-1; MS: m/z = 362 [M]+; Anal. Calcd for C18H19ClN2O4: C, 59.59; H, 5.28; N, 7.72.

Found: C, 59.22; H, 5.11; N, 7.57%.

Methyl 6-chloro-1-methyl-3-[(4-methylpiperazin-1-yl)(oxo)acetyl]-1H-indole-5-carbox-

ylate (5d). mp 107-109 oC; IR (KBr): 3072, 2975, 2919, 1737, 1629, 1534, 1465, 1236,

773 cm-1; MS: m/z = 378 [M+1]+; Anal. Calcd for C18H20ClN3O4: C, 57.22; H, 5.34; N,

11.12. Found: C, 56.90; H, 5.12; N, 10.99%.

Methyl 6-chloro-3-[(4-ethylpiperazin-1-yl)(oxo)acetyl]-1-methyl-1H-indole-5-carboxy-

late (5e). mp 190-191 oC; IR (KBr): 2974, 2943, 1726, 1636, 1528, 1466, 1240, 771 cm-1;

MS: m/z = 393 [M+2]+; Anal. Calcd for C19H22ClN3O4: C, 58.24; H, 5.66; N, 10.72.

Found: C, 57.88; H, 5.53; N, 10.56%.

Methyl 6-chloro-3-[oxo(4-phenylpiperazin-1-yl)acetyl]-1-methyl-1H-indole-5-carboxyl-

ate (5f). mp 160-161 oC; IR (KBr): 3058, 2980, 2937, 1719, 1633, 1530, 1436, 1251, 763




Found: C, 62.50; H, 4.94; N, 9.40%.

Methyl 6-chloro-3-[(dipropan-2-ylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxyl-

ate (5g). mp 120-122 oC; Purity by HPLC: 97 %; IR (KBr): 3019, 2972, 2932, 1731,

1636, 1532, 1470, 1258, 736 cm-1; 1H NMR (300 MHz, CDCl3): δ ppm 1.19-1.21 (d,

J=6.63 Hz, 6H, 2CH3), 1.56-1.59 (d, J=6.82 Hz, 6H, 2CH3), 3.54-3.64 (m, 1H, CH), 3.85

(s, 3H, CH3), 3.91 (s, 3H, OCH3), 3.94-4.00 (m, 1H, CH), 7.45 (s, 1H, ArH), 7.80 (s, 1H,

ArH), 8.82 (s, 1H, ArH). 13C NMR (75 MHz, CDCl3): δ ppm 20.30, 20.79, 33.93, 46.83,

50.13, 52.33, 112.32, 114.33, 118.39, 122.46, 125.95, 130.02, 139.80, 142.12, 163.85,

169.51, 191.76; MS: m/z = 378 [M]+; Anal. Calcd for C19H23ClN2O4: C, 60.24; H, 6.12;

N, 7.39. Found: C, 59.89; H, 6.02; N, 7.25%.

Methyl 6-chloro-1-methyl-3-[oxo(pyrrolidin-1-yl)acetyl]-1H-indole-5-carboxylate (5h).

mp 165-167 oC; IR (KBr): 3022, 2973, 2927, 1725, 1627, 1521, 1453, 1243, 778 cm-1;


C, 58.17; H, 4.72; N, 7.94%.

Methyl 6-chloro-1-methyl-3-[(2-methylpiperidin-1-yl)(oxo)acetyl]-1H-indole-5-carbox-

ylate (5i). mp 170-171 oC; IR (KBr): 3037, 2981, 2944, 1705, 1628, 1528, 1440, 1260,


7.39. Found: C, 59.93; H, 5.98; N, 7.21%.

Methyl 6-chloro-1-methyl-3-[(4-methylpiperidin-1-yl)(oxo)acetyl]-1H-indole-5-carbox-

ylate (5j). mp 173-175 oC; IR (KBr): 3042, 2974, 2940, 1715, 1630, 1525, 1460, 1250,


7.43. Found: C, 60.29; H, 5.37; N, 7.30%.





IR spectra of compound 5g

5007501000125015001750200025003000350040001/cm

0

20

40

60

80

100

%T31

13.2

130

67.8

829

83.0

129

43.4

728

87.5

3

1725

.38

1633

.76

1568

.18

1527

.67

1466

.91

1365

.65

1247

.02

1157

.33

1095

.60

1019

.41

942.

26 857.

3982

5.56

784.

0974

6.48 66

2.57

588.

31

RMG-101 p1

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

105

%T

3105

.50

3043

.77

3019

.66

2972

.40

2932

.86 28

84.6

4

1731

.17

1636

.65

1532

.50

1470

.77

1440

.87

1335

.75

1258

.59

1218

.09

1160

.22

1098

.50

1047

.38

995.

3090

9.47

819.

7773

6.83

613.

38 567.

0949

6.69

460.

04

RMG-107-P

NCl

O

O

O

O

N

CH3 CH3

CH3

CH3

N

O

O

N

Cl

O

O

CH3

CH3CH3

CH3

CH3

CH3




Mass spectrum of compound 5g

N

O

O

N

Cl

O

O

CH3CH3

CH3

CH3

m/z = 352

N

O

O

N

Cl

O

O

CH3

CH3CH3

CH3

CH3

CH3

m/z = 380

Stud

Ind

1H N

1H N

dies on hete

dole-5-carbo

NMR spect

NMR spect

H3

H3

erocyclic…

oxylate deri

trum of com

trum of com

Cl

O

OC3

Cl

O

OC3

ivatives…

mpound 5a

mpound 5g

N

O

O

N

CH

CH3

N

O N

CHCH3

CH3

a

g

O

H3 CH3

O

NCH3

CH3H3

131

Stud

Ind

13C

13C

dies on hete

dole-5-carbo

NMR spec

NMR spec

erocyclic…

oxylate deri

ctrum of co

ctrum of co

OCH3

OCH3

ivatives…

ompound 5

ompound 5

Cl

OO

Cl

O

O

H

a

g

N

O

O

N

CH3 CH

CH3

N

O

O

N

CCH3

CH3

CH3

H3

CH3

CH3

132



HPLC of compound 5a



HPLC of compound 5g



Table-5b: Antimicrobial activity of Methyl 6-chloro-3-[(N,N-dialkylamino)

(oxo)acetyl]-1-methyl-1H-indole-5-carboxylates.

Sr. No.




5a 500 500 200 100 1000 500 500 5b 25 250 200 200 500 1000 1000 5c 62.5 100 100 100 250 500 250 5d 100 500 250 500 500 1000 500 5e 200 200 500 500 250 500 500 5f 200 250 100 100 500 1000 1000 5g 500 200 200 250 500 1000 1000 5h 100 100 62.5 50 250 500 500 5i 250 500 100 200 1000 500 250 5j 250 250 100 250 1000 250 1000











SECTION-II

SYNTHESIS AND BIOLOGICAL EVALUATION OF METHYL 1-BENZYL-6-

CHLORO-3-[(N,N-DIALKYLAMINO)(OXO)ACETYL]-1H-INDOLE-5-

CARBOXYLATES

Literature survey reveals that nitrogen containing heterocyclic compounds like 6-

chloro-indole-5-carboxylate have received considerable attention in medicinal science

due to their biological and pharmacological activities. In view of these findings, it

appeared of interest to synthesize 6-chloro-indole-5-carboxylate derivatives by the

condensation of methyl 1-benzyl-6-chloro-1H-indole-5-carboxylate with oxalyl chloride

and different secondary amine in the presence of DCM.

REACTION SCHEME









NH

O

OCH3

Cl

C6H5CH2ClCS2CO3, dry DMF

(I) (COCl)2, dry DCM(II) Secondary amine N

O

OCH3

Cl

O

O

R

N

O

OCH3

Cl












[A] Preparation of Methyl 1-benzyl-6-chloro-1H-indole-5-carboxylate.

To a stirred suspension of CS2CO3 (2.72 g, 0.02 mol) and methyl 6-chloro-1H-

indole-5-carboxylate (2.09 g, 0.01 mol) in dry DMF (10 ml), after 5.0 minute benzyl

chloride (1.14 ml, 0.01 mol) was added dropwise. The resultant solution was stirred for 5

hour at room temperature, and poured onto crushed ice, the product was isolated and

washed with water and hexane to give pure product. Yield: 94 %, mp 70-72 oC.

[B] General procedure for the preparation of Methyl 1-benzyl-6-chloro-3-[(N,N-

dialkylamino) (oxo)acetyl]-1H-indole-5-carboxylates.

To a stirred cooled (ice bath) solution of methyl 1-benzyl-6-chloro-1H-indole-5-

carboxylate (0.5 g, 1.67 mmol) in dry DCM (12 ml), oxalyl chloride (0.71 ml, 8.35 mmol)

was added dropwise in solution. The obtained solution was stirred at 0 oC for 30.0 minute

and then at 25-30 oC for 1 hour. Dark yellow colored was formed. The solvent was

removed in vacuo, the residue was dissolved in dry DCM (12 ml) then add different

secondary amine (5.01 mmol) was added dropwise. The reaction mixture was stirred at 0 oC for 30.0 minute and then 25-30 oC for another 30.0 minute (monitored by TLC). The

solvent was removed in vacuo. The product was dissolved in water and extracted with

ethylacetate (25 ml × 3). The combined organic layers were washed with water followed

by brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the

solid was triturated with hexane and resulting precipitate was filtered, washed with

hexane and dried to give analytical pure product. The physical constants of the product

are recorder in Table-6a.



[C] Biological evaluation of Methyl 1-benzyl-6-chloro-3-[(N,N-dialkylamino)

(oxo)acetyl]-1H-indole-5-carboxylates.





Table-6a: Physical constants of Methyl 1-benzyl-6-chloro-3-[(N,N-dialkylamino)


Sr. No.


6a NCH3

CH3 C23H23ClN2O4

426.89

83 0.51

6b ON

C23H21ClN2O5

440.87

79 0.42

6c N

C24H23ClN2O4

438.90

85 0.35

6d NN CH3

C24H24ClN3O4

453.91

84 0.44

6e NNCH3

C25H26ClN3O4

467.94

86 0.46

6f NN

C25H26ClN3O4

467.94

78 0.32

6g NCH3

CH3

CH3

CH3

C25H27ClN2O4

454.94 82 0.40

6h N

C23H21ClN2O4

424.87

84 0.43

6i N

CH3

C25H25ClN2O4

452.93

81 0.37

6j N CH3

C25H25ClN2O4

452.93

82 0.36

TLC solvent system:- MeoH : CHCl3 = 2 : 8

N

O

O

Cl

O

O

R

CH3



ANALYTICAL DATA

Methyl 1-benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-1H-indole-5-carboxylate (6a).

mp 78-80 oC; Purity by HPLC: 96 %; IR (KBr): 3038 (Ar, C-H str), 2983 (C-H str), 1725

(ketone, C=O str), 1629 (amide, C=O str), 1519 (Ar, C=C str), 1447 (Ar, C=C str), 1256

(C-H ban), 1165 (C-N str), 780 (C-Cl str) cm-1; 1H NMR (300 MHz, CDCl3): δ ppm 1.18-

1.31 (m, 6H, 2CH3), 3.33-3.40 (q, J=6.96 Hz, 2H, CH2), 3.48-3.55 (q, J=7.08 Hz, 2H,

CH2), 3.95 (s, 3H, OCH3), 5.36 (s, 2H, CH2), 7.13-7.16 (m, 2H, ArH), 7.34-7.38 (m, 4H,

ArH), 7.95 (s, 1H, ArH), 8.85 (s, 1H, ArH). 13C NMR (75 MHz, CDCl3): δ ppm 12.77,

14.41, 39.38, 42.46, 51.26, 52.40, 112.79, 114.42, 124.56, 125.09, 125.96, 126.95,

128.68, 129.26, 134.37, 138.63, 139.92, 163.26, 166.49, 185.31; MS: m/z = 426 [M]+;

Anal. Calcd for C23H23ClN2O4: C, 64.71; H, 5.43; N, 6.56. Found: C, 64.44; H, 5.29; N,

6.41%.

Methyl 1-benzyl-6-chloro-3-[morpholin-4-yl(oxo)acetyl]-1H-indole-5-carboxylate (6b).

mp 98-99 oC; IR (KBr): 3072, 2975, 2926, 1708, 1632, 1547, 1460, 1262, 788 cm-1; MS:

m/z = 440 [M]+; Anal. Calcd for C23H21ClN2O5: C, 62.66; H, 4.80; N, 6.35. Found: C,

62.20; H, 4.70; N, 6.22%.

Methyl 1-benzyl-6-chloro-3-[oxo(piperidin-1-yl)acetyl]-1H-indole-5-carboxylate (6c).

mp 135-137 oC; IR (KBr): 3048, 2968, 2937, 1715, 1645, 1536, 1450, 1278, 756 cm-1;


C, 65.26; H, 5.20; N, 6.23%.

Methyl 1-benzyl-6-chloro-3-[(4-methylpiperazin-1-yl)(oxo)acetyl]-1H-indole-5-carboxy-

late (6d). mp 103-105 oC; IR (KBr): 3065, 2945, 2891, 1720, 1635, 1555, 1468, 1246,


9.26. Found: C, 63.05; H, 5.20; N, 9.07%.

Methyl 1-benzyl-6-chloro-3-[(4-ethylpiperazin-1-yl)(oxo)acetyl]-1H-indole-5-carboxyl-

ate (6e). mp 170-171 oC; IR (KBr): 2996, 2975, 2944, 1727, 1635, 1529, 1464, 1240, 771

cm-1; MS: m/z = 468 [M+1]+; Anal. Calcd for C25H26ClN3O4: C, 64.17; H, 5.60; N, 8.98.

Found: C, 63.83; H, 5.58; N, 8.79%.

Methyl 1-benzyl-6-chloro-3-[oxo(4-phenylpiperazin-1-yl)acetyl]-1H-indole-5-carboxyl-

ate (6f). mp 113-115 oC; IR (KBr): 3031, 2947, 2905, 1726, 1642, 1525, 1499, 1239, 759




Found: C, 67.19; H, 4.95; N, 7.94%.

Methyl 1-benzyl-6-chloro-3-[(dipropan-2-ylamino)(oxo)acetyl]-1H-indole-5-carboxyl-

ate (6g). mp 104-106 oC; IR (KBr): 3038, 2979, 2948, 1728, 1638, 1525, 1447, 1253, 778


Found: C, 65.56; H, 5.87; N, 6.01%.

Methyl 1-benzyl-6-chloro-3-[oxo(pyrrolidin-1-yl)acetyl]-1H-indole-5-carboxylate (6h).

mp 142-144 oC; Purity by HPLC: 93 %; IR (KBr): 3109, 2981, 2959, 1723, 1618, 1524,

1448, 1254, 781 cm-1; 1H NMR (300 MHz, CDCl3): δ ppm 1.91-2.02 (m, 4H, 2CH2),

3.58-3.63 (t, J=6.60 Hz, 2H, CH2), 3.68-3.73 (t, J=6.40 Hz, 2H, CH2), 3.95 (s, 3H,

OCH3), 5.32 (s, 2H, CH2), 7.15-7.17 (m, 2H, ArH), 7.33-7.38 (m, 4H, ArH), 8.34 (s, 1H,

ArH), 8.90 (s, 1H, ArH). 13C NMR (75 MHz, CDCl3): δ ppm 19.57, 20.51, 46.19, 47.55,

51.27, 52.39, 112.75, 114.26, 124.18, 125.06, 126.08, 126.95, 128.30, 129.24, 134.59,



Methyl 1-benzyl-6-chloro-3-[(2-methylpiperidin-1-yl)(oxo)acetyl]-1H-indole-5-carboxy-

late (6i). mp 90-92 oC; IR (KBr): 3040, 2950, 2918, 1719, 1633, 1521, 1458, 1260, 768


Found: C, 65.96; H, 5.46; N, 6.02%.

Methyl 1-benzyl-6-chloro-3-[(4-methylpiperidin-1-yl)(oxo)acetyl]-1H-indole-5-carboxy-

late (6j). mp 181-183 oC; IR (KBr): 3016, 2976, 2922, 1710, 1632, 1510, 1444, 1240, 765


Found: C, 65.93; H, 5.42; N, 6.03%.





IR spectra of compound 6h

5007501000125015001750200025003000350040001/cm

15

30

45

60

75

90

105

%T

3108

.39

3038

.95

2983

.98

1725

.38

1629

.90

1519

.96

1447

.62

1321

.28

1256

.67

1165

.04 11

31.2

9

939.

36

823.

6378

0.23 70

2.11

639.

42

471.

6140

5.06

RMG-201 p

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90%T

3109

.35

2981

.08

2959

.87 28

80.7

8

1723

.45

1618

.33

1524

.78

1448

.59

1367

.58

1328

.03

1254

.74

1237

.38

1170

.83

1153

.47

1088

.85

1006

.88 96

9.26

895.

9678

1.20 74

9.37

703.

0862

2.06 57

3.84

502.

4744

9.43

reaction-99

N

O

OCH3

Cl

O

O

N

CH3 CH3

N

O

O

N

Cl

O

OCH3




Mass spectrum of compound 6h

N

O

O

Cl

O

OCH3

CH3CH3

m/z = 425

N

O

O

Cl

O

OCH3

N

m/z = 424




1H NMR spectrum of compound 6h

N

O

OCH3

Cl

O

O

N

CH3 CH3

N

O

O

N

Cl

O

OCH3



13C NMR spectrum of compound 6a

13C NMR spectrum of compound 6h

N

O

OCH3

Cl

O

O

N

CH3 CH3

N

O

O

N

Cl

O

OCH3



HPLC of compound 6a



HPLC of compound 6h



Table-6b: Antimicrobial activity of Methyl 1-benzyl-6-chloro-3-[(N,N-dialkylamino)


Sr. No.




6a 100 100 500 500 200 250 500 6b 62.5 100 100 100 200 250 250 6c 200 200 250 250 250 500 1000 6d 500 500 125 250 500 500 200 6e 250 500 500 500 250 1000 1000 6f 100 200 250 100 500 500 1000 6g 500 250 250 250 1000 500 500 6h 500 250 500 250 500 250 250 6i 200 125 100 100 250 500 500 6j 250 200 200 250 1000 250 1000











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Glyoxylamide derivatives… 152

INTRODUCTION

6-Chloro-indole-5-carboxamide moieties represent important building blocks in

both natural and synthetic bioactive compounds, which have been shown to possess

diverse therapeutic activities. The nature and the position of the substituent on the indole

moiety influence these activities. Molecules containing 6-chloro-3-

[(diethylamino)(oxo)acetyl]-1H-indole-5-carboxamides have been shown a broad range

of important biological activities.

N

O

O

R2

O

NHR

1

R3

R1 = aryl, R2 = secondary amine,

R3 = alkyl

(1)

Our strategy is based on to develop a new bioactive entity especially with

pharmacological activities bearing heterocyclic ring system. Literature survey reveals that

nitrogen containing heterocyclic compounds like 6-chloro-indole-5-carboxamide have

received considerable attention in medicinal science due to their biological and

pharmacological activities.

SYNTHETIC ASPECT

Various methods for the preparation of indole-5-carboxamide and hydrolysis of

ester have been cited in literature, some of the methods are as under.

HYDROLYSIS

1. J. L. et al.1 have synthesized dihydroindole carboxylic acid ester was hydrolyzed

to the free acid employing potassium hydroxide in aqueous DMSO.

NH

COOEtKOH, DMSO

NH

O

OH

2. S. Mattsson et al.2 have synthesized a mild hydrolysis of esters mediated by

lithium salts.



R1Y

X R3

R2

O

O

R4 R

1YX R

3

R2

OH

OEt3N, LiBrCH3CN, H2O

ACID AMINE COUPLING

3. An effective protocol for a waste-minimized, environmentally benign thermal

condensation of carboxylic acids with amines has been identified by L. J. Gooben

et al.3

R1

O

OH+ NH

R2

R3

neat, 160OC2-24 hr.

R1

N

O

R2

R3

4. Z. Huang et al.4 have prepared borane-tetrahydrofuran complex used to generate

triacyloxyboranes, which can be effectively reacted with various nucleophiles

(alkylamines, arylamines, hydrazides, alcohols, phenols) at reflux temperature in

toluene to provide the corresponding amines.

R1

O

OH

0.35 eq. BH3-THFtoluene, rt., 1 hr.

R1

O

O B

1.2 eq. R2R3NHreflux, 12 hr.

R1

O

N R3

R2

5. The conversion of carboxylic acids to their corresponding acid chlorides occurs

rapidly in the presence a tertiary amine base and 3,3-dichlorocyclopropenes via

aromatic cation-activated nucleophilic acyl substitution to give the corresponding

amides synthesized by D. J. Hardee and coworkers.5

R1

O

OH

DIPEA, CH2Cl2 R1

O

Cl

BnNH2

15 min.R

1O

NHBnClCl

6. G. E. Veitch et al.6 have used magnesium nitride as a convenient source of

ammonia allows a direct transformation of esters to primary amides. Methyl,

ethyl, isopropyl, and tert-butyl esters are converted to the corresponding

carboxamides in good yields.



R1

O

O R2 R

1O

NH2

5 eq. Mg3N2

MeOH, 80OC

7. C. Larrive-Aboussafy et al.7 have synthesized DBU catalyzed corresponding

amides derivatives.

Ph OHO 1.0 - 1.2 eq. CDI

(N,N'-carbonyldiimidazole)

2-methyltetrahydrofuranPh

ON

N1.1 - 1.5 eq. Ar-NH2

DBU, 2-Me THFPh NH

O Ar

8. Multivalent metal salts, such as ferric chloride and sulfate, are active and versatile

catalysts for the amidation of aliphatic fatty acids with long-chain aliphatic amines

was reported by Y. Terada et al.8

O

OH

CH3

+ NH22 mol-% FeCl3.6H2O

mesitylene, reflux NHO( )n

9. J. Bures et al.9 have synthesized 2,2′-dipyridyl diselenide catalyzed a direct

reaction of carboxylic acids with azides and trimethylphosphine at room

temperature.

R1

O

OH+ N3 R

2 Me3P, 2,2'-PySeSePy

toluene, rt.R

1O

NH R2

10. I. Azumaya et al.10 have prepared various tertiary benzanilide derivatives were

effectively synthesized in high yields from a broad range substituted benzoic acid

and N-monoalkylated anilines using dichlorotriphenylphosphorane in chloroform.

Ar N

H

R1

+

Ar'

O

OHPh3PCl2

CHCl3, refluxAr N

R1

O

Ar'

11. Deoxo-Fluor is a versatile and mild reagent for acyl fluoride generation and

subsequent one-flask amide coupling. The conversion of acids to amides and



weinreb amides and the use of deoxo-fluor as peptide-coupling reagent have been

explored. Products were isolated after facile purification in good yields by J. M.

White et al.11

R1

R2

O

OH+ F3S

OCH3

OCH3

DIPEACH2Cl2

R1

R2

O

F

NHR3R4 R1

R2

O

NR

3R

4

12. D. M. Shendage et al.12 have prepared stereoconservative protection and

deprotection method of amino and carboxyl groups includes the generation of N-

phthaloyl N'-alkyl secondary amides from N-phthaloyl amino acids by using a

mixed anhydride method. These secondary amides have been transformed by

thermal rearrangement of the intermediate nitrosoamides to esters with retention

of configuration and excellent yields.

PGNR

1

OOH

(1) isobutyl chloroformate (IBCF)MeNH2, RNH2

(2) 5% NaHCO3PGN

R1

ONHR

2

REACTION MECHANISM

R OH

O

..+ C NN C

N

NH

O

R

O

+N

NN

OH ..

NNNO

RO

+ C

NH

NHO+R

1NH2..R C NH

O

R1+

NN

N

OH




From the literature survey, it was revealed that indole carboxamide derivatives (2)

are better therapeutic agents. B. J. Mavunkel et al.13 have prepared of indolylcarboxamide

derivatives as inhibitors of p38 kinase.

NH

MeO

ON

O

O

N

NCH3

Ph

(2)

G. Shattat et al.14 have synthesized and evaluated anti-hyperlipidemic activity of

N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (3) derivatives. H. B. Rubins and

coworkers15 have studied indole carboxamide derivatives as pharmacological mechanism

of fibrates, including bezafibrate, by the induction of lipoprotein lipase and reduction of

apolipoprotein C-III synthesis leading to increased hydrolysis of triglycerides (TG). S.

Olgen et al.16 and G. Liu et al.17 have studies the potential role for indole carboxamide

derivatives as anti-allergics and antioxidants.

NH

FNH

O

O

(3)

C. Kishor Kumar et al.18 have synthesized 3-oxoisoindoline-5-carboxamides (4)

and their antioxidant activity studies. K. B. Beckman et al.19 and B. Halliwel et al.20 have

studied free radicals and active oxygen species have been related with cardiovascular,

inflammatory diseases and even with a role in cancer.

NH

O

NH

OR

1

(4)



S. Henning et al.21 have reported cyclic indole-3-carboxamides (5), as renin

inhibitors and renin-angiotensin modulators useful in the treatment of hypertension. C.

Zhong et al.22 have synthesized and reported antitumor activities of 1H-indole-5-

carboxamide derivatives. R. Aleksandra et al.23 have documented rational design,

synthesis, and potency of 1H-indole-5-carboxamide as potential fructose 1,6-

bisphosphatase inhibitors.

N

OHCH3

CH3

F

ON NH

(5)

G. A. Doherty et al.24 have synthesized indole-5-carboxamide derivatives (6)

as DP2 receptor modulators for treating immunological diseases. Indole carboxamide

derivatives applied as p38α-selective MAP kinase inhibitor reduces tumor growth in

mouse xenograft models of multiple myeloma and SD-282 reduces inflammation in a

subchronic model to tobacco smoke-induced airway inflammation by S. Medicherla et

al.25,26

N

O

OH

CN

O

NHCl

(6)

H. Timo and coworkers27 have synthesized 1H-indole-5-carboxamide derivatives

(7) as selective 5-HT1A agonists. S. Medicherla et al.28,29 have synthesized arthritis and

nonobese diabetic mice with type I diabetes studies of 1H-indole-5-carboxamide

derivatives.



NH

O

NH2 N

N

OCH3(7)

K. L. Leboulluec et al.30 have synthesized 1H-indole-5-carboxamide (8) and

exhibiting serotonergic binding affinity. Rousseau et al.31 have studied indoline-5-

carboxamide derivatives as antimicrobial agents. Potent nonpeptide GnRH receptor

antagonists derived from substituted indole-5-carboxamides by W. T. Ashton et al.32

NH

O

NH2

NH NH

NH(8)

A. William et al.33 have prepared and formulated of 1H-indole-5-carboxamide (9)

for treatment of migraine. A. Sunjoo et al.34 have studied bis-indole destabilizes

microtubules and display potent in vitro and in vivo antitumor activity in prostate cancer.

NH

O

NH

NR

2

R1

R3

R4

(9)

Synthesis and pharmacological evaluation of 1H-indol derivative (10) as potent

antimitotic agent reported by R. S. Shetty et al.35 B. Gerald et al.36 have synthesized

indole derivatives and studied antitumoral activity in vivo, shows efficacy toward

multidrug-resistant tumor cells, and lacks neurotoxicity.



NH

NH O

O

CH3

O

N

OCH3

(10)

The preparation and evaluation of a novel class of CB2 agonists based on a

1,2,3,4-tetrahydropyrrolo[3,4-b]indole moiety (11) reported by D. Pagea et al.37

R1

NO

N

CH3R1 = methyl, benzyl, ethylSO2, isopropylSO2 etc

(11) Thus with an effort to capitalize the biological potential of the heterocyclic system

and to provide more interesting compounds for biological screening, we have under taken

the synthesis of several indole-5-carboxamides which has been described as under.


DERIVATIVES

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-CHLORO-3-

[(DIETHYLAMINO)(OXO)ACETYL]-1-METHYL-N-ARYL-1H-

INDOLE-5-CARBOXAMIDES

SECTION-II: SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-CHLORO-

3-[(DIETHYLAMINO)(OXO)ACETYL]-1-BENZYL-N-ARYL-1H-

INDOLE-5-CARBOXAMIDES



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-CHLORO-3-

[(DIETHYLAMINO)(OXO)ACETYL]-1-METHYL-N-ARYL-1H-INDOLE-5-

CARBOXAMIDES.

The discovery of indole glyoxylamide derivatives as potent biologically active

agent has led to the exploration of large number of structural variants, containing 6-

chloro-indole-3-yl-glyoxylamide moiety as an invariable ingredient. In view of these

reports, we have synthesize 6-chloro-indole-3-yl-glyoxylamide derivatives by the

condensation of 6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxylic

acid and different aryl amine in the presence of DCC, HOBT and TEA.

REACTION SCHEME









N

O

OCH3

Cl

O

O

N

CH3CH3

CH3

40% NaOHMeOH N

O

OH

Cl

O

O

N

CH3CH3

CH3

N

O

NH

Cl

O

O

N

CH3CH3

CH3

RHOBT, DCC

Et3N, Amine, dyr DCM








on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in DMSO-d6/CDCl3 solution on a Bruker Ac 400 MHz

spectrometer. Purity of the synthesized compounds was checked by HPLC Agilent 1100

series. Elemental analysis of the all the synthesized compounds was carried out on Euro

EA 3000 elemental analyzer and the results are in agreements with the structures

assigned.

[A] Preparation of Methyl 6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-

indole-5-carboxylate.

See, Part-B, Part-1, Section-I Experimental Section [B].

[B] Preparation of Methyl 6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-

indole-5-carboxylic acid.

To a stirred solution of methyl 6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-

1H-indole-5-carboxylate (0.5 g, 1.42 mmol) in MeOH (10 ml), 40% sodium hydroxide (1

ml) solution was added in solution. The reaction mixture was refluxed for 4 hour and the

solvent was removed in vacuo. The viscous oil obtained was neutralized with an aqueous

solution of HCl. The product was extracted with ethylacetate (25 ml × 3), and the

combined organic layers were washed with water followed by brine and dried over

anhydrous Na2SO4. The solvent was removed in vacuo, and the solid product was

obtained. Yield: 85 %, mp 145-147 oC.

[C] General procedure for the preparation of 6-Chloro-3-

[(diethylamino)(oxo)acetyl]-1-methyl-N-aryl-1H-indole-5-carboxamides.

To a stirred cooled (ice bath) solution of 6-chloro-3-

[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxylic acid (0.4 g, 1.19 mmol) in

dry DCM (10 ml), HOBT (N-hydroxybenzotrizole) (0.24 g, 1.78 mmol) and DCC (N,N'-

dicyclohexylcarbodiimide) (0.36 g, 1.78 mmol) was added in solution at 0 oC. The

obtained solution was stirred for 15.0 minute at 0 oC. To this solution arylamine (1.19



mmol) in dry DCM (5 ml) was added dropwise, then after 2.0 minute TEA (0.33 ml 2.38

mmol) was added. The reaction mixture was stirred for 10 hour at room temperature

(monitored by TLC). The solvent was removed in vacuo. The product was extracted with

ethylacetate (20 ml × 3), and the combined organic layers were washed with water

followed by brine and dried over anhydrous Na2SO4. The solvent was evaporated under

vacuum and the residue was purified by column chromatography on silica gel (eluent: 5:5

= E.A. :Hexane) to obtain pure product. The physical constants of the product are


[D] Biological evaluation of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-N-

aryl-1H-indole-5-carboxamides.





Table-7a: Physical constants of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-N-


Sr. No.


7a O

CH3

C23H24ClN3O4

441.90

75 0.60

7b

C23H24ClN3O3

425.90

72 0.52

7c

CH3

C23H24ClN3O3

425.90

76 0.48

7d CH3

C23H24ClN3O3

425.90

71 0.51

7e

F

C22H21ClFN3O3

429.87

78 0.50

7f F

C22H21ClFN3O3

429.87

79 0.49

7g

Cl

C22H21Cl2N3O3

446.32

80 0.53

7h Cl

C22H21Cl2N3O3

446.32

74 0.56

7i O

CH3 C24H24ClN3O4

453.91

75 0.54

7j

C22H22ClN3O3

411.88

70 0.55


N

O

O

N

CH3 CH3

Cl

O

NHR

CH3



ANALYTICAL DATA

6-Chloro-3-[(diethylamino)(oxo)acetyl]-N-(4-methoxyphenyl)-1-methyl-1H-indole-5-

carboxamide (7a). mp 184-186 oC; IR (KBr): 3354 (N-H str), 2949 (C-H str), 2922 (C-H

str), 1708 (ketone, C=O str), 1645 (amide, C=O str), 1512 (Ar, C=C str), 1465 (Ar, C=C

str), 1365 (N-H ban), 1249 (C-H ban), 1206 (C-N str), 854 (C-H o.p. ban), 748 (C-Cl str)

cm-1; 1H NMR (400 MHz, DMSO-d6): δ ppm 0.96-1.23 (m, 6H, 2CH3), 3.24-3.32 (m, 2H,

CH2), 3.42-3.50 (m, 2H, CH2), 3.67 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.52-6.59 (m, 2H,

ArH), 6.87-7.09 (m, 2H, ArH), 7.23 (s, 1H, ArH), 7.78 (s, 1H, ArH), 8.15 (s, 1H, ArH),

10.36 (s, 1H, NH). MS: m/z = 441 [M]+; Anal. Calcd for C23H24ClN3O4: C, 62.51; H,

5.47; N, 9.51. Found: C, 62.16; H, 5.34; N, 9.43%.

N-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-carboxamide

(7b). mp 125-126 oC; Purity by HPLC: 95 %; IR (KBr): 3321, 2941, 2859, 1707, 1625,

1527, 1440, 1246, 771cm-1; 1H NMR (400 MHz, DMSO-d6): δ ppm 1.02-1.23 (m, 6H,

2CH3), 3.22-3.24 (m, 2H, CH2), 3.40-3.44 (m, 2H, CH2), 3.91 (s, 3H, CH3), 4.48 (s, 2H,

CH2), 7.27-7.38 (m, 5H, ArH), 7.84 (s, 1H, ArH), 8.13 (s, 1H, ArH), 8.22 (s, 1H, ArH),

8.93 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): δ ppm 13.12, 14.61, 32.63, 34.12, 39.01,

42.15, 112.32, 114.34, 124.38, 125.12, 125.88, 126.23, 128.90, 129.78, 136.55, 138.11,



6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-N-(3-methylphenyl)-1H-indole-5-

carboxamide (7c). mp 147-149 oC; IR (KBr): 3340, 2968, 2898, 1711, 1627, 1547, 1473,

1250, 758 cm-1; MS: m/z = 425 [M]+; Anal. Calcd for C23H24ClN3O3: C, 64.86; H, 5.68;

N, 9.87. Found: C, 64.51; H, 5.53; N, 9.80%.

6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-N-(4-methylphenyl)-1H-indole-5-

carboxamide (7d). mp 170-171 oC; IR (KBr): 3362, 3020, 2936, 2860, 1716, 1629, 1525,

1467, 1229, 749 cm-1; MS: m/z = 425 [M]+; Anal. Calcd for C23H24ClN3O3: C, 64.86; H,

5.68; N, 9.87. Found: C, 64.60; H, 5.59; N, 9.79%.

6-Chloro-3-[(diethylamino)(oxo)acetyl]-N-(2-fluorophenyl)-1-methyl-1H-indole-5-

carboxamide (7e). mp 110-111 oC; IR (KBr): 3349, 3048, 2961, 2819, 1715, 1632, 1521,

1447, 1263, 763 cm-1; MS: m/z = 430 [M+1]+; Anal. Calcd for C22H21ClFN3O3: C, 61.47;

H, 4.92; N, 9.78. Found: C, 61.11; H, 4.85; N, 9.60%.



6-Chloro-3-[(diethylamino)(oxo)acetyl]-N-(4-fluorophenyl)-1-methyl-1H-indole-5-

carboxamide (7f). mp 118-120 oC; IR (KBr): 3336, 2949, 2945, 1715, 1653, 1517, 1416,

1233, 761 cm-1; MS: m/z = 430 [M+1]+; Anal. Calcd for C22H21ClFN3O3: C, 61.47; H,

4.92; N, 9.78. Found: C, 61.13; H, 4.80; N, 9.61%.

6-Chloro-N-(3-chlorophenyl)-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-

carboxamide (7g). mp 140-142 oC; IR (KBr): 3345, 3023, 2947, 2843, 1706, 1633, 1518,

1440, 1256, 775 cm-1; MS: m/z = 447 [M+1]+; Anal. Calcd for C22H21Cl2N3O3: C, 59.20;

H, 4.74; N, 9.41. Found: C, 58.91; H, 4.64; N, 9.27%.

6-Chloro-N-(4-chlorophenyl)-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-

carboxamide (7h). mp 160-161 oC; IR (KBr): 3342, 2957, 2926, 1710, 1641, 1528, 1434,

1228, 783 cm-1; MS: m/z = 448 [M+2]+; Anal. Calcd for C22H21Cl2N3O3: C, 59.20; H,

4.74; N, 9.41. Found: C, 58.85; H, 4.60; N, 9.29%.

N-(4-Acetylphenyl)-6-chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-1H-indole-5-

carboxamide (7i). mp 168-169 oC; IR (KBr): 3371, 3021, 2974, 2910, 1720, 1636, 1536,


5.33; N, 9.26. Found: C, 63.12; H, 5.24; N, 9.10%.

6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-methyl-N-phenyl-1H-indole-5-carboxamide

(7j). mp 129-130 oC; IR (KBr): 3360, 3055, 2922, 2858, 1705, 1623, 1550, 1414, 1278,

770 cm-1; MS: m/z = 411 [M]+; Anal. Calcd for C22H22ClN3O3: C, 64.15; H, 5.38; N,

10.20. Found: C, 63.89; H, 5.29; N, 10.03%.






5007501000125015001750200025003000350040001/cm

0

20

40

60

80

100

%T33

54.3

2

2949

.26

2922

.25

2850

.88

1708

.99

1645

.33

1512

.24

1465

.95

1440

.87

1365

.65

1282

.71

1249

.91 12

19.0

5 1095

.60 10

26.1

697

6.01

945.

1585

4.49

796.

6374

8.41

678.

9760

3.74

534.

3049

7.65

430.

14

RMG- 303

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3441

.12

3321

.53

2941

.54

2859

.56

2859

.56

1707

.06

1625

.08

1527

.67

1440

.87

1385

.90

1385

.90

1297

.17

1246

.06

1206

.51

1152

.51

1098

.50

985.

6695

1.90

852.

5677

1.55

710.

7966

6.43

577.

7054

2.98

512.

1241

4.71 40

6.99

Reaction-91 p2

NCH3

O

O

N

CH3

O

NH

OCH3

Cl

CH3

NCH3

O

O

N

CH3 CH3

O

NH

Cl





NCH3

O

O

N

CH3 CH3

O

NH

Cl

m/z = 425

m/z = 441

NCH3

O

O

N

CH3 CH3

O

NH

Cl

O

CH3





NCH3

O

O

N

CH3

O

NH

OCH3

Cl

CH3





NCH3

O

O

N

CH3 CH3

O

NH

Cl







HPLC of compound 7b



13C NMR spectrum of compound 7b

NCH3

O

O

N

CH3

O

NH

OCH3

Cl

CH3



Table-7b: Antimicrobial activity of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1- methyl-N-aryl-1H-indole-5-carboxamides.

Sr. No.




7a 250 250 125 200 500 250 500 7b 200 200 100 200 250 500 1000 7c 100 100 100 100 250 1000 1000 7d 500 250 500 500 500 250 250 7e 250 250 500 250 1000 500 250 7f 250 500 200 500 1000 1000 500 7g 250 500 500 250 500 250 250 7h 62.5 100 50 100 250 500 250 7i 200 200 100 200 250 500 500 7j 250 200 100 100 500 1000 1000











SECTION-II

SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-CHLORO-3-

[(DIETHYLAMINO)(OXO)ACETYL]-1-BENZYL-N-ARYL-1H-INDOLE-5-

CARBOXAMIDES.

6-Chloro-indole-3-yl-glyoxylamide moieties represent important building blocks

in both natural and synthetic bioactive compounds, which have been shown to possess

diverse therapeutic activities. Looking to this diversified activities the synthesize of 6-

chloro-indole-3-yl-glyoxylamide derivatives have been undertaken the condensation of 1-

benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-1H-indole-5-carboxylic acid and different

aryl amine in the presence of DCC, HOBT and TEA.

REACTION SCHEME









N

O

OCH3

Cl

O

O

N

CH3CH3

40% NaOHMeOH N

O

OH

Cl

O

O

N

CH3CH3

N

O

NH

Cl

O

O

N

CH3CH3

RHOBT, DCC

Et3N, Amine, dyr DCM








on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in DMSO-d6 solution on a Bruker Ac 400 MHz spectrometer.




[A] Preparation of Methyl 1-benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-1H-

indole-5-carboxylate.

See, Part-B, Part-1, Section-II Experimental Section [B].

[B] Preparation of 1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-1H-indole-5-

carboxylic acid.

To a stirred solution of methyl 1-benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-

1H-indole-5-carboxylate (0.5 g, 1.17 mmol) in MeOH (10 ml), 40% sodium hydroxide (1

ml) solution was added. The reaction mixture was refluxed for 4 hour and the solvent was

removed in vacuo. The viscous oil obtained was neutralized with an aqueous solution of

HCl. The product was extracted with ethylacetate (25 ml × 3), and the combined organic

layers were washed with water followed by brine and dried over anhydrous Na2SO4. The

solvent was removed in vacuo, and the solid product was obtained. Yield: 80%, mp 160-

161 oC.

[C] General procedure for the preparation of 6-Chloro-3-

[(diethylamino)(oxo)acetyl]-1-benzyl-N-aryl-1H-indole-5-carboxamides.

To a stirred cooled (ice bath) solution of 1-benzyl-6-chloro-3-

[(diethylamino)(oxo)acetyl]-1H-indole-5-carboxylic acid (0.4 g, 0.93 mmol) in dry DCM

(10 ml), HOBT (N-hydroxybenzotrizole) (0.18 g, 1.40 mmol) and DCC (N,N'-

dicyclohexylcarbodiimide) (0.28 g, 1.40 mmol) was added in solution at 0 oC. The

obtained soluction was stirred for 15.0 minutes at 0 oC. To this solution arylamine in dry

DCM (5 ml) was added dropwise, then after 2.0 minute TEA (0.26 ml, 1.87 mmol) was



added. The reaction mixture was stirred for 10 hour at room temperature (monitored by

TLC). The solvent was removed in vacuo. The product was extracted with ethylacetate

(20 ml × 3), and the combined organic layer was washed with water followed by brine

and dried over anhydrous Na2SO4. The solvent was evaporated under vacuo and the

residue was purified by column chromatography on silica gel (eluent: 5:5 = E.A.:Hexane)

to obtain pure product. The physical constants of the product are recorder in Table-8a.

[D] Biological evaluation of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-benzyl-N-






Table-8a: Physical constants of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-benzyl-N-


Sr. No.


8a O

CH3

C29H28ClN3O4

518.00

76 0.58

8b

C29H28ClN3O3

502.00

72 0.54

8c

CH3

C29H28ClN3O3

502.00

78 0.55

8d CH3

C29H28ClN3O3

502.00

73 0.56

8e

F

C28H25ClFN3O3

505.96

74 0.60

8f F

C28H25ClFN3O3

505.96

68 0.61

8g

Cl

C28H25Cl2N3O3

522.42

69 0.54

8h Cl

C28H25Cl2N3O3

522.42

70 0.53

8i O

CH3 C30H28ClN3O4

530.01

72 0.55

8j

C28H26ClN3O3

487.97

73 0.52


N

O

O

N

CH3 CH3

Cl

O

NHR



ANALYTICAL DATA

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(4-methoxyphenyl)-1H-indole-5-

carboxamide (8a). mp 89-91 oC; IR (KBr): 3359, 3023, 2952, 2865, 1717, 1638, 1532,


5.45; N, 8.11. Found: C, 66.95; H, 5.40; N, 7.98%.

N,1-Dibenzyl-6-chloro--3-[(diethylamino)(oxo)acetyl]-1H-indole-5-carboxamide (8b).

mp 120-122 oC; Purity by HPLC: 94 %; IR (KBr): 3394 (N-H str), 3032 (Ar, C-H str),

2929 (C-H str), 2856 (C-H str), 1708 (ketone, C=O str), 1627 (amide, C=O str), 1519 (Ar,

C=C str), 1456 (Ar, C=C str), 1300 (N-H ban), 1244 (C-H ban), 794 (C-Cl str) cm-1; 1H

NMR (400 MHz, DMSO-d6): δ ppm 1.05-1.16 (m, 3H, CH3), 1.16-1.23 (m, 3H, CH3),

3.24-3.34 (m, 2H, CH2), 3.34-3.43 (m, 2H, CH2), 4.46 (s, 2H, CH2), 5.61 (s, 2H, CH2),

7.26-7.35 (m, 10H, ArH), 7.83 (s, 1H, ArH), 8.13 (s, 1H, ArH), 8.45 (s, 1H, ArH), 8.98

(s, 1H, NH). MS: m/z = 504 [M+2]+; Anal. Calcd for C29H28ClN3O3: C, 69.38; H, 5.62; N,

8.37. Found: C, 68.99; H, 5.53; N, 8.23%.

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(3-methylphenyl)-1H-indole-5-

carboxamide (8c). mp 97-99 oC; IR (KBr): 3354, 3014, 2977, 1730, 1637, 1523, 1446,

1230, 777 cm-1; 1H NMR (400 MHz, DMSO-d6): δ ppm 1.05-1.08 (t, J=7.2 Hz, 3H, CH3),

1.16-1.19 (t, J=7.2 Hz, 3H, CH3), 2.30 (s, 3H, CH3), 3.23-3.28 (q, J=7.2 Hz, 2H, CH2),

3.42-3.47 (q, J=7.2 Hz, 2H, CH2), 5.64 (s, 2H, CH2), 6.91-6.93 (d, J=7.2 Hz, 1H, ArH),

7.20-7.22 (m, 1H, ArH), 7.24-7.29 (m, 2H, ArH), 7.31-7.38 (m, 3H, ArH), 7.46-7.48 (d,

J=8.0 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.88 (s, 1H, ArH), 8.21 (s, 1H, ArH), 8.50 (s, 1H,

ArH), 10.40 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ ppm 13.15, 14.58, 21.69,

38.67, 42.14, 50.28, 113.07, 113.38, 117.22, 120.49, 121.58, 124.33, 124.90, 126.02,

127.60, 128.41, 129.07, 129.28, 132.56, 136.90, 137.12, 138.40, 139.43, 141.72, 165.74,

166.84, 186.65; MS: m/z = 501 [M-1]+; Anal. Calcd for C29H28ClN3O3: C, 69.38; H, 5.62;

N, 8.37. Found: C, 69.05; H, 5.54; N, 8.25%.

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(4-methylphenyl)-1H-indole-5-

carboxamide (8d). mp 115-116 oC; IR (KBr): 3355, 3078, 2941, 2912, 1705, 1646, 1520,

1468, 1260, 738 cm-1; MS: m/z = 501 [M-1]+; Anal. Calcd for C29H28ClN3O3: C, 69.38;

H, 5.62; N, 8.37. Found: C, 69.01; H, 5.50; N, 8.20%.



1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(2-fluorophenyl)-1H-indole-5-

carboxamide (8e). mp 170-172 oC; IR (KBr): 3356, 3070, 2911, 2831, 1728, 1626, 1528,


H, 4.98; N, 8.30. Found: C, 66.12; H, 4.88; N, 8.12%.

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(4-fluorophenyl)-1H-indole-5-

carboxamide (8f). mp 165-167 oC; IR (KBr): 3344, 3084, 2981, 2901, 1726, 1633, 1520,


H, 4.98; N, 8.30. Found: C, 66.15; H, 4.90; N, 8.21%.

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(3-chlorophenyl)-1H-indole-5-

carboxamide (8g). mp 145-147 oC; IR (KBr): 3378, 3043, 2934, 2876, 1721, 1651, 1526,


H, 4.82; N, 8.04. Found: C, 63.98; H, 4.69; N, 7.89%.

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-(4-chlorophenyl)-1H-indole-5-

carboxamide (8h). mp 137-138 oC; IR (KBr): 3338, 3019, 2942, 2836, 1716, 1646, 1545,


H, 4.82; N, 8.04. Found: C, 64.02; H, 4.75; N, 7.91%.

N-(4-Acetylphenyl)-1-benzyl-6-chloro--3-[(diethylamino)(oxo)acetyl]-1H-indole-5-

carboxamide (8i). mp 85-86 oC; IR (KBr): 3368, 3040, 2935, 2840, 1708, 1630, 1562,

1451, 1216, 791 cm-1; MS: m/z = 529 [M-1]+; Anal. Calcd for C30H28ClN3O4: C, 67.98;

H, 5.32; N, 7.93. Found: C, 67.61; H, 5.23; N, 7.77%.

1-Benzyl-6-chloro-3-[(diethylamino)(oxo)acetyl]-N-phenyl-1H-indole-5-carboxamide

(8j). mp 104-106 oC; IR (KBr): 3350, 3015, 2919, 2860, 1710, 1633, 1548, 1460, 1232,

762 cm-1; MS: m/z = 487 [M]+; Anal. Calcd for C28H26ClN3O3: C, 68.92; H, 5.37; N, 8.61.

Found: C, 68.55; H, 5.30; N, 8.48%.





IR spectra of compound 8c

5007501000125015001750200025003000350040001/cm

20

40

60

80

100

%T33

94.8

3

3032

.20

2929

.97

2856

.67

1708

.99

1627

.97

1519

.96

1456

.30 13

00.0

712

44.1

311

70.8

3

1080

.17

1030

.02 97

4.08

904.

6482

9.42

794.

7070

2.11

530.

4448

0.29

430.

14

RMG- 403

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3481

.63

3354

.32

3014

.84

2977

.23

1730

.21

1637

.62

1523

.82

1446

.66

1336

.71

1254

.74

1232

.55

1168

.90

1095

.60

993.

37

909.

4781

8.81

777.

3474

0.69

700.

18

571.

9151

2.12

414.

7140

3.14

RMG-207

N

O

O

N

CH3 CH3

Cl

O

NH

N

O

O

N

CH3 CH3

Cl

O

NHCH3




Mass spectrum of compound 8c

N

O

O

N

CH3 CH3

Cl

O

NH

m/z = 502

N

O

O

N

CH3 CH3

Cl

O

NHCH3

m/z = 502





N

O

O

N

CH3 CH3

Cl

O

NH




1H NMR spectrum of compound 8c

N

O

O

N

CH3 CH3

Cl

O

NHCH3







HPLC of compound 8b



13C NMR spectrum of compound 8c

N

O

O

N

CH3 CH3

Cl

O

NHCH3



Table-8b: Antimicrobial activity of 6-Chloro-3-[(diethylamino)(oxo)acetyl]-1-benzyl-

N-aryl-1H-indole-5-carboxamides.

Sr. No.




8a 100 100 250 250 1000 1000 1000 8b 62.5 100 50 200 1000 1000 500 8c 200 250 100 100 500 500 1000 8d 200 200 200 12.5 500 500 500 8e 100 10 100 50 250 250 250 8f 500 500 500 250 200 500 1000 8g 200 200 250 200 500 250 250 8h 100 100 50 62.5 250 500 500 8i 250 200 100 200 1000 500 250 8j 500 500 200 250 500 200 500











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Publication… 190

LIST OF PUBLICATION

• D. H. Purohit, B. L. Dodiya, R. M. Ghetiya, P. B. Vekariya and H. S. Joshi*

Synthesis and antimicrobial activity of some new 1,3,4-thiadiazoles and 1,3,4-

thiadiazines containing 1,2,4 triazolo nucleus, Acta chemica slovenica, 58, 53-59,

2011.

• K. M. Thaker, B. L. Dodiya, K. A. Joshi, R. M. Ghetiya, P. B. Vekariya & H. S.

Joshi*, Synthesis and antimicrobial activity of some new aryl amide and

dihydroquinoline derivatives containing benzo[b]thiophene nucleus, Indian journal

of heterocyclic chemistry, 20, 21-24, 2010.

• K. M. Thaker, R. M. Ghetiya, S. D. Tala, B. L. Dodiya, K. A. Joshi, K. L. Dubal &

H. S. Joshi*, Synthesis of oxadiazoles and pyrazolones nucleus as antimycobacterial

and antimicrobial agents, Indian Journal of Chemistry, Section B: Organic

Chemistry Including Medicinal Chemistry, Accepted article [MS No. SCCB-1351

Dt. 03/07/09].

• P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya, P. B. Vekariya and H. S. Joshi*

Synthesis of some new dihydropyrimidines by iodine as a catalyst at ambient

temperature and evaluation of their biological activity, journal of heterocyclic

chemistry, Accepted article [MS No. JHET-10-0340].

• M. J. Joshi, P. B. Vekariya, B. L. Dodiya, R. M. Ghetiya and H. S. Joshi*

Synthesis and biological study of some new chalcones and oxopyrimidines

containing imidazo[1,2-a]pyridine nucleus, journal of heterocyclic chemistry,

Accepted article [MS No. JHET-10-0513].

• M. R. Patel, B. L. Dodiya, R. M. Ghetiya, K. A. Joshi, P. B. Vekariya, A. H.

Bapodara and H. S. Joshi* Synthesis, Antitubercular and Antimicrobial Biological

Evaluation of Pyrazoline derivatives, International journal of chemtech research,

(Accepted article).

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