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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)

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One-pot Synthesis of Some Nitrogen Containing

Heterocycles and Their Biological Activities

MINOR RESEARCH PROJECT

FINIAL WORK DONE REPORT

(05-06-2014 to 04-06-2016)

Submitted to

UNIVERSITY GRANTS COMMISSION

WESTERN REGIONAL OFFICE, PUNE

By

Mr. D. K. Jamale

M. Sc., SET

Department of Chemistry,

Shri Shivaji Mahavidyalaya, Barshi

Barshi – 413411, Maharashtra

2016


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Shri Shivaji Shikshan Prasarak Mandal, Barshi’s

Shri Shivaji Mahavidyalaya, Barshi. ( Arts & Science - Junior & Senior )

NAAC Re-accredited – A Grade Post Box - 4, A/P Barshi - 413411, Dist. - Solapur, MH – India

Prin. Dr. P. R. Thorat, M. Sc., M. Phill., Ph. D.

Off. : (02184) 222382 Fax : (02184) 222382 E-Mail : [email protected]

Jr.Reg.No.HSC/976/13792 (S.Y.)dt. 7-5-1976 Sr. Affi. Letter No. GEN/Affi/2832 dt. 4-3-1964 Shivaji Uni.

P.G.Language / BG / BUTR / I / 30471 dt.27-5-1972 Social Sciences / PW / BUTR / 3906 / dt. 30-9-1972

Reference: SSMB/Sr./UGC/ Date:

To,

The Joint Secretary,

Western Regional Office,

University Grants Commission,

Ganesh khind, Pune-411007

Subject: - Final Report Submission of Minor Research Project

Reference: - File No: 47-616/13(WRO), dated 19 March 2014.

Respected Sir,

I am forwarding herewith, two copies of the Final Completion Report of Minor

Research Project entitled “One-pot Synthesis of Some Nitrogen Containing

Heterocycles and Their Biological Activities” duly completed by Mr. D. K. Jamale

from Chemistry Department of this college, along with the audited statement of

expenditure, utilization certificate, summary report of the project and other related

documents.

I request you to accept the same & kindly release the remaining amount of

Rs.1,05,000/- (In words Rs. One lakh five thousand only) towards the project.

Thanking You

Yours faithfully

Encl:-as above

Copy to: - Director

INFLIBNET Centre, Gandhinagar,

An Inter University Centre of University Grants Commission,

Infocity Gandhinagar - 382007. Gujarat, INDIA.


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INDEX

Sr.

No.

Details Page

No.

1

Previously submitted documents:

Statement of expenditure and Utilization Certificate of 1st

installment of grant.

Annual Report of the work done of the Minor Research Project.

[Annexure III, IV, V and VI (Annual)]

4-10

2 Audited Consolidated Statement of Expenditure with item wise

details under ‘non-recurring & ‘recurring’ heads for the amount

actually incurred duly signed by the Principal & C. A. with stamp &

Registration No. Annexure III (Final)

11-12

3 Statement of Expenditure on Field Work in the prescribed

formats as per UGC guidelines. Annexure IV (Final)

13

4 Audited Consolidated Utilization Certificate for the amount

actually incurred, duly signed by the Principal & C. A. with

stamp. Annexure V (Final)

14

5 Certificate (Utilization of grant within tenure) 15

6 Accession Certificate (Books and Journal) 16

7 Assets Certificate (Equipments) 17

8 A copy of the proof about uploading of Executive summary of

the report, Research documents, monograph, papers published

under Minor Research Project on the website of the College

18-19

11 Final Report of the work done of the Minor Research Project.

Annexure VI (Final) and Appendix-I

20-24

12 Proforma for submission of information at the time of sending the

final report of the work done on the project Annexure VII (Final) 25-29

13 Work Done in the prescribed format Chapters I, II & III 30-93

14 Publications 94-115

15 Acknowledgements 116


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Annexure – III

(Final)


BAHADUR SHAH ZAFAR MARG

NEW DELHI – 110 002

STATEMENT OF EXPENDITURE IN RESPECT OF MINOR RESEARCH

PROJECT

1. Name of Principal Investigator : Mr. D. K. Jamale.

2. Department of PI : Chemistry

Name of College : Shri Shivaji Mahavidyalaya Barshi

3. UGC approval letter No. & date : No 47-616/13(WRO), date: 19 March 2014

4. Title of the Research Project : One Pot Synthesis of Some Nitrogen

Containing Heterocycles and Their

Biological Activities

5. Effective date of starting the Project: 05-06-2014

6. a. Period of Expenditure : From 05-06-2014 to 04-06-2016

b. Details of Expenditure

Sr.

No.

Item Amount

Approved in Rs.

Expenditure

Incurred in Rs.

i Books and Journals 20000 20021

ii Equipment 100000 100079

iii Contingency 40000 40090

iv Field Work / Travel 20000 20125

v Special Need (Hiring Services,

Spectra analysis)

50000 52347

vi Chemicals and Glassware 100000 100683

Total 330000 333345


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7. If as a result of check or audit objection some irregularly is noticed at later date,

action will be taken to refund, adjust or regularize the objected amounts.

8. It is certified that the grant of Rs. 3,30,000/- (Rupees Three lakh, thirty

thousands only) sanctioned from the University Grants Commission under the

scheme of support for Minor Research Project entitled “One Pot Synthesis of Some

Nitrogen Containing Heterocycles and Their Biological Activities” vide UGC

letter File No. 47-616 / 13 (WRO), dated 19 March 2014 has been fully utilized for

the purpose for which it was sanctioned and in accordance with the terms and

conditions laid down by the University grant Commission.

Principal Investigator PRINCIPAL


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Annexure – IV (Final)




STATEMENT OF EXPENDITURE INCURRED ON FIELD WORK

Name of the Principal Investigator: Mr. D. K. Jamale

Certified that the above expenditure is in accordance with the UGC norms for Minor

Research Projects.

SIGNATURE OF PRINCIPAL INVESTIGATOR PRINCIPAL

Name of The Place Visited Duration of The Visit Mode of

Journey

Expenditure

Incurred (Rs.)

Shivaji University, Kolhapur 07 to 08 June 2014 Bus 800

Solapur University, Solapur 13 June 2014 Bus 250

Shivaji University, Kolhapur 17 to 18 June 2014 Train 951

Shivaji University, Kolhapur 26-27 Oct. 2014 Bus 800

Solapur University, Solapur 03 Nov. 2014 Bus 300

Shivaji University, Kolhapur 06-09 Nov. 2014 Bus 900

Shivaji University, Kolhapur 16-17 Jan. 2015 Bus 800

Shivaji University, Kolhapur 30-31 Jan. 2015 Bus 850

Solapur University, Solapur 31 March 2015 Bus 250

Shivaji University, Kolhapur 04-05 May 2015 Bus 850





Shivaji University, Kolhapur 09 July 2015 Train 1024

Shivaji University, Kolhapur 10 June 2015 Car 3500

Solapur University, Solapur 30 Oct 2015 Car 1550

Shivaji University, Kolhapur 07 May 2016 Car 3500

Solapur University, Solapur 28 May 2016 Car 1550

Total 20125


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Annexure – V

(Final)




Utilization certificate

Certified that, the grant of Rs. 3,30,000/- (Rupees Three Lakh Thirty

Thousands only) sanctioned from the University Grants Commission under the

scheme of support for Minor Research Project entitled “One Pot Synthesis of

Some Nitrogen Containing Heterocycles and Their Biological Activities”

vide UGC Letter 47-616/13(WRO), dated 19 March 2014 has been fully utilized

for the purpose for which it was sanctioned and in accordance with the terms

and conditions laid down by the University Grants Commission.

PRINCIPAL INVESTIGATOR PRINCIPAL STATUTORY AUDITOR


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NEW DELHI-110002

(Utilization of Grant within Tenure)

CERTIFICATE

It certified that the grant of Rs.3,30,000/- (Rupees Three Lakh Thirty

Thousands only) sanctioned from the University Grants Commission under the

scheme of support of Minor Research Project entitled “One Pot Synthesis of

Some Nitrogen Containing Heterocycles and Their Biological Activities”

vide UGC letter No. 47-616/13(WRO), dated 19 March 2014, has been

utilized within the period 05-06-2014 to 04-06-2016 of minor research project.

Principal


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NEW DELHI-110002

ACCESSION CERTIFICATE

Minor Research Project: Books and journals

It is certified that the grant of Rs. 20021/- (Rupees Twenty thousand

twenty one only) sanctioned to Mr. D. K. Jamale by University Grants

Commission vide its sanction letter No. 47-616/13(WRO), dated 19 March

2014 has been utilized for the purpose of books and journals and the same have

been accessioned and noted in the accession register from accession No. 9591

to 9612 being maintained by the college. The last accession number prior to the

utilization of these grants for books purchased from UGC was 9590.

Principal Investigator Librarian Principal


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NEW DELHI-110002

ASSETES CERTIFICATE FOR EQUIPMENT

(Minor Research Project)

It is certified that inventories of permanent or semi permanent assets

created / acquired wholly or substantially out of the grants given by the

University Grants Commission vide UGC letter No. 47-616/13(WRO), dated

19 March 2014 for purchase of equipments are being maintained in the

prescribed form and are being kept up to date and the equipment are registered

in the Accession Page No’s 03-05 of Department of Chemistry, Shri Shivaji

Mahavidyalaya Barshi.

Principal Investigator Head of the Department Principal


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NEW DELHI-110002

CERTIFICATE

(Project Report, papers etc. uploading on college website)

It certified that the executive summary of the report, research documents,

monograph, academic papers published under Minor Research Project entitled

“One Pot Synthesis of Some Nitrogen Containing Heterocycles and Their

Biological Activities” funded by University Grants Commission (WRO) Pune

to Mr. D. K. Jamale, Department of Chemistry are uploaded on the College

Website www.ssmbarshi.org.

Principal

http://www.ssmbarshi.org/


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Annexure –VI

Final



NEW DELHI – 110 002.

Final Report of the work done on the Minor Research Project

(Report to be submitted within 6 weeks after completion of each year)

1. Project Report No. 1st / Final : Final

2. UGC Reference No. F. : 47-616 / 13 (WRO), dated 19 March 2014

3. Period of report : from 05-06-2014 to 04-06-2015

4. Title of research project :One pot Synthesis of Some Nitrogen Containing

Heterocycles and Their Biological Activities

5. (a) Name of the Principal Investigator : Mr. D. K. Jamale

(b) Department : Chemistry

(c) College where work has progressed: Shri Shivaji Mahavidyalaya Barshi

6. Effective date of starting of the project : 05-06-2014

7. Grant approved and expenditure incurred during the period of the report:

(a) Total amount approved Rs. : 3,30,000/-

(b) Total expenditure Rs. : 3,33,345/-

(c) Report of the work done : Separate sheet is attached (Appendix–I)

i. Brief objective of the project :

1) To synthesize some nitrogen containing heterocycles like pyridine, pyrimidine,

quinoline or isoquinoline in one pot and by multi-component reactions. The main

objective is ecofriendly synthesis of nitrogen containing heterocycles.


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2) To analyze synthesized compound by spectral analysis like 1H NMR, 13C NMR, IR,

and Mass.

3) To study their biological activities.

ii. Work done so far and results achieved and publications, if any, resulting from the

work (Give details of the papers and names of the journals in which it has been

published or accepted for publication) : The work done will be communicated to

International Journal before completion of project.

iii. Has the progress been according to original plan of work and towards achieving

the objective. if not, state reasons : Yes

iv. Please enclose a summary of the findings of the study. One bound copy of the final

report of work done may also be sent to the concerned Regional Office of the UGC :

N/A

v. Any other information : N/A

SIGNATURE OF THE PRINCIPAL INVESTIGATOR PRINCIPAL


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Appendix – I

Final

Final Report of the Work Done

(First & Second Years)

Project Title: One Pot Synthesis of Some Nitrogen Containing Heterocycles and

Their Biological Activities

First Years:

1) In the first phase, reference work and literature survey on nitrogen containing

heterocycles and their synthesis is done. Chemicals, glass wares and equipments for

project work are purchased.

2) In the first scheme of research work [1,8] –naphthapyridine 3-carbonitrile and their

derivatives were synthesized. It is highly efficient one pot synthesis of [1,8] –

naphthapyridine 3-carbonitrile through three component condensation of aldehyde,

malnonitrile and 2-amino pyridine catalyzed by DAHP (Diammonium hydrogen

phosphate) in aqueous medium at 850C.

3) To increase the scope and versatility of this method, various solvents and catalysts

were investigated. The good yield is obtained in aqueous medium (10 ml H2O +

C2H5OH) catalyzed by DAHP at reflux condition.

CHO

R

+CN

CN NNH2

+

N NH

CN

NH2

R

Water (10 ml) + Ethyl alcohol (5 ml)

DAHP, 850c

4) General Procedure for Preparation of [1,8] –naphthapyridine 3-carbonitrile: A

mixture of aromatic aldehyde (1 mmole), malononitrile (1.2 mmole) and 2-amino


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pyridine(1 mmole) and diammonium hydrogen phosphate (13.2 mg, 10 mol %) in

H2O (10 ml) and C2H5OH (5 ml) are stirred at reflux for 2 hours. The progress of

reaction was monitored by TLC.

5) The synthesized compounds were characterized by spectral analysis.

Second Years:

1) In the second scheme of research work 6-amino-4-(2,4-dichlorophenyl)-3-methyl-

1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives were

synthesized. It is highly efficient one pot synthesis of 6-amino-4-(2,4-dichlorophenyl)-

3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile through

three component condensation of aldehyde, malnonitrile and 3-methyl-1-phenyl-1H-

pyrazol-5-amine in aqueous medium using L-hydroxy proline at room temperature.

2) The reaction in aqueous ethanol (6 mL Ethanol and 4 mL water) using 20 mol % L-

hydroxy proline at ambient temperature was selected as the optimal conditions.

3) General experimental procedure: A mixture of aromatic aldehyde (1 mmol),

malononitrile (1 mmo1), 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol) and L-

hydroxy proline (20 mole %) in 6 mL ethanol and 4 mL water at room temperature

was stirred for the time specified in Table 2. Reaction was monitored by TLC (ethyl

acetate / petroleum ether – 1:1). After completion of the reaction, reaction mixture

was poured into ice cold water; precipitated product was separated by filtration and

washed with excess of water. The solid obtained was dried and recrystallized from 95

% ethanol to afford pure product.


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N

N

CH3

Ph

NH

NH2

CN

R

NN

CH3

Ph

NH2

CHO

R + +

CN

CN

L- hydroxy proline, R.T.

Ethanol (6 ml) + water (4 ml)

1 2 3 4

Scheme: Synthesis of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives

SIGNATURE OF THE PRINCIPAL INVESTIGATOR PRINCIPAL


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Annexure – VII

Final




PROFORMA FOR SUBMISSION OF INFORMATION AT THE TIME OF SENDING

THE FINAL REPORT OF THE WORK DONE ON THE PROJECT

1. Title of the Project: “One-pot Synthesis of Some Nitrogen Containing

Heterocycles and Their Biological Activities”

2. NAME AND ADDRESS OF THE PRINCIPAL INVESTIGATOR: Mr. D. K. Jamale

Department of Chemistry, Shri Shivaji Mahavidyalaya Barshi

3. NAME AND ADDRESS OF THE INSTITUTION: Shri Shivaji Mahavidyalaya Barshi

Dist: Solapur 413411.

4. UGC APPROVAL LETTER NO. & DATE: 47-616/13(WRO), dated: 19 March 2014

5. DATE OF IMPLEMENTATION: 05/06/2014

6. TENURE OF THE PROJECT: Two years (05/06/2014 to 04/06/2016)

7. TOTAL GRANT ALLOCATED : 3,30,000/-

8. TOTAL GRANT RECEIVED: 2,25,000/-

9. FINAL EXPENDITURE : 3,33,345/-

10. TITLE OF THE PROJECT: “One-pot Synthesis of Some Nitrogen Containing

Heterocycles and Their Biological Activities”

11. OBJECTIVES OF THE PROJECT :

a) To synthesize some nitrogen containing heterocyclic compounds through one

pot and by multi-component reactions.


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b) To propose the structure these synthesized N-based heterocycles by spectral

analysis.

c) The main objective is ecofriendly synthesis of nitrogen containing heterocycles

and to study their biological activities.

12. WHETHER OBJECTIVES WERE ACHIEVED (GIVE DETAILS):

a) Some nitrogen containing heterocyclic compounds were synthesized through

one pot and by multi-component reactions.

b) The structures of synthesized N-based heterocycles are characterized by

spectral analysis like 1H NMR, 13C NMR and FT-IR.

c) The present protocol is ecofriendly and the biological activities of synthesized

compounds were studied.

13. ACHIEVEMENTS FROM THE PROJECT

a) Synthesis of Nitrogen containing heterocycles.

b) Characterizations of these compounds by spectral analysis.

c) Development of eco-friendly and green protocol.

14. SUMMARY OF THE FINDINGS ( IN 500 WORDS ):

Nitrogen-containing heterocycles are mostly widespread in nature. These are

structural constituents of many bioactive natural products such as alkaloids,

glycosides, vitamins, hormones, antibiotics and many more compounds which are of

consequence for human and animal health [2]. The nitrogen heterocycle like

pyrimidine is an integral part of genetic materials such as DNA and RNA. A large

number of natural drugs such as atropine, quinine, emetine, codeine, morphine, and


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reserpine include N-based heterocycles [3-4]. Therefore, N-containing heterocyclic

scaffolds are predominantly considered as privilege structures for development of new

drugs [5-6]. Traditional methods of organic synthesis are orders of magnitude too

slow to satisfy the demand for these compounds [12-13]. Thus, the considerable drug

activity of these compounds not only attracted many chemists to synthesize these

heterocyclic compounds but also became an active research area.

In first phase of research [1,8] –naphthapyridine 3-carbonitrile and their

derivatives were synthesized. It is highly efficient one pot synthesis of [1,8] –

naphthapyridine 3-carbonitrile through three component condensation of aldehyde,

malnonitrile and 2-amino pyridine catalyzed by DAHP (Diammonium hydrogen

phosphate) in aqueous medium at 850C. All reactions were successfully performed to

afford a series of 2-amino-4-phenyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile

derivatives with high to excellent yields. The structures of products 4 were assigned

by their FTIR, 1H NMR, HRMS spectroscopy and elemental analysis. This spectral

data is in agreement with their proposed structures. In conclusion, we have developed

convenient and efficient procedure for the synthesis of 2-amino-4-phenyl-1,4-dihydro-

1,8-naphthyridine-3-carbonitrile 4 scaffolds using DAHP as a green catalyst in aqueous

ethanol. The methodology offers several advantages such as aqueous media, simple

operation and excellent yields.

As part of our ongoing agenda to develop highly efficient and environmentally

benign synthetic protocol [18-19, 32-36], herein we report a green procedure for the

synthesis of 6-amino-3-methyl-1,4-diphenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-

5-carbonitrile derivatives catalyzed by L-hydroxy proline in aqueous media at ambient


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temperature (Scheme 1). To the best of our information, there is no statement on the

synthesis of 6-amino-4-(4-methoxyphenyl)-1,3-diphenyl-4,7-dihydro-1Hpyrazolo[3,4-

b]pyridine-5-carbnitriles via one-pot multicomponent reaction of aldehyde,

nalononitrile and 3-methyl-1-phenyl-1H-pyrazol-5-amine, which could be defeated by

our green protocol for the synthesis of desired product. The structures of products

were assigned by their FTIR, 1H NMR, 13C NMR, HRMS spectroscopy and elemental

analysis. This spectral data is in agreement with their proposed structures. The 1H

NMR of product in DMSO-d6 has singlet at δ 1.76 ppm due to CH3 group, singlet at δ

5.56 ppm due to NH2, and signals at δ 7.28-7.78 ppm are due to aromatic protons.

Surprisingly, the NH proton appears as doublet at δ 5.81-5.84 ppm (J=12 Hz) and

benzylic proton appears as doublet at δ 5.22-5.25 ppm (J=12 Hz) which probably due

coupling of these two protons. Further, signal of NH proton was confirmed by D2O

exchange 1H NMR of one sample. We have developed a simple, efficient and green

procedure for the synthesis of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives via

one-pot multi-component reaction of aldehyde, nalononitrile and 3-methyl-1-phenyl-

1H-pyrazol-5-amine using L-hydroxy proline as a catalyst. A variety of these

compounds were synthesized in aqueous media at ambient temperature with good to

excellent yields.

15. CONTRIBUTION TO THE SOCIETY (GIVE DETAILS)

Nitrogen containing heterocycles are having great deal of interest because they are

widely found in many bioactive natural products and are found in many

pharmaceutical agents such as antibacterial, analgesic, anti-inflammatory, anticancer,

antioxidant, antidiabetic, hypnotic, anxiolytic and protein kinase inhibitor. Taking into


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account of these reports, expansion of new methodologies for the synthesis of N-based

scaffold is a appealing and advantageous defy.

Scheme-I: We have developed convenient and efficient procedure for the synthesis of

2-amino-4-phenyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile 4 scaffolds using DAHP as

a green catalyst in aqueous ethanol. The methodology offers several advantages such

as aqueous media, simple operation and excellent yields.

Scheme-II: We have developed a simple, efficient and green procedure for the

synthesis of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives via one-pot multi-

component reaction of aldehyde, nalononitrile and 3-methyl-1-phenyl-1H-pyrazol-5-

amine using L-hydroxy proline as a catalyst.

Advantages: A variety of these compounds were synthesized in aqueous media at

ambient temperature with good to excellent yields. The significant qualities of this

methodology are mild reaction conditions, use of environmentally begin catalyst,

excellent yields, easy workup and no need of chromatographic separation, which

makes it an appropriate route.

Other applications: Green chemistry, Medicinal chemistry, Analytical chemistry

16. WHETHER ANY PH.D. ENROLLED / PRODUCED OUT OF THE PROJECT: No

17. NO. OF PUBLICATIONS OUT OF THE PROJECT: Two (Separate sheet is attached)

(PRINCIPAL INVESTIGATOR) (PRINCIPAL)

(Seal)


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Chapter I

General Introduction and

Literature Survey


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Heterocyclic chemistry is one of the most extensively explored branches of

organic chemistry. The heterocyclic compounds include one or more hetero atom as a

part of ring. These hetero atoms are usually nitrogen, oxygen or sulphur. Many of

these heterocycles are abundantly occurring in nature. They are commonly found in

biologically active natural products like alkaloids, vitamins, hormones and hormones.

They are major constituent of in nucleotide constituting DNA, RNA, haemoglobin and

chlorophyll. Heterocyclic compounds have major allegations in various fields such as

material science, biochemistry, pharmaceuticals and medicinal chemistry. Most of

these heterocycles are either biosynthesized by plants or animals or synthesized in

laboratory. Among the heterocycles, N-based heterocycles have been the point of

significant hub, because N-containing heterocycles are structural components of

natural products and many more compounds which are of significance for human and

animal health [1]. Some of the important basic N-containing heterocyclic rings are as

follows (Scheme 1.1).

N

NH

1H-pyrrole

NNH

1H-pyrazole

NH

N

1H-imidazole

NH

pyrrolidine

NN

pyridazine

N

N N

N

N

pyrimidine 1,3,5-triazine

NN

quinoline isoquinoline

N N

1,8-naphthyridine

pyridine

NH

piperidine

Scheme 1.1


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Nitrogen-containing heterocycles are mostly widespread in nature. These are

structural constituents of many bioactive natural products such as alkaloids,

glycosides, vitamins, hormones, antibiotics and many more compounds which are of

consequence for human and animal health [2]. A large number of natural drugs such

as atropine, quinine, emetine, codeine, morphine, and reserpine include N-based

heterocycles [3-4]. Therefore, N-containing heterocyclic scaffolds are predominantly

considered as privilege structures for development of new drugs [5-6]. Moreover,

many of the nitrogen containing heterocyclic compounds possess a wide range of

biological and pharmacological activities [7-9] such as analgesic, antipyretic, antiviral,

anticancer, anti-inflammatory, diuretic, antihistamine, antidepressant, anti-tubercular,

antifungal and hypertensive etc. Many natural drugs such as quinine, atropine,

morphine, and reserpine are N containing heterocycles [10-11] (Scheme 1.2).

N

H3CO

OHN

CH2

Quinine

O

OHO

N

CH3

Atropine

O

OH

OH

H H

NCH3

ReserpineMorphine

H3CO OCH3NNH

H3CO

OCH3

H3COOC O O

OCH3

Scheme 1.2


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Traditional methods of organic synthesis are orders of magnitude too slow to

satisfy the demand for these compounds [12-13]. Thus, the considerable drug activity

of these compounds not only attracted many chemists to synthesize these heterocyclic

compounds but also became an active research area.

Now a day, green chemistry has become a focus of intensive research

and is widely accepted to protect the human health and environment [15]. Taking into

account of this green chemistry approach, the development of environment caring

organic synthesis has become a demanding and interesting area in synthetic organic

chemistry. One-pot multicomponent reactions (MCRs) are proved to be very efficient

and potent tool in synthetic chemistry [16]. In contrast to conventional multistep

synthetic protocol, MCRs have publicized to afford efficient construction of complex

products in a single step with high atom economy, simplistic implementation,

selectivity and environmental greenness [17]. Moreover, these reactions have come

into view as a crucial tool in synthesis of many biologically active N-based

heterocyclic scaffolds. Owing to the numerous advantages, a significant effort has

been devoted to the improvement of MCRs. Recently our research group extended

one-pot MCRs for the synthesis of 4-hydroxy-2-methyl-6-(phenyl)pyrimidine-5-

carbonitrile derivatives as potent anti-inflammatory agents [18] and uncatalyzed

synthesis of pyrazolopyranopyrimidine scaffolds [19]. Furthermore, in consequence of

this green approach, the use hazardous organic solvents should be diminished. One of

the most outstanding tools is using water as a reaction media. Water is non-toxic,

harmless, environmentally benign and cheap [20]. In green synthetic protocol, the use

of aqueous medium reveals remarkable assistance to environment [20]. Thus there is


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need to avoid the use of harmful organic solvents and develop multicomponent

reactions in aqueous media. From the literature survey, it was found that several

methods are available for synthesis of N-based heterocycles, but herein we report

some of the distinguished methods.

Skraup synthesis:

In 1880, Skraup discovered the synthesis of quinoline. In Skraup synthesis aniline

when heated with conc. H2SO4, glycerol and nitrobenzene to afford corresponding

quinoline[21].

Knorr synthesis:

This synthetic protocol is very widely used for the preparation of quinoline

derivatives. The Knorr quinoline synthesis is a type of intramolecular organic reaction

converting a β-ketanilide to afford 2-hydroxy quinoline in presence of sulfuric acid as

catalyst [22].

Doebner- Miller synthesis:In this reaction α,β-unsaturated carbonyl compound is

prepared in situ from two carbonyl compounds (via an Aldol condensation and to

afford quinoline derivatives. [23].

NNH2

OH

OH

OH+Conc. H2SO4

Nitrobenzene

Scheme 1.3

H2SO4

NH O

CH3

O

NH

CH3

O

Scheme 1.4


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Hantzsch Pyridine Synthesis:

The condensation of an aldehyde with two equivalents of a β-ketoester in the presence

of ammonia to form dihydropyridine derivative is Hantzsch synthesis (Scheme 1.6).

Friedlaender Synthesis:

The starting materials for this quinoline synthesis are o-amino aryl aldehydes or

ketones and a ketone possessing an α-methylene group. After an initial amino-ketone

condensation, the intermediate undergoes base- or acid-catalyzed cyclocondensation

to produce a quinoline derivative (Scheme 1.7).

NH2R H

O

N R

+

Scheme 1.5

R CHO R1

OR2

OO

2+ + NH3

NH

R1

R1

COOR2

COOR2

R

Scheme 1.6

R1

R2

O

NH2

+ R3

R4

O N

R1

R2

R3

R4

Scheme 1.7


Page | 36

References

1. Balaban AT, Oniciu DC, Katritzky AR. Aromaticity as a Cornerstone of Heterocyclic

Chemistry. Chem. Rev. 2004, 104, 2777–2812.

2. Balaban AT, Oniciu DC, Katritzky AR. Aromaticity as a Cornerstone of Heterocyclic

Chemistry. Chem. Rev. 2004;104:2777–2812.

3. Bacolini G. Topics Heterocycl. Syst. Synth. React. Prop. 1996;1:103.

4. Brichacek M, Njardarson JT. Creative approaches towards the synthesis of 2,5-

dihydro- furans, thiophenes, and pyrroles. One method does not fit all. Org. Biomol.

Chem.m 2009;7:1761–1770.

5. Sheldon RA. Catalysis: the key to waste minimization. J. Chem. Technol. Biotechnol.

1997;68:381–388.

6. Dabholkar VV, Ansari FY. Novel pyrimidine derivatives by sonication and traditional

thermal methods. Green Chem. Lett. Rev. 2010;3:245–248.

7. F. J. Dian and T. J. Bardos, J. Med. Chem.1980, 23, 569.

8. C. C. Cheng, Prog. Med.Chem. 1969, 6. 67-75.

9. L. Garuti, M. Roberti, D. Pizzirani, Mini-rev. Med. Chem. 2007, 7, 481-489.

10. Bacolini G. Topics Heterocycl. Syst. Synth. React. Prop. 1996;1:103.

11. Brichacek M, Njardarson JT. Creative approaches towards the synthesis of 2,5-

dihydro- furans, thiophenes, and pyrroles. One method does not fit all.Org.

Biomol. Chem. 2009, 7, 1761–1770.

12. Ballini R, editor. Eco-friendly synthesis of fine chemicals. UK: Royal Society

of Chemistry; 2009. p. 275–292.


Page | 37

13. Santagada V, Perissutti E, Caliendo G. The application of microwave

irradiation as new convenient synthetic procedure in drug discovery. Curr.

Med. Chem. 2002, 9, 1251–1283.

14. a) P. Singh, M. A. Quraishi, S. L. Gupta, A. Dandia, Journal of Taibah

University for Science, 10, 2016, 139-147. b) A. Dandia, S. L. Gupta, P.

Singh, and M. A. Quraishi, Ultrasound-Assisted Synthesis of

Pyrazolo[3,4-b]pyridines as Potential Corrosion Inhibitors for Mild Steel

in 1.0 M HCl, ACS Sustainable Chem. Eng. 2013, 1, 1303−1310.

15. a) P. T. Anastasa, E. S. Beacha. Green chemistry: the emergence of a

transformative framework. Green Chem. Lett. Rev. 2007, 19–24. b) A. R.

Katritzky, C. W. Rees, Comprehensive heterocyclic chemistry. New York:

Pergamon Press; 1984 (Vols.1–8). c) M. Phukan, K. J. Borah, R. Borah, Henry

reaction in environmentally benign methods using imidazole as catalyst. Green

Chem. Lett. Rev. 2009;2:249–253.

16. a) B. Ganem, Acc Chem Res 2009, 42, 463. b) H. Yoshida, H.Fukushima,

J. Ohshita, A. Kunai, J. Am. Chem. Soc. 2006, 128, 11040-11041.

17. a) J. Zhu, H. Bienayme, Multicomponent Reactions, Wiley-VCH,

Weinheim, 2005. b) G. Vasuki, K. Kumaravel, Tetrahedron Lett. 2008,

49, 5636-5638.

18. S. S. Undare, N. J. Valekar, A. A. Patravale, D. K. Jamale, S. S. Vibhute,

L.S. Walekar, G. B. Kolekar, M. B. Deshmukh, P. V. Anbhule, One-pot

synthesis and in vivo biological evaluation of new pyrimidine privileged

scaffolds as potent anti-inflammatory agents, Res Chem Intermed, 2015,


Page | 38

19. K.T. Patil, D. K. Jamale, N. J. Valekar, P. T. Patil, P. P. Warekar, G. B.

Kolekar & P. V. Anbhule, Uncatalyzed four-component synthesis of

pyrazolo pyrano pyrimidine derivatives and their antituberculosis

activities, 2016,

20. a) C. J. Li, Organic reactions in aqueous media-with focus on carbon

carbon bond formation Chem. Rev. 1993, 93, 2023. b) Q. Zhang, B. Liu,

W. Chen, Q. Wu, X. Lin, A green protocol for synthesis of benzo-fused

N,S-,N,O- and N,N-heterocycles in water, green Chem, 2008, 10, 972-977.

21. Z. H. Skraup, Berichte, 1880,13, 2086 (Scheme 3.1).

22. L. Knorr, Justus LiebigsAnnalan der Chemie, 1886, 236, 69-115 (Scheme 3.2).

23. O. Doebner, W. Miller, Ber.188114, 2812 (Scheme 3.5).


Page | 39

Chapter II

Highly Efficient One-pot Synthesis of

[1,8] –Naphthapyridine 3-carbonitrile

using DAHP


Page | 40

2.1 Introduction

Nitrogen containing heterocyclic compounds found very extensively in nature and are

necessary to life. Among the N-based heterocycles, pyridine is one of the most

important scaffolds constitute the largest portion of chemical articles, which are part

of many natural products, biologically active compounds and fine chemicals [1-2].

Naphthyridine derivatives are one of the most significant classes of compounds due to

their widespread occurrence as key structural subunits in numerous natural products

that exhibit many interesting biological activities. The 1,8-naphthyridine derivatives

posses a prominent place in the field of medicinal chemistry [3], as the presence of

two nitrogen atom in the aromatic ring make appropriate linkage sites through

hydrogen bonding with microbes. In medicinal chemistry field, many 1,8-

naphthyridines are used as antibacterial [4], anti-inflammatory [5], antihypertensive

[6] and anticancer activities [7]. Furthermore, from literature survey, it was noticed

that, some biologically active natural product such as Nalidixic acid 1 [8], vosaroxin 2

[9] (diethylamino) ethyl oximes 3 [10], and gemifloxacin 4 [11].

N N

O

COOH

CH3

CH31

H3CHN

N N

O

COOH

N

N S

H3CO

2

N NH

N

COOH

R1

R2

O

N

CH3

CH3

3

NOCH 3

N N

O

COOH

N

NH2

F

4


Page | 41

2.2 Methods of synthesis for 1,8-naphthyridine derivatives

This chapter is mainly paying attention on the synthesis of 1,8-naphthyridine

derivatives. From the wide-ranging literature survey, herein we report some of the

methods of synthesis of 1,8-naphthyridines.

Bolhofer et al. [12] developed preparations of 7-phenyl-1,8-naphthyridin-2-

amine, by reacting 2,6-Pyridinediamine with phenylpropanedial in presence of 85 %

H3PO3 at 95 ° C to afford 59 % yield (Scheme 2.1).

Koller et al. [13] has reported the synthesis of 7-ethyl-1,8-naphthyridin-2-amine by

reaction of 2,6-Pyridinediamine with 1,1-dimethoxybutan-2-one (Scheme 2.2).

Mohamed et al. [14] have synthesized some 4-hydroxy-1,8-naphthyridin-2(1H)-one

derivatives. The reaction of 2-amino pyridine with diethyl malonate occurs at high

temperature to yields desired product (Scheme 2.3).

Ph

CHO

CHO

N NH2NH2

+ 85 % H3PO4

95 °CN N NH2

Ph

Scheme 2.1

N NH2NH2

+OMeMeO

OEt N N NH2Et

Scheme 2.2

N NH2

+

COOEt

COOEt N NH

O

OH

Scheme 2.3


Page | 42

Synthesis of series of 2-phenyl-1,8-naphthyridine-4-carboxylic acid derivatives by the

reaction of benzaldehyde, 2-amino pyridine and pyruvic acid in ethanol at reflux

condition has been developed by Mazza et al.[15] (Scheme 2.4).

Hese et al. [16] have suggested a protocol for the synthesis of pyrido[1,2-

a]pyrimidine3-carbonitrile by the reaction of substituted aromatic aldehydes 2-

aminopyridine and malononitrile using a catalytic amount of Bleaching earth clay (pH

12.5) at 70-80°C for 30-40 minutes in PEG-400 (Scheme 2.5).

Yaqub et al. [17] developed one-pot and facile preparations of highly functionalized

novel 1,8-Naphthyridine derivatives from substituted 2-aminopyridines, aldehydes

and malononitrile. In this protocol Substituted aldehydes and malononitrile were

refluxed in THF followed by the addition of 2-aminopyridine to obtain highly

functionalized novel 1-8-naphthyridine in good to excellent yields (Scheme 2.6).

N NH2

+

COOH

CH3

O

CHO

+

COOH

N N PhEthanol

Scheme 2.4

CHO

N NH2

CN

CN

+ +Bleaching earth clay (pH 12.5)

PEG-400, 70-80°C

N

N

NH2

CN

Scheme 2.5


Page | 43

Naik et al. [18] has reported the multicomponent one-pot synthesis novel substituted

1,8-naphthyridines by reaction of substituted aromatic aldehydes, substituted 2-

aminopyridines, and malononitrile catalyzed by bismuth(III) nitrate pentahydrate

[Bi(NO3)3.5H2O] under solvent-free microwave irradiation (Scheme 2.7).

Despite, the potential utility of these strategies, they exhibit various drawbacks such as

harsh reaction conditions, use of toxic organic solvents, hazardous catalyst,

unsatisfactory yields & tedius experimental procedures. Therefore, development of

clean and efficient procedure for the synthesis of 1,8-naphthyridines is required.

2.2 Present work

All these literature facts attracted us to develop convenient, efficient and green

procedure for the synthesis of 1,8-naphthyridines. Qwing to this approach, in this

chapter, we have described highly efficient one-pot multicomponent and green

protocol for the synthesis of 2-amino-4-phenyl-1,4-dihydro-1,8-naphthyridine-3-

carbonitrile derivatives by reaction of aromatic aldehyde 1 malononitrile 2 and 2-

CHO

N NH2

R

CN

CN

+ +N N

CN

NH2

RTHF, Reflux

Scheme 2.6

CHO

R1N NH2

R2

CN

CN

+ +N N

CN

NH2

R2

R1

[Bi(NO3)3.5H2O]

MW, 160 W

Scheme 2.7


Page | 44

amino pyridine 3 using DAHP (Diammmonium hydrogen phosphate) in aqueous

ethanol (water 10 mL and ethanol 5 mL) at 85 °C (Scheme 2.8).

2.3 Results and discussion

In trial case, reaction of 4nitro benzaldehyde 1 (1 mmol) and malononitrile 2 (1 mmol)

in 10 mL water with 5 mol % DAHP (Diammmonium hydrogen phosphate) were

heated at 85 °C for 5 hour. The progress of the reaction was monitored by TLC. After

5 h heating, the product 4 was obtained in only 50 % yield along with intermediate

Knoevenagel condensate and unreacted starting materials (Table 1, entry 1). To

investigate ideal reaction condition, when we carried out the reaction in aqueous

ethanol (Water 10 mL & ethanol 5 mL) using DAHP (10 mol %), the desired product

2-amino-4-(4-nitrophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonitrile 4 was

achieved in high yield (92 %) after 2 h heating (Table 1, entry 2). For further study,

this reaction was examined at 85 °C in different solvents with different catalysts

resulted in trace or lower yields of 4 (Table 1). Also the reaction was not performed in

absence of catalyst even after prolonged reaction time (Table 1, entry 4). Accordingly,

the reaction in aqueous ethanol (Water 10 mL & ethanol 5 mL) using 20 mol %

DAHP at 85 °C temperature was selected as the optimal conditions (Table 1, entry 2).

CHO

R

+CN

CN N NH2

+

N NH

CN

NH2

R

Water (10 ml) + Ethyl alcohol (5 ml)

DAHP, 850c

1 2 34

Scheme 2.7


Page | 45

All reactions were successfully performed to afford a series of 2-amino-4-phenyl-1,4-

dihydro-1,8-naphthyridine-3-carbonitrile derivatives with high to excellent yields. The

structures of products 4 were assigned by their FTIR, 1H NMR, HRMS spectroscopy

and elemental analysis. This spectral data is in agreement with their proposed

structures.

Table 1 Solvent and catalyst optimization for the synthesis of 4 a

Entry Solvent Catalyst (mol %) Time (h) Yieldb (%)

1 Water DAHP (10) 5 50

2 Water 10 mL & ethanol 5 mL DAHP (10) 2 92

3 Ethanol DAHP (10) 3 90

4 Water 10 mL & ethanol 5 mL No catalyst 10 - c

5 Water 10 mL & ethanol 5 mL DABCO 5 66

6 Water 10 mL & ethanol 5 mL Acetic acid 6 60

7 Water 10 mL & ethanol 5 mL CuO

nanoparticles

5 35

8 Water 10 mL & ethanol 5 mL ZnO

nanoparticles

5 30

9 Water 10 mL & ethanol 5 mL K2CO3 6 trace

a Reactions of 4-nitrobenzaldehyde 1 (1 mmol), malononitrile 2 (1 mmol) and 2-

aminopyridine 3 (1 mmol) were carried out at 85 °C.

b Isolated yield, c Reaction failed to occur, Bold values indicate optimized reaction conditions.


Page | 46

Table 2 Synthesis of 2-amino-4-phenyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile

derivatives in aqueous media at room temperature a

Entry Aldehyde1 Product4 Time (h) Yield b (%)

1

NO2

CHO

N NH

CN

NH2

NO2

4a

2

92

2

Cl

CHO

N NH

CN

NH2

Cl

4b

2

91

3

CHO

N NH

CN

NH2

4c

2.5

90

4

CH3

CHO N N

H

CN

NH2

CH3

4d

2.5

89


Page | 47

2.4 Experimental Part

The progress of reaction was monitored by TLC on Merck TLC silica gel 60 F254

plates. All the chemicals used in this process are purchased from Alfa Aesar, Aldrich,

and Merck chemical companies and used without any purification. Melting points

were determined by open capillary tubes and are uncorrected. 1H NMR spectra were

recorded on 400 MHz Bruker spectrometer using DMSO-d6 solvent. FT-IR spectra

were determined on Thermo Fisher Scientific Nicolet iS-10 FT-IR Spectrometer.

Mass spectra were obtained on Shimadzu Toshvin mass spectrometer.

2.5 General experimental procedure for the synthesis of 2-amino-4-phenyl-1,4-

dihydro-1,8-naphthyridine-3-carbonitrile derivatives

A mixture of 4-nitrobenzaldehyde 1 (1 mmol) and malononitrile 2 (1 mmol)), 2-

aminopyridine 3 (1 mmol) and 10 mole % DAHP in 10 mL water & 5 mL ethanol

were heated in a round bottom at 85 °C for for the time specified in Table 2 . Reaction

was monitored by TLC. The reaction mixture was cooled, precipitate obtained was then

filtered, washed with cold water and finally product was recrystallized from ethanol to

afford pure product 4.

5

OCH3

CHO N N

H

CN

NH2

OCH3

4e

2.5

88

a Reactions of aldehyde 1 (1 mmol), malononitrile 2 (1 mmol) and 2-aminopyridine 3 (1

mmol) were carried out in aqueous ethanol using DAHP at 85 °C.

b Isolated yield


Page | 48

2.6 Spectral data of the synthesized compounds

2-amino-4-(4-nitrophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonitrile(4a):

Brown solid, Yield: 92 %, 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 6.71 (s, J=12 MHz,

1H, CH), 6.90 (d, 1H, NH), 7.55 (s, 2H, NH2,), 7.69-7.76 (m, 4H, ArH), 8.18-8.23 (m, 3H,

ArH); IR (KBr): 3342, 3197, 3083, 2920, 2221, 1662, 1613, 1518, 1460, 1339, 1347, 844,

773, 702 cm-1; HRMS m/z (ESI) : 292.0837 [M-1]; Anal. Calcd for C15H11N5O2 (%): C

(61.43), H (3.78), N (23.88); Found: C (61.56), H (3.82), N (23.84).

2-amino-4-(4-chlorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonitrile (4b):

Brown solid, Yield: 91 %, 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 6.68 (s, J=12 MHz,

1H, CH), 6.90 (d, 1H, NH), 7.49 (s, 2H, NH2,), 7.51-8.19 (m, 7H, ArH); IR (KBr): 3349,

N NH

CN

NH2

NO2

4a

N NH

CN

NH2

Cl

4b


Page | 49

3190, 3081, 2920, 2231, 1652, 1616, 1534, 1468, 1354, 864, 779, 708 cm-1; HRMS m/z

(ESI) : 281.0543 [M-1]; Anal. Calcd for C15H11ClN4 (%): C (63.72), H (3.92), N (19.82);

Found: C (63.79), H (3.98), N (19.86).

2.7 Conclusion

In conclusion, we have developed convenient and efficient procedure for the synthesis

of 2-amino-4-phenyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile 4 scaffolds using DAHP

as a green catalyst in aqueous ethanol. The methodology offers several advantages

such as aqueous media, simple operation and excellent yields.


Page | 50

Table 2, Entry 1 (4a)



Page | 51



Page | 52

Table 2, Entry 2(4b)


Page | 53


Page | 54

2.8 References

1. Hung, H. J. A.; Leung, E.; Reynisson, J.; Barker, D. Eur. J. Med. Chem. 2014, 86, 420.

2. S. K. Srivastava, M. Jaggi, A. T. Singh, A. Madan, N. R. M. Vishnoi, S. K. Agarwal, R.

Mukherjeea and A. C. Burman, Bioorg. Med. Chem. Lett., 2007, 17, 6660-6664

3. L.-R. Wen, C.-Y. Jiang, M. Li and L.-J. Wang, Tetrahedron, 67, 293 (2011).

4. M.A. Seefeld, W.H. Miller, K.A. Newlander, W.J. Burgess, W.E. DeWolf, P.A.

Elkins, M.S. Head, D.R. Jakas, C.A. Janson, P.M. Keller, P.J. Manley, T.D.

Moore, D.J. Payne, S. Pearson, B.J. Polizzi, X. Qiu, S.F. Rittenhouse, I.N.

Uzinskas, N.G. Wallis and W.F. Huffman, J. Med. Chem., 46, 1627 (2003).

5. G. Grossi, M. Di Braccio, G. Roma, V. Ballabeni, M. Tognolini and E. Barocelli,

Eur. J. Med. Chem., 40, 155 (2005).

6. P.L. Ferrarini, C. Mori, V. Calderone, L. Calzolari, P. Nieri, G. Saccomanni and E.

Martinotti, Eur. J. Med. Chem., 34, 505 (1999).

7. S.K. Srivastava, M. Jaggi, A.T. Singh, A. Madan, N. Rani, M. Vishnoi, S.K.

Agarwal, R. Mukherjee and A.C. Burman, Bioorg. Med. Chem. Lett., 17, 6660

(2007).

8. S.K. Bouchillon, D.J. Hoban, J.L. Johnson, B.M. Johnson, D.L. Butler, K.A.

Saunders, L.A. Miller and J.A. Poupard, Int. J. Antimicrob. Agents, 23, 181 (2004).

9. Y.J. Hwang. Chung, E.C. Nam, W.T. Kim, J.B. Youm and C.H. Leem, Korean J.

Physiol. Pharmacol., 17, 537 (2013).

10. P.L. Ferrarini, C. Mori, M. Badawneh, V. Calderone, R. Greco, C. Manera, A.

Martinelli, P. Nieri and G. Saccomanni, Eur. J. Med. Chem., 35, 815 (2000).


Page | 55

11. P.L. Ferrarini, C. Mori, M. Badawneh, V. Calderone, R. Greco, C. Manera, A.

Martinelli, P. Nieri and G. Saccomanni, Eur. J. Med. Chem., 35, 815 (2000).

12. W. A. Bolhofer, J. M. Hoffman, C. N. Habecker, A. M. Pietruszkiewicz, E. J.

Craigoe, and M. L. Torchiana, J. Med. Chem., 1979, 22, 301.

13. G. Koller, Ber. Dtsch. Chem. Ges., 1927, 60, 407.

14. E. A. Mohamed, R.M. Abdel-Rahman, Z. El-Gendy, and M. M. Ismail, J. Indian

Chem. Soc., 1994, 71, 765.

15. F. P. Mazza and C. Migliardi, Atti Accad. Sci. Torino, Classe Sci. fis., Mat. Nat.,

1940, 75, 438; Chem. Abstr., 1942, 36, 5477.

16. S. V. Hese, R. D. Kamble, P. P. Mogle, S. S. Kadam, M. J. Hebade, A. N.

Ambhore and B. S. Dawane; Der Pharma Chemica, 2015, 7(4):249-256.

17. M. Yaqub, M. K. Naveed, M. T. Riaz, R. Perveen, J. Batool, N. Arif and M.

Yaseen; Asian Journal of Chemistry; Vol. 28, No. 1 (2016), 69-74.

18. Tangali R. Ravikumar Naik, Halehatty S. Bhojaya Naik; Mol Divers, 2008, 12; 139-142.


Page | 56

Chapter III

The development of a green protocol

for the synthesis of 4,7-dihydro-1H-

pyrazolo [3,4-b] pyridine derivatives


Page | 57

3.1 Introduction

Nitrogen containing heterocycles have established a great deal of interest because they

are widely found in many bioactive natural products [1] and are ubiquitous in many

pharmaceutical agents [2]. Among them, pyrazolo[3,4-b]pyridines, as condensed

heterocycles, are attractive compounds owing to their diverse pharmacological

properties such as antibacterial [3], analgesic [4], anti-inflammatory [5], anticancer [6-

7], antioxidant [7], antidiabetic [8], hypnotic [9], anxiolytic [10] and protein kinase

inhibitor [11]. For example, pyrazolo[3,4-b]pyridine derivatives (I) and (II) has been

used as anxiolytic drugs [12]. Likewise derivatives (III) and (IV) are protein kinase

inhibitors [13]. In addition to biological activities, some pyrazolo[3,4-b]pyridine

derivatives have been reported as corrosion inhibitor of mild steel [14].

N

N

N

CH3

NH

CH3

O

CH3

O

N

N

N

CH3

NH

CH3

O

CH3

O

CH3

Cartazolate (anxiolytic) Tracazolate (anxiolytic)

(I) (II)

CDK-2 inhibitor

(III)

N

N

NH

OO

CH3

GSK-3 inhibitor

(IV)

N

N

NH

OH

Br

NHO

Figure 1. Some drugs and bioactive compounds having pyrazolopyridine unit.


Page | 58

From the literature survey, it was found that several methods are available for

synthesis of pyrazolo[3,4-b]pyridines. The multicomponent synthesis of pyrazolo[3,4-

b]pyridine derivatives from aromatic aldehyde, active methylene compound or 1,3

diketone and substituted 5-amino 1H-pyrazole have been reported using acetic acid in

ethanol under reflux condition [21], in ionic liquid at 80 °C [22], in acetonitrile by

H2O2 mediated oxidation under reflux condition [23], under microwave irradiation

[24], in presence of sodium dodecylsulphate at 90 °C [25], in presence of CAN

catalyst [26] and using silica sulphuric acid catalyst under reflux conditions [27].

Furthermore, Park et al. [28] synthesized pyrazolearylpyrazole[3,4-b]pyridines from

substituted indole-3-carboxaldehyde and derivatives of aminopyrazoles. L-proline

catalyzed three-component method to synthesize highly functionalized pyrazolo[3,4-

b]pyridines under reflux condition has been developed by Gunasekaran et. al. [29].

Da-Quing et al. [30] have suggested a protocol for the synthesis of pyrazolo[3,4-

b]pyridines by the reaction of 5-aminopyrazole with benzylidenemalononitrile using

of sodium 1-dodecanesulfonic (SDS) in aqueous media. Recently, Eissa et. al. [31]

reported synthesis of 6-amino-4-(4-methoxyphenyl)-1,3-diphenyl-4,7-dihydro-

1Hpyrazolo [3,4-b]pyridine-5-carbnitrile by the reaction of aldehyde, malononitrile, 3-

phenyl-1H-pyrazol -5(4H)-one and ammonium acetate under reflux for 3-5 hours.

Most of these protocols have their own merits, but also suffers with some drawbacks

such as use of harmful solvent, poor yield, long reaction time, drastic reaction

conditions, use of expensive catalyst and tedious workup. Therefore, there is a need of

a simple, efficient, facile and eco-friendly synthetic protocol associated with mild

conditions and excellent yields at room temperature. As part of our ongoing agenda to


Page | 59

develop highly efficient and environmentally benign synthetic protocol [18-19, 32-

36], herein we report a green procedure for the synthesis of 6-amino-3-methyl-1,4-

diphenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives catalyzed

by L-hydroxy proline in aqueous media at ambient temperature (Scheme 1).

3.2 Results and discussion

At the outset, we investigated the model reaction of 2,4-dichlorobenzaldehyde

1 (1 mmol), malononitrile 2 (1 mmol) and 3-methyl-1-phenyl-1H-pyrazol-5-amine 3

(1 mmol) in water using L-hydroxy proline (10 mol %) at room temperature. The

improvement of the reaction was monitored by TLC. After 10 h stirring, the product

4a was obtained in only 30 % yield along with unreacted starting materials (Table 1,

entry 1). To explore ideal reaction condition, when we carried out the reaction in

aqueous ethanol (6 mL Ethanol and 4 mL water) using L-hydroxy proline (10 mol %),

the desired product 6-amino-4-(2,4-dichlorophenyl)-3-methyl-1-phenyl-4,7-dihydro-

1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 4a was obtained in high yield (80 %) after

3 h stirring at room temperature (Table 1, entry 2). During additional optimization

study, it was examined that, the excellent yield (95 %) was obtained with 20 mol % L-

hydroxy proline in aqueous ethanol after 3 h stirring (Table 1, entry 5).

N

N

CH3

Ph

NH

NH2

CN

R

NN

CH3

Ph

NH2

CHO

R + +

CN

CN

L- hydroxy proline, R.T.

Ethanol (6 ml) + water (4 ml)

1 2 3 4

Scheme 1 Synthesis of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives


Page | 60

For further study, reaction was subjected to heating at 80 °C, which does not

make variation in yield of product 4a and also heating for 3 h not causes aromatization

of pyridine ring in product 4a (Table 1, entry 15). With a sight of further optimizing

conditions, this reaction was studied at ambient temperature in different solvents with

different catalysts resulted in trace or lower yields of 4a (Table 1). Moreover, the

reaction was not performed in absence of catalyst even after prolonged reaction time

(Table 1, entry 6).

Table 1 Solvent and catalyst optimization for the synthesis of 4a a

Entry Solvent Catalyst (mol %) Time (h) Yieldb (%)

1 Water L-hydroxy proline (10) 10 30

2 Ethanol (6 mL) + water (4 mL) L-hydroxy proline (10) 3 80

3 Ethanol L-hydroxy proline (10) 3 80

4 Acetonitrile L-hydroxy proline (10) 10 40

5 Ethanol (6 mL) + water (4 mL) L-hydroxy proline (20) 3 95

6 Ethanol (6 mL) + water (4 mL) No catalyst 10 - c

7 Ethanol (6 mL) + water (4 mL) L-proline (20) 3 90

8 Acetonitrile ZnO nanoparticles (10) 10 - c

9 Water ZnO nanoparticles (10) 10 - c

10 Ethanol ZnO nanoparticles (10) 10 30

11 Water Ammonium acetate (20) 10 trace

12 Ethanol Ammonium acetate (20) 10 50


Page | 61

13 Ethanol Glycine (20) 10 trace

14 Ethanol Antranilic acid (20) 10 trace

15d Ethanol (6 mL) + water (4 mL) L-hydroxy proline (20) 3 95

a Reactions of 2,4-dichlorobenzaldehyde 1 (1 mmol), malononitrile 2 (1 mmol) and 3-methyl-

1-phenyl-1H-pyrazol-5-amine 3 (1 mmol) were carried out at room temp. except entry 15.

b Isolated yield, c Reaction failed to occur, d Reaction was carried out at 80 °C.

Bold values indicate optimized reaction conditions.

Consequently, the reaction in aqueous ethanol (6 mL Ethanol and 4 mL water)

using 20 mol % L-hydroxy proline at ambient temperature was selected as the optimal

conditions (Table 1, entry 5). The scope of this protocol was explored under the above

optimal conditions by reacting variety of substituted aromatic aldehydes,

malononitrile and 3-methyl-1-phenyl-1H-pyrazol-5-amine for 1.5 to 7 h, resulting in a

series of 6-amino-3-methyl-1,4-diphenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-

carbonitrile derivatives 4 in 78-96 % yields (Table 2).

Table 2 Synthesis of 6-amino-3-methyl-1,4-diphenyl-4,7-dihydro-1H-pyrazolo[3,4-b]

pyridine-5-carbonitrile derivatives in aqueous media at room temperature a

Entry Aldehyde1 Product4 Time

(h)

Yield b

(%)

M.P.

( °C )

1

Cl

CHO

Cl

N

N

CH3

Ph

NH

NH2

CN

Cl

Cl

4a

3

95

178


Page | 62

2

Cl

CHO N

N

CH3

Ph

NH

NH2

CN

Cl

4b

2

96

176

3

Br

CHO N

N

CH3

Ph

NH

NH2

CN

Br

4c

3.5

92

166

4

CHO

NO2

N

N

CH3

Ph

NH

NH2

CN

NO2

4d

3.5

89

172

5

CHO N

N

CH3

Ph

NH

NH2

CN

4e

2.5

86

74

6

NO2

CHO N

N

CH3

Ph

NH

NH2

CN

NO2

4f

1.5

91

90


Page | 63

7

CHO

Cl

N

N

CH3

Ph

NH

NH2

CN

Cl

4g

2

92

96

8

Cl

CHO

Cl

N

N

CH3

Ph

NH

NH2

CN

Cl

Cl

4h

1.5

91

96

9

NO2

CHO N

N

CH3

Ph

NH

NH2

CN

NO2

4i

1.5

92

98

10

F

CHO N

N

CH3

Ph

NH

NH2

CN

F

4j

2.0

96

146

11

CH3

CHO N

N

CH3

Ph

NH

NH2

CN

CH3

4k

5

94

130


Page | 64

The slight influence of either electron withdrawing or donating substituent on

aromatic ring was observed which results in differentiation of yields and reaction

times. Furthermore, it was noticed that, ortho-substituted aldehydes were needed

12

CHO

Br

N

N

CH3

Ph

NH

NH2

CN

Br

4l

1.5

87

86

13

CHO

F

N

N

CH3

Ph

NH

NH2

CN

F

4m

1.5

92

86

14

OH

CHO

NH

N

N

CH3

NH2

CN

OH

Ph

4n

7

78

---

15

CHO

CF3

N

N

CH3

Ph

NH

NH2

CN

CF3

4o

1.5

96

84

a Reactions of aldehyde 1 (1 mmol), malononitrile 2 (1 mmol) and 3-methyl-1-phenyl-1H-

pyrazol-5-amine 3 (1 mmol) were carried out in aqueous ethanol using L-hydroxy proline at

room temperature

b Isolated yield


Page | 65

longer reaction time than other aldehydes which probably due to steric hindrance.

Aside from that, to our amusement, all reactions were successfully performed to

afford a series of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives with high to

excellent yields (except Table 2, entry 14). To the best of our information, there is no

statement on the synthesis of 6-amino-4-(4-methoxyphenyl)-1,3-diphenyl-4,7-

dihydro-1Hpyrazolo[3,4-b]pyridine-5-carbnitriles via one-pot multicomponent

reaction of aldehyde, nalononitrile and 3-methyl-1-phenyl-1H-pyrazol-5-amine, which

could be defeated by our green protocol for the synthesis of 4a.

The structures of products 4 were assigned by their FTIR, 1H NMR, 13C NMR,

HRMS spectroscopy and elemental analysis. This spectral data is in agreement with

their proposed structures. The 1H NMR of 4a in DMSO-d6 has singlet at δ 1.76 ppm

due to CH3 group, singlet at δ 5.56 ppm due to NH2, and signals at δ 7.28-7.78 ppm

are due to aromatic protons. Surprisingly, the NH proton appears as doublet at δ 5.81-

5.84 ppm (J=12 Hz) and benzylic proton appears as doublet at δ 5.22-5.25 ppm (J=12

Hz) which probably due coupling of these two protons. Further, signal of NH proton

was confirmed by D2O exchange 1H NMR of 4a.

The plausible mechanism for the L-hydroxy proline catalyzed synthesis of 4,7-

dihydro-1H-pyrazolo[3,4-b]pyridine derivatives 4 is depicted in Scheme 2.

Presumably, in first step, Knoevenagel condensation of aromatic aldehyde 1 and

malononitrile 2 achieved by L-hydroxy proline to produce condensate II via formation

of iminium ion I. This Knoevenagel condensate II undergoes Michael type addition

with 3-methyl-1-phenyl-1H-pyrazol-5-amine 3 followed by cyclization and

isomerization to afford desired product 4.


Page | 66

NN

CH3

Ph

NH2

+ +

CN

CNO

Ph

H

NH

COOH

OH

N+

Ph

H

COO-

OH

Ph

HCN

CN

NH

COOH

OH

Ph

H

CN

CN

..

Ph

N

N

CH3

Ph

NH

CN

CN

H

..

Ph

N

N

CH3

Ph

NH2

CN

N

Ph

N

N

CH3

Ph

NH

CN

NH

H

Ph

N

N

CH3

Ph

NH

CN

NH2

1

2

I II

III IV3

4

II

V

Scheme 2 Plausible mechanism for the synthesis of 4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine derivatives 4 using L-hydroxy proline as a catalyst.

3.4 Conclusion:

We have developed a simple, efficient and green procedure for the synthesis of 4,7-

dihydro-1H-pyrazolo[3,4-b]pyridine derivatives via one-pot multi-component reaction

of aldehyde, nalononitrile and 3-methyl-1-phenyl-1H-pyrazol-5-amine using L-

hydroxy proline as a catalyst. A variety of these compounds were synthesized in

aqueous media at ambient temperature with good to excellent yields. The significant

qualities of this methodology are mild reaction conditions, use of environmentally

begin organo-catalyst, excellent yields at ambient temperature, easy workup and no

need of chromatographic separation, which makes it an appropriate route. Moreover,

the applicability of this green protocol was confirmed by green metrics calculations.


Page | 67

3.5 Experimental

All the chemicals used in this process are purchased from Aldrich, Alfa Aesar and

Merck chemical companies and used without any purification. The monitoring of

reaction progress was accomplished by TLC on Merck TLC silica gel 60 F254 plates.

Melting points were determined by open capillary tubes and are uncorrected. 1H NMR

(400 MHz) and 13C NMR (100 MHz) spectra were recorded on 400 MHz Bruker

spectrometer using CDCl3 or DMSO-d6 solvents. FT-IR spectra were determined on

Thermo Fisher Scientific Nicolet iS-10 FT-IR Spectrometer. Mass spectra were

obtained on Shimadzu Toshvin mass spectrometer.

3.6 General experimental procedure for the synthesis of 4,7-dihydro-1H-

pyrazolo[3,4-b]pyridine derivatives:

A mixture of aromatic aldehyde (1 mmol), malononitrile (1 mmo1), 3-methyl-1-

phenyl-1H-pyrazol-5-amine (1 mmol) and L-hydroxy proline (20 mole %) in 6 mL

ethanol and 4 mL water at room temperature was stirred for the time specified in

Table 2. Reaction was monitored by TLC (ethyl acetate / petroleum ether – 1:1). After

completion of the reaction, reaction mixture was poured into ice cold water;

precipitated product was separated by filtration and washed with excess of water. The

solid obtained was dried and recrystallized from 95 % ethanol to afford pure product

4a-o.


Page | 68

3.7 Spectral data of the synthesized compounds

6-amino-4-(2,4-dichlorophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b] pyridine -5-carbonitrile (4a): Yield: 95 %, mp: 178 °c, 1H NMR (400 MHz,

CDCl3): δ (ppm) = 2.25 (s, 3H, CH3), 3.60 (s, 2H, NH2), 4.66-4.68 (d, J=8 MHz, 1H,

CH), 4.94-4.96 (d, J=8 MHz, 1H, NH), 7.28-7.54 (m, 8H, ArH); 1H NMR (400 MHz,

DMSO-d6): δ (ppm) = 1.76 (s, 3H, CH3), 5.56 (s, 2H, NH2, exchanged for D2O), 5.22-

5.25 (d, J=12 MHz, 1H, CH), 5.81-5.84 (d, J=12MHz, 1H, NH, exchanged for D2O),

7.28-7.78 (m, 8H, ArH); 13C NMR (100 MHz, CDCl3): 13.10, 26.51, 39.75, 98.45,

112.01, 112.19, 124.68, 127.60, 128.08, 128.13, 129.67, 130.93, 132.52, 134.97,

135.12, 137.62, 142.50, 147.70; IR (KBr): 3336, 2830, 2252, 1621, 1589, 1495, 1452,

1316, 1108, 917, 889, 791, 759, 696, 666 cm-1; Anal. Calcd for C20H15Cl2N5 (%): C

(60.62), H (3.82), N (17.67); Found: C (60.71), H (3.85), N (17.69).

6-amino-4-(4-chlorophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine-5-carbonitrile (4b): Yield: 96 %, mp: 176 °c, 1H NMR (400 MHz,

CDCl3): δ (ppm) = 2.26 (s, 3H, CH3), 3.51 (s, 2H, NH2), 4.66 (s, 2H, CH, NH), 7.28-

7.52 (m, 9H, ArH); 13C NMR (100 MHz, CDCl3): 12.96, 26.94, 42.19, 100.33,

112.37, 112.42, 124.61, 128.10, 128.60, 129.56, 129.67, 134.45, 134.61, 137.67,

142.34, 147.42; IR (KBr): 3363, 2818, 2253, 1620, 1597, 1493, 1455, 1318, 1210,

919, 894, 761, 700, 688, 647 cm-1; Anal. Calcd for C20H15Cl2N5 (%): C (66.39), H

(4.46), N (19.36); Found: C (66.45), H (4.42), N (19.40).

6-amino-4-(4-bromophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine -5-carbonitrile (4c): Yield: 92 %, mp: 166 °c, 1H NMR (400 MHz,



Page | 69

CH), 4.65-4.67 (d, J=8 MHz, 1H, NH), 7.28-7.60 (m, 9H, ArH); 13C NMR (100 MHz,

CDCl3): 13.10, 26.51, 39.75, 98.45, 112.01, 112.19, 124.68, 127.60, 128.08, 128.13,

129.67, 130.93, 132.52, 134.97, 135.12, 137.62, 142.50, 147.70; IR (KBr): 3363,

2971, 2815, 2251, 1619, 1597, 1566, 1489, 1454, 1317, 1107, 1008, 918, 893, 719,

698, 668, 614 cm-1; Anal. Calcd for C20H16BrN5 (%): C (59.13), H (3.97), N (17.24);

Found: C (59.21), H (3.94), N (17.29).

6-amino-4-(2-nitrophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine-5 -carbonitrile (4d): Yield: 89 %, mp: 172 °c, 1H NMR (400 MHz,



CDCl3): 13.05, 26.88, 38.41, 98.54, 112.08, 112.13, 124.77, 126.22, 128.18, 128.20,

129.60, 129.65, 131.10, 133.29, 137.60, 143.03, 147.39, 149.23; IR (KBr): 3401,

3300, 3210, 2976, 2833, 2253, 1624, 1560, 1519, 1495, 1360, 1299, 1019, 919, 835,

784, 736, 649, 605 cm-1; Anal. Calcd for C20H16N6O2 (%): C (64.51), H (4.33), N

(22.57); Found: C (64.42), H (4.37), N (22.64).

6-amino-3-methyl-1,4-diphenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-

carbonitrile (4e) : Yield: 86 %, mp: 74 °c, 1H NMR (400 MHz, CDCl3): δ (ppm) =

2.28 (s, 3H, CH3), 3.50 (s, 2H, NH2), 4.68 (s, 2H, CH, NH), 7.28-7.48 (m, 10H, ArH);

13C NMR (100 MHz, CDCl3): 12.92, 26.81, 42.46, 100.32, 112.66, 112.72, 124.51,

127.14, 127.92, 128.37, 129.36, 129.61, 136.06, 137.78, 142.65, 147.58; IR (KBr):

3348, 2977, 2254, 1616, 1561, 1496, 1393, 1317, 1159, 1072, 1012, 915, 761, 737,

695, 648 cm-1; Anal. Calcd for C20H17N5 (%): C (73.37), H (5.23), N (21.39); Found: C

(73.45), H (5.26), N (21.42).


Page | 70


b]pyridine-5 -carbonitrile (4f): Yield: 91 %, mp: 90 °c, 1H NMR (400 MHz, CDCl3):

δ (ppm) = 2.21 (s, 3H, CH3), 3.64 (s, 2H, NH2), 4.74-4.76 (d, J=8 MHz, 1H, CH),

4.84-4.86 (d, J=8 MHz, 1H, NH), 7.28-8.26 (m, 9H, ArH); 13C NMR (100 MHz,

CDCl3): 13.09, 26.99, 42.44, 100.17, 112.24, 112.27, 122.45, 123.44, 124.72, 128.30,

129.73, 130.42, 133.48, 137.50, 138.60, 142.46, 147.34, 148.68; IR (KBr): 3345,

2972, 2919, 2256, 1620, 1566, 1525, 1454, 1395, 1349, 1161, 1072, 1022, 918, 761,

720, 697, 648 cm-1; Anal. Calcd for C20H16N6O2 (%): C (64.51), H (4.33), N (22.57);

Found: C (64.45), H (4.36), N (22.61).

6-amino-4-(3-chlorophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine- 5-carbonitrile (4g): Yield: 92 %, mp: 96 °c, 1H NMR (400 MHz,



CDCl3): 12.95, 26.81, 42.24, 100.08, 112.40, 112.43, 124.62, 125.06, 127.75, 128.15,

128.71, 129.68, 130.53, 135.40, 137.56, 138.20, 142.56, 147.50; IR (KBr): 3348,

2971, 2254, 1634, 1567, 1517, 1454, 1394, 1350, 1164, 1073, 1023, 952, 761, 726,

696, 648 cm-1; Anal. Calcd for C20H16ClN5 (%): C (66.39), H (4.46), N (19.36);

Found: C (66.26), H (4.41), N (19.31).

6-amino-4-(3,4-dichlorophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b] pyridine-5-carbonitrile (4h): Yield: 91 %, mp: 96 °c, 1H NMR (400 MHz,



CDCl3): 13.02, 26.91, 41.95, 100.07, 112.24, 112.27, 124.67, 126.37, 128.24, 129.56,


Page | 71

129.71, 131.17, 132.85, 133.70, 136.41, 137.53, 142.37, 147.38 ; IR (KBr): 3347,

2971, 2255, 1616, 1564, 1515, 1454, 1394, 1134, 1072, 1030, 951, 761, 696, 647 cm-1;

Anal. Calcd for C20H15Cl2N5 (%): C (60.62), H (3.82), N (17.67); Found: C (60.75), H

(3.87), N (17.71).


b]pyridine-5 -carbonitrile (4i): Yield: 92 %, mp: 98 °c, 1H NMR (400 MHz, CDCl3):


4.78-4.80 (d, J=8 MHz, 1H, NH), 7.28-7.62 (m, 7H, ArH); 8.31-8.33 (m, 2H, ArH);

13C NMR (100 MHz, CDCl3): 13.03, 26.78, 42.58, 100.02, 112.13, 112.19, 124.47,

124.68, 128.34, 128.43, 129.75, 137.47, 142.39, 143.41, 147.32, 147.61; IR (KBr):

3347, 2971, 2251, 1596, 1515, 1454, 1394, 1347, 1160, 1072, 1022, 901, 833, 761,

738, 696, 644 cm-1; Anal. Calcd for C20H16N6O2 (%): C (64.51), H (4.33), N (22.57);

Found: C (64.47), H (4.35), N (22.65).

6-amino-4-(4-flurophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine-5 -carbonitrile (4j): Yield: 96 %, mp: 146 °c, 1H NMR (400 MHz,

CDCl3): δ (ppm) = 2.25 (s, 3H, CH3), 3.51 (s, 2H, NH2), 4.66 (s, 2H, CH, NH), 7.13-

7.52 (m, 9H, ArH); 13C NMR (100 MHz, CDCl3): 12.95, 27.17, 42.13, 100.60,

112.43, 112.47, 116.30, 116.51, 124.61, 128.08, 128.99, 129.07, 129.66, 131.90,

131.94, 137.69, 142.28, 147.41, 161.13, 163.60; IR (KBr): 3360, 2823, 2255, 1621,

1599, 1508, 1455, 1394, 1316, 1163, 1104, 1070, 942, 896, 832, 759, 712, 697, 647

cm-1; Anal. Calcd for C20H16FN5 (%): C (69.55), H (4.67), N (20.28); Found: C

(69.64), H (4.69), N (20.24);.


Page | 72

6-amino-4-(4-methylphenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine -5-carbonitrile (4k): Yield: 94 %, mp: 130 °c, 1H NMR (400 MHz,

CDCl3): δ (ppm) = 2.30 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.51 (s, 2H, NH2), 4.64 (s,

1H, CH), 4.65 (s, 1H, NH), 7.24-7.52 (m, 9H, ArH); 13C NMR (100 MHz, CDCl3):

12.48, 21.07, 26.87, 42.27, 100.41, 112.59, 112.65, 123.98, 124.51, 126.96, 127.88,

129.44, 129.58, 129.62, 130.05, 130.39, 130.93, 132.89, 137.81, 138.31, 142.49,

147.53; IR (KBr): 3464, 3367, 2971, 2921, 2249 1620, 1599, 1514, 1452, 1395, 1321,

1152, 1069, 1020, 952, 814, 774, 756, 698, 644 cm-1; Anal. Calcd for C21H19N5 (%): C

(73.88), H (5.61), N (20.51); Found: C (73.98), H (5.65), N (20.57).

6-amino-4-(3-bromophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine -5-carbonitrile (4l): Yield: 87 %, mp: 86 °c, 1H NMR (400 MHz, CDCl3):


4.68-4.70 (d, J=8 MHz,1H, NH), 7.28-7.53 (m, 9H, ArH); 13C NMR (100 MHz,

CDCl3): 12.96, 26.81, 42.28, 100.19, 112.32, 112.34, 123.57, 124.65, 125.48, 128.15,

129.68, 130.65, 130.78, 131.68, 137.60, 138.42, 142.41, 147.46,; IR (KBr): 3434,

2919, 2255 1632, 1594, 1514, 1496, 1454, 1394, 1319, 1172, 1073, 1022, 996, 831,

760, 719, 695, 649 cm-1; Anal. Calcd for C20H16BrN5 (%): C (59.13), H (3.97), N

(17.24); Found: C (59.23), H (3.95), N (17.31).

6-amino-4-(3-flurophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-

b]pyridine-5 -carbonitrile (4m): Yield: 92 %, mp: 86 °c, 1H NMR (400 MHz,



CDCl3): 12.90, 26.85, 42.29, 42.30, 100.18, 112.39, 112.43, 114.69, 114,88, 115.48,


Page | 73

115.69, 122.56, 122.59, 122.68, 124.62, 128.12, 128.86,128.90, 129.67, 130.95,

131.03, 137.62, 138.62, 138.68, 142.48, 147.50, 161.91, 164.38; IR (KBr): 3348,

2971, 2259, 2174, 1613, 1591, 1515, 1443, 1352, 1072, 951, 878, 760, 695, 647 cm-1.

6-amino-4-(4-hydroxyphenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]

pyridine-5-carbonitrile (4n): Yield: 78 %,1H NMR (400 MHz, CDCl3): δ (ppm) =

2.25 (s, 3H, CH3), 3.57 (s, 2H, NH2), 4.59 (s, 2H, CH, NH), 6.73-7.75 (m, 10H, OH,

ArH); HRMS m/z (ESI) : 341 [M]+.

6-amino-4-[4-(trifluromethyl)phenyl]-3-methyl-1-phenyl-4,7-dihydro-1H-

pyrazolo[3,4-b] pyridine-5-carbonitrile (4o): Yield: 96 %, mp: 84 °c, 1H NMR (400

MHz, CDCl3): δ (ppm) = 2.25 (s, 3H, CH3), 3.53 (s, 2H, NH2), 4.73 (s, 2H, CH, NH),

7.28-7.74 (m, 9H, ArH); 13C NMR (100 MHz, CDCl3): 12.96, 26.76, 42.54, 100.19,

112.26, 112.31, 124.65, 126.30, 126.33, 126.37, 126.41, 127.73, 128.20, 129.70,

137.57, 140.16, 142.35, 147.40; IR (KBr): 3350, 2970, 2925, 2255, 1619, 1596, 1515,

1455, 1395, 1323, 1164, 1068, 1016, 953, 827, 759, 697, 647 cm-1; Anal. Calcd for

C21H16F3N5 (%): C (63.79), H (4.08), N (17.71); Found: C (63.86), H (4.12), N

(17.73).


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phenyl-1,4-dihydrobenzo[ 4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid

ethyl ester derivatives as an antitubercular agents, Synthetic

Communications, 2016, VOL. 46, NO. 24, 2022–2030.

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d]pyrimidine-2,4(3H)-dione, Res Chem Intermed, DOI 10.1007/s11164-017-

2868-9.

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catalyzed straightforward novel approach for the synthesis of 1,2-bis(4-

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2865-z


Page | 94

Publications


Page | 95

List of Published Papers in Journals

Sr.

No.

Title Journal Impact

Factor

01

Synthesis, antiinflammatory,

ulcerogenic and cyclooxygenase

activities of indenopyrimidine

derivatives

Bioorganic &

medicinal chemistry

letters

2.420

02

One-pot synthesis and in vivo

biological evaluation of new

pyrimidine privileged scaffolds as

potent anti-inflammatory agents

Research on Chemical

Intermediates

1.221

03

An efficient, facile, three-component

synthesis of 4,7-dihydro-1H-

pyrazolo[3,4-b]pyridine derivatives in

aqueous media

Communicated to

Journal of

Heterocyclic

Chemistry

List of Paper Presented in Conference, Seminar, Symposia or Workshop

Sr.

No.

Title of the paper

presented

Title of the conference

/ seminar

Organized

by

Level

01

One pot synthesis of some

novel pyrimidine

derivatives.

National Conference on

“Frontiers In Chemical

& Material Sciences”

Shivaji

University

Kolhapur

National

https://scholar.google.co.in/citations?view_op=view_citation&hl=en&user=xgZDYZgAAAAJ&citation_for_view=xgZDYZgAAAAJ:UeHWp8X0CEIC




http://link.springer.com/article/10.1007/s11164-015-2281-1





Page | 96

02.

Sulphamic acid catalyzed

novel one-pot

multicomponent synthesis

of 5-phenyl-8-thioxo-

5,5a,8,9,9a,11-hexahydro-

7H-4b,7,9,10,11-pentaaza-

benzo [b] fluoren-6-one

derivatives.


“Frontiers In

Agrochemicals & Pest

Management” [FAPM-

2015]

Shivaji

University

Kolhapur

National

\03

Bronsted acid catalyzed

synthesis of some novel

indenoquinolene

derivatives by Friendlander

annulations.


“Frontiers In

Agrochemicals & Pest

Management” [FAPM-

2015]

Shivaji

University

Kolhapur National

04

One pot synthesis of

[1,8] – naphthapyridine

3-carbonitrile via

multicomponent

reaction (MCR) in

aqueous medium


“Recent Challenges in

Advanced Material and

Green Chemistry”.

(RCAMGC-2015)

Dr.

B.A.M.U.,

Sub-

Campus,

Osmanabad

National

05

A Stupendous PTSA

catalysed one pot three

componenet method for the

synthesis of 1,2-bis(4-nitro

phenyl)-1H-benzo[f]

chromen -3-amine


“Recent Advances in

Integrated Pest

Management”.

(RAIPM-2016)

Shivaji

University

Kolhapur National


Page | 97

ACKNOWLEDGEMENT

The author is thankful to the University Grants Commission, Western

Regional Office Pune, for sanctioning and funding this Minor Research Project.

It gives me great pleasure to express my sincere sense of gratitude to

Trustees of Shri Shivaji Shikshan Prasarak Mandal, Barshi and Principal Dr. P. R.

Thorat for all their support, kind co-operation and continuous encouragement.

I wish to express my warm and sincere thanks to Prof P. V. Anbhule

Professor in Organic Chemistry, Shivaji University, Kolhapur for valuable

guidance and co-operation. The author is thankful to Dr. T. N. Lokhande Head of

Chemistry Department and colleagues Mr. S. S. Vibhute, Mr. S. G. Jadhav, Dr. S.

H. Gaikwad, Mr. A. B. Shaikh, Mr. S.H. Patil, Dr. V. M. Gurame, Mr. P. R. Kate,

administrative staff of the college for their full co-operation and help in

completing this research work.

I would like to acknowledge my beloved Parents (Bappa & Aai) and Wife

Sau. Laxmi who are the real source of encouragement, strength and have brought

great deal of happiness to my life not only for the period of this work but

throughout my life.

Mr. D. K. Jamale

one-pot synthesis of some nitrogen containing …ssmbarshi.org/jamale.pdf · heterocycles and their...

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