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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Annexure – III
(Final)
UNIVERSITY GRANTS COMMISSION
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Annexure – IV (Final)
UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
NEW DELHI – 110 002
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 15-16 May 2015 Bus 900
Shivaji University, Kolhapur 24-25 May 2015 Bus 850
Solapur University, Solapur 01 June 2015 Bus 250
Solapur University, Solapur 09 June 2015 Bus 250
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Annexure – V
(Final)
UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
NEW DELHI – 110 002
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Annexure –VI
Final
UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Annexure – VII
Final
UNIVERSITY GRANTS COMMISSION
BAHADUR SHAH ZAFAR MARG
NEW DELHI – 110 002
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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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)
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Chapter I
General Introduction and
Literature Survey
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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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Page | 33
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
Page | 34
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
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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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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,
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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).
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Chapter II
Highly Efficient One-pot Synthesis of
[1,8] –Naphthapyridine 3-carbonitrile
using DAHP
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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Table 2, Entry 1 (4a)
Table 2, Entry 1 (4a)
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Table 2, Entry 1 (4a)
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Table 2, Entry 2(4b)
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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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
Page | 56
Chapter III
The development of a green protocol
for the synthesis of 4,7-dihydro-1H-
pyrazolo [3,4-b] pyridine derivatives
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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
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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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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.
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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.
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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.
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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,
CDCl3): δ (ppm) = 2.25 (s, 3H, CH3), 3.51 (s, 2H, NH2), 4.62-4.64 (d, J=8 MHz, 1H,
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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): δ (ppm) = 2.08 (s, 3H, CH3), 3.68 (s, 2H, NH2), 4.71-4.73 (d, J=8 MHz, 1H,
CH), 5.50-5.52 (d, J=8 MHz, 1H, NH), 7.28-7.74 (m, 9H, ArH); 13C NMR (100 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).
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6-amino-4-(3-nitrophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-
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): δ (ppm) = 2.24 (s, 3H, CH3), 3.57 (s, 2H, NH2), 4.61-4.63 (d, J=8 MHz, 1H,
CH), 4.69-4.71 (d, J=8 MHz, 1H, NH), 7.28-7.51 (m, 9H, ArH); 13C NMR (100 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): δ (ppm) = 2.23 (s, 3H, CH3), 3.59 (s, 2H, NH2), 4.59-4.61 (d, J=8 MHz, 1H,
CH), 4.68-4.70 (d, J=8 MHz, 1H, NH), 7.25-7.54 (m, 8H, ArH); 13C NMR (100 MHz,
CDCl3): 13.02, 26.91, 41.95, 100.07, 112.24, 112.27, 124.67, 126.37, 128.24, 129.56,
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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).
6-amino-4-(4-nitrophenyl)-3-methyl-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-
b]pyridine-5 -carbonitrile (4i): Yield: 92 %, mp: 98 °c, 1H NMR (400 MHz, CDCl3):
δ (ppm) = 2.22 (s, 3H, CH3), 3.58 (s, 2H, NH2), 4.75-4.77 (d, J=8 MHz, 1H, CH),
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);.
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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):
δ (ppm) = 2.24 (s, 3H, CH3), 3.57 (s, 2H, NH2), 4.61-4.63 (d, J=8 MHz, 1H, CH),
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): δ (ppm) = 2.23 (s, 3H, CH3), 3.58 (s, 2H, NH2), 4.63-4.65 (d, J=8 MHz, 1H,
CH), 4.68-4.70 (d, J=8 MHz, 1H, NH), 7.06-7.50 (m, 9H, ArH); 13C NMR (100 MHz,
CDCl3): 12.90, 26.85, 42.29, 42.30, 100.18, 112.39, 112.43, 114.69, 114,88, 115.48,
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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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and in vivo biological evaluation of new pyrimidine privileged scaffolds as
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Ecofriendly synthesis and biological evaluation of 4-(4-nitro-phenyl)-2-
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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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.
35. P. Patil, P. Warekar, K. Patil, D. Jamale, G. Kolekar & P. Anbhule,
Uncatalyzed synthesis of new substituted dihydro-2Hdipyrimido[1,2-a,4,5-
d]pyrimidine-2,4(3H)-dione, Res Chem Intermed, DOI 10.1007/s11164-017-
2868-9.
36. P. Warekar, P. Patil, K. Patil, D. Jamale, G. Kolekar & P. Anbhule, PTSA-
catalyzed straightforward novel approach for the synthesis of 1,2-bis(4-
nitrophenyl)-1Hbenzo[f]chromen-3-amine and the evaluation of their
antituberculosis activity , Res Chem Intermed, DOI 10.1007/s11164-017-
2865-z
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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Publications
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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.
National Conference on
“Frontiers In
Agrochemicals & Pest
Management” [FAPM-
2015]
Shivaji
University
Kolhapur
National
\03
Bronsted acid catalyzed
synthesis of some novel
indenoquinolene
derivatives by Friendlander
annulations.
National Conference on
“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
National Conference on
“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
National Conference on
“Recent Advances in
Integrated Pest
Management”.
(RAIPM-2016)
Shivaji
University
Kolhapur National
Minor Research Project: By D. K. Jamale, Shri Shivaji Mahavidyalaya, Barshi (M.S.)
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