Synthesis of some tetrazole fused pyrido[2,3-c]coumarin derivatives from a one-pot three-component reaction via intramolecular 1,3-dipolar cycloaddition reaction of azide to nitriles

Article abstract of DOI:10.1016/j.tetlet.2012.07.060

Some novel tetrazole fused pyrido[2,3-c]coumarin derivatives 5/7/9 were synthesized from a one-pot three-component reaction of 4-chloro-3- formylcoumarins 2, sodium azide 3, and alkyl/aryl acetonitriles 4/6/8.

Full text of DOI:10.1016/j.tetlet.2012.07.060

Tetrahedron Letters 53 (2012) 5034–5037
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Tetrahedron Letters
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Synthesis of some tetrazole fused pyrido[2,3-c]coumarin derivatives
from a one-pot three-component reaction via intramolecular 1,3-dipolar
cycloaddition reaction of azide to nitriles
⇑
Pallabi Borah, P. Seetham Naidu, Pulak J. Bhuyan
Medicinal Chemistry Division, CSIR-North East Institute of Science Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Some novel tetrazole fused pyrido[2,3-c]coumarin derivatives 5/7/9 were synthesized from a one-pot
Received 11 June 2012
Revised 11 July 2012
Accepted 13 July 2012
Available online 20 July 2012
three-component reaction of 4-chloro-3-formylcoumarins 2, sodium azide 3, and alkyl/aryl acetonitriles
4/6/8.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyrido[2,3-c]coumarin
Tetrazole
Multi-component reactions (MCRs)
Azides
Nitriles
Coumarins are an important class of compounds obtained from
both nature and synthetic origin that possess diverse pharmaceu-
tical and biological activities, often depending on the substituent
they bear in the parent benzopyran moiety.1 As for instance, ben-
zopyranone-pyridine or piperidines interact with DNA,2 for energy
transfer in photophysical processes,3 to act as potential platelet
activating factor antagonists,4 to be depressant or hypotensive
activators5 and potent antipsychotic agents.6 Some of their repre-
sentatives exhibit antibacterial,7 antitumor,8 anticholinergic,9 and
antimicrobial10 activities. Pyridine annelated coumarins also show
antiallergic, anticoagulant, antidiabetic, and analgesic properties.11
Similarly, imidazolo–coumarins act as CNS depressant, mamma-
lian cancer growth inhibitor, and also as phosphor-diesterase VII
inhibitors for the treatment of immunity associated diseases.12
Notably, most of these bioactive compounds are fused 3,4-hetero-
cyclic coumarin derivatives. Therefore, considerable efforts have
been made toward the synthetic manipulation of coumarins to find
more useful compounds. As a result of this effort a number of ann-
elated coumarin derivatives have been obtained with diverse bio-
logical activities.13
binding functionality for CYP450-derived oxidative metabolic pro-
cesses, and tetrazoles have the advantage over carboxylic acids in
terms of escaping most bio-transformations by Phase-II reaction
pathways.16 1H- and 2H-tetrazoles are frequently employed in
Cl
OH
O
DMF + POCl3
CHO
O
O
N
N
O
R1
N
2
1
N
Cl
O
N
O
CHO
5a-c
R1CH2CN
+
R1
NaN3
+
O
O
N
R
1 = CONH2, CO2Et, CN
N
N
3
4a-c
2
O
O
N
O
N
Tetrazoles are an important class of compounds which have
been the subject of intensive research and applied investigations.14
Tetrazoles are regarded as biologically equivalent to the carboxylic
acid group.15 Both carboxylic acid and tetrazoles act as ligand
N
Cl
N
R2
O
CHO
+
CN
NaN3
+
R2
O
O
O
O
6a-d. (R2 = aryl) OR
8a-c. (R2 = indolyl)
3
7a-d. (R2 = aryl) OR
9a-c. (R2 = indolyl)
2
⇑
Corresponding author. Tel.: +91 376 2370121; fax: +91 376 2370011.
E-mail address: pulak_jyoti@yahoo.com (P.J. Bhuyan).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.060

P. Borah et al. / Tetrahedron Letters 53 (2012) 5034–5037
5035
Table 1
Synthesis of tetrazolo[40,50:1,6]pyrido[2,3-c]coumarin derivatives 5/7/9
Entry
Substrate
Product
Reaction time (h)
Yield (%)
N
N
NC
CONH
2
N
N
CONH2
4a
N
1
3
82
83
5a
O
O
O
N
NC COOC H
2
5
N
COOC2H5
4b
N
2
3
5b
O
N
N
N
NC CN
N
CN
4c
N
3
4
3
78
80
5c
O
O
O
N
O
O
N
CN
N
N
4.5
6a
7a
O
N
O
O
N
N
CN
6b
N
5
6
7
8
3.5
3.5
5
83
85
75
78
Cl
Cl
Br
7b
7c
7d
O
N
O
N
N
O
N
O
O
CN
6c
Br
O
N
O
O
N
O
N
N
CN
N
MeO
NC
OMe
6d
O
N
O
O
N
N
5
NH
8a
NH
9a
O
O
OH
Br
OH
Br
N
O
O
O
N
N
N
NC
NC
N
9
4
4
81
86
NH
NH
NH
9b
8b
O
O
O
N
O
N
N
10
NH
9c
8c
O
the lead optimization of ethical drug candidates to enhance the
oral bioavailability. Several successful examples of this strategy
are present in the sartane drug family, which is used to treat
hypertension.17
The attack of cyanide-stabilized carbanions on azide functions
leading to 1,2,3-triazole is a well established conversion in organic
synthesis.18 In an extensive study, the carbanion derived from
diethylacetonedicarboxylate has also been employed in this reac-
tion process, and the triazoles resulting from the reaction undergo
base catalyzed intramolecular condensation at the ortho substitu-
ent to give well functionalized triazolo[1,5-a]quinolines.19
As part of our continued interest on the synthesis of diverse het-
erocyclic compounds of biological significance,20 recently we re-
ported the synthesis of some novel isoxazole and pyrazole fused
pyrido[2,3-c]coumarins via an intramolecular 1,3-dipolar cycload-
dition reaction involving nitrone, nitrile oxide, and nitrile imine as
1,3-dipole.21 There are many other recent examples of the applica-
tion of 1,3-dipolar cycloaddition reaction in the synthesis of com-
plex heterocyclic compounds of biological importance.22 In the
present paper, we report the synthesis of some novel tetrazole fused
pyrido[2,3-c]coumarin derivatives 5/7/9 from a one-pot three-com-
ponent reaction of 4-chloro-3-formylcoumarins 2, sodium azide 3,

5036
P. Borah et al. / Tetrahedron Letters 53 (2012) 5034–5037
R1
NaN3
N
N
N
References and notes
NC
Cl
R1
Cl
O
N
CHO
O
Et3N
1. (a) Murray, R. D. H.; Mendez, J.; Brown, R. A. The Natural Coumarins; John Wiley
Sons: New York, 1982; (b) Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas,
K. E.; Nicolaides, D. N. Curr. Pharm. Des. 2004, 10, 3813.
2. Guillo, L. A.; Beylot, B.; Vigny, P.; Spassky, A. Photochem. Photobiol. 1996, 64,
349.
3. Bangar. Raju, B.; Eliasson, B. J. Photochem. Photobiol. 1998, 116, 135.
4. Guinn, D. E.; Summers, J. B.; Heyman, H. R.; Conway, R. G.; Rhein, D. A.; Albert,
D. H.; Magoc, T.; Carter, G. W. J. Med. Chem. 1992, 35, 2055.
R1CH2CN
3
+
O
[A]
O
4
2
O
O
N
N
N
R1
[B]
N
5. Pars, H. G.; Granchelli, F. E.; Razdan, R. K.; Keller, J. K.; Teiger, D. G.; Rosenberg,
F. J.; Hris, L. S. J. Med. Chem. 1976, 19, 445.
O
O
5
6. (a) Mach, U. R.; Hackling, A. E.; Perachon, S.; Ferry, S.; Wermuth, C. G.;
Schwartz, J.-C.; Sokoloff, P.; Stark, H. Chem. Bio. Chem. 2004, 5, 508; (b) Unangst,
P. C.; Capiris, T.; Connor, D. T.; Heffner, T. G.; MacKenzie, R. G.; Miller, S. R.;
Pugsley, T. A.; Wise, L. D. J. Med. Chem. 1997, 40, 2688; (c) Zhang, M.-R.;
Haradahira, T.; Maeda, J.; Okauchi, T.; Kawabe, K.; Kida, T.; Obayashi, S.; Suzuki,
K.; Suhara, T. Nucl. Med. Biol. 2002, 29, 469.
Scheme 2.
and alkyl/aryl acetonitriles 4/6/8, and by exploring intramolecular
1,3-dipolar cycloaddition reaction of azide to nitriles (Scheme 1).
4-Hydroxy coumarin 1 was taken as starting material in our
reaction strategy which on treatment with Vilsmeier reagent
(DMF + POCl3) afforded the key intermediate 4-chloro-3-formyl
coumarin 2 (Scheme 1).23 In a simple experimental procedure,24
treatment of 4-chloro-3-formyl coumarin 2, sodium azide 3, and
cyanoacetamide 4a for 3 h at 50–60 °C in the presence of catalytic
amounts of triethylamine using dimethylformamide as solvent
afforded after work-up tetrazolo[40,50:1,6]pyrido[2,3-c]coumarin
derivative 5a in excellent yields. The structure of the compound
was ascertained from the spectroscopic data and elemental analy-
sis. Although there was a possibility of the formation of triazolo
fused pyrimido[4,5-c]coumarin derivative, we obtained exclusively
the tetrazole fused coumarin derivative 5a. The generality of the
reaction was established by synthesizing a series of compounds
5a–c, 7a–d, and 9a–c by utilizing 2 and 3 with 4/6/8 and character-
izing them (Table 1). The compounds 6 and 8 were prepared fol-
lowing the standard reaction protocol.25
The formation of the products from the three-component
reactions was confirmed by performing the reactions stepwise
(Scheme 2). First, intermediate [A] was prepared from the conden-
sation of compound 2 with 4 in the presence of catalytic amounts
of triethylamine at room temperature using ethanol as solvent.26
Then the intermediate [A] was reacted with sodium azide 3 at
50–60 °C using DMF as solvent which afforded compound 5.27
The intermediate [B] could not be isolated in all the cases. Simi-
larly, compounds 7 and 9 were synthesized by performing the
reactions stepwise.
It was observed that malononitrile 4c and ethyl-cyanoacetate
4b are more reactive than cyano-acetamide 4a. However, product
5a could be isolated much more easily than the others. Although,
compounds 6 and 8 bearing a variety of either electron donating
or electron withdrawing functional groups at the benzene ring
were efficient for the three-component reaction, those bearing
electron-withdrawing groups were found more reactive and thus
products were obtained in high yields and in shorter reaction time
than the others.
In summary, we have reported the synthesis of some novel tet-
razole fused pyrido[2,3-c]coumarin derivatives from a one-pot
three component reaction via intramolecular 1,3-dipolar cyclo-
addition reaction of azide to nitriles. The work-up procedure of
the reaction is simple; products were isolated simply by filtration
and purified by chromatography. This reaction which can be fur-
ther utilized for the synthesis of many other heterocyclic com-
pounds of biological importance is a valuable addition to the
chemistry of coumarins in particular and heterocyclic compounds
as a whole. Further study of the reaction is in progress.
7. Coumarins: Biology, Applications and Mode of Action; O’Kennedy, R., Thornes, R.
D., Eds.; Wiley: Chichester, 1997.
8. Raev, L. D.; Voinova, E.; Ivanov, I. C.; Popov, D. Pharmazie 1990, 45, 696.
9. Connor, D. T.; Unangst, P. C.; Schwender, C. F.; Sorenson, R. J.; Carethers, M. E.;
Puchalski, C.; Brown, R. E.; Finkel, M. P. J. Med. Chem. 1989, 32, 683.
10. Khan, I. A.; Kulkarni, M. V.; Gopal, M.; Shahabuddin, M. S.; Sun, C. M. Bioorg.
Med. Chem. Lett. 2005, 15, 3584.
11. (a) Ukawa, K.; Ishiguro, T.; Wada, Y.; Nohara, A. Heterocycles 1931, 1986, 24; (b)
Heber, D. Arch. Pharm. 1987, 320, 402; (c) Heber, D.; Berghaus, T. J. Heterocyclic
Chem. 1994, 31, 1353.
12. (a) Savel’ev, V. L.; Pryanishnikova, N. T.; Zagorevskii, V. A.; Chernyakova, I. V.;
Artamonova, O. S.; Shavyrina, V. V.; Malysheva, L. I. Khim. Farm. Zh. 1983, 17,
697; (b) Trkovnik, M.; Kalaj, V.; Kitan, D. Org. Prep. Proced. Int. 1987, 19, 450; (c)
Eggenweiler, M.; Rochus, J.; Wolf, M.; Gassen, M.; Poeschke, O.; Merck Patent
Gmbh, Germany, PCT Int. Appl. 2001.
13. (a) Beccalli, E. M.; Contini, A.; Trimarco, P. Eur. J. Org. Chem. 2003, 3976; (b)
Beccalli, E. M.; Contini, A.; Trimarco, P. Tetrahedron Lett. 2004, 45, 3447; (c)
Gautam, D. R.; Protopappas, J.; Fylaktakidou, C. K.; Litinus, K. E.; Nicolaides, D.
N.; Tsoleridis, C. A. Tetrahedron Lett. 2009, 50, 448.
14. Zubarev, V. Y.; Ostrovskii, V. A. Chem. Het. Comp. 2000, 36, 759.
15. Bulter, R. N. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 5, p 791.
16. Herr, J. R. Bioorg. Med. Chem. 2002, 10, 3379. and the references cited therein.
17. (a) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.; Prendergast, K.;
Smith, R. D.; Timmermans, P. B. M. W. M J. Med. Chem. 1996, 39, 625; (b)
Schmidt, B.; Scieffer, B. J. Med. Chem. 2003, 46, 2261; (c) Schmidt, B.; Drexler,
H.; Scieffer, B. Am. J. Cardiovasc. Drugs 2004, 4, 361.
18. (a) Tennant, G. J. Chem. Soc. C 1966, 2290; (b) Sutherland, D. R.; Tennant, G. J.
Chem. Soc., Per. Trans 1974, I, 534; (c) Westerlurd, C. J. Heterocycl. Chem. 1980,
17, 1765; (d) Lauria, A.; Patella, C.; Diana, P.; Barraja, P.; Montalbano, A.;
Cirrincione, G.; Dattallo, G.; Almerico, A. M. Tetrahedron Lett. 2006, 47, 2187.
19. Smalley, R. K.; Teguiche, M. Synthesis 1990, 654.
20. (a) Baruah, B.; Bhuyan, P. J. Tetrahedron 2009, 65, 7099; (b) Deb, M. L.;
Majumder, S.; Baruah, B.; Bhuyan, P. J. Synthesis 2010, 929; (c) Majumder, S.;
Bhuyan, P. J. Tetrahedron Lett. 2012, 53, 137; (d) Naidu, P. S.; Bhuyan, P. J.
Tetrahedron Lett. 2012, 53, 426; (e) Majumder, S.; Bhuyan, P. J. Tetrahedron Lett.
2012, 53, 762.
21. Majumder, S.; Bora, P.; Bhuyan, P. J. Mol. Diver. 2012, 16, 279.
22. (a) Basolo, L.; Beccalli, E. M.; Borsini, E.; Broggini, G.; Pellegrino, S. Tetrahedron
2008, 64, 8182; (b) Basolo, L.; Beccalli, E. M.; Borsini, E.; Broggini, G.; Khansaa,
M.; Rigamonti, M. Eur. J. Org. Chem. 2010, 1694; (c) Butkovic, K.; Marinic, Z.;
Molcanov, K.; Kojic-Prodic, B.; Sindler-Kulyk, M. Beil. J. Org. Chem. 2011, 1663;
(d) Yonekwa, M.; Koyama, Y.; Kuwata, S.; Takata, T. Org. Lett. 2012, 14, 1164.
23. Andrieux, J.; Battioni, J.-P.; Giraud, M.; Molho, D. Bull. Soc. Chem. Fr. 1973, 6,
2093.
24. Representative
procedure
for
the
synthesis
of
tetrazolo[40,50:1,6]pyrido[2,3-c]coumarins 5/7/9:
4-Chloro-3-formyl coumarin 2 (1 mmol, 208 mg), sodium azide 3 (1.25 mmol,
80 mg) and cyanoacetamide 4a (1.5 mmol, 126 mg) were taken in a round
bottom flask. To this were added DMF (5 ml) and one drop of triethylamine. The
reaction mixture was stirred with a magnetic stirrer at 50–60 °C for 3 h. After
completion of the reaction (monitored by TLC), the mixture was cooled to room
temperature and then poured into water (10 mL) with stirring.
A brown
coloured solid product appears. The mixture was kept in a refrigerator for 3 h.
The solid product was filtered and purified by column chromatography using
petroleum ether and ethyl acetate (7:3) as eluent. The structure of the
compound was ascertained as 5a from the spectroscopic data and elemental
analysis. Yield = 0.203 g (72.24%). Compound 5a: Light brown solid: Mp 228–
229 °C.ꢀIR (KBr)
m .
max = 3419, 2945, 1719, 1702 cmꢁ1 1H NMR (300 MHz, DMSO-
d6): d 6.21 (s, 1H), 7.10 (m, 2H), 7.21 (d, 1H), 7.49 (d, 1H), 7.70 (brs, 2H). 13C NMR
(75 MHz, DMSO-d6) d 114.88, 117.22, 118.85, 124.71, 125.19, 125.57, 125.95,
135.82, 147.78, 148.70, 153.20, 158.33, 161.85. MS (m/z) 281.2 [M+]. Anal. calcd
for C13H7N5O3: C, 55.52; H, 2.49; N, 24.91%. Found: C, 55.43; H, 2.58; N, 24.83%.
Similarly compounds 5b–c/7a–d/9a–c were synthesized and characterized.
25. (a) Slatt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760; (b) Nowwill, R. N.;
Patel, T. J.; Beasley, D. L.; Alvarez, J. A.; Jackso, E., III; Hizer, T.; Ghiviriga, I.;
Mateer, S. C.; Feske, B. D. Tetrahedron Lett. 2011, 52, 2440.
Acknowledgement
The authors thank the DST, New Delhi, for financial support and
P.S.N. thanks UGC, New Delhi for Junior Research Fellowship.

P. Borah et al. / Tetrahedron Letters 53 (2012) 5034–5037
5037
26. Representative procedure for the synthesis of intermediate [A]: To a solution of
4-chloro-3-formylcoumarin (2 mmol, 416 mg) and cyanoacetamide 4a
27. Representative procedure for the reaction of intermediate [A] with sodium
azide 3: To solution of 2-(4-chloro-2-oxo-2H-chromeno-3-yl)-2cyano-
2
a
(2.5 mmol, 210 mg) in ethanol (8 mL) was added one drop of piperidine and
the reaction mixture was allowed to stir at rt for 30 min. The solution was
cooled in a refrigerator for 3 h. The yellow solid which appeared in the reaction
mixture was filtered and washed with ethanol and dried. Yield 430 mg (79%).
mp 200–202 °C. The structure of the compound was ascertained as 2-(4-
chloro-2-oxo-2H-chromeno-3-yl)-2cyano-acrylamide from the spectroscopic
acrylamide [A] (274.5 mg, 1 mmol) and NaN3 (80 mg, 1.25 mmol) in DMF
(10 mL) added catalytic amounts of triethylamine and the reaction mixture
was stirred for four hours at 50–60 °C. The solution was cooled to rt and then
poured into water under continuous stirring. A brown colored solid which
appeared was filtered and purified by preparative TLC using 7:3 petroleum
ether and ethyl acetate as eluent. Yield = 190 mg (67.6 %). Mp 228–229 °C. The
compound was comparable in all respects with 5a obtained from the three-
component reaction.
data. IR (KBr)
DMSO-d6): d 6.62 (s, 1H), 7.39 (m, 2H), 7.60 (m, 1H), 7.89 (m, 1H).
m .
max = 3410, 2889, 2200, 1715, 1698 cmꢁ1 1H NMR (300 MHz,