Sodium bromide catalysed one-pot synthesis of tetrahydrobenzo[b]pyrans via a three-component cyclocondensation under microwave irradiation and solvent free conditions

Article abstract of DOI:10.1016/j.tetlet.2004.09.158

Sodium bromide catalysed three-component cyclocondensation of aryl aldehydes, alkyl nitriles and dimedone proceeds under microwave irradiation in solvent free conditions to give highly functionalised tetrahydrobenzo[b]pyrans in excellent yields.

Full text of DOI:10.1016/j.tetlet.2004.09.158

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8625–8627
Sodium bromide catalysed one-pot synthesis of
tetrahydrobenzo[b]pyrans via a three-component
cyclocondensation under microwave irradiation
and solvent free conditions
Ipsita Devi and Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Received 9 August 2004; revised 21September 2004; accepted 27 September 2004
Abstract—Sodium bromide catalysed three-component cyclocondensation of aryl aldehydes, alkyl nitriles and dimedone proceeds
under microwave irradiation in solvent free conditions to give highly functionalised tetrahydrobenzo[b]pyrans in excellent yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Development of new solid phase (solvent free) reactions
and transferring solution phase reactions to solid phase
are subjects of recent interest in the context of generat-
ing libraries of molecules for the discovery of biologi-
cally active leads and also for the optimisation of drug
candidates.1 One-pot multicomponent reactions
(MCRs) by virtue of their convergence, productivity,
facile execution and generally high yield of products
have attracted considerable attention from the point of
view of ideal synthesis.2 The first MCR was initiated
by Strecker in 1850 for the synthesis of amino acids.3
However, in the past decade there have been tremendous
developments in three- and four-component reactions
and great efforts have been and still are being made to
find and develop new MCRs.4 The potential application
of microwave technology in organic synthesis, particu-
larly in solid phase organic reactions is increasing rap-
idly because of reaction simplicity, less pollution and
minimum reaction times providing rapid access to large
libraries of diverse small molecules.5
pharmacological activities such as anti-coagulant, anti-
cancer, spasmolytic, diuretic, anti-ancaphylactia, etc.7
4H-Pyrans also constitute the structural unit of a series
of natural products.8 A number of 2-amino-4H-pyrans
are useful as photoactive materials.9 In the conventional
reported synthesis of 4H-benzo[b]pyrans, the use of org-
anic solvents like DMF/acetic acid make the work-up
procedure complicated and leads to poor yields of the
products besides polluting the environment.10 Thus
new routes for the synthesis of these molecules have at-
tracted considerable attention in the search for methods
for rapid entry to these heterocycles. Recently, Kaupp
et al. reported a novel method for the synthesis benzo-
[b]pyrans utilising the reactants in solid or molten
state.11 This reaction has its own merit and some limita-
tions: the two-step reaction was performed at very high
temperature and required a longer period of time. More-
over the reaction was applied for the synthesis of only a
few compounds. As part of our continued interest12 in
the development of highly expedient methods for the
synthesis of heterocyclic compounds of biological
importance, we report here a very simple and highly effi-
cient method for the synthesis of 4H-benzo[b]pyrans via
a three-component cyclocondensation reaction under
microwave irradiation using simple and inexpensive
sodium bromide as catalyst in solvent free conditions
(Scheme 1).
4H-Benzo[b]pyrans are an important class of compounds
which have received considerable attention in recent
years due to their wide range of biological activities.6
Compounds with these ring systems have diverse
Keywords: Solvent free reactions; Microwave-assisted reactions; Multi-
component reactions; Sodium bromide; Tetrahydrobenzo[b]pyrans.
In
amounts of benzaldehyde 1a, alkyl nitrile 2a and
a
typical experimental procedure,13 equimolar
*
Corresponding author. Tel.: +91 376 2370121; fax: +91 376
2370011; e-mail: pulak_jyoti@yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.158

8626
I. Devi, P. J. Bhuyan / Tetrahedron Letters 45 (2004) 8625–8627
R1
O
O
R2
NH2
MW
R1CHO
R2CH2CN
+
+
NaBr
O
O
1a:R1=C6H5
4a-i
2a:R2=CN
3
b:R1=4-Cl-C6H4
b:R2=CO2C2H5
c:R2=CONH2
c:R1=4-O2N-C6H4
d:R1=4-CH3O-C6H4
Scheme 1.
R1
R2
dimedone (5,5-dimethyl-1,3-cyclohexanedione) 3, were
mixed thoroughly with a catalytic amount of sodium
bromide. The reaction mixture was irradiated with
microwaves (Synthwave 402 Monomode Reactor from
Prolabo) at 60% power and at 70°C for 10min to afford
the 4H-benzo[b]pyran 4a in excellent yield. The structure
of the compound was confirmed from spectroscopic
data and found to be comparable in all respect with
an authentic sample.14 With suitable conditions estab-
lished for the microwave-assisted reaction, a number
of 4H-benzo[b]pyrans 4b–i were synthesised by utilising
various aromatic aldehydes 1a–d and alkyl nitriles 2a–c,
with dimedone 3 and the structures of the products were
confirmed from spectroscopic data. Although, the reac-
tion is applicable to various alkyl nitriles, the activity of
cyanoacetamide is poor in comparison to malononitrile
and ethyl cyanoacetate. Our observations are recorded
in Table 1.
MW
R1CHO
+
R2CH2CN
-H2O
CN
1
2
[A]
H+
R1
O
R1
O
O
R2
R2
-
H+
4
O
+
OH
O
H
NH
N
H
[B]
3
Scheme 2.
water and eliminating the catalyst and isolated the
cyano olefin intermediate and unreacted 3. Thus it was
concluded that initial protonation of the nitrile group
in the presence of NaBr took place and initiated the
cycloaddition process. Moreover, the ionic catalyst is
not involved in formation of the cyano olefin but must
help its conversion to the cycloadduct.
A mechanism for the reaction is outlined in Scheme 2.
The reaction occurs via initial formation of the cyano
olefin [A] from the condensation of aryl aldehyde 1 and
alkyl nitrile 2, which reacts with 3 to give the intermedi-
ate [B] which subsequently cyclises to afford the desired
compound 4. The water molecule eliminated in the first
step plays a key role in the cyclisation process as no
reaction occurs in its absence. This was evident from
the fact that when the cyano olefin, prepared by conven-
tional Knoevenagel condensation, was reacted directly
with compound 3 under microwave irradiation at 70–
90°C, in the presence of NaBr as catalyst, the starting
materials were found to remain intact. On the other
hand, when the same reaction was performed with the
addition of two drops of water to the reaction mixture,
the reaction occurred smoothly and gave the desired
cycloadduct. In another experiment, we performed the
three-component reaction by adding a few drops of
In conclusion we have demonstrated a novel, sodium
bromide catalysed, one-pot, three-component reaction
under microwave irradiation in solvent free conditions
that offers a simple and efficient route for the synthesis
of 4H-benzo[b]pyrans of biological importance in good
to excellent yields.
References and notes
1. Tanaka, T.; Toda, F. Chem. Rev. 2000, 100, 1025.
2. (a) Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999,
366; (b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Rev. 1996, 29,
123.
3. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
Table 1. Sodium bromide catalysed three-component reactions under microwave irradiation (MW) and solvent free conditions
Product
R1
R2
MW
Yield (%)
Mp (°C)
Reported
Power (%)
Temp (°C)
Time (min)
Found
4a
4b
4c
4d
4e
4f
C6H5
CN
CN
60
60
60
70
60
60
70
70
70
70
70
70
80
70
80
85
85
85
10
10
10
15
10
10
15
15
15
95
90
90
85
85
80
87
63
60
231–233
215–217
177–178
199–201
190–192
256–259
182–184
216–218
189–191
233–23414
21810a
4-Cl–C6H4
4-O2N–C6H4
4-CH3O–C6H4
C6H5
CN
CN
177–17811
198–20010b
Not rep.
Not rep.
Not rep.
Not rep.
Not rep.
CO2–C2H5
CO2–C2H5
CO2–C2H5
CONH2
CONH2
4-Cl–C6H4
4-CH3O–C6H4
C6H5
4g
4h
4i
4-Cl–C6H4

I. Devi, P. J. Bhuyan / Tetrahedron Letters 45 (2004) 8625–8627
8627
4. (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestiopo-
lov, A. A.; Rodinovskaya, L. A.; Niazimbetova, Z. I.;
Evans, D. H. Org. Lett. 2002, 423; (b) List, B.; Castello, C.
Synlett 2001, 1687; (c) Nair, V.; Vinod, A. U.; Rajesh, C.
J. Org. Chem. 2001, 66, 4427; (d) Bagley, M. C.; Cale, J.
W.; Bower, J. Chem. Commun. 2002, 1682; (e) Cheng, J.
F.; Chen, M.; Arthenius, T.; Nadzen, A. Tetrahedron Lett.
2002, 43, 6293; (f) Huma, H. Z. S.; Halder, R.; Kalra, S.
S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6485; (g)
Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002,
4, 3147; (h) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4,
3309; (i) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett.
2003, 5, 435; (j) Dallinger, D.; Gorobets, N. Y.; Kappe, C.
O. Org. Lett. 2003, 5, 1205.
5. (a) Pourashraf, M.; Delair, P.; Rasmaissen, M. O.;
Greene, A. E. J. Org. Chem. 2000, 65, 6966; (b) Cossy,
J.; Willis, C.; Bellosta, V.; Jalmes, L. S. Synthesis 2002,
951.
6. Green, G. R.; Evans, J. M.; Vong, A. K. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1995;
Vol. 5, p 469.
7. (a) Foye, W. O. Prinicipi di Chemico Farmaceutica; Piccin:
Padova, Italy, 1991, p. 416; (b) Andreani, L. L.; Lapi, E.
Bull. Chim. Farm. 1960, 99, 583; (c) Zhang, Y. L.; Chen, B.
Z.; Zheng, K. Q.; Xu, M. L.; Lei, X. H. Yao. Xue. Xue. Bao.
1982, 17, 17; Chem. Abstr. 1982, 96, 135383e; (d) Bonsi-
gnore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med.
Chem. 1993, 28, 517; (e) Witte, E. C.; Neubert, P.; Roesch,
A. Ger. Offen. DE 1986; . Chem. Abstr. 1986, 104, 224915f.
8. (a) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J.
Chem. Soc., Chem. Commun. 1988, 1202; (b) Gonzalez, R.;
Martin, N.; Seoane, C.; Soto, J. J. Chem. Soc., Perkin
Trans. 1 1985, 1202.
9. Arnetso, D.; Horspool, W. M.; Martin, N.; Ramos, A.;
Seaone, C. J. Org. Chem. 1989, 54, 3069.
10. (a) Singh, K.; Singh, J.; Singh, H. Tetrahedron 1996, 52,
14273; (b) Wang, X. S.; Shi, D. Q.; Tu, S. J.; Yao, C. S.
Synth. Commun. 2003, 33, 119.
13. In a simple experimental procedure equimolar amounts of
1a (212mg, 2mmol), 2a (132mg, 2mmol) and 3 (280mg,
2mmol) were mixed thoroughly with a catalytic amount of
sodium bromide (42mg, 0.4mmol) and allowed to react
under microwave irradiation at 60% power and 70°C for
10min. The microwaveÕs automatic mode stirrer helps in
mixing and uniform heating of the reactants. The reaction
vessel was allowed to cool to room temperature and the
solid compound obtained was washed with water and
finally recrystallised from ethanol to afford 4a (558mg, in
95% yield). The structures of the products was fully
characterised by spectroscopic methods. Compound 4a:
1
mp 231–233°C. H NMR (300MHz): d 1.03 (s, 3H), 1.10
(s, 3H), 2.15 (1H, d, J = 16Hz), 2.25 (1H, d, J = 16Hz),
2.48 (br s, 2H), 4.32 (s, 1H), 5.85 (s, 2H), 7.10–7.30 (m,
5H). 13C NMR (75MHz): d 26.3, 27.6, 31.2 (C-7), 35.0
(C-4), 39.8 (C-8), 49.9 (C-6), 60.3 (C-3), 113.0 (C-4a),
118.4 (CN), 126.1, 126.6 (2C), 127.5 (2C), 143.2, 157.7
(C-2), 161.3 (C-8a), 195.1 (C@O). IR (KBr) mmax 3392,
3289, 2930, 2200, 1688, 1600cmÀ1. Similarly the com-
pounds 4b–i were synthesised and characterised (Table 1).
The spectroscopic data of some selected compounds are
given below.
Compound 4e: mp 190–192°C. 1H NMR (300MHz): d
1.01 (s, 3H), 1.09 (s, 3H), 1.25 (t, 3H, J = 7.3Hz), 2.16
(1H, d, J = 16Hz), 2.25 (1H, d, J = 16Hz), 2.46 (br s, 2H),
4.20 (q, 2H, J = 7.3Hz), 4.30 (s, 1H), 5.89 (s, 2H), 7.12–
7.30 (m, 5H). 13C NMR (75MHz): d 19.1, 26.5, 28.1, 31.1
(C-7), 35.2 (C-4), 39.9 (C-8), 50.1 (C-6), 60.4 (C-3), 71.1,
113.3 (C-4a), 126.0, 126.5 (2C), 127.6 (2C), 144.1, 156.9
(C-2), 161.0 (C-8a), 172.3, 195.1 (C@O). IR (KBr) mmax
3416, 2959, 2928, 1745, 1594, 1360cmÀ1
.
Compound 4h: mp 216–218°C. 1H NMR (300MHz): d
1.04 (s, 3H), 1.12 (s, 3H), 2.16 (1H, d, J = 16Hz), 2.28 (1H,
d, J = 16Hz), 2.52 (br s, 2H), 4.38 (s, 1H), 5.88 (s, 2H),
7.10–7.30 (m, 5H). 13C NMR (75MHz): d 26.7, 27.9,
31.2 (C-7), 35.4 (C-4), 40.4 (C-8), 49.9 (C-6), 61.0 (C-3),
113.7 (C-4a), 126.0, 126.7 (2C), 128.1 (2C), 143.7, 157.7
(C-2), 162.1 (C-8a), 171.3, 195.5 (C@O). IR (KBr) mmax
11. Kaupp, G.; Naimi-Zamal, M. R.; Schmeyers, J. Tetrahe-
dron 2003, 59, 3753.
12. (a) Devi, I.; Bhuyan, P. J. Synlett 2004, 283; (b) Devi, I.;
Borah, H. N.; Bhuyan, P. J. Tetrahedron Lett. 2004, 45,
2405.
3399, 3184, 2955, 1687, 1595cmÀ1
.
14. Sharanina, L. G.; Nesterov, V. N.; Klokol, G. V.;
Rodinovovskaya, L. A.; Shklover, V. E. J. Org. Chem.
USSR (Engl. Transl.) 1986, 22, 1185, Zh. Org. Khim. 1986,
22, 1315.