Uncatalyzed reactions in aqueous media: Three-component, one-pot, clean synthesis of tetrahydrobenzo[b]pyran derivatives

Article abstract of DOI:10.1071/CH06461

The synthesis of various tetrahydrobenzo[b]pyran derivatives has been carried out by means of an uncatalyzed, three-component, one-pot clean condensation of aromatic aldehydes, reactive methylene compounds, and dimidone in aqueous medium. Simple workup, and mild and neutral conditions that give quantitative yields of products in pure form, are the attractive features of this method. CSIRO 2007.

Full text of DOI:10.1071/CH06461

Short Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 305–307
Uncatalyzed Reactions in Aqueous Media: Three-
Component, One-Pot, Clean Synthesis of
Tetrahydrobenzo[b]pyran Derivatives
A
A,B
Balaji L. Korbad,A
Sunita B. Bandgar, Babasaheb P. Bandgar,
A
A
Jalinder V. Totre, and Sachin Patil
AOrganic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramanand Teerth Marathwada University, Nanded-431606, India.
B
Corresponding author. Email: bandgar_bp@yahoo.com
The synthesis of various tetrahydrobenzo[b]pyran derivatives has been carried out by means of an uncatalyzed, three-
component, one-pot, clean condensation of aromatic aldehydes, reactive methylene compounds, and dimedone in aqueous
medium. Simple workup, and mild and neutral conditions that give quantitative yields of products in pure form, are the
attractive features of this method.
Manuscript received: 5 December 2006.
Final version: 29 January 2007.
With increasing environmental concerns and the regulatory con-
straints faced in the chemical and pharmaceutical industries,
the development of environmentally benign organic reactions
has become crucial and demanding research. Therefore, more
and more chemists’ synthetic endeavours are devoted toward
Tetrahydrobenzo[b]pyran and its derivatives have attracted
considerable attention from organic and medicinal chemists
because of their useful biological and pharmacological proper-
ties, such as anti-coagulant, spasmolytic, diuretic, anti-cancer,
[1]
[6–10]
and anti-anaphylactin characteristics.
Some 2-amino-
4H-pyrans can be useful as photoactive materials,[ whereas
11]
‘
green chemistry’, which means the reagents, solvents, and cat-
alystsareenvironmentallyfriendly. Recently,Wenderdefinedthe
ideal synthesis as one in which the target components are pro-
duced in one step in quantitative yield from readily available and
inexpensive starting materials in a resource-effective and envi-
ronmentally acceptable process.[ One-pot multi-component
condensations represent a possible instrument to perform a
near ideal synthesis because they possess one of the aforemen-
tioned qualities, namely the possibility of building up complex
molecules with maximum simplicity and brevity.[ The art of
performing efficient chemical transformations by coupling three
or more components in a single operation with or without cat-
alyst and avoiding the stoichiometric use of toxic reagents,
large amounts of organic solvents, and expensive purification
techniques represents a fundamental target of modern organic
polysubstituted 4H-pyran constitutes a structural unit of
Most of the reported
conventional methods of syntheses for 4H-benzo[b]pyran
a series of natural products.[
12,13]
involves use of organic solvents, such as acetic acid or
2]
[14,15]
dimethylformamide.
Some recent reports also describe
the synthesis of tetrahydrobenzo[b]pyrans.[ While each of
the above methods has its own merit, these syntheses are
plagued by the limitations of poor yields, difficult workup,
and effluent pollution. Thus, new routes for the synthesis
of these molecules have attracted considerable attention in
the search for methods for rapid entry to these heterocy-
cles. Recently, tetrahydrobenzo[b]pyrans have been synthesized
16]
3]
[15]
using catalysts such as KF–alumina
under ultrasonic irradiation,
or KF–basic alumina
[17]
hexadecyltrimethyl ammonium
[
4]
[18]
[19]
synthesis.
bromide,
sodium bromide under microwave irradiation,
(S)-proline,[ or using the reactants in solid or molten state
20]
[22]
In recent years in organic synthesis, increasing attention has
been focussed on reactions in aqueous media.[ When a solvent
must be used, water is the most acceptable in terms of cost and
environmental impact. However, despite its large liquid range
and extremely high specific heat capacity, it is frequently over-
looked as a solvent for organic reactions. Most catalysts and
reagents are deactivated or decompose in water and, in general,
organic compounds are insoluble in water. Therefore, carrying
out organic reactions in water poses important challenges in the
area of reaction design. The use of water as a solvent in organic
synthesis is often surprisingly effective even for reactions that
are traditionally carried out under anhydrous conditions, despite
the fact that the reaction involves a dehydration step.
5]
[22]
and microwave irradiation. However, these methods have one
or more limitations such as: (1) multi-step reactions;[
(2) the reactions were performed at very high temperature and
15,21,22]
required longer times;[ (3) catalyst loading is high;
21]
[15,17–20]
(4) the reaction only applies to the synthesis of a limited number
of compounds.[ Consequently, there is scope for further reno-
vation of the method, which avoids both an organic solvent and
the need for a catalyst, and involves simple workup and furnishes
greater yields.
21]
We report here for the first time a general, practi-
cal, and highly efficient route for the synthesis of tetrahy-
drobenzo[b]pyran without catalyst in tap water that involves
©
CSIRO 2007
10.1071/CH06461
0004-9425/07/040305

3
06
S. B. Bandgar et al.
a three-component, one-pot, clean procedure. The title com-
pounds are obtained in almost pure form and in high yield
conditions in tap water without catalyst. It is believed that this
is the first example of a Michael addition without catalyst in
tap water. The active methylene moiety in 3 reacts with the elec-
trophilic C=C double bond to give intermediate 6.Alternatively,
aldehyde 1 reacted with dimedone 3 first, followed by Michael
addition of the methylene compound 2 with olefin 3A to result
in the formation of intermediate 6. The intermediate 6 was then
cyclized by nucleophilic attack of OH on the cyano group and
yielded the intermediate 7. Finally the expected products 4 were
formed by tautomerization of 8.
(
Scheme 1).
Carbonyl compounds undergo a Knoevenagel condensation
with active methylene compounds in the presence of acids or
bases in organic solvents. Recently, however, the Knoevenagel
condensation has been performed in water without a catalyst.[
These results encouraged us to carry out a one-pot sequen-
tial Knoevenagel condensation and Michael addition without
a catalyst in water. The results presented in Table 1 indicate
that electronic effects and the nature of substituents on the aro-
matic ring did not show a strong effect in terms of yield and
reaction time. The three-component cyclocondensation reaction
proceeded smoothly in water under reflux conditions to furnish
excellent yields of products. It is important to note that the pro-
cedure is eco-friendly and involves water as a green solvent; it
does not require catalyst or tedious workup, and the products do
not require purification. Pure products are obtained by simple
filtration.
23]
O
O
O
3
R
O
RCH CN 2
H2O, reflux
ArCH
2
ArCHO
ArCH
C
CN
3A
1
5
O
RCH CN 2
2
In the proposed mechanism (Scheme 2), an aromatic alde-
hyde 1 was first condensed with the reactive methylene com-
pound 2 to afford α-substituted cinnamonitrile derivative 5,
whichunderwentMichaeladditionwithdimedone 3underreflux
O
3
O
Ar
O
Ar
H
R
N
R
C
CN
OH
O
7
6
O
Ar
O
O
R
H2O
ArCHO ꢀ RCH2CN
ꢀ
reflux
O
Ar
O
Ar
O
NH2
H
R
R
1
2
3
4
O
NH
O
NH2
2
Ar ꢁ Aryl; R ꢁ CN, CO Et, CONH2
8
4
Scheme 1.
Scheme 2. Proposed mechanism.
Table 1. Three-component, one-pot, clean synthesis of tetrahydrobenzo[b]pyran derivatives without catalyst
1
Products were characterized using IR, H NMR, mass spectroscopy, and elemental analysis.
YieldA [%]
◦
mp [ C]
Derivative
Ar
R
Time [h]
18]
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
C6H5
4-BrC6H4
4-ClC6H4
CN
CN
CN
CN
CN
CN
CN
CN
3.5
2.0
1.5
2.0
1.5
1.5
1.5
3.0
3.0
3.0
3.0
2.5
3.0
2.5
3.0
3.5
3.0
3.0
3.0
2.5
2.5
4.0
4.0
99
99
98
95
99
98
99
92
96
81
98
99
99
99
92
94
84
95
93
98
99
99
99
228–290[
203–204[
208–209[
208–210[
192–194[
222–223[
177–178[
20]
18]
20]
18]
18]
18]
18]
18]
18]
20]
20]
20]
20]
20]
20]
18]
15]
15]
20]
20]
19]
19]
4-CNC6H4
2,4-Cl2C6H3
2-NO2C6H4
4-NO2C6H4
4-MeC6H4
4-N(Me)2C6H4
3,4-OCH2OC6H3
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
2,4-Cl2C6H4
4-MeC6H4
C6H5
3,4-OCH2OC6H3
C6H5
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
[
215–216
CN
CN
220–222[
211–212[
[
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CONH2
CONH2
182–183
184–185[
153–154[
172–173[
156–157[
155–156[
156–157[
146–147[
[
4-MeC6H4
3-NO2C6H4
4-ClC6H4
C6H5
4-ClC6H4
172–173
190–191[
[
166–167
216–217[
189–190[
AYield of pure isolated products.

One-Pot Synthesis of Tetrahydrobenzo[b]pyran Derivatives
307
In conclusion, we have developed a green procedure for
the synthesis of biologically interesting products, benzopyran
derivatives 8, without a catalyst in tap water under reflux con-
ditions. The products are obtained in almost pure form by
simple filtration or, if necessary, the products were purified by
crystallization in ethanol.
(f) A. Lubineau, J. Auge, Y. Queneau, Synthesis 1994, 741.
doi:10.1055/S-1994-25562
(
g) C. J. Li, Chem. Rev. 1993, 93, 2023. doi:10.1021/CR00022A004
6] W. O. Foye, Prinicipi di Chimica Farmaceutica Piccin 1991, p. 416
Padova: Italy).
[
(
[
[
7] L. L. Andreani, E. Lapi, Bull. Chim. Farm. 1960, 99, 583.
8] Y. L. Zhang, B. Z. Chen, K. Q. Zheng, M. L. Xu, X. H. Lei, Yao Xue
Xue Bao 1982, 17, 17 [Chem. Abstr. 1982, 96, 13538e].
[
9] L. Bonsignore, G. Loy, D. Secci, A. Calignano, Eur. J. Med. Chem.
Experimental
1993, 28, 517. doi:10.1016/0223-5234(93)90020-F
Typical Procedure
[
[
[
[
10] E. C. Whitte, P. Neubert, A. Roesch, German Pat. DE 3427985 1986
[Chem. Abstr. 1986, 104, 224915f].
11] D. Armesto, W. M. Horspool, N. Martin, A. Ramos, C. Seaone, J. Org.
Chem. 1989, 54, 3069. doi:10.1021/JO00274A021
12] S. Hatakeyama, N. Ochi, H. Numata, S. Takano, J. Chem. Soc., Chem.
Commun. 1988, 1202. doi:10.1039/C39880001202
13] R. Gonzalez, N. Martin, C. Scoanc, J. Soto, J. Chem. Soc., Perkin
Trans. 1985, 1, 1202.
14] K. Singh, J. Singh, H. Singh, Tetrahedron 1996, 52, 14237.
15] X.-S. Wang, D.-Q. Shi, S.-J. Tu, C.-S. Yao, Synth. Commun. 2003, 33,
119. doi:10.1081/SCC-120015567
[16] (a)A.-Q. Wang, J.-S. Zhang, F.-S. Zhang, T.-S. Li,Youji Huazue 2004,
24, 1598.
A mixture of 4-chlorobenzaldehyde 1c (1 mmol), dimedone 3
(
1 mmol), and malononitrile 2 (2 mmol) in tap water (10 mL)
was refluxed for 1.5 h. After completion of the reaction (TLC),
the mixture was cooled in ice and filtered to give almost pure
product in 98% yield.
Compound 4c. νmax (KBr) 3300, 3200, 3040, 2990, 2970,
−
1
2
240, 1650, 1610, 1490, 850 cm . δH (CDCl3) 1.01 (s, 3H,
CH3), 1.09 (s, 3H, CH3), 2.22 (s, 2H, CH2), 2.59 (s, 2H, CH2),
.07 (br s, 2H, NH2), 4.30 (s, 1H, CH), 7.30 (m, 4H, ArH).
Found: C 65.7, H 5.3, N 8.4, Cl 10.6%; C18H17N2O2Cl (328.11)
[
[
3
(
requires C 65.9, H 5.2, N 8.5, Cl 10.7%.)
(
b)A. M. Shestopalov,Yu. M. Emelianova,V. N. Nesterov, Russ. Chem.
Bull. 2003, 52, 1164. doi:10.1023/A:1024721710597
(c) S.-J. Tu, H. Jiang, Q.-Y. Zhuang, C.-B. Miao, D.-Q. Shi,
X.-S. Wang, Y. Gao, Youji Huaxue 2003, 23, 488.
Accessory Publication
Spectroscopic data for 4a–w are available from the author or,
until April 2012, the Australian Journal of Chemistry.
(
d) F. Abdel-Latif, M. M. Masahaly, E. H. El-Gawish, J. Chem. Res.
S 1995, 5, 178.
e) B. Saeed, B. Morteza, A. Alimohammad, M. Barahman, Synlett
006, 2, 263.
f) D. Q. Shi, S. Zhang, Q. Y. Zhuang, Chin. J. Org. Chem. 2005,
5, 1570.
17] J.-T. Li, W.-Z. Xu, L.-C. Yang, T.-S. Li, Synth. Commun. 2004, 34,
565. doi:10.1081/SCC-200043233
18] T.-S. Jin, A.-Q. Wang, X. Wang, J.-S. Zhang, T.-S. Li, Synlett 2004, 5,
71. doi:10.1055/S-2004-820025
(
2
(
2
Acknowledgments
B.P.B. thanks CSIR, New Delhi, for financial assistance (project no.
1
/2023/05/EMR-II), and B.L.K. thanks CSIR, New Delhi, for a Junior
[
[
Research Fellowship.
4
References
8
[
1] P. Anastas, T. Williamson, Green Chemistry, Frontiers in Benign
Chemical Synthesis and Procedures 1998 (Oxford Science Publica-
tions: Oxford).
[19] I. Devi, P. J. Bhuyan, Tetrahedron Lett. 2004, 45, 8625. doi:10.1016/
J.TETLET.2004.09.158
[20] S. Balalaie, M. Bararjanian,A. M.Amani, B. Morassagh, Synlett 2006,
2, 263. doi:10.1055/S-2006-926227
[21] G. Kaupp, M. R. Naimi-Jamal, J. Schmeyers, Tetrahedron 2003, 59,
3753. doi:10.1016/S0040-4020(03)00554-4
[22] S.-J. Tu, Y. Gao, C. Guo, D. Shi, Z. Lu, Synth. Commun. 2002, 32,
2137. doi:10.1081/SCC-120005420
[2] P. A. Wender, S. L. Handy, D. L. Wright, Chem. Ind. 1997, 165.
[3] T. Hudlicky, Chem. Rev. 1996, 96, 3. doi:10.1021/CR950012G
[4] N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199. doi:10.1021/
CR960401Q
[
5] (a) A. Lubineau, J. Auge, Top. Curr. Chem. 1999, 206, 1.
(
(
(
(
b) D. Sinou, Top. Curr. Chem. 1999, 206, 41.
[23] (a) R. Maggi, F. Bigi, S. Carloni, A. Mazzacani, G. Sartori, Green
Chem. 2001, 3, 173. doi:10.1039/B101822C
c) C. J. Li, T. H. Chan, Tetrahedron Lett. 1999, 51, 1.
d) C. J. Li, T. H. Chan, Tetrahedron Lett. 1999, 51, 149.
e) F. Fringerelli, O. Piermatti, F. Pirro, Heterocycles 1999, 50, 611.
(b) F. Bigi, M. L. Conforti, R. Maggi, A. Piccinno, G. Sartori, Green
Chem. 2000, 2, 101. doi:10.1039/B001246G