(S)-proline as a neutral and efficient catalyst for the one-pot synthesis of tetrahydrobenzo[b]pyran derivatives in aqueous media

Article abstract of DOI:10.1055/s-2006-926227

(S)-Proline has been used as a mild, efficient and neutral catalyst for synthesis of various 4H-benzo[b]pyran derivatives via a one-pot three-component condensation of aromatic aldehydes, active methylene compounds, and dimedone in aqueous media. This method offers the advantages of proceeding and neutral and mild conditions, giving high to excellent yields of the products and simple workup. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926227

LETTER
263
(S)-Proline as a Neutral and Efficient Catalyst for the One-Pot Synthesis of
Tetrahydrobenzo[b]pyran Derivatives in Aqueous Media
(S)-Proline as
a
C
atalyst for
e
One-Pot
S
e
ynthesis of
d
T
etrahydrobenzo[
b
B
]pyranDerivativ
a
es lalaie,* Morteza Bararjanian, Ali Mohammad Amani, Barahman Movassagh
Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
Fax +98(21)22853650; E-mail: balalaie@kntu.ac.ir
Received 19 September 2005
of low yields, difficult to obtain reagents, long reaction
times, effluent pollution, harsh reaction conditions and
tedious workup procedures. This report describes a very
efficient one-pot three-component synthesis of tetra-
Abstract: (S)-Proline has been used as a mild, efficient and neutral
catalyst for synthesis of various 4H-benzo[b]pyran derivatives via a
one-pot three-component condensation of aromatic aldehydes,
active methylene compounds, and dimedone in aqueous media.
This method offers the advantages of proceeding and neutral and hydrobenzo[b]pyrans catalyzed by (S)-proline in water-
mild conditions, giving high to excellent yields of the products and
based media.
simple workup.
The amino acid proline is a remarkable molecule which
Key words: 4H-benzo[b]pyrans, 4H-chromene, aqueous media,
has become important in asymmetric catalysis; where it
(S)-proline, Knoevenagel–cyclocondensation reaction
can act as a ligand in asymmetric transition-metal cataly-
sis, a chiral modifier in heterogeneously catalyzed hydro-
genations, and most importantly, can itself be an effective
A consequence of the necessity to minimize the amount of
organocatalyst of several powerful asymmetric trans-
toxic waste and by-products from chemical processes is a
formations, such as the aldol, Mannich, and Michael
need for the development of new, more environmentally
reactions.14 Proline is an abundant bifunctional chiral
friendly, synthetic methods. Nowadays, in the develop-
molecule that is inexpensive and available in both enan-
ment of new processes, ecological impact must also be
tiomeric forms. These two functional groups can both act
taken into account and solvents are a central feature, as
as acid or base and can also facilitate chemical transfor-
they are generally used in large quantities such a consid-
mations in concert, similar to enzymatic catalysis.14
eration has prompted synthetic organic chemists to redis-
As part of our work on one-pot multicomponent reactions
cover the potential of water as a solvent for organic
(MCRs) for the synthesis of various heterocyclic com-
reactions.1
pounds of biological importance,15 we wish to report here-
in a highly efficient procedure for the preparation of 4H-
benzo[b]pyrans via a one-pot three-component tandem
4H-Benzo[b]pyrans and their derivatives are of consider-
able interest because of their wide range of biological
property,2 such as spasmolytic, diuretic, anti-coagulant,
Knoevenagel–cyclocondensation reaction using (S)-pro-
anti-cancer, anti-anaphylactic activity.3 In addition, they
line as catalyst in aqueous medium (Scheme 1).
can be used as cognitive enhancers, for the treatment of
neurodegenerative disease, including Alzheimer’s dis-
O
Ar
O
O
O
ease, amyotrophic lateral sclerosis, Huntington’s disease,
Parkinson’s disease, AIDS associated dementia and
Down’s syndrome as well as for the treatment of schizo-
phrenia and myoclonus.4 4H-Pyrans also constitute the
structural unit of a series of natural products.5 Finally, a
number of 2-amino-4H-pyrans are useful as photoactive
materials.6
O
R
CN
R
(S)-proline (5 mol%)
+
+
Ar
H
A) H2O, r.t.
B) aq EtOH, 50 °C
NH2
1
2
3
4
Scheme 1
In a typical general experimental procedure, solutions of
aromatic aldehydes 1, malononitrile or cyanoacetate 2,
and 5,5-dimethyl-1,3-cyclohexanedione (dimedone) 3, in
either water at room temperature, or H2O–EtOH (1:1) at
50 °C, keep mixed thoroughly in the presence of a catalyt-
ic amount of (S)-proline to afford the 4H-benzo[b]pyrans
416 in good to excellent yields. The structures of the prod-
ucts were confirmed from physical and spectroscopic (IR
and 1H NMR) data; 1H NMR spectra of 4H-benzo[b]pyr-
ans 4 show characteristic peaks at d = 4.30–4.60 ppm for
H-4, and two doublets at d = 2.25 and 2.10 ppm for H-6
and H-6¢, respectively.16
The conventional reported syntheses of 4H-benzo[b]pyr-
ans use organic solvents such as DMF or acetic acid;7,8
but, these solvents make the workup procedure complicat-
ed and lead to poor yields of products. Pyrans have also
been synthesized under microwave9 and ultrasound10 irra-
diations. Recently, some two-component11 and three-
component12,13 condensations have been introduced for
the synthesis of benzo[b]pyrans. Each of the above meth-
ods has its own merit, with at least one of the limitations
SYNLETT 2006, No. 2, pp 0263–0266
0
1.
0
2.
2
0
0
6
Advanced online publication: 24.01.2006
DOI: 10.1055/s-2006-926227; Art ID: D28705ST
© Georg Thieme Verlag Stuttgart · New York

264
S. Balalaie et al.
LETTER
When malononitrile, aromatic aldehydes, and dimedone (method B) in the presence of the catalyst; due to lower re-
were treated with (S)-proline in water at room temperature activities of the cyanoacetates compared to malononitrile.
(method A), the desired 2-amino-3-cyano-4-aryl-7,7-di-
methyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran deriv-
atives 4a–p were obtained in high to excellent yields (78–
A proposed mechanism for the reaction is outlined in
Scheme 2. Based on this mechanism, proline is an effec-
tive catalyst for the formation of the cyano olefin 7, readi-
98%, Table 1) within a very short period of time (30 min);
ly prepared in situ from Knoevenagel condensation of aryl
an exception was the derivative 4p for which the reaction
aldehyde 1 and active methylene compound 2, which pro-
ceeds via iminium ion 5 and ammonium ion 6. Proline
also catalyzes the generation of enamine 8 from dimedone
3, which reacts with the cyano olefin 7 followed by
did not go to completion under those conditions. There-
fore the reaction was conducted in refluxing water for two
hours. Longer reaction times and higher temperatures
(50 °C) were required for condensation of cyanoace-
cyclization to give the iminium ion 10; upon hydrolysis of
tates, aromatic aldehydes, and dimedone in H2O–EtOH
this ion the product 4 can be formed.17
Table 1 (S)-Proline-Catalyzed Synthesis of 4H-Benzo[b]pyrans (4a–x) in Aqueous Media
Product
4a
4b
4c
Ar
R
Methoda
Yield (%)b
82
Mp (°C) found
228–230
203–205
209–211
208–210
255–257
192–194
236–238
204–205
237–238
248–249
222–223
212–214
179–180
223–225
219–221
212–213
166–168
190–192
155–157
153–155
172–174
156–158
182–184
183–185
Mp (°C) reported
226–2288
C6H5
CN
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
Ac
B
B
B
B
B
B
B
B
4-Br-C6H4
CN
97
196–1989
4-Cl-C6H4
CN
97
207–2098
4d
4e
4-CN-C6H4
2,3-Cl2-C6H3
2,4-Cl2-C6H3
3-OH-C6H4
4-OH-C6H4
3-OH-4-OCH3-C6H3
4-CH3CONH-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
4-CH3-C6H4
4-CF3-C6H4
4-NMe2-C6H4
4-Cl-C6H4
CN
94
CN
93
4f
CN
78
4g
4h
4i
CN
94
CN
88
206–2089
237–23812
CN
95
4j
CN
96
4k
4l
CN
88
224–22612
208–21112
177–17812
214–21612
CN
98
4m
4n
4o
4p
4q
4r
CN
82
CN
93
CN
95
CN
81
208–2109
167–1688
190–19210
158–1608
150–1528
170–17210
156–1578
182–18410
181–18310
CO2CH3
CO2CH3
CO2CH2CH3
CO2CH2CH3
CO2CH2CH3
CO2CH2CH3
CO2CH2CH3
CO2CH2CH3
95
3-NO2-C6H4
C6H5
95
4s
67
4t
4-Cl-C6H4
92
4u
4v
4w
4x
2,4-Cl2-C6H3
4-CH3-C6H4
3-NO2-C6H4
4-NO2-C6H4
93
82
97
81
a Method A: the reaction was conducted in H2O at r.t. Method B: the reaction was carried out in H2O–EtOH (1:1) at 50 °C.
b Yields refer to those of pure isolated products characterized by IR, 1H NMR and 13C NMR spectroscopic data.
c The reaction was conducted in H2O under reflux for 2 h.
Synlett 2006, No. 2, 263–266 © Thieme Stuttgart · New York

LETTER
(S)-Proline as Catalyst for One-Pot Synthesis of Tetrahydrobenzo[b]pyran Derivatives
265
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COO–
N
R
O
Ar
H
CN
2
5
Ar
H
1
COO–
N
COOH
H
Ar
R
N
H
6
H
CN
Ar
H
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R
7
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COOH
N
N
O
Ar
H
COOH
H
H
O
8
R CN
9
O
O
(9) Tu, S. J.; Gao, Y.; Guo, C.; Shi, D.; Lu, Z. Synth. Commun.
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H
COOH
NH
R
Ar
3
N
HOOC
NH2
O
10
H2O
O
Ar
H
(13) Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 8625.
(14) List, B. Tetrahedron 2002, 58, 5573; and references cited
therein.
R
O
NH2
4
(15) (a) Balalaie, S.; Hashtroudi, M. S.; Sharifi, A. J. Chem. Res.,
Synop. 1999, 392. (b) Balalaie, S.; Arabanian, A.;
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(16) General Experimental Procedure: Method A.
A solution of an aromatic aldehyde 1 (1 mmol), malono-
nitrile (2, 1.2 mmol), 5,5-dimethyl-1,3-cyclohexanedione (3,
1.1 mmol) and (S)-proline (5 mol%) in H2O (20 mL) was
stirred at r.t. for 0.5 h (in the case of 4p, the reaction mixture
was stirred in refluxing H2O for 2 h). Then, the mixture was
cooled in a refrigerator overnight; the solid compound
obtained was filtered off and washed with H2O (30 mL). The
crude products were purified by recrystallization from EtOH
(96%).
Scheme 2 The proposed mechanism for (S)-proline-catalyzed
synthesis of 4H-benzo[b]pyrans (4a–x) in aqueous media
In conclusion, we have demonstrated a rapid and very
efficient, (S)-proline-catalyzed, one-pot three-component
synthesis of tetrahydrobenzo[b]pyran derivatives in aque-
ous media. The current methodology has the advantages
of operational simplicity, neutral and mild reaction condi-
tions, high to excellent yields of products, lack of toxicity,
and low cost.
Acknowledgment
Saeed Balalaie is grateful to the Alexander von Humboldt founda-
tion for a Research Fellowship and Equipment donation. Partial
support of this work by the K. N. Toosi University of Technology
Research Council is gratefully acknowledged.
General Experimental Procedure: Method B.
A mixture of aromatic aldehyde 1 (1 mmol), alkyl cyano-
acetate (2, 1.2 mmol), 5,5-dimethyl-1,3-cyclohexanedione
(3, 1.1 mmol) and (S)-proline (5 mol%) in a mixture of H2O
(15 mL) and EtOH (15 mL) was stirred at 50 °C for 2 h.
After completion of the reaction, the volume of the solution
was reduced to half, and H2O (15 mL) was added. Then the
mixture was cooled in a refrigerator overnight and the solid
compound was collected by filtration. The crude products
References and Notes
(1) (a) Anastas, P. T.; Williamson, T. C. In Green Chemistry,
Designing Chemistry for the Environment; Anastas, P. T.;
Williamson, T. C., Eds.; American Chemical Society:
Washington DC, 1996, 1. (b) Grieco, P. A. In Organic
Synthesis in Water; Thomson Science: Glasgow, 1998, 1.
Synlett 2006, No. 2, 263–266 © Thieme Stuttgart · New York

266
S. Balalaie et al.
LETTER
d, J = 16.0 Hz, H-6¢), 2.48 (2 H, br s, H-8), 3.64 (3 H, s,
OMe), 4.80 (1 H, s, H-4), 6.30 (2 H, br s, NH2), 7.39 (1 H, t,
J = 13.0 Hz, ArH), 7.68 (1 H, dt, J = 13.0, 3.2 Hz, ArH), 8.00
(1 H, m, ArH), 8.08 (1 H, t, J = 3.2 Hz, ArH).
Compound 4s: IR (KBr): nmax = 3404, 3291, 1691, 1655
cm–1. 1H NMR (CDCl3): d = 1.00 (3 H, s, Me), 1.13 (3 H, s,
Me), 1.19 (3 H, t, J = 7.08 Hz, Me), 2.20 (1 H, d, J = 16.0
Hz, H-6), 2.26 (1 H, d, J = 16.0 Hz, H-6¢), 2.46 (2 H, br s, H-
8), 4.06 (2 H, m, OCH2), 4.73 (1 H, s, H-4), 6.22 (2 H, br s,
NH2), 7.14 (1 H, t, J = 7.2 Hz, ArH), 7.24 (2 H, t, J = 7.2 Hz,
ArH), 7.30 (2 H, d, J = 7.5 Hz, ArH).
were recrystallized from EtOH (96%). IR spectra were
obtained on a Shimadzu IR-460 and Perkin-Elmer FT-IR
Spectrum 1 spectrometer. 1H NMR spectra were run on a
Bruker DRX-500 (500 MHz) AVANCE instrument using
TMS as internal standard and DMSO-d6 or CDCl3 as
solvent. Data of selected compounds are given below:
Compound 4d: 1H NMR (DMSO-d6): d = 0.95 (3 H, s, Me),
1.04 (3 H, s, Me), 2.10 (1 H, d, H-6, J = 16.0 Hz), 2.24 (1 H,
d, H-6¢, J = 16.0 Hz), 2.51 (2 H, br s, H-8), 4.29 (1 H, s, H-
4), 7.16 (2 H, br s, NH2), 7.37 (2 H, d, J = 8.05 Hz, ArH),
7.76 (2 H, d, J = 8.05 Hz, ArH).
Compound 4j: 1H NMR (DMSO-d6): d = 0.94 (3 H, s, Me),
1.03 (3 H, s, Me), 2.01 (3 H, s, COMe), 2.08 (1 H, d, J = 16.0
Hz, H-6), 2.24 (1 H, d, J = 16.0 Hz, H-6¢), 2.50 (2 H, br s, H-
8), 4.11 (1 H, s, H-4), 6.99 (2 H, br s, NH2), 7.04 (2 H, d,
J = 8.4 Hz, ArH), 7.45 (2 H, d, J = 8.4 Hz, ArH), 9.87 (1 H,
s, NHCO).
Compound 4q: IR (KBr): nmax = 3429, 3313, 1694, 1653
cm–1. 1H NMR (CDCl3): d = 1.00 (3 H, s, Me), 1.14 (3 H, s,
Me), 2.20 (1 H, d, J = 16.0 Hz, H-6), 2.27 (1 H, d, J = 16.0
Hz, H-6¢), 2.45 (2 H, br s, H-8), 3.65 (3 H, s, OMe), 4.73 (1
H, s, H-4), 6.20 (2 H, br s, NH2), 7.21 (2 H, d, J = 8.4 Hz,
ArH), 7.24 (2 H, d, J = 8.4 Hz, ArH).
Compound 4t: IR (KBr): nmax = 3477, 3317, 1692, 1669
cm–1. 1H NMR (CDCl3): d = 0.98 (3 H, s, Me), 1.11 (3 H, s,
Me), 1.17 (3 H, t, J = 7.1 Hz, Me), 2.17 (1 H, d, J = 16.0 Hz,
H-6), 2.27 (1 H, d, J = 16.0 Hz, H-6¢), 2.44 (2 H, br s, H-8),
4.05 (2 H, m, OCH2), 4.68 (1 H, s, H-4), 6.20 (2 H, br s,
NH2), 7.19 (2 H, d, J = 8.1 Hz, ArH), 7.21 (2 H, d, J = 8.1
Hz, ArH).
Compound 4x: IR (KBr): nmax = 3476, 3338, 1687, 1659
cm–1. 1H NMR (CDCl3): d = 1.00 (3 H, s, Me), 1.15 (3 H, s,
Me), 1.17 (3 H, t, J = 7.1 Hz, Me), 2.20 (1 H, d, J = 16.0 Hz,
H-6), 2.28 (1 H, d, J = 16.0 Hz, H-6¢), 2.49 (1 H, d, J = 16.0
Hz, H-8), 2.50 (1 H, d, J = 16.0 Hz, H-6¢), 4.06 (2 H, m,
OCH2), 4.83 (1 H, s, H-4), 6.32 (2 H, br s, NH2), 7.48 (2 H,
d, J = 8.8 Hz, ArH), 8.12 (2 H, d, J = 8.8 Hz, ArH).
(17) List, B. Synlett 2001, 1675.
Compound 4r: IR (KBr): nmax = 3431, 3315, 1696, 1656,
1532, 1352 cm–1. 1H NMR (CDCl3): d = 0.98 (3 H, s, Me),
1.12 (3 H, s, Me), 2.16 (1 H, d, J = 16.0 Hz, H-6), 2.26 (1 H,
Synlett 2006, No. 2, 263–266 © Thieme Stuttgart · New York