A green synthesis of tetrahydrobenzo[b]pyran derivatives through three-component condensation using N-methylimidazole as organocatalyst

Article abstract of DOI:10.1007/s00706-007-0706-2

An efficient and convenient approach to the synthesis of 2-amino-3-cyano-4-aryl-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran derivatives using N-methylimidazole as the organocatalyst (20∈mol%) is described. This method has several advantages, suc

Full text of DOI:10.1007/s00706-007-0706-2

Monatshefte fu¨r Chemie 139, 129–131 (2008)
DOI 10.1007/s00706-007-0706-2
Printed in The Netherlands
A Green Synthesis of Tetrahydrobenzo[b]pyran Derivatives through
Three-Component Condensation Using N-Methylimidazole as Organocatalyst
ꢀ
Xi-Zhong Lian, Yu Huang, Yi-Qun Li , and Wen-Jie Zheng
Department of Chemistry, Jinan University, Guangzhou, China
Received April 18, 2007; Accepted May 2, 2007; Published online November 30, 2007
# Springer-Verlag 2007
Summary. An efficient and convenient approach to the
synthesis of 2-amino-3-cyano-4-aryl-7,7-dimethyl-5-oxo-4H-
its own merit, with at least one of the drawbacks
of low yields, long reaction times, harsh reaction
5,6,7,8-tetrahydrobenzo[b]pyran derivatives using N-methyl-
conditions, and tedious work-up procedures.
imidazole as the organocatalyst (20 mol%) is described. This
In the past few years organocatalysts have emerged
method has several advantages, such as mild conditions, high
as a powerful approach for the preparation of impor-
tant building blocks or compounds. Organocatalysts
are small organic molecules, like cinchona alkaloids
or L-proline. Their derivatives are readily commer-
cially available catalysts and they have been used in
various transformations with excellent yields [12].
N-Methylimidazole has been used rather seldom
in organic reactions as an organocatalyst [13]. The
use of N-methylimidazole as a catalyst in the synthe-
sis of the 4H-benzo[b]pyran derivatives has not yet
been reported. As part of our work on one-pot mul-
ticomponent reactions catalyzed by organocatalysts
for the synthesis of various heterocyclic compounds
of biological importance we wish to report a general
and highly efficient procedure for the preparation of
this kind of compounds. It is achieved via a one-pot
three-component tandem Knoevenagel-cycloconden-
sation reaction using the inexpensive and commer-
cially available N-methylimidazole as organocatalyst.
yields, and simple work-up procedure.
Keywords. Tetrahydrobenzo[b]pyran; N-Methylimidazole;
Organocatalyst.
Introduction
In recent years, 4H-benzo[b]pyrans and their deriv-
atives become of considerable interest due to their
wide range of biological properties [1], such as
anticoagulant, spasmolytic, diuretic, anticancer, and
antianaphylactin characteristics. A number of 2-
amino-4H-pyrans are useful as photoactive materials
[2]. Furthermore, 4H-benzo[b]pyrans constitute the
structural unit of a series of natural products [3].
The conventional methods for syntheses of 4H-
benzo[b]pyrans use organic solvents, such as acetic
acid or DMF [4]. Recently, there have been many
methods reported for the preparation of 4H-benzo-
[b]pyrans through two-component or three-compo-
nent condensations including the use of microwave
irradiation [5], ultrasonic irradiation [6], or use of
(diethylamino)propylated silica [7], hexadecyltri-
methylammonium bromide (HTMAB) [8], triethyl-
benzylammonium chloride (TEBA) [9], (S)-proline
[10], and rare earth perfluorooctanoate [RE(PFO)3]
[11] as catalysts. Each of the above protocols has
Results and Discussion
When 4-chlorobenzaldehyde, malononitrile, and 5,5-
dimethyl-1,3-cyclohexanedione (dimedone) were
treated with a single drop of N-methylimidazole un-
der three different sets of reaction conditions, name-
ly (i) using traditional ethanol as solvent (Method
A); (ii) using water as reaction medium (Method
ꢀ
Corresponding author. E-mail: tlyq@jnu.edu.cn

130
X.-Z. Lian et al.
Scheme 1
Table 1. Synthesis of tetrahydrobenzo[b]pyrans catalyzed by N-methylimidazole
Entry
Ar
Product
Time=min
Yielda=%
Mp=ꢁC
EtOH
H2O
Grind
EtOH
H2O
Grind
Found
Ref.
1
2
3
4
5
6
7
8
9
10
4-Cl-C6H4
2-Cl-C6H4
2,4-2Cl-C6H3
4-NO2-C6H4
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
60
60
60
10
60
90
150
256
420
120
90
780
–
150
90
420
180
720
540
90
4
38
35
10
2
45
53
36
55
3
95
93
98
92
91
87
87
83
94
95
90
95
–
94
90
87
97
92
95
91
93
89
93
92
91
90
94
87
96
87
209–210
215–216
116–117
177–179
224–225
214–215
217–218
199–200
227–228
216–217
209–211 [10]
217–218 [8]
115–117 [11]
177–178 [8]
226–228 [11]
214–216[8]
214–215 [8]
199–201 [8]
228–230 [5]
218–220 [4b]
b
b
4-Me-C6H4
4-HO-C6H4
4-MeO-C6H4
3-MeO-4-HO-C6H3
furyl
4j
a
Yields refer to those of pure isolated products characterized by spectroscopic data
Mixtures including the desired product and an intermediate
b
B); and (iii) dry grinding in a mortar with pestle
and an intermediate were observed with water as
the reaction medium compared with the other two
methods in the case that a chloride substituent occu-
pied o- and p-positions of the aromatic ring (Table 1,
entry 3).
The catalyst plays a crucial role in the success
of the reaction in terms of the rate and the yields.
Taking the 4-chlorobenzaldehyde reaction with ma-
lononitrile and dimedone as a reference, the reaction
could not be carried out in the absence of the catalyst
at room temperature.
(Method C) at room temperature, the three-compo-
nent cyclocondensation reaction proceeded smoothly
to give the desired products derivatives 2-amino-
3-cyano-4-aryl-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetra-
hydrobenzo[b]pyran in high to excellent yields
(Scheme 1). To explore the scope of this reaction,
we extended the reaction to various aromatic alde-
hydes carrying either electron withdrawing or elec-
tron releasing substituents. Both gave the desired
products. The results are shown Table 1.
As can be seen from Table 1, electronic effects
and the nature of substituents on the aromatic ring
showed strongly obvious effects in terms of reaction
time under the three reaction conditions mentioned
above. When aromatic aldehydes containing electron-
donating groups (such as hydroxy, alkoxy, or methyl
group) were employed (Table 1, entries 6–9), a lon-
ger reaction time was required than those encoun-
tered with electron-withdrawing groups (such as
nitro or halide) on aromatic rings (Table 1, entries
1–4). It is note worthy, that the reaction proceeded
without the protection of acidic hydroxy substituents
(Table 1, entries 7 and 9). It should also be men-
tioned that mixtures including the desired product
Among the above methods, the solvent-free ap-
proach (Method C) provided the best results. Al-
though the reaction carried out in water (Method B)
showed similar results as in ethanol (Method A),
Method A apparently facilitates higher reaction rates
than Method B due to the homogeneous reaction.
In conclusion, we developed a facile and effective
procedure for the synthesis of 2-amino-4-aryl-3-cya-
no-4,6,7,8-tetrahydro-5H-1-benzopyran-5-ones from
aromatic aldehydes, malononitrile, and dimedone in
the presence of the organocatalyst N-methylimida-
zole. Compared to the existing method, it has the
advantages of excellent yields, inexpensive opera-
tion, and environmental friendliness.

A Green Synthesis of Tetrahydrobenzo[b]pyran Derivatives
131
Experimental
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General Experimental Procedure: Methods A and B
A solution of an aromatic aldehyde 1 (3mmol), 198mg ma-
lononitrile (2, 3 mmol), 420 mg dimedone (3, 3 mmol) and
N-methylimidazole (one drop, ca. 20mol%) in 10cm3 95%
EtOH (Method A) or in 10 cm3 H2O (Method B) was vigor-
ously stirred at room temperature for the specific time indicat-
ed in Table 1. The end of the reaction was monitored by TLC.
Then, the mixture was poured into water (Method A) or was
cooled in a refrigerator overnight (Method B) to precipitate
the solid. The crude product obtained was filtered off by suc-
tion and washed with 3ꢂ10 cm3 H2O. The pure product was
obtained by recrystallization from ethanol.
General Experimental Procedure: Method C
A mixture of as given above for Methods A and B was ground
for the appropriate time using a mortar and pestle of appropri-
ate size. The initial syrupy reaction mixture solidified within
4–30 min. The solid was washed with cold water and recrys-
tallized from ethanol.
All of the products are known and the data were found to be
identical with those reported in literature.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 20672046) and the Guangdong Natural Science
Foundation (No. 04010458).