Microwave-promoted sequential three-component synthesis of tetrahydrobenzo[b]pyran in water catlyzed by heterogeneous amine grafted on silica

Article abstract of DOI:10.3987/COM-06-10698

A variety of tetrahydrobenzo[b]pyrans have been synthesized by sequential addition of arylaldehydes, cyanoacetate and then dimedone in water under microwave irradiation. A heterogeneous amine, N,N-diethylamino-propylated silica, was an effective catalyst for the reaction. The reaction with malononitrile provided the same result. The reaction condition was general to apply to the aldehyde having a Cl, NO₂, OH, OMe, or CO₂H group in satisfactory yield.

Full text of DOI:10.3987/COM-06-10698

HETEROCYCLES, Vol. 68, No. 5, 2006
889
HETEROCYCLES, Vol. 68, No. 5, 2006, pp. 889 - 895. © The Japan Institute of Heterocyclic Chemistry
Received, 9th February, 2006, Accepted, 20th March, 2006, Published online, 24th March, 2006. COM-06-10698
MICROWAVE-PROMOTED SEQUENTIAL THREE-COMPONENT
SYNTHESIS OF TETRAHYDROBENZO[b]PYRAN IN WATER
CATLYZED BY HETEROGENEOUS AMINE GRAFTED ON SILICA
a
b
a
b
Hisahiro Hagiwara, * Ayuko Numamae, Kohei Isobe, Takashi Hoshi, and
b
Toshio Suzuki
a
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho,
b
Ikarashi, Niigata 950-2181, Japan. Faculty of Engineering, Niigata University,
8
050,
2-Nocho,
Ikarashi,
Niigata
950-2181,
Japan.
e-mail:
hagiwara@gs.niigata-u.ac.jp
Abstract – A variety of tetrahydrobenzo[b]pyrans have been synthesized by
sequential addition of arylaldehydes, cyanoacetate and then dimedone in water
under
microwave
irradiation.
A
heterogeneous
amine,
N,N-diethylamino-propylated silica, was an effective catalyst for the reaction.
The reaction with malononitrile provided the same result. The reaction condition
was general to apply to the aldehyde having a Cl, NO , OH, OMe, or CO H group
2
2
in satisfactory yield.
A sustainable and environmentally benign process is required in producing organic compounds. In order
to realize such process, a catalytic reaction in environmentally benign reaction media is desired rather
1
than a stoichiometric reaction. A heterogeneous catalyst is preferable to homogeneous catalyst due to its
facile recovery, and an organomolecular catalyst is superior to an organometallic catalyst due to its
flexible design and safe in disposal.
From such standpoint, we reported nucleophilic reactions in environmentally friendly media such as an
ionic liquid, super critical carbon dioxide or water, employing organomolecular catalysts supported on
2
silica gel. The reaction conditions were mild enough to apply to substrates having acid- or base-sensitive
substituents. The catalyst could be recycled several times without deterioration.
Tetrahydrobenzo[b]pyrans (7 and 8) are useful compounds having various biological activities as
3
4
antischistosomal agent, immunomodulator, anticoagulant, anticancer and others. Its synthesis has been

890
HETEROCYCLES, Vol. 68, No. 5, 2006
accomplished by condensation of α,β-unsaturated nitriles (4 or 5) with cyclic-1,3-dicarbonyl compounds
3
4
5
employing mainly a basic catalyst such as triethylamine, ammonium acetate, potassium fluoride, or
6
hexadecylammonium bromide, while silica gel was an effective catalyst under microwave irradiation
7
without a solvent. In spite of a number of two component-condensation methods cited above, there is
only one example of three component condensation mixing aldehyde, cyanoacetate, 1,3-dicarbonyl
8
compound and triethylamine in one pot operation. Another three-component condensation employed a
9
masked aldehyde under acidic reaction conditions.
2
a
Our recent results on Knoevenagel reaction in water catalyzed by amine supported on silica gel,
prompted us to investigate a new protocol leading to tetrahydrobenzo[b]pyrans (7 or 8) under more facile
and environmentally benign reaction conditions (Scheme 1).
2
a
Based on the results of our Knoevenagel reaction, we focused again on catalytic activity of the
heterogeneous amine supported on silica as a catalyst and on water as reaction medium, which has many
advantages from its ability to promote bimolecular reaction due to high cohesive energy density and
1
0
dielectric constant, safety due to non-flammability, non-toxicity as well as economical standpoint. The
2
a
previous Knoevenagel reaction was carried out at room temperature for a few hours. In order to
facilitate the initial Knoevenagel reaction and subsequent condensation, internal heating by microwave
1
1
11b
irradiation was applied, since water has a relatively high loss factor (tan δ) to absorb microwave.
CHO
O
R2
R2
NDEAP (0.1 eq)
+
+
CN
H O/EtOH
Microwave
2
R1
CN
O
R1
2
2
6
1
2 R = CO Et
3
4 R = CO Et
2
2
2
2
R = CN
5 R = CN
R1
O
R2
OMe
O
O
SiO2
Si
NR2
Microwave
O
NH2
NDEAP: R = Et
NAP: R = H
2
7
8
R = CO Et
2
2
R = CN
Scheme 1. One pot sequential three component synthesis of tetrahydrobenzo[b]pyrans (7 and 8)
1
The optimum reaction condition was examined employing the reaction of benzaldehyde (1) (R = H),
ethyl cyanoacetate (2) and dimedone (6) (Table 1) under microwave heating. Initial attempts to mix all
three components (1, 2 and 6) in one portion together with or without catalyst resulted in the exclusive

HETEROCYCLES, Vol. 68, No. 5, 2006
891
formation of dimeric product (9) (Figure 1) by preferential condensation of benzaldehyde (1) and
dimedone (6). This result is not unreasonable due to the higher acidity of dimedone (9) (pKa = 11.2) than
that of ethyl cyanoacetate (2) (pKa = 13.1). Then, sequential addition of dimedone (6) was attempted, in
which a mixture of benzaldehyde (1) and ethyl cyanoacetate (2) with catalyst was heated for a certain
period of time to complete the initial Knoevenagel reaction followed by addition of dimedone (6) and
subsequent heating. Though the dimeric product (9) was still obtained in 90% yield in the absence of a
catalyst under the modified procedure (Table 1, Entry 1), the desired tetrahydrobenzo[b]pyran (7) was
2
f
successfully synthesized in the presence of a heterogeneous amine catalyst (Table 1, Entries 2 and 3).
Among the catalysts, NDEAP (3-N,N-diethylaminpropylated silica) provided better result than NAP
(
3-aminpropylated silica). Addition of ethanol, which has higher tan δ to facilitate rapid heating, was
effective to improve the yield in 91% (Table 1, Entry 4). The reaction in polyethyleneglycol (PEG)
having much higher tan δ than that of ethanol, provided moderate yield of 50 % probably due to
overheating (Table 1, Entry 5). Although conventional external heating showed similar result (Table 1,
Entry 6), microwave heating was apparently superior in the reaction of a less reactive aldehyde such as
1
anisaldehyde (1) (R = OMe) (Table 3, Entry 6). Although present reaction proceeded with 0.1 equiv. of
tributylamine in comparable yield (Table 1, Entry 7), heterogeneous amine catalyst has much advantage
than homogeneous amine catalyst due to lack of contamination and recyclability (vide infra).
a
Table 1. Investigation of effective reaction conditions in the synthesis of tetrahydrobenzo[b]pyran (7)
b
Entry
Catalyst
–
Solvent
Yield (%)
c
1
2
3
4
5
H
2
O
0
d
NAP
NDEAP
13
17
91
50
87
83
e
H
2
2
O/EtOH
PEG
O/EtOH
f
6
7
H
g
3
(n-Bu) N
a
1
The reaction was carried out with benzaldehyde (1) (R = H), ethyl cyanoacetate (2) (1.2 equiv) and the
catalyst (0.1 equiv) in solvent under microwave (100 W) irradiation for 10 min. After addition of
dimedone (6) (1.2 equiv), subsequent reaction was carried out under microwave irradiation for 10 min.
The temperature ramped from room temperature to 80 °C, which was monitored by radiation
thermometer.
Yields are for isolated pure product based on
b
Figure 1. Other products
benzaldehyde (1).
c
A dimeric product of dimedone (9) was obtained
in 90% yield.
O
O
O
d
e
f
3
3
-Aminpropylated silica.
-N,N-Diethylaminpropylated silica.
CO Et
2
External heating at 80 °C for 20 min in an oil
bath.
O
O
NH2
g
1
Anisaldehyde (1) (R = OMe) was employed.
9
10

892
HETEROCYCLES, Vol. 68, No. 5, 2006
12
Employing the optimized reaction condition (Table 1, Entry 4), the catalyst, NDEAP, could be recycled
at least three times as shown in Table 2, though a certain amount of decrease of the catalytic activity
could not be denied as shown in yields and reaction time. The end-capped NDEAP as trimethylsiloxide
showed similar reactivity and recyclability as non-capped NDEAP.
a
Table 2. Recycle use of NDEAP in the synthesis of tetrahydrobenzo[b]pyran (7)
b
Entry
Total irradiation time (min)
Yield (%)
1
2
3
4
19
30
45
57
91
75
69
72
a
See Ref. 12.
b
Yields are for isolated pure product based on benzaldehyde (1).
The present reaction condition (Table 1, Entry 4) was applied to a variety of aldehydes and the results are
compiled in Table 3. Arylaldehydes (1) having not only electron-withdrawing (Table 3, Entries 2 and 3)
but also electron-donating groups (Table 3, Entries 4 and 5) provided the desired products (7). It is worthy
of note that the reaction proceeded without the protection of acidic substituents (Table 3, Entries 7 and 8).
a
Table 3. Synthesis of tetrahydrobenzo[b]pyran (7) from various aldehydes (1)
1
b
c
Entry
Aldehyde (1) (R = )
Time (min)
Yield (%)
1
2
3
4
5
H
NO
Cl
Me
OMe
6
5
91
93
92
86
79
12
65
84
66
29
35
2
12
24
21
20
15
23
30
33
37
d
6
7
8
9
OH
CO H
2
OAc
OTHP
1
1
0
1
Hydrocinnamaldehyde
a
See Ref. 12.
Total irradiation time
Yields are for isolated pure product based on aldehyde (1).
External heating at 80 °C in an oil bath.
b
c
d
In spite of the successful result of 4-acetoxybenzaldehyde (1) (Table 3, Entry 9), the reaction of
arylaldehyde (1) having an OTHP substituent did not give satisfactory results (Table 3, Entry 10) due to
recovery of the starting aldehyde (1). This issue was solved by two- component synthesis starting from
α-cyanocinnamate (4) prepared independently by NAP-catalyzed Knoevenagel condensation in good
2
a
yields (Scheme 2 and Table 4).

HETEROCYCLES, Vol. 68, No. 5, 2006
893
R1
O
O
CO Et
2
CO Et
2
NDEAP (0.1 eq)
Microwave
+
CN
R1
O
O
NH
2
4
6
7
Scheme 2. Synthesis of tetrahydrobenzo[b]pyran (7) from cyanocinnamate (4)
a
Table 4. Synthesis of tetrahydrobenzo[b]pyran (7) from cyanocinnamate (4)
1
b
c
Entry
1
cinnamate (4) (R = )
Time (min)
Solvent
Yield (%)
d
H
H
H
10
10
10
10
18
25
H
2
O
0
14
64
81
2
3
4
5
6
PEG
H
H
2
O/ EtOH
e
OAc
OTHP
74f
56
a
The reaction was carried out with cyanocinnamate (4), dimedone (6) (1.2 equiv) and NDEAP (0.1 equiv)
in water and ethanol (1 : 1) under microwave heating (100 W).
b
Total irradiation time
c
Yields are for isolated pure product based on cinnamate (4).
d
NDEAP was not added.
e
Yield based on recovered cinnamate (4) was 99%.
f
Yield based on recovered cinnamate (4) was 74%.
The reaction with malononitrile also proceeded in satisfactory yields as shown in Table 5. Different from
sequential addition employing ethyl cyanoacetate (2) described above, all three components were added
all at once in the present reaction.
a
Table 5. Synthesis of tetrahydrobenzo[b]pyran (8) with malononitrile (3)
1
b
c
Entry
Aldehyde (1) (R = )
Time (min)
Yield (%)
c
1
H
OMe
Cl
10
24
12
23
19
99
94
96
77
86
2
3
4
6
OH
OTHP
a
The reaction was carried out with arylaldehye (1), malononitrile (3), dimedone (6) (1.2 equiv) and
NDEAP (0.1 equiv) in water and ethanol (1 : 1) under microwave heating (100 W).
b
Total irradiation time
c
Yields are for isolated pure product based on aldehyde (1).

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HETEROCYCLES, Vol. 68, No. 5, 2006
In summary, we have developed a new protocol for synthesis of tetrahydrobenzo[b]pyrans (7 and 8)
catalyzed by heterogeneous amine grafted on silica gel (NDEAP) in water under microwave heating. The
catalyst was effectively recycled. The present reaction is mild, practical, environmentally benign, and
sustainable than the methods developed so far, which would be useful for large-scale preparation.
ACKNOWLEDGEMENTS
This work was partially supported by Grant-in-Aid for Scientific Research on Priority Areas (17035031
for H. H.) from The Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the
Uchida Energy Science Promotion Foundation (for H. H.).
REFERENCES AND NOTES
1
.
P. T. Anastas and J. C. Warner, ‘Green Chemistry: Theory and Practice’, Oxford University Press,
998.
1
2
.
(a) K. Isobe, T. Hoshi, T. Suzuki, and H. Hagiwara, Molecular Diversity, 2005, 9, 317; (b) H.
Hagiwara, J. Hamaya, T. Hoshi, and C. Yokoyama, Tetrahedron Lett., 2005, 46, 393; (c) M.
Fukushima, S. Endou, T. Hoshi, T. Suzuki, and H. Hagiwara, Tetrahedron Lett., 2005, 46, 3287; (d)
H. Hagiwara, A. Koseki, K. Isobe, K. Shimizu, T. Hoshi, and T. Suzuki, Synlett, 2004, 2188; (e) K.
Shimizu, H. Suzuki, T. Kodama, H. Hagiwara, and Y. Kitayama, Stud. Surf. Sci. Catal., 2003, 145,
1
8
45; (f) J. Hamaya, T. Suzuki, T. Hoshi, K. Shimizu, Y. Kitayama, and H. Hagiwara, Synlett, 2003,
73; (g) K. Shimizu, E. Hayashi, T. Inokuchi, T. Kodama, H. Hagiwara, and Y. Kitayama,
Tetrahedron Lett., 2002, 43, 9073; (h) H. Hagiwara, S. Tsuji, T. Okabe, T. Hoshi, T. Suzuki, H.
Suzuki, K. Shimizu, and Y. Kitayama, Green Chemistry, 2002, 4, 461; (i) K. Shimizu, H. Suzuki, E.
Hayashi, T. Kodama, Y. Tsuchiya, H. Hagiwara, and Y. Kitayama, Chem. Commun., 2002, 1068.
M. H. Elnagdini, F. Abdel, F. A. M. A. Aal, and Y. M. Yassin, J. Prakt. Chem., 1989, 331, 971
L. Bonsignore, G. Loy, D. Secci, and A, Calignano, Eur. J. Med. Chem., 1993, 28, 517; W. O. Foye,
Prinicipi di Chimica Farmaceutica Piccin; Padova: Italy, 1991, 416; E. C. Witte, P. Neubert, and A.
Roesch, Ger. Offen DE. 3427985, 1986; Chem. Abstr., 1986, 104, 224915f; Y. L. Zhang, B. Z. Chen,
K. Q. Zheng, M. L. Xu, and X. H. Lei, Yao Xue Xue bao, 1982, 17, 17; Chem. Abst., 1982, 96,
3
4
.
.
1
35383e; L. Lazzeri Andreani, and E. Lapi, Boll. Chim. Farm., 1960, 99, 583.
5
6
7
8
.
.
.
.
X-S. Wang, D-Q. Shi, S-J. Tu, and C-S. Yao, Synth. Commun., 2003, 33, 119.
T-S. Jin, A-Q. Wang, X. Wang, J-S. Zhang, and T-S. Li, Synlett, 2004, 871.
S. Tu, H. Wang, J. Feng, A. Tang, and J. Feng, Synth. Commun., 2001, 31, 2663.
A. M. Shestopalov, Yu. M. Emelianova, and V. N. Nesterov, Russian Chemical Bull., Internat. Ed.,
2
003, 52, 1164 and earlier references cited therein.

HETEROCYCLES, Vol. 68, No. 5, 2006
895
9
1
.
K. Singh, J. Singh, and H. Singh, Tetrahedron, 1996, 52, 14273.
0. C.-J. Li, Chem. Rev., 2005, 105, 3095; E. K. Wilson, Chem. & Eng. News, 2005, 83, 49; U. M.
Lindstrom, Chem. Rev., 2002, 102, 275; S. Ribe and P. Wipf, Chem. Commun., 2001, 299 and earlier
references cited in these references.
1
1
1. (a) B. L. Hayes, Aldrichimica Acta, 2004, 37, 66; (b) C. O. Kappe, Angew. Chem. Int. Ed., 2004, 43,
6
250; (c) R. A. Abramovitch, Org. Prep. Proc. Int., 1991, 23, 685.
2. Typical experimental procedure: Microwave (100 W) was irradiated in a domestic microwave oven
to a mixture of benzaldehyde (1) (50 µL, 0.5 mmol), ethyl cyanoacetate (2) (65 µL, 0.6 mmol) and
NDEAP powder (amine loading: 1.1 mmol/g by combustion analysis, 47 mg, 0.05 mmol) in water
(
0.5 mL) and ethanol (0.5 mL) for 9 min. The temperature was ramped from room temperature to
0 °C, which was monitored by radiation thermometer. After addition of dimedone (4) (71 mg, 0.51
8
mmol), microwave was irradiated for 10 min. Product was dissolved into ethyl acetate by gentle
warming by heat gun. The aqueous layer was extracted with ethyl acetate twice. The combined
organic layer was passed through short silica gel column to remove excess dimedone (4) and
evaporated to dryness. Recrystallization of the residue and subsequent medium-pressure LC
purification (eluent: ethyl acetate : hexane = 1 : 1) of the mother liquor provided hydropyran (5) (155
mg, 91%).
1
1
3. All new compounds have satisfactory analytical data including H-NMR, IR and exact MS.