A clean one-pot synthesis of tetrahydrobenzo[b]pyran derivatives catalyzed by hexadecyltrimethyl ammonium bromide in aqueous media

Article abstract of DOI:10.1055/s-2004-820025

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-tetra-hydrobenzo[b]pyran derivatives using hexadecyltrimethyl ammonium bromide (HTMAB) as the catalyst (10 mol%) is described. This method provid

Full text of DOI:10.1055/s-2004-820025

LETTER
871
A Clean One-pot Synthesis of Tetrahydrobenzo[b]pyran Derivatives
Catalyzed by Hexadecyltrimethyl Ammonium Bromide in Aqueous Media
A
C
lea
n
O
ne-po
o
t
Synthesis
n
of Tetrahydro
g
benzo[
b
]pyr
-
anDeriv
S
atives hou Jin,* Ai-Qing Wang, Xin Wang, Jian-She Zhang, Tong-Shuang Li
Department of Chemistry, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, P. R. China
Fax +86(312)5079361; E-mail: orgsyn@mail.hbu.edu.cn
Received 9 January 2004
pyran derivatives has not been reported. In this manu-
script, we wish to report a general and highly efficient
route for the synthesis of this kind of compound using an
inexpensive and commercially available HTMAB as cat-
Abstract: 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-tetra-
hydrobenzo[b]pyran derivatives using hexadecyltrimethyl ammoni-
um bromide (HTMAB) as the catalyst (10 mol%) is described. This
method provides several advantages such as neutral conditions, alyst. This is a one-pot procedure in aqueous media,
high yields and simple work-up procedure, in addition water was
chosen as a green solvent.
which not only preserves the simplicity but also con-
sistently gives the corresponding products in good to ex-
Key words: tetrahydrobenzo[b]pyran, hexadecyltrimethyl ammo-
nium bromide, aqueous media
cellent yields (Scheme 1).
With increasing environmental concerns, more and more
chemists are devoted to the area of ‘green synthesis’
which means the reagents, solvent and catalyst are en-
vironmentally friendly. In modern organic chemical re-
search, Wender defined the ‘ideal synthesis’ as one in
which the target components are produced in one step, in
quantitative yield from readily available and inexpensive
starting materials in resource-effective and environmen-
tally acceptable process.1 The one-pot multicomponent
condensations represent a possible instrument to perform
a near ideal synthesis because they possess one of the
aforementioned qualities, namely the possibilities of
building-up complex molecules with maximum simplicity
and brevity.2
Scheme 1
In a typical general experimental procedure, a solution of
aromatic aldehyde 1, malononitrile (2), and 5,5-dimethyl-
1, 3-cyclohexanedione (3) in water was heated in the pres-
ence of a catalytic amount of HTMAB, the corresponding
4-H-benzo-[b]-pyrans 413 were obtained in good to excel-
lent yields. The results are summarized in Table 1.
As shown in Table 1, electronic effects and the nature of
substituents on the aromatic ring did not show strongly
obvious effects in terms of yields under the reaction con-
ditions. The three-component cyclocondensation reaction
proceeded smoothly under heated water to give the corre-
sponding products 4 in high yields. Benzaldehyde and
other aromatic aldehydes containing electron-withdraw-
ing groups (such as nitro group, halide) or electron-donat-
ing groups (such as hydroxyl group, alkoxyl group,
dimethylamino group) were employed and reacted well to
give the corresponding benzopyrans in good to excellent
yields.
In recent years, 4H-benzo[b]pyran and their derivatives
have attracted strong interest due to their useful biological
and pharmacological properties, such as anticoagulant,
spasmolytic, diuretic, anticancer, antianaphylactin char-
acteristics.3–7 Some 2-amino-4H-pyrans can be employed
as photoactive materials.8 Furthermore, polysubstituted
4H-pyrans also constitute a structural unit of a series of
natural products.9,10 The conventional reported syntheses
of 4H-benzo[b]pyrans was in organic solvents such as
acetic acid or DMF.11,12 Each of the above methods has its
own merit, while these methods are plagued by the limita-
tion of poor yields, difficult work-up and effluent pollu-
tion. Consequently, there is scope for further work toward
mild conditions, increased variation of the substituents in
the components and better yields.
The catalyst plays a crucial role in the success of the reac-
tion in terms of the rate and the yields. Taking the 4-chlo-
robenzaldehyde reacted with 2 and 3 as an example, the
reaction could be carried out in the absence of the catalyst
when the mixture was heated in water for 3 hours, but the
product was obtained in very poor yield (16%). We have
tested some catalysts such as tetrabutylammonium bro-
mide, benzyltrimethylammonium chloride, sodium dode-
cyl sulfate and hexadecyltrimethylammonium bromide,
the yields of the four catalysts were 76%, 81%, 64% and
94%, respectively, showing that HTMAB was the best
catalyst for this reaction.
HTMAB has been used in a number of organic reactions
as a good phase transfer catalyst. However, the use of
HTMAB as a catalyst in the synthesis of the 4H-benzo[b-
SYNLETT 2004, No. 5, pp 0871–0873
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4.
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Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-820025; Art ID: U00504ST
© Georg Thieme Verlag Stuttgart · New York

872
T.-S. Jin et al.
LETTER
Table 1 Synthesis of Tetrahydrobenzo[b]pyrans Catalyzed by HTMAB in Aqueous Media
Entry
Ar
Product
Yield (%)a
Mp (°C)
Found
Reported12
1
C6H5 1a
4a
4b
4c
4d
4e
4f
91
95
88
94
85
87
83
78
59
86
76
80
89
229–231
217–218
224–225
208–210
224–226
208–211
177–178
214–215
237–239
199–201
220–222
214–216
211–213
226–228
200–202
2
2-ClC6H4 1b
3
3-ClC6H4 1c
4
4-ClC6H4 1d
207–209
5
2-NO2C6H4 1e
3-NO2C6H4 1f
4-NO2C6H4 1g
4-HOC6H4 1h
3-HO-4-CH3OC6H3 1i
4-CH3OC6H4 1j
4-Me2NC6H4 1k
4-CH3C6H4 1l
3,4-OCH2OC6H3 1m
6
210–212
130–132
7
4g
4h
4i
8
9
10
4j
198–200
11
4k
4l
12
208–210
212–214
13
4m
a Isolated yield.
We also studied the effect of the amount of the catalyst on
this reaction. Upon refluxing the mixture (1d, 2 and 3) for
3 hours in the presence of 1 mol% HTMAB the product
4d was isolated in 67% . Increasing the quantity of the cat-
alyst to 5 mol% and 10 mol%, 4d could be obtained in
85% and 94% yields, respectively. Use of just 10 mol%
HTMAB is sufficient to push the reaction forward. Larger
amounts of the catalyst did not improve the results to a
greater extent. All of these reactions were carried out in
water and those products were characterized by 1H NMR,
and IR spectroscopic analyses.
We propose the possible following mechanism to account
for the reaction. An aromatic aldehyde 1 was firstly con-
densed with malononitrile 2 to afford a-cyanocinnamoni-
trile derivative 5; this step (1 + 2 → 5) can be regarded as
a fast Knoevenagel addition. With a model reaction, the
Knoevenagel reaction of malononitrile and aromatic alde-
hydes can be carried out in water without any catalyst.
Thus we think that the second step probably requires the
presence of HTMAB. The active methylene moiety of 3
reacted with the electrophilic C=C double bond giving the
intermediate 6. Then the intermediate 6 cyclized by nu-
cleophilic attack of the OH group on the cyano (CN)
moiety and gave the intermediate 7. Finally, the expected
products 4 were afforded by addition and elimination of
water (7 → 8 → 4). In this process, HTMAB could
promote these reactions as an emulsifier (Scheme 2).
Scheme 2
In conclusion, we have described a procedure for the
preparation of 4H-benzo[b]pyran derivatives catalyzed by
HTMAB in refluxing water. In addition, it is possible to
apply the tenets of green chemistry to the generation of
biologically interesting products using aqueous media
approaches that are less expensive and less toxic than
those with organic solvents.
Acknowledgment
This project was supported by the National Natural Science Found-
ation of China (29872011 and 29572039), Educational Ministry of
China, Educational Department of Hebei Province (990104),
Science and Technology Commission of Hebei Province.
Synlett 2004, No. 5, 871–873 © Thieme Stuttgart · New York

LETTER
A Clean One-pot Synthesis of Tetrahydrobenzo[b]pyran Derivatives
873
Compound 4d. IR (KBr): nmax = 3410, 3310, 3005, 2200,
1695, 1605 cm–1. 1H NMR: d = 0.95 (3 H, s, CH3), 1.04 (3 H,
s, CH3), 2.10 (1 H, d, J = 16.0 Hz, 8-H), 2.25 (1 H, d,
J = 16.0 Hz, 8-H), 2.47–2.55 (2 H, m, 6-H), 4.20 (1 H, s, 4-
H), 7.08 (2 H, s, NH2), 7.17 (2 H, d, J = 8.0 Hz, ArH), 7.35
(2 H, d, J = 8.0 Hz, ArH) ppm.
References
(1) Wender, P. A.; Handy, S. L.; Wright, D. L. Chem. Ind.
(London) 1997, 765.
(2) Hudlicky, T. Chem. Rev. 1996, 96, 3.
(3) Foye, W. O. Prinicipi di Chimica Farmaceutica Piccin;
Padova: Italy, 1991, 416.
Compound 4e. IR (KBr): nmax = 3450, 3310, 3005, 2200,
1695, 1605 cm–1. 1H NMR: d = 0.97 (3 H, s, CH3), 1.08 (3 H,
s, CH3), 2.14 (2 H, m, 8-H), 2.46 (2 H, s, 6-H), 5.05 (1 H, s,
4-H), 5.97 (2 H, s, NH2), 7.47–7.95 (4 H, m, ArH) ppm.
Compound 4f. IR (KBr): nmax = 3400, 3300, 3195, 2200,
1695, 1600 cm–1. 1H NMR: d = 1.01 (3 H, s, CH3), 1.06 (3 H,
s, CH3), 2.26 (2 H, s, 8-H), 2.46–2.52 (2 H, m, 6-H), 4.52 (1
H, s, 4-H), 4.98 (2 H, s, NH2), 7.42–7.98 (4 H, m, ArH) ppm.
Compound 4g. IR (KBr): nmax = 3400, 3300, 3190, 2200,
1690, 1600 cm–1. 1H NMR: d = 1.02 (3 H, s, CH3), 1.05 (3 H,
s, CH3), 2.26 (2 H, s, 8-H), 2.48–2.54 (2 H, m, 6-H), 4.54 (1
H, s, 4-H), 5.05 (2 H, s, NH2), 7.45–8.05 (4 H, m, ArH) ppm.
Compound 4h. IR (KBr): nmax = 3357, 3250, 3163, 2191,
1664, 1558 cm–1. 1H NMR: d = 1.05 (3 H, s, CH3), 1.10 (3 H,
s, CH3), 2.15–2.23 (2 H, m, 8-H), 2.44 (2 H, s, 6-H), 4.26 (1
H, s, 4-H), 5.34 (2 H, s, NH2), 6.75–7.13 (4 H, m, ArH) ppm.
Compound 4i. IR (KBr): nmax = 3310, 3255, 2895, 2192,
1673, 1596 cm–1. 1H NMR: d = 1.04 (3 H, s, CH3), 1.10 (3 H,
s, CH3), 2.20–2.24 (2 H, m, 8-H), 2.40 (2 H, s, 6-H), 3.88 (3
H, s, OCH3), 4.31 (1 H, s, 4-H), 5.25 (2 H, s, NH2), 6.59–6.78
(3 H, m, ArH), 6.85 (1 H, s, OH) ppm.
Compound 4j. IR (KBr): nmax = 3377, 3186, 2964, 2198,
1681, 1655, 1596 cm–1. 1H NMR: d = 0.95 (3 H, s, CH3), 1.03
(3 H, s, CH3), 2.09 (1 H, d, J = 16.0 Hz, 8-H), 2.24 (1 H, d,
J = 16.0 Hz, 8-H), 2.46–2.56 (2 H, m, 6-H), 3.71 (3 H, s,
OCH3), 4.17 (1 H, s, 4-H), 6.84 (2 H, d, J = 8.0 Hz, ArH),
6.95 (2 H, s, NH2), 7.05 (2 H, d, J = 8.0 Hz, ArH) ppm.
Compound 4k. IR (KBr): nmax = 3390, 3300, 3180, 2200,
1690, 1600 cm–1. 1H NMR: d = 1.01 (3 H, s, CH3), 1.04 (3 H,
s, CH3), 2.25 (2 H, s, 8-H), 2.47–2.52 (2 H, m, 6-H), 2.95 (6
H, s, 2 N-CH3), 4.42 (H, s, 14-H), 4.66 (2 H, s, NH2), 7.14–
7.25 (4 H, m, ArH) ppm.
(4) Andreani, L. L.; Lapi, E. Boll. Chim. Farm. 1960, 99, 583.
(5) 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.
(6) Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J.
Med. Chem. 1993, 28, 517.
(7) Witte, E. C.; Neubert, P.; Roesch, A. Ger. Offen DE.,
3427985, 1986; Chem. Abstr., 1986, 104, 224915f.
(8) Armetso, D.; Horspool, W. M.; Martin, N.; Ramos, A.;
Seaone, C. J. Org. Chem. 1989, 54, 3069.
(9) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J. Chem.
Soc., Chem. Commun. 1988, 1202.
(10) Gonzalez, R.; Martin, N.; Seoane, C.; Soto, J. J. Chem. Soc.,
Perkin Trans. 1 1985, 1202.
(11) Singh, K.; Singh, J.; Singh, H. Tetrahedron 1996, 52, 14273.
(12) Wang, X. S.; Shi, D. Q.; Tu, S. J.; Yao, C. S. Synth.
Commun. 2003, 33, 119.
(13) General Coupling Procedure: A mixture of an aromatic
aldehyde (1, 1 mmol), malononitrile (2, 1 mmol), 5,5-
dimethyl-1,3-cyclohexadion (3, 1 mmol) and HTMAB (10
mol%) in H2O (20 mL) was stirred at 85–90 °C for 3 h. Then
the mixture was cooled to r.t., solid was filtered off and
washed with H2O (40 mL). The crude products were purified
by recrystallization with EtOH (95%). Liquid aldehydes
were distilled before use. IR spectra were recorded on a Bio-
Rad FTS-40 spectrometer (KBr). 1H NMR spectra were
measured on a Bruker AVANCE 400 (400 MHz)
spectrometer using TMS as internal reference and CDCl3 or
DMSO as solvent. Data of some compounds are shown
below:
Compound 4a. IR (KBr): nmax = 3390, 3290, 2935, 2200,
1685, 1600 cm–1. 1H NMR: d = 0.98 (3 H, s, CH3), 1.05 (3 H,
s, CH3), 2.15 (1 H, d, J = 16.0 Hz, 8-H), 2.24 (1 H, d,
J = 16.0 Hz, 8-H), 2.45–2.55 (2 H, m, 6-H), 4.32 (1 H, s, 4-
H), 6.08 (2 H, s, NH2), 7.15–7.30 (5 H, m, ArH) ppm.
Compound 4b. IR (KBr): nmax = 3332, 3185, 2965, 2200,
1662, 1558 cm–1. 1H NMR: d = 0.98 (3 H, s, CH3), 1.04 (3 H,
s, CH3), 2.08 (1 H, d, J = 16.0 Hz, 8-H), 2.24 (1 H, d,
J = 16.0 Hz, 8-H), 2.46–2.57 (2 H, m, 6-H), 4.59 (1 H, s, 4-
H), 7.02 (2 H, s, NH2), 7.15–7.36 (4 H, m, ArH) ppm.
Compound 4c. IR (KBr): nmax = 3390, 3290, 3180, 2190,
1660, 1585 cm–1. 1H NMR: d = 1.05 (3 H, s, CH3), 1.12 (3 H,
s, CH3), 2.26 (2 H, s, 8-H), 2.46–2.49 (2 H, m, 6-H), 4.41 (1
H, s, 4-H), 4.58 (2 H, s, NH2), 7.18–7.28 (4 H, m, ArH) ppm.
Compound 4l. IR (KBr): nmax = 3426, 3330, 2957, 2193,
1678, 1640, 1601 cm–1. 1H NMR: d = 0.95 (3 H, s, CH3), 1.04
(3 H, s, CH3), 2.09 (1 H, d, J = 16.0 Hz, 8-H), 2.24 (1 H, d,
J = 16.0 Hz, 8-H), 2.26 (3 H, s, CH3), 2.45–2.56 (2 H, m, 6-
H), 4.12 (1 H, s, 4-H), 6.96 (2 H, s, NH2), 7.02 (2 H, d,
J = 8.0 Hz, ArH), 7.08 (2 H, d, J = 8.0 Hz, ArH) ppm.
Compound 4m. IR (KBr): nmax = 3372, 3203, 2935, 2204,
1654, 1608 cm–1. 1H NMR: d = 0.96 (3 H, s, CH3), 1.03 (3 H,
s, CH3), 2.12 (1 H, d, J = 16.0 Hz, 8-H), 2.24 (1 H, d,
J = 16.0 Hz, 8-H), 2.46–2.57 (2 H, m, 6-H), 4.17 (1 H, s, 4-
H), 5.97 (2 H, s, OCH2O), 6.97 (2 H, s, NH2), 7.02–7.15 (3
H, m, ArH) ppm.
Synlett 2004, No. 5, 871–873 © Thieme Stuttgart · New York