Preparation of 5-oxo-5,6,7,8-tetrahydro-4H-benzo-[b]-pyran derivatives in ionic liquids

Article abstract of DOI:10.3184/030823408X324661

A novel preparation of 5-oxo-5,6,7,8-tetrahydro-4H-benzo-[b]-pyran derivatives promoted by lnCI₃·4H₂O/TMSCI in ionic liquid ([bmin]BF₄) is described. The preparative procedure presented in this paper is operationally simple and environmentally friendly. The reaction media and catalyst used can be recovered and reused for at least four times without loss in the catalytic activity. This method is promising for a mass-production process.

Full text of DOI:10.3184/030823408X324661

JOURNAL OF CHEMICAL RESEARCH 2008
JUNE, 331–333
RESEARCH PAPER 331
Preparation of 5-oxo-5, 6, 7, 8-tetrahydro-4h-benzo-[b]-pyran derivatives
in ionic liquids
Qiang Li, Xueyuan Hu, Wei Li, Fei Yang, Xiaolan Yang, Lili Sun, Liping Zhou, Junsheng Qi and
Yu Yu*
Chongqing University of Medical Sciences, Chongqing 400016, P. R. China
A novel preparation of 5-oxo-5,6,7,8-tetrahydro-4H-benzo-[b]-pyran derivatives promoted by InCl3·4H2O/TMSCl in
ionic liquid ([bmin]BF4) is described. The preparative procedure presented in this paper is operationally simple and
environmentally friendly. The reaction media and catalyst used can be recovered and reused for at least four times
without loss in the catalytic activity. This method is promising for a mass-production process.
Keywords: pyran derivatives, ionic liquid, indium trichloride
The construction of tetrahydropyran rings has attracted
a great deal of interests in recent years,1-3 since these are a
structural units in a number of natural products.4 In addition,
tetrahydropyran derivatives have considerable biological
and pharmacological importance, as anticancer5,6 and
antihypersensitivity agents.7 Therefore, it is not surprising
that many methods have already been developed for the
synthesis of tetrahydropyran derivatives.8-10 However, most
of these methods are not entirely satisfactory with regard
to yields, reaction conditions, generality and operational
simplicity. Thus, a simple, general and efficient procedure for
the synthesis of tetrahydropyran derivatives still remains an
active research area.
on their applications as novel media for various kinds of
organic reactions.11-16 As a continuation of our interest in
the area of clean synthesis using ionic liquids as a green
recyclable alternative to classical molecular solvents,17,18
we now report a novel procedure for the preparation of 5-
oxo-5,6,7,8-tetrahydro-4H-benzo-[b]-pyran derivatives (3)
by an InCl3·4H2O coupling promoted by TMSCI of 1,3-
cyclohexanedione (1) and chalcones (2) in the ionic liquid, 1-
butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4])
(Scheme 1).
Results and discussion
At the start of this study, a mixture of 1,3-cyclohexandione 1
and 1,3-diphenyl-propenone(2a) in [bmin]BF4 was prepared
and stirred at 95°C. After 13 h, the formation of a new
compound was observed by TLC together with remaining
substrates 1 and 2a. The new compound was collected and
separated by column chromatography. Analysis by physical
A frequently used8 pathway to tetrahydropyran derivatives,
involves the Michael addition condensation reaction of 5,
5-dimethyl-1, 3-cyclohexandione and chalcone. However,
this method involved the use of excess glacial acetic acid and
phosphorous pentoxide. Anhydrous zinc chloride has also
been used to catalyse the condensation of 1,3-cyclohexandione
with chalcone in a mixture of toluene/benzene and n-heptane
leading to environmental pollution.9 Recently, condensation of
5, 5-dimethyl-1, 3-cyclohexandione with chalcone promoted
by InCl3·4H2O under microwave irradiation was reported by
our group.10 However, this method is unsuitable for a large
scale process.
The development of environmentally friendly catalysts
and solvents for organic chemistry is an area of considerable
importance. From both an economic and environmental point
of view, the use of non-volatile solvents is very promising.
In the last few years room temperature ionic liquids (RTILs),
especially those based on 1,3-dialkylimidazolium cations
have been recognised as a possible environmentally benign
alternative to chemical volatile solvents. They are non-
volatile, recyclable, non-explosive, easy to handle, and
thermally robust. In many cases, the products are weakly
soluble in the ionic phase so that the products can be easily
separated by simple filtration or extraction with ether. Because
of the great potential of RTILs as novel reaction media for
catalytic processes, much attention has been currently focused
1
and spectral data (IR, H NMR and MS) showed that this
compound was 2, 4-diphenyl-5-oxo-5, 6, 7, 8-tetrahydro-4H-
benzo-[b]-pyran (3a) (Table 1, entry1).
Recently, InCl3 was reported19-21 to be an efficient Lewis
acid catalyst for many organic reactions especially several
condensation processes. Therefore, we added a catalytic
amount of InCl3·4H2O alone into the reaction mixture 1
and 2a with the hope of obtaining an improved yield. To
our delight, InCl3·4H2O enhanced this process by affording
3a. But the yield was still not satisfactory (Table 1, entries
2–4). The combined use of InCl3 and Me3SiCl is more
effective than their use alone.22 The effects of such additive
as TMSCl (trimethylchlorosilane) on this reaction were then
investigated. It can be seen that the yield was significantly
improved by adding TMSCl and the best result was obtained
with the combination of 0.2 equiv of InCl3·4H2O and 1 equiv
of TMSCl (Table 1, entry 6).
In the light of this result, we extended this method to a
variety of substituted chalcones to investigate its scope.
The results are listed in Table 2. It was shown that in a
R1
O
O
O
O
InCl3/TMSCl
R2
[bmin]BF4, 95-100°C
O
R1
R2
1
2
3
Scheme 1
* Correspondent. E-mail: yuyu3519@163.com

332 JOURNAL OF CHEMICAL RESEARCH 2008
Table 1 Synthesis of 3a in [bmim][BF4] at different conditionsa at 95°C
Entry
InCl3·4H2O/mol%
TMSCl/mol%
Reaction time/h
Isolate yields/%
1
2
3
4
5
6
7
8
9
0
10
20
20
20
20
20
20
10
0
0
13
13
13
20
12
12
18
12
12
0.2
12.8
33.5
32.2
46.2
55.6
55.9
40.4
33.1
0
0
50
100
100
150
100
aReaction conditions: 2 ml [bmim][BF4], 2 mmol chalcone, 2 mmol 1,3-cyclohexanedione.
expressed in ppm downfield from internal tetramethylsilane and
coupling constants J are given in Hz. Mass spectra and high resolution
mass spectra were recorded on VBZAB-HS mass spectrometer and
MAT95 mass spectrometer respectively.
similar fashion, a wide range of chalcones underwent smooth
condensation with 1 to give benzo-[b]-pyran derivatives
in moderate yields. We found that the electronic property
of the aromatic ring of chalcones affects the rate of this
condensation process. In general, a shorter reaction time was
needed with substrates bearing electron-withdrawing groups
on the aromatic ring (Table 2, entries 3–7). Substrates bearing
electron-donating groups also produced the corresponding
products in a satisfactory yield, but needed a longer reaction
time (Table 2, entry 2).
The recycling of the solvent and catalyst is beneficial to
the environment in terms of green chemistry. At the end of
the reaction, [bmim][BF4] together with the catalyst could
be recovered easily by drying the aqueous layer at 100°C for
several hours after extraction with ethyl acetate. In order to
examine the recycling of [bmin]BF4 and the catalyst, we used
1 and 2a as the model substrates. The successive reuse of the
recovered ionic liquid and the catalyst is shown in Table 3.
It is obvious that the reaction can give the product with a yield
that is almost as high as that of the first cycle.
In conclusion, we have developed a novel method for the
preparation of benzo-[b]-pyran derivatives promoted by
InCl3·4H2O/TMSCl in [bmin]BF4 with heating. This new
method is operationally simple and environmentally friendly.
The reaction media and catalyst can be recovered and reused
for at least four times without loss of the catalytic activity.
With all these advantages, this method provides an attractive
alternative for the synthesis of benzo-[b]-pyran derivatives
and large scale processes.
General procedure for the preparation of 3a–g
1,3-Cyclohexandione(2 mmol), InCl3·4H2O(0.4 mmol) and
[bmin]BF4 (2 ml) were thoroughly mixed in a 25 ml single-necked
flask, and then TMSCl (2 mmol) was added. After being stirred for
about 10 minutes, the corresponding 1,3-diaryl-propenone(2a–g) was
added to the reaction flask. The mixture was heated to 95–100°C for a
certain period of time (see Table) to complete the reaction (monitored
by TLC). The mixture was cooled and extracted with ethyl acetate
(3 × 5 ml). The organic layer was washed with water and then dried
over Na2SO4 followed by filtering and concentration. The residue
was recrystallised from a mixture of ethyl acetate and hexane to
give 3. All the products were characterised by IR, 1H NMR, and MS.
The catalyst remaining in the aqueous phase was reused by removing
water under reduced pressure for the next reaction.
2,4-Diphenyl-5-oxo-5,6,7,8-tetrahydro-4H-benzo-[b]-pyran (3a):
M.p. 170–172°C (171–173°C23). IR (KBr), n (cm-1): 1677, 1655,
1623, 1576. 1H NMR (CDCl3, 400 MHz)d: 2.04–2.10 (m, 2H, CH2),
2.31–2.44 (m, 2H, CH2), 2.59–2.74 (m, 2H, CH2), 4.51 (d, 1H,
J = 4.8 Hz, CH), 5.70 (d, 1H, J = 5.2 Hz, CH), 7.16 (t, 1H, J = 7.2 Hz,
ArH), 7.24–7.30 (m, 2H, ArH), 7.31–7.39 (m, 5H, ArH), 7.54–7.59
(q, 2H, J = 5.2 Hz, ArH). MS (70eV), m/z (%): 302 (M+, 80.9), 285
(3.2), 246 (4.8), 225 (100), 215 (4.2), 202 (6.4), 165 (3.1), 141 (4.0),
115 (5.6), 105 (4.8), 77 (7.2).
2-Phenyl-4-(4-methylphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
[b]-pyran (3b): M.p. 109–110°C. IR (KBr), n (cm-1): 1676, 1659,
1627,1 577. 1H NMR (CDCl3, 400 MHz)d: 1.99–2.08 (m, 2H, CH2),
2.28 (s, 3H, CH3), 2.30–2.42 (m, 2H, CH2), 2.58–2.73 (m, 2H, CH2),
4.47 (d, 1H, J = 5.2 Hz, CH), 5.69 (d, 1H, J = 5.2 Hz, CH), 7.07 (d,
2H, J = 8.0 Hz, ArH), 7.22 (t, 2H, J = 6.4 Hz, ArH), 7.29–7.37 (m,
3H, ArH), 7.57 (d, 2H, J = 6.4 Hz, ArH). MS (70eV), m/z (%): 316
(M+, 100), 301 (35.1), 260 (9.1), 245 (10.2), 225 (95.8), 215 (6.3),
202 (5.0), 155 (6.2), 141 (5.9), 115 (11.4), 105 (10.4), 77 (15.3).
HRMS: calcd for C22H20O2 316.1463, found 316.1466.
Experimental
Melting points were measured by WC-I microscope melting point
instrument, and were uncorrected. IR spectra were determined on
Perkin-Elmer Spectrum-one Version spectrometer in KBr with
absorption in cm-1.1H NMR spectra were determined on a Bruker
AC 400 spectrometer in CDCl3 solution. Chemical shifts(d) were
2-Phenyl-4-(3-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
[b]-pyran (3c): M.p. 137–138°C. IR (KBr), n (cm-1): 1679, 1660,
1622, 1575. 1H NMR (CDCl3, 400 MHz)d: 2.04–2.15 (m, 2H, CH2),
Table 2 Preparation of 3 promoted by InCl3·4H2O/TMSCl in the ionic liquid
Entry
R1
R2
Time/h
Products
Isolate yields/%
1
2
3
4
5
6
7
H
H
12
19
10
11
10
11
10
3a
3b
3c
3d
3e
3f
56
p-CH3
m- NO2
H
H
52
H
p-Cl
m- NO2
H
H
60
53(449)
49
H
p-Cl
p-NO2
50
61
3g
Table 3 Studies on the reuse of the In (III) and [bmim][BF4]
Round
Reaction time/h
Temperature/°C
Isolate yield/%
Ionic liquid recovered/%
1
2
3
4
5
13
13
13
13
13
95
95
95
95
95
56
54
54
55
55
92
98
96
96
96

JOURNAL OF CHEMICAL RESEARCH 2008 333
2.32–2.43 (m, 2H, CH2), 2.62–2.79 (m, 2H, CH2), 4.63 (d, 1H,
J = 4.8 Hz, CH), 5.64 (d, 1H, J = 5.2 Hz, CH), 7.24–7.45 (m, 4H,
ArH), 7.55–7.59 (m, 2H, ArH), 7.69 (d, 1H, J = 8.0 Hz, ArH),
8.01–8.03 (m, 1H, ArH), 8.14 (t, 1H, J = 1.8 Hz, ArH). MS (70eV),
m/z (%): 347 (M+, 25.1), 330 (92.1), 317 (3.8), 300 (43.8), 272 (3.2),
244 (3.9), 225 (100), 215 (8.3), 202 (7.1), 165(5.9), 155 (9.1), 141
(8.9), 115 (9.5), 105 (11.4), 77 (20.2). HRMS: calcd for C22H17NO4
347.1158, found 347.1164.
2-(4-Chlorophenyl)-4-phenyl-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
[b]-pyran (3d): M.p. 146–147°C (153–154°C 9). IR (KBr), n (cm-1):
1674, 1655, 1623, 1594. 1H NMR (CDCl3, 400 MHz)d: 2.03–2.11
(m, 2H, CH2), 2.30–2.43 (m, 2H, CH2), 2.58–2.73 (m, 2H, CH2), 4.50
(d, 1H, J = 4.8 Hz, CH), 5.68 (d, 1H, J = 4.8 Hz, CH), 7.17 (t, 1H,
J = 7.0 Hz, ArH), 7.24–7.37 (m, 6H, ArH), 7.49 (t, 2H, J = 6.6 Hz,
ArH). MS (70eV), m/z (%): 338 (M + 2, 33.7), 336 (M+, 89.4), 319
(2.4), 301 (3.1), 280 (6.0), 261 (33.9), 259 (100), 245 (3.4), 215 (7.4),
202 (10.1), 139 (19.5), 115 (8.3), 111(9.8), 77 (13.2).
2-(3-Nitrophenyl)-4-phenyl-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
[b]-pyran (3e): M.p. 158–159°C. IR (KBr), n (cm-1): 1677, 1661,
1626, 1534. 1H NMR (CDCl3, 400 MHz)d: 2.07–2.12 (m, 2H, CH2),
2.32–2.44 (m, 2H, CH2), 2.63–2.79 (m, 2H, CH2), 4.54 (d, 1H,
J = 5.2 Hz, CH), 5.85 (d, 1H, J = 5.2 Hz, CH), 7.17 (q, 1H, J = 4.9 Hz,
ArH), 7.20–7.31 (m, 4H, ArH), 7.53 (t, 1H, J = 8.2 Hz, ArH), 7.87
(d, 1H, J = 7.6 Hz, ArH), 8.16 (q, 1H, J = 3.1 Hz, ArH), 8.43 (t, 1H,
J = 1.8 Hz, ArH). MS (70eV), m/z (%): 347(M+, 87.8), 330 (8.3),
317 (6.2), 301 (3.5), 300 (11.8), 272 (3.9), 270 (100), 244 (5.1), 240
(9.6), 224 (39.9), 215 (9.8), 202 (10.1), 168 (10.3), 139 (10.4), 115
(8.6), 104 (7.3), 77 (10.5), 76 (10.7). HRMS: calcd for C22H17NO4
347.1158, found 347.1158.
2-Phenyl-4-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
benzo-[b]-pyran (3f): M.p. 117–118°C. IR (KBr), n (cm-1): 1680,
1662,1624,1589,1578. 1H NMR (CDCl3, 400 MHz)d: 1.99–2.09 (m,
2H, CH2), 2.30–2.42 (m, 2H, CH2), 2.59–2.73 (m, 2H, CH2), 4.48 (d,
1H, J = 4.8 Hz, CH), 5.64 (d, 1H, J = 4.8 Hz,CH), 7.19–7.27 (m, 4H,
ArH), 7.31–7.40 (m, 3H, ArH), 7.56 (q, 2H, J = 3.3 Hz, ArH). MS
(70eV), m/z (%): 338 (M + 2, 28.8), 336 (M+, 75.9), 301 (32.8), 280
(5.6), 225 (100), 215 (6.1), 202 (8.1), 155 (5.1), 141 (7.8), 115 (3.8),
105 (11.9), 77 (13.2). HRMS: calcd for C22H17ClO2 336.0917, found
336.0915.
This work was financially supported by the National Natural
Science Foundation of China under NSFC grant No. 30371632,
30171070 and 30772595, and by Professer Junsheng Qi of
Chonqing Three Gorges University.
Received 29 January 2008; accepted 17 May 2008
Paper 08/5062 doi: 10.3184/030823408X324661
References
1
A.B. Smith Ш, P.R. Verhost, K.P. Minbiole and M. Schelhaas, J. Am.
Chem. Soc., 2001, 123, 4834.
2
A.B. Smith Ш, I.G. Safonov and R.M. Corbet, J. Am. Chem. Soc., 2001,
123, 12426.
3
4
P. Liu and E.N. Jacobsen, J. Am. Chem. Soc., 2001, 123, 10772.
S. Hatokeyama, N. Ochi, H. Numata and S. Takano, Chem. Commun.,
1998, 17,1202.
5
6
T.C. Witte, DE 3427985, 1986, [Chem. Abstr., 1986, 104, 224915f.].
J.L.Wang, D. Liu, Z. zhang, S. Shan, X. I-Ian, S.M. Srinvasula, C.M. Croce,
E.S. Ahlemeri and Z. Huang, Proc. Nat1. Acad. Sci. USA, 2000, 97,
7124.
7
8
9
E. Hyama and H. Saimoto, JP 62181276, 1987, [Chem. Abstr., 1988, 108,
37645p.].
V.K. Ahuwalia, S. Kiran, R. Aggarwal and K.K. Arora, Indian J. Chem.,
Sect B, 1991, 30B(12), 1095.
M.G. Ahmed, S.A. Ahmed, U.K.R. Romman, T. SultanaIndian, M.A.
Hena and S. Kiyooka, Indian J. Chem., Sect B, 2002, 41B(2), 368.
10 X.Y. Hu, X.S. Fan, X.Y. Zhang, G.R. Qu and Y.Z. Li, Can. J. Chem.,
2006, 84, 1054.
11 J. Dupont, R.F. de Souza and P.A.Z. Suarez, Chem. Rev., 2002, 102,
3667.
12 D.B. Zhao, M. Wu, Y. Kou and E.Z. Min, Catal. Today., 2002, 74, 157.
13 H. Olivier-Bourbigou and L. Magna, J. Mol. Catal. A: Chem., 2002, 419,
182.
14 T. Welton., Chem. Rev., 1999, 99, 2071.
15 Z. Li and C.G. Xia, Tetrahedron Lett., 2003, 44, 2069.
16 J.S. Yadav, B.V.B. Reddy, A.K. Basak and A.V. Narsaiah, Tetrahedron
Lett., 2003, 44, 1047.
2-Phenyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
[b]-pyran (3g): M.p. 193–194°C. IR (KBr), n (cm-1): 1663, 1625,
1604, 1593. 1H NMR (CDCl3, 400 MHz)d: 1.99–2.12 (m, 2H, CH2),
2.32–2.44 (m, 2H, CH2), 2.61–2.77 (m, 2H, CH2), 4.54 (d, 1H,
J = 5.2 Hz, CH), 5.90 (d, 1H, J = 5.2 Hz, CH), 7.16–7.21 (m, 1H,
ArH), 7.24–7.31 (m, 4H, ArH), 7.72(d, 2H, J = 9.2 Hz, ArH), 8.21 (d,
2H, J = 9.2 Hz, ArH). MS (70eV), m/z (%): 347 (M+, 100), 330 (12.1),
300 (11.3), 270 (80.2), 224 (33.1), 215 (4.3), 202 (5.2), 104 (6.8), 76
(7.9). HRMS: calcd for C22H17NO4 347.1158, found 347.1162.
17 X. Zhang, X. Fan, H. Niu and J. Wang, Green Chem., 2003, 5, 267.
18 X. Zhang, H. Niu and J. Wang, J. Chem. Res (S)., 2003,33.
19 T.P. Loh, L.C. Feng and L.L. Wei, Tetrahedron, 2001, 57, 4231.
20 Z.G. Li, J.H. Zhang and C.J. Li, Tetrahedron Lett., 2003, 44, 153.
21 D.S. Bose, A.P. Rudradas and M.H. Babu, Tetrahedron Lett., 2002, 43,
9195.
22 Y. Onishi, T. Ito, M. Yasuda and A. Baba, Tetrahedron, 2002, 58, 4231.
23 V.G. Kharchenko, L.I. Markova, N.S. Smirnova, K.M. Korshunova and
G.I. Rybina, Russ. J. Org. Chem., 1982, 18, 2184.