Microwave-assisted one-pot synthesis of dihydrocoumarins from phenols and cinnamoyl chloride

Article abstract of DOI:10.1055/s-2008-1042921

A facile approach has been developed for the synthesis of dihydrocoumarin derivatives through the reaction of phenols and cinnamoyl chloride in the presence of ecofriendly solid-acid catalyst montmorillonite K-10 via a tandem esterification-Friedel-Crafts

Full text of DOI:10.1055/s-2008-1042921

LETTER
1091
Microwave-Assisted One-Pot Synthesis of Dihydrocoumarins from Phenols
and Cinnamoyl Chloride
Synthesisof
D
ih
h
ydrocouma
e
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua
University, Beijing 100084, P. R. of China
Fax +86(10)62792673; E-mail: mayuan@mail.tsinghua.edu.cn
Received 10 December 2007
cation–Friedel–Crafts-alkylation sequence. Initially, the
Abstract: A facile approach has been developed for the synthesis
same catalyst aluminum chloride was attempted. Howev-
er, the esterification products of a,b-unsaturated acyl
chlorides with phenols favored to undergo a Fries rear-
of dihydrocoumarin derivatives through the reaction of phenols and
cinnamoyl chloride in the presence of ecofriendly solid-acid cata-
lyst montmorillonite K-10 via a tandem esterification–Friedel–
Crafts alkylation process under microwave irradiation. The catalyst rangement as those under traditional heating conditions.
could be easily recovered and recycled.
Therefore, an appropriate catalyst for the aimed synthesis
was necessary.
Key words: microwave-assisted synthesis, dihydrocoumarins,
phenols, cinnamoyl chloride, montmorillonite K-10
Mild solid acids have been used to catalyze the synthesis
of coumarin derivatives in recent years.9–12 Use of these
heterogeneous catalysts, such as zeolites, clays, and ion-
exchange resins, results in simplified product recovery
and a reduction in undesirable waste stream associated
with conventional Lewis acid catalysts. Shukla et al.9 syn-
thesized substituted 3,4-dihydrocoumarins from substitut-
ed cinnamic acids and phenol in the H–Y zeolite-
catalyzed procedure. Lee et al.10 prepared dihydrocu-
marins derivatives via the montmorillonite K-10 cata-
lyzed esterification–cyclization reactions of phloro-
glucinol and cinnamoyl chloride under conventional heat-
ing for 12 hours. By condensation of 1,3-dihydroxy-
benzene and 1,3,5-trihydroxybenzene with propenoic
acids using montmorillonite KSF as catalyst under micro-
wave irradiation, de la Hoz et al.11 prepared 4-nonsubsti-
tuted dihydrocoumarins in good yields. With phenols and
cinnamic acids impregnated on solid support, preactivated
montmorillonite K-10 clay, and along with one drop of
concentrated H2SO4, Singh et al.12 have also described the
microwave-assisted solvent-free synthesis of 3,4-dihydro-
4-phenylcoumarins and 4-phenylcoumarins in good
yields.
Dihydrocoumarins, which exist extensively in a number
of natural molecules and show a wide range of biological
activities,1 are important synthetic intermediates for phar-
maceutical industry, useful pesticides, and bioactive com-
pounds. Many synthetic methods for dihydrocoumarin
derivatives have been reported till now: (i) reduction of
coumarins;2 (ii) hydroarylation of substituted cinnamates
or cinnamic acid with phenols in strong acidic conditions
or under Lewis acid catalysis;3 (iii) Lewis acid catalyzed
reaction of acrylonitrile with phenols;4 (iv) rhodium-me-
diated reaction of 3-(2-hydroxyphenyl)-cyclobutanones;5
(v) reaction of chromium Fisher carbene complexes with
ketene acetals.6 However, there are quite a few disadvan-
tages in these accomplished protocols mostly involving
long reaction time,2b,3b,d,e,5 complicated starting materi-
als,3e employment of expensive, non-regenerable and pol-
lutive catalysts3b–e,5 and also lack of substrate generality.
Consequently, there is a great need for efficient and prac-
tical approaches for the synthesis using inexpensive, eas-
ily handled and environmentally friendly catalysts and
starting materials.
Although the synthesis of some dihydrocoumarins has
been successfully approached by employing montmorillo-
nite K-10 catalyst, these reactions usually need long reac-
tion times under the classical heating conditions, or
occurred in solvent-free pattern in a domestic microwave
oven, and only for the electron-rich phenols. In this letter,
we wish to present a facile synthesis of 3,4-dihydrocou-
marins from various phenols and cinnamoyl chloride in
the presence of montmorillonite K-10 under temperature-
controlled microwave irradiation.
Microwave irradiation has been widely applied in organic
synthesis recently and achieved great success for many re-
actions with high efficiency and good yields.7 In our pre-
vious studies, we have reported the microwave-assisted
one-pot synthesis of 1-indanones from substituted ben-
zenes and a,b-unsaturated acyl chlorides under the catal-
ysis of aluminum chloride.8 As continuation of our
previous work and development of a general and facile
method to offer various useful dihydrocoumarin deriva-
tives, the microwave-assisted one-pot synthesis of dihy-
drocoumarins has been examined, starting from phenols
and a,b-unsaturated acyl chlorides via a tandem esterifi-
First, we used conventional heating to preliminarily esti-
mate the reactivity of the selected reaction. Esterification
furnished in almost quantitative yield when a mixture of
2-naphthol and cinnamoyl chloride in chlorobenzene was
stirred at room temperature for 1 hour. After refluxing for
6 hours, the ester converted completely (determined by
SYNLETT 2008, No. 7, pp 1091–1095
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x.
x
x.
2
0
0
8
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1042921; Art ID: W21407ST
© Georg Thieme Verlag Stuttgart · New York

1092
Z. Zhang et al.
LETTER
Table 1 Synthesis of 1,2-Dihydro-1-phenyl-3H-naphtho[2,1-b]pyran-3-one (3a)a
O
O
OH
O
montmorillonite
K-10
+
Cl
Ph
Ph
3a
1a
2
Entry
1
Solvent
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhMe
PhCl
Reaction conditions
r.t. + 130 °Cc
MW,d 140 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
MW, 160 °C
Reaction time
1 h + 6 h
1 min
Catalyst amount (g/mL)
Yield (%)b
0.3
57
2
0.3
Trace
13
3
1 min
0.3
4
3 min
0.3
56
5
5 min
0.3
78
6
10 min
15 min
5 min
0.3
73
7
0.3
62
8
0.25
0.2
81
9
5 min
72
10
11
12e
5 min
0.15
0.25
0.25
62
5 min
30
5 min
Trace
a Reaction scales: 1a (2 mmol), 2 (2 mmol), solvent (4 mL).
b Isolated yields.
c Stirred at r.t. for 1 h and then conventional heating at 130 °C for 6 h.
d Microwave irradiation using a CEM Discover reactor.
e Cinnamic acid was used instead of 2.
TLC) to afford the desired dihydrocoumarin in the yield uct was obtained under the same optimized microwave
of 57% (entry 1, Table 1). However, the product yielded conditions of acyl chloride (entry 12, Table 1).
from phenol and cinnamoyl chloride was relatively low.
With optimal conditions in hand, we expanded the scope
Thus, the reaction of 2-naphthol and cinnamoyl chloride
of the reaction to various substituted phenols (Table 2).
was selected as a model reaction to optimize the reaction
The reaction of cinnamoyl chloride (2) with the electron-
rich 2-naphthol (1a) gave 1,2-dihydro-1-phenyl-3H-naph-
tho[2,1-b]pyran-3-one (3a) in 81% yield (entry 1,
Table 2). Similar reactions with 3,5-dimethylphenol (1b)
and 3,4-dimethylphenol (1c) as multialkyl-substituted
phenols gave the corresponding dihydrocoumarins 3b and
3c plus 3c¢ in high yields, respectively (entries 2 and 3,
Table 2). In the reactions of 2 with cresols, 4-methylphe-
nol (1d), 3-methylphenol (1e), and 2-methylphenol (1f),
the corresponding dihydrocoumarins 3d, 3e plus 3e¢, and
3f were obtained in 66, 54, and 45% yields, respectively
(entries 4–6, Table 2). The reaction with phenol (1g) gave
3,4-dihydro-4-phenylcoumarin (3g) in 47% yield (entry 7,
Table 2). However, the reactions with alkoxyl-substituted
phenols, such as 4-methoxyphenol (1h) and 3,5-
dimethoxyphenol (1i), afforded 3,4-dihydro-6-methoxy-
4-phenylcoumarin (3h) and 3,4-dihydro-5,7-dimethoxy-
4-phenylcoumarin (3i) in comparatively low yields of 42
and 30%, respectively (entries 8 and 9, Table 2). An elec-
tron-deficient phenol, 4-chlorophenol (1j), afforded only
25% yield of dihydrocoumarin (3j, entry 10, Table 2).
conditions. Experimental conditions under microwave ir-
radiation have been carefully investigated via regulating
temperature, solvents, irradiation time, and the amount of
catalyst to get the maximum yield. The results are summa-
rized in Table 1. The ester formed, but did not convert
completely under microwave irradiation at 140 °C for 1
minute (entry 2, Table 1); while complete conversion was
achieved with irradiation at 160 °C for the same time (en-
try 3, Table 1). Therefore, reaction temperature was set at
160 °C. As solvent, toluene was more electron rich than
chlorobenzene and can take part in reaction process and
caused comparatively low yield of desired product (entry
11, Table 1), and nitrobenzene was difficult to remove af-
ter reaction due to its higher boiling point. Thus, chlo-
robenzene was chosen as the solvent. It was found that
entry 7 (Table 1) provided the best preparation of the de-
sired product in 81% yield at 160 °C with 0.25 g/mL of
montmorillonite K-10 under microwave irradiation
(closed-vessel mode) for 5 minutes. The reactivity of cin-
namic acid, which is a much cheaper substrate, was also
investigated. It was a pity that only trace of desired prod-
Synlett 2008, No. 7, 1091–1095 © Thieme Stuttgart · New York

LETTER
Synthesis of Dihydrocoumarins
1093
Generally, electron-rich phenols gave rise to products in We have also examined the reuse and recovery of the cat-
higher yield than electron-deficient ones. In addition to in- alyst on the tandem esterification–Friedel–Crafts alkyla-
ductive effect, steric hindrance of substituents affected the tion of 2-naphthol to get dihydrocoumarin 3a. The results
reactivity obviously (entries 4–6, Table 2).
shown in Table 4 indicated that another attractive behav-
ior of montmorillonite K-10 lies in the fact that it can be
reused after simple washing with ethyl acetate, together
with non-toxicity, cheapness, and commercial availability
of this catalyst, rendering the synthetic process more eco-
nomic.
Both of 3,4-dimethylphenol and 3-methylphenol unex-
pectedly provided structural isomers 3c plus 3c¢ and 3e
plus 3e¢. These two pairs of structural isomers could be
chromatographically separated and characterized via H
NMR. The isomers of 5,6-dimethyl dihydrocoumarin 3c¢
and 7-methyl dihydrocoumarin 3e were isolated as the We also extended the reaction to crotonyl chloride. How-
1
major products with different regioselectivity.
ever, no desired products were obtained except for 3,5-
dimethoxylphenol, which gave rise to the desired product,
3,4-dihydro-5,7-dimethoxy-4-methylcoumarin in 32%
yield.
As electron-rich substrates, 4-methoxyphenol (1h) and
3,5-dimethoxyphenol (1i) should give dihydrocoumarins
(3h and 3i) in high yields, while only 42% and 30% yields
of products were obtained, respectively. We presumed In summary, we have established a general and facile het-
that the methoxy group might have an oxy-atom coordina- erogeneous catalytic approach for the preparation of dihy-
tion with the catalyst montmorillonite K-10, resulting in drocoumarin derivatives from simple starting materials
decrease of efficient catalyst as the effect in the asymmet- using a microwave-assisted one-pot protocol. Straightfor-
ric borane reduction of ketones.13 So we increased the ward operation, nontoxic, low-cost, and recyclable cata-
amount of catalyst and kept other reaction conditions un- lyst, very short reaction time, and simple purification of
changed. The yields of desired products were indeed im- products are the key features of this general method,
proved. Since the reactant mixture became slurry and hard which might make it an attractive alternative to the exist-
to be stirred, the maximum catalyst amount used was lim- ing literature procedures.
ited to 0.6 g/mL. The results are presented in Table 3.
Table 2 Synthesis of Dihydrocoumarins from Phenols and Cinnamoyl Chloridesa,14,15
OH
montmorillonite K-10
MW
O
O
O
R
+
Cl
Ph
PhCl
160 °C
R
Ph
1
2
3
Entry
1
Phenol
Product
Yield (%)b
81
OH
O
O
Ph
1a
3a
OH
Me
O
O
2
3
92
33
42
Me
Me
Me
Ph
O
3b
1b
OH
Me
O
Me
Me
Ph
Me
3c
+
1c
O
O
Me
Me
Ph
3c¢
Synlett 2008, No. 7, 1091–1095 © Thieme Stuttgart · New York

1094
Z. Zhang et al.
LETTER
Table 2 Synthesis of Dihydrocoumarins from Phenols and Cinnamoyl Chloridesa,14,15 (continued)
OH
montmorillonite K-10
MW
O
O
O
R
+
Cl
Ph
PhCl
160 °C
R
Ph
1
2
3
Entry
4
Phenol
Product
Yield (%)b
OH
O
O
O
66
Me
Ph
O
Me
OH
3d
1d
1e
Me
5
35
Me
Ph
O
3e
+
O
19
45
47
42
30
25
Me
3e¢
Ph
O
Me
OH
O
O
Me
6
7
Ph
O
1f
3f
OH
OH
Ph
1g
3g
O
O
8
MeO
Ph
OMe
3h
1h
MeO
O
O
OH
9
MeO
OMe
MeO
Ph
3i
1i
OH
O
O
10
Cl
Ph
Cl
3j
1j
a Reagents and conditions: phenol (2 mmol), cinnamoyl chloride (2 mmol), chlorobenzene (4 mL), catalyst (1 g); all of reactions were irradiated
for 5 min.
b Isolated yields.
Synlett 2008, No. 7, 1091–1095 © Thieme Stuttgart · New York

LETTER
Synthesis of Dihydrocoumarins
1095
Table 3 Synthesis of Dihydrocoumarins 3h and 3i with Increased
(4) Sato, K.; Amakasu, T.; Abe, S. J. Org. Chem. 1964, 29,
2971.
Amounts of Catalysisa
(5) Matsuda, T.; Shigeno, M.; Murakami, M. J. Am. Chem. Soc.
2007, 129, 12086.
Entry
Product
Catalysis amount
(g/mL)
Yield (%)b
(6) Barluenga, J.; Andina, F.; Aznar, F. Org. Lett. 2006, 8, 2703.
(7) For reviews, see: (a) Kappe, C. O.; Stadler, A. In
Microwaves in Organic and Medicinal Chemistry, Vol. 25;
Mannhold, R.; Kubinyi, H.; Folker, G., Eds.; Wiley-VCH:
Weinheim, 2005. (b) In Microwaves in Organic Synthesis;
Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002. (c) For
some examples, see: Xu, J. X. Prog. Chem. 2007, 19, 700.
(d) Liang, Y.; Jiao, L.; Zhang, S. W.; Xu, J. X. J. Org. Chem.
2005, 70, 334. (e) Appukkuttan, P.; Dehaen, W.; Fokin, V.
V.; Van der Eycken, E. Org. Lett. 2004, 6, 4223.
(8) Yin, W.; Ma, Y.; Xu, J. X.; Zhao, Y. F. J. Org. Chem. 2006,
71, 4312.
1
2
3
4
5
3h
3h
3i
0.25
0.5
42
66
30
55
62
0.25
0.5
3i
3i
0.6
a Reagents and conditions: phenol (2 mmol), cinnamoyl chloride (2
mmol), chlorobenzene (4 mL); all of reactions were irradiated for 5
(9) Shukla, M. R.; Patil, P. N.; Wadgaonkar, P. P.; Joshi, P. N.;
Salunkhe, M. M. Synth. Commun. 2000, 30, 39.
min.
b Isolated yields.
(10) Lee, J. M.; Tseng, T. H.; Lee, Y. J. Synthesis 2001, 2247.
(11) De la Hoz, A.; Moreno, A.; Vazquez, E. Synlett 1999, 608.
(12) Singh, J.; Kaur, J.; Nayyar, S.; Kad, G. L. J. Chem. Res.,
Synop. 1998, 280.
(13) (a) Xu, J. X.; Su, X. B.; Zhang, Q. H. Tetrahedron:
Asymmetry 2003, 14, 1781. (b) Xu, J. X.; Lan, Y.; Wei, T.
Z.; Zhang, Q. H. Chin. J. Chem. 2005, 23, 1457.
Table 4 Repeated Use of Montmorillonite K-10 for Synthesis of
1,2-Dihydro-1-phenyl-3H-naphtho[2,1-b]pyran-3-one (3a) under Mi-
crowave Irradiationa
Entry
Number of Reaction time Yield (%)b Recovery of
uses
(min)
catalyst (%)
(14) General Procedure for the Synthesis of
Dihydrocoumarins
1
2
3
1
2
3
5
75
66
61
98
86
80
A solution of phenol (2 mmol), cinnamoyl chloride (2 mmol,
0.33 g), and montmorillonite K-10 (1.0 g) in dried
chlorobenzene (4 mL) was added to a sealed microwave
tube. The reaction mixture was irradiated at a set
temperature of 160 °C for 5 min with stirring using a CEM
Discover microwave reactor in the closed-vessel mode. The
reaction mixture was filtered and the catalyst
montmorillonite K-10 was washed with EtOAc. The organic
filtrates were combined. After removal of solvent, the
residue was separated on a silica gel column with a mixture
of hexane and CH2Cl2 (3:1 to 2:1, v/v) as eluent to afford the
desired pure dihydrocoumarin as product. For
5
10
a Reagents and conditions: 1a (0.5 mmol/mL), 2 (0.5 mmol/mL),
chlorobenzene as solvent, recycled catalyst (0.3 g/mL).
b Isolated yields.
Acknowledgment
We gratefully acknowledge the support of this work by Tsinghua
University and Beijing University of Technology.
dihydrocoumarins 3c and 3c¢ (also for 3e and 3e¢), another
silica gel column chromatography (hexane–EtOAc, 20:1)
was conducted to separate the isomeric products.
(15) Analytic Data for Unknown Products 3c¢ and 3e¢
3,4-Dihydro-5,6-dimethyl-4-phenylcoumarin (3c¢):
yellowish crystals, mp 118–120 °C. 1H NMR (300 MHz,
CDCl3): d = 2.08 (s, 3 H), 2.25 (s, 3 H), 3.01 (dd, J = 15.8,
3.5 Hz, 1 H), 3.03 (dd, J = 15.8, 5.5 Hz, 1 H), 4.47 (dd,
J = 5.3, 3.4 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 7.04 (d,
J = 6.2 Hz, 2 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.20–7.29 (m, 3
H). 13C NMR (75 MHz, CDCl3): d = 15.1, 20.0, 37.7, 38.7,
114.4, 123.1, 127.1, 127.4, 129.1, 130.0, 133.2, 135.1,
140.3, 150.5, 167.4. ESI-MS: m/z = 274.9 [M + Na]+. HRMS
(EI): m/z calcd for C17H16O2: 252.1150; found: 252.1153.
3,4-Dihydro-5-methyl-4-phenylcoumarin (3e¢): yellowish
crystals, mp 110–112 °C. 1H NMR (300 MHz, CDCl3): d =
2.19 (s, 3 H), 3.04 (dd, J = 15.8, 3.1 Hz, 1 H), 3.06 (dd,
J = 15.8, 5.9 Hz, 1 H), 4.41 (dd, J = 5.9, 3.1 Hz, 1 H), 7.00
(d, J = 7.6 Hz, 1 H), 7.03–7.06 (m, 3 H), 7.19–7.30 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 37.6, 38.2, 115.1,
123.2, 126.4, 126.9, 127.5, 128.6, 129.1, 137.0, 140.0,
152.2, 167.2; ESI-MS: m/z = 260.8 [M + Na]+. HRMS (EI):
m/z calcd for C16H14O2: 238.0994; found: 238.0997.
References and Notes
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