Regiospecific synthesis of 3,4-dihydrocoumarins via substrate-controlled [1,3]-or [3,3]-sigmatropic rearrangement

Article abstract of DOI:10.1055/s-0031-1289908

A regiospecific synthesis of 3,4-dihydrocoumarin derivatives has been achieved involving tandem rearrangement-cyclization of (E)-2-(aryloxymethyl)alk- 2-enoates catalyzed by a Pd/Cu bimetallic system. Unexpected substrate-controlled [1,3]- or [3,3]-sigmat

Full text of DOI:10.1055/s-0031-1289908

3026
LETTER
Regiospecific Synthesis of 3,4-Dihydrocoumarins via Substrate-Controlled
[1,3]- or [3,3]-Sigmatropic Rearrangement
S
ynthesis of 3,4-D
i
ihydroc
a
oumarins ngsheng Xu,* Xiaoqing Li, Xinhuan Yan, Hanshen Wang, Yun Deng, Jiangbin Shao
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320799; E-mail: future@zjut.edu.cn
Received 21 October 2011
First, with several monometal catalytic systems tested,
Abstract: A regiospecific synthesis of 3,4-dihydrocoumarin deriv-
only Cu(OTf)2 showed some catalytic activity to give 2a
in 10% yield via a [1,3]-sigmatropic rearrangement–
cyclization process (Table 1, entry 5). A Brønsted acid,
atives has been achieved involving tandem rearrangement–cycliza-
tion of (E)-2-(aryloxymethyl)alk-2-enoates catalyzed by a Pd/Cu
bimetallic system. Unexpected substrate-controlled [1,3]- or [3,3]-
sigmatropic rearrangement was observed in the transformations.
Table 1 Optimization of Reaction Conditions for Access to 2aa
Key words: [1,3]-sigmatropic rearrangement, [3,3]-sigmatropic
rearrangement, palladium/copper bimetallic catalyst, substrate-
controlled selectivity, 3,4-dihydrocoumarin
O
O
OMe
conditions
The 3,4-dihydrocoumarin (DHC) moieties represent an
important class of structural unit frequently found in many
natural and synthetic compounds that exhibit a variety of
pharmacological properties, such as antiherpetic activi-
ty,1a inhibition of protein kinases1b and aldose reductase,1c
activity against several cancer lines,1d-f and selective inhi-
bition of HIV-1 reverse transcriptase.1g Thus, consider-
able efforts have been devoted to the efficient and
selective synthesis of this type of heterocycles.2
O
O
1a
2a
Entry Catalyst
Solvent Temp Time Yield
(°C)
80
80
80
80
80
80
80
80
80
80
80
80
(h)
15
15
20
20
15
20
20
15
20
20
20
15
15
15
15
15
15
(%)b
c
1
2
Pd(OAc)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
c
PdCl2
0
The Baylis–Hillman adducts have been increasingly at-
tractive to synthetic organic chemists, as they are versatile
molecules with a minimum of three functional groups.3
Various cyclic and acyclic compounds could be prepared
from Baylis–Hillman adducts by various chemical trans-
formations.4 Recently, it was found that aryl allyl ethers 1
derived from Baylis–Hillman adducts underwent temper-
ature-controlled [1,3]- or [3,3]-sigmatropic rearrange-
ment to form DHC derivatives with diverse substituted
patterns in moderate to good yields (Scheme 1).5 Howev-
er, such method requires an expensive Au/Ag catalyst and
suffers from high reaction temperature in some cases.
Therefore, an alternative cheap catalytic system would be
needed for this transformation. Herein, we report a re-
giospecific synthesis of DHC via the [1,3]- or [3,3]-sig-
matropic rearrangement of aryl allyl ethers 1 and 3 in the
presence of relatively cheaper Pd(OAc)2/Cu(OTf)2 bime-
tallic catalyst. It is worth to mention that an unexpected
substrate-controlled [1,3]- or [3,3]-sigmatropic rearrange-
ment was observed in the transformations.
c
3
ZnCl2
0
c
4
AlCl3
0
c
5
Cu(OTf)2
10
0
c
6
FeCl3
7
HOTfc
21
65
0
d
8
Pd(OAc)2/Cu(OTf)2
Pd(OAc)2/CuCle
Pd(OAc)2/CuIe
9
10
11
12
13
14
15
16
17
0
e
Pd(OAc)2/CuCl2
0
Pd(OAc)2/HOTf
25
23
0
d
d
d
d
d
Pd(OAc)2/Cu(OTf)2
Pd(OAc)2/Cu(OTf)2
Pd(OAc)2/Cu(OTf)2
Pd(OAc)2/Cu(OTf)2
Pd(OAc)2/Cu(OTf)2
dioxane 100
CH2Cl2
MeCN
toluene
DCE
45
80
11
53
55
A model study was initiated with (E)-methyl 2-(phen-
oxymethyl)-3-phenylacrylate (1a) as substrate. We ex-
pected the formation of DHC in the presence of some
common Lewis acid catalysts.6
110
120
a The reaction was carried out under Ar, using 1a (1.0 mmol) and cat-
alyst in the indicated solvent (2 mL).
b Isolated yield.
SYNLETT 2011, No. 20, pp 3026–3030
x
x
.x
x
.2
0
1
1
c Conditions: 5 mol% catalyst.
Advanced online publication: 28.11.2011
DOI: 10.1055/s-0031-1289908; Art ID: W19411ST
© Georg Thieme Verlag Stuttgart · New York
d Conditions: 5 mol% Pd(OAc)2, 5 mol% Cu(OTf)2.
e Conditions: 5 mol% Pd(OAc)2, 10 mol% Cu catalyst.

LETTER
Synthesis of 3,4-Dihydrocoumarins
3027
R
CO2Me
O
R
R
O
AuCl3/3AgOTf
DCE, 120 °C
AuCl3/3AgOTf
O
O
DCE, 80 °C
O
[3,3]-sigmatropic
rearrangement
[1,3]-sigmatropic
rearrangement
Scheme 1 Temperature-controlled tandem rearrangement–cyclization of (E)-2-(aryloxymethyl)alk-2-enoates catalyzed by AuCl3/3AgOTf
such as HOTf, also gave poor yield of 2a in 21% (Table 1, as dioxane, CH2Cl2, MeCN, and toluene were proved to
entry 7). Fortunately, when Pd(OAc)2/Cu(OTf)2 was used be less effective for the reaction (Table 1, entry 13–16).
as catalyst, the yield of 2a was dramatically improved to
In order to determine whether the rearrangement of (E)-2-
65% with 31% of starting material recovered, and isomer-
(phenyloxymethyl)alk-2-enoates was also temperature-
ic product arising from [3,3]-sigmatropic rearrangement–
depended in the presence of Pd(OAc)2/Cu(OTf)2, com-
cyclization process was not observed according to the
pound 1a was subjected to react under 120 °C (Table 1,
entry 17). Compound 2a was isolated in 55% yield and no
[3,3]-sigmatropic-rearrangement isomer was detected.
NMR and GC-MS analysis. Next, other Pd/Cu bimetallic
catalysts such as Pd(OAc)2/CuCl, Pd(OAc)2/CuI, and
Pd(OAc)2/CuCl2 were investigated; none of them showed
This result is in marked contrast to that of the AuCl3/
catalytic activity (Table 1, entry 8–11). The product yield
3AgOTf-catalyzed reaction, in which case 4-aryl-3-meth-
was also not improved by using the combination of
ylene-3,4-DHC was produced via the [3,3]-sigmatropic
Pd(OAc)2/HOTf (Table 1, entry 12). Other solvents such
rearrangement–cyclization of 1a at 120 °C.5
Table 2 Rearrangement–Cyclization Reactions of (E)-2-(Phenyloxymethyl)alk-2-enoates 1a
Entry
1
Substrates
Products
Yield (%)b
CO2Me
O
65
1a
O
O
2a
2b
2c
Me
CO2Me
2
63
O
Me
1b
O
O
Cl
CO2Me
O
3
51
Cl
1c
O
O
Br
CO2Me
Br
4
58
Me
O
Me
O
O
1d
2d
a General reaction conditions: substrate 1 (1 mmol), Pd(OAc)2 (5 mol%), Cu(OTf)2 (5 mol%), DCE (2 mL), 80 °C, Ar, 15 h.
b Isolated yield.
Synlett 2011, No. 20, 3026–3030 © Thieme Stuttgart · New York

3028
X. Xu et al.
LETTER
OMe
O
CO2Me
CO2Me
R
[Cu]
Pd(0)
R
Ar = phenyl
path A
O
Ar
[Cu]
O
Pd(II)
O
R
1 or 3
[1, 3]
path B Ar = naphthyl
CO2Me
I
Pd(0)
R
O
R
R
O
R
R
O
CO2Me
OH
CO2Me
O
O
OH
4
2
III
II
Scheme 2 Proposed mechanism for the tandem rearrangement and cyclization of (E)-2-(aryloxymethyl)alk-2-enoates catalyzed by Pd/Cu bi-
metallic system
A selection of various (E)-2-(phenyloxymethyl)alk-2- oxidative addition easier. The easy attack of the a-carbon
enoates 1 was investigated using Pd(OAc)2/Cu(OTf)2 as a of the Pd(II) phenolate onto the less substituted carbon of
catalyst in DCE. Table 2 summarizes the results. The me- the allylic cation led to selective [1,3]-sigmatropic rear-
thyl substituent in the para position of the enoates 1b rangement. In the p-allyl–palladium complex, the aryl R1
(Table 2, entry 2) did not much influence the yield as and the ester group prefer the anti configuration due to the
compared to 1a (Table 2, entry 1), whereas 1c, bearing an steric repulsion between them which may lead to the E
electron-withdrawing chloride group in the same position, stereoselectivity. Moreover, the stereochemistry may also
only lowered the yield slightly (Table 2, entry 3).7 The be ascribed to the thermodynamic outcome of metal-cata-
methyl substituent in the para position of phenol side also lyzed double-bond isomerization. At the second step,
had no significant influence on the reaction (Table 2, en- DHC 2 could be eventually formed via the cyclization of
try 4).
intermediate II (Scheme 2, path A).
Next, rearrangement–cyclization reactions of (E)-2- On the other hand, naphthoxyallyl is difficult to form a p-
(naphthyloxymethyl)alk-2-enoates 3 were investigated. allyl–palladium complex. Therefore, the Pd/Cu-catalyzed
Surprisingly, under the optimal conditions for 1a [3,3]-sigmatropic rearrangement of 3 occurs to generate
(Table 1, entry 8), 4-aryl-3-methylene-3,4-DHC 4, arising 3,4-dihydrocourmarins 4 after cyclization of intermediate
from normal Claisen rearrangement–cyclization process III (Scheme 2, path B).
was exclusively obtained. (E)-2-(Naphthyloxymeth-
yl)alk-2-enoates 3 substituted with both electron-with-
drawing and electron-donating groups on the phenyl ring
afforded 4-aryl-3-methylene-3,4-DHC 4 in moderate to
In summary, we have reported a regiospecific synthesis of
3,4-dihydrocoumarin derivatives via substrate-controlled
[1,3]- or [3,3]-sigmatropic rearrangement of (E)-2-(aryl-
oxymethyl)alk-2-enoates catalyzed by a Pd/Cu bimetallic
good yield (Table 3). This is in sharp contrast with the
system. Further investigations on the mechanistic details
AuCl3/AgOTf system where [3,3]-sigmatropic rearrange-
with respect to the stereoselectivity and the role of the Pd
and Cu catalyst are under way in our laboratory.
ment of (E)-2-(naphthyloxymethyl)alk-2-enoates could
only take place at 120 °C.
Although the precise mechanism of this reaction remains
unclear at this moment, we assume that the first step for
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
the transformation of 1 to 2 is the oxidative addition of
Pd(0) to aryl allyl ethers to form a h3–p-allyl complex I,8
which undergoes reductive elimination to afford interme-
diate II and regenerates the catalyst. The coordination of
Cu to the oxygen of the ether and ester groups makes the
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (21076197, 21102130), Natural Science
Synlett 2011, No. 20, 3026–3030 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,4-Dihydrocoumarins
3029
Yield (%)b
81
Table 3 Rearrangement–Cyclization Reactions of (E)-2-(Phenyloxymethyl)alk-2-enoates 3a
Entry
1
Substrates
Products
CO2Me
O
O
O
3a
4a
Me
CO2Me
O
2
3
4
5
6
80
75
79
82
83
O
Me
O
3b
4b
Cl
Cl
Cl
CO2Me
O
O
O
Cl
3c
4c
Br
Br
CO2Me
O
O
O
3d
4d
Cl
CO2Me
O
O
Cl
O
3e
4e
F3C
CO2Me
O
O
F3C
O
3f
4f
a General reaction conditions: substrate 3 (1 mmol), Pd(OAc)2 (5 mol%), Cu(OTf)2 (5 mol%), DCE (2 mL), 80 °C, Ar atmosphere, 15 h.
b Isolated yield.
Foundation of Zhejiang Province (Y4090440), and Qianjiang Ta-
lent Program of Zhejiang Province (2010R10038) for financial sup-
port.
L. J. Heterocycl. Chem. 1988, 25, 89. (f) Jurd, L. J.
Heterocycl. Chem. 1997, 34, 601. (g) Tillekeratne, L. M. V.;
Sherette, A.; Grossman, P.; Hupe, L.; Hupe, D.; Hudson,
R. A. Bioorg. Med. Chem. Lett. 2001, 11, 2763.
(2) (a) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.
Org. Lett. 2008, 10, 2581. (b) Alden-Danforth, E.; Scerba,
M. T.; Lectka, T. Org. Lett. 2008, 10, 4951. (c) Shaabani,
A.; Sarvary, A.; Soleimani, E.; Rezayan, A. H.; Heidary, M.
Mol. Diversity 2008, 12, 197.
(3) For reviews on the Baylis–Hillman reaction, see:
(a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811. (b) Singh, V.; Batra, S. Tetrahedron 2008,
64, 4511. (c) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
References and Notes
(1) (a) Takechi, M.; Tanaka, Y.; Takehara, M.; Nonaka, G.;
Nishioka, I. Phytochemistry 1985, 24, 2245. (b) Hsu, F.-L.;
Nonaka, G.-I.; Nishioka, I. Chem. Pharm. Bull. 1985, 33,
3142. (c) Iinuma, M.; Tanaka, T.; Mizuno, M.; Katsuzaki,
T.; Ogawa, H. Chem. Pharm. Bull. 1989, 37, 1813.
(d) Jurd, L. J. Heterocycl. Chem. 1996, 33, 1227. (e) Jurd,
Synlett 2011, No. 20, 3026–3030 © Thieme Stuttgart · New York

3030
X. Xu et al.
LETTER
Tetrahedron 1996, 52, 8001. (d) Drewes, S. E.; Roos, G. H.
P. Tetrahedron 1988, 44, 4653. (e) Kim, J. N.; Lee, K. Y.
Curr. Org. Chem. 2002, 6, 627. (f) Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005,
26, 1481. (g) Langer, P. Angew. Chem. Int. Ed. 2000, 39,
3049. (h) Krishna, P. R.; Sachwani, R.; Reddy, P. S. Synlett
2008, 2897. (i) Kim, S. H.; Kim, J. N. Bull. Korean Chem.
Soc. 2008, 29, 2039. (j) Declerck, V.; Martinez, J.; Lamaty,
F. Chem. Rev. 2009, 109, 1.
K. C.; Chattopadhyay, B. Tetrahedron Lett. 2008, 49, 4405.
(b) Ito, F.; Fusegi, K.; Kumamoto, T.; Ishikawa, T. Synthesis
2007, 1785. (c) Sarkar, D.; Venkateswaran, R. V. Synlett
2008, 653. (d) Grant, V. H.; Liu, B. Tetrahedron Lett. 2005,
46, 1237. (e) Ollevier, T.; Mwene-Mjeba, T. M.
Tetrahedron Lett. 2006, 47, 4051.
(7) General Experimental Procedure and Spectroscopic
Data
Compound 1a (268.3 mg, 1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), Cu(OTf)2 (18.1 mg, 0.05 mmol), and DCE (2
mL) were added to a 10 mL sealed vessel protected under
Ar. Then the reaction mixture was stirred under reflux
conditions for 15 h. Upon completion of the reaction, the
resulting mixture was diluted with CH2Cl2 (10 mL) and
filtered through Celite. After evaporation of the solvent
under vacuum, the residue was purified by column
chromatography on silica gel (200–300 mesh) using
cyclohexane–EtOAc (12:1) as eluent to give pure 2a (153.7
mg, 65%) as a white solid. 1H NMR (CDCl3, 500 MHz): d =
4.09 (d, J = 2.0 Hz, 2 H), 7.01–7.18 (m, 3 H), 7.35–7.57 (m,
6 H), 7.99 (t, J = 2.0 Hz, 1 H).
(4) (a) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N.
Tetrahedron Lett. 2008, 49, 1670. (b) Kim, J. M.; Kim, K.
H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 3248.
(c) Gowrisankar, S.; Lee, H. S.; Lee, K. Y.; Lee, J.-E.; Kim,
J. N. Tetrahedron Lett. 2007, 48, 8619. (d) Lee, H. S.; Kim,
S. H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2008, 49,
1773. (e) Lee, H. S.; Kim, S. H.; Gowrisankar, S.; Kim, J. N.
Tetrahedron 2008, 64, 7183. (f) Kim, H. S.; Gowrisankar,
S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 3858.
(g) Kim, H. S.; Lee, H. S.; Kim, S. H.; Kim, J. N.
Tetrahedron Lett. 2009, 50, 3154. (h) Liu, Y.; Xu, X.;
Zhang, H.; Xu, D.; Xu, Z.; Zhang, Y. Synlett 2006, 571.
(5) Liu, Y.; Qian, J.; Luo, S.; Xu, Z. Synlett 2009, 2971.
(6) For selected examples related to [3,3]-sigmatropic
rearrangement catalyzed by Lewis acid, see: (a) Majumdar,
(8) (a) Trost, B. M. J. Am. Chem. Soc. 1984, 106, 6837.
(b) Liao, Y. Heteroat. Chem. 1991, 2, 297. (c) Tsuji, J.
J. Organomet. Chem. 1986, 300, 281.
Synlett 2011, No. 20, 3026–3030 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.