Metallic samarium promoted self-coupling of baylis-hillman adducts to functionalized 1,5-hexadienes in the presence of the I2/ClCO 2Et/BiCl3 System

Article abstract of DOI:10.1055/s-0029-1219808

A facile strategy for the self-coupling of Baylis-Hillman adducts to functionalized 1,5-hexadienes has been described. Promoted by the Sm/I ₂/ClCO₂Et/BiCl₃ system, the present method allows for the conversion of MBH adducts to their corresponding 1,5-hexadienes.

Full text of DOI:10.1055/s-0029-1219808

1412
LETTER
Metallic Samarium Promoted Self-Coupling of Baylis–Hillman Adducts to
Functionalized 1,5-Hexadienes in the Presence of the I2/ClCO2Et/BiCl3 System
M
etallic Samarium
a
Promoted
i
S
elf-
C
s
oupling of
h
Baylis–Hill
a
man Adduc
n
t
Bian,a Jian Li,a Chunju Li,a Gan Wang,a Zheng Duan,a Xueshun Jia*a,b
a
Department of Chemistry, Shanghai University, Shanghai 200444, P. R. of China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
b
Fax +86(21)66132408xsjia@mail.shu.edu.cn
Received 1 February 2010
ium is stable in air and has a strong reducing power (Sm3+/
Sm = –2.41 V). Moreover, it is also cheap and easy to
handle. Herein we wish to report a facile strategy for the
self-coupling of Baylis–Hillman adducts promoted by
metallic samarium.
Abstract: A facile strategy for the self-coupling of Baylis–Hillman
adducts to functionalized 1,5-hexadienes has been described. Pro-
moted by the Sm/I2/ClCO2Et/BiCl3 system, the present method al-
lows for the conversion of MBH adducts to their corresponding 1,5-
hexadienes.
Keywords: Baylis–Hillman adduct, metallic samarium, self-
coupling, functionalized 1,5-hexadiene, Lewis acid
COOMe
Ph
H
H
Ph
COOMe
OH
The Morita–Baylis–Hillman (MBH) reaction has become
one of the powerful carbon–carbon bond-forming meth-
ods in organic synthesis.1 The MBH reaction provides
molecules possessing hydroxy, alkenyl, and electron-
withdrawing groups in close proximity, which makes it
valuable in a number of stereoselective transformation
processes.2 Furthermore, many strategies/methodologies
have been successfully employed in the syntheses of bio-
logically active molecules and natural products.3 Among
these transformations, however, using their acetates as
substrates other than the Baylis–Hillman adducts them-
selves predominates since the direct elimination of hy-
droxyl group is usually difficult. As a result, the direct use
of Baylis–Hillman alcohols in organic synthesis without
O-acetylation continues to be a challenge.
2a
+
conditions
COOMe
COOMe
1a
COOMe
3a
COOEt
not observed
Scheme 1
Our initial experiment was carried out by using Baylis–
Hillman adduct 1a as a model substrate (Scheme 1). First-
ly, we investigated the direct transformation of Baylis–
Hillman adducts with metallic samarium and ClCO2Et in
the absence of any additives. At room temperature, no re-
action occurred when substrate 1a was mixed with Sm/
ClCO2Et in THF. Fortunately, 23% yield of self-coupling
product 2a was isolated together with large amount of
reduction product 3a when the reaction was carried out
under refluxing temperature (Table 1, entry 1). Subse-
quently, a series of experimental parameters including ad-
ditive loading were changed to optimize the reaction
conditions. As usual additives, molecular iodine was then
added to activate the metallic samarium powder. It was
noteworthy that the presence of iodine was crucial to the
self-coupling of starting material 1a (Table 1, entry 3).
We tried different amount of iodine added and found that
excessive iodine only led to low yield of product 2a (entry
4). To our delight, applying FeCl3 to this system brought
great improvement. As we can see from Table 1, in the
presence of 5 mol% FeCl3, the self-coupling product 2a
and the reduction product 3a were afforded in 53% and
31% yields, respectively (entry 5). Notably, the reaction
time was greatly shortened to 3 hours from 20 hours. Sev-
eral other Lewis acids were also screened to optimize the
reaction conditions, and the experimental data showed
that 5 mol% amount of BiCl3 appeared to be the best
In the past several years, we paid much attention to the ap-
plication of Baylis–Hillman adducts. For instance, we
have developed a novel strategy to synthesize structurally
unique g-keto esters via the stereoselective C-acetylation
of Baylis–Hillman adducts.4 In addition, we have just re-
ported an efficient preparation of symmetric bisallylic
ethers via the dimerization of MBH adduct.5 On the other
hand, the coupling of Baylis–Hillman adducts to the func-
tionalized 1,5-hexadienes remains a challenge although
SmI2 has proved to be a good choice for such a transfor-
mation.6 However, the application of samarium diiodide
is limited since it is expensive and sensitive to air and wa-
ter. Therefore, the development of more facile and
straightforward method is highly desirable. Recently, the
direct use of metallic samarium as a reducing agent in or-
ganic synthesis has attracted much attention in the past
several years.7 This is due to the fact that metallic samar-
SYNLETT 2010, No. 9, pp 1412–1414
x
x.
x
x.
2
0
1
0
Advanced online publication: 09.04.2010
DOI: 10.1055/s-0029-1219808; Art ID: W01810ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metallic Samarium Promoted Self-Coupling of Baylis–Hilman Adducts
Table 1 Optimization on the Self-Coupling of Baylis–Hillman
Table 2 Facile Self-Coupling of Baylis–Hillman Adducts Promot-
Adducts Promoted by Metallic Samariuma
ed by Sm/I2/ClCO2Et/BiCl3 Systema,b
Entry ClCO2Et I2
(equiv) (mol%)
Lewis acid
Time Yield
(h)
Entry
Ar
Coupling product Yield (%)c
(%)c
2
3
2a
3a
52
50
36
42
31
16
31
36
23
31
37
56
1
2
3
4
5
6
7
Ph
2a
2b
2c
2d
2e
2f
61
66
56
48
63
65
59
23
24
32
30
22
26
27
1
2
1
2
2
2
2
2
2
2
2
2
2
–
–
–
–
–
–
–
20
20
20
20
3
23
28
50
32
53
47
43
31
61
42
20
0
4-ClC6H4
4-MeC6H4
4-t-BuC6H4
2-BrC6H4
4-BrC6H4
3-MeOC6H4
3
5
4
20
5
b
5
FeCl3
b
6
5
RuCl3
3
2g
b
7
5
AlCl3
3
a Unless otherwise noted, all reactions proceeded with 1 mmol
Baylis–Hillman adduct 1, 1.5 mmol Sm powder in the presence of 2
mmol ClCO2Et, 5 mol% BiCl3 and 5 mol% I2.
b
8
5
ZnCl2
3
b
b All reactions were carried out in 15 mL THF under reflux.
c It referred to isolated yields.
9
5
BiCl3
3
10
11
12
5
BiCl3 (15 mol%)
3
b
COOMe
Ar
–
BiCl3
3
H
b
H
5
BiCl3
3
Ar
COOMe
OH
a All attempts were carried out with 1.5 equiv samarium powder and
in 15 mL THF under reflux.
2
+
Sm/ClCO2Et/BiCl3/I2
THF, reflux
COOMe
Ar
b In such cases, 5 mol% Lewis acid is added.
c Isolated yields.
COOMe
Ar
1
3
choice (entry 6–10). In addition, lower yield of 2a was
also observed without molecular iodine (entry 11). In
spite of the important role played by Lewis acid, the em-
ployment of ClCO2Et was also important. During our in-
vestigation, no direct C-acylation product from ClCO2Et
could be detected (Scheme 1). The self-coupling of
Baylis–Hillman adduct did not occur when the corre-
sponding reaction was conducted in the absence of
ClCO2Et (entry 12). In addition, the present transforma-
tion also manifested excellent E-stereoselectivity and no
Z-isomer was observed.8
Scheme 2
Baylis–Hillman adducts. The employment of ClCO2Et
was also crucial to the present conversion. At present
stage, however, we are not quite sure about their exact
role. Further studies on reaction mechanism are still under
way in our laboratory.
In summary, we provided a facile methodology for the
self-coupling of Baylis–Hillman adducts. This new proto-
col allows for the direct conversion of Baylis–Hillman ad-
ducts to the functionalized 1,5-hexadienes. We believe
that our present procedure and the functionalized 1,5-
hexadiene products will find their application in organic
synthesis.
With the Sm/I2/ClCO2Et/BiCl3 system optimized, we then
turned our attention to the substrate generality
(Scheme 2). Various Baylis–Hillman adducts were exam-
ined under the optimal conditions, and the results were
summarized in Table 2.9 In all cases, Baylis–Hillman
adducts bearing both electron-withdrawing and electron-
donating groups on aromatic rings underwent smooth
transformation to the corresponding self-coupling product
2 and reduction product 3 (Table 2, entry 2–7). It seemed
that the presence of electron-withdrawing group on the ar-
omatic ring was favorable to the formation of product 2
together with higher yields (entry 2, 5, and 6). Further-
more, the yields of desired products 2 decreased to some
extent due to the increasing steric hindrance (entry 4).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the National Natural Science Foundation of China (No:
20872087 and 20902057), the Key Laboratory of Synthetic Chemi-
stry of Natural Substances, Chinese Academy of Sciences, Leading
Academic Discipline Project of Shanghai Municipal Education
Commission (No: J50101), and the Innovation Fund of Shanghai
University for financial support.
As to the mechanism, the presence of BiCl3 was consid-
ered to facilitate the elimination of the hydroxyl group in
Synlett 2010, No. 9, 1412–1414 © Thieme Stuttgart · New York

1414
H. Bian et al.
LETTER
(9) All new compounds were characterized by 1H NMR, 13
NMR, elemental analysis, and IR spectroscopy.
C
References and Notes
(1) For reviews, see: (a) Ciganek, E. Org. React. 1997, 51, 201.
(b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001. (c) Basavaiah, D.; Rao, A. J.;
General Procedure for the Synthesis of 1,5-Hexadiene 2
To a stirred solution of Sm powder (1.5 mmol) and ClCO2Et
(2 mmol) in THF (15 mL), BiCl3 (5 mol%), I2 (5 mol%), and
Baylis–Hillman adduct 1 (1 mmol) were added. The
resulting mixture was then allowed to reflux in the air. Until
completion of the reaction, 3 mL HCl (1 M) was then added
to quench the reaction, and the mixture was successively
exacted with EtOAc (2 × 20 mL). The organic phase was
washed with sat. brine (15 mL), dried over anhyd Na2SO4,
filtered. The solvent was removed under reduced pressure to
give the crude products, which were purified by column
chromatography using EtOAc and PE (1:20) as eluent.
Selected Spectroscopic Data of Product 2
Satyanarayana, T. Chem. Rev. 2003, 103, 811. (d) Singh,
V.; Batra, S. Tetrahedron 2008, 64, 4511. (e) Basavaiah,
D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581.
(2) (a) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.;
Reddy, M. V. R.; O’Donnel, M. J. J. Am. Chem. Soc. 2005,
127, 13450. (b) Basavaiah, D.; Roy, S. Org. Lett. 2008, 10,
1819. (c) Declerck, V.; Toupet, L.; Martinez, J.; Lamaty, F.
J. Org. Chem. 2009, 74, 2004. (d) Singh, V.; Saxena, R.;
Batra, S. J. Org. Chem. 2005, 70, 353. (e) Shi, Y. L.; Shi,
M. Chem. Eur. J. 2006, 12, 3374.
(3) For selected examples, see: (a) Radha Krishna, P.;
Nasingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45,
4773. (b) Rodgen, S. A.; Schaus, S. E. Angew. Chem. Int.
Ed. 2006, 45, 3913. (c) Reddy, L. R.; Fournier, J. F.; Reddy,
B. V. S.; Corey, E. J. Org. Lett. 2005, 7, 2699. (d) Trost, B.
M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005,
127, 7014. (e) Konig, C. M.; Harms, K.; Koert, U. Org. Lett.
2007, 9, 4777. (f) Trost, B. M.; Thiel, O. R.; Tsui, H. C.
J. Am. Chem. Soc. 2003, 125, 13155. (g) Lee, S.; Hwang, G.
S.; Shin, S. C.; Lee, T. G.; Jo, R. H.; Ryu, D. H. Org. Lett.
2007, 9, 5087.
(4) Li, S. Y.; Li, J.; Jia, X. S. Synlett 2007, 1115.
(5) Zhao, P. C.; Li, J.; Jia, X. S. Synlett 2008, 932.
(6) Li, J.; Qian, W. X.; Zhang, Y. M. Tetrahedron 2004, 60,
5793.
(7) For review, see: Banik, B. K. Eur. J. Org. Chem. 2002, 2431.
(8) The stereochemistry of products 2 is all E, and the 1H NMR
spectra and the melting points of 2 were well in coincidence
with the reported ones.6
Compound 2d: white solid, mp 171.8–172.3 °C. IR (KBr):
1705, 1629, 1436 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.99 (s, 2 H), 7.70 (s, 2 H), 7.46–7.39 (m, 8 H), 3.78 (s, 6 H),
2.83 (s, 2 H), 1.33 (s, 18 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 169.1, 151.8, 140.4, 132.7, 131.4, 129.6, 125.5,
52.1, 31.4, 27.0 ppm. MS: m/z (%) = 462 (10) [M+], 371
(17), 175 (100). Anal. Calcd for C30H38O4: C, 77.89; H, 8.28.
Found C, 77.78; H, 8.19.
Compound 2e: white solid, mp 168.6–169.0 °C. IR (KBr):
1707, 1560, 1432 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.67 (s, 2 H), 7.60–7.17 (m, 8 H), 3.69 (s, 6 H), 2.58 (s, 4 H)
ppm. 13C NMR (125 MHz, CDCl3): d = 167.9, 139.9, 136.2,
133.6, 132.8, 130.4, 129.7, 127.3, 124.1, 52.1, 27.0 ppm.
MS: m/z (%) = 508 (6) [M+], 397 (52), 174 (70), 115 (100).
Anal. Calcd for C22H20Br2O4: C, 51.99; H, 3.97. Found C,
52.08; H, 3.83.
Synlett 2010, No. 9, 1412–1414 © Thieme Stuttgart · New York

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