Preparation of polystyrene-supported α-seleno acetate and application to solid-phase synthesis of β-keto esters

Article abstract of DOI:10.1055/s-2006-941589

A novel polystyrene-supported α-seleno acetate has been developed. This novel resin was treated with LDA to produce a selenium-stabilized carbanion, which reacted with aldehydes, followed by selenoxide syn-elimination to give β-keto esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941589

LETTER
1547
Preparation of Polystyrene-Supported a-Seleno Acetate and Application to
Solid-Phase Synthesis of b-Keto Esters
P
a
reparation of
P
oly
a
styrene-Su
o
pporte
d
a
-
SelenoA
Q
cetate ian,a,b Xian Huang*b,a
Department of Chemistry, 521 Mail Box, Hangzhou Normal College, Hangzhou 310036, P. R. of China
E-mail: qianhao@mail.hz.zj.cn
b
Department of Chemistry, Zhejiang University, (Xixi Campus), Hangzhou 310028, P. R. of China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
Received 5 March 2006
advantage of the novel polymer reagent is the con-
venience of handling and odorless nature as compared
with the nonpolymer-supported reagents. The preparation
of the polystyrene-supported a-seleno acetate is described
in Scheme 1.
Abstract: A novel polystyrene-supported a-seleno acetate has been
developed. This novel resin was treated with LDA to produce a
selenium-stabilized carbanion, which reacted with aldehydes, fol-
lowed by selenoxide syn-elimination to give b-keto esters.
Key words: solid-phase synthesis, a-seleno acetate, selenoxide
syn-elimination, b-keto esters, polymer reagent
NaBH4
BrCH2COOEt
SeCH2COOEt
SeNa
SeBr
THF/DMF
Solid-phase organic synthesis (SPOS) plays an important
role in parallel synthesis and combinatorial chemistry,
particularly in the area of medicinal chemistry, where the
potential has emerged as a result of the possibility of
automation.1
1
2
3
Scheme 1
Following our published protocol6 and those of the oth-
ers,5 polystyrene-supported selenenyl bromide (1) was
prepared with a loading of 1.71 mmol/g (Br) as deter-
mined by elemental analysis. Resin 1 reacted with sodium
borohydride to give resin 2, which was treated with ethyl
bromoacetate in THF–DMF at room temperature to afford
resin 3 (1.64 mmol/g).7,8
Krief and co-workers reported9 that a-seleno carbanions
obtained according to Sharpless (LDA, THF, –78 °C)
react at this temperature with aldehydes producing b-hy-
droxy selenides in high yield. We examined the same re-
action by the resin 3 (Scheme 2). Thus the resin 3 reacted
with LDA at –78 °C for 30 minutes, then aldehyde was
added. After stirring at –78 °C for another 30 minutes, the
mixture was warmed to room temperature within two
hours, and then the mixture was filtered. The obtained
resin 4 could be converted to b-keto ester by hydrogen
peroxide in good yield.10 The results are shown in Table 1.
On the other hand, over the past 30 years, organoselenium
reagents have been increasingly utilized in highly selec-
tive organic reaction, which are especially useful for the
construction of complex molecules.2 A selenium-stabi-
lized carbanion has played an important role in organic
synthesis because of its easy availability and particularly
good nucleophile, which allows the formation of new
functionalized carbon–carbon bonds when it is used to re-
act with compounds bearing an electrophilic carbon at-
om.3 However, organic selenium reagents always have a
foul smell and are quite toxic, which is often problematic
in organic synthesis. Although polymers with selenium
functionalities have been known for a long time,4 there
remains high interest in this kind of solid-phase organic
chemistry.5
With the continuing evolution of solid-phase organic syn-
thesis (SPOS) comes a growing appreciation for the im-
portance of linker technology, which ideally must
accommodate a wide variety of synthetic transformations
and yet allow for ready product cleavage in the final solid-
phase transformation. It might be argued that selenoxide
syn-elimination provided the principal impetus for the
development of SPOS containing selenium moiety.
R
HO
1. LDA, –78 °C
2. RCHO
SeCH2COOEt
SeCHCOOEt
3
4
H2O2
Our research group has been interested in the application
of organoselenium reagents in the solid-phase organic
synthesis for many years.6 Now, we wish to report the
preparation of polystyrene-supported a-seleno acetate and
its application for synthesis of b-keto esters. A distinct
O
COOEt
R
5
Scheme 2
SYNLETT 2006, No. 10, pp 1547–1548
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941589; Art ID: W04806ST
© Georg Thieme Verlag Stuttgart · New York

1548
H. Qian, X. Huang
LETTER
(3) (a) Krief, A. Tetrahedron 1980, 36, 2531. (b) Chieffi, A.;
Comasseto, J. V. In Organoselenium Chemistry; Back, T.
G., Ed.; Oxford University Press: Oxford, 1999, Chap. 7.
(4) Michels, R.; Kato, M.; Heitz, W. Makromol. Chem. 1976,
177, 2311.
Table 1 Solid-Phase Synthesis of b-Keto Esters
Products
R
Yield
(%)a
Purity
(%)b
Ratio of keto
/enolb
5a
5b
5c
5d
5e
5f
78
80
87
82
81
86
77
>90
>90
>95
>95
>90
>95
>85
15:1
15:1
1:1
(5) (a) Ruhland, T.; Andersen, K.; Pedersen, H. J. Org. Chem.
1998, 63, 9204. (b) Yanada, K.; Fujita, T.; Yanada, R.
Synlett 1998, 971. (c) Fujita, K.; Watanabe, K.; Oishi, A.;
Ikeda, Y.; Taguchi, Y. Synlett 1999, 1760. (d) Nicolaou, K.
C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem.
Commun. 1998, 1947. (e) Zaragoza, F. Angew. Chem. Int.
Ed. 2000, 39, 2077. (f) Fujita, K.; Taka, H.; Oishi, A.; Ikeda,
Y.; Taguchi, Y.; Fujie, K.; Saeki, T.; Sakuma, M. Synlett
2000, 1509. (g) Cohen, R. J.; Fox, D. L.; Salvatore, R. N. J.
Org. Chem. 2004, 69, 4265. (h) Mogemark, M.; Gustafsson,
L.; Bengtsson, C.; Elofsson, M.; Kihlberg, J. Org. Lett. 2004,
6, 4885. (i) Li, Z.; Kulkarni, B. A.; Ganesan, A. Biotechnol.
Bioeng. 2001, 71, 104.
H3CO
O
O2N
1.6:1
7.5:1
3.7:1
1.6:1
H3C
Cl
(6) (a) Qian, H.; Huang, X. Synlett 2001, 1571. (b) Qian, H.;
Huang, X. Tetrahedron Lett. 2002, 43, 1059. (c) Qian, H.;
Huang, X. J. Comb. Chem. 2003, 5, 569. (d) Huang, X.; Xu,
W.-M. Org. Lett. 2003, 5, 4649. (e) Huang, X.; Tang, E.;
Xu, W.-M.; Cao, J. J. Comb. Chem. 2005, 7, 802.
5g
Cl
Cl
(7) Preparation of Polystyrene-Supported a-Seleno Acetate.
Under a nitrogen atmosphere, resin 1 (2 g; elemental
analysis Br, 1.71 mmol/g) was swelled in THF (20 mL)
overnight. The mixture added NaBH4 (10 mmol) stirred at
r.t. for 0.5 h and added 2 mL DMF. After 15 h, ethyl
bromoacetate (15 mmol) was added and the resulting
mixture stirred at r.t. for 12 h. The resin 3 was collected on a
filter and washed alternately with THF (2 × 15 mL), H2O
(4 × 20 mL), EtOH (2 × 15 mL), MeOH (15 mL), THF (2 ×
15 mL), CH2Cl2 (2 × 15 mL), and dried under vacuum. Resin
3 (1.64 mmol/g): IR (KBr): 3058, 3024, 2922, 1730, 1600,
1587, 1568, 1492, 1452, 1365, 1258, 1104, 1028, 758, 698,
540 cm–1.
5h
5i
64
56
>80
>85
13:1
10:1
CH2–
(CH3)2CHCH2–
a Yields of products based on the loading of the resin and the products
were identified by 1H NMR, MS, FT-IR spectra.
b Determined by 1H NMR (400 MHz).
(8) Determined by acid–base titration to be 1.64 mmol/g
(COOH). For analytical purposes, the resin of a-seleno
acetic acid was prepared by reaction of resin 3 (1 g) with
LiOH (1.5 mol/L, 3 mL) in THF (15 mL). After stirred at
35 °C overnight, the resin was washed successively with
H2O, 10% HCl, H2O, THF and CH2Cl2. IR (KBr): 3058,
3024, 2922, 1700, 1600, 1588, 1568, 1492, 1452, 1285,
1106, 758, 698, 541 cm–1.
In conclusion, we have developed a novel polystyrene-
supported a-seleno acetate reagent, which were readily
prepared from polystyrene-supported selenenyl bromide.
This novel resin was treated with LDA to produce a sele-
nium-stabilized carbanion, which reacted with aldehydes,
followed by oxidative selenoxide syn-elimination to give
b-keto esters.
(9) Lucchetti, L.; Krief, A. Tetrahedron Lett. 1978, 19, 2693.
(10) Typical Procedure for the Synthesis of b-Keto Ester.
Under a nitrogen atmosphere, the resin 3 (0.5 g) was
suspended in THF (15 mL) at –78 °C and LDA (1 mmol)
was added with stirring. The mixture was stirred 0.5 h at
–78 °C, then benzaldehyde (1.5 mmol) was added. After
stirring at –78 °C for 0.5 h, the mixture was warmed to r.t. in
2 h. Then, the mixture was filtered. The resin 4d was
collected by filtration and washed with THF (2 × 10 mL),
MeOH (2 × 10 mL), CHCl3 (2 × 10 mL) and THF (2 × 10
mL). The washed resin 4d was suspended in THF (15 mL).
To the mixture was added 30% H2O2 (2 mL) and followed
by stirring for 2 h at r.t. The mixture was filtered and the
resin was washed with CHCl3 (3 × 15 mL). The filtrate was
washed with H2O (2 × 30 mL), dried over MgSO4, and
evaporated to dryness under vacuum to afford 130 mg (82%)
of almost pure ethyl benzoylacetate.
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (Project No.29932020) and the Science Foundation of Hangzhou
Normal College (No.131901, No. 131001) for financial support.
References and Notes
(1) (a) Lorsbach, B. A.; Kurth, M. J. Chem. Rev. 1999, 99,
1549. (b) Guillier, F.; Orain, D.; Bradley, M. Chem. Rev.
2000, 100, 2091. (c) Shuttleworth, S. J.; Allin, S. M.;
Wilson, R. D.; Nasturica, D. Synthesis 2000, 1035.
(d) Sammelson, R. E.; Kurth, M. J. Chem. Rev. 2001, 101,
137.
(2) Nicolaou, K. C.; Petasis, N. A. In Selenium in Natural
Product Synthesis; CIS: Philadelphia, 1984.
Synlett 2006, No. 10, 1547–1548 © Thieme Stuttgart · New York