Efficient preparation of α,α-dialkyl-α-(phenylselanyl) acetates and α,β-unsaturated esters from the corresponding α,α-dialkyl-α-cyanoacetates by a lithium naphthalenide induced reductive selenenylation process

Article abstract of DOI:10.1055/s-2007-990884

An array of α,α-dialkyl-α-(phenylselanyl)acetates has been synthesized very efficiently from readily available α,α- dialkyl-α-cyanoacetates, by use of lithium naphthalenide induced reductive α-selenenylation as a key operation. Moreover, the selanyl esters thus generated in situ could be converted further, in a one-pot treatment with hydrogen peroxide and acetic acid, into the corresponding α,β- unsaturated esters in moderate to high yields. The C=C bond formation was highly regio- and/or diastereoselective in some cases. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990884

PAPER
3659
Efficient Preparation of a,a-Dialkyl-a-(phenylselanyl)acetates and
a,b-Unsaturated Esters from the Corresponding a,a-Dialkyl-a-cyanoacetates
by a Lithium Naphthalenide Induced Reductive Selenenylation Process
Preparationof
a
,
a
-
e
D
ialkyl-
a
-(
n
phenylselany
-
l)acetat
C
es and
a
,
b
-Unsat
h
uratedEstersun Ko, Jia-Liang Zhu*
Department of Chemistry, National Dong-Hwa University, Hualien 974, Taiwan
Fax +886(3)8633570; E-mail: jlzhu@mail.ndhu.edu.tw
Received 20 July 2007; revised 28 August 2007
this gives the corresponding a-(phenylselanyl) ketones
Abstract: An array of a,a-dialkyl-a-(phenylselanyl)acetates has
been synthesized very efficiently from readily available a,a-di-
alkyl-a-cyanoacetates, by use of lithium naphthalenide induced re-
ductive a-selenenylation as a key operation. Moreover, the selanyl
with the overall replacement of the cyano group by a phe-
nylselanyl group. Through this protocol, a great variety of
a-cyano ketones have been efficiently converted into the
esters thus generated in situ could be converted further, in a one-pot corresponding a-(phenylselanyl) ketones with complete
treatment with hydrogen peroxide and acetic acid, into the corre-
control over the regiochemistry. Meeting with these
sponding a,b-unsaturated esters in moderate to high yields. The
promising results, we were interested in extending the
C=C bond formation was highly regio- and/or diastereoselective in
lithium naphthalenide induced reductive selenenylation
some cases.
process to the synthesis of other types of a-(phenylsela-
Key words: nitriles, selenium, reductive selenenylation, lithium
naphthalenide, a,b-unsaturated esters
nyl) carbonyl compounds. In this paper, we wish to report
our findings concerning the efficient preparation of a-
(phenylselanyl) esters from the corresponding a-cyano es-
ters.
a-(Phenylselanyl) carbonyl compounds are of consider-
As a class of highly substituted synthetic intermediates,
able importance in synthetic chemistry.1 They are com-
a,a-dialkyl-a-(phenylselanyl)acetates 1 (Scheme 1) have
monly used as starting materials for the preparation of
been shown to have broad utility in synthetic chemistry,
a,b-unsaturated carbonyl derivatives1a and some other
particularly in the preparation of a,b-unsaturated es-
ters,9,10 as well as the generation of free radicals to under-
go coupling and/or annulation reactions5c–e to establish
complex molecules. Several synthetic routes have been
reported for generating these compounds. For 1 with two
identical alkyl groups (R1 = R2), the direct dialkylation of
a-(phenylselanyl)acetates appears to be the most straight-
forward approach.9 On the other hand, compounds 1 pos-
sessing two different alkyl substituents (R1 π R2) are
usually synthesized either by the selenenylation of the
enolates of a,a-dialkylacetates 2 by use of an appropriate
phenylselenenylating reagent PhSeX (X = Cl, Br, SePh)
(Scheme 1, Approach A),5d,10 or, alternatively, by the
alkylation of the enolates of a-alkyl-a-(phenylselanyl)ac-
etates 3 (Scheme 1, Approach B).9 Selanyl esters 3 can be
synthesized by the substitution of a-alkyl-a-haloacetates
4 with the phenylselenide anion generated from the reac-
tion of diphenyl diselenide with sodium borohydride, or
by the selenenylation of the enolates of a-alkylacetates 5
(Scheme 1).11 These methods suffer from several draw-
backs. For instance, the transformation from 5 to 3 and
then from 3 to 1 in Approach B is often complicated by
side reactions including overselenenylation and competi-
tive alkylation of the selenium atoms.9,12 Additionally, the
starting materials are less available, and this coupled with
the need for relatively strong basic conditions may also
impede the applicability of Approaches A and B.
synthetically useful compounds.1b,c,2–4 Furthermore, their
application as elaborated precursors in the promotion of
various radical-mediated processes5 has also been de-
scribed widely. In addition to their synthetic versatility, a
specific series of a-(phenylselanyl) ketones and acids
have been shown to exhibit antioxidant activity like that
of glutathione peroxidase;6 this indicates that these com-
pounds might have the potential to serve as anticancer, an-
tiviral, and anti-inflammatory agents. Because of their
synthetic and biological importance, it is not surprising to
find that diverse strategies toward the synthesis of a-(phe-
nylselanyl) carbonyl compounds have been reported in
the past years. Among them, methodologies based on the
selenenylation of enolates or enol derivatives of the corre-
sponding carbonyl compounds appear to be the most fre-
quently documented ones.7
We have been working on devising more powerful and
versatile methods for the preparation of a-(phenylselanyl)
carbonyl compounds, and have recently reported a highly
efficient procedure for the preparation of a-(phenylsela-
nyl) ketones from the corresponding a-cyano ketones.8
Our approach is based on the reductive decyanation of a-
cyano ketones: reduction with lithium naphthalenide (LN)
is followed by the rapid one-pot selenenylation of the re-
sulting enolates with phenylselenenyl bromide (PhSeBr);
Our recent studies on some addition and cyclization reac-
tions involving carbon-centered radicals resulting from
C–Se bond cleavage required the efficient generation of
SYNTHESIS 2007, No. 23, pp 3659–3665
Advanced online publication: 13.11.2007
DOI: 10.1055/s-2007-990884; Art ID: F13607SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

3660
Y.-C. Ko, J.-L. Zhu
PAPER
O
X
OR3
R1
4
PhSe–
O
O
O
R2X, base
PhSeX, base
approach A
R1
PhSe
PhSe
R1 R2
OR3
OR3
OR3
approach B
R1
R2
1 (R1 ≠ R2)
3
2
PhSeX
base
O
OR3
R1
5
Scheme 1 Two general synthetic approaches for the synthesis of a,a-dialkyl-a-(phenylselanyl)acetates (1)
highly substituted a-(phenylselanyl)acetates with a broad
structural diversity. On the basis of our previous experi-
ences,8 we envisaged that a process involving the reduc-
tive selenenylation of a-cyano esters might lead to an
attractive method. Our strategy consisted of first introduc-
ing the selected alkyl groups to the a-position of cyano-
acetate 6, to provide a,a-dialkyl-a-cyanoacetates 7
(Scheme 2), which would then be subjected to reductive
selenenylation, thus giving the desired products 1 by in-
tentional control of the substitutions at the quaternary car-
bon center (Scheme 2). To our knowledge, the preparation
of a-(phenylselanyl) ester compounds by such an ap-
proach is unprecedented.
Table 1 Reductive a-Selenenylation of a,a-Dialkyl-a-cyanoace-
tates
O
O
LN (5 equiv), THF, –45 °C, 25 min
NC
PhSe
OR3
OR3
R1 R2
R1 R2
then PhSeBr (1.2 equiv), –45 °C, 15 min
7
1
Entry Starting R1
R2
Product Yieldc
material 7a
1a,b
1a
1b
1c
1d
1e
1f
(%)
95
85
83
80
95
85
76
79
90
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
Bn
Bn
(CH2)5
(CH2)4
O
O
Et
Bn
Bn
Me
Et
O
NC
PhSe
LN
OR3
OR3
(CH2)3OTBDMS
NC
OR3
R1 R2
R1 R2
then PhSeX
i-Pr
i-Pr
Me
Pr
6
7
1
(R1 ≠ R2 or R1 = R2)
(R1 ≠ R2 or R1 = R2)
7g
7h
7i
1g
1h
1i
Scheme 2 Proposed synthesis of 1 by a reductive selenenylation
approach
Et
Et
Our investigation began with the preparation of substrates
7a–i (Table 1, entries 1–3), starting from commercially
available ethyl cyanoacetate. As described below, one of
the salient features of the current process lies in the ease
of introducing two alkyl substituents, either identical or
different, into the acetate unit. Thus, by a modification of
the procedure developed by Oediger and Moller,13 disub-
stituted cyanoacetates 7a–c were easily prepared by treat-
ment of ethyl cyanoacetate with benzyl bromide (2.2
equiv) or 1,5- or 1,4-dibromobutane (1.1 equiv) in N,N-
dimethylformamide and with the use of 1,8-diazabicyc-
lo[5.4.0]undec-7-ene (2.2 equiv) as base at 80 °C for two
hours. Yields were typically around 90%. For cyanoace-
tates 7d–i with two different alkyl groups (Table 1, entries
4–9), a two-step synthetic operation was applied.14 First,
a R3 = Et in all cases.
b The structures of new selanylacetates 1b,c,e–g,i were established
from their spectroscopic data (1H and 13C NMR, IR, and MS).
c Isolated yield of purified product.
the monoalkylated intermediates were prepared by alkyla-
tion of ethyl cyanoacetate with one equivalent iodoethane
(7d,h,i), 3-bromopropyl tert-butyldimethylsilyl ether
(7e),15 or 2-iodopropane (7f,g) in benzene with diazabicy-
clo[5.4.0]undec-7-ene (1.2 equiv) at room temperature for
one day. The monoalkylated intermediates were then
treated with 1.2 equivalents of the appropriate alkylating
agent (BnBr, MeI, EtI, or PrI) and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (1.3 equiv) in N,N-dimethylform-
amide at room temperature for 20 hours; this gave the
Synthesis 2007, No. 23, 3659–3665 © Thieme Stuttgart · New York

PAPER
Preparation of a,a-Dialkyl-a-(phenylselanyl)acetates and a,b-Unsaturated Esters
3661
unsymmetrically substituted cyanoacetates 7. The yields to the reaction mixture at –45 °C, followed by reaction for
over two steps ranged from 75% to 95%. Thus, a broad an additional 30 minutes with the temperature increasing
range of a,a-dialkyl-a-cyanoacetates 7 was prepared, with from –45 °C to –10 °C led to the exclusive formation of
the efficient incorporation of various alkyl groups into the (E)-a,b-unsaturated ester 8a in 85% isolated yield
molecules.
(Scheme 3), with the spectral data (1H and 13C NMR) in
good agreement with those reported in the literature.17 It
deserves to be noted that the methods previously de-
scribed for the preparation of 8a and its analogues often
involve much more drastic reaction conditions than those
described here.18,19 The one-pot selenenylation–oxidative
elimination process was subsequently also applied to oth-
er a-cyano acetates 7b–j, and the results are compiled in
Table 2.
With the required cyanoacetates 7 in hand, we turned our
attention to subjecting them to the key reductive seleneny-
lation reaction (Table 1). To our delight, we found that the
protocol previously developed for a-cyano ketones
proved equally successful for a-cyano esters, as shown by
the results in Table 1. In all cases examined, starting ma-
terials 7a–i were readily reduced (over ca. 25 min) with
lithium naphthalenide16 under mild conditions (–45 °C) to
give the corresponding ester enolates. Subsequent addi-
tion of phenylselenenyl bromide effected the selenenyla-
tion, providing the desired a-(phenylselanyl) esters 1a–i
in synthetically useful yields (76–95%; Table 1). As a typ-
ical example, treatment of ethyl 2-benzyl-2-cyano-3-phe-
nylpropanoate (7a) with five equivalents of lithium
naphthalenide17 in tetrahydrofuran at –45 °C for 25 min-
utes followed by the addition of 1.2 equivalents of phe-
nylselenenyl bromide and further reaction at the same
temperature for an additional 15 minutes afforded ethyl 2-
benzyl-3-phenyl-2-(phenylselanyl)propanoate (1a)9 in
95% yield after the usual workup and chromatographic
purification (Table 1, entry 1). It is noteworthy that
among several phenylselenenylating agents investigated,
phenylselenenyl bromide was found to be superior to its
counterparts, such as phenylselenenyl chloride and diphe-
nyl diselenide, in offering the products in relatively higher
yields. As described above, in conjunction with the effi-
cient means for alkylation of ethyl cyanoacetate, the lithi-
um naphthalenide induced reductive selenenylation of
cyanoacetates provides a useful tool for the preparation of
highly substituted a-(phenylselanyl)acetates. In addition
to broad substrate diversity, this procedure also has the ad-
vantages of operational simplicity, relatively mild reac-
tion conditions, and high-yielding formation of products.
O
O
Bn
Ph
CN
Bn
EtO
EtO
Bn
H
7a
8a
Scheme 3 Conversion of 7a into 8a by the one-pot selenenylation–
oxidative elimination process. Reagents and conditions: 1. LN (5
equiv), THF, –45 °C, 25 min; 2. PhSeBr (1.2 equiv), –45 °C, 15 min;
3. AcOH (4 equiv), H2O2 (8 equiv), H2O, –45 to –10 °C, 30 min; 85%.
As shown in Table 2, under these conditions, the two cy-
clic a-cyano acetates 7b and 7c were both smoothly con-
verted into the corresponding a,b-unsaturated esters 8b
and 8c in 82% and 81% yield, respectively (Table 2, en-
tries 1 and 2). At the same time, application of these con-
ditions to substrates 7 substituted with two different alkyl
groups allowed us to inspect the regio- and stereoselectiv-
ity regarding the introduction of unsaturation more close-
ly (Table 2, entries 3–9). For substrates 7d and 7e bearing
a benzyl group, the procedure was found to proceed with
complete regio- and stereoselectivity, giving products 8d
and 8e, respectively, in high yields exclusively as the E-
isomers (Table 2, entries 3 and 4). Furthermore, the com-
pletely regioselective formation of the C=C double bonds
was also observed for substrates 7f and 7g, in which the in
situ oxidative elimination reaction took place exclusively
on the less substituted b-carbons instead of the more sub-
stituted ones, affording 8f (Table 2, entry 5) or an E,Z-
isomeric mixture of 8g and 8g¢ in favor of the E-form
(E/Z = 62:38) (Table 2, entry 6). With cyanoacetate 7h,
the reaction displayed a moderate degree of regioselectiv-
ity in giving a mixture of two constitutional isomers 8h
and 8h¢ in 73% yield, with the less substituted 8h as the
major product (8h/8h¢ = 59:41) (Table 2, entry 7). In
these cases (Table 2, entries 5–7), the preferential genera-
tion of the less substituted a,b-unsaturated esters can, pre-
sumably, be attributed to the carbanion character of the b-
carbon undergoing the elimination. Therefore, during the
transition state of the oxidative elimination, the less sub-
stituted b-carbon would be more prone to hydrogen ab-
To further demonstrate the synthetic utility of the reduc-
tive selenenylation process, we also attempted to convert
the in situ generated selanylacetates 1 without isolation
into the corresponding a,b-unsaturated esters by a one-pot
treatment with an oxidizing reagent. To date, few cases
have been reported for the transformation of unsymmetri-
cally substituted a,a-dialkyl-a-(phenylselanyl)acetates 1
(R1 1 R2) into the corresponding a,b-unsaturated esters.9
This is presumably due to the lack of efficient preparative
methods for the starting materials. In the light of the effi-
ciency of the above-mentioned protocol, we envisaged
that a one-pot combination of reductive selenenylation
with oxidative elimination would permit the convenient
generation of a series of synthetically useful a,b-unsatur-
ated esters, which are otherwise difficult to synthesize.
This one-pot operation was first attempted with cyano- straction by the selenoxide oxygen than the more
acetate 7a (Scheme 3). We were pleased to find that with substituted one, for stability reasons. This rationalization
the completion of the reductive selenenylation of 7a, as can be further supported by the result shown for the reac-
indicated by TLC analysis, the subsequent addition of wa- tion of 7i (Table 2, entry 8): an equal amount of the two
ter, acetic acid (4 equiv), and hydrogen peroxide (8 equiv) constitutional isomers 8i and 8i¢, both E-isomers, was ob-
Synthesis 2007, No. 23, 3659–3665 © Thieme Stuttgart · New York

3662
Y.-C. Ko, J.-L. Zhu
PAPER
Table 2 Conversion of a-Cyanoacetates into a,b-Unsaturated Esters by the One-Pot Selenenylation–Oxidative Elimination Process
O
O
R1
LN ( 5 equiv), THF, –45 °C, 25 min, then PhSeBr (1.2 equiv), –45 °C, 15 min
CN
R1 R2
R3O
R3O
Entry
1
then H2O, HOAc (4 equiv), H2O2 (8 equiv), –45 °C to –10 °C, 30 min
R4
H
7
8
Starting material 7
Product(s) 8
Yielda (%)
82
O
O
CN
EtO
OEt
8b
8c
7b
O
O
CN
EtO
2
3
81
79
OEt
7c
O
O
Et
CN
EtO
8d
EtO
Et
Bn
H
O
Ph
7d
O
CN
Bn
EtO
EtO
8e
OTBDMS
4
5
85
65
H
Ph
TBDMSO
7e
O
O
i-Pr
H
CN
EtO
8f
EtO
i-Pr
H
7f
O
O
O
i-Pr
i-Pr
Me
EtO
EtO
6
7
52b
CN
Et
+
EtO
i-Pr
Me
8g'
O
H
H
7g
8g
O
O
Et
H
Me
Me
EtO
EtO
EtO
73b
CN
Et
+
EtO
H
O
H
7h
8h
8h'
O
O
Et
Et
Pr
EtO
H
84b
CN
Et
+
8
9
EtO
Pr
H
Me
7i
8i
8i'
O
O
O
i-Pr
Me
i-Pr
t-BuO
t-BuO
Me
77b
CN
Et
+
t-BuO
i-Pr
H
H
7jc
8j
8j'
a Isolated yield.
b Yield of isomeric mixture; 8g/8g¢ = 62:38; 8h/8h¢ = 59:41; 8i/8i¢ = 50:50; 8j/8j¢ = 51:49. The ratios were deduced from the integrations of the
olefinic proton signals in the 1H NMR spectra of the mixtures.
c Compound 7j was synthesized from tert-butyl cyanoacetate by the same procedure used for the synthesis of 7g.
Synthesis 2007, No. 23, 3659–3665 © Thieme Stuttgart · New York

PAPER
Preparation of a,a-Dialkyl-a-(phenylselanyl)acetates and a,b-Unsaturated Esters
3663
solid PhSeBr (290 mg, 1.23 mmol) was added in one portion, and
stirring of the mixture at –45 °C was continued for an additional 15
min. The mixture was quenched with H2O (5 mL) and extracted
with Et2O (2 × 15 mL). The combined extracts were washed with
sat. aq NaCl (10 mL), dried (Na2SO4), and concentrated. Purifica-
tion by chromatography (silica gel, hexane–EtOAc, 25:1) afforded
1a as a viscous oil. Yield: 410 mg (95%).9
5%
2%
TBDMSO
H
10%
O
H
OEt
IR (KBr): 1715, 1578, 1202, 741, 700 cm–1.
Figure 1 Results of NOE experiments of compound 8e
1H NMR (300 MHz, CDCl3): d = 1.12 (t, J = 7.2 Hz, 3 H), 3.27 (d,
J = 14.8 Hz, 2 H), 3.35 (d, J = 14.8 Hz, 2 H), 4.06 (q, J = 7.2 Hz, 2
H), 7.16–7.42 (m, 13 H), 7.59–7.62 (dm, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 41.3, 54.6, 61.2, 126.8, 127.8,
128.0, 128.7, 129.3, 130.4, 137.2, 138.2, 173.3.
tained from 7i possessing two methylene b-carbons. Fi-
nally, application of the procedure to 7j, the tert-butyl
ester analogue of ethyl ester 7g, also resulted in a highly
regioselective reaction to afford a diastereomeric mixture
of 8j and 8j¢ in 77% yield (Table 2, entry 9). However, for
reasons still unclear to us, the E/Z ratio of the products
was lower (8j/8j¢ = 51:49) than that of the products from
7g (Table 2, entry 6), despite the increased steric interac-
tions in the Z-isomer 8j¢.
MS (EI, 70 eV): m/z = 267.2 [M – SePh]+.
Ethyl 1-(Phenylselanyl)cyclohexane-1-carboxylate (1b)
The typical procedure for the preparation of 1a was followed; 7b
(96 mg, 0.53 mmol) was used as starting material. Flash chromatog-
raphy (hexane–EtOAc, 40:1) afforded 1b as a yellowish oil. Yield:
140 mg (85%).
All of the products listed in Table 2 were purified by flash
chromatography on silica gel, and satisfactory spectral
data (1H, 13C NMR, IR, and MS) were obtained for them.
For the known compounds (8b–d, 8f–8j/j¢), the structures
were confirmed by comparison of their spectral data (1H
and 13C NMR) with those reported in the literature.20 For
8e, NOE experiments were carried out to assign its E-con-
figuration (Figure 1).
IR (KBr): 1718, 1577, 1475, 1447, 741, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.16 (t, J = 7.1 Hz, 3 H), 1.26–1.38
(m, 3 H), 1.51–1.57 (m, 1 H), 1.68–1.78 (m, 4 H), 2.13–2.17 (m, 2
H), 4.07 (q, J = 7.1 Hz, 2 H), 7.25–7.41 (m, 3 H), 7.57 (br d, J = 7.5
Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.0, 24.4, 25.4, 34.7, 51.6, 60.7,
126.9, 128.6, 129.1, 138.0, 173.3.
HRMS–FAB: m/z [M+] calcd for C15H20O2Se: 312.0629; found:
In summary, the reductive selenenylation protocol that we
previously described for the preparation of a-(phenylsela-
nyl) ketones has been successfully extended to the gener-
ation of a variety of highly substituted a-(phenyl-
selanyl)acetates from readily available a-cyanoacetates.
Additionally, the synthetic utility of the procedure has
been further extended by the in situ treatment of the a-
(phenylselanyl) esters thus formed with an oxidizing re-
agent, thus conveniently converting them into trisubstitut-
ed or disubstituted a,b-unsaturated esters, many of which
are not easily accessible by existing methods.
312.0631.
Ethyl 1-(Phenylselanyl)cyclopentane-1-carboxylate (1c)
The typical procedure for the preparation of 1a was followed; 7c
(133 mg, 0.8 mmol) was used as starting material. Flash chromatog-
raphy (hexane–EtOAc, 50:1) gave 1c as a pale yellow oil. Yield:
200 mg (83%).
IR (KBr): 1718, 1573, 1475, 1438, 740, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (t, J = 7.1 Hz, 3 H), 1.62–1.73
(m, 2 H), 1.82–1.93 (m, 4 H), 2.13–2.23 (m, 2 H), 4.08 (q, J = 7.1
Hz, 2 H), 7.27–7.40 (m, 3 H), 7.57–7.63 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 24.0, 36.0, 56.2, 60.9, 128.6,
128.7, 129.0, 137.1, 174.5.
All reagents were obtained from commercial suppliers and were
used without further purification. THF was distilled from sodium–
benzophenone, and benzene and DMF were distilled from CaH2 be-
fore use. TLC analysis was carried out on Merck 25 DC-Alufolien
Kieselgel 60F254 aluminum-backed plates, visualized by use of UV
light, or treatment with an EtOH soln of vanillin (5%) with H2SO4
(5%). All products were purified by flash chromatography on
Merck Art. 9385 Kieselgel 60 silica gel (230–400 mesh). NMR
spectra (1H, 13C) were recorded on a Bruker 300 or a Bruker 400
spectrometer, and CDCl3 was used as solvent. NOE experiments of
samples in CDCl3 were performed on a Bruker 400 spectrometer. IR
spectra were recorded on an IR-FT JASCO 410 spectrophotometer
(KBr pellets). HRMS was carried out on an A. E. I. model MS-50
mass spectrometer in FAB mode. GC-MS spectra were recorded on
a Thermo Finnigan TRACE GC mass spectrometer in electron ion-
ization mode.
HRMS–FAB: m/z [M+] calcd for C14H18O2Se: 298.0472; found:
298.0473.
Ethyl 2-Benzyl-5-(tert-butyldimethylsiloxy)-2-(phenylsela-
nyl)pentanoate (1e)
The typical procedure for the preparation of 1a was followed; 7e
(150 mg, 0.40 mmol) was used as starting material. Flash chroma-
tography (hexane–EtOAc, 25:1) yielded 1e as a viscous oil. Yield:
190 mg (95%).
IR (KBr): 1719, 1472, 1438, 835, 741, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.02 (s, 6 H), 0.88 (s, 9 H), 1.15
(t, J = 7.1 Hz, 3 H), 1.69–1.94 (m, 4 H), 3.14 (d, J = 14.2 Hz, 1 H),
3.38 (d, J = 14.2 Hz, 1 H), 3.55 (t, J = 6.0 Hz, 2 H), 3.99–4.09 (m,
2 H), 7.21–7.41 (m, 8 H), 7.60 (dm, J = 8.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = –5.3, 13.9, 18.4, 26.0, 28.8, 30.1,
40.7, 55.9, 61.0, 63.1, 126.8, 127.4, 128.1, 128.8, 129.2, 130.2,
137.0, 137.9, 173.1.
Ethyl 2-Benzyl-3-phenyl-2-(phenylselanyl)propanoate (1a);
Typical Procedure
A 0.365 M soln of LN in THF (14 mL, 5.11 mmol)16 precooled to
–45 °C was quickly added by syringe to a soln of 7a (300 mg, 1.02
mmol) in anhyd THF (14 mL) at –45 °C under a N2 atmosphere. The
resulting dark-green mixture was stirred at –45 °C for 25 min, then
HRMS–FAB: m/z [M + 1]+ calcd for C26H39O3SiSe: 507.1834;
found: 507.1838.
Synthesis 2007, No. 23, 3659–3665 © Thieme Stuttgart · New York

3664
Y.-C. Ko, J.-L. Zhu
PAPER
Ethyl 2,3-Dimethyl-2-(phenylselanyl)butyrate (1f)
The typical procedure for the preparation of 1a was followed; 7f
(100 mg, 0.59 mmol) was used as starting material. Flash chroma-
tography (hexane–EtOAc, 30:1) provided 1f as a yellow viscous oil.
Yield: 150 mg (85%).
13C NMR (75 MHz, CDCl3): d = 14.2, 33.2, 60.9, 126.1, 128.0,
128.5, 128.6, 128.7, 129.2, 131.2, 135.5, 139.6, 140.6, 168.2.
HRMS–FAB: m/z [M + 1]+ calcd for C18H19O2: 267.1385; found:
267.1382.
IR (KBr): 1719, 1577, 1474, 1438, 741, 692 cm–1.
Ethyl (E)-2-Benzylidene-5-(tert-butyldimethylsiloxy)pen-
tanoate (8e)
The typical procedure for the preparation of 8a was followed; 7e
(100 mg, 0.27 mmol) was used as starting material. Flash chroma-
tography (hexane–EtOAc, 25:1) afforded 8e as a colorless oil.
Yield: 75 mg (85%).
1H NMR (400 MHz, CDCl3): d = 0.89 (d, J = 6.8 Hz, 3 H), 1.15 (t,
J = 7.1 Hz, 3 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.39 (s, 3 H), 2.38 (m,
J = 6.8 Hz, 1 H), 3.98–4.11 (m, 2 H), 7.27–7.39 (m, 3 H), 7.58 (br
d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 16.7, 18.1, 18.4, 33.0, 56.3,
60.7, 127.6, 128.6, 129.1, 137.9, 173.9.
IR (KBr): 3060, 3026, 1708, 1630, 1578, 1494, 1471, 1461, 1253,
1099 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6 H), 0.90 (s, 9 H), 1.35
(t, J = 7.1 Hz, 3 H), 1.76–1.83 (m, 2 H), 2.60–2.65 (m, 2 H), 3.68 (t,
J = 6.2 Hz, 2 H), 4.28 (q, J = 7.2 Hz, 2 H), 7.29–7.45 (m, 5 H), 7.67
(s, 1 H).
13C NMR (75 MHz, CDCl3): d = –5.3, 14.3, 18.4, 24.4, 26.0, 32.3,
60.8, 63.1, 128.3, 128.5, 129.5, 133.2, 135.7, 138.8, 168.5.
HRMS–FAB: m/z [M + 1]+ calcd for C20H33O3Si: 349.2199; found:
349.2192.
HRMS–FAB: m/z [M+] calcd for C14H20O2Se: 300.0629; found:
300.0630.
Ethyl 2-Ethyl-3-methyl-2-(phenylselanyl)butyrate (1g)
The typical procedure for the preparation of 1a was followed; 7g
(120 mg, 0.65 mmol) was used as starting material. Flash chroma-
tography (hexane–EtOAc, 25:1) afforded 1g as a viscous oil. Yield:
160 mg (76%).
IR (KBr): 1718, 1577, 1474, 1437, 741, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H), 1.08 (d,
J = 6.9 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H),
1.68 (dq, J = 14.5, 7.3 Hz, 1 H), 1.88 (dq, J = 14.5, 7.3 Hz, 1 H),
2.17 (sept, J = 6.9 Hz, 1 H), 4.12 (qd, J = 7.1, 2.3 Hz, 2 H), 7.26–
7.38 (m, 3 H), 7.60 (br d, J = 7.5 Hz, 2 H).
Acknowledgment
We are grateful to the National Science Council of the Republic of
China and the National Dong-Hwa University for financial support.
13C NMR (100 MHz, CDCl3): d = 10.8, 14.1, 18.6, 19.4, 26.6, 33.2,
60.7, 63.3, 127.7, 128.6, 128.9, 138.2, 173.4.
HRMS–FAB: m/z [M+] calcd for C15H22O2Se: 314.0785; found:
References
(1) (a) Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley-VCH: New York, 1999. (b) Paulmier, C.
Selenium Reagents and Intermediates in Organic Synthesis;
Pergamon: Oxford, 1986. (c) Back, T. G. Organoselenium
Chemistry: A Practical Approach; Oxford University Press:
New York, 1999.
(2) Wirth, T.; Arrica, M. Eur. J. Org. Chem. 2005, 395.
(3) Boivin, S.; Outurquin, F.; Paulmier, C. Tetrahedron 1997,
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314.0781.
Ethyl 2-Ethyl-2-(phenylselanyl)pentanoate (1i)
The typical procedure for the preparation of 1a was followed; 7i
(100 mg, 0.55 mmol) was used as starting material. Flash chroma-
tography (hexane–EtOAc, 30:1) afforded 1i as a yellow oil. Yield:
150 mg (90%).
IR (KBr): 1718, 1577, 1475, 1438, 741, 692 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 3 H), 0.95 (t,
J = 7.3 Hz, 3 H), 1.19 (t, J = 7.2 Hz, 3 H), 1.29–1.38 (m, 1 H), 1.39–
1.51 (m, 1 H), 1.64–1.84 (m, 4 H), 4.08 (q, J = 7.2 Hz, 2 H), 7.29
(br t, J = 7.4 Hz, 2 H), 7.37 (br t, J = 7.4 Hz, 1 H), 7.55 (br d, J = 7.4
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 9.4, 14.0, 14.2, 18.3, 26.8, 35.7,
56.9, 60.8, 127.3, 128.7, 129.0, 137.9, 173.7.
(4) Boivin, S.; Outurquin, F.; Paulmier, C. Tetrahedron Lett.
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(5) (a) Toru, T.; Okumura, T.; Ueno, Y. J. Org. Chem. 1990, 55,
1277. (b) Kusuda, S.; Watanabe, Y.; Ueno, Y.; Toru, T. J.
Org. Chem. 1992, 57, 3145. (c) Hart, D. J.; Krishnamurthy,
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Rosenstein, I. J. Tetrahedron Lett. 1993, 34, 7865.
(e) Newcomb, M.; Filipkowski, A.; Johnson, C. C.
Tetrahedron Lett. 1995, 36, 3643. (f) Ryu, I.; Muraoka, H.;
Kambe, N.; Komatsu, M.; Sonoda, N. J. Org. Chem. 1996,
61, 6396.
HRMS–FAB: m/z [M+] calcd for C15H22O2Se: 314.0785; found:
314.0789.
Ethyl (E)-2-Benzyl-3-phenylacrylate (8a); Typical Procedure
The typical procedure for the preparation of 1a was followed to pro-
duce a reaction mixture containing 1a from 7a (170 mg, 0.58
mmol), LN (2.92 mmol), and PhSeBr (164 mg, 0.70 mmol) in THF
(15 mL) at –45 °C. Then, at the same temperature, H2O (0.1 mL),
glacial AcOH (0.13 mL, 2.32 mmol), and 35% H2O2 (0.41 mL, 4.63
mmol) were successively added. The stirring mixture was slowly
warmed to 0 °C over 30 min, diluted with H2O (5 mL) and extracted
with EtOAc (3 × 10 mL). The combined extracts were washed with
sat. aq NaCl (10 mL) and dried (Na2SO4). After concentration, the
residue was purified by chromatography (silica gel, EtOAc–hexane,
1:10); this gave 8a as a yellow oil. Yield: 131 mg (85%).17
(6) (a) Cotgreave, I. A.; Moldeus, P.; Brattsand, R.; Hallberg,
A.; Andersson, C. M.; Engman, L. Biochem. Pharmacol.
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(7) For recent examples, see: Wang, J.; Li, H.; Mei, Y.; Lou, B.;
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(8) Zhu, J. L.; Ko, Y. C.; Kou, C. W.; Shia, K. S. Synlett 2007,
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(9) Lebarillier, L.; Outurquin, F.; Paulmier, C. Tetrahedron
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(10) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc.
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IR (KBr): 1707, 1632, 1494, 1451, 1202 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.2 Hz, 3 H), 3.97 (s,
2 H), 4.21 (q, J = 7.2 Hz, 2 H), 7.18–7.41 (m, 10 H), 7.94 (s, 1 H).
(11) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem.
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PAPER
Preparation of a,a-Dialkyl-a-(phenylselanyl)acetates and a,b-Unsaturated Esters
3665
(12) Reich, H. J.; Cohen, M. L. J. Am. Chem. Soc. 1979, 101,
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(17) In theory, the reductive decyanation of a-cyano esters
requires only two equivalents of lithium naphthalenide. In
practice, however, we found that the use of less than five
equivalents of lithium naphthalenide (e.g., 4 equiv) often
resulted in incompletion of the reaction under the specified
conditions (–45 °C, 25 min).
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Synthesis 2007, No. 23, 3659–3665 © Thieme Stuttgart · New York