Regioselective conjugate addition of thiols to unsymmetric fumaric esters in the presence of a lithium cation

Article abstract of DOI:10.1016/S0040-4039(01)01824-X

Unsymmetrically substituted fumaric esters underwent highly regioselective conjugate addition of thiols in the presence of a lithium cation in non-coordinative media.

Full text of DOI:10.1016/S0040-4039(01)01824-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8497–8500
Regioselective conjugate addition of thiols to unsymmetric
fumaric esters in the presence of a lithium cation
Akio Kamimura,a,* Fukiko Kawahara,a Yoji Omata,a Norikazu Murakami,a Rie Morita,a
Hirochika Otake,a Hiromasa Mitsudera,a Masashi Shiraib and Akikazu Kakehic
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Ube 755-8611, Japan
bUbe Laboratory, Ube Industries Ltd., Ube 755-8633, Japan
cDepartment of Material Engineering and Chemistry, Faculty of Engineering, Shinshu University, Nagano 380-8553, Japan
Received 5 September 2001; accepted 28 September 2001
Abstract—Unsymmetrically substituted fumaric esters underwent highly regioselective conjugate addition of thiols in the presence
of a lithium cation in non-coordinative media. © 2001 Elsevier Science Ltd. All rights reserved.
The Michael addition is recognized a very useful tool to
construct carbon backbones.1 The existence of two
electron-withdrawing groups attaching to each side of
an olefin enhances its reactivity to the Michael addi-
tion, but incurs a problem of regioselectivity unless the
two groups are identical. One example of such case is
the conjugate addition to unsymmetric fumaric esters,
in which control of the orientation is rather difficult
because the electronic and steric differences between the
two ester groups are small. As a result, this simple but
inherent problem has remained unsolved so far. To the
best of our knowledge, there has only been one report
so far, in which a mixture of the two regioisomers was
formed in poor regioselectivity.2 Otherwise, conjugate
adducts have been prepared in a different way that
involved several steps.3 In this paper, we report an
excellent solution to the problem. The Michael addition
of thiols to unsymmetric fumaric esters was effectively
controlled, and the presence of a lithium cation in an
uncoordinative solvent enhanced the selectivity to a
practically useful level, in which a single regioisomer of
the adducts was obtained in high diastereomeric
purity.4
The Michael addition of thiol to unsymmetric fumaric
ester 1 was examined under various conditions (Scheme
1).5 The results are summarized in Table 1. Ethyl
methyl fumarate 1a, an unsymmetric fumaric ester,
underwent conjugate addition of benzenethiol in the
presence of a catalytic amount of a base to give
Michael adduct 2a in good yield (Scheme 1, Table 1
entry 1). As expected, the adduct contained two
regioisomers, 2a–A and 2a–B, in a 1.51:1 ratio so that
the addition took place almost non-selectively. The
product ratio in the addition to 1a did not change very
much under various reaction conditions (entries 2 and
3). The Michael addition to tert-butyl ethyl fumarate
1b also occurred smoothly under similar basic condi-
tions at −50°C. To our surprise, one of the regioiso-
mers, 2b–A, was formed preferentially in over 11.8:1
ratio (entry 4). The fluoride anion-catalyzed Michael
addition also gave a mixture of 2b–A and 2b–B in
about 10:1 ratio (entry 5). The presence of catalytic
amounts of a lithium thiolate in THF or DME also
gave the adduct 2b in good yields, but the regioselectiv-
ity remained at a similar level (entries 6 and 7). The
selectivity was greatly improved when the reaction was
carried out in CH2Cl2; 2b–A was obtained in 28:1 ratio
(entry 8). Use of toluene as the reaction solvent fur-
nished slightly better regioselectivity, but the yield of 2b
a or b
R1O2C
CO2R2
1
SR
CO2R2
R1O2C
CO2R2
R1O2C
SR
2-A
2-B
Scheme 1. Michael addition of thiols to unsymmetric fumaric
esters. Reagents and conditions: (a) PhSH, base (0.1 equiv.),
−50°C; (b) PhSSiMe3, TBAF (1 equiv.), −50°C.
Keywords: Michael reactions; regiocontrol; thiols.
* Corresponding author. Fax: (81) 836-86-9231; e-mail: ak10@
yamaguchi-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01824-X

8498
A. Kamimura et al. / Tetrahedron Letters 42 (2001) 8497–8500
Table 1. Regioselective Michael addition of thiols to unsymmetric fumaric esters
Entry
R1
R2
R
Time (h)
Conditions
2
Yield (%)a
A/Bb
1
2
3
4
5
6
7
8
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1.5
1.5
1.5
4.5
2.5
12
2
12
24
2.5
12
Et3N/C2H5CN
BuLi/THF
BuLi/CH2Cl2
Et3N/C2H5CN
Bu4NF/CH2Cl2
BuLi/THF
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2d
2e
2f
91 (7)
96 (3)
99 (0)
77 (2)
12 (–)d
75 (0)
82 (0)
84 (0)
42 (42)
92 (0)
87 (0)
75 (0)
86 (0)
0 (100)
1.51
1.49
1.46
11.8
10.1
11.5
11.2
28.4
15.7
41.1
22.4
8.06
6.22
–
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
c
BuLi/DME
BuLi/CH2Cl2
BuLi/toluene
BuLi/CH2Cl2
BuLi/CH2Cl2
BuLi/CH2Cl2
BuLi/CH2Cl2
BuLi/CH2Cl2
9
Ph
10
11
12
13
14
o-MeC6H4-
p-MeC6H4-
Et
HOCH2CH2-
o-MeOC6H4-
12
1.5
42
2g
a Isolated yield. Recovery of the starting fumaric ester is in parentheses.
b Determined by 1H NMR analyses.
c PhSSiMe3 was used instead of PhSH.
d Not determined.
decreased to 42% due to precipitation of most of the
lithium thiolate in toluene (entry 9). No other counter
cations such as sodium, potassium, magnesium or alu-
minum were effective for the smooth progress of the
Michael addition. The best regioselectivity was
observed in the addition of o-thiocresol, the reaction of
which gave 2c–A in 41.1:1 selectivity (entry 10). These
reaction conditions also promoted the addition of
aliphatic thiol to 1b in a regioselective manner (entry
12), while the selectivity decreased for the addition of
oxy-substituted thiols (entries 13 and 14).
In fact, treatment of 5 with PPTS in refluxing benzene
resulted in complete recovery of 5, whereas acidic treat-
ment followed by heating in the presence of PPTS gave
4,5-cis lactone 7 in 86:14 ratio, in which all the ethoxy-
carbonyl group survived during the conversion. Thus,
in the tandem reaction, thiolate attacked the tert-
butoxycarbonyl-attached carbon exclusively, giving 5 in
regiochemically pure form. The configuration of the
two major isomers of 7 was unambiguously determined
to be 4,5-cis on the basis of their X-ray crystallographic
study and NOE experiments,9 although very slight
stereochemical isomerization during the later treatment
might occur. Hence, we conclude that the tandem reac-
tion takes place in a completely regioselective and
highly anti-aldol-selective manner.
The structure of the adducts was determined by chemi-
cal conversion of 2 followed by NMR analyses (Scheme
2). The major adduct of the reaction 2b–A, for example,
was converted to carboxylate 3, which was reduced by
BH3·THF to give 4.6 The a-protons to the ethoxycar-
bonyl group in 4 appeared at 2.58 and 2.69 ppm in an
ABX pattern which unambiguously supported the
structure of 4 shown in Scheme 2. Treatment of 3 with
MeI and DBU afforded a methyl ester,7 which was
identical to 2a–B, the minor isomer formed in the
Michael addition to 1a.
We assume the following reaction mechanism that
accomplishes the present high regioselectivity (Scheme
4). In all cases, lithium thiolate selectively attacked the
b
CO2Bu-t
SPh
a
CO2H
SPh
EtO2C
EtO2C
This high regiocontrol in unsymmetric fumaric esters
2b-A
3
was applied to
a tandem Michael/aldol reaction
(Scheme 3).8 Treatment of 1b in the presence of lithium
thiolate and benzaldehyde, for example, resulted in the
formation of tandem Michael/aldol adduct 5 as a mix-
ture of four diastereoisomers. To determine the
diastereomeric ratio, 5 was converted to the corre-
sponding acetate 8 in 80% yield and NMR analysis of
the mixture indicated that the diastereomeric ratio of
the four isomers in 8 was 66:23:6:5. It should be
mentioned that no g-butyrolactones such as 7 were
found in the reaction mixture; this was in contrast to
the reaction starting from diethyl fumarate that gave
considerable amounts of lactone 7 in the same tandem
procedure.8 This result suggests that the tandem reac-
tion took place in a highly regioselective manner to give
5 exclusively; i.e. no regioisomer of 5 should be formed.
2.58 and 2.69 ppm, ABX pattern
EtO2C
OH
SPh
4
c
CO2Me
EtO2C
3
SPh
2a-B
Scheme 2. Determination of the regiochemistry of 2. Reagents
and conditions: (a) TFA, thioanisole, rt, 98%; (b) BH3·THF,
THF, −10°C to rt, 48%; (c) MeI, DBU, toluene, rt, 74%.

A. Kamimura et al. / Tetrahedron Letters 42 (2001) 8497–8500
8499
should prefer the less bulky ethoxycarbonyl group,
which is then activated. As a result, the Michael addi-
tion of thiolate mainly occurs on the b-carbon of the
coordinated carbonyl group to give diastereomer A in a
highly regioselective way. Further investigation and
application of this reaction are now under way in our
laboratory.
OH
b
a
CO2Et
EtO2C
Ph
PhS
CO2Bu-t
1b
CO2Bu-t
5
OH
EtO2C
Ph
SPh
O
CO2Et
CO2H
c
Ph
PhS
Acknowledgements
O
6
7
4,5-cis/4,5-trans = 86/14
The present work was partially supported by a Grant-
in-Aid for Scientific Research (C-11640536) from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
c
5
no reaction
References
OAc
d
1. Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992.
CO2Et
5
Ph
2. Zaderenko, P.; Lo´pez, M. C.; Ballestros, P. J. Org. Chem.
1996, 61, 6825.
PhS
CO2Bu-t
8 syn/anti = 89/11
3. Allen, N. E.; Boyd, D. B.; Campbell, J. B.; Deeter, J. B.;
Elzey, T. K.; Foster, B. J.; Hatfield, L. D.; Hobbs, Jr., J.
N.; Hornback, W. J. Tetrahedron 1989, 45, 1905.
4. High stereoselectivity was achieved under similar reaction
conditions, see: Miyata, O.; Shinada, T.; Ninomiya, I.;
Naito, T. J. Org. Chem. 1991, 56, 6556.
Scheme 3. Michael/aldol tandem reaction to an unsymmetric
fumaric ester. Reagents and conditions: (a) PhSLi, PhCHO,
CH2Cl2, −50°C, 15 h, 83%; (b) TFA, thioanisole, rt; (c) PPTS,
toluene, 110°C, 89% from 5; (d) Ac2O, DMAP, pyridine, rt, 2
h, 80%.
5. Representative procedure of Michael addition of thiol:
Under a nitrogen atmosphere, BuLi in hexane (0.0625
mL, 0.1 mmol) was added to a solution of o-thiocresol
(128.7 mg, 1.04 mmol) in dry CH2Cl2 (10 mL, distilled
over CaH2) at 0°C. The resulting solution was cooled to
−50°C and unsymmetric fumarate 1b (193.7 mg, 0.967
mmol) was added. The reaction mixture was
allowed to stir at the same temperature for 4 h. The
reaction was quenched with addition of aqueous HCl (1
M, 30 mL) and the organic layer was separated. The
water phase was extracted with EtOAc (3×30 mL) and
the combined organic phase was dried over Na2SO4.
After filtration and evaporation, the crude product was
purified through flash chromatography (silica gel/hexane
then hexane–ether) to give 2c–A as an oil in 92% yield
(289.5 mg).
CO2Et
t-BuO2C
less favorable
SPh
Li SPh
2b-B
O
O
O
O
SPh
PhS
Li
CO2Et
much favorable
t-BuO2C
2b-A = major isomer
coordination and activation by Li+
Scheme 4. Supposed reaction mechanism.
6. Kende, A. S.; Fludzinski, P. Org. Synth. Coll. Vol. VII,
221.
7. Ono, N.; Yamada, T.; Saito, T.; Tanaka, K.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1978, 51, 2401.
tert-butoxycarbonyl site of the unsymmetric fumaric
ester 1b. The selectivity was enhanced when lithium
thiolate was used in a non-coordinating solvent such as
CH2Cl2. It may seem strange that the thiolate prefers to
attack the much bulky tert-butoxycarbonyl side of the
acceptor. This can be rationalized, however, if the
activation of an ester group by the coordination of the
lithium cation is a significant factor in the Michael
addition process. Thus, the lithium cation, which
should not be solvated in CH2Cl2, acts as a strong
Lewis acid,10 and likely coordinates to either of the
carbonyl groups in fumaric ester 1b. Due to steric
bulkiness of the tert-butyl residue, the lithium cation
8. (a) Kamimura, A.; Mitsudera, H.; Asano, S.; Kakehi, A.;
Noguchi, M. Chem. Commun. 1998, 1095; (b) Ono, M.;
Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetrahedron
Lett. 1999, 40, 1509; (c) Kamimura, A.; Mitsudera, H.;
Asano, S.; Kidera, S.; Kakehi, A. J. Org. Chem. 1999, 64,
6353; (d) Mitsudera, H.; Kakehi, A.; Kamimura,
A. Tetrahedron Lett. 1999, 40, 7389; (e) Ono, M.;
Nishimura, K.; Nagata, Y.; Tomioka, K. Tetrahedron
Lett. 1999, 40, 6979; (f) Kamimura, A.; Omata,
Y.; Mitsudera, H.; Kakehi, A. J. Chem. Soc., Perkin
Trans. 1 2000, 4499; (g) Jauch, J. J. Org. Chem. 2001, 66,
609.

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A. Kamimura et al. / Tetrahedron Letters 42 (2001) 8497–8500
9. Crystallographic data (excluding structure factors) for the
N. J. Am. Chem. Soc. 1996, 118, 2095; (b) Grieco, P. A.;
Beck, J. P.; Handy, S. T.; Saito, N.; Daeuble, J. F.
Tetrahedron Lett. 1994, 35, 6783; (c) Grieco, P. A.;
Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc. 1990, 112,
4595 and references cited therein.
structure reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication No. CCDC 166170.
10. (a) Grieco, P. A.; Kaufman, M. D.; Daeuble, J. F.; Saito,