Regioselective Michael addition of thiols to tertiary fumaric amide esters

Article abstract of DOI:10.1016/S0040-4039(02)01824-5

The regiochemistry of the Michael addition of thiols to tertiary fumaric amide esters was efficiently controlled in the presence or absence of base; either of the two isomers was prepared in a highly selective way.

Full text of DOI:10.1016/S0040-4039(02)01824-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7521–7523
Regioselective Michael addition of thiols to tertiary fumaric
amide esters
Akio Kamimura,a,* Norikazu Murakami,a Kakuteru Yokota,a Masashi Shiraib and
Hiroaki Okamotoc
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Ube 755-8611, Japan
bUbe Laboratory, Ube Industries Ltd., Ube 755-8633, Japan
cDepartment of Advance Materials Science and Engineering, Faculty of Engineering, Yamaguchi University, Ube 755-8611, Japan
Received 24 July 2002; revised 21 August 2002; accepted 23 August 2002
Abstract—The regiochemistry of the Michael addition of thiols to tertiary fumaric amide esters was efficiently controlled in the
presence or absence of base; either of the two isomers was prepared in a highly selective way. © 2002 Elsevier Science Ltd. All
rights reserved.
The Michael addition is the most important reaction in
organic synthesis.1 Thiols are known as a good nucle-
ophile for the reaction. Existence of two activating
groups usually enhances the reactivity of the acceptor
alkenes but gives rise to a problem on regioselectivity
that is not always easily solved.2 Recently, we have
demonstrated that the regiochemistry of the Michael
addition of thiols to an unsymmetrical fumaric ester is
efficiently controlled by the presence of lithium cation
in non-coordinative solvent and one of the regioisomer
is formed predominantly.3 In this paper we report that
the regiochemistry of the Michael addition to fumaric
tertiary amide ester was nicely controlled in the pres-
ence or absence of base and either of the two regioiso-
mers was prepared in a highly regioselective manner.
The Michael addition to 1 smoothly proceeded in the
presence of catalytic amounts of base, condition X, to
give the adduct 2a in 85% yield (entry 1). The ratio of
the two regioisomers was found to be 10/90 and
regioisomer B was formed as the major component. We
then examined various reaction conditions in order to
change or improve the regioselectivity. The reaction
proceeded without base even though the reaction rate
became very slow, and 1a disappeared within 24 h.
After solvent was removed, adduct 2a was obtained in
86% yield (entry 2). To our surprise, the crude adduct
contained only a single isomer of 2a which was found
to be 2aA, the opposite regioisomer to the product of
the conventional Michael addition reaction. This
change in regioselectivity was also observed in the
reaction performed in C2H5CN. Other tertiary amide
esters 1b, 1c and 1d also gave adduct 2 in a similar
manner; the base-catalyzed Michael addition (condition
X) led to the formation of regioisomer B preferentially,
while the reaction without base (condition Y) gave
regioisomer A selectively (entries 3–8). It was interesting
that the latter selectivity was very high and the minor
isomer B was not observed in NMR spectra of the
crude adducts. The same tendency was observed in the
reaction with secondary amide, while the reaction rate
under non-basic conditions became very slow; the yield
of the adduct was poor, but the selectivity was high
(entries 9 and 10).4 To enhance the reaction rate for
secondary amides under non-basic conditions, N-ben-
zyloxyamide was used. Good yield and A-selective
addition were achieved under non-basic addition condi-
tions (entry 12), while a mixture of the two regioiso-
We first examined the Michael addition to fumaric
amide ester 1 under the conventional base-catalyzed
conditions (Scheme 1). The results are summarized in
Table 1.
Scheme 1. Reagents and conditions: (X) Et3N (0.1 equiv.),
C2H5CN, rt, 6 h; (Y) CH2Cl2, rt, 48 h.
Keywords: Michael reactions; regiocontrol; thiols.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01824-5

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A. Kamimura et al. / Tetrahedron Letters 43 (2002) 7521–7523
Table 1. Regioselective conjugate addition of thiols to fumaric amide ester 1
Entry
R1
R2
Conditionsa
2
Yield (%)b
A/Bc
1
2
3
4
5
6
7
8
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
ꢀ(CH2)5ꢀ
X
Y
X
Y
X
Y
X
Y
X
Y
X
Y
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
85
86
87
80
46
91
61
52
77
20
93
70
10/90
\99/1
7/93
\98/2
13/87
\98/2
16/84
\98/2
2/98
Bn
Bn
Bn
Bn
ꢀCH2CHꢁCH2
ꢀCH2CHꢁCH2
ꢀCH2CHꢁCH2
ꢀCH2CHꢁCH2
H
H
H
H
9
Bn
Bn
OBn
OBn
10
11
12
83/17d
55/45
82/18
2f
a X: Et3N (0.1 equiv.), C2H5CN, rt, 6 h; Y: CH2Cl2, rt, 48 h.
b Isolated yield.
c Determined by HPLC or NMR analyses.
d Before chromatographic purification. See Ref. 4.
mers A and B was obtained in the reaction performed
in the presence of base (entry 11). Use of Lewis acid
such as BF3·OEt2 failed to progress the reaction and
desired Michael adduct 2 was not obtained. This is
probably because the Lewis acid preferred to make a
direct complex with thiophenol which is then deacti-
vated to the Michael addition.
assumption for the change of the selectivity is summa-
rized in Scheme 3. The ester group usually acts as a
much stronger electron withdrawing group than the
amide group so that the b-carbon to the ester group
should be much activated toward the nucleophilic
attack. The conventional basic conditions efficiently
generate a nucleophilic thiolate anion that prefers to
attack from this side to give regioisomer B in a regiose-
lective manner. Due to high nucleophilicity of the thio-
late anion, the reaction rate is quite fast and it finishes
within an hour. This situation, however, is changed if
the reaction is carried out without base; the concentra-
tion of the thiolate anion becomes small and the direct
attack of the thiolate to the fumaric amide ester must
be suppressed. In fact, the reaction rate became very
slow and took several hours until the reaction was
complete. The thiol proton, in turn, serves as an acid
that can coordinate to the much basic amide carbonyl
to form iminium ion intermediate when tertiary amide
is used. Then the amide group is activated toward the
nucleophilic attack and the b-carbon to the amide unit
now becomes a much more electrophilic site than the
b-carbon to the ester. The Michael addition occurs
from this side to give regioisomer A predominantly.
The secondary amide, however, should not form the
iminium intermediate efficiently so that the reaction
rate becomes very slow. Use of N-benzyloxyamide
improved the yield probably because of the electron
withdrawing property of the amide group. In fact, the
conventional basic conditions resulted in the formation
of a mixture of the two regioisomers.
The structure of the adducts was determined in the
following way (Scheme 2): compound 2aA, for exam-
ple, was reduced by treatment with LiBH4 to give the
corresponding amidealcohol 3 in 45% yield. The NMR
spectrum of 3 indicated that the a-protons of the amide
unit appeared as an ABX pattern around at 2.7 ppm.
This result supported the structure of compound 3 in
which the phenylthio group attached to the b-carbon of
the amide unit so that we concluded the structure 2aA
as shown in Scheme 2. In addition, in the regioisomer
series 2A, the methyl group in the ethyl ester unit
always appeared around 1.15 ppm, which is slightly
upfield than the proton in regioisomer series 2B. This
observation was quite useful to determine the regio-
chemistry of the adducts. The regiochemistry for other
adducts 2 was elucidated on the basis of these results.
The present results showed that nucleophilic attack of
the thiol prefers the b-carbon to the ester group under
the conventional basic conditions, while the attack
occurred predominantly from the b-carbon to the
amide group in the reaction in the absence of base. Our
To show a synthetic application, we attempted to con-
vert the adduct 2 to b-lactam 4.5 Exposure of com-
pound 2fA, for example, to MeI in the presence of
AgClO4 gave sulfonium intermediate. Subsequent basic
treatment afforded b-lactam 4 in good yield through
the intramolecular SN2 reaction (Scheme 4).6
The regiochemistry of the Michael addition of thiol to
tertiary fumaric amide esters was efficiently controlled
by the presence or absence of base. Further application
Scheme 2.

A. Kamimura et al. / Tetrahedron Letters 43 (2002) 7521–7523
7523
Scheme 3.
2. (a) Zaderenko, P.; Lo´pez, M. C.; Ballestros, P. J. Org.
Chem. 1996, 61, 6825; (b) Allen, N. E.; Boyd, D. B.;
Campbell, J. B.; Deeter, J. B.; Elzey, T. K.; Foster, B. J.;
Hatfield, L. D.; Hobbs, J. N., Jr.; Hornback, W. J. Tetra-
hedron 1989, 45, 1905.
3. Kamimura, A.; Kawahara, F.; Omata, Y.; Murakami, N.;
Morita, R.; Otake, H.; Mitsudera, H.; Shirai, M.; Kakehi,
A. Tetrahedron Lett. 2001, 42, 8497.
Scheme 4. Reagents and conditions: (i) MeI, AgClO4, MeCN,
rt; (ii) K2CO3, acetone, reflux, 4 h.
4. It should be remarked that adduct 2e-A isomerized to 2e-B
during the silica gel chromatographic purification. This
isomerization happened only for 2e-A; no isomerization
was observed in any other adducts 2.
of this methodology is now underway in our
laboratory.
5. Miller, M. J.; Bajwa, J. S.; Mattingly, P. G.; Peterson, K.
J. Org. Chem. 1982, 47, 4928.
References
6. Miyata, O.; Fujiwara, Y.; Ninomiya, I.; Naito, T. J. Chem.
Soc., Perkin Trans. 1 1998, 2167.
1. Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992.