'Me2CuLi·TMSCl in CH2Cl2'. The most powerful methylating agent for sterically congested α,β-enoates

Article abstract of DOI:10.1016/S0040-4039(03)00891-8

The reaction of Me₂CuLi with sterically congested α,β-unsaturated esters in the presence of TMSCl in CH₂Cl₂ proceeded very smoothly to produce the conjugate addition products in high yields.

Full text of DOI:10.1016/S0040-4039(03)00891-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4265–4266
‘Me2CuLi·TMSCl in CH2Cl2’. The most powerful methylating
agent for sterically congested a,b-enoates
Naoki Asao, Sunyoung Lee and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 30 October 2002; revised 4 April 2003; accepted 4 April 2003
Abstract—The reaction of Me2CuLi with sterically congested a,b-unsaturated esters in the presence of TMSCl in CH2Cl2
proceeded very smoothly to produce the conjugate addition products in high yields. © 2003 Elsevier Science Ltd. All rights
reserved.
Conjugate addition using organocopper reagents to
a,b-unsaturated esters is one of the most practical and
important methods for CꢀC bond formation in organic
synthesis.1 In 1978, we found that when RCu was
treated with Lewis acids, such as BF3·OEt2, at lower
temperatures, the combined reagent exhibited an
enhanced reactivity toward enoates in comparison with
RCu itself or even with R2CuLi.2 For example, the
conjugate addition of BuCu·BF3 to ethyl tiglate gave
the conjugate adduct in 96% yield, although the addi-
tion with Bu2CuLi afforded the desired product only in
16% yield.2b In contrast, the reactivity of MeCu·BF3
was relatively lower than alkylcoppers·BF3, such as
BuCu·BF3, and in certain cases the conjugate addition
to sterically hindered enoates did not give a satisfactory
result. Later on, it was reported that the addition of
TMSX (X=Cl or I) to MeCu or Me2CuLi dramatically
improved the yield of the conjugate adducts in addi-
tions to a,b-unsaturated esters.3–5
They also reported that the reagent system,
MeCu·TMSI in CH2Cl2, was more efficient than
Me(Th)CuLi·TMSCl in diethyl ether.6 Ullenius and
co-workers reported that the diastereoselectivities in the
conjugate addition of Me2CuLi to the enoate shown in
Eq. (2) were higher in the non-coordinating solvents,
such as CH2Cl2 and toluene, than in Et2O, and even
higher chemical yields of the conjugate adducts were
obtained in the non-coordinating solvents (Eq. (2)).4
(2)
Based on the above results, it occurred to us that MeCu
or Me2CuLi in the presence of TMSX in a non-coordi-
nating solvent would become an efficient methylating
agent for conjugate addition to sterically congested
enoates. This idea was tested in conjugate additions to
1a (Eq. (3)).
Nilsson and co-workers reported that the addition of
MeCu·TMSI to enoates in CH2Cl2 gave the conjugate
adducts in much higher yields than that in diethyl ether
(for example, Eq. (1)).5
(1)
(3)
* Corresponding author. Tel.: +81-22-217-6581; fax: +81-22-217-6784;
e-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00891-8

4266
N. Asao et al. / Tetrahedron Letters 44 (2003) 4265–4266
Table 1. Conjugate addition reaction of ‘Me2CuLi·TMSCl/CH2Cl2’ to 1a
Entry
Substrate 1
Time (h)
2
Yield (%)b
R1
R2
R3
R
1
2
3
4
Me
Me
n-C6H13
iPr
H
H
H
H
Me
Me
Me
Et
Et
Et
Et
PhCH2
PhCH2
Et
1b
1c
1d
1e
1f
6
6
2b
2c
2d
2e
2f
100
94
99
98
63
87
97
(CH2)5
2.5
3
3.5
13
2
Me
H
H
Ph
Me
Me
n-C6H13
5
6c
7c
1f
1g
2f
2g
Me
a The reaction was carried out using 1 (1 equiv.), Me2CuLi (2 equiv.), and TMSCl (2 equiv.) in CH2Cl2 at −78 to 0°C unless otherwise noted.
b Isolated yield.
c Reaction was carried out using Me2CuLi (3 equiv.) and TMSCl (3 equiv.).
smoothly and the conjugate addition product 2g was
As shown in Eq. (3), ‘Me2CuLi·TMSCl/CH2Cl2’ is the
most efficient methylating agent. The use of ether or
toluene as a solvent gave no conjugate adduct at all.
The absence of TMSCl did not afford the desired
product at all even if CH2Cl2 was used as a solvent.
obtained in 97% yield (entry 7).
(4)
‘Me2CuLi·TMSCl/CH2Cl2’
‘MeCu·TMSCl/CH2Cl2’.
was
better
than
The preparation of 2a is representative. To a suspen-
sion of CuI (380 mg, 2 mmol) in ether (2 mL) was
added MeLi (4 mmol, 1.04 M in ether) at 0°C and the
mixture was stirred for 10 min. The solvent was
removed under reduced pressure at 0°C and then
CH2Cl2 (2 mL) was added. The mixture was stirred for
5 min at 0°C, and then the solvent was removed again
in vacuo at 0°C. To the residue was added pre-cooled
CH2Cl2 (15 mL) and the mixture was cooled to −78°C.
To the mixture were added TMSCl (0.25 mL, 2 mmol)
and a solution of 1a (190 mg, 1 mmol) in CH2Cl2 (2
mL), successively. The mixture was allowed to warm to
0°C gradually and the reaction was quenched by addi-
tion of a mixture of aqueous saturated NH4Cl and 28%
NH4OH (1:1). The mixture was extracted with ether
three times and the combined extracts were dried
(Na2SO4) and evaporated to leave the crude product,
which was purified by a silica gel column, and the
product was isolated using hexane/EtOAc=3/1 as elu-
ent; 2a was obtained as a pale yellow oil (197 mg, 0.96
mmol) in 96% yield.
We are now in a position to carry out effectively the
conjugate addition of a methyl group to sterically con-
gested enoates using the ‘Me2CuLi·TMSCl/CH2Cl2’
reagent system. We also investigated whether or not
Bu2CuLi·TMSCl/CH2Cl2 and Ph2CuLi·TMSCl/CH2Cl2
can be used as powerful agents for the conjugate addi-
tion, however, we found that these reagent systems are
not useful.
References
1. For reviews, see: (a) Yamamoto, Y. Angew. Chem., Int.
Ed. Engl. 1986, 25, 947–959; (b) Organocopper Reagents: A
Practical Approach; Taylor, R. J. K., Ed.; Oxford Univer-
sity Press: Oxford, 1994; (c) Lipshutz, B. H.; Sengupta, S.
Org. React. (New York) 1992, 41, 135–631; (d) Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Weinheim, 2002.
2. (a) Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc.
1978, 100, 3240–3241; (b) Yamamoto, Y.; Yamamoto, S.;
Yatagai, H.; Ishihara, Y.; Maruyama, K. J. Org. Chem.
1982, 47, 119–126.
3. (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26,
6015–6018; (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett.
1985, 26, 6019–6022; (c) Alexakis, A.; Berlan, J.; Besace,
Y. Tetrahedron Lett. 1986, 27, 1047–1050.
4. (a) Christenson, B.; Hallnemo, G.; Ullenius, C. Tetra-
hedron 1991, 47, 4739–4752; (b) Christenson, B.; Ullenius,
C.; Hakansson, M.; Jagner, S. Tetrahedron 1992, 48, 3623–
3632.
We next examined the conjugate addition of other
sterically congested a,b-unsaturated esters 1b–g using
‘Me2CuLi·TMSCl/CH2Cl2’ (Eq. (4)) and the results are
summarized in Table 1. In the reactions of the b,b-di-
substituted substrates 1b–e, the corresponding conju-
gate adducts were obtained in more than 90% yields
(entries 1–4). While the reaction of the a,b-disubstituted
substrate 1f afforded 2f in a moderate yield (entry 5),
the chemical yield was increased to 87% when the
equivalents of both Me2CuLi and TMSCl were
increased from two to three (entry 6). Finally, we
examined the reaction of the a,b,b-trisubstituted sub-
strate 1g. To our surprise, the reaction proceeded
5. Bergdahl, M.; Lindstedt, E.-L.; Nilsson, M.; Olsson, T.
Tetrahedron 1988, 44, 2055–2062.
6. Lindstedt, E.-L.; Nilsson, M.; Olsson, T. J. Organomet.
Chem. 1987, 334, 255–261.