Magnesium Chloride-Promoted Michael Addition of Dimethylsilyl Enolates to α-Enones

Article abstract of DOI:10.1055/s-2003-41467

In the presence of MgCl₂, dimethylsilyl (DMS) enolates 1 smoothly reacted with α-enones in DMF to form 1,5-diketones 3 in moderate to high yields. The Michael addition proceeded with moderate to high anti-diastereoselectivity.

Full text of DOI:10.1055/s-2003-41467

2068
LETTER
Magnesium Chloride-Promoted Michael Addition of Dimethylsilyl Enolates
to a-Enones
Michael
Addition
a
of
D
imethy
t
lsilyl
E
s
nolates ukiyo Miura,* Takahiro Nakagawa, Akira Hosomi*
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, and CREST, Japan Science and
Technology Corporation (JST), Tsukuba, Ibaraki 305-8571, Japan
Fax +81(29)8536503; E-mail: hosomi@chem.tsukuba.ac.jp
Received 10 July 2003
reaction resulted in a low conversion (entry 7). The use of
Abstract: In the presence of MgCl2, dimethylsilyl (DMS) enolates
MgCl2 achieved good yields of 3ab with high anti-selec-
tivity (entries 8 and 9). The other metal halides and
Bu4NCl have a reduced or no ability to promote the
1 smoothly reacted with a-enones in DMF to form 1,5-diketones 3
in moderate to high yields. The Michael addition proceeded with
moderate to high anti-diastereoselectivity.
Michael addition to 2b (entries 10–13).
Key words: diastereoselectivity, enones, Michael additions, mag-
nesium, silicon
Table 1 Michael Addition of DMS Enolate 1a to a-Enones in the
Presence of Metal Salts or Bu4NCla
OSiHMe2
O
The Mukaiyama–Michael reaction of silyl enolates with
a-enones is one of the most important processes for effi-
cient and stereocontrolled carbon-carbon bond forma-
tion.1–6 Similar to the Mukaiyama-aldol reaction of silyl
enolates, this process is accelerated by Lewis acids1–4 or
nucleophiles (Lewis bases).5,6 We have previously report-
ed that aldol reactions of dimethylsilyl (DMS) enolates
proceed efficiently in the presence of alkali earth or alkali
metal chlorides (CaCl2, MgCl2, LiCl etc.) (Scheme 1).7
These metal salts would serve to activate DMS enolates
by nucleophilic attack of the chloride ion. Here we de-
scribe the metal chloride-promoted Mukaiyama-
Michael reaction of DMS-enolates with a-enones under
the same conditions. The present study discloses that the
metal ions as well as the counterions strongly affect the re-
action rate.
+
Ph
1a (1.5 equiv.)
Ph
R
2a: R = Ph
2b: R = Me
O
Ph
O
MXn (1.0 equiv.)
DMF, 30 °C, 24 h
conc. HCl
Ph
R
3aa: R = Ph
3ab: R = Me
Entry
1
Enone
2a
MXn
Yield (%)
anti:synb
96:4
CaCl2
CaCl2
93
97
quant.
< 9
0
c
2
2a
97:3
c
3
2a
MgCl2
LiCl
98:2
4
2a
nd
O
OH
R3
OSiHMe2
R2
MXn
5
2a
Bu4NCl
MgBr2
CaCl2
R3CHO
+
R1
R1
DMF, 30 °C, 24 h
6
2a
68
31
78
84
0
98:2
99:1
95:5
95:5
R2
1
7
2b
2b
2b
2b
2b
2b
2b
Scheme 1
8
MgCl2
c
DMS enolate 1a, derived from propiophenone, was se-
lected for the initial study. In the presence of a stoichio-
metric or catalytic amount of CaCl2, 1a smoothly added to
(E)-1,3-diphenyl-2-propen-1-one (chalcone, 2a) to give
the Michael adduct 3aa in a high yield with high anti-se-
lectivity (entries 1 and 2 in Table 1).8 MgCl2 as well as
CaCl2 was quite effective in the Michael addition, while
LiCl and Bu4NCl were almost ineffective (entries 3–5).
The catalytic activity of MgBr2 is not as high as that of
MgCl2 (entry 6). In the case with (E)-4-phenyl-3-buten-2-
one (benzalacetone, 2b), however, the CaCl2-promoted
9
MgCl2
10
11
12
13
BaCl2
LiCld
< 5
0
nd
Bu4NCl
MgBr2
6
nd
a Unless otherwise noted, all reactions were carried with 1a
(Z:E = >98:2, 0.75 mmol), an enone 2 (0.5 mmol), and a promoter
(0.5 mmol) in DMF (1 mL) at 30 °C for 24 h. The resultant mixture
was treated with 35% HCl (1 mL) for 5 min and neutralized with sat-
urated aqueous NaHCO3. See ref.8
b Determined by 270 MHz 1H NMR or GC-MS analysis. nd = not
determined.
SYNLETT 2003, No. 13, pp 2068–2070
1
6
.1
0
.2
0
0
3
c MgCl2 or CaCl2 (0.13 mmol) was used.
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41467; Art ID: U13203ST
© Georg Thieme Verlag Stuttgart · New York
d LiCl (2.0 mmol) was used.

LETTER
Michael Addition of Dimethylsilyl Enolates
2069
With the initial results in hand, we examined the applica- 1,5-diketones 3ac–ae in moderate to good yields (entries
bility of the MgCl2-promoted Michael reaction by using 3–5). In the case with 2d (entry 4), hydrolysis of the reac-
various DMS enolates and a-enones.9 The results are sum- tion mixture with 35% HCl was accompanied by reduc-
marized in Table 2. (E)-1-Phenyl-2-buten-1-one (2c), 2- tion of the cyclohexanone moiety of 3ad. The hydrolysis
cyclohexenone (2d), and 3-buten-2-one (2e) underwent with pure water suppressed the unfavorable reaction. In
the Michael addition of 1a to afford the corresponding entry 5, the cyclized product 4 consisting of one molecule
Table 2 MgCl2-Promoted Michael Addition of Various DMS Enolatesa
O
R3
O
OSiHMe2
R2
O
1) MgCl2
2) H+
+
R1
R4
R1
R3
R4
R2
1
2
3
Entry
1d
DMS Enolateb
Enone
2a
Time (h)
Yield (%)
quant.
84
anti:sync
98:2
1a: R1 = Ph, R2 = Me
24
24
4
2d
2b
95:5
3d
2c: R3 = CH3, R4 = Ph
91
94:6
4e
4
82
nd
O
2d
5d,f
6
2e: R3 = CH3, R4 = CH2
1
24
24
24
4
58 h
92
46 i
42
87
54
68
80
31
69
0i
1b: R1, R2 = (CH2)4
2a
2b
2d
2a
2b
2d
2a
2d
2a
2b
77:23k
nd
7
8e
nd
9f
1c: R1 = Et, R2 = Me
87:13
99:1
nd
10f,g
11e,f
12
24
4
1d: R1 = Ph, R2 = H
1e: R1 = i-Pr, R2 = H
24
4
13e,f
14f
15f
24
24
a See footnote a in Table 1.
b Substrate 1a, Z:E = >98:2; 1b, E only; 1c, Z:E = 37:63.
c See footnote b in Table 1.
d MgCl2 (0.13 mmol) was used.
e The reaction mixture was quenched with H2O.
f Substrate 1 (1.00 mmol) was used.
g The reaction mixture was quenched with 2 M HCl.
h Cyclohexanol 4 was obtained as a byproduct in 16% yield.
i Enone 5 was obtained as a byproduct in 30% yield.
j Dienone 6 was formed as the major product in 40% yield.
k The relative configuration was not determined.
O
Ac
Ac
O
HO
Ph
Ph
i-Pr
Ph
6
4
5
Synlett 2003, No. 13, 2068–2070 © Thieme Stuttgart · New York

2070
K. Miura et al.
LETTER
(4) For Lewis acid-catalyzed asymmetric Michael reactions,
of 1a and two molecules of 2e was obtained as a by-
product. Other DMS enolates 1b–e were available for the
MgCl2-promoted Michael addition although they were not
as reactive as 1a (entries 6–14). The reaction of 1b with
2b provided the Michael adduct 3bb along with the
Robinson annulation product 5 (entry 7). In entry 15,
dienone 6 was mainly formed by an aldol reaction and
subsequent dehydration.
see; (a) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama,
T. Chem. Lett. 1994, 97. (b) Bernardi, A.; Colombo, G.;
Scolastico, C. Tetrahedron Lett. 1996, 37, 8921.
(c) Kitajima, H.; Katsuki, T. Synlett 1997, 568. (d) Evans,
D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am.
Chem. Soc. 2001, 123, 4480.
(5) (a) RajanBabu, T. V. J. Org. Chem. 1984, 49, 2083.
(b) Génisson, Y.; Gorrichon, L. Tetrahedron Lett. 2000, 41,
4881. (c) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2001, 3, 639.
(6) Mukaiyama, T.; Nakagawa, T.; Fujisawa, H. Chem. Lett.
2003, 32, 56.
As shown in Table 1, the reaction rate was strongly affect-
ed by the metal chloride used. In addition, Bu4NCl had no
rate-accelerating ability. These results imply that the
Lewis acidity of the metal center effects the Michael
addition. However, the fact that MgBr2 is not so effective
as MgCl2 indicates that the chloride ion also provides a
positive effect for the rate-acceleration. We have previ-
ously proposed that, in the metal chloride-promoted aldol
reaction of DMS enolates, the chloride ion rather than the
Lewis acidic metal cation plays a crucial role as the
promoter.7 In the present case, MgCl2 may activate both
reactants by the metal center coordinating to the enone
and by aiding nucleophilic attack of the chloride ion at the
silicon of DMS enolates.
(7) Miura, K.; Nakagawa, T.; Hosomi, A. J. Am. Chem. Soc.
2002, 124, 536.
(8) Propiophenone TMS enolate was much less reactive toward
the Michael addition to 2a even in the presence of an
equimolar amount of MgCl2 (7% yield of 3aa, 30 °C, 24 h).
(9) General Procedure for the MgCl2-promoted Michael
Addition of DMS Enolates: Under N2 atmosphere, dry
DMF (1 mL) was added to MgCl2 (12 mg, 0.13 mmol). The
mixture was stirred for 10 min at 30 °C, and a DMS enolate
(0.75 mmol) and an a-enone (0.50 mmol) were introduced
into the resultant solution. After the reaction was completed,
concd HCl (1 mL) was added to the reaction mixture. After
being stirred for 5 min, the mixture was neutralized with
saturated aqueous NaHCO3 and extracted with EtOAc (3 ×
10 mL). The combined organic layer was dried over Na2SO4
and evaporated. The crude product was purified by silica gel
column chromatography. Compound anti-3aa: CAN
[40794-93-2] (ref.10). 1H NMR (270 MHz, CDCl3) d 1.28 (d,
J = 6.8 Hz, 3 H), 3.36–3.53 (m, 2 H), 3.89–4.00 (m, 2 H),
7.06–7.27 (m, 5 H), 7.35–7.55 (m, 6 H), 7.83–7.89 (m, 4 H).
13C NMR (68 MHz, CDCl3) d 14.10 (CH3), 39.87 (CH2),
42.76 (CH), 45.93 (CH), 126.51 (CH), 127.91 (CH × 2),
127.95 (CH × 2), 128.12 (CH × 2), 128.34 (CH × 2), 128.46
(CH × 2), 128.58 (CH × 2), 132.86 (CH), 132.88 (CH),
136.72 (C), 137.07 (C), 142.79 (C), 198.43 (C), 203.23 (C).
The signal for the methyl group of the minor isomer appears
at 1.01 ppm (d, J = 6.6 Hz). According to the report by
Heathcock et al., the major isomer was determined to be anti.
See ref.11 Compound anti-3ab: CAN [111873-77-9] (ref.12).
1H NMR (270 MHz, CDCl3) d 1.21 (d, J = 6.9 Hz, 3 H), 2.00
(s, 3 H), 2.89 (d, J = 7.1 Hz, 2 H), 3.72 (q, J = 7.1 Hz, 1 H),
3.83 (quint., J = 6.9 Hz, 1 H), 7.09–7.26 (m, 5 H), 7.38–7.54
(m, 3 H), 7.80–7.83 (m, 2 H). 13C NMR (68 MHz, CDCl3) d
14.19 (CH3), 30.42 (CH3), 42.71 (CH), 45.08 (CH2), 45.79
(CH), 126.64 (CH), 127.86 (CH × 2), 128.06 (CH × 2),
128.43 (CH × 2), 128.54 (CH × 2), 132.86 (CH), 136.68 (C),
142.54 (C), 203.20 (C), 207.12 (C). Compound anti-3ac:
CAN [95741-11-0] (ref.13). 1H NMR (270 MHz, CDCl3) d
1.07 (d, J = 6.4 Hz, 3 H), 1.23 (d, J = 6.9 Hz, 3 H), 2.17–2.79
(m, 2 H), 3.12 (d, J = 14.5, 2.5 Hz, 1H), 3.62 (qd, J = 6.9, 4.9
Hz, 1 H), 7.37–7.58 (m, 6 H), 7.85–8.06 (m, 4 H). 13C NMR
(68 MHz, CDCl3) d 12.94 (CH3), 18.57 (CH3), 31.91 (CH),
41.24 (CH2), 44.92 (CH), 128.00 (CH × 2), 128.21 (CH × 2),
128.47 (CH × 2), 128.66 (CH × 2), 132.89 (CH), 132.94
(CH), 136.91 (C), 137.05 (C), 199.60 (C), 203.89 (C).
(10) Gorrichon-Guigon, L.; Maroni-Barnaud, Y. Bull. Soc. Chim.
Fr. 1973, 263.
In conclusion, we have demonstrated that, in the presence
of MgCl2, DMS enolates add to a-enones efficiently to
give the Michael adducts stereoselectively. The present
study has disclosed that the behavior of metal halides in
the Michael reaction of DMS enolates is slightly different
from that observed in the aldol reaction.7
Acknowledgment
This work was partly supported by Grants-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Government of Japan. We thank Dow Corning
Toray Silicone Co. Ltd. and Shin-Etsu Chemical Co. Ltd. for a gift
of organosilicon compounds.
References
(1) Pioneer works: (a) Narasaka, K.; Soai, K.; Mukaiyama, T.
Chem. Lett. 1974, 1223. (b) Narasaka, K.; Soai, K.; Aikawa,
K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1976, 49, 779.
(2) Reviews: (a) Oare, D. A.; Heathcock, C. A. In Topics in
Stereochemistry, Vol. 20; Eliel, E. L.; Wilen, S. H., Eds.;
Wiley: New York, 1991, 124. (b) Lee, V. J. In
Comprehensive Organic Synthesis, Vol. 4; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, Chap. 1.3,
139.
(3) (a) Kobayashi, S.; Murakami, M.; Mukaiyama, T. Chem.
Lett. 1985, 953. (b) Heathcock, C. H.; Norman, M. H.;
Uehling, D. E. J. Am. Chem. Soc. 1985, 107, 2797. (c)Sato,
T.; Wakahara, Y.; Otera, J.; Nozaki, H. Tetrahedron Lett.
1990, 31, 1581. (d) Grieco, P. A.; Cooke, R. J.; Henry, K. J.;
VanderRoest, J. M. Tetrahedron Lett. 1991, 32, 4665.
(e) Kobayashi, S.; Hachiya, I.; Takahori, T.; Araki, M.;
Ishitani, H. Tetrahedron Lett. 1992, 33, 6815.
(11) Oare, D. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157.
(12) Bernardi, A.; Dotti, P.; Poli, G.; Scolastico, C. Tetrahedron
1992, 48, 5597.
(f) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett
1993, 472. (g) Ishihara, K.; Hanaki, N.; Funahashi, M.;
Miyata, M.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1995, 68,
1721. (h) Chen, J.; Sakamoto, K.; Orita, A.; Otera, J.
Tetrahedron 1998, 54, 8411. (i) Marx, A.; Yamamoto, H.
Angew. Chem. Int. Ed. 2000, 39, 178.
(13) Inokuchi, T.; Kurokawa, Y.; Kusumoto, M.; Tanigawa, S.;
Takagishi, S.; Torii, S. Bull. Chem. Soc. Jpn. 1989, 62, 3739.
Synlett 2003, No. 13, 2068–2070 © Thieme Stuttgart · New York