1920
K. Miura et al.
LETTER
(8) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(9) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 5644.
(10) For the fluoride ion-catalyzed aldol reaction of ethyl
trimethylsilylacetate, see: (a) Nakamura, E.; Shimizu, M.;
Kuwajima, I. Tetrahedron Lett. 1976, 1699. (b) Nakamura,
E.; Hashimoto, K.; Kuwajima, I. Tetrahedron Lett. 1978,
2079.
(11) a-DMS-esters 1 can be easily prepared from the
corresponding esters by deprotonation with LiNi-Pr2
followed by silylation with Me2SiHCl. See: (a) Miura, K.;
Sato, H.; Tamaki, K.; Ito, H.; Hosomi, A. Tetrahedron Lett.
1998, 39, 2585. (b) Kaimakliotis, C.; Fry, A. J. J. Org.
Chem. 2003, 68, 9893. (c) Typical Procedure for the
Preparation of a-DMS-esters 1
However, the signals of 1a did not shift in the presence of
LiCl. The present reaction may involve reversible forma-
tion of a transient active species such as a chloride ion
bound silicate.
The low rate-accelerating ability of Bu4NCl (Scheme 1
and Scheme 3) suggests that the metal ion of a metal chlo-
ride also plays an important role for the present reaction.
In addition, the fact that MgCl2 promotes the aldol reac-
tion with 5a more effectively than LiCl and CaCl2 seems
to signify the role of the magnesium ion as Lewis acid.
When simple ketones are used as electrophiles, simulta-
neous activation of both 1 and ketones may be required for
a successful aldol reaction to compensate their low elec-
trophilicity.19
Under N2 atmosphere, n-BuLi (1.61 M in hexane, 62 mL,
100 mmol) was added to a solution of i-Pr2NH (14 mL, 100
mmol) in THF (100 mL) over 5 min at 0 °C. After 10 min,
the mixture was cooled to –78 °C. Then, EtOAc (9.3 mL, 95
mmol) was added to the solution of LDA over 5 min. After
2 h, the reaction mixture was treated with chlorodimethyl-
silane (12.2 mL, 110 mmol) and gradually warmed to r.t.
over 12 h. The resultant mixture was diluted with dry
pentane (50 mL) and filtered through Celite®. After
evaporation of the filtrate, the residual oil was diluted with
dry pentane (50 mL) again, filtered through Celite®, and
evaporated. Purification of the crude product by distillation
gave 1a (9.2 g, 63 mmol) in 66% yield.
In conclusion, we have demonstrated that a-DMS-esters 1
work as stable enolate equivalents in the presence of inex-
pensive, disposable metal chlorides such as LiCl, MgCl2,
and CaCl2. The aldol reaction of 1 proceeds efficiently un-
der very mild conditions and it is applicable to a variety of
aldehydes and ketones. The reaction mechanism would
involve nucleophilic activation of 1 by a chloride ion al-
though the participation of metal ions in promoting the
present reaction is also important.
Compound 1a: bp 58–60 °C (180 Torr). IR (neat): 1669
(C=O), 1253, 1205 cm–1. 1H NMR (CDCl3): d = 0.20 (d,
J = 3.6 Hz, 6 H), 1.23 (t, J = 6.9 Hz, 3 H), 1.96 (d, J = 3.3
Hz, 2 H), 4.06 (sept, d, J = 3.6, 3.3 Hz, 1 H), 4.10 (q, J = 6.9
Hz, 2 H). 13C NMR (CDCl3): d = –4.36 (CH3 × 2), 14.09
(CH3), 24.08 (CH2), 59.91 (CH2), 172.54 (C). Anal. Calcd
for C6H14O2Si (%): C, 49.53; H, 9.69. Found: C, 49.27; H,
9.65.
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.
References
(12) General Procedure for the Aldol Reaction of 1 with
Aldehydes 2
(1) (a) Modern Aldol Reactions, Vol. 2; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim Germany, 2004. (b) Miura, K.;
Hosomi, A. In Main Group Metals in Organic Synthesis,
Vol. 2; Yamamoto, H.; Oshima, K., Eds.; Wiley-VCH:
Weinheim Germany, 2004, Chap. 10, 409. (c) Gennari, C.
In Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, Chap. 2.4,
629.
(2) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett.
1973, 1011. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J.
Am. Chem. Soc. 1974, 96, 7503.
(3) (a) Noyori, R.; Yokoyama, K.; Sakata, J.; Kuwajima, I.;
Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1977, 99,
1265. (b) Nakamura, E.; Shimizu, M.; Kuwajima, I.; Sakata,
J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983, 48, 932.
(c) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc.
1983, 105, 1598.
(4) (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J.
Am. Chem. Soc. 1996, 118, 7404. (b) Denmark, S. E.;
Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432; and
references cited therein.
(5) (a) Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2002, 182.
(b) Nakagawa, T.; Fujisawa, H.; Mukaiyama, T. Chem. Lett.
2004, 33, 92; and references cited therein.
(6) Miura, K.; Nakagawa, T.; Hosomi, A. J. Am. Chem. Soc.
2002, 124, 536.
(7) Related works: (a) Miura, K.; Tamaki, K.; Nakagawa, T.;
Hosomi, A. Angew. Chem. Int. Ed. 2000, 39, 1958.
(b) Miura, K.; Nakagawa, T.; Hosomi, A. Synlett 2003,
2068.
Under the atmosphere, dry LiCl (5.5 mg, 0.13 mmol) was
added to a two-necked, round-bottomed flask (10 mL),
which was connected with a nitrogen balloon. After
introduction of nitrogen, DMF (1.0 mL) was added to the
flask. The mixture was warmed to 30 °C under stirring. After
10 min, 2 (0.50 mmol) and 1 (0.60 mmol) were added to the
mixture. After being stirred for 5 h, the reaction mixture was
treated with 2 M aq HCl (1 mL) for 5 min and neutralized
with sat. aq NaHCO3. The aqueous mixture was extracted
with EtOAc (3 × 10 mL). The extract was dried over Na2SO4
and evaporated. The crude product was purified by silica gel
column chromatography.
(13) The Reformatsky reaction of ethyl bromoacetate with 5g
shows much lower stereoselectivity toward equatorial
attack. See: (a) Screttas, C. G.; Smonou, I. C. J. Org. Chem.
1988, 53, 893. (b) Pansard, J.; Gaudemar, M. Bull. Soc.
Chim. Fr. 1973, 3472, Pt. 2.
(14) 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.
(15) Recent reports on the Lewis acid-catalyzed reactions:
(a) Ishihara, K.; Hanaki, N.; Funahashi, M.; Miyata, M.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 1995, 68, 1721.
(b) Chen, J.; Sakamoto, K.; Orita, A.; Otera, J. Tetrahedron
1998, 54, 8411. (c) Marx, A.; Yamamoto, H. Angew. Chem.
Int. Ed. 2000, 39, 178. For asymmetric reactions, see:
(d) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T.
Chem. Lett. 1994, 97. (e) Bernardi, A.; Colombo, G.;
Synlett 2005, No. 12, 1917–1921 © Thieme Stuttgart · New York