i-PrMgBr also showed excellent reactivity (entries 9 and 10).
Remarkably, the TMSCH2 adduct of 1a was not obtained in
any of the reactions, which strongly indicated that TMSCH2
was effectively a dummy group.
Notes and references
1 Excellent textbooks and reviews on Grignard reagents:
(a) Y.-H. Lai, Synthesis, 1981, 585; (b) B. J. Wakefield, Organo-
magnesium Methods in Organic Chemistry, Academic Press,
San Diego, CA, 1995; (c) G. S. Silverman and P. E. Rakita,
Handbook of Grignard Reagents, Marcel Dekker, New York,
1996; (d) H. G. Richey, Jr., Grignard Reagents: New Developments,
Wiley, Chichester, UK, 2000; (e) P. Knochel, W. Dohle,
N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn,
I. Sapountzis and V. A. Vu, Angew. Chem., Int. Ed., 2003, 42,
4302; (f) P. Knochel, Handbook of Functionalized Organometallics,
Wiley-VCH, Weinheim, Germany, 2005.
2 Recent reviews on secondary and tertiary alcohol synthesis:
(a) M. Hatano, T. Miyamoto and K. Ishihara, Curr. Org. Chem.,
2007, 11, 127; (b) M. Hatano and K. Ishihara, Synthesis, 2008, 1647.
3 LiClO4: (a) E. C. Ashby and S. A. Noding, J. Org. Chem., 1979, 44,
4371; (b) J. Ipaktschi and T. Eckert, Chem. Ber., 1995, 128, 1171.
Alkaline metal complexes: (c) H. G. Richery, Jr. and
J. P. DeStephano, J. Org. Chem., 1990, 55, 3281. YbCl3:
(d) S. Matsubara, T. Ikeda, K. Oshima and K. Uchimoto, Chem.
Lett., 2001, 1226. LiCl: (e) A. Krasovskiy and P. Knochel, Angew.
Chem., Int. Ed., 2004, 43, 3333. FeCl3: (f) A. Furstner, H. Krause
and C. W. Lehmann, Angew. Chem., Int. Ed., 2006, 45, 440. FeCl2:
(g) M. Sada and S. Matsubara, Chem. Lett., 2008, 37, 800.
4 (a) T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima and
Y. Kamiya, J. Am. Chem. Soc., 1989, 111, 4392; (b) A. Krasovskiy,
F. Kopp and P. Knochel, Angew. Chem., Int. Ed., 2006, 45, 497;
(c) A. Metzger, A. Gavryushin and P. Knochel, Synlett, 2009,
1433.
5 (a) M. Hatano, T. Matsumura and K. Ishihara, Org. Lett., 2005, 7,
573; (b) M. Hatano, S. Suzuki and K. Ishihara, J. Am. Chem. Soc.,
2006, 128, 9998.
6 Very recently, a ZnCl2ꢂTMEDA-catalyzed nucleophilic substitu-
tion reaction of chlorosilanes with RMgX was reported by
Oshima, et al.: K. Murakami, H. Yorimitsu and K. Oshima,
J. Org. Chem., 2009, 74, 1415.
7 Recent design of ate chemistry: (a) K. Kitagawa, A. Inoue,
H. Shinokubo and K. Oshima, Angew. Chem., Int. Ed., 2000, 39,
2481; (b) T. Iida, T. Wada, K. Tomimoto and T. Mase, Tetra-
hedron Lett., 2001, 42, 4841; (c) M. Uchiyama, S. Nakamura,
T. Ohwada, M. Nakamura and E. Nakamura, J. Am. Chem. Soc.,
2004, 126, 10897.
8 Intramolecular reactions of triorganozincates: T. Harada,
T. Katsuhira, A. Osada, K. Iwazaki, K. Maejima and A. Oku,
J. Am. Chem. Soc., 1996, 118, 11377.
9 Pioneering works using (TMSCH2)2Zn: (a) S. Moorhouse
and G. Wilkinson, J. Organomet. Chem., 1973, 52, C5;
(b) S. Moorhouse and G. Wilkinson, J. Chem. Soc., Dalton Trans.,
1974, 2187. Synthesis of [(TMSCH2)3Zn]ꢀ[K]+: (c) A. P. Purdy
and C. F. George, Organometallics, 1992, 11, 1955. Synthesis of
[(TMSCH2)3Zn]ꢀ[Li]+: (d) E. Rijnberg, J. T. B. H. Jastrzebski,
J. Boersma, H. Kooijman, N. Veldman, A. L. Spek and G. van
Koten, Organometallics, 1997, 16, 2239.
10 R(TMSCH2)Zn have been used as stoichiometric reagents. Addi-
tion to aldehydes: (a) C. Lutz and P. Knochel, J. Org. Chem., 1997,
62, 7895. Michael addition: (b) S. Berger, F. Langer, C. Lutz,
P. Knochel, T. A. Mobley and C. K. Reddy, Angew. Chem., Int.
Ed. Engl., 1997, 36, 1496. Addition to aldimines: (c) J. F. Traverse,
A. H. Hoveyda and M. L. Snapper, Org. Lett., 2003, 5, 3273. Ring-
opening reaction: (d) J. B. Johnson, R. T. Yu, P. Fink, E. A. Bercot
and T. Rovis, Org. Lett., 2006, 8, 4307. Recently, stoichiometric
alkylations with FeCl2–TMSCH2Li–n-Bu2Mg have been reported.
See ref. 3g.
Using the optimized ZnCl2ꢂTMSCH2MgClꢂLiCl system, we
next examined the catalytic addition of Grignard reagents
(RMgBr and MeMgI) to various ketones (Table 2). Without
ZnCl2ꢂTMSCH2MgClꢂLiCl (i.e. traditional Grignard addition
conditions) or with only ZnCl2 catalyst, the yields of the
desired tertiary alcohols were generally low to medium, due
to side reactions. In almost all cases, in addition to undesired
reduction, the starting material was recovered via enolization/
protonation, although a self-aldol product was scarcely
obtained due to the steric hindrance of the ketone. However,
in the presence of ZnCl2ꢂTMSCH2MgClꢂLiCl, not only
aromatic ketones, but also heteroaromatic ketones, aliphatic
ketones, and biaryl ketones gave the corresponding tertiary
alcohols in high yields. Moreover, MeMgI, which is a popular
methylation reagent, could be successfully used in this method
with minimum recovery of the starting material (entries
1, 6, 8). To our delight, arylation such as 4-fluorophenylation
and 1-naphthylation proceeded smoothly under ZnCl2ꢂ
TMSCH2MgClꢂLiCl conditions, while our previous system
with ZnCl2 catalyst did not show the conspicuous improve-
ments (entries 2 and 14). Cyclohexylation as 21-alkylation
other than isopropylation (entry 18), and long chain alkylation
such as n-octylation (entry 10) also proceeded smoothly in the
presence of ZnCl2ꢂTMSCH2MgClꢂLiCl. Other a-functionalized
ketones such as a,a,a-trifluoroacetophenone, an a,a-acetal
ketone, and an a-ketoester were explored, and the corresponding
a-functionalized tertiary alcohols were obtained in high yields
without the decomposition of a-groups (entries 19–21).
Overall, this ZnCl2ꢂTMSCH2MgClꢂLiCl system may offer a
great advantage over traditional Grignard addition or our
previous ZnCl2-catalysis, since highly useful but less reactive
RMgBr and RMgI rather than RMgCl could be used successfully.
Although further investigation is necessary to fully under-
stand the reaction mechanism,13 the key in this catalysis is a
postulated catalytic alkylating ate complex, [R(TMSCH2)2Zn]ꢀ-
[Li]+. The complex [R(TMSCH2)2Zn]ꢀ[Li]+ would be readily
generated in situ from catalytic (TMSCH2)2Zn and
RMgX–LiCl reagents. In sharp contrast, [R3Zn]ꢀ[MgCl]+
has been estimated in the absence of TMSCH2MgCl and LiCl
in our previous ZnCl2 catalysis with RMgCl (Scheme 1).5b
Along with the b-silyl effect of TMSCH2, which would
dramatically activate the anion part of the zinc(II) ate complex
(Fig. 1 and Table 1), the postulated active zinc(II) ate complex
with [Li]+ as the cation part can rationalize why not only
RMgCl but also RMgBr and RMgI can be used in this
catalytic system.
In summary, we have developed highly efficient alkylations
and arylations of ketones with Grignard reagents (RMgBr and
RMgI) using catalytic ZnCl2, TMSCH2MgCl, and LiCl. Desired
tertiary alcohols were obtained in high yields with high
chemoselectivities, while minimizing undesired side products by
reduction and/or enolization. This method is highly attractive for
academic as well as industrial research, since less reactive
RMgBr, which is readily prepared and commercially available,
as well as reactive RMgCl, can be used successfully.
11 b-Silyl effect to metal centers: S. B. Bertz, M. Eriksson, G. Miao
and J. P. Snyder, J. Am. Chem. Soc., 1996, 118, 10906.
12 The strength of the Zn–Ca bond is in the order (TMSCH2)2Zn 4
Et2Zn, n-Pr2Zn, (t-BuCH2)2Zn 4 i-Pr2Zn c t-Bu2Zn. (a) I. E.
Gumrukcuoglu, J. Jeffery, M. F. Lappert, J. B. Pedley and
A. K. Rai, J. Organomet. Chem., 1988, 341, 53; (b) A. Haaland,
J. C. Green, G. S. McGrady, A. J. Downs, E. Gullo, M. J. Lyall,
J. Timberlake, A. V. Tutukin, H. V. Volden and K.-A. Østby,
Dalton Trans., 2003, 4356.
13 Comprehensive investigation of the salt effect on mechanistic
aspects is now underway.
ꢁc
This journal is The Royal Society of Chemistry 2010
2676 | Chem. Commun., 2010, 46, 2674–2676