C O M M U N I C A T I O N S
Table 1. Lewis Acid-Catalyzed Hydroalkylation of Olefin
Substrates
reaction; however, in this case, a metal enolate and a carbocation
are generated, which react to furnish a new C-C bond and the
desired hydroalkylation product. Thus, no oxidant is required for
the overall C-H to C-C transformation.10 A 1,5-relationship
between the electrophilic site and the targeted C-H bond seems
to be a requirement for hydroalkylation to proceed. Substrate 23
containing a 1,4-relationship and substrate 24 containing a 1,6-
relationship each failed to yield hydroalkylation products (Scheme
3), demonstrating the current limitation of this approach to the
formation of six-membered rings.5
In summary, we have demonstrated that the hydridic character
of C-H bonds can be exploited to promote their direct conversion
into C-C bonds. This simple approach has been utilized to
efficiently functionalize tertiary and secondary positions R to
heteroatoms (ethers and carbamates), as well as tertiary benzylic
C-H bonds, under catalytic or substoichiometric conditions. An
important finding was that a variety of Lewis acids functioned as
catalyst. Studies primarily aimed at expanding the scope of this
concept to encompass a variety of acceptor components are ongoing
in our laboratory.
Acknowledgment. This work was supported by the NIGMS,
GlaxoSmithKline, Johnson & Johnson Focused Giving Program,
and Merck Research Laboratories. D.S. is a recipient of the
Astrazeneca Excellence in Chemistry Award, the Pfizer Award for
Creativity in Organic Synthesis, and the Bristol-Myers Squibb
unrestricted research grant. We thank Daniela Buccella and
Professor Gerard Parkin (X-ray).
Note Added after ASAP Publication: There were errors
in Scheme 2 in the version published on the Internet August
16, 2005. The version published August 23, 2005, is correct.
a All reactions were performed in CH2Cl2 (0.025 M substrate) at room
temperature. Isolated yields after flash chromatography. b Diastereomeric
ratio given in parentheses. c Diastereomeric ratio >15:1. d Reaction per-
formed at 50 °C.
Supporting Information Available: Experimental procedures and
spectroscopic data for starting materials and products. This material is
References
Scheme 2
(1) (a) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai,
S. J. Am. Chem. Soc. 2001, 123, 10935 and references therein. (b)
Sakakura, T.; Abe, F.; Tanaka, M. Chem. Lett. 1991, 359. (c) Lin, Y.;
Ma, D.; Lu, X. Tetrahedron Lett. 1987, 28, 3249.
(2) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556.
(3) Although the mechanism in these reports is suggested to proceed through
a 1,5-sigmatropic hydrogen shift, it is possible that a direct hydride transfer
mechanism is operative. Selected examples: (a) Noguchi, M.; Yamada,
H.; Sunagawa, T. J. Chem. Soc., Perkin Trans. 1 1998, 3327. (b) Nijhuis,
W. H. N.; Verboom, W.; El-Fadl, A. A.; Harkema, S.; Reinhoudt, D. N.
J. Org. Chem. 1989, 54, 199. (c) Nijhuis, W. H. N.; Verboom, W.;
Reinhoudt, D. N. J. Am. Chem. Soc. 1987, 109, 3136. (d) Nijhuis, W. H.
N.; Verboom, W.; Reinhoudt, D. N. Synthesis 1987, 641.
(4) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(5) The term “through space” is used to differentiate this process from more
common hydride shifts that proceed through a σ- or π-framework. The
overwhelming majority of these examples proceed through a six-membered
transition state. For selected examples, see: (a) Kanischev, M. I.;
Schegolev, A. A.; Smit, W. A.; Caple, R.; Kelner, M. J. J. Am. Chem.
Soc. 1979, 101, 5660 and references therein. (b) Schulz, J. G. D.;
Onopchenko, A. J. Org. Chem. 1978, 43, 339. (c) Heathcock, C. H.;
Piettre, S.; Ruggeri, R. B.; Ragan, J.; Kath, J. C. J. Org. Chem. 1992, 57,
2544. (d) Krohn, K.; Flo¨rke, U.; Ho¨fker, U.; Tra¨ubel, M. Eur. J. Org.
Chem. 1999, 3495. (e) Wo¨lfling, J.; Frank, EÄ .; Schneider, G.; Tietze, L.
F. Angew. Chem., Int. Ed. 1998, 38, 200. (f) Diaz, D.; Mart´ın, V. S. Org.
Lett. 2000, 2, 335. (g) Diaz, D.; Mart´ın, V. S. Tetrahedron Lett. 2000,
41, 743. (h) Wo¨lfling, J.; Frank, EÄ .; Schneider, G.; Tietze, L. F. Eur. J.
Org. Chem. 2004, 90.
Scheme 3. Mechanistic Rationale for Lewis Acid-Catalyzed
Hydroalkylation: A 1,5-Relationship Is Required
(6) A byproduct stemming from the opening of the spiro-system formed in
this reaction (see the Supporting Information).
(7) (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055. (b)
Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59, 8859.
(8) The relative amount of 14a and 14b is dependent on the reaction time
and the catalyst employed.
(9) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67, 1414.
(10) For oxidative intermolecular C-C bond formation at the R-position of
reactive amines, see: (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae,
T. J. Am. Chem. Soc. 2003, 125, 15312. (b) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2005, 127, 6968 and references therein.
The mechanistic rationale for this transformation is provided in
Scheme 3. Lewis acid complexation with the carbonyl oxygen
activates the olefin and triggers the [1,5]-hydride shift, affording
the zwitterionic intermediate II. This crucial step may be viewed
as an intramolecular variant of the Meerwein-Ponndorf-Verley
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