Acc. Chem. Res., 2009, 42, 743; (f) F. Mongin and M. Uchiyama,
Curr. Org. Chem., 2011, 15, 2340.
2 (a) H. Gilman and R. L. Bebb, J. Am. Chem. Soc., 1939, 61, 109;
(b) G. Wittig and G. Fuhrman, Chem. Ber., 1940, 73, 1197;
(c) W. H. Puterbaugh and C. R. Hauser, J. Org. Chem., 1964, 29, 853.
3 (a) P. E. Eaton, C.-H. Lee and Y. Xiong, J. Am. Chem. Soc., 1989,
111, 8016; (b) G. C. Clososki, C. J. Rohbogner and P. Knochel,
Angew. Chem., Int. Ed., 2007, 46, 7681.
4 (a) Y. Kondo, M. Shilai, M. Uchiyama and T. Sakamoto, J. Am.
Chem. Soc., 1999, 121, 3539; (b) M. Uchiyama, T. Miyoshi,
Y. Kajihara, T. Sakamoto, Y. Otani, T. Ohwada and Y. Kondo,
J. Am. Chem. Soc., 2002, 124, 8514; (c) S. H. Wunderlich and
P. Knochel, Angew. Chem., Int. Ed., 2007, 46, 7685; (d) M. Mosrin,
G. Monzon, T. Bresser and P. Knochel, Chem. Commun., 2009, 5615.
5 S. Usui, Y. Hashimoto, J. V. Morey, A. E. H. Wheatly and
M. Uchiyama, J. Am. Chem. Soc., 2007, 129, 15102.
6 H. Naka, M. Uchiyama, Y. Matsumoto, A. E. H. Wheatley,
M. McPartlin, J. V. Morey and Y. Kondo, J. Am. Chem. Soc.,
2007, 129, 1921.
Scheme 3 Deprotonative functionalization of C(sp3)–H bonds.
7 S. H. Wunderlich, M. Kienle and P. Knochel, Angew. Chem., Int.
Ed., 2009, 48, 7256.
8 M. Schlosser, Organometallics in Synthesis A Manual, John Wiley
& Sons, England, 1994.
9 For leading books, see: (a) A. Berkessel and H. Groger,
Asymmetric Organocatalysis
¨
– From Biomimetic Concepts to
Scheme 4 Reactions of 5a with benzophenones and benzaldehydes.
Applications in Asymmetric Synthesis, Wiley-VCH, Weinheim,
2005; (b) P. I. Dalko, Enantioselective Organocatalysis, Wiley-
VCH, Weinheim, 2007; (c) Organocatalysis, ed. M. T. Reetz,
B. List, S. Jaroch and H. Weinmann, Springer Verlag, Berlin, 2008.
10 For selected examples, see: (a) T. Imahori and Y. Kondo, J. Am.
Chem. Soc., 2003, 125, 8082; (b) M. Ueno, M. Yonemoto,
M. Hashimoto, A. E. H. Wheatley, H. Naka and Y. Kondo,
Chem. Commun., 2007, 2264; (c) K. Kobayashi and Y. Kondo,
Chem.–Eur. J., 2009, 15, 9805; (d) Y. Hirono, K. Kobayashi,
M. Yonemoto and Y. Kondo, Chem. Commun., 2010, 7623.
11 (a) T. D. Krizan and J. C. Martin, J. Am. Chem. Soc., 1983,
105, 6155; (b) S. S. Dua and H. Gilman, J. Organomet. Chem.,
1974, 64, C1; (c) S. Caron and J. M. Hawkins, J. Org. Chem., 1998,
63, 2054; (d) M. Schlosser, L. Guio and F. Leroux, J. Am. Chem.
Soc., 2001, 123, 3822; (e) J. Kristensen, M. Lysen, P. Vedso and
M. Begtrup, Org. Lett., 2001, 3, 1435; (f) E. Vazquez, I. W. Davies
and J. F. Payack, J. Org. Chem., 2002, 67, 7551; (g) H.-Q. Do and
O. Daugulis, Org. Lett., 2009, 11, 421.
acetate 5a using a combination of 3c and a fluoride source
such as P5F or TMAF and produced the corresponding tri-
and disubstituted alkenes 6ad–am in high yields (Scheme 4).
The process tolerates various functional groups such as alkoxy-
carbonyl and cyano groups and halogen atoms.
In summary, the work presented in this communication
contains the first examples of organocatalytic deprotonative
transformations using in situ generated onium amide bases.
This conceptually new, metal-free, C–H functionalization
employs catalytic systems based on the combination of amino-
silanes and several types of fluoride sources that successfully
effect the functionalization of C(sp2)–H bonds of various
heteroarenes under mild reaction conditions. This method
provides a novel approach for manipulating an aromatic
carbanion, and thus offers an operationally simple, applicable,
and sustainable methodology for use in synthetic organic
chemistry. In addition, functionalization of C(sp3)–H bonds
a- to a carbonyl group was also achieved via a similar deproto-
native functionalization process in the presence of an onium
amide base, which represents the versatility of this method.
Future work will focus on investigation of the precise reaction
mechanism of the process and exploration of the further
synthetic scope of this type of deprotonative functionalization.
This work was partly supported by a Grant-in-Aid for Scientific
Research (B) (No.23390002), a Grant-in-Aid for Challenging
Exploratory Research (No. 23659001), and a Grant-in-Aid for
Young Scientists (B) (No. 23790002) from Japan Society for the
Promotion of Science, and a Grant-in-Aid for Scientific Research
on Innovative Areas ‘‘Advanced Molecular Transformations by
Organocatalysts’’ (No. 23390002) from The Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
12 (a) R. Schwesinger, R. Link, P. Wenzl and S. Kossek, Chem.–Eur. J.,
2006, 12, 438; see also: (b) R. Schwesinger, R. Link, G. Thiele,
H. Rotter, D. Honert, H.-H. Limbach and F. Mannle, Angew. Chem.,
Int. Ed. Engl., 1991, 30, 1372.
¨
13 For a review of quaternary ammonium fluorides in organic synthesis,
see: (a) T. Ooi and K. Maruoka, Acc. Chem. Res., 2004, 37, 526; see
also: (b) K. Maruoka, T. Ooi and T. Kano, Chem. Commun., 2007,
1487; (c) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107, 5656.
14 For the pKa values of C–H bonds in heteroarenes used in this
study, see: K. Shen, Y. Fu, J.-N. Li, L. Liu and Q.-X. Guo,
Tetrahedron, 2007, 63, 1568.
15 This deprotonative process produced a mixture of 4aa and its
trimethylsililated compound, which was subjected to the desilylation
using 2.0 M aqueous NaOH in THF.
16 Langlois previously reported the preparation of nucleophilic trifluoro-
methylating reagents using the combination of TTMS 3d and Fꢀ as
base for the deprotonation of fluoroform in DMF, see: (a) T. Billard,
S. Bruns and B. R. Langlois, Org. Lett., 2000, 2, 2101; (b) S. Large,
N. Roques and B. R. Langlois, J. Org. Chem., 2000, 65, 8848.
17 Anhydrous TBAF was prepared according to the DiMagno’s method,
see: H. Sun and S. G. Dimagno, J. Am. Chem. Soc., 2005, 127, 2050.
18 Other fluoride sources such as TASF [tris(dimethylamino)sulfonium
difluorotrimethylsilicate] and DAST (N,N-diethylaminosulfur tri-
fluoride) were also ineffective for the process.
19 In general, unreacted starting materials are recovered when the
reaction gives a decreased yield.
Notes and references
1 For selected recent reviews, see: (a) G. Queguiner, F. Marsais,
V. Snieckus and J. Epsztajn, Adv. Heterocycl. Chem., 1991, 52, 187;
20 In the C(sp2)–H bond functionalization process, aromatic alde-
hydes are not suitable substrates, the reactions of which resulted in
the quantitative recovery of the starting materials.
(b) F. Mongin and G. Que
´
(c) A. Turck, N. Ple, F. Mongin and G. Que
guiner, Tetrahedron, 2001, 57, 4059;
guiner, Tetrahedron,
´
´
21 (a) D. A. Oare and C. H. Heathcock, J. Org. Chem., 1990, 55, 157;
(b) M. L. Hlavinka and J. R. Hagadorn, Tetrahedron Lett., 2006,
47, 5049.
2001, 57, 4489; (d) R. E. Mulvey, F. Mongin, M. Uchiyama and
Y. Kondo, Angew. Chem., Int. Ed., 2007, 46, 3802; (e) R. E. Mulvey,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9771–9773 9773