Communications
[3] For examples of applications of alkyl–alkyl Suzuki cross-coupling
reactions in the total synthesis of natural products, see: a) K. A.
[4] For alkyl–alkyl Suzuki reactions of unactivated secondary alkyl
bromides and/or iodides, see: a) B. Saito, G. C. Fu, J. Am. Chem.
step for this Suzuki reaction of cyclohexyl bromide. In
contrast, for cyclohexyl chloride, the rate of cross-coupling
is dependent on the concentration of the electrophile.
In conclusion, we have developed the first alkyl–alkyl
Suzuki reaction of unactivated secondary alkyl chlorides.
Carbon–carbon bond formation occurs under mild conditions
(at room temperature) with the aid of commercially available
catalyst components. This method, although developed for
the cross-coupling of unactivated secondary chlorides, has
proved to be versatile: without modification, it can be applied
to Suzuki reactions of secondary and primary alkyl bromides
and iodides, as well as primary alkyl chlorides. Mechanistic
investigations suggest that oxidative addition is not the
turnover-limiting step of the catalytic cycle for unactivated
secondary alkyl iodides and bromides, whereas it may be
(partially) for the corresponding alkyl chlorides. Additional
mechanistic and catalyst-development studies of a wide array
of alkyl–alkyl cross-coupling reactions are under way.
[5] For alkyl–aryl Suzuki reactions of unactivated secondary alkyl
iodides, bromides, and chlorides at 608C, see: F. Gonzꢁlez-Bobes,
G. C. Fu, J. Am. Chem. Soc. 2006, 128, 5360 – 5361; see also: J.
[6] Additional details about the reaction: 1) In the absence of
NiBr2·diglyme or ligand 1, essentially none of the desired product
was formed (< 1%). 2) On a gram scale, the Suzuki reaction in
entry 1 of Table 2 proceeded in 79% yield (yield of the isolated
product, average of two experiments). 3) Under our standard
conditions, secondary alkyl boranes, primary alkyl boronate
esters, primary alkyl boronic acids, and primary alkyl trifluor-
oborates did not undergo cross-coupling in good yield. 4) By
11B NMR spectroscopy, we determined that the potassium
alkoxide reacts with the alkyl-9-BBN reagent to form a tetrava-
lent boron complex. This interaction not only activates the trialkyl
borane reagent, but also attenuates the Brønsted basicity of the
reaction mixture. 5) On a 1 mmol scale in a microwave (608C for
3.5 h), the cross-coupling reaction in entry 1 of Table 2 proceeded
in 74% yield. 6) When tBuOMe or Et2O was used as the solvent
in place of iPr2O, product yields were slightly lower, whereas the
use of THF led to a greatly diminished yield.
Received: May 30, 2010
Published online: August 16, 2010
Keywords: alkyl halides · boron · cross-coupling ·
.
homogeneous catalysis · nickel
[7] Under our standard conditions, attempts to cross-couple an
unactivated tertiary chloride, bromide, and iodide led to essen-
tially none of the desired products.
[1] For leading references, see: a) Metal-Catalyzed Cross-Coupling
Reactions (Eds.: A. de Meijere, F. Diederich), Wiley-VCH,
Weinheim, 2004; b) Handbook of Organopalladium Chemistry
for Organic Synthesis (Ed.: E.-i. Negishi), Wiley-Interscience,
New York, 2002; c) Cross-Coupling Reactions: A Practical Guide,
Topics in Current Chemistry Series 219 (Ed.: N. Miyaura),
Springer, New York, 2002.
[8] High selectivity (I > Br> Cl) is often observed in oxidative
addition/abstraction processes that proceed through an inner-
sphere electron-transfer pathway; see, for example: S. L. Scott,
[9] For mechanistic proposals for nickel-catalyzed Negishi reactions
of alkyl electrophiles, see: a) G. D. Jones, J. L. Martin, C. McFar-
land, O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon, T.
Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J. Am. Chem.
[2] a) For a pioneering study of Suzuki reactions of primary alkyl
electrophiles, see: T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki,
reactions of secondary alkyl electrophiles, see: A. Rudolph, M.
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 6676 –6678