C O M M U N I C A T I O N S
Table 2. Alkyl-Alkyl Suzuki Cross-Couplings of Unactivated
Secondary Alkyl Bromides (for conditions, see eq 1)
Table 3. Alkyl-Alkyl Suzuki Cross-Couplings of Unactivated
Secondary and Primary Alkyl Electrophiles (for conditions, see
eq 1)
a Isolated yield (average of two experiments).
perature. We anticipate that the observation that simple, readily
available diamines can furnish active catalysts will greatly facilitate
the development of powerful new methods for cross-coupling alkyl
electrophiles. Efforts to substantiate this hypothesis are underway.
Acknowledgment. This paper is dedicated to the memory of
Prof. Yoshihiko Ito. Dr. Francisco Gonza´lez-Bobes is acknowledged
for preliminary studies. Support has been provided by the National
Institutes of Health (National Institute of General Medical Sciences,
R01-GM62871), the Japan Society for the Promotion of Science
(postdoctoral fellowship to B.S.), Merck Research Laboratories,
Novartis, and Boehringer Ingelheim.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
References
(1) For general reviews of metal-catalyzed cross-coupling reactions, see: (a)
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: New York, 2004. (b) Handbook of Organopalla-
dium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-
Interscience: New York, 2002.
a Isolated yield (average of two experiments). b Diastereoselectivity )
>20:1 (exo:endo). c Ratio of trans/cis ) 65/35. d Eight equivalents of
i-BuOH was used.
(2) For reviews of cross-coupling reactions of alkyl electrophiles, see: (a)
Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-688. (b)
Netherton, M. R.; Fu, G. C. Topics in Organometallic Chemistry: Palla-
dium in Organic Synthesis; Tsuji, J., Ed.; Springer: New York, 2005.
(c) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-
1532.
tive formation of a tetravalent -ate complex by 11B NMR spec-
troscopy (eq 3).
(3) For two pioneering investigations of palladium- and nickel-catalyzed cross-
couplings of alkyl electrophiles, see: (a) Ishiyama, T.; Abe, S.; Miyaura,
N.; Suzuki, A. Chem. Lett. 1992, 691-694. (b) Devasagayaraj, A.; Stu¨de-
mann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2723-2725.
(4) For additional leading references, see: Terao, J.; Kambe, N. Bull. Chem.
Soc. Jpn. 2006, 79, 663-672.
(5) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
(6) For reviews of the Suzuki reaction, see: (a) Reference 1. (b) Miyaura, N.
Top. Curr. Chem. 2002, 219, 11-59.
(7) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (b)
Gonza´lez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360-5361.
(8) Notes: (a) Certain other alcohols (2,2-dimethyl-1-propanol, 2-ethyl-1-
butanol, and s-BuOH) furnish comparable or slightly diminished yields.
(b) In the presence of KOi-Bu (1.2 equiv), rather than KOt-Bu/i-BuOH,
the desired product is generated in 74% yield.
(9) For discussions of transmetalation in the context of palladium-catalyzed
Suzuki reactions, see: (a) Matos, K.; Soderquist, J. A. J. Org. Chem.
1998, 63, 461-470. (b) Miyaura, N. J. Organomet. Chem. 2002, 653,
54-57.
(10) A competition experiment among secondary alkyl halides revealed the
following reactivity order: I > Br . Cl.
(11) Preliminary experiments indicate that, under our standard reaction
conditions, alkylboranes derived from the hydroboration of more highly
substituted olefins, as well as alkylboron reagents that bear certain
nitrogen-containing functional groups, are not suitable cross-coupling
partners. Furthermore, couplings of actiVated secondary alkyl halides (i.e.,
a benzylic bromide and an R-bromoester) have not proceeded cleanly.
We intend to explore the use of different ligands and reactions conditions
to address these limitations.
(12) In the case of the coupling depicted in entry 9 of Table 2, we have
determined that undesired products from elimination, reduction, or
homocoupling of the alkyl bromide are not formed in significant yields.
(13) Notes: (a) We have not yet undertaken optimization studies for cross-
couplings of these families of electrophiles. (b) A competition experiment
among alkyl bromides revealed the following reactivity order: secondary
> primary . tertiary (under our standard conditions, the cross-coupling
of tert-butyl bromide with PhCH2CH2CH2(9-BBN) proceeds in <5%
yield).
This new method can be applied to a range of alkyl-alkyl cross-
couplings of unactivated secondary bromides with alkylboranes
(Table 2). Not only cyclohexyl (entry 1) but also cyclopentyl and
cycloheptyl (entries 2 and 3) bromide are suitable reaction partners.
Bicyclic (entries 4 and 5), as well as acyclic (entry 6), alkyl halides
can be employed. Secondary bromides cross-couple in preference
to chlorides (entry 7).10 In addition to chlorides, other functional
groups can be present in the electrophile and in the organoborane
(e.g., ethers, carbamates, and esters; entries 8-13).11,12
The utility of this Ni/diamine catalyst is not limited to alkyl-
alkyl Suzuki reactions of secondary bromides. Thus, without
modification, the method can be applied to couplings of unactivated
secondary alkyl iodides, primary bromides, and primary iodides
(Table 3).13
In summary, we have established that a commercially available
1,2-diamine serves as an effective ligand for metal-catalyzed cross-
couplings of unactivated alkyl electrophiles at room temperature.
In particular, Ni/trans-N,N′-dimethyl-1,2-cyclohexanediamine pro-
vides the first method for achieving alkyl-alkyl Suzuki reactions
of unactivated secondary alkyl halides with alkylboranes; earlier
success in Suzuki couplings of such electrophiles had been restricted
to reactions with aryl- and vinylboron reagents at elevated tem-
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J. AM. CHEM. SOC. VOL. 129, NO. 31, 2007 9603