C O M M U N I C A T I O N S
Table 2. Negishi Cross-Couplings of Secondary Alkyl Bromides
and Iodides with Alkylzinc Reagents (eq 1; 1.6 equiv of Alkylzinc
Reagent)
wide range of coupling reactions of alkyl electrophiles, as well as
initiating mechanistic studies of these processes.
Acknowledgment. Support has been provided by the National
Institutes of Health (National Institute of General Medical Sciences,
R01-GM62871), Merck, and Novartis. Funding for the MIT De-
partment of Chemistry Instrumentation Facility has been furnished
in part by NSF CHE-9808061 and NSF DBI-9729592.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
References
(1) For reviews of metal-catalyzed cross-coupling reactions, see: (a) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998. (b) Cross-Coupling Reactions: A Practical
Guide; Miyaura, N., Ed.; Topics in Current Chemistry Series 219;
Springer-Verlag: New York, 2002. (c) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience:
New York, 2002.
3
(2) For an overview of the difficulty of achieving coupling reactions of Csp -X
electrophiles, see: Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-
387; Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020. See
also: Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. ReV. 2000, 100,
3187-3204.
Table 3. Negishi Cross-Couplings of Primary Alkyl Bromides and
Iodides with Alkylzinc Reagents (eq 1; 1.6 equiv of Alkylzinc
Reagent)
(3) Suzuki cross-couplings: (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki,
A. Chem. Lett. 1992, 691-694. (b) Netherton, M. R.; Dai. C.; Neuschu¨tz,
K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099-10100. (c) Kirchhoff,
J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945-1947.
(d) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-
3912. (e) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662-13663.
(4) Negishi cross-couplings: (a) Devasagayaraj, A.; Stu¨demann, T.; Knochel,
P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2723-2725. (b) Giovannini,
R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew. Chem., Int. Ed. 1998,
37, 2387-2390. (c) Giovannini, R.; Stu¨demann, T.; Devasagayaraj, A.;
Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-3553. (d) Piber,
M.; Jensen, A. E.; Rottla¨nder, M.; Knochel, P. Org. Lett. 1999, 1, 1323-
1326. (e) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79-85. (f)
Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527-12530.
(5) Kumada cross-couplings: (a) Terao, J.; Watanabe, H.; Ikumi, A.;
Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222-4223. (b)
Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003,
125, 5646-5647.
(6) For a recent example of a stoichiometric coupling of a secondary
alkylnickel with an arylzinc reagent, see: O’Brien, E. M.; Bercot, E. A.;
Rovis, T. J. Am. Chem. Soc. 2003, 125, 10498-10499.
with functional groups such as sulfonamides, ethers, acetals, esters,
and amides.10
(7) (a) Organozinc Reagents, A Practical Approach; Knochel, P., Jones, P.,
Eds.; Oxford: New York, 1999. (b) Erdik, E. Organozinc Reagents in
Organic Synthesis; CRC Press: Boston, 1996. (c) Boudier, A.; Bromm,
L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414-
4435. (d) Hou, S. Org. Lett. 2003, 5, 423-425.
Ni(cod)2/s-Bu-Pybox can also be employed as a catalyst for
Negishi cross-couplings of primary alkyl halides (Table 3), reacting
even with very hindered neopentyl iodide (entry 3). These examples
provide further evidence for the high functional-group tolerance
of the method (e.g., imides and ketones).
In conclusion, we have established that Ni(cod)2/s-Bu-Pybox
catalyzes Negishi reactions of an array of functionalized alkyl
bromides and iodides at room temperature. To the best of our
knowledge, this is the first nickel- or palladium-catalyzed method
for cross-coupling unactivated, â-hydrogen-containing, secondary
alkyl halides. Due to the potential impact on synthetic chemistry,
we are continuing our efforts to develop effective catalysts for a
(8) We observe essentially no n-dodecane (<0.5%), indicating that the
isopropylnickel complex is not undergoing â-hydride elimination to
generate an n-propylnickel complex.
(9) We speculate that the chelating nature of Pybox ligands may disfavor
â-hydride elimination, which requires a vacant coordination site.
(10) Notes: (a) The standard coupling conditions can also be applied to Negishi
reactions of activated alkyl halides. For example, n-nonylZnBr couples
with allyl bromide, benzyl bromide, and benzyl chloride in 60, 89, and
100% yields (by GC, versus a calibrated internal standard), respectively.
(b) The use of secondary organozinc reagents leads to lower yields
(<30%). (c) Alkyl chlorides, alkyl tosylates, and tertiary alkyl bromides/
iodides are not suitable coupling partners under the standard conditions.
JA0389366
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