Hadei et al.
SCHEME 1. General Mechanism of Pd-Catalyzed
Alkyl/Alkyl Cross-Coupling Reaction
until the past few years that general, efficient protocols
with broad functional group tolerance were developed.
Early investigations showed the possibility of cross-
coupling reactions involving alkyl halides and alkyl
Grignard reagents promoted by Fe,2c,6 Cu,2c,7 and Pd8
catalysts. However, the range of substrates was limited
as was functional group tolerance. Moreover, these
reactions were often accompanied by significant byprod-
uct formation. Later, improved alkyl/alkyl Kumada cross-
coupling protocols based on Cu/Mn9 or Cu3p catalysts
were published. Very recently, an active catalyst for
cross-couplings of alkyl halides (RCl, RBr) and tosylates
with primary and secondary alkyl Grignard reagents
employing Ni3k,o or Pd3j (1-3 mol %) and 1,3-butadiene
(10-100 mol %) was disclosed by Kambe and co-workers.
Also, the same group showed that a Cu/butadiene cata-
lyst was suitable for coupling of alkyl bromides and
fluorides, while alkyl chlorides, surprisingly, gave lower
yields.3k
The first cross-coupling reaction of alkyl iodides pos-
sessing â-hydrogens with alkyl-9-BBN derivatives cata-
lyzed by Pd(PPh3)4 was reported in 1992.3r In a series of
communications,3m,n,10 Fu and co-workers reported the
development of Pd-catalyzed protocols for a variety of
primary alkyl chlorides, bromides, and tosylates with
organoboron compounds. After extensive screening, Fu
et al. discovered that PCy3 (Cy ) cyclohexyl) was the
ligand of choice for alkyl halides (RBr, RCl),10b,c while
alkyl tosylates required P(t-Bu)2Me.3m The latter phos-
phine ligand was shown to be effective with alkyl boronic
acids instead of alkyl-9-BBN derivatives.3n A recent
report revealed the first alkyl/alkyl Suzuki reaction with
Pd/N-heterocyclic carbene (NHC) catalyst, although the
yields were low to moderate.11
Ni(acac)2/4-fluorostyrene/Bu4NI.13 Similarly, Kambe ob-
served that Ni/butadiene or Pd/butadiene catalyst was
active in coupling a variety of primary alkyl bromides
and tosylates with primary dialkylzinc reagents.14 A Ni-
catalyzed Negishi reaction with a Ni/terpyridine complex
was published by Vicic et al.15 Fu’s group extended the
Ni-catalyzed Negishi protocol to secondary halides (RI,
RBr) using a Ni(cod)2/s-Bu-pybox catalyst.16 This meth-
odology was further developed into the first enantio-
selective alkyl/alkyl cross-coupling reaction of 2-bromo-
propionamides with organozinc halides.17 Fu et al. also
demonstrated that Pd(PCyp3)2 (Cyp ) cyclopentyl) is an
effective catalyst for Negishi cross-couplings of primary
alkyl halides (RCl, RBr, RI) and tosylates at 80 °C.3h
Compared to electrophiles possessing an unsaturated
moiety at, or immediately adjacent to, the leaving group,
alkyl halides are more reluctant to undergo oxidative
addition.2e,18 Recent mechanistic studies suggest that
palladium insertion into an alkyl halide bond (oxidative
addition) occurs via an SN2-type mechanism and is
enhanced by an electron-rich palladium center.10a Hence,
an active catalyst should readily insert into the carbon/
halogen bond of the alkyl halide while suppressing
â-hydride elimination from the oxidative addition inter-
mediate which leads to unwanted alkene formation
(Scheme 1). Following transmetalation, effective reduc-
tive elimination is dependent on the catalyst’s steric
environment.19 The strong σ-donor properties of NHCs
make this ligand class an attractive platform for develop-
ment of catalysts for alkyl/alkyl cross-coupling reac-
tions.20 In addition, ease of synthesis and variable steric
bulk allow easy tuning of the reactivity of the catalyst
in the reductive elimination step (Figure 1). Previously,
Pd/NHC catalysts were successfully employed in recent
studies on Suzuki,11 Kumada,3i and Sonogashira5b cou-
pling reactions of bromoalkanes possessing â-hydrogens.
Knochel and co-workers pioneered the development of
Ni-catalyzed alkyl/alkyl Negishi cross-coupling reactions.
It was observed that primary alkyl iodides coupled with
primary and secondary dialkylzinc derivatives in the
presence of 10 mol % Ni(acac)2/3-trifluoromethylstyrene
in THF/NMP.12 Later, the method was extended to
primary alkyl halides (RI, RBr) and primary and second-
ary alkylzinc iodides with a catalyst system composed of
(4) (a) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc. 2004,
126, 82-83. (b) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
3718-3719.
(5) (a) Yang, L.-M.; Huang, L.-F.; Luh, T.-Y. Org. Lett. 2004, 6,
1461-1463. (b) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
13642-13643.
(6) (a) Tamura, M.; Kochi, J. J. Organomet. Chem. 1971, 31, 289-
309. (b) Tamura, M.; Kochi, J. Synthesis 1971, 303-305.
(7) (a) Nunomoto, S.; Kawakami, Y.; Yamashita, J. J. Org. Chem.
1983, 48, 1912-1914. (b) Tamura, M.; Kochi, J. K. J. Organomet.
Chem. 1972, 42, 205-228. (c) Kochi, J. K.; Tamura, M. J. Am. Chem.
Soc. 1971, 93, 1485-1487.
(8) (a) Castle, P. L.; Widdowson, D. A. Tetrahedron Lett. 1986, 27,
6013-6016. (b) Yuan, K.; Scott, W. J. J. Org. Chem. 1990, 55, 6188-
6194. (c) Yuan, K.; Scott, W. J. Tetrahedron Lett. 1989, 30, 4779-4782.
(9) Donkervoort, J. G.; Vicario, J. L.; Jastrebski, J. T. B. H.; Gossage,
R. A.; Cahiez, G.; van Koten, G. J. Organomet. Chem. 1998, 558, 61-
69.
(10) (a) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int.
Ed. 2003, 42, 5749-5752. (b) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 1945-1947. (c) Netherton, M. R.; Dai, C.;
Neuschu¨tz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099-10100.
(11) Arentsen, K.; Caddick, S.; Cloke, F. G. N.; Herring, A. P.;
Hitchcock, P. B. Tetrahedron Lett. 2004, 45, 3511-3515.
(12) (a) Giovannini, R.; Stu¨dermann, T.; Devasagayaraj, A.; Dussin,
G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-3553. (b) Giovannini,
R.; Stu¨dermann, T.; Dussin, G.; Knochel, P. Angew. Chem., Int. Ed.
1998, 37, 2387-2390.
(13) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79-85.
(14) (a) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe, N.
Angew. Chem., Int. Ed. 2004, 43, 6180-6182. (b) Terao, J.; Nii, S.;
Chowdhury, F. A.; Nakamura, A.; Kambe, N. Adv. Synth. Catal. 2004,
346, 905-908.
(15) Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc.
2004, 126, 8100-8101.
(16) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
(17) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 126, 4594-4595.
(18) Pearson, R. G.; Figdore, P. E. J. Am. Chem. Soc. 1980, 102,
1541-1547.
(19) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 1991-1994.
(20) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
8504 J. Org. Chem., Vol. 70, No. 21, 2005