However, much less attention has been given to investigat-
ing possibilities of accelerating the rate of the reductive
elimination step, one that is generally considered slower and
more critical to the overall reaction rate, except leveraging
the steric bulk of the phosphine ligand to elevate the ground
state energy. Problems caused by slow reductive elimination
are especially acute for coupling reactions involving alkyl
(Csp3 center) nucleophiles, where the presence of â-hydro-
gens often leads to the deleterious â-elimination pathway,19
especially in the cases of secondary Csp3 centers.20,21 It is
known that non-phosphine, π-acceptor ligands such as maleic
anhydride, fumaronitrile, p-fluorostyrene, as well as other
olefins,22-26 are known to accelerate the reductive elimina-
tion. However, these ligands are known to stabilize Pd(0)
species so much that their tendency toward oxidative addition
is much attenuated. To address this dilemma, we designed
and synthesized two hybrid ligands, which include the
phosphine and electron-deficient olefins shown in Figure 1,
of organometals, we attributed the success of the transforma-
tion to the unexpected rate enhancement of Csp-Pd-Csp3
reductive elimination to using dba as the ligand, which is a
good π-acceptor.30 It was reported that oxidative addition
and transmetallation of the Csp2-Csp3 Negishi coupling are
faster than reductive elimination when PPh3 is used as the
ligand.19,31 However, with in situ reaction monitoring by IR
(ReactIR), we found that the reaction of ArI (3a) and RZnCl
(4a) at room temperature using ligand 1 is complete in less
than 2 min (Figure 2).
Figure 1. Phosphine electron-deficient olefin ligands.
and we demonstrate that they are effective in palladium-
catalyzed Negishi Csp2-Csp3 coupling that can occur at
room temperature and that involves a secondary sp3-carbon
in the presence of a â-H.
Cross-coupling reactions on sp3-carbons are more difficult
than those on sp- and sp2-carbons as a result of a slower
rate of reductive elimination and a facile process of â-H
elimination if available.7,27-29 In the oxidative cross-coupling
(12) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-
7370.
(13) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11.
(14) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411-
2413.
(15) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724.
(16) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 3805-3807.
(17) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. J.
Org. Chem. 2005, 70, 8503-8507.
(18) Campos K. R.; Klapars, A.; Waldman, J., H.; Dormer, P. G.; Chen,
C.-y. J. Am. Chem. Soc. 2006, 128, 3538-3539.
(19) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398-
3416.
(20) Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. ReV. 2000, 100,
3187-3204.
Figure 2. (A) 3D spectrum of ReactIR experiment. (B) Selected
2D spectrum of 3a during the reaction period. Reaction condi-
tions: 2 mmol 4a, 1 mmol 3a, 0.005 mmol PdCl2(CH3CN)2/1 in
total 4 mL THF, 25 °C.
We then further studied the Negishi coupling of 3a with
diethylzinc by employing different ligands.32 The results are
listed in Table 1. The reactions using PPh3 gave only low to
moderate yields (Table 1, entries 1-3). Formation of the
hydridodehalogenated product 13 is an indication of the
(21) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163.
(22) Yamamoto, T.; Abla, M.; Murakami, Y. Bull. Chem. Soc. Jpn. 2002,
75, 1997-2009.
(29) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.;
Weissburger, F.; de Vries, A. H. M.; Schmieder-van de Vondervoort, L.
Chem.-Eur. J. 2006, 12, 8750-8761.
(23) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79-85.
(24) Grundl, M. A.; Kennedy-Smith, J. J.; Trauner, D. Organometallics
2005, 24, 2831-2833.
(30) Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L.
J. Am. Chem. Soc. 2006, 128, 15048-15049.
(31) Casares, J. A.; Espinet, P.; Fuentes, B.; Salas, G. J. Am. Chem.
Soc. 2007, 129, 3508-3509.
(25) Scrivanti, A.; Beghetto, V.; Matteoli, U.; Antonaroli, S.; Marini,
A.; Crociani, B. Tetrahedron 2005, 61, 9752-9758.
(26) Shintani, R.; Duan, W.-L.; Okamoto, K.; Hayashi, T. Tetrahedron:
Asymmetry 2005, 16, 3400-3405.
(27) Cardenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020.
(28) Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. ReV. 2000, 100,
3187-3204.
(32) We try to clarify the capability of ligand 1 in the formation of
Csp2(Ar)-Csp3 bond, in which the possible problem might be the reductive
elimination and â-H elimination. ArI 3a, an electronic-deficient ArI, could
be a good substrate for the oxidative addition. If the oxidative addition is
fast enough and it is not the rate-determining step, we will have a chance
to see the differences between ligand 1 and the others.
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Org. Lett., Vol. 9, No. 22, 2007