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46285-G1
Nucleophilic Substitution/Functionalization Reactions of Transition-Metal Complexes at sp3 Carbon

Suzanne A. Blum, University of California (Irvine)

Palladium-catalyzed carbon-carbon cross-coupling reactions are a staple of modern synthetic chemistry due to the diverse products accessible and functional groups tolerated by these reactions. While powerful, these methods require initial oxidative addition into a carbon-halogen, -oxygen, or -hydrogen covalent (or ionic) bond (e.g., Stille, Heck, Suzuki, Trost-Tsuji, Buchwald-Hartwig,¹ and the ionic Arndtsen modification²). During the last ACS-PRF granting year, we reported the extension of this chemistry from C-X bonds to C-C p-bonds through the employment of alkynes in the place of halides in a Stille-type vinylstannylation reaction. Our reaction provides an expedient route to the monoaddition products, yielding tri- and tetra-substituted olefins^3,4 from alkynes with absolute regioselectivity and high stereoselectivity via a Au(I)/Pd(0) bimetallic catalyst system that combines the characteristics of two metals to produce unique reactivity.⁵ 

We hypothesized that the alkynophilic⁶ Lewis acid Au(I) would lower the LUMO of an alkyne fragment, promoting backbonding (i.e., oxidative addition) from Pd(0) into the alkyne,⁷ which in turn increases palladium-carbon s-bond character (Figure 1).  Andersen reported a conceptually similar, structurally characterized m-ethylene bimetallic complex with Pt(0) as the Lewis base and Yb(II) as the Lewis acid.⁷ To our knowledge, no employment of this structure class as a catalytic intermediate had been developed, despite the potential generality of such a method for accessing late-metal-carbon s-bonds. With an alkyne as the oxidative addition partner, no C-X bond would be necessary for a cross-coupling reaction (i.e., the alkyne serves as a pseudohalide).⁸ 

Figure 1.  Proposed Lewis-acid activation of alkynes leads to an increase in backbonding from Pd(0), permitting Pd(II)-C s-bond reactivity.

In order to explore this hypothesis, dimethyl acetylenedicarboxylate (DMAD) was treated with 20 mol% of PPh₃AuCl/AgSbF₆ and 5 mol% Pd₂(dba)₃ in the presence of one equivalent of tri-n-butylvinylstannane. Gratifyingly, these conditions produced tetrasubstituted olefin 1a in 51% ¹H NMR yield.  Both Au(I) and Pd(0) were required for conversion. Supporting Pd(0)'s role as an oxidative addition partner to the alkyne, Pd(II) is significantly less active.

The utility of the Pd/Au catalyzed method for formation of tri-and tetra-substituted olefins is illustrated by a range of stannane partners (i.e., sp², sp, secondary, oxygenated, b-substituted; Table 1). Complete regioselectivity is maintained even in the presence of a sterically bulky t-butyl ester. Interestingly, no evidence for reentry into the catalytic cycle by the product vinyl stannanes is observed. Presumably, this is because of the increased steric hinderance provided by a branching and b substitution. 

A proposed mechanism for the Au- and Pd-cocatalyzed vinylstannylation of alkynes is detailed in Scheme 1.  Coordination of cationic Au(I) to the alkyne promotes nucleophilic addition/oxidative addition of Pd(0). Transmetallation of tri-n-butylvinylstannane across one of the palladium-carbon s-bonds of 7 results in vinyl transfer to palladium and tin transfer to the nascent olefin. Dissociation of Au(I) followed by reductive elimination forms the observed vinylstannylated product, 10, and regenerates Pd(0).
Table 1.  Scope of Au- and Pd-Catalyzed Alkyne Stille Reaction

Scheme 1.  Proposed catalytic mechanism, showing analogy to the traditional Stille reaction.

We next investigated the ability of the stannyldiene products to participate in traditional cross-coupling reactions with aryl halides. Reaction of crude stannyldiene 1b with iodotoluene in the presence of 5% additional Pd₂(dba)₃ yields the all-carbon trisubstituted olefin 11 in 78% yield (55% over two steps) (eq 1).    This two-step procedure affects an aryl vinylation of the starting alkyne with absolute regioselectivity and high stereoselectivity for the syn addition product.

In conclusion, we have developed a palladium and gold cocatalyzed vinylstannylation of alkynes to form tri- and tetra-substituted olefins with excellent regio- and stereocontrol. The reactions are postulated to proceed via Au(I) activation of the alkynes toward nucleophilic metallation/oxidative addition to Pd(0). In this mechanism, the alkyne serves as a pseudohalide in a Stille-type cross-coupling reaction.  In a broader sense, the reactions reported herein provide an entry into the extensive catalytic chemistry of palladium-carbon s-bonds starting from p-systems.

References

1.         Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.

2.         Davis, J. L.; Dhawan, R.; Arndtsen, B. A. Angew. Chem. Int. Ed. 2004, 43, 590.

3.         Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670.

4.         Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765.

5.         For a review on bimetallic catalysis by late transition metals, see: van den Beuken, E. K.; Feringa, B. L. Tetrahedron 1998, 54, 12985.

6.         Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.

7.         Burns, C. J.; Andersen, R. A. J. Am. Chem. Soc. 1987, 109, 915.

8.         The importance of backbonding from palladium(0) to alkenes was recently highlighted by the work of Stahl and Landis, who showed that palladium(0) has a kinetic preference for binding to electron poor olefins. Popp, B. V.; Thorman, J. L.; Morales, C. M.; Landis, C. R.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 14832.

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