Alkynes As Stille Reaction Pseudohalides: Gold- and Palladium-Cocatalyzed Synthesis of Tri- and Tetra-Substituted Olefins

Alkynes as Stille Reaction Pseudohalides: Gold- and Palladium-Cocatalyzed Synthesis of Tri- and Tetra-Substituted Olefins

R 2 R2 Au(I)/Pd(0) Bu SnR R3 R2 (II)Pd Au 3 3

CO R Bu3Sn CO2R1 CO2R1 2 1

Yili Shi, Sonja M. Peterson, Walter W. Haberaecker III, and Suzanne A. Blum

J. Am. Chem. Soc., 130 (7), 2168 -2169, 2008

Current Literature Chenbo Wang @ Wipf Group 2/16/2008

Chenbo Wang @ Wipf Group 1 2/16/2008 Carbometallation of Alkynes -General Concepts

R R R R 1 2 R4 1 2 syn addition R M R R R3M 3 3 4 R1 R2 R M R R 1 R4 1 4 anti addition R3 R2 R3 R2

• A powerful way to make stereospecifically substituted alkenes. • M can be Cu, Al, Zr, Ti, Zn, B, Mg, Li or a combination of two. • Syn or anti selectivity depends on the nature of substrate, reagent and reaction conditions. • Regioselectivity depends on the polarity of the triple bond, steric factor and complexation by the functional groups of the alkyne. • Polyaddtitions: the product may add to the starting alkyne, resulting polymerization.

For a review, see: Normant, J. F.; Alexakis, A. Synthesis 1981, 841.

Chenbo Wang @ Wipf Group 2 2/16/2008 Carbometallation of Alkynes -Organocopper Reagents

•Unfunctionalized Terminal alkynes: Markownikov rule

R R1 1 + •MgX2 R Cu R2Cu•MgX2 2 •Functionalized alkynes: directed carbometallation

RCu•MHal (CH2)n (CH2)n X X R Cu

n = 0, 1, 2, 3 - X = halogen, SR, OR, O ,NR2,OAc

Chenbo Wang @ Wipf Group 3 2/16/2008 Synthetic Use of Alkenylcopper(I) Derivatives

R1

R1 R2 CO2H R1

R2 R3 R2 I O R3COCl I CO2 2

R R 1 R X R 1 3 1 R3MCl M = Sn, Si, P, S R R R MR 2 3 R Cu 2 3 O 2 O R3 R3 R4 R3CHO R1 OH R1 R2 R1 R3 R2 R O R R 3 2 3 R HO 4

Chenbo Wang @ Wipf Group 4 2/16/2008 Carbometallation of Alkynes -Organoaluminum Reagents

R1

R CO H 2 R1

R I BuLi then CO2

I2 O R1 R cat Cp2ZrCl2 R1 OH 1 R + 3 R R AlR2 R R3Al 3

BuLi then R3X BuLi then R1 R3CHO

R R3

R1

R R3 HO •Complementary to the organocopper reagents

Negishi, E. et al. Chem. Soc. Rev. 1996, 96, 417

Chenbo Wang @ Wipf Group 5 2/16/2008 Carbometallation of Alkynes -Other Metal Reagents

•Organozinc reagents: propagylic, allylic and malonic type organozinc reagents are tolerated

COOEt COOEt BrZn COOEt + R COOEt Me R Me

•Organolithium reagents: mostly intramolecular examples

•Organomagnesium reagents: Often used with catalytic Cu salt

•Organoboron reagents: require exceptionally reactive substrates

Bertrand, M. T. et al. Tetrahedron Lett. 1974, 1945

Chenbo Wang @ Wipf Group 6 2/16/2008 Previous Work on the Carbometallation of Alkynes Catalyzed by Palladium

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

Chenbo Wang @ Wipf Group 7 2/16/2008 Previous Work on the Carbostannylation of Alkynes Catalyzed by Palladium

•Dimerization predominates.

Hiyama, T. et al Bull. Chem. Soc. Jpn. 2001, 74, 637—647

Chenbo Wang @ Wipf Group 8 2/16/2008 Title Paper: Carbostannylation Catalyzed by Palladium and Gold

Without Au(I) With Au(I)

Filled metal molecular orbitals alkyne π* Filled metal molecular orbitals alkyne π* dorbital of Pd-backbonding orbital dorbital of Pd-backbonding orbital to alkyne to alkyne

↑↓ ↑↓ ↑↓

↑↓

Collman, J. P. et al Principles and Applications of Organotransition Metal Chemistry; University Science Books: Sausalito, CA, 1987; pp 155, 645-647 Chenbo Wang @ Wipf Group 9 2/16/2008 Optimization of Reaction Conditions

•Only Au(I) can effect the reaction, other Lewis acids failed. •Weakly coordinating anions are preferred. •Ag cation reduces the reaction yield.

Chenbo Wang @ Wipf Group 10 2/16/2008 Scope of the Reaction

•Alkynes were added slowly to the reaction mixture to prevent polymerization. •Reactions proceeded with high syn-addition selectivity. •Complete regioselectivity is maintained even with t-Bu ester. •Vinylstannanes reacted with retention of configuration (except Entry 5).

Chenbo Wang @ Wipf Group 11 2/16/2008 Further Transformation of the Product

Chenbo Wang @ Wipf Group 12 2/16/2008 Proposed Mechanism

Chenbo Wang @ Wipf Group 13 2/16/2008 Summary

• Carbostannylation of alkynes was realized with palladium-gold catalysis. • The reaction proceeded with high regio- and stereo-selectivity. • The products are synthetically highly versatile. • Future work: other alkyne substrates?

Chenbo Wang @ Wipf Group 14 2/16/2008