Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides

Abstract

The development of transition metal-catalysed cross-coupling reactions has greatly influenced the manner in which the synthesis of complex organic molecules is approached. A wide variety of methods are now available for the formation of C(sp(2))-C(sp(2)) bonds, and more recent work has focused on the use of C(sp(3)) electrophiles and nucleophiles. The use of secondary and tertiary alkyl nucleophiles in cross-coupling reactions remains a challenge because of the propensity of these alkyl groups to isomerize under the reaction conditions. Here, we report the development of a general Pd-catalysed process for the stereoretentive cross-coupling of secondary alkyl azastannatrane nucleophiles with aryl chlorides, bromides, iodides and triflates. Coupling partners with a wide range of electronic characteristics are well tolerated. The reaction occurs with minimal isomerization of the secondary alkyltin nucleophile, and with retention of absolute configuration. This process constitutes the first general method to use secondary alkyltin reagents in cross-coupling reactions.

Figure 1 |. Cross-coupling reactions using configurationally stable, optically active secondary alkyl nucleophiles.

a, Proposed catalytic cycle for the Pd-catalysed cross-coupling of secondary nucleophiles and aryl electrophiles. It is necessary for reductive elimination to occur in the absence of the competing β-hydride elimination pathway to avoid the formation of isomeric by-products. b, Inverse relationship between configurational stability and nucleophilicity in secondary alkyl organometallic nucleophiles. c, Recent advances in Pd-catalysed cross-coupling reactions between isolable, optically active organometallic nucleophiles and aryl halides. The groups of Hoppe, Crudden, Ohmura and Suginome, Molander^,, Hall and Falck have demonstrated the use of isolable, optically active organometallic nucleophiles in cross-coupling reactions. However, nucleophiles in these examples require activation via the presence of a C(sp²) α-carbon, heteroatomic α-carbon and/or a strongly coordinating β-carbonyl group. DMF, dimethylformamide; THF, tetrahydrofuran; CPME, cyclopentyl methyl ether; dba, dibenzylideneacetone; XPhos, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

Figure 2 |. Preparation of alkyl azastannatrane derivatives.

Stable and easily handled alkyl azastannatrane reagents can be prepared by reaction of a variety of organometallic nucleophiles with the azastannatrane chloride. THF, tetrahydrofuran; DMA, dimethylacetamide.

Figure 3 |. Investigation of the stereorentention of transmetallation.

a, Preparation of enantioenriched 10. b, Transfer of stereochemistry in cross-coupling reaction using 10. c, X-ray crystal structure of 11 (thermal ellipsoids at 50% probability).

Figure 4 |. Pd-catalysed cross-coupling reactions using unactivated, optically active secondary alkyl azastannatrane 12.

Cross-coupling can be achieved without significant loss of enantiopurity, even without the potentially stabilizing effect of an α-heteroatom.