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. 2009 Jun 27;65(26):5074-5083.
doi: 10.1016/j.tet.2009.03.096.

A new approach to carbon-carbon bond formation: Development of aerobic Pd-catalyzed reductive coupling reactions of organometallic reagents and styrenes

Keith M Gligorich  1 , Yasumasa Iwai, Sarah A Cummings, Matthew S Sigman
Affiliations

A new approach to carbon-carbon bond formation: Development of aerobic Pd-catalyzed reductive coupling reactions of organometallic reagents and styrenes

Keith M Gligorich et al. Tetrahedron. .

Abstract

Alkenes are attractive starting materials for organic synthesis and the development of new selective functionalization reactions are desired. Previously, our laboratory discovered a unique Pd-catalyzed hydroalkoxylation reaction of styrenes containing a phenol. Based upon deuterium labeling experiments, a mechanism involving an aerobic alcohol oxidation coupled to alkene functionalization was proposed. These results inspired the development of a new Pd-catalyzed reductive coupling reaction of alkenes and organometallic reagents that generates a new carbon-carbon bond. Optimization of the conditions for the coupling of both organostannanes and organoboronic esters is described and the initial scope of the transformation is presented. Additionally, several mechanistic experiments are outlined and support the rationale for the development of the reaction based upon coupling alcohol oxidation to alkene functionalization.

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Figures

Figure 1
Figure 1
(A) Deuterium labeling experiments. (B) Proposed mechanism of the alkene hydroalkoxylation reactions involves coupling an alcohol oxidation to alkene functionalization.
Figure 2
Figure 2
(A) Traditional Pd0-catalyzed cross-coupling with an organic oxidant. (B) Proposed aerobic PdII-catalyzed reductive coupling reaction and (C) mechanistic hypothesis. (D) Competitive oxidative Heck pathway.
Figure 3
Figure 3
(A) Exposing styrene 5a to the alkene hydroalkoxylation conditions with ethanol leads to the formation of the acetal 6. (B) Employing IPA as the solvent with similar reaction conditions unexpectedly produced the hydroalkoxylation product 8.
Figure 4
Figure 4
(A) Time course analysis of the reductive coupling reaction. (B) The compound (−)-sparteine-N-oxide can be synthesized using H2O2 and may inhibit the catalysis.
Figure 5
Figure 5
The initial scope of the reductive coupling reaction of styrenes and organostannanes.
Figure 6
Figure 6
(A) A base is typically required to facilitate transmetalation of boronic esters via a proposed four-member transition state. (B) The proposed mechanism of the Pd-catalyzed aerobic oxidation of alcohols where exogenous base can modulate the rate.
Figure 7
Figure 7
Identification of the optimal organoboronic ester.
Figure 8
Figure 8
The initial scope of the reductive coupling reaction of styrenes and ethylene glycol derived boronic ester derivatives.
Figure 9
Figure 9
Deuterium labeling experiments on the reductive coupling of 5a and PhSnBu3
Figure 10
Figure 10
Reductive coupling of a diene and 9f, which proceeds via the possible PdII-η3-π-allyl intermediate 19.
Figure 11
Figure 11
(A) Attempted synthesis of a PdII-hydride complex via alcohol oxidation. (B) Synthesis of PdII-η3-π-benzyl complex 21.
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