Facile Hydrogenolysis of C(sp³)–C(sp³) σ Bonds

Abstract

The modification of benzylic quaternary, tertiary, and secondary carbon centers through palladium‐catalyzed hydrogenolysis of C(sp3)–C(sp3) σ bonds is presented. When benzyl Meldrum's acid derivatives bearing quaternary benzylic centers are treated under mild hydrogenolysis conditions – palladium on carbon and atmospheric pressure of hydrogen – aromatics substituted with tertiary benzylic centers and Meldrum's acid are obtained with good to excellent yield. Analogously, substrates containing tertiary or secondary benzylic centers yield aromatics substituted with secondary benzylic centers or toluene derivatives, respectively. Furthermore, this strategy is used for the high yielding synthesis of diarylmethanes. The scope of the reductive dealkylation reaction is explored and the limitations with respect to steric and electronic factors are determined. A mechanistic analysis of the reaction is described that consisted of deuterium labelling experiments and hydrogenolysis of enantioenriched derivatives. The investigation shows that the C(sp3)–C(sp3) σ bond‐cleaving events occur through a hybrid SN1/SN2 mechanism, in which the palladium center displaces a carbon‐based leaving group, namely Meldrum's acid, with inversion of configuration, followed by reductive elimination of palladium to furnish a C−H bond.magnified image

The Rise of Carbon‐based Leaving Groups

“…Like N , N ‐dimethylbarbituric acid, Meldrum's acid also possesses a 1,3‐dicarbonyl core and recent articles have demonstrated its leaving group ability. A comprehensive study on hydrogenolysis of C sp3 −C sp3 bond connecting Meldrum's acid to a benzylic center of substrate 17 was carried out by Fillion and his group [18,21] . In this reaction, the carbon‐based leaving, i. e. Meldrum's acid 19 is substituted by a hydride in the presence of Pd/C and H 2 gas (Scheme 10A).…”

“…A comprehensive study on hydrogenolysis of C sp3 À C sp3 bond connecting Meldrum's acid to a benzylic center of substrate 17 was carried out by Fillion and his group. [18,21] In this reaction, the carbon-based leaving, i. e. Meldrum's acid 19 is substituted by a hydride in the presence of Pd/C and H 2 gas (Scheme 10A). The authors found that the CÀ C bond cleavage in substrate 17 undergoes via a hybrid S N 1/ S N 2 mechanism where initially the metal center behaves as the nucleophile.…”

“…Kerr et al, inspired by the insightful work on Meldrum's acid by Fillion and his group, [18,21,32,33] advanced an Sc(OTf) 3 catalyzed method for the synthesis of indolemethanes 27 using the said carbon-based leaving group (Scheme 14). [34] The reaction conditions that Kerr et al employed tolerate the use of ChemistrySelect electron-rich indoles as the nucleophile, which was not possible in harsher reaction conditions of Fillion's group.…”

“…Thus, a range of active methylene compounds has been observed as carbon-based leaving groups throughout the New CÀ H, [18,21] CÀ C, [17,32,44] CÀ N, [28,38,45] CÀ O [43] and CÀ S [34] bonds can be formed at the expense of a CÀ C bond, indicating the vast utility of the CÀ C bond cleaving reaction. While a majority of the ChemistrySelect methods involve Lewis acidic environment for the CÀ C bond cleavage, the existence of catalyst-free, metal-free, or solventfree methods is bound to enthuse future research involving carbon-based leaving groups in greener conditions.…”

“…[20] New CÀ H, CÀ C, CÀ N, CÀ O, and CÀ S bonds may be formed via the cleavage of carbonbased leaving groups. [21][22][23][24] Thus, recent literature on carbonbased leaving groups indicates a vast potential for application in organic synthesis. A comprehensive understanding combined with mindfulness of such readily cleavable carbon-based fragments may also help in predicting reaction outcomes.…”