D4-Symmetric Dirhodium Tetrakis(binaphthylphosphate) Catalysts for Enantioselective Functionalization of Unactivated C-H Bonds.

Dirhodium tetrakis(2,2'-binaphthylphosphate) catalysts were successfully developed for asymmetric C-H functionalization with trichloroethyl aryldiazoacetates as the carbene precursors. The 2,2'-binaphthylphosphate (BNP) ligands were modified by introduction of aryl and/or chloro functionality at the 4,4',6,6' positions. As the BNP ligands are C2-symmetric, the resulting dirhodium tetrakis(2,2'-binaphthylphosphate) complexes were expected to be D4-symmetric, but X-ray crystallographic and computational studies revealed this is not always the case because of internal T-shaped CH-π and aryl-aryl interactions between the ligands. The optimum catalyst is Rh2(S-megaBNP)4, with 3,5-di(tert-butyl)phenyl substituents at the 4,4' positions and chloro substituents at the 6,6' positions. This catalyst adopts a D4-symmetric arrangement and is ideally suited for site-selective C-H functionalization at unactivated tertiary sites with high levels of enantioselectivity, outperforming the best dirhodium tetracarboxylate catalyst developed for this reaction. The standard reactions were conducted with a catalyst loading of 1 mol % but lower catalyst loadings can be used if desired, as illustrated in the C-H functionalization of cyclohexane in 91% ee with 0.0025 mol % catalyst loading (29,400 turnover numbers). These studies further illustrate the effectiveness of donor/acceptor carbenes in site-selective intermolecular C-H functionalization and expand the toolbox of catalysts available for catalyst-controlled C-H functionalization.

Diaryldiazoketones as Effective Carbene Sources for Highly Selective Rh(II)-Catalyzed Intermolecular C-H Functionalization.

A novel donor/acceptor carbene intermediate has been developed using diaryldiazoketones as carbene precursors. In the presence of the chiral dirhodium catalyst, Rh2(S-TPPTTL)4, diaryldiazoketones undergo highly regio-, stereo-, and diastereoselective C-H functionalization of activated and unactivated secondary and tertiary C-H bonds. Computational studies revealed that the arylketo group behaves differently than the carboxylate acceptor group because the orientation of the arylketo group predetermines which face of the carbene will be attacked.

Mechanistic Investigation of Castagnoli-Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones.

The mechanisms for the three- and four-component variants of the Castagnoli-Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the three- and four-component variants of the CCR (3CR and 4CR, respectively). Control experiments paired with in situ reaction monitoring with infrared spectroscopy for the 4CR align with a mechanism in which amide-acids derived from maleic anhydride can reversibly form free amine and cyclic anhydride. Although this equilibrium is unfavorable, the aldehyde present can trap the primary amine through imine formation and react with the enol form of the anhydride through a Mannich-like mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of more than a decade of mechanistic speculation for the 3- and 4CR, enabling the design of new multicomponent reactions that exploit this novel mechanism.