Diastereotopos-differentiation in the Rh-catalyzed amination of benzylic methylene groups in the α-position to a stereogenic center.

The diastereoselectivity of the Rh-catalyzed C-H amination was examined with 18 chiral open-chain substrates, which bear a benzylic methylene group in the α-position to a stereogenic center (-CHMeX), and with four chiral cyclic tetralins, in which the stereogenic center was positioned at carbon atom C2. The C-H amination was performed using trichloroethoxysulfonyl-substituted amine (H(2)NTces) as the nitrogen source, a diacyloxyiodobenzene as the oxidant, and bis[rhodium(α,α,α',α'-tetramethyl-1,3-benzenedipropionate)] [Rh(2)(esp)(2)] as the catalyst. For acyclic substrates a high syn diastereoselectivity (dr > 95/5) was found if the substituent X was Br, PO(OEt)(2), SO(2)Ph, or OOCCF(3) (eight examples). Moderate to good syn selectivities (dr = 80/20 to 91/9) were found for X = NO(2), OAc, COOMe, and CN (eight examples). Only two substrates gave a low diastereoselectivity. Kinetic isotope effect (KIE) experiments revealed that there is no secondary KIE when replacing -CHMeCOOMe by -CDMeCOOMe, but there is a significant primary KIE at the benzylic methylene position (4.8 ± 0.7). Deuteration experiments provided evidence that the reaction proceeds stereospecifically with retention of configuration. A preferred conformation is proposed, which explains the outcome of the reaction. In this conformation the X substituent is antiperiplanar to the C-H bond, which is diastereoselectively attacked, and steric strain between the remaining substituents at the stereogenic and the prostereogenic center is minimized. DFT calculations support this model. They suggest, however, that the reaction is not concerted but occurs via hydrogen atom abstraction and subsequent radical rebound. Further support for an antiperiplanar attack relative to a given substituent X = Br, COOMe, or CN was obtained with the respective 2-substituted tetralins. Attack at C1 provides almost exclusively the trans-amination product. If the size of the X substituent increases [Br < CN < COOMe < PO(OEt)(2)], attack at the carbon atom C4 prevails, delivering the respective trans-amination products at this position.