Evidence is presented for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydroquinazoline (1) by (PCy(3))(2)RhCl. One intermediate (3), a coordination complex of 1 with (PCy(3))(2)RhCl, was identified along the path to the Rh-N-heterocyclic carbene product of this reaction (2). Isotopic labeling and reaction-rate studies were used to demonstrate that C-H activation takes place intramolecularly on the reaction coordinate between 3 and 2. Computational studies corroborate the proposed mechanism and suggest that the rate-limiting step is oxidative addition of the C-H bond to the metal center. The consequences of this mechanism for coupling reactions of N-heterocycles that occur via Rh-catalyzed C-H bond activation are discussed.

[reaction: see text] A new method for the rhodium-catalyzed arylation of a variety of heterocycles has been developed. The reaction provided moderate to good yields of the arylated products. A preliminary mechanistic investigation of this reaction revealed the intermediacy of an isolable N-heterocyclic carbene complex.

The inter- and intramolecular couplings of unactivated alkenes to 3,4-dihydroquinazolines with a Rh(I) catalyst are reported. Coupling between olefins and NH-3,4-dihydroquinazoline was found to occur consecutively with heterocycle dehydrogenation in the presence of a Rh(I)/PCy3/HCl catalyst. The reaction was used to develop an effective method for the synthesis of 2-substituted quinazolines through an oxidative workup step. The regiocontrolled synthesis and Rh-catalyzed cyclization of alkene-tethered 3,4-dihydroquinazolines are also described. Applying this method, the second total synthesis of vasicoline was achieved. The key Rh-catalyzed cyclization step was made possible by the use of a rigid bicyclic phosphine ligand. The synthesis further demonstrates a challenging Cu-catalyzed amidation of an ortho-substituted aryl chloride.

Lithium 2,2,6,6-tetramethylpiperidide (LiTMP)-mediated alpha- and beta-lithiations of epoxides are described. LiTMP displays a markedly higher reactivity than does lithium diisopropylamide, consistent with literature reports. Detailed rate studies of LiTMP/THF and LiTMP/Me(2)NEt mixtures reveal similar rates but significant mechanistic differences. LiTMP-mediated alpha-lithiation of cis-cyclooctene oxide with subsequent oxacarbenoid formation and transannular C-H insertion proceeds via monosolvated dimers in both THF and Me(2)NEt. LiTMP-mediated beta-lithiation of 2,3-dimethyl-2-butene oxide affords the corresponding allylic alcohol via a monosolvated monomer in THF and a monosolvated dimer in Me(2)NEt. We discuss how the solvent-dependent aggregation of LiTMP markedly influences the rate profile. The reaction transition structures are examined with density functional computations.