Stereochemistry and Mechanism of the Bronsted Acid Catalyzed Intramolecular Hydrofunctionalization of an Unactivated Cyclic Alkene

Through employment of deuterium-labeled substrates, the triflic acid catalyzed intramolecular exo addition of the X-H(D) (X = N, O) bond of a sulfonamide, alcohol, or carboxylic acid across the C=C bond of a pendant cyclohexene moiety was found to occur, in each case, with exclusive formation (>= 90%) of the anti-addition product without loss or scrambling of deuterium as determined by H-1 and H-2 NMR spectroscopy and mass spectrometry analysis. Kinetic analysis of the triflic-acid-catalyzed intramolecular hydroamination of N-(2-cyclohex-2'-enyl-2,2-diphenylethyl)-p-toluene-sulfonamide (1a) established the second-order rate law: rate=k(2)[HOTf] [1a] and the activation parameters Delta H-(sic) =(9.7 +/- 0.5) kcal mol(-1) and Delta S-(sic) = (-35 +/- 5) cal K-1 mol(-1). An inverse alpha-secondary kinetic isotope effect of k(D)/k(H) = (1.15 +/- 0.03) was observed upon deuteration of the C2' position of 1a, consistent with partial C-N bond formation in the highest energy transition state of catalytic hydroamination. The results of these studies were consistent with a mechanism for the intramolecular hydroamination of 1a involving concerted, intermolecular proton transfer from an N-protonated sulfonamide to the alkenyl C3' position of 1a coupled with intramolecular anti addition of the pendant sulfonamide nitrogen atom to the alkenyl C2' position.