On the Mechanism of Nitrosoarene-Alkyne Cycloaddition

The thermal reaction between nitrosoarenes and alkyones produces N-hydroxyindoles as the major products. The mechanism of these novel reactions has been probed using a combination of experimental and computational methods. The reaction of nitrosobenzene (NB) with an excess of phenyl acetylene (PA) is determined to be first order in each reactant in benzene at 75 degrees C. The reaction rates have been determined for reactions between phenyl acetylene with a set of p-substituted nitrosoarenes, 4-X-C6H4NO, and of 4-O2N-C6H4NO with a set of p-substituted arylalkynes, 4-Y-C6H4C CH. The former reactions are accelerated by electron-withdrawing X groups (rho = +0.4), while the latter are faster with electron-donating Y groups (rho = -0.9). The kinetic isotope effect for the reaction of C6H5NO/C6D5NO with PhC CH is found to be 1.1 (+/- 0.1) while that between PhC CH/PhC CD with PhNO is also 1.1 (+/- 0.1). The reaction between nitrosobenzene and the radical clock probe cyclopropylacetylene affords 3-cyclopropyl indole in low yield. In addition to 3-carbomethoxy-N-hydroxyinclole, the reaction between PA and o-carbomethoxy-nitrosobenzene also affords a tricyclic indole derivative, 3, likely derived from trapping of an intermediate indoline, nitrone with PA and subsequent rearrangement. Computational studies of the reaction mechanism were carded out with density functional theory at the (U)B3LYP/6-31 +G(d) level. The lowest energy pathway of the reaction of PhNO with alkynes was found to be stepwise; the N-C bond between nitrosoarene and acetylene is formed first, the resulting vinyl diradical undergoes cis- trans isomerization, and then the C-C bond forms. Conjugating substituents Z on the alkyne, Z-C CH, lower the calculated (and observed) activation barrier, Z = -H (19 kcal/mol), -Ph (15.8 kcal/mol), and -C(O)H (13 kcal/mol). The regioselectivity of the reaction, with formation of the 3-substituted inclole, was reproduced by the calculations of PhNO + PhC CH; the rate-limiting step for formation of the 2-substituted indole is higher in energy by 11.6 kcal/mol. The effects of -NO2, -CN, -CI, -Br, -Me, and -OMe substituents were computed for the reactions of p-X-C6H4NO with PhC CH and of PhNO and/or p-NO2-C6H4NO with p-Y-C6H4C CH. The activation energies for the set of p-X-C6H4NO vary by 4.3 kcal/mol and follow the trend found experimentally, with electron-withdrawing X groups accelerating the reactions. The range of barriers for the P-Y-C6H4C CH reactions is smaller, about 1.5 and 1.8 kcal/mol in the cases of PhNO and p-NO2-PhNO, respectively. In agreement with the experiments, electron-donating Y groups on the alkyne accelerate the reactions with p-NO2-C6H4NO, while both ED and EW groups are predicted to facilitate the reaction. The calculated kinetic isotope effect for the reaction of C6H4NO/C6D5NO with PhC CH is negligible (as found experimentally) while that for PhC CH/PhC CD with PhNO (0.7) differs somewhat from the experiment (1.1). Taken together the experimental and computational results point to the operation of a stepwise diradical cycloaddition, with rate-limiting N-C bond formation and rapid C-C connection to form a biyclic cyclohexaclienylN-oxyl diradical, followed by fast tautomerization to the N-hydroxyindole product.