95631-62-2

The mechanism of N-dealkylation mediated by cytochrome P450 (P450) has long been studied and argued as either a single electron transfer (SET) or a hydrogen atom transfer (HAT) from the amine to the oxidant of the P450, the reputed iron-oxene. In our study, tertiary anilinic N-oxides were used as oxygen surrogates to directly generate a P450-mediated oxidant that is capable of N-dealkylating the dimethylaniline derived from oxygen donation. These surrogates were employed to probe the generated reactive oxygen species and the subsequent mechanism of N-dealkylation to distinguish between the HAT and SET mechanisms. In addition to the expected N-demethylation of the product aniline, 2,3,4,5,6-pentafluoro-N,N-dimethylaniline N-oxide (PFDMAO) was found to be capable of N-dealkylating both N,N-dimethylaniline (DMA) and N-cyclopropyl-N-methylaniline (CPMA). Rate comparisons of the N-demethylation of DMA supported by PFDMAO show a 27-fold faster rate than when supported by N,N-dimethylaniline N-oxide (DMAO). Whereas intermolecular kinetic isotope effects were masked, intramolecular measurements showed values reflective of those seen previously in DMAO- and the native NADPH/O2-supported systems (2.33 and 2.8 for the N-demethylation of PFDMA and DMA from the PFDMAO system, respectively). PFDMAO-supported N-dealkylation of CPMA led to the ring-intact product N-cyclopropylaniline (CPA), similar to that seen with the native system. The formation of CPA argues against a SET mechanism in favor of a P450-like HAT mechanism. We suggest that the similarity of KIEs, in addition to the formation of the ring-intact CPA, argues for a similar mechanism of Compound I (Cpd I) formation followed by HAT for N-dealkylation by the native and N-oxide-supported systems and demonstrate the ability of the N-oxide-generated oxidant to act as an accurate mimic of the native P450 oxidant.

The 1-methyl-, 1-ethoxy-, and 1-chlorocyclopropyl radicals have been observed by low-temperature EPR spectroscopy in "frozen" configurations in which the ring hydrogens that are syn and anti to the unpaired elecron's orbital have different hyperfine splittings.The aH(syn)/aH(anti) ratios are 1.5 (CH3), 1.8 (EtO), and 1.9 (Cl), all considerably lower than the ratio of ca. 3.3 found by Kawamura et al. for methyl-substituted 1-fluorocyclopropyl radicals.The out-of-plane angles of the 1-substituent have been calculated from measured a13Cα values to be 22.5 deg (cyclopropyl), 22.9 deg (CH3), 29.1 deg (EtO), and 5.8 deg (MeSi).These angles are considerably smaller than those that have been calculated for some of these radicals by ab initio and other methods.Variable-temperature EPR spectroscopy on 1-methylcyclopropyl yields the following Arrhenius equation for its inversion: log (kinv/s-1) = (13.1 +/- 0.3) - (3.1 +/- 0.2)/2.3RT kcal/mol.For 1-ethoxycyclopropyl the rate constant for rotation about the .C-OEt bond can be represented by log (krot/s-1) = (12.5 +/- 0.2) - (5.8 +/- 0.2)/2.3RT.The barrier to inversion of this radical is >/= 9 kcal/mol.The 1-chlorocyclopropyl radical could only be observed at very low temperatures.

Various approaches to the generation of (1-alkoxycyclopropyl)lithium reagents were investigated.The syntheses of tri-n-butylstannane, cyclopropyl 2,4,6-triisopropylbenzoate, and 1-bromo-1-ethoxycyclopropane were carried out

A variety of cyclobutanones have been prepared in high yield from 1-bromo-1-ethoxycyclopropane via lithiation, addition to aldehydes or ketones, and mild acid-catalyzed rearrangement of the adducts.