Ruthenium-Catalyzed C–H Bond Activation Approach to Azolyl Aminals and Hemiaminal Ethers, Mechanistic Evaluations, and Isomer Interconversion

C­(sp3)–N bond-forming reactions between benzotriazole
and 5,6-dimethylbenzotriazole with N-methylpyrrolidinone,
tetrahydrofuran, tetrahydropyran, diethyl ether, 1,4-dioxane, and
isochroman have been conducted using RuCl3·3H2O/t-BuOOH in 1,2-dichloroethane. In all cases, N1 and N2 alkylation products were obtained,
and these are readily separated by chromatography. One of these products,
1-(isochroman-1-yl)-5,6-dimethyl-1H-benzotriazole,
was examined by X-ray crystallography. It is the first such compound
to be analyzed by this method, and notably, the benzotriazolyl moiety
is quasi-axially disposed, consistent with the anomeric effect. This
has plausible consequences, not observed previously. In contrast to
other hemiaminal ether-forming reactions, which proceed via radicals,
this Ru-catalyzed process is not suppressed in the presence of a radical
inhibitor. Therefore, an oxoruthenium-species-mediated rapid formation
of an oxocarbenium intermediate is believed to occur. In the radical-trapping
experiment, previously unknown products containing both the benzotriazole
and the TEMPO unit have been identified. In these products, it is
likely that the benzotriazole is introduced via a Ru-catalyzed C–N
bond formation, whereas C–O bond-formation with TEMPO occurs
via a radical reaction. We show that reactions of THF with TEMPO are
influenced by ambient light. A competitive reaction of THF and THF-d8 with benzotriazole indicated that C–H
bond cleavage occurs ca. 5 times faster than C–D cleavage.
This is comparable to other metal-mediated radical reactions of THF
but lower than that observed for a reaction catalyzed by n-Bu4N+I–. Detailed mechanistic
experiments and comparisons are described. The catalytic system was
also evaluated for reactions of benzimidazole, imidazole, 1,2,4-triazole,
and 1,2,3-triazole with THF, and successful reactions were achieved
in each case. In the course of our studies, we discovered an unexpected
but significant isomerization of some of the benzotriazolyl hemiaminal
ethers. This is plausibly attributable to the pseudoaxial orientation
of the heterocycle in the products and the stability of oxocarbenium
ions, both of which can contribute to C–N bond cleavage and
reformation. Predominantly, the N2-isomers rearrange
to the N1-isomers even upon storage at low
temperature! This previously unknown phenomenon has also
been studied and described.