Abstract
A range of novel heterocyclic cations have been synthesized by the Rh(III)-catalyzed oxidative C-N and C-C coupling of 1-phenylpyrazole, 2-phenylpyridine, and 2-vinylpyridine with alkynes (4-octyne and diphenylacetylene). The reactions proceed via initial C-H activation, alkyne insertion, and reductive coupling, and all three of these steps are sensitive to the substrates involved and the reaction conditions. Density functional theory (DFT) calculations show that C-H activation can proceed via a heteroatom-directed process that involves displacement of acetate by the neutral substrate to form charged intermediates. This step (which leads to cationic C-N coupled products) is therefore favored by more polar solvents. An alternative non-directed C-H activation is also possible that does not involve acetate displacement and so becomes favored in low polarity solvents, leading to C-C coupled products. Alkyne insertion is generally more favorable for diphenylacetylene over 4-octyne, but the reverse is true of the reductive coupling step. The diphenylacetylene moiety can also stabilize unsaturated seven-membered rhodacycle intermediates through extra interaction with one of the Ph substituents. With 1-phenylpyrazole this effect is sufficient to suppress the final C-N reductive coupling. A comparison of a series of seven-membered rhodacycles indicates the barrier to coupling is highly sensitive to the two groups involved and follows the trend C-N(+) > C-N > C-C (i.e., involving the formation of cationic C-N, neutral C-N, and neutral C-C coupled products, respectively).
Highlights
Methods to form polycyclic heterocycles through the construction of C−Y bonds (Y = C, N and O) are of vital importance for the synthesis of molecules targeting applications in pharmaceuticals and materials science
It has been suggested that C−N coupling might only occur with anionic directing groups that result in neutral heterocycles.1d recently a number of groups have shown that cationic C−N coupled products can be formed with the involvement of a neutral directing group.[5]
Density functional theory (DFT) calculations have accounted for the specific observations and highlight some more general trends of wider relevance beyond this specific study
Summary
We and others recently demonstrated that the Rh- and Ru-catalyzed reactions of 3phenylpyrazoles with internal alkynes lead to C−N coupled heterocycles (Scheme 1a).[2] with 1-phenylpyrazole (1, Scheme 1b) only C−C coupled heterocycles have been reported to date; the precise outcome depends on both the nature of the alkyne and the solvent.[3] Previous studies from our groups have provided some mechanistic insight into the behavior of 1-phenylpyrazole This species undergoes acetate-assisted C−H activation with both [MCl2Cp*]2 (M = Rh, Ir) and [RuCl2(p-cymene)]2 to form cyclometalated products (see Scheme 1c for the Rh complex, 2). Understanding the interplay of these reaction variables is vital in the design of new catalytic processes for C−H functionalization that, as well as being efficient, must allow control in product selectivity
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