Dual vicinal functionalisation of heterocycles via an interrupted Pummerer coupling/[3,3]-sigmatropic rearrangement cascade

Abstract

A dual vicinal functionalisation cascade involving the union of heterocycles and allyl sulfoxides is described. In particular, the approach provides efficient one-step access to biologically relevant and synthetically important C3 thio, C2 carbo substituted indoles. The reaction operates under mild, metal free conditions and without directing groups, via an interrupted Pummerer coupling of activated allyl sulfoxides, generating allyl heteroaryl sulfonium salts that are predisposed to a charge accelerated [3,3]-sigmatropic rearrangement.

Scheme 1. Vicinal S/C substituted heterocycles: important molecular architectures (A); stepwise C–H functionalisation strategy illustrated for indole (B); and, our approach utilising a dual vicinal functionalisation cascade, again, illustrated using indole.

Scheme 2. Exploring the scope of indoles in the dual vicinal functionalisation cascade. ^a 1.5 equivalents of sulfoxide and 1.6 equivalents of TFAA were used.

Scheme 3. Exploring the scope of the allylic sulfoxide in the dual functionalisation cascade of indoles. ^a The corresponding E-allylic sulfoxides were used (i.e. R⁶ = H). ^b3y/4y = 4.8 : 1. ^c Yield determined by ¹H-NMR. ^d3aa/4aa = 3 : 1. ^e Heated at 60 °C, 30 min. ^f3ac/4ac = 3.3 : 1. ^g Heated at 60 °C, 1 h. Regioisomer ratios determined from ¹H-NMR spectra of the crude reaction mixture.

Scheme 4. Preliminary results exploring other heterocycles in the dual vicinal functionalisation cascade. ^a using Na₂CO₃ instead of K₃PO₄. ^b 2 equivalents of sulfoxide and 2.2 equivalents of Tf₂O were used. ^c Yield determined by ¹H-NMR. ^d6k/C3 thio, C2 allyl pyrrole = 1 : 1.6. ^e6l/C3 thio, C2 allyl pyrrole = 1.5 : 1. ^f –78 °C to rt, overnight.

Scheme 5. Proposed mechanism of the dual functionalisation cascade of indoles (A) and probing the effect of N-substitution for the selective generation of C3 thio, C2 allyl indole 3 or C2 thio, C3 allyl indole 4 (B). ^a Conditions as in Scheme 3. ^b Combined yield of 3 + 4. ^c Regioisomer ratios determined by ¹H-NMR of the crude reaction mixture.

Scheme 6. Scalability of the dual functionalisation cascade of indoles and iterative dual functionalisation cascades for the generation of novel bis indolyl sulfides. ^a Conditions as in Scheme 2.