Synthesis of Highly Congested Tertiary Alcohols via the [3,3] Radical Deconstruction of Breslow Intermediates

Abstract

Pericyclic processes such as [3,3]-sigmatropic rearrangements leading to the rapid generation of molecular complexity constitute highly valuable tools in organic synthesis. Herein, we report the formation of particularly hindered tertiary alcohols via rearrangement of Breslow intermediates formed in situ from readily available N-allyl thiazolium salts and benzaldehyde derivatives. Experimental mechanistic studies performed suggest that the reaction proceeds via a close radical pair which recombine in a regio- and diastereoselective manner, formally leading to [3,3]-rearranged products.

Intramolecular Cyclization and a Retro-Ene Reaction Enable the Rapid Fragmentation of a Vitamin B1-derived Breslow Intermediate

“…Related Breslow intermediates have recently been reported to undergo formal [3,3]-sigmatropic rearrangements similar to the pericyclic processes proposed here. [20] Preliminary efforts to evaluate these pathways led to identification of a TS describing such a process from (E)-4a (TS25; Figure S14), although i) this TS could only be located with the M06-2X functional, and ii) IRC calculations suggested that the corresponding barrier is >50 kcal/mol, consistent with the hypothesis that this TS would not be energetically accessible from the ground state of (E)-4a. Preliminary calculations the B3LYP functional with the SMD solvent model and a significantly smaller basis set (3-21G*) identified a pericyclic TS (TS26; Figure S15) that suggested migration of the aminopyrimidine onto the C2α-Ph group as a potential reaction of (Z)-4a (Scheme S6), but efforts to optimize these structures with larger basis sets have thus far been unsuccessful.…”

Influence of Cage Effects in Directing the Outcome of C–X Bond Forming Reactions

“…In 2022, Lindsay and co-workers reported a formal [3,3]-sigmatropic rearrangement of Breslow intermediates that proceeds via a close radical pair and thus generates products in a regio- and diastereoselective manner . The transformation provides access to hindered homoallylic alcohols and can be used to forge one of the C–C bonds that extends from an all-carbon quaternary center.…”

“…In 2022, Lindsay and co-workers reported a formal [3,3]sigmatropic rearrangement of Breslow intermediates that proceeds via a close radical pair and thus generates products in a regio-and diastereoselective manner. 140 The transformation provides access to hindered homoallylic alcohols and can be used to forge one of the C−C bonds that extends from an all-carbon quaternary center. While the addition of TEMPO has only a minor effect on the efficiency of product generation, more reactive radical traps such as the 2-methyl-2nitrosopropane dimer substantially reduced the yield of the rearrangement product, which points to the intermediacy of a short-lived radical pair.…”

Regio- and Diastereoselective Synthesis of E-Allylic Amines through Hydroalkylation of Terminal Alkynes

“…24), and tertiary ( 16) alkyl substituents performed well. The reaction could be successfully performed in the presence of oxygen and nitrogen heterocycles (15, 19, 21, and 33), protected amines (21,25), protected alcohols (13,17), alkyl chlorides (29), esters (30), nitriles ( 22), and acetals (35).…”

“…A plausible alternative mechanism consistent with the results of TEMPO experiments involves the formation of a radical pair followed by the radical recombination that is faster than the diffusion from the solvent cage. 29 To investigate this possibility, we explored the stereochemistry of the reaction (Scheme 5). A stoichiometric reaction with enantioenriched αchloro phthalimide 56 provided a nearly racemic product 38 (6% ee).…”