Palladium-Catalyzed Direct Arylation of Methyl Sulfoxides with Aryl Halides

Abstract

The palladium-catalyzed α-arylation of unactivated sulfoxides has been developed. The weakly acidic α-protons of sulfoxides are reversibly deprotonated by LiOtBu, and a palladium phosphine complex facilitates the arylation. A variety of aryl methyl sulfoxides were coupled with aryl bromides. More challenging coupling partners, such as alkyl methyl sulfoxides (including dimethyl sulfoxide) and aryl chlorides proved to be suitable under the optimized conditions. This method was utilized to synthesize bioactive benzyl sulfoxide intermediates.

Palladium‐Catalyzed Direct α‐Arylation of Benzyl Thioethers with Aryl Bromides

“…As outlined in Table 1, entries 1–3, alkoxide bases MO- t Bu (M = Li, Na, K) did not generate detectable amounts of benzylation products, suggesting they would not be applicable in the arylation of thioethers. Interestingly, these results are in contrast to the arylation of aryl methyl sulfoxides [6] and sulfones, [7] where LiO- t Bu was the optimal base (Scheme 1). On the other hand, benzylation products were observed in increasing conversions, with LiN(SiMe 3 ) 2 < NaN(SiMe 3 ) 2 < KN(SiMe 3 ) 2 (entries 4–6).…”

“…[5] Our initial efforts focused on the direct α-arylation of C–H bonds adjacent to sulfur(II), such as found in sulfoxides, including the parent DMSO (Scheme 1A). [6] Based on these results, we then examined α-C–H arylation of sulfur(IV) of methyl and benzyl sulfones. [7] In both cases, the reactions were promoted by a palladium catalyst employing Kwong’s indole-based phosphine [8, 9] in the presence of LiO- t -Bu at 110 °C (Scheme 1).…”

When cross-coupling partners meet indolylphosphines

“…Suzuki-Miyaura coupling, Direct C-H arylation Kwong and Walsh [24,57,[59][60][61][62] Amidole-phos (L3)…”

“…Walsh and co-workers reported the first Pd-catalyzed direct α-arylation of unactivated sulfoxides with aryl halides [57]. A variety of aryl methyl sulfoxides were successfully coupled with aryl bromides under the Pd(OAc) 2 /NPCy o-Toldole-phos (L2c) system (Table 7, entries [11][12][13][14].…”

Chemo‐ and Regioselective C(sp3)H Arylation of Unactivated Allylarenes by Deprotonative Cross‐Coupling

“…In our efforts to address such challenges, we recently initiated a program for the functionalization of weakly acidic sp 3 -hybridized C–H bonds by palladium catalyzed deprotonative cross-coupling processes (DCCP). Substrates that have been successfully functionalized using this approach include diarylmethanes, [3, 4] sulfoxides, [5] sulfones, [6] amides, [7] and chromium-activated benzylic amines (to produce enantioenriched diarylmethylamines). [8] Based on these results, we hypothesized that it might be possible to functionalize allylbenzene derivatives and control chemo- and regioselectivity.…”