Practical, Modular, and General Synthesis of Benzofurans through Extended Pummerer Annulation/Cross‐Coupling Strategy

Abstract

Operationally simple, efficient, and widely applicable Pummerer annulations of simple phenols with ketene dithioacetal monoxides, with the aid of trifluoroacetic anhydride, have been shown to provide a variety of benzofurans having a methylthio group at the 2-position. Subsequent and newly developed nickel-catalyzed arylation at the methylthio group culminates in diversity-oriented synthesis of multisubstituted benzofurans. Our extended Pummerer annulation/ cross-coupling sequence is powerful enough to synthesize biologically active natural products as well as highly fluorescent benzofuran derivatives. Scheme 1. Modular synthesis of substituted benzofurans. EDG = electron-donating group, EWG = electron-withdrawing group, Tf = trifluoromethanesulfonyl, TFAA = trifluoroacetic anhydride.Scheme 2. Proposed mechanism.

Regioselective synthesis of C3 alkylated and arylated benzothiophenes

“…Based upon our previous and present experimental observations, we propose that an interrupted Pummerer reaction to form I or II , via addition of oxygen of phenols 2 (refs 42, 43, 46) or S E 2′ addition of the silanes 5 (refs 34, 35, 45) and 7 (refs 36, 37, 38) to the sulfur of activated benzothiophene S -oxide III , precedes a charge accelerated [3,3]-sigmatropic rearrangement, resulting in complete regioselective C–C bond formation at the expense of a C–H bond (Fig. 2).…”

“…Recently, we34353637383940 and others41424344454647484950515253545556 reported the metal-free, sulfoxide directed57 C–H functionalization of a variety of molecular scaffolds, which was enabled by an interrupted Pummerer reaction28. Spurred on by these recent achievements, we considered the use of benzothiophene S -oxides 1 for the synthesis of important C3-functionalized benzothiophenes, as the corresponding sulfonium salts I and II , formed after reaction with the coupling partners, lack aromaticity about the five-membered ring and should therefore undergo facile C–C bond formation via [3,3]-sigmatropic rearrangement58, thus delivering unexplored reactivity not accessible in benzothiophenes.…”

“…Thus, 1a , readily prepared from the corresponding benzothiophene by straightforward oxidation with m CPBA/BF 3 ·OEt 2, was treated with trifluoroacetic acid anhydride (TFAA), and reacted with the phenol coupling partner424346. The interrupted Pummerer reaction and, surprisingly, the resulting [3,3]-sigmatropic rearrangement occurred at or below ambient temperature ( cf .…”

Cascades of Interrupted Pummerer Reaction‐Sigmatropic Rearrangement

“…After screening reaction conditions, we found that trifluoroacetic anhydride (TFAA) is the best activator that allows various KDMs to engage in the annulation (Scheme 14). [23] Under the second-generation conditions, unsubstituted, alkyl-substituted, and aryl-substituted KDMs participated to afford 25 a-h in high yields. The scope of phenols is as wide as that in Scheme 12: A variety of functional groups in 25 k-n were compatible and the annulation was regioselective for meta-or ortho-substituted phenols.…”

Palladium‐Catalyzed Zinc‐Amide‐Mediated CH Arylation of Fluoroarenes and Heteroarenes with Aryl Sulfides

“…[2] In contrast, the development of new reactions of aryl sulfides has only been reported only scarcely.T ransition-metalcatalyzed cross-coupling reactions of aryl sulfides [3] are difficult to achieve because sulfur species can permanently poisont he catalysta nd C(sp 2 )ÀSb onds are rather strong and difficult to cleave. To overcome these difficulties, reactive Grignardr eagents were employed as nucleophiles [4] or aryl sulfides were used that have special structures that facilitate efficient conversion. [5][6][7] We are interested in catalytic transformationso fo rganosulfur compounds [4e-g, 8] and recently developed general cross-coupling reactions of aryl sulfides with arylzinc reagents by using ap alladium-NHC complex as catalyst.…”