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. 2023 Dec 6;145(48):25954-25961.
doi: 10.1021/jacs.3c10024. Epub 2023 Nov 27.

Bicyclopentylation of Alcohols with Thianthrenium Reagents

Zibo Bai  1 , Beatrice Lansbergen  1 , Tobias Ritter  1
Affiliations

Bicyclopentylation of Alcohols with Thianthrenium Reagents

Zibo Bai et al. J Am Chem Soc. .

Erratum in

Abstract

Herein we present the first method for the synthesis of bicyclo[1.1.1]pentyl (BCP) alkyl ethers from alcohols. The reaction uses BCP-thianthrenium reagents and is catalyzed by a dual copper/photoredox catalyst system. Unlike known alkylations of tertiary alcohols via carbocation intermediates, our Cu-mediated radical process circumvents the labile BCP carbocations. The approach demonstrates a broad tolerance for functional groups when applied to primary, secondary, and even tertiary alcohols. In addition, we highlight the utility of this method in late-stage functionalizations of both natural products and pharmaceuticals as well as in the rapid construction of BCP analogs of known pharmaceuticals that would otherwise be difficult to access.

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Conflict of interest statement

The authors declare the following competing financial interest(s): T.R. and Z.B. may benefit from thianthrene compound-based sales.

Figures

Figure 1
Figure 1
Synthesis of BCP alkyl ethers. LG, leaving group; PC, photocatalyst.
Figure 2
Figure 2
Reaction development and a mechanistic investigation. aYields were determined by 19F NMR. bIsolated yield. cThe TEMPO–BCP adduct was observed by HRMS. dThe Stern–Volmer plot of Cu(acac)2 was corrected due to the inner filter effect.
Figure 3
Figure 3
Substrate scope. aYields were determined by 19F NMR or 1H NMR.
Figure 4
Figure 4
Mechanistic analysis of the synthesis of BCP–TT+ reagents. (A) Chain process of synthesis of BCP–TT+ reagents. (B) BDEs of different TT+ reagents. (C) Comparison of CF3-TT+ (31) and CF2H-TT+ (32). Ar = 3-fluoro-4-methoxyphenyl.
Figure 5
Figure 5
Synthesis of BCP pharmaceutical analogs. (A) Synthesis of BCP-fluoxetine hydrochloride. (B) Synthesis of BCP-butoxycaine. (C) Synthesis of BCP-safinamide. (D) Synthesis of BCP-pranlukast. (E) Further transformations of 43.
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