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. 2021 Jun 2;143(21):7909-7914.
doi: 10.1021/jacs.1c03459. Epub 2021 May 24.

Site-Selective C-H alkylation of Complex Arenes by a Two-Step Aryl Thianthrenation-Reductive Alkylation Sequence

Beatrice Lansbergen  1 , Paola Granatino  1 , Tobias Ritter  1
Affiliations

Site-Selective C-H alkylation of Complex Arenes by a Two-Step Aryl Thianthrenation-Reductive Alkylation Sequence

Beatrice Lansbergen et al. J Am Chem Soc. .

Erratum in

Abstract

Herein, we present an undirected para-selective two-step C-H alkylation of complex arenes useful for late-stage functionalization. The combination of a site-selective C-H thianthrenation with palladium-catalyzed reductive electrophile cross-coupling grants access to a diverse range of synthetically useful alkylated arenes which cannot be accessed otherwise with comparable selectivity, diversity, and practicality. The robustness of this transformation is further demonstrated by thianthrenium-based reductive coupling of two complex fragments.

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Conflict of interest statement

The authors declare the following competing financial interest(s): A patent application (number EP18204755.5, Germany) dealing with the use of thianthrene and its derivatives for C-H functionalization has been filed and F.B. and T.R. may benefit from royalty payments.

Figures

Scheme 1
Scheme 1. Strategies for Undirected C–H Alkylation of Arenes
(a) Conceptual representation of various strategies for undirected C–H alkylation of arenes. (b) Experimental results for palladium-catalyzed aryl C–H alkylation via bromination versus thianthrenation. Two-step yield given for compounds 1 and 2. aProduct not detected by LCMS, GCMS, 1H NMR spectroscopy, and 13C NMR spectroscopy (see the Supporting Information for details).
Scheme 2
Scheme 2. Mechanistic Investigation
(a) Zinc insertion experiment. (b) Radical clock cyclization of allyl ether thianthrenium salt TT-2 under standard conditions. (c) Radical trapping experiment with TEMPO under standard conditions. (d) Mechanistic hypothesis. S = solvent or pyridine. L1 = amphos. n.o. = not observed.
Scheme 3
Scheme 3. Substrate Scope for the Alkylation of Aryl Thianthrenium Salt
General conditions unless otherwise noted: aryl thianthrenium salt (0.3 mmol), alkyl iodide (0.6 mmol), PdCl2(amphos)2 (15.0 μmol), pyridine (0.15 mmol), DMF (0.3 M). a>20:1 ratio of i-PrAr:n-PrAr product. b3.0 mmol scale. cPyridine was omitted. dReactions carried with aryl thianthrenium salt (0.2 mmol) and MgCl2 (3 equiv) as additive. Yields in blue correspond to yield of C–H thianthrenation. Yields in orange correspond to yield of alkylation of aryl thianthrenium salts. Yields of thianthrenation were obtained from refs (5), (6a), (6b), (6c), (6d), and (6e).
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