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. 2017 Sep 18;56(39):11906-11910.
doi: 10.1002/anie.201705107. Epub 2017 Aug 1.

Decarboxylative Alkynylation

Joel M Smith  1 , Tian Qin  1 , Rohan R Merchant  1 , Jacob T Edwards  1 , Lara R Malins  1 , Zhiqing Liu  2 , Guanda Che  2 , Zichao Shen  2 , Scott A Shaw  3 , Martin D Eastgate  4 , Phil S Baran  1
Affiliations

Decarboxylative Alkynylation

Joel M Smith et al. Angew Chem Int Ed Engl. .

Abstract

The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates.

Keywords: alkynylation; homologation; iron catalysis; nickel catalysis; redox-active esters.

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Figures

Figure 1
Figure 1
(A) Synthesis of an unnatural alkynyl amino acid derivative. B) Traditional synthetic routes from carboxylic acids to terminal alkynes and design of a new terminal alkyne cross-coupling synthetic strategy. (C) Optimization of reaction conditions. TCNHPI = N-hydroxytetrachloro-phthalimide, DIC = N,N′-diisopropylcarbodiimide.
Scheme 1
Scheme 1
Scope of the Ni and Fe-catalyzed decarboxylative alkynylation with TCNHPI redox-active esters. a) Reaction conditions with formula image: RAE (1.0 equiv), NiCl2•6H2O (20 mol %), L1 (20 mol%), ethynylzinc chloride (2.5 equiv), THF/DMF, rt, 12 h. Reaction conditions with formula image: RAE (1.0 equiv), FeBr2•H2O (20 mol%), alkynyl Grignard (1.5 equiv), NMP/THF, 15 min, −15 °C. b) 4.0 mmol scale. c) NMR yield using internal standard. d) in situ reaction with TCNHPI (1.1 equiv) and DIC (1.1 equiv). e) 2.0 mmol scale. f) For details, see Supporting Information. g) in situ reaction with TCNHPI (1.1 equiv) and DCC (1.1 equiv).
Scheme 2
Scheme 2
(A) Radical ring opening of a cyclopropyl methylene RAE (45). (B) Formal Arndt-Eistert transformation. (C) Functionalization of terminal alkyne 26. (D) Copper-assisted azide-alkyne cycloaddition on peptide 44.
Scheme 3
Scheme 3
(A) Brief synthesis of intermediate 53 en route to the synthesis of (+)-sapinofuranone B. (C) Scalable synthesis of alkynyl amino acid derivative and subsequent diversification (See SI for experimental details).
See this image and copyright information in PMC

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