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. 2014 Nov 26;136(47):16563-73.
doi: 10.1021/ja5083014. Epub 2014 Nov 13.

Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism

Reto Frei  1 , Matthew D Wodrich, Durga Prasad Hari, Pierre-Antoine Borin, Clément Chauvier, Jérôme Waser
Affiliations
Free PMC article

Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism

Reto Frei et al. J Am Chem Soc. .
Free PMC article

Abstract

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking. In this article, we describe the mechanism and full scope of the alkynylation of thiols using ethynyl benziodoxolone (EBX) hypervalent iodine reagents. Computations led to the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of thioalkynes.

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Figures

Scheme 1
Scheme 1. Heteroatoms-Substituted Alkynes: The Best of Two Worlds, but How To Access Them?
Scheme 2
Scheme 2. Method To Access Thioalkynes Based on Umpolung of Sulfur or Alkyne
Scheme 3
Scheme 3. Initial Speculative Mechanism for the Alkynylation Reaction
Figure 1
Figure 1
Computed geometries (M06-2X/def2-SVP level) of the van der Waals complexes a0 and b0 for TIPS-EBX (1c) and thiolate 2′. Free energies computed at the PBE0-dDsC/TZ2P//M06-2X/def2-SVP level and include solvation correction in THF determined using COSMO-RS.
Figure 2
Figure 2
Reaction free energy profile [PBE0-dDsC/TZ2P//M06-2X/def2-SVP level in implicit THF solvent (COSMO-RS)] for the two possible mechanistic pathways a (blue) and b (red) for the reaction of TIPS-EBX (1a) with thiolate 2′. *Positive deltaE at the M06-2X/def2-SVP level.
Figure 3
Figure 3
Computed geometries (M06-2X/def2-SVP level) of the relevant structures.
Figure 4
Figure 4
Reaction free energy profile [PBE0-dDsC/TZ2P//M06-2X/def2-SVP level in implicit THF solvent (COSMO-RS)] for the two possible mechanistic pathways a (blue) and b (red) for the reaction of Me-EBX (1b) with thiolate 2′.
Scheme 4
Scheme 4. Scope of the Alkynylation for Benzylic Thiol 14 (A), Thioglycosides 15 (B), and Amino Acid Derivative 16 (C)
See Supporting Information for experimental details (solvents, base).
Scheme 5
Scheme 5. Alkynylation of Thioacids 22 (A) and Sodium Hydrogen Sulfide (23) (B)
See this image and copyright information in PMC

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