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. 2024 Jul 10;146(27):18606-18615.
doi: 10.1021/jacs.4c05136. Epub 2024 Jun 28.

Remote Functionalization by Pd-Catalyzed Isomerization of Alkynyl Alcohols

Simone Scaringi  1 , Baptiste Leforestier  1 , Clément Mazet  1
Affiliations

Remote Functionalization by Pd-Catalyzed Isomerization of Alkynyl Alcohols

Simone Scaringi et al. J Am Chem Soc. .

Abstract

In recent years, progress has been made in the development of catalytic methods that allow remote functionalizations based on alkene isomerization. In contrast, protocols based on alkyne isomerization are comparatively rare. Herein, we report a general Pd-catalyzed long-range isomerization of alkynyl alcohols. Starting from aryl-, heteroaryl-, or alkyl-substituted precursors, the optimized system provides access preferentially to the thermodynamically more stable α,β-unsaturated aldehydes and is compatible with potentially sensitive functional groups. We showed that the migration of both π-components of the carbon-carbon triple bond can be sustained over several methylene units. Computational investigations served to shed light on the key elementary steps responsible for the reactivity and selectivity. These include an unorthodox phosphine-assisted deprotonation rather than a more conventional β-hydride elimination in the final tautomerization event.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Overview of the thermodynamic factors associated with alkyne isomerizations (A, B) and yne–diene isomerizations (C, D), their challenges, and limitations. (A–D) Examples of alkyne and yne–diene isomerizations. (E) This work: long-range isomerization of alkynyl alcohols into α,β-unsaturated carbonyls.
Figure 2
Figure 2
Scope of the Pd-catalyzed isomerization of alkynes into α,β-unsaturated carbonyls. Reaction scale: 0.5 mmol. All products were obtained with E/Z > 20:1. Regioisomeric ratio (rr) measured by 1H NMR of the crude reaction mixture using an internal standard and expressed as the ratio between 5 and all other isomers. (A) Isomerization of aryl alkynyl alcohols. (B) Isomerization of heteroaryl alkynyl alcohols. (C) Isomerization of alkyl alkynyl alcohols. (D) Isomerization with extended chain length. a3 h. bIsolated together with other regioisomers.
Figure 3
Figure 3
(A) Isomerization of allene 6w. (B) Evaluation of the reversibility of the catalytic reaction. (C) Isomerization of an enantioenriched substrate. (D) Isomerization of alkynyl methyl ether 1w.Me. aContains ca. 5% of 4b. bConversion reaches 37% after 3 and 5 h.
Figure 4
Figure 4
Free energy (kcal/mol) of intermediates along the isomerization pathway relative to substrate 1a/SM1–1. Calculated at the DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D3(BJ)/def2-mTZVPP level of theory with CPCM (toluene). Black boxes along the arrows indicate the highest-energy transition state between the linked intermediates in the isomerization sequence, with reference to SM1–1 and C6. The nature of said transition state is indicated in parentheses.
Figure 5
Figure 5
Computed free-energy profile for sequence A of the Pd-catalyzed isomerization of alkynyl alcohol 1a/SM1–1. Level of theory: DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D3(BJ)/def2-mTZVPP with CPCM(toluene). * TSA.4–5 was located as the climbing image of a nudged elastic band (NEB-CI) calculation.
Figure 6
Figure 6
Computed free-energy profile for sequence B of the Pd-catalyzed isomerization of alkynyl alcohol 1a/SM1–1. Level of theory: DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D3(BJ)/def2-mTZVPP with CPCM(toluene).
Figure 7
Figure 7
Computed free-energy profile for sequences C and D of the Pd-catalyzed isomerization of alkynyl alcohol 1a/SM1–1. Level of theory: DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D3(BJ)/def2-mTZVPP with CPCM(toluene).
Figure 8
Figure 8
Computed free-energy profile for sequence E of the Pd-catalyzed isomerization of alkynyl alcohol 1a/SM1–1. Level of theory: DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D3(BJ)/def2-mTZVPP with CPCM(toluene).
See this image and copyright information in PMC

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