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. 2021 Jul 21;143(28):10760-10769.
doi: 10.1021/jacs.1c05422. Epub 2021 Jul 8.

Rh(II)-Catalyzed Alkynylcyclopropanation of Alkenes by Decarbenation of Alkynylcycloheptatrienes

Mauro Mato  1   2 , Marc Montesinos-Magraner  1 , Arnau R Sugranyes  1   2 , Antonio M Echavarren  1   2
Affiliations

Rh(II)-Catalyzed Alkynylcyclopropanation of Alkenes by Decarbenation of Alkynylcycloheptatrienes

Mauro Mato et al. J Am Chem Soc. .

Abstract

Alkynylcyclopropanes have found promising applications in both organic synthesis and medicinal chemistry but remain rather underexplored due to the challenges associated with their preparation. We describe a convenient two-step methodology for the alkynylcyclopropanation of alkenes, based on the rhodium(II)-catalyzed decarbenation of 7-alkynyl cycloheptatrienes. The catalytic system employed circumvents a fundamental problem associated with these substrates, which usually evolve via 6-endo-dig cyclization or ring-contraction pathways under metal catalysis. This unique performance unlocks a rapid access to a diverse library of alkynylcyclopropanes (including derivatives of complex drug-like molecules), versatile intermediates that previously required much lengthier synthetic approaches. Combining experiments and DFT calculations, the complete mechanistic picture for the divergent reactivity of alkynylcycloheptatrienes under metal catalysis has been unveiled, rationalizing the unique selectivity displayed by rhodium(II) complexes.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthetic Approaches and Relevance of Alkynylcyclopropanes
Scheme 2
Scheme 2. Diverse Reactivity Scenarios of 7-Alkynyl-1,3,5-cycloheptatrienes under Metal Catalysis
For 4a–d and 4g, [Au] = [(JohnPhos)Au(MeCN)]SbF6 (5 mol %). For more details about the known reactivity of 7-alkynyl cycloheptatrienes, see previous publications by our group (4a–d), and by Gandon and co-workers (4e, 4f).
Scheme 3
Scheme 3. Scope of the Alkynylcyclopropanation Reaction and Late-Stage Functionalization
Standard conditions: 1 equiv of cycloheptatriene 1 (usually 0.3–0.5 mmol) with 4 equiv of alkene 2, using [Rh2(TFA)4] (5 mol %) as catalyst, in PhMe/hexane (1:1, 0.15 M) at 80 °C until full consumption of 1 (usually 16–24 h). Isolated yield. 60 °C instead of 80 °C. CHCl3 as solvent. 2 equiv of 2 instead of 4. 1 equiv of alkene 2 and 1.5 equiv of 1. PhMe/CHCl3 (2:1) as solvent. Obtained as a 1:1 mixture of the two possible cis products. NPhthal = N-phthalimide.
Scheme 4
Scheme 4. Scope of the Silylalkynylcyclopropanation and One-Pot Assembly of Terminal Alkynylcyclopropanes
Standard conditions: 1 equiv of 1 (usually 0.3–0.5 mmol) with 4 equiv of alkene 2, using [Rh2(TFA)4] (5 mol %) as catalyst, in CHCl3 (0.15 M) at 80 °C until full consumption of 1 (usually 16–24 h). Isolated yield. For the synthesis of terminal alkynes, [Si] = TMS was used in all cases. NPhthal = N-phthalimide.
Scheme 5
Scheme 5. Transfer of a Germanylalkynylcarbene Unit
1 equiv of 1z with 4 equiv of 2, using [Rh2(TFA)4] (5 mol %) as catalyst, in CHCl3 (0.15 M) at 80 °C for 20 h. Isolated yield. NPhthal = N-phthalimide.
Scheme 6
Scheme 6. Gram-Scale Alkynylcyclopropanation: Reactivity and Diversification of Versatile Intermediates
[Au] = [(JohnPhos)Au(MeCN)]SbF6.
Scheme 7
Scheme 7. Gold(I)-Catalyzed Synthesis of Allenylcyclopropanes
[Au] = [(JohnPhos)Au(MeCN)]SbF6. Isolated yield.
Scheme 8
Scheme 8. Reaction Kinetics and Mechanistic Experiments
Scheme 9
Scheme 9. Free-Energy Profile Calculated by DFT for the Divergent Reactivity of 7-Alkynylcycloheptatrienes under Metal Catalysis (kcal·mol–1 at 25 °C)
Scheme 10
Scheme 10. DFT Model of the Alkynylcyclopropanation of Styrene to Rationalize the cis-Diastereoselectivity (kcal·mol–1 at 25 °C)
In the NCI representations, strong attractive interactions are blue (C–C bond formation), weak attractive interactions are green (noncovalent interactions), and strong repulsive interactions are red. Color code: Rh, violet; O, red; F, cyan; C, gray; H, white.
See this image and copyright information in PMC

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