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Synlett 2019; 30(15): 1787-1790
DOI: 10.1055/s-0039-1690130
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© Georg Thieme Verlag Stuttgart · New York

Rhodium(III)-Catalyzed Cyclopropanation of Unactivated Olefins Initiated by C–H Activation

Erik J. T. Phipps
,
Tiffany Piou
,
Tomislav Rovis  ∗
Department of Chemistry, Columbia University, New York, NY, 10027, USA   Email: tr2504@columbia.edu
› Author Affiliations

We thank the National Institute of General Medical Sciences (NIGMS, Grant No. GM80442) for support.
Further Information

Publication History

Received: 23 May 2019

Accepted after revision: 11 July 2019

Publication Date:
22 July 2019 (online)

 
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Abstract

We have developed a rhodium(III)-catalyzed cyclopropanation of unactivated olefins initiated by an alkenyl C–H activation. A variety of 1,1-disubstituted olefins undergo efficient cyclopropanation with a slight excess of alkene stoichiometry. A series of mechanistic interrogations implicate a metal carbene as an intermediate.


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Key words

C–H activation - carbenoid - metal carbene - cyclopropanation - Rhodium(III) catalysis

The synthesis of cyclopropane-containing molecules has intrigued synthetic organic chemists for years because of their prevalence in synthetic targets[1] as well as their susceptibility as reactive intermediates.[2] A plethora of robust methods have been developed to afford cyclopropane motifs from alkenes. Generally, Simmons–Smith and diazo decomposition are regarded as the two most powerful methods for the cyclopropanation of alkenes.[3] [4] Simmons–Smith-type reactions are well-established to deliver cyclopropanes from unactivated olefins with high stereoselectivity; however, these methods are limited by the substitution pattern of the carbenoid reagent[5] and the stoichiometric use of zinc.[6] Rhodium-catalyzed diazo decomposition[7] has also provided complimentary reactivity to access stereodefined cyclopropanes[7] with a more diverse substitution pattern albeit with a notable shortcoming: many of these methods require the use of high-energy diazo compounds.[8]

N-Enoxyphthalimides constitute valuable alternatives to potentially explosive diazo compounds and pyrophoric organozinc reagents due to the mild conditions and the ­allure of C–H functionalization reactions (Scheme [1]).[9]

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Scheme 1 Reactivity profile of N-enoxyphthalimides

Our initial report in 2014 showed that aryl N-enoxyphthalimides undergo C–H activation and smoothly undergo [2+1] annulation with activated olefins bearing electron-withdrawing groups, affording trans-cyclopropanes in good yield and diastereoselectivity.[10] In a follow-up report, we demonstrated that tuning the electronic properties of the cyclopentadienyl (Cp) ligand as well as the phthalimide ring affords access to the cis-cyclopropane scaffold.[11] N-Enoxyphthalimides are also competent reagents for 1,2-carboamination of activated alkenes.[12] Cramer and co-worker have rendered the trans-cyclopropanation reaction asymmetric by employing their chiral Cp ligand to provide trans-cyclopropanes in high e.r.[13] Most recently, we reported a strategy for a directed cyclopropanation of allylic alcohols.[14] The pendant hydroxyl group is necessary for both reactivity and diastereocontrol. In an effort to expand the scope of this transformation, we set out to examine cyclopropanation of unactivated olefins.

A slight modification of our previously developed reaction conditions proved optimal for a general method: [Cp*CF3RhCl2]2 as a pre-catalyst in the presence of 2 equivalents of CsOAc in TFE at room temperature affords cyclopropane 3 in good yield. Importantly, a stoichiometry of 1 equivalent of N-enoxyphthalimide 1 and 1.2 equivalents of unactivated olefin 2 is sufficient (Scheme [2]).

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Scheme 2 Scope of unactivated olefins.[15] Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), [Cp*CF3RhCl2]2 (5 mol%), and CsOAc (0.2 mmol) in 2,2,2-trifluoroethanol (TFE, 0.2 M) at 24 °C for 12 h.

We began by examining 3-methylenepentane as a coupling partner and found modest reactivity as cyclopropane 3aa was afforded in 40% yield. A number of exocyclic alkenes proved to be excellent participants in this reaction giving a wide range of [2.n]spirocyclic ketones. We interrogated the effect of different size carbocycles ranging from four- to eight-membered rings (3ab–af). Notably, methylenecyclohexane gives [2.5]spirocycle 3ad in near quantitative yield. Both tosyl- and Boc-protected methylene piperidines display good reactivity affording cyclopropane 3ag in 72% and 3ah in 84% yield, respectively. Cyclopropanation of a methylene cyclohexane bearing a substituent at the 4-position proceeds efficiently, delivering cyclopropane 3ai in 97% yield and good diastereoselectivity (8.6:1 d.r.).[16]

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Scheme 3 Scope of N-enoxyphthalimides

Varying para- (3bd–dd) and meta- (3ed–gd) arene substitution on the enoxyphthalimide is tolerated, with each substrate displaying excellent yields. ortho-Fluorine-containing enoxyphthalimide delivers cyclopropane 3hd in 59% yield (Scheme [3]). Naphthyl enoxyphthalimide gives cyclopropane 3id in 67% yield. Finally, an alkyl-substituted N-enoxyphthalimide is also a competent substrate, affording cyclopropane 3jd in 98% yield.

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Scheme 4 Mechanistic experiments

Finally, we sought to interrogate the mechanism of this reaction (Scheme [4]). Subjecting 1a to the reaction conditions using TFE-d 1 leads to no deuterium incorporation upon re-isolation of 1a (Scheme [4], eq. 1) In another experiment, we subjected 1a and 2c to the reaction conditions again with TFE-d 1 that gives cyclopropane 3ac′ in 85% yield. From the analysis of the product, we observed a reversible deuterium exchange event at the α-position (54% D incorporation, Scheme [4], eq. 2). We next probed the role of the phthalimide ring by subjecting 1a to 2 equivalents of CsOAc in TFE and observed the formation of dioxazoline 4 in 59% yield, indicating TFE opens the phthalimide ring (Scheme [4], eq. 3). Finally, we subjected 4 to 2c and the reaction conditions. However, only trace product was observed indicating 4 does not significantly contribute as a competent reaction intermediate (Scheme [4], eq. 4). On the basis of these mechanistic experiments, we propose the mechanism shown in Scheme [5].

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Scheme 5 Proposed mechanism

First, the pre-catalyst undergoes salt metathesis with CsOAc to form the active catalyst I. Concurrently, 1 is opened by the solvent to give II which then intercepts I, before dioxazoline 4 formation, and undergoes C–H activation via concerted metalation–deprotonation to afford intermediate III. At this stage, we believe intermediate III displays enolic character to reversibly wash in deuterium before ligand exchange of 2. After exchanging acetic acid for alkene that gives intermediate V, we propose the formation of a Rh-carbene, intermediate V, via cleavage of the N–O bond. Intermediate V then gives way to the desired cyclopropane product.

In summary, we have developed a Rh(III)-catalyzed cyclopropanation protocol for N-enoxyphthalimides and unactivated olefins. The N-enoxyphthalimide has been shown to undergo C–H activation that leads to a proposed metal carbene to induce a [2+1] annulation with alkenes that give a diverse range of cyclopropyl ketones in mild conditions.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690130.
  • Supporting Information


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Zoom Image
Scheme 1 Reactivity profile of N-enoxyphthalimides
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Scheme 2 Scope of unactivated olefins.[15] Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), [Cp*CF3RhCl2]2 (5 mol%), and CsOAc (0.2 mmol) in 2,2,2-trifluoroethanol (TFE, 0.2 M) at 24 °C for 12 h.
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Scheme 3 Scope of N-enoxyphthalimides
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Scheme 4 Mechanistic experiments
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Scheme 5 Proposed mechanism