Rh(III)-Catalyzed Mild Coupling of Nitrones and Azomethine Imineswith Alkylidenecyclopropanes via C−H Activation: Facile Access toBridged CyclesDachang Bai,*,† Teng Xu,† Chaorui Ma,† Xin Zheng,† Bingxian Liu,† Fang Xie,‡ and Xingwei Li*,†,‡

†Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering,Henan Normal University, Xinxiang 453007, China‡Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China

*S Supporting Information

ABSTRACT: Bridged cycles are an important class of struc-tural motif in various biologically active molecules. Rh(III)-catalyzed C−H activation of nitrones and azomethine imines inthe context of dipolar addition with alkylidenecyclopropanes(ACPs) have been realized. By taking advantage of the ringstrain in ACPs, the reaction with aryl nitrones deliveredbridged [3.2.1] bicyclic isoxazolidines, and reaction withazomethine imines afforded bridged tricyclic pyrazolones under the same conditions, where both the nitrone and azomethineimine act as a dipolar directing group. All the reactions occurred under mild conditions with broad substrates scope, highefficiency, and >20:1 diastereoselectivity. The synthetic applications of this protocol have also been demonstrated.

KEYWORDS: rhodium(III), alkylidenecyclopropane, nitrone, azomethine imine, dipolar addition

■ INTRODUCTION

Isoxazolidine and pyrazolone skeletons are not only importantsynthetic intermediates but are also an integral and commonpart of many biologically active natural products, drugs, andagrochemicals.1,2 In addition, as important functional mole-cules, bridged heterocyclic systems containing isoxazolidinesand pyrazolones also exhibited unique properties.3 For example,flueggine A was isolated from the twigs and leaves of Flueggeavirosa.4a The withaferin A analogues are potent apoptoticinducers and offer an attractive approach for the discovery anddevelopment of anticancer agents.4b The azo-bond in suchbridged compounds also has the potential to specifically detectazo-reductase-expressing bacteria (Scheme 1).4c Althoughbridged cyclic products could be synthesized through theDiels−Alder reaction, metal-catalyzed cycloaddition reactions,and other annulation reactions, the development of a newreaction to construct complex structures containing isoxazoli-dine and pyrazolone motifs calls for further exploration, espe-cially starting from readily available substrates through a step-economic process.5

Transition metal-catalyzed C−H bond activation of areneshas been extensively explored as an increasingly importantstrategy for delivering complex organic structures.6 In general,installation of a directing group (DG) constitutes the mostconvenient and effective strategy to ensure both high selec-tivity and activity of the arene substrate. To address thelimitation of using a directing group, multifunctionality hasbeen imparted to DGs so that besides being a chelating groupthey also function as a nucleophilic, electrophilic, and oxidizingfunctional group in postcoupling transformations under in situ

conditions, which has significantly broadened the applicationsof C−H activation chemistry and provided numerous methodsfor rapid construction of cyclic products.6−9 The multi-functionality of DGs is particularly manifested in Cp*Rh(III)-catalyzed C−H activation because the Rh(III)−C speciesresulting from C−H activation is more polarized and allows forefficient intramolecular interactions with the DG.7 Thus, a largenumber of novel and efficient synthetic methods have beendeveloped by coupling arenes with typical unsaturated cou-pling partners such as alkynes, alkenes, allenes, and diazocompounds.7−9

Given the significance of bridged cycles in organic synthesis,it is highly desirable to access these structures via C−Hactivation. However, examples in this regard are rather limited.Previously, they have been accessed via C−H activation andring-retentive coupling with a bicyclic olefin (Scheme 2a).8

In 2016, we reported the synthesis of benzylidene-bridge[3.2.1] bicyclic products through Rh(III)-catalyzed C−H acti-vation of nitrones and coupling with diarylcyclopropenones,where the nitrone acts as a dipolar directing group (Scheme 2b).9g

This has extended the role of arylnitrones as a class of arene inC−H activation.9 However, the scope of the arene is limited toarylnitrones and the scope of diarylcyclopropenone substrates isalso narrow. Very recently, we further reported the synthesis ofbridged cycles via Co(III)-catalyzed C−H activation en route tointramolecular Diels−Alder reaction, but the arenes have been

Received: February 22, 2018Revised: March 30, 2018Published: April 3, 2018

Research Article

pubs.acs.org/acscatalysisCite This: ACS Catal. 2018, 8, 4194−4200

© 2018 American Chemical Society 4194 DOI: 10.1021/acscatal.8b00746ACS Catal. 2018, 8, 4194−4200

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limited to electron-rich ones.10 To realize structural diversity ofbridged cycles, we resort to different classes of dipolar DGs forC−H activation using nonactivated olefins as a dipolarophile,instead of using an electron-poor, activated one generated fromdiarylcyclopropenones. To effect intramolecular dipolar addi-tion, an unactivated olefin moiety is generated in situ and thelow reactivity of the unactivated olefin should be compensated.To address this challenge, we focused on alkylidenecyclopro-panes (ACPs)11i,j which are strained and readily availablesubstrates.11 Insertion of an M−C bond into ACP triggers ringcession to give an M−alkyl, which leads to an olefin via β-Celimination.7i,11l In fact, related properties of ACPs have beenemployed by Cui only in one report of [4 + 3] annulation reac-tions via C−H activation of a specific class of amide, and thering scission via β-C elimination was only observed for furansystems (Scheme 2c).12 Despite the design, the followingpitfalls remain. (1) The M−alkyl species may undergo insertioninto the (electrophilic) directing group without any dipolaraddition. (2) The ACPs may undergo coupling without ringscission (Scheme 2c). (3) The oxidative conditions that arerequired to regenerate an active Rh(III) catalyst may pose chal-lenges in compatibility with the subsequent dipolar addition.(4) The regioselectivity and diastereoselectivity of the dipolaraddition need to be controlled.9h We now report a mild andoxidative synthesis of [3.2.1] bridged cycles by integration ofC−H activation and the dipolar addition assisted by differentdipolar DGs (Scheme 2d).

Scheme 1. Examples of Natural Products and Bioactive Compounds Containing a Bridged Skeleton

Scheme 2. Bridged Cycles Obtained via C−H Activation and Applications of ACPs in C−H Activation

Table 1. Optimization Studiesa

entry catalyst (mol %) oxidant additive T (°C) yield (%)b

1c [Cp*RhCl2]2 AgOAc − 25 232 [Cp*RhCl2]2 AgOAc − 25 623 [Cp*RhCl2]2 Cu(OAc)2 − 25 trace4 [Cp*RhCl2]2 AgOAc − 40 835d [Cp*RhCl2]2 AgOAc − 40 766e [Cp*RhCl2]2 AgOAc − 40 407 [Cp*RhCl2]2 AgOAc − 0 148f [Cp*Rh(OAc)2] AgOAc − 40 829 [Cp*RhCl2]2 AgOAc K2CO3 25 4010 [Cp*RhCl2]2 AgOAc PivOH 25 2411g [Cp*RhCl2]2 AgOAc − 40 5112 [Cp*RhCl2]2 − − 25 −13 − AgOAc − 25 −

aReaction conditions: nitrone 1a (0.2 mmol), ACP 2a (0.5 mmol),[Cp*RhCl2]2 (5 mol %), AgOAc (0.5 mmol), additive (0.3 equiv),CF3CH2OH (2.0 mL), 24 h. bIsolated yields. c2a (0.25 mmol) wasused. dAgOAc (1.0 mmol). eAgOAc (0.25 mmol). f[Cp*Rh(OAc)2](8 mol %). g[Cp*RhCl2]2 (2.5 mol %).

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■ RESULTS AND DISCUSSION

We commenced our studies by exploring the reaction param-eters of the coupling of N-tert-butyl-α-phenylnitrone (1a) with1-(4-tert-phenyl)methylenecyclopropane (2a, Table 1). With[Cp*RhCl2]2 being a catalyst, a coupling did occur in thepresence of AgOAc oxidant in trifluoroethanol (TFE) to affordthe desired bridged cycle 3a in 23% yield as a single diaste-reomer even at room temperature (entry 1). Increasing theamount of ACP improved the yield to 62% (entry 2). SwitchingAgOAc to Cu(OAc)2 only afforded traces of 3a (entry 3). Theyield was improved to 83% when the reaction was conducted at40 °C (entry 4). Further increasing or decreasing the amountof AgOAc resulted in lower efficiency. It was found thatCp*Rh(OAc)2 exhibited comparable catalytic activity, and addi-tion of acids or bases such as K2CO3 and PivOH failed toimprove the coupling efficiency (entries 9 and 10). The reac-tion was sensitive to the solvent, and trifluoroethanol proved tobe optimal. Decreasing the catalyst loading to 2.5 mol % signif-icantly retarded the reaction (entry 11). Our control experi-ments also confirmed that both the rhodium(III) catalyst andAgOAc were necessary (entries 12 and 13). In contrast, noproduct was detected when N-Ph or -Bn nitrones wereemployed, likely because of limited access to the required(Z)-configuration of the nitrone due to lack of steric hindrance.In addition, these nitrones are also more prone to hydrolysis.

Having identified the optimal conditions, we next examinedthe scope and generality of this coupling system (Scheme 3).Arylnitrones bearing various electron-donating and -withdrawinggroups at the para position were fully tolerated (3b−j, 43−91%).The reaction also worked well for meta Me- and Cl- substitutednitrones (3k, 3l), where the C−H activation occurred selectivelyat the less hindered ortho position. Introduction of an orthoMe-, Cl-, or Br-group only slightly attenuated the reactionefficiency (3m−p) likely due to steric reasons. The identity ofthe bicyclic structure 3s has been confirmed as a (Z)-configuredexocyclic olefin (see Supporting Information) by X-ray crys-tallography (CCDC 1585979), and the stereochemistry of the

Scheme 3. Scope of the Coupling of Nitrones with ACPsa

aReaction conditions: nitrone 1 (0.2 mmol), ACP 2 (0.5 mmol),[Cp*Rh(OAc)2] (8 mol %), AgOAc (0.5 mmol), and CF3CH2OH(2.0 mL) at 40 °C, isolated yields. b[Cp*RhCl2]2 (5 mol %) was usedinstead of [Cp*Rh(OAc)2].

Scheme 4. Scope of the Coupling of Azomethine Imines withACPsa

aReaction conditions: azomethine imine 4 (0.2 mmol), ACP 2(0.5 mmol), [Cp*Rh(OAc)2] (8 mol %), AgOAc (0.5 mmol),CF3CH2OH (2.0 mL), 40 °C, isolated yields. b[Cp*RhCl2]2 (5 mol %)was used instead of [Cp*Rh(OAc)2].

Scheme 5. Derivatization of a Bridged Cycle

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olefin stands in sharp contrast to that reported by Cui andco-workers.12 The ACP substrate was further extended tobenzylidenecyclopropanes bearing an alkyl, halogen, and OMegroup at different positions, affording the bridged bicycles inconsistently good yield (3q−x). In all cases only a single diaste-reomeric product was obtained. The ACP substrates are limitedto monoaryl substitution. 1,2-Disubstituted ACPs and 1-alkyl-substituted ACPs all failed to undergo any efficient couplingeven at a higher temperature, indicating the limitation of thiscoupling system.To better define the scope of this reaction system, we extended

the arene to azomethine imines,13 another class of 1,3-dipole(Scheme 4). To our delight, the directly analogous bridgedtricycle (5a) was obtained in 84% yield under the same con-ditions, indicating the generality of this protocol. We then exam-ined the scope of the azomethine imine. Introduction of tBu,methoxy, halogen, ester, CF3, and CN groups to the para posi-tion afforded the desired products (5b−i) in moderate to

high yield. The reaction also tolerated a meta or ortho methylgroup in the azomethine imine, and the corresponding bridgedproducts were obtained in 78% (5j) and 59% (5k) yields, respec-tively. A series of 1-aryl-methylenecyclopropanes were alsocompatible, as in the isolation of tricyclic products 5l−t in45−82% yields.The synthetic utility of the bridged product has been demon-

strated in several derivatization reactions (Scheme 5). Exhaus-tive reduction of 3a by LiAlH4 produced diarylmethane 6 in66% yield. In the presence of Pd/C, 3a was reduced by H2

(1 atm) to give the corresponding saturated bridged cycle 7 in52% yield as the sole diastereomer. Treatment of 3a with O3

at −78 °C afforded dione 8 in 75% yield. When treated withZn/HOAc, the N−O bond in 3a undergoes reductive cleavageto give amine 9 in 69% yield as a single diastereomer, which is auseful synthetic building block.A series of experiments have been conducted to probe the

reaction mechanism,6,7 We first synthesized rhodacyclic

Scheme 6. Mechanistic Studies

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complex 10 according to a literature report.14a As a catalystprecursor, complex 10 successfully catalyzed the coupling of4a and 2a to afford the bridged product 5a in 46% yield, whichindicated relevancy of C−H bond activation in this trans-formation (Scheme 6a). A kinetic isotope effect (KIE) value of6.7 was then obtained for the competitive coupling of a mixtureof 1a and 1a-d5 with 2a at a low yield under the standardconditions (Scheme 6b). A similar KIE value was also obtainedin the competitive coupling between 4a and 4a-d5 with 2a(Scheme 6c). These results indicated that cleavage of the C−Hbond was likely involved in the turnover-limiting step. When anequimolar mixture of 4g and 4i was allowed to competitivelycouple with 2a, products 5g and 5i were obtained in 40% and25% yield, respectively, on the basis of 1H NMR analysis of theproduct mixture, indicating that the electron-poor azomethineimine reacted at a slightly higher rate (Scheme 6d). In anothercompetitive reaction using two electronically different ACPs,the products 5m and 5l were obtained in 3:1 ratio, where theelectron-poor ACP exhibited slightly higher reactivity (Scheme 6e),which is consistent with the higher tendency of insertion into amore electron-poor olefin.On the basis of our experiments and related literature reports,7,9

a proposed catalytic cycle is given in Scheme 7. An active catalyst[Cp*Rh(OAc)2] was generated via halide abstraction. C−Hactivation of 1a produced a rhodacyclic intermediate A. It islikely that the N-tBu in the nitrone offers steric protection againsthydrolysis of the nitrone, and its steric effect also ensuresZ-configuration of the nitrone moiety that is the reactivegeometry for C−H activation. Coordination of ACP 2a withsubsequent migratory insertion of the Rh−aryl bond provides aRh(III)−alkyl intermediate B, which undergoes β-C elimi-nation and ring scission to provide a Rh(III)−alkyl species C.Subsequent β-H elimination of C takes place to give a dieneD together with a Rh(III)−hydride. The Rh(III) active catalystis regenerated upon oxidized by AgOAc. The diene D isproposed to undergo intramolecular [3 + 2] cycloaddition toafford the bridged product 3a likely in the absence of any metalcatalyst.9h,14 This dipolar addition is exo with respect to theregioselectivity.15 The alternative endo cycloaddition has beenselectively realized in our Ru(II)-catalyzed system for intra-molecular addition of nitrones and a polarized olefin bearing a

perfluoroalkyl group.9j However, the endo selectivity was notobserved in this system, likely due to the electronic effect of theweakly biased olefin and the small steric hindrance. The [3,3,0]-cyclic product from the endo addition is thermodynamicallymore stable and is generally obtained for olefins with a rela-tively large substituent.14b,15e

■ CONCLUSIONSIn summary, we have demonstrated an operationally simpleapproach to access bridged bicyclic and tricyclic heterocy-cles through Rh(III)-catalyzed C−H activation/annulation ofarylnitrones and azomethine imines with alkylidenecyclopro-panes. These systems provided bridged products containingisoxazolidine and pyrazolone skeletons as a single diastereomer.The reactions occurred under mild conditions with broadsubstrate scope. The synthetic utility of the bridged cycles havebeen demonstrated in diverse derivatization reactions. Mech-anistic studies including KIE and competition experiments havebeen performed. Further studies on the C−H activation ofother arenes that highlight the unique role of DGs are currentlyunderway in our laboratories.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acscatal.8b00746.

Crystallographic data of compound 3s, screening data,experimental procedures, and NMR and HRMS spectra(PDF)CIF data for 3s (CIF)

■ AUTHOR INFORMATIONCorresponding Author*E-mail: baidachang@126.com.*E-mail: xwli@dicp.ac.cn.

ORCIDDachang Bai: 0000-0001-7342-2966Bingxian Liu: 0000-0001-9872-9876Xingwei Li: 0000-0002-1153-1558

Scheme 7. Proposed Mechanism of the Coupling of Nitrone with ACP

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NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe NSFC (nos. 21525208 and 21472186), research fund fromHenan Normal University (5101034011009), and the Educa-tion Department of Henan Province Natural Science ResearchProgram (18A150010) are gratefully acknowledged.

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