Rh(III)-Catalyzed Mild Coupling of Nitrones and Azomethine Imines

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Rh(III)-Catalyzed Mild Coupling of Nitrones and Azomethine Imines with Alkylidenecyclopropanes via C-H Activation: Facile Access to Bridged Cycles Dachang Bai, Teng Xu, Chaorui Ma, Xin Zheng, Bingxian Liu, Fang Xie, and Xingwei Li ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00746 • Publication Date (Web): 03 Apr 2018 Downloaded from http://pubs.acs.org on April 3, 2018

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Rh(III)-Catalyzed Mild Coupling of Nitrones and Azomethine Imines with Alkylidenecyclopropanes via C-H Activation: Facile Access to Bridged Cycles Dachang Bai,† Teng Xu,† Chaorui Ma,† Xin Zheng,† Bingxian Liu,† Fang Xie,‡ 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

ABSTRACT: Bridged cycles are an important class of structural motif in various biologically active molecules. Rh(III)-catalyzed C-H activation of nitrones and azomethine imines in the context of dipolar addition with alkylidenecyclopropanes (ACPs) have been realized. By taking advantage of the ring strain in ACPs, the reaction with aryl nitrones delivered bridged [3.2.1] bicyclic isoxazolidines, and reaction with azomethine imines afforded bridged tricyclic pyrazolones under the same conditions, where both the nitrone and azomethine imine act as a dipolar directing group. All the reactions occurred under mild conditions with broad substrates

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scope, high efficiency, 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 important synthetic intermediates, but also an integral and common part of many biologically active natural products, drugs, and agrochemicals.1,2 In addition, as important functional molecules, bridged heterocyclic systems containing isoxazolidines and pyrazolones also exhibited unique properties.3

For example,

Flueggines A was isolated from the twigs and leaves of Flueggea virosa.4a The withaferin Aanalogues are potent apoptotic inducers and offer an attractive approach for the discovery and development of anticancer agents.[4b] The azo-bond in such bridged compounds also has the potential to specifically detect azo-reductase expressing bacteria (Scheme 1).4c Although bridged cyclic products could be synthesized through the Diels-Alder reaction, metal-catalyzed cycloaddition reactions, and other annulation reactions, the development of a new reaction to construct complex structures containing isoxazolidine and pyrazolone motifs calls for further exploration, especially starting from readily available substrates through a step-economic process.5


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Scheme 1. Examples of Natural products and Bioactive Compounds Containing a Bridged Skeleton. Transition metal-catalyzed C-H bond activation of arenes has been extensively explored as an increasingly important strategy for delivering complex organic structures.6 In general, installation of a directing group (DG) constitutes the most convenient and effective strategy to ensure both high selectivity and activity of the arene substrate. To address the limitation of using a directing group, multifunctionality has been imparted to DGs so that besides being a chelating group they also function as a nucleophilic, electrophilic, and oxidizing functional group in postcoupling transformations under the in situ conditions, which has significantly broadened the applications of C-H activation chemistry and provided numerous methods for rapid construction of cyclic products.6-9 The multifunctionality of DGs is particularly manifested in Cp*Rh(III)catalyzed C-H activation because the Rh(III)-C species resulting from C-H activation is more polarized and allows for efficient intramolecular interactions with the DG.7 Thus, a large number of novel and efficient synthetic methods have been developed by coupling arenes with typical unsaturated coupling partners such as alkynes, alkenes, allenes, and diazo compounds.7-9 Given the significance of bridged cycles in organic synthesis, it is highly desirable to access these structures via C-H activation. However, examples in this regard are rather limited. Previously, they have been accessed via C-H activation and ring-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 activation 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 in C-H activation.9 However, the scope of the arene is limited to arylnitrones and the scope of diarylcyclopropenone substrates is also


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narrow. Very recently, we further reported the synthesis of bridged cycles via Co(III)-catalyzed C-H activation en route to intramolecular Diels-Alder reaction, but the arenes have been limited to electron-rich ones.10 To realize structural diversity of bridged cycles, we resort to different classes of dipolar DGs for C-H activation using non-activated olefins as a dipolarophile, instead of using an electron-poor, activated one generated from diarylcyclopropenones. To effect intramolecular dipolar addition, an unactivated olefin moiety is generated in situ and the low reactivity of the unactivated olefin should be compensated. To address this challenge, we focused on alkylidenecyclopropanes (ACPs)11i,j which are strained and readily available substrates.11 Insertion of an M-C bond into ACP triggers ring cession to give an M-alkyl, which leads to an olefin via β-C elimination.7i,

11l

In fact, related properties of ACPs have been

employed by Cui only in one report of [4+3] annulation reactions via C-H activation of a specific class of amide, and the ring scission via β-C elimination was only observed for furan systems (Scheme 2c).12 Despite the design, the following pitfalls remain. (1) The M-alkyl species may undergo insertion into the (electrophilic) directing group without any dipolar addition. (2) The ACPs may undergo coupling without ring scission (Scheme 2c). (3) The oxidative conditions that are required to regenerate an active Rh(III) catalyst may pose challenges in compatibility with the subsequent dipolar addition. (4) The regioselectivity and diastereoselectivity of the dipolar addition need to be controlled.9h We now report a mild and oxidative synthesis of [3.2.1] bridged cycles by integration of C-H activation and the dipolar addition assisted by different dipolar DGs (Scheme 2d).


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Scheme 2. Bridged Cycles Obtained via C-H Activation and Applications of ACPs in C-H Activation RESULTS AND DISCUSSION We commenced our studies by exploring the reaction parameters of the coupling of N-tertbutyl-a-phenylnitrone (1a) with 1-(4-tert-phenyl)methylenecyclopropane (2a, Table 1). With [Cp*RhCl2]2 being a catalyst, a coupling did occur in the presence of AgOAc oxidant in trifluoroethanol (TFE) to afford the desired bridged cycle 3a in 23% yield as a single diastereomer even at room temperature (entry 1). Increasing the amount of ACP improved the yield to 62% (entry 2). Switching AgOAc to Cu(OAc)2 only afford traces of 3a (entry 3). The yield was improved to 83% when the reaction was conducted at 40 oC (entry 4). Further increasing or decreasing the amount of AgOAc all resulted in lower efficiency. It was found that Cp*Rh(OAc)2 exhibited comparable catalytic activity, and addition of acids or bases such as K2CO3 and PivOH all failed to improve the coupling efficiency (entries 9 and 10). The reaction


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was sensitive to the solvent, and trifluoroethanol proved to be optimal. Decreasing the catalyst loading to 2.5 mol % significantly retarded the reaction (entry 11). Our control experiments also confirmed that both the rhodium(III) catalyst and AgOAc were necessary (entries 12 and 13). In contrast, no product was detected when N-Ph or -Bn nitrones were employed, 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. Table 1. Optimization Studiesa

entry catalyst (mol %)

oxidant

additive T (oC)

yield (%)b

1c

[Cp*RhCl2]2

AgOAc

--

25

23

2

[Cp*RhCl2]2

AgOAc

--

25

62

3

[Cp*RhCl2]2

Cu(OAc)2 --

25

trace

4

[Cp*RhCl2]2

AgOAc

--

40

83

5d

[Cp*RhCl2]2

AgOAc

--

40

76

6e

[Cp*RhCl2]2

AgOAc

--

40

40

7

[Cp*RhCl2]2

AgOAc

--

0

14


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8f

[Cp*Rh(OAc)2]

AgOAc

--

40

82

9

[Cp*RhCl2]2

AgOAc

K2CO3

25

40

10

[Cp*RhCl2]2

AgOAc

PivOH

25

24

11g

[Cp*RhCl2]2

AgOAc

--

40

51

12

[Cp*RhCl2]2

--

--

25

--

AgOAc

--

25

--

13 a

--

Reaction 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) was used. dAgOAc (1.0 mmol). eAgOAc (0.25 mmol). g

f

[Cp*Rh(OAc)2] (8 mol %).

[Cp*RhCl2]2 (2.5 mol %). Having identified the optimal conditions, we next examined the scope and generality of this

coupling system (Scheme 3). Arylnitrones bearing various electron-donating and -withdrawing groups at the para position were fully tolerated (3b-3j, 43-91%), The reaction also worked well for meta Me- and Cl- substituted nitrones (3k, 3l), where the C-H activation occurred selectively at the less hindered ortho position. Introduction of an ortho Me-, Cl- and Br- group only slightly attenuated the reaction efficiency (3m-3p) likely due to steric reasons. The identity of the bicyclic structure 3s has been confirmed as a (Z)-configured exocyclic olefin by X-ray crystallography (CCDC 1585979), and the stereochemistry of the olefin stands in sharp contrast to that reported by Cui and coworkers.12 The ACP substrate was further extended to benzylidenecyclopropanes bearing an alkyl, halogen, and OMe group at different positions, affording the bridged bicycles in consistently good yield (3q-3x). In all cases only a single


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diastereomeric product has been obtained. The ACP substrates are limited to mono-aryl substitution. 1,2-Disubstituted ACPs and 1-alkyl substituted ACPs all failed to undergo any efficient coupling even at a higher temperature, indicating the limitation of this coupling system.

a

Reaction 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 oC, isolated yields. b[Cp*RhCl2]2 (5 mol %) were used instead of [Cp*Rh(OAc)2]. Scheme 3. Scope of the Coupling of Nitrones with ACPsa 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 bridged


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tricycle (5a) was obtained in 84% yield under the same conditions, indicating the generality of this protocol. We then examined the scope of the azomethine imine. Introduction of tBu, methoxy, halogen, ester, CF3, and CN groups to the para position afforded the desired products (5b-5i) in moderate to high yield. The reaction also tolerated a meta or ortho- methyl group in the azomethine imine, and the corresponding bridged products were obtained in 78% (5j) and 59% (5k) yields, respectively. A series of 1-aryl-methylenecyclopropanes were also compatible, as in the isolation of tricyclic products 5l-5t in 45-82% yields.

a

Reaction 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 oC, isolated yields. b[Cp*RhCl2]2 (5 mol %) were used instead of [Cp*Rh(OAc)2].


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Scheme 4. Scope of the Coupling of Azomethine Imines with ACPsa The synthetic utility of the bridged product has been demonstrated in several derivatization reactions (Scheme 5). Exhaustive reduction of 3a by LiAlH4 produced diarylmethane 6 in 66% yield. In the presence of Pd/C, 3a was reduced by H2 (1 atm) to give the corresponding saturated bridged cycle 7 in 52% yield as the sole diastereomer. Treatment of 3a with O3 at -78 oC afforded a dione 8 in 75% yield. When treated with Zn/HOAc, the N-O bond in 3a undergoes reductive cleavage to give amine 9 in 69% yield as a single diastereomer, which is a useful synthetic building block.

Scheme 5. Derivatization of a Bridged Cycle. A series of experiments have been conducted to probe the reaction mechanism,[6-7] We first synthesized rhodacyclic complex 10 according to a literature report.[13a] As a catalyst precursor, complex 10 successfully catalyzed the coupling of 4a and 2a to afford the bridged product 5a in 46% yield, which indicated relevancy of C-H bond activation in this transformation (Scheme 6a). A kinetic isotope effect (KIE) value of 6.7 was then obtained for the competitive coupling of a mixture of 1a and 1a-d5 with 2a at a low yield under the standard conditions (Scheme 6b). A


10

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similar KIE value was also obtained in the competitive coupling between 4a and 4a-d5 with 2a (Scheme 6c). These results indicated that cleavage of the C-H bond was likely involved in the turnover-limiting step. When an equimolar mixture of 4g and 4i was allowed to competitively couple with 2a, products 5g and 5i were obtained in 40% and 25% yield, respectively, on the basis of 1H NMR analysis of the product mixture, indicating that the electron-poor azomethine imine reacted at a slightly higher rate (Scheme 6d). In another competitive reaction using two electronically different ACP, the products 5m and 5l were obtained in 3:1 ratio, where the electron-poor ACP exhibited slightly higher reactivity (Scheme 6e), which is consistent with the higher tendency of insertion into a more electron-poor olefin.


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Scheme 6. Mechanistic Studies. 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-H activation of 1a produced a rhodacyclic intermediate A. It is likely that the N-tBu in the nitrone offers steric protection against hydrolysis of the nitrone, and its steric effect also ensures Z-


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configuration of the nitrone moiety that is the reactive geometry for C-H activation. Coordination of ACP 2a with subsequent migratory insertion of the Rh-aryl bond provides a Rh(III)-alkyl intermediate B, which undergoes β-C elimination and ring scission to provide a Rh(III)-alkyl species C. Subsequent β-H elimination of C takes place to give a diene D together with a Rh(III)-hydride. The Rh(III) active catalyst is regenerated upon oxidized by AgOAc. The diene D is proposed to undergo intramolecular [3+2] cycloaddition to afford the bridged product 3a likely in the absence of any metal catalyst.9h,14 This dipolar addition is exo with respect to the regioselectivity.15 The alternative endo cycloaddition has been selectively realized in our Ru(II)catalyzed system for intramolecular addition of nitrones and a polarized olefin bearing a perfluoroalkyl group.9j However, the endo selectivity was not observed in this system, likely due to the electronic effect of the weakly biased olefin and the small steric hindrance. The [3,3,0]cyclic product from the endo addition is thermodynamically more stable and is generally obtained for olefins with a relatively large substituent.14b,15e

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


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CONCLUSIONS In summary, we have demonstrated an operationally simple approach to access bridged bicyclic and tricyclic heterocycles through Rh(III)-catalyzed C-H activation/annulation of arylnitrones and azomethine imines with alkylidenecyclopropanes. These systems provided bridged products containing isoxazolidine and pyrazolone skeletons as a single diastereomer. The reactions occurred under mild conditions with and broad substrates scope. The synthetic utility of the bridged cycles has been demonstrated in diverse derivatization reactions. Mechanistic studies including KIE and competition experiments have been performed. Further studies on the C-H activation of other arenes that highlight the unique role of DGs are currently underway in our laboratories. ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author [email protected] Notes The authors declare no competing financial interests. Supporting Information Crystallographic data of compound 3s, screening data, experimental procedures, and NMR and HRMS spectra (PDF and CIF). The Supporting Information is available free of charge on the ACS Publications website. ACKNOWLEDGMENT


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The NSFC (Nos. 21525208 and 21472186), research fund from Henan Normal University (5101034011009), and the Education Department of Henan Province Natural Science Research Program (18A150010) are gratefully acknowledged.

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[5] For selected reviews, see: (a) Filippini, M.-H.; Rodriguez, J. Synthesis of Functionalized Bicyclo[3.2.1]octanes and Their Multiple Uses in Organic Chemistry. Chem. Rev. 1999, 99,

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Mechanism and Scope. Chem. Rev. 2011, 111, 1315-1345. (i) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Towards Mild Metal-Catalyzed C–H Bond Activation. Chem. Soc. Rev. 2011, 40, 4740-4761. (j) Gutekunst, W. R.; Baran, P. S. C–H Functionalization Logic in Total Synthesis. Chem. Soc. Rev. 2011, 40, 1976-1991. (k) McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent Developments in Natural Product Synthesis using Metal-catalysed C– H bond Functionalization. Chem. Soc. Rev. 2011, 40, 1885-1898. (l) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960-9009. (m) Li, B. -J.; Shi, Z. -J.; From C(sp2)–H to C(sp3)–H: Systematic Studies on Transition Metal-catalyzed Oxidative C–C Formation Chem. Soc. Rev. 2012, 41, 5588-5598. (n) Zheng, C.; You, S.-L. Recent Development of Direct Asymmetric Functionalization of Inert C–H bonds. RSC Adv. 2014, 4, 6173-6214. (o) Guo, X. -X.; Gu, D. -W.; Wu, Z.-X; Zhang, W.-B. Copper-Catalyzed C–H Functionalization Reactions: Efficient Synthesis of Heterocycles. Chem. Rev. 2015, 115, 1622-1651. (p) Gandeepan, P.; Cheng, C.-H. Advancements in the Synthesis and Applications of Cationic N-Heterocycles through Transition Metal-Catalyzed C−H Activation. Chem. Asian J. 2016, 11, 448-460. (q)


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Moselage, M.; Li, J.; Ackermann, L. Cobalt-Catalyzed C–H Activation. ACS Catal. 2016, 6, 498-525. [7] For selected reviews on rhodium-catalyzed C–H activation, see: (a) Satoh, T.; Miura, M. Oxidative Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium Catalysis. Chem. Eur. J. 2010, 16, 11212-11222. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Rhodium Catalyzed Chelation-Assisted C–H Bond Functionalization Reactions. Acc. Chem. Res. 2012, 45, 814-825. (c) Kuhl, N.; Schrçder, N.; Glorius, F. Formal SN-Type Reactions in Rhodium(III)-Catalyzed C-H Bond Activation. Adv. Synth. Catal. 2014, 356, 1443-1460. (d) Song, G.-Y.; Li, X.-W. Substrate Activation Strategies in Rhodium(III)-Catalyzed Selective Functionalization of Arenes. Acc. Chem. Res. 2015, 48, 1007-1020. (e) Ye, B.-H.; Cramer, N. Chiral Cyclopentadienyls: Enabling Ligands for Asymmetric Rh(III)-Catalyzed C–H Functionalizations. Acc. Chem. Res. 2015, 48, 13081318. (f) Yang, L.; Huang, H. M. Transition-Metal-Catalyzed Direct Addition of Unactivated C–H Bonds to Polar Unsaturated Bonds. Chem. Rev. 2015, 115, 3468-3517. (g) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Mild Metal-Catalyzed C–H Activation: Examples and Concepts. Chem. Soc. Rev. 2016, 45, 2900-2936. (h) Wang, F.; Yu, S. -J.; Li, X.-W. Transition Metal-catalysed Couplings Between Arenes and Strained or Reactive Rings: Combination of C–H Activation and Ring Scission. Chem. Soc. Rev. 2016, 45, 6462-6477. [8] (a) Dong, W. R; Parthasarathy, K.; Cheng, Y.; Pan, F. F; Bolm, C. Hydroarylations of Heterobicyclic Alkenes through Rhodium-Catalyzed Directed C-H Functionalizations of SAryl Sulfoximines. Chem. Eur. J. 2014, 20, 15732-15736. (b) Cheng, H.-C.; Dong, W.-R.; Dannenberg, C. A.; Dong, S.-X.; Guo, Q.-Q.; Bolm, C. Ruthenium-Catalyzed


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Hydroarylations of Oxa- and Azabicyclic Alkenes. ACS Catal. 2015, 5, 2770-2773. (c) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt-Catalyzed C−H Activation and Intramolecular Nucleophilic Addition. Angew. Chem. Int. Ed. 2016, 55, 4308-4311. (d) Cheng, Y.; Parthasarathy, K.; Bolm, C. Rhodium(III)-Catalyzed Annulation

of

N-Methoxybenzamides

with

Heterobicyclic

Alkenes

by

C–H

Functionalization: Synthesis of Benzo[b]phenanthridinones. Eur. J. Org. Chem. 2017, 2017, 1203-1206. (e) Wang, X. M.; Lerchen, A.; Gensch, T.; Knecht, T.; Daniliuc, C. G.; Glorius, F. Combination of Cp*RhIII-Catalyzed C−H Activation and a Wagner–MeerweinType Rearrangement. Angew. Chem. Int. Ed. 2017, 56, 1381-1384. [9](a) Song, G.-Y; Chen, D.; Su, Y.; Han, K.-L; Pan, C.-L.; Jia, A.-Q; Li, X.-W. Isolation of Azomethine Ylides and Their Complexes: Iridium(III)-Mediated Cyclization of Nitrone Substrates Containing Alkynes. Angew. Chem. Int. Ed. 2011, 50, 7791-7796. (b) Yan, H.; Wang, H.-L.; Li, X.-C.; Xin, X.-Y.; Wang, C.-X.; Wan, B.-S. Rhodium-Catalyzed C-H Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3Diaryl-Substituted Indoles. Angew. Chem. Int. Ed. 2015, 54, 10613-10617. (c) Dateer, R. B.; Chang, S. Selective Cyclization of Arylnitrones to Indolines under External OxidantFree Conditions: Dual Role of Rh(III) Catalyst in the C–H Activation and Oxygen Atom Transfer. J. Am. Chem. Soc. 2015, 137, 4908-4911. (d) Yang, Y.-X.; Wang, X.; Li, Y.-C.; Zhou, B. A [4+1] Cyclative Capture Approach to 3H-Indole-N-oxides at Room Temperature by Rhodium(III)-Catalyzed C-H Activation. Angew. Chem. Int. Ed. 2015, 54, 15400-15404; (e) Zhou, Z.; Liu, G.-X.; Chen, Y.; Lu, X.-Y. Rhodium(III)-Catalyzed Redox-Neutral C-H Annulation of Arylnitrones and Alkynes for the Synthesis of Indole


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Derivatives. Adv. Synth. Catal. 2015, 357, 2944-2950. (f) Pi, C.; Cui, X.; Wu, Y. IridiumCatalyzed Direct C–H Sulfamidation of Aryl Nitrones with Sulfonyl Azides at Room Temperature. J. Org. Chem. 2015, 80, 7333-7339. (g) Xie, F.; Yu, S.-J.; Qi, Z.-S.; Li, X.W. Nitrone Directing Groups in Rhodium(III)-Catalyzed C−H Activation of Arenes: 1,3Dipoles versus Traceless Directing Groups. Angew. Chem. Int. Ed. 2016, 55, 15351-15355. (h) Bai, D.-C.; Jia, Q.-Q.; Xu, T.; Zhang, Q.-Q.; Wu, F.; Ma, C.-R.; Liu, B.-X.; Chang, J.B.; Li, X.-W. Rhodium(III)-Catalyzed C–H Activation of Nitrones and Annulative Coupling with Nitroalkenes. J. Org. Chem., 2017, 82, 9877-9884; (i) Zhao, Y. S.; Li, S. Q.; Zheng, X. S.; Tang, J. B.; She, Z. J.; Gao, G.; You, J. S. Rh/Cu-Catalyzed Cascade [4+2] Vinylic C−H O-Annulation and Ring Contraction of α-Aryl Enones with Alkynes in Air. Angew. Chem. Int. Ed. 2017, 56, 4286-4289. (j) Li, Y.- Y.; Xie, F.; Liu, Y.; Yang, X.-F.; Li, X.-W. Regio- and Diastereoselective Access to Fused Isoxazolidines via Ru(II)Catalyzed C–H Activation of Nitrones and Coupling with Perfluoroalkylolefins. Org. Lett. 2018, 20. 437-440. [10]Zhou, X.-K.; Pan, Y.-P.; Li, X.-W. Catalyst-Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles. Angew. Chem. Int. Ed. 2017, 56, 8163-8167. [11]For reviews, see: (a) Binger, P.; Buech, H. M. Cyclopropenes and Methylenecylopropanes as Multifunctional Reagents in Transition Metal Catalyzed Reactions. Top. Curr. Chem., 1987, 135, 77-151; (b) Brandi, A.; Goti, A. Synthesis of Methylene- and Alkylidenecyclopropane Derivatives. Chem. Rev. 1998, 98, 589-636. (c) Nakamura, E.; Yamago, S. Thermal Reactions of Dipolar Trimethylenemethane Species. Acc. Chem. Res. 2002, 35, 867-877. (d) Nakamura, I.; Yamamoto, Y. Transition Metal-Catalyzed Reactions


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of Methylenecyclopropanes. Adv. Synth. Catal. 2002, 344, 111-129. (e) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Heterocycles from Alkylidenecyclopropanes. Chem. Rev. 2003, 103, 1213-1270. (f) Rubin, M.; Rubina, M.; Gevorgyan, V. Transition Metal Chemistry of Cyclopropenes and Cyclopropanes. Chem. Rev, 2007, 107, 3117-3179. (g) Masarwa, A.; Marek, I. Selectivity in Metal-Catalyzed Carbon-Carbon Bond Cleavage of Alkylidenecyclopropanes. Chem.-Eur. J. 2010, 16, 9712-9721. (h) Shi, M.; Lu, J.-M.; Wei, Y.; Shao, L.-X. Rapid Generation of Molecular Complexity in the Lewis or Brønsted AcidMediated Reactions of Methylenecyclopropanes. Acc. Chem. Res. 2012, 45, 641-652. (i) Lu, B.-L.; Dai, L.; Shi, M. Strained Small Rings in Gold-catalyzed Rapid Chemical Transformations. Chem. Soc. Rev. 2012, 41, 3318-3339. (j) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti. A. Progress in the Synthesis and Transformations of Alkylidenecyclopropanes and Alkylidenecyclobutanes. Chem. Rev. 2014, 114, 7317-7420. (k) Yu, L.-Z.; Chen, K.; Zhu, Z.-S.; Shi, M. Recent Advances in the Chemical Transformations of Functionalized Alkylidenecyclopropanes (FACPs). Chem. Commun. 2017, 53, 5935-5945. (l) Fumagalli, G.; Stanton, S.; Bower. J. F. Recent Methodologies That Exploit C–C Single-Bond Cleavage of Strained Ring Systems by Transition Metal Complexes. Chem. Rev. 2017, 117, 9404-9432. [12]Cui, S.-L.; Zhang, Y.; Wu. Q.-F. Rh(III)-catalyzed C–H Activation/Cycloaddition of Benzamides and Methylenecyclopropanes: Divergence in Ring Formation. Chem. Sci. 2013, 4, 3421-3426. [13]For selected reports, see: (a) Zhen, W.-C.; Wang, F.; Zhao, M.; Du, Z.-Y.; Li, X. W. Rhodium(III)-Catalyzed Oxidative C-H Functionalization of Azomethine Ylides. Angew. Chem. Int. Ed. 2012, 51, 11819-11823. (b) Chen, Y.-Y.; Wang, F.; Zhen, W.-C.; Li, X. W.


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Rhodium(III)-Catalyzed Annulation of Azomethine Ylides with Alkynes via C-H Activation. Adv. Synth. Catal. 2013, 355, 353-359. (c) Xie, F.; Qi, Z.-S.; Yu, S.-J.; Li, X.W. Rh(III)- and Ir(III)-Catalyzed C–H Alkynylation of Arenes under Chelation Assistance. J. Am. Chem. Soc. 2014, 136,4780-4787. [14](a) Jadhav, A. M.; Bhunia, S.; Liao, H.-Y.; Liu, R.-S. Gold-Catalyzed Stereoselective Synthesis of Azacyclic Compounds through a Redox/[2 + 2 + 1] Cycloaddition Cascade of Nitroalkyne Substrates. J. Am. Chem. Soc. 2011, 133, 1769-1771.

(b) Dulla, B.;

Tangellamudi, N. D.; Balasubramanian, S.; Yellanki, S.; Medishetti, R.; Banote, R. K.; Chaudhari, G. H.; Kulkarni, P.; Iqbal, J.; Reiser, O.; Pal, M. Isovanillin Derived N(Un)substituted Hydroxylamines Possessing an ortho-Allylic Group: Valuable Precursors to Bioactive N-Heterocycles. Org. Biomol. Chem. 2014, 12, 2552-2558. [15] For select examples of 1,3-dipolar cycloadditions of nitrone: (a) Gothelf, K. V.; Jørgensen, K. A. Asymmetric 1,3-Dipolar Cycloaddition Reactions. Chem. Rev. 1998, 98, 863-910. (b) Gothelf, K. V.; Jørgensen, K. A. Catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones. Chem. Commun. 2000, 1449-1458. (c) Gioia, C.; Fini, F.; Mazzanti, A.; Bernardi, L.; Ricci, A. J. Organocatalytic Asymmetric Formal [3 + 2] Cycloaddition with in situ-Generated N-Carbamoyl Nitrones. J. Am. Chem. Soc. 2009, 131, 9614-9615. (d) Ma, X.-P.; Zhu, J.-F.; Wu, S.-Y.; Chen, C.-H.; Zou, N.; Liang, C.; Su, G.-F.; Mo. D.-L. Cycloaddition of Fluorenone N-Aryl Nitrones with Methylenecyclopropanes and Sequential 1,3-Rearrangement: An Entry to Synthesis of Spirofluorenylpiperidin-4-ones. J. Org. Chem. 2017, 82, 502-511. (e) Rabasa-Alcaniz, F.; Asensio, A.; Sanchez-Rosello, M.; Escolano, M.; del Pozo, C.; Fustero, S. Intramolecular Nitrone Cycloaddition of α-


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(Trifluoromethyl)styrenes. Roles of the CF3 Group in the Regioselectivity. J. Org. Chem. 2017, 82, 2505-2514.


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Rh(III)-Catalyzed Mild Coupling of Nitrones and Azomethine Imines

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