Synthesis of Unsaturated N-Heterocycles by Cycloadditions of

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Synthesis of Unsaturated N-Heterocycles by Cycloadditions of Aziridines and Alkynes Jian-Jun Feng, and Junliang Zhang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02072 • Publication Date (Web): 29 Aug 2016 Downloaded from http://pubs.acs.org on August 29, 2016

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Synthesis of Unsaturated N-Heterocycles by Cycloadditions of Aziridines and Alkynes Jian-Jun Feng* and Junliang Zhang* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China ABSTRACT: The unique structure and reactivity of the aziridine ring has attracted the interest of organic chemists for many years. Of these, the cycloaddition of alkynes with aziridines via C-C bond & C-N bond cleavage is an atom-efficient and convergent approach to the preparation of valuable unsaturated N-heterocycles. In this Perspective, progress in this field is outlined on the basis of the key intermediate involved in the reaction. Besides the cycloadditions of azomethine ylides generated by carbon-carbon bond cleavage and aziridinium ions & zwitterionic 1,3-dipoles generated by carbonnitrogen bond cleavage, the new type of cycloadditions of aziridines and alkynes involving metalla-azetidine intermediates have been highlighted in this short review. The use of methyleneaziridine in the cycloaddition reactions with alkynes is also discussed. Contrary to non-catalytic cycloadditions of aziridines with alkynes via azomethine ylides or aziridinium ions, the catalytic cycloadditions for synthesis of unsaturated N-heterocycles from aziridines and alkynes have more opportunity to improve the efficiency and selectivity of the reaction and to expand their synthetic utility. KEYWORDS: aziridine, alkyne, cycloaddition, N-heterocycles, C-C bond cleavage, C-N bond cleavage. 1. INTRODUCTION Unsaturated N-heterocycles such as pyrrole and azepine derivatives are ubiquitous structural motifs found in an array of natural products and pharmaceuticals with diverse biological and medicinal properties (Figure 1).1 Thus, it has gained considerable attention in organic synthesis, medicinal chemistry and material science. In light of the great importance of these compound classes, the development of highly efficient synthetic methods to access these compounds has been intensively pursued by synthetic community.2 Among them, cycloadditions are particularly attractive for their remarkable efficiency and convergence in synthesis of these compounds with 100% atom utilization. In particular, using small-ring compounds as cycloaddition partners brings opportunities for developing novel reactions that complement to or surpass traditional cycloadditons.3 Aziridines, the smallest nitrogen-containing heterocycles, were first made over 128 years ago by Gabriel.4 Like other three-membered rings such as cyclopropanes and epoxides, aziridines are highly strained. It means that aziridines are willing to undergo ring cleavage reaction under relatively mild conditions. Therefore, much attention continues to be given to the discovery of reactions that harness the reactivity of aziridines as entry points to the synthesis of valuable nitrogen-containing compounds, such as nucleophilic ring opening reactions, isomerizations, cross-coupling reactions, carbonylations and cycloadditions.5 Among them, the cycloaddition reactions of aziridines with alkynes represent a fruitful direction for synthesis of unsaturated N-heterocycles in a new way.

Figure 1. Representative biologically active unsaturated Nheterocycles.

Scheme 1. General Cycloaddition Modes of Aziridines with Alkynes In general, cycloaddition reactions of aziridines with alkynes could be divided into four different types, according to the key intermediate in the reaction (Scheme 1).

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Type I) [3+2] cycloadditions of alkynes with azomethine ylides 2,6 which are obtained from aziridines via C-C bond heterolysis upon thermolysis, irradiation or Lewis acid, can afford the highly substituted 3-pyrrolines; Type II) aziridines activated by N-sulfonyl or other electronwithdrawing N-substituents easily undergo C-N bond cleavage to afford zwitterionic 1,3-dipoles 3 in the presence of Lewis or Brønsted acids, which could be captured by alkynes to deliver the formal [3+2] or [3+2+2] cycloadducts;5f Type III) The pKaH of NH aziridine is 8.0,31a which indicates substantial nucleophilicity. Thus, aziridinium ions 4,5h easily generated from the Michael addition of the nonactivated aziridines (R1 = H, alkyl) with electrondeficient alkynes, can facilitate aziridine ring-opening processes via C-N bond cleavage to afford the formal [3+2] cycloadducts 9. Alternatively, when additional vinyl group incorporated into the aziridine rings (R2=vinyl), aza-[3,3]-Claisen rearrangement from the corresponding aziridinium ion intermediate would give the formal [5+2] cycloadducts 10. Given a good review have covered reports about the formal [3+2] cycloaddition via aziridinium ions, in this perspective we want to highlight the development of the [5+2] version of this reaction;5e Type IV) oxidative addition of transition-metal-catalyst, such as Rh(I), Ni(0), and Pd(0) etc., to aziridines could generate metalla-azetidines 5 from which [3+2]&[5+2] cycloadducts could be derived through alkyne insertions. This perspective aims to summarize the recent development in the above four types of cycloadditions and formal cycloadditons of aziridines with alkynes. Some appealing cycloadditions of aziridine derivatives, such as methyleneaziridine,7 with alkynes for synthesis of unsaturated Nheterocycles is also included in this paper. 2. Cycloadditions of Aziridines with Alkynes via Azomethine Ylides 2.1 Intermolecular Cycloaddition of Azomethine Ylides with Alkynes 3-Pyrrolines are common structural scaffolds in natural products and bioactive molecules. Therefore, many impressive strategies in the area of 3-pyrrolines synthesis have emerged.2 Among strategies available, the 1,3-dipolar cycloaddition of azomethine ylides with alkynes is considered as the most straightforward convergent one. Azomethine ylides derived from aziridines were first postulated as intermediates by Heine in 1965, who first reported that 3-pyrroline 15 can be easily obtained from 1,2,3triphenylaziridine 13 with diethylacetylene dicarboxylate 14 via the carbon-carbon cleavage of the aziridine ring (Scheme 2).8

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in the presence of dimethylacetylene dicarboxylate (DMAD) gave the [3+2] cycloadducts 18 which can be easily converted to 19 or 20 under identical conditions (Scheme 3).9 They also found that the substituents on nitrogen of the aziridines influences the mode of the reaction. When trans-2-phenyl-3-benzoylaziridine 16a was used as substrate, 19a was obtained as a single product in 80% yield. In contrast, DMAD was observed to react with either trans- or cis-1-cyclohexyl-2-2-phenyl-3-benzoyl aziridine (16b) to form two products (19b or 20b) in high yield. Notably, bearing an electron withdrawing group on the N-unprotected aziridine ring is necessary for the [3+2] cycloaddition. Contrary to Heine’s work, Padwa and Hamilton found that 22 rather than [3+2] cycloadduct was obtained when treatment of 21 with DMAD.

Scheme 3. [3+2] Cycloaddition of Aziridine with DMAD by Padwa and Hamilton et al. Only one year later, the research group of Huisgen has done pioneering work on the connection between the method used to promote azomethine ylide formation and the stereochemical course of their reactions with alkynes.10 Huisgen and co-workers found that the cis- and trans-aziridines 23 lead to trans- and cis-azomethine ylides 24 respectively, which through a conrotatory C-C bond-breaking process upon thermolysis according to the Woodward-Hoffmann theory. Then the trans- and cisazomethine ylides 24 can be trapped by alkynes in concerted 1,3-dipolar cycloadditions to give the corresponding pyrrolines 25. They also found that ring-opening of the cis- and trans-aziridines 23 upon irradiation can take place in a disrotatory way to give the ylides. This finding is opposite to that obtained via thermolysis (Scheme 4).

Scheme 2. [3+2] Cycloaddition of N-Arylaziridine 13 with Diethylacetylene Dicarboxylate 14 In the same year, Padwa and Hamilton also independently demonstrated that thermolysis of aziridines 16

Scheme 4. C-C Bond Heterolysis of Aziridines upon Thermolysis and Irradiation


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The seminal contributions from the group of Heine, Padwa and Hamilton, and Huisgen et al. in the 1960s have led to many studies of intermolecular [3+2] cycloaddition reactions of aziridines with alkynes.6 The reactive intermediates, azomethine ylide, formally bear a positive charge on the N-atom and negative partial charges on both C-atoms, suggesting that the opening of aziridines to azomethine ylides should be accelerated by electronwithdrawing substituents, which are able to stabilize negative charges on the terminal C-atoms of the formed dipoles. Besides the phenyl, acyl and ester groups described above, aziridines with a 2-sulfonyl or 2-cyano group (26 & 29a) reacted with acetylenes smoothly to give the corresponding [3+2] cycloadducts (Scheme 5).11 Moreover, the benzotriazolyl group has emerged as a versatile synthetic auxiliary, capable of stabilizing the azomethine ylides.12 Reaction between 2-benzotriazolylaziridine 32 and diethylacetylene dicarboxylate 14 at 100 oC gave pyrrole 35 in 86% yield, presumably via formation of an azomethine ylide 33 & 34 followed by a [3+2] cycloaddition and aromatization by loss of benzotriazole. Interestingly, in contrast to aziridine 32, the reaction of aziridine 36, which have no aryl group at the C3 position to stabilize the azomethine ylide intermediate, with 14 takes the C-N scission path to form 39 (Scheme 6).

Scheme 5. [3+2] Cycloadditions of 2-Sulfonyl, 2-Ester or 2-Cyano Aziridines with Alkynes

dition with methyl propiolate afforded head-to-head adduct 45 rather than the head-to-tail cycloadduct. Given there was no electron-deficient group to stabilize the azomethine ylide intermediate, the author believe that the biradical intermediate 44 primarily contributes to the current cycloaddition rather than the azomethine ylide (Scheme 7).13

Scheme 7. [3+2] Cycloaddition of Bicyclic Aziridine 43 with Alkyne by Ishii et al. Besides the bicyclic aziridine 43, the [3+2] cycloadditons of other ring-fused aziridines have been reported. In 2009, Khlebnikov and co-workers presented an effective approach to 1-aryl-1,11b-dihydroazirino[1,2-d]dibenz[b,f] [1,4] oxazepines 46a. Heating the ring-fused aziridine 46a with DMAD in toluene under reflux gave effective approach to dibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepine carboxylate 48a in high yield and stereoselectivity, which are privileged motifs occurring in many biologically active pharmaceuticals.14a The same group later extended their investigation to the replacement of the oxazepine moiety of the ring-fused aziridines 46a with azepine.14b The corresponding cycloadditions also proceed smoothly. According to DFT calculations, the reaction proceed via 1,3dipolar cycloadditions of W-shaped ylides only, which does not undergo E,Z-isomerization under the reaction conditions due to the high activation barrier (Scheme 8).

Scheme 8. [3+2] Cycloaddition of Ring-Fused Aziridine 46 with DMAD Scheme 6. [3+2] Cycloadditions of 2-Benzotriazolyl Aziridines with Alkynes As described above, the [3+2] cycloaddition of an azomethine ylide intermediate possessing one electronwithdrawing or aryl group at the ylide carbon and electron-deficient alkyne affords head-to-tail cycloadduct (2,4-disubstituted pyrrolines 42). Recently, the group of Ishii reported that the photochemical C-C bond cleavage of bicyclic aziridine 43 and the subsequent [3+2] cycload-

As described in Scheme 3, the substituents on nitrogen of the aziridines have great influences on the reaction. The substituents on nitrogen of the aziridines can be H, alkyl, and aryl group. What’s more, the use of Naminoaziridines in this field has also been reported which open a direct route to various N-aminoheterocycles. In 1970, the group of Foucaud reported that briefly boiling trans-aziridine 49 and DMAD in benzene gives the 3pyrroline 50 in 25% yield together with a 65% yield of oxazole 51, which can be considered as the product of a 1,5-dipolar electrocyclization of the intermediate ac-


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ylazomethine ylide and its subsequent aromatization by loss of the phthalimide.15 However, no determination of the relative configuration of the cycloadduct was carried out. Thus, Kuznetsov and co-workers have done a systematic work on the [3+2] cycloadditions of tri- and tetrasubstituted N-phthalimidoaziridines with dipolarophiles and found that 50 can be obtained in 60% yield as a single diastereomer when treatment 49 with DMAD at room temperature (Scheme 9). Notably, the structure of 50 was unambiguously established as the trans-isomer by X-ray crystallography which is not in agreement with the Huisgen’s works as described in Scheme 4. To account for the observations, two plausible mechanisms were proposed by Kuznetsov et al.16a Moreover, the [3+2] cycloadditions of 2,3-disubstituted N-phthalimidoaziridines with alkynes were realized by the same group.16b Contrary to the tri- and tetrasubstituted N-phthalimidoaziridines, 2,3disubstituted N-phthalimidoaziridines (e.g., 52) required a higher temperature (up to 220 oC) for complete of the reaction with DMAD and the stereochemical outcomes of the cycloadducts are in agreement with the Huisgen’s works.

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orbital (FMO) theory, HOMOdipole-LUMOdipolarophile matching suggests that the [3+2] cycoladdition of azomethine ylide can take place readily with an electron-poor alkyne. As described above, electron-deficient alkynes are widely used for these transformation, in contrast, only a few examples of using electron-rich alkynes as the dipolarophile have been explored. In 1995, Matsumoto disclosed that cyclooctyne 60 can served as an electron-rich dipolarophile, which underwent 1,3-dipolar cycloaddition with aziridines. However, low yield was obtained for these reaction as a result of HOMO/LUMO mismatch (Scheme 11).17

Scheme 11. 1,3-Dipolar Cycloaddition of Cyclooctyne 60 with Azomethine Ylide

Scheme 9. [3+2] Cycloadditions of N-Aminoaziridines with Alkynes Very recently, the first 1,3-dipolar cycloaddition of spiro-fused N-phthalimidoaziridines with π-systems was reported by the Kuznetsov group.16c The reaction proceeds well with many aziridines (e.g., 54) and DMAD, and enables the efficient synthesis of spiro-fused 3-pyrrolines in moderate to high yield. In many cases tricyclic oxazoles 58 were obtained along with the corresponding cycloadduct, which originate from 1,5-dipolar electrocyclization of the acylazomethine ylides (Scheme 10).

Scheme 10. Synthesis of Spiro-Fused 3-Pyrrolines Azomethine ylides have four π-electrons spread over the three-atom C-N-C unit. As such, it can be considered to be electron-rich. According to the frontier molecular

Scheme 12. Lewis Acid-Catalyzed [3+2] Cycloadditions of Aziridines with alkynes Contrary to above non-catalytic cycloadditions of alkynes with azomethine ylides 2, Lewis acid-catalyzed [3+2] cycloadditions of aziridines with alkynes via selective C-C bond cleavage have more opportunity to improve the efficiency and selectivity of the reaction. Recently, we found that cycloaddition of extremely electron-poor azomethine ylide 64, generated by reaction of N-tosylarylaziridinyl dicarboxylate 62 with the Lewis acid under mild conditions, with electron-rich alkynes can offer highly substituted 3-pyrrolines 65 in good yields as a single regioisomer (Scheme 12).18a Notably, the reaction is not limited to electron-rich alkynes. Electron-deficient alkynes was also compatible, indicating that the electron-rich alkynes and electron-deficient alkynes may proceed different reaction pathway, that is, the electron-rich alkynes favor the interaction of the HOMO of the dipolarophile with the LOMO of the dipole that leads to the formation of the new C-C bond, whereas electron-deficient ones favor the inverse of the interaction. What’s more, our preliminary results showed that treatment of 62 and 63a with 5 mol% Sc(OTf)3 and 5.5 mol% Pybox 66 in DCM at room tem-


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perature can generate the desired product 65a in moderate enantioselectivity. The current Lewis acid catalyzed intermolecular asymmetric [3+2] cycloaddition is complementary to the chiral auxiliary strategies used in thermal or photochemical 1,3-dipolar cycloadditions of aziridines. 2.2 Intramolecular Cycloaddition of Azomethine Ylides with Alkynes While many intermolecular [3+2] cycloadditions of aziridines and alkynes have been developed for synthesis of 3-pyrrolines, only a few intramolecular version of this reaction exist for the preparation of their ring-fused analogues. In 1985, the group of DeShong reported the first intramolecular [3+2] cycloaddition of aziridines and alkynes by using the flash vacuum pyrolysis (FVP) system at 300-400 oC. Contrary to the intermolecular cycloaddition, the intramolecular version of this reaction gave the bicyclic 3-pyrrolines even with alkynes lacking electrondeficient substituent (Scheme 13).19

Scheme 13. Intramolecular [3+2] Cycloadditions of Aziridine-alkynes. For synthesis of 1,2,3,4-tetrasubstituted pyrroles, a strategy featuring intramolecular 1,3-dipolar cycloaddition of aziridine with internal alkyne has been developed by Fukumoto and co-workers. The thermolysis of 70 in the presence of radical scavenger was carried out, but it exert a negative influence on the reaction (scheme 14).20

spectively.21-23 The group of Heathcock found that treatment of 2,2-disubstituted aziridine 73 at 300-350 oC gave the desired cycloadduct 74 in 64% yield, incorporating a quaternary carbon into the product 74 (Scheme 15).21 Very recently, Pinho e Melo and co-workers demonstrated that thermolysis of the 2,3-disubstituted aziridine 75 in refluxing t-BuOH for 18 hours can lead to a 69:31 mixture of compounds 76 and 77 in 39% overall yield. Interestingly, when they carried out the reaction in refluxing toluene for 29 hours, they obtained the chromenopyrrole 77 in 94% yield, which is an appealing structure in medicinal research.22

Scheme 16. Intramolecular [3+2] Cycloadditions of Nphthalimidoaziridines Thermolysis of the similar 2,3-disubstituted aziridine has also been reported by the Kuznetsov group (Scheme 16). When the strong electron-withdrawing cyano group was incorporated into the N-phthalimidoaziridines 78, the reaction can proceed at lower reaction temperature and gave the N-aminochromenopyrroline 79c as a single product in 91% yield. Moreover, the trisubstituted aziridine 81 was also investigated but failed to afford the desired cycloadduct.23 2. Formal Cycloadditions of Aziridines with Alkynes via Zwitterionic 1,3-Dipoles

Scheme 14. Synthesis of Tetrasubstituted Pyrroles

Scheme 15. Intramolecular [3+2] Cycloadditions of 2,2-or 2,3-Disubstituted Aziridines Besides the above N-alkyl aziridines bearing a single carboxyl ester function, [3+2] cycloaddition of doublystabilized azomethine ylides to unactivated alkynes was reported by Heathcock, Pinho e Melo and Kuznetsov re-

Among the unsaturated nitrogen-containing fivemembered heterocycles, 2-pyrrolines are rather unusual because of the enamine skeleton. While [3+2] cycloadditions of aziridines with alkynes has been widely utilized for the formation of 3-pyrrolines via C-C bond heterolysis, the formal [3+2] cycloaddition of zwitterionic 1,3-dipoles generated from aziridines via C-N bond cleavage with alkynes have been reported for the synthesis of 2pyrrolines. In contrast to the formation of azomethine ylides from simple aliphatic N-alkyl- or N-arylaziridines, C-N bond cleavage is usually observed starting from aziridines bearing an electron-withdrawing group (e.g. N-tosyl) and with aryl group on one of the carbon atoms likely to stabilize the two charges of the 1,3-dipole. Furthermore, zwitterionic 1,3-dipoles can be considered to be electron-deficient. As such, the [3+2] cycoladdition of zwitterionic 1,3-dipoles can take place readily with electron-rich alkynes according to the FMO theory (Scheme 17).


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Scheme 19. Formal [3+2] Cycloaddition of Alkylaziridine with Phenylacetylene

Scheme 17. [3+2] Cycloadditions of Aziridines with Alkynes via C-C Bond or C-N Bond Cleavage In 2009, Wender group pioneered the use of Lewis and Brønsted acid to catalyze the formal [3+2] cycloadditions of N-tosylaziridines with alkynes (Scheme 18).24 A wide range of alkynes, not only terminal alkynes but also internal alkynes are suitable substrates, leading to the corresponding [3+2] cycloadducts as a single regioisomer. The reaction is not limited to arylaziridine. Alkylaziridine 88 with a β-silyl group as a cation-stabilizing system, reacted with phenylacetylene in the presence of AgSbF6 to form 90 in 84% yield (Scheme 19). Formation of zwitterionic 1,3-dipole intermediate is suggested by the control experiment using electronically differential phenylacetylenes and the isolation of racemic [3+2] cycloadduct starting from optically pure aziridine.

(e.g., 91b,c) or alkylaziridines (e.g., 91d) did not react with phenylacetylene in the presence of FeCl3. These results suggested that the zwitterionic 1,3-dipoles might be stabilized externally by the double contributions of the aromatic and the arylsulfonyl group. Moreover, one pot protocol for synthesis of the valuable γ–amino ketones have also been achieved by the author and co-workers.

Scheme 20. FeCl3-Catalyzed Formal [3+2] Cycloadditions of Arylaziridines with Alkynes by Wang et al.

Scheme 21. Proposed Mechanism for Formal [3+x] Cycloaddition of Zwitterionic 1,3-Dipoles

Scheme 18. Lewis and Brønsted Acid-Catalyzed Formal [3+2] Cycloadditions of Arylaziridines with Alkynes Subsequently, a FeCl3-catalyzed formal [3+2] cycloadditions of aziridines and alkynes have been reported by the group of Wang to afford functionalized 2-pyrrolines in moderated to high yield (Scheme 20).25 The authors observed that aziridines without the activated tosyl group

A plausible reaction mechanism for the above formal [3+2] cycloadditions of aziridines with alkynes are outlined in Scheme 21. Initially, Lewis acid activates the Ntosyl group in the aziridine to cleave the benzylic C-N bond resulting in the formation of a 1,3-dipole 94, which is trapped by the nucleophilic alkyne to afford the arysubstituted alkenyl cation 95. Subsequently, an intramolecular cyclization gives the desired [3+2] cycloadduct 92 and regenerates the catalyst. Alternatively, when the nucleophilicity of nitrogen anion in the intermediate 96 was reduced by a Brønsted acid, could it be possible for an-


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other alkyne to capture the alkenyl cation 96, thus enabling a subsequent cyclization to form the [3+2+2] cycloadduct? If this approach is successful, it will provide a novel protocol access to valuable azepine architectures in an atom-economic way. Quite recently, the above assumption proved to be right by Li and co-workers (Scheme 22).26 Treatment of 91a with phenylacetylene and 15 mol% HSbF6 in dichloromethane at 40 oC for 24 hours regioselectively afforded the [3+2+2] cycloadduct 98a in 76% yield. Of note, the 2π component is not limited to the same alkynes, two of the different terminal alkynes are suitable substrate for the current cycloaddition. What’s more, the mechanism described in Scheme 21 was supported by the result of the control experiments and the in situ HRMS and 1H NMR analysis.

4. Formal [5+2] Cycloadditions of Aziridines with Alkynes via Aziridinium Ions In 1997, the group of Mattay first observe that the unexpected product 105 and 106 were obtained when they subjected aziridine 102 to the photoinduced electron transfer (PET) condition (Scheme 24).28a Further study has revealed that under mild thermal conditions without irradiation, 105 can also be obtained as the single product through the C-N cleavage, which opened the way for the development of the formal [3+2] cycloaddition via the aziridinium ions. Yudin,28b Ma28c and Pinho e Melo28d-f et al. have done elegant works in this field, and these lie outside the scope of this review.5e Here we describe the formal [5+2] cycloaddition of aziridines via aziridinium ions. In marked contrast to the formal [3+2] cycloaddition, the combination of N-unsubstituted 2-vinylaziridine 108 with electron-deficient alkyne 109 can afford the aziridinium ions 110, which can undergo the following aza-[3,3]-Claisen rearrangement at room temperature to afford the formal [5+2] cycloadduct 112 in quantitative yield. These observations were firstly described by Stogryn and Brois (Scheme 25).29

Scheme 22. Brønsted Acid-Catalyzed Formal [3+2+2] Cycloadditions of Aziridines with Alkynes In contrast to the intermolecular cycloadditions for synthesis of 2-pyrrolines, method for constructing the ring-fused 2-pyrrolines by intramolecular [3+2] cycloadditions of zwitterionic 1,3-dipoles is rarely reported. In 2002, the group of Liu present a novel formal [3+2] cycloaddition of alkynyltungsten functionality with its tethered aziridine (e.g., 99, Scheme 23).27 In presence of various Lewis acids, BF3.Et2O catalysts (50 mol%) most effectively promote the intramolecular [3+2] cycloadditions of transaziridines, delivering bicyclic tungsten-enamines stereoselectively in moderated yields. The cyclization is proposed to involve a tungsten-vinylidenium species 100 via ring opening of the aziridine group by SN2 attack of tungsten fragment. However, cis-aziridines do not undergo the current cycloadditions under similar conditions, which is attributed to steric hindrance as tungstenalkynyl group undergoes SN2 attack at the aziridine group.

Scheme 23. [3+2] Cycloaddition of Alkynyltungsten Complexs with Tethered Aziridines

Scheme 24. Formal [3+2] Cycloadditions Aziridinium Ions by Mattay et al.

via

Scheme 25. First Formal [5+2] Cycloadditions via Aziridinium Ions by Stogryn and Brois et al. Subsequently, Hassner and co-workers extended the scope of the [5+2] cycloadditions to another electrondeficient alkyne 17 (DMAD), which was converted even at -20 oC and no divinylaziridine intermediate was isolated. Notably, 115 rather than 114 was obtained as the final product, which was formed via 114 through removal of the acidic α-ester proton (Scheme 26).30


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Scheme 26. Formal [5+2] Cycloaddition of Aziridine 113 with DMAD Although the above formal [5+2] cycloaddition of vinylaziridine with electron-deficient alkyne provides an efficient and mild access to the azepine architectures, the reaction is limited to unprotected vinylaziridines which are difficult to prepare. Recently, the group of Yudin developed a novel method to synthesis of a series of unprotected vinylaziridines.31 Upon treatment of 116 with DMAD at room temperature in toluene, azepine 117 was obtained in excellent yield. Interestingly, by switching to a DMSO solvent the aminocyclobutane 118 could be obtained selectively. The author proposed an electrocyclization pathway for the formation of 118, which was supported by computational and experimental approach. Of note, the aromatic substituent α to the vinyl group of the aziridine was the ultimate key to this mode of reactivity, which facilitated deprotonation at the benzylic position to generate the conjugated π-system capable of undergoing an electrocyclization (Scheme 27).

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tions from the group of Wender3e and Yu3b,c etc. Atom analogy suggests that vinylaziridines could be analogously activated to generate metalla-azetidine intermediates from which unsaturated N-heterocycles could be derived through alkyne insertions. Although this idea was first proposed by Professor Wender in 2002,2n,24 this hypothesis is hard to realized and may face considerable challenges such as (1) vinylaziridines5c are commonly used as three-atom component in [3+2] cycloadditions with electron-deficient alkenes,32 and the example of vinylaziridines as an aza-three-atom component or as another Ncontaining five-carbon synthons in [3+2] or [5+2] cycloaddition with unactivated alkynes is extremely rare.33 (2) vinylaziridines easily undergo rearrangement34a and isomerization34b to the corresponding 3-pyrrolines and ketimines in the presence of transition-metal catalysts. More recently, our group developed catalyst-controlled divergent intermolecular cycloadditions of vinylaziridines with alkynes (Scheme 28).33a Using [Rh(NBD)2]BF4 as the catalyst, both unactivated and activated alkynes underwent [3+2] cycloaddition reaction to provide 2,3dihydropyroles as a single regioisomer in moderate to good yield. Notably, the chirality of vinylaziridines can be efficiently transferred to the [3+2] cycloadducts. Interestingly, when we switched to using a rhodium catalyst ([Rh(η6-C10H8)(COD)]SbF6) containing a COD ligand, the [5+2] cycloadditions of vinylaziridines with terminal alkynes took place to afford 2,5-dihydroazepines in high selectivity.

Scheme 27. Synthesis of Azepine and Fused Aminocyclobutane from Aziridine and Alkyne As mentioned above, the non-catalytic formal [5+2] cycloadditions of vinylaziridines with alkynes via aziridinium ions are efficient tool for the construction of azepine derivatives. However, these transformations are restricted to unprotected vinylaziridines and electron-poor alkynes. Thus, the development catalytic method to broaden the substrate scope is highly desirable.

Scheme 28. Catalyst-Controlled Divergent Intermolecular Cycloaddition of Vinylaziridines with Alkynes

5. Cycloadditions of Aziridines with Alkynes via Metalla-Azetidines

Having done detailed mechanistic studies, plausible mechanisms are proposed, as shown in Scheme 29. Both the ole-

As a paradigm, rhodium catalyzed [5+x] and [3+x] cycloadditions of vinyl cyclopropanes have emerged as a practical way for synthesis of various carbocycles, including cyclopentanes, cycloheptanes, cyclooctanes and its ring-fused analogy, as described in the seminal contribu-

fin and the nitrogen atom in vinylaziridine (R)-122 could coordinate to the rhodium catalyst to give complex 126, which lead to enyl (σ+π) rhodium species 127 with the retention of configuration formed by oxidative addition. The direct reductive elimination of rhodium species 128 would afford the 3-pyrroline 132, when the N-


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ACS Catalysis

phthalimidovinylaziridine 131 was used as starting material. However, in the presence of alkynes, rhodium species 127 and 128 could be regioselectively captured by alkynes to deliver another two interconvertible enyl (σ+π) rhodium species 129 and 130, followed by irreversible reductive elimination to yield [3+2] cycloadduct (R)-124 and [5+2] cycloadduct 125, respectively, under the catalysis of two different rhodium catalysts.

impact the R/S configuration of the cycloadduct. Of note, the chirality of vinylaziridine-alkyne substrates can be completely transferred to the cycloadducts and both enantiomers of the [5+2] cycloadducts were prepared, representing an atom-economic and enantiospecific protocol for the construction of fused 2,5-dihydroazepines (up to >99% ee) for the first time.33b

Scheme 31. Nickel-Catalyzed Reactions of Aziridinylen-ynes

Scheme 29. Proposed Mechanism While the above intermolecular [5+2] cycloadditions of vinylaziridines with alkynes delivered achiral azepines, the intramolecular version of this reaction gave the ringfused chiral analogues, which represent a privileged structural motif in many biologically active azepines (Scheme 30). By the use of the [Rh(NBD)2]BF4 catalytic system, we found that the intramolecular hetero-[5+2] cycloaddition of vinylaziridines and alkynes could afford a series of ringfused azepine architectures with excellent functionalgroup compatibility. In contrast to the intermolecular version of this reaction, both terminal and internal alkynes were compatible to afford the corresponding [5+2] cycloadducts, which is complementary to Sarpong and Tang’s [4+3] method.35 Furthermore, the E/Z geometry of the C=C bond in the vinylaziridine-alkyne substrates

Scheme 30. Rhodium Catalyzed Intramolecular Hetero-[5+2] Cycloaddition of Vinylaziridine with Alkyne

Interestingly, vinylaziridine-alkyne substrates 135, possessing a bulky protecting group (i.e., trityl (135a), t-butyl (135b) and benzhydryl (135c)) underwent Ni/NHCcatalyzed intramolecular [5+2] cycloaddition to give azepines 136 and 137, arising from C-C cleavage rather than C-N cleavage of the aziridine ring. The author believes that the C-C cleavage mode is strongly influenced by the steric hindrance of the N-protecting group, which prevents the nitrogen atom from coordinating to nickel center and disfavors C-N bond cleavage (Scheme 31).36 6. Cycloadditions of Methyleneaziridines with Alkynes Methyleneaziridine is a kind of densely functionalized aziridine bearing an additional exocyclic double bond. At the HF/6-31G* theory, 2-methyleneaziridine is calculated to possess 12-13 kcal/mol more ring strain than aziridine itself. It means that they are more reactive than the general aziridines and display unique reactivity in the cycloaddition reactions with alkynes.7 During the Shipman group’s ongoing study of the methyleneaziridine chemistry, in 2012, they reported the first Lewis acid promoted intramolecular [3+2] cycloaddition of 2-methyleneaziridine with alkyne, providing the fully substituted pyrrole in moderate yield.37 After investigations by control experiments, a plausible reaction mechanism is outlined in Scheme 32. In the presence of BF3.Et2O, a planar 2-aminoallyl cation 142 was formed via regioselectively cleave the C(sp3)-N bond. Subsequently, it could be captured by alkyne to deliver the unstable dienamine 140, which undergoes a spontaneous isomerization to afford the fully substituted pyrrole 141.

Scheme 32. Intramolecular [3+2] Cycloaddition of 2Methyleneaziridine with Alkyne via C-N Bond Cleavage


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7. CONCLUSIONS

Scheme 33. Nickel-Catalyzed Reactions of 2Methyleneaziridine with Alkyne via C-C Bond Heterolysis While transformations involving C-N cleavage of 2methyleneaziridine have been studied extensively, reactions involving C-C bond heterolysis are much less common. Transition-metal-catalyzed ring expansion reaction via regiospecific C-C bond cleavage of 2methyleneaziridines was firstly reported by Wan’s group (Scheme 33).38 Using Ni(COD)2 as a catalyst, the reaction of 2-methyleneaziridine 143 with diyne 144 afford product 145 in 60% yield. Interestingly, the use of Ni(COD)2/IPr containing a N-heterocyclic carben (NHC) ligand furnishes a fused aniline 146 as the major product. A plausible reaction mechanism is depicted in Scheme 34. In path a, both the C-C double bond in 143 and the C-C triple bond in 144 could coordinate to the nickel complex, which lead to spirocyclic Ni(II) intermediate 147 formed by oxidative cyclometalation. Subsequently, 147 undergoes β-carbon elimination to give a six membered nicklacycle 148. Finally, reductive elimination from this intermediate produces the [3+2] cycloadduct 149, which readily aromatizes to product 145, and regenerates the nickel catalyst. Alternatively, in path b, the catalytic cycle starts with the oxidative cyclization of the diyne 144 on the nickel center to form the nickelacyclopentadiene complex 150. Corrdination of the vinyl moiety of methyleneaziridine 143 and insertion into the Ni(II)-C bond gives intermediate 151. Then, reductive elimination of 151 affords the [2+2+2] cycloadduct 152 and regenerates the catalyst. Finally, 152 isomerize to product 146 via C-C bond cleavage.

Given the crucial utility of unsaturated N-heterocycles in diverse research and application areas, the development of more efficient and selective methodologies has been highly desirable. As mentioned above, cycloaddition reactions of aziridines and alkynes can provide a pratical alternative to traditional methods for the preparation of such compounds. Attractive features of the cycloadditions of aziridines and alkynes are not limited to 1) 100% atom utilization, 2) unique selectivity, 3) readily available starting materials, and 4) its reaction mode diversity. Up to now, there are four key intermediates involved in the cycloadditions of aziridines and alkynes. While azomethine ylides can be obtained from aziridines via C-C bond heterolysis upon thermolysis, irradiation or Lewis acid, cycloadditions of aziridinium ions, zwitterionic 1,3-dipoles and metalla-azetidines with alkyne can gave the unsaturated N-heterocycles via the cleavage of the C-N bond of aziridines. The reaction mode can be affected by many factors such as the substituents on nitrogen or carbon of the aziridines, catalysts, and other reaction conditions. Despite the great success witnessed recently in the development of the cycloadditions of aziridines and alkynes, there is still room for further exploration. Development of new efficient transition-metal-catalyzed cycloaddition reactions of aziridines and alkynes for asymmetric synthesis of valuable unsaturated N-heterocycles, as well as pioneering of the unknown reactivity of aziridine derivatives, will offer further opportunities for the expansion of their synthetic utility.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]; [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We grateful to the funding support of Science and Technology Commission of Shanghai Municipality (15YF1403600), NSFC (21602062, 21425205), 973 Project of MOST (2015CB856600) and the Program of Eastern Scholar at Shanghai Institutions of Higher Learning.

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Scheme 34. Proposed Mechanism

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