Divergent Access to Functionalized Pyrrolidines and Pyrrolines via

Nov 22, 2017 - Interestingly, compared to 1,3-diketone 2a, substrates with an ethyl and an n-butyl group at the α-position deliver the corresponding ...
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Divergent Access to Functionalized Pyrrolidines and Pyrrolines via Iridium-Catalyzed Domino-Ring-Opening Cyclization of Vinyl Aziridines with β‑Ketocarbonyls Tao-Yan Lin, Hai-Hong Wu, 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 North Zhongshan Road, Shanghai 200062, P. R. China S Supporting Information *

ABSTRACT: A useful synthesis of five-membered N-heterocycles has been developed through an iridium-catalyzed domino-ring-opening cyclization of vinylaziridines with βketocarbonyls. α-Substituted 1,3-dicarbonyls reacted with vinylaziridines to give 2-methylenepyrrolidines bearing two adjacent sp3-carbon centers with moderate to excellent diastereoselectivity, while the reaction of α-unsubstituted 1,3dicarbonyls afforded 2-pyrrolines in good yield.

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arylaziridines with active methylene compounds tends to proceed selectively at the benzylic position,5,6 there would appear to be only three previous reports involving the ringopening reactions of vinylaziridines with 1,3-dicarbonyls, but providing the corresponding products via an SN2′ mechanism (Scheme 1a).7 In 2010, Ghorai and co-workers reported their pioneering work on the copper-catalyzed domino ring-opening

yrrolidines and pyrrolines are abundant in many biologically active natural products and pharmaceuticals (Figure 1).1

Scheme 1. Reactions between Vinylaziridines and 1,3Dicarbonyls

Figure 1. Pyrrolidines and pyrrolines structural motifs in biologically active natural products and pharmaceuticals.

Therefore, the discovery of efficient synthetic methodologies to access these compounds continues to attract the attention of organic chemists, and numerous routes have been developed.2 However, the development of simple and efficient methods for the syntheses of structurally diverse, polysubstituted, and functionalized pyrrolidine and pyrroline derivatives is still in great demand. Aziridines, the smallest nitrogen-containing heterocycle, are increasingly being exploited as building blocks for synthesis of various N-heterocycles.3 Among these, nucleophilic ring-opening cyclizations of aziridines with C-nucleophiles bearing both nucleophilic and electrophilic moieties represent powerful tools that permit efficient access to pyrrolidine and pyrroline derivatives.4 Although many reports are known for the above ring-opening cyclization reactions of aryl- or alkylaziridines, the domino ring-opening cyclization involving vinylaziridines with 1,3-dicarbonyls is still limited.4a Moreover, while ring openings of © 2017 American Chemical Society

Received: October 17, 2017 Published: November 22, 2017 6526

DOI: 10.1021/acs.orglett.7b03232 Org. Lett. 2017, 19, 6526−6529

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Organic Letters cyclization of aziridines with enolates for the synthesis of chiral γlactams.4a Unfortunately, there was only one example involving a vinylaziridine in Ghorai’s work and the corresponding γ-lactam product was obtained from SN2-type ring-opening at the C-2 position of the vinylaziridine followed by cyclization. Moreover, the SN2′ nucleophilic ring-opening product was also obtained as a side product (Scheme 1b). To the best of our knowledge, there is no report on the domino ring-opening at the C-3 position with attendant cyclization of vinylaziridines with α-substituted 1,3dicarbonyls to provide products with quaternary centers. As a part of our program of development of new reactions of vinylaziridines to synthesize nitrogen-containing heterocycles,8 herein we report a convenient preparation of 2-methylenepyrrolidines bearing two adjacent stereocenters, one of which is a quaternary carbon stereocenter and functionalized 2,3-dihydropyroles through an iridium-catalyzed domino ring-opening cyclizations of vinylaziridines with β-ketocarbonyls (Scheme 1c).8c,9 An initial scouting reaction was performed with vinylaziridine 1a and methylacetylacetone 2a in the presence of various rhodium catalysts (see Table S1). After many attempts, we found that the reaction afforded the desired 2-methylenepyrrolidine 3aa in 73% NMR yield with 7:1 dr when [Rh(NBD)Cl]2/ AgSbF6 was used as the catalyst. Next, other commonly used transition-metal catalysts were tested. Compound 1a decomposed quickly under the catalysis of Pd(PPh3)47 and Cu(OTf)2.4a Gratifyingly, treatment of 1a and 2a with [Ir(COD)Cl]2/AgSbF6 in DCE for 2 h at room temperature gave 3aa in 90% NMR yield with 10:1 dr, while [Ir(COD)Cl]2 itself failed to catalyze this reaction. With optimal reaction conditions in hand, we set out to investigate the scope of the current reaction with respect to the vinylaziridine. As depicted in Scheme 2, the R2 group of vinylaziridines 1 exhibited general tolerance. Both alkyl (1a−d)

and aryl (1e−h) groups could be readily incorporated, and the reaction gave the corresponding 2-methylenepyrrolidines bearing two adjacent stereocenters, one of which was a quaternary carbon stereocenter, in moderate to good yield with high to excellent diastereoselectivity. The structure and relative stereochemistry of 3ha were confirmed by X-ray crystallography. Of note, the substrate 1b possessing a CF3 group was found to be a suitable substrate, yielding the corresponding product 3ba as a single diastereomer in 78% yield. We next turned our attention to examining the generality of 1,3-diketones 2 in the presence of vinylaziridine 1a and the iridium catalyst. Interestingly, compared to 1,3-diketone 2a, substrates with an ethyl and an n-butyl group at the α-position deliver the corresponding products 3′ab and 3′ac as the major diastereomers, respectively (Scheme 3a). However, 3ab and 3ac Scheme 3. Transformation from 3′ to 3

were obtained as the major diastereomers upon heating the crude product in CHCl3 (Scheme 2). To test whether 3 arose from isomerization of 3′, we subjected 3′ab and 3′ac in CHCl3 at room temperature for 16 h in the absence of the Ir catalyst. Compounds 3ab and 3ac were also obtained as the major diastereomers (Scheme 3b,c). These results indicate that 3 is a thermally more stable diastereomer. Besides alkyl groups (3aa− ac), allyl (3ad) and ester groups (3ae and 3af) were compatible with the standard conditions. Notably, the reaction gave the 2methylenepyrrolidine product 3af rather than the corresponding γ-lactam when 2f was used as the substrate, which is quite different from Ghorai’s work.4a Unsymmetric 1,3-diketone 2g was examined in the reaction and showed good reactivity, yielding 3ag as a single diastereomer. The reaction of 4methylheptane-3,5-dione 2h gave a slightly lower yield of 3ah and diastereoselectivity than that with 2a. Besides acyclic 1,3dicarbonyls, cyclic 1,3-diketone 2i also worked in the current reaction but showed low activity and diastereoselectivity. To further extend the substrate scope, α-unsubstituted 1,3dicarbonyls 2 (R4 = H) were examined under the standard conditions. However, a strikingly different reaction pattern was observed when we applied α-unsubstituted 1,3-dicarbonyls as the substrates. The reaction between 1a and 2j with [Ir(COD)Cl]2/ AgSbF6 in DCE for 2 h at room temperature proceeded smoothly to furnish the 2,3-dihydropyrole 4aj rather than the corresponding 2-methylenepyrrolidine product in 85% yield (Scheme 4). The substrate scope was further investigated with respect to variation of the vinylaziridine component. Varying the vinyl moiety in 1 (bearing both alkyl and aryl subsitituents) was well tolerated and produced 4aj−fj and 4hj in moderate to high yield. The reactions of the N-tosyl 1i, N-nosyl 1j, and N-mesyl 1k proceeded smoothly, thus providing options for N-protection and deprotection of the corresponding pyrrolines. The scope with regard to the β-ketocarbonyl component was also investigated. Both symmetric (2j−k) and unsymmetric (2l−n) 1,3-diketones delivered the corresponding 2,3-dihydropyroles (4aj−an) in 49−71% yield with excellent regioselectivity. We also examined β-ketoester 2o as the nucleophile. The reaction

Scheme 2. Preparation of 2-Methylenepyrrolidinesa

a Standard conditions: 1 (0.2 mmol), 2 (1.5 equiv), [Ir(COD)Cl]2 (5 mol %), AgSbF6 (10 mol %), DCE (2 mL), room temperature, 2 h. Total isolated yield of two isomers and the dr value was determined by H1 NMR of the crude product. bThe reaction was carried out under the standard conditions for 2 h, and then DCE was removed under vacuum followed by heating the crude product at reflux in CHCl3 for 12−18 h.

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Organic Letters Scheme 4. Preparation of 2,3-Dihydropyrolesa

Scheme 6. Chirality Transfer and Control Experiments

Scheme 7. Proposed Mechanism

a

Standard conditions: 1 (0.2 mmol), 2 (1.5 equiv), [Ir(COD)Cl]2 (5 mol %), AgSbF6 (10 mol %), DCE (2 mL), room temperature, 2 h.

afforded 4ao rather than the corresponding γ-lactam in acceptable yield.4a The synthetic application of this methodology was demonstrated in a number of transformations on the highly functionalized 2-methylenepyrrolidine (Scheme 5). The isopropenyl

undergoes oxidative addition to furnish the (η3-allyl)iridium(III) species B. Regioselective nucleophilic attack on the allyl fragment affords the alkylation product 9 and regenerates the catalyst.10,11 Then, intramolecular cyclization of 9 would afford hemiaminal C. Finally, dehydration of C via path a provides 2-methylenepyrrolidine product 3 as the final product. Alternatively, the generation of the 2-pyrroline 4 is most likely preferred when R4 = H (path b). In conclusion, the first iridium-catalyzed domino ring-opening cyclizations of vinylaziridines with β-ketocarbonyls has been achieved. Switchable syntheses of functionalized 2-methylenepyrrolidines and 2-pyrrolines were realized by substrate control. The salient features of this reaction include high atom-economy, mild conditions, general substrate scope, and easy further transformations of the products. Further studies including mechanism and asymmetric catalysis are ongoing in this laboratory and will be reported in due course.

Scheme 5. Synthetic Transformations

group in 3aa could be selectively hydrogenated to produce the corresponding 5aa in 89% yield. The oxidative cleavage of all double bonds was realized by ozonolysis followed by reductive workup, which give the γ-lactam 6aa bearing a quaternary allcarbon stereocenter in good yield and excellent diastereoselectivity. In addition, reduction of the carbonyl group with DIBAL-H afforded 7aa in 90% yield with 3:1 dr. Finally, 2,3dihydropyrole 8aa was obtained in high yield by treatment of 3aa with TsOH−H2O. To gain insight into the reaction mechanism, we examined the reaction of (R)-1a (98% ee) with 2a catalyzed by rhodium and iridium catalysts, respectively (Scheme 6a). The reaction catalyzed by [Rh(NBD)Cl]2/AgSbF6 gave (+)-3aa in 80% ee. In contrast, racemic 3aa was obtained when [Ir(COD)Cl]2/ AgSbF6 was used as the catalyst. Further control experiments revealed that (R)-1a would undergo more rapid racemization in the presence of iridium catalyst than the reaction catalyzed by rhodium catalyst (Scheme 6b). Moreover, the treatment of 1a and 2a with [Ir(COD)Cl]2/AgSbF6 in the presence of 4 Å molecular sieves in DCE for 30 min provided the desired 9aa in 98% NMR yield (Scheme 6c). On the basis of the above results, a plausible mechanism is proposed for the current reaction (Scheme 7). Coordination of vinylaziridine 1 to the iridium catalyst gives complex A, which

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge via the Internet at . Experimental procedures, 1H and 13C NMR spectra and HPLC date for all new products (PDF) X-ray crystallographic data for (R)-3ha(CIF) The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03232. Experimental procedures, 1H and 13C NMR spectra, and HPLC data for all new products and X-ray data for 3ha (PDF) Accession Codes

CCDC 1572755 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 6528

DOI: 10.1021/acs.orglett.7b03232 Org. Lett. 2017, 19, 6526−6529

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Organic Letters

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(8) (a) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. J. Am. Chem. Soc. 2015, 137, 3787. (b) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 15854. (c) Feng, J.-J.; Lin, T.-Y.; Zhu, C.-Z.; Wang, H.; Wu, H.-H.; Zhang, J. J. Am. Chem. Soc. 2016, 138, 2178. (d) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Angew. Chem., Int. Ed. 2017, 56, 1351. (e) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Chem. Commun. 2017, 53, 4688. (9) Representative examples for synthesis of 2-methylene-pyrrolidines and 2-pyrrolines: (a) Liu, K.; Zhu, C.; Min, J.; Peng, S.; Xu, G.; Sun, J. Angew. Chem., Int. Ed. 2015, 54, 12962. (b) Lin, T.-Y.; Zhu, C.-Z.; Zhang, P.; Wang, Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 10844. (c) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Youji Huaxue 2017, 37, 1165. (d) Jing, C.; Xing, D.; Qian, Y.; Shi, T.; Zhao, Y.; Hu, W. Angew. Chem., Int. Ed. 2013, 52, 9289. (e) Jiang, H.; He, J.; Liu, T.; Yu, J.Q. J. Am. Chem. Soc. 2016, 138, 2055. (f) Ma, S.; Yu, F.; Li, J.; Gao, W. Chem. - Eur. J. 2007, 13, 247. (g) Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989. (h) Walker, P. R.; Campbell, C. D.; Suleman, A.; Carr, G.; Anderson, E. A. Angew. Chem., Int. Ed. 2013, 52, 9139. (i) Larquetoux, L.; Kowalska, J. A.; Six, Y. Eur. J. Org. Chem. 2004, 2004, 3517. (j) Mourad, A. K.; Leutzow, J.; Czekelius, C. Angew. Chem., Int. Ed. 2012, 51, 11149. (k) Wender, P. A.; Strand, D. J. Am. Chem. Soc. 2009, 131, 7528. (l) Fan, J.; Gao, L.; Wang, Z. Chem. Commun. 2009, 134, 5021. (10) The rhodium-catalyzed ring-opening of vinylaziridine is different from the current reaction catalyzed by iridium catalyst, which may lead to an enyl (σ+π) iridium intermediate with the retention of configuration formed by oxidative addition. For pioneering work on the enyl (σ+π) rhodium species, see: (a) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. For recent work on the rhodium-catalyzed allylic substitution reaction, see: (b) Evans, P. A.; Oliver, S.; Chae, J. J. Am. Chem. Soc. 2012, 134, 19314. (c) Turnbull, B. W. H.; Oliver, S.; Evans, P. A. J. Am. Chem. Soc. 2015, 137, 15374. (d) Loh, C. C. J.; Schmid, M.; Webster, R.; Yen, A.; Yazdi, S. K.; Franke, P. T.; Lautens, M. Angew. Chem., Int. Ed. 2016, 55, 10074. For a review, see: (e) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48. (f) Leahy, D. K.; Evans, P. A. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Eds.; Wiley-VCH: Weinheim, 2005; Vol. 10, pp 191−214. (11) For recent work on the iridium-catalyzed allylic substitution reaction, see: (a) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647. (b) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741. (c) Liu, X.-J.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 4002. (d) Tu, H.-F.; Zheng, C.; Xu, R.-Q.; Liu, X.-J.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 3237. (e) Yang, Z.-P.; Wu, Q.-F.; Shao, W.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 15899. (f) Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc. 2016, 138, 11093. (g) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 8136. (h) Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7228. (i) Madrahimov, S. T.; Li, Q.; Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 14968. (j) Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603. (k) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2017, 56, 11545. For reviews, see: (l) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258. (m) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (n) Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (o) Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169. (p) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558. (q) Liu, W. B.; Xia, J.-B.; You, S.-L. Top. Organomet. Chem. 2011, 38, 155.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hai-Hong Wu: 0000-0001-6266-8290 Jian-Jun Feng: 0000-0002-6094-3268 Junliang Zhang: 0000-0002-4636-2846 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (21373088, 21425205, 21602062), 973 Program (2015CB856600), and Innovative Research Team in University.

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