Oxidative Dehydrogenative [2 + 3]-Cyclization of Glycine Esters with

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Oxidative Dehydrogenative [2 + 3]-Cyclization of Glycine Esters with Aziridines Leading to Imidazolidines Haitao Li, Songhai Huang, Yajun Wang, and Congde Huo* Key Laboratory of Eco-Environment-Related Polymer Materials of Ministry of Education, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China S Supporting Information *

ABSTRACT: Oxidative dehydrogenative [2 + 3]-cyclization of glycine derivatives with N-sulfonylaziridines is described. A series of complex imidazolidines were produced under mild and simple reaction conditions. A mechanism involving an unusual acid-promoted auto-oxidation is proposed.

midazolidines are an important class of five-membered nitrogen-containing heterocycles that are associated with a broad spectrum of biological activities.1 For instance, some highly functionalized imidazolidines have been found to possess high and selective activity against the proliferative stages of the parasite and can be regarded as anti-Trypanosoma cruzi agents.2 Some imidazolidines have shown anti-inflammatory and analgesic activity,3 and some have nanomolar σ1 affinities and relatively low levels of subtype selectivity.4 In addition, imidazolidines are also widely applied in organometallic chemistry as auxiliaries and ligands.5 Synthetic methods for imidazolidines have been investigated for more than a century. The preparation of simple and symmetrical imidazolidines dates back to 1898.6 Since then, various methods have been developed for the construction of imidazolidine skeletons.7 Because of their unique structural characteristics, the development of versatile methods to synthesize highly functionalized imidazolidines from easily accessible starting materials with a simple operation is still highly desired nowadays. Glycine is the simplest and cheapest natural amino acid on earth. It can be manufactured industrially by treating chloroacetic acid with ammonia. In 2011, an oxidative Povarov/aromatization tandem reaction of N-arylglycine derivatives with alkenes was reported by Richter and Mancheño.8 Since then, oxidative dehydrogenative [4 + 2]-cyclization of N-arylglycine derivatives with electron-rich multiple bonds to form substituted quinoline motifs has been extensively studied (Scheme 1a).9 Since 2014, oxidative dehydrogenative [2 + 3]-cyclization of glycine derivatives has been presented (Scheme 1b). In 2014, Xiao and co-workers reported a visible-light-induced aerobic oxidation/[2 + 3]-cycloaddition/aromatization cascade reaction between glycine derivatives and isocyanides to construct imidazoles.10 In 2015, Liu and co-workers developed a copper-catalyzed aerobic oxidation/[3 + 2]-cycloaddition/oxidative aromatization tandem reaction of glycine derivatives with ethyl diazoacetate to deliever 1,2,3-triazoles.11 We demonstrated a copper-catalyzed aerobic oxidative dehydrogenative formal [2 + 3]-cyclization of glycine derivatives with α-angelicalactone to form complex pyrrolidones in 2015,12a and very recently Wang and co-workers

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© XXXX American Chemical Society

Scheme 1. Oxidative Dehydrogenative Cyclization of Glycine Derivatives

realized the synthesis of 4,5-biscarbonylimidazoles using a similar strategy.12b Received: November 6, 2017

A

DOI: 10.1021/acs.orglett.7b03448 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

or not effective for the process. We then found that the yield of the desired product 3aa was slightly increased to 52% when the loading of the catalyst was decreased to 5% (Table 1, entry 8). Other oxidants such as tert-butyl hydroperoxide (TBHP), tertbutyl peroxybenzoate (TBPB), and di-tert-butyl peroxide (DTBP) were less effective for this transformation. To our delight, the addition of a Brønsted acid accelerates the transformation observably, and acid screening revealed that trifluoroacetic acid (TFA) was the best choice for the reaction (Table 1, entry 17). Other reaction parameters, such as the solvent and reaction temperature were screened also. Finally, the optimal reaction conditions were found to be Cu(OTf)2 (5 mol %) and TFA (20 mol %) in toluene under an oxygen atmosphere at 100 °C. With the optimized reaction conditions successfully established, the scope and generality of this aerobic oxidative dehydrogenative formal [2 + 3]-cyclization reaction of glycine esters with aziridines is illustrated in Scheme 2. It was observed that the desired imidazolidines were obtained in good to high yields with both electron-donating and -withdrawing groups on the phenyl ring of 1 (3aa−ka) (Scheme 2). Polysubstituted glycine ester 1l also delivered the corresponding product 3la in good yield (Scheme 2). However, when ethyl phenylglycinate was used as a substrate, the ring-opened compound could be isolated in high yield, but no desired ring-closed product was observed. Subsequently, substrates with different ester groups were investigated, and the reaction proceeded smoothly to afford the desired products in high yields (3aa, 3ma−wa) (Scheme 2). The allyl group was tolerated in this transformation. It is worth noting that 1s derived from dehydroisoandrosterone (DHEA) was also a suitable substrate for the reaction under the standard conditions, affording the desired product 3sa in 58% isolated yield. This product may have potential utilities in pharmaceutical chemistry. This specific example also helps demonstrate the methodology’s value in providing rapid access to complex compounds. Next, the scope of N-tosylaziridines was investigated. To our delight, aziridines bearing various functional groups on the phenyl ring were tolerated well, delivering the desired products in good yields (3aa−aj) (Scheme 2). Alkylsubstituted aziridine 2k also delivered the corresponding product 3ak in good yield (Scheme 2). The N-benzoyl analogue of 2a was found to be a poor substrate. No desired product was observed under the standard reaction conditions. This transformation showed satisfactory tolerance of halogen atoms (3ia−ka, 3ad− ah) (Scheme 2), which provide useful handles for further transformations. Moreover, substitution with a fluorine atom can also have a significant effect on the pharmacological properties of organic molecules. To demonstrate the efficiency and practicality of this transformation, a scaled-up reaction was performed. The gramscale synthesis of ethyl 4-phenyl-3-(p-tolyl)-1-tosylimidazolidine-2-carboxylate (3aa) was achieved in 66% yield. To gain further insight into the mechanism of this transformation, a series of control reactions were carried out. It was found that intermediate A could be isolated in high yield when the reaction was performed in the presence of a Lewis acid such as Y(OTf)3 (78%), Sc(OTf)3 (76%), or BF3 (69%) for 1 h and in 31% yield even without any catalyst in 1 h (Scheme 3a). The structure of A was identified by X-ray crystallographic analysis.16 These results suggest that Cu(OTf)2 acts as a Lewis acid catalyst to promote the generation of intermediate A. When compound A was subjected to the standard reaction conditions we observed that product 3aa was formed in high yield within 3 h (Scheme 3b,

Aziridines, easily available strained three-membered cyclic amines, have been extensively exploited in the preparation of diverse nitrogen-containing heterocycles.13 They can be considered as masked 1,3-dipoles that can undergo formal [3 + 2]-cyclization with dipolarophiles.14 On the other hand, glycine derivatives can be considered as precursors of dipolarophiles (involving the oxidation of secondary amines to imines). On the basis of these theories, we became interested in determining whether it would be possible to develop a formal [3 + 2]cyclization reaction of aziridines with glycine derivatives to form complex imidazolidines in an oxidative dehydrogenative manner (Scheme 1c). Initially, the reaction of glycine ester 1a and 2-phenyl-1tosylaziridine (2a) was employed to probe the expected transformation. We were pleased to find that the corresponding product 3aa could be obtained in 49% yield by employing Cu(OTf)2 (10 mol %) as the catalyst in toluene at 100 °C under an O2 atmosphere (balloon) for 20 h (Table 1, entry 3). 3aa was Table 1. Screening of Reaction Conditionsa,b,c

a b

Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (3 mL). Isolated yields of the isolated products are shown. cO2 balloon.

obtained as a pair of separable diastereoisomers (2:1). The cis isomer was identified as the major stereoisomer and the trans isomer as the minor stereoisomer in accordance with the singlecrystal X-ray diffraction results, as shown in Table 1.15 The formation of the 2,4-cis isomer as the major product might have occurred because attack of the carbocation from the back side is easier as a result of lower steric hindrance. Other metal salts such as CuCl2, CuCl, Cu(OAc)2, Fe(OTf)2, and Ni(OTf)2 were less B

DOI: 10.1021/acs.orglett.7b03448 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Oxidative Dehydrogenative [2 + 3]-Cyclization Reaction of Glycine Esters with Aziridinesa,b

Scheme 3. Control Experiments

transformation of A to 3aa is an auto-oxidation process. Cu(OTf)2 is not a catalyst for this step. The Brønsted acid can accelerate this O2-induced process. The reaction of A in the absence of molecular oxygen (argon atmosphere) furnished no product (Scheme 3b, entry 5). Furthermore, no reaction occurred when a stoichiometric amount of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or butylated hydroxytoluene (BHT) was employed in the standard reaction as a radical scavenger (Scheme 3b, entries 6 and 7). These results suggest that dioxygen is definitely crucial for the oxidative cyclization and that the reaction includes a radical process. The reaction of imine D with 2a achieved no desired product under the standard reaction conditions (Scheme 3c). This result indicates that compound A, not D, is the intermediate in this transformation. Moreover, hydroperoxide B was detected by HRMS under the standard conditions. When manganese dioxide (5 mol %) was added at the end of the template reaction, gas was evolved. This result may suggest the generation of hydrogen peroxide in the reaction process because MnO2 can catalyze the decomposition of H2O2 into O2 and H2O. According to these results, we were able to propose a tentative mechanism for this oxidative dehydrogenative formal [2 + 3]cyclization reaction, as shown in Scheme 4. Aziridine 1a is initially attacked by glycine derivative 2a to form ring-opened intermediate A (SN2). Intermediate A is then auto-oxidized to give hydroperoxide intermediate B.17,9a Subsequently, iminium ion intermediate C is then formed from B through an acidcatalyzed SN1-type procedure. Finally, intramolecular C−N bond formation results in the desired product 3aa. In summary, we have achieved a straightforward and efficient aerobic oxidative dehydrogenative formal [2 + 3]-cyclization of glycine derivatives with aziridines. The reaction provides facile access to a series of highly functionalized imidazolidine derivatives in an atom-economical manner from easily available starting materials under simple reaction conditions. Further

a

Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Cu(OTf)2 (5 mol %), TFA (20 mol %), toluene (3 mL), O2, 100 °C, 3−10 h. bYields of isolated products and diastereomeric ratios are shown in parentheses.

entry 1). When we subjected A to the reaction conditions but without copper salt, the cyclization product 3aa was formed in essentially quantitative yield in a shorter time (Scheme 3b, entry 3). Moreover, when we subjected A to the reaction conditions but without copper salt and acid (auto-oxidation conditions), we observed full conversion to the cyclization product 3aa in a longer time (Scheme 3b, entry 4). These results suggest that the C

DOI: 10.1021/acs.orglett.7b03448 Org. Lett. XXXX, XXX, XXX−XXX

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Chem. Soc. 2011, 133, 4260. (e) Arai, T.; Tsuchiya, K.; Matsumura, E. Org. Lett. 2015, 17, 2416. (f) Prieto, A.; Halland, N.; Jorgensen, K. A. Org. Lett. 2005, 7, 3897. (6) Bischoff, C. A. Ber. Dtsch. Chem. Ges. 1898, 31, 3248. (7) (a) Swain, S. P.; Shih, Y.-C.; Tsay, S.-C.; Jacob, J.; Lin, C.-C.; Hwang, K.; Horng, J.-C.; Hwu, J. Angew. Chem., Int. Ed. 2015, 54, 9926. (b) Saima, Y.; Khamarui, S.; Gayen, K. S.; Pandit, P.; Maiti, D. K. Chem. Commun. 2012, 48, 6601. (c) Xie, H.; Zhu, J.; Chen, Z.; Li, S.; Wu, Y. J. Org. Chem. 2010, 75, 7468. (d) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Kondrashov, E. V.; Ushakov, I. A.; Rulev, A. U. J. Org. Chem. 2010, 75, 5679. (e) Xuan, J.; Cheng, Y.; An, J.; Lu, L.Q.; Zhang, X.-X.; Xiao, W.-J. Chem. Commun. 2011, 47, 8337. (f) Katritzky, A. R.; Suzuki, K.; He, H.-Y. J. Org. Chem. 2002, 67, 3109. (8) Richter, H.; Mancheño, O. G. Org. Lett. 2011, 13, 6066. (9) (a) Huo, C.; Yuan, Y.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Angew. Chem., Int. Ed. 2014, 53, 13544. (b) Ni, M.; Zhang, Y.; Gong, T.; Feng, B. Adv. Synth. Catal. 2017, 359, 824. (c) Sonobe, T.; Oisaki, K.; Kanai, M. Chem. Sci. 2012, 3, 3249. (d) Xie, Z. Y.; Jia, J.; Liu, X. G.; Liu, L. Adv. Synth. Catal. 2016, 358, 919. (e) Huo, C.; Xie, H.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Chem. - Eur. J. 2015, 21, 5723. (f) Huo, C.; Xie, H.; Chen, F.; Tang, J.; Wang, Y. Adv. Synth. Catal. 2016, 358, 724. (g) Rohlmann, R.; Stopka, T.; Richter, H.; Mancheño, O. G. J. Org. Chem. 2013, 78, 6050. (h) Liu, P.; Wang, Z.; Lin, J.; Hu, X. Eur. J. Org. Chem. 2012, 2012, 1583. (10) Deng, Q.-H.; Zou, Y.-Q.; Lu, L.-Q.; Tang, Z.-L.; Chen, J.-R.; Xiao, W.-J. Chem. - Asian J. 2014, 9, 2432. (11) Li, Y.-J.; Li, X.; Zhang, S.-X.; Zhao, Y.-L.; Liu, Q. Chem. Commun. 2015, 51, 11564. (12) (a) Huo, C.; Yuan, Y.; Chen, F.; Tang, J.; Wang, Y. Org. Lett. 2015, 17, 4208. (b) Xie, J.; Huang, Y.; Song, H.; Liu, Y.; Wang, Q. Org. Lett. 2017, 19, 6056. (13) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, Germany, 2006. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (c) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41, 643. (d) Huo, C.; Sun, C.; Hu, D.; Jia, X.; Xu, X.; Liu, Z. Tetrahedron Lett. 2011, 52, 7008. (14) (a) Baeg, J. O.; Bensimon, C.; Alper, H. J. Am. Chem. Soc. 1995, 117, 4700. (b) Munegumi, T.; Azumaya, I.; Kato, T.; Masu, H.; Saito, S. Org. Lett. 2006, 8, 379. (c) Madhushaw, R. J.; Hu, C.-C.; Liu, R.-S. Org. Lett. 2002, 4, 4151. (d) Nakagawa, M.; Kawahara, M. Org. Lett. 2000, 2, 953. (e) Gandhi, S.; Bisai, A.; Prasad, B. A. B.; Singh, V. J. Org. Chem. 2007, 72, 2133. (f) Baeg, J. O.; Alper, H. J. Org. Chem. 1992, 57, 157. (g) Maas, H.; Bensimon, C.; Alper, H. J. Org. Chem. 1998, 63, 17. (h) Sudo, A.; Morioka, Y.; Koizumi, E.; Sanda, F.; Endo, T. Tetrahedron Lett. 2003, 44, 7889. (15) CCDC no. 1581865 (3aa-cis); CCDC no. 1581866 (3aa-trans). (16) CCDC no. 1581867 (intermediate A). (17) (a) Pinter, A.; Sud, A.; Sureshkumar, D.; Klussmann, M. Angew. Chem., Int. Ed. 2010, 49, 5004. (b) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 7156. (c) Chudasama, V.; Fitzmaurice, R.-J.; Caddick, S. Nat. Chem. 2010, 2, 592. (d) Wang, Y.; Jiang, W.; Huo, C. J. Org. Chem. 2017, 82, 10628.

Scheme 4. Reaction Mechanism

studies on expanding this strategy to the synthesis of other heterocylces are currently underway.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03448. Experimental details, compound characterization, and NMR spectra (PDF) Accession Codes

CCDC 1581865−1581867 contain 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Congde Huo: 0000-0002-3374-7931 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21562037) for financial support of this work. REFERENCES

(1) (a) Jiao, R.-H.; Xu, S.; Liu, J.-Y.; Ge, H.-M.; Ding, H.; Xu, C.; Zhu, H.-L.; Tan, R.-X. Org. Lett. 2006, 8, 5709. (b) Ijzendoorn, D. R.; Botman, P. N. M.; Blaauw, R. H. Org. Lett. 2006, 8, 239. (c) Sakai, R.; Suzuki, K.; Shimamoto, K.; Kamiya, H. J. Org. Chem. 2004, 69, 1180. (d) Katritzky, A. R.; He, H.-Y.; Wang, J. J. Org. Chem. 2002, 67, 4951. (e) Katritzky, A. R.; He, H.-Y.; Verma, A. K. Tetrahedron: Asymmetry 2002, 13, 933. (2) Caterina, M. C.; Perillo, I. A.; Boiani, L.; Pezaroglo, H.; Cerecetto, H.; Gonzalez, M.; Salerno, A. Bioorg. Med. Chem. 2008, 16, 2226. (3) Sharma, V.; Khan, M. S. Y. Eur. J. Med. Chem. 2001, 36, 651. (4) Moussa, I. A.; Banister, S. D.; Manoli, M.; Doddareddy, M. R.; Cui, J.; Mach, R. H.; Kassiou, M. Bioorg. Med. Chem. Lett. 2012, 22, 5493. (5) (a) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (c) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132, 5338. (d) Allen, A. E.; MacMillan, D. W. C. J. Am. D

DOI: 10.1021/acs.orglett.7b03448 Org. Lett. XXXX, XXX, XXX−XXX