Stereoselective Synthesis of Fully Substituted β-Lactams via Metal

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

pubs.acs.org/OrgLett

Stereoselective Synthesis of Fully Substituted β‑Lactams via Metal− Organo Relay Catalysis Long Chen, Kai Wang, Ying Shao, and Jiangtao Sun* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China

Org. Lett. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 05/02/19. For personal use only.

S Supporting Information *

ABSTRACT: A novel three-component reaction of N-hydroxyanilines, enynones, and diazo compounds has been developed via a metal−organo relay catalysis, providing highly functionalized β-lactams containing two quaternary carbon centers in good yields and with excellent diastereoselectivities. This protocol features a sequential reaction of Rh-catalyzed imine formation, Wolff rearrangement, and benzoylquinine-catalyzed Staudinger cyclization using the stable, benign, and readily available Nhydroxyanilines as the N-resources.

E

lectrophilic 2-furyl metal−carbene intermediates,1 generated in situ from the reaction of enynones and transition-metal catalysts, have been intensively investigated and led to the emergence of various transformations in the past decades, including oxidation,2 cyclopropanation,3 aziridination,4 C−H and X−H insertion,5 olefin formation,6 and other valuable transformations (Scheme 1a).7 The versatile reactivity of 2-furyl metal−carbene has inspired chemists to develop novel transformations which cannot be easily achieved by other methods. β-Lactams are prevalent scaffolds found in numerous bioactive compounds and natural products.8 Such fourmembered N-heterocycles which show a wide spectrum of biological activities have attracted chemists to design and develop rational strategies for rapidly assembling polyfunctionalized and synthetically challenging β-lactams.9 In return, this might enable the development of useful synthetic methodologies and the creation of valuable β-lactam scaffolds in drug discovery. In continuation of our research of metal−carbeneinvolved heterocycle synthesis,10 we report herein the synthesis of fully substituted β-lactams incorporated with a furyl group by the reaction of N-hydroxyanilines, enynones, and diazo compounds via a metal−organo relay catalysis (Scheme 1b). Of particular note, different from traditional X−H insertion reactions for C−X single bond formation,5,11 the reaction of Nhydroxyanilines (amphiphilic X−H nucleophiles with O and N nucleophilic properties)12 with 2-furyl rhodium−carbene formed a CN double bond to generate imines as the unique products. We commenced our studies on the one-pot reaction to achieve the β-lactam formation. Initially, N-hydroxyaniline 1a, © XXXX American Chemical Society

Scheme 1. Previous Reports and Our Design

enynone 2a, and diazo compound 3a were utilized as model substrates to establish the optimal reaction conditions (Table 1). Upon examining various reaction parameters, we found that Received: April 10, 2019

A

DOI: 10.1021/acs.orglett.9b01255 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

Scheme 2. Substrate Scopea,b

entry

variation from the standard reaction conditions

yield of 4ab (%)

yield of 5ab (%)

1 2 3 4 5 6 7 8 9 10

none C2 instead of C1 C3 instead of C1 C4 instead of C1 C5 instead of C1 Rh2(esp)2 instead of Rh2(OAc)4 Rh2(OPiv)4 instead of Rh2(OAc)4 Rh2(Oct)4 instead of Rh2(OAc)4 no C1 reaction was run at 60 °C

85 46 60 62 50 46 20:1). Next, the scope of enynones (2) was examined. The R2 groups

a Standard reaction conditions. bIsolated yields dr ratios were determined by NMR analysis of crude products. cThe reaction was performed at 140 °C.

of enynones such as electron-rich and electron-deficient aryls, ferrocene, and cyclopropane all reacted well to deliver the desired products (4g−k) in good yields (62−90%) with excellent dr values. It should be noted that a high reaction temperature is required for 4h and 4i. The R1 of enynones such as carboxylate and benzenesulfonyl were also tolerated, yielding 4l and 4m in 73% and 54% yield, respectively. Finally, the scope of diazo compounds has been evaluated. Both electron-rich and electron-deficient phenyl groups, thienyl groups, and vinyl groups were all suitable substrates, and the B

DOI: 10.1021/acs.orglett.9b01255 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters desired products (4n−s) were obtained in moderate to good yields (51−88%) with excellent dr values (>20:1) except 4o (dr = 15:1). The structure of the products was determined by NMR analysis and further proved by X-ray analysis of 4a. As mentioned above, imine 5a was isolated as the major product in the absence of an organic base (Table 1, entry 9). Clearly, the reaction of 1 and 2 only gave imines as the unique products under rhodium catalysis. Thus, after optimizing the reaction parameters, we determined that 1 mol % of Rh2(OAc)4 can efficiently catalyze the imine formation at ambient temperature for 10 min, providing 5a in 97% yield (see the Supporting Information for details). We then subjected this protocol for a range of imine formation (Scheme 3). The N-hydroxyanilines bearing various electron-donating

Scheme 4. Control Experiments

Scheme 3. Rhodium-Catalyzed Imine Formation from Enynonesa,b

Figure 1. Proposed reaction mechanism.

imine formation, Wolff rearrangement,14 and Staudinger cyclization.15 The whole sequence is initiated by 2-furyl carbene (I) formation. The reaction of amphiphilic nucleophile N-hydroxyaniline 1a with I might generate two ylide intermediates IIA and IIB via N- or O-attack.12 Intramolecular migration or rearrangement would produce intermediates IIIA or IIIB, which release a molecular of H2O to afford the imine 5a. Rh-catalyzed Wolff rearrangement of 3a occurs to yield ketene V. The nucleophilic benzoylquinine (C1) would attack V to form enolate VI. Subsequent intermolecular attack of VI to 5a generates intermediate VII. Then intramolecular cyclization leads to 4a and recovers the organic catalyst. Notably, an umpolung Staudinger cyclization occurs to give 4a in a cis-configuration, in which the imine acts as an electrophile and the ketene-derived enloate VI acts as a nucleophile.13,16 In summary, we have developed a novel three-component reaction to prepare fully substituted β-lactams in good yields and excellent diastereoselectivities (cis only) using Nhydroxyanilines, enynones, and diazo compounds as the starting materials. The reaction proceeds through rhodiumcatalyzed imine formation and sequential Staudinger reaction of ketene with imine to deliver the final products. Notably, a novel imine formation has also been developed by the reaction of N-hydroxyanilines with metal−carbene intermediates.

a

Reactions were carried out with 1 (0.2 mmol), 2 (0.2 mmol), Rh2(OAc)4 (1 mol %) in CH2Cl2 (4 mL) at rt for 10 min. bIsolated yields. The imines were obtained as mixture of stereoisomers.

and electron-withdrawing substituents on the phenyl ring all reacted smoothly with enynone 2a to furnish imines (5b−g) in excellent yields. For the scope of enynones, the reaction tolerated different aryl substituents at the R2 position, furnishing the corresponding imines in excellent yields (5h− k). The reaction of 1a with ferrocene-substituted enynone gave 5l in 89% yield. The use of cyclopropane-substituted enynone afforded 5m in 93% yield. The carboxylate and sulfonyl groups of R1 were amenable to the reaction, and the desired products were obtained over 90% yield. Control experiments were conducted to understand the reaction process. The reaction of 3a and imine 5a catalyzed by Rh2(OAc)4 and C1 provided 4a in 90% yield (Scheme 4, eq 1). Without Rh2(OAc)4, no 4a formed. This indicated that Rh2(OAc)4 not only catalyzed the imine formation but also promoted the Wolff rearrangement of diazo 3 to ketene.14 No reaction occurred between 1a and 3a, only the self-reaction of 1a and the recovery of 3a (Scheme 4, eq 2).12 Moreover, the reaction of 1a′ with 2a did not yield imine 5a (Scheme 4, eq 3), which excluded the initial formation of 1a′ followed by reacting with 2a to form the CN bond. A plausible mechanism has been proposed as Figure 1. Three catalytic cycles exist for the formation of 4a, namely

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01255. C

DOI: 10.1021/acs.orglett.9b01255 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Zhu, S. Angew. Chem., Int. Ed. 2018, 57, 12405. (h) Okamoto, K.; Watanabe, M.; Mashida, A.; Miki, K.; Ohe, K. Synlett 2013, 24, 1541. (8) For selected reviews, see: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437. (b) Pitts, C. R.; Lectka, T. Chem. Rev. 2014, 114, 7930. (9) For recent selected examples, see: (a) Pedroni, J.; Boghi, M.; Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 9064. (b) Li, W.; Liu, C.; Zhang, H.; Ye, K.; Zhang, G.; Zhang, W.; Duan, Z.; You, S.; Lei, A. Angew. Chem., Int. Ed. 2014, 53, 2443. (c) Wang, Y.; Zheng, Z.; Zhang, L. Angew. Chem., Int. Ed. 2014, 53, 9572. (d) Xu, X.; Deng, Y.; Yim, D. N.; Zavalij, P. Y.; Doyle, M. P. Chem. Sci. 2015, 6, 2196. (e) Huang, Z.; Wang, C.; Tokunaga, E.; Sumii, Y.; Shibata, N. Org. Lett. 2015, 17, 5610. (f) Dailler, D.; Rocaboy, R.; Baudoin, O. Angew. Chem., Int. Ed. 2017, 56, 7218. (g) Hogg, K. F.; Trowbridge, A.; Alvarez-Pérez, A.; Gaunt, M. J. Chem. Sci. 2017, 8, 8198. (h) Shu, T.; Zhao, L.; Li, S.; Chen, X.-Y.; von Essen, C.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2018, 57, 10985. (10) (a) Liu, K.; Zhu, C.; Min, J.; Peng, S.; Xu, G.; Sun, J. Angew. Chem., Int. Ed. 2015, 54, 12962. (b) Zhu, C.; Xu, G.; Sun, J. Angew. Chem., Int. Ed. 2016, 55, 11867. (c) Xu, G.; Liu, K.; Sun, J. Org. Lett. 2017, 19, 6440. (d) Min, J.; Xu, G.; Sun, J. Chem. Commun. 2017, 53, 4350. (e) Liu, S.; Yang, P.; Peng, S.; Zhu, C.; Cao, S.; Li, J.; Sun, J. Chem. Commun. 2017, 53, 1152. (11) For a review, see: Gillingham, D.; Fei, N. Chem. Soc. Rev. 2013, 42, 4918. (12) (a) Wang, Y.; Ye, L.; Zhang, L. Chem. Commun. 2011, 47, 7815. (b) Wang, Y.; Liu, L.; Zhang, L. Chem. Sci. 2013, 4, 739. (c) Chen, J.M.; Chang, C.-J.; Ke, Y.-J.; Liu, R.-S. J. Org. Chem. 2014, 79, 4306. (d) Huple, D. B.; Mokar, B. D.; Liu, R.-S. Angew. Chem., Int. Ed. 2015, 54, 14924. (e) Fisher, D. J.; Burnett, G. L.; Velasco, R.; Read de Alaniz, J. J. Am. Chem. Soc. 2015, 137, 11614. (f) Mokar, B. D.; Huple, D. B.; Liu, R.-S. Angew. Chem., Int. Ed. 2016, 55, 11892. (g) Kulandai Raj, A. S.; Kale, B. S.; Mokar, B. D.; Liu, R.-S. Org. Lett. 2017, 19, 5340. (h) Hsu, Y.-C.; Hsieh, S.-A.; Li, P.-H.; Liu, R.-S. Chem. Commun. 2018, 54, 2114. (13) (a) France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206. (b) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592. (14) (a) Taylor, E. C.; Davies, H. M. L. Tetrahedron Lett. 1983, 24, 5453. (b) Kirmse, W. Eur. J. Org. Chem. 2002, 2002, 2193. (c) Mandler, M. D.; Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Org. Lett. 2014, 16, 740. (15) For selected reviews on the Staudinger cyclization, see: (a) Tuba, R. Org. Biomol. Chem. 2013, 11, 5976. (b) Cossío, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925. (c) Fu, N.; Tidwell, T. T. Tetrahedron 2008, 64, 10465. (16) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060.

Experimental procedures along with characterizing data and copies of NMR spectra (PDF) Accession Codes

CCDC 1860108 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

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

Ying Shao: 0000-0002-7379-8266 Jiangtao Sun: 0000-0003-2516-3466 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (No. 21572024), Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology (BM2012110), and the Green Manufacturing Collaborative Innovation Center for their financial support.

■

REFERENCES

(1) For leading reviews, see: (a) Chen, L.; Chen, K.; Zhu, S. Chem. 2018, 4, 1208. (b) Chen, L.; Liu, Z.; Zhu, S. Org. Biomol. Chem. 2018, 16, 8884. (2) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001, 123, 5814. (3) (a) Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 5260. (b) Vicente, R.; González, J.; Riesgo, L.; González, J.; López, L. A. Angew. Chem., Int. Ed. 2012, 51, 8063. (c) Ma, J.; Jiang, H.; Zhu, S. Org. Lett. 2014, 16, 4472. (d) González, M. J.; López, E.; Vicente, R. Chem. Commun. 2014, 50, 5379. (4) Luo, H.; Chen, K.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 5208. (5) (a) Clark, J. S.; Boyer, A.; Aimon, A.; García, P. E.; Lindsay, D. M.; Symington, A. D. F.; Danoy, Y. Angew. Chem., Int. Ed. 2012, 51, 12128. (b) González, J.; González, J.; Pérez-Calleja, C.; López, L. A.; Vicente, R. Angew. Chem., Int. Ed. 2013, 52, 5853. (c) Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu, S. Angew. Chem., Int. Ed. 2016, 55, 8452. (d) Yu, Y.; Yi, S.; Zhu, C.; Hu, W.; Gao, B.; Chen, Y.; Wu, W.; Jiang, H. Org. Lett. 2016, 18, 400. (e) Yang, J.-M.; Li, Z.-Q.; Li, M.-L.; He, Q.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2017, 139, 3784. (f) Ren, Y.; Meng, L.-G.; Peng, T.; Wang, L. Org. Lett. 2018, 20, 4430. (g) Wang, K.; Chen, P.; Ji, D.; Zhang, X.; Xu, J.; Sun, J. Angew. Chem., Int. Ed. 2018, 57, 12489. (6) (a) Xia, Y.; Qu, S.; Xiao, Q.; Wang, Z.-X.; Qu, P.; Chen, L.; Liu, Z.; Tian, L.; Huang, Z.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2013, 135, 13502. (b) González, J.; López, L. A.; Vicente, R. Chem. Commun. 2014, 50, 8536. (c) Mata, S.; González, M. J.; González, J.; López, L. A.; Vicente, R. Chem. - Eur. J. 2017, 23, 1013. (d) Liu, P.; Sun, J. Org. Lett. 2017, 19, 3482. (7) (a) Xia, Y.; Chen, L.; Qu, P.; Ji, G.; Feng, S.; Xiao, Q.; Zhang, Y.; Wang, J. J. Org. Chem. 2016, 81, 10484. (b) Hong, S. Y.; Jeong, J.; Chang, S. Angew. Chem., Int. Ed. 2017, 56, 2408. (c) Yu, Y.; Chen, Y.; Wu, W.; Jiang, H. Chem. Commun. 2017, 53, 640. (d) Zhu, C.-Z.; Sun, Y.-L.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2017, 359, 1263. (e) Liang, L.; Dong, X.; Huang, Y. Chem. - Eur. J. 2017, 23, 7882. (f) Dong, J.; Bao, L.; Hu, Z.; Ma, S.; Zhou, X.; Hao, M.; Li, N.; Xu, X. Org. Lett. 2018, 20, 1244. (g) Zhu, D.; Chen, L.; Zhang, H.; Ma, Z.; Jiang, H.; D

DOI: 10.1021/acs.orglett.9b01255 Org. Lett. XXXX, XXX, XXX−XXX