Arylsulfonyl Radical Triggered 1,6-Enyne Cyclization: Synthesis of γ

Letter Cite This: Org. Lett. 2018, 20, 449−452

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Arylsulfonyl Radical Triggered 1,6-Enyne Cyclization: Synthesis of γ‑Lactams Containing Alkenyl C−X Bonds Xia Cao, Xiao Cheng, and Jun Xuan* Department of Chemistry, Anhui University, Hefei, Anhui 230601, China S Supporting Information *

ABSTRACT: Cascade radical cyclization of 1,6-enynes for the synthesis of biologically important γ-lactams containing alkenyl C−X bonds is reported. In these radical cascade processes, three new chemical bonds, including C−S, C−C, and C−X bonds, are formed in one step. The method is attractive and valuable due to its mild reaction conditions, broad substrate scope, and the importance of the corresponding γ-lactam products. knowledge, the synthesis of γ-lactam structures via radical cascade cyclization of 1,n-enynes is a largely unexplored research area. In 2016, the Studer group reported an elegant method to construct polycyclic γ-lactams from the nitrogen-tethered 1,6enyne 1 via electron catalysis (Scheme 1).12 The reaction was

he γ-lactams are one of the most important five-membered heterocyclic compounds which can be widely found in a large number of biologically active natural isolates and drug candidates.1 As shown in Figure 1, the (+)-lactacystin is a

T

Scheme 1. 1,6-Enyne as Radical Acceptor for the Construction of Different Types of γ-Lactams

Figure 1. Examples of some biologically important molecules containing γ-lactam motifs.

structurally novel microbial product which was isolated from the Streptomyces strain.2 (−)-Pramanicin is an inhibitor of Cryptococcus neoformans which was isolated from a sterile fungus.3 More importantly, cynometrine appears to possess potential as an analgesic.4 Driven by their rich biological activity, various synthetic approaches toward γ-lactam skeletons, such as ring expansion of β-lactam derivatives,5 metal carbene C−H insertion,6 formal [3 + 2] annulations,7 and others,8 have been successfully developed in the past several years. Despite the above significant achievements, it is still highly desirable to develop novel and robust methodologies in the construction of γ-lactams so that the substitution patterns of these biologically important heterocycles can be further expanded. 1,n-Enynes have been identified as highly versatile substrates for the synthesis of cyclic ring compounds because of its generally easy to vary functionalities and ready accessibility. Traditionally, 1,n-enynes were most frequently used in transition-metal-catalyzed cyclization or cycloisomerization reactions.9 As potential radical acceptors, the utilization of 1,nenynes in radical cascade cyclization processes to construct carbocycles and heterocycles has also attracted considerable attention in the past four years.10,11 However, to the best of our © 2017 American Chemical Society

proposed starting from the addition of aryl radicals to the activated carbon−carbon double bond of 1,6-enyne 1, followed by 5-exo cyclization to give the key alkenyl radical intermediate A. In their case, the formed alkenyl radical was trapped by intramolecular cyclization onto arene to provide the final polycyclic γ-lactam products (R = Ar). Motivated by these findings, we assumed that the formed alkenyl radical intermediate A might be trapped by suitable radical partners through radical coupling if the R group is not arene. Considering the great synthetic potential of alkenyl C−X bonds,13 we herein demonstrate an arylsulfonyl radical triggered radical cyclization of 1,6-enyne 1. In our reaction, the formed alkenyl radical intermediate A could be successfully trapped by halogen atoms, Received: December 5, 2017 Published: December 29, 2017 449

DOI: 10.1021/acs.orglett.7b03794 Org. Lett. 2018, 20, 449−452

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Organic Letters

Scheme 2. Substrate Scope of Arylsulfonyl Hydrazidea

thus providing an efficient route to various biologically important γ-lactams which containing valuable alkenyl C−X bonds (Scheme 1). Initially, we investigated the reaction of nitrogen tethered 1,6enyne 1a and benzenesulfonyl hydrazide 2a by using tert-butyl hydroperoxide (TBHP) as the oxidant (Table 1). When 1.2 Table 1. Reaction Optimization between 1a and 2aa

entry

I source

solvent

t (°C)

yieldb (%)

c

NIS NIS NIS NIS NIS NIS NIS I2 n-Bu4NI NIS NIS

EtOAc DCE toluene Et2O 1,4-dioxane DMF CH3CN CH3CN CH3CN CH3CN CH3CN

80 80 80 80 80 80 80 80 80 60 40

91 90 89 91 88 NR 94 74 trace 86 80

1 2c 3c 4c 5c 6 7d 8c 9 10d 11d

a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), TBHP (0.2 mmol), and I source (0.12 mmol) in solvent (2.0 mL) were stirred at 80 °C for 16 h under argon atmosphere. bIsolated yield. cZ/E = 1.2:1. d Z/E = 1.6:1. TBHP = tert-butyl hydroperoxide. NIS = Niodosuccinimide

a

Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), TBHP (0.2 mmol), and NIS (0.12 mmol) in CH3CN (2.0 mL) were stirred at 80 °C for 16 h under argon atmosphere. bIsolated yield. cThe ratio of Z/ E isomer is detected by 1H NMR.

confirmed by X-ray diffraction analysis (Figure 2). Moreover, incorporation of a methyl or bromo group at the ortho-position

equiv of N-iodosuccinimide (NIS) was involved as the iodine source, 91% yield of the desired γ-lactam 3aa was obtained with EtOAc as the reaction media at 80 °C for 16 h (Table 1, entry 1). Encouraged by this preliminary result, other reaction parameters were systematically screened in order to further improve the reaction efficiency. As summarized in Table 1, excellent yields and moderate Z/E ratio of 3aa could be obtained when the reaction was performed in other solvents, such as DCE, toluene, Et2O, and 1,4-dioxane (Table 1, entries 2−5). However, no product was observed when DMF was involved (Table 1, entry 6). To our delight, the yield of 3aa could be further improved to 94% when CH3CN was used as the reaction media (Table 1, entry 7). To further increase the product yield, the influence of iodine sources was next examined (Table 1, entries 8 and 9). With I2, the yield decreased to 74%, while only trace amount of 3aa was obtained when n-Bu4NI was used as the iodine source. Note that the reaction temperature had a significant influence on the reaction yield. Upon decreasing the reaction temperature to 60 and 40 °C, the yield of 3aa decreased to 86% and 80%, respectively (Table 1, entries 10 and 11). With the best reaction conditions established (Table 1, entry 7), we next investigated the scope and limitations of this radical cascade process by using various arylsulfonyl hydrazides 2 in combination with the 1,6-enyne 1a as the reaction partner. As shown in Scheme 2, various electron-rich (−Me, −OMe) or electron-deficient (−F, −Cl, −Br, −NO2, −CN) substituents can be successfully introduced at C4-positions of arylsulfonoyl hydrazides, and the corresponding γ-lactams 3ab−ah were isolated in excellent yield with moderate Z/E ratios. Those results clearly revealed that the electronic modification of arylsulfonyl hydrazides did not substantially alter the reaction efficiency. Note that the structure of 3ac was unambiguously

Figure 2. X-ray structure of product (E)-3ac.

of arylsulfonyl hydrazides 2 also proved to be successful (3ai, 80%, and 3aj, 82%). However, our attempts to employ 2,4,6trimethylbenzenesulfonohydrazide as arylsulfonyl radical precursor turned out to be unfruitful, likely for steric reasons (3ak, 0%). Besides different substituted phenylsulfonyl hydrazides, the naphthalene-2-sulfonohydrazide and thiophene-2-sulfonohydrazide were also the adaptable substrates for this radical cascade process, providing γ-lactam product 3al and 3am in 87% and 32% yields, respectively. Next, the scope of the reaction with respect to nitrogentethered 1,6-enyne 1 was also studied (Scheme 3). Both of the electron-donating and electron-withdrawing substituents are well tolerated at the para-position of the R2-aryl group, and the corresponding products 3ba−da were obtained in 75−86% yields. The R2-aryl substituent can be replaced by an alkyl 450

DOI: 10.1021/acs.orglett.7b03794 Org. Lett. 2018, 20, 449−452

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Organic Letters Scheme 3. Substrate Scope of 1,6-Enynea

Scheme 5. Follow-up Chemistry

To gain some mechanistic insight into this γ-lactam formation process, some control experiments were conducted. The process was completely suppressed by adding 2.0 equiv of TEMPO to the reaction system, suggesting the existence of a radical mechanism. Moreover, this radical cascade reaction did not take place without the addition of TBHP oxidant. Based on above results and previous reports, a plausible reaction mechanism is proposed in Scheme 6. Initially, arylsulfonyl hydrazide can a Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), TBHP (0.2 mmol), and NIS (0.12 mmol) in CH3CN (2.0 mL) were stirred at 80 °C for 16 h under argon atmosphere. bIsolated yield. cThe ratio of Z/ E isomer is detected by 1H NMR.

Scheme 6. Plausible Reaction Mechanism

substituent as documented for the methyl and cyclohexyl congeners. The corresponding heterocyclic compounds 3ea and 3fa were isolated in 95% and 92% yield, respectively. Excellent yield was also obtained when the activating methyl ester moiety was replaced by ethyl ester (3ga, 86%), while a bulkier tert-butyl ester activating moiety decreased the reaction yield to 54% (3ha). To our delight, the N-phenyl- and N-benzyl-protected 1,6-enyne substrates were also suitable for this transformation, giving the corresponding γ-lactams 3ia and 3ja in 34% and 77% yields. To further highlight the versatility of this methodology, we then investigated the reactivity of other halogen sources by exchanging NIS with N-bromosuccinimide (NBS) and Nchlorosuccinimide (NCS) (Scheme 4). To our delight, the transfer to arylsulfonyl radical with the release of nitrogen gas under the oxidative conditions.15 Then, chemoselective addition of the formed arylsulfonyl radical to the activated alkene of 1,6enyne 1a delivers tertiary alkyl radical, which subsequently undergoes a 5-exo cyclization to give alkenyl radical intermediate. Finally, the radical cross-coupling of the formed alkenyl radical with iodine radical gives the final γ-lactam 3aa. In conclusion, we have developed a radical cascade cyclization reaction of 1,6-enynes with arylsulfonyl radicals. The reaction was performed under mild reaction conditions by using arylsulfonyl hydrazides as arylsulfonyl radical precursors and provided a variety of biologically important γ-lactam derivatives in good yields. More importantly, the formed alkenyl radical intermediate in the process could be efficiently trapped by the halogen atom, thus providing the final γ-lactams containing valuable alkenyl C−X bonds (X = I, Br). The further discovery of new radical cascade reactions by using 1,n-enynes as radical acceptors in the synthesis of other heterocyclic compounds is currently underway in our laboratory.

Scheme 4. Reactivity of NBS and NCS

corresponding γ-lactam 4 containing the expected alkenyl C−Br bond was obtained in 67% isolated yield with a 3:1 Z/E ratio, while N-chlorosuccinimide (NCS) did not work at all in this radical cascade process under the best reaction conditions. The synthetic value of this developed protocol was demonstrated by investigating the follow-up chemistry using 3ac as the starting material (Scheme 5). The corresponding deprotected γ-lactam 6 can be obtained in 85% yield by treating 3ac under acidic conditions for 1 h at room temperature.12,14 Suzuki−Miyaura cross-coupling reaction provided the arylation product 7 in 62% isolated yield.13 451

DOI: 10.1021/acs.orglett.7b03794 Org. Lett. 2018, 20, 449−452

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Synth. Catal. 2006, 348, 2203−2211. (d) Zhang, B.; Wee, A. G. H. Org. Lett. 2010, 12, 5386−5389. (e) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364−5367. (7) (a) Lettan, R. B.; Galliford, C. V.; Woodward, C. C.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 8805−8814. (b) Comesse, S.; Sanselme, M.; Daich, A. J. Org. Chem. 2008, 73, 5566−5569. (c) Sun, P.-P.; Chang, M.-Y.; Chiang, M. Y.; Chang, N.-C. Org. Lett. 2003, 5, 1761− 1763. (8) (a) Pelletier, S. M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2009, 11, 4512−4515. (b) Campbell, C. L.; Hassler, C.; Ko, S. S.; Voss, M. E.; Guaciaro, M. A.; Carter, P. H.; Cherney, R. J. J. Org. Chem. 2009, 74, 6368−6370. (c) Teng, H.-L.; Luo, F.-L.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2011, 13, 5600−5603. (d) Espinosa-Jalapa, N. Á .; Ke, D.; Nebra, N.; Le Goanvic, L.; Mallet-Ladeira, S.; Monot, J.; Martin-Vaca, B.; Bourissou, D. ACS Catal. 2014, 4, 3605−3611. (e) Gesmundo, N. J.; Grandjean, M.; Nicewicz, D. A. Org. Lett. 2015, 17, 1316−1319. (9) (a) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326−3350. (b) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791−2805. (c) López, F.; Mascarenas, J. L. Beilstein J. Org. Chem. 2011, 7, 1075−1094. (d) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513−6556. (e) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012, 3, 2899−2919. (f) Wille, U. Chem. Rev. 2013, 113, 813−853. (10) Xuan, J.; Studer, A. Chem. Soc. Rev. 2017, 46, 4329−4346. (11) For selected recent examples, see: (a) Chen, M.; Weng, Y.; Guo, M.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2008, 47, 2279−2282. (b) Mondal, S.; Mohamed, R. K.; Manoharan, M.; Phan, H.; Alabugin, I. V. Org. Lett. 2013, 15, 5650−5653. (c) Luo, J.-Y.; Hua, H.-L.; Chen, Z.-S.; Zhou, Z.-Z.; Yang, Y.-F.; Zhou, P.-X.; He, Y.-T.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2014, 50, 1564−1566. (d) Liu, Y.; Zhang, J.-L.; Song, R.-J.; Qian, P.-C.; Li, J.-H. Angew. Chem., Int. Ed. 2014, 53, 9017− 9020. (e) Kong, W.; Fuentes, N.; García-Domínguez, A.; Merino, E.; Nevado, C. Angew. Chem., Int. Ed. 2015, 54, 2487−2491. (f) Fuentes, N.; Kong, W. Q.; Fernandez-Sanchez, L.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 964−973. (g) Hu, M.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2015, 54, 608−612. (h) Qiu, J.-K.; Jiang, B.; Zhu, Y.-L.; Hao, W.-J.; Wang, D.-C.; Sun, J.; Wei, P.; Tu, S.-J.; Li, G.-G. J. Am. Chem. Soc. 2015, 137, 8928−8931. (i) Zhu, Y.-L.; Jiang, B.; Hao, W.-J.; Qiu, J.-K.; Sun, J.; Wang, D.-C.; Wei, P.; Wang, A.-F.; Li, G.-G.; Tu, S.-J. Org. Lett. 2015, 17, 6078−6081. (j) Chen, Z.-Z.; Liu, S.; Hao, W.-J.; Xu, G.; Wu, S.; Miao, J.-N.; Jiang, B.; Wang, S.-L.; Tu, S.-J.; Li, G. Chem. Sci. 2015, 6, 6654−6658. (k) Zhao, Y.; Hu, Y.; Wang, H.; Li, X.; Wan, B. J. Org. Chem. 2016, 81, 4412−4420. (l) Xuan, J.; Gonzalez-Abradelo, D.; Strassert, C. A.; Daniliuc, C.-G.; Studer, A. Eur. J. Org. Chem. 2016, 2016, 4961−4964. (m) Fu, R.; Hao, W.-J.; Wu, Y.-N.; Wang, N.-N.; Tu, S.-J.; Li, G.; Jiang, B. Org. Chem. Front. 2016, 3, 1452−1456. (n) Zhang, L.; Chen, S.; Gao, Y.; Zhang, P.; Wu, Y.; Tang, G.; Zhao, Y. Org. Lett. 2016, 18, 1286−1289. (o) Hao, W.-J.; Du, Y.; Wang, D.; Jiang, B.; Gao, Q.; Tu, S.-J.; Li, G. Org. Lett. 2016, 18, 1884−1887. (p) Lv, L.; Lu, S.; Chen, Y.; Li, Z. Org. Chem. Front. 2017, 4, 2147−2152. (q) Huang, H.; Li, Y. J. Org. Chem. 2017, 82, 4449−4457. (12) Xuan, J.; Daniliuc, C.-G.; Studer, A. Org. Lett. 2016, 18, 6372− 6375. (13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467−4470. (b) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866−867. (14) Deng, J.-C.; Chen, W.-Y.; Zhu, C.; Chuang, S.-C. Adv. Synth. Catal. 2015, 357, 1453−1462. (15) (a) Li, X.; Xu, X.; Zhou, C. Chem. Commun. 2012, 48, 12240− 12242. (b) Zhang, J.; Shao, Y.; Wang, H.; Luo, Q.; Chen, J.; Xu, D.; Wan, X. Org. Lett. 2014, 16, 3312−3315. (c) Tang, S.; Wu, Y.; Liao, W.; Bai, R.; Liu, C.; Lei, A. Chem. Commun. 2014, 50, 4496−4499. (d) Singh, R.; Allam, B. K.; Singh, N.; Kumari, K.; Singh, S. K.; Singh, K. N. Org. Lett. 2015, 17, 2656−2659. (e) Zhu, Y.-L.; Jiang, B.; Hao, W.-J.; Wang, A.-F.; Qiu, J.-K.; Wei, P.; Wang, D.-C.; Li, G.-G.; Tu, S.-J. Chem. Commun. 2016, 52, 1907−1910. (f) Zheng, L.; Zhou, Z.; He, Y.; Li, L.; Ma, J.; Qiu, Y.; Zhou, P.; Liu, X.; Xu, P.; Liang, Y. J. Org. Chem. 2016, 81, 66−76.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03794. Experimental procedures, characterization data, and 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1539849 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.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jun Xuan: 0000-0003-0578-9330 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (No. 21702001) and the Start-up Grant from Anhui University for financial support of this work. We thank Prof. Armido Studer, Westfälische Wilhelms-Universität, for helpful discussions and Dr. Constantin G. Daniliuc, Westfälische Wilhelms-Universität, for X-ray diffraction analysis.

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REFERENCES

(1) For selected papers, see: (a) Fishwick, C. W. G.; Foster, R. J.; Carr, R. E. Tetrahedron Lett. 1996, 37, 3915−3918. (b) Corey, E. J.; Li, W.-D. Z. Chem. Pharm. Bull. 1999, 47, 1−10. (c) Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, D. J. J. Org. Chem. 1999, 64, 6005−6018. (d) Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.; Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.; Berkers, C.; Nicholson, B.; Chao, T. H.; Neuteboom, S. T.; Richardson, P.; Palladino, M. A.; Anderson, K. C. Cancer Cell 2005, 8, 407−419. (e) Shenvi, R. A.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 5746−5747. (f) Chen, J.-R.; Yu, X.-Y.; Xiao, W.-J. Synthesis 2015, 47, 604−629. (2) (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. J. Antibiot. 1991, 44, 113−116. (b) Omura, S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa, A. J. J. Antibiot. 1991, 44, 117−118. (3) Schwartz, R. E.; Helms, G. L.; Bolessa, E. A.; Wilson, K. E.; Giacobbe, R. A.; Tkacz, J. S.; Bills, G. F.; Liesch, J. M.; Zink, D. L.; Curotto, J. E.; Pramanik, B.; Onishi, J. C. Tetrahedron 1994, 50, 1675− 1686. (4) Fishwick, C. W. G.; Foster, R. J.; Carr, R. E. Tetrahedron Lett. 1996, 37, 3915−3918. (5) (a) Banfi, L.; Guanti, G.; Rasparini, M. Eur. J. Org. Chem. 2003, 2003, 1319−1336. (b) Alcaide, B.; Almendros, P.; Alonso, J. M. J. Org. Chem. 2004, 69, 993−996. (c) Park, J.-H.; Ha, J.-R.; Oh, S.-J.; Kim, J.A.; Shin, D.-S.; Won, T.-J.; Lam, Y.-F.; Ahn, C. Tetrahedron Lett. 2005, 46, 1755−1757. (d) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005, 7, 3981−3984. (e) Sakai, T.; Yamada, K.; Tomioka, K. Chem. - Asian J. 2008, 3, 1486−1493. (6) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861−2904. (b) Choi, M. K.-W.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081−1084. (c) Grohmann, M.; Buck, S.; Schäffler, L.; Maas, G. Adv. 452

DOI: 10.1021/acs.orglett.7b03794 Org. Lett. 2018, 20, 449−452