Stereoselective Synthesis of Functionalized Tetrahydro-1H-1,2

Letter pubs.acs.org/OrgLett

Stereoselective Synthesis of Functionalized Tetrahydro‑1H‑1,2diazepines by N‑Heterocyclic Carbene-Catalyzed [3 + 4] Annulation Shi-Ya Zhu, Yuanzhen Zhang, Wei Wang, and Xin-Ping Hui* State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China S Supporting Information *

ABSTRACT: An efficient N-heterocyclic carbene (NHC)catalyzed asymmetric [3 + 4] annulation reaction of N-Ts hydrazones with 2-bromoenals has been developed. A series of functionalized tetrahydro-1H-1,2-diazepines with two consecutive stereocenters was obtained using NHCs as the catalyst in good yields with excellent diastereo- and enantioselectivities.

D

consecutive stereocenters. Recently, Enders et al.10c developed an asymmetric synthesis of spiro-1,2-diazepines by the NHCcatalyzed [3 + 4] annulation of isatin-derived enals with α-chloro N-Ts hydrazones. Therefore, new strategies for the enantioselective construction of functionalized 1,2-diazepines, especially with consecutive stereocenters, are always in great demand. In continuation of our research on the development of NHCcatalyzed asymmetric reactions,11 herein, we demonstrate an efficient annulation of N-Ts hydrazones with 2-bromoenals for the stereoselective synthesis of functionalized tetrahydro-1H-1,2diazepines (Scheme 1). The desired products bearing two consecutive stereocenters were obtained using NHCs as catalysts in good yields with excellent diastereo- and enantioselectivities.

iazepine-based nitrogen heterocycles are frequently found in numerous bioactive molecules, pharmaceuticals, and natural products.1a−c Owing to the promising biological activities of such compounds and their potential for use as antidepressant, antimicrobial, and antiviral agents,1d−g the development of synthetic methods to these structural motifs has drawn extensive attention.2 Moreover, 1,2-diazepines have been widely applied in organic synthesis as valuable intermediates because of their versatile reactivity.3 In recent decades, interest in asymmetric synthesis that uses Nheterocyclic carbenes (NHCs) as organocatalysts has increased dramatically.4 To date, annulations, especially [2 + 3],5 [3 + 3],6 and [2 + 4],7 catalyzed by NHCs have been extensively studied for the synthesis of diverse cyclic compounds. The direct [3 + 4] annulation represents one of the most straightforward entries to access seven-membered heterocyclic compounds. ε-Lactones, which exist as structural motifs in various biologically active natural and unnatural products, can be efficiently synthesized by NHC-catalyzed asymmetric [3 + 4] annulations. In 2013, Ye8a and Scheidt’s8b group independently reported two NHCcatalyzed strategies for the enantioselective synthesis of benzoε-lactones through the annulation of enals with o-quinone methides. Stereoselective synthesis of benzofuran/indole-containing ε-lactones8c and thiazole-fused ε-lactones8d were described by the NHC-catalyzed annulations of enals with heterocyclic enones. Very recently, enantioselective synthesis of 1,5-benzothiazepines was demonstrated by NHC-catalyzed [3 + 4] annulation of 2-aminobenzenethiols with 2-bromoenals.9 Although asymmetric [3 + 4] annulations catalyzed by NHCs have been applied for the synthesis of some seven-membered heterocycles, few protocols have been developed for the asymmetric synthesis of 1,2-diazepines. In 2014, the group of Chi10a disclosed the NHC-catalyzed [3 + 4] cycloaddition of azomethine imines and enals to generate dinitrogen-fused sevenmembered heterocyclic products with high optical purities. Glorius and co-workers10b reported the NHC-catalyzed asymmetric formal [3 + 4] annulation of enals with cyclic αchloro N-Boc hydrazones to afford fused 1,2-diazepines with two © 2017 American Chemical Society

Scheme 1. NHC-Catalyzed Stereoselective [3 + 4] Annulation

Given that N-Ts hydrazone is an efficient 1,4-bis-nucleophile, we initially focused on the NHC-catalyzed [3 + 4] annulation reaction of ethyl 3-phenyl-3-(2-tosylhydrazono)-propanoate (1a) with (Z)-2-bromo-3-phenylacrylaldehyde (2a). To our delight, the reaction proceeded and the desired product 3a was obtained in 28% yield with >20:1 dr and 75% ee when 15 mol % of NHC precatalyst A was employed as catalyst and 1.1 equiv of DBU as a base in toluene at rt for 16 h (Table 1, entry 1). Subsequently, other NHC precatalysts were evaluated, and a relatively higher yield and enantioselectivity were observed by using precatalyst D (entry 4). After screening several bases, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), K2CO3, DMAP, and Et3N, the latter proved to be the best base, and an enormous Received: August 26, 2017 Published: September 26, 2017 5380

DOI: 10.1021/acs.orglett.7b02657 Org. Lett. 2017, 19, 5380−5383

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

entry

catalyst

base

solvent

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9e 10f 11e 12e 13e,g 14e,h

cat. A cat. B cat. C cat. D cat. D cat. D cat. D cat. D cat. D cat. D cat. D cat. D cat. D cat. D

DBU DBU DBU DBU TBD K2CO3 NEt3 DMAP NEt3 NEt3 NEt3 NEt3 NEt3 NEt3

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DCM THF toluene toluene

16 16 16 16 16 12 4 12 4 4 4 24 24 24

28 50 32 42 nr 50 79 45 85 82 35 nr 72 70

Table 2. Substrates Scope of the NHC-Catalyzed Reactiona

drc

ee (%)d

>20:1 >20:1 >20:1 >20:1

75 72 81 82

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1

94 93 91 94 93 89

>20:1 >20:1

96 90

entry

R1 (1), R2 (2)

time (h)

yield (%)b

drc

ee (%)d

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Ph (1a), Ph (2a) Ph (1a), 4-FPh (2b) Ph (1a), 2-ClPh (2c) Ph (1a), 3-ClPh (2d) Ph (1a), 4-ClPh (2e) Ph (1a), 3-BrPh (2f) Ph (1a), 4-BrPh (2g) Ph (1a), 2-MePh (2h) Ph (1a), 3-MePh (2i) Ph (1a), 4-MePh (2j) Ph (1a), 4-EtOPh (2k) Ph (1a), 1-C10H7 (2l) Ph (1a), 2-C10H7 (2m) 3-ClPh (1b), Ph (2a) 4-ClPh (1c), Ph (2a) 3-BrPh (1d), Ph (2a) 4-BrPh (1e), Ph (2a) 4-MePh (1f), Ph (2a) 2-thienyl (1g), Ph (2a) 4-O2NPh (1h), Ph (2a)

4 12 10 10 10 10 12 12 12 8 48 12 12 12 12 12 12 18 24 12

85 (3a) 81 (3b) 80 (3c) 78 (3d) 83 (3e) 89 (3f) 85 (3g) 83 (3h) 83 (3i) 86 (3j) 70 (3k) 85 (3l) 82 (3m) 79 (3n) 83 (3o) 78 (3p) 88 (3q) 79 (3r) 80 (3s) 48 (3t)

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

94 90 87 90 89 87 93 96 95 95 >99 98 90 98 95 95 97 90 93 91

a

Reaction conditions: 1a/2a/NEt3 = 1:1.5:1.65 (molar ratio). Isolated yield. cDetermined by 1H NMR analysis. dDetermined by chiral HPLC analysis.

a

Reaction conditions: 1a/2a/base = 1:1:1.1 (molar ratio). bIsolated yield. cDetermined by 1H NMR analysis. dDetermined by chiral HPLC analysis. e1a/2a/NEt3 = 1:1.5:1.65 (molar ratio). f1a/2a/NEt3 = 1:1.75:1.93 (molar ratio). gReaction temperature: 0 °C. h4 Å MS (100 mg) was added.

b

addition, naphthyl substituted 2-bromoenals 2l−2m were also investigated, and the desired products were obtained in good yields with excellent diastereo- and enantioselectivities (entries 12−13). It is regrettable that the asymmetric reaction did not occur for alkyl-substituted 2-bromoenals. Next, we turned our efforts to the scope of the N-Ts hydrazones 1b−1g. In the course of the experiment, we found that aromatic and heterocyclic aromatic rings provided the products in good yield with excellent diastereo- and enantioselectivities (entries 14−19). The Ts-hydrazones 1b− 1e with electron-withdrawing substituents gave excellent enantioselectivities (entries 14−17), and the Ts-hydrazones 1f−1g bearing electron-rich aromatic rings showed lower reaction activity and slightly low enantioselectivities (entries 18−19). With respect to a phenyl substituted with a strong electron-withdrawing group, as in N-Ts hydrazone 1h, product 3t was afforded in 48% yield with 91% ee (entry 20). The reaction of an alkyl substituted N-Ts hydrazone gave an intramolecular cyclization product, 3-methyl-1-tosyl-1H-pyrazol-5(4H)-one, instead of the desired product. α,β-Unsaturated acylazolium intermediates, which were used as 1,3-bis-electrophiles for 1,4- or 1,2-addition reactions, can also be obtained from enals with oxidation,6d,f,12 α,β-unsaturated acid fluorides,7d,13 or ynals6c,e,14 catalyzed by NHCs. Based on the above asymmetric reaction, we imagined that the annulation of α,β-enals with N-Ts hydrazones catalyzed by NHCs might proceed. The results showed that the annulation of N-Ts hydrazone 1a with E-cinnamaldehyde (4) occurred smoothly in the presence of NHC precatalyst D (10 mol %), NEt3 (20 mol %), and oxidant 5 (1.1 equiv). The desired product 3a was obtained in 61% yield, >20:1 dr, and 96% ee (Scheme 2). This

improvement in the yield and enantioselectivity was achieved (entry 7). When the amount of 2-bromoenal 2a was increased to 1.5 equiv, a fast reaction rate was observed, and the product 3a was isolated in 85% yield, >20:1 dr, and 94% ee (entry 9). A further increase in the 2-bromoenal 2a to 1.75 equiv led to slightly lower yield and enantioselectivity being obtained (entry 10). A screen of solvents revealed toluene to be preferred (entries 9, 11−12). Further reduction of the reaction temperature to 0 °C and addition of 4 Å MS led to moderate yields (entries 13−14). For N-Ts-hydrazones 1, which were substituted with a cyano or nitro group instead of a carboxylic ester, the annulation did not occur. Finally, the best result was observed under the conditions of entry 9. To demonstrate the generality of the NHC precatalyst D catalyzed asymmetric [3 + 4] annulation reaction, a variety of NTs hydrazones and 2-bromoenals was examined (Table 2). When the asymmetric reactions of N-Ts hydrazones 1a and 2bromoenals 2a−2m were examined under the optimized conditions, as expected, the desired tetrahydro-1H-1,2-diazepines 3a−3m were obtained in high yields with excellent diastereo- and enantioselectivities (entries 1−13). The asymmetric reaction for 2-bromoenals 2a−2m, which contain electron-donating groups (entries 8−11), gave the desired products in higher enantioselectivities than those containing electron-withdrawing groups (entries 2−7). For 4-nitrophenyl substituted 2-bromo-enal, trace product was afforded. It should be noted that 2-bromoenal 2k with a 4-ethyloxyphenyl group exhibited the best enantioselectivity (>99% ee) (entry 11). In 5381

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Organic Letters reaction proved that the N-Ts hydrazones have a good applicability with regard to affording the corresponding tetrahydro-1H-1,2-diazepines.

the intermediate IV. Intermediate IV undergoes proton transfer and an intramolecular lactamization to give the desired products 3 and to regenerate the NHC catalyst. In summary, we have developed an efficiently NHC-catalyzed asymmetric [3 + 4] annulation of N-Ts hydrazones with 2bromoenals to synthesize functionalized tetrahydro-1H-1,2diazepines with two consecutive stereocenters in good yields with excellent diastereo- and enantioselectivities. In addition, the functionalized tetrahydro-1H-1,2-diazepines can also be accessed via the [3 + 4] cycloaddition reaction of N-Ts hydrazones with α,β-enals catalyzed by NHCs in the presence of an oxidant. Further cycloaddition reactions using NHCs as organocatalysts to construct diverse heterocycles are underway in our laboratory.

Scheme 2. Another Synthesis of Tetrahydro-1H-1,2-diazepines

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ASSOCIATED CONTENT

S Supporting Information *

The absolute configuration of the products was determined to be (4R, 5S)-3s by single-crystal X-ray analysis (Figure 1). The absolute configuration of the other products was assigned tentatively by analogy.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02657. Experimental procedures, analytical data, and copies of the 1 H NMR, 13C NMR, and HPLC charts for all new products (PDF) Crystallographic data for 3s (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xin-Ping Hui: 0000-0001-9108-7209 Notes

Figure 1. X-ray crystallography of compound 3s.

The authors declare no competing financial interest.

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A plausible catalytic cyclic for this annulation is proposed as shown in Figure 2.10b The cycloaddition reaction begins with the addition of the NHC catalyst to 2-bromoenals 2 to form the Breslow intermediate, which goes through tautomerization and debromination to form α,β-unsaturated acylazolium II. The Michael addition of N-Ts hydrazones 1 to the intermediate II, assisted by a H-bonding interaction (intermediate III), leads to

ACKNOWLEDGMENTS We are grateful for the financial support of the National Natural Science Foundation (21372106) and Program “111”. REFERENCES

(1) (a) Attwood, M. R.; Hassall, C. H.; Krohn, A.; Lawton, G.; Redshaw, S. J. Chem. Soc., Perkin Trans. 1 1986, 1011. (b) Ogawa, H.; Yamashita, H.; Kondo, K.; Yamamura, Y.; Miyamoto, H.; Kan, K.; Kitano, K.; Tanaka, M.; Nakaya, K.; Nakamura, S.; Mori, T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1996, 39, 3547. (c) Tabata, H.; Nakagomi, J.; Morizono, D.; Oshitari, T.; Takahashi, H.; Natsugari, H. Angew. Chem., Int. Ed. 2011, 50, 3075. (d) Danneberg, P.; Weber, K. H. Br. J. Clin. Pharmacol. 1983, 16, 231S. (e) Szucs, T. Drugs 1991, 41 (Suppl 1), 18. (f) Michelini, S.; Cassano, G. B.; Frare, F.; Perugi, G. Pharmacopsychiatry 2007, 29, 127. (g) Chakraborty, S.; Shah, N. H.; Fishbein, J. C.; Hosmane, R. S. Bioorg. Med. Chem. Lett. 2011, 21, 756. (2) Ryan, J. H.; Hyland, C.; Meyer, A. G.; Smith, J. A.; Yin, J. Prog. Heterocycl. Chem. 2012, 24, 493. (3) Snieckus, V.; Streith, J. Acc. Chem. Res. 1981, 14, 348. (4) For selected reviews on NHC catalysis, see: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (b) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (c) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (d) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (e) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (f) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. (g) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (h) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (i) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. (5) For recent examples, see: (a) Sun, L.-H.; Shen, L.-T.; Ye, S. Chem. Commun. 2011, 47, 10136. (b) Lv, H.; Tiwari, B.; Mo, J.; Xing, C.; Chi,

Figure 2. Possible catalytic cycle. 5382

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Organic Letters Y. R. Org. Lett. 2012, 14, 5412. (c) Candish, L.; Forsyth, C. M.; Lupton, D. W. Angew. Chem., Int. Ed. 2013, 52, 9149. (d) Ni, Q.; Zhang, H.; Grossmann, A.; Loh, C. C. J.; Merkens, C.; Enders, D. Angew. Chem., Int. Ed. 2013, 52, 13562. (e) Jang, K. P.; Hutson, G. E.; Johnston, R. C.; McCusker, E. O.; Cheong, P. H.-Y.; Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 76. (f) Zheng, C.; Yao, W.; Zhang, Y.; Ma, C. Org. Lett. 2014, 16, 5028. (g) Guo, C.; Schedler, M.; Daniliuc, C. G.; Glorius, F. Angew. Chem., Int. Ed. 2014, 53, 10232. (h) Wu, X.; Liu, B.; Zhang, Y.; Jeret, M.; Wang, H.; Zheng, P.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int. Ed. 2016, 55, 12280. (6) For recent examples, see: (a) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080. (b) Mahatthananchai, J.; Kaeobamrung, J.; Bode, J. W. ACS Catal. 2012, 2, 494. (c) Kravina, A. G.; Mahatthananchai, J.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9433. (d) Xie, D.; Yang, L.; Lin, Y.; Zhang, Z.; Chen, D.; Zeng, X.; Zhong, G. Org. Lett. 2015, 17, 2318. (e) Gao, Z.-H.; Chen, X.-Y.; Zhang, H.-M.; Ye, S. Chem. Commun. 2015, 51, 12040. (f) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. Angew. Chem., Int. Ed. 2016, 55, 268. (7) For recent examples, see: (a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2011, 133, 4694. (b) Jian, T.-Y.; Sun, L.-H.; Ye, S. Chem. Commun. 2012, 48, 10907. (c) Allen, S. E.; Mahatthananchai, J.; Bode, J. W.; Kozlowski, M. C. J. Am. Chem. Soc. 2012, 134, 12098. (d) Candish, L.; Levens, A.; Lupton, D. W. J. Am. Chem. Soc. 2014, 136, 14397. (e) Levens, A.; Ametovski, A.; Lupton, D. W. Angew. Chem., Int. Ed. 2016, 55, 16136. (f) Chen, X.-Y.; Liu, Q.; Chauhan, P.; Li, S.; Peuronen, A.; Rissanen, K.; Jafari, E.; Enders, D. Angew. Chem., Int. Ed. 2017, 56, 6241. (8) (a) Lv, H.; Jia, W.-Q.; Sun, L.-H.; Ye, S. Angew. Chem., Int. Ed. 2013, 52, 8607. (b) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am. Chem. Soc. 2013, 135, 10634. (c) Wang, M.; Rong, Z.-Q.; Zhao, Y. Chem. Commun. 2014, 50, 15309. (d) Liang, Z.-Q.; Yi, L.; Chen, K.-Q.; Ye, S. J. Org. Chem. 2016, 81, 4841. (9) Fang, C.; Lu, T.; Zhu, J.; Sun, K.; Du, D. Org. Lett. 2017, 19, 3470. (10) (a) Wang, M.; Huang, Z.; Xu, J.; Chi, Y. R. J. Am. Chem. Soc. 2014, 136, 1214. (b) Guo, C.; Sahoo, B.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17402. (c) Wang, L.; Li, S.; Blümel, M.; Philipps, A. R.; Wang, A.; Puttreddy, R.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2016, 55, 11110. (11) (a) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.-P. Org. Lett. 2013, 15, 4750. (b) Yang, Y.-J.; Zhang, H.-R.; Zhu, S.-Y.; Zhu, P.; Hui, X.-P. Org. Lett. 2014, 16, 5048. (c) Yang, Y.-J.; Ji, Y.; Qi, L.; Wang, G.; Hui, X.-P. Org. Lett. 2017, 19, 3271. (12) (a) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed. 2008, 47, 8727. (b) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266. (c) Wanner, B.; Mahatt-hananchai, J.; Bode, J. W. Org. Lett. 2011, 13, 5378. (13) (a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131, 14176. (b) Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836. (c) Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2013, 135, 58. (14) (a) Mahatthananchai, J.; Zheng, P.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50, 1673. (b) Zhu, Z.-Q.; Xiao, J.-C. Adv. Synth. Catal. 2010, 352, 2455. (c) Du, D.; Hu, Z.; Jin, J.; Lu, Y.; Tang, W.; Wang, B.; Lu, T. Org. Lett. 2012, 14, 1274. (d) Romanov-Michailidis, F.; Besnard, C.; Alexakis, A. Org. Lett. 2012, 14, 4906. (e) Zhou, B.; Luo, Z.; Li, Y. Chem. Eur. J. 2013, 19, 4428.

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