b School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China;
c State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China
Direct one step substitution of C—H bonds with C—C bonds represents an economic and efficient alternative to traditional approaches depending on functional group transformations [1, 2]. Among these, considerable efforts have been made in the oxidative C(sp3)—H functionalization of benzylic ethers [3, 4]. However, current studies predominantly focused on the functionalization of the methylene C—H bond of primary benzylic ether for secondary ether construction . The direct manipulation of the methine C—H bond in a secondary benzylic ether for tertiary ether synthesis remains elusive, probably due to the increased steric hindrance of the substrate and 1, 1-disubstituted oxocarbenium ion intermediate . A bimolecular oxidative C—H functionalization of secondary benzylic ethers for new C—C bond construction has never been reported to date.
The isochroman skeleton is present in a number of natural products and synthetic pharmaceuticals exhibiting a wide range of biological activities . In particular, such structural motif bearing two different substituents at the α-position has been demonstrated to possess antioxidative, anticancer, antibacterial, antifungal, antiviral, and antidepressive activities . On the other hand, the nitrile group is also an important building block in numerous natural products and synthetic materials with important pharmaceutical activities . Moreover, the nitrile moiety also serves as a versatile handle for further carbon elongations and functional group transformations. Accordlingly, direct bimolecular oxidative C—H cyanation of α-monosubstituted isochromans would be a highly desirable project to pursue .
DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) has been widely adopted as an efficient oxidant in the C—H functionalization of a series of primary benzylic ethers. In this context, Shi and Wang disclosed a DDQ-mediated oxidative C—H cyanation of isochroman substrates leading to corresponding secondary ethers [10b]. Accordingly, α-phenyl substituted isochroman 1a was facilely prepared (the details are given in Supporting information) , and then subjected to the C—H functionalization with trimethylsilyl cyanide (TMSCN) using DDQ as the oxidant for optimization (Scheme 1). A systematic investigation of the cyanation source, solvent, and temperature identified that DDQmediated C—H cyanation of 1a with TMSCN proceeded smoothly in toluene at 80 ℃ for 1 h, providing the expected tertiary ether 2a in 92% yield. No expected 2a was observed when KCN was used as the cyanation agent.
The scope of oxidative C—H cyanation of α-substituted isochromans 1 was next investigated (Scheme 2). Characterization data of the target compounds are presented in Supporting information. Isochromans bearing either electron-donating aryl groups (1b) or electron-withdrawing ones (1e and 1f) at the α- position proved to be suitable components in good yields, though the latter exhibited an inferior efficiency to the former. Substrates with a substituent at either the meta- (1c) or ortho-position (1d) on the α-aryl group were also well compatible with the C—H cyanation process, though the latter provided a slightly decreased yield. The observation might be ascribed to the increased steric hindrance of both the ether substrate and highly substituted oxocarbenium intermediate. Isochroman having a heteroaryl moiety at the α-position was well tolerated, as demonstrated by the generation of 2-thiophenyl substituted 2g in 90% yield. The substituent effect on the isochroman skeleton was next evaluated (Scheme 2). Electronically varied isochromans 1h–1m participated in the oxidative C—H cyanation efficiently, furnishing respective tertiary ethers 2h–2m in 81%–94% yields. No expected tertiary ether 2n was observed for α-alkyl substituted isochroman 1n.
|Scheme 2. Scope of oxidative C—H cyanation of α-substituted isochromans. Reaction conditions: 1 (0.1 mmol), TMSCN (0.12 mmol), and DDQ (0.11 mmol) in toluene (1.0 mL) at 80 ℃ for 1 h. The yield refers to isolated yield.|
Under the standard oxidation conditions, a gram-scale C—H cyanation reaction of 1g proceeded in 85% yield, thus suggesting the practicability of the method (Scheme 3).
Based on the existing mechanistic studies on DDQ-promoted ether oxidation, a mechanism for the C—H cyanation of secondary benzylic ethers was proposed (Scheme 4) . α-Monosubstituted isochroman 1 underwent an initial single electron transfer (SET) to DDQ gave the radical cation 3 together with the DDQ radical anion 4. The radical cation 3 can either undergo a hydrogen atom transfer (HAT) to 4 or a proton abstraction by 4 followed by another SET providing 1, 1-disubstituted oxocarbenium intermediate 5. A nucleophilic attack of TMSCN on to 5 yielded the expected tertiary ether 2.
Insummary, we have developed a practical and efficientoxidative C—H cyanation of secondary benzylic ethers with TMSCN in the presence of DDQ.The metal-free process is well tolerated with a wide variety of electronically varied α-monosubstituted isochromans, facilely furnishing a library of isochromans bearing α-aryl α-cyano substituent patterns for further diversification and bioactive small molecule identification.Acknowledgments
This work was financial supported by the National Natural Science Foundation of China (No. 21722204), Fok Ying Tung Education Foundation (No. 151035), the Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University) (No. CHEMR2016-B09), and Guangxi Funds for Distinguished expert.Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.cclet.2019.03.019.
(a) K. Godula, D. Sames, Science 312 (2006) 67-72;
(b) W.R. Gutekunst, P.S. Baran, Chem. Soc. Rev. 40 (2011) 1976-1991;
(c) R. Giri, B.F. Shi, K.M. Engle, N. Maugel, J.Q. Yu, Chem. Soc. Rev. 38 (2009) 3242-3272;
(d) J. Robertson, J. Pillai, R.K. Lush, Chem. Soc. Rev. 30 (2001) 94-103;
(e) H.M.L. Davies, Angew. Chem. Int. Ed. 45 (2006) 6422-6425;
(f) S.Y. Zhang, F.M. Zhang, Y.Q. Tu, Chem. Soc. Rev. 40 (2011) 1937-1949.
(a) P.A. Wender, V.A. Verma, T.J. Paxton, T.H. Pillow, Acc. Chem. Res. 41 (2008) 40-49;
(b) B.M. Trost, Acc. Chem. Res. 35 (2002) 695-705.
(a) C.J. Li, Z. Li, Pure Appl. Chem. 78 (2006) 935-945;
(b) S. Murahashi, D. Zhang, Chem. Soc. Rev. 37 (2008) 1490-1501;
(c) C.J. Li, Acc. Chem. Res. 42 (2009) 335-344;
(d) C.J. Scheuermann, Chem. -Asian J. 5 (2010) 436-451;
(e) M. Klussmann, D. Sureshkumar, Synthesis (2011) 353-369;
(f) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 111 (2011) 1780-1824;
(g) C.L. Sun, B.J. Li, Z.J. Shi, Chem. Rev. 111 (2011) 1293-1314;
(h) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 41 (2012) 3464-3484;
(i) S.H. Cho, J.Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 40 (2011) 5068-5083;
(j) J. Le Bras, J. Muzart, Chem. Rev. 111 (2011) 1170-1214;
(k) C.S. Yeung, V.M. Dong, Chem. Rev. 111 (2011) 1215-1292;
(l) R. Rohlmann, O. García Mancheño, Synlett 24 (2013) 6-10;
(m) S.A. Girard, T. Knauber, C.J. Li, Angew. Chem. Int. Ed. 53 (2014) 74-100.
(a) Z. Li, C.J. Li, J. Am. Chem. Soc. 126 (2004) 11810-11811;
(b) Z. Li, R. Yu, H. Li, Angew. Chem. Int. Ed. 47 (2008) 7497-7450;
(c) F. Yang, J. Li, J. Xie, Z.Z. Huang, Org. Lett. 12 (2010) 5214-5217;
(d) D.P. Hari, B. König, Org. Lett. 13 (2011) 3852-3855;
(e) E.Boess, D.Sureshkumar, A.Sud, etal., J.Am.Chem.Soc.133 (2011) 8106-8109;
(f) E. Boess, C. Schmitz, M. Klussmann, J. Am. Chem. Soc. 134 (2012) 5317-5325;
(g)S.I.Murahashi, T.Nakae, H.Terai, N.Komiya, J.Am.Chem.Soc.130 (2008) 11005-11012;
(h)S.I. Murahashi, N. Komiya, H.Terai, T.Nakae, J.Am.Chem.Soc.125 (2003) 15312-15313;
(i) W. Muramatsu, K. Nakano, C.J. Li, Org. Lett. 15 (2013) 3650-3653;
(j) Z. Xie, L. Liu, W. Chen, et al., Angew. Chem. Int. Ed. 53 (2014) 3904-3908;
(k) J. Zhang, B. Tiwari, C. Xing, X. Chen, Y.R. Chi, Angew. Chem. Int. Ed. 51 (2012) 3649-3652;
(l)G. Zhang, Y. Ma, S. Wang, Y.Zhang, R. Wang, J. Am. Chem. Soc.134 (2012) 12334-12337;
(m) D.A. DiRocco, T. Rovis, J. Am. Chem. Soc. 134 (2012) 8094-8097;
(n) G. Bergonzini, C.S. Schindler, C.J. Wallentin, E.N. Jacobsen, C.R.J. Stephenson, Chem. Sci. 5 (2014) 112-116;
(o)X.Liu, Z.Meng, C.Li, H.Lou, L.Liu, Angew.Chem.Int.Ed.54 (2015)6012-6015;
(p) X. Liu, S. Sun, Z. Meng, H. Lou, L. Liu, Org. Lett. 17 (2015) 2396-2399;
(q) Z. Xie, X. Liu, L. Liu, Org. Lett. 18 (2016) 2982-2985;
(r) G. Wei, C. Zhang, F. Bureš, et al., ACS Catal. 6 (2016) 3708-3712.
(a) Y. Zhang, C.J. Li, Angew. Chem. Int. Ed. 45 (2006) 1949-1952;
(b) Y. Zhang, C.J. Li, J. Am. Chem. Soc. 128 (2006) 4242-4243;
(c) W.Y. Tu, L. Liu, P.E. Floreancig, Angew. Chem. Int. Ed. 47 (2008) 4184-4187;
(d) L. Liu, P.E. Floreancig, Org. Lett. 11 (2009) 3152-3155;
(e) M. Ghobrial, K. Harhammer, M.D. Mihovilovic, M. Schnürch, Chem. Commun. 46 (2010) 8836-8838;
(f) H. Richter, R. Rohlmann, O. García Mancheño, Chem. -Eur. J. 17 (2011) 11622-11627;
(g) M. Ghobrial, M. Schnürch, M.D. Mihovilovic, J. Org. Chem. 76 (2011) 8781-8793;
(h) S.J. Park, J.R. Price, M.H. Todd, J. Org. Chem. 77 (2012) 949-955;
(i) D.J. Clausen, P.E. Floreancig, J. Org. Chem. 77 (2012) 6574-6582;
(j) X. Liu, B. Sun, Z. Xie, et al., J. Org. Chem. 78 (2013) 3104-3112;
(k) W. Chen, Z. Xie, H. Zheng, H. Lou, L. Liu, Org. Lett. 16 (2014) 5988-5991;
(l) Z. Meng, S. Sun, H. Yuan, H. Lou, L. Liu, Angew. Chem. Int. Ed. 53 (2014) 543-547;
(m) W. Muramatsu, K. Nakano, Org. Lett. 16 (2014) 2042-2045;
(n) M. Xiang, Q.Y. Meng, J.X. Li, et al., Chem. -Eur. J. 21 (2015) 18080-18084;
(o) M. Xiang, Q.Y. Meng, X.W. Gao, et al., Org. Chem. Front. 3 (2016) 486-490;
(p) Z. Peng, Y. Wang, Z. Yu, et al., J. Org. Chem. 83 (2018) 7900-7906;
(q) A. Lee, R.C. Betori, E.A. Crane, K.A. Scheidt, J. Am. Chem. Soc. 140 (2018) 6212-6216;
(r) L. Jin, J. Feng, G. Lu, C. Cai, Adv. Synth. Catal. 357 (2015) 2105-2110.
L. Liu, P.E. Floreancig, Angew. Chem. Int. Ed. 49 (2010) 5894-5897. DOI:10.1002/anie.201002281
(a) S.D. Roughley, A.M. Jordan, J. Med. Chem. 54 (2011) 3451-3479;
(b) Z. Lu, Z. Lin, W. Wang, et al., J. Nat. Prod. 71 (2008) 543-546;
(c) R.E. TenBrink, C.L. Bergh, J.N. Duncan, J. Med. Chem. 39 (1996) 2435-2437;
(d) U. Albrecht, M. Lalk, P. Langer, Bioorg. Med. Chem. 13 (2005) 1531-1536;
(e) S. Bräse, A. Encinas, J. Keck, C.F. Nising, Chem. Rev. 109 (2009) 3903-3990;
(f) D.R. McMullin, T.K. Nsiama, J.D. Miller, J. Nat. Prod. 77 (2014) 206-212.
(a) M.B. Sommer, O. Nielsen, H. Petersen, Patent, US 2011/0065938 (2011);
(b) T. Giridhar, G. Srinivasulu, K.S. Rao, Patent, US 2011/0092719 (2011);
(c) N. Chinkov, A. Warm, E.M. Carreira, Angew. Chem. Int. Ed. 50 (2011) 2957-2961.
(a) D. Enders, J.P. Shilvock, Chem. Soc. Rev. 29 (2000) 359-373;
(b) F.F. Fleming, Nat. Prod. Rep. 16 (1999) 597-606;
(c) F.F. Fleming, L. Yao, P.C. Ravikumar, L. Funk, B.C. Shook, J. Med. Chem. 53 (2010) 7902-7917.
(a) S. Kamijo, T. Hoshikawa, M. Inoue, Org. Lett. 13 (2011) 5928-5931;
(b) S. Kong, L. Zhang, X. Dai, et al., Adv. Synth. Catal. 357 (2015) 2453-2456;
(c) C. Yan, Y. Liu, Q. Wang, RSC Adv. 4 (2014) 60075-60078;
(d) F. Le Vaillant, T. Courant, J. Waser, Chem. Sci. 8 (2017) 1790-1800;
(e) M.X. Sun, Y.F. Wang, B.H. Xu, X.Q. Ma, S.J. Zhang, Org. Biomol. Chem. 16 (2018) (1971);
(f) Y. Xia, L. Wang, A. Studer, Angew. Chem. Int. Ed. 57 (2018) 12940-12944.
S. Dasgupta, T. Rivas, M.P. Watson, Angew. Chem. Int. Ed. 54 (2015) 14154-14158. DOI:10.1002/anie.201507373
H.H. Jung, P.E. Floreancig, Tetrahedron 65 (2009) 10830-10836. DOI:10.1016/j.tet.2009.10.088