Ag-Catalyzed cycloisomerization of 1,6-enynamide: an intramolecular type II Alder-ene reaction

Abstract

Promoted by a silver catalyst, 1,6-enynamides with a cyclic ene moiety can undergo cycloisomerization to fused N-heterobicycles. This transformation presents an unusual type II Alder-ene reaction and is believed to proceed through a catalytic cycle of formation of a keteneiminium silver intermediate, subsequent 6-endo-trig cyclization and protodemetalation.

---

The Alder-ene reaction¹ is a powerful chemical transformation that efficiently combines two unsaturated components (ene donor and enophile) through C–C bond formation and its intramolecular version, i.e., Alder-ene cycloisomerization,² is highly useful for ring construction. Alkynes are frequently used as enophiles in the intramolecular ene reaction. Electro-deficient alkynes normally react readily with alkenyl ene donors.³ Although electroneutral alkynes are less reactive enophiles for thermal ene reactions with ordinary alkenes, related cycloisomerization can be realized by introduction of ring strain⁴ or a metal catalyst.⁵ On the other hand, electron rich alkynes are rarely reported as enophiles in the Alder-ene reaction. In line with our interest in ene rections⁶ and in order to answer the question whether electron rich alkynes can participate in Alder-ene reactions as enophiles, we started a program studying the Alder-ene cycloisomerization of ynamides, a typical class of electron-rich alkynes.⁷

1,6-Enynamide 1a, formed conveniently by coupling of 4-bromophenylethynyl bromide with related alkenyl sulfonamide,⁸ was used for an initial evaluation (Table 1). Refluxing of 1a in toluene for 10 hours resulted in no reaction (entry 1). Then we turned our attention to metal catalysis. To our delight, a catalytic amount of a rhodium complex RhCl(PPh₃)₃ can promote the Alder-ene cycloisomerization to give a single product 2a in a modest yield at lower temperature (entry 2, 80 °C). Fused bicycle 2a is a type II intramolecular Alder-ene product,⁹ and interestingly, the expected type I congener spiro 3a was not detected.¹⁰ Copper salts CuCl and CuSO₄ can also affect this reaction, giving similar yields (entries 3 and 4). Further research found that Ag₂SO₄ as a catalyst was superior to the more cationic silver salts AgOTf and AgSbF₆ and was able to increase the yield of 2a to 50% under the same conditions (entries 5–7).¹¹ Brief solvent screening study indicated that dichloroethane (DCE) was a better medium than toluene, dichloromethane (DCM) and chloroform for this reaction (entries 7–10).

Table 1 Optimization of conditions for Alder-ene cycloisomerization^a

Entry	Catalyst	Solvent	Temp. (°C)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), catalyst (0.04 mmol, 20 mol%), solvent (2 mL), 60, 80 or 120 °C oil bath, N2, 10 h in a sealed tube. b Isolated yield.
1	—	PhMe	120	—
2	RhCl(PPh3)3	PhMe	80	34
3	CuCl	PhMe	80	36
4	CuSO4	PhMe	80	42
5	AgOTf	PhMe	80	40
6	AgSbF6	PhMe	80	28
7	Ag2SO4	PhMe	80	50
8	Ag2SO4	DCM	60	45
9	Ag2SO4	CHCl3	80	20
10	Ag 2 SO 4	DCE	80	55

---

Next, using DCE as the solvent and Ag₂SO₄ as the catalyst, more N-Ts ynamides 1 were subjected to this reaction to investigate the substrate scope (Table 2). 1b–g, substrates with variously substituted phenylethynyl groups were all effectively suitable for this reaction, giving the corresponding octahydroisoquinolines 2b–g efficiently with yields ranging from 41% to 61%. Furanyl and thiophenyl enynamides 1h and 1i were successfully transformed into the corresponding N-heterobicycles 2h and 2i in good yields. Ynamide 1j with a methyl group on the cyclohexenyl moiety reacted smoothly as well. Benzene-fused cyclohexene in 1k can serve as a nice ene donor and tricycle 2k was obtained in 70% yield. Cyclopentenyl substrate 1l and its benzene-fused homologue 2m were subjected to the same reaction conditions to give the corresponding bicyclic products 2l and 2m with comparable yields. Switching the N-tosyl group to the N-nosyl group delivered similar outcomes. A complex reaction mixture was observed for alkyl ynamide 1o under the same conditions, suggesting that the aryl ynamide is required for this reaction. Analysis of the NMR spectra of this reaction mixture indicates that it might be composed of the desired product mixed with by-products derived from hydrolysis of both the substrate and product and isomerization of the eynamide moiety (such as the 1,3-H-shift). The cyclic alkene is also critical for the success of this cycloisomerization process evidenced by a complex reaction mixture obtained for 1p, which carries a noncyclic ene donor.

Table 2 Silver sulfate catalyzed type II Alder-ene cycloisomerization of N-sulfonyl enynamides^a,b

Substrate	Product, yield (%)	Substrate	Product, yield (%)	Substrate	Product, yield (%)
a Reaction conditions: 1 (0.2 mmol), Ag2SO4 (0.04 mmol, 20 mol%), DCE (2 mL), 80 °C oil bath, N2, 10 h. b Isolated yield.
					Complex
					Complex

---

The structure of 2n was determined unambiguously by the single crystal X-ray analysis. The ORTEP picture shows clearly that there is an octahydroisoquinoline core and an exocyclic alkene group with Z-geometry (Fig. 1). The structure of other products was assigned accordingly by analogy of NMR data.

Fig. 1 The ORTEP drawing of 2n (CCDC 1951227†).

According to the above findings, a reaction mechanism was proposed (Scheme 1). Coordination of the silver cation with enynamide 1 followed by ynamide activation gives a keteneiminium silver intermediate II; then, a 6-endo-trig attack of the cycloalkene on the keteneiminium moiety led to a vinyl silver intermediate III which underwent protodemetalation affording the fused bicyclic product. This mechanism can explain both the exclusive formation of the type II ene product over the spiro type I ene product and the Z-configuration of the exocyclic alkene.

Scheme 1 Proposed mechanism for the Alder-ene cycloisomerization.

Conclusions

In summary, a silver catalyzed Alder-ene cycloisomerization of 1,6-enynamide has been achieved for the first time to give unusual type II Alder-ene products. The reaction provides a facile method for the efficient construction of fused N-heterocyclic scaffolds bearing an endo and a Z-exocyclic C–C double bonds selectively, which is valuable in both organic synthesis and medicinal chemistry.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 21672027) for financial support. This work is also supported by the High-Level Entrepreneurial Talent Team of Jiangsu Province (2017-37) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Notes and references

1. (a) H. M. R. Hoffmann, Angew. Chem., Int. Ed. Engl., 1969, 8, 556; (b) T. J. J. Mueller, in Comprehensive Organic Synthesis II, ed. P. Knochel, Elsevier B.V., 2014, vol. 5, p. 1.
2. D. F. Taber, in Intramolecular Diels–Alder and Alder-Ene Reactions, ed. D. F. Taber, Springer-Verlag, Berlin, 1984, p. 61.
3. (a) K. Mikami, K. Takahashi, T. Nakai and T. Uchimaru, J. Am. Chem. Soc., 1994, 116, 10948; (b) E. M. Groen-Piotrowska and M. B. Groen, Recl. Trav. Chim. Pays-Bas, 1993, 112, 627; (c) K. Mikami, K. Takahashi and T. Nakai, J. Am. Chem. Soc., 1990, 112, 4035.
4. (a) D. Niu and T. R. Hoye, Nat. Chem., 2013, 6, 34; (b) D. A. Candito, D. Dobrovolsky and M. Lautens, J. Am. Chem. Soc., 2012, 134, 15572; (c) D. A. Candito, J. Panteleev and M. Lautens, J. Am. Chem. Soc., 2011, 133, 14200; (d) R. Karmakar, P. Mamidipalli, S. Y. Yun and D. Lee, Org. Lett., 2013, 15, 1938; (e) I. Tabushi, H. Yamada, Z. Yoshida and R. Oda, Bull. Chem. Soc. Jpn., 1977, 50, 285; (f) M. N. Protopopova and A. Galminas, Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 1229.
5. (a) B. M. Trost, Acc. Chem. Res., 1990, 23, 34; (b) M. P. Munoz, J. Adrio, J. C. Carretero and A. M. Echavarren, Organometallics, 2005, 24, 1293; (c) T. Shibata, M. Yamasaki, S. Kadowaki and K. Takagi, Synlett, 2004, 2812; (d) S. J. Sturla, N. M. Kablaoui and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 1976; (e) B. M. Trost, G. J. Tanoury, M. Lautens, C. Chan and D. T. MacPherson, J. Am. Chem. Soc., 1994, 116, 4255; (f) B. M. Trost, D. L. Romero and F. Rise, J. Am. Chem. Soc., 1994, 116, 4268; (g) B. M. Trost and B. A. Czeskis, Tetrahedron Lett., 1994, 35, 211; (h) B. M. Trost and Y. Shi, J. Am. Chem. Soc., 1993, 115, 9421; (i) B. M. Trost and Y. Shi, J. Am. Chem. Soc., 1991, 113, 701; (j) A. Knierzinger, A. Grieder and P. Schoenholzer, Helv. Chim. Acta, 1991, 74, 517.
6. T.-S. Liu, H. Zhou, P. Chen, X.-R. Huang, L.-Q. Bao, C.-L. Zhuang, Q.-S. Xu, M.-H. Shen and H.-D. Xu, Org. Lett., 2018, 20, 3156.
7. (a) A. Mekareeya, P. R. Walker, A. Couce-Rios, C. D. Campbell, A. Steven, R. S. Paton and E. A. Anderson, J. Am. Chem. Soc., 2017, 139, 10104; (b) C.-Z. Zhong, P.-T. Tung, T.-H. Chao and M.-C. P. Yeh, J. Org. Chem., 2017, 82, 481; (c) M.-C. P. Yeh, Y.-S. Shiue, H.-H. Lin, T.-Y. Yu, T.-C. Hu and J.-J. Hong, Org. Lett., 2016, 18, 2407; (d) M.-C. P. Yeh, C.-J. Liang, H.-F. Chen and Y.-T. Weng, Adv. Synth. Catal., 2015, 357, 3242; (e) C. D. Campbell, R. L. Greenaway, O. T. Holton, P. R. Walker, H. A. Chapman, C. A. Russell, G. Carr, A. L. Thomson and E. A. Anderson, Chem. – Eur. J., 2015, 21, 12627; (f) C. D. Campbell, R. L. Greenaway, O. T. Holton, H. A. Chapman and E. A. Anderson, Chem. Commun., 2014, 50, 5187; (g) P. R. Walker, C. D. Campbell, A. Suleman, G. Carr and E. A. Anderson, Angew. Chem., Int. Ed., 2013, 52, 9139; (h) K. A. DeKorver, X.-N. Wang, M. C. Walton and R. P. Hsung, Org. Lett., 2012, 14, 1768; (i) R. L. Greenaway, C. D. Campbell, O. T. Holton, C. A. Russell and E. A. Anderson, Chem. – Eur. J., 2011, 17, 14366; (j) H. Wakamatsu, M. Sakagami, M. Hanata, M. Takeshita and M. Mori, Macromol. Symp., 2010, 293, 5; (k) S. Couty, C. Meyer and J. Cossy, Angew. Chem., Int. Ed., 2006, 45, 6726; (l) J. R. Dunetz and R. L. Danheiser, J. Am. Chem. Soc., 2005, 127, 5776; (m) N. Saito, Y. Sato and M. Mori, Org. Lett., 2002, 4, 803; (n) J. Huang, H. Xiong, R. P. Hsung, C. Rameshkumar, J. A. Mulder and T. P. Grebe, Org. Lett., 2002, 4, 2417.
8. (a) X.-N. Wang, H.-S. Yeom, L.-C. Fang, S. He, Z.-X. Ma, B. L. Kedrowski and R. P. Hsung, Acc. Chem. Res., 2014, 47, 560; (b) C. Jiang, P.-P. Yu, Q. Zhang, H.-D. Xu and M.-H. Shen, Chin. Chem. Lett., 2019, 30, 266; (c) Y. Zhang, R. P. Hsung, M. R. Tracey, K. C. M. Kurtz and E. L. Vera, Org. Lett., 2004, 6, 1151.
9. W. Oppolzer and V. Snieckus, Angew. Chem., Int. Ed. Engl., 1978, 17, 476.
10. B. M. Trost, M. Lautens, C. Chan, D. J. Jebaratnam and T. Mueller, J. Am. Chem. Soc., 1991, 113, 636.
11. For selected recent reviews on silver catalysed reactions, see: (a) G. Fang, X. Cong, G. Zanoni, Q. Liu and X. Bi, Adv. Synth. Catal., 2017, 359, 1422; (b) Y. Wang, R. K. Kumar and X. Bi, Tetrahedron Lett., 2016, 57, 5730; (c) G. Fang and X. Bi, Chem. Soc. Rev., 2015, 44, 8124.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental details, characterization data and NMR spectra for all new compounds. CCDC 1951227. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9qo01258c

---