Copper-catalyzed aminotrifluoromethylation of alkenes: a facile synthesis of CF₃-containing lactams

Abstract

Copper-catalyzed aminotrifluoromethylation of alkenes using amides as nucleophiles has been developed. It provides a rapid and efficient access to a variety of CF₃-containing lactams. The reaction proceeds under mild conditions with a good scope and functional group tolerance, offering a valuable method to prepare CF₃-containing lactams that are of great potential in pharmaceuticals and agrochemicals.

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Qiu Wang

Professor Qiu Wang received her Ph.D. in organic chemistry from Emory University under the direction of Professor Albert Padwa (2005). She undertook postdoctoral trainings with Professor Andrew Myers at Harvard University (2005–2007) and Professor Stuart Schreiber at the Broad Institute of Harvard and MIT (2007–2011). She started her independent career in 2011 as an assistant professor of chemistry at Duke University. Her research interests focus on the synthesis and chemical biology of biologically important nitrogen-containing molecules.

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The pharmacological profile of organic molecules can be significantly improved through the introduction of fluorine.¹ In particular, the trifluoromethyl group has attracted substantial attention in the fields of pharmacology and agrochemistry due to its favorable influence on lipophilicity, hydrophobicity, and metabolic stability.² A variety of synthetic methods have been developed towards the installation of the trifluoromethyl group into organic molecules.^2–4 Over the past several years, transition-metal-mediated alkene trifluoromethylation has emerged as a powerful approach.³ For example, copper-catalyzed allylic trifluoromethylation of terminal alkenes has been reported by several groups (Scheme 1a).⁵ In addition, multiple alkene difunctionalization reactions incorporating trifluoromethylation have been successfully established,^6,7 including carbotrifluoromethylation,⁸ oxytrifluoromethylation,⁹ and aminotrifluoromethylation¹⁰ of simple alkenes (Scheme 1b). The Buchwald group reported an elegant study on the copper-catalyzed intramolecular oxytrifluoromethylation of alkenes with Togni's reagent, employing carboxylic acids, phenols or alcohols as nucleophiles to form oxygen-containing heterocycles.^9d,e Recently, aminotrifluoromethylation of terminal alkenes with Togni's reagent has been reported by the Sodeoka^10c and Liu^10d,e groups using amines or protected amines as nucleophiles to construct trifluoromethylated aziridines, pyrrolidines and indolines. Though a wide range of trifluoromethylated scaffolds are accessible through current methods, there are no examples of the aminotrifluoromethylation of unsaturated amides towards the synthesis of CF₃-containing lactams. In contrast to the successful oxytrifluoromethylation of unsaturated carboxylic acids, it remains challenging to employ amides as nucleophiles in trifluoromethylation-incorporated olefin difunctionalization.^9d With the ubiquitous presence of lactams in synthetic building blocks, bioactive compounds, natural products and pharmaceuticals,¹¹ it would be of great value to synthesize CF₃-containing lactams. Herein, we report the first example of the introduction of the trifluoromethyl group into lactams via aminotrifluoromethylation of simple alkenes.

Scheme 1 Alkene trifluoromethylation.

Recently, our group has reported a copper-catalyzed alkene diamination reaction in which the protecting group on the amide played a critical role in the formation of the lactam products.¹² We postulated that the protecting group on the amide would once again be critical in the proposed aminotrifluoromethylation reaction. Thus, we examined the copper-catalyzed reactions of 2-vinylbenzamides 1 containing different protecting groups using Togni's reagent 2 (Table 1). Interestingly, two types of trifluoromethylation products were observed depending on the protecting groups. In the case of 1a–1c with H, Ph, or Bn groups, trifluoromethylated alkenes 3a′–3c′ were formed.¹³ However, in the reaction of 1d with an OMe group, aminotrifluoromethylated lactam 3d was successfully formed. These results suggested that the alkoxyl group on the nitrogen played an important role in the trifluoromethylation reaction and facilitating the radical cyclization via nitrogen trapping.

Table 1 Trifluoromethylation reactions of 2-vinylbenzamides^a

a Reaction conditions: 1 (0.2 mmol, 1 equiv.), 2 (0.3 mmol, 1.5 equiv.), Cu(CH₃CN)₄PF₆ (0.04 mmol, 20 mol%), MeOH (1 mL), 80 °C, and 2 h.

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With our preliminary success, we next used unactivated 2-allyl-N-methoxybenzamide 1e as the model substrate to optimize the aminotrifluoromethylation conditions (Table 2). In contrast to the successful formation of isoindolinone product 3d, aminotrifluoromethylated product 3,4-dihydroisoquinolinone 3e was formed in only 17% yield under the initial conditions with Cu(CH₃CN)₄PF₆ as the catalyst in MeOH at 80 °C (Table 2, entry 1). Among the set of copper catalysts examined, Cu(acac)₂ was found to be the best, providing 3e in 49% yield (Table 2, entries 1–8). Methanol proved to be the optimal solvent for the formation of the desired product 3e (Table 2, entries 8–15). Lowering the reaction temperatures resulted in a significant decrease in efficiency (Table 2, entries 16–18). Finally, increasing the amount of Togni's reagent (2 equivalents) led to a much improved yield of 3e (72%), which was chosen as the standard conditions for alkene aminotrifluoromethylation.

Table 2 Condition optimization for alkene aminotrifluoromethylation^a

Entry	Catalyst	Solvent	Temp. (°C)	Yield^b
a Reaction conditions: 1 (0.2 mmol, 1 equiv.), 2 (0.30 mmol, 1.5 equiv.), Cu(acac)2 (0.04 mmol, 20 mol%), MeOH (2 mL), 80 °C, and 12 h, unless otherwise noted. b Yields determined by ^19F NMR with CF3Ph as an internal standard. c 2 (0.4 mmol, 2 equiv.), 12 h.
1	Cu(CH3CN)4PF6	MeOH	80	17%
2	CuOTf	MeOH	80	14%
3	CuOAc	MeOH	80	33%
4	CuTc	MeOH	80	32%
5	CuCN	MeOH	80	17%
6	CuCl	MeOH	80	28%
7	Cu(OAc)2	MeOH	80	30%
8	Cu(acac)2	MeOH	80	49%
9	Cu(acac)2	DMF	80	7%
10	Cu(acac)2	Toluene	80	5%
11	Cu(acac)2	DCE	80	11%
12	Cu(acac)2	1,4-Dioxane	80	3%
13	Cu(acac)2	THF	80	3%
14	Cu(acac)2	MTBE	80	25%
15	Cu(acac)2	CH3CN	80	8%
16	Cu(acac)2	MeOH	60	45%
17	Cu(acac)2	MeOH	40	18%
18	Cu(acac)2	MeOH	rt	3%
19	Cu(acac) 2	MeOH	80	72%

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With these optimized conditions, we examined the scope of this alkene aminotrifluoromethylation (Table 3). Both 5- and 6-membered lactam products (isoindolinone 3d and 3,4-dihydroisoquinolinone 3e) were readily formed in 82% and 89% yields, respectively. The reaction showed compatibility with a wide range of substitutions on the aryl group, including those that were electron-donating (3f), electron-withdrawing (3g), or located at a sterically obstructing ortho position (3h). In addition to N-methoxybenzamides 1d–1h, N-methoxyamides 1i–1n bearing different substituents on the alkenyl chain underwent smooth 5-exo cyclization to afford γ-lactams 3i–3n. In the amide substrates that contained a stereocenter, moderate to good diastereoselectivity was observed in the formation of lactams 3l–3n. Finally, the formation of 6-membered lactam 3o was also effective.

Table 3 . Aminotrifluoromethylation of unactivated alkenes^a

a Reaction conditions: 1 (0.3 mmol, 1 equiv.), 2 (0.6 mmol, 2 equiv.), Cu(acac)₂ (0.06 mmol, 20 mol%), MeOH (3 mL), 80 °C, and 2–5 h. Isolation yields. b dr = diastereomeric ratio, determined by ¹⁹F NMR of the crude reaction mixture. The isolated yield includes both isomers. c dr determined by GC-MS of the crude reaction mixture, only one diastereomer is isolated.

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When 1,1-disubstituted terminal alkenes 1p and 1q were examined under standard conditions, interestingly, the desired aminotrifluoromethylation products were not observed; rather the oxytrifluoromethylation products 3p and 3q were formed upon the subsequent acid-catalyzed hydrolysis. These results suggest that O-trapping is favored over N-trapping upon the increased steric hindrance (Scheme 2).¹⁴

Scheme 2 Oxytrifluoromethylation of 1,1-disubstituted alkenes.

While the mechanistic details of this copper-catalyzed aminotrifluoromethylation reaction remain unclear at present, the current results suggest it would be analogous to copper-catalyzed oxytrifluoromethylation.^9d,e Furthermore, the addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a known radical scavenger, was found to largely inhibit the aminotrifluoromethylation reaction.¹⁵

To demonstrate the synthetic utility of the products derived from this reaction, 3,4-dihydroisoquinolinone 3e was treated with Mo(CO)₆, readily providing free lactam 4e in 82% yield (Scheme 3). Furthermore, reduction using LiAlH₄ afforded the CF₃-containing tetrahydroisoquinoline 5e, providing effective access to trifluoromethylated piperidine derivatives.

Scheme 3 Deprotection of N-methoxyamide 3e.

Conclusions

In summary, an efficient copper-catalyzed aminotrifluoro-methylation of alkenes has been achieved using amides as nucleophiles under mild conditions. These reactions provide CF₃-containing lactams in good yields. It offers a useful method to access a variety of CF₃-containing lactams, which are valuable building blocks in organic synthesis and drug discovery. Further investigations of the reaction mechanism are currently underway.

Acknowledgements

We acknowledge financial support of Duke University and the National Science Foundation (CHE-1455220) to this work.

Notes and references

1. (a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications, Wiley-VCH, Weinheim, 2004; (b) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317, 1881; (c) J.-A. Ma and D. Cahard, Chem. Rev., 2008, 108, PR1; (d) D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308; (e) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320; (f) K. Uneyama, T. Katagiri and H. Amii, Acc. Chem. Res., 2008, 41, 817; (g) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359; (h) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Chichester, UK, 2009; (i) S. Lectard, Y. Hamashima and M. Sodeoka, Adv. Synth. Catal., 2010, 352, 2708; (j) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (k) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214.
2. For reviews on trifluoromethylation reactions, see: (a) T. Umemoto, Chem. Rev., 1996, 96, 1757; (b) S. G. K. Prakash and A. K. Yudin, Chem. Rev., 1997, 97, 757; (c) M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2005, 44, 214; (d) M. Schlosser, Angew. Chem., Int. Ed., 2006, 45, 5432; (e) J.-A. Ma and D. Cahard, J. Fluorine Chem., 2007, 128, 975; (f) Y. Zheng and J.-A. Ma, Adv. Synth. Catal., 2010, 352, 2745; (g) S. Roy, B. T. Gregg, G. W. Gribble, V.-D. Le and S. Roy, Tetrahedron, 2011, 67, 2161; (h) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475; (i) X.-F. Wu, H. Neumann and M. Beller, Chem. – Asian J., 2012, 7, 1744; (j) A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8950; (k) Y. Ye and M. S. Sanford, Synlett, 2012, 2005.
3. For recent reviews, see: (a) Z. Jin, G. B. Hammond and B. Xu, Aldrichimica Acta, 2012, 45, 67; (b) P. Chen and G. Liu, Synthesis, 2013, 2919.
4. Recent selected examples on trifluoromethylation of aromatic compounds: (a) M. Oishi, H. Kondo and H. Amii, Chem. Commun., 2009, 1909; (b) X. Wang, L. Truesdale and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 3648; (c) E. J. Cho, T. D. Cenecal, T. Kinzel, Y. Zhang, D. A. Watson and S. L. Buchwald, Science, 2010, 328, 1679; (d) R. Shimizu, H. Egami, T. Nagi, J. Chae, Y. Hamashima and M. Sodeoka, Tetrahedron Lett., 2010, 51, 5947; (e) M. S. Wiehn, E. V. Vinogradova and A. Togni, J. Fluorine Chem., 2010, 131, 951; (f) L. Chu and F.-L. Qing, Org. Lett., 2010, 12, 5060; (g) T. D. Senecal, A. T. Parson and S. L. Buchwald, J. Org. Chem., 2011, 76, 1174; (h) H. Morimoto, T. Tsubogo, N. D. Litvinas and J. F. Hartwig, Angew. Chem., Int. Ed., 2011, 50, 3793; (i) T. Knauber, F. Arikan, G.-V. Röschenthaler and L. J. Gooßen, Chem. – Eur. J., 2011, 17, 2689; (j) J. Xu, D.-F. Luo, B. Xiao, Z.-J. Liu, T.-J. Gong, Y. Fu and L. Liu, Chem. Commun., 2011, 47, 4300; (k) T. Liu and Q. Shen, Org. Lett., 2011, 13, 2342; (l) X. Mu, S. Chen, X. Zhen and G. Liu, Chem. – Eur. J., 2011, 17, 6039; (m) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224; (n) Z. Weng, R. Lee, W. Jia, Y. Yuan, W. Wang, X. Feng and K.-W. Huang, Organometallics, 2011, 30, 3229; (o) A. T. Parsons, T. D. Senecal and S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51, 2947; (p) Z. He, T. Luo, M. Hu, Y. Cao and J. Hu, Angew. Chem., Int. Ed., 2012, 51, 3944; (q) L. Chu and F.-L. Qing, J. Am. Chem. Soc., 2012, 134, 1298; (r) Y. Ye and M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034; (s) X.-G. Zhang, H.-X. Dai, M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2012, 134, 11948.
5. (a) A. T. Parsons and S. L. Buchwald, Angew. Chem., Int. Ed., 2011, 50, 9120; (b) J. Xu, Y. Fu, D. Luo, Y. Jiang, B. Xiao, Z. Liu, T. Gong and L. Liu, J. Am. Chem. Soc., 2011, 133, 15300; (c) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2011, 133, 16410; (d) R. Shimizu, H. Egami, Y. Hamashima and M. Sodeoka, Angew. Chem., Int. Ed., 2012, 51, 4577; (e) L. Chu and F. Qing, Org. Lett., 2012, 14, 2106; (f) S. Mizuta, O. Galicia-López, K. M. Engle, S. Verhoog, K. Wheelhouse, G. Rassias and V. Gouverneur, Chem. – Eur. J., 2012, 18, 8583; (g) S. Mizuta, K. M. Engle, S. Verhoog, O. Galicia-López, M. O'Duill, M. Médebielle, K. Wheelhouse, G. Rassias, A. L. Thompson and V. Gouverneur, Org. Lett., 2013, 15, 1250.
6. For review, see: H. Egami and M. Sodeoka, Angew. Chem., Int. Ed., 2014, 53, 8294.
7. Examples of hydrotrifluoromethylation of alkenes: (a) X. Wu, L. Chu and F. Qing, Angew. Chem., Int. Ed., 2013, 52, 2198; (b) S. Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. O'Duill, K. Wheelhouse, G. Rassias, M. Médebielle and V. Gouverneur, J. Am. Chem. Soc., 2013, 135, 2505.
8. (a) X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo and G. Liu, J. Am. Chem. Soc., 2012, 134, 878; (b) H. Egami, R. Shimizu, S. Kawamura and M. Sodeoka, Angew. Chem., Int. Ed., 2013, 52, 4000; (c) H. Egami, R. Shimizu and M. Sodeoka, J. Fluorine Chem., 2013, 152, 51; (d) X. Dong, R. Sang, Q. Wang, X.-Y. Tang and M. Shi, Chem. – Eur. J., 2013, 19, 16910; (e) P. Xu, J. Xie, Q. Xue, C. Pan, Y. Cheng and C. Zhu, Chem. – Eur. J., 2013, 19, 14039; (f) P. Gao, X.-B. Yan, T. Tao, F. Yang, T. He, X.-R. Song, X.-Y. Liu and Y.-M. Liang, Chem. – Eur. J., 2013, 19, 14420; (g) H. Egami, R. Shimizu, Y. Usui and M. Sodeoka, Chem. Commun., 2013, 49, 7346; (h) W. Kong, M. Casimiro, E. Merino and C. Nevado, J. Am. Chem. Soc., 2013, 135, 14480; (i) N. O. Ilchenko, P. G. Janson and K. J. Szabó, J. Org. Chem., 2013, 78, 11087; (j) X. Liu, F. Xiong, X. Huang, L. Xu, P. Li and X. Wu, Angew. Chem., Int. Ed., 2013, 52, 6962; (k) Z.-M. Chen, W. Bai, S.-H. Wang, B.-M. Yang, Y.-Q. Tu and F.-M. Zhang, Angew. Chem., Int. Ed., 2013, 52, 9781; (l) F. Yang, P. Klumphu, Y.-M. Liang and B. H. Lipshutz, Chem. Commun., 2014, 50, 936; (m) Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu and Y.-M. Liang, Org. Lett., 2014, 16, 270.
9. (a) P. G. Janson, I. Ghoneim, N. O. Ilchenko and K. J. Szabó, Org. Lett., 2012, 14, 2882; (b) Y. Li and A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8221; (c) Y. Yasu, T. Koike and M. Akita, Angew. Chem., Int. Ed., 2012, 51, 9567; (d) R. Zhu and S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 12462; (e) R. Zhu and S. L. Buchwald, Angew. Chem., Int. Ed., 2013, 52, 12655; (f) Y.-T. He, L.-H. Li, Y.-F. Yang, Y.-Q. Wang, J.-Y. Luo, X.-Y. Liu and Y.-M. Liang, Chem. Commun., 2013, 49, 5687; (g) Q. Yu and S. Ma, Chem. – Eur. J., 2013, 19, 13304; (h) D.-F. Lu, C.-L. Zhu and H. Xu, Chem. Sci., 2013, 4, 2478; (i) X.-Y. Jiang and F.-L. Qing, Angew. Chem., Int. Ed., 2013, 52, 14177.
10. (a) E. Kim, S. Choi, H. Kim and E. J. Cho, Chem. – Eur. J., 2013, 19, 6209; (b) Y. Yasu, T. Koike and M. Akita, Org. Lett., 2013, 15, 2136; (c) H. Egami, S. Kawamura, A. Miyazaki and M. Sodeoka, Angew. Chem., Int. Ed., 2013, 52, 7841; (d) J.-S. Lin, Y.-P. Xiong, C.-L. Ma, L.-J. Zhao, B. Tan and X.-Y. Liu, Chem. – Eur. J., 2014, 20, 1332; (e) J.-S. Lin, X.-G. Liu, X.-L. Zhu, B. Tan and X.-Y. Liu, J. Org. Chem., 2014, 79, 7084.
11. Recent reviews on lactams: (a) T. Janecki, Natural Lactones and Lactams: Synthesis, Occurrence and Biological Activity, Wiley-VCH, Weinheim, 2013; (b) L.-W. Ye, C. Shu and F. Gagosz, Org. Biomol. Chem., 2014, 12, 1833 and references cited therein.
12. (a) K. Shen and Q. Wang, Chem. Sci., 2015, 6, 4279. Other examples using N-methoxyamides as substrates, see: (b) D. J. Wardrop, E. G. Bowen, R. E. Forslund, A. D. Sussman and S. L. Weerasekera, J. Am. Chem. Soc., 2010, 132, 1188; (c) G. Yang, C. Shen and W. Zhang, Angew. Chem., Int. Ed., 2011, 51, 9141; (d) Z.-Q. Zhang and F. Liu, Org. Biomol. Chem., 2015, 13, 6690.
13. (a) H. Egami, R. Shimizu and M. Sodeoka, Tetrahedron Lett., 2012, 53, 5503; (b) X.-P. Wang, J.-H. Lin, C.-P. Zhang, J.-C. Xiao and X. Zheng, Beilstein J. Org. Chem., 2013, 9, 2635; (c) C. Feng and T.-P. Loh, Chem. Sci., 2012, 3, 3458; (d) C. Feng and T.-P. Loh, Angew. Chem., Int. Ed., 2013, 52, 12414.
14. The observed O-trapping pathway may also arise from the different electronic nature of the 1,1-disubstituted alkenes.
15. The formation of 3e was decreased significantly (12% ¹H NMR yield) with the addition of TEMPO under the optimized reaction conditions, indicating the involvement of radical intermediates.
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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00353a

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