Room temperature copper-catalyzed oxidative amidation of terminal alkynes for the synthesis of α-ketoamides using O-benzoyl hydroxylamines as aminating reagent and oxidant

Abstract

A novel and convenient copper-catalyzed oxidative amidation for the synthesis of α-ketoamides has been successfully developed, which uses easily available O-benzoyl hydroxylamines as aminating reagent and oxidant. The reaction proceeds smoothly at room temperature and is compatible with a range of substrates to give the desired products in moderate to good yields.

---

α-Ketoamides are important functional scaffolds in many natural products, biological compounds, pharmaceuticals, and synthetic intermediates.¹ Significant efforts have been made toward the development of efficient methods for their preparation. Traditional approaches for accessing α-ketoamides mainly involve the condensation of their corresponding α-keto acids or α-keto acyl halides with amines.² Some alternative methods, such as double carbonylation reactions,³ oxidative reactions⁴ and other methods⁵ have also been developed. Recently, the copper-catalyzed oxidative reaction for the synthesis of α-ketoamides has attracted much attention,^4a–d especially using commercially available terminal alkynes as coupling partners.⁶ For example, Jiao et al. and Shah et al. have successfully developed copper-catalyzed methods for the preparation of α-ketoamides involving terminal alkynes as coupling partners with amines (Scheme 1, eqn (1) and (2)).^6a,b While generally effective, the methods require external oxidants, additives and heating conditions. Therefore, developing new methods for the synthesis of α-ketoamides using easily available starting materials under mild conditions is still of promising interest. In the past decade, O-benzoyl hydroxylamines (BzO-NR₁R₂) have received great attention because of easy handling and preparation and high reactivity in amination reactions as a convenient nitrogen source under mild conditions.⁷ Herein, we present a novel and convenient copper-catalyzed oxidative amidation of terminal alkynes for the synthesis of α-ketoamides employing easily available O-benzoyl hydroxylamines (BzO-NR₁R₂) as dually a reactive aminating reagent and oxidant at room temperature (Scheme 1, eqn (3)).

Scheme 1 Synthesis of α-ketoamides.

Initially, the synthesis of α-ketoamides with phenylacetylene 1a and N-(benzoyloxy)piperidine 1b was investigated in the presence of copper catalyst to identify and optimize the reaction parameters (Table 1). To our delight, when the reaction was carried out with CuI (10 mol%) and DBU (2 eq.) in THF (3.0 mL) at ambient temperature under nitrogen, the desired product could be detected (Table 1, entry 1). It was found that the copper catalysts such as CuCl₂, CuI, CuBr, Cu(OTf)₂ affected the reaction yield significantly (Table 1, entries 1–4). The best result was obtained in the presence of 10 mol% of Cu(OTf)₂ (0.05 mmol, 0.018 g), phenylacetylene (2.0 mmol, 0.204 g) and N-(benzoyloxy)piperidine (0.5 mmol, 0.103 g), DBU (1.0 mmol, 0.152 g) in THF (3.0 mL) at room temperature for 12 h, and 84% yield was got (Table 1, entry 4), while increasing the catalyst loading did not improve the product yield (Table 1, entry 5). No reaction occurred in the absence of copper catalyst (Table 1, entry 6). Notably, the copper-catalyzed oxidative amidation reaction did not have external oxygen source (Table 1, entries 1–5). Meanwhile, addition of other oxidants such as benzoyl peroxide (BPO, 1 eq.) or oxygen into the catalytic system decreased the yield obviously (Table 1, entries 7 and 8). Therefore, we surmised that N-(benzoyloxy)piperidine could serve as dually aminating reagent and oxidant. During the study of bases, we noticed that the addition of DBU to the reaction showed the best efficiency (Table 1, entries 9–13). Then, the reaction was investigated in other solvents and THF was found to be the best choice (Table 1, entries 14–16). The reaction temperature was also screened and the reaction yields decreased obviously at lower or higher reaction temperatures (Table 1, entries 17 and 18). Thus, the optimized reaction conditions for the oxidative amidation of terminal alkynes involved using O-benzoyl hydroxylamines as dually aminating reagent and oxidant, Cu(OTf)₂ as the catalyst, DBU as the base, THF as the solvent and conducting the reaction at room temperature under nitrogen.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Base	Solvent	T (°C)	1c^b (%)
a General reaction conditions: copper catalyst (0.05 mmol, 10 mol%), phenylacetylene (2.0 mmol, 0.204 g, 4.0 equiv.) and N-(benzoyloxy)piperidine (0.5 mmol, 0.103 g, 1.0 equiv.), base (1.0 mmol, 2.0 equiv.), solvent (3.0 mL), N2, 12 h.b Isolated yield based on 1b.c Cu(OTf)2 (0.1 mmol) was added as the catalyst.d No copper catalyst was used, n.r. = no reaction.e Benzoyl peroxide (BPO, 0.5 mmol) was added.f The reaction was performed under oxygen balloon.g No base was used.
1	CuI	DBU	THF	RT	52
2	CuBr	DBU	THF	RT	68
3	CuCl2	DBU	THF	RT	62
4	Cu(OTf)2	DBU	THF	RT	84
5	Cu(OTf)2	DBU	THF	RT	82^c
6	—	DBU	THF	RT	n.r.^d
7	Cu(OTf)2/BPO	DBU	THF	RT	38^e
8	Cu(OTf)2/O2	DBU	THF	RT	46^f
9	Cu(OTf)2	Na2CO3	THF	RT	n.r.
10	Cu(OTf)2	K2CO3	THF	RT	n.r.
11	Cu(OTf)2	t-BuOK	THF	RT	Trace
12	Cu(OTf)2	Et3N	THF	RT	n.r.
13	Cu(OTf)2	—	THF	RT	n.r.^g
14	Cu(OTf)2	DBU	Toluene	RT	70
15	Cu(OTf)2	DBU	Dioxane	RT	Trace
16	Cu(OTf)2	DBU	H2O	RT	n.r.
17	Cu(OTf)2	DBU	THF	35	72
18	Cu(OTf)2	DBU	THF	15	24

---

With the optimized reaction conditions in hand, we evaluated the scope of the copper-catalyzed oxidative amidation for the synthesis of α-ketoamides. As shown in Table 2, the reaction yields were slightly influenced by the electronic effect of substituents of terminal alkynes. Terminal alkynes with electron-donating methyl, tertiary butyl and pentyl groups (Table 2, entries 2–4) and electron-withdrawing fluoro and chloro groups (Table 2, entries 5–6) generated the desired products in moderate to good yields. Various O-benzoyl hydroxylamines with acyclic and cyclic N-alkyl substituents were explored by reacting with phenylacetylene (1a) under the optimum reaction conditions (Table 2, entries 7–12). The five-membered cyclic amines 2b bearing a pyrrolidine moiety, the six-membered cyclic amines 1b and 3b bearing a piperidine and morpholine moiety, and the seven-membered cyclic amines 4b bearing a azepane moiety are compatible to the reaction conditions (Table 2, entries 7–9). O-benzoyl hydroxylamines which were derived from N,N-diethyl 5b, N,N-di-n-butyl 6b, and N-n-butyl-N-ethyl 7b amines were smoothly converted to α-ketoamides 10c–14c in 60–76% yields (Table 2, entries 10–14). An O-benzoyl-N-phenylhydroxylamine 8b, which is prepared from primary phenylamine, could not be utilized in this protocol to furnish the desired compound 15c, presumably because of the weak oxidative ability of 8b (Table 2, entry 15). Aliphatic alkynes 1-hexyne 7a also could not reacted with N-(benzoyloxy)piperidine 1b under the optimized reaction condition (Table 2, entry 16).

Table 2 Scope of copper-catalyzed oxidative amidation for the synthesis of α-ketoamides^a

Entry	a	b	c	Yield^b (%)
a Reaction conditions: copper(II) trifluoromethanesulfonate (0.05 mmol, 0.018 g, 10 mol%), terminal alkyne a (2.0 mmol, 4.0 equiv.) and O-benzoyl hydroxylamine b (0.5 mmol, 1.0 equiv.), DBU (1.0 mmol, 0.152 g, 2.0 equiv.), THF (3.0 mL), N2, RT, 12 h.b Isolated yield based on b.
1				84
2		1b		82
3		1b		64
4		1b		72
5		1b		80
6		1b		78
7	1a			80
8	1a			72
9	1a			62
10	1a			68
11	1a			76
12	1a			60
13	2a	5b		65
14	6a	5b		61
15	1a			0
16		1b		0

---

To gain some understanding of the mechanism for this reaction, some control experiments were tentatively examined under the optimized reaction conditions (for mechanism details, see ESI†). We have concluded that oxygen source of the product 1c come from N-(benzoyloxy)piperidine 1b (Table 1, entries 1–8), and the detected phenyl(piperidin-1-yl)methanone 1d also confirmed our speculation (Scheme 2, eqn (1)). We used O-benzoyl-N,N-dibutylhydroxylamine 6b to repeat the reaction, N,N-dibutylbenzamide 11d was also detected from the reaction (Scheme 2, eqn (2)). When the reaction was carried out with two equivalents of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), it could proceed smoothly and the reaction may not undergo a radical mechanism (Scheme 2, eqn (3)). When 2.0 mL THF and 1.0 mL H₂¹⁸O used as the solvent to repeat the reaction, no product was detected, and the oxygen of the products did not come from the H₂O in THF (Scheme 2, eqn (4)).

Scheme 2 Control experiments.

In summary, we have developed a novel and convenient copper-catalyzed oxidative amidation of terminal alkynes for synthesis of α-ketoamides. This protocol displays attractive features including using easily available O-benzoyl hydroxylamines (BzO-NR₁R₂) as aminating reagent and oxidant, and conducting the reaction at room temperature. The reaction also exhibits some functional group tolerance and allows for the preparation of a number of α-ketoamides in moderate to good yields. The importance of the α-ketoamides scaffold would render this protocol attractive for both synthetic and medicinal chemistry.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 21402079) and the Shandong Provincial Natural Science Foundation of China (ZR2015PB004).

Notes and references

1. (a) J. L. Jesuraj and J. Sivaguru, Chem. Commun., 2010, 46, 4791; (b) Z. Zhang, Q. Zhang, Z. Ni and Q. Liu, Chem. Commun., 2010, 46, 1269; (c) Y. H. Chen, Y. H. Zhang, H. J. Zhang, D. Z. Liu, M. Gu, J. Y. Li, F. Wu, X. Z. Zhu, J. Li and F. J. Nan, J. Med. Chem., 2006, 49, 1613; (d) S. Alvarez, R. Alvarez, H. Khanwalkar, P. Germain, G. Lemaire, F. Rodriguez-Barrios, H. Gronemeyer and A. R. de Lera, Bioorg. Med. Chem., 2009, 17, 4345; (e) L. Yang, D. X. Wang, Z. T. Huang and M. X. Wang, J. Am. Chem. Soc., 2009, 131, 10390; (f) G. G. Xu and F. A. Etzkorn, Org. Lett., 2010, 12, 696; (g) D. Tomita, K. Yamatsugu, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 6946; (h) H. Xu and C. Wolf, Angew. Chem., Int. Ed., 2011, 50, 12249.
2. (a) R. P. Singh and J. M. Shreeve, J. Org. Chem., 2003, 68, 6063; (b) G. M. Dubowchik, V. M. Vrudhula, B. Dasgupta, J. Ditta, T. Chen, S. Sheriff, K. Sipman, M. Witmer, J. Tredup, D. M. Vyas, T. A. Verdoorn, S. Bollini and A. Vinitsky, Org. Lett., 2001, 3, 3987; (c) A. Chiou, T. Markidis, V. C. Kokotou, R. Verger and G. Kokotos, Org. Lett., 2000, 2, 347; (d) G. M. Dubowchik, J. L. Ditta, J. J. Herbst, S. Bollini and A. Vinitsky, Bioorg. Med. Chem. Lett., 2000, 10, 559; (e) J. Chen and R. F. Cunico, J. Org. Chem., 2004, 69, 5509; (f) R. Hua, H. Takeda, Y. Abe and M. Tanaka, J. Org. Chem., 2004, 69, 974.
3. (a) J. Liu, R. Zhang, S. Wang, W. Sun and C. Xia, Org. Lett., 2009, 11, 1321; (b) E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L. Buchwald and K. F. Jensen, Angew. Chem., Int. Ed., 2007, 46, 1734; (c) M. Iizuka and Y. Kondo, Chem. Commun., 2006, 1739; (d) T. Fukuyama, S. Nishitani, T. Inouye, K. Morimoto and I. Ryu, Org. Lett., 2006, 8, 1383.
4. (a) C. Zhang, Z. J. Xu, L. R. Zhangand and N. Jiao, Angew. Chem., Int. Ed., 2011, 50, 11088; (b) F. T. Du and J. X. Ji, Chem. Sci., 2012, 3, 460; (c) C. Zhang, X. Zong, L. Zhang and N. Jiao, Org. Lett., 2012, 14, 3280; (d) J. Zhang, Y. Wei, S. Lin, F. Liang and P. Liu, Org. Biomol. Chem., 2012, 10, 9237; (e) J. M. Grassot, G. Masson and J. Zhu, Angew. Chem., Int. Ed., 2008, 47, 947; (f) M. Bouma, G. Masson and J. Zhu, J. Org. Chem., 2010, 75, 2748; (g) W. Wei, Y. Shao, H. Hu, F. Zhang, C. Zhang, Y. Xu and X. Wan, J. Org. Chem., 2012, 77, 7157; (h) X. Zhang and L. Wang, Green Chem., 2012, 14, 2141; (i) W. P. Mai, H. H. Wang, Z. C. Li, J. W. Yuan, Y. M. Xiao, L. R. Yang, P. Mao and L. B. Qu, Chem. Commun., 2012, 48, 10117.
5. (a) R. Mossetti, T. Pirali, G. C. Tron and J. Zhu, Org. Lett., 2010, 12, 820; (b) D. Coffinier, L. E. Kaim and L. Grimaud, Org. Lett., 2009, 11, 1825; (c) Q. Liu, S. Perreault and T. Rovis, J. Am. Chem. Soc., 2008, 130, 14066; (d) Z. F. Al-Rashid, W. L. Johnson, R. P. Hsung, Y. Wei, P. Y. Yao, R. Liu and K. Zhao, J. Org. Chem., 2008, 73, 8780.
6. (a) C. Zhang and N. Jiao, J. Am. Chem. Soc., 2010, 132, 28; (b) M. Kumar, S. Devari, A. Kumar, S. Sultan, Q. N. Ahmed, M. Rizvi and B. A. Shah, Asian J. Org. Chem., 2015, 4, 438.
7. (a) N. Matsuda, K. Hirano, T. Satoh and M. Miura, Angew. Chem., Int. Ed., 2012, 51, 3642; (b) R. P. Rucker, A. M. Whittaker, H. Dang and G. Lalic, J. Am. Chem. Soc., 2012, 134, 6571; (c) N. Matsuda, K. Hirano, T. Satoh and M. Miura, J. Am. Chem. Soc., 2013, 135, 4934; (d) Q. Xiao, L. M. Tian, R. C. Tan, Y. Xia, D. Qiu, Y. Zhang and J. B. Wang, Org. Lett., 2012, 14, 4230; (e) X. Y. Yan, C. Chen, Y. Q. Zhou and C. J. Xi, Org. Lett., 2012, 14, 4750; (f) N. Matsuda, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2011, 13, 2860; (g) E. J. Yoo, S. Ma, T. S. Mei, K. S. L. Chan and J. Q. Yu, J. Am. Chem. Soc., 2011, 133, 7652; (h) C. Grohmann, H. Wang and F. Glorius, Org. Lett., 2013, 15, 3014; (i) Z. Dong and G. Dong, J. Am. Chem. Soc., 2013, 135, 18350; (j) J. He, T. Shigenari and J. Q. Yu, Angew. Chem., Int. Ed., 2015, 54, 6545; (k) M. Shang, S. H. Zeng, S. Z. Sun, H. X. Dai and J. Q. Yu, Org. Lett., 2013, 15, 5286; (l) K. Wu, Z. L. Fan, Y. Xue, Q. Z. Yao and A. Zhang, Org. Lett., 2014, 16, 42; (m) T. Matsubara, S. Asako, L. Ilies and E. Nakamura, J. Am. Chem. Soc., 2014, 136, 646; (n) Q. Gou, G. Liu, Z. N. Liu and J. Qin, Chem.–Eur. J., 2015, 21, 15491; (o) J. He, T. Shigenari and J. Q. Yu, Angew. Chem., 2015, 127, 6645.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra15219h

---