Efficient Cu-catalyzed intramolecular O-arylation for synthesis of benzoxazoles in water

Abstract

An efficient method was developed for synthesis of benzoxazoles by Cu-catalyzed intramolecular O-arylation of o-halobenzanilides in water. This strategy provides several advantages, such as high yields, water as a green solvent and functional groups tolerance.

---

Benzoxazole derivatives not only exist in several important natural products, but are also present in many important classes of organic compounds due to their biological, pharmaceutical and catalytic properties, which have attracted more and more attention from pharmaceutical and synthetic chemists (Fig. 1).^1,2 Commonly, the preparation of benzoxazoles has attracted considerable attention. Traditional methods to construction of 2-aryl benzoxazoles involve the condensation of 2-aminophenol with carboxylic acids or aldehydes under oxidative conditions, which unfortunately often suffer from the use of harsh reaction conditions involving strong acids or highly toxic reagents in combination with high temperatures.³

Fig. 1 Examples of biologically and pharmaceutically benzoxazoles.

In the last decades, some of these drawbacks have been overcome by the development of transition-metal-catalyzed processes for C–O bond formations under comparatively milder reaction conditions.⁴ Until now, there are various reactions reported for the construction of benzoxazoles by intramolecular O-arylation of orthohaloanilides under milder reaction conditions.⁵ Evindar et al. have improved the formation of benzoxazoles via a CuI/1,10-phenanthroline-catalyzed cyclization of o-haloanilides in the presence of Cs₂CO₃ in DMF.^6a Saha et al. have reported cobalt(II)/1,10-phenanthroline-catalyzed the intramolecular C–O cross-couplings of o-halobenzanilides to give benzoxazoles in DMSO.^6b Dai et al. have prepared 2-substituted benzoxazoles via Cu-catalysed intramolecular coupling cyclization reactions using methyl 2-methoxybenzoate (MMB) as the ligand in DMF.^7a Bonnamour et al. have obtained benzoxazole derivatives by iron-catalyzed intramolecular O-arylation reaction and 2,2,6,6-tetramethyl-3,5 heptanedione (TMHD) as the cocatalyst in DMF.^7b Tapia et al. described an efficient synthesis of 2-arylbenzoxazoles using (IPr)CuCl via intramolecular coupling cyclization of 2-haloanilides in DMF.⁸ Although many improvements have been achieved for the synthesis of 2-substituted benzoxazoles from o-halobenzanilides through intramolecular O-arylation by transition-metal-catalyzed processes, many approaches reported so far were harsh conditions, such as long reaction time, costly and toxic solvents.^3,9 Therefore, there is still worthwhile to develop an economic, efficient and eco-friendly catalytic system (Scheme 1).

Scheme 1 Intramolecular O-arylation for the synthesis of benzoxazoles.

To the best of our knowledge, no report on the synthesis of benzoxazoles from o-halobenzanilides in water has been reported so far. In initiatory work, we have found that 1-[2-(N-(3-diphenylphosphinopropyl))aminoethyl]pyrrolidine (DPPAP) could promoted transition metal-catalyzed reactions as NNP-type pincer ligand, which accelerated Cu-catalyzed intramolecular O-arylation of o-halobenzanilides to form benzoxazoles in water. In present work, we optimum reaction conditions based on initiatory study, and report a new, efficient and green Cu-catalyzed synthesis of benzimidazoles in water.

Reaction between N-(2-bromophenyl)benzamide (1a) was selected as a model substrate and various copper sources were tested including CuI, CuSO₄, Cu(OAc)₂ and Cu(OTf)₂ to check and identify optimization of reaction conditions. As shown in Table 1, the reaction results were distinguishable catalyzed by various copper sources. In general, CuI could lead to product in low yield, and CuSO₄ was not active to this action and no product was obtained (Table 1, entries 1–6). To our surprise, Cu(OTf)₂ and Cu(OAc)₂ enhanced the reaction yields obviously (Table 1, entries 7–15). In order to study the effects of different types of bases on the reaction, 4 bases were employed including inorganic and organic base such as K₃PO₄, K₂CO₃, TMEDA and Et₃N. We could see that compound 2a was formed in the presence of TMEDA and Et₃N in better yields than that of K₃PO₄ and K₂CO₃, and there was nearly no difference.

Table 1 Optimization of reaction conditions for the synthesis of 2a^a,b

Entry	[Cu]	Base	T (°C)	Time (h)	Yield (%)
a All reactions were performed using 1a (1 mmol), [Cu] (5 mol%), DPPAP (10 mol%), base (2 mmol) in water (3 mL).b Isolated yield after chromatographic purification.
1	CuI	K2CO3	100	12	22
2	CuI	K3PO4	100	12	20
3	CuI	TMEDA	100	12	38
4	CuI	Et3N	100	12	36
5	CuSO4	TMEDA	100	12	Trace
6	CuSO4	Et3N	100	12	Trace
7	Cu(OTf)2	TMEDA	100	12	64
8	Cu(OTf)2	Et3N	100	12	62
9	Cu(OAc)2	TMEDA	100	12	84
10	Cu(OAc)2	Et3N	100	12	83
11	Cu(OAc)2	Et3N	90	12	70
12	Cu(OAc)2	Et3N	110	12	89
13	Cu(OAc)2	Et3N	110	6	62
14	Cu(OAc)2	Et3N	110	24	81
15	Cu(OAc)2	Et3N	120	12	72

---

Furthermore, we examined the effects of temperature and time on the reaction. With the increasing of temperature from 90 °C to 110 °C, the yield had increased to 89% (Table 1, entry 12). However, further increasing temperature led to decline of yield(Table 1, entry 15). In addition, reaction time from 6 h to 12 h was favorable to reaction obviously. However, further increase of reaction time to 24 h had negative effect on the yield of benzoxazole (Table 1, entry 14). Therefore, it was clear that the best reaction was performed taking Cu(OAc)₂ (5 mol%) and DPPAP (10 mol%) as the catalyst in water in present of Et₃N (2 eq.) for 12 h at 110 °C.

With the optimal reaction conditions in hand, a series of o-halobenzanilides were investigated to study the scope of Cu-catalyzed intramolecular O-arylation. As shown in Table 2, to our delight, the O-arylation of various substituted 2-bromobenzanilides or 2-iodobenzanilides under standard reaction condition gave the corresponding title products in good to high yields, and 2-iodobenzanilides were more active than 2-bromobenzanilides (Table 2). In order to study the influence of substituted groups, various substituted o-halobenzanilides were performed including electron donating groups (CH₃, C₂H₅, CH₃O, F, Cl, Br) and withdrawing group (CF₃). From the results, we could find that this reaction condition was beneficial to prepare 2-substituted benzoxazoles, and substitutions on amide were tolerated. In general, electron donating groups afforded the corresponding benzoxazoles in higher yields than that of CF₃. Especially, N-(2-iodophenyl)-4-methoxybenzamide formed 2d in the best yield (93%), and N-(2-bromophenyl)-2,3,4,5-tetrafluorobenzamide formed 2g in the lowest yield (70%).

Table 2 Cu-catalyzed synthesis of benzoxazoles from 2-iodo/bromophenylbenzanilides using DPPAP as the ligand^a,b

Entry	1	2	Yield^c (%)
			present	reported
a All reactions were carried out using o-halobenzanilides (1 mmol), Cu(OAc)2 (0.05 mmol), DPPAP (0.1 mmol), Et3N (2 mmol) in water (3 mL) for 12 h at 110 °C.b Isolated yield.c ‘—’ presented no report yield from o-halobenzanilides.
1			89	78 (ref. 7a)
2			92	87 (ref. 7a)
3			90	79 (ref. 8)
4			92	87 (ref. 8)
5			81	—
6			87	—
7			88	75 (ref. 8)
8			93	82 (ref. 8)
9			82	—
10			85	—
11			74	80 (ref. 7a)
12			81	91 (ref. 7a)
13			70	—
14			77	—
15			79	77 (ref. 8)
16			85	86 (ref. 8)
17			74	—
18			83	—
19			86	—
20			89	—
21			83	92 (ref. 6a)
22			90	—
23			76	—
24			88	—
25			76	—
26			85	—
27			73	—
28			78	—
29			89	—
30			92	—

---

In addition, the intramolecular O-arylation of various ortho, meta and para substituted o-halobenzanilides were carried out using the Cu(OAc)₂/DPPAP catalyst system. As shown in Table 2, all desired products were obtained in good yields, and position of both electron donating and withdrawing groups did not have obvious influence on applicability. It was gratified that N-(2-bromophenyl)-2,3,4,5-tetrafluorobenzamide, N-(2-iodophenyl)-2,3,4,5-tetrafluoro benzamide, N-(2-bromophenyl)-3,5-dichlorobenzamide and N-(2-iodophenyl)-3,5-dichlorobenzamide could afford the corresponding products 2g and 2j in good yields (70%, 77%, 86% and 89%, respectively) under optimal reaction conditions.

From above results, our improved protocol for synthesis of benzoxazoles by intramolecular O-arylation of o-halobenzanilides (Br, I) in water is significantly applicative under Cu/DPPAP catalyst system. Delighted with this results, we were eager to study O-arylation of 2-chlorobenzanilides. Therefore, six 2-chlorobenzanilides bearing different substituted groups were selected as the model reaction under standard conditions. As shown in Table 3, 2-chlorobenzanilides displayed poor reactivity under this conditions, and benzoxazoles were obtained in low yields (<30%), respectively.

Table 3 Cu-catalyzed synthesis of benzoxazoles from N-(2-chloro phenyl)benzanilides using standard condition^a,b

Entry	1	2	Yield (%)
a All reactions were carried out using o-chlorobenzanilides (1 mmol), Cu(OAc)2 (0.05 mmol), DPPAP (0.1 mmol), Et3N (2 mmol) in water (3 mL) for 12 h at 110 °C.b Isolated yield.
1			22
2			28
3			13
4			25
5			Trace
6			15

---

In addition, we performed the reaction on a gram-scale by taking 10 mmol of N-(2-iodophenyl)-4-methoxybenzamide in 30 mL water at 110 °C for 12 h (Scheme 2). The reaction proceeded smoothly to form desired product 2d (2.05 g, 91% yield).

Scheme 2 Gram-scale synthesis of benzoxazole 2d.

Although the mechanism of the present reaction was not yet clear, based on experimental results mentioned and copper-catalyzed C–O bond formations in the literature,^6a,10 the most probable mechanism was proposed and depicted for the Cu-catalytic intramolecular O-arylation of o-halobenzanilides as shown in Scheme 3. Firstly, o-halobenzanilide converted to enol I, followed by coordination of the CuL catalyst and Et₃N to give II. Subsequently, intermediate III was formed by oxidative insertion. After that, III underwent reductive elimination to give benzoxazole as well as CuLX. Finally, CuLX was transformed into CuL catalyst for reuse in presence of Et₃N.

Scheme 3 Possible mechanism of intramolecular O-arylation.

Conclusions

In conclusion, we have developed an efficient method for synthesis of benzoxazoles by Cu-catalyzed intramolecular O-arylation of o-halobenzanilides in water. This protocol is applicable to a wide variety of o-halobenzanilides bearing electron donating as well as electron withdrawing groups, which features high yields, water as green solvent and functional groups tolerable. The simple and green catalytic system provides a valuable synthetic approach for industrial applications.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81560620), the Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Yunnan University of Chinese Medicine (2017FF117(-023)).

Notes and references

1. (a) S. M. Johnson, S. Connelly, I. A. Wilson and J. W. Kelly, J. Med. Chem., 2008, 51, 260; (b) N. Mishra, A. S. Singh, A. K. Agrahari, S. K. Singh, M. Singh and V. K. Tiwari, ACS Comb. Sci., 2019, 21, 389; (c) G. Daletos, N. J. de Voogd, W. E. G. Muller, V. Wray, W. Lin, D. Feger, M. Kubbutat, A. H. Aly and P. Proksch, J. Nat. Prod., 2014, 77, 218; (d) S. Aiello, G. Wells, E. L. Stone, H. Kadri, R. Bazzi, D. R. Bell, M. F. G. Stevens, C. S. Matthews, T. D. Bradshaw and A. D. Westwell, J. Med. Chem., 2008, 51, 5135.
2. (a) L. Leventhal, M. R. Brandt, T. A. Cummons, M. J. Piesla, K. E. Rogers and H. A. Harris, Eur. J. Pharmacol., 2006, 553, 146; (b) L. Q. Sun, J. Chen, M. Cruce, J. A. Deskus, J. R. Epperson, K. Takaki, G. Johnson, L. Iben, C. D. Malhe, E. Ryan and C. Xu, Bioorg. Med. Chem. Lett., 2004, 14, 3799; (c) E. Oksuzoglu, O. Temiz-Arpaci, B. Tekiner-Gulbas, H. Eroglu, G. Sen, S. Alper, I. Yildiz, N. Diril, E. Aki-Sener and I. Yalcin, Med. Chem. Res., 2007, 16, 1; (d) J. Boyer, E. Arnoult, M. Médebielle, J. Guillemont and J. Unge, J. Med. Chem., 2011, 54, 7974.
3. (a) K. Bougrin, A. Loupy and M. Soufiaoui, Tetrahedron Lett., 1998, 54, 8055; (b) J. Chang, K. Zhao and S. Pan, Tetrahedron Lett., 2002, 43, 951; (c) K. Bougrin, A. Loupy and M. Soufiaoui, Tetrahedron, 1998, 54, 8055; (d) S. M. Inamdar, V. K. More and S. K. Mandal, Tetrahedron Lett., 2013, 54, 579; (e) Y. Kawashita, N. Nakamichi, H. Kawabata and M. Hayashi, Org. Lett., 2003, 5, 3713.
4. (a) N. Barbero, M. Carril, R. SanMartin and E. Domínguez, Tetrahedron, 2007, 63, 10425; (b) S. Ueda and H. Nagasawa, Angew. Chem., Int. Ed., 2008, 47, 6411; (c) N. Khatun, S. Guin, S. K. Rout and B. K. Patel, RSC Adv., 2014, 4, 10770; (d) J. Peng, C. Zong, M. Ye, T. Chen, D. Gao, Y. Wang and C. Chen, Org. Biomol. Chem., 2011, 9, 1225; (e) A. D. G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008, 108, 3054; (f) A. Ahmed, R. Singha and J. K. Ray, Tetrahedron Lett., 2015, 56, 2167; (g) X. Zhang, W. Zeng, Y. Yang, H. Huang and Y. Liang, Org. Lett., 2014, 16, 876; (h) L. Xiao, H. Gao, J. Kong, G. Liu, X. Peng and S. Wang, Chin. J. Org. Chem., 2014, 34, 1048.
5. (a) S. Sasmal, I. Sen, R. G. Hall and S. Pal, Tetrahedron Lett., 2015, 56, 1374; (b) Y. Yuan, I. Thomé, S. H. Kim, D. Chen, A. Beyer, J. Bonnamour, E. Zuidema, S. Chang and C. Bolm, Adv. Synth. Catal., 2010, 352, 2892; (c) N. Barbero, M. Carril, R. SanMartin and E. Domínguez, Tetrahedron, 2007, 63, 10425; (d) R. D. Viirre, G. Evindar and R. A. Batey, J. Org. Chem., 2008, 73, 3452; (e) N. Barbero, M. Carril, R. SanMartin and E. Domínguez, Tetrahedron, 2007, 63, 10425; (f) J. Sedelmeier, F. Lima, A. Litzler, B. Martin and F. Venturoni, Org. Lett., 2013, 15, 5546; (g) D. Suresh, A. Dhakshinamoorthy and K. Pitchumani, Tetrahedron Lett., 2013, 54, 6415.
6. (a) G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71, 1802; (b) P. Saha, M. A. Ali, P. Ghosh and T. Punniyamurty, Org. Biomol.Chem., 2010, 8, 5692.
7. (a) F. Wu, J. Zhang, Q. Wei, P. Liu, J. Xie, H. Jiang and B. Dai, Org. Biomol. Chem., 2014, 12, 9696; (b) J. Bonnamour and C. Bolm, Org. Lett., 2008, 10, 2665.
8. J. I. Urzúa, R. Contreras, C. O. Salas and R. A. Tapia, RSC Adv., 2016, 6, 82401.
9. (a) K. Bougrin, A. Loupy and M. Soufiaoui, Tetrahedron, 1998, 54, 8055; (b) G. Alenhoff and F. Glorius, Adv. Synth. Catal., 2004, 346, 1661; (c) J. Chang, K. Zhao and S. Pan, Tetrahedron Lett., 2002, 43, 951; (d) M. Carril, R. SanMartin, I. Tellitu and E. Domínguez, Org. Lett., 2006, 8, 1467.
10. (a) G. D. Allred and L. S. Liebskind, J. Am. Chem. Soc., 1996, 118, 2748; (b) E. R. Strieter, D. G. Blackmond and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 4120.

---

Footnotes

† Electronic supplementary information (ESI) available: Experimental details and spectra data. See DOI: 10.1039/d0ra00570c

‡ These authors contributed equally to this work.

---