CuI-catalyzed oxidative cross coupling of oximes with tetrahydrofuran: a direct access to O-tetrahydrofuran-2-yl oxime ethers

Abstract

An efficient copper(I)-catalyzed oxidative tetrahydrofuranylation of oximes has been developed. This reaction shows good functional group tolerance and various substituted ketoximes and aldoximes coupled smoothly with THF to give the corresponding O-tetrahydrofuran-2-yl oxime ethers in high yields.

---

The C–O bond construction is one of the fundamental researches in organic chemistry.¹ Traditional methods for the construction of C–O bonds, such as Ullmann-type C–O coupling and the Williamson reaction, have been established in the past few decades.² However, most of these reactions were conducted under relatively harsh conditions. In recent years, palladium-catalyzed cross-coupling of aryl chlorides (bromides) and phenols or aliphatic alcohols for the construction of C–O bonds under mild conditions has been developed by the groups of Buchwald³ and Hartwig.⁴ Apparently, these methods all required prefunctionalized of substrates. Recently, the direct C–H bond oxidative coupling has emerged as an excellent strategy in organic synthesis since their atom-economical and environmental beneficial properties.⁵ Therefore, the constructing C–O bond via direct C–H oxidative coupling would be an attractive area of research.⁶

The α-functionalized ether derivatives are prevalent in many functional molecules or natural products.⁷ They are useful synthetic intermediates in organic chemistry. Therefore, the method for the synthesis of α-functionalized ethers via C–H oxidative coupling has been attracting great interest.⁸ In 2013, DDQ-mediated C–O bond formation through oxidative coupling of isochroman and oxime has been developed by Bao and coworkers.⁹ Recently, oxidative coupling of THF with arylboronic acid, alkene, alkynes, 2-aryl-metal reagents, alcohols, phenols and carboxylic acids has been developed to synthesize various α-functionalized tetrahydrofuranyl derivatives.¹⁰ However, to our knowledge, the oxidative coupling of oximes and tetrahydrofuran has not been developed. Based on our interest in Cu-catalyzed coupling reaction of oxime derivatives,¹¹ we report herein a CuI-catalyzed oxidative cross-coupling of oximes with tetrahydrofuran for the synthesis of O-tetrahydrofuran-2-yl oxime ethers.

We began our investigation by examining the coupling of acetophenone oxime 1a and THF in the presence of CuI and TBHP at 120 °C. Unfortunately, no reaction occurred (Table 1, entry 1). Recently, allyl and benzyl system have been extensively investigated as the propagator of the radical chain due to their promotion to the radical formation of THF.^10h Therefore, allyl bromide, allyl chloride, benzyl bromide and benzyl chloride were screened in the reaction (Table 1, entries 2–5). To our delight, the desired product 2a was indeed obtained in 70% yield when allyl bromide was used as the additive (Table 1, entry 2). Allyl chloride, benzyl bromide and benzyl chloride were inactive for the reaction (Table 1, entries 3–5). Further experiments showed that CuI was superior to other copper catalysts (Table 1, entries 6–10). Notably, no reaction occurred in the absence of the copper catalyst (Table 1, entry 11). Optimizing with various oxidants, such as BPO, DCP and DTBP, revealed that DTBP was the most effective oxidant for this reaction, improving the yield of 2a to 77% (Table 1, entries 12–14). Finally, the yield of 2a was further increased to 88% by adding 4 equiv. of DTBP (Table 1, entry 15).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Oxidant	Additive	Yield (%)
a Reaction conditions: acetophenone oxime 1a (0.5 mmol), oxidant (1.0 mmol), additive (1.0 mmol), catalyst (0.05 mmol), THF (5 mL), 120 °C, Ar; isolated yield. TBHP = tert-butyl hydroperoxide, BPO = benzoyl peroxide, DCP = dicumyl peroxide, DTBP = di-tert-butyl-peroxide.b 4 equiv. DTBP.
1	CuI	TBHP	—	<5
2	CuI	TBHP	Allyl bromide	70
3	CuI	TBHP	Allyl chloride	<5
4	CuI	TBHP	Benzyl bromide	<5
5	CuI	TBHP	Benzyl chloride	<5
6	CuBr	TBHP	Allyl bromide	50
7	CuCl	TBHP	Allyl bromide	47
8	CuBr2	TBHP	Allyl bromide	49
9	CuCl2	TBHP	Allyl bromide	49
10	Cu(OAc)2	TBHP	Allyl bromide	51
11	—	TBHP	Allyl bromide	0
12	CuI	BPO	Allyl bromide	<5
13	CuI	DCP	Allyl bromide	63
14	CuI	DTBP	Allyl bromide	77
15^b	CuI	DTBP	Allyl bromide	88

---

With the optimized reaction conditions established, a series of ketoximes and aldoximes were investigated to extend the substrate scope (Table 2). This transformation displayed high functional group tolerance. Ketoximes with both electron-donating and electron-withdrawing substituents on the aromatic rings showed similar reactivity to give the target products 2a–2f in good yields (70–88%). Halogen substituents such as fluoro and chloro were tolerated as well in this reaction to afford the corresponding products 2d–2e in 84% and 85% yields, respectively. 2-Naphthyl ketoxime 1g also reacted smoothly with THF to give the 2g in 80% yield. Furthermore, phenyl alkyl ketoximes with different alkyl groups, such as ethyl, iso-propyl, tert-butyl and benzyl, reacted smoothly to afford the corresponding ether products 2h–2l in 68–81% yields.

Table 2 Copper-catalyzed oxidative C–O coupling reaction of oximes and tetrahydrofuran^a

a Reaction conditions: 1 (0.5 mmol), DTBP (2.0 mmol), allyl bromide (1.0 mmol), CuI (0.05 mmol), THF (5 mL), 120 °C, Ar; isolated yield.

---

Subsequently, the cyclic ketoximes derived from α-tetralones and indanones were investigated under the standard conditions to extend the substrate scope. Satisfactorily, the desired products 2m–2p were obtained in 67–78% yields. Moreover, the derivatives of benzophenone oximes were also tolerated in the reaction to give the desired products 2q and 2r in moderate yields. It should be noted that aromatic aldoximes exhibited similar reactivity with ketoxime to give the corresponding products 2s–2t in good yields. In addition, 2-furaldoxime was also converted to the target product 2u in 51% yield.

Next, various ethers, such as glycol dimethyl ether, 1,4-dioxane, pyran and 4-methylmorpholine were investigated to extend the substrate scope. Unfortunately, no desired reaction occurred and acetophenone was observed as the main byproduct in these reactions.

To gain more insight into the mechanism of the reaction, a radical-trapping reagent, (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO), was added to the reaction under the standard conditions (Scheme 1). Formation of O-tetrahydrofuran-2-yl oxime ether 2a was completely suppressed, implying that the oxidative coupling reaction probably proceeds through a radical pathway.

Scheme 1 Investigation of the reaction mechanism.

On the basis of the aforementioned results and previous studies, a tentative mechanism for this copper-catalyzed oxidative coupling reaction was proposed in Scheme 2. Firstly, the α-C–H bond of THF is oxidated by DTBP to generate 2-tetrahydrofuranyl radical A.^10b,10d,10f Next, intermediate A was transformed to 2-bromo-tetrahydrofuranyl B via radical transfer with allyl bromide.^10h The allyl radical intermediate C was captured by a tert-butyl peroxy radical to give the 4,4-dimethylpent-1-ene. In cycle, the initial step involves the transformation of oxime 1 into an Cu(I)oxime complex E, followed by reacting with 2-bromo-tetrahydrofuranyl B to give the intermediate F. Finally, the reductive elimination of intermediate F provides the product 2.¹²

Scheme 2 Tentative mechanisms of the reaction.

In summary, we have developed a novel Cu-catalyzed cross coupling of oximes with THF for the synthesis of O-tetrahydrofuran-2-yl oxime ethers. The reaction shows good functional group tolerance and affords a series of substituted O-tetrahydrofuran-2-yl oxime ethers in good yields. Further investigations on the transformations of oximes are in progress in our laboratory.

Acknowledgements

This work was supported by generous grants from the Fund of Shanxi Province (2014JQ2078) and National Natural Science Foundation of China (21272183 and 21472147).

Notes and references

1. (a) A. Corma, A. Leyva-Pérez and M. J. Sabater, Chem. Rev., 2011, 111, 1657; (b) N. Krause and C. Winter, Chem. Rev., 2011, 111, 1994; (c) C. I. Herrerías, X. Yao, Z. Li and C.-J. Li, Chem. Rev., 2007, 107, 2546; (d) E. M. Beccalli, G. Broggini, M. Martinelli and S. Sottocornola, Chem. Rev., 2007, 107, 5318; (e) E. Fuhrmann and J. Talbiersky, Org. Process Res. Dev., 2005, 9, 206.
2. (a) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2008, 47, 3096; (b) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954; (c) A. B. Naidu, E. A. Jaseer and G. Sekar, J. Org. Chem., 2009, 74, 3675; (d) A. B. Naidu and G. Sekar, Synthesis, 2010, 579; (e) R. Hosseinzadeh, M. Tajbakhsh, M. Mohadjerani and M. Alikarami, Synlett, 2005, 1101; (f) K. Takaishi, M. Kawamoto, A. Muranaka and M. Uchiyama, Org. Lett., 2012, 14, 3252; (g) Y. Peng and G. Song, Green Chem., 2002, 4, 349.
3. (a) A. V. Vorogushin, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 8146; (b) C. H. Burgos, T. E. Barder, X. Huang and S. L. Buchwald, Angew. Chem., Int. Ed., 2006, 45, 4321; (c) K. W. Anderson, T. Ikawa, R. E. Tundel and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 10694; (d) X. Wu, B. P. Fors and S. L. Buchwald, Angew. Chem., Int. Ed., 2011, 50, 9943; (e) L. Salvi, N. R. Davis, S. Z. Ali and S. L. Buchwald, Org. Lett., 2012, 14, 170; (f) N. C. Bruno and S. L. Buchwald, Org. Lett., 2013, 15, 2876.
4. (a) J. F. Hartwig, Organotransition Metal Chemistry: From Bonding to Catalysis, University Science Books, Sausalito, CA, 2010; (b) Q. Shelby, N. Kataoka, G. Mann and J. Hartwig, J. Am. Chem. Soc., 2000, 122, 10718; (c) N. Kataoka, Q. Shelby, J. P. Stambuli and J. F. Hartwig, J. Org. Chem., 2002, 67, 5553; (d) C. S. Sevov and J. F. Hartwig, J. Am. Chem. Soc., 2013, 135, 9303.
5. For recent reviews of the direct C–H bond oxidative coupling, see: (a) Q. Liu, R. Jackstell and M. Beller, Angew. Chem., Int. Ed., 2013, 52, 13871; (b) A. E. Allen, R. R. Walvoord, R. Padilla-Salinas and M. C. Kozlowski, Chem. Rev., 2013, 113, 6234; (c) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (d) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (e) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem., Int. Ed., 2011, 50, 11062; (f) Z. Shao and F. Peng, Angew. Chem., Int. Ed., 2010, 49, 9566; (g) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094.
6. (a) Z. Huang, L. Jin, Y. Feng, P. Peng, H. Yi and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 7151; (b) E. Jijy, P. Prakash, M. Shimi, P. M. Pihko, N. Josepha and K. V. Radhakrishnan, Chem. Commun., 2013, 49, 7349; (c) Y. Unoh, Y. Hashimoto, D. Takeda, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2013, 15, 3258; (d) X. Wang, Y. Lu, H.-X. Dai and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 12203; (e) L. V. Desai, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 9542.
7. (a) V. Mammoli, A. Bonifazi, F. D. Bello, E. Diamanti, M. Giannella, A. L. Hudson, L. Mattioli, M. Perfumi, A. Piergentili, W. Quaglia, F. Titomanlio and M. Pigini, Bioorg. Med. Chem., 2012, 20, 2259; (b) I. A. Katsoulis, G. Kythreoti, A. Papakyriakou, K. Koltsida, P. Anastasopoulou, C. I. Stathakis, I. Mavridis, T. Cottin, E. Saridakisa and D. Vourloumis, ChemBioChem, 2011, 12, 1188; (c) S. Aoki, Y. Watanabe, M. Sanagawa, A. Setiawan, N. Kotoku and M. Kobayashi, J. Am. Chem. Soc., 2006, 128, 3148; (d) F. A. Macías, J. L. G. Galindo, R. M. Varela, A. Torres, J. M. G. Molinillo and F. R. Fronczek, Org. Lett., 2006, 8, 4513; (e) S. M. Miles, S. P. Marsden, R. J. Leatherbarrow and W. J. Coates, J. Org. Chem., 2004, 69, 6874.
8. (a) B. D. Barve, Y.-C. Wu, M. El-Shazly, M. Korinek, Y.-B. Cheng, J.-J. Wang and F.-R. Chang, Org. Lett., 2014, 16, 1912; (b) Z. Xie, Y. Cai, H. Hu, C. Lin, J. Jiang, Z. Chen, L. Wang and Y. Pan, Org. Lett., 2013, 15, 4600; (c) Z. Jiao, S. Zhang, C. He, Y. Tu, S. Wang, F. Zhang, Y. Zhang and H. Li, Angew. Chem., Int. Ed., 2012, 51, 8811; (d) S.-K. Xiang, B. Zhang, L.-H. Zhang, Y. Cui and N. Jiao, Sci. China: Chem., 2012, 55, 50; (e) P. P. Singh, S. Gudup, S. Ambala, U. Singh, S. Dadhwal, B. Singh, S. D. Sawant and R. A. Vishwakarma, Chem. Commun., 2011, 47, 5852; (f) T. He, L. Yu, L. Zhang, L. Wang and M. Wang, Org. Lett., 2011, 13, 5016; (g) S. Pan, J. Liu, H. Li, Z. Wang, X. Guo and Z. Li, Org. Lett., 2010, 12, 1932.
9. H.-F. He, K. Wang, B. Xing, G. Sheng, T. Ma and W. Bao, Synlett, 2013, 211.
10. (a) D. Liu, C. Liu, H. Li and A. Lei, Chem. Commun., 2014, 50, 3623; (b) D. Liu, C. Liu, H. Li and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 4453; (c) M.-K. Wang, Z.-l. Zhou, R.-Y. Tang, X.-G. Zhang and C.-l. Deng, Synlett, 2013, 24, 737; (d) G. S. Kumar, B. Pieber, K. R. Reddy and C. O. Kappe, Chem.–Eur. J., 2012, 18, 6124; (e) H. Gunduz, V. Kumbaraci and N. Talinli, Synlett, 2012, 23, 2473; (f) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X. Wan, Chem.–Eur. J., 2011, 17, 4085; (g) S. Y. Zhang, F. M. Zhang and Y. Q. Tu, Chem. Soc. Rev., 2011, 40, 1937; (h) L. Troisi, C. Granito, L. Ronzini, F. Rosato and V. Videtta, Tetrahedron Lett., 2010, 51, 5980; (i) T. Akindele, K.-I. Yamada and K. Tomioka, Acc. Chem. Res., 2009, 42, 345.
11. (a) W. Du, M.-N. Zhao, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan, Chem. Commun., 2014, 50, 7437; (b) M.-N. Zhao, R.-R. Hui, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan, Org. Lett., 2014, 16, 3082; (c) L. Ran, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan, Green Chem., 2014, 16, 112; (d) H. Liang, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan, Chem.–Eur. J., 2013, 19, 9789; (e) M.-N. Zhao, H. Liang, Z.-H. Ren and Z.-H. Guan, Synthesis, 2012, 44, 1501; (f) Z.-H. Ren, Z.-Y. Zhang, B.-Q. Yang, Y.-Y. Wang and Z.-H. Guan, Org. Lett., 2011, 13, 5394; (g) Z.-H. Guan, Z.-Y. Zhang, Z.-H. Ren, Y.-Y. Wang and X. Zhang, J. Org. Chem., 2011, 76, 339; (h) L. Ran, H. Liang and Z.-H. Guan, Chin. J. Org. Chem., 2013, 33, 66.
12. (a) S.-L. Zhang and H.-J. Fan, Organometallics, 2013, 32, 4944; (b) G. Lefevre, G. Franc, A. Tlili, C. Adamo, M. Taillefer, I. Ciofini and A. Jutand, Organometallics, 2012, 31, 7694; (c) R. A. Altman, A. M. Hyde, X.-H. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2008, 130, 9613.

---

Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and spectral data for all products. See DOI: 10.1039/c5ra27899f

---