One-pot synthesis of acyloxy carbonyl compounds from ketones using a Pybox–copper(II) catalyst

Abstract

We have described the first efficient one-pot method for the synthesis of acyloxy carbonyl compounds from ketones catalyzed by a Pybox–Cu(II) complex under mild conditions. A series of α-acyloxy ketone products were obtained in good to excellent yields.

---

Acyloxy ketones are important organic synthetic intermediates in organic synthesis and versatile building blocks for natural products and pharmaceuticals.¹ Thus, many efforts have been devoted to finding efficient synthetic approaches to α-acyloxy ketones and their derivatives using different synthetic methods by a large number of research groups. A variety of protocols have been reported including transition metal-catalyzed and organocatalytic methods. In 1998, Ohfune and co-workers reported the copper-catalyzed insertion of α-diazoketones into carboxylic acids to give α-acyloxy ketones.² In 2009, the Cadierno group described the addition of carboxylic acids to propargyl alcohols leading to the formation of α-acyloxy ketones, which was catalyzed by Ru complexes.³ However, in contrast to transition metal catalysts, organocatalysts have been more extensively explored for the catalyzing the α-acyloxylation of ketones, with examples including the dimsyl anion,⁴ (hypo)iodite,⁵ N-heterocyclic carbenes (NHCs),⁶ amines,⁷ 2-tritylpyrrolidine⁸ as well as Bu₄NI.⁹ Although these organocatalyst-based reactions are robust and useful for the synthesis of a variety of α-acyloxyl carbonyl compound architectures containing a range of functional groups, the transition metal-catalyzed reaction of propiophenone to generate α-acyloxylation products has not been reported.

Herein, we have reported an efficient one-pot method for the synthesis of α-acyloxy carbonyl compounds in the presence of both moisture and air, catalyzed by a Pybox–Cu(II) complex. Treatment of a variety of ketones with [(Dm-Pybox)Cu(II)Br₂] and K₄[Fe(CN)₆]·3H₂O provides the α-acyloxy ketone products in isolated yield of 67–97%. The transformation is regiospecific in the discrimination of electron-deficient intermediate, in the case of non-symmetrical substrates.

Recently, we developed an efficient method for the synthesis of α-amino ketones and esters under aerobic oxidative conditions using a [(Dm-Pybox)CuBr₂] complex as a catalyst, which proceeded through an α-bromo carbonyl intermediate.¹⁰ In our continued effort to develop environmentally benign protocols for the synthesis of biologically and pharmacologically active compounds,¹¹ we attempted to extend this nucleophile-catalyzed aerobic oxidation protocol to the synthesis of aromatic α-cyano ketones from ketones with potassium hexacyanoferrate as a CN⁻ source.¹² In this previous work, when propiophenone and potassium hexacyanoferrate were combined under the reaction conditions the expected compound, 2-methyl-3-oxo-3-phenylpropanenitrile, was not observed. Instead, an unexpected compound was obtained as the major product.

With this rather unexpected result in hand, we started our study using the model reaction shown in Table 1: propiophenone (0.5 mmol) and potassium hexacyanoferrate(II) (2.4 equiv.) in DMF (1 mL). However, no reaction took place after heating the mixture at 110 °C for 9 h either with or without any ligand (Table 1, entry 1 and entry 2, L = Dm-Pybox). The α-acyloxylation product was obtained in only 48% yield when using CuBr₂ as a catalyst (Table 1, entry 3), however, to our delight, 90% yields of the desired product were observed when using 2,6-bis[4′,4′-dimethyloxazolin-2′-yl]pyridine (Dm-Pybox) as the ligand (Table 1, entry 4). We then chose [(Dm-Pybox)Cu(II)Br₂] complex as the catalyst to test the influence of solvents on the reaction yield (Table 1, entries 5–7). To our delight, DMF was the best solvent for this transformation. However, a lower yield was obtained with a lower catalyst loading of 5 mol% [(Dm-Pybox)Cu(II)Br₂] and it required a longer reaction time of 16 hours (Table 1, entry 8). The yield remained unchanged when using 15 mol% [(Dm-Pybox)Cu(II)Br₂], but the reaction time was shortened to 6 hours (Table 1, entry 9). In order to ascertain that O₂ was necessary (as shown in proposed mechanism later in Scheme 2) for the reaction to proceed, a control reaction was carried out in presence of N₂. In the absence of O₂, only 9% of the desired product was obtained (Table 1, entry 10), which clearly demonstrated the role that O₂ played in this reaction. Finally, the amount of K₄[Fe(CN)₆]·3H₂O was also surveyed, with only 9% of the desired product obtained in the presence of 10 mol% CN⁻ source (Table 1, entry 11). It is proven that an equivalent of K₄[Fe(CN)₆]·3H₂O was necessary for the reaction to proceed. A control experiment with 20 mol% TEMPO showed no reaction (Table 1, entry 12). This result might support the formation of an intermediate, E, in the radical mechanism pathway shown in Scheme 2.

Table 1 Initial studies toward the α-acyloxylation of propiophenone

Entry	Cu catalyst (10 mol%)	Ligand (mol%)	Solvent	Yield^a^,^b (%)
a Isolated yield.b Reaction conditions: 1 mL DMF as solvent, under air, 110 °C.c 5 mol% catalyst, reaction time: 16 h.d 15 mol% catalyst, reaction time: 6 h.e Under N2.f 0.0083 mmol K4[Fe(CN)6]·3H2O.g 20 mol% TEMPO was added, NR = no reaction.h 1.2 mmol CuCN.i 0.6 mmol Zn(CN)2.
1			DMF	NR
2		L	DMF	NR
3	CuBr2		DMF	48
4	Cu complex		DMF	90
5	Cu complex		DMSO	11
6	Cu complex		NMP	NR
7	Cu complex		DMF	91
8	Cu complex		DMF	73^c
9	Cu complex		DMF	92^d
10	Cu complex		DMF	9^e
11	Cu complex		DMF	9^f
12	Cu complex		DMF	NR^g
12	Cu complex		DMF	50^h
12	Cu complex		DMF	33^i

---

Scheme 1 The gram-scale synthesis of 2a.

Scheme 2 A proposed catalytic mechanism for the α-acyloxylation of ketones.

In order to explore the generality and scope of the present α-acyloxylation method, several ketone compounds were examined as substrates using the optimized reaction conditions. Propiophenone derivatives, which were substituted with electron-donating or electron-withdrawing groups, gave the corresponding α-benzoyloxy ketones 1a–5a in good to excellent yields. The configuration of 1a was determined by X-ray crystallographic analysis (Fig. 1). Interestingly, the efficient conversion of electron-deficient ketones was achieved at low temperature (Table 2, entry 5). Notably, 2-butyrylfuran and 2-butyrylthiophene were also tested, and these reactions proceeded smoothly to give 6a and 7a in a good and moderate yield, respectively, in the presence of 15 mol% of the [(Dm-Pybox)Cu(II)Br₂] catalyst.

Fig. 1 The molecular structure of 1a with thermal ellipsoids drawn at the 30% level. All hydrogen atoms are omitted for clarity.

Table 2 The [(Dm-Pybox)Cu(II)Br₂] catalyzed α-acyloxylation of ketones

Entry	Substrate	Product	Time (h)	Yield^a^,^b (%)
a Isolated yield.b Reaction conditions: 0.5 mmol carbonyl compound, 0.2 mmol K4[Fe(CN)6]·3H2O, 10 mol% [(Dm-Pybox)Cu(II)Br2], 1 mL DMF as solvent, under air.c 90 °C.d 15 mol% [(Dm-Pybox)Cu(II)Br2].
1			9	90
2			8	97
3			8	94
4			8	93
5			10	73^c
6			15	87^d
7			15	79^d

---

In general, the selectivity of the reaction is determined by electronic effects, so control experiments were carried out to test the selectivity of α-acyloxylation reaction. Equimolar amounts of 1-p-tolylpropan-1-one and 1-(4-chlorophenyl)propan-1-one were heated in the presence of 10 mol% [(Dm-Pybox)Cu(II)Br₂] catalyst and 2.4 equivalents of CN⁻ in DMF to give 8a in 88% yield (Table 3). No other side products were observed in this transformation. The configuration of 8a was also determined by X-ray crystallographic analysis (Fig. 2). The electron-withdrawing group on the aromatic ring of 1-(4-chlorophenyl)propan-1-one more favors the formation of an intermediate that then results in the asymmetrical α-acyloxylation product. Propiophenone and 1-phenylbutan-1-one also transformed well under the standard conditions, and the desired products 1-oxo-1-phenylpropan-2-yl-4-chlorobenzoate (9a) and 1-oxo-1-phenylbutan-2-yl-4-chlorobenzoate (10a) were obtained in 71% and 89% yields, respectively (Table 3). Interestingly, the heterocyclic substrate 1-(thiophen-2-yl)butan-1-one underwent this transformation to provide 12a in acceptable yields.

Table 3 Studying the reaction selectivity of the α-acyloxylation of different ketones^a,b

a Isolated yield.b Reaction conditions: 1 mL DMF as solvent, 0.2 mmol K₄[Fe(CN)₆]·3H₂O, 9 h, under air, 100 °C.c 20 h.

---

Fig. 2 The molecular structure of 8a with thermal ellipsoids drawn at the 30% level. All hydrogen atoms are omitted for clarity.

To further evaluate the practical utility of the catalyst system, a model reaction was carried out on a gram scale using the optimized conditions, and the desired product was obtained in 94% yield (Scheme 1).

To gain further insight into the reaction mechanisms of the Cu-catalyzed cross-coupling reaction, a different starting material, either benzoic acid or benzoyl cyanide, was added to investigate the viability of the intermediate. The desired products were observed in both cases indicating the involvement of benzoic acid and benzoyl cyanide in the mechanistic process (see ESI†). Based on documented precedent and experiment results, a reaction mechanism was proposed as shown in Scheme 2. Initially, a cyanohydrin intermediate A is formed by cyanide addition to propiophenone. Intermediate A can then undergo oxidation to yield benzoyl cyanide B under aerobic oxidation conditions, which is hydrolyzed in situ to give the benzoic acid (C) in wet organic solvents,¹³ then decarbonylation results in the formation of (D). Meanwhile, propiophenone can undergo bromination at the α-carbonyl to generate 2-bromo-1-phenylpropan-1-one (E) in the presence of the [(Dm-Pybox)Cu(II)Br₂] catalyst.¹⁴ Intermediate E is then further hydrolyzed to afford 2-hydroxy-1-phenylpropan-1-one (F), which can react with intermediate D to afford the final product. The existence of intermediate F is supported by the MS spectra. In addition, the Cu(II) catalyst is regenerated by the oxygen-mediated reoxidation of Cu(I).

Conclusions

In conclusion, we have described the first efficient and one-pot green method for the synthesis of α-acyloxy carbonyl compounds from ketones catalyzed by a Pybox–Cu(II) complex under mild conditions. A series of α-acyloxylation products were obtained in good to excellent yields. This method provides an excellent alternative to organocatalysts. A detailed reaction mechanism is still under investigation.

Acknowledgements

This work was supported by the National Nature Science Foundation of China (21102004), the NSF of Anhui province (1208085MB25) and the Project-sponsored by SRF for ROCS and Special and Excellent Research Fund of Anhui Normal University. We are grateful to Prof. Shaowu Wang and Zhuo Chai for their valuable suggestions.

Notes and references

1. (a) M. Shindo, Y. Yoshimura, M. Hayashi, H. Soejima, T. Yoshikawa, K. Matsumoto and K. Shishido, Org. Lett., 2007, 9, 1963–1966; (b) W. W. Pei, S. H. Li, X. P. Nie, Y. W. Li, J. Pei, B. Z. Chen, J. Wu and X. L. Ye, Synthesis, 1998, 1298–1304; (c) C. M. Loner, F. A. Luzzio and D. R. Demuth, Tetrahedron Lett., 2012, 53, 5641–5644.
2. T. Shinada, T. Kawakami, H. Sakai, I. Takada and Y. Ohfune, Tetrahedron Lett., 1998, 39, 3757–3760.
3. (a) V. Cadierno, J. Francos and J. Gimeno, Green Chem., 2010, 12, 135–143; (b) V. Cadierno, J. Francos and J. Gimeno, Organometallics, 2011, 30, 852–862; (c) D. Devanne, C. Ruppin and P. H. Dixneuf, J. Org. Chem., 1988, 53, 925–926.
4. O. Bortolini, G. Fantin, V. Ferretti, M. Fogagnolo, P. P. Giovannini, A. Massi, S. Pacifico and D. Ragno, Adv. Synth. Catal., 2013, 355, 3244–3252.
5. M. Uyanik, D. Suzuki, T. Yasui and K. Ishihara, Angew. Chem., Int. Ed., 2011, 50, 5331–5334.
6. R. N. Reddi, P. V. Malekar and A. Sudalai, Org. Biomol. Chem., 2013, 11, 6477–6482.
7. (a) C. S. Beshara, A. Hall, R. L. Jenkins, K. L. Jones, T. C. Jones, N. M. Killeen, P. H. Taylor, S. P. Thomas and N. C. O. Tomkinson, Org. Lett., 2005, 7, 5729–5732; (b) D. A. Smithen, C. J. Mathews and N. C. O. Tomkinson, Org. Biomol. Chem., 2012, 10, 3756–3762.
8. T. Kano, H. Mii and K. Maruoka, J. Am. Chem. Soc., 2009, 131, 3450–3451.
9. S. Guo, J.-T. Yu, Q. Dai, H. Yang and J. Cheng, Chem. Commun., 2014, 50, 6240–6242.
10. W.-G. Jia, D.-D. Li, Y.-C. Dai, H. Zhang, L.-Q. Yan, E.-H. Sheng, Y. Wei, X.-L. Mu and K.-W. Huang, Org. Biomol. Chem., 2014, 12, 5509–5516.
11. (a) A. Park and S. Lee, Org. Lett., 2012, 14, 1118–1121; (b) J. Shen, D. Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu and R. Liu, Org. Lett., 2014, 16, 350–353.
12. (a) T. Chatterjee, R. Dey and B. C. Ranu, J. Org. Chem., 2014, 79, 5875–5879; (b) D. Zhang, H. Sun, L. Zhang, Y. Zhou, C. Li, H. Jiang, K. Chen and H. Liu, Chem. Commun., 2012, 48, 2909–2911; (c) T. D. Senecal, W. Shu and S. L. Buchwald, Angew. Chem., Int. Ed., 2013, 52, 10035–10039.
13. Y.-J. Kim, N. Y. Kim and C.-H. Cheon, Org. Lett., 2014, 16, 2514–2517.
14. R. W. Evans, J. R. Zbieg, S. Zhu, W. Li and D. W. C. MacMillan, J. Am. Chem. Soc., 2013, 135, 16074–16077.

---

Footnote

† Electronic supplementary information (ESI) available: Additional copies of NMR spectra. Crystallographic information files (CIFs) CCDC 1012733 and 1012734 for complex 1a and 8a. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra02186g

---