CuO-catalyzed oxidation of aryl acetates with aqueous tert -butyl hydroperoxide for the synthesis of α-ketoesters

Abstract

A practical method to access α-ketoesters from readily available aryl acetates is developed. In this approach, aqueous tert-butyl hydroperoxide and CuO are employed. No additional solvents are required and it was found that the peroxide side products in the reaction can be decomposed by pyridine.

Introduction

α-Ketoesters are important compounds because of their bioactivities ¹ and applications in natural product synthesis ² and chemical transformations. ³ There are several methods to synthesize α-ketoesters, such as reactions of organometallic reagents with oxalic acid derivatives, ⁴ oxidation of α-hydroxy esters, ⁵ double carbonylation of organic halides, ⁶ and transformations of aryl acetates.^7–15 Among these synthetic methods, commonly used is the reaction of organometallic reagents with oxalic acid derivatives ¹⁶ but this needs harsh conditions. It is worthwhile to find a more flexible way to produce α-ketoesters.

Aryl acetates are ideal raw materials for commercialization. The conversion of aryl acetates into α-ketoesters has been reported via two main ways: direct oxidation and through a multistep process (Scheme 1). The first example of the oxidation of arylacetic esters to arylglyoxylic esters was carried out with a vanadium-pillared montmorillonite catalyst (V-PILC) in a dry solvent (Scheme 1(a)). ⁹ Rh, ¹⁰ Mo, ¹¹ Cu^12–14 and Co ¹⁵ can also be used to realize this procedure, but complex catalysts needed to be prepared or long reaction times were necessary. Examples of multistep syntheses of α-ketoesters include Wasserman and Ives’s ⁷ work involving enamino carbonyl systems (Scheme 1(b)) and Wang’s work ⁸ employing oxidation of a diazo group (Scheme 1(c)). One-step direct oxidations show higher efficiencies than multistep processes. In order to enhance the economy of the direct oxidation, we studied various oxidation systems and found a new and practical method to prepare α-ketoesters.

Scheme 1.

Approaches for the synthesis of α-ketoesters from aryl acetates: : (a) a direct oxidation in a dry solvent; (b) a multistep process involving enamino carbonyl systems; (c) a multistep process employing a diazo group; (d) this work.

In this work, we report a new method to access α-ketoesters from readily available aryl acetates using aqueous tert-butyl hydroperoxide (TBHP) as an oxidant and CuO as a catalyst under reflux conditions without any additional solvent (Scheme 1(d)). We also found that the peroxide side products could be removed with pyridine.

Results and discussion

Initially, 0.2 equiv. of CuI and 3.0 equiv. of aq TBHP ¹⁷ were used to oxidize methyl 2-phenylacetate (1a) at 50 °C. To our delight, proton nuclear magnetic resonance (¹H NMR) analysis of the crude reaction mixture indicated that the desired product, methyl 2-oxo-2-phenylacetate (2a), was obtained (Scheme 2(a), Figure 1(a)). However, purification through silica gel column chromatography was unsuccessful, because the side product and 2a had identical R_f values. The ¹H NMR data of the side product were as follows: δ 7.45–7.40 (m, 2H), 7.38–7.34 (m, 3H), 5.38 (s, 1H), 3.76 (s, 3H), 1.28 (s, 9H). Combined with the reaction characteristics of TBHP^10,18,19 and the ¹H NMR data of methyl 2-tert-butoxy-2-phenylacetate, ²⁰ we speculated that the side product was peroxide 3. Minisci’s research demonstrated that mixed peroxides could be decomposed mainly to carbonyl compounds and tert-butanol by pyridine bases. ¹⁸ When 3.0 equiv. of pyridine, 0.2 equiv. of CuI and 3.0 equiv. of aq TBHP were used to oxidize 1a at 50 °C in one pot, substrate 1a was unexpectedly left intact (Scheme 2(b), Figure 1(b)). However, when the reaction mixture of CuI, aq TBHP and 1a was treated with pyridine, peroxide 3 disappeared leaving 1a and 2a in the system (Scheme 2(c), Figure 1(c)). Through the latter protocol, pure 2a was achieved in 13% yield (Figure 1(d)).

Scheme 2.

Initial results for the oxidation of methyl 2-phenylacetate: (a) the reaction of CuI, TBHP and 1a; (b) the reaction of CuI, TBHP, 1a and pyridine; (c) the reaction of CuI, TBHP and 1a was treated with pyridine.

Figure 1.

¹H NMR spectra of different systems in CDCl₃: (a) the crude mixture of the reaction of CuI, TBHP and 1a; (b) the crude mixture of the reaction of CuI, TBHP, 1a and pyridine; (c) the crude mixture of the reaction of CuI, TBHP and 1a, which was treated with pyridine; and (d) purified product 2a from the reaction of CuI, TBHP and 1a, which was treated with pyridine.

In order to improve the yield, different solvents (MeOH, EtOAc, THF, DMF, DMSO and CH₃CN) and other oxidants (H₂O₂ and cumene hydroperoxide) were introduced to the reacting system, however, in all these cases, no 2a was detected. Catalyst screening showed that CuO and Cu(OAc)₂ gave the best yield among CuI, MnO₂, FeCl₃ and Fe(acac)₃ (Table 1, entries 1–6). CuO was chosen as the catalyst. Elevating the reaction temperature was beneficial to obtain a higher yield (Table 1, entries 7–8), and 110 °C was found to be the best. Extending the reaction time to 12 h increased the yield slightly to 55% (Table 1, entry 9). Further prolonging the reaction time to 24 h attenuated the yield (Table 1, entry 10). In view of time-saving, 4.5 h was selected as the reaction time. Loading of aq TBHP and CuO had only a small effect on the yield (Table 1, entries 11–14). Therefore, 0.1 equiv. of CuO and 3.0 equiv. of aq TBHP were chosen for lower consumption.

Table 1.

Optimization of the reaction conditions.

Entry	Catalyst(equiv.)	aq TBHP(equiv.)	Temperature(°C)	Time(h)	Yield(%) a
1	CuI (0.2)	3	50	4.5	13
2	CuO (0.2)	3	50	4.5	36
3	Cu(OAc)2 (0.2)	3	50	4.5	36
4	MnO2 (0.2)	3	50	4.5	23
5	FeCl3 (0.2)	3	50	4.5	18
6	Fe(acac)3 (0.2)	3	50	4.5	24
7	CuO (0.2)	3	80	4.5	51
8	CuO (0.2)	3	110	4.5	52
9	CuO (0.2)	3	110	12	55
10	CuO (0.2)	3	110	24	39
11	CuO (0.2)	5	110	4.5	52
12	CuO (0.2)	10	110	4.5	55
13	CuO (0.1)	3	110	4.5	53
14	CuO (0.6)	3	110	4.5	49

TBHP: tert-butyl hydroperoxide.

a

Isolated yield after purification by column chromatography.

With optimized reaction conditions in hand, various aryl acetates were used to synthesize α-ketoesters (Table 2). Methyl ester 2a, ethyl ester 2b, isobutyl ester 2c and even esters containing a benzyl group (2d and 2e) were generated in good yields. Aryl acetates with electron-donating and electron-withdrawing groups, such as methoxy, methyl, tert-butyl, halogen and carboxylic ester, at the para positions of the aryl rings afforded the corresponding products with high yields (entries 6–12). meta-Substituted aryl product 2m and ortho-substituted aryl product 2n were achieved with low yields perhaps because of steric hindrance (entries 13 and 14). 1-Naphthyl and 3-thienyl α-ketoesters were also accessible (entries 15 and 16). Furthermore, a large-scale reaction gave 2.3 g (59%) of methyl 2-(4-methoxyphenyl)-2-oxoacetate (2f) (Scheme 3). Methyl 3-oxo-3-phenylpropanoate (4) ²¹ was obtained instead of methyl 2-oxo-3-phenylpropanoate (2q) when methyl 3-phenylpropanoate (1q) was used as the reactant (Scheme 4).

Table 2.

Scope of the aryl acetates. ^a

Entry	Substrate	Product b	Yield (%) c
1			53
2			72
3			61 d
4			47
5			61
6			69
7			85
8			55
9			43 d
10			63 d
11			42
12			71 d
13			35
14			16
15			48
16			31

a

Reaction conditions: (1) 1 (2.0 mmol), CuO (0.2 mmol), aq TBHP (6.0 mmol), 110 °C and 4.5 h; (2) pyridine (0.5 mL), 50 °C and 4.0 h.

b

All the products were identified by comparison of their analytical data with those reported in the literature.

c

Isolated yield.

d

Compounds 1 and 2 were obtained and the yields were calculated based on the total measured mass of product 2 contaminated by unreacted 1 and from their ¹H NMR spectra.

Scheme 3.

Large-scale preparation of 2f.

Scheme 4.

Oxidation of methyl 3-phenylpropanoate.

Based upon the above reaction facts and the relevant publications,^18,19 a possible reaction mechanism is proposed in Scheme 5. Catalysed by CuO, aryl acetate 1 is converted into peroxide 5 in the presence of TBHP with part of the peroxide decomposing to give α-ketoester 2. The remaining peroxide can be changed into α-ketoester 2 by further treatment with pyridine.

Scheme 5.

Possible reaction mechanism.

Conclusion

In conclusion, a practical method to access α-ketoesters from readily available aryl acetates under reflux conditions has been developed. In the approach, aq TBHP and CuO are employed and no additional solvents are required. Besides, the peroxide side products in the reaction could be decomposed to α-ketoesters by pyridine.

Experimental section ^a

Typical procedure for the synthesis of α-ketoesters

Aryl acetate 1a (2.0 mmol, 1.0 equiv.), CuO (0.2 mmol, 0.1 equiv.) and aq TBHP (6.0 mmol, 3.0 equiv.) were added to a flask connected to a reflux condenser. The flask was heated at 110 °C for 4.5 h and then cooled to room temperature. Pyridine (0.5 mL, 3.0 equiv.) was added and the mixture was heated to 50 °C and stirred for 4.0 h. Thereafter, an aqueous solution of Na₂S₂O₃ (0.5 mol L⁻¹, 10.0 mL) was added, and the mixture was extracted with EtOAc (×3). The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column chromatography over silica gel (200–300 mesh) using petroleum ether/EtOAc (25:1) to afford the desired compound 2a (172.3 mg, 53% yield) as a colourless oil. ¹H NMR (600 MHz, CDCl₃): δ 8.05–7.99 (m, 2H), 7.68–7.63 (m, 1H), 7.54–7.48 (m, 2H) and 3.97 (s, 3H).

Supplemental Material

Supporting_Information_pdf – Supplemental material for CuO-catalyzed oxidation of aryl acetates with aqueous tert-butyl hydroperoxide for the synthesis of α-ketoesters

Supplemental material, Supporting_Information_pdf for CuO-catalyzed oxidation of aryl acetates with aqueous tert-butyl hydroperoxide for the synthesis of α-ketoesters by Jin Jiang in Journal of Chemical Research