A Cu-catalyzed practical approach to α-ketoesters under air: an efficient aerobic oxidative dehydrogenative coupling of alcohols and α-carbonyl aldehydes

Abstract

A novel and efficient approach to α-ketoesters has been developed with wide functional group tolerance. This copper-catalyzed oxidative dehydrogenative coupling reaction of alcohols and α-carbonyl aldehydes employs air as the oxidant and generates H₂O as the only by-product. Broad substrate scope, high atom economy and mild reaction conditions make this chemistry very practical.

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α-Ketoesters are ubiquitous units in many biologically active compounds.¹ Furthermore, they have been widely used as useful precursors in organic synthesis.² Consequently, a lot of effort has been made to construct α-ketoesters. For example, esterification of α-ketoacyl halides and α-ketoacids (1, Scheme 1),³ oxidation of α-hydroxy ester (2, Scheme 1),⁴ double carbopalladative esterification (3, Scheme 1),⁵ and other methods have been widely used (4, Scheme 1).⁶ Despite the numerous efforts toward the synthesis of α-ketoesters, development of mild, efficient, and environmentally friendly methods is still desirable.

Scheme 1 Methods of synthesizing α-ketoester.

In recent years, copper catalyzed aerobic oxidative cross dehydrogenative coupling (CDC) has been demonstrated to be an efficient tool in organic transformations.^7,8 Recently, by using Cu-catalysis, we developed a novel approach to construct α-ketoesters through C–C bond cleavage (eqn (1)).⁹ However, some drawbacks may limit its application: (1) an excess amount of alcohol substrate (3.0 eq.) is required for this transformation; (2) since the fragmentation of the intermediate could couple with alcohol to afford the byproduct, the atom-economy is not high; (3) pure molecular oxygen is required in that method to ensure high efficiency. Based on previous research, we developed an efficient copper catalyzed aerobic oxidative dehydrogenative coupling reaction of α-carbonyl aldehydes with alcohols for the synthesis of α-ketoesters (eqn (2)).¹⁰ Broad substrate scope and mild reaction conditions under air make this chemistry very practical.

Under air conditions, the CuBr-catalyzed reaction of phenylglyoxal monohydrate (1a) with 2-phenylethanol (2a) afforded phenethyl 2-oxo-2-phenylacetate (3aa) in 88% yield (entry 1, Table 1). Other copper salts, such as Cu(OH)₂, Cu(NO₃)₂·3H₂O, CuCl and Cu₂O, can also catalyze this reaction affording the desired product in moderate yields (entries 2–5, Table 1). However, CuI did not work well (entry 6, Table 1). We then surveyed the effect of different solvents. The reactions gave low yields in MeCN or DCE respectively (entries 7 and 8, Table 1). This chemistry nearly did not afford the desired product when using 1,4-dioxane, DMF or DMSO as the solvent (entries 9–11, Table 1).

Table 1 Screening of the reaction conditions^a

Entry	Cu	Solvent	Yield of 3aa^b (%)
a Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), catalyst (0.025 mmol), pyridine (0.125 mmol), solvent (1.5 mL), Air (1 atm), at 90 °C for 18 h. b Isolated yield.
1	CuBr	Toluene	88
2	Cu(OH)2	Toluene	50
3	Cu(NO3)2·3H2O	Toluene	80
4	CuCl	Toluene	75
5	Cu2O	Toluene	72
6	CuI	Toluene	Trace
7	CuBr	MeCN	35
8	CuBr	DCE	15
9	CuBr	1,4-Dioxane	Trace
10	CuBr	DMF	Trace
11	CuBr	DMSO	Trace

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Under optimized conditions, the substrate scope of alcohols (2) was investigated (Table 2). Besides 2-phenylethanol (2a), various primary alcohols also worked well (3ab–3ao, Table 2). When using benzyl alcohol derivatives as starting materials, substrates with electron donating and withdrawing groups at the para-position were examined. The results indicate that the electronic variation of the functional groups did not obviously affect the yield of desired products (3ab–3aj, Table 2). Furthermore, the steric hindrance of the substituent at the ortho-positions of the arene group did not affect the efficiency (3ac, Table 2). In addition, chloro- and bromo-substituted benzyl alcohol afforded the desired product in good yields (3ai and 3aj, Table 2). It is noteworthy that simple alkyl alcohols also worked well under this reaction system (3ak–3am, Table 2). Notably, the alcohol substrate containing an alkenyl group performed well and afforded the desired product in 81% yield (3al, Table 2), which could not be achieved by our recent work (eqn (1)).⁹ Under the standard conditions, some secondary alcohols, such as cyclohexanol and 1-hydroxyhydrindene, also worked well (3an and 3ao, Table 2). However, tertiary alcohols, such as tertiary butanol, cannot afford the desired product under these reaction conditions.

Table 2 Substrate scope of alcohol^a

a Reaction conditions: 1a (0.25 mmol), 2 (0.375 mmol), CuBr (0.025 mmol), pyridine (0.0125 mmol), toluene (1.5 mL) at 90 °C under air condition for 18 h. Isolated yield.

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The scope of substituted α-carbonyl aldehydes 1 was also investigated (Table 3). This aromatic ring of α-carbonyl aldehyde derivates was found to be tolerant to both electron-rich groups, such as methoxyl (3ba), and electron-deficient groups, such as the fluoride group (3ca, 3da and 3ea) and the trifluoromethyl group (3fa). Furthermore, heteroaryl substituted α-carbonyl aldehyde performed well under these conditions affording 3ga in 79% yield. However, aliphatic α-carbonyl aldehyde, such as 2-oxopropanal, did not work.

Table 3 Substrate scope of α-carbonyl aldehyde^a

a Reaction conditions: 1 (0.25 mmol), 2a (0.375 mmol), CuBr (0.025 mmol), pyridine (0.0125 mmol), toluene (1.5 mL) at 90 °C under air condition for 18 h. Isolated yield.

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Because complex target molecules are very difficult to obtain, the late-stage modification of bio-active molecule is very important for medical chemistry studies. We selected androsterone, testosterone and cholesterol as starting materials to illustrate the advantage of this method in late-stage esterification to synthesize complex α-ketoester molecules (eqn (3)–(5)). These results indicate that the present Cu-catalyzed aerobic oxidative coupling reaction is very efficient and practical. In contrast to the low yield (33%) by the reported method,⁹ the reaction of androsterone produced the corresponding α-ketoester in 74% yield (eqn (3)).

Moreover, the control reaction of 1a and 2a in the presence of ¹⁸O₂ generated showed that no oxygen-atom incorporation is involved in this transformation. Air is proved only as a very efficient oxidant in this case.

On the basis of the above results and our previous studies, a plausible mechanism for the copper-catalyzed aerobic oxidative coupling reaction is illustrated in Scheme 2. The interconversion between 2-oxo-2-phenylacetaldehyde hydrate (1a) and 2,2-dihydroxy-1-phenylethanone (1a) should be involved in this reaction process.¹¹ Under this reaction system, the addition of alcohol (2a) to arylglyoxal (1a) to afford the hemiacetal intermediate 7.¹² The carbonyl group of α-carbonyl aldehyde could facilitate this process.¹³ Subsequently, copper-catalyzed aerobic oxidation of intermediate 7 occurs to produce α-ketoamide 3aa.^14,15

Scheme 2 The proposed mechanisms.

In conclusion, we have demonstrated a practical and efficient approach to α-ketoesters, which are widely spread units in many biologically active compounds. Using air as the oxidant, various commercially available α-carbonyl aldehyde substrates and alcohol derivatives could be smoothly transformed into desired products. Broad substrate scope, high atom economy and mild reaction conditions make this chemistry very practical. Further investigations of the synthetic application are ongoing in our group.

Financial support from the National Science Foundation of China (no. 21325206, 21172006), the National Young Top-notch Talent Support Program, and the Ph.D. Programs Foundation of the Ministry of Education of China (no. 20120001110013) are greatly appreciated. We thank Xiaoyang Wang in this group for reproducing the results of 3am and 6b.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00041a

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