NHC-Assisted One-Pot Domino Oxidation of Aldehydes into Carboxylic Acids using Sodium Hydride under Oxygen Atmosphere

Abstract

Domino reactions are powerful tools in synthetic chemistry for the formation of target molecules in a single flask without the isolation of intermediates, and hence the number of reaction steps is reduced and waste may be minimized. As part of a wider research program aimed at exploring new domino reactions, we became interested in developing a new strategy for the oxidation of aldehydes to the corresponding carboxylic acids. Surprisingly, despite impressive advances in the area of oxidation, domino reactions have not been applied to the oxidation of aldehydes to carboxylic acids. Very recently, we began to explore the utility of sodium hydride-molecular oxygen (NaH-O2) system and successfully applied to the oxidation of benzoins to benzils, and the oxidative cleavage of benzoins to benzoic acids. Based on these results, we envisioned that the combination of the selfbenzoin condensation of aldehyde and the oxidative cleavage of benzoin using NaH-O2 could provide a conceptually new domino oxidation reaction. Herein we report our preliminary results on NHC-assisted one-pot domino oxidation. To identify the feasibility of our approach, we first carried out domino benzoin condensation/NaH-O2 oxidation with pchlorobenzaldehyde 1a. Thus, self-benzoin condensation reaction of 1a in the presence of 50 mol % N-heterocyclic carbene (NHC) precatalyst 3c with K2CO3 as a base in CH2Cl2 for 24 h yielded the intermediate I. The successive addition of 1 equivalent of NaH in a mixed solvent of THF and CH2Cl2 under oxygen atmosphere, provided the desired p-chlorobenzoic acid 2a in a 77% yield after 10 min (Scheme 1). We next attempted to develop one-pot domino reactions by employing NHC precatalyst/NaH-O2 together. Our studies began with an initial examination of the catalytic activities of several NHCs 3a-e for the domino oxidation of 1a. The results are summarized in Table 1. The NHC precatalysts 3a, 3b derived from imidazolium salt produced the desired product 2a in 58% and 78% yields after 30 min and 2 h, respectively (Table 1, entries 1-2). Among the imidazolium salts 3a-c, 3c is capable of catalyzing the reaction in undegassed dry THF to give 2a in a 72% yield after only 10 min under NaH-O2 system (Table 1, entry 3). Noteworthy is that the current one-pot, domino oxidation methodology is superior to the sequencing reaction in terms of reaction rate. Even if the turnover frequency in the benzoin formation step is much lower than that in the oxidative cleavage step, presumably, 1a was quickly consumed in relatively large quantities by NaH/O2, thereby producing the desired product 2a within 10 min. In contrast, the reaction was sluggish and gave lower yield (32%) without oxygen atmosphere (Table 1, entry 4), which was attributed to the remaining selfbenzoin product I. We also investigated the effects of solvent and NaH loading. Replacing the solvent THF with EtOAc or toluene led to lower chemical yields (Table 1, entries 7-8). With the use of precatalyst 3c (10 mol %) and NaH (0.6 equiv) under oxygen atmosphere, the desired product was formed in poor yield (32%) due to the major portion of unreacted aldehyde 1a, the formation of the 4,4'-chloro-