TBAI-catalyzed oxidative coupling of β-ketoesters with carboxylic acid: synthesis of α-carboxylic-β-ketoesters

TBAI-catalyzed oxidative coupling of β-ketoesters with carboxylic acid using TBHP as oxidant has been established. This transformation provides a facile and direct strategy for the synthesis of α-carboxylic-β-ketoesters.


Introduction
α-Carboxylic-β-ketoesters are important intermediates for the synthesis of a variety of heterocyclic 1 and natural products. 2The conventional approach towards the synthesis of αcarboxylic-β-ketoesters involved the chlorination of the β-ketoesters with sulfuryl chloride followed by treatment with a mixture of a carboxylic acid and a base in DMF (Scheme 1. Eq. 1). 1 This route was undesirable because the chlorination process was not environmentally friendly.Some modified methods, such as the reaction of α-diazo-β-ketoesters with carboxylic acids (Eq.2) 3 as well as the reaction of β-ketoesters with benzoyl peroxide (Eq. 3) 2a also suffered from the use of not easily handed starting materials.From both environmental and economical points of view, the direct cross-dehydrogenative coupling (CDC) of β-ketoesters with carboxylic acid was the excellent protocol for the synthesis of α-carboxylic-β-ketoesters, which has been realized by using stoichiometric amount of polyvalent iodine reagents as oxidants (Eq.4). 4 Recently, replacement of stoichiometric polyvalent iodine reagents with catalytic amount of hypervalent iodine reagent have been increasingly attractive to synthetic organic chemists, as they are more environmentally friendly and economical. 5Among them, a novel oxidizing system which features the use of quaternary ammonium iodide(TBAI) as the catalyst and H2O2 or tertbutyl hydroperoxide (TBHP) as the stoichiometric oxidant has been widely employed to realize the intermolecular C-O and C-N coupling. 6In particular, Ishihara and co-workers developed the TBAI/TBHP system catalyzed α-oxyacylation of carbonyl compounds with carboxylic acids.6c However, compared to the well studied α-oxyacylation of ketones, the scope and limitation of the α-oxyacylation of β-ketoesters were few studied.Herein, we report in detail the direct coupling of β-ketoesters with carboxylic acids by the Bu4NI/TBHP system to construct αcarboxylic-β-ketoesters.Scheme 1. Synthesis of α-carboxylic-β-ketoesters.

Results and Discussion
At the begining of our study, ethyl 2-benzoylacetate 1a and benzoic acid (2a) were chosen as coupling partners using the Bu4NI/TBHP system in MeCN at 60 °C to achieve the transformation.Gratifyingly, the desired α-carboxylic-β-ketoester 3a was obtained in 83% yield after 5 h (Table 1, entry 1).In control reactions without TBAI as catalyst (entry 2) or without TBHP as oxidant (entry 3), no target product was obtained.The yield decreased when TBAI was replaced by KI (entry 4) or TBHP was replaced by H2O2 (entry 5).When EtOAc was used as solvent, slightly low yield was obtained (entry 6).Reducing the reaction temperature also decreased the yield (entry 7).The substrate scope toward this oxidative coupling was further investigated, and the results were listed in Table 2.A wide array of β-ketoesters was examined in the reaction with benzoic acid 2a, and moderate to good yields were obtained in producing the corresponding αcarboxylic-β-ketoesters (Table 2, entries 1-7).β-ketoesters derivatives, which bear substituted groups such as methyl, methoxyl, chloro and bromo at para or ortho positions, all reacted smoothly with 2a to afford the desired corresponding products.Naphthyl substituted β-ketoesters and ethyl acetoacetate also reacted smoothly, albeit in lower yield (entries 7-8).Generally, βketoesters derivatives bearing electron-withdrawing groups were reacted faster than those bearing electron-donating groups.Varied carboxylic acid were also suitable partners for ethyl 2benzoylacetate (1a) to access the corresponding α-carboxylic-β-ketoesters. Similarly, benzoic acids, which bear substituents such as methyl, methoxyl, chloro and bromo at para or ortho positions, all reacted smoothly with 1a to afford the desired corresponding products in good to excellent yields (entries 8-13).In contract to the substituent effect of β-ketoesters derivatives, benzoic acids bearing electron-donating groups showed higher reactivity.Aliphatic carboxylic acids were also suitable partners for 1a to form the α-carboxylic-β-ketoesters (entries 14-16) in moderate to good yields.Moreover, a-benzoxylation of diethyl malonate could also take place to form the desired product in 64% yield (entry 18).Table 2. Synthesis of α-carboxylic-β-ketoesters 3 via the TBAI-catalyzed oxidative coupling of 1 and

Conclusions
In summary, we have reported a facile, economical and efficient method for the synthesis of αcarboxylic-β-ketoesters by the direct coupling of β-ketoesters with carboxylic acids.TBAI/TBHP system acts as a recyclable hypervalent iodine reagent in this process.The reaction occurs in air under mild conditions with easily accessible starting materials.Use of TBAI/TBHP system for the coupling of other C-O and C-N bonds is ongoing in our laboratory.

Experimental Section
General.All reagents and solvents were purchased from commercial suppliers and used without purifications.Melting points are uncorrected.The 1 H NMR and 13 C NMR spectra were recorded at 25 °C in CDCl3 at 500 and 125 MHz, respectively, with TMS as the internal standard.Chemical shifts (δ) are expressed in ppm and coupling constants J are given in Hz.The IR spectra were recorded on an FT-IR spectrometer.High resolution mass spectra (HRMS) were obtained on a TOF MS instrument with ESI or EI source.

Table 1 .
Optimization of reaction conditions for access to 3a a a General reaction conditions: 0.5 mmol of 1a, 0.6 mmol of 2a, 10 mol% of TBAI and 1.0 mmol of TBHP in 2 mL of MeCN at 60 o C. b Isolated yield.c Room temperature.
o C. b Isolated yield.According to the above results and previous reports, 6a,h a plausible reaction mechanism could be presumed as Scheme 2. Plausible reaction mechanism.