A novel approach for the synthesis of β-keto esters: one-pot reaction of carboxylic acids with chlorosulfonyl isocyanate

β-Keto esters were synthesized by direct carboxylation of various 4-and 5-oxo-carboxylic acid derivatives in the presence of chlorosulfonyl isocyanate in excellent yield under mild conditions. Additionally, optimization conditions were examined for synthesis β-keto esters. Finally, it has been found that trifluoroacetic acid is efficient in DCM under optimized conditions. This efficient one-pot novel method is very usefull, fair price and easy to handle of β-keto esters.


Introduction
β-Keto esters are multi-coupling reagents that have both a nucleophilic carbon and an electrophilic carbonyl group.These molecules are very significant intermediates for the synthesis of a wide range of bioactive and natural products such as 1,4-dihydropyridines, arylcoumarins, and 3,4-dihydropyrimidinones, 1 chokol, 2 syncarpic acid, 3 and polyoxamic acid. 4Furthermore, they are also used preparation of catalysis, 5 polymer stabilization, 6 synthesis of metal microfilms impregnation and liquid crystal preparation technology. 7herefore, various methods have been investigated for the synthesis of their derivatives. 1Common methods for the synthesis of β-keto esters mostly rely on Claisen reaction 8 and related condensations of enolates with alkyl carbonates and oxalates followed by decarbonylation. 9,10heme 1. Methods for the synthesis of β-keto ester derivatives.
In recent years, with the increasing demands to β-keto esters, synthesis of these molecules has been reported alkoxycarboxylation of halomethylketones with Pd-catalyzed (Scheme 1a). 11Meanwhile, synthesis of β-keto esters by C-H insertion reactions of diazoesters with Niobium(V) chloride catalyzed were reported by the Yadav group (Scheme 1b). 12Synthesis of β-keto esters by aza-Knoevenagel reactions of tertiary amides have been also developed (Scheme 1c). 13Recent developments in the synthetic use of CSI are known in the literature. 14Previously, we completed reaction of a range of benzoic acid derivatives with CSI that were yielded sulfamate derivatives. 15n this work, we reported novel and efficient one-pot synthetic method for the synthesis of β-keto esters (2an) from carboxylic acid derivatives (1a-n) under mild conditions in good yields (Scheme 1).

Results and Discussion
Initially, the reaction of 5-oxo-5-phenylpentanoic acid with CSI (1a) was chosen that as the model reaction which was carried out in various solvents, acids, bases.The solvent effect was investigated with dichloromethane (DCM) and acetonitrile in the absence of acid and base at room temperature.In these reactions, 2-benzoylpentanedioate (2a) was observed in 54% and 42% isolated yield, respectively.The structure of dimethyl 2-benzoylpentanedioate (2a) was verified with 1 H-and 13 C-NMR, IR, and HRMS.Then, acid or base effect was examined with the triflic acid (TfOH), trifluoroacetic acid (TFA), triethylamine (NEt 3 ), and pyridine.The use of TfOH gave the dimethyl 2-benzoylpentanedioate (2a) in good yield (entry 2 and 7).The desired product 2a yielded the use of NEt 3 , or pyridine in poor yield (entry 4, 5, 9, and 10).The desired product dimethyl 2-benzoylpentanedioate (2a) was obtained in 92% yield, when the reaction was performed in DCM with TFA (entry 8).Thus, the optimized reaction condition for alternative and novel intramolecular synthesis of β-keto esters from 4-and 5-oxocarboxylic acid derivatives was concluded finally to be the use DCM as solvent with TFA as additive under mild conditions at room temperature for 3 h.Table 2. Novel synthesis of β-keto esters from carboxylic acids using TFA a,b,c a Reaction conditions: 1.0 mmol of Carboxylic acid (1a-n), 1.0 mmol TFA, 1.1 mmol of CSI, 10 mL DCM, reaction was stirred for 2h and added 2 mL MeOH for 1 h.b Isolated yield.c Lit.

AUTHOR(S)
Scheme 2. Possible mechanism for synthesis of β-keto ester.
In the first step, OH group of carboxylic acid attacks to carbonyl group of isocyanate as nucleophilic.Intermadiate carbamate is being tautomerization (I) and following the intramolecular attack of α-carbon to carbonyl carbamate (II, III and IV).Then, sulfamoyl chloride (NH 2 SO 2 Cl) leave from relating molecule to form cyclic anhydride (V).Finally, β-keto ester was occured by ring opening reaction of cyclic anhydride (3).

Conclusions
A pratical novel alternative method, one-pot synthesis β-keto esters with chlorosulfonyl isocyanate from 4and 5-oxocarboxylic acid derivatives, were developed in high yields under mild conditions.This novel method highly useful environmentally and benign for organic chemists and pharmaceutical industry without any metal or oxidations, and easy to handle, under mild conditions, short reaction time.Moreover, a wide variety of βketo esters can be obtained in good yields.

Experimental Section
General.Solvents are commercially available and used without further purification.4-and 5-oxo-carboxylic acid derivatives were synthesized as in the literature. 19 1H and 13 C NMR spectra were recorded a Bruker 400 MHz in CDCl 3 with and NMR shifts are presented as  in ppm.FTIR spectras were mesaured with a Perkin Elmer spectrophotometers in CH 2 Cl 2 and by solutions in 0.1mm cells.High resolution mass spectra (HRMS) were obtained with a AB-Sciex 4600 QTOF MS spectrometer.
General procedure Synthesis of β-Keto ester.Carboxylic acid (1a-n) (1.0 eq) was dissolved in 10 mL DCM.The reaction mixture was added CSI (1.1 eq) and TFA (1.0 eq) and stirred for 2 h at room temperature.Then, it was added 2 mL MeOH and stirred for 1h.The reaction mixture was extracted with dichloromethane.The organic extract was dried over sodium sulfate, filtrate and evaporation in vacuo.The resulting residue was purified by thin-layer chromatography (TLC) on silica gel.Dimethyl 2-benzoylpentanedioate (2a).Yellowish oil (316 mg, yield 92%), 1