A new and efficient protocol for preparation of thiol esters from carboxylic acids and thiols in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU)

A novel and convenient method has been developed for the synthesis of thiol esters from the corresponding carboxylic acids and thiols at room temperature using 2-(1 H -benzotriazole-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as the coupling reagent.


Introduction
Thiol esters show higher reactivity and selectivity toward nucleophiles than their oxygen analogues.They play important roles in biological systems such as acyl coenzyme A, and Sacetyl dihydrolipolic acid. 1 Thiol esters are used as mild acyl transfer reagents, 2 as intermediates in the synthesis of ketones 3 , for asymmetric aldol reactions 4 and in the preparation of macrocyclic lactones. 5The growing importance of thiol esters in organic synthesis has stimulated recent extensive research towards improved methods for their preparation. 6Thiol esters are generally prepared from compounds having an active carbonyl group such as acid chlorides 6j,6l-n or carboxylic acid anhydrides.6k We have recently reported the synthesis of thiol esters from Nacylphthalimides and thiols in the presence of KF/Al 2 O 3 . 7Recently, Katritzky and coworkers introduced a procedure for preparation of thiol esters by reactions of N-acylbenzotriazoles with thiols. 8oupling of carboxylic acids with a variety of nucleophiles to prepare amides, esters, thiol esters, etc. continues to be one of the most commonly used transformations in organic chemistry. 1Modern coupling reagents utilize an equimolar amount of acid and nucleophile.
Besides being effective and easily handled, it is crucial that the conditions employed are mild and compatible with a wide variety of functional groups including the most commonly protecting groups. 9,10oupling reactions of carboxylic acids with thiols using carbodiimides such as DCC and EDC{1- [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride} are common methods for synthesis of thiol esters. 11Although the procedure gives the products in good yields, 11 equimolar amounts of highly insoluble ureas are formed which can cause difficulties in purification of the main product.A recent method 12 using tetramethylfluoroformamidinium hexafluorophosphate (TFFH) as the coupling reagent for the reaction of carboxylic acids with thiols gave the corresponding thiol esters in 60-94% yields.

Results and Discussion
Here we wish to report our results demonstrating the use of TBTU as a coupling reagent in the reaction of carboxylic acids with thiols for the synthesis of thiol esters (Scheme 1).

Scheme 1
The results are summarised in Table 1.The reaction can be performed with aromatic and aliphatic carboxylic acids and thiols at room temperature.The yields of thiol esters are in the range 72-92%.The structures of all the products were established from their analytical and spectral (IR, 1 H and 13 C NMR) properties.The reactions between various carboxylic acids and aromatic thiols are in general very fast and complete in 15-45 min.The results show clearly the need for much longer reaction times for aliphatic thiols (benzyl mercaptan, entries 5 and 7, Table 1).The effects of several solvents were examined and the best results were obtained with ethyl acetate (EtOAc).
The proposed mechanism for this coupling reaction is depicted (Scheme 2).X-Ray crystallographic studies have revealed that TBTU exists, at least in the solid state, as zwitterion 1 comprising a triazol-N-oxide and a guanidinium moiety. 16N,N'-Diisopropylethylamine (DIPEA) removes the acidic hydrogen from the carboxylic acid, and the carboxylate anion reacts with TBTU.The intermediate acyloxy-aminium/uronium salt 2 cannot be detected and reacts immediately with the benzotriazole derivative to give 3, which reacts with thiol to give the corresponding thiol ester 4 and 1-hydroxybenzotriazole (HOBt, 5) as a water-soluble by-product.

Conclusions
In summary, TBTU has been introduced as an efficient S-acylating reagent of thiols to give diverse thiol esters in high to excellent yields.The present method has the advantages of operational simplicity, mild reaction conditions, ready availability and use of non-toxic materials, fast reaction rates, and simple reaction work-up.

Experimental Section
General Procedures.TBTU was purchased from Zhejiang company (China).All products were characterized by comparison of their spectroscopic data with those of known samples.IR spectra were obtained using an ABB FTLA 2000 instrument.NMR spectra were recorded on a Bruker AQS 300 Avance instrument at 300 MHz for 1 H and at 75 MHz for 13 C NMR in CDCl 3 solutions.

Table 1 .
Thiol esters from carboxylic acids and thiols using TBTU ARKAT USA, Inc.