General Papers ARKIVOC 2007 (xiii) 47-52
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
9,10
groups.
Coupling 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.11 Although 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 method12 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.
The coupling reagent field has clearly evolved in the last decade from carbodiimides to onium (phosphonium and uronium) salts. One of such onium salts is 2-(1-H-benzotriazole-1-yl)1,1,3,3- tetramethyluronium tetrafluoroborate (TBTU) which has been used as an activating agent of carboxylic acids for preparation of 1,2,4, oxadiazoles,13 amides and phenylhydrazides,14 and esters.15
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).
R1CO2H TBTU, DIPEA R2SH R1COSR2 EtOAc 25 oC
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, 1H and 13C 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.16 N,N'-Diisopropylethylamine (DIPEA)
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