The system PhIO/Ph 3 P as an efficient reagent for mild and direct coupling of alcohols with carboxylic acids

The PhIO/Ph 3 P system acts as an efficient mild reagent for the direct esterification of carboxylic acids with alcohols. (Diacyloxyiodo)benzenes, which are in situ generated in DCM solution from carboxylic acids and iodosylbenzene, react smoothly with triphenylphosphine and an alcohol at refluxing DCM in the presence of catalytic amount of DMAP to give the respective esters from good to high yields.


Introduction
Ester functionality is widely present among a variety of natural products, lipids, pharmaceuticals, polymers, perfumes, food preservatives, cosmetics and synthetic materials of current interest. 1ccordingly, its importance continues to feed interest in research towards the discovery of new formation methods.Further to the numerous classical synthetic methods which have been developed so far, the direct coupling of alcohols with carboxylic acids are of particular importance. 2This transformation often requires special equipment or dehydrating agents and always the presence of coupling reagents, which are usually metal salts and organometallic reagents.These reagents and dehydrating agents are often toxic and/or expensive.As such, remains a need to develop mild and efficient methods towards the effective formation of ester functionality, using environmentally benign and readily recyclable coupling reagents.[6][7][8][9][10][11][12][13][14][15][16][17] In the light of these properties of organoiodine reagents, Zhang et al., 18 reported recently a method of broad scope for the coupling of carboxylic acids with amines or alcohols, using the hypervalent iodine lactone 1 as coupling reagent (Scheme 1).Treatment of carboxylic acids with amines or alcohols in the presence of lactone 1, triphenylphosphine and dimethylaminopyridine (DMAP), gave respective amides or esters in high yields.However, the use of all reagents, including lactone 1, which was costly to prepare, in stoichiometric amount as well the necessity for prolonged heating in chloroform at reflux are drawbacks for the method.Attempts to replace 1 with (diacetoxyiodo)benzene (PIDA) or [bis(trifluoroacetoxy)iodo]benzene (PIFA) led to the respective acetates as main products.
Scheme 1. Coupling of carboxylic acids with amines and alcohols a hypervalent iodine reagent.

Results and Discussion
Many years ago, Varvoglis and one of us reported that the reaction of (diacyloxyiodo)benzenes with triphenylphosphine afforded the respective carboxylic acid anhydrides, which were isolated chromatographically (Scheme 2). 30The dicarboxylates were prepared in situ by reaction of iodosylbenzene (PhIO) with carboxylic acids or from dichloroiodosobenzene with sodium carboxylates.The formation of intermediates 2 and 3 was postulated and evidence for the in situ generation of 3 was provided.
Taking into account the above findings, we considered that a reaction of (diacyloxyiodo)benzenes with triphenylphosphine in the presence of an alcohol could afford the respective ester via a nucleophilic attack to intermediate 3 by the alcohol.Since the (diacyloxyiodo)benzenes can be prepared in situ from iodosylbenzene (PhIO) and carboxylic acids this approach would lead to the esterification of added alcohols.Worthy to note was that a similar intermediate to 3 was also proposed by Zhang et al. 18 Scheme 2. Conversion of carboxylic acids into anhydrides via (diacyloxyiodo)benzenes.
To this end, we initially studied the reaction of a number of alcohols with the commercially available (diacetoxyiodo)benzene (PIDA) in the presence of triphenylphosphine and an organic base, expecting the formation of the respective acetates.The best results were obtained when the reaction was carried out in dichloromethane (DCM) heated at reflux using 1.5 equivalents of each of PIDA and Ph 3 P and 0.15 equivalents of DMAP as a base (Table 1).Longer reaction times were required and lower yields were obtained at room temperature or when Et 3 N or pyridine were used as base.
An inspection of Table 1 reveals that primary and secondary alcohols were readily acetylated in mild conditions and high yields.In contrast, acetylation of tertiary alcohols was unsuccessful, and the alcohols were recovered.Interestingly, trifluoroacetylation was easily achieved (entry 2).These findings indicate that the system PIDA/Ph 3 P can be used as a mild reagent for protection of primary and secondary alcohols.Taking into account these results, we turned our attention to widening the scope of the method by using carboxylic acids as starting materials and converting them in situ to the respective (diacyloxyiodo)benzenes in DCM solution, before the addition of triphenylphosphine and an alcohol.In a typical procedure, the carboxylic acid and PhIO were treated in DCM at rt under stirring in the presence of molecular sieves, until the dissolution of the latter (< 30 min).Then the alcohol, DMAP and triphenylphosphine were added, and after 4 h heating at reflux, the solvent was evaporated and the mixture chromatographed on a silica gel column.The results are depicted in Table 2.
In general, yields, which were not optimized, are somewhat lower than those in Table 1, but it is reasonably expected from a two-step one-pot reaction compared to a one-step reaction.][33][34][35][36][37][38][39][40][41] Compared to the Zhang protocol, our method applies milder condition, lower temperatures, shorter reaction times and avoids the toxic chloroform as solvent.The base (DMAP) is used catalytically (10-15%), and the organoiodine coupling reagent is cheap and readily available.In addition, the system PIDA/Ph 3 P can be applied for protection of primary and secondary alcohols.Further work to establish the scope and limitations of the PhIO/Ph 3 P system is underway.

Table 1 .
Acetylation of alcohols with PIDA

Table 1 (continued)
a PIFA was used instead of PIDA; b Yields were based on alcohol.

Table 2 .
Coupling of carboxylic acids with alcohols using PhIO as a coupling reagent

Table 2 (continued)
a Yields were based on alcohol.