Mild and eco-friendly chemoselective acylation of amines in aqueous medium

Amines in the form of amine hydrochlorides are efficiently acylated with anhydrides in an aqueous medium on addition of NaHCO 3 . Both cyclic and acyclic anhydrides react with equal ease with an amine and amines of various stereo-electronic factors react with the same rates with an anhydride. No chromatographic separation is needed for isolation of the acylated product. Reactions in aqueous medium, innocuous by-products and chemoselective acylation of amines in the presence of phenols and thiols have been achieved with high selectivity.


Introduction
The acylation of amines is a common and often used as a protecting group in organic synthesis as it provides an efficient and inexpensive means for protecting an amino functionality in a multi-step synthetic process. 1 Acetic anhydride and acetyl chloride are generally used in the presence of acidic 2 or basic 3 catalysts in an organic medium.These reactions have advantages and drawbacks, recently described by Katritzky. 4Some of these reagents and catalysts lead to waste as well as some reactions involving organic solvents, often toxic and polluting, hence unacceptable in the present days.One of the major factors for a green chemical process in solution involves the choice of cheap, safe and non-toxic solvents.Water being abundant in nature is the first choice.In addition to satisfying the above criteria it has also special effects on reaction arising from intra-and inter-molecular non-covalent interactions leading to assembly processes.After Breslow's discovery of positive effect on the reaction rates and selectivities of Diels-Alder reaction, which is otherwise insensitive to solvent effects, special attention was focused on the origin of the aqueous acceleration. 5,6Thus, development of an efficient and convenient synthetic methodology in water is an important area of research.Considering the importance of acylation and environmental factors as well as our interest in green chemical processes, 7 we report in this letter acylation of amines in an aqueous medium, which fulfils many of the above requirements.

Results and Discussion
Acetylation of aromatic amines has been carried out in aqueous media but with a limited number of substrates. 8The same has been achieved using amine, hydrochloric acid, concentrated solution of sodium acetate (5 M) and acetic anhydride. 9We thought to add sodium bicarbonate to an aqueous solution of amine hydrochloride, which will liberate free amine and react with acetic anhydride and convert the liberated acetic acid to sodium acetate in the medium.Aliphatic and aromatic amines are basic in nature and can easily be protonated by mineral acids.To test our hypothesis and to optimise the reaction conditions, aniline 4 was converted to water-soluble anilinium hydrochloride using aqueous HCl.The protonated ammonium species is nonnucleophilic due to non-availability of the lone pair of electrons on the nitrogen atom.Thus, when acetic anhydride was added to an aqueous solution of amine hydrochloride no acetylation occurred.However, upon addition of basic salts, such as NaHCO 3 to the above medium, free amines were liberated, which reacted immediately with acetic anhydride, precipitating the acetylated product with the evolution of carbon dioxide.The reaction works best when the final pH of the medium is ca.5.5, approximately one pKa unit higher compared to that of acetic acid (pKa 4.8).Protonation of amine in an acidic medium has been confirmed by hypochromic shifts at 226 nm and 276 nm for (π-π*) and (n-π*) respectively, by titrating a dilute solution of 2fluoroaniline 5 with a dilute solution of HCl using UV spectrophotometer.A hyperchromic shift of these transitions upon addition of a dilute solution of sodium bicarbonate confirms the regeneration of free amines.
As shown in Table 1 several amines underwent acetylation very smoothly in good yields.The optimised acetylation reaction was performed by adding acetic anhydride (1.5 equiv) to the substrate amine hydrochloride (pH ca.1.6)dissolved in water followed by addition of NaHCO 3 in one lot to obtain a final pH ca.5.5.The methodology works well for both aliphatic, 1-2 and aromatic, 3-9 amines, as reported in Table 1. 10 Primary amines of varying electronic and steric factors, substrate 3-9 were examined.It is interesting to note that in most of these cases the product precipitates in less than 5 minutes.It has been observed that the acetylation of aryl amines performed in an organic reaction medium, substrate containing electron-donating groups in the aromatic ring facilitate the reaction, whereas electron-withdrawing groups slow down the reaction.No such effect was observed by the present methodology and all the substrates react with equal rates.However, aryl amines gave better yields as compared to alkyl amines.Chiral amines 10 can be easily acetylated with complete retention of optical activity.Phenol and thiophenol reacted slowly under the identical conditions giving poor yields.Thus, by taking advantage of the differential reactivity between nucleophiles, we were able to carry out chemoselective acetylation of amines over phenols and thiols.Thus, in a competitive acetylation reaction with an equimolar mixture of aniline 4 and phenol by this procedure, the amine is acetylated selectively leaving the phenol unaffected.In an analogous reaction between aniline 4 and thiophenol, the thiophenol remains unaffected.Similar selectivity was observed for intramolecular reaction as well.Thus, acetylation of 4-aminophenol 11 and 2-aminothiophenol 12 produced the corresponding acetamides; the phenolic and thiophenolic moiety remained untouched with one equivalent of the reagent.The selective acetylation is of significant interest for the preparation of antipyretic and analgesic drugs paracetamol 11a.Monoacetylation of 1,2-phenylenediamine 13 demonstrates the efficacy of the method.However, no chemoselectivity was observed for symmetrical diamine 1,4-phenylenediamine 14 even with one equivalent of the acetic anhydride.
When 2-aminothiophenol 12 was treated with one equivalent of acetic anhydride under the identical conditions; along with a trace amount of diacetylated product 12aa (<5 %) and monoacetylated product 12a (>28%) and an interesting heterocyclic product 2-methylbenzothiazole 12ab was obtained (ca.40%).The formation of 2-methyl-benzothiazole 12ab is via acetylation of amine followed by a nucleophilic attack of thiophenolic group on the carbonyl carbon of the amide and subsequent water elimination.Formation of 2-methyl-benzothiazole 12ab confirmed the chemoselective acetylation of amines over thiols.In most of these cases the acetylated product precipitated out from the aqueous reaction medium and in few cases it was extracted with ethyl acetate to yield the pure product, except in the case of substrates 1and 2 the product required extraction and in the case of substrates 13 and 14 the products required extraction as well as chromatographic separation.It was found that primary amines underwent smooth acetylation where as secondary amines such as diphenylamine remained inert under the present experimental conditions.The by-product sodium acetate is a useful buffering agent and can be recovered from the aqueous effluent by concentrating the aqueous medium, if desired.
The novel aspect of the present methodology was applied to cyclic anhydride such as succinic and maleic anhydride.In this case the anhydride 1.2 equivalent was used per equivalent of amine.All the substrate reacts easily as shown in Table 2, giving good yields.The reaction took place readily with simultaneous precipitation of white solid product.Finally the methodology was tested with an aromatic cyclic anhydride, phthalic anhydride.Finely powdered phthalic anhydride, 1 equivalent, was added to the amine hydrochloride solution followed by solid sodium bicarbonate.This has been tested with a number of aromatic amines and the result is summarised in Table 2.Besides acetic anhydride this method is also amenable to acyclic, cyclic, aliphatic and aromatic anhydrides, Table 2. 10 Propionylation of aliphatic 2 and aromatic amine 4 using propionic anhydride was carried out under the identical conditions as described for acetic anhydride.Here again the amino functionality has been chemoselectively propionylated in the presence of phenols and thiols as demonstrated for 4-aminophenol 11 and 2-aminothiol 12 respectively.Substrate 2-aminothiol 12 gave heterocyclic product 2-ethylbenzothiazole 12bb as the exclusive product and N-(2-mercapto-phenyl)-propionamide 12b as the minor product thereby supporting the chemoselective propionylation of amines over thiols.Benzoylation of aliphatic amine 2, benzylamine 3, aromatic amine 4 and chemoselective benzoylation of 4aminophenol 11 further proves the efficacy and chemoselectivity of the present aqueous methodology.In this case benzoic anhydride (1 equivalent) was added to an amine hydrochloride solution followed by solid sodium bicarbonate.The product precipitated into lumps, which can be recrystallised either from acetonitrile or from ethyl acetate.The by-product sodium benzoate can be recovered from the aqueous medium if desired.

Conclusions
In conclusion, this method represents a tremendous opportunity for the practice of green chemistry.The notable advantages of the method are: (i) operational simplicity, (ii) moderate to good yields, (iii) no chromatographic separation, (iv) excellent selectivity for aryl amines over phenols and thiols and (v) general applicability.The method is environmentally friendly with respect to by-products and the effluent are innocuous.The by-product sodium acetate / benzoate is a useful buffering agent.We believe this will present a better and more practical alternative to the existing methodologies for selective acylation of primary amines and thus will find useful application in the synthesis of complex natural products where selective protection of hydroxy, thio and amino groups is required.

Experimental Section
Typical Experimental Procedure.To a stirred heterogeneous suspension of amine (1 mmol) in water (5 mL) was added 6N HCl (in the volume range of 240-400 µL) until the solution became homogeneous (pH ca.1.5).The resulting homogenous solution was cooled in an ice bath.To this was then added anhydride (1-1.5 mmol) followed by solid sodium bicarbonate (185-300 mg) until there was no further effervescence or pH of the mixture becomes ca 5.5.The precipitate product was filtered, washed with water (2 × 1 mL), dried by pressing between folds of filter paper and finally dried in a vacuum desiccator.In cases, where product did not precipitate out the reaction mixture was extracted with ethyl acetate (2 × 10 mL).The organic extract was dried over anhydrous Na 2 SO 4 and the solvent was evaporated in a rotary evaporator under reduced pressure to yield the pure product which were identified by comparison of their NMR, IR, GC and GC co-injection with authentic samples prepared by known methods.

a
Confirmed by comparison with IR, 1 H and 13 C NMR of the authentic sample.b Isolated yields.c Rest of the products being diacetylated product 12aa and 2-methyl-benzothiazole 12ab.d Based on the recovery of starting material.e 3 equivalent of Ac 2 O was used.

Table 1 .
Acetylation of amines with acetic anhydride