Chemoselective N-benzoylation of aminophenols employing benzoylisothiocyanates

1 Introduction

Chemoselectivity in organic reactions is of immense importance to synthetic organic chemists as it reduces unnecessary protection and deprotection steps and hence reduces the cost of the overall process (Kumar et al., 2013). The reaction of a particular functional group selectively in polyfunctionalized compounds toward highly reactive reagents, however, is a challenging endeavor (Afagh and Yudin, 2010). The benzoylisothiocyanates are long known in organic chemistry as valuable synthetic precursors and their utility has been investigated since the early 1980s for the synthesis of thiourea derivatives (Uher et al., 1983; Upadhyaya and Srivastava, 1982). Varsheny et al. (2012) have synthesized some thiourea derivative recently using benzoylisothiocyanate. Furthermore, the reaction of benzoylisothiocyanate with 2-aminobenzothiophenes has been employed in the synthesis of annulated thiophene derivatives (El-Sharkawi et al., 2012). Patel and coworkers have demonstrated the application of benzoylisothiocyanates as efficient thiocyanate transfer reagents (Palsuledesai et al., 2009).

It has been observed that the reactivity of di- and trifunctionalized compounds containing heteroatoms like oxygen, nitrogen, and sulfur toward heterocumulenes investigated by our group such as diarylketenes (Singh, 2006; Singh and Pheko, 2007) and benzoylisothiocyanates (Singh et al., 2013a; Singh et al., 2013b) often depends on the structure of reactive intermediates besides the other substrate in the reaction, solvents, and reaction conditions. The reaction of 1,2-phenylenediamines with benzoylisothiocyanates has been reported recently to afford 2-arylbenzimidazole (Scheme 1) via the formation of bis-thiourea derivatives (Singh et al., 2013a). The salicylamide reacted with benzoylisothiocyanates through its hydroxyl group leading to the formation of benzoxazine derivatives (Scheme 1) (Singh et al., 2013b). In continuation of these studies, it was considered pertinent to investigate the reaction of benzoylisothiocyanates with 2-aminophenol with an objective to synthesize the corresponding benzoxazole (Scheme 2). The reaction of benzoylisothiocyanates with 2-aminophenol, however, afforded the product of chemoselective N-benzoylation of 2-aminophenol forming N-(2-hydroxyphenyl)benzamides. Also, the generality of this reaction has been demonstrated using 4-aminophenol as the substrate.

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Scheme 1 Reactions of benzoylisothiocyanates with ortho-phenylideneamine and salicylamide

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Scheme 2 Reaction of benzoylisothiocyanates with aminophenols.

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There are several reports in the literature on chemoselective acylation of amines using diverse reagents under different conditions. A few examples include the chemoselective acylation and benzoylation of the amino group in preference to the hydroxyl group by carboxylic anhydrides in the presence of sodium dodecyl sulfate as a catalyst (Naik et al., 2004a), by carboxylic acids using carbonyldiimidazole (Kumar et al., 2007), Fe(III)-montmorillonite (Choudhary et al., 2007) or zinc acetate (Brahmachari et al., 2010) as a catalyst. In the latter case, the reaction mixture was irradiated with microwaves. Chemoselective N-acylation has also been achieved using amine hydrochlorides and anhydrides in the presence of sodium bicarbonate (Naik et al., 2004b). Nair and Joshua have reported mixed benzoic dithiocarbamic anhydrides as benzoylating reagent (Nair and Joshua, 1972). Looking at the disadvantages in use of acyl chlorides and carboxylic acids for N-acylation, Katritzky et al. (2000) suggested N-acylbenzotriazoles as useful acylating reagents for amines.

2 Material and methods

The melting points have been recorded on a GallenKamp m. p. apparatus and uncorrected. The IR spectra were recorded on a Perkin-Elmer-781 spectrophotometer as a KBr disk. The ¹H and ¹³C NMR spectra were recorded on a Jeol-FX 90 MHz NMR spectrometer in DMSO-d6. Aminophenols were the Aldrich products and benzoylisothiocyanates were accessed easily by treating acyl chlorides with ammonium thiocyanate (Ambelang and Johnson, 1939).

3 Results and discussion

An equimolar reaction of benzoylisothiocyanate 1a with 2-aminophenol 2 in refluxing pyridine afforded a white crystalline product. This product was characterized as N-(2-hydroxyphenyl)benzamide 3a on the basis of satisfactory elemental analysis (Table 1) and spectral (IR, ¹H and ¹³C NMR) data. The IR spectra showed a broad band from 3350 to 3500 cm⁻¹ due to OH and NH groups and a strong absorption band at 1645 cm⁻¹ corresponding to the amide carbonyl group. The ¹H NMR spectra in DMSO-d₆ showed two downfield broad singlets at δ 12.08 and 10.81 ppm besides nine aromatic protons from δ 8.17 to 7.27 ppm. The ¹³C NMR spectra showed the carbonyl carbon at δ 163.3 ppm besides other ten aromatic carbon signals at δ 150.5 (C-OH), 141.8, 131.0, 129.5, 127.8, 127.0, 125.4, 124.5, 119.5, and 110.1 ppm. These NMR data are in good agreement with reported spectral data (Kumar et al., 2007) for this compound. The presence of the phenolic hydroxyl group was also ascertained by FeCl₃ test as well.

A similar reaction of the other substituted benzoylisothiocyanates 1b-g with 2-aminophenol 2 also afforded the corresponding N-benzoylated products 3b-g without any significant effect of the substituents present. All the products were characterized by comparison of their physical and spectral data with those reported in the literature (Kumar et al., 2007; Ramana and Kantharaj, 1995; Sener et al., 2000). Having achieved the chemoselective N-benzoylation in 2-aminophenol, the study was extended to 4-aminophenol as well. In this case also, the reaction of benzoylisothiocyanates afforded the corresponding N-benzoylated products 3h-j that were identified by comparison of the melting points and spectra data with the reported values (Kumar et al., 2007).

The most plausible explanation for the formation of the product 3a can be a chemoselective reaction of 1a with the amino group in 2-aminophenol 2 to form the product 4a containing a thiourea functional group (Scheme 2). The high reactivity of the amino group of aminophenols toward benzoylisothiocyanates forming thiourea derivatives has been evidenced earlier (Venkatesh and Pandeya, 2009) and was confirmed in the present study by carrying out the reaction in pyridine at room temperature for a short period. The product 4a was isolated and characterized using analytical and spectral data (see experimental). The melting point of the product 4a obtained by us, however, is considerably higher than the reported value which is probably due to a less degree of purity in the compound reported previously. An elimination of thiocyanic acid (HSCN) in the presence of pyridine from the intermediate product 4a may lead to the formation of product 3a. The removal of thiocyanic acid has been observed by our group in previous studies of the reactions of benzoylisothiocyanates with 1,2-phenylenediamine and salicylamide (Singh et al., 2013a; Singh et al., 2013b). It is assumed that the nucleophilic attack of the aromatic nitrogen on the carbonyl carbon of the tautomer of thiourea 4 triggers the elimination of thiocyanic acid.

It is noteworthy to mention that the products N-(hydroxyphenyl)benzamides are important building blocks in organic synthesis (Ramana and Kantharaj, 1995) and compounds of biological interest. Many N-aryl-substituted amides are reported to exhibit antimicrobial (Kumar et al., 2007; Sener et al., 2000), antithyroidal (Upadhyaya and Srivastava, 1982), and molluscidal (Shoeb, 1980) activities.

4 Conclusions

In conclusion, the paper reports benzoylisothiocyanates, easily accessible in the laboratory, as a new class of compounds that can be used for a chemoselective benzoylation of the amino group in preference to the phenolic hydroxyl group in aminophenols forming N-(hydroxyphenyl)benzamides that are compounds of biological interest. The reaction, which can be performed by conventional heating, does not require any catalyst and the solvent pyridine works as a base as well.