Research Journal of Chemistry and Environment__________________________________Vol. 25 (12) December (2021) Res. J. Chem. Environ. 116 Microwave assisted Acetylation of Amines using Imidazole Hydrochloride under solvent-free condition Chikkulapalli Anil and Sumathi S. * School of Advanced Sciences, VIT University, Vellore-632014, INDIA *saianilrao.ch@gmail.com Abstract A simple and novel microwave irradiation method has been developed for N-acetylation of both aliphatic and aromatic amines with N,N-dimethylacetamide via N- acetyl imidazole by using Imidazole hydrochloride under solvent-free condition. The method proved more eco-friendly and economic. Keywords: N-Acetylation, Amine, N,N-Dimethylacetaide (DMAc), Imidazole hydrochloride, Microwave irradiation. Introduction Amides 1 are one of the most important organic functional group and occurred in many natural products, pharmaceuticals, polymers and agrochemicals 2 . The acetylation of amino group is commonly used as protecting group to avoid unwanted side reactions. Acetylation is often used in a multistep synthesis to construct a target molecule. Generally, acetylation of amines relies on activation of carboxylic acid derivatives. Most of the methods available at present for the N-acetylation of amines require harsh reaction conditions, energetic reagents, inert atmosphere, hazardous chemicals, need of dry solvents and also resulting in tedious workup and isolation. Conventionally amides have been synthesised by the coupling of amines with carboxylic acid or their derivatives such as lachrymatory acetyl chloride, acetic anhydride and esters. Among them, several catalytic methods have been reported recently for the acetylation of amine by using acetyl chloride and acetic anhydride in the presence of various catalysts such as Fe(NO3)3·9H2O 3 , Ir(III) 4 , sulfonic acid functionalized hyper-cross-linked poly(2-naphthol) 5 , ruthenium metal 6 , mesoporous aluminophosphate solid acids 7 , yttrium triflate 8 , silica, sulfuric acid 9 , silica- supported boric acid 10 , TiO2 NPs 11 , zirconyl triflate 12 , copper 13 , Fe(III) 14 , Pd(OAc)2 15 , Zn(II) chloride and other Lewis acids 16 , ZnO 17 , indium 18 , carbon nanotube-gold nanohybrid (Au-CNT) 19 , nanocerium oxide 20 , K3PO4 21 , heteropolyanion-based ionic liquids (HPAILS) 22 , oaryl oxide−N-heterocyclic carbene ruthenium(II) ([Ru-NHC] complex) 23 , molybdate sulfuric acid 24 and sulfuric acid on silica 25 . However, most of these catalytic methods suffer from secral drawbacks such as use of expensive solvents and catalysts, formation of byproducts, critical workup procedures, long reaction timing with lower yields. In view of the above catalytic methods, we step forwarded to green methodology for acetylation of various amines. Herein we report the acetylation of various amines with N,N-dimethylacetamide (DMAc) in the presence of Imidazole hydrochloride under microwave assisted solvent-free condition. Material and Methods All reagents were procured from the commercially available sources and used directly without any additional purification. All reactions were performed under inert atmosphere to maintain the dry condition. General procedure for the N-acylation of amines with DMAc and Imidazole hydrochloride under microwave condition: Amines (1a-r) (1.0 equiv), Imidazole hydrochloride (1.5 equiv) and N,N-Dimethyl acetamide (2.0 equiv) were taken into a quartz tube and then subjected to microwave irradiation at 480 W for 8 min (irradiation continued at 130-135 °C). After 8 min, TLC analysis of the reaction mixture showed the complete conversion of the starting material. The reaction mixture was cooled to 20-25 °C and diluted with water (15 mL), then extracted with ethyl acetate (2 x 10 mL). Organic layers were combined and washed with brine solution (15 mL), dried over anhydrous Na2SO4 and filtered. The filtered solvent was concentrated under vacuum to provide the corresponding acetylated products (2a-r). All the products are well characterized by NMR spectroscopy and comparison of their physical properties is listed in table 1 with those of authentic samples 35 . Results and Discussion Previously, we have reported a convenient method for N- acetylation of amines with DMAc in the presence of carbonyldiimidazole (CDI) which proceeds through formation of 1-acetylimidazole 5 . This observation has lead to the use of Imidazole hydrochloride as an efficient acetylation agent. The success of this acetylation relies on the in situ generation of 1-acetylimidazole by heating N,N- dimethylacetamide with Imidazole hydrochloride at 130-135 o C. Thus initial experiment encouraged us to explore further on this unique acetylation reaction. To optimize the reaction conditions, we carried out acetylation reaction on aniline with DMAc (Table 1) and clearly observed that this is a temperature dependent reaction. Initially, the reaction was performed in the absence of imidazole hydrochloride at 100-105 o C. Reaction temperature over the period of 16 hours gave only 6% of the desired product (Table 1, entry 1). By using 1.5 equivalent of Imidazole hydrochloride at 100-105 o C, the reaction provided the amide in 83% yield (Table 1, entry 2). Gratifyingly, increasing the reaction temperature to 130-135