Acetylation of Alcohols, Amines, Phenols, Thiols Under Catalyst and Solvent-Free Conditions

Home , Acetic anhydride, Acetyl chloride, Acylation, Diphenylmethanol

Article Acetylation of Alcohols, Amines, Phenols, Thiols under Catalyst and Solvent-Free Conditions

Nagaraj Anbu 1, Nagarathinam Nagarjun 1, Manju Jacob 2, J. Mary Vimala Kumari Kalaiarasi 2 and Amarajothi Dhakshinamoorthy 1,*

1 School of Chemistry, Madurai Kamaraj University, Madurai-625 021, Tamil Nadu, India 2 Department of Advanced Zoology and Biotechnology, Loyola College, Chennai 600 034, Tamil Nadu, India * Correspondence: [email protected]; Tel.: +91-99764-73669

Received: 12 June 2019; Accepted: 8 July 2019; Published: 10 July 2019

Abstract: In the present study, an easy and an efficient approach is reported for the acetylation of alcohols, amines, phenols, and thiols under solvent- and catalyst-free conditions. The experimental conditions were milder than conventional methods and the reactions were completed in shorter reaction time. The examined substrates afforded higher yields of the acetylated products under the short reaction time. Comparison of this work with earlier reported procedures reveals that this method offers some advantages than with reported catalysts and solvents. The as-synthesized products were characterized by 1H-NMR and GC-MS techniques to ensure their purity and identity. In addition, a possible mechanism was also proposed for this reaction.

Keywords: acetylation; phenol; amines; green chemistry; solvent-free; catalyst-free

1. Introduction Acetylation is one of the most important reactions in organic synthesis because acetyl groups can be conveniently used to protect a wide range of functional groups including alcohols, amines, phenols, and thiols, among others [1,2]. Acetylation with acyl halides or acid anhydrides has been reported using either homogeneous or heterogeneous acid catalysts [3–12] or base catalysts [13–17]. Subsequently, a wide range of homogeneous transition-metal-based or organocatalysts have been developed for the acetylation of alcohols using RuCl3 [18], CeCl3 [19], ZrCl4 [20], La(NO3) 6H2O[21], Al(OTf)3 [22], AgOTf [23], Co(II)salen-complex [24], · + NiCl2 [25], CoCl2 [26], iodine [27], Ph3P CH2COMeBr− [28], Cp2ZrCl2 [29], Mg(NTf2)2 [30], H [P(Mo O ) ] nH O[31], 3-nitrobenzeneboronic acid [32], (4-dimethylaminopyridine) [33], 3 3 10 4 · 2 (4-(N,N0-dimethylamino)pyridine hydrochloride) [34], CuZr(PO4)2 NPs [35], melamine trisulfonic acid [36], tin(IV)porphyrin-hexamolybdate [37], and NaOAc 3H O[38]. Furthermore, acetylation · 2 has also been reported with a series of heterogeneous catalysts, such as ionic liquids [39], ZnO [40,41], CuO-ZnO [42], nano γ-Fe2O3 [43], Fe3O4@PDA-SO3H[44], polymer-supported Gd(OTf)3 [45], silica-sulfamic acid [46], borated zirconia [47], ZnAl2O4 [48], P2O5/Al2O3 [49], poly(N-vinylimidazole) [50], CMK-5-SO3H[51], 4-dimethylaminopyridine-microporous organic nanotube networks [52], maghemite-ZnO [53], and graphene-grafted N-methyl-4-pyridinamine [54]. These methods exhibit some obvious advantages like low reaction temperature, higher conversions of substrates at short reaction time, and the ability of heterogeneous catalysts to be recycled. On the other hand, some of these reported methods use either acid or base, metal salts, and metal nanoparticles, thus experiencing some limitations in the work-up procedure and puriﬁcation process. Nardi and co-workers have reported sustainable methods for the protection of functional groups which include Er(OTf)3 as an environmentally benign catalyst for the protection and derivatization

Chemistry 2019, 1, 69–79; doi:10.3390/chemistry1010006 www.mdpi.com/journal/chemistry Chemistry 2019, 1 70 Chemistry 2019, 1, x FOR PEER REVIEW 2 of 11 ofmicrowave biomolecules-assisted [55 ],conditions derivatization [56] and of functionala simple and groups an efficient employing method aqueous for the microwave-assistedremoval of Fmoc in conditionsan ionic liquid [56] [57] and. a simple and an efficient method for the removal of Fmoc in an ionic liquid [57]. In contra contrastst to these reports, Ranu and co co-workers-workers have developed a simple and efficient efficient method for the acetylation of alcohols, alcohols, amines,amines, and thiols with acetic anhydride or acetyl chloride under solvent-solvent- and catalyst-freecatalyst-free conditions under nitrogen atmosphere atmosphere at 80–85 80–85 ◦°C[C [58]58].. However, this method possesses some limitations limitations,, includ includinging the requirement of high reaction temperature (80–85(80–85 ◦°C)C),, the need of inert atmosphere throughout the reaction time,time, and incomplete conversion of some substrates under the optimized reaction conditions.conditions. Therefore, there is a space to develop an eefficientfficient protocol for the acetylation reaction involving solvent and catalyst-freecatalyst-free conditions under mild reaction temperature. Hence, the present work aims to provide an alternative method to the prev previouslyiously reported procedures by developing a simple andand eefficientfficient method for the acetylation of alcohols,alcohols, amines, phenols,phenols, and thiols using acetic anhydride (Scheme 11)) underunder solvent-solvent- andand catalyst-freecatalyst-free conditions. conditions. ThisThis methodmethod providesprovides completecomplete conversionconversion of substratessubstrates with very high selectivity of the desired products at moderate reaction temperature under air atmosphere.atmosphere. TheThe optimizedoptimized reaction reaction conditions conditions are are further further extended extended to to synthesize synthesize a seriesa series of acetylatedof acetylated derivatives derivatives with with very very high high yields. yields.

O (CH3CO)2O R XH R Solvent free, 60 oC X CH3 X= NH, O, S R= Alkyl and Aryl Scheme 1. 1. AcetylationAcetylation of ofalcohols, alcohols, phenols, phenols, thiols, thiols and amines, and amines under catalyst under and catalyst solvent-free and solvent conditions.-free 2. Resultsconditions.

2. ResultsIn the initial stage of our investigation, benzyl alcohol was selected as a model substrate to optimize the reaction conditions. The observed results are presented in Table1. The acetylation of In the initial stage of our investigation, benzyl alcohol was selected as a model substrate to benzyl alcohol with acetic anhydride gave 63% conversion with 100% selectivity of benzyl acetate optimize the reaction conditions. The observed results are presented in Table 1. The acetylation of after 24 h at room temperature (Table1, entry 1). Interestingly, complete conversion of benzyl alcohol benzyl alcohol with acetic anhydride gave 63% conversion with 100% selectivity of benzyl acetate with 100% selectivity to benzyl acetate was achieved at 60 ◦C after 7 h (Table1, entry 1). The benzyl after 24 h at room temperature (Table 1, entry 1). Interestingly, complete conversion of benzyl alcohol conversion was only 88% when the reaction mixture was stirred magnetically under identical alcohol with 100% selectivity to benzyl acetate was achieved at 60 °C after 7 h (Table 1, entry 1). The conditions (Table1, entry 1). Therefore, further experiments were carried out at moderate temperature benzyl alcohol conversion was only 88% when the reaction mixture was stirred magnetically under (60 ◦C) without magnetic stirring to accomplish complete conversion of substituted benzyl alcohols identical conditions (Table 1, entry 1). Therefore, further experiments were carried out at moderate within a short reaction time. With these optimized conditions in hand, a series of benzyl alcohols with temperature (60 °C) without magnetic stirring to accomplish complete conversion of substituted electron-donating and electron-withdrawing substituents were examined and achieved more than 99% benzyl alcohols within a short reaction time. With these optimized conditions in hand, a series of conversions with 100% selectivities of the corresponding acetylated products after 8 h (Table1, entries benzyl alcohols with electron-donating and electron-withdrawing substituents were examined and 2–4). However, 4-nitrobenzyl alcohol provided quantitative conversion with 100% selectivity after 12 h achieved more than 99% conversions with 100% selectivities of the corresponding acetylated under identical conditions (Table1, entry 5). Furthermore, a heterocyclic alcohol like furfuryl alcohol products after 8 h (Table 1, entries 2–4). However, 4-nitrobenzyl alcohol provided quantitative gave complete conversion and selectivity after 7 h (Table1, entry 6). On the other hand, the aliphatic and conversion with 100% selectivity after 12 h under identical conditions (Table 1, entry 5). alicyclic alcohols like 1-octanol and cyclohexanol furnished quantitative conversions to their respective Furthermore, a heterocyclic alcohol like furfuryl alcohol gave complete conversion and selectivity esters with high selectivities after 7 and 8 h, respectively (Table1, entries 7 and 8). Moreover, sterically after 7 h (Table 1, entry 6). On the other hand, the aliphatic and alicyclic alcohols like 1-octanol and crowded substrates like 1-phenylethanol and diphenylmethanol aﬀorded more than 99% and 98% cyclohexanol furnished quantitative conversions to their respective esters with high selectivities conversions, respectively, after 20 h (Table1, entries 9 and 10). Furthermore, the substrate scope was after 7 and 8 h, respectively (Table 1, entries 7 and 8). Moreover, sterically crowded substrates like further expanded to generalize this method by examining phenols and their derivatives under identical 1-phenylethanol and diphenylmethanol afforded more than 99% and 98% conversions, respectively, conditions. Phenol exhibited quantitative conversion with complete selectivity towards phenylacetate after 20 h (Table 1, entries 9 and 10). Furthermore, the substrate scope was further expanded to after 12 h (Table1, entry 11). Substituted phenols such as 4-methyl-, 3-bromo- and 4-nitrophenols generalize this method by examining phenols and their derivatives under identical conditions. resulted in more than 99% conversions to their corresponding esters after 20 h (Table1, entries 12–14). Phenol exhibited quantitative conversion with complete selectivity towards phenylacetate after 12 h In addition, α- and β-naphthols showed more than 98% and 99% conversions, respectively, to their (Table 1, entry 11). Substituted phenols such as 4-methyl-, 3-bromo- and 4-nitrophenols resulted in corresponding esters after 20 h (Table1, entries 15 and 16). In general, the observed data under more than 99% conversions to their corresponding esters after 20 h (Table 1, entries 12–14). In the present experimental conditions show that phenols reacted comparatively slower than alcohols, addition, α- and β-naphthols showed more than 98% and 99% conversions, respectively, to their and this may be due to the reduced nucleophilic character of phenols. Similarly, the feasibility of corresponding esters after 20 h (Table 1, entries 15 and 16). In general, the observed data under the present experimental conditions show that phenols reacted comparatively slower than alcohols, and

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Acetylation 1. 1.Acetylation a..Acetylation a.. of alcohols,of of alcohols, alcohols, phenols, phenols, phenols, amines, amines amines, andand, and thiols thiols thiols under under catalyst catalyst- catalyst- and- andand solvent solvent-free solvent-free-free conditions . conditions.conditions. a. a.. b b b b conditions.Tableconditions.Table 1. 1.Acetylation Acetylation a. of of alcohols, alcohols, phenols, phenols, amines amines, andTime, andTime thiols thiols Conv. under Conv. under b catalyst b catalyst Sel.-Sel. and- b and b solventIsolated solventIsolated-free- freeYield Yield Tableconditions.Tableconditions. 1. 1.Acetylation aAcetylation. of of alcohols, alcohols, phenols, phenols, amines amines, andTime, andTime thiols thiols Conv. under Conv. under b catalyst b catalyst Sel.-Sel. and- b and b solvent Isolated solventIsolated-free-free Yield Yield EntryEntry SubstrateSubstratea. a. ProductProduct TimeTime Conv.Conv. b b Sel.Sel. b b IsolatedIsolated Yield Yield EntryEntryTableconditions. Tableconditions. 1. Substrate 1.AcetylationSubstrate Acetylation of of alcohols, alcohols,Product phenols,Product phenols, amines amines, andTime, (h)andTime (h) thiols thiols Conv. under Conv.(%) under(%) b catalyst b catalyst bSel.(%)-Sel. (%)and- b and b solventIsolated solventIsolatedb (%)-free(%)- freeYield Yield EntryEntryEntryconditions. conditions. SubstrateSubstrate a. a. ProductProduct Time(h)Time Time(h) (h)Conv.Conv.(%)(%)Conv. b b Sel.(%)Sel.(%) b b Sel.IsolatedIsolated(%)(%)(%) Yield Yield Isolated Yield (%) EntryEntry SubstrateSubstratea. ProductProduct (h)(h) (%)(%) b b (%)(%) b b (%)(%) EntryEntryconditions. conditions. SubstrateSubstrate a. 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a Reactiona Reaction conditions: conditions: Substrate Substrate (1 (1mmol), mmol), acetic acetic anhydride anhydride (1.5 (1.5 mmol), mmol), 60 60 °C; °C; b Conversionb Conversion and and selectivityselectivity were were determined determined by by GC; GC; c Atc At room room temperature; temperature; d Performedd Performed with with stirring; stirring; e At e At 70 70 °C; °C; f f ReactionReaction conditions: conditions: Substrate Substrate (10 (10 mmol), mmol), acetic acetic anhydride anhydride (15 (15 mmol), mmol), 60 60 °C. °C. 3.3.DiscussionDiscussion InIn order order to to illustrate illustrate some some benefits benefits of of this this method, method, the the observed observed results results we werere compar compareded with with previousprevious reports reports using using homogeneous homogeneous and and heterogeneous heterogeneous catalysts catalysts, and, and they they are are shown shown in in Table Table 2 . 2. TheseThese comparisons comparisons reveal reveal that that the the present present work work offers offers many many advantages advantages, such, such as as short short reaction reaction time, time, Chemistry 2019, 1 72 Chemistry 2019, 1, x FOR PEER REVIEW 4 of 11 ChemistryChemistry 2019 2019, 1,, x1, FOR x FOR PEER PEER REVIEW REVIEW 4 of4 of11 11 ChemistryChemistry 2019 2019, 1,, x1, FOR x FOR PEER PEER REVIEW REVIEW 4 of4 of11 11 ChemistryChemistry 2019 2019, 1,, x1, FOR x FOR PEER PEER REVIEW REVIEW 4 of4 of11 11 ChemistryChemistry 2019 2019, 1,, x1, FOR x FOR PEER PEER REVIEW REVIEW Table 1. Cont. 4 of4 of11 11 Chemistry12Chemistry 2019 2019, 1,, x1, FOR x FOR PEER PEER REVIEW REVIEW 20 >99 100 4 of4 of119 5 11 ChemistryChemistry 2019 2019, 1,,, x1,1, FOR xx FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 4 of4 of11 11 Chemistry12Chemistry12 20192019 2019,, 1,1,, xx1, FORFOR x FOR PEERPEER PEER REVIEWREVIEW REVIEW 2020 >99>99 100100 959 445 of4 of1111 11 EntryChemistry1212 2019, Substrate1, x FOR PEER REVIEW Product20 Time20 (h) >99>99Conv. b (%)100100 Sel. b (%)959 45 of Isolated11 Yield (%) 1212 2020 >99>99 100100 959 5 1212 2020 >99>99 100100 959 5 1212 2020 >99>99 100100 959 5 1212 2020 >99>99 100100 959 5 1312 12 2020 20 >99>99>99 100100 100 959 5 97 13131213 2020 20 >99>99 >99100100 1009759 7 97 1313 2020 >99>99 100100 979 7 1313 2020 >99>99 100100 979 7 1313 2020 >99>99 100100 979 7 1313 2020 >99>99 100100 979 7 1313 2020 20 >9999>9999 99 100100 100 9769 67 96 96 1313 2020 20 >9999>99 99100100 1009679 7 141413 14 2020 >999999 100100 9679 6 141414 2020 9999 100100 969 6 1414 20242420 24 97999799f f 97f f 100100 100 9956959 6 95 95 20242024 24 97999799f f 97 100100 1009956995 6 1414 2020 9999f f 100100 969 6 1414 20242024 97999799 100100 9956995 6 14 242024 979997f f 100100 959695 1414 f f 1414 2424 9797f f 100100 9595 14 2424 9797f f 100100 9595 2424 9797ff f 100100 9595 1515 20242024 >9897>9897f 100100 9595 151515 15 2020 2020 >98>98>98>98100100 100 1009595 95 95 1515 2020 >98>98 100100 9595 1515 2020 >98>98 100100 9595 1515 2020 >98>98 100100 9595 1515 2020 >98>98 100100 9595 1515 2020 >98>98 100100 9595 1616 2020 >99>99 e e 100100 9898 e e 1616 2020 >99>99 e 100100 9898 161616 16 2020 2020 >99>99 e>99 e>99 e100100 100 1009898 98 98 1616 2020 >99>99 e e 100100 9898 e e 1616 2020 >99>99 e e 100100 9898 1616 2020 >99>99 e e 100100 9898 16171716 0.5200.520 >99100>99100 e e 100100 98979798 171617 0.5200.5 >99100100 e 100100 979897 1717 17 0.50.5 0.5 100100 100 100100 100 9797 97 171717 0.50.5 0.5 100100 100100100 1009797 97 1717 0.50.5 100100 100100 9797 1717 0.50.5 100100 100100 9797 18171817 0.50.5 100100 100100 98979897 1818 0.50.5 100100 100100 9898 1818 0.50.5 100100 100100 9898 1818 18 0.50.5 0.5 100100 100 100100 100 9898 98 181818 0.50.5 0.5 100100 100100100 1009898 98 1818 0.50.5 100100 100100 9898 1818 0.50.5 100100 100100 9898 191819 0.50.5 100100 100100 9898 1919 0.50.5 0.5 100100 100 100100 100 9898 98 1919 0.50.5 100100100100 f f 100100 9898 98 0.50.5 0.5 100100100100 f f 100100100 1009898 1919 0.50.5 100100 f f 100100 9898 191919 19 0.50.5 100100100100 100100 9898 19 0.50.5 100100100 f f 100100 9898 1919 f f f f 98 1919 0.50.5 0.50.5 100100 f 100 f 100 100100 100 1009898 98 19 0.50.5 100100 f f 100100 9898 2020 0.50.5 100100100100 f f f 100100 98979798 2020 0.50.5 100100100100 f 100100 97989798 2020 0.50.5 100100 100100 9797 2020 0.50.5 100100 100100 9797 202020 20 0.50.5 0.50.5 100100 100 100 100100 100 1009797 97 97 2020 0.50.5 100100 100100 9797 20212120 0.50.5 100100 100100 97969697 212021 0.50.5 100100 100100 969796 2121 0.50.5 100100 100100 9696 2121 0.50.5 100100 100100 9696 2121 0.540.5 4 100100 1009810098 96949694 212121 21 0.54 0.5 40.50.5 100100 100 100 1009810098 100 10096949496 96 96 22212221 0.540.5 4 100100 1009810098 94969496 2222 154 15 4 9910099 100e,f e,f 9898 94969694 2222 154 15 4 9910099 100e,f e,f 9898 94969496 2222 154 15 4 4 9910099 100e,f e,f100 9898 98 94969496 94 2222 154 15 4 49910099 100e,f e,f 1009898 98 94969496 94 2222 4 100e,f e,f 98 94 222223 2322 156 15 6 9910099 100e,f e,f 98979897 96959695 222222 15 99e,f e,f e,f 98 96 232223 156 15 615 15 9910099 100e,fe,f 99e,f 99 e,f 98979798 98 98 96959596 96 96 2323 156 15 6 9910099 100e,f 97989798 95969596 2323 6 6 100100 9797 9595 2323 6 6 100100 9797 9595 2323 6 6 100100e e 9797 9595 2323242423 206 20 6 61008686100 1009797 9795808095 95 232423 24 206 20 6 8610086 e 100e 9797 97 809580 95 2424 2020 8686 e e 9797 8080 2424 2020 8686 e e 9797 8080 e e 2424 2020 8686 e e 9797 8080 2424 a a 2020 8686 9797b b 8080 ReactionReaction conditions: conditions: Substrate Substrate (1 (1mmol), mmol), acetic acetic anhydride anhydride (1.5 (1.5 mmol), mmol),e e 60 60 °C; °C; ConversionConversion and and 2424 a a 2020 8686 e e 97b97 b 8080 2424 ReactionReaction conditions: conditions: Substrate Substrate (1 (1mmol), mmol), acetic acetic anhydride anhydride2020 (1.5 (1.5 mmol),86 mmol),86 e 60e 60 e°C; 97°C; 97 Conversion Conversion 80and 80 and 242424 selectivitya Reactionselectivitya Reaction wereconditions: wereconditions: determined determined Substrate Substrate by by GC;(1 GC; (1mmol), c Atmmol), c At room roomacetic acetic temperature; temperature; anhydride anhydride20 2020 d (1.5 Performed d (1.5Performed mmol),86 mmol), 86 with 8660 with 60 °C; stirring;97°C; stirring;b Conversionb Conversion97 e At e At 9770 70 80 °C;and °C;and f f 80 80 selectivitya Reactionselectivitya Reaction wereconditions: wereconditions: determined determined Substrate Substrate by by GC;(1 GC; (1mmol), c Atmmol), c At room roomacetic acetic temperature; temperature; anhydride anhydride d (1.5Performed d (1.5Performed mmol), mmol), with60 with 60°C; stirring; °C; stirring;b Conversionb Conversion e At e At 70 70 °C;and °C;and f f a a c c d d b b e e f f aReactionselectivity ReactionaReactionselectivity Reaction conditions: conditions:wereconditions: conditions:were determined determined Substrate Substrate Substrate by (10by GC;(10(1 mmol), GC; (1 mmol), mmol), mmol),At At roomacetic roomacetic acetic temperature;anhydride temperature;anhydrideanhydride anhydride (15 (15 (1.5mmol),Performed (1.5mmol),Performed mmol), mmol), 60 60 °C. with 60°C. with60 °C; stirring;°C; stirring;b Conversionb Conversion At At 70 70 °C;and °C;and a a Reaction conditions: Substrate (1c mmol),c acetic anhydrided d(1.5 mmol), 60 °C;b b Conversione e andf f aReactionselectivitya ReactionReactionaselectivity Reaction conditions: wereconditions:conditions: conditions:were determined determined Substrate Substrate Substrate by (10by GC;(10(1 mmol), GC; (1 mmol), mmol), Atmmol), At roomacetic roomacetic acetic temperature;anhydride temperature;anhydrideanhydride anhydride (15 (15 (1.5mmol),Performed (1.5mmol),Performed mmol), mmol), 60 60 °C. with 60°C. with60 °C; stirring;°C; stirring;bb Conversionb Conversion At At 70 70 °C;and °C;and ReactionReaction conditions: conditions: Substrate Substrate (1 (1mmol),c mmol),c acetic acetic anhydride anhydride d(1.5 d (1.5 mmol), mmol), 60 60°C; °C; ConversionConversione e and andf f a selectivityReactiona ReactionselectivityReaction conditions: were conditions:conditions: were determined determined Substrate Substrate by (10by GC; (10(1 mmol),GC; mmol),At c At room acetic roomacetic temperature; anhydride temperature; anhydrideanhydride (15 (15 (1.5Performed mmol),d Performedmmol), mmol), 60 60 °C.with 60 °C.with °C; stirring; b stirring;b Conversion At e At 70 70 °C;and °C; f 3.Reaction3.DiscussionaDiscussion Reactionselectivity conditions: conditions: were determined Substrate Substrate (1by mmol),(1 GC; mmol),c c At acetic roomacetic anhydride temperature; anhydride (1.5 d (1.5 d Performed mmol), mmol), 6060 with◦ C;°C; stirring;ConversionConversione b e At 70 and and °C;f selectivityf were ReactionselectivityselectivityReaction conditions: conditions:were conditions: were determined determined Substrate SubstrateSubstrate by (10by GC;(10 mmol),GC;(1 mmol),c mmol),At c At roomacetic roomacetic acetic temperature;anhydride temperature;anhydride anhydride (15 d(15 mmol),Performed d Performedmmol), (1.5 60 mmol), 60°C. with °C. with stirring; 60 stirring; °C; e At Conversione At 70 70 °C; °C; f f and 3.3.DiscussionDiscussionselectivityselectivity were were cdetermined determined by by GC; GC; c At c At roomd room temperature; temperature; d Performed d Performede with with stirring; stirring;f e At e At 70 70°C; °C; f f 3.determined3.DiscussionDiscussionReactionselectivityReaction by conditions: GC;wereconditions: determinedAt Substrate room Substrate temperature; by (10 GC;(10 mmol), mmol),c At roomacetic Performedacetic temperature;anhydride anhydride with (15 (15d stirring; mmol),Performed mmol), 60 60 °C.At with °C. 70 stirring;◦C; Reaction e At 70 conditions:°C; f Substrate InReactionIn Reactionorder order conditions:to conditions:to illustrate illustrate Substrate Substratesome some benefits (10 benefits (10 mmol), mmol), cof of aceticthis aceticthis method, anhydride method, anhydride the (15the (15observed mmol), observed mmol),d 60 60 results°C. results°C. we werere compar compareed ed with with f 3.(103.Discussion mmol),selectivityDiscussionReactionReaction acetic conditions: were conditions: anhydride determined Substrate Substrate (15 mmol), by(10 (10 GC;mmol), mmol), 60 At aceticC. roomacetic anhydride anhydridetemperature; (15 (15 mmol), mmol), Performed 60 60°C. °C. with stirring; At 70 °C; 3. 3.DiscussionDiscussionInReactionIn order order conditions:to to illustrate illustrate Substrate some some benefits (10 benefits mmol), of ◦ ofaceticthis this method, anhydride method, the (15the observed mmol), observed 60 results°C. results we werere compar compareded with with 3.previous3.previousDiscussionReactionDiscussionInIn order reportsorder reports conditions:to to illustrateusing illustrateusing homogeneous Substrate homogeneoussome some benefits benefits(10 mmol),and andof of heterogeneousthis heterogeneous aceticthis method, method, anhydride the catalysts the catalysts observed (15observed mmol),, and, and results theyresults 60 they °C. arewe arewe reshown re showncompar compar in in Tableed Tableed with with 2. 2. 3.previousprevious3.DiscussionDiscussionIn Inorder reportsorder reports to to illustrateusing illustrateusing homogeneous homogeneoussome some benefits benefits and andof heterogeneousofthis heterogeneous this method, method, the catalysts the catalysts observed observed, and, and results theyresults they arewe are we reshown reshowncompar compar in in Tableed Tableed with with 2. 2. Theseprevious3.ThesepreviousDiscussionIn comparisonsIn order comparisons orderreports reports to toillustrate using illustrate usingreveal reveal homogeneous homogeneous thatsome thatsome the benefitsthe presentbenefits present and andof work ofheterogeneous thiswork heterogeneousthis offersmethod, offersmethod, many many the catalysts the advantages catalystsobserved advantages observed, and, and results, theysuchresults, suchthey areaswe asare weshort reshown short reshowncompar reactioncompar reaction in in edTable Tableed time,with time,with 2. 2. 3. Discussion3.ThesepreviousDiscussionThesepreviousIn comparisonsIn order comparisons reportsorder reports to to illustrateusing illustrate usingreveal reveal homogeneous homogeneousthatsome thatsome the benefitsthe presentbenefits present and andof workof heterogeneous thiswork heterogeneousthis offersmethod, offersmethod, many many the catalysts the advantagescatalysts observed advantages observed, and, and results, theysuchresults, suchthey areaswe as areshortwe reshown short re showncompar reactioncompar reaction in inTableed edTable time,with time,with 2. 2. previousThesepreviousTheseInIn comparisons In order comparisons reportsorder reports to toillustrate illustrateusing illustrate usingreveal reveal homogeneous homogeneoussomethatsome thatsome the benefitsbenefitsthe presentbenefits present and andofof work heterogeneousof thisthiswork heterogeneous this offersmethod,method, offersmethod, many many thethe catalysts the catalysts advantages observedobserved advantages observed, and, and resultsresults, theysuchresults, theysuch are aswe areas shortwe rereshown short re showncompar reactioncompar reaction in inTableed Tableed time,with time,with 2. 2. ThesepreviouspreviousTheseIn comparisons order comparisons reports reports to illustrateusing usingreveal reveal homogeneous homogeneousthatsome that the benefitsthe present present and andof work heterogeneous this workheterogeneous offersmethod, offers many many the catalysts catalystsadvantages observed advantages, and, and results, theysuch, theysuch areaswe are asshort reshown short showncompar reaction reaction in in Tableed Table time,with time, 2. 2. previousTheseThesepreviousIn comparisonsorder comparisons reports reports to illustrate using usingreveal reveal homogeneous homogeneousthat some that the the benefitspresent present and and work heterogeneousof work heterogeneous this offers offers method, many many catalysts advantagescatalyststhe advantages observed,, and, and, theysuch, suchthey results areas as areshort shown short shownwe reaction rereaction in compar inTable Table time, time, 2ed.. 2. with ThesepreviousInThese order comparisons comparisons reports to illustrate using reveal reveal homogeneous that some that the the present beneﬁts present and work heterogeneous work of offers this offers many method, many catalysts advantages advantages the, and observed, suchthey, such asare as short shown short results reaction reaction in Table were time, time, 2 compared. with TheseThese comparisons comparisons revealreveal reveal thatthat that thethe the presentpresent present workwork work offersoffers offers manymany many advantagesadvantages advantages,, suchsuch, such asas as shortshort short reactionreaction reaction time,time, time, previouspreviousThese reportscomparisons reports using using reveal homogeneoushomogeneous that the present and work and heterogeneous offers heterogeneous many advantages catalysts catalysts,,, suchand asthey andshort are theyreaction shown are time, in shown Table 2 in. Table2. These comparisons reveal that the present work offers many advantages, such as short reaction time, These comparisons reveal that the present work oﬀers many advantages, such as short reaction time, minimal use of acetic anhydride, and the achievement of higher yields in the absence of catalyst and solvent. Furthermore, it is interesting to note that the present experimental conditions could provide catalytic results comparable to those data either with homogeneous or heterogeneous catalysts. Chemistry 2019, 1 73

Therefore, the method in this work can be considered as an alternative method for acetylation reaction from a green chemistry perspective.

Table 2. Comparison of the present catalytic data with literature reports for the acetylation reaction.

Entry Substrate (mmol) (CH3CO)2O (mmol) Catalyst Solvent T (◦C) Time (h) Ref.

1 1 2 Cu(OTf)2 DCM RT 2 [11]

2 1 1.2 RuCl3 CH3CN RT 10 min–72 h [18] + 3 1 1.5–2 Ph3P CH2COMeBr− - RT 0.5–3.5 [28]

4 55.5 83 Gd(OTf)3 CH3CN 25 5 min–14 h [59] 5 1 5 Co(II)salen-complex - 50 0.5–2 [24]

6 5 6 CoCl2 - RT 10–50 min [26] 7 1 1.1 NaOAc 3H O - RT 10 min [38] · 2 8 10 11 DMAP HCl Toluene RT-110 4–28 [34] · a 9 0.1 0.15 DMAP-MONN CH2Cl2 RT 0.5–5 [52] 10 6.9 7.6 Maghemite-ZnO - RT 3 [53] 11 1 1.5 G-NMPA a - 35 2–10 [54]

12 0.5 0.55 CBr4 - 60 3–6 [60]

13 2.5 2.5 InCl3 - RT 30 min [61] 14 2 4 Cu(BDC) - RT 24 [62]

15 1 1.5 H14[NaP5W30O110] - RT 0.5–3 [63]

16 2 4–20 LiClO4 - 25–40 4–48 [64] 17 1 1.5 - - 60–70 7–20 Present work a Additionally 1.5 equivalent triethylamine was used.

Based on the observed results in Table1, a suitable mechanism is proposed for the acetylation of alcohols, phenols, and amines (Scheme2). The lone pair of electrons on oxygen and nitrogen attack the carbonyl group in acetic anhydride to give an adduct which later eliminates acetic acid to give the corresponding ester (Path I). Furthermore, the liberated acetic acid can also participate in this mechanism. Initially, acetic acid protonates the carbonyl group of acetic anhydride to give a cationic intermediate which is further attacked by the nucleophile to give an alcohol-type intermediate. Later, this intermediate undergoes a series of steps including electron migration to eliminate acetic acid followed by the removal of a proton to give the final desired product (Path II). In order to demonstrate the feasibility of this method in a gram-scale synthesis, a series of experiments were performed at a gram scale under identical conditions, and the observed data are shown in Table1 and Figure1. It is clearly evident that the present method a fforded quantitative yields of 4-nitrobenzylacetate, 4-bromoacetanilide, and 4-nitrophenylacetate from 4-nitrobenzyl alcohol, 4-bromoaniline, and 4-nitrophenol, respectively, under the optimized conditions as shown in Table1. One of the main advantages of this method is the isolation of the desired products without column chromatography purification, and it can be readily scaled up without any difficulty. Figure1 shows the isolated products of 4-nitrobenzylacetate, 4-bromoacetanilide, and 4-nitrophenylacetate in a gram-scale synthesis. Chemistry 2019, 1 74 Chemistry 2019, 1, x FOR PEER REVIEW 6 of 11

SchemeScheme 2.2. AA plausibleplausible mechanismmechanism forfor thethe acetylationacetylation ofof alcohols,alcohols, amines,amines, phenols,phenols, andand thiolsthiols underunder catalyst-catalyst- andand solvent-freesolvent-free conditions.conditions.

In order to demonstrate the feasibility of this method in a gram-scale synthesis, a series of experiments were performed at a gram scale under identical conditions, and the observed data are shown in Table 1 and Figure 1. It is clearly evident that the present method afforded quantitative yields of 4-nitrobenzylacetate, 4-bromoacetanilide, and 4-nitrophenylacetate from 4-nitrobenzyl alcohol, 4-bromoaniline, and 4-nitrophenol, respectively, under the optimized conditions as shown in Table 1. One of the main advantages of this method is the isolation of the desired products without column chromatography purification, and it can be readily scaled up without any difficulty. Figure 1 shows the isolated products of 4-nitrobenzylacetate, 4-bromoacetanilide, and 4-nitrophenylacetate in a gram-scale synthesis.

Chemistry 2019, 1 75 Chemistry 2019, 1, x FOR PEER REVIEW 7 of 11

Figure 1. A gram-scale synthesis of (A) 4-nitrobenzylacetate, (B) 4-bromoacetanilide, and Figure 1. A gram-scale synthesis of (A) 4-nitrobenzylacetate, (B) 4-bromoacetanilide, and (C) 4-nitrophenylacetate under the optimized reaction conditions. (C) 4-nitrophenylacetate under the optimized reaction conditions. 4. Materials and Methods 4. Materials and Methods 4.1. Materials 4.1. Materials Alcohols, amines, phenols, and thiols were purchased from Sigma-Aldrich and used as received withoutAlcohols, further amines, purification. phenols Solvents, and thiols were were purchased purchased from from Merck Sigma and-Aldrich Sigma-Aldrich and used andas received used as withoutreceived further without purification. any further Solvents purification were processes. purchased from Merck and Sigma-Aldrich and used as received without any further purification processes. 4.2. General Procedure for the Acetylation of Alcohols, Phenols, Thiols, and Amines under Solvent-Free Conditions 4.2. GeneralIn a typical Procedure reaction, for the a 25Acetylatio mL round-bottomn of Alcohols, flask Phenols was, Thiols charged, and with Amines 1 mmol under of Solvent substrate-Free (amine, Conditionsalcohol, phenol, or thiol) followed by the addition of 1.5 mmol acetic anhydride. This mixture was homogeneouslyIn a typical reaction, mixed with a 25 the mL help round of a-bottom glass rod flask and was later charged placed inwith a preheated 1 mmol of oil substrate bath maintained (amine, alcohol,at 60 ◦C phenol for the, requiredor thiol) time.followed A known by the amount addition of of sample 1.5 mmol was takenacetic periodicallyanhydride. This from m theixture reaction was homogeneouslymixture at different mixed time with intervals the help and diluted of a glass with rod diethyl and ether later to placed monitor in a the preheated completion oil of bath the maintainedreaction by gasat 60 chromatography. °C for the required Furthermore, time. A known the conversion amount of and sample selectivity was weretaken also periodically determined from by thegas chromatographyreaction mixture at at a different given time. time After intervals completion and of dilute thed reaction, with diethyl the mixture ether was to monitordiluted with the completiondiethyl ether of and the washed reaction two by times gas with chromatography. sodium bicarbonate, Furthermore, and then the the conversion ether layer and was selectivitydried with weresodium also sulfate. determined Conversion by gas andchromatography selectivity were at a determined given time. by After Agilent completion gas chromatography of the reaction, using the mixturean internal was standard diluted method.with diethyl The productsether and were washed characterized two times by with1H-NMR sodium and bicarbonate GC-MS (Supporting, and then theInformation; ether layer Figures was driedS1–S23). with sodium sulfate. Conversion and selectivity were determined by Agilent gas chromatography using an internal standard method. The products were characterized 5. Conclusions by 1H-NMR and GC-MS (Supporting Information; Figures S1–S23). In summary, we have developed a convenient and general method for the acetylation of alcohols, 5.amines, Conclusions phenols, and thiols in the absence of solvent and catalyst. The experimental conditions were milder,In and summary, the reactions we have were developed completed a in convenient shorter reaction and times. general Interestingly, method for most the of acetylation the substrates of alcohols,were transformed amines, to phenols their respective, and thiols acetylated in the products absence inof higher solvent yields and under catalyst. the Theoptimized experimental reaction conditions were milder, and the reactions were completed in shorter reaction times. Interestingly,

Chemistry 2019, 1 76 conditions. The synthesized products were characterized by GC-MS and their purity were conﬁrmed by 1H-NMR spectra.

Supplementary Materials: The following are available online at http://www.mdpi.com/2624-8549/1/1/6/s1. GC-MS spectra for all the acetylated compounds are given in the supporting information file. Author Contributions: N.A. and M.J. executed all the experiments while N.N. contributed to characterizing the products. A.D. planned the work and wrote the manuscript and J.M.V.K.K. assisted in writing the manuscript. Funding: A.D. thanks University Grants Commission, New Delhi, for the award of Assistant Professorship under its Faculty Recharge Program. A.D.M. also thanks the Department of Science and Technology, India, for the financial support through EMR project (EMR/2016/006500). Conflicts of Interest: The authors declare no conflict of interest.

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