A mild and eco-friendly one-pot two-step procedure was developed for the synthesis of 2-hydroxy-N-arylacetamides from 2-chloro-N-arylacetamides. The procedure overcomes the cleavage of the amide linkage in 2-chloroacetamides which is usually observed under reflux condition with the hydroxide when the nucleophilic substitution of the halide is attempted. The reactions were performed by refluxing 2-chloro-N-arylacetamides with Cu(OAc)2 and DIPEA in ethanol medium to facilitate an acetate exchange with the halogen. Subsequently by the addition of ethanolic KOH solution to the same reaction flask the ester linkage was selectively cleaved in the presence of the amide taking advantage of the difference in electrophilicity. The procedure affords good yields of the desired products which are valuable intermediates for several biologically active molecules, in short reaction time with ease of isolation The experimental conditions employed are simple and offers the possibility of scale up to higher quantities.
Research Article
A mild and eco-friendly, one-pot synthesis of 2-hydroxy-N-arylacetamides from 2-chloro-N-arylacetamides
https://doi.org/10.21203/rs.3.rs-3251914/v1
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2-Hydroxy-N-arylacetamide
Diisopropyl ethylamine
Copper(II) acetate
Nucleophilic substitution
The 2-hydroxy amides are an important class of intermediates in organic synthesis and pharmaceuticals. The applications of molecules derived from this intermediate were demonstrated in the fields of science and medicine [1], such as metalloprotease inhibitors, anticonvulsants, antibiotics, antimycobacterial agents and γ-secretase inhibitors [2] (Fig. 1). Among the reports available, the 2-hydroxy amides were synthesized from α-ketoamides through hydrogen transfer from a zirconium-based metal-organic framework [3], by chemoselective reduction of α-ketoamides using polymethylhydrosiloxane in the presence of Ni-catalyst [4] or potassium phosphate (K3PO4) [5]. Other known strategies are the metal and ligand-free chemoselective reduction by tetrabutylammonium fluoride in the presence of Ph3SiH [6], and sodium formate mediated conversion of α-ketoamides to 2-hydroxyamides [7]. Glycolic acid and substituted anilines were reacted at higher temperatures in the absence of solvent [8]. N,N-dimethylcarbamoyl(trimethyl)silane and aldehydes were reacted to access 2-hydroxy amides under sealed-tube conditions [9]. Catalytic borinic acid facilitated α-addition to isocyanides with aldehydes and water has also been reported for the synthesis of 2-hydroxy amides [10]. Amination of 2-hydroxy amides using a variety of aromatic and aliphatic amines were carried out in the presence of commercially available [Ru3(CO)12]/DCPE catalyst to obtain amino acid amides [11].
The stereoselective synthesis of chiral 2-hydroxy amides include enzyme catalyzed reactions with α-oxo esters [12], one-pot asymmetric epoxidation of α,β-unsaturated amides followed by Pd-catalysed epoxide opening [13], from aldehydes by a bienzymatic cascade combining hydroxynitrile and nitrile hydratase [14], and reaction of the α-hydroxy esters with amines in the presence of Candida antarctica lipase [15]. Asymmetric reduction of α-keto amides for the steresoselective synthesis of 2-hydroxy amides were accomplished by hydrogenation with chiral Ru-[BINAP] complex [16], chiral CuII/(S)-DTBM-SEGPHOS catalyzed hydrosilylation [17], and organocatalytic Henry reactions using chiral bisoxazolidine and Cu(OTf)2 [18]. The chiral bisphosphoramide-SiCl4 system catalyzed reaction between aldehydes and isocyanides afforded the chiral 2-hydroxy amides [19] with good stereoselectivity through a Passerini reaction [20]. A similar strategy was developed for the preparation of chiral α-hydroxy-β-amino amides from N-protected chiral amino aldehydes and isonitriles, using TFA and pyridine [21]. 3Aryl-2-hydroxy amides were synthesized by regioselective ring opening of 2,3-epoxy amides using active manganese [22]. The use of these synthetic intermediates was demonstrated in an efficient and eco-friendly one-pot metal-free synthesis of isatins by IBX [23] or H2O2 as the oxidant [24]. Indole fused 2-hydroxy amides were obtained by different strategies such as Friedel-Crafts hydroxyalkylation of indole with α-keto amides in the presence of K3PO4 and nBu4NBr in aqueous medium [25], palladium mediated coupling of ortho-halo substituted anilides with α-keto amides in toluene [26] as well as by nickel in DME and THF [27], TFA or scandium promoted intramolecular Friedel-Crafts reaction [28, 29] and zinc-catalyzed chemoselective addition [30].
Based on the literature, we decided to explore an economic and efficient process for the synthesis of 2-hydroxy-N-phenylacetamide from 2-chloro-N-phenylacetamide. To facilitate a direct nucleophilic substitution reaction, KOH was chosen as the nucleophilic partner, and was refluxed with 2-chloro-N-phenylacetamide in ethanolic medium. The progress of the reaction was observed over a period of 12 hours. Hydrolysis of the amide bond was observed as a major competing reaction which led to the formation of aniline and chloro/hydroxy acetic acid as the undesired products. This could be reasoned to the higher affinity of the hard base hydroxide towards the harder of the two electrophilic centres, the carbonyl group of the 2-chloro-N-phenylacetamide. Thus the reaction witnessed the cleavage of the starting material affording very poor yields of the desired 2-hydroxy-N-phenylacetamide upon completion (Scheme 1).
| Entry | Additive | Time (h) | Yield, 3a (%) |
|---|---|---|---|
| 1 | Cu(OAc)2 | 2 | 92 |
| 2 | Zn(OAC)2 | 8 | 74 |
| 3 | Ni(OAc)2 | 8 | 76 |
| 4 | Pb(OAc)2 | 16 | 60 |
| 5 | NaOAc | 24 | 80 |
| 6 | NH4OAc | 24 | NR |
2-Chloro-N-phenylacetamide (1.0 mmol), DIPEA (1.1 mmol), Additive (1.1 mmol), EtOH (10 mL/mmol), Reflux temp.
The cleavage of the amide in 2-chloro-N-phenylacetamide prompted us to explore milder conditions and our efforts were directed towards nucleophilic substitution of the chloride by acetate so as obtain 2-oxo-2-(phenylamino)ethyl acetate (Scheme 2). The interest stems from the fact that under basic conditions the hydrolysis of the ester would be faster than the amide and shall provide 2-hydroxy-N-phenylacetamide. With this objective, the effect of various acetates in promoting the nucleophilic substitution on 2-chloro-N-phenylacetamide was examined (Table 1). Among them, the inexpensive Cu(OAc)2 afforded impressive results and was chosen for further studies. This may be attributed to the Lewis acidic character of the Cu(OAc)2 that polarizes the carbon-halogen bond and facilitates a stronger attack by the acetate anion on the partially positive carbon centre. The subsequent hydrolysis of the acetate derivative can be achieved in the same-reaction flask by refluxing with ethanolic solution of KOH in time span of 10 minutes without affecting the amide linkage. This mild and ecofriendly procedure proceeds with a high conversion, and excellent product yields.
| Entry | Base | Time (h) | Yield, 3a (%) |
|---|---|---|---|
| 1 | TEA | 8 | 79 |
| 2 | DIPEA | 2 | 92 |
| 3 | NaH* | 4 | 60 |
| 4 | KOH | 12 | 24 |
| 5 | K2CO3 | 8 | 45 |
| 6 | NaOtBu* | 4 | 55 |
| 7 | --- | 24 | 40 |
2-Chloro-N-phenylacetamide (1.0 mmol), Base (1.1 mmol), Cu(OAc)2 (1.1 mmol), EtOH or *CH3CN (10 mL/mmol), Reflux temp.
Examination of the acetates of the three transition metals nickel, zinc, and copper indicated the efficiency of Cu(II) ions in promoting the reaction. This could be rationalized to the better chelating ability of copper when compared to the other two transition metals and the ability to have the variable + 1 and + 2 oxidation states. To augment this inference, the reaction when performed with lead acetate failed to achieve any satisfactory results. While the reaction was highly discouraging with ammonium acetate, the reaction gave good yields with NaOAc, probably due to a better ionization. However, the reaction was too slow and took 24 hours to give any appreciable yields, which defines the necessity of chelation. Considering the factors of time and yield in the conversion of 2-chloro-N-phenylacetamide to 2-oxo-2-(phenylamino)ethyl acetate, Cu(OAc)2 was chosen for further studies. We inferred that Cu(OAc)2 serves not only as an excellent Lewis acid to chelate, but also as a good acetate source for nucleophilic substitution on 2-chloro-N-arylacetamides. Optimization studies indicated the requirement of stoichiometrically equivalent amounts of the starting material, copper acetate and DIPEA.
The role of the base may be examined from the perspective of forming 2-chloro-1-(phenylamino)ethen-1-olate from the corresponding acetamide. The enolate coordinates with Cu(OAc)2 and later transforms to 2-oxo-2-(phenylamino)ethyl acetate intermediate. Different bases were examined on the model substrate, 2-chloro-N-phenylacetamide (Table 2). The reaction was poor with hydroxide and modest with sodium hydride. The use of milder non-nucleophilic bases like K2CO3 improved the course of the reaction while tertiary amines appeared more promising. With triethyl amine the yields were appreciable but the reaction took a longer duration to complete. An attempt with DIPEA gave an impressive overall yield of 92% in 2 hours. Therefore, DIPEA was employed for reactions with other 2-chloro-N-arylacetamides also.
| Entry | Solvent | Time (h) | Yield, 3a (%) |
|---|---|---|---|
| 1 | Acetonitrile | 2.5 | 76 |
| 2 | Methanol | 4 | 78 |
| 3 | Ethanol | 2 | 92 |
| 4 | THF | 24 | 20 |
| 5 | DMF | 1 | 87 |
| 6 | DMSO | 0.5 | 89 |
| 7 | 1,4 Dioxane | 24 | 22 |
2-Chloro-N-phenylacetamide (1.0 mmol), DIPEA (1.1 mmol), Cu(OAc)2 (1.1 mmol), Solvent (10 mL/mmol), Reflux temp.
Assuming the existence of the charged enolate ion stabilized as the corresponding copper enolate through which the reaction proceeds, polar solvents were expected to facilitate the reaction. Therefore, screening of the solvents was done for the transformation of 2-chloro-N-phenylacetamide to the corresponding ester intermediate (Table 3). The reaction when performed in ether solvents, THF or 1,4-dioxane did not provide good yields. However, with the polar solvents DMSO or DMF, there was a dramatic increase in the rate of the reaction as well as the yields. Satisfactory yields were obtained with acetonitrile providing an opportunity to improve the reactions still further. The results were highly impressive with the greener solvent ethanol. Being polar protic in nature, additional stabilization of the transition state by hydrogen bonding is facilitated apart from the dipolar solute-solvent interaction.
| Entry | Temp (oC) | Time (h) | Yield, 3a (%) |
|---|---|---|---|
| 1 | 0–5 | 24 | 10 |
| 2 | RT | 24 | 22 |
| 3 | 40 | 14 | 58 |
| 4 | 60 | 7 | 72 |
| 5 | 80 | 2 | 92 |
2-Chloro-N-phenylacetamide (1.0 mmol), DIPEA (1.1 mmol), Cu(OAc)2 (1.1 mmol), EtOH (10 mL/mmol)
The temperature was found to be a significant factor influencing the kinetics of the reaction (Table 4). The yields were very poor when the reactions were performed at room temperature or below. The reaction could not be driven to any significant extent even after 24 hours at these temperatures. Experiments done at further increments of 20oC witnessed high conversions, with time reductions from 14 hours to 2 hours for a temperature change from 40oC to reflux. The reactions at higher temperatures provide a significantly large concentration of the reactant molecules that could cross the energy barrier to form the 2-oxo-2-(phenylamino)ethyl acetate. With the optimized conditions of temperature and stoichiometric equivalents of Cu(OAc)2 and diisopropyl ethyl amine, 2-hydroxy-N-arylacetamides were synthesized by a one-pot two-step sequential reaction in ethanol medium through the ester intermediate. The intermediate was converted to the desired product in the same reaction flask by the addition of ethanolic solution of KOH, under reflux condition. The reactions afforded good yields in a short reaction time. Aromatic amides containing electron-donating groups provided marginally better yields than the electron-withdrawing groups (Table 5). The scalability of the reaction was examined by converting one gram of 2-chloro-N-phenylacetamide to 2-hydroxy-N-phenylacetamide, and a yield of 90% was obtained.
Based on the results obtained a mechanism was proposed for the reaction (Scheme 3). Aniline as the model substrate was treated with chloroacetyl chloride to prepare the starting material (1a) for the synthesis of 2-hydroxy-N-phenylacetamide. The amide obtained from the reaction was treated with Cu(OAc)2 and DIPEA. The abstraction of a proton from the α-carbon of 2-chloro-N-phenylacetamide by the base forms 2-chloro-1-(phenylamino)ethen-1-olate (1a1), which coordinates with Cu(OAc)2 to form the corresponding copper enolate by loss of an acetate ion and thereafter shall form the copper complex (1a2). The enolate gets neutralized by abstracting the proton from the conjugate acid of the base DIPEA. Meanwhile the C-Cl bond is polarized by the copper developing a partial positive charge on the α-carbon which facilitates the attack by the acetate anion and converting 2-chloro-1-(phenylamino)ethen-1-olate to copper coordinated 2-chloro-N-phenylacetamide (1a3) and then to 2-oxo-2-(phenylamino)ethyl acetate (2a). Further, on treatment of this intermediate (2a) with ethanolic KOH the more electrophilic ester carbonyl undergoes hydrolysis in preference to the amide, and forms the desired 2-hydroxy-N-phenylacetamide (3a). Thus, a two-step one-pot procedure which involved the nucleophilic substitution of halide with acetate and then the base mediated hydrolysis of the resulting ester intermediate afforded 2-hydroxy-N-phenylacetamide (3a) from 2-chloro-N-phenylacetamide under eco-friendly reaction conditions within a short time, and good yields.
All the chemicals were purchased from commercial suppliers and used as received. The reactions were performed in oven-dried glassware under appropriate atmosphere. The reaction is monitored by thin-layer chromatography (TLC) on 0.25 mm Merck Silica gel 60 F254 plates using UV light for visualization. The column chromatography was performed with 100–200 mesh silica gel using hexane and ethyl acetate as eluents. NMR spectra were recorded on a Jeol ECZ 400R spectrometer (1H at 400 MHz and 13C at 100 MHz) using CDCl3 or DMSO-d6 as the solvent with TMS as the internal standard. Chemical shifts (\(\delta\)) are reported relative to residual solvent signals (CDCl3, 7.25 ppm for 1H NMR and triplet centered at 77.00 ppm for 13C NMR; DMSO-d6, 2.5 ppm for 1H NMR and 39.5 ppm for 13C NMR). High resolution mass spectrometric analysis was carried out in ESI quadrupole time of flight Agilent mass spectrometer.
General procedure for the preparation of 2-hydroxy-N-phenylacetamide
To a solution of 2-chloro-N-arylacetamide (1.0 mmol) in ethanol, diisopropyl ethyl amine (0.14g, 1.1 mmol) and Cu(OAc)2.H2O (0.22g, 1.1 mmol) were added and the resulting mixture was stirred in an oil bath at reflux temperature (80oC) for 2 hours. After completion of the reaction as monitored by thin layer chromatography, KOH (0.06g, 1.1 mmol) was added to the reaction mixture and refluxed for another 10 minutes. The progress of the reaction was monitored by TLC and upon completion the reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with CH2Cl2 (3x15 mL) and washed with water. The combined organic layer was dried over anhydrous Na2SO4, evaporated under vacuum, and purified by column chromatography on silica gel (60–120 mesh) with ethyl acetate-petroleum ether mixture (30:70) as the eluting solvent to obtain the desired product.
2-Hydroxy-N-phenylacetamide (3a)
White solid; Yield: 92%; m.p.: 74–76℃; 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.49–7.54 (m, 2H), 7.29–7.34 (m, 2H), 7.10–7.15 (m, 1H), 4.17 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 170.12, 136.91, 129.20, 124.93, 120.11, 62.50; HRMS (ESI): C8H7Cl2NO2 [M + H]+; calculated: 152.0633; found: 152.0744.
N-(2-chlorophenyl)-2-hydroxyacetamide (3b)
White solid; Yield: 88%; m.p.: 90–92℃; 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.12–8.20 (m, 1H), 7.46–7.51 (m, 1H), 7.29–7.34 (m, 1H), 7.09–7.14 (m, 1H), 3.99 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 170.22, 133.81, 129.26, 127.81, 125.22, 123.41, 121.53, 62.78; HRMS (ESI): C8H8ClNO2 [M + H]+; calculated: 186.0244; found: 186.0357.
N-(3-chlorophenyl)-2-hydroxyacetamide (3c)
White solid; Yield: 87%; m.p.: 104–106℃; 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.62–7.72 (m, 1H), 7.34–7.43 (m, 1H), 7.23–7.27 (m, 1H), 7.05–7.13 (m, 1H), 4.22 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 169.46, 138.18, 134.85, 130.16, 124.83, 120.00, 117.84, 62.60; HRMS (ESI): C8H8ClNO2 [M + H]+; calculated: 186.0244; found: 186.0339.
N-(4-fluorophenyl)-2-hydroxyacetamide (3d)
Pale yellow solid; Yield: 85%; m.p.: 90–92℃; 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.45–7.52. (m, 2H), 6.97–7.05 (m, 2H), 4.19 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 169.39, 138.86, 135.45, 124.71, 118.07, 62.59; HRMS (ESI): C8H8FNO2 [M + H]+; calculated: 170.0539; found: 170.0634.
N-(4-chlorophenyl)-2-hydroxyacetamide (3e)
White solid; Yield: 87%; m.p.: 144–146℃; 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.48–7.57 (m, 2H), 7.28–7.32 (m, 2H), 4.26 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 171.64, 138.04, 129.02, 127.51, 121.70, 62.41; HRMS (ESI): C8H8ClNO2 [M + H]+; calculated: 186.0244; found: 186.0329.
N-(4-bromophenyl)-2-hydroxyacetamide (3f)
White solid; Yield: 84%; m.p.: 170–172℃; 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.46–7.51 (m, 2H), 7.41–7.46 (m, 2H), 4.25 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 171.66, 138.44, 131.92, 122.08, 115.55, 62.45; HRMS (ESI): C8H8BrNO2 [M + H]+; calculated: 229.9738; found: 229.9831.
2-Hydroxy-N-(o-tolyl)acetamide (3g)
White solid; Yield: 89%; m.p.: 112–114℃; 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 7.75–7.81 (m, 1H), 7.14–7.20 (m, 2H), 7.03–7.09 (m, 1H), 4.09 (s, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.83, 134.75, 130.67, 129.42, 126.85, 125.67, 122.74, 62.49, 17.55; HRMS (ESI): C9H11NO2 [M + H]+; calculated: 166.0790; found: 166.0932.
2-Hydroxy-N-(m-tolyl)acetamide (3h)
White solid; Yield: 90%; m.p.: 96–98℃; 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.35 (s, 1H), 7.29–7.33 (m, 1H), 7.17–7.22 (m, 1H), 6.91–6.97 (m, 1H), 4.16 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.99, 139.13, 136.84, 128.98, 125.70, 120.72, 117.18, 62.51, 21.49; HRMS (ESI): C9H11NO2 [M + H]+; calculated: 166.0790; found: 166.0878.
2-Hydroxy-N-(p-tolyl)acetamide (3i)
White solid; Yield: 90%; m.p.: 76–78℃; 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.78–7.85 (m, 1H), 7.13–7.21 (m, 2H), 7.03–7.10 (m, 1H), 4.13 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.52, 130.68, 126.89, 125.60, 122.64, 62.56, 17.58; HRMS (ESI): C9H11NO2 [M + H]+; calculated: 166.0790; found: 166.0912.
2-Hydroxy-N-(4-methoxyphenyl)acetamide (3j)
White solid; Yield: 92%; m.p.: 102–104℃; 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.40–7.44 (m, 2H), 6.83–6.86 (m, 2H), 4.17 (s, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.68, 156.82, 130.08, 121.86, 114.33, 62.49, 55.55; HRMS (ESI): C9H11NO3 [M + H]+; calculated: 182.0739; found: 182.0869.
2-Hydroxy-N-(2-methoxyphenyl)acetamide (3k)
White solid; Yield: 91%; m.p.: 108–110℃; 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.31–8.36 (m, 1H), 7.03–7.07 (m, 1H), 6.92–6.96 (m, 1H), 6.85–6.88 (m, 1H), 4.21 (s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.78, 148.38, 126.81, 124.36, 121.12, 120.00, 110.20, 62.78, 55.78; HRMS (ESI): C9H11NO3 [M + H]+; calculated: 182.0739; found: 182.0849.
N-(2,4-dimethylphenyl)-2-hydroxyacetamide (3l)
White solid; Yield: 92%; m.p.: 76–78℃; 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 7.43 (d, 1H), 6.98 − 7.00 (m, 1H), 6.92–6.95 (m, 1H), 3.95 (s, 2H), 2.20 (s, 3H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.67, 135.40, 132.12, 131.31, 129.56, 127.35, 122.94, 62.47, 20.93, 17.53; HRMS (ESI): C10H13NO2 [M + H]+; calculated: 180.0946; found: 180.1109.
N-(2,6-dimethylphenyl)-2-hydroxyacetamide (3m)
White solid; Yield: 92%; m.p.: 78–80℃; 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.06–7.08 (d, 1H), 7.03–7.06 (m, 2H), 4.09 (s, 2H), 2.17 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 171.08, 135.44, 132.90, 128.31, 127.65, 62.21, 18.34; HRMS (ESI): C10H13NO2 [M + H]+; calculated: 180.0946; found: 180.1100.
N-(2,3-dichlorophenyl)-2-hydroxyacetamide (3n)
White solid; Yield: 82%; m.p.: 138–140℃; 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 8.32–8.37 (m, 1H), 7.19–7.23 (m, 2H), 4.28 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 169.88, 135.55, 132.97, 127.93, 125.72, 121.87, 119.28, 62.88; HRMS (ESI): C8H7Cl2NO2 [M + H]+; calculated: 219.9854; found: 219.9959.
N-(3,5-dichlorophenyl)-2-hydroxyacetamide (3o)
White solid; Yield: 82%; m.p.: 72–74℃; 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.53 (d, 2H), 7.12 (t, 1H), 4.24 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 169.39, 138.86, 135.45, 124.71, 118.07, 62.59; HRMS (ESI): C8H7Cl2NO2 [M + H]+; calculated: 219.9854; found: 219.9955.
N-(2-fluorophenyl)-2-hydroxyacetamide (3p)
Pale yellow solid; Yield: 85%; m.p.: 84–86℃; 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.83–8.02 (m,1H), 7.19–7.36 (m, 1H), 7.07–7.19 (m, 2H), 4.00 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 170.59, 154.12, 151.69, 125.22, 121.97, 115.23, 115.04, 62.56; HRMS (ESI): C8H8FNO2 [M + H]+; calculated: 170.0539; found: 170.0634.
An efficient and eco-friendly one-pot two-step procedure was developed for the synthesis of 2-hydroxy-N-arylacetamides from 2-chloro-N-arylacetamides using Cu(OAc)2 and diisopropyl ethyl amine in ethanolic medium under reflux condition. The reaction proceeds through nucleophilic substitution of chloride by acetate to form 2-oxo-2-(phenylamino)ethyl acetate, which was then converted to the desired product by ethanolic KOH solution and refluxing for another 10 minutes. Both electron-donating and withdrawing substituents on the arylamide were well tolerated and excellent yields were obtained in a short duration of time. No amide cleaved products were observed during this procedure and could easily be scaled up. The procedure also employs ecofriendly conditions with inexpensive reagents making it attractive both in terms of ease of operation and economy.
Ethical Approval
Not Applicable - No human and/ or animal studies. involved
Competing Interests
The authors declare no conflict of interest either of a financial or personal nature)
Authors' Contributions
V.Y.R – Synthesis of the compounds
G.L.K – Characterization of the compounds
B.S.V – Analysis of the compounds
V.A.N. – Manuscript review and Correspondence
Funding
We acknowledge with gratitude the funding received in the form of a research grant (Grant No. 02/0447/21/EMR-II) from the Human Resource Development Group, Council of Scientific and Industrial Research, Government of India.
Availability of data and materials
Experimental Details, 1H NMR, 13C NMR and High Resolution Mass Spectra of all the synthesized compounds can be found in the Electronic Supplementary Content of this article.
- C. Lamberth, A. Jeanguenat, F. Cederbaum, A.D. Mesmaeker, M. Zeller, H.J. Kempf, R. Zeun, Bioorg. Med. Chem. 16, 1531 (2008)
- S. Y. Park, I.S. Hwang, H.J. Lee, C.E. Song, Nature Commun. 8, 14877 (2017)
- A.A. Mishra, B.M. Bhanage, New J. Chem. 43, 6160 (2019)
- N.C. Mamillapalli, G. Sekar, Chem. Commun. 50, 7881 (2014)
- A. Muthukumar, N.C. Mamillapalli, G. Sekara, Adv. Synth. Catal. 358, 643 (2016)
- N.C. Mamillapalli, G. Sekar, RSC Adv. 4, 61077 (2014)
- F. Hao, Z. Gu, G. Liu, W. Yao, H. Jiang, J. Wu, Eur. J. Org. Chem. 34, 5985 (2019)
- J.M. Hung, H.J. Arabshahi, E. Leung, J. Reynisson, D. Barker, Eur. J. Med. Chem. 86, 420 (2014)
- Y. Yao, W. Tonga, J. Chen, Mendeleev Commun. 24, 176 (2014)
- T. Soeta, Y. Kojima, Y. Ukaji, K. Inomata, Tetrahedron Lett. 52, 2557 (2011)
- M. Zhang, S. Imm, S. Bahn, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 50, 11197 (2011)
- Y. Salinas, R.M. Oliart, M. Ramírez-Lepe, A. Navarro-Ocaña, G. Valerio-Alfaro, Appl. Microbiol. Biotechnol. 75, 297 (2007)
- T. Nemoto, H. Kakei, V. Gnanadesikan, S. Tosaki, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc. 124, 14544 (2002)
- S.V. Pelt, F.V. Rantwijk, R.A. Sheldon, Adv. Synth. Catal. 351, 397 (2009)
- G. Valerio-Alfaro, H.S. Garc´ıa, H. Luna, R.C. Almanza, Biotechnology Lett. 22, 575 (2000)
- B. Ma, T. Miao, Y. Sun, Y. He, J. Liu, Y. Feng, H. Chen, Q.H. Fan, Chem. Eur. J. 20, 9969 (2014)
- N.C. Mamillapalli, G. Sekar, Chem. Eur. J. 21, 18584 (2015)
- H. Xu, C. Wolf, Angew. Chem. Int. Ed. 50, 12249 (2011)
- S.E. Denmark, Y. Fan, J. Am. Chem. Soc. 125, 7825 (2003)
- S.E. Denmark, Y. Fan, J. Org. Chem. 70, 9667 (2005)
- J.E. Semple, T.D. Owens, K. Nguyen, O.E. Levy, Org. Lett. 2, 2769 (2000)
- J.M. Concellon, P.L. Bernad, H. Rodriguez-Solla, P. Diaz, Adv. Synth. Catal. 351, 2178 (2009)
- Y. Wang, X. Cheng, Z. Zhan, X. Ma, R. Nie, L. Hai, Y. Wu, RSC Adv. 6, 2870 (2016)
- J. Li, X. Cheng, X. Ma, G. Lv, Z. Zhan, M. Guan, Y. Wu, Synlett. 27, 2485 (2016)
- A. Muthukumar, G. Sekar, J. Org. Chem. 83, 8827 (2018)
- I. Shin, S.D. Ramgren, M.J. Krische, Tetrahedron 71, 5776 (2015)
- J.X. Hu, H. Wu, C.Y. Li, W.J. Sheng, Y.X. Jia, J.R. Gao, Chem. Eur. J. 17, 5234 (2011)
- I. Gorokhovik, L. Neuville, J. Zhu, Org. Lett. 13, 5536 (2011)
- H.L. Wang, Y.M. Li, G.W. Wang, H. Zhang, S.D. Yang, Asian J. Org. Chem. 2, 486 (2013)
- A. Muthukumara, G. Sekar, Org. Biomol. Chem. 15, 691 (2017)
Schemes 1 to 3 are available in the Supplementary Files section
No competing interests reported.
- GA.png
Graphical Abstract
- SupportingInformation.docx
- Scheme1.png
Scheme 1. Reaction of 2-chloro-N-phenylacetamide with ethanolic KOH solution
- Scheme2.png
Scheme 2. Synthesis of 2-hydroxy-N-phenylacetamide
- Scheme3.png
Scheme 3. A plausible mechanism for the formation of 2-hydroxy-N-phenylacetamide
