Sulfanilic acid catalysed one pot three component mannich reaction for synthesis of β amino ketones

Cite this paper: Vietnam J Chem., 2020, 58(5), 675-687 Article DOI: 10.1002/vjch.202000090 Sulfanilic acid catalysed one-pot three-component Mannich reaction for synthesis of β-amino ketones Pramod Kulkarni Department of Chemistry, Hutatma Rajguru Mahavidyalaya, Rajgurunagar, Pune-410505, MS India Submitted June 1, 2020; Accepted August 18, 2020 Abstract We have reported sulfanilic acid as an exceedingly competent catalyst for one-pot Mannich reaction to give βamino carbonyl compounds in good to excellent yield within a short reaction time The various organic acids have screened; like gallic acid, 4-hydroxy benzoic acid, 4-amino benzoic acid, phenylacetic acid, chloroacetic acid, sulfosalicylic acid, sulfanilic acid, chloro benzoic acid, phthalic acid, salicylic acid, cinnamic acid, hippuric acid, 1naphthyl acetic acid, o-amino benzoic acid, p-TSA, succinic acid, malic acid, and among them sulfanilic acid is a suitable catalyst The reaction condition was optimized with respect to the solvent, the amount of catalyst as well as the variation of the ketone, aldehyde, and amine substrates The procedure is mild, effective, ecofriendly, and the use of the minimum amount of catalyst Keywords Aldehydes, amino ketone, organic acid, multicomponent, Mannich reaction INTRODUCTION Multicomponent reaction is unique important reactions in organic synthesis These reactions in the last two decades have acknowledged the consideration of organic chemists because of various merits over conventional traditional synthesis Multicomponent reactions have significant applications in medicinal chemistry for the creation of diverse scaffolds and combinatorial libraries for drug development.[1] In the multicomponent reactions, three or more components have been reacted to form preferably one product, which has been containing the crucial units of all the original materials MCRs have been good for the environment by decreasing the number of synthetic steps, energy consumption, and waste creation Therefore, the discovery of novel MCRs and elaborating on the formerly known MCRs are substantial attention Individual example of, this type is the preparation of β-amino carbonyl compounds by the Mannich reaction Several βamino ketones and their analogues, show the effective medicinal properties[2-13] are shown in figure β-amino ketones, have vital intermediates in the preparation of various nitrogen-containing natural products, and pharmaceutically important compounds.[14] It is evidence that the reaction comprises two equilibrating constituents (imine formation and enol 675 Wiley Online Library tautomerization) and therefore, demands harsh reaction conditions Due to this, it is afflicted by some severe weaknesses, namely complex work-up, and purification procedures, and unwanted side products.[15] From the first report of the Mannich reaction, numerous studies have published to improve the reaction conditions and present new and efficient catalysts for this reaction The Mannich reactions of ketones, aldehydes, and amines have been reported through Lewis acid,[16-19] Lewis base,[20] Brønsted acids,[21-23] Metal Triflates,[24-27] and transition metal salts.[28-30] Even with the merits of these methodologies; use of transition metal compounds and heavy metal compounds as the catalyst, preparation of the catalyst, problems recycling and reusing of the catalysts, toxic reagents, and solvents, drastic reaction conditions, toxicity, or difficulty in product separation has persisted disquiets Hence, the exploration of the newfangled green method has stagnant being keenly pursued On the other hand, because of growing concerns about environmental effects; execution of organic reactions using organocatalyst has extremely needed in recent years Apart from being environmentally friendly, organocatalyst has obeyed green chemistry principle like casings mild conditions, consequently saving energy, oxygen-stable reagents and does not require anhydrous conditions, reducing the cost of the synthesis, less toxic and safer substances, stop the creation of metallic waste and avoids traces of © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH Vietnam Journal of Chemistry metals in the products.[31] Here, we have used Sulfanilic acid as organocatalyst in a one-pot three- Pramod Kulkarni component Mannich reaction for the synthesis of βamino ketone Figure 1: Medicinal properties of β-amino ketone Sulfanilic acid is valuable, low-cost, and ecofriendly, and occurs as a grayish-white powder, which is stable and incompatible with strong oxidizing agents The literature survey reveals that it has been applied as a catalyst for the synthesis of a variety of heterocyclic compounds.[32-39] The sulfanilic acid that occurs in solid form is present as a zwitterion Sulfonic acid groups (-SO3H) can be deprotonated to become negative sulfonate (-SO3-) and amino groups which can be protonated to become positive ammonium groups (-NH3+) The zwitterionic property of sulfanilic acid may be responsible for the excellent catalytic property in organic synthesis Sulfanilic acid is commercially available, economical, non polluting and easy to handle, non-inflammable, and a stable catalyst related to other organoacid catalysts which are eroding, costly and afford intensely acidic conditions.[40] Here we reported the use of sulfanilic as organocatalyst in one-pot three-component Mannich reaction for the synthesis of β-amino ketone recorded at ambient temperature on a BRUKER AVANCE DRX-500 MHz spectrophotometer using CDCl3 as the solvent and TMS as an internal standard The purity of newly synthesized compounds and the changes of reaction were observed by thin layer chromatography (TLC) on Merck pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light MATERIALS AND METHODS Spectral data of synthesized compounds All the starting materials were got from commercially accessible sources and used without further purification Melting points were measured by open capillary technique and are uncorrected FTIR spectra were noted on alpha T BRUKER model 1H-NMR and 13C-NMR spectra were 2-[(3,7-dimethyl-1-(phenylamino)octa-2,6-dien1-yl)] cyclohexanone (table Entry 3, 4c): Yield 45 %, m p 127-129 ºC IRνmax cm-1: 1567, 1630, 1702, 3362 1H-NMR (500 MHz, CDCl3, δ ppm): 1.73 (s, 9H), 1.78-1.125 (m, 2H), 1.911.82 (m, 4H), 2.08-2.03 (m, 4H), 2.35-2.28 (m, 2H), 2.70-2.65 (m, 1H), 4.85 (br, s, 1H), 4.85- General preparative procedure of β-Amino ketone: A mixture of ketone (5 mmol), substituted benzaldehyde (5mmol), substituted aniline (5mmol) and sulfanilic acid (20 mol%) in 10 mL ethanol was stirred at room temperature for the respective time specified in tables and The progress of the reaction was checked by TLC Subsequent completion of the reaction, the reaction mass is poured on crushed ice The precipitate was filtered off, and washed with cold ethanol and dried in air to get pure product The solid product was purified by recrystallization in the ethanol and the oily product was purified by column chromatography © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 676 Vietnam Journal of Chemistry 4.80 (m, 1H), 5.28-5.23 (m, 1H), 5.52-5.46 (m, 1H), 6.62-6.57 (m, 2H), 6.73-6.69 (m, 1H), 7.067.01 (m, 2H); 13C NMR (125 MHz, CDCl3, δ ppm): 20.4, 22.1, 24.8, 25.0, 25.1, 25.8, 27.1, 40.4, 41.5, 48.8, 54.9, 113.1, 117.3, 123.8, 129.7, 131.6, 134.1, 135.3, 147.3, 210.8 ESIMS (m/z): 325.24 (M+), 326.22 (M+1)+ Anal Calcd for C22H31NO: C 81.18, H 9.60, and N 4.30%; found C 81.15, H 959, and N 4.24 % 2-[(3-hydroxy-4-methoxyphenyl) (phenylamino) methyl)] cyclohexanone (table Entry 5, 4e): Yield 84 %, m p 157 ºC IRνmax cm-1: 1278, 1704, 3308; 1H-NMR (500 MHz, CDCl3, δ ppm): 1.70-1.65 (m, 2H), 1.92-1.81 (m, 4H), 2.40-2.34 (m, 2H), 2.66-2.63 (m, 1H), 3.87 (s, 3H), 4.76 (br, s, 1H), 4.73-4.67 (m, 1H), 6.636.58 (m, 2H), 6.71-6.68 (m, 1), 6.90-6.84 (m, 3H), 7.03-6.98 (m, 2H), 11.44 (s, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 24.3, 24.9, 25.3, 41.7, 55.9, 56.2, 57.6, 113.4, 114.6, 116.5, 117.6, 121.7, 129.3, 134.8, 142.4, 147.2, 151.3, 211.2 ESI-MS (m/z): 325.17 (M+), 326.30 (M+1)+ Anal Calcd for C20H23NO3: C 73.82, H 7.12, and N 4.30 %; found C 73.76, H 7.11, and N 4.26 % 2-[3-phenyl-1-(phenylamino)prop-2-en-1yl]cyclohexanone (table Entry 7, 4g): Yield 82 %, m p 127-128 ºC IRνmax cm-1: 1534, 1706, 3352; 1H-NMR (500 MHz, CDCl3, δ ppm): 1.71-1.67 (m, 2H), 1.94-1.88 (m, 4H), 2.43-2.38 (m, 2H), 2.73-2.67 (m, 1H), 4.90 (br, s, 1H), 4.94-4.89 (m, 1H), 6.23-6.21 (dd, J = Hz, 14.5 Hz, 1H), 6.50-6.45 (m, 2H), 6.57-6.54 (d, J = 14.5 Hz, 1H), 6.62-6.58 (m, 1H), 7.02-7.98 (d, J = 8.3 Hz, 2H) 7.34-7.26 (m, 5H); 13C NMR (125 MHz, CDCl3, δ ppm): 25.5, 25.9, 26.7, 41.6, 54.1, 55.3, 113.2, 116.8, 126.7, 127.8, 128.4, 129.1, 129.8, 135.4, 135.9, 147.9, 210.9 ESIMS (m/z) : 305.16 (M+), 306.23 (M+1)+ Anal Calcd for C21H23NO: C 82.58, H 7.59, and N 4.59 %; found C 82.57, H 7.57, and N 4.56 % 2-[(5-bromo-2hydroxyphenyl)(phenylamino)methyl]cyclohexa none (table Entry 9, 4i): Yield 76 %, m p 1125-177 ºC IRνmax cm-1: 1698, 3356, 3408; 1HNMR (500 MHz, CDCl3, δ ppm): 1.63-1.57 (m, 2H), 1.86-1.80 (m, 4H), 2.38-2.33 (m, 2H), 2.842.81 (m, 1H), 4.34 (br, s, 1H), 4.68-4.64 (m, 1H), 6.53-6.48 (m, 2H), 6.61-6.58 (m, 1H), 6.656.62 (d, J = 8.3 Hz 1H), 7.06-7.02 (m, 2H), 7.13-7.08 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 7.197.15 (d, J = 2.4 Hz, 1H), 11.32 (s, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 24.2, 24.8, Sulfanilic acid catalysed one-pot three-component… 25.6, 41.6, 55.6, 56.9, 113.8, 115.3, 118.2, 118.9, 129.9, 130.3, 130.8, 134.6, 147.3, 153.6, 211.3 ESI-MS (m/z): 373.07 (M+), 374.11 (M+1)+ Anal Calcd for C19H20BrNO2: C 60.97, H 5.39, Br 21.35 and N 3.74 %; found C 60.95, H 5.38, Br 21.34 and N 3.73 % 2-[(3-hydroxyphenyl) (phenylamino) methyl]cyclohexanone (table Entry 10, 4j): Yield 80 %, m.p 171-172 ºC IRνmax cm-1: 1695, 3340, 3414; 1H-NMR (500 MHz, CDCl3, δ ppm): 1.60-1.55 (m, 2H), 1.83-1.78 (m, 4H), 2.32-2.28 (m, 2H), 2.77-2.73 (m, 1H), 4.18 (br, s, 1H), 4.56-4.53 (m, 1H), 6.45-6.40 (m, 2H), 6.54-6.51 (m, 1H), 6.62-6.59 (m, 1H), 6.66-6.63 (m, 1H), 6.70-6.67 (m, 1H), 7.06-7.02 (m, 3H), 11.56(s, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 23.7, 24.5, 25.2, 40.9, 56.2, 57.4, 112.7, 113.2, 113.7, 116.8, 120.4, 128.4, 130.7, 141.5, 146.9, 158.1, 211.7 ESI-MS (m/z): 295.16 (M+), 296.11 (M+1)+ Anal Calcd for C19H21NO2: C 77.26, H 7.17 and N 4.74 %; found C 77.25, H 7.14 and N 4.73 % 3-(anthracen-9-yl)-1-phenyl-3(phenylamino)propan-1-one (table Entry 1, 8a): Yield 76 %, m.p 212 ºC IRνmax cm-1: 1692, 3323; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.05-2.98 (d, J = Hz, 2H), 4.67-4.62 (br s, 1H), 5.04-5.01 (t, J = Hz, 1H), 6.43-6.39 (m, 2H), 6.52-6.49 (m, 1H), 7.01-6.98 (m, 2H), 7.32-7.28 (m, 2H), 7.38-7.35 (m, 2H), 7.44-7.41 (m, 2H), 7.48-7.45 (m, 1H), 7.54-7.51 (s, 1H), 7.64-7.61 (m, 2H), 7.76-7.72 (m, 2H), 7.93-9.90 (m, 2H); 13 C NMR (125 MHz, CDCl3, δ ppm): 51.3, 73.6, 112.8, 117.6, 124.8, 125.7, 126.3, 126.8, 127.3, 127.9, 128.2, 128.8, 128.9, 129.4, 129.6, 130.3, 133.4, 134.2, 136.4, 137.5, 147.8, 200.4 ESIMS (m/z): 401.19 (M+), 402 22 (M+1)+ Anal Calcd for C29H23NO: C 86.125, H 5.77 and N 3.49%; found C 86.74, H 5.76 and N 3.45% 3-(2,5-dimethoxyphenyl)-1-phenyl-3(phenylamino)propan-1-one (table Entry 3, 8c): Yield 82 %, m.p 212 ºC IRνmax cm-1: 1265, 1340, 1634, 1684, 3393; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.14-3.10 (d, J = 6.8 Hz, 2H), 3.84 (s, 3H), 3.91 (s, 3H), 4.55-4.51 (br s, 1H), 4.96-4.93 (t, J = Hz, 1H), 6.43-6.39 (m, 2H), 6.63-6.45 (m, 5H), 7.07-7.04 (s, 1H), 7.18-7.12 (m, 2H), 7.56-7.42 (m, 3H), 7.88-7.83 (m, 2H); 13 C NMR (125 MHz, CDCl3, δ ppm): 47.5, 55.6, 55.8, 74.1, 111.8, 112.5, 114.3, 115.4, 117.9, 128.6, 129.1, 132.0, 133.5, 136.7, 147.1, 147.8, 148.1, 151.2, 154.2, 200.2 ESI-MS (m/z): 361.17 (M+), 362 19 (M+1)+ Anal Calcd for © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 677 Vietnam Journal of Chemistry C23H23NO3: C 76.43, H 6.41 and N 3.88 %; found C 76.37, H 6.38 and N 3.87 % 3-(4-nitrophenylamino-3-(4-methoxyphenyl)-1phenylpropan-1-one (table Entry 6, 8f): Yield 82 %, m.p 137-139 ºC IRνmax cm-1: 1238, 1367, 1424, 1457, 1611, 1687, 3368; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.34-3.34 (d, J = 6.4 Hz, 2H), 3.92 (s, 3H), 4.80-4.125 (br s, 1H), 5.175.12 (t, J = 6.4 Hz, 1H), 6.72-6.67 (d, J = 8.2 Hz, 2H), 6.80-6.77 (d, J = 7.8 Hz, 2H), 7.046.97 (d, J = 7.8 Hz, 2H), 7.38-7.34 (m, 2H), 7.47-7.43 (m, 1H), 7.84-7.80 (m, 2H), 8.04-7.99 (d, J = 8.2 Hz, 2H); 13C-NMR (125 MHz, CDCl3, δ ppm): 50.3, 55.6, 72.5, 114.3, 114.8, 121.5, 127.8, 128.3, 128.8, 133.5, 135.7, 136.6, 153.5, 158.9, 200.3 ESI-MS (m/z): 376.14 (M+), 377.16 (M+1)+ Anal Calcd for C22H20N2O4: C 70.20, H 5.36, and N 7.44 %; found C 70.19, H 5.36, and N 7.46 % 3-(2-mercaptophenylamino)-3-(3hydroxyphenyl)-1-phenylpropan-1-one (table Entry 7, 8g): Yield 70 %, m.p 118 ºC IRνmax cm-1: 1243, 1373, 1428, 1443, 1620, 1682, 2569, 3359; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.23-3.17 (d, J = 7.6 Hz, 2H), 4.04 (s, -SH, 1H), 4.76-4.72 (br s, 1H), 5.06-4.99 (t, J = 7.6 Hz, 1H), 6.30-6.27 (m, 1H), 6.43-6.38 (m, 1H), 6.56-6.48 (m, 2H), 6.65-6.62 (m, 1H), 6.84-6.81 (m, 1H), 6.94-6.91 (m, 1H), 7.06-7.03 (m, 1H), 7.32-7.28 (m, 2H), 7.42-7.39 (m, 1H), 7.86-7.81 (m, 2H), 11.87 (s, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 52.4, 71.7, 112.4, 113.2, 113.8, 116.5, 117.6, 119.2, 125.2, 128.3, 128.9, 130.7, 133.1, 136.9, 144.3, 144.9, 158.5, 200.1 ESIMS (m/z): 349.11 (M+), 350.15 (M+1)+ Anal Calcd for C21H19NO2S: C 72.18, H 5.48, N 4.01 and S 9.18 %; found C 72.17, H 5.42, N 3.99 and S 9.17 % 10 3-(2-chlorophenylamino)-3-(3-hydroxyphenyl)1-phenylpropan-1-one (table Entry 8, 8h): Yield 73 %, m.p 108 ºC IRνmax cm-1 1437, 1614, 1678, 3367; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.27-3.24 (d, J = 6.9 Hz, 2H), 4.68-4.64 (br s, 1H), 4.97-4.92 (t, J = 6.9 Hz, 1H), 6.336.30 (m, 1H), 6.47-6.43 (m, 1H), 6.60-6.53 (m, 2H), 6.68-6.64 (m, 1H), 6.88-6.84 (m, 1H), 6.966.93 (m, 1H), 7.09-7.04 (m, 1H), 7.35-7.32 (m, 2H), 7.44-7.41 (m, 1H), 7.89-7.85 (m, 2H), 11.70(s, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 52.8, 71.9, 112.8, 113.6, 113.9, 118.4, 119.5, 122.8, 125.7, 128.4, 129.6, 130.4, 133.4, 137.6, 144.6, 145.4, 157.6, 200.6 ESI-MS (m/z): 351.11 (M+), 352.12 (M+1)+ Anal Calcd for Pramod Kulkarni C21H18ClNO2: C 71.69, H 5.16, Cl 10.8 and N 3.98 %; found C 71.64, H 5.15, Cl 10.7 and N 3.97 11 3-(benzo[d]thiazol-2-ylamino)-3-(4bromophenyl)-1-phenylpropan-1-one (table Entry 9, 8i): Yield 40 %, m.p 145-147 ºC IRνmax cm-1 1456, 1625, 1674, 3354; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.06-2.99 (d, J = 7.2 Hz, 2H), 4.84-4.80 (br s, 1H), 5.04-4.97 (t, J = 7.2 Hz, 1H), 7.06-7.03 (d, J = 8.4, 2H), 7.307.26 (m, 2H), 7.42-7.40 (d, J = 8.4, 2H), 7.487.45 (m, 1H), 7.60-7.56 (m, 2H), 7.93-7.90 (m, 2H), 8.14-8.10 (m, 1H), 8.28-8.21 (m, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 53.4, 72.6, 121.6, 122.2, 122.7, 124.8, 125.8, 126.3, 128.4, 129.1, 131.9, 133.7, 136.2, 142.3, 149.1, 174.6, 200.2 ESI-MS (m/z): 437.42 (M+), 438.46 (M+1)+ Anal Calcd for C22H17BrN2OS: C 60.42, H 3.92, Br 18.27, N 6.41 and S 7.33 %; found C 60.43, H 3.90, Br 18.24, N 6.40 and S 7.32 % 12 3-(4-(trifluoromethyl)phenylamino)-1,5diphenylpent-4-en-1-one (table Entry 10, 8j): Yield 33 %, m.p 140-142 ºC IRνmax cm-1 1630, 1683, 3373; 1H-NMR (500 MHz, CDCl3, δ ppm): 2.83-2.68 (d, J = 7.2 Hz, 2H), 3.78-3.68 (dt, J = 7.2 Hz, 6.4 Hz, 1H), 4.20-4.12 (br s, 1H), 6.16-6.12 (dd, J = 15.3 Hz, 6.4 Hz, 1H), 6.32-6.28 (d, J = 8.3 Hz, 2H), 6.45-6.42 (d, J = 15.3 Hz, 1H), 7.10-7.05 (m, 1H), 7.18-7.14 (m, 2H), 7.29-7.25 (d, J = 8.3 Hz, 2H), 7.52-7.38 (m, 5H), 7.88-7.81 (m, 2H); 13C NMR (125 MHz, CDCl3, δ ppm): 51.2, 53.6, 113.4, 119.8, 124.1, 126.6, 127.1, 128.4, 128.7, 128.8, 129.3, 133.6, 135.7, 137.1, 151.2, 200.9 ESI-MS (m/z): 395.12 (M+), 396.17 (M+1)+ Anal Calcd for C24H20F3NO: C 72.90, H 5.10, F 14.41 and N 3.54 %; found C 72.87, H 5.09, F 14.39 and N 3.52 13 3-(4H-1,2,4-triazol-4-ylamino)-1,5diphenylpent-4-en-1-one (table Entry 11, 8k): Yield %, m.p 109-111 ºC IRνmax cm-1 1610, 1645, 1688, 3356; 1H-NMR (500 MHz, CDCl3, δ ppm): 2.78-2.61 (d, J = 7.6 Hz, 2H), 3.72-3.60 (dt, J = 7.6 Hz, 6.9 Hz, 1H), 4.15-4.05 (br s, 1H), 6.20-6.15 (dd, J = 15.9 Hz, 6.9 Hz, 1H), 6.49-6.45 (d, J = 15.9 Hz, 1H), 7.33-7.12 (m, 5H), 7.48-7.37 (m, 3H), 7.89-7.85 (m, 2H), 8.228.18 (s, 2H); 13C NMR (125 MHz, CDCl3, δ ppm): 49.2, 51.1, 126.6, 127.7, 128.2, 128.5, 128.8, 129.3, 129.6, 133.4, 135.9, 137.0, 144.6, 200.3 ESI-MS (m/z): 318.20 (M+), 319.21 (M+1)+ Anal Calcd for C19H18N4O: C 71.68, © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 678 Vietnam Journal of Chemistry H 5.70, and N 17.60 %; found C 71.67, H 5.66, and N 17.58 14 3-(4-fluorophenylamino)-1,5-diphenylpent-4-en1-one (table Entry 12, 8l): Yield 82 %, m p 126-128 ºC IRνmax cm-1 1623, 1679, 3368; 1HNMR (500 MHz, CDCl3, δ ppm): 2.80-2.65 (d, J = 7.5 Hz, 2H), 3.72-3.60 (dt, J = 7.5 Hz, 6.9 Hz, 1H), 4.73-4.65 (br s, 1H), 6.21-6.17 (dd, J = 15.6 Hz, 6.9 Hz, 1H), 6.37-6.33 (d, J = 7.9 Hz, 2H), 6.48-6.44 (d, J = 15.6 Hz, 1H), 6.85-6.81 (d, J = 7.9 Hz, 2H), 7.36-7.21 (m, 5H), 7.567.41 (m, 3H), 7.86-7.81 (m, 2H); 13C NMR (125 MHz, CDCl3, δ ppm): 50.7, 53.3, 115.3, 116.7, 126.9, 127.8, 128.1, 128.5, 128.8, 128.9, 129.7, 133.3, 135.1, 136.6, 144.3, 151.6, 200.5 ESIMS (m/z): 345.17 (M+), 346.18 (M+1)+ Anal Calcd for C23H20FNO: C 79.98, H 5.84, F 5.50 and N 4.06 %; found C 79.97, H 5.49, F 5.52 and N 4.05 % 15 3-(1-phenylethylamino)-1,5-diphenylpent-4-en1-one (table Entry 13, 8m): Yield 78 %, m p 134-137 ºC IRνmax cm-1 1612, 1676, 3338; 1HNMR (500 MHz, CDCl3, δ ppm): 1.27-1.22 (d, J = 6.8Hz, 3H), 2.74-2.68 (d, J = 7.8 Hz, 2H), 3.69-3.54 (dt, J = 7.8 Hz, 6.2 Hz, 1H), 4.55-4.43 (br s, 1H), 4.87-4.83 (q, J = 6.8 Hz, 1H), 6.156.12 (dd, J = 15.1 Hz, 6.2 Hz, 1H), 6.43-6.38 (d, J = 15.1 Hz, 1H), 7.27-7.05 (m, 10H), 7.53-7.41 (m, 3H), 7.91-7.88 (m, 2H); 13C NMR (125 MHz, CDCl3, δ ppm): 21.4, 47.3, 51.4, 55.5, 126.1, 127.4, 127.6, 128.2, 128.4, 128.7, 128.9, 129.0, 129.3, 129.6, 133.4, 135.1, 136.8, 137.9, 138.2, 200.1 ESI-MS (m/z): 355.20 (M+), 356.23 (M+1)+ Anal Calcd for C25H25NO: C 84.47, H 7.09, and N 3.94 %; found C 84.49, H 7.08, and N 3.93 % 16 3-(2-chlorophenylamino-3-(anthracen-9-yl)-1phenylpropan-1-one (table Entry 14, 8n): Yield 62 %, m.p 181-184 ºC IRνmax cm-1 1634, 1683, 3361; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.13-2.96 (d, J = 7.1 Hz, 2H), 4.284.10(dt, J = 7.1 Hz, 6.7 Hz, 1H), 4.74-4.61 (br s, 1H), 6.57-6.40 (m, 2H), 7.05-6.90 (m, 2H), 7.35-7.26 (m, 7H), 7.55-7.50 (s, 1H), 7.76-7.62 (m, 4H),7.93-7.89 (m, 2H); 13C NMR (125 MHz, CDCl3, δ ppm): 49.9, 73.1, 115.2, 118.3, 122.1, 125.3, 125.9, 126.0, 126.3, 126.8, 127.1, 127.8, 128.3, 128.8, 129.2, 129.6, 129.9, 133.3, 134.1, 136.7, 137.2, 200.2 ESI-MS (m/z): 435.15 (M+), 436.17 (M+1)+ Anal Calcd for C29H22ClNO: C 79.90, H 5.09, Cl 8.13, and N 3.21 %; found C 79.89, H 5.10, Cl 8.11, and N 3.20 % Sulfanilic acid catalysed one-pot three-component… 17 3-(2-mercaptophenylamino)-1-phenyl-3-ptolylpropan-1-one (table Entry 15, 8o): Yield 60 %, m.p 164-166 ºC IRνmax cm-1: 1234, 1363, 1443, 1457, 1631, 1678, 2573, 3331; 1H-NMR (500 MHz, CDCl3, δ ppm): 2.38 (s, 3H), 3.142.98 (d, J = 7.7 Hz, 2H), 4.12 (s, -SH, 1H), 4.674.60 (br s, 1H), 5.01-4.92 (t, J = 7.7 Hz, 1H), 6.35-6.31 (m, 1H), 6.48-6.41 (m, 1H), 6.84-6.78 (m, 1H), 6.95-6.91 (m, 1H), 6.99-6.95 (d, J = 8.4 Hz, 2H), 7.05-7.03 (d, J = 8.4 Hz, 2H), 7.357.30 (m, 2H), 7.46-7.41 (m, 1H), 7.88-7.84 (m, 2H); 13C-NMR (125 MHz, CDCl3, δ ppm): 24.5, 53.5, 72.8, 113.9, 116.1, 117.8, 126.1, 127.2, 128.6, 128.9, 129.1, 130.3, 135.9, 136.3, 136.9, 140.7, 144.1, 200.0 ESI-MS (m/z): 347.14 (M+), 348.17 (M+1)+ Anal Calcd for C22H21NOS: C 76.04, H 6.09, N 4.03 and S 9.23 %; found C 76.06, H 6.08, N 4.03 and S 9.22 % 18 3-(2-hydroxyphenylamino)-3-(3-bromophenyl)1-phenylpropan-1-one (table Entry 16, 8q): Yield 74 %, m.p 169-172 ºC IRνmax cm-1: 1220, 1369, 1620, 1672, 3358; 1H-NMR (500 MHz, CDCl3, δ ppm): 3.10-2.93 (d, J = 7.3 Hz, 2H), 4.48-4.44 (br s, 1H), 4.94-4.90 (t, J = 7.3 Hz, 1H), 6.32-6.28 (m, 1H), 6.43-6.39 (m, 1H), 6.54-6.48(m, 1H), 6.67-6.63 (m, 1H), 7.13-7.03 (m, 2H), 7.32-7.24 (m, 2H), 7.37-7.33 (m, 2H), 7.49-7.44 (m, 1H), 7.87-7.82(m, 2H), 11.87 (s, 1H); 13C NMR (125 MHz, CDCl3, δ ppm): 53.1, 72.2, 115.1, 116.4, 118.8, 122.3, 123.1, 126.2, 128.3, 128.9, 129.8, 130.5, 131.9, 133.4, 136.3, 139.4, 141.8, 145.4, 200.6 ESI-MS (m/z): 395.06 (M+), 396.10 (M+1)+ Anal Calcd for C21H18BrNO2: C 63.65, H 4.58, Br 20.16 and N 3.53 %; found C 63.64, H 4.57, Br 20.14 and N 4.52 % RESULTS AND DISCUSSION The reaction of cyclohexanone, benzaldehyde and aniline were designated as a classic reaction (scheme 1) Primarily, we have several organic acids such as gallic acid, 4-hydroxy benzoic acid, 4-amino benzoic acid, phenylacetic acid, chloroacetic acid, sulfosalicylic acid, sulfanilic acid, chlorobenzoic acid, phthalic acid, salicylic acid, cinnamic acid, hippuric acid, 1-naphthyl acetic acid, o-amino benzoic acid, p-TSA, succinic acid, malic acid as a catalyst for the condensation reaction in 10mL as solvent at the room temperature, and the outcomes are summarized in table The designated reaction was accomplished in a 50 mL RB flask using, mmol of cyclohexanone, mmol of benzaldehyde, 5mmol of aniline, and 20mol% of catalyst in 10 mL © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 679 Vietnam Journal of Chemistry ethanol under the stirring condition at the room temperature Fromt 1, it is seen that sulfanilic acid was found an effective catalyst, for the synthesis of 2-(β- Pramod Kulkarni aminobenzyl)-1-cyclohexanone with a 93% yield Gallic acid, phenylacetic acid, chloroacetic acid, phthalic acid, and salicylic acid have not given the desired product, and afford the unidentified product Scheme 1: Model reaction for the screening of catalyst Table 1: Screening of catalyst for one-pot three-component Mannich reaction using cyclohexanone, benzaldehyde and aniline in 10 mL EtOH at RTa Entry Catalyst Product Time (h) %Yieldb 10 11 12 13 14 15 16 17 Gallic acid 4-hydroxy benzoic acid 4-amino benzoic acid Phenylacetic acid Chloroacetic acid Sulfosalicylic acid Sulfanilic acid Chloro benzoic acid Phthalic acid Salicylic acid Cinnamic acid Hippuric acid 1-naphthyl acetic acid o-amino benzoic acid p-TSA Succinic acid Malic acid 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 3.5 4.5 3.5 0.10 0.15 3.25 4.10 4.5 4 Unidentified product 79 80 Unidentified product Unidentified product 74 93 Unidentified product Unidentified product Unidentified product 48 63 82 62 61 63 83 a : Reaction conditions: mmol of cyclohexanone, mmol of benzaldehyde, mmol of aniline and 20 mmol of catalyst in 10 mL ethanol under stirring condition at RT b: Isolated yield after purification Likewise cyclohexanone (5 mmol), benzaldehyde (5 mmol), and aniline (5 mmol) was selected as the classical substrates to optimize the amount of sulfanilic acid (scheme 2) The catalyst has been optimized by increasing the amount of sulfanilic acid from to 40 mol% on a mmol scale reaction When the reaction was carried out in the absence of a catalyst the product formed in minor quantity, and time required to form a product was long (table 2, Entry 1) The yield has increased with the increased amount of catalyst (table 2, Entry 2-4) Though, there was a very small increase in the yield when the catalyst loading has been increased from 20 to 40 mol% From table 2, it had been observed that 20 mol% of the catalyst were enough to achieve the best yield Though reaction has also well proceeded with 10 mol% achieving good yields requires a longer time Furthermore, to find the best solvent, the synthesis of (4a) (scheme 3) has been accomplished by using solvents like ethanol, water, n-hexane, THF, DCM, DMF, MeCN, CHCl3 and solvent-free condition at room temperature (table 3, Entries 1-8) as noticeable in table 3, the reaction in EtOH has been selected as the appropriate solvent Therefore, all further reactions were performed using 20 mol% of sulfanilic acid, in EtOH at room temperature © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 680 Vietnam Journal of Chemistry Sulfanilic acid catalysed one-pot three-component… Scheme 2: Model reaction for optimization of catalyst amount Table 2: Optimizing the amount of catalyst on mol % for synthesis of 2-(β-anilinobenzyl)-1-cyclohexanonea Entry Catalyst Mol % Time (min.) % yieldb (without catalyst) 10 20 30 40 240 120 30 15 15 15 NR 40 82 93 93 93 a : reaction conditions: mmol of cyclohexanone, mmol of benzaldehyde, mmol of aniline and mol% of catalyst in 10 ml ethanol at RT b: Isolated yield after purification Scheme 3: Model reaction for optimization of solvent Table 3: Optimization of solvent for synthesis of 2-(β-anilinobenzyl)-1-cyclohexanonea Entry Solvent Time (min.) % Yieldb n-Hexane THF DCM DMF MeCN CHCl3 H2O Solvent Free Ethanol 40 60 50 180 510 420 120 10 15 48 36 65 NR 78 42 74 58 93 a : Reaction conditions: mmol of cyclohexanone, mmol of benzaldehyde, mmol of aniline and 20 %mol of catalyst in 10 ml ethanol under stirring condition at RT b: isolated yield after purification With the developed reaction conditions in hand, the convenience of the method was estimated, using a diversity of aryl aldehydes and anilines for the synthesis of a series of β-amino carbonyl compounds (scheme 4) The results have summed up in table The nature and position of functional groups on the aromatic ring pretentious the reaction time, and yield of the product The results have indicated, those aryl © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 681 Vietnam Journal of Chemistry Pramod Kulkarni aldehydes containing functional groups such as –Br, -NO2, -OH has been afforded the high yield of the product O-substituted aryl aldehydes have given the corresponding product, in moderate yield, due to its higher crowded steric effects Scheme 4: Sulfanilic acid-catalyzed one-pot three-component Mannich reaction between cyclohexanone, substituted benzaldehyde and aniline Table 4: Sulfanilic acid catalyzed Mannich reactions of ketones, various aldehydes and anilinea Entry Aldehyde Product Time (min.) % Yieldb p.p (oC) 15 93 141-142 [41] 25 90 113-115 [42] 65 45 127-129 81 78 145-147 [41] 84 125 157 a 4b 4c 4 d 4e © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 682 Vietnam Journal of Chemistry Sulfanilic acid catalysed one-pot three-component… 60 89 136-137 [43] 35 82 127-128 10 88 154-155 [42] 15 76 125-177 45 80 171-172 4f 4g h 4i 10 4j a : Reaction condition: mmol of Cyclohexanone, mmol of aldehyde, mmol of aniline and 20 mol% of sulfanilic acid in 10 ml ethanol under stirring condition at RT b: All yields of isolated product Next, we have extended the scope of the reaction with an aromatic ketone, various aromatic aldehydes, and various aromatic amine (scheme 5) The reaction has well proceeded with electrondonating and electron-withdrawing groups on aromatic aldehydes (table 5) The ortho-substituted benzaldehydes have been afforded a low yield due to steric hindrance The 2-nitrobenzaldehyde did not give product due to, –M, -I, and steric effect The reaction has proceeded well with aromatic amines, with electron-donating as well as an electronwithdrawing group The ortho-substituted anilines with an electron-donating group have been afforded the low yield due to steric hindrance, while the electron-withdrawing group has not been afforded the product due to –M, -I, and steric effect Scheme 5: Sulfanilic acid - catalyzed one-pot three-component Mannich reaction between acetophenone, substituted benzaldehyde and substituted aniline © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 683 Vietnam Journal of Chemistry Pramod Kulkarni Table 5: Sulfanilic acid catalyzed Mannich reactions of acetophenone, aldehydes and substituted anilinesa Entry Aldehyde Amines Time (min.) Yieldb Product (8) m.p (ºC) 76 212 600 NRc - 400 82 164-166 [44] 30 85 161-162 [45] 240 78 113-114 [46] 90 82 137-139 45 70 118 43 73 108 500 40 145-147 8a 8b 8c 8d 8e 8f 8g 8h 8i © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 684 Vietnam Journal of Chemistry Sulfanilic acid catalysed one-pot three-component… 10 500 33 140-142 45 24 109-111 82 126-128 125 78 134-137 62 181-184 200 60 164-166 230 74 169-172 400 NRc 360 NRc - 8j 11 8k 12 8l 13 8m 14 8n 15 8o 16 8p 17 8q 18 8r a : Reaction condition: mmol of acetophenone, mmol of substituted aldehyde, mmol of substituted aniline and 20 mol% of catalyst in 10 ml ethanol under stirring condition at RT b: All yields of isolated product cNR: no reaction © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 685 Vietnam Journal of Chemistry Pramod Kulkarni CONCLUSION Here we report, an efficient synthesis of a series of β-amino carbonyl compounds from various ketones, aldehydes, and anilines using sulfanilic acid as an organocatalyst The method has been congenial with various functional groups present on the aryl aldehydes, and anilines The better yield of the product was perceived in the solvent than solventfree conditions, and ethanol was found to be a best solvent for the reaction The method has offered several merits, which include a small amount of catalyst loading, functional group tolerance, mild conditions, operational easiness, high yield, use of non-hazardous chemicals, and ecofriendly method 11 12 13 REFERENCES 10 A Davoodnia, A Tavakoli-Nishaburi, N TayakoliHoseini Carbon-based solid acid catalyzed one-pot Mannich reaction: A facile synthesis of β-amino carbonyl compounds, Bull Korean Chem Soc., 2011, 32, 635-638 G X Tang, J F.Yan, L Fan, J Xu, X L Song, L Jiang, L F Luo, D C Yang Synthesis of novel βamino ketones containing a p-aminobenzoic acid moiety and evaluation of their antidiabetic activities, Science China Chemistry, 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β-amino carbonyl compounds, Org Commun., 2014, 7, 123129 H Li, H Zeng, H Shao Bismuth(III) chloridecatalyzed one-pot Mannich reaction: three component synthesis of β-amino carbonyl compounds, Tetrahedron Lett., 2009, 50, 6858-6860 B Zhao, L Jiang, Z Liu, D Qigang, L Wang, B Song, Y Gao Microwave-assisted Michael addition of 2-amino pyridine to chalcones under catalyst-free conditions, Res Chem Intermed., 2015, 49, 58095819 Corresponding author: Pramod Kulkarni Department of Chemistry, Hutatma Rajguru Mahavidyalaya Rajgurunagar, Pune-410505, MS India E-mail: pramodskulkarni3@gmail.com © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 687 ... 4-hydroxy benzoic acid 4-amino benzoic acid Phenylacetic acid Chloroacetic acid Sulfosalicylic acid Sulfanilic acid Chloro benzoic acid Phthalic acid Salicylic acid Cinnamic acid Hippuric acid 1-naphthyl... Scheme 4: Sulfanilic acid- catalyzed one-pot three-component Mannich reaction between cyclohexanone, substituted benzaldehyde and aniline Table 4: Sulfanilic acid catalyzed Mannich reactions of ketones, ... sulfanilic acid, chlorobenzoic acid, phthalic acid, salicylic acid, cinnamic acid, hippuric acid, 1-naphthyl acetic acid, o-amino benzoic acid, p-TSA, succinic acid, malic acid as a catalyst for the