AlCl3-Catalysed trans N-acylation of Acetanilides with-Chloropropionyl Chloride$%H. R. Sonawane,* A. V. Pol, B. S. Nanjundiah and A. Sudalai*National Chemical Laboratory, Pune, 411008, Indiatrans N-acylation of acetanilides with -chloropropionyl chloride catalysed byAlCl3 has been shown to occur efficiently, affording2-chloro-N-phenylpropanamides in preparative yields.Friedel¡ÓCrafts acylation reactions of aromatic compoundswith acid chlorides and anhydrides, catalysed by Lewisacids, have been extensively employed for the synthesis ofaryl ketones.1 There is growing interest in recent yearsin the synthesis of potential drug intermediates such asa-chloropropiophenones (2) as they can be readily re-arranged, either photochemically2 or by Lewis acids,3 to a-arylpropionic acids, a class of non-steroidal and anti-inammatory drugs.4 In our continuing eorts to providea practical route to Flurbiprofen, an important anti-inammatory agent, we required p-amino substituted a-chloropropiophenone (2) as the starting material.Accordingly, when acetanilide 1 (R = H) was subjected toFriedel¡ÓCrafts acylation with a-chloropropionyl chloridein the presence of 1.1 mol of anhyd.AlCl3, a polymericmaterial was obtained. However, when the AlCl3 employedwas catalytic (0.3 mol), the reaction proceeded exceedinglywell to aord the trans N-acylated product 3 instead of theexpected p-acylated one (2) (Scheme 1). In this context, it ispertinent to note that the only example of C-acylation ofacetanilides was reported some time ago.1trans N¡Óacylation, in which one amide function is directlyconverted into another, is an important reaction, ndingwidespread application both in amino sugars5 and in peni-cillin and cephalosporin derivatives.6 However, a fewmethods of trans N-acylation with either acids or anhydridesat high temperatures have been reported using highlyacidic catalysts such as triuoroacetic acid¡Ótriuoroaceticanhydride (TFAA),6 TFAA¡ÓDBN7 and AlCl3.8 The utilityof zeolites as ecient catalysts has been recently reportedby our group.9 In view of the synthetic applications of a-chloroanilides, particularly in the synthesis of agrochemicals(as herbicides),10 we wish to report a new catalytic methodfor the trans N-acylation of anilides with a-chloropropionylchloride, catalysed by AlCl3.The results are summarized in Table 1.Evidently, thescope and generality of the reaction is wide; even the NO2group has increased the substrate reactivity (entry f).Thelow yield of product formation in the case of cyclohexyl-acetamide is due to the formation of many unidentiedproducts.Mechanistically, it may be reasoned that the acyl cationMeCHClCO+ attacks the nitrogen of the amide preferen-tially to form the diacylated product 4, which in turn equili-brates with the acetanilide, leading to the formation of thetrans acylated product (Scheme 2). The overall low yieldmay be explained in terms of the reversible nature of thereaction.These results thus establish the synthetic utility of theprocess toward the synthesis of a variety of trans N-acylatedproducts in preparative yields in most of the examplesstudied. However, it may be mentioned that this method isunsatisfactory as far as aliphatic acetamides are concerned,e.g.cyclohexylacetamide (entry j).ExperimentalAll mps are uncorrected. IR spectra were recorded on a PerkinElmer Model 137E spectrometer. 1H and 13C NMR spectra (d inppm from TMS) were obtained on Varian 60 MHz, Varian FT/80A80MHz and Bruker FT 200MHz spectrometers.Mass spectra wererecorded on an automated Finnagan-MAT 1020C mass spectrometer.General Procedure.To a mixture of acetanilide (1.35 g, 10 mmol)and anhyd. AlCl3 (400 mg, 3 mmol) in dichloroethane (20 ml)was added slowly -chloropropionyl chloride (1.4 g, 11 mmol) in5¡Ó10 min. The mixture was boiled under reux for 16 h, cooled anddecomposed with cold water.The organic layer was separated,washed with NaHCO3 and H2O and dried over anhyd. Na2SO4.The crude product was puried by column chromatography.2-Chloro-N-phenylpropanamide (3a).Mp 82¡Ó83 8C; max/cm£¾1(Nujol) 3280, 1680 (CONH), 1620, 1560, 1460, 1210, 1090, 1010,850, 650; H (80 MHz, CDCl3) 1.88 (d, 3 H, CH3 J 8 Hz,), 4.5 (q, 1H, CHCl, J 7.5 Hz), 7.1¡Ó7.8 (m, 5 H, ArH); m/z 183 (M+, 5%), 148(3), 120 (100), 119 (65), 93 (85), 92 (84), 77 (19), 65 (8).2-Chloro-N-(2-methylphenyl)propanamide (3b).Mp 101¡Ó102 8C;max/cm£¾1 (Nujol) 3260, 1660 (CONH), 1620, 1550, 1460, 1370,1250, 1200, 1080, 1000, 760; H (80 MHz, CDCl3) 1.82 (d, 3 H, CH3J 8 Hz), 2.26 (s, 3 H, ArCH3), 4.55 (q, 1 H, CHCl, J 6 Hz), 6.93¡Ó7.33 (m, 3 H, ArH), 7.78 (dd, 1 H, ArH , J 2Hz each), 8.22 (br, 1H, NH); m/z 197 (M+, 4%), 134 (72), 133 (56), 107 (53), 106 (100),105 (54), 91 (27), 90 (26), 71 (13), 63 (2).2-Chloro-N-(2-uorophenyl)propanamide (3a).Mp 74¡Ó76 8C;max/cm£¾1 (Nujol) 3260, 1680, 1550, 1500, 1460, 1370, 1300, 1250,1000, 810, 770; H (80 MHz, CDCl3) 1.8 (d, 3 H, CH3, J 7.5 Hz), 4.5(q, 1 H, CHCl, J 8 Hz), 6.9¡Ó7.32 (m, 3 H, ArH), 8.25 (m, 1 H,ArH), 8.51 (br, 1 H, NH); C (200 MHz, CDCl3) 22.7, 56.2 (CH),J.Chem. Research (S),1998, 90¡Ó91$Scheme1Scheme 2$This is a Short Paper as dened in the Instructions for Authors,Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-fore no corresponding material in J. Chem. Research (M).%NCL Communication No. 6213.*To whom the correspondence should be addressed.90 J. CHEM. RESEARCH (S), 1998115.0, 115.3, 121.8, 124.7, 124.8, 125.3, 150.4 (CF), 167.7 (CO); m/z 203 (M +2, 51%), 202 (M+1, 12), 201 (M+, 100), 138 (38), 111 (30), 109 (21), 90 (12), 83 (42), 63 (10). 2-Chloro-N-(2-chlorophenyl)propanamide (3d).�¢Mp 60¡¾62 8C; max/cm¢§1 (Nujol) 3260, 1670, 1600, 1540, 1450, 1200, 1060, 1000, 770; H (60 MHz, CDCl3) 1.88 (d, 3 H, CH3, J 8 Hz), 4.56 (q, 1 H, CHCl, J 8 Hz), 6.88¡¾7.44 (m, 3 H, ArH), 8.31 (d, 1 H, ArH, J 6 Hz), 8.88 (br, 1 H, NH); m/z 219 (M +2, 16%), 218 (M+ 1, 1), 217 (M+, 20); 184 (27), 182 (100), 154 (39), 146 (15), 129 (20), 127 (66), 126 (55), 99 (33), 90 (20), 63 (34). 2-Chloro-N-(2-bromophenyl)propanamide (3e).�¢mp 73¡¾76 8C; max/cm¢§1 (Nujol) 3260, 1675, 1600, 1550, 1450, 1050, 770; H (80 MHz, CDCl3) 1.88 (d, 3 H, CH3, J 7.5 Hz), 4.5 (q, 1 H, CHCl, J 6 Hz), 6.82¡¾7.56 (m, 3 H, ArH), 8.25 (dd, 1 H, ArH, J 2Hz each), 8.87 (br, 1 H, NH); m/z 263 (M+2, 7%), 261 (M+, 5), 200 (16), 198 (19), 184 (30), 182 (100), 173 (23), 172 (17), 171 (23), 170 (10), 146 (29), 119 (9), 90 (8). 2-Chloro-N-(2-nitrophenyl)propanamide (3f ).�¢Mp 68¡¾70 8C max/ cm¢§1 (Nujol) 3360, 1700, 1610, 1600, 1510, 1350, 810, 760; H (60 MHz, CDCl3) 1.76 (d, 3 H, CH3, J 8 Hz), 4.4 (q, 1 H, CHCl, J 7.5 Hz), 6.73¡¾8.0 (m, 4 H, ArH), 10.45 (br, 1 H, NH); m/z 230 (M+2, 15%), 229 (M +1, 5), 228 (M+, 46), 184 (31), 182 (100), 165 (47), 145 (23), 138 (76), 121 (41), 92 (29), 91 (36), 90 (29), 65 (25), 63 (50). 2-Chloro-N-(4-methoxyphenyl)propanamide (3g).�¢Mp 101¡¾ 102 8C; max/cm¢§1 (Nujol) 3280, 1670, 1560, 1520, 1400, 1260, 950, 850; H (60 MHz, CDCl3) 1.76 (d, 3 H, CH3, J 8 Hz), 3.75 (s, 3 H, OCH3), 4.43 (q, 1 H, CHCl, J 7 Hz), 6.75 (d, 2 H, ArH, J 10 Hz), 7.26 (d, 2 H, ArH, J 10 Hz); 8.0 (br, 1 H, NH); C (200 MHz, CDCl3) 22.6, 55.6, 56.1, 114.3, 122.2, 130.2, 157.2, 167.7; m/z 215 (M+2, 15%), 214 (M +1, 5), 213 (M+, 52), 178 (8), 150 (20), 123 (52), 122 (100), 108 (47), 95 (13), 63 (8). 2-Chloro-N-(4-chlorophenyl)propanamide (3h).�¢Mp 112¡¾114 8C; max/cm¢§1 (Nujol) 3220, 1650, 1580, 1520, 1480, 1385, 1220, 1180, 1080, 1060, 800, 820; H (80 MHz, CDCl3) 1.82 (d, 3 H, CH3, J 7.5 Hz), 4.5 (q, 1 H, CHCL, J 6 Hz), 7.25¡¾7.5 (AB quartet, 4 H, ArH, J 10 Hz), 8.25 (br, 1 H, NH); m/z 219 (M+ 2, 70%), 218 (M +1, 10), 217 (M+, 98), 182 (10), 156 (32), 154 (100), 129 (29), 127 (77), 126 (29), 99 (8). 2-Chloro-N-(4-bromophenyl)propanamide (3i).�¢Mp 122¡¾125 8C; max/cm&cenujol) 3230, 1675, 1600, 1550, 1500, 1410, 1310, 1250, 1200, 1085, 1020, 820; H (80 MHz, CDCl3) 1.81 (d, 3 H, CH3, J 7.5 Hz), 4.5 (q, 1 H, CHCl, J 6 Hz), 7.44 (s, 4 H, ArH), 8.25 (br, 1 H, NH); m/z 265 (M+ 4, 26%), 263 (M +2, 100), 261 (M+, 90), 200 (75), 198 (80), 173 (94), 172 (50), 171 (96), 170 (41), 147 (5). 2-Chloro-N-cyclohexylpropanamide (3j).�¢Mp 104 8C; max/cm¢§1 (Nujol) 3250, 1640, 1550, 1450, 1370; H (80 MHz, CDCl3) 1.25¡¾ 2.15 (m, 10 H, cyclohexyl CH2), 1.88 (d, 3 H, CH3, J 8 Hz), 3.81 (br, 1 H, CHNH), 4.5 (q, 1 H, CHCl, J 7 Hz), 6.56 (br, 1 H, NH).Received, 7th August 1997; Accepted, 24th October 1997 Paper E/7/05770I References 1 Friedel¡¾Crafts and Related Reactions, ed. 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Table 1 AlCl3-catalysed trans N-acylation of anilides with a-chloropropionyl chloride Substrates Product (3) Mp(lit.c )11 No. (1) R yielda(%) ( 8C) a H 57c 82^83 (82) b 2-CH3 67 101^102 (101^102) c 2-F 32d 74^76 (74^76) d 2-Cl 33c,d 60^62 (62) e 2-Br 45 73^76 (73^76) f 2-NO2 60 68^70 (70) g 4-OMe 44c 101^102 (101^102) h 4-Cl 68 112^114 (112) i 4-Br 35 122^125 (124) j Cyclohexylacetamide 10 104 (105) aIsolated after column chromatographic purification; the rest is essentially unreacted anilide. b20%Yield obtained in the absence of catalyst. cEven with the use of 2molar equivalent of -chloropropionyl chloride, no significant improvement in yield was realised. dNo reaction took place in the absence of catalyst. J. CHEM. RESEARCH (S), 1998