AlCl3-Catalysed trans N-acylation of Acetanilides with α-Chloropropionyl Chloride

Article abstract of DOI:10.1039/a705770i

trans N-acylation of acetanilides with α-chloropropionyl chloride catalysed by AlCl₃ has been shown to occur efficiently, affording 2-chloro-N-phenylpropanamides in preparative yields.

Full text of DOI:10.1039/a705770i

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90 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 90±91
AlCl3-Catalysed
N-acylation of Acetanilides with
-Chloropropionyl Chloride
H. R. Sonawane,* A. V. Pol, B. S. Nanjundiah and A. Sudalai*
National Chemical Laboratory, Pune, 411008, India
trans N-acylation of acetanilides with -chloropropionyl chloride catalysed byAlCl3 has been shown to occur efficiently, affording
2-chloro-N-phenylpropanamides in preparative yields.
Friedel±Crafts acylation reactions of aromatic compounds
with acid chlorides and anhydrides, catalysed by Lewis
acids, have been extensively employed for the synthesis of
aryl ketones.1 There is growing interest in recent years
in the synthesis of potential drug intermediates such as
a-chloropropiophenones (2) as they can be readily re-
arranged, either photochemically2 or by Lewis acids,3 to a-
arylpropionic acids,
in¯ammatory drugs.4 In our continuing e€orts to provide
practical route to Flurbiprofen, an important anti-
a class of non-steroidal and anti-
a
in¯ammatory agent, we required p-amino substituted a-
chloropropiophenone (2) as the starting material.
Accordingly, when acetanilide 1 (R = H) was subjected to
Friedel±Crafts acylation with a-chloropropionyl chloride
in the presence of 1.1 mol of anhyd. AlCl3, a polymeric
material was obtained. However, when the AlCl3 employed
was catalytic (0.3 mol), the reaction proceeded exceedingly
well to a€ord the trans N-acylated product 3 instead of the
expected p-acylated one (2) (Scheme 1). In this context, it is
pertinent to note that the only example of C-acylation of
acetanilides was reported some time ago.1
Scheme 1
studied. However, it may be mentioned that this method is
unsatisfactory as far as aliphatic acetamides are concerned,
e.g. cyclohexylacetamide (entry j).
Experimental
All mps are uncorrected. IR spectra were recorded on a Perkin
Elmer Model 137E spectrometer. 1H and 13C NMR spectra (d in
ppm from TMS) were obtained on Varian 60 MHz, Varian FT/80A
80 MHz and Bruker FT 200 MHz spectrometers. Mass spectra were
recorded on an automated Finnagan-MAT 1020C mass spectrometer.
General Procedure.ÐTo 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) in
5±10 min. The mixture was boiled under re¯ux for 16 h, cooled and
decomposed with cold water. The organic layer was separated,
washed with NaHCO3 and H2O and dried over anhyd. Na2SO4.
The crude product was puri®ed by column chromatography.
trans N±acylation, in which one amide function is directly
converted into another, is an important reaction, ®nding
widespread application both in amino sugars5 and in peni-
cillin and cephalosporin derivatives.6 However,
a few
methods of trans N-acylation with either acids or anhydrides
at high temperatures have been reported using highly
acidic catalysts such as tri¯uoroacetic acid±tri¯uoroacetic
anhydride (TFAA),6 TFAA±DBN7 and AlCl3.8 The utility
of zeolites as ecient catalysts has been recently reported
by 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 method
for the trans N-acylation of anilides with a-chloropropionyl
chloride, catalysed by AlCl3.
The results are summarized in Table 1. Evidently, the
scope and generality of the reaction is wide; even the NO2
group has increased the substrate reactivity (entry f). The
low yield of product formation in the case of cyclohexyl-
acetamide is due to the formation of many unidenti®ed
products.
Mechanistically, it may be reasoned that the acyl cation
MeCHClCO+ 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 the
trans acylated product (Scheme 2). The overall low yield
may be explained in terms of the reversible nature of the
reaction.
1
2-Chloro-N-phenylpropanamide (3a).ÐMp 82±83 8C; max/cm
(Nujol) 3280, 1680 (CONH), 1620, 1560, 1460, 1210, 1090, 1010,
850, 650;
(80 MHz, CDCl3) 1.88 (d, 3 H, CH3 J 8 Hz,), 4.5 (q, 1
H
H, CHCl, J 7.5 Hz), 7.1±7.8 (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).ÐMp 101±102 8C;
max/cm (Nujol) 3260, 1660 (CONH), 1620, 1550, 1460, 1370,
1
1250, 1200, 1080, 1000, 760;
(80 MHz, CDCl3) 1.82 (d, 3 H, CH3
H
J 8 Hz), 2.26 (s, 3 H, ArCH3), 4.55 (q, 1 H, CHCl, J 6 Hz), 6.93±
7.33 (m, 3 H, ArH), 7.78 (dd, 1 H, ArH , J 2 Hz each), 8.22 (br, 1
H, 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).ÐMp 74±76 8C;
max/cm (Nujol) 3260, 1680, 1550, 1500, 1460, 1370, 1300, 1250,
1
1000, 810, 770;
(80 MHz, CDCl3) 1.8 (d, 3 H, CH3, J 7.5 Hz), 4.5
H
(q, 1 H, CHCl, J 8 Hz), 6.9±7.32 (m, 3 H, ArH), 8.25 (m, 1 H,
ArH), 8.51 (br, 1 H, NH); (200 MHz, CDCl3) 22.7, 56.2 (CH),
C
These results thus establish the synthetic utility of the
process toward the synthesis of a variety of trans N-acylated
products in preparative yields in most of the examples
To whom the correspondence should be addressed.
This is a Short Paper as de®ned 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.
Scheme 2

View Article Online
J. CHEM. RESEARCH (S), 1998 91
2-Chloro-N-(4-chlorophenyl)propanamide (3h).ÐMp 112±114 8C;
max/cm (Nujol) 3220, 1650, 1580, 1520, 1480, 1385, 1220, 1180,
Ta bl e 1 AlCl3-catalysed trans N-acylation of anilides with
a-chloropropionyl chloride
1
1080, 1060, 800, 820;
(80 MHz, CDCl3) 1.82 (d, 3 H, CH3, J
H
Substrates
(1) R
Product (3)
Mp (lit.c)11
7.5 Hz), 4.5 (q, 1 H, CHCL, J 6 Hz), 7.25±7.5 (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).
No.
yielda(%)
( 8C)
a
b
c
d
e
f
H
57c
67
82^83 (82)
2-CH3
101^102 (101^102)
74^76 (74^76)
60^62 (62)
2-F
32d
33c,d
45
2-Chloro-N-(4-bromophenyl)propanamide (3i).ÐMp 122±125 8C;
max/cm (Nujol) 3230, 1675, 1600, 1550, 1500, 1410, 1310, 1250,
1
2-Cl
1200, 1085, 1020, 820;
(80 MHz, CDCl3) 1.81 (d, 3 H, CH3, J
H
2-Br
73^76 (73^76)
68^70 (70)
101^102 (101^102)
112^114 (112)
122^125 (124)
104 (105)
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-NO2
60
g
h
i
4-OMe
44c
68
4-Cl
4-Br
1
35
10
2-Chloro-N-cyclohexylpropanamide (3j).ÐMp 104 8C; max/cm
j
Cyclohexylacetamide
(Nujol) 3250, 1640, 1550, 1450, 1370;
(80 MHz, CDCl3) 1.25±
H
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).
aIsolated after column chromatographic purification; the rest is
essentially unreacted anilide. b20% Yield obtained in the absence
of catalyst. cEven with the use of 2 molar equivalent of
Received, 7th August 1997; Accepted, 24th October 1997
Paper E/7/05770I
-chloropropionyl chloride, no significant improvement in yield was
realised. dNo reaction took place in the absence of catalyst.
115.0, 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).
References
2-Chloro-N-(2-chlorophenyl)propanamide (3d).ÐMp 60±62 8C;
max/cm (Nujol) 3260, 1670, 1600, 1540, 1450, 1200, 1060, 1000,
1 Friedel±Crafts and Related Reactions, ed. G. A. Olah, Wiley±
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1
770;
(60 MHz, CDCl3) 1.88 (d, 3 H, CH3, J 8 Hz), 4.56 (q, 1 H,
H
CHCl, J 8 Hz), 6.88±7.44 (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).Ðmp 73±76 8C;
1
max/cm (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±7.56 (m, 3 H, ArH), 8.25 (dd, 1 H, ArH, J 2 Hz 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).
4 H. R. Sonawane, B. S. Nanjundiah, J. R. Ahuja and D. G.
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2-Chloro-N-(2-nitrophenyl)propanamide (3f).ÐMp 68±70 8C
cm (Nujol) 3360, 1700, 1610, 1600, 1510, 1350, 810, 760;
/
max
1
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±8.0 (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).
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2-Chloro-N-(4-methoxyphenyl)propanamide
(3g).ÐMp
102 8C; max/cm (Nujol) 3280, 1670, 1560, 1520, 1400, 1260, 950,
850; (60 MHz, CDCl3) 1.76 (d, 3 H, CH3, J 8 Hz), 3.75 (s, 3 H,
101±
1
10 K. Kobayashi and S. Yamagiwa, Jpn. Kokai Tokkyo Koho,
1990, JP 02,225,648 (Chem. Abstr., 1991; 114, 142 892p); T.
Yoshimoto, K. Igarashi and Y. Takasawa, CHEMTECH, 1989,
19, 431; H. Yang, X. Li, Z. Zhang and M. Chang, Chem. Abstr.,
1993, 119, 8873h.
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); (200 MHz,
C
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).
11 G. Snatzke and M. M. El-Abadelah, Chem. Ber., 1973, 106,
2072.