One-pot synthesis of salicylanilides by direct amide bond formation from salicyclic acid under microwave irradiation

Article abstract of DOI:10.1080/00397911.2010.481745

A highly efficient protocol for the preparation of aromatic amides is described by the direct reactions between salicyclic acid and aromatic amines in the presence of phosphorous trichloride under microwave irradiation. The method has several advantages over the conventional methods, including operational simplicity, good yield, and reduced reaction time.

Full text of DOI:10.1080/00397911.2010.481745

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One-Pot Synthesis of Salicylanilides
by Direct Amide Bond Formation
from Salicyclic Acid Under Microwave
Irradiation
a
a
a
a
Cheng-Rong Lu , Bei Zhao , Ying-Peng Jiang , Hao Ding & Sheng
a
Yang
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Dushu Lake
Campus, Soochow University, Suzhou, Jiangsu, China
Available online: 30 Mar 2011
To cite this article: Cheng-Rong Lu, Bei Zhao, Ying-Peng Jiang, Hao Ding & Sheng Yang (2011):
One-Pot Synthesis of Salicylanilides by Direct Amide Bond Formation from Salicyclic Acid Under
Microwave Irradiation, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 41:9, 1257-1266
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1
Synthetic Communications , 41: 1257–1266, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481745
ONE-POT SYNTHESIS OF SALICYLANILIDES BY
DIRECT AMIDE BOND FORMATION FROM SALICYCLIC
ACID UNDER MICROWAVE IRRADIATION
Cheng-Rong Lu, Bei Zhao, Ying-Peng Jiang, Hao Ding, and
Sheng Yang
Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials Science,
Dushu Lake Campus, Soochow University, Suzhou, Jiangsu, China
GRAPHICAL ABSTRACT
Abstract A highly efficient protocol for the preparation of aromatic amides is described by
the direct reactions between salicyclic acid and aromatic amines in the presence of phos-
phorous trichloride under microwave irradiation. The method has several advantages over
the conventional methods, including operational simplicity, good yield, and reduced reaction
time.
Keywords Microwave irradiation; salicylanilide; synthesis
INTRODUCTION
Salicylanilide skeletons exist in many synthetic biologically active materials,
and their derivatives are applied in various pharmaceutical and biochemical fields.
Specifically functionalized salicylanilide and its derivatives may possess potential
biological properties, including antifungal, antibacterial, antimycobacterial, and
[
1]
antitubercular activities and may act as potassium channel activators. Thus, much
attention has been paid to developing efficient methods for the synthesis of the
structural unit of salicylanilides.
According to the literature, amides were typically synthesized by the aminolysis
[
1d,2]
reaction of esters, nitrile, isocyanide, and other derivatives of carboxylic acid.
Recently, effective oxidative amidations of aldehydes with amines to generate amides
[3]
have been described in a few papers. The smooth rearrangement of ketones with
TMSN in the presence of FeCl to provide the corresponding amides has also been
3
3
Received August 14, 2009.
Address correspondence to Bei Zhao, Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials Science, Dushu Lake Campus, Soochow
University, Suzhou, Jiangsu 215123, China. E-mail: zhaobei@suda.edu.cn
1
257

1258
C.-R. LU ET AL.
4]
[
reported by J. S. Yadav and coworkers. In addition, direct amidation of carboxylic
acid is perhaps the most crucial and well-known transformation. However, in most
cases, because of the poor reactivity of carboxylic acids, activation either separately
prior to actual amidation or in situ using coupling reagents was required for a
[5]
smooth reaction. In this way, the application of the direct amidation of carboxylic
acid is limited to some extent. Thus, we can see that these methods have several dis-
advantages, such as expensive reagents, long reaction time, complicated operation,
and low to moderate yields.
With the development of MORE (microwave-induced organic reaction
enhancement) chemistry, the direct amidation of carboxylic acid is modified success-
[6]
fully under microwave activation. However, in these studies a limited number of
[
6a,f,g]
aromatic amines were employed to afford the desired amides.
With our growing
interest in microwave (MW)–assisted organic chemistry, we performed reactions of
various aromatic amines with salicylic acid as acyl donors in the presence of phos-
phorous trichloride under MW-assisted conditions. Herein, we present this efficient
approach.
In a preliminary study, amide formation between aniline and salicyclic acid was
used as the model reaction to screen the reaction conditions. The reaction tempera-
ꢀ
ture was set to 150 C to favor shifting the equilibrium by removal of HCl. Mean-
while, for sake of comparison with conventional heating, almost the same
conditions including molar ratio of the starting materials and solvent were applied.
Neat compounds were mixed in a flask and irradiated under 500 W for 1 min to dis-
solve in xylene. Then phosphorous trichloride was added dropwise during the second
period of microwave irradiation (Scheme 1).
After 10 min of irradiation, many materials were recovered under 100 W and
00 W. By-products were observed when the power was raised to 400 W or 500 W.
2
The best result was gained under 300 W. Consequently, the reaction times were
screened under the appropriate power. In Table 1, almost quantitative yield of salicyl-
anilide was obtained under microwave irradiation with reduced reaction time
(
(
33 min), which is obviously better than with conventional heating using an oil bath
4 h, 85%). It revealed that the use of microwave activation can improve efficiency
and reduce waste production. We studied the relationship between the amount of
PCl and the reaction efficiency subsequently. It can be seen from Table 2 that
3
4
0% molar ratio of PCl afforded the best result.
3
Encouraged by these results, various aromatic amines were subjected to the
reaction conditions, and representative examples are shown in Table 3. The reactions
were monitored by thin-layer chromatography (TLC). Most of the aromatic amines,
either bearing electron-withdrawing groups (such as halides and nitro group) or
electron-donating groups (such as alkyl or alkoxyl groups), gave the expected salicy-
lamide products with moderate to good yields under microwave conditions. All of
Scheme 1. Salicylanilide syntheses.

ONE-POT SYNTHESIS OF SALICYLANILIDES
1259
Table 1. Optimization of the reaction time of MW-assisted amide formation
a
Yield (%)
Entry
Reaction time (min)
1
2
3
4
5
6
7
8
9
10
15
50
57
72
92
95
97
98
96
85
25
30
31
32
33
34
b
240
a
b
In isolated products. Conditions: 40 mol% PCl
By conventional heating (using an oil bath).
3
, in xylene, 300 W.
Table 2. Optimization of the amount of PCl
3
in the MW-assisted amide formation
a
Yield (%)
Entry
PCl
3
(molar ratio)
1
2
3
4
5
5
10
20
30
40
58
72
77
94
98
a
In isolated products. Conditions: 33 min in xylene, 300 W.
1
13
the products were characterized by H NMR, C NMR, infrared (IR), and elemen-
tal analysis. The reaction times varied from 32 min to 55 min, which indicated the
electronic effect of the substituents plays a critical role in this nucleophilic reaction.
However, no desired products can be observed when N-methylaniline was reacted
with salicyclic acid. This suggested that steric hinderance has significant effects on
this reaction.
In this reaction, three possible products between phosphorous trichloride and
[
salicylic acid were formulated in Fig. 1 (see also Scheme 2). It is noticed that the
7]
molar ratio of PCl to salicylic acid should be 1.09 to form the intermediates I and
3
II. However, from our screening experiments for the amount of PCl , we know that
3
the optimal amount of this reagent is about 30–40% of the molar ratio of the sub-
strate, so we propose the following possible mechanism to explain the reaction.
First, phosphorous trichloride reacts with salicylic acid in a 3:1 molar ratio to give
salicylic chloride, which is proved by successfully recovering salicylic chloride quan-
titively after the reaction just between phosphorous trichloride and salicylic acid in
a 3:1 molar ratio. Then protonation of the oxygen in the carbonyl group proceeds.
In rate-determining step 3, the nitrogen atom of aniline acts as a nucleophile to
attack the carbonyl group and give a tetrahedral intermediate IV. The tetrahedral
intermediate eliminates the chloride to renew the carbonyl group rapidly. Finally,
the deprotonation reaction is accomplished smoothly. In most cases, very impor-
tant specific nonthermal microwave effects are evidenced, especially in the case of
[8]
sluggish reactions. The increase of polarity of the system will favor the progress

1260
C.-R. LU ET AL.
a
Table 3. Salicyl amide derivatives formed via MW-assisted synthesis
b
c
Entry
a
Amine
Product
Reaction time (min)
Yield (%)
33
45
98
b
87
c
32
35
82
75
d
e
38
97
f
37
42
45
44
85
87
80
75
g
h
i
d
55 (240 )
d
73 (44 )
j
a
In isolated products. Conditions: 40 mol% PCl
3
, in xylene, 300 W.
The time required for the disappearance of salicyclic acid on TLC.
b
c
Isolated yields by recrystallization except entries a, e, and j.
By conventional heating (using an oil bath).
d

ONE-POT SYNTHESIS OF SALICYLANILIDES
1261
Figure 1. Hypothesis of the intermediate of the reaction of aniline and salicyl acid.
Scheme 2. Possible mechanism of the reaction of aniline and salicyl acid.
[9]
of the reaction concerned. The processes of step 2 and step 4 increase the polarity
of the system and favor the formation of polar amide. As the result, the reaction
time is shortened distinctly.
In conclusion, a direct MW-mediated amidation between salicyclic acid and
aromatic amines has been developed to afford desired salicyl amides, which was
more efficient and wider in scope compared to traditional routes to these com-
pounds. The important features of this method include short reaction time, con-
venient workup, and moderate to good yields.
EXPERIMENTAL
Reactants and Equipment
The commercial MW reactor was a multimode system (MAS-1, 100–1000 W,
Shanghai Sineo Microwave Chemistry Science and Technology Co. Ltd., Shanghai,

1262
C.-R. LU ET AL.
China) with focused waves operating at 2.45 GHz. The temperature was controlled
throughout the reaction and measured by an IR detector, which indicated the surface
temperature. Mechanical stirring during the irradiation period provided good
homogeneity (power and temperature).
1
The IR spectra were recorded on a Nicolet Magna-IR 550 spectrometer. H
1
3
NMR and C NMR spectra were obtained using a Unity Inova-400 spectrometer.
Carbon, hydrogen, and nitrogen analyses were performed by direct combustion on a
Carlo-Erba EA-1110 instrument, and the quoted data are the averages of at least two
independent determinations.
General Procedure for the Synthesis of Amides
In a 100-mL flask, a solution of salicyclic acid (12.5 mmol) and aromatic amine
12.5 mmol) was mixed in 10 mL of xylene. The flask was positioned in the
(
irradiation cavity, and the mixture was heated with stirring under MW irradiation
with 500 W of input power for 1 min. The mixture was cooled to ambient tempera-
ture, and then an input power was set at 300 W for the appropriate reaction times.
Meanwhile, PCl (0.4 mL, 4.6 mmol) was added dropwise. After completion, the
3
mixture was cooled to room temperature, and the crude product was precipitated,
filtered, and purified by crystallization from EtOH, if necessary. The purity of the
final product was measured (>99%) by high-performance liquid chromatography
(HPLC) using CH OH=H O=HOAc (75:25:0.05) as the moving phase on a Kromasil
column.
3 2
Selected Data
Salicylanilide (3a). Solid; white powder; mp 137–138 C. IR (KBr): 3294,
ꢀ
ꢁ1 1
3
032, 2669, 2561, 1612, 1550, 1496, 1450, 1373, 1334, 1234, 748, 709, 679 cm . H
NMR (400 MHz, CDCl ): d ¼ 11.99 (s, 1H, OH), 7.93 (s, 1H, NH), 7.58 (d, 2H,
3
J ¼ 8.0 Hz, ArH), 7.52 (d, 1H, J ¼ 8.0 Hz, ArH), 7.48–7.39 (m, 3H, ArH), 7.21 (t,
1
H, J ¼ 7.2 Hz, ArH), 7.04 (d, 1H, J ¼ 8.0 Hz, ArH), 6.93 (t, 1H, J ¼ 7.2 Hz, ArH).
1
3
C NMR (100 MHz, CDCl ): d ¼ 168.6, 162.1, 136.8, 135.0, 129.5, 125.64, 125.57,
3
1
C, 72.99; H, 5.12; N, 6.66.
21.4, 119.2, 114.7. Anal. calcd. for C H NO : C, 73.23; H, 5.20; N, 6.57. Found:
2
1
3
11
ꢀ
Salicylyl naphthylamine (3b). Solid; white powder; mp 186–187 C. IR
KBr): 3217, 3040, 1643, 1612, 1550, 1497, 1450, 1404, 1350, 1303, 1226, 764, 733,
(
ꢁ1 1
6
48, 602 cm . H NMR (400 MHz, CDCl ): d ¼ 12.02 (s, 1H, OH), 8.26 (s, 1H,
3
NH), 7.92 (t, 2H, J ¼ 6.4 Hz, ArH), 7.84 (t, 2H, J ¼ 6.4 Hz, ArH), 7.68 (d, 1H,
J ¼ 8.0 Hz, ArH), 7.57–7.47 (m, 4H, ArH), 7.06 (d, 1H, J ¼ 8.0 Hz, ArH), 6.98 (t,
1
3
1
H, J ¼ 7.2 Hz, ArH). C NMR (100 MHz, DMSO-d ): d ¼ 167.9, 159.6, 135.0,
6
1
34.9, 134.3, 130.7, 129.6, 128.9, 127.5, 127.3, 126.9, 123.1, 122.9, 120.5, 118.5,
18.4. Anal. calcd. for C H NO : C, 77.55; H, 4.98; N, 5.32. Found: C, 77.33;
H, 5.01; N, 5.42.
1
1
7
13
2
ꢀ
4’-Methoxysalicylanilide (3c). Solid; white powder; mp 158–160 C. IR
KBr): 3311, 3172, 2956, 2840, 2701, 2555, 1628, 1567, 1512, 1458, 1358, 1250,
(
ꢁ
1
1
1
026, 833, 749, 656, 525 cm . H NMR (400 MHz, CDCl ): d ¼ 12.10 (s, 1H,
3
OH), 10.48 (s, 1H, NH), 7.92 (d, 1H, J ¼ 8.0 Hz, ArH), 7.51 (d, 1H, J ¼ 8.0 Hz,

ONE-POT SYNTHESIS OF SALICYLANILIDES
1263
ArH), 7.44 (d, 2H, J ¼ 9.2 Hz, ArH), 7.02 (t, 1H, J ¼ 8.4 Hz, ArH), 6.96–6.90 (m, 3H,
1
3
ArH), 3.83(s, 3H, OCH ). C NMR (100 MHz, DMSO-d ): d ¼ 168.2, 160.5, 157.5,
3
6
135.1, 132.4, 130.1, 124.3, 120.3, 118.7, 118.3, 115.3, 56.7. Anal. calcd. for
C H NO : C, 69.12; H, 5.39; N, 5.76. Found: C, 68.83; H, 5.29; N, 5.78.
1
4
13
3
ꢀ
4’-Methylsalicylanilide (3d). Solid; white powder; mp 155–157 C. IR (KBr):
325, 3047, 2939, 2862, 2731, 2584, 1605, 1551, 1512, 1458, 1373, 1334, 1234, 903,
3
8
(
2
2
ꢁ
1 1
10, 748, 687, 509 cm . H NMR (400 MHz, CDCl ): d ¼ 12.08 (s, 1H, OH), 7.89
3
s, 1H, NH), 7.52 (d, 1H, J ¼ 8.0 Hz, ArH), 7.46 (d, 3H, J ¼ 8.0 Hz, ArH), 7.21 (d,
H, J ¼ 8.0 Hz, ArH), 7.04 (d, 1H, J ¼ 8.0 Hz, ArH), 6.93 (t, 1H, J ¼ 7.6 Hz, ArH),
1
3
.37 (s, 3H, CH ). C NMR (100 MHz, CDCl ): d ¼ 162.1, 135.5, 134.9, 134.1,
14 13 2
3
3
130.1, 130.0, 125.6, 125.5, 121.6, 119.2, 114.8, 21.2. Anal. calcd. for C H NO :
C, 73.99; H, 5.77; N, 6.16. Found: C, 73.69; H, 5.98; N, 5.96.
ꢀ
2’-Methylsalicylanilide (3e). Solid; white powder; mp 144–145 C. IR (KBr):
305, 3086, 2935, 2731, 1628, 1581, 1551, 1504, 1458, 1381, 1334, 1234, 1034, 941,
3
8
(
ꢁ
1 1
25, 756, 679, 509 cm . H NMR (400 MHz, CDCl ): d ¼ 12.07 (s, 1H, OH), 7.82
3
s, 1H, NH), 7.74 (d, 1H, J ¼ 7.6 Hz, ArH), 7.54 (d, 1H, J ¼ 8.0 Hz, ArH), 7.47 (t,
1
7
H, J ¼ 8.4 Hz, ArH), 7.29 (t, 2H, J ¼ 7.2 Hz, ArH), 7.20 (t, 1H, J ¼ 7.2 Hz, ArH),
.05 (d, 1H, J ¼ 8.0 Hz, ArH), 6.95 (t, 1H, J ¼ 8.0 Hz, ArH), 2.36 (s, 3H, CH ).
3
1
3
C NMR (100 MHz, DMSO-d ): d ¼ 166.5, 158.9, 136.9, 134.4, 131.1, 130.3,
6
1
C, 73.99; H, 5.77; N, 6.16. Found: C, 73.85; H, 5.89; N, 5.93.
27.1, 127.0, 126.0, 124.8, 120.0, 118.0, 114.9, 18.5. Anal. calcd. for C H NO :
2
1
4
13
ꢀ
3’-Chrolosalicylanilide (3f). Solid; white powder; mp 171–173 C. IR (KBr):
280, 3010, 2894, 2825, 2670, 2555, 1621, 1567, 1482, 1459, 1366, 1335, 1235, 1204,
3
1
ꢁ
1 1
096, 996, 880, 849, 780, 749, 718, 687, 533, 448 cm . H NMR (400 MHz, CDCl ):
3
d ¼ 11.83 (s, 1H, OH), 7.94 (s, 1H, NH), 7.73 (t, 1H, J ¼ 2.0 Hz, ArH), 7.53–7.42 (m,
3
H, ArH), 7.33 (t, 1H, J ¼ 8.0 Hz, ArH), 7.17 (d, 1H, J ¼ 8.0 Hz, ArH), 7.04 (d, 1H,
1
3
J ¼ 8.0 Hz, ArH), 6.94 (t, 1H, J ¼ 8.0 Hz, ArH). C NMR (100 MHz, DMSO-d ):
6
d ¼ 167.8, 159.3, 141.0, 134.9, 134.2, 131.6, 130.4, 124.9, 121.4, 120.4, 120.3, 119.0,
1
H, 4.28; N, 5.65.
18.4. Anal. calcd. for C H ClNO : C, 63.04; H, 4.07; N, 5.66. Found: C, 62.79;
13 10 2
ꢀ
4’-Chrolosalicylanilide (3g). Solid; white powder; mp 165–167 C. IR (KBr):
295, 3033, 2933, 2848, 2701, 2578, 1613, 1551, 1489, 1451, 1381, 1327, 1235, 1204,
3
1
ꢁ
1 1
158, 1096, 903, 826, 756, 687, 664, 509, 432 cm . H NMR (400 MHz, CDCl ):
3
d ¼ 11.89 (s, 1H, OH), 7.94 (s, 1H, NH), 7.56–7.51 (m, 3H, ArH), 7.47 (t, 1H,
J ¼ 8.4 Hz, ArH), 7.37 (d, 2H, J ¼ 8.0 Hz, ArH), 7.05 (d, 1H, J ¼ 8.0 Hz, ArH),
1
3
6
.94 (t, 1H, J ¼ 7.6 Hz, ArH). C NMR (100 MHz, DMSO-d ): d ¼ 167.5, 159.1,
6
138.1, 134.6, 130.0, 129.5, 128.7, 123.3, 120.0, 118.6, 118.1. Anal. calcd. for
C H ClNO : C, 63.04; H, 4.07; N, 5.66. Found: C, 63.15; H, 4.19; N, 5.45.
1
3
10
2
ꢀ
4’-Bromosalicylanilide (3h). Solid; white powder; mp 173–174 C. IR (KBr):
294, 3056, 2924, 2855, 2677, 1605, 1551, 1481, 1450, 1373, 1327, 1234, 1204, 1157,
3
1
(
ꢁ1 1
072, 903, 818, 748, 709, 679, 610, 556 cm . H NMR (400 MHz, CDCl ): d ¼ 11.82
3
s, 1H, OH), 7.88 (s, 1H, NH), 7.51–7.43 (m, 6H, ArH), 7.02 (d, 1H, J ¼ 8.0 Hz,
1
3
ArH), 6.91 (t, 1H, J ¼ 7.6 Hz, ArH). C NMR (100 MHz, DMSO-d ): d ¼ 167.6,
6

1264
C.-R. LU ET AL.
159.2, 138.6, 134.7, 132.5, 130.1, 123.8, 120.0, 118.7, 118.2, 116.8. Anal. calcd. for
C H BrNO : C, 53.42; H, 3.42; N, 4.79. Found: C, 53.67; H, 3.47; N, 4.88.
1
3
10
2
ꢀ
4’-Fluoro-3’-chrolosalicylanilide (3i). Solid; white powder; mp 200–202 C.
IR (KBr): 3326, 3056, 2940, 2856, 2724, 2593, 1621, 1559, 1505, 1459, 1389, 1235,
ꢁ1
1
. H NMR (400 MHz, CDCl3):
1
212, 1157, 880, 810, 741, 687, 648, 525 cm
d ¼ 11.79 (s, 1H, OH), 7.91 (s, 1H, NH), 7.80–7.77 (m, 1H, ArH), 7.51–7.48 (m,
2
H, ArH), 7.42–7.39 (m, 1H, ArH), 7.18 (t, 1H, J ¼ 8.8 Hz, ArH), 7.05 (d, 1H,
1
3
J ¼ 8.0 Hz, ArH), 6.94 (t, 1H, J ¼ 7.2 Hz, ArH). C NMR (100 MHz, DMSO-d ):
6
d ¼ 167.2, 158.7, 136.2, 134.4, 130.2, 129.8, 123.0, 122.0, 120.0, 119.8, 118.5, 117.9,
1
5
17.5. Anal. calcd. for C H FClNO : C, 58.77; H, 3.41; N, 5.27. Found: C,
13 9 2
8.89; H, 3.49; N, 5.08.
ꢀ
4’-Nitrosalicylanilide (3j). Solid; yellow powder; mp 228–229 C. IR (KBr):
256, 3056, 2940, 2856, 1644, 1620, 1558, 1512, 1458, 1334, 1258, 1234, 1118, 933,
3
8
(
ꢁ1 1
56, 756, 718, 694, 509, 463, 440 cm . H NMR (400 MHz, DMSO-d ): d ¼ 11.4
6
s, 1H, OH), 10.8 (s, 1H, NH), 8.26 (d, 2H, J ¼ 8.8 Hz, ArH), 8.00 (d, 2H, J ¼ 8.8 Hz,
ArH), 7.87 (d, 1H, J ¼ 8.0 Hz, ArH), 7.45 (t, 1H, J ¼ 7.2 Hz, ArH), 7.03–6.98 (m, 2H,
1
3
ArH). C NMR (100 MHz, DMSO-d ): d ¼ 167.4, 158.2, 145.7, 143.5, 134.7, 130.6,
6
1
1
25.9, 121.0, 120.2, 119.8, 118.0. Anal. calcd. for C H N O : C, 60.46; H, 3.88; N,
13 10 2 4
0.85. Found: C, 60.19; H, 3.99; N, 10.80.
ACKNOWLEDGMENT
We are grateful to the Junzheng Scholar Project of Soochow University for
financial support.
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