Synthesis of Substituted Salicylanilides under Microwave Irradiation

Article abstract of DOI:10.1007/s00706-003-0014-4

Salicylanilides were prepared in 70-95% yields in 4-8 min from phenyl salicylate or phenyl 4-methoxysalicylate and substituted anilines under microwave irradiation under solvent free conditions.

Full text of DOI:10.1007/s00706-003-0014-4

Monatshefte f€ur Chemie 134, 1215–1219 (2003)
DOI 10.1007/s00706-003-0014-4
Synthesis of Substituted Salicylanilides
under Microwave Irradiation
1
1
1;ꢀ
Eva Veverkova , Maria Meciarova , Stefan Toma , and Jozef Balko2
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1
Comenius University, Faculty of Natural Sciences, Department of Organic Chemistry,
SK-842 15 Bratislava, Slovak Republic
2
Research Institute for Chemical Technology, Nobelova 34, SK-836 03 Bratislava, Slovak Republic
Received October 17, 2002; accepted October 22, 2002
Published online July 3, 2003 # Springer-Verlag 2003
Summary. Salicylanilides were prepared in 70–95% yields in 4–8 min from phenyl salicylate or
phenyl 4-methoxysalicylate and substituted anilines under microwave irradiation under solvent free
conditions.
Keywords. Salicylanilides; Microwave irradiation.
Introduction
Salicylanilides have been of interest for synthetic organic chemists for long time
due to their biological activity (antimicrobial and tuberculostatic activity) [1].
Anilides of salicylic acid based on phenylenediamine derivatives are known as
nonvolatile antioxidants for plastics and rubber [2].
The classical synthesis of salicylanilides involves the interaction of chlorides or
phenyl esters of substituted salicylic acids with amines in various solvents [3, 4] or
under solvent-free conditions [5]. The main goal of this work was to improve the
synthesis of salicylanilides from phenyl salicylates, which is the most frequently
used method because it does not need protection and deprotection of the OH group.
Results and Discussion
The beneficial effect of microwave irradiation on several organic reactions is well
documented [6–11] and we decided therefore to explore if it could be applied for
the synthesis of substituted salicylanilides. The method consists of a short exposure
of a mixture of phenyl salicylates and anilines under microwave irradiation under
solvent-free conditions. The temperature profile of this reaction was monitored by
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Corresponding author. E-mail: toma@fns.uniba.sk

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E. Veverkova et al.
1216
Fig. 1. Temperature profile of microwave assisted reaction of phenyl salicylate with 4-methyl-3-
nitroaniline
Scheme 1
computer using Synthewave 402+ (Fig. 1). The reaction route for the substituted
salicyanilide derivatives is depicted in Scheme 1.
From the results in Table 1 follows that high yields (70–95%) of the products
3a–3m were achieved after only 3–7 min of microwave irradiation. The versatility
of this method was demonstrated by testing a wide range of different aromatic
amines. This method can be also applied to 1,4-phenylenediamine (R2 ¼ H,
R3 ¼ NH2). In these cases the products of reactions on both amino groups were
isolated in small amounts (4a 6%, 4b 13%) (Fig. 2).
To examine if the reaction could be performed without microwave irradiation,
an equimolar mixture of salicylanilide and 4-methyl-3-nitroaniline was immersed
in a hot oil bath. When the temperature of the reaction mixture reached 162ꢁC (the
highest temperature in the microwave experiment) the mixture was kept at this
temperature for 5 min. However, no product was observed (HPLC) (Entry 8). This
could be explained by a specific microwave effect which is a consequence of the
polar transition state interaction with the electric field [12].

Synthesis under Microwave Irradiation
1217
Table 1. Microwave-assisted preparation of substituted salicylanilides
a
Entry
Substrate
Tfin ꢁC
Time min
Yieldb %
1
2
3a
3b
3c
3d
3e
3f
171
157
205
210
186
201
162
162
192
154
210
220
205
192
4
8
4
7
5
5
5
5
7
4
4
7
7
5
95
95
96
92
93
97
98
0c
3
4
5
6
7
3g
3g
3h
3i
8
9
94
98
99
75
70
92
10
11
12
13
14
3j
3k
3l
3m
a
Tfin is temperature of the reaction mixture reached at the end of reaction; b yields refer to isolated
c
products; yield of the reaction performed under thermal heating without microwave irradiation
Fig. 2. Formulae of by-products 4a and 4b
In conclusion, the advantages of the presented method are high yields, the
solvent-free technique, easy work-up as well as purification, and short reaction
time. This method can be applied also for the synthesis of 30–50 g samples of
starting materials.
Experimental
1H NMR and 13C NMR spectra were measured on a Varian Gemini 2000 instrument at 300MHz and
75MHz. CDCl3 and DMSO were used as solvents and tetramethylsilane as internal standard. Micro-
analyses were carried out on a Carlo Erba Strumenstacione Milano CHN analyser, model 1106. The
results agreed with the calculated values. Melting points were determined on a Kofler apparatus and are
not corrected. All microwave experiments were carried out in a SYNTHEWAVE 402+, PROLABO
reactor. The temperature of the reaction mixture was monitored by an IR thermometer.

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E. Veverkova et al.
1218
General Procedure
A mixture of phenyl salicylate (or phenyl 4-methoxysalicylate) (0.1mol) and the amine (0.1mol) was
stirred under microwave irradiation in the microwave reactor (240W input power) for 5 min. After
cooling to room temperature, the reaction mixture was, treated with 50cm3 of CH2Cl2. The undis-
solved impurities were filtered off by suction, the solvent was evaporated, and formed phenol was
distilled off under reduced pressure. The residue was recrystallized from iso-hexane=ethyl acetate
(4=1) or purified by column chromatography on silica using CHCl3=ethyl acetate (19=1) as eluent
to give pure salicylanilides. The results are summarized in Table 1. Melting points and NMR data of
products 3a [5, 13], 3b [5, 14], 3c [15], 3d [2], 3e [2], 3h [16, 17], and 3j [16] were found to be
identical with the data described in literature.
2-Hydroxy-N-[4-[(1,3-dimethylbutyl)amino]phenyl]benzamide (3f, C19H24N2O2)
White solid; m.p. 56–58ꢁC; 1H NMR (CDCl3, 300 MHz): ꢀ ¼ 0.91 (d, J ¼ 6.0 Hz, CH3), 0.93
(d, J ¼ 6.0 Hz, CH3), 1.18 (d, J ¼ 6.0 Hz, CH3), 1.27–1.34 (m, CHAHB), 1.42–1.53 (m, CHAHB),
1.68–1.77 (m, CH(CH3)2), 3.48–3.55 (m, CHNH), 6.31 (d, J ¼ 9.0 Hz, 2Harom), 6.87 (t, J ¼ 8.1 Hz,
1Harom), 7.01 (d, J ¼ 9.0 Hz, 1Harom), 7.31 (d, J ¼ 9 Hz, 2Harom), 7.42 (t, J ¼ 8.1 Hz, 1Harom), 7.52 (d,
J ¼ 7.8 Hz, 2Harom), 7.86 (bs, NH), 12.18 (s, OH) ppm; 13C NMR (CDCl3, 75MHz): ꢀ ¼ 20.8, 22.5,
22.9, 25.1, 46.6, 113.7, 114.7, 118.8, 118.8, 123.7, 125.4, 134.3, 161.8, 168.3 ppm.
2-Hydroxy-N-(4-methyl-2-nitrophenyl)benzamide (3g, C14H12N2O4)
1
Yellow solid; m.p. 190ꢁC; H NMR (CDCl3, 300 MHz): ꢀ ¼ 2.43 (s, CH3), 6.96–7.06 (m, 2Harom),
7.46–7.56 (m, 3Harom), 8.10 (s, 1Harom), 8.73 (d, J ¼ 8.7 Hz, 1Harom), 11.39 (s, NH), 11.83 (s, OH)
ppm; 13C NMR (CDCl3, 75MHz): ꢀ ¼ 20.6, 114.5, 119.0, 119.5, 122.5, 125.8, 125.9, 131.8, 134.4,
135.3, 137.0, 162.3, 169.0 ppm.
2-Hydroxy-4-methoxy-N-(4-methyl-2-nitrophenyl)benzamide (3i, C15H14N2O5)
Yellow solid; m.p. 174–175ꢁC; 1H NMR (CDCl3, 300 MHz): ꢀ ¼ 2.42 (s, CH3), 3.85 (s, CH3),
6.50–6.56 (m, 2Harom), 7.51 (d, J ¼ 8.54Hz, 1Harom), 7.57 (d, J ¼ 8.85Hz, 1Harom), 8.07 (s, 1Harom),
8.70 (d, J ¼ 8.54Hz, 1Harom), 11.23 (s, NH), 12.17 (s, OH) ppm; 13C NMR (CDCl3, 75MHz):
ꢀ ¼ 20.6, 55.6, 101.8, 107.5, 108.0, 122.4, 125.8, 127.4, 132.2, 133.9, 136.6, 137.0, 164.7, 165.3,
168.8ppm.
N-(4-Aminophenyl)-2-hydroxy-4-methoxybenzamide (3k, C14H14N2O3)
Grey solid; m.p. 260–263ꢁC; 1H NMR (DMSO, 300 MHz): ꢀ ¼ 3.78 (s, OCH3), 6.52–6.54 (m, 2Harom),
7.39 (d, J ¼ 8.4 Hz, 2Harom), 7.80 (d, J ¼ 8.4 Hz, 2Harom), 8.06 (d, J ¼ 8.7 Hz, 1Harom), 10.46 (bs, NH),
12.39 (s, OH) ppm; 13C NMR (DMSO, 75MHz): ꢀ ¼ 55.5, 101.4, 106.3, 109.0, 122.2, 123.5, 127.7,
130.5, 137.7, 161.5, 163.84, 167.2ppm.
2-Hydroxy-4-methoxy-N-[4-(phenylamino)phenyl]benzamide (3l, C20H18N2O3)
1
Grey solid; m.p. 164–165ꢁC; H NMR (DMSO, 300MHz): ꢀ ¼ 3.79 (s, CH3), 6.48 (s, 1Harom), 6.50
(d, J ¼ 9.0 Hz, 1Harom), 6.71 (t, J ¼ 6.9 Hz, 1Harom), 7.03–7.09 (m, 4Harom), 7.19–7.24 (m, 2Harom),
7.51 (d, J ¼ 9.0 Hz, 2Harom), 7.98 (d, J ¼ 9.0 Hz, 1Harom), 8.13 (s, NH), 10.11 (s, NH), 12.65 (s, OH)
ppm; 13C NMR (DMSO, 75 MHz): ꢀ ¼ 55.2, 101.2, 110.6, 112.9, 118.1, 118.3, 121.2, 129.6, 132.8,
134.6, 138.3, 141.5, 161.9, 162.5, 166.4 ppm.

Synthesis under Microwave Irradiation
1219
2-Hydroxy-4-methoxy-N-[4-[(1,3-dimethylbutyl)amino]phenyl]benzamide (3m, C15H14N2O5)
Grey solid; m.p. 99–101ꢁC; 1H NMR (CDCl3, 300 MHz): ꢀ ¼ 0.90 (d, J ¼ 6.0 Hz, CH3), 0.93
(d, J ¼ 6.0 Hz, CH3), 1.15 (d, J ¼ 6.0 Hz, CH3), 1.27–1.34 (m, CHAHB), 1.42–1.53 (m, CHAHB)
1.72 (m, CH), 3.51 (m, CH), 3.81 (OCH3), 6.44 (d, J ¼ 8.44Hz, 1Harom), 6.47 (s, 1Harom), 6.58
(d, J ¼ 8.7 Hz, 2Harom), 7.26 (d, J ¼ 8.7 Hz, 2Harom), 7.38 (d, J ¼ 8.44Hz, 1Harom), 7.66 (bs, NH),
12.61 (s, OH) ppm; 13C NMR (CDCl3, 75 MHz): ꢀ ¼ 20.9, 22.5, 22.9, 25.1, 46.7, 47.0, 55.5, 101.7,
107.1, 107.5, 113.4, 123.8, 126.1, 126.6, 145.4, 164.1, 164.4, 168.3 ppm.
N,N0-1,4-Phenylenebis(2-hydroxybenzamide) (4a, C15H14N2O5)
Grey solid; m.p. 318ꢁC; 1H NMR (DMSO, 300MHz): ꢀ ¼ 6.94–7.00 (m, 4Harom), 7.42 (d, J ¼ 8.4 Hz,
2Harom), 7.71 (s, J ¼ 7.5 Hz, 4Harom), 7.98 (d, J ¼ 7.5 Hz, 2Harom), 10.41 (s, 2NH), 11.87 (s, 2OH) ppm;
13C NMR (DMSO, 75MHz): ꢀ ¼ 117.2, 117.3, 119.0, 121.3, 128.9, 133.6, 134.3, 158.6, 166.15ppm.
N,N0-1,4-Phenylenebis(2-hydroxy-4-methoxybenzamide) (4b, C22H20N2O6)
Grey solid; m.p. 322–322ꢁC; 1H NMR (DMSO, 300MHz): ꢀ ¼ 3.78 (s, 2OCH3), 6.51 (s, 2Harom), 6.56
(d, J ¼ 8.4 Hz, 2Harom), 7.67 (s, 4Harom), 7.99 (d, J ¼ 8.4 Hz, 2Harom), 10.24 (s, 2OH) ppm; 13C NMR
(CDCl3, 75 MHz): ꢀ ¼ 55.4, 101.3, 106.3, 108.8, 121.5, 129.9, 134.2, 161.8, 163.8, 167.2 ppm.
Acknowledgements
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Our thanks are due to Dr. E. Solꢀcaniova for NMR measurements, Dr. K. Gaplovska (both of Institute of
Chemistry, Faculty of Natural Sciences, Comenius University) for microanalyses and to the Slovak
Grant Agency VEGA for the financial support (Grant No. 1=7348=20).
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