A new route of synthesis of 5-(N-phenethylamino)salicylic acid derivatives by rapid and selective reduction of the amide group with NaBH4/acetic acid

Article abstract of DOI:10.1080/00397910801982001

A good yield of 5-(N-phenethylamino)salicylic acid derivatives was successfully obtained from the corresponding methyl 2-acetoxy-5-(N- phenethylamino)benzoate esters by rapid and selective reduction of the amide group in the acyl protected salicylic acid

Full text of DOI:10.1080/00397910801982001

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A New Route of Synthesis of
5‐(N‐Phenethylamino)salicylic Acid
Derivatives by Rapid and Selective Reduction
of the Amide Group with NaBH4/Acetic Acid
Young‐Gyun Shin a , Ho‐Joon Park a , HaeUn Lee a & Sung‐Hwa Yoon a
a Department of Molecular Science and Technology , Ajou University ,
Suwon, South Korea
Published online: 09 May 2008.
To cite this article: Young‐Gyun Shin , Ho‐Joon Park , HaeUn Lee & Sung‐Hwa Yoon (2008) A New Route of
Synthesis of 5‐(N‐Phenethylamino)salicylic Acid Derivatives by Rapid and Selective Reduction of the Amide
Group with NaBH4/Acetic Acid, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 38:11, 1822-1829, DOI: 10.1080/00397910801982001
To link to this article: http://dx.doi.org/10.1080/00397910801982001
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Synthetic Communicationsw, 38: 1822–1829, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801982001
A New Route of Synthesis of
5-(N-Phenethylamino)salicylic Acid
Derivatives by Rapid and Selective
Reduction of the Amide Group
with NaBH4/Acetic Acid
Young-Gyun Shin, Ho-Joon Park, HaeUn Lee,
and Sung-Hwa Yoon
Department of Molecular Science and Technology, Ajou University,
Suwon, South Korea
Abstract: A good yield of 5-(N-phenethylamino)salicylic acid derivatives was
successfully obtained from the corresponding methyl 2-acetoxy-5-(N-phenethylamino)-
benzoate esters by rapid and selective reduction of the amide group in the acyl protected
salicylicacid withNaBH4/acetic acid in dioxane followed by hydrolysis of the ester group.
Keywords: Acetic acid, aromatic amide, selective reduction, sodium borohydride
INTRODUCTION
5-(N-Phenethylamino)salicylic acid derivatives have recently attracted much
attention because of their potent neuroprotective activity against N-methyl-D-
aspartic acid (NMDA) neurotoxicity as well as strong antioxidant activity.[1]
Usually, N-substituted 5-aminosalicylic acid derivatives are prepared by either
the direct N-alkylation of 5-aminosalicylic acid with the corresponding alkyl
halides or the reductive amination of 5-aminosalicylic acid with the correspond-
ing aldehydes.[2] However, these methods cannot be applied to the synthesis of
various 5-(N-phenethylamino)salicylic acid derivatives because the direct
Received August 3, 2007
Address correspondence to Sung-Hwa Yoon, Department of Molecular Science and
Technology, Ajou University, San 5 Wonchun-Dong, Suwon 443-749, South Korea.
E-mail: shyoon@ajou.ac.kr
1822

Synthesis of 5-(N-Phenethylamino)salicylic Acid Derivatives
1823
N-alkylation method almost always produces many side products as a result of
the low reactivity of the amino group of 5-aminosalicylic acid, and the
required phenylacetaldehydes for the reductive amination are commercially
limited, possibly because of the enolization of the aldehyde group.
As part of our project for developing 5-(N-phenethylamino)salicylic acid
derivatives as novel neuroprotective agents; for the treatment of various
neurodegenerative diseases, we needed to find a practical method for
synthesis of various 5-(N-phenethylamino)salicylic acid derivatives that can
also be applied to scaled-up production.
Here, we report a new synthetic method for various 5-(N-phenethylami-
no)salicylic acid derivatives from the corresponding salicylic acid esters by
the rapid and selective reduction of the amide group over the ester group
with sodium borohydride/acetic acid in a dioxane system[3] followed by
hydrolysis of the ester group.
In comparison with the previous methods described, the advantage of this
method is that various carboxamide compounds can easily be synthesized
from the coupling reaction of the acyl protected 5-aminosalicylic acid with
phenylacetic acids, most of which are commercially available.
RESULTS AND DISCUSSION
To test the selective reduction of the amide group in the presence of the ester
group, we first prepared the methyl 2-acetoxy-5-(N-phenethylamino)benzoate
esters by dicyclohexylcarbodiimide (DCC)-mediated coupling reaction of
methyl 2-acetoxy-5-aminosalicylate ester with various phenylacetic acids
(Scheme 1). We then attempted to selectively reduce the amide group with the
previously reported reducing agents such as the aluminum hydride–triethyl-
amine complex,[4] lithium aminoborohydride,[5] lithium borohydride,[6]
sodium (dimethylamino) borohydrides,[7] diisobutylaluminum hydride,[8] and
lithium aluminum hydride[9] under different reaction conditions. Unfortunately,
none of these reduction conditions could reduce the amide group selectively
because the ester group was always reduced faster than the amide group under
normal reduction conditions. For example, when compound 1a was reduced
with lithium aluminum hydride at room temperature, only the aromatic ester
Scheme 1. Reagents: (a) methyl 2-acetoxy-5-aminosalicylate ester, DCC, CH2Cl2;
(b) NaBH4, AcOH, dioxane, reflux; (c) 6N HCl, AcOH, reflux.

1824
Y.-G. Shin et al.
group was reduced into the corresponding alcohol, whereas both functional
groups were reduced under refluxing conditions.
The borane-amine complex, which selectively reduced the amide group
in the acyl protected nucleoside derivatives,[10] was also tested for compound
1a. Although selective reduction was achieved on a small scale (1.00 g) with
a reaction time of 50 h in 50% yield, the reaction was not complete
even when the reaction was left for 1 week for the scaled-up production
of compound 1a. To make it worse, the reagent is too expensive to use
in scaled-up production ($3.1 per gram, reagent grade, from Aldrich Co.).
While searching for a better reducing agent for the selective reduction of
the amide group over the ester group, we judiciously selected sodium borohy-
dride to use as a reducing agent because of its low cost for scaled-up pro-
duction ($0.54 per gram, reagent grade, from Aldrich Co.). After numerous
attempt under various reaction conditions, we found the optimal reaction con-
ditions for the successful selective reduction of the amide group were with
sodium borohydride/acetic acid and afforded isolated yields of compound 2
in the 62–70% range. The results are summarized in Table 1. The general
procedure is as follows: To methyl 2-acetoxy-5-(N-phenethylamino)benzoate
ester (1.00 g, 2.78 mmol) and sodium borohydride (500 mg, 14.0 mmol)
suspended in dioxane (technical grade, 20.0 cm3), glacial acetic acid
(800 mL, 14.0 mmol) in dioxane (technical grade, 10.0 cm3) was added over
a period of 20 min at 208C, and the resulting mixture was heated under
reflux. The completion of the reaction was monitored by thin-layer chromato-
graphy (TLC), and the reaction was generally completed within 30 min after
addition of glacial acetic acid. It is of interest to note that the longer the
reaction, the more side products were produced. Finally, the methyl ester
compound was hydrolyzed in 6N HCl to give the desired salicylic acid
products in about 90% yield.
We then tested whether this synthetic method could be applied in
large-scale synthesis of methyl 2-acetoxy-5-(2-(4-(trifluoromethyl)phenyl)a-
cetamido)benzoate 1g. When compound 1g (2.00 kg, 4.93 mol) was reduced
with our system, the desired product was obtained in 64% yield with a
reaction time of about 2 h longer than for the small-scale reaction.
In summary, we have developed a practical method to prepare 5-(N-phe-
nethylamino)salicylic acid derivatives through the rapid and selective
reduction of the aromatic amide group of the corresponding methyl ester
compounds with NaBH4/acetic acid in dioxane, followed by hydrolysis of
the ester group.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Varian Mercury 400 spec-
trometer. Melting-points were determined on a Fisher-Johns melting-point
apparatus and were uncorrected.

Synthesis of 5-(N-Phenethylamino)salicylic Acid Derivatives
1825
Table 1. Reaction conditions for the selective reduction of carboxamides by NaBH4
and acetic acid in dioxane system
Addition
time
(min)
Reflux
time
(min)
Scale
(mmol)
Yield
(%)
Entry
R
1a
20
20
20
20
15
20
25
20
2.8
2.8
2.8
2.8
70
64
65
67
1b
1c
1d
1e
20
30
2.8
62
1f
20
65
30
2.8
69
64
1g
120
4.93
General Procedure for the Selective Reduction of the Aromatic
Amide Group
To a stirred suspension of sodium borohydride (500 mg, 14.0 mmol) and methyl
2-acetoxy-5-[2-(4-methoxyphenyl)acetylamino]benzoate ester 1a (1.00 g,
2.80 mmol) in dioxane (technical grade, 20.0 cm3), glacial acetic acid
(800 mL, 14.0 mmol.) in dioxane (technical grade, 10.0 cm3) was added over a

1826
Y.-G. Shin et al.
Table 2. Physical and spectral data of compounds 2a–2g
Compound
1H NMR (CDCl3)
13C NMR (CDCl3)
Mp (8C)
2a
7.18–7.16 (d, 1H), 7.10–
7.06 (d, 2H), 6.90–6.80
(m, 3H), 6.70–6.62
170.0, 164.9, 157.9, 145.7,
141.1, 130.6, 129.3, 123.9,
122.9, 117.3, 114.3, 113.8,
55.1, 52.0, 45.2, 34.2, 20.8
49–50
(white
solid)
(q, 1H), 3.83 (s, 3H),
3.77 (s, 3H), 3.34–3.29
(t, 2H), 2.82–2.78
(t, 2H), 2.28 (s, 3H)
2b
2c
2d
7.18–7.14 (d, 1H), 7.14–
7.02 (q, 4H), 6.88–6.83
(d, 1H), 6.72–6.67
(q, 1H), 3.82 (s, 3H),
3.37–3.32 (t, 2H),
2.88–2.82 (t, 2H), 2.33
(s, 3H)
170.2, 165.0, 145.7, 141.3,
135.9, 135.5, 129.2, 128.4,
124.1, 123.0, 117.6, 114.6,
52.1, 45.2, 34.8, 21.1, 21.0
61–62
(white
solid)
7.18–7.13 (m, 3H), 7.02– 170.1, 162.3, 145.9, 141.2,
65–67
(white
solid)
6.98 (m, 2H), 6.82–6.80
(d, 1H), 6.64–6.62
129.5, 129.4, 124.0, 123.1,
117.2, 115.1, 114.9, 114.4,
52.1, 43.3, 32.8, 31.0, 21.0
(q, 1H), 3.84 (s, 3H),
3,16–3.14 (t, 2H), 2.68–
2.66 (t, 2H), 2.22 (s, 3H),
1.86–1.84 (m, 2H)
7.39–7.34 (d, 1H), 7.32–
7.28 (d, 1H), 7.19–
170.2, 164.9, 145.2, 141.5,
139.0, 132.3, 130.5, 130.4,
130.3, 128.0, 124.2, 123.2,
117.6, 114.5, 52.2, 44.7,
34.53, 21.0
90–91
(white
solid)
7.15(d, 1H), 7.06–7.01
(q, 1H), 6.92–6.86
(d, 1H), 6.74–6.70
(q, 1H), 3.84 (s, 3H),
3.40–3.36 (t, 2H), 2.88–
2.84 (t, 2H), 2.32 (s, 3H)
2e
7.18–7.15 (d, 1H), 7.00–
6.94 (m, 1H), 6.91–6.86
(m, 2H), 6.86–6.83
170.2, 164.9, 159.4, 159.4,
158.0, 158.0, 157.0, 155.7,
146.3, 141.3, 127.6, 127.5,
127.4, 124.1, 123.0, 117.4,
117.1, 117.1, 116.9, 116.8,
116.3, 116.2, 116.0, 115.9,
114.4, 114.4, 114.3, 114.2,
114.1, 52.0, 43.6, 29.0, 20.9
55
(white
solid)
(d, 1H), 6.73–6.69
(q, 1H), 3.83 (s, 3H),
3.37–3.32 (t, 2H), 2.89–
2.85 (t, 2H), 2.30 (s, 3H)
2f
7.34 (q, 2H), 7.21 (t, 3H),
7.18 (d, 1H), 6.88
170.1, 165.0, 145.9,
141.2, 141.1, 128.3, 128.2,
125.8, 124.0, 123.0, 117.2,
114.4, 52.0, 43.5, 33.35,
21.0
70
(white
solid)
(d, 1H), 6.65 (d, 1H),
3.91 (s, 3H), 3.21 (t, 2H),
2.78 (t, 2H), 2.31 (s, 3H)
(continued)

Synthesis of 5-(N-Phenethylamino)salicylic Acid Derivatives
Table 2. Continued
1827
Compound
1H NMR (CDCl3)
13C NMR (CDCl3)
Mp (8C)
2g
7.54 (d, 2H), 7.29 (d, 2H), 170.5, 165.3, 145.7, 143.3,
93
(white
solid)
7.15 (d, 1H), 6.87
141.7, 129.2, 125.6, 125.6,
125.5, 124.5, 123.5, 117.8,
114.7, 52.4, 45.1, 35.4, 21.3
(d, 1H), 6.70 (d, 1H),
3.94 (s, 3H), 3.42 (t, 2H),
2.94 (t, 2H), 2.30 (s, 3H)
Table 3. Physical and spectral data of compounds (3a–3g)
1H NMR
(DMSO-d6)
13C NMR
(DMSO-d6)
Yield
(%)
Compound
Mp (8C)
3a
7.23 (s, 1H),
7.18 (d, 2H),
6.84 (d, 2H),
6.68 (t, 1H),
6.62 (d, 1H),
4.91 (s, 3H),
3.23 (t, 2H),
2.91 (t, 2H)
7.18 (m, 5H),
6.67 (q, 1H),
6.60 (d, 1H),
3.21 (t, 2H),
2.81 (t, 2H)
166.7, 150.0,
145.7, 131.7,
123.50, 121.2,
112.2, 110.7,
108.01, 107.2,
105.4, 46.3,
39.0
.300 8C
(white solid)
95
3b
172.4, 153.5,
139.4, 136.5,
134.7, 128.7,
128.3, 120.3,
116.7, 116.1,
112.9, 46.4,
34.4, 20.7
.300 8C
(white solid)
90
3c
7.20 (q, 2H),
7.04–6.95
(m, 3H),
171.7, 161.6,
159.2, 153.2,
139.9, 134.9,
129.6, 129.5,
121.7, 116.9,
114.5, 114.3,
112.1, 111.4,
43.6, 32.6, 30.3
173.0, 153.3,
141.4, 139.5,
130.62, 130.5,
130.1, 129.0,
128.4, 119.9,
117.7, 115.8,
113.5, 45.5,
34.4
.300 8C
(white solid)
92
6.84 (q, 1H),
6.73 (d, 1H),
2.93 (t, 2H),
2.65 (t, 2H),
1.81 (m, 2H)
7.30 (m, 2H),
7.08 (s, 1H),
6.97 (d, 1H),
6.82 (d, 1H),
6.71 (d, 1H),
3.21 (t, 2H),
2.83 (t, 2H)
3d
.300 8C
(white solid)
94
(continued)

1828
Y.-G. Shin et al.
Table 3. Continued
1H NMR
(DMSO-d6)
13C NMR
(DMSO-d6)
Yield
(%)
Compound
Mp (8C)
3e
7.26 (d, 1H),
7.14 (m, 2H),
7.01 (m, 2H),
6.78 (q, 1H),
6.71 (d, 1H),
3.29 (t, 2H),
2.98 (t, 2H)
175.8, 160.9,
159.4, 158.5,
157.1, 154.7,
141.0, 129.8,
129.8, 129.63,
121.0, 120.0,
118.3, 118.2,
118.1, 118.0,
117.4, 117.2,
117.1, 117.0,
116.9, 115.6,
115.2, 115.1,
114.9, 114.8,
46.2, 29.8
.300 8C
(white solid)
90
3f
7.23 (m, 5H),
7.01 (d, 1H),
6.85 (m, 1H),
6.76 (m, 1H),
2.98 (t, 2H),
2.62 (t, 2H)
171.7, 152.9,
141.5, 140.5,
128.0, 127.8,
125.5, 121.7,
117.2, 112.7,
111.4, 43.6,
32.6
.300 8C
(white solid)
88
3g
7.62 (d, 2H),
7.47 (d, 2H),
6.99 (d, 1H),
6.88 (q, 1H),
6.76 (d, 1H),
3.24 (t, 2H),
2.91 (t, 2H)
171.5, 155.5,
143.7, 136.2,
129.4, 128.3,
127.4, 127.1,
126.8, 126.5,
126.6, 124.9,
124.9, 124.9,
124.4, 122.9,
120.2, 117.7,
115.8, 113.10,
47.1, 33.5
.300 8C
(white solid)
85
period of 20 min at 208C. The resulting mixture was stirred under reflux for about
20 min and then concentrated. The excess reagent was decomposed with water
and extracted with ethyl acetate. The extract was washed with water, dried
over anhydrous sodium sulfate, filtered, and concentrated. The crude residue
was diluted with methylene chloride (30.0 cm3), and silica gel (5.00 g) was
added. The resulting mixture was stirred at room temperature for 30 min and
filtered through Celiterw, and the filtrate was evaporated. The residue was
purified by recrystallization from ethyl acetate and hexane to give the product
(Table 2).

Synthesis of 5-(N-Phenethylamino)salicylic Acid Derivatives
1829
General Procedure for the Hydrolysis of Compounds 2
A solution of 2a (1.45 mmol) and glacial acetic acid (10.0 cm3) in 6N HCl
(20.0 cm3) was heated under reflux for 6 h. The solution was evaporated to
give a solid, which was washed with H2O and diethyl ether and filtered to give
3a as a white solid (Table 3).
ACKNOWLEDGMENT
This study was supported by the Post Brain Korea 21 program.
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