A simple, mild, and practical method for the esterification and thioesterification of anthranilic acid utilizing N -(2-Aminobenzoyl) benzotriazole

Article abstract of DOI:10.1055/s-0033-1339469

A convenient and efficient method for the preparation of anthranilic esters and anthranilic thioesters has been developed by the treatment of N-(2-aminobenzoyl)benzotriazoles with alcohols and thiols in the presence of 4-(dimethylamino)pyridine (DMAP).

Full text of DOI:10.1055/s-0033-1339469

PAPER
▌2551
paper
A Simple, Mild, and Practical Method for the Esterification and Thioesteri-
fication of Anthranilic Acid Utilizing N-(2-Aminobenzoyl)benzotriazole
Esterification and Thioesterification of Anthranilic Acid
Şule Kökten, İlhami Çelik*
Department of Chemistry, Faculty of Science, Anadolu University, 26470 Eskişehir, Turkey
Fax +90(222)3204910; E-mail: ilcelik@anadolu.edu.tr
Received: 01.05.2013; Accepted after revision: 26.06.2013
like alkyl halides,11a dialkyl carbonate,11b diazometh-
Abstract: A convenient and efficient method for the preparation of
ane,11c polymer-supported triazine (PST),11d or dimethyl
anthranilic esters and anthranilic thioesters has been developed by
carbonate/diethyl carbonate;11e (ii) the reaction of 2-nitro-
the treatment of N-(2-aminobenzoyl)benzotriazoles with alcohols
benzoic acid 2 with an alcohol, followed by catalytic re-
duction of the nitro group;12 (iii) the reaction of isatoic
anhydride 3 with alcohols;13 (iv) the metal-catalyzed
methoxycarbonylation of 2-bromoaniline 4;14 and (v) the
reduction of o-halobenzoates15a,b 5 or the amination of o-
azidobenzoates in the presence of various reagents.15c
and thiols in the presence of 4-(dimethylamino)pyridine (DMAP).
Key words: alcohols, esterification, esters, heterocycles, thiols
The synthesis of anthranilic acid derivatives is an impor-
tant and useful task in organic chemistry owing to their
importance in the preparation of nitrogen-containing
heterocycles1 with biologically or pharmacologically im-
portant activity, such as antitumor, antihypertensive, anal-
gesic, or antibacterial activity. In addition to the use of
anthranilic acid derivatives in the synthesis of heterocy-
clic compounds, some amide derivatives of anthranilic
acid show biological activity2 or they serve as starting ma-
terials for o-aminonitriles, which are versatile synthons
for useful heterocycles.3 Because of their powerful and
pleasant scents and tastes, some anthranilic acid esters
find more application in the fragrance and flavor indus-
tries.4 Contributing to their industrial and synthetic impor-
tance, some ester derivatives of anthranilic acid also
exhibit antibacterial and antifungal activity against
microorganism5 and some are effective as a repellent to
prevent birds feeding on crops.6 Glafenine, a useful an-
thranilic acid ester derivative, is used as an analgesic.7
Like most anthranilic acid derivatives, thioester deriva-
tives of anthranilic acid are also useful substrates for the
O
O
O
OH
NO2
R1
R1
O
N
H
O
ii
2
3
iii
O
Br
iv
i
OH
OR2
NH2
R1
R1
R1
NH2
NH2
4
1
6
v
O
OR3
R1
X = Cl, Br, I, N3
X
5
Scheme 1 The preparation of anthranilic esters; for i–v see the dis-
cross coupling of organostannanes to give ketones,8 for cussion
the protection of various thiols,9 and for the preparation of
symmetrical disulfides that have significant activity
Acetyl CoA is an important thioesters that appears in
many biological processes.16 Apart from their biological
importance, thioesters have also widespread applications
in synthetic organic chemistry for the preparation of nu-
merous compounds. However, only two methods are re-
ported for anthranilic thioesters 7 (Scheme 2): (i) the
thermolysis of methyl anthranilate 6 with thiophenol;17
and (ii) the reaction of isatoic anhydride 3 with various
thiols.8,9,13a
against human malignant cell lines including chemothera-
py-resistant subclones, and they can serve as starting ma-
terials for the synthesis of various novel derivatives of
quinolinone.1c
There are many studies that employed different routes and
reagents to anthranilamides in the literature. However,
most studies on the synthesis of anthranilic acid esters and
thioesters are mainly based on the esterification of anthra-
nilic acid or isatoic anhydride with an alcohol and thiol.
Literature methods to anthranilic esters 6 include (Scheme
1): (i) the reaction of anthranilic acid 1 with alcohols in the
presence of acid catalysts4,5,10 or with an alkylating agent,
O
O
O
OR2
SR3
NH2
O
ii
i
R1
R1
R1
NH2
N
H
O
6
7
3
SYNTHESIS 2013, 45, 2551–2556
Advanced online publication: 19.07.2013
DOI: 10.1055/s-0033-1339469; Art ID: SS-2013-T0326-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 The preparation of anthranilic thioesters; for i and ii see
the discussion
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2552
Ş. Kökten, İ. Çelik
PAPER
Esterification of anthranilic acid with an alcohol is often of anthranilic acid at this active center was considered as
conducted under strongly acidic conditions. However, the cause of the low yield of 6m (24%).
acid-catalyzed esterification of anthranilic acid is ex-
tremely difficult owing to the presence of the ortho-sub-
stituted amine functionality. Large amounts of acid are
required to block the ortho position of anthranilic acid be-
fore it is esterified with an alcohol. Using acid in large
amounts leads to disposal problems after the reaction.4,5,10
Alkylating agents used in some methods for the synthesis
of anthranilic esters are toxic and explosive;11c in addition,
some are unstable at room temperature11d or are not suffi-
ciently reactivity,11e hence high reaction temperatures and
long reaction times are required. The reaction of isatoic
anhydride with an alcohol is a well-known general meth-
od for the preparation of anthranilic esters and thioesters.
However, this method commonly requires the handling of
toxic reagents to prepare suitable isatoic anhydrides.18
Steric hindrance and the nature and the activity of the nu-
cleophile may also stimulate the formation of byprod-
ucts.13a There are few studies and a limited variety of
substrates for the synthesis of anthranilic acid thioesters.
The methods used in these studies mainly employed isato-
ic anhydrides. These literature procedures have some
drawbacks like high temperatures,8,13a,17 long reaction
times,9 or unsatisfactory yields.17 In the light of these
facts, there is still a need for more general methods and al-
ternative active derivatives of anthranilic acid, capable of
reacting with nucleophiles directly under mild conditions.
Table 1 Preparation of Anthranilic Acid Esters 6a–n
O
O
R2OH
OR2
NH2
Bt
NH2
R1
R1
DMAP, CH2Cl2
r.t.
8
6a–n
Entry
Product R1
R2
Ph
Yield (%)
1
6a
6b
6c
6d
6e
6f
H
80 (92)a
91
2
3-Me
4-Me
5-Me
6-Me
5-OMe
4-Cl
4-MeOC6H4
CH2CH2OEt
Ph
3
67
4
78 (91)a
55
5
cyclopentyl
Cy
6
94
7
6g
6h
6i
i-Pr
84
8
5-Cl
Pr
97
9
5-Br
(CH2)3Ph
4-ClC6H4
Pr
98
10
11
12
13
14
6j
5-I
97
6k
6l
3,5-Cl2
3,5-Br2
4,5-(OMe)2
92
N-Acylbenzotriazoles are stable crystalline compounds
and that are readily prepared in one step from carboxylic
acids even in cases where an acid-sensitive functionality
is present. They are of great importance in the synthesis of
heterocycles19a and ketones,19b for the conversion of
amines into amides,19c,d and for the acylation of alcohols
and thiols to give esters19e and thioesters.19e,f
(CH2)4Me
CH2CH2Br
88
6m
6n
24
3,4,5-(OMe)3 (CH2)3CH=CH2 90
a Reported yields.13b
We have recently synthesized amide derivatives of an-
thranilic acid using N-acylbenzotriazoles in high yields.20
We first prepared N-(2-aminobenzoyl)benzotriazoles by
activation of anthranilic acid with benzotriazole using
mild N,N′-dicyclohexylcarbodiimide coupling conditions
and then treatment with ammonia or primary and second-
ary amines to synthesize anthranilic acid amides. In con-
tinuation of our previous work, we herein aimed to
synthesize the ester and thioester derivatives of anthranil-
ic acids.
The structure of anthranilic acid esters 6a–n was proven
by various spectroscopic methods. The disappearance of
the signals observed at δ = 8.37–8.17 as doublets and at
δ = 7.69–7.55 as triplets in 1H NMR indicated the loss of
the benzotriazolyl group during the reaction. The 13C
NMR spectra of compounds clearly showed a signal at
δ = 166.3–167.9 corresponding to the ester carbonyl
groups of the products. Moreover, mass and IR spectral
data were also in accordance with the proposed structures.
Treatment of N-(2-aminobenzoyl)benzotriazoles 8 with
various thiols bearing alkyl, aryl, thiol, and ester moieties
resulted in the formation of anthranilic acid thioesters 7a–
i with different structural features. The reactions proceed-
ed in dichloromethane with 4-(dimethylamino)pyridine as
the catalyst at room temperature. Anthranilic acid thioes-
ters were successfully synthesized in high yields (Table
2). NMR spectral data supported the structural assign-
ments of anthranilic acid thioesters. In addition to the ab-
Anthranilic acid esters 6a–n were synthesized by the reac-
tion of various alcohols with N-(2-aminobenzoyl)benzo-
triazoles 8 in the presence of 4-(dimethylamino)pyridine
at room temperature (Table 1). Using this method, a wide
variety of anthranilic acid esters with alkyl, aryl, ether, cy-
cloalkyl, haloalkyl, and alkenyl moieties attached to the
ester oxygen were synthesized under mild reaction condi-
tions in high yields. The method worked well for all kinds
of alcohols, except in the case of the synthesis of 6e and
6m. Due to the steric effect of the 6-methyl group, conver-
sion into 6e was achieved in only 55% yield. The alcohol
used in the synthesis of 6m has an active carbon attached
to bromide. Therefore, the attack of the free amino group
1
sence of benzotriazole signals observed by H and 13C
13
NMR, C NMR spectra of the products 7a–i revealed a
characteristic signal in the region δ = 189.8–196.7, which
corresponds to the thioester carbonyl carbon. Data ob-
Synthesis 2013, 45, 2551–2556
© Georg Thieme Verlag Stuttgart · New York

PAPER
Esterification and Thioesterification of Anthranilic Acid
2553
Phenyl 2-Aminobenzoate (6a)
Eluent: EtOAc–hexane, 1:3; white solid; yield: 0.171 g (80%); mp
70–71 °C.
tained from mass spectrometry and IR spectroscopy were
compatible with the NMR results.
IR (KBr): 3468, 3363, 1691 cm–1.
Table 2 Preparation of Anthranilic Acid Thioesters 7a–i
1H NMR: δ = 8.14 (d, J = 8.0 Hz, 1 H), 7.47 (t, J = 7.9 Hz, 2 H), 7.38
(t, J = 7.7 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1
H), 6.77–6.74 (m, 2 H), 5.81 (br s, 2 H).
13C NMR: δ = 166.9, 151.3, 150.8, 134.9, 131.6, 129.5, 125.8,
122.0, 116.8, 116.4, 109.7.
MS (EI): m/z = 213.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C13H12NO2: 214.0868;
O
O
R2SH
SR2
NH2
Bt
R1
R1
DMAP, CH2Cl2
r.t.
NH2
7a–i
8
Entry
Product
R1
R2
Yield (%)
found: 214.0863.
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
H
CH2CH2SH
Ph
80
85
100
97
71
90
91
92
96
4-Methoxyphenyl 2-Amino-3-methylbenzoate (6b)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.234 g (91%); mp
136–137 °C.
IR (KBr): 3490, 3361, 1709 cm–1.
1H NMR: δ = 8.04 (d, J = 8.5 Hz, 1 H), 7.29 (d, J = 6.0 Hz, 1 H),
7.13 (d, J = 7.0 Hz, 2 H), 6.98 (d, J = 9.0 Hz, 2 H), 6.69 (t, J = 7.5
Hz, 1 H), 5.91 (br s, 2 H), 3.83 (s, 3 H), 2.28 (s, 3 H).
13C NMR: δ = 168.7, 158.2, 150.7, 145.2, 136.3, 130.3, 123.8,
123.5, 116.5, 115.2, 109.9, 56.0, 17.6.
MS (EI): m/z = 257.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C15H16NO3: 258.1130;
3-Me
3-Me
4-Me
5-Me
4,5-(OMe)2
4-Cl
CH2CO2Et
Ph
CH2CH2SH
CH2CO2Et
CH2CO2Et
Ph
7g
7h
7i
5-Br
5-I
Et
found: 258.1122.
2-Ethoxyethyl 2-Amino-4-methylbenzoate (6c)
Eluent: EtOAc–hexane, 1:4; yellow oil; yield: 0.150 g (67%).
IR (KBr): 3479, 3371, 1689 cm–1.
1H NMR: δ = 7.81 (d, J = 8.5 Hz, 1 H), 6.50–6.49 (m, 2 H), 5.67 (br
s, 2 H), 4.43 (t, J = 4.8 Hz, 2 H), 3.77 (t, J = 5.0 Hz, 2 H), 3.60 (q,
J = 7.0 Hz, 2 H), 2.29 (s, 3 H), 1.25 (t, J = 7.0 Hz, 3 H).
13C NMR: δ = 168.0, 150.5, 144.9, 131.4, 117.8, 116.8, 108.4, 68.5,
66.7, 63.4, 21.7, 15.2.
MS (EI): m/z = 223.1 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C12H18NO3: 224.1287;
In conclusion, we have used a new and general method to
prepare a series of anthranilic acid esters and thioesters
with different functionalities utilizing readily accessible
N-(2-aminobenzoyl)benzotriazoles. The free amino group
in the substrates did not cause any side reactions except
for 6m and the products were obtained in high yields. The
method used in the synthesis has the advantage of opera-
tional simplicity, mild reaction condition, ready availabil-
ity of substrates, and simple reaction work up, compared
to literature methods for the preparation of anthranilic
acid esters and thioesters.
found: 224.1276.
Phenyl 2-Amino-5-methylbenzoate (6d)
Eluent: EtOAc–hexane, 1:5; yellow solid; yield: 0.178 g (78%); mp
60–61 °C.
IR (KBr): 3486, 3378, 1704 cm–1.
1H NMR: δ = 7.93 (s, 1 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.30 (t, J = 8.0
Hz, 1 H), 7.23–7.20 (m, 3 H), 6.68 (d, J = 8.0 Hz, 1 H), 5.65 (br s,
2 H), 2.32 (s, 3 H).
13C NMR: δ = 167.9, 151.8, 150.1, 136.9, 131.9, 130.3, 126.5,
126.3, 122.8, 117.7, 110.2, 20.4.
MS (EI): m/z = 227.1 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C14H14NO2: 228.1025;
Column chromatography was performed on silica gel 70–230 mesh.
All melting points were determined on a Mettler Toledo apparatus
1
and uncorrected. H and 13C NMR spectra were recorded at 500
MHz and 125 MHz respectively on a Bruker Advance 500 DPX
spectrometer in CDCl3 using TMS as an internal reference. IR spec-
tra of products were obtained on a Perkin Elmer 100 FTIR spectro-
photometer. Mass spectral data were taken on a Thermo Finnigan
PolarisQ GC-MS spectrometer and Waters SYNAPT MS System
HRMS spectrometer. N-(2-Aminobenzoyl)benzotriazoles were
synthesized by reaction of the corresponding acids with BtH in the
presence of DCC following the reported one-step procedure.20
Other reagents obtained commercially were used without further
purification.
found: 228.1028.
Cyclopentyl 2-Amino-6-methylbenzoate (6e)
Eluent: EtOAc–hexane, 1:4; yellow oil; yield: 0.120 g (55%).
IR (KBr): 3481, 3377, 1683 cm–1.
1H NMR: δ = 7.09 (t, J = 7.8 Hz, 1 H), 6.55 (d, J = 7.5 Hz, 2 H),
5.47–5.44 (m, 1 H), 5.15 (br s, 2 H), 2.45 (s, 3 H), 1.99–1.96 (m, 2
H), 1.91–1.89 (m, 2 H), 1.82–1.79 (m, 2 H), 1.70–1.68 (m, 2 H).
13C NMR: δ = 169.1, 149.0, 139.9, 131.8, 120.4, 114.6, 65.9, 32.9,
23.8, 23.0, 15.3.
2-Aminobenzoates 6a–n and 2-Aminothiobenzoates 7a–i;
General Procedure
A mixture of N-(2-aminobenzoyl)benzotriazole 8 (1.0 mmol), alco-
hol (1.2 mmol) or thiol (1.2 mmol), and DMAP (0.122 g, 1.0 mmol)
in CH2Cl2 (5 mL) was stirred for 6–12 h ( 6) or 4–6 h (7) at r.t. After
the completion of the reaction, the solvent was removed under re-
duced pressure. The residue was purified by column chromatogra-
phy to afford the desired product.
MS (EI): m/z = 219.1 [M+].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2551–2556

2554
Ş. Kökten, İ. Çelik
PAPER
HRMS-MALDI: m/z [M + H]+ calcd for C13H18NO2: 220.1338;
MS (EI): m/z = 372.9 [M+].
found: 220.1325.
HRMS-MALDI: m/z [M + H]+ calcd for C13H10ClINO2: 373.9445;
found: 373.9460.
Cyclohexyl 2-Amino-5-methoxybenzoate (6f)
Eluent: EtOAc–hexane, 1:4; yellow oil; yield: 0.235 g (94%).
Propyl 2-Amino-3,5-dichlorobenzoate (6k)
Eluent: hexane; white solid; yield: 0.228 g (92%); mp 33–35 °C.
IR (KBr): 3479, 3375, 1689 cm–1.
1H NMR: δ = 7.43 (d, J = 3.0 Hz, 1 H), 6.97 (dd, J = 9.0, 3.0 Hz, 1
H), 6.68 (d, J = 8.5 Hz, 1 H), 5.50 (br s, 2 H), 5.03–5.01 (m, 1 H),
3.80 (s, 3 H), 1.98–1.95 (m, 2 H), 1.82–1.80 (m, 2 H), 1.63–1.58 (m,
2 H), 1.50–1.44 (m, 2 H).
13C NMR: δ = 167.3, 150.7, 144.7, 122.4, 118.3, 114.0, 112.0, 72.6,
55.9, 31.7, 25.5, 23.7.
MS (EI): m/z = 249.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C14H20NO3: 250.1443;
IR (KBr): 3496, 3356, 1698 cm–1.
1H NMR: δ = 7.81 (d, J = 2.5 Hz, 1 H), 7.42 (d, J = 2.5 Hz, 1 H),
4.26 (t, J = 6.8 Hz, 2 H), 1.81 (p, J = 7.0 Hz, 2 H), 1.04 (t, J = 7.5
Hz, 3 H).
13C NMR: δ = 167.8, 146.3, 134.1, 130.1, 121.5, 120.4, 113.2, 67.1,
22.2, 10.6.
MS (EI): m/z = 247.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C10H12Cl2NO2: 248.0245;
found: 250.1444.
found: 248.0236.
Isopropyl 2-Amino-4-chlorobenzoate (6g)
Pentyl 2-Amino-3,5-dibromobenzoate (6l)
Eluent: EtOAc–hexane, 1:10; yellow oil; yield: 0.178 g (84%).
Eluent: EtOAc–hexane, 1:4; colorless oil; yield: 0.322 g (88%).
IR (KBr): 3480, 3372, 1689 cm–1.
IR (KBr): 3484, 3355, 1694 cm–1.
1H NMR: δ = 7.81 (d, J = 9.0 Hz, 1 H), 6.68 (d, J = 2.0 Hz, 1 H),
6.62 (dd, J = 8.5, 2.0 Hz, 1 H), 5.84 (br s, 2 H), 5.22 (h, J = 6.3 Hz,
1 H), 1.33 (d, J = 6.0 Hz, 6 H).
13C NMR: δ = 167.1, 151.2, 139.8, 132.6, 116.6, 115.9, 110.0, 67.9,
22.0.
MS (EI): m/z = 213.1 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C10H13ClNO2: 214.0635;
1H NMR: δ = 7.99 (d, J = 2.5 Hz, 1 H), 7.70 (d, J = 2.0 Hz, 1 H),
6.39 (br s, 2 H), 4.30 (t, J = 6.8 Hz, 2 H), 1.80–1.76 (m, 2 H), 1.43–
1.41 (m, 4 H), 0.96 (t, J = 6.8 Hz, 3 H).
13C NMR: δ = 166.6, 146.6, 139.0, 133.0, 113.0, 111.1, 106.4, 65.4,
28.3, 28.1, 22.4, 14.0.
MS (EI): m/z = 362.9 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C12H16Br2NO2: 363.9548;
found: 214.0634.
found: 363.9555.
Propyl 2-Amino-5-chlorobenzoate (6h)
2-Bromoethyl 2-Amino-4,5-dimethoxybenzoate (6m)
Eluent: EtOAc–hexane, 1:3; yellow oil; yield: 0.206 g (97%).
Eluent: CH2Cl2); white solid; yield: 0.074 g (24%); mp 95–96 °C.
IR (KBr): 3485, 3373, 1694 cm–1.
IR (KBr): 3449, 3341, 1669 cm–1.
1H NMR: δ = 7.35 (s, 1 H), 6.17 (s, 1 H), 5.61 (br s, 2 H), 4.59 (t,
J = 6 Hz, 2 H), 3.90 (s, 3 H), 3.86 (s, 3 H), 3.66 (t, J = 6.3 Hz, 2 H).
13C NMR: δ = 167.0, 155.2, 147.4, 140.7, 112.6, 101.5, 99.3, 63.4,
56.4, 55.8, 29.2.
MS (EI): m/z = 303.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C11H15BrNO4: 304.0184;
1H NMR: δ = 7.85 (d, J = 2.5 Hz, 1 H), 7.23 (dd, J = 9.0, 2.5 Hz, 1
H), 6.63 (d, J = 9.0 Hz, 1 H), 5.77 (br s, 2 H), 4.25 (t, J = 6.8 Hz, 2
H), 1.83–1.79 (m, 2 H), 1.05 (t, J = 7.5 Hz, 3 H).
13C NMR: δ = 167.3, 149.0, 134.0, 130.4, 120.6, 118.0, 111.8, 66.3,
22.1, 10.6.
MS (EI): m/z = 213.2 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C10H13ClNO2: 214.0635;
found: 304.0182.
found: 214.0645.
Pent-4-enyl 2-Amino-3,4,5-trimethoxybenzoate (6n)
3-Phenylpropyl 2-Amino-5-bromobenzoate (6i)
Eluent: EtOAc–hexane, 1:4; yellow oil; yield: 0.266 g (90%).
Eluent: EtOAc–hexane, 1:4; yellow oil; yield: 0.328 g (98%).
IR (KBr): 3492, 3375, 1687 cm–1.
IR (KBr): 3487, 3376, 1694 cm–1.
1H NMR: δ = 7.18 (s, 1 H), 5.90–5.85 (m, 1 H), 5.70 (br s, 2 H), 5.09
(dd, J = 15.5, 1.5 Hz, 1 H), 5.03 (dd, J = 10.0, 1.0 Hz, 2 H), 4.31 (t,
J = 6.5 Hz, 2 H), 3.97 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 2.23 (q,
J = 7.2 Hz, 2 H), 1.88 (p, J = 7.0 Hz, 2 H).
13C NMR: δ = 167.6, 147.4, 143.5, 140.9, 140.4, 137.6, 115.3,
108.5, 105.1, 63.8, 60.9, 60.3, 56.5, 30.3, 28.0.
MS (EI): m/z = 295.1 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C15H22NO5: 296.1498;
1H NMR: δ = 7.96 (d, J = 2.5 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 3 H), 7.25
(d, J = 7.5 Hz, 3 H), 6.59 (d, J = 8.5 Hz, 1 H), 5.79 (br s, 2 H), 4.32
(t, J = 6.5 Hz, 2 H), 2.81 (t, J = 7.5 Hz, 2 H), 2.16–2.12 (m, 2 H).
13C NMR: δ = 167.1, 149.4, 141.1, 136.8, 133.3, 128.5, 128.4,
126.1, 118.4, 112.2, 107.3, 64.1, 32.4, 30.2.
MS (EI): m/z = 333.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C16H17BrNO2: 334.0443;
found: 334.0438.
found: 296.1489.
4-Chlorophenyl 2-Amino-5-iodobenzoate (6j)
Eluent: EtOAc–hexane, 1:4; pink solid; yield: 0.360 g (97%); mp
96–97 °C.
IR (KBr): 3460, 3353, 1694 cm–1.
1H NMR: δ = 8.36 (d, J = 2.0 Hz, 1 H), 7.57 (dd, J = 8.8, 2.3 Hz, 1
H), 7.42 (d, J = 8.5 Hz, 2 H), 7.15 (d, J = 9.0 Hz, 2 H), 6.53 (d, J =
9.0 Hz, 1 H), 5.85 (br s, 2 H).
S-2-Mercaptoethyl 2-Aminobenzothioate (7a)
Eluent: EtOAc–hexane, 1:3; yellow oil; yield: 0.170 g (80%).
IR (KBr): 3479, 3368, 1641 cm–1.
1H NMR: δ = 7.90 (d, J = 10.0 Hz, 1 H), 7.30 (t, J = 5.0 Hz, 1 H),
6.70–6.67 (m, 2 H), 5.87 (s, 2 H), 3.26 (t, J = 5.0 Hz, 2 H), 2.81 (q,
J = 10.0 Hz, 2 H), 1.72 (t, J = 7.5 Hz, 1 H).
13C NMR: δ = 192.1, 148.3, 134.5, 130.2, 118.1, 117.1, 116.4, 32.8,
24.9.
13C NMR: δ = 166.3, 151.6, 149.9, 144.0, 140.5, 132.2, 130.4,
124.0, 119.7, 112.0, 76.4.
MS (EI): m/z = 213.0 [M+].
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HRMS-MALDI: m/z [M + H]+ calcd for C9H12NOS2: 214.0360;
MS (EI): m/z = 299.2 [M+].
found: 214.0358.
HRMS-MALDI: m/z [M + H]+ calcd for C13H17NO5S: 299.0827;
found: 299.0820.
S-Phenyl 2-Amino-3-methylbenzothioate (7b)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.268 g (85%); mp
118–120 °C.
IR (KBr): 3497, 3377, 1651 cm–1.
Ethyl 2-(2-Amino-4-chlorobenzoylthio)acetate (7g)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.248 g (91%); mp
108–110 °C.
1H NMR: δ = 7.96 (d, J = 10.0 Hz, 1 H), 7.56–7.48 (m, 5 H), 7.28
(t, J = 7.5 Hz, 1 H), 6.70 (t, J = 7.5 Hz, 1 H), 5.95 (br s, 2 H), 2.19
(s, 3 H).
IR (KBr): 3472, 3355, 1734, 1655 cm–1.
1H NMR: δ = 7.82 (d, J = 10.0 Hz, 1 H), 6.68–6.65 (m, 2 H), 5.96
(br s, 2 H), 4.25 (q, J = 7.5 Hz, 2 H), 3.83 (s, 2 H), 1.33 (t, J = 7.5
Hz, 3 H).
13C NMR: δ = 191.8, 147.8, 135.7, 135.4, 129.4, 129.2, 128.3,
128.2, 123.6, 117.1, 115.9, 17.4.
MS (EI): m/z = 243.0 [M+].
13C NMR: δ = 190.2, 169.0, 149.1, 140.9, 131.6, 116.9, 116.3,
116.1, 61.9, 31.3, 14.2.
HRMS-MALDI: m/z [M + H]+ calcd for C14H14NOS: 244.0796;
MS (EI): m/z = 273.0 [M+].
found: 244.0791.
HRMS-MALDI: m/z [M + H]+ calcd for C11H13ClNO3S: 274.0305;
found: 274.0316.
Ethyl 2-(2-Amino-3-methylbenzoylthio)acetate (7c)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.252 g (100%);
mp 58–60 °C.
IR (KBr): 3482, 3369, 1741, 1630 cm–1.
S-Phenyl 2-Amino-5-bromobenzothioate (7h)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.282 g (92%); mp
146–148 °C.
1H NMR: δ = 7.83 (d, J = 10.0 Hz, 1 H), 5.96 (br s, 2 H), 4.25 (q,
J = 5.0 Hz, 2 H), 3.83 (s, 2 H), 2.19 (s, 3 H), 1.32 (t, J = 5.0 Hz, 3 H).
13C NMR: δ = 191.2, 169.3, 146.8, 135.4, 128.3, 123.5, 117.1,
IR (KBr): 3485, 3371, 1653 cm–1.
1H NMR: δ = 8.14 (d, J = 5.0 Hz, 1 H), 7.54–7.49 (m, 5 H), 7.39 (dd,
J = 10.0, 5.0 Hz, 1 H), 6.60 (d, J = 5.0 Hz, 1 H), 5.86 (br s, 2 H).
115.9, 61.8, 31.4, 17.3, 14.2.
MS (EI): m/z = 253.0 [M+].
13C NMR: δ = 190.7, 147.4, 137.4, 135.6, 132.3, 129.7, 129.3,
127.3, 118.9, 118.8, 107.4.
HRMS-MALDI: m/z [M + H]+ calcd for C12H16NO3S: 254.0851;
MS (EI): m/z = 307.0 [M+].
found: 254.0854.
HRMS-MALDI: m/z [M + H]+ calcd for C13H11BrNOS: 307.9745;
found: 307.9751.
S-Phenyl 2-Amino-4-methylbenzothioate (7d)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.236 g (97%); mp
101–102 °C.
IR (KBr): 3437, 3346, 1639 cm–1.
S-Ethyl 2-Amino-5-iodobenzothioate (7i)
Eluent: EtOAc–hexane, 1:3; yellow solid; yield: 0.295 g (96%); mp
76–78 °C.
1H NMR: δ = 7.92 (d, J = 10.0 Hz, 1 H), 7.55–7.47 (m, 5 H), 6.57
(d, J = 10.0 Hz, 1 H), 6.50 (s, 1 H), 5.87 (br s, 2 H), 2.32 (s, 3 H).
13C NMR: δ = 190.7, 148.6, 145.8, 135.7, 130.3, 129.1, 128.1,
IR (KBr): 3421, 3319, 1628 cm–1.
1H NMR: δ = 8.16 (s, 1 H), 7.50 (d, J = 10.0 Hz, 1 H), 6.48 (d, J =
10.0 Hz, 1 H), 5.85 (br s, 2 H), 3.05 (q, J = 10.0 Hz, 2 H), 1.36 (t,
J = 5.0 Hz, 3 H).
118.1, 117.2, 115.5, 21.7.
MS (EI): m/z = 242.8 [M+].
13C NMR: δ = 192.3, 147.3, 142.3, 138.4, 120.8, 119.3, 75.8, 23.5,
14.8.
HRMS-MALDI: m/z [M + H]+ calcd for C14H14NOS: 244.0796;
found: 244.0785.
MS (EI): m/z = 307.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C9H11INOS: 307.9606;
found: 307.9621.
S-2-Mercaptoethyl 2-Amino-5-methylbenzothioate (7e)
Eluent: EtOAc–hexane, 1:3; yellow oil; yield: 0.162 g (71%).
IR (KBr): 3479, 3368, 1641 cm–1.
1H NMR: δ = 7.96 (s, 1 H), 7.13 (d, J = 10.0 Hz, 1 H), 6.61 (d, J =
10.0 Hz, 1 H), 3.26 (t, J = 7.5 Hz, 2 H), 2.81 (q, J = 10.0 Hz, 2 H),
2.28 (s, 3 H), 1.72 (t, J = 7.5 Hz, 1 H).
13C NMR: δ = 191.9, 146.1, 135.8, 129.7, 125.6, 118.0, 117.3, 32.8,
24.9, 20.4.
Acknowledgment
It is gratefully acknowledged that this work was supported financi-
ally by Anadolu University (Project No: 1002F88) and we are also
grateful to AUBIBAM for providing 1H and 13C NMR spectra.
MS (EI): m/z = 227.0 [M+].
HRMS-MALDI: m/z [M + H]+ calcd for C10H14NOS2: 228.1025;
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