A new protocol for the synthesis of primary, secondary and tertiary anthranilamides utilizing N-(2-aminoarylacyl)benzotriazoles

Article abstract of DOI:10.3998/ark.5550190.0013.818

A convenient route for efficient conversion of unprotected anthranilic acids into the corresponding N-(2-aminoarylacyl)benzotrazoles is described. N-(2-Aminoarylacyl)-benzotrazoles have been successfully used to synthesize primary, secondary and tertiary anthranilamides in high yields (71-96%). ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.0013.818

General Papers
ARKIVOC 2012 (viii) 198-213
A new protocol for the synthesis of primary, secondary and tertiary
anthranilamides utilizing N-(2-aminoarylacyl)benzotriazoles
Nevin Kanışkan, Şule Kökten, and İlhami Çelik*
Department of Chemistry, Faculty of Science, Anadolu University, Eskişehir – 26470, Turkey
E-mail: ilcelik@anadolu.edu.tr
Abstract
A convenient route for efficient conversion of unprotected anthranilic acids into the
corresponding
N-(2-aminoarylacyl)benzotrazoles is
described.
N-(2-Aminoarylacyl)-
benzotrazoles have been successfully used to synthesize primary, secondary and tertiary
anthranilamides in high yields (71-96%).
Keywords: Anthranilic acid, benzotriazole, N-(2-aminoarylacyl)benzotrazoles, anthranilamides
Introduction
Amides are of great importance in synthetic organic chemistry because of the numerous natural
products (e.g. peptides and proteins) and potential drug compounds that contain amide bond, like
acetaminophen, an analgesic; lidocaine (Xylocaine), a local anaesthetic and loperamide
(Imodium AD), an anti-diarrheal. Amides are also used in different areas of industry1 (e.g. plastic
and rubber industry, and paper industry). As a consequence, much effort has been put onto
synthesize new derivatives of amides using mild ways. Anthranilamides are an example of useful
compounds containing amide bond since they are used as a starting compound or an intermediate
in the synthesis of biologically important compounds such as quinazolones,2 quinazolinones3a-c
and benzoxazinones.3c,4 In addition, some amide derivatives of anthranilic acid show biological
activities5 or they are the starting materials for o-aminonitriles which are versatile synthons to get
some useful heterocycles.6 Literature methods for synthesizing anthranilamides are: (i) the
reaction of anthranilic acid with amine in the presence of various reagents (SOCl2,7a EDC /
HOBt,7b CDI,7c BAC,7d HOSu / DCC,7e DCC / HOBt7f) (ii) the reaction of anthranilesters with
amines,8 (iii) the catalytically reduction of 2-nitrobenznitriles,9 (iv) the reaction of 2-nitrobenzoic
acid activated by SOCl2 with an amine, and then catalytically reduction of nitro group,7f,10 and
(v) the reaction of isatoic anhydride with various amines7c,f,11,12 (Scheme 1). These methods
developed to get anthranilamides have some disadvantages like being lack of wide generality in
use, having harsh reaction conditions or complex reaction steps. Conventional activation of a
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carboxyl group using thionyl chloride cannot be safely employed in the presence of a free amino
group.7a The reactions having coupling reagents require anhydrous reaction conditions and
activated anthranilic acid intermediates cannot usually be stored, handled in moist air or
isolated.7b, e,f In addition, the method including CDI coupling with amine needs using of
phosgene in the preparation of CDI.7c The reaction of anthranilesters with amines, on the other
hand, requires harsh reaction conditions.8 Moreover, the synthesis of anthranilamides from 2-
nitrobenzonitriles involves the reduction of nitro group and the hydrolysis of nitrile group. The
difficulty in purification of the products cause low yields.9 The synthesis of anthranilamides from
2-nitro benzoic acids also has some disadvantages like the difficulty in activation of carboxylic
acid group with thionyl chloride and purification of products obtained by the reduction of nitro
group.10 The reaction of isatoic anhydride with amine is a well-known general method for the
preparation of anthranilamides. However, this method requires handling of phosgene in the
preparation of isatoic anhydride.11 Therefore, newer and versatile methods having simple
reaction procedure and reagents to prepare these compounds would be advantageous.
Scheme 1. Literature methods for synthesizing anthranilamides.
Being one of the versatile benzotriazole intermediates, N-acylbenzotriazoles have found wide
application in the acylation of various nucleophiles because of the good leaving ability of
benzotriazole group. They are widely employed in heterocyclic synthesis,13a,b N-acylation,14a-c C-
acylation,14b,15a,b S-acylation14b,16a,b and O-acylation.17 Unlike the conventional acylating agents
which are unstable to moisture and difficult to prepare and store at room temperature, N-
acylbenzotriazoles are stable crystalline compounds and they are easy to use and store at room
temperature.14a, 18 They can be prepared directly from carboxylic acids even in cases where an
acid sensitive functionality is present. In literature, N-acylbenzotriazoles are synthesized from
the reaction of carboxylic acids (i) with 1-(methylsulfonyl)benzotriazole in the presence of
triethylamine14a or (ii) with the excess amount of benzotriazole in the presence of
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thionylchloride19 and from the reaction of various aldehydes with N-chlorobenzotriazole.20 So far
today, various N-acylbenzotriazole derivatives have been synthesized from alkyl-, aryl-,
heterocyclic- and unsaturated carboxylic acids or carboxylic acids with different functionality.
However, there have been no reported studies on the direct synthesis of N-acylbenzotriazoles
using anthranilic acids. Anthranilic acid component has two different functional groups (COOH
and NH2). The presence of a free amino group makes the activation of carboxylic group difficult
and decreases the yield. Therefore, the protection and subsequent deprotection of amino group
are necessary to regenerate the amine functionality. However, the use of protecting groups has
some drawbacks, like being not economical and causing time loss.
We now report a mild one pot procedure for efficient conversion of anthranilic acids into the
corresponding N-acylbenzotriazoles having free amino group and subsequent reaction of N-
acylbenzotriazoles with ammonia, primary and secondary amines to afford substantial
anthranilamides.
Results and Discussion
As mentioned before, N-acylbenzotriazoles are highly efficient acylating agents to prepare
various kinds of compounds comparing to the conventional acylating agents which are mostly
sensitive to air and so, difficult to prepare and store at room temperature. Moreover, as an
auxiliary group benzotriazole can be recovered almost quantitatively after the reaction.
Therefore, this method has also the potential of recycling the starting material.
In the present work, anthranilic acid derivatives were successfully converted into the
corresponding N-acylbenzotriazoles in the presence of free amino group (Scheme 2). Activation
of anthranilic acid with benzotriazole was succeeded by using mild DCC coupling condition. The
presence of ortho-substituted free amine functionality in the molecules did not cause any troubles
except for 2e and 2f. The resulting compounds 2a-o were successfully isolated and purified by
column chromatography as stable, yellow colored solids in 14 – 93% yields (Table 1). All of the
N-acylbenzotriazole derivatives prepared are novel compounds and structures of products 2a-o
1
were fully characterized by IR, H NMR and 13C NMR spectroscopy. Elemental analysis and
mass spectroscopy also supported the proposed structures. The most characteristic 1H-NMR data
indicating that benzotriazole attached to the molecules are the signals which were observed for
the protons on the benzotriazole ring as doublets at 8.37 – 8.17 ppm and as triplets at 7.69 – 7.55
1
ppm. In addition to the H-NMR spectral data, 12 signals were observed for the carbons in
aromatic rings of the products in the 13C-NMR spectra.
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Scheme 2. Synthesis of N-(2-aminoarylacyl)benzotriazoles (2a-o).
Table 1. Synthesized N-(2-aminoarylacyl)benzotriazoles 2a-o from the proposed method
Yield
(%)
Mp
Yield
(%)
Mp
(oC)
R
R
(oC)
H
78
82
76
40
132 – 133
99 – 100
135 – 136
104 – 106
5-bromo
5-iodo
3,5-dichloro
3,5-dibromo
53
55
93
83
174 – 176
138 – 140
170 – 172
174 – 176
decomposed >
220
a
b
c
i
j
k
l
3-methyl
4-methyl
5-methyl
d
6-methyl
5-methoxy
4-chloro
25
14
92
74
106 – 108
107 – 109
160 – 162
153 – 155
3,5-diiodo
64
70
75
e
f
m
n
4,5-dimethoxy
3,4,5-
trimethoxy
93 – 95
115 – 117
g
h
o
5-chloro
During the preparation of N-(2-aminoarylacyl)benzotriazoles 2a-o, it was noticed that a by-
product 2′ (Figure 1) was formed with the desired products because of the nature and position of
the substituents in the corresponding anthranilic acids. The yields of by-products were almost
negligible except for 2e and 2f. The by-products 2e′ and 2f′ were isolated by column
1
chromatography in 27 % and 42 yields respectively. Their structures were supported by H and
13C NMR spectra. The expected signals which belong to benzotriazole ring weren’t observed in
13
1H and C NMR spectra. Moreover, for the two carbonyl carbons in the structures, two signals
were observed in 13C NMR spectra. MS spectra also support the structures of these side products.
Steric hindrance of the methyl group, which is in ortho position to the carboxylic acid, caused the
low yield of the desired product 2e. In case of 2f, the methoxy group present in para position to
amino group increased nucleofilicity of amino group and caused the formation of by-product.
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Figure 1. The by-product produced during the activation of anthranilic acids with benzotriazole.
The reaction of N-(2-aminoarylacyl)benzotriazoles with ammonia, various primary and
secondary amines gives primary, secondary and tertiary anthranilamides. In spite of having free
amino groups, no complications were observed and the reactions were rather straight forward.
Therefore, anthranilamides were synthesized in high yields (71-96%). Spectroscopic studies have
provided strong evidence that amides formed. Especially, the disappearance of the benzotriazole
1
signals in the aromatic region of H-NMR spectra indicates the loss of the benzotriazolyl group
during the reaction and shows the formation of amides. Characteristic amide peaks were
observed for all compounds on IR spectra. Moreover, mass spectra show that the expected
molecular ion and the fragmentation are in accordance with the proposed structures.
Primary anthranilamides were efficiently synthesized by treatment of N-acylbenzotriazoles
o
with excess ammonium hydroxide (27% aqueous solution) in THF at 0 C for 2 hours (Scheme
3). The products were isolated by column chromatography in 82-96% yields (Table 2) and
1
characterized spectrally and by elemental analyses. The H-NMR spectrum showed two broad
signals for each proton of amino groups attached to the carbonyl group at 8.06-7.58 ppm and
7.47-6.44 ppm, which are in agreement with the reported values for these types of
compounds.21a,b Similarly, the signals in the 13C-NMR spectra for carbonyl carbons were
observed at 172.8-170.5 ppm, apart from six carbon signals for aromatic ring in the aromatic
region. In addition to spectral and elemental analysis, the melting points of the products were
measured (Table 2).
Scheme 3. Synthesis of primary amides (3a-g) from N-(2-aminoarylacyl)benzotriazoles.
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Table 2. Preparation of primary amides 3a-g
Yield
(%)
Lit. Yield
(%)
mp
R
(oC)
H
96
93
88
93
89
82
85
90 (Ref. 22)
86 (Ref. 21b)
83 (Ref. 23)
100 (Ref. 24)
82 (Ref. 25)
100 (Ref. 26)
54 (Ref. 27)
112 – 113
148 – 149
180 – 182
185 – 187
177 – 178
148 – 149
214 – 215
a
b
c
d
e
f
4-methyl
4-chloro
5-bromo
5-iodo
4,5-dimethoxy
3,5-dibromo
g
Various primary amines were treated with anthranilbenzotriazoles in dichloromethane to give
a series of secondary anthranilamides 4a-i (Scheme 4). The reactions were completed in 2-6
hours at room temperature with high yields (71-95%). The synthesized compounds gave
satisfactory proton and carbon NMR data. The most characteristic signal for the secondary
amides is the broad singlet which was observed at 6.35-5.82 ppm for the protons of the amide
1
nitrogen atom in H-NMR. Elemental analysis, IR and mass spectroscopy also supported the
structures of 4a-i. The isolated yields, literature yields and observed melting points were
summarized in Table 3.
Scheme 4. Synthesis of secondary amides (4a-i) from N-(2-aminoarylacyl)benzotriazoles.
Table 3. Preparation of secondary amides 4a-i
Yield
(%)
71
79
86
86
82
93
87
Lit. Yield
(%)
95 (Ref. 28)
65 (Ref. 29)
novel
novel
novel
74 (Ref. 30)
novel
mp
R
R1
(oC)
a
b
c
d
e
f
g
h
i
H
benzyl
n-propyl
cyclohexyl
cyclohexyl
n-propyl
methyl
isopropyl
n-propyl
methyl
121 – 122
105 – 106
150 – 151
201 – 202
72 – 74
3-methyl
4- methyl
5- methyl
5-methoxy
4-chloro
5-bromo
3,5-dichloro
4,5-dimethoxy
96 – 97
188 – 189
143 – 144
117 – 119
95
84
novel
80 (Ref. 31)
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Treatment of N-(2-aminoarylacyl)benzotriazoles with secondary amines in CH2Cl2 at room
temperature gave the corresponding tertiary amides in excellent yields (77-96%) (Scheme 5,
Table 4). Structures of the products were confirmed by the results of NMR measurements. The
most important evidence proving the formation of tertiary amides is the signals which were
observed for the substituents attached to the amide nitrogen atom. Moreover, no broad singlet
was observed except for the one accounting for the amino group on the anthranilic acid ring.
Scheme 5. Synthesis of tertiary amides (5a-h) from N-(2-aminoarylacyl)benzotriazoles.
Table 4. Preparation of Tertiary Amides 5a-h
Yield
(%)
Lit. yield
(%)
mp
(oC)
R
R1+R2
H
(-CH2)5
(-CH2)5
(-CH2)4
90
86
94
90
89
89
96
93
83 (Ref. 31)
98 (Ref. 31)
novel
novel
novel
novel
novel
novel
74 – 76
80 – 81
78 – 79
130 – 131
134 – 135
oil
a
b
c
d
e
f
g
h
3-methyl
6- methyl
5-chloro
5-iodo
3,5-dibromo
3,5-diiodo
(-CH2)4O
(-CH2)4
(-CH2CH3)2
(-CH2)4O
128 – 130
oil
3,4,5-trimethoxy (-CH2CH3)2
Conclusions
In conclusion, a series of N-(2-aminoarylacyl)benzotriazoles were synthesized from unprotected
orthoaminoarylcarboxylic acids. By the treatment of synthesized N-(2-
aminoarylacyl)benzotriazoles with ammonia, primary and secondary amines, we have developed
a new and practical protocol for the synthesis of anthranilamides. Advantages of this method
compared to the existing methodologies are: providing neutral reaction conditions for the
compounds possessing acid – base sensitive substituents, using N-acylbenzotriazoles which are
more useful and stable than the corresponding acyl halides or other activated derivatives of
carboxylic acids, general application and good yields that are comparable to the literature.
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Experimental Section
General. Column chromatography was conducted on silica gel 70 – 230 meshes. Melting points
were determined on a Mettler Toledo apparatus and uncorrected. All NMR spectra were recorded
on a Bruker Advance 500 DPX spectrometer in CDCl3 or DMSO-d6 with TMS as the internal
1
reference for H (500 MHz) and 13C (125 MHz). Reagents obtained commercially were used
without further purification. MS analyses were obtained with a GC–MS/MS (Thermo Finnigan
PolarisQ). Elemental analysis was performed for all compounds with a Thermo Finnigan Flash
EA 1112 instrument. FTIR spectra were determined on a PerkinElmer 100 FTIR spectrometer.
General experimental procedure for the preparation of N-(2-aminoarylacyl)benzotriazoles
(2a-p). A mixture of appropriate anthranilic acid (6 mmol), benzotriazole (5 mmol, 0.595 gr) and
DCC (7 mmol, 1.44 gr) was stirred in CH2Cl2 (10 mL) overnight at room temperature. After
completion of the reaction, the solvent was removed under reduced pressure. Purification of the
residue by column chromatography over silica gel with EtOAc/ n-Hexane (1:3) or CH2Cl2 gave
the desired product.
(2-Aminophenyl) (benzotriazole-1-yl)methanone (2a). Yellow solid (0.928 g, 78%); mp 132-
1
133 °C; IR υmax (KBr) 3476, 3356, 1680 cm-1; H NMR (CDCl3) δ 8.29 (d, J 8.3 Hz, 1H), 8.19
(d, J 8.3 Hz, 1H), 8.07 (d, J 8.2 Hz, 1H), 7.70 (t, J 7.7 Hz, 1H), 7.55 (t, J 7.7 Hz, 1H), 7.43 (t, J
7.7 Hz, 1H), 6.84 – 6.79 (m, 2H), 5.81 (br s, 2H); 13C NMR δ 167.3, 151.9, 145.7, 135.4, 134.3,
132.7, 129.9, 125.9, 120.2, 117.0, 116.5, 114.5, 111.8; MS (EI): m/z [M+] calcd. for C13H10N4O:
238.08, found: 238.0; Anal. Calc. for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C, 65.63;
H, 4.28; N, 23.63.
(2-Amino-3-methylphenyl) (benzotriazole-1-yl)methanone (2b). Yellow solid (1.03 g, 82%);
mp 99-100 °C; IR υmax (KBr) 3473, 3369, 1670 cm-1; 1H NMR (CDCl3) δ 8.26 (d, J 8.3 Hz, 1H),
8.18 (d, J 8.3 Hz, 1H), 7.89 (d, J 8.2 Hz, 1H), 7.68 (t, J 7.7 Hz, 1H), 7.54 (t, J 7.7 Hz, 1H), 7.34
(d, J 7.2 Hz, 1H), 6.74 (t, J 7.7 Hz, 1H), 5.34 (br s, 2H), 2.25 (s, 3H); 13C NMR δ 167.8, 150.3,
145.7, 136.1, 132.7, 132.4, 129.8, 125.9, 123.2, 120.1, 115.8, 114.4, 111.3, 17.5; MS (EI): m/z
[M+] calcd. for C14H12N4O: 252.10, found: 252.0; Anal. Calc. for C14H12N4O: C, 66.65; H, 4.79;
N, 22.21. Found: C, 66.72; H, 4.92; N, 22.38.
(2-Amino-4-methylphenyl) (benzotriazole-1-yl)methanone (2c). Yellow solid (0.958 g, 76%);
1
mp 135-136 °C; IR υmax (KBr) 3465, 3351, 1675 cm-1; H NMR (CDCl3) δ 8.24 (d, J 8.3 Hz,
1H), 8.17 (d, J 8.3 Hz, 1H), 7.96 (d, J 8.3 Hz, 1H), 7.66 (t, J 7.7 Hz, 1H), 7.52 (t, J 7.6 Hz, 1H),
13
6.61-6.59 (m, 2H), 6.22 (br s, 2H), 2.36 (s, 3H); C NMR δ 168.0, 153.4, 147.7, 146.5, 135.0,
133.6, 130.5, 126.5, 120.7 118.8, 117.7, 115.1, 109.9, 22.0; MS (EI): m/z [M+] calcd. for
C14H12N4O: 252.10, found: 252.0; Anal. Calc. for C14H12N4O: C, 66.65; H, 4.79; N, 22.21.
Found: C, 66.57; H, 4.76; N, 22.22.
(2-Amino-5-methylphenyl) (1H-benzotriazole-1-yl)methanone (2d). Yellow solid (0,504 g,
40%); mp 104-106 °C; IR υmax (KBr) 3477, 3367, 1682 cm-1; 1H NMR (CDCl3) δ 8.26 (d, J 8.3
Hz, 1H), 8.18 (d, J 8.3 Hz, 1H), 7.82 (br s, 1H), 7.69 (t, J 7.7 Hz, 1H), 7.54 (t, J 7.7 Hz, 1H),
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13
7.25 (d, J 8.4 Hz, 1H), 6.75 (d, J 8.4 Hz, 1H), 5.67 (br s, 2H), 2.29 (s, 3H); C NMR δ 168.3,
150.8, 146.6, 137.5, 134.4, 133.5, 130.6, 126.6, 120.8, 117.8, 115.2, 112.5, 20.5; MS (EI): m/z
[M+] calcd. for C14H12N4O: 252.10, found: 252.0; Anal. Calc. for C14H12N4O: C, 66.65; H, 4.79;
N, 22.21. Found: 66.91; H, 4.90; N, 22.25.
(2-Amino-6-methylphenyl) (benzotriazole-1-yl)methanone (2e). Yellow solid (0.315 g, 25%);
1
mp 106-108 °C; IR υmax (KBr) 3436, 3369, 1707 cm-1; H NMR (CDCl3) δ 8.37 (d, J 8.5 Hz,
1H), 8.18 (d, J 8.0 Hz, 1H), 7.73 (t, J 8.0 Hz, 1H), 7.58 (t, J 8.3 Hz, 1H), 7.26 (t, J 7.8 Hz, 1H),
13
6.73 (d, J 7.5 Hz, 1H), 6.70 (d, J 8.0 Hz, 1H), 4.14 (br s, 2H), 2.11 (s, 3H); C NMR δ 168.9,
146.4, 145.6, 137.5, 132.2, 131.3, 130.5, 126.5, 120.6, 120.4, 119.3, 114.5, 114.4, 20.4; MS (EI):
m/z [M+] calcd. for C14H12N4O: 252.10, found: 252.0; Anal. Calc. for C14H12N4O: C, 66.65; H,
4.79; N, 22.21. Found: C, 66.50; H, 4.80; N, 22.43.
(2-Amino-5-methoxyphenyl) (benzotriazole-1-yl)methanone (2f). Yellow solid (0.188 g,
14%); mp 107-109 °C; IR υmax (KBr) 3478, 3371, 1687 cm-1; 1H NMR (CDCl3) δ 8.31 (d, J 8.3
Hz, 1H), 8.19 (d, J 8.4 Hz, 1H), 7.71 (t, J 7.7 Hz, 1H), 7.62 (d, J 2.9 Hz, 1H), 7.56 (t, J 7.7 Hz,
1H), 7.13 (dd, J 9.0, 2.9 Hz, 1H), 6.83 (d, J 9.0 Hz, 1H), 5.80 (br s, 2H), 3.80 (s, 3H); 13C NMR
δ 166.9, 150.7, 146.3, 145.7, 132.7, 130.0, 126.0, 124.9, 120.1, 118.8, 115.8, 114.6, 112.1, 55.9;
MS (EI): m/z [M+] calcd. for C14H12N4O2: 268.09, found: 268.0; Anal. Calc. for C14H12N4O: C,
62.69; H, 4.48; N, 20.9. Found: C, 62.51; H, 4.61; N, 20.89.
(2-Amino-4-chlorophenyl) (benzotriazole-1-yl)methanone (2g). Yellow solid (1.25 g, 92%);
1
mp 160-162 °C; IR υmax (KBr) 3464, 3338, 1687 cm-1; H NMR (CDCl3) δ 8.27 (d, J 8.2 Hz,
1H), 8.18 (d, J 8.2 Hz, 1H), 8.07 (d, J 8.7 Hz, 1H), 7.70 (t, J 7.6 Hz, 1H), 7.55 (t, J 7.7 Hz, 1H),
13
6.83 (s, 1H), 6.77 (d, J 8.7 Hz, 1H), 5.94 (br s, 2H); C NMR δ 167.3, 153.6, 146.6, 142.6,
136.6, 133.4, 130.8, 126.8, 120.9, 117.8, 117.0, 115.2, 110.9; MS (EI): m/z [M+] calcd. for
C13H9ClN4O: 272.04, found: 272.0; Anal. Calc. for C13H9ClN4O: C, 57.25; H, 3.33; N, 20.54.
Found: C, 57.28; H, 3.40; N, 20.58.
(2-Amino-5-chlorophenyl) (benzotriazole-1-yl)methanone (2h). Yellow solid (1.01 g, 74%);
1
mp 153-155 °C; IR υmax (KBr) 3465, 3333, 1679 cm-1; H NMR (CDCl3) δ 8.28 (d, J 8.3 Hz,
1H), 8.20 (d, J 8.3 Hz, 1H), 8.11 (d, J 2.3 Hz, 1H), 7.71 (t, J 7.6 Hz, 1H), 7.57 (t, J 7.7 Hz, 1H),
7.36 (dd, J 8.9, 2.3, 1H), 6.78 (d, J 8.9 Hz, 1H), 5.83 (br s, 2H) 13C NMR δ 167.3, 151.3, 146.6,
136.2, 134.0, 133.4, 131.0, 126.9, 121.8, 121.0, 119.1, 115.2, 113.2; MS (EI): m/z [M+] calcd. for
C13H9ClN4O: 272.04, found: 271.9; Anal. Calc. for C13H9ClN4O: C, 57.25; H, 3.33; N, 20.54.
Found: C, 57.36; H, 3.36; N, 20.33.
(2-Amino-5-bromophenyl) (benzotriazole-1-yl)methanone (2i). Yellow solid (0.840 g, 53%);
1
mp 151-153 °C; IR υmax (KBr) 3465, 3330, 1677 cm-1; H NMR (CDCl3) δ 8.28 (d, J 8.3 Hz,
1H), 8.24 (d, J 2.3 Hz, 1H), 8.20 (d, J 8.3 Hz, 1H), 7.72 (t, J 7.6 Hz, 1H), 7.57 (t, J 7.6 Hz, 1H),
13
7.49 (dd, J 8.9, 2.3 Hz, 1H), 6.73 (d, J 8.9 Hz, 1H), 5.83 (br s, 2H); C NMR δ 166.2, 150.7,
145.7, 138.0, 136.1, 132.5, 130.1, 126.2, 120.3, 118.7, 114.5, 113.1, 107.7; MS (EI): m/z [M+]
calcd. for C13H9BrN4O: 315.99, found: 315.9; Anal. Calc. for C13H9BrN4O: C, 49.23; H, 2.86; N,
17.67. Found: C, 49.27; H, 2.95; N, 17.54.
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(2-Amino-5-iodophenyl) (benzotriazole-1-yl)methanone (2j). Yellow solid (1.00 g, 55%); mp
1
138-140 °C; IR υmax (KBr) 3489, 3382, 1691 cm-1; H NMR (CDCl3) δ 8.34 (d, J 2.0 Hz, 1H),
8.25 (d, J 8.3 Hz, 1H), 8.18 (d, J 8.3 Hz, 1H), 7.70 (t, J 7.7 Hz, 1H), 7.61 (dd, J 8.8, 2.0 Hz, 1H),
13
7.55 (t, J 7.7 Hz, 1H), 6.61 (d, J 8.8 Hz, 1H), 5.86 (br s, 2H); C NMR δ 166.0, 151.2, 145.7,
143.3, 142.0, 132.5, 130.2, 126.2, 120.2, 119.1, 114.5, 113.9, 76.1; MS (EI): m/z [M+] calcd. for
C13H9IN4O: 363.98, found: 363.9; Anal. Calc. for C13H9IN4O: C, 42.88; H, 2.49; N, 15.39.
Found: C, 43.00; H, 2.59; N, 15.17.
(2-Amino-3, 5-dichlorophenyl) (benzotriazole-1-yl)methanone (2k). Yellow solid (1.43 g,
93%); mp 170-172 °C; IR υmax (KBr) 3486, 3367, 1679 cm-1; 1H NMR (CDCl3) δ 8.30 (d, J 8.2
Hz, 1H), 8.21 (d, J 8.3 Hz, 1H), 8.07 (d, J 2.4 Hz, 1H), 7.74 (t, J 7.7 Hz, 1H), 7.60-7.57 (m, 2H),
6.26 (br s, 2H); 13C NMR δ 166.0, 146.4, 145.8, 134.5, 132.5, 132.2, 130.4, 126.4, 121.2, 120.4,
120.3, 114.6, 113.3; MS (EI): m/z [M+] calcd. for C13H8Cl2N4O: 306.00, found: 305.9; Anal.
Calc. for C13H8Cl2N4O: C, 50.65; H, 2.62; N, 18.18. Found: C, 50.87; H, 2.76; N, 17.86.
(2-Amino-3, 5-dibromophenyl) (benzotriazole-1-yl)methanone (2l). Yellow solid (1.64 g,
83%); mp 174-176 °C; IR υmax (KBr) 3488, 3366, 1608 cm-1; 1H NMR (CDCl3) δ 8.29 (d, J 8.3
Hz, 1H), 8.22 – 8.20 (m, 2H), 7.85 (d, J 2.2 Hz, 1H), 7.74 (t, J 7.7 Hz, 1H), 7.59 (t, J 7.7 Hz,
13
1H), 6.32 (br s, 2H); C NMR δ 165.8, 147.5, 145.8, 140.1, 135.8, 132.5, 130.4, 126.4, 120.4,
114.6, 113.8, 111.5, 106.9; MS (EI): m/z [M+] calcd. for C13H8Br2N4O: 393.90, found: 393.8;
Anal. Calc. for C13H8Br2N4O: C, 39.32; H, 2.03; N, 14.11. Found: C, 39.56; H, 2.19; N, 13.78.
(2-Amino-3, 5-diiodophenyl) (benzotriazole-1-yl)methanone (2m). Yellow solid (1.57 g,
64%); mp decomposed > 220 °C; IR υmax (KBr) 3489, 3375, 1667 cm-1; 1H NMR (CDCl3) δ 8.30
13
– 8.19 (m, 4H), 7.73 (t, J 7.7 Hz, 1H), 7.59 (t, J 7.7 Hz, 1H), 6.35 (br s, 2H); C NMR δ 165.8,
151.6, 149.9, 145.8, 142.6, 132.5, 130.4, 126.4, 120.4, 114.5, 113.8, 87.3, 75.9; MS (EI): m/z
[M+] calcd. for C13H8I2N4O: 489.87, found: 489.7; Anal. Calc. for C13H8I2N4O: C, 31.80; H,
1.64; N, 11.41. Found: C, 32.00; H, 1.78; N, 11.33.
(2-Amino-4, 5-dimethoxyphenyl) (benzotriazole-1-yl)methanone (2n). Yellow solid (1.04 g,
70%); mp 93-95 °C; IR υmax (KBr) 3470, 3361, 1672 cm-1; 1H NMR (CDCl3) δ 8.25 (d, J 8.3 Hz,
1H), 8.17 (d, J 8.3 Hz, 1H), 7.72 (s, 1H), 7.68 (t, J 7.7 Hz, 1H), 7.53 (t, J 7.6 Hz, 1H), 6.27 (s,
13
1H), 6.05 (br s, 2H), 3.96 (s, 3H), 3.84 (s, 3H); C NMR δ 165.9, 156.6, 150.6, 145.5, 140.8,
133.0, 129.6, 125.7, 120.0, 115.0, 114.5, 102.7, 99.0, 56.4, 56.0; MS (EI): m/z [M+] calcd. for
C15H14N4O3: 298.10, found: 298.0; Anal. Calc. for C15H14N4O3: C, 60.39; H, 4.73; N, 18.78.
Found: C, 60.45; H, 4.79; N, 18.89.
(2-Amino-3, 4, 5-trimethoxyphenyl) (benzotriazole-1-yl)methanone (2o). Yellow solid (1.23
1
g, 75%); mp 115-117 °C; IR υmax (KBr) 3465, 3342, 1664 cm-1; H NMR (CDCl3) δ 8.28 (d, J
8.3 Hz, 1H), 8.18 (d, J 8.3 Hz, 1H), 7.69 (t, J 7.6 Hz, 1H), 7.55 (t, J 7.6 Hz, 1H), 7.52 (s, 1H),
13
6.08 (br s, 2H), 4.07 (s, 3H), 3.95 (s, 3H), 3.82 (s, 3H); C NMR δ 166.3, 148.8, 145.6, 144.0,
143.5, 139.9, 132.9, 129.8, 125.8, 120.0, 114.6, 111.1, 105.2, 61.0, 60.5, 56.4; MS (EI): m/z [M+]
calcd. for C16H16N4O4: 328.11, found: 328.0; Anal. Calc. for C16H16N4O4: C, 58.53; H, 4.91; N,
17.07. Found: C, 58.70; H, 4.93; N, 17.24.
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General experimental procedure for the preparation of primary anthranilamides (3a-g). N-
(2-Aminoarylacyl)benzotriazoles (1 mmol) were treated with excess ammonium hydroxide (10
mmol) in THF (10 mL) cooled in an ice bath for 2 hours. After the completion of the reaction,
the solvent was removed under reduced pressure and then the residue was purified by column
chromatography over slica gel with EtOAc/ n-Hexane (1:1) to give the desired primary amides as
white solids.
o
2-Aminobenzamide (3a). White solid (0.130 g, 96%); mp112-113 C; IR υmax (KBr) 3409.5,
3316.0, 3201.3, 1660.4 cm-1; 1H NMR (DMSO-d6) δ 7.74 (br s, 1H), 7.52 (d, J 7.9 Hz, 1H), 7.13
(t, J 7.6 Hz, 1H), 7.06 (br s, 1H), 6.67 (d, J 8.2 Hz, 1H), 6.55 (br s, 2H), 6.48 (t, J 7.5 Hz, 1H);
13C NMR δ 172.8, 151.5, 133.2, 130.0, 117.6, 115.6, 114.8; MS (EI): m/z [M+] calcd. for
C7H8N2O: 136.06, found: 136.0; Anal. Calc. for C7H8N2O: C, 61.75; H, 5.92; N, 20.58. Found:
C, 61.95; H, 6.28; N, 20.20.
o
2-Amino-4-methylbenzamide (3b). White solid (0.140 g, 93%); mp148-149 C; IR υmax (KBr)
1
3409.5, 3294.8, 3172.3, 1674.9 cm-1; H NMR (DMSO-d6) δ 7.65 (br s, 1H), 7.43 (d, J 8.1 Hz,
1H), 6.95 (br s, 1H), 6.54 (br s, 2H), 6.48 (s, 1H), 6.30 (d, J 8.0 Hz, 1H), 2.16 (s, 3H); 13C NMR
δ 172.8, 151.7, 143.0, 130.0, 117.7, 116.9, 112.2, 21.7; MS (EI): m/z [M+] calcd. for C8H10N2O:
150.07, found: 150.0; Anal. Calc. for C8H10N2O: C, 63.98; H, 7.19; N, 18.64. Found: C, 64.21;
H, 7.19; N, 18.20.
o
2-Amino-4-chlorobenzamide (3c). White solid (0.150 g, 88%); mp180-182 C; IR υmax (KBr)
1
3496.3, 3351.7, 3164.6, 3085.5, 1667.2 cm-1; H NMR (DMSO-d6) δ 7.80 (br s, 1H), 7.54 (d, J
13
8.4 Hz, 1H), 7.16 (br s, 1H), 6.83 (br s, 2H), 6.74 (s, 1H), 6.50 (t, J 8.4 Hz, 1H); C NMR δ
172.0, 152.8, 137.6, 131.8, 116.3, 115.2, 113.5; MS (EI): m/z [M+] calcd. for C7H7ClN2O:
170.02, found: 170.0; Anal. Calc. for C7H7ClN2O: C, 49.27; H, 4.13; N, 16.42. Found: C, 49.18;
H, 4.48; N, 16.06.
o
2-Amino-5-bromobenzamide (3d). White solid (0.200 g, 93%); mp 185-187 C; IR υmax (KBr)
1
3395.1, 3287.1, 3164.6, 1674.9 cm-1; H NMR (DMSO-d6) δ 7.86 (br s, 1H), 7.70 (d, J 2.5 Hz,
13
1H), 7.26 (dd, J 9.0, 2.0 Hz, 1H), 7.19 (br s, 1H), 6.71 (br s, 2H), 6.66 (d, J 8.5 Hz, 1H); C
NMR δ 170.5, 149.8, 134.8, 131.2, 119.0, 115.6, 105.2; MS (EI): m/z [M+] calcd. for
C7H7BrN2O: 213.97, found: 214.0; Anal. Calc. for C7H7BrN2O: C, 39.09; H, 3.28; N, 13.03.
Found: C, 39.40; H, 3.57; N, 12.88.
o
2-Amino-5-iodobenzamide (3e). White solid (0.232 g, 89%); mp 177-178 C; IR υmax (KBr)
1
3395.1, 3287.1, 3172.3, 1674.9 cm-1; H NMR (DMSO-d6) δ 7.85 (br s, 1H), 7.81 (d, J 1.5 Hz,
13
1H), 7.38 (dd, J 9.0, 2.0 Hz, 1H), 7.16 (br s, 1H), 6.70 (br s, 2H), 6.55 (d, J 8.5 Hz, 1H); C
NMR δ 171.4, 151.1, 141.2, 137.8, 120.2, 117.3, 75.4; MS (EI): m/z [M+] calcd. for C7H7IN2O:
261.95, found: 262.0; Anal. Calc. for C7H7IN2O: C, 32.08; H, 2.69; N, 10.69. Found: C, 32.45;
H, 3.01; N, 10.36.
2-Amino-4,5-dimethoxybenzamide (3f). White solid (0.160 g, 82%); mp 148-149oC; IR υmax
1
(KBr) 3438.5, 3337.2, 3238.0 cm-1, 1681.6; H NMR (DMSO-d6) δ 7.58 (br s, 1H), 7.12 – 7.09
(m, 1H), 6.82 (br s, 1H), 6.44 (br s, 2H), 6.30 – 6.26 (m, 1H), 3.72 (s, 3H), 3.67 (s, 3H); 13C
NMR δ 172.4, 154.3, 148.1, 140.2, 114.1, 105.3, 100.8, 57.4, 55.9; MS (EI): m/z [M+] calcd. for
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C9H12N2O3: 196.08, found: 196.0; Anal. Calc. for C9H12N2O3: C, 55.09; H, 6.17; N, 14.28.
Found: C, 55.28; H, 6.54; N, 13.92.
2-Amino-3,5-dibromobenzamide (3g). White solid (0.250 g, 85%); mp 214-215oC; IR υmax
1
(KBr) 3366.1, 3322.7, 3179.1, 1652.7 cm-1; H NMR (DMSO-d6) δ 8.06 (br s, 1H), 7.79 – 7.76
13
(m, 1H), 7.74 – 7.72 (m, 1H), 7.47 (br s, 1H), 6.80 (br s, 2H); C NMR δ 170.7, 147.3, 137.9,
131.9, 118.0, 111.5, 106.0; MS (EI): m/z [M+] calcd. for C7H6 Br2N2O: 291.88, found: 291.9;
Anal. Calc. for C7H6 Br2N2O: C, 28.60; H, 2.06; N, 9.53. Found: C, 28.85; H, 2.43; N, 9.23.
General experimental procedure for the preparation of secondary (4a-i) and tertiary
athranilamides (5a-h). N-(2-Aminoarylacyl)benzotriazoles (1 mmol) and various primary and
secondary amines (1.2 mmol) were left to stir in CH2Cl2 (10 mL) for 2-6 hours at room
temperature. After the reaction ended, the solvent was removed under reduced pressure. The
residue was purified by column chromatography over slica gel with EtOAc/ n-hexane prepared
in different proportions to afford secondary and tertiary amides.
2-Amino-N-benzylbenzamide (4a). White solid (0.160 g, 71%); mp 121-122 oC; IR υmax (KBr)
1
3467.4, 3359.4, 3301.5, 1638.2 cm-1; H NMR (CDCl3) δ 7.41 – 7.38 (m, 4H), 7.36 – 7.33 (m,
2H), 7.26 – 7.22 (m, 1H), 6.72 (d, J 8.2 Hz, 1H), 6.66 (t, J 7.5 Hz, 1H), 6.35 (br s, 1H), 5.62 (br
s, 2H), 4.64 (d, J 5.6 Hz, 2H); 13C NMR δ 169.2, 148.8, 138.3, 132.4, 128.8, 127.8, 127.6, 127.1,
117.4, 116.7, 115.9, 43.8; MS (EI): m/z [M+] calcd. for C14H14N2O: 226.11, found: 226.1; Anal.
Calc. for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 74.02; H, 6.37; N, 12.09.
o
2-Amino-3-methyl-N-propylbenzamide (4b). White solid (0.152 g, 79%); mp 105-106 C; IR
υmax (KBr) 3424.0, 3301.5, 1623.8 cm-1; 1H NMR (CDCl3) δ 7.23 (d, J 7.8 Hz, 1H), 7.15 (d, J 7.3
Hz, 1H), 6.62 (t, J 7.6 Hz, 1H), 6.10 (br s, 1H), 5.63 (br s, 2H), 3.40 (q, J 6.7 Hz, 2H), 2.19 (s,
13
3H), 1.65 (sex, J 7.3 Hz, 2H), 1.01 (t, J 7.4 Hz, 3H); C NMR δ 170.9, 147.7, 133.8, 125.6,
124.6, 116.8, 41.7, 23.1, 17.6, 11.6; MS (EI): m/z [M+] calcd. for C11H16N2O: 192.12, found:
192.1; Anal. Calc. for C11H16N2O: C, 68.72; H, 8.39; N, 14.57. Found: C, 68.68; H, 8.36; N,
14.36.
o
2-Amino-N-cyclohexyl-4-methylbenzamide (4c). White solid (0.200 g, 86%); mp 150-151 C;
1
IR υmax (KBr) 3474.1, 3359.4, 3301.5, 1638.2 cm-1; H NMR (CDCl3) δ 7.20 (d, J 8.0 Hz, 1H),
6.52 (s, 1H), 6.49 (d, J 8.0 Hz, 1H), 5.89 (d, J 6.5 Hz, 1H), 5.57 (br s, 2H), 3.97 – 3.91 (m, 1H),
2.25 (s, 3H), 2.05 – 2.01 (m, 2H), 1.79 – 1.75 (m, 2H), 1.69 – 1.65 (m, 1H), 1.48 – 1.40 (m, 2H),
13
1.20 – 1.28 (m, 3H); C NMR δ 168.4, 148.6, 142.6, 126.9, 117.9, 117.7, 114.0, 48.2, 33.3,
25.6, 24.9, 21.4; MS (EI): m/z [M+] calcd. for C14H20N2O: 232.15, found: 232.1; Anal. Calc. for
C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.01; H, 8.69; N, 11.86.
2-Amino-N-cyclohexyl-5-methylbenzamide (4d). White solid (0.200 g, 86%); mp 201-202 oC;
1
IR υmax (KBr) 3417.2, 3294.8, 1631.5 cm-1; H NMR (CDCl3) δ 7.11 (s, 1H), 7.06 (d, J 8.8 Hz,
1H), 6.68 (d, J 8.5 Hz, 1H), 5.96 (br s, 1H), 5.40 (br s, 2H), 3.95 – 3.93 (m, 1H), 2.29 – 2.24 (m,
2H), 2.05 – 2.02 (m, 2H), 1.79 – 1.76 (m, 2H), 1.69 – 1.66 (m, 1H), 1.46 – 1.41 (m, 2H), 1.30 –
1.22 (m, 4H); 13C NMR δ 169.4, 146.2, 133.7, 127.9, 127.2, 118.6, 118.0, 48.6, 33.5, 25.8, 25.1,
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20.6; MS (EI): m/z [M+] calcd. for C14H20N2O: 232.15, found: 232.1; Anal. Calc. for C14H20N2O:
C, 72.38; H, 8.68; N, 12.06. Found: C, 72.15; H, 8.85; N, 11.84.
o
2-Amino-5-methoxy-N-propylbenzamide (4e). White solid (0.171 g, 82%); mp 72-74 C; IR
υmax (KBr) 3413.4, 3301.5, 1654.6 cm-1; 1H NMR (CDCl3) δ 6.90 – 6.87 (m, 2H), 6.68 (d, J 8.5
Hz, 1H), 6.22 (br s, 1H), 5.01 (br s, 2H), 3.77 (s, 3H), 3.38 (q, J 6.7 Hz, 2H), 1.64 (sex, J 7.2 Hz,
13
2H), 0.99 (t, J 7.5 Hz, 3H); C NMR δ 169.0, 151.3, 142.0, 118.8, 118.7, 118.1, 112.3, 56.1,
41.5, 23.0, 11.5; MS (EI): m/z [M+] calcd. for C11H16N2O2: 208.12, found: 208.1; Anal. Calc. for
C11H16N2O2: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.48; H, 7.86; N, 13.74.
2-Amino-4-chloro-N-methylbenzamide (4f). White solid (0.172 g, 93%); mp 96-97 oC; IR υmax
(KBr) 3467.4, 3366.1, 3337.2, 1638.2 cm-1; 1H NMR (CDCl3) δ 7.24 (d, J 8.4 Hz, 1H), 6.69 (d, J
2.0 Hz, 1H), 6.60 (dd, J 8.4, 2.0 Hz, 1H), 6.19 (br s, 1H), 5.66 (br s, 2H), 2.96 (d, J 5.2 Hz, 3H);
13C NMR δ 169.3, 149.7, 137.9, 128.4, 116.6, 116.5, 114.5, 26.6; MS (EI): m/z [M+] calcd. for
C8H9ClN2O: 184.03, found: 184.0; Anal. Calc. for C8H9ClN2O: C, 52.03; H, 4.91; N, 15.17.
Found: C, 52.34; H, 5.22; N, 14.86.
o
2-Amino-5-bromo-N-isopropylbenzamide (4g). White solid (0.224 g, 87%); mp 188-189 C;
1
IR υmax (KBr) 3467.4, 3366.1, 3287.1, 1631.5 cm-1; H NMR (CDCl3) δ 7.40 (d, J 2.2 Hz, 1H),
7.29 (dd, J 8.5, 2.4 Hz, 1H), 6.59 (d, J 8.7 Hz, 1H), 5.82 (br s, 1H), 5.53 (br s, 2H), 4.24 (sep, J
13
6.6 Hz, 1H), 1.28 (d, J6.6 Hz, 6H); C NMR δ 168.3, 148.5, 135.5, 130.3, 119.6, 118.8, 108.3,
42.0, 23.0; MS (EI): m/z [M+] calcd. for C10H13BrN2O: 256.02, found: 256.0; Anal. Calc. for
C10H13BrN2O: C, 46.71; H, 5.10; N, 10.89. Found: C, 46.69; H, 5.43; N, 10.55.
o
2-Amino-3,5-dichloro-N-propylbenzamide (4h). White solid (0.234 g, 95%); mp 143-144 C;
IR υmax (KBr) 3430.7, 3287.1, 1638.2 cm-1; 1H NMR (CDCl3) δ 7.36 (d, J 2.3 Hz, 1H), 7.24 (d, J
2.3 Hz, 1H), 6.06 (br s, 1H), 5.98 (br s, 2H), 3.39 (q, J 6.7 Hz, 2H), 1.66 (sex, J 7.3 Hz, 2H),
13
1.01 (t, J 7.4 Hz, 3H); C NMR δ 168.6, 144.5, 132.3, 126.1, 122.0, 120.8, 118.8, 41.9, 23.0,
11.5; MS (EI): m/z [M+] calcd. for C10H12Cl2N2O: 246.03, found: 246.0; Anal. Calc. for
C10H12Cl2N2O: C, 48.58; H, 4.89; N, 11.33. Found: C, 48.82; H, 5.23; N, 11.07.
2-Amino-4,5-dimethoxy-N-methylbenzamide (4i). White solid (0.176 g, 84%); mp 117-119
oC; IR υmax (KBr) 3455.8, 3390.2, 3336.2, 1631.5 cm-1; 1H NMR (CDCl3) δ 6.84 (s, 1H), 6.20 (s,
1H), 6.19 (br s, 1H), 5.40 (br s, 2H), 3.85 (s, 3H), 3.80 (s, 3H) 2.94 (d, J 4.5 Hz, 3H); 13C NMR δ
169.7, 153.1, 144.6, 140.8, 110.9, 107.3, 100.8, 56.9, 55.7, 26.5; MS (EI): m/z [M+] calcd. for
C10H14N2O3: 210.09, found: 210.1; Anal. Calc. for C10H14N2O3: C, 57.13; H, 6.71; N, 13.33.
Found: C, 57.08; H, 6.66; N, 13.61.
o
(2-Aminophenyl)(piperidin-1-yl)methanone (5a). White solid (0.184 g, 90%); mp 74-76 C;
1
IR υmax (KBr) 3488.5, 3359.4, 3251.4, 1652.7 cm-1; H NMR (CDCl3) δ 7.15 (t, J 7.7 Hz, 1H),
7.07 (dd, J 7.5, 1.5 Hz, 1H), 6.72 – 6.69 (m, 2H), 4.28 (s, 2H), 3.55 (br s, 4H), 1.68 – 1.60 (m,
13
6H); C NMR δ 169.7, 145.4, 130.3, 127.6, 120.5, 117.4, 116.6, 26.4, 26.2, 24.6; MS (EI): m/z
[M+] calcd. for C12H16N2O: 204.12, found: 204.1; Anal. Calc. for C12H16N2O: C, 70.56; H, 7.90;
N, 13.71. Found: C, 76.56; H, 8.22; N, 13.77.
(2-Amino-3-methylphenyl)(piperidin-1-yl)methanone (5b). White solid (0.188 g, 86%); mp
80-81 oC; IR υmax (KBr) 3430.7, 3351.7, 1617.0 cm-1; 1H NMR (CDCl3) δ 7.05 (s, J 7.5 Hz, 1H),
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6.95 (s, J 7.5 Hz, 1H), 6.64 (t, J 7.5 Hz, 1H), 4.25 (s, 2H), 3.55 (br s, 4H), 2.17 (s, 3H), 1.67 –
1.59 (m, 6H); 13C NMR δ 170.1, 143.5, 131.2, 125.4, 123.3, 120.0, 117.0, 26.2, 26.1, 24.6, 17.5;
MS (EI): m/z [M+] calcd. for C13H18N2O: 218.14, found: 218.1; Anal. Calc. for C13H18N2O: C,
71.53; H, 8.31; N, 12.83. Found: C, 71.19; H, 8.31; N, 13.20.
(2-Amino-6-methylphenyl)(pyrrolidin-1-yl)methanone (5c). White solid (0.192 g, 94%); mp
1
78-79 oC; IR υmax (KBr) 3430.8, 3330.5, 3229.2, 1617.0 cm-1; H NMR (CDCl3) δ 7.05 (t, J 7.8
Hz, 1H), 6.63 (d, J 7.5 Hz, 1H), 6.56 (d, J 8.0 Hz, 1H), 3.79 (br s, 2H), 3.73 – 3.64 (m, 2H), 3.28
– 3.23 (m, 1H), 3.19 – 3.14 (m, 1H), 2.24 (s, 3H), 2.02 – 1.88 (m, 4H); 13C NMR δ 170.0, 143.4,
135.1, 130.0, 125.4, 121.0, 114.2, 47.6, 45.5, 26.1, 24.8, 19.1; MS (EI): m/z [M+] calcd. for
C12H16N2O: 204.12, found: 204.0; Anal. Calc. for C12H16N2O: C, 70.56; H, 7.90; N, 13.71.
Found: C, 70.92; H, 8.17; N, 13.67.
(2-Amino-5-chlorophenyl) (morpholino) methanone (5d). Pale yellow solid (0.216 g, 90%);
o
1
mp 130-131 C; IR υmax (KBr) 3424.0, 3337.2, 3236.9, 1617.0 cm-1; H NMR (CDCl3) δ 7.14
(dd, J 8.6, 2.3 Hz, 1H), 7.05 (d, J 2.3 Hz, 1H), 6.67 (d, J 8.6 Hz, 1H), 4.35 (br s, 2H), 3.72 – 3.64
13
(m, 8H); C NMR δ 169.6, 145.2, 131.5, 128.2, 122.9, 121.0, 118.7, 67.4 (2C); MS (EI): m/z
[M+] calcd. for C11H13ClN2O2: 240.06, found: 240.0; Anal. Calc. for C11H13ClN2O2: C, 54.88; H,
5.83; N, 11.64. Found: C, 54.89; H, 6.01; N, 11.34.
(2-Amino-5-iodophenyl)(pyrrolidin-1-yl)methanone (5e). Brown solid (0.280 g, 89%); mp
o
1
134-135 C; IR υmax (KBr) 3417.2, 3322.7, 3208.0, 1645.9 cm-1; H NMR (CDCl3) δ 7.49 (d, J
2.5 Hz, 1H), 7.42 (dd, J 8.5, 2.0 Hz, 1H), 6.52 (d, J 8.5 Hz, 1H), 4.58 (br s, 2H), 3.63 (s, 2H),
13
3.49 (s, 2H), 1.97 (s, 2H), 1.92 (s, 2H); C NMR δ 167.8, 145.6, 139.1, 136.2, 122.9, 118.8,
49.6, 46.1, 26.4, 24.4; MS (EI): m/z [M+] calcd. for C11H13IN2O: 316.00, found: 315.9; Anal.
Calc. for C11H13IN2O: C, 41.79; H, 4.15; N, 8.86. Found: C, 42.07; H, 4.61; N, 8.60.
2-Amino-3,5-dibromo-N,N-diethylbenzamide (5f). Colourless oil (0.312 g, 89%); IR υmax
(KBr) 3452.9, 3344.9, 1617.0 cm-1; 1H NMR (CDCl3) δ 7.53 (d, J 2.2 Hz, 1H), 7.13 (d, J 2.2 Hz,
1H), 4.62 (s, 2H), 3.41 (br s, 4H), 1.17 (br s, 6H); 13C NMR δ 168.2, 141.7, 135.1, 128.6, 123.6,
111.0, 108.5, 43.4, 39.8, 39.5, 13.5; MS (EI): m/z [M+] calcd. for C11H14Br2N2O: 347.94, found:
348.0; Anal. Calc. for C11H14Br2N2O: C, 37.74; H, 4.03; N, 8.00. Found: C, 37.69; H, 4.44; N,
7.85.
(2-Amino-3,5-diiodophenyl) (morpholino) methanone (5g). White solid (0.440 g, 96%); mp
o
1
128-130 C; IR υmax (KBr) 3467.4, 3378.7, 3336.2, 1631.5 cm-1; H NMR (CDCl3) δ 7.95 (d, J
13
1.0 Hz, 1H), 7.32 (d, J 1.5 Hz, 1H), 4.84 (br s, 2H), 3.71 – 3.63 (m, 8H); C NMR δ 167.5,
147.3, 145.3, 136.0, 120.8, 87.1, 77.7, 66.9, 31.0; MS (EI): m/z [M+] calcd. for C11H12I2N2O2:
457.89, found: 457.9; Anal. Calc. for C11H12I2N2O2: C, 28.84; H, 2.64; N, 6.12. Found: C, 29.03;
H, 2.86; N, 6.45.
2-Amino-N,N-diethyl-3,4,5-trimethoxybenzamide (5h). Dark yellow oil (0.262 g, 93%); IR
1
υmax (KBr) 3452.9, 3351.7, 1631.5 cm-1; H NMR (CDCl3) δ 6.48 (s, 1H), 3.91 (s, 3H), 3.90 (s,
13
3H), 3.80 (s, 3H), 3.45 (br s, 6H), 1.23 (s, 6H); C NMR δ 170.2, 145.2, 143.7, 141.9, 133.1,
116.5, 106.3, 60.9, 60.5, 56.7, 13.6; MS (EI): m/z [M+] calcd. for C14H22N2O4: 282.15, found:
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282.1; Anal. Calc. for C14H22N2O4: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.19; H, 7.51; N,
10.29.
Acknowledgements
This work is dedicated to Professor Cemil Öğretir, who died on 19th January, 2011. It is
gratefully acknowledged that this work was supported financially by Anadolu University
1
13
(Project No: 1002F88) and we are also grateful to AUBIBAM for providing H and C NMR
spectra.
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