The reaction of 2-(acylamino)benzonitriles with primary aromatic amines: A convenient synthesis of 2-substituted 4-(arylamino)quinazolines

Article abstract of DOI:10.1055/s-0034-1380322

Abstract 2-Substituted 4-(arylamino)quinazolines were prepared from 2-(acylamino)benzonitriles and primary arylamines by refluxing in either ethanol using trifluoroacetic acid as a catalyst or acetic acid. The 2-aminobenzonitrile was acylated by reaction with anhydrides, isocyanates, or ethyl chloroformate at room temperature.

Full text of DOI:10.1055/s-0034-1380322

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6
<17+(6,6
Supporting Information
for DOI: 10.1055/s-0034-1380322
Georg Thieme Verlag KG Stuttgart · New York 2015
©
Thieme

Supporting Information
The reaction of 2-(acylamino)benzonitriles with primary aromatic amines: a
convenient synthesis of 2-substituted 4-(arylamino)quinazolines
Elina Marinho and M. Fernanda Proença*
Chemistry Department, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax: +351 253678983;
E-mail: fproenca@quimica.uminho.pt.
Table of contents
Page
S2
General experimental details
Experimental procedures for compounds 2, 3 and 4
S3
1
13
NMR Spectra ( H and C NMR) for compounds 2a-h
S11
S20
S32
1
13
NMR Spectra ( H and C NMR) for compounds 3a-l
1
13
NMR Spectra ( H and C NMR) for compounds 4a-c
1

General experimental details:
All compounds were fully characterized by elemental analysis and spectroscopic data. The NMR spectra were
1
13
recorded at room temperature, on a Varian Unity Plus ( H: 300 MHz, C: 75 MHz), or on a Bruker Avance III
1
13
1
13
4
00 ( H: 400 MHz, C: 100 MHz) including the H- C correlation spectra (HMQC and HMBC). Deuterated
DMSO was used as solvent. The chemical shifts are expressed in δ (ppm) and the coupling constants, J, are
reported in hertz (Hz). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q,
quartet and br, broad. IR spectra were recorded on a FT-IR Bomem MB 104 using Nujol mulls and and NaCl
cells. The reactions were monitored by thin layer chromatography (TLC) using silica gel 60 F254 (Merck and
Macherey-Nagel). The melting points were determined on a Stuart SMP3 melting point apparatus and are
uncorrected. Elemental analyses were performed on a LECO CHNS-932 instrument.
2

Experimental procedures for compounds 2, 3 and 4
Synthesis of N-(2-cyanophenyl)acetamide (2a)
O
CH3
NH
CN
Triethylamine (40 μl) was added to a solution of anthranilonitrile 1a (0.43 g; 3.64 mmol) in acetic anhydride
1.49 g; 14.56 mmol; 1375 μl; 4 equiv) at room temperature. After 10 min a white solid precipitated and was
filtered and washed with water leading to the pure product N-(2-cyanophenyl)acetamide 2a (0.51 g; 3.14 mmol;
6%).
(
8
Synthesis of N-(5-chloro-2-cyanophenyl)acetamide (2b)
O
CH3
Cl
NH
CN
Acetic anhydride (2.72 g; 26.60 mmol; 2510 μl; 4 equiv) was added to 2-amino-4-chlorobenzonitrile 1b (1.02 g;
.65 mmol), followed by triethylamine (40 μl). The yellow suspension was stirred at room temperature. After 16
6
h, the starting materials were no longer present (evidence by TLC). The yellow solid was filtered and washed
with water. The product was identified as N-(5-chloro-2-cyanophenyl)acetamide 2b (1.25 g; 6.40 mmol; 96%),
Synthesis of N-(2-cyanophenyl)benzamide (2c)
O
Ph
NH
CN
Benzoic anhydride (0.95 g; 4.20 mmol; 2.1 equiv) and triethylamine (40 μl) were added to a solution of
anthranilonitrile 1a (0.23 g; 1.98 mmol) in acetonitrile (3 ml), at room temperature. The solution was reflux for 2
h. The solvent was evaporated in the rotary evaporator and the oil was cooled in an ice bath. After 2 h, the white
solid (0.08 g) was filtered and washed with diethyl ether. Removal of the solvent from the mother liquor and
addition of diethyl ether led to the isolation of a second crop of white solid (0.18 g). Both products were identical
by IR spectroscopy and were combined and identified as N-(2-cyanophenyl)benzamide 2c (0.26 g; 1.17 mmol;
59%).
Synthesis of (2Z)-4-[(2-cyanophenyl)amino]-4-oxobut-2-enoic acid (2d)
O
NH
O
OH
CN
Maleic anhydride (1.92 g; 19.56 mmol; 2 equiv) was added to a solution of anthranilonitrile 1a (1.16 g; 9.78
mmol) in acetonitrile (3 ml). Triethylamine (40 μl) was also added and the yellow solution immediately evolved
3

to an orange solution. The reaction mixture was stirred at room temperature. After 45 min the white precipitate
was filtered and washed with water. The pure product was identified as (2Z)-4-[(2-cyanophenyl)amino]-4-
oxobut-2-enoic acid 2d (1.73 g; 8.02 mmol; 82%).
Synthesis of ethyl (2-cyanophenyl)carbamate (2e)
O
OEt
NH
CN
Ethyl chloroformate (0.46 g; 4.24 mmol; 404 μl; 2 equiv) was added to a yellow solution of anthranilonitrile 1a
0.25 g; 2.12 mmol) in water (2 ml) and ethanol (2 ml). The reaction mixture was stirred at room temperature for
.5 h. The white precipitate was filtered and washed with water. The pure product was identified as ethyl (2-
(
1
cyanophenyl)carbamate 2e (0.35 g; 1.86 mmol; 88%).
Synthesis of ethyl 5-chloro-2-cyanophenylcarbamate (2f)
O
OEt
Cl
NH
CN
Ethyl chloroformate (0.18 g; 1.65 mmol; 160 μl; 1 equiv) was added to a yellow suspension of 2-amino-4-
chlorobenzonitrile 1b (0.25 g; 1.65 mmol) in water (2 ml) and ethanol (2 ml). The reaction mixture was heated
under reflux leading immediately to a yellow solution. Ethyl chloroformate was added in 1 M equiv portions
every 15 min for a total of 2 h. A solid precipitated upon addition of water and was filtered and washed with HCl
6
M and water leading the pure product ethyl 5-chloro-2-cyanophenylcarbamate 2f (0.29 g; 1.38 mmol; 79%).
Synthesis of N-(2-cyanophenyl)formamide (2g)
O
H
NH
CN
A solution of anthranilonitrile 1a (0.20 g; 1.70 mmol) in formic acid (0.26 g; 5.10 mmol; 215 μl; 3 equiv) was
stirred at room temperature. After 3.5 h a white solid precipitated and was filtered and washed with ethanol. The
pure product was identified as N-(2-cyanophenyl)formamide 2g (0.08 g; 0.55 mmol; 33%). The solid that
precipitated from the mother liquor was a mixture of product 2g and 2-(4-oxoquinazolin-3(4H)-yl)benzonitrile in
1
a 1.3:1 molar ratio, by H NMR.
Synthesis of 1-(2-cyanophenyl)-3-phenylurea (2h)
O
NH
NH
CN
4

Phenylisocyanate (0.33 g; 2.76 mmol; 300 μl; 1.1 equiv) was added to a yellow solution of anthranilonitrile 1a
0.30 g; 2.51 mmol) in acetonitrile (1 ml), under nitrogen atmosphere and the mixture was stirred at room
(
temperature. After 2 h, the yellow solution was kept at -18 ºC overnight. The solid precipitate (0.03 g) was
filtered and washed with acetonitrile. A second crop (0.29 g) was isolated from the mother liquor upon addition
of acetonitrile. The two crops were combined as they were pure by TLC and were identified as 1-(2-
cyanophenyl)-3-phenylurea 2h (0.32 g; 1.33 mmol; 53%).
Reaction of 2a and 4-methoxyaniline leading to N-(4-methoxyphenyl)-2-methylquinazolin-4-
3
amine (3a) (lit. )
1
N
8
8
a
2
CH
7
6
3
N
3
4
a
4
5
2'
HN
3'
1
'
4
'
6
'
OMe
5'
Method A: 4-Methoxyaniline (0.06 g; 0.47 mmol; 1.1 equiv) and TFA (1 equiv; 35 μl) were added to a solution
of N-(2-cyanophenyl)acetamide 2a (0.07 g; 0.43 mmol) in ethanol (5 ml). The brown solution was refluxed for
4
6 h. The solution was kept at -18 ºC and after 2.5 days the yellow solid precipitate was filtered and washed with
diethyl ether. The product was identified as the trifluoroacetate salt of N-(4-methoxyphenyl)-2-
methylquinazolin-4-amine 3a (0.09 g; 0.24 mmol; 56%). Removal of the solvent from the mother liquor led to a
1
mixture of the starting material 2a and product 3a (1.6:1, molar ratio), identified by H NMR.
Method B: A grey suspension of N-(2-cyanophenyl)acetamide 2a (0.07 g; 0.45 mmol) and 4-methoxyaniline
(
0.07 g; 0.50 mmol; 1.1 equiv) in acetic acid (11.6 equiv; 0.3 ml) was refluxed for 45 min. After cooling, a
greenish solid precipitate was filtered and washed with diethyl ether. The product was identified as of N-(4-
methoxyphenyl)-2-methylquinazolin-4-amine 3a (0.06 g; 0.23 mmol; 51%).
Method C: A brown suspension of N-(2-cyanophenyl)acetamide 2a (0.05 g; 0.34 mmol) and 4-methoxyaniline
(
0.05 g; 0.37 mmol; 1.1 equiv) in acetic acid (11.6 equiv; 230 μl) was stirred at 80 ºC, for 14 h. Diethyl ether was
added to the cold reaction mixture leading to a off-white solid precipitate. The solid was filtered and washed
with diethyl ether. The product was identified as of N-(4-methoxyphenyl)-2-methylquinazolin-4-amine 3a (0.03
1
g; 0.10 mmol; 29%), by H NMR. Removal of the solvent from the mother liquor and addition of water led to the
isolation of a second crop of solid. The product was identified as 3-(4-methoxyphenyl)-2-methylquinazolin-
1
4
(3H)-one 4a (0.01 g; 0.04 mmol; 10%), by H NMR.
Reaction of 2a and 4-fluoroaniline leading to N-(4-fluorophenyl)-2-methylquinazolin-4-amine (3b)
N
CH3
N
HN
F
Method A: 4-Fluoroaniline (0.08 g; 0.70 mmol; 67 μl; 1.1 equiv) and TFA (1 equiv; 35 μl) were added to a
yellow solution of N-(2-cyanophenyl)acetamide 2a (0.10 g; 0.64 mmol) in ethanol (2 ml). The reaction mixture
was refluxed for 9 h. The solution was kept at -18 ºC overnight (16 h) and the yellow solid precipitate was
filtered and washed with diethyl ether. The product was identified as the trifluoroacetate salt of N-(4-
fluorophenyl)-2-methylquinazolin-4-amine 3b (0.15 g; 0.41 mmol; 64%).
5

Method B: A yellow solution of N-(2-cyanophenyl)acetamide 2a (0.07 g; 0.44 mmol) and 4-fluoroaniline (0.05
g; 0.48 mmol; 46 μl; 1.1 equiv) in acetic acid (11.6 equiv; 0.3 ml) was refluxed for 2 h. A saturated aqueous
solution of NaHCO was added to the reaction mixture. The emulsion was extracted with dichlorometane (3x 5
3
ml). The organic layer was dried and concentrated in the rotary evaporator. Addition of diethyl ether led to a
yellow solid precipitate that was filtered and washed with diethyl ether. The product was identified as N-(4-
fluorophenyl)-2-methylquinazolin-4-amine 3b (0.02 g; 0.08 mmol; 18%). The solid that precipitated from the
mother liquor was a mixture of starting material 2a (45%), product 3b (14%), 4c (16%) and a compound
1
tentatively identified as quinazoline 4 (R = 4-FC H , 25%) identified by H NMR.
3
6
4
Reaction of 2a and 4-aminophenol leading to 4-(2-methylquinazolin-4-ylamino)phenol (3c)
N
CH3
N
HN
OH
Method A: 4-Aminophenol (0.05 g; 0.45 mmol; 1.1 equiv) and TFA (1 equiv; 25 μl) were added to a solution of
N-(2-cyanophenyl)acetamide 2a (0.07 g; 0.41 mmol) in ethanol (2 ml). The brown solution was refluxed for 17
h. The solution was kept at -18 ºC overnight (17 h) and the yellow solid precipitate was filtered and washed with
diethyl ether. The product was identified as the trifluoroacetate salt of 4-(2-methylquinazolin-4-ylamino)phenol
3
c (0.10 g; 0.27 mmol; 66%).
Method B: A brown solution of N-(2-cyanophenyl)acetamide 2a (0.05 g; 0.32 mmol) and 4-aminophenol (0.04
g; 0.35 mmol; 1.1 equiv) in acetic acid (11.6 equiv; 220 μl) was stirred at 60 ºC for 21 h. Addition of water led to
1
a dark solid suspension that was filtered and washed with water (0.02 g). The solid was identified by H NMR as
a mixture of 3c and 4b, in a 1:6.1 molar ratio, slightly contaminated with other unidentified side-products.
Removal of the solvent from the mother liquor and addition of water led to the isolation of a second crop of
greenish solid (0.04 g). The product was identified as 4-(2-methylquinazolin-4-ylamino)phenol 3c (0.04 g; 0.16
mmol; 50%).
Reaction of 2a and 4-bromoaniline leading to N-(4-bromophenyl)-2-methylquinazolin-4-amine
(3d)
N
CH3
N
HN
Br
4
-Bromoaniline (0.13 g; 0.77 mmol; 1.1 equiv) and TFA (1 equiv; 25 μl) were added to a yellow solution of N-
(
2-cyanophenyl)acetamide 2a (0.11 g; 0.70 mmol) in ethanol (2 ml). The solution was refluxed for 9.5 h. The
solution was kept at -18 ºC overnight (16 h) and the yellow precipitate was filtered and washed with diethyl
ether. The product was identified as the trifluoroacetate salt of N-(4-bromophenyl)-2-methylquinazolin-4-amine
3
d (0.14 g; 0.33 mmol; 47%).
Reaction of 2a and 3-bromoaniline leading to N-(3-bromophenyl)-2-methylquinazolin-4-amine
(3e)
6

N
CH3
N
HN
Br
Method A: 3-Bromoaniline (0.29 g; 1.70 mmol; 185 μl; 1.2 equiv) and TFA (1 equiv; 109 μl) were added to a
colorless solution of N-(2-cyanophenyl)acetamide 2a (0.22 g; 1.42 mmol) in ethanol (3 ml). The reaction
mixture was refluxed and after 22 h, the yellow solid that precipitated was filtered and washed with diethyl ether.
The product was identified as the trifluoroacetate salt of N-(3-bromophenyl)-2-methylquinazolin-4-amine 3e
(
0.07 g; 0.16 mmol; 11%). The solid that precipitated from the mother liquor was identified as the starting
material 2a (13%), by IR.
Method B: A yellow solution of N-(2-cyanophenyl)acetamide 2a (0.18 g; 1.17 mmol) and 3-bromoaniline (0.24
g; 1.40 mmol; 152 μl; 1.2 equiv) in acetic acid (11.6 equiv; 0.8 ml) was refluxed for 2.5 h. Addition of water led
to a yellow precipitate that was filtered and washed with water. The product was identified as N-(3-
bromophenyl)-2-methylquinazolin-4-amine 3e (0.07g; 0.24 mmol; 21%).
Reaction of 2a and 4-chloroaniline leading to N-(4-chlorophenyl)-2-methylquinazolin-4-amine
(3f)
N
CH3
N
HN
Cl
A grey solution of N-(2-cyanophenyl)acetamide 2a (0.11 g; 0.67 mmol) and 4-chloroaniline (0.09 g; 0.74 mmol;
.1 equiv) in acetic acid (11.6 equiv; 0.5 ml) was refluxed for 2 h. Addition of water led to a yellow solid that
1
1
was filtered and washed with water. The solid (0.09 g) was identified as a complex mixture, by H NMR. A
second crop (0.05 g) was isolated from the mother liquor upon addition of NaHCO (0.36 g) and was filtered and
3
washed with water. The product was identified as N-(4-chlorophenyl)-2-methylquinazolin-4-amine 3f (0.05g;
0
.19 mmol; 28%).
Reaction of 2b and 4-methoxyaniline leading to 7-chloro-N-(4-methoxyphenyl)-2-
methylquinazolin-4-amine (3g)
Cl
N
CH3
N
HN
OMe
Method A: 4-Methoxyaniline (0.18 g; 1.46 mmol; 2 equiv) was added to a white suspension of N-(5-chloro-2-
cyanophenyl)acetamide 2b (0.14 g; 0.73 mmol) in ethanol (5 ml), leading to a brown suspension. TFA (1 equiv;
56 μl) was added and the suspension was refluxed leading immediately to a brown solution. After 72 h, the
yellow solid precipitate was filtered and washed with diethyl ether and dichloromethane, leading to a pure
product identified as the trifluoroacetate salt of 7-chloro-N-(4-methoxyphenyl)-2-methylquinazolin-4-amine 3g
(
0.07 g; 0.17 mmol; 23%).
7

Method B: A beige suspension of N-(5-chloro-2-cyanophenyl)acetamide 2b (0.07 g; 0.37 mmol) and 4-
methoxyaniline (0.05 g; 0.41 mmol; 1.1 equiv) in acetic acid (11.6 equiv; 0.3 ml) was refluxed for 2 h. Addition
of water led to a beige precipitate that was filtered and washed with water and ethanol (1:1). The product was
identified as 7-chloro-N-(4-methoxyphenyl)-2-methylquinazolin-4-amine 3g (0.02 g; 0.07 mmol; 19%). The
solid that precipitated from the mother liquor was identified as a mixture of product 3g and a compound
1
tentatively identified as 4 (R = 4-OMeC H ) in a 1.7:1 molar ratio, by H NMR.
3
6
4
Reaction of 2c and 4-methoxyaniline leading to N-(4-methoxyphenyl)-2-phenylquinazolin-4-
amine (3h)
m
o
8
5
p
8
a
N
2 i
7
6
m'
N
o'
4
a
4
2'
HN
3'
1
'
4
'
6
'
OMe
5'
4
-Methoxyaniline (0.04 g; 0.35 mmol; 1.1 equiv) was added to a suspension of N-(2-cyanophenyl)benzamide 2c
(
0.07 g; 0.31 mmol) in ethanol (2 ml) leading to an orange solution. TFA (1 equiv; 25 μl) was added and the
solution was refluxed for 13.5 h. The yellow precipitate was filtered and washed with ethanol. The product was
identified as the trifluoroacetate salt of N-(4-methoxyphenyl)-2-phenylquinazolin-4-amine 3h (0.06 g; 0.14
mmol; 45%).
Reaction of 2c and 4-chloroaniline leading to N-(4-chlorophenyl)-2-phenylquinazolin-4-amine (3i)
N
N
HN
Cl
4
2
-Chloroaniline (0.05 g; 0.41 mmol; 1.2 equiv) was added to a yellow solution of N-(2-cyanophenyl)benzamide
c (0.08 g; 0.34 mmol) in ethanol (10 ml). TFA (1 equiv; 30 μl) was added and the solution was refluxed for 50
h. The solvent was removed in the rotary evaporator and diethyl ether was added to the oil leading to a solid
precipitate. The yellow solid was filtered and washed with petroleum ether. The product was identified as the
trifluoroacetate salt of N-(4-chlorophenyl)-2-phenylquinazolin-4-amine 3i (0.02g; 0.06 mmol; 18%). The green
solid (0.12 g) that precipitated from the mother liquor was mainly the amine contaminated with traces of starting
material 2c and other unidentified by-products.
Reaction of 2h and 4-methoxyaniline leading to 4-(4-methoxyphenylamino)quinazolin-2(1H)-one
(3j)
H
N
O
N
HN
OMe
8

Method A: 4-Methoxyaniline (0.07 g; 0.51 mmol; 1.2 equiv) was added a solution of 1-(2-cyanophenyl)-3-
phenylurea 2h (0.11 g; 0.46 mmol) in ethanol (10 ml), leading to an orange solution. TFA (1 equiv; 36 μl) was
added and the solution was refluxed for 72 h. After 18 h a deep-red solution was obtained. The solution was kept
at -18 ºC for 1 day and the white solid precipitate was filtered and washed with n-hexane. The product was
identified as 4-(4-methoxyphenylamino)quinazolin-2(1H)-one 3j (0.05 g; 0.19 mmol; 41%).
Method B: 4-Methoxyaniline (0.08 g; 0.68 mmol; 1.1 equiv) was added to a solution of ethyl (2-
cyanophenyl)carbamate 2e (0.12 g; 0.62 mmol) in ethanol (5 ml), leading to an orange solution. TFA (1 equiv;
4
8 μl) was added and the solution was refluxed for 97 h. The solution was kept at -18 ºC for 1 day and the white
solid precipitate was filtered and washed with diethyl ether. The product was identified as the trifluoroacetate
salt of 4-(4-methoxyphenylamino)quinazolin-2(1H)-one 3j (0.01 g; 0.04 mmol; 7%). The solid that precipitated
from the mother liquor was the starting material 2e (13%). The aromatic amine was recovered as the third crop
1
(
7%). The fourth crop was a mixture of starting material 2e and amine (1.5:1), by H NMR.
Reaction of 2h and 4-chloroaniline leading to 4-(4-chlorophenylamino)quinazolin-2(1H)-one (3k)
H
N
O
N
HN
Cl
4
-Chloroaniline (0.06 g; 0.45 mmol; 1.1 equiv) was added to a solution of 1-(2-cyanophenyl)-3-phenylurea 2h
(
0.10 g; 0.41 mmol) in ethanol (10 ml), leading to a yellow solution. TFA (1 equiv; 32 μl) was added and the
solution was refluxed for 96 h. The solution was kept at -18 ºC for 5 h and the white solid precipitate was filtered
and washed with n-hexane. The product was identified as 4-(4-chlorophenylamino)quinazolin-2(1H)-one 3k
(
0.02g; 0.07 mmol; 17%).
Reaction of 2g and 4-methoxyaniline leading to N-(4-methoxyphenyl)quinazolin-4-amine (3l)
8
8
a
N
7
6
2
N
4
a
4
5
2'
HN
3'
1
'
4
'
6
'
OMe
5
'
4
-Methoxyaniline (0.11 g; 0.86 mmol; 1.1 equiv) and concentrated HCl (0.4 equiv; 25 μl) were added to a white
suspension of N-(2-cyanophenyl)formamide 2g (0.11 g; 0.78 mmol) in ethanol (3 ml), leading to a yellow
solution. The reaction mixture was refluxed and after 12 h, the yellow solid that precipitated was filtered and
washed with diethyl ether. The product was identified as N-(4-methoxyphenyl)quinazolin-4-amine 3l (0.09 g;
0
.35 mmol; 41%).
Reaction of 2a and 4-methoxyaniline leading to 3-(4-methoxyphenyl)-2-methylquinazolin-4(3H)-
one (4a)
N
CH3
N
O
OMe
9

A brown solution of N-(2-cyanophenyl)acetamide 2a (0.07 g; 0.46 mmol) and 4-methoxyaniline (0.06 g; 0.51
mmol; 1.1 equiv) in acetic acid (11.6 equiv; 0.3 ml) was refluxed for 2 h. After cooling, water was added to the
reaction mixture and the yellow solid precipitate was filtered and washed with water. The product was identified
as 3-(4-methoxyphenyl)-2-methylquinazolin-4(3H)-one 4a (0.01 g; 0.04 mmol; 9 %). The mother liquor was
1
mainly a mixture of compound 3a and acetate salt of 4-methoxyaniline (1:1 M ratio), by H NMR.
Reaction of 2a and 4-aminophenol leading to 3-(4-hidroxyphenyl)-2-methylquinazolin-4(3H)-one
(4b)
N
O
CH3
N
OH
A yellow solution of N-(2-cyanophenyl)acetamide 2a (0.07 g; 0.46 mmol) and 4-aminophenol (0.06 g; 0.51
mmol; 1.1 equiv) in acetic acid (11.6 equiv; 0.3 ml) was refluxed for 2 h. A saturated aqueous solution of
NaHCO was added to the reaction mixture. The emulsion was extracted with dichlorometane (3x 5 ml). The
3
organic layer was dried and concentrated in the rotary evaporator. Addition of diethyl ether led to a greenish
precipitate that was filtered and washed with diethyl ether. The product was identified as 3-(4-hydroxyphenyl)-2-
methylquinazolin-4(3H)-one 4b (0.01 g; 0.04 mmol; 9%).
Reaction of 2a and 3-chloroaniline leading to 2-methylquinazolin-4(3H)-one (4c)
N
CH3
NH
O
A yellow solution of N-(2-cyanophenyl)acetamide 2a (0.11 g; 0.71 mmol) and 3-chloroaniline (0.10 g; 0.78
mmol; 82 μl; 1.1 equiv) in acetic acid (11.6 equiv; 0.5 ml) was refluxed for 3.5 h. After cooling, water was
added to the reaction mixture and the white solid precipitate was filtered and washed with water. The product
was identified as 2-methylquinazolin-4(3H)-one 4c (0.06 g; 0.37 mmol; 52 %).
1
0

1
13
H and C NMR spectra for compounds 2a-h
1
1

1
2

1
3

1
4

1
5

1
6

1
7

1
8

1
9

1
13
H and C NMR spectra for compounds 3a-l
2
0

2
1

2
2

2
3

2
4

2
5

2
6

2
7

2
8

2
9