A general synthesis of 4-arylaminoquinazoline-2-carbonitriles

Article abstract of DOI:10.1515/znb-2009-0715

4-Arylaminoquinazoline-2-carbonitriles 5a - i were obtained by a one-step synthesis in moderate to good yield by reacting 2-aminoarylbenzimidamides 3a - i with tetracyanoethylene (TCNE, 4) in ethyl acetate at r. t. for 4 - 6 h. The structure of the select

Full text of DOI:10.1515/znb-2009-0715

A General Synthesis of 4-Arylaminoquinazoline-2-carbonitriles
Kamal M. El-Shaieba, Henning Hopfb, and Peter G. Jonesc
a Chemistry Department, Faculty of Science, Minia University, El-Minia, Egypt
b Institute of Organic Chemistry, Hagenring 30, TU Braunschweig, 38106 Braunschweig, Germany
c Institute of Inorganic and Analytical Chemistry, Hagenring 30, TU Braunschweig,
38106 Braunschweig, Germany
Reprint requests to Dr. Kamal M. El-Shaieb. Fax: +2-086-2342601. E-mail: kmelshaieb@yahoo.com
Z. Naturforsch. 2009, 64b, 858 – 864; received February 4, 2009
4-Arylaminoquinazoline-2-carbonitriles 5a – i were obtained by a one-step synthesis in moderate
to good yield by reacting 2-aminoarylbenzimidamides 3a – i with tetracyanoethylene (TCNE, 4) in
ethyl acetate at r. t. for 4 – 6 h. The structure of the selected benzimidamide 3c was determined by
single crystal X-ray diffraction.
Key words: Aminobenzonitrile, Anilines, Cyanoquinazolines, Tetracyanoethylene
Introduction
This goal was achieved by diminishing the fusion
time from 1 h to 20 – 30 min and lowering the reaction
Quinazolines are a class of heterocyclic compounds
that have attracted much attention within the last
decades due to their widespread application and their
pharmacological importance [1 – 7]. Quinazolines gen-
erally have been obtained from amides or amidines
[2, 3, 6, 10]. Although 4-arylaminoquinazoline deriva-
tives have recently been synthesized very simply [6],
there has been little progress in the study of their chem-
ical behavior. Certain quinazoline derivatives have
been efficiently prepared by condensation of acids
[8] or aldehydes [9] with 2-aminoarylbenzimidamide
derivatives, produced from fusing primary or sec-
ondary amines with nitriles in the presence of AlCl3
as a catalyst [11 – 13]. The synthesized amidines were
found to have a wide range of biological activities
[14, 15].
◦
◦
temperature from 200 C to 170– 180 C in addition
to using equimolar ratios of the reactants (see Experi-
mental Section). The use of high temperatures and long
reaction times together with excess amounts of the cat-
alyst could lead to either formation of stable complexes
between catalyst and reactants or polymerization reac-
tions causing a lowering in yield or even absence of
products, as in the case of the alkoxy-substituted com-
pounds. Moreover, we noticed that in the literature the
1H NMR data of the starting materials were measured
in [D6]DMSO and [D6]acetone [9] although we have
found that all samples dissolved easily in CDCl3. Fur-
thermore no 13C NMR data have been published for
all of the previously obtained samples, a gap which we
also wanted to fill. The second aim of our present work
was to synthesize 4-arylaminoquinazoline-2-carboni-
trile derivatives 5a – i, which could not be obtained by
the usual protocol. To achieve this goal we reacted the
obtained amidine derivatives with tetracyanoethylene
(TCNE, 4) at r. t. in ethyl acetate for 4 – 6 h (Scheme 2).
The target compounds precipitated from the reaction
solutions, and the products were collected by filtration
and recrystallized from chloroform. This simple and
efficient method made several heterocyclic compounds
accessible that could not be synthesized by the usual
approaches [16 – 22].
Results and Discussion
Our present work has two main goals: the first
one is to improve the yield of the products ob-
tained by the reaction of 2-aminobenzonitrile (1) and
various aniline derivatives 2a – i. In the method de-
scribed in the literature [9] the yields of the re-
spective amidines were low, and the applied protocol
could not be used to synthesize alkoxy derivatives.
This prompted us to synthesize various 2-aminoaryl-
benzimidamide derivatives 3a – i containing a variety
of substituents including alkoxy and dihalo moieties
(Scheme 1).
A mechanism proposed for the formation of com-
pounds 5a – i is shown in Scheme 3. The aro-
matic amino group attacks an olefinic carbon atom
c
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K. M. El-Shaieb et al. · A General Synthesis of 4-Arylaminoquinazoline-2-carbonitriles
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a, R = R1 = R2 = H
d, R = R2 = H, R1 = Br
e, R1 = R2 = H, R = I
f, R1 = H, R = R2 = CH3
g, R1 = H, R = R2 = Cl
b, R = R2 = H, R1 = CH3
c, R = R2 = H, R1 = Cl
h, R = R1 = H, R2 = OCH3
i, R = R2 = H, R1 = OCH3
Scheme 1. Synthesis of 2-aminoaryl-
benzimidamides 3a – i.
Scheme 2. Synthesis of 4-arylamino-
quinazoline-2-carbonitriles 5a – i.
Scheme 3. Rational pathway for the
formation of compounds 5a – i.
of TCNE first, thus releasing one equivalent of the formation of the intermediates 7, which lose
HCN. Subsequently the amidine amino group at- a malononitrile molecule and rearrange to products
tacks the same olefinic carbon atom. This leads to 5a – i.
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860
(a)
K. M. El-Shaieb et al. · A General Synthesis of 4-Arylaminoquinazoline-2-carbonitriles
tons. Finally, the mass spectra showed the molecular
ion peaks in accordance with the products 5a – i.
Conclusion
On the basis of the above experimental results, it is
concluded that a series of 4-arylaminoquinazoline-2-
carbonitriles have been synthesized for the first time by
a one-step protocol at r. t. in moderate to good yields.
Experimental Section
(b)
Starting materials
All reagents were purchased from Alfa Aesar, Fluka and
Aldrich companies and were used without further purifica-
tion. The melting points were measured in capillary tubes
without corrections using a Bu¨chi 530 melting point appa-
ratus. The NMR spectra were recorded on a Bruker AM
400 MHz spectrometer with TMS as internal standard; the
coupling constants are given in Hz. The mass spectra (EI)
were performed using a Finnigan MAT 8430 spectrometer.
IR spectra were run as KBr discs using a Bruker Tensor 27
instrument.
Synthesis of compounds 3a – i
Fig. 1. (a) Molecular structure of compound 3c in the crys-
tal (displacement ellipsoids at the 50 % probability level);
(b) packing diagram of compound 3c (see text).
General procedure
0.01 mol of 2-aminobenzonitrile (1) was fused with
0.01 mol of the aniline derivative (2a – i) to form a homo-
geneous solution. Then 0.01 mol of anhydrous AlCl3 was
The structure of the products 3a – i and 5a – i were
elucidated by using the usual spectroscopic methods
such as IR and NMR spectroscopy. Moreover, the
structure of the benzimidamide 3c was further con-
firmed by single crystal X-ray methods (Fig. 1a). The
double bond N2=C7 has been identified by its length
◦
added, and the reaction mixture was heated at 170 – 180 C
for 20 – 30 min. 10 % aqueous HCl solution was added, and
the mixture was heated for 5 min. The resulting solution was
filtered while hot into a conical flask containing 10 % aque-
ous NaOH solution. The colorless precipitate that formed
was collected by filtration under suction, washed with water
until the filtrate was neutral, and left to dry at r. t. overnight
to give the 2-aminoarylbenzimidamide products 3a – i in 50 –
65 % yield.
˚
of 1.299(2) A, and all hydrogens of the NH2 groups
were freely refined. The interplanar angle between the
planes (C1-7, N1-3) and (C8-13, N2, Cl) is 63◦. An in-
tramolecular hydrogen bond N1–HN1B···N2 (H···N
˚
1.99(2) A) is observed. The molecules are connected
in the direction [101] by the rather long classical hy- (Z)-2-Amino-Nꢀ-phenylbenzimidamide (3a)
¯
˚
drogen bond N3–HN3A···N1 (H···N 2.57(2) A) and
1.◦26 g (60 %), m. p. 140 – 141 ◦C (lit. [9]: m. p. 146 –
by the H···π interactions HN1A···Cent(C8 – 13) and
148 C). – 1H NMR (400 MHz, CDCl3): δ = 4.77 (br. s,
2 H, NH2), 6.00 (br. s, 2 H, NH2), 6.67 – 6.72 (m, 2 H),
6.97 – 7.06 (m, 2 H), 7.07 – 7.11 (m, 1 H), 7.16 – 7.21 (m,
1 H), 7.33 – 7.46 ppm (m, 3 H). – 13C NMR (100 MHz,
CDCl3): δ = 116.47 (C), 116.59 (CH), 117.16 (CH), 121.83
(2 CH), 123.13 (CH), 127.27 (CH), 129.57 (2 CH), 131.14
(CH), 147.96 (C), 148.91 (C), 155.76 ppm (C).
˚
H6···Cent(C8 – 13), both 2.76 A (Fig. 1b). The chains
are connected in the third dimension by the interaction
˚
H10···Cent(C1 – 6) 2.59 A (not shown in the Figure).
The IR spectra of these products showed two ab-
sorption peaks at 3343– 3375 and 2251– 2200 cm−1
which are characteristic for NH and CN, respectively.
The carbon atoms of the cyano groups resonated at
115.03– 115.70 ppm. Furthermore, the 1H NMR spec-
trum revealed, in addition to the aromatic protons, a
(Z)-2-Amino-Nꢀ-p-tolylbenzimidamide (3b)
1.◦45 g (64 %), m. p. 145 – 147 ◦C (lit. [9]: m. p. 152 –
peak at 7.34 – 10.37 ppm originating from the NH pro- 153 C). – 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3H,
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CH3), 4.77 (br. s, 2H, NH2), 6.01 (br. s, 2 H, NH2), 6.68 – 1.41 Hz, 1 H), 7.41 – 7.43 ppm (dd, J = 1.40, 7.66 Hz, 1 H). –
6.71 (m, 2 H), 6.88 – 6.91 (m, 2 H), 7.15 – 7.20 (m, 3 H), 13C NMR (100 MHz, CDCl3): δ = 17.58 (CH3), 21.00
7.40 – 7.43 ppm (dd, J = 1.46, 7.88 Hz, 1 H). – 13C NMR (CH3), 116.46 (CH), 117.12 (CH), 121.89 (CH), 123.97
(100 MHz, CDCl3): δ = 20.82 (CH3), 116.55 (CH), 116.63 (CH), 126.11 (C), 127.25 (CH), 130.69 (CH), 131.04 (CH),
(C), 117.12 (CH), 121.63 (2 CH), 127.27 (CH), 130.13 136.57 (2 C), 147.26 (C), 148.14 (C), 154.95 ppm (C). – MS
(2 CH), 131.04 (CH), 132.46 (C), 146.18 (C), 147.95 (C), (EI, 70 eV): m/z (%) = 239 (100), 224 (50), 206 (10), 195
155.89 ppm (C).
(8), 180 (4), 145 (4), 121 (70), 106 (30), 92 (18), 77 (14), 65
(12). – C15H17N3 (239.32): calcd. C 75.28, H 7.16, N 17.56;
found C 75.02, H 7.11, N 17.25.
(Z)-2-Amino-Nꢀ-(4-chlorophenyl)benzimidamide (3c)
1.30 g (53 %), m. p. 149 – 151 ◦C (lit. [9]: m.p. 161 –
162 ◦C). – 1H NMR (400 MHz, CDCl3): δ = 4.80 (br. s, 2 H,
NH2), 5.94 (br. s, 2 H, NH2), 6.67 – 6.75 (m, 2 H), 6.90 –
6.95 (m, 2 H), 7.20 – 7.23 (m, 1 H), 7.30 – 7.35 (m, 2 H),
7.40 – 7.43 ppm (dd, J = 1.44, 7.88 Hz, 1 H). – 13C NMR
(100 MHz, CDCl3): δ = 116.17 (CH), 116.19 (C), 116.67
(CH), 117.22 (CH), 123.25 (2 CH), 127.25 (CH), 128.30 (C),
129.08 (C), 129.61 (2 CH), 131.34 (CH), 147.42 (C), 147.89
(C), 156.12 ppm (C).
(Z)-2-Amino-Nꢀ-(2,5-dichlorophenyl)benzimidamide (3g)
Colorless solid, 1.81 g (65 %), m. p. 76 – 77 ◦C. – IR
(film): ν = 3470, 3368, 3320, 3076 (NH2), 1626 (C=N),
1576 cm−1 (C=C). – 1H NMR (400 MHz, CDCl3): δ =
4.82 (br. s, 2 H, NH2), 5.86 (br. s, 2 H, NH2), 6.63 – 6.67
(m, 1 H), 6.96 – 7.02 (dd, J = 2.48, 8.49 Hz, 1 H), 7.05 (d,
J = 2.44 Hz, 1 H), 7.17 – 7.22 (m, 1 H), 7.37 – 7.44 ppm (m,
2 H). – 13C NMR (100 MHz, CDCl3): δ = 116.63 (CH),
117.20 (CH), 118.76 (C), 123.19 (CH), 124.07 (CH), 127.44
(CH), 130.13 (C), 130.98 (CH), 131.63 (CH), 133.06 (C),
147.65 (C), 148.14 (C), 156.47 ppm (C). – MS (EI, 70 eV):
m/z (%) = 283 (12), 281 (62), 279 (100), 262 (40), 244 (80),
227 (10), 200 (8), 192 (12), 143 (4), 109 (8), 92 (36), 75 (4),
65 (20). – C13H11Cl2N3 (280.15): calcd. C 55.73, H 3.96,
N 15.00; found C 55.57, H 3.91, N 14.82.
(Z)-2-Amino-Nꢀ-(4-bromophenyl)benzimidamide (3d)
1.53 g (53 %), m. p. 159 – 161 ◦C (lit. [9]: m. p. 167 –
168 ◦C). – 1H NMR (400 MHz, CDCl3): δ = 4.78 (br. s, 2 H,
NH2), 5.94 (br. s, 2 H, NH2), 6.67 – 6.72 (m, 2 H), 6.86 – 6.90
(m, 2 H), 7.17 – 7.22 (m, 1 H), 7.39 – 7.48 ppm (m, 3 H). –
13C NMR (100 MHz, CDCl3): δ = 115.96 (C), 116.14 (C),
116.68 (CH), 117.24 (CH), 123.73 (2 CH), 127.25 (CH),
131.37 (CH), 132.57 (2 CH), 147.92 (C), 147.94 (2 C),
156.02 ppm (C).
(Z)-2-Amino-Nꢀ-(3-methoxyphenyl)benzimidamide (3h)
Yellowish brown solid, 0.920 g (38 %), m. p. 35 – 37 ◦C. –
IR (film): ν = 3461, 3367, 3224, 3216 (NH2), 1605 (C=N),
1571 cm−1 (C=C). – 1H NMR (400 MHz, CDCl3): δ = 3.78
(s, 3H, OCH3), 4.82 (br. s, 2 H, NH2), 5.95 (br. s, 2 H, NH2),
6.54 – 6.57 (m, 1 H), 6.59 – 6.62 (m, 1 H), 6.63 – 6.66 (m,
1 H), 6.67 – 6.72 (m, 2 H), 7.14 – 7.20 (m, 1 H), 7.22 – 7.27
(m, 1 H), 7.38 – 7.42 ppm (dd, J = 1.34, 7.90 Hz, 1H). –
13C NMR (100 MHz, CDCl3): δ = 55.32 (OCH3), 107.40
(CH), 109.13 (CH), 114.17 (CH), 116.71 (CH), 117.23 (CH),
127.43 (CH), 130.41 (CH), 131.24 (CH), 147.81 (C), 150.18
(C), 155.86 (C), 160.72 ppm (C). – MS (EI, 70 eV): m/z
(%) = 241 (100), 240 (40), 224 (20), 209 (4), 195 (4), 181
(4), 154 (4), 147 (12), 133 (20), 113 (4), 94 (36), 92 (28), 77
(18), 65 (16). – C14H15N3O (241.30): calcd. C 69.69, H 6.27,
N 17.41; found C 69.48, H 6.24, N 17.24.
(Z)-2-Amino-Nꢀ-(2-iodophenyl)benzimidamide (3e)
◦
Deep-brown solid, 1.51 g (45 %), m. p. 140 – 143 C. –
IR (film): ν = 3448, 3319 (NH2), 1619 (C=N), 1568 cm−1
(C=C). – 1H NMR (400 MHz, CDCl3): δ = 4.78 (br. s,
2 H, NH2), 5.96 (br. s, 2 H, NH2), 6.46 – 6.67 (m, 4 H),
7.31 – 7.36 (m, 1 H), 7.44 – 7.50 ppm (m, 3 H). – 13C NMR
(100 MHz, CDCl3): δ = 116.77 (CH), 117.09 (CH), 121.98
(CH), 122.14 (CH), 123.27 (CH), 124.38 (CH), 127.34 (CH),
129.69 (CH), 131.21 (C), 133.16 (C), 139.60 (C), 148.83 (C),
156.13 ppm (C). – MS (EI, 70 eV): m/z (%) = 339 (4), 338
(20), 337 (100), 320 (28), 310 (6), 236 (84), 211 (42), 193
(26), 166 (20), 139 (8), 92 (68), 65 (40), 57 (18), 44 (14). –
C13H12IN3 (337.17): calcd. C 46.31, H 3.59, N 12.46; found
C 46.19, H 3.54, N 12.28.
(Z)-2-Amino-Nꢀ-(4-methoxyphenyl)benzimidamide (3i)
(Z)-2-Amino-Nꢀ-(2,5-dimethylphenyl)benzimidamide (3f)
Brown solid, 1.14 g (47 %), m. p. 139 – 140 ◦C. – IR
◦
Pale-brown solid, 1.30 g (54 %), m. p. 49 – 51 C. – IR (film): ν = 3484, 3435, 3381 (NH2), 1611 (C=N), 1573,
(film): ν = 3463, 3365, 3304, 3216 (NH2), 1627 cm−1 1535 cm−1 (C=C). – 1H NMR (400 MHz, CDCl3): δ =
(C=N). – 1H NMR (400 MHz, CDCl3): δ = 2.10 (s, 3 H, 3.80 (s, 3 H, OCH3), 4.79 (br. s, 2 H, NH2), 6.02 (br. s,
CH3), 2.25 (CH3), 4.64 (br. s, 2 H, NH2), 6.08 (br. s, 2 H, 2 H, NH2), 6.76 – 6.65 (m, 2 H), 6.92 (s, 4 H), 7.22 – 7.15
NH2), 6.62 – 6.70 (m, 3 H), 6.79 – 6.82 (d, J = 7.68 Hz, (m, 1 H), 7.43 – 7.39 ppm (dd, J = 1.24, 7.77 Hz, 1 H). –
1 H), 7.10 – 7.13 (d, J = 7.65 Hz, 1 H), 7.16 – 7.20 (d, J = 13C NMR (100 MHz, CDCl3): δ = 55.51 (OCH3), 114.90
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K. M. El-Shaieb et al. · A General Synthesis of 4-Arylaminoquinazoline-2-carbonitriles
(2 CH), 116.55 (CH), 117.12 (CH), 122.67 (2 CH), 127.27 (C=C). – 1H NMR (400 MHz, [D6]DMSO): δ = 7.51 –
(CH), 131.02 (CH), 147.92 (C), 155.67 (C), 156.29 ppm 7.55 (m, 2 H), 7.81 – 7.85 (m, 3 H), 7.87 – 7.90 (m, 1 H),
(C). – MS (EI, 70 eV): m/z (%) = 241 (66), 224 (18), 209 7.90 – 7.93 (m, 1 H), 7.99 – 8.03 (m, 1 H), 8.65 (d, J =
(12), 196 (4), 181 (6), 147 (6), 133 (8), 123 (74), 108 (100), 8.45 Hz, 1 H), 10.37 ppm (br. s, 1 H, NH). – 13C NMR
92 (20), 80 (12), 65 (16), 53 (10), 44 (22). – C14H15N3O (100 MHz, [D6]DMSO): δ = 115.50 (C), 116.82 C), 123.40
(241.30): calcd. C 69.69, H 6.27, N 17.41; found C 69.51, (CH), 124.70 (2 CH), 128.12 (CH), 128.60 (2 CH), 128.73
H 6.26, N 17.28.
(C), 129.11 (C), 134.48 (CH), 136.98 (C), 139.78 (C), 148.85
(C), 158.27 ppm (C). – MS (EI, 70 eV): m/z (%) = 281 (60),
280 (68), 279 (100), 252 (8), 244 (30), 219 (4), 217 (8), 204
(4), 192 (8), 190 (6), 164 (6), 140 (8), 122 (8), 111 (12), 102
(18), 96 (14), 84 (8), 75 (16), 51 (8). – C15H9ClN4 (280.72):
calcd. C 64.18, H 3.23, N 19.96, Cl 12.63; found C 63.88,
H 3.19, N 19.75, Cl 12.31.
Reactions of 3a – i with tetracyanoethylene (TCNE)
General procedure
One mmol of 2-aminoarylbenzimidamides 3a – i was dis-
solved in 10 mL of dry ethyl acetate, and this solution was
added to a solution of 2 mmol of tetracyanoethylene (4) in
10 mL of dry ethyl acetate; the color of the reaction mixture
changed from yellow to yellowish red. The reaction mixture
was stirred at r. t. for 4 – 6 h. The colorless to yellow solid
that precipitated was collected by filtration and was recrys-
tallized from chloroform to give 4-arylaminoquinazoline-2-
carbonitriles 5a – i in 57 – 73 % yield.
4-(4-Bromophenylamino)quinazoline-2-carbonitrile (5d)
◦
Colorless crystals, 179 mg (55 %), m. p. 176 – 177 C. –
IR (film): ν = 3343 (NH), 2251 (CN), 1611 (C=N),
1599 cm−1 (C=C). – 1H NMR (400 MHz, CDCl3): δ =
10.37 (br. s, 1 H, NH), 8.61 – 8.63 (d, J = 7.70 Hz, 1 H),
7.96 – 8.03 (m, 1 H), 7.89 – 7.93 (m, 1 H), 7.82 – 7.86 (m,
1 H), 7.75 – 7.79 (m, 2 H), 7.64 – 7.68 ppm (m, 2 H). –
13C NMR (100 MHz, CDCl3): δ = 115.51 (C), 116.80
(C), 116.88 (C), 123.39 (CH), 125.02 (2 CH), 128.12 (CH),
129.12 (CH), 131.52 (2 CH), 134.49 (CH), 137.41 (C),
139.75 (C), 148.85 (C), 158.22 ppm (C). – MS (EI, 70 eV):
m/z (%) = 325 (100), 298 (2), 281 (4), 244 (40), 217 (6), 192
(8), 155 (6), 132 (4), 122 (18), 102 (14), 90 (10), 75 (8), 50
(4), 41 (12). – C15H9BrN4 (325.17): calcd. C 55.41, H 2.79,
Br 24.57, N 17.23; found C 55.26, H 2.76, N 17.04.
4-(Phenylamino)quinazoline-2-carbonitrile (5a)
Yellow solid, 175 mg (71 %), m. p. 84 – 85 ◦C. – IR
(film): ν = 3374 (NH), 2200 (CN), 1613 (C=N), 1566 cm−1
(C=C). – 1H NMR (400 MHz, CDCl3): δ = 7.21 – 7.28 (m,
1 H), 7.42 – 7.48 (m, 2 H), 7.68 – 7.73 (m, 2 H), 7.75 – 7.80
(m, 2 H), 7.88 – 7.93 (m, 1 H), 7.95 (br. s, 1 H, NH), 7.96 –
8.01 ppm (m, 1H). – 13C NMR (100 MHz, CDCl3): δ =
115.13 (C), 116.64 (C), 120.46 (CH), 121.78 (2 CH), 125.42
(CH), 129.21 (CH), 129.25 (2 CH), 129.52 (CH), 134.09
(CH), 137.13 (C), 140.60 (C), 149.45 (C), 157.57 ppm (C). –
MS (EI, 70 eV): m/z (%) = 246 (40), 254 (100), 236 (4), 218
(8), 192 (4), 166 (4), 139 (2), 123 (4), 104 (8), 102 (6), 96 (8),
77 (12), 66 (4), 51 (8), 41 (4). – C15H10N4 (246.27): calcd.
C 73.16, H 4.09, N 22.75; found C 72.97, H 4.11, N 22.63.
4-(2-Iodophenylamino)quinazoline-2-carbonitrile (5e)
Brown solid, 153 mg (41 %), m. p. 89 – 90 ◦C. – IR
(film): ν = 3366 (NH), 2200 (CN), 1613 (C=N), 1593 cm−1
(C=C). – 1H NMR (400 MHz, CDCl3): δ = 6.94 – 7.00 (m,
1 H), 7.44 – 7.53 (m, 2 H), 7.71 – 7.78 (m, 1 H), 7.89 – 7.92
(m, 2 H), 7.94 – 8.98 (m, 2 H), 8.13 ppm (br. s, 1 H, NH). –
13C NMR (100 MHz, CDCl3): δ = 111.92 (C), 120.65 (CH),
121.77 (C), 123.08 (CH), 129.37 (CH), 129.67 (CH), 129.77
(CH), 134.38 (CH), 137.48 (C), 138.18 (C), 139.11 (CH),
134.48 (CH), 136.98 (C), 139.78 (C), 149.54 ppm (C). – MS
(EI, 70 eV): m/z (%) = 372 (40), 371 (78), 320 (20), 245
(100), 218 (8), 192 (8), 166 (6), 139 (4), 122 (4), 96 (8), 63
(4), 51 (6). – C15H9IN4 (372.17): calcd. C 48.41, H 2.44,
N 15.05; found C 48.29, H 2.41, N 14.89.
4-(p-Tolylamino)quinazoline-2-carbonitrile (5b)
◦
Colorless solid, 160 mg (62 %), m. p. 130 – 131 C. – IR
(film): ν = 3363 (NH), 2201 (CN), 1608 (C=N), 1564 cm−1
(C=C). – 1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H,
CH3), 7.23 – 7.26 (m, 2 H), 7.35 (br. s, 1 H, NH), 7.61 –
7.64 (m, 2 H), 7.68 – 7.72 (m, 1 H), 7.87 – 7.95 ppm (m,
3 H). – 13C NMR (100 MHz, CDCl3): δ = 20.99 (CH3),
115.14 (C), 116.68 (C), 120.48 (CH), 121.93 (2 CH), 129.08
(CH), 129.48 (CH), 129.76 (2 CH), 133.96 (CH), 134.52 (C),
135.34 (C), 140.76 (C), 149.44 (C), 157.63 ppm (C). – MS
(EI, 70 eV): m/z (%) = 260 (44), 259 (100), 244 (12), 232 (8),
205 (4), 192 (4), 154 (6), 129 (12), 116 (8), 102 (12), 91 (8),
77 (6), 51 (6), 44 (8). – C16H12N4 (260.30): calcd. C 73.83,
H 4.65, N 21.52; found C 73.62, H 4.64, N 21.33.
4-(2,5-Dimethylphenylamino)quinazoline-2-carbonitrile
(5f)
◦
Colorless crystals, 125 mg (46 %), m. p. 172 – 173 C. –
4-(4-Chlorophenylamino)quinazoline-2-carbonitrile (5c)
IR (film): ν = 3345 (NH), 2244 (CN), 1618 (C=N),
Yellow crystals, 159 mg (57 %), m. p. 208 – 210 C. – IR 1588 cm−1 (C=C). – 1H NMR (400 MHz, CDCl3): δ = 2.30
◦
(film): ν = 3357 (NH), 2205 (CN), 1601 (C=N), 1568 cm−1 (s, 3 H, CH3), 2.39 (s, 3 H, CH3), 7.05 (d, 1 H, J = 7.74 Hz),
Unauthenticated
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K. M. El-Shaieb et al. · A General Synthesis of 4-Arylaminoquinazoline-2-carbonitriles
863
7.20 (d, J = 7.65 Hz, 1 H), 7.40 (s, 1H), 7.58 (br. s, 1 H, NH), (8), 129 (4), 116 (8), 102 (6), 84 (12), 77 (8), 43 (14). –
7.66 – 7.70 (m, 1 H), 7.90 – 7.96 (m, 2 H), 7.98 – 8.01 ppm C16H12N4O (276.29): calcd. C 69.55, H 4.38, N 20.28; found
(m, 1 H). – 13C NMR (100 MHz, CDCl3): δ = 17.70 (CH3), C 69.34, H 4.36, N 20.09.
21.15 (CH3), 115.09 (C), 116.62 (C), 120.52 (CH), 125.44
(CH), 127.61 (CH), 128.75 (C), 129.01 (CH), 129.58 (CH),
130.80 (CH), 133.97 (CH), 134.91 (C), 136.86 (C), 149.60
(C), 158.34 ppm (C). – MS (EI, 70 eV): m/z (%) = 274 (50),
259 (100), 248 (20), 244 (10), 230 (6), 205 (8), 192 (4), 164
(4), 137 (14), 129 (12), 120 (18), 103 (16), 65 (4), 51 (8), 41
(10). – C17H14N4 (274.33): calcd. C 74.43, H 5.14, N 20.42;
found C 74.28, H 5.16, N 20.30.
4-(4-Methoxyphenylamino)quinazoline-2-carbonitrile (5i)
Deep-red solid, 190 mg (69 %), m. p. 90 – 91 ◦C. – IR
(film): ν = 3370 (NH), 2199 (CN), 1602 (C=N), 1578 cm−1
(C=C). – 1H NMR (400 MHz, CDCl3): δ = 3.75 (s, OCH3),
6.86 (d, J = 9.06 Hz, 2H), 7.54 (d, J = 9.05 Hz, 2H), 7.66 –
7.61 (m, 2H), 7.74 (br. S, NH2), 7.88 – 7.83 (m, 2H). –
13C NMR (100 MHz, CDCl3): δ = 55.63 (OCH3), 114.43
(2 CH), 117.51 (C), 120.95 (CH), 124.10 (2 CH), 129.17
(CH), 129.23 (CH), 134.06 (CH), 139.21 (C), 139.59 (C),
149.18 (C), 158.72 (C), 159.33 ppm (C). – MS (EI, 70 eV):
m/z (%) = 276 (28), 275 (100), 260 (46), 245 (18), 232 (20),
204 (4), 179 (6), 165 (64), 158 (8), 129 (4), 116 (8), 102
(6), 84 (12), 77 (8), 43 (14). – C16H12N4O (276.29): calcd.
C 69.55, H 4.38, N 20.28; found C 69.38, H 4.37, N 20.12.
4-(2,5-Dichlorophenylamino)quinazoline-2-carbonitrile
(5g)
Yellow solid, 176 mg (56 %), m. p. 72 – 73 ◦C. – IR
(film): ν = 3398 (NH), 2204 (CN), 1628 (C=N), 1572 cm−1
(C=C). – 1H NMR (400 MHz, [D6]DMSO): δ = 7.42 – 7.46
(dd, J = 2.51, 8.62 Hz, 1 H), 7.46 – 7.51 (m, 1 H), 7.63 (d,
J = 8.64 Hz, 1 H), 7.75 – 7.79 (m, 1 H), 7.82 (d, J = 2.45 Hz,
1 H), 8.33 (d, J = 8.04 Hz, 1 H), 10.57 (s, 1 H), 12.05 ppm
(br. s, 1 H, NH). – 13C NMR (100 MHz, [D6]DMSO): δ =
109.87 (C), 117.32 (CH), 118.01 (C), 123.77 (CH), 124.45
(CH), 128.18 (CH), 129.03 (CH), 129.13 (C), 130.86 (CH),
131.45 (C), 135.28 (CH), 135.50 (C), 140.21 (C), 156.93 (C),
160.32 ppm (C). – MS (EI, 70 eV): m/z (%) = 318 (12), 316
(64), 314 (100), 304 (10), 279 (100), 267 (8), 244 (24), 221
(8), 207 (12), 192 (6), 165 (8), 149 (14), 125 (18), 111 (14),
97 (12), 83 (20), 71 (24), 57 (18). – C15H8Cl2N4 (315.16):
calcd. C 57.17, H 2.56, N 17.78; found C 56.98, H 2.51,
N 17.57.
X-Ray structure determination of 3c
Crystal data: C13H12ClN3, Mr = 245.71, monoclinic,
P21/n, T = −170 ◦C, a = 5.7◦795(2), b = 26.6025(10),
3
˚
˚
c = 7.6992(4) A, β = 96.442(5) , U = 1176.3 A , Z = 4,
F(000) = 512, λ(CuKα) = 1.54184 A, µ = 2.7 mm−1, Dx =
˚
1.387 g cm−3
.
Data collection: A colorless prism of ca. 0.35 × 0.1 ×
0.1 mm3 was mounted in inert oil on a glass fibre and trans-
ferred to the cold gas stream of an Oxford Diffraction Nova
Atlas diffractometer. Data were recorded to 2θ = 151◦ and
were 99.9 % complete to 145◦.
4-(3-Methoxyphenylamino)quinazoline-2-carbonitrile (5h)
Structure refinement: The structure was refined using
SHELXL-97 [23]. NH hydrogen atoms were refined freely,
other H atoms were included using a riding model. The final
wR2 (all reflections) was 0.084 for 2446 intensities and 170
parameters, with R1 [I ≥ 2σ(I)] 0.032; S 1.05, max. ∆ρ =
Deep-red crystals, 141 mg (51 %), m. p. 66 – 67 ◦C. –
IR (film): ν = 3336 (NH), 2199 (CN), 1603 (C=N), 1570
(C=C) cm−1. – 1H NMR (400 MHz, [D6]DMSO): δ = 3.81
(s, 3 H, OCH3), 6.81 – 6.85 (m, 1 H), 7.36 – 7.40 (m, 1 H),
4.39 – 7.42 (m, 1 H), 7.46 – 7.50 (m, 1 H), 7.80 – 7.84 (m,
1 H), 7.86 – 7.90 (m, 1 H), 7.95 – 8.01 (m, 1 H), 8.62 (d,
J = 7.84 Hz, 1 H), 10.22 ppm (br. s, 1 H, NH). – 13C NMR
(100 MHz, [D6]DMSO): δ = 55.10 (OCH3), 108.84 (CH),
110.24 (CH), 115.15 (CH), 115.50 (C), 116.87 (C), 123.34
(CH), 128.04 (CH), 128.91 (CH), 129.37 (CH), 134.26 (CH),
139.17 (C), 139.85 (C), 148.80 (C), 158.21 (C), 159.39 ppm
(C). – MS (EI, 70 eV): m/z (%) = 276 (40), 275 (100),
260 (28), 245 (8), 232 (20), 204 (4), 179 (6), 165 (64), 158
−3
˚
0.22 e A
.
CCDC 723205 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data request/cif.
Acknowledgement
Kamal M. El-Shaieb thanks the Egyptian Government for
a post-doctoral fellowship and financial support.
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