A facile synthesis of novel unsymmetrical N-(4-oxo-2-phenyl-3(4H)- quinazolinoyl)-N-(aryl)acetamidines

Article abstract of DOI:10.1016/j.cclet.2010.04.009

A series of novel unsymmetrical N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N- (aryl)acetamidines was synthesized by reacting ethyl(1E)-N-(4-oxo-2- phenylquinazolin-3(4H)-yl)ethanimidoate (2) and suitable reactive aromatic amines. Structures' determination of

Full text of DOI:10.1016/j.cclet.2010.04.009

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Chinese Chemical Letters 21 (2010) 905–910
www.elsevier.com/locate/cclet
A facile synthesis of novel unsymmetrical
N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines
b,
b
Rasool Khan a, , Mohammad Arfan , Javeed Mahmood ,
*
*
Shazia Anjum c, M. Iqbal Choudhary d
a Department of Chemistry, Abdul Wali Khan University, Mardan-23200, NWFP, Pakistan
b Institute of Chemical Sciences, University of Peshawar, Peshawar-25120, Pakistan
c University of Saskatchewan, Department of Chemistry, Saskatoon S7N 5C9, Canada
d HEJRIC, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
Received 15 October 2009
Abstract
A series of novel unsymmetrical N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines was synthesized by reacting
ethyl(1E)-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)ethanimidoate (2) and suitable reactive aromatic amines. Structures’ determina-
tion of the synthesized compounds was carried out using spectroscopic techniques including IR, 1H NMR, and mass spectrometry.
Structural effects on reactivity were also studied.
# 2010 Rasool Khan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 3-Amino-2-phenyl-4(3H)-quinazolinone; Triethylorthoacetate; Unsymmetrical N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)ace-
tamidines
Amidine functionality finds its presence in many natural products and amidines are useful intermediates in the
synthesis of many bioactive heterocyclic compounds [1,2]. Consequently, a plethora of methods have been reported
for synthesis of amidines [3–8a,b]. Acetamidines and propinoamidines exhibit interesting biological activities such as
anti-histamines, anti-hypertensive, anti-bacterial, anti-inflammatory, cardio-active, anti-diabetic, CNS depressant,
antiprotozoal, anti-psychotic and anxiolytic [9–15]. Increasing interest in the chemistry of acetamidines is due to its
ability to act as ligand for bridging metals, and also to produce chiral complexes [1].
Quinazolinones are cyclic amidine based heterocycles having significant role in synthetic chemistry. This class of
compounds have drawn much attention because of their diverse biological activities such as hypnotic, sedative,
analgesic, anticonvulsant, anti-tussive, anti-bacterial, anti-diabetic, anti-inflammatory, antitumor and HIV-1 reverse
transcriptase inhibitor [16–23].
In recent years, the emphasis of drug design has focused on combination of pharmacophoric units resulting in
chimerical molecules having more than one privileged structural moieties [24–26]. This prompted us to synthesize
some new unsymmetrical quinazolin-4-one based acetamidines which are expected to prove as potential precursors for
* Corresponding authors.
E-mail addresses: rasoolkhan@awkum.edu.pk, rasoolkhan1@hotmail.com (R. Khan), m_arfan@upesh.edu.pk (M. Arfan).
1001-8417/$ – see front matter # 2010 Rasool Khan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.04.009

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R. Khan et al. / Chinese Chemical Letters 21 (2010) 905–910
the synthesis of novel heterocyclic skeletons as well as pharmacologically lead compounds. Although the chemistry of
quinazolin-4-ones is well explored however, to the best of our knowledge, the quinazolin-4-ones based acetamidines
are being reported here for the first time.
1. Experimental
Chemicals and solvents used were of synthetic grade and further purified before use according to the standard
methods. TLC analysis was done on aluminium supported pre-coated silica gel TLC plates (Merck). Melting points
1
were determined in open capillary using Gallen kamp melting point apparatus. H NMR spectra were recorded on
Bruker 300 MHz and in CDCl3, CD3OD or DMSO-d6 as solvent, using TMS as internal standard, while mass spectra
were recorded on MAT312 instrument.
1.1. Ethyl(1E)-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)ethanimidoate (2)
A mixture of 3-amino-2-phenyl-4(3H)-quinazolinone (0.2 g, 0.85 mmol), triethylorthoacetate (0.37 mL,
2.02 mmol) and 0.5 mL of glacial acetic were refluxed with continuous stirring for 5 h. After completion of
reaction, the reaction mixture was poured into ice cold water, the product was separated as a white crystalline solid
which was filtered, washed with water and recrystallized from ethanol to give 3 as white crystals; yield 83%. mp 132–
133 8C; EI-MS m/z: 307 (M+, 2), 279 (85), 237 (23), 202 (5), 105 (100), 77 (45), 51 (10); IR (KBr) ymax (cmÀ1): 3335
(28 N–H, str), 3233 ( C–H, str), 2868 (C–H, str), 1840 (C C, overtone), 1720 (C O, str), 1659 (C C, str), 1431 (C–
C–H, bend), 1217 (C–O, str), 1172; 1H NMR (300 MHz, CDCl3): d 9.02 (d, 1H, J = 8), 8.175 (d, 2H, J = 8), 7.92 (d,
1H, J = 7.8), 7.54 (m, 3H), 7.24 (m, 2H), 3.7 (q, 2H,), 2.65 (s, 3H), 1.24 (t, 3H).
1.2. General procedure for the synthesis of acetamidines (3–12)
Ethyl(1E)-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)ethanimidoate (2) (0.2 g, 0.65 mmol) and suitable substituted
aromatic amine (0.65 mmol) in equimolar ratio were fused to melt followed by adding glacial acetic acid (1–2 mL)
and refluxed for 4-5 h. The completion of reaction was monitored by TLC. After completion the reaction mixture was
evaporated under reduced pressure and the remaining mixture was allowed to cool to room temperature. The solid
formed upon cooling was then treated with 0.8 mol/L HCl–MeOH and recrystallized from ethanol to yield the target
amidines (3–12) in (46–95%) yield.
1.2.1. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-( p-tolyl)acetamidine (3)
Aromatic amine = p-toluidine (0.069 g, 0.65 mmol); yield (69%); mp 227–229 8C; IR (KBr) ymax (cmÀ1): 3233
( C–H, str), 2868 (C–H, str), 1720 (C O, str), 1659 (C C, str), 1431 (C–C–H, bend), 1217 (C–O, str), 1172 (C–C,
str), 813 (C–H, bend, arom), 765 (C–H, bend, arom), 685 (C–H, bend); MS (FAB, +ve, Àve) m/z: 369, 367; MS–EI (m/
z); 368 (M+, 35), 340 (7), 324 (4), 291 (73), 135 (3), 132 (14), 105 (100), 77 (81); 1H NMR (300 MHz, CDCl3): d 10.9
(b, s, 1H, N–H), 8,47 (d, 1H, J = 7.8), 7.96 (m, 3H, Ar–H), 7.61 (m, 5H, Ar–H), 7.12 (q, 4H, Ar–H), 2.38 (s, 3H,), 2.16
(s, 3H).
1.2.2. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-( p-bromophenyl)acetamidine (4)
Aromatic amine = p-bromoaniline (0.112 g, 0.65 mmol); yield (90%); mp 244–246 8C; IR (KBr) ymax (cmÀ1):
3240 (N–H, str), 3078 ( C–H, str), 3005 (–C–H, str), 1668 (C O, str), 1599 (C C, str), 1424 (–C–H, bend), 1311 (C–
H, str), 1258 (C C, str), 1095 (bend), 881 (C–H, bend), 694 (–C–Br, str); EI-MS m/z: 434 (M+1, 11), 433 (10), 406 (3),
404 (3), 357 (18), 355 (18), 276 (2), 96 (3), 179 (6), 152 (1), 105 (100), 77 (89), 76 (9), 51 (13); 1H NMR (300 MHz,
CDCl3): d 10.92 (s, 1H, NH), 7.916 (d, 3H, J = 6.98), 7.77 (d, 2H, J = 8), 7.638–7.453 (m, 6H), 7.127–7.077 (t, 1H,
J = 7.5), 7.0 (d, 1H, J = 7.64), 2.37 (s, 3H, CH3).
1.2.3. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(phenyl)acetamidine (5)
Aromatic amine = aniline (0.0605 g, 0.65 mmol); yield (57%); mp 233–236 8C; IR (KBr) ymax (cmÀ1): 3222 (N–H,
str), 3078 ( C–H, str), 2992 (C–H, str), 1680 (C O, str), 1614 (C N, str), 1574 (C C, str), 1424 ( C–H, bend), 1311
( C–H, bend), 1258 (C–C, str), 881, 772, 752 (C–H, bend, arom); MS (FAB, +ve, Àve) m/z: (340, 338); EI-MS m/z:

R. Khan et al. / Chinese Chemical Letters 21 (2010) 905–910
907
354 (M+, 81), 339 (12), 328 (39), 313 (12), 277 (86), 264 (27), 261 (41), 222 (89), 209 (18), 181 (55), 133 (31), 105
(100), 103 (16), 77 (83), 58 (12), 54 (14); 1H NMR (300 MHz, DMSO-d6): d 11.05 (b, s, 1H, N–H), 8.09 (d, 1H, J = 8),
7.3 (d, 2H, J = 8), 7.88–7.83 (m, 4H), 7.76 (t, 1H, J = 8), 7.61–7.57 (m, 3H), 7.07 (d, 2H, J = 8), 6.97 (t, 1H, J = 8),
2.34 (s, 3H, CH3).
1.2.4. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(3-bromophenyl)acetamidine (6)
Aromatic amine = 3-bromoaniline (0.112 g, 0.65 mmol); yield (60%); mp 222–225 8C; IR (KBr) ymax (cmÀ1):
3301 (N–H, str), 3078 ( C–H, str), 2992 (C–H, str) 1680 (C O, str) 1614 (C N, str), 1579 (C C, str) 1424 ( C–H,
bend), 1258 (C–C, str), 1174 (C–C, str), 982, 846 (C–H, ben, arom), 752 (C–Br, str); EI-MS m/z: 434 (M+1, 11), 433
(10), 406 (3), 404 (3), 357 (18), 355 (18), 276 (2), 196 (3), 179 (6), 152 (1), 105 (100), 77 (89), 76 (9), 51 (13); 1H NMR
(300 MHz, DMSO-d6): d 11.05 (b, s, 1H, N–H), 8.09 (d, 1H, J = 8), 7.93 (d, 2H, J = 8), 7.88 (s, 1H), 7.76 (d, 1H, J = 8),
7.61 (m, 6H), 7.07 (t, 1H, J = 8), 6.97 (d, 1H, J = 8), 2.34 (s, 3H, CH3).
1.2.5. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(3-naphthyl)acetamidine (7)
Aromatic amine = 2-naphthylamine (0.093 g, 0.65 mmol); yield (66%); mp 218–220 8C; IR (KBr) ymax (cmÀ1):
3241 (N–H, str), 2933 (C–H, str), 2866 (C–H, str), 1651 (C O, str), 1520 (C C, str), 1417 (C–H, bend), 1203 (C–C,
str), 975, 885, 780 (C–H, bend, arom); EI-MS m/z: 404 (M+, 23), 376 (8), 327 (42), 299 (4), 261 (2), 230 (2), 222 (71),
168 (12), 127 (22) 105 (100), 77 (70); 1H NMR (300 MHz, CDCl3): d 10.53 (s, 1H, N–H), 7.95 (d, 1H, J = 8), 7.83 (t,
1H, J = 8.3), 7.78 (t, 2H, J = 8), 7.71 (d, 2H, J = 7.6), 7.65–7.61 (m, 6H), 7.43–7.39 (m, 2H), 7.27 (t, 1H, J = 8.3), 7.12
(d, 1H, J = 7.89), 2.35 (s, 3H).
1.2.6. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(4-methoxyphenyl)acetamidine (8)
Aromatic amine = 4-anisidine (0.08 g, 0.65 mmol); yield (62%); mp 224–226 8C; IR (KBr) ymax (cmÀ1): 3312 (N–
H, str), 3116 ( C–H, str), 2924 (C–H, str), 1167 (C O, str), 1611 (C C, str), 1586 (C N, str), 1447 ( C–H, str), 1401
( C–H, bend), 1322 (C–H, bend), 1304 (C–O, str), 1248 (C–C, str), 833, 745, 678 (C–H, bend, arom); EI-MS m/z: 384
(M+, 36), 356 (6), 307 (49), 279 (2), 148 (9), 105 (100), 77 (74), 50 (10); 1H NMR (300 MHz, CDCl3): d 10.9 (b, s, 1H,
N–H), 7.96 (m, 4H, Ar–H), 7.61 (m, 5H, Ar–H), 7.12 (m, 4H, Ar–H), 3.8 (s, 3H, OCH3), 2.38 (s, 3H, CH3).
1.2.7. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(2,4,6-trimethoxyphenyl)acetamidine (9)
Aromatic amine = 2,4,6-trimethylphenylamine (0.088 g, 0.65 mmol); yield (60%); mp 165–168 8C; IR (KBr) ymax
(cmÀ1): 3241 (N–H, str), 2940 ( C–H, str), 1670 (C O, str), 1630 (N C, str), 1611 (C C, str), 1447 ( C–H, bend),
1401 (C–H, bend), 1187 (C–C, str), 821, 745, 640 (C–H, bend, arom); EI-MS m/z: 396 (M+, 2), 319 (2), 177 (40), 135
(100), 120 (54), 104 (15), 91 (28), 77 (24), 65 (12); 1H NMR (300 MHz, CDCl3): d 11.01 (b, s, 1H), 8.14 (d, 1H, J = 8),
8.0–7.6 (m, 6H), 7.3 (d, 1H, J = 8), 6.93 (d, 1H, J = 8.34), 6.8 (s, 2H), 2.2 (s, 3H), 2.1 (s, 6H), 2.0 (s, 3H).
1.2.8. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(4-chlorophenyl)acetamidine (10)
Aromatic amine = p-chlorophenylamine (0.166 g, 1.3 mmol); yield (80%); mp 252–255 8C; FAB-MS (+ve, Àve):
389, 387; EI-MS: 390 (M+1, 20), 388 (M+, 54), 371 (6), 362 (5), 360 (59), 344 (6), 314 (27), 313 (27), 312 (17), 311
(87), 154 (4), 152c (11), 111 (8), 106 (8), 105 (100), 77 (44), 75 (4), 51 (5), 44 (8); 1H NMR (300 MHz, CDCl3): d 9.01
(s, 1H), 8.36 (d, 1H, J = 8.3), 8.23 (d, 2H, J = 8.6), 8.02 (t, 1H, J = 9), 7.771 (d, 1H, J = 8.6), 7.68–7.63 (m, 1H), 7.39
(d, 1H, J = 9), 7.34 (t, 1H, J = 9), 7.15 (d, d, 2H, J = 8,3), 6.95 (d, 2H, J = 8.1), 2.23 (s, 3H, CH3).
Scheme 1. General scheme for the synthesis of N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines (3–12). (a) Triethylorthoacetate,
acetic acid, stirred, reflux, 5–6 h and (b) substituted aromatic amine, acetic acid, reflux, 6 h.

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R. Khan et al. / Chinese Chemical Letters 21 (2010) 905–910
1.2.9. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(4-iodophenyl)acetamidine (11)
Aromatic amine = p-iodophenylamine (0.284 g, 1.3 mmol); yield (81%); mp 248–250 8C; FAB-MS (+ve, Àve):
(482, 479); IR (KBr) ymax (cmÀ1): 3222 (N–H, str), 3078 (C–H, str), 1921 (overtone), 1668 (C O, str), 1614 (C C,
str), 1504 (C N, str), 1424 (C–H, bend), 1174 (C–C, str), 982, 846, 752 (C–H, bend, arom); EI-MS m/z: 480 (M+, 89),
479 (9), 463 (7), 453 (5), 452 (21), 436 (7), 404 (16), 403 (81), 354 (11), 278 (4), 277 (23), 276 (20), 233 (4), 179 (5),
106 (9), 105 (100), 77 (50), 76 (12), 51 (6); 1H NMR (300 MHz, CDCl3): d 10.5 (b, s, 1H, NH), 8.43 (d, 1H, J = 8),
8.02–7.97 (m, 2H), 7.71–7.69 (m, 2H), 7.63–7.59 (m, 3H), 7.532–7.51 (m, 2H), 7.365 (t, 1H, J = 7.8), 7.15 (d, 2H,
J = 8.1), 2.23 (s, 3H, CH3).
1.2.10. N-(4-Oxo-2-phenyl-3(4H)-quinazolininyl)-N-(4-hydroxyphenyl)acetamidine (12)
Aromatic amine = p-hydroxyaniline (0.1068 g, 0.979 mmol); yield; 77%, mp 255–258 8C; FAB-MS (+ve, Àve):
(371, 369); IR (KBr) ymax (cmÀ1): 3471 (O–H, str), 3251 (N–H, str), 2880 (C–H, str), 1664 (C O, str), 1603 (C N,
str), 1540 (C C, str), 1449 (C–H, bend), 1255 (C–C, str), 796, 757, 700 (C–H, bend, arom); EI-MS m/z: 370 (M+,
8.59), 369 (14), 293 (34), 106 (12), 105 (100), 93 (5), 78 (9), 77 (87), 65 (13), 51 (10); 1H NMR (300 MHz, CDCl3): d
Table 1
List of N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines (3–12) synthesized.
No.
R
3
4
5
6
7
8
9
10
11
12

R. Khan et al. / Chinese Chemical Letters 21 (2010) 905–910
909
11.03 (b, s, 2H, NH), 7.92 (d, 1H, J = 9.6), 7.80 (d, 2H, J = 8.7), 7.767 (t, 1H, J = 8.6), 7.61 (d, 1H, J = 8.6), 7.58–7.53
(m, 1H), 7.748–7.35 (m, 3H), 7.29 (d, 2H, J = 7.9), 6.97 (d, 2H, J = 8.23), 2.01 (s, 3H, CH3).
2. Results and discussion
2-Phenyl-3-amino-(4H)-3,1-benzoxazinone-4-one prepared according to our recently reported method [22], upon
further reflux with triethylorthoacetate in glacial acetic acid gave ethyl(1E)-N-(4-oxo-2-phenylquinazolin-3(4H)-
yl)ethanimidoate (2) via modification of the reported procedure [27]. Eventually the synthesis of a series of novel
quinazolin-4(3H)-ones based acetamidines was accomplished by reacting compound 2 with selected aromatic amines
(Scheme 1). Interesting electronic effects on the reactivity of aromatic amines with the imidate ester 2 were observed.
Aromatic amines with electron-withdrawing groups failed to react with 2 while aromatic amines having electron-
donating substituents reacted smoothly and gave the target compounds (3–12) in good yields (Table 1).
Similarly alkyl amines namely butylamine, propylamine, ethylenediamine, and benzylamine failed to react. This
explanation is supported by the higher reactivity in case of aromatic amines having electron-donating substituents on
benzene ring. Mass spectrometry, both EI and FAB along with 1H NMR and IR were used for structure elucidation.
Molecular ion peaks were confirmed from both FAB (+ve, Àve) mass data, while EI was used for the determination of
the fragmentation pattern.
3. Conclusions
Ethyl(1E)-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)ethanimidoate (2) gave the corresponding acetamidines in good
yields on reaction with aromatic primary amines and amine having electron-donating groups, while failed to react with
aromatic amines possessing electron-withdrawing groups. Alkylamines were also found to afford the desired products
under the same reaction conditions. Thus the reaction is controlled by the nucleophilicity of the amines and the
thermodynamic stabilization through tautomerism. The synthesized quinazolinylacetamidines are expected as
biologically active new compounds and the potential activities are in the process of exploration.
Acknowledgments
The authors (MA and RK) acknowledge the financial support provided by the University of Peshawar, Pakistan in
the form of a research grant and HEJRIC University of Karachi, Pakistan for providing access to spectroscopic
instruments.
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