Synthesis and basicity of 4-amino-2-phenylquinazolines

Article abstract of DOI:10.1007/s007060070067

A new group of 6-and 7-substituted compounds of 4-amino-2-phenylquinazoline were synthesized by reaction of N-arylbenzimidoyl chlorides with cyanamide in the presence of TiCl₄. The products were identified by spectroscopic methods, their dissoc

Full text of DOI:10.1007/s007060070067

Monatshefte fuÈr Chemie 131, 895±899 (2000)
Synthesis and Basicity of 4-Amino-
2-phenylquinazolines
Ã
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Wojciech Zielinski and Agnieszka Kudelko
Institute of Organic Chemistry and Technology, Silesian University of Technology, PL-44101
Gliwice, Poland
Summary. A new group of 6- and 7-substituted compounds of 4-amino-2-phenylquinazoline were
synthesized by reaction of N-arylbenzimidoyl chlorides with cyanamide in the presence of TiCl4.
The products were identi®ed by spectroscopic methods, their dissociation constants were determined
and are discussed.
Keywords. 4-Amino-2-phenylquinazolines; UV/Vis spectroscopy; NMR spectroscopy; pKa values;
Tautomerism.
Introduction
Earlier investigations on the synthesis of aminoquinazoline derivatives have
con®rmed that methods using N-arylbenzimidoyl chlorides may be ef®ciently
applied for the preparation of new quinazoline derivatives of potential biological
activity [1±3]. Many methods exist for the generation of 4-aminoquinazolines, the
most popular one being the nucleophilic transformation of the appropriate 4-
substituted quinazolines with ammonia [4] or amines [5]. Other methods start from
o-aminobenzonitriles and proceed via cyclization [6] or cross-dimerization reactions
[7]. In this paper we report on the synthesis of 6- and 7-substituted 4-amino-2-
phenylquinazolines by reaction of N-arylbenzimidoyl chlorides with cyanamide.
Bearing in mind that acid-base interactions are of importance for the pharmacolo-
gical activity of the title compounds, their pKa values have also been determined.
Results and Discussion
The presented synthetic pathway originates from Meerwein's report on the reaction
of N-phenylbenzimidoyl chloride with some nitriles [8] and from our method for
the preparation of 4-N,N-dimethylaminoquinazoline derivatives [9]. N-Arylbenza-
mides (1) were reacted with PCl5 in benzene at elevated temperatures to afford
the corresponding N-arylbenzimidoyl chlorides (2). These were treated with
cyanamide at room temperature, yielding 1-amino-4-aryl-1-chloro-3-phenyl-2,4-
diaza-1,3-butadienes (3) as intermediates. After several hours of heating in benzene
Ã
Corresponding author

Â
W. Zielinski and A. Kudelko
896
Scheme 1
in presence of the Lewis acid catalyst TiCl4, 3 underwent cyclization to highly
stable quinazoline-catalyst complexes (4 Á TiCl4).
As acid catalyzed decomposition of the quinazoline-catalyst complexes afforded
mainly 2-phenyl-4-quinazolones, their hydrolysis was effected by concentrated
NaOH. To avoid rapid consecutive hydrolysis of 4 to the corresponding quinazolones
4
1
(k ˆ 2 Á 10 s ), which proceeds about 50 times faster in systems without a
substituent at the amino nitrogen atom compared with substituted derivatives [9], the
products were immediately extracted with benzene. Thus we obtained eight new
derivatives of 4-amino-2-phenylquinazoline substituted at positions 6 and 7 (4b±i)
Their structure was con®rmed by spectroscopic and elementary analysis. The yields
of the products varied considerably due to dif®culties of isolation and ± mainly ±
because of the hydrolysis of 4 to the corresponding quinazolones. An in¯uence of the
substituent type on the yields could also be explained on the basis of the above
mentioned process.
The determination of the dissociation constants of 4a±i was performed according
to the spectrophotometric method of Albert and Serjeant [10] in 50% aqueous
5
methanol solution (10 M, room temperature). The absorptions maxima of the
quinazoline ions were selected as analytical wavelengths, bearing in mind their
considerable shifts relative to the maxima of the non-protonated forms. The results
show that electron-donating groups in positions 6 or 7 of the quinazoline ring cause
an increase in basicity compared with the pKa value of the parent compound 4a
(R ˆ H); the opposite holds for electron-withdrawing groups. Generally, 4-amino-2-

4-Amino-2-phenylquinazolines
897
Scheme 2
phenylquinazolines are weaker bases than the corresponding 4-N,N-dimethylamino-
2-phenylquinazolines (pKa ˆ 4.42±6.61) [11]. According to MNDO calculations, the
amino group remains rather untwisted in the ring plane (twist angle: 11.3ꢀ), thus
enabling the free electron pair of the amino nitrogen atom to couple with the ꢀ
electrons of the aromatic system. In spite of resonance and inductive phenomena, the
steric effect resulting from the twist of the bulky dimethylamino group (twist angle:
73.3ꢀ) is not strong enough to cause a decrease in basicity. A different behaviour was
observed in the case of 1-amino- (pKa ˆ 7.27) and 1-N,N-dimethylamino-3-methyl-
isoquinoline (pKa ˆ 6.29) where the secondary steric effect connected with the
twisting of the dimethylamino group from the ring plain indeed leads to a decrease in
basicity originating from electron coupling limitations [12]. According to this it is
supposed that there are additional effects in¯uencing the electron effect transfer in
the systems under consideration. The 1H NMR spectra of 4b±e show two singlets for
the NH groups at low ®eld. On account of these observation we conclude that a
tautomerism between amino and imino forms (Scheme 2) might be responsible for
the considerable changes in basicity.
In contrast to 4-amino-2-phenylquinazolines with electron-donating substituents
which mainly occur in the imino form, quinazolines with electron-withdrawing
substituents (4f±i) occur both in the amino (broad singlet at higher ®eld) and the
imino forms (singlet at low ®eld). Up to now it has been assumed from UV
spectroscopic evidences that aminoquinazolines do not exist in the imino form
[3, 13]. This investigation has shown that the problem is more complicated and that
tautomeric equilibria cannot be excluded in the title compounds.
Experimental
UP spectra were recorded with a Shimadzu UV-2102 spectrophotometer, basic medium: 0.05 M
NaOH in 50% aqueous methanol, acidic medium: 0.05 M HCl in 50% aqueous methanol. Absorption
mixima of the quinazoline ions (B-band) were selected as analytical wavelenghts. Elementary
analyses were carried out with a Perkin-Elmer 240c analyzer their results were in satisfactory
1
agreement with the calculated values. H NMR spectra were recorded on a Varian Inova 300 at
300 MHz spectrometer in DMSO-d6 solutions. MS spectra run on a Shimadzu QP-200 mass
spectrometer. Thin layer chromatography was carried out on silica gel 60 F254 (Merck) thin layer
chromatography plates using benzene: ethyl acetate ˆ 3:1 (v/v) as the mobile phase.
4-Amino-2-phenyl-6,7-substituted quinazolines (4-i); general procedure
The appropriate N-arylbenzamide (1, 0.05 mol), anhydrous benzene (70 cm3), and PCl5 (11.5 g,
0.055 mol) were gently heated at about 50ꢀC until 1 had disappeared completely (TLC). Then
benzene and POCl3 were removed using a rotary evaporator. The crude N-arylbenzimidoyl chloride
(2) was dissolved in 70 cm3 anhydrous benzene, and cyanamide (2.1 g, 0.05 mol) in anhydrous

Â
W. Zielinski and A. Kudelko
898
diethyl ether (5 cm3) was added. The mixture was left for 1-2 h; then, TiCl4 (5 cm3, 0.05 mol) in
anhydrous benzene was gradually added, and agitation was continued at 50ꢀC for about 3 h. The
solvent was decanted from the resulting gluey solid (salts of 4-aminoquinazolines), and 100 cm3 of
20% aqueous NaOH were added. After the rapid decomposition reaction had subsided, the mixture
was immediately extracted with benzene in order to avoid a hydrolysis to 2-phenyl-4-quinazolones.
The combined extracts were dried over MgSO4 and concentrated yielding an oily residue to
which 50 cm3 of methanol and 1 g of decolorizing charcoal were added followed by boiling under
re¯ux (5 min). After ®ltration, the methanol was removed using a rotary evaporator, and compounds
4 were crystallized from ethanol or acetone. In case of dif®culties with respect to crystalization, the
quinazolines were converted to their hydrochlorides by saturation with gaseous HCl.
4-Amino-2-phenylquinazoline (4a; C14H11N3)
Yield: 33.0%; m.p.: 146±147ꢀC (Refs. [14, 15]); Rf ˆ 0.47; 1H NMR: ꢁ ˆ 5.80 (1H, br s, NH2), 7.14
(1H, dd, H-40, J ˆ 7.5, 7.5 Hz) 7.36 (2H, dd, H-30,50, J ˆ 7.5, 6.9 Hz), 7.48±7.57 (3H, m, H-5,6,7),
7.68 (1H, d, H-8, J ˆ 8.7 Hz), 7.92 (2H, d, H-20,60, J ˆ 6.9 Hz), 10.20 (1H, s, NH) ppm; UV: ꢂmax
(" Á 10 3) ˆ 201.9 (41.25), 261.2 (14.84), 315.5 (8.90) nm (acidic); 215.4 (13.52), 261.9 (12.79),
‡
316.0 (7.00) nm (basic); MS: m/z (%) ˆ 221 (M , 100); pKa ˆ 5.44Æ0.23.
6-Methyl-4-amino-2-phenylquinazoline (4b; C15H13N3)
1
Yield: 34.5%; m.p.: 260±261ꢀC (4b Á H2O Á HCl); Rf ˆ 0.56; H NMR: ꢁ ˆ 2.50 (3H, s, CH3), 7.64±
7.77 (3H, m, H-30,40,50), 7.90 (1H, d, H-7, J ˆ 8.4 Hz) 8.19 (1H, d, H-8, J ˆ 8.4 Hz), 8.36 (1H, s, H-
5), 8.40 (2H, d, H-20, 60, J ˆ 7.2 Hz), 9.72 (1H, br s, NH), 9.78 (1H, br s, NH) ppm; UV: ꢂmax
(" Á 10 3) ˆ 209.1 (35.35), 266.5 (35.19), 325.1 (10.31) nm (acidic); 213.4 (19.65), 251.8 (37.56),
‡
303.7 (13.53) nm (basic); MS: m/z (%) ˆ 235 (M , 100); pKa ˆ 5.16Æ0.18.
7-Methyl-4-amino-2-phenylquinazoline (4c; C15H13N3)
1
Yield: 31.0%; m.p.: 245±246ꢀC (4c Á H2O Á HCl); Rf ˆ 0.45; H NMR: ꢁ ˆ 2.49 (3H, s, CH3), 7.60
(1H, d, H-6), J ˆ 8.7 Hz) 7.65 (2H, dd, H-30,50, J ˆ 6.9, 7.2 Hz), 7.71 (1H, dd, H-40, J ˆ 7.2, 7.2 Hz),
7.78 (1H, s, H-8), 8.22 (1H, d, H-5, J ˆ 8.7 Hz), 8.32 (2H, d, H-2060, J ˆ 6.9 Hz), 9.70 (1H, br s, NH),
9.80 (1H, br s, NH) ppm; UV: ꢂmax (" Á 10 3) ˆ 212.8 (22.90), 253.3 (38.68), 303.7 (12.28) nm
‡
(acidic); 208.4 (34.49), 264.0 (33.90), 316.0 (10.00) nm (basic); MS: m/z (%) ˆ 235 (M , 100);
pKa ˆ 5.53Æ0.11.
6-Methoxy-4-amino-2-phenylquinazoline (4d; C15H13N3O)
1
Yield: 25.5%; m.p.: 235±236ꢀC (4d Á H2O Á HCl); Rf ˆ 0.10; H NMR: ꢁ ˆ 3.99 (3H, s, CH3), 7.60±
7.76 (4H, m, H-7,30,40,50), 7.80 (1H, s, H-5), 7.92 (1H, d, H-8, J ˆ 9.0 Hz) 8.30 (2H, d, H-20,60,
J ˆ 7.2 Hz), 9.60 (1H, br s, NH) 9.72 (1H, br s, NH) ppm; UV: ꢂmax (" Á 10 3) ˆ 212.4 (30.49), 268.3
(33.55), 340.2 (10.40) nm (acidic); 214.4 (25.46), 250.7 (35.43), 304.1 (14.90) nm (basic); MS: m/z
‡
(%) ˆ 251 (M , 100); pKa ˆ 5.33Æ0.08.
7-Methoxy-4-amino-2-phenylquinazoline (4e; C15H13N3O)
1
Yield: 36.0%; m.p.: 230±232ꢀC (4e Á H2O Á HCl); Rf ˆ 0.50; H NMR: ꢁ ˆ 3.96 (3H, s, CH3), 7.36
(1H, d, H-6, J ˆ 9.0 Hz) 7.65±7.77 (4H, m, H-8,30,40,50) 8.41 (2H, d, H-20,60, J ˆ 6.9 Hz), 8.45 (1H, d,
H-5, J ˆ 9.0 Hz), 9.56 (1H, br s, NH), 9.70 (1H, br, s, NH) ppm; UV: ꢂmax (" Á 10 3) ˆ 211.0 (28.39),
255.2 (42.73), 322.1 (14.72) nm (acidic); 211.9 (21.45), 250.6 (46.54), 308.9 (11.97) nm (basic);
‡
MS: m/z (%) ˆ 251 (M , 100); pKa ˆ 5.62Æ0.07.

4-Amino-2-phenylquinazolines
899
6-Nitro-4-amino-2-phenylquinazoline (4f; C14H10N4O2)
Yield: 41.5%; m.p.: 193±195ꢀC; Rf ˆ 0.29; 1H NMR: ꢁ ˆ 5.40 (1H, br s, NH2), 7.57 (2H, dd, H-30,50,
J ˆ 7.2, 7.2 Hz) 7.65 (1H, dd, H-40, J ˆ 7.2, 7.2 Hz), 7.91 (1H, s, H-5), 7.98 (2H, d, H-20,60,
J ˆ 7.2 Hz), 8.07 (1H, d, H-7, J ˆ 9.3 Hz), 8.28 (1H, d, H-8, J ˆ 9.3 Hz), 10.80 (1H, s, NH) ppm; UV:
ꢂmax (" Á 10 3) ˆ 225.2 (13.72), 320.8 (17.48) nm (acidic); 214.6 (17.65), 323.6 (15.82) nm (basic);
‡
MS: m/z(%) ˆ 266 (M , 55); pKa ˆ 4.54Æ0.27.
7-Nitro-4-amino-2-phenylquinazoline (4g; C14H10N4O2)
1
Yield: 50.5%; m.p.: 138±140ꢀC; Rf ˆ 0.41; H NMR: ꢁ ˆ 5.20 (1H, br s, NH2), 7.57 (1H, dd, H-40
J ˆ 6.9, 6.9 Hz) 7.64 (2H, dd, H-30,50, J ˆ 6.9, 6.9 Hz), 7.97 (1H, d, H-5, J ˆ 8.4 Hz), 8.01 (2H, d, H-
20,60, J ˆ 6.9 Hz), 8.22 (1H, d, H-6, J ˆ 8.4 Hz), 8.83 (1H, s, H-8), 10.76 (1H, s, NH) ppm; UV: ꢂmax
(" Á 10 3) ˆ 211.3 (20.00), 259.0 (25.42) nm (acidic); 211.0 (18.12), 261.1 (26.38) nm (basic); MS:
‡
m/z(%) ˆ 266 (M , 43); pKa ˆ 4.27Æ0.32.
6-Bromo-4-amino-2-phenylquinazoline (4h; C14H10N3Br)
Yield: 82.5%; m.p.: 188±190ꢀC (4h; H2O Á HCl); Rf ˆ 0.65; 1H NMR: ꢁ ˆ 4.10 (1H, br s, NH2), 7.30±
8.40 (8H, m), 11.10 (1H, s, NH) ppm; UV: ꢂmax (" Á 10 3) ˆ 201.0 (24.36), 225.5 (17.89), 235.3 (17.40)
‡
nm (acidic); 208.0 (16.76), 236.2 (20.5) nm (basic); MS: m/z(%) ˆ 300 (M , 51); pKa ˆ 4.78Æ0.08.
6-Chloro-4-amino-2-phenylquinazoline (4i; C14H10N3Cl)
Yield: 26.0%; m.p.: 230±231ꢀC (4i; H2O Á HCl); Rf ˆ 0.40; 1H NMR: ꢁ ˆ 4.55 (1H, br s, NH2), 7.25±
780 (4H, m), 7.95 (2H, d, H-20,60, J ˆ 6.9 Hz), 8.07 (1H, d, H-7, J ˆ 9.0 Hz), 8.18 (1H, d, H-8,
J ˆ 9.0 Hz), 10.95 (1H, NH) ppm; UV: ꢂmax (" Á 10 3) ˆ 211.0 (32.03), 274.1 (23.38), 324.9 (8.58)
‡
nm (acidic); 214.2 (24.58), 253.6 (32.19), 302.1 (13.51) nm (basic); MS: m/z(%) ˆ 255 (M , 100);
pKa ˆ 4.98Æ0.06.
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Received February 14, 2000. Accepted February 26, 2000