A convenient synthesis of novel series of 4-cyclohexyl-2-substituted [1,2,4]triazolo[1,5-a]quinazolin-5(4H)-ones. Novel isomers of H1 antihistaminic activite agents

Article abstract of DOI:10.3987/COM-07-11311

A novel series of 2,4-disubstituted-1,2,4-triazolo[ 1,5-a]-quinazolin-5(4H)-ones were prepared by Dimroth rearrangement of their respective isomers namely 1,4-disubstituted[1,2,4]triazolo[4,3-a]-quinazolin-5(4H)-ones. The latter were prepared via new synthetic strategy based on 1,5-elecrocyclization of the respective N-(4-oxo-3-cyclohexylquinazolin-2-yl)nitrilimines.

Full text of DOI:10.3987/COM-07-11311

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HETEROCYCLES, Vol. 75, No. 6, 2008, pp. 1479 - 1488. © The Japan Institute of Heterocyclic Chemistry
Received, 18th December, 2007, Accepted, 8th February, 2008, Published online, 15th February, 2008. COM-07-11311
A CONVENIENT SYNTHESIS OF NOVEL SERIES OF 4-CYCLOHEXYL-
2-SUBSTITUTED [1,2,4]TRIAZOLO[1,5-a]QUINAZOLIN-5(4H)-ONES.
NOVEL ISOMERS OF H1 ANTIHISTAMINIC ACTIVITE AGENTS
Ahmad S. Shawali,* Hamdi M. Hassaneen, and Nabil K. Shurrab
Department of Chemistry, Faculty of Science, University of Cairo, Giza, 12613,
Egypt
E-mail: as_shawali@mail.com
Abstract – A novel series of 2,4-disubstituted-1,2,4-triazolo[1,5-a]-quinazolin-
5(4H)-ones were prepared by Dimroth rearrangement of their respective isomers
namely 1,4-disubstituted[1,2,4]triazolo[4,3-a]-quinazolin-5(4H)-ones. The latter
were prepared via new synthetic strategy based on 1,5-elecrocyclization of the
respective N-(4-oxo-3-cyclohexylquinazolin-2-yl)nitrilimines.
INTRODUCTION
Literature survey reveals that several quinazolines and condensed quinazoline derivatives exhibit
excellent antihistaminic activity.1-3 For example, 1-substituted-4-cyclohexyl[1,2,4]triazolo[4,3-a]-
quinazolin-5(4H)-ones having alkyl/alicyclic amine substitution at position 1 were reported recently to
protect guina-pigs from histamine induced broncospasm significantly.4 In view of this finding, it was
interesting to explore the antihistaminic activity of the isomers of such compounds namely the title
compounds. A literature survey reveals, however, that the target title compounds have not been reported
hitherto and that the only method for synthesis of such ring system depends on the reaction of
2-hydrazinobenzoic acid with N-cyanoimidates.5 Thus, to achieve our objective, it was necessary to
develop a new convenient and general method for synthesis of the title compounds prior exploring their
biological activity. In continuation of our ongoing studies dealing with the chemistry of nitrilimines and
their precursors,6-10 we wish to report herein the synthesis of the title compounds via a novel innovative
route (Scheme 1). This route involves 1,5-electrocyclization of N-(4-oxo-3-cyclohexylquinazolin-2-yl)
nitrilimines 4 (Scheme 1), generated in situ by oxidation of the respective hydrazones 3 and subjecting the
resulting 1,2,4- triazolo[4,3-a]quinazolines 5 to Dimroth rearrangement to give the title compounds 6.

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This adopted strategy for synthesis of the intermediate 1,2,4-triazolo[4,3-a]quinazolines 5 seems to be
of more applicability than the one reported in literature which depends on the cyclization of 2-hydrazino-
3-substituted-quinazolin-4(3H)-ones with various one carbon donors.11, 12
O
O
C6H11
C6H11
RCHO
2
N
N
NHN=CHR
N
NHNH2
O
N
3
1
O
C6H11
FeCl3
C6H11
N
N
-
N
N
N
N
N
4
5
+
N
R
R
O
N
C6H11
N
KOH
N
N
6
R
R : a, C6H5; b, 4-MeC6H4; c, 4-ClC6H4; d, 4-MeOC6H4;
e, 4-O2NC6H4; f, 1-naphthyl; g, 2-furyl; h, 2-thienyl
Scheme 1
RESULTS AND DISCUSSION
The key starting aldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazones 3 which have
not been reported hitherto, were prepared in this study by refluxing 2-hydrazino-3-
cyclohexylquinazolin-4(3H)-one 1 with the appropriate aldehydes 2 in ethanol in the presence of acetic
acid as a catalyst (Scheme 1). The structures of these new hydrazones were evidenced by their elemental
1
1
analyses and spectral (MS, IR and H NMR) data (see Experimental). For example, their H NMR in
CDCl3 revealed, in each case, three characteristic signals in the regions δ 1.2 - 2.7, 8.2 - 8.5 and 9.2 -
9.5 corresponding to the cyclohexyl, –N=CH- and hydrazone –NH-N=C protons, respectively.

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When each of the hydrazones 3 was treated with equivalent amount of iron(III) chloride in ethanol for 30
min., it furnished, in each case, one crystalline product as evidenced by tlc analysis. The isolated products
proved to be the respective 4-cyclohexyl-1-substituted-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones 5
(Scheme 1). Their structures were confirmed by their elemental analyses and mass spectra. For example,
both elemental analysis and mass spectrum of each compound revealed that it has two hydrogens less
1
than the respective hydrazone 3. Also, their H NMR spectra showed the absence of the –N=CH- and
hydrazone –NH-N=C proton signals. Their IR spectra showed a carbonyl (C=O) absorption band near
1680 cm-1. Their mass spectra showed two common peaks at m/z 227 and 145 assignable to
3-cyclohexylquinazoline cation and quinazolin-4-one moiety, respectively. The conversion of 3 into 5 is
considered to result from 1,5-electrocyclization of the initially formed nitrilimines 4 (Scheme 1). This
suggested pathway is reminiscent of other related oxidative cyclization of aldehyde
N-heteroarylhydrazones with iron(III) chloride, which was reported to proceed via generation of the
respective nitrilimines 4 which undergo in situ 1,5-electrocyclization to give the respective fused
heterocycles.13,14
Next, Dimroth rearrangement15-19 of 4-cyclohexyl-1-substituted[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-
ones 5 was examined. In our hands, treatment of 5 with potassium hydroxide in refluxing ethanol yielded,
in each case one product that was identified as the respective [1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one 6
(Scheme 1). The structures assigned to the latter isolated products 6 were consistent with their analytical
1
and spectral MS, H NMR, IR) data (see Experimental). The conversion of 5 into 6 is analogous to
rearrangement of 1,2,4-triazolo[4,3-a]pyrimidines in alkali to the isomeric 1,2,4-triazolo-
[1,5-a]pyrimidines.15-19
In conclusion, we have developed a general convenient method for synthesis of 1,4-
disubstituted[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones 5 and their isomers namely 2,4-disubstituted-
[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-ones 6. The synthesized compounds together with their acyclo
C-nucleosides are under evaluation for in vivo antihistaminic and sedative-hypnotic activities and the
results will be published in due course. Our current studies are directed to extend the scope of the
presented method to cover additional heterocyclic systems.
EXPERIMENTAL
All melting points were determined on an electrothermal Gallenkamp apparatus and are uncorrected. The
1
IR spectra were measured on a Pye-Unicam SP300 instrument in potassium bromide discs. The H-NMR
spectra were recorded on a Varian Mercury VXR-300 spectrometer (300 MHz) in CDCl3 or DMSO. The
mass spectra were recorded on a GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers, the
ionizing voltage was 70 eV. Elemental analyses were carried out by the Microanalytical Center of Cairo

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University, Giza, Egypt. The starting 3-cyclohexyl-2-hydrazino-quinazolin-4(3H)-one (1) was prepared
by hydrazinolysis of 3-cyclohexyl-2-thioxo-quinazoline-4(1H,3H)-one according to literature method.20
Aldehyde N-(3- cyclohexyl -3,4-dihydro-4-oxoquinazolin-2-yl)hydrazones (3a-h):
General Procedure. - To a mixture of 2-hydrazino-3-cyclohexylquinazolin-4(3H)-one 1 (1.3 g, 5 mmol)
and the appropriate aldehyde 2 (5 mmol) in EtOH (50 mL), a few drops of acetic acid were added and the
reaction mixture was refluxed for 3 h and then cooled. The reaction mixture was poured on ice-water. The
precipitate formed was filtered off, washed with water then ethanol and finally crystallized from an
appropriate solvent to give the corresponding hydrazone derivative 3. The various hydrazone derivatives
3a-h prepared are listed below together with their physical constants and spectral data.
Benzaldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3a): yellow crystals (yield
91%), mp 230 oC (EtOH-dioxane), IR (KBr) ν 3263 (-NH-), 1651 (C=O), 1615 (C=N) cm-1. 1H NMR
(CDCl3): δ 1.3-2.7 (m, 10H, cyclohexyl), 5.1 (m, 1H, CH-N, cyclohexyl), 6.9 – 8.1 (m, 9 H, ArH), 8.5
(s, 1H, N=CH), 9.3 (s, 1H, NH). MS m/z (%): 348 (M++2, 5), 347 (M+ +1, 5), 346 (M+, 18), 277 (12), 265
(100), 263 (18), 250 (18), 227 (2), 187 (28), 161 (25), 145 (15), 119 (20), 90 (19), 89 (7), 77 (7). Anal.
Calcd for C21H22N4O (346.44): C, 72.81; H, 6.40; N, 16.17. Found: C, 72.78; H, 6.35; N, 16.02 %.
4-Tolaldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3b): yellow crystals
(yield 88%), mp 235 oC (EtOH-dioxane). IR (KBr) ν 3299 (-NH-), 1652 (C=O), 1614 (C=N). 1H NMR
(CDCl3): δ 1.3-2.7 (m, 10H, cyclohexyl), 2.4 (s, 3H, CH3), 5.1 (m, 1H, CH-N, cyclohexyl), 6.9 – 8.0
(m, 8 H, ArH), 8.4 (s, 1H, N=CH), 9.3 (s, 1H, NH). MS: m/z (%) 362 (M++2, 10), 361 (M++1, 25),
360 (M+, 32), 279 (100), 280 (24), 264 (19), 234 (7), 200 (19), 187 (41), 161 (72), 145 (22), 119 (31), 104
(18), 90 (20), 79 (8). 77 (11). Anal. Calcd for C22H24N4O (360.45): C, 73.31; H, 6.71; N, 15.54.
Found: C, 73.24; H, 6.67; N, 15.14 %.
4-Chlorobenzaldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3c): yellow
crystals (yield 92%), mp 262 oC (EtOH-dioxane). IR (KBr) ν 3284 (-NH-), 1655 (C=O), 1616 (C=N)
cm-1. 1H NMR (CDCl3): δ 1.3-2.7 (m, 10H, cyclohexyl), 5.1 (m, 1H, CH-N, cyclohexyl), 6.9 – 8.1 (m,
8 H, ArH), 8.4 (s, 1H, N=CH), 9.2 (s, 1H, NH). . MS: m/z (%):382 (M++2, 8), 381 (M++1, 6), 380 (M+,
18), 299 (100), 284 (13), 227 (1), 220 (15), 187 (27), 161 (42), 145 (20), 120 (11), 119 (31), 90 (16), 77
(6). Anal. Calcd for C21H21 ClN4O (380.87): C, 66.22; H, 5.56; N, 14.71. Found: C, 66.28; H, 5.67; N,
14.59 %.

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4-Methoxybenzaldehyde-N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3d): yellow-
o
green crystals (yield 93%), mp 208 C (EtOH-dioxane), IR (KBr) ν 3294 (-NH-), 1659 (C=O), 1617
1
(C=N).cm-1. H NMR (CDCl3): δ 1.3-2.7 (m, 10H, cyclohexyl), 3.8 (s, 3H, CH3), 5.1 (m, 1H, CH-N,
cyclohexyl), 6.9 – 8.0 (m, 8 H, ArH), 8.4 (s, 1H, N=CH), 9.3 (s, 1H, NH). MS: m/z (%) 378 (M++2, 4),
377 (M++1, 17), 376 (M+, 36), 295 (61), 280 (23), 242 (11), 216 (25), 161 (100), 145 (17), 119 (31), 91
(23), 77 (14). Anal. Calcd for C22H24N4O2 (376.45): C, 70.19; H, 6.43; N, 14.88. Found: C, 70.28; H,
6.33; N, 14.76 %.
4-Nitrobenzaldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)-hydrazone (3e): orange
crystals (yield 91%), mp 270 oC (EtOH-DMF). IR (KBr) ν 3339 (-NH-), 1680 (C=O), 1621 (C=N) cm-1.
1H NMR (CDCl3): δ 1.2-2.7 (m, 10H, cyclohexyl), 5.1 (m, 1H, CH-N, cyclohexyl), 7.0 – 8.3 (m, 8 H,
ArH), 8.5 (s, 1H, N=CH), 9.3 (s, 1H, NH). MS: m/z (%) 393 (M++2, 3), 392 (M++1, 2), 391 (M+, 9), 310
(100), 231 (18), 227 (1), 187 (27), 161 (26), 145 (19), 119 (24), 90 (14), 77 (5).
Anal. Calcd for
C21H21N5O3 (391.42): C, 64.44; H, 5.41; N, 17.89. Found: C, 64.34; H, 5.25; N, 17.75 %.
1-Naphthaldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3f): yellow crystals
o
1
(yield 92%), mp 163 C (EtOH-dioxane). IR (KBr) ν 3279 (-NH-), 1664 (C=O), 1617 (C=N) cm-1. H
NMR (CDCl3): δ 1.4-2.7 (m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 6.9 – 8.6 (m, 11 H,
ArH), 9.2 (s, 1H, N=CH), 9.3 (s, 1H, NH). MS: m/z (%) 397 (M++1, 19), 396 (M+, 37), 315 (100), 300
(12), 242 (18), 187 (29), 162 (29), 154 (21), 145 (28), 127 (23), 119 (29), 90 (24), 77 (12). Anal. Calcd
for C25H24N4O (396.48): C, 75.73; H, 6.10; N, 14.13. Found: C, 75.77; H, 6.08; N, 13.95 %.
2-Furfuraldehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3g): yellow crystals
o
1
(yield 90%), mp 197 C (EtOH). IR (KBr) ν 3249 (-NH-), 1656 (C=O), 1614 (C=N) cm-1. H NMR
(CDCl3): δ 1.3-2.7 (m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 6.5 – 8.0 (m, 7 H, ArH), 8.3
(s, 1H, N=CH), 9.3 (s, 1H, NH). MS: m/z (%): 337 (M++1, 17), 336 (M+, 29), 255 (100), 240 (33), 227
(7), 197 (20), 187 (19), 161 (90), 145 (24), 119 (46), 117 (10), 90 (38), 77 (7).
C19H20N4O2 (336.39): C, 67.84; H, 5.99; N, 16.65. Found: C, 67.64; H, 5.60; N, 16.47 %.
Anal. Calcd for
2-Thiophenealdehyde N-(3-cyclohexyl-3,4-dihydro-4-oxoquinazolin-2-yl)hydrazone (3h): pale yellow
o
1
crystals (yield 92%), mp 132 C (EtOH). IR (KBr) ν 3248 (-NH-), 1682 (C=O), 1616 (C=N)cm-1. H
NMR (CDCl3): δ 1.3-2.7 (m, 10H, cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl) 6.9 – 8.0 (m, 7 H, ArH),
8.5 (s, 1H, N=CH), 9.5 (s, 1H, NH). MS: m/z (%): 354 (M++2, 5), 353 (M++1, 16) 352 (M+, 30), 271

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(100), 256 (27), 241 (17), 192 (40), 187 (26), 161 (80), 145 (14), 119 (38), 96 (25), 90 (20), 81 (10), 77
(13).
Anal. Calcd for C19H20N4OS (352.45): C, 64.75; H, 5.72; N, 15.90. Found: C, 64.63; H, 6.06; N,
15.71 %.
4-Cyclohexyl-1-substituted[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones (5a-h):
General procedure: To a solution of each of the appropriate hydrazone 3 (2.5 mmol) in EtOH (50 mL)
was added a solution of ferric chloride (2 M, 2 mL) and the mixture was refluxed for 30 min, then left
overnight at rt, water was added to it. The solid that precipitated was filtered off, washed with water,
dried and finally recrystallized from appropriate solvent to give the respective1,4-
substituted[1,2,4]-triazolo- [1,5-a]quinazolin-5(4H)-one 5. The compounds prepared together with their
physical constants and spectral data are listed below.
4-Cyclohexyl-1-phenyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5a): white crystals (yield 82%), mp
o
175 C (EtOH-water),. IR (KBr) ν 1690 (C=O), 1608 (C=N) cm-1. 1H NMR (CDCl3): δ 1.4-2.8 (m,
10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 7.1 – 8.4 (m, 9 H, ArH). MS: m/z (%): 345 (M++1, 1),
344 (M+, 8), 343 (13), 264 (24), 263 (100), 261 (58), 227 (7), 145 (6), 119 (5), 104 (8), 90 (7), 77 (5).
Anal. Calcd for C21H20N4O (344.41) : C, 73.23; H, 5.85; N, 16.27. Found: C, 73.17; H, 5.78; N, 16.12 %.
4-Cyclohexyl-1-(4-tolyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5b): pale yellow crystals (yield
o
85%), mp 234 C (EtOH). IR (KBr) ν 1696 (C=O), 1610 (C=N) cm-1. 1H NMR (CDCl3): δ 1.4-2.8
(m, 10H, cyclohexyl), 2.5 (s, 3H, CH3), 5.2 (m, 1H, CH-N, cyclohexyl) 7.2 – 8.4 (m, 8 H, ArH). MS: m/z
(%): 360 (M++2, 2), 359 (M++1, 2), 358 (M+, 5), 277 (100), 275 (69), 227 (2), 219 (3), 192 (4), 160 (3),
145 (5), 133 (5), 117 (5), 104 (10), 90 (12), 77 (6). Anal. Calcd for C22H22N4O (358.44): C, 73.72; H,
6.19; N, 15.63. Found: C, 73.61; H, 6.05; N, 15.50 %.
4-Cyclohexyl-1-(4-chlorophenyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5c): white yellow crystals
o
1
(yield 83%), mp 266 C (EtOH-dioxane). IR (KBr) ν 1700 (C=O), 1610 (C=N) cm-1. H NMR
(CDCl3): δ 1.4-2.8 (m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 7.1 – 8.4 (m, 8 H, ArH).
MS: m/z (%): 380 (M++2, 2), 379 (M++1, 3) 378 (M+, 3), 297 (100), 295 (37), 227 (2), 213 (2), 160 (3),
145 (4), 104 (8), 77 (4). Anal. Calcd for C21H19ClN4O (378.85): C, 66.58; H, 5.05; N, 14.79. Found: C,
66.49; H, 5.25; N, 14.56 %.
4-Cyclohexyl-1-(p-methoxyphenyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5d): white yellow
o
1
crystals (yield 82%), mp 204 C (EtOH),. IR (KBr) ν 1694 (C=O), 1613 (C=N) cm-1. H NMR

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(CDCl3): δ 1.3-2.8 (m, 10H, cyclohexyl), 3.9 (s, 3H, CH3), 5.2 (m, 1H, CH-N, cyclohexyl) 7.0 – 8.4 (m,
8 H, ArH).MS: m/z (%) : 375 (M++1, 4), 374 (M+, 9), 293 (100), 248 (11), 227 (3), 209 (4), 192 (6),
144 (3), 133 (13), 120 (5), 90 (19), 77 (8). Anal. Calcd for C22H22N4O2 (374.44): C, 70.57; H, 5.92; N,
14.96. Found: C, 70.29; H, 5.74; N, 14.81 %.
4-Cyclohexyl-1-(4-nitrophenyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5e): white crystals (yield
o
1
85%), mp 275 C (EtOH-dioxane). IR (KBr) ν 1671 (C=O), 1606 (C=N) cm-1. H NMR (CDCl3): δ
1.3-2.8 (m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 7.1 – 8.5 (m, 8 H, ArH). MS: m/z (%):391
(M++2, 3), 390 (M++1, 3), 389 (M+, 5), 308 (100), 306 (19), 262 (19), 227 (1), 177 (4), 145 (2), 105 (2),
91 (2), 77 (4), Anal. Calcd for C21H19N5O3 (389.41): C, 64.77; H, 4.92; N, 17.98. Found: C, 64.55; H,
5.20; N, 17.70 %.
4-Cyclohexyl-1-(1-naphthyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5f): white yellow crystals
o
1
(yield 80%), mp 120 C (EtOH-water). IR (KBr) ν 1677 (C=O), 1611 (C=N) cm-1. H NMR (CDCl3):
δ 1.2-3.7 (m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 6.5 – 8.4 (m, 11 H, ArH). MS: m/z
(%): 396 (M++2, 1), 395 (M++1, 2), 394 (M+, 9), 339 (4), 313 (100), 311 (88), 241 (6), 227 (6), 228 (10),
145 (4), 135 (22) 127 (4), 90 (8), 77 (5). Anal. Calcd for C25H22N4O (394.47): C, 76.12; H, 5.62; N, 14.20.
Found: C, 76.07; H, 5.72; N, 14.47 %.
1-(2-Furyl)-4-cyclohexyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5g): white yellow crystals (yield
o
1
83%), mp 215 C (EtOH ). IR (KBr) ν 1696 (C=O), 1604 (C=N) cm-1. H NMR (CDCl3): δ 1.2-2.8
(m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 6.7 – 8.4 (m, 7 H, ArH). MS: m/z (%): 335 (M++1,
3), 334 (M+, 9), 255 (3), 253 (100), 251 (7), 227 (1), 198 (20), 195 (5), 169 (5), 145 (4), 130 (4), 90 (8),
77 (4). Anal. Calcd for C19H18N4O2 (334.37): C, 68.25; H, 5.43; N, 16.76. Found: C, 68.10; H, 5.23; N,
16.38 %.
1-(2-Thienyl)-4-cyclohexy[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (5h): pale green crystals (yield
o
1
85%), mp 210 C (EtOH). IR (KBr) ν 1679 (C=O), 1610 (C=N) cm-1. H NMR (CDCl3): δ 1.2-2.8
(m, 10H, cyclohexyl), 5.2 (m, 1H, CH-N, cyclohexyl) 7.2 – 8.4 (m, 7 H, ArH). MS: m/z (%): 352 (M++2,
2) 351 (M++1, 3), 350 (M+, 6), 269 (100), 267 (38), 227 (4), 212 (3), 185 (7), 145 (8), 109 (7), 104 (11),
90 (15), 77 (9). Anal. Calcd for C19H18N4OS (350.44): C, 65.12; H, 5.18; N, 15.99. Found: C, 64.99; H,
5.02; N, 15.72 %.
2,4-Disubstituted[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-ones (6):

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General procedure - To a solution of 5 (1 mmol) in absolute EtOH (15 mL) was added potassium
hydroxide (0.25 g) and the mixture was refluxed for 4 h and cooled. The solid that precipitated upon
neutralization with hydrochloric acid (6 M), was filtered, washed with water, dried and finally crystallized
from an appropriate solvent. The various products that were isolated are listed below together with their
physical constants and spectral data.
2-Phenyl-4-cyclohexy[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6a): white solid (yield 78%), mp
228oC (EtOH). IR (KBr) ν 1701 (C=O), 1590 (C=N) cm-1. 1H NMR (DMSO-d6): δ 1.2-1.9 (m, 10H,
cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl) 7.2 – 8.0 (m, 9 H, ArH). MS: m/z (%): 345 (M++1, 2), 344
(M+, 3), 343 (4), 319 (9) 280 (37), 263 (72), 261 (38), 235 (100), 227 (3), 226 (11), 224 (12), 160 (6), 145
(7), 132 (17), 105 (21), 90 (13), 77 (22). Anal. Calcd for C21H20N4O (344.41) : C, 73.23; H, 5.85; N,
16.27. Found: C, 73.12; H, 5.65; N, 16.36 %.
2-(4-Tolyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6b): white crystals (yield 75%), mp
o
1
276 C (EtOH -DMF). IR (KBr) ν 1703 (C=O), 1588 (C=N) cm-1. H NMR (DMSO-d6): δ 1.1-1.9
(m, 10H, cyclohexyl), 2.2 (s, 3H, CH3), 5.3 (m, 1H, CH-N, cyclohexyl), 7.0 – 8.0 (m, 8 H, ArH). MS: m/z
(%): 359 (M++1, 4), 358 (M+, 5), 313 (15), 295 (6), 293 (22), 277 (100), 275 (52), 249 ( (14), 177 (4), 160
(10), 133 (13), 104 (8), 90 (8), 77 (4). Anal. Calcd for C22H22N4O (358.44): C, 73.72; H, 6.19; N,
15.63. Found: C, 73.65; H, 6.04; N, 15.76 %.
2-(4-Chlorophenyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6c): brown crystals (yield
82%), mp 243 oC (EtOH -DMF). IR (KBr) ν 1704 (C=O), 1585 (C=N) cm-1. 1H NMR (DMSO-d6): δ
1.1-1.9 (m, 10H, cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl) 7.2 – 8.0 (m, 8 H, ArH). MS: m/z (%): 379
(M++1, 2) 378 (M+, 3), 353 (12), 341 (7) 317 (8), 314 (49) 299 (32), 297 (100), 271 (28), 269 (89), 260
(14), 227 (4), 184 (5), 145 (8), 139 (11), 90 (8), 77 (8). Anal. Calcd for C21H19ClN4O (378.85): C, 66.58;
H, 5.05; N, 14.79. Found: C, 66.41; H, 5.08; N, 14.68 %.
2-(4-Methoxyphenyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6d): white crystals (yield
o
1
77%), mp 215 C (EtOH -DMF). IR (KBr) ν 1671 (C=O), 1608 (C=N) cm-1. H NMR (DMSO-d6):
δ 1.1-1.9 (m, 10H, cyclohexyl), 3.7 (s, 3H, CH3), 5.3 (m, 1H, CH-N, cyclohexyl), 6.8 – 8.0 (m, 8 H,
ArH). MS: m/z (%): 375 (M++1, 4), 374 (M+, 6), 319 (4), 293 (100), 248 (10), 227 (3), 160 (4), 145 (8),
103 (5), 90 (9), 77 (3). Anal. Calcd for C22H22N4O2 (374.44): C, 70.57; H, 5.92; N, 14.96. Found: C,
70.40; H, 5.73; N, 14.82 %.

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2-(4-Nitrophenyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6e): yellow brown crystals
o
1
(yield 78%), mp 202 C (EtOH -water). IR (KBr) ν 1659 (C=O), 1567 (C=N) cm-1. H NMR
(DMSO-d6): δ 1.1-1.9 (m, 10H, cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl) 7.3 – 8.1 (m, 8 H, ArH).
MS: m/z (%):391 (M++2, 3), 390 (M++1, 3), 389 (M+, 5), 311 (100), 308 (100), 277 (91), 118 (55), 105
(18), 91 (27), 82 (25), 76 (41),. Anal. Calcd for C21H19N5O3 (389.41): C, 64.77; H, 4.92; N, 17.98. Found:
C, 64.50; H, 4.61; N, 17.70 %.
2-(1-Naphthyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6f):
white crystals (yield
75%), mp 228 oC (EtOH-DMF). IR (KBr) ν 1668 (C=O), 1566 (C=N) cm-1. 1H NMR (DMSO-d6): δ
1.0-2.0 (m, 10H, cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl) 7.3 – 8.2 (m, 11 H, ArH). MS: m/z (%):
395 (M++1, 6), 394 (M+, 9), 357 (6), 313 (100), 277 (81), 275 (41), 242 (4), 227 (6), 160 (6) 153 (13), 144
(3), 132 (9) 118 (5), 90 (5), 77 (3). Anal. Calcd for C25H22N4O (394.47): C, 76.12; H, 5.62; N, 14.20.
Found: C, 76.05; H, 5.76; N, 13.88 %.
2-(2-Furyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6g): white crystals (yield 75%), mp
235 oC (EtOH -DMF). IR (KBr) ν 1704 (C=O), 1593 (C=N) cm-1. 1H NMR (DMSO-d6): δ 1.0-1.9
(m, 10H, cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl), 5.7 – 8.1 (m, 7H, ArH). MS: m/z (%): 334 (M+, 2),
309 (9), 253 (18), 227 (3), 225 (100), 216 (17), 172 (37), 145 (11), 146 (23), 105 (6), 90 (10), 77 (11).
Anal. Calcd for C19H18N4O2 (334.37): C, 68.25; H, 5.43; N, 16.76. Found: C, 68.18; H, 5.27; N, 16.38 %.
2-(2-Thienyl)-4-cyclohexyl[1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one (6h): white crystals (yield 76%),
o
1
mp 246 C (EtOH -DMF). IR (KBr) ν 1703 (C=O), 1590 (C=N) cm-1. H NMR (DMSO-d6): δ
1.0-1.9 (m, 10H, cyclohexyl), 5.3 (m, 1H, CH-N, cyclohexyl), 6.3 – 8.1 (m, 7H, ArH). MS: m/z (%):
351 (M++1, 3), 350 (M+, 5), 325 (5), 286 (23), 269 (100), 241 (32), 227 (3), 185 (8), 145 (6), 132 (5), 90
(7), 77 (5). Anal. Calcd for C19H18N4OS (350.44): C, 65.12; H, 5.18; N, 15.99. Found: C, 65.05; H,
5.09; N, 15.70 %.
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