Synthesis of novel 2-methylsulfanyl-4h-[1,2,4]triazolo[1,5-a]quinazolin-5- one and derivatives

Article abstract of DOI:10.1080/00397911.2010.518780

A novel 2-methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one was synthesized using dimethyl-n-cyanoimidodithiocarbonate and 2-hydrazinobenzoic acid as building blocks. Chemical transformation of the inherent lactam moiety in the targeted 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazolin-5-one offered access to a variety of derivatives.

Full text of DOI:10.1080/00397911.2010.518780

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Synthesis of Novel 2-Methylsulfanyl-4H-
[1,2,4]triazolo[1,5-a]quinazolin-5-one
and Derivatives
Rashad Al-Salahi a & Detlef Geffken b
a Department of Pharmaceutical Chemistry, College of Pharmacy,
King Saud University, Riyadh, Saudi Arabia
b Department of Chemistry, Institute of Pharmacy, University of
Hamburg, Hamburg, Germany
Available online: 31 May 2011
To cite this article: Rashad Al-Salahi & Detlef Geffken (2011): Synthesis of Novel 2-Methylsulfanyl-4H-
[1,2,4]triazolo[1,5-a]quinazolin-5-one and Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:23, 3512-3523
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Synthetic Communications1, 41: 3512–3523, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518780
SYNTHESIS OF NOVEL 2-METHYLSULFANYL-4H-
[1,2,4]TRIAZOLO[1,5-a]QUINAZOLIN-5-ONE AND
DERIVATIVES
Rashad Al-Salahi1 and Detlef Geffken2
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud
University, Riyadh, Saudi Arabia
2Department of Chemistry, Institute of Pharmacy, University of Hamburg,
Hamburg, Germany
GRAPHICAL ABSTRACT
Abstract A novel 2-methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one was synthe-
sized using dimethyl-n-cyanoimidodithiocarbonate and 2-hydrazinobenzoic acid as building
blocks. Chemical transformation of the inherent lactam moiety in the targeted 2-methylsulfanyl-
[1,2,4]triazolo[1,5-a]quinazolin-5-one offered access to a variety of derivatives.
Keywords Alkylation; chlorination; dimethyl-N-cyanoimidodithiocarbonate; 2-hydrazi-
nobenzoic acid; thionation
INTRODUCTION
N-Cyanoimidocarbonates are versatile reagents and play an important role as
building blocks for bioactive compounds, containing a modified cyanoguanidine
moiety, such as synthesis of cyanoguanidine functionality of cimetidine (a potent
H2-histamine antagonist)[1–3] and preparation of pinacidil (antihypertensive
agent),[4,5] and they offer access to a great variety of heterocyclic systems.[6–8] A novel
series of triazoloquinazolines, which originated from N-cyanoimidocarbonates as
synthons, have been shown to exhibit diverse biological activities. For example, tria-
zoloquinazolines of type I were found to be potent proteinkinase inhibitors,[9]
whereas our recently reported alkylated derivatives of triazoloquinazolines II have
been proven to be excellent agents for controlling plant growth diseases caused by
Received June 13, 2010.
Address correspondence to Rashad Al-Salahi, Department of Pharmaceutical Chemistry, College
of Pharmacy, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia. E-mail: salahi76@
yahoo.com
3512

SYNTHESIS OF TRIAZOLOQUINAZOLINE
3513
fungal pathogens.[10] In view of the aforementioned biological activities of diverse
triazoloquinazolines and in continuation of our ongoing studies dealing with the
chemistry of N-cyanoimidocarbonates and their precursors, we report herein the
results of our study of cyclocondensation of dimethyl-N-cyanoimidodithiocarbonate
with hydrazinobenzoic acid to give 2-methylsulfanyl[1,2,4]triazolo[1,5-a]
quinazolin-5-one.
RESULTS AND DISCUSSION
It has been found that the reaction of cyanamide with carbon disulfide in the
presence of KOH followed by alkylation with methyl iodide gives dimethyl N-
cyanoimidodithiocarbonate.[11] Based on the high reactivity of N-cyanoimidocarbo-
nates toward hydrazines to produce 1,2,4-triazole derivatives,[12–14] analogously
reaction of 1 with 2 in ethanol under ice cooling in the presence of triethylamine
provided the intermediate 1,2,4-triazole derivative 4, which upon treatment with
hydrochoric acid (36%) produced the 2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazo-
lin-5-one compound 5 in 60% yield (Scheme 1).[10] The structure of the novel
2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazolin-5-one 5 was confirmed by infrared
1
(IR), H NMR, 13C NMR spectra, and microanalysis.
Scheme 1.

3514
R. AL-SALAHI AND D. GEFFKEN
=
The IR spectrum of compound 5 is characterized by a strong (C O)-stretching
band at 1689 cmꢀ1 and its mass spectrometry (MS) gave the molecular ion peak at
m=z ¼ 232 (Mþ, 100%).
Alkylation of lactams with alkyl halides may give rise to N- and=or
O-alkylated products, the outcome of the reaction being dependent on the pH of
the reaction, temperature, the nature of solvents, and the reactivity of the alkylating
agents.[15–17] Accordingly, when the [1,2,4]triazolo[1,5-a]quinazolin-5-one 5 was
allowed to react with alkyl halides in a molar ratio of 1:1.5 in absolute dimethyl for-
mamide at room temperature in the presence of potassium carbonate, the corre-
sponding 4-alkyl[1,2,4]triazolo[1,5-a]quinazolin-5-ones (6a–c) resulted in 62–87%
yield (Scheme 2).[18] Under these conditions, formation of the isomeric lactim ether
was not observed. The products 6a–c were obtained as colored solid compounds, and
their IR spectra display a strong (C O)-absorption band at 1668–1679 cmꢀ1. Treat-
=
ment of compound 5 with lithium aluminum hydride in absolute tetrahydrofuran
(THF) at room temperature furnished the targeted 4,5-dihydro[1,2,4]triazolo[1,5-
a]quinazoline (7) in 71% yield.[19] The compound 7 was obtained after column chro-
matography as a colorless solid, and its structure was verified with spectral data. Its
infrared (IR) spectrum showed a band at (n, cmꢀ1) 3191 (NH) and confirmed the
1
disappearance of a (C O) at 1689, whereas the H NMR spectrum showed a signal
=
=
at d 4.25 ppm for CH2 that resulted from reduction of (C O), and its mass
spectrometry (MS) gave the molecular ion peak at m=z ¼ 218.
Scheme 2.

SYNTHESIS OF TRIAZOLOQUINAZOLINE
3515
Refluxing equimolar amounts of [1,2,4]triazolo[1,5-a]quinazolin-5-one 5 and
phosphorus pentasulfide in absolute pyridine for 2 h gave 2-methylsulfanyl-4H-
[1,2,4]triazolo[1,5-a]quinazolin-5-thione (8) in excellent yield of 91% as a yellow solid
(Scheme 2).[20] The IR spectrum revealed the disappearance of a (C O) absorption
=
band at 1689 cmꢀ1 (previously found in compound 5), confirming the formationꢀo1f
=
the product 8, and also displayed a weak absorption band of a (C S) at 1264 cm
.
13
=
Moreover, the C NMR spectrum of compound 8 is characterized by a (C S) res-
onance at 185.61 ppm, and its MS gave the molecular ion peak at m=z ¼ 248 (Mþ,
100%).
Conversion of 2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-one 5 into
5-chloro[1,2,4]triazolo[1,5-a]quinazoline (9) has been successfully achieved by chlori-
nation with either oxalyl chloride in boiling 1,1,2-trichloroethane for 19 h[21] or with
phosphorus oxychloride in boiling benzene for 2 h, followed by trituration with a
saturated aqueous solution of potassium carbonate.[22] The formation of compound
=
9 was accompanied by the gradual disappearance of the characteristic (C O) band
of 5 at 1689 cmꢀ1, and its MS gave the molecular ion peak at m=z ¼ 250 (Mþ, 100%).
Although both methods gave acceptable yield, the reaction of 5 with phosphorus
oxychloride is more advantageous with regard to short reaction time and greater
yield (95% compared to 78% with oxalyl chloride).
As outlined in Scheme 3, hydrazinolysis of 9 in refluxing ethanol formed the
corresponding [1,2,4]triazolo[1,5-a]quinazolin-5-yl-hydrazine (10) in good yield of
78%,[23] which upon treatment with an equimolar amout of aldehyde or ketone furn-
ished the targeted hydrazones (11a,b) in 70% and 83% yield.[24]
1
The H NMR spectrum of compound 10 showed signals of NH2 and NH at d
5.24 and 10.27 ppm respectively, and its MS gave the molecular ion peak at
m=z ¼ 246 (Mþ, 92%), whereas the structures of the hydrazones 11a,b were con-
1
firmed by disappearance of the signal of the NH2 group through its H NMR spec-
tra. Replacement of the chlorine in compound 9 by different hydrazides occurred
smoothly in refluxing toluene to produce the [1,2,4]triazoloquinazolin-5-
yl-carbohydrazides (12a,b) in 65% and 76% yields,[25] which themselves deserve inter-
est as suitable intermediates and furthermore should open access to a number of
triazolo-annelated compounds such as bis-[1,2,4]triazoloquinazolines. Inspection of
=
the IR spectra of products 12a,b revealed the presence of (C O) and (NH) signals
at 1665, 1670 and 3189, 3210 cmꢀ1 respectively. Analogously to the reaction with
hydrazides, the corresponding reaction of compound 9 with carbazides according
to literature[25] produced the respective [1,2,4]triazoloquinazolin-5-yl-hydrazine-
carboxylic acid esters of type 13a,b in 75% and 80% yields as colorless solids.
=
The IR spectra of 13a,b are characterized by a strong (C O) absorption band
at 1709, 1718 and a weak (NH) absorption band at 3261 and 3280 cmꢀ1
.
Treatment of amidrazones 12a,b with phosphorus oxychloride at refluxing tem-
perature for 2 h, followed by neutralization with saturated potassium carbonate sol-
ution or aqueous ammonia, delivered the targeted 14a,b in 67% and 65% yields.[26]
The completion of the internal cyclization was monitored by IR spectroscopy: disap-
=
pearance of the (C O) and (NH) absorption bands at 1665, 1670 and 3189,
3210 cmꢀ1 signaled complete conversion of 12 to the tetracyclic compounds 14.
Heating of 5-chloro[1,2,4]triazoloquinazoline 9 with sodium azide in a molar ratio
of 1:1.2 in absolute dimethyl formamide for 24 h at 90 ꢁC (Scheme 3) cleanly afforded

3516
R. AL-SALAHI AND D. GEFFKEN
Scheme 3.
the corresponding tetrazolo[4,3-c][1,2,4]triazolo[1,5-a]quinazoline (15) as a colorless
solid in 60% yield.[27]
1
The structure of compound 15 was characterized by H NMR and 13C NMR
spectra, and its mass spectrometry (MS) gave the molecular ion peak at m=z ¼ 257
(Mþ, 100%).
EXPERIMENTAL
Melting points were determined on open glass capillaries using a Mettler FP 62
apparatus and are uncorrected. Elemental analyses were carried out with a Heraeus
CHN-O-Rapid Instrument. The IR (KBr, n, cmꢀ1) spectra were recorded on a
1
Shimadzu Fourier transform (FT)–IR 8300. H NMR (400.1 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker AMX 400 spectrometer, and chemical

SYNTHESIS OF TRIAZOLOQUINAZOLINE
3517
shifts are given in parts per million (ppm) downfield from tetramethylsilane (TMS)
as an internal standard. Dimethylsulfoxide (DMSO) is used as solvent. Mass spectra
were recorded on a Finnigan MAT 311A and on a VG 70-250S (VG Analytical)
instrument.
The reactions were followed and the purity of compounds was checked wih
thin-layer chromatography (TLC) on DC-Mikrokarten polygram SIL G=UV254
from the Macherey-Nagel Firm, Duren (thickness: 0.25 m). Column chromato-
,
˚
graphy was conducted on silica gel (ICN silica 100–200, active 60 A).
2-Methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one (5)
Hydrazinobenzoic acid 2 (0.01 mol) was added portion wise to a stirred sol-
ution of 1 (0.01 mol) in ethanol (20 mL) at 0 ꢁC. Afterward, triethylamine
(0.03 mol) was added dropwise over a period of 30 min. After the addition was com-
plete, the reaction mixture was left to stir overnight at room temperature. Acidifi-
cation of the mixture was performed by concentrated HCl under ice cooling
followed by refluxing for 1–3 h. After cooling, the mixture was poured into ice water,
and the resulting solid was filtered off, washed with water, and dried. Recrystalliza-
tion from tetrahydrofuran (THF) gave analytically white solid 5 (1.4 g, 60%); mp
ꢀ1
1
238–240 ꢁC. IR (KBr, n, cm ): 1689 (C O); H NMR (DMSO-d6, d ppm): 2.78
=
(s, 3H, CH3), 7.54–8.45 (m, 4H, Ar-H), 13.85 (s, 1H, NH); 13C NMR (DMSO-d6,
d ppm): 13.92 (CH3), 114.65, 116.83, 125.50, 128.58, 135.72, 136.12 (Ar-C), 149.11
þ
=
(C-guanidine), 159.94 (C O), 162.30 (C-isothiourea). MS, m=z (%): 232 (M ,
100). Anal. calcd. for C10H8N4OS: C, 51.71; H, 3.47; N, 24.12; S, 13.80. Found:
C, 51.82; H, 3.40; N, 24.24; S, 13.91.
Compounds 6a–c
Potassium carbonate (0.0012 mol) was added portionwise to a solution of com-
pound 5 (0.001 mol) in dimethyl formamide (5 mL) over a period of 10 min at room
temperature. After stirring for 20 min, the appropriate alkyl halide (0.0015 mol) was
added dropwise, and the reaction mixture was stirred for 18 h at room temperature.
The mixture was poured into ice water, and the precipitate was filtered off, washed
with water, and dried. Analytically pure products 6a–c were obtained after recrystal-
lization from THF.
4-Benzyl-2-methylsulfanyl[1,2,4]triꢀa1zolo[1,5-a]quinazolin-5-one
(6a).
1
Mp 173–175 ꢁC. IR spectrum (KBr, n, cm ): 1675 (C O); H NMR (DMSO-d6,
d ppm): 2.78 (s, 3H, CH3), 5.32 (s, 2H, CH2), 7.10–8.25 (m, 9H, Ar-H); 13C NMR
(DMSO-d6, d ppm): 13.35 (CH3), 60.70 (CH2), 112.86, 116.86, 117.79, 125.80,
=
128.89, 129.11, 131.66, 132.45, 135.52 (Ar-C), 141.79 (C-guanidine), 155.24
þ
=
(C O), 160.35 (C-isothiourea). MS, m=z (%): 322 (M , 100). Anal. cald. for
C17H14N4OS: C, 63.34; H, 4.38; N, 17.38; S, 9.95. Found: C, 63.38; H, 4.40; N,
17.30; S, 10.07.
4-Ethyl-2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-one (6b). Mp
ꢀ1
1
147–149 ꢁC. IR spectrum (KBr, n, cm ): 1668 (C O); H NMR (DMSO-d6, d
ppm): 1.32 (t, 3H, J ¼ 7.04 Hz, CH3), 4.11 (s, 3H, SCH3), 4.29 (q, 2H, J ¼ 14.31 Hz,
=

3518
R. AL-SALAHI AND D. GEFFKEN
CH2), 7.68–8.39 (m, 4H, Ar-H); 13C NMR (DMSO-d6, d ppm): 12.92 (CH3), 52.74
(CH2), 57.18 (SCH3), 114.73, 116.22, 125.71, 128.79, 133.20, 135.02 (Ar-C), þ148.49
=
(C-guanidine), 157.34 (C O), 167.89 (C-isothiourea). MS, m=z (%): 260 (M , 88).
Anal. calcd. for C12H12N4OS: C, 55.37; H, 4.65; N, 21.52; S, 12.32. Found: C,
55.30; H, 4.62; N, 21.61; S, 12.25.
4-Allyl-2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-one (6c). Mp
ꢀ1
1
130–132 ꢁC. IR spectrum (KBr, n, cm ): 1679 (C O); H NMR (DMSO-d6, d
ppm): 4.03 (s, 3H, CH3), 4.73 (d, 2H, J ¼ 4.70 Hz, -CH2 ¼ CH-CH2), 5.24–5.28 (m,
2H, -CH2 ¼ CH-CH2), 6.09–6.24 (m, 1H, -CH2 ¼ CH-CH2), 7.46–8.31 (m, 4H,
Ar-H); 13C NMR (DMSO-d6, d ppm): 45.53 (-CH2 ¼ CH-CH2), 57.34 (CH3),
114.27 (Ar-C), 116.78 (-CH2 ¼ CH-CH2), 117.28, 125.83, 128.82, 132.86 (Ar-C),
=
=
135.42 (-CH2 ¼ CH-CH2), 135.86 (Ar-C), 148.79 (C-guanidine), 156.89 (C O),
166.73 (C-isothiourea). MS, m=z (%): 272 (Mþ, 90). Anal. calcd. for C13H12N4OS:
C, 57.34; H, 4.44; N, 20.57; S, 11.77. Found: C, 57.25; H, 4.41; N, 20.49; S, 11.83.
4,5-Dihydro-2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazoline (7)
A solution of compound 5 (0.001 mol) in dry THF (5 mL) was added dropwise
to a stirred suspension of LiAlH4 (0.003 mol) in dry THF (10 mL). After stirring at
room temperature for 3 h, water (0.4 mL) was added carefully, and the mixture was
stirred for an additional 30 min. The reaction mixture was filtered, and the solvent
was removed under reduced pressure. The residue was dissolved in THF and passed
through short column chromatography, the solvent was removed under reduced
pressure, and the obtained solid was recrystallized from ethyl acetate=n-hexane to
1
give compound 7 (0.155 g, 71%), mp 126–128 ꢁC. H NMR (DMSO-d6, d ppm):
3.80 (s, 3H, CH3), 4.25 (s, 2H, CH2-quinazoline), 7.15–7.63 (m, 4H, Ar-H), 7.85
(s, 1H, NH); 13C NMR (DMSO-d6, d ppm): 13.05 (CH3), 69.00 (CH2-quinazoline),
114.23, 119.64, 124.50, 126.23, 130.75, 149.79 (Ar-C), 158.60 (C-guanidine), 161.86
(C-isothiourea). MS, m=z (%): 218 (Mþ, 100). Anal. calcd. for C10H10N4S: C,
55.03; H, 4.62; N, 25.67; S, 14.69. Found: C, 55.10; H, 4.59; N, 25.75; S, 14.82.
2-Methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-thione (8)
Compound
5 (0.001 mol) was refluxed with phosphorus pentasulfide
(0.001 mol) in absolute pyridine (5 mL) for 2 h. Afterward, the reaction mixture
was cooled and poured into ice water, and the yellow precipitate was separated by
filtration and washed thoroughly with water. Recrystallization from aqueous
dimethyl formamide furnished analytically pure 9 (0.225 g, 91%), mp 230–232 ꢁC.
1
IR (KBr, n, cmꢀ1): 1264 (C S); H NMR (DMSO-d6, d ppm): 2.92 (s, 3H, CH3),
=
7.72–8.96 (m, 4H, Ar-H), 14.62 (s,1H, NH); 13C NMR (DMSO-d6, d ppm): 13.95
(CH3), 114.65, 122.43, 125.83, 131.77, 132.01, 132.23 (Ar-C), 141.28 (C-guanidine),
=
163.18 (C-isothiourea), 185.61 (C S). MS, m=z (%): 248 (M , 100). Anal. calcd.
þ
for C10H8N4S2: C, 48.37; H, 3.25; N, 22.56; S, 25.82. Found: C, 48.32; H, 3.25; N,
22.47; S, 25.91.

SYNTHESIS OF TRIAZOLOQUINAZOLINE
3519
5-Chloro-2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazoline (9)
Method A. Compound 5 (0.002 mol) was refluxed with oxalyl chloride
(0.006 mol) in 1,1,2-trichloroethane (12 mL) for 19 h at 105 ꢁC. The solution was
cooled, and methanol (0.2 mL) was added dropwise. The obtained solid was filtered,
washed with n-hexane, dried, and recrystallized from THF–hexane.
Method B. Compound 5 (0.001 mol) was refluxed with phosphorus oxychlor-
ide (1 mL) in benzene (7 mL) for 2 h. The solvent was evaporated, and the residue
was treated with a saturated solution of potassium carbonate. The solid was filtered
off, washed thoroughly with water, dried, and recrystallized from THF=hexane to
1
give pure 9 (0.238 g, 95%), mp 161–163 ꢁC. H NMR (DMSO-d6, d ppm): 2.76 (s,
3H, CH3), 7.74–8.45 (m, 4H, Ar-H); 13C NMR (DMSO-d6, d ppm): 13.88 (CH3),
114.50, 116.83, 125.51, 128.57, 135.74, 136.19 (Ar-C), 141.11 (C-guanidine), 156.45
(C-Cl), 165.59 (C-isothiourea). MS, m=z (%): 250 (Mþ, 100). Anal. calcd. for
C10H7ClN4S: C, 47.91; H, 2.81; N, 22.35; S, 12.79. Found: C, 48.02; H, 2.73; N,
22.40; S, 12.92.
2-Methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-yl-hydrazine (10)
A mixture of compound 9 (0.001 mol) and hydrazine hydrate (0.005 mol) was
heated under reflux in ethanol (8 mL) for 3 h. After cooling, the precipitate was fil-
tered off and washed with water. Recrystallization from ethanol afforded 10 as pure
solid (0.182 g, 78%), mp 219–221 ꢁC. IR (KBr, n, cmꢀ1): 3254 (NH-NH2); . 1H NMR
(DMSO-d6, d ppm): 2.87 (s, 3H, CH3), 5.24 (s, 2H, NH2), 7.73–8.70 (m, 4H, Ar-H),
10.27 (s, 1H, NH); 13C NMR (DMSO-d6, d ppm): 13.76 (CH3), 110.37, 124.40,
124.77, 125.40, 129.35, 134.68 (Ar-C), 154.77 (C-guanidine), 156.72 (C-hydrazine),
163.07 (C-isothiourea). MS, m=z (%): 246 (Mþ, 92). Anal. calcd. for C10H10N6S:
C, 48.77, H, 4.09; N, 34.12; S, 13.02. Found: C, 48.68; H, 4.12; N, 34.11; S, 12.93.
Compounds 11a,b
A mixture of compound 10 (0.001 mol) and aldehyde or ketone (0.001 mol) was
refluxed in ethanol (10 mL) for 3 h. The solvent was removed under reduced pressure,
and the resulting solids were recrystallized from ethanol.
N-Benzylidene-N’-(2-methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-
1
yl)hydrazine (11a). Mp 203–205 ꢁC. H NMR (DMSO-d6, d ppm): 3.13 (s, 1H,
CH), 3.68 (s, 3H, CH3), 7.32–8.67 (m, 9H, Ar-H), 11.92 (s, 1H, NH); 13C NMR
(DMSO-d6, d ppm): 13.84 (CH3), 110.93, 121.53, 124.69, 128.18, 128.46, 131.32,
135.08, 135.74, 136.18 (Ar-C), 138.62 (C-guanidine), 142.72 (CH), 154.69
(C-hydrazone), 168.86 (C-isothiourea). MS, m=z (%): 334 (Mþ, 70). Anal. cald. for
C17H14N6S: C, 61.06; H, 4.22; N, 25.13; S, 9.59. Found: C, 60.95; H, 4.31; N,
25.07; S, 9.70.
N-(2-Methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-yl)-N’-isopropylidene-
hydrazine (11b). Mp 195–197 ꢁC. 1H NMR (DMSO-d6, d ppm): 2.32 (s, 3H, CH3-
isopropyl), 2.35 (s, 3H, CH3-isopropyl), 2.85 (s, 3H, SCH3), 7.37–8.54 (m, 4H,
Ar-H), 10.45 (s, 1H, NH); 13C NMR (DMSO-d6, d ppm): 13.08 (SCH3), 18.67

3520
R. AL-SALAHI AND D. GEFFKEN
(CH3-isopropyl), 25.28 (CH3-isopropyl), 114.63, 124.90, 125.75, 126.06, 128.29,
129.67 (Ar-C), 134.82 (C-guanidine), 147.46 (C-isopropyl), 153.94 (C-hydrazone),
163.72 (C-isothiourea). MS, m=z (%): 286 (Mþ, 100). Anal. calcd. for C13H14N6S:
C, 54.53, H, 4.93; N, 29.35; S, 11.20. Found: C, 54.52; H, 4.84; N, 29.26; S,
11.08.
Compounds 12a,b
A mixture of compound 9 (0.001 mol) and the corresponding carbohydrazide
(0.0022 mol) was refluxed in toluene (10 mL) for 2.5 h. After cooling, the solid was
collected by filtration. Analytically pure products 12a,b were obtained by recrystal-
lization from methanol.
N-(2-Methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolꢀin1-5-yl)isonicotinic-
hydrazide (12a). Mp 152–154 ꢁC. IR spectrum (KBr, n, cm ): 1665 (C O), 3210
=
1
(NH); H NMR (DMSO-d6, d ppm): 3.88 (s, 3H, CH3), 7.55–8.44 (m, 8H, Ar-H),
10.43 (s, 1H, NH), 11.64 (s, 1H, NH); 13C NMR (DMSO-d6, d ppm): 13.72
(CH3), 109.89, 114.94, 121.73, 124.88, 125.36, 128.45, 133.20, 135.21, 139.04
=
(Ar-C), 150.81 (C-guanidine), 152.96 (C-hydrazide), 155.84 (C O), 165.89
(C-isothiourea). MS, m=z (%): 351 (Mþ, 75). Anal. calcd. for C16H13N7OS:C,
54.69; H, 3.73; N, 27.90; S, 9.12. Found: C, 54.62; H 3.70; N 27.99; S, 9.20.
N-(2-Methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-yl)-benzohydrazide
ꢀ1
1
(12b). Mp 182–184 ꢁC. IR spectrum (KBr, n, cm ): 1670 (C O); 3189 (NH); H
NMR (DMSO-d6, d ppm): 2.95 (s, 3H, CH3), 7.34–8.80 (m, 9H, Ar-H), 9.98 (s,
1H, NH), 10.82 (s, 1H, NH); 13C NMR (DMSO-d6, d ppm): 13.76 (CH3), 110.75,
114.88, 124.93, 125.29, 127.81, 128.87, 129.07, 132.21, 132.81, 133.03 (Ar-C),
=
=
145.74 (C-guanidine), 154.98 (C-hydrazide), 157.70 (C O), 167.07 (C-isothiourea).
MS, m=z (%): 350 (Mþ, 82). Anal. calcd. for C17H14N6OS: C, 58.27; H, 4.03; N,
23.98; S, 9.15. Found: C, 58.18; H, 4.10; N, 23.90; S, 9.07.
Compounds 13a,b
A mixture of compound 9 (0.001 mol) and benzyl carbazide or ethyl carbazide
(0.0022 mol) was refluxed in benzene (10 mL) for 2.5 h. The solvent was removed
under reduced pressure, and the resulting solid was filtered off and recrystallized
from methanol.
N-(2-Methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-yl)hydrazine-
carboxylic acid ethylester (13a). Mp 213–215 ꢁC. IR (KBr, n, cmꢀ1): 1709
(C O), 3261 (NH); 1H NMR (DMSO-d6, d ppm): 1.43 (t, J ¼ 7.78 Hz, 3H,
=
OCH3), 2.79 (s, 3H, SCH3), 4.19 (q, J ¼ 10.05 Hz, 2H, OCH2), 7.98–8.83 (m, 4H,
Ar-H), 9.82 (s, 1H, NH), 10.51 (s, 1H, NH); 13C NMR (DMSO-d6, d ppm): 13.83
(SCH3), 14.69 (OCH3), 61.38 (OCH2), 110.75, 124.75, 125.21, 127.07, 133.70,
=
134.53 (Ar-C), 135.93 (C-guanidine), 154.37 (C-carbazide), 156.93 (C O), 164.53
(C-isothiourea). MS, m=z (%): 350 (Mþ, 80). Anal. calcd. for C13H14N6O2S: C,
49.05; H, 4.43; N, 26.40; S, 10.07. Found: C, 49.13; H, 4.38; N, 26.44; S, 10.00.

SYNTHESIS OF TRIAZOLOQUINAZOLINE
3521
N-(2-Methylsulfanyl[1,2,4]triazolo[1,5-a]quinazolin-5-yl)hydrazine-
carboxylic acid benzylester (13b). Mp 188–190 ꢁC. IR (KBr, n, cmꢀ1): 1718
1
=
(C O), 3280 (NH); H NMR (DMSO-d6, d ppm): 4.21 (s, 3H, CH3), 5.23 (s, 2H,
CH2), 7.25–8.36 (m, 9H, Ar-H), 9.48 (s, 1H, NH), 10.52 (s, 1H, NH); 13C NMR
(DMSO-d6, d ppm): 13.78 (CH3), 66.78 (CH2), 109.67, 124.75, 125.25, 126.25,
128.54, 128.81, 135.11, 135.33, 135.73 (Ar-C), 136.88 (C-guanidine), 152.83
þ
=
(C-carbazide), 157.18 (C O), 168.92 (C-isothiourea). MS, m=z (%): 380 (M , 91).
Anal. calcd. for C18H16N6O2S: C, 56.83; H, 4.24; N, 22.09; S, 8.43. Found: C,
56.74; H, 4.23; N, 22.15; S, 8.51.
Compounds 14a,b
A mixture of compound 12 (0.0005 mol) and phosphorus oxychloride (5 mL)
was refluxed at 100 ꢁC for 2 h. After cooling, the excess of phosphorus oxychloride
was removed under reduced pressure, and the residue was treated with saturated sol-
ution of NH4OH or K2CO3 under ice cooling. The resulting solids were collected by
filtration and recrystallized from methanol to afford 14a,b as pure products.
2-Methylsulfanyl-3-pyridyl-bis[1,2,4]triazolo[1,5-a:4,3-c]quinazoline (14a).
Mp 221–223 ꢁC, 1H NMR (DMSO-d6, d ppm): 3.89 (s, 3H, CH3), 7.85–8.99 (m, 8H,
Ar-H); 13C NMR (DMSO-d6, d ppm): 13.49 (CH3), 111.72, 115.23, 124.39, 124.75,
127.29, 129.80, 130.59, 142.52 (Ar-C), 145.67 (C-guanidine), 151.33 (C-quinazoline),
154.95 (C-triazole), 162.34 (C-isothiourea). MS, m=z (%): 333 (Mþ, 83). Anal. calcd.
for C16H11N7S: C, 57.65; H, 3.33; N, 29.41; S, 9.62. Found: C, 57.54; H, 3.27; N,
29.47; S, 9.70.
2-Methylsulfonyl-3-phenyl-Bis[1,2,4]triazolo[1,5-a:4,3-c]quinazoline (14b).
1
Mp 200–202 ꢁC; H NMR (DMSO-d6, d ppm): 2.79 (s, 3H, CH3), 7.85–8.71 (m,
9H, Ar-H); 13C NMR (DMSO-d6, d ppm): 14.01 (CH3), 112.99, 115.17, 124.56,
126.12, 127.09, 128.35, 129.80, 130.89, 131.29, 132.90 (Ar-C), 143.76 (C-guanidine),
147.71 (C-quinazoline), 149.74 (C-triazole), 161.44 (C-isothiourea). MS, m=z (%):
332 (Mþ, 100). Anal. calcd. for C17H12N6S: C, 61.43; H, 3.64; N, 25.28; S, 9.65.
Found: C, 61.34; H, 3.57; N, 25.27; S, 9.79.
2-Methylsulfanyl-tetrazolo[4,3-c][1,2,4]triazolo[1,5-a]quinazolines
(15)
A mixture of compound 9 (0.001 mol) and NaN3 (0.0012 mmol) in absolute
dimethyl formamide (5 mL) was heated at 90 ꢁC in a nitrogen atmosphere for 24 h.
After cooling, the reaction mixture was poured into water and saturated with brine
solution. The resulting solid was filtered off. Recrystallization from methanol
afforded compound 15 (0.154 g, 60%); mp 171–173 ꢁC. 1H NMR spectrum
(DMSO-d6, d ppm): 3.99 (s, 3H, CH3), 7.18–7.95 (m, 4H, Ar-H); 13C NMR
(DMSO-d6, d ppm): 13.86 (CH3), 114.67, 116.23, 125.81, 128.27, 134.74, 136.49
(Ar-C), 145.21 (C-guanidine), 157.32 (C-quinazoline), 167.54 (C-isothiourea). MS,
m=z (%): 257 (Mþ, 100). Anal. cald. for C10H7N7S: C, 46.69; H, 2.74; N, 38.11; S,
12.46. Found: C, 46.71; H, 2.70; N, 38.21; S, 12.34.

3522
R. AL-SALAHI AND D. GEFFKEN
REFERENCES
1. Borchers, A.; Engler, H.; Szelenyi, I.; Schunack, W. Synthesis and H2-antihistaminic
activity of N,N0-bisimidazole substituted thioureas, cyanoguanidines and 2-nitro-1,1-
ethenediamines. Arzneim. Forsch. 1982, 32, 1509–1512.
2. Barzen, R.; Schunack, W. H2-antihistaminics, VII: Synthesis and H2-antihistaminic
activity of N,N0-substituted thioureas, cyanoguanidines and dithiooxamides. Arch.
Pharm. (Weinheim) 1981, 314, 617–622.
3. Webb, L. R.; Eggleston, D. S.; Labaw, C. S.; Lewis, J. J.; Wert, K. Diphenyl cyancarbo-
nimidate and dichlorodiphenoxymethane as synthons for the construction of heterocyclic
systems of medicinal interest. J. Heterocycl. Chem. 1987, 24, 275–278.
4. Hansen, E. T.; Petersen, H. J. Synthesis of N-alkyl-N0-cyano-N00-4-pyridylguanidines from
4-pyridyldithiocarbamic acid via N-alkyl-N0-4-pyridylthioureas, or via 4-pyridylcyanimi-
nothiocarbamic acid. Synth. Commun. 1984, 14, 1275–1283.
5. Jozsef, R.; Laszlo, P. A novel process for preparing N00-cyano-N0-(4-pyridyl)-N-
(1,2,2-trimethylpropyl)-guanidine. WO Patent 9517387, 1995; Chem. Abstr. 1995, 123,
198638.
6. Wittenbrook, L. S. New pyrimidine derivatives of cyanimidodithiocarbonates.
J. Heterocycl. Chem. 1975, 12, 37.
7. Tilley, J. W.; Ramuz, H. The synthesis of 3,5-diamino-1,2,4-oxadiazoles. Helv. Chim. Acta
1980, 63, 832–840.
8. Stefan, W. Verfahren zur Herstellung von 4,6-disubstituierten 2-Amino-s-triazinen. DE
Patent 19523206, 1997; Chem. Abstr. 1997, 126, 117993.
9. Pierce, A. C.; Arnost, M.; Davies, R. J.; Forster, C. J.; Galullo, V.; Grey, R.; Ledeboer,
M.; Tian, S.-K.; Xu, J.; Binch, H.; Ledford, B.; Messersmith, D.; Nanthakumar, S.;
Jayaraj, A. Diaminotriazoles useful as inhibitors of protein kinases. WO Patent
2004046120, 2004; Chem. Abstr. 2004, 141, 23537.
10. Berezank, J. F.; Chan, D.; Geffken, D.; Hanagan, M. A.; Lepone, G. E; Pasteris, R.;
Swan, S. T. (E.I. Dupont de Nomerous & Co.) Fungicidal tricyclic 1,2,4-triazole. WO
Patent 2008103357; Chem. Abstr. 2008, 1042828.
11. Hantzsch, A.; Wolvekamp, M. Constitution of the so-called dithiocyanic acid and
perthiocyanic acid. Annal. Chem. 1904, 331, 265–297.
12. Selby, T. P.; Lepone, G. E. Synthesis and structure elucidation of 3-methoxy-1-methyl-
1H-1,2,4-triazol-5-amine and 5-methoxy-1-methyl-1H-1,2,4-triazol-3-amine. J. Hetero-
cycl. Chem. 1984, 21, 61–64.
13. Kristinsson, H.; Winkler, T. Heterocyclic amine precursors to sulfonylurea herbicides.
Helv. Chim. Acta 1983, 66, 1129–1136.
14. Webb, L. R.; Labaw, C. S. Diphenyl cyanocarbonimidate: A versatile synthon for the
construction of heterocyclic systems. J. Heterocycl. Chem. 1982, 19, 1205–1206.
15. Sheehan, J. C.; Nafissi-V, M. M. a-lactams. VIII: O-Alkylation of a-lactams. J. Org.
Chem. 1970, 12, 4246–4248.
16. Takahata, H.; Hashizume, T.; Yamazaki, T. N-Alkylation of lactams with phase transfer
catalyst. Heterocycles 1979, 12, 1449–1451.
17. Muin, D. Z.; Misic-V, M. M.; Petrovic, S. D. Alkylation of N-substituted 2-phenylaceta-
mides. J. Serb. Chem. Soc. 2004, 69, 711–736.
18. Hardtman, G. E.; Koleter, G.; Pfister, O. R. Chemistry of 2H-3,1-benzoxazine-2,4-
(1H)-dione (isatoic anhydrides): Synthesis of N-substituted 2H-3,1-benzoxazine-2,4
(1H)-diones. J. Heterocycl. Chem. 1975, 12, 565–572.
19. Al-Salahi, R.; Geffken, D. Synthesis of novel 2-alkoxy(araloxy)-4H-[1,2,4]triazolo[1,5-a]-
quinazolin-5-ones starting with dialkyl-N-cyanoimidocarbonates. J. Heterocycl. Chem.
2011, 48, 656–662.

SYNTHESIS OF TRIAZOLOQUINAZOLINE
3523
20. Taylor, E. C.; Martin, A. E. A new synthesis of phenanthridine. J. Chem. Soc. 1952, 11,
6295.
21. Heckendorn, R.; Winkler, T. Synthesis of [1,2,4]triazolo]1,5-a]quinazolines. Effect of sub-
stituent orientation on carbon-13 chemical shift. Part III: Deduction of the conformation
of substituents by carbon-13 NMR spectroscopy. Helv. Chim. Acta 1980, 63, 1–9.
22. Gamage, S. A.; Spicer, J. A.; Rewcastle, G. W.; Milton, J.; Sohal, S.; Dangerfield, W.;
Mistry, P.; Vicker, N.; Charlton, P. A.; Denny, W. A. Structure-activity relationships
for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as
topoisomerase-targeted anticancer agents. J. Med. Chem. 2002, 45, 740–743.
23. Pfeiffer, W.-D.; Hetzheim, A.; Pazdera, P.; Bodtke, A.; Muecke, J. Synthesis and reac-
tivity of 1,2,4-triazolo[1,5-c]quinazolines. J. Heterocycl. Chem. 1999, 36, 1327–1336.
24. Badawy, M. A.; Abdel-Hady, S. A.; Ibrahim, Y. A. Reaction of 4-aryl-1,2,4-triazines with
hydrazine. J. Heterocycl. Chem. 1981, 18, 953–956.
25. Wade, P. C.; Vogt, B. R.; Toeplitz, B.; Puan, M. S. 1,2,4-Triazolo- and 1,2,5-
triazino[4,3-d][1,4]benzodiazepinone ring systems: Synthesis and barrier to ring inversion.
J. Org. Chem. 1979, 44, 88–99.
26. El-Kashef, H.; Farghaly, A. A. H.; Haider, N.; Wobus, A. Unexpected hydrazinolysis
behaviour of 1-Chloro-4-methyl-5H-pyridazino[4,5-b]indole and a convenient synthesis
of new [1,2,4]-triazolo[40,30:1,6]pyridazino[4,5-b]indoles. Molecules 2004, 9, 849–859.
27. Thota, S.; Argade, A.; Singh, R.; Lu, H. H.; Huang, P. Preparation of tetrazoloquinoline
derivatives as inhibitors of HCV. WO Patent 2005030774; Chem. Abstr. 2005, 142, 373704.