Domino cyclization of 2-isothiocyanatobenzonitrile with carboxylic hydrazides - One-pot synthesis of 1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thiones

Article abstract of DOI:10.1002/1099-0690(200301)2003:1<182::AID-EJOC182>3.0.CO;2-S

One-pot reactions between carboxylic hydrazides and 2-isothiocyanatobenzonitrile afforded pharmacologically relevant 1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thiones in good yields. These compounds were transformed into the corresponding amino-substituted derivatives in good yields in one of two steps. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/1099-0690(200301)2003:1<182::AID-EJOC182>3.0.CO;2-S

FULL PAPER
Domino Cyclization of 2-Isothiocyanatobenzonitrile with Carboxylic
Hydrazides ؊ One-Pot Synthesis of
1,2,4-Triazolo[1,5-c]quinazoline-5(6H)-thiones
Janet Blank,[a] Madeleine Kandt,[a] Wolf-Diethard Pfeiffer,*[a] Annemarie Hetzheim,[a] and
Peter Langer*[a]
Keywords: Cyclizations / Domino reactions / Isothiocyanates / Nitrogen heterocycles
One-pot reactions between carboxylic hydrazides and 2-iso-
thiocyanatobenzonitrile afforded pharmacologically relevant
1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thiones in good yields.
These compounds were transformed into the corresponding
amino-substituted derivatives in good yields in one or two
steps.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
In recent years, we have reported a number of cyclization
reactions of dianions and electroneutral dinucleophiles with
1,2-dielectrophiles for the synthesis of heterocyclic frame-
works.[11] Here we wish to report cyclizations between carb-
oxylic hydrazides and 2-isothiocyanatobenzonitrile (1) Ϫ a
new and interesting type of 1,5-dielectrophile.[12] The cyc-
lization proceeds by a domino process that, to the best of
our knowledge, has not yet been reported.[13Ϫ16] We have
studied this reaction widely, and it has allowed efficient
one-pot syntheses of a great variety of pharmacologically
relevant 1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thiones.
The development of efficient syntheses of triazoloquina-
zolines is of considerable current interest. These compounds
combine the pharmacologically relevant triazole and quina-
zoline moieties and exhibit a significant and broad activity
spectrum. For example, 1,2,4-triazolo[5,1-b]quinazolines
show antihypertonic activity.[1] Antirheumatic and antiana-
phylactic activity has been recognized for 3-heteroaryl-
1,2,4-triazolo[5,1-b]quinazolines,[2] while 1,2,4-triazolo[1,5-
c]quinazolines possess antiasthmatic, tranquilizing, and
neuro-stimulating activity.[3] Aryl- and heteroaryl-substituted
derivatives have been shown to possess benzodiazepine
binding activity.[4] In addition, anti-inflammatory, antihyp- Results and Discussion
ertonic, and antiviral activity has been reported.[5] Chlorin-
ated 1,2,4-triazolo[1,5-c]quinazolines and the isomeric
1,2,4-triazolo[4,3-c]quinazolines exhibit anti-inflammatory
and sedative activity.[6]
Treatment of acetic hydrazide (2b) with 2-isothiocyanato-
benzonitrile (1) at room temperature resulted in the forma-
tion of an open-chain product. Heating of a solution of the
starting materials at reflux afforded the 1,2,4-triazolo[1,5-
c]quinazoline-5(6H)-thione 3b in up to 88% yield. The
formation of 3b can be explained by attack of the hydrazide
onto the central carbon of the isothiocyanate (intermediate
A), subsequent cyclization by attack of the hydrazide nitro-
gen onto the nitrile to give intermediate B, attack of the
amidine nitrogen onto the carbonyl group and, finally, ex-
trusion of water (Scheme 1). In this reaction, three new
bonds were formed in only one synthetic operation. The
reaction was monitored by TLC and IR (analysis of the
diagnostic CϵN and CϭO absorptions): intermediate A
was formed predominantly when the reaction was carried
out at 0 °C rather than under reflux, while intermediate B
was formed predominantly when the reaction time (reflux)
was too short.
1,2,4-Triazolo[1,5-c]quinazolines have previously been
prepared by treatment of 4-hydrazinoquinazolines with ali-
phatic carboxylic acids.[7] The use of orthoesters resulted
in the formation of 1,2,4-triazolo[4,3-c]quinazolines, which
could be transformed into the corresponding isomers by
heating under reflux with aliphatic acids (by an azaanalog-
ous Dimroth rearrangement).[8,9] Other syntheses rely on
ring-transformation reactions of benzoxazine derivatives.[10]
1,2,4-Triazolo[1,5-c]quinazoline-5(6H)-ones have been pre-
pared by cyclization of 2-(1,2,4-triazol-3-yl)benzamides
with Pb(OAc)4 and NaOBr[4] and by oxidative cyclization
of 4-quinazolinecarbaldehyde hydrazones.[7]
[a]
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-
Universität Greifswald,
Soldmannstr. 16, 17487 Greifswald, Germany
Fax: (internat.) ϩ49Ϫ(0)3834/864373
E-mail: peter.langer@uni-greifswald.de
The structures of heterocycles 3 were confirmed by spec-
troscopic methods, by comparison of their data with those
182
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0182 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 182Ϫ189

Domino Cyclization of 2-Isothiocyanatobenzonitrile with Carboxylic Hydrazides
Table 1. Products and yields
FULL PAPER
Entry
R1
3 [%][a]
4 [%][a]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
H
CH3
73
88
96
80
73
99
67
73
93
71
98
96
76
94
95
82
72
99
91
93
72
74
87
96
83
87
95
79
76
75
83
74
79
82
CH3(CH2)14
(NC)CH2
(C6H5)CH2
(C6H5)OCH2
C6H5
4-CH3(C6H4)
4-Br(C6H4)
4-Cl(C6H4)
2,4-Cl2(C6H3)
3,5-Cl2(C6H3)
4-NO2(C6H4)
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Furyl
Scheme 1. Synthesis of 1,2,4-triazolo[1,5-c]quinazoline-5(6H)-
thiones 3a؊q (solvent ϭ EtOH, iPrOH, or CH2Cl2)
[a]
Isolated yields (by methods A and B, see Exp. Sect. for details).
of independently prepared products and by their chemical
behaviour (vide infra). All products were isolated as colour-
less solids, showing very strong UV absorptions in
220Ϫ267 nm range (first absorption) and the 246Ϫ340 nm
range (second absorption).
Unlike the corresponding oxo derivatives, 5-thioxo-sub-
stituted quinazolines 3 can be used as starting materials for
the synthesis of 5-substituted quinazolines, since the thio-
carbonyl group can readily be transformed into an excellent
leaving group. This was demonstrated by transformation of
heterocycles 3 into 5-amino-1,2,4-triazolo[1,5-c]quinazol-
ines 5, via the corresponding thioethers 4.[14] Treatment of
selected thioethers 4 with secondary amines (such as mor-
pholine, piperidine, and pyrrolidine) afforded the 5-amino-
quinazolines 5aϪk in high yields (Scheme 2, Table 2). From
previous findings,[14] compounds 5aϪk could also be pre-
pared directly from 3: treatment of the latter with H2O2
gave sulfonic acid intermediates, which reacted with the nu-
cleophile.[17] However, the reactions proceeded less cleanly
and yields were lower than those obtained by the stepwise
procedure. This can be explained by hydrolysis of the sul-
fonic acid intermediates under the reaction conditions to
give oxo-analogues of 3. Heterocycles 4 and 5 were isolated
as colourless solids that showed very strong UV absorptions
in similar ranges to quinazolines 3. Amino-substituted
1,2,4-triazolo[1,5-c]quinazolines related to 5 are adenosine
For the optimization, the choice of solvent (EtOH,
iPrOH, or CH2Cl2), temperature (reflux), reaction time
(2Ϫ6 h) and concentration (0.25Ϫ0.025 ) proved to be im-
portant parameters. This can be explained by the influence
of these parameters on the solubility of the starting mat-
erials and of intermediate B. This usually precipitated dur-
ing the reaction and slowly dissolved upon cyclization to
give 3. The reaction time was generally shorter for aliphatic
hydrazides than for their aromatic counterparts, which can
be explained by the higher electrophilicity of aliphatic car-
bonyl derivatives relative to aromatic carbonyl derivatives
and by the higher solubility of aliphatic starting materials
and intermediates relative to the aromatic derivatives.
To study the preparative scope of the reaction, the hy-
drazide component was varied systematically (Scheme 1,
Table 1). Treatment of formyl hydrazide 2a with 1 afforded
the unsubstituted parent 1,2,4-triazolo[1,5-c]quinazoline-
5(6H)-thione (3a). From acetyl and hexadecanoic hy-
drazides, the methyl- and pentadecyl-substituted quinazol-
ines 3b and 3c, respectively, were obtained. Cyclization of 1
with cyanomethyl, benzyl, and phenoxymethyl hydrazides
afforded the corresponding quinazolines 3d؊f. By starting
with 2g؊m, the aryl-substituted quinazolines 3g؊m were
formed. Treatment of 1 with hydrazides 2n؊q gave the pyri-
dyl- and furyl-substituted 1,2,4-triazolo[1,5-c]quinazolines
3n؊q. The products, which in most cases had not previ-
ously been prepared, were isolated in good to excellent
yields (67Ϫ99%).
Quinazolines 3a؊q were next transformed into the cor-
responding thioethers 4a؊q by a procedure recently re-
ported by us.[14] These compounds represent excellent start-
ing materials for nucleophilic displacement reactions (vide
infra) and are much more soluble than the thioxo derivat-
ives 3 in many solvents.
Scheme 2. Functionalization of quinazolines 3 by treatment with
amines
Eur. J. Org. Chem. 2003, 182Ϫ189
183

J. Blank, M. Kandt, W.-D. Pfeiffer, A. Hetzheim, P. Langer
FULL PAPER
C9H6N4S (202.24): calcd. C 53.45, H 2.99, N 27.7; found C 53.69,
H 2.83, N 27.57.
antagonists selective to the human A3 receptor, which medi-
ates processes of inflammation, hypotension, and mast cell
degranulation and plays an important role in the central
nervous system.[18]
2-Methyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3b): This
product was obtained from 1 in EtOH (40 mL) and 2b in EtOH
(10 mL). Yield: 1.90 g (88%), colourless needles (EtOH), m.p.
282Ϫ284 °C. IR (KBr): ν˜ ϭ 3185 (m), 3113 (m), 2936 (m), 1629
(s), 1548 (s), 1476 (s), 1386 (s), 1340 (s), 1298 (s), 1253 (m), 1230
(m), 1099 (m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 227.85 (4.61), 300.8
(4.31), 336.6 (4.01) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 2.63
(s, 3 H, CH3), 7.43Ϫ8.22 (m, 4 H, Ar-H), 13.80 (s, 1 H, NH) ppm.
13C NMR ([D6]DMSO, 75 MHz): δ ϭ 12.9, 14.1, 111.85, 116.2,
123.9, 125.3, 132.9, 136.1, 148.6, 166.3 ppm. MS: m/z ϭ 216 (100)
[Mϩ], 146 (17), 145 (18), 144 (27), 120 (16), 102 (13) ppm.
C10H8N4S (216.25): calcd. C 55.54, H 3.73, N 25.91; found C 55.49,
H 3.85, N 25.86.
Table 2. Synthesis of amino-substituted quinazolines 5a؊k
4
5
R1
R2
A [%][a]
B [%][a]
b
g
p
c
b
g
p
c
a
b
c
d
e
f
g
h
i
CH3
C6H5
4-Pyridyl
CH3(CH2)14
CH3
Ϫ(CH2)2O(CH2)2Ϫ 86
Ϫ(CH2)2O(CH2)2Ϫ 74
Ϫ(CH2)2O(CH2)2Ϫ 90
Ϫ(CH2)2O(CH2)2Ϫ 90
85
73
34
96
88
83
67
95
86
97
92
Ϫ(CH2)5Ϫ
Ϫ(CH2)5Ϫ
Ϫ(CH2)5Ϫ
Ϫ(CH2)5Ϫ
Ϫ(CH2)4Ϫ
Ϫ(CH2)4Ϫ
Ϫ(CH2)4Ϫ
92
86
73
97
89
95
98
C6H5
4-Pyridyl
CH3(CH2)14
CH3
C6H5
4-Pyridyl
2-Pentadecanyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3c):
This product was obtained from 1 in EtOH (40 mL) and 2c in
EtOH (20 mL). Yield: 3.96 g (96%), colourless needles (EtOH),
m.p. 156 °C. IR (KBr): ν˜ ϭ 3205 (m), 2948 (s), 2850 (s), 1632 (s),
1601 (s), 1563 (m), 1488 (m), 1440 (m), 1337 (m), 1322 (m), 1300
(m), 1229 (m), 1114 (m), 1099 (m) cmϪ1. UV (EtOH): λmax (lgε) ϭ
228.37 (4.60), 256.85 (4.14), 277.24 (4.02), 301.12 (4.30), 335.37
(3.97) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ 0.85Ϫ0.90 (t, 3 H,
CH3), 1.25Ϫ1.41 (m, 26 H, CH2), 2.96Ϫ3.02 (t, 2 H, CH2),
7.48Ϫ8.37 (m, 4 H, ArH), 11.21 (s, 1 H, NH) ppm. 13C NMR
(CDCl3, 75 MHz): δ ϭ 14.1, 22.7, 28.3, 28.9, 29.4, 29.5, 29.7, 31.9,
112.5, 115.2, 125.2, 126.0, 133.2, 135.5, 149.0, 167.1, 169.8 ppm.
MS: m/z ϭ 413 (62) [Mϩ], 412 (34), 379 (17), 271 (21), 229 (100),
216 (95). C24H36N4S (412.64): calcd. C 69.86, H 8.79, N 13.58;
found C 69.88, H 9.07, N 13.16.
b
g
p
j
k
In summary, we report a new and efficient one-pot syn-
thesis of a variety of 1,2,4-triazolo[1,5-c]quinazoline-5(6H)-
thiones. These products are of great pharmacological relev-
ance and can be functionalized further by treatment with
amines.
Experimental Section
General: All solvents were distilled prior to use. Melting points are
uncorrected. The NMR measurements were carried out on a
Bruker Model ARX 300 spectrometer. The deuterated solvents in-
dicated were used. Elemental analyses were performed on a Leco
2-Cyanomethyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3d):
This product was obtained from 1 in EtOH (40 mL) and 2d in
EtOH (20 mL). Yield: 1.93 g (80%), colourless prisms (EtOH), m.p.
316 °C. IR (KBr): ν˜ ϭ 3188 (m), 3166 (m), 3105 (m), 3074 (m),
3004 (m), 2910 (s), 2256 (w), 1630 (s), 1601 (m), 1548 (s), 1546 (s),
1300 (s), 1252 (s), 1241 (m), 1118 (m) cmϪ1. UV (iPrOH): λmax
(lgε) ϭ 227.49 (4.59), 302.09 (4.30), 338.66 (3.96) nm. 1H NMR
([D6]DMSO, 300 MHz): δ ϭ 4.52 (s, 2 H, CH2CN), 7.51Ϫ8.22 (m,
4 H, ArH), 14.09 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 17.86, 112.0, 116.4, 116.6, 124.1, 125.7, 133.4, 136.5,
149.6, 158.7, 166.4 ppm. MS: m/z ϭ 241 (100) [Mϩ], 214 (75), 161
(14), 146 (9), 143 (8), 102 (18). C11H7N5S (241.27): calcd. C 54.76,
H 2.92, N 29.03; found C 54.63, H 2.67, N 28.92.
CHNS-932 elemental analyser. For UV/Vis spectra
a
PerkinϪElmer Lambda 19 UV/Vis/NIR spectrometer was used. IR
Spectra were obtained on a Nicolet 205 FT-IR spectrometer.
General Procedure for the Synthesis of 1,2,4-Triazolo[1,5-c]quinazo-
line-5(6H)-thiones 3a؊q: A solution of the appropriate carboxylic
hydrazide 2aϪq (10 mmol) was added to a solution of 2-isothiocy-
anatobenzonitrile (1) (1.60 g, 10 mmol) in EtOH, iPrOH, or
CH2Cl2 (40Ϫ400 mL). The mixture was heated at reflux for 2Ϫ6 h.
After cooling, a colourless precipitate formed, and this was filtered
off and recrystallized from EtOH, iPrOH, or DMF. Compounds
3n؊p were dried in vacuo at 100 °C over phosphorus pentoxide.
For the synthesis of 3a and 3b, 1 (10 mmol) and 2a or 2b were
dissolved in CH2Cl2 (50 mL). The mixture was heated at reflux for
165 min (3a) or for 105 min (3b). In the case of 3cϪ3q the reaction
mixture was heated at reflux for 6 h.
2-Benzyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3e): This
product was obtained from 1 in EtOH (40 mL) and 2e in EtOH
(450 mL). Yield: 2.13 g (73%), colourless prisms (EtOH), m.p. 222
°C. IR (KBr): ν˜ ϭ 3183 (m), 3024 (m), 1632 (s), 1561 (s), 1542 (s),
1476 (s), 1380 (s), 1322 (s), 1300 (s), 1254 (m), 1157 (m), 1115 (m),
1099 (m) cmϪ1. UV (EtOH): λmax (lgε) ϭ 229.45 (4.63), 247.96
(4.21), 277.72 (4.03), 301.52 (4.33), 335.65 (3.98) nm. 1H NMR
([D6]DMSO, 300 MHz): δ ϭ 4.26 (s, 2 H, CH2), 7.24Ϫ8.19 (m, 9
H, ArH), 13.94 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 34.17, 111.9, 116.2, 123.9, 125.3, 126.5, 128.4, 128.8,
132.9, 136.2, 137.2, 148.9, 166.1, 166.5 ppm. MS: m/z ϭ 292 (100)
[Mϩ], 131 (9), 115 (8), 103 (12), 91 (18). C16H12N4S (292.36): calcd.
C 65.73, H 4.14, N 19.16; found C 65.79, H 4.40, N 18.96.
1,2,4-Triazolo[1,5-c]quinazoline-5(6H)-thione (3a): This product
was obtained from 1 in EtOH (40 mL) and 2a in EtOH (300 mL).
Yield: 1.47 g (73%), colourless prisms (EtOH), m.p. 335 °C. IR
(KBr): ν˜ ϭ 3177 (m), 3108 (m), 3027 (m), 2954 (m), 1639 (s), 1541
(s), 1477 (s), 1343 (s), 1283 (m), 1261 (m), 1226 (m), 1165 (s), 1087
(s) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 226.47 (4.53), 246.29 (4.09),
256.90 (4.07), 264.93 (4.03), 274.33 (3.99), 301.53 (4.30), 336.12
(4.02) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 2.63 (s, 3 H,
2-Phenoxymethyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3f):
CH3), 7.43Ϫ7.77 (m, 3 H, ArH), 8.22 (d, 1 H, C10-H, J ϭ 8.1 Hz), This product was obtained from 1 in iPrOH (80 mL) and 2f in
13.80 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ ϭ iPrOH (70 mL). Yield: 3.05 g (99%), colourless needles (EtOH),
112.3, 116.3, 123.9, 125.4, 133.0, 136.2, 148.3, 154.5, 166.8 ppm. m.p. 251 °C. IR (KBr): ν˜ ϭ 3193 (m), 3147 (m), 3058 (m), 1632
MS: m/z ϭ 202 (100) [Mϩ], 161 (20), 129 (10), 120 (9), 102 (10). (s), 1600 (s), 1588 (m), 1567 (m), 1541 (s), 1496 (m), 1476 (s), 1247
184
Eur. J. Org. Chem. 2003, 182Ϫ189

Domino Cyclization of 2-Isothiocyanatobenzonitrile with Carboxylic Hydrazides
FULL PAPER
(s), 1223 (s), 1099 (m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 228.29 in iPrOH (70 mL). Yield: 3.40 g (98%), colourless needles (DMF),
(4.67), 302.50 (4.25), 337.38 (3.96) nm. 1H NMR ([D6]DMSO, m.p. 287 °C. IR (KBr): ν˜ ϭ 3107 (m), 3087 (m), 3016 (m), 1633
300 MHz): δ ϭ 5.36 (s, 2 H, CH2), 7.55Ϫ8.25 (m, 9 H, ArH), 14.05 (s), 1540 (s), 1302 (s), 1231 (m), 1137 (m), 1106 (m), 1089 (m), 980
(s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ ϭ 63.2, (m), 756 (s) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 203.07 (4.49), 225.76
112.3, 115.0, 116.7, 121.6, 124.4, 126.0, 130.0, 133.7, 136.7, 149.5,
(4.52), 253.15 (4.60) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ
158.2, 163.2, 166.9 ppm. MS: m/z ϭ 308 (86) [Mϩ], 215 (100), 161 7.57Ϫ8.34 (m, 7 H, ArH), 13.91 (s, 1 H, NH) ppm. 13C NMR
(42), 102 (13), 66 (17). C16H12N4OS (308.36): calcd. C 62.32, H ([D6]DMSO, 75 MHz): δ ϭ 112.0, 116.4, 124.2, 125.5, 127.7, 130.2,
3.92, N 18.17; found C 62.10, H 3.87, N 17.92.
133.2, 133.3, 135.6, 136.5, 148.8, 161.6, 166.5 ppm. MS: m/z ϭ 348
(14) [Mϩ], 346 (22), 313 (38), 312 (19), 311 (100). C15H8Cl2N4S
(347.22): calcd. C 51.89, H 2.32, N 16.14; found C 51.94, H 2.02,
N 16.13.
2-Phenyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3g): This
product was obtained from 1 in EtOH (40 mL) and 2g in EtOH
(250 mL). Yield: 1.86 g (67%), colourless prisms (EtOH), m.p. 311
°C. IR (KBr): ν˜ ϭ 3197 (m), 3141 (m), 3031 (m), 1631 (s), 1530
(s), 1473 (s), 1446 (s), 1325 (s), 1253 (m), 1233 (m), 1132 (m), 1080
(m) cmϪ1. UV (EtOH): λmax (lgε) ϭ 251.85 (4.70), 278.53 (4.39),
290.31 (4.36), 307.49 (4.21), 338.20 (4.05) nm. 1H NMR
([D6]DMSO, 300 MHz): δ ϭ 7.56Ϫ8.32 (m, 9 H, ArH), 14.01 (s, 1
H, NH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ ϭ 112.1, 116.3,
124.1, 125.4, 126.9, 129.0, 129.4, 130.7, 133.7, 133.1, 136.3, 149.4,
163.5, 166.5 ppm. MS: m/z ϭ 278 (100) [Mϩ], 277 (86), 146 (12),
120 (11), 118 (18), 103 (12). C15H10N4S (278.33): calcd. C 64.73, H
3.62, N 20.13; found C 64.58, H 3.52, N 19.92.
2-(3,5-Dichlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3l): This product was obtained from 1 in iPrOH (80 mL) and 2l
in iPrOH (220 mL). Yield: 3.33 g (96%), colourless prisms (DMF),
m.p. 360 °C. IR (KBr): ν˜ ϭ 3111 (m), 3080 (m), 3016 (m), 1632
(s), 1541 (s), 1503 (s), 1475 (m), 1301 (s), 1232 (m), 1085 (m), 976
(m), 756 (m) cmϪ1. UV (DMF): λmax (lgε) ϭ 303.03 (4.28), 342.81
(4.02) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 7.57Ϫ8.34 (m, 7
H, ArH), 14.15 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 5.3, 6.9, 55.9, 125.2, 130.1, 133.4, 134.9, 136.6, 149.8,
166.4, 221.2 ppm. MS: m/z ϭ 347 (65) [Mϩ], 346 (100), 345 (72),
186 (14), 146 (22), 120 (24). C15H8Cl2N4S, (347.22): calcd. C 51.89,
H 2.32, N 16.14; found C 52.08, H 2.17, N 16.52.
2-Tolyl-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3h): This
product was obtained from 1 in iPrOH (80 mL) and 2h in iPrOH
(120 mL). Yield: 2.13 g (73%), colourless prisms (EtOH), m.p. 315
°C. IR (KBr): ν˜ ϭ 3192 (m), 3139 (m), 3068 (m), 1631 (s), 1611
(m), 1536 (s), 1469 (s), 1299 (s), 1253 (m), 1131 (m), 982 (m), 750
(s) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 220.04 (4.26), 255.04 (4.61),
2-(4-Nitrophenyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3m): This product was obtained from 1 in iPrOH (80 mL) and 2m
in iPrOH (130 mL). Yield: 2.46 g (76%), colourless rods (EtOH),
m.p. 335 °C. IR (KBr): ν˜ ϭ 3103 (m), 3068 (m), 2981 (m), 1632
(s), 1603 (s), 1551 (s), 1536 (s), 1472 (s), 1343 (s), 1313 (s), 1247 (m),
1107 (m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 235.98 (4.43), 282.04
(4.25) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 7.55Ϫ8.51 (m, 8
H, ArH), 14.12 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 112.1, 116.4, 124.1, 124.3, 125.5, 128.1, 133.3, 135.3,
136.5, 148.6, 149.9, 161.6, 166.5 ppm. MS: m/z ϭ 323 (100) [Mϩ],
322 (43), 175 (63), 149 (36), 120 (43), 104 (19). C15H9N5O2S
(323.33): calcd. C 55.72, H 2.81, N 21.66; found C 55.73, H 2.45,
N 21.65.
1
293.85 (4.40), 339.11 (3.92) nm. H NMR ([D6]DMSO, 300 MHz):
δ ϭ 1.03Ϫ1.08 (s, 3 H, CH3), 7.39Ϫ8.31 (m, 8 H, ArH), 13.99 (s,
1 H, NH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ ϭ 21.0, 112.1,
116.3, 124.1, 125.4, 126.8, 127.0, 129.7, 133.1, 136.9, 140.7, 149.5,
163.6, 166.4 ppm. MS: m/z ϭ 292 (100) [Mϩ], 291 (89), 146 (15),
132 (15), 20 (11). C16H12N4S (292.36): calcd. C 65.73, H 4.14, N
19.16; found C 65.91, H 4.29, N 19.54.
2-(4-Bromophenyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3i): This product was obtained from 1 in iPrOH (80 mL) and 2i
in iPrOH (50 mL). Yield: 3.32 g (93%), colourless needles (DMF),
m.p. 342 °C. IR (KBr): ν˜ ϭ 3114 (m), 3086 (m), 3068 (m), 1631
(s), 1536 (s), 1405 (s), 1299 (s), 1131 (m), 1081 (m), 1012 (m), 982
(m), 753 (s) cmϪ1. UV (DMF): λmax (lgε) ϭ 277.23 (4.54), 338.57
(4.16) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 7.54Ϫ8.32 (m, 8
H, ArH), 13.94 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 112.1, 116.5, 124.1, 124.3, 125.5, 128.6, 128.9, 132.1,
133.2, 136.6, 149.6, 162.6, 166.4 ppm. MS: m/z ϭ 357 (100) [Mϩ],
356 (94), 355 (58), 196 (11), 146 (13), 138 (13), 120 (12).
C15H9BrN4S (357.24): calcd. C 50.43, H 2.54, N 15.68; found C
50.33, H 2.36, N 15.62.
2-(2-Pyridyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3n):
This product was obtained from 1 in iPrOH (80 mL) and 2n in
iPrOH (50 mL). Yield: 2.62 g (94%), colourless prisms (DMF),
m.p. 374 °C. IR (KBr): ν ϭ 3148 (w), 3108 (w), 3090 (w), 3019 (w),
1637 (s), 1600 (m), 1561 (s), 1552 (s), 1475 (s), 1419 (s), 1256 (m),
1244 (m), 1155 (m), 1114 (m), 1081 (m) cmϪ1. UV (iPrOH): λmax
(lgε) ϭ 245.07 (4.58), 339.98 (3.50) nm. 1H NMR ([D6]DMSO,
300 MHz): δ ϭ 7.57Ϫ8.80 (m, 8 H, ArH, pyridyl) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ ϭ 112.3, 123.0, 124.1, 125.2, 125.5, 133.1,
136.4, 137.3, 148.2, 149.4, 150.0, 163.2, 166.7 ppm. MS: m/z ϭ 279
(100) [Mϩ], 251 (39), 250 (14), 123 (22), 102 (14), 78 (29). C14H9N5S
(279.32): calcd. C 60.20, H 3.25, N 25.07; found C 60.13, H 2.83,
N 24.97.
˜
2-(4-Chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3j): This product was obtained from 1 in iPrOH (80 mL) and 2j
in iPrOH (70 mL). Yield: 2.22 g (71%), colourless needles (EtOH),
m.p. 345 °C. IR (KBr): ν˜ ϭ 3200 (m), 3139 (m), 3118 (m), 3068
(m), 3027 (m), 1632 (s), 1536 (s), 1447 (s), 1409 (s), 1315 (s), 1299
(s), 1253 (m), 1132 (m), 753 (s) cmϪ1. UV (iPrOH): λmax (lgε) ϭ
267.23 (3.48), 338.19 (3.96) nm. 1H NMR ([D6]DMSO, 300 MHz):
δ ϭ 7.56Ϫ8.31 (m, 8 H, ArH), 13.91 (s, 1 H, NH) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ ϭ 55.9, 112.1, 116.3, 124.1, 125.4, 128.3,
128.7, 129.2, 133.2, 135.4, 136.4, 149.6, 162.5, 166.4 ppm. MS: m/z
ϭ 313 (45) [Mϩ], 312 (100), 311 (74), 151 (17), 146 (15), 120 (16),
102 (16). C15H9ClN4S (312.78): calcd. C 57.60, H 2.90, N 17.91;
found C 57.87, H 2.88, N 18.02.
2-(3-Pyridyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3o):
This product was obtained from 1 in iPrOH (80 mL) and 2o in
iPrOH (40 mL). Yield: 2.65 g (95%), colourless rods (DMF), m.p.
347 °C. IR (KBr): ν˜ ϭ 3108 (w), 3062 (w), 1636 (s), 1601 (m), 1562
(s), 1548 (s), 1477 (s), 1412 (s), 1380 (s), 1307 (s), 1299 (s), 1140 (s),
1088 (m) cmϪ1. UV (DMF): λmax (lgε) ϭ 266.60 (4.42), 338.62
(4.14) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 7.57Ϫ9.40 (m, 8
H, ArH, pyridyl), 14.08 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 112.1, 116.3, 124.2, 125.4, 133.2, 134.4, 136.4, 147.7,
149.6, 151.4, 161.5, 166.4 ppm. MS: m/z ϭ 279 (100) [Mϩ], 278
(82), 146 (15), 119 (17), 102 (13). C14H9N5S (279.32): calcd. C
60.20, H 3.25, N 25.07; found C 60.26, H 3.28, N 25.10.
2-(2,4-Dichlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
(3k): This product was obtained from 1 in iPrOH (80 mL) and 2k
Eur. J. Org. Chem. 2003, 182Ϫ189
185

J. Blank, M. Kandt, W.-D. Pfeiffer, A. Hetzheim, P. Langer
FULL PAPER
2-(4-Pyridyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione
This product was obtained from 1 and 2p in DMF (50 mL). Yield:
2.29 g (82%), colourless needles (DMF), m.p. 335 °C. IR (KBr):
(3p):
0.85Ϫ0.90 (t, 3 H, CH3), 1.25Ϫ1.92 (m, 26 H, CH2), 2.81 (s, 3 H,
SCH3), 2.96Ϫ3.01 (t, 2 H, CH2), 7.57Ϫ8.46 (m, 4 H, ArH) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 13.4, 14.1, 22.7, 28.5, 28.9, 29.4,
ν˜ ϭ 3195 (m), 3012 (m), 2956 (m), 1636 (s), 1538 (s), 1485 (s), 1377 29.5, 29.7, 31.9, 115.8, 123.7, 126.9, 127.2, 131.8, 143.5, 150.6,
(m), 1328 (m), 1302 (s), 1261 (m), 1238 (m), 1139 (m), 1085 (m)
167.9 ppm. MS: m/z ϭ 427 (6) [Mϩ], 285 (18), 243 (44), 231 (13),
cmϪ1. UV (EtOH): λmax (lgε) ϭ 249.86 (4.62), 310.55 (4.03), 341.18 230 (100). C25H38N4S (426.67): calcd. C 70.38, H 8.98, N 13.13;
(4.02) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ 7.57Ϫ8.83 (m, 8 found C 70.29, H 8.76, N 13.32.
H, ArH, pyridyl), 14.12 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
2-Cyanomethyl-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline
75 MHz): δ ϭ 112.1, 116.3, 124.2, 125.5, 133.2, 134.4, 136.4, 147.7,
(4d): Yield: 0.92 g (72%), colourless prisms (EtOH), m.p. 190 °C.
149.6, 151.4, 161.5, 166.4 ppm. MS: m/z ϭ 279 (100) [Mϩ], 278
IR (KBr): ν˜ ϭ 2968 (m), 2256 (w), 1622 (s), 1592 (m), 1506 (s),
(75), 146 (14), 120 (12), 102 (10). C14H9N5S (279.32): calcd. C
1490 (m), 1375 (m), 1356 (m), 1314 (m), 1088 (m), 966 (m), 767
60.20, H 3.25, N 25.07; found C 60.49, H 3.47, N 24.98.
(m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 222.18 (4.50), 249.38 (4.58),
2-(2-Furyl)-1,2,4-triazolo[1,5-c]quinazoline-5(6H)-thione (3q): This 279.64 (4.10), 309.23 (3.58), 323.24 (3.59) nm. 1H NMR (CDCl3,
product was obtained from 1 in iPrOH (80 mL) and 2q in iPrOH
(30 mL). Yield: 1.93 g (72%), colourless rods (iPrOH), m.p. 333 °C.
IR (KBr): ν˜ ϭ 3190 (m), 3146 (m), 3117 (m), 1633 (s), 1620 (s),
300 MHz): δ ϭ 2.8 (s, 3 H, SCH3), 4.1 (s, 3 H, CN-CH3), 7.28Ϫ8.39
(m, 4 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.4, 18.7,
115.0, 115.4, 123.7, 127.3, 127.4, 132.5, 143.4, 149.3, 151.3,
1530 (s), 1509 (s), 1429 (m), 1316 (s), 1300 (s), 1181 (m), 1131 (m), 157.1 ppm. MS: m/z ϭ 255 (48) [Mϩ], 215 (19), 102 (5), 57 (10), 32
755 (s) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 233.76 (4.14), 231.11 (25), 28 (100). C12H9N5S (255.3): calcd. C 56.45, H 3.55, N 27.43;
(4.15), 259.51 (4.48), 278.46 (4.37), 297.37 (4.45), 341.21 (3.86) nm.
1H NMR ([D6]DMSO, 300 MHz): δ ϭ 6.77Ϫ8.29 (m, 7 H, ArH,
furfuryl), 14.02 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 112.3, 112.7, 113.2, 116.8, 124.5, 125.9, 133.7, 137.0,
145.0, 146.0, 149.7, 156.8, 166.7 ppm. MS: m/z ϭ 268 (100) [Mϩ],
240 (24), 210 (25), 120 (12), 107 (21). C13H8N4OS (268.29): calcd.
C 58.20; H. 3.01, N 20.88; found C 58.21, H 2.89, N 20.61.
found C 56.69, H 3.41, N 27.70.
2-Benzyl-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline
(4e):
Yield: 1.13 g (74%), colourless needles (EtOH), m.p. 130 °C. IR
(KBr): ν˜ ϭ 2923 (w), 1622 (m), 1589 (s), 1504 (s), 1487 (s), 1460
(m), 1372 (s), 1308 (m), 1275 (m), 1149 (w), 1087 (m), 965 (m), 768
(m) cmϪ1. UV (DMF): λmax (lgε) ϭ 265.60 (4.09), 280.54 (4.06),
309.71 (3.58), 323.76 (3.62) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ
2.81 (s, 3 H, CH3), 4.35 (s, 2 H, CH2), 7.24Ϫ8.43 (m, 9 H, ArH)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.4, 35.1, 115.8, 123.8,
General Procedure for the Preparation of the 5-Methylsulfanyl-1,2,4-
triazolo[1,5-c]quinazolines (4a؊4q): Compounds 3a؊3q (5 mmol)
were dissolved in aqueous sodium hydroxide (0.02  60 mL). 126.7, 126.9, 127.2, 128.6, 129.0, 131.9, 137.2, 143.5, 149.4,
Methyl iodide (1.00 g. 7.00 mmol) was added dropwise, and the
mixture was heated to 60 °C over a period of 5 minutes. The colour-
less precipitate formed on cooling was filtered off, washed with
water, and recrystallized from ethanol.
166.0 ppm. MS: m/z ϭ 306 (100) [Mϩ], 305 (12), 259 (30), 215 (58),
189 (12), 91 (23). C17H14N4S (306.39): calcd. C 66.64, H 4.61, N
18.29; found C 66.47, H 4.48, N 18.32.
5-Methylsulfanyl-2-phenoxymethyl-1,2,4-triazolo[1,5-c]quinazoline
(4f): Yield: 1.40 g (87%), colourless prisms (EtOH), m.p. 163 °C.
IR (KBr): ν˜ ϭ 2931 (w), 1620 (m), 1597 (m), 1588 (s), 1496 (s),
1461 (m), 1364 (m), 1309 (m), 1238 (s), 1224 (s), 1088 (m), 1033
5-Methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline (4a): Yield: 1.07 g
(99%), colourless rods (EtOH), m.p. 135 °C. IR (KBr): ν˜ ϭ 3015
(w), 2927 (w), 1620 (s), 1589 (s), 1505 (s), 1463 (s), 1380 (s), 1310
(s), 1276 (m), 1198 (m), 1166 (m), 1075 (s) cmϪ1. UV (iPrOH): λmax (m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 223.49 (4.60), 249.53 (4.61),
(lgε) ϭ 220.92 (4.58), 248.47 (4.46), 279.52 (4.11), 308.07 (3.51), 270.00 (4.13), 277.15 (4.16), 309.02 (3.65), 323.06 (3.65) nm. 1H
1
322.07 (3.58) nm. H NMR (CDCl3, 300 MHz): δ ϭ 2.79 (s, 3 H,
NMR (CDCl3, 300 MHz): δ ϭ 2.83 (s, 3 H, SCH3), 5.41 (s, 2 H,
SCH3), 7.30Ϫ7.87 (m, 4 H, ArH), 8.39 (s, 1 H, C2-H) ppm. 13C OCH2), 7.28Ϫ8.51 (m, 9 H, ArH) ppm. 13C NMR (CDCl3,
NMR (CDCl3, 75 MHz): δ ϭ 13.4, 115.9, 123.5, 127.0, 127.1, 75 MHz): δ ϭ 13.4, 25.3, 63.5, 90.1, 115.0, 115.8, 121.4, 123.9,
131.9, 143.3, 149.6, 150.1, 154.4 ppm. MS: m/z ϭ 216 (100) [Mϩ], 127.2, 127.3, 129.5, 132.3, 143.5, 149.6, 151.2, 158.3, 162.6 ppm.
215 (33), 189 (34), 145 (24), 114 (19), 102 (17). C10H8N4S (216.26):
calcd. C 55.54, H 3.73, N 25.91; found C 55.83, H 3.72, N 25.88.
MS: m/z ϭ 322 (87) [Mϩ], 230 (31), 229 (100), 188 (33), 186 (39),
160 (13). C17H14N4OS (322.40): calcd. C 63.34, H 4.38, N 17.38;
found C 63.27, H 4.18, N 17.13.
2-Methyl-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline
(4b):
Yield: 1.02 g (91%), colourless needles (EtOH), m.p. 151 °C. IR
5-Methylsulfanyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline
(4g):
(KBr): ν˜ ϭ 3005 (w), 2929 (w), 1624 (m), 1592 (s), 1559 (m), 1516 Yield: 1.40 g (96%), colourless rods (EtOH), m.p. 170 °C. IR (KBr):
(s), 1509 (s), 1491 (s), 1468 (m), 1369 (m), 1303 (s) cmϪ1. UV (iP-
rOH): λmax (lgε) ϭ 223.09 (4.47), 248.99 (4.57), 278.60 (4.08),
ν˜ ϭ 1621 (m), 1596 (s), 1585 (m), 1521 (m), 1499 (s), 1476 (s), 1444
(s), 1366 (s), 1317 (m), 1131 (m), 1069 (m), 964 (m) cmϪ1. UV
285.92 (4.05), 309.12 (3.59), 323.09 (3.63) nm. 1H NMR (CDCl3, (iPrOH): λmax (lgε) ϭ 211.64 (4.37), 252.51 (4.70), 258.58 (4.73),
1
300 MHz): δ ϭ 2.69 (s, 3 H, CH3), 2.81 (s, 3 H, SCH3), 7.55Ϫ8.41 311.67 (3.82), 325.92 (3.67) nm. H NMR ([D6]DMSO, 300 MHz):
(m, 4 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.4, 14.6, δ ϭ 2.81 (s, 3 H, S-CH3), 7.60Ϫ8.30 (m, 9 H, ArH) ppm. 13C NMR
115.7, 123.6, 127.0, 127.3, 131.9, 143.5, 149.2, 150.7, 163.9 ppm. ([D6]DMSO, 75 MHz): δ ϭ 12.9, 115.4, 123.4, 127.0, 127.3, 129.0,
MS: m/z ϭ 230 (100) [Mϩ], 229 (22), 189 (62), 188 (38), 184 (30), 129.5, 130.7, 132.4, 142.8, 149.5, 150.6, 156.4, 162.9, 180.6,
145 (29), 114 (23). C11H10N4S (230.29): calcd. C 57.37, H 4.38, N
24.33; found C 57.42, H 4.51, N 24.17.
238.1 ppm. MS: m/z ϭ 292 (100) [Mϩ], 291 (20), 245 (24), 189 (34),
188 (13), 145 (15), 118 (9). C16H12N4S (292.35): calcd. C 65.73, H
4.14, N 19.16; found C 65.82, H 4.47, N 19.03.
5-Methylsulfanyl-2-pentadecanyl-1,2,4-triazolo[1,5-c]quinazoline
(4c): Yield: 1.98 g (93%), colourless rods (EtOH), m.p. 85 °C. IR
5-Methylsulfanyl-2-tolyl-1,2,4-triazolo[1,5-c]quinazoline (4h): Yield:
(KBr): ν˜ ϭ 2949 (m), 2917 (s), 2850 (s), 1623 (m), 1592 (m), 1509 1.27 g (83%), colourless prisms (EtOH), m.p. 194 °C. IR (KBr):
(s), 1492 (m), 1472 (m), 1372 (m), 1316 (m), 1088 (m) cmϪ1. UV ν˜ ϭ 2925 (w), 1616 (s), 1591 (s), 1573 (m), 1557 (m), 1497 (s), 1477
(iPrOH): λmax (lgε) ϭ 224.13 (4.45), 248.96 (4.62), 278.90 (4.08),
309.14 (3.59), 323.09 (3.64) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ (iPrOH): λmax (lgε) ϭ 217.59 (4.38), 261.09 (4.72), 271.30 (4.66),
(s), 1446 (s), 1364 (s), 1313 (m), 1130 (m), 1072 (m) cmϪ1. UV
186
Eur. J. Org. Chem. 2003, 182Ϫ189

Domino Cyclization of 2-Isothiocyanatobenzonitrile with Carboxylic Hydrazides
FULL PAPER
312.60 (3.62), 326.13 (3.47) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ SCH3), 7.67Ϫ8.59 (m,8 H, ArH) ppm. 13C NMR (CDCl3,
1.22 (s, 3 H, CH3), 2.83 (s, 3 H, SCH3), 7.61Ϫ8.54 (m, 8 H, ArH) 75 MHz): δ ϭ 13.5, 25.4, 115.8, 123.9, 124.0, 127.3, 127.5, 128.5,
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.4, 21.6, 25.4, 116.0, 132.4, 136.2, 143.6, 149.1, 149.7, 151.4, 162.0 ppm. MS: m/z ϭ 337
123.9, 126.9, 127.2, 127.3, 127.6, 129.4, 131.9, 140.7, 143.5, 149.7,
(100) [Mϩ], 336 (14), 290 (12), 189 (37), 188 (21), 145 (15).
151.0, 164.3 ppm. MS: m/z ϭ 306 (100) [Mϩ], 305 (18), 259 (26), C16H11O2N5S (337.36): calcd. C 56.97, H 3.29, N 20.76; found C
189 (45), 188 (17), 145 (18). C17H14N4S (306.37): calcd. C 66.64, H
4.61, N 18.29; found C 66.48, H 4.67, N 17.96.
56.68, H 3.03, N 20.47.
5-Methylsulfanyl-2-(2-pyridyl)-1,2,4-triazolo[1,5-c]quinazoline (4n):
Yield: 1.22 g (83%), colourless rods (EtOH), m.p. 226 °C. IR (KBr):
ν˜ ϭ 1620 (m), 1592 (s), 1499 (s), 1475 (m), 1461 (m), 1420 (s), 1365
(s), 1309 (m), 1275 (m), 1158 (m), 1075 (m), 964 (s) cmϪ1. UV
(iPrOH): λmax (lgε) ϭ 239.50 (4.60), 249.33 (4.60), 275.17 (4.43),
2-(4-Bromophenyl)-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline
(4i): Yield: 1.61 g (87%), colourless prisms (EtOH), m.p. 204 °C.
IR (KBr): ν˜ ϭ 1623 (m), 1591 (s), 1572 (m), 1561 (m), 1500 (s),
1476 (m), 1459 (m), 1441 (s), 1367 (m), 1308 (m), 1274 (m), 1131
(m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 217.65 (4.32), 261.96 (4.75),
273.52 (4.68), 326.20 (3.45) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ
2.82 (s, 3 H, SCH3), 7.61Ϫ8.50 (m, 8 H, ArH) ppm. 13C NMR
(CDCl3, 75 MHz): δ ϭ 13.4, 115.9, 123.8, 125.0, 127.0, 127.3,
129.1, 129.2, 131.9, 132.1, 143.5, 149.6, 151.1, 163.3 ppm. MS: m/z
ϭ 372 (100) [Mϩ], 370 (67), 325 (17), 323 (15), 189 (68), 188 (27),
145 (29), 102 (39). C16H11BrN4S (371.26): calcd. C 51.76, H 2.99,
N 15.09; found C 51.90, H 2.96, N 15.13.
1
325.94 (3.64) nm. H NMR (CDCl3, 300 MHz): δ ϭ 2.85 (s, 3 H,
SCH3), 7.41Ϫ8.88 (m, 8 H, ArH, pyridyl) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 13.5, 116.1, 123.2, 124.2, 124.9, 127.2, 128.8, 130.1,
132.2, 136.9, 143.6, 149.0, 150.3, 151.4, 163.4 ppm. MS: m/z ϭ 293
(100) [Mϩ], 260 (50), 218 (10), 189 (12), 145 (17), 143 (14), 105
(28). C15H11N5S (293.35): calcd. C 61.42, H 3.78, N 23.87; found
C 61.63, H 3.64, N 23.93.
5-Methylsulfanyl-2-(3-pyridyl)-1,2,4-triazolo[1,5-c]quinazoline (4o):
Yield: 1.08 g (74%), colourless needles (EtOH), m.p. 209 °C. IR
(KBr): ν˜ ϭ 1620 (m), 1589 (s), 1573 (s), 1561 (s), 1498 (s), 1475
2-(4-Chlorophenyl)-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline
(4j): Yield: 1.55 g (95%), colourless needles (EtOH), m.p. 400 °C.
IR (KBr): ν˜ ϭ 2926 (w), 1623 (m), 1593 (m), 1572 (m), 1503 (s),
1476 (m), 1442 (s), 1362 (m), 1309 (m), 1130 (m), 1087 (m), 1072
(m), 969 (m), 746 (s) cmϪ1. UV (DMF): λmax (lgε) ϭ 266.78 (4.50),
(m), 1443 (m), 1363 (s), 1294 (m), 1139 (m), 1174 (m), 769 (s) cmϪ1
.
UV (iPrOH): λmax (lgε) ϭ 255.08 (4.66), 311.42 (3.71), 326.16
1
(3.55) nm. H NMR (CDCl3, 300 MHz): δ ϭ 2.83 (s, 3 H, SCH3),
1
336.11 (4.03) nm. H NMR ([D6]DMSO, 300 MHz): δ ϭ 2.82 (s, 3
7.44Ϫ9.59 (m, 8 H, ArH, pyridyl) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 13.4, 115.8, 123.5, 123.9, 126.3, 127.1, 127.4, 132.2,
134.9, 143.5, 149.0, 149.7, 151.2, 151.3, 161.9 ppm. MS: m/z ϭ 293
(100) [Mϩ], 292 (18), 260 (17), 246 (21), 189 (835), 188 (18), 145
(18). C15H11N5S (293.35): calcd. C 61.42, H 3.78, N 23.87; found
C 61.63, H 3.79, N 23.94.
H, SCH3), 7.29Ϫ8.27 (m, 8 H, ArH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ ϭ 114.0, 122.3, 122.9, 124.3, 128.3, 128.8, 129.2, 130.0,
131.0, 134.1, 144.4, 149.9, 159.5, 165.9 ppm. MS: m/z ϭ 326 (100)
[Mϩ], 325 (14), 279 (21), 189 (52), 188 (18), 145 (17), 102 (14).
C16H11ClN4S (326.80): calcd. C 58.80, H 3.39, N 17.15; found C
58.53, H 3.28, N 17.27.
5-Methylsulfanyl-2-(4-pyridyl)-1,2,4-triazolo[1,5-c]quinazolo (4p):
Yield: 1.16 g (79%), colourless rods (EtOH), m.p. 69 °C. IR (KBr):
ν˜ ϭ 1620 (s), 1606 (m), 1593 (s), 1519 (m), 1497 (s), 1476 (s), 1448
(m), 1418 (m), 1366 (s), 1355 (m), 1293 (m), 996 (s) cmϪ1. UV
(iPrOH): λmax (lgε) ϭ 234.95 (4.53), 244.37 (4.52), 252.99 (4.54),
258.44 (4.55), 311.64 (3.71), 326.48 (3.52) nm. 1H NMR (CDCl3,
300 MHz): δ ϭ 2.83 (s, 3 H, SCH3), 7.63Ϫ8.80 (m, 8 H, ArH,
pyridyl) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.4, 115.8, 121.6,
123.8, 127.2, 127.4, 132.3, 137.6, 143.5, 149.7, 150.5, 151.3,
161.9 ppm. MS: m/z ϭ 293 (100) [Mϩ], 292 (19), 246 (13), 189 (42),
188 (21), 145 (22). C15H11N5S (293.35): calcd. C 61.42, H 3.78, N
23.87; found C 61.27, H 3.83, N 23.69.
2-(2,4-Dichlorophenyl)-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quina-
zoline (4k): Yield: 1.43 g (79%), colourless needles (EtOH), m.p.
227 °C. IR (KBr): ν˜ ϭ 1621 (m), 1593 (s), 1500 (s), 1473 (m), 1459
(m), 1442 (m), 1363 (m), 1301 (m), 1104 (m), 1047 (m), 965 (m),
765 (m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 222.70 (4.58), 253.72
(4.70), 324.69 (3.55) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ 2.84 (s,
3 H, SCH3), 7.39Ϫ8.54 (m, 7 H, ArH) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 13.43, 115.9, 123.9, 127.2, 127.4, 128.0, 130.7, 132.2,
133.0, 134.4, 136.4, 143.6, 150.5, 161.9, 165.3 ppm. MS: m/z ϭ 361
(24) [Mϩ], 360 (100), 327 (36), 325 (96), 315 (26), 313 (32), 294
(22), 292 (63), 189 (57), 146 (33). C16H10Cl2N4S (361.26): calcd. C
53.19, H 2.79, N 15.51; found C 53.06, H 2.87, N 15.48.
2-(2-Furyl)-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quinazoline
(4q):
2-(3,5-Dichlorophenyl)-5-methylsulfanyl-1,2,4-triazolo[1,5-c]quina-
zoline (4l): Yield: 1.37 g (76%), colourless needles (EtOH), m.p. 245
°C. IR (KBr): ν˜ ϭ 2931 (w), 1620 (m), 1594 (s), 1503 (s), 1432 (m),
1397 (s), 1365 (m), 1357 (m), 1301 (m), 1078 (m), 966 (m), 801 (m)
cmϪ1. UV (iPrOH): λmax (lgε) ϭ 222.20 (4.59), 235.08 (4.59),
259.56 (4.70), 311.75 (3.73), 326.65 (3.48) nm. 1H NMR (CDCl3,
300 MHz): δ ϭ 2.85 (s, 3 H, SCH3), 7.47Ϫ8.53 (m, 7 H, ArH) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 13.5, 115.8, 123.8, 126.0, 127.2,
127.4, 130.3, 132.3, 133.1, 135.5, 143.6, 149.7, 151.3, 161.8 ppm.
MS: m/z ϭ 361 (30) [Mϩ], 360 (90), 315 (21), 313 (22), 189 (100),
188 (37), 145 (27). C16H10Cl2N4S (361.26): calcd. C 53.20, H 2.79,
N 15.51; found C 53.32, H 2.68, N 15.63.
Yield: 1.16 g (82%), colourless needles (EtOH), m.p. 194 °C. IR
(KBr): ν˜ ϭ 1616 (s), 1589 (s), 1556 (m), 1510 (s), 1499 (s), 1474
(m), 1429 (s), 1362 (s), 1306 (s), 1078 (s), 964 (s), 753 (s) cmϪ1. UV
(DMF): λmax (lgε) ϭ 277.99 (4.63), 327.33 (3.39) nm. 1H NMR
([D6]DMSO, 300 MHz): δ ϭ 2.81 (s, 3 H, SCH3), 6.77Ϫ8.45 (m, 7
H, ArH, furfuryl) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ ϭ
13.3, 112.7, 113.3, 115.5, 123.8, 127.4, 127.9, 133.1, 143.3, 145.1,
145.9, 149.9, 150.8, 156.1 ppm. MS: m/z ϭ 282 (Mϩ,100), 265 (51),
254 (11), 253 (18), 236 (9), 160 (9), 102 (11). C14H10N4OS (282.32):
calcd. C 59.56, H 3.57, N 19.85; found C 59.86, H 3.57, N 19.67.
General Procedures for the Preparation of the 1,2,4-Triazolo[1,5-
c]quinazolines (5a؊5k)
5-Methylsulfanyl-2-(4-nitrophenyl)-1,2,4-triazolo[1,5-c]quinazoline
(4m): Yield: 1.26 g (75%), colourless needles (EtOH), m.p. 265 °C.
IR (KBr): ν˜ ϭ 1622 (m), 1608 (m), 1590 (m), 1561 (w), 1519 (s), Method A: Compounds 4b, 4g, or 4p (10 mmol) were dissolved at
1502 (s), 1476 (m), 1460 (m), 1419 (m), 1343 (s), 1308 (m), 724 (s) 70 °C in the respective secondary amine (12Ϫ14 mL) and the solu-
cmϪ1. UV (iPrOH): λmax (lgε) ϭ 242.82 (4.59), 252.90 (4.49),
295.92 (4.48) nm. H NMR (CDCl3, 300 MHz): δ ϭ 2.86 (s, 3 H, the precipitated product was filtered and washed with methanol.
tion was refluxed for 16 hours. After cooling to room temperature,
1
Eur. J. Org. Chem. 2003, 182Ϫ189
187

J. Blank, M. Kandt, W.-D. Pfeiffer, A. Hetzheim, P. Langer
FULL PAPER
Method B: Compounds 3b, 3c, 3g, or 3p (10 mmol) were dissolved
in the respective secondary amine (8 mL) at 80 °C. To the solution
was added hydrogen peroxide (30%, 5 mL). After cooling the pre-
cipitate was filtered, washed with water and recrystallized from
methanol or ethanol.
°C. IR (KBr): ν˜ ϭ 3035 (w), 2937 (m), 2929 (m), 2853 (m), 1620
(s), 1600 (s), 1563 (s), 1524 (s), 1502 (m), 1473 (m), 1463 (s), 1410
(m), 1382 (s), 1302 (s), 1237 (s) cmϪ1. UV (EtOH): λmax (lgε) ϭ
222.17 (4.44), 246.41 (4.58), 253.29 (4.53), 287.57 (4.21), 326.10
1
(3.57) nm. H NMR (CDCl3, 300 MHz): δ ϭ 1.70Ϫ1.84 (m, 6 H,
CH2), 2.65 (s, 3 H, CH3), 3.92Ϫ3.96 (t, 4 H, N-CH2), 7.36Ϫ8.33
(m, 4 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.6, 24.7,
25.6, 49.1, 114.6, 123.4, 124.4, 126.1, 131.8, 144.1, 145.4, 153.9,
162.4 ppm. MS: m/z ϭ 267 (100) [Mϩ], 266 (32), 252 (17), 238 (24),
226 (34), 225 (10), 799 (18), 198 (21). C15H17N5 (267.33): calcd. C
67.39, H 6.41, N 26.20; found C 67.45, H 6.52, N 26.31.
2-Methyl-5-morpholino-1,2,4-triazolo[1,5-c]quinazoline (5a): Yield
A: 2.32 g (86%), B: 2.29 g (85%), colourless prisms (MeOH), m.p.
126Ϫ127 °C. IR (KBr): ν˜ ϭ 3021 (w), 2958 (m), 2856 (m), 1621
(s), 1602 (s), 1562 (s), 1526 (s), 1503 (m), 1474 (m), 1465 (m), 1446
(s), 1309 (m), 1253 (s), 1200 (s), 1177 (s) cmϪ1. UV (EtOH): λmax
(lgε) ϭ 221.43 (4.42), 245.42 (4.59), 276.74 (4.15), 285.16 (4.16),
1
324.74 (3.62) nm. H NMR (CDCl3, 300 MHz): δ ϭ 2.64 (s, 3 H,
2-Phenyl-5-piperidino-1,2,4-triazolo[1,5-c]quinazoline (5f): Yield A:
2.83 g (86%), B: 2.73 g (83%), colourless needles (EtOH), m.p.
129.5 °C. IR (KBr): ν˜ ϭ 2935 (m), 2849 (m), 1625 (s), 1583 (m),
1564 (s), 1530 (s), 1484 (m), 1463 (m), 1444 (s), 1407 (m), 1381 (m),
1329 (m), 1303 (m), 1230 (m), 1194 (m) cmϪ1. UV (EtOH): λmax
(lgε) ϭ 254.15 (4.70) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ
1.77Ϫ1.87 (m, 6 H, CH2), 4.02Ϫ4.05 (t, 4 H, NH2), 7.41Ϫ8.43 (m,
9 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 2.47, 25.7, 49.2,
114.9, 123.8, 124.3, 126.1, 127.5, 128.7, 130.2, 130.5, 131.9, 144.2,
145.5, 154.3, 162.8 ppm. MS: m/z ϭ 329 (100) [Mϩ], 300 (14), 273
(16), 247 (15), 245 (25), 226 (36), 118 (24). C20H19N5 (329.39):
calcd. C 72.92, H 5.82, N 21.26; found C 73.20, H 6.29, N 21.23.
CH3), 3.92Ϫ3.96 (m, 4 H, N-CH2), 4.01Ϫ4.05 (m, 4 H, OCH2),
7.41Ϫ8.33 (m, 4 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
14.5, 48.2, 66.6, 114.7, 123.4, 124.9, 126.2, 131.9, 143.7, 144.7,
153.8, 162.6 ppm. MS: m/z ϭ 269 (100) [Mϩ], 268 (46), 239 (22),
238 (30), 224 (54), 212 (61), 199 (23), 185 (25). C14H15N5O (269.31):
calcd. C 62.44, H 5.61, N 26.01; found C 62.51, H 5.65, N 26.28.
5-Morpholino-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline (5b): Yield
A: 2.45 g (74%), B: 2.42 g (73%), colourless prisms (EtOH), m.p.
182 °C. IR (KBr): ν˜ ϭ 3060 (w), 2959 (w), 2901 (w), 2860 (m),
1625 (s), 1604 (s), 1528 (s), 1443 (s), 1399 (s), 1377 (m), 1333 (m),
1202 (s), 1119 (s), 1002 (s) cmϪ1. UV (EtOH): λmax (lgε) ϭ 252.78
(4.68), 326.27 (3.56) nm. 1H NMR ([D6]DMSO, 300 MHz): δ ϭ
3.86Ϫ3.89 (t, 4 H, N-CH2), 4.04Ϫ4.07 (t, 4 H, O-CH2), 7.54Ϫ8.38
(m, 9 H, Ar-H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ ϭ 47.9,
65.7, 114.3, 123.3, 124.8, 125.9, 126.9, 128.9, 129.7, 130.5, 132.3,
143.3, 144.6, 153.6, 161.7, 178.0 ppm. MS: m/z ϭ 331 (100) [Mϩ],
330 (44), 301 (20), 300 (24), 288 (19), 286 (36), 274 (42), 245 (52).
C19H17N5O (331.38): calcd. C 68.87, H 5.17, N 21.13; found C
69.15, H 5.42, N 21.18.
5-Piperidino-2-(4-pyridyl)-1,2,4-triazolo[1,5-c]quinazoline
(5g):
Yield A: 2.41 g (73%), B: 2.21 g (67%), colourless prisms (EtOH),
m.p.163Ϫ164 °C. IR (KBr): ν˜ ϭ 2975 (m), 2945 (m), 2873 (m),
1623 (s), 1605 (s), 1567 (s), 1538 (s), 1510 (m), 1502 (m), 1479 (s),
1456 (m), 1430 (s), 1343 (s), 1268 (m) cmϪ1. UV (EtOH): λmax
(lgε) ϭ 219.93 (4.42), 245.60 (4.64), 253.07 (4.64), 279.51 (4.28),
288.19 (4.33), 333.61 (3.72) nm. 1H NMR ([D6]DMSO, 300 MHz):
δ ϭ 1.25Ϫ2.34 (m, 6 H, CH2), 4.00Ϫ4.03 (t, 4 H, N-CH2),
7.42Ϫ8.79 (m, 8 H, ArH, pyridyl) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 24.7, 25.7, 49.2, 114.7, 121.4, 123.7, 124.6, 126.2,
132.2, 140.0, 144.2, 145.2, 150.4, 154.6, 160.6 ppm. MS: m/z ϭ 330
(100) [Mϩ], 329 (34), 301 (19), 274 (12), 248 (19), 226 (28), 118
(24). C19H18N6 (330.38): calcd. C 69.07, H 5.49, N 25.44; found C
68.57, H 6.01, N 25.82.
5-Morpholino-2-(4-pyridyl)-1,2,4-triazolo[1,5-c]quinazoline
(5c):
Yield A: 3.0 g (90%), B: 1.13 g (34%), colourless prisms (EtOH),
m.p. 217 °C. IR (KBr): ν˜ ϭ 2966 (w), 2912 (w), 2859 (w), 1625 (s),
1605 (s), 1567 (m), 1527 (s), 1448 (m), 1416 (m), 1371 (m), 1262
(m), 1202 (m), 1119 (s), 1003 (m) cmϪ1. UV (EtOH): λmax (lgε) ϭ
245.01 (4.69), 330.00 (3.66) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ
3.97Ϫ4.00 (t, 4 H, N-CH2), 4.10Ϫ4.13 (m, 4 H, O-CH2), 7.48Ϫ8.80
(m, 8 H, ArH, pyridyl) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
48.4, 66.6, 114.9, 121.4, 123.8, 125.2, 126.4, 132.4, 137.8, 144.6,
150.5, 154.6, 160.9, 182.3 ppm. MS: m/z ϭ 332 (100) [Mϩ], 331
(31), 301 (17), 288 (33), 275 (45), 247 (20), 246 (17). C18H16N6O
(332.37): calcd. C 65.05, H 4.85, N 25.29; found C 65.19, H 5.06,
N 25.17.
2-Pentadecanyl-5-piperidino-1,2,4-triazolo[1,5-c]quinazoline
(5h):
Yield A: 4.50 g (97%), B: 4.41 g (95%), colourless rods (EtOH),
m.p. 68 °C. IR (KBr): ν˜ ϭ 2918 (s), 2850 (s), 1622 (m), 1600 (s),
1566 (s), 1529 (s), 1467 (m), 1415 (m), 1385 (m), 1337 (m), 1304
(m), 1234 (m), 1134 (m) cmϪ1. UV (EtOH): λmax (lgε) ϭ 246.63
(4.55), 252.93 (4.50), 287.77 (4.16), 325.92 (3.46) nm. 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.85Ϫ0.90 (t, 3 H, CH3), 1.20Ϫ1.89 (m,
32 H, CH2), 2.92Ϫ2.97 (t, 2 H, CH2), 3.94Ϫ3.98 (t, 4 H,N-CH2),
7.38Ϫ8.35 (m, 4 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
14.1, 22.7, 24.7, 25.4, 25.6, 27.4, 28.3, 28.9, 29.3, 29.4, 29.5, 29.6,
29.7, 31.9, 49.1, 114.7, 123.5, 124.2, 126.1, 131.7, 144.1, 145.5,
153.8, 166.2 ppm. MS: m/z ϭ 463 (100) [Mϩ], 322 (11), 280 (24),
267 (46), 266 (16). C29H45N6 (463.69): calcd. C 75.11, H 9.78, N
15.11; found C 75.14, H 9.42, N 14.89.
5-Morpholino-2-pentadecanyl-1,2,4-triazolo[1,5-c]quinazoline (5d):
Yield A: 4.20 g (90%), B: 4.47 g (96%), colourless prisms (EtOH),
m.p. 85 °C. IR (KBr): ν˜ ϭ 3228 (w), 2953 (m), 2922 (s), 2850 (s),
1627 (m), 1604 (s), 1566 (m), 1530 (s), 1466 (m), 1404 (m), 1378
(m), 1335 (m) cmϪ1. UV (iPrOH): λmax (lgε) ϭ 223.37 (4.45),
245.14 (4.54), 277.18 (4.12), 324.09 (3.59) nm. 1H NMR (CDCl3,
300 MHz): δ ϭ 0.85Ϫ0.90 (t, 3 H,CH3), 1.21Ϫ1.91 (m, 26 H, CH2),
2.92Ϫ2.97 (t, 2 H, CH2), 3.93Ϫ3.96 (m, 4 H, N-CH2), 4.05Ϫ4.08
(m, 4H; CH2), 7.40Ϫ8.38 (m, 4 H, ArH) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 14.1, 22.7, 28.3, 28.9, 29.4, 29.5, 29.6, 29.7, 29.7,
31.9, 48.2, 66.6, 112.5, 114.9, 123.6, 124.9, 125.2, 125.9, 126.3,
131.9, 135.7, 143.7, 144.9, 153.8, 166.5 ppm. MS: m/z ϭ 465 (100)
[Mϩ], 424 (14), 408 (19), 338 (11), 324 (17), 282 (42), 269 (86).
C28H43N5O (465.66): calcd. C 72.22, H 9.31, N 15.04; found C
71.90, H 8.98, N 14.91.
2-Methyl-5-pyrrolidino-1,2,4-triazolo[1,5-c]quinazoline (5i): Yield A:
2.25 g (89%), B: 2.18 g (86%), colourless prisms (MeOH), m.p.
166Ϫ167 °C. IR (KBr): ν˜ ϭ 2965 (m), 2952 (m), 2870 (m), 1626
(s), 1605 (s), 1568 (s), 1538 (s), 1504 (m), 1476 (s), 1459 (s), 1441
(m), 1420 (m), 1342 (s), 1315 (m), 1297 (m) cmϪ1. UV (EtOH):
λmax (lgε) ϭ 218.78 (4.40), 245.55 (4.60), 253.04 (4.60), 279.29
(4.23), 287.90 (4.28), 333.44 (3.65) nm. 1H NMR (CDCl3,
300 MHz): δ ϭ 1.98Ϫ2.03 (m, 4 H, CH2), 2.58 (s, 3 H, CH3),
4.04Ϫ4.09 (m, 4 H, N-CH2), 7.23Ϫ8.24 (m, 4 H, ArH) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ 14.5, 25.5, 50.1, 113.6, 123.0, 123.4,
2-Methyl-5-piperidino-1,2,4-triazolo[1,5-c]quinazoline (5e): Yield A:
2.46 g (92%), B: 2.35 g (88%), colourless rods (MeOH), m.p. 130
188
Eur. J. Org. Chem. 2003, 182Ϫ189

Domino Cyclization of 2-Isothiocyanatobenzonitrile with Carboxylic Hydrazides
FULL PAPER
[4]
J. E. Francis, W. D. Cash, W. D. Barbaz, P. S. Bernard, R. A.
Lovell, G. C. Mazzenga, R. C. Friedmann, J. L. Hyun, A. F.
Braunwalder, P. S. Loo, D. A. Bennett, J. Med. Chem. 1991,
34, 281.
J. Francis, K. O. Gelotte, Chem. Abstr. 1986, 105, 153069.
F. Kathawala, G. E. Hardtmann, Ger. Offen. 2,146,076
(1972), Chem. Abstr. 1972, 77, 48501.
Hardtmann, Ger. Offen. 2,261,095 (1971), Chem. Abstr. 1973,
79, 66385. [6c] M. M. Gineinah, A. M. Ismaiel, M. M. El-Kerd-
awy, J. Het. Chem. 1990, 27, 723.
K. Spirkova, S. Stankovsky, J. Hornacek, Chem. Papers 1993,
47, 382.
K. T. Potts, E. G. Brugel, J. Org. Chem. 1970, 35, 3448.
For related rearrangements, see:
Beilfuß, D. M. Burness, G. A. Reynolds, J. F. Trinker, J. A. van
Allan, J. Org. Chem. 1959, 24, 787.
125.3, 131.8, 143.5, 145.2, 153.8, 162.0 ppm. MS: m/z ϭ 253 (100)
[Mϩ], 252 (27), 238 (18), 225 (60), 224 (34), 184 (56). C14H15N5
(253.31): calcd. C 66.38, H 5.97, N 27.65; found C 66.51, H 6.01,
N 27.53.
[5]
[6] [6a]
2-Phenyl-5-pyrrolidino-1,2,4-triazolo[1,5-c]quinazoline (5j): Yield A:
3.00 g (95%), B: 3.06 g (97%), colourless prisms (EtOH), m.p. 182
°C. IR (KBr): ν˜ ϭ 3062 (w), 3041 (s), 2969 (w), 2954 (w), 2874 (w),
1624 (s), 1606 (s), 1563 (s), 1530 (s), 1445 (s), 1359 (m), 1295 (m),
1217 (m), 1252 (m), 1070 (s) cmϪ1. UV (iPrOH): λmax (lgε) ϭ
203.58 (4.49), 254.66 (4.71), 333.05 (3.71) nm. 1H NMR (CDCl3,
300 MHz): δ ϭ 1.98Ϫ2.03 (m, 4 H, CH2), 4.08Ϫ4.13 (t, 4 H, N-
CH2), 7.29Ϫ8.34 (m, 9 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 25.5, 50.1, 113.8, 122.9, 123.7, 125.3, 127.3, 128.6, 130.0, 130.6,
131.8, 143.5, 145.3, 154.1, 162.5 ppm. MS: m/z ϭ 315 (100) [Mϩ],
314 (37), 287 (49), 286 (20), 260 (24), 245 (27), 184 (31). C19H17N5
(315.37): calcd. C 72.36, H 5.43, N 22.21; found C 72.31, H 5.83,
N 22.21.
[6b]
F. Kathawala, G. E.
[7]
[8]
[9]
[9a]
C. F. H. Allen, H. R.
[9b]
K. T. Potts, H. R.
Burton, S. K. Roy, J. Org. Chem. 1966, 31, 265.
W. Ried, J. Valentin, Chem. Ber. 1968, 101, 2106.
For reviews of work from our laboratory, see:
Chem. Eur. J. 2001, 7, 3858.
Org. Chem. 2002, 221.
[10]
[11]
[11a]
P. Langer,
[11b]
P. Langer, M. Döring, Eur. J.
P. Langer, Synthesis 2002, 441.
[11c]
2-(4-Pyridyl)-5-pyrrolidino-1,2,4-triazolo[1,5-c]quinazoline
(5k):
[12]
[13]
P. Pazdera, E. Nocacek, D. Ondracek, Chem. Papers 1989,
43, 465.
Yield A: 3.10 g (98%), B: 2.91 g (92%), colourless prisms (EtOH),
m.p. 233 °C. IR (KBr): ν˜ ϭ 2969 (m), 2878 (m), 1623 (s), 1567 (s),
1533 (s), 1481 (s), 1456 (s), 1410 (m), 1343 (m), 1294 (m), 1109 (m),
1011 (w) cmϪ1. UV (EtOH): λmax (lgε) ϭ 249.08 (4.70), 333.38
An isolated example of a related reaction has been reported:
J. Francis, W. D. Cash, S. Psychoyos, G. Ghai, P. Wenk, R. C.
Friedmann, C. Atkins, V. Warren, P. Furness, J. L. Hyun, G. A.
Stone, M. Desai, M. Williams, J. Med. Chem. 1988, 31, 1014.
For a stepwise synthesis of 3 by reaction of 1 with hydrazine
hydrate, see: W.-D. Pfeiffer, A. Hetzheim, P. Pazdera, A.
Bodtke, J. Mücke, J. Het. Chem. 1999, 36, 1327.
For the reaction between hydrazine hydrate and methyl 2-iso-
thiocyanatobenzoate, see: E. Cherbuliez, B. Willhalm, O. Es-
pejo, S. Jaccard, J. Rabinowitz, Helv. Chim. Acta 1967, 50,
2563.
1
(3.73) nm. H NMR (CDCl3, 300 MHz): δ ϭ 2.01Ϫ2.16 (m, 4 H,
CH2), 4.11Ϫ4.15 (m, 4 H, 2N-CH2), 7.27Ϫ8.77 (m, 8 H, ArH, pyri-
dyl) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 25.5, 50.0, 113.7,
121.3, 123.2, 123.7, 125.4, 132.2, 138.1, 143.3, 145.3, 150.4, 154.4,
160.4 ppm. MS: m/z ϭ 316 (100) [Mϩ], 315 (26), 288 (43), 287 (23),
261 (18), 247 (14), 184 (17). C18H16N6 (316.36): calcd. C 68.33, H
5.10, N 26.57; found C 68.11, H 5.30, N 26.65.
[14]
[15]
[16]
Treatment of hydrazides with 2-isocyanatobenzonitrile, the O-
Acknowledgments
P. L. thanks the Deutsche Forschungsgemeinschaft for financial
support (Heisenberg scholarship and Normalverfahren).
analogue of 1, has been reported to give open-chain products:
[16a]
G. Zinner, H. Klein, H. Kahnert, Chem.-Ztg. 1987, 111,
341. [16b] A. Thom, G. Zinner, Arch. Pharm. (Weinheim) 1994,
327, 469.
For the reaction between thioxo-quinazolines and amines, see:
K. Kottke, K. Kühnstedt, G. Griesner, Pharmazie 1983, 38,
367.
Y.-C. Kim, X.-d. Ji, K. A. Jacobson, J. Med. Chem. 1996, 39,
4142.
[17]
[18]
[1]
K. C. Liu, M. K. Hu, Arch. Pharm. (Weinheim) 1986, 319, 188.
K. Kottke, H. Kuehmstedt, I. Graefe, H. Wehlau, D. Knocke,
[2]
DD 253623 (1988), Chem. Abstr. 1988, 109, 17046.
C. Cianci, T. D. Y. Chung, N. Menwell, H. Putz, M. Hagen,
[3]
R. J. Colonno, M. Krystal, Antiviral Chem. Chemother. 1996,
7, 353.
Received July 29, 2002
[O02430]
Eur. J. Org. Chem. 2003, 182Ϫ189
189