Microwave-assisted synthesis of s-triazino[2,1-b][1,3]benzoxazoles, s-triazino[2,1-b][1,3]benzothiazoles, and s-triazino[1,2-a]benzimidazoles

Article abstract of DOI:10.1055/s-2006-926290

2-Amino-4-oxo-derivatives of s-triazino[2,1e][1,3]benzoxazoles, s-triazino[2,1,b][1,3]benzothiazoles, and s-triazino[1,2-a]benzimidazoles were synthesized by carbonylation of 2-benz-oxazolylguanidines, 2- benzothiazolylguanidines, and 2-benzimidazolylguanidines with phenyl isocyanate under microwave irradiation (180°C, 15 minutes). Using phenyl isothiocyanate instead of phenyl isocyanate under the same conditions led to the successful ring closure via thiocarbonylation of 2-benzoxazolylguanidines. However, the formation of 2-imino-4-phenylimino-s-triazino[2,1-b][1,3]benzothiazoles from 2-benzothiazolylguanidines was observed instead under microwave irradiation conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926290

PAPER
597
Microwave-Assisted Synthesis of s-Triazino[2,1-b][1,3]benzoxazoles,
s-Triazino[2,1-b][1,3]benzothiazoles, and s-Triazino[1,2-a]benzimidazoles1
M
icrowave-Assist
n
e
d
Synthesis
t
of
F
use
o
d
s
-Triazine
n
s
V. Dolzhenko,a Wai-Keung Chui,*a Anna V. Dolzhenkob
a
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
Perm State Pharmaceutical Academy, 48 Lenin Street, Perm 614990, Russian Federation
Fax +6567791554; E-mail: phacwk@nus.edu.sg
b
Received 10 March 2005; revised 27 September 2005
Dedicated to Professor B. Ya. Syropyatov on the occasion of his 65th birthday
tosyl isocyanate and phenyl isothiocyanate in dioxane,12
by modifying the previously reported procedures and then
extending this methodology to the synthesis of s-triazi-
no[1,2-a]benzimidazoles.
Abstract: 2-Amino-4-oxo-derivatives of s-triazino[2,1-b][1,3]benz-
oxazoles, s-triazino[2,1-b][1,3]benzothiazoles, and s-triazino[1,2-
a]benzimidazoles were synthesized by carbonylation of 2-benz-
oxazolylguanidines, 2-benzothiazolylguanidines, and 2-benzimida-
zolylguanidines with phenyl isocyanate under microwave
irradiation (180 °C, 15 minutes). Using phenyl isothiocyanate in-
stead of phenyl isocyanate under the same conditions led to the
successful ring closure via thiocarbonylation of 2-benz-
oxazolylguanidines. However, the formation of 2-imino-4-
phenylimino-s-triazino[2,1-b][1,3]benzothiazoles from 2-benzo-
thiazolylguanidines was observed instead under microwave irradi-
ation conditions.
2-Benzoxazolylguanidines 2a–c were prepared from the
corresponding 2-aminophenols 1a–c by cyclocondensa-
tion with cyanoguanidine by the known procedure.13
Microwave-assisted reaction of 2a–c with phenyl isocy-
anate as well as phenyl isothiocyanate led to the formation
of 2-amino-4-oxo-s-triazino[2,1-b][1,3]benzoxazole 3a–c
or their 4-thioxo-analogues 3d–f, respectively
(Scheme 1). The reactions proceeded at 180 °C in 1,2-
dimethoxyethane affording compounds 3a–f in high yield
and purity (Table 1).
Key words: carbonylation, microwave irradiation, triazinobenzox-
azoles, triazinobenzothiazoles, triazinobenzimidazoles
Recently the use of microwave-assisted synthesis has
gained popularity in the preparation of new compounds
with potential medicinal value.2 The application of micro-
wave irradiation in the synthesis of heterocyclic com-
pounds, which have wide-ranging biological activities,
have been reviewed recently.3 However, there is no report
on the microwave-assisted synthesis of the titled hetero-
cyclic systems, particularly the 2-amino-4-(thi)oxo-deriv-
atives. We are interested in such heterocyclic systems,1,4
potential inhibitors of the enzyme dihydrofolate reduc-
tase, as they may exhibit antitumor, antibacterial, or anti-
parasitic properties.5
R
NH2
OH
1a–c
NH2
N
1) EtOH, HCl, reflux, 2–4 h;
2) 10% KOH
N
NH
H
H2N
NH
R
N
O
a
b
c
R = H
R = Me
R = Cl
NH
2a–c
2-Amino(imino)-4-oxo-s-triazino[1,2-a]benzimidazoles
have been prepared via two different pathways – an aza-
Wittig-type reaction mechanism starting from 2-ami-
nobenzimidazole,6 or carbonylation and ring closure of 2-
benzimidazolylguanidine.7–12 The syntheses of similar s-
PhNCX
DME, MW 180 °C, 15 min
X
N
X
N
NH
N
NH2
R
NH
R
N
triazino[2,1-b][1,3]benzoxazole
and
s-triazino[2,1-
N
b][1,3]benzothiazole have been reported only via ring-
closure carbonylation of 2-benzoxazolylguanidine or 2-
benzothiazolylguanidine using DEAD10,11 or aryl
isocyanates12 in refluxing solvents.
O
O
3a–f
Scheme 1 For R and X of 3a–f, see Table 1
We attempted to apply microwave irradiation to the syn-
thesis of s-triazino[2,1-b][1,3]benzoxazoles and s-triazi-
no[2,1-b][1,3]benzothiazoles from 2-benzoxazolyl-
guanidine or 2-benzothiazolylguanidine in reactions with
All new compounds 3a–f were fully characterized
(Table 3). The signals at 165.9–166.0 ppm in the 13C
NMR spectra confirmed the presence of the carbonyl
group in 3a–c, while the thiocarbonyl group on the triaz-
ine ring of 3d–f appeared at 1380–1382 cm–1 in the IR
spectra and at 176.6–176.9 ppm in the 13C NMR spectra.
The anisotropic effect of the oxygen (sulfur) atom led to
SYNTHESIS 2006, No. 4, pp 0597–0602
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926290; Art ID: F04905SS
© Georg Thieme Verlag Stuttgart · New York

598
A. V. Dolzhenko et al.
PAPER
Table 1 s-Triazino[2,1-b][1,3]benzoxazoles 3a–f
b][1,3]benzothiazoles 6a–c were prepared in good yields
(Table 2). Similarly to 3a and 3c, compounds 6a–c were
found to exist in DMSO as their imino tautomers. The an-
alytical and spectroscopic data are in agreement with the
proposed structures (Table 3).
Compd
3a
X
O
O
O
S
R
Yield (%)
Mp (°C)
>360
H
90
92
90
94
98
92
3b
Me
Cl
H
293–295
298
Unexpected results were obtained in the reaction of 2-ben-
zothiazolylguanidines 5a–c and phenyl isothiocyanate
(Scheme 3). It has been reported that 2-amino-4-thioxo-s-
triazino[2,1-b][1,3]benzothiazole12 or N-[(1H-benzothia-
zol-2-ylamino)(imino)methyl]-N¢-phenylthiourea15 were
obtained under conventional reaction conditions from the
reaction of 2-benzothiazolylguanidine (5a) and phenyl
isothiocyanate. In our study, under microwave irradiation,
2-imino-4-phenylimino-s-triazino[2,1-b][1,3]benzothiaz-
ole (7a) formed. Analogously, diimino compounds 7b and
7c were prepared from the appropriate benzothiazol-
ylguanidines (5b and 5c) under identical conditions.
Looking at the literature, we discovered that s-triazi-
no[2,1-b][1,3]benzothiazole 7a had in fact been prepared
3c
3d
289
3e
S
Me
Cl
305–306
310
3f
S
the downfield shift of H-6 to 7.90–7.98 and 8.86–9.06
ppm in the 1H NMR spectra for the 4-oxo derivatives 3a–
c and 4-thioxo derivatives 3d–f, respectively. These find-
ings confirmed the formation of the s-triazine ring and are
in agreement with literature data.12
Interestingly, the s-triazino[2,1-b][1,3]benzoxazoles 3a–f before from 2-aminobenzothiazole or 2-benzothiazol-
were found as their imino tautomers in DMSO. This was ylguanidine,16 however the reactions were reported to re-
supported by the evidence of two definite D2O exchange- quire several days and afford very low yields (7.5% and
able singlets (7.75–8.41 ppm) in the 1H NMR spectra cor- 4.3%, respectively).
responding to the N(3)H and the imino group of 3a–f.
H2N
2-Benzothiazolylguanidines 5a–c were synthesized from
R
NH
N
the corresponding 2-aminothiophenols 4a–c by cyclocon-
densation with cyanoguanidine according to the reported
method.14
NH
S
5a–c
The ring-closure carbonylation of 2-benzothiazolyl-
guanidines 5a–c was successfully achieved under micro-
wave irradiation using phenyl isocyanate (Scheme 2).
Thus 2-imino-4-oxo-2,3-dihydro-4H-[1,3,5]triazino[2,1-
PhNCS
DME, MW 180 °C, 15 min
PhN
NH
NH
a
b
c
R = H
R = Cl
R = CF3
R
N
R
NH2
SH
N
S
7a–c
4a–c
NH2
PhN
PhHN
N
1) H2O, HCl, 80 °C, 1–4 h;
2) 50% NaOH
N
N
N
NH
NH2
NH
R
R
H
N
N
S
N
N
H2N
R
S
NH
N
S
NH
Scheme 3
5a–c
Table 2 s-Triazino[2,1-b][1,3]benzothiazoles 6a–c and 7a–c
PhNCO
DME, MW 180 °C, 15 min
Compd
6a
R
Yield (%)
Mp (°C)
343–344
>360
H
96
90
95
28
30
14
O
N
O
N
NH
N
6b
Cl
CF3
H
NH2
R
NH
R
N
N
6c
324
S
S
7a
300
6a–c
a
b
c
R = H
R = Cl
R = CF3
7b
Cl
CF3
288–290
265
7c
Scheme 2
Synthesis 2006, No. 4, 597–602 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of Fused s-Triazines
599
R
NH2
NH2
Several tautomeric forms are possible for compounds 7a–
c because of the amino-imino tautomerism of two poten-
tial amino groups. The 2-amino-tautomeric form may be
eliminated based on the two definite D2O exchangeable
singlets for NH protons in the 1H NMR spectra of s-triaz-
ino[2,1-b][1,3]benzothiazoles 7a–c (Table 3). In a NOE-
SY experiment conducted on compounds 7a–c, cross-
peaks were observed between the ortho-protons of the
phenyl ring and H-6 but not the NH protons. The absence
of the cross-peaks between NH and H-6 indicated the pre-
dominance of the diimino tautomeric form in DMSO. The
cross-peaks observed between the ortho-protons of the
phenyl ring and H-6 of the heterocyclic system strongly
support a 4Z-configuration for 7a–c. This configuration
would result in an anisotropic effect from the coplanarity
of the phenyl ring and the downfield shift of H-6 signal in
1H NMR spectra of 7a–c (Table 3).
8a,b
NH2
N
1) H2O, HCl, reflux, 2–4 h
2) 10% KOH
N
H
NH
H2N
R
NH
N
NH
N
H
9a,b
PhNCO
DME, MW 180 °C, 15 min
O
N
NH
NH2
a
b
R = H
R = Me
N
Reaction of 2-benzimidazolylguanidines 9a and 9b with
phenyl isocyanate under microwave irradiation proceeded
in a similar way as described for fused s-triazines 3a–c
and 6a–c. The reaction led to the formation of 2-amino-4-
oxo-3H-[1,3,5]triazino[1,2-a]benzimidazoles 10a and
10b (Scheme 2). There have been many methods reported
for the synthesis of 10a.7–10 However, the reaction of 9a
with phenyl isocyanate in pyridine under reflux has been
reported to afford N-[(1H-benzimidazol-2-ylamino)(imi-
no)methyl]-N¢-phenylurea.8 Therefore it seems likely that
microwave irradiation can facilitate elimination of aniline
from the addition product to furnish 10a and 10b.
R
N
10a,b
Scheme 4
the precipitate was filtered, mixed with H2O (100 °C, 100 mL), and
KOH (10%; 25 mL) was added. After cooling, the precipitated 2-
guanidinobenzoxazole 2a–c was removed by filtration, washed
with cold H2O, dried, and recrystallized (EtOH, 20%).
2-Benzoxazolylguanidine (2a)
Yield: 68%; mp 186 °C (Lit.13 182–184 °C).
Microwave irradiation has been shown to improve the se-
lectivity of several reactions;17 however, we found that the
reaction of asymmetric 5-methylbenzimidazolyl-2-guani-
dine (9b) with phenyl isocyanate gave a mixture of regio-
isomeric 7- and 8-methyl substituted products (10b) in
equal measure. The same ratio of isomeric forms was also
observed in the reaction of 9b with DEAD in refluxing
ethanol.18
5-Methylbenzoxazolyl-2-guanidine (2b)
Yield: 72%; mp 236–237 °C.
1H NMR (300 MHz): d = 2.34 (s, 3 H, Me), 6.83 (dd, 1 H, J = 7.9,
1.1 Hz, H-6), 7.10 (s, 1 H, H-4), 7.18 (br s, 4 H, NH), 7.19 (d, 1 H,
J = 7.9 Hz, H-7).
13C NMR (75 MHz, DMSO-d6): d = 21.0 (Me), 107.9 (C-7), 115.6
(C-4), 121.4 (C-6), 131.9.0 (C-5), 142.6 (C-3a), 144.6 (C-7a), 159.7
(C=NH), 166.5 (C-2).
The microwave-assisted method we report herein is limit-
ed to phenyl isocyanates, the thioxo analogues of 10a and
10b did not result from the reaction of 8a and 8b with phe-
nyl isothiocyanate – instead, a complex mixture of several
compounds was formed. However, ring-closure thiocar-
bonylation of 8a has been reported to be possible using
carbon disulfite in basic conditions,8,9,19 therefore, further
optimization of the microwave-assisted reaction is war-
ranted.
Anal. Calcd for C9H10N4O: C, 56.83; H, 5.30; N, 29.46. Found: C,
56.80; H, 5.35; N, 29.38.
5-Chlorobenzoxazolyl-2-guanidine (2c)
Yield: 63%; mp 205–207 °C.
1H NMR (300 MHz): d = 7.03 (dd, 1 H, J = 8.3, 2.3 Hz, H-6), 7.24
(br s, 4 H, NH), 7.31 (d, 1 H, J = 2.3 Hz, H-4), 7.33 (d, 1 H, J = 8.3
Hz, H-7).
13C NMR (75 MHz): d = 109.5 (C-7), 114.8 (C-4), 120.3 (C-6),
127.0 (C-5), 144.1 (C-3a), 145.3 (C-7a), 159.9 (C=NH), 167.3 (C-
2).
Mps (uncorrected) were determined on a Gallenkamp melting point
apparatus. IR spectra were collected on a Jasco FT-IR-430 spectro-
photometer as KBr pellets. 1H and 13C NMR spectra were recorded
on a Bruker DPX-300 spectrometer, using DMSO-d6 as a solvent
and TMS as an internal reference. Microwave-assisted syntheses
were carried out using a microwave synthesizer InitiatorTM (Biotage
AB, Sweden).
Anal. Calcd for C8H7ClN4O: C, 45.62; H, 3.35; N, 26.60. Found: C,
45.33; H, 3.50; N, 26.51.
2-Benzothiazolylguanidines 5a–c; General Procedure
A mixture of o-aminothiophenol (4a–c; 0.05 mol), cyanoguanidine
(4.2 g, 0.05 mol), and concd HCl (10 mL, 0.1 mol) in H2O (20 mL)
was heated at 80 °C. After 1–4 h, NaOH (50%; 8 mL, 0.1 mol) was
added and the mixture was stirred for 10 min at 80 °C. After cool-
ing, the precipitated 2-guanidinobenzothiazole 5a–c was removed
by filtration, washed with cold H2O, dried, and recrystallized (aq
EtOH).
2-Benzoxazolylguanidines 2a–c; General Procedure
A mixture of o-aminophenol 1a–c (0.1 mol), cyanoguanidine (8.4 g,
0.1 mol), and concd HCl (10 mL, 0.1 mol) in EtOH (40 mL) was
heated under reflux for 2–6 h. The reaction mixture was cooled and
Synthesis 2006, No. 4, 597–602 © Thieme Stuttgart · New York

600
A. V. Dolzhenko et al.
PAPER
2-Benzimidazolylguanidines 9a and 9b; General Procedure
A mixture of o-phenylenediamine 8a or 8b (0.1 mol), cyanoguani-
dine (8.4 g, 0.1 mol) and concd HCl (20 mL, 0.2 mol) in H2O (200
mL) was heated under reflux for 1 h, cooled to 0 °C, and KOH
(10%; 50 mL) was added slowly. Precipitated 2-guanidinobenzimi-
dazole was removed by filtration, washed with H2O, dried, and use
in further reactions without further purification.
Benzothiazolyl-2-guanidine (5a)
Yield: 95%; mp 172–173 °C (Lit.14 173–176 °C).
1H NMR (300 MHz): d = 7.07 (td, 1 H, J = 7.5, 1.1 Hz, H-6), 7.2 (br
s, 4 H, NH), 7.25 (td, 1 H, J = 7.7, 1.1 Hz, H-5), 7.45 (d, 1 H, J = 7.9
Hz, H-4), 7.66 (d, 1 H, J = 7.5 Hz, H-7).
13C NMR (75 MHz): d = 118.2 (C-4), 120.6 (C-7), 121.5 (C-6),
125.1 (C-5), 130.2 (C-7a), 152.0 (C-3a), 158.1 (C=NH), 173.9 (C-
2).
2-Benzimidazolylguanidine (9a)
Yield: 78%; mp 243–244 °C (Lit.20 245 °C).
Anal. Calcd for C8H8N4S: C, 49.98; H, 4.19; N, 29.14. Found: C,
49.78; H, 4.45; N, 29.01.
5-Methylbenzimidazolyl-2-guanidine (9b)
Yield: 82%; mp 220–221 °C.
5-Chlorobenzothiazolyl-2-guanidine (5b)
1H NMR (300 MHz): d = 2.32 (s, 3 H, Me), 6.72 (dd, 1 H, J = 7.9,
0.8 Hz, H-6), 6.7 (br s, 4 H, NH), 6.96 (s, 1 H, H-4), 7.03 (d, 1 H,
J = 7.9 Hz, H-7), 10.84 [br s, 1 H, N1-H].
Yield: 92%; mp 228–229 °C.
1H NMR (300 MHz): d = 7.09 (dd, 1 H, J = 8.3, 1.9 Hz, H-6), 7.23
(br s, 4 H, NH), 7.46 (d, 1 H, J = 1.9 Hz, H-4), 7.68 (d, 1 H, J = 8.3
Hz, H-7).
13C NMR (75 MHz): d = 117.5 (C-4), 121.2 (C-6), 121.9 (C-7),
128.9 (C-5), 129.8 (C-7a), 153.2 (C-3a), 158.2 (C=NH), 175.5 (C-
2).
Anal. Calcd for C9H11N5: C, 57.13; H, 5.86; N, 37.01. Found: C,
56.88; H, 6.02; N, 36.82.
2-Imino-4-(thi)oxo-2,3-dihydro-4H-[1,3,5]triazino-[2,1-
b][1,3]benzoxazoles 3a–f, 2-Imino-4-oxo-2,3-dihydro-4H-
[1,3,5]triazino[2,1-b][1,3]benzothiazoles 6a–c, 2-Imino-4-phen-
ylimino-2,3-dihydro-4H-[1,3,5]triazino[2,1-b][1,3]benzothiaz-
oles 7a and 7b, and 2-Amino-4-oxo-3H-[1,3,5]triazino[1,2-
a]benzimidazoles 10a and 10b; General Procedure
A mixture of heterylguanidine (2a–c, 5a–c, 9a, or 9b; 5 mmol) and
phenyl iso(thio)cyanate (5 mmol) in DME (5 mL) were heated at
180 °C under microwave irradiation for 15 min. After cooling, the
precipitated target compound was removed by filtration, washed
with DME, and dried. Compounds 3a–f, 6a–c, 10a, and 10b pre-
pared in this manner were sufficiently pure, however they could be
recrystallized from DMF (3a–f, 6a–c) or DMSO (10a and 10b).
Compounds 7a and 7b required recrystallization from DMF.
Anal. Calcd for C8H7ClN4S: C, 42.39; H, 3.11; N, 15.64. Found: C,
42.54; H, 3.56; N, 15.31.
5-Trifluoromethylbenzothiazolyl-2-guanidine (5c)
Yield: 90%; mp 225–226 °C.
1H NMR (300 MHz): d = 7.28 (br s, 4 H, NH), 7.37 (d, 1 H, J = 8.3
Hz, H-6), 7.71 (s, 1 H, H-4), 7.90 (d, 1 H, J = 8.3 Hz, H-7).
13C NMR (75 MHz): d = 114.2 (q, J = 3.9 Hz, C-4), 117.5 (q,
J = 3.9 Hz, C-6), 121.6 (C-7), 124.6 (q, J = 272.1 Hz, CF3), 126.1
(q, J = 31.6 Hz, C-5), 134.8 (C-7a), 152.1 (C-3a), 158.4 (C=NH),
175.5 (C-2).
Anal. Calcd for C8H7ClN4S: C, 41.54; H, 2.71; N, 21.90. Found: C,
41.23; H, 2.98; N, 21.62.
Table 3 Spectroscopic Data of s-Triazino[2,1-b][1,3]benzoxazoles 3a–f and s-Triazino[2,1-b][1,3]benzothiazoles 6a–c and 7a–c
Compd
Molecular
formulaa
IR (KBr) (cm–1)
1H NMR (300 MHz)
13C NMR (75 MHz)
3a
C9H6N4O2
(202.2)
3359 (NH), 3075 (NH),
1703 (C=O), 1691, 1666,
1472, 1440, 1077, 760
7.44 (td, 1 H, J = 7.2, 1.5 Hz, H-8), 7.46 111.0 (C-6), 114.0 (C-9), 125.3 (C-
(td, 1 H, J = 7.2, 1.9 Hz, H-7), 7.71 (dd, 7),b 125.5 (C-8),b 126.0 (C-5a), 143.4
1 H, J = 7.2, 1.9 Hz, H-9), 7.78 (s, 1 H, (C-9a), 151.1 (C-2), 161.3 (C-10a),
NH), 7.80 (s, 1 H, NH), 7.98 (dd, 1 H, 166.0 (C=O)
J = 7.2, 1.5 Hz, H-6)
3b
3c
3d
C10H8N4O2
(216.2)
3372 (NH), 3318 (NH),
3191 (NH), 3034, 1705
(C=O), 1668, 1651, 1486, H-9), 7.75 (s, 1 H, NH), 7.76 (s, 1 H,
2.43 (s, 3 H, Me), 7.22 (dd, 1 H, J = 8.3, 20.9 (Me), 110.5 (C-6), 114.2 (C-9),
1.1 Hz, H-8), 7.56 (d, 1 H, J = 8.3 Hz, 125.8 (C-8), 125.9 (C-5a), 135.0 (C-
7), 141.5 (C-9a), 151.0 (C-2), 161.4
(C-10a), 165.9 (C=O)
1439, 1074, 782
NH), 7.78 (s, 1 H, H-6)
C9H5ClN4O2 3266 (NH), 3081 (NH),
(236.6)
7.49 (dd, 1 H, J = 8.7, 2.3 Hz, H-8),
112.5 (C-6), 113.6 (C-9), 125.2 (C-
1741, 1728, 1473, 1436,
1085, 776, 667
7.75 (d, 1 H, J = 8.7 Hz, H-9), 7.86 (s, 1 8), 127.3 (C-5a), 129.2 (C-7), 142.4
H, NH), 7.87 (s, 1 H, NH), 7.90 (d, 1 H, (C-9a), 150.7 (C-2), 161.6 (C-10a),
J = 2.3 Hz, H-6)
165.9 (C=O)
C9H6N4OS
(218.2)
3299 (NH), 3163 (NH),
1670, 1617, 1470, 1435,
1380 (C=S), 1325, 1057,
966, 774, 750
7.47 (td, 1 H, J = 7.5, 1.1 Hz, H-8), 7.52 110.9 (C-6), 116.5 (C-9), 124.5 (C-
(td, 1 H, J = 7.5, 1.5 Hz, H-7), 7.75 (dd, 7), 126.5 (C-8), 127.2 (C-5a), 143.7
1 H, J = 7.5, 1.5 Hz, H-9), 8.15 (s, 1 H, (C-9a), 159.7 (C-2), 161.2 (C-10a),
NH), 8.29 (s, 1 H, NH), 9.03 (dd, 1 H, 176.9 (C=S)
J = 7.5, 1.1 Hz, H-6)
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Microwave-Assisted Synthesis of Fused s-Triazines
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Table 3 Spectroscopic Data of s-Triazino[2,1-b][1,3]benzoxazoles 3a–f and s-Triazino[2,1-b][1,3]benzothiazoles 6a–c and 7a–c (continued)
Compd
Molecular
formulaa
IR (KBr) (cm–1)
1H NMR (300 MHz)
13C NMR (75 MHz)
3e
C10H8N4OS
(232.3)
3363 (NH), 3279 (NH),
3134 (NH), 1649, 1611,
1489, 1433, 1382 (C=S),
1366 (Me), 1321, 1052,
969, 802, 773
2.46 (s, 3 H, Me), 7.31 (dd, 1 H, J = 8.3, 21.2 (Me), 110.4 (C-6), 116.7 (C-9),
1.1 Hz, H-8), 7.61 (d, 1 H, J = 8.3 Hz,
H-9), 8.13 (s, 1 H, NH), 8.28 (s, 1 H,
NH), 8.86 (s, 1 H, H-6)
126.9 (C-8), 127.2 (C-5a), 134.1 (C-
7), 141.8 (C-9a), 159.8 (C-2), 161.2
(C-10a), 176.9 (C=S)
3f
C9H5ClN4OS 3303 (NH), 3157 (NH),
7.59 (dd, 1 H, J = 8.7, 2.3 Hz, H-8),
112.3 (C-6), 115.9 (C-9), 126.2 (C-
(252.7)
1685, 1616, 1472, 1454,
1430, 1381 (C=S), 1170,
1051, 957, 808, 768, 657
7.80 (d, 1 H, J = 8.7 Hz, H-9), 8.25 (s, 1 8), 128.2 (C-5a),b 128.4 (C-7),b 142.7
H, NH), 8.41 (s, 1 H, NH), 9.06 (d, 1 H, (C-9a), 160.0 (C-2), 161.2 (C-10a),
J = 2.3 Hz, H-6)
176.6 (C=S)
6a
C9H6N4OS
(218.2)
3332 (NH), 3107 (NH),
1722, 1702, 1648, 1554,
1507, 1455, 1428, 1112,
779, 758, 636
7.46 (td, 1 H, J = 7.5, 1.1 Hz, H-8), 7.54 117.7 (C-6), 121.6 (C-5a), 122.9 (C-
(td, 1 H, J = 7.7, 1.1 Hz, H-7), 7.63 (s, 1 9), 125.9 (C-8), 127.0 (C-7), 135.7
H, NH), 7.70 (s, 1 H, NH), 7.98 (dd, 1 (C-9a), 151.6 (C-2), 163.5 (C=O),
H, J = 7.7, 1.1 Hz, H-9), 8.63 (dd, 1 H, 170.2 (C-10a)
J = 7.9, 1.1 Hz, H-6)
6b
6c
C9H5ClN4OS 3306 (NH), 3108 (NH),
7.54 (dd, 1 H, J = 8.3, 2.2 Hz, H-8),
7.70 (s, 1 H, NH), 7.76 (s, 1 H, NH),
8.01 (d, 1 H, J = 8.3 Hz, H-9), 8.62 (d, 1 (C-9a), 151.3 (C-2), 163.5 (C=O),
H, J = 2.2 Hz, H-6)
117.2 (C-6), 120.7 (C-5a), 124.4 (C-
9), 125.8 (C-8), 131.5 (C-7), 136.6
(252.7)
1721, 1699, 1674, 1578,
1565, 1510, 1469, 1455,
1438, 1226, 1120, 799,
768, 636
170.5 (C-10a)
C10H5F3N4OS 3283 (NH), 3123 (NH),
7.71 (s, 1 H, NH), 7.78 (s, 1 H, NH),
7.82 (dd, 1 H, J = 8.3, 1.1 Hz, H-8),
8.23 (d, 1 H, J = 8.3 Hz, H-9), 8.91 (d, 1 Hz, CF3), 124.2 (C-9), 126.9 (q,
113.9 (q, J = 4.5 Hz, C-6), 122.4 (q,
J = 3.7 Hz, C-8), 123.9 (q, J = 272.6
(286.2)
1713 (C=O), 1652, 1609,
1561, 1513, 1442, 1334,
1249, 1126, 776, 734, 663 H, J = 1.1 Hz, H-6)
J = 1.2 Hz, C-5a), 127.3 (q, J = 32.1
Hz, C-7), 136.1 (C-9a), 151.5 (C-2),
163.5 (C=O), 170.4 (C-10a)
7a
C15H11N5S
(293.4)
3437 (NH), 3145 (NH),
1662, 1633, 1578, 1564,
1509, 1488, 1451, 1430,
1227, 1001, 782, 762, 690 NH), 7.37 (s, 1 H, NH), 7.44 (td, 1 H,
J = 7.5, 1.1 Hz, H-8), 7.52 (td, 1 H,
J = 7.5, 1.1 Hz, H-7), 7.96 (d, 1 H,
J = 7.5 Hz, H-9), 9.21 (d, 1 H, J = 8.3
Hz, H-6)
6.93 (t, 1 H, J = 7.2 Hz, H-4¢), 7.12 (d, 119.2 (C-6), 121.3 (C-4¢), 121.4 (C-
2 H, J = 7.5 Hz, H-2¢, H-6¢), 7.25 (t, 2 H, 5a), 122.5 (C-9), 123.2 (C-2¢, C-6¢),
J = 7.7 Hz, H-3¢, H-5¢), 7.25 (s, 1 H,
125.5 (C-8), 126.6 (C-7), 128.2 (C-3¢,
C-5¢), 136.1 (C-9a), 146.8 (C-1¢),
148.8 (C-2), 159.4 (C-4), 169.5 (C-
10a)
7b
7c
C15H10ClN5S 3434 (NH), 3113 (NH),
6.95 (t, 1 H, J = 7.2 Hz, H-4¢), 7.11 (d, 118.7 (C-6), 120.6 (C-5a), 121.5 (C-
2 H, J = 7.5 Hz, H-2¢, H-6¢), 7.27 (t, 2 H, 4¢), 123.1 (C-2¢, C-6¢), 123.9 (C-9),
(327.8)
1660, 1640, 1581, 1566,
1510, 1487, 1454, 1425,
J = 7.7 Hz, H-3¢, H-5¢), 7.33 (s, 1 H,
125.3 (C-8), 128.3 (C-3¢, C-5¢), 131.0
1234, 1021, 757, 707, 549 NH), 7.46 (s, 1 H, NH), 7.51 (dd, 1 H, (C-7), 137.0 (C-9a), 146.7 (C-1¢),
J = 8.5, 2.0 Hz, H-8), 7.98 (d, 1 H,
J = 8.5 Hz, H-9), 9.27 (d, 1 H, J = 2.0
Hz, H-6)
148.6 (C-2), 159.3 (C-4), 169.8 (C-
10a)
C16H10F3N5S 3444 (NH), 3183 (NH),
6.96 (t, 1 H, J = 7.2 Hz, H-4¢), 7.16 (d, 115.4 (q, J = 4.3 Hz, C-6), 121.6 (C-
2 H, J = 7.5 Hz, H-2¢, H-6¢), 7.27 (t, 2 H, 4¢), 121.9 (q, J = 2.9 Hz, C-8), 123.2
(361.4)
1663, 1630, 1582, 1515,
1489, 1430, 1334, 1231,
1144, 1126, 1000, 781,
761, 732
J = 7.7 Hz, H-3¢, H-5¢), 7.37 (s, 1 H,
(C-2¢, C-6¢), 123.6 (C-9), 124.0 (q,
NH), 7.49 (s, 1 H, NH), 7.81 (dd, 1 H, J = 272.2 Hz, CF3), 126.8 (q, J = 1.2
J = 8.3, 1.1 Hz, H-8), 8.21 (d, 1 H,
J = 8.3 Hz, H-9), 9.61 (d, 1 H, J = 1.1
Hz, H-6)
Hz, C-5a), 126.9 (q, J = 32.1 Hz, C-
7), 128.3 (C-3¢, C-5¢), 136.5 (C-9a),
146.7 (C-1¢), 148.4 (C-2), 159.3 (C-
4), 169.7 (C-10a)
a Satisfactory elemental analyses were obtained (C 0.27, H 0.28, N 0.34).
b Assignments may be reversed.
2-Imino-4-phenylimino-7-trifluoromethyl-2,3-dihydro-4H-
[1,3,5]triazino[2,1-b][1,3]benzothiazoles (7c)
15 min. The solvent was evaporated, the residue was washed with
hot EtOH, and recrystallized (DMF).
A mixture of 5-trifluoromethylbenzothiazolyl-2-guanidine (5c;
1.30 g, 5 mmol) and phenyl isothiocyanate (0.68 g, 5 mmol) in
DME (5 mL) was heated at 180 °C under microwave irradiation for
2-Amino-4-oxo-3H-[1,3,5]triazino[1,2-a]benzimidazole (10a)
Yield: 95%; mp >360 °C.
Synthesis 2006, No. 4, 597–602 © Thieme Stuttgart · New York

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A. V. Dolzhenko et al.
PAPER
IR (KBr): 3415 (NH), 3219 (NH), 3123 (NH), 2997, 2886, 2800,
1717 (C=O), 1616, 1601, 1526, 1457, 1405, 774, 736 cm–1.
(2) Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med. Chem.
2002, 9, 1251.
(3) Xu, Y.; Guo, Q. X. Heterocycles 2004, 63, 903.
(4) Lee, H. K.; Chui, W. K. Bioorg. Med. Chem. 1999, 7, 1255.
(5) (a) Then, R. L. J. Chemotherapy 2004, 16, 3. (b) Ridley, R.
G. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13362.
(c) Gilbert, I. H. Biochim. Biophys. Acta 2002, 1587, 249.
(6) (a) Hoesl, C. E.; Nefzi, A.; Houghten, R. A. J. Comb. Chem.
2003, 5, 155. (b) Molina, P.; Lorenzo, A.; Aller, E. Synthesis
1992, 297.
1H NMR (300 MHz): d = 7.19 (br s, 1 H, NH2), 7.25 (td, 1 H, J =
7.7, 1.1 Hz, H-8), 7.34 (td, 1 H, J = 7.7, 1.5 Hz, H-7), 7.42 (d, 1 H,
J = 7.2 Hz, H-9), 8.09 (d, 1 H, J = 7.5 Hz, H-6), 12.20 (br s, 1 H,
NH).
13C NMR (75 MHz): d = 112.6 (C-6), 113.9 (C-9), 121.8 (C-7),
124.7 (C-8), 126.6 (C-5a), 133.1 (C-9a), 150.3 (C-2), 153.7 (C=O),
162.9 (C-10a).
(7) Capuano, L.; Schrepfer, H. J.; Jaeschke, M. E.; Porschen, H.
Anal. Calcd for C9H7N5O: C, 53.73; H, 3.51; N, 34.81. Found: C,
53.54; H, 3.64; N, 34.50.
Chem. Ber. 1974, 107, 62.
(8) Martin, D.; Graubaum, H.; Kempter, G.; Ehrlichmann, W. J.
Prakt. Chem. 1981, 323, 303.
(9) Martin, D.; Graubaum, H.; Kochmann, W. Pat. DD 149937,
1981; Chem. Abstr. 1982, 96, 52339.
2-Amino-7(8)-methyl-4-oxo-3H-[1,3,5]triazino[1,2-a]benzimid-
azoles (10b)
Yield: 92%; mp >360 °C.
(10) Furukawa, M.; Kawanabe, K.; Yoshimi, A.; Okawara, T.;
Noguchi, Y. Chem. Pharm. Bull. 1983, 31, 2473.
(11) Kihara, Y.; Kabashima, S.; Yamasaki, T.; Ohkawara, T.;
Furukawa, M. J. Heterocycl. Chem. 1990, 27, 1213.
(12) Krylsky, D. V.; Shikhaliev, Kh. S.; Solovyev, A. S. Chem.
Heterocycl. Compd. 2001, 37, 524.
1H NMR (300 MHz): d = 2.41 (s, 3 H, C8-Me), 2.42 (s, 3 H, C7-
Me), 7.07 (d, 1 H, J = 8.3 Hz, H-7), 7.08 (br s, 4 H, NH2), 7.15 (d,
1 H, J = 8.3 Hz, H-8), 7.20 (s, 1 H, H-9), 7.28 (d, 1 H, J = 8.3 Hz,
H-9), 7.92 (s, 1 H, H-6), 7.93 (d, 1 H, J = 8.3 Hz, H-6).
Anal. Calcd for C10H9N5O: C, 55.81; H, 4.22; N, 32.54. Found: C,
55.78; H, 4.53; N, 32.15.
(13) Smith, G. B. L.; Kane, J. H.; Mason, C. W. J. Am. Chem.
Soc. 1929, 51, 2522.
1H NMR spectra of 10b (mixture of regioisomers, 1:1) is in agree-
ment with that prepared earlier in our group from the reaction of 9b
with DEAD.18
(14) (a) Weiss, S.; Krommer, H.; Prietzel, H. Chem.-Ztg. 1975,
99, 291. (b) Krommer, H.; Prietzel, H.; Weiss, S. Pat. DE
2418913, 1975; Chem. Abstr. 1976, 84, 31048.
(15) Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.;
Yamasaki, T.; Furukawa, M. Synthesis 1990, 1020.
(16) Bennion, C.; Robinson, D. Pat. EP 93515, 1983; Chem.
Abstr. 1984, 100, 85727.
Acknowledgment
This work is supported by the Academic Research Fund from the
National University of Singapore.
(17) De La Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Curr. Org.
Chem. 2004, 8, 903.
(18) Dolzhenko, A. V.; Chui, W. K. J. Heterocycl. Chem. 2005,
in press.
References
(19) Badawey, E. A. M.; Kappe, T. Arch. Pharm. (Weinheim,
Ger.) 1997, 330, 59.
(20) King, F. E.; Acheson, R. M.; Spensley, P. C. J. Chem. Soc.
1948, 1366.
(1) Part 3 in the series ‘Fused Heterocyclic Systems with an s-
Triazine Ring’, for Part 2, see: Dolzhenko, A. V.; Chui, W.
K.; Dolzhenko, A. V.; Chan, L. W. J. Fluorine Chem. 2005,
126, 759.
Synthesis 2006, No. 4, 597–602 © Thieme Stuttgart · New York