5-{3-Methyl-3-[(phenyloxy)carbonyl]triazen-1-yl}imidazole-
4-carboxamide 13
Experimental
General
A suspension of nitrile 12 (1.35 g, 5.0 mmol) in a mixture of
concentrated HCl (22 mL) and acetic acid (11 mL) was stirred
vigorously at 60–65 ЊC (bath temperature) until the solids
had dissolved (approx. 20 min). The solution was heated for an
additional 5 min, cooled to room temperature and diluted with
water (3 portions of 10 mL) which induced crystallisation of
the product. After 16 h at 4 ЊC the mixture was filtered, the
product was washed thoroughly with water and dried in vacuo
to give 1.07 g (3.72 mmol, 74%) of carboxamide 13, mp 170 ЊC
(dec) (Found: C, 49.84; H, 4.28; N, 28.94. C12H12N6O3 requires
C, 50.00; H, 4.20; N, 29.15%); νmax/cmϪ1 (KBr) 3432, 1749,
1683, 1598; δH (d6-DMSO) 13.4 (1H, br, NH), 8.00 and 7.34
(2 × 1H, br, NH2), 7.92 (1H, s, 2-H), 7.51 (2H, m, ArH), 7.35
(3H, m, ArH), 3.54 (3H, s, CH3); δC (d6-DMSO) 158.9, 151.9,
150.6, 141.5, 136.2, 129.6, 126.3, 121.7, 121.2, 31.37.
All reagents and solvents were used as commercially avail-
able, unless indicated otherwise. Flash chromatography refers
to purification using the indicated eluents and Janssen Chimica
silica gel 60 (0.030–0.075 mm). Melting points were measured
with a Leitz melting point microscope. Elemental analyses were
performed by Kolbe, Mülheim an der Ruhr, Germany. Infrared
(IR) spectra were obtained from CHCl3 solutions unless
indicated otherwise, using a Bruker IFS 28 FT-spectro-
photometer and wavelengths are reported in cmϪ1. Proton
nuclear magnetic resonance (1H NMR) spectra and carbon
nuclear magnetic resonance (13C NMR; APT) spectra were
determined in CDCl3 at 300 K using a Bruker ARX 400
spectrometer, unless indicated otherwise.
5-Nitro-1-(tetrahydropyran-2-yl)imidazole-4-carbonitrile 8
A mixture of 5-nitroimidazole-4-carbonitrile 714 (4.14 g,
30 mmol), 3,4-dihydro-2H-pyran (5.49 mL, 60 mmol) and
p-TsOH (0.15 g) in EtOAc (60 mL) was stirred at room
temperature during 2 h. Et3N (0.105 mL) and light petroleum
(90 mL) were added and the solution was slowly filtered over
silica (15 g). The silica was washed with EtOAc (150 mL) and
the solvents were removed in vacuo. The residue obtained after
further drying (1 mbar, 45 ЊC) was stirred with a few mL light
petroleum to induce crystallisation. Yield: 6.38 g (2.93 mmol,
97.5%), mp 87–88 ЊC (Found: C, 48.77; H, 4.50; N, 25.12.
C9H10N4O3 requires C, 48.65; H, 4.54; N, 25.21%); νmax/cmϪ1
(KBr) 3140, 2951, 2859, 2242, 1566, 1475; δH 7.82 (1H, s), 5.45
(1H, m), 4.22 (1H, m), 3.77 (1H, m), 1.7–2.3 (6H, m);
δC (d6-DMSO) 136.1, 107.9, 102.1, 86.0, 69.2, 32.1, 24.5, 22.3.
Temozolomide 1
N2 was bubbled through a suspension of 13 (0.100 g,
0.347 mmol) in a mixture of acetone (10 mL) and methanol
(5 mL) in a normal 20 mL glass test tube. The mixture was
irradiated at room temperature in a Rayonet RS at 366 nm
during 1 h. Evaporation of the solvents and trituration with
acetone produced temozolomide 1 (0.053 g, 0.273 mmol, 79%)
as a slightly coloured crystalline solid, mp 175 ЊC (dec), liter-
ature values 212 ЊC (dec)7 or 185 ЊC (dec);8 νmax/cmϪ1 (KBr)
3494, 3124, 1745, 1680; δH (d6-DMSO) 8.83 (1H, s, 2-H), 7.80
and 7.68 (2 × 1H, br, NH2), 3.89 (3H, s, CH3); δC (d6-DMSO)
161.5, 139.2, 134.6, 130.5, 128.4, 36.13.
Azoxy dimer 14
From an earlier synthesis of nitrosoimidazole 10 the azoxy
dimer 14 was obtained, δH (selected signals) 7.94 (1H, s, 2-H),
7.88 (1H, s, 2Ј-H), 5.80 (1H, dd, J 10.5 and 2.1, N–CH–O), 5.45
(1H, dd, J 10.5 and 2.4, N–CH–O).
5-{3-Methyl-3-[(phenyloxy)carbonyl]triazen-1-yl}imidazole-
4-carbonitrile 12
10% Pt on carbon (0.20 g) was added to a solution of 8 (2.18 g,
10.0 mmol) in EtOAc (50 mL) and the mixture was stirred
vigorously under 1 atm of H2 during 1 h. The reaction was
followed with TLC (silica, eluent: EtOAc). The crystallised
product was dissolved by adding some ethanol and the catalyst
was removed by filtration over Celite. The solids were washed
with EtOAc (50 mL), the filtrate was cooled in ice, and under
vigorous stirring an ice-cold solution of NaIO4 (4.28 g,
20.0 mmol) in water (80 mL) was added quickly. Vigorous
stirring was continued for 30 min, the layers were separated and
the green organic layer was washed once with water (25 mL)
and dried over Na2SO4. Evaporation of the solvents gave
nitrosoimidazole 10 as an oil which was used without puri-
fication in the next step, δH 7.87 (1H, s, 2-H), 5.52 (1H, dd,
J 10.5 and 2.5, N–CH–O), 4.21 (1H, m), 3.77 (1H, m), 2.25 (1H,
m) 2.13 (1H, m), 2.0 (1H, m), 1.7 (3H, m).
A solution of nitrosoimidazole 10 (prepared from 10.0 mmol
8) in a mixture of DCM (15 mL) and acetic acid (6 mL) was
cooled in ice, phenyl methylcarbazate 1116 (1.83 g, 11 mmol)
was added and the cooling bath was removed. After stirring the
solution at room temperature for 2 h the DCM was removed
in vacuo and the resulting acetic acid solution was diluted with
methanol (10 mL) and trifluoroacetic acid (3 mL). Crystalliz-
ation started after ca. 1 h, and after a reaction time of 5 h the
mixture was cooled in ice and filtered. The yellow triazene 12
(2.05 g, 7.59 mmol, 76% from 8) was washed 3 times with cold
methanol and dried in vacuo, mp 105–110 ЊC (Found: C, 53.24;
H, 3.85; N, 31.02. C12H10N6O2 requires C, 53.44; H, 3.73;
N, 31.10%); νmax/cmϪ1 (KBr) 3578, 3451, 3120, 2233, 1739,
1637; δH (d6-DMSO) 13.84 (1H, br, NH), 8.00 (1H, s, 2-H), 7.50
(2H, m, ArH), 7.34 (3H, m, ArH), 3.52 (3H, s, CH3); in
13C NMR only 7 signals were observed; increasing the relax-
ation times or the temperature did not give improvement,
δC (d6-DMSO) 151.8, 150.7, 138.5, 129.6, 126.2, 121.6, 31.01.
Irradiation of 12 in d6-DMSO
A solution of 12 (4.0 mg) in d6-DMSO (0.6 mL) was kept in
1
diffuse daylight (window-sill) during 0.5 h. H NMR showed
starting material (54%), cyanotemozolomide (16) and phenol
(each 46%). Cyanotemozolomide 16: δH (d6-DMSO) 9.07 (1H,
s, 2-H), 3.93 (3H, s, CH3); phenol: 9.33 (1H, s), 7.17 (2H, m),
6.76 (3H, m).
Irradiation of 12 in CDCl3
A solution of 12 (4.0 mg) in CDCl3 (0.6 mL) was kept in diffuse
1
daylight (window-sill) during 4 h. In the H NMR spectrum
starting material (2-H at 7.63 ppm), an unidentified imidazole
(2-H at 7.76 ppm) and phenyl methylcarbamate δH 7–7.5
(5H, m, ArH), 4.95 (1H, br, NH), 2.90 (3H, d, J 4.7, CH3) were
observed.
References
1 E. S. Newlands, M. F. G. Stevens, S. R. Wedge, R. T. Wheelhouse
and C. Brock, Cancer Treat. Rev., 1997, 23, 35–61.
2 H. S. Friedman, T. Kerby and H. Calvert, Clin. Cancer Res., 2000,
6, 2585–2597.
3 R. Stupp, M. Gander, S. Leyvraz and E. Newlands, Lancet Oncol.,
2001, 2, 552–560.
4 M. F. G. Stevens, J. A. Hickman, S. P. Langdon, D. Chubb,
L. Vickers, R. Stone, G. Baig, C. Goddard, N. W. Gibson,
J. A. Slack, C. G. Newton, E. Lunt, C. Fizames and F. Lavelle,
Cancer Res., 1987, 47, 5846–5852.
5 B. J. Denny, R. T. Wheelhouse, M. F. G. Stevens, L. L. H. Tsang
and J. A. Slack, Biochemistry, 1994, 33, 9045–9051.
6 A. S. Clark, B. Deans, M. F. G. Stevens, M. J. Tisdale, R. T.
Wheelhouse, B. J. Denny and J. A. Hartley, J. Med. Chem., 1995, 38,
1493–1504.
J. Chem. Soc., Perkin Trans. 1, 2002, 1877–1880
1879