4234 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 13
Oresmaa et al.
δ ) 11.37 (q); 125.65 (s); 131.42 (s); 135.47 (d); 141.91 (d); MS
(EI): Calcd for C5H7N3O m/z )125.05836. Found 125.05861.
Anal. (C5H7N3O‚H2O): C, H, N.
ally. Topical administration of the nitrolic acids had no
effect on IOP. Elevated concentrations of cGMP in iris-
ciliary body incubation were measured for all nitrolic
acids except 3c (3d not assayed). This finding may be
interpreted as evidence of nitric oxide donation of these
compounds.
1-Methylimidazole-2-carbaldehyde Oxime (2g). Pre-
pared according to the general method. Aldehyde 1g 1 g (9.1
mmol), NH2OH‚HCl 0.96 g (13.8 mmol) in water (8 mL),
NaHCO3 1.16 g (13.8 mmol), reaction time 1 h at 70 °C. Yield
80%. 1H NMR (DMSO-d6): δ ) 3.80 (s, 3H), 6.98 (s, 1H), 7.26
(s, 1H), 8.05 (s, 1H), 11.53 (s, 1H) 1H NMR shifts are in
agreement with the literature.29 MS (ESI): Calcd for C5H8N3O1
[M + H]+ ) 126.06619. Found [M + H]+ ) 126.06637.
(E)- and (Z)-1-(H)-Imidazole-2-carbaldehyde Oxime
(2h). Prepared according to the general method. Aldehyde 1h
1 g (10.4 mmol), NH2OH‚HCl 1.44 g (20.7 mmol), water (8 mL),
Na2CO3 1.1 g (10.4 mmol), reaction time 1 h at ambient
temperature. Yield 44%. 1H NMR (DMSO-d6): δ ) 7.09 (s),
7.14 (s), 7.45 (s), 7.95 (s); MS (EI): Calcd for C4H5N3O m/z )
111.04271. Found 111.04260. Anal. (C4H5N3O): C, H.
General Method for Preparation of Nitrolic Acids. The
solution of the oxime in glacial acetic acid was cooled in an
ice bath. Fuming nitric acid was added dropwise. The ice bath
was removed, and the mixture was stirred at ambient tem-
perature. The reaction mixture was poured into ice and NaOH
(2 M) was added dropwise until the pH was about 3-4. The
precipitate was filtered and washed with cold water.
Experimental Section
Chemistry. Unless otherwise indicated, all common re-
agents and solvents together with the compounds 1c, 1g, and
1h were obtained from commercial suppliers and were used
without further purification. 1-Benzylimidazole-5-carbalde-
hyde (1a),25 1-methylimidazole-5-carbaldehyde (1b),25 1(H)-
imidazole-4(5)-carbaldehyde oxime (2c),26 1-benzylimidazole-
2-carbaldehyde (1f),27 and 1-benzylimidazole-2-carbaldehyde
oxime (2f)27 were prepared according to literature procedures
and oximes 2b28 and 2g29 according to slightly modified ones.
1H and 13C NMR spectra were recorded on a Bruker Avance
250 NMR spectrometer. The mass spectrometry measurements
were performed on a Bruker BioApex 47e Fourier transform
ion cyclotron resonance (FTICR) mass spectrometer (Bruker
Daltonics, Billerica, MA), equipped with an Infinity cell, 4.7
T 160-mm-bore superconducting magnet (Magnex Scientific
Ltd., Abingdon, UK), and an external electron ionization (EI)
or electrospray ion source (ESI) (Analytica of Branford Inc.,
Branford, CT). Elemental analyses were performed on a CE
Instruments EA 1110 elemental analyzer.
1-Benzylimidazole-5-nitrolic Acid (3a). Prepared ac-
cording to the general method. Oxime 2a (0.25 g, 1.24 mmol),
glacial acetic acid (1 mL), fuming nitric acid (0.15 mL), reaction
1
time 1 h. Yield 48%. H NMR (DMSO-d6): δ ) 5.14 (s, 2H),
General Method for Preparation of Oximes. Hydroxyl-
amine hydrochloride was dissolved in water and neutralized
with Na2CO3. Aldehyde was added, and the solution was
stirred at 70 °C for 1-4 h. Oxime was filtered out and washed
with water.
7.02-7.06 (m, 2H), 7.26-7.34 (m, 3H), 7.36 (s, 1H), 8.12 (s,
1H); 13C NMR (DMSO-d6): δ ) 49.59 (t), 115.84 (s), 127.28
(d), 128.07 (d), 128.65 (d), 133.81 (d), 135.95 (s), 140.96 (d),
151.58 (s). MS(ESI): Calcd for C11H11N4O3 [M + H]+
)
247.08257. Found [M + H]+ ) 247.08180. Anal. (C11H10N4O3):
C, H, N.
(E)- and (Z)-1-Benzylimidazole-5-carbaldehyde Oxime
(2a). Prepared according to the general method. Aldehyde 1a
1 g (5.4 mmol), NH2OH‚HCl, 1.5 g (21.6 mmol), water (3 mL),
Na2CO3 1.14 g (10.8 mmol), reaction time 1 h at 70 °C. The
product was a mixture of (E)- and (Z)-isomers and was used
1-Methylimidazole-5-nitrolic Acid (3b). Prepared ac-
cording to the general method. Oxime 2b (0.25 g, 2 mmol),
AcOH (1 mL), fuming HNO3 (0.25 mL), reaction time 0.5 h.
Yield 47%. 1H NMR (DMSO-d6): δ ) 3.54 (s, 3H), 7.36 (s, 1H),
7.91 (s, 1H). 13C NMR (DMSO-d6): δ ) 32.54 (k), 116.69 (s),
133,73 (d), 141.15 (d), 151.79 (s). MS(ESI): Calcd for C5H7N4O3
[M + H]+ ) 171.05148. Found [M + H]+ ) 171.05127. Anal.
(C5H6N4O3): C, H.
1-Methylimidazole-5-nitrolic Acid (3b) HNO3 Salt. The
salt form could be obtained by filtering the resulting precipitate
after pouring the reaction mixture in water. 1H NMR (DMSO-
d6): δ ) 3.74 (q, 3H, CH3), 8.04 (s, 1H), 9.20 (s, 1H) 13C NMR
(DMSO-d6): δ ) 34.74 (q), 118.85 (s), 124.93 (d), 138.62 (d),
148.78 (s). Anal. (C5H7N5O6): C, H, N.
1-(H)-Imidazole-5-nitrolic Acid (3c). Prepared according
to the general method. Oxime 2c 0.25 g (2.25 mmol), AcOH
(1.5 mL), fuming HNO3 (0.1 mL), reaction time 0.5 h. After
the pH was adjusted to 3, NaCl was added until 3c precipi-
tated. Yield 46%. 1H NMR (DMSO-d6): δ ) 7.68 (s, 1H), 8.10
(s, 1H), 12.76 (s, br); 13C NMR (DMSO-d6): δ ) 123.7 (s), 124.7
(d), 136.5 (d), 156.5 (s); MS (ESI): Calcd for C4H5N4O3 [M +
H]+ ) 157.03562. Found [M + H]+ ) 157.03564. Anal.
(C4H4N4O3): C, H.
1
for the next step without further purification. Yield 70%. H
NMR (DMSO-d6): δ ) 5.42 (s, 2 H), 7.14-7.36 (m, 5 H), 7.46
(s, 1 H), 7.80 (s, 1 H), 7.96 (s, 1H), 11.67 (s, 1 H); 5.47 (s, 2 H),
7.14-7.36 (m, 5 H), 7.90 (s, 1H), 8.08 (s, 1H), 11.10 (s, 1H);
13C NMR (DMSO-d6): δ ) 47.69, 122.67, 126.78, 127.77,
128.81, 133.43, 135.99, 137.29, 139.38; 48.97, 125.29, 127.21,
127.51, 128.63, 132.05, 137.74, 139.17, 141.16; MS (EI): Calcd
for C11H11N3O1 m/z ) 201.08966. Found m/z ) 201.09093.
Anal. (C11H11N3O): C, H, N.
(E)- and (Z)-1-Methylimidazole-5-carbaldehyde Oxime
(2b). Prepared according to the general method. Aldehyde 1b
1 g (9.1 mmol), NH2OH‚HCl 1.26 g (18.1 mmol), Na2CO3 0.96
g (9.1 mmol), water (7 mL), reaction time 1.5 h at 70 °C. Yield
68%. The product was a mixture of (E)- and (Z)-isomers. The
compound was used for the next step without further purifica-
tion. Recrystallization for elemental analyses from methanol.
1H NMR (DMSO-d6): δ ) 3.71 (s, 3H), 3.74 (s, 3H), 7.17 (s,
1H), 7.53 (s, 1H), 7.69 (2H), 7.74 (s, 1), 8.12 (s, 1H), 11.12 (s,
br, 1H), 11.65 (s, Br, 1H); 13C NMR (DMSO-d6): δ ) 31.76 (q),
33.80 (q), 123.5 (s), 125.86 (s), 131.87 (d), 133.61 (d), 135.54
(d) 139.39 (d) 139.63 (d) 141.31 (d); MS (EI): Calcd for
C11H11N3O1 m/z ) 125.05836. Found m/z ) 125.05808; Anal.
(C5H7N3O): C, H, N.
1(H)-2-Phenylimidazole-4(5)-carbaldehyde Oxime (2d).
Prepared according to the general method. Aldehyde 1d 1 g
(5.81 mmol), NH2OH‚HCl 0.81 g (11.6 mmol), water (10 mL),
Na2CO3 0.62 g (5.81 mmol), reaction time 1.5 h at ambient
temperature. Yield 82%. 1H NMR (DMSO-d6): δ ) 7.32-7.52
(m, 4H), 7.99-8.05 (m, 3H). MS (EI): Calcd for C10H9N3O m/z
) 187.07401. Found 187.07434.
1(H)-2-Phenylimidazole-4(5)-nitrolic Acid (3d). Pre-
pared according to the general method. Oxime 2d 0.25 g (1.34
mmol), AcOH (0.70 mL), fuming HNO3 (0.18 mL). The reaction
1
time was 0.5 h. Yield 68%. H NMR (DMSO-d6): δ ) 7.38-
7.51 (m, 3H); 7.92-7.95 (m, 2H), 8.23 (s, 1H); 13C NMR
(DMSO-d6): δ ) 124.50 (s), 125.56 (d), 126.25 (d), 128.96 (d),
129.11 (s), 129.32 (d), 146.36 (s), 156.41 (s). MS(ESI): Calcd
for C10H9N4O3 [M + H]+ ) 233.0669. Found 233.0663.
1(H)-4(5)-Methylimidazole-4(5)-nitrolic Acid (3e). Pre-
pared according to the general method. Oxime 2e 0.25 g (2
mmol), AcOH (1 mL); fuming nitric acid (0.25 mL), reaction
time 0.5 h. Yield 30%. 1H NMR (DMSO-d6): δ ) 2.25 (s, 3H);
7.69 (s, 1H); 12.68 (br); 13C NMR (DMSO-d6): δ ) 11.54 (k),
121.09 (s, br), 132.88 (s, br), 135.82 (d), 157.02 (s). MS (ESI):
Calcd for C5H7N4O3 [M + H]+ ) 171.05127. Found [M + H]+
) 171.05284.
1(H)-4(5)-Methylimidazole-5(4)-carbaldehyde Oxime
(2e). Prepared according to the general method. Aldehyde 1e
1 g (9.08 mmol), NH2OH‚HCl 1.26 g (18.2 mmol), water (8 mL),
Na2CO3 0.96 g (9.08 mmol), reaction time 1.5 h at ambient
temperature. Yield 69% 1H NMR (DMSO-d6): δ ) 2.25 (s, 3H),
7.55 (s, 1H), 8.02 (s, 1H), 10.80 (s, 1H); 13C NMR (DMSO-d6):