M. F. A. Adamo et al. / Tetrahedron 63 (2007) 2684–2688
2687
at 65 ꢀC for 2 h, before diethyl malonate 2 (580 mg,
3.6 mmol, 1.2 equiv) was added. The reaction was continued
at 65 ꢀC for further 3 h, then diluted with 36% w/v HCl
(20 mL) and refluxed for 24 h. The reaction mixture was
then cooled to room temperature and extracted with diethyl
ether (100 mLꢃ2). The organic layer was concentrated in
vacuo and the sodium salt of the carboxylic acids 4a–c
was then extracted from the organic layer using a saturated
aqueous solution of NaHCO3 (20 mL). The water layer
was acidified to pH 4 by dropwise addition of concd HCl.
The product was finally extracted into chloroform, dried
over MgSO4 and concentrated in vacuo. The spectroscopic
data of compounds 4a–c were reported in a previous
communication.9
157.3, 145.1, 142.1, 132.6, 114.0, 113.0, 112.6, 112.5, 40.2
(CH), 39.1 (CH2), 33.3 (CH2), 11.8 (CH3). HRMS found:
(MꢁH+) 322.0582, C14H13ClN3O4 requires 322.0595; m/z:
322 (100%, MꢁH+).
3.1.4. Procedure for the preparation of compounds 5a–c
and 6a–c. Compound 4a–c or 10a–c (1 mmol) was com-
bined with SnCl2$2H2O (490 mg, 6.6 mmol, 2.2 equiv),
THF (20 mL), water (20 mL) and concd HCl (1 mL). The re-
actants were refluxed at 80 ꢀC for 16 h and were then cooled
to room temperature. The THF was evaporated in vacuo and
the water layer was extracted with diethyl ether (100 mLꢃ5).
The ether layer was dried over MgSO4, concentrated invacuo
and the product was crystallised from ethanol.
3.1.3. Procedure for the preparation of compounds
10a–c. In a round-bottomed flask were put compounds 4a–c
(3.0 mmol), NaOH (120 mg, 3.0 mmol, 1 equiv) and hydr-
azine hydrate (0.15 mL, 3.0 mmol, 1 equiv). The reaction
mixture was stirred at 75 ꢀC for 8 h. It was then transferred
into a large beaker, diluted with water (120 mL) and cooled
with an ice-bath. It was acidified with 3 M HCl until a white
precipitate was obtained. The precipitate was extracted into
ethyl acetate (50 mLꢃ2), washed with water (50 mL), dried
over Na2SO4 and evaporated in vacuo.
3.1.4.1.
3-Methyl-7-phenyl-4,6,7,8-tetrahydro-1H-
1,2,4-triaza-azulen-5-one 6a. Colourless solid (171 mg,
71% yield), Rf ¼0.3 (acetone/petroleum ether 4:6), mp
225–227 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3460–3320b,
1681s; dH (400 MHz, d6-DMSO) 13.31 (1H, s, HNC]O),
11.93 (1H, s, HN–N), 7.19–7.06 (5H, m, Ph), 3.45 (1H,
app. t, J¼7, CHPh), 3.10–3.05 (2H, m, CH2, CH2C]O),
2.40 (1H, dd, J¼15, J¼6, PyrCH2), 2.28 (1H, dd, J¼15,
J¼6, PyrCH2), 2.00 (3H, s, CH3); dC (100 MHz, CDCl3)
171.9 (C]O), 154.3, 153.1, 135.5, 132.8, 132.0, 129.9,
121.1, 39.8 (CH), 39.1 (CH2), 32.0 (CH2), 8.2 (CH3C]N).
HRMS found: (MꢁH+) 240.1125, C14H14N3O requires
240.1137; m/z: 242.1 (50%, M+H+).
3.1.3.1.
4-(5-Methyl-4-nitro-2H-pyrazol-3-yl)-3-
phenyl-butyric acid 10a. Colourless solid (280 mg, 97%
yield), Rf ¼0.4 (ethyl acetate/petroleum ether 50:50), mp
181–182 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3445–3220b,
1687s; dH (400 MHz, CDCl3) 7.29–7.18 (5H, m, Ph), 6.78
(2H, br, OH and NH), 3.76–3.69 (1H, m, CHPh), 3.62–3.50
(2H, m, PyrCH2), 2.78–2.74 (2H, m, CH2COOH), 2.47 (3H,
s, CH3C]N); dC (100 MHz, CDCl3) 172.4 (C]O), 155.0,
140.8, 129.9, 128.4, 127.0, 126.6, 40.2 (CH2), 39.5 (CH),
33.4 (CH2), 11.2 (CH3). HRMS found: (MꢁH+) 288.0988,
C14H14N3O5 requires 288.0984; m/z: 289 (100%, M+).
3.1.4.2. 7-(4-Chloro-phenyl)-3-methyl-4,6,7,8-tetra-
hydro-1H-1,2,4-triaza-azulen-5-one 6b. Colourless solid
(280 mg, 76% yield), Rf ¼0.34 (ethyl acetate/acetone/
petroleum ether 1:1:2), mp 228–230 ꢀC (ethanol); nmax
(Film)/cmꢁ1: 3460–3341b, 1665s; dH (400 MHz, d6-DMSO)
13.4 (1H, s, HNC]O), 12.06 (1H, s, HN–N), 7.31 (2H, d,
J¼8, p-ClC6H4), 7.24 (2H, d, J¼8, p-ClC6H4), 3.52 (1H,
app. t, J¼7, CH(p-ClC6H4)), 3.14 (2H, d, J¼3, CH2C]O),
2.64 (1H, dd, J¼15, J¼6, PyrCH2), 2.44 (1H, dd, J¼15,
J¼6, PyrCH2), 2.50 (3H, s, CH3); dC (100 MHz, CDCl3)
171.8 (C]O), 154.5, 153.9, 140.5, 132.3, 128.3, 128.2,
121.6, 39.5 (CH), 39.2 (CH2), 32.3 (CH2), 9.2 (CH3C]N).
HRMS found: (MꢁH+) 274.0742, C14H13N3OCl requires
274.0747; m/z: 274 (100%, MꢁH+).
3.1.3.2. 3-(4-Chloro-phenyl)-4-(5-methyl-4-nitro-2H-
pyrazol-3-yl)-butyric acid 10b. Colourless solid (969 mg,
100% yield), Rf ¼0.6 (ethyl acetate), mp 188–190 ꢀC (etha-
nol); nmax (Film)/cmꢁ1: 3445–3220b, 1687s; dH (400 MHz,
acetone-d6) 7.31 (2H, d, J¼8, p-ClC6H4), 7.29 (2H, d,
J¼8, p-ClC6H4), 3.73–3.65 (1H, m, CHC6H4(p-Cl)), 3.36
(1H, dd, J¼14, J¼7, Pyr–CHaHb), 3.26 (1H, dd, J¼14, J¼8,
Pyr–CHaHb), 2.77 (1H, dd, J¼15, J¼6, CHaHbCOOH),
2.70 (1H, dd, J¼15, J¼9, CHaHbCOOH), 2.50 (3H, s,
CH3C]N); dC (100 MHz, acetone-d6) 172.1 (C]O), 165.2,
145.2, 142.8, 142.1, 131.2, 128.8, 127.8, 39.5 (CH), 39.0
(CH2), 33.4 (CH2), 11.5 (CH3). HRMS found: (MꢁH+)
322.0582, C14H13ClN3O4 requires 322.0595; m/z: 322
(100%, MꢁH+).
3.1.4.3. 7-(3-Chloro-phenyl)-3-methyl-4,6,7,8-tetra-
hydro-1H-1,2,4-triaza-azulen-5-one 6c. Colourless solid
(239 mg, 87% yield), Rf ¼0.16 (acetone/petroleum ether 4:6),
mp 218–219 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3460–3341b,
1675s; dH (400 MHz, d6-DMSO) 12.2 (1H, s, HNC]O),
9.18 (1H, s, HN–N), 7.41 (1H, s, m-ClC6H4), 7.36 (1H,
app. t, J¼7, m-ClC6H4), (2H, d, J¼7, m-ClC6H4), 3.50–3.46
(1H, m, CH(m-ClC6H4)), 3.12 (2H, d, J¼3, CH2C]O), 2.57
(1H, dd, J¼15, J¼6, PyrCH2), 2.49 (1H, dd, J¼15, J¼6,
PyrCH2), 2.1 (3H, s, CH3); dC (100 MHz, d6-DMSO) 171.8
(C]O), 154.5, 145.9, 133.1, 130.4, 126.7, 126.4, 125.5,
117.0, 121.6, 42.5 (CH2), 39.3 (CH2), 32.7 (CH), 9.1
(CH3). HRMS found: (MꢁH+) 274.0739, C14H13N3OCl
requires 274.0747; m/z: 274.1 (100%, MꢁH+).
3.1.3.3. 3-(3-Chloro-phenyl)-4-(5-methyl-4-nitro-2H-
pyrazol-3-yl)-butyric acid 10c. Colourless solid (920 mg,
95% yield), Rf ¼0.6 (ethyl acetate/petroleum ether 50:50),
mp 168–171 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3415–3195b,
1688s; dH (400 MHz, acetone-d6) 7.28–7.21 (4H, m,
m-ClC6H4), 3.75–3.67 (1H, m, CHC6H4(m-Cl)), 3.35 (1H,
dd, J¼14, J¼7, Pyr–CHaHb), 3.27 (1H, dd, J¼14, J¼8,
Pyr–CHaHb), 2.82 (1H, dd, J¼15, J¼6, CHaHbCOOH),
2.75 (1H, dd, J¼15, J¼9, CHaHbCOOH), 2.53 (3H, s,
CH3C]N); dC (100 MHz, acetone-d6) 171.8 (C]O),
3.1.5. 5-Ethoxy-3-methyl-7-phenyl-7,8-dihydro-6H-
isoxazolo[4,5-b]azepine 9a. Compound 4a (1 mmol) was
combined with SnCl2$2H2O (490 mg, 6.6 mmol, 2.2 equiv),
ethanol (20 mL), water (20 mL) and concd HCl (1 mL). The