9744
M. F. A. Adamo et al. / Tetrahedron 63 (2007) 9741–9745
dC (100.6 MHz, CDCl3) 170.4, 155.3, 134.2, 132.5, 130.9,
127.4, 116.8, 112.3, 40.8, 32.9, 11.2; HRMS found:
[MꢁH+] 396.0932, C18H14N5O6 requires 396.0944; m/z:
396 (100%, MꢁH+).
CDCl3) 12.07 (2H, br, CO2H), 7.21 (5H, s, Ar), 3.37–3.33
(1H, m, CH2CHCH2), 2.61–2.59 (2H, m, CH2CH), 2.50–
2.47 (2H, m, CHCH2); dC (100.6 MHz, CDCl3) 175.3,
141.2, 135.9, 128.1, 126.2, 36.4, 20.6; HRMS found:
[MꢁH+] 207.0741, C11H11O4 requires 207.0736; m/z:
207.2 (100%, MꢁH+).
3.3. General procedure for the preparation of
compounds 5a–f (Table 2)
3.3.5. 3-(4-Nitrophenyl)-pentanedioic acid 5e. Colourless
solid (137 mg, 0.54 mmol, 54% yield), mp: 141–144 ꢀC
(ethyl acetate/toluene 1:1); Rf¼0.3 (40% ethyl acetate in
petroleum spirits); nmax (KBr)/cmꢁ1: 3561, 1699, 1481; dH
(400 MHz, CDCl3) 12.22 (2H, br, CO2H), 8.14 (2H, d,
J¼8.0, Ar), 7.67 (2H, J¼8.0, Ar), 3.69–3.66 (1H, m,
CH2CHCH2), 2.71–2.68 (2H, m, CH2CH), 2.59–2.54 (2H,
m, CHCH2); dC (100.6 MHz, CDCl3) 178.1, 154.6, 145.9,
131.9, 129.5, 37.9, 20.0; HRMS found: [MꢁH+] 252.0581,
C11H10NO6 requires 252.0586; m/z: 252.1 (100%, MꢁH+).
To a stirred solution of 3,5-dimethyl-4-nitroisoxazole 1
(0.23 g, 1.6 mmol) in tetrahydrofuran (10 mL), were added
piperidine (138 mg, 1.6 mmol, 1.0 equiv) and an aromatic
aldehyde 2a–f (3.2 mmol, 2.0 equiv). The resulting solution
was reacted at 70–80 ꢀC for 12 h. The reaction mixture was
then cooled to room temperature and treated with a solution
made of potassium permanganate (0.850 g, 5.4 mmol,
12 equiv), water (30 mL) and acetone (10 mL), which was
added dropwise. The addition required 5 h. After this time,
the reaction mixture was treated with saturated solution
of aqueous sodium sulfite (40 mL) and acidified with con-
centrated hydrochloric acid (8.0 mL) to reach pH 1–2. The
reaction mixture was then concentrated and the solid
obtained was filtered and crystallised from mixtures of ethyl
acetate/toluene.
3.3.6. 3-(4-Cyanophenyl)-pentanedioic acid 5f. Pale
yellow solid (135 mg, 0.58 mmol, 58% yield), mp: 128–
134 ꢀC (ethyl acetate/toluene 1:1); Rf¼0.3 (40% ethyl ace-
tate in petroleum spirits); nmax (KBr)/cmꢁ1: 3561, 2262,
1681; dH (400 MHz, CDCl3) 12.12 (2H, br, CO2H), 7.59
(2H, d, J¼8.0, Ar), 7.32 (2H, J¼8.0, Ar), 3.59–3.54 (1H,
m, CH2CHCH2), 2.68–2.64 (2H, m, CH2CH), 2.61–2.58
(2H, m, CHCH2); dC (100.6 MHz, CDCl3) 173.8, 142.1,
130.8, 129.6, 127.4, 118.1, 37.1, 21.2; HRMS found:
[MꢁH+] 232.0682, C12H10NO4 requires 232.0688; m/z:
232.1 (100%, MꢁH+).
3.3.1. 3-p-Tolyl-pentanedioic acid 5a. Colourless solid
(136 mg, 0.61 mmol, 61% yield), mp: 118–121 ꢀC (ethyl
acetate/toluene 1:1); Rf¼0.3 (40% ethyl acetate in petroleum
spirits); nmax (KBr)/cmꢁ1: 3564, 1744, 1271; dH (400 MHz,
CDCl3) 12.05 (2H, br, CO2H), 7.14 (2H, d, J¼8.0, Ar), 7.07
(2H, J¼8.0, Ar), 3.37 (1H, m, CH2CHCH2), 2.64–2.58 (2H,
m, CH2CH), 2.51–2.44 (2H, m, CHCH2), 2.25 (3H, s, CH3–
Ar); dC (100.6 MHz, CDCl3) 172.8, 140.3, 135.3, 128.7,
127.2, 37.5, 20.5; HRMS found: [MꢁH+] 221.0886,
C12H13O4 requires 221.0892; m/z: 221 (100%, MꢁH+).
3.4. General procedure for the preparation of
compounds 6a–f (Table 3)
To a stirred solution of 3,5-dimethyl-4-nitroisoxazole 1
(0.23 g, 1.6 mmol) in ethanol (10 mL), were added piperi-
dine (138 mg, 1.6 mmol, 1.0 equiv) and an aromatic alde-
hyde 2a–f (3.2 mmol, 2.0 equiv). The resulting solution
was reacted at 70–80 ꢀC for 12 h, then hydrazine hydrate
(60% in water, 1.1 mmol, 1.1 equiv) was added and the reac-
tion mixture was reacted at 80 ꢀC for 4 h. At the end of this
time the reaction mixture was allowed to reach room temper-
ature, diluted with water (20 mL) and extracted with ethyl
acetate (25 mLꢃ2). The combined organic layer was
washed with water (10 mLꢃ2), then brine (10 mL), dried
over Na2SO4 and finally concentrated under reduced pres-
sure. The crude product was triturated with 10% ethyl ace-
tate in petroleum ether to afford the pure products 6a–f.
3.3.2. 3-(4-Methoxyphenyl)-pentanedioic acid 5b. Colour-
less solid (140 mg, 0.59 mmol, 59% yield), mp: 103–106 ꢀC
(ethyl acetate/toluene 1:1); Rf¼0.4 (40% ethyl acetate in
petroleum spirits); nmax (KBr)/cmꢁ1: 3563, 1685, 1298; dH
(400 MHz, CDCl3) 12.10 (2H, br, CO2H), 7.76 (2H, d,
J¼8.0, Ar), 7.49 (2H, J¼8.0, Ar), 3.85 (3H, s, –OCH3),
3.50–3.41 (1H, m, CH2CHCH2), 2.69–2.64 (2H, m,
CH2CH), 2.62–2.56 (2H, m, CHCH2); dC (100.6 MHz,
CDCl3) 174.4, 159.0, 141.8, 128.7, 121.6, 61.3, 35.7, 20.8;
HRMS found: [MꢁH+] 237.0839, C12H13O5 requires
237.0841; m/z: 237 (100%, MꢁH+).
3.3.3. 3-(4-Chlorophenyl)-pentanedioic acid 5c. Colour-
less solid (153 mg, 0.63 mmol, 63% yield), mp: 136–
141 ꢀC (ethyl acetate/toluene 1:1); Rf¼0.3 (40% ethyl ace-
tate in petroleum spirits); nmax (KBr)/cmꢁ1: 3469, 1684,
1286; dH (400 MHz, CDCl3) 12.15 (2H, br, CO2H), 7.33
(2H, d, J¼8.0, Ar), 7.29 (2H, J¼8.0, Ar), 3.44–3.37 (1H,
m, CH2CHCH2), 2.68–2.62 (2H, m, CH2CH), 2.55–2.48
(2H, m, CHCH2); dC (100.6 MHz, CDCl3) 172.6, 142.4,
130.9, 129.4, 128.0, 37.3, 20.1; HRMS found: [MꢁH+]
241.0349, C11H10ClO4 requires 241.0346; m/z: 241 (100%,
MꢁH+).
3.4.1. 2-(p-Tolyl)-1,3-di(3-methyl-4-nitro 1H-pyrazol-5-
yl) propane 6a. Colourless solid (353 mg, 0.92 mmol,
92% yield), mp: 191–193 ꢀC (ethanol); nmax (KBr)/cmꢁ1
:
3291, 1572, 1439; dH (400 MHz, CDCl3) 13.50 (2H, br,
N–NH), 7.14–7.13 (4H, m, Ar), 3.75–3.72 (1H, m,
CH2CHCH2), 3.35 (4H, dd, J¼8.0, J¼14.5, CHCH2), 2.56
(6H, s, CH3C]N), 2.30 (3H, s, CH3–Ar); dC (100.6 MHz,
CDCl3) 157.3, 145.5, 142.8, 135.3, 129.8, 128.8, 127.0,
41.3, 33.4, 20.5, 11.6; HRMS found: [MꢁH+] 383.1463,
C18H19N6O4 requires 383.1468; m/z: 383 (100%, MꢁH+).
3.3.4. 3-Phenyl-pentanedioic acid 5d. Colourless solid
(125 mg, 0.60 mmol, 60% yield), mp: 105–108 ꢀC (ethyl
acetate/toluene 1:1); Rf¼0.4 (40% ethyl acetate in petroleum
spirits); nmax (KBr)/cmꢁ1: 3669, 1741, 1289; dH (400 MHz,
3.4.2. 2-(4-Methoxyphenyl)-1,3-di(3-methyl-4-nitro 1H-
pyrazol-5-yl) propane 6b. Colourless solid (360 mg,
0.90 mmol, 90% yield), mp: 179–185 ꢀC (ethanol); nmax
(KBr)/cmꢁ1: 3162, 1451, 1237; dH (400 MHz, CDCl3)