The Journal of Organic Chemistry
Note
mixture was purged with nitrogen through a Teflon-lined cap followed
by replacement with a new Teflon-lined solid cap. After the reaction
vial was moved to a preheated reaction block, the reaction mixture was
stirred at 90 °C. After 6 h, the reaction mixture was cooled to 25 °C
and concentrated. The residue was purified by flash column
chromatography (hexanes/EtOAc = 5:2) to provide pyrazole 18a as
a white solid (152 mg, 60% yield). Mp 99−100 °C; IR (film) 3130,
chromatography (hexanes/EtOAc = 6:1) to provide pyrazole 20a as
a yellow oil (757 mg, 94% yield). IR (film) 3133, 3079, 2978, 2940,
2852, 1506, 1407, 1302 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.11 (s,
1H), 8.08 (s, 1H), 5.89−5.63 (m, 1H), 5.16−4.94 (m, 2H), 4.16 (t, J =
6.6 Hz, 2H), 2.13−1.96 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
136.4, 135.8, 135.6, 128.5, 116.5, 52.7, 30.3, 28.7; HRMS (ESI) calcd
for C8H12N3O2 [M + H]+ 182.0924, found 182.0914.
4-Methylene-3-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine
(20b). For the intramolecular alkenylation reaction, 20a (91 mg, 0.50
mmol), 1,4-dioxane (5.0 mL, 0.10 M), Cu(OAc)2·H2O (200 mg, 1.0
mmol), pyridine (8.1 μL, 0.10 mmol), and Pd(OAc)2 (11 mg, 0.050
mmol) were used. Purification by flash column chromatography
(hexanes/EtOAc = 4:1) provided alkenylated pyrazole 20b as a yellow
solid (40 mg, 45% yield). Mp 44−47 °C; IR (film) 3129, 2966, 2855,
1531, 1504, 1417 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H),
6.61 (s, 1H), 5.65 (s, 1H), 4.28 (t, J = 6.2 Hz, 2H), 2.71−2.54 (m,
2H), 2.21−2.07 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 138.4, 136.7,
130.0, 128.8, 122.1, 49.7, 31.0, 22.7; HRMS (ESI) calcd for
C8H10N3O2 [M + H]+ 180.0768, found 180.0767.
1-(Hex-5-en-1-yl)-4-nitro-1H-pyrazole (21a). Similar to the syn-
thesis of 20a, 21a was prepared from a reaction of 4-nitro-1H-pyrazole
(599 mg, 5.30 mmol), K2CO3 (879 mg, 6.36 mmol), 6-bromo-1-
hexene (0.850 mL, 6.36 mmol), and DMF (8.00 mL). Purification by
flash column chromatography (hexanes/EtOAc = 5:1) provided
pyrazole 21a as a white solid (1.01 g, 98% yield). Mp 27−29 °C; IR
(film) 3134, 3077, 2933, 2860, 1530, 1510 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.12 (s, 1H), 8.07 (s, 1H), 5.85−5.67 (m, 1H), 5.12−4.87
(m, 2H), 4.15 (t, J = 7.1 Hz, 2H), 2.16−2.04 (m, 2H), 1.99−1.87 (m,
2H), 1.48−1.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 137.6, 135.5,
128.4, 115.2, 53.2, 32.9, 29.0, 25.4; HRMS (ESI) calcd for C9H14N3O2
[M + H]+ 196.1081, found 196.1074.
4-Methylene-3-nitro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]-
azepine (21b). For the intramolecular alkenylation reaction, 21a (98
mg, 0.50 mmol), 1,4-dioxane (5.0 mL, 0.10 M), Cu(OAc)2·H2O (200
mg, 1.0 mmol), pyridine (8.1 μL, 0.10 mmol), and Pd(OAc)2 (11 mg,
0.050 mmol) were used. Purification by flash column chromatography
(hexanes/EtOAc = 4:1) provided alkenylated pyrazole 21b as a white
solid (56 mg, 58% yield). Mp 58−60 °C; IR (film) 3126, 2937, 2857,
1549, 1504, 1466 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H),
5.73 (s, 1H), 5.52 (s, 1H), 4.26 (t, J = 4.9 Hz, 2H), 2.47 (t, J = 5.6 Hz,
3H), 1.98−1.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 142.5, 135.9,
134.2, 124.6, 54.8, 35.4, 30.6, 26.8; HRMS (ESI) calcd for C9H12N3O2
[M + H]+ 194.0924, found 194.0925.
1
2982, 1711, 1607,1531, 1510, 1408, 1302 cm−1; H NMR (300 MHz,
CDCl3) δ 8.13 (s, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.35 (d,
J = 8.3 Hz, 2H), 6.46 (d, J = 15.5 Hz, 1H), 6.29−6.13 (m, 1H), 4.45−
4.25 (m, 4H), 2.85 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 166.3, 140.9, 135.9, 135.6, 132.9, 129.9,
129.5, 128.6, 126.9, 126.0, 61.0, 52.9, 33.4, 14.4; HRMS (ESI) calcd
for C16H18N3O4 [M + H]+ 316.1292, found 316.1299.
(E)-Ethyl 4-((3-Nitro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-
ylidene)methyl)benzoate (18b). For the intramolecular alkenylation
reaction, 18a (79 mg, 0.25 mmol), 1,4-dioxane (2.5 mL, 0.10 M),
Cu(OAc)2·H2O (100 mg, 0.50 mmol), pyridine (4.0 μL, 0.050 mmol),
and Pd(OAc)2 (5.6 mg, 0.025 mmol) were used. Purification by flash
column chromatography (hexanes/EtOAc = 9:4) provided alkenylated
pyrazole 18b as a yellow solid (44 mg, 56% yield). Mp 161−163 °C.
1
IR (film) 3101, 2979, 1715, 1605, 1538, 1411, 1387 cm−1; H NMR
(300 MHz, CDCl3) δ 8.20 (s, 2H), 8.10 (d, J = 7.4 Hz, 2H), 7.54 (d, J
= 7.8 Hz, 2H), 4.48−4.35 (m, 4H), 3.66 (t, J = 5.1 Hz, 2H), 1.42 (t, J
= 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 146.2, 143.4,
142.0, 140.2, 130.4, 130.1, 130.0, 129.2, 127.8, 61.3, 48.3, 32.5, 14.4;
HRMS (ESI) calcd for C16H15N3O4Na [M + Na]+ 336.0955, found
336.0959.
(E)-4-Nitro-1-(5-phenylpent-4-en-1-yl)-1H-pyrazole (19a). Follow-
ing a reported procedure, the Heck reaction was carried out.30 To an 8
mL glass vial equipped with a magnetic stir bar were sequentially
added 20a (181 mg, 1.0 mmol), N,N-diisopropylethylamine (0.350 μL,
2.0 mmol), acetonitrile (2.00 mL, 0.50 M), bromobenzene (105 μL,
1.0 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), and P(o-tolyl)3 (45.7
mg, 0.15 mmol). The reaction mixture was purged with argon through
a Teflon-lined cap followed by replacement with a new Teflon-lined
solid cap. After the reaction vial was moved to a preheated reaction
block, the reaction mixture was stirred at 90 °C. After 12 h, the
reaction mixture was cooled to 25 °C and concentrated. The residue
was purified by recrystallization with EtOAc and hexanes to provide
pyrazole 19a as a white solid (57 mg, 22% yield). Mp 66−67 °C; IR
(film) 3131, 3024, 2922, 1529, 1480, 1369 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.13 (s, 1H), 8.09 (s, 1H), 7.37−7.27 (m, 4H), 7.24−7.18
(m, 1H), 6.41 (d, J = 16.2 Hz, 1H), 6.22−6.06 (m, 1H), 4.20 (t, J = 6.7
Hz, 2H), 2.26 (q, J = 7.2 Hz, 2H), 2.11 (d, J = 7.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 137.1, 136.0, 131.8, 128.7, 128.6, 128.0, 127.5,
126.1, 52.8, 29.8, 29.2; HRMS (EI) calcd for C14H15N3O2 [M]+
257.1164, found 257.1163.
Butyl 1-Methyl-1,4-dihydropyrrolo[3,2-c]pyrazole-5-carboxylate
(22). To an 8 mL glass vial equipped with a magnetic bar were
sequentially added 2a (121 mg, 0.48 mmol), PPh3 (315 mg, 1.20
mmol), and o-dichlorobenzene (2.00 mL, 0.24 M). The reaction
mixture was stirred at 180 °C. After 24 h, the reaction mixture was
cooled to 25 °C. The residue was purified by flash column
chromatography (hexanes/EtOAC = 3:1) to provide pyrazole 22 as
a brown solid (54 mg, 51% yield). Mp 89−90 °C; IR (film) 3227,
(E)-4-Benzylidene-3-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyridine (19b). For the intramolecular alkenylation reaction, 19a (38
mg, 0.15 mmol), 1,4-dioxane (1.5 mL, 0.10 M), Cu(OAc)2·H2O (60
mg, 0.30 mmol), pyridine (2.4 μL, 0.030 mmol), and Pd(OAc)2 (3.4
mg, 0.015 mmol) were used. Purification by flash column
chromatography (hexanes/EtOAc = 7:2) provided alkenylated
pyrazole 19b as a yellow solid (21 mg, 56% yield). Mp 77−78 °C;
1
2954, 2869, 1694, 1528, 1455 cm−1; H NMR (300 MHz, CDCl3) δ
8.44 (br s, 1H), 7.37 (s, 1H), 6.70 (s, 1H), 4.32 (t, J = 6.6 Hz, 2H),
3.96 (s, 3H), 1.74 (pentet, J = 7.0 Hz, 2H), 1.47 (sextet, J = 7.4 Hz,
2H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.4,
138.6, 130.4, 129.5, 119.3, 93.7, 64.9, 37.3, 30.8, 19.3, 13.8; HRMS
(ESI) calcd for C11H16N3O2 [M + H]+ 222.1237, found 222.1231.
1-Methyl-5-phenyl-1,4-dihydropyrrolo[3,2-c]pyrazole (23). To an
8 mL glass vial equipped with a magnetic bar were sequentially added
2f (115 mg, 0.50 mmol), PPh3 (328 mg, 1.25 mmol), and o-
dichlorobenzene (2.00 mL, 0.25 M). The reaction mixture was stirred
at 180 °C. After 36 h, The reaction mixture was cooled to 25 °C. The
residue was purified by flash column chromatography (hexanes/EtOAc
= 2:3) to provide pyrazole 23 as a brown solid (54 mg, 55% yield). Mp
185−186 °C; IR (film) 3177, 3062, 2931, 2854, 1602, 1503 cm−1; 1H
NMR (300 MHz, CDCl3) δ 7.83 (br s, 1H), 7.58−7.56 (m, 2H), 7.42
(t, J = 7.7 Hz, 2H), 7.34−7.31 (m, 2H), 6.34 (s, 1H), 3.97 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 141.7, 140.4, 133.2, 129.1, 128.3, 127.7,
124.9, 118.9, 86.7, 37.3; HRMS (ESI) calcd for C12H12N3 [M + H]+
198.1026, found 198.1026.
1
IR (film) 2929, 1523, 1426, 1343, 1254 cm−1; H NMR (300 MHz,
CDCl3) δ 8.20 (s, 1H), 8.09 (s, 1H), 7.48−7.28 (m, 5H), 4.29 (t, J =
6.2 Hz, 2H), 2.89 (t, J = 5.5 Hz, 2H), 2.10 (pentet, J = 6.3 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 138.8, 138.2, 136.2, 135.9, 129.5, 128.5,
128.1, 123.4, 49.6, 25.2, 22.7; HRMS (ESI) calcd for C14H14N3O2 [M
+ H]+ 256.1081, found 256.1073.
4-Nitro-1-(pent-4-en-1-yl)-1H-pyrazole (20a). To a stirred solution
of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol) in DMF (3.00 mL) at 25
°C were added K2CO3 (732 mg, 5.30 mmol) and 5-bromo-1-pentene
(0.630 mL, 5.30 mmol). After 13 h, the reaction mixture was treated
with water (15 mL) and EtOAc (20 mL). After shaking in a 125 mL
separatory funnel, the separated aqueous phase was extracted with
EtOAc (20 mL × 2). The combined organic layers were washed with
brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated, and the residue was purified by flash column
H
J. Org. Chem. XXXX, XXX, XXX−XXX