Journal of Medicinal Chemistry
Article
solution was stirred for 7 h at room temperature. On completion of
the reaction, methanol was evaporated under reduced pressure and
the obtained crude product was then chromatographed on silica gel,
with ethyl acetate (30−40%)/hexanes (70−60%) as eluent, to afford
1
5
1
the title compound 21 as a red solid (0.255 g, 84%). Mp 130−132
1
3
1
°C; H NMR (CDCl , 600 MHz) δ 12.66 (s, 1H), 12.60 (s, 1H),
3
6
7.2, 31.6, 30.6, 25.7, 22.6, 22.1 (2C), 14.1, 11.3; HRMS (ESI) calcd
12.50 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.86
(s, 1H), 6.80 (s, 1H), 6.62 (s, 1H), 6.02 (s, 1H), 5.99 (s, 1H), 4.04 (s,
2H), 3.96 (s, 3H), 3.78 (s, 3H), 2.54 (s, 3H), 2.39 (t, J = 7.3 Hz, 2H),
+
for C H NO (M + H) 238.1802; found 238.1795.
14
24
2
Isopropyl 4-Butyl-5-methyl-1H-pyrrole-2-carboxylate (20b).
1
13
Yield: 4.74 g (73%) white amorphous solid; mp 67−69 °C;
NMR (CDCl , 600 MHz) δ 9.09 (br s, 1H), 6.71 (d, J = 1.8 Hz, 1H),
H
1.54 (m, 2H), 1.34 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H); C NMR
3
(CDCl , 150 MHz) δ 165.6, 158.3, 147.6, 145.5, 143.1, 130.6, 129.9
3
5
.19 (s, 1H), 2.38 (t, J = 7.5 Hz, 2H), 2.23 (s, 3H), 1.53 (m, 2H),
(2C), 127.8, 127.4, 124.9, 121.3, 121.1, 118.5, 114.8, 114.1 (2C),
110.8, 92.5, 58.6, 55.2, 33.8, 31.4, 29.9, 25.3, 22.5, 14.1, 12.3; HRMS
1
.37 (m, 2H), 1.33 (d, J = 6.3 Hz, 6H), 0.94 (t, J = 7.3 Hz, 3H); 13
C
+
NMR (CDCl , 150 MHz) δ 160.9, 130.1, 122.7, 120.1, 115.5, 67.2,
(ESI) calcd for C H N O (M + H) 444.2646; found 444.2641.
3
28 34
3
2
3
3.1, 25.4, 22.4, 22.1 (2C), 14.0, 11.3; HRMS (ESI) calcd for
Synthesis of 5′-(4-Hydroxybenzyl)-4-methoxy-1H,1′H-[2,2′-bi-
pyrrole]-5-carbaldehyde (22). To a stirred suspension of 8 (1.0 g,
3.2 mmol) in anhydrous DCM (250 mL) was added dropwise BBr3
(1.0 M in DCM; 6.45 mL, 6.45 mmol) under an argon atmosphere at
−78 °C. The resulting suspension was stirred for 8 h while it was
allowed to warm up to room temperature. The reaction mixture was
quenched with water (50 mL), and the DCM was evaporated under
reduced pressure. Then, the crude material was filtered by a sintered
funnel and washed with water and DCM (50 mL) to afford the pure
+
C H NaNO [M + Na] 246.1465; found 246.1458.
13
21
2
Isopropyl 4-Hexyl-5-methyl-1H-pyrrole-2-carboxylate (20c).
1
Yield: 5.02 g (67%) white amorphous solid; mp 71−73 °C;
NMR (CDCl , 600 MHz) δ 8.74 (br s, 1H), 6.71 (d, J = 2.5 Hz, 1H),
H
3
5.18 (s, 1H), 2.37 (t, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.53 (m, 2H),
1
.32 (d, J = 6.2 Hz, 6H), 1.31 (m, 6H), 0.90 (t, J = 7.0 Hz, 3H); 13
C
NMR (CDCl , 100 MHz) δ 160.9, 130.1, 122.8, 120.1, 115.5, 67.2,
3
3
1.8, 30.9, 29.1, 25.7, 22.7, 22.1 (2C), 14.1, 11.3; HRMS (ESI) calcd
+
1
for C H NaNO [M + Na] 274.1778; found 274.1767.
compound 22 as a pale green solid (0.87 g, 91%). Mp > 200 °C; H
15
25
2
Isopropyl 4-Heptyl-5-methyl-1H-pyrrole-2-carboxylate (20d).
NMR (DMSO-d , 600 MHz) δ 11.28 (s, 1H), 10.98 (s, 1H), 9.25 (s,
6
1
Yield: 5.52 g (69%) white amorphous solid; mp 63−65 °C;
NMR (CDCl , 600 MHz) δ 9.17 (br s, 1H), 6.72 (d, J = 2.5 Hz, 1H),
H
1H), 7.07 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H), 6.62 (s, 1H),
1
3
3
6.22 (d, J = 2.4 Hz, 1H), 5.84 (s, 1H), 3.82 (s, 3H), 3.79 (s, 2H);
C
5
.19 (s, 1H), 2.37 (t, J = 7.5 Hz, 2H), 2.23 (s, 3H), 1.54 (m, 2H),
.34 (d, J = 6.3 Hz, 6H), 1.36−1.29 (m, 8H), 0.90 (t, J = 7.2 Hz, 3H);
NMR (DMSO-d , 150 MHz) δ 171.5, 159.3. 156.1, 135.0, 134.0,
6
1
1
30.4, 129.7 (2C), 122.9, 117.7, 115.6 (2C), 109.3, 108.3, 91.0, 58.2,
13
+
C NMR (CDCl , 150 MHz) δ 161.0, 130.2, 122.8, 120.1, 115.5,
3
33.1; HRMS (ESI) calcd for C H N O (M + H) 297.1234; found
17 17 2 3
6
7.2, 31.9, 30.9, 29.3, 29.2, 25.7, 22.7, 22.1 (2C), 14.1, 11.3; HRMS
297.1225.
+
(ESI) calcd for C H NO (M + H) 266.2115; found 266.2107.
Synthesis of HBPGs 2−5. Compounds 2−5 were synthesized
and purified in excellent yields (82−85%) by the same procedure as
described for 21 from 22 and their corresponding dialkyl pyrroles 9a−
d.
16
28
2
Synthesis of Intermediates 9a−d. Compounds 9a−d were
synthesized and purified in good yields (75−82%) by the same
procedure as described for 17 from 20a−d.
2
-Methyl-3-pentyl-1H-pyrrole (9a). Yield: 2.26 g (79%) clear oil;
4-((4′-Methoxy-5′-((5-methyl-4-pentyl-1H-pyrrol-2-yl)-
1
H NMR (CDCl , 600 MHz) δ 7.73 (br s, 1H), 6.62 (t, J = 2.7 Hz,
methylene)-1H,5′H-[2,2′-bipyrrol]-5-yl)methyl)phenol (2). Yield:
3
1
1
1
H), 6.04 (t, J = 2.7 Hz, 1H), 2.41 (t, J = 7.6 Hz, 2H), 2.21 (s, 3H),
0.130 g (83%) red solid; mp 146−148 °C; H NMR (CDCl , 400
3
1
3
.56 (m, 2H), 1.39−1.34 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H); C NMR
MHz) δ 12.63 (br s, 1H), 12.58 (br s, 1H), 12.50 (br s, 1H), 7.24 (d,
J = 8.3 Hz, 2H), 6.90 (s, 1H), 6.84 (s, 1H), 6.80 (d, J = 8.3 Hz, 2H),
6.65 (s, 1H), 6.05 (s, 1H), 6.03 (s, 1H), 4.95 (br s, 1H), 4.04 (s, 2H),
4.00 (s, 3H), 2.55 (s, 3H), 2.40 (t, J = 7.4 Hz, 2H), 1.55 (m, 2H),
(CDCl , 100 MHz) δ 123.2, 119.8, 114.8, 108.9, 31.8, 31.1, 25.9, 22.7,
3
+
1
4.2, 11.0; HRMS (ESI) calcd for C H N (M + H) 152.1434;
10 18
found 152.1431.
1
3
3
-Butyl-2-methyl-1H-pyrrole (9b). Yield: 2.28 g (82%) clear oil;
1.34 (m, 4H), 0.92 (t, J = 6.4 Hz, 3H); C NMR (CDCl , 100 MHz)
3
1
H NMR (CDCl , 600 MHz) δ 7.72 (br s, 1H), 6.63 (t, J = 2.6 Hz,
δ 165.7, 154.6, 147.7, 145.7, 143.3, 130.5, 130.2 (2C), 128.0, 127.6,
125.0, 121.4, 121.1, 118.7, 115.7 (2C), 114.9, 111.0, 92.7, 58.8, 33.9,
31.6, 30.0, 25.5, 22.6, 14.2, 12.4; HRMS (ESI) calcd for C H N O
2
3
1
1
H), 6.06 (t, J = 2.6 Hz, 1H), 2.44 (t, J = 7.7 Hz, 2H), 2.23 (s, 3H),
1
3
.57 (m, 2H), 1.42 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); C NMR
2
7
32
3
+
(CDCl , 150 MHz) δ 123.2, 119.7, 114.8, 108.9, 33.6, 25.6, 22.6, 14.1,
(M + H) 430.2489; found 430.2478.
3
+
1
1
1.0; HRMS (ESI) calcd for C H N (M + H) 138.1277; found
4-((5′-((4-Butyl-5-methyl-1H-pyrrol-2-yl)methylene)-4′-methoxy-
9
16
38.1275.
-Hexyl-2-methyl-1H-pyrrole (9c). Yield: 2.55 g (77%) clear oil;
H NMR (CDCl , 600 MHz) δ 7.72 (br s, 1H), 6.62 (t, J = 2.7 Hz,
1H,5′H-[2,2′-bipyrrol]-5-yl)methyl)phenol (3). Yield: 0.129 g (85%)
1
3
red solid; mp > 200 °C; H NMR (CDCl
3
, 600 MHz) δ 12.67 (s,
1
1H), 12.62 (s, 1H), 12.55 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.90 (s,
1H), 6.85 (t, J = 2.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 2.0
Hz, 1H), 6.05 (t, J = 2.3 Hz, 1H), 6.03 (t, J = 1.7 Hz, 1H), 4.74 (br s,
1H), 4.05 (s, 2H), 4.00 (s, 3H), 2.55 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H),
3
1
H), 6.05 (t, J = 2.7 Hz, 1H), 2.41 (t, J = 7.8 Hz, 2H), 2.21 (s, 3H),
1
3
1
.56 (m, 2H), 1.40−1.31 (m, 6H), 0.92 (t, J = 7.0 Hz, 3H); C NMR
(CDCl , 100 MHz) δ 123.2, 119.8, 114.8, 108.9, 31.9, 31.4, 29.3, 25.9,
3
+
13
2
2.7, 14.2, 11.0; HRMS (ESI) calcd for C H N (M + H) 166.1590;
1.54 (m, 2H), 1.40−1.34 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); C NMR
1
1
20
found 166.1586.
(CDCl , 150 MHz) δ 165.6, 154.5, 147.6, 145.6, 143.1, 130.1 (2C),
3
3
-Heptyl-2-methyl-1H-pyrrole (9d). Yield: 2.55 g (75%) clear oil;
130.0, 127.9, 127.5, 124.9, 121.3, 121.0, 118.5, 115.5 (2C), 114.8,
1
H NMR (CDCl , 600 MHz) δ 7.72 (br s, 1H), 6.62 (t, J = 2.5 Hz,
110.8, 92.5, 58.6, 33.8, 32.4, 25.1, 22.3, 14.0, 12.3; HRMS (ESI) calcd
3
+
1
1
H), 6.05 (t, J = 2.5 Hz, 1H), 2.42 (t, J = 7.6 Hz, 2H), 2.22 (s, 3H),
for C26H
N
30
3
O
2
(M + H) 416.2333; found 416.2320.
1
3
.57 (m, 2H), 1.37−1.29 (m, 8H), 0.92 (t, J = 6.7 Hz, 3H); C NMR
4-((5′-((4-Hexyl-5-methyl-1H-pyrrol-2-yl)methylene)-4′-me-
thoxy-1H,5′H-[2,2′-bipyrrol]-5-yl)methyl)phenol (4). Yield: 0.133 g
(CDCl , 150 MHz) δ 123.2, 119.8, 114.8, 108.9, 32.0, 31.4, 29.6, 29.3,
3
1
+
(
1
6
82%) red solid; mp 142−144 °C; H NMR (CDCl , 600 MHz) δ
2
1
5.9, 22.7, 14.2, 11.0; HRMS (ESI) calcd for C H N (M + H)
3
1
2
22
2.63 (s, 1H), 12.58 (s, 1H), 12.49 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H),
.89 (s, 1H), 6.84 (t, J = 3.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 2H), 6.65
80.1747; found 180.1742.
Synthesis of 4′-Methoxy-5-(4-methoxybenzyl)-5′-((5-methyl-4-
pentyl-1H-pyrrol-2-yl)methylene)-1H,5′H-2,2′-bipyrrole (21). To a
stirred solution of intermediates 8 (0.2 g, 0.64 mmol) and 9a (0.19 g,
1
(s, 1H), 6.05 (s, 1H), 6.02 (s, 1H), 4.99 (br s, 1H), 4.04 (s, 2H), 3.99
(s, 3H), 2.53 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 1.54 (m, 2H), 1.35−
1
3
.29 mmol) in anhydrous methanol (50 mL) was added a few drops
1.27 (m, 6H), 0.91 (t, J = 6.3 Hz, 3H); C NMR (CDCl , 100 MHz)
3
of methanolic HCl (3 N, catalytic amount) under an argon
atmosphere at room temperature. The resulting bright red-colored
δ 165.7, 154.7, 147.7, 145.6, 143.3, 130.4, 130.2 (2C), 128.0, 127.6,
125.0, 121.4, 121.1, 118.8, 115.7 (2C), 114.9, 111.0, 92.7, 58.8, 33.9,
8
748
J. Med. Chem. 2021, 64, 8739−8754