ꢀꢀꢀꢁ
4ꢀ ꢀA.I. Subota et al.: Synthesis and properties of 7-methyl-4-azaindole
addition of compound 13 (50.4 g, 0.17 mol). The mixture was stirred was added dropwise and the mixture was concentrated. MeOH
overnight at 95°C, then cooled and poured in H2O (1500 mL). The (150 mL) and concentrated aqueous HCl (20 mL) were added to the
mixture was neutralized with 15% aqueous HCl and the resultant residue. The mixture was stirred under reflux for 6 h, then cooled
precipitate was filtered, washed with H2O (2ꢀ×ꢀ250 mL) and hexanes and concentrated under reduced pressure. An aqueous solution of
(2ꢀ×ꢀ100 mL) and dried under reduced pressure. The crude product NaOH (20%, 50 mL) was added to the residue, and the product was
was taken up in CHCl3/hexane (2:3, 1000 mL). The mixture was fil- extracted with Et2O (4ꢀ×ꢀ15 mL). The organic layers were combined,
tered and the filtrate was concentrated; yield 30.1 g (49%) of orange dried over Na2SO4 and concentrated under reduced pressure. The
solid; mp 182–183°C; the compound exists as a 9:1 mixture of tautom- crude product was purified by silica gel column chromatography
ers; 1H NMR (CDCl3), major tautomer: δ 8.86 (s, 1H), 5.15 (s, 1H), 2.52 (s, eluting with CHCl3/MeOH (9:1); yield 1.43 g (71%) of white solid; mp
1
3H), 1.50 (s, 9H); 1H NMR (CDCl3), minor tautomer: δ 15.63 (br s, 1H), 97–99°C; H NMR (CDCl3): δ 7.76 (d, Jꢀ=ꢀ5.1 Hz, 1H), 6.71 (d, Jꢀ=ꢀ5.1 Hz,
7.84 (d, Jꢀ=ꢀ6.5 Hz, 1H), 2.38 (s, 3H), 1.54 (s, 9H); 13C NMR (CDCl3), major 1H), 3.60 (t, Jꢀ=ꢀ8.6 Hz, 2H), 3.60 (br s, 1H, NH), 3.12 (t, Jꢀ=ꢀ8.6 Hz, 2H),
tautomer: δ 160.6, 152.3, 141.3, 136.0, 124.8, 112.7, 86.1, 43.8, 28.1, 27.5, 2.08 (s, 3H); 13C NMR (CDCl3): δ 151.1, 143.6, 139.0, 125.2, 122.6, 45.1,
+
18.8; MS (CI): m/z 356/358 (1:1, MH ). Anal. Calcd for C13H14BrN3O4: C, 31.2, 16.2; Rf 0.28 eluting with CHCl3/MeOH (9:1); MS (CI): m/z 135
+
43.84; H, 3.96; N, 11.80. Found: C, 43.45; H, 3.81; N, 11.86.
(MH ). Anal. Calcd for C8H10N2: C, 71.61; H, 7.51; N, 20.88. Found: C,
71.43; H, 7.80; N, 20.64.
2-(5-Bromo-4-methyl-3-nitropyridin-2-yl)acetonitrile (11)
(3aR*,7R*,7aR*)-7-Methyloctahydro-1H-pyrrolo[3,2-b]
pyridine sulfate (16ꢁ·ꢁH2SO4)
To a solution of compound 14 (25.0 g, 70.2 mmol) in MeCN (500 mL),
an aqueous solution of HCl (17%, 250 mL) was added. The mixture
was heated under reflux for 2 h, then cooled and concentrated under
reduced pressure. The residue was taken up in an aqueous saturated
solution of NaHCO3 (250 mL), and the product was extracted with
EtOAc (4ꢀ×ꢀ300 mL). The extract was dried over MgSO4 and concen-
trated under reduced pressure. The crude product was purified by
silica gel flash chromatography eluting with hexanes/EtOAc (1:1) and
crystallized from Et2O/hexanes; yield 16.5 g (92%) of beige solid; mp
A mixture of compound 15 (1.00 g, 7.50 mmol), 10% Pd(OH)2-C
(1.00 g), MeOH (50 mL) and concentrated aqueous HCl (1.5 mL) was
hydrogenated at 35 bar of H2 at 60°C for 24 h. The catalyst was fil-
tered and the filtrate was concentrated under reduced pressure. An
aqueous solution of NaOH (10%, 15 mL) was added to the residue,
and the product was extracted with Et2O (4ꢀ×ꢀ30 mL). The combined
organic extracts were dried over Na2SO4 and concentrated under
reduced pressure. The crude product was dissolved in aqueous 96%
EtOH (30 mL) and the solution was treated with concentrated H2SO4
to adjust to pH 4. The resultant diamine sulfate was filtered and
crystallized from aqueous 96% EtOH (120 mL); yield 1.36 g (76%) of
1
107–108°C; H NMR (CDCl3): δ 8.81 (s, 1H), 3.95 (s, 2H), 2.46 (s, 3H);
13C NMR (CDCl3): δ 152.2, 146.8, 140.8, 140.6, 123.9, 114.0, 23.6, 18.3; Rf
+
0.57 eluting with hexanes/EtOAc (1:1); MS (CI): m/z 256/258 (1:1, MH ).
Anal. Calcd for C8H6BrN3O2: C, 37.53; H, 2.36; N, 16.41. Found: C, 37.48;
H, 2.06; N, 16.70.
1
white solid; mpꢀꢀ>ꢀꢀ200°C (dec.); H NMR (D2O): δ 4.20 – 4.05 (m, 1H,
3a-CH), 3.98 (t, Jꢀ=ꢀ4.7 Hz, 1H, 7a-CH), 3.85 – 3.70 (m, 1H, 1-CHH), 3.62
– 3.43 (m, 2H, 1-CHH and 5-CHH), 3.11 (td, Jꢀ=ꢀ13.1, 3.0 Hz, 1H, 5-CHH),
2.67 (ddt, Jꢀ=ꢀ15.1, 11.2, 7.5 Hz, 1H, 2-CHH), 2.48 – 2.25 (m, 2H, 7-CH and
2-CHH), 2.00 – 1.88 (m, 1H, 6-CHH), 1.88 – 1.67 (m, 1H, 6-CHH), 1.20
(d, Jꢀ=ꢀ7.1 Hz, 3H, CH3); NHs are exchanged with HDO; 13C NMR (DMSO-
7-Methyl-1H-pyrrolo[3,2-b]pyridine (6)
+
A mixture of compound 11 (14.0 g, 54.7 mmol) and 10% Pd/C (8.0 g)
in aqueous 96% EtOH (400 mL) was hydrogenated under 50 bar of
H2 at room temperature for 30 h. The catalyst was filtered and the fil-
trate was concentrated under reduced pressure. Aqueous saturated
NaHCO3 was added to the residue to adjust to pH 8, and the mixture
was concentrated. The residue was treated with hot i-PrOH (400 mL)
filtered, and the filtrate was concentrated under reduced pressure.
The crude product was purified by silica gel flash chromatography
eluting with CHCl3/MeOH (4:1); yield 6.07 g (84%) of beige solid;
d6): δ 58.7, 52.7, 40.6, 40.1, 25.2, 24.8, 20.9, 14.3; MS (CI): m/z 141 (MH ).
Anal. Calcd for C8H18N2O4S: C, 40.32; H, 7.61; N, 11.76; S, 13.45. Found:
C, 40.52; H, 7.81; N, 11.9; S, 13.26.
7-Methyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (17)
A mixture of compound 6 (3.00 g, 22.7 mmol) and hexamethylene-
tetramine (4.91 g, 35.0 mmol) in a mixture of acetic acid (20 mL)
and H2O (50 mL) was heated under reflux for 6 h, then cooled and
concentrated under reduced pressure. A saturated aqueous solu-
tion of NaHCO3 (50 mL) was added to the residue, and the product
was extracted with EtOAc (4ꢀ×ꢀ50 mL). The organic layers were com-
bined, dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatogra-
phy eluting with CHCl3/MeOH (4:1); yield 2.25 g (62%) of light yel-
1
mp 185–187°C (dec); H NMR (DMSO-d6): δ 11.49 (br s, 1H), 8.20 (d,
Jꢀ=ꢀ4.7 Hz, 1H), 7.62 (s, 1H), 6.91 (d, Jꢀ=ꢀ4.6 Hz, 1H), 6.55 (d, Jꢀ=ꢀ2.3 Hz,
1H), 2.50 (s, 3H); 13C NMR (DMSO-d6): δ 145.3, 142.2, 129.1, 128.5, 128.4,
117.0, 101.6, 16.3; Rf 0.60 eluting with CHCl3/MeOH (4:1); MS (CI): m/z
+
133 (MH ). Anal. Calcd for C8H8N2: C, 72.7; H, 6.10; N, 21.2. Found: C,
72.49; H, 6.13; N, 21.37.
1
low solid; mp 210–212°C; H NMR (CD3OD): δ 10.12 (s, 1H), 8.33 (d,
7-Methyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (15)
Jꢀ=ꢀ4.9 Hz, 1H), 8.26 (s, 1H), 7.12 (d, Jꢀ=ꢀ4.9 Hz, 1H), 2.57 (s, 3H); NH is
exchanged with CD3OD; 13C NMR (CD3OD): δ 187.2, 146.5, 144.4, 138.9,
To a stirred solution of compound 6 (1.98 g, 15.0 mmol) in dry THF 134.6, 132.6, 121.5, 119.3, 17.4; Rf 0.56 eluting with CHCl3/MeOH (4:1);
+
(100 mL), BH3ꢀ·ꢀMe2S (16.0 g, 12.8 mL, 210 mmol) was added, and the MS (CI): m/z 161 (MH ). Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N,
mixture was heated under reflux for 11 h. After cooling, MeOH (25 mL) 17.49. Found: C, 67.31; H, 5.43; N, 17.19.
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