V. Stockmann et al. / Tetrahedron 64 (2008) 11180–11184
11183
3b, TIPS-4b, 5b and 12 were synthesised by methods similar to
4.5. Pyrido[4,3-e]furano[2,3-c]pyridazine (5b)
previously described procedures for preparation of the corre-
sponding thiophene compounds.1 All reactions were conducted
under nitrogen atmosphere unless otherwise noted.
The title compound was prepared by diazocoupling1 from amine
13 (32.4 mg, 0.202 mmol) in dry MeCN (5 ml) and NOBF4 (117 mg,
1.00 mmol) in dry MeCN (5 mL). Purification by flash chromato-
graphy (10% MeOH/CH2Cl2) afforded pyridazine 5b (26.3 mg, 76%)
as a white solid, pure by NMR. Rf 0.45 (10% MeOH/CH2Cl2); mp
>200 ꢀC (decomp.); 1H NMR (300 MHz, CDCl3): dH 10.09 (1H, d,
J 0.9, py-H2), 8.87 (1H, d, J 6.0, py-H6), 8.17 (1H, d, J 2.4, furan-H5),
7.99 (1H, dd, J 6.0, 0.9, py-H5), 7.40 (1H, d, J 2.4, furan-H4); 13C NMR
(100 MHz, CDCl3): dC 162.9 (furan-C2), 156.3 (py-C2), 148.8 (furan-
C5), 147.2 (py-C6), 143.0 (py-C3), 126.1 (py-C4), 116.2 (py-C5), 115.3
(furan-C3), 105.4 (furan-C4); NMR assignments are based on HMBC
experiments; IR (KBr) nmax 3098w, 1619s, 1502s, 1401m, 1225m,
1113m, 1048m, 869m, 844m, 776s cmꢁ1; MS m/z (%)171 (Mþ, 17%),
170 (100), 114 (40), 88 (47); EI-HRMS calcd for C9H5N3O: 171.0433;
obsd: 171.0436. Anal. Calcd for C9H5N3O: C, 63.16; H, 2.94; N, 24.55.
Found: C, 62.72; H, 2.54; N, 24.23.
4.2. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b)
The title compound was prepared by diazocoupling1 from amine
11 (58.0 mg, 0.64 mmol) in dry MeCN (7 mL) and NOBF4 (110 mg,
0.942 mmol) in dry MeCN (5 mL). Product 3b was obtained as an
off-white solid (47.0 mg, 77%) after flash chromatography on
a Al2O3 column (gradient; 0–5% MeOH in CH2Cl2), pure by NMR. Rf
0.38 (5% MeOH in CH2Cl2, Al2O3-TLC); mp >232 ꢀC (decomp.); 1H
NMR (400 MHz, DMSO): dH 13.36 (1H, br, NH), 9.81 (1H, s, py-H2),
8.77 (1H, d, J 6.0, py-H6), 8.32 (1H, d, J 6.0, py-H5), 8.09 (1H, t, J 2.8,
pyrrole-H5), 7.32 (1H, dd, J 2.8, 1.6, pyrrole-H4); 13C NMR (100 MHz,
DMSO): dC 154.1 (py-C2), 148.9 (pyrrole-C2), 145.8 (py-C6), 139.9
(py-C3), 130.9 (pyrrole-C5), 124.8 (py-C4), 116.6 (py-C5), 112.5
(pyrrole-C3), 100.4 (pyrrole-C4); NMR assignments are based on
HSQC and HMBC experiments; IR (KBr) nmax 3265br, 3069m,
3010m, 1651s, 1434m, 1245m, 1113s, 813s, 767s cmꢁ1; MS m/z (%)
170 (Mþ, 100), 115 (84), 88 (20); EI-HRMS calcd for C9H6N4:
170.0593; obsd: 170.0587.
4.6. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triiso-
propylsilyl)-1H-pyrrole (8)5,6
The title compound was prepared according to the literature5,6
from pyrrole via TIPS-pyrrole (1-(triisopropylsilyl)-1H-pyrrole);
4.3. Pyrido[3,4-b]-(1-triisopropylsilyl-1H-pyrrolo)[3,2-
d]pyrrole (TIPS-4b)
(i) pyrrole (1.94 mL, 28 mmol), dry THF (45 mL), n-BuLi (18.1 mL,
30.8 mmol) and TIPS-Cl (5.7 mL, 26.9 mmol) afforded TIPS-
pyrrole as a yellow oil (5.99 g, 99%) after extraction, pure by
NMR;12 Rf 0.95 (EtOAc/pentane 2:1), used without further
purification;
(ii) pin2B2 (1.24 g, 4.88 mmol), [IrCl(COD)]2 (69.5 mg, 0.103 mmol),
dtbpy (58.8 mg, 0.219 mmol) and TIPS-pyrrole (6.41 g,
28.7 mmol) in octane (20 mL), gave a black crude product after
stirring for 48 h at 80 ꢀC and subsequent evaporation of the
solvent. Excess TIPS-pyrrole was removed by distillation (4–
6 mbar, approx. 80 ꢀC) and flash chromatography of the resi-
due (EtOAc/pentane 1:5) afforded product 8 as a white solid
(2.61 g, 77% from pin2B2), pure by NMR. Rf 0.85 (EtOAc/pentane
1:5); mp 70–71 ꢀC; 1H NMR (300 MHz, CDCl3): dH 7.23 (1H, dd,
J 1.4, 2.6), 6.81 (1H, dd, J 2.6, 2.1), 6.62 (1H, dd, J 2.6, 1.4), 1.46
(3H, sep, J 7.4), 1.32 (12H, s), 1.09 (18H, d, J 7.4).
The title compound was prepared by thermal decomposition1 of
azide 16 (107 mg, 0.313 mmol) in dry n-decane (60 mL). The re-
action mixture was heated to reflux and kept stirring for 40 min,
cooled to room temperature and decane was distilled off. Flash
chromatography (gradient; 1–10% MeOH/CH2Cl2) afforded TIPS-4b
as an off-white solid (70 mg, 71%), pure by NMR. Rf 0.11 (10% MeOH
in CH2Cl2); mp >95 ꢀC (decomp.); 1H NMR (400 MHz, CDCl3): dH
8.71 (1H, s, py-H2), 8.26 (1H, d, J 5.6, py-H6), 7.57 (1H, d, J 5.6, py-
H5), 6.76 (1H, d, J 3.2, pyrrole-H5), 6.64 (1H, d, J 3.2, pyrrole-H4),
1.63 (3H, sep, J 7.6, CH(CH3)2), 1.18 (18H, d, J 7.6, CH(CH3)2); 1H NMR
(400 MHz, DMSO-d6): dH 10.91 (1H, br s, NH), 8.63 (1H, s, py-H2),
8.09 (1H, d, J 5.6, py-H6), 7.51 (1H, d, J 5.6, py-H5), 6.83 (1H, d, J 3.2,
pyrrole-H5), 6.58 (1H, d, J 3.2, pyrrole-H4), 1.76 (3H, sep, J 7.6,
CH(CH3)2), 1.10 (18H, d, J 7.6, CH(CH3)2); 13C NMR (100 MHz, CDCl3):
dC 146.5 (pyrrole-C2), 137.7 (py-C6), 137.5 (py-C3), 132.4 (py-C2),
126.7 (py-C4), 125.1 (pyrrole-C5), 113.2 (py-C5), 109.9 (pyrrole-C3),
102.4 (pyrrole-C4), 18.0 (TIPS-CH3), 12.2 (TIPS-CH); NMR assign-
ments are based on HMBC experiments; IR (KBr) nmax 3379w br,
3105m br, 3067m, 2947s, 2867s, 1609m, 1524m, 1095s, 883m,
707s cmꢁ1; ESI-HRMS: calcd for [MþH]þ C18H28N3Si: 314.2047;
obsd: 314.2050.
4.7. N-[4-(1H-Pyrrol-3-yl)pyridin-3-yl]pivalamide (10)
A
solution of 7 (1.04 g, 4.04 mmol), pyrrole 8 (1.70 g,
4.87 mmol), K3PO4$3H2O (2.16 g, 8.11 mmol), Pd2dba3 (109 mg,
0.119 mmol), SPhos (97 mg, 0.236 mmol) in n-butanol (30 mL) and
distilled water (12 mL) was heated to 100 ꢀC, stirred overnight
and cooled to room temperature.3 The solution was concentrated
and water (20 mL) was added. After extraction with ether
(3ꢂ20 mL), evaporation of the solvent and flash chromatography
(gradient; 1–5% MeOH/CH2Cl2) product 10 was obtained as
a white solid (804 mg, 82%), pure by NMR spectroscopy. Rf 0.20
(5% MeOH/CH2Cl2); mp >135 ꢀC (decomp.); 1H NMR (400 MHz,
CDCl3): dH 9.54 (s, 1H, py-H2), 9.05 (br s, 1H, NH), 8.32 (d, 1H,
J 5.2, py-H6), 7.92 (1H, br s, NH), 7.22 (d, 1H, J 5.2, py-H5), 6.99 (m,
2H, pyrrole-H2/H5), 6.39 (dd, 1H, J 4.2, 2.8, pyrrole-H4), 1.27 (s,
9H, C(CH3)3); 13C NMR (100 MHz, CDCl3): dC 176.7 (C]O), 145.1
(py-C6), 143.2 (py-C2), 134.4 (py-C4), 132.3 (py-C3), 123.9 (py-C5),
120.1 (pyrrole-C2), 118.6 (pyrrole-C3), 117.6 (pyrrole-C5), 108.5
(pyrrole-C4), 40.0 (CMe3), 27.8 (C(CH3)3); NMR assignments are
based on HSQC and HMBC experiments; IR (KBr) nmax 3318s br,
2966w, 1653s, 1419m, 1307s, 1034m, 789m cmꢁ1; MS m/z (%) 243
(Mþ, 51), 159 (35), 131 (18), 104 (8); EI-HRMS calcd for C14H17N3O:
243.1373; obsd: 243.1372.
4.4. Pyrido[3,4-b]-(pyrrolo)[3,2-d]pyrrole (4b)
To an NMR sample of TIPS-4b (approx. 4 mg in 1 mL CDCl3) was
added TBAF (excess). Quantitative conversion to 4b took place
within an hour, as shown by 1H NMR spectroscopy. 1,2,4,5-Tetra-
chlorobenzene was used as internal standard. Compound 4b: Rf
0.15 (MeOH); 1H NMR (400 MHz, CDCl3): dH 8.75 (1H, s, py-H2), 8.12
(1H, d, J 5.6, py-H6), 7.44 (1H, d, J 5.6, py-H5), 6.81 (1H, d, J 3.2,
pyrrole-H5), 6.35 (1H, d, J 3.2, pyrrole-H4); 1H NMR (400 MHz,
DMSO-d6): dH 11.26 (2H, br s, 2ꢂNH), 8.55 (1H, s, py-H2), 8.04 (1H,
d, J 5.2, py-H6), 7.45 (1H, d, J 5.2, py-H5), 6.75 (1H, d, J 3.2, pyrrole-
H5), 6.35 (1H, d, J 3.2, pyrrole-H4); 13C NMR (100 MHz, CDCl3): dC
142.7 (pyrrole-C2), 137.7 (py-C6), 137.1 (py-C3), 132.5 (py-C2), 127.1
(py-C4), 119.1 (pyrrole-C5), 113.2 (py-C5), 107.1 (pyrrole-C3), 99.7
(pyrrole-C4); NMR assignments are based on HSQC and HMBC
experiments; ESI-HRMS calcd for [MþH]þ C9H8N3: 158.0713; obsd:
158.0712.