The Journal of Organic Chemistry
NOTE
(dd, J = 7.0, 1.5 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.96ꢀ7.90 (m, 2 H),
7.85ꢀ7.79 (m, 2 H), 7.65 (d, J = 8.2 Hz, 2 H), 7.15 (d, J = 7.9 Hz, 2 H),
2.35 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 147.9, 140.8, 139.5,
137.8, 134.6, 134.4, 130.4, 129.2, 129.0, 127.8, 127.0, 126.6, 125.2, 20.9;
LRMS (ESI) 321 (M + Na), 299 (M + H).
1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.35ꢀ7.20 (m, 2 H), 7.06ꢀ7.04 (m, 1 H),
2.96 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 149.4, 137.6, 135.7, 128.3,
121.9, 119.9, 119.5, 115.73, 115.67, 115.6, 115.4, 18.6; HRMS (ESI)
calcd for C12H11N2 (M + H) 183.0917, found 183.0912.
9-Methylpyrido[1,2-b]indazole (3e): yield 49 mg (90%); beige
solid; mp 133 °C (lit.5 mp 116ꢀ121 °C); 1H NMR (300 MHz, CDCl3)
δ 8.68 (d, J = 7.1 Hz, 1 H), 8.04 (dt, J = 8.2, 1.0 Hz, 1 H), 7.90 (quint, J =
0.9 Hz, 1 H), 7.79 (d, J = 8.7 Hz, 1 H), 7.54 (ddd, J = 8.6, 6.7, 1.1 Hz, 1
H), 7.18 (ddd, J = 8.1, 6.8, 0.8 Hz, 1 H), 7.02 (dd, J = 7.1, 1.9 Hz, 1 H),
2.55 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 150.0, 135.4, 133.0, 128.3,
127.2, 119.8, 119.1, 118.5, 116.8, 115.3, 114.5, 21.2; IR (KBr) 1648,
1608, 1356, 804, 747 cmꢀ1; HRMS (ESI) calcd for C12H11N2 (M + H)
183.0917, found 183.0912.
Ethyl pyrido[1,2-b]indazole-9-carboxylate (3f). yield 65 mg
(90%); slightly yellow solid; mp 98 °C; 1H NMR (300 MHz, CDCl3) δ
8.86ꢀ8.82 (m, 1 H), 8.76 (d, J = 7.2 Hz, 1 H), 8.16 (dd, J = 8.3, 0.9 Hz, 1
H), 7.91 (dd, J = 8.7, 0.7 Hz, 1 H), 7.77 (dd, J = 7.2, 1.9 Hz, 1 H),
7.66ꢀ7.58 (m, 1 H), 7.38ꢀ7.30 (m, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.46
(t, J = 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 164.9, 150.1, 134.3,
128.8, 127.3, 123.3, 121.4, 120.1, 119.7, 116.9, 116.4, 115.5, 61.6, 14.3;
IR (KBr) 1605, 1278, 759, 714 cmꢀ1; HRMS (ESI) calcd for
C14H13N2O2 (M + H) 241.0972, found 241.0968.
Pyrido[1,2-b]indazole-9-carbonitrile (3g): yield 38 mg (66%);
yellow green solid; mp 65 °C; 1H NMR (300 MHz, CDCl3) δ 8.83 (dd,
J = 7.2, 0.9 Hz, 1 H), 8.51 (dd, J = 1.9, 0.9 Hz, 1 H), 8.14 (dt, J = 8.3, 1.0
Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 7.68 (ddd, J = 8.6, 6.8, 1.1 Hz, 1 H),
7.41 (ddd, J = 8.2, 6.8, 0.8 Hz, 1 H), 7.33 (dd, J = 7.2, 1.9 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ 150.2, 133.9, 129.5, 128.3, 123.4, 122.5,
119.5, 117.6, 116.7, 116.4, 116.3, 103.9; IR (KBr) 2225, 1523, 1451,
1361, 1284, 803, 753, 728, 718 cmꢀ1; HRMS (ESI) calcd for C12H8N3
(M + H) 194.0713, found 194.0709.
N,N-Dimethylpyrido[1,2-b]indazol-9-amine (3h): yield 25
mg (40%); yellow green solid; mp 170ꢀ171 °C ; 1H NMR (400
MHz, CDCl3) δ 8.57 (d, J = 7.7 Hz, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.65
(d, J = 8.6 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 6.98
(d, J = 2.5 Hz, 1 H), 6.73 (dd, J = 7.7, 2.8 Hz, 1 H), 3.09 (s, 6 H); 13C
NMR (100 MHz, CDCl3) δ 150.1, 146.5, 137.3, 128.7, 128.2, 120.3,
117.5, 114.3, 114.0, 105.9, 95.0, 40.3; HRMS (ESI) calcd for C13H14N3
(M + H) 212.1182, found 212.1176.
8-Bromopyrido[1,2-b]indazole (3i): yield 31 mg (29%); off-
white solid; mp 103 °C; 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 1 H),
8.05 (d, J = 8.3 Hz, 1 H), 8.00 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1
H), 7.59 (ddd, J = 1.0, 6.8, 7.9 Hz, 1 H), 7.44 (dd, J = 9.1, 1.6 Hz, 1 H),
7.30ꢀ7.25 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 149.7, 133.9, 128.7,
128.2, 125.1, 120.6, 119.5, 118.1, 115.9, 115.2, 110.9; HRMS (ESI) calcd
for C11H8BrN2 (M + H) 246.9865, found 246.9861.
Compound 5. To a 10 mL microwave-adaptive vial equipped with a
stir bar was added 925 mg of 2-bromobenzaldehyde (5 mmol), followed
by 696 mg of 4-ethynyltoluene (6 mmol, 1.2 equiv). Et3N (1 mL) and
DMF (4 mL) were added, followed by PdCl2(PPh3)2 (70 mg, 0.1 mmol,
2 mol %) and CuI (38 mg, 0.2 mmol, 4 mol %). The vial was sealed and
irradiated with microwave at 100 °C for 2 h. The mixture was cooled to
room temperature, poured into 50 mL of EtOAc, and washed three
times with brine. The organic layer was dried over MgSO4, filtered, and
evaporated. The residue was purified by column chromatography (15:1
petroleum ether/EtOAc) to afford 850 mg of 2-(p-tolylethynyl)-
benzaldehyde (77% yield) as a brown solid. This compound (2 mmol)
was added to a 25 mL round-bottom flask equipped with a stir bar
containing 409 mg of p-toluenesulfonyl hydrazide (2.2 mmol, 1.1 equiv)
and 5 mL of absolute MeOH. The mixture was stirred at room
temperature for 2 h, and the volatiles were evaporated in vacuo. The
residue was recrystallized from a minimum amount of MeOH to afford
640 mg of N0-(2-alkynylbenzylidene)tosylhydrazides (82% yield) as
white crystals: mp 159ꢀ161 °C; 1H NMR (300 MHz, CDCl3) δ 8.35 (s,
1 H), 7.97 (s, 1 H), 7.95ꢀ7.93 (m, 1 H), 7.89 (d, J = 8.3 Hz, 2 H),
7.52ꢀ7.46 (m, 1 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.35ꢀ7.30 (m, 4 H),
7.17 (d, J = 7.9 Hz, 2 H), 2.40 (s, 3 H), 2.38 (s, 3 H); LRMS (ESI) 411
(M + Na), 389 (M + H).
General Procedures for the Preparation of the Pyrido[1,2-
b]indazole. To a 10 mL round-bottom flask equipped with a stir bar
was added N-tosylpyridinium imide 1 (0.3 mmol), followed by the aryne
precursor 4 (0.36 mmol) and THF (4 mL). The mixture was briefly
stirred before the addition of CsF (ca. 0.9 mmol). The flask was fitted
with a reflux condenser and sealed with a septum. A balloon was added
on top, and the mixture was stirred in a 70 °C oil bath for 24 h. Upon
completion as judged by TLC, the mixture was diluted with EtOAc and
brine. The layers were separated and the aqueous layer was extracted
twice with EtOAc. Combined extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column chroma-
tography (petroleum ether/EtOAc) to afford the desired product.
Pyrido[1,2-b]indazole (3a): yield 43 mg (85%); light yellow
solid; mp 85 °C (lit.1d mp 83ꢀ84 °C); 1H NMR (300 MHz, CDCl3)
δ 8.80 (dt, J = 6.9, 1.0 Hz, 1 H), 8.17ꢀ8.06 (m, 2 H), 7.85 (dt, J = 8.7, 0.8
Hz, 1 H), 7.57 (ddd, J = 1.1, 6.8, 7.9 Hz, 1 H), 7.36 (ddd, J = 1.0, 6.9, 8.1
Hz, 1 H), 7.25ꢀ7.15 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 149.6,
135.4, 128.4, 127.9, 121.9, 119.8, 119.7, 117.9, 116.2, 115.5, 115.2; IR
(KBr) 1644, 1604, 1510, 1430, 1360, 1213, 1141, 741, 718 cmꢀ1; HRMS
(ESI) calcd for C11H9N2 (M + H) 169.0760, found 169.0760.
10-Bromopyrido[1,2-b]indazole (3i0): yield 49 mg (62%); off-
white solid; mp 141 °C; 1H NMR (300 MHz, CDCl3) δ 8.78 (dd, J = 6.9,
0.8 Hz, 1 H), 8.63 (dt, J = 8.5, 1.0 Hz, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.61
(ddd, J = 8.7, 6.8, 1.1 Hz, 1 H), 7.55 (dd, J = 7.5, 0.7 Hz, 1 H), 7.31 (ddd,
J = 8.4, 6.8, 0.9 Hz, 1 H), 7.05 (t, J = 7.2 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 149.9, 133.2, 128.7, 126.9, 125.3, 122.1, 120.4, 116.0, 115.7,
113.8; HRMS (ESI) calcd for C11H8BrN2 (M + H) 246.9865, found
246.9868.
2,3-Dimethoxypyrido[1,2-b]indazole (3b): yield 60 mg
(88%); white solid; mp 132 °C; 1H NMR (300 MHz, CDCl3) δ 8.67
(d, J = 7.0 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.31 (s, 1 H), 7.27ꢀ7.22
(m, 1 H), 7.16 (s, 1 H), 7.02 (td, J = 6.9, 1.2 Hz, 1 H), 4.02 (s, 3 H), 4.01
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 152.4, 146.0, 134.7, 127.70,
127.67, 121.1, 116.9, 114.0, 108.0, 98.0, 94.8, 56.0, 55.8; HRMS (ESI)
calcd for C13H13N2O2 (M + H) 229.0972, found 229.0968.
1-Methoxypyrido[1,2-b]indazole (3c): yield 46 mg (77%); off-
white solid; mp 100 °C; 1H NMR (300 MHz, CDCl3) δ 8.76 (dt, J = 6.9,
0.9 Hz, 1 H), 8.34 (dt, J = 8.4, 1.3 Hz, 1 H), 7.49ꢀ7.41 (m, 2 H), 7.34
(apparent t, J = 7.8 Hz, 1 H), 7.16 (td, J = 6.9, 1.5 Hz, 1 H), 6.53 (d, J =
7.3 Hz, 1 H), 4.08 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 155.5,
151.2, 135.1, 129.2, 127.5, 122.3, 120.1, 115.6, 107.8, 107.0, 97.8, 55.4;
HRMS (ESI) calcd for C12H11N2O (M + H) 199.0866, found 199.0861.
7-Methylpyrido[1,2-b]indazole (3d): yield 51 mg (93%); beige
solid; mp 70 °C (lit.5 mp 63ꢀ64 °C); 1H NMR (400 MHz, CDCl3) δ
8.10 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 8.6 Hz, 1 H), 7.93 (d, J = 8.4 Hz,
8-Fluoropyrido[1,2-b]indazole (3j): yield 13 mg (24%); white
solid; mp 91ꢀ92 °C; 1H NMR (300 MHz, CDCl3) δ 8.71 (dd, J = 4.3,
2.0 Hz, 1 H), 8.14ꢀ8.04 (m, 2 H), 7.85 (d, J = 8.7 Hz, 1 H), 7.61ꢀ7.54
(m, 1 H), 7.30ꢀ7.24 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 155.5
(d, 1JCF = 241.3 Hz), 150.1 (d, 4JCF = 2.1 Hz), 132.9, 128.1, 120.5, 119.3,
3
2
117.9 (d, JCF = 9.4 Hz), 115.6, 115.5 (d, JCF = 39.7 Hz), 115.3
2
(overlapped with the d at 115.5), 113.1 (d, JCF = 24.3 Hz); HRMS
(ESI) calcd for C11H8FN2 (M + H) 187.0666, found 187.0664.
10-Fluoropyrido[1,2-b]indazole (3j0): yield 25 mg (45%);
white solid; mp 95ꢀ96 °C; 1H NMR (300 MHz, CDCl3) δ 8.63
6841
dx.doi.org/10.1021/jo200863e |J. Org. Chem. 2011, 76, 6837–6843