PAPER
Functionalization of 4,5-Dihydrobenzo[g]indazoles Using
3669
column chromatography (silica gel, pentane–Et2O, 8:2), 19c was
isolated as a pale yellow oil (249 mg, 68%).
4-(1-Ethoxymethyl-4,5-dihydro-1H-benzo[g]indazol-3-yl)ben-
zoic Acid Ethyl Ester (24a)
According to GP3, the 3-zincated heterocycle 23 (1 mmol) was
transmetallated with ZnCl2 (1mL, 1.0 M, 1 mmol) and stirred for 10
min at 25 °C. Ethyl 4-iodobenzoate (331 mg, 1.2 mmol) was dis-
solved in THF (1 mL) and mixed with Pd(dba)2 (28 mg, 0.05 mmol)
and (o-furyl)3P (23 mg, 0.10 mmol). This mixture was added to the
zinc reagent at 25 °C. After purification by column chromatography
(silica gel, pentane–Et2O, 9:1), 24a was isolated as a white solid
(233 mg, 62%); mp 114–116 °C.
IR (Diamond ATR): 1496 (w), 1453 (m), 1438 (m), 1290 (m), 1124
(w), 1097 (w), 1025 (m), 728 (s), 696 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 8.19 (d, JH,H = 7.4 Hz, 1 H), 7.25–
7.21 (m, 2 H), 7.13–6.94 (m, 11 H), 5.80 (s, 1 H), 5.21 (d, JH,H = 4.5
Hz, 2 H), 4.54 (br s, 1 H), 2.62–2.49 (m, 2 H), 2.45–2.38 (m, 1 H),
2.25–2.15 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 148.0, 141.7, 141.6, 140.5, 138.0,
136.7, 130.3, 128.6, 128.5, 128.5, 127.6, 127.5, 127.4, 127.0, 126.4,
122.9, 116.1, 67.0, 53.7, 29.6, 19.4.
MS (EI, 70 eV): m/z (%) = 367 (22), 366 (M+, 100), 365 (5), 364 (8),
350 (5), 349 (5), 348 (11), 347 (15), 276 (5), 275 (29), 273 (3), 271
(6), 260 (4), 259 (17), 258 (3), 257 (9), 229 (6), 228 (4), 197 (9), 169
(5), 115 (4), 105 (10), 92 (4), 91 (49), 77 (4).
IR (Diamond ATR): 1707 (s), 1611 (m), 1444 (w), 1387 (w), 1366
(w), 1277 (s), 1228 (w), 1178 (w), 1112 (m), 1085 (s), 1020 (m),
862 (m), 806 (w), 780 (m), 765 (m), 722 (s), 706 (m), 650 cm–1 (w).
1H NMR (600 MHz, CDCl3): d = 8.11 (d, JH,H = 8.1 Hz, 2 H), 7.93
(d, JH,H = 7.7 Hz, 1 H), 7.80 (d, JH,H = 8.3 Hz, 2 H), 7.36–7.32 (m,
2 H), 7.28–7.26 (m, 1 H), 5.71 (s, 2 H), 4.40 (q, JH,H = 7.2 Hz, 2 H),
3.76 (q, JH,H = 7.0 Hz, 2 H), 2.93 (s, 4 H), 1.41 (t, JH,H = 7.1 Hz, 3
H), 1.23 (t, JH,H = 7.0 Hz, 3 H).
HRMS (EI): m/z calcd for C25H22N2O: 366.1732; found: 366.1731.
13C NMR (150 MHz, CDCl3): d = 166.5, 146.2, 140.3, 137.9, 137.3,
129.9, 129.4, 128.5, 127.9, 127.3, 127.0, 126.9, 123.9, 117.3, 79.5,
64.4, 61.0, 30.6, 20.5, 14.9, 14.4.
MS (EI, 70 eV): m/z (%) = 376 (M+, 5), 332 (30), 331 (100), 303
(13), 258 (4), 216 (4), 143 (3), 115 (3).
3-Allyl-2-benzyl-4,5-dihydro-2H-benzo[g]indazole (19d)
According to GP2, the 3-magnesiated heterocycle 17 (1 mmol) was
transmetallated with CuCN·2LiCl (1.0 mL, 1.0 M, 1 mmol). After
stirring for 15 min at –30 °C, it was reacted with allyl bromide (144
mg, 1.2 mmol). The mixture was slowly allowed to warm up to
25 °C. After purification by column chromatography (silica gel,
pentane–Et2O, 9:1), 19d was isolated as a pale yellow solid (222
mg, 74%); mp 61–62 °C.
HRMS (EI): m/z calcd for C23H24N2O3: 376.1787; found: 376.1777.
(2-Chlorophenyl)(1-ethoxymethyl-4,5-dihydro-1H-benzo[g]in-
dazol-3-yl)methanone (24b)
IR (Diamond ATR): 2942 (w), 1738 (s), 1640 (w), 1485 (m), 1456
(m), 1379 (m), 1319 (m), 1207 (m), 917 (m), 765 (m), 736 (s), 699
cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.90 (d, JH,H = 7.6 Hz, 1 H), 7.32–
7.18 (m, 6 H), 7.13–7.11 (m, 2 H), 5.81–5.71 (m, 1 H), 5.36 (s, 2 H),
5.07–4.97 (m, 2 H), 3.28 (td, JH,H = 5.8 = 1.6 Hz, 2 H), 2.95 (t,
JH,H = 7.4 Hz, 2 H), 2.68 (t, JH,H = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 147.1, 137.5, 136.5, 135.5, 133.4,
130.1, 128.6, 128.2, 127.4, 127.1, 126.7, 126.5, 122.1, 116.5, 115.5,
53.2, 29.6, 28.6, 18.9.
MS (EI, 70 eV): m/z (%) = 301 (23), 300 (M+, 100), 299 (37), 298
(6), 285 (8), 271 (10), 259 (13), 258 (4), 257 (10), 223 (18), 210 (7),
209 (34), 207 (6), 183 (6), 181 (6), 178 (4), 168 (5), 165 (7), 152 (5),
115 (7), 92 (6), 91 (62), 83 (4), 65 (8), 44 (15).
According to GP3, the 3-zincated heterocycle 23 (1 mmol) was
transmetallated with CuCN·2LiCl (1 mL, 1.0 M, 1.0 mmol) at
–20 °C. After stirring for 15 min at –20 °C, it was reacted with 2-
chlorobenzoyl chloride (209 mg, 1.2 mmol). The mixture was slow-
ly allowed to warm up to 25 °C. After purification by column chro-
matography (silica gel, pentane–Et2O, 9:1), 24b was isolated as a
pale yellow solid (219 mg, 55%); mp 132–134 °C.
IR (Diamond ATR): 2980 (w), 2931 (w), 2880 (w), 1648 (m), 1589
(w), 1435 (m), 1356 (w), 1309 (w), 1274 (w), 1193 (w), 1162 (w),
1111 (m), 1090 (s), 1057 (m), 958 (m), 892 (m), 807 (m), 757 (s),
735 cm–1 (s).
1H NMR (600 MHz, CDCl3): d = 7.89 (d, JH,H = 7.7 Hz, 1 H), 7.55
(d, JH,H = 7.5 Hz, 1 H), 7.45–7.39 (m, 2 H), 7.36–7.32 (m, 3 H),
7.29–7.26 (m, 1 H), 5.64 (s, 2 H), 3.67 (q, JH,H = 7.0 Hz, 2 H), 3.07
(t, JH,H = 7.6 Hz, 2 H), 2.94 (t, JH,H = 7.4 Hz, 2 H), 1.19 (t, JH,H = 7.0
Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 190.3, 145.3, 140.6, 139.0, 137.5,
131.7, 131.1, 130.0, 129.8, 128.7, 128.3, 127.2, 126.2, 126.1, 123.7,
122.5, 80.0, 64.5, 30.0, 19.8, 14.8.
MS (EI, 70 eV): m/z (%) = 368 (14), 367 (10), 366 (M+, 41), 324
(19), 323 (30), 322 (55), 321 (71), 310 (9), 309 (31), 308 (17), 307
(52), 306 (9), 293 (11), 287 (21), 286 (9), 285 (25), 272 (10), 227
(8), 216 (9), 215 (20), 197 (24), 195 (15), 184 (15), 183 (96), 182
(10), 181 (34), 169 (17), 154 (9), 141 (33), 139 (100), 115 (14), 113
(11), 111 (32), 75 (10).
HRMS (EI): m/z calcd for C21H20N2: 300.1626; found: 300.1622.
Deprotonation of 1-Ethoxymethyl-4,5-dihydro-1H-benzo[g]in-
dazole (20) Using TMP2Zn·2MgCl2·2LiCl (22); General Proce-
dure (GP3)
A dry and argon flushed 10 mL pressurized vial, equipped with a
magnetic stirring bar, was charged with 20 (228 mg, 1.0 mmol) dis-
solved in THF (1 mL). The zinc base 22 (1.5 mL, 0.4 M in THF, 0.6
mmol) was added and the reaction mixture was heated using a Dis-
cover BenchMate® Microwave system at 80 °C and 200 W for 2 h.
The completion of the metallation was checked by GC analysis of
reaction aliquots quenched with I2 in anhyd THF. After complete
metallation and cooling to 25 °C, the organozinc reagent 23 was ei-
ther used directly in a Negishi cross-coupling reaction or was
cooled to –20 °C and transmetallated with CuCN·2LiCl (1.0 mL,
1.0 M in THF, 1.0 mmol) to react with an acyl chloride. The con-
sumption of the zinc reagent was checked by GC analysis, using tet-
radecane as internal standard. After completion of the reaction, the
mixture was quenched with aq sat. NH4Cl [20 mL; in the presence
of copper, 25% aq NH3 (20 mL) was also added to the mixture] and
extracted with Et2O (3 × 50 mL). The combined organic extracts
were dried (Na2SO4), filtered, and concentrated in vacuum. Purifi-
cation by column chromatography afforded the desired C3-func-
tionalized 4,5-dihydro-1H-benzo[g]indazoles 24a,b.
HRMS (EI): m/z calcd for C21H19ClN2O2: 366.1135; found:
366.1129.
Deprotonation of 1-Ethoxymethyl-4,5-dihydro-1H-benzo[g]in-
dazole (20) Using TMPMgCl·LiCl (9); General Procedure
(GP4)
A flame-dried round-bottomed flask equipped with a magnetic stir-
ring bar, an argon inlet, and a rubber septum was charged with 20
(228 mg, 1.0 mmol) dissolved in THF (1 mL). TMPMgCl·LiCl (9;
1.1 mL, 1.1 M in THF, 1.0 mmol) was added slowly at –20 °C and
the resulting mixture was stirred for 24 h. The completion of the ex-
Synthesis 2009, No. 21, 3661–3671 © Thieme Stuttgart · New York