Intramolecular Cyclization of δ-Iminoacetylenes
CuI (7.6 mg, 0.04 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (23.1 mg, 0.02 mmol) in dry DMF (2 mL) was
stirred at 60 °C until no more starting product was detectable
by TLC analysis. Then, the reaction mixture was diluted with
HCl 0.1 M solution (100 mL) and extracted with ethyl acetate
(2 × 30 mL). The organic layer, dried over sodium sulfate, was
evaporated to dryness and the crude purified by flash chro-
matography over a silica gel column.
yielding progressively 3,4-dihydropyrazino[1,2-a]indoles 2′ and/
or pyrazino[1,2-a]indole 2 (for yields and times, see Table 6).
3-[1-Phenylmeth-(Z)-ylidene]-3,4-dihydropyrazino[1,2-
a]indole 2′b. Eluent for chromatography: PE/EtOAc (98:2).
1
Dark yellow solid. Mp: 121 °C. IR: ν ) 1612, 1560 cm-1. H
NMR: δ ) 4.94 (d, 2H, CH2, 4J ) 1.5 Hz), 6.34 (s, 1H, dC-H),
6.84 (s, 1H, C10-H arom), 7.16-7.45 (m, 6H, arom), 7.72 (d,
1H, arom 3J ) 7.7 Hz), 7.91 (d, 2H, arom 3J ) 7.3 Hz), 8.36 (s,
1H, C1-H arom) ppm. 13C NMR: δ ) 44.5, 105.2, 109.5, 121.2,
123.1, 125.2, 126.0, 127.8, 128.3, 128.5, 128.9, 130.8, 136.1,
137.9, 138.0, 149.1 ppm. Anal. Calcd for C18H14N2 (258.32):
C, 83.69; H, 5.46; N, 10.84. Found: C, 83.58; H, 5.42; N, 10.80.
3-Benzylpyrazino[1,2-a]indole 2b. Eluent for chroma-
tography: PE/EtOAc (98:2). Dark yellow solid. Mp: 89 °C.
1-(3-Phenylprop-2-ynyl)-1H-indole-2-carbaldehyde 1b.
Reaction time: 1 h. Eluent for chromatography: PE/EtOAc
(95:5). Yield: 202 mg, 78%. Yellow solid. Mp: 76 °C. IR: ν )
1
1668, 1613 cm-1. H NMR: δ ) 5.71 (s, 2H, CH2), 7.22-7.41
3
(m, 7H, arom), 7.51 (m, 1H, arom), 7.65 (dd, 1H, arom, J )
4
3
4
8.6, J ) 1.1 Hz), 7.79 (dd, 1H, arom, J ) 8.1, J ) 1.1 Hz),
9.94 (s, 1H, CHO) ppm. 13C NMR: δ ) 35.0, 84.0, 84.5, 111.4,
118.9, 121.7, 122.7, 123.8, 126.9, 127.6, 128.5, 128.7, 132.1,
134.8, 140.5, 183.0 ppm. ESI-MS m/z: 260 [M+ + 1] (100), 199
(15). Anal. Calcd for C18H13NO (259.30): C, 83.37; H, 5.05; N,
5.40. Found: C, 83.31, H, 5.05; N, 5.38.
IR: ν ) 1619, 1530 cm-1
6.98 (s, 1H, C10-H arom), 7.37-7.43 (m, 7H, arom), 7.84-7.93
(m, 3H, arom), 9.03 (d, 1H, C1-H arom, 4J ) 1.5 Hz) ppm. 13
.
1H NMR: δ ) 4.14 (s, 2H, CH2),
C
NMR: δ ) 41.3, 95.2, 111.1, 114.5, 122.3, 122.5, 123.8, 126.8,
128.8, 128.9, 129.4, 129.8, 136.1, 139.4, 147.2 ppm (one signal
obscured). ESI-MS m/z: 259 [M+ + 1] (100). Anal. Calcd for
C18H14N2 (258.32): C, 83.69; H, 5.46; N, 10.84. Found: C,
83.57; H, 5.48; N, 10.79.
1-[1-(3-Phenylprop-2-ynyl)-1H-indol-2-yl]ethanone 1g.
Reaction time: 3 h. Eluent for chromatography: PE/EtOAc
(98:2). Yield: 200 mg, 73%. White solid. Mp: 112-113 °C. IR:
ν ) 1663, 1614 cm-1. 1H NMR: δ ) 2.65 (s, 3H, CH3), 5.71 (s,
2H, CH2), 7.16-7.28 (m, 4H, arom), 7.32-7.40 (m, 3H, arom),
1-Methyl-3-[1-phenylmeth-(Z)-ylidene]-3,4-dihydropy-
razino[1,2-a]indole 2′g. Eluent for chromatography: PE/
1
3
EtOAc (98:2). Yellow oil. IR: ν ) 1613, 1556 cm-1. H NMR:
7.44 (m, 1H, arom), 7.59 (d, 1H, arom, J ) 7.7 Hz), 7.72 (d,
4
3
δ ) 2.60 (s, 3H, CH3), 4.86 (d, 2H, CH2, J ) 1.1 Hz), 6.21 (s,
1H, arom, J ) 7.7 Hz) ppm. 13C NMR: δ ) 28.2, 35.2, 83.9,
1H, dC-H), 6.87 (s, 1H, C10-H arom), 7.15-7.41 (m, 6H, arom),
84.7, 111.2, 113.5, 121.5, 122.9, 123.3, 126.4, 126.6, 128.4,
128.5, 132.0, 133.9, 139.8, 191.7 ppm. ESI-MS m/z: 274 [M+
+ 1] (100), 232 (10). Anal. Calcd for C19H15NO (273.33): C,
83.49; H, 5.53; N, 5.12. Found: C, 83.41; H, 5.49; N, 5.14.
7.68 (d, 1H, arom
3J ) 8.1 Hz), 7.92 (d, 2H, arom 3J ) 7.3 Hz)
ppm. 13C NMR: δ ) 22.5, 44.3, 103.8, 109.8, 121.0, 122.9,
123.5, 125.0, 127.5, 127.8, 128.1, 128.2, 131.0, 136.0, 138.0,
156.9 ppm (one signal obscured). ESI-MS m/z: 273 [M+ + 1]
(100), 211 (10). Anal. Calcd for C19H16N2 (272.34): C, 83.79;
H, 5.92; N, 10.29. Found: C, 83.69; H, 5.96; N, 10.25.
3-Benzyl-1-methylpyrazino[1,2-a]indole 2g. Eluent for
chromatography: PE/EtOAc (98:2). Dark yellow oil. IR: ν )
1617, 1517 cm-1. 1H NMR: δ ) 2.80 (s, 3H, CH3), 4.14 (s, 2H,
CH2), 6.98 (s, 1H, C10-H arom), 7.29-7.42 (m, 7H, arom),
7.70-7.90 (m, 3H, arom) ppm. 13C NMR: δ ) 22.2, 41.1, 97.0,
111.2, 113.1, 121.6, 122.4, 123.7, 126.8, 128.6, 128.9, 129.5,
130.0, 136.4, 139.1, 154.9 ppm (one signal obscured). ESI-MS
m/z: 273 [M+ + 1] (100), 195 (20). Anal. Calcd for C19H16N2
(272.34): C, 83.79; H, 5.92; N, 10.29. Found: C, 83.74; H, 5.98;
N, 10.25.
Phenyl[1-(3-phenylprop-2-ynyl)-1H-indol-2-yl]metha-
none 1l. Reaction time: 1.5 h. Eluent for chromatography:
PE/EtOAc (95:5). Yield: 320 mg, 90%. Yellow oil. IR: ν ) 1635,
1614 cm-1. 1H NMR: δ ) 5.71 (s, 2H, CH2), 7.07 (s, 1H, C3-H
arom), 7.18-7.36 (m, 6H, arom), 7.42-7.72 (m, 6H, arom), 7.96
(dd, 2H, arom, 3J ) 6.6, 4J ) 1.5 Hz) ppm. 13C NMR: δ )
35.2, 84.2, 84.6, 111.2, 116.3, 121.5, 122.8, 123.4, 126.5, 126.6,
128.4, 128.5, 128.6, 130.0, 132.0, 132.5, 134.3, 139.5, 140.0,
188.8 ppm. ESI-MS m/z: 336 [M+ + 1] (100), 251 (38). Anal.
Calcd for C24H17NO (335.40): C, 85.94; H, 5.11; N, 4.18.
Found: C, 86.21; H, 5.18; N, 4.13.
General Methods for Cyclization Reactions of 2-Car-
bonyl-1-alkynylindoles 1. Conventional Thermal Cy-
clizations. A stirred solution of the appropriate indole 1 (0.3
mmol) in dry ammonia in methanol (NH3/MeOH 2 M solution,
3 mL) was heated at 90-150 °C in a sealed tube for 3-387 h
until no more starting product was detectable by TLC. The
solvent was then evaporated under reduced pressure. The
crude product was purified by flash chromatography over silica
gel column yielding progressively 3,4-dihydropyrazino[1,2-a]-
indoles 2′ and/or pyrazino[1,2-a]indole 2 (for yields, times, and
temperatures, see Table 2).
Microwave-Assisted Cyclizations. A stirred solution of
the appropriate indole 1 (0.3 mmol) in dry ammonia in
methanol (NH3/MeOH 2 M solution, 3 mL) was heated at 150
°C in a sealed tube for 25-300 min in a multimode microwave
oven until no more starting product was detectable by TLC.
The solvent was then evaporated under reduced pressure. The
crude product was purified by flash chromatography over silica
gel column yielding progressively 3,4-dihydropyrazino[1,2-a]-
indoles 2′ and/or pyrazino[1,2-a]indole 2 (for yields and times,
see Table 4).
TiCl4-Catalyzed Cyclizations. In a sealed tube, to a
solution of the appropriate indole 1 (0.3 mmol) in dry ammonia
in methanol (NH3/MeOH 2 M solution, 3 mL), was carefully
added TiCl4 (171 mg, 99 µL, 0.9 mmol) (caution!). The stirred
reaction mixture was warmed at 100 °C with a silicon oil bath
for 120-1020 min, or alternatively heated at 130 °C in a
multimode microwave oven for 43-313 min, until no more
starting product was detectable by TLC. The solvent was
evaporated under reduced pressure. The crude product was
purified by flash chromatography over silica gel column
1-Phenyl-3-[1-phenylmeth-(Z)-ylidene]-3,4-dihydropy-
razino[1,2-a]indole 2′l. Eluent for chromatography: PE/
EtOAc (99:1). Yellow orange solid. Mp: 65 °C. IR: ν ) 1613,
1
1527 cm-1. H NMR: δ ) 4.97 (s, 2H, CH2), 6.35 (s, 1H, dC-
H), 6.87 (s, 1H, C10-H arom), 7.16-7.44 (m, 6H, arom), 7.55
(m, 3H, arom), 7.69 (dd, 1H, arom 3J ) 8.1, 4J ) 0.7 Hz), 8.06
(m, 4H, arom) ppm. 13C NMR: δ ) 44.1, 106.6, 109.5, 121.0,
123.0, 124.8, 124.9, 127.6, 127.8, 128.1, 128.5, 128.7, 129.4,
130.6, 130.9, 136.5, 137.6, 138.0, 138.1, 157.2 ppm. ESI-MS
m/z: 335 [M+ + 1] (100). Anal. Calcd for C24H18N2 (334.41):
C, 86.20; H, 5.43; N, 8.38. Found: C, 86.28; H, 5.45; N, 8.35.
3-Benzyl-1-phenylpyrazino[1,2-a]indole 2l. Eluent for
chromatography: PE/EtOAc (99:1). Yellow orange solid. Mp:
1
145 °C. IR: ν ) 1638, 1530 cm-1. H NMR: δ ) 4.22 (s, 2H,
CH2), 6.83 (d, 1H, C10-H arom, 4J ) 0.8 Hz), 7.18 (m, 2H,
arom), 7.20-7.60 (m, 6H, arom), 7.65 (m, 1H, arom), 7.83 (m,
2H, arom), 7.92 (m, 4H, arom) ppm. (This compound was
obtained in a too low amount to perform 13C NMR and
elemental analysis.)
Acknowledgment. We are grateful to MIUR (Min-
istero dell’Istruzione, dell’ Universita` e della Ricerca)
for financial support.
Supporting Information Available: General experimen-
tal details, characterization data for compounds 1c-e,h-j,m-
o, 2a,c-f,h-k,m, and 2′c-e,h-j,m-o, computational meth-
ods, and details of NMR kinetic studies. This material is
JO0502246
J. Org. Chem, Vol. 70, No. 10, 2005 4095