3444 J . Org. Chem., Vol. 67, No. 10, 2002
Huang et al.
yl)benzaldehyde, and 2-(4-(tetrahydropyran-2-yloxy)but-1-
ynyl)benzaldehyde can be found in Supporting Information.
Rep r esen ta tive P r oced u r e for P r ep a r a tion of Im i-
n es: N-(2-P h en ylet h yn ylb en zylid en e)-ter t-b u t yla m in e
(1). To a solution of 2-bromobenzaldehyde (1.86 g, 10.0 mmol)
and phenylacetylene (1.22 g, 12.0 mmol) in Et3N (40 mL) were
added PdCl2(PPh3)2 (140 mg, 2 mol %) and CuI (20 mg, 1 mol
%). The resulting mixture was then heated under an Ar
atmosphere at 50 °C. The reaction was monitored by TLC to
establish completion. When the reaction was complete, the
mixture was allowed to cool to room temperature, and the
ammonium salt was removed by filtration. The solvent was
removed under reduced pressure, and the residue was purified
by flash column chromatography using 20:1 hexane/EtOAc to
afford 1.94 g (94%) of 2-(2-phenylethynyl)benzaldehyde as a
yellow oil with spectral properties identical to those previously
reported.9 To 2-(phenylethynyl)benzaldehyde (1.03 g, 5.0 mmol)
in a 4 dram vial was added t-BuNH2 (6 equiv). The mixture
was then stirred under an Ar atmosphere at room temperature
for 24 h. The resulting mixture was extracted with ether. The
combined organic layers were dried (Na2SO4) and filtered.
Removal of the solvent afforded 1.30 g of the desired compound
in 100% yield as a yellow solid: mp 53-54 °C; 1H NMR (CDCl3)
δ 1.34 (s, 9H), 7.28-7.35 (m, 5H), 7.49-7.54 (m, 3H), 8.07-
8.10 (m, 1H), 8.94 (s, 1H); 13C NMR (CDCl3) δ 30.0, 58.0, 86.9,
95.1, 123.3, 124.1, 126.2, 128.7, 128.7, 128.8, 129.9, 131.6,
132.4, 138.8, 154.2; IR (CHCl3, cm-1) 3060, 2214, 1637; HRMS
calcd for C19H19N 261.1518, found 261.1518.
Sch em e 3
Con clu sion s
In conclusion, a procedure for the efficient synthesis
of a wide variety of substituted isoquinolines has been
developed that employs very mild reaction conditions.
This methodology accommodates a variety of iminoalkynes
and affords the anticipated substituted isoquinolines in
moderate to excellent yields.
Characterization of all other imines prepared in this study
can be found in Supporting Information.
Typ ica l P r oced u r e for Cycliza tion Rea ction s: 4-Iod o-
3-p h en ylisoqu in olin e (2). To a 2 dram vial were added 0.381
g of I2 (1.50 mmol), 62 mg of NaOCOCH3 (0.75 mmol), and 5
mL of CH3CN. The iminoalkyne 1 (65 mg, 0.25 mmol) in 2
mL of CH3CN was added dropwise to the vial. The vial was
flushed with Ar, and the reaction mixture was stirred at room
temperature for 0.5 h. The reaction mixture was then diluted
with 25 mL of ether, washed with 25 mL of saturated Na2S2O3,
dried (Na2SO4), and filtered. The solvent was evaporated under
reduced pressure, and the product was purified by flash
chromatography (3:1 hexane/EtOAc) to afford 56 mg (68%)
(Table 2, entry 1) of the product as a yellow solid: mp 84-85
°C; 1H NMR (CDCl3) δ 7.26-7.52 (m, 3H), 7.61-7.70 (m, 3H),
7.70-7.85 (m, 2H), 7.95 (d, J ) 8.1 Hz, 1H), 8.22 (d, J ) 8.4
Hz, 1H); 13C NMR (CDCl3) δ 98.3, 128.1, 128.2, 128.3, 128.5,
130.3, 132.4, 132.6, 138.8, 143.9, 152.2, 157.4 (one sp2 carbon
missing due to overlap); IR (CHCl3, cm-1) 3055, 1630, 1549;
HRMS calcd for C15H10IN 330.9858, found 330.9862.
Exp er im en ta l Section
Gen er a l. The 1H and 13C NMR spectra were recorded at
300 and 75 MHz or 400 and 100 MHz, respectively. Thin-layer
chromatography was performed using commercially prepared
60 mesh silica gel plates, and visualization was effected with
short wavelength UV light (254 nm) and basic KMnO4 solution
[3 g of KMnO4 + 20 g of K2CO3 + 5 mL of NaOH (5%) + 300
mL of H2O]. All melting points are uncorrected. Low-resolution
mass spectra were recorded on a triple quadrupole mass
spectrometer. High-resolution mass spectra were recorded on
a double focusing magnetic sector mass spectrometer using
EI at 70 eV. All reagents were used directly as obtained
commercially unless otherwise noted. 2-Bromopyridine-3-
carboxaldehyde,13 3-bromopyridine-4-carboxaldehyde,13 and
PhSCl14 were prepared according to literature procedures. The
preparation and characterization of the starting materials 2-(2-
propenylethynyl)benzyl alcohol, 2-(2-propenylethynyl)benzal-
dehyde, 2-(phenylethynyl)benzaldehyde, 2-(2-cyclohex-1-enyl-
ethynyl)benzaldehyde, 2-(3,4,5-trimethoxyphenylethynyl)benz-
aldehyde, 2-(4-methoxyphenylethynyl)benzaldehyde, 4,5-me-
thylenedioxy-2-(phenylethynyl)benzaldehyde, 2-(phenylethyn-
yl)pyridine-3-carboxaldehyde, 2-(1-octyn-1-yl)pyridine-3- car-
boxaldehyde, 3-(phenylethynyl)pyridine-4-carboxaldehyde, 2-(4-
trifluoromethylphenylethynyl)benzaldehyde, 2-(cyclohexylethyn-
Characterization of all other isoquinolines and naphthyr-
idines prepared in this study can be found in Supporting
Information.
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of the starting materials; characterization
data for compounds 2, 3, 5, 7, 9, 11, 13, 15, 17-20, 22-32,
34, 35, 37, 39, and 41-45; and copies of 1H and 13C NMR
spectra for compounds 1-32 and 34-45. This material is
(13) (a) Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999, 2, 306.
(b) Bjork, P.; Aakermann, T.; Hornfeldt, A.; Gronowitz, S. J . Heterocycl.
Chem. 1995, 32, 751. (c) Melnyk, P.; Gasche, J .; Thal, C. Synth.
Commun. 1993, 2727.
(14) (a) Harpp, D. N.; Friedlander, B. T.; Smith, R. A. Synthesis
1979, 3, 181. (b) Mueller, W. H.; Butler, P. E. J . Am. Chem. Soc. 1968,
90, 2075.
J O020020E