A convenient synthesis of 1,4-disubstituted isoquinolines by reactions of α-substituted 2-lithio-β-methoxystyrenes with nitriles

Article abstract of DOI:10.1055/s-2006-950186

It has been found that halogen-lithium exchange between α-substituted 2-bromo-β-methoxystyrene derivatives and n-butyllithium generates α-substituted 2-lithio-β-methoxystyrene derivatives, which successfully react with a range of nitriles to afford the co

Full text of DOI:10.1055/s-2006-950186

2934
PAPER
A Convenient Synthesis of 1,4-Disubstituted Isoquinolines by Reactions of
a-Substituted 2-Lithio-b-methoxystyrenes with Nitriles
S
ynthesis of 1,4-D
a
isubstituted
z
Isoquinoli
unes hiro Kobayashi,* Kazutaka Hayashi, Kazuna Miyamoto, Osamu Morikawa, Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 13 April 2006; revised 19 May 2006
a-Substituted 2-bromo-b-methoxystyrene derivatives 14
Abstract: It has been found that halogen–lithium exchange be-
were obtained as mixtures of stereoisomers, in good
tween a-substituted 2-bromo-b-methoxystyrene derivatives and
yields, by the reaction of readily available o-bromophenyl
n-butyllithium generates a-substituted 2-lithio-b-methoxystyrene
ketones5,6 with (methoxymethylene)triphenylphosphoran.
derivatives, which successfully react with a range of nitriles to af-
ford the corresponding 1,4-disubstituted isoquinolines in reason- The reactions used for the preparation of 1,4-disubstituted
able yields.
isoquinolines 3 were carried out as shown in Scheme 1.
Thus, bromine–lithium exchange of 1 through treatment
with n-butyllithium in diethyl ether at 0 °C generated a-
substituted 2-lithio-b-methoxystyrene derivatives 2. Al-
most quantitative generation of 2-lithio-b-methoxy-a-
phenylstyrene from 2-bromo-b-methoxy-a-phenylstyrene
(1a) was confirmed by the observation that b-methoxy-a-
phenylstyrene7 was formed in high yields (>95%) after
quenching with aqueous ammonium chloride. Subse-
quently, these lithium products were allowed to react with
nitriles at the same temperature to give, after the usual
aqueous workup followed by purification by preparative
TLC on silica gel, the desired isoquinoline derivatives 3 in
the yields summarized in Table 1. It can be seen that the
reactions of 1a and a-(4-chlorophenyl)-2-bromo-b-meth-
oxystyrene (1b) with aromatic nitriles provide satisfacto-
ry yields of the corresponding isoquinoline derivatives
(Entries 1–6, 11 and 12). Nitriles bearing an a-hydrogen
proved to give similar results (Entries 9 and 10).
Key words: benzyl anion, isoquinoline, nitrile, organolithium, sty-
rene
After our recent finding that the reaction of 2-(2-meth-
oxyethenyl)benzonitrile derivatives with organolithiums
affords isoquinoline derivatives,1 we wished to extend this
study and investigate the possibility of reacting a-substi-
tuted 2-lithio-b-methoxystyrene derivatives 2 with ni-
triles, for the preparation of isoquinoline derivatives such
as 3. This would constitute an improvement of the previ-
ous method, since the precursors of these lithium
compounds, a-substituted 2-bromo-b-methoxystyrene de-
rivatives 1, are simpler to prepare than the 2-(2-methoxy-
ethenyl)benzonitrile derivatives, and a wider range of
nitriles are available, compared to organolithiums. We
now report a new synthesis of isoquinolines, which en-
abled us to prepare a range of 1,4-disubstituted deriva-
tives. Since compounds based on the isoquinoline
skeleton have received considerable attention because of
their biological utilities,2 a number of approaches for the
construction of this system have recently been devel-
oped.3
In order to investigate the scope of the present method, re-
actions using pyridine-2-carbonitrile, cinnamonitrile, and
propanenitrile were carried out. In all cases, the desired
products were obtained albeit in somewhat lower yields
(Entries 7, 8 and 13, respectively). Subsequently, we ex-
amined halogenated nitriles; however, the reaction of 2-
lithio-b-methoxy-a-phenylstyrene (2a) with trichloroace-
tonitrile, under the same conditions, gave a rather com-
plex mixture of products, from which only trace amounts
of the desired product could be isolated. Similarly, the re-
actions with 4-bromobutanenitrile and 2-bromomethyl-
benzonitrile both failed to produce the corresponding
isoquinoline derivatives.
R2
R2
R1
OMe
R1
OMe
n-BuLi
Et2O, 0 °C
Br
1a R1 = H, R2 = Ph
1b R1 = H, R2 = 4-ClC6H4
1c R1 = OMe, R2 = Ph
1d R1 = H, R2 = Me
Li
2
R2
R1
2-Bromo-b,4-dimethoxy-a-phenylstyrene (1c) and 2-bro-
mo-b-methoxy-a-methylstyrene (1d) could also be used
in the present isoquinoline synthesis, but the product
yields were somewhat lower than those using 1a and 1b.
This decrease in yield is probably due to the lower stabil-
ity of the benzyl anion intermediates 5, arising from attack
of the nitrogen anion of 4 on the a-carbon atom of the
methoxyvinyl moiety (Scheme 2).8 In the case of 1d, it
was necessary to raise the reaction temperature to room
R3CN
0 °C (or to r.t.)
N
R3
3
Scheme 1 For R3, see Table 1
SYNTHESIS 2006, No. 17, pp 2934–2938
x
x.
x
x
.
2
0
0
6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950186; Art ID: F05706SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1,4-Disubstituted Isoquinolines
2935
Melting points were determined on a Laboratory Devices MEL-
TEMP II melting-point apparatus and are uncorrected. The IR spec-
tra were recorded on a Shimadzu FTIR-8300 spectrometer. The 1H
NMR spectra were determined using TMS as an internal reference
with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz
in CDCl3. Low-resolution mass spectra were recorded on a JEOL
AUTOMASS 20 spectrometer (Center for Joint Research and De-
velopment, this University). Thin-layer chromatography (TLC) was
carried out on Merck Kieselgel 60 PF254. All solvents used were
dried over appropriate drying agents and distilled under argon prior
to use.
(2-Bromophenyl)phenylmethanone5, 2-bromophenyl(4-chlorophen-
yl)methanol,6 (2-bromo-5-methoxyphenyl)phenylmethanone,6 and
1-bromo-2-(2-methoxy-1-methylethenyl)benzene (1d)4 were pre-
pared by literature methods. All other chemical used in this study
were commercially available.
Table 1 Preparation of 1,4-Disubstituted Isoquinolines 3
Entry
1
1
R3 of R3CN
Ph
3 (Yield/%)a
3a (73)
3b (64)
3c (68)
3d (68)
3e (66)
3f (52)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
2
o-Tol
3
2-FC6H4
4-ClC6H4
4-CF3C6H4
Naphthalen-1-yl
Pyridin-2-yl
(E)-PhCH=CH
i-Pr
4
5
6
7
3g (38)
3h (38)
3i (62)
8
2-Bromophenyl(4-chlorophenyl)methanone
9
This compound was prepared by the oxidation of 2-bromophenyl(4-
chlorophenyl)methanol6 with PCC at r.t. in DCE.
10
11
12
13
14
15
16
17
18
Cy
3j (62)
Yield: 89%; yellow oil; Rf = 0.42 (EtOAc–hexane, 1:5).
IR (neat): 1668 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.3–7.5 (5 H, m), 7.65 (1 H, dd,
J = 7.3, 1.3 Hz), 7.75 (2 H, d, J = 8.9 Hz).
Ph
3k (71)
3l (51)
Phenanthren-9-yl
Et
3m (40)
3n (43)
3o (45)
3p (44)
3q (43)
3r (36)b
Anal. Calcd for C13H8BrClO: C, 52.83; H, 2.73. Found: C, 52.71;
H, 3.01.
Ph
4-ClC6H4
4-CF3C6H4
t-Bu
Bromo-2-(2-methoxy-1-phenylethenyl)benzene (1a)
To a stirred suspension of (methoxymethyl)triphenylphosphonium
chloride (6.9 g, 20 mmol) in THF (40 mL) at 0 °C was added n-BuLi
(1.6 M in hexane, 20 mmol) dropwise. After 15 min, a solution of
(2-bromophenyl)phenylmethanone (2.1 g, 8.1 mmol) in THF (7
mL) was added and stirring was continued for an additional 30 min.
The mixture was treated with H2O (50 mL) and the organic materi-
als were extracted with Et2O (2 × 20 mL). The combined extracts
were washed with brine (20 mL) and dried over anhydrous Na2SO4.
After evaporation of the solvent, the residue was purified by column
chromatography on silica gel (EtOAc–hexane, 1:20) to give 1a as a
mixture of stereoisomers (E:Z = ca. 7:3). Yield: 1.8 g (75%); pale-
yellow oil.
Ph
a Isolated yields.
b Reaction was allowed to come to room temperature after addition of
PhCN.
temperature in order to allow the reaction to reach com-
pletion.
An analytical specimen of each isomer was obtained by fractional
column chromatography.
In the present work, we have demonstrated an efficient
synthetic method that allows access to 1,4-disubstituted
isoquinolines. The operational simplicity, together with
the ready availability of the starting materials, makes this
new procedure attractive. Work on investigating the pos-
sibility of preparing related heterocycles, using reactions
of 2-lithio-b-methoxystyrene derivatives with other elec-
trophiles, are currently in progress in our laboratory.
E-Isomer
Pale-yellow oil; Rf = 0.45 (Et2O–hexane, 1:20).
IR (neat): 1636 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.81 (3 H, s), 6.25 (1 H, s), 7.14–
7.19 (2 H, m), 7.26–7.34 (4 H, m), 7.37 (2 H, dd, J = 7.8, 0.9 Hz),
7.59 (1 H, d, J = 8.2 Hz).
Anal. Calcd for C15H13BrO: C, 62.30; H, 4.53. Found: C, 62.14; H,
4.60.
Z-Isomer
R2
R2
Li
N
R1
OMe
Li
White solid; mp 80–82 °C (hexane–Et2O).
IR (KBr): 1645 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.74 (3 H, s), 6.67 (1 H, s), 7.12
(2 H, d, J = 7.8 Hz), 7.17 (2 H, dd, J = 7.8, 7.3 Hz), 7.23–7.26 (3 H,
m), 7.33 (1 H, t, J = 7.3 Hz), 7.64 (1 H, d, J = 7.8 Hz).
R1
OMe
R3CN
2
N
R3
R3
4
5
Anal. Calcd for C15H13BrO: C, 62.30; H, 4.53. Found: C, 61.94; H,
4.54.
– LiOMe
3
Scheme 2
Synthesis 2006, No. 17, 2934–2938 © Thieme Stuttgart · New York

2936
K. Kobayashi et al.
PAPER
1-Bromo-2-[2-methoxy-1-(4-chlorophenyl)ethenyl]benzene
(1b)
This compound was prepared from 2-bromophenyl(4-chlorophen-
yl)methanone,6 in a manner similar to that described for the prepa-
ration of 1a, as a mixture of stereoisomers (E:Z = ~7:3). Yield:
74%; colorless oil.
1H NMR (500 MHz, CDCl3): d = 2.14 (3 H, s), 7.31–7.43 (4 H, m),
7.46–7.52 (2 H, m), 7.54–7.61 (4 H, m), 7.65 (1 H, ddd, J = 8.2, 6.9,
1.4 Hz), 7.73 (1 H, d, J = 8.2 Hz), 7.98 (1 H, d, J = 8.7 Hz), 8.57
(1 H, s).
MS (EI): m/z (%) = 294 (100) [M+].
Anal. Calcd for C22H17N: C, 89.46; H, 5.80; N, 4.74. Found: C,
89.39; H, 5.86; N, 4.68.
An analytical specimen of each isomer was obtained by fractional
column chromatography.
E-Isomer
1-(2-Fluorophenyl)-4-phenylisoquinoline (3c)
White solid; mp 116–118 °C (hexane–Et2O).
IR (KBr): 1616 cm–1.
Colorless oil; Rf = 0.41 (CH2Cl2–hexane, 1:4).
IR (neat): 1634 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.27 (1 H, ddd, J = 8.7, 7.3, 0.9
Hz), 7.36 (1 H, ddd, J = 7.8, 7.3, 0.9 Hz), 7.50–7.59 (7 H, m), 7.62
(1 H, td, J = 7.3, 1.8 Hz), 7.67 (1 H, ddd, J = 8.2, 6.9, 1.4 Hz), 7.89
(1 H, dd, J = 8.2, 2.7 Hz), 7.98 (1 H, d, J = 8.2 Hz), 8.60 (1 H, s).
1H NMR (500 MHz, CDCl3): d = 3.82 (3 H, s), 6.26 (1 H, s), 7.19
(1 H, ddd, J = 9.2, 6.3, 2.4 Hz), 7.22 (2 H, d, J = 8.7 Hz), 7.29–7.34
(4 H, m), 7.59 (1 H, dd, J = 7.8, 1.4 Hz).
Anal. Calcd for C15H12BrClO: C, 55.67; H, 3.74. Found: C, 55.65;
H, 3.81.
MS (EI): m/z (%) = 299 (100) [M+].
Anal. Calcd for C21H14FN: C, 84.26; H, 4.71; N, 4.68. Found: C,
84.24; H, 4.69; N, 4.53.
Z-Isomer
White solid; mp 74–78 °C (hexane–Et2O).
IR (KBr): 1638 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.75 (3 H, s), 6.66 (1 H, s), 7.03
(2 H, d, J = 8.7 Hz), 7.16–7.24 (4 H, m), 7.34 (1 H, ddd, J = 7.8,
7.3, 1.4 Hz), 7.64 (1 H, dd, J = 7.8, 1.4 Hz).
1-(4-Chlorophenyl)-4-phenylisoquinoline (3d)
Colorless needles; mp 155–157 °C (hexane–Et2O).
IR (KBr): 1616 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.47–7.59 (8 H, m), 7.67 (1 H,
ddd, J = 8.2, 6.9, 1.4 Hz), 7.70 (2 H, d, J = 8.2 Hz), 7.98 (1 H, d,
J = 8.7 Hz), 8.12 (1 H, d, J = 8.2 Hz), 8.56 (1 H, s).
Anal. Calcd for C15H12BrClO: C, 55.67; H, 3.74. Found: C, 55.44;
H, 3.84.
MS (EI): m/z (%) = 315 (86) [M+], 314 (100).
1-Bromo-4-methoxy-2-(2-methoxy-1-phenylethenyl)benzene
(1c)
This compound was prepared from (2-bromo-5-methoxyphen-
yl)phenylmethanone,6 in a manner similar to that described for the
preparation of 1a, as a mixture of stereoisomers (E:Z = ~1:1). Yield:
63%; colorless oil.
Anal. Calcd for C21H14ClN: C, 79.87; H, 4.47; N, 4.44. Found: C,
79.56; H, 4.53; N, 4.40.
4-Phenyl-1-(4-trifluoromethylphenyl)isoquinoline (3e)
White solid; mp 115–118 °C (hexane–Et2O).
IR (KBr): 1616 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.49–7.61 (6 H, m), 7.69 (1 H,
ddd, J = 8.2, 6.9, 1.4 Hz), 7.83 (2 H, d, J = 7.8 Hz), 7.87 (2 H, d,
J = 7.8 Hz), 8.00 (1 H, d, J = 8.7 Hz), 8.09 (1 H, d, J = 8.2 Hz), 8.59
(1 H, s).
IR (neat): 1637 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.75, 3.77, 3.80, and 3.82 (com-
bined 6 H, 4 × s), 6.26 (0.5 H, s), 6.66 (0.5 H, s), 6.73–6.76 (1 H,
m), 6.79 (0.5 H, d, J = 3.2 Hz), 6.88 (0.5 H, d, J = 3.2 Hz), 7.12–
7.29 (4 H, m), 7.39 (1 H, dd, J = 8.2, 1.4 Hz), 7.46 (0.5 H, d, J = 8.7
Hz), 7.52 (0.5 H, d, J = 8.7 Hz).
MS (EI): m/z (%) = 349 (100) [M+].
Anal. Calcd for C16H15BrO2: C, 60.21; H, 4.74. Found: C, 59.98; H,
4.84.
Anal. Calcd for C22H14F3N: C, 75.64; H, 4.04; N, 4.01. Found: C,
75.38; H, 4.09; N, 3.98.
1,4-Diphenylisoquinoline (3a);9 Typical Procedure
1-(Naphthalen-1-yl)-4-phenylisoquinoline (3f)
Colorless viscous oil; Rf = 0.12 (EtOAc–hexane, 1:2).
IR (neat): 1614 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36 (1 H, ddd, J = 7.8, 7.3, 1.4
Hz), 7.42 (1 H, ddd, J = 8.2, 6.9, 1.4 Hz), 7.48–7.54 (3 H, m), 7.58
(2 H, dd, J = 7.8, 7.3 Hz), 7.62–7.67 (5 H, m), 7.69 (1 H, d, J = 8.2
Hz), 7.97 (1 H, dd, J = 7.8, 1.4 Hz), 8.01–8.03 (2 H, m), 8.66 (1 H,
s).
To a stirred solution of 1a (0.25 g, 0.85 mmol) in Et2O (4 mL) at
0 °C was added n-BuLi (1.6M in hexane, 0.85 mmol) dropwise. Af-
ter 1 h, PhCN (97 mg, 0.94 mmol) was added and the mixture was
stirred at the same temperature for an additional 30 min. H2O (10
mL) was added and the organic materials were extracted with Et2O
(2 × 15 mL). The combined extracts were washed with brine (10
mL) and dried over anhydrous Na2SO4. After evaporation of the sol-
vent, the residue was purified by preparative TLC on silica gel
(Et2O–hexane, 1:3). Yield: 0.18 g (73%); white solid; mp 139–
140 °C (hexane–Et2O) (Lit.9 141 °C).
MS (EI): m/z (%) = 331 (76) [M+], 330 (100).
Anal. Calcd for C25H17N: C, 90.60; H, 5.17; N, 4.23. Found: C,
90.58; H, 5.26; N, 4.16.
IR (KBr): 1614 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.45–7.65 (9 H, m), 7.66 (1 H, t,
J = 8.2 Hz), 7.74 (2 H, dd, J = 8.2, 1.3 Hz), 7.98 (1 H, d, J = 7.9
Hz), 8.18 (1 H, dd, J = 8.2, 1.3 Hz), 8.57 (1 H, s).
4-Phenyl-1-(pyridin-2-yl)isoquinoline (3g)
Yellow viscous oil; Rf = 0.23 (hexane–Et2O, 1:2).
IR (neat): 1625 cm–1.
MS (EI): m/z (%) = 281 (96) [M+], 280 (100).
1H NMR (500 MHz, CDCl3): d = 7.43 (1 H, ddd, J = 7.8, 7.3, 1.4
Hz), 7.49–7.57 (5 H, m), 7.61 (1 H, ddd, J = 8.2, 6.9, 1.4 Hz), 7.67
(1 H, ddd, 8.2, 6.9, 1.4 Hz), 7.94 (1 H, td, J = 7.3, 1.8 Hz), 7.97
(1 H, d, J = 8.7 Hz), 8.03 (1 H, dd, J = 6.9, 0.9 Hz), 8.59 (1 H, s),
8.64 (1 H, dd, J = 9.1, 0.9 Hz), 8.81–8.84 (1 H, m).
1-(2-Methylphenyl)-4-phenylisoquinoline (3b)
Pale-yellow oil; Rf = 0.17 (hexane–THF, 3:1).
IR (neat): 1614 cm–1.
Synthesis 2006, No. 17, 2934–2938 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Disubstituted Isoquinolines
2937
MS (EI): m/z (%) = 282 (100) [M+].
Anal. Calcd for C29H18ClN: C, 83.75; H, 4.36; N, 3.37. Found: C,
83.72; H, 4.45; N, 3.27.
Anal. Calcd for C20H14N2: C, 85.08; H, 5.00; N, 9.92. Found: C,
84.94; H, 5.13; N, 9.85.
4-(4-Chlorophenyl)-1-ethylisoquinoline (3m)
Pale-yellow solid; mp 70–73 °C (hexane–Et2O).
IR (KBr): 1616 cm–1.
4-Phenyl-1-[(E)-2-phenylvinyl]isoquinoline (3h)
Pale-yellow oil; Rf = 0.31 (hexane–CH2Cl2, 1:1).
IR (neat): 1628, 1615, 1601 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.49 (3 H, t, J = 7.3 Hz), 3.48
(2 H, q, J = 7.3 Hz), 7.43 (2 H, d, J = 8.7 Hz), 7.49 (2 H, d, J = 8.7
Hz), 7.60–7.67 (2 H. m). 7.85 (1 H, dd, J = 7.8, 1.8 Hz), 8.25 (1 H,
dd, J = 7.8, 1.8 Hz), 8.36 (1 H, s).
1H NMR (500 MHz, CDCl3): d = 7.35 (1 H, t, J = 7.3 Hz), 7.44
(2 H, dd, J = 7.6, 7.3 Hz), 7.46–7.51 (1 H, m), 7.52–7.57 (5 H, m),
7.64–7.68 (2 H, m), 7.73 (1 H, d, J = 7.6 Hz), 7.94–7.97 (1 H, m),
8.02 (1 H, d, J = 15.6 Hz), 8.07 (1 H, d, J = 15.6 Hz), 8.44–8.47
(1 H, m), 8.53 (1 H, s).
MS (EI): m/z (%) = 267 (58) [M+], 266 (100).
Anal. Calcd for C17H14ClN: C, 76.26; H, 5.27; N, 5.23. Found: C,
76.02; H, 5.28; N, 5.16.
MS (EI): m/z (%) = 307 (61) [M+], 306 (100).
Anal. Calcd for C23H17N: C, 89.87; H, 5.57; N, 4.56. Found: C,
89.81; H, 5.58; N, 4.54.
6-Methoxy-1,4-diphenylisoquinoline (3n)10
White solid; mp 107–108 °C (hexane–Et2O).
1-(1-Methylethyl)-4-phenylisoquinoline (3i)
IR (KBr): 1618 cm–1.
Pale-yellow oil; Rf = 0.29 (hexane–Et2O, 10:1).
IR (neat): 1615 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.50 (6 H, d, J = 6.9 Hz), 4.03
(1 H, sept, J = 6.9 Hz), 7.44–7.54 (5 H, m), 7.59–7.65 (2 H, m),
7.89–7.93 (1 H, m), 8.29–8.32 (1 H, m), 8.44 (1 H, s).
1H NMR (500 MHz, CDCl3): d = 3.82 (3 H, s), 7.17 (1 H, dd,
J = 9.2, 2.6 Hz), 7.23 (1 H, d, J = 2.6 Hz), 7.45–7.6 (8 H, m), 7.71
(2 H, d, J = 8.3, 2.0 Hz), 8.07 (1 H, d, J = 9.2 Hz), 8.45 (1 H, s).
MS (EI): m/z (%) = 311 (87) [M+], 310 (100).
1-(4-Chlorophenyl)-6-methoxy-4-phenylisoquinoline (3o)
White solid; mp 117–120 °C (hexane–Et2O).
IR (KBr): 1618 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.82 (3 H, s), 7.18 (1 H, dd,
J = 9.2, 2.2 Hz), 7.24 (1 H, d, J = 2.2 Hz), 7.47–7.58 (7 H, m), 7.67
(2 H, d, J = 8.2 Hz), 8.01 (1 H, d, J = 9.2 Hz), 8.47 (1 H, s).
MS (EI): m/z (%) = 247 (99) [M+], 220 (100).
Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
87.28; H, 7.00; N, 5.52.
1-Cyclohexyl-4-phenylisoquinoline (3j)
Colorless oil; Rf = 0.54 (hexane–CH2Cl2, 1:2).
IR (neat): 1616 cm–1.
MS (EI): m/z (%) = 345 (100) [M+].
1H NMR (500 MHz, CDCl3): d = 1.37–1.46 (1 H, m), 1.52–1.61
(2 H, m), 1.82–2.05 (7 H, m), 3.59–3.65 (1 H, m), 7.43–7.53 (5 H,
m), 7.58–7.63 (2 H, m), 7.89–7.92 (1 H, m), 8.28–8.31 (1 H, m),
8.43 (1 H, s).
Anal. Calcd for C22H16ClNO: C, 76.41; H, 4.66; N, 4.05. Found: C,
76.45; H, 4.95; N, 3.95.
6-Methoxy-4-phenyl-1-(4-trifluoromethylphenyl)isoquinoline
(3p)
MS (EI): m/z (%) = 287 (39) [M+], 286 (43), 232 (100).
White solid; mp 142–145 °C (hexane–Et2O).
IR (KBr): 1620 cm–1.
Anal. Calcd for C21H21N: C, 87.76; H, 7.36; N, 4.87. Found: C,
87.71; H, 7.49; N, 4.69.
1H NMR (500 MHz, CDCl3): d = 3.82 (3 H, s), 7.20 (1 H, dd,
J = 9.2, 2.7 Hz), 7.25 (1 H, d, J = 2.7 Hz), 7.48–7.53 (1 H, m), 7.55–
7.59 (4 H, m), 7.81 (2 H, d, J = 8.2 Hz), 7.84 (2 H, d, J = 8.2 Hz),
7.98 (1 H, d, J = 9.2 Hz), 8.49 (1 H, s).
4-(4-Chlorophenyl)-1-phenylisoquinoline (3k)
White solid; mp 105–107 °C (hexane–Et2O).
IR (KBr): 1612 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.49–7.57 (8 H, m), 7.68 (1 H,
ddd, J = 8.7, 6.9, 1.4 Hz), 7.73 (2 H, dd, J = 8.2, 1.4 Hz), 7.92 (1 H,
d, J = 8.7 Hz), 8.18 (1 H, d, J = 8.2 Hz), 8.54 (1 H, s).
MS (EI): m/z (%) = 379 (100) [M+].
Anal. Calcd for C23H16F3NO: C, 72.82; H, 4.25; N, 3.69. Found: C,
72.80; H, 4.40; N, 3.68.
MS (EI): m/z (%) = 315 (76) [M+], 314 (100).
1-(1,1-Dimethylethyl)-6-methoxy-4-phenylisoquinoline (3q)
Pale-yellow oil; Rf = 0.28 (hexane–CHCl3, 1:1).
IR (KBr): 1620 cm–1.
Anal. Calcd for C21H14ClN: C, 79.87; H, 4.47; N, 4.44. Found: C,
79.67; H, 4.45; N, 4.39.
4-(4-Chlorophenyl)-1-(phenanthren-9-yl)isoquinoline (3l)
White solid; mp 188–190 °C (hexane–Et2O).
IR (KBr): 1614 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.41–7.48 (2 H, m), 7.50 (1 H, d,
J = 7.8 Hz), 7.57 (2 H, d, J = 9.2 Hz), 7.59 (2 H, d, J = 9.2 Hz),
7.64–7.70 (3 H, m), 7.75 (1 H, t, J = 7.3 Hz), 7.78 (1 H, d, J = 8.2
Hz), 7.91 (1 H, s), 7.94 (1 H, d, J = 7.8 Hz), 7.98 (1 H, d, J = 8.2
Hz), 8.66 (1 H, s), 8.80 (1 H, d, J = 8.2 Hz), 8.83 (1 H, d, J = 8.2
Hz).
1H NMR (500 MHz, CDCl3): d = 1.69 (9 H, s), 3.78 (3 H, s), 7.18–
7.20 (2 H, m), 7.43–7.53 (5 H, m), 8.31 (1 H, s), 8.53 (1 H, dd,
J = 7.8, 2.3 Hz).
MS (EI): m/z (%) = 291 (32) [M+], 290 (40), 249 (100).
Anal. Calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C,
82.43; H, 7.30; N, 4.79.
4-Methyl-1-phenylisoquinoline (3r)11
After addition of PhCN, the reaction temperature was raised to
room temperature.
MS (EI): m/z (%) = 415 (68) [M+], 414 (100).
White solid; mp 71–74 °C (hexane–Et2O) (lit.11 75–76 °C). Spectral
data (IR and 1H NMR) were identical to those reported previously.11
Synthesis 2006, No. 17, 2934–2938 © Thieme Stuttgart · New York

2938
K. Kobayashi et al.
PAPER
(3) For recent reports, see: (a) Tsubakiyama, M.; Sato, Y.;
Acknowledgment
Mori, M. Heterocycles 2004, 64, 27. (b) Ishikawa, T.;
Manabe, S.; Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004,
6, 2361. (c) Janin, Y. L.; Decaudin, D.; Monneret, C.;
Poupon, M.-F. Tetrahedron 2004, 60, 5481. (d) Palacios,
F.; Alonso, C.; Rodoriguez, M.; Martinez de Marigorta, E.;
Rubiales, G. Eur. J. Org. Chem. 2005, 1795. (e) Korivi, R.
P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179; see also pertinent
references cited in these papers.
We thank Mrs. Miyuki Tanmatsu of this Department for determi-
ning mass spectra and performing combustion analyses.
References
(1) (a) Kobayashi, K.; Shiokawa, T.; Morikawa, O.; Konishi, H.
Chem. Lett. 2004, 33, 236. (b) Kobayashi, K.; Shiokawa, T.;
Omote, H.; Hashimoto, K.; Morikawa, O.; Konishi, H. Bull.
Chem. Soc. Jpn. 2006, 79, 1126.
(2) For recent reports, see: (a) Barber, C. G.; Dickinson, R. P.;
Fish, P. V. Bioorg. Med. Chem. Lett. 2005, 14, 3227.
(b) Jiang, J.; Thomas, C. J.; Neumann, S.; Lu, X.; Rice, K.
C.; Gershengorn, M. C. Bioorg. Med. Chem. Lett. 2005, 15,
733. (c) He, M.; Yuan, D.; Lin, W.; Pang, R.; Yu, X.; Yang,
M. Bioorg. Med. Chem. Lett. 2005, 15, 3978; see also
pertinent references cited in these papers.
(4) Compound 1d is a known compound, see: Wuensch, B.;
Hoefner, G.; Bauschke, G. Arch. Pharm. 1993, 326, 513.
(5) Wagner, P. J.; Sedon, J. H.; Gudmundsdottir, A. J. Am.
Chem. Soc. 1996, 118, 746.
(6) Bauer, V. J.; Duffy, B. J.; Hoffmann, D.; Klioze, S. S.;
Kosely, R. W. Jr.; McFadden, A. R.; Martin, L. L.; Ong, H.
H.; Geyer, H. M. III J. Med. Chem. 1976, 19, 1315.
(7) Kitamura, T.; Kobayashi, S.; Taniguchi, H. J. Am. Chem.
Soc. 1986, 108, 2641.
(8) A possibility of the formation of 3 via 6p electrocyclization
of 4 followed by elimination of lithium methoxide cannot be
excluded.
(9) Krabbe, W.; Böhlk, H. H.; Heinz, K. Ber. Dtsch. Chem. Ges.
B. 1938, 71, 64.
(10) Ardabilchi, N.; Fitton, A. O.; Haidi, A.; Hamid, B. A.;
Thompson, J. R. J. Chem. Res., Synop. 1982, 156.
(11) Kopczynski, T. Pol. J. Chem. 1985, 59, 375.
Synthesis 2006, No. 17, 2934–2938 © Thieme Stuttgart · New York