New synthesis of isoquinoline and 3,4-dihydroisoquinoline derivatives

Article abstract of DOI:10.1246/bcsj.79.1126

A simple and efficient synthesis of isoquinoline and 3,4- dihydroisoquinoline derivatives is described. 1-Alkyl-(or aryl)isoquinoline and 1-isoquinolinamine derivatives were obtained by intramolecular cyclization of 2-(2-methoxyethenyl) benzonitriles initiated by the addition of alkyl(or aryl)lithiums and lithium dialkylamides to the nitrile carbons, respectively. Synthesis of 4-aryl-3,4-dihydroisoquinolines was achieved by reactions of 2-(1-arylethenyl)benzonitriles with organolithiums, followed by aqueous workup. Treatment of the reaction mixtures with electrophiles prior to aqueous workup allowed the synthesis of 4,4-disubstituted 3,4-dihydroisoquinolines.

Full text of DOI:10.1246/bcsj.79.1126

1126 Bull. Chem. Soc. Jpn. Vol. 79, No. 7, 1126–1132 (2006)
Ó 2006 The Chemical Society of Japan
New Synthesis of Isoquinoline and 3,4-Dihydroisoquinoline Derivatives
ꢀ
Kenichi Hashimoto, Osamu Morikawa, and Hisatoshi Konishi
Kazuhiro Kobayashi, Taiyo Shiokawa, Hiroki Omote,
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552
Received January 30, 2006; E-mail: kkoba@chem.tottori-u.ac.jp
A simple and efficient synthesis of isoquinoline and 3,4-dihydroisoquinoline derivatives is described. 1-Alkyl-
(or aryl)isoquinoline and 1-isoquinolinamine derivatives were obtained by intramolecular cyclization of 2-(2-methoxy-
ethenyl)benzonitriles initiated by the addition of alkyl(or aryl)lithiums and lithium dialkylamides to the nitrile carbons,
respectively. Synthesis of 4-aryl-3,4-dihydroisoquinolines was achieved by reactions of 2-(1-arylethenyl)benzonitriles
with organolithiums, followed by aqueous workup. Treatment of the reaction mixtures with electrophiles prior to aque-
ous workup allowed the synthesis of 4,4-disubstituted 3,4-dihydroisoquinolines.
Recently, we described a new and efficient synthesis of 2,4-
disubstituted quinolines via a sequence of addition and intra-
molecular ring closure between 2-isocyano-ꢀ-methoxystyrene
derivatives and nucleophiles, such as organolithiums1 and lith-
ium dialkylamides.1b As an extension of this synthesis, we
found that the 1-alkyl(or aryl)isoquinoline 2 and 1-isoquinolin-
amine derivatives 3 could be obtained by reactions of the 2-(2-
methoxyethenyl)benzonitriles (2-cyano-ꢀ-methoxystyrenes) 1
with alkyl(or aryl)lithiums and lithium dialkylamides.2 Over
recent years, development of new methods for the preparation
of isoquinolines,3 including 1-isoquinolinamines,4 has attract-
ed much attention due to their biological activities.5 Further-
more, it has been found that the reaction of the 2-(1-arylethen-
yl)benzonitriles 6 with organolithiums led to formation of the
4-aryl-3,4-dihydroisoquinoline derivatives 7. 3,4-Dihydroiso-
quinolines are an important class of heterocycles; thus, nu-
merous elaborations of 3,4-dihydroisoquinoline derivatives to
more complex and important molecules that possess pharma-
cological activities have been reported.6 Moreover, some
3,4-dihydroisoquinoline derivatives have been reported to
exhibit biological activities.7 3,4-Dihydroisoquinoline deriva-
tives have been prepared by the Bischler–Napieralski reac-
tion.8 Recently, new and excellent methods for the synthesis
of 3,4-dihydroisoquinoline derivatives have been described.9
For example, Janin et al. reported on a synthesis of 1-aryl-
3,4-dihydroisoquinoline derivatives using a modified Ritter
reaction procedure.9d In this paper, we wish to describe the
results of our investigation, which provide a convenient meth-
od to prepare isoquinoline derivatives.
aqueous workup and purification using preparative TLC on
silica gel, the desired isoquinolines were obtained. The yields
of the products were generally fair to good as summarized in
Table 1 (Entries 1–5). A similar sequence between 4-methoxy-
2-(2-methoxy-1-phenylethenyl)benzonitrile (1b) (a mixture of
E and Z isomers; ca. 2:1) and phenyllithium also proceeded
and the desired isoquinoline derivative 2f could be obtained
but in a somewhat diminished yield (Entry 6).
Conducting reactions of 2-(2-methoxyethenyl)benzonitrile
(E-1c) and 2-(2-methoxy-1-methylethenyl)benzonitrile (E-1d)
with phenyllithium, 1-phenylisoquinoline (2g) and 4-methyl-1-
phenylisoquinoline (2h) could be prepared in moderate to fair
yields (Entries 7 and 9, respectively). The corresponding Z-
isomers of these starting nitriles proved to be less reactive to
R2
R2
R1
R1
OMe
DME
R3Li
+
N
−78 °C to rt
CN
R3
1a R1 = H, R2 = Ph
2
1b R1 = OMe, R2 = Ph
1c R1 = R2 = H
1d R1 = H, R2 = Me
Scheme 1.
Table 1. Preparation of Isoquinolines 2
Entry
1
R3 in R3Li
2 (Yield/%)a)
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1b
E-1c
Z-1c
E-1d
Z-1d
Ph
n-Bu
s-Bu
t-Bu
2-Furyl
Ph
Ph
Ph
Ph
Ph
2a (76)
2b (54)
2c (70)
2d (68)
2e (51)
2f (41)
2g (38)
2g (22)
2h (65)
2h (51)
We first investigated reactions of 2-(2-methoxy-1-phenyl-
ethenyl)benzonitrile (1a) (a mixture of E and Z isomers; ca.
1:1) with alkyl(or aryl)lithiums, and found that these reactions
resulted in the formation of the 1-alkyl(or aryl)-4-phenyliso-
quinolines 2a–2e, as shown in Scheme 1. Thus, organolithi-
ums were added to a solution of 1a in DME at ꢁ78 ꢂC. After
10 min, the mixture was warmed to room temperature, and stir-
ring was continued for an additional 1 h at the same tempera-
ture. The attack of organolithiums on the nitrile carbon of 1a
followed by ring closure proceeded smoothly. After the usual
a) Isolated yields.
Published on the web July 4, 2006; doi:10.1246/bcsj.79.1126

K. Kobayashi et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 7 (2006) 1127
R2
Ph
R1
R1
OMe
−78 °C
rt
THF
1
+ Nu−
1a, b + LiNR3
N−
Nu
2
N
−78 °C to rt
NR3
2
4
3
R2
Scheme 2.
R1
OMe
−
−OMe
2, 3
N
Table 2. Preparation of 1-Isoquinolinamines 3
Nu
5
Entry
1
NR3
3 (Yield/%)a)
2
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1b
NEt2
N(i-Pr)2
Pyrrolidin-1-yl
Piperidino
3a (59)
3b (62)
3c (62)
3d (65)
3e (64)
3f (67)
3g (29)
Scheme 3.
R3
N
Ar
Ar
R1
R1
i, R2Li, − 78 to 0 °C
4-Methylpiperazin-1-yl
Morpholino
Piperidino
ii, electrophile
CN
R2
6
7
a) Isolated yields.
Scheme 4.
Table 3. Preparation of 3,4-Dihydroisoquinolines 7
Entry
6
R2
Electrophile
R3 in 7
7 (Yield/%)a)
1
2
3
4
5
6
7
8
9
6a (R1 = H, Ar = Ph)
6a
6a
6a
6a
6a
6a
6a
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
n-Bu
Ph
H2O
MeI
EtBr
BnBr
H
Me
Et
7a (69)
7b (59)
7c (52)
7d (62)
7e (55)
7f (62)b)
7g (55)
7h (50)
7i (60)
7j (53)
7k (36)
Bn
t-BuOCOCH2
EtCH(OH)
t-BuOCOCH2Br
EtCHO
H2O
H
Me
H
Bn
H
MeI
H2O
BnBr
H2O
6b (R1 = H, Ar = p-ClC6H4)
6b
6c (R1 = OMe, Ar = Ph)
10
11
Ph
Ph
a) Isolated yields. b) Two diastereomers were produced and separated from each other by fractional recrys-
tallization (ca. 6:4). The stereochemistry of each diastereomer could not be determined.
phenyllithium in the present sequence giving poorer results
than those using E-isomers (Entries 8 and 10).
the nitrile carbon of 1 at ꢁ78 ꢂC results in the formation of
the nitrogen anion intermediate 4. When the reaction temper-
ature is raised to room temperature, attack of this anion at
the terminal carbon atom of the vinyl moiety occurs to give
the benzyl anion 5. Subsequent loss of methoxide gives rise
to the isoquinoline derivatives 2 and 3. It is reasonable that
the poorer results were obtained in the cases of using 1b, while
the lower stability of the corresponding intermediate benzyl
anions due to the methoxy substituent at the benzene nucleus
is taken into consideration.
The procedure we developed for the preparation of the
4-aryl-3,4-dihydroisoquinoline derivatives 7 is shown in
Scheme 4. First, we treated 2-(1-phenylethenyl)benzonitrile
(6a) with phenyllithium at ꢁ78 ꢂC for 30 min, then the temper-
ature was allowed to gradually warm to 0 ꢂC, and stirring was
continued for an additional 1 h. Aqueous workup followed by
purification using preparative TLC on silica gel afforded 1,4-
diphenyl-3,4-dihydroisoquinoline (7a) in good yield, as indi-
cated in Table 3, Entry 1. We successfully introduced substitu-
ents at the 4-position of 1,4-diphenyl-3,4-dihydroisoquinoline
Subsequently, we discovered that the same addition/intra-
molecular ring closure sequence could be carried out using
lithium dialkylamides in the place of alkyl(or aryl)lithiums
to afford the N,N-dialkyl-1-isoquinolinamines 3. Thus, accord-
ing to the procedure mentioned above for the preparation of
the 1-alkyl(or aryl)isoquinolines 2, the 2-(2-methoxy-1-phen-
ylethenyl)benzonitriles 1a and 1b were allowed to react with
lithium dialkylamides in THF (instead of DME) to afford 3
as illustrated in Scheme 2. The yields of the products were
generally fair, as summarized in Table 2. The reaction using
4-methoxy-2-(2-methoxy-1-phenylethenyl)benzonitrile (1b)
proved to give a rather diminished yield of the desired product
3g. It should be noted that attempts to obtain the expected iso-
quinolinamines from the reactions of 1c and 1d with lithium
piperidide were unsuccessful; an intractable mixture of prod-
ucts was obtained in each case.
The probable pathway to the isoquinoline derivatives 2 and
3 is outlined in Scheme 3. Thus, addition of a nucleophile to

1128 Bull. Chem. Soc. Jpn. Vol. 79, No. 7 (2006)
Synthesis of Isoquinoline Derivatives
Devices MEL-TEMP II melting-point apparatus and are uncor-
rected. The IR spectra were recorded on a Shimadzu FTIR-8300
spectrometer. The 1H NMR spectra were determined using SiMe4
as an internal reference with a JEOL JNM-GX270 FT NMR spec-
trometer operating at 270 MHz in CDCl3. Low-resolution mass
spectra were recorded on a JEOL AUTOMASS 20 spectrometer
(Center for Joint Research and Development, Tottori University).
Thin-layer chromatography (TLC) was carried out on Merck
Kieselgel 60 PF254. All of the solvents used were dried over the
appropriate drying agents and distilled under argon prior to use.
All of the reactions were carried out under argon.
Ar
Ar
R1
R1
R2Li
6
N
N
R2
R2
8
9
electrophile
7
Scheme 5.
Starting Materials.
(2-Bromophenyl)phenylmethanone,10
(2-bromo-5-methoxyphenyl)phenylmethanone,11 2-acetylbenzo-
nitrile,12 and (2-bromophenyl)(4-chlorophenyl)methanol13 were
prepared according to the appropriate reported procedures. All
other chemicals used in this study were commercially available.
products by treating the reaction mixture with electrophiles
prior to aqueous workup. These results are also summarized
in Table 3, Entries 2–6, which indicate that not only various
alkyl halides but also an aldehyde, such as propanal, was usa-
ble in the present procedure as electrophiles. In the case of
using propanal, two possible diastereoisomers were obtained,
which were separable from each other by fractional recrystal-
lization (ca. 6:4). However, the stereochemistry of each isomer
cannot be determined yet. Analogously, 1-butyl-4-phenyl-3,4-
dihydroisoquinolines were prepared from 6a and butyllithium,
but the yields of the products 7g and 7h were somewhat lower
compared to those using phenyllithium (Entries 7 and 8). Fol-
lowing the above procedures, 2-[1-(4-chlorophenyl)ethenyl]-
benzonitrile (6b) and 4-methoxy-2-(1-phenylethenyl)benzo-
nitrile (6c) were converted into the corresponding 3,4-dihy-
droisoquinolines 7i–7k in reasonable yields (Entries 9–11).
The aryl substituent at the ꢁ-position of 6 was essential for
production of the 3,4-dihydroisoquinolines 7. For example,
the reaction of 2-(1-methylethenyl)benzonitrile with phenyl-
lithium resulted in the formation of an intractable mixture of
products, from which no more than a trace of the desired prod-
uct, 4-methyl-1-phenyl-3,4-dihydroisoquinoline, was isolated.
The formation of the 3,4-dihydroquinolines 7 from the 2-
(1-arylethenyl)benzonitriles 6 and organolithiums may be ex-
plained as illustrated in Scheme 5. An organolithium attacks
the cyano carbon of 6 to give the nitrogen anion intermediate
8, which undergoes intramolecular cyclization to lead to the
benzyl anion intermediate 9. Finally, trapping of this anion
with an electrophile gives rise to 7. The rather lower yield of
the product from 6c is thought to be ascribable to the instabil-
ity of the corresponding benzyl anion intermediate due to the
4-methoxy group.
2-Benzoylbenzonitrile.14
(2-Bromophenyl)phenylmetha-
none10 was treated with CuCN in DMF under the conditions
reported by Friedman et al.15 to give the title keto nitrile in 81%
yield: a white solid; mp 85–86 ꢂC (hexane–Et2O) (lit.,14 83–84 ꢂC).
2-Benzoyl-4-methoxybenzonitrile. This compound was pre-
pared in 82% yield by the treatment of (2-bromo-5-methoxy-
phenyl)phenylmethanone11 with CuCN under Friedman’s condi-
tions:15 a white solid; mp 130–131 ꢂC (hexane–THF); IR (KBr
disk) 2226 and 1665 cmꢁ1 1H NMR ꢂ 3.89 (3H, s), 7.05–7.15
;
(2H, m), 7.50 (2H, dd, J ¼ 7:9 and 7.3 Hz), 7.65 (1H, tt, J ¼ 7:3
and 1.3 Hz), 7.74 (1H, d, J ¼ 9:2 Hz), and 7.83 (2H, dd, J ¼ 7:9
and 1.3 Hz); MS m=z (%) 237 (Mþ, 45) and 105 (100). Anal.
Found: C, 75.92; H, 4.84; N, 6.00%. Calcd for C15H11NO2: C,
75.94; H, 4.67; N, 5.90%.
2-(2-Methoxy-1-phenylethenyl)benzonitrile (1a).
To a
stirred suspension of (methoxymethyl)triphenylphosphonium
chloride (3.4 g, 9.9 mmol) in DME (70 mL) at 0 ꢂC was added
dropwise butyllithium (1.6 M in hexane; 9.9 mmol) (1 M = 1
mol dmꢁ3). After 5 min, the resulting ylide was treated with a
solution of 2-benzoylbenzonitrile (1.6 g, 7.5 mmol) in DME (15
mL), and stirring was continued for an additional 10 min at the
same temperature. Water (30 mL) was added and the mixture
was extracted with Et2O twice (30 mL each). The combined ex-
tracts were washed with water and then brine, dried over anhy-
drous Na2SO4, and evaporated. The residue was purified by col-
umn chromatography on silica gel (2:1 hexane–Et2O) to give 1a
(1.3 g, 73%): a yellow oil; Rf 0.36; a mixture of stereoisomers
1
(E:Z = ca. 1:1); IR (neat) 2225 and 1634 cmꢁ1; H NMR ꢂ 3.82
and 3.84 (combined 3H, 2s), 6.49 (0.5H, s), 6.69 (0.5H, s), 7.11
(1H, dd, J ¼ 7:9 and 1.6 Hz), 7.2–7.4 (6H, m), 7.45–7.6 (1H,
m), and 7.72 and 7.76 (combined 1H, 2d, J ¼ 7:9 and 8.6 Hz,
respectively). Anal. Found: C, 81.37; H, 5.52; N, 5.90%. Calcd
for C16H13NO: C, 81.68; H, 5.57; N, 5.95%.
It should be noted that all attempts to obtain 1-dialkyl-
amino-3,4-dihydroisoquinolines by reactions of 6 with lithium
dialkylamides were unsuccessful. In each case, a complex re-
action mixture containing neither the starting 6 nor the corre-
sponding dialkylaminoamidine derivative, arising from proton-
ation of the intermediate 9 (R2 = dialkylamino), was obtained,
though we cannot give any explicit explanation of the reason
for these results at the present time.
4-Methoxy-2-(2-methoxy-1-phenylethenyl)benzonitrile (1b).
This compound was prepared from 2-benzoyl-4-methoxybenzo-
nitrile in a manner similar to that described above for 1a in 75%
yield (E:Z = ca. 2:1); Rf 0.31 (2:1 hexane–Et2O); a yellow oil;
1
IR (neat) 2222 and 1638 cmꢁ1; H NMR ꢂ 3.79, 3.80, 3.82, and
In summary, we have demonstrated a convenient synthesis
of isoquinoline derivatives. The present method has advantages
over previous methods:3,9 the ease of operations as well as the
ready availability of the starting materials. It may offer the pos-
sibility to access compounds of potential biological interest.
3.84 (combined 6H, 4s), 6.49 (0.33H, s), 6.67 (0.67H, s), 6.77
(1H, dd, J ¼ 6:9 and 2.3 Hz), 6.8–6.9 (1H, m), 7.1–7.4 (5H, m),
7.58 (0.33H, d, J ¼ 8:4 Hz), and 7.64 (0.67H, d, J ¼ 8:8 Hz).
Anal. Found: C, 77.11; H, 6.01; N, 5.23%. Calcd for C17H15NO2:
C, 76.96; H, 5.70; N, 5.28%.
2-(2-Methoxyethenyl)benzonitrile (1c). This compound was
prepared from 2-cyanobenzaldehyde in a manner similar to that
described above for 1a in 71% yield (E:Z = ca. 2:1). E-1c: a yel-
Experimental
General. The melting points were determined on a Laboratory

K. Kobayashi et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 7 (2006) 1129
low liquid; Rf 0.32 (2:1 hexane–Et2O); IR (neat) 2220 and 1639
cmꢁ1
7.25 (2H, m), 7.4–7.5 (2H, m), and 7.57 (1H, d, J ¼ 7:6 Hz). Anal.
Found: C, 75.43; H, 5.93; N, 8.75%. Calcd for C10H9NO: C,
75.45; H, 5.70; N, 8.80%. Z-1c: a yellow liquid; Rf 0.29 (2:1
hexane–Et2O); IR (neat) 2215 and 1651 cmꢁ1 1H NMR ꢂ 3.80
;
(3H, s), 5.63 (1H, d, J ¼ 6:9 Hz), 6.34 (1H, d, J ¼ 6:9 Hz), 7.18
(1H, td, J ¼ 7:9 and 1.3 Hz), 7.49 (1H, td, J ¼ 7:9 and 1.3 Hz),
7.57 (1H, dd, J ¼ 7:9 and 1.3 Hz), and 8.14 (1H, d, J ¼ 7:9 Hz).
Anal. Found: C, 75.19; H, 5.77; N, 8.79%. Calcd for C10H9NO:
C, 75.45; H, 5.70; N, 8.80%.
1-(2-Furyl)-4-phenylisoquinoline (2e): A yellow solid; mp
204–205 ꢂC (Et2O); IR (KBr disk) 1614 cmꢁ1 1H NMR ꢂ 7.5–
;
7.75 (10H, m), 7.99 (1H, dd, J ¼ 7:9 and 1.3 Hz), 8.60 (1H, s),
and 9.03 (1H, dd, J ¼ 7:3 and 2.0 Hz); MS m=z (%) 271 (Mþ,
55) and 235 (100). Anal. Found: C, 84.28; H, 4.57; N, 5.38%.
Calcd for C19H13NO: C, 84.11; H, 4.83; N, 5.16%.
;
1H NMR ꢂ 3.76 (3H, s), 6.10 (1H, d, J ¼ 13:2 Hz), 7.1–
6-Methoxy-1,4-diphenylisoquinoline (2f): mp 108 ꢂC (hex-
;
ane–AcOEt); IR (KBr disk) 1618 cmꢁ1 1H NMR ꢂ 3.82 (3H,
s), 7.17 (1H, dd, J ¼ 9:2 and 2.6 Hz), 7.23 (1H, d, J ¼ 2:6 Hz),
7.45–7.6 (8H, m), 7.71 (2H, dd, J ¼ 8:3 and 2.0 Hz), 8.07 (1H,
d, J ¼ 9:2 Hz), and 8.45 (1H, s); MS m=z (%) 311 (Mþ, 87) and
310 (100). Anal. Found: C, 85.12; H, 5.47; N, 4.33%. Calcd for
C22H17NO: C, 84.86; H, 5.50; N, 4.50%.
1-Phenylisoquinoline (2g): A yellow solid; mp 100–101 ꢂC
(hexane–Et2O) (lit.,17 mp 97 ꢂC); IR (KBr disk) 1633 and 1612
cmꢁ1; 1H NMR ꢂ 7.45–7.7 (8H, m), 7.89 (1H, d, J ¼ 8:2 Hz), 8.11
(1H, dd, J ¼ 8:2 and 1.0 Hz), and 8.61 (1H, d, J ¼ 5:6 Hz); MS
m=z (%) 205 (Mþ, 100).
2-(2-Methoxy-1-methylethenyl)benzonitrile (1d). This com-
pound was prepared from 2-acetylbenzonitrile12 in a manner sim-
ilar to that described above for 1a in 70% yield (E:Z = ca. 2:1).
E-1d: a yellow liquid; Rf 0.36 (6:1 hexane–Et2O); IR (neat) 2222
and 1659 cmꢁ1; 1H NMR ꢂ 2.04 (3H, d, J ¼ 1:6 Hz), 3.76 (3H, s),
6.38 (1H, q, J ¼ 1:6 Hz), 7.2–7.35 (2H, m), 7.47 (1H, ddd, J ¼
8:9, 7.6, and 1.3 Hz), and 7.62 (1H, dd, J ¼ 7:6 and 1.3 Hz). Anal.
Found: C, 76.23; H, 6.41; N, 8.05%. Calcd for C11H11NO: C,
76.28; H, 6.40; N, 8.09%. Z-1d: a yellow liquid; Rf 0.34 (6:1 hex-
ane–Et2O); IR (neat) 2226 and 1666 cmꢁ1; 1H NMR ꢂ 1.94 (3H, d,
J ¼ 1:6 Hz), 3.65 (3H, s), 6.14 (1H, q, J ¼ 1:6 Hz), 7.25–7.35
(2H, m), 7.33 (1H, td, J ¼ 7:9 and 1.3 Hz), and 7.64 (1H, dd, J ¼
7:9 and 1.3 Hz). Anal. Found: C, 76.21; H, 6.51; N, 7.98%. Calcd
for C11H11NO: C, 76.28; H, 6.40; N, 8.09%.
Typical Procedure for the Reaction of 1 with Organolithi-
um Leading to 2. 1,4-Diphenylisoquinoline (2a):16 To a stir-
red solution of 1a (0.23 g, 0.98 mmol) in DME (7 mL) at ꢁ78 ꢂC
was added dropwise PhLi (0.94 M in cyclohexane–Et2O; 2.0
mmol). After 10 min, the mixture was allowed to warm to room
temperature and stirring was continued for an additional 1 h. Satu-
rated aqueous NH4Cl (15 mL) was added and organic products
were extracted with Et2O twice (15 mL each). The combined ex-
tracts were washed with brine, and then dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was purified
by preparative TLC on silica gel (5:1 hexane–AcOEt) to give 2a
(0.21 g, 76%): a white solid; mp 141 ꢂC (hexane–Et2O) (lit.,16 131
ꢂC); IR (KBr disk) 1614 cmꢁ1; 1H NMR ꢂ 7.45–7.65 (9H, m), 7.66
(1H, t, J ¼ 8:2 Hz), 7.74 (2H, dd, J ¼ 8:2 and 1.3 Hz), 7.98 (1H,
d, J ¼ 7:9 Hz), 8.18 (1H, dd, J ¼ 8:2 and 1.3 Hz), and 8.57 (1H,
s); MS m=z (%) 281 (Mþ, 96) and 280 (100).
4-Methyl-1-phenylisoquinoline (2h): A yellow solid; mp 77–
78 ꢂC (hexane–Et2O) (lit.,18 mp 75–76 ꢂC); IR (neat) 1614 cmꢁ1
;
1H NMR ꢂ 2.68 (3H, d, J ¼ 1:0 Hz), 7.4–7.8 (7H, m), 8.02 (1H,
d, J ¼ 8:6 Hz), 8.11 (1H, dd, J ¼ 8:6 and 0.7 Hz), and 8.46 (1H,
s); MS m=z (%) 219 (Mþ, 69) and 218 (100).
Typical Procedure for the Reaction of 1 with Lithium Di-
alkylamide Leading to 3. 1-Diisopropylamino-4-phenylisoqui-
noline (3b): To a stirred solution of LDA (1.1 mmol; generated
from diisopropylamine and butyllithium by the standard method)
in THF (3 mL) at ꢁ78 ꢂC was added dropwise a solution of 1a
(0.14 g, 0.57 mmol) in THF (2 mL). After 10 min, the mixture
was allowed to warm to room temperature and stirring was contin-
ued for an additional 30 min. Work-up similar to that used for the
preparation of 2a followed by purification by preparative TLC on
silica gel (5:1 hexane–AcOEt) gave 3b (0.11 g, 62%): a pale-
1
orange oil; Rf 0.71; IR (neat) 1614 cmꢁ1; H NMR ꢂ 1.16 (12H,
d, J ¼ 6:6 Hz), 3.87 (2H, septet, J ¼ 6:6 Hz), 7.35–7.6 (7H, m),
7.81 (1H, dd, J ¼ 7:9 and 1.6 Hz), 8.27 (1H, s), and 8.60 (1H, dd,
J ¼ 7:6 and 1.6 Hz); MS m=z (%) 304 (Mþ, 48) and 261 (100).
Anal. Found: C, 83.03; H, 7.89; N, 8.88%. Calcd for C21H24N2:
C, 82.85; H, 7.95; N, 9.20%.
1-Diethylamino-4-phenylisoquinoline (3a):
Rf 0.63 (2:1
hexane–AcOEt); IR (neat) 1612 and 1603 cmꢁ1; H NMR ꢂ 1.24
(6H, t, J ¼ 6:9 Hz), 3.51 (4H, q, J ¼ 6:9 Hz), 7.35–7.6 (7H, m),
7.83 (1H, dd, J ¼ 7:3 and 1.3 Hz), 8.10 (1H, s), and 8.22 (1H, dd,
J ¼ 7:3 and 1.3 Hz); MS m=z (%) 276 (Mþ, 30) and 247 (100).
Anal. Found: C, 82.30; H, 7.29; N, 9.95%. Calcd for C19H20N2:
C, 82.57; H, 7.29; N, 10.14%.
1
1-Butyl-4-phenylisoquinoline (2b): A yellow oil; Rf 0.54
1
(CH2Cl2); IR (neat) 1616 cmꢁ1; H NMR ꢂ 1.02 (3H, t, J ¼ 7:3
Hz), 1.5–1.6 (2H, m), 1.8–2.0 (2H, m), 3.35 (2H, t, J ¼ 7:9 Hz),
7.35–7.7 (7H, m), 7.90 (1H, dd, J ¼ 8:2 and 2.0 Hz), 8.22 (1H, dd,
J ¼ 7:2 and 1.6 Hz), and 8.38 (1H, s); MS m=z (%) 261 (Mþ, 16),
246 (21), 232 (43), and 219 (100). Anal. Found: C, 87.29; H, 7.36;
N, 5.11%. Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36%.
4-Phenyl-1-(pyrrolidin-1-yl)isoquinoline (3c): A white sol-
id; mp 104 ꢂC (hexane–Et2O); IR (KBr disk) 1599 cmꢁ1; 1H NMR
ꢂ 1.95–2.05 (4H, m), 3.8–3.9 (4H, m), 7.35–7.55 (7H, m), 7.79
(1H, dd, J ¼ 7:6 and 1.3 Hz), 7.98 (1H, s), and 8.26 (1H, dd, J ¼
7:6 and 1.3 Hz); MS m=z (%) 274 (Mþ, 39) and 245 (100). Anal.
Found: C, 83.27; H, 6.73; N, 10.16%. Calcd for C19H18N2: C,
83.18; H, 6.61; N, 10.21%.
1-(1-Methylpropyl)-4-phenylisoquinoline (2c):
A yellow
oil; Rf 0.58 (5:1 hexane–AcOEt); IR (neat) 1615 cmꢁ1; H NMR
ꢂ 0.96 (3H, t, J ¼ 7:3 Hz), 1.46 (3H, d, J ¼ 6:9 Hz), 1.75–1.9 (1H,
m), 2.0–2.15 (1H, m), 3.77 (1H, sextet, J ¼ 6:9 Hz), 7.4–7.65 (7H,
m), 7.91 (1H, dd, J ¼ 8:6 and 2.0 Hz), 8.29 (1H, dd, J ¼ 7:3 and
2.6 Hz), and 8.45 (1H, s); MS m=z (%) 261 (Mþ, 29), 246 (72),
and 233 (100). Anal. Found: C, 87.26; H, 7.50; N, 5.13%. Calcd
for C19H19N: C, 87.31; H, 7.33; N, 5.36%.
1
4-Phenyl-1-piperidino-4-phenylisoquinoline (3d): A white
solid; mp 120–121 ꢂC (hexane–Et2O); IR (KBr disk) 1605 cmꢁ1
;
1H NMR ꢂ 1.7–1.95 (6H, m), 3.35–3.45 (4H, m), 7.35–7.6 (7H,
m), 7.82 (1H, dd, J ¼ 7:6 and 2.0 Hz), 8.10 (1H, s), and 8.17
(1H, dd, J ¼ 7:6 and 2.0 Hz); MS m=z (%) 288 (Mþ, 100). Anal.
Found: C, 83.39; H, 7.22; N, 9.71%. Calcd for C20H20N2: C,
83.30; H, 6.99; N, 9.71%.
1-(1,1-Dimethylethyl)-4-phenylisoquinoline (2d): A yellow
oil; Rf 0.68 (CH2Cl2); IR (neat) 1614 cmꢁ1; 1H NMR ꢂ 1.71 (9H,
s), 7.4–7.6 (7H, m), 7.91 (1H, dd, J ¼ 7:9 and 2.0 Hz), 8.39 (1H,
s), and 8.61 (1H, dd, J ¼ 8:2 and 1.6 Hz); MS m=z (%) 261 (Mþ,
64) and 219 (100). Anal. Found: C, 86.97; H, 7.44; N, 5.16%.
Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36%.
1-(4-Methylpiperazin-1-yl)-4-phenylisoquinoline (3e):
A
white solid; mp 133–134 ꢂC (hexane–Et2O–CH2Cl2); IR (KBr

1130 Bull. Chem. Soc. Jpn. Vol. 79, No. 7 (2006)
Synthesis of Isoquinoline Derivatives
disk) 1612 cmꢁ1; 1H NMR ꢂ 2.43 (3H, s), 2.73 (4H, t, J ¼ 4:8 Hz),
3.50 (4H, t, J ¼ 4:8 Hz), 7.35–7.65 (7H, m), 7.83 (1H, dd, J ¼ 7:9
and 2.0 Hz), 8.11 (1H, s), and 8.17 (1H, dd, J ¼ 7:9 and 2.3 Hz);
MS m=z (%) 303 (Mþ, 7.5) and 233 (100). Anal. Found: C, 79.01;
H, 6.84; N, 13.72%. Calcd for C20H21N3: C, 79.17; H, 6.98; N,
13.85%.
1H NMR ꢂ 3.83 (3H, s), 5.47 (1H, s), 5.86 (1H, s), 6.84 (1H, d,
J ¼ 2:6 Hz), 6.92 (1H, dd, J ¼ 8:6 and 2.6 Hz), 7.25–7.35 (5H,
m), and 7.62 (1H, d, J ¼ 8:6 Hz). Anal. Found: C, 81.63; H, 5.81;
N, 6.03%. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95%.
Typical Procedure for the Reaction of 6 with Organolithium
Leading to 7. 1,4-Diphenyl-3,4-dihydroisoquinoline (7a): To a
stirred solution of 6a (0.15 g, 0.76 mmol) in DME (10 mL) at
ꢁ78 ꢂC was added PhLi (0.94 M in cyclohexane–Et2O; 0.91
mmol). After stirring for 30 min, the mixture was allowed to warm
to 0 ꢂC and stirring was continued for an additional 1 h. The result-
ing deep green solution was quenched by adding aqueous saturat-
ed NH4Cl (15 mL), and organic materials were extracted with
Et2O three times (10 mL each). The combined extracts were dried
over anhydrous Na2SO4 and evaporated. The residue was purified
by preparative TLC on silica gel (1:2 AcOEt–hexane) to give
7a (0.15 g, 69%): a pale yellow solid; mp 126–127.5 ꢂC (Et2O–
1-Morpholino-4-phenylisoquinoline (3f): A white solid; mp
151–152 ꢂC (hexane–Et2O–CH2Cl2); IR (KBr disk) 1612 cmꢁ1
;
1H NMR ꢂ 3.46 (4H, t, J ¼ 4:6 Hz), 4.01 (4H, t, J ¼ 4:6 Hz),
7.35–7.65 (7H, m), 7.85 (1H, dd, J ¼ 7:6 and 1.6 Hz), 8.12 (1H,
s), and 8.20 (1H, dd, J ¼ 7:6 and 1.6 Hz); MS m=z (%) 290 (Mþ,
95) and 298 (100). Anal. Found: C, 78.31; H, 6.27; N, 9.51%.
Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65%.
6-Methoxy-4-phenyl-1-piperidinoisoquinoline (3g): A white
solid; mp 136–137 ꢂC (hexane–AcOEt); IR (KBr disk) 1616 cmꢁ1
;
1H NMR ꢂ 1.65–1.75 (2H, m), 1.8–1.9 (4H, m), 3.3–3.4 (4H, m),
3.78 (3H, s), 7.1–7.2 (2H, m), 7.35–7.5 (5H, m), 8.04 (1H, s), and
8.09 (1H, dd, J ¼ 8:9 and 1.0 Hz); MS m=z (%) 318 (Mþ, 80) and
235 (100). Anal. Found: C, 78.94; H, 6.94; N, 8.83%. Calcd for
C21H22N2O: C, 79.21; H, 6.96; N, 8.80%.
1
hexane); IR (neat) 1608 cmꢁ1; H NMR ꢂ 4.00 (1H, dd, J ¼ 13:2
and 9.5 Hz), 4.15–4.3 (2H, m), 6.99 (1H, d, J ¼ 7:0 Hz), 7.25–7.5
(11H, m), and 7.6–7.7 (2H, m); MS m=z (%) 283 (Mþ, 61) and
282 (100). Anal. Found: C, 89.17; H, 6.19; N, 4.57%. Calcd for
C21H17N: C, 89.01; H, 6.05; N, 4.94%.
2-(1-Phenylethenyl)benzonitrile (6a).19 To a stirred suspen-
sion of methyltriphenylphosphonium iodide (1.4 g, 3.5 mmol) in
DME (20 mL) at 0 ꢂC was added dropwise butyllithium (3.5
mmol; 1.54 M in hexane). After 15 min, a solution of 2-benzoyl-
benzonitrile (0.60 g, 2.9 mmol) in DME (12 mL) was added to
the resulting yellow solution. Stirring was continued for an addi-
tional 30 min before adding water (30 mL). The mixture was
extracted with Et2O three times (15 mL each). The combined
extracts were washed brine, dried over anhydrous Na2SO4, and
evaporated. The residue was purified by column chromatography
on silica gel to give 6a (0.53 g, 89%): a yellow oil; Rf 0.53 (1:2
4-Methyl-1,4-diphenyl-3,4-dihydroisoquinoline (7b): Com-
pound 1a (0.21 g, 1.0 mmol) was treated with PhLi (0.94 M solu-
tion in cyclohexane–Et2O; 1.3 mmol) in a similar manner as
described above for the preparation of 7a. To the resulting deep
green solution was added iodomethane (0.18 g, 1.3 mmol), and
stirring was continued for 15 min. After a similar work up as de-
scribed above, the crude product was purified by reparative TLC
on silica gel to give 7b (0.18 g, 59%): a pale-yellow solid; mp
133–134 ꢂC (Et2O–hexane); IR (KBr disk) 1609 cmꢁ1 1H NMR
;
ꢂ 1.70 (3H, s), 3.81 (1H, d, J ¼ 15:8 Hz), 4.12 (1H, d, J ¼ 15:8
Hz), and 7.1–7.55 (14H, m); MS m=z (%) 297 (Mþ, 74) and
296 (100). Anal. Found: C, 88.73; H, 6.31; N, 4.52%. Calcd for
C22H19N: C, 88.85; H, 6.44; N, 4.71%.
1
AcOEt–hexane); IR (neat) 2226 and 1614 cmꢁ1; H NMR ꢂ 5.49
(1H, s), 5.88 (1H, s), 7.2–7.4 (6H, m), 7.44 (1H, dd, J ¼ 7:6 and
1.3 Hz), 7.57 (1H, td, J ¼ 7:6 and 1.3 Hz), and 7.71 (1H, dd, J ¼
7:6 and 1.3 Hz).
4-Ethyl-1,4-diphenyl-3,4-dihydroisoquinoline (7c):
This
2-Bromophenyl(4-chlorophenyl)methanone.20
This com-
compound was prepared as described for the preparation of 7b.
7c: a pale-yellow solid; mp 102–103 ꢂC (Et2O–hexane); IR (KBr
pound was prepared by the oxidation of (2-bromophenyl)(4-chlo-
rophenyl)methanol13 with PCC in 1,2-dichloroethane at room tem-
perature in 89% yield: a yellow oil; Rf 0.42 (1:5 EtOAc–hexane);
1
disk) 1614 cmꢁ1; H NMR ꢂ 0.93 (3H, t, J ¼ 7:3 Hz), 2.05–2.25
(2H, m), 3.88 (1H, d, J ¼ 16:2 Hz), 4.46 (1H, d, J ¼ 16:2 Hz),
and 7.15–7.5 (14H, m); MS m=z (%) 311 (Mþ, 19) and 284 (100).
Anal. Found: C, 88.73; H, 6.90; N, 4.55%. Calcd for C23H21N: C,
88.71; H, 6.80; N, 4.50%.
1
IR (neat) 1668 cmꢁ1; H NMR ꢂ 7.3–7.5 (5H, m), 7.65 (1H, dd,
J ¼ 7:3 and 1.3 Hz), and 7.75 (2H, d, J ¼ 8:9 Hz).
2-(4-Chlorobenzoyl)benzonitrile.21 This compound was pre-
pared by the treatment of 2-bromophenyl(4-chlorophenyl)metha-
none with CuCN in DMF under conditions reported by Friedman
et al.15 in 66% yield: a white solid; mp 119–120 ꢂC (hexane–
4-Benzyl-1,4-diphenyl-3,4-dihydroisoquinoline (7d): This
compound was prepared as described for the preparation of 7b.
7d: a pale-yellow solid; mp 144.5–146 ꢂC (Et2O–hexane); IR
(KBr disk) 1610 cmꢁ1; 1H NMR ꢂ 3.33 (1H, d, J ¼ 13:2 Hz), 3.60
(1H, d, J ¼ 13:2 Hz), 3.84 (1H, d, J ¼ 13:2 Hz), 4.49 (1H, d, J ¼
13:2 Hz), 6.77 (2H, dd, J ¼ 7:9 and 2.3 Hz), 7.05–7.4 (15H, m),
7.52 (1H, td, J ¼ 7:3 and 1.6 Hz), and 7.64 (1H, d, J ¼ 6:9 Hz);
MS m=z (%) 373 (Mþ, 5.9), 372 (7.2), and 282 (100). Anal.
Found: C, 90.20; H, 6.38; N, 3.64%. Calcd for C28H23N: C, 90.04;
H, 6.21; N, 3.75%.
1
THF); IR (KBr disk) 2230 and 1661 cmꢁ1; H NMR ꢂ 7.48 (2H,
d, J ¼ 8:9 Hz), 7.6–7.75 (3H, m), 7.76 (2H, d, J ¼ 8:9 Hz), and
7.84 (1H, dd, J ¼ 8:7 and 0.9 Hz).
2-[1-(4-Chlorophenyl)ethenyl]benzonitrile (6b). This com-
pound was prepared from 2-(4-chlorobenzoyl)benzonitrile in a
manner similar to that described for the preparation of 6a in 68%
yield: a white solid; mp 73–73.5 ꢂC (hexane–Et2O); IR (KBr disk)
1
2224 and 1618 cmꢁ1; H NMR ꢂ 5.50 (1H, s), 5.86 (1H, s), 7.19
t-Butyl (1,4-Diphenyl-3,4-dihydroisoquinolin-4-yl)acetate
(7e): This compound was prepared as described for the prepara-
tion of 7b. 7e: a yellow viscous oil; Rf 0.25 (1:3 AcOEt–hexane);
(2H, d, J ¼ 8:6 Hz), 7.30 (2H, d, J ¼ 8:6 Hz), 7.35 (1H, dd, J ¼
7:6 and 1.3 Hz), 7.44 (1H, td, J ¼ 7:6 and 1.3 Hz), 7.58 (1H, td,
J ¼ 7:6 and 1.3 Hz), and 7.71 (1H, dd, J ¼ 7:6 and 1.3 Hz). Anal.
Found: C, 75.19; H, 4.23; N, 5.83%. Calcd for C15H10ClN: C,
75.16; H, 4.21; N, 5.84%.
IR (neat) 1724 cmꢁ1
;
1H NMR ꢂ 1.27 (9H, s), 3.00 (1H, d, J ¼
15:0 Hz), 3.06 (1H, d, J ¼ 15:0 Hz), 4.20 (1H, d, J ¼ 16:1 Hz),
4.62 (1H, d, J ¼ 16:1 Hz), and 7.1–7.5 (14H, m); MS m=z (%)
397 (Mþ, 4.8) and 340 (100). Anal. Found: C, 81.53; H, 7.01;
N, 3.42%. Calcd for C27H27NO2: C, 81.58; H, 6.85; N, 3.52%.
4-(1-Hydroxypropyl)-1,4-diphenyl-3,4-dihydroisoquinoline
(7f): This compound was prepared as described for the prepara-
4-Methoxy-2-(1-phenylethenyl)benzonitrile (6c). This com-
pound was prepared from 2-benzoyl-4-methoxybenzonitrile17 as
described for the preparation of 6a in 83% yield: a yellow oil;
Rf 0.32 (1:2 AcOEt–hexane); IR (neat) 2222 and 1599 cmꢁ1
;

K. Kobayashi et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 7 (2006) 1131
tion of 7b. Two diastereomers were obtained separately by frac-
tional recrystallization (ca. 6:4). First recrystallized and minor
diastereomer: a white solid; mp 210–211 ꢂC (hexane–CHCl3);
2002, 1696; Q. Huang, J. A. Hunter, R. C. Larock, J. Org. Chem.,
2002, 67, 3437; Q. Huang, R. C. Larock, Tetrahedron Lett. 2002,
43, 3557; S. K. Chattopadhyay, S. Maity, B. K. Pal, S. Panja,
Tetrahedron Lett. 2002, 43, 5079; G. Dai, R. C. Larock, J. Org.
Chem. 2002, 67, 7042; T. V. V. Ramakrishna, P. R. Sharp, Org.
Lett. 2003, 5, 877; B. Pal, P. Jaisankar, V. S. Giri, Synth. Commun.
2003, 33, 2339; S. G. Lim, J. H. Lee, C. W. Moon, J. B. Hong,
C. H. Jun, Org. Lett. 2003, 5, 2759; M. Tsubakiyama, Y. Sato,
M. Mori, Heterocycles 2004, 64, 27; T. Ishikawa, S. Manabe, T.
Aikawa, T. Kudo, S. Saito, Org. Lett. 2004, 6, 2361; Y. L. Janin,
D. Decaudin, C. Monneret, M.-F. Poupon, Tetrahedron 2004, 60,
5481; F. Palacios, C. Alonso, M. Rodoriguez, E. Martinez de
Marigorta, G. Rubiales, Eur. J. Org. Chem. 2005, 1795; R. P.
Korivi, C.-H. Cheng, Org. Lett., 2005, 7, 5179. See also pertinent
references cited in these papers.
1
IR (KBr disk) 3217, 1628, and 1601 cmꢁ1; H NMR ꢂ 1.11 (3H,
t, J ¼ 7:3 Hz), 1.35–1.55 (2H, m), 1.75–1.85 (1H, m), 3.74 (1H,
d, J ¼ 15:8 Hz), 4.25–4.35 (1H, m), 4.93 (1H, d, J ¼ 15:8 Hz),
7.1–7.4 (12H, m), 7.36 (1H, td, J ¼ 7:6 and 1.6 Hz), and 7.64 (1H,
dd, J ¼ 7:6 and 1.0 Hz); MS m=z (%) 341 (Mþ, 35) and 284 (100).
Anal. Found: C, 84.40; H, 6.60; N, 4.09%. Calcd for C24H23NO:
C, 84.42; H, 6.79; N, 4.10%. Later recrystallized and major dia-
stereomer: a white solid; mp 181.5–182.5 ꢂC (hexane–Et2O); IR
(KBr disk) 3194, 1618, and 1601 cmꢁ1 1H NMR ꢂ 1.00 (3H, t,
;
J ¼ 7:3 Hz), 1.4–1.65 (2H, m), 1.86 (1H, brs), 4.02 (1H, d, J ¼
16:2 Hz), 4.38 (1H, brd, J ¼ 10:2 Hz), 4.71 (1H, d, J ¼ 16:2 Hz),
7.1–7.4 (12H, m), 7.54 (1H, ddd, J ¼ 8:6, 7.6, and 1.6 Hz), and
7.86 (1H, d, J ¼ 8:6 Hz); MS m=z (%) 341 (Mþ, 37) and 284
(100). Anal. Found: C, 84.10; H, 6.77; N, 4.05%. Calcd for
C24H23NO: C, 84.42; H, 6.79; N, 4.10%.
4
For reports on the synthesis and biological importance of
1-isoquinolinamines: T. Saito, T. Ohkubo, H. Kuboki, M. Maeda,
K. Tsuda, T. Karakasa, S. Satsumabayashi, J. Chem. Soc., Perkin
Trans. 1 1998, 3065; J. B. M. Rewinkle, H. Lucas, M. J. Smith,
A. B. J. Noach, T. G. van Dinther, A. M. M. Rood, A. J. S. M.
Jenneboer, C. A. A. van Boeckel, Bioorg. Med. Chem. Lett.
1999, 9, 2837; J. D. Tovar, T. M. Swager, J. Org. Chem. 1999,
64, 6499.
1-Butyl-4-phenyl-3,4-dihydroisoquinoline (7g): This com-
pound was prepared as described for the preparation of 7a. 7g:
a yellow viscous oil; Rf 0.18 (1:4 AcOEt–hexane); IR (neat) 1628
and 1603 cmꢁ1; 1H NMR ꢂ 0.94 (3H, t, J ¼ 7:3 Hz), 1.3–1.5 (2H,
m), 1.55–1.7 (2H, m), 2.78 (2H, t, J ¼ 7:3 Hz), 3.83 (1H, dd, J ¼
16:2 and 12.2 Hz), 3.95–4.05 (2H, m), 6.93 (1H, d, J ¼ 8:9 Hz),
7.19 (2H, dd, J ¼ 8:3 and 1.6 Hz), 7.25–7.4 (5H, m), and 7.55
(1H, dd, J ¼ 6:9 and 2.3 Hz); MS m=z (%) 263 (Mþ, 2.3), 248
(5.5), 234 (16), and 221 (100). Anal. Found: C, 86.53; H, 8.35;
N, 5.28%. Calcd for C19H21N: C, 86.65; H, 8.04; N, 5.32%.
1-Butyl-4-methyl-4-phenyl-3,4-dihydroisoquinoline (7h):
This compound was prepared as described for the preparation of
7b. 7h: a yellow viscous oil; Rf 0.22 (1:4 AcOEt–hexane); IR
5
J. A. Joule, K. Mills, G. F. Smith, Heterocyclic Chemistry,
3rd ed., Stanley Thrones, London, 1995, Chap. 6, pp. 120–145;
K. S. Chen, F. N. Ko, C. M. Teng, Y. C. Wu, J. Nat. Prod.
1996, 59, 531; Y. Yoshida, D. Barrett, H. Azami, C. Morinaga,
S. Matsumoto, Y. Matsumoto, H. Takasugi, Bioorg. Med. Chem.
1999, 7, 2647; Q. Chao, L. Deng, H. C. Shih, L. M. Leoni, D.
Genini, D. A. Carson, H. B. Cottam, J. Med. Chem. 1999, 42,
3860; J. E. Van Muijlwijk-Koezen, H. Timmerman, H. Van der
Goot, W. M. P. B. Menge, J. F. Von Kuenzel, M. De Groote,
A. P. Ijzerman, J. Med. Chem. 2000, 43, 2227; M. Croisy-Delcey,
A. Croisy, D. Carrez, C. Huel, A. Chiaroni, P. Ducrot, E. Bisagni,
L. Jun, G. Lecelercq, Bioorg. Med. Chem. 2000, 8, 2629; R. Y.
Kuo, F. R. Chang, C. C. Wu, R. Patnam, W. Y. Wang, Y. C.
Du, Y. C. Wu, Bioorg. Med. Chem. Lett. 2003, 13, 2789; C. G.
Barber, R. P. Dickinson, P. V. Fish, Bioorg. Med. Chem. Lett.
2005, 14, 3227; J. Jiang, C. J. Thomas, S. Neumann, X. Lu,
K. C. Rice, M. C. Gershengorn, Bioorg. Med. Chem. Lett. 2005,
15, 733; M. He, D. Yuan, W. Lin, R. Pang, X. Yu, M. Yang,
Bioorg. Med. Chem. Lett. 2005, 15, 3978.
1
(neat) 1630 and 1599 cmꢁ1; H NMR ꢂ 0.82 (3H, t, J ¼ 7:3 Hz),
1.15–1.25 (2H, m), 1.35–1.55 (2H, m), 1.61 (3H, s), 2.55–2.75
(2H, m), 3.62 (1H, d, J ¼ 15:2 Hz), 4.25 (1H, d, J ¼ 15:2 Hz),
7.1–7.45 (8H, m), and 7.53 (1H, dd, J ¼ 7:6 and 1.6 Hz); MS
m=z (%) 277 (Mþ, 10), 276 (14), 262 (30), 248 (41), and 235
(100). Anal. Found: C, 86.22; H, 8.64; N, 4.71%. Calcd for
C20H23N: C, 86.59; H, 8.36; N, 5.05%.
We are very grateful to Mrs. Miyuki Tanmatsu of this
Department for determining mass spectra and performing
combustion analyses.
´ `
For recent reports: M. Nyerges, A. Viranyi, A. Pinter,
6
L. To˜ke, Tetrahedron Lett. 2003, 44, 793; P. Ploypradith, W.
Jianglueng, C. Pavaro, S. Ruchirawat, Tetrahedron Lett. 2003,
44, 1363; L. Liu, Synthesis 2003, 1705; M. Heydenreich, A. Koch,
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