Diastereoselective allylation of 3,4-dihydro-4-phenylisoquinoline. Convenient methods for the preparation of cis- and trans-1-allyl-4-phenyl-1,2,3, 4-tetrahydroisoquinoline#

Article abstract of DOI:10.1246/bcsj.80.2418

Diastereoselective allylation of 3,4-dihydro-4-phenylisoquinoline by several allylating reagents was examined. Reactions using allyltin or allylsilane in the presence of alkyl chloroformate and a catalytic amount of trimethylsilyl triflate gave trans-1-allyl-4-phenyl-1,2,3,4- tetrahydroisoquinoline with moderate diastereoselectivity. In contrast, cis-1-allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline was obtained predominantly in the reactions using allyllithium, triallylborane, allylzinc bromide, and diallylzinc. cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline was transformed to (6S*,10bR*)-hexahydro-6-phenylpyrrolo[2,1-a]isoquinoline, a potential antidepressant agent, in five steps.

Full text of DOI:10.1246/bcsj.80.2418

2418 Bull. Chem. Soc. Jpn. Vol. 80, No. 12, 2418–2424 (2007)
ꢀ 2007 The Chemical Society of Japan
Diastereoselective Allylation of 3,4-Dihydro-4-phenylisoquinoline.
Convenient Methods for the Preparation of cis- and trans-1-Allyl-
4-phenyl-1,2,3,4-tetrahydroisoquinoline#
ꢀ
Ayako Taketoshi, Naoya Hosoda, Yoshitaka Yamaguchi, and Masatoshi Asami
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
Tokiwadai, Hodogaya-ku, Yokohama 240-8501
Received July 10, 2007; E-mail: m-asami@ynu.ac.jp
Diastereoselective allylation of 3,4-dihydro-4-phenylisoquinoline by several allylating reagents was examined. Re-
actions using allyltin or allylsilane in the presence of alkyl chloroformate and a catalytic amount of trimethylsilyl triflate
gave trans-1-allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline with moderate diastereoselectivity. In contrast, cis-1-allyl-4-
phenyl-1,2,3,4-tetrahydroisoquinoline was obtained predominantly in the reactions using allyllithium, triallylborane,
ꢀ
ꢀ
allylzinc bromide, and diallylzinc. cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline was transformed to (6S ,10bR )-
hexahydro-6-phenylpyrrolo[2,1-a]isoquinoline, a potential antidepressant agent, in five steps.
Diastereoselective allylation of imines or imine derivatives
provides functionalized amines, which are useful intermediates
in the synthesis of biologically active compounds and pharma-
ceutical substances.1,2 3,4-Dihydroisoquinoline derivatives,
including imine N-oxides and iminium ions, have been em-
ployed as suitable precursors for preparations of various iso-
quinoline alkaloids and their analogues.3 Although allylation
of 3-substituted 3,4-dihydroisoquinolines has been reported,4
there has been no report on the diastereoselective allylation
of 4-substituted 3,4-dihydroisoquinolines to the best of our
knowledge. Thus, we started an investigation of diastereo-
selective allylation of 3,4-dihydro-4-phenylisoquinoline (1)
using various allylating reagents, because the allyl group can
be later transformed conveniently to various functional groups,
for example, alcohol via hydroboration, carbonyl group via ox-
idative cleavage, etc. After examination of allylating reagents
and reaction conditions, we found complementary methods
for the preparation of trans- and cis-1-allyl-4-phenyl-1,2,3,4-
(Table 1, Entry 1). Then, trimethylsilyl triflate (0.2 molar
amount) was added together with allyltributyltin to improve
the yield, because trimethylsilyl triflate is known to promote
the reaction.5 The reaction was completed in 1 h, and the yield
was 70%, but the diastereoselectivity decreased (cis-2a:trans-
2a = 33:67) (Table 1, Entry 2). When the reaction was carried
out using allyltriphenyltin in place of allyltributyltin, both the
yield and the diastereoselectivity improved (90% yield, cis-
2a:trans-2a = 29:71) (Table 1, Entry 3). Next, a reaction
using allylsilane, a less toxic reagent than allyltin, was carried
out under the same reaction conditions in the presence of tri-
methylsilyl triflate, and the diastereoselectivity improved
slightly (cis-2a:trans-2a = 27:73) (Table 1, Entry 4). When
Table 1. Allylation of 1 Using Allyltin or Allylsilane
CO2R
N
N
ClCO2R (1.5 mol. amt.)
CH2Cl2, rt, 30 min
ꢀ
ꢀ
Cl
tetrahydroisoquinoline. (6S ,10bR )-Hexahydro-6-phenylpyr-
rolo[2,1-a]isoquinoline, a potential antidepressant agent, was
obtained from cis-1-allyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line in five steps.
Ph
Ph
( )-1
M
(2.0 mol. amt.)
Me3SiOTf (0.2 mol. amt.)
CO2R
CO2R
N
N
Results and Discussion
1 h
First, diastereoselective allylation of 3,4-dihydro-4-phenyl-
isoquinoline (1) was examined using allyltin or allylsilane in
the presence of imino group activator as high trans-selectivity
has been reported in the reaction of 3-substituted 3,4-dihydro-
isoquinoline derivatives in a similar manner.4 Namely, isobu-
tyl chloroformate (1.5 molar amount) was added to a CH2Cl2
solution of 1 at room temperature, and the solution was stirred
at the temperature for 30 min. Then, allyltributyltin (2.0 molar
amount) was added to the solution. After 24 h, allyl adduct 2a
was obtained in 57% yield as a mixture of diastereomers. The
diastereomers were separated by preparative thin-layer chro-
matography, and the ratio of cis-2a and trans-2a was 30:70
Ph
cis-2
Ph
trans-2
R
M
2
Yield/%
cis-2:trans-2
1aÞ
2
3
4
5
6
i-Bu
i-Bu
i-Bu
i-Bu
Bn
SnBu3
SnBu3
SnPh3
SiMe3
SiMe3
SiMe3
a
a
a
a
b
c
57
70
90
87
80
85
30:70
33:67
29:71
27:73
32:68
31:69
Et
a) Reaction was carried out for 24 h without using trimethyl-
silyl triflate.
Published on the web December 13, 2007; doi:10.1246/bcsj.80.2418

A. Taketoshi et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007) 2419
the reaction was carried out using benzyl chloroformate or
ethyl chloroformate in place of isobutyl chloroformate, the
diastereomer ratios were cis-2b:trans-2b = 32:68 and cis-
2c:trans-2c = 31:69, respectively (Table 1, Entries 5 and 6).
The stereochemistry of the products was assigned by compar-
ing with authentic samples, prepared from cis- or trans-3 and
the corresponding alkyl chloroformate, and the stereochemis-
try of trans-3 was determined based on the X-ray crystallo-
graphic analysis of trans-4 (vide infra).
The stereochemical course of the reaction is explained
by assuming a non-chelating open-chain transition state, de-
picted in Fig. 1. Allyltin or allylsilane approaches from less
hindered side of the iminium intermediate to form trans-2
predominantly.
Next, allylation of 1 using an allylmetallic reagent, which
can interact with nitrogen atom of the imine 1 and may enable
the formation of a cyclic transition state, was examined to im-
prove the stereoselectivity. At first, a Grignard reagent was
employed. Allylmagnesium bromide, prepared from freshly
distilled allyl bromide and magnesium turnings in THF at
ꢁ5 ꢂC, was added to a THF solution of 1 at ꢁ78 ꢂC, and
the reaction mixture was stirred at that temperature for 1 h.
1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (3) was ob-
tained in 86% yield; however, the diastereoselectivity was low
(cis-3:trans-3 = 44:56) (Table 2, Entry 1). The stereochemis-
try of the products was determined as follows: After separation
of the diastereomers by preparative thin-layer chromatogra-
phy, the less polar isomer was treated with di-tert-butyl di-
carbonate and NaOH in dioxane–water to give a crystalline
compound, which was determined to be tert-butyl trans-
1-allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate
(trans-4) by X-ray crystallographic analysis (Fig. 2).
Then, other allylmetallic reagents, such as allyllithum,6 tri-
allylborane,7 and allylzinc bromide,8 were examined to deter-
mine their effects on the diastereoselectivity of the reaction
(Table 2, Entries 2–4). Interestingly, all these reagents gave
cis-3 predominantly, and the best result (82% yield, cis-
3:trans-3 = 84:16) was obtained when allylzinc bromide was
employed (Table 2, Entry 4). Although the diastereoselectivity
was improved slightly using diallylzinc,9 the yield was lower
(Table 2, Entry 5). The reaction of allylzinc bromide in Et2O,
cyclopentyl methyl ether (CPME), dimethoxymethane, or
toluene did not improve the diastereoselectivity (Table 2,
Entries 6–9).
M
Ph
RO2CN
H
Ph
H
cis-2
H
N
O
Ph
H
OR
RO2CN
M
M: Sn or Si
trans-2
major
We assume that the diastereoselectivity of the reaction of 1
and allyllithium, triallylborane, and allylzinc reagent is due to
the following: Two six-membered chair-like cyclic transition
states, TS-A and TS-B, are possible by the coordination of
Fig. 1. Proposed stereochemical course of the allylation of
1 with allyltin or allylsilane in the presence of alkyl
chloroformate.
Table 2. Diastereoselective Allylation of 1 Using Allylmetallic Reagents
M
N
NH
NH
Ph
( )-1
Ph
cis-3
Ph
trans-3
Reagent
Solvent
Condition
Yield/% cis-3:trans-3
1
2
3
allylmagnesium bromide (2.5 mol amt.)
allyllithium (2.5 mol amt.)
triallylborane (1.1 mol amt.)
THF
THF
THF
ꢁ78 ꢂC, 1 h
ꢁ78 ꢂC, 1 h
ꢁ78 ꢂC, 1 h
86
79
82
44:56
67:33
65:35
ꢁ78 ꢂC, 2 h then
rt, 1 h
4
5
6
7
8
9
allylzinc bromide (1.5 mol amt.)
diallylzinc (3.0 mol amt.)
THF
THF
82
76
76
86
79
86
84:16
86:14
77:23
80:20
77:23
78:22
ꢁ78 ꢂC, 2 h then
rt, 1 h
ꢁ78 ꢂC, 2 h then
rt, 1 h
allylzinc bromide (3.0 mol amt.)
allylzinc bromide (3.0 mol amt.)
allylzinc bromide (3.0 mol amt.)
allylzinc bromide (3.0 mol amt.)
Et2O
ꢁ78 ꢂC, 2 h then
CPME
rt, 1 h
ꢁ78 ꢂC, 2 h then
rt, 1 h
dimethoxymethane
toluene
ꢁ78 ꢂC, 2 h then
rt, 1 h

2420 Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007)
Diastereoselective Allylation
NH (Boc)2O, NaOH aq.
N Boc
1,4-Dioxane-H2O
0 °C, 1.5 h
Ph
cis-3
Ph
cis-4
89%
OH
N Boc
1) BH3-THF, THF, 0 °C, 7 h
2) 3 M NaOH aq., 30% H2O2 aq.
rt, 2 h
Ph
5
82%
Fig. 2. ORTEP drawing of trans-4 with thermal ellipsoids
drawn at the 50% probability level. Some hydrogen atoms
are omitted for clarity (Black = Carbon, Red = Oxygen,
Blue = Nitrogen, and Gray = Hydrogen).
OTs
N Boc
TsCl
Pyridine, 0 °C, 6 h
N
M
Ph
+
6
Ph
M: Li, B, Zn
1
H
H
CF3COOH
N
CH2Cl2, 0 °C, 3 h
Ph
Ph
N
H
N
M
Ph
H
M
H4
Hv
(6S*,10bR*)-7
79%
TS-A
TS-B
Scheme 1. Synthesis of hexahydro-6-phenylpyrrolo[2,1-a]-
isoquinoline (7).
The hydroxy group of 5 was converted to a leaving group
by tosylation, and removal of t-butoxycarbonyl group of the
ꢀ
ꢀ
tosylate 6 with trifluoroacetic acid afforded (6S ,10bR )-hexa-
hydro-6-phenylpyrrolo[2,1-a]isoquinoline (7) in 79% from 5
by spontaneous intramolecular cyclization (Scheme 1).
Ph
Ph
NH
NH
trans-3
In summary, we developed a diastereoselective allylation
reaction of 3,4-dihydro-4-phenylisoquinoline (1). Either cis- or
trans-1-allyl-4-substituted 1,2,3,4-tetrahydroisoquinoline was
obtained by choosing the appropriate allylating reagent.
Namely, reaction using allylsilane in the presence of alkyl
chloroformate and a catalytic amount of trimethylsilyl triflate
gave trans-1-allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline with
moderate diastereoselectivity, whereas cis-1-allyl-4-phenyl-
1,2,3,4-tetrahydroisoquinoline was obtained in good diastereo-
selectivity in the reaction using allylzinc bromide. The method
cis-3
major
Fig. 3. Proposed transition states for the allylation of 1 with
allylmetallic reagent (Li, B, and Zn).
the nitrogen atom of imine 1 to the allylmetallic reagent. Steric
repulsion arises in TS-A between axial hydrogen (H4) in C-4
position of dihydroisoquinoline ring and terminal vinylic hy-
drogen (Hv), whereas this repulsion is avoided in TS-B to give
cis-3 predominantly (Fig. 3).
ꢀ
ꢀ
was applied to the synthesis of (6S ,10bR )-hexahydro-6-
phenylpyrrolo[2,1-a]isoquinoline.
As cis-3 was obtained in good diastereoselectivity, the meth-
ꢀ
ꢀ
Experimental
od was applied to the synthesis of (6S ,10bR )-hexahydro-
6-phenylpyrrolo[2,1-a]isoquinoline (7), which is a potential
antidepressant agent.10 Initially, the amino group in cis-3
was protected using di-tert-butyl dicarbonate, and tert-butyl
cis-1-allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxyl-
ate (cis-4) was obtained in 89% yield. Then, hydroboration of
cis-4 with BH3–THF complex, followed by oxidation with
NaOH–H2O2, gave the corresponding alcohol 5 in 82% yield.
General. Melting points were determined on a Stuart melting
point apparatus SMP3 and are uncorrected. IR spectra were
recorded on a HORIBA FT-730 spectrometer. 1H and 13C NMR
spectra were measured on a JEOL JNM-EX-270 spectrometer.
Chemical shift values are expressed in ppm relative to internal
tetramethylsilane. Elemental analyses were carried out on a Vario
EL III Elemental analyzer. Thin-layer chromatography analyses

A. Taketoshi et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007) 2421
were done on silica-gel 60 F254-coated plates (E. Merck AG,
Germany). Column chromatography was carried out with
Wakogel C-200 gel and the indicated eluent. Preparative thin-
layer chromatography was performed on silica-gel-coated plates
(Wakogel B-5F, 20 cm ꢃ 20 cm). Diethyl ether (Et2O) (Dehydrat-
ed) and tetrahydrofuran (THF) (Dehydrated, stabilizer free), pur-
chased from Kanto Chemical Co., Inc., were used in anhydrous
reactions. Other solvents were purified according to standard
procedures.
Addition Reaction of Allyltrimethylsilane to 3,4-Dihydro-
4-phenylisoquinoline (1) in the Presence of Isobutyl Chloro-
formate and Trimethylsilyl Triflate (Table 1, Entry 4). Under
an argon atmosphere, to a solution of 3,4-dihydro-4-phenyliso-
quinoline (1)11 (60.9 mg, 0.29 mmol) in CH2Cl2 (3 mL) was added
isobutyl chloroformate (57 mL, 0.44 mmol) at room temperature.
After stirring for 30 min, allyltrimethylsilane (94 mL, 0.59 mmol)
and trimethylsilyl triflate (11 mL, 0.06 mmol) were added to the
reaction mixture. Then, the reaction mixture was stirred for 1 h.
CH2Cl2 and saturated aqueous NaHCO3 were added to the reac-
tion mixture, and the organic layer was separated. The aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed successively with water and brine and dried over an-
hydrous Na2SO4. The solvent was removed under reduced pres-
sure, and the residue was separated by preparative thin-layer chro-
matography (silica-gel, hexane/Et2O = 10/1 ꢃ3) to give trans-
2a (67.9 mg, 64%) and cis-2a (24.7 mg, 23%).
Isobutyl trans-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line-2-carboxylate (trans-2a): Colorless solid. mp: 65.4–65.6 ꢂC
(from hexane); IR (KBr, cmꢁ1): 3025, 2960, 1694, 1427, 1219,
1127, 914, 752, 699; 1H NMR (CDCl3): ꢀ 0.58–0.91 (6H, m),
1.40–1.54 and 1.83–1.92 (1H, m), 2.64 (2H, t, J ¼ 7:9 Hz), 3.38
(1H, dd, J ¼ 6:6, 10.2 Hz), 3.55–3.81 (2H, m), 4.11–4.31 (2H, m),
5.01–5.09 (2H, m), 5.28–5.33 and 5.47–5.52 (1H, m), 5.82–5.98
(1H, m), 6.95 (3H, t, J ¼ 9:7 Hz), 7.10–7.25 (6H, m); 13C NMR
(CDCl3): ꢀ 18.9, 19.0, 19.1, 27.7, 28.0, 41.1, 41.5, 44.5, 44.7,
53.6, 71.2, 71.4, 117.2, 117.5, 126.2, 126.5, 126.7, 128.1, 128.1,
129.9, 134.4, 134.7, 135.9, 136.9, 143.9, 155.7; Found: C, 78.99;
H, 7.78; N, 3.82%. Calcd for C23H27NO2: C, 79.05; H, 7.79; N,
4.01%.
53.8, 66.8, 67.0, 117.4, 126.4, 126.6, 126.8, 126.8, 127.4, 127.5,
127.8, 128.0, 128.2, 130.0, 134.6, 135.8, 136.3, 136.8, 143.9,
155.5; Found: C, 81.37; H, 6.67; N, 3.51%. Calcd for C26H25NO2:
C, 81.43; H, 6.57; N, 3.65%.
Benzyl cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-
2-carboxylate (cis-2b): Colorless oil. IR (neat, cmꢁ1): 3028,
1
2935, 1699, 1428, 1220, 1125, 914, 736, 700; H NMR (CDCl3):
ꢀ 2.69 (2H, dd, J ¼ 8:1, 17.3 Hz), 3.17–3.34 (1H, m), 4.09–4.21
(1H, m), 4.35 (dd, J ¼ 5:9, 13.7 Hz) and 4.49 (dd, J ¼ 5:9, 13.7
Hz) (1H), 5.00–5.25 (4H, m), 5.31 (t, J ¼ 6:9 Hz) and 5.45 (t,
J ¼ 6:9 Hz) (1H), 5.76–5.99 (1H, m), 6.80 (1H, t, J ¼ 9:1 Hz),
7.05 (1H, t, J ¼ 5:8 Hz), 7.11–7.35 (12H, m); 13C NMR (CDCl3):
ꢀ 41.2, 41.4, 44.5, 44.8, 45.0, 45.3, 54.2, 54.5, 67.0, 67.3, 117.3,
117.6, 126.1, 126.2, 126.4, 126.5, 126.6, 126.7, 126.8, 126.9,
127.5, 127.8, 127.9, 128.0, 128.3, 128.5, 128.9, 129.0, 129.4,
129.6, 134.4, 134.5, 136.9, 137.1, 137.3, 137.6, 142.1, 154.9,
155.0; Found: C, 81.32; H, 6.57; N, 3.44%. Calcd for C26H25NO2:
C, 81.43; H, 6.57; N, 3.65%.
Ethyl trans-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-
2-carboxylate (trans-2c): Colorless oil. IR (neat, cmꢁ1): 3024,
1
2979, 1693, 1427, 1220, 1127, 914, 752, 699; H NMR (CDCl3):
ꢀ 0.75 (t, J ¼ 6:9 Hz) and 1.19 (br) (3H), 2.63 (2H, t, J ¼ 7:6 Hz),
3.60 (1H, dd, J ¼ 3:3, 12.9 Hz), 3.70 (2H, q, J ¼ 7:8 Hz), 4.04–
4.31 (2H, m), 5.02–5.09 (2H, m), 5.31–5.51 (1H, m), 5.81–5.97
(1H, m), 6.91–7.00 (3H, m), 7.11–7.25 (6H, m); 13C NMR
(CDCl3): ꢀ 14.1, 41.1, 44.6, 44.7, 53.4, 53.7, 60.9, 117.2, 126.2,
126.6, 126.8, 128.0, 128.1, 128.2, 129.9, 134.8, 135.8, 137.1,
143.9, 155.7; Found: C, 78.49; H, 7.33; N, 4.25%. Calcd for
C21H23NO2: C, 78.47; H, 7.21; N, 4.36%.
Ethyl cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-2-
carboxylate (cis-2c): Colorless solid. mp 81.6–82.4 ꢂC (from
hexane); IR (KBr, cmꢁ1): 3027, 2980, 1696, 1441, 1222, 1129,
916, 759, 709; 1H NMR (CDCl3): ꢀ 1.24–1.31 (3H, m), 2.70 (2H,
dd, J ¼ 6:8, 11.1 Hz), 3.14–3.31 (1H, m), 4.07–4.23 (3H, m), 4.29
(dd, J ¼ 5:9, 13.5 Hz) and 4.47 (dd, J ¼ 5:9, 13.5 Hz) (1H), 5.05–
5.13 (2H, m), 5.29 (t, J ¼ 6:9 Hz) and 5.43 (t, J ¼ 6:9 Hz) (1H),
5.82–6.00 (1H, m), 6.81 (1H, t, J ¼ 8:4 Hz), 7.04–7.09 (1H, m),
7.11–7.36 (7H, m); 13C NMR (CDCl3): ꢀ 14.7, 41.2, 41.4, 44.2,
44.8, 44.9, 45.2, 54.0, 54.3, 61.3, 117.2, 117.4, 126.0, 126.4,
126.5, 126.7, 126.8, 126.8, 128.5, 128.9, 129.0, 129.3, 129.6,
134.4, 134.6, 137.1, 137.2, 137.3, 137.7, 142.2, 155.2; Found: C,
78.35; H, 7.22; N, 4.13%. Calcd for C21H23NO2: C, 78.47; H,
7.21; N, 4.36%.
Addition Reaction of Allylmagnesium Bromide to 3,4-Di-
hydro-4-phenylisoquinoline (1) (Table 2, Entry 1). Under an
argon atmosphere, to magnesium turnings (214 mg, 8.8 mmol) in
THF (2 mL) was added a small amount of 1,2-dibromoethane as
initiator at room temperature. Then, freshly distilled allyl bromide
(484 mg, 4.0 mmol) in THF (2 mL) was added to a reaction mix-
ture over 40 min at ꢁ5 ꢂC. After 1 h, the clear supernatant solution
of allylmagnesium bromide (0.93 mL, 0.93 mmol) was added
slowly (10 min) to the stirred solution of 3,4-dihydro-4-phenyliso-
quinoline (1) (77.4 mg, 0.37 mmol) in THF (4 mL) using a syringe
at ꢁ78 ꢂC under an argon atmosphere. After stirring for 1 h, satu-
rated aqueous NH4Cl and ethyl acetate were added to the reaction
mixture. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate. The combined organic layers
were washed successively with water and brine and dried over an-
hydrous Na2SO4. The solvent was removed under reduced pres-
sure, and the residue was separated by preparative thin-layer chro-
matography (silica-gel, hexane/Et2O = 1/1 ꢃ3) to give cis-3
(35.2 mg, 38%) and trans-3 (44.3 mg, 48%).
Isobutyl
line-2-carboxylate (cis-2a):
cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
Colorless oil. IR (neat, cmꢁ1):
3027, 2960, 1699, 1427, 1219, 1126, 915, 758, 704; 1H NMR
(CDCl3): ꢀ 0.95 (6H, dd, J ¼ 4:0, 6.6 Hz), 1.96 (1H, m), 2.71 (2H,
t, J ¼ 8:1 Hz), 3.15–3.33 (1H, m), 3.82–3.99 (2H, m), 4.11–4.23
(1H, m), 4.30 (dd, J ¼ 5:9, 13.9 Hz) and 4.47 (dd, J ¼ 6:3, 13.5
Hz) (1H), 5.06–5.13 (m, 2H), 5.28 (t, J ¼ 7:0 Hz) and 5.43 (t,
J ¼ 7:0 Hz) (1H), 5.85–6.00 (1H, m), 6.81 (1H, t, J ¼ 8:4 Hz),
7.05–7.35 (8H, m); 13C NMR (CDCl3): ꢀ 19.2, 19.3, 28.1, 41.2,
41.4, 44.4, 44.8, 45.1, 45.4, 54.1, 54.6, 71.5, 71.7, 117.2, 117.5,
126.1, 126.1, 126.4, 126.6, 126.7, 126.8, 126.9, 127.0, 128.5,
128.6, 128.9, 129.0, 129.4, 129.6, 134.5, 134.6, 137.1, 137.3,
137.8, 142.3, 155.4; Found: C, 78.78; H, 7.83; N, 3.79%. Calcd
for C23H27NO2: C, 79.05; H, 7.79; N, 4.01%.
In a manner similar to 2a, trans- and cis-2b, 2c were obtained.
Benzyl trans-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line-2-carboxylate (trans-2b): Colorless oil. IR (neat, cmꢁ1):
3028, 2935, 1694, 1426, 1219, 1126, 915, 753, 731; 1H NMR
(CDCl3): ꢀ 2.62–2.74 (2H, m), 3.64 (1H, dd, J ¼ 4:0, 13.5 Hz),
4.11–4.35 (2H, m), 4.62 (1H, d, J ¼ 12:5 Hz), 4.83 (1H, d, J ¼
12:5 Hz), 4.86–5.25 (2H, m), 5.31–5.36 and 5.50–5.55 (1H, m),
5.72–5.98 (1H, m), 6.84 (1H, d, J ¼ 3:6 Hz), 6.93–7.00 (3H, m),
7.11–7.49 (10H, m); 13C NMR (CDCl3): ꢀ 41.1, 44.4, 44.7,

2422 Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007)
Diastereoselective Allylation
cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (cis-3):
Oil. IR (neat, cmꢁ1): 3024, 2927, 1638, 1600, 1492, 1450, 916,
755, 701; 1H NMR (CDCl3): ꢀ 1.75 (1H, br, NH), 2.63–2.71 (2H,
m), 3.20 (1H, dd, J ¼ 4:9, 13.1 Hz), 3.30 (1H, dd, J ¼ 4:9, 13.1
Hz), 4.07–4.16 (2H, m), 5.09–5.17 (2H, m), 5.80–5.96 (1H, m),
6.93 (1H, d, J ¼ 7:6 Hz), 7.08–7.32 (8H, m); 13C NMR (CDCl3):
ꢀ 40.5, 44.8, 48.8, 55.2, 117.6, 125.6, 126.0, 126.1, 128.0, 128.7,
130.2, 135.1, 137.3, 139.0, 144.8; Found: C, 86.49; H, 7.63; N,
5.41%. Calcd for C18H19N: C, 86.70; H, 7.68; N, 5.62%.
(9.9 mL) was added phenyllithium (4.6 mL, 1.14 M in cyclohex-
ane–Et2O, 5.3 mmol) at room temperature. Stirring was stopped
after 30 min, and the clear supernatant solution of allyllithium
(2.5 mL, 0.88 mmol) was added slowly (20 min) to a stirred solu-
tion of 3,4-dihydro-4-phenylisoquinoline (1) (71.1 mg, 0.34 mmol)
in THF (6 mL) using a syringe at ꢁ78 ꢂC under an argon atmo-
sphere. The reaction mixture was stirred for 1 h at that tempera-
ture. Ethyl acetate and saturated aqueous NH4Cl were added to
the reaction mixture. After the same work-up procedure described
in the reaction using allylmagnesium bromide, cis-3 (45.0 mg,
53%) and trans-3 (22.4 mg, 26%) were obtained.
trans-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (trans-
3): Oil. IR (neat, cmꢁ1): 3024, 2941, 1638, 1600, 1492, 1451,
1
915, 747, 701; H NMR (CDCl3): ꢀ 1.88 (1H, br, NH), 2.51–2.78
Addition Reaction of Triallylborane7 to 3,4-Dihydro-4-phen-
ylisoquinoline (1) (Table 2, Entry 3). Under an argon atmo-
sphere, to a solution of 3,4-dihydro-4-phenylisoquinoline (1)
(73.5 mg, 0.35 mmol) in THF (6 mL) was added triallylborane
(52.3 mg, 0.39 mmol) at ꢁ78 ꢂC. After stirring for 1 h, 3 M aque-
ous NaOH and ethyl acetate were added to the reaction mixture.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. After the same work-up procedure
described in the reaction using allylmagnesium bromide, cis-3
(46.6 mg, 53%) and trans-3 (25.5 mg, 29%) were obtained.
Addition Reaction of Allylzinc Bromide8 to 3,4-Dihydro-4-
phenylisoquinoline (1) (Table 2, Entry 4). To a suspension
of zinc powder (820 mg, 12.5 mmol) in THF (2 mL) was added
chlorotrimethylsilane (48 mL), and the reaction mixture was stirred
for 15 min at room temperature under an argon atmosphere. Then,
1,2-dibromoethane (41 mL) was added to the mixture. After stir-
ring for 30 min, freshly distilled allyl bromide (605 mg, 5.0 mmol)
in THF (3 mL) was added to the suspension of activated zinc over
40 min at 0 ꢂC. After 1 h, stirring was stopped, and excess zinc
powder was allowed to deposit on the bottom of the flask. The
clear supernatant solution of allylzinc bromide (0.47 mL, 0.47
mmol) was added slowly (5 min) to the stirred solution of 3,4-
dihydro-4-phenylisoquinoline (1) (64.5 mg, 0.31 mmol) in THF
(3 mL) using a syringe at ꢁ78 ꢂC under an argon atmosphere.
After stirring for 2 h, the reaction mixture was warmed to room
temperature and stirred for 1 h. The reaction was quenched with
saturated aqueous NH4Cl, and then, 2 M aqueous NaOH was
added until the solution became pH 9. Et2O was added to the mix-
ture and the organic layer was separated. The aqueous layer was
extracted with Et2O. After the same work-up procedure described
in the reaction using allylmagnesium bromide, cis-3 (53.6 mg,
69%) and trans-3 (10.1 mg, 13%) were obtained.
Addition Reaction of Diallylzinc9 to 3,4-Dihydro-4-phenyl-
isoquinoline (1) (Table 2, Entry 5). Under an argon atmosphere
at ꢁ5 ꢂC, to a solution of zinc chloride (204 mg, 1.5 mmol) in THF
(2 mL) was added allylmagnesium bromide, prepared from allyl
bromide (363 mg, 3.0 mmol) and magnesium turnings (160 mg,
6.6 mmol) in THF (3 mL). Stirring was continued for 1 h at ꢁ5
ꢂC, and the resulting clear supernatant solution of diallylzinc
(2.6 mL, 0.78 mmol) was added slowly (15 min) to the stirred
solution of 3,4-dihydro-4-phenylisoquinoline (1) (54.1 mg, 0.26
mmol) in THF (3 mL) using a syringe at ꢁ78 ꢂC under an argon
atmosphere. The reaction mixture was warmed to room tempera-
ture after stirring for 2 h, and stirring was continued for 1 h. The
reaction was quenched with saturated aqueous NH4Cl, and 2 M
aqueous NaOH was added until the solution became pH 9. Then,
Et2O was added to the mixture, and the organic layer was separat-
ed. The aqueous layer was extracted with Et2O. After the same
work-up procedure described in the reaction using allylmagnesi-
um bromide, cis-3 (42.6 mg, 65%) and trans-3 (6.9 mg, 11%) were
obtained.
(2H, m), 3.01 (1H, dd, J ¼ 8:2, 12.5 Hz), 3.45 (1H, dd, J ¼ 5:3,
12.6 Hz), 4.10 (1H, dd, J ¼ 5:6, 7.6 Hz), 4.21 (1H, dd, J ¼ 3:3,
8.6 Hz), 5.13–5.23 (2H, m), 5.77–5.93 (1H, m), 6.85 (1H, d, J ¼
7:6 Hz), 7.04–7.32 (8H, m); 13C NMR (CDCl3): ꢀ 40.6, 46.1, 50.1,
55.3, 117.7, 125.3, 125.9, 126.1, 128.1, 128.7, 129.7, 135.2, 138.3,
138.6, 144.3; Found: C, 86.33; H, 7.59; N, 5.47%. Calcd for
C18H19N: C, 86.70; H, 7.68; N, 5.62%.
tert-Butyl cis-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line-2-carboxylate (cis-4):
To a solution of cis-3 (190 mg,
0.76 mmol) in 1,4-dioxane (6 mL) and water (3 mL) were added
1 M (¼ 1 mol dmꢁ3) aqueous NaOH (1 mL) and di-tert-butyl di-
carbonate (200 mg, 0.92 mmol) at 0 ꢂC, and the reaction mixture
was stirred for 1.5 h at that temperature. After removal of 1,4-di-
oxane under reduced pressure, citric acid (0.5 M in water) was
added to the residue until the solution became pH 2. CH2Cl2 was
added to the mixture, and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with water and brine and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography (silica-gel,
hexane/ethyl acetate = 8/1) to give cis-4 (238 mg, 89%). Color-
less oil. IR (neat, cmꢁ1): 3063, 2976, 1691, 1462, 1409, 1226,
1154, 926, 753, 708; 1H NMR (CDCl3): ꢀ 1.47 (s) and 1.49 (s)
(9H), 2.66 (2H, t, J ¼ 8:4 Hz), 3.06–3.27 (1H, m), 4.08–4.16 (1H,
m), 4.23 (dd, J ¼ 5:9, 17.2 Hz) and 4.47 (dd, J ¼ 5:9, 13.5 Hz)
(1H), 5.05–5.13 (2H, m), 5.21–5.26 and 5.39–5.44 (1H, m), 5.87–
6.00 (1H, m), 6.81 (1H, t, J ¼ 8:4 Hz), 7.00–7.08 (1H, m), 7.12–
7.36 (7H, m); 13C NMR (CDCl3): ꢀ 28.5, 41.3, 41.5, 43.7, 45.0,
45.3, 53.5, 54.6, 79.7, 80.0, 117.0, 117.4, 126.0, 126.1, 126.3,
126.5, 126.8, 126.8, 128.5, 128.6, 128.9, 129.0, 129.3, 129.7,
134.8, 134.9, 137.4, 137.6, 138.0, 142.4, 142.5, 154.2; Found: C,
79.04; H, 7.85; N, 3.78%. Calcd for C23H27NO2: C, 79.05; H,
7.79; N, 4.01%.
tert-Butyl trans-1-Allyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line-2-carboxylate (trans-4): By a similar method described for
cis-4, trans-4 was obtained in 77% yield as colorless solid, which
was recrystallized from hexane to give the single crystalline for
X-ray crystallographic analysis; mp 82.5–83.3 ꢂC (from hexane).
IR (KBr, cmꢁ1): 3025, 2975, 2937, 2890, 1672, 1418, 1228,
1163, 1012, 921, 745, 722; 1H NMR (CDCl3): ꢀ 1.06 (s) and 1.36
(s) (9H), 2.61 (2H, t, J ¼ 7:8 Hz), 3.57 (1H, dd, J ¼ 3:1, 13.4 Hz),
4.10–4.29 (2H, m), 5.01–5.08 (2H, m), 5.24–5.28 and 5.43–5.47
(1H, m), 5.90 (1H, td, J ¼ 7:3, 16.8 Hz), 6.91–7.01 (3H, m), 7.10–
7.25 (6H, m); 13C NMR (CDCl3): ꢀ 27.9, 28.3, 41.1, 44.8, 52.9,
78.9, 116.9, 126.1, 126.5, 126.7, 126.9, 128.0, 128.3, 130.0, 135.0,
135.8, 137.5, 144.2, 154.4; Found: C, 78.76; H, 7.80; N, 3.77%.
Calcd for C23H27NO2: C, 79.05; H, 7.79; N, 4.01%.
Addition Reaction of Allyllithium6 to 3,4-Dihydro-4-phenyl-
isoquinoline (1) (Table 2, Entry 2). Under an argon atmo-
sphere, to a solution of allyltriphenyltin (1.95 g, 5.0 mmol) in Et2O

A. Taketoshi et al.
Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007) 2423
tert-Butyl cis-1-(3-Hydroxypropyl)-4-phenyl-1,2,3,4-tetra-
hydroisoquinoline-2-carboxylate (5). To a THF solution (5 mL)
of cis-4 (176 mg, 0.50 mmol) was added 1.17 M BH3–THF solu-
tion (0.86 mL, 1.01 mmol) under an argon atmosphere at 0 ꢂC, and
the reaction mixture was stirred for 7 h at room temperature. Then,
3 M aqueous NaOH (2.3 mL) and 30% H2O2 (2.3 mL) were added
to the mixture, and the stirring was continued for 2 h. Next, satu-
rated aqueous Na2S2O3 and Et2O were added to the reaction
mixture, and the organic layer was separated. The aqueous layer
was extracted with Et2O. The combined organic layers were wash-
ed with water and brine and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the residue
was purified by preparative thin-layer chromatography (silica-
gel, hexane/Et2O = 1/3) to give 5 (152 mg, 82%). Colorless
oil. IR (neat, cmꢁ1): 3416, 2932, 1692, 1422, 1365, 1165, 1124,
Table 3. Summary of Crystal Data for Compound trans-4
Empirical formula
Formula weight
Crystal color, habit
Crystal size/mm3
Crystal system
C23H27NO2
349.47
colorless, needle
0:62 ꢃ 0:22 ꢃ 0:10
monoclinic
Space group
Lattice parameters
P21=n (no. 14)
˚
a/A
16.563(7)
6.103(4)
19.673(4)
96.78(3)
1974(1)
4
˚
b/A
˚
c/A
ꢄ/ꢂ
3
˚
V/A
Z
Dcalcd/g cmꢁ3
1.175
1
757, 703; H NMR (CDCl3): ꢀ 1.48 (9H, s), 1.67–1.80 (2H, m),
F000
752.00
0.74
9352
1.96–2.04 (2H, m), 2.59 (br) and 2.92 (br) (1H), 3.04–3.24 (1H,
m), 3.71–3.76 (2H, m), 4.09–4.45 (2H, m), 5.13–5.19 and 5.31–
5.37 (1H, m), 6.79 (1H, t, J ¼ 7:3 Hz), 7.02 (1H, t, J ¼ 6:1 Hz),
7.10–7.33 (7H, m); 13C NMR (CDCl3): ꢀ 28.4, 29.1, 29.6, 33.3,
33.3, 43.5, 44.7, 45.0, 45.2, 53.7, 54.7, 62.1, 62.4, 79.9, 80.0,
125.9, 126.0, 126.2, 126.3, 126.5, 126.7, 126.8, 126.8, 128.4,
128.5, 128.8, 128.9, 129.2, 129.5, 137.1, 137.6, 138.2, 138.3,
142.3, 142.3, 154.4, 154.7.
ꢅ(Mo Kꢁ)/cmꢁ1
Reflections measured
Independent reflections
4905 (0.054)
(Rint
)
No. of Reflections (All)
No. variables
4905
343
Reflection/parameter ratio
Residuals: R; RW
Residuals: R1
14.30
0.088; 0.096
0.049
Ã
Ã
(6S ,10bR )-Hexahydro-6-phenylpyrrolo[2,1-a]isoquinoline
(7). To a solution of 5 (140 mg, 0.38 mmol) in pyridine (3 mL)
was added TsCl (145 mg, 0.76 mmol) at 0 ꢂC. The mixture was
stirred at room temperature for 6 h. After addition of water and
Et2O, the organic layer was separated, and the aqueous layer
was extracted with Et2O. The combined organic layers were dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure, and trifluoroacetic acid (0.5 mL) in CH2Cl2 (2 mL) was
added to the residue at 0 ꢂC. The reaction mixture was then stirred
for 3 h. After neutralization of the reaction mixture with 1 M aque-
ous NaOH, CH2Cl2 was added to the mixture. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with water and brine
and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography (silica-gel, ethyl acetate/MeOH = 9/1) to give
7 (74.8 mg, 79%).
No. of reflections to calc
R1
Goodness of fit Indicator
2754 (I > 2:0ꢆðIÞ)
1.28
ꢁ3
˚
ꢀꢇmax; ꢀꢇmin/e A
0.22; ꢁ0:23
angles in the range of 28.62–29.73ꢂ. Three standard reflections
were monitored at every 150 measurements. In the reduction of
the data, Lorentz and polarization corrections and an empirical
absorption correction (ꢀ scan) were made.
Crystallographic data and the results of measurements are sum-
marized in Table 3. The structures were solved by direct methods
(SIR 92)13 and expanded using Fourier techniques.14 All of the
non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were located from difference Fourier maps and refined iso-
tropically. All calculations were performed on a SGI indy comput-
er using the teXsan crystallographic software package of the Mo-
lecular Structure Corporation.15 Crystallographic data have been
deposited with Cambridge Crystallographic Data Centre: Deposi-
tion number CCDC-658110 for compound trans-4. Copies of the
data can be obtained free of charge via http://www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge, CB2 1EZ,
UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Oil. IR (neat, cmꢁ1): 3022, 2965, 2783, 2730, 1492, 1451,
1
1376, 1164, 1117, 915, 738, 701; H NMR (CDCl3): ꢀ 1.76–2.00
(3H, m), 2.35 (1H, dd, J ¼ 9:9, 17.5 Hz), 2.64 (1H, dd, J ¼ 8:6,
17.8 Hz), 2.89 (1H, dd, J ¼ 5:1, 11.1 Hz), 2.91–3.00 (1H, m), 3.03
(1H, dd, J ¼ 5:4, 11.1 Hz), 3.56 (1H, t, J ¼ 8:2 Hz), 4.19 (1H, t,
J ¼ 5:1 Hz), 6.89 (1H, d, J ¼ 7:6 Hz), 7.03–7.11 (1H, m), 7.14–
7.30 (7H, m); 13C NMR (CDCl3): ꢀ 22.4, 30.5, 46.3, 54.3, 56.2,
63.7, 125.6, 125.9, 125.9, 126.1, 128.0, 128.8, 129.2, 137.3, 138.8,
145.9; Found: C, 86.33; H, 7.72; N, 5.37%. Calcd for C18H19N: C,
86.70; H, 7.68; N, 5.62%.
Authors are grateful to Mr. Shinji Ishihara (Instrumental
Analysis Center of Yokohama National University) for his
technical assistance in the elemental analysis.
These values are consistent with those reported in the litera-
ture.12
Experimental Procedure for X-ray Crystallography of
trans-4. Suitable single crystal trans-4 was obtained by recrystal-
lization from hexane and was mounted on a glass fiber. Diffraction
measurement of trans-4 was made on a Rigaku AFC-7R automat-
ed four-circle diffractometer by using graphite-monochromated
Supporting Information
Spectroscopic data of 2a, 2b, 2c, 3, 4, 5, and 7. These materials
are available free of charge on the web at http://www.csj.jp/
journals/bcsj/.
˚
Mo Kꢁ radiation (ꢂ ¼ 0:71069 A). The data collections were car-
ried out at ꢁ50 ꢄ 1 ꢂC using the !-2ꢃ scan technique to a maxi-
mum 2ꢃ value of 55.0ꢂ. Cell constants and an orientation matrix
for data collection were determined from 25 reflections with 2ꢃ
References
#
Dedicated to the late Professor Yoshihiko Ito for his out-
standing contribution to synthetic organic chemistry.

2424 Bull. Chem. Soc. Jpn. Vol. 80, No. 12 (2007)
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