Reissert-like alkenylation of azaaromatic compounds with alkenylzirconocene chloride complexes

Article abstract of DOI:10.3987/COM-12-S(N)7

Reissert-like alkenylation of azaaromatic compounds by the use of alkenylzirconocene chloride as a nucleophile was carried out in the presence of a stoichiometric amount of ClCO₂Et. The regioselectivity of the nucleophilic attack depends on reacting heterocycles, solvent, and the presence of copper catalyst. Thus, the reaction of quinoline derivatives with alkenylzirconocene chloride in MeNO₂ proceeded in a preferential 1,2-addition manner to give N-ethoxycarbonyl-2-alkenyl-1,2-dihydroquinolines, and the reaction of pyridine in CH₂Cl₂ under Cu(I)-catalyzed conditions proceeded in a 1,4-addition manner to give N-ethoxycarbonyl-4-alkenyl-1,4-dihydropyridine. The alkenylation of 3,4- dihydroisoquinoline with alkenylzirconocene chloride was also carried out in an enantioselective manner under Cu(I)/chiral Box-catalyzed conditions to give alkenylated tetrahydroisoquinoline compound (75%ee).

Full text of DOI:10.3987/COM-12-S(N)7

HETEROCYCLES, Vol. 86, No. 1, 2012
267
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 267 - 280. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 21st March, 2012, Accepted, 16th April, 2012, Published online, 19th April, 2012
DOI: 10.3987/COM-12-S(N)7
REISSERT-LIKE ALKENYLATION OF AZAAROMATIC COMPOUNDS
WITH ALKENYLZIRCONOCENE CHLORIDE COMPLEXES
Akio Saito,¶,* Kohei Sudo, Koichi Iimura, Miki Hayashi, and Yuji Hanzawa*
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University,
3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan;
hanzaway@ac.shoyaku.ac.jp.
Abstract –Reissert-like alkenylation of azaaromatic compounds by the use of
alkenylzirconocene chloride as a nucleophile was carried out in the presence of a
stoichiometric amount of ClCO2Et. The regioselectivity of the nucleophilic attack
depends on reacting heterocycles, solvent, and the presence of copper catalyst.
Thus, the reaction of quinoline derivatives with alkenylzirconocene chloride in
MeNO2 proceeded in
a
preferential 1,2-addition manner to give
N-ethoxycarbonyl-2-alkenyl-1,2-dihydroquinolines, and the reaction of pyridine
in CH2Cl2 under Cu(I)-catalyzed conditions proceeded in a 1,4-addition manner to
give N-ethoxycarbonyl-4-alkenyl-1,4-dihydropyridine. The alkenylation of 3,4-
dihydroisoquinoline with alkenylzirconocene chloride was also carried out in an
enantioselective manner under Cu(I)/chiral Box-catalyzed conditions to give
alkenylated tetrahydroisoquinoline compound (75%ee).
INTRODUCTION¶
Nucleophilic additions of carbon nucleophiles to N-acyliminium ions provide us with efficient procedures
for the preparation of amine derivatives, and the procedure has been applied to the synthesis of alkaloids
and medicinally significant molecules. 1 One of the typical reactions applied to azaaromatics, known as
the Reissert reaction, employs a cyanide nucleophile in the presence of N-acylating agents affording
N-acyl-2-cyano-1,2-dihydroheterocycles (Scheme 1).2 On the other hand, Reissert-like reactions of the
azaaromatic compounds using organometallics (Mg,3 Cu,4 Sn,5 and their allyl6 or alkynyl species7) or
metal enolates8 instead of the cyanide nucleophile have been extensively studied to enhance the chemical
value of the Reissert reaction. Recently, it was shown that alkenyl boronic acid (Petasis-type reaction)9 or
¶
Present address: Division of Applied Chemistry, Institute of Engineering, Tokyo University of
Agriculture and Technology, 2-24-16 Nakamachi, Koganei 184-8588, Japan

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HETEROCYCLES, Vol. 86, No. 1, 2012
of the aluminum10 was another choice of organometallics for the Reissert-like alkenylation process.
KCN
+
RCOCl
N
N
N
CN
CN
COR
COR
Scheme 1. Reissert reaction
In our continuous study about the carbon-carbon bond formation using organozirconocene chloride
complexes as a synthetic reagent,11,12 we are tempted to examine the use of organozirconocene chloride
complexes for the Reissert-like alkenylation. Although the alkenylzirconocene chlorides are readily
accessible through the hydrozirconation of alkyne compounds with Schwartz reagent [Cp2Zr(H)Cl]13 or
by the treatment of alkenyl halide with Negishi reagent [Cp2Zr-nBu2],14 the poor reactivity of the
complexes toward the electrophiles, such as aldehydes, ketones and imines, often hampered their use for
organic synthesis. Thus, the search for catalysts and/or activating agents is necessitated to achieve the
objective carbon-carbon bond forming reactions. Our recent work revealed that the reaction of
alkenylzirconocene chloride complexes and 3,4-dihydroisoquinoline in the presence of acylating agent
brought about the enantioselective formation of 1-alkenyl-2-acyltetrahydroisoquinoline under the
Cu(I)/chiral Box-catalyzed conditions.15 It was also found that Reissert-like alkenylation of quinoline
with alkenylzirconocene chloride was promoted by the activation through acylating agent without the use
of Cu(I)-catalyst, albeit the poor regioselectivity (1,2- vs 1,4-addition).15 In this paper, we describe the
influence upon the regioselectivity of the Reissert-like alkenylation of azaaromatic compounds with
alkenylzirconocene chlorides.
RESULTS AND DISCUSSION
At the outset, we focused on the improvement of the regioselectivity in the reaction of quinoline (1a) and
(E)-styrylzirconocene chloride (2a, 2 equiv) in the presence of ethyl chloroformate (ClCO2Et, 1.2 equiv)
(Table 1). In CH2Cl2 solvent, treatment of 1a with ClCO2Et at 0 °C for 30 min followed by the addition of
2a to the reaction mixture proceeded the Reissert-like alkenylation at ambient temperature within 2 h (by
TLC) to afford a mixture of 1,2-adduct 3a (70%) and 1,4-adduct 4a (25%) (3a/4a = 2.8/1) (entry 1). The
use of nitromethane (MeNO2) solvent, however, suppressed the formation of 1,4-adduct 4a (3-7%, entries
5-7), and the yield of 1,2-adduct 3a was improved up to 82% in the presence of 2.4 equiv of ClCO2Et
(3a/4a = 27/1) (entry 7). Thus, the solvent choice is important for the regioselective formation of
1-acyl-2-alkenylation product 3a, albeit other examined solvents (toluene, THF and CH3CN) are
unattractive (entries 2-4). Based on the results, the Reissert-like reactions of quinoline derivatives 1 with

HETEROCYCLES, Vol. 86, No. 1, 2012
269
2a and ClCO2Et were examined in either CH2Cl2 or MeNO2 solvent (Table 2). The reactions of quinoline
derivatives 1a-d in CH2Cl2 completed at ambient temperature within 2 h (by TLC), except for the
nitro-substituted 1e (24 h). In all cases examined, however, a considerable amount of 1,4-adducts 4a-e
(10-36%) were formed along with 1,2-adducts 3a-e (63-83%) (left column, Table 2). The use of MeNO2
as a solvent brought about the improved 1,2-regioselectivities for the additions (3a-e: 52-93%, 4a-e:
3-9%) (right column).
Table 1. Optimization for the regioselective Reissert-like alkenylation of quinoline (1a) with 2a
Ph
Cl
ZrCp2
Ph
2a (2 equiv)
+
+
ClCO2Et
solvent, rt
N
(1.2 equiv)
N
Ph
N
1a
CO2Et
CO2Et
3a (1,2-adduct)
4a (1,4-adduct)
Yield
Recovery
Entry
Solvent
Time (h)
3a (%)a
70b
38
4a (%)a
of 1a (%)a
1
2
3
4
CH2Cl2
toluene
THF
MeCN
MeNO2
MeNO2
MeNO2
CH2Cl2
2
2
2
2
2
14
14
2
25b
23
35
6
-
11
17
43
40
7
36
26
33
5
4
6
49
7
7c
82b
46
3b
35
-
-
8d
a The yield was determined by 1H-NMR analysis. b Isolated yield. c ClCO2Et: 2.4equiv.
d Additive: 10 mol% CuBr.
Table 2. Reissert-like alkenylation of quinoline derivatives 1 with 2a
Ph
Cl
ZrCp2
Ph
R1
R2
R1
R2
R1
R2
2a (2 equiv)
+
+
ClCO2Et
CH2Cl2 or MeNO2, rt
N
(1.2 or 2.4 equiv)
N
Ph
N
1
CO2Et
CO2Et
3 (1,2-adduct)
4 (1,4-adduct)
a
b
Reaction in CH2Cl2
Time (h)
Reaction in MeNO2
Time (h)
1
R1
R2
3 (%)c
70
4 (%)c
25
3 (%)c
82
4 (%)c
1a
1b
1c
1d
1e
H
H
Me
MeO
NO2
H
Me
H
H
H
2
2
2
2
24
14
14
14
14
22
3
5
4
5
9
70
83
63
66
22
10
36
23
82
93
74
52
a ClCO2Et: 1.2 equiv. b ClCO2Et: 2.4equiv. c Isolated yield.

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HETEROCYCLES, Vol. 86, No. 1, 2012
In the reaction of pyridine (5) and 2a in the presence of ClCO2Et, however, the use of MeNO2 afforded a
mixture of regioisomers 6 and 7 (53%) with a poor 1,2-regioselectivity (6/7 = 3.8/1) (Scheme 2). It should
be noted that the alkenylation in CH2Cl2 brought about the nonselective formation of products (67%, 6/7
= 1/1.4). The 1,4-regioselectivity was remarkably enhanced by the addition of catalytic CuBr (10 mol%)
to the reaction mixture at -78 °C to give a mixture of products in high yield (95%, 6/7 = 1/18). Contrary
to the reaction of pyridine, CuBr-catalyzed reaction of quinoline (1a) did not give an improved selectivity
of regioisomers (81%, 3a/4a = 1.3/1) (Table 1, entry 8) under otherwise identical conditions with pyridine.
The presence of ClCO2Et is essential to bring about the reaction in every examined case. Thus, it is
necessary to activate the azaaromatic compounds as shown in Scheme 1. Although details about the
solvent effect and the role of the Cu(I)-catalyst for the regioselectivity remain uncertain at present,16 it has
been reported that the addition of Cu(I)-catalysts to Grignard reagents3a or the use of organocoppers4 led
to the preferred formation of the Reissert-like 1,4-addition product.
Ph
Cl
ZrCp2
Ph
2a (2 equiv)
+
+
ClCO2Et
CH2Cl2 or MeNO2
N
(2.4 equiv)
N
Ph
N
5
CO2Et
CO2Et
6 (1,2-adduct)
7 (1,4-adduct)
MeNO2,
CH2Cl2,
CH2Cl2,
rt, 24 h
rt, 3 h
-78 °C, 3 h
42%
27%
5%
11%
40%
90%
Additive: 10mol% CuBr
Scheme 2. Reissert-like alkenylation of pyridine (5) with 2a
The alkenylation of isoquinoline derivative 8a or 8b with 2a in the presence of ClCO2Et proceeded
smoothly in CH2Cl2 at ambient temperature giving rise to the corresponding product 9a or 9b as a sole
product in high yield (Scheme 3). Extension of the alkenylation using 2a to 3,4-dihydroisoquinoline (10)
reveals that Cu(I) catalyst in the coexisitence of N-acylating agent is required to bring about the efficient
formation of alkenylated tetrahydroisoquinoline 11a (Table 3). Among the examined Cu(I) catalysts,17
Cu(OTf) (Entry 3) or [Cu(MeCN)4]PF6 (Entries 4-7) showed high efficiency for the formation of 11, and
alkyl-substituted alkenylzirconocene chlorides (2b, 2c and 2d) were also efficient nucleophiles in the
reaction.

HETEROCYCLES, Vol. 86, No. 1, 2012
271
Cl
R
R
ZrCp2
2a (2 equiv)
Ph
+
ClCO2Et
N
N
CH2Cl2, rt, 2 h
CO2Et
(1.2 equiv)
8a (R=H)
8b (R=Br)
9a 88%
9b 92%
Ph
Scheme 3. Alkenylation of isoquinolines 8 with 2a
Table 3. Reissert-like alkenylation of 3,4-dihydroisoquinoline (10) with 2a
Cl
ZrCp2
R1
R2
2 (2 equiv)
+
ClCO2Et
N
N
Cu(I) catalyst (10 mol%)
CH2Cl2, rt, 2 h
CO2Et
(1.2 equiv)
10
R2
R1
Entry
2
2a
R1
Ph
R2
H
Cu(I)
11
11a
Yield (%)a
1b
2
-
36
68
81
87
78
72
80
CuBr
CuOTf
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
3
4
5
6
2b
2c
2d
nBu
tBu
Et
H
H
Et
11b
11c
11d
7
a Isolated yield. b Reaction time: 16 h.
An attempt to carried out the enantioselective addition of 2a to 10 using Cu(I)/chiral ligand catalytic
systems indicated that chiral Box ligands to Cu(I) catalyst turned out to be fairly efficient in a sense of
chiral induction (Table 4). Thus, by using a [Cu(MeCN)4]PF6 and (S,S)-Box ligand 12,18 the reaction of
10 with 2a and di-t-butyl dicarbonate [(Boc)2O] as an N-acylating agent at 0 °C for 24 h afforded (S)-13
(75%ee) in 65% yield (Entry 12). The absolute configuration of (S)-13 was determined by the conversion
to compound 1419 whose absolute configuration has been established (Scheme 4).
Table 4. Enantioselective reactions of 2a and 10
Cl
ZrCp2
O
O
N
Ph
O
O
N
N
2a
N
N
(S,S)-PyBox
Ph
Ph
Cu(I) / chiral ligand
(10 mol%)
R
R
N
Boc
(S,S)-Box-Ph: R = Ph
(S,S)-Box-Bn: R = Bn
O
O
N
(Boc)2O
N
N
(S,S)-Box-iPr: R = iPr
10
CH2Cl2, rt, 6 h
(S,S)-Box-tBu: R =tBu
(S)-13
But
tBu
12
Ph

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HETEROCYCLES, Vol. 86, No. 1, 2012
Yield (%)a
ee (%)b
ligand
Entry
Cu(I)
1
2
CuOTf
(S,S)-PyBox-Ph
(S,S)-Box-Ph
(S,S)-Box-Bn
(S,S)-Box-iPr
(S,S)-Box-tBu
(S,S)-Box-tBu
(S,S)-Box-tBu
12
67
87
89
84
74
90
63
65
22
30
32
40
44
50
68
75
3
4
5
6
[Cu(MeCN)4]PF6
7c
8c
a Isolated yield. b Ee was determined by HPLC analysis (Chiralpak AD). c 0 °C, 24 h.
1) H2 / 10% Pd-C
N
NH
2) TMSOTf / CH2Cl2
(84% by 2steps)
Boc
(S)-13
(S)-14
[]D = - 18.9°
(lit.: [] = - 23.5°)18
[]D = 122.7°
D
Ph
Ph
Scheme 4. Determination of the absolute configuration of (S)-13
CONCLUSIONS
The alkenylzirconocene chloride complex was found to be an efficient nucleophile for the Reissert-type
alkenylation of azaaromatic compounds in the presence of a stoichiometric amount of ClCO2Et. In the
reaction, solvent effect (MeNO2 or CH2Cl2) and/or the presence of Cu-catalyst are important for the
regioselectivity of the alkenylation of quinolines and pyridines. The enantioselective addition of the
alkenylzirconocene chloride to 3,4-dihydroisoquinoline was also achieved by the Cu(I)/chiral Box ligand
catalytic system to give the biologically attractive tetrahydroisoquinoline compound in an optically active
form.20 We believe that the reactivity of alkenylzirconocene chloride described in the present paper
indicates a new possibility for the use of organozirconocene complexes in organic synthesis.
EXPERIMENTAL
All melting points were taken on a Yanaco SP-M1 melting point apparatus (Yanagimoto Co.) and were
13
uncorrected. IR spectra were taken on a HORIBA FT-710 FT-IR spectrometer. 1H and C NMR spectra
were measured in CDCl3 with a Bruker AV300M FT NMR spectrometer at 300 and 75 MHz, and the
1
13
chemical shifts are given in ppm using CHCl3 (7.26 ppm) for H NMR and CDCl3 (77.0 ppm) for C
NMR as an internal standard, respectively. Mass spectra and HRMS were recorded by FAB method on a

HETEROCYCLES, Vol. 86, No. 1, 2012
273
JMS-HX110 Mass spectrometer. Elemental analysis were measured on a Perkin-Elmer 240B or
Elemental Vavio EL. For the TLC analysis, Merck precoated TLC plates (silica gel 60 F254) were used.
Column chromatography was performed on Silica gel 60N (63-200 m, Kanto Kagaku Co., Ltd.). All of
the organic solvents were dried over appropriate drying agents. Unless otherwise stated, all reactions were
conducted under an argon atmosphere.
Starting Materials. 3,4-dihydroisoquinoline (10) was prepared by previously reported procedure.21 All
other compounds were commercially available.
General procedure for the preparation of alkenylzirconocene chlorides 2 in CH2Cl2. To a suspension
of Cp2Zr(H)Cl (258 mg, 1.0 mmol) in CH2Cl2 (2.0 mL) was added an alkyne compound (1.2 mmol) at an
ambient temperature. After the reaction mixture was stirred for 30 min at the same temperature, the
CH2Cl2 solutions were used in the following experiments without any changes.
Preparation of (E)-styrylzirconocene chloride (2a) in MeNO2. According to the above manner, the
solution of 2a in CH2Cl2 (2.0 mL) was prepared from Cp2Zr(H)Cl (258 mg, 1.0 mmol) and phenylalkyne
(132 L, 1.2 mmol). After the CH2Cl2 was removed in vacuo, MeNO2 (2.0 mL) was added to the residue.
General procedure for the Reissert-like alkenylation of 2 with azaaromatic compounds. A premixed
solution (30 min at 0 °C) of an azaaromatic compound (0.5 mmol) and ClCO2Et (0.6 or 1.2 mmol) in
CH2Cl2 or MeNO2 (3.0 mL) was added to a solution of 2 (1.0 mmol) in CH2Cl2 or MeNO2 (2.0 mL) at an
ambient temperature. After the consumption of the starting material (by TLC analysis), the reaction
mixture was diluted with ether and filtered through a short alumina column. After concentration of the
filtrate to dryness, the subsequent purification gave the corresponding acyl-alkenylated compound 3, 4, 6,
7, and/or 9.
1
Ethyl 2-[(E)-styryl]quinoline-1(2H)-carboxylate (3a). IR (neat)  1716 cm-1; H-NMR (300 MHz,
CDCl3)  1.33 (t, 3H, J = 7.1 Hz), 4.21-4.35 (m, 2H), 5.66-5.70 (m, 1H), 6.00-6.08 (m, 2H), 6.47-6.56 (m,
13
1H), 7.00-7.09 (m, 2H), 7.14-7.28 (m, 6H), 7.61 (br.d, 1H, J = 7.9 Hz); C NMR (75 MHz, CDCl3) 
14.5, 54.3, 62.2, 124.1, 124.3, 125.6, 126.4, 126.7, 126.9, 127.1, 127.6, 127.7, 128.5, 131.5, 134.7, 136.5,
154.3; FAB-LM m/z 305.3 (M+H+); FAB-HM Calcd for C20H20NO2 306.1494, Found 306.1481. Anal.
Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.59; H, 6.36; N, 4.57.
1
Ethyl 4-[(E)-styryl]quinoline-1(4H)-carboxylate (4a). IR (neat)  1716 cm-1; H-NMR (300 MHz,
CDCl3)  1.36 (t, 3H, J = 7.1 Hz), 4.16 (dd, 1H, J = 8.0, 5.0 Hz), 4.32 (q, 2H, J = 7.1 Hz), 5,28 (dd, 1H, J
= 7.8, 5.0 Hz), 6.16 (dd, 1H, J = 15.7, 8.0 Hz), 6.41 (d, 1H, J = 15.7 Hz), 7.06-7.34 (m, 9H), 8.04 (d, 1H,
13
J = 7.5 Hz); C NMR (75 MHz, CDCl3)  14.5, 41.5, 62.5, 111.1, 121.4, 125.0, 126.2, 126.3, 127.4,
128.5, 128.7, 129.4, 131.6, 135.8, 137.0, 152.6; FAB-LM m/z 304.2 (M+H+); FAB-HM Calcd for
C20H20NO2 306.1494, Found 306.1483.

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HETEROCYCLES, Vol. 86, No. 1, 2012
1
Ethyl 3-methyl-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3b). IR (neat)  1712 cm-1; H-NMR (300
MHz, CDCl3)  1.34 (t, 3H, J = 7.1 Hz), 1.97 (s, 3H), 4.19-4.39 (m, 2H), 5.44 (d, 1H, J = 7.3 Hz), 6.00
(dd, 1H, J = 15.7, 7.3 Hz), 6.30 (s, 1H), 6.35 (d, 1H, J = 15.7 Hz), 7.00-7.06 (m, 2H), 7.11-7.31 (m, 6H),
13
7.59 (m, 1H); C NMR (75 MHz, CDCl3)  14.6, 20.7, 58.9, 62.2, 121.4, 124.0, 124.1, 124.4, 125.7,
126.6, 126.7, 127.7, 128.4, 131.8, 133.4, 136.5, 136.7, 154.2; FAB-LM m/z 319.2 (M+H+); FAB-HM
Calcd for C21H22NO2 320.1651. Found 320.1658.
1
Ethyl 3-methyl-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4b). IR (neat)  1719 cm-1; H-NMR (300
MHz, CDCl3)  1.36 (t, 3H, J = 7.1 Hz), 1.83 (s, 3H), 3.91 (d, 1H, J = 8.3 Hz), 4.32 (q, 2H, J = 7.1 Hz),
6.08 (dd, 1H, J = 15.5, 8.3 Hz), 6.41 (d, 1H, J = 15.5 Hz), 6.83-6.84 (m, 1H), 7.09-7.37 (m, 8H), 8.01 (d,
13
1H, J = 8.3 Hz); C NMR (75 MHz, CDCl3)  14.5, 18.5, 47.6, 62.4, 119.7, 121.3, 121.5, 124.8, 126.4,
126.6, 127.3, 128.5, 128.6, 129.3, 130.3, 131.6, 135.8, 137.0, 152.6; FAB-LM m/z 319.2 (M+H+);
FAB-HM Calcd for C21H22NO2 320.1651. Found 320.1642.
1
Ethyl 6-methyl-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3c). IR (neat)  1722 cm-1; H-NMR (300
MHz, CDCl3)  1.33 (t, 3H, J = 7.1 Hz), 2.29 (s, 3H), 4.20-4.38 (m, 2H), 5.65-5.70 (mt, 1H), 5.99-6.09
(m, 2H), 6.47-6.53 (m, 2H), 6.90 (d, 1H, J = 1.7 Hz), 7.00 (dd, 1H, J = 8.3, 1.7 Hz), 7.15-7.29 (m, 5H),
7.48-7.50 (m, 1H); 13C NMR (75 MHz, CDCl3)  14.5, 20.8, 54.3, 62.1, 124.1, 125.7, 126.6, 126.7, 126.9,
127.7, 128.3, 128.4, 131.4, 132.2, 133.6, 136.6, 154.4; FAB-LM m/z 319.3 (M+H+); FAB-HM Calcd for
C21H22NO2 320.1651. Found 320.1659. Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C,
78.81; H, 6.72; N, 4.29.
Ethyl 6-methyl-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4c). Mp 50 °C; IR (KBr)  1729 cm-1;
1H-NMR (300 MHz, CDCl3)  1.34 (t, 3H, J = 7.1 Hz), 2.29 (s, 3H), 4.12 (dd, 1H, J = 8.0, 5.0 Hz), 4.32
(q, 2H, J = 7.1 Hz), 5.26 (dd, 1H, J = 8.0, 5.0 Hz), 6.16 (dd, 1H, J = 15.7, 8.0 Hz), 6.42 (d, 1H, J = 15.7
Hz), 6.95-7.08 (m, 3H), 7.19-7.38 (m, 5H), 7.94 (d, 1H, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3)  14.5,
20.7, 41.6, 62.4, 110.9, 121.2, 126.2, 126.4, 127.4, 127.5, 128.5, 129.1, 129.2, 131.8, 133.3, 134.5, 137.1,
152.6; FAB-LM m/z 319.2 (M+H+); FAB-HM Calcd for C21H22NO2 320.1651, Found 320.1641.
Ethyl 6-methoxy-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3d). IR (neat)  1716 cm-1; 1H-NMR (300
MHz, CDCl3)  1.28 (t, 3H, J = 7.1 Hz), 3.79 (s, 3H), 4.16-4.33 (m, 2H), 5.65-5.69 (m, 1H), 5.99-6.07 (m,
2H), 6.45-6.52 (m, 2H), 6.62 (d, 1H, J = 2.9 Hz), 6.74 (dd, 1H, J = 8.9, 2.9 Hz), 7.13-7.28 (m, 5H),
7.50-7.52 (m, 1H); 13C NMR (75 MHz, CDCl3)  14.6, 54.2, 55.5, 62.1, 111.2, 113.1, 125.5, 125.6, 126.6,
127.7, 128.0, 128.4, 131.5, 136.5, 154.4, 156.1; FAB-LM m/z 335.2 (M+H+); FAB-HM Calcd for
C21H22NO3 336.1600. Found 336.1602.
Ethyl 6-methoxy-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4d). IR (neat)  1716 cm-1; 1H-NMR (300
MHz, CDCl3)  1.35 (t, 3H, J = 7.1 Hz), 3.96 (s, 3H), 4.12 (dd, 1H, J = 8.0, 4.9 Hz), 4.31 (q, 2H, J = 7.1

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Hz), 5,24 (dd, 1H, J = 7.8, 4.9 Hz), 6.14 (dd, 1H, J = 15.7, 8.0 Hz), 6.32 (d, 1H, J = 15.7 Hz), 6.68 (d, 1H,
J = 3.0 Hz), 6.78 (dd, 1H, J = 9.2, 3.0 Hz), 7.04-7.07 (m, 1H), 7.16-7.43 (m, 4H), 7.99 (d, 1H, J = 9.2
Hz); 13C NMR (75 MHz, CDCl3)  14.5, 41.8, 55.5, 62.4, 110.5, 112.2, 113.4, 122.5, 126.1, 126.4, 127.4,
128.5, 129.5, 130.1, 130.8, 131.5, 152.6, 156.6; FAB-LM m/z 335.2 (M+H+); FAB-HM Calcd for
C21H22NO3 336.1600. Found 336.1598.
Ethyl 6-nitro-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3e). Mp 125 °C; IR (KBr)  1720 cm-1;
1H-NMR (300 MHz, CDCl3)  1.38 (t, 3H, J = 7.1 Hz), 4.31-4.38 (m, 2H), 5.71-5.75 (m, 1H), 6.03 (dd,
1H, J = 15.8, 6.6 Hz), 6.10-6.24 (m, 1H), 6.47-6.52 (m, 1H), 6.61-6.65 (m, 1H), 7.19-7.30 (m, 5H),
7.81-7.90 (m, 1H), 7.97-8.12 (m, 2H); 13C NMR (75 MHz, CDCl3)  14.4, 45.1, 54.8, 63.1, 121.8, 122.9,
124.1, 124.5, 126.6, 127.2, 128.2, 131.8, 132.5, 135.9, 140.2, 143.5, 153.7; FAB-LM m/z 351.3 (M+H+);
FAB-HM Calcd for C20H19N2O4 351.1345. Found 351.1344. Anal. Calcd for C20H18N2O4: C, 68.56; H,
5.18; N, 8.00. Found: C, 68.85; H, 5.26; N, 7.74.
Ethyl 6-nitro-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4e). Mp 71 °C; IR (KBr)  1735 cm-1;
1H-NMR (300 MHz, CDCl3)  1.40 (t, 3H, J = 7.1 Hz), 4.26 (dd, 1H, J = 8.1, 5.0 Hz), 4.37 (q, 2H, J = 7.1
Hz), 5,34 (dd, 1H, J = 7.8, 5.0 Hz), 6.15 (dd, 1H, J = 15.7, 8.1 Hz), 6.47 (d, 1H, J = 15.7 Hz), 7.10 (d, 1H,
J = 7.8 Hz), 7.22-7.41 (m, 5H), 8.06-8.29 (m, 3H); 13C NMR (75 MHz, CDCl3)  14.4, 41.3, 63.4, 110.7,
115.6, 121.8, 121.9, 122.3, 124.4, 125.7, 126.5, 127.8, 128.6, 130.1, 130.3, 130.7, 136.4, 144.3; FAB-LM
m/z 351.3 (M+H+); FAB-HM Calcd for C20H19N2O4 351.1345. Found 351.1351.
1
Ethyl 2-[(E)-styryl]pyridine-1(2H)-carboxylate (6). Mp 52 °C; IR (KBr)  1716 cm-1; H-NMR (300
MHz, CDCl3)  1.34 (t, 3H, J = 7.1 Hz), 4.20-4.30 (m, 2H), 5.26-5.59 (m, 3H), 5.99-6.04 (m, 1H),
6.18-6.25 (m, 1H), 6.44-6.58 (m, 1H), 6.70-6.84 (m, 1H), 7.21-7.41 (m, 5H); 13C NMR (75 MHz, CDCl3)
 14.5, 53.3, 62.3, 105.3, 120.5, 122.0, 124.9, 125.6, 127.7, 128.5, 131.2, 136.7, 155.7; FAB-LM m/z
255.2 (M+H+); FAB-HM Calcd for C16H18NO2 256.1338. Found 256.1336.
1
Ethyl 4-[(E)-styryl]pyridine-1(4H)-carboxylate (7). IR (neat)  1718 cm-1; H-NMR (300 MHz,
CDCl3)  1.32 (t, 3H, J = 7.1 Hz), 3.74-3.77 (m, 1H), 4.26 (q, 2H, J = 7.1 Hz), 4.86-4.93 (m, 2H), 6.15
(dd, 1H, J = 15.8, 7.4 Hz), 6.36 (d, 1H, J = 15.8 Hz), 6.77-6.92 (m, 2H), 7.20-7.42 (m, 5H); 13C NMR (75
MHz, CDCl3)  14.5, 36.2, 62.5, 108.5, 120.8, 122.8, 126.3, 127.0, 128.5, 132.9, 137.2, 150.2; FAB-LM
m/z 254.2 (M+H+); FAB-HM Calcd for C16H18NO2 256.1338. Found 256.1332.
1
Ethyl 1-[(E)-styryl]isoqunoline-2(1H)-carboxylate (9a). IR (neat)  1712 cm-1; H-NMR (300 MHz,
CDCl3)  1.36 (t, 3H, J = 7.1 Hz), 4.26-4.39 (m, 2H), 5.87 (d, 1H, J = 7.8 Hz), 6.01 (br.s, 1H), 6.29 (dd,
1H, J = 15.8, 6.0 Hz), 6.38 (d, 1H, J = 15.8 Hz), 6.96 (br.s, 1H), 7.07-7.34 (m, 9H); 13C NMR (75 MHz,
CDCl3)  14.4, 57.3, 62.2, 108.0, 124.7, 124.9, 126.6, 126.7, 127.0, 127.6, 127.8, 128.3, 130.9, 136.5,
153.1; FAB-LM m/z 305.2 (M+H+); FAB-HM Calcd for C20H20NO2 306.1494. Found 306.1489.

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1
Ethyl 4-bromo-1-[(E)-styryl]isoqunoline-2(1H)-carboxylate (9b). IR (neat)  1733 cm-1; H-NMR
(300 MHz, CDCl3)  1.34 (t, 3H, J = 7.1 Hz), 4.25-4.32 (m, 2H), 5.80-6.03 (m, 1H), 6.20-6.27 (m, 1H),
6.35 (d, 1H, J = 15.7 Hz), 6.89-7.35 (m, 9H), 7.48-7.51 (m, 1H); 13C NMR (75 MHz, CDCl3)  14.5, 57.2,
62.9, 103.3, 124.9, 125.6, 128.3, 128.5, 131.0, 136.1,153.5; FAB-LM m/z 383.1 (M+H+); FAB-HM Calcd
for C20H19NO2Br 384.0599. Found 383.0526. Anal. Calcd for C20H18NO2Br: C, 62.51; H, 4.72; N, 3.65.
Found: C, 62.65; H, 5.11; N, 3.57.
Cu(I)-catalyzed acyl-alkenylation of 2a with pyridine (5). A premixed solution (30 min at 0 °C) of
pyridine (40 mL, 0.5 mmol) and ClCO2Et (114 mL, 1.2 mmol) in CH2Cl2 (3.0 mL) was added to solution
of 2a (1.0 mmol) with CuBr (7.2 mg, 50 mmol) in CH2Cl2 (2.0 mL) at -78 °C. After being stirred at
1
-78 °C for 3 h, the yields of 6 and 7 was determined by H-NMR analysis using toluene as a internal
standard.
Cu(I)-catalyzed acyl-alkenylation of 2 with 3,4-dihydroisoquinoline (10). A premixed solution (30
min at 0 °C) of pyridine (40 mL, 0.5 mmol) and ClCO2Et (114 mL, 1.2 mmol) in CH2Cl2 (3.0 mL) was
added to solution of 2a (1.0 mmol) with [Cu(MeCN)4]PF6 (18.6 mg, 50 mol) in CH2Cl2 (2.0 mL) at an
ambient temperature. After the consumption of the starting material (by TLC analysis), workup and
purification as above described yielded 11.
Ethyl 3,4-dihydro-1-[(E)-styryl]isoquinoline-2(1H)-carboxylate (11a). IR (neat)  1704 cm-1; 1H-NMR
(300 MHz, CDCl3)  1.29 (t, 3H, J = 7.1 Hz), 2.73-2.81 (m, 1H), 2.90-3.01 (m, 1H), 3.29-3.33 (m, 1H),
4.12-4.25 (m, 2H), 5.78-5.81 (m, 1H), 6.32 (dd, 1H, J = 15.8, 5.6 Hz), 6.41 (d, 1H, J = 15.8 Hz),
7.13-7.37 (m, 10H); 13C NMR (75 MHz, CDCl3)  14.8, 28.7, 38.5, 56.3, 61.5, 126.2, 126.5, 126.8, 127.7,
128.1, 129.0, 129.1, 131.4, 134.7, 136.6, 155.6; FAB-LM m/z 307.4 (M+H+); FAB-HM Calcd for
C20H22NO2 308.1651. Found 308.1644. Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C,
77.98; H, 7.09; N, 4.52.
Ethyl 1-[(E)-hex-1-enyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (11b). IR (neat)  1714 cm-1;
1H-NMR (300 MHz, CDCl3)  0.88 (t, 3H, J = 7.1 Hz), 1.24-1.38 (m, 4H), 1.29 (t, 3H, J = 7.1 Hz), 2.02
(dt, 2H, J = 6.8, 6.8 Hz), 2.73 (dt, 1H, J = 16.0, 3.7 Hz), 2.86-2.99 (m, 1H), 3.19-3.33 (m, 1H), 4.03-4.32
(m, 3H), 5.49 (dt, 1H, J = 14.9, 6.8 Hz), 5.50-5.66 (m, 2H), 7.08-7.23 (m, 4H); 13C NMR (75 MHz,
CDCl3)  13.8, 14.7, 22.1, 28.6, 31.2, 31.8, 38.1, 56.1, 61.2, 125.9, 126.5, 127.9, 128.7, 129.3, 132.9,
134.4, 135.6, 155.4; FAB-LM m/z 288.3 (M+H+); FAB-HM Calcd for C18H26NO2 288.1964. Found
288.1956. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.01; H, 8.76; N, 4.74.
Ethyl 3,4-dihydro-1-[(E)-3,3-dimethylbut-1-enyl]isoquinoline-2(1H)-carboxylate (11c). IR (neat) 
1
1716 cm-1; H-NMR (300 MHz, CDCl3)  0.99 (s, 9H), 1.28 (t, 3H, J = 7.1 Hz), 2.73 (dt, 1H, J = 16.0,
3.7 Hz), 2.86-3.00 (m, 1H), 3.18-3.30 (m, 1H), 4.12-4.31 (m, 3H), 5.46 (dd, 1H, J = 15.4, 5.5 Hz),

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13
5.51-5.67 (m, 2H), 7.07-7.25 (m, 4H); C NMR (75 MHz, CDCl3)  14.7, 28.7, 29.4, 32.9, 38.1, 56.3,
61.2, 123.9, 126.0, 126.5, 127.9, 128.8, 134.5, 135.8, 143.7, 155.5; FAB-LM m/z 288.3 (M+H+);
FAB-HM Calcd for C18H26NO2 288.1964. Found 288.1971.
Ethyl 1-[(E)-hex-3-en-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (11d). IR (neat)  1704 cm-1;
1H-NMR (300 MHz, CDCl3)  0.87 (t, 3H, J = 7.5 Hz), 1.05 (t, 3H, J = 7.5 Hz), 1.27 (t, 3H, J = 7.1 Hz),
1.94-2.09 (m, 3H), 2.13-2.28 (m, 1H), 2.71 (dt, 1H, J = 16.0, 3.8 Hz), 2.84-3.01 (m, 1H), 3.19-3.37 (m,
1H), 3.92-4.35 (m, 3H), 4.80 (t, 1H, J = 7.2 Hz), 5.59-5.85 (m, 1H), 6.98-7.05 (m, 1H), 7.08-7.20 (m,
3H); 13C NMR (75 MHz, CDCl3)  13.6, 14.3, 14.7, 20.8, 21.6, 28.1, 37.5, 58.3, 61.2, 125.4, 126.5, 128.6,
131.8, 135.2, 135.4, 141.0, 155.7; FAB-LM m/z 288.3 (M+H+); FAB-HM Calcd for C18H26NO2 288.1964.
Found 288.1965. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 74.95; H, 8.84; N,
4.66.
Enantioselective acyl-alkenylation of 2a with 3,4-dihydroisoquinoline (10). A premixed solution (30
min at 0 °C) of 10 (65.6 mg, 0.5 mmol) and (Boc)2O (131 mg, 1.2 mmol) in CH2Cl2 (3.0 mL) was added
at 0 °C to solution of 2a (1.0 mmol) in CH2Cl2 (2.0 mL), which was pretreated with a premixed solution
(5 min at a ambient temperature) of [Cu(MeCN)4]PF6 (18.6 mg, 50 mol) and Box ligand 12 (11.8 mg, 50
mol) in CH2Cl2 (1.0 mL). After being stirred at 0 °C for 24 h, the workup and purification as above
described yielded 13 (115.7 mg, 69%, 75% ee, []D = 122.7).
tert-Butyl 3,4-dihydro-1-[(E)-styryl]isoquinoline-2(1H)-carboxylate (13). IR (neat)  1698 cm-1;
1H-NMR (300 MHz, CDCl3)  1.52 (s, 9H), 2.71-2.79 (m, 1H), 2.88-2.99 (m, 1H), 3.23-3.29 (m, 1H),
4.07-4.13 (m, 1H), 5.69-5.71 (m, 1H), 6.29 (dd, 1H, J = 15.8, 5.8 Hz), 6.40 (d, 1H, J = 15.8 Hz),
7.12-7.34 (m, 9H); 13C NMR (75 MHz, CDCl3)  28.5, 28.8, 79.9, 126.2, 126.3, 126.5, 126.8, 127.6,
128.1, 128.5, 128.9, 129.3, 131.1, 134.9, 134.9, 136.7, 154.7; FAB-LM m/z 336.4 (M+H+); FAB-HM
Calcd for C22H26NO2 336.1964. Found 336.1962. Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N, 4.18.
Found: C, 78.84; H, 7.63; N, 4.18.
Conversion of 13 to (R)-1,2,3,4-tetrahydro-1-phenethylisoquinoline (14). Under hydrogen atmosphere,
a solution of 13 (124.4 mg, 0.37 mmol, 75% ee) and 10% Pd-C (150 mg) was stirred at an ambient
temperature for 12 h. After concentration of the obtained filtrate by the removal of Pd-C, a solution of the
residue in CH2Cl2 (5.0 mL) was treated with TMSOTf (130 L, 0.72 mmol) at an ambient temperature for
10 min. The reaction mixture was quenched with sat. NaHCO3 and extrated with AcOEt. The combined
organic extracts was dried over anhydrous MgSO4 and concentrated on vacuo. The residue was purified
on silica gel column chromatography to give 14 (73.5 mg, 84%, []D = -18.9). 14 was identified by
1H-NMR spectrum reported in the literature.19

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ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific Research (C), Japan Society for the Promotion of
Science (No 22590016).
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