Ruthenium-catalyzed chemo-and enantioselective hydrogenation of isoquinoline carbocycles

Article abstract of DOI:10.1021/acs.joc.8b00190

A chemoselective hydrogenation of isoquinoline carbocycles was achieved by using the catalyst prepared from Ru(methallyl)₂(cod) and trans-chelate chiral ligand PhTRAP. The unique chemoselectivity achieved in this hydrogenation could be ascribed to the trans-chelation of the chiral ligand. The procedure for preparing the catalyst strongly affects the reproducibility of the carbocycle hydrogenation. Various 5-, 6-, 7-, and 8-substituted isoquinolines were selectively hydrogenated at their carbocycles to afford 5,6,7,8-tetrahydroisoquinolines as major products in high yields with moderate or good enantioselectivities. Some mechanistic studies suggested that the stereogenic center was created during the initial addition of H₂ to the aromatic ring in the hydrogenation of 5-substituted isoquinolines. In other words, the stereochemical control was accompanied by the dearomatization.

Full text of DOI:10.1021/acs.joc.8b00190

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Ruthenium-Catalyzed Chemo- and Enantioselective
Hydrogenation of Isoquinoline Carbocycles
Yushu Jin, Yusuke Makida, Tatsuya Uchida, and Ryoichi Kuwano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00190 • Publication Date (Web): 16 Mar 2018
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Ruthenium-Catalyzed Chemo- and Enantioselective Hydrogenation of Isoquinoline
Carbocycles
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Yushu Jin,† Yusuke Makida,† Tatsuya Uchida,‡,§ and Ryoichi Kuwano*,†
†Department of Chemistry, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku,
Fukuoka 819-0395, Japan
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‡International Institute for Carbon-Neutral Energy Research (I2CNER), Kyushu University, 744
Motooka, Nishi-ku, Fukuoka 819-0395, Japan
§Faculty of Arts and Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395,
Japan
TOC GRAPHIC
ABSTRACT
A chemoselective hydrogenation of isoquinoline carbocycles was achieved by using the
catalyst prepared from Ru(methallyl)2(cod) and trans-chelate chiral ligand PhTRAP. The unique
chemoselectivity achieved in this hydrogenation could be ascribed to the trans-chelation of the
chiral ligand. The procedure for preparing the catalyst strongly affects the reproducibility of the
carbocycle hydrogenation. Various 5-, 6-, 7-, and 8-substituted isoquinolines were selectively
hydrogenated at their carbocycles to afford 5,6,7,8-tetrahydroisoquinolines as major products in
high yields with moderate or good enantioselectivities. Some mechanistic studies suggested that
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the stereogenic center was created during the initial addition of H2 to the aromatic ring in the
hydrogenation of 5-substituted isoquinolines. In other words, the stereochemical control
accompanied with the dearomatization.
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INTRODUCTION
Hydrogenation of isoquinolines offers a straightforward and powerful approach for
constructing hydroisoquinoline structures. The heterocyclic structural motif is often seen in
biologically active compounds, such as isoquinoline alkaloids1 and drug candidates.2 The
reaction has been classically carried out with heterogeneous metal particle catalysts under harsh
reaction conditions,3,4 because the isoquinoline rings are unreactive to the hydrogenation due to
their own aromatic stabilization. Commonly, the dearomative reduction selectively takes place
on the pyridine ring to give 1,2,3,4-tetrahydroisoquinolines as the major product. Some
transition-metal complexes are also known to work as catalysts for the hydrogenation of
isoquinolines under mild conditions (Scheme 1a).5 With the homogeneous iridium catalyst,
Zhou5a,b,d,e,h and Mashima5c,f independently developed the hydrogenation of isoquinolines to
exclusively produce the 1,2,3,4-tetrahydroiqoquinolines with high enantioselectivities. Zhang
recently reported that a chiral rhodium catalyst is also useful for the transformation.5g
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Scheme 1. Chemo- and Enantioselective Hydrogenation of Isoquinolines
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8
9
Selective hydrogenation of the benzene ring in the isoquinoline may be unforeseen for
many chemists, because the carbocycle is much more stabilized with the aromaticity than the
heteroarene. Nevertheless, some catalysts are known to preferentially reduce the isoquinoline
carbocycles.3a,b,4,6 The chemoselective reduction of isoquinoline carbocycles is enabled by
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6a
3a,4a-e
RuH2(η2-H2)2(PCy3)2 as well as heterogeneous metal-supported catalysts, such as PtO2
and Raney Nickel.3b There has been no report on the enantioselective hydrogenation of
isoquinoline carbocycles, although the chiral 5,6,7,8-tetrahydroisoquinoline motifs are often used
as an important pharmacophore in drug development.7
A variety of substituted heteroarenes can be converted to the corresponding chiral
heterocycles with high enantioselectivities through the hydrogenation with asymmetric
catalysis.8 Meanwhile, enantioselective hydrogenation of carbocyclic arenes still remains one of
the formidable issues in asymmetric catalysis. In 2011, Glorius had reported the enantioselective
hydrogenation of quinoxaline carbocycles with a chiral NHC–ruthenium catalyst.9 This report is
the first success in the enantioselective hydrogenation of carbocyclic arenes with asymmetric
catalysis. Our group has also developed the asymmetric hydrogenations of naphthalenes10,11 and
quinoline carbocycles12 by using the ruthenium complex bearing chiral trans-chelate
bisphosphine ligand, (R,R)-2,2”-bis[(S)-(diphenylphosphino)ethyl-1,1”-biberrocene [(S,S)-(R,R)-
PhTRAP] (L1).13 It is noteworthy that the pyridine ring remained intact during the reduction
process in the asymmetric hydrogenation of quinolines. In this context, we applied the L1–
ruthenium catalyst to the chemo- and enantioselective hydrogenation of isoquinoline carbocycles
(Scheme 1b). The catalyst allowed the hydrogenation to proceed with no formation of 1,2,3,4-
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tetrahydroisoquinolines when 5- or 8-substituted isoquinolines were used as the substrate.
Furthermore, the ruthenium-catalyzed hydrogenation could provide the chiral 5,6,7,8-
tetrahydroisoquinolines with up to 91:9 enantiomer ratio (er).
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RESULTS AND DISCUSSION
Optimization of Procedure and Reaction Conditions. First, the hydrogenation of 5-
phenylisoquinoline (1a) was attempted in i-PrOH at 80 °C under 5.0 MPa of H2 for 24 h in the
presence of in situ generated Ru(methallyl)2(cod)–L1 catalyst as shown in Scheme 2. The
reaction condition is optimal for the selective hydrogenation of quinoline carbocycles.12 As with
the reaction of quinolines, the hydrogenation could take place on the carbocycle of 1a to give
5,6,7,8-tetrahydroisoquinoline 2a as the sole product in up to 37% NMR yield with 78:22 er, but
the hydrogenation lacked reproducibility. From the reaction mixture, the substrate–ruthenium
complex, RuCl2(1a)4, was isolated after a chromatographic purification. The formation of
RuCl2(1a)4 suggested that the chelation of L1 to the ruthenium might be obstructed by the strong
interaction between the isoquinoline and metal atom. Furthermore, the poor solubility of L1 in
the alcoholic solvent at ambient temperature might be disadvantageous for the complexation of
the ligand and the catalyst precursor.
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Scheme 2. Initial Attempts at the Hydrogenation of Isoquinoline Carbocycles
To overcome this difficulty, the preparation method of the L1–ruthenium catalyst was
investigated. The hydrogenation of 1a was attempted with [RuCl(p-cymene)(L1)]Cl catalyst,
which was employed for the enantioselective hydrogenation of naphthalenes (Table 1, entry 1).10
However, no hydrogenation was observed in the reaction mixture. Next, the catalyst was
prepared by mixing Ru(methallyl)2(cod) and L1 in i-PrOH in the absence of 1a for certain hours
(entries 2–6). When the solution of the catalyst precursor and L1 was stirred for 18 h, the
desired hydrogenation product 2a was obtained quantitatively with 79:21 er (entry 5). Various
solvents were next evaluated for the catalyst preparation (entries 7–9). Using CH2Cl2 or toluene
caused significant decrease in the yield of 2a, while the desired product was quantitatively
obtained with the L1–ruthenium catalyst prepared in THF. The catalyst efficiency was affected
by the premixing time in the case of preparing the catalyst in THF (entries 10 and 11). Even with
the catalyst prepared in THF, i-PrOH is the solvent of choice for the hydrogenation. The
hydrogenation in aprotic solvents including THF resulted in no or a little production of 2a
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(entries 12–14). Use of primary alcohols led to slight increase in the enantioselecitivity of the
hydrogenation, but it caused a deterioration of the catalytic activity (entries 15 and 16). The
hydrogenation scarcely proceeded in tert-amyl alcohol probably due to the poor solubility of
substrate and catalyst in this solvent (entry 17). Lowering the reaction temperature slightly
improved the enantioselectivity without loss of the chemoselectivity as well as the yield of 2a
(entry 18). It is noteworthy that no formation of 1,2,3,4-tetrahydroisoquinoline 3a was detected
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1
in the H NMR analyses of the crude mixtures in these experiments except for entry 13.
Moreover, the stereoselectivity was hardly affected by the reaction parameters.
Table 1. Optimization of Procedure and Reaction Parametersa
entry
x (h)
yield of 2a yield of 3a 2a:3ab
er of 2ac
A
B
(%)b
(%)b
1d
2
–
–
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
0
0
–
–
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
CH2Cl2
toluene
THF
0.5
4
0
0
–
–
3
13
2
>99e
76
8
0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
–
4
12
18
24
8
0
–
5
0
79:21
80:20
–
6
0
7
0
8
9f
8
11
>99e
0
–
8
0
79:21
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10f
11f
12
THF
THF
THF
THF
THF
THF
THF
THF
THF
4
i-PrOH
i-PrOH
THF
80
24
0
0
0
0
5
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0
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0
100:0
100:0
–
79:21
0.5
8
–
–
13
8
toluene
EtOAc
MeOH
EtOH
15
0
75:25
–
–
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14
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–
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15
8
31
53
0
100:0
100:0
–
81:19
82:18
–
16
8
17
18f,g
8
t-AmylOH
8
i-PrOH
>99e
100:0
80:20
aReaction were conducted on a 0.1 mmol scale under 5.0 MPa of H2 at 80 ˚C for 24 h unless otherwise noted. The
ratio of 1a (0.2 M)/Ru/L1/K2CO3 was 40/1.0/1.1/8.0. bDetermined by H NMR analysis. cDetermined by chiral
1
HPLC analysis. d[RuCl(p-cymene)(L1)]Cl (1.0 mmol%) was used in place of Ru(methallyl)2(cod)/L1. e2a was
f
g
isolated from the reaction mixture quantitatively. On a 0.2 mmol scale. At 60 ˚C.
Effect of Ligand on Chemoselectivity. To shed light on the origin of the unique
chemoselectivity, the hydrogenation of 1a was attempted by using various phosphine ligands in
place of L1 (Table 2). Monophosphine–ruthenium catalysts could reduce the isoquinoline, but
the reduction exclusively took place on the pyridine ring to give 1,2,3,4-tetrahydroisoquinoline
3a in low yield as the sole product (entry 1). The undesired 3a was also formed as the major
product when typical bidentate bisphosphines were employed as the ligand (entries 2–4). As
increasing in bite angle of the ligand, the ruthenium catalyst facilitated the hydrogenation of the
carbocycle. The use of Xantphos (L5), which was designed to chelate a metal atom with large
bite angle,14 resulted in slightly increasing the yield of 2a (entry 5). The chemoselectivity toward
the carbocycle reduction was remarkably enhanced by the catalyst composed of
Ru(methallyl)2(cod) and (R,R,R)-SKP (L6),15 which can form trans-chelate metal complex as
with L1. The reaction using L6 gave an approximately 1:1 mixture of 2a and 3a, and the
enantiomer ratio of 2a was moderate (entry 6). These results suggest that the extremely large
bite angle of L1 is crucial for the unusual chemoselectivity in the present reaction.
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Table 2. Effect of Ligand on the Chemoselectivity
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entry ligand yield of 2a (%)b yield of 3a (%)b 2a:3ab er of 2ac
d
1
2
3
4
5
6
7e
PPh3
L2
L3
L4
L5
L6
L1
0
21
21
92
77
49
44
0
0:100
0:100
2:98
–
–
–
–
–
0
2
5
6:94
9
16:84
54
>99f
55:45 70:30
100:0 79:21
aReactions were conducted on a 0.1 mmol scale under 5.0 MPa of H2 at 80 ˚C for 24 h unless otherwise noted. The
1
ratio of 1a (0.2 M)/Ru/L1/K2CO3 was 40/1.0/1.1/8.0. bDetermined by H NMR analysis. cDetermined by chiral
f
HPLC analysis. d5.5 mol% of PPh3 was used. eOn a 0.2 mmol scale. 2a was isolated from the reaction mixture
quantitatively.
Scope and Limitation. A series of 5- or 8-substituted isoquinolines were submitted to
the hydrogenation using PhTRAP–ruthenium catalyst (Table 3). In the hydrogenations of 5-
substituted isoquinolines 1a–1i, no formation of the undesired 1,2,3,4-tetrahydroisoquinolines
was observed in each reaction. The enantioselectivity of the reaction was affected by the
electronic property of the aryl group. The substrate 1b bearing p-anisyl group was converted to
2b in 96% yield with 87:13 er. The absolute configuration of the hydrogenation product was
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assigned to be S by its X-ray crystallography. Meanwhile, the trifluoromethyl group of 1c
caused the significant decrease in the enantioselectivity. The stereoselectivity was scarcely
affected by the methoxy group on the meta position in 1d. The alkyl-substituted carbocycles of
1e and 1f were also exclusively saturated in good enantioselectivities. The silyloxy group at the
benzylic position of 1g had little effect on the enantioselectivity. The product 2g could be
performed as a key intermediate for the syntheses of natural product dihydronitraraine.16
Methoxyisoquinoline 1h gave the chiral product 2h with 88:12 er, but the hydrogenation was
accompanied by the formation of 5,6,7,8-tetrahydroisoquinoline. The methoxy group in 2h
would readily undergo the hydrogenolysis because it is located on the benzylic position.12
Secondary amide is compatible with the ruthenium catalysis. The L1–ruthenium catalyst
converted 1i to 2i in 91% yield with moderate er.
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As with the reactions of 1a–1i, the reduction exclusively took places on the carbocycles
in the ruthenium-catalyzed hydrogenation of the 8-substituted isoquinolines 1j–1n. The reaction
of phenylisoquinoline 1j proceeded in poorer enantioselectivity than that of 1a. The
stereoselectivity was hardly affected by the electronic property of the aryl substituent. The
methoxy- and N-acylamidoisoquinolines 1m and 1n were transformed into 2m and 2n with good
enantiomer ratios, but the former product underwent the undesired hydrogenolysis. The latter
chiral amide may be a useful chiral building block for developing an aldosterone synthase
(CYP11B2) inhibitor, which may be used for the treatment of hypertension and renal disorders.7e
Table 3. Chemo- and Enantioselective Hydrogenation of 5- and 8-Substituted Isoquinolinesa
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aReactions were conducted on a 0.2 mmol scale in 1.0 mL i-PrOH at 60 ˚C for 24 h unless otherwise noted. The
ratio of 1/Ru/L1/K2CO3 was 40/1.0/1.1/8.0. Isolated yields of 2 were given in all cases. The enantiomer ratios were
determined by chiral HPLC analysis. bAt 80 ˚C. cThe hydrogenolysis product was formed in 15% and 11% NMR
d
6
yield from 2h and 2m, respectively. For 48 h.
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9
The L1–ruthenium catalyst is also applicable to the hydrogenation of 6- or 7-substituted
isoquinolines 1o–1t (Table 4). The reactions were carried out at higher temperature (80–100 °C)
to achieve complete conversion of the isoquinoline substrate. The substituent at 6- or 7-position
might hinder the catalytic reduction of the isoquinoline carbocycle. Furthermore, the undesired
1,2,3,4-tetrahydroisoquinolines 3 were formed as side products in considerable yields. The
reaction of 6-phenylisoquinoline (1o) give 2o in 85% yield with 91:9 er, but 3o was concurrently
formed in 12% NMR yield (entry 1). The methoxy group on the aryl substituent of 1p caused a
significant decrease in the chemoselectivity (entry 2). In contrast, the hydrogenation of
trifluoromethylated substrate 1q occurred on its isoquinoline carbocycle with high
chemoselectivity (entry 3). Both the methoxy and trifluoromethyl groups caused decrease in the
enantioselectivity. Methoxyisoquinoline 1r could be converted to 2r with good chemo- and
enantioselectivities, but its reactivity was much lower than other isoquinolines (entry 4). Poor
chemoselectivity was observed in the reaction of 7-phenylisoquinoline (1s) (entry 5), while 7-
methoxyisoquinoline 1t was converted to 2t in high yield without formation of 3t (entry 6).
Small amount (<5% yield) of the undesired hydrogenolysis product was detected in the
hydrogenation of 1r, while the side reaction was not observed at all in the reduction of 1t.
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Table 4. Chemo- and Enantioselective Hydrogenation of 6- and 7-Substituted Isoquinolinesa
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entry R1
R2
H
2:3b
yield of 2 (%)c er of 2d
1
1
Ph
88:12 85
63:37 61
95:5 91
87:13 41
69:31 67
100:0 93
91:9
1o
1p
1q
1r
1s
1t
2
4-MeOC6H4
H
87:13
87:13
81:19
82:18
71:29
3
4-CF3C6H4
H
4e
MeO
H
H
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5
Ph
6f
H
MeO
aReactions were conducted on a 0.2 mmol scale in 1.0 mL solvent at 100 ˚C for 24 h unless otherwise noted. The
ratio of 1/Ru/L1/K2CO3 was 40/1.0/1.1/8.0. bDetermied by H NMR analysis. cIsolated yields. dDetermined by
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e
chiral HPLC analysis. 61% conversion. The hydrogenolysis product was formed in 3% NMR yield. fAt 80 ˚C for
36 h.
Mechanistic Study. To get some mechanic insights of the ruthenium-catalyzed
hydrogenation of isoquinoline carbocycles, we conducted some reactions of 1a by using
deuterium-labelled compound. In eq. 1, the hydrogenation of 1a was carried out in 2-propanol-
d8. The reaction provided 2a in 92% yield with 82:28 er. No deuterium atom was incorporated
in the product. This observation suggests that the i-PrOH solvent did not participate in the
hydrogenation of isoquinoline carbocycles as a reducing agent. Next, the deuteration of 1a was
carried out in i-PrOH under 1.0 MPa of D2 at 80 °C for 72 h (eq. 2). The reaction provided a 2:1
mixture of the deuterated starting material 1a-D and the desired product 2a-D. In the product,
four deuterium atoms were incorporated at each of the 5-, 6-, 7-, and 8-positions on its
carbocycle. The former three deuterium atoms were positioned one another in cis-
configurations. Although the stereochemistry of the 8-position is impossible to be directly
assigned with the NMR analyses, it is deduced that the deuterium on C8 locates in the cis-
position to other deuterium atoms because the addition of H2 ordinarily proceeds through syn
stereochemistry. The deuterium distribution indicates that the hydrogenation of isoquinolines
proceeds through the pathway similar to that of quinolines.12 Three possible pathways can be
proposed for the hydrogenation of 1a as shown in Scheme 3. Path A starts from the addition of
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H2 across the less congested C7–C8 double bond to give achiral dihydroisoquinoline 4. If the
hydrogenation proceeded through path A, diastereoisomeric 6,7-trans-2a-D would also be
formed in the above deuteration of 1a (Chart 1). In the reaction, the intermediate 4-D resulting
from the first addition of D2 has two vicinal stereogenic centers. However, these stereogenic
centers are impossible to control the stereochemistry of the second addition of H2 to 4-D.
Therefore, path A is inconsistent with the result of eq. 2. Meanwhile, in path B or C, the
isoquinoline 1a is dearomatized through the hydrogenation of C5–C6 double bond or the 1,4-
addition of H2 to give the intermediate 5 or 6, respectively. In each case, the initial hydrogen
addition was accompanied by providing a new stereogenic center at the 5-position. The phenyl
substituent on the stereogenic center can sterically hinder the catalyst from accessing one of the
enantiofaces of remaining C–C double bond, leading to the selective formation of 2a-D with all
cis stereochemistry in the deuteration. Consequently, path B or C is more plausible than path A
in the present hydrogenation of isoquinoline carbocycles.
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The hydrogen atoms on the 1- and 3-carbons were significantly replaced by deuterium
ones in the product 2a-D in eq. 2.17 The H/D scrambling between D2 and the pyridine ring
would take place independently of the hydrogenation of the carbocycle, because it was observed
in the recovered starting material 1a-D. The deuterium atoms were incorporated into the
pyridine ring when the solution of the hydrogenation product 2a was exposed to pressurized D2
in the presence of L1–ruthenium catalyst (eq. 3). Consequently, the deuterium atoms on the
pyridine ring in the product 2a-D were installed before and after the reduction of the quinoline
carbocycle. Furthermore, these observations may suggest that the L1–ruthenium catalyst is
capable of cleaving the pyridine C–H bond through the oxidative addition.18
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Scheme 3. Three Possible Pathways for the Hydrogenation of Isoquinoline Carbocycles
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Chart 1
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CONCLUSION
We found that the hydrogenation of isoquinolines selectively took place on their
carbocycles with the ruthenium catalyst, which was generated in situ from Ru(methallyl)2(cod)
and optically active bisphosphine ligand, PhTRAP (L1). It is surprising that the heterocyclic
moiety of the isoquinoline remained intact in the reduction of the carbocycle, despite the fact that
pyridine is generally more reactive for the dearomative reaction than benzene. The bite angle of
the chelate bisphosphine ligand is crucial for achieving the unforeseen chemoselectivity. The
trans-chelation of L1 may lead to the selective formation of 5,6,7,8-tetrahydroisoquinolines.
With the L1–ruthenium catalyst, various 5- and 8-substituted isoquinoline carbocycles were
exclusively transformed into the corresponding 5,6,7,8-tetrahydroisoquinolines, while the
hydrogenations of 6- and 7-substituted isoquinolines proceed with moderate to high
chemoselectivities. Furthermore, the hydrogenation products were obtained with moderate to
good enantioselectivities (up to 91:9 er).
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EXPERIMENTAL SECTION
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General Information. All NMR spectra were measured with Bruker AVANCE 400 or AVANCE
III HD 400 Nanobay spectrometer. Optical rotations, IR spectra, and melting points were
measured with JASCO P-1020, JASCO FT/IR-4100, and Büchi Melting Point B-545,
respectively. Elemental analyses were performed by Service Centre of Elementary Analysis of
Organic Compounds, Kyushu University. High-resolution mass spectra (FAB) were measured
on a JEOL JMS-700 double-focusing mass spectrometer by Network Joint Research Center for
Materials and Devices (Institute for Materials Chemistry and Engineering, Kyushu University).
Unless otherwise noted, all reactions were carried out under nitrogen atmosphere in dry solvent.
Hydrogenations were conducted in stainless autoclaves. Ru(methallyl)2(cod),19 (S,S)-(R,R)-
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PhTRAP
(L1),13b
[RuCl(p-cymene)(L1)]Cl,20
5-phenylisoquinoline
(1a),21
8-
methoxyisoquinoline (1m),22 6-phenylisoquinoline (1o),23 6-methoxyisoquinoline (1r),24 and 7-
methoxyisoquinoline (1t)25 were prepared according to literature procedures. All other reagents
were purchased from commercial suppliers and used without further purification.
Preparation of Isoquinoline Substrates 1.
5-(4-Methoxyphenyl)isoquinoline (1b).26 A mixture of 5-bromoisoquinoline27 (416 mg, 2.0
mmol), 4-methoxyphenylboronic acid (456 mg, 3.0 mmol), Pd(PPh3)4 (116 mg, 0.10 mmol), and
Na2CO3 (382 mg, 3.6 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was stirred at 85 ˚C for
20 h. The resulting mixture was dilueted with water, and then extracted twice with EtOAc. The
combined organic layer was dried with Na2SO4, and then evaporated under reduced pressure.
The residue was purified with a flash column chromatography on alumina (EtOAc/Hexane = 1/5
1
to 1/3) to give 1b (416 mg, 1.8 mmol, 88%) as an off-white solid: H NMR (400 MHz, CDCl3,
TMS) δ 3.91 (s, 3H), 7.06 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.63–7.68 (m, 2H), 7.75
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(d, J = 6.1 Hz, 1H), 7.94–7.99 (m, 1H), 8.48 (d, J = 6.1 Hz, 1H), 9.30 (s, 1H); C {1H} NMR
(101 MHz, CDCl3) δ 55.2, 113.9, 118.5, 126.67, 126.73, 128.9, 130.7, 130.8, 131.2, 134.1,
138.7, 143.1, 152.7, 159.2.
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5-[4-(Trifluoromethyl)phenyl]isoquinoline (1c). The procedure for preparing 1b was followed
with use of 5-bromoisoquinoline27 (208 mg, 1.0 mmol) and 4-(trifluoromethyl)phenylbronic acid
(285 mg, 1.5 mmol). The crude product was purified with a flash column chromatography on
alumina (EtOAc/hexane = 1/5 to 1/3) to give 1c (272 mg, 1.0 mmol, >99%) as an off-white solid:
mp. 53.5–53.6 ˚C; 1H NMR (400 MHz, CDCl3, TMS) δ 7.59–7.72 (m, 5H), 7.79 (d, J = 8.0 Hz,
2H), 8.05 (ddd, J = 0.9, 1.6, 7.7 Hz, 1H), 8.52 (d, J = 6.0 Hz, 1H), 9.34 (s, 1H); C {1H} NMR
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(101 MHz, CDCl3) δ 117.9, 124.1 (q, J = 272 Hz), 125.5 (q, J = 4 Hz), 126.7, 127.9, 128.8,
129.9 (q, J = 33 Hz), 130.2, 130.9, 133.7, 137.6, 142.6, 143.7, 153.0; IR (thin film) 3046, 1617,
1325, 1166, 1123, 1067, 837, 762 cm–1; Anal. Calcd for C16H10F3N: C, 70.33; H, 3.69; N, 5.13.
Found: C, 70.29; H, 3.70; N, 5.17.
5-(3-Methoxyphenyl)isoquinoline (1d). The procedure for preparing 1b was followed with use
of 5-bromoisoquinoline27 (208 mg, 1.0 mmol) and 3-methoxyphenylbronic acid (228 mg, 1.5
mmol). The crude product was purified with a flash column chromatography on alumina
(EtOAc/hexane = 1/10 to 1/7) to give 1d (416 mg, 1.8 mmol, 88%) as an off-white solid: mp.
70.5–70.6 ˚C; 1H NMR (400 MHz, CDCl3, TMS) δ 3.87 (s, 3H), 6.69–7.03 (m, 2H), 7.07 (dt, J =
7.5, 1.2 Hz, 1H), 7.40–7.46 (m, 1H), 7.63–7.69 (m, 2H), 7.75 (dt, J = 6.0, 0.9 Hz, 1H), 7.97–8.02
(m, 1H), 8.49 (d, J = 6.0 Hz, 1H), 9.31 (d, J = 0.9 Hz, 1H); 13C {1H} NMR (101 MHz, CDCl3) δ
55.3, 113.2, 115.5, 118.5, 122.3, 126.7, 127.2, 128.9, 129.5, 130.7, 134.1, 139.0, 140.4, 143.4,
152.8, 159.6; IR (thin film) 3055, 2947, 2836, 1583, 1475, 1291, 1169, 1043, 790 cm–1; Anal.
Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.46; H, 5.57; N, 5.87.
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5-Cyclopentylisoquinoline (1e). The procedure for preparing 1b was followed with use of 5-
bromoisoquinoline27 (312 mg, 1.5 mmol) and 1-cyclopentenylbronic acid (252 mg, 2.3 mmol).
The crude product was purified with a flash column chromatography on silica gel
(EtOAc/hexane = 1/5 to 1/3) to give 5-(1-cyclopentenyl)isoquinoline (273 mg, 1.4 mmol, 93%)
as yellow oil.
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A suspension of 5-(1-cyclopentenyl)isoquinoline (195 mg, 1.0 mmol) and 5% palladium on
carbon (42.0 mg, 20 µmol) in MeOH (3.0 mL) was vigorously stirred under 1.0 MPa of H2 at
room temperature for 12 h. After the resulting mixture was filtered through a Celite pad, the
resulting filtrate was evaporated under reduced pressure. The residue was purified with column
chromatography on silica gel (EtOAc/Hexane = 1/3) to give 5-cyclopentylisoquinoline 1e (168
1
mg, 0.85 mmol, 85%) as colorless oil: H NMR (400 MHz, CDCl3) δ 1.70–1.94 (m, 6H), 2.15–
2.25 (m, 2H), 3.71 (quintet, J = 8.0 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H),
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7.81 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 6.1 Hz, 1H), 8.54 (d, J = 6.1 Hz, 1H), 9.24 (s, 1H); C
NMR (150 MHz, CDCl3) δ 25.3, 33.5, 40.7, 116.9, 125.7, 126.1, 126.9, 129.0, 134.8, 141.6,
142.8, 153.2; IR (neat): 2952, 2869, 1588, 1380, 1261, 1038, 907, 757 cm–1; HRMS (FAB) m/z:
[M+H]+ Calcd for C14H16N 198.1283; Found 198.1287.
5-Octylisoquinoline (1f). To a solution of 5-bromoisoquinoline27 (624 mg, 3.0 mmol),
PdCl2(PPh3)2 (105 mg, 0.15 mmol), and CuI (68.6 mg, 0.36 mmol) in MeCN (10 mL) were
added 1-octyne (0.88 mL, d 0.75 g/mL, 6.0 mmol) and Et3N (1.2 mL, d 0.73 g/mL, 9.0 mmol).
The reaction mixture was stirred at 90 ˚C for 12 h. The resulting mixture was diluted with
EtOAc and then filtered through a Celite pad. After diluted with water, the filtrate was extracted
twice with EtOAc. The combined organic layer was dried with Na2SO4, and then evaporated
under reduced pressure. The residue was purified with column chromatography on silica gel
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(EtOAc/Hexane = 1/7) to give 5-(1-octynyl)isoquinoline (719 mg) as brown oil. The product
was immediately used for the following step, because it is thermally unstable.
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A mixture of the brown oil (719 mg) and 5% palladium on carbon (120 mg, 60 µmol) in
MeOH (3.0 mL) was vigorously stirred under 2.0 MPa of H2 at 40 ˚C for 24 h. After the
resulting mixture was filtered through a Celite pad, the filtrate was evaporated under reduced
pressure. The residue was purified with column chromatography on silica gel (EtOAc/Hexane =
1/5) to give an E/Z isomeric mixture of 5-(1-octenyl)isoquinoline (568 mg, 2.4 mmol, 79% for
two steps, Z/E > 10/1) as yellow oil.
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A suspension of 5-(1-octenyl)isoquinoline (192 mg, 0.8 mmol) and 5% palladium on carbon
(Degussa type E, 105NN/W) (37.6 mg, 8.0 µmol) in MeOH (2.0 mL) was vigorously stirred
under 1.0 MPa of H2 at room temperature for 3 h. After the mixture was filtered through a Celite
pad, the filtrate was evaporated under reduced pressure. The residue was purified with a flash
column chromatography on silica gel (EtOAc/hexane = 1/3) to give 1f (185 mg, 0.77 mmol,
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96%) as colorless oil: H NMR (400 MHz, CDCl3, TMS) δ 0.88 (t, J = 6.9 Hz, 3H), 1.20–1.47
(m, 10H), 1.73 (quintet, J = 7.6 Hz, 2H), 3.03 (t, J = 7.8 Hz, 2H), 7.50–7.55 (m, 2H), 7.79–7.85
(m, 2H), 8.54 (d, J = 6.0 Hz, 1H), 9.24 (d, J = 0.8 Hz 1H); 13C {1H} NMR (101 MHz, CDCl3) δ
14.1, 22.6, 29.2, 29.4, 29.7, 30.7, 31.8, 32.3, 116.8, 125.8, 126.9, 129.0, 129.8, 134.6, 138.3,
142.9, 153.2; IR (neat) 2926, 2857, 1621, 1584, 1460, 1378, 821, 756 cm–1; Anal. Calcd for
C17H23N: C, 84.59; H, 9.60; N, 5.80. Found: C, 84.46; H, 9.60; N, 5.83.
5-(tert-Butyldimethylsilyloxymethyl)isoquinoline (1g). Methyl isoquinoline-5-carboxylate
was prepared with a modified procedure for the palladium-catalyzed alkoxycarbonylation of
bromoarenes.28 To a mixture of 5-bromoisoquinoline27 (624 mg, 3.0 mmol), Pd(OAc)2 (13.5 mg,
60 ꢀmol), and Xantphos (69.4 mg, 0.12 mmol) were added MeOH (1.2 mL, 30 mmol) and Et3N
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(6.0 mL) under CO atmosphere. The reaction mixture was stirred vigorously at 70 ˚C for 24 h.
After the mixture was filtered through a Celite pad, the filtrate was evaporated under reduced
pressure. The residue was purified with a flash column chromatography on silica gel
(EtOAc/hexane = 1/2) to give methyl isoquinoline-5-carboxylate (554 mg, 3.0 mmol, 99%) as a
pale yellow solid.
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A solution of methyl isoquinoline-5-carboxylate (187 mg, 1.0 mmol) in THF (4.0 mL) was
added dropwise to a suspension of LiAlH4 (75.9 mg, 2.0 mmol) in THF (4.0 mL) at ambient
temperature. The reaction mixture was stirred for 2 h. 1 N KOH aq. was carefully added to the
resulting mixture with vigorously stirring until the hydrogen gas evolution ceased. After stirred
for 10 min, the mixture was diluted with THF, and then filtered through a Celite pad. The filtrate
was dried with Na2SO4, and then evaporated under reduced pressure. The residue was used in
the next step without further purification.
To a solution of the residue in THF (5.0 mL) were added imidazole (81.7 mg, 1.2 mmol) and
TBDMSCl (181 mg, 1.2 mmol). The reaction mixture was stirred at ambient temperature for 24
h. After diluted with water, the resulting mixture was extracted twice with EtOAc. The
combined organic layer was dried with Na2SO4, and then evaporated under reduced pressure.
The residue was purified with a flash column chromatography on silica gel (EtOAc/hexane =
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1/5) to give 1g (234 mg, 0.86 mmol, 86% for two steps) as pale yellow oil: H NMR (400 MHz,
CDCl3, TMS) δ 0.13 (s, 6H), 0.95 (s, 9H), 5.16 (s, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.76–7.80 (m,
2H), 7.89 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 6.1 Hz, 1H), 9.26 (s, 1H); 13C {1H} NMR (101 MHz,
CDCl3) δ –5.3, 18.4, 25.9, 62.7, 116.4, 126.8, 126.9, 127.8, 128.6, 133.5, 136.1, 143.0, 153.0; IR
(neat) 2947, 2859, 1464, 1255, 1115, 1070, 838, 773 cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for
C16H24NOSi 274.1627; Found 274.1625.
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N-(5-Isoquinolinyl)propionamide (1i).29 To a solution of 5-aminoisoquinoline (216 mg, 1.5
mmol) in pyridine (1.5 mL) was added propionic anhydride (0.29 mL, d 1.01 g/mL, 2.3 mmol).
The reaction mixture was stirred at ambient temperature for 24 h. After diluted with water, the
resulting mixture was extracted twice with CH2Cl2. The combined organic layer was washed
twice with saturated Na2CO3 aq., dried with Na2SO4, and then filtered. The filtrate was
evaporated under reduced pressure to give 1i (246 mg, 1.2 mmol, 82%) as an off-white solid:
mp. 164.2–164.3 ˚C; 1H NMR (400 MHz, CDCl3, TMS) δ 1.36 (br t, J = 6.9 Hz, 3H), 2.58 (br q,
J = 7.2 Hz, 2H), 7.54 (br, 1H), 7.62 (t, J = 7.9 Hz, 2H), 7.83 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 7.4
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Hz, 1H), 8.57 (d, J = 5.9 Hz, 1H), 9.27 (s, 1H); C {1H} NMR (101 MHz, CDCl3) δ 9.8, 30.5,
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113.9, 124.7, 125.0, 127.2, 129.0, 129.7, 131.7, 143.1, 153.0, 172.7; IR (thin film) 3265, 2979,
1657, 1529, 1379, 1216, 813 cm–1; Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99.
Found: C, 71.79; H, 6.05; N, 13.95.
8-Phenylisoquinoline (1j).23 The procedure for preparing 1b was followed with use of 8-
bromoisoquinoline (208 mg, 1.0 mmol) and phenylboronic acid (183 mg, 1.5 mmol). The crude
product was purified with a flash column chromatography on silica gel (EtOAc/hexane = 1/5 to
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1/3) to give 1j (203 mg, 0.99 mmol, 99%) as a pale yellow oil: H NMR (400 MHz, CDCl3,
TMS) δ 7.45–7.55 (m, 6H), 7.69–7.76 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 5.5 Hz,
1H), 9.31 (s, 1H); 13C {1H} NMR (101 MHz, CDCl3) δ 120.5, 126.0, 126.7, 127.9, 128.2, 128.5,
129.9, 130.1, 136.2, 138.7, 141.1, 142.8, 151.2.
8-(4-Methoxyphenyl)isoquinoline (1k).30 The procedure for preparing 1b was followed with
use of 8-bromoisoquinoline (208 mg, 1.0 mmol) and 4-methoxyphenylboronic acid (228 mg, 1.5
mmol). The crude product was purified with a flash column chromatography on silica gel
(EtOAc/hexane = 1/5 to 1/3) to give 1k (221mg, 0.94 mmol, 94%) as a pale yellow solid: mp.
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(d, J = 8.7 Hz, 2H), 7.51 (dd, J = 7.0, 1.1 Hz, 1H), 7.68–7.74 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H),
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8.54 (d, J = 5.7 Hz, 1H), 9.34 (s, 1H); C {1H} NMR (101 MHz, CDCl3) δ 55.4, 114.0, 120.5,
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125.6, 126.8, 128.1, 129.9, 131.0, 131.2, 136.2, 140.7, 142.8, 151.3, 159.4; IR (thin film) 3050,
1612, 1387, 838, 758, 699 cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for C15H12N 206.0970; Found
206.0996.
8-[4-(Trifluoromethyl)phenyl]isoquinoline (1l). The procedure for preparing 1b was followed
with use of 8-bromoisoquinoline (208 mg, 1.0 mmol) and 4-(trifluoromethyl)phenylboronic acid
(285 mg, 1.5 mmol). The crude product was purified with a flash column chromatography on
silica gel (EtOAc/hexane = 1/5 to 1/3) to give 1l (234.7 mg, 0.86 mmol, 86%) as a colorless
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solid: mp. 72.9–73.0 ˚C; H NMR (400 MHz, CDCl3, TMS) δ 7.53 (dd, J = 1.1, 7.1 Hz, 1H),
7.65 (d, J = 8.0 Hz, 2H), 7.72–7.82 (m, 4H), 7.89 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 5.6 Hz, 1H),
9.24 (s, 1H); C {1H} NMR (101 MHz, CDCl3) δ 120.6, 124.1 (q, J = 272 Hz), 125.5 (q, J = 4
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Hz), 126.4, 126.8, 128.3, 129.8, 130.2 (q, J = 33 Hz), 130.4, 136.2, 139.4, 142.4, 143.2, 150.6;
IR (KBr pellet) 3049, 1613, 1401, 1326, 1165, 1114, 1064, 838 cm–1; Anal. Calcd for C16H10F3N:
C, 70.33; H, 3.69; N, 5.13. Found: C, 70.27; H, 3.65; N, 5.15.
N-(8-Isoquinolinyl)propionamide (1n). The procedure for preparing 1i was followed with use
of 8-aminoisoquinoline (216 mg, 1.5 mmol). The crude product was purified with a flash
column chromatography on silica gel (EtOAc/hexane = 1/1 to 2/1 to EtOAc) to give 1n (276 mg,
1.4 mmol, 92%) as an off-white solid: mp. 138.7–138.8 ˚C; 1H NMR (400 MHz, CDCl3, TMS) δ
1.32 (br t, J = 6.8 Hz, 3H), 2.57 (br q, J = 6.8 Hz, 2H), 7.58–7.68 (br m, 3H), 7.98 (br d, J = 5.1
Hz, 1H), 8.18 (br s, 1H), 8.52 (br d, J = 5.6 Hz, 1H), 9.37 (s, 1H); C {1H} NMR (101 MHz,
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CDCl3) δ 9.7, 30.1, 120.6, 122.5 (2C), 123.7, 130.4, 133.7, 136.3, 142.5, 146.8, 173.6; IR (thin
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film) 3276, 3060, 2984, 1663, 1540, 1403, 1213, 835 cm–1; Anal. Calcd for C12H12N2O: C,
71.98; H, 6.04; N, 13.99. Found: C, 72.05; H, 6.01; N, 13.98.
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6-(4-Methoxyphenyl)isoquinoline (1p).31 The procedure for preparing 1b was followed with
use of 6-bromoisoquinoline (416 mg, 2.0 mmol) and 4-methoxyphenylboronic acid (456 mg, 3.0
mmol). The crude product was purified with a flash column chromatography on alumina
(EtOAc/hexane = 1/7 to 1/5) to give 1p (428 mg, 1.8 mmol, 91%) as an off-white solid: 1H NMR
(400 MHz, CDCl3, TMS) δ 3.89 (s, 3H), 7.05 (d, J = 8.8 Hz, 2H), 7.65–7.70 (m, 3H), 7.85 (dd, J
= 1.8, 8.5 Hz, 1H), 7.95 (br s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 8.53 (d, J = 5.9 Hz, 1H), 9.25 (s,
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1H); C {1H} NMR (101 MHz, CDCl3) δ 55.4, 114.5, 120.5, 123.3, 126.9, 127.5, 128.1, 128.7,
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132.6, 136.2, 142.6, 143.4, 152.2, 159.9.
6-[4-(Trifluoromethyl)phenyl]isoquinoline (1q). The procedure for preparing 1b was followed
with use of 6-bromoisoquinoline (312 mg, 1.5 mmol), and 4-(trifluoromenthyl)phenylboronic
acid (427 mg, 2.3 mmol). The crude product was purified with a flash column chromatography
on silica gel (EtOAc/hexane = 1/3 to 1/2) to give 1q (373 mg, 1.4 mmol, 91%) as an off-white
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solid: mp. 70.3–70.4 ˚C; H NMR (400 MHz, CDCl3, TMS) δ 7.71–7.87 (m, 6H), 8.03 (s, 1H),
8.09 (d, J = 8.5 Hz, 1H), 8.59 (d, J = 5.8 Hz, 1H), 9.31 (s, 1H); C {1H} NMR (101 MHz,
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CDCl3) δ 120.6, 124.1 (q, J = 272 Hz), 124.8, 125.9 (q, J = 4 Hz), 126.7, 127.88, 127.94, 128.5,
130.2 (q, J = 32 Hz), 135.9, 141.5, 143.68, 143.73, 152.3; IR (KBr pellet) 3057, 1619, 1411,
1331, 1161, 1109, 1067, 836 cm–1; Anal. Calcd for C16H10F3N: C, 70.33; H, 3.69; N, 5.13.
Found: C, 70.19; H, 3.70; N, 5.13.
7-Phenylisoquinoline (1s).30 The procedure for preparing 1b was followed with use of 7-
bromoisoquinoline (208 mg, 1.0 mmol) and phenylboronic acid (183 mg, 1.5 mmol). The crude
product was purified with a flash column chromatography on silica gel (EtOAc/hexane = 1/5 to
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1/3) to give 1s (161 mg, 0.79 mmol, 79%) as an off-white solid: mp. 91.5–91.6 ˚C; H NMR
(400 MHz, CDCl3, TMS) δ 7.42 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.68 (d, J = 5.8 Hz,
1H), 7.71–7.75 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 1.8, 8.6 Hz, 1H), 8.17 (br m, 1H),
8.54 (d, J = 5.7 Hz, 1H), 9.33 (s, 1H); 13C {1H} NMR (101 MHz, CDCl3) δ 120.2, 125.3, 127.0,
127.4, 127.9, 129.0, 130.1, 134.9, 140.13, 140.19, 143.1, 152.8; IR (KBr pellet) 3006, 1581,
1481, 1348, 1222, 1025, 938, 799, 755 cm–1; Anal. Calcd for C15H11N: C, 87.77; H, 5.40; N,
6.82. Found: C, 87.51; H, 5.40; N, 6.84.
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General Procedure for the Chemo- and Enantioselective Hydrogenation of Isoquinolines 1.
In a nitrogen-filled drybox, a mixture of Ru(methallyl)2(cod) (1.6 mg, 5.0 µmol) and (S,S)-(R,R)-
PhTRAP (L1) (4.4 mg, 5.5 µmol) in THF (1.0 mL) was stirred at ambient temperature for 8 h.
The solvent was then removed in vacuo. To the residue were added K2CO3 (5.6 mg, 40 µmol),
isoquinoline 1 (0.2 mmol), and i-PrOH (1.0 mL). After removed from the drybox, the mixture
was transferred into a nitrogen-purged stainless autoclave. After the autoclave was charged with
5.0 MPa of H2, the reaction mixture was vigorously stirred at 60–100 ˚C for 24–48 h. The
resulting mixture was evaporated under reduced pressure. The residue was purified with a
column chromatography on silica gel (EtOAc/hexane or CH2Cl2/MeOH) to give the desired
5,6,7,8-tetrahydroisoquinoline 2.
(+)-5-Phenyl-5,6,7,8-tetrahydroisoquinoline (2a). The general procedure was followed with
use of 5-phenylisoquinoline (1a) (41.0 mg, 0.20 mmol). The reaction was carried out at 60 ˚C
for 24 h. The crude product was purified with a column chromatography on silica gel
(EtOAc/hexane = 1/3 to 1/2) to give 2a (41.8 mg, 0.20 mmol, >99%) as an off-white solid:
[α]D28 +16.2 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3, TMS) δ 1.74–1.92 (m, 2H), 1.92–2.02
(m, 1H), 2.15–2.23 (m, 1H), 2.80–2.95 (m, 2H), 4.04 (t, J = 6.9 Hz, 1H), 6.73 (d, J = 5.2 Hz,
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1H), 7.06–7.10 (m, 1H), 7.21–7.26 (m, 1H), 7.28–7.33 (m, 2H), 8.22 (d, J = 5.2 Hz, 1H), 8.39 (d,
J = 0.6 Hz, 1H); 13C {1H} NMR (101 MHz, CDCl3) δ 20.8, 26.5, 32.6, 45.1, 124.4, 126.4, 128.5,
128.7, 133.1, 145.5, 146.7, 148.2, 150.5; IR (thin film) 2934, 2863, 1593, 1488, 1444, 1411, 831,
753, 700 cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for C15H16N 210.1283; Found 210.1315. The
enantiomer ratio of 2a was determined to be (+):(–) = 80:20 (60% ee) by the HPLC analysis with
Chiralcel OD-H.
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(S)-5-(4-Methoxyphenyl)-5,6,7,8-tetrahydroisoquinoline (2b). The general procedure was
followed with use of 5-(4-methoxyphenyl)isoquinoline (1b) (47.1 mg, 0.20 mmol). The reaction
was carried out at 60 ˚C for 24 h. The crude product was purified with a column
chromatography on silica gel (EtOAc/hexane = 1/5 to 1/3) to give 2b (45.9 mg, 0.19 mmol,
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96%) as an off-white solid: [α]D +35.2 (c 1.01, CHCl3); H NMR (400 MHz, CDCl3, TMS) δ
1.72–1.89 (m, 2H), 1.91–2.01 (m, 1H), 2.11–2.20 (m, 1H), 2.78–2.93 (m, 2H), 3.80 (s, 3H), 3.99
(t, J = 6.7 Hz, 1H), 6.74 (d, J = 5.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H),
8.22 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H); C {1H} NMR (101 MHz, CDCl3) δ 20.9, 26.5, 32.7,
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44.3, 55.2, 113.8, 124.4, 129.6, 133.1, 137.6, 146.7, 148.6, 150.4, 158.2; IR (thin film) 2936,
2861, 1604, 1509, 1247, 1177, 1034, 829 cm–1; Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N,
5.85. Found: C, 80.13; H, 7.15; N, 5.90. The enantiomer ratio of 2b was determined to be
(S):(R) = 87:13 (74% ee) by the HPLC analysis with Chiralcel OD-H. The absolute
configuration of 2b was determined to be S by its X-ray crystallography. Suitable crystals of 2b
for the diffraction study were obtained from its solution in MeOH by slow evaporation. All
measurements as well as refinement details are given in Supporting Information and its CIF file,
which have been deposited with the Cambridge Crystallographic Data Centre (CCDC 1586482).
(+)-5-[4-(Trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinoline (2c).
The general
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procedure was followed with use of 5-[4-(trifluoromethyl)phenyl]isoquinoline (1c) (54.7 mg,
0.20 mmol). The reaction was carried out at 60 ˚C for 24 h. The crude product was purified with
a column chromatography on silica gel (EtOAc/hexane = 1/5 to 1/3) to give 2c (51.0 mg, 0.18
mmol, 92%) as pale yellow oil: [α]D27 +5.0 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3, TMS)
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δ 1.75–1.90 (m, 2H), 1.92–2.01 (m, 1H), 2.15–2.25 (m, 1H), 2.82–2.96 (m, 2H), 4.12 (t, J = 6.8
Hz, 1H), 6.69 (d, J = 5.1 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 8.24 (d, J =
5.1 Hz, 1H), 8.42 (s, 1H); 13C {1H} NMR (101 MHz, CDCl3) δ 20.7, 26.4, 32.5, 45.0, 124.1 (q, J
= 272 Hz), 124.2, 125.5 (q, J = 4 Hz), 128.8 (q, J = 32 Hz), 129.0, 133.2, 146.9, 147.1, 149.6,
150.7; IR (neat) 2939, 2866, 1693, 1593, 1414, 1325, 1120, 836 cm–1; HRMS (FAB) m/z:
[M+H]+ Calcd for C16H15F3N 278.1157; Found 278.1165. The enantiomer ratio of 2c was
determined to (+):(–) = 70:30 (40% ee) by the HPLC analysis with Chiralcel OD-H.
(+)-5-(3-Methoxyphenyl)-5,6,7,8-tetrahydroisoquinoline (2d). The general procedure was
followed with use of 5-(3-methoxyphenyl)isoquinoline (1d) (47.1 mg, 0.20 mmol). The reaction
was carried out at 80 ˚C for 24 h. The crude product was purified with a column
chromatography on silica gel (EtOAc/hexane = 1/2) to give 2d (45.0 mg, 0.19 mmol, 94%) as
pale brown oil: [α]D28 +14.1 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3, TMS) δ 1.73–1.92 (m,
2H), 1.93–2.02 (m, 1H), 2.14–2.23 (m, 1H), 2.79–2.94 (m, 2H), 3.77 (s, 3H), 4.01 (t, J = 7.0 Hz,
1H), 6.62 (t, J = 2.1 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 6.78 (ddd, J =
0.8, 2.6, 8.2 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 8.22 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H); C {1H}
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NMR (101 MHz, CDCl3) δ 20.9, 26.5, 32.4, 45.2, 55.1, 111.4, 114.8, 121.1, 124.4, 129.4, 133.1,
146.7, 147.1, 148.1, 150.4, 159.7; IR (neat) 2936, 2863, 1592, 1485, 1442, 1257, 1159, 1046,
837, 781, 705 cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for C16H18NO 240.1388; Found 240.1394.
The enantiomer ratio of 2d was determined to be (+):(–) = 80:20 (59% ee) by the HPLC analysis
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(–)-5-Cyclopentyl-5,6,7,8-tetrahydroisoquinoline (2e). The general procedure was followed
with use of 5-cyclopentylisoquinoline (1e) (39.5 mg, 0.20 mmol). The reaction was carried out
at 80 ˚C for 24 h. The crude product was purified with a column chromatography on silica gel
(EtOAc/hexane = 1/3) to give 2e (39.8 mg, 0.20 mmol, 99%) as a pale yellow oil: [α]D27 –12.5 (c
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1.02, CHCl3); 1H NMR (400 MHz, CDCl3, TMS) δ 1.11–1.22 (m, 1H), 1.31–1.42 (m, 1H), 1.43–
1.59 (m, 2H), 1.59–1.83 (m, 7H), 1.88–1.99 (m, 1H), 2.04–2.16 (m, 1H), 2.64 (dt, J = 8.1, 5.2
Hz, 1H), 2.72 (dt, J = 16.5, 6.8, Hz, 1H), 2.77 (dt, J = 16.5, 6.1, Hz, 1H), 7.07 (d, J = 5.2 Hz,
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1H), 8.26 (d, J = 5.2 Hz, 1H), 8.29 (s, 1H); C NMR (101 MHz, CDCl3) δ 19.1, 24.7, 25.29,
25.33, 26.1, 29.5, 31.5, 41.8, 44.3, 123.6, 132.8, 146.0, 149.9, 150.4; IR (neat) 2946, 2867, 1684,
1593, 1442, 1412, 1284, 827 cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for C14H20N 202.1596;
Found 202.1608. The enantiomer ratio of 2e was determined to be (–):(+) = 88:12 (75% ee) by
the HPLC analysis with Chiralpak AD-H.
(–)-5-Octyl-5,6,7,8-tetrahydroisoquinoline (2f). The general procedure was followed with use
of 5-octylisoquinoline (1f) (48.3 mg, 0.20 mmol). The reaction was carried out at 80 ˚C for 24 h.
The crude product was purified with a column chromatography on silica gel (EtOAc/hexane =
1/3) to give 2f (47.1 mg, 0.19 mmol, 96%) as colorless oil: [α]D27 –7.8 (c 1.02, CHCl3); 1H NMR
(400 MHz, CDCl3, TMS) δ 0.88 (t, J = 6.9 Hz, 3H), 1.20–1.47 (m, 12H), 1.48–1.59 (m, 1H),
1.60–1.77 (m, 3H), 1.81–1.93 (m, 2H), 2.65–2.79 (m, 3H), 7.06 (d, J = 5.1 Hz, 1H), 8.26–8.33
(m, 2H); 13C {1H} NMR (101 MHz, CDCl3) δ 14.1, 19.7, 22.6, 26.6, 26.9, 27.1, 29.3, 29.5, 29.8,
31.9, 36.0, 37.0, 123.0, 132.8, 146.6, 150.3, 150.4; IR (neat) 2926, 2857. 1639, 1598, 1458, 826
cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for C17H28N 246.2222; Found 246.2223. The
enantiomer ratio of 2f was determined to be (–):(+) = 86:14 (71% ee) by the HPLC analysis with
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(+)-5-(tert-Butyldimethylsilyloxymethyl)-5,6,7,8-tetrahydroisoquinoline (2g). The general
procedure was followed with use of 5-(tert-butyldimethylsilyloxymethyl)isoquinoline (1g) (54.7
mg, 0.20 mmol). The reaction was carried out at 80 ˚C for 24 h. The crude product was purified
with a column chromatography on silica gel (EtOAc/hexane = 1/5) to give 2g (54.9 mg, 0.20
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mmol, 99%) as colorless oil: [α]D +3.3 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3, TMS) δ
0.02 (s, 3H), 0.04 (s, 3H), 0.89 (s, 9H), 1.69–1.93 (m, 4H), 2.65–2.79 (m, 2H), 2.87–2.95 (m,
1H), 3.67 (dd, J = 7.9, 10.0 Hz, 1H), 3.76 (dd, J = 5.5, 10.0 Hz, 1H), 7.14 (d, J = 5.1 Hz, 1H),
8.29 (d, J = 5.1 Hz, 1H), 8.31 (s, 1H); C {1H} NMR (101 MHz, CDCl3) δ –5.5, –5.4, 18.3,
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19.3, 24.6, 25.9, 26.6, 39.8, 66.7, 123.7, 133.5, 146.45, 146.47, 150.4; IR (neat) 2936, 2861,
1598, 1465, 1409, 1254, 1099, 837, 776 cm–1; HRMS (FAB) m/z: [M+H]+ Calcd for C16H28NOSi
278.1940; Found 278.1942. The enantiomer ratio of 2g was determined to be (+):(–) = 87:13
(73% ee) by the HPLC analysis with Chiralpak AD-H.
(–)-5-Methoxy-5,6,7,8-tetrahydroisoquinoline (2h). The general procedure was followed with
use of 5-methoxyisoquinoline (1h) (31.8 mg, 0.20 mmol). The reaction was carried out at 80 ˚C
for 24 h. The crude product was purified with a column chromatography on silica gel
(EtOAc/hexane = 1/3 to 1/1) to give 2h (27.4 mg, 0.17 mmol, 84%) as colorless oil: [α]D28 –20.8
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(c 0.98, CHCl3); H NMR (400 MHz, CDCl3, TMS) δ 1.71–1.83 (m, 1H), 1.85–1.95 (m, 1H),
1.96–2.08 (m, 2H), 2.71 (dt, J = 16.9, 6.1 Hz, 1H), 2.81 (dt, J = 16.9, 6.2 Hz, 1H), 3.48 (s, 3H),
4.29 (dd, J = 4.0, 6.8 Hz, 1H), 7.29 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H), 8.40 (d, J = 5.1 Hz, 1H);
13C {1H} NMR (101 MHz, CDCl3) δ 18.8, 25.9, 26.9, 56.5, 75.8, 122.8, 132.6, 145.2, 147.0,
150.5; IR (neat) 2941, 1640, 1417, 1350, 1280, 1193, 1094 cm–1; HRMS (FAB) m/z: [M+H]+
Calcd for C10H14NO 164.1075; Found 164.1076. The enantiomer ratio of 2h was determined to
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(+)-N-(5,6,7,8-Tetrahydroisoquinolin-5-yl)propionamide (2i). The general procedure was
followed with use of N-(5-isoquinolinyl)propionamide (1i) (40.0 mg, 0.20 mmol). The reaction
was carried out at 60 ˚C for 48 h. The crude product was purified with a column
chromatography on silica gel (EtOAc/hexane = 1/1 to EtOAc to CH2Cl2/MeOH = 20/1) to give
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1
2i (37.3 mg, 0.18 mmol, 91%) as a pale brown solid: [α]D +59.4 (c 1.04, CHCl3); H NMR
(400 MHz, CDCl3, TMS) δ 1.21 (t, J = 7.6 Hz, 3H), 1.65–1.75 (m, 1H), 1.81–1.97 (m, 2H),
2.08–2.17 (m, 1H), 2.28 (q, J = 7.6 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 5.20 (dt, J = 5.6, 8.3 Hz,
1H), 5.64 (br d, J = 8.6 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 8.33–8.38 (m, 2H); C {1H} NMR
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(101 MHz, CDCl3) δ 9.9, 20.1, 25.9, 29.64, 29.70, 46.4, 122.3, 132.8, 146.0, 147.0, 150.2, 173.5;
IR (thin film) 3281, 3061, 2940, 1648, 1546, 1455, 1235, 1111, 1063, 831 cm–1; HRMS (FAB)
m/z: [M+H]+ Calcd for C12H17N2O 205.1341; Found 205.1340. The enantiomer ratio of 2i was
determined to be (+):(–) = 79:21 (59% ee) by the HPLC analysis with Chiralpak ID.
(–)-8-Phenyl-5,6,7,8-Tetrahydroisoquinoline (2j). The general procedure was followed with
use of 8-phenylisoquinoline (1j) (41.0 mg, 0.20 mmol). The reaction was carried out at 60 ˚C for
24 h. The crude product was purified with a column chromatography on silica gel
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(EtOAc/hexane = 1/3 to 1/2) to give 2j (40.6 mg, 0.19 mmol, 97%) as an off-white solid: [α]D
1
–3.5 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3, TMS) δ 1.71–1.82 (m, 1H), 1.84–1.95 (m,
2H), 2.13–2.22 (m, 1H), 2.80 (dt, J = 17.7, 5.9 Hz, 1H), 2.89 (dt, J = 17.7, 6.8 Hz, 1H), 4.14 (t, J
= 6.6 Hz, 1H), 7.04 (d, J = 5.0 Hz, 1H), 7.07 (d, J = 7.0 Hz, , 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.29
(t, J = 7.3 Hz, 2H), 8.08 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H); C {1H} NMR (101 MHz, CDCl3) δ
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20.0, 28.9, 32.7, 42.8, 123.6, 126.3, 128.4, 128.6, 135.2, 146.0, 146.4, 146.6, 151.7; IR (thin
film) 2934, 1635, 1488, 1414, 751, 697 cm–1; Anal. Calcd for C15H15N: C, 86.08; H, 7.22; N,
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