An expeditious approach to 1-aminoisoquinolines via an unexpected reaction of 2-alkynylbenzaldoxime, carbodiimide, with bromine

Article abstract of DOI:10.1016/j.tet.2011.04.063

A three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, and bromine provides a novel and efficient approach to functionalized 1-aminoisoquinolines. This unexpected reaction proceeds through electrophilic cyclization, [3+2] cycloaddition, rearra

Full text of DOI:10.1016/j.tet.2011.04.063

Tetrahedron 67 (2011) 4628e4632
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An expeditious approach to 1-aminoisoquinolines via an unexpected reaction
of 2-alkynylbenzaldoxime, carbodiimide, with bromine
,b,
Shengqing Ye a, Huanhuan Wang a, Jie Wu a
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2011
Received in revised form 8 April 2011
Accepted 15 April 2011
Available online 21 April 2011
A three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, and bromine provides a novel and
efficient approach to functionalized 1-aminoisoquinolines. This unexpected reaction proceeds through
electrophilic cyclization, [3þ2] cycloaddition, rearrangement and hydrolyzation.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylbenzaldoxime
1-Aminoisoquinoline
Bromine
Carbodiimide
Three-component reaction
1. Introduction
of large amount of phosphonium salt to promote the reaction with
the corresponding N-oxides. Thus, development of novel and effi-
Isoquinolines are ubiquitous features in many nature products
and small molecule chemotherapeutics.1 Among the family of iso-
quinolines, 1-aminoisoquinolines have attracted less attention al-
though remarkable biological activities have been displayed for this
kind of compound. For instance, it was reported that 1-amino-
isoquinolines could serve as selective inhibitors of mutant protein
kinase and anti-tumor reagents.2 They are also valuable in-
termediates in organic synthesis, since they are easily converted
into functionalized isoquinolines. So far, several methods have
appeared for the formation of 1-aminoisoquinoline derivatives,
such as substitutional reaction of 1-haloisoquinolines by amines,3
or transition metal-catalyzed cross-coupling reactions of 1-hal-
oisoquinolines with amines.4 However, the methods usually re-
quired high temperature, strong base, or expensive metal catalysts.
Additionally, toxic compounds, such as POCl3 are inevitable for
1-haloisoquinolines formation,5 which restricts the generation of
a collection of structurally complex and diverse 1-aminoisoquino-
lines. Recently Londregan and co-workers reported the synthesis of
2-aminopyridines through the phosphonium salt activated reaction
of pyridine-N-oxide with amine.6 In this reaction, one example was
presented for the generation of 1-aminoisoquinoline under the
standard conditions. However, this method required the utilization
cient routes under mild conditions for the preparation of func-
tionalized 1-aminoisoquinolines is highly desirable.
Recently, we reported an efficient pathway for the generation of
1-(isoquinolin-1-yl)ureas7a via three-component reaction of 2-
alkynylbenzaldoxime, carbodiimide, with electrophile (bromine or
iodine monochloride) under mild conditions (Scheme 1).7b The
reaction proceeded smoothly at room temperature in the presence
of DABCO as a base in CH2Cl2/DMF. Only a trace amount of product
was detected without the addition of base when the reaction was
performed in CH2Cl2. The desired product could be isolated as well
when DMF was used as the co-solvent, along with a new product
with a trace amount. In this reaction, we conceived that the pres-
ence of a base or Lewis base (such as DMF) served as a scavenging
agent of HX (X¼Br or Cl). However, what was the new product
formed simultaneously? With these considerations in mind, thus
we started to explore the possibility of this transformation.
O
R3
R3
OH
R2
N
N
H
Br2
C
N
DABCO, rt
R1
R3
N
+
N
R1
CH2Cl2, DMF
ref 7b
N
R3
R2
Br
Scheme 1. Three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, and
* Corresponding author. E-mail address: jie_wu@fudan.edu.cn (J. Wu).
bromine.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.063

S. Ye et al. / Tetrahedron 67 (2011) 4628e4632
4629
Table 2
2. Results and discussion
Synthesis of 1-aminoisoquinoline 3 via three-component reaction of 2-alkyny-
benzaldoxime 1, carbodiimide 2, and bromine
The initial attempt was carried out with the three-component
reaction of 2-alkynylbenzaldoxime 1a, carbodiimide 2a, and bro-
mine (Table 1). When dichloroethane (DCE) was utilized as the co-
solvent in the reaction at room temperature, to our surprise, we did
not obtain the desired 1-(isoquinolin-1-yl)urea product. The new
compound was generated, whereas in low yield (8%), and the struc-
ture was identified as 1-aminoisoquinoline 3a. The yield increased to
52% when the reaction occurred at 60 ꢀC. With this interesting result
in hand, we further screened other solvents. It was found that the
reaction worked the most efficiently when 1,4-dioxane was used as
the co-solvent, which generated compound 3a in 86% yield (Table 1,
entry 7). Although it is no doubt that 1-aminoisoquinoline 3a was
furnished via hydrolyzation of the corresponding 1-(isoquinolin-1-
yl)urea,8 this reaction provides a novel and expeditious approach to
1-aminoisoquinolines with high efficiency under mild conditions.
Additionally, heavy metal salts and harsh reaction conditions are
avoided compared with previous reports.3,4 In the reaction process,
we reasoned that HBr generated in situ might play the key role for the
hydrolyzation of 1-(isoquinolin-1-yl)urea. Usually, high temperature
or oxidant is required for cleavage of ureas.8,9 It seems that the ad-
vantage of the mild conditions presented here is clear, which pro-
vides an alternative route for hydrolysis of ureas.
Entry
R1, R2
R3
Yield (%)a
1
2
3
4
5
6
7
8
H, Ph (1a)
H, Ph (1a)
5-F, Ph (1b)
5-F, Ph (1b)
4-F, Ph (1c)
4-F, Ph (1c)
5-Cl, Ph (1d)
5-Cl, Ph (1d)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
Cy (2a)
i-Pr (2b)
86 (3a)
63 (3b)
98 (3c)
80 (3d)
78 (3e)
68 (3f)
77 (3g)
94 (3h)
66 (3i)
72 (3j)
41 (3k)
82 (3l)
70 (3m)
68 (3n)
65 (3o)
52 (3p)
86 (3q)
89 (3r)
77 (3s)
67 (3t)
94 (3u)
99 (3v)
86 (3w)
85 (3x)
77 (3y)
77 (3z)
9
5-Me, Ph (1e)
5-Me, Ph (1e)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-OMe, Ph (1f)
H, 4-ClC6H4 (1g)
H, 4-ClC6H4 (1g)
H, 4-MeC6H4 (1h)
H, 4-MeC6H4 (1h)
H, 4-MeOC6H4 (1i)
5-F, 4-MeC6H4 (1j)
5-F, 4-MeC6H4 (1j)
4-F, 4-MeC6H4 (1k)
4-F, 4-MeC6H4 (1k)
5-Cl, cyclopropyl (1l)
5-Cl, cyclopropyl (1l)
5-F, cyclopropyl (1m)
5-F, cyclopropyl (1m)
4-F, cyclopropyl (1n)
4-F, cyclopropyl (1n)
Table 1
Initial studies for the synthesis of 1-aminoisoquinoline 3a via three-component
reaction of 2-alkynylbenzaldoxime 1a, carbodiimide 2a, and bromine
a
Isolated yield based on 2-alkynylbenzaldoxime 1.
Entry
Solvent
Yield (%)a
The possible mechanism was described in Scheme 2. As pre-
vious report,7b 4-bromoisoquinoline-N-oxide A would be formed
from the reaction of 2-alkynylbenzaldoxime 1 with bromine via
6-endo cyclization. Then, 4-bromoisoquinoline-N-oxide A reacted
with carbodiimide 2 via [3þ2] cycloaddition giving rise to the
key intermediate B, which underwent an intramolecular rear-
rangement to afford 4-bromo-1-(isoquinolin-1-yl)urea C. The
subsequent hydrolyzation of 4-bromo-1-(isoquinolin-1-yl)urea
C furnished the 1-aminoisoquinoline 3.
1
2
3
4
5
6
CH2Cl2/DMF
CH2Cl2/DCE
CH2Cl2/THF
CH2Cl2/MeCN
CH2Cl2/CHCl3
CH2Cl2/1,4-dioxane
Trace
52
60
24
61
86
a
Isolated yield based on 2-alkynylbenzaldoxime 1a.
We next applied the optimized reaction conditions (CH2Cl2/
1,4-dioxane, 60 ꢀC) to a variety of 2-alkynylbenzaldoxime 1 (Table 2).
All reactions worked well to generate the desired 1-aminoisoquino-
lines 3 in good to excellent yields. Not only N-((cyclohexylimino)
methylene)-cyclohexanamine 2a but also N-((isopropylimino)meth-
ylene)-propan-2-amine 2b was suitable partner in the trans-
formation. For instance, 5-fluoro-substituted 2-alkynylbenzaldoxime
1b reacted with carbodiimide 2a leading to the corresponding
1-aminoisoquinolines 3c in 98% yield (Table 2, entry 3). Compound
3d was afforded in 80% yield when carbodiimide 2b was employed
in the above reaction (Table 2, entry 4). As mentioned in our pre-
vious reports,7b the reaction proceeded through intramolecular
electrophilic cyclization first to produce the bromo-containing iso-
quinoline-N-oxide intermediate, which then underwent further
[3þ2] cycloaddition reaction. Thus, 2-alkynylbenzaldoximes with
electron-donating group attached on the aromatic ring would di-
minish the reactivity. As expected, a low yield was observed for the
reaction of methoxy-substituted 2-alkynylbenzaldoxime 1f, carbo-
diimide 2a, with bromine (41% yield, Table 2, entry 11). We next
examined the reactions of 2-alkynylbenzaldoximes 1 with different
groups attached to the C^C triple bond. No big difference was dis-
played for the substrates with aryl or alkyl group (such as cyclopropyl
group) attached on the position.
OH
O
N
Br2
R1
N
R1
6-endo cyclization
R2
OH
1
R2
A
N
Br
R3
R1
[3+2]
R2
R3
N
C N
2
Br
cycloaddition
R3
O
N
N
O
R3
R3
R3
R3
Base
NH
N
N
N
H
H
hydrolysis
N
N
R1
R1
R1
R2
R2
R2
B
3
Br
Br
C
Br
Scheme 2. Possible mechanism for 1-aminoisoquinoline 3 generation.
3. Conclusions
In conclusion, we have described a novel and efficient route for
the synthesis of 1-amino-4-bromoisoquinolines via three-

4630
S. Ye et al. / Tetrahedron 67 (2011) 4628e4632
component reaction of 2-alkynylbenzaldoxime, carbodiimide, and
bromine. This method provides an excellent complement for the
1-aminoisoquinoline generation. Moreover, the preparation of
diverse 1-aminoisoquinolines could be expected since further dec-
orations through palladium-catalyzed cross-coupling reactions are
known. The advantages of this method, which include high effi-
ciency, good substrate generality, mild reaction conditions, and ex-
perimental ease will prompt us for the further library construction.
CDCl3) d 1.21e1.32 (m, 3H), 1.38e1.46 (m, 2H), 1.62e1.66 (m, 1H),
1.72e1.77 (m, 2H), 2.14 (dd, J¼3.3, 12.1 Hz, 2H), 4.14e4.20 (m, 1H),
5.08 (d, J¼7.3 Hz, 1H), 7.19 (dt, J¼2.6, 8.4 Hz, 1H), 7.36e7.47 (m, 3H),
7.10 (dd, J¼5.1, 9.1 Hz, 1H), 7.77 (d, J¼6.9 Hz, 2H), 7.96 (dd, J¼2.2,
10.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.9, 25.8, 33.2, 49.5,
4
2
103.6 (d, JCF¼4.6 Hz), 112.1 (d, JCF¼23.7 Hz), 115.2, 115.4 (d,
3
2JCF¼24.4 Hz), 124.3 (d, JCF¼9.9 Hz), 127.5, 128.0, 130.0, 139.0 (d,
3JCF¼9.9 Hz), 141.4, 151.4, 152.6, 163.9 (d, JCF¼248.8 Hz); HRMS
1
(ESI) calcd for C21H20BrFN2: 399.0872 (MþHþ), found: 399.0869.
4. Experimental section
4.1.6. 4-Bromo-6-fluoro-N-isopropyl-3-phenylisoquinolin-1-amine
(3f). Yellow solid; melting point: 84.1e84.8 ꢀC. 1H NMR (400 MHz,
4.1. General procedure for the synthesis of
1-aminoisoquinoline 3 via a three-component reaction of
2-alkynylbenzaldoxime 1, carbodiimide 2, and bromine
CDCl3)
d
1.31 (d, J¼6.5 Hz, 6H), 4.47e4.51 (m, 1H), 5.02 (d, J¼6.9 Hz,
1H), 7.20 (dt, J¼2.6, 8.4 Hz, 1H), 7.38e7.47 (m, 3H), 7.73 (dd, J¼5.5,
9.2 Hz, 1H), 7.77 (d, J¼7.7 Hz, 2H), 7.88 (dd, J¼2.6, 10.6 Hz, 1H); 13C
4
2-Alkynylbenzaldoxime 1 (0.2 mmol) was added to a solution of
bromine (0.20 mmol) in CH2Cl2 (0.5 mL). After stirred at room tem-
perature for 10 min, carbodiimide 2 (0.5 mmol) was added followed
by 1,4-dioxane (2.0 mL). The mixture was stirred at 60 ꢀC. After com-
pletion of the reaction as indicated by TLC(overnight), the reactionwas
quenched with aqueous NH4Cl (10 mL, 1.0 M), extracted with EtOAc
(2ꢁ10 mL), dried over anhydrous Na2SO4. Evaporation of the solvent
followed by purification on silica gel provided the product 3.
NMR (100 MHz, CDCl3)
d
22.8, 42.8, 103.8 (d, JCF¼4.6 Hz), 112.1
2
2
(d, JCF¼23.7 Hz), 115.2, 115.5 (d, JCF¼24.4 Hz), 124.4 (d,
3JCF¼9.9 Hz), 127.5, 128.0, 129.9, 138.9 (d, JCF¼9.9 Hz), 141.4, 151.5,
3
152.7, 163.9 (d, 1JCF¼248.8 Hz); HRMS (ESI) calcd for C18H16BrFN2:
359.0559 (MþHþ), found: 359.0550.
4.1.7. 4-Bromo-7-chloro-N-cyclohexyl-3-phenylisoquinolin-1-amine
(3g). Yellow solid; melting point: 53.6e54.6 ꢀC. 1H NMR (400 MHz,
CDCl3)
d 1.21e1.31 (m, 3H), 1.37e1.46 (m, 2H), 1.62e1.67 (m, 1H),
4.1.1. 4-Bromo-N-cyclohexyl-3-phenylisoquinolin-1-amine
1.72e1.78 (m, 2H), 2.13 (dd, J¼3.3, 12.4 Hz, 2H), 4.12e4.20 (m, 1H),
5.01 (d, J¼7.3 Hz, 1H), 7.35e7.46 (m, 4H), 7.57 (dd, J¼1.8, 9.2 Hz, 1H),
7.67 (d, J¼1.8 Hz, 1H), 7.77 (d, J¼6.6 Hz, 1H), 8.14 (d, J¼8.8 Hz, 1H);
(3a). Yellow solid; melting point: 93.4e93.9 ꢀC. 1H NMR (400 MHz,
CDCl3)
d 1.20e1.32 (m, 3H), 1.38e1.48 (m, 2H), 1.62e1.68 (m, 1H),
1.74e1.78 (m, 2H), 2.15 (dd, J¼2.9, 11.7 Hz, 2H), 4.15e4.24 (m, 1H),
5.13 (d, J¼6.9 Hz, 1H), 7.37e7.49 (m, 4H), 7.65e7.73 (m, 2H),
7.78e7.89 (m, 2H), 8.22 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3)
d 24.9, 25.8, 30.1, 49.6,104.0,119.0,120.7,
126.5,127.5,128.0,129.5,130.0,131.1,135.1,141.2,150.5,151.8; HRMS
(ESI) calcd for C21H20BrClN2: 415.0577 (MþHþ), found: 415.0580.
CDCl3)
d 24.9, 25.9, 33.2, 49.4, 104.6, 118.5, 121.2, 126.1, 127.5, 127.6,
127.8, 130.1, 130.6, 136.6, 141.7, 150.1, 152.8; HRMS (ESI) calcd for
4.1.8. 4-Bromo-7-chloro-N-isopropyl-3-phenylisoquinolin-1-amine
C21H21BrN2: 381.0966 (MþHþ), found: 381.0961.
(3h). Yellow oil. 1H NMR (400 MHz, CDCl3)
d
1.31 (d, J¼6.2 Hz, 6H),
4.46e4.50 (m, 1H), 4.97 (d, J¼6.9 Hz, 1H), 7.37e7.47 (m, 3H), 7.60
(dd, J¼1.8, 9.2 Hz, 1H), 7.70 (d, J¼1.8 Hz, 1H), 7.77 (d, J¼8.4 Hz, 2H),
4.1.2. 4-Bromo-N-isopropyl-3-phenylisoquinolin-1-amine (3b). White
solid; melting point: 71.9e72.4 ꢀC. 1H NMR (400 MHz, CDCl3)
d
1.32
8.16 (d, J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 22.8, 42.9, 104.2,
(d, J¼6.2 Hz, 6H), 4.48e4.51 (m, 1H), 5.07 (d, J¼6.6 Hz,1H), 7.37e7.52
119.0, 120.7, 127.5, 128.0, 129.5, 130.0, 131.1, 131.9, 135.1, 141.3, 150.5,
151.9; HRMS (ESI) calcd for C18H16BrClN2: 375.0264 (MþHþ),
found: 375.0260.
(m, 4H), 7.67e7.73 (m, 2H), 7.78 (d, J¼8.4 Hz, 2H), 8.23 (d, J¼8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 22.9, 42.7, 104.8, 118.4, 121.3, 126.2,
127.5, 127.6, 127.8, 130.1, 130.6, 136.6, 141.7, 150.2, 152.8; HRMS (ESI)
calcd for C18H17BrN2: 341.0653 (MþHþ), found: 341.0666.
4.1.9. 4-Bromo-N-cyclohexyl-7-methyl-3-phenylisoquinolin-1-amine
(3i). Yellow oil. 1H NMR (400 MHz, CDCl3)
d 1.25e1.32 (m, 3H),
4.1.3. 4-Bromo-N-cyclohexyl-7-fluoro-3-phenylisoquinolin-1-amine
(3c). Yellow solid; melting point: 118.0e118.2 ꢀC. 1H NMR
(400 MHz, CDCl3) d 1.22e1.32 (m, 3H), 1.37e1.46 (m, 2H), 1.62e1.66
1.38e1.46 (m, 2H), 1.63e1.68 (m, 1H), 1.74e1.79 (m, 2H), 2.16 (dd,
J¼3.3,12.1 Hz, 2H), 2.53 (s, 3H), 4.16e4.22 (m,1H), 5.07 (d, J¼6.9 Hz,
1H), 7.36e7.40 (m, 1H), 7.42e7.51 (m, 4H), 7.79 (d, J¼8.4 Hz, 2H),
(m, 1H), 1.73e1.77 (m, 2H), 2.14 (d, J¼3.3, 12.4 Hz, 2H), 4.13e4.21
8.11 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.6, 24.9, 25.9,
(m, 1H), 4.92 (d, J¼7.3 Hz, 1H), 7.33e7.46 (m,5H), 7.77 (d, J¼6.9 Hz,
33.2, 49.4, 104.7, 118.5, 120.6, 127.4, 127.5, 127.7, 130.1, 132.4, 134.7,
136.2, 141.7, 146.9, 152.4; HRMS (ESI) calcd for C22H23BrN2:
395.1123 (MþHþ), found: 395.1112.
2H), 8.22 (dd, J¼5.8, 9.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.9,
25.9, 33.1, 49.6, 104.2, 105.8 (d, 2JCF¼21.4 Hz), 119.0 (d, 3JCF¼6.9 Hz),
2
3
120.0 (d, JCF¼23.7 Hz), 127.5, 127.9, 130.1, 130.5 (d, JCF¼8.4 Hz),
4
4
133.5, 141.3, 149.5 (d, JCF¼2.3 Hz), 152.2 (d, JCF¼3.8 Hz), 160.7
4.1.10. 4-Bromo-N-isopropyl-7-methyl-3-phenylisoquinolin-1-amine
1
(d, JCF¼247.3 Hz); HRMS (ESI) calcd for C21H20BrFN2: 399.0872
(3j). Yellow oil. 1H NMR (400 MHz, CDCl3)
d
1.31 (d, J¼6.6 Hz, 6H),
(MþHþ), found: 399.0854.
2.53 (s, 3H), 4.47e4.51 (m, 1H), 5.01 (d, J¼6.6 Hz, 1H), 7.35e7.39 (m,
1H), 7.42e7.46 (m, 2H), 7.49e7.53 (m, 2H), 7.78 (d, J¼8.4 Hz, 2H),
4.1.4. 4-Bromo-7-fluoro-N-isopropyl-3-phenylisoquinolin-1-amine
(3d). Yellow solid; melting point: 146.7e147.6 ꢀC.1H NMR (400 MHz,
8.11 (d, J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.6, 22.9, 42.7,
104.8, 118.5, 120.6, 127.4, 127.5, 127.7, 130.1, 132.4, 134.6, 136.2, 141.7,
149.1, 152.4; HRMS (ESI) calcd for C19H19BrN2: 355.0810 (MþHþ),
found: 355.0810.
CDCl3)
d
1.31 (d, J¼6.6 Hz, 6H), 4.45e4.49 (m, 1H), 4.87 (d, J¼6.9 Hz,
1H), 7.34e7.46 (m, 5H), 7.77 (d, J¼8.8 Hz, 2H), 8.24 (dd, J¼5.5, 9.2 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 22.8, 42.9, 104.3, 105.9
(d, 2JCF¼21.4 Hz), 119.0 (d, 3JCF¼6.9 Hz), 120.1 (d, 2JCF¼23.7 Hz),127.6,
127.9, 130.0, 130.5 (d, 3JCF¼8.4 Hz),133.5,141.4,149.6 (d, 4JCF¼3.1 Hz),
152.3 (d, 4JCF¼3.8 Hz), 160.8 (d, 1JCF¼247.3 Hz); HRMS (ESI) calcd for
C18H16BrFN2: 359.0559 (MþHþ), found: 359.0562.
4.1.11. 4-Bromo-N-cyclohexyl-6-methoxy-3-phenylisoquinolin-1-
amine (3k). White solid; melting point: 211.4e212.0 ꢀC. 1H NMR
(400 MHz, CDCl3) d 1.23e1.31 (m, 3H), 1.38e1.47 (m, 2H), 1.63e1.67
(m, 1H), 1.73e1.78 (m, 2H), 2.14 (dd, J¼2.9, 12.1 Hz, 2H), 3.97 (s, 3H),
4.14e4.22 (m,1H), 5.01 (d, J¼7.3 Hz,1H), 7.09 (dd, J¼2.6, 9.2 Hz,1H),
7.37e7.47 (m, 3H), 7.55 (d, J¼2.6 Hz, 1H), 7.64 (d, J¼9.2 Hz, 1H), 7.77
4.1.5. 4-Bromo-N-cyclohexyl-6-fluoro-3-phenylisoquinolin-1-amine
(3e). White solid; melting point: 93.7e94.7 ꢀC. 1H NMR (400 MHz,
(d, J¼6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 24.9, 25.9, 33.3, 49.4,

S. Ye et al. / Tetrahedron 67 (2011) 4628e4632
4631
55.5, 104.3, 106.8, 113.1, 117.6, 123.3, 127.5, 127.8, 130.1, 138.7, 141.5,
150.9, 152.7, 161.4; HRMS (ESI) calcd for C22H23BrN2O: 411.1072
(MþHþ), found: 411.1069.
9.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
21.3, 22.8, 42.8, 104.2, 105.8
(d, 2JCF¼21.4 Hz),118.9 (d, 3JCF¼6.9 Hz),120.0 (d, 2JCF¼23.6 Hz), 128.3,
129.9, 130.4 (d, 3JCF¼8.4 Hz),133.5,137.7,138.5,149.6 (d, 4JCF¼2.3 Hz),
152.2 (d, 4JCF¼3.8 Hz), 160.7 (d, 1JCF¼247.3 Hz); HRMS (ESI) calcd for
C19H18BrFN2: 373.0716 (MþHþ), found: 373.0706.
4.1.12. 4-Bromo-3-(4-chlorophenyl)-N-cyclohexylisoquinolin-1-amine
(3l). Yellow oil. 1H NMR (400 MHz, CDCl3)
d 1.22e1.32 (m, 3H),
1.34e1.48 (m, 2H), 1.62e1.68 (m, 1H), 1.73e1.78 (m, 2H), 2.13 (dd,
J¼2.9, 12.1 Hz, 2H), 4.12e4.20 (m, 1H), 7.41 (d, J¼8.4 Hz, 2H), 7.47 (dt,
J¼1.1, 7.5 Hz, 1H), 7.66e7.75 (m, 4H), 8.21 (d, J¼8.4 Hz, 1H); 13C NMR
4.1.19. 4-Bromo-N-cyclohexyl-6-fluoro-3-p-tolylisoquinolin-1-amine
(3s). Yellow solid; melting point: 54.7e55.3 ꢀC. 1H NMR (400 MHz,
CDCl3)
d 1.21e1.29 (m, 3H), 1.36e1.47 (m, 2H), 1.62e1.66 (m, 1H),
(100 MHz, CDCl3)
d
24.9, 25.9, 33.1, 49.5, 104.6, 118.5, 121.3, 126.4,
1.72e1.77 (m, 2H), 2.13 (dd, J¼3.3, 12.1 Hz, 2H), 2.42 (s, 3H),
4.14e4.22 (m, 1H), 5.06 (d, J¼6.9 Hz, 1H), 7.17 (dt, J¼2.6, 8.4 Hz, 1H),
7.26 (d, J¼8.0 Hz, 2H), 7.67e7.72 (m, 3H), 7.85 (dd, J¼2.6, 11.0 Hz,
127.6, 127.7, 130.7, 131.5, 133.7, 136.5, 140.1, 148.8, 152.8; HRMS (ESI)
calcd for C21H20BrClN2: 415.0577 (MþHþ), found: 415.0581.
1H); 13C NMR (100 MHz, CDCl3)
d 21.4, 24.9, 25.8, 33.2, 49.5,
4
2
4.1.13. 4-Bromo-3-(4-chlorophenyl)-N-isopropylisoquinolin-1-amine
103.5 (d, JCF¼3.8 Hz), 112.0 (d, JCF¼23.6 Hz), 115.1, 115.3
(3m). Yellow oil. 1H NMR (400 MHz, CDCl3)
d
1.31 (d, J¼6.6 Hz, 6H),
(d, JCF¼24.4 Hz), 124.3 (d, JCF¼9.9 Hz), 128.3, 129.9, 137.9, 138.5,
2
3
3
4.44e4.49 (m, 1H), 5.10 (d, J¼6.2 Hz, 1H), 7.41 (d, J¼8.4 Hz, 2H), 7.50
139.0 (d, JCF¼9.9 Hz), 151.4, 152.6, 163.8 (d, 1JCF¼248.8 Hz); HRMS
(dt, J¼1.1, 7.5 Hz, 1H), 7.67e7.75 (m, 4H), 8.22 (d, J¼8.0 Hz, 1H); 13C
(ESI) calcd for C22H22BrFN2: 413.1029 (MþHþ), found: 413.1032.
NMR (100 MHz, CDCl3)
d 22.8, 42.8, 104.7, 118.5, 121.3, 126.4, 127.6,
127.7, 130.7, 131.5, 133.7, 136.5, 140.1, 148.9, 152.9; HRMS (ESI) calcd
4.1.20. 4-Bromo-6-fluoro-N-isopropyl-3-p-tolylisoquinolin-1-amine
(3t). White solid; melting point: 118.5e119.0 ꢀC. 1H NMR
for C18H16BrClN2: 375.0264 (MþHþ), found: 375.0268.
(400 MHz, CDCl3)
d
1.30 (d, J¼6.2 Hz, 6H), 2.42 (s, 3H), 4.47e4.51
4.1.14. 4-Bromo-N-cyclohexyl-3-p-tolylisoquinolin-1-amine
(m, 1H), 5.00 (d, J¼6.9 Hz, 1H), 7.19 (dt, J¼2.6, 8.4 Hz, 1H), 7.26 (d,
J¼8.4 Hz, 2H), 7.68 (d, J¼8.1 Hz, 2H), 7.71 (dd, J¼5.1, 8.8 Hz,1H), 7.86
(3n). Yellow oil. 1H NMR (400 MHz, CDCl3)
d 1.22e1.31 (m, 3H),
1.37e1.48 (m, 2H), 1.62e1.66 (m, 1H), 1.72e1.77 (m, 2H), 2.15 (dd,
J¼3.3, 12.1, 2H), 2.42 (s, 3H), 4.16e4.22 (m, 1H), 5.12 (d, J¼6.9 Hz,
1H), 7.26 (d, J¼8.4 Hz, 2H), 7.46 (t, J¼7.7 Hz, 1H), 7.65e7.71 (m, 4H),
(dd, J¼2.6,11.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 21.4, 22.8, 42.8,
103.7, 112.1 (d, 2JCF¼23.7 Hz), 115.1, 115.3 (d, 2JCF¼24.4 Hz), 124.3 (d,
3JCF¼9.9 Hz), 128.3, 129.9, 137.9, 138.6, 139.0 (d, 3JCF¼9.9 Hz), 151.5,
152.6, 163.9 (d, 1JCF¼248.8 Hz); HRMS (ESI) calcd for C19H18BrFN2:
373.0716 (MþHþ), found: 373.0721.
8.21 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.4, 24.9, 25.9,
33.2, 49.4, 104.5, 118.4, 121.2, 126.0, 127.5, 128.2, 130.0, 130.5, 136.7,
137.6,138.8,150.1,152.7; HRMS (ESI) calcd for C22H23BrN2: 395.1123
(MþHþ), found: 395.1131.
4.1.21. 4-Bromo-7-chloro-N-cyclohexyl-3-cyclopropylisoquinolin-1-
amine (3u). Yellow solid; melting point: 74.7e75.3 ꢀC. 1H NMR
4.1.15. 4-Bromo-N-isopropyl-3-p-tolylisoquinolin-1-amine
(400 MHz, CDCl3) d 0.90e0.95 (m, 2H), 1.09e1.12 (m, 2H), 1.19e1.28
(3o). White solid; melting point: 89.2e89.6 ꢀC. 1H NMR (400 MHz,
(m, 3H),1.38e1.49 (m, 2H),1.65e1.69 (m,1H),1.75e1.79 (m, 2H), 2.08
(dd, J¼2.9,12.1 Hz, 2H), 2.56e2.64 (m,1H), 3.92e4.00 (m,1H), 4.89 (d,
J¼6.9 Hz,1H), 7.50(dd, J¼1.8,8.8 Hz,1H), 7.57(d, J¼2.2 Hz,1H), 7.97 (d,
CDCl3)
d
1.31 (d, J¼6.6 Hz, 6H), 2.42 (s, 3H), 4.48e4.52 (m, 1H), 5.06
(d, J¼6.6 Hz, 1H), 7.26 (d, J¼8.1 Hz, 2H), 7.47 (dt, J¼1.1, 4.7 Hz, 1H),
7.65e7.71 (m, 4H), 8.22 (d, J¼8.8 Hz, 1H); 13C NMR (100 MHz,
J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 9.0, 16.0, 25.0, 25.9, 33.0,
50.0, 104.5, 118.4, 120.6, 128.2, 130.5, 130.8, 134.6, 151.8, 152.3; HRMS
CDCl3)
d
21.4, 22.9, 42.7, 104.7, 118.4, 121.2, 126.1, 127.6, 128.3, 130.0,
130.5, 136.6, 137.6, 138.9, 150.2, 152.8; HRMS (ESI) calcd for
(ESI) calcd for C18H20BrClN2: 379.0577 (MþHþ), found: 379.0585.
C19H19BrN2: 355.0810 (MþHþ), found: 355.0798.
4.1.22. 4-Bromo-7-chloro-3-cyclopropyl-N-isopropylisoquinolin-1-
4.1.16. 4-Bromo-N-isopropyl-3-(4-methoxyphenyl)isoquinolin-1-amine
amine (3v). Yellow oil. 1H NMR (400 MHz, CDCl3)
d 0.92e0.96 (m,
(3p). White solid; melting point: 101.7e102.2 ꢀC. 1H NMR (400 MHz,
2H), 1.10e1.14 (m, 2H), 1.28 (d, J¼6.1 Hz, 6H), 2.59e2.64 (m, 1H),
4.27e4.30 (m,1H), 4.84 (d, J¼6.6 Hz,1H), 7.51 (dd, J¼1.8, 8.8 Hz,1H),
7.58 (d, J¼1.8 Hz, 1H), 7.98 (d, J¼9.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
1.32 (d, J¼6.6 Hz, 6H), 3.87 (s, 3H), 4.50e4.54 (m,1H), 5.06 (d,
J¼6.6 Hz, 1H), 6.98 (d, J¼8.8 Hz, 2H), 7.47 (dt, J¼1.1, 7.5 Hz, 1H),
7.66e7.72 (m, 2H), 7.78 (d, J¼8.8 Hz, 2H), 8.22 (d, J¼8.0 Hz, 1H); 13C
CDCl3)
d 9.1, 16.0, 22.7, 42.9, 104.7, 118.4, 120.6, 128.2, 130.5, 130.8,
NMR (100 MHz, CDCl3)
d
22.9, 42.7, 55.2, 104.5, 112.9, 118.3, 121.3,
134.6, 151.9, 152.3; HRMS (ESI) calcd for C15H16BrClN2: 339.0264
126.0, 127.5, 130.5, 131.5, 134.2, 136.7, 149.7, 152.7, 159.3; HRMS (ESI)
(MþHþ), found: 339.0265.
calcd for C19H19BrN2O: 371.0759 (MþHþ), found: 371.0758.
4.1.23. 4-Bromo-N-cyclohexyl-3-cyclopropyl-7-fluoroisoquinolin-1-
amine (3w). Yellow solid; melting point: 102.5e102.9 ꢀC. 1H NMR
(400 MHz, CDCl3) d 0.90e0.94 (m, 2H), 1.08e1.12 (m, 2H), 1.20e1.30
4.1.17. 4-Bromo-N-cyclohexyl-7-fluoro-3-p-tolylisoquinolin-1-amine
(3q). Yellow solid; melting point: 61.2e62.2 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
1.22e1.31 (m, 3H), 1.36e1.47 (m, 2H), 1.62e1.67 (m, 1H),
(m, 3H), 1.39e1.49 (m, 2H), 1.65e1.69 (m, 1H), 1.75e1.79 (m, 2H),
2.09 (dd, J¼3.3, 12.4 Hz, 2H), 2.57e2.64 (m, 1H), 3.93e4.00 (m, 1H),
4.79 (d, J¼5.8 Hz, 1H), 7.24 (dd, J¼2.6, 9.5 Hz, 1H), 7.35 (dt, J¼2.2,
8.6 Hz, 1H), 8.05 (dd, J¼5.5, 9.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
1.72e1.77 (m, 2H), 2.14 (dd, J¼3.3, 12.1 Hz, 2H), 2.42 (s, 3H), 4.12e4.20
(m, 1H), 4.90 (d, J¼6.9 Hz, 1H), 7.26 (d, J¼8.1 Hz, 2H), 7.34 (dd, J¼2.2,
9.5 Hz, 1H), 7.41 (dt, J¼2.2, 8.6 Hz, 1H), 7.68 (d, J¼8.1 Hz, 2H), 8.22 (dd,
J¼5.5, 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
3
21.3, 24.9, 25.9, 33.1,
d
8.8, 15.8, 25.0, 25.9, 33.1, 50.0, 104.6, 105.7 (d, 2JCF¼21.0 Hz), 118.2,
2
2
3
49.6, 104.0, 105.8 (d, JCF¼21.4 Hz), 118.9 (d, JCF¼6.9 Hz), 120.0 (d,
119.7 (d, JCF¼23.8 Hz), 129.1 (d, JCF¼7.6 Hz), 133.1, 151.1 (d,
4JCF¼1.9 Hz), 152.2 (d, 4JCF¼4.8 Hz), 160.0 (d, 1JCF¼245.0 Hz); HRMS
(ESI) calcd for C18H20BrFN2: 363.0872 (MþHþ), found: 363.0879.
2JCF¼23.7 Hz), 128.3, 130.0, 130.4 (d, JCF¼8.4 Hz), 133.6, 137.7, 138.5,
3
4
1
149.5, 152.2 (d, JCF¼4.6 Hz), 160.7 (d, JCF¼247.3 Hz); HRMS (ESI)
calcd for C22H22BrFN2: 413.1029 (MþHþ), found: 413.1035.
4.1.24. 4-Bromo-3-cyclopropyl-7-fluoro-N-isopropylisoquinolin-1-
amine (3x). Yellow solid; melting point: 82.2e82.9 ꢀC. 1H NMR
4.1.18. 4-Bromo-7-fluoro-N-isopropyl-3-p-tolylisoquinolin-1-amine
(3r). White solid; melting point: 76.5e77.2 ꢀC. 1H NMR (400 MHz,
(400 MHz, CDCl3)
d 0.91e0.95 (m, 2H), 1.10e1.14 (m, 2H), 1.28 (d,
CDCl3)
d
1.30 (d, J¼6.2 Hz, 6H), 2.41 (s, 3H), 4.45e4.49 (m, 1H), 4.85
J¼6.2 Hz, 6H), 2.58e2.65 (m, 1H), 4.28e4.31 (m, 1H), 4.73 (d,
(d, J¼6.9 Hz, 1H), 7.26 (d, J¼8.1 Hz, 2H), 7.34 (dd, J¼2.2, 9.6 Hz, 1H),
7.42 (dt, J¼2.6, 8.6 Hz, 1H), 7.67 (d, J¼8.0 Hz, 2H), 8.23 (dd, J¼5.5,
J¼6.2 Hz, 1H), 7.24 (dd, J¼2.6, 9.5 Hz, 1H), 7.35 (dt, J¼2.6, 8.6 Hz,
1H), 8.06 (dd, J¼5.5, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 8.9,

4632
S. Ye et al. / Tetrahedron 67 (2011) 4628e4632
15.9, 22.8, 42.9, 104.8, 105.7 (d, 2JCF¼21.4 Hz), 118.3 (d, 3JCF¼6.9 Hz),
Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y. J. Nat. Prod. 1999, 62, 780e781; (d)
Kaneda, T.; Takeuchi, Y.; Matsui, H.; Shimizu, K.; Urakawa, N.; Nakajyo, S. J.
Pharm. Sci. 2005, 98, 275e282; (e) Marchand, C.; Antony, S.; Kohn, K. W.;
Cushman, M.; Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier, Y.
Mol. Cancer Ther. 2006, 5, 287e295; (f) Balasubramanian, M.; Keay, J. G. In Iso-
quinoline Synthesis; McKillop, A. E., Katrizky, A. R., Rees, C. W., Scrivem, E. F. V.,
Eds.; Comprehensive Heterocyclic Chemistry II; Elsevier: Oxford, 1996; Vol. 5,
pp 245e300; (g) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341e3370.
2
3
119.8 (d, JCF¼24.4 Hz), 129.1 (d, JCF¼8.4 Hz), 133.1, 151.1 (d,
4JCF¼2.3 Hz), 152.3 (d, 4JCF¼4.6 Hz), 160.0 (d, 1JCF¼245.0 Hz); HRMS
(ESI) calcd for C15H16BrFN2: 323.0559 (MþHþ), found: 323.0544.
4.1.25. 4-Bromo-N-cyclohexyl-3-cyclopropyl-6-fluoroisoquinolin-1-
amine (3y). Yellow oil. 1H NMR (400 MHz, CDCl3)
d 0.91e0.95 (m,
2H), 1.10e1.14 (m, 2H), 1.18e1.30 (m, 3H), 1.39e1.49 (m, 2H),
1.65e1.70 (m, 1H), 1.75e1.80 (m, 2H), 2.09 (dd, J¼2.9, 12.1 Hz, 2H),
2.57e2.62 (m, 1H), 3.94e4.02 (m, 1H), 4.95 (d, J¼6.6 Hz, 1H), 7.06
(dt, J¼2.6, 8.6 Hz, 1H), 7.60 (dd, J¼5.5, 9.2 Hz, 1H), 7.68 (dd, J¼2.6,
2. (a) Smith, A. L.; DeMorin, F. F.; Paras, N. A.; Huang, Q.; Petkus, J. K.; Doherty, E.
M.; Nixey, T.; Kim, J. L.; Whittington, D. A.; Epstein, L. F.; Lee, M. R.; Rose, M. J.;
Babij, C.; Fernando, M.; Hess, K.; Le, Q.; Beltran, P.; Carnahanz, J. J. Med. Chem.
2009, 52, 6189e6192; (b) Yang, S. H.; Van, H. T. M.; Le, T. N.; Khadka, D. B.; Cho,
S. H.; Lee, K.-T.; Chung, H.-J.; Lee, S. K.; Ahn, C.-H.; Lee, Y. B.; Cho, W.-J. Bioorg.
Med. Chem. Lett. 2010, 20, 5277e5281; (c) Meredith, E. L.; Ardayfio, O.; Beattie,
K.; Dobler, M. R.; Enyedy, I.; Gaul, C.; Hosagrahara, V.; Jewell, C.; Koch, K.; Lee,
W.; Lehmann, H. J.; McKinsey, T. A.; Miranda, K.; Pagratis, N.; Pancost, M.; Pat-
naik, A.; Phan, D.; Plato, C.; Qian, M.; Rajaraman, V.; Rao, C.; Rozhitskaya, O.;
Ruppen, T.; Shi, J.; Siska, S. J.; Springer, C.; Eis, M.; Vega, R. B.; Matt, A.; Yang, L.;
Yoon, T.; Zhang, J.-H.; Zhu, N.; Monovich, L. G. J. Med. Chem. 2010, 53,
5400e5421; (d) Govek, S. P.; Oshiro, G.; Anzola, J. V.; Beauregard, C.; Chen, J.;
Coyle, A. R.; Gamache, D. A.; Hellberg, M. R.; Hsien, J. N.; Lerch, J. M.; Liao, J. C.;
Malecha, J. W.; Staszewski, L. M.; Thomas, D. J.; Yanni, J. M.; Noble, S. A.; Shiau, A.
K. Bioorg. Med. Chem. Lett. 2010, 20, 2928e2932; (e) Sirisoma, N.; Pervin, A.;
Zhang, H.; Jiang, S.; Willardsen, J. A.; Anderson, M. B.; Mather, G.; Pleiman, C. M.;
Kasibhatla, S.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2010, 20,
2330e2334; (f) Ghosh, B.; Antonio, T.; Zhen, J.; Kharkar, P.; Reith, M. E. A.; Dutta,
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K.; McEwan, M. A.; Karki, R.; Llamas, L.; Yusuff, N.; He, F.; Li, Y.; Sun, Y.; Dai, M.;
Perez, L.; Michael, W.; Sheng, T.; Lei, H.; Zhang, R.; Williams, J.; Bourret, A.;
Ramamurthy, A.; Yuan, J.; Guo, R.; Matsumoto, M.; Vattay, A.; Maniara, W.;
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Hanzer, A.; Zuiderveld, O. P.; Guaita, E.; Adami, M.; Coruzzi, G.; Leurs, R. J. Med.
Chem. 2008, 51, 2457e2467; (c) Fish, P. V.; Barber, C. G.; Brown, D. G.; Butt, R.;
Collis, M. G.; Dickinson, R. P.; Henry, B. T.; Horne, V. A.; Huggins, J. P.; King, E.;
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2007, 50, 2341e2451.
11.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 9.1, 16.2, 25.0, 25.9, 33.1,
4
2
50.0, 104.2 (d, JCF¼3.8 Hz), 110.8 (d, JCF¼23.7 Hz), 114.1 (d,
3
3
2JCF¼24.4 Hz), 114.7, 124.2 (d, JCF¼9.2 Hz), 138.4 (d, JCF¼9.9 Hz),
1
152.6, 153.3, 163.8 (d, JCF¼248.8 Hz); HRMS (ESI) calcd for
C18H20BrFN2: 363.0872 (MþHþ), found: 363.0879.
4.1.26. 4-Bromo-3-cyclopropyl-6-fluoro-N-isopropylisoquinolin-1-
amine (3z). White solid; melting point: 130.8e131.4 ꢀC. 1H NMR
(400 MHz, CDCl3)
d 0.92e0.97 (m, 2H), 1.12e1.16 (m, 2H), 1.28 (d,
J¼6.6 Hz, 6H), 2.58e2.63 (m, 1H), 4.28e4.32 (m, 1H), 4.88 (d,
J¼6.2 Hz, 1H), 7.07 (dt, J¼2.6, 8.6 Hz, 1H), 7.61 (dd, J¼5.5,
9.2 Hz, 1H), 7.69 (dd, J¼2.6, 11.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
9.2, 16.2, 22.8, 42.8, 104.3 (d, 4JCF¼4.6 Hz), 110.8 (d, 2JCF¼23.6 Hz),
2
3
114.1 (d, JCF¼24.4 Hz), 114.7, 124.2 (d, JCF¼9.9 Hz), 138.4 (d,
3JCF¼9.9 Hz),152.7,153.4, 163.8 (d, 1JCF¼248.8 Hz); HRMS (ESI) calcd
for C15H16BrFN2: 323.0559 (MþHþ), found: 323.0547.
Acknowledgements
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Financial support from National Natural Science Foundation of
China (No. 20972030) and the Science & Technology Commission of
ShanghaiMunicipality(No.09JC1404902)isgratefullyacknowledged.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.04.063. This data include
MOL file and InChiKey of the most important compound described
in this article.
References and notes
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9. (a) Edman, P. Acta Chem. Scand. 1950, 4, 277e283; (b) Kollonitsch, J.; Hajos, A.;
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Gabor, V. Chem. Ber. 1956, 89, 2288e2292; (c) Weinstein, B.; Ho, T. N. S.; Fukura,
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