Generation of diverse 1-(isoquinolin-1-yl)guanidines via a sequential multi-component/cross-coupling reaction

Article abstract of DOI:10.1016/j.tet.2012.03.081

A multi-component reaction of 2-alkynylbenzaldehyde, 4- methylbenzenesulfonohydrazide, carbodiimide, and bromine is reported, which generates 1-(4-bromoisoquinolin-1-yl)guanidines in good yields under mild conditions. The products could be further elaborated via a palladium-catalyzed Suzuki-Miyaura coupling reaction, leading to the diverse 1-(isoquinolin-1-yl) guanidines.

Full text of DOI:10.1016/j.tet.2012.03.081

Tetrahedron 68 (2012) 5197e5202
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Generation of diverse 1-(isoquinolin-1-yl)guanidines via a sequential
multi-component/cross-coupling reaction
,
b
b,
Chao Ye a, Zhiyuan Chen a , Huanhuan Wang , Jie Wu
*
*
a Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical Engineering, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A multi-component reaction of 2-alkynylbenzaldehyde, 4-methylbenzenesulfonohydrazide, carbodii-
mide, and bromine is reported, which generates 1-(4-bromoisoquinolin-1-yl)guanidines in good yields
under mild conditions. The products could be further elaborated via a palladium-catalyzed Suzu-
kieMiyaura coupling reaction, leading to the diverse 1-(isoquinolin-1-yl)guanidines.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 1 February 2012
Received in revised form 9 March 2012
Accepted 20 March 2012
Available online 28 March 2012
Keywords:
2-Alkynylbenzaldehyde
Bromine
Carbodiimide
1-(Isoquinolin-1-yl)guanidine
4-Methylbenzenesulfonohydrazide
1. Introduction
compound afforded H-pyrazolo[5,1-a]isoquinoline-1-carboxylates
in good yields.5a 1-(Isoquinolin-1-yl)guanidines were synthesized
During the drug development and drug discovery process, li-
braries of small molecules are in great demand.1 Among the small
molecules selected, natural product-like compounds are attractive
due to their well known advantages. We have been involved in this
field for several years using the strategy of diversity-oriented syn-
thesis.2 As an ongoing program for the generation of natural
product-like compounds with privileged scaffolds,3 we are in-
terested in 1-(isoquinolin-1-yl)guanidines and related compounds,
which show promising results as PTP1B inhibitor and HCT-116 in-
hibitor.4 The discovery of lead compounds prompted us to develop
efficient protocol for its library construction and evaluate the
resulting analogous compounds. Thus, efficient approaches for the
preparation of diverse 1-(isoquinolin-1-yl)guanidine molecules are
highly desirable.
As a practical and efficient tool, multi-component reactions have
been widely applied in drug discovery programs for providing large
collections of small molecules.5 Recently, we have developed multi-
component reactions using 2-alkynylbenzaldehydes as starting
materials for the formation of N-heterocycles.6 For instance, a silver
triflate-catalyzed three-component reaction of 2-alkynylbenzal-
through a silver triflate-catalyzed three-component reaction of 2-
alkynylbenzaldehyde, sulfonohydrazide, with carbodiimide.3
Based on these results, we envisioned that the diverse 1-(iso-
quinolin-1-yl)guanidines could be generated via a four-component
reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, bromine,
and carbodiimide. The proposed synthetic route is presented in
Scheme 1. Theoretically, N0-(2-alkynylbenzylidene)hydrazide A
would be formed after condensation of 2-alkynylbenzaldehyde 1
with 4-methylbenzenesulfonohydrazide. The subsequent bromine-
mediated cyclization would occur to produce bromo-substituted
isoquinolinium-2-yl amide B.7 A [3þ2] cycloaddition would take
place when carbodiimide was introduced to the reaction. After an
intramolecular rearrangement, 1-(4-bromoisoquinolin-1-yl)guani-
dine 3 would be obtained. The further palladium-catalyzed Suzu-
kieMiyaura coupling reaction8 could be expected to furnish the
desired 1-(isoquinolin-1-yl)guanidine 4. With the above consider-
ation in mind, we started to explore the feasibility of this
hypothesis.
2. Results and discussion
dehyde, sulfonohydrazide, and
a,b-unsaturated carbonyl
Initially, the studies were carried out for the reaction of 2-
alkynylbenzaldehyde 1a, 4-methylbenzenesulfonohydrazide, bro-
mine, and N-((cyclohexylimino)methylene)cyclohexanamine 2a
* Corresponding authors. E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.081

5198
C. Ye et al. / Tetrahedron 68 (2012) 5197e5202
Table 2
NTs
R3
NTs
Base-promoted multi-component reaction of 2-alkynylbenzaldehyde 1, 4-
methylbenzenesulfonohydrazide, bromine, and carbodiimide 2
R3
R3
R3
R3
N
N
H
N
C N
2
N
N
H
R3
N
NTs
+
R1
N
N
NHTs
R3
R3
R1
R2
N
Ts
H2N
CHO
R1
[Pd] (cat.)
R4B(OH)2
N
N
H
R2
R4
4
DABCO
CH2Cl2/CH3CN
rt
R1
R2
B
+
Br2
C
Br
3
R3
N
Br
N
R1
Palladium-catalyzed
Suzuki-Miyaura couplings
R2
N
N
R2
1
2
R3
3
CHO
Br
R1
NHTs
+
1
R1
Br2
+
TsNHNH2
Entry
R1, R2
R3
Yielda (%)
R2
A
R2
1
2
3
4
5
6
7
8
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
Cy (2a)
63 (3a)
61 (3b)
60 (3c)
55 (3d)
60 (3e)
57 (3f)
60 (3g)
47 (3h)
53 (3i)
52 (3j)
50 (3k)
53 (3l)
65 (3m)
60 (3n)
53 (3o)
58 (3p)
60 (3q)
51 (3r)
68 (3s)
52 (3t)
Trace
4-ClC6H4 (2b)
4-MeC6H4 (2c)
Cy (2a)
4-ClC6H4 (2b)
Cy (2a)
4-MeOC6H4 (2d)
Cy (2a)
4-ClC6H4 (2b)
Cy (2a)
4-MeOC6H4 (2d)
Cy (2a)
Cy (2a)
Cy (2a)
4-MeOC6H4 (2d)
Cy (2a)
Scheme 1. A proposed route for the generation of diverse 1-(isoquinolin-1-yl)guani-
dines via a sequential multi-component/cross-coupling reaction.
H, 4-EtC6H4 (1b)
H, 4-EtC6H4 (1b)
H, 4-MeC6H4 (1c)
H, 4-MeC6H4 (1c)
H, 4-MeOC6H4 (1d)
H, 4-MeOC6H4 (1d)
H, 4-FC6H4 (1e)
H, 4-FC6H4 (1e)
H, 3-FC6H4 (1f)
(Table 1). This base-promoted metal-free reaction was performed at
room
temperature.
Since
the
condensation
of
2-
9
alkynylbenzaldehyde with 4-methylbenzenesulfonohydrazide
worked most efficiently at dichloromethane, at the outset the re-
action occurred in the presence of triethylamine in dichloro-
methane (Table 1, entry 1). However, only a trace amount of
product was observed under the conditions. The corresponding
product was obtained in 8% yield when a mixed solvent (CH2Cl2/
CH3CN) was used (Table 1, entry 2). Treatment of the reaction with
KOH provided the expected product 3a in 28% yield (Table 1, entry
3). A lower yield was isolated by switching the additive to K3PO4
(Table 1, entry 4). Changing the base to K2CO3 led to production
with 46% yields (Table 1, entry 5). A similar outcome was obtained
when Na2CO3 or NaHCO3 was used as a replacement (Table 1, en-
tries 6 and 7). The yield was increased to 63% when DABCO was
employed in the reaction (Table 1, entry 8). Further screening of
solvents revealed that the combination of dichloromethane with
acetonitrile was the best choice (Table 1, entries 9e13).
10
11
12
13
14
15
16
17
18
19
20
21
22
H, cyclopropyl (1g)
4-F, C6H5 (1h)
4-F, C6H5 (1h)
4-F, 4-EtC6H4 (1i)
4-F, 4-MeC6H4 (1j)
4-F, 4-FC6H4 (1k)
4-F, 4-FC6H4 (1k)
4-F, 4-FC6H4 (1k)
4-OMe, C6H5 (1l)
5-Me, C6H5 (1m)
Cy (2a)
Cy (2a)
4-ClC6H4 (2b)
4-MeOC6H4 (2d)
Cy (2a)
Cy (2a)
Trace
a
Isolated yield based on 2-alkynylbenzaldehyde 1.
2 were evaluated. Besides N-((cyclohexylimino)methylene)cyclo-
hexanamine 2a, carbodiimides 2bed were demonstrated as good
partners in the transformation. For instance, 2-alkynylbenzaldehyde
1a reacted with bromine, 4-methylbenzenesulfonohydrazide, and
4-chloro-N-((p-tolylimino)methylene)benzenamine 2b leading to
the desired 1-(4-bromoisoquinolin-1-yl)guanidine 3b in 61% yield
(Table 2, entry 2). The yield was similar when carbodiimide 2c was
utilized in the reaction (60% yield, Table 2, entry 3). 2-
Alkynylbenzaldehydes 1 bearing either aryl or alkyl substituents
on the triple bond (R2 position) were converted to the desired
products with good reactivity (Table 2, entries 4e13). The methyl,
methoxy, and fluoro groups were tolerated under the reaction
conditions. Additionally, the reactions were workable for the 2-
alkynylbenzaldehydes 1 with a fluoro group attached on the aro-
matic ring, affording the expected products in moderate yields
(Table 2, entries 14e20). However, the reactions were failed when
methyl- or methoxy-substituted 2-alkynylbenzaldehyde 1l or 1m
were examined in the multi-component reactions (Table 2, entries
21 and 22).
More diversity could be introduced due to the reactivity of 1-(4-
bromoisoquinolin-1-yl)guanidine 3. Therefore, we further explored
the palladium-catalyzed SuzukieMiyaura coupling reactions
(Scheme 2). Initially, the reaction of 1-(4-bromoisoquinolin-1-yl)
guanidine 3a with 4-chlorophenylboronic acid was examined. We
found that the conversion worked efficiently in the presence of
PdCl2(PPh3)2 (10 mol %) and K2CO3 in DMF/H2O at 70 ꢀC. The cor-
responding product 5a was obtained in 75% yield. 1-(Isoquinolin-1-
yl)guanidine 5b was produced in 90% yield when 4-
methoxyphenylboronic acid was employed as a reactant. Re-
actions of other 1-(4-bromoisoquinolin-1-yl)guanidines and aryl-
boronic acids were investigated. As expected, all products were
isolated in good to excellent yields.
Table 1
Initial studies for the base-promoted reaction of 2-alkynylbenzaldehyde 1a, 4-
methylbenzenesulfonohydrazide, bromine, and N-((cyclohexylimino)methylene)
cyclohexanamine 2a
NTs
Cy
Cy
CHO
N
N
H
Cy
NHTs
+
Br2
H2N
base
N
C
N
+
N
solvent
Cy
2a
Ph
Ph
1a
3a
Br
Entry
Solvent
CH2Cl2
Base
Yielda (%)
1
2
3
4
5
6
7
8
Et3N
Et3N
KOH
Trace
8
28
20
46
50
44
63
20
41
18
Trace
26
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/THF
CH2Cl2/DCE
CH2Cl2/DMF
CH2Cl2/toluene
CH2Cl2/EtOH
K3PO4
K2CO3
Na2CO3
NaHCO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
9
10
11
12
13
a
Isolated yield based on 2-alkynylbenzaldehyde 1a.
Next, the scope of the multi-component reaction of 2-
alkynylbenzaldehyde 1, 4-methylbenzenesulfonohydrazide, bro-
mine, and carbodiimide 2 under the optimized conditions (DABCO,
CH2Cl2/MeCN, rt) was studied. The results are summarized in Table
2. Various substituted 2-alkynylbenzaldehydes 1 and carbodiimides
The above compounds were evaluated in a PTP1B assay. It was
demonstrated that protein tyrosine phosphatase 1B (PTP1B) is

C. Ye et al. / Tetrahedron 68 (2012) 5197e5202
5199
NTs
4.2. General experimental procedure for the multi-
NTs
R3
R3
+
R3
R3
component reaction of 2-alkynylbenzaldehyde, 4-
methylbenzenesulfono-hydrazide, carbodiimide, and
bromine
N
N
H
N
N
H
PdCl2(PPh3)2
(10 mol %)
N
N
R1
R1
R4 B(OH)2
K2CO3, DMF/H2O
R2
R2
Cy
70 ο
C
4
A mixture of 2-alkynylbenzaldehyde 1 (0.20 mmol) and 4-
methylbenzenesulfonohydrazide (0.24 mmol, 1.2 equiv) in anhy-
drous dichloromethane (0.5 mL) was stirred at room temperature
for half an hour. Then bromine (0.24 mmol, 1.2 equiv) and DABCO
(0.24 mmol, 1.2 equiv) were added. After stirred at room temper-
ature for 10 min, carbodiimide 2 (0.40 mmol, 2.0 equiv) in anhy-
drous acetonitrile (1.0 mL) was added. After completion of reaction
as indicated by TLC, the reaction was quenched with a saturated
NH4Cl solution (3.0 mL). The mixture was stirred for an additional
10 min and extracted with EtOAc (3.0 mLꢁ3). The combined or-
ganic layers were dried over Na2SO4, filtered, and concentrated in
vacuum. The crude residue was purified by flash column chroma-
tography (EtOAc/n-hexane, 1:4) to give the desired 1-(4-
bromoisoquinolin-1-yl)guanidine 3.
R4
3
Br
5
NTs
NTs
NTs
Cy
Cy
Cy
Cy
Cy
N
N
H
N
N
H
N
N
H
N
N
N
Ph
C6H4p-OMe
Ph
C6H4p-Cl
C6H4p-Me
C6H4p-OMe
5a, 75% yield
5b, 90% yield
5c, 98% yield
NTs
Cy
NTs
NTs
Cy
Cy
Cy
Cy
Cy
N
N
H
N
N
H
N
N
H
N
N
N
4.2.1. N-(((4-Bromo-3-phenylisoquinolin-1-yl)(cyclohexyl)amino)(-
cyclohexylamino)methylene)-4-methylbenzenesulfonamide
F
C6H4p-F
C6H4p-Me
C6H4p-Me
C6H4p-Me
5d, 97% yield
C6H4p-Me
C6H4p-Cl
5e, 78% yield
(3a). Yield: 63%; 1H NMR (400 MHz, CDCl3):
d 0.65e1.63 (m, 21H),
5f, 91% yield
2.18 (br, 1H), 2.38 (s, 3H), 4.86e4.90 (m, 1H), 7.02 (d, J¼8.0 Hz, 1H),
7.27 (d, J¼8.0 Hz,1H), 7.40e7.50 (m, 3H), 7.68 (dd, J¼8.0 Hz,1H), 7.74
(d, J¼8 Hz, 2H), 7.82e7.87 (m, 3H), 8.13 (d, J¼8.0 Hz, 1H), 8.36 (d,
Scheme 2. Palladium-catalyzed SuzukieMiyaura coupling reactions of 1-(4-
bromoisoquinolin-1-yl)guanidine 3.
J¼8.4 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 21.4, 24.5, 24.9, 25.3, 25.9,
31.9, 33.1, 53.4, 60.8, 116.8, 125.1, 125.7, 126.3, 127.5, 127.9, 128.6,
129.1,129.9,132.3,137.7,139.8,140.8,142.1,150.3,151.3,157.6; HRMS
(ESI) calcd for C35H39BrN4O2Sþ [MþH]þ: 659.2055, found 659.2066.
a target for diabetes and obesity, which has effects in the negative
regulation of insulin signaling pathway.9 Interestingly, compound
5f was found as the most effective one (IC50 2.05 mM). This prom-
ising result would encourage us for its library construction.
4.2.2. N-(((4-Bromo-3-phenylisoquinolin-1-yl)(4-chlorophenyl)
amino)(4-chlorophenylamino)methylene)-4-methylbenzenesulfona-
mide (3b). Yield: 61%; 1H NMR (400 MHz, CDCl3):
d 2.36 (s, 3H),
3. Conclusions
6.62 (d, J¼8.4 Hz, 2H), 6.77 (d, J¼6.8 Hz, 2H), 6.84 (d, J¼8.4 Hz, 2H),
7.02e7.09 (m, 4H), 7.47e7.48 (m, 4H), 7.61e7.62 (m, 4H), 7.82 (d,
J¼7.2 Hz, 2H), 8.26 (d, J¼8 Hz, 1H), 9.17 (s, 1H); 13C NMR (100 MHz,
In summary, we have developed a multi-component reaction of
2-alkynylbenzaldehyde, 4-methylbenzenesulfonohydrazide, car-
bodiimide, and bromine. The transformation proceeds smoothly to
afford 1-(4-bromoisoquinolin-1-yl)guanidines in good yields under
mild conditions. The products could be further elaborated via
a palladium-catalyzed SuzukieMiyaura coupling reaction, leading
to the diverse 1-(isoquinolin-1-yl)guanidines. Library construction
and subsequent biological evaluations are in progress in our
laboratory.
CDCl3):
d 21.5, 117.4, 124.1, 124.9, 126.0, 126.2, 126.4, 127.7, 127.9,
128.5, 128.7,129.2, 129.4, 130.0, 131.7,131.9,132.1,134.7,138.3, 138.5,
139.4, 140.8, 142.9, 150.4, 151.3, 157.1; HRMS calcd for
C35H26BrCl2N4O2Sþ2 [MþH]þ: 715.0337, found 715.0357.
4.2.3. N-(((4-Bromo-3-phenylisoquinolin-1-yl)(p-tolyl)amino)(p-tol-
ylamino)methylene)-4-methylbenzenesulfonamide (3c). Yield: 60%;
1HNMR (400 MHz, CDCl3):
d 2.22(s, 3H), 2.33 (s, 3H), 2.41 (s, 3H), 6.49
(d, J¼8 Hz, 2H), 6.61 (d, J¼8 Hz, 2H), 6.72 (d, J¼8 Hz, 2H), 6.89 (d,
J¼8 Hz, 2H), 7.06 (d, J¼7.8 Hz, 2H), 7.13 (s,1H), 7.40e7.48 (m, 4H), 7.66
(t, J¼8Hz,4H), 7.74(d, J¼8.8Hz,1H), 8.19(d, J¼8.8 Hz,1H), 9.12(s,1H);
4. Experimental section
4.1. General methods
13CNMR(100MHz, CDCl3):
d20.9, 21.5, 21.8,116.6,124.4,125.1,125.19,
125.4,126.5,127.3, 127.8, 128.0,128.4,128.9,129.1,129.5,130.2, 131.4,
133.6, 135.7, 136.0, 138.1, 139.1, 139.6, 140.0, 142.4, 151.8, 157.8; HRMS
calcd for C37H32BrN4O2Sþ [MþH]þ: 675.1424, found 675.1436.
Unless otherwise stated, all commercial reagents were used as
received. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using
ꢀ
silica gel (60-A pore size, 32e63
mm, standard grade). Analytical
4.2.4. N-(((4-Bromo-3-(4-ethylphenyl)isoquinolin-1-yl)(cyclohexyl)
amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonamide
thin-layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230e400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography plates
were visualized by exposure to ultraviolet light. Organic solutions
were concentrated on rotary evaporators at w20 Torr at 25e35 ꢀC.
Nuclear magnetic resonance (NMR) spectra are recorded in parts
(3d). Yield: 55%; 1H NMR (400 MHz, CDCl3):
d 0.80e1.67 (m, 24H),
2.01e2.019 (m, 1H), 2.36 (s, 3H), 2.64e2.70 (m, 2H), 4.78e4.82 (m,
1H), 6.93 (d, J¼8 Hz, 1H), 7.19e7.24 (m, 4H), 7.56e7.61 (m, 2H),
7.73e7.79 (m, 3H), 8.03 (d, J¼8 Hz, 1H), 8.28 (d, J¼8 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 15.2, 21.4, 24.5, 24.9, 25.3, 25.8, 28.7, 31.9,
per million from internal tetramethylsilane on the
d
scale. 1H and
33.1, 53.4, 60.7, 116.7, 125.1, 125.6, 126.3, 127.4, 127.5, 128.9, 129.0,
129.9, 132.2, 137.1,137.7, 140.8, 142.1, 144.7,150.3, 151.2, 157.5; HRMS
calcd for C37H44BrN4O2Sþ [MþH]þ: 687.2363, found 687.2378.
13C NMR spectra were recorded in CDCl3 on a Bruker DRX-400
spectrometer operating at 400 MHz and 100 MHz, respectively.
All chemical shift values are quoted in ppm and coupling constants
quoted in hertz. High resolution mass spectrometry (HRMS) spectra
were obtained on a micrOTOF II Instrument.
4.2.5. N-(((4-Bromo-3-(4-ethylphenyl)isoquinolin-1-yl)(4-chloroph-
enyl)amino)(4-chlorophenylamino)methylene)-4-methylbenzenesul-

5200
C. Ye et al. / Tetrahedron 68 (2012) 5197e5202
fonamide (3e). Yield: 60%; 1H NMR (400 MHz, CDCl3):
d
1.28e1.36
140.7, 142.1, 144.7, 149.2, 151.4, 157.5, 161.5, 164.0; HRMS calcd for
C
(m, 3H), 2.36 (s, 3H), 2.75e2.79 (m, 2H), 6.62 (d, J¼8.4 Hz, 2H), 6.78
(d, J¼8.4 Hz, 2H), 6.83 (d, J¼8.4 Hz, 2H), 7.03 (d, J¼8 Hz, 2H), 7.08 (d,
J¼8.8 Hz, 2H), 7.32 (d, J¼8 Hz, 2H), 7.44 (t, J¼4 Hz, 1H), 7.56 (d,
J¼8 Hz, 2H), 7.63 (d, J¼8 Hz, 2H), 7.68e7.71 (m, 2H), 8.25 (d,
35H39BrFN4O2Sþ [MþH]þ: 677.1956, found 677.1958.
4.2.11. N-(((4-Bromo-3-(4-fluorophenyl)isoquinolin-1-yl)(4-metho-
xyphenyl)amino)(4-methoxyphenylamino)methylene)-4-methylben-
J¼8.4 Hz, 1H), 9.16 (br, 1H); 13C NMR (100 MHz, CDCl3):
d
15.3, 21.5,
zenesulfonamide (3k). Yield: 50%; 1H NMR (400 MHz, CDCl3):
d 2.40
28.7, 117.2, 124.0, 124.9, 126.2, 126.4, 127.4, 127.7, 128.4, 128.6, 129.2,
129.27, 130.1, 131.7, 131.8, 132.1, 134.7, 136.7, 138.3, 138.6, 140.8,
142.8, 144.8, 151.2, 157.1; HRMS calcd for C37H29BrCl2N4NaO2Sþ
[MþNa]þ: 765.0469, found 765.0460.
(s, 3H), 3.54 (s, 3H), 3.71 (s, 3H), 6.31 (d, J¼8 Hz, 2H), 6.46 (d, J¼8 Hz,
2H), 6.61 (d, J¼8 Hz, 2H), 6.76 (d, J¼8 Hz, 2H), 7.11e7.16 (m, 4H), 7.42
(t, J¼8 Hz, 1H), 7.59e7.68 (m, 5H), 7.78 (d, J¼8 Hz, 1H), 8.10 (d,
J¼8 Hz, 1H), 9.08 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 21.5, 55.3,
55.4, 113.6, 114.2, 114.6, 114.8, 124.4, 125.3, 126.5, 126.9, 127.3, 128.1,
129.1, 131.6, 132.0, 132.1, 135.5, 138.1, 139.3, 142.5, 149.2, 157.7, 157.8,
157.9, 161.8, 165.1; HRMS calcd for C37H31BrFN4O4Sþ [MþH]þ:
725.1228, found 725.1246.
4.2.6. N-(((4-Bromo-3-p-tolylisoquinolin-1-yl)(cyclohexyl)amino)(-
cyclohexylamino)methylene)-4-methylbenzenesulfonamide
(3f). Yield: 57%; 1H NMR (400 MHz, CDCl3):
d 0.66e1.78 (m, 21H),
2.17 (br, 1H), 2.41 (s, 3H), 2.44 (s, 3H), 4.75e4.95 (m, 1H), 7.00 (d,
J¼8 Hz, 1H), 7.26e7.31 (m, 3H), 7.64e7.68 (m, 3H), 7.81e7.87 (m,
3H), 8.11 (d, J¼8 Hz, 1H), 8.35 (d, J¼8 Hz, 1H); 13C NMR (100 MHz,
4.2.12. N-(((4-Bromo-3-(3-fluorophenyl)isoquinolin-1-yl)(cyclohex-
yl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonam-
CDCl3):
d
21.4, 21.49, 24.5, 24.9, 25.3, 25.8, 33.1, 53.4, 60.7, 116.6,
ide (3l). Yield: 53%; 1H NMR (400 MHz, CDCl3):
d 0.68e1.64 (m,
125.1, 125.6, 126.3, 127.5, 128.6, 128.9, 129.1, 129.9, 132.2, 136.9,
137.7, 138.6, 140.8, 142.1, 150.3, 151.2, 157.5; HRMS calcd for
C36H41BrN4O2Sþ [MþH]þ: 673.2212, found 673.2231.
21H), 2.11e2.18 (m, 1H), 2.41 (s, 3H), 4.77e4.93 (m, 1H), 7.04 (d,
J¼8 Hz, 1H), 7.13 (t, J¼6.4 Hz, 1H), 7.28 (d, J¼8 Hz,1H), 7.42e7.48 (m,
2H), 7.54 (d, J¼8 Hz,1H), 7.71 (d, J¼8 Hz,1H), 7.84e7.88 (m, 3H), 8.13
(d, J¼8 Hz, 1H), 8.37 (d, J¼8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
4.2.7. N-(((4-Bromo-3-p-tolylisoquinolin-1-yl)(4-methoxyphenyl)
amino)(4-methoxyphenylamino)methylene)-4-methylbenzenesulfo-
d 21.5, 22.7, 24.5, 24.9, 25.4, 25.8, 30.9, 31.9, 33.1, 53.5, 60.8, 115.5,
115.6, 116.3, 117.0, 125.1, 125.7, 125.8, 126.3, 127.6, 129.1, 129.4,
129.45, 129.5, 132.4, 137.6, 140.6, 141.7, 141.8, 142.2, 148.8, 150.6,
151.5,157.6,161.0,163.5; HRMS calcd for C35H39BrFN4O2Sþ [MþH]þ:
677.1956, found 677.1968.
namide (3g). Yield: 60%; 1H NMR (400 MHz, CDCl3):
d 2.41 (s, 3H),
2.46 (s, 3H), 3.55 (s, 3H), 3.78 (s, 3H), 6.32 (d, J¼8.8 Hz, 2H), 6.47 (d,
J¼8.8 Hz, 2H), 6.62 (d, J¼8.8 Hz, 2H), 6.78 (d, J¼8.4 Hz, 2H), 7.06 (d,
J¼8 Hz, 2H), 7.26e7.29 (m, 2H), 7.38e7.42 (m, 1H), 7.55 (d, J¼8 Hz,
2H), 7.64e7.68 (m, 3H), 7.76 (d, J¼8 Hz, 1H), 8.19 (d, J¼8.8 Hz, 1H),
4.2.13. N-(((4-Bromo-3-cyclopropylisoquinolin-1-yl)(cyclohexyl)
amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonamide
9.04 (br, 1H); 13C NMR (100 MHz, CDCl3):
d 21.4, 21.5, 55.3, 55.4,
113.6, 114.1, 124.3, 125.3, 126.5, 126.9, 127.3, 127.9, 128.5, 129.1, 130.1,
131.4, 135.5, 136.8, 138.1, 138.4, 139.3, 142.3, 150.3, 151.8, 157.6, 157.7,
158.1; HRMS calcd for C38H34BrN4O4Sþ [MþH]þ: 721.1479, found
721.1475.
(3m). Yield: 65%; 1H NMR (400 MHz, CDCl3):
d 0.80e1.56 (m, 25H),
1.74 (br,1H), 2.33 (s, 3H), 2.69e2.71 (m,1H), 4.77e4.79 (m, 1H), 6.91
(d, J¼8 Hz, 1H), 7.21 (d, J¼8 Hz, 1H), 7.44e7.48 (m, 1H), 7.68e7.69
(m, 1H), 7.78 (d, J¼8 Hz, 2H), 7.89 (d, J¼8 Hz, 1H), 8.12 (d, J¼8 Hz,
1H); 13C NMR (100 MHz, CDCl3):
d 9.19, 20.4, 23.4, 23.9, 24.4, 24.8,
4.2.8. N-(((4-Bromo-3-(4-methoxyphenyl)isoquinolin-1-yl)(cyclohe-
xyl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonam-
28.6, 31.9, 52.1, 59.3, 115.7, 123.9, 125.2, 125.4, 126.8, 128.0, 130.9,
136.0, 139.7, 141.0, 150.2, 151.6, 156.4; HRMS calcd for
C32H40BrN4O2Sþ [MþH]þ: 623.2050, found 623.2057.
ide (3h). Yield: 47%; 1H NMR (400 MHz, CDCl3):
d 0.67e1.63 (m,
21H), 2.13 (m, 1H), 2.41 (s, 3H), 3.89 (s, 3H), 4.85e4.87 (m, 1H),
6.92e7.03 (m, 3H), 7.27e7.30 (m, 2H), 7.63e7.74 (m, 2H), 7.80e7.87
(m, 3H), 8.10 (d, J¼8 Hz, 1H), 8.35 (d, J¼8 Hz, 1H); 13C NMR
4.2.14. N-(((4-Bromo-6-fluoro-3-phenylisoquinolin-1-yl)(cyclohexyl)
amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonamide
(100 MHz, CDCl3):
d
21.5, 24.5, 24.9, 25.3, 25.8, 33.1, 53.4, 55.3, 60.7,
(3n). Yield: 60%; 1H NMR (400 MHz, CDCl3):
d 1.02e1.57 (m, 21H),
113.3, 116.4, 125.0, 125.5, 126.3, 127.5, 128.8, 129.1, 131.4, 132.1, 137.8,
140.8, 142.1, 149.9, 151.1, 157.5, 159.8. HRMS calcd for
C36H42BrN4O3Sþ [MþH]þ: 689.2156, found 689.2156.
2.13 (br, 1H), 2.34 (s, 3H), 4.74e4.77 (m, 1H), 6.96 (d, J¼8 Hz, 1H),
7.20 (d, J¼8 Hz, 1H), 7.31e7.44 (m, 4H), 7.65 (d, J¼8.8 Hz, 2H), 7.77
(d, J¼8 Hz, 2H), 7.91e7.94 (m, 1H), 8.08e8.11 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 21.5, 24.5, 24.8, 25.3, 25.8, 32.0, 33.2, 53.5, 60.9,
4.2.9. N-(((4-Bromo-3-(4-methoxyphenyl)isoquinolin-1-yl)(4-chlo-
rophenyl)amino)(4-chlorophenylamino)methylene)-4-methylbenze-
111.8, 112.0, 115.7, 119.3, 119.5, 122.8, 126.3, 128.0, 128.6, 128.7, 128.8,
129.1,129.8,139.5,139.8,139.9,140.6,142.2,151.3,151.4,157.6,163.4,
165.8; HRMS calcd for C35H39BrFN4O2Sþ [MþH]þ: 677.1961, found
677.1982.
nesulfonamide (3i). Yield: 53%; 1H NMR (400 MHz, CDCl3):
d 2.37 (s,
3H), 3.91 (s, 3H), 6.61e6.64 (m, 2H), 6.76e6.94 (m, 4H), 6.96e7.21
(m, 7H), 7.43e7.58 (m,1H), 7.59e7.73 (m, 5H), 8.24 (d, J¼8.4 Hz,1H),
9.18 (br, 1H); 13C NMR (100 MHz, CDCl3):
d
21.5, 55.4, 113.3, 116.9,
4.2.15. N-(((4-Bromo-6-fluoro-3-phenylisoquinolin-1-yl)(4-
methoxyphenyl)amino)(4-methoxyphenylamino)methylene)-4-
methylbenzenesulfonamide (3o). Yield: 53%; 1H NMR (400 MHz,
123.9, 124.9,126.24, 126.27, 126.4, 127.7, 128.2, 128.6, 129.22, 129.29,
131.5, 131.7, 131.79, 131.8, 132.1. 134.7, 138.4, 138.6, 140.8, 142.9,
150.0, 151.1, 157.1, 159.9; HRMS calcd for C36H28BrCl2N4O3Sþ
[MþH]þ: 745.0437, found 745.0452.
CDCl3):
d
2.37 (s, 3H), 3.57 (s, 3H), 3.71 (s, 3H), 6.37 (d, J¼8.8 Hz, 2H),
6.52 (d, J¼8.8 Hz, 2H), 6.62 (d, J¼8.8 Hz, 2H), 6.76 (d, J¼8.8 Hz, 2H),
7.05 (d, J¼8 Hz, 2H), 7.13 (s, 1H), 7.47 (t, J¼3.6 Hz, 3H), 7.65 (t,
J¼1.2 Hz, 4H), 7.77e7.86 (m, 2H), 9.08 (s, 1H); 13C NMR (100 MHz,
4.2.10. N-(((4-Bromo-3-(4-fluorophenyl)isoquinolin-1-yl)(cyclohex-
yl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonam-
CDCl3): d 21.5, 55.3, 55.4, 111.5, 111.7, 113.7, 114.3, 118.1, 118.3, 121.4,
ide (3j). Yield: 52%; 1H NMR (400 MHz, CDCl3):
d
0.67e1.72 (m,
126.5, 126.7, 126.8, 127.8, 128.7, 128.79, 128.8, 129.1, 129.19, 130.1,
135.4,139.2,139.4, 142.5, 151.4, 151.9,157.7,157.9, 158.0, 162.7,164.7;
HRMS calcd for C37H31BrFN4O4Sþ [MþH]þ: 725.1228, found
725.1244.
21H), 2.14 (br, 1H), 2.41 (s, 3H), 4.87 (m, 1H), 7.02 (d, J¼8 Hz, 1H),
7.06e7.11 (m, 2H), 7.28 (d, J¼8 Hz,1H), 7.56e7.67 (m, 3H), 7.68e7.72
(m, 3H), 8.11 (d, J¼8 Hz, 1H), 8.35 (d, J¼8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 21.5, 22.6, 22.9, 24.5, 24.9, 25.4, 25.8, 32.0, 33.1,
38.7, 38.9, 53.5, 60.8, 114.9, 115.1, 115.6, 116.7, 125.1, 125.7, 126.3,
127.5, 128.0, 129.1, 129.2, 129.6, 131.3, 131.8, 131.9, 132.4, 135.8, 137.7,
4.2.16. N-(((4-Bromo-3-(4-ethylphenyl)-6-fluoroisoquinolin-1-
yl)(cyclohexyl)amino)(cyclohexylamino)methylene)-4-methylbenze-

C. Ye et al. / Tetrahedron 68 (2012) 5197e5202
5201
nesulfonamide (3p). Yield: 58%; 1H NMR (400 MHz, CDCl3):
d
(0.4 mmol, 2.0 equiv), and PdCl2(PPh3)2 (0.02 mmol, 10 mol %) in
0.8 mL of DMF/H2O (5:1, v/v) was stirred at 70 ꢀC for about 8e10 h
under nitrogen atmosphere. After completion of the reaction as
indicated by TLC, water (10 mL) was added to quench the reaction.
The mixture was extracted with ethyl acetate (10 mLꢁ3). The
combined organic layer was washed with brine (15 mL), dried over
Na2SO4. Evaporation of the solvent followed by purification on
silica gel provided the corresponding product 5.
0.61e1.94 (m, 24H), 2.13 (br, 1H), 2.33 (s, 3H), 2.65 (q, 1J¼1.9 Hz,
2J¼3.8 Hz, 2H), 4.73e4.75 (m,1H), 6.93 (d, J¼8 Hz,1H), 7.19 (d, J¼8 Hz,
2H), 7.24 (d, J¼8 Hz,1H), 7.29e7.34 (m,1H), 7.59 (d, J¼8 Hz, 2H), 7.77
(d, J¼8 Hz, 2H), 7.89e7.92 (m, 1H), 8.06e8.10 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 15.2, 21.4, 24.5, 24.9, 25.3, 25.9, 28.7, 33.2, 53.5,
61.0, 111.7, 112.0, 115.5, 115.58, 119.0, 119.3, 122.7, 126.3, 127.4, 128.6,
128.7, 129.1, 129.8, 136.8, 139.9, 140.0, 140.7, 142.1, 145.0, 151.2, 151.5,
157.6, 163.2, 165.8; HRMS calcd for C37H43BrFN4O2Sþ [MþH]þ:
705.2274, found 705.2277.
4.3.1. N-((Cyclohexyl(4-(4-methoxyphenyl)-3-phenylisoquinolin-1-
yl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonam-
4.2.17. N-(((4-Bromo-6-fluoro-3-p-tolylisoquinolin-1-yl)(cyclohexyl)
ide (5a). Yield:90%;1HNMR(400MHz, CDCl3):
d0.65e1.62(m, 21H),
amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonamide
2.24 (br, 1H), 2.41 (s, 3H), 3.85 (s, 3H), 4.91e4.93 (m, 1H), 6.93 (d,
J¼8 Hz, 2H), 7.01 (d, J¼8 Hz,1H), 7.11 (d, J¼8 Hz, 2H), 7.19 (t, J¼3.6 Hz,
2H), 7.27 (d, J¼8 Hz, 2H), 7.34e7.35 (m, 2H), 7.58 (t, J¼3.6 Hz, 2H),
7.65e7.66 (m, 1H), 7.87 (d, J¼8 Hz, 2H), 8.11e8.13 (m, 1H); 13C NMR
(3q). Yield: 60%; 1H NMR (400 MHz, CDCl3):
d 0.71e1.63 (m, 21H),
2.09 (s, 1H), 2.33 (s, 3H), 2.36 (s, 3H), 4.74e4.76 (m, 1H), 6.95 (d,
J¼8 Hz, 1H), 7.18e7.23 (m, 3H), 7.30e7.34 (m, 1H), 7.56 (d, J¼8 Hz,
2H), 7.77 (d, J¼8 Hz, 2H), 7.89e7.92 (m, 1H), 8.06e8.10 (m, 1H); 13C
(100 MHz, CDCl3): d 21.4, 24.8, 25.0, 25.4, 25.9, 53.6, 55.3, 60.6, 74.7,
NMR (100 MHz, CDCl3):
d
21.3, 21.4, 24.4, 24.9, 25.3, 25.8, 31.9, 33.1,
114.1, 124.5, 124.6, 126.1, 126.3, 127.2, 127.6, 127.9, 128.3, 129.0, 130.1,
130.7, 132.2, 139.4, 140.0, 141.1, 142.6, 153.1, 157.7, 159.1; HRMS calcd
for C42H47N4O3Sþ [MþH]þ: 687.3369, found 687.3351.
53.5, 61.0, 111.7, 111.9, 115.4, 115.5, 119.0, 119.3, 122.7, 126.3, 128.6,
128.7, 129.1, 129.8, 136.6, 138.8, 139.9, 140.0, 140.7, 142.1, 151.2, 151.5,
157.6, 163.2; HRMS calcd for C36H41BrFN4O2Sþ [MþH]þ: 691.2118,
found 691.2100.
4.3.2. N-(((4-(4-Chlorophenyl)-3-phenylisoquinolin-1-yl)(cyclohex-
yl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonami-
4.2.18. N-(((4-Bromo-6-fluoro-3-(4-fluorophenyl)isoquinolin-1-
yl)(cyclohexyl)amino)(cyclohexylamino)methylene)-4-methylbenze-
nesulfonamide (3r). Yield: 51%; 1H NMR (400 MHz, CDCl3):
de (5b). Yield: 75%; 1H NMR (400 MHz, CDCl3):
d 0.69e1.63 (m,
21H), 2.24e2.27 (m, 1H), 2.42 (s, 3H), 4.91e4.93 (m, 1H), 7.01 (d,
J¼8 Hz, 2H), 7.15 (d, J¼8 Hz, 2H), 7.23e7.31 (m, 2H), 7.37e7.38 (m,
3H), 7.39e7.43 (m, 2H), 7.60e7.61 (m, 3H), 7.87 (d, J¼8 Hz, 2H),
d
0.71e1.59 (m, 20H), 2.10 (s, 2H), 2.34 (s, 3H), 4.74e4.76 (m, 1H),
6.97 (d, J¼8 Hz, 1H), 7.09 (d, J¼8 Hz, 2H), 7.20 (d, J¼8 Hz, 1H),
7.32e7.36 (m, 1H), 7.64e7.67 (m, 2H), 7.77 (d, J¼8 Hz, 2H),
7.90e7.93 (m, 1H), 8.07e8.11 (m, 1H); 13C NMR (100 MHz, CDCl3):
8.15e8.17 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 21.4, 24.8, 24.9,
25.4, 25.9, 33.3, 53.6, 60.7, 74.7, 124.8, 125.7, 126.3, 127.5, 127.8,
128.1, 128.9, 129.1, 129.2, 130.1, 131.0, 132.5, 133.8, 135.4, 139.5, 141.8,
142.6, 152.1, 157.8, 162.3; HRMS calcd for C41H44ClN4O2Sþ [MþH]þ:
691.2868, found 691.2861.
d
21.4, 22.6, 24.5, 24.8, 25.3, 25.8, 32.0, 33.1, 53.5, 61.0, 111.8, 112.0,
114.9, 115.1, 115.5, 115.6, 119.3, 119.6, 122.8, 126.3, 128.6, 128.7, 129.1,
131.7, 131.8, 135.5, 135.53, 139.8, 139.9, 140.6, 142.2, 150.4, 151.4,
157.6, 161.7, 163.3, 164.2, 165.9; HRMS calcd for C35H38BrF2N4O2Sþ
[MþH]þ: 695.1861, found 695.1863.
4.3.3. N-((Cyclohexyl(4-(4-methoxyphenyl)-3-p-tolylisoquinolin-1-
yl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonami-
de (5c). Yield: 98%; 1H NMR (400 MHz, CDCl3):
d 0.67e1.61 (m,
4.2.19. N-(((4-Bromo-6-fluoro-3-(4-fluorophenyl)isoquinolin-1-
yl)(4-chlorophenyl)amino)(4-chlorophenylamino)methylene)-4-
methylbenzenesulfonamide (3s). Yield: 68%; 1H NMR (400 MHz,
21H), 2.10e2.25 (m, 1H), 2.29 (s, 3H), 2.42 (s, 3H), 3.86 (s, 3H),
4.92e4.94 (m, 1H), 6.95 (d, J¼8 Hz, 2H), 7.01 (d, J¼8 Hz, 2H), 7.12 (d,
J¼8 Hz, 2H), 7.25e7.29 (m, 4H), 7.54e7.66 (m, 3H), 7.87 (d, J¼8 Hz,
CDCl3):
d
2.30 (s, 3H), 6.60 (d, J¼8.8 Hz, 2H), 6.69 (d, J¼8.4 Hz, 2H),
2H), 8.10e8.12 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 21.1, 21.4, 22.7,
6.80 (d, J¼8.8 Hz, 2H), 6.98e7.09 (m, 4H), 7.12e7.18 (m, 2H),
24.8, 24.9, 25.4, 25.9, 31.9, 33.2, 53.6, 55.3, 60.4, 60.5, 103.5, 114.1,
124.3, 124.6, 126.1, 126.3, 127.7, 128.4, 129.0, 129.1, 129.9, 130.0,
130.6, 132.1,137.0,138.5,141.0,141.9,148.5,151.3, 157.7,159.0; HRMS
calcd for C43H49N4O3Sþ [MþH]þ: 701.3525, found 701.3539.
7.37e7.56 (m, 6H), 8.18e8.20 (m, 1H), 9.19 (s, 1H); 13C NMR
(100 MHz, CDCl3):
d 21.5, 108.6, 108.8, 114.9, 115.1, 116.9, 122.2,
122.5, 126.1, 126.3, 126.4, 128.7, 129.2, 129.4, 130.9, 131.0, 131.9,
132.0, 132.3, 134.8, 135.0, 135.1, 135.4, 138.6, 140.2, 143.0, 149.1,
150.8, 156.9, 160.1, 161.7, 162.6, 164.1; HRMS calcd for
C35H23BrCl2F2N4NaO2Sþ [MþNa]þ: 772.9968, found 772.9987.
4.3.4. N-((Cyclohexyl(3,4-dip-tolylisoquinolin-1-yl)amino)(cyclohe-
xylamino)methylene)-4-methylbenzenesulfonamide
(5d). Yield:
97%; 1H NMR (400 MHz, CDCl3):
d
0.66e1.62 (m, 21H), 2.23e2.24
4.2.20. N-(((4-Bromo-6-fluoro-3-(4-fluorophenyl)isoquinolin-1-
yl)(4-methoxyphenyl)amino)(4-methoxyphenylamino)methylene)-4-
methylbenzenesulfonamide (3t). Yield: 52%; 1H NMR (400 MHz,
(br, 1H), 2.29 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 4.92e4.94 (m, 1H),
6.98e7.02 (m, 3H), 7.09 (d, J¼8 Hz, 2H), 7.21 (d, J¼8 Hz, 2H),
7.26e7.29 (m, 3H), 7.55e7.64 (m, 3H), 7.87 (d, J¼8 Hz, 2H),
CDCl3):
d
2.33 (s, 3H), 3.57 (s, 3H), 3.71 (s, 3H), 6.30 (d, J¼8.8 Hz, 2H),
8.10e8.12 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 21.1, 21.3, 21.4,
6.44 (d, J¼8.8 Hz, 2H), 6.56 (d, J¼8.8 Hz, 2H), 6.68 (d, J¼8.8 Hz, 2H),
24.8, 24.9, 25.4, 25.9, 53.6, 60.5, 76.4, 124.3, 124.5,126.1, 126.3, 127.7,
128.4, 129.0, 129.3, 130.0, 130.2, 130.6, 130.9, 134.0, 137.0, 137.1,
137.3, 138.4, 141.0, 141.9, 148.3, 151.3, 157.7; HRMS calcd for
C43H49N4O2Sþ [MþH]þ: 685.3571, found 685.3582.
7.02e7.47 (m, 5H), 7.53e7.61 (m, 4H), 7.77e7.86 (m, 2H), 9.08 (s,
1H); 13C NMR (100 MHz, CDCl3):
d 21.5, 55.3, 55.4, 111.5, 111.7, 113.7,
114.3, 114.7, 114.9, 118.2, 118.4, 121.4, 126.5, 126.8, 126.89, 128.7,
128.8, 129.1, 132.0, 132.1, 135.3, 139.2, 140.2, 140.3, 142.5, 150.2,
150.3, 152.0, 157.8, 157.9, 157.96, 158.0, 162.7, 167.1; HRMS calcd for
C37H30BrF2N4O4Sþ [MþH]þ: 743.1134, found 743.1147.
4.3.5. N-(((4-(4-Chlorophenyl)-3-p-tolylisoquinolin-1-yl)(cyclohex-
yl)amino)(cyclohexylamino)methylene)-4-methylbenzenesulfonami-
de (5e). Yield: 78%; 1H NMR (400 MHz, CDCl3):
d 0.68e1.64 (m,
4.3. General experimental procedure for the palladium-
catalyzed SuzukieMiyaura coupling reaction of 1-(4-
bromoisoquinolin-1-yl)guanidine 3 with arylboronic acid
21H), 2.26 (br, 1H), 2.41 (s, 3H), 2.42 (s, 3H), 4.92e4.94 (m, 1H),
7.01e7.04 (m, 3H), 7.15 (d, J¼8 Hz, 2H), 7.22 (d, J¼8 Hz, 2H),
7.26e7.30 (m, 2H), 7.39 (d, J¼8 Hz, 2H), 7.56e7.65 (m, 2H), 7.87 (d,
J¼8 Hz, 2H), 8.13e8.15 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 21.1,
A
solution of 1-(4-bromoisoquinolin-1-yl)guanidine
3
21.4, 24.8, 24.9, 25.4, 25.9, 53.6, 60.6, 124.3,124.7,125.6,126.3,127.9,
128.6, 128.8, 129.0, 129.9, 130.0, 130.9, 132.4, 133.7, 135.6, 136.6,
(0.2 mmol), arylboronic acid (0.24 mmol, 1.2 equiv), K2CO3

5202
C. Ye et al. / Tetrahedron 68 (2012) 5197e5202
137.4, 137.9, 140.9, 142.0, 148.6, 151.9, 157.7; HRMS calcd for
References and notes
C42H46ClN4NaO2Sþ [MþNa]þ: 727.2849, found 727.2856.
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4.3.6. N-((Cyclohexyl(6-fluoro-3-(4-fluorophenyl)-4-p-tolylisoquino-
lin-1-yl)amino)(cyclohexylamino)methylene)-4-methyl-
benzenesulfonamide (5f). Yield: 91%; 1H NMR (400 MHz, CDCl3):
d
0.66e1.63 (m, 22H), 2.21 (br, 1H), 2.42 (s, 6H), 4.93e4.94 (m, 1H),
6.86e6.90 (m, 2H), 7.01e7.09 (m, 3H), 7.17e7.25 (m, 2H), 7.26e7.35
(m, 4H), 7.56e7.66 (m, 2H), 7.87 (d, J¼8 Hz, 1H), 8.11e8.14 (m, 1H);
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13C NMR (100 MHz, CDCl3):
d 21.3, 21.4, 24.8, 24.9, 25.4, 25.9, 33.3,
53.6, 60.5, 114.5, 114.7, 124.4, 124.6, 126.1, 126.3, 128.0, 129.0, 129.4,
130.4, 130.8, 130.9, 131.81, 131.89, 133.6, 135.9, 137.6, 138.3, 141.0,
142.0, 147.3, 151.5, 157.7, 158.7; HRMS calcd for C42H45F2N4O2Sþ
[MþH]þ: 707.3231, found 707.3256.
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Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
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Med. Chem. 2002, 9, 1241.
€
ꢁ
Acknowledgements
Financial support from National Natural Science Foundation of
China (No. 20972030) is gratefully acknowledged. We thank Prof.
Jia Li (The National Center for Drug Screening, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences) for providing the
biological assays.
6. For selected examples, see: (a) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010, 5238;
(b) Yu, X.; Ye, S.; Wu, J. Adv. Synth. Catal. 2010, 352, 2050; (c) Yu, X.; Wu, J. J.
Comb. Chem. 2010, 12, 238; (d) Yu, X.; Ding, Q.; Wu, J. J. Comb. Chem. 2010, 12,
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Neel, B. G. Cell 1992, 68, 545; (b) Woodford-Thomas, T. A.; Rhodes, J. D.; Dixon, J.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.03.081. These data in-
clude MOL file and InChIKey of the most important compounds
described in this article.