An expeditious approach to 1-(isoquinolin-1-yl)guanidines via a three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, with carbodiimide

Article abstract of DOI:10.1016/j.tet.2011.06.056

A small library of 1-(isoquinolin-1-yl)guanidine is constructed efficiently via a silver triflate-catalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, with carbodiimide. The preliminary biological screens of these isoquinoline library members have been evaluated, which show promising results as PTP1B inhibitor and HCT-116 inhibitor.

Full text of DOI:10.1016/j.tet.2011.06.056

Tetrahedron 67 (2011) 5871e5877
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An expeditious approach to 1-(isoquinolin-1-yl)guanidines via a three-component
reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, with carbodiimide
,
a,c,
Huanhuan Wang a, Shengqing Ye a, Hanpeng Jin a, Jianping Liu b , Jie Wu
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b EENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, China
c 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:
A small library of 1-(isoquinolin-1-yl)guanidine is constructed efficiently via a silver triflate-catalyzed
three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, with carbodiimide. The pre-
liminary biological screens of these isoquinoline library members have been evaluated, which show
promising results as PTP1B inhibitor and HCT-116 inhibitor.
Received 9 May 2011
Accepted 21 June 2011
Available online 25 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylbenzaldehyde
Carbodiimide
1-(Isoquinolin-1-yl)guanidine
Silver triflate
Sulfonohydrazide
1. Introduction
Multi-component reactions have been applied successfully for
the formation of natural product-like compounds.6 We also utilized
Library construction of small molecules has been recognized as
an important step in drug development and drug discovery process,
and intense interest has been directed toward the combinatorial
synthesis of natural product-like compounds with privileged scaf-
folds using a diversity-oriented synthesis.1 Among the skeletons,
extensive studies have been toward the preparation of isoquino-
lines due to their immense biological importance.2 Many methods
including the PomeranzeFritsch,3a,b BischlereNapieralski,3c Pic-
teteSpengler reactions,3d and metal-catalyzed reactions4 have
been developed. However, generally either harsh reaction condi-
tions and/or tedious reaction procedures are required for these
approaches, which limit their application for library synthesis.
Recently, we developed an efficient route for the synthesis of 1-
(isoquinolin-1-yl)ureas starting from 2-alkynylbenzaldoxime.5 The
1-(isoquinolin-1-yl)urea, which possesses hydrogen bond donor/
acceptor capabilities could be expected to confer interesting bi-
ological properties. Duo to the structural similarity of urea and
guanidine, we conceived that 1-(isoquinolin-1-yl)guanidine would
display the similar functions. Consequently, we started to consider
for the library construction of diverse 1-(isoquinolin-1-yl)guani-
dines, which could be evaluated against various biological screens.
this strategy for the preparation of a variety of N-heterocycles due
to its high efficiency.7 For instance, four-component reaction of 2-
alkynylbenzaldehyde, sulfonohydrazide, alcohol, and
a,b-un-
saturated aldehyde or ketone was demonstrated efficiently to
generate the diverse H-pyrazolo[5,1-a]isoquinolines.7a Among the
reaction process, N0-(2-alkynylbenzylidene)hydrazide, which was
formed in situ from 2-alkynylbenzaldehyde and sulfonohydrazide
was believed to be the active species. As mentioned above, 1-(iso-
quinolin-1-yl)ureas were generated via AgOTf-catalyzed reaction of
2-alkynylbenzaldoxime with carbodiimide.5b We envisioned that
1-(isoquinolin-1-yl)guanidine would be formed through a similar
transformation starting from N0-(2-alkynylbenzylidene)hydrazide
with carbodiimide. As shown in Scheme 1, we conceived that after
condensation of 2-alkynylbenzaldehyde 1 with sulfonohydrazide,
N0-(2-alkynylbenzylidene)hydrazide A would be generated, which
then underwent intramolecular cyclization to afford the key in-
termediate isoquinolinium-2-yl amide B in the presence of silver
triflate catalyst.8 After the subsequent [3þ2] cycloaddition reaction
with carbodiimide 2 and further intramolecular rearrangement, the
desired 1-(isoquinolin-1-yl)guanidine 3 would be produced. Thus,
we started to explore the feasibility of this three-component re-
action of 2-alkynylbenzaldehyde 1, sulfonohydrazide, and carbo-
diimide 2 for rapid access to functionalized 1-(isoquinolin-1-yl)
guanidines 3.
* Corresponding authors. E-mail address: jie_wu@fudan.edu.cn (J. Liu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.056

5872
H. Wang et al. / Tetrahedron 67 (2011) 5871e5877
NHTs
the diversity reagents of 2-alkynylbenzaldehydes 1 and carbodii-
N
N
R1
AgOTf (cat.)
N
Ts
mide 2 are presented in Fig. 1 and Fig. 2. The corresponding results
are shown in Table 2. We noticed that all reactions worked well to
afford the expected 1-(isoquinolin-1-yl)guanidines in moderate to
good yields. Not only aryl substituted carbodiimides but also alkyl
substituted carbodiimides are good partners in this three-
component reaction. Moreover, various substitutions attached on
the triple bond or in the aromatic ring of 2-alkynylbenzaldehydes 1
do not affect the final outcome. Additionally, all products were
obtained by a simple purification on silica gel. From the results, it
seems that this solution-phase synthesis has the advantages with
good substrate generality, mild conditions, and experimental ease.
A wide variety of functionality could be readily accommodated and
the diversity could be introduced easily.
R1
6-endo
TsNHNH2
CHO
R2
cyclization
B
A
R2
R3
[3+2]
N
C N
2
R1
cycloaddition
R3
NTs
N R3
R3
R3
R3
R2
R1
1
Base
N
N
H
N
H
N
Ts
rearrangement
N
N
R1
R2
R2
3
C
Scheme 1. Proposed synthetic route for formation of 1-(isoquinolin-1-yl)guanidines
via three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and
a
carbodiimide.
Cl
CHO
CHO
F
CHO
CHO
2. Results and discussion
F
During our initial studies, 2-alkynylbenzaldehyde 1{1}, sulfo-
nohydrazide, and N-((cyclohexylimino)methylene)-cyclohexan-
amine 2{1} were selected as the substrates for reaction
development. To simplify the optimization process, the reaction
was performed in two steps. Thus, after condensation of 2-
alkynylbenzaldehyde 1{1} with sulfonohydrazide, reaction of N0-
(2-alkynylbenzylidene)hydrazide A1 and N-((cyclohexyl-imino)
methylene)cyclohexanamine 2{1} was investigated. Since silver
triflate has been demonstrated as the most efficient catalyst for
intramolecular cyclization of N0-(2-alkynylbenzylidene)-hydra-
zide,8 this model reaction was performed in the presence of
10 mol % of silver triflate in different solvents at 50e60 ꢀC (Table 1).
As expected, the desired product 3{1,1} was isolated in 91% yield
when the reaction worked in dichloroethane (Table 1, entry 1). A
good yield (81%) was observed as well when acetonitrile was used
as a replacement (Table 1, entry 2). However, the yield was dra-
matically decreased when the reaction occurred in DMF, THF, or
1,4-dioxane (Table 1, entries 3e5). Additionally, a diminished re-
activity was displayed when the catalytic amount of silver triflate
was reduced or the reaction temperature was lower (data not
shown in Table 1). With these results in hand, we re-examined the
three-component reaction of 2-alkynylbenzaldehyde 1{1}, sulfo-
nohydrazide, and N-((cyclohexylimino)methylene)cyclo-hexan-
amine 2{1} in a one-pot manner under the best conditions (Table 1,
entry 1). We found that this reaction proceeded smoothly as well to
furnish the corresponding product 3{1,1} in 52% yield.
Ph
Ph
Ph
Ph
1
2
3
4
CHO
CHO
CHO
F
p-ClC6H4
p-MeC6H4
p-MeC6H4
CHO
7
6
5
CHO
F
CHO
F
Ph
p-MeC6H4
p-MeOC6H4
10
8
9
Fig. 1. Diversity reagents 1 {1e10}.
N
C
N
N
C
N
N
N
C
N
1
3
2
N
C
N
Cl
N
C
Cl
4
5
Fig. 2. Carbodiimide reagents 2 {1e5}.
After successful generation of this 1-(isoquinolin-1-yl)guani-
dine library, the preliminary biological results from this library
have proven quite interesting. Although no active compounds were
found for the Aurora A assay. Compound 3{5,2} shows interesting
Table 1
Initial studies for reaction of 2-alkynylbenzaldehyde 1{1}, sulfonohydrazide, and N-
((cyclohexylimino)-methylene)cyclohexanamine 2{1}
result as HCT-116 inhibitor (IC50 17.378 mg/mL). In the meantime,
Cy
these compounds were screened in a PTP1B assay, and the active
hits are displayed in Table 3. Protein tyrosine phosphatase 1 B
(PTP1B) is a novel target for diabetes and obesity because it plays an
important role in the negative regulation of insulin signaling
pathway. Therefore, the sensitivity of insulin signaling could be
improved by inhibition of PTP1B’s activity.9 As shown in Table 3, it
is found that the results are promising. Among the compounds, 3
NTs
N
C N
CHO
NHTs
Ph
Cy
Cy
TsNHNH2
Cy
N
2{1}
N
N
H
AgOTf (10 mol %)
solvent, 50~60 ο
N
C
1{1}
3{1}
Ph
A1
Ph
Entry
Solvent
Yield (%)a
{9,2} is the most effective one (IC50 6.38 mg/mL).
1
2
3
4
5
DCE
91
81
27
70
26
MeCN
DMF
THF
3. Conclusions
1,4-Dioxane
a
Isolated yield based on 2-alkynylbenzaldehyde 1.
In conclusion, a small library of 1-(isoquinolin-1-yl)guanidines
has been rapidly constructed utilizing an AgOTf-catalyzed three-
component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide,
with carbodiimide. The method readily accommodates a wide va-
riety of functionality and the diversity could be introduced by using
the easily available building blocks. The preliminary biological
screens of these isoquinoline library members have been evaluated,
Having identified the optimized conditions (10 mol % of silver
triflate, ClCH2CH2Cl, 50e60 ꢀC), we then explored the reaction
scope of this three-component reaction.
A
series of 2-
alkynylbenzaldehydes 1 and carbodiimides 2 were employed and

H. Wang et al. / Tetrahedron 67 (2011) 5871e5877
5873
Table 2
a solution of 2-alkynylbenzaldehyde 1 (0.2 mmol), sulfonohy-
drazide (0.2 mmol), and carbodiimide compound 2 (0.4 mmol,
2.0 equiv) in DCE (2.0 mL). The solution was stirred at 50e60 ꢀC for
overnight. After completion of reaction as indicated by TLC, the
reaction was quenched by addition of saturated aqueous NH4Cl
(5.0 mL), and the mixture was extracted with EtOAc (4.0 mLꢁ3).
The combined organic layer was dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel to provide the desired product 3.
Silver triflate-catalyzed three-component reaction of 2-alkynylbenzaldehyde 1,
sulfonohydrazide, with carbodiimide 2
NTs
CHO
R3
R3
R3
AgOTf (10 mol %)
ClCH2CH2Cl
R1
N
N
H
+
+
N C N
TsNHNH2
R3
50~60 ο
C
N
R1
R2
1
2
3
R2
Entry
Substrate 1
Carbodiimide 2
Product
Yield (%)a
1
2
3
4
5
6
7
8
1{1}
1{2}
1{3}
1{4}
1{5}
1{6}
1{7}
1{8}
1{9}
1{10}
1{1}
1{2}
1{3}
1{4}
1{5}
1{6}
1{7}
1{8}
1{9}
1{10}
1{1}
1{4}
1{5}
1{6}
1{8}
1{10}
1{1}
1{4}
1{5}
1{6}
1{8}
1{10}
1{1}
1{6}
1{8}
1{10}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{4}
2{4}
2{4}
2{4}
2{4}
2{4}
2{5}
2{5}
2{5}
2{5}
3{1,1}
3{2,1}
3{3,1}
3{4,1}
3{5,1}
3{6,1}
3{7,1}
3{8,1}
3{9,1}
3{10,1}
3{1,2}
3{2,2}
3{3,2}
3{4,2}
3{5,2}
3{6,2}
3{7,2}
3{8,2}
3{9,2}
3{10,2}
3{1,3}
3{4,3}
3{5,3}
3{6,3}
3{8,3}
3{10,3}
3{1,4}
3{4,4}
3{5,4}
3{6,4}
3{8,4}
3{10,4}
3{1,5}
3{6,5}
3{8,5}
3{10,5}
52
54
51
70
45
37
32
43
30
30
67
65
51
66
57
51
58
52
52
40
61
80
65
77
82
84
88
73
85
76
66
83
88
56
60
88
4.1.1. 1,3-Dicyclohexyl-1-(3-phenylisoquinolin-1-yl)-2-
tosylguanidine (3{1,1}). 1H NMR (500 MHz, CDCl3)
d 0.55e0.60 (m,
2H), 0.64e0.71 (m, 2H), 0.80e0.87 (m, 1H), 0.91e0.99 (m, 1H),
1.20e1.33 (m, 7H), 1.53e1.64 (m, 7H), 2.00e2.01 (m, 1H), 2.43 (s,
3H), 4.90e4.96 (m, 1H), 7.00 (d, J¼7.0 Hz, 1H), 7.30 (d, J¼8.0 Hz, 2H),
7.43 (t, J¼8.0 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H), 7.51 (d, J¼7.0 Hz, 1H),
7.57 (t, J¼8.5 Hz, 1H), 7.69 (t, J¼7.5 Hz, 1H), 7.88e7.90 (m, 3H), 8.08
(t, J¼9.0 Hz, 2H), 8.13 (d, J¼7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
d
21.4, 24.3, 24.8, 25.3, 25.8, 32.9, 33.8, 53.2, 60.3, 115.7, 124.8, 124.9,
126.3, 126.4, 127.4, 128.2, 128.8, 129.0, 130.9, 137.3, 138.7, 141.0,
141.9, 149.0, 152.1, 157.5; HRMS (ESI) calcd for C35H40N4O2S:
581.2950 (MþHþ), found: 599.2940.
4.1.2. 1,3-Dicyclohexyl-1-(7-fluoro-3-phenylisoquinolin-1-yl)-2-
tosylguanidine (3{2,1}). 1H NMR (500 MHz, CDCl3)
d 0.57e0.62 (m,
2H), 0.68e0.75 (m, 2H), 0.80e0.87 (m, 1H), 0.91e0.96 (m, 1H),
2.06e2.07 (m, 1H), 2.43 (s, 3H), 4.91 (t, J¼10.5 Hz, 1H), 7.00 (d,
J¼6.5 Hz,1H), 7.30 (d, J¼7.5 Hz, 2H), 7.44 (d, J¼7.5 Hz,1H), 7.49e7.52
(m, 3H), 7.71 (dd, J¼2.0, 9.0 Hz, 1H), 7.89e7.94 (m, 3H), 8.09 (s, 1H),
8.11 (d, J¼7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 21.4, 24.3, 24.8,
2
25.3, 25.8, 30.0, 53.4, 60.4, 108.3 (d, JCF¼21.5 Hz), 115.4, 121.8 (d,
2JCF¼25.6 Hz),126.2,126.4,128.8,128.9,129.0, 130.1 (d, 3JCF¼9.3 Hz),
135.8, 137.9, 141.0, 142.0, 148.8, 151.6, 151.7, 157.4, 161.4 (d,
JCF¼250.0 Hz); HRMS (ESI) calcd for C35H39FN4O2S: 599.2856
(MþHþ), found: 599.2834.
4.1.3. 1,3-Dicyclohexyl-1-(6-fluoro-3-phenylisoquinolin-1-yl)-2-
tosylguanidine (3{3,1}). 1H NMR (500 MHz, CDCl3)
d 0.55e0.62 (m,
2H), 0.66e0.74 (m, 2H), 0.80e0.87 (m, 1H), 0.91e0.99 (m, 1H),
1.22e1.35 (m, 7H), 1.53e1.65 (m, 7H), 2.02e2.04 (m, 1H), 2.43 (s,
3H), 4.88e4.94 (m, 1H), 7.03 (d, J¼6.5 Hz, 1H), 7.29e7.31 (m, 3H),
7.45 (d, J¼7.5 Hz, 1H), 7.49e7.52 (m, 3H), 7.89 (d, J¼8.5 Hz, 2H), 8.03
a
Isolated yield based on 2-alkynylbenzaldehyde 1.
(s, 1H), 8.11e8.13 (m, 3H); 13C NMR (125 MHz, CDCl3)
d 21.4, 24.3,
Table 3
Biological screening results for 1-(isoquinolin-1-yl)guanidines (PTP1B activity assay)
2
24.8, 25.3, 25.8, 33.0, 53.3, 60.5, 110.6 (d, JCF¼20.6 Hz), 115.7 (d,
2
3JCF¼5.0 Hz), 118.6 (d, JCF¼25.5 Hz), 122.0, 126.3, 126.5, 128.1 (d,
Compound
Concentration
Result type
Result unit
Percent
Result
3JCF¼9.8 Hz),128.9, 129.0, 129.2, 137.9, 140.3, 140.4, 140.9, 142.0,
150.2, 152.2, 157.6, 163.5 (d, JCF¼253.9 Hz); HRMS (ESI) calcd for
C35H39FN4O2S: 621.2675 (MþNaþ), found: 621.2641.
3{4,2}
3{4,2}
3{7,2}
3{7,2}
3{8,2}
3{8,2}
3{9,2}
3{9,2}
3{4,3}
3{4,3}
20
20
20
20
20
m
m
m
m
m
g/mL
g/mL
g/mL
g/mL
g/mL
%Inhibition
IC50
%Inhibition
IC50
%Inhibition
IC50
%Inhibition
IC50
58.12
10.24
70.65
12.33
57.26
18.54
85.93
6.38
m
g/mL
Percent
g/mL
Percent
g/mL
Percent
g/mL
Percent
g/mL
m
4.1.4. 1-(7-Chloro-3-phenylisoquinolin-1-yl)-1,3-dicyclohexyl-2-
tosylguanidine (3{4,1}). 1H NMR (500 MHz, CDCl3)
d 0.55e0.62 (m,
m
2H), 0.70e0.77 (m, 2H), 0.83e0.88 (m, 1H), 0.93e0.98 (m, 1H),
1.22e1.36 (m, 7H), 1.53e1.65 (m, 7H), 2.04e2.06 (m, 1H), 2.43 (s,
3H), 4.92 (m, 1H), 6.98 (s, 1H), 3.30 (d, J¼7.5 Hz, 2H), 7.44 (t,
J¼7.5 Hz, 1H), 7.51 (t, J¼7.5 Hz, 2H), 7.62 (d, J¼9.0 Hz, 1H), 7.85 (d,
J¼9.0 Hz, 1H), 7.90 (d, J¼7.5 Hz, 2H), 8.06 (d, J¼7.0 Hz, 2H), 8.11 (d,
m
%Inhibition
IC50
89.46
8.94
m
which show promising results as PTP1B inhibitor and HCT-116
inhibitor.
J¼7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 17.5, 21.4, 24.3, 24.7,
25.3, 25.8, 33.0, 33.8, 53.4, 60.4, 115.4, 123.4, 125.5, 126.2, 126.4,
128.4, 128.9, 129.0, 129.1, 132.2, 134.1, 137.0, 137.8, 141.0, 141.9, 149.5,
151.3, 157.4. HRMS (ESI) calcd for C35H39ClN4O2S: 615.2560
(MþHþ), found: 615.2557.
4. Experimental section
4.1. General
4.1.5. 1,3-Dicyclohexyl-1-(3-p-tolylisoquinolin-1-yl)-2-
General procedure for AgOTf-catalyzed three-component re-
action of 2-alkynylbenzaldehyde 1, sulfonohydrazide, with carbo-
diimide 2. Silver triflate (0.02 mmol, 10 mol %) was added to
tosylguanidine (3{5,1}). 1H NMR (500 MHz, CDCl3)
d 0.55e0.60 (m,
2H), 0.64e0.70 (m, 2H), 0.80e0.86 (m, 1H), 0.90e0.98 (m, 1H),
1.20e1.32 (m, 7H), 1.52e1.61 (m, 7H), 2.01e2.02 (m, 1H), 2.43 (s,

5874
H. Wang et al. / Tetrahedron 67 (2011) 5871e5877
3H), 4.87e4.97 (m, 1H), 7.03 (d, J¼6.5 Hz, 1H), 6.99 (d, J¼6.0 Hz),
7.29e7.31 (m, 4H), 7.55 (t, J¼7.5 Hz, 1H), 7.67 (t, J¼7.5 Hz, 1H), 7.86
(d, J¼8.5 Hz,1H), 7.89 (d, J¼8.0 Hz, 2H), 8.02e8.07 (m, 4H); 13C NMR
J¼7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 21.4, 22.2, 24.4, 24.9,
25.3, 25.6, 25.9, 33.1, 33.9, 53.3, 60.2, 115.7, 123.3, 125.2,126.3, 126.4,
127.3,128.7,128.8,129.0,133.3,137.0,138.4, 138.7,141.2,141.9,148.2,
151.3, 157.4; HRMS (ESI) calcd for C36H42N4O2S: 595.3107 (MþHþ),
found: 595.3086.
(125 MHz, CDCl3) d 21.2, 21.4, 24.3, 24.8, 25.3, 25.8, 33.8, 53.2, 60.3,
115.2, 124.7, 126.2, 126.3, 127.3, 128.0, 128.9, 129.0, 129.6, 130.8,
135.5, 138.7, 138.9, 141.0, 141.9, 149.1, 152.0, 157.5. HRMS (ESI) calcd
for C36H42N4O2S: 595.3107 (MþHþ), found: 595.3099.
4.1.11. 1,3-Diisopropyl-1-(3-phenylisoquinolin-1-yl)-2-
tosylguanidine (3{1,2}). 1H NMR (500 MHz, CDCl3)
d 0.53 (s, 6H),
4.1.6. 1-(3-(4-Chlorophenyl)isoquinolin-1-yl)-1,3-dicyclohexyl-2-
1.23 (s, 6H), 2.37e2.40 (m, 1H), 2.13 (s, 3H), 5.34e5.40 (m, 1H), 6.90
(d, J¼7.0 Hz, 1H), 7.30 (d, J¼8.0 Hz, 2H), 7.42 (t, J¼7.5 Hz, 1H), 7.50 (t,
J¼7.5 Hz, 2H), 7.57 (t, J¼8.0 Hz, 1H), 7.69 (t, J¼7.5 Hz, 1H), 7.89e7.92
(m, 3H), 8.04 (d, J¼8.5 Hz, 1H), 8.08 (s, 1H), 8.14 (d, J¼7.5 Hz, 2H);
tosylguanidine (3{6,1}). 1H NMR (500 MHz, CDCl3)
d 0.50e0.58 (m,
2H), 0.64e0.71 (m, 2H), 0.78e0.85 (m, 1H), 0.91e0.98 (m, 1H),
1.21e1.33 (m, 7H),1.54e1.64 (m, 7H),1.97e1.98 (m,1H), 2.45 (s, 3H),
4.90e4.95 (m, 1H), 7.01 (d, J¼7.5 Hz, 1H), 7.30 (d, J¼7.5 Hz, 2H), 7.46
(d, J¼9.0 Hz, 2H), 7.58 (t, J¼7.5 Hz, 1H), 7.70 (t, J¼8.0 Hz, 1H),
7.88e7.90 (m, 3H), 8.05e8.09 (m, 4H). 13C NMR (125 MHz, CDCl3)
13C NMR (125 MHz, CDCl3)
d 21.3, 22.8, 46.1, 52.6, 115.8, 124.5, 124.6,
126.4, 126.5, 127.5, 128.2, 128.8, 128.9, 129.0, 130.9, 138.2, 138.8,
140.8, 142.0, 149.0, 152.0, 157.8; HRMS (ESI) calcd for C29H32N4O2S:
501.2324 (MþHþ), found: 501.2331.
d
21.4, 24.4, 24.8, 25.3, 25.9, 33.0, 33.9, 53.3, 60.4, 115.7, 124.8, 125.0,
126.3, 127.4, 127.7, 128.5, 129.0, 131.1, 135.0, 136.7, 138.6, 141.0, 142.0,
147.8, 152.3, 157.5; HRMS (ESI) calcd for C35H39ClN4O2S: 615.2560
(MþHþ), found: 615.2549.
4.1.12. 1-(7-Fluoro-3-phenylisoquinolin-1-yl)-1,3-diisopropyl-2-
tosylguanidine (3{2,2}). 1H NMR (400 MHz, CDCl3)
d 0.58 (d,
J¼6.2 Hz, 6H), 1.22 (d, J¼6.6 Hz, 6H), 2.43 (s, 3H), 2.45e2.47 (m, 1H),
5.31e5.34 (m, 1H), 6.89 (d, J¼7.68 Hz, 1H), 7.30 (d, J¼8.0 Hz, 2H),
7.41e7.52 (m, 4H), 7.66 (dd, J¼2.2, 9.1 Hz, 1H), 7.89e7.93 (m, 3H),
4.1.7. 1,3-Dicyclohexyl-1-(6-fluoro-3-p-tolylisoquinolin-1-yl)-2-
tosylguanidine (3{7,1}). 1H NMR (500 MHz, CDCl3)
d 0.55e0.62 (m,
2H), 0.66e0.73 (m, 2H), 0.79e0.88 (m, 1H), 0.90e0.98 (m, 1H),
1.22e1.35 (m, 7H), 1.53e1.64 (m, 7H), 2.00e2.02 (m, 1H), 2.42 (s,
3H), 2.43 (s, 3H), 4.87e4.93 (m, 1H), 7.01 (d, J¼7.01 Hz, 1H),
7.28e7.32 (m, 5H), 7.45 (dd, J¼2.5, 9.5 Hz, 1H), 7.88 (d, J¼8.0 Hz,
2H), 7.98 (s, 1H), 8.01 (d, J¼8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
8.08 (s, 1H), 8.11e8.13 (m, 3H); 13C NMR (125 MHz, CDCl3)
d
21.4,
2
22.8, 46.3, 52.8, 108.2 (d, JCF¼22.9 Hz), 115.6, 121.8 (d,
2JCF¼25.6 Hz), 125.5 (d, 3JCF¼7.8 Hz), 126.4, 128.9, 129.0, 129.1, 130.2
3
(d, JCF¼8.9 Hz), 135.9, 137.9, 140.8, 142.1, 148.4, 151.5, 151.6, 157.7,
161.4 (d, JCF¼249.8 Hz); HRMS (ESI) calcd for C29H31FN4O2S:
d
21.2, 21.4, 24.3, 24.8, 25.3, 25.9, 33.0, 53.3, 60.5, 110.5 (d,
519.2230 (MþHþ), found: 519.2226.
3
2
2JCF¼20.8 Hz), 114.6 (d, JCF¼5 Hz), 118.4 (d, JCF¼24.4 Hz), 121.9,
3
126.3, 126.5, 128.1 (d, JCF¼10 Hz), 128.3, 129.1, 129.6, 135.2, 139.3,
4.1.13. 1-(6-Fluoro-3-phenylisoquinolin-1-yl)-1,3-diisopropyl-2-
140.4, 140.9, 142.0, 150.3, 152.1, 157.6, 163.5 (d, JCF¼252.8 Hz); HRMS
tosylguanidine (3{3,2}). 1H NMR (400 MHz, CDCl3)
d 0.57 (d,
(ESI) calcd for C36H41FN4O2S: 613.3013 (MþHþ), found: 613.3008.
J¼6.2 Hz, 6H), 1.23 (d, J¼6.2 Hz, 6H), 2.38e2.42 (m, 1H), 2.43 (s, 3H),
5.33e5.36 (m, 1H), 6.92 (d, J¼7.7 Hz, 1H), 7.30e7.35 (m, 3H),
7.42e7.46 (m, 1H), 7.48e7.52 (m, 3H), 7.90 (d, J¼8.1 Hz, 2H), 8.02 (s,
4.1.8. 1,3-Dicyclohexyl-1-(7-fluoro-3-p-tolylisoquinolin-1-yl)-2-
tosylguanidine (3{8,1}). 1H NMR (500 MHz, CDCl3)
d
0.55e0.62 (m,
1H), 8.08 (dd, J¼5.5, 9.5 Hz, 1H), 8.12 (d, J¼6.9 Hz, 2H); 13C NMR
2
2H), 0.67e0.75 (m, 2H), 0.79e0.88 (m, 1H), 0.89e0.97 (m, 1H),
1.22e1.35 (m, 7H),1.52e1.64 (m, 7H), 2.02e2.04 (m,1H), 2.42 (s, 3H),
2.43 (s, 3H), 4.88e4.92 (m, 1H), 6.99 (d, J¼5.0 Hz, 1H), 7.29e7.32 (m,
4H), 7.46 (td, J¼2.0, 8.0 Hz, 1H), 7.69 (dd, J¼2, 9.5 Hz, 1H), 7.88e7.90
(m, 3H), 8.01 (d, J¼8.5 Hz, 2H), 8.04 (s, 1H); 13C NMR (125 MHz,
(125 MHz, CDCl3)
d
21.4, 22.8, 46.2, 52.8, 110.7 (d, JCF¼21.1 Hz),
2
115.2, 115.3, 118.6 (d, JCF¼25.5 Hz), 121.7, 126.4, 126.6, 128.0 (d,
3JCF¼9.8 Hz), 128.9, 129.1, 129.2, 137.9, 140.5 (d, 3JCF¼9.8 Hz), 140.7,
142.1, 150.2, 152.1, 157.9, 163.5 (d, JCF¼252.8 Hz); HRMS (ESI) calcd
for C29H31FN4O2S: 519.2230 (MþHþ), found: 519.2220.
CDCl3)
d 21.2, 21.4, 24.3, 24.8, 25.3, 25.8, 33.0, 53.4, 60.4, 108.3, (d,
2
3
2JCF¼22.1 Hz), 114.9, 121.8 (d, JCF¼25.9 Hz), 125.7 (d, JCF¼8.9 Hz),
4.1.14. 1-(7-Chloro-3-phenylisoquinolin-1-yl)-1,3-diisopropyl-2-
3
126.3, 129.1, 129.6, 129.9, 130.0 (d, JCF¼7.6 Hz), 135.2, 135.8, 139.1,
tosylguanidine (3{4,2}). 1H NMR (400 MHz, CDCl3)
d 0.60 (d,
141.0, 142.0, 148.9, 151.5, 151.6, 157.4, 161.3 (d, JCF¼249.5 Hz); HRMS
J¼6.2 Hz, 6H), 1.23 (d, J¼7.0 Hz, 6H), 2.43 (s, 3H), 2.48e2.50 (m, 1H),
5.30e5.34 (m, 1H), 6.85 (d, J¼7.7 Hz, 1H), 7.30 (d, J¼8.0 Hz, 2H),
7.42e7.46 (m, 1H), 7.49e7.52 (m, 2H), 7.63 (dd, J¼1.84, 8.8 Hz, 1H),
7.85 (d, J¼8.8 Hz, 1H), 7.9 (d, J¼8.4 Hz, 2H), 8.00 (d, 1H), 8.05 (d, 1H),
(ESI) calcd for C36H41FN4O2S: 613.3013 (MþHþ), found: 613.3008.
4.1.9. 1,3-Dicyclohexyl-1-(6-fluoro-3-(4-methoxyphenyl)isoquinolin-
1-yl)-2-tosylguanidine (3{9,1}). 1H NMR (500 MHz, CDCl3)
8.11e8.13 (m. 2H); 13C NMR (125 MHz, CDCl3)
d 21.4, 21.5, 22.9, 46.4,
d
0.55e0.62 (m, 2H), 0.66e0.73 (m, 2H), 0.80e0.88 (m, 1H),
52.9, 115.5,123.4, 125.2, 126.4, 126.5, 128.9, 129.1, 129.2, 132.2, 134.2,
137.1, 137.8, 140.9, 142.1, 149.5, 151.2, 157.8; HRMS (ESI) calcd for
C29H31ClN4O2S: 557.1754 (MþNaþ), found: 557.1749.
0.91e0.98 (m, 1H), 1.22e1.35 (m, 7H), 1.53e1.65 (m, 7H), 2.01e2.04
(m, 1H), 2.43 (s, 3H), 3.88 (s, 3H), 4.86e4.92 (m, 1H), 7.02e7.03 (m,
3H), 7.28e7.31 (m, 3H), 7.44 (dd, J¼2.5, 8.5 Hz,1H), 7.88 (d, J¼7.5 Hz,
2H), 7.92 (s, 1H), 8.04e8.09 (m, 3H); 13C NMR (125 MHz, CDCl3)
4.1.15. 1,3-Diisopropyl-1-(3-p-tolylisoquinolin-1-yl)-2-
d
21.4, 24.3, 24.9, 25.3, 25.9, 33.0, 42.6, 53.3, 55.4, 60.4, 110.4 (d,
tosylguanidine (3{5,2}). 1H NMR (400 MHz, CDCl3)
d 0.53 (d,
2JCF¼22.0 Hz), 113.8, 113.9, 114.0, 114.3, 118.2 (d, 2JCF¼25.8 Hz), 121.7,
126.3, 127.9, 128.1 (d, 3JCF¼10.0 Hz), 129.1, 130.5, 140.4, 140.9, 150.1,
152.1, 157.6, 161.6 (d, JCF¼232 Hz); HRMS (ESI) calcd for
C36H41FN4O3S: 629.2962 (MþHþ), found: 629.2960.
J¼5.12 Hz, 6H), 1.22 (d, J¼4.8 Hz, 6H), 2.37e2.39 (m, 1H), 2.42 (s,
3H), 2.43 (s, 3H), 5.34e5.38 (m, 1H), 6.88 (d, J¼7.68 Hz, 1H), 7.30 (d,
J¼8.1 Hz, 4H), 7.54e7.57 (m, 1H), 7.66e7.70 (m, 1H), 7.87 (d,
J¼8.0 Hz, 1H), 7.90 (d, J¼8.1 Hz, 2H), 8.01e8.04 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d 21.2, 21.4, 22.8, 115.3, 124.4, 124.6, 126.3, 126.4,
4.1.10. 1,3-Dicyclohexyl-1-(7-methyl-3-phenylisoquinolin-1-yl)-2-
127.4, 128.0, 129.1, 129.6, 130.9, 135.5, 138.8, 139.0, 140.8, 142.0,
149.0, 151.8, 157.8; HRMS (ESI) calcd for C30H34N4O2S: 537.2300
(MþNaþ), found: 537.2306.
tosylguanidine (3{10,1}). 1H NMR (500 MHz, CDCl3)
d 0.52e0.59 (m,
2H), 0.64e0.72 (m, 2H), 0.78e090 (m, 1H), 0.91e0.99 (m, 1H),
1.20e1.34 (m, 7H), 1.52e1.68 (m, 7H), 2.00e2.01 (m, 1H), 2.43 (s,
3H), 2.54 (s, 3H), 4.91e4.97 (m, 1H), 6.95 (d, J¼4.5 Hz, 1H), 7.29 (d,
J¼7.5 Hz, 2H), 7.41 (t, J¼7.0 Hz, 1H), 7.47e7.53 (m, 3H), 7.78 (d,
J¼8.5 Hz, 1H), 7.82 (s, 1H), 7.89 (d, J¼8.5 Hz, 2H), 8.04 (s, 1H), 8.11 (d,
4.1.16. 1-(3-(4-Chlorophenyl)isoquinolin-1-yl)-1,3-diisopropyl-2-
tosylguanidine(3{6,2}). 1HNMR (400 MHz, CDCl3)
6H),1.22 (d, J¼6.2 Hz, 6H), 2.37e2.38 (m,1H), 2.43 (s, 3H), 5.33e5.37
d
0.54 (d, J¼5.8 Hz,

H. Wang et al. / Tetrahedron 67 (2011) 5871e5877
5875
(m, 1H), 6.91 (d, J¼7.72 Hz, 1H), 7.31 (d, J¼8.0 Hz, 2H), 7.46 (d,
J¼8.44 Hz, 2H), 7.59 (t, J¼7.7 Hz,1H), 7.71 (t, J¼7.4 Hz,1H), 7.88e7.91
6.73e6.74 (m, 3H), 6.83 (s, 3H), 7.01 (d, J¼7.3 Hz, 3H), 7.07 (t,
J¼7.7 Hz, 4H), 7.38 (dd, J¼2.2, 8.8 Hz, 1H), 7.46e7.49 (m, 4H), 7.62 (s,
1H), 7.64e7.67 (m, 2H), 7.86 (s, 1H), 8.01 (d, J¼6.7 Hz, 2H), 9.37 (s,
(m, 3H), 8.03e8.08 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 21.4, 22.8,
46.1, 52.7, 115.8, 124.6, 124.7126.4, 127.5, 127.7, 128.5, 129.0, 129.1,
131.1, 135.0, 136.7, 138.7, 140.7, 142.1, 147.8, 152.1, 157.8; HRMS (ESI)
calcd for C29H31ClN4O2S: 535.1934 (MþHþ), found: 535.1922.
1H); 13C NMR (125 MHz, CDCl3)
d 21.5, 115.5, 119.2, 123.8, 124.0,
124.8, 125.0, 125.9, 126.0, 126.4, 126.6, 128.4, 128.6, 128.7, 128.8,
129.2, 131.2, 132.7, 136.3, 137.5, 137.7, 138.8, 142.1, 142.6, 149.6, 152.0,
157.6; HRMS (ESI) calcd for C35H27ClN4O2S: 603.1621 (MþHþ),
found: 603.1598.
4.1.17. 1-(6-Fluoro-3-p-tolylisoquinolin-1-yl)-1,3-diisopropyl-2-
tosylguanidine (3{7,2}). 1H NMR (400 MHz, CDCl3)
d 0.56 (d,
J¼5.8 Hz, 6H), 1.22 (d, J¼6.2 Hz, 6H), 2.39e2.40 (m, 1H), 2.42 (s, 3H),
2.43 (s, 3H), 6.90 (d, J¼7.7 Hz, 1H), 7.28e7.32 (m, 5H), 7.47 (dd,
J¼2.6, 9.2 Hz 1H), 7.89 (d, J¼8.0 Hz, 2H), 7.97 (s, 1H), 8.01 (d,
4.1.23. 1,3-Diphenyl-1-(3-p-tolylisoquinolin-1-yl)-2-tosylguanidine
(3{5,3}). 1H NMR (500 MHz, CDCl3)
d 2.33 (s, 3H), 2.43 (s, 3H),
6.68 (t, J¼7.0 Hz, 1H), 6.77e6.83 (t, 6H), 6.97 (t, J¼7.0 Hz, 1H), 7.04
(d, J¼7.5 Hz, 2H), 7.07 (d, J¼8.0 Hz, 2H), 7.19 (t, J¼7.5 Hz, 1H), 7.27
(d, J¼8.0 Hz, 2H), 7.44 (t, J¼7.0 Hz, 1H), 7.57 (d, J¼8.0 Hz, 1H),
7.65e7.67 (m, 3H), 7.82 (s, 1H), 7.90 (d, J¼8.5 Hz, 2H), 9.37 (s, 1H);
J¼8.1 Hz, 2H), 8.06 (dd, J¼5.5, 9.1 Hz, 1H); 13C NMR (125 MHz,
2
CDCl3)
d
21.2, 21.4, 22.8, 46.2, 52.8, 110.6 (d, JCF¼20.8 Hz), 114.7,
2
3
114.8, 118.4 (d, JCF¼13.3 Hz), 121.6, 126.4 (d, JCF¼9.9 Hz), 127.9,
128.0,129.1,129.6,135.1,139.4,140.6,140.8,142.1,150.3,152.0,157.9,
163.4 (d, JCF¼252.5 Hz); HRMS (ESI) calcd for C30H33FN4O2S:
533.2387 (MþHþ), found: 533.2377.
13C NMR (125 MHz, CDCl3)
d 21.2, 21.4, 115.4, 123.1, 124.7, 124.9,
125.0, 125.5, 125.7, 126.4, 126.5, 126.9, 127.1, 128.3, 128.7, 129.1,
129.4, 130.1, 135.4, 136.3, 138.6, 139.1, 139.2, 142.3, 142.6, 149.1,
152.7, 157.5; HRMS (ESI) calcd for C36H30N4O2S: 583.2168(MþHþ),
found: 583.2168.
4.1.18. 1-(7-Fluoro-3-p-tolylisoquinolin-1-yl)-1,3-diisopropyl-2-
tosylguanidine (3{8,2}). 1H NMR (400 MHz, CDCl3)
d 0.57 (d,
J¼6.2 Hz, 6H), 1.21 (d, J¼6.6 Hz, 6H), 2.42 (s, 3H), 2.43 (s, 3H),
2.45e2.49 (m, 1H), 5.30e5.33 (m, 1H), 6.88 (d, J¼7.7 Hz, 1H), 7.27 (s,
1H), 7.30 (d, J¼8.1 Hz, 3H), 7.47 (dt, J¼2.6, 8.6 Hz, 1H), 7.64 (dd,
J¼2.2, 9.2 Hz, 1H), 7.88e7.91 (m, 3H), 8.00e8.03 (m, 3H); 13C NMR
4.1.24. 1-(3-(4-Chlorophenyl)isoquinolin-1-yl)-1,3-diphenyl-2-
tosylguanidine (3{6,3}). 1H NMR (500 MHz, CDCl3)
d 2.35 (s, 3H),
6.71 (q, J¼4.5, 8.5 Hz, 1H), 6.80e6.83 (m, 6H), 6.99 (d, J¼7.0 Hz, 1H),
7.04 (d, J¼8.0 Hz, 2H), 7.08 (d, J¼7.5 Hz, 2H), 7.22 (d, J¼7.0 Hz, 2H),
7.40 (d, J¼8.0 Hz, 2H), 7.47 (t, J¼7.0 Hz, 1H), 7.59 (d, J¼9.0 Hz, 1H),
7.64 (d, J¼8.5 Hz, 2H), 7.69 (d, J¼8.5 Hz, 1H), 7.83 (s, 1H), 7.90 (d,
(125 MHz, CDCl3)
d 21.2, 21.4, 22.9, 46.3, 52.7, 108.2 (d,
2
3
2JCF¼21.6 Hz), 115.1, 121.8 (d, JCF¼26.6 Hz), 125.3 (d, JCF¼9.0 Hz),
3
126.3, 126.4, 129.1, 129.6, 130.1 (d, JCF¼9.1 Hz), 135.2, 135.9, 139.1,
J¼8.5 Hz, 2H), 9.39 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 21.4, 115.8,
140.9, 142.1, 148.9, 151.5, 157.7, 161.4 (d, JCF¼249.8 Hz); HRMS (ESI)
123.3, 124.7, 124.9, 125.0, 125.7, 125.8, 126.0, 126.4, 127.2, 127.4,
127.8, 128.3, 128.7, 128.8, 129.1, 130.3, 134.6, 136.3, 136.6, 139.1,
142.4, 147.8, 152.9, 157.3; HRMS (ESI) calcd for C35H27ClN4O2S:
603.1621 (MþHþ), found: 603.1636.
calcd for C30H33FN4O2S: 533.2387 (MþHþ), found: 533.2380.
4.1.19. 1-(6-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-yl)-1,3-
diisopropyl-2-tosylguanidine (3{9,2}). 1H NMR (400 MHz, CDCl3)
d
0.57 (d, J¼6.2 Hz, 6H), 1.22 (d, J¼6.2 Hz, 6H), 2.40e2.41 (m, 1H),
4.1.25. 1-(7-Fluoro-3-p-tolylisoquinolin-1-yl)-1,3-diphenyl-2-
2.43 (s, 3H), 3.88 (s, 3H), 5.31e5.35 (m, 1H), 6.90 (d, J¼7.7 Hz, 1H),
7.02 (d, J¼9.1 Hz, 2H), 7.28e7.36 (m, 3H), 7.45 (dd, J¼9.2 Hz, 1H),
tosylguanidine (3{8,3}). 1H NMR (500 MHz, CDCl3)
d 2.35 (s, 3H),
2.45 (s, 3H), 6.71e6.74 (m, 1H), 6.81e8.83 (m, 6H), 7.00 (d, J¼7.5 Hz,
1H), 7.05e7.09 (m, 5H), 7.22 (td, J¼2.5, 8.5 Hz, 1H), 7.29 (d, J¼8.5 Hz,
2H), 7.66e7.69 (m, 3H), 7.84 (s, 1H), 7.91 (d, J¼8.5 Hz, 2H), 9.36 (s,
7.88e7.92 (m, 3H), 8.02e8.02 (m, 3H); 13C NMR (125 MHz, CDCl3)
2
d
21.4, 22.8, 46.3, 52.7, 55.4, 110.5 (d, JCF¼21.8 Hz), 114.0, 114.1,
2
3
114.3, 118.2 (d, JCF¼25.5 Hz), 121.3, 126.4, 127.9 (d, JCF¼10.5 Hz),
129.1, 130.5, 140.5, 140.6, 140.7, 142.1, 150.5, 151.9, 157.8, 160.7, 163.5
(d, JCF¼252.8 Hz); HRMS (ESI) calcd for C30H33FN4O3S: 549.2366
(MþHþ), found: 549.2348.
1H); 13C NMR (125 MHz, CDCl3)
d 21.2, 21.4, 108.6, 108.7 (d,
2
2JCF¼23.0 Hz), 115.1, 119.2, 120.9 (d, JCF¼25.6 Hz), 124.8, 125.0,
125.8, 125.9, 126.4, 126.5, 128.4, 128.6, 129.0, 129.2, 129.5, 129.7,
3
129.8, 135.1, 136.3, 138.9 (d, JCF¼8.8 Hz), 142.0, 142.5, 148.9, 152.2
(d, 3JCF¼5.8 Hz), 157.6, 160.2 (d, JCF¼247.5 Hz); HRMS (ESI) calcd for
C36H29FN4O2S: 623.1893(MþNaþ), found: 623.1874.
4.1.20. 1,3-Diisopropyl-1-(7-methyl-3-phenylisoquinolin-1-yl)-2-
tosylguanidine (3{10,2}). 1H NMR (500 MHz, CDCl3)
d 0.55 (s, 6H),
1.21 (s, 6H), 2.43 (s, 3H), 2.44e2.46 (m, 1H), 2.54 (s, 3H), 5.34e5.40
(m, 1H), 7.30 (d, J¼7.5 Hz, 2H), 7.41 (t, J¼7.5 Hz, 1H), 7.57e7.53 (m,
3H), 7.79 (d, J¼9.0 Hz, 2H), 7.91 (d, J¼8.5 Hz, 2H), 8.03 (s, 1H), 8.12
4.1.26. 1-(7-Methyl-3-phenylisoquinolin-1-yl)-1,3-diphenyl-2-
tosylguanidine (3{10,3}). 1H NMR (500 MHz, CDCl3)
d 2.29 (s, 3H),
2.31 (s, 3H), 6.73 (t, J¼6.5 Hz, 1H), 6.81e6.86 (m, 6H), 6.96 (d,
J¼7.5 Hz, 1H), 7.02e7.06 (m, 4H), 7.31 (d, J¼8.5 Hz, 1H), 7.34 (d,
J¼7.0 Hz, 1H), 7.40e7.42 (m, 2H), 7.61 (d, J¼8.5 Hz, 1H), 7.64 (d,
J¼8.5 Hz, 2H), 7.85 (s, 1H), 7.97 (d, J¼6.5 Hz, 2H), 9.34 (s, 1H); 13C
(d, J¼7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 21.4, 22.1, 22.8, 46.2,
52.2, 115.8, 123.1, 124.9, 126.4, 127.4, 128.7, 128.8, 129.1, 133.3, 137.1,
138.4, 138.6, 141.0, 141.9, 148.2, 151.2, 157.7; HRMS (ESI) calcd for
C30H34N4O2S: 515.2481 (MþHþ), found: 515.2465.
NMR (125 MHz, CDCl3)
d 21.4, 21.9, 115.9, 119.0, 122.1, 123.6, 123.8,
124.7, 124.8, 125.2, 125.8, 126.4, 126.5, 127.0, 128.3, 128.5, 128.6,
128.7, 129.1, 132.5, 136.4, 137.4, 137.6, 138.3, 139.1, 142.4, 148.3,
152.2, 157.5; HRMS (ESI) calcd for C36H30N4O2S: 583.2168 (MþHþ),
found: 583.2168.
4.1.21. 1,3-Diphenyl-1-(3-phenylisoquinolin-1-yl)-2-tosylguanidine
(3{1,3}). 1H NMR (500 MHz, CDCl3)
d
2.34 (s, 1H), 6.70 (t, J¼7.0 Hz,
1H), 6.79e6.85 (m, 6H), 6.98 (t, J¼7.5 Hz, 1H), 7.04e7.08 (m, 4H),
7.21e7.24 (m, 1H), 7.42e7.49 (m, 4H), 7.61 (d, J¼9.0 Hz, 1H), 7.66 (d,
J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, 1H), 7.87 (s, 1H), 8.00 (d, J¼7.0 Hz,
4.1.27. 1-(3-Phenylisoquinolin-1-yl)-1,3-dip-tolyl-2-tosylguanidine
2H), 9.37 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
21.5, 115.9, 123.3,
(3{1,4}). 1H NMR (400 MHz, CDCl3)
d 1.89 (s, 3H), 2.20 (s, 3H), 2.37
124.8, 125.0, 125.1, 125.6, 125.8, 126.4, 126.6, 127.1, 127.2, 128.3,
128.7, 128.8, 129.1, 130.2, 136.4, 138.2, 139.2, 142.4, 142.6, 149.1,
152.8, 157.5; HRMS (ESI) calcd for C35H28N4O2S: 569.2011 (MþHþ),
found: 669.2024.
(s, 3H), 6.55 (q, J¼8.4 Hz, 4H), 6.72 (d, J¼8.1 Hz, 2H), 6.88 (d,
J¼8.1 Hz, 2H), 7.10e7.14 (m, 3H), 7.20e7.24 (m, 1H), 7.40e7.48 (m,
3H), 7.58 (d, J¼8.4 Hz, 1H), 7.67 (d, J¼8.4 Hz, 1H), 7.70 (d, J¼8.4 Hz,
2H), 7.83 (s, 1H), 8.00 (d, J¼7.0 Hz, 2H), 9.23 (s, 1H); 13C NMR
(125 MHz, CDCl3)
d 20.3, 20.7, 21.3, 115.6, 123.3, 124.9, 125.0, 125.9,
4.1.22. 1-(7-Chloro-3-phenylisoquinolin-1-yl)-1,3-diphenyl-2-
126.4, 126.5, 126.9, 127.0, 128.5, 128.7, 129.0, 129.1, 129.3, 129.9,
133.7,135.3,135.6,138.1,139.0,139.2,140.1,142.2,150.0,152.7,157.9;
tosylguanidine (3{4,3}). 1H NMR (400 MHz, CDCl3)
d 2.34 (s, 3H),

5876
H. Wang et al. / Tetrahedron 67 (2011) 5871e5877
HRMS (ESI) calcd for C37H32N4O2S: 597.2324 (MþHþ), found:
6.71 (d, J¼9.0 Hz, 2H), 6.75e6.79 (m, 4H), 7.07 (d, J¼9.0 Hz, 2H), 7.11
(d, J¼7.5 Hz, 2H), 7.24e7.30 (m, 2H), 7.48 (t, J¼8.0 Hz, 2H), 7.53 (t,
J¼8.0 Hz, 2H), 7.65 (d, J¼8.0 Hz, 2H), 7.74 (d, J¼8.0 Hz, 2H), 7.91 (s,
1H), 7.97 (d, J¼6.5 Hz, 2H), 9.30 (s, 1H); 13C NMR (125 MHz, CDCl3)
597.2312.
4.1.28. 1-(7-Chloro-3-phenylisoquinolin-1-yl)-1,3-diphenyl-2-
tosylguanidine (3{4,4}). 1H NMR (500 MHz, CDCl3)
d
1.94 (s, 3H),
d 21.4, 116.2, 123.0, 124.6, 126.0, 126.1, 126.3, 126.5, 127.4, 127.5,
2.22 (s, 3H), 2.39 (s, 3H), 6.58 (s, 4H), 6.71 (d, J¼8.0 Hz, 2H), 6.90 (d,
J¼8.5 Hz, 2H), 7.14 (d, J¼8.5 Hz, 2H), 7.38 (dd, J¼2.0, 7.0 Hz, 1H),
7.44e7.46 (m, 2H), 7.50 (t, J¼7.0 Hz, 2H), 7.61 (d, J¼8.0 Hz, 1H), 7.70
(d, J¼8.0 Hz, 2H), 7.84 (s, 1H), 8.04 (d, J¼7.5 Hz, 2H), 9.22 (s, 1H); 13C
128.5, 128.7, 128.8, 129.0, 129.2, 129.5, 130.5, 131.4, 131.7, 134.8,
137.9, 138.8, 139.2, 141.0, 142.7, 149.3, 152.2, 157.1; HRMS (ESI) calcd
for C35H26Cl2N4O2S: 637.1232 (MþHþ), found: 637.1227.
NMR (125 MHz, CDCl3)
d
20.5, 20.8, 21.5, 115.4, 123.9, 124.3, 124.9,
4.1.34. 1,3-Bis(4-chlorophenyl)-1-(3-(4-chlorophenyl)isoquinolin-1-
125.4, 126.5, 126.7, 128.7, 128.8, 128.9, 129.0, 129.1, 129.2, 129.6,
131.0, 132.4,133.8,135.8,136.0, 137.5,137.8, 139.7,142.5, 149.6, 152.1,
158.2; HRMS (ESI) calcd for C37H31ClN4O2S: 631.1934 (MþHþ),
found: 631.1900.
yl)-2-tosylguanidine (3{6,5}). 1H NMR (500 MHz, CDCl3)
d 2.35 (s,
3H), 6.71 (q, J¼8.0 Hz,1H), 6.80e6.83 (m, 5H), 7.05 (d, J¼8.0 Hz,1H),
7.08 (d, J¼7.5 Hz, 2H), 7.22 (t, J¼7.0 Hz, 2H), 7.41 (d, J¼8.0 Hz, 2H),
7.47 (t, J¼8.0 Hz, 1H), 7.59 (d, J¼9.0 Hz, 1H), 7.64 (d, J¼8.5 Hz, 2H),
7.69 (d, J¼8.5 Hz,1H), 7.83 (s,1H), 7.91 (d, J¼8.5 Hz, 2H), 9.39 (s,1H);
4.1.29. 1,3-Dip-tolyl-1-(3-p-tolylisoquinolin-1-yl)-2-tosylguanidine
13C NMR (125 MHz, CDCl3)
d 21.5, 116.1, 123.1, 124.7, 126.0, 126.1,
(3{5,4}). 1H NMR (500 MHz, CDCl3)
d
1.90 (s, 3H), 2.20 (s, 3H), 2.31
126.4, 127.5, 127.8, 128.6, 128.9, 129.1, 1129.2, 130.7, 131.5, 131.9,
134.8, 135.0, 136.4, 138.8, 139.2, 141.0, 142.9, 148.1, 152.4, 157.1;
HRMS (ESI) calcd for C35H25Cl3N4O2S: 671.0842 (MþHþ), found:
671.0813.
(s, 1H), 2.37 (s, 3H), 2.43 (s, 3H), 6.55 (m, 4H), 6.71 (d, J¼8.5 Hz, 2H),
6.87 (d, J¼8.0 Hz, 2H), 7.11e7.14 (m, 3H), 7.18 (t, J¼7.5 Hz, 1H), 7.27
(d, J¼8.0 Hz, 2H), 7.44 (t, J¼8.5 Hz, 1H), 7.55 (d, J¼8.5 Hz, 1H), 7.64
(d, J¼8.5 Hz, 1H), 7.71 (d, J¼8.0 Hz, 2H), 7.80 (s, 1H), 7.90 (d,
J¼8.0 Hz, 2H), 9.22 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
20.4, 20.8,
4.1.35. 1,3-Bis(4-chlorophenyl)-1-(7-fluoro-3-tolylisoquinolin-1-yl)-
21.4, 21.8, 115.2, 123.2, 125.0, 125.1, 126.0, 126.4, 126.5, 126.7, 127.0,
128.9, 129.0, 129.1, 129.2, 129.4, 129.9, 133.8, 135.4, 135.5, 135.6,
138.6, 139.2, 140.2, 142.3, 149.2, 152.7, 158.0; HRMS (ESI) calcd for
C38H34N4O2S: 611.2481 (MþHþ), found: 611.2487.
2-tosylguanidine (3{8,5}). 1H NMR (500 MHz, CDCl3)
d 2.36 (s, 3H),
2.45 (s, 3H), 6.73e6.81 (m, 6H), 7.04 (d, J¼9.0 Hz, 1H), 7.08 (d,
J¼9.0 Hz, 2H), 7.11 (d, J¼7.5 Hz, 2H), 7.27e7.31 (m, 3H), 7.64 (d,
J¼8.0 Hz, 2H), 7.73 (dd, J¼5.5, 9.5 Hz,1H), 7.87e7.88 (m, 3H), 9.31 (s,
1H); 13C NMR (125 MHz, CDCl3)
d
21.2, 21.5, 108.3 (d, 2JCF¼22.9 Hz),
4.1.30. 1-(3-(4-Chlorophenyl)isoquinolin-1-yl)-1,3-dip-tolyl-2-
115.4, 121.1 (d, 2JCF¼25.6 Hz), 123.7, 123.8, 126.0, 126.3, 126.4, 128.6,
tosylguanidine (3{6,4}). 1H NMR (500 MHz, CDCl3)
d
1.91 (s, 3H),
129.2, 129.6,130.0, 130.1, 131.6, 131.9, 134.8, 136.4, 138.7, 139.1, 140.5,
3
2.21 (s, 3H), 2.39 (s, 3H), 6.55 (s, 4H), 6.70 (d, J¼8.0 Hz, 2H), 6.88 (d,
J¼8.0 Hz, 2H), 7.13 (d, J¼8.5 Hz, 2H), 7.25 (d, J¼8 Hz, 1H), 7.41 (d,
J¼7.5 Hz, 2H), 7.48 (t, J¼8.0 Hz, 1H), 7.60 (d, J¼8.5 Hz,1H), 7.67e7.69
(m, 4H), 7.81 (s, 1H), 7.91 (d, J¼8.5 Hz, 2H), 9.24 (s, 1H); 13C NMR
142.8, 149.1, 151.7 (d, JCF¼5.9 Hz), 157.2, 160.4 (d, JCF¼248.9 Hz);
HRMS (ESI) calcd for C36H27Cl2FN4O2S: 669.1294 (MþHþ), found:
669.1280.
(125 MHz, CDCl3)
d
20.4, 20.8, 21.5, 115.6, 123.4, 124.9, 125.0, 125.2,
4.1.36. 1,3-Bis(4-chlorophenyl)-1-(7-methyl-3-phenylisoquinolin-1-
126.0,126.5,127.1,127.2,127.8,128.8,128.9,129.1,129.4,130.2,133.7,
134.6, 135.5, 135.8, 136.7, 139.1, 140.1, 142.4, 147.8, 153.0, 157.9;
HRMS (ESI) calcd for C37H31ClN4O2S: 631.1934 (MþHþ), found:
631.1910.
yl)-2-tosylguanidine (3{10,5}). 1H NMR (500 MHz, CDCl3)
d 2.32 (s,
3H), 2.33 (s, 3H), 6.73 (d, J¼8.0 Hz, 2H), 6.78e6.79 (m, 3H), 7.07 (t,
J¼9.0 Hz, 4H), 7.32 (s, 1H), 7.37 (d, J¼8.5 Hz, 1H), 7.42 (d, J¼7.5 Hz,
1H), 7.46 (m, J¼7.5 Hz, 2H), 7.63e7.66 (m, 3H), 7.88 (s, 2H), 7.94 (d,
J¼7.5 Hz, 2H), 9.28 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 21.4, 22.0,
4.1.31. 1-(7-Fluoro-3-p-tolylisoquinolin-1-yl)-1,3-dip-tolyl-2-
116.2, 123.3, 123.4, 125.9, 126.2, 126.3, 126.4, 127.2, 128.4, 128.7,
129.0, 129.2, 129.5, 131.2, 131.7, 132.8, 134.9, 137.6, 137.8, 138.0,
138.9, 141.0, 142.6, 148.5, 151.6, 157.2; HRMS (ESI) calcd for
C36H28Cl2N4O2S: 651.1388 (MþHþ), found: 651.1384.
tosylguanidine (3{8,4}). 1H NMR (500 MHz, CDCl3)
d 1.93 (s, 3H),
2.21 (s, 3H), 2.38 (s, 3H), 2.44 (s, 3H), 6.56e6.60 (m, 4H), 6.70 (d,
J¼8.5 Hz, 2H), 6.88 (d, J¼8.5 Hz, 2H), 7.06 (d, J¼10.0 Hz, 1H), 7.13 (d,
J¼7.5 Hz, 2H), 7.20 (td, J¼2.0, 8.0 Hz, 1H), 7.29 (d, J¼8.0 Hz, 2H), 7.65
(dd, J¼5.5, 9.0 Hz, 1H), 7.70 (d, J¼7.5 Hz, 2H), 7.81 (s, 1H), 9.3 (d,
Acknowledgements
J¼8.0 Hz, 2H), 9.24 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 20.4, 20.8,
2
2
21.2, 21.4, 108.9 (d, JCF¼22.9 Hz), 114.9, 120.6 (d, JCF¼26.0 Hz),
124.9, 125.2, 126.4, 126.5, 128.8, 129.1, 129.5 (d, 3JCF¼8.3 Hz), 133.8,
135.2, 135.6, 135.8, 136.3, 138.8, 139.2, 139.7, 142.4, 148.9, 152.2 (d,
3JCF¼5.9 Hz), 158.1, 160.1 (d, JCF¼247.8 Hz); HRMS (ESI) calcd for
C38H37FN4O2S: 629.2387 (MþHþ), found: 629.2366.
Financial support from the National Natural Science Foundation
of China (No. 21032007) and the Science & Technology Commission
of Shanghai Municipality (09JC1404902) is gratefully acknowl-
edged. We thank Prof. Jia Li (The National Center for Drug Screen-
ing, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences) for providing the biological assays.
4.1.32. 1-(7-Methyl-3-phenylisoquinolin-1-yl)-1,3-dip-tolyl-2-
tosylguanidine (3{10,4}). 1H NMR (500 MHz, CDCl3)
d 1.94 (s, 3H),
2.22 (s, 3H), 2.39 (s, 3H), 6.56e6.60 (m, 4H), 6.70 (d, J¼8.5 Hz, 2H),
6.90 (d, J¼8.0 Hz, 2H), 7.38 (dd, J¼2.0, 8.0 Hz, 1H), 7.43e7.46 (m,
2H), 7.48e7.51 (m, 2H), 7.61 (d, J¼8.0 Hz, 1H), 7.70 (d, J¼8.0 Hz, 2H),
7.84 (s, 1H), 8.04 (d, J¼7.5 Hz, 2H), 9.22 (s, 1H); 13C NMR (125 MHz,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.06.056. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
CDCl3)
d 20.4, 20.8, 21.4, 21.9, 15.7, 23.7, 123.8, 124.9, 125.0, 126.0,
126.4, 126.5, 126.9, 128.4, 128.7, 129.0, 129.1, 129.2, 129.3, 132.3,
133.9, 135.3, 135.7, 137.1, 137.5, 138.3, 139.4, 140.0, 142.2, 148.3,
152.2, 158.0; HRMS (ESI) calcd for C38H34N4O2S: 611.2481 (MþHþ),
found: 611.2494.
References and notes
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tosylguanidine (3{1,5}). 1H NMR (500 MHz, CDCl3)
d 2.35 (s, 3H),

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5877
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