Synthesis of H -pyrazolo[5,1- A ]isoquinolines via silver(I)-catalyzed tandem reaction of N ′-(2-alkynylbenzylidene)hydrazides with propargyl amine derivatives

Article abstract of DOI:10.1055/s-0033-1340486

We have developed a tandem reaction of N′-(2-alkynylbenzylidene) hydrazides with propargyl amine derivatives catalyzed by silver triflate to provide 2-(aminomethyl)-H-pyrazolo[5,1-a]isoquinolines. This reaction proceeds through a tandem 6-endo-cyclization, nucleophilic addition, 5-endo-cyclization and aromatization, leading to the cycloadducts in moderate to good yields with exclusive regioselectivity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340486

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PAPER
pSaypenr thesis of H-Pyrazolo[5,1-a]isoquinolines via Silver(I)-Catalyzed Tandem Reac-
tion of N′-(2-Alkynylbenzylidene)hydrazides with Propargyl Amine Derivatives
Synthesis of H-Pyrazolo[5,1-a]isoquinolines
Hongliang Liu,a Zhiyong Wang,*b Shouzhi Pu,a Gang Liu*a
a
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang 330013, P. R. of China
b
School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, P. R. of China
Fax +86(23)65102531; E-mail: zwang@cqu.edu.cn
Received: 15.11.2013; Accepted after revision: 05.12.2013
a]pyridine frameworks (Figure 1), show important bio-
Abstract: We have developed a tandem reaction of N′-(2-alkynyl-
logical activities for the inhibition of CDC25B, TC-PTP
benzylidene)hydrazides with propargyl amine derivatives catalyzed
and PTP1B.6a Several procedures are known for the syn-
by silver triflate to provide 2-(aminomethyl)-H-pyrazolo[5,1-a]iso-
quinolines. This reaction proceeds through a tandem 6-endo-cycli-
thesis of H-pyrazolo[5,1-a]isoquinolines.6,7 Recently, Wu
zation, nucleophilic addition, 5-endo-cyclization and aromatization, and co-workers have reported the preparation of a series
leading to the cycloadducts in moderate to good yields with exclu-
sive regioselectivity.
of H-pyrazolo[5,1-a]isoquinolines from N′-(2-alkynyl-
benzylidene)hydrazides via [3+2]-cyclization reaction us-
ing a range of electrophiles,6 while Peng and co-workers
Key words: N′-(2-alkynylbenzylidene)hydrazides, propargyl amine
derivatives, silver triflate, tandem reactions, 1,3-dipolar cycloaddi-
tion reactions
have disclosed a metal-cocatalyzed approach through a
combination of C–H activation and cyclization.7 The
pharmacological records of these privileged motifs
prompted us to develop an atom-economical, one-pot,
Currently, new synthetic methods for the rapid and reli-
able construction of heterocyclic frameworks from easily
available precursors are in great demand in the process of
drug discovery. Synthetic approaches that enable straight-
forward syntheses of several different heterocyclic frame-
works from a common intermediate are especially
attractive. On the other hand, it is well-known that 1,3-di-
polar cycloaddition reactions play a pivotal role in the
area of heterocycle synthesis because of their ability to in-
crease the molecular complexity and diversity in a single
synthetic step.1 Recently, as a versatile building block,
azomethine imines have received significant attention in
1,3-dipolar cycloadditions due to their stability and ease
of synthesis, which has led to a new family of synthetic
methods toward a variety of valuable nitrogen-containing
heterocycles.2,3 For example, pyrazolidines and pyrazo-
lines can now be accessed through cycloaddition reactions
of azomethine imines with alkenes2a,b,3g–j and alkynes.3a–f
two-step cascade method for the production of com-
pounds incorporating the two aforementioned heterocy-
clic systems. On the other hand, as powerful and versatile
building blocks, allenamides have been widely applied in
organic synthesis.8 It is noteworthy that propargyl amides
have also been identified as an allenamide equivalent as
allenamides can be prepared via the base-induced isomer-
ization of propargyl amides.9 Encouraged by the afore-
mentioned results and as a part of our continuing
exploration on the formation of nitrogen-containing het-
erocycles through tandem reactions,10 we conceived that
propargyl amine derivatives might be a good partner for
the cycloaddition reaction with isoquinoline-based C,N-
cyclic azomethine imines. Herein, we disclose an efficient
synthesis of 2-(aminomethyl)-H-pyrazolo[5,1-a]isoquin-
olines 3 by silver(I)-catalyzed tandem reaction of N′-(2-
alkynylbenzylidene)hydrazides 1 with propargyl amine
derivatives 2.
Isoquinolines and pyrazolo[1,5-a]pyridines are consid-
ered privileged heterocycles and are found in many bioac-
tive compounds. The isoquinoline derivatives often
feature as building blocks in pharmaceutical compounds.4
For example, lamellarin D, which possesses an interesting
pyrroloisoquinoline subunit, is a potent inhibitor of hu-
man topoisomerase I.4e The pyrazolo[1,5-a]pyridine de-
rivatives have attracted much attention due to their wide
applications in drug discovery.5 For instance, several of
these compounds show potent antiherpetic and diuretic
activity, and are effective adenosine agonists and antago-
nists.5d,e H-Pyrazolo[5,1-a]isoquinoline derivatives, the
hybrid structure of the isoquinoline and pyrazolo[1,5-
N
isoquinoline
N
pyrazolo[1,5-a]pyridine
Figure 1 H-Pyrazolo[5,1-a]isoquinoline as a hybrid structure of iso-
quinoline and pyrazolo[1,5-a]pyridine
In an initial investigation, the reaction of N′-(2-alkynyl-
benzylidene)hydrazide 1a with propargyl amine deriva-
tive 2a was examined (Table 1). Silver triflate (AgOTf)
has been used previously as an effective catalyst for iso-
quinoline-based C,N-cyclic azomethine imine formation
via 6-endo-cyclization of N′-(2-alkynylbenzylidene)hy-
drazides;6i however, no reaction occurred in the presence
SYNTHESIS 2014, 46, 0600–0606
Advanced online publication: 10.01.2014
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DOI: 10.1055/s-0033-1340486; Art ID: SS-2013-H0745-OP
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of H-Pyrazolo[5,1-a]isoquinolines
601
of 10 mol% AgOTf in tetrahydrofuran at room tempera- conversion (Table 1, entries 9–15), and the yield was in-
ture, and essentially none of the target heterocycle 3a was creased to 73% in methanol (entry 9). Various bases were
generated (Table 1, entry 1). In contrast, when t-BuOK also tested, and K2CO3 proved to be the most suitable for
(1.0 equiv) was used as the base, the desired 1,3-dipolar this reaction (76% yield; Table 1, entry 19). Various Lewis
cycloaddition proceeded cleanly, affording the product 3a acids as additives [CuI, PdCl2, Zn(OTf)2, Cu(OTf)2] were
as a single regioisomer (55% yield; Table 1, entry 5). The evaluated; however, the results were inferior (data given
structure of compound 3a was confirmed by X-ray dif- in Supporting Information).
fraction analysis.11 Further screening of the conditions re-
vealed that an increase in the amount of base loading was
With the optimized conditions in hand, we evaluated the
reaction scope using a variety of N′-(2-alkynylbenzyli-
ineffective and led to a lower yield of 3a (Table 1, entries
dene)hydrazides 1 with propargyl amine derivative 2a at
6 and 7). The result was improved when the reaction tem-
a catalyst loading of 10 mol% on a 0.3-mmol scale (Table
perature was increased to 60 °C (65% yield; Table 1, entry
2). We found a broad substrate scope with respect to the
substituent on the aromatic ring of the N′-(2-alkynylben-
9). The choice of solvent was found to be important in the
zylidene)hydrazides 1. In all cases, compound 1 reacted
with 2a to afford the desired H-pyrazolo[5,1-a]isoquino-
lines 3 in moderate to good yields. For instance, N′-(2-al-
kynylbenzylidene)hydrazides 1 possessing an electron-
rich (entries 2 and 3) or electron-deficient (entries 4 and
5) group on the aromatic backbone showed similar effi-
Table 1 Optimization of the Reaction Conditionsa
Ts
N
AgOTf (10 mol%)
Bn
N
NNHTs
Ph
Bn
+
base, solvent
heat
N
Ts
N
2a
1a
Ph
Table 2 N′-(2-Alkynylbenzylidene)hydrazide Scopea
3a
Yieldb
(%)
NNHTs
R1
Entry
Base
(equiv)
Solvent
Temp
(°C)
Ts
R2
N
1
2
–
THF
25
25
25
25
25
25
25
40
60
60
60
60
60
60
60
60
60
60
60
60
n.r.
trace
29
40
55
35
19
62
65
42
40
71
73
50
55
69
25
15
76
71
1
+
Bn
AgOTf (10 mol%)
Bn
N
t-BuOK (0.1)
t-BuOK (0.2)
t-BuOK (0.5)
t-BuOK (1.0)
t-BuOK (1.5)
t-BuOK (2.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
DBU (1.0)
THF
K2CO3 (1.0 equiv)
MeOH, 60 °C
N
R1
N
3
THF
R2
Ts
2a
3
4
THF
Entry
R1, R2 (1)
Yieldb (%)
5
THF
6
THF
1
2
H, Ph (1a)
76 (3a)
78 (3b)
55 (3c)
47 (3d)
51 (3e)
77 (3f)
57 (3g)
82 (3h)
86 (3i)
46 (3j)
51 (3k)
68 (3l)
7
THF
4-OMe, Ph (1b)
5-Me, Ph (1c)
5-F, Ph (1d)
8
THF
3
9
THF
4
10
11
12
13
14
15
16
17
18
19
20
1,4-dioxane
MeCN
EtOH
MeOH
DCE
5
4-F, Ph (1e)
6
H, 4-MeOC6H4 (1f)
H, 4-Tol (1g)
H, 4-ClC6H4 (1h)
H, 4-FC6H4 (1i)
H, n-Bu (1j)
7
8
9
toluene
MeOH
MeOH
MeOH
MeOH
MeOH
10
11
12
H, c-Pr (1k)
Et3N (1.0)
H, t-Bu (1l)
Ph
KHCO3 (1.0)
K2CO3 (1.0)
Cs2CO3 (1.0)
13
47 (3m)
S
NNHTs
(1m)
a Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), AgOTf (0.03
mmol), base, solvent (2.0 mL), under N2.
a Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), AgOTf (0.03
mmol), K2CO3 (0.3 mmol), MeOH (2.0 mL), 60 °C, under N2.
b Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
b Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1a;
n.r. = no reaction.
© Georg Thieme Verlag Stuttgart · New York
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602
H. Liu et al.
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Table 3 Propargyl Amide Scopea
NTs
MeOH
60 °C
N
•
+
3a
NNHTs
NTsBn
Ph
5
R3
no additive
K2CO3
AgOTf
K2CO3 + AgOTf
10%
trace
trace
trace
4a
Ph
N
R4
R5
1a
AgOTf (10 mol%)
+
N
K2CO3 (1.0 equiv)
MeOH, 60 °C
R3
N
R5
N
NTs
Ph
MeOH
60 °C
N
R4
Ph
3a
+
3
NTsBn
2
2a
4a
Entry
R3, R4, R5 (2)
Yieldb (%)
no additive
K2CO3
K2CO3 + AgOTf
n.r.
n.r.
80%
1
2
3
4
5
Ph, Ts, H (2b)
Bn, Boc, H (2c)
n-Bu, Ts, H (2d)
Ph, Me, H (2e)
Bn, Ts, Ph (2f)
66 (3n)
63 (3o)
69 (3p)
n.r.
Scheme 1 Reaction of C,N-cyclic azomethine imine 4a with 5 or 2a
ciency in this cyclization reaction (Table 2). We further
examined the substrate scope by differing the nature of the
R2 substituent of the N′-(2-alkynylbenzylidene)hydra-
zides 1, under the same reaction conditions. Both aryl-
and alkyl-substituted 1 proved to be good partners in the
transformation. Moreover, it was found that substrates
with an aryl group as R2 were more reactive than those
with an alkyl group (Table 2, entries 6–12). Furthermore,
heterocyclic substrate 1m also underwent this transforma-
tion, with a slight decrease in the yield (Table 2, entry 13).
n.r.
a Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), AgOTf (0.03
mmol), K2CO3 (0.3 mmol), MeOH (2.0 mL), 60 °C, under N2.
b Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1a;
n.r. = no reaction.
ative 2c was used as the reactant, the corresponding ad-
duct 3o was obtained in 63% yield (Table 3, entry 3).
However, reaction of 1a with N-phenyl-N-methyl-substi-
tuted propargyl amine 2e gave none of the desired product
(Table 3, entry 4). Further screening revealed that an in-
ternal alkyne is not a suitable substrate for this reaction
(Table 3, entry 5).
Next, a series of propargyl amine derivatives were tested
(Table 3). N-Phenyl-substituted derivative 2b gave 3n in
moderate yield, while its butyl analogue 2d afforded the
desired product 3p in a slightly improved yield (Table 3,
entries 1 and 3). When N-Boc-N-benzyl-substituted deriv-
NTsBn
Ag
(path a)
1,2 addition
NHTs
NTs
N
N
R1
Ag
R1
BnTsN
R2
6
R2
1
intramolecular
cyclization
AgOTf
base
AgOTf
NTsBn
B–
NTs
N
H
BnTsN
2a
R1
N
Ts
N
R2
R1
4
R2
7
base
aromatization
NTsBn
NTsBn
5
N
N
R1
1,3-dipolar
cycloaddition
(path b)
R2
3
Scheme 2 Possible mechanism for the silver triflate catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazides with propargyl amine derivatives
Synthesis 2014, 46, 600–606
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Synthesis of H-Pyrazolo[5,1-a]isoquinolines
603
13C NMR (100 MHz, CDCl3): δ = 148.6, 143.0, 139.9, 137.9, 137.5,
135.9, 133.5, 129.3, 129.2, 129.0, 128.8, 128.2, 128.0, 127.9, 127.5,
127.2, 127.0, 123.6, 123.3, 112.2, 97.9, 50.5, 43.8, 21.3.
HRMS: m/z [M + H]+ calcd for C32H28N3O2S+: 518.1897; found:
518.1874.
To gain some preliminary understanding of the reaction
mechanism, several experiments were carried out. The re-
sults are listed in Scheme 1. In the absence of AgOTf and
K2CO3, C,N-cyclic azomethine imine 4a could react with
allenamide 5, which was generated from 2a in the pres-
ence of a base, and afforded the cycloadduct 3a in poor
yield. With AgOTf or K2CO3, or both, only a trace of the
corresponding product could be observed. These results
indicated that the allenamide might not be an intermediate
in the reaction. On the other hand, the reaction did not pro-
ceed when intermediate 4a was treated with 2a without
the metal catalyst or base, or both (Scheme 1). In addition,
we also discovered that terminal alkynes are essential in
this transformation (Table 3, entry 5). Therefore, we pro-
pose that the cycloadduct 3 is mainly produced via a step-
wise reaction mechanism3f,6h involving nucleophilic
addition of alkyne to the azomethine imine 4 followed by
intramolecular 5-endo-cyclization (path a) instead of a
concerted pathway (path b).3a–d,3h,j Subsequently, the in-
termediate 7 would undergo aromatization to furnish the
desired product 3 (Scheme 2).
N-Benzyl-N-((8-methoxy-5-phenylpyrazolo[5,1-a]isoquinolin-
2-yl)methyl)-4-methylbenzenesulfonamide (3b)
Yield: 128 mg (78%); yellow solid; mp 159–160 °C.
IR (KBr): 3063, 3034, 2920, 1637, 1487, 1336, 1157, 1059 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.79 (m, 3 H), 7.69 (d, J =
7.2 Hz, 2 H), 7.48–7.47 (m, 3 H), 7.28–7.21 (m, 5 H), 7.16–7.09 (m,
4 H), 6.92 (s, 1 H), 6.52 (s, 1 H), 4.52 (s, 2 H), 4.45 (s, 2 H), 3.90 (s,
3 H), 2.30 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.3, 148.7, 142.9, 140.0, 138.2,
137.5, 135.9, 133.5, 130.6, 129.3, 129.2, 129.2, 128.8, 128.2, 128.0,
127.5, 127.2, 124.9, 117.8, 117.1, 112.0, 107.9, 96.7, 55.4, 50.5,
43.9, 21.3.
HRMS: m/z [M + H]+ calcd for C33H30N3O3S+: 548.2002; found:
548.1987.
N-Benzyl-4-methyl-N-((9-methyl-5-phenylpyrazolo[5,1-a]iso-
quinolin-2-yl)methyl)benzenesulfonamide (3c)
Yield: 88 mg (55%); white solid; mp 124–125 °C.
In summary, this methodology will serve as an important
tool for the efficient synthesis of new nitrogen-containing
compounds with pharmacological activity. This new
method for the construction of 2-(aminomethyl)-H-pyr-
azolo[5,1-a]isoquinolines via silver(I)-catalyzed tandem
reaction of N′-(2-alkynylbenzylidene)hydrazides with
propargyl amine derivatives is practical and reliable. A
IR (KBr): 2988, 2915, 1543, 1496, 1342, 1153, 1053 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.80–7.78 (m, 2 H), 7.70 (d, J =
6.0 Hz, 3 H), 7.60 (d, J = 6.8 Hz, 1 H), 7.47 (s, 3 H), 7.35 (d, J = 8.0
Hz, 2 H), 7.29–7.23 (m, 4 H), 7.14 (d, J = 7.2 Hz, 2 H), 6.97 (s, 1
H), 6.60 (s, 1 H), 4.54 (s, 2 H), 4.46 (s, 2 H), 2.54 (s, 3 H), 2.32 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 142.9, 139.8, 137.7, 137.4,
possible reaction pathway, which proceeds through a tan- 137.1, 135.9, 133.6, 129.6, 129.4, 129.3, 129.1, 128.8, 128.3, 128.0,
127.5, 127.3, 127.0, 126.8, 123.7, 123.1, 112.2, 97.7, 50.5, 43.8,
21.7, 21.3.
HRMS: m/z [M + H]+ calcd for C33H30N3O2S+: 532.2053; found:
532.2043.
dem 6-endo-cyclization, nucleophilic addition, 5-endo-
cyclization and aromatization, has been proposed. Efforts
to investigate the detailed reaction mechanism and to
broaden the application of the method are currently under-
way in our laboratory.
N-Benzyl-N-((9-fluoro-5-phenylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)-4-methylbenzenesulfonamide (3d)
Yield: 75 mg (47%); white solid; mp 107–108 °C.
IR (KBr): 3078, 3030, 2923, 1609, 1492, 1326, 1156, 1053 cm–1.
NMR spectra were recorded on a Bruker AV 400 spectrometer (400
MHz for 1H, 100 MHz for 13C) with CDCl3 as solvent at 20–25 °C.
High-resolution mass spectra (HRMS) were obtained with a Finni-
gan MAT8430 Q-TOF mass spectrometer. IR spectra were recorded
with a Spectrum Two-FTIR spectrophotometer (PerkinElmer). All
commercial materials were used without further purification. Col-
umn chromatography was performed using silica gel (300–400
mesh).
1H NMR (400 MHz, CDCl3): δ = 7.78–7.75 (m, 2 H), 7.68 (d, J =
8.0 Hz, 2 H), 7.64–7.60 (m, 1 H), 7.46–7.44 (s, 4 H), 7.26 (d, J = 7.2
Hz, 2 H), 7.23–7.18 (m, 4 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.91 (s, 1
H), 6.49 (s, 1 H), 4.52 (s, 2 H), 4.43 (s, 2 H), 2.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.3 (d, 1JCF = 247.7 Hz), 148.5,
143.0, 139.0, 137.4, 137.1, 135.7, 133.0, 129.2, 129.2, 128.6, 128.2,
128.0, 127.4, 127.1, 125.4, 124.7, 116.5 (d, 2JCF = 23.4 Hz), 111.5,
108.4 (d, 2JCF = 22.9 Hz), 98.2, 50.4, 43.6, 21.2.
N-Benzyl-4-methyl-N-((5-phenylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)benzenesulfonamide (3a); Typical Procedure
A mixture of AgOTf (7.7 mg, 0.03 mmol) and N′-(2-alkynylbenzyl-
idene)hydrazide 1a (112 mg, 0.3 mmol) in MeOH (2.0 mL) was
stirred at 60 °C under N2 for 2 h. K2CO3 (42 mg, 0.3 mmol) and
propargyl amide 2a (135 mg, 0.45 mmol) were added subsequently.
The reaction mixture was stirred at 60 °C until completion of the re-
action, as indicated by TLC. Evaporation of the solvent followed by
purification of the remaining material on silica gel afforded the cor-
responding product 3a.
HRMS: m/z [M + H]+ calcd for C32H27FN3O2S+: 536.1803; found:
536.1801.
N-Benzyl-N-((8-fluoro-5-phenylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)-4-methylbenzenesulfonamide (3e)
Yield: 82 mg (51%); white solid; mp 110–111 °C.
IR (KBr): 3052, 2965, 2856, 1635, 1485, 1342, 1163, 1055 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.94–7.90 (m, 1 H), 7.80–7.78 (m,
2 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.51–7.50 (m, 3 H), 7.38–7.35 (m, 1
H), 7.31–7.21 (m, 6 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.94 (s, 1 H), 6.66
(s, 1 H), 4.53 (s, 2 H), 4.44 (s, 2 H), 2.33 (s, 3 H).
Yield: 118 mg (76%); white solid; mp 149–150 °C.
IR (KBr): 3062, 3028, 2921, 1635, 1495, 1342, 1164, 1055 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.90–7.88 (m, 1 H), 7.81–7.78 (m,
2 H), 7.71–7.67 (m, 3 H), 7.52–7.47 (m, 5 H), 7.29–7.19 (m, 5 H),
7.11 (d, J = 8.0 Hz, 2 H), 6.98 (s, 1 H), 6.64 (s, 1 H), 4.54 (s, 2 H),
4.46 (s, 2 H), 2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.0 (d, 1JCF = 247.9 Hz), 149.2,
143.1, 139.7, 139.1, 137.5, 135.9, 133.2, 130.8, 129.5, 129.4, 129.3,
2
128.8, 128.3, 128.2, 127.6, 127.3, 125.7, 120.1, 116.0 (d, JCF
=
24.0 Hz), 111.9 (d, 2JCF = 21.8 Hz), 111.5, 97.8, 50.7, 44.0, 21.4.
© Georg Thieme Verlag Stuttgart · New York
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H. Liu et al.
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HRMS: m/z [M + H]+ calcd for C32H27FN3O2S+: 536.1803; found:
536.1801.
N-Benzyl-N-((5-butylpyrazolo[5,1-a]isoquinolin-2-yl)methyl)-
4-methylbenzenesulfonamide (3j)
Yield: 69 mg (46%); white solid; mp 40–41 °C.
N-Benzyl-N-((5-(4-methoxyphenyl)pyrazolo[5,1-a]isoquinolin-
2-yl)methyl)-4-methylbenzenesulfonamide (3f)
IR (KBr): 3031, 2958, 2866, 1643, 1546, 1455, 1328, 1156, 1055
cm–1.
Yield: 126 mg (77%); yellow solid; mp 150–151 °C.
1H NMR (400 MHz, CDCl3): δ = 7.86–7.85 (m, 1 H), 7.64–7.63 (m,
1 H), 7.49–7.47 (m, 3 H), 7.32–7.22 (m, 6 H), 7.15 (d, J = 7.6 Hz, 2
H), 6.76 (s, 1 H), 6.54 (s, 1 H), 4.58 (s, 2 H), 4.51 (s, 2 H), 3.00 (t,
J = 7.6 Hz, 2 H), 2.30 (s, 3 H), 1.83–1.76 (m, 2 H), 1.51–1.46 (m, 2
H), 1.00 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 143.5, 142.9, 139.2, 139.0,
135.9, 134.7, 129.2, 128.9, 128.8, 128.3, 128.0, 127.7, 127.5, 127.4,
127.2, 123.2, 109.2, 97.5, 50.5, 43.9, 30.5, 28.9, 22.5, 21.5, 13.9.
IR (KBr): 3031, 2925, 2857, 1635, 1547, 1455, 1341, 1151, 1058
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.89–7.86 (m, 1 H), 7.76 (d, J =
8.8 Hz, 2 H), 7.71–7.66 (m, 3 H), 7.51–7.48 (m, 2 H), 7.30–7.20 (m,
5 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.00 (d, J = 8.8 Hz, 2 H), 6.95 (s, 1
H), 6.61 (s, 1 H), 4.55 (s, 2 H), 4.47 (s, 2 H), 3.86 (s, 3 H), 2.29 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 160.2, 148.4, 143.0, 139.9, 137.6,
137.5, 135.9, 130.7, 129.3, 129.1, 128.7, 128.2, 127.9, 127.5, 127.2,
127.0, 126.8, 125.7, 123.2, 113.4, 111.5, 97.8, 55.3, 50.5, 43.9,
21.3.
HRMS: m/z [M + H]+ calcd for C30H32N3O2S+: 498.2210; found:
498.2190.
N-Benzyl-N-((5-cyclopropylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)-4-methylbenzenesulfonamide (3k)
Yield: 74 mg (51%); yellow solid; mp 54–58 °C.
HRMS: m/z [M + H]+ calcd for C33H30N3O3S+: 548.2002; found:
548.2005.
IR (KBr): 3064, 2970, 2860, 1597, 1454, 1325, 1240, 1159, 1054
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.83 (m, 1 H), 7.60–7.58 (m,
1 H), 7.47–7.45 (m, 3 H), 7.27–7.16 (m, 6 H), 7.06–7.05 (m, 2 H),
7.00 (s, 1 H), 6.56 (s, 1 H), 4.62 (s, 2 H), 4.50 (s, 2 H), 2.56–2.49
(m, 1 H), 2.31 (s, 3 H), 1.16–1.11 (m, 2 H), 0.90–0.86 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.5, 143.4, 142.9, 140.6, 139.3,
137.7, 136.0, 129.7, 129.3, 128.8, 128.3, 128.3, 128.1, 127.5, 127.3,
127.2, 123.2, 106.1, 97.7, 50.7, 44.2, 21.3, 13.6, 11.0, 7.2.
N-Benzyl-4-methyl-N-((5-(p-tolyl)pyrazolo[5,1-a]isoquinolin-2-
yl)methyl)benzenesulfonamide (3g)
Yield: 91 mg (57%); white solid; mp 128–129 °C.
IR (KBr): 2987, 2922, 2857, 1638, 1548, 1446, 1349, 1151, 1050
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.90–7.88 (m, 1 H), 7.71–7.67 (m,
5 H), 7.52–7.50 (m, 2 H), 7.30–7.22 (m, 7 H), 7.12 (d, J = 8.0 Hz, 2
H), 6.97 (s, 1 H), 6.62 (s, 1 H), 4.55 (s, 2 H), 4.46 (s, 2 H), 2.44 (s,
3 H), 2.30 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.6, 143.0, 139.9, 139.2, 138.0,
137.6, 135.9, 130.6, 129.3, 128.8, 128.8, 128.2, 127.9, 127.5, 127.3,
127.1, 127.0, 123.5, 123.3, 111.9, 97.8, 50.6, 44.0, 21.4, 21.3.
HRMS: m/z [M + H]+ calcd for C29H28N3O2S+: 482.1897; found:
482.1899.
N-Benzyl-N-((5-tert-butylpyrazolo[5,1-a]isoquinolin-2-yl)meth-
yl)-4-methylbenzenesulfonamide (3l)
Yield: 101 mg (68%); yellow solid; mp 94–95 °C.
HRMS: m/z [M + H]+ calcd for C33H30N3O2S+: 532.2053; found:
532.2047.
IR (KBr): 3031, 2963, 2851, 1629, 1538, 1451, 1313, 1238, 1159,
1044 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.83 (m, 1 H), 7.63–7.62 (m,
1 H), 7.49–7.47 (m, 3 H), 7.26–7.18 (m, 6 H), 7.06–7.04 (m, 2 H),
6.86 (s, 1 H), 6.53 (s, 1 H), 4.47 (s, 2 H), 4.36 (s, 2 H), 2.25 (s, 3 H),
1.59 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 147.3, 143.2, 142.9, 140.4, 138.6,
137.6, 134.4, 129.6, 129.2, 128.8, 128.4, 128.3, 128.1, 127.6, 127.4,
127.1, 122.9, 108.0, 96.8, 50.3, 43.7, 36.7, 30.0, 21.2.
N-Benzyl-N-((5-(4-chlorophenyl)pyrazolo[5,1-a]isoquinolin-2-
yl)methyl)-4-methylbenzenesulfonamide (3h)
Yield: 136 mg (82%); yellow solid; mp 139–140 °C.
IR (KBr): 3031, 2975, 2859, 1635, 1546, 1407, 1325, 1151, 1050
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 6.4 Hz, 1 H), 7.73–
7.68 (m, 5 H), 7.54–7.51 (m, 2 H), 7.45–7.42 (m, 2 H), 7.23–7.22
(m, 5 H), 7.14 (d, J = 7.2 Hz, 2 H), 6.96 (s, 1 H), 6.66 (s, 1 H), 4.54
(s, 2 H), 4.44 (s, 2 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.8, 143.0, 139.9, 137.4, 136.6,
135.8, 135.0, 131.8, 130.6, 129.3, 128.7, 128.6, 128.2, 128.0, 127.5,
127.5, 127.2, 127.1, 123.6, 123.3, 112.3, 98.0, 50.6, 43.9, 21.3.
HRMS: m/z [M + H]+ calcd for C30H32N3O2S+: 498.2210; found:
498.2193.
N-Benzyl-4-methyl-N-((5-phenylpyrazolo[1,5-a]thieno[2,3-
c]pyridin-8-yl)methyl)benzenesulfonamide (3m)
Yield: 74 mg (47%); yellow solid; mp 109–110 °C.
HRMS: m/z [M + H]+ calcd for C32H27ClN3O2S+: 552.1507; found:
552.1508.
IR (KBr): 3072, 2957, 2852, 1628, 1547, 1456, 1325, 1162, 1057
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.78 (m, 2 H), 7.69 (d, J =
8.4 Hz, 2 H), 7.49–7.48 (m, 4 H), 7.32–7.22 (m, 6 H), 7.13 (d, J =
7.2 Hz, 3 H), 6.29 (s, 1 H), 4.52 (s, 2 H), 4.46 (s, 2 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.2, 143.0, 137.5, 137.2, 135.8,
134.7, 133.7, 129.3, 129.3, 129.1, 128.8, 128.6, 128.3, 128.1, 127.5,
127.2, 126.8, 124.4, 108.2, 95.8, 50.5, 43.7, 21.4.
N-Benzyl-N-((5-(4-fluorophenyl)pyrazolo[5,1-a]isoquinolin-2-
yl)methyl)-4-methylbenzenesulfonamide (3i)
Yield: 138 mg (86%); white solid; mp 102–103 °C.
IR (KBr): 2988, 2901, 1600, 1545, 1407, 1394, 1250, 1154, 1056
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.88–7.86 (m, 1 H), 7.77–7.74 (m,
2 H), 7.71–7.65 (m, 3 H), 7.53–7.47 (m, 2 H), 7.24–7.11 (m, 9 H),
6.93 (s, 1 H), 6.63 (s, 1 H), 4.53 (s, 2 H), 4.45 (s, 2 H), 2.29 (s, 3 H).
+
HRMS: m/z [M + H]+ calcd for C30H26N3O2S2 : 524.1461; found:
13C NMR (100 MHz, CDCl3): δ = 163.0 (d, 1JCF = 249.4 Hz), 148.6,
524.1465.
3
143.0, 139.8, 137.4, 136.7, 135.8, 131.2 (d, JCF = 8.1 Hz), 129.2,
128.8, 128.6, 128.2, 127.9, 127.5, 127.3, 127.1, 127.0, 123.5, 123.2,
4-Methyl-N-phenyl-N-((5-phenylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)benzenesulfonamide (3n)
115.0 (d, 2JCF = 21.6 Hz), 112.1, 97.9, 50.6, 43.9, 21.2.
HRMS: m/z [M + H]+ calcd for C32H27FN3O2S+: 536.1803; found:
536.1822.
Yield: 100 mg (66%); yellow solid; mp 51–52 °C.
IR (KBr): 3060, 2963, 2851, 1549, 1490, 1345, 1161, 1092 cm–1.
Synthesis 2014, 46, 600–606
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of H-Pyrazolo[5,1-a]isoquinolines
605
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 7.2 Hz, 1 H), 7.64–
7.61 (m, 3 H), 7.51–7.46 (m, 4 H), 7.41–7.40 (m, 3 H), 7.23–7.16
(m, 7 H), 7.11 (s, 1 H), 6.89 (s, 1 H), 5.00 (s, 2 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.2, 143.4, 140.0, 139.2, 137.8,
135.0, 133.3, 129.4, 129.2, 129.1, 128.9, 128.7, 128.6, 128.0, 127.9,
127.6, 127.6, 127.2, 126.9, 123.6, 123.4, 112.2, 97.6, 48.9, 21.4.
Maguire, A. R. Chem. Soc. Rev. 2010, 39, 845. (h) Patil, N.
T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395.
(2) For selected examples of the reactions of C,N-cyclic
azomethine imines, see: (a) Hashimoto, T.; Maeda, Y.;
Omote, M.; Nakatsu, H.; Maruoka, K. J. Am. Chem. Soc.
2010, 132, 4076. (b) Hashimoto, T.; Omote, M.; Maruoka,
K. Angew. Chem. Int. Ed. 2011, 50, 3489. (c) Soeta, T.;
Tamura, K.; Ukaji, Y. Org. Lett. 2012, 14, 1226.
HRMS: m/z [M + H]+ calcd for C31H26N3O2S+: 504.1740; found:
504.1769.
(3) For selected examples of the reactions of N,N′-cyclic
azomethine imines, see: (a) Shintani, R.; Fu, G. C. J. Am.
Chem. Soc. 2003, 125, 10778. (b) Suárez, A.; Downey, C.
W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11244.
(c) Keller, M.; Sani Souna Sido, A.; Pale, P.; Sommer, J.
Chem. Eur. J. 2009, 15, 2810. (d) Yoshimura, K.; Oishi, T.;
Yamaguchi, K.; Mizuno, N. Chem. Eur. J. 2011, 17, 3827.
(e) Luo, N.; Zheng, Z.; Yu, Z. Org. Lett. 2011, 13, 3384.
(f) Imaizumi, T.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2012, 134, 20049. (g) Chen, W.; Yuan, X.-H.; Li, R.;
Du, W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Adv. Synth. Catal.
2006, 348, 1818. (h) Chen, W.; Du, W.; Duan, Y.-Z.; Wu,
Y.; Yang, S.-Y.; Chen, Y.-C. Angew. Chem. Int. Ed. 2007,
46, 7667. (i) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett.
2007, 9, 97. (j) Sibi, M. P.; Rane, D.; Stanley, L. M.; Soeta,
T. Org. Lett. 2008, 10, 2971. (k) Li, J.; Lian, X.; Liu, X.; Lin,
L.; Feng, X. Chem. Eur. J. 2013, 19, 5134. (l) Na, R.; Jing,
C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J. C.; Wang,
M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H. C.;
Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337. (m) Wang,
D.; Deng, H.-P.; Wei, Y.; Xu, Q.; Shi, M. Eur. J. Org. Chem.
2013, 401. (n) Liu, Y.; Zhen, W.; Dai, W.; Wang, F.; Li, X.
Org. Lett. 2013, 15, 874. (o) Qian, Y.; Zavalij, P. J.; Hu, W.;
Doyle, M. P. Org. Lett. 2013, 15, 1564.
tert-Butyl Benzyl((5-phenylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)carbamate (3o)
Yield: 88 mg (63%); yellow oil.
IR (KBr): 3061, 2973, 2870, 1688, 1457, 1324, 1239, 1115 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.2 Hz, 1 H), 7.90 (d,
J = 6.8 Hz, 2 H), 7.68 (s, 1 H), 7.53–7.48 (m, 5 H), 7.31–7.20 (m, 5
H), 7.06–6.94 (m, 2 H), 4.67 (s, 1 H), 4.58 (s, 1 H), 4.56 (s, 1 H),
4.49 (s, 1 H), 1.55–1.51 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 155.8, 151.1, 150.9, 140.3, 138.1,
133.6, 129.4, 129.2, 129.1, 128.4, 128.3, 128.1, 127.8, 127.5, 127.2,
127.0, 123.7, 123.4, 112.1, 80.0, 49.8, 43.5, 28.4.
+
HRMS: m/z [M + H]+ calcd for C30H30N3O2 : 464.2333; found:
464.2327.
N-Butyl-4-methyl-N-((5-phenylpyrazolo[5,1-a]isoquinolin-2-
yl)methyl)benzenesulfonamide (3p)
Yield: 100 mg (69%); yellow solid; mp 39–40 °C.
IR (KBr): 3030, 2961, 2869, 1634, 1547, 1327, 1154, 1041 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.2 Hz, 1 H), 7.65–
7.62 (m, 1 H), 7.50–7.46 (m, 3 H), 7.29–7.25 (m, 3 H), 7.16 (d, J =
8.0 Hz, 2 H), 7.08 (d, J = 7.2 Hz, 2 H), 6.98 (d, J = 7.2 Hz, 1 H),
6.77 (s, 1 H), 6.56 (s, 1 H), 4.58 (s, 2 H), 3.01 (t, J = 7.6 Hz, 2 H),
2.32 (s, 3 H), 1.61–1.41 (m, 4 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 142.9, 139.1, 136.0, 129.8,
129.3, 129.0, 128.8, 128.6, 128.3, 127.8, 127.6, 127.3, 126.2, 124.1,
123.3, 109.2, 97.6, 50.6, 44.0, 30.5, 25.3, 22.5, 13.9.
(4) For selected examples, see: (a) Dzierszinski, F.; Coppin, A.;
Mortuaire, M.; Dewally, E.; Slomianny, C.; Ameisen, J.-C.;
Debels, F.; Tomavo, S. Antimicrob. Agents Chemother.
2002, 46, 3197. (b) Kletsas, D.; Li, W.; Han, Z.;
Papadopoulos, V. Biochem. Pharmacol. 2004, 67, 1927.
(c) Muscarella, D. E.; O’Brien, K. A.; Lemley, A. T.;
Bloom, S. E. Toxicol. Sci. 2003, 74, 66. (d) Marco, E.; Laine,
W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly,
C.; Gago, F. J. Med. Chem. 2005, 48, 3796. (e) Kluza, J.;
Gallego, M.-A.; Loyens, A.; Beauvillain, J.-C.; Fernandez
Sousa-Faro, J.-M.; Cuevas, C.; Marchetti, P.; Bailly, C.
Cancer Res. 2006, 66, 3177.
HRMS: m/z [M + H]+ calcd for C29H30N3O2S+: 484.2053; found:
484.2053.
Acknowledgment
We thank Professor Jie Wu for his invaluable advice during the
course of this research. Financial support from the National Science
Foundation Project of CQ (CSTC, 2011BB4054), Fundamental Re-
search Funds for the Central Universities (CDJRC11220001) and
the National Natural Science Foundation of China (No. 21302236)
is gratefully acknowledged.
(5) (a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 2002, 12, 2377. (b) Hasen, J. B.; Weis, J.; Suzdak, P.
D.; Eskesen, K. Bioorg. Med. Chem. Lett. 1994, 4, 695.
(c) Bettinetti, L.; Schlotter, K.; Hubner, H.; Gmeiner, P.
J. Med. Chem. 2002, 45, 4594. (d) Johns, B. A.;
Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Samano,
V. A.; Ray, J. A.; Freeman, G. A.; Boyd, F. L. Jr.; Sexton, C.
J.; Selleseth, D. W.; Creech, K. L.; Moniri, K. R. Bioorg.
Med. Chem. 2005, 13, 2397. (e) Akahane, A.; Katayama, H.;
Mitsunaga, T.; Kato, T.; Kinoshita, T.; Kita, Y.; Kusunoki,
T.; Terai, T.; Yoshida, K.; Shiokawa, Y. J. Med. Chem.
1999, 42, 779.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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E-mail: deposit@ccdc.cam.ac.uk] or via
www.ccdc.cam.ac.uk/data_request/cif.
Synthesis 2014, 46, 600–606
© Georg Thieme Verlag Stuttgart · New York