Synthesis of functionalized H-pyrazolo[5,1-a]isoquinolines via sequential reactions of N′-(2-alkynylbenzylidene)hydrazides

Article abstract of DOI:10.1039/b914265g

Diversity-oriented synthesis of functionalized H-pyrazolo[5,1-a] isoquinolines via sequential reactions of N′-(2-alkynylbenzylidene) hydrazide is described. Bromine-mediated electrophilic cyclization, Ag-catalyzed alkyne nucleophilic addition, and palladi

Full text of DOI:10.1039/b914265g

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Synthesis of functionalized H-pyrazolo[5,1-a]isoquinolines via sequential
reactions of N¢-(2-alkynylbenzylidene)hydrazides†
Zhiyuan Chen,a Mingchao Su,a Xingxin Yua and Jie Wu*a,b
Received 16th July 2009, Accepted 18th August 2009
First published as an Advance Article on the web 16th September 2009
DOI: 10.1039/b914265g
Diversity-oriented synthesis of functionalized H-pyrazolo[5,1-a]isoquinolines via sequential reactions
of N¢-(2-alkynylbenzylidene)hydrazide is described. Bromine-mediated electrophilic cyclization,
Ag-catalyzed alkyne nucleophilic addition, and palladium-catalyzed cross-coupling reaction were
involved in the transformation.
a]isoquinoline molecules (Fig. 1), with the hope of finding more
active hits for our particular biological assays.
Introduction
The use of methodology development and library approaches for
the discovery of small-molecule enzyme inhibitors or receptor
ligands is well-established.1 Among the strategies utilized in
combinatorial chemistry, the development of cascade or sequential
reactions for the efficient construction of small molecules is
attractive from the viewpoint of assembly efficiency.2,3 In con-
nection with our continuing research toward the development of
Fig. 1 H-Pyrazolo[5,1-a]isoquinoline.
new methods for the expeditious synthesis of privileged organic
architectures,4 we recently reported an efficient synthesis of fused
Our proposed synthetic route was shown in Scheme 1, eqn
(1). Prompted by the recent results for electrophilic cycliza-
1,2-dihydroisoquinolines via Ag(I)-catalyzed tandem reactions
of N¢-(2-alkynylbenzylidene)hydrazides with various alkynes.5
tion of N¢-(2-alkynylbenzylidene)hydrazides,6 we envisioned that
Subsequently, a promising result was obtained in the preliminary
in the presence of electrophiles such as iodine or bromine,
screening of a HCT-116 inhibition assay. Thus, the discovery of
N¢-(2-alkynylbenzylidene)hydrazide would undergo electrophilic
cyclization, leading to halo-containing isoquinolinium-2-yl
promising lead antitumor compounds and their moderate activity
warranted the evaluations of analogous structures in the search
amides. Followed by nucleophilic addition of alkyne, the halo-
for better inhibitors. Therefore, we initiated a program to develop
containing H-pyrazolo[5,1-a]isoquinolines would be generated,
which then underwent the palladium-catalyzed cross-coupling
efficient methods for the synthesis of diverse H-pyrazolo[5,1-
reaction to afford the desired functionalized H-pyrazolo[5,1-
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 (0)21 6510 2412;
Tel: +86 (0)21 5566 4619
a]isoquinolines. Thus, we started to investigate the possibility of
this projected synthetic route.
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai, 200032, China
Results and discussion
As described above, in this approach, treatment of N¢-(2-
alkynylbenzylidene)hydrazide 1 with an electrophile should af-
ford isoquinolinium-2-yl amide which may undergo nucleopilic
† Electronic supplementary information (ESI) available: General experi-
1
mental information, characterization data, H and 13C NMR spectra of
compound 6 and 7. See DOI: 10.1039/b914265g
Scheme 1 Proposed synthetic route.
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Table 1 Initial studies for reaction of halo-containing isoquinolinium-2-
yl amide and alkyne 4aa
addition in the presence of alkyne. Subsequent aromatization
may lead to the formation of H-pyrazolo[5,1-a]isoquinoline
frameworks (Scheme 1, eqn (1)). To identify suitable conditions
for the proposed electrophile-mediated domino process, reac-
tion screening involving N¢-(2-alkynylbenzylidene)hydrazide 1a,
bromine, and 4-methoxyphenylacetylene was carried out in the
presence of silver triflate as catalyst (Scheme 1, eqn (2)). Various
bases and solvents were examined, however, no desired product
was detected. The reaction failed as well when other Lewis acids
were employed as catalysts in the transformation. To improve the
efficiency of the cascade process, further optimization was carried
out using iodo-containing isoquinolinium-2-yl amide 2a and 4-
methoxyphenylacetylene 4a as substrates (Table 1).
The results of this preliminary survey are shown in Table 1.
In an initial experiment, complicated mixture was generated when
AgOTf (10 mol%) was employed in the reaction as catalyst at room
temperature in CCl4 in the presence of DBU as base. Parameters
including solvents, bases, and other Lewis acids were investigated.
Similar results were observed when other solvents such as DCE
and DCM were utilized (Table 1, entries 2–3). The results could
not be improved when other Lewis acids [CuI, CuBr, Cu(OTf)2,
Zn(OTf)2) were used as replacement (Table 1, entries 4–7). To our
delight, we observed the formation of the desired product 5a (31%
yield) when the reactionwas catalyzedby Ag2O(10mol%) (Table 1,
entry 8). Under the same conditions, reaction of bromo-containing
isoquinolinium-2-yl amide 3a and 4-methoxyphenylacetylene 4a
afforded the expected product 6a in 78% yield (Table 1, entry
9). Inferior results were displayed when other bases were used
(Table 1, entries 10–12). When the catalytic amount of Ag2O was
decreased to 5 mol%, the desired product 6a was afforded in 74%
yield (Table 1, entry 13). Subsequent examination revealed that
the yield increased to 91% when AgOTf was employed as the
catalyst in CH2Cl2 (Table 1, entry 15). As described previously,5
the alkyne would act as a nucleophile to attack the isoquinolinium
compound 3a in the presence of base and silver salt, which gave
rise to the intermediate A. Subsequent intramolecular 5-endo
cyclization of intermediate A and aromatization of intermediate B
would generate the desired product 6a (Scheme 2). However, the
possible concerted 1,3-dipolar cycloaddition pathway could not
be excluded meanwhile.
Lewis
Entry Substrate acid
Base
Solvent Product yield (%)b
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
AgOTf
AgOTf
AgOTf
CuI
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
K3PO4
K2CO3
CCl4
DCE
DCM
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
Complicated
Complicated
Complicated
Complicated
Complicated
Complicated
Complicated
31 (5a)
CuBr
Zn(OTf)2
Cu(OTf)2
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
AgOTf
AgOTf
9
78 (6a)
10
11
12
13c
14
15
53 (6a)
51 (6a)
NaOAc CCl4
40 (6a)
DBU
DBU
DBU
CCl4
CCl4
DCM
74 (6a)
86 (6a)
91 (6a)
a Reaction conditions: Substrate 2a or 3a (0.1 mmol), alkyne 4a (1.5
equiv.), Lewis acid (10 mol%), base (2.5 equiv.), solvent (1.0 mL), room
temperature. b Isolated yield based on substrate 2a or 3a. c In the presence
of 5 mol% of Ag2O.
With this promising result in hands, we started to in-
vestigate the scope of this reaction. Thus, various N¢-(2-
alkynylbenzylidene)hydrazides 1 were employed in the reactions
of bromine and alkynes under the AgOTf-catalyzed condi-
tions [AgOTf (10 mol%), DBU (2.5 equiv.), CH2Cl2, room
temperature] (Table 2). For most cases, the desired 6-bromo-
H-pyrazolo[5,1-a]isoquinolines were generated in good yields.
This silver-catalyzed H-pyrazolo[5,1-a]isoquinoline formation
was found to be workable with teminal acetylenes 4a–4e bear-
ing aryl, cyclopropyl, butyl, and hydroxy functionality, as well
as N¢-(2-alkynylbenzylidene)hydrazide substrates with electron
Scheme 2 Possible mechanism.
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Table 2 Reactions of N¢-(2-alkynylbenzylidene)hydrazides with bromine
Table 3 Palladium-catalyzed Suzuki couplings of 6-bromo-H-
pyrazolo[5,1-a]isoquinoline 6
and alkynesa
Entry
1
R1/R2
Alkyne 4
Yield (%)b
Entry
Compound 6
R4B(OH)2
Yield (%)a
1a
1b
4a
91 (6a)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6k
6l
4-MeC6H4B(OH)2
4-MeC6H4B(OH)2
4-MeOC6H4B(OH)2
4-MeC6H4B(OH)2
4-MeC6H4B(OH)2
4-MeC6H4B(OH)2
4-MeOC6H4B(OH)2
4-MeOC6H4B(OH)2
C6H5B(OH)2
80 (7a)
83 (7b)
84 (7c)
86 (7d)
50 (7e)
88 (7f)
86 (7g)
80 (7h)
94 (7i)
2
3
4
1a
1a
1a
4b
4c
4d
70 (6b)
71 (6c)
80 (6d)
5
6
1a
4e
82 (6e)
4a
72 (6f)
a Isolated yield based on 6-bromo-H-pyrazolo[5,1-a]isoquinoline 6.
7
8
1b
1c
4d
4a
61 (6g)
50 (6h)
in moderate to good yields. For example, as expected, com-
pound 6a reacted with 4-methylphenylboronic acid leading to
the corresponding H-pyrazolo[5,1-a]isoquinoline 7a in 80% yield
(Table 3, entry 1). It is noteworthy that the hydroxy group in the
transformation could be tolerated. Reaction of substrate 6e with 4-
methylphenylboronic acid afforded the expected coupling product
7e in 50% yield (Table 3, entry 5).
1c
1d
9
10
4b
4a
60 (6i)
65 (6j)
11
1d
1d
4d
4c
65 (6k)
Conclusions
12
13
60 (6l)
—
1e
4a
In summary, we have described an efficient and facile route for
the synthesis of functionalized H-pyrazolo[5,1-a]isoquinolines
via sequential electrophilic cyclization, nucleophilic addition,
and palladium-catalyzed cross-coupling reactions of N¢-(2-
alkynylbenzylidene)hydrazides, bromine with alkynes. The sub-
stituents diversity could be easily introduced in the transforma-
tions. Construction of small library and biological screening of
these small molecules are under investigation in our laboratory,
and the results will be reported in due course.
14
1f
4a
—
a Reaction conditions: N¢-(2-alkynylbenzylidene)hydrazide 1 (0.50 mmol),
bromine (1.0 equiv.), alkyne 1 (0.75 mmol, 1.5 equiv.), AgOTf (10 mol%),
DBU (2.5 equiv.), CH2Cl2, room temperature. b Isolated yield based on
N¢-(2-alkynylbenzylidene)hydrazide 1.
Experimental
withdrawing substituents on the aromatic backbone. For instance,
N¢-(2-alkynylbenzylidene)hydrazide 1a reacted with bromine
and prop-2-yn-1-ol 4e gave rise to the desired 6-bromo-H-
pyrazolo[5,1-a]isoquinoline 6e in 82% yield (Table 2, entry 5)
In addition to N¢-(2-alkynylbenzylidene)hydrazide with phenyl
group attached to the triple bond, the substrate with n-butyl group
attached to the triple bond was a good partner as well (Table 2, en-
tries 6 and 7). However, the N¢-(2-alkynylbenzylidene)hydrazides
with electron-donating group attached on the aromatic ring were
not good substrates in the reactions, which might be due to their
lower electrophilicity toward nucleophilic attack (Table 2, entries
13 and 14). Thus far, compounds 1e and 1f have not been workable
as substrates in the transformation.
All reactions were performed in test tubes under nitrogen at-
mosphere. Flash column chromatography was performed using
˚
silica gel (60-A pore size, 32–63 mm, standard grade). Analytical
thin-layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230–400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography
plates were visualized by exposure to ultraviolet light. Organic
solutions were concentrat◦ed on rotary evaporators at ~20 Torr
(house vacuum) at 25–35 C. Commercial reagents and solvents
were used as received.
General procedure for reaction of N¢-(2-alkynylbenzy-
lidene)hydrazide 1 with bromine and alkyne 4: bromine (0.3 mmol,
1.0 equiv.) in 2.0 mL of CH2Cl2 was added dropwisely to a
mixture of N¢-(2-alkynylbenzylidene)hydrazide 1 (0.30 mmol) in
CH2Cl2 (4.0 mL). The reaction was stirred at room temperature.
After completion of reaction as indicated by TLC, the reaction
The 6-bromo-H-pyrazolo[5,1-a]isoquinoline 6 could be further
elaborated via palladium-catalyzed cross-coupling reactions. All
the reactions proceeded smoothly to generate the desired products
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mixture was then diluted with CH2Cl2 (25 mL), washed with
saturated aqueous Na2S2O3 (25 mL), dried (Na2SO4) and filtered.
The solvent was then evaporated and the residue was dissolved
in 2.0 mL of CH2Cl2. Then DBU (2.5 equiv.) and AgOTf (10
mol%) were added. Subsequently, alkyne 4 (1.5 equiv.) in 1.0 mL of
CH2Cl2 was added dropwise at room temperature under air atmo-
sphere. The reaction mixture was stirred at room temperature for
about 5 h. After completion of reaction as indicated by TLC, the
mixture was diluted with CH2Cl2, washed by water. The organic
layer was combined, dried over Na2SO4, and purified by column
chromatography on silica gel to afford the desired product 6.
6-Bromo-2-(4-methoxyphenyl)-5-phenylpyrazolo[5,1-a]isoqui-
noline 6a. Yield: 91%; 1H NMR (400 MHz, CDCl3): 3.81 (s, 3H),
6.89–6.91 (m, 2H), 7.28 (s, 1H), 7.54–7.65 (m, 7H), 7.76–7.79 (m,
2H), 8.12–8.15 (m, 1H), 8.21–8.23 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 55.4, 94.6, 108.5, 114.1, 123.8, 123.9, 125.8, 127.8,
127.9, 128.2, 128.3, 128.6, 128.7, 129.3, 130.7, 134.2, 137.9, 139.7,
152.6, 159.9; IR (cm-1): 2965, 2904, 2832, 1618, 1521, 1459, 1434,
1378, 1251, 1173, 1024; m/z (ESI): 429 (M++H); HRMS calcd
for C24H18BrN2O (M+H) 429.0603, found 429.0621.
6-Bromo-2,5-diphenylpyrazolo[5,1-a]isoquinoline 6b. Yield:
70%; 1H NMR (400 MHz, CDCl3): 7.27–7.31 (m, 1H), 7.34–
7.38 (m, 3H), 7.52–7.64 (m, 7H), 7.84–7.86 (m, 2H), 8.12–8.14
(m, 1H), 8.20–8.22 (m, 1H);13C NMR (100 MHz, CDCl3): d 95.1,
108.9, 123.7, 123.9, 126.5, 127.9, 128.3, 128.4, 128.5, 128.6, 128.7,
129.3, 130.7, 133.0, 134.1, 137.9, 139.7, 152.7. IR (cm-1): 3052,
2945, 2919, 2842, 1618, 1598, 1540, 1492, 1470, 1456, 1381, 1319,
1173, 1079; m/z (ESI): 399 (M++H); HRMS calcd for C23H16BrN2
(M+H) 399.0497, found 399.0513.
7.59 (m, 2H), 7.92–7.98 (m, 2H), 8.04–8.06 (m, 1H), 8.08–8.12(m,
1H); 13C NMR (100 MHz, CDCl3) d 14.0, 22.9, 28.8, 31.3, 55.4,
94.4, 107.4, 114.2, 123.2, 123.6, 126.1, 127.1, 127.4, 127.7, 128.3,
128.4, 139.1, 139.5, 152.1, 159.9. IR (cm-1): 2960, 2919, 2852,
1613, 1525, 1460, 1437, 1316, 1250, 1174, 1029; m/z (ESI): 409
(M++H); HRMS calcd for C22H22BrN2O (M+H) 409.0916, found
409.0913.
6-Bromo-5-butyl-2-cyclopropylpyrazolo[5,1-a]isoquinoline 6g.
Yield: 61%; 1H NMR (400 MHz, CDCl3): 0.89–0.94 (m, 2H), 0.99
(t, J = 7.36 Hz, 3H), 1.03–1.07 (m, 2H), 1.47–1.56 (m, 2H), 1.74–
1.81 (m, 2H), 2.14–2.19 (m, 1H), 3.48 (t, J = 7.36 Hz, 2H), 6.64 (s,
1H), 7.46–7.57 (m, 2H), 7.94–7.97 (m, 1H), 8.06–8.08 (m, 1H); 13
C
NMR (100 MHz, CDCl3) d 9.15, 9.77, 14.0, 22.8, 28.9, 31.3, 94.1,
106.7, 122.9, 123.5, 127.0, 127.2, 128.3, 128.4, 138.6, 139.3, 157.1.
IR (cm-1): 2956, 2926, 2847, 1618, 1598, 1541, 1496, 1449, 1392,
1316, 1070; m/z (ESI): 343 (M++H); HRMS calcd for C18H20BrN2
(M+H) 343.0810, found 343.0819.
6-Bromo-9-fluoro-2-(4-methoxyphenyl)-5-phenylpyrazolo[5,1-
a]isoquinoline 6h. Yield: 50%; 1H NMR (400 MHz, CDCl3):
3.82 (s, 3H), 6.89–6.92 (m, 2H), 7.24 (s, 1H), 7.33–7.37 (m, 1H),
7.54–7.60 (m, 5H), 7.75–7.81 (m, 3H), 8.20–8.24 (m, 1H); 13C
2
NMR (100 MHz, CDCl3) d 55.4, 95.2, 107.8, 108.9 (d, JCF
=
2
22.9 Hz), 114.1, 117.1 (d, JCF = 22.9 Hz), 125.1, 125.2, 125.5,
127.8, 128.4, 129.4, 130.6, 130.7, 133.9, 137.3, 138.9, 152.7, 160.0,
162.2 (d, JCF = 248.9 Hz). IR (cm-1): 2960, 2924, 2842, 1603,
1
1516, 1485, 1458, 1434, 1372, 1250, 1178, 1034; m/z (ESI): 447
(M++H); HRMS calcd for C24H17BrFN2O (M+H) 447.0508,
found 447.0512.
6-Bromo-9-fluoro-2,5-diphenylpyrazolo[5,1-a]isoquinoline 6i.
1
6-Bromo-2-butyl-5-phenylpyrazolo[5,1-a]isoquinoline
6c.
Yield: 60%; H NMR (400 MHz, CDCl3): 7.35–7.54 (m, 7H),
1
Yield: 71%; H NMR (400 MHz, CDCl3): 0.92 (t, J = 7.3 Hz,
3H), 1.36–1.41 (m, 2H), 1.64–1.71 (m, 2H), 2.75 (t, J = 7.80 Hz,
2H), 6.86 (s, 1H), 7.51–7.62 (m, 7H), 8.05–8.07 (m, 1H), 8.16–8.19
(m, 1H);13C NMR (100 MHz, CDCl3) d 14.0, 22.6, 28.4, 31.9,
96.7, 107.9, 123.6, 123.8, 127.7, 128.1, 128.4, 128.5, 129.3, 130.5,
134.4, 137.7, 139.0, 155.9. IR (cm-1): 3057, 2955, 2928, 2852, 1588,
1541, 1493, 1481, 1465, 1383, 1322; m/z (ESI): 379 (M++H);
HRMS calcd for C21H20BrN2 (M+H) 379.0810, found 379.0828.
6-Bromo-2-cyclopropyl-5-phenylpyrazolo[5,1-a]isoquinoline
6d. Yield: 80%; 1H NMR (400 MHz, CDCl3): 0.74–0.78 (m, 2H),
0.93–0.99 (m, 2H), 2.04–2.12 (m, 1H), 6.61 (s, 1H), 7.51–7.61 (m,
7H), 8.00–8.02 (m, 1H), 8.16–8.18 (m, 1H);13C NMR (100 MHz,
CDCl3) d 9.31, 9.84, 93.2, 107.8, 123.5, 123.6, 127.7, 128.1, 128.4,
128.5, 129.3, 130.5, 134.3, 137.6, 139.1, 157.9. IR (cm-1): 2955,
2924, 2854, 1618, 1588, 1543, 1492, 1444, 1383, 1337, 1045;
m/z (ESI): 363 (M++H); HRMS calcd for C20H16BrN2 (M+H)
363.0497, found 363.0510.
7.59–7.65 (m, 1H), 7.70–7.73 (m, 4H), 8.14–8.17 (m, 1H), 8.38–
8.41 (m, 1H); 13C NMR (100 MHz, CDCl3) d 86.1, 95.5, 110.9(d,
2
2JCF = 21.9 Hz), 118.1, 119.2, 121.8, 122.4(d, JCF = 25.7 Hz),
124.4, 128.1, 128.6, 129.7, 129.9, 132.3, 133.6, 140.3, 142.6, 147.2,
1
152.5, 161.9 (d, JCF = 250.8 Hz). IR (cm-1): 3057, 2960, 2919,
2842, 1618, 1546, 1493, 1439, 1419, 1393, 1301, 1170; m/z (ESI):
317 (M++H); HRMS calcd for C23H15BrFN2 (M+H) 417.0403,
found 417.0413.
6-Bromo-8-fluoro-2-(4-methoxyphenyl)-5-phenylpyrazolo[5,1-
a]isoquinoline 6j. Yield: 65%; 1H NMR (400 MHz, CDCl3):
3.80 (s, 3H), 6.87–6.89 (m, 2H), 7.18 (s, 1H), 7.29–7.34 (m,
1H), 7.54–7.58 (m, 5H), 7.73–7.76 (m, 2H), 7.85–7.89(m, 1H),
8.06–8.10(m, 1H); 13C NMR (100 MHz, CDCl3) d 55.3, 94.3,
107.2, 113.4 (d, 2JCF = 24.8 Hz), 114.0, 116.8 (d, 2JCF = 23.8 Hz),
120.4, 125.5, 126.1, 127.7, 128.3, 129.4, 130.6, 130.7, 133.9, 138.9,
1
139.3, 152.8, 159.9, 162.6 (d, JCF = 246.9 Hz). IR (cm-1): 3057,
2924, 2831, 1614, 1518, 1477, 1451, 1437, 1380, 1250, 1171, 1026;
m/z (ESI): 447 (M++H); HRMS calcd for C24H17BrFN2O (M+H)
447.0508, found 447.0515.
(6-Bromo-5-phenylpyrazolo[5,1-a]isoquinolin-2-yl)methanol
6e. Yield: 82%; 1H NMR (400 MHz, CDCl3)): 4.70 (s, 2H), 7.00 (s,
1H), 7.45–7.62 (m, 7H), 8.01–8.04 (m, 1H), 8.15–8.18 (m, 1H);13C
NMR (100 MHz, CDCl3) d 59.0, 96.6, 109.1, 123.6, 123.7, 127.8,
128.3, 128.4, 128.6, 128.8, 129.5, 130.3, 134.0, 137.5, 139.2, 154.3.
IR (cm-1): 3401, 3052, 2925, 2847, 1613, 1588, 1540, 1492, 1444,
1411, 1381, 1319, 1032; m/z (ESI): 353 (M++H); HRMS calcd for
C18H14BrN2O (M+H) 353.0290, found 353.0304.
6-Bromo-5-butyl-2-(4-methoxyphenyl)pyrazolo[5,1-a]isoqui-
noline 6f. Yield: 72%; 1H NMR (400 MHz, CDCl3): 1.03 (t, J =
7.32 Hz, 3H), 1.54–1.58 (m, 2H), 1.83–1.87 (m, 2H), 3.56 (t, J =
7.80 Hz, 2H), 3.86 (s, 3H), 6.99–7.01 (m, 2H), 7.21 (s, 1H), 7.50–
6-Bromo-2-cyclopropyl-8-fluoro-5-phenylpyrazolo[5,1-a]isoqui-
noline 6k. Yield: 65%; 1H NMR (400 MHz, CDCl3): 0.74–0.79 (m,
2H), 0.96–0.99 (m, 2H), 2.04–2.08 (m, 1H), 6.56 (s, 1H), 7.27–7.32
(m, 1H), 7.51–7.59 (m, 5H), 7.84–7.87 (m, 1H), 7.99–8.03 (m,
1H); 13C NMR (100 MHz, CDCl3) d 9.33, 9.83, 93.1, 113.3 (d,
2
2JCF = 24.8 Hz), 116.7 (d, JCF = 23.8 Hz), 120.2, 125.9, 126.1,
128.5, 129.5, 130.3, 130.6, 134.0, 138.7, 138.8, 158.3, 162.5 (d,
1JCF = 246.0 Hz). IR (cm-1): 3052, 2961, 2909, 2852, 1621, 1544,
1499, 1445, 1398, 1378, 1268, 1166; m/z (ESI): 381 (M++H);
HRMS calcd for C20H15BrFN2 (M+H) 381.0403, found 381.0412.
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6-Bromo-2-butyl-8-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline
6l. Yield: 60%; 1H NMR (400 MHz, CDCl3): 0.92 (t, J = 7.32 Hz,
3H), 1.34–1.41 (m, 2H), 1.64–1.68 (m, 2H), 2.74 (t, J = 7.80 Hz,
2H), 6.81 (s, 1H), 7.29–7.34 (m, 1H), 7.50–7.56 (m, 5H), 7.85–7.88
(m, 1H), 8.03–8.07 (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.9,
123.4, 123.7, 126.7, 127.0, 127.5, 127.7, 128.1, 128.7, 130.2, 131.3,
131.6, 133.3, 133.4, 136.1, 136.6, 139.4, 157.4. IR (cm-1): 3042,
2955, 2923, 2852, 1536, 1513, 1493, 1449, 1398, 1342, 1301, 1178,
1075; m/z (ESI): 375 (M++H); HRMS calcd for C27H23N2 (M+H)
375.1861, found 375.1878.
2
22.6, 28.3, 31.9, 96.5, 106.7, 113.3 (d, JCF = 24.8 Hz), 116.7(d,
(5-Phenyl-6-p-tolylpyrazolo[5,1-a]isoquinolin-2-yl)methanol
2JCF = 23.8 Hz), 120.4, 126.1, 128.5, 129.5, 130.4, 130.5, 130.6,
7e. Yield: 50%; H NMR (400 MHz, CDCl3)): 2.32 (s, 3H), 4.84
1
1
134.1, 138.7, 156.3, 162.5 (d, JCF = 246.9 Hz). IR (cm-1): 3057,
(s, 2H), 7.04–7.09 (m, 5H), 7.27–7.33 (m, 5H), 7.41–7.43 (m, 2H),
7.54–7.57 (m, 1H), 8.15 (d, J = 8.24 Hz, 1H);13C NMR (100 MHz,
CDCl3) d 21.3, 59.6, 95.9, 123.6, 123.9, 124.0, 126.9, 127.4, 127.9,
128.3, 128.8, 130.2, 131.2, 131.5, 133.1, 133.2, 136.2, 136.8, 139.6,
153.7. IR (cm-1): 3354, 3052, 2920, 2847, 1593, 1536, 1513, 1490,
1454, 1388, 1332, 1033; m/z (ESI): 365 (M++H); HRMS calcd for
C25H21N2O (M+H) 365.1654, found 365.1665.
2955, 2927, 2858, 1621, 1541, 1484, 1444, 1398, 1378, 1311, 1269,
1166; m/z (ESI): 397 (M++H); HRMS calcd for C21H19BrFN2
(M+H) 397.0716, found 397.0715.
General procedure for palladium-catalyzed Suzuki couplings of
6-bromo-H-pyrazolo[5,1-a]isoquinoline 6. A mixture of 6-bromo-
H-pyrazolo[5,1-a]isoquinoline 6 (0.12 mmol), arylboronic acid
(1.2 equiv.), PdCl2(PPh3)2 (10 mol%) and K2CO3 (2.0 equiv.) in
1.0 mL of DMF–H2O (5 : 1, v/v) was stirred under N2 atmosphere
at 50–60 ◦C. After completion of reaction as indicated by TLC, the
mixture was cooled to room temperature and water (10 mL) was
added. The mixture was extracted with ethyl acetate (5.0 mL ¥ 3)
and the organic layer was combined, which was then washed with
brine, dried over Na2SO4, and purified by column chromatography
on silica gel to afford the desired product 7.
5-Butyl-2-(4-methoxyphenyl)-6-p-tolylpyrazolo[5,1-a]isoqui-
noline 7f. Yield: 88%; 1H NMR (400 MHz, CDCl3): 0.86 (t, J =
7.32 Hz, 3H), 1.31–1.38 (m, 2H), 1.74–1.79 (m, 2H), 2.48 (s, 3H),
3.03 (t, J = 7.80 Hz, 2H), 3.87 (s, 3H), 6.98–7.03 (m, 2H), 7.18–7.25
(m, 4H), 7.31–7.38 (m, 3H), 7.45–7.49 (m, 1H), 7.97–8.02 (m, 2H),
8.13 (d, J = 7.80 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 13.9,
21.4, 22.9, 28.9, 30.3, 55.4, 93.9, 114.2, 121.9, 123.2, 123.4, 126.3,
126.4, 126.7, 127.4, 127.7, 129.3, 130.4, 130.9, 134.0, 137.3, 137.8,
139.6, 151.8, 159.8; IR (cm-1): 2957, 2929, 2868, 1612, 1527, 1510,
1482, 1460, 1438, 1248, 1173, 1106, 1034; m/z (ESI): 421 (M++H);
HRMS calcd for C29H29N2O (M+H) 421.2280, found 421.2296.
5-Butyl-2-cyclopropyl-6-(4-methoxyphenyl)pyrazolo[5,1-a]iso-
quinoline 7g. Yield: 86%; 1H NMR (400 MHz, CDCl3): 0.81 (t, J =
7.32 Hz, 3H), 0.92–0.95 (m, 2H), 1.04–1.09 (m, 2H), 1.28–1.30 (m,
2H), 1.67–1.71 (m, 2H), 2.17–2.22 (m, 1H), 2.95 (t, J = 7.80 Hz,
2H), 3.90 (s, 3H), 6.68 (s, 1H), 7.02–7.05 (m, 2H), 7.17–7.23 (m,
3H), 7.41–7.48 (m, 2H), 8.02 (d, J = 7.80 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 9.10, 9.86, 13.9, 22.8, 28.9, 30.2, 55.4, 93.3,
113.9, 114.2, 122.9, 123.3, 126.1, 126.2, 127.3, 127.8, 129.3, 130.6,
132.2, 137.9, 156.6, 159.0; IR (cm-1): 2956, 2927, 2852, 1607, 1510,
1456, 1342, 1276, 1245, 1173, 1106, 1040; m/z (ESI): 371 (M++H);
HRMS calcd for C25H27N2O (M+H) 371.2123, found 371.2135.
2-Cyclopropyl-8-fluoro-6-(4-methoxyphenyl)-5-phenylpyra-
zolo[5,1-a]isoquinoline 7h. Yield: 80%; 1H NMR (400 MHz,
CDCl3): 0.79–0.82 (m, 2H), 0.98–1.02 (m, 2H), 2.09–2.14 (m,
1H), 3.79 (s, 3H), 6.60 (s, 1H), 6.77–6.82 (m, 2H), 7.02–7.07 (m,
3H), 7.21–7.35 (m, 6H), 8.04–8.07 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 9.29, 9.95, 55.2, 92.4, 111.8 (d, 2JCF = 22.9 Hz), 113.7,
115.7 (d, 2JCF = 23.8 Hz), 120.3, 121.8, 125.7, 127.8, 128.1, 128.3,
131.1, 132.4, 132.7, 133.2, 137.3, 139.1, 157.8, 158.7, 161.9 (d, 1JCF
= 245.0 Hz); IR (cm-1): 2924, 2852, 1608, 1512, 1500, 1449, 1403,
1342, 1285, 1246, 1175, 1024; m/z (ESI): 409 (M++H); HRMS
calcd for C27H22FN2O (M+H) 409.1716, found 409.1710.
2-(4-Methoxyphenyl)-5-phenyl-6-p-tolylpyrazolo[5,1-a]isoqui-
noline 7a. Yield: 80%; 1H NMR (400 MHz, CDCl3): 2.32 (s, 3H),
3.81 (s, 3H), 6.88–6.92 (m, 2H), 7.05–7.09 (m, 4H), 7.26–7.29 (m,
3H), 7.32 (s, 1H), 7.38–7.44 (m, 4H), 7.52–7.55 (m, 1H), 7.82–7.85
(m, 2H), 8.18 (d J = 8.24 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.3, 55.4, 94.1, 114.0, 123.5, 123.6, 123.9, 126.3, 126.9, 127.2,
127.5, 127.6, 127.7, 128.0, 128.8, 130.3, 131.5, 131.6, 133.3, 133.4,
136.4, 136.7, 139.9, 152.1, 159.7. IR (cm-1): 2945, 2914, 2837,
1608, 1526, 1458, 1429, 1248, 1163, 1024; m/z (ESI): 441 (M++H);
HRMS calcd for C31H25N2O (M+H) 441.1967, found 441.1980.
2,5-Diphenyl-6-p-tolylpyrazolo[5,1-a]isoquinoline 7b. Yield:
83%; 1H NMR (400 MHz, CDCl3): 2.33 (s, 3H), 7.06–7.11 (m, 4H),
7.24–7.32 (m, 4H), 7.36–7.44 (m, 7H), 7.53–7.59 (m, 1H), 7.90–
7.93 (m, 2H), 8.20–8.23 (m, 1H); 13C NMR (100 MHz, CDCl3) d
21.3, 94.6, 123.6, 123.9, 124.0, 126.5, 126.9, 127.3, 127.6, 127.7,
128.0, 128.1, 128.6, 128.8, 130.3, 131.5, 131.6, 133.3, 133.5, 136.5,
136.8, 139.9, 152.2. IR (cm-1): 3052, 3016, 2914, 2858, 1588, 1536,
1506, 1456, 1378, 1342, 1178, 1081, 1014; m/z (ESI): 411 (M++H);
HRMS calcd for C30H23N2 (M+H) 411.1861, found 411.1873.
2-Butyl-6-(4-methoxyphenyl)-5-phenylpyrazolo[5,1-a]isoqui-
1
noline 7c. Yield: 84%; H NMR (400 MHz, CDCl3): 0.94 (t, J
= 7.32 Hz, 3H), 1.39–1.45 (m, 2H), 1.68–1.74 (m, 2H), 2.80 (t,
J = 7.80 Hz, 2H), 3.78 (s, 3H), 6.77–6.81 (m, 2H), 6.91 (s, 1H),
7.04–7.08 (m, 2H), 7.24–7.29 (m, 3H), 7.31–7.34 (m, 2H), 7.38–
7.41 (m, 2H), 7.48–7.54 (m, 1H), 8.13 (d, J = 7.76 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 14.0, 22.7, 28.5, 32.1, 55.2, 96.1, 113.5,
122.6, 123.5, 123.8, 126.7, 127.0, 127.4, 127.8, 128.1, 128.7, 130.3,
131.2, 132.8, 133.5, 136.4, 139.2, 155.4, 158.5. IR (cm-1): 3052,
2955, 2929, 2858, 1603, 1512, 1475, 1460, 1337, 1245, 1168, 1034;
m/z (ESI): 407 (M++H); HRMS calcd for C28H27N2O (M+H)
407.2123, found 407.2141.
2-Cyclopropyl-5-phenyl-6-p-tolylpyrazolo[5,1-a]isoquinoline
7d. Yield: 86%; 1H NMR (400 MHz, CDCl3): 0.80–0.84 (m, 2H),
0.96–1.04 (m, 2H), 2.10–2.14 (m, 1H), 2.31 (s, 3H), 6.65 (s, 1H),
7.02–7.07 (m, 4H), 7.25–7.28 (m, 3H), 7.31–7.36 (m, 2H), 7.37–
7.40 (m, 2H), 7.48–7.51 (m, 1H), 8.07 (d, J = 8.28 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 9.28, 9.96, 21.3, 92.6, 122.8,
2-Butyl-8-fluoro-5,6-diphenylpyrazolo[5,1-a]isoquinoline 7i.
1
Yield: 94%; H NMR (400 MHz, CDCl3): 0.94 (t, J = 7.32 Hz,
3H), 1.37–1.45 (m, 2H), 1.67–1.75 (m, 2H), 2.79 (t, J = 7.80 Hz,
2H), 6.86 (s, 1H), 6.97–7.08 (m, 1H), 7.15–7.20 (m, 2H), 7.24–7.31
(m, 9H), 8.09–8.12 (m, 1H); 13C NMR (100 MHz, CDCl3) d
2
14.0, 22.7, 28.5, 32.0, 95.9, 111.7 (d, JCF = 22.9 Hz), 115.7 (d,
2JCF = 23.8 Hz), 120.5, 122.3, 125.7, 127.3, 127.8, 128.2, 128.4,
1
131.1, 131.7, 132.0, 133.0, 136.1, 137.3, 138.9, 155.9, 161.9 (d,
JCF = 245.0 Hz); IR (cm-1): 3062, 2955, 2921, 2847, 1620, 1540,
1486, 1464, 1443, 1400, 1342, 1321, 1265, 1191; m/z (ESI): 395
(M++H); HRMS calcd for C27H24FN2 (M+H) 395.1924, found
395.1945.
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Acknowledgements
Financial support from National Natural Science Foundation of
China (20772018), the Science and Technology Commission of
Shanghai Municipality (09JC14049), and Program for New Cen-
tury Excellent Talents in University (NCET-07-0208) is gratefully
acknowledged.
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4646 | Org. Biomol. Chem., 2009, 7, 4641–4646
This journal is
The Royal Society of Chemistry 2009
©