Synthesis of Pyrazolo[5,1-a]isoquinolines and 8-Methylenepyrazolo[5,1-a]isoindoles via Regioselective C-C Coupling and Alkyne Hydroamination

Article abstract of DOI:10.1021/acs.joc.5b01620

An efficient and convenient synthesis of pyrazolo[5,1-a]isoquinolines has been achieved via palladium-catalyzed Sonogashira coupling of terminal alkynes with 5-(2-bromophenyl)-1H-pyrazoles, in situ formed from the condensation of 1-(2-bromophenyl)buta-2,3-dien-1-ones with hydrazine hydrate, followed by 6-endo intramolecular alkyne hydroamination. More interestingly, 8-methylenepyrazolo[5,1-a]isoindoles, the regioisomer of pyrazolo[5,1-a]isoquinolines, could also be selectively synthesized from the same starting materials through an initial intermolecular hydroamination of terminal alkynes with 5-(2-bromophenyl)-1H-pyrazoles followed by a palladium-catalyzed 5-exo intramolecular Heck coupling reaction.

Full text of DOI:10.1021/acs.joc.5b01620

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Article
Synthesis of pyrazolo[5,1-a]isoquinolines and 8-methylenepyrazolo[5,1-
a]isoindoles via regio-selective C-C coupling and alkyne hydroamination
Xuesen Fan, Meng Yan, Yuanyuan Wang, and Xinying Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01620 • Publication Date (Web): 12 Oct 2015
Downloaded from http://pubs.acs.org on October 17, 2015
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Synthesis of pyrazolo[5,1-a]isoquinolines and 8-methylenepyrazolo[5,1-a]isoindoles via
regio-selective C-C coupling and alkyne hydroamination
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Xuesen Fan*, Meng Yan, Yuanyuan Wang, and Xinying Zhang*
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School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Green
Chemical Media and Reactions, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China
E-mail: xuesen.fan@htu.cn; xinyingzhang@htu.cn
R2
R3
R2
R3
R3
O
N
N
•
1)
1) NH2NH2 H2O
R4
NH2NH2 H2O
N
N
R1
R1
R1
H
R4
3) [Pd]/L
R2
2) R4
, KOH
R2
2)
, [Pd]/L
Br
Br
R4
R3
R2
R3
4 bonds and 2 rings formed with controlled selectivity;
Sonogashira coupling and 6-endo alkyne hydroamination
vs alkyne hydroamination and 5-exo Heck coupling
N
N
R1
N
N
R1
R4
R4
Abstract: An efficient and convenient synthesis of pyrazolo[5,1ꢀa]isoquinolines has been
achieved via palladiumꢀcatalyzed Sonogashira coupling of terminal alkynes with
5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀpyrazoles, in situ formed from the condensation of 1ꢀ(2ꢀbromophenyl)
butaꢀ2,3ꢀdienꢀ1ꢀones with hydrazine hydrate, followed by 6ꢀendo intramolecular alkyne
hydroamination. More interestingly, 8ꢀmethylenepyrazolo[5,1ꢀa]isoindoles, the regioꢀisomer
of pyrazolo[5,1ꢀa]isoquinolines, could also be selectively synthesized from the same starting
materials through an initial intermolecular hydroamination of terminal alkynes with
5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀpyrazoles followed by palladiumꢀcatalyzed 5ꢀexo intramolecular Heck
coupling reaction.
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INTRODUCTION
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Fused nitrogenꢀcontaining heterocycles constitute one of the most prominent entities as
candidates for new drugs and functional materials.1 Among them, isoquinoline2 and
pyrazolo[1,5ꢀa]pyridine3 are well recognized privileged structures embedded in a significant
number of pharmaceutically relevant compounds. Consequently, it is not surprising that
pyrazolo[5,1ꢀa]isoquinoline (PIQ), as the hybrid structure of isoquinoline and pyrazolo[1,5ꢀa]
pyridine, is found to be the origin of remarkable biological activities.4 Due to its importance,
numerous synthetic strategies have been developed for the construction of the PIQ scaffold,
and one of the most frequently used protocols involves the tandem reaction of
N′ꢀ2ꢀalkynylbenzylidenehydrazide with various nucleophiles such as alkynes, proparygyl
amines and alcohols under the catalysis of Lewis acids.5 Another elegant approach toward
PIQs is based on a copperꢀcatalyzed threeꢀcomponent reaction of 1ꢀ(2ꢀbromophenyl)ꢀ
3ꢀphenylpropꢀ2ꢀynꢀ1ꢀone with hydrazine and active methylene compounds.6 More recently,
Wu et al described a tandem reaction of 2ꢀalkynylbromobenzene with pyrazole to provide a
facile route toward PIQs via copper(I)ꢀcatalyzed hydroamination and C–H activation.4
Alternatively, Ackermann et al discovered an efficient new pathway toward PIQs through
Ruꢀcatalyzed alkyne annulations with substituted 1Hꢀpyrazoles.7 While these literature
procedures are generally efficient and reliable, the development of simple methods in which
both the required pyrazole and the alkyne units are introduced in situ along with the
construction of the isoquinoline and the pyrazolo[1,5ꢀa]pyridine framework via a oneꢀpot
procedure featured with facile operation and easily accessible starting materials remains an
attractive but still challenging task.
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Meanwhile, allene derivatives as valuable synthetic building blocks have attracted
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tremendous attention due to their diverse reactivity.8 Among various kinds of functionalized
allenes, the electronꢀdeficient allenic ketones are good receptors for nucleophilic conjugate
addition. More interestingly, this Michael type addition is often followed by simultaneous
intramolecular cyclizations to afford various carboꢀ or heterocyclic compounds. In this regard,
our own effort has resulted in an efficient synthesis of substituted pyrazoles by reacting
allenic ketones with hydrazine hydrate under extremely mild conditions.9 As a continuation of
our study in developing novel synthetic strategies by using allene derivatives as substrates,10
we envisioned a novel synthesis of PIQs via the oneꢀpot multiꢀcomponent reaction of the
easily obtainable 1ꢀ(2ꢀbromophenyl)butaꢀ2,3ꢀdienꢀ1ꢀone with the commercially available
hydrazine hydrate and terminal alkyne (shown in Scheme 1).
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Scheme 1. Proposed synthetic pathway toward pyrazolo[5,1ꢀa]isoquinoline
RESULTS AND DISCUSSION
Initially, 1ꢀ(2ꢀbromophenyl)butaꢀ2,3ꢀdienꢀ1ꢀone (1a) was treated with hydrazine hydrate (2)
in DMF at room temperature for 10 min. Then, ethynylbenzene (3a), Pd(OAc)2, PPh3 and
o
K2CO3 were added. The resulting mixture was allowed to react at 100 C under nitrogen for
12 h. From this reaction, the expected 2ꢀmethylꢀ5ꢀphenylpyrazolo[5,1ꢀa]isoquinoline (4a) was
obtained in a yield of 52% along with its regioꢀisomer 8ꢀbenzylideneꢀ2ꢀmethylꢀ8Hꢀpyrazolo
[5,1ꢀa]isoindole (5a) in 7% yield (Table 1, entry 1). To improve the efficiency, other catalysts
such as Pd(PPh3)2Cl2, PdCl2, and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) were then
tried. However, they were found to be less effective than Pd(OAc)2 in catalyzing this reaction
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Table 1. Optimization studies on the synthesis of 4a a
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Yield (%) b
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Entry
Catalyst
Coꢀcatalyst Ligand
Base
Solvent
T (°C)
4a
5a
1
2
Pd(OAc)2
Pd(PPh3)2Cl2
PdCl2
ꢀ
PPh3
PPh3
PPh3
PPh3
phen
SPhos
XPhos
TFP
TCHP
ꢀ
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOH
NaOAc
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
85
52
7
ꢀ
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35
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30
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58
68
50
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35
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36
59
65
52
57
6
3
ꢀ
trace
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4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
5
ꢀ
trace
5
6
ꢀ
7
ꢀ
6
8
ꢀ
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
6
9
ꢀ
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19
20
21
22
ꢀ
ꢀ
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
ꢀ
ꢀ
ꢀ
ꢀ
DABCO
Et3N
ꢀ
ꢀ
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ꢀ
ꢀ
dioxane
DMSO
DMF
DMF
DMF
100
100
120
100
100
ꢀ
CuBr
CuI
8
a Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), 3a (0.75 mmol), catalyst (0.025 mmol), ligand
(0.05 mmol), base (1.5 mmol), solvent (4 mL), N2, 12 h; b Isolated yield.
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(entries 2ꢀ4). Next, the effect of different ligands including 1,10ꢀphenanthroline (phen),
2ꢀdicyclohexylphosphinoꢀ2',6'ꢀdimethoxybiphenyl (SPhos), 2ꢀdicyclohexylphosphinoꢀ2′,4′,6′
ꢀtriisopropylbiphenyl (XPhos), tris(2ꢀfuranyl)phosphine (TFP), and tricyclohexylphosphine
(TCHP) was tested (entries 5ꢀ9). We were pleased to find that with TFP as the ligand, the
yield of 4a could be improved to 68% while 5a was formed only in a trace amount (entry 8).
It was also found that in the absence of any ligand the yield of 4a was very low (entry 10).
Next, the suitability of several inorganic and organic bases was studied (entries 11ꢀ16).
Among them, NaOAc could give similar result as that of K2CO3 (entry 13 vs 8). When other
solvents such as DCE, dioxane, or DMSO were used to replace DMF as the reaction medium,
the yield of 4a decreased (entries 17ꢀ19 vs 8). Increasing the reaction temperature from 100 to
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o
120 C did not give higher yield of 4a (entry 20 vs 8). Finally, addition of CuI or CuBr as
coꢀcatalyst resulted in decreased yield of 4a but increased yield of 5a (entries 21ꢀ22 vs 8).
With the optimized conditions in hand (Table 1, entry 8), we then studied the scope and
generality of this oneꢀpot threeꢀcomponent cascade reaction leading to PIQ (4). Firstly, with
3a as a model substrate, the reactions of different 2ꢀbromophenyl allenic ketones (1) were
studied. The results listed in Table 2 showed that substrates 1 with various substituents on the
phenyl ring underwent this cascade reaction smoothly to afford 4aꢀ4h in moderate to good
yields. Various functional groups, from the electronꢀdonating methoxy to the electronꢀ
withdrawing trifluoromethyl, were well compatible with the reaction conditions, and the
electronic nature of the substrates did not show obvious effect on the yield of the
corresponding products. Interestingly, using allenic ketones with a methyl or ethyl group on
the internal or terminal position of the allenic moiety, the reactions still proceeded smoothly
and gave the corresponding products (4iꢀ4l) with reasonably good yields.
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Table 2. Substrate scope for the preparation of 4 (I) a, b
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4a, 68%
4e, 70%
4i, 58%
4b, 66%
4f, 65%
4j, 56%
4c, 75%
4g, 70%
4k, 55%
4d, 79%
4h, 66%
4l, 50%
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 3a (0.75 mmol), Pd(OAc)2 (0.025 mmol), TFP (0.05
mmol), K2CO3 (1.5 mmol), DMF (4 mL), 100 oC, N2, 12 h; b Isolated yield.
Next, the scope of the alkyne substrate (3) was screened. Thus, 1ꢀchloroꢀ4ꢀethynylbenzene
(3b), 1ꢀethynylꢀ4ꢀfluorobenzene (3c), 1ꢀethynylꢀ4ꢀmethoxybenzene (3d), and 1ꢀethynylꢀ3ꢀ
methylbenzene (3e) were chosen to react with different allenic ketones (1) and hydrazine
hydrate (2). The results listed in Table 3 indicated that ethynylbenzenes (3) bearing different
substituents on the phenyl ring could take part in this tandem reaction smoothly to give PIQ
derivatives 4mꢀ4p in moderate yields. Functional groups such as chloro, fluoro, methoxy and
methyl were well tolerable, and the electronic and steric nature of the substituents did not
show obvious effect on the yield of 4. When 3bꢀ3d were reacted with allenic ketones bearing
a methyl or ethyl group on the internal or terminal positions of the allenic moiety, the
corresponding products (4qꢀ4w) were obtained in an equally efficient manner. Interestingly,
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in addition to aryl substituted alkynes, propꢀ2ꢀynylbenzene was also found to be a suitable
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substrate for this cascade reaction to give 4x.
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Table 3. Substrate scope for the preparation of 4 (II) a, b
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4m, 50%
4q, 48%
4u, 51%
4n, 60%
4r, 58%
4v, 49%
4o, 56%
4s, 55%
4w, 47%
4p, 54%
4t, 52%
4x, 41%
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 3 (0.75 mmol), Pd(OAc)2 (0.025 mmol), TFP (0.05
mmol), K2CO3 (1.5 mmol), DMF (4 mL), 100 oC, N2, 12 h; b Isolated yield.
Based on the above results and previous reports,11 a plausible pathway to account for the
formation of 4a and 5a from the reaction of 1a, 2 and 3a is proposed in Scheme 2. Initially,
condensation of 1ꢀ(2ꢀbromophenyl)butaꢀ2,3ꢀdienꢀ1ꢀone (1a) with hydrazine hydrate (2)
affords 5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀpyrazole (I). Then, oxidative insertion of Pd(0) into the C–Br
bond of I gives a Pd(II) intermediate (A). The following coordination of the triple bond of
ethynylbenzene (3a) with Pd(II) gives a new palladium complex (B). In the next stage,
reductive elimination occurs with B to regenerate the Pd(0) catalyst and afford the key
intermediate C, which then undergoes an intramolecular 6ꢀendo hydroamination to give 4a
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(path a). Alternatively, an intramolecular 5ꢀexo hydroamination of C would afford 5a (path b).
Under the reaction conditions as shown in Table 1, path a is preferred. Therefore, 4a is
eventually obtained as the dominating product.
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Scheme 2. Plausible pathways for the formation of 4a and 5a
The proposed reaction mechanism as shown in Scheme 2 is partly confirmed by the
following control experiments (Scheme 3). Firstly, 5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀpyrazole (I) was
treated with (Boc)2O in the presence of DMAP to give pyrazole derivative II. II was then
treated with 3a under the standard Sonogashira coupling conditions to give III. By treating
III with CF3CO2H, the protecting group in III was removed to give
3ꢀmethylꢀ5ꢀ(2ꢀ(phenylethynyl) phenyl)ꢀ1Hꢀpyrazole (C). Upon subjected to the standard
reaction conditions as listed in Table 1, entry 8, C was transformed into 4a in 82% yield. This
result should be considered as positive evidence in supporting the proposed reaction pathway,
in which C acts as a key intermediate for the formation of 4a.
Scheme 3. Control experiment in supporting the proposed mechanism for the formation of 4a
Having established an efficient synthesis of PIQs (4) via the condensation, Sonogashira
coupling and intramolecular hydroamination cascade from 1ꢀ(2ꢀbromophenyl)butaꢀ2,3ꢀdienꢀ1
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ꢀones (1), hydrazine hydrate (2) and alkynes (3), we moved our attention to study the
possibility of developing a selective synthesis of 8ꢀmethylenepyrazolo[5,1ꢀa]isoindole (5), the
regioꢀisomer of 4, by using the same starting materials. This challenging task turns out to be
quite attractive as pyrazolo[5,1ꢀa]isoindoles are endowed with a plethora of biological
activities and thus have played an active role in pharmaceutical chemistry.12ꢀ15 Despite of their
importance, efficient and reliable methods for the preparation of pyrazolo[5,1ꢀa]isoindole
derivatives have only been sporadically reported.16ꢀ22
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Meanwhile, we noticed that the Heck type coupling between enamines and aryl halides
usually occurs regioꢀselectively on the inner carbon atom of the enamine unit.23ꢀ24 Inspired by
these observations, we designed a new synthetic approach toward 5 as shown in Scheme 4.
Thus, 5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀpyrazole (I), in situ formed through the condensation of 1a with
2, was reacted with 3a in the presence of KOH to afford (Z)ꢀ5ꢀ(2ꢀbromophenyl)ꢀ3ꢀmethylꢀ1ꢀ
styrylꢀ1Hꢀpyrazole (6a).25 Next, 6a was treated with Pd(OAc)2/PPh3/K2CO3 in DMF at 100
oC for 24 h. To our delight, the expected 5ꢀexo intramolecular Heck reaction (IHR) took place
to afford 5a in a yield of 21%. It was also noted that under these conditions the formation of
the 6ꢀendo product 4a was not observed.
Scheme 4. Preparation of 5a from 1a through a hydroamination and Heck coupling sequence
To improve the yield of 5a, various ligands such as triꢀ(tertꢀbutyl)phosphoniumtetrafluoroꢀ
borate (TBPF), P(oꢀtol)3, SPhos, TCHP, and TFP were screened (Table 4, entries 2ꢀ6).
Among them, TFP turned out to be the most efficient. Then, Pd(PPh3)2Cl2, PdCl2, and
Pd2(dba)3 were used to replace Pd(OAc)2 as the catalyst, and Pd2(dba)3 was found to be the
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best (entries 6ꢀ9). Next, Et3N, Cs2CO3, and DBU were tried as the base to promote this cross
coupling reaction, but they were found less effective than K2CO3 (entries 10ꢀ12). In addition
to DMF, CH3CN and DMSO were also tested as possible media. To our delight, the yield of
5a increased to 41% when the reaction was carried out in DMSO (entry 14). Finally, it was
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o
also found that elevating the reaction temperature to 120 C (entry 15) or using CuI as a
coꢀcatalyst (entry 16) did not improve the efficiency. As a summary of the optimization study,
treatment of 6a with 0.1 equiv of Pd2(dba)3, 0.2 equiv of TFP and 2 equiv of K2CO3 in DMSO
under nitrogen at 100 ºC for 24 h gave 5a in a yield of 41%.
Table 4. Optimization studies on the synthesis of 5a a
Entry
1
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh)3Cl2
PdCl2
Coꢀcatalyst
Ligand
PPh3
TBPF
P(oꢀtol)3
SPhos
TCHP
TFP
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Et3N
Yield (%) b
T(°C)
100
100
100
100
100
100
100
100
100
90
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
21
18
2
3
15
4
19
5
12
6
24
7
TFP
16
8
TFP
33
9
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
TFP
36
10
11
12
13
14
TFP
12
TFP
Cs2CO3
DBU
DMF
DMF
CH3CN
DMSO
100
100
80
35
TFP
15
TFP
K2CO3
K2CO3
trace
41
TFP
100
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Pd2(dba)3
Pd2(dba)3
ꢀ
TFP
TFP
K2CO3
K2CO3
DMSO
DMSO
120
100
40
38
CuI
a Reaction conditions: 6a (0.5 mmol), catalyst (0.05 mmol), ligand (0.1 mmol), base (1 mmol), solvent (4
mL), N2, 24 h; b Isolated yield.
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Following the optimization study, the scope and generality of this novel protocol for the
preparation of 5 was studied. For this purpose, a series of (Z)ꢀ5ꢀ(2ꢀbromophenyl)ꢀ1ꢀstyrylꢀ
1Hꢀpyrazoles (6) were prepared via a oneꢀpot cascade reaction of 1ꢀ(2ꢀbromophenyl)butaꢀ
2,3ꢀdienꢀ1ꢀone (1) with hydrazine hydrate (2) and terminal alkynes (3) by firstly reacting 1
with 2 in DMSO at room temperature for 0.5 h followed by treatment of the resulting mixture
with 3 under the promotion of KOH at 120 oC for 1.5 h. The results were listed in Table 5.
Table 5. Substrate scope for the preparation of 6 a, b
6a, 81%
6e, 81%
6i, 82%
6b, 79%
6f, 80%
6j, 77%
6c, 82%
6d, 82%
CH3
CH3
N
N
N
N
Cl
CH3
Br
Br
6g, 79%
6h, 75%
CH3
H3C
N
N
OCH3
Br
6k, 78%
6l, 80%
a Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), 3 (1.2 mmol), KOH (1.25 mmol), DMSO (2 mL), N2; b
Isolated yield.
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Next, the (Z)ꢀ5ꢀ(2ꢀbromophenyl)ꢀ1ꢀstyrylꢀ1Hꢀpyrazole substrates (6) were subjected to the
optimized reaction conditions as described above. The results included in Table 6 firstly
indicated that substrates 6 with hydrogen, chloro, methyl or methoxy group on the
2ꢀbromophenyl moiety underwent this coupling reaction smoothly to afford the desired
products (5aꢀ5e) in moderate yields, and the electronic nature of the substrates did not show
obvious effect on the efficiency. Secondly, substrates 6 bearing chloro, fluoro, methyl or
methoxy group on the R4 unit could also take part in this reaction smoothly to give the
corresponding products 5fꢀ5l.
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Table 6. Substrate scope for the preparation of 5 a, b
CH3
N
N
Ph
5a, 41%
5b, 46%
5f, 40%
5c, 38%
5d, 42%
5h, 34%
CH3
N
N
Cl
5e, 40%
5g, 36%
5i, 42%
5j, 39%
5k, 44%
5l, 37%
a Reaction conditions: 6 (0.5 mmol), Pd2(dba)3 (0.05 mmol), TFP (0.1 mmol), K2CO3 (1 mmol), DMSO
(4 mL), 100 oC, N2; b Isolated yield.
Based on previous reports,23ꢀ24 a plausible pathway for the formation of 5a was described in
Scheme 5. Initially, the active Pd(0) inserts into the C–Br bond of 6a, generating the
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arylpalladium complex C, which then undergoes an intramolecular carbopalladation in a
5ꢀexo manner to afford intermediate D. In the next stage, D undergoes a βꢀhydride elimination
to generate 5a and the palladium(II) bromide, which, after reductive elimination of HBr under
the promotion of potassium carbonate, regenerates the active Pd(0) species for the next
catalytic cycle.
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Scheme 5. Plausible pathway for the formation of 5a
CONCLUSION
In summary, we have developed a novel and convenient synthesis of pyrazolo[5,1ꢀa]
isoquinolines via palladiumꢀcatalyzed Sonogashira coupling of 5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀ
pyrazoles with terminal alkynes, followed by 6ꢀendo intramolecular alkyne hydroamination.
More interestingly, a selective synthesis of 8ꢀmethylenepyrazolo[5,1ꢀa]isoindoles, the regioꢀ
isomer of pyrazolo[5,1ꢀa]isoquinolines, from the same starting materials has also been
established through an initial intermolecular terminal alkyne hydroamination with
5ꢀ(2ꢀbromophenyl)ꢀ1Hꢀpyrazoles followed by palladiumꢀcatalyzed 5ꢀexo intramolecular Heck
coupling reaction. Compared with literature procedures for the preparation of pyrazolo[5,1ꢀa]
isoquinoline and pyrazolo[5,1ꢀa]isoindole derivatives, the synthetic strategies developed
herein exhibit advantages such as easily obtainable or commercially available starting
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materials, broad substrate scope, simple procedure, and divergent reaction patterns toward
different products with tunable selectivity.
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EXPERIMENTAL SECTION
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General Methods
Commercial reagents were used without further purification and solvents were dried prior
to use. 1ꢀ(2ꢀBromophenyl)butaꢀ2,3ꢀdienꢀ1ꢀones (1) were synthesized through oxidation of the
corresponding homopropargyl alcohols,26 which were prepared through zinc promoted
propargylation of aldehydes.27 1H and C NMR spectra were recorded at 400 and 100 MHz,
13
respectively. Chemical shifts were reported in ppm from tetramethylsilane (TMS) as internal
standard in CDCl3 solutions. Multiplicity was indicated as follows: s (singlet), d (doublet), t
(triplet), m (multiplet), q (quadruplet), dd (doublet of doublets). Coupling constants were
given in Hz. Highꢀresolution mass spectra (HRMS) were obtained by using a MicrOTOF
mass spectrometer. All the reactions were monitored by thinꢀlayer chromatography (TLC)
using silica gel plates (silica gel 60 F254 0.25 mm).
Typical procedure for the synthesis of 4a and spectroscopic data of 4a-4w
A solution of 1ꢀ(2ꢀbromophenyl)butaꢀ2,3ꢀdienꢀ1ꢀone (1a, 111 mg, 0.5 mmol) and hydrazine
hydrate (2, 80%, 37 ꢁL, 0.6 mmol) in DMF (4 mL) was stirred at room temperature for 10
min. It was then added with ethynylbenzene (3a, 77 mg, 0.75 mmol), Pd(OAc)2 (6 mg, 0.025
mmol), TFP (12 mg, 0.05 mmol), and K2CO3 (207 mg, 1.5 mmol). The resulting mixture was
stirred at 100 ºC under N2 atmosphere. Upon completion as indicated by TLC analysis, the
reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate (10
mL×3). The combined organic layers were washed with brine, and then dried over anhydrous
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Na2SO4. The solvent was evaporated under vacuum and the crude product was purified by
column chromatography on silicaꢀgel eluting with petroleum etherꢀethyl acetate (30:1) to
afford 4a in 68% yield. 4bꢀ4w were obtained in a similar manner.
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2-Methyl-5-phenylpyrazolo[5,1-a]isoquinoline (4a)
o
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (88 mg, 68%), mp: 78ꢀ79 C. IR
(KBr) 3055, 2928, 2848, 1472, 1459, 1450, 1396, 1329, 828, 746, 701 cm−1; H NMR (400
1
MHz, CDCl3) δ: 2.57 (s, 3H), 6.89 (s, 1H), 6.98 (s, 1H), 7.50ꢀ7.58 (m, 5H), 7.71 (d, J = 7.6
Hz ,1H), 7.98 (d, J = 7.2 Hz, 2H), 8.06 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ:
14.4, 97. 7, 111.7, 123.5, 123.7, 127.09, 127.13, 127.8, 128.4, 129.3, 129.5, 134.1, 138.3,
140.3, 150.6. HRMS (ESIꢀTOF) calcd for C18H15N2: 259.1230 [M+H]+, found: 259.1238.
9-Chloro-2-methyl-5-phenylpyrazolo[5,1-a]isoquinoline (4b)
o
Eluent: petroleum etherꢀethyl acetate (30:1); White solid (96 mg, 66%), mp: 157ꢀ158 C; IR
(KBr) 3065, 2960, 2924, 2852, 1552, 1482, 1465, 1446, 1396, 1305, 1078, 1020, 850, 759,
730, 689 cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.52 (s, 3H), 6.85 (s, 1H), 6.91 (s, 1H),
7.44ꢀ7.54 (m, 4H), 7.63 (d, J = 8.4 Hz ,1H), 7.91 (d, J = 6.8 Hz, 2H), 8.01 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ: 14.3, 98.1, 110.9, 122.9, 124.6, 127.6, 128.2, 128.4, 128.5, 129.4, 129.5,
132.8, 133.6, 138.5, 139.2, 150.9. HRMS (ESIꢀTOF) calcd for C18H14ClN2: 293.0840 [M+H]+,
found: 293.0845.
9-Fluoro-2-methyl-5-phenylpyrazolo[5,1-a]isoquinoline (4c)
o
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (104 mg, 75%), mp: 84ꢀ85 C; IR
(KBr) 3052, 2931, 1610, 1554, 1492, 1472, 1445, 1401,1322, 1251, 1164, 852, 805, 739, 733,
686 cm−1; 1H NMR (400 MHz, CDCl3) δ : 2.54 (s, 3H), 6.80 (s, 1H), 6.90 (s, 1H), 7.22ꢀ7.24
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(m, 1H), 7.50ꢀ7.56 (m, 3H), 7.61ꢀ7.66 (m, 2H), 7.92ꢀ7.94 (m, 2H). 13C NMR (100 MHz,
5
6
7
2
2
CDCl3) δ: 14.3, 98.2, 108.6 (d, JCꢀF = 22.1 Hz), 110.9, 116.4 (d, JCꢀF = 23.6 Hz), 124.9 (d,
8
9
3JCꢀF = 9.1 Hz), 125.8 (d, 4JCꢀF = 2.2 Hz), 128.4, 129.3 (d, 3JCꢀF = 9.1 Hz), 129.5, 133.8, 137.6
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4
1
(d, JCꢀF = 2.3 Hz), 139.47, 139.52, 150.6, 161.5 (d, JCꢀF = 245.4 Hz). HRMS (ESIꢀTOF)
calcd for C18H14FN2: 277.1136 [M+H]+, found: 277.1141.
8-Fluoro-2-methyl-5-phenylpyrazolo[5,1-a]isoquinoline (4d)
o
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (109 mg, 79%), mp: 133ꢀ134 C;
IR (KBr) 3061, 2928, 1634, 1622, 1555, 1488, 1456, 1402, 1323, 1226, 1142, 867, 732, 687
cm−1; H NMR (400 MHz, CDCl3) δ: 2.52 (s, 3H), 6.81 (s, 1H), 6.87 (s, 1H), 7.22ꢀ7.27 (m,
1
1H), 7.32ꢀ7.35 (m, 1H), 7.50ꢀ7.55 (m, 3H), 7.92 (d, J = 7.2 Hz, 2H), 8.00ꢀ8.22 (m, 1H). 13C
4
2
NMR (100 MHz, CDCl3) δ: 14.3, 97.4, 110.8 (d, JCꢀF = 3.8 Hz), 111.7 (d, JCꢀF = 21.3 Hz),
2
4
3
115.8 (d, JCꢀF = 24.4 Hz), 120.3 (d, JCꢀF = 1.5 Hz), 125.7 (d, JCꢀF = 9.2 Hz), 128.4, 129.5,
3
1
130.9 (d, JCꢀF = 9.1 Hz), 133.7, 139.3, 139.9, 150.9, 162.0 (d, JCꢀF = 245.4 Hz). HRMS
(ESIꢀTOF) calcd for C18H14FN2: 277.1136 [M+H]+, found: 277.1139.
9-Methoxy-2-methyl-5-phenylpyrazolo[5,1-a]isoquinoline (4e)
o
Eluent: petroleum etherꢀethyl acetate (30:1); Red solid (101 mg, 70%), mp: 121ꢀ122 C; IR
(KBr) 3058, 2925, 2834, 1616, 1546, 1497, 1476, 1465, 1447, 1349, 1257, 1234, 1197, 1179,
1032, 846, 740, 689 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.55 (s, 3 H), 3.98 (s, 3H), 6.86 (s,
1H), 6.94 (s, 1H), 7.15ꢀ7.18 (m, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.48ꢀ7.55 (m, 3H), 7.65 (d, J =
8.8 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 14.3, 55.6, 97.5, 104.7,
111.6, 117.7, 123.5, 124.8, 128.3, 128.7, 129.0, 129.4, 134.1, 136.2, 139.9, 150.2, 158.8.
HRMS (ESIꢀTOF) calcd for C19H17N2O: 289.1335 [M+H]+, found: 289.1343.
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2,8-Dimethyl-5-phenylpyrazolo[5,1-a]isoquinoline (4f)
5
6
o
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (89 mg, 65%), mp: 97ꢀ98 C; IR
(KBr) 3052, 2918, 1634, 1553,1488, 1457, 1446, 1323, 1307, 840, 769, 746, 736, 693 cm−1;
1H NMR (400 MHz, CDCl3) δ: 2.51 (s, 3H), 2.58 (s, 3H), 6.83 (s, 1H), 6.91 (s, 1H), 7.35 (d, J
= 8.4 Hz, 1H), 7.48 (s, 1H), 7.52ꢀ7.59 (m, 3H), 7.94ꢀ8.00 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ: 14.4, 21.7, 97.2, 111.6, 121.5, 123.4, 126.8, 128.4, 128.7, 129.2, 129.5, 129.6,
134.2, 137.7, 138.3, 140.4, 150.5. HRMS (ESIꢀTOF) calcd for C19H17N2: 273.1386 [M+H]+,
found: 273.1387.
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2-Methyl-5-phenyl-9-(trifluoromethyl)pyrazolo[5,1-a]isoquinoline (4g)
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (114 mg, 70%), mp: 148ꢀ149 oC; IR
(KBr) 2924, 1552, 1472, 1448, 1394, 1319,1253, 1144, 1106, 1069, 900, 855, 748, 694, 684
cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.55 (s, 3H), 6.93 (d, J = 6.4 Hz, 2H), 7.52ꢀ7.55 (m, 3H),
13
7.69 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.93ꢀ7.95 (m, 2H), 8.28 (s, 1H). C NMR
3
(100 MHz, CDCl3) δ: 14.3, 98.5, 110.6, 120.8 (q, JCꢀF = 4.6 Hz), 123.1, 123.7 (q, 3JCꢀF = 3.1
Hz), 124.2 (q, 1JCꢀF = 270.5 Hz), 127.7, 128.4, 128.6 (q, 2JCꢀF = 32.8 Hz), 129.5, 129.7, 131.4,
133.4, 139.7, 140.2, 151.2. HRMS (ESIꢀTOF) calcd for C19H14F3N2: 327.1104 [M+H]+, found:
327.1106.
2-Methyl-5-phenyl-[1,3]dioxolo[4,5-g]pyrazolo[5,1-a]isoquinoline (4h)
o
Eluent: petroleum etherꢀethyl acetate (20:1); Yellow solid (99 mg, 66%), mp: 150ꢀ151 C; IR
(KBr) 3052, 2988, 2908, 1546, 1484, 1472, 1454, 1413, 1273, 1244, 1212, 1032, 942, 913,
865, 827, 746, 730, 690 cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.53 (s, 3H), 6.07 (s, 2H), 6.69
(s, 1H), 6.84 (s, 1H), 7.05 (s, 1H), 7.38 (s, 1H), 7.48ꢀ7.55 (m, 3H), 7.94 (d, J = 7.2 Hz, 2H).
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13C NMR (100 MHz, CDCl3) δ: 14.3, 96.3, 101.5, 101.9, 105.0, 111.5, 119.2, 125.3, 128.4,
129.1, 129.4, 134.0, 136.7, 140.3, 147.9, 148.4, 150.4. HRMS (ESIꢀTOF) calcd for
C19H15N2O2: 303.1128 [M+H]+, found: 303.1132.
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2-Ethyl-5-phenylpyrazolo[5,1-a]isoquinoline (4i)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow oil (78 mg, 58%). H NMR (400 MHz,
CDCl3) δ: 1.40 (t, J = 7.6 Hz, 3H), 2.92 (q, J = 7.6 Hz, 2H), 6.94 (s, 1H), 7.00 (s, 1H),
7.49ꢀ7.55 (m, 5H), 7.73 (d, J = 7.2, Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ: 14.1, 22.0, 95.9, 111.7, 123.5, 123.8, 127.07, 127.09, 127.7,
128.3, 129.2, 129.3, 129.5, 134.0, 138.3, 140.1, 156.6. HRMS (ESIꢀTOF) calcd for C19H17N2:
273.1386 [M+H]+, found: 273.1377.
5-Phenyl-2-propylpyrazolo[5,1-a]isoquinoline (4j)
1
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow oil (80 mg, 56%). H NMR (400 MHz,
CDCl3) δ: 1.11 (t, J = 7.6 Hz, 3H), 1.85ꢀ1.91 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H), 6.95 (s, 1H),
7.00 (s, 1H), 7.52ꢀ7.58 (m, 5H), 7.72ꢀ7.74 (m, 1H), 8.01 (d, J = 6.4 Hz, 2H), 8.09ꢀ8.11 (m,
1H). 13C NMR (100 MHz, CDCl3) δ: 14.2, 23.2, 30.9, 96.5, 111.7, 123.5, 123.8, 127.1, 127.7,
128.3, 129.26, 129.29, 129.5, 134.1, 138.3, 140.1, 155.2. HRMS (ESIꢀTOF) calcd for
C20H19N2: 287.1543 [M+H]+, found: 287.1551.
1,2-Dimethyl-5-phenylpyrazolo[5,1-a]isoquinoline (4k)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (75 mg, 55%), mp: 145ꢀ146 C; IR
(KBr) 3053, 2922, 2852, 1477, 1486, 1458, 1449, 1399, 1320, 838, 767, 744, 697 cm−1; H
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NMR (400 MHz, CDCl3) δ: 2.57 (s, 3H), 2.62 (s, 3H), 6.94 (s, 1H), 7.50ꢀ7.62 (m, 5H), 7.71
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(d, J = 7.6 Hz, 1H), 8.05 (d, J = 6.4 Hz, 2H), 8.32 (d, J = 8.0 Hz, 1H). C NMR (100 MHz,
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CDCl3) δ: 10.8, 12.3, 107.9, 111.4, 123.0, 125.3, 126.8, 126.9, 127.0, 128.3, 129.2, 129.5,
129.7, 134.2, 135.7, 138.3, 149.5. HRMS (ESIꢀTOF) calcd for C19H17N2: 273.1386 [M+H]+,
found: 273.1385.
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1-Ethyl-2-methyl-5-phenylpyrazolo[5,1-a]isoquinoline (4l)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (72 mg, 50%), mp: 101ꢀ102 C; IR
(KBr) 3058, 2965, 2921, 2851, 1563, 1481, 1465, 1448, 1399, 1332, 1307, 838, 771, 762, 745,
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695 cm−1; H NMR (400 MHz, CDCl3) δ: 1.36 (t, J = 7.6 Hz, 3H), 2.47 (s, 3H), 3.06 (q, J =
7.6 Hz, 2H), 6.91 (s, 1H), 7.49ꢀ7.60 (m, 5H), 7.72 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz,
2H), 8.27 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 12.1, 14.3, 18.1, 111.4, 114.8,
122.8, 125.0, 127.0, 127.2, 128.2, 128.3, 128.5, 129.1, 129.5, 129.8, 134.3, 138.4, 149.1.
HRMS (ESIꢀTOF) calcd for C20H19N2: 287.1543 [M+H]+, found: 287.1550.
5-(4-Chlorophenyl)-2-methylpyrazolo[5,1-a]isoquinoline (4m)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (73 mg, 50%), mp: 124ꢀ125 C; IR
(KBr) 3055, 2918, 1550, 1486, 1466, 1415, 1324, 1091, 1014, 934, 864, 817, 763, 733, 722,
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660 cm−1; H NMR (400 MHz, CDCl3) δ: 2.55 (s, 3H), 6.88 (s, 1H), 6.94 (s, 1H), 7.50ꢀ7.56
(m, 4H), 7.69ꢀ7.72 (m, 1H), 7.90 (d, J = 8.4 Hz, 2H), 8.05ꢀ8.07 (m, 1H). 13C NMR (100 MHz,
CDCl3) δ: 14.3, 97.8, 111.7, 123.5, 123.8, 127.1, 127.3, 127.9, 128.6, 129.1, 130.8, 134.4,
135.2, 137.1, 140.2, 150.7. HRMS (ESIꢀTOF) calcd for C18H14ClN2: 293.0840 [M+H]+, found:
293.0849.
5-(4-Fluorophenyl)-2-methylpyrazolo[5,1-a]isoquinoline (4n)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (83 mg, 60%), mp: 112ꢀ113 C; IR
(KBr) 3054, 2922, 2853, 1634, 1604, 1552, 1511, 1468, 1096, 1016, 937, 822, 734 cm−1; 1H
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NMR (400 MHz, CDCl3) δ: 2.54 (s, 3H), 6.90 (s, 1H), 6.95 (s, 1H), 7.23 (t, J = 8.4 Hz, 2H),
7.54ꢀ7.56 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.93ꢀ7.96 (m, 2H), 8.06ꢀ8.08 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ: 14.3, 97.7, 111.6, 115.4 (d, 2JCꢀF = 21.3 Hz), 123.5, 123.7, 127.0, 127.2,
127.8, 129.2, 130.0 (d, 4JCꢀF = 3.0 Hz), 131.4 (d, 3JCꢀF = 7.7 Hz), 137.2, 140.3, 150.7, 163.3 (d,
1JCF = 247.6 Hz). HRMS (ESIꢀTOF) calcd for C18H14FN2: 277.1136 [M+H]+, found:
277.1135.
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5-(4-Methoxyphenyl)-2-methylpyrazolo[5,1-a]isoquinoline (4o)
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Eluent: petroleum etherꢀethyl acetate (20:1); White solid (81 mg, 56%), mp: 120ꢀ121 C; IR
(KBr) 3052, 3017, 2971, 2921, 1631, 1605, 1572, 1510, 1465, 1182, 1024, 937, 827, 740
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cm−1; H NMR (400 MHz, CDCl3) δ: 2.55 (s, 3H), 3.91 (s, 3H), 6.89 (s, 1H), 6.95 (s, 1H),
7.07 (d, J = 8.8 Hz, 2H), 7.52ꢀ7.54 (m, 2H), 7.70ꢀ7.72 (m, 1H), 7.92 (d, J = 8.8 Hz, 2H),
8.05ꢀ8.08 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.4, 55.4, 97.5, 110.9, 113.8, 123.45,
123.48, 126.4, 126.8, 126.9, 127.7, 129.4, 130.9, 138.1, 140.3, 150.5, 160.4. HRMS
(ESIꢀTOF) calcd for C19H17N2O: 289.1335 [M+H]+, found: 289.1343.
2-Methyl-5-m-tolylpyrazolo[5,1-a]isoquinoline (4p)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow oil (74 mg, 54%). H NMR (400 MHz,
CDCl3) δ: 2.51 (s, 3H), 2.58 (s, 3H), 6.90 (s, 1H), 6.98 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.46
(t, J = 7.6 Hz, 1H), 7.53ꢀ7.55 (m, 2H), 7.71ꢀ7.78 (m, 3H), 8.07ꢀ8.09 (m, 1H). 13C NMR (100
MHz, CDCl3) δ: 14.4, 21.6, 97.6, 111.6, 123.5, 123.7, 126.7, 127.0, 127.7, 128.3, 129.3,
130.08, 130.11, 134.0, 138.0, 138.5, 140.2, 150.6. HRMS (ESIꢀTOF) calcd for C19H17N2:
273.1386 [M+H]+, found: 273.1385.
5-(4-Chlorophenyl)-1,2-dimethylpyrazolo[5,1-a]isoquinoline (4q)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (73 mg, 48%), mp: 161ꢀ162 C; IR
(KBr) 3052, 2920, 2852, 1629, 1594, 1566, 1490, 1462, 1253, 1017, 926, 818, 742 cm−1; 1H
NMR (400 MHz, CDCl3) δ: 2.46 (s, 3H) , 2.60 (s, 3H), 6.89 (s, 1H), 7.48ꢀ7.60 (m, 4H), 7.72
(d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 8.32 (d, J = 8.0 Hz, 1H).13C NMR (100 MHz,
CDCl3) δ: 10.8, 12.3, 108.0, 111.4, 123.0, 125.4, 127.05, 127.11, 128.5, 129.5, 130.8, 132.6,
135.0, 135.7, 137.1, 149.6. HRMS (ESIꢀTOF) calcd for C19H16ClN2: 307.0997 [M+H]+, found:
307.0995.
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5-(4-Fluorophenyl)-1,2-dimethylpyrazolo[5,1-a]isoquinoline (4r)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (84 mg, 58%), mp: 141ꢀ142 C; IR
(KBr) 3054, 2922, 2853, 1636, 1603, 1569, 1509, 1450, 1095, 1018, 924, 824, 747 cm−1; 1H
NMR (400 MHz, CDCl3) δ: 2.47 (s, 3H), 2.60 (s, 3H), 6.88 (s, 1H), 7.21 (t, J = 8.8 Hz, 2H),
7.50ꢀ7.60 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 8.4, 5.6 Hz, 2H), 8.32 (d, J = 8.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ: 10.5, 12.2, 108.0, 111.3, 115.3 (d, JCꢀF = 22.2 Hz),
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137.3, 149.6, 163.2 (d, JCꢀF = 246.9 Hz). HRMS (ESIꢀTOF) calcd for C19H16FN2: 291.1292
[M+H]+, found: 291.1295.
5-(4-Methoxyphenyl)-1,2-dimethylpyrazolo[5,1-a]isoquinoline (4s)
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Eluent: petroleum etherꢀethyl acetate (30:1); White solid (83 mg, 55%), mp: 155ꢀ156 C; IR
(KBr) 3054, 3008, 2963, 2929, 2838, 1637, 1608, 1571, 1513, 1460, 819, 753 cm−1; 1H NMR
(400 MHz, CDCl3) δ: 2.47 (s, 3H), 2.60 (s, 3H), 3.90 (s, 3H), 6.88 (s, 1H), 7.05 (d, J = 8.4 Hz,
2H), 7.51ꢀ7.57 (m, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 7.6 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ: 10.8, 12.3, 55.4, 107.8, 110.7, 113.7, 123.0, 125.1, 126.6,
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126.9, 129.9, 130.8, 135.7, 138.0, 149.3, 160.3. HRMS (ESIꢀTOF) calcd for C20H19N2O:
303.1492 [M+H]+, found: 303.1495.
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1,2-Dimethyl-5-m-tolylpyrazolo[5,1-a]isoquinoline (4t)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (74 mg, 52%), mp: 101ꢀ102 oC. H
NMR (400 MHz, CDCl3) δ: 2.47 (s, 6H), 2.61 (s, 3H), 6.89 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H),
7.42 (t, J = 7.6 Hz, 1H), 7.50ꢀ7.58 (m, 2H), 7.70ꢀ7.73 (m, 3H), 8.32 (d, J = 8.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 10.8, 12.3, 21.6, 107.8, 111.3, 123.0, 125.3, 126.66, 126.73,
126.9, 127.0, 128.2, 129.8, 129.97, 130.04, 134.1, 135.7, 137.9, 138.5, 149.4. HRMS
(ESIꢀTOF) calcd for C20H19N2: 287.1543 [M+H]+, found: 287.1545.
1-Ethyl-5-(4-fluorophenyl)-2-methylpyrazolo[5,1-a]isoquinoline (4u)
o
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (78 mg, 51%), mp: 115ꢀ116 C; IR
(KBr) 3053, 2962, 2920, 2851, 1637, 1599, 1567, 1508, 1480, 1095, 1015, 934, 823, 742
cm−1; H NMR (400 MHz, CDCl3) δ: 1.36 (t, J = 7.6 Hz, 3H), 2.47 (s, 3H), 3.06 (q, J = 7.2
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Hz, 2H), 6.88 (s, 1H), 7.21 (t, J = 8.4 Hz, 2H), 7.52ꢀ7.58 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H),
7.89ꢀ7.93 (m, 2H), 8.27 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 12.0, 14.3, 18.1,
111.3, 114.9, 115.3 (d, 2JCꢀF = 21.4 Hz), 122.8, 124.9, 127.1 (d, JCꢀF = 3.2 Hz), 127.2, 129.7,
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130.2, 130.3, 131.4 (d, JCꢀF = 8.7 Hz), 135.2, 137.3, 149.2, 163.2 (d, JCꢀF = 246.9 Hz).
HRMS (ESIꢀTOF) calcd for C20H18FN2: 305.1449 [M+H]+, found: 305.1450.
1-Ethyl-5-(4-methoxyphenyl)-2-methylpyrazolo[5,1-a]isoquinoline (4v)
o
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow solid (77 mg, 49%), mp: 120ꢀ121 C; IR
(KBr) 3050, 2960, 2923, 2868, 2852, 1633, 1604, 1563, 1513, 1464, 1249, 1027, 941, 824,
738 cm−1; H NMR (400 MHz, CDCl3) δ: 1.36 (t, J = 7.6 Hz, 3H), 2.47 (s, 3H), 3.06 (q, J =
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7.6 Hz, 2H), 3.91 (s, 3H), 6.88 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.49ꢀ7.58 (m, 2H), 7.71 (d, J
= 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 8.26 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ: 12.1, 14.4, 18.1, 55.4, 110.8, 113.7, 114.8, 122.8, 124.7, 126.6, 126.7, 126.9, 127.0, 129.9,
130.9, 135.2, 138.1, 149.0, 160.2. HRMS (ESIꢀTOF) calcd for C21H21N2O: 317.1648 [M+H]+,
found: 317.1656.
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1-Ethyl-2-methyl-5-m-tolylpyrazolo[5,1-a]isoquinoline (4w)
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Eluent: petroleum etherꢀethyl acetate (30:1); Yellow oil (71 mg, 47%). H NMR (400 MHz,
CDCl3) δ: 1.37 (t, J = 7.6 Hz, 3H), 2.48 (s, 6H), 3.07 (q, J = 7.6 Hz, 2H), 6.89 (s, 1H), 7.31 (d,
J = 7.6 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.51ꢀ7.58 (m, 2H), 7.71ꢀ7.73 (m, 3H), 8.27 (d, J =
8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 12.1, 14.3, 18.1, 21.6, 111.3, 114.8, 122.8, 124.9,
126.7, 126.9, 127.0, 127.1, 128.2, 129.8, 129.9, 130.1, 132.3, 134.2, 137.9, 138.6, 149.1.
HRMS (ESIꢀTOF) calcd for C21H21N2: 301.1699 [M+H]+, found: 301.1695.
5-Benzyl-2-methylpyrazolo[5,1-a]isoquinoline (4x)
Eluent: petroleum etherꢀethyl acetate (30:1); Yellow oil (56 mg, 41%); IR (neat) 3027, 2924,
1638, 1548, 1485, 1470, 1452, 1409,1327, 1031, 841, 753, 706, 692, 678 cm−1; 1H NMR (600
MHz, CDCl3) δ: 2.59 (s, 3H), 4.52 (s, 2H), 6.44 (s, 1H), 6.87 (s, 1H), 7.33ꢀ7.35 (m, 1H),
7.39ꢀ7.42 (m, 4H), 7.45ꢀ7.51 (m, 2H), 7.54 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H). 13C
NMR (125 MHz, CDCl3) δ: 14.2, 36.9, 97.6, 109.7, 123.2, 123.4, 126.6, 126.7, 126.9, 127.5,
128.6, 129.1, 130.0, 137.0, 138.7, 139.6, 150.3. HRMS (ESIꢀTOF) calcd for C19H17N2:
273.1386 [M+H]+, found: 273.1390.
Typical procedure for the synthesis of 6a and spectroscopic data of 6a-6l
A solution of 1ꢀ(2ꢀbromophenyl)butaꢀ2,3ꢀdienꢀ1ꢀone (1a, 222 mg, 1 mmol) and hydrazine
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hydrate (2, 80%, 73 ꢁL, 1.2 mmol) in DMSO (2 mL) was stirred at room temperature for 30
min. Then, to the mixture were added ethynylbenzene (3a, 122 mg, 1.2 mmol) and KOH (70
mg, 1.25 mmol). The resulting mixture was then stirred at 120 ºC under N2 atmosphere. Upon
completion as indicated by TLC analysis, the reaction was quenched with water and the
mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were
washed with water and brine, and then dried over anhydrous Na2SO4. The solvent was
evaporated under vacuum, and the crude product was purified by column chromatography on
silicaꢀgel eluting with petroleum etherꢀethyl acetate (20:1) to afford 6a in 81% yield.
(Z)-5-(2-Bromophenyl)-3-methyl-1-styryl-1H-pyrazole (6a)
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Eluent: petroleum etherꢀethyl acetate (20:1); 274 mg, 81%. H NMR (400 MHz, CDCl3) δ:
2.08 (s, 3H), 6.58 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 7.05ꢀ7.07 (m, 2H), 7.17ꢀ7.21
(m, 1H), 7.25ꢀ7.27 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.65ꢀ7.69 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ: 11.4, 107.5, 122.2, 124.3, 127.4, 128.4, 128.48, 128.53, 129.0, 129.2, 131.2, 133.5,
134.0, 134.6, 139.6, 151.2. HRMS (ESIꢀTOF) calcd for C18H16BrN2: 339.0491 [M+H]+,
found: 339.0495.
(Z)-5-(2-Bromo-5-chlorophenyl)-3-methyl-1-styryl-1H-pyrazole (6b)
Eluent: petroleum etherꢀethyl acetate (20:1); 294 mg, 79%. IR (neat) 3056, 2919, 2862, 1646,
1448, 1433, 1355, 1384, 1025, 1008, 910, 785, 757, 727, 692, 677 cm−1; 1H NMR (400 MHz,
CDCl3) δ: 2.06 (s, 3H), 6.54 (d, J = 9.2 Hz, 1H), 6.68 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H),
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7.08ꢀ7.12 (m, 3H), 7.25ꢀ7.29 (m, 3H), 7.52 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H). C
NMR (100 MHz, CDCl3) δ: 11.4, 107.3, 119.8, 124.0, 128.4, 128.47, 128.53, 128.9, 129.0,
130.9, 133.4, 133.9, 134.5, 136.0, 139.8, 149.9. HRMS (ESIꢀTOF) calcd for C18H15BrClN2:
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(Z)-5-(2-Bromo-4-methylphenyl)-3-methyl-1-styryl-1H-pyrazole (6c)
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Eluent: petroleum etherꢀethyl acetate (20:1); 289 mg, 82%. IR (neat) 3067, 2915, 2853, 1499,
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1448, 1421, 1345, 1275, 1138, 956, 874, 1036, 844, 832, 797, 762, 689 cm−1; H NMR (400
MHz, CDCl3) δ: 2.04 (s, 3H), 2.33 (s, 3H), 6.54 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 6.0 Hz, 1H),
7.03ꢀ7.05 (m, 2H), 7.10 (d, J = 5.2 Hz, 1H), 7.22ꢀ7.25 (m, 3H), 7.46 (s, 1H), 7.54 (d, J = 5.2
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 11.3, 20.9, 107.4, 121.8, 124.3, 128.27, 128.30,
128.4, 128.5, 129.0, 130.9, 131.7, 133.9, 134.0, 139.4, 139.5, 151.2. HRMS (ESIꢀTOF) calcd
for C19H18BrN2: 353.0648 [M+H]+, found: 353.0649.
(Z)-5-(2-Bromo-4-methoxyphenyl)-3-methyl-1-styryl-1H-pyrazole (6d)
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Eluent: petroleum etherꢀethyl acetate (20:1); 302 mg, 82%. H NMR (400 MHz, CDCl3) δ:
2.11 (s, 3H), 3.78 (s, 3H), 6.57 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 6.75ꢀ6.78 (m, 1H), 6.85 (dd,
J = 8.8, 1.2 Hz, 1H), 7.06ꢀ7.08 (m, 2H), 7.20ꢀ7.28 (m, 4H), 7.51 (dd, J = 8.8, 1.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 11.4, 55.6, 107.4, 112.5, 115.3, 116.3, 124.1, 128.0, 128.2, 128.4,
129.0, 134.1, 135.2, 139.5, 151.1, 158.8. HRMS (ESIꢀTOF) calcd for C19H18BrN2O: 369.0597
[M+H]+, found: 369.0598.
(Z)-5-(2-Bromophenyl)-3,4-dimethyl-1-styryl-1H-pyrazole (6e)
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Eluent: petroleum etherꢀethyl acetate (20:1); 287 mg, 81%. H NMR (400 MHz, CDCl3) δ:
1.95 (s, 3H), 1.98 (s, 3H), 6.52 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 7.08ꢀ7.10 (m,
2H), 7.19ꢀ7.26 (m, 4H), 7.32ꢀ7.36 (m, 1H), 7.43ꢀ7.45 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 9.1, 9.9, 113.8, 124.2, 124.6, 127.2, 128.3, 128.4, 129.1, 129.6,
132.2, 132.7, 134.0, 135.5, 136.7, 151.6. HRMS (ESIꢀTOF) calcd for C19H18BrN2: 353.0648
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[M+H]+, found: 353.0650.
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(Z)-5-(2-Bromophenyl)-1-(3-fluorostyryl)-3-methyl-1H-pyrazole (6f)
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Eluent: petroleum etherꢀethyl acetate (20:1); 285 mg, 80%. IR (neat) 3071, 2922, 1650, 1610,
1581, 1484, 1441, 1352, 1250, 1239, 1024, 954, 877, 788, 757, 726, 686, 675 cm−1; 1H NMR
(400 MHz, CDCl3) δ: 2.12 (s, 3H), 6.46 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 6.84 (d, J = 9.2 Hz,
1H), 6.88ꢀ6.95 (m, 3H), 7.15ꢀ7.23 (m, 2H), 7.31ꢀ7.35 (m, 1H), 7.64ꢀ7.71 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ: 11.4, 107.7, 115.2 (d, 2JCꢀF = 21.4 Hz), 115.8 (d, 2JCꢀF = 22.2 Hz), 122.2,
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124.9, 125.1 (d, JCꢀF = 3.1 Hz), 126.0 (d, JCꢀF = 1.6 Hz), 127.4, 129.3, 129.8 (d, JCꢀF = 7.9
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Hz), 131.2, 133.5, 134.5, 136.1 (d, JCꢀF = 7.9 Hz), 139.6, 151.4, 162.6 (d, JCꢀF = 243.8 Hz).
HRMS (ESIꢀTOF) calcd for C18H15BrFN2: 357.0397 [M+H]+, found: 357.0401.
(Z)-5-(2-Bromophenyl)-1-(4-chlorostyryl)-3-methyl-1H-pyrazole (6g)
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Eluent: petroleum etherꢀethyl acetate (20:1); 294 mg, 79%. H NMR (400 MHz, CDCl3) δ:
2.10 (s, 3H), 6.45 (d, J = 9.2 Hz, 1H), 6.63 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.4
Hz, 2H), 7.15ꢀ7.19 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.31ꢀ7.35 (m, 1H), 7.64ꢀ7.69 (m, 2H).
13C NMR (100 MHz, CDCl3) δ: 11.4, 107.7, 122.2, 124.5, 126.3, 127.5, 128.6, 129.3, 130.4,
131.2, 132.5, 133.5, 134.0, 134.5, 139.5, 151.3. HRMS (ESIꢀTOF) calcd for C18H15BrClN2:
373.0102 [M+H]+, found: 373.0106.
(Z)-5-(2-Bromophenyl)-3-methyl-1-(4-methylstyryl)-1H-pyrazole (6h)
Eluent: petroleum etherꢀethyl acetate (20:1); 264 mg, 75%. IR (neat) 2958, 2920, 2853, 1644,
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1546, 1511, 1431, 1364, 1185, 1164, 1022, 956, 949, 820, 794, 759, 745, 725, 675 cm−1; H
NMR (400 MHz, CDCl3) δ: 1.98 (s, 3H), 2.23 (s, 1H), 6.47ꢀ6.50 (m, 2H), 6.71 (d, J = 5.6 Hz,
1H), 6.83 (d, J = 5.2 Hz, 2H), 6.97 (d, J = 5.2 Hz, 2H), 7.09ꢀ7.12 (m, 1H), 7.25 (t, J = 5.2 Hz,
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1H), 7.57 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 11.4,
21.3, 107.3, 123.5, 127.2, 127.3, 128.8, 129.1, 129.2, 131.0, 131.1, 131.2, 133.4, 134.7, 138.4,
139.5, 151.1. HRMS (ESIꢀTOF) calcd for C19H18BrN2: 353.0648 [M+H]+, found: 353.0651.
(Z)-5-(2-Bromophenyl)-1-(4-fluorostyryl)-3,4-dimethyl-1H-pyrazole (6i)
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Eluent: petroleum etherꢀethyl acetate (20:1); 304 mg, 82%. H NMR (400 MHz, CDCl3) δ:
1.93 (s, 3H), 2.03 (s, 3H), 6.48 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.91ꢀ6.95 (m,
2H), 7.04ꢀ7.07 (m, 2H), 7.22ꢀ7.26 (m, 1H), 7.33ꢀ7.39 (m, 1H), 7.65ꢀ7.67 (m, 1H). 13C NMR
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135.3, 136.6, 151.7, 162.4 (d, JCꢀF = 247.7 Hz). HRMS (ESIꢀTOF) calcd for C19H17BrFN2:
371.0554 [M+H]+, found: 371.0556.
(Z)-5-(2-Bromophenyl)-1-(4-chlorostyryl)-3,4-dimethyl-1H-pyrazole (6j)
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Eluent: petroleum etherꢀethyl acetate (20:1); 297 mg, 77%. H NMR (400 MHz, CDCl3) δ:
1.93 (s, 3H), 2.03 (s, 3H), 6.45 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.02ꢀ7.04 (m,
2H), 7.20ꢀ7.26 (m, 3H), 7.35ꢀ7.37 (m, 2H), 7.66ꢀ7.68 (m, 1H). 13C NMR (100 MHz, CDCl3) δ:
8.9, 9.9, 114.1, 124.1, 124.9, 126.6, 127.1, 128.5, 129.7, 130.5, 132.1, 132.4, 132.7, 133.9,
135.2, 136.6, 151.8. HRMS (ESIꢀTOF) calcd for C19H17BrClN2: 387.0258 [M+H]+, found:
387.0261.
(Z)-5-(2-Bromophenyl)-1-(4-methoxystyryl)-3,4-dimethyl-1H-pyrazole (6k)
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Eluent: petroleum etherꢀethyl acetate (20:1); 299 mg, 78%. H NMR (400 MHz, CDCl3) δ:
1.94 (s, 3H), 2.02 (s, 3H), 3.78 (s, 3H), 6.49 (d, J = 8.8 Hz, 1H), 6.72ꢀ6.78 (m, 3H), 6.97 (dd,
J = 6.8, 2.0 Hz, 2H), 7.21ꢀ7.25 (m, 1H), 7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.41 (dd, J = 7.6, 1.6
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Hz, 1H), 7.66 (dd, J = 8.0, 1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 9.0, 9.9, 55.2, 113.6,
113.7, 122.8, 124.1, 126.5, 127.1, 128.7, 129.5, 130.5, 132.2, 132.6, 135.5, 136.6, 151.5,
159.5. HRMS (ESIꢀTOF) calcd for C20H20BrN2O: 383.0754 [M+H]+, found: 383.0752.
(Z)-5-(2-Bromophenyl)-4-ethyl-1-(4-methoxystyryl)-3-methyl-1H-pyrazole (6l)
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Eluent: petroleum etherꢀethyl acetate (20:1); 317 mg, 80%. H NMR (400 MHz, CDCl3) δ:
0.95 (t, J = 7.6 Hz, 3H), 2.01 (s, 3H), 2.36 (q, J = 7.6 Hz, 2H), 3.78 (s, 3H), 6.50 (d, J = 8.8
Hz, 1H), 6.72ꢀ6.77 (m, 3H), 6.96 (d, J = 8.8 Hz, 2H), 7.22ꢀ7.28 (m, 1H), 7.33ꢀ7.41 (m, 2H),
7.66 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 9.9, 15.2, 17.1, 55.2, 113.7, 120.2,
122.8, 124.3, 126.5, 127.0, 128.9, 129.5, 130.5, 132.2, 132.6, 135.7, 136.3, 150.9, 159.5.
HRMS (ESIꢀTOF) calcd for C21H22BrN2O: 397.0910 [M+H]+, found: 397.0907.
Typical procedure for the synthesis of 5a from 6a and spectroscopic data of 5a-5l
To a flask containing (Z)ꢀ(2ꢀbromophenyl)ꢀ3ꢀmethylꢀ1ꢀstyrylꢀ1Hꢀpyrazole (6a, 169 mg, 0.5
mmol) in DMSO (4 mL) were added Pd(dba)2 (46 mg, 0.05 mmol), TFP (24 mg, 0.1 mmol)
and K2CO3 (138 mg, 1 mmol). Then, the mixture was stirred at 100 ºC under N2 atmosphere.
Upon completion as indicated by TLC analysis, the reaction was quenched with water and
extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with water
and brine, and then dried over anhydrous Na2SO4. The solvent was evaporated under vacuum,
and the crude product was purified by column chromatography on silicaꢀgel eluting with
petroleum etherꢀethyl acetate (20:1) to afford 5a in 41% yield.
(Z)-8-Benzylidene-2-methyl-8H-pyrazolo[5,1-a]isoindole (5a)
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Eluent: petroleum etherꢀethyl acetate (20:1); Yellow oil (53 mg, 41%). H NMR (400 MHz,
CDCl3) δ: 2.44 (s, 3H), 6.23 (s, 1H), 6.82 (s, 1H), 7.35ꢀ7.39 (m, 3H), 7.46ꢀ7.54 (m, 3H), 7.73
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(d, J = 7.2 Hz, 1H), 8.37 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 14.8, 97.6,
111.0, 120.2, 120.4, 127.2, 128.1, 128.2, 128.6, 128.7, 130.8, 131.0, 133.5, 137.9, 146.5,
154.4. HRMS (ESIꢀTOF) calcd for C18H15N2: 259.1230 [M+H]+, found: 259.1232.
(Z)-8-Benzylidene-5-chloro-2-methyl-8H-pyrazolo[5,1-a]isoindole (5b)
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Eluent: petroleum etherꢀethyl acetate (20:1); Yellow oil (67 mg, 46%); IR (neat) 3059, 2920,
2850, 1651, 1600, 1584, 1494, 1448, 1028, 941, 887, 799, 750, 692 cm−1; 1H NMR (400 MHz,
CDCl3) δ: 2.09 (s, 3H), 6.59ꢀ6.63 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 7.04ꢀ7.07 (m, 2H),
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NMR (100 MHz, CDCl3) δ: 11.3, 107.3, 119.8, 124.0, 128.4, 128.48, 128.53, 128.9, 129.0,
130.9, 133.4, 133.9, 134.5, 136.0, 139.8, 149.9. HRMS (ESIꢀTOF) calcd for C18H14ClN2:
293.0840 [M+H]+, found: 293.0842.
(Z)-8-Benzylidene-2,6-dimethyl-8H-pyrazolo[5,1-a]isoindole (5c)
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Eluent: petroleum etherꢀethyl acetate (20:1); Yellow solid (52 mg, 38%), mp 83ꢀ84 C; IR
(KBr) 3061, 2922, 2852, 1645, 1590, 1568, 1496, 1452, 1034, 918, 885, 825, 759, 689 cm−1;
1H NMR (400 MHz, CDCl3) δ: 2.42 (s, 3H), 2.47 (s, 3H), 6.17 (s, 1H), 6.78 (s, 1H), 7.19 (d, J
= 7.6 Hz, 1H), 7.36ꢀ7.42 (m, 2H), 7.45ꢀ7.49 (m, 2H), 7.54 (s, 1H)，8.36 (d, J = 7.6 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ: 13.7, 20.8, 96.1, 109.5, 118.9, 110.0, 124.6, 127.2, 127.4,
128.5, 129.7, 130.1, 132.6, 136.2, 137.2, 145.6, 153.2. HRMS (ESIꢀTOF) calcd for C19H17N2:
273.1386 [M+H]+, found: 273.1388.
(Z)-8-Benzylidene-6-methoxy-2-methyl-8H-pyrazolo[5,1-a]isoindole (5d)
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Eluent: petroleum etherꢀethyl acetate (20:1); Yellow solid (60 mg, 42%), mp 109ꢀ110 C; IR
(KBr) 3064, 2922, 2851, 1617, 1585, 1486, 1455, 1223, 1024, 930, 865, 826, 742, 691 cm−1;
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