Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines via silver triflate-catalyzed or electrophile-mediated one-pot tandem reaction

Article abstract of DOI:10.3762/bjoc.10.238

An efficient one-pot tandem cyclization/[3 + 2] cycloaddition reaction of N '-(2-alkynylbenzylidene)hydrazides with ethyl 4,4,4- trifluorobut-2-ynoate under silver triflate-catalyzed or electrophile-mediated conditions is described. Various trifluoromethy

Full text of DOI:10.3762/bjoc.10.238

Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines
via silver triflate-catalyzed or electrophile-mediated
one-pot tandem reaction
Xiaoli Zhou1, Meiling Liu1, Puying Luo*2, Yingjun Lai1, Tangtao Yang1
and Qiuping Ding*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2286–2292.
1Key Laboratory of Small Functional Organic Molecule, Ministry of
Education and Jiangxi's Key Laboratory of green chemistry, Jiangxi
Normal University, Nanchang, Jiangxi 330022, P. R. China and
2Department of Obstetrics and Gynecology, Jiangxi Provincial
people's Hospital, Nanchang, Jiangxi 330006, P. R. China
doi:10.3762/bjoc.10.238
Received: 19 May 2014
Accepted: 18 September 2014
Published: 30 September 2014
Email:
Associate Editor: D. O'Hagan
Puying Luo* - luopuying1979@gmail.com; Qiuping Ding* -
dingqiuping@jxnu.edu.cn
© 2014 Zhou et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Tel.: +86 791 88120380; fax: +86 791 88120380
Keywords:
[3 + 2] cycloaddition; electrophile; N’-(2-alkynylbenzylidene)hydrazide;
silver triflate; tandem
Abstract
An efficient one-pot tandem cyclization/[3 + 2] cycloaddition reaction of N’-(2-alkynylbenzylidene)hydrazides with ethyl 4,4,4-
trifluorobut-2-ynoate under silver triflate-catalyzed or electrophile-mediated conditions is described. Various trifluoromethylated
pyrazolo[5,1-a]isoquinolines were afforded in moderate to excellent yield by this developed method.
Introduction
Isoquinolines and isoquinoline-derived heterocycles are preva- line derivatives showing activities for the inhibition of
lent structural motifs in natural products and pharmaceuticals CDC25B, TC-PTP, and PTP1B [4].
that exhibit remarkable biological activities [1,2]. Therefore,
great attention has been directed toward the development of It has been proved that the physical, chemical, and biological
efficient methods for the selective functionalization of the activity of organic molecules can be dramatically improved by
isoquinoline cores. Among these, pyrazolo[5,1-a]isoquinoline is substitution of hydrogen with fluorine atoms because of the
an important class of isoquinoline derivatives. Recently, much strong electronegativity, the small size, the strength of the C–F
effort has been spent on the synthesis of these compounds due bond, and the low polarizability of the fluorine atom. Statisti-
to their promising biological activities [3-18]. For instance, in cally, more than 20% of the pharmaceuticals and 40% of the
2010, Wu and co-workers found some pyrazolo[5,1-a]isoquino- agrochemicals contain one or more fluorine atoms. Thus, there
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has been considerable interest in developing an efficient method Results and Discussion
for the synthesis of fluorinated heterocycles. Perfluoro- Based on Wu’s work on the silver triflate-catalyzed tandem
alkynoate is a versatile and powerful building block for gener- reaction of N’-(2-alkynylbenzylidene)hydrazides with dimethyl
ating functionalized perfluoroalkylated compounds, especially acetylenedicarboxylate [28], we started our research by exam-
fluorinated heterocycles, by tandem reactions [19-26]. For ining the reaction of N’-(2-alkynylbenzylidene)hydrazides 1a
example, 2-perfluoroalkynoates have been widely used in (0.3 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (2, 0.6 mmol)
synthesizing fluorinated heterocycles, such as benzodiazepines using NaOAc (0.45 mmol) as base, in the presence of AgOTf
[22], chromenes [21,25], and 2-oxopyridine-fused 1,3-diaza- (5 mol %) and 4 Å MS (75 mg) in CH2Cl2 (3 mL) at room
heterocycles [26].
temperature overnight. Surprisingly, the unexpected [3 + 2]
cycloaddition product pyrazolo[5,1-a]isoquinoline derivative 3a
As part of our ongoing efforts in developing synthetic instead of the isoquinoline-based azomethine ylide [28] was
approaches for the functionalization of isoquinoline cores obtained in good yield (84%, Table 1, entry 1). Similar yields
[11,14] and the synthesis of novel fluorinated heterocycles [27] were obtained when NaHCO3 or K2CO3 were used as base
with potential biological applications, herein, we describe an (83% and 86% yield, respectively, Table 1, entries 2 and 3).
efficient method for the one-pot synthesis of trifluoro- Several other inorganic or organic bases were examined, and
methylated pyrazolo[5,1-a]isoquinoline derivates via a Lewis the results showed that CsF was the best choice (91% yield,
acid (AgOTf) or an electrophile- (I2 or ICl) promoted annula- Table 1, entry 8). The control experiment also showed that the
tion of N’-(2-alkynylbenzylidene)hydrazides followed by an base was important for the reaction to proceed (8% yield,
1,3-dipolar cycloaddition.
Table 1, entry 13). Subsequently, a range of solvents, such as
Table 1: Screening of conditions for the silver triflate-catalyzed reaction of N’-(2-alkynylbenzylidene)hydrazide 1a with ethyl 4,4,4-trifluorobut-2-ynoate
2a.
Entry
Base (1.5 equiv)
Solvent
Yield (%)b
1
NaOAc
NaHCO3
K2CO3
Cs2CO3
NaOH
t-BuOK
KF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
toluene
THF
84
83
86
63
51
trace
80
91
60
61
50
37
8
2
3
4
5
6
7
8
CsF
9
DABCO
NEt3
10
11
12
13
14
15
16
17
18
19
DBU
Pyridine
–
CsF
65
69
71
76
87
65
CsF
CsF
CsF
dioxane
DMA
CsF
CsF (1.0 equiv)
CH2Cl2
aReaction conditions: N’-(2-alkynylbenzylidene)hydrazide 1a (0.3 mmol), AgOTf (5 mol %), solvent (3 mL), ethyl 4,4,4-trifluorobut-2-ynoate (2,
0.6 mmol, 2.0 equiv), base (1.5 equiv), 4 Å MS (75 mg), rt, overnight. bIsolated yield based on 1a.
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Beilstein J. Org. Chem. 2014, 10, 2286–2292.
acetonitrile, toluene, THF, dioxane and DMA were screened, To explore the scope of this tandem cyclization/[3 + 2] cycload-
and the results revealed that CH2Cl2 was the best one, and most dition reaction, a range of N’-(2-alkynylbenzylidene)hydrazides
of the others were exhibited good yields (Table 1, entry 8 and 1a–j were prepared from the corresponding aldehydes and
entries 14–18). The yield (65%) was reduced obviously when applied to the synthesis of trifluoromethylated pyrazolo[5,1-
the loading of base was decreased to 1.0 equiv (Table 1, entry a]isoquinoline derivatives 3 under the optimized conditions
19).
(Table 1, entry 8). As shown in Table 2, for most cases, N’-(2-
Table 2: Silver triflate-catalyzed tandem reactions of N’-(2-alkynylbenzylidene)hydrazides 1 with ethyl 4,4,4-trifluorobut-2-ynoate 2.
Entry R1, R2/1
Product 3
Yield (%)a Entry R1, R2/1
Product 3
Yield (%)a
R1 = H
R2 =
4-FC6H4
R1 = H
R2 = Ph
1a
1
2
3
91
86
75
6
7
8
80
1f
3a
3f
R1 = H
R2 =
4-MeC6H4
1b
R1 = H
R2 =
4-AcC6H4
1g
87
3g
3b
3c
3d
3e
R1 = H
R2 =
4-MeOC6H4
1c
R1 = H
R2 =
4-NO2C6H4
1h
47
3h
R1 = H
R2 =
4-EtOC6H4
1d
R1 = H
R2 =
cyclopropyl
1i
4
89
9
90
3i
R1 = H
R2 =
4-ClC6H4
1e
R1 = 3-F
R2 = Ph
1j
5
85
10
44
3j
aIsolated yields based on N’-(2-alkynylbenzylidene)hydrazides 1.
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Beilstein J. Org. Chem. 2014, 10, 2286–2292.
alkynylbenzylidene)hydrazides 1 reacted with ethyl 4,4,4-triflu- alkynylbenzylidene)hydrazides 1, electrophiles (I2 or ICl), and
orobut-2-ynoate 2 affording the corresponding products 3 in ethyl 4,4,4-trifluorobut-2-ynoate (2) were carried out under
good to excellent yields. For instance, substrate 1b bearing an mild conditions. The results are summarized in Table 3. For all
electron-donating substituent (methyl) reacted with 2 under the cases, this tandem reaction worked well leading to the corres-
present reaction conditions gave the desired product 3b in good ponding iodinated fluorine-containing pyrazolo[5,1-a]isoquino-
yield (86%, Table 2, entry 2). The structure of 3b was verified lines 4 in moderate to excellent yields. Various functional
by 1H and 13C NMR, HRMS, as well as X-ray diffraction groups, such as methyl, methoxy, ethoxy, halogen, acetyl, nitro,
analysis (Figure 1, for details, see Supporting Information and cyclopropyl groups were tolerated under the reaction condi-
File 1). As expected, the substrates 1e–h with electron-with- tions. In general, substrates bearing electron-donating
drawing substituents are suitable partners in this process and the substituents show better reactivity than those with electron-
corresponding pyrazolo[5,1-a]isoquinolines 3e–h were obtained withdrawing substituents. For instance, methyl-substituted
in good yields. Fortunately, alkyl-substituted N’-(2-alkynyl- N’-(2-alkynylbenzylidene)hydrazide 1b reacted with iodine and
benzylidene)hydrazide was demonstrated to be good partner in ethyl 4,4,4-trifluorobut-2-ynoate (2) in the presence of CsF and
the transformation. For instance, N’-(2-alkynylbenzylidene)hy- 4 Å MS leading to the desired product 4b in 90% yield
drazide 1i reacted with 2, leading to the desired pyrazolo[5,1- (Table 3, entry 3). A relatively lower yield was obtained when
a]isoquinoline 3i in 90% yield (Table 2, entry 9).
nitro substituted N’-(2-alkynylbenzylidene)hydrazide 1h was
used, and the desired product 4g was obtained in 50% yield
Subsequently, based on our previous reports on electrophile- (Table 3, entry 9). Alkyl-substituted product 4h was obtained in
mediated electrophilic cyclization reaction [28,29], one-pot good yields when substrate 1i reacted with iodine or ICl
tandem electrophilic cyclization/[3 + 2] cycloaddition of N’-(2- (Table 3, entries 10 and 11), the structure of 4h was verified by
Figure 1: ORTEP diagrams of 3b and 4h.
Table 3: One-pot tandem reactions of N’-(2-alkynylbenzylidene)hydrazides 1, electrophiles, and ethyl 4,4,4-trifluorobut-2-ynoate (2)a.
Entry
1
X2
4
Yield (%)b Entry
1
X2
4
Yield (%)b
1
1a
I2
71
7
1f
I2
62
4a
4e
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Beilstein J. Org. Chem. 2014, 10, 2286–2292.
Table 3: One-pot tandem reactions of N’-(2-alkynylbenzylidene)hydrazides 1, electrophiles, and ethyl 4,4,4-trifluorobut-2-ynoate (2)a. (continued)
2
1a
ICl
4a
78
8
1g
I2
84
4f
3
4
5
1b
1b
1c
I2
90
82
80
9
1h
ICl
50
85
62
4b
4b
4g
ICl
10
1i
I2
4h
4h
I2
11
1i
ICl
4c
6
1d
I2
88
12
1j
I2
50
4i
4d
aReaction conditions: N’-(2-alkynylbenzylidene)hydrazide 1a (0.3 mmol), I2 or ICl (1.3 equiv), solvent (3 mL), ethyl 4,4,4-trifluorobut-2-ynoate (2,
0.6 mmol, 2.0 equiv), base (1.5 equiv), 4 Å MS (75 mg), rt, overnight. bIsolated yields based on N’-(2-alkynylbenzylidene)hydrazides 1.
1H and 13C NMR, HRMS, as well as X-ray diffraction analysis synthesized in moderate to excellent yield by this developed
(Figure 1, for details, see Supporting Information File 1). Based method.
on this one-pot tandem electrophilic cyclization/[3 + 2] cycload-
Experimental
dition reactions, highly functionalized pyrazolo[5,1-a]isoquino-
lines can be obtained via palladium-catalyzed cross-coupling General
reaction.
All reactions were performed in test tubes under N2-atmos-
phere. Flash column chromatography was performed with silica
gel (200–300 mesh). Analytical thin-layer chromatography
Conclusion
In conclusion, we have developed an efficient one-pot tandem was performed on glass plates pre-coated with 0.25 mm
cyclization/[3 + 2] cycloaddition reaction of N’-(2-alkynylbenz- 230–400 mesh silica gel impregnated with a fluorescent indi-
ylidene)hydrazides with ethyl 4,4,4-trifluorobut-2-ynoate under cator (254 nm). Thin-layer chromatography plates were visual-
silver triflate-catalyzed or electrophiles-mediated conditions. ized by exposure to ultraviolet light. Organic solutions were
Highly functionalized pyrazolo[5,1-a]isoquinolines can be concentrated on rotary evaporators at 25–35 °C. Commercial
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Beilstein J. Org. Chem. 2014, 10, 2286–2292.
reagents and solvents were used as received. 1H and 13C NMR Acknowledgements
spectra were recorded on a Bruker AV 400 at 400 MHz (1H) Financial Supported from the National Natural Science Founda-
and 100 MHz (13C) at ambient temperature. Chemical shifts are tion of China (21262016), Jiangxi Educational Committee
reported in parts per million (ppm) on the delta scale (δ) and (GJJ12169), the Project of Jiangxi Youth Scientist
referenced to tetramethylsilane (0 ppm). HRMS analyses were (20122BCB23012), and Natural Science Foundation of Jiangxi
performed in ESI mode on a Bruker mass spectrometer.
Province of China (20133ACB20008, 20132BAB203006) is
gratefully acknowledged.
General procedure for the silver triflate-catalyzed one-pot
tandem reaction of N’-(2-alkynylbenzylidene)hydrazide 1 with
ethyl 4,4,4-trifluorobut-2-ynoate 2: A mixture of N’-(2-alkynyl-
benzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv) and silver
triflate (5 mol %) in anhydrous dichloromethane (3.0 mL) was
stirred at room temperature overnight. Then a solution of ethyl
4,4,4-trifluorobut-2-ynoate (2, 0.60 mmol, 2.0 equiv) in
dichloroethane (2.0 mL), 4 Å MS (75 mg) and CsF (0.45 mmol,
1.5 equiv) were added and stirred for another 3 h. After comple-
tion of the reaction as indicated by TLC, the reaction mixture
was purified by flash column chromatography on silica gel to
provide the corresponding product 3.
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