A facile route to H -Pyrazolo[5,1- A ]isoquinolines through a multicomponent reaction of 2-Alkynylbenzaldehyde, sulfonylhydrazine, and benzyne

Article abstract of DOI:10.1055/s-0033-1341102

A facile and efficient route for the generation of H-pyrazolo[5,1-a] isoquinolines via a silver triflate catalyzed three-component reaction of 2-alkynylbenzaldehyde, tosylhydrazine, and benzyne is reported. This reaction proceeds smoothly under mild conditions with high efficiency. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341102

1362▌
SPECIAL TOPIC
sApecFialatocpiicle Route to H-Pyrazolo[5,1-a]isoquinolines through a Multicomponent
Reaction of 2-Alkynylbenzaldehyde, Sulfonylhydrazine, and Benzyne
H-Pyrazolo[5,1-a]isoquinolines
Jinming Yang,a Xingxin Yu,b Jie Wu*b,c
a
School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu 224051, P. R. of China
b
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
c
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
Fax +86(21)65641740; E-mail: jie_wu@fudan.edu.cn
Received: 09.02.2014; Accepted after revision: 13.03.2014
skeleton of H-pyrazolo[5,1-a]isoquinoline.6–9 One conve-
Abstract: A facile and efficient route for the generation of H-pyr-
nient route starts from an N′-(2-alkynylbenzylidene)hy-
azolo[5,1-a]isoquinolines via a silver triflate catalyzed three-com-
drazide,7 which could be easily accessed by condensation
ponent reaction of 2-alkynylbenzaldehyde, tosylhydrazine, and
of 2-alkynylbenzaldehyde with a sulfonylhydrazine; dur-
ing the tandem process, isoquinolinium-2-ylamide was
demonstrated to be the key intermediate.
benzyne is reported. This reaction proceeds smoothly under mild
conditions with high efficiency.
Key words: 2-alkynylbenzaldehyde, benzyne, H-pyrazolo[5,1-
a]isoquinoline, silver triflate, tosylhydrazine
It is known that aryne is a highly reactive species and it is
readily generated in situ from 2-(trimethylsilyl)aryl tri-
flate in the presence of a fluoride source. A wide range of
heterocycles and carbocycles have been constructed using
aryne as the starting material.10 Moreover, excellent reac-
tivity has been shown when aryne is used as a dipolaro-
phile in 1,3-dipolar cycloaddition reactions.11 As
mentioned above, isoquinolinium-2-yl amide is readily
formed from N′-(2-alkynylbenzylidene)hydrazide via a 6-
endo cyclization catalyzed by a suitable Lewis acid or
promoted by electrophiles, and N′-(2-alkynylbenzyli-
dene)hydrazide is produced from the reaction of 2-al-
kynylbenzaldehyde with a sulfonylhydrazine. Prompted
by these results and the advancement of aryne chemistry,
we anticipated that aryne could participate in a reaction of
2-alkynylbenzaldehyde 1 with a sulfonylhydrazine. As
shown in Scheme 1, in the presence of silver(I) catalyst
and fluoride source, isoquinolinium-2-yl amide A would
react with the aryne via a [3+2] cycloaddition to afford
compound B; subsequent aromatization would give the
corresponding H-pyrazolo[5,1-a]isoquinolines.
Great advances have been in the use of metal salts as cat-
alysts to facilitate chemical transformations.1 It is well
recognized that metal catalysis has historically dominated
organic synthesis, although organocatalysis has been de-
veloped over the last decade.2 Extensive efforts have been
made to understand of the properties of metals and the ap-
plications of their versatile reactivity patterns in various
transformations.
Diversity-oriented synthesis is a known strategy in the
drug discovery process,3 and multicomponent reactions4
are a powerful tool for the preparation of libraries of small
molecules. A wide range of advantages offered by multi-
component reactions, such as a high degree of atom econ-
omy, convergence, ease of execution, and access to
complex molecules, have now been identified. Therefore,
it would be attractive to construct complex small mole-
cules using multicomponent reactions.
As a privileged scaffold, pyrazole derivatives are found
broadly in lead drug identification and drug discovery
programs, such as cyclooxygenase inhibitors (e.g., SC-
558, tepoxalin, and celecoxib) and cannabinoid-1 inverse
agonists, which are very promising for reducing obesity
(e.g., rimonabant).5 Some derivatives of fused heterocy-
cles containing a pyrazole framework, such as H-pyrazo-
lo[5,1-a]isoquinolines, also exhibited remarkable
biological activity for the inhibition of CDC25B, TC-
PTP, and PTP1B.6 Thus, efforts have been made to syn-
thesize H-pyrazolo[5,1-a]isoquinoline derivatives. So far,
there are several approaches for the construction of the
Initial studies focused on the model reaction of 2-alkynyl-
benzaldehyde 1a and tosylhydrazine with 2-(trimethylsi-
lyl)phenyl trifluoromethanesulfonate (2) in the presence
of 10 mol% of silver triflate at room temperature. The re-
sults of the preliminary screening are presented in Table
1. The target product 3a was obtained in 41% yield when
the reaction was performed in 1,2-dichloroethane in the
presence of cesium fluoride (entry 1). A better yield was
observed when benzyltriethylammonium chloride (25
mol%) was added as an additive (entry 2). Different sol-
vents were subsequently screened. It was found that tolu-
ene and ethanol were not suitable for this transformation
(entries 3 and 4), leading to either a low yield, or a trace
amount of the desired product. In contrast, the yields dra-
matically improved when acetonitrile, tetrahydrofuran, or
1,4-dioxane were used as the solvent (entries 5–7). Grati-
SYNTHESIS 2014, 46, 1362–1366
Advanced online publication: 28.03.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341102; Art ID: SS-2014-C0162-OP
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
H-Pyrazolo[5,1-a]isoquinolines
1363
source instead of cesium fluoride to promote the genera-
tion of benzyne did not improve the yield (entries 12 and
13). Moreover, reducing the amount of the additive
(Et3NBnCl) from 25 mol% to 10 mol% also resulted in
lower yield (entry 14).
base
TMS
"F'
R1
H
N
OTf
[3+2]
cycloaddition
2
N
Ts
NTs
R2
R2
With the optimized conditions in hand, we next explored
the scope of this three-component reaction of 2-alkynyl-
benzaldehyde, tosylhydrazine, and benzyne. The results
are summarized in Scheme 2. It was found that the substit-
uents on the aromatic ring, such as fluoro, methyl, and
methoxy, were well tolerated in the reactions, giving the
corresponding products 3c–g in good to excellent yields.
When substrate with heteroaromatic ring (thienyl group)
was employed in the transformation, the corresponding
product 3h was obtained in 83% yield. Additionally, sub-
strates 1 bearing a cyclopropyl substituent on the triple
bond worked efficiently under the standard conditions,
producing the expected products of 3b and 3e in 87% and
98% yields, respectively. This result indicated that the cy-
clopropyl group is also compatible with these conditions.
The structures of all the products were unambiguously
characterized by NMR and HRMS. Moreover, the struc-
ture of compound 3g was further confirmed by X-ray sin-
gle crystal diffraction (Figure 1).12
N
B
R1
aromatization
R1
A
TsNHNH2
AgOTf
condensation and
cyclization
CHO
N
N
R1
R2
3
R2
1
Scheme 1 A proposed route to H-pyrazolo[5,1-a]isoquinolines
through a three-component reaction
fyingly, the use of a mixed solvent, 1,4-dioxane–acetoni-
trile, gave the best 86% yield (entry 8), while other
combinations of solvents only provided relatively low
yields of 3a (entries 9–11). However, using potassium flu-
oride or tetrabutylammonium fluoride as the fluoride
Table 1 Initial Studies for the Three-Component Reaction of 2-Alkynylbenzaldehyde 1a, Tosylhydrazine, and Benzyne 2
CHO
TMS
AgOTf (10 mol%)
+
+
TsNHNH2
"F", additive, solvent
N
OTf
N
Ph
1a
2
Ph
3a
Entry
‘F’
Additive
Solvent
Yieldb (%)
1
2
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
KF
–
DCE
41
52
18
trace
70
72
71
86
70
50
64
58
75
72
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
Et3NBnCl
DCE
3
toluene
4
EtOH
5
MeCN
6
THF
7
1,4-dioxane
1,4-dioxane–MeCN
THF–MeCN
1,4-dioxane–CH2Cl2
1,4-dioxane–DMF
1,4-dioxane–MeCN
1,4-dioxane–MeCN
1,4-dioxane–MeCN
8
9
10
11
12
13
14c
TBAF
CsF
a Reaction conditions: 2-alkylbenzaldehyde 1a (0.3 mmol), TsNHNH2 (0.3 mmol), benzyne precursor 2 (0.45 mmol), AgOTf (10 mol%), ‘F’
source (3 equiv), additive (25 mol%), solvent (3.0 mL).
b Isolated yield based on 2-alkynylbenzaldehyde 1a.
c In the presence of 10 mol% of additive.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1362–1366

1364
J. Yang et al.
SPECIAL TOPIC
TsNHNH2
CHO
R1
AgOTf (10 mol%)
R1
+
TMS
OTf
CsF, Et3NBnCl
N
N
MeCN–1,4-dioxane
R2
1
R2
3
2
F
N
N
N
N
N
N
Ph
Ph
3c 90%
3a 86%
3b 87%
F
F
N
Ph
N
N
N
N
N
Ph
3f 94%
3d 93%
3e 98%
MeO
MeO
S
N
N
N
N
Ph
3g 98%
Ph
3h 83%
Scheme 2 Synthesis of H-pyrazolo[5,1-a]isoquinolines through a three-component reaction of 2-alkynylbenzaldehyde, tosylhydrazine, and
benzyne
benzyne. This reaction proceeds smoothly under mild
conditions with high efficiency, producing the corre-
sponding products in good to excellent yields.
Unless otherwise stated, all commercial reagents were used as re-
ceived. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using
silica gel (60 Å pore size, 32–63 μm, standard grade). Analytical
thin-layer chromatography (TLC) was performed using glass plates
pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). TLC plates were visualized by ex-
posure to ultraviolet light. Organic solutions were concentrated on
rotary evaporators at ~20 Torr at 25–35°C. Nuclear magnetic reso-
nance (NMR) spectra are quoted in ppm on the δ scale with tetra-
methylsilane as the internal standard; coupling constants are quoted
in Hz. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruker
DRX-400 spectrometer operating at 400 MHz and 100 MHz, re-
spectively. High-resolution mass spectrometry (HRMS) was car-
Figure 1 ORTEP illustration of compound 3g (30% probability el-
ried out using a micrOTOF II instrument.
lipsoids)
Silver Triflate Catalyzed Three-Component Reaction of 2-Al-
kynylbenzaldehyde 1, Tosylhydrazine, and Benzyne 2; General
In conclusion, we have provided a facile and efficient
Procedure
route for the generation of H-pyrazolo[5,1-a]isoquino-
lines via a silver triflate catalyzed three-component reac-
tion of 2-alkynylbenzaldehyde, tosylhydrazine, and
2-Alkynylbenzaldehyde 1 (0.3 mmol) was added to a solution of
TsNHNH2 (0.3 mmol) in 1,4-dioxane (1.0 mL). The mixture was
stirred at r.t. for 30 min. Then AgOTf (7.7 mg, 10 mol%) was added
Synthesis 2014, 46, 1362–1366
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
H-Pyrazolo[5,1-a]isoquinolines
1365
and the mixture was heated to 70 °C with vigorous stirring for 1 h.
Subsequently, benzyne precursor 2 (0.45 mmol, 1.5 equiv), CsF
(0.9 mmol, 3.0 equiv), Et3NBnCl (0.075 mmol, 0.25 equiv), and
MeCN (2.0 mL) were added. The mixture was stirred vigorously at
50 °C until completion of the reaction. The mixture was diluted
with EtOAc (5.0 mL), and quenched with H2O (5.0 mL). The organ-
ic layer was washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by column chro-
matography (silica gel) to provide the desired product 3.
13C NMR (100 MHz, CDCl3): δ = 7.8, 11.8, 109.5, 109.6, 111.3 (d,
2
2JCF = 21 Hz), 116.1 (d, JCF = 24 Hz), 116.3, 117.4, 120.9, 121.2,
124.5 (d, 3JCF = 9 Hz), 127.3, 129.9 (d, 3JCF = 9 Hz), 130.4, 141.9,
148.8, 161.1 (d, 1JCF = 248 Hz).
HRMS: m/z [M + H]+ calcd for C18H14FN2: 277.1141; found:
277.1145.
2-Methyl-6-phenylindazolo[3,2-a]isoquinoline (3f)
Yellow solid; yield: 86.9 mg (94%).
1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 7.21–7.26 (m, 3 H),
7.43–7.56 (m, 5 H), 7.90–7.94 (m, 3 H), 8.29 (s, 1 H), 8.37 (d,
J = 8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.2, 116.8, 116.9, 117.6, 121.2,
122.2, 125.8, 126.5, 127.1, 127.4, 128.5, 128.9, 129.5, 129.8, 131.2,
134.2, 137.5, 138.3, 148.9.
6-Phenylindazolo[3,2-a]isoquinoline (3a)
Yellow solid; yield: 75.8 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 7.6 Hz, 1 H), 7.34 (s,
1 H), 7.47–7.56 (m, 5 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.78 (d, J = 7.8
Hz, 1 H), 7.92–7.97 (m, 3 H), 8.41 (d, J = 8.2 Hz, 1 H), 8.62 (d,
J = 8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 116.8, 116.9, 117.7, 121.2, 121.5,
122.7, 125.7, 127.2, 127.6, 128.2, 128.6, 129.6, 129.8, 131.5, 134.1,
138.4, 148.9.
HRMS: m/z [M + H]+ calcd for C22H17N2: 309.1392; found:
309.1402.
2,3-Dimethoxy-6-phenylindazolo[3,2-a]isoquinoline (3g)
White solid; yield: 104.1 mg (98%).
1H NMR (400 MHz, CDCl3): δ = 3.98 (s, 3 H), 4.13 (s, 3 H), 7.16
(s, 1 H), 7.24–7.30 (m, 2 H), 7.48–7.56 (m, 4 H), 7.90–7.98 (m, 4
H), 8.33 (d, J = 8.2 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C21H15N2: 295.1235; found:
295.1247.
6-Cyclopropylindazolo[3,2-a]isoquinoline (3b)
White solid; yield: 67.3 mg (87%).
13C NMR (100 MHz, CDCl3): δ = 56.1, 56.2, 103.1, 107.5, 115.9,
116.2, 117.4, 120.4, 120.6, 120.8, 123.8, 127.1, 128.5, 129.3, 129.7,
131.2, 134.3, 136.7, 149.0, 149.7, 150.6.
HRMS: m/z [M + H]+ calcd for C23H19N2O2: 355.1447; found:
355.1450.
1H NMR (400 MHz, CDCl3): δ = 0.89–0.93 (m, 2 H), 1.23–1.30 (m,
2 H), 2.84–2.91 (m, 1 H), 6.88 (s, 1 H), 7.26 (t, J = 7.6 Hz, 1 H),
7.42 (t, J = 7.1 Hz, 1 H), 7.49–7.54 (m, 2 H), 7.61 (d, J = 7.8 Hz, 1
H), 8.02 (d, J = 8.7 Hz, 1 H), 8.34 (d, J = 8.7 Hz, 1 H), 8.49 (d,
J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.6, 12.0, 110.8, 116.9, 117.4,
121.2, 121.3, 122.5, 124.8, 126.9, 127.2, 127.3, 128.4, 131.0, 140.8,
148.9.
HRMS: m/z [M + H]+ calcd for C18H15N2: 259.1235, found:
259.1247.
5-Phenylthieno[3′,2′:3,4]pyrido[1,2-b]indazole (3h)
Yellow solid; yield: 74.7 mg (83%).
1H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 7.3 Hz, 1 H), 7.42–7.43
(m, 1 H), 7.52–7.57 (m, 6 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.99 (d,
J = 7.3 Hz, 2 H), 8.17 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 112.4, 114.8, 116.7, 120.4, 120.5,
124.0, 127.1, 128.0, 128.1, 128.6, 128.8, 129.5, 129.7, 131.1, 134.2,
137.2, 149.1.
HRMS: m/z [M + H]+ calcd for C19H13N2S: 301.0799; found:
301.0813.
3-Fluoro-6-phenylindazolo[3,2-a]isoquinoline (3c)
White solid; yield: 84.2 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.21–7.28 (m, 2 H), 7.36–7.54 (m,
6 H), 7.89–7.95 (m, 3 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.54–8.55 (m, 1
H).
2
13C NMR (100 MHz, CDCl3): δ = 112.2 (d, JCF = 22 Hz), 115.9,
116.3, 117.1 (d, 2JCF = 24 Hz), 117.8, 120.9, 121.6, 122.4, 124.9 (d,
Acknowledgment
3JCF = 9 Hz), 127.4, 128.6, 129.8, 129.9, 130.2 (d, JCF = 9 Hz),
3
131.2, 133.7, 139.4, 149.0, 161.3 (d, 1JCF = 247 Hz).
Financial support from the National Natural Science Foundation of
China (No. 21372046) is gratefully acknowledged.
HRMS: m/z [M + H]+ calcd for C21H14FN2: 313.1141; found:
313.1147.
2-Fluoro-6-phenylindazolo[3,2-a]isoquinoline (3d)
Supporting Information for this article is available online at
Yellow solid; yield: 87.0 mg (93%).
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
1
are experimental procedure, characterization data, and H and 13C
1H NMR (400 MHz, CDCl3): δ = 7.20–7.25 (m, 2 H), 7.32–7.39 (m,
2 H), 7.43–7.54 (m, 4 H), 7.88–7.93 (m, 3 H), 8.26 (d, J = 7.8 Hz, 1
H), 8.49–8.50 (m, 1 H).
NMR spectra of compounds 3. SnugIiofop
maotrinuSgIpionmf
r
t
rorat
t
2
13C NMR (100 MHz, CDCl3): δ = 112.2 (d, JCF = 21 Hz), 115.9,
References and Notes
116.3, 117.1 (d, 2JCF = 24 Hz), 117.8, 120.8, 121.6, 122.4, 124.9 (d,
3JCF = 9 Hz), 127.4, 128.6, 129.8, 129.9, 130.2 (d, JCF = 9 Hz),
3
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Organic Synthesis: Building Blocks and Fine Chemicals,
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VCH: Weinheim, 2004. (b) D’Souza, D. M.; Müller, T. J. J.
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HRMS: m/z [M + H]+ calcd for C21H14FN2: 313.1141; found:
313.1144.
6-Cyclopropyl-2-fluoroindazolo[3,2-a]isoquinoline (3e)
Yellow solid; yield: 81.1 mg (98%).
1H NMR (400 MHz, CDCl3): δ = 0.85–0.89 (m, 2 H), 1.20–1.25 (m,
2 H), 2.79–2.86 (m, 1 H), 6.66 (s, 1 H), 7.15–7.23 (m, 3 H), 7.47 (t,
J = 7.6 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 8.11 (d, J = 8.7 Hz, 1 H),
8.24–8.28 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York
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Oxford University Press: New York, 1998. (b) Zhu, J.;
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(12) Structural parameters for 3g: data collection: Rigaku
Mercury CCD area detector; crystal size: 0.40 × 0.20 × 0.15
mm3; C20H30NO2, Mr = 316.45, monoclinic, space group
P21/c, a = 11.550(4), b = 14.071(5), c = 21.111(8) Å,
β = 96.766(5), V = 3407 (2) Å3, Z = 8, Dcalcd = 1.234 g cm–3,
R[I > 2σ(I)] = 0.1774, wR[I > 2σ(I)] = 0.4292.
Synthesis 2014, 46, 1362–1366
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