An efficient approach to H-pyrazolo[5,1-a]isoquinolines via a silver triflate-catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazide with allenoate

Article abstract of DOI:10.1016/j.tet.2012.02.013

A silver triflate-catalyzed reaction of N′-(2-alkynylbenzylidene) hydrazide with allenoate under mild conditions is described, which provides an efficient approach to diverse H-pyrazolo[5,1-a]isoquinolines. This reaction proceeds with a wide substrate sco

Full text of DOI:10.1016/j.tet.2012.02.013

Tetrahedron 68 (2012) 2765e2769
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient approach to H-pyrazolo[5,1-a]isoquinolines via a silver
triflate-catalyzed reaction of N0-(2-alkynylbenzylidene)hydrazide with allenoate
,
b,
Liang Gao a, Shengqing Ye b, Qiuping Ding a, Zhiyuan Chen a , Jie Wu
*
*
a Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang,
Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
A silver triflate-catalyzed reaction of N0-(2-alkynylbenzylidene)hydrazide with allenoate under mild
conditions is described, which provides an efficient approach to diverse H-pyrazolo[5,1-a]isoquinolines.
This reaction proceeds with a wide substrate scope with good functional groups tolerance.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 7 December 2011
Received in revised form 12 January 2012
Accepted 7 February 2012
Available online 11 February 2012
Keywords:
Allenoate
N0-(2-Alkynylbenzylidene)hydrazide
Isoquinolinium-2-yl amide
H-Pyrazolo[5,1-a]isoquinoline
Silver triflate
1. Introduction
alkynylbenzylidene)hydrazide 1.6 So far, different reaction partners
have been used in the reactions.6,8 Prompted by the advancement of
In the last decade, the chemistry of allenes has been extensively
explored, and their potentials in organic chemistry have been
demonstrated.1 The reactivity of allenes, which is different from
those of alkenes and alkynes, has been recognized and successfully
applied in organic synthesis.2 For instance, allenoate as a versatile
building block has been utilized in different transformations.3,4
Recently, we are interested in the generation of natural product-
like compounds used in different biological assays.5 A novel
structure, H-pyrazolo[5,1-a]isoquinoline, shows promising activi-
ties for inhibition of CDC25B, TC-PTP, and PTP1B.6f Additionally,
a hit has been discovered based on control of diamondback moth at
50 ppm in level 3 insecticide screen. The discovery of lead com-
pounds but their moderate activity prompted us to develop effi-
cient synthesis protocol and test the resulting compounds in order
to find better inhibitors. Consequently, we initiated a program for
the methodology development and library construction of diverse
H-pyrazolo[5,1-a]isoquinoline molecules.
allene chemistry, we conceived that the functionalized H-pyrazolo
[5,1-a]isoquinolines could be prepared as well for the reaction of N0-(2-
alkynylbenzylidene)hydrazide and allenoate. The proposed synthetic
route is presented in Scheme 1. Theoretically, after the formation of
isoquinolinium-2-yl amide A, allenoate 2 would involve in the con-
version via a [3þ2] cycloaddition to afford intermediate B. The sub-
sequent double bond migration and aromatization would occur to
R3
CO2R4
R4O2C
NTs
R2
R3
2
N
N
Ts
R1
N
R1
[3+2]
6-endo
R2
cycloaddition
A
cyclization
B
AgOTf
NHTs
N
R3
R3
R1
In our previous reports, the scaffold of H-pyrazolo[5,1-a]isoquino-
R4O2C
R4O2C
line could be prepared via reactions of N0-(2-alkynylbenzylidene)hy-
R2
1
drazides.6 During the reaction process,
a
key intermediate,
N
B
H
N
Ts
aromatization
N
N
R1
R1
isoquinolinium-2-yl amide A, could be formed through a silver
triflate-catalyzed electrophilic 6-endo-cyclization7 of N0-(2-
R2
R2
3
C
Scheme 1. Generation of H-pyrazolo[5,1-a]isoquinolines via a silver triflate-catalyzed
reaction of N0-(2-alkynylbenzylidene)hydrazide with allenoate.
* Corresponding authors. E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.013

2766
L. Gao et al. / Tetrahedron 68 (2012) 2765e2769
Table 2
furnish the expected H-pyrazolo[5,1-a]isoquinoline 3. To test this hy-
Scope investigation for the silver triflate-catalyzed reaction of N0-(2-
alkynylbenzylidene)hydrazide 1 with allenoate 2
pothesis, we started to examine the feasibility of this transformation.
R3
2. Results and discussion
R4O2C
NHTs
AgOTf
CO2R4
N
R1
(10 mol %)
Initially, the studies were performed for the reaction of N0-(2-
alkynylbenzylidene)hydrazide 1a and n-butyl allenoate 2a (Table
1). No product was detected when the reaction was treated with
10 mol % of silver triflate in dichloroethane (DCE) at room tem-
perature (Table 1, entry 1). The corresponding H-pyrazolo[5,1-a]
isoquinoline 3a was formed with 33% yield when the temperature
was elevated to 55 ꢀC (Table 1, entry 2). However, only a trace
amount of product was observed when the solvent was changed to
toluene (Table 1, entry 3). Since dichloroethane has been demon-
strated as the best choice for the formation of isoquinolinium-2-yl
amide A, a mixed solvent was then screened (Table 1, entries 4e8).
From the results, it seemed that the combination of DCE and DMF in
the reaction gave rise to a better yield (Table 1, entry 8). Recently,
the concept of cooperative catalysts has attracted much attention in
organic synthesis.9 Thus, several metal catalysts (10 mol %) were
added in the reaction system (Table 1, entries 9e12). The yield
could be improved when PdCl2, CuI, or Yb(OTf)3 was employed as
an additive. Lewis base was also considered, since allenoates is
typically facilitated by phosphine.3 Indeed, treatment of N0-(2-
alkynylbenzylidene)hydrazide 1a and n-butyl allenoate 2a with
PPh3 (20 mol %) provided the expected product 3a in 60% yield
(Table 1, entry 13). Switching the additive to other Lewis bases,
however, led to production with lower yields (Table 1, entries
14e16). The yield could be increased to 65% when 2 equiv of n-butyl
allenoate 2a was employed in the reaction (Table 1, entry 17).
+
N
R3
PPh3
(20 mol %)
DCE/DMF
N
R1
R2
3
R2
2
1
Entry
Substrate 1
Allene 2
Yielda (%)
NHTs
Ph
N
CO Bu
1
65 (3a)
2a
1a
CO Et
2
3
1a
1a
80 (3b)
61 (3c)
Ph
2b
2c
2d
CO Et
CO Et
H C
H C
H C
4
5
6
1a
1a
Trace
CO Et
CH
Ph
Trace
2e
NHTs
Ph
N
2a
63 (3d)
1b
7
8
1b
1b
2b
2c
62 (3e)
65 (3f)
Table 1
NHTs
Initial studies for the silver triflate-catalyzed reaction of N0-(2-alkynylbenzylidene)
hydrazide 1a with n-butyl buta-2,3-dienoate 2a
N
9
2c
2b
2a
73 (3g)
60 (3h)
52 (3i)
MeO
Cl
n
Bu O2C
Ph
1c
NHTs
AgOTf
N
n
CO2 Bu
NHTs
N
N
(10 mol %)
+
N
10
11
solvent
3a
Ph
additive
1d
1e
Ph
Ph
1a
2a
F
NHTs
N
N
Entry
Solvent
Additive
T (ꢀC)
Yielda (%)
Ph
1
DCE
d
25
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
NR
33
Trace
29
28
37
33
41
50
45
53
42
60
41
37
42
65
2
DCE
d
12
13
1e
1e
2b
2c
75 (3j)
62 (3k)
3
Toluene
d
4
5
6
7
8
9
10
11
12
13
14
15
16
17b
DCE/MeCN
DCE/THF
DCE/MeOH
DCE/1,4-dioxane
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
d
d
NHTs
Ph
d
14
15
16
2a
2b
2a
40 (3l)
F
d
1f
d
PdCl2
CuI
1f
63 (3m)
60 (3n)
NHTs
N
Yb(OTf)3
In(OTf)3
PPh3
PnBu3
DABCO
Et3N
PPh3
1g
17
18
1g
1g
2b
2c
60 (3o)
70 (3p)
NHTs
N
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1a.
In the presence of 2 equiv of n-butyl buta-2,3-dienoate.
MeO
19
2a
60 (3q)
b
1h
20
21
1h
1h
2b
2c
72 (3r)
75 (3s)
With conditions highlighted above (10 mol % of AgOTf, 20 mol %
of triphenylphosphine, DCE/DMF, 55e60 ꢀC), the scope of the re-
action of N0-(2-alkynylbenzylidene)hydrazide 1 with allenoate 2
was studied. Table 2 shows the summary of results for the evalu-
ation of various substituted N0-(2-alkynylbenzylidene)hydrazides 1
and allenoate 2. Besides n-butyl buta-2,3-dienoate 2a, ethyl 4-
phenylbuta-2,3-dienoate 2b, and ethyl 4-methylbuta-2,3-dienoate
F
NHTs
N
22
2a
60 (3t)
1i

L. Gao et al. / Tetrahedron 68 (2012) 2765e2769
2767
Table 2 (continued )
triflate under mild conditions has been successfully developed.
Diverse H-pyrazolo[5,1-a]isoquinolines are generated in good
yields. This reaction proceeds with a wide substrate scope with
good functional groups tolerance. Library construction and sub-
sequent biological assays are in progress in our laboratory.
Entry
Substrate 1
Allene 2
Yielda (%)
NHTs
N
F
23
24
2c
2a
61 (3u)
61 (3v)
4. Experimental section
4.1. General
1j
NHTs
Ph
S
N
Unless otherwise stated, all commercial reagents were used as
received. All solvents were dried and distilled according to standard
1k
procedures. Flash column chromatography was performed using
25
26
1k
1k
2b
2c
70 (3w)
68 (3x)
ꢀ
silica gel (60-A pore size, 32e63
mm, standard grade). Analytical
a
thin-layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230e400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography plates
were visualized by exposure to ultraviolet light. Organic solutions
were concentrated on rotary evaporators at w20 Torr at 25e35 ꢀC.
Nuclear magnetic resonance (NMR) spectra are recorded in parts
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
2c were demonstrated as good partner as well. For instance, N0-(2-
alkynylbenzylidene)hydrazide 1a reacted with ethyl 4-phenylbuta-
2,3-dienoate 2b leading to the desired H-pyrazolo[5,1-a]isoquino-
line 3b in 80% yield (Table 2, entry 2). The structural elucidation was
confirmed by X-ray diffraction analysis (Fig. 1). However, only
a trace amount of product was detected when allenoate 2d or 2e
was employed in the reaction of N0-(2-alkynylbenzylidene)hydra-
zide 1a (Table 2, entries 4 and 5). It might be due to the steric hinder
during the reaction.
per million from internal tetramethylsilane on the
d
scale. 1H and
13C NMR spectra were recorded in CDCl3 on a Bruker DRX-400
spectrometer operating at 400 MHz and 100 MHz, respectively.
All chemical shift values are quoted in ppm and coupling constants
quoted in Hertz. High resolution mass spectrometry (HRMS)
spectra were obtained on a micrOTOF II instrument.
4.2. General experimental procedure for the silver triflate-
catalyzed reaction of N0-(2-alkynylbenzylidene)hydrazide 1
with allenoate 2
Silver triflate (10 mol %) was added to a solution of N0-(2-
alkynylbenzylidene)hydrazide 1 (0.2 mmol) in DCE (0.5 mL). The
solution was stirred at 55 ꢀC in air for 1 h. After consumption of N0-
(2-alkynylbenzylidene)hydrazide 1, PPh3 (20 mol %), allenoate 2
(2.0 equiv), and DMF (1.5 mL) was then added. The mixture was
stirred at 60 ꢀC in air for 3e10 h. After completion of reaction as
indicated by TLC, the reactionwas quenched byaddition of saturated
aqueous NH4Cl (5.0 mL), and the mixture was extracted with EtOAc
(4.0 mLꢁ3). The combined organic layer was dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel to provide the desired product 3.
4.2.1. Butyl 2-methyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-1-
carboxylate (3a). 1H NMR (400 MHz, CDCl3)
d
1.00 (t, J¼7.4, 3H),
1.47e1.56 (m, 2H), 1.77e1.84 (m, 2H), 2.63 (s, 3H), 4.40 (t, J¼6.9 Hz,
2H), 7.08 (s, 1H), 7.47e7.50 (m, 3H), 7.54e7.58 (m, 2H), 7.68 (d,
J¼7.3 Hz, 1H), 7.81 (d, J¼6.4 Hz, 2H), 9.56 (d, J¼7.8 Hz, 1H); 13C NMR
Fig. 1. X-ray ORTEP illustration of H-pyrazolo[5,1-a]isoquinoline 3b (30% probability
ellipsoids).
(100 MHz, CDCl3)
d 13.7, 15.9, 19.4, 30.8, 64.3, 106.3, 114.5, 123.4,
Noticeably, reactions of N0-(2-alkynylbenzylidene)hydrazides 1
bearing either electron-rich or electron-poor substituents on the
aromatic ring (R1 position) were converted to the desired products
with good reactivity. The methyl, methoxy, chloro, and fluoro
groups were tolerated under the reaction conditions. Additionally,
the reactions were workable for the substrates 1 with a cyclopropyl
group attached on the R2 position, affording the corresponding
products in good yields (Table 2, entries 16e23). Moreover, re-
actions of thiophenyl-incorporated hydrazide 1k were examined in
the meantime. As expected, this substrate was proven to be a good
partner for the transformation, and no influence was observed for
the final output (Table 2, entries 24e26).
126.9, 127.0, 127.1128.1, 128.9, 129.2, 129.6, 130.8, 133.5, 137.7, 140.2,
153.3, 165.2; HRMS (ESI) calcd for C23H22N2O2: 359.1760 (MþHþ),
found: 359.1760.
4.2.2. Ethyl 2-benzyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-1-
carboxylate (3b). 1H NMR (400 MHz, CDCl3)
d
1.26 (t, J¼6.9 Hz,
3H), 4.28 (m, 2H), 4.45 (s, 2H), 7.16 (s, 2H), 7.23e7.26 (m, 4H), 7.49
(d, J¼8.0 Hz, 3H), 7.57e7.80 (m, 2H), 7.72e7.73 (m, 1H), 7.87 (d,
J¼8.0 Hz, 2H), 9.44 (d, J¼4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
14.2, 34.9, 60.4, 106.2, 114.8, 123.5, 125.8, 126.9, 127.1, 127.3, 128.1,
128.2, 128.4, 129.0, 129.3, 129.7, 130.8, 133.5, 137.9, 139.8, 140.3,
154.8, 164.9; HRMS (ESI) calcd for C27H20N2O2: 407.1760 (MþHþ),
found: 407.1773.
3. Conclusions
4.2.3. Ethyl 2-ethyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-1-
In summary,
a
novel and efficient reaction of N0-(2-
carboxylate (3c). 1H NMR (400 MHz, CDCl3)
d
1.33 (t, J¼7.4 Hz,
alkynylbenzylidene)hydrazide with allenoate catalyzed by silver
3H), 1.48 (t, J¼7.1 Hz, 3H), 3.05e3.11 (m, 2H), 4.46e4.51 (m, 2H),

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L. Gao et al. / Tetrahedron 68 (2012) 2765e2769
7.14 (s, 1H), 7.32 (d, J¼6.9 Hz, 3H), 7.55e7.65 (m, 2H), 7.66e7.81 (m,
1H), 7.88 (d, J¼7.0 Hz, 2H), 9.46 (d, J¼4.0 Hz, 1H); 13C NMR
J¼8.0 Hz, 3H), 4.27e4.31 (m, 2H), 4.45 (s, 2H), 7.12e7.86 (m, 11H),
7.86e7.88 (m, 2H), 9.58e9.61(m, 1H); 13C NMR (100 MHz, CDCl3)
d
120.3, 127.0 (1JCF¼230 Hz), 128.2, 128.3, 129.6, 129.8 (2JCF¼20 Hz),
130.0, 132.9, 133.0, 133.1, 138.9, 139.7, 140.3, 155.1, 162.5
(1JCF¼249 Hz), 164.8; HRMS (ESI) calcd for C27H21FN2O2: 425.1665
(MþHþ), found: 425.1688.
(100 MHz, CDCl3)
d
13.9, 14.3, 22.7, 60.5, 105.5, 114.5, 123.5, 126.8,
14.2, 35.0, 60.5, 105.9, 111.5 (2JCF¼22 Hz), 114.0, 115.9 (2JCF¼20 Hz)
127.0, 127.2, 128.2, 128.9, 129.2, 129.7, 130.8, 133.6, 137.9, 140.1,
158.3, 165.4; HRMS (ESI) calcd for C22H20N2O2: 345.1603 (MþHþ),
found: 345.1603.
4.2.4. Butyl 2,9-dimethyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-1-
carboxylate (3d). 1H NMR (400 MHz, CDCl3)
d
1.01 (t, J¼8.0 Hz,
4.2.11. Ethyl
2-ethyl-9-fluoro-5-phenylH-pyrazolo[5,1-a]isoquino-
3H), 1.51e1.56 (m, 2H), 1.80e1.85 (m, 2H), 2.59 (s, 3H), 2.63 (s, 3H),
4.41e4.44 (m, 2H), 7.10 (s, 1H), 7.43e7.63 (m, 5H), 7.82e7.84 (m,
line-1-carboxylate (3k). 1H NMR (400 MHz, CDCl3)
d
1.30 (t, J¼8.0 Hz,
3H), 1.45 (t, J¼8.0 Hz, 3H), 3.02e3.06 (m, 2H), 4.43e4.46 (m, 2H),
2H), 9.35 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 13.8, 15.9, 19.4, 22.1,
7.07e7.85 (m, 9H), 9.57e9.61 (m, 1H); 13C NMR (100 MHz, CDCl3)
30.9, 64.4, 107.8, 114.5, 123.5, 126.6, 126.9, 128.2, 128.7, 129.2, 129.7,
130.7, 133.7, 136.7, 137.3, 140.1; HRMS (ESI) calcd for C24H24N2O2:
373.1916 (MþHþ), found: 373.1923.
d
13.8, 14.3, 22.8, 60.5, 105.6, 111.49 (2JCF¼22 Hz), 113.7, 115.7, 115.9,
128.2, 129.5, 129.7, 129.9, 130.0, 132.9, 133.3, 138.9, 140.1, 158.6, 165.3;
HRMS (ESI) calcd for C22H19FN2O2: 363.1509 (MþHþ), found: 363.1543.
4.2.5. Ethyl 2-benzyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-1-
4.2.12. Butyl 8-fluoro-2-methyl-5-phenylH-pyrazolo[5,1-a]isoquino-
carboxylate (3e). 1H NMR (400 MHz, CDCl3)
d
1.27 (t, J¼8.0 Hz,
line-1-carboxylate (3l). 1H NMR (400 MHz, CDCl3)
d 1.01 (t,
3H), 2.59 (s, 3H), 4.28e4.33 (m, 2H), 4.44 (s, 2H), 7.14e7.16 (m, 2H),
7.23e7.26 (m, 4H), 7.42e7.50 (m, 4H), 7.64 (d, J¼6.4 Hz, 1H), 7.86 (d,
J¼7.3 Hz, 3H), 1.48e1.56 (m, 2H), 1.79e1.86 (m, 2H), 2.63 (s, 3H),
4.40 (t, J¼12.0 Hz, 2H), 7.07 (s, 1H), 7.25e7.37 (m, 2H), 7.52e7.52 (m,
3H), 7.82e7.83 (m, 2H), 9.69 (m, 1H); 13C NMR (100 MHz, CDCl3)
J¼4.0 Hz, 2H), 9.22 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 14.2, 22.1,
34.9, 60.4, 106.0, 114.7, 123.6, 125.8, 126.4, 127.0, 128.1, 128.2, 128.4,
128.7,129.2, 129.7, 130.7,133.6, 137.1, 137.4, 139.9, 140.1,154.8, 165.0;
HRMS (ESI) calcd for C28H24N2O2: 421.1916 (MþHþ), found:
421.1931.
d
15.1(1JCF¼227 Hz), 19.59, 30.99, 64.60, 76.82, 77.14, 77.45, 106.21,
111.5 (2JCF¼22 Hz), 113.88, 116.0 (2JCF¼22 Hz) 128.40, 129.7
(3JCF¼13 Hz), 130.36, 133.32, 138.94, 140.17, 140.5 (2JCF¼21 Hz),
153.80, 163.79, 165.38; HRMS (ESI) calcd for C23H21FN2O2: 377.1665
(MþHþ), found: 377.1660.
4.2.6. Ethyl
2-ethyl-9-methyl-5-phenylH-pyrazolo[5,1-a]isoquino-
1.32 (t,
line-1-carboxylate (3f). 1H NMR (400 MHz, CDCl3)
d
4.2.13. Ethyl 2-benzyl-8-fluoro-5-phenylH-pyrazolo[5,1-a]isoquino-
J¼16.0 Hz, 3H), 1.48 (t, J¼16.0 Hz, 3H), 2.58 (s, 3H), 3.04e3.09 (m,
2H), 4.46e4.51 (m, 2H), 7.10 (s,1H), 7.41e7.51 (m, 4H), 7.62e7.64 (m,
1H), 7.86e7.87 (m, 2H), 9.23 (s, 1H); 13C NMR (100 MHz, CDCl3)
line-1-carboxylate (3m). 1H NMR (400 MHz, CDCl3)
d 1.26 (t,
J¼16.0 Hz, 3H), 4.26e4.31 (m, 2H), 4.44 (s, 2H), 7.10 (s, 1H),
7.15e7.37 (m, 7H), 7.49e7.50 (m, 3H), 7.85 (d, J¼4.0 Hz, 2H), 9.56 (m,
d
13.9, 14.3, 22.1, 22.6, 60.4, 105.3, 114.4, 123.6, 126.4, 126.9, 128.1,
1H); 13C NMR (100 MHz, CDCl3)
d 14.1, 35.0, 60.5, 111.4, 111.6, 113.9,
128.7,129.1,129.7,130.5,133.8,137.1,137.2,139.9,158.2,165.4; HRMS
114.0, 114.9 (2JCF¼23 Hz), 120.3, 125.9, 128.2(3JCF¼9.0 Hz), 128.3,
129.6, 129.9 (2JCF¼23 Hz), 130.0 (3JCF¼9.0 Hz), 133.0, 133.1, 138.9,
139.7, 155.1, 161.2, 163.7, 164.8; HRMS (ESI) calcd for C27H21FN2O2:
425.1665 (MþHþ), found: 425.1693.
(ESI) calcd for C23H22N2O2: 359.1760 (MþHþ), found: 359.1782.
4.2.7. Ethyl 2-ethyl-8-methoxy-5-phenylH-pyrazolo[5,1-a]isoquino-
line-1-carboxylate (3g). 1H NMR (400 MHz, CDCl3)
d 1.32 (t,
J¼8.0 Hz, 3H), 1.46 (t, J¼8.0 Hz, 3H), 3.03e3.09 (m, 2H), 3.92 (s, 1H),
4.43e4.49 (m, 2H), 7.06e7.10 (m, 2H), 7.20e7.21 (m, 1H), 7.48e7.50
(m, 2H), 7.85e7.87 (m, 2H), 9.48 (d, J¼8.0 Hz, 1H); 13C NMR
4.2.14. Butyl 5-cyclopropyl-2-methylH-pyrazolo[5,1-a]isoquinoline-
1-carboxylate (3n). 1H NMR (400 MHz, CDCl3)
d 0.89e0.90 (m, 2H),
1.01 (t, J¼7.3 Hz, 3H), 1.17e1.22 (m, 2H), 1.50e1.56 (m, 2H),
1.79e1.84 (m, 2H), 2.72e2.76 (m, 4H), 4.41 (t, J¼6.4 Hz, 2H), 6.72 (s,
1H), 7.53e7.63 (m, 3H), 9.54 (d, J¼4.0 Hz, 1H); 13C NMR (100 MHz,
(100 MHz, CDCl3)
d 13.8, 14.3, 22.8, 55.3, 60.3, 104.3, 107.6, 114.2,
116.9, 117.8, 128.1, 128.9, 129.2, 129.7, 132.9, 133.6, 138.2, 140.5,
158.4, 159.8, 165.3; HRMS (ESI) calcd for C23H22N2O3: 375.1709
(MþHþ), found: 375.1698.
CDCl3) d 7.5, 11.4,13.8,15.9,19.4, 30.9, 64.3, 108.4, 122.7,126.3, 126.4,
127.0, 128.8, 130.9, 139.9, 140.4, 153.4, 165.4; HRMS (ESI) calcd for
C20H22N2O2: 323.1760 (MþHþ), found: 323.1777.
4.2.8. Ethyl 2-benzyl-9-chloro-5-phenylH-pyrazolo[5,1-a]isoquino-
line-1-carboxylate (3h). 1H NMR (400 MHz, CDCl3)
d
1.30 (t,
4.2.15. Ethyl 2-benzyl-5-cyclopropylH-pyrazolo[5,1-a]isoquinoline-1-
J¼8.0 Hz, 3H), 4.31e4.34 (m, 2H), 4.45 (s, 2H), 7.14e7.25 (m, 6H),
carboxylate (3o). 1H NMR (400 MHz, CDCl3)
d 0.90e0.93 (m, 2H),
7.50e7.67 (m, 5H), 7.85e7.86 (m, 2H), 9.56 (s, 1H); 13C NMR
1.19e1.21 (m, 2H), 1.26 (t, J¼7.3 Hz, 3H), 2.77e2.80 (m, 1H),
4.27e4.32 (m, 2H), 4.53 (s, 2H), 6.75 (s, 1H), 7.16e7.26 (m, 5H),
7.53e7.62 (m, 3H), 9.41 (d, J¼8.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d 14.1, 34.9, 60.7, 106.6, 114.0, 124.5, 125.9, 126.4,
128.1, 128.2, 128.4, 129.1, 129.5, 129.6, 129.7, 133.1, 133.2, 138.2,
139.2, 139.6, 155.3, 164.6; HRMS (ESI) calcd for C27H21ClN2O2: 441.
1370 (MþHþ), found: 441.1372.
d
7.6,11.4,14.2, 35.1, 60.4,106.1,108.5,122.8,125.8,126.4,126.4,126.8,
128.1,128.4,128.8,130.9,139.8,139.9,140.6,154.7,165.0; HRMS (ESI)
calcd for C24H22N2O2: 371.1760 (MþHþ), found: 371.1741.
4.2.9. Butyl 9-fluoro-2-methyl-5-phenylH-pyrazolo[5,1-a]isoquino-
line-1-carboxylate (3i). 1H NMR (400 MHz, CDCl3)
d
1.00 (t,
4.2.16. Ethyl 5-cyclopropyl-2-ethylH-pyrazolo[5,1-a]isoquinoline-1-
J¼8.0 Hz, 3H), 1.49e1.55 (m, 2H), 1.80e1.83 (m, 2H), 2.62(s, 3H),
4.38e4.41 (m, 2H), 7.05 (s, 1H), 7.24e7.36 (m, 2H), 7.50 (s, 3H),
7.81e7.82 (m, 2H), 9.68e9.71 (m, 1H); 13C NMR (100 MHz, CDCl3)
carboxylate (3p). 1H NMR (400 MHz, CDCl3)
d 0.89e0.90 (m, 2H),
1.17e1.24 (m, 2H), 1.36 (t, J¼8.0 Hz, 3H), 1.44 (t, J¼8.0 Hz, 3H),
2.74e2.79 (m,1H), 3.11e3.16 (m, 2H), 4.44e4.49 (m, 2H), 6.70 (s,1H),
7.52e7.53 (m, 2H), 7.54e7.61 (m,1H), 9.42 (d, J¼8.0 Hz,1H); 13C NMR
d
13.8, 16.0, 19.4, 30.8, 64.4, 105.6, 111.4 (2JCF¼22 Hz), 113.8, 115.8
(2JCF¼23 Hz), 120.2, 128.3, 129.5, 129.7, 130.2, 133.2, 133.3, 138.8,
140.6, 153.7, 162.3 (1JCF¼249 Hz), 165.3; HRMS (ESI) calcd for
C23H21FN2O2: 377.1665 (MþHþ), found: 377.1672.
(100 MHz, CDCl3) d 7.6, 11.3, 14.1, 14.3, 22.8, 29.7, 60.4, 105.4, 108.2,
122.8,126.3,126.8,128.7,130.8,139.7,140.6,158.3,165.3; HRMS (ESI)
calcd for C19H20N2O2: 309.1603 (MþHþ), found: 309.1585.
4.2.10. Ethyl 2-benzyl-9-fluoro-5-phenylH-pyrazolo[5,1-a]isoquino-
4.2.17. Butyl
5-cyclopropyl-8-methoxy-2-methylH-pyrazolo[5,1-a]
line-1-carboxylate (3j). 1H NMR (400 MHz, CDCl3)
d 1.27 (t,
isoquinoline-1-carboxylate (3q). 1H NMR (400 MHz, CDCl3)

L. Gao et al. / Tetrahedron 68 (2012) 2765e2769
2769
d
0.87e0.89 (m, 2H), 0.99 (t, J¼8.0 Hz, 1H), 1.17e1.19 (m, 2H),
3H); 1.48 (t, J¼8.0 Hz, 3H), 3.08e3.12 (m, 2H), 4.47e4.51 (m, 2H),
7.28 (s, 1H), 7.27e7.38 (m, 1H), 7.49e7.51 (m, 3H), 7.66e7.67 (m,
1.49e1.50 (m, 2H), 1.71e1.82 (m, 2H), 2.69e2.72 (m, 4H), 3.90 (s,
3H), 4.38 (t, J¼8.0 Hz, 2H), 6.64 (s, 1H), 6.9e7.25 (m, 2H), 9.52 (d,
1H), 7.86e7.88 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 13.6,14.5, 22.3,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
7.6, 11.4, 13.8, 16.1, 19.5,
60.0, 101.0, 110.2, 123.5, 127.0, 128.2, 129.2, 129.6, 130.8, 133.6, 137.4,
137.9, 139.6; HRMS (ESI) calcd for C20H18N2O2S: 351.1167 (MþHþ),
found: 351.1205.
30.9, 55.3, 64.2, 106.8, 108.0, 116.2, 117.1, 129.1, 133.0, 140.8, 153.5,
159.7, 165.4; HRMS (ESI) calcd for C21H24N2O3: 353.1865 (MþHþ),
found: 353.1876.
Acknowledgements
4.2.18. Ethyl
2-benzyl-5-cyclopropyl-8-methoxyH-pyrazolo[5,1-a]
0.91 (t,
isoquinoline-1-carboxylate (3r). 1H NMR (400 MHz, CDCl3)
d
Financial support from National Natural Science Foundation of
China (GS1) (No. 20972030) is gratefully acknowledged.
J¼8.0 Hz, 3H), 1.19e1.28 (m, 2H), 3.91 (s, 1H), 4.24e4.28 (m, 2H),
4.51 (s, 1H), 6.68 (s, 1H), 7.02e7.25 (m, 7H), 9.42 (d, J¼12.0 Hz, 1H);
13C NMR (100 MHz, CDCl3)
d 7.7, 11.4, 14.2, 35.2, 55.3, 60.2, 107.0,
Supplementary data
108.2, 116.3, 117.2, 125.8, 128.1, 128.4, 128.9, 133.0, 138.0, 139.9,
140.3, 141.1, 154.8, 159.8, 165.0; HRMS (ESI) calcd for C25H24N2O3:
401.1865 (MþHþ), found: 401.1869.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.02.013. These data include MOL file and
InChiKeys of the most important compound described in this
article.
4.2.19. Ethyl 5-cyclopropyl-2-ethyl-8-methoxyH-pyrazolo[5,1-a] iso-
quinoline-1-carboxylate (3s). 1H NMR (400 MHz, CDCl3)
d
0.86e0.89 (m, 2H), 1.15e1.24 (m, 2H), 1.37 (t, J¼8.0 Hz, 3H), 1.45 (t,
References and notes
J¼8.0 Hz, 3H), 3.09e3.31 (m, 2H), 3.88 (s, 3H), 4.41e4.46 (m, 2H),
6.61 (s, 1H), 6.97 (d, J¼4.0 Hz, 1H), 7.11e7.14 (m, 1H), 9.43 (d,
€
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J¼12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 7.7, 11.3, 14.1, 14.3, 22.9,
55.2, 60.2, 104.2, 106.8, 107.7, 116.1, 117.1, 128.8, 133.0, 140.1, 141.0,
158.4, 159.6, 165.3; HRMS (ESI) calcd for C20H22N2O3: 339.1709
(MþHþ), found: 339.1718.
4.2.20. Butyl 5-cyclopropyl-9-fluoro-2-methylH-pyrazolo[5,1-a] iso-
quinoline-1-carboxylate (3t). 1H NMR (400 MHz, CDCl3)
d
0.89e0.91 (m, 2H), 1.01 (t, J¼7.3 Hz, 3H), 1.20e1.25 (m, 2H),
1.50e1.56 (m, 2H), 1.78e1.84 (m, 2H), 2.71e2.74 (m, 4H), 4.40 (t,
J¼6.9 Hz, 2H), 6.63 (s, 1H), 7.23e7.27 (m, 2H), 9.63e9.64 (m, 1H);
13C NMR (100 MHz, CDCl3)
d 7.74, 11.4, 13.7, 16.1, 19.4, 30.8, 64.4,
105.5, 107.5, 110.7 (2JCF¼21 Hz), 115.0 (2JCF¼23 Hz), 119.5, 130.0,
131.1, 132.8, 139.5, 141.6, 153.6, 162.3 (1JCF¼250 Hz), 165.3; HRMS
(ESI) calcd for C20H21FN2O2: 341.1665 (MþHþ), found: 341.1683.
4.2.21. Ethyl
5-cyclopropyl-2-ethyl-8-fluoroH-pyrazolo[5,1-a]iso-
0.91 (d,
quinoline-1-carboxylate (3u). 1H NMR (400 MHz, CDCl3)
d
J¼4.0 Hz, 2H), 1.18e1.25 (m, 3H), 1.38 (t, J¼8.0 Hz, 3H), 1.37 (t,
J¼8.0 Hz, 2H), 2.76e2.78 (m, 2H), 3.11e3.16 (m, 2H), 4.43e4.48 (m,
2H), 6.62 (s, 1H), 7.22e7.26 (m, 2H), 9.53e9.56 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 7.86, 11.3, 13.9,14.3, 22.9, 64.4,105.2, 107.3, 110.7
(2JCF¼21 Hz), 114.9 (2JCF¼23 Hz), 119.5, 129.8, 129.9, 132.9, 133.0,
139.6, 141.8, 158.5, 162.3 (1JCF¼249 Hz), 165.3; HRMS (ESI) calcd for
C19H19FN2O2: 327.1509 (MþHþ), found: 327.1500.
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4.2.22. Butyl
8-methyl-5-phenylpyrazolo[1,5-a]thieno[2,3-c]pyri-
0.99 (t,
dine- 9-carboxylate (3v). 1H NMR (400 MHz, CDCl3)
d
J¼8.0 Hz, 3H), 1.48e1.54 (m, 2H), 1.80e1.84 (m, 2H), 2.65 (s, 3H),
4.40e4.43 (m, 2H), 7.25 (s, 1H), 7.36 (d, J¼8.0 Hz, 1H), 7.48e7.50 (m,
3H), 7.66 (d, J¼8.0 Hz, 1H), 7.82e7.84 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d 13.8, 15.3, 19.4, 31.0, 64.0, 110.1, 123.4, 128.3, 129.3, 129.6,
130.9, 133.6, 137.2, 137.9, 153.6, 164.6; HRMS (ESI) calcd for
C21H20N2O2S: 365.1324 (MþHþ), found: 365.1332.
4.2.23. Ethyl 8-benzyl-5-phenylpyrazolo[1,5-a]thieno[2,3-c]pyridine-
9-carboxylate (3w). 1H NMR (400 MHz, CDCl3)
d
1.33 (t, J¼8.0 Hz,
3H), 4.37e4.42 (m, 2H), 4.47 (s, 2H), 7.25e7.40 (m, 7H), 7.50e7.52
8. Zhao, J.; Wu, C.; Li, P.; Ai, W.; Chen, H.; Wang, C.; Larock, R. C.; Shi, F. J. Org. Chem.
2011, 76, 6837.
(m, 3H), 7.67e7.69 (m, 1H), 7.88e7.89 (m, 2H); 13C NMR (100 MHz,
9. For selected recent reviews on cooperative catalysts, see: (a) Ajamian, A.;
Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43, 3754; (b) Lee, J. M.; Na, Y.; Han, H.;
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CDCl3) d 14.5, 34.4, 60.1, 101.6, 123.5, 125.9, 127.1, 128.1, 128.3, 128.7,
129.3, 129.7, 131.0, 133.5, 137.4, 138.0, 139.6; HRMS (ESI) calcd for
C25H20N2O2S: 413.1343 (MþHþ), found: 413.1324.
4.2.24. Ethyl 8-ethyl-5-phenylpyrazolo[1,5-a]thieno[2,3-c]pyridine-
9-carboxylate (3x). 1H NMR (400 MHz, CDCl3)
d
1.33 (t, J¼8.0 Hz,