An efficient approach to pyrazolo[5,1-a]isoquinolin-2-amines via a silver(i)-catalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile

Article abstract of DOI:10.1039/c1ob05917c

A three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile catalyzed by silver triflate under mild conditions is reported, which generates pyrazolo[5,1-a]isoquinolin-2-amines in good to excellent yields.

Full text of DOI:10.1039/c1ob05917c

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An efficient approach to pyrazolo[5,1-a]isoquinolin-2-amines via a
silver(I)-catalyzed three-component reaction of 2-alkynylbenzaldehyde,
sulfonohydrazide, and nitrile†
Xingxin Yu,a Qin Yang,b Honglei Lou,a Yiyuan Peng*b and Jie Wu*a
Received 8th June 2011, Accepted 27th June 2011
DOI: 10.1039/c1ob05917c
A three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile catalyzed by silver
triflate under mild conditions is reported, which generates pyrazolo[5,1-a]isoquinolin-2-amines in good
to excellent yields.
The development of novel and efficient methods using diversity-
oriented synthesis approaches for the formation of small molecules
with privileged scaffolds is an important part of chemical genetics,1
and continues to be of major importance in synthetic organic
chemistry.2 Among the strategies, multi-component reactions
represent an effective and straightforward methodology for the
synthesis of cyclic and polycyclic structures, which has attracted
much attention.3 In our laboratory, it has been our aim to develop
new cascade processes4 for the generation of natural product-like
compounds.5 Recently, we have developed a facile route for the
construction of diverse pyrazolo[5,1-a]isoquinolines starting from
2-alkynylbenzaldehyde or N¢-(2-alkynylbenzylidene)hydrazide.6
Subsequent biological assays discovered that some of these
compounds exhibit promising biological activities for inhibition of
CDC25B, TC-PTP, and PTP1B.6d Additionally, various biological
Scheme 1 A possible mechanism for AgOTf-catalyzed three-component
reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile.
effects7 including antitumor activity8 have been reported for
isoquinoline-fused polycyclic compounds such as pyrimido[2,1-
a]isoquinolines and imidazo[2,1-a]isoquinolines. In order to get
of N¢-(2-alkynylbenzylidene)hydrazide,6 we hypothesized that
more active hits from the corresponding biological evalua-
the conversion could be traced back to 2-alkynylbenzaldehyde,
tion, we need to introduce more diversities to the scaffold of
sulfonohydrazide, and nitrile. As illustrated in Scheme 1, 2-
pyrazolo[5,1-a]isoquinolines for the construction of functional-
alkynylbenzaldehyde 1 condenses with sulfonohydrazide 2 to
ized pyrazolo[5,1-a]isoquinolines.
afford N¢-(2-alkynylbenzylidene)hydrazide A. In the presence of
Therefore, pyrazolo[5,1-a]isoquinolin-2-amine was selected as
a catalytic amount of silver triflate, isoquinolinium compound
the model compound for reaction development (Scheme 1).
B could be produced via an intramolecular 6-endo cyclization.
The introduction of an amino group in the scaffold would be
Subsequently, substituted acetonitrile 3 could become involved,
beneficial for its further elaboration. In continuation of our
to act as a nucleophile in the presence of a base to attack
recently developed methods for the silver-catalyzed reaction
the isoquinolinium B. After generation of intermediate C, an
intramolecular nucleophilic attack of nitrile could occur to furnish
compound D, which could then undergo tautomerization and
aromatization to produce the expected pyrazolo[5,1-a]isoquinolin-
2-amine 4.
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: 86 21 6564 1740; Tel: 86
21 6510 2412
bKey Laboratory of Functional Small Organic Molecules, Ministry of
On the basis of this chemistry, our first attempt to effect
the reaction of N¢-(2-alkynylbenzylidene)hydrazide A1 and mal-
ononitrile 3a was performed in the presence of 10 mol% of
silver triflate (Scheme 2). Different bases and solvents were
examined. Initially, a variety of bases such as K3PO4, Cs2CO3,
Education and College of Chemistry & Chemical Engineering, Jiangxi
Normal University, Nanchang, Jiangxi, 330022, China
† Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of compounds
4, and a CIF file of compound 4e. CCDC reference number 826050. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05917c
i
K2CO3, Et3N, DABCO, Pr2NEt were added to the reaction in
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Table 1 Synthesis of pyrazolo[5,1-a]isoquinolin-2-amines via AgOTf-
catalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfono-
hydrazide, and nitrile
Scheme
2
Initial studies for the synthesis of pyrazolo[5,1-a]-
isoquinolin-2-amine 4a.
Entry 2-Alkynylbenzaldehyde Nitrile
1
Product Yield (%)a
toluene. To our delight, the reaction worked most efficiently when
DABCO was employed as the base, and the desired product 4a
was obtained in 67% yield. Subsequently, several solvents were
screened. A similar result was observed when the reaction took
place in THF (70% yield) or MeCN (71% yield). A higher yield
was isolated when the reaction occurred in dichloroethane (85%
yield). A further survey showed that the reaction performed in
1,4-dioxane afforded the corresponding product in 90% yield.
With these results in hand, we re-explored the three-component
reaction of 2-(2-phenylethynyl)benzaldehyde 1a, sulfonohydrazide
2, and malononitrile 3a under the conditions mentioned above.
Gratifyingly, pyrazolo[5,1-a]isoquinolin-2-amine 4a was produced
in 85% yield.
4a
85
2
3
1a
4b
4c
96
91
4
5
1b
1c
4d
4e
65
99
Next, investigations with various 2-alkynylbenzaldehydes 1
were conducted under the optimized conditions (10 mol% of
AgOTf, DABCO, 1,4-dioxane). Table 1 shows the summary of
results for the evaluation of the reactions. An excellent yield
(96%) was obtained when 2-(2-phenylethynyl)benzaldehyde 1a,
sulfonohydrazide 2, and ethyl 2-cyanoacetate 3b were put in a
single pot (entry 2). The substitution by a cyclopropyl group at
the triple bond position of 2-alkynylbenzaldehydes 1b showed
a similar reactivity when sulfonohydrazide 2 and malononitrile
3a were involved in the reaction (91% yield, entry 3). Reaction
of 2-alkynylbenzaldehydes 1b, sulfonohydrazide 2, and ethyl 2-
cyanoacetate 3b decreased the yield of the desired product 4d
(65% yield, entry 4). Noticeably, 2-alkynylbenzaldehyde 1c reacted
with sulfonohydrazide 2 and malononitrile 3a leading to the
corresponding pyrazolo[5,1-a]isoquinolin-2-amine 4e in an almost
quantitative yield (entry 5). Additionally, the structure of com-
pound 4e was unambiguously identified by X-ray crystallography
analysis (see the ESI†). A slightly lower yield was obtained when
ethyl 2-cyanoacetate 3b was used as a replacement in the reaction
(90% yield, entry 6). Interestingly, 2-alkynylbenzaldehydes 1d
with a trimethylsilyl group attached to the triple bond was a
good substrate in this transformation (entries 7 and 8), which
was in contrast to the previous reports.6 However, the product
obtained was the desilylated one. Finally, reactions of a series
of substituted 2-alkynylbenzaldehydes 1 with electron-donating
groups or electron-withdrawing groups attached on the aromatic
ring were explored under the standard conditions. All the reactions
worked well to afford the desired pyrazolo[5,1-a]isoquinolin-2-
amines in good to excellent yields (entries 9–18). For example,
the conditions could be applicable to the reaction of fluoro-
substituted 2-alkynylbenzaldehydes 1h, sulfonohydrazide 2, and
ethyl 2-cyanoacetate 3b, which gave rise to the expected product
4p in 98% yield (entry 16).
6
7
4f
90
4g
99b
8
9
1d
1e
1f
4h
4i
93b
84
10
11
4j
90
96
4k
12
13
4l
88
66
4m
14
15
1g
1h
4n
4o
98
87
In summary, we have described a novel and efficient route to
pyrazolo[5,1-a]isoquinolin-2-amines by a three-component cas-
cade cyclization strategy. This AgOTf-catalyzed three-component
reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile
proceeds smoothly with the formation of one carbon–carbon and
16
4p
98
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Table 1 (Contd.)
69.2, 109.7, 116.0, 120.1, 122.0, 127.0, 127.1, 129.3, 130.0, 138.5,
139.7, 159.2; HRMS calcd for C16H16N4 (M+ + H): 265.1453,
found: 265.1464.
2-Aminopyrazolo[5,1-a]isoquinoline-1-carbonitrile (4d). 1H
NMR (400 MHz, DMSO-d6): d 6.29 (s, 2H), 7.24 (d, J = 6.4 Hz,
1H), 7.65–7.73 (m, 2H), 7.89–7.91 (m, 1H), 8.26 (d, J = 6.4 Hz,
1H), 8.40 (d, J = 6.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d
69.0, 112.2, 115.9, 121.2, 122.2, 126.1, 127.7, 128.1, 129.4, 129.8,
139.3, 159.7; HRMS calcd for C12H8N4 (M+ + Na): 231.0647,
found: 231.0660.
Entry 2-Alkynylbenzaldehyde Nitrile
17
Product Yield (%)a
4q
96
2-Amino-8-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline-1-car-
bonitrile (4e). 1H NMR (400 MHz, DMSO-d6): d 6.34 (s, 2H), 7.28
(s, 1H), 7.50–7.59 (m, 4H), 7.71–7.76 (m, 3H), 8.46 (dd, J = 8.4,
5.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d 69.7, 111.9, 112.1
(d, 2JCF = 22 Hz), 115.8, 116.9 (d, 2JCF = 24 Hz), 117.7, 125.1 (d,
3JCF = 10 Hz), 128.1, 129.4, 132.2 (d, 3JCF = 10 Hz), 132.7, 138.1,
140.2, 159.1, 161.9 (d, 1JCF = 246 Hz); HRMS calcd for C18H11FN4
(M+ + Na): 325.0865, found: 325.0861.
18
1i
4r
68
a Isolated yield based on 2-alkynylbenzaldehyde 1. b Desilylated compound
was obtained (R2 = H).
three carbon–nitrogen bonds. Diverse pyrazolo[5,1-a]isoquinolin-
2-amines are generated in good to excellent yields under mild
conditions starting from easily available materials. Library con-
struction and subsequent biological evaluation are in progress in
our laboratory.
2-Amino-5-butyl-8-fluoropyrazolo[5,1-a]isoquinoline-1-carbo-
nitrile (4f). 1H NMR (400 MHz, DMSO-d6): d 0.92 (t, J =
7.2 Hz, 3H), 1.34–1.43 (m, 2H), 1.69–1.72 (m, 2H), 2.92–2.96
(m, 2H), 6.35 (s, 2H), 7.07 (s, 1H), 7.51–7.55 (m, 1H), 7.65 (d, J =
9.6 Hz, 1H), 8.39–8.42 (m, 1H); 13C NMR (100 MHz, DMSO-
2
d6) d 13.7, 21.9, 28.2, 30.1, 69.2, 109.0, 111.4 (d, JCF = 22 Hz),
2
3
115.8, 116.1 (d, JCF = 24 Hz), 117.0, 124.9 (d, JCF = 10 Hz),
Experimental section
3
1
132.2 (d, JCF = 10 Hz), 139.5, 139.6, 159.1, 161.9 (d, JCF
=
General experimental procedure for the synthesis of pyrazolo[5,1-
a]isoquinolin-2-amines via an AgOTf-catalyzed three-component
reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile:
A mixture of 2-alkynylbenzaldehyde 1 (0.3 mmol, 1.0 equiv),
AgOTf (7.7 mg, 10 mol%), and sulfonohydrazide 2 (0.3 mmol,
1.0 equiv) in 1,4-dioxane (1.0 mL) was stirred at 70 ◦C vigorously
for 1 h. Then nitrile 3 (0.6 mmol, 2.0 equiv) and DABCO
(0.6 mmol, 2.0 equiv) were added. After completion of the reaction
as indicated by TLC, the reaction mixture was quenched with
water (5.0 mL) and diluted with ethyl acetate (5.0 mL). The
organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel to provide the desired
product 4.
2-Amino-5-phenylpyrazolo[5,1-a]isoquinoline-1-carbonitrile
(4a). 1H NMR (400 MHz, DMSO-d6): d 6.32 (s, 2H), 7.29 (s, 1H),
7.47–7.53 (m, 3H), 7.65–7.70 (m, 2H), 7.77–7.79 (m, 2H), 7.91–
7.93 (m, 1H), 8.46–8.48 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d 69.7, 112.6, 115.9, 120.7, 122.1, 127.7, 127.9, 128.1, 129.2, 129.4,
129.5, 130.1, 133.0, 137.2, 140.4, 159.2; HRMS calcd for C18H12N4
(M+ + H): 285.1140, found: 285.1147.
246 Hz); HRMS calcd for C16H15FN4 (M+ + Na): 305.1178, found:
305.1189.
2-Amino-9-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline-1-car-
1
bonitrile (4g). H NMR (400 MHz, DMSO-d6): d 6.34 (s, 2H),
7.30 (s, 1H), 7.49–7.55 (m, 4H), 7.75–7.76 (m, 2H), 7.98–8.00 (m,
2
2H); 13C NMR (100 MHz, DMSO-d6) d 69.9, 106.6 (d, JCF
=
=
2
3
24 Hz), 112.2, 115.6, 118.5 (d, JCF = 24 Hz), 121.5 (d, JCF
3
10 Hz), 127.0, 128.1, 129.2, 129.4, 130.8 (d, JCF = 9 Hz), 132.8,
136.6, 139.5, 159.1, 160.6 (d, JCF = 245 Hz); HRMS calcd for
1
C18H11FN4 (M+ + H): 303.1046, found: 303.1057.
2-Amino-5-cyclopropyl-9-fluoropyrazolo[5,1-a]isoquinoline-1-
1
carbonitrile (4h). H NMR (400 MHz, DMSO-d6): d 0.90–0.91
(m, 2H), 1.08–1.10 (m, 2H), 2.45–2.50 (m, 1H), 6.42 (s, 2H), 7.02
(s, 1H), 7.53–7.57 (m, 1H), 7.88–7.91 (m, 1H), 7.98 (d, J = 9.6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) d 7.4, 11.1, 69.5, 106.3,
2
2
106.5(d, JCF = 24 Hz), 115.8, 118.4(d, JCF = 24 Hz), 120.6 (d,
3JCF = 10 Hz), 127.3, 130.2 (d, JCF = 9 Hz), 138.9, 139.8, 159.3,
3
160.1 (d, 1JCF = 243 Hz); HRMS calcd for C15H11FN4 (M+ + Na):
289.0865, found: 289.0879.
2-Amino-9-methyl-5-phenylpyrazolo[5,1-a]isoquinoline-1-car-
1
bonitrile (4i). H NMR (400 MHz, DMSO-d6): d 2.47 (s, 3H),
2-Amino-5-cyclopropylpyrazolo[5,1-a]isoquinoline-1-carbo-
nitrile (4b). H NMR (400 MHz, DMSO-d6): d 0.90–0.91 (m,
6.26 (s, 2H), 7.20 (s, 1H), 7.44–7.49 (m, 4H), 7.75–7.76 (m, 3H),
8.18 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 21.5, 69.4, 112.5,
116.0, 120.7, 121.2, 127.5, 127.9, 128.1, 129.1, 129.4, 131.0, 133.0,
136.3, 137.4, 139.9, 159.0; HRMS calcd for C19H14N4 (M+ + H):
299.1297, found: 299.1321.
1
2H), 1.07–1.09 (m, 2H), 2.45–2.50 (m, 1H), 6.34 (s, 2H), 6.93 (s,
1H), 7.59–7.61 (m, 2H), 7.77–7.78 (m, 1H), 8.39–8.40 (m, 1H); 13
C
NMR (100 MHz, DMSO-d6): d 7.4, 11.1, 69.4, 106.5, 116.0, 119.8,
122.0, 127.0, 127.1, 129.2, 130.2, 139.7, 140.2, 159.3; HRMS calcd
for C15H12N4 (M+ + Na): 271.0960, found: 271.0977.
Ethyl 2-amino-5-phenylpyrazolo[5,1-a]isoquinoline-1-carbo-
1
xylate (4j). H NMR (400 MHz, CDCl3): d 1.48 (t, J = 7.2 Hz,
2-Amino-5-butylpyrazolo[5,1-a]isoquinoline-1-carbonitrile (4c).
1H NMR (400 MHz, DMSO-d6): d 0.89 (t, J = 7.2 Hz, 3H), 1.33–
1.38 (m, 2H), 1.67–1.71 (m, 2H), 2.91–2.94 (m, 2H), 6.31 (s, 2H),
7.03 (s, 1H), 7.61–7.62 (m, 2H), 7.79–7.80 (m, 1H), 8.38–8.40 (m,
1H); 13C NMR (100 MHz, DMSO-d6): d 13.7, 21.9, 28.3, 30.1,
3H), 4.44–4.50 (m, 2H), 5.16 (s, 2H), 7.07 (s, 1H), 7.48–7.51
(m, 3H), 7.56–7.59 (m, 2H), 7.69–7.71 (m, 1H), 7.77–7.79
(m, 2H), 9.67–9.70 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 14.8, 60.6, 93.4, 114.3, 123.2, 127.1, 127.2, 127.7, 128.5,
129.2, 129.6, 129.9, 131.5, 134.1, 137.8, 140.5, 158.5, 164.9;
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HRMS calcd for C20H17N3O2 (M+ + H): 332.1399, found:
332.1396.
CDCl3) d 7.3, 11.3, 14.2, 59.9, 91.9, 107.0, 111.1 (d, 2JCF = 26 Hz),
2
3
117.4 (d, JCF = 24 Hz), 122.1 (d, JCF = 11 Hz), 127.7, 129.1
3
1
Ethyl 2-amino-5-cyclopropylpyrazolo[5,1-a]isoquinoline-1-car-
boxylate (4k). 1H NMR (400 MHz, CDCl3): d 0.86–0.90 (m, 2H),
1.14–1.19 (m, 2H), 1.48 (t, J = 7.2 Hz, 3H), 2.56–2.63 (m, 1H),
4.44–4.50 (m, 2H), 5.29 (s, 2H), 6.17 (s, 1H), 7.50–7.62 (m, 3H),
9.62–9.64 (m, 1H); 13C NMR (100 MHz, CDCl3) d 7.3, 11.5, 14.5,
60.2, 92.9, 108.0, 122.1, 126.0, 126.2, 127.2, 128.6, 131.2, 139.9,
158.3, 164.6; HRMS calcd for C17H17N3O2 (M+ + H): 296.1399,
found: 296.1397.
(d, JCF = 9 Hz), 137.8, 139.2, 158.4, 159.6 (d, JCF = 240 Hz),
163.9; HRMS calcd for C17H16FN3O2 (M+ + Na): 336.1124, found:
336.1143.
Ethyl 2-amino-9-methyl-5-phenylpyrazolo[5,1-a]isoquinoline-
1
1-carboxylate (4r). H NMR (400 MHz, CDCl3): d 1.50 (t, J =
7.2 Hz, 3H), 2.58 (s, 3H), 4.46–4.51 (m, 2H), 5.18 (s, 2H), 7.05
(s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.46–7.52 (m, 3H), 7.61 (d,
J = 8.0 Hz, 1H), 7.77–7.79 (m, 2H), 9.46 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 14.5, 22.0, 60.2, 92.7, 113.9, 122.9, 126.7,
126.8, 128.1, 129.0, 129.1, 129.5, 130.5, 133.9, 136.7, 139.7, 147.0,
158.3, 164.6; HRMS calcd for C21H19N3O2 (M+ + H): 346.1556,
found: 346.1558.
Ethyl 2-amino-5-butylpyrazolo[5,1-a]isoquinoline-1-carboxy-
1
late (4l). H NMR (400 MHz, CDCl3): d 0.99 (t, J = 7.2 Hz,
3H), 1.48 (t, J = 7.2 Hz, 3H), 1.43–1.53 (m, 2H), 1.78–1.85 (m,
2H), 3.03–3.07 (m, 2H), 4.44–4.49 (m, 2H), 5.22 (s, 2H), 6.89 (s,
1H), 7.50–7.57 (m, 2H), 7.63–7.65 (m, 1H), 9.62–9.64 (m, 1H); 13
C
NMR (100 MHz, CDCl3) d 14.3, 14.9, 22.8, 29.2, 31.2, 60.5, 93.1,
111.2, 122.7, 126.3, 126.6, 127.6, 128.9, 131.5, 139.0, 140.0, 158.5,
165.0; HRMS calcd for C18H21N3O2 (M+ + H): 312.1712, found:
312.1721.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (No. 21032007) is gratefully acknowledged.
Ethyl 2-aminopyrazolo[5,1-a]isoquinoline-1-carboxylate (4m).
1H NMR (400 MHz, CDCl3): d 1.48 (t, J = 7.2 Hz, 3H), 4.44–4.49
(m, 2H), 5.23 (s, 2H), 7.05 (d, J = 7.2 Hz, 1H), 7.56–7.61 (m, 2H),
Notes and references
7.67–7.70 (m, 1H), 8.01 (d, J = 7.2 Hz, 1H), 9.65–9.68 (m, 1H); 13
C
1 (a) D. P. Walsh and Y.-T. Chang, Chem. Rev., 2006, 106, 2476; (b) P.
Arya, D. T. H. Chou and M.-G. Baek, Angew. Chem., Int. Ed., 2001, 40,
339; (c) S. L. Schreiber, Science, 2000, 287, 1964.
NMR (100 MHz, CDCl3) d 14.9, 60.7, 93.2, 113.5, 123.9, 125.9,
127.3, 127.5, 128.0, 129.2, 131.3, 139.6, 159.2, 164.8; HRMS calcd
for C14H13N3O2 (M+ + H): 256.1086, found: 256.1101.
2 For a general review, see: J. A. Joule and K. Mills, in Heterocyclic
Chemistry, 4th edn., Blackwell Science Ltd., Cambridge, MA, 2000.
3 For selected examples of multi-component reactions, see: (a) Multicom-
ponent Reactions, J. Zhu and H. Bienayme, ed., Wiley-VCH, Weinheim,
Germany, 2005; (b) D. J. Ramon and M. Yus, Angew. Chem., Int. Ed.,
2005, 44, 1602; (c) V. Nair, C. Rajesh, A. U. Vinod, S. Bindu, A. R.
Sreekenth and L. Balagopal, Acc. Chem. Res., 2003, 36, 899; (d) R. V. A.
Orru and M. D. Greef, Synthesis, 2003, 1471; (e) G. Balme, E. Bossharth
and N. Monteiro, Eur. J. Org. Chem., 2003, 4101; (f) A. Domling and I.
Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168; (g) H. Bienayme, C. Hulme,
G. Oddon and P. Schmitt, Chem.–Eur. J., 2000, 6, 3321; (h) L. Weber, K.
Illgen and M. Almstetter, Synlett, 1999, 366; (i) I. Ugi, A. Domling and
B. Werner, J. Heterocycl. Chem., 2000, 37, 647; (j) J. Zhu, Eur. J. Org.
Chem., 2003, 1133; (k) C. Hulme and V. Gore, Curr. Med. Chem., 2003,
10, 51; (l) L. Weber, Curr. Med. Chem., 2002, 9, 1241.
Ethyl 2-amino-8-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline-1-
carboxylate (4n). 1H NMR (400 MHz, DMSO-d6): d 1.37 (t, J =
6.8 Hz, 3H), 4.35–4.40 (m, 2H), 6.05 (s, 2H), 7.33 (s, 1H), 7.45–
7.55 (m, 4H), 7.70–7.76 (m, 3H), 9.68–9.72 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) d 14.3, 59.9, 92.0, 111.4 (d, 2JCF = 20 Hz),
112.7, 115.5 (d, 2JCF = 24 Hz), 118.9, 128.1, 129.2, 129.5, 129.8 (d,
3
3JCF = 9 Hz), 133.0 (d, JCF = 10 Hz), 133.4, 137.9, 138.9, 158.3,
1
161.6 (d, JCF = 246 Hz), 163.9; HRMS calcd for C20H16FN3O2
(M+ + H): 350.1305, found: 350.1321.
Ethyl 2-amino-5-butyl-8-fluoropyrazolo[5,1-a]isoquinoline-1-
1
carboxylate (4o). H NMR (400 MHz, CDCl3): d 0.99 (t, J =
4 For selected reviews, see: (a) L. F. Tietze, G. Brasche and K. Ger-
icke, Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
Germany, 2006; (b) A. Meijere, P. V. Zezschwitz and S. Bra¨se, Acc.
Chem. Res., 2005, 38, 413; (c) P. Lu and Y.-G. Wang, Synlett, 2010, 165;
(d) E. J. Yoo and S. Chang, Curr. Org. Chem., 2009, 13, 1766; (e) K. C.
Nicolaou, E. W. Yue and T. Oshima, in The New Chemistry, N. Hall
ed., Cambridge University Press, Cambridge, 2001, p. 168; (f) L. F.
Tietze and F. Hautner, in Stimulating Concepts in Chemistry F. Vo¨gtle,
J. F. Stoddart and M. Shibasaki, ed.,Wiley-VCH, Weinheim, 2000, p.
38; (g) L. F. Tietze, Chem. Rev., 1996, 96, 115; (h) L. F. Tietze and U.
Beifuss, Angew. Chem., Int. Ed. Engl., 1993, 32, 131.
5 For recent examples, see: (a) Z. Chen, D. Zheng and J. Wu, Org. Lett.,
2011, 13, 848; (b) Y. Luo, X. Pan and J. Wu, Org. Lett., 2011, 13, 1150;
(c) H. Ren, Y. Luo, S. Ye and J. Wu, Org. Lett., 2011, 13, 2552; (d) Y.
Luo, L. Hong and J. Wu, Chem. Commun., 2011, 47, 5298; (e) Z. Chen,
C. Ye, L. Gao and J. Wu, Chem. Commun., 2011, 47, 5623; (f) G. Qiu, Q.
Ding, K. Gao, Y. Peng and J. Wu, ACS Comb. Sci., 2011, 13, 13; (g) S.
Ye, H. Wang and J. Wu, ACS Comb. Sci., 2011, 13, 120.
6 (a) S. Li and J. Wu, Org. Lett., 2011, 13, 712; (b) X. Yu, X. Pan and J.
Wu, Tetrahedron, 2011, 67, 1145; (c) Z. Chen, X. Pan and J. Wu, Synlett,
2011, 964; (d) Z. Chen and J. Wu, Org. Lett., 2010, 12, 4856; (e) S. Ye,
X. Yang and J. Wu, Chem. Commun., 2010, 46, 5238; (f) X. Yu, S. Ye
and J. Wu, Adv. Synth. Catal., 2010, 352, 2050; (g) X. Yu, Z. Chen, X.
Yang and J. Wu, J. Comb. Chem., 2010, 12, 374; (h) H. Ren, S. Ye, F.
Liu and J. Wu, Tetrahedron, 2010, 66, 8242; (i) Z. Chen, X. Yang and
J. Wu, Chem. Commun., 2009, 3469; (j) Z. Chen, Q. Ding, X. Yu and J.
Wu, Adv. Synth. Catal., 2009, 351, 1692; (k) Z. Chen, M. Su, X. Yu and
J. Wu, Org. Biomol. Chem., 2009, 7, 4641.
7.2 Hz, 3H), 1.47 (t, J = 7.2 Hz, 3H), 1.43–1.52 (m, 2H), 1.75–1.83
(m, 2H), 3.01–3.04 (m, 2H), 4.43–4.48 (m, 2H), 5.21 (s, 2H), 6.80 (s,
1H), 7.21–7.25 (m, 2H), 9.70–9.74 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 14.2, 14.8, 22.8, 29.1, 31.1, 60.6, 93.0, 110.4, 110.7 (d,
2JCF = 22 Hz), 115.1 (d, 2JCF = 23 Hz), 119.4, 130.6 (d, 3JCF = 9 Hz),
133.5 (d, 3JCF = 9 Hz), 139.9, 140.0, 158.4, 162.6 (d, 1JCF = 248 Hz),
164.8; HRMS calcd for C18H20FN3O2 (M+ + H): 330.1618, found:
330.1592.
Ethyl 2-amino-9-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline-1-
carboxylate (4p). 1H NMR (400 MHz, DMSO-d6): d 1.38 (t, J =
6.8 Hz, 3H), 4.35–4.41 (m, 2H), 6.09 (s, 2H), 7.39 (s, 1H), 7.48–7.58
(m, 4H), 7.75–7.77 (m, 2H), 7.98 (t, J = 6.8 Hz, 1H), 9.45–9.48
(m, 1H); 13C NMR (100 MHz, DMSO-d6) d 14.2, 60.0, 92.1, 111.3
2
2
(d, JCF = 25 Hz), 113.0, 118.9 (d, JCF = 24 Hz), 119.0, 123.1,
127.7, 128.1, 129.0, 129.6, 130.0, 133.5, 136.4, 158.3, 160.2 (d,
1JCF = 232 Hz), 163.9; HRMS calcd for C20H16FN3O2 (M+ + H):
350.1305, found: 350.1305.
Ethyl 2-amino-5-cyclopropyl-9-fluoropyrazolo[5,1-a]isoquino-
line-1-carboxylate (4q). 1H NMR (400 MHz, CDCl3): d 0.84–0.85
(m, 2H), 1.03–1.05 (m, 2H), 1.35 (t, J = 6.8 Hz, 3H), 2.45–2.50 (m,
1H), 4.32–4.34 (m, 2H), 6.09 (s, 2H), 6.94 (s, 1H), 7.38–7.42 (m,
1H), 7.72–7.75 (m, 1H), 9.30–9.33 (m, 1H); 13C NMR (100 MHz,
7036 | Org. Biomol. Chem., 2011, 9, 7033–7037
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7 (a) D. A. Handley, R. G. Van Valen, M. K. Melden, W. J. Houlihan
and R. N. Saunders, J. Pharmacol. Exp. Ther., 1988, 247, 617; (b) W. J.
Houlihan, S. H. Cheon, V. A. Parrino, D. A. Handley and D. A. Larson,
J. Med. Chem., 1993, 36, 3098; (c) D. Scholz, H. Schmidt, E. E. Prieschl,
R. Csonga, W. Scheirer, V. Weber, A. Lembachner, G. Seidl, G. Werner, P.
Mayer and T. Baumruker, J. Med. Chem., 1998, 41, 1050; (d) R. J. Griffin,
G. Fontana, B. T. Golding, S. Guiard, I. R. Hardcastle, J. J. Leahy, N.
Martin, C. Richadson, L. Rigoreau, M. Stockley and G. C. M. Smith,
J. Med. Chem., 2005, 48, 569.
8 (a) S. Danhauser-Riedl, S. B. Felix, W. J. Houlihan, M. Zafferani, G.
Steinhauser, D. Oberberg, H. Kalvelage, R. Busch, J. Rastetter and
W. E. Berdel, Cancer Res., 1991, 51, 43; (b) W. J. Houlihan, P. G.
Munder, D. A. Handley, S. H. Cheon and V. A. Parrino, J. Med.
Chem., 1995, 38, 234; (c) A. D. C. Parenty, L. V. Smith, K. M.
Guthrie, D. L. Long, J. Plumb, R. Brown and L. Cronin, J. Med.
Chem., 2005, 48, 4504; (d) L. V. Smith, A. D. C. Parenty, K. M.
Guthrie, J. Plumb, R. Brown and L. Cronin, ChemBioChem, 2006, 7,
1757.
This journal is
The Royal Society of Chemistry 2011
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