A silver(I)-rhodium(I) cooperative catalysis in the reaction of N′-(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane

Article abstract of DOI:10.1016/j.tet.2012.12.018

A novel and efficient route to H-pyrazolo[5,1-a]isoquinoline-1- carbaldehydes via a tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane is described. The reaction proceeds through a silver(I)-rhodium(I) cooperative catalysis.

Full text of DOI:10.1016/j.tet.2012.12.018

Tetrahedron 69 (2013) 1476e1480
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Tetrahedron
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A silver(I)erhodium(I) cooperative catalysis in the reaction of
N0-(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane
,
,
b,
Hongliang Liu a, Gang Liu a b, Guanyinsheng Qiu b, Shouzhi Pu a , Jie Wu
*
*
a Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang 330013, 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
Article history:
A novel and efficient route to H-pyrazolo[5,1-a]isoquinoline-1-carbaldehydes via a tandem reaction of
N0-(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane is described. The reaction proceeds through
a silver(I)erhodium(I) cooperative catalysis.
Received 11 November 2012
Received in revised form 30 November 2012
Accepted 7 December 2012
Available online 17 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N0-(2-Alkynylbenzylidene)hydrazide
H-Pyrazolo[5,1-a]isoquinoline-1-
carbaldehyde
(Triphenylphosphine)rhodium(I) chloride
Silver triflate
2-Vinyloxirane
1. Introduction
O
further
R3
N
elaboration
H
Recently, cooperative catalysis as a powerful approach has been
demonstrated in organic transformations.1 The merging of two or
more catalysts in one pot would enable the reactivities of reactants,
leading to the successful transformations. Examples of combination
of metal catalyst and organocatalyst, or two metal catalysts have
been appeared.1
N
R1
R2
Fig. 1. Diverse H-pyrazolo[5,1-a]isoquinolines.
Currently, continuous efforts have been focused on the prep-
aration of biologically and pharmaceutically important N-hetero-
cyclic compounds in the drug discovery process.2 During our
efforts for the combinatorial synthesis of N-heterocycles with
privileged scaffolds, we are interested in H-pyrazolo[5,1-a]iso-
quinoline compounds, which show promising biological acitiv-
ities.3 Although there are several methods for the synthesis of
H-pyrazolo[5,1-a]isoquinolines,4 an efficient approach for the
generation of diverse H-pyrazolo[5,1-a]isoquinolines is in great
demand. If a carbonyl group (such as aldehyde) could be installed
in the skeleton of H-pyrazolo[5,1-a]isoquinoline (Fig. 1), a small
library of diverse H-pyrazolo[5,1-a]isoquinolines would be
expected.
formation of H-pyrazolo[5,1-a]isoquinoline-1-carbaldehydes via
a silver/iron co-catalyzed reaction of N0-(2-alkynylbenzylidene)hy-
drazides with tertiary amines (Scheme 1). This proposed route was
inspired by Li’s work for the synthesis of
b-1,3-dicarbonyl alde-
hydes,6 inwhich
a,b-unsaturated aldehyde was the key intermediate
generated by tertiary amine oxidation in situ. However, the
installation of aldehyde into the H-pyrazolo[5,1-a]isoquinoline
scaffold was failed based on this strategy.7 Thus, we shifted our focus
on 2-vinyloxirane, which could serve as the precursor for the
introduction of aldehyde in the presence of transition metal catalyst
(such as rhodium salt) as well. The proposed pathway is present in
Scheme 2.
We conceived that an oxidative addition of rhodium(I) to 2-
vinyloxirane would occur first to generate intermediate B1. An
equilibrium between B1 and B3 via allylic rhodium complex
would be existed. In the meantime, silver triflate-catalyzed 6-endo
cyclization of N0-(2-alkynylbenzylidene)hydrazide 1 would give
Recently, we found that N0-(2-alkynylbenzylidene)hydrazide
could work as a good reactant for the construction of H-pyrazolo
[5,1-a]isoquinolines.5 Initially, we designed a tandem reaction for the
* 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.
http://dx.doi.org/10.1016/j.tet.2012.12.018

H. Liu et al. / Tetrahedron 69 (2013) 1476e1480
1477
Table 1
AgOTf (cat.)
Fe2(CO)9
Initial studies for the tandem reaction of N0-(2-alkynylbenzylidene)hydrazide 1a
with 2-vinyloxirane 2a
(cat.) X
oxidant
O
Et3N
OHC
CH3
NHTs
R2
NHTs
H
AgOTf (10 mol %)
[M] (cat.)
solvent, air
N
N
R1
N
O
+
N
N
R1
N
R2
1
Ph
O
3a
Ph
2a
1a
AgOTf (cat.)
[M] (cat.)
?
Entry
[M] (cat.)
T (ꢀC)
Solvent
Yielda (%)
Scheme 1. A proposed route to H-pyrazolo[5,1-a]isoquinoline-1-carbaldehydes.
1
2
3
4
5
6
7
8
d
25
25
25
25
25
25
50
50
50
50
50
50
50
50
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
MeCN
DCM
Toluene
1,4-Dioxane
DCE
Trace
Trace
41
13
7
Trace
77
46
65
57
Rh(OAc)2 (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Pd(PPh3)4 (10 mol %)
CuI (10 mol %)
Au(PPh3)Cl (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Rh(PPh3)3Cl (10 mol %)
Rh(PPh3)3Cl (2 mol %)
Rh(PPh3)3Cl (5 mol %)
9
10
11
12
13
14
30
17
32
58
DCE
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1a.
concurrently (Fig. 2, also see Supplementary data). We also tested
other transition metal salts, such as Pd(PPh3)4, CuI, and Au(PPh3)3Cl
(Table 1, entries 4e6). However, the results were inferior. The yield
was dramatically increased to 77% when the reaction occurred at
50 ꢀC (Table 1, entry 7). We further examined the reaction in various
solvents, and no better results were obtained (Table 1, entries
8e12). The yield was lower when the amount of Rh(PPh3)3Cl was
decreased (Table 1, entries 13 and 14).
Scheme 2. A possible mechanism for the reaction of N0-(2-alkynylbenzylidene)hy-
drazide with 2-vinyloxirane.
rise to isoquinolinium-2-yl amide A,5 which would then undergo
a [3þ2] cycloaddition with intermediate B3 to generate rhodiu-
m(III) species C. After
b-hydrogen elimination and reductive
elimination, aldehyde E would be produced. The subsequent
rearrangement with the release of tosyl group would happen to
afford intermediate H, which would then produce H-pyrazolo
[5,1-a]isoquinoline-1-carbaldehyde 3 via aromatization in air
(Scheme 2).
2. Results/discussion
Fig. 2. X-ray ORTEP illustration of H-pyrazolo[5,1-a]isoquinoline-1-carbaldehyde 3a.
With the above consideration in mind, we started to explore the
possibility of this transformation. The initial studies were con-
ducted with a model reaction of N0-(2-alkynylbenzylidene)hydra-
zide 1a with 2-vinyloxirane 2a. Only isoquinolinium-2-yl amide
was obtained in the absence of an additional transition metal cat-
alyst (Table 1, entry 1). A trace amount of product was detected
when Rh(OAc)2 was added as the co-catalyst (Table 1, entry 2).
Interestingly, the expected compound 3a was formed in 41% yield
when the reaction was performed in the presence of Rh(PPh3)3Cl
(10 mol %) at room temperature (Table 1, entry 3). The structure of
compound 3a was confirmed by X-ray diffraction analysis
Under the optimal conditions as mentioned in Table 1 (entry 7),
we then explored the scope and generality of this silver(I)erho-
dium(I) cooperative catalysis in the tandem reaction1d,8 of N0-
(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane. The results
are presented in Scheme 3. This transformation shows high effi-
ciency, which leads to the corresponding H-pyrazolo[5,1-a]iso-
quinoline-1-carbaldehyde 3 in moderate to good yields. Different
functional groups were compatible during the conversion. Addi-
tionally, thethienyl-substitutedN0-(2-alkynylbenzylidene)hydrazide

1478
H. Liu et al. / Tetrahedron 69 (2013) 1476e1480
was a suitable substrate as well, giving rise to the desired product 3f
in 82% yield. However, the reactions failed to furnish the
expected products under the standard conditions when N0-
(2-alkynylbenzylidene)hydrazide 1a reacted with 2-vinyloxiranes
2bed (Scheme 4). This might be due to the steric hindrance of
2-vinyloxiranes, which hampered the efficiency of the reaction.
pyrazolo[5,1-a]isoquinolines. Currently, construction of other N-
heterocycles using the strategy of cooperative catalysis is under
investigation in our laboratory.
4. Experimental section
4.1. General procedure of the tandem reaction of
N0-(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane
O
AgOTf (10 mol %)
CH3
NHTs
H
RhCl(PPh3)3
(10 mol %)
Silver triflate (0.03 mmol, 7.7 mg) was added to a solution of
N0-(2-alkynylbenzylidene)hydrazide 1 (0.3 mmol) in DCE (2.0 mL),
and the solution was stirred at 70 ꢀC under N2 for 2 h. Subsequently,
RhCl(PPh3)3 (0.03 mmol, 28 mg) and 2-vinyloxirane 2a (0.45 mmol,
32 mg) were added. The reaction was stirred at 50 ꢀC under air.
After completion of the reaction as indicated by TLC, the solvent
was evaporated and the residue was purified on silica gel by flash
column chromatograph (eluting with PE/EA¼8/1) to afford the
product 3.
N
R1
O
O
+
N
(CH2Cl)2, air
N
R1
R2
R2
3
2a
1
O
O
H
O
CH3
CH3
CH3
CH3
N
H
H
H
N
N
N
F
N
N
N
N
Ph
Ph
Ph
F
Ph
3a, 77% yield
3b, 75% yield
3c, 71% yield
3d, 70% yield
4.1.1. 2-Methyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-1-carbaldehyde
3a. 1H NMR (400 MHz, CDCl3):
d
10.32 (s, 1H), 7.70e7.67 (m, 1H),
7.85e7.83 (m, 2H), 7.80e7.78 (m, 1H), 7.70e7.68 (m, 2H), 7.54e7.52
(m, 3H), 7.25 (s, 1H), 2.71 (s, 3H); 13C NMR (100 MHz, CDCl3):
183.5,
O
H
O
O
O
CH3
CH3
CH3
N
CH3
H
H
H
d
N
N
N
N
S
N
N
N
156.1, 139.9, 137.8, 133.1, 131.2, 130.0, 129.7, 129.5, 128.3, 127.7, 127.5,
126.8, 123.5, 115.6, 114.1, 13.2; HRMS calcd for C19H14N2NaOþ
[MþNa]þ: 309.0998, found 309.0996.
O
Ph
Ph
C6H4p-F
C6H4p-Cl
3e, 70% yield 3f, 82% yield
3g, 68% yield
3h, 60% yield
O
O
O
O
4.1.2. 9-Fluoro-2-methyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-
CH3
N
CH3
CH3
H
CH3
N
H
H
H
1-carbaldehyde 3b. 1H NMR (400 MHz, CDCl3):
d 10.24 (s, 1H),
N
N
9.61e9.58 (m, 1H), 7.83e7.56 (m, 3H), 7.54e7.528 (m, 3H),
N
N
N
N
7.45e7.41 (m, 1H), 7.24 (s, 1H), 2.71 (s, 3H); 13C NMR (100 MHz,
n
t
1
C6H4p-Me
C6H4p-OMe
Bu
Bu
CDCl3):
d
183.6, 161.4 (d, JCF¼251.1 Hz), 156.6, 139.4, 137.5, 133.1,
3i, 62% yield
3j, 60% yield
3k, 61% yield
3l, 45% yield
129.9, 129.8, 129.26, 128.4, 128.1, 125.0, 115.5, 115.0, 114.3, 113.2
(d, JCF¼24.6 Hz), 13.3; HRMS calcd for C19H14FN2NaOþ [MþNa]þ:
2
O
O
O
O
CH3
CH3
CH3
CH3
327.0904, found 327.0906.
H
H
H
H
N
N
F
N
N
Cl
N
N
N
N
4.1.3. 2,9-Dimethyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-
1-carbaldehyde 3c. 1H NMR (400 MHz, CDCl3):
d 10.35 (s, 1H), 9.41
(s, 1H), 7.84e7.82 (m, 2H), 7.69 (d, J¼8.0 Hz, 1H), 7.52e7.51 (m, 4H),
3n, 50% yield
3o, 68% yield
3m, 53% yield
3p, 81% yield
7.21 (s, 1H), 2.70 (s, 3H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3):
Scheme 3. Synthesis of H-pyrazolo[5,1-a]isoquinoline-1-carbaldehydes via a tandem
reaction of N0-(2-alkynylbenzylidene)hydrazide with 2-vinyloxirane.
d
183.7, 156.1, 139.8, 138.0, 137.1, 133.3, 131.7, 129.8, 129.7, 129.2,
128.2, 126.8, 123.2, 115.8, 115.3, 114.14, 22.0, 13.5; HRMS calcd for
C20H16N2NaOþ [MþNa]þ: 323.1155, found 323.1167.
Ph
O
2b
4.1.4. 8-Fluoro-2-methyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-
1-carbaldehyde 3d. 1H NMR (400 MHz, CDCl3):
d 10.23 (s, 1H),
AgOTf (10 mol %)
9.60e9.56 (m, 1H), 7.82e7.81 (m, 2H), 7.78e7.74 (m, 1H), 7.53e7.52
NHTs
RhCl(PPh3)3
(10 mol %)
O
N
(m, 3H), 7.44e7.40 (m, 1H), 7.23 (s, 1H), 2.70 (s, 3H); 13C NMR
+
2c
trace
1
(100 MHz, CDCl3):
d
183.4, 161.3 (d, JCF¼247.4 Hz), 156.5, 139.2,
(CH2Cl)2, air
Ph
137.3, 132.9, 129.7, 129.0, 128.3, 127.9, 124.9, 115.3, 114.9, 114.2, 113.0
Ph
(d, JCF¼24.6 Hz), 13.1; HRMS calcd for C19H13FN2NaOþ [MþNa]þ:
2
1a
O
2d
327.0904, found 327.0917.
Scheme 4. Reactions of N0-(2-alkynylbenzylidene)hydrazide 1a with other 2-
vinyloxiranes.
4.1.5. 8-Methoxy-2-methyl-5-phenylH-pyrazolo[5,1-a]isoquinoline-
1-carbaldehyde 3e. 1H NMR (400 MHz, CDCl3):
d 10.21 (s, 1H),
9.67e9.65 (m, 1H), 7.83e7.81 (m, 2H), 7.52e7.50 (m, 3H), 7.27e7.24
3. Conclusions
(m, 1H), 7.15 (s, 1H), 7.10e7.09 (m, 1H), 3.92 (s, 3H), 2.66 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d 183.2, 160.7, 156.3, 140.0, 138.2, 133.4,
In summary, we have described
a
silver(I)erhodium(I)
129.8, 128.2, 117.9, 117.4, 115.4, 114.9, 113.3, 107.5, 107.0, 55.3, 12.9;
cooperative catalysis in the reaction of N0-(2-alkynylbenzylidene)
hydrazide with 2-vinyloxirane. During the tandem process, multi-
ple bonds are formed and H-pyrazolo[5,1-a]isoquinoline-
1-carbaldehydes could be obtained in moderate to good yields
under mild conditions. The presence of carbonyl group in
the scaffold of H-pyrazolo[5,1-a]isoquinoline could be further
elaborated, which would allow the generation of diverse H-
HRMS calcd for C20H16N2NaO2þ [MþNa]þ: 339.1104, found 339.1109.
4.1.6. H-Pyrazolo[5,1-a]isoquinoline-1-carbaldehyde 3f. 1H NMR
(400 MHz, CDCl3):
(d, J¼5.2 Hz, 1H), 7.53e7.51 (m, 3H), 7.43 (d, J¼5.2 Hz, 1H), 7.37
(s, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3):
182.7, 154.9, 139.1,
138.0, 137.4, 133.2, 131.4, 129.7, 129.5, 128.3, 127.2, 123.4, 111.3, 111.0,
d
10.15 (s, 1H), 7.83 (d, J¼6.0 Hz, 2H), 7.72
d

H. Liu et al. / Tetrahedron 69 (2013) 1476e1480
1479
12.7; HRMS calcd for C17H12N2NaOSþ [MþNa]þ: 315.0563, found
131.4, 129.2, 126.8, 126.2, 122.9, 114.2, 109.6, 22.1, 13.2, 11.2, 7.6;
315.0587.
HRMS calcd for C17H16N2NaOþ [MþNa]þ: 287.1155, found 287.1172.
4.1.7. 5-(4-Fluorophenyl)-2-methylH-pyrazolo[5,1-a]isoquinoline-
4.1.15. 9-Chloro-5-cyclopropyl-2-methylH-pyrazolo[5,1-a]isoquino-
1-carbaldehyde 3g. 1H NMR (400 MHz, CDCl3):
d
10.32 (s, 1H),
line-1-carbaldehyde 3o. 1H NMR (400 MHz, CDCl3):
d 10.21 (s, 1H),
9.68e9.66 (m, 1H), 7.85e7.77 (m, 3H), 7.70e7.68 (m, 2H), 7.22e7.19
9.66 (s, 1H), 7.54e7.53 (m, 2H), 6.74 (s, 1H), 2.76e2.68 (m, 4H),
(m, 3H), 2.70 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 183.6, 163.4
1.24e1.21 (m, 2H), 0.94e0.92 (m, 2H); 13C NMR (100 MHz, CDCl3):
(d1JCF¼249.5 Hz), 156.3, 140.0, 136.9, 131.8, 131.2, 130.2, 129.2, 127.9,
d 183.2, 156.3, 140.9, 138.3, 132.5, 130.2, 129.4, 127.4, 126.8, 123.5,
2
127.7, 127.0, 123.6, 115.8, 115.2 (d, JCF¼22.8 Hz), 114.3, 13.1; HRMS
114.2, 108.9, 13.2, 11.5, 7.9; HRMS calcd for C16H13ClN2NaOþ
calcd for C19H13FN2NaOþ [MþNa]þ: 327.0904, found 327.0906.
[MþNa]þ: 307.0609, found 307.0634.
4.1.8. 5-(4-Chlorophenyl)-2-methylH-pyrazolo[5,1-a]isoquinoline-
4.1.16. 5-Cyclopropyl-9-fluoro-2-methylH-pyrazolo[5,1-a]isoquino-
1-carbaldehyde 3h. 1H NMR (400 MHz, CDCl3):
d
10.32 (s, 1H),
line-1-carbaldehyde 3p. 1H NMR (400 MHz, CDCl3):
d 10.21 (s, 1H),
9.68e9.66 (m, 1H), 7.39 (d, J¼8.4 Hz, 3H), 7.71e7.69 (m, 2H), 7.50 (d,
9.46 (dd, J¼10.8, 1.8 Hz, 1H), 7.65e7.62 (m, 1H), 7.39e7.34 (m, 1H),
J¼8.4 Hz, 2H), 7.24 (s, 1H), 2.71 (s, 3H); 13C NMR (100 MHz, CDCl3):
6.79 (s, 1H), 2.77e2.69 (m, 4H), 1.25e1.22 (m, 2H), 0.91e0.88 (m,
d
183.6, 156.3, 139.0, 136.8, 135.6, 131.5, 131.1, 130.2, 128.5, 128.0,
2H); 13C NMR (100 MHz, CDCl3):
d
183.3, 160.7 (d, 1JCF¼246.5 Hz),
127.7, 127.0, 123.7, 115.9, 115.4, 114.3, 13.0; HRMS calcd for
156.3, 139.9, 138.7, 127.9, 123.8, 118.6, 114.1, 112.80 (d, 2JCF¼23.9 Hz),
109.3, 13.1, 11.5, 7.7; HRMS calcd for C16H13FN2NaOþ [MþNa]þ:
291.0904, found 291.0929.
C19H13ClN2NaOþ [MþNa]þ: 343.0609, found 343.0627.
4.1.9. 2-Methyl-5-p-tolylH-pyrazolo[5,1-a]isoquinoline-1-
carbaldehyde 3i. 1H NMR (400 MHz, CDCl3):
d 10.34 (s, 1H),
Acknowledgements
9.70e9.68 (m, 1H), 7.81e7.78 (m, 1H), 7.74 (d, J¼8.0 Hz, 2H),
7.70e7.68 (m, 2H), 7.34 (d, J¼8.0 Hz, 2H), 7.25 (s, 1H), 2.71 (s, 3H),
Financial support from National Natural Science Foundation of
China (Nos. 21032007, 21172038) is gratefully acknowledged.
2.46 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 183.7, 156.3, 140.0, 139.7,
138.1, 131.4, 130.1, 129.7, 129.3, 128.9, 127.7, 126.9, 123.5, 115.6, 115.1,
114.2, 21.5, 13.1; HRMS calcd for C20H16N2NaOþ [MþNa]þ: 323.1155,
found 323.1181.
Supplementary data
Experimental procedure, characterization data, 1H and 13C NMR
spectra of compounds 3, and a CIF file of compound 3a are available.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.12.018. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
4.1.10. 5-(4-Methoxyphenyl)-2-methylH-pyrazolo[5,1-a]isoquino-
line-1-carbaldehyde 3j. 1H NMR (400 MHz, CDCl3):
d 10.32 (s, 1H),
9.68e9.64 (m, 1H), 7.81e7.75 (m, 3H), 7.67e7.65 (m, 2H), 7.21
(s, 1H), 7.04 (d, J¼8.0 Hz, 2H), 3.89 (s, 3H), 2.71 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 183.8, 160.7, 156.3, 140.1, 137.9, 131.5, 131.3,
130.1, 127.6, 126.9, 125.6, 123.5, 115.4, 114.9, 114.2, 113.7, 55.6, 13.2;
HRMS calcd for C20H16N2NaO2þ [MþNa]þ: 339.1104, found 339.1122.
References and notes
4.1.11. 5-Butyl-2-methylH-pyrazolo[5,1-a]isoquinoline-
1-carbaldehyde 3k. 1H NMR (400 MHz, CDCl3):
d 10.30 (s, 1H), 9.59
1. 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.;
Chang, S. Chem. Soc. Rev. 2004, 33, 302; (c) Wasilke, J. C.; Brey, O. S. J.; Baker, R. T.;
Bazan, G. C. Chem. Rev. 2005, 105, 1001; (d) Enders, D.; Grondal, C.; Huttl, M. R.
Angew. Chem., Int. Ed. 2007, 46, 1570; (e) Chapman, C. J.; Frost, C. G. Synthesis
2007, 1; (f) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477; (g) Wang, C.; Xi,
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(d, J¼7.2 Hz, 1H), 7.73e7.61 (m, 3H), 7.04 (s, 1H), 3.18 (t, J¼7.6 Hz,
2H), 2.75 (s, 3H), 1.90e1.82 (m, 2H), 1.54e1.48 (m, 2H), 1.01
(t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 183.6, 156.0, 139.5,
139.2, 131.3, 129.8, 127.4, 127.0, 126.3, 123.0, 114.2, 112.8, 30.7, 29.0,
22.4, 14.09, 13.0; HRMS calcd for C17H18N2NaOþ [MþNa]þ: 289.1311,
found 289.1342.
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4.1.12. 5-tert-Butyl-2-methylH-pyrazolo[5,1-a]isoquinoline-
1-carbaldehyde 3l. 1H NMR (400 MHz, CDCl3):
d
10.34 (s, 1H), 9.60
(d, J¼8.4 Hz, 1H), 7.76e7.74 (m, 1H), 7.68e7.62 (m, 2H), 7.16 (s, 1H),
2.76 (s, 3H), 1.68 (s, 9H); 13C NMR (100 MHz, CDCl3):
183.7, 154.8,
d
€
Acad. Sci. U.S.A. 2011, 108, 6699; (k) Hubel, K.; Leßmann, T.; Waldmann, H. Chem.
146.0, 140.8, 131.3, 129.7, 127.2, 126.8, 123.2, 113.3, 111.7, 111.2, 36.2,
28.4,13.2; HRMS calcd for C17H18N2NaOþ [MþNa]þ: 289.1311, found
289.1345.
Soc. Rev. 2008, 37,1361; (l) Schreiber, S. L. Chem. Eng. News2003, 81, 51; (m) Drewry,
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D. H.; Macarron, R. Curr. Opin. Chem. Biol. 2010,14, 289;(n) Bleicher, K. H.; Bohm, H.-
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J.; Muller, K.; Alanine, A. I. Nat. Rev. Drug Discovery 2003, 2, 369; (o) Dandapani, S.;
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ꢀ
4. (a) Hernandez, S.; SanMartin, R.; Tellitu, I.; Domínguez, E. Org. Lett. 2003, 5, 1095;
4.1.13. 5-Cyclopropyl-2-methylH-pyrazolo[5,1-a]isoquinoline-
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1-carbaldehyde 3m. 1H NMR (400 MHz, CDCl3):
d 10.32 (s, 1H), 9.69
(d, J¼8.0 Hz, 1H), 7.69e7.61 (m, 3H), 6.83 (s, 1H), 2.78e2.71 (m, 4H),
1.24e1.21 (m, 2H), 0.95e0.91 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
183.6, 156.1, 140.6, 139.5, 131.3, 129.8, 127.4, 126.9, 126.3, 122.8,
114.3, 109.7, 13.4, 11.2, 7.7; HRMS calcd for C16H14N2NaOþ [MþNa]þ:
273.0998, found 273.1015.
4.1.14. 5-Cyclopropyl-2,9-dimethylH-pyrazolo[5,1-a]isoquinoline-
1-carbaldehyde 3n. 1H NMR (400 MHz, CDCl3):
d 10.35 (s, 1H), 9.32
5. Chen, Z.; Gao, L.; Ye, S.; Ding, Q.; Wu, J. Chem. Commun. 2012, 3975 and
references cited therein.
6. Liu, W.; Liu, J.; Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org. Lett. 2011, 13, 6272 and
references cited therein.
(s, 1H), 7.58 (d, J¼8.0 Hz, 1H), 7.46 (d, J¼7.6 Hz, 1H), 6.80 (s, 1H),
2.78e2.69 (m, 4H), 2.56 (s, 3H), 1.23e1.19 (m, 2H), 0.93e0.89
(m, 2H); 13C NMR (100 MHz, CDCl3):
d
183.6, 156.0, 139.7, 137.1,
7. Ye, C.; Yu, X.; Qiu, Q.; Wu, J. RSC Adv. 2012, 2, 5961.

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H. Liu et al. / Tetrahedron 69 (2013) 1476e1480
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