Efficient generation of biologically active H-pyrazolo[5,1- a]isoquinolines via multicomponent reaction

Article abstract of DOI:10.1021/ol101988q

A highly efficient multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, alcohol, and α,β-unsaturated aldehyde or ketone is disclosed, which generates the diverse H-pyrazolo[5,1-a]isoquinolines in good yields. This reaction proceeds with good functional group tolerance under mild conditions with high efficiency and excellent selectivity. Preliminary biological assays show that some of these compounds display promising activities as CDC25B inhibitor, TC-PTP inhibitor, and PTP1B inhibitor.

Full text of DOI:10.1021/ol101988q

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4856-4859
Efficient Generation of Biologically
Active H-Pyrazolo[5,1-a]isoquinolines via
Multicomponent Reaction
Zhiyuan Chen† and Jie Wu*,†,‡
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai 200433,
China and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
jie_wu@fudan.edu.cn
Received August 23, 2010
ABSTRACT
A highly efficient multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, alcohol, and r,ꢀ-unsaturated aldehyde or ketone is
disclosed, which generates the diverse H-pyrazolo[5,1-a]isoquinolines in good yields. This reaction proceeds with good functional group
tolerance under mild conditions with high efficiency and excellent selectivity. Preliminary biological assays show that some of these compounds
display promising activities as CDC25B inhibitor, TC-PTP inhibitor, and PTP1B inhibitor.
Drug discovery programs use large collections of small
molecules to look for lead structures from biological assays.
Thus, availability of practical and efficient devices for
generation of natural product-like compounds is of utmost
urgency and importance. Currently, diversity-oriented syn-
thesis has been successfully applied for the synthesis of
structurally diverse and complex collections of natural
product-like compounds.1 Among the strategies utilized,
multicomponent reactions (MCRs) are of increasing impor-
tance due to their high efficiency for delivering molecular
diversity.2 As part of an ongoing program in our laboratory
for generation of small molecules used in different biological
assays,3,4 we are interested in the methodology development
of multicomponent reactions for accessing privileged scaf-
folds.
Recently, we reported a metal and N-heterocyclic carbene
cocatalyzed three-component reaction of N′-(2-alkynylben-
zylidene)hydrazide, methanol, and R,ꢀ-unsaturated aldehyde
(2) For selected examples of multicomponent reactions, see: (a) Mul-
ticomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005,
44, 1602. (c) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekenth,
A. R.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (d) Orru, R. V. A.; de
Greef, M. Synthesis 2003, 1471. (e) Balme, G.; Bossharth, E.; Monteiro,
N. Eur. J. Org. Chem. 2003, 4101. (f) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168. (g) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem.sEur. J. 2000, 6, 3321. (h) Sunderhaus, J. D.; Martin, S. F.
Chem.sEur. J. 2009, 15, 1300. (i) Ugi, I.; Domling, A.; Werner, B.
J. Heterocycl. Chem. 2000, 37, 647. (j) Zhu, J. Eur. J. Org. Chem. 2003,
1133. (k) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. (l) Weber,
L. Curr. Med. Chem. 2002, 9, 1241.
(3) For recent selected examples, see: (a) Ye, S.; Yang, X.; Wu, J. Chem.
Commun. 2010, 46, 2950. (b) Yu, X.; Chen, Z.; Yang, X.; Wu, J. J. Comb.
Chem. 2010, 12, 374. (c) Yu, X.; Wu, J. J. Comb. Chem. 2010, 12, 238.
(d) Ye, S.; Gao, K.; Zhou, H.; Yang, X.; Wu, J. Chem. Commun. 2009,
5406. (e) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. 2009, 3469. (f) Chen,
Z.; Yu, X.; Su, M.; Yang, X.; Wu, J. AdV. Synth. Catal. 2009, 351, 2702.
(g) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. AdV. Synth. Catal. 2009, 351, 1692.
(h) Ding, Q.; Wang, Z.; Wu, J. J. Org. Chem. 2009, 74, 921. (i) Yu, X.;
Wu, J. J. Comb. Chem. 2009, 11, 895. (j) Chen, Z.; Su, M.; Yu, X.; Wu,
J. Org. Biomol. Chem. 2009, 7, 4641. (k) Yu, X.; Ye, S.; Wu, J. AdV. Synth.
Catal. 2010, 352, 2050. (l) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010,
46, 5238.
† Fudan University.
‡ Chinese Academy of Sciences.
(1) (a) Walsh, D. P.; Chang, Y.-T. Chem. ReV. 2006, 106, 24. (b) Arya,
P.; Chou, D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40, 339. (c)
Schreiber, S. L. Science 2000, 287, 1964.
10.1021/ol101988q  2010 American Chemical Society
Published on Web 09/27/2010

isoquinoline and pyrazolo[1,5-a]pyridine skeletons. It is well-
known that isoquinolines and their derivatives stand out as
privileged frameworks in naturally occurring alkaloids and
biologically active molecules.5 Therefore, there has been
considerable interest concerning the synthesis of these
compounds.6 As a member of this family, the fused iso-
quinoline has attracted much attention recently due to the
remarkable biological activities.7 For example, Lamellarin
D is found as a potent inhibitor of human topoisomerase I7b
and lamellarin R-20-sulfate shows selective inhibition against
HIV-1 integrase in vitro (Figure 1).7c,d The scaffold could
Scheme 1
.
Preliminary Result for H-Pyrazolo[5,1-a]isoquinoline
Generation
(Scheme 1, eq 1).4a This reaction proceeded with high
efficiency to afford 2-amino-1,2-dihydroisoquinolines in good
yields. However, it was found that the R2 group attached to
the triple bond of N′-(2-alkynylbenzylidene)hydrazide was
crucial for successful conversion. Only the aryl group
was effective and no reactions occurred when the group was
replaced by the n-butyl or the cyclopropyl group. With an
expectation to broaden the scope of this transformation, we
reinvestigated the reaction of N′-(2-alkynylbenzylidene)hy-
drazide A. To avoid competitive reactions, the key interme-
diate isoquinolinium B was directly employed in the reaction
of cinnamaldehyde 2a with methanol at room temperature
(Scheme 1, eq 2). At the outset, the reaction occurred in
THF in the presence of different bases (2.0 equiv) and
IPr·HCl (5 mol %). No product was detected when DBU,
DABCO, NaOAc, or Et3N was employed in the reaction. A
trace amount of product was observed when t-BuOK was
used as a replacement. A product was generated when
patassium hydroxide was utilized as the base. However,
surprisingly structural identification by X-ray diffraction
analysis (see the Supporting Information) showed that this
product was the unexpected 5-cyclopropyl-1-(methoxy(phe-
nyl)methyl)H-pyrazolo[5,1-a]isoquinoline 3a instead of the
desired 2-amino-1,2-dihydroisoquinoline. From this result,
we doubted the role of N-heterocyclic carbene in the reaction.
Thus, a blank experiment without the addition of IPr·HCl
was examined, which gave rise to compound 3a as well in
60% yield. Further screening of solvents identified that 1,2-
dichloroethane (DCE) was the best choice (73% yield). The
reaction performed in other solvents afforded inferior
yields.
Figure 1
a]pyridines.
. Examples of fused isoquinolines and pyrazolo[1,5-
be efficiently synthesized via tandem cyclization/1,3-dipolar
cycloaddition reaction.8 On the other hand, pyrazolo[1,
5-a]pyridines represent an important class of heterocycls in
drug discovery as they display numerous biological activities
(Figure 1).9-11 For instance, several of these compounds as
effective D3 and D4 agonists and antagonists are used in
(5) For selected examples, see: (a) Bentley, K. W. The Isoquinoline
Alkaloids; Harwood Academic: Amsterdam, The Netherlands, 1998; Vol.
1. (b) Trotter, B. W.; Nanda, K. K.; Kett, N. R.; Regan, C. P.; Lynch, J. J.;
Stump, G. L.; Kiss, L.; Wang, J.; Spencer, R. H.; Kane, S. A.; White, R. B.;
Zhang, R.; Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.; Beshore, D. C.;
Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006, 49, 6954. (c) Ramesh,
P.; Reddy, N. S.; Venkateswarlu, Y. J. Nat. Prod. 1999, 62, 780. (d) Kaneda,
T.; Takeuchi, Y.; Matsui, H.; Shimizu, K.; Urakawa, N.; Nakajyo, S.
J. Pharmacol. Sci. 2005, 98, 275. (e) Mikami, Y.; Yokoyama, K.; Tabeta,
H.; Nakagaki, K.; Arai, T. J. Pharmacobio-Dyn. 1981, 4, 282. (f) Marchand,
C.; Antony, S.; Kohn, K. W.; Cushman, M.; Ioanoviciu, A.; Staker, B. L.;
Burgin, A. B.; Stewart, L.; Pommier, Y. Mol. Cancer Ther. 2006, 5, 287.
(g) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg, G. M.;
Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat. Prod.
1986, 49, 995.
(6) For selected examples, see: (a) Balasubramanian, M.; Keay, J. G.
Isoquinoline Synthesis. In ComprehensiVe Heterocyclic Chemistry II;
McKillop, A. E., Katrizky, A. R., Rees, C. W., Scrivem, E. F. V., Eds.;
Elsevier: Oxford, UK, 1996; Vol. 5, pp 245-300. (b) For a review on the
synthesis of isoquinoline alkaloid, see: Chrzanowska, M.; Rozwadowska,
M. D. Chem. ReV. 2004, 104, 3341.
With this promising result in hand, we were interested in
the scaffold of compound 3a, which incorporated both
(4) (a) Chen, Z.; Yu, X.; Wu, J. Chem. Commun. 2010, 46, 6356. (b)
Ye, S.; Wu, J. Tetrahedron Lett. 2009, 50, 6273. (c) Zhou, H.; Jin, H.; Ye,
S.; He, X.; Wu, J. Tetrahedron Lett. 2009, 50, 4616. (d) Yu, X.; Ding, Q.;
Wang, W.; Wu, J. Tetrahedron Lett. 2008, 49, 4390. (e) Ding, Q.; Yu, X.;
Wu, J. Tetrahedron Lett. 2008, 49, 2752. (f) Ye, Y.; Ding, Q.; Wu, J.
Tetrahedron 2008, 64, 1378. (g) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959.
(h) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611. (i) Sun, W.; Ding, Q.;
Sun, X.; Fan, R.; Wu, J. J. Comb. Chem. 2007, 9, 690. (j) Ding, Q.; Wang,
B.; Wu, J. Tetrahedron 2007, 63, 12166.
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Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796. (c) Reddy, M. V. R.;
Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.; Bushman, F. D.;
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references cited therein.
Org. Lett., Vol. 12, No. 21, 2010
4857

the treatment of neurological disorders including schizo-
phrenia, attentiondeficit disorder, and Parkinson’s disease.9
Additionally, some derivatives show potent antiherpetic and
diuretic activity due to their ability to act as adenosine
agonists and antagonists.10 Inspired by these results, we
envisioned that we could construct a focused library of
H-pyrazolo[5,1-a]isoquinolines (Scheme 2), which incorpo-
dehyde 1 with sulfonohydrazide would lead to N′-(2-
alkynylbenzylidene)hydrazide, which then underwent cy-
clization to furnish isoquinolinium intermediate in the
presence of suitable metal catalyst. Meanwhile, the enolate
would be produced in situ via nucleophilic attack of alcohol
to R,ꢀ-unsaturated aldehyde or ketone 2. Thus, after subse-
quent transformation (including intermolecular nucleophilic
addition, intramolecular condensation, and aromatization),3k
the desired H-pyrazolo[5,1-a]isoquinoline 3 would be af-
forded. With these considerations in mind, we started to
explore the possibility of this multicomponent reaction of
2-alkynylbenzaldehyde, sulfonohydrazide, alcohol, and R,ꢀ-
unsaturated aldehyde or ketone.
Scheme 2
.
Proposed Synthetic Route for Generation of Diverse
H-Pyrazolo[5,1-a]isoquinolines
In our previous reports,3 we have demonstrated that silver
triflate is an efficient catalyst for isoquinolinium B forma-
tion via 6-endo cyclization of N′-(2-alkynylbenzylidene)hy-
drazide. Thus, the multicomponent reaction of 2-alkynyl-
benzaldehyde 1a, sulfonohydrazide, cinnamaldehyde 2a, and
methanol was initially catalyzed by 5 mol % of silver triflate
in the presence of KOH (3.0 equiv) in DCE at room
temperature. Gratifyingly, this reaction worked well leading
to the desired product 3a in 51% yield (Table 1, entry 1).
No improvement was observed by changing other metal
Table 1. Generation of Diverse H-Pyrazolo[5,1-a]isoquinolines
via Multicomponent Reaction of 2-Alkynylbenzaldehyde,
Sulfonohydrazide, Methanol, and R,ꢀ-Unsaturated Aldehyde or
Ketone
rated both isoquinoline and pyrazolo[1,5-a]pyridine skel-
etons. We expected the compounds with the scaffold in
Scheme 2 would display interesting biological activities as
well, and hopefully some hits would be generated from these
compounds in our specific biological assays.
As mentioned above, reaction of isoquinolinium B with
cinnamaldehyde 2a and methanol gave rise to compound 3a
in 73% yield in the presence of KOH in DCE at room
temperature. The result in Scheme 1 and our continued
interest in tandem reactions prompted us to search a more
efficient way for generation of diverse H-pyrazolo[5,1-
a]isoquinolines. Encouraged by the above results and our
previous efforts in the tandem reaction of N′-(2-alkynylben-
zylidene)hydrazide, we conceived that the starting materials
of this transformation could be traced back to 2-alkynylben-
zaldehyde 1, sulfonohydrazide, alcohol, and R,ꢀ-unsaturated
aldehyde or ketone 2 (Scheme 2). For this multicomponent
reaction, we anticipated that treatment of 2-alkynylbenzal-
entry
R1, R2
R3, R4
yield (%)a
1
2
3
4
5
6
7
8
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, Ph (1b)
H, Ph (1b)
H, Ph (1b)
H, Ph (1b)
H, Ph (1b)
C6H5, H (2a)
51 (3a)
76 (3b)
78 (3c)
72 (3d)
77 (3e)
78 (3f)
84 (3g)
76 (3h)
92 (3i)
67 (3j)
54 (3k)
88 (3l)
91 (3m)
76 (3n)
68 (3o)
93 (3p)
80 (3q)
62 (3r)
62 (3s)
66 (3t)
77 (3u)
66 (3v)
55 (3w)
70 (3x)
4-BrC6H4, H (2b)
4-MeOC6H4, H (2c)
-(CH2)3- (2d)
C6H5, H (2a)
4-BrC6H4, H (2b)
4-MeOC6H4, H (2c)
4-MeC6H4, H (2e)
Et, H (2f)
3-pyridinyl, H (2g)
2-furanyl, H (2h)
4-BrC6H4, H (2b)
-(CH2)3- (2d)
4-BrC6H4, H (2b)
-(CH2)3- (2d)
4-BrC6H4, H (2b)
4-BrC6H4, H (2b)
4-MeOC6H4, H (2c)
-(CH2)3- (2d)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H, Ph (1b)
H, Ph (1b)
(9) (a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
2002, 12, 2377. (b) Hasen, J. B.; Weis, J.; Suzdak, P. D.; Eskesen, K. Bioorg.
Med. Chem. Lett. 1994, 4, 695. (c) Bettinetti, L.; Schlotter, K.; Hubner, H.;
Gmeiner, P. J. Med. Chem. 2002, 45, 4594.
H, 4-MeC6H4 (1c)
H, 4-MeC6H4 (1c)
H, 4-ClC6H4 (1d)
H, 4-ClC6H4 (1d)
H, nBu (1e)
5-Cl, Ph (1f)
5-Cl, Ph (1f)
5-Cl, Ph (1f)
5-Cl, Ph (1f)
(10) (a) Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.;
Samano, V. A.; Ray, J. A.; Freeman, G. A.; Boyd, F. L., Jr.; Sexton, C. J.;
Selleseth, D. W.; Creech, K. L.; Moniri, K. R. Bioorg. Med. Chem. 2005,
13, 2397. (b) Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.;
Kinoshita, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa,
Y. J. Med. Chem. 1999, 42, 779. (c) Kuroda, S.; Akahane, A.; Itani, H.;
Nishimura, S.; Durkin, K.; Kinoshita, T.; Tenda, Y.; Sakane, K. Bioorg.
Med. Chem. Lett. 1999, 9, 1979.
4-MeC6H4, H (2e)
5-Cl, cyclopropyl (1g) 4-BrC6H4, H (2b)
(11) For selected examples of synthesis of pyrazolo[1,5-a]pyridines, see:
(a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9,
97. (b) Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.; Peckham,
G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.; Chamberlain, S. D.; Peel,
M. R. Org. Lett. 2005, 7, 4753. (c) Valenciano, J.; Cuadro, A. M.; Vaquero,
J. J.; Builla, J. A.; Castano, O. J. Org. Chem. 1999, 64, 9001. (d) Mousseau,
J. J.; Fortier, A.; Charette, A. B. Org. Lett. 2010, 12, 516.
5-F, nBu (1h)
4-F, Ph (1i)
4-BrC6H4, H (2b)
4-BrC6H4, H (2b)
4-BrC6H4, H (2b)
4-OMe, Ph (1j)
a Isolated yield based on 2-alkynylbenzaldehyde 1.
4858
Org. Lett., Vol. 12, No. 21, 2010

catalysts or reducing the amount of base. Thus, under the
preliminary optimized conditions, we started to explore the
scope of this multicomponent reaction of 2-alkynylbenzal-
dehyde, sulfonohydrazide, methanol, and R,ꢀ-unsaturated
aldehyde or ketone. The results are presented in Table 1.
From Table 1, we found that all reactions proceeded
smoothly to afford the expected H-pyrazolo[5,1-a]isoquino-
lines in moderate to good yields. For instance, reaction of
2-(2-cyclopropylethynyl)benzaldehyde 1a, 4-methylbenze-
nesulfonohydrazide, methanol, and (E)-3-(4-bromophenyl)-
acrylaldehyde 2b gave rise to the corresponding H-pyra-
zolo[5,1-a]isoquinoline 3b in 76% yield under the standard
conditions (entry 2). A similar result was generated when
(E)-3-(4-methoxyphenyl)acrylaldehyde 2c was employed as
a replacement (78% yield, entry 3). Cyclohex-2-enone 2d
was a suitable partner in the above reaction as well, which
afforded the desired product 3d in 72% yield (entry 4). When
2-alkynylbenzaldehyde 1b was utilized as the substrate in
this multicomponent reaction, not only 3-arylacrylaldehyde
but also 3-alkylacrylaldehyde was workable in this trans-
formation (entries 5-9). In addition, good results were
obtained when (E)-3-(pyridin-3-yl)acrylaldehyde 2g or (E)-
3-(furan-2-yl)acrylaldehyde 2h was employed as a substrate
in the reaction of 2-alkynylbenzaldehyde 1b, sulfonohy-
drazide, with methanol (entries 10 and 11). Subsequently
we examined other 2-alkynylbenzaldehydes with various
substituents on the aromatic ring or attached to the triple
bond. As expected, all reactions worked well to furnish the
desired H-pyrazolo[5,1-a]isoquinolines (entries 12-24).
Meanwhile, reactions with ethanol as a partner instead of
methanol under the standard conditions were tested (Scheme
3). Compound 3y was obtained in 45% yield in the reaction
zolo[1,5-a]pyridine skeletons, should be regarded as a
privileged scaffold as well. Thus, these compounds were
screened with several biological assays. No active com-
pounds were found for the DPP4 and SHP-1 assays.
Compound 3t shows an interesting result as an Aurora A
inhibitor (IC50 13.43 µM). Other assays including CDC25B,
TC-PTP, and PTP1B assays were screened meanwhile, and
the preliminary results were displayed in the Supporting
Information. It is well-known that the inhibitor of CDC25B
is recognized as one of the feasible channels of preventing
and curing malignant tumors.12 On the other hand, protein
tyrosine phosphatase 1 B (PTP1B) has been proved to be a
novel target for diabetes and obesity since it plays an
important role in the negative regulation of insulin signaling
pathway. Inhibition of PTP1B’s activity could improve the
sensitivity of insulin signaling.13 From the screening, it was
found that H-pyrazolo[5,1-a]isoquinolines showed promising
results for the above assays. Among the compounds, H-pyra-
zolo[5,1-a]isoquinoline 3t was the most effective one
(CDC25B, IC50 2.19 µg/mL; TC-PTP, IC50 4.50 µg/mL;
PTP1B, IC50 1.75 µg/mL. (For details, please see the
Supporting Information.)
In summary, we have described a novel and highly
efficient route for the generation of diverse H-pyrazolo[5,
1-a]isoquinolines via a multicomponent reaction of 2-alky-
nylbenzaldehyde, sulfonohydrazide, alcohol, and R,ꢀ-
unsaturated aldehyde or ketone. The advantages of this
method include good substrate generality, mild conditions,
and easy availability of starting materials. Subsequent
biological assays show that some of these compounds display
promising activities for inhibition of CDC25B, TC-PTP, and
PTP1B. The focused library of H-pyrazolo[5,1-a]isoquinoline
is constructed currently.
Acknowledgment. We thank Prof. Jia Li (The National
Center for Drug Screening, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences) for providing the
biological assays. Financial support from the National Natural
Science Foundation of China (20972030) is gratefully
acknowledged.
Scheme 3. Multicomponent Reaction of 2-Alkynylbenzaldehyde,
Sulfonohydrazide, Ethanol, and R,ꢀ-Unsaturated Aldehyde
Supporting Information Available: Experimental pro-
cedures, characterization data, biological screening results,
1H and 13C NMR spectra of compounds 3, and X-ray crystal
data of compound 3a. This material is available free of charge
via the Internet at http://pubs.acs.org.
of 2-(2-cyclopropylethynyl)benzaldehyde 1a, 4-methylben-
zenesulfonohydrazide, ethanol, and (E)-3-(4-methoxyphe-
nyl)acrylaldehyde 2c. 2-Alkynylbenzaldehyde 1g reacted
with (E)-3-(4-methylphenyl)acrylaldehyde 2e, 4-methylben-
zenesulfonohydrazide, and ethanol leading to the expected
product 3z in 33% yield.
OL101988Q
(12) For a review, see: Cheng, J.; Fu, Q.; Wu, G. Chin. J. Cancer PreV.
Treat. 2007, 14, 872.
(13) For selected examples, see: (a) Frangioni, J. V.; Beahm, P. H.;
Shifrin, V.; Jost, C. A.; Neel, B. G. Cell 1992, 68, 545. (b) Woodford-
Thomas, T. A.; Rhodes, J. D.; Dixon, J. E. J. Cell Biol. 1992, 117, 401. (c)
Haj, F. G.; Verveer, P. J.; Squire, A.; Neel, B. G.; Bastiaens, P. I. Science
2002, 295, 1708.
As described above, the generated H-pyrazolo[5,1-a]iso-
quinoline, which incorporated both isoquinoline and pyra-
Org. Lett., Vol. 12, No. 21, 2010
4859