Multicomponent approaches to 8-carboxylnaphthyl-functionalized pyrazolo[3,4-b]pyridine derivatives

Article abstract of DOI:10.1039/c1ob06624b

A simple and novel protocol for the efficient synthesis of a series of 8-carboxylnaphthyl functionalized pyrazolo[3,4-b]pyridine derivatives was developed through a one-pot, three-component reaction involving acenaphthylene-1,2-dione and 1H-pyrazol-5-amin

Full text of DOI:10.1039/c1ob06624b

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Multicomponent approaches to 8-carboxylnaphthyl-functionalized
pyrazolo[3,4-b]pyridine derivatives†
Yan Hao, Xiao-Ping Xu,* Tao Chen, Li-Li Zhao and Shun-Jun Ji*
Received 23rd September 2011, Accepted 15th November 2011
DOI: 10.1039/c1ob06624b
A simple and novel protocol for the efficient synthesis of
a series of 8-carboxylnaphthyl functionalized pyrazolo[3,4-
b]pyridine derivatives was developed through a one-pot,
three-component reaction involving acenaphthylene-1,2-
dione and 1H-pyrazol-5-amine in acetic acid medium. The
reaction represents the first facile conversion of acenaph-
thenequinone to naphthoic acid via C–C bond cleavage
without need for multi-step transformation.
plicable as potential multifunctional materials. Nevertheless, the
preparation of these compounds still remained unknown.
In recent years, much attention has been paid to the modification
and synthesis of the pyrazolo[3,4-b]pyridine scaffold for drug
discovery purposes.21 The main strategies for the construction
of pyrazolo[3,4-b]pyridines were focused on the three-component
reaction of 5-aminopyrazoles, aldehydes and appropriate cyclic
ketones by various methods.22 Because 8-formyl-1-naphthoic acid
is not readily available, functionalization at the 8-position of
naphthoic acid is often accessed by using acenaphthenequinone
as a precursor via multi-step transformation.23 Recently, we found
that three-component reaction of acenaphthylene-1,2-dione, 1H-
pyrazol-5-amines and ketones could be performed facilely in
acetic acid to provide the 8-carboxylnaphthyl-functionalized
pyrazolo[3,4-b]pyridine derivatives. To the best of our knowledge,
the reaction was the first synthesis of 8-heterocycle-functionalized
naphthoic acid in a one-pot, cascade manner. Herein, we report
these results.
Our studies commenced with the reaction of 3-(1-methyl-1H-
indol-3-yl)-3-oxopropanenitrile (1b), acenaphthylene-1,2-dione
(2) and 3-methyl-1-phenyl-1H-pyrazol-5-amine (3b) in HOAc
medium at 120 ◦C. In our previous work, three-component
reaction of 1b, 3b and isatin in HOAc/H2O solvent was found to
produce spirooxindole derivatives.24 Similar results were observed
as well by Shi et al. in the reaction of 2, 3b and 1,3-dicarbonyl
compounds.25 So, our initial attempt for the selected reaction
was to generate spiro-compound 4¢ (Scheme 1). However, unex-
pectedly, a new product different from 4¢ was obtained. All the
analytical data showed that the three reactants were all included
in the formation of final product, producing a novel naphthoic
acid functionalized with pyrazolo[3,4-b]pyridine, 4b (Scheme 1).
The definite structure of 4b was further confirmed by X-ray single
crystal analysis (Fig. 1).26 This surprising result is of value to us
not only because we are interested in the design of the new three-
component reaction27 but also because we were unable to find
examples of other methods allowing for such convenient synthesis
of pyrazolo[3,4-b]pyridines simultaneously containing naphthoic
acid and indole units in the related literature.
The pyrazolo[3,4-b]pyridine ring system1 is present in a number of
pharmaceutically important compounds targeted, for instance, to
inhibit (or potentially inhibit) glycogen synthase kinase-3 (GSK-
3),2 xanthine oxidases,3 cholesterol formation,4 A1 adenosine
receptors,5 phosphodiesterase 4 (PDE4) in immune and inflam-
matory cells,6 p38 as anti-inflammatory drugs,7 and to treat
Alzheimer’s disease, gastrointestinal diseases, anorexia nervosa,
drug and alcohol withdrawal symptoms, drug addiction and
infertility.8 Naphthoic acid is also a key motif which often occurs
in several biologically active natural products and pharmaceutical
compounds,9–13 and its derivatives have been reported to play
a vital role in the development of new drugs against several
human ailments and infectious diseases.14–17 Functionalization
of naphthoic acid at the 8-position with macrocycles such as
porphyrin exhibited interesting properties. Chang et al. disclosed
that Co(II) 1-naphthylporphyrin-substituted with a carboxyl group
at the 8-naphthyl position displayed significant enhancement in O2
affinity.18 Unmetallated trans-porphyrin bearing two 8-carboxyl-
functionalized naphthalene spacers represented a unique example
of a reversible, redox-controlled porphyrin-porphodimethane in-
terconversion via a sequential intramolecular ring opening and
closure reaction.19 In comparison to the case of macrocycles,
introduction of other heterocyclic systems into the 8-position
of naphthoic acid has rarely been investigated.20 Taking these
facts into account, we conceived that molecules bearing both
pyrazolo[3,4-b]pyridine and naphthoic acid units would be ap-
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chem-
istry, Chemical Engineering and Materials Science, Soochow University,
Suzhou215123, China. E-mail: xuxp@suda.edu.cn, chemjsj@suda.edu.cn;
Fax: +86 512 6588 0307; Tel: +86 512 6588 0307
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H and 13C NMR spectra of compounds
4. CCDC reference number 844424. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob06624b
Encouraged by the result, we next made an effort to optimize the
reaction conditions. It was found that in HOAc medium, lowering
the reaction temperature led to inhibition of the reaction and thus
a relatively poor yield of product (Table 1, entries 1–3). Other
protic solvents such as EtOH, H2O were examined as well under
refluxing condition. However, no desired reaction was observed
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Scheme 1 An unexpected formation of product 4b.
Table 1 Optimization of reaction conditionsa
Entry
Solventb
T/◦C
Time/h
Yield (%)c
1
AcOH
AcOH
AcOH
EtOH
H2O
EtOH
H2O
120
100
80
80
100
80
100
155
80
8
76
2
20
36
48
24
48
24
24
24
54
3
4
5
26
0
0
0
6d
7d
8d
9d
0
DMF
CH3CN
complex mixture
complex mixture
a Molar ratio 1b : 2 : 3b = 1 : 1 : 1. b 4 mL solvent was used. c Isolated
yield. d These reactions were carried out in the presence of 30 mol% p-
toluenesulfonic acid.
conditions, 3-methyl-1H-pyrazol-5-amine remained intact and
only condensation between 1 and 2 occurred. We supposed that
the lower electronic density of the pyrazole ring might result in its
weak nucleophilicity. Thus, 3-methylisoxazol-5-amine was selected
as an analog of 3 for further inspection; however, no promising
result was obtained under optimal conditions.
On the basis of the experiments, a possible mechanism was
proposed for the formation of 4 as shown in Scheme 2. First,
condensation of 1 and 2 occurred to generate the intermediate
A. Then, intermolecular Michael addition of 3 to A, followed
by an intramolecular nucleophilic cyclization via B, led to the
formation of C. After elimination of water, D was thus produced.
In the presence of an oxidant such as oxygen, D was oxidized and
converted to product 4.
After successful access to the indole containing pyrazolo[3,4-
b]pyridine-functionalized naphthoic acid, our curiosity was turned
to seeking substitutes for 1 for wider generality of the reaction.
It was fortunately found that a 1,3-dicarbonyl compound and
its analog were also proven to be good candidates for this
transformation. Two representative examples are listed in Scheme
3. The yields of desired products were higher than those with 1 as
reactant.
Fig. 1 X-Ray crystal structure of product 4b.
under the conditions (Table 1, entries 4–5). Then we turned our
attention to the use of Brønsted acid catalysis. When 30 mol% p-
toluenesulfonic acid was added to the reaction mixture in EtOH or
H2O, respectively, no expected reaction occurred (Table 1, entries
6–7). Aprotic solvents including DMF and acetonitrile were also
employed in the presence of 30 mol% p-toluenesulfonic acid, but
the reactions were messy which resulted in complex mixtures which
were impossible to separate into analytically pure products (Table
1, entries 8–9).
Having established the optimal conditions (120 ◦C, HOAc),
we subsequently investigated the substrate scope of the trans-
formation. As shown in Table 2, substituents such as methyl,
bromo, methoxycarbonyl, benzyl in the indole ring, and phenyl
and methyl in the pyrazole ring, were well tolerated in the reactions,
leading to the final products in satisfactory yields (up to 85%).
To our surprise, when 3-methyl-1H-pyrazol-5-amine (R3 = H),
one candidate in the compound 3 series, was introduced in the
reaction, no positive outcome was returned. Under the standard
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Table 2 Substrate scope studya
Entry
R1
R2
R3
Product
Yield (%)b
1
2
3
4
5
6
7
8
H
H
4-Me
5-Me
6-Me
7-Me
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
Bn
Bn
H
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Ph
Me
Ph
Me
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
72
76
62
70
75
72
76
71
78
70
73
85
80
82
75
70
H
9
5-Me
6-Me
7-Me
5-Br
5-Br
H
10
11
12
13
14
15
16
H
4-COOMe
a Molar ratio 1 : 2 : 3 = 1 : 1 : 1. b Isolated yield.
Scheme 2 A possible mechanism for the formation of 4.
In conclusion, we have developed a novel and efficient
approach to 8-carboxylnaphthyl-functionalized pyrazolo[3,4-
b]pyridine derivatives via a one-pot, three-component conden-
sation involving acenaphthylene-1,2-dione and 1H-pyrazol-5-
amine in HOAc medium. It was the first direct conversion of
acenaphthenequinone to a naphthoic acid fragment via C–C
bond cleavage without the need for multi-step transformation.
An overall study concerning the impact of structural and func-
tional motifs on the reaction is currently in progress in our
laboratory.
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11 J. Y. L. Chang, D. Zhao, D. L. Hughes and E. J. J. Grabowski,
Tetrahedron, 1993, 49, 5767–5776.
12 I. Rivero-Cruz, L. Acevedo, J. A. Guerrero, S. Martinez, R. Bye, R.
Pereda-Miranda, S. Franzblau, B. N. Timmermann and R. Mata, J.
Pharm. Pharmacol., 2005, 5, 1117–1126.
13 J. Pandey, M. Mishira, S. S. Bisht, A. Sharma and R. P. Tripathi,
Tetrahedron Lett., 2008, 49, 695–698.
14 J. A. Aikins, M. Haurez, J. R. Rizzo, J. P. Van Hoeck, W. Brione, J. P.
Kestemont, C. Stevens, X. Lemair, G. A. Stephenson, E. Marlot, M.
Forst and I. N. Houpis, J. Org. Chem., 2005, 70, 4695–4705.
15 D. P. Rotella, Z. Sun, Y. Zhu, J. Krupinski, R. Pongrac, L. Seliger,
D. Normandin and J. E. Macor, J. Med. Chem., 2000, 43, 5037–
5043.
16 G. Xu, T. L. Hartman, H. Wargo, J. A. Turpin, R. W. Buckheit and M.
Cushman, Bioorg. Med. Chem., 2002, 10, 283–290.
17 L. M. V. Tillekeratne, A. Sherette, P. Grossman, L. Hupe, D. Hupe
and R. A. Hudson, Bioorg. Med. Chem. Lett., 2001, 11, 2763–
2767.
18 C. K. Chang and M. P. Kondylis, J. Chem. Soc., Chem. Commun., 1986,
Scheme 3 Synthesis of 4q and 4r using 1,3-dicarbonyl compounds as
316–318.
19 M. Harmjanz, H. S. Gill and M. J. Scott, J. Am. Chem. Soc., 2000, 122,
10476–10477.
substrates.
20 (a) A. M. Kates, G. D. Tirzit and G. Y. Dubur, Chem. Heterocycl.
Compd., 1972, 8, 188–189; (b) M. Matschke, R. Beckert, L. Kubicova
and C. Biskup, Synthesis, 2008, 2957–2962.
Acknowledgements
21 For recent examples, see: (a) K. Bedjeguelal, R. Rabot, EI B. Kaloun,
P. Mayer, A. Marchand, N. Rahier, P. Schambel, H. Bienayme,
WO2011045344 A1, 2011; (b) H. A. Rajapakse, K. P. Moore, P.
G. Nantermet, J. M. Sanders, S. Parmentier-Batteur, R. J. Mark,
US20100113415 A1, 2010; (c) J. Dotson, T. Heffron, A. G. Olivero,
D. P. Sutherlin, S. Staben, S. Wang, B.-Y. Zhu, I. S. Chuckowree, A. J.
Folkes, N. C. Wan, WO2010059788 A1, 2010; (d) M. Tandon, S. M.
Ali, M. Ashwell, J. Wang, N. Namdev, J. Hill, D. Neil, C. Brassard, A.
Filikov, R. Palma, D. Vensel, WO2010078427 A1, 2010; (e) Z. Huang,
Y. Hu, Y. Zhou and D. Shi, ACS Comb. Sci., 2011, 13, 45–49; (f) P. K.
Sharma, K. Singh, S. Kumar, S. N. Dhawan, S. Lal, H. Ulbrich and
G. Dannhardt, Med. Chem. Res., 2011, 20, 239–244; (g) B. Jiang, Y.-P.
Liu and S.-J. Tu, Eur. J. Org. Chem., 2011, 3026–3035; (h) J. Quiroga, Y.
Diaz, B. Insuasty, R. Abonia, M. Nogueras and J. Cobo, Tetrahedron
Lett., 2010, 51, 2928–2930; (i) S. Lee and S. B. Park, Org. Lett., 2009,
11, 5214–5217; (j) X. Zhang, X. Li, X. Fan, X. Wang, J. Wang and G.
Qu, Aust. J. Chem., 2009, 62, 382–388; (k) Y.-L. Zhong, M. G. Lindale
and N. Yasuda, Tetrahedron Lett., 2009, 50, 2293–2297; (l) T. E. Ali,
Eur. J. Med. Chem., 2009, 44, 4385–4392.
22 (a) J. Quiroga, D. Mejia, B. Insuasty, R. Abonia, M. Nogueras, A.
Sanchez, J. Cobo and J. N. Low, Tetrahedron, 2001, 57, 6947–6953;
(b) J. Quiroga, A. Hormaza, B. Insuasty, C. Saitz and C. Jullian, J.
Heterocycl. Chem., 1998, 35, 575–578; (c) I. Drizin, R. J. Altenbach, S.
A. Buckner, K. L. Whiteaker, V. E. Scott, J. F. Darbyshire, V. Jayanti,
R. F. Henry, M. J. Coghlan, M. Gopalakrishnan and W. A. Carroll,
Bioorg. Med. Chem., 2004, 12, 1895–1904; (d) J. Quiroga, J. Portilla, H.
Serrano, R. Abonia, B. Insuasty, M. Nogueras and J. Cobo, Tetrahedron
Lett., 2007, 48, 1987–1990; (e) B. Jiang, X. Wang, F. Shi, S. J. Tu and G.
G. Li, Org. Biomol. Chem., 2011, 9, 4025–4028; (f) B. Jiang, G. Zhang,
N. Ma, F. Shi, S. J. Tu, P. Kaur and G. G. Li, Org. Biomol. Chem., 2011,
9, 3834–3838.
The work was partially supported by the National Natural Science
Foundation of China (No. 21042007, 21172162), Nature Science
Basic Research of Jiangsu Province for Higher Education (No.
10KJB150016), the Priority Academic Program Development of
Jiangsu Higher Education Institutions and Key Project in Science
and Technology Innovation Cultivation Program of Soochow
University.
Notes and References
1 G. L. Beutner, J. T. Kuethe, M. M. Kim and N. Yasuda, J. Org. Chem.,
2009, 74, 789–794.
2 5-Aryl-pyrazolo[3,4-b]pyridines: (a) J. Witherington, V. Bordas, S. L.
Garland, D. M. B. Hickey, R. J. Ife, J. Liddle, M. Saunders, D. G. Smith
and R. W. Ward, Bioorg. Med. Chem. Lett., 2003, 13, 1577–1580; (b) 6-
aryl-pyrazolo[3,4-b]pyridines: J. Witherington, V. Bordas, A. Gaiba, N.
S. Garton, A. Naylor, A. D. Rawlings, B. P. Slingsby, D. G. Smith, A. K.
Takle and R. W. Ward, Bioorg. Med. Chem. Lett., 2003, 13, 3055–3057.
6-Heteroaryl-pyrazolo[3,4-b]pyridines: (c) J. Witherington, V. Bordas,
A. Gaiba, N. S. Garton, A. Naylor, A. D. Rawlings, B. P. Slingsby, D.
G. Smith, A. K. Takle and R. W. Ward, Bioorg. Med. Chem. Lett., 2003,
13, 3059–3062.
3 B. Lynck, M. Khan, H. Teo and F. Pedrotti, Can. J. Chem., 1988, 66,
420–428.
4 Y. Fujikama, M. Suzuki, H. Iwasaki, M. Sakashita, M. Kitahara, EP
339358, 1989 [Chem. Abstr., 1990, 113, 23903].
5 F. Manetti, S. Schenone, F. Bondavalli, C. Brullo, O. Bruno, A. Ranise,
L. Mosti, G. Menozzi, P. Fossa, M. L. Trincavelli, C. Martini, A.
Martinelli, C. Tintori and M. Botta, J. Med. Chem., 2005, 48, 7172–
7185.
6 J. N. Hamblin, T. D. R. Angell, S. P. Ballantine, C. M. Cook, A.
W. J. Cooper, J. Dawson, C. J. Delves, P. S. Jones, M. Lindvall, F.
S. Lucas, C. J. Mitchell, M. Y. Neu, L. E. Ranshaw, Y. E. Solanke, D. O.
Somers and J. O. Wiseman, Bioorg. Med. Chem. Lett., 2008, 18, 4237–
4241.
23 (a) M. Harmjanz and M. J. Scott, Inorg. Chem., 2000, 39, 5428–5429;
(b) M. Harmjanz, H. S. Gill and M. J. Scott, J. Org. Chem., 2001, 66,
5347–5383; (c) M. Harmjanz and M. J. Scott, Chem. Commun., 2000,
397–398.
24 T. Chen, X.-P. Xu and S.-J. Ji, J. Comb. Chem., 2010, 12, 659–
663.
25 H. Chen and D. Q. Shi, J. Comb. Chem., 2010, 12, 571–576.
26 Crystallographic data for the structure of 4b·DMF reported in this
paper have been deposited at the Cambridge Crystallographic Data
Centre with No. CCDC 844424. Structural parameters for 4b·DMF:
data collection: Rigaku Mercury CCD area detector; crystal size: 0.60 ¥
0.50 ¥ 0.20 mm3; C37H30N6O3, Mr = 606.67, monoclinic, space group
7 L. Revesz, E. Blum, F. E. Di Padova, T. Buhl, R. Feifel, H. Gram,
P. Hiestand, U. Manning, U. Neumann and G. Rucklin, Bioorg. Med.
Chem. Lett., 2006, 16, 262–266.
8 Y. L. Chen, WO9534563 A1, 1995.
˚
P21/c, a = 11.3442(11), ◦b = 19.9830(18), c = 13.8952(13) A, a = 90.00,
9 (a) J. A. Lowe, US4891375, 1990; (b) S. P. Hollinshead, B. E. Huff,
WO9904778, 1999; (c) S. F. Barnett, D. C. Heimbrook, WO9910523,
1999; (d) C. Z. Ding, R. S. Bhide, WO9918951, 1999.
10 G. D. Hartman, M. S. Egberston, W. Halczenko, W. L. Laswell, M.
E. Duggan, R. L. Smith, A. M. Naylor, P. D. Manno, R. J. Lynch,
G. Zhang, C. T. Chang and R. J. Gould, J. Med. Chem., 1992, 35,
4640–4642.
3
-3
˚
b = 99.660(3), g = 90.00 , V = 3105.3(5) A , Z = 4, Dc = 1.298 g cm ,
R[I > 2s(I)] = 0.0789, wR[I > 2s(I)] = 0.1621.
27 (a) Z.-L. Shen, S.-J. Ji, S.-Y. Wang and X.-F. Zeng, Tetrahedron, 2005,
61, 10552–10558; (b) C. Sun, S.-J. Ji and Y. Liu, Tetrahedron Lett., 2007,
48, 8987–8989; (c) S.-L. Zhu, S.-J. Ji and Y. Zhang, Tetrahedron, 2007,
63, 9365–9372; (d) S.-L. Zhu, S.-J. Ji, X.-M. Su and Y. Liu, Tetrahedron
This journal is
The Royal Society of Chemistry 2012
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©

View Article Online
Lett., 2008, 49, 1777–1781; (e) S.-L. Zhu, S.-J. Ji and Y. Liu, Tetrahedron
Lett., 2008, 49, 2578–2582; (f) X.-J. Wu, R. Jiang, B. Wu, X.-M. Su,
X.-P. Xu and S.-J. Ji, Adv. Synth. Catal., 2009, 351, 3150–3156; (g) K.
Zhao, X.-P. Xu, S.-L. Zhu, D.-Q. Shi, Y. Zhang and S.-J. Ji, Synthesis,
2009, 2697–2708; (h) X.-J. Wu, X.-P. Xu, X.-M. Su, G. Chen, Y. Zhang
and S.-J. Ji, Eur. J. Org. Chem., 2009, 4963–4970; (i) Z.-L. Shen, X.-P.
Xu and S.-J. Ji, J. Org. Chem., 2010, 75, 1162–1167; (j) X. Zhu, X.-P.
Xu, C. Sun, H.-Y. Wang, K. Zhao and S.-J. Ji, J. Comb. Chem., 2010,
12, 822–828; (k) K. Zhao, S.-L. Zhu, D.-Q. Shi, Y. Zhang, X.-P. Xu
and S.-J. Ji, Synthesis, 2010, 1793–1803; (l) X.-J. Wu, R. Jiang, X.-P.
Xu, X.-M. Su, W.-H. Lu and S.-J. Ji, J. Comb. Chem., 2010, 12, 829–
835; (m) X. Zhu, X.-P. Xu, C. Sun, T. Chen, Z.-L. Shen and S.-J. Ji,
Tetrahedron, 2011, 67, 6375–6387; (n) T. Chen, X.-P. Xu, H.-F. Liu and
S.-J. Ji, Tetrahedron, 2011, 67, 5469–5476.
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