Multicomponent synthesis of 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b] pyridine-1,6-diones: A novel heterocyclic scaffold with antibacterial activity

Article abstract of DOI:10.1016/j.tetlet.2011.10.012

A multicomponent reaction of 3-aminopyrazol-5-ones with substituted salicylic aldehydes and acetylacetic ester leading to the formation of novel 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones was discovered. The elucidation of the reaction s

Full text of DOI:10.1016/j.tetlet.2011.10.012

Tetrahedron Letters 52 (2011) 6643–6645
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Multicomponent synthesis of
2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones: a novel
heterocyclic scaffold with antibacterial activity
Liliya V. Frolova a, Indranil Malik b, Pavel Y. Uglinskii c, Snezna Rogelj b, Alexander Kornienko a,
Igor V. Magedov a,
⇑
a Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA
b Department of Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA
c Department of Organic Chemistry, Timiryazev Agriculture Academy, Moscow 127550, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A multicomponent reaction of 3-aminopyrazol-5-ones with substituted salicylic aldehydes and acetyl-
acetic ester leading to the formation of novel 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,
6-diones was discovered. The elucidation of the reaction scope revealed that 5-aminopyrazoles, 3-
amino-1,2,4-triazoles and 6-aminouracil could be used as the heterocyclic amine component. Selected
heterocyclic products were found to possess notable antibacterial activities.
Received 6 September 2011
Revised 3 October 2011
Accepted 4 October 2011
Available online 12 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
MCR
Aminopyrazole
Antibacterial activity
Benzopyranopyridines
Multicomponent reactions (MCRs) are a powerful synthetic
tool. In this approach, three or more reactants are combined
together in a single reaction flask to generate a product incorporat-
ing most of the atoms contained in the starting materials. MCRs
have been widely exploited in combinatorial and medicinal chem-
istry and they are particularly useful for the preparation of poly-
condensed heterocyclic systems.1
Specifically, we found that combining 3-aminopyrazol-5-ones
1a–c with substituted salicylic aldehydes 2a–h and acetylacetic
ester (3) leads to the formation of 2,3-dihydrochromeno[4,3-d]pyr-
azolo[3,4-b]pyridin-1,6-diones 4a–o (Scheme 1). Generally good
yields of these polyheterocyclic compounds are obtained when
mixtures of the three starting components and one drop of piper-
idine are refluxed in acetic acid for 3 h. This three-component pro-
cess works well in any tested combination of substituted salicylic
aldehydes 2 and 3-aminopyrazol-5-ones 1. The desired products
precipitate upon cooling of the reaction mixtures and a simple fil-
tration provides analytically pure material (>95%).26
In this connection, hetero-fused benzopyranopyridines are a
poorly studied class of polycondensed heterocycles (Fig. 1a). Only
four types of scaffolds (A and C–E) have been reported in the liter-
ature out of the six possible molecular frameworks (A–F) and the
synthetic approaches used by researchers to access these struc-
tures have invariably involved multistep sequences.2–13 Impor-
tantly, compounds based on these heterocyclic systems have
We propose that the mechanistic route for this transformation
involves an in situ formation of 3-acetylcoumarins 5 and their sub-
sequent condensation with aminopyrazolones
1 (Scheme 2).
been reported to possess anti-inflammatory,2 antibacterial2,10
,
Indeed, we demonstrated that this process can be conducted step-
wise by condensing salicylic aldehyde (2a) with acetylacetic ester
(3) and isolating 3-acetylcoumarin (5a) in a quantitative yield
(Scheme 2a). Compound 5a was further reacted with 3-amino-
1H-pyrazol-5(4H)-one (1a) under the same reaction conditions
and gave a comparable yield of polyheterocycle 4a (Scheme 2b).
To investigate the scope of this process with respect to the acet-
ylacetic ester component, we attempted to replace it with ethyl
benzoylacetate. However, the reaction was unsuccessful in this
case, possibly due to the change in electronic and steric environ-
ment of the ketone carbonyl. On the other hand, the replacement
and antifungal10 activities (Fig. 1b). As part of our efforts aimed
at the discovery of MCRs to synthesize compounds with anti-can-
cer and -bacterial activities,14–25 we discovered a new approach to
access the type C molecular framework. Herein, we describe this
synthetic finding as well as the preliminary biological evaluation
of compounds synthesized using this new method.
⇑
Corresponding author. Tel.: +1 575 835 6886; fax: +1 575 835 5364.
E-mail address: imagedov@nmt.edu (I.V. Magedov).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.012

6644
L. V. Frolova et al. / Tetrahedron Letters 52 (2011) 6643–6645
(a)
(b)
Het
Het
Het
N
Het
N
O
N
N
Het
Het
N
O
N
O
A
O
O
O
B
O
O
C
O
F
O
O
O
D
E
NH
NH
O
N
O
N
O
O
O
anti-inflammatory
antibacterial
antifungal
antibacterial
antimycobacterial
antifungal
Figure 1. (a) Six possible types of hetero-fused benzopyranopyridines (b) and representative compounds with biological activities.
R1
R2
3
NH
1 N2
R3
OH
HO
O
O
11
4
piperidine
R2
N
+
CO2Et
+
N
5
R1
NH2
AcOH, reflux
3 h
N
10
O
3
6
2a-h
2a R2 = R3 = H
9
1a-c
O
O
8
7
R3
1a R1 = H
4a-o
2b R2 = 5-Br, R3 = H
1b R1 = Ph
2c R2 = 3-Cl, R3 = 5-Cl
2d R2 = 5-NO2, R3 = H
2e R2 = 5-Cl, R3 = H
2f R2 = 5-Me, R3 = H
2g R2 = 3-OMe, R3 = H
2h R2 = 4-OH, R3 = H
1c R1 = 2,5-di-Cl-Ph
4a R1 = R2 = R3 = H
60%
67%
77%
73%
63%
53%
70%
74%
82%
79%
76%
71%
64%
74%
66%
4b R1 = R3 = H, R2 = 10-Br
4c R1 = R3 = H, R2 = 10-NO2
4d R1 = R3 = H, R2 = 10-Cl
4e R1 = R3 = H, R2 = 8-MeO
4f R1 = R3 = H, R2 = 9-OH
4g R1 = Ph, R2 = R3 = H
4h R1 = Ph, R2 = 10-Br, R3 = H
4i R1 = Ph, R2 = 8-Cl, R3 = 10-Cl
4j R1 = Ph, R2 = 10-NO2, R3 = H
4k R1 = Ph, R2 = 10-Cl, R3 = H
4l R1 = Ph, R2 = 10-Me, R3 = H
4m R1 = Ph, R2 = 8-MeO, R3 = H
4n R1 = 2,5-di-Cl-Ph, R2 = 10-Me, R3 = H
4o R1 = 2,5-di-Cl-Ph, R2 = 8-MeO, R3 = H
Scheme 1. MCR synthesis of 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridin-1,6-diones 4a–o.
O
(a)
piperidine
O
OH
+
CO2Et
O
O
O
2a
3
5a (96%)
HN
O
NH
(b)
O
O
HO
HN
N
O
AcOH,
reflux, 3h
+
NH2
N
O
5a
O
1a
4a (67%)
Scheme 2. 3-Acetylcoumarins as intermediates in the discovered MCR.
of the aminoheterocyclic component was much more forgiving.
Thus, we explored the corresponding reactions of 5-amino-1-phe-
nyl-3-methylpyrazole (6), 3-amino-1,2,4-triazole (7), and 6-
aminouracil (8, Scheme 3). The desired polyheterocycles 9–11
were obtained in acceptable yields, indicating the potential of this
MCR to be used as a general method to access polyheterocyclic
scaffolds C (see Fig. 1).27
The initial evaluation of the synthesized polyheterocycles for
antimicrobial activities revealed significant antibacterial proper-
ties associated with several analogs specifically against Gram-(+)

L. V. Frolova et al. / Tetrahedron Letters 52 (2011) 6643–6645
6645
(a)
H2N
Ph
N
N
N
O
piperidine
+
+
CO2Et
OH
2a
N
Ph
N
AcOH, reflux
3 h
O
3
6
O
O
9 (65%)
(b)
N
H2N
HN
N
N
O
N
piperidine
N
O
+
+
CO2Et
OH
2a
N
AcOH, reflux
6 h
O
3
7
O
10 (53%)
(c)
O
O
H
N
NH2
HN
NH
O
piperidine
+
HN
+
CO2Et
OH
2a
O
N
AcOH, reflux
12 h
O
8
O
3
O
O
11 (57%)
Scheme 3. MCR synthesis of polyheterocycles 9–11.
19. Magedov, I. V.; Manpadi, M.; Evdokimov, N. M.; Elias, E. M.; Rozhkova, E.;
Ogasawara, M. A.; Bettale, J. D.; Przeval’skii, N. M.; Rogelj, S.; Kornienko, A. Bioorg.
Med. Chem. Lett. 2007, 17, 3872.
20. Manpadi, M.; Uglinskii, P. Y.; Rastogi, S. K.; Cotter, K. M.; Wong, Y.-S. C.;
Anderson, L. A.; Ortega, A. J.; Van slambrouck, S.; Steelant, W. F. A.; Rogelj, S.;
Tongwa, P.; Antipin, M. Y.; Magedov, I. V.; Kornienko, A. Org. Biomol. Chem.
2007, 5, 3865.
21. Magedov, I. V.; Luchetti, G.; Evdokimov, N. M.; Manpadi, M.; Steelant, W. F. A.;
Van slambrouck, S.; Tongwa, P.; Antipin, M. Yu.; Kornienko, A. Bioorg. Med.
Chem Lett. 2008, 18, 1392.
22. Magedov, I. V.; Manpadi, M.; Ogasawara, M. A.; Dhawan, A. S.; Rogelj, S.; Van
slambrouck, S.; Steelant, W. F. A.; Evdokimov, N. M.; Uglinskii, P. Y.; Elias, E. M.;
Knee, E. J.; Tongwa, P.; Antipin, M. Y.; Kornienko, A. J. Med. Chem. 2008, 51,
2561.
strains. Thus, compounds 4i and 4o inhibited the growth of Staph-
ylococcus epidermidis with the MIC values of 6.3 and 25 M, respec-
tively. Furthermore, heterocycle 4i was also effective against
methicillin-resistant Staphylococcus aureus (MRSA), inhibiting the
growth of this clinically important nosocomial pathogen with an
MIC value of 25 lM. Further exploration of the MCR scope and
antimicrobial activities associated with these novel heterocyclic
structures are underway and will be reported in due course.
l
Acknowledgment
23. Frolova, L. V.; Evdokimov, N. M.; Hayden, K.; Malik, I.; Rogelj, S.; Kornienko, A.;
Magedov, I. V. Org. Lett. 2011, 13, 1118.
24. Evdokimov, N. M.; Van slambrouck, S.; Heffeter, P.; Tu, L.; Le Calve, B.; Lamoral-
Theys, D.; Hooten, C. J.; Uglinskii, P. Y.; Rogelj, S.; Kiss, R.; Steelant, W. F. A.;
Berger, W.; Bologa, C. J.; Yang, J. J.; Kornienko, A.; Magedov, I. V. J. Med. Chem.
2011, 54, 2012.
US National Institutes of Health (Grants RR-16480 and CA-
99957) are gratefully acknowledged for financial support of this
work.
References and notes
25. Magedov, I. V.; Frolova, L.; Manpadi, M.; Bhoga, U. D.; Tang, H.; Evdokimov, N.
M.; George, O.; Georgiou, K. H.; Renner, S.; Getlik, M.; Kinnibrugh, T. L.;
Fernandes, M. A.; Van slambrouck, S.; Steelant, W. F. A.; Shuster, C. B.; Rogelj,
S.; van Otterlo, W. A. L.; Kornienko, A. J. Med. Chem. 2011, 54, 4234.
26. Synthetic procedure (4a–o, 9–11): To a mixture of acetylacetic ester, substituted
salicylic aldehyde (2a–h) and aminoheterocycle (1a–c, 6–8) was added 1 drop of
piperidine. The mixture was stirred for 15 min after which time acetic acid
(5 mL) was added and the reaction mixture was refluxed for 3–12 h. The desired
products precipitate upon cooling of the reaction mixtures, and a simple
filtration and washing with ethanol provides analytically pure material (>95%).
Selected characterization data: 4a: 60%; 1H NMR (DMSO-d6, 373 K) d 9.95 (d,
J = 7.98 Hz, 1H), 7.67 (t, J = 7.14 Hz, 1H), 7.42–7.36 (m, 2H), 2.96 (s, 3H); 13C NMR
(DMSO-d6, 373 K) d 164.9, 157.3, 152.9, 133.9, 131.9, 124.6, 117.6, 117.1, 113.7,
28.1; HRMS m/z (ESI) calcd for C14H9N3O3À HÀ 266.0566, found 266.0562. 9:
65%; 1H NMR (DMSO-d6, 373 K) d 8.33 (d, J = 7.68 Hz, 1H), 8.19 (d, J = 7.17 Hz,
2H), 7.73 (t, J = 7.24 Hz, 1H), 7.59–7.30 (m, 6H), 3.36 (s, 3H), 3.02 (s, 3H); 13C NMR
(DMSO-d6, 373 K) d 162.9, 159.8, 152.9, 143.8, 139.2, 133.9, 130.4, 129.8, 129.6,
127.3, 124.8, 122.5, 122.2 117.6, 117.6, 111.2, 28.0, 19.3; HRMS m/z (ESI) calcd
for C21H15N3O2+ Na+ 364.1062, found 364.1067. 10: 53%; 1H NMR (DMSO-d6,
373 K) d 9.79 (d, J = 8.25 Hz, 1H), 8.94 (s, 1H), 7.93 (t, J = 7.68 Hz, 1H), d 7.65 (d,
J = 8.25 Hz, 1H), 7.59 (d, J = 7.98 Hz, 1H), 3.11 (s, 3H); 13C NMR (DMSO-d6, 373 K)
d 167.6, 158.3, 156.2, 154.7, 136.5, 130.6, 126.0, 118.0, 117.6, 112.3, 106.0, 27.9;
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H
NMR (DMSO-d6, 323 K) d 10.27 (bs, 1H), 9.87 (bs, 1H) 8.17 (d, J = 8.22 Hz, 1H),
7.65 (t, J = 8.22 Hz, 1H), 7.37 (d, J = 8.22 Hz, 1H), 7.27 (t, J = 8.25 Hz, 1H), 3.05 (s,
3H); 13C NMR (DMSO-d6, 323 K) d 169.1, 166.3, 162.4, 159.1, 156.2, 152.9, 150.7,
134.4, 132.8, 123.6, 117.0, 116.1, 113.1, 103.2, 27.7; HRMS m/z (ESI) calcd for
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C
15H10N3O4 + H+ 296.0671, found 296.0670.
27. As our work was in progress, a similar reaction between salicylic aldehyde,
acetylacetic ester, and 3-methyl-5-aminopyrazole leading to the formation 1,4-
dihydropyridine analogs of 9, appeared in the literature: Svetlik, J.; Veizerova, L.;
Mayer, T. U.; Catarinella, M. Bioorg. Med. Chem. Lett. 2010, 20, 4073.