Convenient one-step synthesis of a medicinally relevant benzopyranopyridine system

Article abstract of DOI:10.1016/j.tetlet.2006.10.110

Benzopyrano[2,3-b]pyridine is an important privileged medicinal scaffold. A three-component reaction of salicylaldehydes, thiols and 2 equiv of malononitrile that leads to the formation of a series of compounds incorporating 2,4-diamino-3-cyano-5-sulfanyl

Full text of DOI:10.1016/j.tetlet.2006.10.110

Tetrahedron Letters 47 (2006) 9309–9312
Convenient one-step synthesis of a medicinally relevant
benzopyranopyridine system
Nikolai M. Evdokimov,a Artem S. Kireev,b Andrey A. Yakovenko,c
b,
Mikhail Yu. Antipin,c,d Igor V. Magedova,e, and Alexander Kornienko
*
*
aDepartment of Organic Chemistry, Timiryazev Agriculture Academy, Moscow 127550, Russia
bDepartment of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, USA
cDepartment of Natural Sciences, New Mexico Highlands University, Las Vegas, New Mexico 87701, USA
dInstitute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia
eIntelbioscan Ltd., Timiryazevsky Proesd 2, Moscow 127550, Russia
Received 9 October 2006; revised 18 October 2006; accepted 19 October 2006
Available online 9 November 2006
Abstract—Benzopyrano[2,3-b]pyridine is an important privileged medicinal scaffold. A three-component reaction of salicylalde-
hydes, thiols and 2 equiv of malononitrile that leads to the formation of a series of compounds incorporating 2,4-diamino-3-
cyano-5-sulfanylbenzopyrano[2,3-b]pyridine framework is described. A proposed mechanism with the supporting experimental data
is presented.
Ó 2006 Elsevier Ltd. All rights reserved.
The rapid assembly of molecular diversity utilizing
multi-component reactions has received a great deal of
attention, most notably for the construction of hetero-
cyclic ‘drug-like’ libraries.1 These methodologies are of
particularly great utility when they lead to the formation
of ‘privileged medicinal scaffolds,’ defined as molecular
frameworks serving as the basis for the generation of
ligands for functionally and structurally discreet bio-
logical receptors.2 Such chemistry greatly facilitates
the development of pharmaceutical agents for diverse
applications.
Me
O
Me
CO2H
NH2
Me
HO2C
O
N
O
N
amlexanox
anti-allergic
pranoprofen
NSAID
SR NH2
CN
NH2
X
O
N
A
Benzopyrano[2,3-b]pyridine scaffold is of a significant
medicinal relevance. The examples of approved thera-
peutic agents incorporating this molecular framework
include amlexanox and pranoprofen (Fig. 1).
NH2
SR
CN
NH2
X
X
O
N
O
N
B
C
gastric
antisecretory agents
In addition, many of these compounds possess anti-pro-
liferative,3 cancer chemopreventive,4 anti-bacterial
(including anti-tubercular),5 anti-myopic,6 anti-histami-
nic,7 hypotensive,8 anti-rheumatic9 and anti-asthmatic
inhibitors of
TNFα production
Figure 1.
activities.10 Many synthetic pathways to such medicinal
libraries have been reported.11 However, the diverse
pharmacological properties associated with benzopyr-
anopyridines warrant the development of novel pro-
cesses allowing the synthesis of previously inaccessible
Keywords: Multicomponent reaction; Privileged medicinal scaffold;
Drug-like heterocycle.
*
Corresponding authors. Tel.: +1 505 835 5884; fax: +1 505 835 5364
(A.K.); e-mail addresses: intelbioscan@mtu-net.ru; akornien@
nmt.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.110

9310
N. M. Evdokimov et al. / Tetrahedron Letters 47 (2006) 9309–9312
O
Z
CN
CN
CN
RSH
CN
H
X
Et3N, EtOH, reflux
Z = OH
Z = H
X
X
SR NH2
CN
OH
X
NC
CN
NC
CN
SR
O
N
NH2
SPh NH2
H2N
N
SR
A
H2N
N
Me
CN
D
E
O
N
NH2
Figure 2.
4
analogues for biological evaluation. In this letter, we de-
scribe a multi-component strategy for the rapid prepara-
tion of library A (Fig. 1). Examples of structurally
relevant biologically active compounds are benzopyr-
anopyridines B, found to inhibit mitogen-activated pro-
tein kinase-activated protein kinase 2 and attenuate the
production of pro-inflammatory TNFa,12 and C, re-
ported to inhibit histamine-stimulated gastric acid secre-
tion in animals.13
Figure 3.
The reaction works well for all salicylaldehyde and thiol
combinations tested. The products precipitate from
refluxing ethanolic solutions and are isolated by simple
filtration. The yields of recrystallized benzopyranopyri-
dines are given in Table 1.16,17
Our proposed mechanistic interpretation of the diver-
gence in reaction paths for o,o-unsubstituted aldehydes,
leading to formation of pyridines D, and salicylic alde-
hydes, resulting in benzopyranopyridines A, is shown
in Figure 4.
We previously disclosed a one-step three-component
synthesis of 3,5-dicyanopyridines D starting from vari-
ous aldehydes, thiols and malononitrile (Fig. 2).14
In an attempt to extend the method for the preparation
of pyridines E we employed salicylic aldehydes and ob-
tained a library of compounds whose elemental analysis
data and the NMR spectra were inconsistent with the
expected structures. The X-ray analysis showed these
Base-catalyzed Michael addition of thiols to Knoevena-
gel adducts F, produced from o,o-unsubstituted alde-
hydes, to form G is reversible and non-productive.
However, the formal assembly process I leads irrevers-
ibly to the formation of dihydropyridines K, thermody-
namically stabilized by the push–pull interactions of the
compounds to have
a benzopyrano[2,3-b]pyridine
framework A (Fig. 3).15
Table 1. One-step synthesis of benzopyranopyridines
RS
NH2
N
R3
R2
CHO
OH
R3
R2
CN
Et3N
EtOH,
reflux
CN
CN
2
RSH
O
NH2
R1
R1
1-11
Benzopyranopyridine
R1
R2
H
R3
H
R
Yield (%)
86
1
H
H
Ph
2
H
H
H
Me
Me
55
O
3
4
5
H
H
H
H
H
H
PhCH2
Ph
PhCH2
51
69
52
6
H
H
OMe
H
H
Me
63
O
Mes
Ph
Ph
Ph
7
8
H
H
Et2N
OH
H
Me
H
H
H
NO2
56
57
63
63
73
9
10
11
H
H
4-F–Ph

N. M. Evdokimov et al. / Tetrahedron Letters 47 (2006) 9309–9312
9311
O
CN
CN
Ar
H
base
CN
SR
Ar
X
CN
CN
X
X
CN
NH
CN
NC
N
CN
SR
RSH
base
Ar =
RSH
base
OH
O
Ar
CN
O
M
NH2
N
I
L
F
CN
CN
base
RSH base
Ar
SR
NC
CN
SR
N
C
X
RS
Ar
CN
CN
CN
HN
N
O
NH2
N
G
J
N
Ar
SR NH
SR NH2
Ar
X
NC
CN
SR
X
CN
NH
CN
NC
H2N
CN
SR
[O]
H2N
N
H
K
O
N
O
N
NH2
N
D
H
A
O
Figure 4.
donor (positions 2 and 6) and acceptor (positions 3 and
5) substituents. Oxidative aromatization then affords
pyridines D. In contrast, Knoevenagel intermediates F,
produced from salicylaldehydes, undergo intramolecular
cyclization to give powerful Michael acceptors L that
react with strongly nucleophilic thiols to form thermo-
dynamically stable chromenes M irreversibly. Lastly,
the addition of another equivalent of malononitrile
results in benzopyranopyridines A.
Further exploration of this chemistry and biological
testing of the synthesized benzopyranopyridines are in
progress and will be reported in due course.
Acknowledgements
A.K. thanks the US National Institutes of Health (CA-
99957 and RR-16480) for financial support of this work.
A.A.Y. and M.Yu.A. are grateful to NSF/DMR (Grant
0420863) for the acquisition of X-ray single crystal dif-
fractometer and to the Distributed Nanomaterials Char-
acterization Network in the framework of New Mexico
NSF EPSCoR Nanoscience initiative.
In support of the proposed mechanism we obtained
experimental evidence for each of the key steps in Figure
4. Thus, o-hydroxybenzaldehyde reacts with 1 equiv of
malononitrile to form iminochromene 12 in a 64% iso-
lated yield after recrystallization (Fig. 5). This com-
pound undergoes an addition with thiophenol to
afford phenylsulfanylchromene 13 in a quantitative
yield. Finally, when 13 is treated under the same reac-
tion conditions with another equivalent of malono-
References and notes
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1
Figure 5.

9312
N. M. Evdokimov et al. / Tetrahedron Letters 47 (2006) 9309–9312
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mixture of a selected salicylaldehyde (1.5 mmol), malono-
nitrile (3 mmol) and a desired thiol (1.5 mmol) in 7 mL of
anhydrous ethanol was added Et3N (0.1 mmol) dropwise
at room temperature. The resulting mixture was refluxed
for 3–3.5 h and then allowed to cool to room temperature.
The formed precipitate was isolated by filtration. The
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crystallization of the product. The formed crystals were
isolated by filtration to yield a corresponding pure
benzopyranopyridine (1–11).
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17. Selected characterization data: 4: 69%; mp 275–276 °C
(DMF); 1H NMR (DMSO-d6) d 2.24 (s, 3H), 5.69 (s, 1H),
6.32 (br s, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.78 (br s, 2H),
6.83 (dd, J = 1.3, 7.3 Hz, 2H), 6.91 (d, J = 1.5 Hz, 1H),
7.01 (dd, J = 1.5, 8.2 Hz, 1H), 7.13 (t, J = 7.3 Hz, 2H),
7.28 (dd, J = 1.2, 7.3 Hz, 1H); 13C NMR (DMSO-d6) d
160.2, 160.0, 156.9, 149.2, 136.6, 132.9, 131.2, 129.5, 129.4,
129.2, 129.0, 128.6, 121.8, 116.9, 116.0, 86.6, 70.6, 43.3,
20.7; IR (KBr) 3480, 3410, 3374, 3144, 2926, 2204, 1658,
1616, 1500, 1478, 1398, 1332, 1262, 1226, 1164, 1076, 1024,
900, 820, 780, 740, 692, 644, 532 cmÀ1. Anal. Calcd for
C20H16N4OS (360.442): C, 66.64; H, 4.48; N, 15.55; S,
8.89. Found: C, 66.51; H, 4.52; N, 15.68; S, 8.83.
Compound 6: 63%; mp 240–242 °C (DMF); 1H NMR
(DMSO-d6) d 2.31 (s, 3H), 3.50 (d, J = 14.0 Hz, 1H), 3.57
(d, J = 14.0 Hz, 1H), 5.43 (s, 1H), 6.02 (dd, J = 0.9,
3.0 Hz, 1H), 6.26 (d, J = 1.8 Hz, 1H), 6.39 (br s, 2H), 6.65
(br s, 2H), 6.98 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 1.8 Hz,
1H), 7.11 (dd, J = 1.8, 8.8 Hz, 1H), 7.41 (dd, J = 0.9,
1.8 Hz, 1H); 13C NMR (DMSO-d6) d 160.7, 160.3, 157.1,
151.2, 149.4, 142.7, 133.8, 129.7, 129.0, 116.9, 116.5, 111.0,
107.8, 87.1, 71.0, 25.9, 20.9; IR (KBr) 3458, 3350, 3240,
3160, 2918, 2200, 1628, 1606, 1575, 1498, 1472, 1398, 1332,
1262, 1226, 1155, 1008, 780, 745, 538 cmÀ1. Anal. Calcd
for C19H16N4O2S (364.431): C, 62.62; H, 4.43; N, 15.38; S,
8.80. Found: C, 62.45; H, 4.31; N, 15.52; S, 8.91.
Compound 8: 57%; mp 254–255 °C (DMF); 1H NMR
(DMSO-d6) d 3.72 (s, 3H), 5.74 (s, 1H), 6.30 (br s, 2H),
6.74 (dd, J = 1.4, 7.9 Hz, 1H), 6.80 (br s, 2H), 6.84 (dd,
J = 1.2, 7.3 Hz, 2H), 6.90 (dd, J = 1.4, 7.9 Hz, 1H), 7.01
(t, J = 7.9 Hz, 1H), 7.12 (t, J = 7.3 Hz, 2H), 7.28 (dt,
J = 1.2, 7.3 Hz, 1H); 13C NMR (DMSO-d6) d 160.3, 160.1,
156.9, 147.5, 141.3, 136.4, 131.3, 129.4, 128.8, 123.9, 123.0,
120.5, 117.1, 111.9, 86.7, 70.9, 56.5, 43.4; IR (KBr) 3452,
3340, 3272, 2866, 2208, 1656, 1630, 1606, 1590, 1486, 1408,
1350, 1270, 1220, 1172, 1116, 1096, 794, 778, 764, 748,
710 cmÀ1. Anal. Calcd for C20H16N4O2S (376.442): C,
63.81; H, 4.29; N, 14.89; S, 8.52. Found: C, 63.95; H 4.08;
N, 14.81; S, 8.63.
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15. Crystallographic data for compound 4: C20H16N4OS,
ꢀ
Mr = 360.43, triclinic space group P1, a = 7.3717(6),
˚
b = 9.5840(7), c = 12.8924(10) A, a = 103.820(2), b =
3
˚
92.975(2), c = 99.441(2)°, V = 868.55(12) A , Z = 2, T =
120(2) K, F(000) = 376, Dcalcd = 1.378 g cmÀ3
, hmax =
29.99°, 9671 reflections measured and 4882 unique
(Rint = 0.0190) reflections, full matrix least-squares refine-
ment on F2, R1 (obs) = 0.0494, and wR2 (all data) =
0.1037. Supplementary data in the form of CIFs have been
deposited with the Cambridge Crystallographic Data
Centre (CCDC 622796). Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].