An efficient synthesis of 6-nitro-and 6-amino-3H-imidazo[4,5-b ]pyridines by cyclocondensation of 1-substituted 1H-imidazol-5-amines with 3-nitro-4H-chromen-4-one

Article abstract of DOI:10.1055/s-0030-1258538

The reaction of 3-nitro-4H-chromen-4-one with in situ generated 1-substituted 5-amino-1H-imidazoles affords a set of 1-substituted 6-nitro-3H-imidazo[4,5-b]pyridines which represent potential adenosine deaminase (ADA) inhibitors. Reduction of the nitro group results in the formation of the corresponding 6-amino-3H-imidazo[4,5-b]pyridines. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258538

LETTER
2299
An Efficient Synthesis of 6-Nitro- and 6-Amino-3H-imidazo[4,5-b]pyridines
by Cyclocondensation of 1-Substituted 1H-Imidazol-5-amines with
3-Nitro-4H-chromen-4-one
S
ynthesis of 6-Nitr
m
o- and 6-Amino-3
H
y
-imidazo[4,5
t
-
b
]pyr
r
idines o Ostrovskyi,a Viktor O. Iaroshenko,*a,b Andranik Petrosyan,a Sergii Dudkin,a Iftikhar Ali,a
Alexander Villinger,a Andrei Tolmachev,b,c Peter Langer*a,d
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: viktor.iaroshenko@uni-rostock.de; E-mail: iva108@googlemail.com; E-mail:
peter.langer@uni-rostock.de
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
b
c
‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kyiv, Ukraine
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
d
Received 11 May 2010
state of the enzyme activity.14 Pentostatin (I), coformycin
and their analogues represent ADA transition-state analo-
gous inhibitors which show a strong, nearly irreversible
interaction with the receptor15 (Scheme 1). Pyrimidine nu-
Abstract: The reaction of 3-nitro-4H-chromen-4-one with in situ
generated 1-substituted 5-amino-1H-imidazoles affords a set of 1-
substituted 6-nitro-3H-imidazo[4,5-b]pyridines which represent
potential adenosine deaminase (ADA) inhibitors. Reduction of the
nitro group results in the formation of the corresponding 6-amino- cleosides II, III, containing a tetrahedral carbon or phos-
3H-imidazo[4,5-b]pyridines.
phorus atom instead of carbon atom C(4), are potent
inhibitors of cytidine deaminase (CDA,16 Scheme 1).
Key words: cyclization, chromones, N-heterocycles, imidazoles,
purine isosteres
Zebularine (pyrimidin-2-one ribonucleoside) binds in a
hydrated form (zebularine 3,4-dihydrate II) to the active
site of the enzyme.16a
Imidazo[4,5-b]pyridines (1-desazapurines) constitute an
important class of heterocyclic compounds which exhibit
a wide range of pharmacological properties.1 Some of the
1-desazapurines are potential phosphodiesterase inhibi-
tors,2 GPR4 receptor antagonists,3a or inhibitors of aurora
kinase.3b,c
H
OH
NH
OH
H
OH
N
N
HN
N
O
NH
O
O
N
R
N
O
HO
HO
In the recent two decades, 1-desazapurines became one of
the most important scaffolds for the design and synthesis
of adenosine deaminase (ADA) inhibitors. Adenosine
deaminase (adenosine aminohydrolase, ADA) and adeny-
late deaminase (5¢-adenylic acid deaminase, AMP deami-
nase, AMPDA) are metalloenzymes which are involved in
the purine salvage metabolic pathway and catalyze the
deamination of adenosine and 5¢-phosphate adenosine
(adenylic acid, AMP) to the corresponding inosines.4
ADA enzymes play a key role in the purine de novo bio-
synthesis.5–8 ADA enzymes became important targets for
drug design, since it was found that disorders of the ADA
function impairs the action of the human immune system.
This results in severe combined immunodeficiency
(SCID), characterized by severe T-lymphocyte dysfunc-
tion and agammaglobulinemia.9 Furthermore, ADA en-
zyme abnormalities have been reported also in acquired
immunodeficiency syndrome (AIDS),10 in tuberculosis,11
in Parkinson’s disease,12a in viral hepatitis,12b in some leu-
kemia diseases,13 and in many other diseases including
cancer.13
HO
OH
HO
II
III
tetrahydrouridine
(THU, Ki = 10–7 M)
ZEB 3,4-dehydrate
I
pentostatin
HO
H
N
N
N
N
NH
H2O
N
O
N
N
in vivo
O
HO
HO
HO
OH
HO
OH
IV
nebularine
V
Scheme 1 Potent ADA and CDA inhibitors
Recently, it has been demonstrated that purine-type nucle-
osides and nucleotides, which are able to undergo cova-
lent hydration in the aglycone ring system, are potent
inhibitors of the enzymes adenosine deaminase (ADA)
and AMP deaminase, respectively. Commercially avail-
able drug nebularine (IV) exhibits a strong anticancer ac-
tivity and represents another potent ADA inhibitor.17a The
correspondent 5¢-monophosphate is a selective AMPDA
inhibitor.17b The mechanism of action is mainly based on
enzyme-catalyzed stereospecific addition of a water mol-
ecule or hydroxide ion, in the presence of a Zn2+ ion, to the
One popular strategy in drug design to achieve the best in-
hibition of a current enzyme is to mimic the transition
SYNLETT 2010, No. 15, pp 2299–2303
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.07.2010
DOI: 10.1055/s-0030-1258538; Art ID: G12910ST
© Georg Thieme Verlag Stuttgart · New York

2300
D. Ostrovskyi et al.
LETTER
C(6) position of IV to give 6-hydroxy-1,6-dihydropurine venient synthetic approach to 6-nitro-3H-imidazo[4,5-
ribonucleoside (HDPR) V.18 This mechanism was estab- b]pyridines VI (Scheme 2, EWG = NO2).
lished by X-ray structures of the complex HDPR with the
5-Aminoimidazoles 4a–q were generated in situ, follow-
native and mutant ADA.18
ing our previously reported procedure,24 by reaction of
methyl N-(cyanomethyl)formimidate (1) with amines 2a–
q to give 3a–q and subsequent cyclization (Scheme 3).
H
OH
EWG
R1
EWG
R1
N
N
N
N
H2O
O
in vivo
N
N
NO2
NO2
H
N
N
R
R
i
VI
VII
+
4a–q
N
O
i
5
Scheme 2 6-Acceptor-substituted 3H-imidazo[4,5-b]pyridines as
R
new potential ADA and CDA inhibitors
HO
6a–q
Continuing our research program dedicated to the design
and synthesis of novel inhibitors of ADA, we searched for
new purine-type scaffolds VI which, with respect to the
position of the electron-withdrawing substituents, would
facilitate the above-mentioned addition of a water mole-
cule. We believe that the introduction of a strong electron-
withdrawing group (EWG) located at position 1 of the pu-
rine or pseudo purine system will increase the electron de-
ficiency of position 6. This would result in a facile
addition of water in vivo leading to the formation of the
hydrate VII (Scheme 2). We have focussed our attention
to the nitro group, because of its strong electron-with-
drawing properties. In addition, it is known that 3-nitropy-
ridines as well as their heteroannulated analogues are able
to react with O-, N-, and C-nucleophiles to give stable
Meisenheimer-type compounds.19 It is known that the
above-mentioned nitro derivatives undergo, depending on
the pH, a reaction with water to give stable hydrates.19,20
Therefore, they are expected to be promising scaffolds for
the development of ADA transition-state mimetics.
O
NO2
NO2
N
N
N
N
O
N
H
OH
HO
R
H2N
C
R
H
O
OH
O
NO2
H
NO2
N
O
N
A
N
H2N
B
N
H2N
R
R
Scheme 4 Reagents and conditions: (i) CH2Cl2, reflux, 5 h.
Treatment of the in situ generated imidazoles 4a–q with
an equivalent amount of 3-nitro-4H-chromen-4-one (5)
afforded the 1-substituted 6-nitro-3H-imidazo[4,5-b]-
pyridines 6a–q in good to excellent yields (Scheme 4).25,26
The reaction was carried out in dichloromethane under ar-
gon atmosphere under reflux for 5 hours. In most cases,
the reaction was complete after 1–2 hours, and the product
could be isolated by simple filtration of the precipitate
formed.
N
CN
OMe
1
N
CN
N
N
i
i
+
NH
NH2
R
NH2
R
3a–q
R
2a–q
4a–q
generated
in situ
NO2
NH2
N
N
N
N
i
N
N
Scheme 3 Reagents and conditions: (i) CH2Cl2, argon, reflux, 2 h.
R
R
HO
6a–q
HO
7a–q
Based on our experience in the chemistry of electron-rich
aminoheterocycles,21 we have developed a new synthetic
approach to 6-nitro-3H-imidazo[4,5-b]pyridines and the
results of our efforts are reported herein.
Scheme 5 Reagents and conditions: (i) MeOH, H2, Pd/C (10
mol%), 20 °C, 2 d.
3-Nitro-4H-chromen-4-one22 (5) and its derivatives are
readily available in three steps from commercially avail-
able 4-hydroxy-2H-chromen-2-one. The chemistry of 5
has not been extensively studied so far.23 Reactions of 5
with ureas, thioureas, amidines, and 1,3,5-tricarbonyl
compounds have been reported. It occurred to us that the
reaction of 5 with 5-aminoimidazoles may provide a con-
The formation of products 6a–q can be explained by con-
jugate addition of the enamine carbon atom of 4a–q to the
double bond of 5 to give intermediate A. Subsequent py-
rone ring opening delivers intermediate type B. The in-
tramolecular attack of the amino group to the carbonyl
group affords intermediate C which undergoes elimina-
tion of water to give pyridines 6.
Synlett 2010, No. 15, 2299–2303 © Thieme Stuttgart · New York

LETTER
Synthesis of 6-Nitro- and 6-Amino-3H-imidazo[4,5-b]pyridines
2301
the nitro group afforded the corresponding 6-amino-3H-
imidazo[4,5-b]pyridines. We have shown that the devel-
oped procedure can be applied to the synthesis of diverse
sets of functional druglike scaffolds. The biological eval-
uation of the synthesized compounds is currently studied
in our laboratories.
Table 1 Yields of Imidazo[4,5-b]pyridines 6a–q and 7a–q
6, 7
R
Yield of 6 Yield of 7
(%)a
96c
41c
86b
69b
77c
82c
85b
99b
87c
76b
79b
72b
91c
73b
82c
76b
88c
(%)a
92c
82c,e
84c
86d
92c
85c
83c
82d
78c
76c
71c
78c
75c
79c
80c
79c
81c
a
b
c
t-Bu
All
n-heptyl
Acknowledgment
d
e
cyclopropyl
Financial support by the State of Mecklenburg-Vorpommern (scho-
larships for V.O.I., D.O., A.P., and S.D.) and by the State of Paki-
stan (HEC scholarship for I.A.) is gratefully acknowledged.
cyclopentyl
f
cyclohexyl
References and Notes
g
h
i
4-methoxybenzyl
3-methoxybenzyl
2,3-(dimethoxy)benzyl
2-(chloro)benzyl
4-(chloro)benzyl
2-[(4-methoxy)phenyl]ethyl
2-[(3,4-dimethoxy)phenyl]ethyl
2-[(2-methoxy)phenyl]ethyl
2-(phenyl)ethyl
(pyridin-4-yl)methyl
2-(pimethylamino)ethyl
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j
k
l
m
n
o
p
q
a Yields of isolated products.
b Isolated by filtration.
c Isolated by column chromatography (EtOAc–i-PrOH).
d Isolated by filtration through Celite.
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6 in the presence of Pd/C (10 mol%, Scheme 5).29
The hydrogenation of 6a–q afforded the 6-aminoimida-
zo[4,5-b]pyridines 7a–q30 with excellent yields. It is note-
worthy that, in the case of 7g–k, no cleavage of the benzyl
group was observed, and in a case of 6b allyl group was
reduced to propyl to give the corresponding 2-(6-amino-
3-propyl-3H-imidazo[4,5-b]pyridin-5-yl)phenol (7b).
In conclusion, we have reported a new facile method for
the synthesis of functionalized 6-nitro-3H-imidazo[4,5-
b]pyridines by cyclocondensation of 3-nitro-4H-
chromen-4-one with 5-aminoimidazoles. The reduction of
Synlett 2010, No. 15, 2299–2303 © Thieme Stuttgart · New York

2302
D. Ostrovskyi et al.
LETTER
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To a Schlenk flask, set with reflux, CH2Cl2 (2.5 mL),
primary amine (0.00131 mol), and methyl N-(cyanomethyl)-
formimidate (1, 0.128 g, 0.00131 mol) were added under an
argon atmosphere at r.t. The reaction mixture was refluxed
during 2 h and after that, the mixture was cooled down to r.t.,
and then to 0 °C on an ice bath. Afterwards 3-nitro-4H-
chromen-4-one (0.25 g, 0.00131 mol) was added, and the
mixture continued to stir at the same temperature for 15–20
min (the color of reaction mixture became intensively red)
and then refluxed for 5 h. The formed precipitate was
filtered, and the obtained solid was washed with CH2Cl2 and
dried. In the case of homogenous solution, the solvent was
evaporated to dryness, and the residue was purified by
column chromatography (EtOAc–i-PrOH = 5:1), to give 6a–
q as light yellow crystals.
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1H NMR (300 MHz, DMSO-d6): d = 1.82 (s, 9 H, t-Bu), 6.87
(d, 1 H, H-6¢, 3J = 9 Hz), 7.01 (t, 1 H, H-4¢, 3J = 9 Hz), 7.30
(t, 1 H, H-5¢, 3J = 9 Hz), 7.57 (d, 1 H, H-3¢, 3J = 9 Hz), 8.71
(s, 1 H, H-5), 8.74 (s, 1 H, H-2), 9.95 (s, 1 H, OH). 13C NMR
(250 MHz, DMSO-d6): d = 28.5 (CH3), 57.7 [(CH3)3C],
115.1 (C-4¢), 119.5 (C-6¢), 123.6 (C-5¢), 125.7 (C-3¢), 130.2
(C-2¢), 130.5 (C-1¢), 133.9 (C-7), 142.8 (C-4), 144.7 (C-5),
147.1 (C-9), 148.2 (C-6), 154.5 (C-2). MS (EI): m/z
(%) = 313 [M + 1]+(11), 312 [M]+(98), 210 [M –
C12H9N3O]+(77).
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(27) CCDC-782287 contain the crystallographic data (excluding
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can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 (1223)336033; e-mail: deposit@ccdc.cam.ac.uk or via
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(29) General Procedure for the Synthesis of Compounds 7a–q
To a 100 mL Schlenk flask, filled with 200 mg of
corresponding imidazo[4,5-b]pyridine 6a–q in MeOH (30
mL), Pd/C (20 mg, 10 mol%) was added. The flask was
fitted with a septum, and then held under vacuum for 3 min,
after that it was filled with hydrogen. Holding under vacuum
was repeated one more time, and after sequent filling with
hydrogen, the reaction mixture has been stirred for 2 d under
H2 atmosphere. After the reaction was stopped, the mixture
was filtered through Celite pad and filtrate was evaporated to
dryness or (if necessary) was purified by column chroma-
tography (EtOAc–i-PrOH = 5:1) to give 7a–q as light brown
crystals.
(20) Seeliger, F.; Blazej, S.; Bernhardt, S.; Makosza, M.; Mayr,
H. Chem. Eur. J. 2008, 14, 6108.
(21) (a) Iaroshenko, V. O.; Sevenard, D. V.; Kotljarov, A. V.;
Volochnyuk, D. M.; Tolmachev, A. O.; Sosnovskikh, V. Ya.
Synthesis 2009, 731. (b) Iaroshenko, V. O.; Wang, Y.;
Sevenard, D. V.; Volochnyuk, D. M. Synthesis 2009, 1851.
(c) Iaroshenko, V. O.; Sevenard, D. V.; Volochnyuk, D. M.;
Wang, Y.; Martiloga, A.; Tolmachev, A. O. Synthesis 2009,
1865. (d) Iaroshenko, V. O.; Wang, Y.; Zhang, B.;
Volochnyuk, D. M.; Sosnovskikh, V. Ya. Synthesis 2009,
2393. (e) Kotljarov, A.; Irgashev, R. A.; Iaroshenko, V. O.;
Sevenard, D. V.; Sosnovskikh, V. Ya. Synthesis 2009, 3233.
(f) Kotljarov, A.; Iaroshenko, V. O.; Volochnyuk, D. M.;
Irgashev, R. A.; Sosnovskikh, V. Ya. Synthesis 2009, 3869.
(g) Iaroshenko, V. O. Synthesis 2009, 3967.
Synlett 2010, No. 15, 2299–2303 © Thieme Stuttgart · New York

LETTER
Synthesis of 6-Nitro- and 6-Amino-3H-imidazo[4,5-b]pyridines
2303
(30) 2-(3-tert-Butyl-6-amino-3H-imidazo[4,5-b]pyridin-5-
yl)phenol (7a)
1 H, OH). 13C NMR (250 MHz, DMSO-d6): d = 28.6 (CH3),
56.1 [(CH3)3C], 113.5 (C-4¢), 116.7 (C-6¢), 119.4 (C-5¢),
127.2 (C-3¢), 129.1 (C-2¢), 131.7 (C-1¢), 136.2 (C-9), 137.5
(C-5), 140.2 (C-6), 141.0 (C-7), 142.6 (C-4), 154.6 (C-2).
MS (EI): m/z (%) = 282 [M]+(71), 225 [M –
C12H9N4O]+(100).
1H NMR (300 MHz, DMSO-d6): d = 1.75 (s, 9 H, t-Bu), 4.86
(s, 2 H, NH2), 6.97 (t, 1 H, H-4¢, 3J = 9 Hz), 6.98 (d, 1 H, H-
6¢, 3J = 9 Hz), 7.28 (t, 1 H, H-5¢, 3J = 9 Hz), 7.47 (d, 1 H, H-
3¢, 3J = 9 Hz), 7.48 (s, 1 H, H-5), 8,25 (s, 1 H, H-2), 10.27 (s,
Synlett 2010, No. 15, 2299–2303 © Thieme Stuttgart · New York