Synthesis of heteroannulated 3-nitro- and 3-aminopyridines by cyclocondensation of electron-rich aminoheterocycles with 3-nitrochromone

Article abstract of DOI:10.1016/j.tet.2011.06.101

3-Nitrochromone reacts with electron-rich aminoheterocycles (in glacial acetic acid at reflux) and anilines (in a mixture of DMF and TMSCl at 100-140 °C) to give a variety of hetero(carbo)annulated 3-nitropyridines. The reaction, involving a formal [3+3] cyclocondensation, proceeds in high yields and appears not to be influences greatly by the nature of the 1,3-C,N-dinucleophile as seen from the thorough scope study. The synthetic utility of the products was demonstrated by their conversion into the corresponding 3-aminopyridine derivatives. An NMR study and X-ray crystallographic analysis are reported.

Full text of DOI:10.1016/j.tet.2011.06.101

Tetrahedron 68 (2012) 2532e2543
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of heteroannulated 3-nitro- and 3-aminopyridines by
cyclocondensation of electron-rich aminoheterocycles with 3-nitrochromone
,
b
,
a
,
,
Viktor O. Iaroshenko a , Satenik Mkrtchyan c, Ashot Gevorgyan a c, Marcelo Vilches-Herrera a,
*
Dmitri V. Sevenard d, Alexander Villinger a, Tariel V. Ghochikyan c, Ashot Saghiyan c,
Vyacheslav Ya. Sosnovskikh e, Peter Langer a
,f,
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33 01033, Ukraine
c Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
d Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstrasse 1, 28359 Bremen, Germany
e Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russia
f
€
€
Leibniz-Institut fur Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2011
Received in revised form 15 June 2011
Accepted 27 June 2011
Available online 2 July 2011
3-Nitrochromone reacts with electron-rich aminoheterocycles (in glacial acetic acid at reflux) and ani-
lines (in a mixture of DMF and TMSCl at 100e140 ꢀC) to give a variety of hetero(carbo)annulated 3-
nitropyridines. The reaction, involving a formal [3þ3] cyclocondensation, proceeds in high yields and
appears not to be influences greatly by the nature of the 1,3-C,N-dinucleophile as seen from the thorough
scope study. The synthetic utility of the products was demonstrated by their conversion into the cor-
responding 3-aminopyridine derivatives. An NMR study and X-ray crystallographic analysis are reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chromones
Cyclocondensation
Aminoheterocycles
Anilines
Purine isosteres
Regioselectivity
1. Introduction
give stable hydrates. In the case of 5,6-bicyclic systems, these hy-
drates II are expected to be promising scaffolds for the de-
Nitrogen containing heterocycles are of considerable pharma-
cological relevance.1 Heteroannulated pyridines attracted signifi-
cant attention because of their various pharmacological
activities.2,3 3-Nitro- and 3-aminopyridines, their heteroannulated
analogues,4 and functionalized quinolines represent attractive lead
structures for drug discovery.5 We have been particularly interested
in purine-type scaffolds I containing electron-withdrawing sub-
stituents (EWG) at the 1-position of the purine core structure. We
believe that such structures represent promising patterns for the
development of inhibitors of adenosine deaminase (ADA), since
some 3-nitropyridines are known to undergo hydration at the 4-
position to form stable Meisenheimer type hydrates.6 3-
Nitropyridines as well as their heteroannulated analogues un-
dergo, depending on the pH of the solution, a reaction with water to
velopment of ADA transition state mimetics (Fig. 1).
H
OH
EWG
R
EWG
R
H2O
in vivo
Het
Het
N
H
N
II
I
Fig. 1. 5,6-Bicyclic systems as promising scaffolds for the development of ADA tran-
sition state mimetics.
On the other hand, 3-substituted chromones (3-acyl-,7 3-
methoxalyl-,8 3-cyanochromones9) are used as valuable synthetic
intermediates in the preparation of pharmacologically relevant
products and new heterocyclic systems. Introduction of an
electron-withdrawing group into the 3-position of chromones
radically changes the reactivity of the pyrone ring toward nucleo-
philic reagents and opens up a broad synthetic scope of this im-
portant oxygen-containing heterocyclic system. Being essentially
gem-activated alkenes, 3-substituted chromones exhibit a variety of
* Corresponding authors. Tel.: þ49 381 4986410; fax: þ49 381 49864112; e-mail
addresses: viktor.iaroshenko@uni-rostock.de (V.O. Iaroshenko), peter.langer@uni-
rostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.101

V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
2533
properties and can undergo additional transformations through
opening of the -pyrone ring and heterocyclizations at the carbonyl
centers.7 Owing to this, 3-substituted chromones as 1,3-
dielectrophiles and electron-rich aminoheterocycles as 1,3-
dinucleophiles have attracted attention as excellent building
blocks for the preparation of various fused pyridines and pyrimi-
dines.11,12 These compounds can be considered as purine isosteres
and are of a great interest as privileged scaffolds in medicinal
chemistry and drug design.3b,13
g
carbon atom because of the presence of a good leaving group
(phenolate anion). However, 3-nitrochromones have not received
much attention despite their potential interest as building blocks in
organic synthesis for the construction of heterocyclic compounds
bearing a nitro group.
Based on the retrosynthetic analysis and on our previous work
related to the development of new cyclocondensation reactions of
electron-rich aminoheterocycles,10 we envisaged that 3-nitro(thio)
chromones are suitable substrates for the synthesis of hetero-
annulated 3-nitropyridines. We are reporting now on the formation
of this type of heterocycles from 3-nitrochromones 1 and various
electron-rich heterocyclic amines and anilines 2 (Fig. 2).
Routes for the synthesis of 2-unsubstituted 3-nitrochromone
1a are scarce, only two methods are known. The first and the
most utilized method follows a three-step procedure via 4-
hydroxy-3-nitrocoumarin, starting from commercially available
4-hydroxycoumarin and producing 1a in moderate yields by
formylation of 20-hydroxy-2-nitroacetophenone with acetic for-
mic anhydride. The latter was prepared by decarbonylation of 4-
hydroxy-3-nitrocoumarin with aqueous sodium hydroxide.14 An
alternative synthesis of 6-substituted 3-nitrochromones relies on
the nitration of the corresponding 3-hydroxymethyl- or 3-
formylchromones, however this reaction worked only when the
aromatic ring was deactivated toward electrophilic substitution.15
Moreover, regioselective method for the radical 3-nitration of
flavones that allows the synthesis of 3-nitroflavones has been
reported.16 2-Methyl-3-nitrochromone 1b has been previously
synthesized by acetylation of 20-hydroxy-2-nitroacetophenone
with acetic anhydride in pyridine in low yield (18%).14a There-
fore, simpler and high yield approaches toward 3-
nitrochromones would be desirable. In this work, the best re-
action conditions for the synthesis of 3-nitrochromones 1aee
were found (see Experimental) and of special interest is the
formation of these compounds in the reaction of 20-hydroxy-2-
nitroacetophenone with triethyl orthocarboxylates in 82e88%
yields (Scheme 1).
O
O
O
NO2
R
NO2
NO2
O
O
S
1a: R = H,
1d: R = H,
1e: R = Me
1f
R
1b: R = Me,
1c: R = Et
Me
NC
S
N
NH2
Alk2N
NH2
NH2
N
N
R
N
Ph
2a
2b: Alk2N = NMe2,
2e: R = t-Bu,
2c: Alk2N = piperidino,
2d: Alk2N = morpholino
2f: R = 4-MeO-benzyl,
2g: R = cyclohexyl
O
O
O
NO2
NO2
R
NH2
N
O
N
R1
N
RC(OEt)3
reflux
R1
OH
O
1a-e
NH2
N
O
N
R2
NH2
NH2
N
H2N
R2
2k: R1 = R2 = Me;
2l: R1 = H, R2 = Me;
2m: R1 = R2 = H
2n
2h: R1 = Ph, R2 = H;
2i: R1 = Me, R2 = H;
2j: R1 = H, R2 = Me
Chromone 1
R
H
Reaction time (h) Yield (%)
6
3
4
5
5
82
84
83
88
85
a
b
c
OMe
Me
Et
MeO
Ph
d
e
MeO
NH2
MeO
NH2
Me
Me2N
NH2
p-Tol
2q
2o
2p
Scheme 1.
OH
In addition, 3-nitroflavones 1d,e were also prepared by nitration
of flavones using ammonium nitrate and trifluoroacetic anhy-
dride,16 while nitration of thiochroman-4-one with 65% nitric acid
in acetic acid produced 3-nitrothiochromone 1f in 57% yield.17 The
latter reaction is a straightforward and convenient route to 1f,
which makes this little-known compound suitable for further in-
vestigations (Scheme 2). All our attempts to prepare 3-nitro-2-
(trifluoromethyl)chromone and methyl 3-nitrochromone-2-
carboxylate by reactions of 20-hydroxy-2-nitroacetophenone with
trifluoroacetic anhydride and methyl 2-chloro-2-oxoacetate, failed.
To the best of our knowledge, very scarce information is avail-
able about the reactivity of 3-nitro(thio)chromones 1. There have
been only a handful of papers describing some reactions of 1a with
amines, benzamidine, phenylhydrazine, and enamines, including 5-
amino-1-isopropyl-3-methylpyrazole and 5-amino-3-(4-pyridyl)
N
N
S
N
Ph
NH2
HS
N
NH2
2r
2s
Fig. 2. 3-Nitro(thio)chromones 1 and electron-rich amines 2 used for the synthesis of
heteroannulated 3-nitropyridines and 3-nitroquinolines 3.
2. Results and discussion
Chromones, having electron-withdrawing substituents at the
3-position, undergo reactions with dinucleophiles at the 2-
position of the chromone system, followed by pyrone ring open-
ing and intramolecular cyclization via another electrophilic

2534
V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
DMF and TMSCl as a water scavenger;22 the reactions were con-
O
O
O
ducted in a pressure tube at 100e140 ꢀC for several hours (method
B). The TMSCl-mediated reaction of 1 with pyrimidines 2m,n and 4-
amino-1-methyl-3-phenyl-1H-imidazole-2(3H)-thione 2r, which is
unstable in acetic acid, afforded products 3m,n,r (yields 65e95%).
It should be noted that formal [3þ3] cyclocondensation leading to
fused pyridines 3 from 3-nitrochromone 1a is not limited to the use
of the heterocyclic amines. The less reactive electron-rich anilines
2oeq also undergo a similar reaction (DMF/TMSCl) to give 3-
nitroquinolines 3oeq as the only isolated products in 62e91%
yield (Table 1).
NO2
Ar
NH4NO3
TFAA
O
Ar
1d: R = Ph (78%),
1e: R = p-Tol (64%)
O
S
O
NO2
HNO3
AcOH
This result clearly shows that the present methodology could be
applicable to various types of heterocyclic amines and anilines,
providing a rapid route to the synthesis of a great variety of het-
ero(carbo)annulated pyridines bearing a NO2 group located at the
S
1f (57%)
Scheme 2.
b-position of the pyridine core. In connection with this, it was of
interest to evaluate the reactivity of 2-methyl- and 2-ethyl-3-
nitrochromones 1b,c, 3-nitroflavones 1d,e, and 3-nitrothio-
chromone 1f toward some heterocyclic amines 2. Unfortunately,
all our attempts to obtain the corresponding fused pyridines by
treatment of chromones 1bee with amines 2 under the same re-
action conditions (methods A and B) were unsuccessful and only
starting materials were recovered. In some cases, the reaction gave
tarry multicomponent mixtures from which no fused pyridines of
type 3 could be isolated. Thus, the reaction turned out to be very
sensitive to the nature of the substituent at the C-2 atom and
afforded pyridines 3 only when the chromone 1a was used. This is
probably a result of the steric and conjugation factors. It was also
found that 3-nitrothiochromone 1f is much less reactive than 3-
nitrochromone 1a and all attempts to obtain the corresponding
pyridines under the same and even more drastic conditions
(dimethylacetamide, TMSCl, 170 ꢀC), failed. The observed differ-
ences in reactivity between 1a and 1f appears to be connected with
the difficulty met by the nucleophile in cleaving the thiopyrone
SeC bond arising from the less electronegative character of the
sulfur atom, which strongly reduces the electrophilicity of the 2-
position, and the greater aromaticity of the thiochromone system
as compared with chromones.23 Although we were unable to pre-
pare 3-nitro-2-(trifluoromethyl)chromone, the corresponding
pyrazolo[3,4-b]pyridine 3t was obtained in low yield (10%) by
three-component reaction of 20-hydroxy-2-nitroacetophenone
with trifluoroacetic anhydride and 5-amino-3-methyl-1-
phenylpyrazole 2a (Scheme 3). The low yield logically can be
isoxazole,18 as well as reactions of 1b with amidines, guanidine,
acid hydrazides, S-methylisothiourea, and hydroxylamine.19 We
have recently shown20 that the reaction of 1a with in situ generated
1-substituted 5-amino-1H-imidazoles affords
a range of 1-
substituted 6-nitro-3H-imidazo[4,5-b]pyridines, which represent
potential adenosine deaminase (ADA) inhibitors.21 All these re-
actions proceed by nucleophilic 1,4-addition followed by intra-
molecular condensation at the carbonyl group to yield various nitro
derivatives.
Our efficient procedures for the preparation of 3-nitrochro-
mones 1 allowed us to investigate their chemical properties in
more detail. Here we have examined the behavior of 1 in their re-
actions with a wide set of electron-rich aminoheterocycles and
anilines 2 with the purpose of development of a simple and pre-
parative synthetic approach to hetero(carbo)annulated 3-
nitropyridines 3. After some optimization, it was found that treat-
ment of 3-nitrochromone 1a with amines 2ael,s (1.1 equiv) in
glacial acetic acid at reflux for several hours (method A) resulted in
the formation of annulated pyridines 3ael,s with an excellent
regioselectivity. A wide range of amines 2 can effectively participate
in the reaction with high yields (up to 98%). In most cases, the re-
action was complete after 1e7 h, and the products could be isolated
by simple filtration of the precipitate formed. The progress of the
reaction was monitored by TLC, and the results are summarized in
Table 1. In a different set of reactions we have used a mixture of
Table 1
Synthesis of compounds 3 and 4
Products
3 (R¼NO2)
Timea (h)
Yield 3a,b (%)
Timec (h)
Yield 3b,c (%)
4 (R¼NH2)
Yield 4b (%)
Me
R
N
3a
1
97
1
88
4a
87
N
N
OH
R
R
S
NMe2
3b
3c
4
65
71
4
43
32
4b
4c
48
70
N
N
OH
S
N
15
15
N
N
OH

V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
2535
Table 1 (continued )
Products
3 (R¼NO2)
Timea (h)
Yield 3a,b (%)
Timec (h)
Yield 3b,c (%)
4 (R¼NH2)
Yield 4b (%)
R
S
N
N
O
3d
1
90
1
44
4d
66
77
N
OH
CN
R
3e
7
67
7
28
4e
N
N
Me
Me
OH Me
CN
R
3f
1
1
93
81
1
1
31
27
4f
64
78
N
N
OH
OMe
CN
R
R
3g
4g
N
N
OH
O
N
3h
5
2
98
87
5
2
77
63
4h
78
96
N
N
H
OH
O
R
N
Me
3i
4i
N
H
N
OH
O
R
NH
3j
4
78
4
54
4j
92
N
N
Me
OH
O
R
Me
O
N
3k
4
6
97
73
4
6
44
32
4k
66
88
N
N
Me
OH
O
R
NH
3l
4l
N
N
O
Me
OH
O
R
NH
3m
2
84
2
40
4m
97
N
N
H
O
(continued on next page)
OH

2536
V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
Table 1 (continued )
Products
3 (R¼NO2)
Timea (h)
Yield 3a,b (%)
Timec (h)
Yield 3b,c (%)
4 (R¼NH2)
Yield 4b (%)
NH2
N
R
3n
2
Mix.
4
65
4n
93
N
N
NH2
OMe
OH
OMe
R
R
3o
3p
2
2
Mix.
Mix.
18
62
83
4o
4p
80
93
N
OH
OMe
OMe
2
N
OH
R
Me
3q
2
2
Mix.
Mix.
10
10
91
95
4q
94
N
N
Me
OH
Me
R
N
S
d
3r
d
N
N
Ph
OH
OH
R
N
d
3s
3
79
3
35
d
N
N
SH
OH
a
b
c
Method A (AcOH, reflux).
Yields of isolated products.
Method B (TMSCl/DMF, 100 ꢀC; 140 ꢀC for 3p).
d
Reaction did not occur.
explained by taking into account that the correspondent amino-
pyrazole 2g can react with trifluoroacetic anhydride delivering
corresponding acylated product, the latest was detected by 19F
NMR as a major reaction product.
The formation of fused pyridines 3 can be explained by conju-
gate addition of the enamine carbon atom of 2 to the double bond
of 1a to give intermediate A. Subsequent pyrone ring opening de-
livers intermediate type B. The intramolecular attack of the amino
group to the carbonyl group affords intermediate C, which un-
dergoes elimination of water to give products 3 (Scheme 4).
The structures of fused pyridines 3a,e,f,k,o,r were confirmed by
X-ray crystal structure analyses (Figs. 3 and 4; and Supplementary
data).24 The ORTEP diagram of all investigated crystals shows the
planar cores of heterocyclic framework; compounds 3o and 3r
contain the intramolecular hydrogen bonds OeH$N.
Next, taking into account the availability of the fused 3-
nitropyridine 3 and due to the biological importance of 3-
aminopyridine derivatives, especially 5-amino-7-azaindoles,25 we
studied their synthesis by hydrogenation of 3 in the presence of Pd/
C (10 mol %). The reduction of the nitro group of compounds 3aeq
afforded the expected fused 3-aminopyridines and 3-
aminoquinolines 4aeq in good to excellent yields (Scheme 5,
Table 1). It is noteworthy that, in the case of 3f, no cleavage of the
benzyl group was observed. Taking into account that the amino
Scheme 3.

V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
2537
group can easily be removed by desamination, this is also a method
for preparation of novel 3-unsubstituted pyridines and quinolines
derivatives bearing 2-hydroxyphenyl moiety at the a-position of
the pyridine core. In the same time the reduction reaction of
products 3r and 3s experienced a failure, here we have most
probably encountered with the poisoning effect that sulfur-
containing compounds tending to demonstrate. Given the actual
interest in these compounds as pharmaceutical intermediates,3b,13
this simple entry to pyridine derivatives is useful and comple-
ments the published synthetic methods.
O2N
H2N
i
N
N
OH
OH
3a-q
4a-q
Scheme 5. Reagents and conditions: (i) MeOH, H2, Pd/C (10 mol %), 20 ꢀC, 2 days.
3. Conclusion
Scheme 4. Possible mechanism of the formation of heterocycles 3. Reagents and
conditions see Table 1.
In conclusion, we have developed a simple and convenient
method for the synthesis of functionalized heteroannulated 3-
nitropyridines and 3-nitroquinolines by [3þ3] cyclocondensation
of 3-nitrochromone with electron-rich aminoheterocycles and an-
ilines. The reduction of the nitro group afforded the corresponding
heteroannulated 3-aminopyridines and 3-aminoquinolines. The
products are drug-like scaffolds, which are not readily available by
other methods. The biological evaluation of the synthesized com-
pounds is currently studied in our laboratories.
4. Experimental
4.1. General
NMR spectra were recorded on a Brucker Avance 250 II and
Brucker AV 300 instruments. IR spectra were recorded on a Per-
kineElmer FT IR 1600 spectrometer (ATR). Mass spectra were
obtained on a HewlettePackard HPGC/MS 5890/5972 instrument
(EI, 70 eV) by GC inlet or on an MX-1321 instrument (EI, 70 eV) by
direct inlet. Column chromatography was performed on silica gel
(63e200 mesh, Merck), silica gel Merck 60F254 plates were used for
TLC. All solvents were purified and dried by standard methods. 3-
Nitrothiochromone 1f was prepared according to described
procedure.17
Fig. 3. Molecular structure of compound 3a.
4.1.1. 4-Hydroxy-3-nitrocoumarin. To
a
suspension
of
4-
hydroxycoumarin (40.0 g, 0.25 mol) and sodium nitrite (0.8 g,
0.012 mol) in acetic acid (120 mL) was added 65% nitric acid (35 mL)
in small portions with stirring at room temperature. The reaction
mixture was heated with stirring at 60 ꢀC for 15 min and the
resulting solid was filtered and washed with water to give green
crystals in 87% yield (44.6 g), mp 174e175 ꢀC (lit.14a mp 177 ꢀC).
4.1.2. 20-Hydroxy-2-nitroacetophenone. 4-Hydroxy-3-nitrocoumarin
(12.6 g, 0.06 mol) was dissolved in 450 mL of 5% aqueous solution of
sodium hydroxide and the resulting reddish solution was heated at
60 ꢀC for 3 h. After cooling, the reaction mixture was acidified with
stirring by dropwise addition of acetic acid to the pH 5. The solid that
formed was rapidly filtered and washed with water to afford a col-
orless solid in 81% yield (8.8 g), mp 106 ꢀC (lit.14a mp 106e107 ꢀC).
4.1.3. 3-Nitrochromone (1a). To
a
solution of 20-hydroxy-2-
nitroacetophenone (13.3 g, 0.074 mol) in trimethyl orthoformate
(66.4 mL) was added concentrated sulfuric acid (0.36 g). The
Fig. 4. Molecular structure of compound 3o.

2538
V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
reaction mixture was then refluxed for 6 h and distilled to a dry
residue. The solid that formed was washed with water and
recrystallized from methanol to give a brown solid in 84% yield
(11.7 g), mp 149e150 ꢀC (lit.14b,c mp 149e151 ꢀC, 151e152 ꢀC).
Chromones 1bee were obtained by the analogous procedure.
936 (w), 901 (s), 861 (m), 827 (m), 781 (m), 765 (s), 745 (s), 729 (s),
695 (m), 667 (s), 619 (m), 581 (m), 537 (s).
4.2.3. 2-[6-Nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-5-yl]phe-
nol (3c). Method A, the compound was purified by a column
chromatography (heptane/EtOAc/1.5:1, Rf¼0.65 (EtOAc)). Yellow
4.1.4. 2-Ethyl-3-nitrochromone
(1c). Colorless
solid,
mp
solid, mp 109e110 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.74 (s, 6H,
178e179 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
1.40 (t, 3H, 3J¼7.5 Hz,
3CH2), 3.72 (s, 4H, 2CH2), 6.86 (m, 1H), 7.02 (dd, 1H, 3J¼8.2 Hz,
Me), 2.82 (q, 2H, 3J¼7.5 Hz, CH2), 7.42e7.52 (m, 2H, H-6, H-8),
4J¼1.0 Hz), 7.22e7.31 (m, 2H), 8.34 (s, 1H, Py), 9.95 (br s, 1H, OH);
7.71e7.76 (m, 1H, H-7), 8.19 (dd, 2H, 3J¼8.0 Hz, 4J¼1.5 Hz, H-5); 13
C
13C NMR (62.9 MHz, CDCl3)
d 23.9, 25.4, 50.1, 118.1, 119.8, 119.9,
NMR (75.5 MHz, DMSO-d6)
d
11.0, 25.1, 118.1, 122.5, 123.3, 126.3,
123.0, 126.5, 129.4, 131.6, 138.8, 149.8, 156.1, 164.8, 172.6; MS (EI,
134.9, 138.3, 155.2, 167.2, 168.2; MS (GC, 70 eV) m/z (%) 219 (Mþ,
70 eV) m/z (%) 356 (Mþ, 54), 310 (100); HRMS (EI): calcd for
100); HRMS (EI): calcd for C11H9NO4 (Mþ) 219.0522, found
C17H16N4O3S (Mþ) 356.09376, found 356.09383; IR (ATR, cmꢁ1
) n
219.0523; IR (ATR, cmꢁ1
)
n
2993 (w), 1732 (w), 1654 (s), 1615 (m),
3066 (w), 2937 (w), 2855 (w),1595 (w),1537 (s),1447 (m), 1416 (w),
1306 (s), 1213 (m), 1157(w), 1118 (m), 1037 (w), 1009 (m), 969 (w),
952 (w), 904 (w), 886 (m), 832 (w), 782 (m), 750 (s), 709 (m), 680
(w), 629 (w), 595 (m), 568 (w).
1568 (w), 1519 (s), 1456 (s), 1372 (s), 1326 (m), 1209 (w), 1140 (m),
1042 (m), 969 (w), 902 (m), 787 (s), 768 (s), 596 (m).
4.2. General procedures for the synthesis of compounds 3
4.2.4. 2-(2-Morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)phenol
(3d). Method A, the compound was precipitated from the reaction
mixture, filtered off and washed with i-PrOH/EtOAc/2:1. Yellow
Method A (in acetic acid). 3-Nitrochromone 1a (2 mmol, 0.38 g)
and the corresponding amine 2 (2.2 mmol) were dissolved in acetic
acid (20 mL) and heated under reflux in an inert atmosphere during
1e15 h (controlled by TLC, Table 1). Then this solution was evapo-
rated under reduced pressure, treated with water, filtrated, and
dried on the air and recrystallized from an appropriate solvent, or
was subjected to a column chromatography over silica gel.
Method B (in DMF/TMSCl). 3-Nitrochromone 1a (2 mmol, 0.38 g)
and the corresponding amine 2 (2.2 mmol) were placed in pressure
tube under the flow of dry argon and dissolved in dry DMF (10 mL)
containing 1 mL of TMSCl. The mixture was heated at 100e140 ꢀC
during 2e12 h (controlled by TLC, Table 1). Then this solution was
evaporated under reduced pressure, treated with water, filtrated,
and dried on the air and recrystallized from an appropriate solvent,
or was subjected to a column chromatography over silica gel.
solid, mp 229e231 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.72e3.76
(m, 8H, 4CH2), 6.82 (dd, 1H, 3J¼8.1 Hz, 4J¼0.8 Hz), 6.94 (td, 1H,
3J¼7.5 Hz, 4J¼1.0 Hz), 7.26 (m, 1H), 7.49 (dd, 1H, 3J¼7.6 Hz,
4J¼1.7 Hz), 8.89 (s, 1H, Py), 9.84 (s, 1H, OH); 13C NMR (75.5 MHz,
CDCl3)
d 48.1, 65.4, 114.9, 119.2, 122.7, 125.5, 126.6, 130.2, 130.3,
140.2, 149.0, 154.4, 165.6, 173.2; MS (EI, 70 eV) m/z (%) 358 (Mþ, 34),
312 (100), 69 (13); HRMS (ESI): calcd for C16H14N4O4S (Mþ1)
359.0809, found 359.0805; IR (ATR, cmꢁ1
) n 3517 (w), 3408 (w),
1599(w), 1540 (s), 1492 (m), 1470 (w), 1448 (w), 1433 (w), 1409 (m),
1394 (w), 1345 (m), 1329 (s), 1311 (s), 1283 (s), 1238 (m), 1212 (w),
1182 (w), 1126 (w), 1112 (s), 1083 (w), 1068 (w), 1028 (m), 931 (w),
896 (s), 864 (w), 840 (w), 821 (w), 781 (w), 759 (s), 711 (w), 674 (w),
631 (m), 609 (m), 543 (w).
4.2.1. 2-(3-Methyl-5-nitro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)
phenol (3a). Method A, the compound was precipitated from the
reaction mixture, filtered off and washed with water. Yellow solid,
4.2.5. 1-tert-Butyl-6-(2-hydroxyphenyl)-5-nitro-1H-pyrrolo[2,3-b]
pyridine-3-carbonitrile (3e). Method A, the compound was pre-
cipitated from the reaction mixture, filtered off and washed with
MeOH. Colorless solid, mp 244e245 ꢀC; 1H NMR (300 MHz, DMSO-
mp 204e206 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 2.69 (s, 3H, Me),
6.87 (d, 1H, 3J¼7.6 Hz), 7.01 (t, 1H, 3J¼7.2 Hz), 7.30e7.37 (m, 2H),
d6)
d
1.78 (s, 9H, t-Bu), 6.86 (dd, 1H, 3J¼8.0 Hz, 4J¼0.8 Hz), 7.00 (td,
7.55 (t, 2H, 3J¼7.6 Hz), 7.65 (m, 1H), 8.22 (d, 2H, 3J¼7.6 Hz), 9.09 (s,
1H, 3J¼7.5 Hz, 4J¼0.9 Hz), 7.29 (m, 1H), 7.56 (dd, 1H, 3J¼7.6 Hz,
1H, Py), 10.05 (s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 12.3,
4J¼1.6 Hz), 8.72 (s, 1H), 8.78 (s, 1H), 10.01 (s, 1H, OH); 13C NMR
114.5, 115.1, 119.6, 120.5, 125.2, 126.3, 128.3, 129.3, 130.5, 130.9,
138.4, 142.3, 145.2, 149.3, 150.9, 154.7; MS (GC, 70 eV) m/z (%) 346
(Mþ, 100), 316 (10), 300 (63), 283 (30), 221 (10), 77 (18); HRMS
(ESI): calcd for C19H14N4O3 (Mþ1) 347.1136, found 347.1141; IR
(62.9 MHz, DMSO-d6) d 28.6, 59.4, 83.5, 114.5, 115.1, 118.3, 119.6,
124.6, 125.2, 130.3, 130.5, 139.6, 142.7, 145.1, 146.3, 154.7; MS (GC,
70 eV) m/z (%) 336 (Mþ, 96), 306 (15), 280 (100), 263 (10), 250 (47),
234 (84), 206 (34), 195 (16), 180 (13), 152 (10), 57 (68), 41 (33);
HRMS (ESI): calcd for C18H16N4O3 (Mþ1) 337.1295, found 337.1292;
(ATR, cmꢁ1
) n 3393 (m), 3085 (w), 2917 (w), 1606 (w), 1592 (m),
1575 (m),1523 (m), 1495 (s),1452 (m),1421 (m),1383 (w),1364 (w),
1322 (w), 1308 (s), 1286 (m), 1212 (m), 1193 (m), 1154 (w), 1118 (m),
1103 (m), 1176 (w), 1039 (w), 1013 (w), 982 (w), 916 (m), 897 (w),
861 (w), 845 (m), 807 (w), 780 (m), 752 (s), 691 (s), 682 (m), 672
(m), 653 (w), 639 (m), 632 (m), 564 (m), 540 (m).
IR (ATR, cmꢁ1
) n 3293 (w), 2980 (w), 2240 (m), 1671 (w), 1605 (w),
1595 (w), 1567 (m), 1522 (s), 1450 (m), 1412 (m), 1400 (w), 1372 (m),
1352 (s), 1341 (s), 1295 (m), 1255 (m), 1197 (s), 1123 (m), 1101 (m),
1092 (m), 1043 (s), 1007 (w), 945 (w), 920 (m), 852 (w), 838 (m),
819 (w), 784 (s), 761 (s), 700 (m), 667 (s), 625 (s), 615 (s), 600 (m),
557 (m), 532 (m).
4.2.2. 2-[2-(Dimethylamino)-6-nitrothiazolo[4,5-b]pyridin-5-yl]phe-
nol (3b). Method A, the compound was purified by a column
chromatography (heptane/EtOAc/1:5, Rf¼0.58 (MeOH/EtOAc/2:1)).
4.2.6. 1-(4-Methoxybenzyl)-6-(2-hydroxyphenyl)-5-nitro-1H-pyr-
rolo[2,3-b]pyridine-3-carbonitrile (3f). Method A, the compound
was precipitated from the reaction mixture, filtered off and washed
with water. Colorless solid, mp 166e167 ꢀC; 1H NMR (300 MHz,
Brown solid, mp 266e268 ꢀC; 1H NMR (300 MHz, CDCl3)
d 3.25 (s,
6H, Me2N), 6.82 (d, 1H, 3J¼8.0 Hz), 6.94 (t,1H, 3J¼7.4 Hz), 7.25 (t, 1H,
3J¼7.4 Hz), 7.48 (d, 1H, 3J¼7.0 Hz), 8.86 (s, 1H, Py), 9.81 (s, 1H, OH);
DMSO-d6) d 3.71 (s, 3H, MeO), 5.50 (s, 2H, CH2), 6.85e6.92 (m, 3H),
13C NMR (75.5 MHz, CDCl3)
d
39.7, 114.9, 119.2, 123.2, 125.7, 126.3,
7.01 (td, 1H, J¼7.5 Hz, 4J¼0.9 Hz), 7.27e7.37 (m, 3H), 7.56 (dd, 1H,
3
130.1, 130.2, 139.8, 149.0, 154.4, 166.0, 173.1; MS (GC, 70 eV) m/z (%)
316 (Mþ, 39), 270 (100), 254 (17), 227 (17), 207 (49); HRMS (ESI):
calcd for C14H12N4O3S (Mþ1) 317.0703, found 317.0707; IR (ATR,
3J¼7.6 Hz, 4J¼1.6 Hz), 8.77 (s, 1H), 8.83 (s, 1H), 10.00 (s, 1H, OH); 13
C
NMR (62.9 MHz, DMSO-d6)
d 48.1, 55.1, 84.7, 114.1, 114.2, 115.1, 116.
9, 119.5, 125.0, 125.1, 128.2, 129.5, 130.5, 130.6, 140.9, 143.2, 145.9,
146.7, 154.6, 159.0; MS (EI, 70 eV) m/z (%) 400 (Mþ, 27),121 (100), 91
(13), 77 (20); HRMS (ESI): calcd for C22H16N4O4 (Mþ1) 401.1244,
cmꢁ1
) n 3090 (w), 2921 (w), 2852 (w), 1601 (w), 1549 (s), 1497 (w),
1450 (w), 1408 (m), 1345 (w), 1325 (m), 1307 (s), 1279 (s), 1228 (s),
1181 (m), 1153 (m), 1115 (m), 1098 (s), 1079 (m), 1035 (m), 972 (w),
found 401.1242; IR (ATR, cmꢁ1
) n 3116 (w), 3020 (w), 2841 (w), 1609

V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
2539
(m), 1581 (w), 1573 (w), 1515 (s), 1475 (w), 1462 (w), 1437 (s), 1389
(m), 1361 (w), 1341 (s), 1324 (m), 1305 (w), 1282 (m), 1252 (s), 1216
(m), 1174 (s), 1160 (m), 1121 (w), 1094 (w), 1029 (m), 953 (w), 910
(w), 884 (w), 868 (w), 845 (m), 817 (m), 790 (m), 766 (s), 727 (m),
700 (w), 686 (w), 666 (w), 644 (m), 627 (w), 609 (m), 569 (w), 554
(m), 528 (w).
DMSO-d6) d 33.2, 102.0, 115.0, 119.3, 125.7, 127.9, 130.2, 130.5, 140.5,
148.9, 151.2, 154.0, 154.5; MS (EI, 70 eV) m/z (%) 286 (Mþ, 52), 241
(100); HRMS (ESI): calcd for C13H10N4O4 (Mþ1) 287.06789, found
287.03788; IR (ATR, cmꢁ1
) n 256(w), 1488 (w), 1453 (w), 1404 (w),
1369 (w), 1349 (m), 1288 (w), 1230 (m), 1160 (m), 1116 (w), 1063
(w), 1015 (w), 933 (w), 920 (w), 844 (w), 820 (w), 769 (m), 751 (s),
684 (m), 672 (m), 656 (m), 617 (m), 599 (m).
4.2.7. 1-Cyclohexyl-6-(2-hydroxyphenyl)-5-nitro-1H-pyrrolo[2,3-b]
pyridine-3-carbonitrile (3g). Method A, the compound was pre-
cipitated from the reaction mixture, filtered off and washed with
water. Yellow solid, mp 226e227 ꢀC; 1H NMR (300 MHz, DMSO-d6)
4.2.11. 7-(2-Hydroxyphenyl)-1,3-dimethyl-6-nitropyrido[2,3-d]py-
rimidine-2,4(1H,3H)-dione (3k). Method A, the compound was
precipitated from the reaction mixture, filtered off and washed
with water. Yellow solid, mp 280e282 ꢀC; 1H NMR (300 MHz,
d
1.23e2.06 (m, 10H, 5CH2), 4.78 (m, 1H, CHN), 6.87 (d, 1H,
3J¼8.0 Hz), 7.01 (t, 1H, 3J¼7.5 Hz), 7.31 (td, 1H, 3J¼8.0 Hz, 4J¼1.6 Hz),
CDCl3)
d
3.33 (s, 3H, Me), 3.61 (s, 3H, Me), 6.87 (d, 1H, 3J¼7.9 Hz),
7.56 (dd, 1H, 3J¼7.6 Hz, 4J¼1.5 Hz), 8.78 (s, 1H), 8.92 (s, 1H), 9.97 (s,
7.01 (t, 1H, 3J¼7.3 Hz), 7.36 (td, 1H, 3J¼8.0 Hz, 4J¼1.6 Hz), 7.64 (dd,
1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 24.7, 25.0, 32.2, 54.5,
1H, 3J¼7.6 Hz, 4J¼1.5 Hz), 8.73 (s, 1H, Py), 10.29 (s, 1H, OH); 13C NMR
84.5, 114.4, 115.0, 116.9, 119.3, 124.9, 125.1, 130.4, 138.9, 143.1, 145.6,
146.3, 154.6; MS (GC, 70 eV) m/z (%) 362 (Mþ, 96), 280 (100), 234
(58), 206 (17), 55 (19); HRMS (ESI): calcd for C20H18N4O3 (Mþ1)
(62.9 MHz, DMSO-d6) d 28.3, 29.7, 108.5, 115.2, 119.6, 123.8, 130.6,
131.9,133.2,141.8,150.9,151.3,154.4,155.0,159.7; MS (GC, 70 eV) m/
z (%) 328 (Mþ, 1), 281 (100), 253 (28), 196 (12), 169 (41); HRMS
(ESI): calcd for C15H12N4O5 (Mþ1) 329.0880, found 329.0883; IR
363.1452, found 363.1446; IR (ATR, cmꢁ1):
n 3117 (w), 2942 (w),
2856 (w), 2227 (m),1607 (m),1580 (w),1563 (w),1531 (s),1496 (w),
1478 (m), 1450 (w), 1431 (s), 1395 (m), 1311 (w), 1289 (w), 1263 (m),
1230 (w), 1202 (m), 1161 (w), 1142 (w), 1114 (w), 1094 (w), 1034 (w),
995 (w), 948 (w), 921 (w), 891 (w), 875 (w), 822 (w), 788 (m), 766
(s), 756 (m), 703 (w), 641 (m), 623 (m), 543 (w).
(ATR, cmꢁ1
) n 3256 (w), 3076 (w), 2952 (w), 1706 (m), 1650 (s), 1594
(s), 1582 (s), 1537 (m), 1504 (w), 1488 (w), 1446 (m), 1419 (m), 1401
(w), 1372 (m), 1353 (s), 1289 (m), 1268 (m), 1197 (m), 1163 (w), 1116
(w), 1096 (m), 1067 (w), 1038 (w), 1010 (w), 969 (w), 949 (w), 928
(w), 844 (w), 827 (w), 795 (m), 779 (m), 765 (s), 756 (s), 700 (s), 679
(m), 650 (m), 593 (m), 546 (m).
4.2.8. 6-(2-Hydroxyphenyl)-5-nitro-2-phenyl-1,2-dihydropyrazolo
[3,4-b]pyridin-3-one (3h). Method A, the compound was pre-
cipitated from the reaction mixture, filtered off and washed with
water. Green solid, mp 248e250 ꢀC; 1H NMR (300 MHz, DMSO-d6)
4.2.12. 7-(2-Hydroxyphenyl)-1-methyl-6-nitropyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (3l). Method A, the compound was pre-
cipitated from the reaction mixture, filtered off and washed with
water. Yellow solid, mp 230e232 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
6.88 (d, 1H, 3J¼8.0 Hz), 6.99 (t, 1H, 3J¼7.4 Hz), 7.28e7.37 (m, 2H),
7.51e7.56 (m, 3H, Ph), 7.92 (d, 2H, 3J¼8.0 Hz, Ph), 8.75 (s, 1H, Py),
d
3.53 (s, 3H, Me), 6.86 (d, 1H, 3J¼8.0 Hz), 7.00 (td, 1H, 3J¼7.4 Hz,
10.14 (s, 1H, OH), 12.0e13.5 (br s, 1H, NH); 13C NMR (75 MHz,
4J¼0.7 Hz), 7.35 (m, 1H), 7.63 (dd, 1H, 3J¼7.6 Hz, 4J¼1.6 Hz), 8.67 (s,
DMSO-d6)
d
107.9, 115.3, 119.4,119.9, 124.0, 125.8, 129.2, 130.2, 131.2,
1H, Py), 10.28 (s, 1H, OH), 12.01 (s, 1H, NH); 13C NMR (62.9 MHz,
131.4, 136.8, 140.3, 153.8, 154.7, 157.3; MS (EI, 70 eV) m/z (%) 348
(Mþ, 47), 318 (48), 303 (100), 289 (9), 274 (19), 183 (22), 156 (12), 77
(42); HRMS (ESI): calcd for C18H12N4O4 (Mþ1) 349.0931, found
DMSO-d6) d 28.8, 109.3, 115.3, 119.6, 123.9, 130.6, 131.9, 132.9, 141.6,
150.6, 152.7, 154.4, 155.0, 160.1; MS (GC, 70 eV) m/z (%) 314 (Mþ,
100), 281 (11), 267 (55), 225 (57), 207 (27), 195 (15), 168 (63), 140
(17), 115 (13), 92 (13); HRMS (ESI): calcd for C14H10N4O5 (Mþ1)
349.0926; IR (ATR, cmꢁ1
) n 3055 (w), 1652 (w), 1635 (w), 1605 (m),
1583 (m), 1527 (m), 1497 (w), 1483 (w), 1453 (w), 1407 (m), 1339 (s),
1310 (m), 1275 (m), 1240 (m), 1195 (m), 1179 (m), 1157 (m), 1113 (w),
1098 (w), 1072 (w), 1042 (w), 982 (w), 950 (w), 918 (w), 885 (w),
843 (w), 815 (w), 791 (s), 763 (m), 746 (s), 702 (s), 679 (s), 650 (s),
639 (s), 611 (s), 596 (m), 558 (m).
315.0724, found 315.0725; IR (ATR, cmꢁ1
) n 3288 (w), 3153 (w),
3014 (w), 2820 (w), 1707 (w), 1674 (m), 1602 (m), 1536 (m), 1498
(w), 1446 (m), 1426 (w), 1402 (m), 1372 (m), 1343 (s), 1284 (m), 1196
(m), 1155 (m), 1077 (m), 1038 (w), 976 (m), 935 (w), 863 (m), 842
(m), 815 (m), 781 (m), 765 (s), 749 (s), 737 (s), 677 (m), 659 (m), 588
(m), 551 (s).
4.2.9. 6-(2-Hydroxyphenyl)-2-methyl-5-nitro-1,2-dihydropyrazolo
[3,4-b]pyridin-3-one (3i). Method A, the compound was pre-
cipitated from the reaction mixture, filtered off and washed with
water. Red solid, mp 295e297 ꢀC; 1H NMR (300 MHz, DMSO-d6)
4.2.13. 7-(2-Hydroxyphenyl)-6-nitropyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (3m). Method B, the compound was precipitated
from the reaction mixture, filtered off and washed with MeOH/
H2O/1:1. Yellow solid, mp 317e319 ꢀC; 1H NMR (300 MHz, DMSO-
d
3.48 (s, 3H, Me), 6.85 (d, 1H, 3J¼8.1 Hz), 6.95 (td, 1H, 3J¼7.4 Hz,
4J¼0.7 Hz), 7.30 (m, 1H), 7.48 (dd, 1H, 3J¼7.6 Hz, 4J¼1.6 Hz), 8.65 (s,
d6)
d
6.86 (d, 1H, 3J¼8.1 Hz), 6.98 (t, 1H, 3J¼7.5 Hz), 7.34 (m, 1H), 7.50
1H, Py), 10.01 (s, 1H, OH), 12.5e13.0 (br s, 1H, NH); 13C NMR
(dd, 1H, 3J¼7.5 Hz, 4J¼1.0 Hz), 8.64 (s, 1H, Py), 10.19 (s, 1H, OH), 11.75
(62.9 MHz, DMSO-d6)
d 30.6, 105.7, 115.1, 119.3, 125.1, 130.1, 130.9,
(s, 1H, NH), 12.24 (s, 1H, NH); 13C NMR (62.9 MHz, DMSO-d6)
140.8, 153.0, 154.4, 154.5, 157.1; MS (EI, 70 eV) m/z (%) 286 (Mþ, 32),
256 (79), 241 (37), 183 (23), 169 (23), 156 (16), 131 (26),119 (25), 105
(18), 77 (29), 69 (100); HRMS (ESI): calcd for C13H10N4O4 (Mþ1)
d 108.4, 115.2, 119.3, 123.8, 130.4, 131.6, 132.8, 141.9, 150.3, 153.5,
154.8, 155.5, 161.2; MS (GC, 70 eV) m/z (%) 300 (Mþ, 96), 270 (100),
255 (40), 231 (13), 211 (35), 182 (11), 168 (21), 156 (17), 128 (10);
HRMS (ESI): calcd for C13H8N4O5 (Mþ1) 301.05675, found
287.07748, found 287.07720; IR (ATR, cmꢁ1
) n 2929 (w), 2746 (w),
1645 (m), 1621 (m), 1582 (m), 1532 (m), 1504 (m), 1447 (m), 1318
(m), 1292 (m), 1240 (m), 1177 (w), 1116 (w), 1092 (w), 1033 (w), 999
(w), 961 (w), 939 (w), 861 (m), 793 (s), 755 (s), 701 (s), 634 (s).
301.05635; IR (ATR, cmꢁ1
) n 3306 (w), 3012 (w), 2824 (w), 1722 (w),
1668 (m),1599 (m),1574 (m),1537 (m),1494 (w),1348 (s),1300 (m),
1274 (m), 1203 (m), 1145 (w), 1114 (w), 1096 (w), 1017 (w), 978 (w),
884 (w), 841 (w), 808 (w), 794 (w), 751 (s), 656 (m), 590 (m), 559
(m).
4.2.10. 6-(2-Hydroxyphenyl)-1-methyl-5-nitro-1,2-dihydropyrazolo
[3,4-b]pyridin-3-one (3j). Method A, the compound was pre-
cipitated from the reaction mixture, filtered off and washed with
water. Yellow solid, mp 272e274 ꢀC; 1H NMR (300 MHz, DMSO-d6)
4.2.14. 2-(2,4-Diamino-6-nitropyrido[2,3-d]pyrimidin-7-yl)phenol
(3n). Method B, the compound was precipitated from the reaction
mixture, filtered off and washed with i-PrOH/heptane/10:1. Yellow
d
3.86 (s, 3H, Me), 6.83 (d, 1H, 3J¼8.1 Hz), 6.97 (td, 1H, 3J¼7.5 Hz,
4J¼0.8 Hz), 7.29 (m, 1H), 7.53 (dd, 1H, 3J¼7.6 Hz, 4J¼1.5 Hz), 8.77 (s,
solid, mp 285e287 ꢀC; 1H NMR (250 MHz, DMSO-d6)
d
6.91e7.03
1H, Py), 9.91 (s, 1H, OH), 11.63 (s, 1H, NH); 13C NMR (75.5 MHz,
(m, 2H), 7.33e7.39 (m, 1H), 7.53e7.57 (m, 1H), 8.08 (s, 1H, NH), 8.84

2540
V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
(s,1H, NH), 9.31 (s,1H, NH), 9.49 (s,1H, Py), 9.62 (s,1H, NH),10.41 (s,
1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
103.6, 115.3, 119.4, 123.4,
379.0860; IR (ATR, cmꢁ1
) n 3082 (w), 2249 (w), 1615 (w), 1602 (w),
d
1576 (w), 1534 (m), 1500 (m), 1466 (s), 1424 (s), 1376 (m), 1347 (m),
1323 (s), 1286 (s), 1245 (m), 1226 (m), 1198 (s), 1158 (m), 1114 (m),
1079 (m), 1043 (w), 1027 (w), 1003 (w), 988 (w), 956 (w), 936 (w),
904 (s), 894 (m), 830 (w), 806 (s), 782 (w), 766 (s), 753 (s), 726 (s),
711 (s), 686 (s), 647 (s), 603 (m), 556 (s).
130.3, 131.8, 132.0, 142.6, 151.0, 155.0, 156.0, 156.7, 162.7; MS (GC,
70 eV) m/z (%) 298 (Mþ, 100), 282 (15), 266 (33), 220 (28); HRMS
(ESI): calcd for C13H10N6O3 (Mþ1) 299.08871, found 299.08841; IR
(ATR, cmꢁ1
) n 3324 (w), 3119 (w),1681 (w),1645 (m),1606 (m),1515
(m), 1464 (w), 1450 (w), 1425 (m), 1402 (m), 1358 (m), 1300 (m),
1200 (m),1158 (m), 989 (w), 977 (w), 921 (w), 870 (w), 795 (m), 755
(m), 650 (m).
4.2.19. 7-(2-Hydroxyphenyl)-2-mercapto-6-nitropyrido[2,3-d]pyr-
imidin-4-ol (3s). Method A, the compound was precipitated from
the reaction mixture, filtered off and washed with water. Yellow
4.2.15. 2-(5,7-Dimethoxy-3-nitroquinolin-2-yl)phenol (3o). Method
B, the compound was purified by a column chromatography
(heptane/EtOAc/4:1, Rf¼0.60 (EtOAc)). Yellow solid, mp
solid, mp 307e309 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 6.86 (d, 1H,
3J¼8.2 Hz), 6.99 (td, 1H, 3J¼7.5 Hz, 4J¼0.8 Hz), 7.35 (m, 1H), 7.52 (dd,
1H, 3J¼7.6 Hz, 4J¼1.7 Hz), 8.64 (s, 1H, Py), 10.25 (s, 1H, OH), 12.86 (s,
208e209 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.97 (s, 3H, MeO), 4.00 (s,
1H, SH), 13.53 (s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 110.5,
3H, MeO), 6.55 (m, 1H), 6.86e6.94 (m, 2H), 7.08 (dd, 1H, 3J¼8.3 Hz,
115.2,119.4,123.5, 130.5,131.5,132.7,142.5,152.3,154.8,155.7,158.7,
176.7; MS (GC, 70 eV) m/z (%) 316 (Mþ, 100), 286 (11), 270 (48), 253
(19); HRMS (ESI): calcd for C13H8N4O4S (Mþ1) 317.0339, found
4J¼1.0 Hz), 7.27 (dd, 1H, 3J¼8.0 Hz, 4J¼1.4 Hz), 7.34 (m, 1H), 8.88 (s,
1H, Py), 11.70 (s, 1H, OH); 13C NMR (62.9 MHz, CDCl3)
d 56.0, 56.1,
98.8, 99.9, 113.5, 118.3, 118.5, 119.6, 129.1, 129.7, 132.3, 140.8, 148.5,
151.5, 156.8, 157.5, 165.0; MS (GC, 70 eV) m/z (%) 326 (Mþ, 73), 318
(48), 280 (100), 265 (27), 222 (20), 194 (12); HRMS (ESI): calcd for
317.0336; IR (ATR, cmꢁ1
) n 3188 (w), 3014 (w), 2887 (w), 1683 (m),
1621 (w), 1605 (m), 1584 (m), 1520 (m), 1505 (m), 1485 (w), 1464
(m), 1455 (m), 1417 (w), 1352 (s), 1308 (m), 1262 (m), 1236 (m), 1194
(w), 1159 (m), 1131 (s), 969 (w), 948 (m), 857 (m), 805 (s), 792 (s),
744 (s), 692 (s), 659 (s), 629 (s), 592 (m), 558 (s), 535 (s).
C17H14N2O5 (Mþ1) 327.0975, found 327.0976; IR (ATR, cmꢁ1
) n 3108
(w), 2971 (w),1609 (m),1582 (m),1500 (m),1452 (s),1382 (m),1237
(s), 1204 (m), 1160 (s), 1135 (s), 1039 (m), 970 (w), 939 (m), 831 (s),
797 (s), 774 (m), 751 (s), 742 (s), 722 (m), 703 (m), 667 (m), 641 (s).
4.2.20. 2-(3-Methyl-5-nitro-1-phenyl-4-trifluoromethyl-1H-pyr-
azolo[3,4-b]pyridin-6-yl)phenol (3t). To a solution of 20-hydroxy-2-
nitroacetophenone (0.30 g, 1.66 mmol) in dry dioxane (4.5 mL) was
added dry pyridine (0.28 g, 3.5 mmol) and trifluoroacetic anhydride
(0.73 g, 3.5 mmol). The reaction mixture was kept at 90 ꢀC for 2 h
and 5-amino-3-methyl-1-phenylpyrazole 2a (0.32 g, 1.82 mmol)
was added. Again, the resulting mixture was kept at 90 ꢀC for 2 h,
distilled to a dry residue, dried under reduced pressure, subjected
to flash-chromatography (4.5 g of silica gel, CHCl3), and recrystal-
lized from methanol to give yellow crystals. Yield 67 mg (10%), mp
4.2.16. 2-(6,7-Dimethoxy-3-nitroquinolin-2-yl)phenol (3p). Method
B, the compound was purified by a column chromatography
(heptane/EtOAc/4:1, Rf¼0.45 (EtOAc)). Red solid, mp 202e204 ꢀC;
1H NMR (300 MHz, DMSO-d6)
d 3.94 (s, 3H, MeO), 4.01 (s, 3H, MeO),
6.79 (s, 1H), 6.85 (d, 1H, 3J¼7.9 Hz), 6.98 (t, 1H, 3J¼7.5 Hz), 7.09 (s,
1H), 7.27e7.33 (m, 1H), 7.59 (dd, 1H, 3J¼7.5 Hz, 4J¼1.3 Hz), 8.82 (s,
1H, Py), 9.95 (s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 56.0,
56.5, 99.7, 100.1, 112.8, 114.9, 119.3, 125.3, 127.1, 130.3, 130.6, 141.9,
150.4, 150.8, 154.6, 156.5, 164.3; MS (GC, 70 eV) m/z (%) 326 (Mþ,
73), 280 (100), 265 (27), 236 (13), 222 (21), 194 (11); HRMS (ESI):
calcd for C17H14N2O5 (Mþ1) 327.09755, found 327.09798; IR (ATR,
224e226 ꢀC; 1H NMR (300 MHz, CDCl3)
d
2.73 (q, 3H, 6J¼1.6 Hz,
Me), 6.88e6.96 (m, 2H), 7.32e7.41 (m, 2H), 7.53e7.58 (m, 2H),
8.07e8.10 (m, 2H), 8.44 (dd, 1H, 3J¼8.0 Hz, 4J¼1.8 Hz), 12.23 (s, 1H,
cmꢁ1
)
n
2970 (w), 1609 (w), 1591 (m), 1525 (m), 1499 (w), 1453 (m),
OH); 19F NMR (300 MHz, DMSO-d6) e65.9 (s, CF3); 13C NMR
d
1382 (m), 1346 (s), 1237 (m), 1204 (m), 1160 (s), 1134 (s), 1039 (m),
939 (m), 831 (s), 797 (m), 751 (s), 742 (s), 703 (m), 667 (m), 641 (s).
(62.9 MHz, DMSO-d6)
d
14.4 (q, 5J¼3.8 Hz, Me), 108.5, 117.9, 118.2,
119.5,120.7 (q, 1J¼277 Hz, CF3),121.5,127.3,127.6,129.3,129.7,134.1,
137.7, 142.9, 148.4 (q, 2J¼39.8 Hz, CeCF3), 153.9, 160.4, 161.3; MS
(GC, 70 eV) m/z (%) 414 (Mþ, 1), 370 (100); HRMS (ESI): calcd for
4.2.17. 2-(7-(Dimethylamino)-3-nitroquinolin-2-yl)phenol
(3q). Method B, the compound was precipitated from the reaction
mixture, filtered off and washed with H2O/MeOH/1:2. Dark red
C20H13N4O3F3 (Mþ1) 415.1552, found 415.1554; IR (ATR, cmꢁ1
) n
2928 (w), 1580 (m), 1512 (w), 1479 (w), 1446 (m), 1375 (m), 1344
(m), 1304 (w), 1248 (m), 1212 (s), 1140 (s), 1084 (w), 1060 (m), 1033
(m), 993 (m), 908 (w), 877 (w), 859 (w), 811 (m), 752 (s), 739 (s),
685 (m), 660 (m), 649 (m), 637 (m).
solid, mp 236e238 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.18 (s, 6H,
Me2N), 6.98e7.03 (m, 2H), 7.19 (s, 1H), 7.38 (m, 1H), 7.52 (m, 1H),
7.59 (dd,1H, 3J¼7.5 Hz, 4J¼1.2 Hz), 8.11 (d, 1H, 3J¼9.5 Hz), 9.13 (s,1H,
Py), 10.0e10.8 (br s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 48.6,
100.3, 115.3, 118.2, 118.8, 119.2, 121.8, 130.3, 131.0, 131.7, 135.5, 138.9,
146.1, 149.2, 154.4, 155.0; MS (GC, 70 eV) m/z (%) 309 (Mþ, 45), 263
(100), 247 (35), 219 (15); HRMS (EI): calcd for C17H15N3O3 (Mþ)
4.3. General procedure for the synthesis of compounds 4
In a 50 mL Schlenk flask under a flow of dry argon were placed
the corresponding pyridine 3 (1.0 mmol) and 0.05 g of Pd/C (10%).
Afterward, 25 mL of degassed methanol was added. The system was
washed three times with hydrogen. The hydrogenation was con-
ducted with the help of a glass burette under atmospheric pressure.
After 3 equiv of hydrogen was consumed, the mixture was stirred
for 2 days at 20 ꢀC (controlled by TLC). The reaction mixture was
filtered through a Celite pad (2e3 cm). The Celite was washed three
times with methanol. The solvent of the filtrate was removed under
reduced pressure. In many cases, the compounds isolated did not
demand further purification, however, some of substances were
purified by a column chromatography (silica gel, heptane/EtOAc) or
recrystallized from an appropriate solvent.
309.11079, found 309.11112; IR (ATR, cmꢁ1
) n 3202 (w), 2914 (w),
2562 (w), 1644 (w), 1603 (w), 1573 (m), 1515 (m), 1443 (w), 1421
(w), 1331 (m), 1268 (m), 1216 (w), 1158 (m), 1101 (w), 1066 (w), 1017
(m), 956 (w), 900 (m), 858 (w), 823 (m), 771 (m), 755 (s), 713 (m),
623 (m), 611 (m).
4.2.18. 5-(2-Hydroxyphenyl)-1-methyl-6-nitro-3-phenyl-1H-imidazo
[4,5-b]pyridine-2(3H)-thione (3r). Method B, the compound was
purified by a column chromatography (heptane/EtOAc/1:1, Rf¼0.58
(EtOAc)). Orange solid, mp 164e166 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.86 (s, 3H, Me), 6.79e6.92 (m, 2H), 7.19e7.30 (m, 2H), 7.51e7.59
(m, 5H, Ph), 7.93 (s, 1H, Py), 8.58 (s, 1H, OH); 13C NMR (75.5 MHz,
CDCl3) 31.6, 112.8, 117.9, 119.7, 120.5, 124.7, 127.7, 129.3, 129.7,
d
129.9, 131.9, 133.3, 142.1,145.5, 145.8, 155.1, 174.5; MS (EI, 70 eV) m/z
(%) 378 (Mþ, 100), 348 (60), 332 (90), 316 (12), 77 (14), 57 (10);
HRMS (ESI): calcd for C19H14N4O3S (Mþ1) 379.0859, found
4.3.1. 2-(5-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-
yl)phenol (4a). The compound was precipitated from the reaction
mixture, filtered off and washed with heptane/i-PrOH/1:1. Brown

V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
2541
solid, mp 160e162 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
2.55 (s, 3H,
(w), 1012 (w), 941 (w), 881 (m), 858 (m), 753 (s), 695 (m), 675 (m),
624 (s).
Me), 4.0e6.0 (br s, 2H, NH2), 6.94e7.03 (m, 2H), 7.19 (tt, 1H,
3J¼7.4 Hz, 4J¼1.0 Hz), 7.31 (m, 1H), 7.41 (dd, 1H, 3J¼7.6 Hz,
4J¼1.6 Hz), 7.44e7.49 (m, 2H), 7.52 (s, 1H, Py), 8.28e8.31 (m, 2H),
4.3.6. 5-Amino-1-(4-methoxybenzyl)-6-(2-hydroxyphenyl)-1H-pyr-
9.5e10.5 (br s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d
12.3, 112.8,
rolo[2,3-b]pyridine-3-carbonitrile (4f). Yellow solid, mp 78e80 ꢀC
116.5, 118.7, 119.9, 124.2, 126.5, 129.0, 129.8, 131.5, 138.0, 139.8,
140.8, 145.1, 147.2, 155.0, 162.3; MS (GC, 70 eV) m/z (%) 315 (Mþ,
100), 300 (10).
(from heptane/i-PrOH/1:3); 1H NMR (300 MHz, DMSO-d6)
d 3.70 (s,
3H, MeO), 4.90 (br s, 2H, NH2), 5.35 (s, 2H, CH2), 6.87e6.90 (m, 2H),
6.94e7.01 (m, 2H), 7.26e7.32 (m, 3H), 7.38 (dd, 1H, 3J¼7.6 Hz,
4J¼1.0 Hz), 7.46 (s, 1H, Py), 8.36 (s, 1H, ]CHN), 9.5e10.5 (br s, 1H,
4.3.2. 2-[6-Amino-2-(dimethylamino)thiazolo[4,5-b]pyridin-5-yl]
phenol (4b). The compound was purified by a column chroma-
tography (heptane/EtOAc/1:1, Rf¼0.45 (EtOAc)). Yellow solid, mp
OH); 13C NMR (62.9 MHz, DMSO-d6)
d 47.0, 55.0, 80.5, 112.1, 114.0,
115.9,116.4,119.4, 119.5,126.2, 129.1, 129.2, 129.5, 131.5, 136.3, 138.9,
140.0, 142.2, 154.7, 158.8; MS (EI, 70 eV) m/z (%) 370 (Mþ, 46), 121
(100); HRMS (ESI): calcd for C22H18N4O2 (Mþ1) 371.1431, found
158e160 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.14 (s, 6H, Me2N),
4.85 (s, 2H, NH2), 6.88e6.95 (m, 2H), 7.20e7.26 (m, 1H), 7.54 (dd,
371.1430; IR (ATR, cmꢁ1
) n 3348 (w), 3114 (w), 2929 (w), 2215 (m),
1H, 3J¼7.8 Hz, 4J¼1.6 Hz), 7.61 (s, 1H, Py), 10.75 (br s, 1H, OH); 13
C
1609 (w), 1581 (w), 1512 (m), 1484 (w), 1428 (m), 1372 (m), 1303
(m),1276 (m),1244 (s), 1172 (s),1124 (m), 1026 (m), 819 (m), 757 (s),
675 (m), 652 (m), 626 (m), 608 (s).
NMR (62.9 MHz, DMSO-d6)
d 39.4, 116.6, 117.5, 119.0, 124.5, 125.2,
129.0, 130.5, 136.1, 140.4, 155.0, 156.3, 167.0; MS (EI, 70 eV) m/z
(%) 286 (Mþ, 90), 270 (25); HRMS (EI): calcd for C14H14N4OS (Mþ)
286.08046, found 286.08045; IR (ATR, cmꢁ1
)
n
3324 (w), 2923
4.3.7. 5-Amino-1-cyclohexyl-6-(2-hydroxyphenyl)-1H-pyrrolo[2,3-b]
(w), 1583 (s), 1537 (s), 1487 (w), 1435 (m), 1403 (s), 1351 (m),
1274 (m), 1233 (m), 1204 (m), 1121 (m), 1073 (m), 1039 (w), 975
(w), 920 (w), 859 (m), 826 (m), 755 (s), 729 (s), 615 (m), 572 (m),
553 (m).
pyridine-3-carbonitrile (4g). Yellow solid, mp 206e208 ꢀC (from
heptane/i-PrOH/1:3); 1H NMR (300 MHz, DMSO-d6)
d 1.2e2.0 (m,
10H, 5CH2), 4.58 (m, 1H, CHN), 4.82 (br s, 2H, NH2), 6.92e6.98 (m,
2H), 7.25e7.35 (m, 2H), 7.42 (s,1H, Py), 8.41 (s,1H, ]CHN), 9.89 (br s,
1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 24.9, 25.1, 32.5, 53.5, 80.2,
4.3.3. 2-[6-Amino-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-5-yl]phe-
nol (4c). The compound was purified by a column chromatog-
raphy (heptane/EtOAc/1.5:1, Rf¼0.18 (EtOAc)). Yellow solid, mp
111.8, 115.8, 116.2, 119.4, 119.6, 126.3, 129.4, 131.6, 134.0, 138.9, 139.7,
141.8, 154.7; MS (GC, 70 eV) m/z (%) 332 (Mþ, 47), 250 (100); HRMS
(ESI): calcd for C20H20N4O (Mþ1) 333.1710, found 333.1711; IR (ATR,
126e128 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
1.63 (s, 6H, 3CH2),
cmꢁ1
) n 3329 (w), 3131 (w), 2931 (w), 2853 (w), 1607 (w), 1575 (w),
3.55 (s, 4H, 2CH2), 4.86 (br s, 2H, NH2), 6.88e6.95 (m, 2H), 7.22 (t,
1523 (m), 1435 (s), 1395 (m), 1374 (m), 1300 (m), 1260 (m), 1232 (m),
1175 (m), 1147 (m), 1121 (w), 1052 (w), 989 (m), 935 (m), 887 (m),
859 (m), 808 (m), 747 (s), 697 (m), 666 (m), 627 (m), 613 (s).
1H, 3J¼7.05 Hz), 7.52 (d, 1H, 3J¼8.05 Hz), 7.59 (s, 1H, Py),
10.3e11.0 (br s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 23.6,
24.8, 48.8, 116.6, 117.4, 119.0, 124.2, 125.3, 129.1, 130.6, 136.4,
140.4, 155.0, 156.0, 166.8; MS (EI, 70 eV) m/z (%) 326 (Mþ, 100),
310 (41), 257 (13); HRMS (ESI): calcd for C17H18N4OS (Mþ1)
4.3.8. 5-Amino-6-(2-hydroxyphenyl)-2-phenyl-1,2-dihydropyrazolo
[3,4-b]pyridin-3-one (4h). Green solid, mp 195e196 ꢀC (from i-
327.12013, found 327.12830; IR (ATR, cmꢁ1
)
n
2935 (w), 2852 (w),
PrOH/EtOAc/1:1); 1H NMR (300 MHz, DMSO-d6)
d 4.5e5.5 (br s, 2H,
1558 (m), 1531 (s), 1418 (s), 1307 (s), 1246 (s), 1195 (m), 1155 (m),
1120 (m), 1074 (m), 1010 (m), 885 (m), 851 (m), 749 (s), 679 (m),
629 (m), 586 (s).
NH2), 6.93e7.02 (m, 2H), 7.23e7.54 (m, 6H), 7.95 (m, 2H), 10.0e11.0
(br s, 1H, OH), 15.01 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
d
110.3, 116.4, 117.0, 119.0, 119.3, 124.7, 125.6, 128.9, 130.0, 131.1, 137.9,
138.6, 150.0, 151.5, 154.7, 159.4; MS (EI, 70 eV) m/z (%) 318 (Mþ, 100),
302 (28); HRMS (ESI): calcd for C18H14N4O2 (Mþ1) 319.1132, found
4.3.4. 2-(6-Amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)phenol
(4d). The compound was precipitated from the reaction mixture,
filtered off and washed with heptane/i-PrOH/1:1. Brown solid, mp
319.1130; IR (ATR, cmꢁ1
) n 3301 (w), 1645 (m), 1593 (m), 1487 (m),
1455 (w), 1422 (s), 1343 (w), 1304 (m), 1292 (m), 1274 (m), 1211 (m),
1150 (m),1116 (w),1082 (w),1038 (w), 949 (w), 911 (w), 845 (w), 815
(w), 788 (w), 753 (s), 705 (m), 684 (s), 664 (s), 603 (s).
148e150 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.72e3.75 (m, 8H,
4CH2), 4.87e4.91 (br s, 2H, NH2), 6.82 (d, 1H, 3J¼8.6 Hz), 6.94 (t, 1H,
3J¼7.2 Hz), 7.25 (m, 1H), 7.50 (dd, 1H, 3J¼7.7 Hz, 4J¼1.6 Hz), 8.89 (s,
1H, Py), 9.83 (s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d
47.8, 65.5,
4.3.9. 5-Amino-6-(2-hydroxyphenyl)-2-methyl-1,2-dihydropyrazolo
[3,4-b]pyridin-3-one (4i). The compound was precipitated from the
reaction mixture, filtered off and washed with heptane/i-PrOH/1:1.
116.5, 117.2, 119.1, 124.0, 125.3, 129.1, 130.7, 136.9, 140.8, 154.9, 155.5,
167.4; MS (EI, 70 eV) m/z (%) 328 (Mþ, 100), 312 (14), 91 (17); HRMS
(ESI): calcd for C16H16N4O2S (Mþ1) 329.10667, found 329.10649; IR
Red solid, mp 281e283 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.34 (s,
(ATR, cmꢁ1
)
n
3333 (w), 2961 (w), 2850 (w), 1564 (m), 1525 (s),1486
3H, Me), 4.5e5.3 (br s, 2H, NH2), 6.91e7.00 (m, 2H), 7.26e7.35 (m,
(w), 1422 (s), 1375 (m), 1339 (m), 1275 (m), 1234 (s), 1211 (m), 1182
(m), 1111 (s), 1073 (m), 1025 (m), 974 (w), 937 (w), 896 (m), 860 (m),
755 (s), 679 (m), 646 (s), 597 (m).
2H), 7.46 (s, 1H, Py), 9.7e10.7 (br s, 1H, OH), 12.6 (br s, 1H, NH); 13C
NMR (62.9 MHz, DMSO-d6)
d 30.4, 109.9, 116.4, 117.0, 119.3, 125.6,
129.8, 131.1, 138.0, 148.8, 151.1, 154.6, 159.8; MS (EI, 70 eV) m/z (%)
256 (Mþ, 100), 73 (21), 44 (29); HRMS (ESI): calcd for C13H12N4O2
4.3.5. 5-Amino-1-tert-butyl-6-(2-hydroxyphenyl)-1H-pyrrolo[2,3-b]
(Mþ1) 257.10330, found 257.10293; IR (ATR, cmꢁ1
) n 3363 (w), 3017
pyridine-3-carbonitrile (4e). Colorless solid, mp 191e193 ꢀC (from
(w), 1637 (m), 1569 (m), 1478 (m), 1449 (m), 1426 (m), 1325 (w),
1295 (w), 1259 (m), 1234 (m), 1184 (m), 1161 (m), 1098 (w), 1055
(w), 1035 (w), 1018 (w), 959 (w), 904 (w), 851 (w), 834 (w), 759 (s),
685 (s), 654 (m).
heptane/i-PrOH/1:3); 1H NMR (300 MHz, DMSO-d6)
d 1.73 (s, 9H, t-
Bu), 4.91 (br s, 2H, NH2), 6.93e7.00 (m, 2H), 7.25e7.30 (m, 1H), 7.38
(dd, 1H, 3J¼7.6 Hz, 4J¼1.5 Hz), 7.43 (s, 1H, Py), 8.29 (s, 1H, ]CHN),
10.09 (br s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 28.7, 57.8,
79.4, 112.0, 116.3, 116.4, 119.5, 120.9, 126.8, 129.3, 131.6, 134.7, 138.1,
140.6, 141.1, 154.6; MS (GC, 70 eV) m/z (%) 306 (Mþ, 50), 249 (100),
233 (13); HRMS (ESI): calcd for C18H18N4O (Mþ1) 307.1553, found
4.3.10. 5-Amino-6-(2-hydroxyphenyl)-1-methyl-1,2-dihydropyrazolo
[3,4-b]pyridin-3-one (4j). The compound was precipitated from the
reaction mixture, filtered off and washed with heptane/i-PrOH/1:1.
307.1554; IR (ATR, cmꢁ1
)
n
3376 (w), 3305 (w), 3128 (w), 1607 (w),
Red solid, mp 255e257 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.66 (s,
1575 (w), 1519 (m), 1484 (w), 1462 (w), 1407 (m), 1368 (m), 1350
(m), 1304 (w), 1270 (m), 1231 (m), 1211 (s), 1154 (m), 1097 (m), 1046
3H, Me), 4.0e6.0 (br s, 2H, NH2), 6.92e6.98 (m, 2H), 7.26e7.32 (m,
1H), 7.40 (dd, 1H, 3J¼7.6 Hz, 4J¼1.6 Hz), 7.44 (s, 1H, Py), 9.0e12.0 (br

2542
V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d
33.3, 104.4, 114.1, 116.6,
269.11528; IR (ATR, cmꢁ1
) n 3306 (w), 3108 (w), 1633 (m), 1595
126.5, 129.7, 131.4, 135.6, 147.2, 148.2, 152.0, 154.8; MS (EI, 70 eV) m/
z (%) 256 (Mþ, 32), 240 (27), 201 (26), 183 (23), 152 (11), 77 (21);
HRMS (ESI): calcd for C13H12N4O2 (Mþ1) 257.10330, found
(m), 1514 (w), 1479 (w), 1434 (m), 1409 (m), 1384 (m), 1352 (m),
1293 (m), 1241 (m), 1154 (w), 1100 (w), 1007 (w), 831 (w), 753 (m),
701 (m).
257.10349; IR (ATR, cmꢁ1
) n 2931 (w), 2672 (w), 1605 (m), 1582 (m),
1550 (m), 1504 (w), 1475 (w), 1455 (w), 1425 (w), 1379 (w), 1299
(w), 1247 (m), 1229 (m), 1153 (m), 1112 (w), 1068 (w), 1014 (w), 885
(w), 809 (m), 759 (s), 699 (m), 682 (m), 647 (s), 614 (m).
4.3.15. 2-(3-Amino-5,7-dimethoxyquinolin-2-yl)phenol
(4o). The
compound was precipitated from the reaction mixture, filtered off
and washed with i-PrOH/EtOAc/1:1. Brown solid, mp 166e168 ꢀC;
1H NMR (300 MHz, DMSO-d6)
d 3.84 (s, 3H, MeO), 3.94 (s, 3H, MeO),
4.3.11. 6-Amino-7-(2-hydroxyphenyl)-1,3-dimethylpyrido[2,3-d]py-
rimidine-2,4(1H,3H)-dione (4k). The compound was precipitated
from the reaction mixture, filtered off and washed with heptane/i-
PrOH/1:1. Green solid, mp 299e301 ꢀC; 1H NMR (300 MHz, DMSO-
5.04 (br s, 2H, NH2), 6.56 (m, 1H), 6.84 (m, 1H), 6.91e7.02 (m, 2H),
7.30 (m, 1H), 7.57 (d, 1H, 3J¼7.5 Hz), 7.70 (s, 1H, Py), 10.5e11.5 (br s,
1H, OH); 13C NMR (75.5 MHz, DMSO-d6)
d 55.2, 55.8, 98.0, 98.9,
112.2, 116.3, 116.4, 119.0, 124.8, 129.8, 130.5, 138.5, 142.1, 149.1, 154.0,
155.5, 157.5; MS (EI, 70 eV) m/z (%) 296 (Mþ, 92), 280 (35); HRMS
(ESI): calcd for C17H16N2O3 (Mþ1) 297.12337, found 297.12324; IR
d6)
6.91e7.02 (m, 2H), 7.28e7.41 (m, 2H), 7.80 (s, 1H, Py), 9.4e11.0 (br
s, 1H, OH); 13C NMR (75.5 MHz, DMSO-d6)
28.0, 28.9, 109.4, 116.3,
d 3.30 (s, 3H, Me), 3.50 (s, 3H, Me), 4.5e5.7 (br s, 2H, NH2),
d
(ATR, cmꢁ1
) n 3386 (w), 2934 (w), 2833 (w), 1626 (w), 1582 (m),
119.3, 121.5, 125.2, 130.2, 131.4, 139.1, 141.8, 148.3, 150.6, 154.7,
161.0; MS (GC, 70 eV) m/z (%) 298 (Mþ, 100), 281 (18), 207 (19);
HRMS (ESI): calcd for C15H14N4O5 (Mþ1) 299.1139, found
1446 (m), 1422 (w), 1396 (m), 1347 (w), 1331 (w), 1273 (m), 1204 (s),
1156 (s), 1104 (m), 975 (w), 950 (w), 935 (w), 911 (m), 827 (m), 753
(s), 700 (s), 642 (m), 626 (s), 576 (s).
299.1138; IR (ATR, cmꢁ1
) n 3427 (w), 3349 (w), 3271 (w), 3078 (w),
2945 (w), 1694 (m), 1634 (s), 1604 (s), 1470 (m), 1447 (s), 1427 (m),
1356 (s), 1300 (s), 1257 (m), 1228 (m), 1105 (m), 1066 (m), 1018 (m),
981 (m), 911 (m), 834 (w), 804 (w), 781 (m), 738 (s), 692 (m), 675
(m), 638 (m).
4.3.16. 2-(3-Amino-6,7-dimethoxyquinolin-2-yl)phenol
(4p). The
compound was precipitated from the reaction mixture, filtered off
and washed with heptane/i-PrOH/1:1. Brown solid, mp 177e179 ꢀC;
1H NMR (300 MHz, DMSO-d6)
d 3.84 (s, 3H, MeO), 3.94 (s, 3H, MeO),
5.16 (br s, 2H, NH2), 6.56 (s, 1H), 6.85 (s, 1H), 6.89e7.01 (m, 2H), 7.29
4.3.12. 6-Amino-7-(2-hydroxyphenyl)-1-methylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (4l). The compound was precipitated from
the reaction mixture, filtered off and washed with heptane/i-PrOH/
1:1. Brown solid, mp 290e292 ꢀC; 1H NMR (300 MHz, DMSO-d6)
(m, 1H), 7.56 (d, 1H, 3J¼7.6 Hz), 7.69 (s, 1H, Py), 10.93 (s, 1H, OH); 13
C
NMR (62.9 MHz, DMSO-d6)
d 55.2, 55.8, 97.9, 98.9, 112.2, 116.4,
116.5, 118.8, 125.0, 129.8, 130.6, 138.6, 142.2, 149.3, 154.0, 155.8,
157.5; MS (GC, 70 eV) m/z (%) 295 (Mþ, 100), 280 (27); HRMS (ESI):
calcd for C17H16N2O3 (Mþ) 296.11554, found 296.11544; IR (ATR,
d
3.44 (s, 3H, Me), 5.10 (br s, 2H, NH2), 6.92e7.01 (m, 2H), 7.30 (m,
1H), 7.40 (dd,1H, 3J¼7.6 Hz, 4J¼1.5 Hz), 7.76 (s,1H, Py),10.0e12.0 (br
cmꢁ1
) n 3314 (w), 2936 (w), 2834 (w), 1626 (w), 1582 (m), 1504 (w),
s, 2H, OH, NH); 13C NMR (62.9 MHz, DMSO-d6)
d
28.0, 110.2, 116.4,
1445 (m), 1396 (w), 1348 (w), 1330 (w), 1272 (m), 1204 (s), 1155 (m),
1126 (m), 1104 (m), 1046 (m), 935 (w), 911 (m), 826 (m), 751 (s), 700
(m), 642 (m), 626 (m), 575 (m).
119.3, 121.4, 125.2, 130.2, 131.2, 138.9, 143.1, 148.1, 150.4, 154.7, 161.5;
MS (GC, 70 eV) m/z (%) 284 (Mþ, 100), 240 (14), 78 (15); HRMS (ESI):
calcd for C14H12N4O5 (Mþ1) 285.09822, found 285.09838; IR (ATR,
cmꢁ1
)
n
3341 (w), 3152 (w), 3041 (w), 2844 (w), 1681 (s), 1610 (m),
4.3.17. 2-(3-Amino-7-(dimethylamino)quinolin-2-yl)phenol
(4q). The compound was precipitated from the reaction mixture,
filtered off and washed with heptane/i-PrOH/1:1. Brown solid, mp
1586 (m),1468 (m), 1451 (m), 1411 (s), 1379 (m), 1286 (m), 1229 (m),
1206 (w), 1149 (w), 1103 (w), 1077 (w), 998 (w), 943 (m), 914 (w),
813 (m), 788 (m), 765 (w), 734 (s), 723 (s), 687 (m), 665 (w), 636
(m), 583 (s), 566 (m).
240e242 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 2.98 (s, 6H, Me2N),
4.91 (br s, 2H, NH2), 6.91e6.99 (m, 3H), 7.18e7.31 (m, 2H), 7.41 (s,
1H), 7.55 (d, 1H, 3J¼8.5 Hz), 7.68 (dd, 1H, 3J¼7.5 Hz, 4J¼1.4 Hz),
4.3.13. 6-Amino-7-(2-hydroxyphenyl)pyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (4m). The compound was precipitated from the
reaction mixture, filtered off and washed with heptane/i-PrOH/1:1.
11.0e11.8 (br s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6)
d 40.4,
106.3, 116.6, 117.3, 117.8, 118.9, 121.2, 124.6, 125.8, 130.0, 130.2, 137.5,
142.3, 148.7, 148.8, 155.9; MS (GC, 70 eV) m/z (%) 279 (Mþ, 100), 262
(37); HRMS (ESI): calcd for C17H17N3O (Mþ1) 280.14444, found
Brown solid, mp 309e311 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 5.00
(br s, 2H, NH2), 6.91 (t, 1H, 3J¼7.4 Hz), 6.99 (d, 1H, 3J¼7.8 Hz), 7.28
(m, 1H), 7.35 (dd, 1H, 3J¼7.8 Hz, 4J¼1.5 Hz), 7.68 (s, 1H, Py),
10.0e12.0 (br s, 3H, OH, NH); 13C NMR (62.9 MHz, DMSO-d6)
280.14436; IR (ATR, cmꢁ1
) n 3392 (w), 3324 (w), 2919 (w), 1623 (m),
1602 (w), 1573 (w), 1553 (w), 1505 (m), 1428 (m), 1280 (m), 1244
(m), 1223 (m), 1184 (m), 1148 (m), 1008 (m), 971 (w), 936 (w), 918
(w), 884 (w), 823 (m), 793 (m), 757 (s), 725 (m), 693 (s).
d
109.0, 116.4, 119.0, 120.7, 124.6, 130.2, 130.9, 139.0, 143.4, 149.1,
150.2, 154.9, 162.6; MS (GC, 70 eV) m/z (%) 270 (Mþ, 96), 224 (16),
160 (17), 128 (100), 97 (31); HRMS (ESI): calcd for C13H10N4O3
(Mþ1) 271.08257, found 271.08298; IR (ATR, cmꢁ1
)
n
3246 (w),
4.4. X-ray crystallographic data
3043 (w), 1682 (m), 1608 (m), 1487 (w), 1416 (m), 1385 (m), 1299
(w), 1275 (w), 1239 (w), 1215 (w), 1101 (w), 1043 (w), 888 (w), 851
(m), 813 (w), 749 (m), 677 (w), 624 (m), 574 (s).
X-ray crystallographic data (excluding structure factors) for the
structure 3a, 3e, 3f, 3k, 3o, and 3r, reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. 829051e829056, can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44 1223 336033; e-mail: depos-
it@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_request/cif.
4.3.14. 2-(2,4,7-Triaminopyrido[3,2-d]pyrimidin-6-yl)phenol
(4n). The compound was precipitated from the reaction mixture,
filtered off and washed with heptane/i-PrOH/1:1. Green solid, mp
169e171 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 5.04 (br s, 2H, NH2),
6.94 (m, 1H), 7.07 (d, 1H, 3J¼8.0 Hz), 7.30 (m, 2H), 7.94 (s, 1H, Py),
8.84 (s, 1H, NH), 9.10 (s, 1H, NH), 10.33 (br s, 1H, OH), 12.50 (br s,
2H, NH2); 13C NMR (62.9 MHz, DMSO-d6)
d
104.5, 116.3, 119.3,
Supplementary data
124.2, 130.5, 130.9, 140.5, 141.2, 151.4, 154.7, 155.1, 162.3, 162.9; MS
(GC, 70 eV) m/z (%) 267 (Mþ, 100), 252 (22), 207 (15), 84 (17);
HRMS (ESI): calcd for C13H12N6O (Mþ1) 269.11454, found
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.06.101.

V.O. Iaroshenko et al. / Tetrahedron 68 (2012) 2532e2543
2543
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www.ccdc.cam.ac.uk/data_request/cif.
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