Reactions of chromone-3-carboxylic acid and chromone-3-carboxamides with cyanoacetic acid hydrazide

Article abstract of DOI:10.1016/j.mencom.2016.01.028

Chromone and chromone-3-carboxylic acid react with cyanoacetic acid hydrazide in the presence of NaOEt in boiling ethanol to form 6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one (58-62% yields), whereas reaction between chromone-3-carboxamides and cyanoacetic acid hydrazide under the same conditions affords 1-amino-2,5-dioxo-2,5-dihydro-1H-chromeno[4,3-b]pyridine-3-carbonitriles (50-67% yields).

Full text of DOI:10.1016/j.mencom.2016.01.028

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Mendeleev
Communications
Mendeleev Commun., 2016, 26, 72–74
Reactions of chromone-3-carboxylic acid and
chromone-3-carboxamides with cyanoacetic acid hydrazide
Mikhail Yu. Kornev,a Vladimir S. Moshkin,a Oleg S. Eltsovb and Vyacheslav Ya. Sosnovskikh*a
a Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg, Russian Federation.
Fax: +7 343 261 5978; e-mail: vy.sosnovskikh@urfu.ru
b Institute of Chemistry and Technology, Ural Federal University, 620002 Ekaterinburg, Russian Federation
DOI: 10.1016/j.mencom.2016.01.028
Chromone and chromone-3-carboxylic acid react with cyanoacetic acid hydrazide in the presence of NaOEt in boiling ethanol to form
6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one (58–62% yields), whereas reaction between chromone-3-carboxamides
and cyanoacetic acid hydrazide under the same conditions affords 1-amino-2,5-dioxo-2,5-dihydro-1H-chromeno[4,3-b]pyridine-
3-carbonitriles (50–67% yields).
Recently, chromones bearing electron-withdrawing groups at the
3-position (CHO, COR or CN) received considerable attention
since their g-pyrone ring represents geminally activated alkene
with three electrophilic centers (the C-2 and C-4 atoms and the
3-substituent) and a good leaving group at C-2 (the phenolate
anion). Of the three possible sites of a nucleophilic attack,
conjugated addition at C-2, which is usually accompanied by
pyrone ring opening and recyclizations with the participation of
the phenol oxygen atom or the second nucleophilic center of the
reagent, most frequently occurs.1 This provides great synthetic
opportunities, however, it is difficult to define the site of an
initial attack and the direction of the subsequent recyclization.
Therefore, the regiochemistry of the end products formed from
3-substituted chromones is the problem of priority importance.2
w-formyl-2-hydroxyacetophenone 3 in the reactions with amines
and cyanoacetamide6 (Scheme 1).
On the basis of the 1H NMR spectrum, Ibrahim6 preferred the
doubtful 1,2-diazepine structure of compound 5 with enolized
amide carbonyl for the product of a reaction of acid 1a with
cyanoacetic acid hydrazide (CAH) among two proposed struc-
tures 4 and 5 (Scheme 2).
O
X
O
1a X = CO2H
1d X = H
In the series of 3-substituted chromones, the best studied com-
NaOEt, EtOH,
NCCH2CONHNH2
5
p
ounds are 3-formyl-,1 3-aroyl-,3 3-polyhaloacyl-,4 3-methoxalyl-3,
O
and 3-cyanochromones.2 At the same time, in spite of the high
synthetic value of 3-R-chromones, chromone-3-carboxylic acid
1a and its amide 1b have been first systematically studied by
Ibrahim.6–8 In 1974, the rearrangement of ethyl chromone-
3-carboxylate 1c into 4-hydroxy-3-formylcoumarin 2 in a basic
medium9 was described for the first time. In this context, it
would be reasonable to expect that compounds 1a and 1b could
behave as the synthetic equivalents of coumarin 2 in reactions
with nucleophiles. Indeed, chromones 1a and 1b give the appro-
priate derivatives of 4-hydroxy-3-formylcoumarin 2 with amines,
hydrazines, hydroxylamine, guanidines and thiourea.6–8 Further-
more, acid 1a undergoes decarboxylation and acts as hidden
CN
HO
O
NH
a
O
C
NH2
HN
O
N
b
NH2
OH
route b
?
route a
this work
O
ref. 6
4
CN
NC
OH
5
NH
6'
3'
N
O
N
5'
4'
N
H
6
N
H
N
HO
HO
NH2
H
O
5
4
OH
O
O
O
O
Scheme 2
H2O
Base
H
X
On reproducing this synthesis (boiling in EtOH in the presence
of NaOEt for 2 h), we isolated a product (62% yield), which
coincided with that obtained by Ibrahim6 in its spectral charac-
teristics and elemental analysis data. We also obtained the same
COX
O
X = OH
– CO2
X = OH, NH2,
OEt
1a–c
– HX
c
ompound from unsubstituted chromone 1d; this fact was indicative
OH
O
O
OH
O
O
of the decarboxylation of acid 1a in the course of reaction and its
participation as a synthetic equivalent of w-formyl-2-hydroxy-
acetophenone 3. We assigned its structure to pyrazolo[3,4-b]-
H
H
O
1
3
a X = OH
b X = NH2
c X = OEt
pyridine derivative 6 based on a comparison of its H NMR
2
spectra with that of close analogue 2-(2-hydroxyphenyl)-7,7-di-
methyl-7,8-dihydroquinolin-5(6H)-one 710 recorded in DMSO-d6
(Figure 1). In the IR spectrum, an absorption band characteristic
Scheme 1
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 72 –

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Mendeleev Commun., 2016, 26, 72–74
O
O
3-carboxamide 8d failed (see Online Supplementary Materials).
We assume that the initially formed intermediate A with the
Z-configuration of the double bond is isomerized into E-A through
bipolar intermediate B. Because of the contiguous arrangement
of reaction centers, E-A is cyclized into coumarin derivative 9
with the release of water and ammonia molecules (Scheme 3).
This isomerization occurs more rapidly than the interaction
between the amino and cyano groups of intermediate Z-A since
the formation of products 10 was not observed. In this context,
note that the reaction of chromones 8 with cyanoacetamide gives
2-pyridones 11.7,14
8.20
8.31
J 8.6 Hz
J 8.5 Hz
7.70
8.22
NH
Me
Me
7.96
8.08
N
N
N
H
H
13.68
H
13.98
O
O
7
6
Figure 1 1H NMR (DMSO-d6) data for compounds 6 and 7.
of CN group in the region 2200–2250 cm–1 was absent.† Further-
more, it is well known that b-keto aldehydes,11 b-diketones12
and isoflavones13 react with CAH or its cyclic form, 5-amino-
1H-pyrazol-3(2H)-one, to afford pyrazolo[3,4-b]pyridines.
A probable reaction mechanism includes the nucleophilic
addition of methylene active CAH at the C-2 atom of chromones
1a,d with the subsequent pyrone ring opening, decarboxylation
(in the case of 1a) and tandem cyclization into pyrazolopyridine
6, in which the carbonyl group of chromone is attacked by the
nitrogen atom of the nitrile group rather than hydrazino group
(see Scheme 2).
The reaction of 3-carbamoylchromones 8a–c (8a = 1b) with
CAH was not studied earlier. We established that, in contrast to
acid 1a, amides 8a–c react with CAH under analogous conditions
in a completely different manner to give previously unknown
1-amino-2,5-dioxo-2,5-dihydro-1H-chromeno[4,3-b]pyridine-
3-carbonitriles 9a–c in 50–67% yields (Scheme 3).‡ Our attempts
to isolate a corresponding product with 6-nitro-4-oxochromene-
The regioisomeric structure 12 was excluded based on an
analysis of the results of 1H–13C HSQC and HMBC 2D experi-
ments performed for compound 9b. The most informative cross
peaks of the 2D HMBC spectrum are the peaks H4/CN, H4/C10b
,
H4/C5, H4/C2, NH2/C10b, NH2/C2. In addition, the cross peaks
of the H-4 atom with nitrogen atoms are absent from the 2D
1H–15N HMBC spectrum (see Online Supplementary Materials).
1
Note that, in the H NMR spectra of chromeno[4,3-b]pyridines
9a–c, the signal of the H-10 proton occurs in an uncommonly
low field at d 9.62–9.90 ppm; this is due to the angular structure of
the skeleton rather than the deshielding effect of the NH2 group.15
The synthesis of 1-amino-3-cyano-8-fluoro-2-oxo-1,2-dihydro[1,2]-
benzoxathiino[4,3-b]pyridine 5,5-dioxide from phenyl 7-fluoro-
chromone-3-sulfonate and CAH is the nearest analogue of the
described reaction.16
O
H2N
CN
†
The NMR spectra were recorded on Bruker DRX-400 andAVANCE-500
O
O
N
spectrometers with TMS as an internal standard. The IR spectra were
recorded on a Nicolet 6700 instrument (FTIR mode, ZnSe crystal).
6-(2-Hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one 6. This
compound was prepared according to a published procedure.6 Yield,
140 mg (62%), yellow powder, mp > 300°C (lit.,6 mp > 300°C). 1H NMR
(400 MHz, DMSO-d6) d: 6.89 (t, 1H, H-5', J 7.7 Hz), 6.90 (d, 1H, H-3',
J 7.8 Hz), 7.27 (td, 1H, H-4', J 7.7, 1.3 Hz), 7.70 (d, 1H, H-5, J 8.5 Hz),
7.96 (d, 1H, H-6', J 7.8 Hz), 8.20 (d, 1H, H-4, J 8.5 Hz), 10.80 (br.s,
1H, NH), 12.12 (br.s, 1H, NH), 13.68 (s, 1H, OH). 13C NMR (126 MHz,
DMSO-d6) d: 103.5, 111.7, 117.9, 119.1, 119.6, 128.1, 131.6, 131.7,
149.4, 154.2, 156.6, 158.8. IR (n/cm–1): 3279, 2936, 2567, 1663, 1603,
1578, 1556, 1505, 1490, 1430. Found (%): C, 63.30; H, 4.04; N, 18.10.
Calc. for C12H9N3O2 (%): C, 63.43; H, 3.99; N, 18.49. Product 6 was also
obtained from chromone 1d under the same conditions in 58% yield.
R
R
NCCH2CONHNH2
NaOEt, EtOH,
NH2
O
O
O
a R = H
b R = Me
c R = Cl
8a–c
9a–c
– H2O,
– NH3
O
OH
R
O
O
CN
H2NHN
O
NH2
CN
R
H2N
CONH2
N
O
OH
H
‡
A mixture of chromone-3-carboxamide 8 (1.0 mmol), CAH (0.10 g,
Z-A
E-A
OH
R
O
O
1 mmol) and sodium ethoxide, which was prepared by dissolving sodium
(0.023 g, 1.0 mmol) in 4 ml of absolute ethanol, was refluxed for 2 h.
After cooling, the reaction mixture was neutralized with dilute HCl. The
solid obtained was filtered and crystallized from DMF–butanol (1:5) to
give 9 as colored crystals.
1-Amino-2,5-dioxo-2,5-dihydro-1H-chromeno[4,3-b]pyridine-3-carbo-
nitrile 9a.Yield, 126 mg (50%), red powder, mp 235° (decomp.). 1H NMR
(500 MHz, DMSO-d6) d: 6.51 (s, 2H, NH2), 7.48 (td, 1H, H-9, J 7.8,
1.0 Hz), 7.51 (dd, 1H, H-7, J 8.3, 1.0 Hz), 7.81 (td, 1H, H-8, J 7.8, 1.2 Hz),
8.75 (s, 1H, H-4), 9.79 (dd, 1H, H-10, J 8.6, 1.2 Hz). 13C NMR (126 MHz,
DMSO-d6) d: 100.7, 102.8, 113.1, 115.0, 117.9, 124.4, 130.6, 134.9, 144.9,
148.7, 153.6, 157.8, 159.8. IR (n/cm–1): 3297, 3204, 3133, 3063, 2235
(CºN), 1730 (C=O), 1679 (C=O), 1609, 1526, 1488, 1455. Found (%):
C, 61.40; H, 2.74; N, 16.54. Calc. for C13H7N3O3 (%): C, 61.66; H, 2.79;
N, 16.59.
NH2
CN
H2N
HN
O
O
B
OH
R
O
O
NC
NH2
N
O
NH
R
NH2
CONHX
O
10 X = NH2
11 X = H
12
Scheme 3
1-Amino-9-methyl-2,5-dioxo-2,5-dihydro-1H-chromeno[4,3-b]pyridine-
3-carbonitrile 9b.Yield, 156 mg (58%), light brown powder, mp 244–247°C.
1H NMR (500 MHz, DMSO-d6) d: 2.42 (s, 3H, Me), 6.51 (s, 2H, NH2),
7.41 (d, 1H, H-7, J 8.4 Hz), 7.63 (dd, 1H, H-8, J 8.4, 1.5 Hz), 8.73 (s, 1H,
H-4), 9.62 (d, 1H, H-10, J 1.5 Hz). 13C NMR (126 MHz, DMSO-d6) d:
20.9, 100.6, 102.7, 112.7, 115.0, 117.6, 130.1, 133.5, 135.7, 144.9, 148.6,
151.7, 157.9, 159.7. IR (n/cm–1): 3300, 3228, 3211, 3133, 3062, 2235
(CºN), 1730 (C=O), 1677 (C=O), 1614, 1594, 1527, 1487, 1455. Found
(%): C, 62.61; H, 3.25; N, 15.65. Calc. for C14H9N3O3 (%): C, 62.92;
H, 3.39; N, 15.72.
1-Amino-9-chloro-2,5-dioxo-2,5-dihydro-1H-chromeno[4,3-b]pyridine-
3-carbonitrile 9c.Yield, 194 mg (67%), light brown powder, mp 237–239°C.
1H NMR (500 MHz, DMSO-d6) d: 6.49 (s, 2H, NH2), 7.55 (d, 1H, H-7,
J 8.5 Hz), 7.87 (d, 1H, H-8, J 8.5 Hz), 8.76 (s, 1H, H-4), 9.90 (s, 1H,
H-10). 13C NMR (126 MHz, DMSO-d6) d: 101.6, 103.1, 114.3, 114.8,
119.8, 128.0, 129.5, 134.4, 144.9, 147.8, 152.3, 157.4, 159.7. IR (n/cm–1):
3304, 3199, 3133, 3056, 2232 (CºN), 1729 (C=O), 1682 (C=O), 1632,
1605, 1593, 1569, 1514, 1474, 1410. Found (%): C, 54.04; H, 2.30;
N, 14.56. Calc. for C13H6ClN3O3 (%): C, 54.28; H, 2.10; N, 14.61.
– 73 –

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Mendeleev Commun., 2016, 26, 72–74
References
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the step of hydrazone 1418 (Scheme 4).
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NHCOCH2CN
N
O
H
13
14
Scheme 4
Thus, the reactions of CAH with 3-R-chromones (R = CO2H,
CONH2, and CHO) in the presence of NaOEt in boiling EtOH
occur differently depending on the nature of the substituent R to
give three types of products. In these cases, CAH acts either as a
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This work was supported by the Russian Science Foundation
(grant no. 14-13-00388).
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.01.028.
Received: 19th June 2015; Com. 15/4653
– 74 –