Structure of reaction products of 3-cyanochromones with ethylenediamine

Article abstract of DOI:10.1007/s11172-010-0372-0

A reaction of 3-cyanochromones with ethylenediamine in ethanol afforded N,N′-ethyl-ene-bis(2-amino-3-iminomethylchromones), which depending on the time of reflux in acetic acid give 2-amino-3-formylchromones or products of their dimerization, 2-(chromon-3-yl)-5H-chromeno[2,3-d]pyrimidin-5-ones.

Full text of DOI:10.1007/s11172-010-0372-0

Russian Chemical Bulletin, International Edition, Vol. 59, No. 11, pp. 2151—2154, November, 2010
2151
Structure of reaction products of 3ꢀcyanochromones with ethylenediamine
V. Ya. Sosnovskikh,a V. S. Moshkin,a and O. S. El´tsovb
aA. M. Gorky Ural State University,
51 prosp. Lenina, 620083 Ekaterinburg, Russian Federation.
Fax: +7 (343) 261 5978. Eꢀmail: Vyacheslav.Sosnovskikh@usu.ru
bB. N. Eltsyn Ural State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation
A reaction of 3ꢀcyanochromones with ethylenediamine in ethanol afforded N,N´ꢀethylꢀ
eneꢀbis(2ꢀaminoꢀ3ꢀiminomethylchromones), which depending on the time of reflux in acetic
acid give 2ꢀaminoꢀ3ꢀformylchromones or products of their dimerization, 2ꢀ(chromonꢀ3ꢀyl)ꢀ
5Hꢀchromeno[2,3ꢀd]pyrimidinꢀ5ꢀones.
Key words: 3ꢀcyanochromones, ethylenediamine, recyclization, 2ꢀaminoꢀ3ꢀformylꢀ
chromones, 2ꢀaminoꢀ3ꢀiminomethylchromones, 2ꢀ(chromonꢀ3ꢀyl)ꢀ5Hꢀchromeno[2,3ꢀd]ꢀ
pyrimidinꢀ5ꢀones.
It is known that introduction of a nitrile group into
chromones at position 3 significantly changes reactivity of
the pyrone ring with respect to nucleophilic agents and
provides wide synthetic possibilities of this very important
oxygenꢀcontaining heterocyclic system.1 Recently,2 we
have shown that the reaction of 3ꢀcyanochromones 1 with
primary aromatic and aliphatic amines begins from the
attack on the unsubstituted atom C(2) and is accompaꢀ
nied by the pyrone ring opening, that leads to the formaꢀ
tion of a mixture of Zꢀ and Eꢀ3ꢀaryl/alkylaminoꢀ2ꢀ(2ꢀ
hydroxyaroyl)acrylonitriles 2, which readily and irreversꢀ
ibly cyclize to 2ꢀaminoꢀ3ꢀ(aryl/alkyliminomethyl)chromꢀ
ones 3 (Scheme 1).
From these data, it followed that the product of the
reaction of 1 with oꢀphenylenediamine should have the
structure of 2ꢀaminoꢀ3ꢀ(2ꢀaminophenyliminomethyl)ꢀ
chromone 6, rather than the benzodiazepine structures 4
or 5 as was indicated in the literature,3,4 which was conꢀ
firmed by us based on the spectroscopic data.5 Taking into
account the results obtained,2,5 it could have been expected
that the reaction of 3ꢀcyanochromone 1 with more nucleoꢀ
philic ethylenediamine would lead to bisꢀimine 7.
Scheme 1
R = H (a), Me (b), Et (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2097—2100, November, 2010.
1066ꢀ5285/10/5911ꢀ2151 © 2010 Springer Science+Business Media, Inc.

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Sosnovskikh et al.
Analysis of published reports showed that this reaction
has been already studied, however, the 1,5ꢀdiazocine strucꢀ
ture 8 was assigned to the products obtained based on the
spectral data and the fact that they hydrolyze to 2ꢀaminoꢀ
3ꢀformylchromones upon reflux in acetic acid.6 The
present study was undertaken in order to clear the arisen
contradiction with respect to the structure of the products
of reaction of 3ꢀcyanochromones 1 with ethylenediamine.
spectroscopic data, after reflux of compound 7a in ethanol
for 3.5 h the reaction mixture contained 9a—10a (3 : 2),
while the full transformation 7a,b → 10a,b required
10—12 h. In addition, it turned out that other 2ꢀaminoꢀ3ꢀ
iminomethylchromones 3 can be also involved into the
selfcondensation reaction. For instance, reflux of comꢀ
pound 3a with R´ = Pri and 2ꢀHOC6H4 in acetic acid
gives dimer 10a in 28 and 60% yields, respectively (Scheme 2).
Earlier, dimers 10a,b have been obtained on reflux of
3ꢀcyanochromones 1a,b with ammonium acetate in aceꢀ
tic acid,3 the equimolar mixture of chromones 1a,b and
9a,b in acetic acid,3 chromone 9a in toluene in the presꢀ
ence of pꢀtoluenesulfonic acid,7 as well as from 2ꢀaminoꢀ
3ꢀ(pꢀtolyliminomethyl)chromones 3a,b (R´ = 4ꢀMeC6H4)
in boiling DMF (see Ref. 8). The mechanism of formation
of compounds 10 either was not discussed at all7, or
was considered as 1,2ꢀaddition of the NH2 group of
chromone 9 at the CN group of chromone 1 with subseꢀ
quent intramolecular cyclization involving arising amiꢀ
dine functional group and CHO group.3 The case of
chromones 3a,b (R´ = 4ꢀMeC6H4)8 assumed a possibiꢀ
lity of partial reverse transformation of 3 to 1 with further
1,2ꢀaddition at the CN group and cyclization involvꢀ
ing the CH=NC6H4Meꢀ4 fragment similarly to chromꢀ
one 9.3
Results and Discussion
Heating 3ꢀcyanochromones 1a,b (1 equiv.) with ethꢀ
ylenediamine (0.5 equiv.) in ethanol for 10 min gives
84—86% yields of products, whose structure was inferred
1
from the elemental analysis data and H NMR spectroꢀ
scopic data and found as N,N´ꢀethyleneꢀbis(2ꢀaminoꢀ3ꢀ
1
iminomethylchromones) 7a,b. Thus, the H NMR specꢀ
tra of these compounds in DMSOꢀd6, in addition to the
signals for the aromatic protons, exhibit singlets for the
CH2 and CH=N groups at δ 3.8 and 8.7, respectively,
while the protons of the NH2 group, which are nonequivaꢀ
lent due to the intramolecular hydrogen bonds (IMHB),
are found as somewhat broadened singlets at δ 8.8 and
10.8 These results are in good agreement with the data for
2ꢀaminoꢀ3ꢀiminomethylchromones 3 described by us in
the preceding work2 and allow us to reject the diazocine
structure 8 suggested earlier6 for the products of the reacꢀ
tion under consideration in favor of bisꢀimines 7. The
work6 also reported that diazocines 8a,b (in fact, bisꢀimiꢀ
nes 7a,b) on reflux in acetic acid for 0.5 h hydrolyze to
2ꢀaminoꢀ3ꢀformylchromones 9a,b. We found that if this
reaction is carried out over longer time, the initially formed
chromones 9a,b undergo selfcondensation to chromenoꢀ
[2,3ꢀd]pyrimidinꢀ5ꢀones 10a,b. According to the 1H NMR
Taking into account the fact that the results in works3,9
on the study of 3ꢀcyanochromones 1, which assumed
a possibility of nucleophilic 1,2ꢀaddition at the cyano
group, later were not confirmed,5,10—12 we suggest that
chromeno[2,3ꢀd]pyrimidinꢀ5ꢀones 10 are formed without
involvement of 1 and are the products of selfcondensation
of 2ꢀaminoꢀ3ꢀformylchromones 9 or their imines 3; the
latter give the reaction either due to their iminoꢀenamine
form, or are initially hydrolyzed to compounds 9, which in
Scheme 2
R = H (a), Me (b); R´ = Pri, 2ꢀHOC6H4, 4ꢀMeC6H4

Reaction of 3ꢀcyanochromones with ethylenediamine Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010 2153
Scheme 3
turn give 10. A plausible mechanism of this reaction is
given in Scheme 3 and includes in the first step (1,2 AN—E
between the NH2 group of one molecule and the CH=X
group of another molecule) formation of the intermediate
A, whose further intramolecular cyclization can proceed
through the 1,2 AN—E (a) or 1,4 AN—E (b) pathways.
Judging from our data, the first direction leading to diazoꢀ
cine 8 is not realized, while the second gives the spirointꢀ
ermediate B, which further recyclize to chromenopyrimiꢀ
dine 10 through the intermediates C and D.
J = 7.9 and 1.7 Hz. The signals for the protons H(2´) and
H(4) are the most downfield and are observed at δ 9.1 and
9.6, respectively.
In conclusion, the reaction of 3ꢀcyanochromones 1
with ethylenediamine leads to the formation of bisꢀimines
7 rather than 1,5ꢀdiazocines 8, as it has been indicated
earlier.6 The imines on reflux in acetic acid through the
step of formation of 2ꢀaminoꢀ3ꢀformylchromones 9 are
transformed to chromenopyrimidines 10. The acid and
base catalyzed selfcondensation of compounds 3 and 9 to
dimers 10 is a characteristic property of 2ꢀaminoꢀ3ꢀ
formylchromones and their imines. Therefore, the data in
the work,13 in which the structure of 1,5ꢀdiazocine 8c was
assigned to the product of selfcondensation of 3ꢀcyanoꢀ6ꢀ
ethylchromone in the presence of piperidine, are doubtful
and need to be verified.
The structure of dimers 10a,b was confirmed by the 1H
and 13C NMR spectroscopic data, the full assignment of
all the signals, which has not been made earlier, was perꢀ
1
formed based on analysis of the H—13C HSQC and
HMBC 2Dꢀexperiments using 10a as an example. The
most informative were the crossꢀpeaks in the 2D HMBC
spectrum in DMSOꢀd6: H(2´)/C(3´), H(2´)/C(8a´),
H(2´)/C(2), H(2´)/C(4´), H(4)/C(4a), H(4)/C(2),
H(4)/C(10a) and H(4)/C(5). A specific feature of the
1H NMR spectra of compounds 10 consists in the double
set of signals for the aromatic protons, which are very
close in chemical shifts and partially overlap, as a result in
the case of 10a, doublets of doublets for the protons H(6)
and H(5´) are found at δ 8.21 as a triplet of doublets with
Experimental
IR spectra were recorded on a Perkin—Elmer Spectrum
1
BXꢀII spectrometer in KBr pellets. H and 13C NMR spectra
were recorded on a Bruker DRXꢀ400 and Bruker Avance II
spectrometers in DMSOꢀd6 (400 and 100 MHz, respectively)
with Me4Si as an internal standard. Solvents were purified acꢀ

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Sosnovskikh et al.
cording to the standard procedures. Chromones 1a,b and 3a
(R´ = Pri) have been described earlier.2,3
(C(8´)), 121.6 (C(3´)), 122.5 (C(4a´)), 124.5 (C(5a)), 125.5
(C(5´)), 125.6 (C(6´)), 126.0 (C(6)), 126.3 (C(7)), 134.6 (C(7´)),
136.5 (C(8)), 155.0 (C(8a´)), 155.3 (C(9a)), 158.5 (C(4)), 160.9
(C(2´)), 164.2 (C(2)), 165.2 (C(10a)), 173.0 (C(4´)), 175.7 (C(5)).
Dimer 10a was also obtained from 7a (40% yield) and 3a
(R´ = Pri) (28% yield) under similar conditions except that reflux
in acetic acid continued for 10—12 h.
7ꢀMethylꢀ2ꢀ(6ꢀmethylchromonꢀ3ꢀyl)ꢀ5Hꢀchromeno[2,3ꢀd]ꢀ
pyrimidinꢀ5ꢀone (10b). A solution of bisꢀimine 7b (200 mg,
0.5 mmol) in glacial acetic acid (3.5 mL) was refluxed for 12 h,
cooled, crystals formed were filtered off, washed with acetic
acid, ethanol, and dried. The yield was 53 mg (31%), yellow fine
crystal, m.p. 303—304 °C (cf. Ref. 3: m.p. 297 °C). 1H NMR, δ:
2.48 (s, 6 H, 2 Me); 7.68 (d, 1 H, H(8´), J = 8.6 Hz); 7.72
(d, 1 H, H(9), J = 8.6 Hz); 7.72 (dd, 1 H, H(7´), J = 8.6 Hz,
J = 2.3 Hz); 7.80 (dd, 1 H, H(8); J = 8.6 Hz, J = 2.3 Hz); 7.98
(d, 1 H, H(5´), J = 2.3 Hz); 8.02 (d, 1 H, H(6), J = 2.3 Hz); 9.09
(s, 1 H, H(2´)); 9.56 (s, 1 H, H(4)).
2ꢀAminoꢀ3ꢀ(2ꢀhydroxyphenyliminomethyl)chromone (3a)
(R´ = 2ꢀHOC6H4). A solution of chromone 9a (200 mg, 1.06 mmol)
and oꢀaminophenol (120 mg, 1.1 mmol) in dry toluene (5 mL)
was refluxed for 5 h, cooled, a precipitate formed was filtered
off, washed with toluene, and dried. The yield was 260 mg (88%),
yellow lamellar crystals, m.p. 225—227 °C. Found (%): C, 68.71;
H, 4.18; N, 10.08. C16H12N2O3. Calculated (%): C, 68.56;
H, 4.32; N, 9.99. IR, ν/cm–1: 3266, 3147, 1655, 1614, 1555,
1494, 1462. 1H NMR, δ: 6.84 (td, 1 H, H(5´), J = 7.5 Hz,
J = 1.4 Hz); 6.89 (dd, 1 H, H(3´), J = 8.0 Hz, J = 1.4 Hz); 7.03
(ddd, 1 H, H(4´), J = 8.0 Hz, J = 7.3 Hz, J = 1.6 Hz); 7.09 (dd, 1 H,
H(6´), J = 7.8 Hz, J = 1.6 Hz); 7.41—7.46 (m, 2 H, H(6), H(8));
7.71 (ddd, 1 H, H(7), J = 8.5 Hz, J = 7.2 Hz, J = 1.7 Hz); 8.05
(dd, 1 H, H(5), J = 7.8 Hz, J = 1.7 Hz); 9.00 (s, 1 H, =CH); 9.20
(br.s, 1 H, OH); 9.29 (br.s, 1 H, NH); 10.84 (br.s, 1 H, NH).
2ꢀAminoꢀ3ꢀ{2ꢀ[(2ꢀaminochromonꢀ3ꢀyl)methylidene]aminoꢀ
ethyl}iminomethylchromone (7a) was obtained according to the
procedure described earlier.6 The yield was 84%, m.p. 225—227 °C
(cf. Ref. 6: m.p. 210 °C for 8a). Found (%): C, 65.73; H, 4.53;
N, 14.00. C22H18N4O4. Calculated (%): C, 65.66; H, 4.51;
N, 13.92. 1H NMR, δ: 3.81 (s, 2 H, CH2); 7.35 (dd, 1 H, H(8),
J = 8.2 Hz, J = 1.0 Hz); 7.36 (ddd, 1 H, H(6), J = 8.2 Hz,
J = 7.2 Hz, J = 1.0 Hz); 7.65 (ddd, 1 H, H(7), J = 8.2 Hz,
J = 7.2 Hz, J = 1.7 Hz); 7.97 (dd, 1 H, H(5), J = 8.2 Hz,
J = 1.7 Hz); 8.69 (s, 1 H, CH=N); 8.82 (s, 1 H, NH); 10.88
(s, 1 H, NH).
References
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42, 1035.
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2ꢀAminoꢀ6ꢀmethylꢀ3ꢀ{2ꢀ[(2ꢀaminoꢀ6ꢀmethylchromonꢀ3ꢀyl)ꢀ
methylidene]aminoethyl}iminomethylchromone (7b) was obtained
according to the procedure described earlier.6 The yield
was 86%, m.p. 233—235 °C (cf. Ref. 6: m.p. 215 °C for 8b).
Found (%): C, 66.63; H, 5.16; N, 13.12. C24H22N4O4. Calculatꢀ
1
ed (%): C, 66.97; H, 5.15; N, 13.02. H NMR, δ: 2.37 (s, 3 H,
Me); 3.80 (s, 2 H, CH2); 7.25 (d, 1 H, H(8), J = 8.3 Hz); 7.46
(dd, 1 H, H(7), J = 8.3 Hz, J = 1.8 Hz); 7.75 (s, 1 H, H(5)); 8.67
(s, 1 H, CH=N); 8.78 (s, 1 H, NH); 10.83 (s, 1 H, NH).
2ꢀ(Chromonꢀ3ꢀyl)ꢀ5Hꢀchromeno[2,3ꢀd]pyrimidinꢀ5ꢀone (10a).
A solution of chromone 3a (R´ = 2ꢀHOC6H4) (200 mg,
0.71 mmol) in glacial acetic acid (5 mL) was refluxed for 3 h,
partially concentrated, followed by addition of water (5 mL).
A precipitate formed on cooling was filtered off, washed with
dilute acetic acid, and dried. The yield was 73 mg (60%), a yellow
powder, m.p. 254—256 °C (cf. Ref. 7: m.p. 254 °C). 1H NMR, δ:
7.59 (ddd, 1 H, H(6´), J = 7.9 Hz, J = 7.2 Hz, J = 1.0 Hz); 7.60
(ddd, 1 H, H(7), J = 7.9 Hz, J = 7.2 Hz, J = 1.0 Hz); 7.78 (dd, 1 H,
H(8´), J = 8.5 Hz, J = 1.0 Hz); 7.81 (dd, 1 H, H(9), J = 8.5 Hz,
J = 1.0 Hz); 7.90 (ddd, 1 H, H(7´), J = 8.5 Hz, J = 7.2 Hz,
J = 1.7 Hz); 7.98 (ddd, 1 H, H(8), J = 8.5 Hz, J = 7.2 Hz,
J = 1.7 Hz); 8.20 (dd, 1 H, H(5´), J = 7.9 Hz, J = 1.7 Hz); 8.22
(dd, 1 H, H(6), J = 7.9 Hz, J = 1.7 Hz); 9.14 (s, 1 H, H(2´)); 9.57
(s, 1 H, H(4)). 13C NMR, δ: 112.6 (C(4a)), 118.6 (C(9)), 118.7
9. C. K. Ghosh, D. K. SinhaRoy, K. K. Mukhopadhyay,
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Received July 8, 2010;
in revised form October 13, 2010