Synthesis of 2-substituted 3-iodo-4H-chromen-4-ones

Article abstract of DOI:10.1007/s11172-014-0466-1

3-Iodochromones containing phenyl and furyl fragments at position 2 were synthesized by heterocyclization of β-ketoenamines.

Full text of DOI:10.1007/s11172-014-0466-1

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 543—545, February, 2014
543
Brief Communications
Synthesis of 2ꢀsubstituted 3ꢀiodoꢀ4Hꢀchromenꢀ4ꢀones*
K. A. Myannik,a V. N. Yarovenko,a M. M. Krayushkin,a and K. S. Levchenkob
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: yarov@ioc.ac.ru
b"Tekhnomash" Cental Scientific Technological Institute,
4 ul. Ivana Franko, 121108 Moscow, Russian Federation
3ꢀIodochromones containing phenyl and furyl fragments at position 2 were synthesized by
heterocyclization of ꢀketoenamines.
Key words: iodochromones, ꢀketoenamines, furans, heterocyclization reactions.
Chromone structure is a part of many natural and synꢀ
thetic pharmaceutical agents possessing various biological
activity.1 Their halo derivatives are of significant interest
as stimulants of the central nervous system, as well as the
agents exhibiting high antiviral, antibacterial, antifungal,
antiallergic, and neuroleptic activity.2 Also note a high
synthetic potential of these compounds,2 especially iodo
substituted derivatives,3,4 which readily react with nucleoꢀ
philes and can be involved in the crossꢀcoupling reactions
leading to the synthesis of a wide variety of benzopyrans.
Among existing approaches to the chromone halo deꢀ
group and leads to chromones 3 containing no substituꢀ
ents at position 2 (see Scheme 1).
Scheme 1
rivatives, reactions of halogens with ꢀketoenamines4,5
2
(obtained by the reaction of hydroxyacetophenones with
dimethylformamide diacetal) is one of the most conveꢀ
nient methods (Scheme 1). It should be emphasized that
in this case the heterocyclization involves the hydroxy
i. Me2NCH(OR)2; ii. X2
X = Br, I
* On the occasion of the 80th anniversary of the N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0543—0545, February, 2014.
1066ꢀ5285/14/6302ꢀ0543 © 2014 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Myannik et al.
The approaches dealing with the syntheses of 3ꢀhalo
products strongly depend on the presence of light and solꢀ
vent. The reaction of ꢀketoenamine with the furyl subꢀ
stituent 4a with iodine in chloroform led to the formation
of iodo derivative 7a in 23% yield, whereas in methanol
the yield of the product increased up to 33%. When the
reaction was carried out in the dark in methanol, the corꢀ
responding iodo derivative 7a was isolated in 66% yield,
whereas the iodination of ꢀketoenamines with phenyl and
tolyl substituents 4b,c gave 65—76% yields of the products
(see Scheme 3).
chromones with substituents at position 2 based on ꢀketoꢀ
enamines are less developed. This method requires introꢀ
duction of the corresponding substituent R into the
ꢀketoenamine fragment of compound 4 (Scheme 2).
There are the literature data describing preparation of such
enaminones with the limited set of substituents R (alkyl
and phenyl groups)6,7 and there is the only example of the
transformation of the enaminone with the methyl group
(R = Me) to the corresponding 3ꢀbromo derivative upon
treatment with bromine.
Scheme 3
Scheme 2
7: R = 2ꢀFuryl (a), Ph (b), 4ꢀMeꢀC6H4 (c)
It should be noted that attempted synthesis of comꢀ
pound 7a using methods described earlier10—12 was unsucꢀ
cessful.
In conclusion, we suggested an approach to the synꢀ
thesis of 3ꢀiodochromones containing furyl (7a) and aryl
(7b,c) fragments at position 2. Note that no synthesis of
either ꢀketoenamine 4a or chromone 3ꢀiodo derivative
7a with furanyl moieties was described earlier. The latter
can be a valuable starting compound in the preparation of
photoactive benzopyrans.13
4—6: R = 2ꢀFuryl (a), Ph (b), 4ꢀMeꢀC6H4 (c)
In the present work, we suggest an approach to the
synthesis of 2ꢀsubstituted 4Hꢀchromenꢀ4ꢀones with the
iodine atoms at position 3 (Schemes 2 and 3). The prepaꢀ
ration of the intermediate products 4a—c was carried out
according to the Scheme 2 by the reaction of the primary
amine with 3ꢀacylꢀ2ꢀhetarylchromones 5a—c obtained by
us earlier8 or with benzopyrans 6a—c with substituents at
position 2 described in the literature.9 The use in these
processes of benzylamine in ethanol leads to the high yields
of ꢀketoenamines 4a—c, which were within 85—89% (see
Scheme 2). It should be noted that in the course of the
reaction with 3ꢀacylꢀ2ꢀhetarylchromones, the formation
of ꢀketoenamines is accompanied by deacylation. The
Experimental
1
H NMR spectra were recorded on Bruker ACꢀ200 (200
MHz) and Bruker AMꢀ300 (300 MHz) spectrometers in CDCl3,
13C NMR spectra were recorded on a Bruker AMꢀ300 spectroꢀ
meter (75 MHz) in CDCl3, using signals for residual protons and
carbon atoms of the solvent as the references. Melting points
were determined on a Boetius heating stage and were not corꢀ
rected. TLC on Merck Silica gel 60 F254 UVꢀ254 plates was
used to analyze all reaction mixtures and control purity of isolatꢀ
ed compounds.
1
structures of compounds obtained were confirmed by H
and 13C NMR spectroscopy. The signal for the NH group
at  13 in the 1H NMR spectrum is explained by the intraꢀ
molecular interaction of the proton of the amino group
with the keto group, that confirms the shown configuraꢀ
tion of compounds.
Since chromones 6 are obtained from the same 1,3ꢀdiꢀ
ketones as chromones 5, but require lesser number of steps,
their use is preferable in the synthesis of ꢀketoenamines.
The studies of the iodination reaction of ꢀketoꢀ
enamines obtained showed that the yields of the target
Synthesis of ꢀketoenamines 4a—c (general procedure). A soꢀ
lution of 4Hꢀchromenꢀ4ꢀone 5a—c or 6a—c (10 mmol) and
benzylamine (30 mmol) in ethanol was refluxed for 48 h. Then,
the reaction mixture was concentrated, a dry residue was disꢀ
solved in dichloromethane with some light petroleum. The prodꢀ
ucts were isolated by column chromatography in the system
CH2Cl2 : light petroleum (9 : 1).
3ꢀBenzylaminoꢀ3ꢀ(furanꢀ2ꢀyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)propenꢀ
one (4a). The yield was 85%, m.p. 122—123 C. 1H NMR
(300.13 MHz, CDCl3)), : 13.34 (s, 1 H, NH); 11.32 (s, 1 H,
OH); 7.73 (d, 1 H, HAr, J = 8 Hz); 7.61 (d, 1 H, HFur, J = 1.47 Hz);

2ꢀSubstituted 3ꢀiodoꢀ4Hꢀchromenꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
545
7.45—7.30 (m, 6 H, HAr+Fur); 6.96 (d, 1 H, HAr, J = 7.3 Hz);
6.85 (m, 2 H, HAr); 6.54 (m, 1 H, HFur); 6.25 (s, 1 H, HC=C);
4.79 (d, 2 H, CH2—Ph, J = 6.2 Hz). 13C NMR (50.32 MHz,
CDCl3), : 191.44, 162.31, 154.55, 147.83, 144.78, 137.97 (2 C);
133.78, 129.01, 127.8 (2 C); 127.03 (2 C); 120.88 (2 C); 118.38,
114.66, 112.03, 89.99, 49.45. Found (%): C, 75.27; H, 5.24;
N, 4.42. C20H17NO3. Calculated (%): C, 75.22; H, 5.37; N, 4.39.
3ꢀBenzylaminoꢀ1ꢀ(2ꢀhydroxyphenyl)ꢀ3ꢀphenylpropenone (4b).
The yield was 86%, m.p. 97 C (Ref. 14: m.p. 100 C). 1H NMR
(300.13 MHz, CDCl3), : 13.41 (s, 1 H, NH); 11.29 (s, 1 H,
OH); 7.63 (d, 1 H, HAr, J = 8 Hz); 7.50—7.37 (m, 6 H, HAr);
7.37—7.26 (m, 3 H, HAr); 7.23 (d, 2 H, HAr, J = 7.1 Hz); 6.95
(d, 1 H, HAr, J = 8.3 Hz); 6.79 (t, 1 H, HAr, J = 7.4 Hz); 5.85 (s, 1 H,
HC=C); 4.46 (d, 2 H, CH2—Ph, J = 6.4 Hz). 13C NMR (50.32
MHz, CDCl3, : 191.47, 167.51, 162.44, 138.44, 135.36, 133.8
(2 C); 129.89, 128.93 (2 C); 128.76 (2 C); 127.92, 127.75 (3 C);
127.7, 126.92 (2 C); 120.68, 92.78, 48.82. Found (%): C, 80.3;
H, 5.7; N, 4.1. C22H19NO2. Calculated (%): C, 80.22; H, 5.81;
N, 4.25.
128.4 (2 C); 127.2, 125.9, 120.3, 117.9, 88.4. Found (%): C, 52.01;
H, 2.62. C15H9IO2. Calculated (%): C, 51.75; H, 2.61.
3ꢀIodoꢀ2ꢀ(pꢀtolyl)chromenꢀ4ꢀone (7c). The yield was 76%,
m.p. 127—129 C (Ref. 16: m.p. 126 C). 1H NMR (CDCl3,
300.13 MHz): 8.30 (d, 1 H, HAr, J = 7.7 Hz); 7.84 (d, 1 H, HAr
,
J = 8 Hz); 7.72 (d, 2 H, Tol, J = 8.1 Hz); 7.57—7.44 (m, 2 H,
HAr); 7.34 (d, 2 H, Tol, J = 7.9 Hz); 2.48 (s, 3 H, CH3). 13C NMR
(50.32 MHz, CDCl3), : 174.92, 165.11, 156.03, 142.15, 141.75,
134.34, 129.59 (2 C); 125.96, 125.11, 120.03, 118.09, 117.73
(2 C); 87.92, 21.7. Found (%): C, 53.01; H, 3.00. C16H11IO2.
Calculated (%): C, 53.06; H, 3.06.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 13ꢀ03ꢀ01054ꢀa).
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Received November 27, 2013;
in revised form December 27, 2013