2-[6-Alkyl-3-hetaryl-4-oxo-9,10-dihydro-4H,8H-chromeno-[8,7-e][1,3] oxazin-9-yl]acetic acids

Article abstract of DOI:10.1007/s10593-007-0091-0

The interaction has been studied of a series of substituted 3-hetaryl-7-hydroxychromones with amino acids and formaldehyde (reactants ratio 1: 1: 2 respectively). In the case of glycine and Het = 3-isoxazolyl the product of aminomethylation at position 8 of the chromone was obtained, and with other Het (including Het = 4-phenyl-1,2,4-triazol-3-yl) 2-[6-alkyl-3-hetaryl-4-oxo-9, 10-dihydro-4H,8H-chromeno[8,7-e][1,3]-oxazin-9-yl]acetic acids were formed. With β-alanine and Het = 4-phenyl-1,2,4-triazol-3-yl the corresponding β-substituted propionic acid was synthesized, but proline did not participate in the reaction, leading to bis(6-ethyl-3-hetaryl-7-hydroxychromon- 8-yl)methane.

Full text of DOI:10.1007/s10593-007-0091-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
2-[6-ALKYL-3-HETARYL-4-OXO-9,10-DIHYDRO-4H,8H-CHROMENO-
[8,7-e][1,3]OXAZIN-9-YL]ACETIC ACIDS
N. V. Gorbulenko, T. M. Tkachuk, T. V. Shokol, V. V. Semeniuchenko,
A. V. Turov, and V. P. Khilya
The interaction has been studied of a series of substituted 3-hetaryl-7-hydroxychromones with amino acids
and formaldehyde (reactants ratio 1 : 1 : 2 respectively). In the case of glycine and Het = 3-isoxazolyl the
product of aminomethylation at position 8 of the chromone was obtained, and with other Het (including
Het = 4-phenyl-1,2,4-triazol-3-yl) 2-[6-alkyl-3-hetaryl-4-oxo-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]-
oxazin-9-yl]acetic acids were formed. With β-alanine and Het = 4-phenyl-1,2,4-triazol-3-yl the
corresponding β-substituted propionic acid was synthesized, but proline did not participate in the
reaction, leading to bis(6-ethyl-3-hetaryl-7-hydroxychromon-8-yl)methane.
Keywords: amino acids, 3-hetaryl-7-hydroxychromones, 3-hetaryl-4-oxo-9,10-dihydro-4H,8H-chromeno-
[8,7-e][1,3]oxazines, Mannich reaction, formaldehyde.
It is known that Mannich bases obtained on interaction of equimolar quantities of a chromone (reacting
at position 8 or 6), formaldehyde, and an amine [1], possess a broad spectrum of biological activity [2]. With the
presence of a OH group at position 7 of an isoflavone, the use of a twofold excess of formaldehyde, and α-amino
acid esters, derivatives of 9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazine are formed containing a
CHRCOOR1 group in position 9 [3]. The indicated products, unlike noncyclic Mannich amino acid bases, did
not display antimicrobial activity [3]. The acids (9-CHRCOOH) corresponding to them were not synthesized
since on hydrolysis of the esters fission of the oxazine ring occurs (in acidic medium) or destruction of the
chromone nucleus (in alkaline medium).
It should be noted that 9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones, similar to the
considered compound, obtained analogously from coumarins [4-12], display antibacterial [8-12], amebicidal,
antitrichomonal [8], antispasmolytic, and antihistamine activity [7]. They are patented as sun-protective,
fungicidal, and antitumor agents [6].
The problem of the present work comprised the clarification of the possibility of aminomethylation of
hetaryl-substituted chromones with amino acids for subsequent determination of the biological activity of the
products obtained, and the clarification of the effect on it of substitution of the aryl substituent by a heterocycle.
To this aim we studied the interaction of 3-hetaryl-7-hydroxychromones 1a-c, 2-7, 8a,b with amino acids
(glycine, β-alanine, proline), and formaldehyde at a molar ratio of reactants equal to 1 : 1 : 2 respectively (see
Scheme). The reaction was carried out by boiling in aqueous alcohol for 8-10 h.
It is known that the most reactive position for electrophilic attack in 7-hydroxychromones is position 8
[13]. If this is substituted aminomethylation by reactive agents occurs at position 6 [14].
__________________________________________________________________________________________
Taras
Shevchenko
Kiev
National
University,
Kiev
01033,
Ukraine;
e-mail:
shokol_tv@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 683-689,
May, 2007. Original article submitted January 19, 2006; revision submitted July 24, 2006.
0009-3122/07/4305-0569©2007 Springer Science+Business Media, Inc.
569

COOH
O
N
O
Et
Het
15
O
8
H2N(CH2)2COOH
Et
O
Et
R3
HO
OH
COOH
N
H
HO
O
O
R1
O
O
2
R
1b, 8
Het
16, 17
O
Het
1– 8
Het
H2N(CH2)2COOH
1a, 2a
2b, 3
4
1b,c, 5, 8
COOH
Complex mixture
of unidentified products
H
N
COOH
N
R1
HO
O
O
O
2
R
N
Me
Het
O
O
O
9
10a,b, 11-14
1a–c, 10a,b, 16 Het =
Me
;
2a,b Het =
;
CO2Me
O
N
Me
N
;
4, 9 Het =
N
3 Het =
;
5, 11 Het =
;
S
N
O
N
N
S
N
N
Het =
6, 12 Het =
; 7, 13
Ph
;
8, 14, 15, 17 Het =
S
N
N
Ph
1a R1 = CF3, R2 = H, R3 = Me; 1b, 2b, 3, 5, 7, 8 R1 = R3 = H, R2 = Et;
1c R1 = CF3, R2 = Et, R3 = H; 2a R1 = R2 = H, R3 = Me; 4 R1 = R3 = H , R2 = Me;
6 R1 = R3 = H, R2 = Pr; 9 R1 = H, R2 = Me; 10a, 11, 13-17 R1 = H, R2 = Et;
10b R1 = CF3, R2 = Et; 12 R1 = H, R2 = Pr
570

TABLE 1. Characteristics of Compounds 9-17
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield, %
mp, °С*
N
S
9
C16H14N2O6
8.40
8.48
3.44
3.28
2.64
2.83
7.08
7.25
6.38
6.42
9.45
9.35
12.93
12.96
12.67
12.55
—
—
—
207-208
207
49
37
54
45
38
51
50
32
36
35
10a
10b
11
С22H21NO8
C23H20 F3NO8
C19H18N2O5S
C23H20N2O5S
C23H19N3O5S
C23H20N4O5
C24H22N4O5
C37H32O12
197
8.16
8.30
7.30
7.35
7.27
7.13
—
—
—
—
188-189
186-187
205
12
13
14
186
15
217
16*2
17*3
—
176
C39H30N6O6
12.41
12.38
>300
_______
* Solvent for recrystallization: ethanol (compounds 9, 11-14), acetonitrile
(compound 10a), toluene–petroleum ether (compound 10b), methanol
(compound 15), 2-propanol (compound 16), methanol–water (compound 17).
*2 Found, %: C 66.43; H 4.95. Calculated, %: C 66.46; H 4.82.
*3 Found, %: C 69.04; H 4.41. Calculated, %: C 69.01; H 4.46.
Under the indicated conditions glycine did not react with formaldehyde and 8-methyl-substituted
chromones 1a and 2a. The latter were isolated almost completely from the reaction medium. It is probable that
this is linked with the low reactivity of the free position 6 of the initial chromones. In the case of 6-ethyl-
7-hydroxy-3-quinolyl- (2b) and -3-pyridylchromone (3) a complex mixture of products was obtained, which was
not studied further. The product of aminomethylation at position 8 was obtained from 7-hydroxy-3-(isoxazol-
3-yl)-6-methylchromone (4) in 49% yield. The substituted amino acetic acid 9, an analog of isoflavone
derivatives, was formed as a result of a similar reaction at an equimolar ratio of reactants [3]. The composition
and structure of acid 9 were confirmed by the results of elemental analysis (Table 1) and data of 1H NMR spectra
(Table 2). In the case of 2-R1-6-alkyl-7-hydroxy-chromones, containing the following substituents in position 3:
2-methoxycarbonyl-5-methyl-4-furyl 1b,c, 4-methylthiazol-2-yl (5), benzothiazol-2-yl (6), 5-phenyl-1,3,4-
thiadiazol-2-yl (7), and 4-phenyl-1,2,4-triazol-3-yl (8), the corresponding 2-[(6-alkyl-3-hetaryl-4-oxo)-9,10-
4H,8H-chromeno[8,7-e][1,3]oxazin-9-yl]acetic acids 10a,b, 11-14 were formed in 37-54% yield as a result of
their interaction with glycine and a twofold quantity of formaldehyde. The character of the substituent R1 has no
effect on the yield of the desired products.
Compounds 10-14 were colorless crystalline substances, the composition and structure of which were
1
confirmed by the results of elemental analysis and data of H NMR spectra (Tables 1, 2). Additional
confirmation of the structure of compound 14 was obtained from the results of DEPT 13C NMR spectra and also
the HMQC and HMBC spectra for 13C and 1H heteronuclear correlations. In the DEPT spectrum with complete
multiplicity editing, as was expected, there were signals of four methylene groups, one methyl, and six
nonequivalent signals of aromatic CH fragments (two of them had double intensity). Since assignment of the
signals in the proton spectra did not give rise to doubt, the link of protons with carbon atoms distant one bond
571

from them was established with the aid of HMQC spectra. Carbon atoms distant from protons by 2-3 chemical
bonds were identified by correlation in the HMBC spectrum. The most important of them, serving as a basis for
assigning the carbon atom signals, are shown by arrows in the formula of compound 14 below. The found values
of the chemical shifts of the protons and carbon atoms are given near the corresponding atoms:
172.1
COOH
3.52
H2C54.0
7.35
4.22
N
5.03
129.3
7.41
45.4
83.9
124.9
130.1
108.5
8.72
O
O
157.4
131.2
153 .5
158.3
135.2
14.2
7.41
116.5
Me
1.08
113.9
22.6
N
147.2
146.0
C
H2
122.4
173.6
8.96
2.54
O
N
N
7.51
Compound 14
The use of β-alanine for aminomethylating chromone 8 led in low yield (30%) to a homolog of
1
compound 14, viz. propionic acid 15, containing the analogous tricyclic substituent in the β-position. In the H
NMR spectrum of compound 15, in difference to the spectrum of acid 14, only two two-proton singlets were
observed in the 4-5 ppm region for the methylene groups of the dihydrooxazine fragment, and the protons of the
β-alanine fragment appear as two characteristic triplets at 2.58 and 2.98 ppm.
It is known that the Mannich reaction involving amino acids and isoflavones or their 3-phenoxy-
substituted analogs occurs most successfully with secondary amino acids, such as proline, but in the case of
primary amines a series of side products are formed [3, 15]. However we were unsuccessful in introducing
proline to react with formaldehyde and hetarylchromones 1b, 8, for which, as was shown above, on using
glycine and β-alanine under the same conditions the corresponding aminomethylation products 10a, 14, and 15
1
were obtained in moderate yield. In the H NMR spectra of the compounds isolated from the reaction mixture
there were no signals for proline and a singlet of the H-8 proton of the initial chromones, but the remaining
signals of the latter were present and as was the two-proton singlet characteristic of a CH2 group linking the
residue of certain di- and trihydroxychromones [15]. The data given and also comparison of the integral intensity
of the proton signals and the results of elemental analysis indicate that in the examples considered products of
the interaction of two molecules of chromone 1b or 8 with a molecule of formaldehyde are formed, viz.
substituted bis(chromon-8-yl)methanes 16 or 17 respectively. To confirm the structure of compound 16 we, as in
the case of product 14, carried out an analysis of the DEPT 13C NMR and the HMQC and HMBC heteronuclear
correlation spectra. In the DEPT spectra with complete editing for multiplicity there were, as expected, signals
for three methyl groups, two methylene groups, and three aromatic CH signals. The most important of the
correlations found in the HMBC spectrum are shown below in a fragment of compound 16 by arrows (the
second residue of chromone, identical to that given, is not shown). We were therefore able
572

successfully to make a complete assignment of the signals of carbon atoms in the molecule of compound 16. The
values of the chemical shifts found for protons and carbon atoms are shown below near the corresponding atoms:
2.39
Me
7.68
141.9
14.0
O
O
H
O
154.9
2.69
23.7
158.7
123.1
1.23
14.5
174.7
115.4
3.82
130.9
121.7
O
Me
52.0
116.4
154.8
123.1
154.2
H
161
114.2
H
7.30
HO
O
8.34
16.5 CH2 4.36
Fragment of the compound 16 molecule
TABLE 2. 1H NMR Spectra of Compounds 9-17
Com-
pound
Chemical shifts, δ, ppm. (SSCC, J, Hz)*
9
2.25 (3H, s, CH3); 3.40 (2Н, s, СН2СООН); 4.26 (2Н, s, СН2N); 7.05 (1H, s, H-4');
7.78 (1H, s, H-5); 8.66 (1H, s, H-2); 8.83 (1H, s, H-5')
10a
1.23 (3H, t, J = 7.6, CH3CH2); 2.40 (3H, s, 2'-CH3); 2.65 (2H, q, J = 7.6, CH3CH2);
3.50 (2Н, s, СН2СООН); 3.82 (3H, s, СOOCH3); 4.24 (2Н, s, С(10)Н2); 5.03 (2Н, s, С(8)Н2);
7.29 (1H, s, H-4'); 7.72 (1H, s, H-5); 8.26 (1H, s, H-2)
10в
11
1.24 (3H, t, J = 7.6, CH3CH2); 2.23 (3H, s, 2'-CH3); 2.67 (2H, q, J = 7.6, CH3CH2);
3.63 (2Н, s, СН2СООН); 3.83 (3H, s, СOOCH3 ); 4.25 (2Н, s, С(10)Н2); 5.08 (2Н, s, С(8)Н2);
7.01 (1H, s, H-4'); 7.71 (1H, s, H-5); 8.26 (1H, s, H-2); 12.36 (1Н, br. s, СООН)
1.25 (3H, t, J = 7.6, CH3CH2); 2.46 (3H, s, 4'-CH3); 2.68 (2H, q, J = 7.6, CH3CH2);
3.52 (2Н, s, СН2СООН); 4.29 (2Н, s, С(10)Н2); 5.06 (2Н, s, С(8)Н2); 7.14 (1H, s, H-5');
7.82 (1H, s, H-5); 9.04 (1H, s, H-2)
12
0.99 (3H, t, J = 7.6, CH3CH2CH2); 1.66 (2H, m, CH3CH2CH2);
2.65 (2H, t, J = 7.6, CH3CH2CH2); 3.52 (2Н, s, СН2СООН); 4.32 (2Н, s, С(10)Н2);
5.06 (2Н, s, С(8)Н2); 7.39 (1Н, t, J = 8.0, Н-6′);7.48 (1Н, t, J = 8.0, Н-5');
7.84 (1H, s, H-5); 7.97 (1Н, d, J = 8.0, Н-7', 8.04 (1Н, d, J = 8.0, Н-4'); 9.27 (1H, s, H-2)
13
14
15
1.25 (3H, t, J = 7.6, CH3CH2); 2.67 (2H, q, J = 7.6, CH3CH2); 3.52 (2Н, s, СН2СООН);
4.30 (2Н, s, С(10)Н2); 5.07 (2Н, s, С(8)Н2); 7.53 (3H, m, H-3',4',5' Ph); 7.83 (1H, s, H-5);
8.02 (2H, m, H-2',6' Ph); 9.33 (1H, s, H-2); 12.39 (1Н, br. s, СООН)
1.17 (3H, t, J = 7.6, CH3CH2); 2.59 (2H, q, J = 7.6, CH3CH2); 3.51 (2Н, s, СН2СООН);
4.25 (2Н, s, С(10)Н2); 5.03 (2Н, s, С(8)Н2); 7.41 (5Н, s, C6H5); 7.52 (1H, s, H-5);
8.62 (1H, s, H-5'); 8.79 (1H, s, H-2); 12.43 (1Н, br. s, СООН)
1.18 (3H, t, J = 7.6, CH3CH2); 2.58 (2Н, t, J = 6.8, СН2СООН);
2.63 (2H, q, J = 7.6, CH3CH2); 2.98 (2Н, t, J = 6.8, NСН2CH2); 4.20 (2Н, s, С(10)Н2);
5.00 (2Н, s, С(8)Н2); 7.40 (5Н, s, C6H5); 7.52 (1H, s, H-5); 8.60 (1H, s, H-5');
8.76 (1H, s, H-2); 12.08 (1Н, br. s, СООН)
16
17
1.23 (6H, t, J = 7.6, 2CH3CH2); 2.39 (6H, s, 2⋅2'-CH3);
2.69 (4H, q, J = 7.6, 2CH3CH2); 3.82 (6H, s, 2СOOCH3 ); 4.36 (2Н, s, 8-СН2);
7.30 (2H, s, 2H-4'); 7.68 (2H, s, 2H-5); 8.34 (2H, s, 2H-2)
1.18 (6H, t, J = 7.6, 2CH3CH2); 2.64 (4H, q, J = 7.6, 2CH3CH2); 4.36 (2Н, s, 8-СН2);
7.39 (10Н, s, 2C6H5); 7.49 (2H, s, 2H-5); 8.73 (2H, s, 2H-5'); 8.76 (1H, s, 2H-2)
_______
* The absence from the spectra of certain compounds of the signal for the
proton of the OH (9, 16, 17), NH (9), and COOH groups (9-12) is
explained by deuterium exchange with D2O (contaminant in DMSO-d6).
573

The linking of each residue of hetarylchromone with a CH2 group at position 8 is confirmed by
correlations in the HMBC spectrum for the C(8), C(7), and C(8′) atoms.
The results obtained indicate that the possibility of aminomethylating 3-hetarylchromones with
formaldehyde and amino acids is determined mainly by the structure of the 3-Het substituent but also by the
initial amino acid.
EXPERIMENTAL
The purity of the synthesized compounds was checked by TLC on Silufol UV 254-plates, eluent was
1
13
chloroform-methanol, 9 : 1. The H, C, DEPT, HMQC, and HMBC NMR spectra were recorded in DMSO-d6
on a Varian Mercury 400 (400 MHz) spectrometer, internal standard was TMS.
{[7-Hydroxy-3-(3-isoxazolyl)-6-methyl-4-oxo-4H-chromen-8-ylmethyl]-amino}acetic Acid (9) and 2-(2-
R1-6-Alkyl-3-hetaryl-4-oxo-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-9-yl)acetic Acids (10a,b,11-14). A
solution of glycine (0.3 g, 4 mmol) in water (5 ml) and 37% formalin solution (3 ml) were added to a solution of
2-R1-6-alkyl-3-hetaryl-7-hydroxychromone (1b,c, 4-8) (2 mmol) in ethanol (20 ml) and the mixture was boiled
for 8-10 h (check by TLC). The alcohol was distilled off, the residue was triturated with water, the solid was
filtered off, and recrystallized.
3-[6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-9,10-4H,8H-chromeno[8,7-e][1,3]oxazin-9-yl]propi-
onic Acid (15) was obtained by the procedure described above from chromone 8 and β-alanine.
Bis(6-ethyl-3-hetaryl-7-hydroxychromon-8-yl)methanes (16, 17) were obtained by the procedure
given above when using 6-ethyl-3-hetaryl-7-hydroxychromones 1b, 8, formaldehyde, and proline respectively.
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