Synthesis of 9-azolyl-3-(4-phenyl-4h-1,2,4-triazol-3-yl)-4h,8h-pyrano-[2,3- f]chromene-4,8-diones

Article abstract of DOI:10.1007/s10593-009-0402-8

The reaction of 6-ethyl-8-formyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3- yl)chromone with 2-azolyl-acetonitriles gave 8-iminopyrano[2,3-f]chromen-4-ones, whose acid hydrolysis led to pyrano-[2,3-f]chromene-4,8-diones containing azaheterocyclic substitue

Full text of DOI:10.1007/s10593-009-0402-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
SYNTHESIS OF 9-AZOLYL-3-(4-PHENYL-
4H-1,2,4-TRIAZOL-3-YL)-4H,8H-PYRANO-
[2,3-f]CHROMENE-4,8-DIONES
T. V. Shokol1*, O. A. Lozinskii1, A. V. Turov1, and V. P. Khilya1
The reaction of 6-ethyl-8-formyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3-yl)chromone with 2-azolyl-
acetonitriles gave 8-iminopyrano[2,3-f]chromen-4-ones, whose acid hydrolysis led to pyrano-
[2,3-f]chromene-4,8-diones containing azaheterocyclic substituents at C-3 and C-9.
Keywords: 2-azolylacetonitriles, 8-formyl-7-hydroxychromones, pyrano[2,3-f]chromene-4,8-diones,
condensation.
The pyrano[2,3-f]chromene-4,8-dione system contains fragments of coumarin and chromone, both
pharmacophoric molecules. 2-Aryl, 3-aryl, and 2-hetaryl derivatives of this system have bactericidal activity
[1, 2]. Methyl derivatives have been proposed as photo reagents for DNA [3].
The pyrano[2,3-f]chromene-4,8-dione system may be obtained starting from both coumarins by
completion of the γ-pyrone ring [1, 2, 4-6] and from chromones by annelation of the α-pyrone ring [1, 3, 7-13].
Derivatives with hetaryl groups at C-2 were obtained by the former approach: by the condensation of
o-hydroxyacetylcoumarins with hetaroyl chlorides and subsequent rearrangement and cyclization [2, 5].
Derivatives with hetaryl substituents at C-9 were obtained in our laboratory using the second approach by the
reaction of 8-formyl-7-hydroxyisoflavones with hetarylacetonitriles [13]. 3-Hetaryl derivatives of this system
have not yet been reported.
In order to extend the range of heterocyclic derivatives of pyrano[2,3-f]chromene-4,8-dione we synthesized
products containing azaheterocyclic substituents at C-3 and C-9.
We used 6-ethyl-8-formyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3-yl)chromone (1) [14], which
already has a heterocycle at C-3, as the starting compound. Chromone 1 was obtained by two methods:
1) formylation of 6-ethyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3-yl)chromone (2) using the Duff reaction
and 2) heating the corresponding 8-diethylaminomethyl derivative 3 [15] in acetic acid at reflux in the presence
of hexamethylenetetramine.
1
The H NMR spectrum of chromone 1 in DMSO-d6 shows a singlet for the formyl proton at 10.54 ppm
but lacks signals characteristic for the starting chromone 2 (6.91 ppm for H-8) and chromone 3 (Et2NCH2 group
signals). The signal for the 7-OH group is shifted downfield by 2 ppm as a consequence of formation of an
_______
* To whom correspondence should be addressed, e-mail: shokol_tv@mail.univ.kiev.ua.
1Taras Shevchenko Kiev State University, Kiev 01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1361-1367, September, 2009.
Original article submitted February 13, 2008.
0009-3122/09/4509-1089©2009 Springer Science+Business Media, Inc.
1089

intramolecular hydrogen bond with the formyl group oxygen atom. The chelate structure of chromone 1 is
indicated by its red-brown color in ethanolic ferric chloride [7, 16] and the broad IR band at 3080-3150 cm-1.
The formyl group C=O and chormone carbonyl stretching vibrations give rise to a strong band at 1645 cm-1.
NEt2
O
HO
Et
O
O
HO
Et
Ph
Ph
N
N
O
N
N
2
N
N
3
(CH2)6N4
AcOH
Ar
O
NH
N
O
HO
Et
Ph
ArNHNH2
O
HO
N
EtOH
Ph
N
O
Et
N
1
N
O
N
N
HetCH2CN
C5H10NH
i-PrOH
4a,b
Het
Het
HN
O
O
O
HCl +AcOH
O
O
O
Ph
Ph
N
N
Et
Et
O
N
N
N
N
5a–e
6a–d
4 a Ar = Ph; b Ar = 2,4-(NO2)2C6H3;
Me
5, 6 a Het =
Br
N
S
N
, b Het =
,
c Het =
,
N
S
S
N
N
N
,
d Het =
5e Het =
S
N
Ph
Me
The reaction of chromone 1 with arylhydrazines in ethanol gives brightly colored, high-melting
arylhydrazones 4a and 4b. The composition and structure of these products were confirmed by their elemental
1
analysis and H NMR spectra (Tables 1 and 2). The structure of hydrazone 4b was additionally supported by
analysis of the 13C NMR DEPT spectra as well as HMQC and HMBC 13C-1H heteronuclear correlation spectra.
As expected, the DEPT spectra with complete multiplicity editing have signals for one methyl group, one
methylene group, and also ten nonequivalent CH signals (two of which have double intensity). The most
1090

important of the correlations found in the HMBC spectrum are shown below by arrows. This result along with
analysis of the 2D heteronuclear correlation spectra permitted the complete assignment of the carbon atom
signals. The protonated carbon atoms were assigned using the HMQC spectra. Thus, it proved possible to obtain
a complete assignment of the carbon atom signals in the spectrum of hydrazone 4b.
The Knoevenagel reaction of chromone 1 with 2-cyanomethyl derivatives of 4-methyl-1,3-thiazole,
4-(4-bromophenyl)-1,3-thiazole, benzothiazole, 5-phenyl-1,3,4-thiadiazole, and 1-methylbenzimidazole in the
presence of catalytic amounts of piperidine was used to synthesize 3,9-diazolylpyrano[2,3-f]chromene-
4,8-diones. Carrying out this reaction in ethanol permitted us to isolate previously unreported 8-imino
derivatives of this system 5.
8.58
7.86
O2N
130.0
138.6
115.5
143.7
123.7
7.84
NH
9.27
9.14
132.9
N
NO2
7.77
143.7
150.5
131.2
105.1
8.53
164.0
O
HO
154.7
108.1
105.4
135.8
7.70
11.2
Me
1.39
130.9
115.5
22.1
C
N
174.7
9.29
146.9
126.7
H2
144.6
2.94
N
O
N
8.14
Fig. 1. Assignment of the signals in the 1H NMR spectra of hydrazone 4b. The arrows indicate the
most important HMBC correlations, serving as the basis for assignment of the quaternary carbon
atoms. The chemical shifts of the protons and carbon atoms are given next to the corresponding
atoms.
The hydrolysis of imines 5 in a mixture of hydrochloric and acetic acids leads to the formation of
9-azolyl-3-(4-phenyl-4H-1,2,4-triazol-3-yl)pyrano[2,3-f]chromene-3,4-diones 6. Both imino derivatives 5 and
α-pyrono[2,3-f]chromene-4,8-diones 6 are high-melting compounds with blue fluorescence in UV light.
The composition and structure of imines 5 and diones 6 were supported by elemental analysis as well as
IR and NMR spectroscopy (Tables 1 and 2). The IR spectra of α-pyrono[2,3-f]chromones 6 show a strong band
for the C=O stretching vibrations of the chromone carbonyl group, which is also characteristic for imines 5 as
well as an additional strong band for the lactone carbonyl at 1720-1730 cm-1, which corresponds to previous
1
results [2, 11, 13]. The H NMR spectra of diones 6 taken in CF3CO2D show the same set of characteristic
signals for the protons of the chromone, triazole, and azaheterocyclic parts of the molecular as for imino
derivatives 5 but the singlets of the protons at lowest field H-10 are shifted downfield by 0.2-0.3 ppm. Analysis
of the 13C NMR DEPT spectrum as well as HMQC and HMBC heteronuclear correlation spectra was used to
1091

14.26
H3C
7.82
2.82
123.1
N
S
7.80
163.1
9.63
O
7.71
160.9
8.81
163.0
O
O
158.9
154.3
133.2
7.67
149.1
3.12
24.0
13.7
N
133.2
9.47
176.2
146.7
CH3
1.46
O
N
N
8.52
Fig. 2. Assignment of the signals in the 13C NMR spectrum of dione 6a. The most important
correlations found in the HMBC spectrum are shown by arrows. The chemical shifts of the
protons and carbon atoms are given near the corresponding atoms.
TABLE 1. Characteristics of the Compounds Synthesized 1, 4-6
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
N
S
1
C20H15N3O4
11.68
11.63
15.53
15.51
18.00
18.11
14.67
14.55
11.18
11.25
13.63
13.53
15.53
15.43
16.31
16.33
11.60
11.61
8.87
8.99
10.72
10.81
12.74
12.84
—
—
—
243
278
–*
62
74
46
75
58
57
41
86
67
65
64
4а
4b
5a
5b
5c
5d
5e
6a
6b
6c
6d
C26H21N5O3
C26H19N7O7
> 300
265
C26H19N5O3S
C31H20BrN5O3S
C29H19N5O3S
C30H20N6O3S
C30H22N6O3
6.49
6.66
5.27
5.15
6.06
6.20
5.77
5.89
> 300
181
> 300
275
—
C26H18N4O4S
C31H19BrN4O4S
C29H18N4O4S
C30H19N5O4S
6.53
6.65
5.28
5.14
6.10
6.18
5.72
5.88
279
> 300
> 300
> 300
_______
* Yield of compounds 1 46% (method A) and 36% (method B).
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confirm the structure of dione 6a as in the case of hydrazone 4b. As expected, the DEPT spectrum with
complete multiplicity editing shows signals for one methylene group, two methyl groups, and eight
nonequivalent aromatic CH fragments (two of which have double intensity).
Thus, the reaction of 6-ethyl-8-formyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3-yl)chromone (1) with
2-azolylacetonitriles under mild conditions gives previously unreported 8-iminopyrano[2,3-f]chromen-4-ones,
whose acid hydrolysis leads to pyrano[2,3-f]chromene-4,8-diones containing azaheterocyclic substituents at C-3
and C-9.
TABLE 2. 1H NMR Spectra of Products 1, 4-6
Com-
pound
Chemical shifts, δ, ppm (SSCS, J, Hz)*
1
1.21 (3H, t, J = 7.6, 6-CH3CH2); 2.67 (2H, q, J = 7.6, 6-CH3CH2); 7.42 (5Н, s, C6H5);
7.91 (1H, s, H-5); 8.74 (1H, s, H-2); 8.81 (1H, s, H-5' Tr);*2 10.54 (1H, s, CHO);
12.82 (1H, s, OH)
4a
1.40 (3H, t, J = 7.2, 6-CH3CH2); 2.93 (2H, q, J = 7.2, 6-CH3CH2); 7.62 (5Н, s, NНС6H5);
7.69 (2H, d, J = 7.6, H-2'',6'' Ph); 7.78 (2Н, t, J = 7.6, H-3'',5'' Ph);
7.86 (1Н, t, J = 7.6, H-4'' Ph); 8.22 (1H, s, H-5); 8.53 (1H, s, H-2); 9.32 (1H, s, 8-CH);
9.34 (1H, s, H-5' Tr)
4b
5a
1.39 (3H, t, J = 7.2, 6-CH3CH2); 2.94 (2H, q, J = 7.2, 6-CH3CH2);
7.70 (2H, d, J = 8.0, H-2'',6'' Ph); 7.77 (2Н, t, J = 8.0, H-3'',5'' Ph);
7.84 (1Н, t, J = 8.0, H-4'' Ph); 7.86 (1H, d, J = 9.2, H-6'''); 8.14 (1H, s, H-5);
8.53 (1H, s, H-2); 8.58 (1H, dd, J5''',6''' = 9.2, J5''',3''' = 2.0, H-5"'); 9.14 (1H, s, 8-CH);
9.27 (1H, d, J = 2.0, H-3'''); 9.29 (1H, s, H-5' Tr)
1.43 (3H, t, J = 7.6, 6-CH3CH2); 2.66 (3H, s, CH3-4′′′ Th);
3.13 (2H, q, J = 7.6, 6-CH3CH2); 7.55 (1H, s, H-5′′′ Th); 7.61 (2H, d, J = 7.6, H-2'',6'' Ph);
7.66 (2Н, t, J = 7.6, H-3'',5'' Ph); 7.73 (1Н, t, J = 7.6, H-4'' Ph); 8.53 (1H, s, H-5);
8.80 (1H, s, H-2); 9.21 (1H, s, H-5' Tr); 9.47 (1H, s, H-10)
5b
5c
1.58 (3H, t, J = 7.6, 6-CH3CH2); 3.27 (2H, q, J = 7.6, 6-CH3CH2);
7.75-7.87 (9H, m, C6H5, p-BrC6H4); 8.06 (1H, s, H-5′′ Th); 8.66 (1H, s, H-5);
8.98 (1H, s, H-2); 9.41 (1H, s, H-5' Tr); 9.60 (1H, s, H-10)
1.49 (3H, t, J = 7.6, 6-CH3CH2); 3.19 (2H, q, J = 7.6, 6-CH3CH2);
7.65-7.77 (5H, m, C6H5); 7.97-8.04 (2H, m, H-5''',6''' Bt); 8.23 (1Н, d, J = 8.0, H-7''' Bt);
8.29 (1Н, d, J = 8.0, H-4''' Bt); 8.58 (1H, s, H-5); 8.91 (1H, s, H-2);
9.37 (1H, s, H-5' Tr); 9.52 (1H, s, H-10)
5d
5e
6a
1.57 (3H, t, J = 7.6, 6-CH3CH2); 3.52 (2H, q, J = 7.6, 6-CH3CH2);
7.73-8.17 (10H, m, 2C6H5); 8.46 (1H, s, H-5); 8.88 (1H, s, H-2); 9.39 (1H, s, H-5' Tr);
9.66 (1H, s, H-10)
1.49 (3H, t, J = 7.6, 6-CH3CH2); 3.19 (2H, q, J = 7.6, 6-CH3CH2);
4.30 (3H, s, N–CH3); 7.62-7.77 (5H, m, C6H5); 7.92–7.99 (4H, m, H-4'',5'',6'',7'');
8.73 (1H, s, H-5); 8.76 (1H, s, H-2); 9.50 (1H, s, H-5' Tr); 9.54 (1H, s, H-10)
1.46 (3H, t, J = 7.6, 6-CH3CH2); 2.82 (3H, s, CH3-4′′′ Th);
3.12 (2H, q, J = 7.6, 6-CH3CH2); 7.67 (2H, d, J = 8.0, H-2'',6'' Ph);
7.71 (2Н, t, J = 8.0, H-3'',5'' Ph); 7.80 (1Н, t, J = 8.0, H-4'' Ph); 7.82 (1H, s, H-5′′′ Th);
8.52 (1H, s, H-5); 8.81 (1H, s, H-2); 9.47 (1H, s, H-5' Tr); 9.63 (1H, s, H-10)
6b
6c
1.48 (3H, t, J = 7.6, 6-CH3CH2); 3.21 (2H, q, J = 7.6, 6-CH3CH2);
7.66-7.84 (9H, m, C6H5, p-BrC6H4); 8.27 (1H, s, H-5′′ Th); 8.55 (1H, s, H-5);
8.82 (1H, s, H-2); 9.42 (1H, s, H-5' Tr); 9.86 (1H, s, H-10)
1.48 (3H, t, J = 7.6, 6-CH3CH2); 3.16 (2H, q, J = 7.6, 6-CH3CH2);
7.67 (2H, d, J = 7.6, H-2'',6'' Ph); 7.72 (2Н, t, J = 7.6, H-3'',5'' Ph);
7.80 (1Н, t, J = 7.6, H-4'' Ph); 7.96 (1H, t, J = 8.0, H-6''' Bt);
8.04 (1H, t, J = 8.0, H-5''' Bt); 8.32 (1Н, d, J = 8.0, H-7''' Bt);
8.37 (1Н, d, J = 8.0, H-4''' Bt); 8.58 (1H, s, H-5); 8.85 (1H, s, H-2);
9.46 (1H, s, H-5' Tr); 9.83 (1H, s, H-10)
6d
1.44 (3H, t, J = 7.6, 6-CH3CH2); 3.12 (2H, q, J = 7.6, 6-CH3CH2);
7.62-8.16 (10H, m, 2C6H5); 8.50 (1H, s, H-5); 8.77 (1H, s, H-2); 9.43 (1H, s, H-5' Tr);
9.74 (1H, s, H-10)
_______
* The spectra were taken in DMSO-d6 (chromone 1) and CF3CO2D (4-6).
*2 Bt – benzothiazole, Th = thiazole, Tr = triazole.
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EXPERIMENTAL
1
The H NMR spectra were taken on a Varian Mercury 400 spectrometer at 400 MHz with TMS as the
internal standard. The 13C NMR, DEPT, HMQC, and HMBC spectra were taken in CF3CO2D. The IR spectra
were taken on a UR-20 spectrometer for KBr pellets. The purity of the products was monitored by thin-layer
chromatography on Silufol UV-254 plates using 9:1 chloroform–methanol as the eluent.
6-Ethyl-8-formyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3-yl)chromone (1). A. A solution of
chromone 2 [14] (3.33 g, 10 mmol) and hexamethylenetetramine (8.41 g, 60 mmol) in glacial acetic acid
(30 ml) was heated on a steam bath for 8 h, poured into 30 ml of a 1:2 mixture of concentrated hydrochloric acid
and water heated at reflux, and diluted by adding 40 ml water. After several hours, the precipitate formed was
filtered off and recrystallized from ethanol to give 1.66 g chromone 1.
B. A solution of chromone 3 [15] (0.42 g, 1 mmol) and hexamethyltetramine (0.25 g, 1.8 mmol) was
heated in acetic acid (2.5 ml) at reflux for 1 h, poured into a mixture of ice and 4 ml hydrochloric acid, and
diluted by adding 10 ml water. After 12 h, the precipitate formed was filtered off to give 0.13 g chromone 1.
Arylhydrazones of 6-Ethyl-8-formyl-7-hydroxy-3-(4-phenyl-4H-1,2,4-triazol-3-yl)chromone 4a,b. The
aryl hydrazine (0.5 mmol) was added to a solution of chromone 1 (0.18 g, 0.5 mmol) in ethanol (10 ml), heated at
reflux for 30 min. After cooling, the precipitate was filtered off. The products were recrystallized from DMF.
9-Azolyl-6-ethyl-8-imino-3-(4-phenyl-4H-1,2,4-triazol-3-yl)pyrano[2,3-f]chromen-4-ones
5a-e.
Corresponding 9-azolylacetonitrile (1 mmol) and three drops of piperidine were added to a solution of chromone
1 (0.36 g, 1 mmol) in 2-propanol (35 ml) and maintained at room temperature for 12 h. The precipitate formed
was filtered off and washed with 2-propanol.
9-Azolyl-6-ethyl-3-(4-phenyl-4H-1,2,4-triazol-3-yl)pyrano[2,3-f]chromen-4,8-diones 6a-d. The
corresponding
9-azolyl-6-ethyl-8-imino-3-(4-phenyl-4H-1,2,4-triazol-3-yl)pyrano[2,3-f]chromen-4-one
5
(1 mmol) in a mixture acetic acid (5 ml) and hydrochloric acid (1 ml) was heated at reflux for 10 min. After
cooling, the precipitate formed was filtered off, washed with water, and recrystallized from DMF.
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