7-Hydroxy-3-phenoxy-8-formylchromones, analogs of natural flavonoids

Article abstract of DOI:10.1007/s10600-009-9345-7

7-Hydroxy-3-phenoxy-8-formylchromones were synthesized using the Duff reaction and were reacted with 2,4-dinitrophenylhydrazine to produce hydrazones and with an excess of hydrazine hydrate to produce the pyrazole recyclization products. Derivatives of α-

Full text of DOI:10.1007/s10600-009-9345-7

Chemistry of Natural Compounds, Vol. 45, No. 3, 2009
7-HYDROXY-3-PHENOXY-8-FORMYLCHROMONES,ANALOGS
OF NATURAL FLAVONOIDS
T. V. Shokol, O. A. Lozinskii, T. M. Tkachuk, and V. P. Khilya*
UDC 547.814.5
7-Hydroxy-3-phenoxy-8-formylchromones were synthesized using the Duff reaction and were reacted with
2,4-dinitrophenylhydrazine to produce hydrazones and with an excess of hydrazine hydrate to produce the
pyrazole recyclization products. Derivatives of α-pyrono[2,3-f]chromones were synthesized using the
Knoevenagel condensation with 2-azahetarylacetonitriles and the Perkin reaction.
Key words: 7-hydroxy-8-formylchromones, condensation, α-pyrono[2,3-f]chromones.
Few 7-hydroxy-8-formylchromones (isounonal 1) and their partially hydrogenated derivatives, lavinal (2), and
4,7-dihydroxy-6-methyl-5-methoxy-8-formylflavan (3) have been discovered within the broad class of natural flavonoids.
O
O
O
HO
Me
O
O
HO
Me
O
O
HO
Me
O
OH
OH
OMe OH
1
2
3
The first two occur together in plants of the family Annonaceae [1-6] such as Dasymaschalon rostratum [1], Desmos
chinensis Lour [2], Desmos cochinchinensis [3], and Unona lawii Hook. f. & Thoms [4]. The last is found in roots of Desmos
cochinchinensis [3]. A mixture of all three flavonoids isolated from D. cochinchinensis [3] exhibited antimalarial activity
whereas lavinal itself was viewed as a potentialAIDS agent [7]. Phenoxychromones are also found in nature [8]. This enabled
us to combine these two classes into one in order to study properties different from those of each class individually but
characteristic of the system as a whole.
The classical method for synthesizing 7-hydroxy-8-formylchromones is the Duff reaction [9-15]. Starting 7-hydroxy-
3-phenoxy-8-formylchromones 4-10 were synthesized using the Duff reaction by heating chromones 11-17 with urotropine in
acetic acid with subsequent work up of the reaction mixture by HCl solution. PMR spectra of these compounds in DMSO-d
6
showed a singlet for the formyl group near 10.5 ppm and a broad singlet for the hydroxyl proton that was shifted to weak field
relative to the resonance of the hydroxyl in the starting chromone by 1.6-1.7 ppm as a result of the formation of an intramolecular
H-bond.
The presence of the formyl group was also confirmed by formation of the 2,4-dinitrophenylhydrazone 18 upon
reaction of 8 with 2,4-dinitrophenylhydrazine. The PMR spectrum of 18 exhibited resonances for aromatic protons characteristic
of starting chromone 8; 1H doublets for H-5′′ and H-6′′ at 8.39 and 7.89 ppm, respectively; and a singlet for H-3′′ of the
2,4-dinitrophenyl group at 8.90 ppm.
The reaction of 8-formylchromone 6 with an excess of hydrazine hydrate did not stop at the formation of the hydrazone
but led to recyclization of theγ-pyrone ring to form pyrazole 19. This was confirmed by a broad singlet typical of the pyrazole
NH proton at 12.90 ppm, singlets for two hydroxyls at 11.78 and 12.07, and a 2H singlet at 6.69 for the hydrazone amino group
in the PMR spectrum recorded in DMSO-d .
6
Taras Shevchenko Kiev National University, 01033, Kiev, ul. Vladimirskaya, 64, Ukraine, e-mail:
vkhilya@mail.univ.kiev.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 298-302, May-June, 2009. Original
article submitted January 29, 2009.
©
350
0009-3130/09/4503-0350 2009 Springer Science+Business Media, Inc.

O
O
O
O
O
O
O
O
O
O
OMe
O
OMe
OMe
20
21
22
N
O
O
OH
O
O
O
Me
O
O
O
OH
OH
23
24
The hydroxyl located in the position ortho to the carbonyl provides several possibilities for annelating O-containing
heterocycles to the chromone system. The furo[2,3-h]chromone system is the basis of naturally occurring elliptone (20) [9,
10] and caraniine (21) [12, 13]. The α-pyrono[2,3-f]chromone core is found in clausenidin (22) [16, 17], calomelanol D (23)
[18], and schumanniophytine (24) [19, 20].
The synthesis of compounds similar to angular α-pyrono[2,3-f]chromones is promising because they are active against
S. aureus and E. coli [21, 22]. Derivatives of this system were synthesized previously starting with 7-hydroxy-8-
formylchromones using the Perkin [11, 23, 24] and Knoevenagel [24, 25] reactions. We used both methods to synthesize
3-phenoxy derivatives of this system. 2-Methyl-3-(4-chlorophenoxy)pyrano[2,3-f]chromen-4,8-dione (25) was prepared via
reaction of 7-hydroxy-8-formylchromone (5) with acetic anhydride and sodium acetate. The PMR spectrum of 25 showed
doublets at 6.97 and 8.72 ppm due to splitting of vicinal protons H-9 and H-10 of the α-pyrone ring. The doublet for H-10 at
8.72 shifted to weaker field, which was characteristic for a system of conjugated vinyl and carbonyl groups and occurred in
−1
α,β-unsaturated carbonyl compounds. A strong band for lactone carbonyl at 1745 cm in the IR spectrum was indicative of
an α-pyrone ring.
The reaction of 7-hydroxy-3-phenoxy-8-formylchromones 4, 5, and 8 with 2-azolylacetonitriles was carried out in
propan-2-ol with basic catalysis by piperidine. Intermediates 9-azolyl-8-imino-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4-
ones 26-29 could be isolated under these conditions. The structures of the isolated intermediates 26-29 were confirmed by the
−1
presence in the IR spectra of NH stretching bands at 3330-3285 cm and a strong-field singlet for H-10 in the α-pyrone ring
at 9.34-9.56 ppm in the PMR spectra recorded in CF CO D. Hydrolysis of 26-29 to the corresponding 9-hetaryl-3-phenoxy-
3
2
4H,8H-pyrano[2,3-f]chromen-4,8-diones 30-32 was carried out in acetic acid or its mixture with HCl.
Pure imines could not be isolated from the reaction of 5, 8, and 9 with 2-azinylacetonitriles and 4-(benzodioxol-5-
yl)thiazol-2-ylacetonitrile because of their partial hydrolysis. In this instance the mixture was hydrolyzed to the corresponding
diones 33-35, analogously to 26-29.
The Knoevenagel reaction was performed in DMF with addition of catalytic amounts of piperidine and subsequent
hydrolysis by H SO (3%) because of the poor solubility of 8-formylchromones 7 and 9 in propan-2-ol. This produced the
2
4
corresponding α-pyrono[2,3-f]chromones 36 and 37 in a one-flask method.
The weak-field shift of the resonance for H-10 by 0.4-0.5 ppm relative to the corresponding resonance of imino
derivatives 26-29 in PMR spectra recorded in CF CO D and the presence of stretching vibrations of anγ-pyrone ring at 1660-
3
2
−1
−1
1640 cm and an α-pyrone ring at 1745-1725 cm in the IR spectra proved the structures of products 30-37.
Thus, previously unknown 7-hydroxy-3-phenoxy-8-formylchromones were synthesized. Their reactivity toward
hydrazines was investigated. An α-pyrone ring was added to the chromone core using the Knoevenagel and Perkin reactions.
351

O N
2
NO
2
Het
NH
N
HN
2
H
N
N
O
O
O
O
R
O
OH
HO
O
O
O
CH
O
3
HO
O
O
O
CH
R
1
3
O
N
N
H
19
R
2
26 - 29
Cl
25
c
18
f
b
d
e
30 - 32
O
Het
HO
O
R
HO
O
O
R
O
O
g
a
O
O
O
R
O
33 - 35
36, 37
O
R
1
R
1
O
h
R
1
R
2
R
2
11 - 17
4 - 10
R
2
30 - 37
4, 11: R = CH , R = H, R = CO CH ; 5, 12: R = CH , R = H, R = Cl; 6, 13: R = CH , R = R = H
3
1
2
2
3
3
1
2
3
1
2
7, 14: R = R = H, R = OCH ; 8, 15: R = R = R = H; 9, 16: R = R = H, R = F; 10, 17: R = CF , R = R = H
2
1
3
1
2
1
2
3
1
2
26: R = CH , R = H, R = CO CH ; 27, 30: R = CH , R = H, R = Cl; 28, 31: R = CH , R = H, R = Cl
3
1
2
2
3
3
1
2
3
1
1
2
29, 32: R = R = R = H; 33: R = CH , R = H, R = Cl; 34: R = R = H, R = F; 35: R = R = R = H
1
2
3
1
1
2
1
2
2
36: R = R = H, R = F; 37: R = H, R = OCH , R = H
1
2
3
2
Ph
H C
3
N
N
S
Het:
N
( 26, 27, 30 )
( 28, 31 )
( 29, 32 )
(33)
S
S
N
N
CH
3
O
O
Br
H C
3
(34)
(36)
(35)
S
(37)
O
N
S
S
N
NH
N
N
a. (CH ) N , AcOH; b. H NNHC H (NO ) ; c. N H ·H O; d. NaOAc, Ac O; e. HetCH CN, i-PrOH, pip; f. AcOH, HCl
2 6
4
2
2
6
3
2 2
2
4
2
2
2
g. 1. HetCH CN, i-PrOH, pip, 2. AcOH, HCl; h. 1. HetCH CN, DMF, pip, 2. 3% H SO
4
2
2
EXPERIMENTAL
The purity of products was monitored by TLC on Silufol UV-254 plates with elution by CHCl :CH OH (9:1). PMR
3
3
spectra in DMSO-d and CF CO D were recorded on a Varian Mercury 400 spectrometer relative to TMS (internal standard);
6
3
2
IR spectra in KBr disks, on a UR-20 instrument. Elemental analyses of all compounds agreed with those calculated.
General Method for Synthesizing 7-Hydroxy-3-phenoxy-8-formylchromones 4-10. 7-Hydroxy-3-
phenoxychromone (11-17, 5 mmol) and hexamethylenetetramine (4.9 g, 35 mmol) in glacial acetic acid (20 mL) were heated
352

for 6 h on a water bath, poured into a mixture (20 mL) of HCl and water (1:1), cooled, treated in portions with water (40 mL),
and left overnight. The resulting precipitate was filtered off, washed with water, and recrystallized as necessary from an
appropriate solvent.
7-Hydroxy-2-methyl-3-(4-methoxycarbonyl)-8-formylchromone (4). Yield 58%, mp 182°C, C H O . PMR
19 14
7
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.45 (3H, s, CH -2), 3.84 (3H, s, CO CH ), 7.01 (2H, d, J = 8.8, H-2′, H-6′),
6
3
2
3
7.07 (1H, d, J = 9.2, H-6), 7.90 (2H, d, J = 8.8, H-3′, H-5′), 8.15 (1H, d, J = 9.2, H-5), 10.58 (1H, s, CHO-8), 12.27 (1H, s,
−1
OH-7). IR spectrum (KBr, ν, cm ): 1640 (C=O), 1705 (C=Oest).
7-Hydroxy-2-methyl-8-formyl-3-(4-chlorophenoxy)chromone (5). Yield 73%, mp 182°C (MeOH), C H ClO .
17 11
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.45 (3H, s, CH -2), 6.94 (2H, d, J = 8.8, H-2′, H-6′), 7.05 (1H, d, J = 9.2,
6
3
H-6), 7.26 (2H, d, J = 8.8, H-3′, H-5′), 8.15 (1H, d, J = 9.2, H-5), 10.58 (1H, s, CHO-8), 12.54 (1H, s, OH-7). IR spectrum
−1
(KBr, ν, cm ): 1640 (C=O).
7-Hydroxy-2-methyl-3-phenoxy-8-formylchromone (6). Yield 56%, mp 150°C, C H O . PMR spectrum
17 12
5
(400 MHz, DMSO-d , δ, ppm, J/Hz): 2.44 (3H, s, CH -2), 6.90 (2H, d, J = 8.0, H-2′, H-6′), 7.00 (1H, t, J = 8.0, H-4′), 7.05 (1H,
6
3
d, J = 9.2, H-6), 7.26 (2H, t, J = 8.0, H-3′, H-5′), 8.14 (1H, d, J = 9.2, H-5), 10.57 (1H, s, CHO-8), 12.25 (1H, s, OH-7).
−1
IR spectrum (KBr, ν, cm ): 1640 (C=O).
7-Hydroxy-3-(2-methoxyphenoxy)-8-formylchromone (7). Yield 49%, mp 125°C, C H O . PMR spectrum
17 12
6
(400 MHz, DMSO-d , δ, ppm, J/Hz): 3.86 (3H, s, CH O-2′), 6.83-7.03 (4H, m, H-3′, H-4′, H-5′, H-6′), 7.08 (1H, d, J = 9.2,
6
3
−1
H-6), 8.22 (1H, d, J = 9.2, H-5), 8.26 (1H, s, H-2), 10.51 (1H, s, CHO-8), 12.92 (1H, s, OH-7). IR spectrum (KBr, ν, cm ):
1650, 1640 (C=O).
7-Hydroxy-3-phenoxy-8-formylchromone (8). Yield 50%, mp 130°C, C H O . PMR spectrum (400 MHz,
16 10
5
DMSO-d , δ, ppm, J/Hz): 6.96 (2H, d, J = 8.0, H-2′, H-6′), 7.03 (1H, t, J = 8.0, H-4′), 7.09 (1H, d, J = 9.2, H-6), 7.29 (2H, t,
6
J = 8.0, H-3′, H-5′), 8.21 (1H, d, J = 9.2, H-5), 8.54 (1H, s, H-2), 10.54 (1H, s, CHO-8), 12.28 (1H, s, OH-7). IR spectrum
−1
(KBr, ν, cm ): 1660, 1640 (C=O).
7-Hydroxy-8-formyl-3-(4-fluorophenoxy)chromone (9). Yield 53%, mp 146°C (i-PrOH), C H FO . PMR
16
9
5
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 6.90-7.06 (4H, m, H-2′, H-3′, H-5′, H-6′), 7.09 (1H, d, J = 9.2, H-6), 8.19 (1H,
6
−1
d, J = 9.2, H-5), 8.56 (1H, s, H-2), 10.53 (1H, s, CHO-8), 12.29 (1H, s, OH-7). IR spectrum (KBr, ν, cm ): 1645 (C=O).
7-Hydroxy-3-phenoxy-8-formyl-2-trifluoromethylchromone (10). Yield 39%, mp 156°C, C H F O . PMR
17 9 3
5
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.01 (2H, d, J = 8.0, H-2′, H-6′), 7.08 (1H, t, J = 8.0, H-4′), 7.17 (1H, d, J = 8.8,
6
H-6), 7.30 (2H, t, J = 8.0, H-3′, H-5′), 8.15 (1H, d, J = 8.8, H-5), 10.51 (1H, s, CHO-8), 12.37 (1H, s, OH-7). IR spectrum
−1
(KBr, ν, cm ): 1664, 1650 (C=O).
7-Hydroxy-4-oxo-3-phenoxy-4H-chromen-8-carbaldehyde 2,4-Dinitrophenylhydrazone (18). A solution of 8
(0.17 g, 0.6 mmol) in EtOH (10 mL) was treated with 2,4-dinitrophenylhydrazine (0.12 g, 0.6 mmol), heated until dissolved,
and left at room temperature for 12 h. The precipitate was filtered off and washed with EtOH and Et O. Yield 50%, mp 138°C,
2
C H N O . PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 6.98 (2H, d, J = 7.6, H-2′, H-6′), 7.03 (1H, t, J = 7.6,
22 14
4
8
6
H-4′), 7.08 (1H, d, J = 8.8, H-6), 7.29 (2H, t, J = 7.6, H-3′, H-5′), 7.89 (1H, d, J = 9.2, H-6′′), 8.00 (1H, d, J = 8.8, H-5),
8.39 (1H, d, J = 9.2, H-5′′), 8.70 (1H, s, H-2), 8.90 (1H, s, H-3′′), 9.28 (1H, s, H-9), 11.54 (1H, s, NH), 11.92 (1H, s, OH-7).
−1
IR spectrum (KBr, ν, cm ): 3400 (NH ), 3290 (NH ), 1660 (C=O ).
as
s
γ
2,6-Dihydroxy-3-(5-methyl-4-phenoxy-1H-pyrazol-3-yl)benzaldehyde Hydrazone (19). A solution of 6 (0.29 g,
1 mmol) in EtOH (10 mL) was treated with hydrazine hydrate (0.1 g, 3 mmol), heated for 15 min until the solid dissolved, and
cooled. The precipitate was filtered off and washed with EtOH. Yield 49%, mp 280°C, C H N O . PMR spectrum
12 16
4 3
(400 MHz, DMSO-d , δ, ppm, J/Hz): 2.09 (3H, s, CH -3), 6.16 (1H, d, J = 8.0, H-5), 6.69 (2H, s, NH ), 6.89 (2H, d, J = 8.0,
6
3
2
H-2′, H-6′), 6.98 (1H, t, J = 8.0, H-4′), 7.27 (2H, t, J = 8.0, H-3′, H-5′), 7.38 (1H, d, J = 8.0, H-6), 8.33 (1H, s, CH=N), 11.78
−1
(1H, s, OH-4), 12.07 (1H, s, OH-2), 12.90 (1H, br.s, NH). IR spectrum (KBr, ν, cm ): 3400 (NH ), 3290 (NH ).
as
s
2-Methyl-3-(4-chlorophenoxy)-4H,8H-pyrano-2,3-f-chromen-4,8-dione (25). A solution of 5 (0.33 g, 1 mmol) in
acetic anhydride (10 mL, 0.1 mol) was treated with sodium acetate (1 g, 12 mmol), heated for 6 h on an oil bath at 175-180°C,
and poured into water (30 mL). The resulting precipitate was filtered off after two days. Yield 85%, mp 214°C (AcOH),
C H ClO . PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.19 (3H, s, CH -2), 6.94 (2H, d, J = 8.8, H-2′, H-6′), 6.97
19 11
5
3
2
3
(1H, d, J = 9.6, H-9), 7.33 (2H, t, J = 8.8, H-3′, H-5′), 7.69 (1H, d, J = 9.2, H-6), 8.63 (1H, d, J = 9.2, H-5), 8.72 (1H, d, J = 9.6,
−1
H-10). IR spectrum (KBr, ν, cm ): 1745 (C=O ), 1650 (C=O ).
α
γ
353

General Method for Synthesizing 9-Hetaryl-8-imino-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4-ones 26-29.
A solution of 7-hydroxy-8-formyl-3-phenoxychromone 4, 5, or 8 (2 mmol) in i-PrOH (30 mL) was treated with
2-hetarylacetonitrile (2 mmol) and three drops of piperidine and held at room temperature for 12 h. The precipitate was
filtered off and washed with MeOH and Et O.
2
9-(Benzthiazol-2-yl)-8-imino-2-methyl-3-(4-methoxycarbonylphenoxy)-4H,8H-pyrano[2,3-f]chromen-4-one
(26). Yield 59%, mp 267°C (DMF), C H N O S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.78 (3H, s,
28 18
2
6
3
2
CH -2), 4.09 (3H, s, CO CH ), 7.13 (2H, d, J = 8.8, H-2′, H-6′), 7.71 (1H, t, J = 8.0, H-6′′), 7.76 (1H, t, J = 8.0, H-5′′), 7.92
3
2
3
(1H, d, J = 8.8, H-6), 8.11 (1H, d, J = 8.0, H-4′′), 8.16 (2H, d, J = 8.8, H-3′, H-5′), 8.25 (1H, d, J = 8.0, H-7′′), 8.89 (1H, d,
−1
J = 8.8, H-5), 9.47 (1H, s, H-10). IR spectrum (KBr, ν, cm ): 1640 (C=O ), 1705 (C=O), 3285 (NH).
γ
9-(Benzthiazol-2-yl)-8-imino-2-methyl-3-(4-chlorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4-one (27). Yield
69%, mp 284°C (DMF), C H ClN O S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.76 (3H, s, CH -2), 6.93
26 15
2
4
3
2
3
(2H, d, J = 8.8, H-2′, H-6′), 7.32 (2H, d, J = 8.8, H-3′, H-5′), 7.70 (1H, t, J = 8.0, H-6′), 7.75 (1H, t, J = 8.0, H-5′′), 7.89 (1H,
d, J = 9.2, H-6), 8.09 (1H, d, J = 8.0, H-4′′), 8.24 (1H, d, J = 8.0, H-7′′), 8.88 (1H, d, J = 9.2, H-5), 9.46 (1H, s, H-10). IR
−1
spectrum (KBr, ν, cm ): 1640 (C=O ), 3310 (NH).
γ
8-Imino-2-methyl-9-(5-phenyl-1,3,4-thiadiazol-2-yl)-3-(4-chlorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4-one
(28). Yield 80%, mp 278°C (i-PrOH), C H ClN O S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.75 (3H, s,
27 16
3
4
3
2
CH -2), 6.94 (2H, d, J = 8.8, H-2′, H-6′), 7.33 (2H, d, J = 8.8, H-3′, H-5′), 7.72 (2H, t, J = 7.6, H-3′′, H-5′′), 7.80 (1H, t, J = 7.6,
3
H-4′′), 7.94 (1H, d, J = 9.2, H-6), 8.09 (2H, d, J = 7.6, H-2′′, H-6′′), 8.96 (1H, d, J = 9.2, H-5), 9.56 (1H, s, H-10). IR spectrum
−1
(KBr, ν, cm ): 1640 (C=O ), 3320 (NH).
γ
8-Imino-9-[4-(4-methylphenyl)-1,3-thiazol-2-yl]-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4-one (29). Yield 59%,
mp 248°C (DMF), C H N O S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.43 (3H, s, CH -4′′′), 7.14 (2H, d,
28 18
2
4
3
2
3
J = 7.6, H-2′, H-6′), 7.28 (1H, t, J = 7.6, H-4′), 7.35 (2H, d, J = 7.6, H-3′′, H-5′′′), 7.46 (2H, t, J = 7.6, H-3′, H-5′), 7.77 (2H, d,
J = 7.6, H-2′′′, H-6′′′), 7.88 (1H, d, J = 9.2, H-6), 7.89 (1H, s, H-5′′ ), 8.34 (1H, s, H-2), 8.93 (1H, d, J = 9.2, H-5), 9.34 (1H,
Th
−1
s, H-10). IR spectrum (KBr, ν, cm ): 1650 (C=O ), 3330 (NH).
γ
General Method for Synthesizing 9-Hetaryl-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4,8-diones 30-37.
Method A. Pure 9-hetaryl-8-imino-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4-one (21-24, 1 mmol) or partially
hydrolyzed product was refluxed inAcOH (2 mL) or inAcOH (1 mL) and HCl (2 mL) with stirring and held at room temperature
for 12 h. The precipitate was filtered off and washed with EtOH and Et O.
2
Method B. Asolution of 7-hydroxy-3-phenoxy-8-formylchromone (7 or 9, 1 mmol) in DMF (2 mL) was treated with
the appropriate 2-hetarylacetonitrile (1 mmol) and piperidine (three drops), heated for 5 min, held at room temperature for
12 h, treated with H SO (10 mL, 3%), refluxed for 5 h, and cooled. The precipitate was filtered off and recrystallized from
2
4
DMF.
9-(Benzthiazol-2-yl)-2-methyl-3-(4-chlorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4,8-dione (30). Method A
(AcOH + HCl). Yield 56%, mp >300°C, C H ClNO S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.74 (3H, s,
26 14
5
3
2
CH -2), 6.94 (2H, d, J = 8.8, H-2′, H-6′), 7.33 (2H, d, J = 8.8, H-3′, H-5′), 7.79 (1H, d, J = 9.2, H-6), 7.96 (1H, t, J = 8.4, H-6′′),
3
8.04 (1H, t, J = 8.4, H-5′′), 8.32 (1H, d, J = 8.4, H-4′′), 8.4 (1H, d, J = 8.4, H-7′′), 8.88 (1H, d, J = 9.2, H-5), 9.88 (1H, s, H-10).
−1
IR spectrum (KBr, ν, cm ): 1735 (C=O ), 1640 (C=O ).
α
γ
2-Methyl-9-(5-phenyl-1,3,4-thiadiazol-2-yl)-3-(4-chlorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4,8-dione (31).
Method A (AcOH + HCl). Yield 83%, mp >300°C, C H ClN O S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz):
27 15
2
5
3
2
2.75 (3H, s, CH -2), 6.94 (2H, d, J = 8.0, H-2′, H-6′), 7.32 (2H, d, J = 8.0, H-3′, H-5′), 7.78-7.81 (3H, m, H-6, H-3′′, H-5′′), 7.96
3
(1H, t, J = 7.6, H-4′′), 8.18 (2H, d, J = 7.6, H-2′′, H-6′′), 8.82 (1H, d, J = 8.8, H-5), 9.93 (1H, s, H-10). IR spectrum (KBr,
−1
ν, cm ): 1730 (C=O ), 1650 (C=O ).
α
γ
9-[4-(4-Methylphenyl)-1,3-thiazol-2-yl]-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4,8-dione (32). Method A
(AcOH). Yield 65%, mp >300°C (DMF), C H NO S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.52 (3H, s,
28 17
5
3
2
CH -4′′′), 7.15 (2H, d, J = 8.0, H-2′, H-6′), 7.30 (1H, t, J = 8.0, H-4′), 7.45-7.50 (4H, m, H-3′′′, H-5′′′, H-3′, H-5′), 7.71 (2H, d,
3
J = 7.2, H-2′′′, H-6′′′), 7.78 (1H, d, J = 9.2, H-6), 8.13 (1H, s, H-5′′ ), 8.32 (1H, s, H-2), 8.91 (1H, d, J = 9.2, H-5), 9.87 (1H,
Th
−1
s, H-10). IR spectrum (KBr, ν, cm ): 1725 (C=O ), 1650 (C=O ).
α
γ
2-Methyl-9-(pyridin-2-yl)-3-(4-chlorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4,8-dione (33). MethodA(AcOH).
Yield 81%, mp 276°C (AcOH), C H ClNO . PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.72 (3H, s, CH -2),
24 14
5
3
2
3
6.94 (2H, d, J = 8.8, H-2′, H-6′), 7.33 (2H, d, J = 8.8, H-3′, H-5′), 7.78 (1H, d, J = 9.2, H-6), 8.22 (1H, m, H-4′′), 8.82-8.86
354

−1
(3H, m, H-3′′, H-5′′, H-5), 9.03 (1H, d, J = 6.0, H-6′′), 9.68 (1H, s, H-10). IR spectrum (KBr, ν, cm ): 1740 (C=O ), 1645
α
(C=O ).
γ
9-(6-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(4-fluorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4,8-dione
(34). Method A (AcOH + HCl). Yield 68%, mp >300°C (DMF), C H FN O . PMR spectrum (400 MHz, CF CO D, δ,
27 15
2
6
3
2
ppm, J/Hz): 2.76 (3H, s, CH -6′′), 7.15 (4H, d, J = 5.6, H-2′, H-3′, H-5′, H-6′), 7.78 (1H, d, J = 9.2, H-6), 8.08 (1H, d, J = 8.4,
3
H-7′′), 8.10 (1H, d, J = 8.4, H-8′′), 8.23 (1H, s, H-2), 8.42 (1H, s, H-5′′), 8.98 (1H, d, J = 9.2, H-5), 10.11 (1H, s, H-10).
−1
IR spectrum (KBr, ν, cm ): 1725 (C=O ), 1680 (C=O), 1660 (C=O ).
α
γ
9-[4-(1,3-Benzodioxol-5-yl)-1,3-thiazol-2-yl]-3-phenoxy-4H,8H-pyrano[2,3-f]chromen-4,8-dione (35). Method
A (AcOH + HCl). Yield 80%, mp >300°C, C H NO S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 6.12 (2H, s,
28 15
7
3
2
OCH O), 7.07 (1H, d, J = 8.4, H-7′′′), 7.12 (2H, d, J = 8.0, H-2′, H-6′), 7.27 (2H, m, H-4′, H-4′′′), 7.36 (1H, d, J = 8.4,
2
H-6′′′), 7.46 (2H, t, J = 8.0, H-3′, H-5′), 7.76 (1H, d, J = 9.2, H-6), 8.06 (1H, s, H-5′′ ), 8.30 (1H, s, H-2), 8.89 (1H, d, J = 9.2,
Th
−1
H-5), 9.85 (1H, s, H-10). IR spectrum (KBr, ν, cm ): 1745 (C=O ), 1650 (C=O ).
α
γ
9-(4-Methyl-1,3-thiazol-2-yl)-3-(4-fluorophenoxy)-4H,8H-pyrano[2,3-f]chromen-4,8-dione (36). Method B.
Yield 69%, mp >300°C (DMF), C H FNO S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 2.84 (3H, s, CH -4′′),
22 12
5
3
2
3
6.94 (4H, d, J = 5.6, H-2′, H-3′, H-5′, H-6′), 7.75 (1H, d, J = 9.2, H-6), 7.78 (1H, s, H-5′′′ ), 8.29 (1H, s, H-2), 8.88 (1H, d,
Th
−1
J = 9.2, H-5), 9.69 (1H, s, H-10). IR spectrum (KBr, ν, cm ): 1735 (C=O ), 1650 (C=O ).
α
γ
9-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-3-(2-methoxyphenoxy)-4H,8H-pyrano[2,3-f]chromen-4,8-dione (37).
Yield 72%, mp 255°C (DMF), C H BrNO S. PMR spectrum (400 MHz, CF CO D, δ, ppm, J/Hz): 4.06 (3H, s, CH O-2′),
28 16
6
3
2
3
7.08-7.31 (4H, m, H-3′, H-4′, H-5′, H-6′), 7.69 (2H, d, J = 8.4, H-2′′, H-6′′), 7.75 (1H, d, J = 9.2, H-6), 7.81 (2H, d, J = 8.4,
H-3′′, H-5′′), 8.19 (1H, s, H-5′′ ), 8.26 (1H, s, H-2), 8.91 (1H, d, J = 9.2, H-5), 9.88 (1H, s, H-10). IR spectrum (KBr,
Th
−1
ν, cm ): 1725 (C=O ), 1660 (C=O ).
α
γ
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