Furo[2,3-h]Chromones and Pyrano[2′,3′:5,6]Chromeno [4,3-B]Pyridines Based on Natural Isoflavones

Article abstract of DOI:10.1007/s10600-018-2556-z

Furo[2,3-h]chromone and pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine derivatives were synthesized from 7-hydroxy-8-formylisoflavones, which were prepared from natural isoflavones using a Duff reaction, via reactions with bromoacetophenones and ethyl 3-aminocr

Full text of DOI:10.1007/s10600-018-2556-z

DOI 10.1007/s10600-018-2556-z
Chemistry of Natural Compounds, Vol. 54, No. 6, November, 2018
FURO[2,3-h]CHROMONES AND PYRANO[2′,3′:5,6]CHROMENO
[4,3-b]PYRIDINES BASED ON NATURAL ISOFLAVONES
1*
1
2
T. V. Shokol, N. V. Gorbulenko, M. S. Frasinyuk,
1
and V. P. Khilya
Furo[2,3-h]chromone and pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine derivatives were synthesized from
7-hydroxy-8-formylisoflavones, which were prepared from natural isoflavones using a Duff reaction, via
reactions with bromoacetophenones and ethyl 3-aminocrotonate, respectively.
Keywords: 7-hydroxy-8-formylisoflavones, furo[2,3-h]chromones, pyrano[2′,3′:5,6]chromeno[4,3-b]pyridines.
Angular hetarenochromones provide a template for a broad spectrum of natural flavonoids and a few alkaloids.
Furo[2,3-h]flavones 1a–d were isolated from plants of the genus Pongamia (Fabaceae) and possessed antibacterial, antifungal,
and cytotoxic activity [1, 2]. Pyridine alkaloids were represented by schumanniophytine (2) from plants of the genus
Schumanniophyton [3].
N
R
2
R
3
O
9
1
7 O
O
O
O
O
Me
3
R
4
5
R
1
O
OH
1a - d
2
a: R = R = R = R = H (lanceolatin B)
1
2
3
4
b: R = OH, R = R = R = H (pongaglabol)
1
2
3
4
c: R = R = H, R + R = -O-CH -O- (pongaglabrone)
1
4
2
3
2
d: R = R = R = H, R = OMe (karanjin)
1
2
3
4
Two reported approaches to the synthesis of chromones annelated by heterocycles at the C(7)–C(8) bond involve
annelation of a heterocycle to a chromone core and annelation of a γ-pyrone ring to a benzohetarene [4]. 7-Hydroxy-8-
formylchromones are convenient synthons for synthesizing angular hetarenochromones by the first approach [5]. Previously,
8-formylformononetin (3a) was used by us to synthesize α-pyrono[2,3-f]isoflavones [6].
The goal of the present work was to annelate furan and α-pyronopyridine rings to natural isoflavone cores.
The starting materials were 8-formylformononetin (3a) and 7-hydroxy-8-formylisoflavone (3b) and its 2-methyl derivative
(3c), which were prepared by a Duff reaction from natural isoflavones 4b (isolated from Echinops echinatus [7]) and 4c (from
roots of Glycyrrhiza glabra [8]).
The Hantzsch reaction was a convenient one-step method for annelation of α-pyrone and pyridine rings to a chromone
[9]. Use of this reaction of 7-hydroxy-8-formylisoflavones 3a–c and ethyl 3-aminocrotonate in AcOH afforded
–1
5H,9H-pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine-5,9-diones 5a–c. Their IR spectra showed strong bands at 1742–1723 cm
–1
that were characteristic of ethoxycarbonyl and α-pyrone C=O stretching vibrations and bands at 1653–1644 cm that
corresponded to γ-pyrone. PMR spectra of 5a–c were characterized by two methyl singlets at 2.69–2.72 ppm and CO Et
2
1) Taras Shevchenko Kiev National University, 64/13 Vladimirskaya St., Kiev 01601, Ukraine;
e-mail: shokol_tv@univ.kiev.ua; 2) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of
Ukraine, 1 Murmanskaya St., Kiev-94, 02660, Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 6,
November–December, 2018, pp. 904–906. Original article submitted April 10, 2018.
©
1064
0009-3130/18/5406-1064 2018 Springer Science+Business Media, LLC

proton resonances and were missing weak-field singlets at 10.5 and 12.2 ppm for CHO and OH protons of starting 7-hydroxy-
8-formylisoflavones 3a–c. The structures of 5a–c differed from those of the classical Hantzsch reaction by the position of the
Py N atom. The proposed mechanism of the transformation [9] included attack of the 7-hydroxy-8-formylchromone formyls
at the N-nucleophilic center of aminocrotonate to form Schiff bases that then added a second aminocrotonate molecule whereas
ortho-unsubstituted benzaldehydes were attacked by the aminocrotonate C-nucleophilic center [10]. X-ray structure studies
confirmed that type 5 compounds and not the isomers with the schumanniophytine skeleton formed [11]. The yields of 5a and
5b, which were unsubstituted in the 11-position, were much less (18–23%) than those of 11-methyl derivative 5c (56%) and
other previously reported 11-methyl-5H,9H-pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine-5,9-diones [9, 11] regardless of the
heating and stirring time (up to 20 h).
O
N
HO
O
R
1
HO
O
R
1
N
N
N
a
O
O
R
2
R
2
3a-c
4a-c
O
NH
2
R
3
EtO
O
Br
Me
CO Et
K CO , DMF
2
3
AcOH
2
4
Me
Me
O
O
N
R
3
12c
8
9
O
O
R
1
O
11
O
4
R
1
9
7
6
8
O
R
2
O
R
2
5a-c
6a,b, 7a
3a–7a: R = H, R = OMe, 7a: R = NO ; 3b–6b: R = R = H; 6a,b: R = OMe; 3c–5c: R = Me, R = H
1
2
3
2
1
2
3
1
2
a. 1. AcOH, 100°C, 6–8 h; 2. HCl, H O
2
Previously, a furan ring was annelated to the chromone core of 7-hydroxy-8-formylisoflavones using bromoacetic
[12] or bromomalonic ester [13–16]. Condensation of 8-benzoyl-7-hydroxy-2-methylchromone with various para-substituted
phenacylbromides in Me CO in the presence of potash synthesized 8-benzoyl-2-methyl-9-phenylfuro[2,3-h]chromones [17].
2
We adapted this method to the synthesis of 8-benzoylfuro[2,3-h]isoflavones 6a, 6b, and 7a. Reaction of 7-hydroxy-8-
formylisoflavones 3a and 3b and 4-methoxy- or 4-nitrobromoacetophenones with a two-fold excess of potash with heating in
DMF gave high yields (78–93%) of 6a, 6b, and 7a. PMR spectra of these compounds in the aromatic region showed characteristic
doublets for protons of a para-substituted phenyl and a singlet for 9-H at 7.94–7.96 ppm (6a and 6b) and 8.10 ppm (7a).
–1
IR spectra contained benzoyl and γ-pyrone C=O stretching bands at 1645 and 1631 cm , respectively.
Thus, 7-hydroxy-8-formylisoflavones, which were prepared by Duff reactions of natural isoflavones, were used to
synthesize furo[2,3-h]chromone and pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine derivatives.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F plates using CHCl –MeOH
254
3
(9:1). Melting points were measured on a Kofler apparatus. PMR spectra were recorded in DMSO-d –CCl (1:1) with TMS
6
4
13
internal standard; C NMR spectra, in DMSO-d and CF CO D on a Varian Mercury-400 spectrometer. Elemental analyses
6
3
2
were obtained using a Vario micro Cube analyzer and agreed with those calculated. Compound 3a was prepared and characterized
by us earlier [6].
7-Hydroxy-4-oxo-3-phenyl-4H-8-chromenecarbaldehyde (3b). C H O , prepared analogously to 3a, yield 69%,
16 10
4
–1
1
mp 194–195°Ñ (lit. [13]: mp 197–198°Ñ). IR spectrum (KBr, ν, cm ): 3423 (ÎÍ), 1639 (Ñ=Î). Í NMR spectrum (δ, ppm,
J/Hz): 7.06 (1Í, d, J = 9.2, Í-6), 7.36–7.54 (3Í, m, Í-3′, 4′, 5′), 7.56 (2Í, d, J = 9.2, Í-2′, 6′), 8.29 (1Í, d, J = 9.2, Í-5), 8.38
13
(1Í, s, Í-2), 10.55 (1Í, s, ÑÍÎ), 12.26 (1Í, s, OÍ). C NMR spectrum (DMSO-d –CCl , δ, ppm): 109.67, 116.44, 123.49,
6
4
125.61, 128.47, 128.59, 129.30, 131.85, 134.79, 153.44, 161.70, 167.02, 173.94, 191.42.
1065

7-Hydroxy-2-methyl-4-oxo-3-phenyl-4H-8-chromenecarbaldehyde (3c). C H O , prepared analogously to 3a,
17 12
4
–1
1
yield 69%, mp 165–166°Ñ (lit. [12]: mp 164–165°Ñ). IR spectrum (KBr, ν, cm ): 3417 (ÎÍ), 1634 (Ñ=Î). Í NMR spectrum
(δ, ppm, J/Hz): 2.35 (3Í, s, ÑÍ ), 7.01 (1Í, d, J = 9.2, Í-6), 7.24 (2Í, d, J = 7.2, Í-2′, 6′), 7.35–7.44 (3Í, m, Í-3′, 4′, 5′), 8.17
3
13
(1Í, d, J = 9.2, Í-5), 10.56 (1Í, s, ÑÍÎ), 12.23 (1Í, s, OÍ). C NMR spectrum (DMSO-d , δ, ppm): 19.34, 109.92, 115.98,
6
116.18, 123.66, 128.34, 128.77, 131.08, 133.28, 134.17, 157.10, 163.41, 166.30, 174.61, 191.09.
Ethyl 10-Aryl-2,4-dimethyl-5,9-dioxo-5H,9H-pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine-3-carboxylates (5a–c)
(general method). A solution of 3a–c (1 mmol) in AcOH (5 mL) was treated with ethyl 3-aminocrotonate (0.52 g, 4 mmol)
and stirred vigorously with heating for 18–20 h. The resulting precipitate was filtered off and rinsed with alcohol.
Ethyl 2,4-Dimethyl-5,9-dioxo-10-(4-methoxyphenyl)-5H,9H-pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine-3-
–1
carboxylate (5a). C H NO ,yield 0.11g (23%), mp 177–178°Ñ.IR spectrum (KBr, ν, cm ): 1723 (Ñ=Î
), 1645 (C=O ).
27 21
7
ester+α
γ
1
Í NMR spectrum (δ, ppm, J/Hz): 1.44 (3H, t, J = 7.2, CH CH CO -3), 2.69 (3H, s, CH -2), 2.71 (3H, s, CH -4), 3.84 (3H, s,
3
2
2
3
3
CH O), 4.47 (2H, q, J = 7.2, CH CH CO -3), 6.96 (2H, d, J = 8.0, H-3′, 5′), 7.42 (1H, d, J = 8.8, H-7), 7.56 (2H, d, J = 8.0,
3
3
2
2
13
H-2′, 6′), 8.36 (1H, d, J = 8.8, H-8), 8.44 (1Í, s, Í-11). C NMR spectrum (DMSO-d , δ, ppm): 14.59, 19.74, 24.21, 62.71,
6
108.34, 114.40, 115.37, 121.62, 124.65, 128.70, 128.82, 129.73, 131.27, 131.88, 148.92, 151.61, 154.02, 155.02, 156.39,
158.55, 159.80, 167.55, 174.37.
Ethyl 2,4-Dimethyl-5,9-dioxo-10-phenyl-5H,9H-pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine-3-carboxylate (5b).
–1
C H NO , yield 0.08 g (18%), mp 217–218°Ñ. IR spectrum (KBr, ν, cm ): 1742 (Ñ=Î
), 1734 (C=O ), 1653 (C=O ).
26 19
6
ester
α γ
1
Í NMR spectrum (δ, ppm, J/Hz): 1.43 (3H, t, J = 7.2, CH CH CO -3), 2.70 (3H, s, CH -2), 2.72 (3H, s, CH -4), 4.47 (2H, q,
3
2
2
3
3
J = 7.2, CH CH CO -3), 7.39–7.47 (4H, m, Í-7, 3′, 4′, 5′), 7.64 (2H, d, J = 6.8, H-2′, 6′), 8.40 (1H, d, J = 8.0, H-8), 8.54 (1Í,
3
2
2
13
s, Í-11). C NMR spectrum (DMSO-d , δ, ppm): 14.59, 19.74, 24.21, 62.71, 108.34, 114.40, 115.37, 121.62, 124.65, 128.70,
6
128.82, 129.73, 131.27, 131.88, 148.92, 151.61, 154.02, 155.02, 156.39, 158.55, 159.80, 167.55, 174.37.
Ethyl 2,4,11-Trimethyl-5,9-dioxo-10-phenyl-5H,9H-pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine-3-carboxylate
–1
(5c). C H NO , yield 0.26 g (56%), mp 246–247°Ñ. IR spectrum (KBr, ν, cm ): 1723 (Ñ=Î
), 1645 (C=O ).
27 21
6
ester+α
γ
1
Í NMR spectrum (δ, ppm, J/Hz): 1.44 (3H, t, J = 7.2, CH CH CO -3), 2.45 (3H, s, CH -11), 2.68 (3H, s, CH -2), 2.72 (3H, s,
3
2
2
3
3
CH -4), 4.47 (2H, q, J = 7.2, CH CH CO -3), 7.39–7.47 (4H, m, Í-7, 3′, 4′, 5′), 7.64 (2H, d, J = 6.8, H-2′, 6′), 8.40 (1H, d,
3
3
2
2
13
J = 8.0, H-8), 8.54 (1Í, s, Í-11). C NMR spectrum (DMSO-d + CCl , δ, ppm): 14.61, 19.69, 19.73, 24.16, 62.50, 107.96,
6
4
114.34, 114.74, 120.75, 123.74, 128.26, 128.71, 129.91, 130.98, 131.29, 133.05, 149.14, 151.74, 153.75, 156.37, 158.34,
159.82, 164.06, 167.37, 174.76.
3
3-Aryl-8-(4-R -benzoyl)-4H-furo[2,3-h]chromen-4-ones (6a, 6b, 7a) (general method). A solution of 3a or 3b
(1 mmol) and 4-methoxy- or 4-nitrobromoacetophenone (1 mmol) in DMF (5 mL) was treated with K CO (0.28 g, 2 mmol),
2
3
stirred vigorously with heating for 20 h, cooled, diluted with H O, and neutralized with HCl. The precipitate was filtered off
2
and recrystallized from DMF.
8-(4-Methoxybenzoyl)-3-(4-methoxyphenyl)-4H-furo[2,3-h]chromen-4-one (6a). C H O , yield 0.40 g (93%),
26 18
6
–1
1
mp 241–242°Ñ (DMF). IR spectrum (KBr, ν, cm ): 1645 (Ñ=Î), 1631 (Ñ=Î ). Í NMR spectrum (δ, ppm, J/Hz): 3.68 (3Í,
γ
s, ÑÍ Î-4′), 3.93 (3Í, s, ÑÍ Î-4′′), 6.97 (2Í, d, J = 8.0, H-3′, 5′), 7.10 (2H, d, J = 8.0, H-3′′, 5′′), 7.54 (2Í, d, J = 8.0, H-2′,
3
3
6′), 7.79 (1Í, d, J = 8.8, H-6), 7.94 (1Í, s, Í-9), 8.10 (2Í, d, J = 8.0, H-2′′, 6′′), 8.28 (1Í, d, J = 8.8, Í-5), 8.45 (1Í, s, Í-2).
13
C NMR spectrum (CF CO D, δ, ppm): 57.14, 57.40, 115.00, 116.63, 117.14, 119.40, 120.29, 124.77, 124.82, 128.07,
3
2
128.41, 130.06, 133.27, 135.13, 155.06, 155.69, 159.21, 161.38, 162.61, 167.42, 181.36, 187.92.
8-(4-Methoxybenzoyl)-3-phenyl-4H-furo[2,3-h]chromen-4-one (6b). C H O , yield 0.31 g (78%),
25 16
5
–1
1
mp 248–249°Ñ (DMF). IR spectrum (KBr, ν, cm ): 1645 (Ñ=Î), 1631 (Ñ=Î ). Í NMR spectrum (δ, ppm, J/Hz): 3.93 (3Í,
γ
s, ÑÍ Î), 7.10 (2H, d, J = 8.0, H-3′′, 5′′), 7.44–7.59 (3Í, m, H-3′, 4′, 5′), 7.59 (2Í, d, J = 8.0, H-2′, 6′), 7.81 (1Í, d, J = 8.8,
3
13
H-6), 7.96 (1Í, s, Í-9), 8.11 (2Í, d, J = 8.0, H-2′′, 6′′), 8.29 (1Í, d, J = 8.8, Í-5), 8.51 (1Í, s, Í-2). C NMR spectrum
(CF CO D, δ, ppm): 57.14, 115.18, 117.10, 119.39, 120.25, 128.35, 128.67, 130.01, 131.17, 131.45, 131.94, 135.13, 155.07,
3
2
155.70, 159.47, 162.60, 167.46, 181.13, 187.79.
3-(4-Methoxyphenyl)-8-(4-nitrobenzoyl)-4H-furo[2,3-h]chromen-4-one (7a). C H NO , yield 0.38 g (86%),
25 15
7
–1
1
mp 287–288°Ñ (DMF). IR spectrum (KBr, ν, cm ): 1645 (Ñ=Î), 1631 (Ñ=Î ). Í NMR spectrum (δ, ppm, J/Hz): 3.85 (3Í,
γ
s, ÑÍ Î), 6.98 (2H, d, J = 6.8, H-3′, 5′), 7.56 (2Í, d, J = 6.8, H-2′, 6′), 7.80 (1Í, d, J = 8.4, H-6), 8.10 (1Í, s, Í-9), 8.32–8.43
3
13
(6Í, m, H-2′′, 3′′, 5′′, 6′′, 5, 2). C NMR spectrum (CF CO D, δ, ppm): 57.19, 114.59, 116.82, 118.23, 119.07, 119.18,
3
2
124.74, 125.92, 126.53, 128.22, 129.22, 132.61, 132.93, 142.70, 152.61, 155.55, 158.88, 161.17, 169.67, 181.31, 187.16.
1066

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