Modified coumarins. 21. Synthesis of neoflavones produced by Marila pluricostata and their derivatives

Article abstract of DOI:10.1007/s10600-006-0060-3

Natural neoflavones 5-hydroxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3- f]chromen-2-one and 5-hydroxy-8,8-dimethyl-6-propionyl-4-phenyl-9,10- dihydropyrano[2,3-f]chromen-2-one and their derivatives were synthesized. 2006 Springer Science+Business Medi

Full text of DOI:10.1007/s10600-006-0060-3

Chemistry of Natural Compounds, Vol. 42, No. 2, 2006
MODIFIED COUMARINS. 21. SYNTHESIS OF NEOFLAVONES
PRODUCED BY
AND THEIR DERIVATIVES
Marila pluricostata
V. S. Moskvina,1 Ya. L. Garazd,1 M. M. Garazd,2 and V. P. Khilya1
UDC 547.814.5
f
Natural neoflavones 5-hydroxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3- ]chromen-2-one and
f
5-hydroxy-8,8-dimethyl-6-propionyl-4-phenyl-9,10-dihydropyrano[2,3- ]chromen-2-oneandtheirderivatives
were synthesized.
Key words:
coumarins, 4-phenylcoumarins, neoflavones, pyranocoumarins, furocoumarins.
Neoflavones form a group of compounds based on the 4-phenylcoumarin skeleton that are widelydistributed in nature
1
[1, 2]. Several neoflavones including 5-hydroxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3- ]chromen-2-one ( ) and
f
2
5-hydroxy-8,8-dimethyl-6-propionyl-4-phenyl-9,10-dihydropyrano[2,3- ]chromen-2-one( )wereisolatedfrom leavesof
f
Marila
1
(Clusiaceae) [3]. Some of these compounds possess cytotoxic [3] and anti-HIV activity [4]. A synthesis of and
pluricostata
2
1
has also been reported [3]. Coumarin was prepared by cyclization in acidic medium of 5,7-dihydroxy-8-(3-methylbut-
2
1
2-enyl)-4-phenylcoumarin; , by Friedel—Krafts acylation of with propionylchloride in the presence of AlCl .
3
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
OH
PhCOCH COOEt
2
+
EtOH, H SO
2
4
OMe
OMe Ph
OH Ph
(MeO) SO ,
2
2
3
4
1
K CO
2
3
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
Ac O, Py
(EtCO) O, Py
AlCl
3
2
2
Me
OAc Ph
O
Ph
OH Ph
OH Ph
Me
6
5
1
2
O
MeCOCHRHaI K CO
2
3
Me
Me
Me
Me
1. 1N NaOH
2. 1N H SO
O
O
O
O
O
R
O
O
2
4
Me
O
Ph
O
Ph
Me
7, 8
9, 10
R
7, 9: R = H; 8, 10: R = Me
1)TarasShevchenkoKievNational University, 01033, Ukraine, Kiev, ul. Vladimirskaya, 64; 2) InstituteofBioorganic
Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Kiev, ul. Murmanskaya, 1, e-mail:
gmm@i.com.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 107-109, March-April, 2006. Original article
submitted December 15, 2005.
0009-3130/06/4202-0129 ©2006 Springer Science+Business Media, Inc.
129

In this investigation, we took a different approach to the synthesis of 1 and 2.
We used 7-methoxy-2,2-dimethylchroman-5-ol (3) [5] as the starting material. It is known that use of 3 in the
Pechmann condensation causes demethylation of the product as a side reaction [5]. Reaction of 3 and ethylbenzoylacetate in
the presence of conc. H SO as the condensing agent produced a mixture of 1 and 5-methoxy-8,8-dimethyl-4-phenyl-9,10-
2
4
dihydropyrano[2,3-f]chromen-2-one (4), which was easily separated by basic extraction.
Acetylation of 1 with acetic anhydride in pyridine gave acetoxycoumarin 5. Methoxy derivative 4 was also prepared
by methylation of 1 with dimethylsulfate in the presence of anhydrous potash.
Coumarin 1 was used as a key intermediate in the synthesis of natural neoflavone 2. Acylation of 1 by propionic
anhydride in pyridine produced 5-propionoxycoumarin 6. Fries rearrangement of5 in the presenceofanhydrousAlCl at 120°C
3
formed 6-propionylneoflavone 2.
Hydroxycoumarin 1 was also used as starting material for synthesizing of 5,5-dimethyl-6,7-dihydrofuro[2,3-f]-
pyrano[2,3-h]chromen-9-ones. The MacLeod method was used toannelate the furan ring tothe dihydropyranocoumarin system
[6]. Alkylation of 1 under Williamson conditions using chloroacetone and 3-chlorobutan-2-one formed oxoethers 7 and 8,
respectively, which were heated with NaOH solution (1 N) and then hydrolyzed with acid to cyclize smoothlyand in high yields
to 5,5-dimethyl-11-phenyl-6,7-dihydrofuro[2,3-f]pyrano[2,3-h]chromen-9-ones 9 and 10, respectively.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F254 plates with elution by
CHCl :CH OH (9:1). Melting points were determined on a Kofler block. IR spectra were measured on a Nicolet Nexus
3
3
475 FTIR; PMRspectra, on Varian VXR-300 and Mercury400 spectrometers at300and400MHz, respectively, relative toTMS
(internal standard). Elemental analyses of all compounds agreed with those calculated.
Chromanol 3 was prepared as before [5].
8,8-Dimethyl-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-ones 1 and 4. A solution of 3 (4.50 g, 20 mmol) and
ethylbenzoylacetate (3.6 mL, 20 mmol) in ethanol (10 mL) was stirred vigorously and treated dropwise with conc. H SO
2
4
(20 mL). The resulting mixture was held at 50°C for 4 h, left overnight at room temperature, and transferred into icewater
(100 mL). The resulting precipitate was dissolved in CHCl (50 mL) and treated with NaOH solution (1 N, 2 × 50 mL) and
3
saturated NaCl solution. The organic phase was dried with anhydrous MgSO . The solvent was removed in vacuo in a rotary
4
evaporator. The oily residue was crystallized from CH OH to afford 4. The combined extracts of the alkaline solution were
3
acidified to pH 4. The resulting precipitate of 1 was filtered off and crystallized from CH OH.
3
5-Hydroxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (1). Yield 4.42 (63%), C H O ,
20 18
4
mp 317-318°C (lit. [3] 274-275°C).
-1
IR spectrum (KBr, cm ): 3248, 1702, 1690, 1592, 1562, 1440, 1428, 1360, 1160, 1112.
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.82 (6H, s, 2×CH -8), 1.56 (2H, t, J = 6.8, CH -9), 2.56 (2H,
6
3
2
t, J = 6.8, CH -10), 5.67 (1H, s, H-3), 6.37 (1H, s, H-6), 7.20 (2H, m, H-2′, H-6′), 7.34 (3H, m, H-3′, H-4′, H-5′), 10.38 (1H,
2
s, OH-5).
5-Methoxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (4). Yield 2.32 g (32%), C H O ,
21 20
4
mp 133-134°C.
IR spectrum (KBr, cm ): 1706, 1685, 1620, 1590, 1430, 1350, 1140.
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.37 (6H, s, 2×CH -8), 1.87 (2H, t, J = 6.8, CH -9), 2.81 (2H,
-1
6
3
2
t, J = 6.8, CH -10), 3.37 (3H, s, OMe-5), 5.81 (1H, s, H-3), 6.18 (1H, s, H-6), 7.23 (2H, m, H-2′, H-6′), 7.36 (3H, m, H-3′, H-4′,
2
H-5′).
5-Acetoxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (5). A solution of 1 (0.96 g, 3 mmol)
in absolute pyridine (2 mL) was treated with acetic anhydride (1 mL). The reaction mixture was held at room temperature for
24 h. The resulting precipitate was filtered off and crystallized from propan-2-ol. Yield 0.98 g (90%), C H O ,
22 20
5
mp 138-139°C.
IR spectrum (KBr, cm ): 1745, 1708, 1690, 1620, 1580, 1455, 1340, 1130.
-1
130

PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.85 (6H, s, 2×CH -8), 1.60 (2H, t, J = 6.6, CH -9), 2.64 (3H, s,
3
2
3
CH COO-5), 2.52 (2H, t, J = 6.6, CH -10), 6.09 (1H, s, H-3), 6.71 (1H, s, H-6), 7.23 (2H, m, H-2′, H-6′), 7.37 (3H, m, H-3′,
3
2
H-4′, H-5′).
5-Methoxy-8,8-dimethyl-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (4). A hot solution of 1 (0.96 g,
3 mmol) in absolute acetone (20 mL) was treated with freshly calcined potash (1.24 g, 9 mmol), stirred vigorously, heated
(50-56°C), and treated with dimethylsulfate (0.46 mL, 3.3 mmol). The reaction mixture was held for 2 h with heating and
vigorous stirring (course of reaction monitored by TLC). When the reaction was complete the mixture was cooled to room
temperature, transferred to icewater (100 mL), and acidified to pH 4. The precipitate was filtered off and crystallized from
CH OH. Yield 0.87 g (86%).
3
8,8-Dimethyl-5-propionoxy-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (6) was prepared analogously to
5 using 1 (1.61 g, 5 mmol), absolute pyridine (2 mL), and propionic anhydride (0.96 mL, 7.5 mmol). Yield 1.55 g (82%),
C H O , mp 143-144°C.
23 22
5
-1
IR spectrum (KBr, cm ): 1742, 1705, 1695, 1620, 1580, 1455, 1340, 1130.
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.85 (6H, s, 2×CH -8), 1.30 (3H, t, J = 7.2, CH -3″), 1.60 (2H, t,
3
3
3
J = 6.6, CH -9), 2.51 (2H, t, J = 6.6, CH -10), 2.64 (2H, q, J = 7.2, CH -2″), 6.08 (1H, s, H-3), 6.71 (1H, s, H-6), 7.23 (2H, m,
2
2
2
H-2′, H-6′), 7.37 (3H, m, H-3′, H-4′, H-5′).
5-Hydroxy-8,8-dimethyl-4-phenyl-6-propionyl-9,10-dihydropyrano[2,3-f]chromen-2-one (2). A ground mixture
of 6 (1.13 g, 3 mmol) and AlCl (1.20 g, 9 mmol) was held at 120°C for 1 h, cooled, and treated with HCl solution (1 N,
3
100 mL). The resulting precipitate was filtered off and crystallized from CH OH. Yield 0.71 g (63%), C H O ,
3
23 22 5
mp 286-287°C (lit. [3] 274-275°C).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.84 (6H, s, 2×CH -8), 1.38 (3H, t, J = 7.2, CH -3″), 1.62 (2H,
6
3
3
t, J = 6.6, CH -9), 2.59 (2H, t, J = 6.6, CH -10), 2.85 (2H, q, J = 7.2, CH -2″), 5.93 (1H, s, H-3), 7.20 (2H, m, H-2′, H-6′), 7.35
2
2
2
(3H, m, H-3′, H-4′, H-5′), 13.20 (1H, br.s, OH-5).
8,8-Dimethyl-5-(2-oxopropoxy)-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (7)waspreparedanalogously
to 4 from 1 (1.61 g, 5 mmol), anhydrous potash (2.07 g, 15 mmol), and chloroacetone (0.44 mL, 5.5 mmol). Yield 1.63 g
(86%), C H O , mp 171-172°C.
23 22
5
-1
IR spectrum (KBr, cm ): 1710, 1692, 1602, 1552, 1424, 1380, 1360, 1164, 1134, 1108.
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.83 (6H, s, 2×CH -8), 1.59 (2H, t, J = 6.4, CH -9), 2.21 (3H,
6
3
2
s, CH -3″), 2.60 (2H, t, J = 6.4, CH -10), 4.88 (3H, s, CH -1″), 5.79 (1H, s, H-3), 6.52 (1H, s, H-6), 7.21 (2H, m, H-2′, H-6′),
3
2
2
7.36 (3H, m, H-3′, H-4′, H-5′).
8,8-Dimethyl-5-(1-methyl-2-oxoproproxy)-4-phenyl-9,10-dihydropyrano[2,3-f]chromen-2-one (8) was prepared
analogously to 4 from 1 (1.61 g, 5 mmol), anhydrous potash (2.07 g, 15 mmol), and 3-chloro-2-butanone (0.56 mL, 5.5 mmol)
as a yellow oil and was used for further transformations without additional purification.
5,5-Dimethyl-11-phenyl-6,7-dihydrofuro[2,3-f]pyrano[2,3-h]chromen-9-ones 9 and 10. A solution of 7 or 8
(3 mmol) in propan-2-ol (10 mL) was treated with NaOH solution (1 N, 10 mL). The reaction mixture was heated at 80-90°C
for 3 h (course of reaction monitored by TLC). After the reaction was complete the mixture was cooled to room temperature,
transferred towater (100 mL), and acidified topH4. The resulting precipitate was filtered offand crystallized from propan-2-ol.
3,5,5,-Trimethyl-11-phenyl-6,7-dihydrofuro[2,3-f]pyrano[2,3-h]chromen-9-one (9). Yield1.01g(94%), C H O ,
23 20
4
mp 248-249°C.
IR spectrum (KBr, cm ): 1726, 1692, 1610, 1568, 1466, 1420, 1384, 1358, 1312, 1160, 1118, 1104.
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.84 (6H, s, 2×CH -5), 1.65 (2H, t, J = 6.4, CH -6), 2.45 (3H,
-1
6
3
2
s, CH -3), 2.80 (2H, t, J = 6.4, CH -7), 5.93 (1H, s, H-10), 7.21 (2H, m, H-2′, H-6′), 7.37 (3H, m, H-3′, H-4′, H-5′), 7.55 (1H,
3
2
d, J = 1.6, H-2).
2,3,5,5-Tetramethyl-11-phenyl-6,7-dihydrofuro[2,3-f]pyrano[2,3-h]chromen-9-one (10). Yield 1.02 g (91%),
C H O , mp 162°C.
24 22
4
-1
IR spectrum (KBr, cm ): 1722, 1692, 1612, 1568, 1444, 1380, 1352, 1310, 1222, 1160, 1088.
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.84 (6H, s, 2×CH -5), 1.64 (2H, t, J = 6.4, CH -6), 2.38, 2.39
6
3
2
(6H, 2s, CH -3, CH -2), 2.78 (2H, t, J = 6.4, CH -7), 5.90 (1H, s, H-10), 7.22 (2H, m, H-2′, H-6′), 7.38 (3H, m, H-3′, H-4′,
3
3
2
H-5′).
131

ACKNOWLEDGMENT
We thank OAO "Eximed" (Kiev, Ukraine) for assistance in performing this work.
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