Synthesis of new difurocoumarins

Article abstract of DOI:10.1023/A:1026186002637

5,7-Dihydroxy-4-methyl- and 5,7-dihydroxy-4-trifluoromethylcoumarins are starting compounds in the synthesis of new 10-methyl-8H-difuro[2,3-f;2,3-h]-8- ones and 10-trifluoromethyl-8H-difuro[2,3-f;2,3-h]chromen-8-ones with high yields.

Full text of DOI:10.1023/A:1026186002637

Chemistry of Heterocyclic Compounds, Vol. 39, No. 7, 2003
SYNTHESIS OF NEW DIFUROCOUMARINS
V. F. Traven, N. Ya. Podkhalyuzina, and D. S. Kanevskii
5
,7-Dihydroxy-4-methyl- and 5,7-dihydroxy-4-trifluoromethylcoumarins are starting compounds in the
synthesis of new 10-methyl-8H-difuro[2,3-f;2,3-h]-8-ones and 10-trifluoromethyl-8H-difuro-
2,3-f;2,3-h]chromen-8-ones with high yields.
[
Keywords: difurocoumarins, 10-methyl-8H-difuro[2,3-f;2,3-h]chromen-8-one, Fries rearrangement,
cyclization.
Preparations based on furocoumarins and their derivatives have been used successively in the treatment
of various blood diseases [1]. Certain furocoumarins, containing angelicin and allopsoralen fragments in the
molecule, form only monoadducts with DNA molecules [2] and can presumably exhibit the lower photo- and
genotoxicity characteristic of this class [3-5].
In this paper we report on the synthesis of new furocoumarins containing not only angelicin and
allopsoralen fragments but also hydrocarbon and ester substituents.
The number of papers on the synthesis of difuro[2,3-f;2,3-h]chromen-8-ones is extremely limited.
Thus, Singh and coworkers were able to synthesize 2,5,10-trimethyl-8H-difuro[2,3-f;2,3-h]chromen-8-
one and 2,5-dimethyl-8H-difuro[2,3-f;2,3-h]chromen-8-one [6]. The starting compounds were 5,7-dihydroxy-
and 4-methyl-5,7-dihydroxycoumarins, which were alkylated with allyl bromide. The obtained ethers were
subjected to a Claisen rearrangement followed by cyclization of the rearrangement products in the presence of
acid. The synthesized compounds were dehydrogenated with Pd/C in diphenyl ether to the corresponding
2
,5-dimethyl-8H-difuro[2,3-f;2,3-h]chromen-8-ones. The total yield of the difurocoumarins including the four
stages amounted to 15% [6].
In [2] a different method was proposed for the cyclization of the product of the Claisen rearrangement:
Protection of the hydroxyl groups by acylation, bromination of the obtained compound, and subsequent alkaline
cyclization of the 6,8-bisdibromopropyl derivative to difurocoumarin with an overall yield of 2%.
It should be noted that the methods described only gave difurocoumarins with methyl substituents and
only at the α-positions of the furan rings. Moreover, the yields of the final products were low.
We have developed new methods for the synthesis of difuro[2,3-f;2,3h]chromen-8-one and its
substituted derivatives. In particular, by using base-catalyzed cyclization of the acylmethyl ethers of
dihydroxycoumarins 2 and Fries rearrangement of the chloroacetates of the dihydroxycoumarins, we obtained
good yields of 10-methyl-8H-difuro[2,3-f;2,3-h]chromen-8-one and its derivatives 3-5,
We synthesized the initial 5,7-dihydroxycoumarins 1 by the familiar procedure from phloroglucinol and
the corresponding acetoacetic esters [7, 8].
For the production of dufurocoumarins containing methyl and phenyl substituents at the β-positions of
the furan rings we used the method and conditions that we used earlier in the synthesis of various
monofurocoumarins [9]. The 5,7-dihydroxycoumarins were alkylated with chloroacetone and
_
_________________________________________________________________________________________
D. I. Mendeleev Russian Chemical Technology University, Moscow 125047; e-mail:
traven@muctr.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1006-1011, July,
2
003. Original article submitted March 12, 2001.
8
66 0009-3122/03/3907-0866$25.00©2003 Plenum Publishing Corporation

α-chloroacetophenone in the presence of potassium carbonate, and the obtained acylmethyl ethers were
submitted to base-catalyzed cyclization in a water–alcohol solution of potassium hydroxide. It should be noted
that the yields of the difurocoumarins obtained according to this scheme hardly differed at all from the yields of
the monofurocoumarins that we synthesized earlier by this method (65-85%).
R'
OH
R
O
R
O
Me CO
2
O
O
+
R'
K CO
2
3
Cl
R'
HO
O
O
O
O
R' = Me, Ph
1
a,b
O
2a–c
O
R
R'
1
. KOH (1N)
+
2
. H
O
O
O
R' 3a–b
a R = Me, b R = CF ; 2, 3 a R = R' = Me, b R = Me, R' = Ph, c R = CF , R' = Me
1
3
3
We realized the synthesis of the diacetoxy-substituted difurocoumarin 6 according to Scheme 1.
Acylation of the dihydroxycoumarin 1a with chloroacetyl chloride was used on account of the strong
resinification of the reaction mixture under mild conditions with gentle heating in DMF, whereas in the
acylation of monohydroxycoumarins the reaction is conducted with boiling in chloroacetyl chloride. The
bischloroacetate of dihydroxycoumarin 4 was then submitted to the Fries rearrangement, and the reaction
product was treated with a solution of sodium acetate in acetic anhydride. Earlier we used this method for the
production of acetoxy derivatives in the synthesis of various monofurocoumarins [10]. The required compound
6
was synthesized with a yield of 61%, calculated in the initial dihydroxycoumarin.
Scheme 1
O
Cl
O
Me
O
O
O
DMF
O
o
AlCl , t C
1
a
3
+
Cl
Cl
Cl
O
O
4
Me
O
Me
O
O
AcO
Ac O, NaOAc
2
O
O
O
O
O
O
OAc
5
6
8
67

TABLE 1. The Characteristics of the Synthesized Compounds
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
mp, °С
Yield, %
С
H
2
2
2
3
3
3
4
5
6
7
a
b
c
C
C
C
C
C
C
C
C
C
C
16
H
26
H
16
H
16
H
26
H
16
H
14
H
14
H
18
H
14
H
16
20
13
12
16
O
6
6
63.11
5.22
5.30
154-155
225-226
175
6
7
6
7
7
7
8
8
8
3
7
1
4
3
6
0
4
5
6
4
6
3.15
O
72.79
4.68
7
2.89
4.71
F
3
O
6
53.58
3.63
3.66
5
3.64
a
b
c
O
4
4
71.60
4.57
271-273
220-221
203
7
1.64
4.51
O
79.47
4.08
4.11
7
9.58
59.56
9.64
48.66
9
3
F O
4
2.85
5
2.82
10Cl
2
O
6
2.96
2.92
174-175
285-286
235-236
242-243
4
8.72
8
O
6
61.65
2.98
6
1.77
2.96
12
8
O
8
60.65
3.35
3.39
6
0.68
O
4
69.88
3.38
7
0.00
3.36
For the synthesis of unsubstituted difurocoumarin 7 we reduced the difuranone 5, and we then
dehydrated the obtained product. The required compound was isolated with a yield of 35%.
O
Me
1
2
. NaBH , dioxane
4
5
. 35% H SO
2
4
O
O
O
7
The yields and the spectral characteristics of the synthesized substances are presented in Tables 1-3.
1
TABLE 2. The H NMR Spectra of Compounds 2-7
Com-
Chemical shifts, δ, ppm (J, Hz)*
pound
1
2
2
a
2.16 (3H, s, 7-OCH
2
–CO–CH
3
); 2.17 (3H, s, 5-OCH
2
–CO–CH
3
);
2
4
6
.57 (3H, d, J = 0.9, 4-CH
3
); 4.92 (2H, s, 7-OCH
2
–CO–CH
3
);
.98 (2H, s, 5-OCH
2
-CO–CH ); 6.02 (1H, dd, J = 0.9, 3-H); 6.44 (1H, d, J6,8 = 2.5, 6-H);
3
.53 (1H, d, J8,6 = 2.5, 8-H)
2
2
b
c
2.83 (3H, d, J-CH3,3-H = 1.1, 4-CH
3
); 5.66 (2H, s, 7-O–CH
.03 (1H, dd, J3-H,-CH3 = 1.1, 3-H); 6.69 (1H, d, J8,6 = 1.8, 8-H);
.73 (1H, d, J6,8 = 1.8, 6-H); 7.52-7.73 (6H, m, 2×(m-, p-Ph)); 7.99-8.06 (4H, m, 2×(o-Ph))
2
–); 5.72 (2H, s, 5-O–CH
2
–);
6
6
2.27 (3H, s, 7-OCH
2
–CO–CH
3
); 2.28 (3H, s, 5-OCH
2
–CO–CH
3
);
4
6
.63 (2H, s, 7-OCH
2
–CO–CH
3
); 4.67 (2H, s, 5-OCH
2
–CO–CH
3
);
.26 (1H, d, J8,6 = 2.5, 8-H); 6.43 (1H, d, J6,8 = 2.5, 6-H); 6.71 (1H, s, 3-H)
8
68

TABLE 2 (continued)
1
2
3
3
a
2.45 (3H, d, J6-CH ,5-H = 1.3, 6-CH
3
), 2.47 (3H, d, J3-CH ,2-H = 1.3, 3-CH
3
),
3
3
2
.74 (3H, d, J10-CH ,9-H = 1.2, 10-CH ), 6.33 (1H, dd, J9-H, 10-CH3 = 1.2, 9-H),
3
3
7
.87 (1H, dd, J5-H,6-CH3 = 1.2, 5-H), 7.93 (1H, dd, J2-H,3-CH3 = 1.2, 2-H).
b
c
2.79 (3H, d, J10-CH3,9-H = 1.2, 10-CH
3
); 6.36 (1H, dd, J9-H,10-CH3 = 1.2, 9-H);
7
.44-7.54 (6H, m, m-, p-Ph); 7.66-7.68 (2H, m, o-Ph); 7.88-7.91 (2H, m, o-Ph');
8
.22 (1H, s, 5-H); 8.49 (1H, s, 2-H)
3
4
2.42 (3H, d, J = 1.3, 6-CH
3
); 2.43 (3H, d, J = 1.3, 3-CH
3
); 6.98 (1H, s, 9-CH
3
);
7
3
.88 (1H, d, J = 1.3, 5-CH ); 7.94 (1H, d, J = 1.3, 2-CH
3
)
2.51 (3H, d, J-CH3,3-H = 1.2, 4-CH
3
); 4.30 (2H, s, 7-CO–CH –Cl);
2
4
6
.33 (2H, s, 5-CO–CH
2
–Cl); 6.24 (1H, dd, J3-H,-CH = 1.2, 3-H);
3
.97 (1H, d, J8,6 = 2.0, 8-H); 7.16 (1H, d, J6,8 = 2.0, 6-H)
5
6
7
2.55 (3H, d, J = 1.2, 10-CH
.28 (1H, dd, J = 1.2, 9-H)
2.42 (3H, s, 6-OC(O)CH
3
); 5.01 (2H, s, 5-H); 5.07 (2H, s, 2-H);
6
3
); 2.43 (3H, s, 3-OC(O)CH
3
); 2.75 (3H, d, J = 0.2, 10-CH );
3
6
.41 (1H, dd, J = 0.2, 9-H); 8.28 (1H, s, 5-H); 8.38 (1H, s, 3-H)
2.87 (3H, d, J = 1.9, 10-CH
3
); 6.26 (1H, dd, J = 1.9, 9-CH
3
); 7.11 (1H, d, J = 2.0, 6-CH );
3
7
.21 (1H, d, J = 2.0, 3-CH ); 7.70 (1H, d, J = 2.0, 5-CH
3
3
); 7.70 (1H, d, J = 2.0, 2-CH )
3
_
*
5
______
1
The H NMR spectra were recorded in DMSO-d
6
(compounds 2a,b, 3a-c,
, and 6) and CDCl (compounds 2c, 4, and 7).
3
TABLE 3. Mass-spectral Dissociation of the Synthesized Compounds
Com-
m/z (Irel, %)
pound
+
+
2
2
2
a
b
c
304 [M ] (100), 261 [M –CH
3
CO] (45)
+
+
428 [M ] (32), 105 [M –PhCO] (100)
+
+
+
358 [M ] (46), 315 [M –CH
3
CO] (28), 287 [M –CH
3
CO, –CO] (21),
+
2
47 [M –CH
3
CO, –CO,–C
2
O] (100)
+
+
3
3
3
4
5
6
7
a
b
c
268 [M ] (77), 240 [M –CO] (100)
+
+
392 [M ] (100), 364 [M –CO] (88)
+
+
+
322 [M ] (83), 294 [M –CO] (100), 265 [M –CO, –HCO] (20)
+
+
349 [M +1] (4), 317 [M –CO] (3)
+
+
+
272 [M ] (100), 244 (M –CO] (65), 215 [M –CO, –HCO] (79)
+
+
+
356 [M ] (5), 314 [M –CH
2
CO] (28), 272 [M –CH
2
CO, –CH CO] (100)
2
+
+
240 [M ] (75), 212 [M –CO] (100)
EXPERIMENTAL
1
The H NMR spectra were obtained on a Bruker AC-200 spectrometer (200 MHz) with TMS as internal
standard. The mass spectra were obtained on a Finnigan MAT SSQ-710 instrument at 70 eV. The reactions were
monitored by TLC in Silufol UV-254 plates. Chromatographic separation was realized on silica gel 60 (Merck)
with CHCl
,7-Bis(acetonyloxy)-4-methyl-2H-chromen-2-one (2a). To
dihydroxycoumarin 1a (3.0 g, 15.6 mmol) in the smallest amount of DMF we added chloroacetone (3.0 g,
3
as eluent.
5
a
solution of 4-methyl-5,7-
3
2.8 mmol) and anhydrous potassium carbonate (5 g). The mixture was stirred for 5 h. It was then poured into of
water (250 ml) with vigorous stirring for 15 min. The precipitated product was filtered off and washed with
several portions of water. The substance was purified by boiling in ethanol. After drying 3.18 g of the product
was obtained.
8
69

5
,7-Bis(benzoylmethoxy)-4-methyl-2H-chromen-2-one (2b). The compound was obtained from
compound 1a and α-chloroacetophenone by analogy with compound 2a.
5
,7-Bis(acetonyloxy)-4-(trifluoromethyl)-2H-chromen-2-one (2c). The compound was obtained by
analogy with compound 2a from compound 1b and chloroacetone and was purified on a chromatographic
column.
3
,6,10-Trimethyl-8H-difuro[2,3-f;2,3-h]chromen-8-one (3a). We boiled compound 2a (2 g,
6
.58 mmol) for 6 h with a reflux condenser with stirring in a 1 N solution of potassium hydroxide (75 ml), and
we cooled the mixture to room temperature. The reaction mass was then acidified to pH 3 with 1 N hydrochloric
acid with stirring. It was cooled for 1 h to complete the crystallization. The precipitate was filtered off and
washed by boiling in methanol (15 ml). We obtained 1.29 g of the product 3a.
1
0-Methyl-3,6-diphenyl-8H-difuro[2,3-f;2,3-h]chromen-8-one (3b). The compound was obtained
from compound 2b by analogy with compound 3a.
3
,6-Dimethyl-10-(trifluoromethyl)-8H-difuro[2,3-f;2,3-h]chromen-8-one (3c). The compound was
obtained from compound 2c by analogy with compound 2a. After acidification the reaction mass was extracted
with chloroform, and the solvent was evaporated. The product was purified on a chromatographic column.
5
,7-Bis(chloroacetoxy)-4-methyl-2H-chromen-2-one (4). To a solution of compound 1a (3 g,
1
5.6 mmol) in DMF (10 ml) we added chloroacetyl chloride (4 ml, 47.96 mmol). The mixture was stirred with
heating at 65-70°C for 5 h. The reaction mass was poured onto ice. The precipitate was stirred for 15 min on a
magnetic stirrer to complete hydrolysis of the chloroacetyl chloride, filtered, and washed with several portions
of water. After drying we obtained 4.52 g of the product, which can be used in the next reaction without further
purification.
1
0-Methyl-2,3,5,6-tetrahydro-(8H)-difuro[2,3-f;2,3h]chromene-3,6,8-trione (5). In a dry flat-bottom
flask we mixed thoroughly ground dichloroacetate 4 (4 g, 11.6 mmol) and anhydrous aluminum chloride (6.20 g,
6.4 mmol). The mixture was heated on an oil bath at 120-130°C (bath temperature) for 1 h. After cooling the
4
dark-brown reaction mixture, crushed iced (100 g) and then 1 N hydrochloric acid (20 ml) were added to the
flask. The mixture was stirred vigorously on a magnetic stirrer until a uniform precipitate had formed. The
precipitate was filtered off, washed with several portions of water, dried, and purified by boiling in ethanol. We
obtained 2.37 g of the dry product.
3
,6-Diacetoxy-10-methyl-8H-difuro[2,3-f;2,3-h]chromen-8-one (6). A mixture of the trione 5 (0.5 g,
1
.84 mmol) and acetic anhydride (5 ml) was heated on a water bath in the presence of an excess of sodium
acetate for 1 h. The reaction mass was poured into a beaker of ice. The precipitate was filtered off and washed
with water. We obtained 0.56 g of the dry analytically pure product.
1
0-Methyl-8H-difuro[2,3-f;2,3-h]chromen-8-one (7). To a solution of difurocoumarin 5 (1 g,
.68 mmol) in dioxane (15 ml) and methanol (0.5 ml) we added in portions an excess of sodium borohydride
3
while stirring on a magnetic stirrer. The reaction mass was stirred for 6 h while fresh portions of sodium
borohydride were added. The solvent was distilled, 35% sulfuric acid (25 ml) was added, the mixture was
heated on a water bath for 2 h, and it was then poured into cold water (50 ml). The precipitate was filtered off,
washed with water, dried, and purified by vacuum sublimation. We obtained 0.3 g of the product.
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