Synthesis of regioisomeric functionalized benzodifurans and angelicins

Article abstract of DOI:10.1002/hlca.200800421

Arenofurans have important biological and pharmacological activities. Compared to benzofurans, the reports on the synthesis of benzodifurans are rather limited. Here, we report the synthesis of a linear and an angular 3,3′-bis(carboxymethyl)substituted benzodifuran and 4′- carboxymethyl-substituted angelicins from phloroglucinol, using 4-halomethyl-substituted dipyrones as key intermediates in the synthetic route. This strategy shows that the stability of a pyrone ring depends on the type of substituent at C(4) and the conditions used.

Full text of DOI:10.1002/hlca.200800421

Helvetica Chimica Acta – Vol. 92 (2009)
1309
Synthesis of Regioisomeric Functionalized Benzodifurans and Angelicins
a
b
a
c
b
a
by Elꢀas Quezada ) ), Giovanna Delogu* ), Dolores Vi n˜ a ), Lourdes Santana ), Gianni Podda ),
a
b
a b
Maria Joao Matos ) ), and Carmen Picciau ) )
a) Dipartimento Farmaco Chimico Tecnologico, Universit a` degli Studi di Cagliari, I-09124 Cagliari
(
phone: þ 390706758675; fax: þ 390706758553; e-mail: delogug@unica.it)
b) Departamento de Quꢀmica Org a´ nica, Facultad de Farmacia, Universidad de Santiago de Compostela,
SP-15782 Santiago de Compostela
c) Departamento de Farmacologꢀa, Facultad de Farmacia, Universidad de Santiago de Compostela,
SP-15782 Santiago de Compostela
Arenofurans have important biological and pharmacological activities. Compared to benzofurans,
the reports on the synthesis of benzodifurans are rather limited. Here, we report the synthesis of a linear
and an angular 3,3’-bis(carboxymethyl)substituted benzodifuran and 4’-carboxymethyl-substituted
angelicins from phloroglucinol, using 4-halomethyl-substituted dipyrones as key intermediates in the
synthetic route. This strategy shows that the stability of a pyrone ring depends on the type of substituent
at C(4) and the conditions used.
Introduction. – Arenofurans have important biological and pharmacological
activities [1 – 4] and potential applications as fluorescent dyes and probes, and as
photosensitizers [5][6]. Among arenofurans, benzofurans have been the subject of the
most extensive studies, and numerous synthetic methods have been developed for them
[
1][2][7 – 9]. Compared to benzofurans, the reports on the synthesis of benzodifurans
are rather limited [3][7][10]. The most important route for the synthesis of various
arene ring-fused furan derivatives is the intramolecular formation of a furan moiety
starting from properly substituted arenes via dehydrative cyclization either of o-
alkoxycarbonyl compounds or a-aryloxycarbonyl compounds. Continuing our research
on a convenient contraction reaction of the coumarin pyrone ring, we now describe a
facile synthesis of a linear and an angular 3,3’-bis(carboxymethyl)-substituted
benzodifuran and functionalized angelicins from phloroglucinol involving an alkali-
mediated rearrangement of 4-(halomethyl)-coumarins via a,b-unsaturated acids
(
Scheme 1) [11].
Results and Discussion. – From phloroglucinol (1) and ethyl 4-chloro-3-oxobuta-
noate, angular and linear dipyrons 2 and 3, respectively, precursors for the synthesis of
angular and linear benzodifurans, as well as coumarin 4, were obtained, following a
synthetic route previously described by us (Scheme 2) [12].
Under strong alkaline conditions, the pyrone ring of 3, condensed with the furan
ring, undergoes hydrolysis and generates one furanoacetic fragment. Simultaneously,
the pyrone ring with the 4-(chloromethyl) group undergoes a contraction reaction
forming the other furanoacetic fragment of the final benzodifuran skeleton of
ꢁ
2009 Verlag Helvetica Chimica Acta AG, Zꢂrich

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310
Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 1
compound 6, as it had been observed in the formation of compound 5 from 2 [12]. In
others words, the synthetic strategy allows to obtain linear or angular benzodifurans,
starting either from the angular or linear benzodipyrone, respectively. The synthesis of
this type of benzodifurans is also possible starting from 4-bis(chloromethyl)-substituted
dipyrones for contraction of both pyrone rings [11].
The spectroscopic data of the compound 6 are very similar to those obtained for
1
benzodifuran 5 [12]. In both cases, the H-NMR spectrum shows two very intense
singlets that integrate for two H-atoms each between 3.7 and 3.8 ppm, corresponding to
the two CH groups. Two signals for aromatic H-atoms appear at 7.67 and 7.69 ppm that
2
correspond to the furan ring H-atoms. Finally, a broad singlet that integrates for two H-
13
atoms appears at 12.31 ppm, corresponding to the two acid groups. The C-NMR data
confirm the existence of the two CH groups with two signals very close to 30 ppm, and
2
the appearance of two signals very close to 172 ppm, that correspond to the two acid
groups.
Therefore, NOE experiments were necessary for the unequivocal assignment of
both isomers. When 6 was irradiated at the frequency of the OH signal, an intense NOE
of 10.9% was observed for a singlet in the aromatic zone, assigning that this OH group
correlates to one H-atom in o-position, i.e., HꢀC(5), whereas irradiation of the OH
group of 5 did not provide a NOE for the H-atom of the benzene ring.
When 4 [12] was treated with H O, the Cl-atom was replaced by a OH group to give
2
(
hydroxymethyl)coumarin 7. The treatment of this compound with ethyl 4-chloro-3-
oxobutanoate under Pechmann conditions led to the dipyrone 8. For this dipyrone,
contraction either of one or both pyrone rings can be performed. Treatment of 8 with
3
m NaOH, at room temperature, causes the contraction of both pyrone rings, which

Helvetica Chimica Acta – Vol. 92 (2009)
1311
Scheme 2
a) Ethyl 4-chloro-3-oxobutanoate, 12m H SO , r.t., 12 h. b) 3m NaOH, r.t., 30 min, 3m HCl. c) H O,
2
4
2
reflux, 48 h; d) 0.1m NaOH, 08, 30 min.

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Helvetica Chimica Acta – Vol. 92 (2009)
gives the angular benzodifuran 6 in a yield of 70%. As compound 3 was obtained in a
very low yield from phloroglucinol, the above described way could be considered a very
suitable alternative to access compound 6. When soft conditions – 0.1m NaOH at 08 –
are used, the angular furocoumarin 9 [12] is obtained from dipyrone 8, because the
pyrone ring bearing the 4-hydroxymethyl group remains stable under these reaction
conditions.
This stability of the pyrone ring is more evident when the substituent at the 4-
position is not a good leaving group. In fact, when the benzodipyrones 10 and 11 [13]
(
1
Scheme 2) react in the presence of 3m NaOH at room temperature, the furocoumarins
2 and 13 are obtained as major compounds, in 86 and 62% yield, respectively. The used
synthetic route determinates that the presence of a stable group, such as 4-
methoxymethyl) or Me, in one of the rings guarantees the stability of those rings
(
under basic conditions, while the stability in the presence of the 4-(hydroxymethyl)
group depends on the used conditions. The application of the contraction reaction of a
benzopyrone ring to a benzofuran allows to obtain a wide number of 4’-(carboxy-
methyl)-substituted furocoumarins, which are difficult to obtain otherwise in an
efficient, direct, and versatile way.
Experimental Part
General. Silica gel (SiO ; 35 – 60 mesh) was used for flash chromatography (FC). Anal. TLC: on
2
plates precoated with silica gel (Merck 60 F254, 0.25 mm). M.p.: Reichert Kofler thermophan or in
capillary tubes with a Bꢀchi 510 apparatus; uncorrected. IR Spectra: Perkin-Elmer 1640FT spectrometer
ꢀ1
13
1
(
KBr in cm ). C- and H-NMR spectra: ca. 10% in (D )DMSO; at r.t. in 5 mm outsider diameter
6
tubes; Me Si as internal standard, chemical shifts d are expressed in ppm, J in Hz. One-dimensional
4
13
C-NMR: Bruker AMX 500 spectrometer, at 125.77 MHz, typically with a 308 pulse flip angle, a pulse
repetition time of 1.8 s and a spectral width of 31250 with 32 K data points. EI-MS: Hewlett-Packard
988A spectrometer (70 eV). Elemental analyses: Perkin-Elmer 240B microanalyser; within ꢁ 0.4% of
calc. values in all cases.
0-(Chloromethyl)-5-hydroxy-4-(hydroxymethyl)-2H,8H-pyrano[2,3-f]chromene-2,8-dione (8). A
mixture of 7 (5,7-dihydroxy-4-(hydroxymethyl)-2H-chromen-2-one; 200 mg, 0.96 mmol), 12m H SO
5
1
2
4
(
20 ml), and ethyl 4-chloro-3-oxobutanoate (0.649 ml, 790 mg, 4.803 mmol) was stirred at r.t. overnight,
and then quenched with ice (100 ml). The resulting solid was filtered off, washed with cold H O until
2
pH 7.0, and purified by FC (SiO , hexane/AcOEt, 4 :1) to afford pure 8 as a white solid. Yield: 85%. M.p.
2
1
2
508 (dec). IR (KBr): 3468, 2940, 1680, 1620, 1598, 836. H-NMR ((D )DMSO): 4.60 (br., CH OH); 4.83
6
2
13
(
(
(
(
s, CH OH); 5.13 (s, CH Cl); 6.49 (s, HꢀC(3), HꢀC(9)); 6.64 (s, HꢀC(6)); 12.01 (br., OH). C-NMR
2
2
(D )DMSO): 44.88 (CH Cl); 61.48 (CH OH); 98.81 (C(6)); 99.41 (C(10a)); 104.58 (C(4a)); 106.64
6
2
2
C(3)); 112.13 (C(9); 149.95 (C(10); 152.22 (C(4)); 156.35 (C(5)); 158.34 (C(2)); 158.73 (C(8)); 159.40
C(10b)); 159.43 (C(6a)). EI-MS: 308 (11, M ), 270 (3), 209 (4), 185 (5), 129 (4), 54 (100). Anal. calc. for
þ
C H ClO (308.67): C 54.48, H 2.94; found: C 54.55, H 3.00.
14
9
6
General Procedure for Contraction of 4-Substituted Pyrone Rings. A mixture of 3 (596 mg,
.05 mmol) in 3m NaOH (10 ml), was stirred at r.t. for 3 h. Once the reaction had been completed, the
2
mixture was acidified with 3m HCl until pH 6.0, and a dark brown solid precipitated, which was filtered
and washed with H O until neutral pH. The solid was purified by FC (SiO , CH Cl /MeOH, 9 :1). 362 mg
2
2
2
2
(
yield: 61%) of pure 6 were obtained as a light brown solid. Compounds 6, 12, and 13 were also obtained
from 8, 10, and 11 resp., by the same procedure.
2
,2’-(4-Hydroxybenzo[1,2-b:3,4-b’]difuran-3,8-diyl)diacetic Acid (6). Yield from 3: 61%, from 8:
1
7
0%. M.p. 1508 (dec). IR (KBr): 3520, 1746, 1620, 1599, 830. H-NMR ((D )DMSO): 3.74, 3.77 (2s, 2
6
CH ); 6.73 (s, HꢀC(5)); 7.67, 7.69 (2s, HꢀC(2), HꢀC(7)); 9.99 (br., OH); 12.31 (br., 2 COOH).
2
13
C-NMR ((D )DMSO): 29.75, 29.78 (2 CH ); 91.97; 106.38; 112.82; 112.00; 114.31; 140.96; 141.02;
6
2

Helvetica Chimica Acta – Vol. 92 (2009)
1313
þ
1
48.20; 149.96; 154.23; 171.85, 172.23 (2 CO). EI-MS: 290 (0.5, M ), 261 (12), 247 (58), 231 (12), 203
(
100), 201 (15). Anal. calc. for C H O (290.23): C 57.94, H 3.47; found: C 57.99, H 3.52.
14 10 7
[
5-Hydroxy-4-(methoxymethyl)-2-oxo-2H-furo[2,3-h]chromen-9-yl]acetic Acid (12). Yield 86%.
1
M.p. 2778 (dec). IR (KBr): 3520, 2920, 2810, 1710, 1599, 1422, 1100, 1095, 822. H-NMR ((D )DMSO):
6
3
1
1
1
5
.32 (s, Me); 3.85 (s, CH CO); 4.71 (s, CH O); 6.30 (s, HꢀC(3)); 6.80 (s, HꢀC(6)); 7.58 (s, HꢀC(8));
2
2
13
0.16 (s, 2 OH). C-NMR ((D )DMSO): 31.03 (CH CO); 58.89 (Me); 70.48 (CH O); 93.79 (C(6));
6
2
2
08.89 (C(3)); 110.81; 112.63; 116.70; 144.36 (C(8)); 147.40; 150.62; 151.16; 156.92 (C(2)); 157.03 (C(6a));
þ
73.03 (CH CO). EI-MS: 304 (100, M ), 275 (29), 261 (9), 214 (21). Anal. calc. for C H O (304.25): C
2
15 12
7
9.22, H 3.98; found: C 59.10, H 4.02.
(
5-Hydroxy-4-methyl-2-oxo-2H-furo[2,3-h]chromen-9-yl)acetic Acid (13). Yield 62%. M.p. 3148
1
(
dec). IR (KBr): 3550, 2949, 2840, 1790, 1657, 1599, 1432, 1108, 1088, 832. H-NMR ((D )DMSO): 2.44 (s,
6
Me); 3.72 (s, CH CO); 6.04 (s, HꢀC(3)); 6.81 (s, HꢀC(6)); 7.66 (s, HꢀC(8)); 10.67 (br., COOH); 12.33
2
1
3
(
(
(
3
br., OH). C-NMR ((D )DMSO): 24.34 (Me); 29.82 (CH ); 94.57 (C(6)); 105.57; 108.93; 111.43; 113.79
6
2
C(3)); 142.66 (C(8)); 149.46; 155.11; 156.00; 157.24 (C(2); 159.29 (C(6a)); 172.10 (COOH). EI-MS: 274
100, M ), 230 (89), 228 (66), 202 (5). Anal. calc. for C H O (274.23): C 61.32, H 3.68; found C 61.65, H
þ
14
10
6
.97.
The authors acknowledge the Xunta de Galicia (PGIDIT05BTF 20302PR-2), Ministerio de Sanidad
y Consumo (PI061457) for their financial support and Progetto Ricerca Scientifica 2006-Universit a` di
Cagliari. We thank Ramon Gesto for his technical assistance.
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Received November 24, 2008