Synthesis of benzofuranofuran derivatives: Model of natural products

Article abstract of DOI:10.1081/SCC-100000191

Several benzofuranofuran derivatives were synthesized employing intramolecular cycloaddition reactions of ketenes with alkenes. (Alkenyloxy)ketenes, prepared from the tosylate by treatment with triethylamine, easily undergo intramolecular [2 + 2] cycloadd

Full text of DOI:10.1081/SCC-100000191

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SYNTHESIS OF BENZOFURANOFURAN DERIVATIVES:
MODEL OF NATURAL PRODUCTS
Paulo Marcos Donate a , Rosangela da Silva a , Gil Valdo José da Silva a & Carlos Alemán b
c
a Departamento de Química da Faculdade de Filosofia , Universidade de São Paulo ,
Ciências e Letras de Ribeirão Preto da
b Universitat Politécnica de Catalunya , Avenida Bandeirantes, 3900, 14040-901—Ribeirão
Preto, SP, E-08028, Brazil
c Departament d'Enginyería Química, E.T.S. d'Enginyers Industrials de Barcelona ,
Diagonal 647, Barcelona, Spain
Published online: 09 Nov 2006.
To cite this article: Paulo Marcos Donate , Rosangela da Silva , Gil Valdo José da Silva & Carlos Alemán (2001) SYNTHESIS
OF BENZOFURANOFURAN DERIVATIVES: MODEL OF NATURAL PRODUCTS, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:1, 151-154, DOI: 10.1081/SCC-100000191
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SYNTHETIC COMMUNICATIONS, 31(1), 141–150 (2001)
SYNTHESIS OF BENZOFURANOFURAN
DERIVATIVES: MODEL OF NATURAL
PRODUCTS
Paulo Marcos Donate,∗,1 Rosangela da Silva,1 Gil Valdo
Jose´ da Silva,1 and Carlos Alema´n2
1Departamento de Qu´ımica da Faculdade de Filosofia,
Cieˆncias e Letras de Ribeira˜o Preto da
Universidade de Sa˜o Paulo
2Avenida Bandeirantes, 3900, 14040-901—Ribeira˜o Preto,
SP, Brazil, Departament d’Enginyer´ıa Qu´ımica, E.T.S.
d’Enginyers Industrials de Barcelona, Universitat
Polite´cnica de Catalunya, Diagonal 647,
Barcelona E-08028, Spain
ABSTRACT
Several benzofuranofuran derivatives were synthesized em-
ploying intramolecular cycloaddition reactions of ketenes with
alkenes. (Alkenyloxy)ketenes, prepared from the tosylate by treat-
ment with triethylamine, easily undergo intramolecular [2 + 2]
cycloaddition to give tricyclic benzocyclobutafuranones. Baeyer-
Villigeroxidationofthecycloadductsgivesbenzofurano-furanones,
which are closely related to natural products with anticoagulant and
antimalarial properties.
∗ To whom correspondence should be addressed.
141
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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DONATE ET AL.
Figure 1.
The skeleton of the tricyclic compound 3a,8a-dihydro-2H,3H,3aH,8aH-
benzo[b]oxolano[3,2-d]furan 1 (see Fig. 1) appears as a moiety in a large number
of natural products (1–6).
These compounds show very interesting properties that depend on their
chemical constitution (see Fig. 2). Many of them are highly toxic, mutagenic, or
carcinogenic, among other activities. Aflatoxin B1 (2) belongs to a group of acutely
toxic and highly carcinogenic mold metabolites produced by Aspergillus flavus
(1). Pseudosemiglabrin (3) and semiglabrin (4) have anticoagulant and antimalar-
ial activities (2). Microminutinin (5) pertains to a class of compounds that displays
in vivo activity in the lymphocytic leukemia test system (3–5), while several other
compounds with the benzofuranofuranone unit, e.g., 6 and 7, have anticoagulant
activity (6). Furthermore, very recent theoretical studies have revealed that the
five-membered rings of the benzofuranofuran derivatives present complex con-
formational properties (7). The relevant biological and chemical properties render
these compounds interesting as synthetic targets. In this work, the intramolecular
Figure 2.

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143
Scheme 1.
[2 + 2] cycloaddition of alkoxyketenes with alkenes developed by Snider and Hui
(8) and by Brady and Giang (9) was used as a useful synthetic method to obtain
these polycyclic compounds.
The syntheses of model compounds of the natural products shown in Figure 2
were carried out by the procedure presented in Schemes 1–2.
Reaction of the alkoxide from 2-alkenylphenol 8 (R = H or CH3) with
bromoacetic acid (8,9) furnished the acid 9 [yield: 83% (R = H), 62% (R =
CH3)]. Compound 9, by reaction with tosyl chloride and triethylamine (10),
afforded the tricyclic ketone 10 [yield: 69% (R = H), 70% (R = CH3)], an
Scheme 2.

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DONATE ET AL.
intramolecular [2 + 2] cycloaddition product. Lactone 11, which can be regarded
as a model compound of natural products 6 and 7, was obtained through a Baeyer-
Villiger reaction of compound 10 [yield: 95% (R = H), 85% (R = CH3). Lactol 12
(R = H), was prepared from the reduction of lactone 11 (R = H) with DIBAL
(11) (yield: 74%). The latter compound provided the compound 1 (yield: 52%)
(12) after treatment with triethylsilane/trifluoroacetic acid (11). Treatment of 11
(R = CH3) with LDA/PhSeCl (13,14) afforded compound 13 (yield: 64%), which,
after treatment with H2O2, furnished a mixture of the compounds 14 and 14a in
a 2:3 ratio (yield: 90%). It was observed that the α-methylene-γ -butyrolactone
14 isomerizes to the butenolide 14a during the chromatographic purification on a
silica gel column.
The treatment of compound 14 with DIBAL (11) yielded compound 15 (not
isolated), which, by reaction with Et3SiH/BF3 · OEt2 (15), furnished compound 16
(yield: 46% over two steps). This compound is the model of microminutinin (5).
The synthesis of natural product microminutinin and its analogues by ap-
plying this methodology is in progress (16).
EXPERIMENTAL
Melting points were determined on a Reichert Kofler block melting point ap-
paratus and are uncorrected. NMR spectra were recorded using a Bruker
DPX-300 (300 MHz 1H NMR and 75 MHz 13C NMR) instrument. GC-MS spec-
tra were obtained by EI ionization at 70 eV on a HP-5988-A spectrometer. IR
spectra were measured with a Perkin-Elmer 1600 FT spectrometer. Elemental
analyses were carried out on a CE instrument EA-1110. TLC was performed on
precoated silica gel 60 F254 (0.25 mm thick, Merck), and for column chromatog-
raphy silica gel 60 70-230 mesh (Merck) was used. Given yields correspond to
materials with the same purity as the samples used in the subsequent steps. The
reaction products were isolated from solution by evaporation under water-aspirator
vacuum at room temperature, using a rotary evaporator.
General Procedure for Preparation of (2-Alkenylphenoxy)
Acetic Acids (8,9)
The alkenylphenol (30 mmol) was dissolved in anhydrous THF under N2 and
treatedwithNaH(65mmol, 60%dispersioninmineraloil). Themixturewasstirred
for 20 min and treated with 1 equiv of bromoacetic acid. After effervescence had
subsided, the mixture was heated at reflux for 4–6 h and stirred at room temperature
overnight. The reaction was diluted with ether and quenched with saturated brine
and enough water to dissolve all the salts. The aqueous layer was adjusted to
pH 10.5 with Na2CO3 solution. The aqueous layer was separated, washed twice

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145
with ether, acidified to pH 1 with concentrated HCl, and extracted with three
portions of ether. The combined extracts were washed with water and brine, dried
(Na2SO4), and evaporated in vacuum to give the pure (alkenylphenoxy) acetic
acids.
2-(2-Vinylphenoxy)acetic acid (9, R = H)
4.43 g (83% yield) of this acid were obtained with mp 124◦–127◦C (8); IR
(KBr) 3415, 2924, 1455, 1713, 1220 cm−1; 1H NMR (CDCl3) δ 8.20 (br.s, 1H);
7.51–6.97 (m, 4H), 7.10 (dd, 1H, J = 17.7 Hz, J = 11.3 Hz) 5.80 (dd, 1H, J =
17.7 Hz, J = 1.5 Hz), 5.31 (dd, 1H, J = 11.3 Hz, J = 1.5 Hz), 4.70 (s, 2H); MS m/z
(rel. intensity) 178 (M+, 72), 133 (53), 105 (76), 91 (100), 77 (49).
2-[(2-Prop-1-enyl)phenoxy)]acetic acid (9, R = CH3)
3.57 g (62% yield) of this acid were obtained with mp 101◦–102◦C (lit. (9):
1
101◦–102◦C); H NMR (CDCl3) δ 8.70 (br.s, 1H), 7.55–6.95 (m, 5H), 6.30 (m,
1H), 4.65 (s, 2H), 1.89 (dd, 3H, J = 1.7 Hz, J = 6.6 Hz); MS m/z (rel. intensity)
192 (M+, 100), 133 (71), 131 (64), 105 (84), 91 (63), 77 (37).
General Procedure for Conversion of Acids into Tosylates
and Subsequent Intramolecular Cycloaddition (10)
A solution of (2-alkenylphenoxy)acetic acid (4.5 mmol) in benzene (50 mL)
was added over 5 h through a syringe to a refluxing solution of trietylamine
(22.5 mmol) and p-toluenesulfonyl chloride (9 mmol) in benzene (50 mL). After
addition was completed, the mixture was gently refluxed for 2–6 h. Upon cooling,
the mixture was washed with water (3 × 50 mL) and then concentrated under water
aspirator vacuum to about 30 mL. This concentrate was stirred with 3% aqueous
sodium NaOH solution (250 mL) for 10 h to remove excess tosyl chloride. The
benzene layer was dried with anhydrous magnesium sulfate, filtered, and the ben-
zene evaporated. The residue was purified by column chromatography on silica
gel, eluting with 3% ethyl acetate in hexane, to give cycloaddition product.
1,2a,7b-Trihydrobenzo[b]cyclobuta[1,2-d]furan-2-one (10, R = H)
Acid 9 (R = H) (92.3 mg, 0.518 mmol) was converted to the tosylate and
added to trietylamine in benzene at reflux for 2 h as described above. Normal
workup, followed by chromatography on silica gel, eluting with CH2Cl2, gave

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DONATE ET AL.
57.6 mg (69%) of pure 10 (R = H) as white solid mp 30◦–32◦C (lit. (8): 31◦–
32◦C); IR (KBr) 2907, 1744, 1240 cm−1; 1H NMR (CDCl3) δ 7.30–6.85 (m, 4H),
5.65 (dt, 1H, J = 7.5 Hz, J = 3.0 Hz, J = 3.0 Hz), 4.20 (ddd, 1H, J = 7.5 Hz,
J = 3.8 Hz, J = 8.4 Hz), 3.65 (ddd, 1H, J = 8.4 Hz, J = 3.0 Hz, J = 17.7 Hz),
3.05 (ddd, 1H, J = 3.8 Hz, J = 3.0 Hz, J = 17.7 Hz); 13C NMR (CDCl3) δ 205.6
(C), 160.9 (C), 129.1 (C), 127.9 (CH), 125.8 (CH), 125.8 (CH), 110.7 (CH), 94.4
(CH), 55.8 (CH), 35.1 (CH2); MS m/z (rel. intensity) 160 (M+, 2), 131 (30), 118
(100), 103 (9), 90 (20), 77 (14).
1-Methyl-1,2a,7b-trihydrobenzo[b]cyclobuta[1,2-d]furan-2-one
(10, R = CH3)
Acid 9 (R = CH3) (517.2 mg, 2.69 mmol) was converted to the tosylate
and added to trietylamine in benzene at reflux for 3 h as described above. Normal
workup, followed by chromatography on silica gel, eluting with CH2Cl2, gave
330.6 g (70%) of pure 10 (R = CH3) as white solid mp 65◦–67◦C (lit. (9): 65◦–
1
66◦C); H NMR (CDCl3) δ 7.30–6.85 (m, 4H), 5.75 (dd, 1H, J = 8.3 Hz, J =
2.8 Hz), 4.29 (dd, 1H, J = 8.3 Hz, J = 8.9 Hz), 3.80 (m, 1H), 1.05 (d, 3H, J = 7.3
Hz); MS m/z (rel. intensity) 174 (M+, 3), 145 (5), 118 (100), 103 (2), 90 (9), 63
(6), 39 (5).
General Procedure for Baeyer-Villiger Oxidation (8)
Solid NaHCO3 (3 equiv) and m-chloroperoxybenzoic acid (85% pure, 1.05
equiv) were added rapidly to a solution of tricyclic ketone (34 mmol) in dry CH2Cl2
(5 mL) under stirring. The reaction mixture was stirred for 2 h, diluted with CH2Cl2
(20 mL), and quenched with 10% aqueous Na2CO3 solution. The organic layer
was washed with 10% Na2CO3 solution and brine, dried over anhydrous sodium
sulfate, and evaporated to give the product.
3,3a,8a-Trihydrobenzo[b]furano[3,2-d]furan-2-one (11, R = H)
Baeyer-Villiger oxidation of ketone 10 (R = H) (45.5 mg, 0.284 mmol)
as described above gave 47.7 mg (95%) of pure 11 (R = H) as white solid mp
123◦–126◦C (lit. (8): 124◦–126◦C); IR (KBr) 2994, 1782, 1221 cm−1; 1H NMR
(CDCl3) δ 7.33–6.90 (m, 4H), 6.55 (d, 1H, J = 9.7 Hz), 4.24 (dt, 1H, J = 9.7 Hz,
J = 2.4 Hz, J = 9.7 Hz), 3.10 (dd, 1H, J = 9.7 Hz, J = 17.9 Hz), 2.83 (dd, 1H,
J = 2.4 Hz, J = 17.9 Hz); 13C NMR (CDCl3) δ 173.6 (C), 157.2 (C), 129.9 (CH3),
126.6(C), 124.7(CH), 122.9(CH), 110.9(CH), 107.6(CH), 42.3(CH), 34.6(CH2);
MS m/z (rel. intensity) 176 (M+, 46), 147 (100), 131 (12), 103 (70), 91 (37).

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3-Methyl-3,3a,8a-trihydrobenzo[b]furano[3,2-d]furan-2-one (11, R = CH3)
Baeyer-Villiger oxidation of ketone 10 (R = CH3) (261.0 mg, 1.5 mmol)
as described above gave 242.2 mg (85%) of pure 11 (R = CH3) as white solid
mp 140◦–142◦C; 1H NMR (CDCl3) δ 7.33–6.90 (m, 4H arom), 6.55 (d, 1H, J =
7.0 Hz), 4.25 (dd, 1H, J = 7.0 Hz, J = 11.6 Hz), 3.22 (m, 1H), 1.42 (d, 3H,
J = 9.1Hz); MS m/z (rel. intensity) 190 (M+, 69), 161 (100), 145 (22), 115 (45),
105 (55), 91 (19), 77 (30); Anal. calcd for C11H10O3: C, 69.47; H, 5.26. Found:
C, 69.41; H, 5.04.
3a,8a-Dihydro-2H,3H,3aH,8aH-benzo[b]oxolano[3,2-d]furan (12)
Lactone 11 (R = H) (41 mg 0.233 mmol) was dissolved in dry toluene
(2 mL) under N2 and then cooled at −78◦C. DIBAL-H (0.35 mL, 0.349 mmol,
1 M in toluene) was added, and the solution was stirred for 1.5 h. After addi-
tion of crushed ice, acetic acid (0.15 mL), and chloroform (3 mL), the mixture
was stirred for another 30 min. The organic layer was separated, washed with
saturated NaHCO3 solution and brine, and dried over anhydrous magnesium sul-
fate. Evaporation of the solvent under reduced pressure gave 30.7 mg (74%) of
lactol 12 (R = H) as colorless oil. This oil was dissoved in CH2Cl2 (3 mL), and
cooled at −78◦C under nitrogen atmosphere. Triethylsilane (60.1 mg, 0.517 mmol)
and trifluoroacetic acid (58.9 mg, 0.517 mmol) were added, and the solution was
stirred for 3.5 h at 0◦C. Then 5% NaHCO3 solution (2 mL) was added and the
mixture stirred for 10 min. The organic layer was separated, washed with brine,
and dried over anhydrous magnesium sulfate. Evaporation of the solvent under
reduced pressure gave 17.1 mg of crude 1. Chromatography on silica gel, eluting
with a mixture of dichlorometane:hexane (1:1), gave 14.4 mg (52%) as colorless
oil (12); IR 3047, 2975, 1595, 1458, 1241, 1076 cm−1; 1H NMR (CDCl3) δ 7.33–
6.85 (m, 4H), 6.42 (d, 1H, J = 5.7 Hz), 4.05 (m, 1H), 4.02 (m, 1H), 3.65 (m, 1H),
2.30 (m, 1H), 2.05 (m, 1H); 13C NMR (CDCl3) δ 159.4 (C), 128.7 (CH), 127.6
(C), 124.7 (CH), 121.1 (CH), 110.9 (CH), 109.2 (CH), 67.2 (CH2), 46.5 (CH),
29.0 (CH2); MS m/z (rel. intensity) 162 (M+, 100), 147 (63), 119 (29), 105 (50),
91 (40), 77 (50); Anal. calcd for C10H10O2: C, 74.07; H, 6.17. Found: C, 74.32;
H, 6.32.
3-Methyl-3-(phenylselenamethyl)3,3a,8a-trihydrobenzo[b]furano[3,2-
d]furan-2-one (13)
A solution of n-butyllithium (1.16 mmol, 1.1 M in hexane) was added to a
solution of diisopropylamine (122.5 mg, 1.21 mmol) in anhydrous THF (5 mL),

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DONATE ET AL.
maintained at 0◦C under nitrogen atmosphere. After stirring for 10 min at 0◦C,
the solution was cooled to −78◦C and, after 15 min, a solution of compound
11 (R = CH3) (200.7 mg, 1.05 mmol) in anhydrous THF (2 mL) was added.
Stirring was continued for 30 min, and then a solution of phenylselenenyl chlo-
ride (201 mg, 1.05 mmol) in THF (1 mL) was added. After stirring for 2 h at
−20◦C, the reaction mixture was quenched by addition of a saturated aqueous
solution of NH4Cl, diluted with water, and extracted with ether. The ethereal
solution was washed with water, dried over anhydrous magnesium sulfate, and
evaporated. The residue was purified by column chromatography through silica
gel, eluting with hexane:ethyl acetate (9:1), to give 231.8 mg (64%) compound
1
13 as yellow solid mp 122◦–124◦C; H NMR (CDCl3) δ 7.82–6.90 (m, 9H),
5.91 (d, 1H, J = 5.7 Hz), 4.25 (d, 1H, J = 5.7 Hz), 1.41 (s, 3H); 13C NMR
(CDCl3) δ 175.1 (C), 157.2 (C), 138.1 (CH), 130.5 (CH), 130.2 (CH), 129.5
(CH), 126.8 (C), 122.3 (CH), 111.3 (CH), 104.7 (CH), 54.7 (CH), 47 (C), 20.5
(CH3); MS m/z (rel. intensity) 346 (M+, 17), 161 (100), 158 (28), 145 (13),
77 (29); Anal. calcd for C17H14O3Se: C, 59.3; H, 4.07. Found: C, 59.54; H,
4.21.
3-Methylene-3a,8a-dihydrobenzo[b]furano[3,2-d]furan-2-one (14)
and 3-methyl-8a-hydrobenzo[b]furano[3,2-d]furan-2-one (14a) (13,14)
Aqueous H2O2 (30%, 0.5 mL) was added to a solution of compound 13
(226.1 mg, 0.65 mmol) in dichlorometane (2 mL), and cooled at 0◦C. The reaction
mixture was stirred at room temperature for 40 min and then diluted with water. The
organic layer was washed with water, dried over anhydrous magnesium sulfate, and
evaporated. The residue was purified by column chromatography through silica
gel, eluting with hexane:ethyl acetate (9:1), to give the compounds 14 (48.4 mg,
39%) and 14a (62.4 mg, 51%).
Compound 14: mp 120◦–122◦C; 1H NMR (CDCl3) δ 7.32–6.81 (m, 4H),
6.55 (d, 1H, J = 6.2 Hz), 6.35 (d, 1H, J = 1.8 Hz), 6.01 (d, 1H, J = 1.8 Hz), 4.70
(d, 1H, J = 6.2 Hz); 13C NMR (CDCl3) δ 167.4 (C), 157.3 (C), 135.4 (C), 130.1
(CH), 125.0 (C), 124.2 (CH), 123.7 (CH2), 122.9 (CH), 111.0 (CH), 105.0 (CH),
47.1 (CH); MS m/z (rel. intensity) 188 (M+, 23), 159 (100), 131 (40), 115 (57),
105 (13), 77 (29), 63 (12); Anal. calcd for C11H8O3: C, 70.21; H, 4.26. Found: C,
70.35; H, 4.16.
1
Compound 14a: mp 92◦–94◦C; H NMR (CDCl3) δ 7.32–7.01 (m, 4H),
6.57 (q, 1H, J = 1.9 Hz), 2.07 (d, 3H, J = 1.9 Hz); 13C NMR (CDCl3) δ 172.7
(C), 163.6 (C), 160.6 (C), 133.3 (CH), 124.2 (CH), 123.1 (CH), 122.5 (C), 120.6
(C), 112.5 (CH), 106.9 (CH), 9.86 (CH3); MS m/z (rel. intensity) 188 (M+, 54),
160 (19), 131 (100), 115 (27), 103 (23), 77 (30), 63 (20), 51 (26); Anal. calcd for
C11H8O3: C, 70.21; H, 4.26. Found: C, 70.32; H, 4.31.

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3-Methylene-2,3a,8a-trihydrobenzo[b]furano[3,2-d]furan (16) (15)
DIBAL-H (0.3 mL, 0.3 mmol, 1 M in toluene) was added to a solution of
compound 14 (48.1 mg, 0.26 mmol) in toluene (2 mL), maintained at −78◦C un-
der nitrogen atmosphere. After stirring for 1 h at −78◦C, the reaction mixture was
quenched by addition of crushed ice and acetic acid (0.3 mL). Chloroform (7 mL)
was added and the mixture was stirred for 30 min. Then the layers were separated,
and the organic layer was washed with saturated Na2CO3 solution and brine, and
dried over anhydrous magnesium sulfate. The crude product, assumed to be the
lactol 15, obtained by evaporation of the solvent under reduced pressure, was dis-
solved in CH2Cl2 (3 mL), cooled at −78◦C under nitrogen atmosphere, and treated
with triethylsilane (45.3 mg, 0.39 mmol) and BF3 · OEt2 (55 mg, 0.39 mmol). The
solution was stirred for 1 h at 0◦C and then a 5% NaHCO3 solution (2 mL) was
added. The organic layer was separated, washed with brine, and dried over an-
hydrous magnesium sulfate. The residue was purified by column chromatography
through silica gel, eluting with a mixture of hexane:ethyl acetate (9:1), to give 20.5
mg (46%) of compound 16 as a white solid mp 36◦–37◦C; IR (KBr) 2968, 1671,
1
1596, 1478, 1461, 1220, 1072 cm−1; H NMR (benzene) δ 7.01–6.70 (m, 4H),
6.10 (d, 1H, J = 5.7 Hz), 4.85 (dt, 1H, J = 2.6 Hz, J = 1.6 Hz), 4.55 (dt, 1H, J =
2.2 Hz, J = 1.6 Hz), 4.08 (ddt, 1H, J = 12.3 Hz, J = 2.4 Hz, J = 1.6 Hz); 3.99
(dt, 1H, J = 12.3 Hz, J = 1.6 Hz), 3.67 (br.d, 1H, J = 5.7 Hz); 13C NMR (CDCl3)
δ 158.6 (C), 147.9 (C), 129.1 (CH), 126.7 (C), 124.3 (CH), 121.3 (CH), 111.4
(CH), 109.7 (CH), 106.2 (CH2), 70.5 (CH2), 51.4 (CH); MS m/z (rel. intensity)
174 (M+, 100), 145 (99), 131 (36), 115 (37), 91 (20), 77 (16), 51 (23), 39 (17);
Anal. calcd for C11H10O2: C, 75.86; H, 5.74. Found: C, 75.92; H, 5.78.
ACKNOWLEDGMENTS
The authors wish to thank to Fundac¸a˜o de Amparo a` Pesquisa do Estado
de Sa˜o Paulo (FAPESP) and to Coordenadoria de Aperfeic¸oamento de Pessoal do
Ensino Superior (CAPES) for financial support.
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Received April 2, 2000

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