Synthetic studies towards the preparation of 2-benzyl-2-hydroxybenzofuran- 3(2H)-one, the prototype of naturally occurring hydrated auronols

Article abstract of DOI:10.1002/hlca.200490232

Various synthetic approaches were employed to prepare 2-benzyl-2- hydroxybenzofuran-3(2H)-one (8), the prototype of naturally occurring auronols. While the base-induced ring transformation of 3-hydroxyflavanone (2) as well as the hydration of 2-benzylidenebenzofuran-3(2H)-one (=aurone; 6) proved to be inappropriate, the hydrogenolytic epoxide-ring opening of 2′- phenylspiro[benzofuran-2(3H),2′-oxiran]-3-one (7), obtained from 6, represents an efficient method to afford the auronol 8.

Full text of DOI:10.1002/hlca.200490232

Helvetica Chimica Acta Vol. 87 (2004)
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Synthetic Studies Towards the Preparation of 2-Benzyl-2-
hydroxybenzofuran-3(2H)-one, the Prototype of Naturally Occurring
Hydrated Auronols
by Reik Lˆsera), Marta Chlupacovaa)b), Ales Mareceka)b), Veronika Opletalovab), and Michael G¸tschow*a)
a) Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universit‰t Bonn, Kreuzbergweg 26,
D-53115 Bonn (phone: ‡49228732317; fax: ‡49228732567; e-mail: guetschow@uni-bonn.de)
b
¬
¬
¬
¬
) Farmaceuticka fakulta v Hradci Kralove, Univerzita Karlova v Praze, Heyrovskeho 1203,
¬
¬
500 05 Hradec Kralove, Czech Republic
Various synthetic approaches were employed to prepare 2-benzyl-2-hydroxybenzofuran-3(2H)-one (8), the
prototype of naturally occurring auronols. While the base-induced ring transformation of 3-hydroxyflavanone
(2) as well as the hydration of 2-benzylidenebenzofuran-3(2H)-one (ˆaurone; 6) proved to be inappropriate,
the hydrogenolytic epoxide-ring opening of 2'-phenylspiro[benzofuran-2(3H),2'-oxiran]-3-one (7), obtained
from 6, represents an efficient method to afford the auronol 8.
Introduction.
Flavonoids represent a large group of plant natural products
exhibiting multiple biological activities and are very abundant in nutrients such as fruits
and vegetables [1]. Joining together the shikimate and polyketide pathways, they are
secondary metabolites of mixed biosynthetic origin. However, in contrast to the
detailed knowledge concerning the biosynthesis, the biodegradation of these com-
pounds is poorly investigated [2]. It has been shown that the degradation of the
hydroxyflavone quercetin (A) to phloroglucinol and (3,4-dihydroxyphenyl)pyruvic
acid by Eubacterium ramulus, a strictly anaerobic bacterium living in the human gut,
proceeds via the hydroxyflavanone taxifolin (B) and the auronol derivative alphitonin
(C) [3]. When compared to phenylchromanones (ˆ2,3-dihydro-2-phenyl-4H-1-ben-
zopyran-4-ones), aurones (ˆ2-benzylidenebenzofuran-3(2H)-ones) are less-investi-
gated flavonoids. To study the bioactivity of auronols, it is necessary to develop suitable
preparative methods to provide sufficient amounts for biological investigations.
Herein, we wish to report an efficient synthetic route to 2-benzyl-2-hydroxybenzofur-
an-3(2H)-one (8) as a prototype of auronols. The key step of this route is based on the
regioselective reductive ring opening of the aurone-derived epoxide 7. Auronol 8 has
already been isolated in small amounts from the wood of the Australian tree Flindersia
brasii [4].
Results and Discussion. It has been reported by Kiehlmann and Li that taxifolin
(B) underwent a ring contraction to alphitonin (C) after prolonged heating. Due to
dehydrogenation, quercetin (A) was formed as the by-product [5]. In an attempt to
prepare aurone derivative 8 in a similar manner, the hydroxyflavanone 2 was required.
Starting from 1, we prepared racemic 2 in a one-pot procedure including epoxidation
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

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Helvetica Chimica Acta Vol. 87 (2004)
and subsequent intramolecular opening of the epoxide (AlgarÀFlynnÀOyamada
reaction [6]). This conversion took place as a b-cyclization with respect to the attack of
the 2'-phenolic group; products of an a-cyclization [7] were not observed. The trans-
configuration of 2 was confirmed by the 3J coupling constant, which indicated the anti-
periplanar geometry of the HÀC(2) and HÀC(3). In the next step, 2 was subjected to
different conditions of a ring transformation to produce 8.
The conversion of taxifolin (B) to alphitonin (C) was achieved upon heating B in
H2O in a sealed tube at 1158 for 93 h [5]. Since hydroxyflavanone 2 is less soluble in
H2O than B, a mixture of iPrOH and H2O was used in an attempt to prepare 8 from 2.
However, the reaction proceeded very slowly and was, therefore, performed under base
catalysis. Thus, 2 was treated with a 1:2 mixture of iPrOH and 0.15n NaOH under an
inert atmosphere in a sealed tube at 1208 for a prolonged time. The formation of the
hydroxyflavone 4 [8] was detected by TLC, besides other unidentified products. To
avoid dehydrogenation of 2, the reaction was conducted in the presence of HCl and Zn
dust, again resulting in a mixture of products, from which the undesired flavanone 3 was
isolated in small amounts.
Next, aurone (6) was prepared by condensation of benzofuran-3(2H)-one (5) with
benzaldehyde on an alumina surface (Scheme), according to a methodology of Varma
and Varma [9]. Aurone (6) was subjected to conditions of a direct, acid-catalyzed
hydration, as described for other electron-deficient enol ethers [10]. This approach was
unsuccessful, too.
Therefore, it was envisaged to prepare 8 by reductive opening of aurone-derived
epoxide 7 under Pd-catalyzed hydrogenolysis. This transformation seemed to be
reliable and should proceed regioselectively because the hydrogenolysis of the
−benzylic× PhCHÀO bond is favored over the −nonbenzylic× PhCHCÀO bond [11].
¾
To prepare the required epoxide 7, aurone (6) was treated with H2O2 and Triton
B
[12]. NMR Data of the product indicated the presence of a single diastereoisomer.
Epoxide 7 in EtOH was then exposed to H2 in the presence of 10% Pd/C as catalyst, but
the desired product could not be obtained, probably due to decomposition of the

Helvetica Chimica Acta Vol. 87 (2004)
2599
starting material. By changing the solvent from EtOH to toluene, a defined reaction
course took place, and the products were isolated by prep. chromatography. When the
reaction was carried out at room temperature, a product mixture of auronol 8 and a-
hydroxy ketone 9 was obtained, whereby 9 was the main product (30%). This over-
reduction to 9 is assumed to be caused by hydrogenolysis of the −oxabenzylic× CÀO
bond in the furanone ring subsequent to epoxide opening rather than by hydrogenation
of the carbonyl group in the open-chain 1,2-diketone 8a that might be formed from
intermediate 8.
Scheme
However, performance of the reaction at temperatures ranging from À 25 to À 208
and thorough TLC control led to a more-convenient product distribution. Thus, the
desired 2-benzyl-2-hydroxybenzofuran-3(2H)-one (8) was obtained in 65% yield.
NMR Analysis of 8 in CDCl3 at 308 revealed the occurrence of a ring-chain tautomeric
equilibrium [13] between 8 and the 1,2-diketone 8a (ratio 1:0.15). This tautomerism,
however, was not observed in a DMSO solution of 8.
Conclusions. The hydrogenolysis of aurone-derived epoxides promises to be an
efficient newmethod to prepare auronols, as demonstrated in the preparation of the
parent compound, 2-benzyl-2-hydroxybenzofuran-3(2H)-one (8). The applicability of
this method to the synthesis of polyhydroxylated auronols is under current inves-
tigation in our laboratories and will be reported in the future.
The authors wish to thank M. Fischer, Bonn, for recording the NMR spectra. Financial support from the
Erasmus Program to M . C.and A. M. is gratefully acknowledged.

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Helvetica Chimica Acta Vol. 87 (2004)
Experimental Part
General. The 2'-hydroxychalcone (ˆ1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one; 1) was purchased
from Merck, Darmstadt, Germany, 3-hydroxyflavone (ˆ 3-hydroxy-2-phenyl-4H-1-benzopyran-4-one; 4) and
aluminum oxide from Aldrich, Steinheim, Germany, and benzofuran-3(2H)-one (5) from Fluka, Buchs,
Switzerland. TLC: Merck aluminum sheets, silica gel 60 F 254. Melting points: not corrected. 1H- and 13C-NMR
Spectra: at 500 and 125 MHz, resp.; CDCl3 solns., unless otherwise stated; d in ppm, J in Hz. MS: electron-
impact ionization (EI) at 70 eV; in m/z (rel. %).
(Æ)-trans-2,3-Dihydro-3-hydroxy-2-phenyl-4H-1-benzopyran-4-one (2). A mixture of 1 (2 g, 8.9 mmol),
Et2NH (3.25 g, 44.5 mmol), and dioxane (135 ml) was stirred at 0 58. Then, a 30% aq. H2O2 soln. (112 ml) was
added within 40 min. The mixture was kept at 58 for 40 h, and the precipitate was filtered off: 2 (690 mg, 32%).
M.p. 178 1808 ([14]: 1788). 1H-NMR: 3.65 (d, J ˆ 1.9, OH); 4.63 (dd, J ˆ 12.3, 1.9, HÀC(3)); 5.13 (d, J ˆ 12.3,
HÀC(2)); 7.02 7.06 (m, HÀC(8)); 7.08 7.12 (m, HÀC(6)); 7.40 7.49 (m, HÀC(3'), HÀC(4'), HÀC(5'));
7.52 7.60 (m, HÀC(7), HÀC(2'), HÀC(6')); 7.92 (dd, J ˆ 7.9, 1.6, HÀC(5)). 13C-NMR: 73.62 (C(3)); 83.87
(C(2)); 118.13 (C(8)); 118.50 (C(4a)); 122.11 (C(6)); 127.33 (C(5)); 127.53 (C(2'), C(6')); 128.71 (C(3'), C(5'));
.
‡
129.33 (C(4')); 136.28 (C(1')); 136.94 (C(7)); 161.72 (C(8a)); 194.22 (C(4)). EI-MS: 240 (40, M ), 211 (100),
121 (72).
i
(Æ)-2,3-Dihydro-2-phenyl-4H-1-benzopyran-4-one (3). A mixture of H2O (200 ml) and PrOH (100 ml)
was degassed in an ultrasonic bath and treated with N2 (each 15 min). Compound 2 (1.50 g, 6.2 mmol), Zn dust
(500 mg, 7.6 mmol), and 6n HCl (5 ml) were added. The mixture was refluxed for 95 h under Ar, extracted with
CH2Cl2, and subjected to column chromatography (silica gel): 3 (35 mg, 2%). M.p. 60 618 ([15]: 75 768).
1H-NMR: 2.88 (dd, J ˆ 17.0, 3.0, 1 H, CH2); 3.07 (dd, J ˆ 17.0, 13.5, 1 H, CH2); 5.47 (dd, J ˆ 13.5, 3.0, HÀC(2));
7.02 7.06 (m, HÀC(6), HÀC(8)); 7.35 7.51 (m, 6 arom. H); 7.92 (dd, J ˆ 8.1, 1.6, HÀC(5)). 13C-NMR: 44.68
(C(3)); 79.60 (C(2)); 118.13 (C(8)); 120.93 (C(4a)); 121.62 (C(6)); 126.14 (C(2'), C(6')); 127.05 (C(5)); 128.78
(C(4')); 128.85 (C(3'), C(5')); 136.20 (C(7)); 138.73 (C(1')); 161.56 (C(8a)); 191.98 (C(4)). EI-MS: 224 (100,
.
‡
M
), 223 (65), 147 (43), 120 (72), 104 (20).
(Z)-2-Benzylidenebenzofuran-3(2H)-one (6). Aluminium oxide (16.25 g; activated, basic, type 5016A
Brockmann I) was added to a soln. of 5 (0.67 g, 5 mmol) and benzaldehyde (1.00 g, 9.33 mmol) in CH2Cl2
(0.67 g, 5 mmol). The mixture was thoroughly stirred for 6 h at r.t. under exclusion of light. The suspension was
filtered off, the residue washed with CH2Cl2 (4 Â 75 ml), and the washes were combined with the filtrate. The
solvent was evaporated and the residue recrystallized from CH2Cl2/MeOH: 6 (0.74 g, 68%). M.p. 106 1088
([16]: 110 1118). 1H-NMR: 6.90 (s, PhCH); 7.19 7.23 (m, HÀC(5)); 7.31 7.33 (m, HÀC(7)); 7.37 7.41
(m, HÀC(4')); 7.43 7.47 (m, HÀC(3'), HÀC(5')); 7.62 7.66 (m, HÀC(6)); 7.80 (dd, J ˆ 7.6, 1.3, HÀC(4));
7.90 7.93 (m, HÀC(2'), HÀC(6')). 13C-NMR: 112.94 (C(7)); 113.05 (PhCH); 121.64 (C(3a)); 123.47 (C(5));
124.68 (C(4)); 128.89 (C(3'), C(5')); 129.89 (C(4')); 131.54 (C(2'), C(6')); 132.30 (C(1')); 136.89 (C(6)); 146.88
.
‡
(C(2)); 166.16 (C(7a)); 184.81 (C(3)). EI-MS: 222 (60, M ), 221 (100).
(Æ)-trans-3'-Phenylspiro[benzofuran-2(3H),2'-oxiran]-3-one (7). To a soln. of 6 (1 g, 4.5 mmol) in dioxane
(60 ml), simultaneously, 30% aq. H2O2 soln. (3 ml) and 40% benzyltrimethylammonium hydroxide in MeOH
¾
(Triton B; 1 ml) were added dropwise. The mixture was stirred at r.t. for 40 min and poured onto ice-water
(200 ml). The precipitate was filtered off, washed with cold H2O, and dried. The crude product was dissolved in
CHCl3, and the soln. was poured onto ligroin. The precipitate formed was filtered off: 7 (0.37 g, 35%). M.p.
128 1338 ([12]: 133 1348). 1H-NMR: 4.55 (s, HÀC(3')); 7.09 7.12 (m, HÀC(7)); 7.14 7.18 (m, HÀC(5));
7.39 7.44 (m, HÀC(3''), HÀC(4''), HÀC(5'')); 7.48 7.51 (m, HÀC(2''), HÀC(6'')); 7.61 7.65 (m, HÀC(6));
7.72 (ddd, 3J ˆ 7.7, 4J ˆ 1.4, 5J ˆ 0.7, HÀC(4)). 13C-NMR: 62.94 (C(3')); 89.46 (C(2)); 113.84 (C(7)); 120.08
(C(3a)); 123.27 (C(5)); 124.41 (C(4)); 127.55 (C(2''), C(6'')); 128.38 (C(3''), C(5'')); 129.18 (C(4'')); 131.70
.
‡
(C(1'')); 138.67 (C(6)); 170.33 (C(7a)); 192.26 (C(3)). EI-MS: 238 (100, M ), 210 (30), 121 (25), 118 (40), 90
(58).
Hydrogenolysis of 7. A Schlenk tube containing 10% Pd/C (315 mg, 0.29 mmol) was evacuated and flushed
with Ar. The tube was provided with H2 (balloon) and cooled to À 258. A soln. of 7 (200 mg, 0.84 mmol) in
degassed and dried toluene (20 ml) was injected via septum. The temp. was kept at À 25 to À 208, and the
reaction was followed by TLC (toluene/MeCN 4 :1). After 2.5 h, the reaction was stopped by filtration of the
catalyst, the filtrate evaporated, and the yellowoil (191 mg) subjected to column chromatography (silica gel
(16 g), CH2Cl2/AcOEt 99 :1): 8 (132 mg, 65%) and 9 (40 mg, 20%).
Data of (Æ)-2-Benzyl-2-hydroxybenzofuran-3(2H)-one (8): Yellowsolid. M.p. 93 95 8 ([8]: 102 1038; [4]:
1058). 1H-NMR ((D6)DMSO): 3.08 (d, J ˆ 13.9, 1 H, CH2); 3.16 (d, J ˆ 13.9, 1 H, CH2); 6.95 7.00
(m, HÀC(5)); 7.04 (d, J ˆ 8.6, HÀC(7)); 7.07 7.16 (m, 5 arom. H); 7.46 (dd, J ˆ 7.7, 0.8, HÀC(4)); 7.58 7.62

Helvetica Chimica Acta Vol. 87 (2004)
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(m, HÀC(6)); 7.82 (s, OH). 13C-NMR ((D6)DMSO): 41.35 (CH2); 105.22 (C(2)); 113.04, 121.74 (C(5), C(7));
119.59 (C(3a)); 124.22 (C(4)); 126.76 (C(4')); 127.87 (C(3'), C(5')); 130.52 (C(2'), C(6')); 133.83 (C(1')); 139.03
.
‡
(C(6)); 169.98 (C(7a)); 199.16 (C(3)). EI-MS: 240 (10, M ), 121 (100), 91 (30).
Data of (Æ)-2-Hydroxy-1-(2-hydroxyphenyl)-3-phenylpropan-1-one (9): Yellowoil [4][17]. 1H-NMR: 2.96
(dd, J ˆ 14.2, 7.0, 1 H, CH2); 3.22 (dd, J ˆ 14.2, 4.1, 1 H, CH2); 3.48 (d, J ˆ 7.9, CHOH); 5.32 5.37 (m, CHOH);
6.92 6.96 (m, HÀC(5')); 7.05 (dd, J ˆ 8.7, 1.1, HÀC(3')); 7.11 7.14 (m, HÀC(2), HÀC(6)); 7.20 7.28
(m, HÀC(3), HÀC(4), HÀC(5)); 7.51 7.55 (m, HÀC(4')); 6.69 (dd, J ˆ 8.2, 1.6, HÀC(6')); 11.57
(s, OHÀC(2')). 13C-NMR: 42.80 (CH2); 72.85 (CHOH); 116.60 (C(1')); 119.02, 119.33 (C(3'), C(5')); 127.03
(C(4)); 128.46 (C(3), C(5)); 129.39 (C(6')); 129.40 (C(2), C(6)); 135.95 (C(1)); 137.25 (C(4')); 162.77 (C(2'));
.
‡
205.26 (CO). EI-MS: 242 (6, M ), 224 (23), 213 (10), 121 (100), 91 (21).
Selected NMR Data of 8 and 1-(2-Hydroxyphenyl)-3-phenylpropane-1,2-dione (8a) in CDCl3: 1H-NMR
(400 MHz): 3.09 (d, J ˆ 13.9, 1 H, CH2, 8); 3.18 (d, J ˆ 13.9, 1 H, CH2, 8); 3.53 (s, 1 H, OH, 8); 4.10 (s, 2 H, CH2,
8a); 6.70 7.60 (m, arom. H, 8 and 8a); 11.21 (s, 1 H, OH, 8a). 13C-NMR (100 MHz): 41.62 (CH2, 8); 45.65 (CH2,
8a); 103.60 (C(2), 8); 163.85 (CÀOH, 8a); 170.44 (C(7a), 8); 196.54 (C(2), 8a); 197.91 (C(1), 8a); 198.45 (C(3),
8).
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Received May 7, 2004