Studies on synthesis of 3(2H)-benzofuranone derivatives

Article abstract of DOI:10.1081/SCC-120006003

Two known methods were used for synthesis of 2,6-disubstituted-3(2H)-benzofuranone derivatives. It was found that depending on the reaction conditions, degradation products or the products of oxidation were isolated. This latter reaction became the main process when the ring closure was performed starting from methoxy- or 2-propoxy-desoxybenzoin and diethyl bromo-(or chloro-)-malonate to give D,L- and meso-dimers of the substituted 3(2H)-benzofuranones.

Full text of DOI:10.1081/SCC-120006003

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STUDIES ON SYNTHESIS OF 3(2H)-BENZOFURANONE
DERIVATIVES
Sándor Bokotey a , Mária Kövári-Rádkai a , Benjámin Podányi a , Imola Ritz a , Miklós Hanusz a
& Sándor Bátori b
a CHINOIN Pharmaceutical and Chemical Works Co. Ltd. , P.O. Box 110, Budapest, H-1325,
Hungary
b CHINOIN Pharmaceutical and Chemical Works Co. Ltd. , P.O. Box 110, Budapest, H-1325,
Hungary
Published online: 16 Aug 2006.
To cite this article: Sándor Bokotey , Mária Kövári-Rádkai , Benjámin Podányi , Imola Ritz , Miklós Hanusz & Sándor Bátori
(2002) STUDIES ON SYNTHESIS OF 3(2H)-BENZOFURANONE DERIVATIVES, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:15, 2325-2343, DOI: 10.1081/SCC-120006003
To link to this article: http://dx.doi.org/10.1081/SCC-120006003
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 15, pp. 2325–2343, 2002
STUDIES ON SYNTHESIS OF
3(2H)-BENZOFURANONE DERIVATIVES
Sandor Bokotey,Ma ria Kovari-Radkai,
Benjamin Podanyi,Imola Ritz,Miklo s Hanusz,
*
and Sandor Batori
CHINOIN Pharmaceutical and Chemical Works Co.
Ltd., H-1325 Budapest, P.O. Box 110, Hungary
ABSTRACT
Two known methods were used for synthesis of 2,6-disubsti-
tuted-3(2H)-benzofuranone derivatives. It was found that
depending on the reaction conditions, degradation products
or the products of oxidation were isolated. This latter reaction
became the main process when the ring closure was performed
starting from methoxy- or 2-propoxy-desoxybenzoin and
diethyl bromo-(or chloro-)-malonate to give D,L- and meso-
dimers of the substituted 3(2H)-benzofuranones.
Key Words: Benzofuranones; Bibenzofuranoids; Hoesch
reaction; Dimerization; Transbromination
INTRODUCTION
Among the biologically active isoflavones, ipriflavon[1] (7-(2-propoxy)-
3-phenylisoflavone) is applied in human therapy[2,3] in several European
*Corresponding author. Fax: þ361-370-5412; E-mail: sandor.batori@sanofi-
synthelabo.com
2325
DOI: 10.1081/SCC-120006003
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2326
BOKOTEY ET AL.
countries and in Japan as an antiosteoporotic agent. The ongoing interest
prompted us to find structurally related structures that might have similar or
better antiosteoprotic activity.
Isoflavonoid compounds (benzopyran-4-ones, such as ipriflavon
(Figure 1) and other naturally occurring isoflavones (e.g., genistein) and
flavonols (e.g., quercetin) have close structural similarities to the benzo-
furan-3-one skeleton (I), and naturally occurring benzofurane derivatives
e.g., vignafuran) have isoflavonoid origin in their biosynthesis.[4]
Although different synthetic routes are reported for the 3(2H)-benzo-
furanones,[5–7] most of them suffer in yield and involve difficult reaction
conditions.
RESULTS AND DISCUSSION
During the plant-production of ipriflavon, the 1-(2,4-dihydroxyphe-
nyl)-2-phenylethanone (1) (Scheme 1) is synthesized in large quantity. Our
first idea was to use this as starting material for the synthesis of 6-hydroxy-
2-phenyl-3(2H)-benzofuranone by bromination of the active methylene
group followed by an intramolecular ring closure to give the benzofuranone
derivative. A similar reaction was described earlier by Hanaya et al.[8] to
produce 2-phenyl-3(2H)-benzofuranone derivatives.
Figure 1.
Scheme 1.

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3(2H )-BENZOFURANONE DERIVATIVES
2327
Scheme 2.
The bromination of 1 in the presence of AlCl3 in diethyl ether or
without AlCl3 in acetic acid–sodium acetate led only to the core-brominated
product (3). The attempted bromination with NBS gave a multicomponent
mixture from which no definite product was isolated.
Chopin et al. reported[9] the synthesis of multisubstituted 3(2H)-ben-
zofuranones using the Hoesch reaction conditions for the reaction of a-
hydroxy- or a-haloaryl acetonitriles with polyphenols. According to the
given conditions we reacted resorcinol (4) with a-hydroxyphenylacetonitrile
(5) but, instead of the desired benzofuranone 13, a multicomponent mixture
was formed from which only small amount of 6, 8 and 13 could be isolated
(see Ref. [10]). Under milder conditions, the 2-hydroxyethanone derivative 6
was obtained in ꢀ14% yield. The structure elucidation of 6 was based on the
1H- and 13C-NMR spectra as well as elemental analysis (Scheme 2).
The cyclization of 6 was attempted by dehydration using P2O5. No
reaction occurred after several days. When concentrated H2SO4 was used,
the 2-benzoyloxy-4-hydroxybenzoic acid (8) was isolated. Its formation can
only be explained by the first formation of the desired 3(2H)-benzofuranone
13 that decomposed under the strong acidic conditions used. The structure of
the benzoic acid 8 is based on spectral and elemental analytical data and on
the fact that its esterification resulted in two esters: methyl 2-benzoyl-4-
hydroxybenzoate (9) and methyl 2,4-dihydroxybenzoate (10). The a-chloro-
ethanone 7 was formed when the dehydration of 6 was attempted by thionyl
chloride (Method A). This latter compound (7) was prepared in 37%
yield according to the modified procedure of Chopin et al.[9] (Method B).
The reaction of resorcinol (4) with a-chlorophenylacetonitrile, accord-
ing to the original procedure of Anger et al.,[9c] gave in our case the desired
benzofuranone 13 in low (6%) yield (Method A). Much better yield (46%)
was achieved when the cyclization of the a-chloro compound 7 was
performed using sodium acetate as base (Method B).
The NMR investigations showed that the compound can exist in two
tautomeric forms (13a and 13b) and that their ratio depends on the solvent

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2328
BOKOTEY ET AL.
Scheme 3.
used for the investigation. The assignment of the 1H- and 13C NMR signals
was done according to the 2D HMBC, 2D HMQC and DEPT-135 mea-
surements. The distinction between the two tautomeric forms was based
on the difference of the chemical shifts of C-2 and C-3 atoms in the
13C NMR spectrum. In the case of the oxo-form, the chemical shifts of C-
2 and C-3 were 86.2 and 196.3 ppm, while those of in the enol-form were
134.2 and 137.4 ppm, respectively.
In acidic conditions, the benzofuranone 13 decomposes easily to give
the benzoic acid derivative 8, isolated as by-product (Scheme 3). An oxida-
tion process can also take place to form the dimer 12. When longer reaction
time was used for the cyclization of 7 with sodium acetate (reflux for 4 h,
then stirring for 2 days at room temperature), the dimer 12 was isolated in
20% yield. The formation of this dimer can be observed even under the
conditions of the NMR investigations. Moreover a complete dimerization
takes place when the solution in DMSO is exposed to air for several days
(followed the reaction by TLC). Brewer et al.[11] and Badin et al.[12]
described similar autooxidation of 3(2H)-benzfuranone derivatives earlier.
Hasegawa et al.[13] prepared bibenzofuranoids on photochemical route and
Bekker et al.[14] reported recently about the first example of the formation of
bibenzofuranoids with attachment through C2–C70.
We tried the alkylation of the 6-hydroxy derivative 13 with 2-propyl
bromide to achieve a 6-(2-propoxy) derivative having a similar structure to
ipriflavon. The reaction gave a complex mixture from which no definite
product could be isolated.
Kanvinde et al.[7] reported recently an easy and elegant way to prepare
substituted 2-aryl-3(2H)-benzofuranone derivatives by the reaction of
2-hydroxydeoxybenzoins with ethyl bromomalonate. We repeated their
experiment under the given conditions using 1-(2-hydroxy-4-methoxy)-
phenyl-2-phenylethanone (14a) as starting material (Scheme 4).

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3(2H )-BENZOFURANONE DERIVATIVES
2329
Scheme 4.
After work up of the reaction mixture we isolated a white solid
material in 28% yield with a m.p. of 248–250ꢁC that is just above the
m.p. given for the reported product, 6-methoxy-2-phenyl-3(2H)-benzofura-
none[7] (234ꢁC). The compound isolated by us has a carbonyl frequency at
1715 cmÀ1 (reported in the publication[7]: 1725 cmÀ1), but differed from the
1
given H NMR data (based on a not too high quality spectrum) in the
original publication; we were not able to find the signal of the proton H-
2. The detailed 1H- and 13C NMR analysis showed that instead of the
desired monomer we had isolated its dimer, the D,L-(6-methoxy-2-phenyl-
3(2H)-benzofuranone-2-yl)-6-methoxy-2-phenyl-3(2H)-benzofuranone
(15a). The chemical shift of the quaternary C-2 was 91.2 ppm. The MS
investigation gave a similar conclusion: the molecular ion at m/z: 478
(2.6%) clearly showed the dimeric nature of the molecule. The configuration
of the two C-2 atom was unambiguously proved by adding the chiral solvat-
ing reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE) to the sol-
ution of the 15a (in benzene-d6). Two sets of signals were observed in the
1H NMR spectrum; thus the configuration of the two C-2 atoms was the
same (R,R or S,S) which means that 15a corresponds to the D,L-pair.
The chromatography of the mother liquor resulted in the isolation of
further products. The other possible dimer, the meso-(6-methoxy-
2-phenyl-3(2H)-benzofuranone-2-yl)-6-methoxy-2-phenyl-3(2H)-benzofur-
anone (16a) was also isolated in 28% yield. The configuration of the two C-2

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2330
BOKOTEY ET AL.
Figure 2. ORTEP view of dimer 16b. There is crystallographic center of symmetry
on the C2-C2* bond.
atoms was proved by using TFAE as was mentioned above. No splitting of
NMR signals was observed, which means that 16a corresponds to the
meso-form. A further proof for the structure was provided by the single-
crystal X-ray analysis of the dimer (16b). The ORTEP view of the structure
is depicted in Figure 2.
The (probable) oxidative process that led to the dimerization resulted
in the formation of other types of 3(2H)-benzofuranone (17a: 3% and 18:
23%) too. Diethyl malonate (19) was also formed during the reaction, which
was isolated in 30% yield. Interestingly, the same products (in similar pro-
portion) were formed when we repeated the reaction under an argon atmos-
phere. This shows that very probably the diethyl bromomalonate had to be
the oxidizing agent and during this process it was reduced to diethyl mal-
onate (19). When the reaction was performed from 1-(2-hydroxy-4-(2-
propoxy))phenyl-2-phenylethanone (14b) the same type of products (15b,
16b,17b and 19) were isolated but the yield were somewhat lower than in
the previous case. The same compounds (15b, 16b and 19) but in much lower
yield were isolated when diethyl chloromalonate was used instead of bro-
momalonate. In this case a further type of 3(2H)-benzofuranone (21) was
also isolated in 7% yield.
Kanvinde et al.[7] gave a possible mechanism for the formation of the
benzofuranone derivatives. According to this, ‘‘probably the diethyl bromo-
malonate is acting as a brominating agent and bringing about bromination

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3(2H )-BENZOFURANONE DERIVATIVES
2331
Scheme 5.
at the reactive methylene followed by cyclization, thus furnishing 2-aryl-
3(2H)-benzofuranones.’’ No proof was given in the article for this mechan-
ism and since that time no details were found in the literature.
Although the bromination with diethyl bromomalonate seems not to
be so obvious, we were able to find some data that support this concept.
The reaction of the 1-(2,4-dimethoxyphenyl)-2-phenylethanone (22)
with diethyl bromomalonate (Scheme 5) was performed under the same
reaction condition as in the former cases. Two different compounds were
formed: 2-bromo-1-(2,4-dimethoxy)phenyl-2-phenylethanone (23a: 66%
based on the recovered starting materials) and diethyl 2,3-(diethoxycarbo-
nyl)fumarate (24: 91.7%). The formation of 23a in high yield clearly
shows the possibility of a transbromination process. The formation of 24
was a result of the alkylation of the bromomalonate anion by one molecule
of diethyl bromomalonate followed by dehydrobromination. The diethyl
chloromalonate reacts similarly; the chlorinated ketone 23b was isolated
in 44% yield together with the fumarate derivative 24 (73%).
On the basis of our results it is obvious that the 3(2H)-benzofuranone
derivatives can easily undergo oxidative reactions to form at least two
different types of dimers. The procedure given for synthesis of 3(2H)-ben-
zofuranone derivatives (Ref. [7]), in contrast to the publication, led in our
case to dimeric benzofuranone derivatives. The given procedure may cause
difficulties in synthesis of monomeric type 3(2H)-benzofuranones.
EXPERIMENTAL
General
The thin-layer chromatography was performed on Merck Kieselgel 60
254 (0.2 mm) sheets. Kieselgel 60 (Merck) was used for column chromatog-
F
raphy. Melting points were determined with a BUCHI 535 apparatus and
are uncorrected. A Bruker IFS-28 instrument was used for registration of

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2332
BOKOTEY ET AL.
the IR spectra. BRUKER DRX-400 spectrometer was used for recording
1
the H and 13C NMR spectra (TMS standard); J values are quoted in Hz.
Mass spectra were obtained on a VG-TS mass spectrometer (70 eV, EI,
direct inlet or FAB). Microanalysis were performed on CARLO ERBA
MOD 1106 apparatus. The X-ray measurement was made on a Rigaku
AFC6S diffractometer with graphite monochromated CuKa radiation.
1-(3-Bromo-2,4-dihydroxyphenyl)-2-phenylethanone (3): Compound 1
(11.41 g, 50 mmol) was dissolved in diethyl ether (100 mL) and dry AlCl3
(0.5 g, 4 mmol) was added. The mixture was cooled to 0ꢁC and bromine
(7.99 g, 2.6 mL, 50 mmol) was dropped to the stirred reaction mixture at
3–4ꢁC (ꢀ20 min). The excess of the bromine was flushed by air, and the
precipitated material was filtered off, washed with petroleum ether to give
2.45 g of crude product. It was recrystallized from a mixture of CH2Cl2
(50 mL) and 1,2-dichloroethane (20 mL) to give 1.4 g (9.1%) of white nee-
dles, m.p. 191–192ꢁC; IR (KBr): 3400, 3280, 3060, 3020, 2970, 2900, 1620,
1560, 1500, 1420, 1390, 1360, 1330, 1300, 1240, 1210, 1150, 1035, 1010 cmÀ1
;
1H NMR (DMSO-d6): ꢀ 4.34 (s, 2H, CH2), 6.61 (d, J ¼ 8.7 Hz, 1H, H-5),
7.24 (m, 1H, H-40(phenyl)), 7.30 (m, 4H, H-20,30,50,60(phenyl)), 8.01
(d, J ¼ 8.6 Hz, 1H, H-6). Anal. calcd. for C14H11BrO3: C, 54.75; H, 3.61;
Br, 26.02. Found: C, 54.68; H, 3.60; Br, 26.22.
1-(2,4-Dihydroxyphenyl)-2-hydroxy-2-phenylethanone (6): Gaseous
HCl was introduced into a mixture of resorcinol (4, 6.05 g, 55 mmol), man-
delonitrile (5, 6.66 g, 6.0 mL, 50 mmol) and freshly dried ground ZnCl2
(6.81 g, 50 mmol) in dry diethyl ether (70 mL) at 5–10ꢁC for 4 h. The reaction
mixture was stored in refrigerator for 2 days, the ether was decanted, the
solid material was washed twice with diethyl ether and mixed with water
(100 mL). The mixture was first stirred at room temperature for 2 h, then
refluxed for 3 h. The cooled mixture was extracted with ethyl acetate
(3 Â 30 mL). The organic extract was dried over Na2SO4, filtered and the
solvent was evaporated to dryness. The residue was chromatographed on
silica gel, eluted first by CHCl3 then by a mixture of CHCl3 and ethyl acetate
(9 : 1) to give 1.65 g (13.5%) of white crystals, m.p. 166–167ꢁC; IR (KBr):
3417, 3181, 3071, 3035, 1622, 1589, 1501, 1442, 1397, 1329, 1269, 1225, 1172,
1130, 1079, 1055, 1003, 986, 959 cmÀ1; 1H NMR (DMSO-d6): ꢀ 6.01 (s, 1H,
H-1), 6.23 (d, J ¼ 2.3 Hz, 1H, H-7), 6.31 (dd, J ¼ 2.3 Hz, J ¼ 8.8 Hz, 1H,
H-5), 7.24 (m, 1H, H-40), 7.33 (m, 2H, H-30,50), 7.45 (m, 2H, H-20,60), 7.95
(d, J ¼ 8.8 Hz, 1H, H-4); 1H NMR (CDCl3): ꢀ 4.42 (d, J ¼ 6.7 Hz, 1H, 1-OH),
5.63 (bs, 1H, 6-OH), 5.88 (d, J ¼ 6.7 Hz, 1H, H-1), 6.27 (dd, J ¼ 8.8 Hz,
J ¼ 2.4 Hz, 1H, H-5), 6.37 (d, J ¼ 2.4 Hz, 1H, H-7), 7.36 (m, 5H,
H-20,30,40,50,60), 7.51 (d, J ¼ 8.8 Hz, 1H, H-4), 12.05 (s, 1H, 8-OH);
1H NMR (MeOD): ꢀ 6.01 (s, 1H, H-1), 6.25 (m, 2H, H-7, H-5), 7.27 (m,
1H, H-40), 7.33 (m, 2H, H-30,50), 7.43 (m, 2H, H-20,60), 7.71 (d, J ¼ 9.6 Hz,

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3(2H )-BENZOFURANONE DERIVATIVES
2333
1H, H-4); 13C NMR (DMSO-d6): ꢀ 74.7 (C-1), 102.5 (C-7), 108.2 (C-5),
110.7 (C-3), 127.0 (C-30,50), 127.7 (C-4), 128.4 (C-20,60), 133.4 (C-40), 104.2
(C-10), 164.7 (C-6), 165.0 (C-8), 202.4 (C-2); 13C NMR (MeOD): ꢀ 76.2
(C-1), 103.8 (C-7), 109.2 (C-5), 111.8 (C-3), 128.6 (C-30,50), 129.4 (C-4),
129.9 (C-20,60), 134.0 (C-40), 141.2 (C-10), 166.7, 167.0 (C-6, C-8), 203.0
(C-2). Anal. calcd. for C14H12O4: C, 68.85; H, 4.91. Found: C, 69.10; H,
4.50.
2-Chloro-1-(2,4-dihydroxyphenyl)-2-phenylethanone (7), Method A: A
solution of ketone 6 (100 mg, 0.4 mmol) in dry acetonitrile (3 mL) was stirred
with SOCl2 (49 mg, 0.4 mmol) at 25ꢁC for 2 days. The reaction mixture was
evaporated to dryness, the residue was chromatographed on silica gel eluted
first by CHCl3 then by a mixture of CHCl3 and ethyl acetate (9 : 1) to give
30 mg (28%) of white crystals, m.p. 143–145ꢁC; IR (KBr): 3078, 3006, 1618,
1
1566, 1508, 1327, 1238, 1137, 968 cmÀ1; H NMR (DMSO-d6): ꢀ 6.29 (d,
J ¼ 2.5 Hz, 1H, H-7), 6.35 (dd, J ¼ 2.5 Hz, J ¼ 9.2 Hz, 1H, H-5), 7.00 (s, 1H,
CH), 7.36 (m, 3H, H-30,40,50), 7.51 (m, 2H, H-20,60), 7.85 (d, J ¼ 9.2 Hz, 1H,
H-4). Anal. calcd. for C14H11ClO3: C, 64.00; H, 4.22; Cl, 13.49. Found:
C, 64.45; H, 4.31; Cl, 13.61.
Method B: Gaseous HCl was introduced into a mixture of resorcinol
(4, 5.93 g, 54 mmol), a-chlorophenylacetonitrile (11, 7.58 g, 50 mmol) and
freshly dried, ground ZnCl2 (1.94 g, 14 mmol) in dry diethyl ether (78 mL)
at 0–5ꢁC for 4 h. The reaction mixture was stored in refrigerator for 3 days
and evaporated to dryness. The residue was triturated with acetone, and the
yellow solid material was filtered off, solved in 1% HCl (250 mL) and the
solution was stirred at 75ꢁC for 1 h. The precipitate was filtered off,
washed with water and hexane to give 4.83 g (36.8%) of white crystals,
m.p. 143–145ꢁC. The compound was identical with that obtained by
Method A.
2-Benzoyloxy-4-hydroxybenzoic acid (8): Compound
6 (100 mg,
0.4 mmol) was stirred in concentrated H2SO4 (3 mL) at 25ꢁC for 4 h. The
mixture was poured on crushed ice and extracted with ethyl acetate
(3 Â 10 mL). The organic extract was dried over Na2SO4, filtered, evapo-
rated, the residue was suspended in CHCl3 and filtered off to give 60 mg
(57%) of white crystals, m.p. 163–165ꢁC (then solidifies and melts again at
253–258ꢁC); IR (KBr): 3292, 3040, 3000, 2862, 2813, 2659, 2555, 1701, 1620,
1521, 1447, 1413, 1369, 1330, 1289, 1253, 1177, 1099 cmÀ1 1H NMR
;
(DMSO-d6): ꢀ 6.66 (d, J ¼ 2.3 Hz, 1H, H-7), 6.80 (dd, J ¼ 2.3 Hz,
J ¼ 8.9 Hz, 1H, H-5), 7.59 (m, 2H, H-30,50), 7.72 (m, 1H, H-40), 7.86 (d,
J ¼ 8.8 Hz, 1H, H-4), 8.09 (m, 2H, H-20,60), 10.61 (s, 1H, 6-OH), 12.49 (s,
1H, COOH); 13C NMR (DMSO-d6): ꢀ 110.5 (C-7), 113.2 (C-5), 114.5 (C-3),
128.8 (C-30,50), 129.4 (C-10), 129.8 (C-20,60), 133.4 (C-4), 133.7 (C-40), 152.2
(C-2), 162.3 (C-6), 164.6 (C¼O), 165.2 (COOH); MS m/z: 258, 241, 213, 197,

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2334
BOKOTEY ET AL.
154, 137, 136, 122, 105, 77. Anal. calcd. for C14H10O5: C, 65.12; H, 3.90.
Found: C, 64.92; H, 3.86.
Esterification of 2-benzoyloxy-4-hydroxybenzoic acid (8): Gaseous HCl
was introduced into a stirred solution of acid 8 (100 mg, 0.39 mmol) in
methanol (3 mL) under reflux for 15 min. The reaction mixture was stirred
at room temperature for 20 h then refluxed for 1 h. The cooled reaction
mixture was concentrated and the components were separated by ‘‘dry-
column flesh chromatography’’[15] on silica gel, eluted first by CH2Cl2
then by a mixture of CH2Cl2/ethyl acetate (95 : 5) to give 2 compounds.
Methyl 2-benzoyloxy-4-hydroxybenzoate (9, 10 mg, 9.5%); 1H NMR
(CDCl3): ꢀ 3.68 (s, 3H, OCH3), 6.57 (d, J ¼ 2.4 Hz, 1H, H-3), 6.66 (dd,
J ¼ 2.4 Hz, J ¼ 8.8 Hz, 1H, H-5), 7.51 (m, 2H, H-30,50), 7.63 (m, 1H, H-40),
7.92 (d, J ¼ 8.8 Hz, 2H, H-6), 8.21 (m, 2H, H-20,60).
Methyl 2,4-dihydroxybenzoate (10, 30 mg, 46%), m.p. 112–114ꢁC; IR
(KBr): 3341, 3201, 3064, 2958, 1641, 1504, 1435, 1358, 1268, 1174, 1147,
1
1092, 980, 947 cmÀ1; H NMR (CDCl3): ꢀ 3.91 (s, 3H, OCH3), 6.37 (dd,
J ¼ 2.4 Hz, J ¼ 8.5 Hz, 1H, H-5), 6.40 (d, J ¼ 2.4 Hz, 1H, H-3), 7.72 (d,
J ¼ 8.5 Hz, 1H, H-6), 11.00 (s, 1H, OH). Anal. calcd. for C8H8O4:
C, 57.14; H, 4.76. Found: C, 57.47; H, 5.08.
(6-Hydroxy-2-phenyl-3(2H)-benzofuranon-2-yl)-6-hydroxy-2-phenyl-
3(2H)-benzofuranone (12): A mixture of 7 (1.06 g, 4 mmol) and sodium acet-
ate (0.66 g, 8 mmol) in ethanol (15 mL) was refluxed for 4 h and stirred at
room temperature for 2 days. The solid was filtered off washed with ethanol
and the mother liquor was mixed with water (20 mL) and extracted with
ethyl acetate (3 Â 30 mL). The organic extract was dried over Na2SO4, fil-
tered and concentrated. The residue was mixed with diethyl ether (30 mL),
the precipitate was filtered off, washed with diethyl ether to give 0.18 g
(20%) of white crystals, m.p. 314–315ꢁC; IR (KBr): 3203, 3000, 1683,
1593, 1492, 1447, 1395, 1292, 1236, 1204, 1168, 1105, 1015, 847 cmÀ1
;
1H NMR (DMSO-d6): ꢀ 6.49, 6.52 (d, J ¼ 1.9 Hz, 4H, 4 Â H-7); 6.54, 6.57
(dd, J ¼ 8.4 Hz, J ¼ 1.9 Hz, 4H, 4 Â H-5); 7.28, 7.42 (m, 20H,
4 Â H-20,30,40,50,60); 11.10 (s, 4H, 4 Â OH); H NMR (Pyridine-d5): ꢀ 6.74,
1
6.75 (dd, J ¼ 1.5 Hz, J ¼ 8.4 Hz, 4H, 4 Â H-5); 6.89, 6.92 (d, J ¼ 1.5 Hz, 4H,
4 Â H-7); 7.28 (m, 12H, 4 Â H-30,40,50), 7.65 (d, J ¼ 8.4 Hz, 4H, 4 Â H-4),
8.02 (m, 8H, 4 Â H-20,60); 1H NMR (Acetone-d6): ꢀ 6.53, 6.58 (d,
J ¼ 1.9 Hz, 4H, 4 Â H-7); 6.60, 6.62 (dd, J ¼ 1.9 Hz, J ¼ 8.4 Hz, 4H,
4 Â H-5); 7.23, 7.29 (m, 8H, 4 Â H-30,50); 7.39, 7.44 (d, J ¼ 8.4 Hz, 4H,
4 Â H-4); 7.47, 7.52 (m, 8H, 4 Â H-20,60); 9.81 (s, 4H, 4 Â OH); 13C-NMR
(DMSO-d6): ꢀ 89.5, 90.3 (4 Â C-2); 97.8, 98.1 (4 Â C-7); 112.0, 112.3, 112.3,
112.5 (4 Â C-3a, 4 Â C-5); 125.8, 126.0 (4 Â C-40); 127.1, 127.2
(4 Â C-20,30,50,60); 128.7 (4 Â C-4); 130.9, 131.9 (4 Â C-10); 167.3, 167.4
(4 Â C-6); 172.4, 172.8 (4 Â C-7a); 192.6, 193.0 (4 Â C-3); 13C NMR

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3(2H )-BENZOFURANONE DERIVATIVES
2335
(Pyridine-d5): ꢀ 90.5, 91.5 (4 Â C-2); 98.7, 98.9 (4 Â C-7); 112.8, 112.9 (4 Â C-
5); 113.1, 113.6 (4 Â C-3a); 126.0, 126.2 (4 Â C-40); 127.2, 127.3, 128.2, 128.3
(4 Â C-20,30,50,60); 128.6, 128.7 (4 Â C-4); 132.9, 133.0 (4 Â C-10); 168.5, 168.7
(4 Â C-6); 173.4, 173.9 (4 Â C-7a); 193.4, 193.9 (4 Â C-3). According to the
NMR data the product was a mixture of the two possible dimeric forms
(meso and d,l). Their separation was not performed. MS m/z (%): 450 (0.2),
226 (100), 225 (83), 197 (78), 120 (26), 92 (20), 77 (20). Anal. calcd. for
C28H18O6: C, 74.66; H, 4.03. Found: C, 74.43; H, 4.31.
6-Hydroxy-2-phenyl-3(2H)-benzofuranone (13), Method A: The reac-
tion was performed according to given in Ref. [9c]: gaseous HCl was
introduced into
a mixture of resorcinol (4, 3.1 g, 28 mmol), a-
chlorophenylacetonitrile (11, 3.9 g, 26 mmol) and freshly dried, ground
ZnCl2 (0.5 g, 3.7 mmol) in dry diethyl ether (40 mL) at 0–5ꢁC for 4 h. The
reaction mixture was stored in refrigerator for 2 days and evaporated to
dryness. The residue was refluxed in 1% HCl (150 mL) for 6 h. The reaction
mixture was cooled, extracted with ethyl acetate (3 Â 50 mL). The organic
extract was dried over Na2SO4, filtered and concentrated. The residue (5.8 g
of brown oil) was chromatographed on silica gel with CHCl3/n-
hexane ¼ 2 : 1, CHCl3 and CHCl3/ethyl acetate ¼ 3 : 1 to give 13 (0.35 g,
5.9%) as white crystals, m.p. 164–167ꢁC (changed, melted at 285–290ꢁC)
Lit.[9c] m.p. 284–286ꢁC); IR (KBr): 3165, 3072, 2966, 1679, 1600, 1500, 1246,
1208, 1110, 1030, 850, 750 cmÀ1; 1H NMR (CDCl3): ꢀ 5.54 (s, 1H, H-2), 6.60
(dd, J ¼ 8.2 Hz, J ¼ 2.1 Hz, 1H, H-5), 6.62, (d, J ¼ 2.1 Hz, 1H, H-7), 7.39
(m, 5H, H-20,30,40,50,60), 7.58 (d, J ¼ 8.2 Hz, 1H, H-4); H NMR (C6D6): ꢀ
1
5.11 (s, 1H, H-2), 5.15 (s, 1H, OH), 6.04 (dd, J ¼ 8.5 Hz, J ¼ 2.1 Hz, 1H, H-
5), 6.19 (d, J ¼ 2.1 Hz, 1H, H-7), 7.06 (m, 3H, H-30,40,50), 7.34 (m, 2H, H-
20,60), 7.39 (d, J ¼ 8.5 Hz, 1H, H-4); 1H NMR (DMSO-d6): ꢀ keto-form
(13a): 5.78 (s, 1H, H-2), 6.61 (d, J ¼ 1.8 Hz, 1H, H-7), 6.62, (dd,
J ¼ 8.5 Hz, J ¼ 1.8 Hz, 1H, H-5), 7.29 (m, 2H, H-20,60), 7.38 (m, 3H, H-
30,40,50), 7.50 (d, J ¼ 8.5 Hz, 1H, H-4), 11.10 (s, 1H, 6-OH); enol-form
(13b): 6.72 (dd, J ¼ 8.5 Hz, J ¼ 2.1 Hz, 1H, H-5), 6.83, (d, J ¼ 2.1 Hz, 1H,
H-7), 7.18 (m, 1H, H-40), 7.38 (m, 3H, H-30,50), 7.55 (d, J ¼ 8.5 Hz, 1H, H-4),
7.86 (m, 2H, H-20,60), 9.64 (s, 1H, 3-OH), 9.91 (s, 1H, 6-OH); 13C NMR
(DMSO-d6): ꢀ keto-form (13a): 86.2 (C-2), 98.5 (C-7), 111.8 (C-3a), 112.7
(C-5), 126.3 (C-40), 126.5 (C-20,60,4), 129.0 (C-30,50), 131.4 (C-10), 167.6 (C-6),
175.1 (C-7a), 196.3 (C-3); enol-form (13b): 97.9 (C-7), 112.0 (C-5), 116.5
(C-3a), 119.8 (C-4), 123.0 (C-30,50), 125.7 (C-40), 128.8 (C-20,60), 134.6 (C-
10), 135.2 (C-2), 137.4 (C-3), 153.1 (C-6), 156.6 (C-7a); MS m/z (%): 226
(100), 197 (69), 120 (54), 92 (19), 63 (10). Anal. calcd. for C14H10O3: C,
74.33; H, 4.46. Found: C, 74.36; H, 4.58.
Method B: A stirred mixture of 7 (2.63 g, 10 mmol) and dry sodium
acetate (1.64 g, 15 mmol) in ethanol (25 mL) was refluxed for 20 min. The

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2336
BOKOTEY ET AL.
solvent was evaporated, the residue was tritrated with hot toluene (30 mL),
filtered and cooled. The precipitated crystals were filtered off, washed
with n-hexane (2 Â 10 mL) to give 13 (1.06 g, 46.9%) as white crystals,
m.p. 166–169ꢁC (changed, melted at 285–290ꢁC). The compound was iden-
tical with that obtained earlier.
Reaction of 1-(2-hydroxy-4-methoxyphenyl)-2-phenylethanone (14a)
with diethyl bromomalonate: A mixture of ketone 14a[16] (1.8 g, 7.4 mmol),
diethyl bromomalonate (2.73 g, 1.95 mL, 11.4 mmol) and dry K2CO3
(3.15 g, 23 mmol) in methyl ethyl ketone (24 mL) was refluxed for 12 h. The
mixture was filtered off while hot and washed with hot methyl ethyl ketone.
The organic solvent was evaporated, the residue was suspended in diethyl
ether (10 mL), the crystals were filtered off washed with ethanol and diethyl
ether to give D,L-(6-methoxy-2-phenyl-3(2H)-benzofuranon-2yl)-6-methoxy-
2-phenyl-3(2H)-benzofuranone (15a, 0.5 g, 28.1%), m.p. 248–250ꢁC; IR
(KBr): 3057, 3012, 2975, 2940, 2890, 2844, 1715, 1620, 1496, 1444, 1339,
1
1288, 1208, 1185, 1154, 1118, 1085, 1050, 1020 cmÀ1; H NMR (CDCl3): ꢀ
3.84 (s, 6H, 2 Â OCH3), 6.54 (dd, J ¼ 1.9 Hz, J ¼ 8.5 Hz, 2H, 2 Â H-5), 6.57,
(d, J ¼ 1.9 Hz, 2H, 2 Â H-7), 7.24 (m, 4H, 2 Â H-30,50), 7.33 (m, 2H, 2 Â H-40),
7.44 (d, J ¼ 8.5 Hz, 2H, 2 Â H-4), 7.57 (m, 4H, 2 Â H-20,60); 13C NMR
(CDCl3): ꢀ 55.8 (2 Â OCH3), 91.2 (2 Â C-2), 96.1 (2 Â C-7), 111.7 (2 Â C-5),
114.7 (2 Â C-3a), 125.6 (2 Â C-40), 127.2 (2 Â C-30,50), 127.8 (2 Â C-20,60),
128.7 (2 Â C-4), 131.8 (2 Â C-10), 168.2 (2 Â C-6), 173.2 (2 Â C-7a), 193.9
(2 Â C-3); MS m/z (%): 478 (2.6), 327 (4), 239 (100), 211 (14), 134 (8), 77
(11). Anal. calcd. for C30H22O6: C, 75.30; H, 4.63. Found: C, 75.36; H, 4.72.
The mother liquor was concentrated and chromatographed on silica
gel to give different compounds.
1-(2-hydroxy-4-methoxyphenyl)-2-phenylethanone (14a, 30 mg, 1.7%).
Recovered starting material.
meso-(6-Methoxy-2-phenyl-3(2H)-benzofuranone3-2-yl)-6-methoxy-2-
phenyl-3(2H)-benzofuranone (16a, 0.5 g, 28.1%), m.p. 193–195ꢁC; IR
(KBr): 3065, 2976, 2839, 1712, 1613, 1595, 1499, 1447, 1339, 1277, 1200,
1
1185, 1162, 1118, 1100, 1085, 1023 cmÀ1; H NMR (DMSO-d6): ꢀ 3.86 (s,
6H, 2 Â OCH3), 6.69 (dd, J ¼ 2 Hz, J ¼ 8.6 Hz, 2H, 2 Â H-5), 6.91, (d,
J ¼ 1.9 Hz, 2H, 2 Â H-7), 7.26 (m, 4H, 2 Â H-30,50), 7.33 (m, 2H, 2 Â H-
40), 7.41 (m, 4H, 2 Â H-20,60), 7.48 (d, J ¼ 8.6 Hz, 2H, 2 Â H-4); 13C NMR
(DMSO-d6): ꢀ 56.7 (OCH3), 89.8 (C-2), 96.7 (C-7), 112.6 (C-5), 113.3
(C-3a), 125.9 (C-40), 127.5 (C-30,50), 127.5 (C-20,60), 129.2 (C-4), 132.0
(C-10), 168.7 (C-6), 173.5 (C-7a), 193.6 (C-3). Anal. calcd. for C30H22O6:
C, 75.30; H, 4.63. Found: C, 75.21; H, 4.63.
2-((Di-(ethoxycarbonyl))methyl)-6-methoxy-2-phenyl-3(2H)-benzofura-
none hydrate (17a, 100 mg, 3.2%, pale yellow viscous oil); IR (KBr): 3064,
2983, 2934, 1739, 1616, 1595, 1498, 1447, 1370, 1279, 1158, 1099, 1025 cmÀ1
;

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3(2H )-BENZOFURANONE DERIVATIVES
2337
1H NMR (CDCl3) ꢀ 0.97 (t, J ¼ 7.1 Hz, 3H, CH2CH3), 1.01 (t, J ¼ 7.1 Hz,
3H, CH2CH3), 3.91 (s, 3H, OCH3), 4.02 (q, J ¼ 7.1 Hz, 2H, CH2CH3), 4.05
(q, J ¼ 7.1 Hz, 2H, CH2CH3), 4.66 (s, 1H, CH ), 6.65 (dd, J ¼ 2.1 Hz,
J ¼ 8.6 Hz, 1H, H-5), 6.80, (d, J ¼ 2.1 Hz, 1H, H-7), 7.30 (m, 3H,
H-30,40,50), 7.54 (d, J ¼ 8.6 Hz, 1H, H-4), 7.60 (m, 2H, H-20,60); 13C NMR
(CDCl3): ꢀ 13.6 (CH2CH3), 13.9 (CH2CH3), 55.9 (OCH3), 58.8 (CH), 89.3
(C-2), 96.4 (C-7), 112.0 (C-5), 113.1 (C-3a), 124.9 (C-20,60), 126.0 (C-4),
128.4 (C-30,50), 128.5 (C-40), 135.1 (C-10), 165.4 (C¼O), 165.8 (C¼O),
168.2 (C-6), 174.0 (C-7a), 196.2 (C-3); FAB-MS measured (MþH)þ:
399.1494. Required for C22H22O7: 399.1444. Anal. calcd. for
C22H22O7 Â H2O: C, 63.45; H, 5.81. Found: C, 63.36; H, 6.14.
6-Methoxy-2-(5-methoxy-2-phenylacetylphenoxy)-2-phenyl-3(2H)-ben-
zofuranone (18, 0.4 g, 22.8%, pale yellow solid foam); IR (KBr): 3064, 3035,
2970, 2942, 2841, 1721, 1675, 1616, 1497, 1441, 1340, 1280, 1197, 1157, 1099,
1015, 972 cmÀ1; H NMR (CDCl3): ꢀ 3.66 (s, 3H, 500-OCH3), 3.93 (s, 3H,
1
6-OCH3), 4.40 (s, 2H, CH2), 6.55 (dd, J ¼ 2.3 Hz, J ¼ 8.7 Hz, 1H, H-400),
6.66, (d, J ¼ 2.1 Hz, 1H, H-7), 6.67, (d, J ¼ 2.3 Hz, 1H, H-600), 6.68 (dd,
J ¼ 2.1 Hz, J ¼ 8.6 Hz, 1H, H-5), 7.19 (m, 3H, H-3000,4000,5000), 7.24 (m, 2H,
H-2000,6000), 7.39 (m, 3H, H-30,40,50), 7.55 (d, J ¼ 8.5 Hz, 1H, H-4), 7.61 (d,
J ¼ 8.7 Hz, 1H, H-300), 7.69 (m, 2H, H-20,60); 13C NMR (CDCl3): ꢀ 49.9
(CH2), 55.4 (OCH3), 56.1 (OCH3), 96.4 (C-7), 106.4 (C-600), 106.5 (C-2),
109.6 (C-400), 111.1 (C-3a), 112.7 (C-5), 124.7 (C-200), 126.3 (C-20,60), 126.4
(C-40), 126.9 (C-4), 128.2 (C-2000,6000), 128.8 (C-30,50), 129.8 (C-3000,4000,5000),
132.2 (C-300), 133.2 (C-10), 135.3 (C-1000), 153.6 (C-100), 162.8 (C-500), 169.2
(C-6), 172.8 (C-7a), 191.6 (C-3), 198.6 (C¼O). Anal. calcd. for C30H24O6: C,
74.98; H, 5.03. Found: C, 74.71; H, 5.21.
Diethyl malonate: (19, 0.55 g, 29.9%, colourless oil); 1H-NMR
(CDCl3): ꢀ 1.26 (t, J ¼ 7.2 Hz, 6H, CH2CH3), 3.34 (s, 2H, CH2), 4.18 (q,
J ¼ 7.2 Hz, 4H, CH2CH3). The compound was identical with an authentic
sample.
Diethyl 2,3-bis-ethoxycarbonylsuccinate: (20, 30 mg, colourless heavy
1
oil); H NMR (CDCl3): ꢀ 1.28 (t, J ¼ 7.2 Hz, 12H, CH2CH3), 4.14 (s, 2H,
CH), 4.22 (q, J ¼ 7.2 Hz, 8H, CH2CH3); FAB-MS measured (MþH)þ:
319.1335. Required for C14H22O8: 319.1393.
Reaction of 1-(2-hydroxy-4-(2-propoxy)phenyl)-2-phenylethanone (14b)
with diethyl bromomalonate: A mixture of ketone 14b[17] (0.68 g, 2.5 mmol),
diethyl bromomalonate (0.91 g, 0.65 mL, 3.8 mmol) and dry K2CO3 (1.05 g,
7.6 mmol) in methyl ethyl ketone (8 mL) was refluxed for 5 h. The mixture
was filtered off while hot and washed with hot methyl ethyl ketone
(2 Â 5 mL). The organic solvent was evaporated, the residue was suspended
in hot n-hexane (10 mL), the solvent was decanted and the procedure was
repeated 2 times. The residue (100 mg) was suspended in hot ethanol

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2338
BOKOTEY ET AL.
(10 mL). the crystals were filtered off washed with ethanol to give D,L-(6-
(2-propoxy)-2-propoxy)-2phenyl-3(2H)-benzofuranone-2-yl)-6-(2-propoxy)-2-
phenyl-3(2H)-benzofuranone (15b, 80 mg, 11.9%), m.p. 261–263ꢁC; IR
(KBr): 3075, 3057, 2978, 2935, 2869, 1712, 1616, 1591, 1494, 1443, 1386,
1374, 1278, 1184, 1162, 1115, 1098, 1053, 1002, 833 cmÀ1 1H NMR
;
(CDCl3): ꢀ 1.35 (d, J ¼ 6.1 Hz, 6H, CH(CH3)2), 1.37 (d, J ¼ 6.1 Hz, 6H,
CH(CH3)2), 4.60 (m, 2H, 2 Â CH(CH3)2), 6.50 (dd, J ¼ 2.0 Hz, J ¼ 8.5 Hz,
2H, 2 Â H-5), 6.56, (d, J ¼ 1.9 Hz, 2H, 2 Â H-7), 7.25 (m, 6H, 2 Â H-30,40,50),
7.43 (d, J ¼ 8.6 Hz, 2H, 2 Â H-4), 7.61 (m, 4H, 2 Â H-20,60); 1H NMR
(DMSO-d6): ꢀ 1.32 (d, J ¼ 6.3 Hz, 12H, 2 Â CH(CH3)2), 4.76 (m, 2H,
2 Â CH(CH3)2), 6.60 (dd, J ¼ 8.8 Hz, J ¼ 1.6 Hz, 2H, 2 Â H-5), 6.71 (d,
J ¼ 1.6 Hz, 1H, 2 Â H-7), 7.27 (m, 6H, 2 Â H-30,40,50), 7.39 (d, J ¼ 8.8 Hz,
2H, 2 Â H-4), 7.53 (m, 4H, 2 Â H-20,60); 1H NMR (C6D6): ꢀ 0.86 (d,
J ¼ 6.0 Hz, 12H, 2 Â CH(CH3)2), 3.84 (m, 2H, 2 Â CH(CH3)2), 6.21 (dd,
J ¼ 8.9 Hz, J ¼ 1.8 Hz, 2H, 2 Â H-5), 6.34 (d, J ¼ 1.8 Hz, 1H, 2 Â H-7),
7.07 (m, 2H, 2 Â H-40), 7.14 (m, 4H, 2 Â H-30,50), 7.37 (d, J ¼ 8.9 Hz, 2H,
2 Â H-4), 8.11 (m, 4H, 2 Â H-20,60); 1H NMR (CF3COOD): ꢀ 1.45 (d,
J ¼ 6.2 Hz, 12H, 2 Â CH(CH3)2), 4.77 (m, 2H, 2 Â CH(CH3)2), 6.62 (dd,
J ¼ 8.8 Hz, J ¼ 1.6 Hz, 2H, 2 Â H-5), 6.76 (d, J ¼ 1.6 Hz, 1H, 2 Â H-7),
7.25 (m, 6H, 2 Â H-30,40,50), 7.45 (d, J ¼ 8.8 Hz, 2H, 2 Â H-4), 7.86 (m, 4H,
2 Â H-20,60); 13C NMR (CDCl3): ꢀ 21.7 (CH(CH3)2), 2.19 (CH(CH3)2), 70.8
(2 Â CH(CH3)2), 91.1 (2 Â C-2), 97.1 (2 Â C-7), 112.7 (2 Â C-5), 114.2 (2 Â C-
3a), 125.6 (2 ÂC-40), 127.2, 127.8 (2 Â C-20,30,40,50), 128.6 (2 Â C-4), 132.0
(2 Â C-10), 166.6 (2 Â C-6), 173.2 (2 Â C-7a), 193.8 (2 Â C-3); 13C NMR
(DMSO-d6): ꢀ 21.2 (2 Â CH(CH3)2), 70.9 (2 Â CH(CH3)2), 90.4 (2 Â C-2),
97.6 (2 Â C-7), 112.3 (2 Â C-5), 113.5 (2 Â C-3a), 124.8 (2 Â C-40), 126.7
(2 Â C-30,50), 126.9 (2 Â C-20,60), 128.2 (2 Â C-4), 131.8 (2 Â C-10), 166.4
(2 Â C-6), 172.2 (2 Â C-7a), 192.4 (2 Â C-3); 13C NMR (C6D6): ꢀ 21.2
(CH(CH3)2), 21.3 (CH(CH3)2), 70.2 (2 Â CH(CH3)2), 91.8 (2 Â C-2), 97.2
(2 Â C-7), 112.6 (2 Â C-5), 114.9 (2 Â C-3a), 125.9 (2 Â C-40), 127.3 (2 Â
C-30,50), 128.4 (2 Â C-20,60), 128.7 (2 Â C-4), 132.8 (2 Â C-10), 166.5 (2 Â C-
6), 173.3 (2 Â C-7a), 193.3 (2 Â C-3); 13C NMR (CF3COOD); ꢀ 22.6
(CH(CH3)2), 22.7 (CH(CH3)2, 75.5 (2 Â CH(CH3)2), 94.5 (2 Â C-2), 99.5
(2 Â C-7), 115.7 (2 Â C-3a), 117.8 (2 Â C-5), 128.8 (2 Â C-40), 129.4 (2 Â
C-30,50), 130.4 (2 Â C-20,60), 132.0 (2 Â C-4), 133.0 (2 Â C-10), 172.4 (2 Â C-
6), 178.5 (2 Â C-7a), 201.7 (2 Â C-3). Anal. calcd. for C34H30O6: C, 76.39; H,
5.66. Found: C, 76.43; H, 5.92.
The mother liquor was concentrated and chromatographed on silica
gel to give different compounds.
meso-(6-(2-Propoxy)-2-phenyl-3(2H)-benzofuranone-2-yl)-6-(2-propoxy)-2-
phenyl-3(2H)-benzofuranone: (16b, 87 mg, 12.9%), m.p. 197–199ꢁC; IR (KBr):
3064, 3035, 2980, 2927, 1711, 1615, 1588, 1491, 1444, 1385, 1272, 1181, 1161,

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3(2H )-BENZOFURANONE DERIVATIVES
2339
1
1113, 1097, 1032, 1014 cmÀ1; H NMR (CDCl3): ꢀ 1.32 (d, J¼ 6.1 Hz, 12H,
CH(CH3)2), 4.58 (m, 2H, CH(CH3)2), 6.46, (d, J¼ 2.0 Hz, 2H, 2 Â H-7), 6.52
(dd, J¼ 2Hz, J¼ 8.6 Hz, 2H, 2 Â H-5), 7.20 (m, 4H, 2 Â H-30,50), 7.25 (m, 2H,
2Â H-40), 7.45 (d, J¼ 8.6 Hz, 2H, 2 Â H-4), 7.49 (m, 4H, 2 Â H-20,60);
13CNMR (CDCl3): ꢀ 21.7 (CH(CH3)2), 21.8 (CH(CH3)2), 70.8 (2 Â
CH(CH3)2), 90.4 (2 Â C-2), 97.0 (2 Â C-7), 112.6 (2 Â C-5), 113.9 (2 Â C-3a),
125.8 (2 Â C-40), 127.0 (2 Â C-30,50), 127.8 (2 Â C-20,60), 128.6 (2 Â C-4), 132.0
(2 Â C-10), 166.7 (2 Â C-6), 173.6 (2 Â C-7a), 194.3 (2 Â C-3). Anal. calcd. for
C32H30O6: C, 75.28; H, 5.92. Found: C, 75.30; H, 5.61.
X-ray measurement: The data were collected at room temperature
using the !-2ꢁ scan technique. Omega scans of several intense reflections,
made prior to data collection, had an average width at half-height of 0.20ꢁ
with a take-off angle of 6.0ꢁ. Scans of (1.00 þ 0.30 tan ꢁ)ꢁ were made at a
speed of 8.0ꢁ/min (in !). The weak reflections (I<10.0ꢂ(I)) were rescanned
(maximum of 4 scans) and the counts were accumulated to ensure good
counting statistics. The data were collected for Lorentz and polarization
effect, but no absorption correction was applied. The structure was solved
by direct methods using SHELXS-86 and refined using SHELXL-93. The
non-hydrogen atoms were refined anisotropically. Hydrogen atoms were
included but not refined. Refinement was based on F2 for all reflections.
Weighted R-factors wR and all goodnesses of fit S are based on F2, conven-
tional R-factors R are based on F, with F set to zero for negative F2. The
final cycle of full-matrix least-squares refinement on F was based on 776
observed reflections (I>2.00ꢂ(I)) and 184 variable parameters.
Crystal data: C17H14O3, colourless plate crystal, 0.30 Â 0.25 Â
0.10 mm, M ¼ 266.28, monoclinic, P21/c, a ¼ 9.666(3) A, b ¼ 8.834(4) A,
c ¼ 15.736(12) A, ꢃ ¼ 94.71(7) V ¼ 1339.1(12) A3, D ¼ 1.321 g ¼ cmÀ3
,
Z ¼ 4. Collected data range: 4.59<Â<75.24 (À 7 ꢂ h ꢂ 12, À 9 ꢂ h ꢂ 11,
À 19 ꢂ h ꢂ 18); 2809 reflections collected, 2656 symmetry-independent reflec-
tions. Goodness of fit for all 1.033, for observed 1.193. Final R ¼ 0.2712 (for
all 2656) R ¼ 0.0635 (for observed 776), wR ¼ 0.2512 (for all), wR ¼ 0.1456
(for observed).
2 - ((Di-(ethoxycarbonyl))methyl)-6-(2-propoxy)-2-phenyl-3(2H)-benzo-
furanone (17b, 64 mg, 6.4%, pale yellow viscous oil); IR (KBr): 3069, 2979,
2933, 1738, 1711, 1614, 1592, 1492, 1446, 1370, 1274, 1159, 1096, 1034 cmÀ1
;
1H NMR (CDCl3): ꢀ 0.93 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 0.97 (t, J ¼ 7.2 Hz,
3H, CH2CH3), 1.39 (d, J ¼ 5.8 Hz, 6H, CH(CH3)2), 3.96 (q, J ¼ 7.2 Hz, 2H,
CH2CH3), 4.01 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 4.65 (m, 1H, CH(CH3)2), 4.66
(s, 1H, CH), 6.61 (dd, J ¼ 2.1 Hz, J ¼ 8.6 Hz, 1H, H-5), 6.75 (d, J ¼ 2.1 Hz,
1H, H-7), 7.29 (m, 3H, H-30,40,50(phenyl)), 7.51 (d, J ¼ 8.6 Hz, 1H, H-4),
7.60 (m, 2H, H-20,60(phenyl)); 13C NMR (CDCl3): ꢀ 13.4 (CH2CH3), 13.5
(CH2CH3), 21.7 (CH(CH3)2), 21.8 (CH(CH3)2), 58.8 (CH), 61.3 (CH2CH3),

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2340
BOKOTEY ET AL.
61.9 (CH2CH3), 70.9 (CH(CH3)2), 89.2 (C-2), 97.4 (C-7), 112.6 (C-3a), 112.9
(C-5), 124.8 (C-20,60), 126.0 (C-4), 128.3 (C-40), 128.4 (C-30,50), 135.3 (C-10),
165.3 (C¼O), 165.8 (C¼O), 166.7 (C-6), 174.0 (C-7a), 196.0 (C-3). Anal.
calcd. for C24H26O7: C, 67.59; H, 6.15. Found: C, 67.57; H, 6.23.
Diethyl malonate: (19, 0.21 g, 34.4%). The compound was identical
with an authentic sample.
Reaction of 1-(2-hydroxy-4-(2-propoxy)phenyl)-2-phenylethanone (14b)
with diethyl chloromalonate: A mixture of ketone 14b (1.35 g, 5 mmol),
diethyl chloromalonate (1.6 g, 1.4 mL, 8 mmol) and dry K2CO3 (2.1 g,
15 mmol) in methyl ethyl ketone (15 mL) was refluxed for 5.5 h. The mixture
was filtered off while hot and washed with hot methyl ethyl ketone
(2 Â 10 mL). The organic solvent was evaporated; the residue was chroma-
tographed on silica gel to give different products.
D,L-(6-(2-Propoxy)-2-phenyl-3(2H)-benzofuranone-2-yl)-6-(2-propoxy)-
2-phenyl-3(2H)-benzofuranone: (15b, 20 mg, 0.7%), m.p. 261–263ꢁC. The
compound was identical with that obtained earlier.
meso-(6-(2-Propoxy)-2-phenyl-3(2H)-benzofuranone-2-yl)-6-(2-propoxy)-
2-phenyl-3(2H)-benzofuranone: (16b, 19mg, 0.7%), m.p. 197–199ꢁC. The
compound was identical with that obtained earlier.
2-((Di-(ethoxycarbonyl))methyl)-6-(2-propoxy)-2-phenyl-3-(2H)-benzo-
furanone: (17b, 0.18 g, 8.3%). The compound was identical with that
obtained earlier.
Diethyl malonate: (19, 0.21 g, 16.5%). The compound was identical
with an authentic sample.
3-Benzyl-2-ethoxycarbonyl-6-(2-propoxy)benzofurane: (21, 0.13 g,
1
7.7%, pale yellow viscous oil); H NMR (CDCl3): ꢀ 1.35 (d, J ¼ 5.3 Hz,
6H, CH(CH3)2), 1.40 (t, J ¼ 7.1 Hz, 3H, CH2CH3), 4.44 (m, 4H, CH2–Ph
and CH2CH3), 4.52 (m, 1H, CH(CH3)2), 6.81 (dd, J ¼ 2.2 Hz, J ¼ 8.7 Hz,
1H, H-5), 7.01 (d, J ¼ 2.2 Hz, 1H, H-7), 7.17 (m, 1H, H-40), 7.24 (m, 2H,
H-30,50), 7.31 (m, 3H, H-4 and H-20,60); H NMR (C6D6): ꢀ 1.02 (m, 9H,
1
CH(CH3)2 and CH2CH3), 4.04 (m, 1H, CH(CH3)2), 4.13 (q, J ¼ 7.1 Hz,
2H, CH2CH3), 4.45 (s, 2H, CH2–Ph), 6.77 (dd, J ¼ 2.2 Hz, J ¼ 8.7 Hz, 1H,
H-5), 6.82 (d, J ¼ 2.2 Hz, 1H, H-7), 7.00 (m, 1H, H-40), 7.07 (m, 2H,
H-30,50), 7.11 (d, J ¼ 8.7 Hz, 1H, H-4), 7.29 (m, 2H, H-20,60); 13C NMR
(CDCl3):
ꢀ
14.3 (CH2CH3), 21.7 (2 Â CH(CH3)2), 30.1 (CH2–Ph),
60.9 (CH2CH3), 70.3 (CH(CH3)2), 97.3 (C-7), 114.7 (C-5), 121.3 (C-3a),
122.0 (C-4), 126.2 (C-40), 128.3, 128.4 (C-20,30,50,60), 128.5 (C-3), 138.9
(C-10), 140.2 (C-2), 155.9 (C-6), 158.7 (C-7a), 160.2 (C¼O); 13C NMR
(C6D6):
ꢀ
14.3 (CH2CH3), 21.7 (2 Â CH(CH3)2), 30.5 (CH2–Ph),
60.7 (CH2CH3), 70.1 (CH(CH3)2), 97.3 (C-7), 115.2 (C-5), 121.8 (C-3a),
122.5 (C-4), 126.5 (C-40), 128.0 (C-3), 128.8, 128.9 (C-20,30,50,60),
139.7 (C-10), 141.1 (C-2), 156.5 (C-6), 159.3 (C-7a), 160.3 (C¼O); MS

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3(2H )-BENZOFURANONE DERIVATIVES
2341
m/z (%): 338 (80), 294 (46.7), 267 (84.7), 250 (100), 221 (30), 165 (50), 91
(12), 77 (8).
Reaction of 1-(2,4-dimethoxy)phenyl-2-phenylethanone (22) with diethyl
bromomalonate: A mixture of ketone 22[16] (1.92 g, 7.5 mmol), diethyl bro-
mamalonate (2.73 g, 1.95 mL, 11.4 mmol) and K2CO3 (3.15 g, 22.8 mmol) in
methyl ethyl ketone (24 mL) was refluxed for 12 h. The mixture was filtered
off while hot and washed with hot methyl ethyl ketone (2 Â 10 mL). The
organic solvent was evaporated, the residue was chromatographed on silica
gel with CH2Cl2 to give 3 different products.
1-(2,4-Dimethoxy)phenyl-2-phenylethanone: (22), yield: 1.2 g (62.5%).
Recovered starting material.
2-Bromo-1-(2,4-dimethoxy)phenyl-2-phenylethanone: (23a), yield: 0.62 g
(24.7%; based on the recovered starting material: 66%), m.p. 105–107ꢁC;
1H NMR (CDCl3): ꢀ 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.40 (d,
J ¼ 2.3 Hz, 1H, H-7), 6.54 (dd, J ¼ 8.8 Hz, J ¼ 2.3 Hz, 1H, H-5), 6.65 (s,
1H, CH–Ph), 7.31 (m, 3H, H-30,40,50), 7.47 (m, 2H, H-20,60), 7.86 (d,
J ¼ 8.8 Hz, 1H, H-4); 13C NMR (CDCl3): ꢀ 55.5 (OCH3, C-1), 55.6
(OCH3), 98.3 (C-7), 105.9 (C-5), 118.4 (C-3), 128.5 (C-40), 128.6 (C-30,50),
129.3 (C-20,60), 134.2 (C-4), 136.9 (C-10), 160.1, 165.6 (C-6, C-8), 191.4
(C¼O); MS m/z (%): 334 (0.1), 279 (0.4), 256 (1.7), 240 (1.8), 227 (3.7),
211 (2), 197 (0.5), 181 (1.1), 165 (100), 91 (7.3).
Diethyl 2,3-(diethoxycarbonyl)fumarate: (24), yield: 1.65 g (91.7%),
m.p. 55–57ꢁC [lit.,[18] m.p. 55–56ꢁC]; IR (KBr): 2976, 2942, 1740, 1616,
;
1458, 1369, 1253, 1096, 1027, 859 cmÀ1 1H NMR (CDCl3): ꢀ 1.32 (t,
J ¼ 7.2 Hz, 12H, CH2CH3), 4.32 (q, J ¼ 7.2 Hz, 8H, CH2CH3). Anal.
calcd. for C14H20O8: C, 53.16; H, 6.37. Found: C, 53.00; H, 6.20.
Reaction of 1-(2,4-dimethoxy)phenyl-2-phenylethanone: (22) with diethyl
chloromalonate: A mixture of ketone 22 (1.28 g, 5 mmol), diethyl chloroma-
lonate (1.69 g, 1.3 mL, 8.7 mmol) and K2CO3 (2.1 g, 15.2 mmol) in methyl
ethyl ketone (16 mL) was refluxed for 6 h. The mixture was filtered off while
hot and washed with hot methyl ethyl ketone (2 Â 10 mL). The organic
solvent was evaporated; the residue was chromatographed on silica gel
with CH2Cl2 to give 4 different products.
1-(2,4-Dimethoxy)phenyl-2-phenylethanone (22), yield: 1.2 g (93.7%).
Recovered starting material.
Diethyl chloromalonate: (0.4 g, 23.7%). Recovered starting material.
2-Chloro-1-(2,4-dimethoxy)phenyl-2-phenylethanone: (23b), yield: 40 mg
(2.7%; based on the recovered starting material: 44.4%), m.p. 103–105ꢁC;
IR (KBr): 3012, 2976, 2942, 2835, 1764, 1740, 1677, 1621, 1598, 1498, 1452,
1
1413, 1300, 1263, 1198, 1099, 1021, 802 cmÀ1; H NMR (CDCl3): ꢀ 3.83 (s,
3H, OCH3), 3.86 (s, 3H, OCH3), 6.38 (d, J ¼ 2.2 Hz, 1H, H-7), 6.52 (dd,
J ¼ 2.3 Hz, J ¼ 8.8 Hz, 1H, H-5), 6.58 (s, 1H, CH–Ph), 7.30 (m, 3H, H-

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2342
BOKOTEY ET AL.
30,40,50), 7.41 (m, 2H, H-20,60), 7.84 (d, J ¼ 8.8 Hz, 1H, H-4); 13C NMR
(CDCl3): ꢀ 55.4 (OCH3), 55.5 (OCH3), 65.4 (C-1), 98.2 (C-7), 105.8 (C-5),
118.6 (C-3), 128.5 (C-40), 128.6, 128.7, (C-20,30,50,60), 134.0 (C-4), 136.8
(C-10), 160.0, 165.0 (C-6, C-8), 191.6 (C¼O); MS m/z: 290, 227, 165, 150,
135, 125, 122, 107, 91. Anal. calcd. for C16H15ClO3: C, 66.10; H, 5.20.
Found: C, 66.02; H, 5.55.
Diethyl 2,3-(diethoxycarbonyl)fumarate (24): yield: 1.32 g (73.4%),
m.p. 55–57ꢁC. The compound was identical with that obtained earlier.
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3(2H )-BENZOFURANONE DERIVATIVES
2343
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Received in the USA May 22, 2001

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