A facile one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones

Article abstract of DOI:10.1016/S0968-0896(01)00388-1

An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-diarylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the 'hard soft acid base' principle. The reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones. Copyright

Full text of DOI:10.1016/S0968-0896(01)00388-1

Bioorganic & Medicinal Chemistry 10 (2002) 1137–1142
A Facile One-Pot Synthesis of
4,5-Diaryl-2,2-dimethyl-3(2H)-furanones
Ki-Wha Lee, Young Hoon Choi, Yung Hyup Joo, Jin Kwan Kim, Song Seok Shin,
Young Joo Byun, Yeonjoon Kim and Shin Chung*
Drug Discovery, Pacific Corporation R&D Center, 314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-729, South Korea
Received 3 September 2001; accepted 23 October 2001
Abstract—An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-dia-
rylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the ‘hard soft acid base’ principle. The
reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives
other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
tion is not cost-effective due to the expensive nature of
palladium reagents, (2) the coupling reaction often
Recently, a novel class of 4,5-diaryl-2,2-dimethyl-3(2H)-
furanone derivatives 1 has been reported to possess
strong oral anti-inflammatory potency originating from
their selective inhibition of cyclooxygenase-2 over
cyclooxygenase-1.1 It is notable that 3(2H)-furanone
derivatives showed extremely high potency in adjuvant
arthritis by therapeutic model. In particular, compound
1a showed an adjuvant arthritis ED50 of 0.03 mg/kg/day
(daily once and oral). In the same measurement condi-
tions, blockbuster comparator celecoxib showed an
adjuvant arthritis ED50 of 0.2 mg/kg/day. Such pro-
nounced activities of 1 in adjuvant arthritis would be
one of the strongest among the reported cyclooxygease-
2 inhibitors of 1,2-diarylalkene type or its structural
equivalent.2 Thus, 3(2H)-furanone derivatives 1 could
be a promising candidate for clinical evaluation against
arthritis (Fig. 1).
requires chromatographic separation for purification of
the coupling products, and (3) the purified coupling
products are still likely to be contaminated with a sig-
4
nificantamountof residual palladium species,
which
would often make such a scale-up process incompatible
with good manufacturing practice (GMP) guidelines.
Furthermore, our experience with Scheme 1 suggests
that many of the reactions of Scheme 1 require chro-
matographic purification.1 Thus, a huge amountof
efforts should be needed to solve the issue of purifica-
tion in order for Scheme 1 to be a cost-effective scale-up
process for our developmentcandidate.
In this article, an efficient process will be presented
where 4,5-diaryl-2,2-dimethyl-3(2H)furanone deriva-
tives 1 can be prepared through a one-pot reaction
starting from 1,2-diarylethanones by adopting ‘hard
5
softacid base (HSAB)’ principle.
Previously, 3(2H)-furanone derivatives 1 were prepared
as described in Scheme 1,1 involving Suzuki coupling3 as
a key reaction. Even though the Suzuki coupling reac-
tion played an essential role in generating structural
diversity for structure–activity relationship assessment,
the coupling reaction may not be appropriate for scale-
up synthesis of the specific candidate among 1 due to
the following several reasons: (1) Suzuki coupling reac-
Results and Discussion
In order to prepare 1 by a process compatible with
GMP guidelines, a retrosynthetic consideration was
applied to the structure of 1 to identify the key synthons
of 1,2-diarylethanone 26 and 2-bromoisobutyryl bro-
mide or its structural equivalent (Scheme 2). Scheme 2 is
quite simple and straightforward, and may be an
attractive option for a scale-up process for 3(2H)-fura-
none derivatives 1.
*Corresponding author. Tel.: +82-31-280-5910; fax: +82-31-281-
8391; e-mail: schung@pacific.co.kr
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00388-1

1138
K.-W. Lee et al. / Bioorg. Med. Chem. 10 (2002) 1137–1142
Figure 1.
Scheme 1. (i) n-BuLi (2.2 equiv), THF; (ii) 4-(methylthio)benzaldehyde (81% in two steps); (iii) MnO2, CH2Cl2 (81%); (iv) Et2NH, MeOH (75%);
(v) OXONE1, THF/MeOH/H2O; (vi) bis(trifluoroacetoxy)iodobenzene, I2, CCl4 (82% in two steps); (vii) arylboronic acid, Pd(PPh3)4, aq NaHCO3/
toluene/EtOH (40–70%).
Scheme 2. Retrosynthetic analysis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones 1.
Scheme 2 addresses a classical issue of ‘C- versus O-
acylation’ to an ambivalent enolate. Learning from
ample documented cases for selective C-acylation of an
enolate, two simple approaches were conceived to effect
selective C-acylation.7 Increase of covalency between
the enolate oxygen and a counter metal ion tends to
make C-acylation favorable. On the other hand, by the
choice of an appropriate soft electrophile, it is possible
to make the balance between C- and O-acylation shift to
the desired C-acylation. In this study, both possibilities
were examined and the latter approach turned out to be
operative significantly better for construction of the
3(2H)-furanone derivatives.
the enolate from reacting with 2-bromoisobutyryl bro-
mide.8 Usually the reaction of the enolate yielded many
products amenable to chromatographic separation,
which mightnotbe suiat ble for scale-up in ht is specific
case of 3(2H)-furanones.
In order to solve the ‘C- versus O-acylation’ issue, we
replaced 2-bromoisobutyryl bromide with 2-bromo-
isobutyryl cyanide,9 an extreme case of soft electrophile.
When the sodium enolate 2 was reacted with 2-bromo-
isobutyryl cyanide, the C-acylation reaction became
highly dominant.10 Interestingly, the C-acylation pro-
duct 4 was further cyclized completely to 3(2H)-fura-
nones in the presence of excess base, ‘sodium hydride’ in
this case. In other words, the reaction of 2-bromo-
isobutyryl cyanide can be further optimized to be a one-
potsynhtesis of 3( 2H)-furanone derivatives 5 from
appropriate 1,2-diarylethanones. In the one-pot reac-
tion, the cyclization product 5 was isolated as crystals in
good to excellent yield in many cases (Table 1).11 Such
generality appears to work for many derivatives of 5,
which makes the 2-bromoisobutyryl cyanide an attrac-
tive choice of electrophile for a scale-up process com-
patible with GMP guidelines.
When the sodium enolate 2 was reacted with commer-
cially available 2-bromoisobutyryl bromide in THF at
0 ꢀC, mainly O-acylation product 3 was isolated (see
Experimental for 3c). Switching the counter ion to
magnesium from sodium yielded C-acylation product 4
predominantover O-acylation product 3 (see Experi-
mental of Method B for 5b). An attempt to effect the
C-acylation by using lithium enolate was not successful,
suggesting that the lithium enolate might not possess
covalency strong enough to screen the oxygen atom of

K.-W. Lee et al. / Bioorg. Med. Chem. 10 (2002) 1137–1142
1139
Scheme 3. (i) Sodium bis(trimethylsilyl)amide, 2-bromoisobutyryl cyanide, THF; (ii) NaH, THF; (iii) OXONE1, THF/MeOH/H2O.
Table 1. One-potsynthesis of 3( 2H)-furanone 5 from 1,2-diaryletha-
nonesa and 2-bromoisobutyryl cyanide in the presence of NaH
Table 2. Cyclization of 1-aryl-1-alkanones using 2-bromoisobutyryl
cyanide (Scheme 3)
Entry
R1
Z
Yield of 5 (%)b
Entry
R2
Z
Yield of 8 or 9 (%)
1
2
3
4
5
6
7
3-F, 5-F
3-F
H
H
3-Cl
CH3S
CH3S
H
CH3S
CH3S
CH3S
CH3S
5a
5b
5c
5d
5e
5f
71
81
65
80
77
57
40
1
2
3
4
5
6
CH3
CH(CH3)2
C(CH3)3
Cyclohexyl
Heptyl
CH3S
CH3S
CH3S
CH3S
F
8a
8b
8c
8d
9a
9b
66
8a
a,b
—
—
a
20
31
4-NO2
4-CH3O
Pentyl
F
5g
aPoor reaction yields for these cases might suggest a clue to a potential
side reaction.12
b2-Bromo-3,3-dimethyl-1-[4-(methylthio)phenyl]-1-butanone (11) was
obtained as a major product in 37% yield.
aR1 and Z are the same as those of 2 in Scheme 2.
bYields were not optimized and might be subject to improvement.
Actual synthetic examples are presented in the Experi-
mental to manifest that the reaction of 2-bromoisobu-
tyryl cyanide would find a broad range of application in
the construction of 3(2H)-furanone derivatives. It is
notable that it would be difficult to prepare 8 or 9 through
Suzuki coupling reaction as in Scheme 1. Thus, 2-
bromoisobutyryl cyanide should be a reagent of choice
to prepare 2,2-dimethyl-3(2H)-furanone derivatives.
Figure 2.
The following synthetic example demonstrates well the
simplicity and efficiency of this one-pot reaction between
2-bromoisobutyryl cyanide and the sodium enolate of
1,2-diarylethanone: To a stirred solution of 2-(3-fluoro-
phenyl)-1-[4-(methylthio)phenyl]ethanone (2b, 100 g,
384 mmol) in anhydrous THF (1000 mL) at0 ꢀC, was
added 95% sodium hydride (26 g, 1.03 mol) portion-
wise. The reaction mixture was stirred for an hour at the
same temperature, to which was added drop-wise 2-
bromoisobutyryl cyanide (69 g, 392 mmol). Then the
mixture was allowed to warm to room temperature, and
stirred for another 5 h. The reaction was quenched by
slowly adding water drop-wise. The mixture was con-
centrated under reduced pressure, and then the resulting
residue was extracted with ethyl acetate and brine. The
organic layer was dried over MgSO4, and concentrated
in vacuo. The residue was purified by recrystallization
from MeOH to give 102 g of 2,2-dimethyl-4-(3-fluoro-
phenyl)-5-[4-(methylthio)phenyl]-3(2H)-furanone (5b,
81%; see Experimental for physical data).
Conclusion
An efficientone-potsynhtesis for 4,5-diaryl-2,2-dime-
thyl-3(2H)-furanone derivatives was achieved from 1,2-
diarylethanones by applying the HSAB principle.
2-Bromoisobutyryl cyanide turned out to be a preferred
choice of soft electrophile for the one-pot-synthesis
leading to the novel class of orally active cyclooxygen-
ase-2 inhibitors. The scope of the one-pot reaction can
be further extended to 2,2-dialkyl-3(2H)-furanones, if
an appropriate 2-bromo-2,2-dialkylacetyl cyanide is
available.
Experimental
Reagents and solvents were obtained from commercial
suppliers and used as received, unless noted otherwise.
Dry solvents were purchased from Aldrich and used
without further drying manipulation. Column chroma-
tography was performed on silica gel (Merck, grade 60/
230–400 mesh). NMR (1H NMR; 300 MHz) spectra
were recorded on a Varian Gemini 2000 FT-NMR
spectrometer with TMS as an internal standard. Melt-
Even though the afore-mentioned one-pot synthesis
using 2-bromoisobutyryl cyanide was developed pri-
marily for the scale-up synthesis of COX-2 inhibitors 1,
the scope of the reaction can be extended to generate
structural diversity of 2,2-dimethyl-3(2H)-furanone
derivatives. For example, by replacing the 2-position of
aromatic group in 1,2-diarylethanone 2 with an alipha-
tic group, some 4-alkyl-5-aryl-2,2-dimethyl-3(2H)-fura-
none derivatives 8 and 9 could be generated (Scheme 3,
Table 2 and Fig. 2).
ing points were measured on
a Thomas-Hoover
melting point apparatus and are uncorrected. Mass
spectral analyses were carried out either in-house on
a Hewlett-Packard GC/MS (HP5890-2 GC+HP5971

1140
K.-W. Lee et al. / Bioorg. Med. Chem. 10 (2002) 1137–1142
Series Mass) or at the National Instrumentation Center
for Environmental Management (NICEM), Suwon,
Korea. High resolution mass spectra were recorded at
the Inter-University Center for Natural Science
Research Facilities at Seoul National University, Seoul,
Korea. Infrared spectra were recorded on a BioRad FT-
IR spectrometer (FTS-40).
pressure, and then the resulting residue was subjected to
extraction with ethyl acetate and brine. The organic
layer was concentrated in vacuo and the resulting resi-
due was purified by column chromatography (EtOAc–
hexane=1:10) to afford 5a (410 mg, 33%) as a solid.
2,2-Dimethyl-4,5-diphenyl-3(2H)-furanone (5c). By a
similar method employed for 5a, deoxybenzoin (2c,
200 mg, 1.02 mmol) was converted to 5c (176 mg, 65%)
as an oil after purification by column chromatography
(EtOAc–hexane=1:10), which turned into a solid upon
Typical procedure for the synthesis of 4,5-diaryl-2,2-di-
methyl-3(2H)-furanones. 4-(3,5-Difluorophenyl)-2,2-di-
methyl-5-[4-(methylthio)phenyl]-3(2H)-furanone (5a). To
prolonged standing. Mp 76.5–78 ꢀC; H NMR (CDCl3,
1
a
stirred solution of 2-(3,5-difluorophenyl)-1-[4-
300 MHz) d 1.55 (s, 6 H), 2.51 (s, 3H), 6.71–6.78 (m,
1H), 6.84–6.92 (m, 2H), 7.21 (d, J=8.7 Hz, 2H), 7.55 (d,
J=8.7 Hz, 2H); IR (neat, cmÀ1) 1694 (carbonyl), 1623,
1389; MS (EI) m/z 264 (M+); HRMS (EI) calcd for
C18H16O2 264.1150 (M+), found 264.1151.
(methylthio)phenyl]ethanone (2a, 5.86 g, 21.05 mmol) in
anhydrous THF (50 mL) at0 ꢀC was added 60%
sodium hydride (2.1 g, 52.5 mmol) portion-wise. The
reaction mixture was stirred for an hour at the same
temperature, to which was added drop-wise 2-bromoi-
sobutyryl cyanide (4.5 g, 25.57 mmol). Then the mixture
was allowed to warm to room temperature, and stirred
overnight. The reaction was quenched by slowly adding
water drop-wise. The mixture was concentrated under
reduced pressure, and then the resulting residue was
extracted with ethyl acetate and brine. The organic layer
was dried over MgSO4, and concentrated in vacuo. The
residue was purified by recrystallization from MeOH to
2,2-Dimethyl-5-[4-(methylthio)phenyl]-4-phenyl-3(2H)-
furanone (5d). By a similar method employed for 5a, 1-
[4-(methylthio)phenyl]-2-phenylethanone (2d, 2.0 g,
8.25 mmol) was converted to 5d (2.51 g, 80%) as a solid
after purification by recrystallization from MeOH. Mp
109–110 ꢀC; 1H NMR (CDCl3, 300 MHz) d 1.55 (s, 6H),
2.49 (s, 3H), 77.15–7.22 (m, 3H), 7.27–7.31 (m, 2H),
7.33–7.36 (m, 1H), 7.54 (d, J=8.7 Hz, 2H); IR (neat,
cmÀ1) 1693 (carbonyl), 1623, 1596, 1386; MS (EI) m/z
310 (M+); HRMS (EI) calcd for C19H18O2S 310.1027
(M+), found 310.1044.
give 5a (5.55 g, 71%) as a solid. Mp 122–123 ꢀC; H
1
NMR (CDCl3, 300 MHz) d 1.54 (s, 6H), 7.13 (d,
J=8.4 Hz, 2H), 7.24–7.37 (m, 6H), 7.58 (d, J=8.7 Hz,
2H); IR (neat, cmÀ1) 1696 (carbonyl), 1623, 1602, 1390;
MS (ESI) m/z 347 (MH+); HRMS (CI) calcd for
C19H17F2O2S 347.0918 (MH+), found 347.0920.
4-(3-Chlorophenyl)-2,2-dimethyl-5-[4-(methylthio)phe-
nyl]-3(2H)-furanone (5e). By
a
similar method
employed for 5a, 2-(3-chlorophenyl)-1-[4-(methylthio)-
phenyl]ethanone (2e, 11.4 g, 14.24 mmol) was converted
to 5e (10.98 g, 77%) as a solid after purification by
recrystallization from MeOH. Mp 85–86.5 ꢀC; 1H NMR
(CDCl3, 300 MHz) d 1.55 (s, 6H), 2.51 (s, 3H), 6.71–6.78
(m, 1H), 6.84–6.92 (m, 2H), 7.21 (d, J=8.7 Hz, 2H),
7.55 (d, J=8.7 Hz, 2H); IR (neat, cmÀ1) 1693 (car-
bonyl), 1609, 1596, 1361; MS (EI) m/z 344 (M+);
HRMS (EI) calcd for C19H17ClO2S 344.0638 (M+),
found 344.0627.
2,2-Dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio)phenyl]-
3(2H) - furanone (5b). Method A. The procedure was
described in the text. Mp 106–106.5 ꢀC; 1H NMR
(CDCl3, 300 MHz) d 1.55 (s, 6H), 2.50 (s, 3H), 6.97–7.11
(m, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.26–7.36 (m, 1H),
7.55 (d, J=9.0 Hz, 2H); IR (neat, cmÀ1) 1694 (car-
bonyl), 1617, 1599, 1387; MS (ESI) m/z 329 (MH+);
HRMS (CI) calcd for C19H17FO2S 329.1012 (MH+),
found 329.1008.
2,2-Dimethyl-5-[4-(methylthio)phenyl]-4-(4-nitrophenyl)-
3(2H)-furanone (5f). By a similar method employed for
5a, 1-[4-(methylthio)phenyl]-2-(4-nitrophenyl)ethanone
(2f, 1.0 g, 3.48 mmol) was converted to 5f (0.70 g, 57%)
as an oil after purification by column chromatography
(EtOAc–hexane=1:6), which turned into a solid upon
Method B. To a stirred slurry of bromomagnesium
diisopropylamide13 (8.45 mmol) in anhydrous diethyl
ether (50 mL) at À78 ꢀC was added drop-wise a solution
of 2-(3-fluorophenyl)-1-(4-methylthiophenyl)ethanone
(2b, 1.0 g, 3.84 mmol) dissolved in 10 mL anhydrous
THF. The reaction solution was stirred at room tem-
perature for an h, to which was added 2-bromoisobu-
tyryl bromide (1.06 g, 4.61 mmol) drop-wise at 0 ꢀC.
Then the mixture was allowed to warm to room tem-
perature, and stirred for another 2 h. The reaction was
quenched by addition of water. Then the mixture was
subjected to extraction with ethyl acetate and brine. The
organic layer was dried over MgSO4, and concentrated
under reduced pressure. The resulting residue was dis-
solved in anhydrous THF (50 mL), to which was added
95% sodium hydride (0.18 g, 7.12 mmol). After the
reaction solution was stirred for 2 h at room tempera-
ture, the reaction was quenched by drop-wise addition
of water. The mixture was concentrated under reduced
prolonged standing. Mp 90–92 ꢀC; H NMR (CDCl3,
1
300 MHz) d 1.57 (s, 6H), 2.51 (s, 3H), 7.21 (d,
J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.54 (d,
J=9.0 Hz, 2H), 8.21 (d, J=8.7 Hz, 2H); IR (neat, cmÀ1
)
1692 (carbonyl), 1597, 1514, 1344; MS (EI) m/z 355
(M+); HRMS (EI) calcd for C19H17NO4S 355.0878
(M+), found 355.0871.
2,2-Dimethyl-4-(4-methoxyphenyl)-5-[4-(methylthio)phe-
nyl]-3(2H)furanone)-furanone (5g). By a similar method
employed for 5a, 2-(4-methoxyphenyl)-1-[4-(methyl-
thio)phenyl]ethanone (2g, 3.01 g, 11.05 mmol) was con-
verted to 5g (1.51 g, 40%) as a solid after purification by
recrystallization from MeOH. Mp 116–117 ꢀC; 1H

K.-W. Lee et al. / Bioorg. Med. Chem. 10 (2002) 1137–1142
1141
NMR (CDCl3, 300 MHz) d 1.54 (s, 6H), 2.49 (s, 3H),
3.83 (s, 3H), 6.91 (d, J=9.0 Hz, 2H), 7.16 (d, J=8.7 Hz,
2H), 7.23 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H);
IR (neat, cmÀ1) 1693 (carbonyl), 1597, 1512, 1386; MS
(EI) m/z 340 (M+); HRMS (EI) calcd for C20H20O3S
340.1133 (M+), found 340.1131.
(80 mg, 0.29 mmol) was oxidized by a similar condition
as described for 10a. The resulting 10b (85 mg, 95%)
was obtained initially as an oil after purification by col-
umn chromatography (EtOAc–hexane=1:6), which
turned into a solid upon prolonged standing. Mp 83–
85 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 1.30 (d,
J=6.9 Hz, 6H), 1.43 (s, 6H), 2.83 (sept, J=6.9 Hz, 1H),
3.10 (s, 3H), 7.84 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.7 Hz,
2H); IR (neat, cmÀ1) 1694 (carbonyl), 1317; MS (EI)
m/z 308 (M+); HRMS (CI) calcd for C16H21O4S
309.1161 (MH+), found 309.1154.
Typical procedure for the synthesis of 4-alkyl-5-aryl-2,2-
dimethyl-3(2H)-furanones. 2,2-Dimethyl-4-methyl-5-[4-
(methylsulfonyl)phenyl]-3(2H)furanone)-furanone (10a).
To a stirred solution of 1-[4-(methylthio)phenyl]-1-pro-
panone (6a, 1.0 g, 5.55 mmol) in anhydrous THF
(15 mL) at À78 ꢀC was added sodium bis(trimethyl-
silyl)amide (11.1 mL of 1 M THF solution) drop-wise.
The reaction mixture was stirred for an hour at the same
temperature, to which was added 2-bromoisobutyryl
cyanide (1.46 g, 8.29 mmol) drop-wise at0 ꢀC. Then the
mixture was allowed to warm to room temperature, and
stirred for another 7 h. The reaction was quenched by
slowly adding water drop-wise. The mixture was con-
centrated under reduced pressure, and then the resulting
residue was extracted with ethyl acetate and brine. The
organic layer was dried over MgSO4, and concentrated
in vacuo. The resulting residue was dissolved in anhy-
drous THF (15 mL), to which was added 95% sodium
hydride (0.23 g 9.10 mmol) at0 ꢀC. After the reaction
solution was stirred at room temperature overnight, the
reaction was quenched by adding water drop-wise. The
mixture was concentrated under reduced pressure, and
then the resulting residue was subjected to extraction
with ethyl acetate and brine. The organic layer was
concentrated in vacuo and the resulting residue was
purified by column chromatography (EtOAc–hex-
ane=1:10) to afford 2,2-dimethyl-4-methyl-5-[4-
(methylthio)phenyl]-3(2H)-furanone (8a, 0.91 g, 66%)
2,2-Dimethyl-5-(4-fluorophenyl)-4-heptyl-3(2H)-furanone
(9a). By a similar method employed for 8a, 1-(4-fluoro-
phenyl)-1-nonanone (7a, 350 mg, 1.48 mmol) was con-
verted to 9a (90 mg, 20%) as an oil after purification by
column chromatography (EtOAc–hexane=1:15): 1H
NMR (CDCl3, 300 MHz) d 0.87 (m, 3H), 1.29 (m, 8H),
1.43 (s, 6H), 1.49 (m, 2H), 2.39 (dd, J=7.5, 8.1 Hz, 2H),
7.19 (m, 2H), 7.79 (m, 2H), IR (neat, cmÀ1) 2927, 1688,
1587, 1390, 1093, 844, MS (EI) m/z 304 (M+); HRMS
(EI) calcd for C19H25FO2 304.1839 (M+), found
304.1832.
2,2-Dimethyl-5-(4-fluorophenyl)-4-pentyl-3(2H)-furanone
(9b). To a stirred solution of 1-(4-fluorophenyl)-1-hepta-
none (7b, 410 mg, 1.97 mmol) in anhydrous THF (5 mL)
at À78 ꢀC was added sodium bis(trimethylsilyl)amide
(12 mL of 1 M THF solution) drop-wise. The reaction
mixture was stirred for an hour at the same tempera-
ture, to which was added 2-bromoisobutyryl cyanide
(500 mg, 2.84 mmol) drop-wise. Then the mixture was
allowed to warm to room temperature, and stirred for
another 7 h. The reaction was quenched by slowly add-
ing water drop-wise. The mixture was extracted with
ethyl acetate and brine. The organic layer was dried
over MgSO4, and concentrated in vacuo. The resulting
residue was purified by column chromatography
(EtOAc–hexane=1:15) to afford 9b (170 mg, 31%) as
an oil. 1H NMR (CDCl3, 300 MHz) d 0.88 (m, 3H), 1.32
(m, 4H), 1.44 (s, 6H), 1.51 (m, 2H), 2.39 (m, 2H), 7.19
(m, 2H), 7.80 (m, 2H), IR (neat, cmÀ1) 2928, 1690, 1610,
1508, 1390, 1093, 844, MS (EI) m/z 276 (M+); HRMS
(EI) calcd for C17H21FO2 276.1526 (M+), found
276.1540.
1
as an oil. H NMR (CDCl3, 300 MHz) d 1.45 (s, 6H),
1.99 (s, 3H), 2.54 (s, 3H), 7.34 (d, J=8.4 Hz, 2H), 7.75
(d, J=8.4 Hz, 2H). A solution of 8a (0.80 g, 3.22 mmol)
in tetrahydrofuran (20 mL), MeOH (20 mL), and water
(20 mL) was stirred with OXONE1 (5.94 g, 9.66 mmol)
for 3 h at room temperature. The mixture was con-
centrated under reduced pressure, and then the resulting
residue was subjected to extraction with ethyl acetate
and brine. The organic layer was dried over MgSO4,
and concentrated in vacuo. The residue was purified by
recrystallization from EtOAc/hexane to give 10a (0.85 g,
94%) as a solid. Mp 135.5–136.5 ꢀC; H NMR (CDCl3,
Typical procedure for O-acylation product. 1,2-Diphenyl-
vinyl 2 - bromo - 2 - methylpropionate (3c). To a stirred
solution of deoxybenzoin (2c, 500 mg, 2.55 mmol) in
1
300 MHz) d 1.47 (s, 6H), 2.03 (s, 3H), 3.10 (s, 3H), 8.02
(d, J=8.4 Hz, 2H), 8.09 (d, J=8.4 Hz, 2H); IR (neat,
cmÀ1) 1694 (carbonyl), 1315; MS (EI) m/z 280 (M+);
HRMS (EI) calcd for C14H16O4S 280.0769 (M+), found
280.0763.
ꢀ
anhydrous THF (10 mL) at0 C was added portion-wise
95% sodium hydride (193 mg 7.64 mmol). After stirring
at the same temperature for 1 h, 2-bromoisobutyryl
bromide (700 mg, 3.04 mmol) was added drop-wise.
Then the mixture was allowed to warm to room tem-
perature, and stirred for another 5 h. The reaction was
quenched by drop-wise addition of water. The mixture
was concentrated under reduced pressure, and then the
resulting residue was extracted with ethyl acetate and
brine. The organic layer was dried over MgSO4, and
concentrated in vacuo. The resulting residue was puri-
fied by recrystallization from ethyl acetate/hexane to
afford 3c (659 mg, 75%). Mp 42–44 ꢀC; 1H NMR
(CDCl3, 300 MHz) d 2.01 (s, 6H), 6.73 (s, 1H), 7.27–7.62
2,2-Dimethyl-4-isopropyl-5-[4-(methylsufonyl)phenyl]-
3(2H) - furanone (10b). By a similar method employed
for 8a, 3-methyl-1-[4-(methylthio)phenyl]-1-butanone
(6b, 1.0 g, 4.80 mmol) was converted to 2,2-dimethyl-4-
isopropyl-5-[4-(methylthio)phenyl]-3(2H)-furanone (8b,
102 mg, 8%) as an oil after purification by column
chromatography (EtOAc–hexane=1:10). 1H NMR
(CDCl3, 300 MHz) d 1.29 (d, J=6.9 Hz, 6H), 1.41 (s,
6H), 2.53 (s, 3H), 2.91 (sept, J=6.9 Hz, 1H), 7.32 (d,
J=8.7 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H). Then 8b

1142
K.-W. Lee et al. / Bioorg. Med. Chem. 10 (2002) 1137–1142
(m, 10H); IR (neat, cmÀ1) 1748 (carbonyl), 1448, 1253,
1136; MS (EI) m/z 344 and 346 (M+); HRMS (CI) calcd
for C18H18BrO2 345.0490 (MH+), found 345.0500.
3. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513. (b) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull.
Chem. Soc. Jpn. 1988, 61, 3008.
4. Zhang, T. Y.; Allen, M. J. Tetrahedron Lett. 1999, 40, 5813.
5. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987;
p 318.
6. 1,2-Diarylethanones were prepared by Friedel–Crafts reac-
tion of phenylacetyl chlorides with thioanisole using alumi-
num chloride in good yield, by using a similar procedure as
described in the following literature: Lee, S. H.; Lee, S.-G.;
Song, C. E.; Kim, I. O.; Chung, B. Y. Kor. J. Med. Chem.
1997, 7, 34.
7. March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley
& Sons: New York, 1985; p 436 and references therein.
8. The lithium enolates 2, prepared by treating with LDA or
n-BuLi at À78 ꢀC, were reacted with 2-bromoisobutyryl bro-
mide similarly as described in the Experimental for 3c.
9. 2-Bromoisobutyryl cyanide was prepared according to the
following literature: Herrmann, K.; Simchen, G. Synthesis
1979, 204.
10. When the acylation reaction was performed below
À30 ꢀC, the reaction stopped at the stage of the C-acylation
product and the cyclization reaction did not proceed. 1H
NMR data for 4d (Z=CH3S, R1=H): (CDCl3, 300 MHz) d
1.88 (d, J=8.1 Hz, 6H), 2.48 (s, 3H), 6.57 (s, 1H), 7.19–7.39
(m, 7H), 7.90 (d, J=8.7 Hz, 2H).
11. Some of 5 were isolated initially as an oil after column
chromatography, which frequently turned into a solid upon
prolonged standing.
Reaction of 3,3-dimethyl-1-[4-(methylthio)phenyl]-1-buta-
none with 2-bromoisobutyryl cyanide. 3,3-Dimethyl-1-[4-
(methylthio)phenyl]-1-butanone (6c, 1.0 g, 4.5 mmol)
was reacted with 2-bromoisobutyryl cyanide (1.2 g,
6.82 mmol), similarly as described for the preparation of
8a. Instead of the desired 4-t-butyl-2,2-dimethyl-5-[4-
(methylthio)phenyl]-3(2H)-furanone (8c), however, was
isolated a major product ascribable to 2-bromo-3,3-
dimethyl-1-[4-(methylthio)phenyl]-1-butanone (11) in
37.1% yield (0.50 g) after recrystallization from
MeOH.16 Mp 86–88 ꢀC; H NMR (CDCl3, 300 MHz) d
1
1.21 (s, 9H), 2.53 (s, 3H), 5.07 (s, 1H), 7.28 (d,
J=8.4 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H); IR (neat, cmÀ1
)
1685 (carbonyl), 1585, 1404, 1275; MS (EI) m/z 300 and
302 (M+); HRMS (CI) calcd for C13H18BrOS 301.0262
(MH+), found 301.0257.
Acknowledgements
We would like to thank Mrs. Hyea-Sook Shin and the
Inter-University Center for Natural Science Research
Facilities at Seoul National University for HRMS.
12. These results suggest that 2-bromoisobutyryl cyanide,
depending on the nature of an enolate, can be a brominating
agent reminiscent of cyanogen bromide reaction. Enolates of
strong basicity would undergo bromination rather than the
desired C-acylation. However, the unwanted bromination
might be circumvented by switching the bromine of 2-bromo-
ispbutyryl cyanide to chlorine, a harder atom for nucleophilic
attack by an enolate.
References and Notes
1. Shin, S. S.; Noh, M.-S.; Byun, Y. J.; Choi, J. K.; Kim, J. Y.;
Lim, K. M.; Ha, J.-Y.; Kim, J. K.; Lee, C. H.; Chung, S.
Bioorg. Med. Chem. Lett. 2001, 11, 165.
2. (a) Reitz, D. B.; Seibert, K. Ann. Rep. Med. Chem. 1995,
30, 179. (b) Carter, J. S. Exp. Opin. Ther. Pat. 2000, 10, 1011.
13. Krafft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24,
1345.