An improved and practical synthesis of 5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonylphenyl)-2-(5H)-furanone (DFP - A selective inhibitor of cyclooxygenase-2)

Article abstract of DOI:10.1016/j.tet.2003.08.021

DFP, a highly selective and potent COX-2 inhibitor, has been synthesized by a modified approach. Three modifications of the existing method enabled us to prepare DFP in good quantity.

Full text of DOI:10.1016/j.tet.2003.08.021

Tetrahedron 59 (2003) 7915–7920
An improved and practical synthesis of 5,5-dimethyl-3-(2-
propoxy)-4-(4-methanesulfonylphenyl)-2-(5H)-furanone
(DFP—a selective inhibitor of cyclooxygenase-2)q
*
Srinivas Padakanti, Manojit Pal and Koteswar Rao Yeleswarapu
*
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 050, India
Received 31 May 2003; revised 17 July 2003; accepted 13 August 2003
Abstract—DFP, a highly selective and potent COX-2 inhibitor, has been synthesized by a modified approach. Three modifications of the
existing method enabled us to prepare DFP in good quantity.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
ulceration, bleeding and perforation. In contrast COX-2 is
inducible by pro-inflammatory molecules and plays a major
role in the biosynthesis of PGs in inflammatory cells
(monocytes and macrophages).3a,d The traditional non-
steroidal anti-inflammatory drugs (NSAIDs) inhibit both
COX-1 and COX-2 and thus down regulate the PGs in
almost all cells and tissues. This accounts for their anti-
inflammatory activity as well as undesired side effects
associated with their uses.3e However, selective inhibition
of COX-2 over COX-1 is beneficial for the treatment of
inflammatory diseases with reduced ulcerogenic side
effects. In accordance with this hypothesis, like rofecoxib,
DFP showed significantly reduced gastrointestinal side
effects and has been considered as a potent COX-2 inhibitor
for the treatment of chronic pain.
DFP [5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonyl-
phenyl)-2(5H)-furanone] 1, one of the most selective
cyclooxygenase-2 (COX-2) inhibitors recently discovered
by Merck,1 belongs to the 3,4-disubstituted furanone class
of compounds that includes rofecoxib 22 (Fig. 1). DFP has
been shown to be a more potent and more selective inhibitor
of COX-2 isozyme than rofecoxib. Cyclooxygenase (COX),
the first enzyme involved in the biosynthesis of prosta-
glandins (PGs), prostacyclins and thromboxanes from
arachidonic acid, is known to exist in two distinct
isoforms,3a,b namely COX-1 and COX-2. COX-1 is consti-
tutively expressed in the kidney as well as in the gastro-
intestinal tract and is responsible for gastric cytoprotection
and for platelet aggregation.3c Thus interruption of COX-1
activity may lead to gastro-intestinal toxicity such as
In continuation with our ongoing project for the develop-
ment of selective COX-2 inhibitors4 we were in need of a
large quantity of DFP for an in-house experiment. A number
of methods have been described in the literature for the
synthesis of 3,4-diarylfuranones4d,e,5 including rofecoxib.6
However these methods were not suitable for the synthesis
of DFP because of its relatively different structural feature,
Figure 1. Structure of DFP (1) and rofecoxib (2).
q DRF Publication No. 192.
Keywords: anti-inflammatory agents; furanones; 2-isopropoxyacetic acid.
*
Corresponding authors. Tel.: þ91-40-2304-5439; fax: þ91-40-2304-
Scheme 1. Reported synthesis of DFP (Ref. 1): Reagents and conditions:
method A (a) ClCOCH2OAc, Py; (b) DBU; (c) PrI, Ag2CO3; method B
i
5438; e-mail: manojitpal@drreddys.com;
e-mail: koteswarraoy@drreddys.com
fax: þ91-40-304-5007;
i
(a) PrOCH2COOH, CMC, DMAP; (b) DBU or NaH.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.021

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S. Padakanti et al. / Tetrahedron 59 (2003) 7915–7920
namely the presence of an alkoxy side chain in place of an
aryl moiety at the C-3 position of the furanone ring. Thus a
different approach was adopted for the synthesis of DFP and
its analogues.1,7 The original synthesis1 of DFP is illustrated
in Scheme 1. The crucial steps for the synthesis of DFP
involve coupling of acetoxyacetyl chloride (method A) or
2-alkoxyacetic acid (method B) with the tertiary alcohol 3
followed by base-promoted intramolecular cyclization of
the resulting ester. Method B appeared as a better choice for
the preparation of DFP on large scale due to (a) availability
of the required reagents, (b) it does not involve the use of
a moisture sensitive acid chloride. Following method B we,
however, failed to prepare DFP in good yield even after
several attempts. Due to the presence of base-labile
methylsulfonyl (MeSO2-) group8a,b the cyclization step led
to the formation of a number of unidentified side products
along with the partial hydrolysis of ester8c thereby
decreasing the yield of the desired compound in a small-
scale preparation. On the other hand this step was found to
be sluggish when applied to the large-scale preparation of
DFP. Moreover, preparation of the tertiary alcohol 3 via
oxidation of the methylsulfanyl precursor often led to the
formation of 4-methylsulfonylbenzoic acid (via cleavage
of C–C bond)8d as a side product. Therefore, to establish a
more convenient method by addressing all these problems
we have modified the existing procedure to access an
improved and cost-effective method for the synthesis of
DFP in 10 g scale. Here, in this paper we wish to present
our modified synthesis of DFP using readily available and
inexpensive reagents.
(a) coupling of the a-hydroxyacetophenone 7 with 2-iso-
propoxyacetic acid 6 before oxidation of the methylsulfanyl
group, (b) replacement of the coupling reagent CMC
[1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-
p-toluenesulfonate] with less expensive DCC (1,3-dicyclo-
hexylcarbodiimide), (c) conversion of the methylsulfanyl
derivative 8 to the sulfone 1 in the last step. We have
also established a practical route for the synthesis of
2-isopropoxyacetic acid 6 as shown in Scheme 2.
The reported method1,9 for the synthesis of 2-isopropoxy-
acetic acid 6 involves nucleophilic displacement of chlorine
from sodium 2-chloroacetate by isopropanol in the presence
of sodium hydride. However in our hands sodium 2-chloro-
acetate participated in a self-condensation reaction to
provide a polymeric material when employed under the
same reaction conditions. To avoid this side reaction we
decided to use the protected acid in the form of its ester.
Thus commercially available ethyl-2-bromoacetate 4
reacted smoothly with sodium isopropoxide generated in
situ from metallic sodium and isopropanol to afford the
corresponding ether 5 in 82% yield. However, 5 was
characterized as its isopropyl ester rather than the ethyl one
due to the participation of the ethyl ester in a trans-
esterification reaction during the above conversion. Alka-
line hydrolysis of 5 in methanol provided the desired acid 6
in 94% yield. 2-Isopropoxyacetic acid was thus prepared in
77% overall yield.
The other key starting compound a-hydroxyacetophenone 7
was prepared1 by acylating thioanisole using 2-methylpro-
pionyl chloride in the presence of aluminium chloride
followed by hydroxylation10 at the tertiary center under
phase transfer conditions (Scheme 2). In our initial attempt
the hydroxylation was carried out according to the
procedure described earlier10d using a combination of
readily available NaOH, KCl and NaOCl at 258C for 20 h
in water. This procedure proved to be less efficient mainly
because of formation of the corresponding benzoic acid
2. Results and discussion
Our synthesis of DFP is shown in Scheme 2. We anticipated
that the presence of the methylsulfanyl (CH3S-) group in
place of the methylsulfone would favor the base mediated
cyclization reaction more efficiently without generating
undesired side products. Thus our modifications included
Scheme 2. Improved synthesis DFP: Reagents and conditions: (a) iPrOH, Na, reflux, 1 h. (b) 10% NaOH, MeOH, 858C, 1 h. (c) Isobutyryl chloride, AlCl3,
258C, 4 h. (d) NaOH, CCl4–toluene, Aliquat 336, 15–258C, 22 h. (e) 6, DCC, DMAP, CH2Cl2, 0–258C, 4 h. (f) DBU, CH3CN, 808C, 18 h. (g) Oxone,
acetone–H2O, 258C, 3 h.

S. Padakanti et al. / Tetrahedron 59 (2003) 7915–7920
7917
(,45% yield) as a side product. Thus we adopted the same
procedure that was used for the synthesis of DFP earlier and
the reaction was carried out smoothly using sodium
hydroxide and Aliquot 336 in a mixture of carbon tetra-
chloride and toluene. Hydroxyketone 7 was obtained in 71%
yield from thioanisole. Esterification of 7 with 2-isopropoxy-
acetic acid 6 was initially carried out using CMC and
DMAP (dimethylaminopyridine) in dichloromethane. How-
ever, low conversion (50%) and the cost of CMC were
major concerns of this process. Use of alternative coupling
agents such as a combination of DABCO and EDC [1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride]
in toluene was also attempted but only a marginal
improvement in yield was observed when compared with
the CMC-mediated esterification process. We therefore
focused on the use of the cheaper (than CMC) and still
effective coupling reagent DCC11 for the esterification.
Experimentally, the reaction was carried out using a-hydroxy-
acetophenone 7 (1 equiv.), 2-isopropoxyacetic acid 6
(1.4 equiv.), DCC (1.4 equiv.) and DMAP (0.4 equiv.) in
dichloromethane at 0–258C for 3 h. Good conversion was
observed and the desired ester was isolated in 75% yield
after usual work-up and purification.
performing any further purification procedure and was used
directly for pharmacological studies. We have used this
coupling-cyclization–oxidation reaction sequence to pre-
pare 10 g of DFP and applied this procedure for the large-
scale production of 1. To assess the merit of this new
strategy, the synthesis of DFP was carried out according to
the reported method as well as the present method
simultaneously. The original route via 2-isopropoxyacetic
acid (method B, Scheme 1) led to the synthesis of 1 in 23%
overall yield from the hydroxyketone 3 whereas the overall
yield from 7 was 40% (Scheme 2) according to the present
method. Moreover, we have observed remarkable improve-
ment in handling each step while following the new route
compared to the earlier one.
All the intermediates synthesized including the final com-
pound were characterized by 1H NMR and IR spectrometry
and by Mass spectrometry. Lactone 8 was identified by
the appearance of IR absorption at 1752 and 1627 cm21
(characteristic of highly substituted furanone ring) in its IR
spectra. The methylsulfanyl moiety of 8, which appeared at
2.52 ppm, was shifted to 3.07 ppm, a characteristic peak of
methylsulfone group attached to an aromatic ring, in the 1H
NMR spectra of 1 after the oxidation reaction.
The ester thus obtained was then treated with a base to
facilitate the intramolecular ring closure. A number of
bases including diisopropylamine, NaH and KOtBu were
examined for this purpose and all were found to be effective.
However, the duration of the reaction was 3 days in the case
of diisopropylamine and although the reaction was much
faster with the other two bases, use of a large quantity of
moisture-sensitive NaH or KOtBu was not acceptable for
safety reasons. Finally, DBU (1,8-diazabicyclo [5.4.0]
undec-7-ene) was used for this reaction. Experimentally
the reaction was carried out in acetonitrile at 808C for 18 h
to effect the intramolecular ring closure. After completion
the reaction mixture was quenched with 2N HCl in order to
neutralize the DBU and to effect the complete dehydration
of the intermediate 4-hydroxyfuranone generated during the
reaction. This also helped in separating out of the product as
a solid from the reaction mixture. Extraction followed by
purification of the crude product provided the lactone 8 in
54% yield. Unlike the original procedure1 (step b of method
B, Scheme 1) as mentioned earlier, cyclization proceeded
well in this case and no formation of side products was
observed. DBU mediated similar type of intramolecular ring
closure reaction of phenacyl ester in the presence of aerial
oxygen yielded corresponding maleic anhydrides rather
than desired furanones.4b,c We, however, did not observe
formation of any such products when the cyclization was
performed in the presence of atmospheric oxygen perhaps
due to the absence of methylene hydrogens in the furanone
ring of 8.
Mechanistically,4c the cyclization of ester proceeds through
a Dieckmann condensation reaction in the presence of DBU
followed by facile dehydration of the resulting 4-hydroxy-
furanone leading to the formation of lactone 8.
3. Conclusion
In conclusion, we have described an improved and efficient
method for the synthesis of a selective COX-2 inhibitor DFP
that allowed its preparation in large quantities. We also
developed a practical method for the synthesis of one of
its key starting materials i.e. 2-isopropoxyacetic acid. The
formation of a side product during the conversion of the
methylsulfanyl group to a methylsulfone was avoided by
shifting this oxidation step to the end of the reaction
sequence. Distinct advantages of this modified approach
over the published procedure are (a) smooth conversion and
cleaner reaction product at the crucial ring closure step (b)
cost-effectiveness and (c) robustness. The modified method
is therefore amenable for large-scale production of DFP.
The methodology has been utilized for the synthesis of a
similar class of compounds having anti-inflammatory
activities.4a Further applications of this procedure to more
complex systems are under active investigation.
4. Experimental
Oxidation of 8 was carried out using oxone (2KHSO5·-
KHSO4·K2SO4) in aqueous acetone to afford the final
compound 1 in quantitative yield. No over oxidation of the
resulting compound or partial cleavage of C–C bond (as
noted during preparation of the tertiary alcohol 3 according
to the procedure reported earlier) was observed in this step.
The reaction mixture was diluted with water to effect
product crystallization and the separated product was
isolated by filtration. Purity of 1 was achieved without
4.1. General methods
All the solvents used are commercially available. Reactions
were monitored by thin layer chromatography (TLC) on
silica gel plates (60 F254; Merck), visualizing with
ultraviolet light or Iodine spray. Flash chromatography
was performed on silica gel (SRL 230–400 mesh) using
distilled petroleum ether (40–608C), ethyl acetate, dichloro-
methane, chloroform and methanol. 1H and 13C NMR

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S. Padakanti et al. / Tetrahedron 59 (2003) 7915–7920
spectra were determined in CDCl3, DMSO-d6 or MeOH-d4
solution on Varian Gemini 200 and 50 MHz spectrometers
respectively. Proton chemical shifts (d) are relative to
tetramethylsilane (TMS, d¼0.00) as internal standard and
expressed in ppm. Spin multiplicities are given as s
(singlet), d (doublet), t (triplet) and m (multiplet) as well
as b (broad). Coupling constants (J) are given in hertz.
Infrared spectra were recorded on a Perkin–Elmer 1650
FT-IR spectrometer. UV spectra were recorded on
Shimadzu UV 2100S UV–VIS recording spectrophoto-
meter. Melting points were determined using Buchi melting
point B-540 apparatus and are uncorrected. Thermal
analysis data were generated with the help of Shimadzu
DSC-50 detector. MS spectra were obtained on a HP-5989A
mass spectrometer. Purity was determined by HPLC
(AGIL-AUTO) using the conditions specified in each
case: column, mobile phase (range used), flow rate (ranges
used), detection wavelength, retention times.
mixture at 258C with vigorous stirring. Stirring was
continued for 4 h at 258C and the mixture was then poured
into crushed ice (250 g) and extracted with chloroform
(3£200 mL). The combined organic layers were washed
with water (3£100 mL), dried over anhydrous Na2SO4 and
concentrated under vacuum to give the title compound
(70 g, 89% yield) as a pale yellow solid, mp 45–468C
1
(lit.,12b 44–458C); H NMR (CDCl3) 7.87 (d, J¼8.3 Hz,
2H), 7.26 (d, J¼8.3 Hz, 2H), 3.54–3.47 (m, 1H, CHMe2),
2.51 (s, 3H, SCH3), 1.20 (d, J¼6.8 Hz, 6H, CH3); IR (KBr,
cm21): 1677 (s, CvO), 1589 (s); MS (CI, i-Butane): 194
(Mþ, 100%).
4.1.4. Preparation of 2-hydroxy-2-methyl-1-(4-methyl-
sulfanylphenyl)-1-propanone (7).12c To a mixture of
2-methyl-1-(4-methylsulfanylphenyl)-1-propanone (70 g,
0.36 mol), Aliquot 336 (27 mL, 0.06 mol) and carbon
tetrachloride (51.5 mL, 0.53 mol) in toluene (100 mL) was
added NaOH (31.4 g, 0.786 mol) slowly and portion wise
over 30 min. The mixture was then stirred for 2 h at 158C
and 20 h at 258C. After completion of the reaction the
mixture was diluted with water (300 mL), acidified with 2N
HCl (100 mL) and extracted with ethyl acetate (3£200 mL).
The combined organic layers were washed with water
(2£200 mL), dried over anhydrous Na2SO4 and concen-
trated under vacuum. The crude compound thus obtained
was purified by column chromatography using 10%
EtOAc–petroleum ether to provide the title compound
(60 g, 80% yield) as colorless oil, bp 148–1498C at 0.1 Torr
(lit.,12c 1508C at 0.1 Torr); 1H NMR (CDCl3) 7.97 (d,
J¼8.5 Hz, 2H), 7.27 (d, J¼8.6 Hz, 2H), 4.13 (bs, 1H, OH),
2.51 (s, 3H, SCH3), 1.63 (s, 6H, CH3); IR (KBr, cm21):
3447 (bs, OH), 1666 (s, CvO), 1588 (s); MS (CI, i-Butane):
210 (Mþ, 100%).
4.1.1. Preparation of isopropyl-2-isopropoxyacetate
(5).12a Sodium metal (8 g, 0.35 mol) was added portionwise
to isopropanol (600 mL) at 258C with vigorous stirring and
the mixture was heated to reflux for 2 h. To this mixture was
added ethyl-2-bromoacetate (56.3 g, 0.33 mol) dropwise
over 2 h at refluxing temperature. The reaction mixture then
cooled to 258C and stirred for 48 h at the same temperature.
Solvent was removed under reduced pressure and the
residue was treated with water (400 mL). The aqueous
mixture was extracted with ethyl acetate (3£100 mL). The
organic layers were collected, washed with cold water
(2£100 mL), dried over anhydrous Na2SO4 and concen-
trated under vacuum to afford the title compound (40 g, 82%
yield) as a light brown oil, bp 162–1648C (lit.,12a 164.5–
166.58C); 1H NMR (CDCl3) 5.02–5.00 (m, 1H, –OCHMe2),
4.01 (s, 2H, CH2), 3.65–3.45 (m, 1H, –OCHMe2), 1.26–
1.17 (m, 12H, CH3); IR (KBr, cm21): 1751 (s, CvO); MS
(CI, i-Butane): 160 (Mþ, 38), 117 (100%).
4.1.5. Preparation of 1,1-dimethyl-2-(4-methylsulfanyl-
phenyl)-2-oxoethyl-2-isopropoxyacetate. To a mixture of
2-hydroxy-2-methyl-1-(4-methylsulfanylphenyl)-1-propa-
none (50 g, 0.24 mol), 2-isopropoxyacetic acid (40 g,
0.34 mol), DMAP (11.6 g, 0.09 mol) in dichloromethane
(500 mL) was added DCC (70.30 g, 0.34 mol) slowly over
30 min at 08C with stirring. The mixture was then warmed to
258C and stirring continued for 3 h. After completion of the
reaction the mixture was filtered through celite, the filtrate
was collected and concentrated under vacuum. The residue
was purified over silica gel using 8% EtOAc–petroleum
ether (2 L) to give the required ester (55 g, 75% yield) as
a colorless solid, mp 478C; 1H NMR (CDCl3) 7.91 (d,
J¼8.3 Hz, 2H), 7.21 (d, J¼8.3 Hz, 2H), 3.96 (s, 2H, CH2),
3.45–3.39 (m, 1H, CHMe2), 2.49 (s, 3H, SCH3), 1.65 (s,
6H, CH3), 1.09 (d, J¼6.9 Hz, 6H, CH3); 13C NMR (CDCl3,
50 MHz) d 197.71, 169.86, 145.25, 130.47, 128.99 (2C),
128.86, 124.80, 84.88, 72.49, 65.81, 25.27 (2C), 21.59 (2C),
14.63; IR (KBr, cm21): 1752 (s, CvO), 1681 (s, CvO),
1593 (s); IR (KBr, cm21): 1755 (s, O–CvO), 1681 (s,
CvO), 1589 (s); MS (CI, i-Butane): 310 (Mþ, 100%);
HRMS Calcd for C16H23O4S (MþHþ): 311.1317. Found:
311.1317.
4.1.2. Preparation of 2-isopropoxyacetic acid (6).9a To a
solution of isopropyl-2-isopropoxyacetate (40 g, 0.250 mol)
in methanol (200 mL) was added an aqueous solution of
10% NaOH slowly with stirring at 258C. The mixture was
then stirred for 1 h at the same temperature and methanol
was removed under vacuum. The aqueous mixture was then
washed with ethyl acetate (2£75 mL) and then acidified
with 2N HCl (100 mL). The mixture was extracted with
ethyl acetate (2£100 mL). The organic layers were
collected, combined and washed with water (2£100 mL),
dried over anhydrous Na2SO4 and concentrated under
vacuum to provide the title compound (30 g, 94% yield)
as a light yellow oil.9; 1H NMR (CDCl3) 8.05 (bs, 1H, OH),
4.01 (s, 2H, CH2), 3.74–3.59 (m, 1H, –OCHMe2), 1.21
(d, J¼6.1 Hz, 6H, CH3); IR (KBr, cm21): 3410 (bs), 1734
(s, CvO); MS (CI, i-Butane): 118 (Mþ, 30), 117 (100%).
4.1.3. Preparation of 2-methyl-1-(4-methylsulfanyl-
phenyl)-1-propanone.12b To a suspension of aluminium
chloride (63.0 g, 0.48 mol) in dichloromethane (250 mL)
was added 2-methylpropanoyl chloride (47 mL, 0.48 mol)
dropwise over 15 min at 08C. The reaction mixture was then
stirred at 258C for 2 h until a clear solution was obtained. A
solution of thioanisole (50 g, 0.403 mol) in dichloromethane
(200 mL) was added slowly and dropwise over 1.5 h to this
4.1.6. Preparation of 3-isopropoxy-5,5-dimethyl-4-(4-
methylsulfanylphenyl)-2,5-dihydro-2-furanone (8). To a
solution of 1,1-dimethyl-2-(4-methylsulfanylphenyl)-2-oxo-
ethyl-2-isopropoxyacetate (40 g, 0.129 mol) in acetonitrile

S. Padakanti et al. / Tetrahedron 59 (2003) 7915–7920
7919
Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.;
O’Neill, G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.;
Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Vickers, P.;
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Gordon, R.; Gresser, M.; Guay, J.; Kargman, S.; Kennedy, B.;
Leblanc, Y.; Leger, S.; Mancini, J.; O’Neill, G. P.; Ouellet, M.;
Patrick, D.; Percival, M. D.; Perrier, H.; Prasit, P.; Rodger, I.;
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(250 mL) was added DBU (38.4 ml, 0.258 mol) slowly over
15 min under a nitrogen atmosphere at 258C. The mixture
was stirred for 0.5 h at 258C and then heated to reflux for
18 h. The mixture was cooled to room temperature, diluted
with water (100 mL) and 2N HCl (50 mL) and then
extracted with EtOAc (3£100 mL). The organic layers
were collected, combined, washed with water (2£100 mL)
and dried over anhydrous Na2SO4. After removal of solvent
under vacuum the crude product was purified by column
chromatography over silica gel using 6% EtOAc–petro-
leum ether (400 ml) to give the desired product (10 g, 54%
yield) as a white semisolid; 1H NMR (CDCl3) 7.63 (d,
J¼8.3 Hz, 2H), 7.28 (d, J¼8.3 Hz, 2H), 5.11–5.05 (m, 1H,
CHMe2), 2.52 (s, 3H, SCH3), 1.64 (s, 6H, CH3), 1.27 (d,
J¼6.3 Hz, 6H, CH3); 13C NMR (CDCl3, 50 MHz) d 165.74,
141.18, 140.09, 139.07, 134.97, 128.17 (2C), 127.05 (2C),
85.91, 73.06, 26.61 (2C), 22.08 (2C), 15.90; IR (KBr,
cm21): 1752 (s, CvO), 1627 (s, CvC), 1593 (s); MS (CI,
i-Butane): 292 (Mþ, 25), 250 (80), 177 (100%); Anal. calcd
for C16H20O3S: C, 65.73; H, 6.89. Found: C, 65.70; H, 6.90.
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T. R. Indian J. Chem. 1986, 25B, 760. (c) Wakharkar, R. D.;
Deshpande, V. H.; Landge, A. B.; Upadhye, B. K. Synth.
Commun. 1987, 17, 1513. Synthesis via magnesium mediated
carbometallation of propargyl alcohols: (d) Forgione, P.;
Wilson, P. D.; Fallis, A. G. Tetrahedron Lett. 2000, 41, 17. and
references cited therein. Synthesis by palladium catalyzed
reactions (e) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992,
57, 6972. (f) Mahon, R.; Richecoeur, A. M. E.; Sweeney, J. B.
J. Org. Chem. 1999, 64, 328. (g) Rossi, R.; Bellina, F.; Raugei,
E. Synlett 2000, 1749, and references cited therein.
4.1.7. Preparation of 3-isopropoxy-5,5-dimethyl-4-(4-
methylsulfonylphenyl)-2,5-dihydro-2-furanone (1). To a
solution of 3-isopropoxy-5,5-dimethyl-4-(4-methylsulfanyl-
phenyl)-2,5-dihydro-2-furanone (10 g, 0.034 mol) in
acetone (200 mL) was added a solution of oxone (52.60 g,
0.086 mol) in water (200 mL). The reaction mixture was
stirred vigorously for 3 h at 258C. After completion of the
reaction the solvent was removed under reduced pressure
and water (200 mL) was added. The mixture was then
extracted with EtOAc (2£100 mL), organic layers collected,
combined, dried over anhydrous Na2SO4 and concentrated
under vacuum to give the title compound (11 g, 99% yield)
as an off white powder, mp 126–1278C; 1H NMR (CDCl3)
7.98 (d, J¼8.8 Hz, 2H), 7.83 (d, J¼8.8 Hz, 2H), 5.28–5.20
(m, 1H), 3.07 (s, 3H), 1.64 (s, 6H), 1.26 (d, J¼6.7 Hz, 6H);
13C NMR (CDCl3, 50 MHz) d 166.14, 140.78, 140.05,
139.97, 135.37, 128.47 (2C), 127.15 (2C), 82.91, 73.36,
43.93, 26.38 (2C), 22.28 (2C); IR (KBr, cm21): 1747 (s),
1652 (s), 1595 (s); MS (CI, i-Butane): 325 (Mþ, 100), 283
(40), 237 (20%). HPLC: 97.56%, Novapak C18 (150 mm),
water–acetonitrile (50:50), 1 mL/min, 290 nm, retention
time: 4.76 min. Anal. calcd for C16H20O5S: C, 59.24; H,
6.21. Found: C, 59.20; H, 6.22.
´
´
6. (a) Therien, M.; Gauthier, J. Y.; Leblanc, Y.; Leger, S.;
Perrier, H.; Prasit, P.; Wang, Z. Synthesis 2001, 1778. (b) For a
list of methods see: Sorbera, L. A.; Rabasseda, X.; Castaner, J.
Drugs Future 1998, 23, 1287.
Acknowledgements
The authors thank Dr A. Venkateswarlu, Dr R. Rajagopalan
and Professor J. Iqbal for their constant encouragement and
the Analytical Department for spectral support.
7. Leblanc, Y.; Roy, P.; Wang, Z.; Li, C. S.; Chauret, N.; Nicoll-
Griffith, D. A.; Silva, J. M.; Aubin, Y.; Yergey, J. A.; Chan,
C. C.; Riendeau, D.; Brideau, C.; Gordon, R.; Xu, L.; Webb, J.;
Visco, D. M.; Prasit, P. Bioorg. Med. Chem. Lett. 2002, 12, 3317.
8. For the generation of methylsulfonyl carbanion from MeSO2-
moiety in the presence of a base such as NaH or KOtBu and its
subsequent reaction with carbonyl group, see: (a) House, H. O.;
Larson, J. K. J. Org. Chem. 1968, 33, 61. (b) Becker, H.-D.;
Russell, G. A. J. Org. Chem. 1963, 28, 1896. (c) For the
cleavage of similar type of ester linkage, see: House, H. O.;
Wilkins, J. M. J. Org. Chem. 1976, 41, 3067. (d) Aakel, L. E.;
Launay, F.; Atlamsani, A.; Bregeault, J.-M. Chem. Commun.
2001, 21, 2218.
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