Synthesis of a 5-((Aryloxy)methyl)-3-(4-(trifluoromethyl)phenyl)[1,2,4] thiadiazole derivative: A promising PPARα,δ agonist

Article abstract of DOI:10.1021/op700141u

The preparation of the PPARα,δ agonist 2-methyl-2-(2-methyl-4- (3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazol-5-ylmethoxy)phenoxy)propionic acid sodium salt (17) is described and compared with earlier in-house preparations of this important target compound. Key concerns around a large-scale synthesis of this thiadiazole derivative were a large number of purification steps, the use of dichlorobenzene as a solvent, and a possible large-scale Baeyer-Villiger oxidation. This paper describes a straightforward preparation of the target agonist using methylhydroquinone (MHQ) as an inexpensive precursor that eliminates the need of an oxidation step.

Full text of DOI:10.1021/op700141u

Organic Process Research & Development 2007, 11, 1010–1014
Synthesis of a 5-((Aryloxy)methyl)-3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazole
Derivative: A Promising PPARr,δ Agonist
Michael Reuman,* Zhiyong Hu, Gee-Hong Kuo, Xun Li, Ronald K. Russell, Lan Shen, Scott Youells, and Yongzheng Zhang
Johnson and Johnson Pharmaceutical Research & DeVelopment, LLC, 1000 Route 202, Raritan, New Jersey 08869, U.S.A.
Scheme 1. Discovery Chemistry Route: Thiadiazole 4b
Abstract:
The preparation of the PPARr,δ agonist 2-methyl-2-(2-methyl-
4-(3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazol-5-ylmethoxy)phe-
noxy)propionic acid sodium salt (17) is described and compared
with earlier in-house preparations of this important target com-
pound. Key concerns around a large-scale synthesis of this
thiadiazole derivative were a large number of purification steps,
the use of dichlorobenzene as a solvent, and a possible large-scale
Baeyer–Villiger oxidation. This paper describes a straightforward
preparation of the target agonist using methylhydroquinone
(MHQ) as an inexpensive precursor that eliminates the need of
an oxidation step.
Introduction
purifications and, due to its toxicity, to avoid the use of
o-dichlorobenzene as a solvent in the dipolar addition step. The
latter issue was easily addressed by changing from o-dichlo-
robenzene (bp 178–180 °C) to o-xylene (bp 142 °C) at the cost
of a longer reaction time. To partially offset the longer reaction
time, the sequence of steps could be made more efficient by
combining the preparation of 2 and 3; therefore, the solvent
switch to o-xylene was also included in the first step. An
additional concern was the use of excess (2 equiv) of chloro-
carbonylsulfenyl chloride (ClCOSCl) for the initial preparation
of 2. This reagent presents a potential hazard, and the excess
reagent may have unexpected consequences if significant
residual amounts are carried over to the next operation. The
amount of this reagent was reduced to 1.2 equiv; to minimize
loss of ClCOSCl to the scrubber, the reaction temperature was
reduced from 110 °C (reflux in toluene) to 80 °C. With these
modifications at hand, amide 1 was prepared3 from the acid
chloride and NH4OH (100%) and converted to oxothiazolone
2 (Scheme 3) (xylene, 80 °C, 1.2 equiv of ClCOSCl); after this
step was complete (HPLC), 70% of the solvent volume was
removed by vacuum distillation to ensure removal of residual
ClCOSCl (bp 98 °C). Next, ethyl cyanoformate was added and
the temperature was increased to enable the dipolar addition to
occur.4 After this step was complete (5 days, determined by
HPLC and 1H NMR), the o-xylene was removed under vacuum.
The weight of the crude thiadiazole 3 indicated a 93% yield,
with a purity of 91.5% (area % at 210 nm). As this product
was of high purity, this material was converted directly to
alcohol 4a (NaBH4, THF–EtOH) in 85% yield from amide 1.
The NaBH4 reduction step required a much larger volume of
2-Methyl-2-(2-methyl-4-(3-(4-(trifluoromethyl)phenyl)[1,2,4]
thiadiazol-5-ylmethoxy)phenoxy)propionic acid sodium salt (17)
is a potent and selective PPARR/δ dual agonist with PPARR
EC50 ) 94 nM and PPARδ EC50 ) 3 nM.1 Compounds with
PPARR,δ agonist activity are important in the possible treatment
of metabolic disorders such as diabetes, hyperlipidemia, and
atherosclerosis.2 The discovery and synthesis of this key target
compound 17, initially carried out by our Discovery team, is a
convergent synthesis requiring the preparation and coupling of
the thiadiazole 4b (Scheme 1) and phenol 8 (Scheme 2). The
initial preparation has drawbacks that were of concern in a large-
scale preparation: these include the large number of chromato-
graphic separations, the use of dichlorobenzene (because of its
toxicity) as the solvent for the thiadiazole preparation, and the
Baeyer–Villiger (peracid) oxidation step. An additional restric-
tion that we faced was to limit the reaction temperature of the
dipolar addition step to 130-140 °C because of the heat transfer
medium and temperature capabilities in our local pilot plant
facilities.
Results and Discussion
The primary concerns for the scale-up of the thiadiazole
portion of our target was to eliminate the chromatographic
* To whom correspondence should be addressed.
(1) Shen, L.; Zhang, Y.; Wang, A.; Sieber-McMaster, E.; Chen, X.; Pelton,
P.; Xu, J. Z.; Yang, M.; Zhu, P.; Zhou, L.; Reuman, M.; Hu, Z.; Russell,
R.; Gibbs, A. C.; Ross, H.; Demarest, K.; Murray, W. V.; Kuo, G.-H.
J. Med. Chem. 2007, 50, 3954.
(2) (a) Leibowitz, M. D.; Fievet, C.; Hennuyer, N.; Peinado-Onsurbe, J.;
Duez, H.; Berger, J.; Cullinan, C. A.; Sparrow, C. P.; Baffic, J.; Berger,
G. D.; Santini, C.; Marquis, R. W.; Tolman, R. L.; Smith, R. G.; Moller,
D. E.; Auwerx, J. FEBS Lett. 2000, 473, 333. (b) Shi, Y.; Hon, M.;
Evans, R. M. Proc. Natl. Acad. Sci. USA 2002, 99, 2613. (c) Oliver,
W. R., Jr.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.;
Bodkin, N. L.; Lewis, M. C.; Winega, D. A.; Sznaidman, M. L.;
Lambert, M. H.; Xu, H. E.; Sternbach, D. D.; Kliewer, S. A.; Hansen,
B. C.; Willson, T. M Proc. Natl. Acad. Sci. USA 2001, 98, 5306.
(3) Suzuki, H.; Kimura, Y. J. Fluorine Chem. 1991, 52, 341 (describes
this method applied to a similar amide).
(4) The dipolar addition reaction of nitrile sulfides and ethyl cyanoformate
has been described in: Howe, R. K.; Franz, J. E. J. Org. Chem. 1974,
39, 962.
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10.1021/op700141u CCC: $37.00
2007 American Chemical Society
Published on Web 11/16/2007

Scheme 2. Discovery Chemistry Route: Phenol 8
quinone (MHQ).6 Without any attempt to improve this method,7
the less hindered phenol of MHQ was converted to the
triisopropylsilyl derivative 10 using TIPS triflate (67%); this
was alkylated with ethyl bromoisobutyrate to give the ether 11
(96%). Finally, removal of the TIPS blocking group (NH4F) gave
8, which was identical with the material prepared by the initial
route and avoided a large-scale oxidation step (Scheme 4).
Scheme 3. Improved Thiadiazole Preparation
Scheme 4. Preparation of Phenol 8
solvent than the prior step, and this necessitated a switch to a
larger flask. These modifications effectively compressed three
discrete steps and their respective workups into nearly a one-
pot sequence and gave 353 g of intermediate 4a in one
campaign without any chromatographic purification to this point.
A potential issue ahead was the possible preparation of 4b
(Scheme 1), as this was initially prepared using CBr4-Ph3P to
generate the bromide, thus mandating a purification step. It
seemed reasonable to consider an alternate coupling method,
not needing 4b; to this end the thiadiazole alcohol 4a was
converted into its mesylate derivative 4c. The mesylate was
easily prepared (MsCl, Et3N) in high purity (99%, HPLC),
needing no additional purification of any kind.
The next concern was the preparation of phenol intermediate
8. While the Baeyer–Villiger oxidation provides a direct
synthesis to 8 from 6, an approach that avoided m-CPBA or
any related oxidation on a large scale was important from a
safety standpoint.5 The most expeditious approach was to use
a published route starting from readily available methylhydro-
It was important to confirm the structure of 8 prepared by
the MHQ alternate method. To accomplish this, both isomers
were prepared on a small scale by unambiguous routes as their
acetates 14 and 15 (Scheme 5). The commercially available
acetophenone 12 was alkylated (ethyl bromoisobutyrate,
Cs2CO3) and subjected to Baeyer–Villiger conditions to provide
acetate 14. For comparison, phenol 8 was converted to acetate
15 (Ac2O, DMAP). These isomers were readily distinguished
by chemical shift differences in the H NMR. For example,
the aromatic CH3 groups for 14 and 15 had chemical shifts of
δ 2.11 and 2.22 ppm in CDCl3, respectively.
The coupling of the phenol and thiadiazole parts was
accomplished using the mesylate derivative 4c. This was
1
(6) (a) Stanton, J. L.; Cahill, E.; Dotson, R.; Tan, J.; Tomaselli, H. C.;
Wasvary, J. M.; Stephan, Z. F.; Steele, R. E. Bioorg. Med. Chem. Lett.
2000, 10, 1661. (b) Mazzinni, F.; Alpi, E.; Salvadori, P.; Netscher, T.
Eur. J. Org. Chem. 2003, 2840.
(7) (a) Other phenol blocking methods can be considered:Masada, H., Oishi,
Y. Chem. Lett. 1978, 57. (b) Stern, A.; Swenton, J. S. J. Org. Chem.
1987, 52, 2763. (c) Schmid, H. Monatsh. Chem. 1911, 32, 435.
(5) (a) Kubota, A.; Takeuchi, H. Org. Process Res. DeV. 2004, 8, 1076.
(b) Gillespie, J. S., Jr.; Acharya, S. P.; Shamblee, D. A.; Davis, R. E
Tetrahedron 1975, 31, 3. (c) Brand, W. W. Chem. Eng. News 1978,
56, 88. (d) For another alternative to the conventional Baeyer-Villiger
reaction see: Yoshida, A.; Hao, X.; Yamazaki, O.; Nishikido, J. QSAR
Comb. Sci. 2006, 25, 697 and references cited therein.
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Scheme 5. Structure Proof of Phenol 8
achieved by the addition of the potassium salt of 8 (KOt-Bu in
THF) in THF to a chilled (0–5 °C) solution of 4c in THF. After
extractive workup the ester 16 was obtained in 89% purity with
three impurities >1%. Crude 16 was subjected to flash
chromatography to provide the ester in 75% yield and 97%
purity. The target sodium salt 17 was obtained (NaOH, EtOH)
by hydrolysis (85%) in high purity (99% HPLC) (Scheme 6).
4a the solvent was changed to 60/40 MeCN/water (w/0.05%
TFA); for benzamide 1 a Phenomenex Luna C18 column (4.6
mm × 50 mm × 5 µM) using 30/70 MeCN/water (w/0.05%
TFA) with detection at 215 nm, for this method a gradient
starting at 30% MeCN (time ) 0), reaching 40% MeCN at 1
min, 90% MeCN at 4–8 min, and 30% MeCN at 10 min.
Preparation of 4-(Trifluoromethyl)benzamide (1). A 5 L
four-neck Morton flask equipped with an overhead stirrer,
thermocouple, addition funnel, and condenser was charged with
concentrated NH4OH (324.8 g, 5.35 mol) and water (2.0 L).
The mixture was stirred, and the acid chloride (360.0 g, 1.73
mol) was added portionwise from the addition funnel over 45
min. The reaction mixture was stirred at 20 °C for an additional
3 h. The solid was filtered, washed with water (2 × 1 L), and
air-dried followed by oven drying at 50 °C under house vacuum
Scheme 6. Coupling of Thiadiazole 4a and Phenol 8
1
(200 ( 50 mmHg) to provide amide 1 (325.4 g, 100%). H
NMR (DMSO-d6, 300 MHz): δ 8.2 (s, 1H, NH), 8.07 (m, 2H),
Conclusion
7.82 (m, 2H), 7.62 (s, 1H, NH).
An efficient, streamlined process was developed for the
preparation of thiadiazole 4a by conducting three steps sequen-
tially without the need for isolation. A safety concern was
addressed by the adoption of a literature method for the selective
blocking of MHQ, providing an alternative to a large-scale
Baeyer–Villiger oxidation. Finally, a coupling route for our
target precursor 16 was developed that avoided a potentially
difficult chromatographic purification of bromide 4b employed
in the initial synthesis. In this campaign, the preparations of
phenol 8 and its TIPS precursor 10 were not optimized and
these intermediates were subjected to column chromatography.
Outside of this, our target 17 was prepared in seven steps in
43% overall yield with only one chromatographic purification
after the preparation of ester 16.
Preparation of Thiadiazole 4a. Oxothiazolone 2. A 5 L
four-neck Morton flask was equipped with an overhead stirrer,
a condenser, a nitrogen inlet adapter, a thermocouple, and a
nitrogen bubbler, and a scrubber (Büchi Model B-414) was
connected to the end of the nitrogen bubbler. The reaction flask
was charged with amide 1 (300 g, 1.59 mol), o-xylene (2 L),
and ClCOSCl (249 g, 1.90 mol), followed by an additional
portion of o-xylene (1 L). The stirred mixture was slowly heated
to 80 °C, and the reaction progress was followed by HPLC.
After the reaction was determined to be complete (3 days), the
mixture was cooled, the condenser was replaced by a distillation
head, and the excess reagent and a portion of the solvent were
removed by vacuum distillation (60–70 °C, <120 mmHg). The
volume of all the distillate in any flasks used and the dry ice
traps was 2.1 L. The reaction mixture was used in the next
step without isolation. 1H NMR (DMSO-d6, 400 MHz): δ 8.12
(d, 2H, J ) 8.5 Hz), 7.94 (d, 2H, J ) 8.5 Hz).
Thiadiazole 3. Additional fresh o-xylene (1 L) was added
back to the reaction mixture to bring the concentration to
approximately 0.8 M. The mixture was charged with ethyl
cyanoformate (453.2 g, 4.51 mol), placed under nitrogen, and
heated to reflux. The reaction was followed by HPLC, and after
the reaction was judged complete (5 days), the solvent and
excess reagent was removed by distillation. The crude material
was used without purification in the next step. 1H NMR (CDCl3,
400 MHz): δ 8.50 (d, 2H, J ) 8.2 Hz), 7.76 (d, 2H, J ) 8.2
Hz), 4.57 (q, 2H, J ) 7.2 Hz), 1.49 (t, 3H, J ) 7.2 Hz).
Experimental Section
4-(Trifluoromethyl)benzoyl chloride was obtained from
SynQuest Laboratories., Inc., Alachua, FL. All other starting
materials, reagents, and solvents were obtained from commercial
1
suppliers and used without any purification. H NMR spectra
were recorded at 300 or 400 MHz on a Bruker Avance
instrument in the solvent noted in this section. Mass spectra
were obtained on an Agilent Series 180 LC/MS instrument.
Chemical purity was determined on an Agilent Series 1100
system at 210 nm using the following methods: for ester 16
and salt 17 a Zorbax XDB C18 column (4.6 mm i.d. × 150
mm × 3.5 µM) at 35 °C using 80/20 MeCN/water (w/0.05%
TFA) with a flow rate of 1 mL/min; for compounds 2, 3, and
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Preparation of Thiadiazole Alcohol 4a. A 12 L four-neck
Morton flask equipped with an overhead stirrer, a nitrogen inlet
adapter, and a thermocouple was charged with ester 3 (448 g,
1.48 mol), THF (1.5 L), and EtOH (2.7 L). This mixture was
stirred to dissolve the substrate, and then NaBH4 (37.1 g, 0.98
mol) was added in portions at a rate that kept the internal
temperature e40 °C. After complete addition of NaBH4, the
reaction mixture was stirred overnight. The reaction was
quenched by the addition of acetone (60 mL) to consume excess
NaBH4 followed by HCl (500 mL, 20% v/v). The mixture was
concentrated on a rotary evaporator to remove most of the
solvents; the residue was suspended in water, filtered, and rinsed
with water (4 L) to give a tan solid. The product was air-dried
and dried under vacuum (40 °C, 200 ( 50 mmHg) to give
alcohol 4a (353 g, 85% based on amide 1). 1H NMR (CDCl3,
400 MHz): δ 8.40 (d, 2H, J ) 8.1 Hz), 7.74 (d, 2H, J ) 8.1
Hz), 5.19 (s, 2H), 2.0 (br s, 4H, OH + water). LCMS: [MH]+
m/z 261. Anal Calcd for C10H7F3N2OS: C, 46.15; H, 2.71; F,
21.90; N, 10.76; S, 12.32. Found: C, 45.94; H, 2.78; F, 21.56;
N, 10.49; S, 12.22; residual B, 0.05.
Preparation of Thiadiazole Mesylate 4c. A 12 L four-neck
Morton flask equipped with an overhead stirrer, thermocouple,
nitrogen inlet adapter, and addition funnel was charged with
thiadiazole alcohol 4a (300 g, 1.15 mol), CH2Cl2 (5.25 L), and
Et3N (241 mL, 1.73 mol). The mixture was cooled to -20 °C,
methanesulfonyl chloride (89.6 mL, 1.15 mol) was added
dropwise over 30 min, and the mixture was stirred at -20 °C
for 1 h and then allowed to warm to room temperature. The
mixture was washed with 1N HCl solution (4 L), saturated
NaHCO3 (4 L), brine (4 L) and dried over Na2SO4 and
concentrated to 700 mL on a rotary evaporator. The precipitate
was filtered, rinsed with CH2Cl2 (50 mL), and dried (50 °C,
200 ( 50 mmHg) to give 307 g (79% yield, 99% purity) of
mesylate 4c as yellow needles. This material was used in the
next step without further purification. LCMS: [MH]+ m/z 339,
[M + Na]+ m/z 361. 1H NMR (CDCl3, 300 MHz): δ 8.40 (d,
2H, J ) 8.2 Hz), 7.75 (d, 2H, J ) 8.2 Hz), 5.69 (s, 2H), 3.21
(s, 3H).
2.26 mol). The reaction mixture was heated to 100 °C and
stirred for 24 h. The reaction mixture was quenched with H2O
(4.0 L) and extracted with EtOAc (3.0 L × 2). The organic
layer was concentrated in vacuo to give the crude product 11
(539 g). 1H NMR for crude 11 (CDCl3, 400 MHz): δ 6.69–6.52
(m, 3H), 4.25 (q, 2H, J ) 7.1 Hz), 2.18 (s, 3H), 1.35–1.15
(complex m, 6H (impure), this contains a triplet at δ 1.28, J )
7.1 Hz), 1.08 (m, 20 H (impure)).
Preparation of Phenol 8. A 5 L four-neck flask equipped
with a thermocouple controller, an overhead stirrer, and a
nitrogen inlet adaptor was charged with 11 (538 g, 1.36 mol),
MeOH (1.0 L), and 0.50 M NH4F in MeOH (1.60 L, 0.8 mol).
The reaction mixture was stirred at 22 °C for 24 h. The reaction
mixture was quenched with H2O (4.0 L) and extracted with
CH2Cl2 (1.0 L × 3). The organic layer was concentrated in
vacuo to yield 499 g of crude product. Purification by column
chromatography (silica gel (2 kg), 60/40 hexane/EtOAc (v/v))
produced phenol 8 (252 g, 78%). 1H NMR (CDCl3, 300 MHz):
δ 6.61 (d, 1H, J ≈ 8.7 Hz), 6.62 (overlapping d, 1H), 6.49 (dd,
1H, J ≈ 8.7 Hz, J ≈ 3 Hz), 5.0 (br s, 1H), 4.25 (q, 2H, J ) 7.2
Hz), 2.17 (s, 3H), 1.53 (s, 6H), 1.28 (t, 3H, J ) 7.2 Hz).
Coupling of Mesylate 4c and Phenol 8. A 12 L four-neck
Morton flask equipped with an overhead stirrer, thermocouple,
nitrogen inlet adapter, and stopper was charged with the
thiadiazole mesylate 4c (232 g, 0.686 mol) and THF (6 L). The
mixture was cooled to 0–5 °C using ice–water. A 5 L four-
neck Morton flask equipped with an overhead stirrer, thermo-
couple, nitrogen inlet adapter, and addition funnel was charged
with phenol 8 (180 g, 0.755 mol) and THF (1.5 L). The mixture
was cooled to 0–5 °C, and then t-BuOK (755 mL, 1.0 M
solution in THF) was added over 30 min while the temperature
was maintained at 0–5 °C. After the addition, the mixture was
stirred at 0–5 °C for 30 min and then transferred to the mesylate
solution via cannula over 30 min. This resulting mixture was
stirred for 6 h while the temperature changed from 5 to 18 °C.
The mixture was diluted with EtOAc (5 L), washed with 1 N
HCl (6 L) and brine (6 L), and dried over Na2SO4. The solvent
was evaporated via rotary evaporation to afford a tar-like residue
(327 g, 89% purity) that was purified by a flash column (5%
EtOAc in heptane, 3.5 kg of silica gel). There was obtained
246.5 g (75% yield, 97% purity) of 16 as a light yellow solid.
LCMS: [MH]+ m/z 481, [M + Na]+ m/z 503. 1H NMR (CDCl3,
300 MHz): δ 8.42 (d, 2H, J ) 8.2 Hz), 7.75 (d, 2H, J ) 8.2
Hz), 6.86 (s, 1H), 6.71 (two nearly superimposed s, 2H), 5.46
(s, 2H), 4.26 (q, 2H, J ) 7.1 Hz), 2.25 (s, 3H), 1.56 (s, 6H),
1.28 (t, 3H, J ) 7.1 Hz).
Preparation of TIPS-Blocked Methylhydroquinone 10.
A 12 L four-neck flask equipped with a thermocouple controller,
an overhead stirrer, and a nitrogen inlet adaptor was charged
with methylhydroquinone (500.0 g, 4.0 mol), ether (7.0 L), and
Et3N (650 mL, 4.66 mol). The reaction mixture was cooled to
-78 °C, and TIPSOSO2CF3 (885 mL, 4.0 mol) was added
dropwise over 30 min. The reaction mixture was warmed to
22 °C and stirred for 24 h. The reaction mixture was
concentrated in vacuo to yield 2.30 kg of crude product.
Purification by column chromatography (silica gel (2 kg), 90/
10 hexane/acetone (v/v)) provided hydroquinone 10 (767.85
g, 68%). 1H NMR (CDCl3, 300 MHz): δ 6.65 (d, 1H, J ≈ 2.5
Hz), 6.61 (d, 1H, J ≈ 8.5 Hz), 6.57 (dd, 1H, J ≈ 8.5 Hz, J ≈
2.5 Hz), 2.19 (s, 3H), 1.2 (complex m, 3H), 1.09 (two singlets,
18 H).
Preparation of 2-Methyl-2-(2-methyl-4-(3-(4-(trifluoro-
methyl)phenyl)[1,2,4]thiadiazol-5-ylmethoxy)phenoxy)pro-
pionic Acid Sodium Salt 17. A 5 L four-neck Morton flask
equipped with an overhead stirrer, thermocouple, condenser with
a nitrogen inlet adapter, and stopper was charged with ester 16
(245 g, 0.51 mol) and EtOH (2.5 L). A portion of 2 N NaOH
solution (255 mL, 0.51 mol) was added, and then the mixture
was heated at 40 °C overnight. A precipitate was isolated by
filtration and rinsed with EtOH (300 mL). The filtrate was
concentrated to 1 L via rotary evaporation, and the second
precipitate was isolated by filtration and rinsed with EtOH (100
mL). The combined precipitate was dried in a vacuum oven
Alkylation of 10 with Ethyl Bromoisobutyrate. A 12 L
four-neck flask equipped with a thermocouple controller, an
overhead stirrer, condenser, and a nitrogen inlet adaptor was
charged with 10 (400.0 g, 1.43 mol), dioxane (6.0 L), ethyl
2-bromoisobutyrate (320 mL, 2.18 mol), and Cs2CO3 (736 g,
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(60 °C, 200 ( 50 mmHg) for 2 days to afford 17 as a white
solid: 206 g (85% yield, 99% purity). H NMR (DMSO-d6,
(8.0 g, 0.05 mol), CH2Cl2 (100 mL), m-CPBA (12.30 g, 0.05
mol), and p-TsOH (0.60 g, 0.003 mol). The reaction mixture
was heated to 40 °C and stirred for 24 h. The reaction mixture
was quenched with H2O (100 mL) and extracted with EtOAc
(100 mL × 2) to yield 10.79 g of crude product. Purification
by column chromatography (silica gel (300 g), 90/10 (v/v)
1
300 MHz): δ 8.44 (d, 2H, J ) 8.3 Hz), 7.93 (d, 2H, J ) 8.3
Hz), 6.93 (d, 1H, J ) 8.9 Hz), 6.88 (d, 1H, J ) 3.1 Hz), 6.72
(dd, 1H, J ) 8.9 Hz, J ) 3.1 Hz), 5.62 (s, 2H), 2.11 (s, 3H),
1.35 (s, 6H). LCMS: [MH]+ m/z 453, [M + Na]+ m/z 475.
Anal. Calcd for C21H18N2O4F3SNa: C, 52.46; H, 3.87; F, 11.94;
N, 5.87; S, 6.72; Na, 4.81. Found: C, 52.94; H, 3.64; F, 12.29;
N, 5.82; S, 6.67; Na, 4.78; water (KF) 0.63%.
Structure Proof of Phenol 8 by Acetate Derivatives 14
and 15. Preparation of Acetophenone 13. To a 500 mL four-
neck flask equipped with a thermocouple controller, an overhead
stirrer, a condenser, and a nitrogen inlet adaptor was charged
with 4-hydroxy-2-methylacetophenone (5.5 g, 0.036 mol),
dioxane (100 mL), ethyl 2-bromoisobutyrate (6.50 g, 0.033
mol), and Cs2CO3 (17.0 g, 0.052 mol). The reaction mixture
was heated to 100 °C and stirred for 24 h. The reaction mixture
was quenched with H2O (400 mL) and extracted with EtOAc
(100 mL × 2) to yield 10.32 g of crude product. Purification
by column chromatography (silica gel (300 g), 80/20 (v/v)
hexane/EtOAc) produced acetophenone 13 (8.50 g, 90%). 1H
NMR (CDCl3, 300 MHz): δ 7.69 (d, 1H, J ) 6.8 Hz), 6.68 (2,
1H, J ) 2.6 Hz), 6.63 (dd, 1H, J ) 2.6 Hz, J ) 8.6 Hz), 4.24
(q, 2H, J ) 7.1 Hz), 2.54 (s, 3H, (CdO)CH3), 2.52 (s, 3H,
ArCH3), 1.23 (t, 3H, J ) 7.1 Hz).
1
hexane/EtOAc) produced acetate 14 (5.38 g, 69%). H NMR
(CDCl3, 400 MHz): δ 6.86 (d, 1H, J ) 8.8 Hz), 6.73 (d, 1H,
J ) 2.9 Hz), 6.66 (dd, 1H, J ) 8.8 Hz, J ) 2.9 Hz), 4.23 (q,
2H, J ) 7.1 Hz), 2.29 (s, 3H, O(CdO)CH3), 2.11 (s, 3H,
ArCH3), 1.25 (t, 3H, J ) 7.1 Hz).
Preparation of Acetate 15 by Acetylation of Phenol 8. A
100 mL single-neck flask was charged with phenol 8 (1.0 g,
4.2 mmol), acetic anhydride (4 mL), and DMAP (12 mg). After
the solution was briefly warmed to reflux with a heat gun, it
was cooled and condensed in vacuo on a rotary evaporator at
50 °C (5 mmHg). The residue was dissolved in a minimal
amount of CH2Cl2 and passed through a small bed of SiO2 (∼30
mL) using 85/15 (v/v) heptane/EtOAc. Solvent removal af-
forded 15 (1.0 g, 85%) as a clear liquid. 1H NMR (CDCl3, 400
MHz): δ 6.87 (d, 1H, J ) 2.9 Hz), 6.77 (d, 1H, J ) 2.9 Hz),
6.75 (d, 1H, J ) 2.9 Hz), 4.23 (q, 2H, J ) 7.1 Hz), 2.25 (s,
3H, O(CdO)CH3), 2.22 (s, 3H, ArCH3), 1.25 (t, 3H, J ) 7.1
Hz).
Preparation of Acetate 14. A 500 mL four-neck flask
equipped with a thermocouple controller, an overhead stirrer,
condenser, and a nitrogen inlet adaptor was charged with 13
Received for review June 19, 2007.
OP700141U
1014
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Vol. 11, No. 6, 2007 / Organic Process Research & Development