A convenient synthesis of thiofibrate analogs from aryl sulfonyl chlorides

Article abstract of DOI:10.1081/SCC-100000575

An expedient synthesis of pharmacologically relevant thioisobutyric acid esters from aryl sulfonyl chlorides is described.

Full text of DOI:10.1081/SCC-100000575

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A CONVENIENT SYNTHESIS OF THIOFIBRATE
ANALOGS FROM ARYL SULFONYL CHLORIDES
Eric E. Boros , Istvan Kaldor , Peter J. Brown & Virgil L. Styles
To cite this article: Eric E. Boros , Istvan Kaldor , Peter J. Brown & Virgil L. Styles (2001) A
CONVENIENT SYNTHESIS OF THIOFIBRATE ANALOGS FROM ARYL SULFONYL CHLORIDES,
Synthetic Communications, 31:4, 505-510, DOI: 10.1081/SCC-100000575
To link to this article: http://dx.doi.org/10.1081/SCC-100000575
Published online: 16 Aug 2006.
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Date: 19 January 2016, At: 08:35

SYNTHETIC COMMUNICATIONS, 31(4), 505–510 (2001)
A CONVENIENT SYNTHESIS OF
THIOFIBRATE ANALOGS FROM ARYL
SULFONYL CHLORIDES
Eric E. Boros,∗ Istvan Kaldor, Peter J. Brown,
and Virgil L. Styles
Glaxo Wellcome Research and Development,
Five Moore Drive, Research Triangle Park, NC 27709
ABSTRACT
An expedient synthesis of pharmacologically relevant thio-
isobutyric acid esters from aryl sulfonyl chlorides is described.
The fibric acid pharmacophore has been of interest to medicinal chemists
ever since the initial discovery that ethyl chlorophenoxyisobutyrate (1) possessed
hypolipidemic properties (1). Since that time, clofibrate (1) (2) and other fibrate
analogs such as bezafibrate (2) (2) have been developed for the treatment of hy-
perlipidemia in humans.
O
CO2H
O
O
CO2Et
N
H
Cl
Cl
1
2
∗Corresponding author.
505
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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506
BOROS ET AL.
t
S
CO2H
S
CO2 Bu
F
O
O
N
N
N
H
F
O
3
4
Scheme 1.
In a recent communication (3), the novel ureido-thioisobutyric acid 3
(GW9578), a subtype selective PPARα agonist with potent lipid lowering proper-
ties, was disclosed. Compound 3 was prepared in eight steps from p-bromothio-
phenol via the phthalimide-protected phenethylamino precursor 4 (Scheme 1).
The thioisobutyric acid (TiBA) moiety in 3 was introduced by a standard thioisobu-
tyrate synthesis (4) involving alkylation of p-bromothiophenol with tert-butyl
bromoisobutyrate. A subsequent Heck reaction with vinyl phthalimide followed by
hydrogenation of the double bond in the presence of 5 mol% Wilkinson’s catalyst
provided the requisite intermediate (4).
In the course of a medicinal chemistry effort targeting TiBA analogs as
potential lipid-lowering agents, a convenient route to congeners of 4 that avoided
toxic and costly transition metal catalysts and malodorous thiophenols was desired.
(The cost of 0.05 mole of Wilkinson’s catalyst is ca. $1,000.) We now describe an
expedient synthesis of thiofibrate analogs through sulfenylation of commercially
available dimethyl ketene acetal 7 with benzene sulfenyl chlorides (Scheme 2).
Synthesisofthenovelo-fluorinatedTiBAester14exemplifiesthisalternative
methodology (Scheme 3). Reduction of sulfonyl chloride 9 to the disulfide 10 was
accomplished with sodium bisulfite in acetic acid with a small amount of sodium
iodide. Iodide is regenerated in situ from the iodine produced during the reaction
by dropwise addition of aqueous bisulfite (5). Although a variation of this simple
OTMS
OMe
S
CO2Me
SO2Cl
SCl
7
O
N
Cl
Cl
6
8
5
O
Scheme 2.

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REPRINTS
THIOFIBRATE ANALOGS
507
F
F F
NaHSO3
Nal, HOAc, ∆
SO2Cl
S S
Cl
Cl
Cl
9
10
SO2Cl2 CH2Cl2
3
F
F
S
4
7, CH2Cl2
SCl
CO2Me
6
Cl
Cl
12
11
DMF, ∆ K-Phth., TBAI
F
F
S
H2NNH2
MeOH, ∆
S
CO2Me
CO2Me
O
N
H2N
13
14
O
Scheme 3.
and cost effective reduction is known for a nitrobenzene sulfonyl chloride (5),
the method has not found general application in the synthesis of polysubstituted
aromatic disulfides.
Methyl thioisobutyrate 12 was prepared in quantitative yield from disul-
fide 10 by treatment with sulfuryl chloride in CH2Cl2 and reaction of the inter-
mediate sulfenyl chloride 11 with commercially available methyl trimethylsilyl
dimethylketene acetal 7. The two-step conversion of 10 to the TiBA intermedi-
ate 12 required no workup and provided analytically pure product (12) follow-
ing distillation of the reaction medium (CH2Cl2/TMSCl). The regiochemistry of
the trisubstituted benzene ring in 12 was supported by nuclear Overhauser and
exchange spectroscopy (NOESY), which showed NOEs between the benzylic
methylene protons and phenyl protons H-4 and H-6. Chloride displacement from
12 with potassium phthalimide followed by deprotection of 13 with hydrazine
gave the pure amine (14) in 26% overall yield from 9 without chromatography.

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BOROS ET AL.
The protected TiBA intermediate 8 may be prepared from 5 using a similar pro-
cedure (Scheme 2).
Despite the limited precedence of silyl ketene acetal sulfenylations (6,7), the
convenient use of 7 to access the medicinally relevant thio-fibrate pharmacophore
has, to our knowledge, not been described. Fluorinated thioisobutyric acid esters
12 and 14 are versatile synthetic intermediates for the preparation of TiBA analogs
as potential hypolipidemic agents.
EXPERIMENTAL
Benzene sulfonyl chloride 9 was prepared by chlorosulfonation of 4-
(2-chloroethyl)-1-fluorobenzene employing standard procedures (8). All reagent
chemicals were used without purification. Elemental analyses were performed by
Atlantic Microlabs, Norcross, Georgia. All 1H NMR spectra were recorded at 300
or 400 MHz. Chemical shifts are reported in ppm relative to the residual protonated
solvent resonance of CDCl3 (δ 7.24). Positive ion flow electrospray mass spectra
(MS) are reported in the form m/z (positive ion, relative intensity).
5-(2-Chloroethyl)-2-fluorophenyl Disulfide (10)
5-(2-Chloroethyl)-2-fluorobenzenesulfonyl chloride (9) (20.7 g, 80.5 mmo-
le) was dissolved in glacial acetic acid (50 mL), and sodium iodide (1.0 g, 6.67
mmole) was added. The iodine generated in situ was reduced by dropwise addition
of saturated aqueous NaHSO3. The reaction mixture was heated to 90◦C and the
resulting dark color (iodine) was repeatedly removed by titration with aqueous
NaHSO3. Once iodine production ceased, the reaction was partially concentrated at
reduced pressure and partitioned between EtOAc and saturated aqueous NaHCO3.
The organic layer was washed with NaHCO3 and brine, and dried over Na2SO4.
Filtration and evaporation of the solvent and trituration of the crude material with
Et2O/hexanes provided 10 as a light yellow oil (8.6 g, 56%). This material was ca.
95% pure by 1H NMR and was used immediately in the next step without further
purification. 1H NMR (CDCl3) δ 7.45 (dd, 1H, J = 7, 2 Hz), 7.11 (ddd, 1H, J =
9, 5, 2 Hz), 7.01 (t, 1H, J = 9 Hz), 3.65 (t, 2H, J = 7 Hz), 3.01 (t, 2H, J = 7 Hz).
5-(2-Chloroethyl)-2-fluorophenylsulfenyl Chloride (11)
The disulfide 10 (8.6 g, 22.7 mmole) was dissolved in a 1-M solution of
SO2Cl2 in CH2Cl2 (50 mL) and the reaction was stirred at 0◦C for 1 h. The
solution was concentrated at reduced pressure to afford 11 as a red oil (10.2 g,
1
100%) which was used immediately in the next step (ca. 95% pure): H NMR

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509
(CDCl3) δ 7.56 (dd, 1H, J = 7, 2 Hz), 7.30 (ddd, 1H, J = 9, 5, 2 Hz), 7.12 (t, 1H,
J = 9 Hz), 3.72 (t, 2H, J = 7 Hz), 3.07 (t, 2H, J = 7 Hz).
Methyl 2-(5-(2-Chloroethyl)-2-fluorophenylthio)-
2-methylpropionate (12)
A solution of the sulfenyl chloride 11 (10.2 g, 22.7 mmole) in CH2Cl2
(30 mL) was added dropwise to a stirring solution of methyl trimethylsilyl dimethy-
lketene acetal (9.1 g, 52.2 mmole) in CH2Cl2 (30 mL) cooled to −78◦C. The
resulting colorless solution was concentrated at reduced pressure to provide 12 as
a nearly colorless oil (13.2 g, 100%): 1H NMR (CDCl3) δ 7.31 (dd, 1H, J = 6.7,
2 Hz), 7.23 (ddd, 1H, J = 8.3, 5, 2 Hz), 7.05 (t, 1H, J = 8.3 Hz), 3.68 (t, 2H, J =
7.1 Hz), 3.67 (s, 3H), 3.02 (t, 2H, J = 7.1 Hz), 1.49 (s, 6H); MS m/z (%) 313
(M+Na+, 30), 315 (11), 279 (100); Anal. calcd for C13H16ClFO2S: C, 53.70; H,
5.55; S, 11.03. Found: C, 53.58; H, 5.51; S, 10.95.
Methyl 2-(2-Fluoro-5-(2-phthalimidoethyl)phenylthio)-
2-methylpropionate (13)
A mixture of 12 (4.55 g, 15.7 mmole), potassium phthalimide (3.19 g,
17.22 mmole), tetrabutyl ammonium iodide (5.78 g, 15.7 mmole) and 18-crown-6
(2.07 g, 7.83 mmole) in DMF was stirred at 55◦C for 4 h. Most of the DMF was
removed by rotovap under high vacuum and the crude product was reconstituted in
EtOAc and washed with water. The EtOAc layer was dried over Na2SO4, filtered
and concentrated to an oil. Excess phthalimide was removed by precipitation from
toluene. The supernatant was concentrated and the resulting oil was recrystallized
from Et2O/hexanes to afford 13 as a white solid (3.74 g, 60%): mp 95◦–96◦C; 1H
NMR (CDCl3) δ 7.83 (dd, 2H, J = 5.4, 3.1 Hz), 7.71 (dd, 2H, J = 5.4, 3.1 Hz),
7.32 (dd, 1H, J = 7, 2.5 Hz), 7.28 (m, 1H), 7.03 (t, 1H, J = 8.3 Hz), 3.90 (t, 2H,
J = 7.6 Hz), 3.69 (s, 3H), 2.96 (t, 2H, J = 7.6 Hz), 1.43 (s, 6H); Anal. calcd for
C21H20FNO4S: C, 62.82; H, 5.02; N, 3.49; S, 7.99 Found: C, 62.92; H, 5.04; N,
3.50; S, 7.91.
Methyl 2-(5-(2-Aminoethyl)-2-fluorophenylthio)-
2-methylpropionate (14)
Hydrazine hydrate (2 mL, 41 mmole) was added to a solution of intermediate
13 (1.87 g, 4.66 mmole) in MeOH (16 mL) and the mixture was heated at reflux
for 1 h. The reaction mixture was cooled to rt, diluted with Et2O, and filtered.

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Evaporation of the filtrate provided a crude oil, which was reconstituted in Et2O
and washed with 0.1 M NaOH and brine. The Et2O layer was dried over Na2SO4,
filtered, and concentrated to afford 14 as a nearly colorless oil (0.96 g, 76%); 1H
NMR (CDCl3) δ 7.27 (dd, 1H, J = 7, 2 Hz), 7.21 (ddd, 1 H, J = 8, 5, 2 Hz), 7.04
(t, 1H, J = 8 Hz), 3.69 (s, 3H), 2.96 (t, 2H, J = 7 Hz), 2.72 (t, 2H, J = 7 Hz),
1.49 (s, 6H); MS m/z (%) 272 (M+H+, 100); Anal. calcd for C13H18FNO2S·(0.25
H2O): C, 56.60; H, 6.76; N, 5.08; S, 11.62. Found: C, 56.49; H, 6.60; N, 5.09;
S, 11.75.
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J.M.; Kliewer, S.A.; Willson, T.M. J. Med. Chem. 1999, 42, 3785.
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Received in the USA May 26, 2000

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