An environmentally-friendly one-pot synthesis of 4-sulfonyl benzoic acids

Article abstract of DOI:10.1016/j.tetlet.2014.02.092

This Letter reports an environmentally-friendly one-pot S_NAr reaction of thiols to 4-halobenzoic acid methyl esters to provide 4-substituted sulfone benzoic acids and picolinic acids after bleach-mediated oxidative workup. These acid intermediates were synthesized on gram scale, are perfect partners for library synthesis, and have good physical chemical properties useful for drug discovery.

Full text of DOI:10.1016/j.tetlet.2014.02.092

Tetrahedron Letters 55 (2014) 3295–3298
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An environmentally-friendly one-pot synthesis of 4-sulfonyl benzoic
acids
⇑
Bryan A. Frieman
Vertex Pharmaceuticals Inc, 11010 Torreyana Road, San Diego, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter reports an environmentally-friendly one-pot SNAr reaction of thiols to 4-halobenzoic acid
methyl esters to provide 4-substituted sulfone benzoic acids and picolinic acids after bleach-mediated
oxidative workup. These acid intermediates were synthesized on gram scale, are perfect partners for
library synthesis, and have good physical chemical properties useful for drug discovery.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 10 January 2014
Revised 21 February 2014
Accepted 24 February 2014
Available online 13 April 2014
Keywords:
SNAr
Sulfones
Sulfide oxidation
Bleach oxidation
Introduction
O
Aryl sulfones are an important moiety in drug discovery. Sulf-
ones are generally stable toward heat, acids, bases, oxidation, and
reduction and often improve the crystallinity of drug products.1
AstraZeneca’s androgen receptor inhibitor Bicalutamide (Caso-
dexÒ) (1) and Merck’s Cox-2 inhibitor Rofecoxib (VioxxÒ) (2) are
two examples of drugs containing aryl sulfones (Fig. 1). Sulfones
are strong H-bond acceptors and are classical bioisosteres2 of
carbonyl containing compounds.
S
O
F
CF3
O
CN
O
O
S
O
O
N
H
HO
Bicalutamide (1)
Rofecoxib (2)
There have been several reviews which have detailed the many
methods used to prepare non-complex aryl sulfones.1,3 These
methods include alkylation of sulfinic acid salts,4 sulfonylation of
simple arenes via Friedel Crafts-type chemistry,5 palladium-cata-
lyzed addition of an organostanane to an arylsulfonyl chloride,6
and palladium catalyzed cross-coupling chemistry of aryl halides
with organo thiols.7–10
Another common method to prepare aryl sulfones has been
through a two-step method. First, a thiol reacts with an aryl halide
or pseudohalide through nucleophilic aromatic substitution (SNAr)
followed by oxidation using a variety of oxidants in a second step
to form an aryl sulfone. Common oxidants include MCPBA, H2O2,11
KMnO4,12 RuO4,13 and oxone.14
Figure 1. Commercial sulfone containing drugs.
mercially available from reliable vendors. This has been verified
as some of these building blocks were needed for an in-house
library effort and were synthesized based on lack of commercial
availability. The in situ bleach oxidation was very nice in that
the foul smelling mercaptan products and excess thiolates that
were employed in the reaction were oxidized in situ to alleviate
the foul odor. In addition, bleach is very inexpensive and is char-
acterized as an environmentally-friendly oxidant16 due to its
extremely fast dissociation in water and offers low environmental
harm to the community. This Letter reports the first one-pot SNAr
reaction of thiols to 4-halobenzoic acid methyl esters to provide
4-substituted sulfone benzoic acids after bleach oxidative
workup. These acid intermediates are perfect partners for library
synthesis and have good physical chemical properties for drug
discovery.
Despite the well-known SNAr literature for preparing aryl-
thioethers,15 and the simple oxidative conversion to aryl sulfones,
less than 100 functionalized 4-substituted benzoic acids are com-
⇑
Tel.: +1 (858) 404 6621; fax: +1 (858) 404 6726.
E-mail address: Bryan_Frieman@vrtx.com
http://dx.doi.org/10.1016/j.tetlet.2014.02.092
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3296
B. A. Frieman / Tetrahedron Letters 55 (2014) 3295–3298
O
O
Results and discussions
R
+
NaS R2
The reaction of methyl 4-bromobenzoate (3) with sodium iso-
propylthiolate (4) was used to optimize this process. A solvent
screen was performed to find the best reaction conditions in our
system. We found that 1.1 equiv of the isopropylthiolate in DMF
at 65 °C cleanly provided methyl 4-(isopropylthio) benzoate in
3 h, but 2.5 equiv of the isopropylthiolate was needed to cleanly
provide 4-(isopropylthio) benzoic acid (5). Such thiolate mediated
ester deprotections are well known.17 Performing the same reac-
tion on 4-bromobenzoic acid resulted in no conversion to product.
This showed that this reaction proceeds through a two-step mech-
anism where first, the SNAr reaction takes place, followed by
deprotection of the methyl ester to the carboxylate. Suitable sol-
vents for the SNAr reaction were typical polar aprotic solvents such
as DMF, DMSO, DMA, and NMP. Unsuitable solvents that showed
no reaction and recovered starting material were THF, dioxane,
acetonitrile, diglyme, dichloroethane, and methanol. Water or 1 N
sodium hydroxide only resulted in conversion of the starting mate-
rial methyl ester to the corresponding carboxylic acid (Table 1).
The use of polar aprotic solvents is necessary to avoid the bivalent
reactivity of thio anions (i.e., as nucleophiles and as reductants
through radical pathways).18
Br
Brine/EtOAc
Extraction
Aqueous
(Keep)
Organic
(Discard)
1) Bleach
2) Acidify (1NHCl)
Extraction
EtOAc:Brine
O
R
HO
Organic
Aqueous
(Discard)
O
(Product)
S
R2
O
Scheme 1. Flow chart for SNAr-oxidation protocol.
4-(isopropylsulfonyl)benzoic acid as a white solid without the
need for purification (Scheme 1).19
In order to test the ability of different commercial and in situ
prepared sodium thiolates in the SNAr reaction, a few reactions
were performed using methyl 4-bromobenzoate. Isopropylthiolate,
the more sterically hindered t-butyl thiolate, and isobutyl thiolate
worked efficiently to provide the desired sulfone carboxylic acids
in respectable yields. As expected, the in situ prepared pyrimi-
dine-2-thiolate did not undergo the SNAr reaction due to the poor
nucleophilicity of the pyrimidine thiolate (Table 2).
In order to evaluate the utility of this methodology, substrates
were chosen based on varying substitution pattern and electronics
of the benzoate, functional group compatibility, and reactivity with
different thiolates (Table 3). Both electron rich and electron defi-
cient aryl halides had no effect on the SNAr reaction and led to good
After performing an SNAr reaction with a thiolate, a common
work-up after extraction is to add bleach to the waste to oxidize
any remaining thiol and eliminate the foul odor of the thiol
employed in the reaction. Instead, we envisioned that perhaps
we could use this work-up for the extracted product to oxidize
the thio ether during work-up and provide the sulfone product
without the need for purification. We began by performing the
reaction of methyl 4-bromobenzoate with 2.5 equiv of sodium iso-
propylthiolate in DMF. After 3 h, the reaction was quenched with
brine and extracted with ethyl acetate. The ethyl acetate layer
was washed with brine three times to remove all of the carboxylate
product. The ethyl acetate layer was discarded. The aqueous layer
was then treated with commercial bleach and stirred for 10 min.
Complete oxidation of the thio ether to the sulfone was seen by
LCMS. Acidification of the mixture to pH 1 using 1 N HCl followed
by extraction with ethyl acetate and concentration provided
Table 2
SNAr-oxidation reaction of thiolates with methyl 4-bromobenzoate
O
O
R
DMF, 65°C
O
HO
+
NaS R2
Table 1
O
Br
S
O
Solvent screen for optimizing SNAr reaction conditions
R2
O
O
solvent, 65°C, 3h
HO
O
Entry
1
Thiol/thiolate
Product
Yield (%)
82
+
Na S
O
O
O
O
S
Br
NaS
3
4
5
HO
HO
HO
HO
O
O
O
O
Entry
Equivalents (4)
Solvent
Conversionc (%)
S
S
S
S
O
O
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
DMF
DMF
DMSO
THF
Dioxane
Toluene
Water
1 N NaOH
Diglyme
DMA
100a
100
100
0
NaS
NaS
2
3
79
70
0
0
0b
0b
0
100
100
Trace
100
100
NMP
DCE
MeOH
ACN
NaS
N
a
b
c
N
4
NR
Methyl ester product formed.
Carboxylic acid of starting material formed.
Conversion percent determined by Sciex LCMS (1–99% ACN/H2O) averaging the
N
N
220 nm and 254 nm trace.

B. A. Frieman / Tetrahedron Letters 55 (2014) 3295–3298
3297
Table 3
Preparation of 4-sulfone benzoic and picolinic acids references
O
O
R
R
DMF, 65°C
O
HO
+
Na
S
R2
O
X
S
R2
Entry
1
Aryl halide
Thiol/thiolate
Product
Yield (%)
O
O
NaS
NaS
NaS
O
HO
O
81
99
F
S
O
O
O
O
O
O
CN
Br
CN
HO
2
O
S
O
O
O
CHO
F
CHO
HO
3
4
5
6
O
S
40
60
86
0
O
O
O
NaS
NaS
NaS
OMe
F
OMe
HO
O
S
O
O
O
O
O
O
HO
O
S
Br
Br
O
O
O
HO
O
S
O
O
NaS
N
N
O
HO
86a
51b
O
S
7
X
aX=Br
bX=NO2
O
a
4-Br picolinic ester
4-NO2 picolinic ester
b
yields of the corresponding sulfones (entries 1, 2, & 5). Somewhat
reactive functionalities such as aldehydes and methoxy groups in
the presence of isopropyl and ethyl thiolate were tolerated but
resulted in lower yields (entries 3 & 4). As expected, ortho substi-
tution was not tolerated (entry 6) due to changing the electronics
of the ring and the conjugation into the ester resulting in only
recovery of the carboxylic acid. In the literature, there are no
reports of thiol additions to electron rich ortho benzoic acid esters.
All examples use transition metals such as palladium or copper for
this transformation.20 This methodology also works very well for
picolinic acids (entry 7). 4-Bromo-picolinic acid methyl ester was
cleanly converted to the isopropyl sulfone in excellent yield (entry
7a). It is noteworthy that other electron withdrawing groups such
as nitro can act as pseudo halides and react with thiolates to pro-
vide the SNAr product but in lower yields (entry 7b).
been employed on multi-gram scale to prepare these simple build-
ing blocks and was used in a drug discovery effort.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2014.02.092.
References and notes
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Francis, 2001; 22, pp 251–275.
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In brief, we have successfully developed an environmentally
friendly one-pot synthesis of 4-substituted sulfone benzoic acids
and picolinic acids. In general, these building blocks are prepared
from simple commercially available starting materials and can be
isolated without the need for purification. This methodology has

3298
B. A. Frieman / Tetrahedron Letters 55 (2014) 3295–3298
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19. Representative procedure: 4-Isopropylsulfonyl benzoic acid (Table 2, entry 1). To
a 100 mL rbf were added methyl 4-fluorobenzoate (1.075 g, 5 mmol), DMF
(20 mL), and sodium propane-2-thiolate (1.227 g, 12.5 mmol) and the reaction
was heated for 3 h at 65 °C. The reaction was found to be complete by LCMS
analysis. The reaction was removed from the oil bath and was allowed to cool
to rt. The reaction was quenched with brine and allowed to stir for 20 min. The
reaction mixture was then extracted with EtOAc 3 times and the aqueous layer
was collected in a 1 L Erlenmeyer flask. The aqueous layer was then treated
with 100 mL of commercial bleach and the reaction mixture immediately
turned colorless and transparent. The reaction mixture was then allowed to stir
for 10 min. The reaction was then treated with 1 N HCl until the reaction was
pH 1. The reaction was then extracted with EtOAc 3 times and the organic
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to provide 4-isopropylsulfonyl benzoic acid (931 mg, 81.6%) as a white solid.
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