Development of the large-scale preparation of 2-(Methanesulfonyl) benzenesulfonyl chloride

Article abstract of DOI:10.1021/op2002744

A practical and scalable process is described for the preparation of 2-(methansulfonyl)benzenesulfonyl chloride, a key building block used in the synthesis of several drug candidates. The material is prepared by an efficient four-step sequence from inexpe

Full text of DOI:10.1021/op2002744

Article
pubs.acs.org/OPRD
Development of the Large-Scale Preparation of 2-
(Methanesulfonyl)benzenesulfonyl Chloride
Harold Meckler and R. Jason Herr*
Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, New York 12203, United States
ABSTRACT: A practical and scalable process is described for the preparation of 2-(methansulfonyl)benzenesulfonyl chloride, a
key building block used in the synthesis of several drug candidates. The material is prepared by an efficient four-step sequence
from inexpensive 1,2-dichlorobenzene and methanethiol, and the process has been demonstrated on a multikilogram scale in 32%
overall yield with a chemical purity of >98%.
chloride (9) by this route was calculated at 59% yield for the
four-step process, which was initiated with 100 g of 1,2-
dichlorobenzene for the first step, but elaborated through the
later stages below 20-g scale.
INTRODUCTION
■
As part of a previous drug development program, we required
multikilogram quantities of a key building block 2-
(methanesulfonyl)benzenesulfonyl chloride (8). While the
material is currently commercially available, it is expensive,
available at times only in gram quantities, and at the time
convenient processes for preparation on large scale were
lacking. In order to meet an aggressive timeline, it was a high
priority to rapidly develop a practical and scalable synthesis of
8, which has more recently found use as an important raw
material for the synthesis of several lead drug and candidate
molecules.1
We elected to follow the guidelines of this route, with an eye
toward modifications that allowed for multikilogram scale
preparation, and our ultimate process is described in Scheme 2.
For the first step, we were encouraged by literature that
suggested the monodisplacement of 1,2-dichlorobenzene with
alkali metal salts of alkanethiols could be achieved at high
temperature without the need for catalysis.3 Initially we set out
to examine the reaction of 1 with commercially available
sodium methanethiolate to produce 2-chlorophenylthioanisole
(2), conducting the reaction in a variety of higher-boiling
solvents at 100−120 °C, with and without phase-transfer
catalysis. Eventually we settled our concerns of reagent cost and
availability by using methanethiol gas (methyl mercaptan) and
one equivalent of finely ground potassium hydroxide to
generate the metal alkanethiol in situ. On scale-up (typically
a 5-L batch of 1), methyl mercaptan was introduced into the
flask subsurface over 4 h through the gas inlet tube, operating
with a gas outlet through a mechanically stirred aqueous
sodium hypochlorite/sodium hydroxide scrubber. During the
gas addition, exothermic heating of the reaction mixture
increased the internal reaction temperature to 50 °C, which
was maintained throughout the gas addition, after which the
mixture was heated to 100 °C to stir for 30 min. Although the
amount of potassium methanethiolate was controlled to one
equivalent to avoid bis-substitution of 1,2-dichlorobenzene,
experiments showed that excess amounts of the reagent
generated at 100 °C did not generate significant amounts of
the bis-substituted byproduct. While the amount of methyl
mercaptan charged on large scale was not measured, we found
on smaller-scale experiments that the charging of approximately
three equivalents of the gas were necessary to ensure complete
generation of the equivalent of potassium methanethiolate to
consume substrate 1. Upon completion, a quench with one
volume of water at room temperature followed by extraction of
the product with two volumes of hexanes produced 2 as an
RESULTS AND DISCUSSION
■
At the time we began this research effort, we based our strategy
for the preparation of 2-(methanesulfonyl)benzenesulfonyl
chloride on a route described in the patent literature for the
production of 2-substituted arylsulfonyl chlorides from ortho-
dichloroaromatics and alkyl metal sulfides as depicted in
Scheme 1.2 Specified in this process was the nucleophilic
substitution of 1,2-dichlorobenzene (1) with potassium alkyl
mercaptides, requiring the use of polyethylene glycol (PEG)
ether reagents as catalysts. Exemplified were the substitution
reactions to provide the methyl aryl thioether 2 (147-g scale)
and the n-propyl aryl thioether congener 3 (100-g scale).
Oxidation of the resulting aryl alkyl sulfide 3 by various
conditions (exemplified by the bleach conditions shown on a
9.3-g scale) afforded 2-chlorophenyl n-propyl sulfone (5) in
good overall yields. In contrast, the transformation from 2 to 4
was simply referred to in the text as an example, but without
yield or details. Aryl n-propyl sulfone 5 was subjected to a
second nucleophilic aromatic substitution to generate the 2-
substituted-aryl n-propyl sulfone product 7, although a biphasic
solvent system was used for the 2.2-g scale transformation.
Again, the process was described as amenable for the thiolation
of 4 to provide the adduct 6, but without yield or details.
Finally, oxidative chlorination of the alkylthio moiety to
transform the final intermediates into the corresponding 2-
substituted-arylsulfonyl chlorides was described, with both the
conversion of methyl thioanisole 6 to 8 (13.2-g scale) and the
conversion of n-propyl thioanisole 7 to 9 (18.7-g scale). The
overall preparation of 2-(n-propylsulfonyl)benzenesulfonyl
Received: October 4, 2011
Published: March 5, 2012
© 2012 American Chemical Society
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Scheme 1. Patent literature synthetic route to 2-substituted-arylsulfonyl chlorides 8 and 9
Scheme 2. Scale-up process for 2-(methanesulfonyl)benzenesulfonyl chloride synthesis
Table 1. Selected exploratory conditions for the oxidation of thioanisole 2 to sulfone 4
entry
conditions
outcome
1
2
3
4
5
6
7
8
9
5% aq NaOCl, nBu4NHSO4, EtOAc, rt, 24 h
5% aq NaOCl, DMF, rt, 24 h
incomplete, unclean conversion of 10 to 4
incomplete, unclean conversion of 10 to 4
incomplete conversion of 10 to 4
35% aq H2O2, HOAc, reflux, 1 h
oxone, MeOH/H2O, reflux, 18 h
incomplete, unclean conversion of 10 to 4
incomplete conversion of 10 to 4
oxone, H2O, bentonite clay, CH2Cl2, rt, 16 h
NaIO4, RuCl3, 1:2:1 MeCN/H2O/CHCl3, rt, 17 h
NaIO4, RuCl3, 1:4:1 MeCN/H2O/CHCl3, rt, 22 h
NaIO4, RuCl3, 1:2:1 MeCN/H2O/DCE, rt, 3.5 h
NaIO4, RuCl3, 1:2:1 MeCN/H2O/CH2Cl2, rt, 4 h
complete, but unclean conversion of 2 to 4
incomplete, unclean conversion of 10 to 4
complete, clean conversion of 2 to 4
complete, clean conversion of 2 to 4
opaque, colorless oil that was suitable for further use in the next
step without further purification. Typically the material was
measured at >95% purity by 1H NMR analysis, and this process
functioned well at up to 7-kg scale. Although the product was
isolated by evaporation to dryness, we anticipated that a simple
solvent exchange in the subsequent step would avoid the
stripping operation on further scale-up. In general, however, we
were pleased to find that our first transformation was at least on
par with the patent description (Scheme 1), and was amenable
to the preparation of much larger quantities.
Discovering a suitable and reproducible method for the
oxidation of thioether 2 to the aryl methyl sulfone 4 was more
challenging (Scheme 2). Initial attempts to doubly oxidize 2
using the patent procedure (Scheme 1) failed to provide the
requisite sulfone, as several experiments to optimize the
conditions were inadequate to push the full conversion of the
intermediate sulfoxide 10 to 4 (Table 1, entry 1). After
examination of conditions with several reagents and reagent
combinations (some shown in Table 1),4 we eventually settled
on an efficient oxidation system using 2 equiv of sodium
periodate under catalysis by ruthenium trichloride.5 Modifica-
tions demonstrated that a biphasic water/acetonitrile/methyl-
ene chloride mixture at 2:1:1 was critical for clean conversion
(entry 9), and that portionwise addition of the ruthenium
catalyst was necessary to control the mild but immediate
exothermic reaction. Sodium periodate readily oxidizes 2 to the
sulfoxide intermediate 10, so the ruthenium reagent is only
required to catalyze the second oxidation to the sulfone product
4, and was optimized to 0.05 mol % loading on a typical 3-kg
scale run.
Upon completion of the reaction, the product 4 was
extracted with methylene chloride, washed with water to
remove the sodium iodate byproduct, and subjected to charcoal
treatment to remove the catalyst. The crude product solution
was partially concentrated and triturated with hexanes to
produce clean 2-chlorophenyl methyl sulfone (4) as a free-
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Table 2. Selected small-scale exploratory chloroxidation conditions
entry
conditions
outcome
incomplete, unclean conversion of 6 to 8; formation of adduct 14; inadequate extraction and isolation
1
2
3
NCS, H2O/HOAc, rt to 50 °C, 4 h
SO2Cl2, CH2Cl2/H2O/HOAc, 0 to 50 °C, 6 h incomplete, unclean conversion of 6 to 8 and 14; inadequate extraction and isolation
5% aq NaOCl, 4 N HCl/CH2Cl2, 0 °C to rt,
incomplete conversion of 6 to 8; formation of adduct 14; solubility problems; inadequate
extraction and isolation
12 h
4
5
6
7
mCPBA, CH2Cl2, 0 °C, 1 h; SO2Cl2, reflux, 12 h clean conversion of 6 to 14, but no conversion of 14 to 8
Cl2, H2O/dioxane, rt, 12 h
incomplete conversion of 6 to 8; solubility problems; inadequate extraction and isolation
Cl2, H2O/HOAc/CH2Cl2, rt, 12 h
Cl2, H2O/HOAc, rt to 50 °C, 5 h
incomplete conversion of 6 to 8; inadequate extraction and isolation
complete conversion of 6 to 8
flowing powder. Typically the material was measured at >95%
purity by H NMR analysis, and we were pleased that our
process was not only comparable to the patent procedure
(Scheme 1) but also adaptable to the synthesis of much larger
amounts of material.
observed at early stages in the progress of most reactions, but
were not seen in significant amounts in the final product
analyses. These fleeting adducts could never be completely
identified as either sulfenyl chloride 11 or disulfide 12 and
sulfoxide 13, all of which are purported intermediates in the
oxidative chlorination mechanism.6 However, the sulfone
adduct 14, proposed as a nonproductive side product from
an earlier step in the transformation, was also often isolated in
significant amounts (entries, 1, 2, and 5) and could not be
separated from the product mixture to a satisfactory degree. In
one experiment (entry 6) we intentionally produced the sulfone
compound 14, but could not convert it to 8, which is consistent
with observations from the literature. Other experiments
(entries 3 and 4) did produce the desired product 8 in
relatively clean amounts, but required an extraction step for
their purification, and therefore were deemed less efficient than
the later experiments where product 8 was isolated more
directly. In the case of entry 5, in which the biphasic conditions
required a high volume of water, there was also the
complication of precipitation of components from the mixture
during the course of the reaction.
Upon examination of conditions to produce 8 from 6 using
chlorine gas and water as reagents (entries 7−10), we
ultimately found that the use of acetic acid as a solvent was
preferable to mixed solvent systems in terms of workup, as the
product could be isolated upon reaction completion by simple
trituration with water followed by vacuum filtration. We also
found that complete conversion to product could be achieved
through heating the mixture for a defined time period after the
exothermic portion of the reaction had subsided. Monitoring of
the reaction during this heating period was critical, as
prolonged reaction at 50 °C led to yield losses resulting from
the hydrolysis of product 8 to the corresponding sulfonic acid.
Thus, to effect the transformation on scale (typically run with
2.3-kg lots), chlorine gas (about 5 equiv, measured by weight)
was introduced subsurface to a slurry of the thioanisole 6
(contaminated at 4−7% with intermediate 4) in glacial acetic
acid and 2−3 equiv of water as the oxygen source, with the gas
addition at a rate which maintained the exothermic heating
below 60 °C, followed by heating at 50 °C for no more than 4 h
(Scheme 2). Upon completion, the mixture was reverse
quenched with ice water and stirred for 1 h, and the solids
were collected by vacuum filtration to provide 2-
(methanesulfonyl)benzenesulfonyl chloride (8) with near
1
We next investigated other methods for the second
nucleophilic aromatic substitution step from 4 to 2-
(thiomethyl)phenyl methyl sulfone (6), as the patent
experimental procedure (Scheme 1) did not describe the actual
setup or workup of the transformation, and only a GLC analysis
was reported. Ultimately, however, we relied on the use of the
same method that we defined in step one to achieve our step-
three transformation (Scheme 2). One drawback, however, was
that the use of multiple equivalents of potassium methanethio-
late (reagent controlled by the amount of milled potassium
hydroxide used), always led to the retention of 10−15% of the
unreacted chloro substrate 4 that could not be pushed to
product. Rather than resubject the incomplete precursor/
product mixture to the reaction conditions, we eventually
devised a method to remove most of the unreacted 4 through
an aqueous wash, and the residual impurity was carried into the
final step where the remainder was removed. Workup of this
reaction on scale (typically 6-kg runs) was to dilute the mixture
at room temperature with water followed by stirring for 2 h and
vacuum filtration to provide the 2-(thiomethyl)-substituted
product 6 as a white solid, contaminated only with 4−7% of the
2-chloro-substituted starting material 4. Although this purifica-
tion method significantly diminished the yield for this step, the
1
material was typically measured at >90% purity by H NMR
analysis. Even with the lower throughput in comparison to the
yield described for the analogous substrate exemplified in the
patent procedure (Scheme 1), we demonstrated that our
process was amenable to the production of kilogram quantities
of our pure desired product.
We initially devoted a small amount of effort toward
identifying an oxidative chlorination process different from
the patent procedure (Scheme 1) for the conversion of
thioanisole 6 to aryl sulfonyl chloride 8, although we ultimately
elected to utilize the chlorine gas oxidation method to complete
our campaign. Small-scale exploratory experiments (some
shown in Table 2)6 were performed with conditions known
to oxidatively chlorinate aryl alkyl sulfides, many of which in
our hands led to incomplete conversion of 6 to desired sulfonyl
chloride 8. Formation of in-process intermediates were often
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complete rejection of the contaminant 4. Typically the material
was measured at >98% purity by both HPLC and H NMR
resulting solution was extracted with hexanes (2 × 10 L). The
combined organic layers were washed with water (12 L) and
saturated aqueous sodium chloride solution (2 L). The solvent
was removed under reduced pressure (30 mmHg vacuum, final
bath temperature 45 °C) on a rotary evaporator to produce 2 as
an opaque, light-yellow oil that was suitable for further use
without purification (6.36 kg, 90% yield): TLC Rf (1:19 ethyl
acetate/hexanes) = 0.72; 1H NMR (300 MHz, CDCl3) δ 7.36−
7.08 (m, 4H), 2.48 (s, 3H); ESI MS m/z 158 [M]+. The
spectral data were also identical to those of a sample obtained
commercially.
1
analyses. Interestingly, the impurity 4 could subsequently be
recovered for recycle by further dilution of the filtrate with
water, stirring for 1 h and filtration. About 2−5% of 2-
chlorophenyl intermediate 4 could be reclaimed in this manner
in varying degrees of purity (typically 80−90%), and in one
case several batches of the reclaimed material were combined
and triturated from water to provide a single lot of 4 that was
clean enough to carry forward.
The apparent disparity between the good yields reported for
the patent procedure (Scheme 1) and lower throughput
reported for our process (Scheme 2) seems to rest largely on
the difference in scale. In our hands the patent procedure
(reported at 84% on 13.2-g scale) worked very well on smaller-
scale demonstration reactions, but returned lower yields upon
successively large-scale preparations. This lowering of through-
put from 6 to 8 directly correlated with the amount of sulfonyl
chloride hydrolysis byproduct (sulfonic acid) observed in the
aqueous filtrates from the product isolation step. Although the
extent of sulfonic acid byproduct formation was difficult to
quantitate precisely (both from the mother liquors and from in-
process reaction samples), we concluded that amount of
hydrolysis was related to the amount of water in the reaction
required as a reagent (more than 3 equiv was sometimes used)
as well as the necessity for prolonged heating at the reaction
stage on larger scale. Additionally, the solubility of product 8 in
the reaction solvent (acetic acid) required large volumes of
water to precipitate it from the reaction mixture, but even so,
this purification and isolation step was never optimized and in
some runs significantly diminished the yield for this final step.
Nevertheless, we were pleased to find that our oxidative
chlorination procedure was sufficient for the preparation of the
multikilogram lots of material we required to meet an
aggressive timeline. We also noted that there was no significant
hydrolysis of the isolated solid product observed, even in lots of
solid retainer samples analyzed several years afterward.
2-Chlorophenyl Methyl Sulfone (4).8a,9 A flask was
charged with methylene chloride (10 L), acetonitrile (10 L),
and water (20 L). To this biphasic mixture was added 2-
chlorothioanisole (2, 3.00 kg, 18.9 mol) and then sodium
metaperiodate (8.49 kg, 39.7 mol, 2.1 equivalents). Ruthenium
trichloride hydrate (2.0 g, 19 mmol, 0.05 mol %) was
introduced in 500-mg portions at 15-min intervals to minimize
the immediate exothermic heating of the reaction mixture,
which increased the internal reaction temperature to 50 °C
during the 1-h addition. The reaction mixture was stirred for an
additional 4 h, during which time the mixture cooled to room
temperature. Water (60 L) was added, the organic layer was
collected, the aqueous layer was extracted with methylene
chloride (2 × 10 L), and the combined organic layers were
washed with water (20 L) and saturated aqueous sodium
chloride solution (4 L). The solvent was removed under
reduced pressure (25 mmHg vacuum, final bath temperature 50
°C) on a rotary evaporator to produce a dark-green oil which
was triturated with hexanes (4 L) and stirred on a rotary
evaporator (no heat or vacuum) for 14 h. The precipitates were
collected by filtration and washed with hexanes (1 L) to
produce 4 as a light-green powder (3.30 kg, 91% yield): TLC Rf
(3:7 ethyl acetate/hexanes) = 0.41; mp 89−91 °C (lit.8a 93−94
°C); 1H NMR (300 MHz, CDCl3) δ 8.16 (dd, J = 1.6, 8.5 Hz,
1H), 7.67−7.56 (m, 2H), 7.55−7.43 (m, 1H), 3.28 (s, 3H); ESI
MS m/z 190 [M]+. The spectral data were also identical to
those of a sample obtained commercially.
In conclusion, we have devised a practical and scalable
multikilogram-scale process for the preparation of 2-
(methanesulfonyl)benzenesulfonyl chloride (8), a key building
block used in the synthesis of several drug candidates.7 The
material can be prepared by an efficient four-step sequence
using inexpensive precursors (1,2-dichlorobenzene, methane-
thiol, potassium hydroxide, water, and chlorine gas), demon-
strating a throughput in 32% overall yield and with a product
chemical purity of >98%.
2-Thiomethylphenyl Methyl Sulfone (6). A flask was
equipped with a gas outlet bubbler leading to a mechanically
stirred aqueous sodium hypochlorite scrubber. The flask was
charged with N,N-dimethylformamide (20 L), 2-chlorophenyl
methyl sulfone (4, 5.99 kg, 31.4 mol), and finely ground
potassium hydroxide (1.94 kg, 34.6 mol, 1.1 equiv). Methyl
mercaptan (3 equiv estimated) was introduced into the flask
over 2.5 h through the gas inlet tube below the surface of the
reaction mixture. During this time, the gas addition had caused
an exothermic heating of the reaction mixture, increasing the
internal reaction temperature to 75 °C, and this temperature
was maintained throughout the gas addition. The methyl
mercaptan flow was then terminated, and the reaction mixture
was heated to 100 °C and stirred for 1 h, after which it was
cooled to room temperature over 12 h. Water (40 L) was
added to the mixture, and the resulting slurry was stirred at
room temperature for 1 h. The precipitate was collected by
filtration and washed with water (2 L). The solid product was
dried over 12 h (30 mmHg vacuum, 60 °C) to provide 6 as a
light-tan solid that was shown to contain unreacted starting
material 4 as a 5% impurity, but was used in the next step
without further purification (4.39 kg, 69% yield): TLC Rf (3:7
EXPERIMENTAL PROCEDURES
■
2-Chlorothioanisole (2).3b,8 A flask was equipped with a
gas outlet bubbler leading to a mechanically stirred aqueous
sodium hypochlorite scrubber. The flask was charged with N,N-
dimethylformamide (30 L), 1,2-dichlorobenzene (1, 5.0 L, 6.5
kg, 44.4 mol), and finely ground potassium hydroxide (2.7 kg,
48.9 mol, 1.1 equiv). Methyl mercaptan (3 equiv estimated)
was introduced into the flask over 3.5 h through the gas inlet
tube, below the surface of the reaction mixture. During this
time, the gas addition had caused an exothermic heating of the
reaction mixture, increasing the internal reaction temperature
to 60 °C, and this temperature was maintained throughout the
gas addition. The methyl mercaptan flow was then terminated,
and the reaction mixture was heated at 100 °C for 1.5 h. The
reaction mixture was then cooled to room temperature over 12
h. Water (28 L) was added to the reaction mixture, and the
1
ethyl acetate/hexanes) = 0.34; mp 71−73 °C; H NMR (300
MHz, CDCl3) δ 8.06 (dd, J = 1.2, 8.0 Hz, 1H), 7.57 (dt, J = 1.3,
7.4 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H),
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3.24 (s, 3H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
139.80, 137.27, 133.78, 130.03, 126.72, 124.93, 41.66, 16.16;
ESI MS m/z 202 [M]+.
A.; Perez, S.; Galiano, S.; Juanenea, L.; Erviti, O.; Frigola, C.; Aldana,
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Dong, H.; Sisco, R. M.; Doss, G. A.; Leiting, B.; Patel, R. A.; Wu, J. K.;
Marsilio, F.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett.
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Bencsik, J. R.; Josey, J. A. J. Comb. Chem. 2007, 9, 1177−1187.
(i) Zhao, S.-H.; Berger, J.; Clark, R. D.; Sethofer, S. G.; Krauss, N. E.;
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D.; Tio, C.; Kagan, N.; Eisennagel, S.; Dasgupta, M.; Tomczuk, B.;
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Tiwari, R.; Tjarks, W. Nucleosides, Nucleotides Nucleic Acids 2008, 27,
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(2) (a) Josey, A. D. U.S. Patent 4,683,091, 1987. (b) Josey, A. D. U.S.
Patent 4,783,285, 1988.
2-Methanesulfonylbenzenesulfonyl Chloride (8).2,7,10
A flask was equipped with a coldfinger condenser operating at
−78 °C as a gas outlet bubbler. The flask was charged with
glacial acetic acid (7.5 L), water (640 mL, 35.4 mol), and 2-
thiomethylphenyl methyl sulfone (6, 2.31 kg, 11.4 mol,
contaminated at 5% with intermediate 4). Chlorine gas
(about 6 equiv) was introduced into the flask over 5 h through
the gas inlet tube below the surface of the reaction mixture at a
rate which kept the internal reaction temperature from
exothermic heating in the 45−55 °C range. [Note: During
this time, TLC analysis of the reaction mixture showed the
formation of a more polar component (Rf = 0.16; 1:1 ethyl
acetate/hexanes), which later converted to the less polar
product component.] The chlorine flow was then terminated,
and the reaction mixture was heated to 50 °C and stirred for 3.5
h, after which it was cooled to room temperature over 12 h. Ice
and water (10 L) were added, and the resulting slurry was
stirred for 1 h, after which the precipitate was collected by
filtration. The solids were then dried overnight (30 mmHg
vacuum, 50 °C) to produce 8 as a white solid (1.57 kg, 57%
yield): TLC Rf (1:1 ethyl acetate/hexanes) = 0.54; mp (DSC)
136 °C (lit.10 136−137 °C); IR (KBr) 2108, 1570, 1426, 1372,
(3) With sodium methanethiolate: (a) Chianelli, D.; Testaferri, L.;
Tiecco, M.; Tingoli, M. Synthesis 1982, 475−478. (b) Kemmitt, T.;
Levason, W. Organometallics 1989, 8, 1303−1308. (c) Zeller, W. E.
Methanethiol In e-EROS Encyclopedia of Reagents for Organic Synthesis;
John Wiley & Sons, Ltd: Chichester, UK, 2001. With other metal
alkanethiolates: (d) Landini, D.; Montanari, F.; Rolla, F. J. Org. Chem.
1983, 48, 604−605. (e) Hay, J. V. Pestic. Sci. 1990, 29, 247−261.
(f) Clayden, J.; Cooney, J. J. A.; Julia, M. J. Chem. Soc., Perkin Trans. 1
1995, 7−14.
1
1323 cm−1; H NMR (300 MHz, CDCl3) δ 8.42 (dt, J = 1.4,
7.5 Hz, 2H), 7.98−7.26 (m, 2H), 3.41 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 136.04, 134.66, 133.09, 131.61, 45.02; ESI MS
m/z 255 [M + H]+. Anal. Calcd. For C7H7ClO4S2: C, 33.01; H,
2.77. Found: C, 33.12; H, 2.67. HPLC analysis (Keystone
Scientific Kromasil C18 column, 4.6 mm × 150 mm, 25 °C, 1:1
acetonitrile/water, 1.0 mL/min flow, retention time = 5.22
min) showed one peak, with a total purity of 99.1% (area %).
The spectral data were also identical to those of a sample
obtained commercially. The filtrate was further diluted with
water (30 L), and the resulting slurry was stirred for 30 min,
after which the precipitate was collected by filtration and
washed with water (1 L). The solids were then dried overnight
(30 mmHg vacuum, 50 °C) to produce 2-chlorophenyl methyl
sulfone (4) as a light-yellow solid (47 g, 41% recovery from the
second step).
(4) Representative citation for oxidation using sodium hypochlorite
with phase transfer catalyst: (a) Ramsden, J. H.; Drago, R. S.; Riley, R.
J. Am. Chem. Soc. 1989, 111, 3958−3961. Representative citations for
oxidation using sodium hypochlorite: (b) Wood, A. E.; Travis, E. G. J.
Am. Chem. Soc. 1928, 50, 1226−1228. (c) Khurana, J. M.; Panda, A.;
Ray, A.; Gogia, A. Org. Prep. Proced. Int. 1996, 28, 234−237.
Representative citations for oxidation using peracetic acid (H2O2/
HOAc): (d) Beck, J. R.; Yahner, J. A. J. Org. Chem. 1978, 43, 2048−
2052. (e) Bergman, A.; Wachtmeister, C. A. J. Labelled Compd.
Radiopharm. 1987, 24, 925−930. (f) Tiecco, M.; Tingoli, M.;
Testaferri, L.; Chianelli, D.; Maiolo, F. Synthesis 1982, 6, 478−480.
Representative citations for oxidation using potassium peroxymono-
sulfate (Oxone): (g) Kennedy, R. J.; Stock, A. M. J. Org. Chem. 1960,
25, 1901−1906. (h) Trost, B. M.; Curran, D. P. Tetrahedron Lett.
1981, 22, 1287−1290. Representative citations for oxidation using
potassium peroxymonosulfate (Oxone) with bentonite clay: (i) Hirano,
M.; Tomaru, J.; Morimoto, T. Chem. Lett. 1991, 3, 523−524.
(j) Hirano, M.; Tomaru, J.; Morimoto, T. Bull. Chem. Soc. Jpn. 1991,
64, 3752−3754.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rjason.herr@amriglobal.com.
■
Notes
The authors declare no competing financial interest.
(5) Su, W. Tetrahedron Lett. 1994, 35, 4955−4958.
(6) General reviews on oxidative chlorination methods: (a) Taylor;
P. C. Comprehensive Organic Functional Group Transformations;
Pergamon: Elsevier Science Ltd., 1995, Vol. 2, 674. (b) Hudlicky,
M. Oxidations in Organic Chemistry; ACS Monograph 186, American
Chemical Society, Washington, DC, 1990, 250. Representative
citations for oxidative chlorination using N-chlorosuccinimide
(NCS): (c) Nishiguuchi, A.; Maeda, K.; Miki, S. Synthesis 2006,
4131−4134. (b) Xia, M.; Chen, S.; Bates, D. K. J. Org. Chem. 1996, 61,
9289−9292. (d) See also the use of 2,4-dichloro-5,5-dimethyl
hydantoin (DCDMH): Pu, Y.-M.; Christesen, A.; Ku, Y.-Y.
Tetrahedron Lett. 2010, 51, 418−421. (e) Representative citation
for oxidative chlorination using sodium hypochlorite: Wright, S. W.;
Hallstrom, K. N. J. Org. Chem. 2006, 71, 1080−1084. Leading
citations using chlorine gas in aqueous acidic solutions: (f) Roblin, R.
O.; Clapp, J. W. J. Am. Chem. Soc. 1950, 72, 4890−4892. (g) Conrow,
R. E.; Dean, D.; Zinke, P. W.; Deason, M. E.; Sproull, S. J. Org. Process
Res. Dev. 1999, 3, 114−120. (h) Wang, C.; Hamilton, C.; Meister, P.;
ACKNOWLEDGMENTS
■
We thank AMRI colleagues Mary Ellen Buckley and Maria
Maychack for help in retrieving archived files and materials, and
Drs. David Lathbury and Keith Barnes for critical review of the
manuscript.
REFERENCES
■
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