Aqueous process chemistry: The preparation of aryl sulfonyl chlorides

Article abstract of DOI:10.1021/op9000862

The use of aqueous acidic conditions for the preparation of arylsulfonyl chlorides from diazonium salts in the presence of copper salts, preferably CuCl, together with thionyl chloride as the sulfur dioxide source, has considerable advantages over recommended literature procedures, whereby reactions are carried out in acetic acid with minimisation of water content of the solvent. The method has been shown to be successful for a wide range of electron-deficient and electron-neutral aryl substrates. The sulfonyl chlorides are protected from hydrolysis by their low solubility in water, which results in their direct precipitation from the reaction mixture in good yields (>70%) and high strength (>98% w/w). The aqueous process, which is additionally safer and more robust, can be readily scaled up and has significant environmental benefits.

Full text of DOI:10.1021/op9000862

Organic Process Research & Development 2009, 13, 875–879
Aqueous Process Chemistry: The Preparation of Aryl Sulfonyl Chlorides
Philip J. Hogan* and Brian G. Cox
AstraZeneca PR&D, Silk Road Industrial Park, Charter Way, Macclesfield, Cheshire SK10 2NA, U.K.
Abstract:
Scheme 1. Formation of sulfonamide 3
The use of aqueous acidic conditions for the preparation of
arylsulfonyl chlorides from diazonium salts in the presence of
copper salts, preferably CuCl, together with thionyl chloride as
the sulfur dioxide source, has considerable advantages over
recommended literature procedures, whereby reactions are carried
out in acetic acid with minimisation of water content of the solvent.
The method has been shown to be successful for a wide range of
electron-deficient and electron-neutral aryl substrates. The sulfonyl
chlorides are protected from hydrolysis by their low solubility in
water, which results in their direct precipitation from the reaction
mixture in good yields (>70%) and high strength (>98% w/w).
The aqueous process, which is additionally safer and more robust,
can be readily scaled up and has significant environmental benefits.
Scheme 2. Formation of sulfonyl chloride 1
Introduction
Reaction rates in liquid-liquid and solid-liquid two-phase
systems are proportional to the reactant solubility in the reacting
1
phase. One consequence of this is that substrates highly
susceptible to hydrolysis may be stable in the presence of water,
provided that their aqueous solubility is sufficiently low. We
wish to show that this can be used to advantage in the
development of a manufacturing process for aryl sulfonyl
chlorides, in particular, 2-chloropyridine-3-sulfonyl chloride, 1,
used to form sulfonamide 3, isobutyl [(2-chloropyridin-3-
yl)sulfonyl](5-methylpyrazin-2-yl)carbamate, via reaction with
isobutyl (5-methylpyrazin-2-yl)carbamate, 2, in the presence of
sodium hydride, Scheme 1.
3a
introduced by Meerwein , involving reaction of the appropriate
diazonium salt with sulfur dioxide in the presence of copper
salts. This is illustrated in Scheme 2, which includes recom-
mended literature conditions for the transformation. These
include the use of acetic acid as solvent, concentrated aq HCl
with NaNO to effect diazotisation, and addition of the
2
diazonium salt, 6, to sulfur dioxide in acetic acid in the presence
of an appropriate copper salt to generate the desired sulfonyl
chloride. An important additional factor is the minimisation
of the water content of the system.
In preliminary work, we found it is necessary to avoid
temperatures above 5 °C in order to prevent uncontrolled
decomposition of the intermediate diazonium salt, 6, and that
the use of copper(I) chloride, in preference to commonly used
copper(II) chloride, enabled a considerable reduction in copper
The sulfonamide, 3, is a common intermediate in the
preparation of a series of endothelium antagonists, such as N-(3-
4-7
methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-
2
3-sulfonamide, 4.
2
usage (0.02 equiv compared with typically 0.25 equiv of CuCl ).
In practice, reaction according to Scheme 2 proceeded well,
with nonisolated yields of over 70%, the major impurities being
the Sandmeyer product, 2,3-dichloropyridine (7), the hydrolysis
The most convenient way of producing aryl sulfonyl
chlorides, such as 1, is by a modified Sandmeyer reaction,
(
3) Meerwein, H; Dittmar, G.; Gollner, R.; Hafner, K; Mensch, F; Steiner,
O. Chem. Ber. 1957, 90, 841.
(
4) Gilbert, E. E. Synthesis 1969, 1, 3.
*
Author to whom correspondence should be addressed. E-mail:
(5) Saunders, K. H.; Allen, R. L. M. Aromatic Diazo Compounds, 3rd
ed.; Edward Arnold: London, 1985.
philip.hogan@tiscali.co.uk.
(1) Atherton, J. H.; Carpenter, K. J. Process DeVelopment: Physicochem-
ical Concepts; Oxford University Press: New York, 1994; Chapter
(6) Krishnan, L; Wilk, B. K.; Varriano, J. P. (Wyeth). PCT Int. Appl.
US02/34900, 2001.
8
.
(7) Lebegue, N.; Gallet, S.; Flouquent, N.; Carato, P.; Pfeiffer, B.; Renard,
P.; L e´ once, S.; Pierr e´ , A.; Chavatte, P.; Berthelot, P. J. Med. Chem.
2005, 48, 7363–7373.
(
2) Bradbury, R. Hugh; Butlin, R. J.; James, R. (Zeneca Limited, UK).
PCT Int. Appl. 9640681, 1996.
1
0.1021/op9000862 CCC: $40.75  2009 American Chemical Society
Vol. 13, No. 5, 2009 / Organic Process Research & Development
•
875
Published on Web 09/03/2009

Scheme 3. Formation of disulfide 9
Scheme 5. Aqueous process for the formation of sulfonyl
chloride 1
Scheme 4. Conversion of disulfide 9 to sulfonyl chloride 1
Scheme 6. Mechanism of sulfonyl chloride formation
product, 2-chloropyridine-3-sulfonic acid (8), the disulfide, 3,3′-
dithiobis(2-chloropyridine (9), and the sulfone, 3,3′sulfonylbis(2-
chloropyridine (10).
The process developed is illustrated in Scheme 5. As
expected, the product precipitated from the reaction mixture
(>98% w/w), thus being protected from hydrolysis, with an
overall yield of 72%. It could be isolated as the solid or extracted
into toluene and used directly in the subsequent stage (Scheme
1). Furthermore, additional benefits arose from the increased
thermal stability of the aqueous diazonium solution, compared
with that in acetic acid as solvent, and the avoidance of the
need in the earlier process to neutralise the acetic acid and
organic extracts with aqueous base. The latter enabled a
considerable reduction in the effluent load of the process.
The in situ reaction of thionyl chloride with water to generate
The requirement of an acid-free sulfonyl chloride in the
subsequent reaction stage (Scheme 1), however, necessitated
an aqueous drown-out, followed by neutralisation of the acid,
and extraction and crystallisation of the product. Two major
issues arose: (1) losses due to hydrolysis during isolation were
considerable, with the result that isolated yields at large scale
were typically around 45% and showed considerable variability,
and (2) the effluent load was very high. The product losses could
be reduced by cold and rapid neutralisation, but this becomes
increasingly difficult on scale-up. Additionally, SO dissolution
2
via headspace saturation took a significant time (>10 h) at larger
scales.
In view of these difficulties we decided to explore alternative
reaction workup conditions and reaction schemes, as described
below.
SO
2
for the second stage of this aqueous process, rather than
, was found to be very beneficial; the latter
saturated aq SO
2
gave only a 10% yield of a low-purity product (32% w/w). The
successful use of thionyl chloride suggests that the accompany-
ing high levels of chloride generated by the hydrolysis of thionyl
2
chloride to SO are needed for efficient generation of 1 under
aqueous conditions. The proposed reaction mechanism, Scheme
3,8
6,
necessarily includes reaction with chloride, but we note
that reactions of the diazonium ions with SO in acetic acid do
not require HCl additional to that produced during diazonium
2
3-7
formation. In practice, the use of thionyl chloride rather than
SO is also operationally more convenient, and this point was
Results and Discussion
2
Attempted variations in the workup and changes to the
sulfonation stage to include acetic acid/dichloromethane mix-
tures, from which a product-rich dichloromethane phase sepa-
rated, did not give significant benefits to either yield or effluent
generation. An alternative pathway, based on the oxidation of
disulfide, 9, was then investigated. It was prepared in 45%
isolated yield using an all-aqueous process, Scheme 3, in which
thionyl chloride was used as the SO source.
2
The reaction was not optimised, but the major byproduct
was the sulfone, 10.
Oxidation of the disulfide with Cl in aq 36% HCl gave the
2
desired sulfonyl pyridine, 1, Scheme 4.
Remarkably, the product crystallised from the aqueous
reaction mixture in a very pure state (∼100% w/w) and in a
yield of 84%. The overall yield (equivalent to 34% from
not explored further.
The method illustrated in Scheme 5 has been extended to
several other substrates, and the outcomes are listed in Table
1.
Quantitative studies of the reactivity of the various substrates
were not carried out, but it was apparent from the rate of gas
evolution during the preparations that the reaction times
decreased directly as the electron-withdrawing power of the aryl
system increased. The conversion of the diazonium ions to
sulfonyl chloride became increasingly slow as the aromatic
system became more electron neutral, and for electron-rich rings,
such as aniline and 4-aminotoluene, product formation was
almost completely inhibited. This is in contrast to reactions
carried out under standard literature conditions involving
2
reaction of the diazonium ion with SO in acetic acid. We
have not explored this further and are unsure of the reason for
the difference; it may reflect a different mechanism for
daizonium conversion under aqueous conditions.
3-7
3-amino-2-chloropyridine) was unsatisfactory, but the observa-
tion that 1 separates from the aqueous mixture in high purity
and with minimum hydrolysis suggested the possibility of using
an all-aqueous process based in Scheme 2 for the manufacture
of 1.
(8) Waters, W. A. J. Chem. Soc. 1942, 266.
8
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Table 1. Preparation of aryl sulfonyl chlorides
a
Structure confirmed by mass spectral analysis. b 3-Pyridinesufonyl chloride is an oil which is soluble in the reaction mixture and was obtained after extraction into
c
dichloromethane. In the benzene series the amine hydrochlorides were precipitated as solids during the addition of the amine to the aqueous hydrochloric acid. To ensure
complete salt formation the mixture was heated at 30 to 50 °C for up to 60 min prior to cooling and addition of the aqueous sodium nitrite solution (diazonium reagent
d
formation). The products were obtained in two crops, the second crop being precipitated from the combined aqueous mother liquor and wash filtrates.
e
4
-Chlorobenzenesulfonyl chloride, 4-(chlorosulfonyl)benzoic acid, and 2-bromobenzenesulfonyl chloride were precipitated from their reaction mixtures after allowing them to
f 1 13
warm to 20 °C and stirring at that temperature for 65, 17, and 27 h respectively. H and C NMR spectra of the products are consistent with those of the commercially
available compounds. Mp of standard commercial sample. 3-Nitrobenzenesulfonyl chloride separated from the reaction mixture as an oil which crystallised during the
g
h
i
agitation hold period prior to filtration. The soluble 3-quinolinesulfonyl chloride product was initially formed but hydrolysed in solution and precipitated as the corresponding
sulfonic acid; j DMSO-d
.
6
For very strongly electron-deficient systems, such as 4-ami-
nopyrine, 2-amino-3-nitropyridine, and 2-amino-5-chloropyri-
dine, the diazonium ions were insufficiently stable to allow
successful reactions.
on the chlorine gas oxidation of aryl propyl sulfides in formic
acid. Product isolation was achieved by quenching with cold
water and cooling to below 5 °C, resulting in product precipita-
tion with a purity of ∼97%.
The manufacture of 2-chloropyridine-3-sulfonyl chloride, 1,
has been successfully carried out in-house on the multikilogram
scale. We note that the HCl/salt-rich reaction mixtures and
process liquors are highly corrosive to mild and stainless steel,
and therefore the use of glass-, plastic-, or rubber-lined vessels
is required. Hastelloy C-276 metal, although not corroded, is
coated with an insoluble black material on contact with the
reaction mixtures or process liquors, and this can be difficult
to remove. Details of the hazard evaluation of these reactions
are given below.
Hazard Evaluation of Diazonium Salt Formation and
Reaction. Addition of Hydrochloric Acid. The heat of reaction
was determined, and thermal stability tests were carried out.
The reaction mixture after addition was shown to be stable to
well above processing temperatures. Similarly the exotherm
associated with the heat of reaction was shown to be insufficient
to generate any hazard.
Addition of Sodium Nitrite: Batch Thermal Stability. Screen-
ing and adiabatic thermal stability testing were carried out on
the diazonium solutions. The results showed that if cooling were
to be lost, then the batch would self-heat. The maximum batch
temperature attained, however, was only 44 °C, which is below
the boiling point of the batch and the temperatures from which
further exothermic decomposition could be accessed. Therefore
9
Wang et. al describe a successful alternative multikilogram-
scale process for the preparation of aryl sulfonyl chlorides, based
(
9) Wang, C; Hamilton, C; Meister, P; Menning, C. Org. Process Res.
DeV. 2007, 11, 52.
Vol. 13, No. 5, 2009 / Organic Process Research & Development
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the system was not hazardous, provided that the gas could be
safely vented (see below).
found to be advantageous for the preparation of a range of
electron-deficient or electron-neutral arylsulfonyl chlorides.
11
Addition of Sodium Nitrite: Heat of Reaction. The addition
was shown to be exothermic, such that uncontrolled addition
would result in decomposition of the diazonium ion. Decom-
position could be avoided by carrying out the addition in a
controlled manner, with agitation, and balanced against the
available cooling.
The product arylsulfonyl chlorides precipitate directly from the
reaction mixture in good yield and high quality. The omission
of acetic acid as cosolvent (which solubilises the product)
eliminates the need for extensive neutralisation of the reaction
mixtures prior to isolation, which can cause significant product
hydrolysis and yield loss.
Gas EVolution. It was shown that no significant gas was
evolved at the proposed reaction temperature. Should cooling
be lost, however, gas would be generated; adiabatic experiments
were carried out to determine the maximum gas rate. The vent
system was such that it could cope with the maximum gas rate
Experimental Section
Materials. Inorganic chemicals and starting aryl amines were
high-purity commercial reagents and were used without further
purification.
(
including a safety factor of 2).
Preparation of 2-Chloropyridine-3-sulfonyl Chloride, 1,
(Scheme 4). Hydrochloric acid (36% w/w, 20 mL) was added,
with agitation, to 3,3′-dithiobis(2-chloropyridine) (2.0 g) at 20
°C to give a pale-yellow solution. Water (5 mL) was added,
and chlorine gas bubbled through the solution for 1 h,
maintaining the temperature of the mixture at 20-23 °C. Water
(25 mL) was added dropwise to the reaction mixture, maintain-
ing the temperature at 20-29 °C. A white solid precipitated
during this addition, and after cooling the mixture to 20 °C the
suspended solid was collected by vacuum filtration, washed with
water (3 × 25 mL), and dried under vacuum at below 35 °C to
give 2-chloropyridine-3-sulfonyl chloride (2.47 g; 83.6% yield);
mp 51 °C.
Stability of Diazo in the Presence of Hastelloy C-276 and
Stainless Steel 316. Formation of diazonium ion was tested in
the presence of Hastelloy C-276. No gas was observed during
the reaction or during a subsequent hold period at 0 °C. Loss
of cooling, in the presence of Hastelloy, was investigated using
adiabatic calorimetry. The associated temperature rise and gas
rates were measured and shown to be slightly higher than in
the absence of Hastelloy, but not sufficient to generate any
hazard.
Similar work to the above, but with stainless steel 316 led
to the conclusion that the presence of large amounts of stainless
steel (e.g., in transfer lines) would result in the diazotised batch
evolving gas. It was recommended that stainless steel should
not be used for transfer lines. Work did, however, confirm that
trace amounts of stainless steel would not have any significant
effect on the stability of the diazotised batch.
1
H NMR (CDCl , 270 MHz, 300 K): δ 7.54-7.58 (m, 1H),
3
6
13
8.45-8.50 (m, 1H), 8.75-8.77 (m, 1H). C NMR (CDCl3,
270 MHz, 300 K): δ 123.0, 138.8, 139.1, 148.2, 154.8. Mass
+
+
Spec EI 211 (M ), 176 (M - Cl), 112 (M - SO Cl), 76 (112
2
General Hazards of Aqueous Diazotisation. Diazonium salt
solutions/slurries gas slowly even at low temperatures. There-
fore, transfer lines should not be sealed when containing
diazonium salt solutions, and pressure buildup between a pump
and a closed valve should not be possible.
Some diazonium salts when dry are capable of decomposing
explosively and may be friction-, shock-, and heat sensitive.
Therefore the diazonium salt solution should not be allowed to
dry out. After transfer of the diazonium salt solution, the reactor
and transfer lines etc. should be washed thoroughly. Contact
of diazonium salts with copper or nickel can result in reduced
stability and should be avoided.
- HCl).
Preparation of 2-Chloropyridine-3-sulfonyl Chloride, 1,
(Scheme 5). (a) Thionyl chloride (42 mL) was added dropwise
over 60 min to water (250 mL), cooled to 0 °C, maintaining
the temperature of the mixture 0-7 °C. The solution was
allowed to warm to 18 °C over 17 h. Copper(I) chloride (0.151
g) was added to the mixture, and the resultant yellow-green
solution was cooled to -3 °C using an acetone/ice bath
(b) Hydrochloric acid (36% w/w, 135 mL) was added, with
agitation, to 3-amino-2-chloropyridine (17.3 g), maintaining the
temperature of the mixture below 30 °C with ice cooling. The
reaction mixture was cooled to -5 °C using an ice/acetone bath
and a solution of sodium nitrite (10.0 g) in water (40 mL) was
added dropwise over 45 min, maintaining the temperature of
the reaction mixture between -5 to 0 °C, the resultant slurry
was cooled to -2 °C and stirred for 10 min.
Sodium nitrite can form explosive mixtures with amines,
sulphamates, and ammonium salts. Inadvertent mixing of
sodium nitrite with other chemicals should therefore be avoided.
Finally, we note that aqueous aromatic diazonium ions,
typically prepared by the action of mineral acids and sodium
nitrite on aromatic amines, are used extensively in the manu-
facture of azo dyes, to the extent of thousands of tons per
(c) The slurry from step b was cooled to -5 °C and added
to the solution obtained from step a over 95 min, maintaining
the temperature of the reaction mixture between -3 to 0 °C
(the slurry from step b was maintained at -5 °C throughout
the addition). As the reaction proceeded, a solid began to
precipitate. When the addition was complete, the reaction
mixture was agitated at 0 °C for 75 min. The suspended solid
was collected by vacuum filtration, washed with water (2 ×
10
annum. They can, therefore, be handled safely, provided that
precautions such as those described above are taken.
Summary
The use of totally aqueous acidic conditions for generation
and reaction of the diazonium ion intermediates, combined with
use of thionyl chloride as the sulfur dioxide source, has been
125 mL), and dried under vacuum at below 35 °C to give
2-chloropyridine-3-sulfonyl chloride (19.6 g; 70% yield.); mp
42 °C.
(
10) Kroschwitz, J. Kirk-Othmer Encyclopedia of Chemical Technology;
John Wiley & Sons: New York, 1992; Vol. 3, Azo Dyes, p 821.
(11) Hogan P. J. (Zeneca Limited, UK). PCT Int. Appl. 9840332, 1998.
8
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1H NMR (CDCl
.45-8.50 (m, 1H), 8.72-8.75 (m, 1H). C NMR (CDCl
70 MHz, 300 K): δ 123.5, 139.5, 140.0, 149.0, 155.0. Mass
, 270 MHz, 300 K): δ 7.50-7.60 (m, 1H),
1H NMR (CD
CN, 270 MHz, 300 K): δ 7.66-7.71 (m, 2H),
3
3
6
13
13
8
2
3
,
8.69 (dd, 2H), 8.79 (dd, 2H). C NMR (CD CN, 270 MHz,
3
+
300 K): δ 124.8, 134.9, 143.5, 148.6, 155.8. Mass Spec EI
+
+
Spec EI 211 (M ), 176 (M - Cl), 112 (M - SO
HCl).
Preparation of 3,3′-Dithiobis(2-chloropyridine), 9. (a)
2
Cl), 76 (112
+
2
88 (M ), 189 [M - (SO
2
+ Cl)], 160, 112, 76 (112 - HCl).
-
The product was then obtained in two solid crops as follows:
the filtrates and water washes from above were diluted with
water (800 mL), and the mixture was stirred at 20 °C for 120
min during which time a white solid was precipitated. The
suspended solid was collected by vacuum filtration, washed with
water (2 × 100 mL), and dried under vacuum at below 35 °C
Thionyl chloride (42 mL) was added dropwise over 30 min to
water (250 mL) cooled to 0 °C, maintaining the temperature
of the mixture 0-7 °C. The solution was allowed to warm to
15 °C over 17 h. Copper(I) chloride (1.33 g) was added to the
mixture to give a yellow-green solution and KI (1.42 g) added,
precipitating a beige solid. The resultant mixture was cooled
to -3 °C using an acetone/ice bath.
(
first crude solid yield, 5.52 g). Again the filtrates and water
washes from above were diluted with water (100 mL), and the
mixture was stirred at 20 °C for several days during which time
a second crop of solid precipitated. The suspended solid was
collected by vacuum filtration, washed with water (2 × 100
mL), and dried under vacuum at below 35 °C (crude second
crop yield, 3.72 g). The combined crude solid product crops
were dissolved in acetontrile (250 mL) at reflux, hot filtered to
remove unwanted insoluble material, and then cooled to 20 °C
for 17 h. The recrystallised suspended white solid was collected
by vacuum filtration, washed with acetonitrile (20 mL), and
dried under vacuum at below 35 °C to give the 3,3′-dithiobis(2-
(b) Hydrochloric acid (36% w/w, 135 mL) was added, with
agitation, to 3-amino-2-chloropyridine (17.3 g), maintaining the
temperature of the mixture below 30 °C with ice cooling. The
reaction mixture was cooled to -3 °C using an ice/acetone bath,
and a solution of sodium nitrite (10.0 g) in water (40 mL) was
added dropwise over 40 min, maintaining the temperature of
the reaction mixture between -3 to 0 °C; the resultant slurry
was cooled to -2 °C and stirred for 10 min.
(
c) The slurry from step b was cooled to -3 °C and added
to the solution obtained from step a over 55 min, maintaining
the temperature of the reaction mixture between -3 to 3 °C
the slurry from step b was maintained at -5 °C throughout
chloropyridine) (7.77 g; 40.9% yield.); mp 215-216 °C.
(
1
H NMR (CDCl , 270 MHz, 300 K): δ 7.15-7.20 (m, 2H),
3
the addition). When the addition was complete, the reaction
mixture was agitated at 0 °C for 150 min, during which time a
solid began to precipitate. The suspended solid was collected
by vacuum filtration, washed with water (2 × 100 mL), and
dried under vacuum at below 35 °C to give crude byproduct,
+
+
7
(
.78 (dd, 2H), 8.19 (dd, 2H). Mass Spec ES 291 (MH ), 289
+
M ), 250, 214 (250 - HCl).
Acknowledgment
We thank Stephen Hallam for hazard evaluation and advice
relating to the work described above.
3,3′-bis(2-chloropyridine)sulphone (5.0 g), which after dissolu-
tion in dichloromethane, washing with aqueous sodium hy-
droxide, filtration to remove precipitated inorganics, separation
and evaporation of the lower organic filtrate phase, and
recrystallisation from aqueous acetonitrile gave a white solid
byproduct 3,3′-bis(2-chloropyridine)sulfone (3.60 g, 18.9%
yield).
Received for review April 7, 2009.
OP9000862
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879