A novel preparation of 2-naphthyl and 5-benzo[B]thienyl methanesulfonyl chlorides

Article abstract of DOI:10.1081/SCC-120015818

Electron rich arylmethylsulfonyl chlorides can be prepared from arylmethyl bromides by phase transfer sulfonation and chlorination with PCl₅.

Full text of DOI:10.1081/SCC-120015818

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A Novel Preparation of 2-Naphthyl and 5-
Benzo[B]thienyl Methanesulfonyl Chlorides
Graham Walker a & Kishore K. Rana a
a GlaxoSmithKline , New Frontiers Science Park, Harlow, Essex, UK
Published online: 16 Aug 2006.
To cite this article: Graham Walker & Kishore K. Rana (2003) A Novel Preparation of 2-Naphthyl and 5-Benzo[B]thienyl
Methanesulfonyl Chlorides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:4, 627-632, DOI: 10.1081/SCC-120015818
To link to this article: http://dx.doi.org/10.1081/SCC-120015818
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 627–632, 2003
A Novel Preparation of 2-Naphthyl and
5-Benzo[B]thienyl Methanesulfonyl Chlorides
*
Graham Walker and Kishore K. Rana
GlaxoSmithKline, New Frontiers Science Park,
Harlow, Essex, UK
ABSTRACT
Electron rich arylmethylsulfonyl chlorides can be prepared from
arylmethyl bromides by phase transfer sulfonation and chlorination
with PCl5.
Key Words: Sulfonyl chlorides; Phase transfer sulfonation.
*Correspondence: Graham Walker,
GlaxoSmithKline,
Department
of
Medicinal Chemistry, New Frontiers Science Park, Coldharbour Road,
Harlow, Essex, CM19 5AD, UK; Fax: 01279-622790; E-mail: graham_r_
walker@gsk.com.
627
DOI: 10.1081/SCC-120015818
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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628
Walker and Rana
We recently required a preparation of naphthylmethylsulfonyl
chloride 1 and benzothienylsulfonyl chloride 2 from the corresponding
arylmethyl halides (Sch. 1).
A recent report of the synthesis of 1 by reaction of the sodium sulfo-
nate 3a with phosphorus oxychloride in acetonitrile–sulfolane at 70ꢀC[1] in
our hands was found to give a 2:1 mixture of 1 and the corresponding
chloride 4, which could only be separated with difficulty (Sch. 2).
Problems of this sort have been described previously in the prepara-
tion of benzylic and other electron rich sulfonyl chlorides,[2] and such
sulfonyl chlorides are also known to easily be decomposed to the benzyl
chloride.[3] Alternative routes have therefore been used in which benzylic
sulfonyl chlorides are formed by oxidation of disulfides or thiols,[4] but
such methods are unsuitable for easily oxidized systems such as 2. More
recently described methods use the reaction of tetrabutylammonium
sulfonates with triphosgene or triphenylphosphine–sulfuryl chloride,[5]
but these methods have not been applied to benzylic sulfonates.
We therefore prepared the tetrabutylammonium salt 3b and investi-
gated its chlorination with the above reagents and also with phosphorous
pentachloride. All three reagents gave mixtures of sulfonyl chloride 1 and
benzyl chloride 4, but by reducing the reaction temperature to ꢁ20ꢀC or
below the yield of benzyl chloride 4 could be reduced to less than 1%.
Both triphosgene and phosphorous pentachloride cleanly converted 3b
to 1 in over 90% yield under these conditions.
We then turned to the benzothienyl derivative 2. Unexpectedly, when
bromide 5 was treated with sodium sulfite, alcohol 6 and aldehyde 7 were
formed as well as the desired sulfonate 8a (Sch. 3). In a typical example
we obtained 37% of 6, 7% of 7, and 21% of 8a, butht ese yields were
Scheme 1.
Scheme 2.

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Preparation of Methanesulfonyl Chlorides
629
Scheme 3.
variable and in some instances none of the desired sulfonate was formed.
Corresponding by-products were also formed in the preparation of the
naphthylmethyl sulfonate 3a, but in much smaller amounts, typically
<10% total. We therefore investigated phase transfer conditions for
the direct conversion of bromide 5 to tetrabutylammonium sulfonate
8b. Normal phase transfer catalysis is not possible in this system however,
since as soon as sulphonate and bromide ions begin to be formed they
sequester the catalytic cation into the organic phase and reaction ceases.
We have now found that complete reaction can take place provided that
two equivalents of the phase transfer cation are used. Thus reaction of
1 mole of bromide 5 with 2 moles of sodium sulfite, 2 moles of
tetrabutylammonium bisulfate and 2 moles of sodium hydroxide in
dichloromethane–water gave full conversion to a 1:1 mixture of tetra-
butylammonium bromide and 8b. The use of only 1 equivalentof
tetrabutylammonium bisulfate and sodium hydroxide led to the same
productmixutre in only 50% yield. 5 and 2-naphthylmethyl bromide
were both converted to the corresponding tetrabutylammonium sulfo-
nates in >80% yield during 16 h at room temperature.
Finally we have shown that although the tetrabutylammonium
bromide present in these products cannot easily be removed, it
does not interfere in the subsequent preparations of the sulfonyl
chlorides. Best results were obtained using reverse addition to phosphor-
ous pentachloride. The phase transfer derived products 3b and
8b were added to phosphorous pentachloride in dichloromethane
at ꢁ20ꢀC and the reaction worked up by subsequent filtration of
the reaction mixture through silicagel. Sulfonyl chlorides 1 and 2 were
produced in >70% yield with minimal formation of chloromethyl
by-product.

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630
Walker and Rana
We have successfully used this route for the preparation of 5–10 g
batches of sulfonyl chlorides 1 and 2, and are investigating its utility for
the preparation of other arylmethyl sulfonyl chlorides.
EXPERIMENTAL
Tetrabutylammonium Naphthalene-2-methanesulfonate 3b
Sodium naphthalene-2-methanesulfonate[1] (12.5 g, 50 mmol) was
added to a mixture of tetrabutylammonium bisulfate (17.0 g, 50 mmol),
sodium hydroxide (2.0 g, 50 mmol), water (100 mL), and dichloromethane
(100 mL). After stirring for 15 min at room temperature the organic
layer was separated, washed with water (100 mL), dried (MgSO4), and
evaporated. Recrystallization from ethyl acetate gave 3b as rhombs,
17.5 g (76%). M.p. 115–118ꢀC; 1H NMR. (400 MHz, CDCl3) 7.88 (s,
1H), 7.72–7.78 (m, 2H), 7.69 (m, 2H), 7.39–7.44 (m, 2H), 4.20 (s, 2H),
2.86–2.90 (m, 8H), 1.25–1.37 (m, 16H), and 0.89–0.92 (m, 12H);
13C NMR (63 MHz, CDCl3) 133.4, 132.2, 129.6, 129.1, 127.8, 127.4,
126.9, 125.5, 125.3, 58.0, 57.9, 23.9, 19.8, and 13.3; MS (ESꢁ): 221
(RSOꢁ3 ) and 684 [(RSO3ꢁ)2Bþ]; Found C 69.77, H 9.79, N 3.01,
C27H45NO3S requires C 69.93 H 9.78 N 3.02.
Also prepared as described below for 8b in 76% yield.
Tetrabutylammonium Benzo[b]thiophene-
5-methanesulfonate 8b
A mixture of 5-bromomethylbenzo[b]thiophene[6] (40 g, 0.18 mol),
tetrabutylammonium bisulfate (122 g, 0.36 mol), sodium hydroxide
(14.4 g, 0.36 mol), sodium sulfite (45.4 g, 0.36 mol), water (300 mL), and
dichloromethane (300 mL) was stirred overnight at room temperature.
The separated organic layer was washed with water (300 mL), dried
(MgSO4), and evaporated. Recrystallization from tetrahydrofuran–ether
(1:1) gave an approximately 1:1 mixture of 8b and tetrabutylammonium
bromide, 123 g (88%). 1H NMR (400 MHz, CDCl3) 7.92 (s, 1H), 7.75 (d,
1H, J ¼ 8.4 Hz), 7.50 (d, 1H, J ¼ 8.4 Hz), 7.37 (d, 1H, J ¼ 5.6 Hz), 7.27 (d,
1H, J ¼ 5.6 Hz), 4.18 (s, 2H), 3.19–3.23 (m, 16H), 1.53–1.61 (m, 16H),
1.37–1.43 (m, 16H), and 0.96–1.00 (m, 24H); 13C NMR (63 MHz,
CDCl3) 139.9, 137.8, 131.8, 127.6, 126.0, 125.6, 123.9, 121.5, 58.7, 57.6,
24.3, 19.7, and 13.7; MS (ESꢁ) 227 ðRSO3ꢁ and 696 [(RSO3ꢁ)2Bþ].

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Preparation of Methanesulfonyl Chlorides
Benzo[b]thiophene-5-methanesulfonyl Chloride 2
631
Sulfonate 8b produced as above (30 g, equivalentot 38 mmol) in
dichloromethane (150 mL) was added over 10 min to phosphorous penta-
chloride (8.3 g, 40 mmol) in dichloromethane (150 mL) at ꢁ20ꢀC. The
reaction was warmed to þ20ꢀC during 25 min then filtered through
silica (150 g) washing with ethyl acetate–hexane (1:1, 300 mL).
Evaporation of the total eluate and recrystallization from hexane gave
2 as plates, 7.4 g (79%). M.p. 105–107ꢀC; H NMR (400 MHz, CDCl3)
1
7.95 (d, 1H, J ¼ 8.4 Hz), 7.93 (s, 2H), 7.53 (d, 1H, J ¼ 5.5 Hz), 7.39 (d, 1H,
J ¼ 8.4 Hz), 7.36 (d, 1H, J ¼ 5.5 Hz) and 4.99 (s, 2H); 13C NMR (63 MHz,
CDCl3) 141.6, 140.0, 128.7, 126.8, 126.5, 123.7, 123.3, 122.0, and 71.1;
MS (ESꢁ): 227(RSO3ꢁ) only; Found C 43.91, H 2.76, C9H7ClO2S2
requires C 43.81, H 2.86.
Naphthalene-2-methanesulfonyl Chloride 1[1]
Prepared in the same way from 3b in 71% yield.
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Received in the UK September 21, 2001