Applications of the (PhO)3PCl2 reagent: A new protocol for mild cleavage of sulfinamides and sulfonamides

Article abstract of DOI:10.1080/10426500500542927

The triphenyl phosphite-chlorine reagent, freshly in situ prepared by the action of chlorine on a solution of triphenyl phosphite in dichloromethane, is successfully used in the cleavage of both sulfinamides and sulfonamides under extremely mild conditions (-15°C to r.t.). Final amines are easily recovered by a simple acid/base extraction, and no further purification is required. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500542927

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Phosphorus, Sulfur, and Silicon
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Applications of the (PhO)3PCl2
Reagent: A New Protocol for
Mild Cleavage of Sulfinamides
and Sulfonamides
Alberto Spaggiari a & Fabio Prati a
a Dipartimento di Chimica , Università di Modena e
Reggio Emilia , Modena, Italy
Published online: 01 Feb 2007.
To cite this article: Alberto Spaggiari & Fabio Prati (2006) Applications of the
(PhO)3PCl2 Reagent: A New Protocol for Mild Cleavage of Sulfinamides and
Sulfonamides, Phosphorus, Sulfur, and Silicon and the Related Elements, 181:8,
1825-1830, DOI: 10.1080/10426500500542927
To link to this article: http://dx.doi.org/10.1080/10426500500542927
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Phosphorus, Sulfur, and Silicon, 181:1825–1830, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500542927
Applications of the (PhO)3PCl2 Reagent: A New Protocol
for Mild Cleavage of Sulfinamides and Sulfonamides
Alberto Spaggiari
Fabio Prati
Universita` di Modena e Reggio Emilia, Dipartimento di Chimica,
Modena, Italy
The triphenyl phosphite-chlorine reagent, freshly in situ prepared by the action of
chlorine on a solution of triphenyl phosphite in dichloromethane, is successfully
used in the cleavage of both sulfinamides and sulfonamides under extremely mild
conditions (−15◦C to r.t.). Final amines are easily recovered by a simple acid/base
extraction, and no further purification is required.
Keywords Amines; chlorine; cleavage; sulfinamides; sulfonamides; triphenyl phosphite
INTRODUCTION
Sulfinamides and sulfonamides represent two classes of highly ver-
satile intermediates in chemical synthesis.1−3 Along with their use-
fulness, however, they are strictly endowed with a remarkably strong
chemical stability, which makes them either resistant and, conversely,
quite difficult to cleave off,4 thus often discouraging their application
as protective groups. In the course of our recent investigations into
the chemistry of the triphenyl phosphite-chlorine reagent,5,6 we had
already faced N-monosubstituted amides and had reported a highly
efficient, and so far the mildest, method for the deacylation of such
compounds.5 Thus, spurred by the gratifying success obtained in those
circumstances and encouraged by the intrinsic structural resemblance,
we decided to make a preliminary study aimed at exploring whether
Received March 31, 2005; accepted September 27, 2005.
We thank Riccardo Rubbiani for preliminary experiments and Prof. Franco Ghelfi (Di-
partimento di Chimica, Universita` di Modena e Reggio Emilia, Modena, Italy) for kindly
providing the chlorine delivery plant. The authors are also grateful to the Fondazione
Cassa di Risparmio di Modena (Modena, Italy) for financial support.
Address correspondence to Alberto Spaggiari, Universita` di Modena e Reggio Emilia,
Dipartimento di Chimica, via Campi, 183, Modena, 41100, Italy. E-mail: spaggiari.
alberto@unimore.it
1825

1826
A. Spaggiari and F. Prati
the same reagent could be conveniently employed also in the cleavage
of more resistant sulfinamides.
Available methods described in the literature for carrying out the
removal of the sulfur-containing fragment in sulfinamides often deal
with severe reaction conditions, like acidic7,8 or basic9 hydrolysis. Acid-
catalyzed alcoholysis to sulfinates10 and, more recently, the use of a pe-
riodinane reagent reported by Davis et al.11 as well as the reaction with
thiols associated to Lewis’ acid settled by Li et al.1 represent the only
attempts to provide milder methods for cleavage. Also, sulfonamides
usually require severe conditions to be cleaved, such as, for instance,
the action of organolithium reagents,12 alkali metals,13 arene radical
anions,14 and hydrobromic acid.15 Thus, the quest for a general cleav-
age protocol under mild conditions would be a desirable issue in organic
sulfur chemistry, and this communication therefore aims to propose a
novel route that can possibly be applied to all kinds of amides by simply
exploiting the high versatility of the same phosphorus-based halogenat-
ing reagent.
RESULTS AND DISCUSSION
In this context, we describe here our preliminary results when sulfi-
namides 1–3 were treated with (PhO)3PCl2 in dry dichloromethane,
according to the reaction pathway, as depicted in Scheme 1.
SCHEME 1
The reagent was prepared in situ, by bubbling chlorine in a solution
of triphenyl phosphite in anhydrous dichloromethane at −15◦C. A sub-
strate was added, quickly followed by triethylamine, and the reaction
mixture was left to stir at this temperature over a three-hour period.16
A large excess of ethylene glycol was then added, and the mixture
was stirred for an additional twelve-hour period. Dichloromethane was
then removed under reduced pressure and replaced by water. Vigorous

Applications of the (PhO) PCl Reagent
1827
3
2
TABLE I (PhO)3PCl2-Promoted Cleavage
Results on Sulfur-Containing Amides
Entry
R
Yield (%)
1
2
3
4
5
6
7
p-tolyl
41
50
52
61
47
50
40
CH(CH3)Ph (α-phenylethyl)
CH2CH2Ph (β-phenylethyl)
p-tolyl
CH(CH3)Ph (α-phenylethyl)
CH2CH2Ph (β-phenylethyl)
p-tolyl
stirring was continued for two hours and a final acid/base extraction
with dichloromethane yielded the expected amines in 41–52%, as re-
ported in Table I (entries 1–3).
According to the same procedure, we also tried to assess the fea-
sibility of this protocol when applied to sulfonamides (Scheme 2), yet
another valuable class of compounds largely used in organic synthesis.
Again, when substrates 4–6 were first exposed to the (PhO)3PCl2
reagent at −15◦C in dry dichloromethane in the presence of triethy-
lamine and then treated with an excess of ethylene glycol, the corre-
sponding amines were easily recovered in a 47–61% yield (Table I, en-
tries 4–6), thus demonstrating that the oxophilic phosphorus reagent
can exert its action independently in the presence of more than one oxy-
gen atom, and, consequently, by the oxidation state of the sulfur atom
as well.
SCHEME 2
By close analogy to tosylamides, mesylamides also, as in the case of
p-tolylmesylamide 7, proved to be sensitive when exposed to the same
reaction conditions.
As far as the mechanistic insights are concerned, these preliminary
results would suggest that, similar to carboxyamides, sulfonamides and

1828
A. Spaggiari and F. Prati
sulfinamides also proceed to amines through an iminosulfinyl- or imi-
nosulfonyl chloride analogue (Scheme 3).
SCHEME 3
This initial transformation is achieved by a means of the halogenat-
ing action of the oxophilic phosphorus reagent (PhO)3PCl2 which, in
turn, is converted to triphenyl phosphate, according to its already ex-
plored reactivity.5 A final alcoholysis of the iminochloride with ethylene
glycol and water finally reveals the expected amine, along with either
p-toluenesulfonyl or p-toluenesulfinyl acid, which remains, as sodium
salt, in the aqueous layer at the end of the extraction.17 To the best
of our knowledge, although this method does not represent the most
efficient protocol for the cleavage of sulfur-based amides, and despite
its limitation to the N-monosubstituted amides, it involves, however,
the mildest reaction conditions, avoiding both harsh reagents and high
temperatures, thus becoming a potentially intriguing choice for per-
forming these deprotections when sensitive functionalities are present
everywhere in the substrates. This circumstance seriously blocks the
route of the most common (and severe) procedures of cleavage. We are
at present undertaking further investigations into this reaction, as well
as into mechanistic studies, and will report fully in due course.
EXPERIMENTAL
General
All glassware used in the reaction was oven dried and argon flushed.
Dichloromethane was dried according to the standard procedure. Triph-
enyl phosphite was purchased from Aldrich and used without further
purification. Chlorine used in the synthesis of the (PhO)3PCl2 was
checked, and it had a 99.8% title. Triethylamine was purchased from
Acros Organics and distilled and stored over KOH before using. Sul-
fonamides and sulfinamides 1–7 were prepared according to standard
procedures.

Applications of the (PhO) PCl Reagent
1829
3
2
General Procedure for the Cleavage of Sulfinamides
and Sulfonamides
In a two-necked 50 mL round-bottom flask, anhydrous dichloromethane
(15 mL) was cooled to −15◦C under an argon atmosphere, and triph-
enyl phosphite (1100 µL, 4.2 mmol) was added. Chlorine was then
bubbled in until the solution became intensely yellow. The color was
discharged by the addition of a few drops of triphenyl phosphite, and
sulfonamide 4 (1000 mg, 3.8 mmol) was added, quickly followed by tri-
ethylamine (610 µL, 4.4 mmol). The reaction was stirred at this temper-
ature over a two-hour period, and then the cold bath was removed, and
the mixture was slowly warmed to r.t. After two hours, ethylene glycol
(4000 µL, 49 mmol) was added, and the stirring continued overnight.
Dichloromethane was removed under reduced pressure and replaced
by water (10 mL). After two hours, the mixture was acidified to pH of
about 4 by 10% HCl, and the aqueous phase was then basified to pH
11 by 20% NaOH. A final extraction with dichloromethane yielded the
expected p-toluidine in 61%.
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Prati, Ars Pharm., 46, 167 (2005).
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[16] For more detailed information on the nature of this reagent and related exper-
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Fisher, US Patent 4,230,644, (1980); Chem. Abstr., 94, 156523 (1981); L. D. Hatfield,

1830
A. Spaggiari and F. Prati
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[17] A GC-MS analysis of the crude reaction mixture in the course of desulfonylation of
amide 4 revealed the presence of p-toluenesulfonyl chloride.