Synthesis of sulfonic acid derivatives by oxidative deprotection of thiols using tert-butyl hypochlorite

Article abstract of DOI:10.1021/ol400865b

Starting from alkyl halides or Michael acceptors, thioacetates were prepared in situ and further treated with t-BuOCl, affording the corresponding sulfonyl chlorides which were trapped with nucleophiles such as water, alcohol, or amines. The three steps can be achieved in a one-pot procedure. Oxidative deprotection also proved to be efficient with S-trityl and S-tert-butyl groups, making it a convenient route toward cysteic acid derivatives.

Full text of DOI:10.1021/ol400865b

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2294–2297
Synthesis of Sulfonic Acid Derivatives
by Oxidative Deprotection of Thiols
Using tert-Butyl Hypochlorite
†
Yoann Joyard, Cyril Papamicael, Pierre Bohn, and Laurent Bischoff*
†
‡
,†
€
ꢀ
ꢁ
UMR CNRS 6014 COBRA, Universite de Rouen ꢀ INSA Rouen, rue Tesniere 76130
Mont-Saint-Aignan, France, and Centre Henri Becquerel, rue d’Amiens, 76000 Rouen,
France
laurent.bischoff@univ-rouen.fr
Received March 30, 2013
ABSTRACT
Starting from alkyl halides or Michael acceptors, thioacetates were prepared in situ and further treated with t-BuOCl, affording the corresponding
sulfonyl chlorides which were trapped with nucleophiles such as water, alcohol, or amines. The three steps can be achieved in a one-pot procedure.
Oxidative deprotection also proved to be efficient with S-trityl and S-tert-butyl groups, making it a convenient route toward cysteic acid derivatives.
Sulfonic acid derivatives have always been the subject
of intensive research in organic synthesis. Sulfonamides
exhibit numerous biological properties, and they are most
well-known as antibacterial compounds.1 Sulfonic esters
are widely used as intermediates for nucleophilic displace-
ment of alcohols, and sulfonic acid salts are among the
most efficient solubilizing groups. Therefore, there is still
much ongoing research in this area. The common precur-
sor for such compounds generally consists of the sulfonyl
chloride, most often obtained via chlorination of the
parent sulfonic acids with harsh, HCl-generating reagents
such as PCl5, SOCl2, POCl3, and triphosgene, which are
not compatible with sensitive functional groups or require
difficult purifications. Milder methods, for instance using
groups on the substrates. The most widely used method
consists of bubbling gaseous Cl2 into an aqueous or a
biphasic mixture containing thiols.4
Scheme 1. Oxidation of Disulfides
cyanuric chloride2 or PPh3 Cl2,3 also give good results,
3
however with concomitant formation of stoichiometric
amounts of byproducts. On the other hand, oxidative
processes, generally starting from thiols or disulfides, are
widely used since they afford a better scope of functional
Althoughhighyieldsare generally obtained, thismethod
is not safe and the reaction medium is highly acidic and
oxidizing. Thus, other methodologies using milder reagents5
(4) (a) Watson, R. J.; Batty, D.; Baxter, A. D.; Hannah, D. R.; Owen,
D. A.; Montana, J. G. Tetrahedron Lett. 2002, 43 (4), 683–685.
(b) Percec, V.; Bera, T. K.; De, B. B.; Sanai, Y.; Smith, J.; Holerca,
†
ꢀ
Universite de Rouen ꢀ INSA Rouen.
‡ Centre Henri Becquerel.
(1) Obreza, A.; Gobec, S. Curr. Med. Chem. 2004, 11, 3263.
(2) Blotny, G. Tetrahedron Lett. 2003, 44, 1499.
(3) Kataoka, T.; Iwama, T.; Setta, T.; Takagi, A. Synthesis 1998, 423.
ꢀ
M. N.; Barboiu, B.; Grubbs, R. B.; Frechet, J. M. J. J. Org. Chem. 2001,
66 (6), 2104–2117. (c) Caldwell, W. T.; Kornfeld, E. C. J. Am. Chem. Soc.
1942, 64 (7), 1695–1698.
r
10.1021/ol400865b
Published on Web 04/19/2013
2013 American Chemical Society

dichloromethane, toluene, acetonitrile, and 1,4-dioxane,
acetonitrile was chosen because of the high yields and good
dissociative properties required for further one-pot sub-
stitutionꢀoxidation reactions.
Table 1. Oxidation of Disulfides
Moreover, as most thiols and disulfides are stench re-
agents, we were even more interested in developing a one-pot
methodology for the nucleophilic introduction of the sulfur
atom by means of a thioacetate, followed by t-BuOCl
oxidation and trapping of the sulfonyl chloride with alcohols
or amines.
Recently, another group6a has published an efficient
method for the straight conversion of thioesters into sulfonyl
chlorides, using N-chlorosuccinimide. We tested this reagent
for the oxidation of benzyl thioacetate and observed a good
yield of sulfonyl chloride. However, as an excess (4 equiv) of
reagent was used, further trapping with benzylamine yielded
stoichiometric amounts of the imine PhCHdN;CH2Ph,
as a result of the oxidation of the amine. Surprisingly, with
3 equiv of NCS, the sulfonyl chloride was cleanly obtained,
but further trapping with benzylamine only afforded a 20%
yield of sulfonamide. When using t-BuOCl, 3 equiv also
afforded a complete oxidation, and any excess of the reagent
and side products could be evaporated from the crude reaction
medium. As we needed a reactive and versatile reagent, we
kept tert-butyl hypochlorite as the oxidizing agent.
have been developed during the past decade, such as TMSCl/
KNO3,5a ZrCl4/H2O2,5b,c trichloroisocyanuric acid,5d and
N-chlorosuccinimide.5As we needed a traceless, organic
solvent-soluble reagent, we turned our attention toward
t-BuOCl. This reagent is commercially available; however,
it can be very easily prepared using bleach and t-BuOH in
acetic acid and can be stored for months at 4 °C over a 50 g
scale. Its handling is safe provided that there is neither
contact with rubber or reducing agents nor prolonged
exposure to direct sunlight. In addition, one of its advan-
tages relies on its ability to release the basic tert-butoxide
anion, thus avoiding the use of an additional base to
neutralize HCl, as required with Cl2 oxidations. Moreover,
t-BuOH, isobutene, or tert-butyl chloride are the final
byproducts; thus a simple concentration in vacuo affords
ready-to-use, clean sulfonyl chlorides.
Having these conditions in hand, we focused on one-pot
reactions, which would include the preliminary formation
Scheme 2. One-Pot Reactions
First, we sought the optimal conditions for the oxidation,
using dibenzyl disulfide as a model substrate (Scheme 1).
For more convenience, we preferred to trap the sulfonyl
chloride with benzylamine in order to obtain stable and
easy-to-purify sulfonamides. In a preliminary experiment,
we observed that treatment of dibenzyl disulfide with the
minimum amount of t-BuOCl required (5 molar equiv)
gave a 60% conversion. We presumed that the oxygen
atoms of the sulfonyl chloride arose from the tert-butoxide
anion with further isobutene elimination. In order to
achieve a faster transformation of Sþ;Cl to SdO bonds,
we added a stoichiometric amount of water, i.e. 5 molar
equiv (Table 1). The use of water was also proposed with
TCCA5d and N-chlorosuccinimide.6
Under those conditions, the oxidation proceeded at 0 °C
in a very short reaction time (15 min). Further quenching
with excess diethylamine or benzylamine afforded the
expected sulfonamides with high yields (88ꢀ96%, Table 1,
entries 1ꢀ4). We alsochecked thesuitability ofthismethod
for the formation of the stable neopentyl ester (entry 5); in
this case pyridine was added to afford the esterification.
Among various solvents that we tried, i.e. chloroform,
of thioacetates in the reaction sequence (Scheme 2). As listed
in Table 2 (entry 1) a preliminary attempt with preformed
benzyl thioacetate gave a 90% yield from oxidation/
trapping, using 3 equiv of t-BuOCl at 0 °C. Then, we exam-
ined the formation of thioesters by means of nucleophilic
substitution with potassium thioacetate. The in situ forma-
tion of this substrate from benzyl bromide and CH3COSK
(1:1 ratio) followed by the same oxidative procedure afforded
a slightly lower 80% yield (entry 2).
As expected, less reactive, nonbenzylic alkyl substrates
gave modest yields (entries 3ꢀ6). The nature of the leaving
group (bromide vs tosylate) did not have a significant influ-
ence on the yields. Interestingly, displacement of halide with
potassium thiotosylate, followed by oxidation with 3 equiv of
t-BuOCl, gave an excellent yield of sulfonyl chloride. However
the use of this substrate is limited due to the concomitant
formation of tosyl chloride (entry 7).
(5) (a) Prakash, G. K. S.; Mathew, T.; Panja, C.; Olah, G. A. J. Org.
Chem. 2007, 72, 5847–5850. (b) Bahrami, K.; Khodaei, M. M.; Soheilizad,
M. J. Org. Chem. 2009, 74, 9287–9291. (c) Bahrami, K.; Khodaei, M. M.;
Soheilizad, M. Synlett 2009, 2773–2776. (d) Massah, A. R.; Sayadi, S.;
Ebrahimi, S. RSC Adv. 2012, 2, 6606.
(6) (a) Nishiguchi, A.; Maeda, K.; Miki, S. Synthesis 2006, 24, 4131.
(b) Veisi, H.; Ghorbani-Vagheit, R.; Hemmatia, S.; Mahmoodic, J.
Synlett 2011, 2315–2320.
Org. Lett., Vol. 15, No. 9, 2013
2295

Table 2. One-Pot Formation of Sulfonamides
Scheme 3. Cysteic Acid Derivatives
a Previously prepared thioester as the substrate. b Water/NaOAc as
nucleophile.
Considering that thioesters may also be readily prepared
via Michael addition, we examined the one-pot reaction of
thioacetic acid onto ethyl acrylate or methyl propiolate
followed by the oxidation in the same solvent (CH3CN). In
this case, there is a need for a 1:1 molar ratio of the initial
reagents. Upon completion of the addition (TLC), the
reaction medium was cooled to 0 °C and treated under the
previous conditions. The expected sulfonamides were ob-
tained, though with modest yields, whereas NMR of the
crude reaction mixtures before trapping showed a com-
plete and clean formation of the sulfonyl chlorides. In the
case of methyl propiolate, the sodium sulfonate was tar-
geted, in order to avoid the possible Michael addition of the
amine on the residual activated double bond. As an accurate
amount of sodium hydroxide may be difficult to measure,
we used an exact stoichiometric amount of sodium acetate
as the source of the sodium cation, in the presence of water.
Eventually, we turned our attention toward the use of
this oxidative deprotection method in the field of amino
acid derivatives. Cysteine is an important and common
amino acid, and its oxidized derivative cysteic acid is well-
known. It can be used as a strong solubilizing group or as a
nonprotonable, stable isostere of aspartate.7 When pur-
chased from chemical suppliers for solid-phase synthesis,
cysteine is often provided under its S-trityl protected form.
As S-Trt deprotections are performed under strong acidic
conditions, we thought that the intermediate chlorosulfo-
nium ꢀSþ(Cl)-Trt could easily release the trityl cation. As
depicted in Scheme 3, we observed a rapid oxidative
deprotection with subsequent amidification using the same
protocol, affording protected cysteic acid sulfonamides
12b,c. Interestingly, even the very stable tert-butyl group
could be deprotected during the oxidation process. It is
worth noting that, when replacing acetonitrile with THF,
our method is suitable for N-Boc-bearing substrates. In-
deed, the electrophilic cleavage of S-Trt or S-t-Bu by
t-BuOCl isselective of the sulfuratom, making our method
compatible with a N-Boc protecting group. As expected,
the N-Fmoc protecting group remained unchanged during
the oxidation process, though some deprotection occurred
during the reaction with benzylamine. A peptidic substrate
is also compatible with this method, for instance the
dipeptide Cbz-Phg-Cys(Trt)-OMe gave a good 88% yield
of the corresponding cysteic acid derivative 13. With the
aim of finding a clean route toward peptide coupling with
the formation of water-soluble cysteic acid containing pep-
tides, we used the sulfonyl chloride as an internal coupling
agent for the carboxylic acid. Thus, treating the intermediate
acid/sulfonyl chloride with pyridine prior to coupling with
the amine would give rise to the cyclic carboxysulfonic
anhydride 14 postulated in Scheme 3.
Pleasingly, the formation of the carboxamide, although
with a low yield after reversed-phase chromatography, gave
support to this proposal. However, as solid-phase peptide
syntheses generally use a high excess of the activated acid,
we can expect better yields under solid-phase conditions.
In this work, we developed a new, versatile, and easy-to-
use oxidation method for the formation of sulfonyl chlorides,
using t-BuOCl as a cheap and rather safe reagent. As its
reactivity is higher than observed with other chlorinat-
ing agents, it allowed the in situ S-deprotection of thioesters,
S-trityl and even S-tert-butyl thioethers, with concomitant
oxidation and subsequent reaction with nucleophiles,
making the method particularly convenient for amino acid
derivatives.
(7) (a) Zhang, L.; Tam, J. P. J. Am. Chem. Soc. 1997, 119, 2363. (b)
Bischoff, L.; David, C.; Roques, B. P.; Fournie-Zaluski, M.-C. J. Org.
Chem. 1999, 64, 1420.
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Org. Lett., Vol. 15, No. 9, 2013

Acknowledgment. The authors thank the Association
Nationale de la Recherche et de la Technologie (Grant
#543/2010) and la Ligue contre le Cancer (CD76) for
funding Y.J. We also thank Simon Colanges and Maxime
Lemer (I.U.T. de Rouen, professional BSc), for technical
assistance.
Supporting Information Available. Experimental pro-
cedures and full analytical, spectroscopic data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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