Benzylsulfonyl: A valuable protecting and deactivating group in phenol chemistry

Article abstract of DOI:10.1016/S0040-4039(02)02745-4

We introduce benzylsulfonyl (Bns) as a valuable protecting group in phenol chemistry. Bns proved to be stable under drastic reaction conditions and towards many common reagents. The deprotection proceeds quantitatively using catalytic hydrogenolysis. Additionally the Bns deactivating properties make this protecting group useful for tuning the reactivity of phenolic substrates.

Full text of DOI:10.1016/S0040-4039(02)02745-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 965–967
Benzylsulfonyl: a valuable protecting and deactivating group in
phenol chemistry
Anne Briot,a Corinne Baehr,b Raymond Brouillard,a Alain Wagnerb,* and Charles Mioskowskib,*
aLaboratoire de Chimie des Polyphe´nols, UMR 7509 du CNRS, Institut Le Bel, Universite´ Louis Pasteur, Faculte´ de Pharmacie,
74, route du Rhin, 67400 Illkirch, France
bLaboratoire de Synthe`se Bioorganique, UMR 7514 du CNRS, Universite´ Louis Pasteur, Faculte´ de Pharmacie,
74, route du Rhin, 67400 Illkirch, France
Received 15 November 2002; revised 26 November 2002; accepted 30 November 2002
Abstract—We introduce benzylsulfonyl (Bns) as a valuable protecting group in phenol chemistry. Bns proved to be stable under
drastic reaction conditions and towards many common reagents. The deprotection proceeds quantitatively using catalytic
hydrogenolysis. Additionally the Bns deactivating properties make this protecting group useful for tuning the reactivity of
phenolic substrates. © 2003 Elsevier Science Ltd. All rights reserved.
Protecting groups not only temporarily block reactive
sites but they also modify the intrinsic reactivity of the
substrates.1 Usually this side effect is considered by the
chemist as a negative aspect of protecting group strate-
gies. However, sometimes, the reactivity alteration
induced by the protecting group becomes synthetically
useful. As an example, Trost reported a lithiation of a
trioxygenated benzene by inhibiting the ortho directing
effect of an oxygen substituent when introducing a
t-butyldimethylsilyl protection.2 Also, we have recently
shown that the regioselectivity of aromatic electrophilic
substitution can be inverted by converting a phenol
group into its methanesulfonate derivative. Indeed, the
strong electron withdrawing effect of sulfonyl residue
neutralizes the phenol ortho/para directing effect.3 The
use of ‘Not-so-innocent bystanders’ protecting groups,
as stated by Kocienski,4 to affect and influence the
quently encountered protecting groups in polyphenol
chemistry.
Therefore, we searched for a phenol protecting group
that would combine both deactivating properties and
mild hydrogenolysis cleavage feature. An interesting
candidate appeared to be the benzylsulfonyl (Bns)
group. Although Bns has only been rarely reported in
the literature6 it is readily introduced, using inexpensive
commercially available benzylsulfonyl chloride in the
presence of triethylamine or pyridine. Surprisingly, no
mild deprotection method has been described.
Herein we describe the reactivity chart of Bns esters.
We show that while stable under acidic and basic
conditions, Bns can be readily cleaved under an hydro-
gen atmosphere using catalytic Raney Nickel (Scheme
1). Moreover, Bns exhibits the same deactivating prop-
erties as its methanesulfonic parent.
outcome of
opportunities.
a reaction, provides novel synthetic
The ‘deactivating’ properties of sulfonic esters would be
very useful in polyphenol chemistry since it would
enhance the stability of the various intermediates. How-
ever, we and others5 have observed that conditions for
deprotection of aromatic methanesulfonic esters are not
compatible with polyphenol skeletons.
To evaluate the scope and the limitations of the Bns as
a phenol protecting group and to define a reactivity
chart, a model compound (ArOH=4-ethylphenol) was
Until now, because of the mildness of hydrogenolytic
cleavage, benzyl-type ethers are among the most fre-
Scheme 1. General scheme for catalytic hydrogenolysis of
benzylsulfonyl protecting groups (Bns).
* Corresponding authors. E-mail: alwag@aspirine.u-strasbg.fr;
mioskowski@bioorga.u-strasbg.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02745-4

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A. Briot et al. / Tetrahedron Letters 44 (2003) 965–967
subjected to a range of chemical conditions (Table 1).
We tested various media derived from prototype
reagents given by Greene in his reactivity charts.1
First we noticed that the Bns group is specifically
removed under hydrogen with Raney Nickel, while it
proves to be inert under various other catalytic hydro-
genation conditions (Pd/C, Lindlar catalyst, Rh/C…).
Interestingly the Bns and benzyl groups appear orthog-
onally stable to each other.
Table 1. Reactivity chart for benzylsulfonyl protecting
groupb
The Bns group is cleaved by some basic media but
remains stable to classic organic bases at room temper-
ature. Indeed relative rates have to be taken into
account when using basic conditions as only partial
cleavage could be observed. With NaOH 1.2N in
EtOH/H2O or with K2CO3 in MeOH, we only observed
15% of deprotected product after 48 h at room temper-
ature. Otherwise this protecting group exhibits high
stability under acidic conditions even at high tempera-
tures. Various sets of conditions were tested, namely
media typically involved in electrophilic aromatic sub-
stitution processes (H2SO4, AcOH 2/3 under heating).
An illustrative amidomethylation of benzylsulfonyl-
guaiacol is reported below.
With organometallic reagents, the stability of the ben-
zylsulfonyl functionality depends on the reaction condi-
tions. They should be determined experimentally as
shown in the vinylation with Grignard reagents, which
proceeds quantitatively in diethyl ether but affords
more than 20% by-products in THF (Scheme 2).
Organolithium compounds proved to be incompatible
and with t-butoxide potassium, a-sulfonylation of the
sulfonic ester has been reported.7
Under mild reductive conditions (NaBH4) the Bns
group is not affected, allowing, as reported, selective
ketone reduction on steroid structures.8
Among other characteristics of the Bns group, its elec-
tron withdrawing character has to be emphasized. As
previously reported, isoguaiacol derivatives could be
obtained by derivatization of guaiacol as a methanesul-
fonic ester. Now we report the advantageous replace-
ment of the mesyl group by the Bns. Indeed, Bns
provides milder deprotection conditions while enabling
identical regiochemical control (Scheme 3).
Benzylsulfonylguaiacol subjected to 2 equiv. of acet-
amide, 1 equiv. of aldehyde at 80°C for 6 h in a mixture
a
Hydrogenation are conducted with 10% catalyst in EtOH 0.04 M at
room temperature.
b Reactivity is classified in three levels:
– S(Stable) indicates that the protective group is stable under the
corresponding conditions, 100% of the starting material is recov-
ered.
– R(Removed) indicates that the protective group is removed quan-
titatively to give the deprotected phenol.
– U(Unstable) indicates that neither the protected product nor the
deprotected phenol are recovered.
c The stability of the Bns group depends on the reaction conditions as
described below.
Scheme 2. Vinylation with Grignard reagents.

A. Briot et al. / Tetrahedron Letters 44 (2003) 965–967
967
Acknowledgements
We thank Alain Valleix (CEA, Saclay) for recording
mass spectra.
References
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Chemistry; 3rd ed.; John Wiley & Sons: New
York, 1999.
2. Trost, B. M.; Saulnier, M. G. Tetrahedron Lett. 1985, 26,
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3. (a) Bensel, N.; Pevere, V.; Desmurs, J. R.; Wagner, A.;
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Tetrahedron Lett. 1999, 40, 879–882; (c) Bensel, N.;
Pevere, V.; Desmurs, J. R.; Wagner, A.; Mioskowski, C.
Tetrahedron Lett. 2002, 43, 4281–4283.
Scheme 3. Amidomethylation.
4. Kocienski, P. J. Protecting Groups; Thieme, 1994.
5. Kawamoto, H.; Nakatsubo, F.; Murakami, K. J. Wood
Chem. Technol. 1989, 9, 35–52.
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3968–3970.
2:3 sulfuric acid/acetic acid mixture, leads regioselec-
tively to 90% of the desired 5-substituted guaiacol.
Removal of the Bns group is then achieved by stirring
under hydrogen atmosphere in ethanol with 10% Raney
Nickel. After 10 min the free phenol is obtained in 99%
yield. The amidomethyl moiety remains unaffected
(Scheme 3).
8. Schwarz, G.; Weber, G.; Schreiber, M. Pharmazie 1975,
30, 17–21.
In summary, Bns proved to be stable under drastic
conditions and towards many common reagents. The
subsequent deprotection proceeds almost quantitatively
using catalytic hydrogenolysis.9 These results enlarge
the available methods in protecting group chemistry.
Additionally deactivating properties of Bns make this
protecting group useful for tuning the reactivity of
phenolic substrates. These properties open new perspec-
tives in polyphenol chemistry. Investigations in total
synthesis of natural products are underway.
9. Caution: Raney Nickel should never be allowed to dry.
Experimental: To a solution of 4-ethylphenol benzylsul-
fonyl ester (80 mg) in ethanol (4 mL) is added Raney
Nickel (8 mg, 10% of the mass). The mixture is then
degassed and stirred under an hydrogen atmosphere at
room temperature. The reaction is monitored by TLC.
Subsequent work-up of the reaction consists of filtration
through Celite.