Deprotection of 2-pyridyl sulfonyl group from pyridine-2-sulfonamides by magnesium in methanol

Article abstract of DOI:10.1081/SCC-100104475

Convenient deprotection of various pyridine-2-sulfonamides prepared by sulfonylation of primary and secondary amines with pyridine-2-sulfonylchloride was achieved by magnesium in methanol at 0°C to the corresponding amines in good yield.

Full text of DOI:10.1081/SCC-100104475

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DEPROTECTION OF 2-PYRIDYL SULFONYL GROUP
FROM PYRIDINE-2-SULFONAMIDES BY MAGNESIUM IN
METHANOL
Chwang Siek Pak a & Dong Sung Lim a
a Korea Research Institute of Chemical Technology , Yusung-Ku Jang-Dong 100, Taejeon,
305-600, S. Korea
Published online: 09 Nov 2006.
To cite this article: Chwang Siek Pak & Dong Sung Lim (2001) DEPROTECTION OF 2-PYRIDYL SULFONYL GROUP FROM
PYRIDINE-2-SULFONAMIDES BY MAGNESIUM IN METHANOL, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:14, 2209-2214, DOI: 10.1081/SCC-100104475
To link to this article: http://dx.doi.org/10.1081/SCC-100104475
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SYNTHETIC COMMUNICATIONS, 31(14), 2209–2214 (2001)
DEPROTECTION OF 2-PYRIDYL
SULFONYL GROUP FROM
PYRIDINE-2-SULFONAMIDES BY
MAGNESIUM IN METHANOL
Chwang Siek Pak* and Dong Sung Lim
Korea Research Institute of Chemical Technology, Yusung-Ku
Jang-Dong 100, Taejeon, 305-600, S. Korea
ABSTRACT
Convenient deprotection of various pyridine-2-sulfonamides
prepared by sulfonylation of primary and secondary amines
with pyridine-2-sulfonylchloride was achieved by magnesium
in methanol at 0ꢀC to the corresponding amines in good yield.
Among a number of amine protection methods, sulfonylation with
various substituted phenylsulfonyl chlorides has been widely used since
the resulting sulfonamide is usually a crystalline solid and resistant to
nucleophilic attack.1 For the deprotection of a typical N-tosyl group,
harsh conditions such as sodium in liquid ammonia,2 sodium amalgam in
a protic solvent,3 sodium naphthalenide,4 or refluxing 48% HBr in the pres-
ence of phenol5 were frequently employed.
Recently, milder deprotection methods including SmI2,6 n-Bu3SnH-
AIBN,7 electrolysis8 and Mg/MeOH under sonication9 were reported and
complement previous severe conditions. Additional efforts were also made
by modifying arenesulfonamide to the more labile heteroarenesulfona-
* Corresponding author.
2209
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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PAK AND LIM
mides.10,11 These milder methods except for SmI2 were effective only on
sulfonamides activated with an N-Boc or N-acyl group so they are only
applicable to primary amines. For example desulfonylation of N-acyl-
N-phenylbenzenesulfonamide was effected by n-Bu3SnH under neutral
conditions, whereas an inactivated secondary sulfonamide like N,N-diben-
zylbenzenesulfonamide was inert.7 Desulfonylation of both N-benzenesulfo-
namides or N-p-toluenenesulfonamides of primary and secondary amine in
refluxing THF in the presence of DMPU (N,N0-dimethylpropylenurea)6 was
achieved by SmI2. Furthermore removal of N-pyridine-2-sulfonyl groups in
the absence of DMPU at room temperature from the corresponding N-
pyridine-2-sulfonamides prepared from both primary and secondary
amines was reported.11 Recently desulfonylation of doubly activated
amines such as N-Boc or N-acylarenesulfonamide using Mg in methanol
under ultrasonic conditions was reported.9 Under these conditions parent
amines are limited to only primary amines which should be activated by N-
Boc or N-acyl group for desulfonylation. In order to overcome these limita-
tions and to expand the utility of Mg in methanol as desulfonylation
reagent,12 it prompted us to try desulfonylation of primary amine sulfona-
mide such as N-tosylaniline, but it was inert to Mg/MeOH at room tem-
perature even with sonication whereas activated N-Boc-N-tosylaniline was
easily desulfonylated to N-Boc aniline (Scheme 1).
Since p-toluenesulfonyl or phenylsulfonyl group of sulfonamide turned
Scheme 1.
out to be an inappropriate for desulfonylation without activation, we were
led to find another appropriate sulfonyl group under these conditions. With
our previous experience of C-S cleavage,12 attempts for N-S cleavage were
made to desulfonylate pyridine-2-sulfonamides derived from various pri-
mary and secondary amines using Mg in methanol (Scheme 2).

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DEPROTECTION OF 2-PYRIDYL SULFONYL
2211
Scheme 2.
In contrast to resistant p-toluenesulfonamide desulfonylation pro-
ceeded readily to provide the parent amines in good yields.13 The results
are summarized in Table 1. All the pyridine-2-sulfonamides from alkyl and
aryl amines except entries 2 and 4 are prepared by direct sulfonylation of
Table 1. Desulfonylation of Pyridine-2-Sulfonamides by Mg/MeOH

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PAK AND LIM
the parent amines with pyridine-2-sulfonylchloride according to the repor-
ted procedures11 and are isolated as stable solids except entry 9. Entries 2
and 4 were prepared by phenylation of pyridine-2-sulfonamides, entry 1
and entry 3, respectively with triphenylbismuth.14 Although yields are
not optimized, desulfonylation proceeded smoothly with 10 equiv Mg at
0ꢀC regardless of the type of amine to give the corresponding parent
amines in good yields. In general, reaction rate for desulfonylation was
much faster than that of SmI2 with either N-p-toulenesulfonamides
(1.5ꢁ11 hr)6 or 2-pyridinesulfonamides(4 hr).12 As in the case of pyri-
dine-2-sulfonamides with SmI2,12 the rate of desulfonylation does not
seem to be much different for sulfonamides derived from primary or sec-
ondary amines indicating that steric effects are not critical. Isolation of
some amines (entries 7 and 10) was achieved by acetylation after work up
due to their high polarity. By control experiments subjecting pyridine-
2-sulfonamides to methanolic Mg(OMe)2 solution in which no reaction
takes place, possibility of desulfonylation via methanolysis under the reac-
tion conditions was eliminated. Thus we assumed that desulfonylation
occur via single electron transfer to form a putative radical intermediate.
In an attempt to trap the aminyl radical which might be formed in the
course of an electron transfer reaction, N-butyl-N-1-penten-5-ylaminesul-
fonamide (entry 9) was subjected to the reaction conditions hoping to
obtain substituted pyrrolidine as radical cyclization product,12,15 but it
only resulted in desulfonylation product. Chiral amine sulfonamides
(entry 11 and 12) were subjected to the reaction condition. No racemiza-
tion was observed for entry 9, however, partial racemization ([ꢀ]D À2.3
(c¼1,MeOH),16% e.e.) and ester exchange were observed for entry 12. In
order to measure optical yield the deprotected ester was converted to its
N-Cbz form and compared with literature value.16 In contrast to the pre-
viously reported selective desulfonylation of TsNAc(Bn) to give
HNAc(Bn) under sonication condition,9 that of pyridine-2-sulfonamide(en-
try 14) proceeded deacetylation first to provide 2-PySO2NHBn followed by
desulfonylation like entry 3 to give BnNH2.17 We could verify that it is
from methanolysis by subjecting the sulfonamide to methanolic solution of
Mg(OMe)2 to obtain 2-PySO2NHBn as a single spot in TLC. However, we
could isolate the desulfonylated product HNAc(Bn) in 47% yield which
must be formed from reaction of benzyl amine and methylacetate in the
reaction mixture.
In conclusion, regardless of primary or secondary amine the corre-
sponding stable solid pyridine-2-sulfonamides were conveniently desulfony-
lated with Mg in methanol. It is apparent that 2-pyridinesulfonyl group can
be used as a convenient amine protecting group in case Mg in methanol is
employed for desulfonylating reagent.

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DEPROTECTION OF 2-PYRIDYL SULFONYL
ACKNOWLEDGMENT
2213
We thank for financial support of Ministry of Science and Technology
and helpful comments of Dr. Dennis Jackman (Bayer, Kansas City).
REFERENCES
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3. Tanner, D.; Ming, H.H.; Bergdahl, M. Tetrahedron Lett. 1988, 29,
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4. Ji, S.; Gortler, L.B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W.D.;
Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311.
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13. General Procedure: A solution of N,N-diphenylpyridine-2-sulfonamide
(155 mg, 0.5 mmol) in dry methanol (4 ml) was added to Mg powder
(122 mg, 5mmol) in an ice bath. The reaction mixture was stirred for
2 hr under a nitrogen atmosphere until the substrate disappeared by
TLC. To the reaction mixture equal volumes of diethyl ether and
saturated aqueous NH4Cl were added and the whole mixture was stir-
red for 2 hr. The organic layer was separated and the aqueous layer
washed with ether. The combined organic layers were dried over
MgSO4 and then concentrated in vacuo to give 81 mg (96%) of diphe-
nylamine in almost pure form.
14. Chan, D.M. Tetrahedron Lett. 1996, 37, 9013. Direct sulfonylation of
N-substituted aniline with 2-pyridinesulfonyl chloride did not take

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PAK AND LIM
place. Sulfonamide proton was successfully substituted with phenyl
group by triphenybithmus prepared from BiCl3 and PhMgBr as
described in this reference.
15. Bowman, W.R.; Broadhurst, M.J.; Coghlan, D.R.; Lewis, K.A.
Tetrahedron Lett. 1997, 38, 6301.
16. Kreuzfeld, H.-J.; Dobler, C.; Krause, H.W.; Facklam, C. Tetrahedron
Asymmetry 1993, 4, 2047.
17. According to TLC analysis, deacetylated product and BnNH2
appeared within 20 min. In order to compare with sonication con-
dition, TsNAc(Bn) was subjected to reaction condition without sonica-
tion to give HN(Bn)-Ts(10 eq Mg/MeOH,rt,20 min). Furthermore,
complete deacetylation was observed within 5min when it was sub-
jected to methanolic Mg(OMe)2.
Received in the UK May 12, 2000

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