2-nitro- and 2,4-dinitrobenzenesulfonamides as protecting groups for primary amines

Article abstract of DOI:10.1055/s-2001-15158

Procedures for the deprotection of the 2-nitro- and 2,4-dinitrobenzenesulfonamides to give the corresponding primary amines were developed. The 2-Nitrobenzenesulfonyl group was effectively removed by HSCH₂CH₂OH/DBU or PhSH/Cs₂

Full text of DOI:10.1055/s-2001-15158

LETTER
1167
2-Nitro- and 2,4-Dinitrobenzenesulfonamides as Protecting Groups for
Primary Amines
Ken-ichi Nihei,a Massuo J. Kato,a Tetsuo Yamane,b Mario S. Palma,c Katsuhiro Konno*c
aInstitute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-900, Brazil
bLaboratory of Molecular Toxinology, Institute Butantan, Av. Vital Brasil, 1500, São Paulo, SP 05503-900, Brazil
cCenter of Study of Social Insects, Institute of Biosciences of Rio Claro, São Paulo State University, Av. 24-A, 1515, Rio Claro, Brazil
Fax +55-19-534-8523; E-mail: kk-gon@rc.unesp.br
Received 25 April 2001
NHR
Abstract: Procedures for the deprotection of the 2-nitro- and 2,4-
dinitrobenzenesulfonamides to give the corresponding primary
amines were developed. The 2-Nitrobenzenesulfonyl group was ef-
fectively removed by HSCH2CH2OH/DBU or PhSH/Cs2CO3 in
DMF under mild conditions to give the corresponding primary
amines in high to excellent yield. For removal of the 2,4-dinitroben-
zenesulfonyl group, the use of thiol alone (HSCH2CH2OH or PhSH)
was quite effective. Selective deprotection of 2,4-dinitrobenzene-
sulfonamide in the presence of 2-nitrobenzenesulfonamide has also
been achieved.
O2S
X
RNH2
2a: X=NO2, Y=H
2b: X=H, Y=NO2
2c: X=Y=NO2
1
Y
R'X/Base
NRR'
X
O2S
Key words: 2-nitrobenzenesulfonamide, 2,4-dinitrobenzene-
sulfonamide, protecting groups, deprotection, primary amines
R
R'
R''SH
Base
N
H
3a: X=NO2, Y=H
3b: X=H, Y=NO2
3c: X=Y=NO2
4
Y
2- and 4-Nitrobenzenesulfonamides, 2a and 2b, are
unique among the amino protective groups. They are
readily prepared from primary amines 1, then easily N-
alkylated to give N,N-disubstituted sulfonamides 3a,b,
with subsequent removal of the arylsulfonyl groups to af-
ford secondary amines 4. Accordingly, since introduced
by Fukuyama et al.,1 these protecting/activating groups
have been widely used for the preparation of secondary
amines both in solution- and solid-phase syntheses.2,3 2,4-
Dinitrobenzenesulfonamides 3c can be utilized in the
same manner and, in addition, it is selectively deprotected
in the presence of 2-nitrobenzenesulfonamides 3a, lead-
ing to a wide variety of diamines with the combined use
of these groups.4 Direct transformation of 2c to amides,
ureas, thioamides, and thioureas through a deprotection/
functionalization sequence has also been reported.5 How-
ever, simple deprotection of 2 to reproduce the corre-
sponding primary amines 1 has not been fully
investigated; thus, deprotection of 2-nitrobenzenesulfona-
mide 2a resulted in low yield6 or should be carried out in-
directly through further protection with urethane groups.7
Only a few such successful results have been reported.8 In
fact, we have encountered difficulty during our studies on
the synthesis of acylpolyamine spider toxins, which
prompted us to investigate the deprotection of 2 to 1. We
report herein the procedures for the deprotection of 2-ni-
tro- and 2,4-dinitrobenzenesulfonamides, 2a and 2c, to di-
rectly give the corresponding primary amines 1. Selective
deprotection of 2,4-dinitrobenzeneulfonamide in the pres-
ence of 2-nitrobenzenesulfonamide on diamine is also de-
scribed.
Scheme 1
A variety of conditions for removing the 2-nitrobenzene-
sulfonyl (Ns) group from 2-nitrobenzenesulfonamide 2a
were examined using 4-methoxybenzylamine as a model
substrate (Entry 1 in Table 1). Consequently, we found
that the use of HSCH2CH2OH/DBU (Method A) and
PhSH/Cs2CO3 (Method B) in DMF were the most effec-
tive, giving the primary amine in 86% and 88% yield, re-
spectively, at 0 °C-room temperature for 30 min. Table 1
summarizes the results of a variety of substrates. In Meth-
od A, DBU can be replaced by Cs2CO3 and, in Method B,
Cs2CO3 can be replaced by DBU; thus, any combination
of HSCH2CH2OH or PhSH as a thiol with DBU or
Cs2CO3 as a base may essentially give the same results.
Furthermore, when using PhSH/DBU, acetonitrile
(MeCN) can be used as the solvent instead of DMF. Un-
der the conditions of Methods A and B, no racemization
took place when applied to the optically active -branched
amines (Entries 3 and 4). Fukuyama’s standard proce-
dures using PhSH/K2CO3/DMF and HSCH2CO2H/LiOH
for secondary sulfonamides were sluggish and did not go
to completion. The conditions similar to Method A have
been successfully used for the deprotection of secondary
2-nitrobenzensulfonamides in the solid-phase.2c,h Accord-
ingly, the conditions employing HSCH2CH2OH/DBU/
DMF may be the most widely used and the method of
choice for any situation, primary or secondary sulfona-
mide and solution- or solid-phase synthesis.
Synlett 2001, No. 7, 1167–1169 ISSN 0936-5214 © Thieme Stuttgart · New York

1168
K. Nihei et al.
LETTER
Table 1 Deprotection of the 2-nitirobenzenesulfonamides
Table 2 Deprotection of the 2,4-dinitirobenzenesulfonamides
Method Aa
Method Bb
Method Ca Method Db
(% isolated yield)
Entry
1
Sulfonamide
Entry
1
Sulfonamide
(% isolated yield)
NHNs
NHDNs
86
88
98
91
MeO
MeO
NHNs
NHDNs
2
3
95
96
2
3
92
94
87c
91c
NHDNs
NHNs
85c
83c
NHNs
CO2Me
NHDNs
CO2Me
91c,d
81c,d
88c,d
96c,d
4
5
4
5
NHNs
85d
86d
NHDNs
83d
98d
MeO2C
MeO2C
a HSCH2CH2OH (2.0 eq), DBU (1.5 eq), DMF, 0 ºC - rt, 30 min.
b PhSH (2.0 eq), Cs2CO3 (1.2 eq), DMF, 0 ºC - rt, 30 min.
c The enantiopurity was confirmed by 1H NMR analysis of its MTPA
amide.
a HSCH2CH2OH (2.0 eq), DMF, rt, 1 h.
b PhSH (2.0 eq), DMF, rt, 15 min.
c The enantiopurity was confirmed by 1H NMR analysis of its MTPA
amide.
d Isolated as the HCl salt.
d Isolated as the HCl salt.
respectively, without affecting the Ns group at all
(Scheme 2).
For removal of the 2,4-dinitrobenzenesulfonyl (DNs)
group from 2c, the use of the thiol alone (HSCH2CH2OH
or PhSH) was quite effective. Table 1 summarizes the re-
sults of a variety of 2,4-dinitrobenzensulfonamides. The
NH2
NHDNs
reaction smoothly proceeded with
2
equiv of
NsHN
NsHN
HSCH2CH2OH (Method C) or PhSH (Method D) in DMF
and went to completion within 1 h or 15 min, respectively,
with excellent yields. For Method C, no other solvent is
Method C (97%)
or Method D (92%)
6
5
compatible, but various solvents (CH2Cl2, THF, MeCN Scheme 2
and MeOH) can be used as well as DMF for Method D.
Under these conditions, no racemization occurred as
In this study, we found the conditions for the deprotection
of the 2-nitro- and 2,4-dinitrobenzenesulfonamides to re-
produce primary amines, demonstrating that these groups
are useful protective groups for primary amines as well as
secondary amines and, therefore, the scope of these pro-
tective groups will become much wider and more useful.
Moreover, the 2,4-dinitrobenzenesulfonyl group is prefer-
entially deprotected in the presence of the 2-nitrobenzene-
sulfonyl group, which would also be useful for the
synthesis of a variety of polyamine compounds.
shown in Entries 3 and 4. In all cases, Fukuyama’s origi-
nal procedures for the secondary sulfonamides using n-
PrNH2 or HSCH2CO2H/Et3N gave only a poor yield or a
complex mixture. Employing i-PrNH2 or NH3 aq. instead
of n-PrNH2 did not improve the results, nor any conditions
with the combined use of thiol (HSCH2CO2H,
HSCH2CH2OH, PhSH) and base (NaHCO3, pyridine,
Et3N, imidazole). Consequently, the procedures for
deprotecting primary 2,4-dinitrobenzenesulfonamides are
distinct from those of secondary 2,4-dinitrobenzene-
sulfonamides.
For the secondary sulfonamides, the DNs group is prefer-
entially removed in the presence of the Ns group as Fuku-
yama et al. reported.4a A similar transformation was
realized for the primary sulfonamides as well. When the
disulfonamide 5, prepared from mono-nosylated pu-
trescine 62h in high yield, was subjected to the conditions
for deprotecting the DNs group (Methods C and D), the
primary amine 5 was obtained in 97% and 92% yields,
Representative experimental procedures
Method A: To a stirred solution of N-(4-methoxybenzyl)-2-ni-
trobenzenesulfonamide (258 mg, 0.80 mmol) in DMF (3 mL),
HSCH2CH2OH (125 mg, 1.60 mmol, 2 equiv) and DBU (182 mg,
1.20 mmol, 1.5 equiv) were slowly added at 0 °C. After stirring 30
min at room temperature, the reaction mixture was directly chro-
matographed on silica gel (8% MeOH-CHCl3 and then 1: 3: 36 i-
PrNH2-MeOH-CHCl3) to give 4-methoxybenzylamine (94 mg,
86%) as a colorless oil.
Synlett 2001, No. 7, 1167–1169 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
2-Nitro- and 2,4-Dinitrobenzenesulfonamides as Protecting Groups
1169
Method B: To a stirred solution N-(4-methoxybenzyl)-2-nitroben-
zenesulfonamide (258 mg, 0.80 mmol) in DMF (3 mL), PhSH (176
mg, 1.60 mmol, 2 equiv) and Cs2CO3 (313 mg, 0.96 mmol, 1.2
equiv) were slowly added at 0 °C. After stirring for 0.5 h at room
temperature, the reaction mixture was directly chromatographed on
silica gel (8% MeOH-CHCl3 and then 1: 3: 36 i-PrNH2-MeOH-
CHCl3) to give 4-methoxybenzylamine (96 mg, 88%) as a colorless
oil.
Cummins, L. L.; Griffy, R. H.; Bharadwaj, R.; Haly, B. D.;
Fraser, A. S.; Wilson-Lingardo, L.; Risen, L. M.; Wyatt, J. R.;
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Method C: To a stirred solution of N-(4-methoxybenzyl)-2,4-dini-
trobenzenesulfonamide (294 mg, 0.80 mmol) in DMF (2 mL),
HSCH2CH2OH (125 mg, 1.60 mmol, 2 equiv) was added. After stir-
ring 1 h at room temperature, the reaction mixture was directly chro-
matographed on silica gel (8% MeOH-CHCl3 and then 1: 3: 36 i-
PrNH2-MeOH-CHCl3) to give 4-methoxybenzylamine (107 mg,
98%) as a colorless oil.
Method D: To a stirred solution of N-(4-methoxybenzyl)-2,4-dini-
trobenzenesulfonamide (294 mg, 0.80 mmol) in DMF (2 mL),
PhSH (176 mg, 1.60 mmol, 2 equiv) was added. After stirring 15
min at room temperature, the reaction mixture was directly chro-
matographed on silica gel (8% MeOH-CHCl3 and then 1: 3: 36 i-
PrNH2-MeOH-CHCl3) to give 4-methoxybenzylamine (100 mg,
91%) as a colorless oil.
(3) For 4-nitrobenzensulfonamides, see: (a) Bhatt, U.; Mohamed,
N.; Just, G.; Roberts, E. Tetrahedron Lett. 1997, 38, 3679.
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Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 999. (c) Wuts, P. G.
M.; Northuis, J. M. Tetrahedron Lett. 1998, 39, 3889.
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Tetrahedron Lett. 1997, 38, 5831. (b) Kobayashi, S., Peng, G.;
Fukuyama, T. Tetrahedron Lett. 1999, 40, 1519. (c) Hone, N.
D.; Payne, L. J. Tetrahedron Lett. 2000, 41, 6149.
(5) (a) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O.
Tetrahedron Lett. 1998, 39, 1669. (b) Messeri, T.; Sternbach,
D. D.; Tomkinson, N. C. O. Tetrahedron Lett. 1998, 39, 1673.
(6) Strømgaard, K.; Brierley, M. J.; Andersen, K.; Slak, F. A.;
Mellor, I. R.; Usherwood, P. N. R.; Krogsgaard-Larsen, P.;
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Acknowledgement
We are grateful to Drs. Toshiyuki Kan (The University of Tokyo)
and Shojiro Maki (The University of Electro-Communications) for
their helpful discussions and technical assistance. K. K. is a fellow
from the State of São Paulo Research Foundation (FAPESP, 1998/
11693-5). M. S. P. is a researcher for the Brazilian Council for Sci-
entific and Technological Development (CNPq, proc. 500079/90-
0).
(7) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
(8) (a) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62, 1586.
(b) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J.
Tetrahedron Lett. 1997, 38, 5253. (c) Miller, S. C.; Scanlan,
T. S. J. Am. Chem. Soc. 1998, 120, 2690.
References and Notes
(1) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
(2) For 2-nitrobenzenesulfonamides, see: (a) An, H.; Cook, P. D.
Tetrahedron Lett. 1996, 37, 7233. (b) Yang, L.; Chiu, K.
Tetrahedron Lett. 1997, 38, 7307. (c) Swayze, E. E.
Tetrahedron Lett. 1997, 38, 8643. (d) Miller, S. C.; Scanlan,
T. S. J. Am. Chem. Soc. 1997, 119, 2301. (e) An, H.;
Article Identifier:
1437-2096,E;2001,0,07,1167,1169,ftx,en;S01301ST.pdf
Synlett 2001, No. 7, 1167–1169 ISSN 0936-5214 © Thieme Stuttgart · New York