Deprotection of 2-nitrobenzenesulfonamides using fluorous and solid phase reagents

Article abstract of DOI:10.1016/j.tetlet.2004.09.015

2-Nitrobenzenesulfonamides are cleaved by C₈F ₁₇(CH₂)₂SH in the presence of K ₂CO₃ or a solid-supported base. The fluorinated byproduct is separated using FluoroFlash SPE to afford the free amine or amide in high yield and purity. The 2-nitrobenzenesulfonyl group was efficiently removed from primary and secondary amines as well as amides with a perfluorinated thiol under mild conditions. The resulting perfluorinated byproduct was removed via a solid phase extraction through perfluorinated silica gel making this a fast and simple procedure for parallel deprotection.

Full text of DOI:10.1016/j.tetlet.2004.09.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7991–7993
Deprotection of 2-nitrobenzenesulfonamides using
fluorous and solid phase reagents
Caspar Christensen, Rasmus P. Clausen, Mikael Begtrup and Jesper L. Kristensen*
Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark
Received 14 July 2004; revised 23 August 2004; accepted 2 September 2004
Available online 18 September 2004
Abstract—The 2-nitrobenzenesulfonyl group was efficiently removed from primary and secondary amines as well as amides with a
perfluorinated thiol under mild conditions. The resulting perfluorinated byproduct was removed via a solid phase extraction through
perfluorinated silica gel making this a fast and simple procedure for parallel deprotection.
Ó 2004 Elsevier Ltd. All rights reserved.
The monoalkylation of primary amines is a simple, yet
challenging transformation, and many solutions to this
problem have been reported. Very often this has
involved protection of the primary amine followed by
alkylation and subsequent deprotection. Various pro-
tecting groups have been used in this sequence, but espe-
cially the 2-nitrobenzenesulfonamides introduced by
Fukuyama and co-workers have become very popular,
due to ease of synthesis, enhanced nucleophilicity and
mild deprotection.1,2
separated from nonfluorinated products using an
orthogonal fluorous phase or through fluorous solid
phase extraction (F-SPE).4
We became interested in perfluorinated thiols for
the deprotection of 2-nitrobenzenesulfonamides as
the formed perfluorinated 2-nitrobenzenethioether 3
(Scheme 1) could in principle be removed via a simple
F-SPE.
A series of 2-nitrobenzenesulfonamides 2a–g was there-
fore prepared (Scheme 1). The 2-nitrobenzenesulfon-
amides 2a–g were treated with the commercially avail-
able perfluorinated thiol, C8F17CH2CH2SH (2.5equiv)
and K2CO3 (5equiv) in MeCN at 50°C overnight.
Recently, perfluorinated reagents and scavengers have
emerged as an attractive alternative to solid phase
synthesis, combining solution-phase and solid-phase
advantages.3 Highly fluorinated compounds are readily
H
N
R1
R2
1a-g
R1
a or b
c
FluoroFlashTM SPE
NO2
NH
R2
O
S O
N
R1
R2
C8F17
S
NO2
3
1a-g
2a-g
Scheme 1. Reagents and conditions: (a) 2-nitrobenzenesulfonyl chloride 1.2equiv, K2CO3 (aq) or Et3N (a–f); (b) AcCl, DMAP (cat.), Et3N, CH2Cl2
(g); (c) C8F17C2H4SH (2.5equiv)/K2CO3 (5equiv) in MeCN, followed by F-SPE.
Keywords: Fluorous reagents; 2-Nitrobenzenesulfonamides; Deprotection.
*
Corresponding author. Tel.: +45 35306487; fax: +45 35306040; e-mail: jekr@dfuni.dk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.015

7992
C. Christensen et al. / Tetrahedron Letters 45 (2004) 7991–7993
Table 1. Deprotection of 2-nitrobenzenesulfonamides 2a–g5
Entry
Sulfonamide 2
Product 1
Yielda (%)
91 (>95)
1) HSCH2CO2Et (5 eq)
Amberlyst A-21 (10 eq.)
HO
HO
NHSO2Ar
NH2
2a
65%
O
O
MeO
MeO
NHSO2Ar
NH2
5
6
O
O
O
Scheme 3. Purification via product immobilization.
OH
OH
2b
MeO
N
MeO
N
96 (>95)
NHSO2Ar
NH2
O
from the solid support, while the free amino acid 6
was retained.
2c
2d
2e
76 (86)
N
NH
SO2Ar
Subsequently, 6 was isolated simply by washing the solid
support with excess of AcOH/MeCN (1:1) followed by
evaporation of the solvent.6
43b (>95)
72(>95)
NHSO2Ar
NH2
NH2
NHSO2Ar
In conclusion, we have demonstrated that 2-nitrobenz-
enesulfonamides are readily cleaved by the commercially
available perfluorinated thiol, C8F17(CH2)2SH, in the
presence of K2CO3 or a solid-supported base. The fluor-
inated byproduct can be easily separated via a Fluoro-
FlashTM SPE to afford the free amine or amide in high
purity and yield. In addition, the use of a solid-
supported base and ethyl thioglycolate allows for the
direct isolation of free amino acids.
NSO2Ar
Me
NH
Me
2f
77 (>95)
81 (>95)
NSO2Ar
Ac
NH
Ac
2g
a Yields in brackets refer to isolated yields of the fluorinated byproduct
3. Ar = 2-NO2–C6H4.
b The modest yield is due to the volatility of the product.
Acknowledgements
TLC showed full conversion of 2a–g to 1a–g and 3. The
fluorinated byproduct 3 was readily removed by Fluoro-
FlashTM SPE to afford the desired compounds in high
yield and purity (Table 1).
We are grateful to Fluorous Technologies Inc. for a gen-
erous supply of perfluorinated thiol.3 The Carlsberg
Foundation is thanked for financial support.
This procedure is well suited for parallel synthesis, as the
products are obtained in sufficient purity for subsequent
manipulation or biological screening. However, it can-
not be excluded that the products may contain traces
of K2CO3. Although this is usually not a problem, we
probed the possibility of employing a solid-supported
base instead of K2CO3, thus immobilizing everything
but the product. Indeed, deprotection of 2a using
Amberlyst A-21 as base gave 1a in identical yield, free
of organic or inorganic impurities (Scheme 2).
References and notes
1. Fukuyama, T.; Cheung, M.; Jow, C. K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831–5834.
2. Review: Kan, T.; Fukuyama, T. Chem. Commun. 2004,
353–359.
3. Perfluorinated compounds and cartridges can be obtained
from Fluorous Technologies Inc.
4. Review: Zhang, W. Tetrahedron 2003, 59, 4475–
4489.
5. Representative experimental procedure: To a solution of
N-(2-nitrobenzenesulfonyl)-serine methyl ester (100mg,
0.33mmol) and K2CO3 (227mg, 5equiv) in MeCN (3mL),
1H,1H,2H,2H-perfluorodecane-1-thiol (289lL, 2.5equiv)
was added, and the mixture was stirred at 50°C for 16h.
The resulting yellow solution was filtered, evaporated in
vacuo, redissolved in MeOH/H2O (4/1), loaded onto a 5g
FluoroFlashTM SPE cartridge pre-conditioned with MeOH/
H2O (4/1). The cartridge was eluted with 15mL MeOH/
H2O (4/1). Evaporation of the solvent afforded serine
methyl ester in 96% yield with spectral data identical to
those of an authentic sample. The yellowish cartridge was
then washed with MeOH (10mL) and acetone until it was
colourless. Evaporation of the solvent afforded the per-
fluorinated thioether adduct 3 in quantitative yield as a
The use of a solid-supported base enables immobiliza-
tion of the product when an acidic group is present in
the molecule. In the deprotection of the amino acid
derivative 5 (Scheme 3) ethyl thioglycolate was used in
excess, in the presence of Amberlyst A-21. The formed
thioether and excess ethyl thioglycolate were washed
1) C8F17C2H4SH (2.5 eq.)
Amberlyst A-21 (5 eq.)
MeCN
2) FSPE
MeO
MeO
NHSO2Ar
NH2
1a
90 %
1
O
O
yellow solid. H NMR (CDCl3, 300MHz): d 8.25 (1H, dd,
J = 8.2, 1.5Hz), 7.63 (1H, m), 7.41–7.31 (m, 2H), 3.26–3.20
(m, 2H), 2.59–2.42 (m, 2H).
6. Representative experimental procedure: To a solution of N-
(2-nitrobenzenesulfonyl)-phenylalanine (100mg, 0.29 mmol)
2a
Scheme 2. Deprotection with solid-supported base and fluorinated
thiol.

C. Christensen et al. / Tetrahedron Letters 45 (2004) 7991–7993
7993
and Amberlyst A-21 (L = 1mmol/g, 10equiv) in MeCN
(3mL) ethyl thioglycolate (170mg, 5equiv) was added and
the mixture was stirred at rt for 48h. The resulting yellow
solution was filtered and the resin eluted with MeCN. Then,
the resin was eluted with AcOH/MeCN (1/1) and the
resulting filtrate was evaporated in vacuo to afford pure
phenylalanine in 65% yield with spectral data identical to
those of an authentic sample.