Solid phase deprotection of 2-nitrobenzenesulfonamides: Synthesis of simple 2-(alkylamino)-pyrroles

Article abstract of DOI:10.1016/j.tetlet.2005.06.082

The 2-nitrobenzenesulfonamide cleavage using a solid-phase thiophenolate reagent gives simple 2-(alkylamino)-pyrroles without the presence of the competing nucleophilic substitution product.

Full text of DOI:10.1016/j.tetlet.2005.06.082

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5715–5717
Solid phase deprotection of 2-nitrobenzenesulfonamides:
synthesis of simple 2-(alkylamino)-pyrroles
Michael De Rosa,*, Nicola Stepani, Todd Cole, Jaclyn Fried, Lisa Huang-Pang,
Lori Peacock and Michael Pro
Department of Chemistry, The Pennsylvania State University Delaware County, 25 Yearsley Mill Road, Media, PA 19063, USA
Received 27 April 2005; revised 16 June 2005; accepted 16 June 2005
Available online 5 July 2005
Abstract—The 2-nitrobenzenesulfonamide cleavage using a solid-phase thiophenolate reagent gives simple 2-(alkylamino)-pyrroles
without the presence of the competing nucleophilic substitution product.
Ó 2005 Elsevier Ltd. All rights reserved.
No general method exists for the preparation of simple
2-(alkylamino)-pyrroles without further substitution on
the pyrrole ring.1 Only a few scattered references to their
preparation are known. Recently routes to more highly
substituted derivatives have appeared.2,3 We have
shown that it is possible to obtain previously unknown
simple 2-aminopyrrole derivatives by removing the
imide group from N-(1-substituted-1H-pyrrol-2-
yl)phthalimide derivatives.4 An analogous strategy using
2-nitrobenzenesulfonamide derivatives can be used to
prepare simple 2-(alkylamino)-pyrroles.
To this end a model benzenesulfonamide derivative 4a
(X = H, Y = NO2 and R = 2-propyl) was prepared as
indicated in the scheme below. The structure of 4 was
confirmed by NMR and exact mass spectroscopy.8
Yields of 4 appeared to be influenced by the steric bulk
of R. It should be noted that the NMR spectra of deriv-
atives 4a–c indicated the possibility of restricted rota-
tion.9 For example, in the case of the 2-propyl
derivative 4a, two non-equivalent methyl groups were
observed by proton NMR.
Y
H
R
Cl
R
Fukuyama and co-workers reported that the 2-nitro-
and 4-nitrobenzenesulfonamide groups can be removed
with either thioacetic acid or thiophenol in LiOH/
DMF to give amine derivatives.5,6 Previously we re-
ported that 1-methylpyrrole (3) reacts with N-chloro-
N-(4-substituted-phenyl)benzene sulfonamides to give a
pyrrole derivative in which the benzenesulfonamide
group was incorporated at C2 of the pyrrole ring.7
Removal of the benzenesulfonamide group using the
N
N
SO2
SO2
NaOCl
CHCl3
3/CHCl3
SO2
X
X
X
N
R
N
NaHCO3
CH3
Y
1a (R=2-propyl)
1b (R=
1c (R=
1d (R=
Y
2a 97%
2b 98%
2c 96%
2d 86%
4a 19%
4b 63%
4c 38%
4d 15%
n
-propyl)
n-butyl)
-butyl)
Fukuyama method would give
derivative.
a 2-aminopyrrole
t
The benzenesulfonamide group was successfully
removed with thiophenol/LiOH/DMF but not with
thioacetic acid/LiOH/DMF. Proton NMR spectra of
reaction mixtures indicated that conversion was not
complete (benzenesulfonamide moiety still present).
Yields of 5a were not affected by either increasing the
reaction time or the amounts of thiophenol and LiOH
relative to the benzenesulfonamide 4a. The desired prod-
uct was unstable and decomposed during attempts to
Keywords: 2-(Alkylamino)-pyrroles; 2-Nitrobenzenesulfonamides;
Solid phase deprotection.
*
Corresponding author. Tel.: +1 610 892 1416; fax: +1 610 892
1357; e-mail: mxd19@psu.edu
On sabbatical leave September 2005–June 2006, Faculty of Natural
´ ´
Sciences, Matej Bel University, Tajovskeho 40, 974 01 Banska
Bystrica, Slovakia.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.082

5716
M. De Rosa et al. / Tetrahedron Letters 46 (2005) 5715–5717
isolate it by column chromatography. Simple 2-amino-
pyrroles have been isolated as their tetraphenylborate
salts but the analogous salt of 5a was unstable.4
H
N
S-
O
thiophenolate resin
Wuts and Northuis reported that during the thiolate
cleavage of a 4-nitrobenzenesulfonamide derivative
nucleophilic displacement of the nitro group was also
observed.10 This was not observed when a 2-nitro deriv-
ative was used. It was proposed that the effect was steric
in nature. This suggested that nucleophilic substitution
of the 4-nitro group by the thiophenolate group to give
the para isomer of 6 was competing with the desired
sulfonamide cleavage to give 5a. Based on this, the
synthesis of 5 was attempted with the 2-nitrobenzene-
sulfonamide derivative 4a (X = NO2, Y = H and
R = 2-propyl) but nucleophilic displacement of the nitro
group (30%) was still observed as a side reaction. An
attempt was made to prepare the analogous 2,4-dinitro-
sulfonamide derivative of 4 [X = Y = NO2 and R = 2-
propyl], but cleavage of the 2-propyl group occurred
during the N-chlorination step.11 The 4-fluorobenzene-
sulfonamide (X = H, Y = F and R = 2-propyl) and 2,4-
difluorobenzenesulfonamide (X = Y = F and R = 2-pro-
pyl) derivatives of 4 were prepared. Nucleophilic substi-
tution of the fluoro group was also observed. And in the
case of the 4-fluorobenzenesulfonamide derivative,
nucleophilic displacement of the fluoro group was the
only reaction observed. Proton NMR confirmed the
structure of the para isomer of 6.12 Cleavage was
attempted using 2,6-dimethylthiophenol/LiOH but even
with this hindered thiophenolate nucleophilic substitu-
tion successfully competed with benzenesulfonamide
cleavage.
The 2-nitrobenzenesulfonamide derivative 4a (0.08
mmol, ca. 25 mg) was combined with two equivalents
of the treated resin in 1.0 mL of DMF-d7, the stirred
mixture was heated for 12 h at 100 °C under argon
and the resin removed by filtration. Proton NMR of
the DMF-d7 solution indicated that the only product
present in solution was the 2-(alkylamino)-pyrrole
5a.15 Similar results were obtained for the other
2-(alkylamino)-pyrroles 5b–d. Yields were obtained by
proton NMR spectroscopy using 1,4-dimethoxybenzene
as the internal standard.
Given the large number of possible benzenesulfonamide
derivatives possible this method is a general route to
2-(alkylamino)-pyrroles. The solid-phase method
described here is an alternative to the solution reaction
developed by Fukuyama and co-workers. Its use would
be appropriate in situations where nucleophilic substitu-
tion of the nitro group is problematic or where the use of
a volatile thiol is to be avoided.
Acknowledgements
This work was supported by grants from the National
Science Foundation. We thank Dr. J. Honovich (Drexel
University) for mass spectra.
References and notes
SO2 SC6H5
C6H5SH/LiOH
DMF
H
+
N
R
N
N
N
4
1. Cirrincione, G.; Almerico, A. M.; Aiello, E.; Dattolo, G.
In Pyrroles, Part Two: The Synthesis, Reactivity, and
Physical Properties of Substituted Pyrroles; Jones, R. A.,
Ed.; John Wiley & Sons: New York, 1992, Chapter 3.
2. Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66,
4427–4429.
R
CH3
CH3
(X=NO2, Y=H)
5
6
Resin
3. Marchand, E.; Morel, G.; Sinbandhit, S. Eur. J. Org.
Chem. 1999, 1729–1738.
4. De Rosa, M.; Sellitto, L.; Issac, R. P.; Ralph, J.; Timken,
M. D. J. Chem. Res., Synop. 1999, 262–263.
5. Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–
359.
5a (67%)
5b (42%)
5c (79%)
5d (64%)
6. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373–6374.
7. De Rosa, M.; Cabrera Nieto, G. Gazz. Chim. Ital. 1991,
121, 73–74.
Given these results a solid-phase method was developed
for carrying out the cleavage of the 2-nitrobenzenesulfo-
namide group in 4a (R = 2-propyl). It would be expected
that if the thiophenolate group was attached to a solid
support the nucleophilic substitution product analogous
to 6 would remain bound to the resin. Filtration of the
reaction mixture would then give pure product. Synthe-
sis of pure 5a, in solution, has been realized using a com-
mercial resin containing a protected thiophenol group
that, when unmasked, generates the thiophenolate
group shown below.13 This method can be compared
to a recent study that used a perfluorinated thiol for
deprotection followed by solid phase extraction to give
the amine.14
8. Compound 4a (R = 2-propyl): 1H NMR (300 MHz,
CDCl3): d 7.84–7.56 (m, 4H), 6.65 (br, 1H), 6.07 (br,
1H), 5.78 (br, 1H), 4.72–4.53 (m, 1H), 3.47 (s, 3H), 1.09 (t,
6H); HRMS (M+H) expected 324.1018, experimental
324.1012.
9. This will be the subject of a separate publication.
10. Wuts, P. G. M.; Northuis, J. M. Tetrahedron Lett. 1998,
39, 3889–3890.
11. Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831–5834.
12. Compound 6 (R = 2-propyl, para isomer): 1H NMR
(300 MHz, C2D7NO): d 7.91–7.05 (m, 9H), 6.64 (br,

M. De Rosa et al. / Tetrahedron Letters 46 (2005) 5715–5717
5717
1H), 6.01 (br, 1H), 5.60 (br, 1H), 4.60–4.38 (m, 1H),
3.58 (s, 3H), 1.02 (d, J = 3.7 Hz, 3H), 0.85 (d, J = 5.5 Hz,
3H).
14. Christensen, C.; Clausen, R. P.; Begtrup, M.; Kristensen,
J. L. Tetrahedron Lett. 2004, 45, 7991–7993.
15. Compound 5a: 1H NMR (300 MHz, C2D7NO): d 8.34–
8.25 (m, 1H), 7.94–7.86 (m, 1H), 7.79–7.70 (m, 1H), 1.35
(d, J = 5.5 Hz, 6H); peaks for N–CH3 and isopropyl CH
are covered by signal for water.
13. NovabiochemÕs 3-(4-(tritylmercapto)phenyl)propionyl
AM resin 100–200 mesh and 0.88 mmol/g was activated
according to the manufacturerÕs instructions.