PS-SNAP, a practical polymer-supported nitrosation reagent in organic synthesis

Article abstract of DOI:10.1016/j.tetlet.2010.02.135

PS-SNAP was designed and evaluated as a practical nitrosating polymer-supported reagent for the nitrosation of sec-amines. Nitrosated dialkyl amines, alkyl anilines, and bis-anilines were obtained in good yields and high purities after shaking the corresponding amines in the presence of an excess of the newly described reagent followed by simple filtration and removal of solvents.

Full text of DOI:10.1016/j.tetlet.2010.02.135

Tetrahedron Letters 51 (2010) 2277–2280
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Tetrahedron Letters
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PS-SNAP, a practical polymer-supported nitrosation reagent in organic synthesis
b
c
a
a
Didier Roche a, , Claude Lardy , Lucie Tournier , Marc Prunier , Eric Valeur
*
a Merck Serono, 4 Avenue du Président F. Mitterand, F91380 Chilly-Mazarin, France
b Edelris, 115 Avenue Lacassagne, 69003 Lyon, France
c Groupe Solabia, Route d’Oulins, 28260 Anet, France
a r t i c l e i n f o
a b s t r a c t
Article history:
PS-SNAP was designed and evaluated as a practical nitrosating polymer-supported reagent for the nitro-
sation of sec-amines. Nitrosated dialkyl amines, alkyl anilines, and bis-anilines were obtained in good
yields and high purities after shaking the corresponding amines in the presence of an excess of the newly
described reagent followed by simple filtration and removal of solvents.
Received 24 January 2009
Revised 16 February 2010
Accepted 19 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Nitrosation
Polymer-supported reagents
PS-SNAP
The N-nitrosation of amines is an important and well-estab-
lished reaction in organic synthesis,1,2 and the most common pro-
cedure involves the use of nitrous acid generated from sodium
nitrite and mineral acids in water. However, the method is not very
practical on a parallel synthesis perspective. In the frame of our
work on the discovery of new biologically active compounds
having both antioxidant and nitric oxide donor properties,3 we
addressed the possibility of using polymer-supported reagents to
synthesize N-nitroso derivatives. Indeed, the development of new
solid-supported reagents has increased dramatically over the past
decade,4 with the essential advantages of being able to drive reac-
tions by mass action, and the associated ease of purification. Some
heterogeneous nitrosating reagents have recently been described5–7
and we report herein the design, synthesis, and evaluation of
PS-SNAP as a novel polymer-supported nitrosating reagent.8
The classical aqueous conditions associated with the N-nitrosa-
tion of amines were clearly not compatible with the hydrophobic
nature of the most commonly used resins, such as polystyrene.
Our interest rapidly focused on the design of alkylnitrites or thioni-
trites reagents that could be utilized under neutral or basic condi-
tions, with the additional feature of allowing the use of a wider
range of non aqueous solvents. Thionitrites are much less known
than the corresponding alkyl nitrites, probably because of their
generally lower stability.9,10 However, S-Nitroso-N-acetylpenicilla-
mine (SNAP)11 is a stable solid which has been used as a nitric
oxide generator in a range of in vivo and in vitro experiments.12,13
It was also described as a reagent for the transnitrosation of
amines,14 thiols, and phenols.15,16 Therefore, we considered that
the immobilization of SNAP on a solid support could provide us
with the desired nitrosating reagent in a form that was stable
and reactant enough to undergo transnitrosation of amines.
PS-SNAP was prepared in two steps from commercially avail-
able aminomethyl-polystyrene resin (Scheme 1). The resin (Nova-
biochem, 1.13 mmol/g loading) was treated overnight with a DMF
solution of N-acetyl-DL-penicillamine N-hydroxysuccinimidate 117
at room temperature to provide a colorless resin PS-2 which gave
a negative result in the Kaiser colorimetric test.18 IR analysis of the
resin confirmed the presence of the expected weak SH band at
2750 cmÀ1. The S-nitrosation was attempted under various condi-
tions of solvents (DCM, H2O, MeOH, AcOH/dioxane/water, CHCl3)
using sodium nitrite, ethyl nitrite, tert-butylnitrite, or NOBF4 as
nitrosonium source. Best conditions were obtained using sodium
nitrite in a mixture of solvents AcOH/dioxane/water. The reaction
was monitored by the appearance of a green coloration of the
beads ( Fig. 1) characteristic of tert-butylthionitrites9,10 and the
disappearance of the SH band by IR spectroscopic analysis of the
beads. Elemental analysis of the PS-SNAP resin prepared under
the optimized conditions indicated a 70% immobilization yield
based on the initial loading. PEG-SNAP was similarly prepared
from the commercially available PEG-aminomethyl resin. The
butyric thionitrite analog (PS-5) was also prepared under similar
conditions from aminomethyl-polystyrene resin and 3-mercapto-
3-methyl-butyric acid.19
The S-Nitroso reagents were then evaluated in the transnitrosa-
tion of amines. Based on our experience in the synthesis of N-nitro-
so compounds, the nitrosation of biphenyl amine 6 (Fig. 2) was
chosen as a model study. Indeed, its N-nitroso derivative 7 is a sta-
ble compound easy to characterize by NMR or HPLC.3 The kinetics
* Corresponding author at present address: Edelris 115 Avenue Lacassagne, F-
69003 Lyon, France. Tel.: +33 0 4 37 56 16 60; fax: +33 0 4 72 33 84 59.
E-mail address: didier.roche@edelris.com (D. Roche).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.135

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D. Roche et al. / Tetrahedron Letters 51 (2010) 2277–2280
O
O
N
O
O
SH
O
NaNO2 (5 eq.), AcOH (20 eq.)
Dioxane/H2O 10%
O
N
NHAc
1
N
H
S
O
N
H
SH
NHAc
DMF, rt, 12 h
NHAc
PS-2
PS-SNAP
PEG-2
NH2
PEG-SNAP
PS-Aminomethyl
PEG-Aminomethyl
O
O
O
HO
SH
NaNO2 (5 eq.), AcOH (20 eq.)
Dioxane/H2O 10%
N
3
N
H
S
O
N
SH
H
DIC, DMF, rt, 12 h
PS-4
PS-5
Scheme 1. Preparation of S-NO polymer-supported reagents.
Figure 1. Microscopic view of PS-2 (colorless) and PS-SNAP (green) resins (Leica/Sony 3CCD).
O
N
O
N
H
S
O
H
N
N
N
R
3 eq.
H
N
H
N
O
O
solvent
O
N
O
6
7
N
Figure 2. Kinetics of nitrosation of compound 6 with PS-SNAP and PS-5.

D. Roche et al. / Tetrahedron Letters 51 (2010) 2277–2280
2279
Table 1
R1NHR2?R1R2N–NO17
Entry
R1R2N–NO
MW
253
% Weight recovered
LC/MS
% Conversion
1H NMR (%)
R1NHR2 (%)
N
N
O
O
1
95
n.d.
92
67
8
CN
2
N
N
196
105
55% (DAD 200) MS ES+ 167, 197
33
O
O
N
N
3
4
5
224
243
146
96
99
95
92% (DAD 200) MS ES+ 225
>90
0
N
O
NO2
N
0% (ELSD)
0
100
100
N
0% (ELSD)
0
N
O
O
6
176
93
0% (ELSD)
0
100
N
N
O
N
O
7
8
136
166
97
98
51% (DAD 200) MS ES+ 137
69
0
0
N
N
O
92% (DAD 200) MS ES+ 137, 167
>90
O
N
O
O
9
236
90
94% (ELSD) MS ES+ 237
n.d.
n.d.
N
N
O
O
O
10
11
222
162
97
95
87% (DAD 200) MS ES+ 223
80% (DAD 200) MS ES+ 163
90
10
0
N
N
O
N
>90
N
O
of the formation of compound 7 using 3 equiv of polymer-sup-
ported reagent in various solvents are presented in Figure 2 (as of-
ten with polymer-supported reagents, an excess of reagent proved
to be necessary to drive the reaction to completion). In CDCl3, ini-
tially used to monitor the reaction by 1H NMR, 92% conversion was
obtained after 72 h (n1 curve). Similar results were obtained in
dichloromethane (n2 curve) while the reaction was considerably
slower in THF (n5 curve). Interestingly the reagent could be regen-
erated using sodium nitrite/acetic acid in dioxane/water and re-
used without loosing the reactivity or decreasing the final purity
of the nitrosated amine (n3 curve). Furthermore, the reagent
proved to be stable as the reaction performed with a batch of PS-
SNAP kept for six month in the dark at 4 °C provided similar re-
sults. In comparison, the kinetics of transnitrosation obtained with

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D. Roche et al. / Tetrahedron Letters 51 (2010) 2277–2280
PEG-SNAP and PS-5 under the same conditions were considerably
slower (n4 and n6 curves, respectively).
References and notes
1. Keefer, L. K.; Williams, D. L. H. Methods in Nitric Oxide Research; John Wiley &
Sons, Ltd: New York, 1996. pp 509–519.
2. Vogels Text Book of Practical Organic Chemistry, 4th ed.; Longman: London and
New York, 1986.
3. (a) Lardy, C.; Guedat, P.; Caputo, L. FR. Demande 2005, FR 2862966.; (b) Lardy,
C.; Festal, D.; Caputo, L.; Guerrier, D. FR. Demande 2003, FR 2836917.
4. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc.,
The PS-SNAP reagent was then evaluated in the nitrosation of
various sec-amines. The reactions were carried out by shaking
the substrate in dichloromethane in the presence of 3 equiv of
PS-SNAP for 140 h (Table 1).20 LC/MS and 1H NMR were used to
determine the purity and to characterize the products.
Several bis-anilines could be nitrosated in moderate to good
yields including both the carbazole and iminodibenzyl moieties
(entries 1–3). Discoloration of the beads from green to pale yellow
was self-indicative of the substrate reactivity. The presence of a
strong electron withdrawing group in the para position, such as
the nitro group, prevented any reaction and the starting material
was fully recovered (entry 4). Similarly, both the transnitrosation
of indole and 4-methoxyindole did not provide the desired N-nitro-
so derivatives (entries 5 and 6), probably because of the poor
nucleophilicity of the indolic nitrogen (no discoloration of the
PS-SNAP beads in these experiments). Overall, the transfer reac-
tion was successful with many nucleophiles and several nitrosated
alkyl anilines or dialkyl amines were obtained in very good yields
(entries 7–11). The reaction was considerably faster with these
substrates (100% completion after 20–30 h) and no degradation
was observed on pursuing the reaction longer. It is worth noting
that although this method is considerably slower compared to a
typical sodium nitrite N-nitrosation, its ease of use makes it partic-
ularly attractive for automation.
To conclude, PS-SNAP is a stable, thionitrite-derived reagent,
easy and safe to handle. Caution should be given nevertheless in
handling reagents leading to potentially carcinogenic N-nitrosoam-
ines. Bis-anilines, alkyl anilines, and dialkyl amines were cleanly
nitrosated and the method is perfectly designed for an automated
parallel synthesis strategy. Application of the PS-SNAP reagent to
the synthesis of libraries of nitrosated amines as well as further
applications of the reagent in organic synthesis are in progress
and will be reported in due course.
Perkin Trans.
1 2000, 3815–4195; (b) Kirschning, A.; Monenschain, H.;
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Iranpoor, N.; Firouzabadi, H.; Pourali, A. Synth. Commun. 2005, 35, 1517–1526.
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7019–7026.
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Kalyanaraman, B. J. Lipid Res. 1995, 36, 1756–1762.
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1279–1282.
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688.
17. Compound 1 was prepared in quantitative yield from the reaction of ( )-N-
acetylpenicillamine (24 g, 125 mmol) with N-hydroxysuccinimide (14.4 g,
125 mmol) in the presence dicyclohexylcarbodiimide (25.8 g, 125 mmol) in
THF (500 mL) at rt for 12 h.
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595–598.
19. 3-Mercapto-3-methyl-butyric acid was prepared according to: Sweetman, B. J.
J. Med. Chem. 1971, 14, 868–872.
20. Typical procedure: PS-SNAP (100 mg, 3 equiv) was added to a solution of 6
(10 mg, 0.03 mmol) in dichloromethane (3 ml) and the mixture was stirred
with an orbital shaker for 140 h. After filtration, the resin was washed with
dichloromethane and the filtrate was concentrated to afford 7 (10 mg, 91%
yield) as a pale yellow solid.
Acknowledgment
We would like to thank Dr. P. Guedat for helpful discussions and
for providing us with the succinimidate intermediate 1.