The reduction of aromatic nitro groups on solid supports using sodium hydrosulfite (Na2S2O4)

Article abstract of DOI:10.1016/S0040-4039(00)00959-X

An improved method for reducing aromatic nitro compounds on solid-phase supports using sodium hydrosulfite is presented. Conditions have been optimized to enable the use of this reagent for reductions on both polyethyleneglycol-polystyrene (PEG) resins an

Full text of DOI:10.1016/S0040-4039(00)00959-X

Tetrahedron Letters 41 (2000) 6531±6535
The reduction of aromatic nitro groups on solid supports
using sodium hydrosul®te (Na S O )
2
2 4
Randall A. Scheuerman* and David Tumelty
A€ymax Research Institute, 4001 Miranda Avenue, Palo Alto, CA 94304, USA
Received 28 April 2000; revised 5 June 2000; accepted 8 June 2000
Abstract
An improved method for reducing aromatic nitro compounds on solid-phase supports using sodium
hydrosul®te is presented. Conditions have been optimized to enable the use of this reagent for reductions
on both polyethyleneglycol-polystyrene (PEG) resins and traditional polystyrene (PS) resins. # 2000
Published by Elsevier Science Ltd.
In solution-phase chemistry, the reduction of aromatic nitro groups is readily accomplished
with a wide variety of reagents. Many of these methods, however, require either heavy metal
catalysts, acidic conditions, high temperatures or pressure, which renders most of them unsuitable
for use in solid-phase organic chemistry. The most common method currently in use for reduction
1
of solid-phase bound nitro groups utilizes tin(II) chloride. This reagent works well under a
variety of conditions and generally provides reliable and clean conversion to the corresponding
aniline. Several reports have also appeared, which use other transition metal-containing
compounds, such as chromium.2
Despite the advantages of tin reduction, we have found that substantial quantities of tin
by-products remain bound within the resin matrix and are liberated upon acid cleavage of the
desired product. Several cell lines useful in biological compound screening have proven intolerant
3
to tin at these levels. Although attempts to rigorously wash away any tin species remaining
within the resin by employing a variety of methods (e.g. chelating agents, solvents, crown ethers,
mild acids and bases) were partially successful, we were prompted to investigate alternative
reducing agents. In searching for a solid-phase compatible method, which would be reliable,
inexpensive, non-toxic, non-nucleophilic, neutral, and speci®c to the reduction of nitro
compounds in the presence of other functionalities, we carried out a rigorous examination of
sodium hydrosul®te.4
*
Corresponding author. Fax 650 855 1445; e-mail: rscheuerman@xenoport.com
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00959-X

6
532
Initial experiments on a variety of resins quickly demonstrated the advantages and
disadvantages of this reagent. Use of the reagent had been previously reported to e€ect reduction
5
on polystyrene resin by re¯uxing in ethanol. However, on further investigation, it quickly
became apparent that these were not the conditions of choice. While sodium hydrosul®te is stable
ꢀ
at temperatures below 50 C, it rapidly disproportionates at higher temperatures, decreasing the
e€ectiveness of the reagent. Owing to the poor solubility of sodium hydrosul®te in organic
solvents, we employed water as the solvent of choice. Indeed, sodium hydrosul®te is readily
soluble in water, and a 1 M concentration can be readily obtained at ambient temperature. An
aqueous 1 M solution of sodium hydrosul®te eciently reduces aromatic nitro groups on PEG-PS
1
1
resins such as Argogel and Tentagel . It also works eciently on some of the newer modi®ed
1
resins, such as Argopore , although here the addition of limited amounts up to 20% (v/v) of
organic modi®ers (such as EtOH, NMP or DMF) was useful (Fig. 1).
Figure 1. Model system for testing reduction methods. (a) PPh Br , DCM; (b) benzylamine, DMF; (c) nitroarene
3
2
2.
2
; (e) SnCl 2H O, DMF; (f) TFA
carboxylic acid, DIC, NMP; (d) aq. Na
2
S
2
O
4
, K
2
CO
3
1
A more extensive survey of the reduction of various nitroarenes was conducted on Tentagel
1
resin. Tentagel MB PHB (10 g, 0.4 mmol/g loading, resin 1) was treated with 200 mL of 0.25 M
PPh Br in DCM for 16 h at rt. The corresponding bromide was displaced with 100 mL of 1 M
3
2
ꢀ
benzylamine in DMF at 70 C for 1 h to a€ord resin 2. The resin was divided into 100 mg
aliquots, and treated with a mixture of various nitroarene carboxylic acids (100 equiv.) and DIC
(50 equiv.) in 1 mL NMP for 16 h at rt. The resulting nitroarene benzamides 3 were split into
equal portions of 50 mg each, and treated with either 2 mL of 0.5 M aqueous sodium
hydrosul®te/0.5 M potassium carbonate for 16 h at rt, or 2 mL of 1 M tin(II)chloride dihydrate in
ꢀ
DMF at 50 C for 16 h to give the resin-bound reduced products 4. The ®nal products 5 were
obtained by cleavage with TFA for 1 h. The results of the two di€erent reduction procedures are
summarized in Table 1. Both reaction conditions were quite e€ective in cleanly reducing the nitro
functionality, with the sodium hydrosul®te reagent giving improved results in the more dicult
reductions of heteroaromatic nitro compounds.

6
533
Table 1
Results of nitro reduction using sodium hydrosul®te and tin(II) chloridea

6534
As expected, however, the hydrosul®te reagent in aqueous solution was unable to reduce
aromatic nitro groups on regular polystyrene resin due to the known hydrophobicity of the solid
support, and its inability to swell in an aqueous environment. Attempts were made with the
introduction of co-solvents such as NMP, DMF, MeOH, THF, dioxane, and EtOH in
concentrations up to 50%, with little bene®cial results observed. The use of viologen dibromide as
6
an electron phase-transfer catalyst for similar reductions in solution has been reported. This
prompted an investigation into such a system for the reduction of aromatic nitro groups on
polystyrene. 4-Nitrobenzoic acid was coupled to PS-Rink resin to give 6 (Fig. 2). This resin was
treated with a mixture of 0.5 M sodium hydrosul®te and 0.5 M potassium carbonate in
DCM:water (9:1), employing a variety of dialkylbipyridinium dihalides as electron phase-transfer
catalysts to give the reduced resin-bound intermediate 7. The extent of the reduction reaction was
assessed by acidolysis to release the product 8. In all cases, the quantitative reduction of the nitro
group on polystyrene resin was observed, independent of the catalyst employed.7
Figure 2. Cyclic pathway for the viologen-mediated reduction of nitroarenes with sodium hydrosul®te
Overall, we have demonstrated that sodium hydrosul®te is a useful alternative to metal-based
reducing agents and may be superior in some cases. The use of this reagent in the preparation of
combinatorial chemical libraries will be reported in due course.
Acknowledgements
The authors thank Drs. Brian Evans and Brian Marron for useful comments and Drs. Ted
Baer and Chris Holmes for critically reading the manuscript.
References
1
. (a) Schwarz, M. K.; Tumelty, D.; Gallop, M. A. J. Org. Chem. 1999, 64, 2219±2231. (b) Tumelty, D.; Schwarz,
M. K.; Needels, M. C. Tetrahedron Lett. 1998, 39, 7467±7470. (c) Kiselyov, A. S.; Smith II, L.; Armstrong, R. W.

6
535
Tetrahedron 1998, 54, 5089±5096. (d) Meyers, H. V.; Dilley, G. J.; Durgin, T. L.; Powers, T. S.; Winssinger, N. A.;
Zhu, H.; Pavia, M. R. Mol. Diversity 1995, 1, 13±20.
. Hari, A.; Miller, B. L. Tetrahedron Lett. 1999, 40, 245±248.
2
3
4
. Unpublished results, A€ymax Research Institute, 1999.
. Sodium hydrosul®te (also known as sodium dithionite) has been used in solution-phase chemistry for reduction
reactions of this type, e.g.: Khurana, J. M.; Singh, S. J. Indian Chem. Soc. 1996, 73, 487±488.
. Hughes, I. Tetrahedron Lett. 1996, 37, 7595±7598.
. Park, K. K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett 1993, 34, 7445±7446.
. In a typical reaction: To 50 mg of resin-bound nitrobenzamide 6 was added 0.2 mL of 0.5 M sodium hydrosul®te/
5
6
7
0
.5 M potassium carbonate and 1.8 mL of DCM, followed by the addition of 2 mg of the phase-transfer catalyst
2
+
(
PTC-V ). The reaction was shaken for 16 h at rt to a€ord 7. The ®nal product 8 was obtained by cleavage with
0 0
5
0% TFA in DCM for 1 h. Six di€erent 1,1 -diX-4,4 -bipyridinium dibromide or dichloride reagents were used,
where X=ethyl, phenyl, benzyl, heptyl, octyl and octadecyl. Each was equally e€ective under the described
conditions.