Heterogeneous catalyzed reduction of polymer-bound nitroarenes

Article abstract of DOI:10.1081/SCC-120003608

Deposition of palladium as a catalyst on polymer beads, such as Merrifield resin or TentaGel, allows the reduction of polymer-bound 4-nitro benzoate to the corresponding anilines with dilute hydrazine hydrate solution in DMF at room temperature.

Full text of DOI:10.1081/SCC-120003608

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HETEROGENEOUS CATALYZED REDUCTION OF POLYMER-
BOUND NITROARENES
a
b
b
a
Martin Rödel , Florian Thieme , Herwig Buchholz & Burkhard König
a
Institut für Organische Chemie , Universität Regensburg , D-93040, Regensburg, Germany
b
Merck KGaA , Darmstadt, Germany
Published online: 16 Aug 2006.
To cite this article: Martin Rödel , Florian Thieme , Herwig Buchholz & Burkhard König (2002) HETEROGENEOUS CATALYZED
REDUCTION OF POLYMER-BOUND NITROARENES, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 32:8, 1181-1187, DOI: 10.1081/SCC-120003608
To link to this article: http://dx.doi.org/10.1081/SCC-120003608
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SYNTHETIC COMMUNICATIONS, 32(8), 1181–1187 (2002)
HETEROGENEOUS CATALYZED
REDUCTION OF POLYMER-BOUND
NITROARENES
1
Martin Rodel, Florian Thieme, Herwig Buchholz,
¨
2
2
1
,
and Burkhard Ko
¨
nig *
1
Institut fur Organische Chemie, Universitat
¨
Regensburg, D-93040 Regensburg, Germany
¨
2
Merck KGaA, Darmstadt, Germany
ABSTRACT
Deposition of palladium as a catalyst on polymer beads, such
as Merrifield resin or TentaGel, allows the reduction of poly-
mer-bound 4-nitro benzoate to the corresponding anilines
with dilute hydrazine hydrate solution in DMF at room
temperature.
Reactions of polymer-bound organic substrates have become very
1
important in the last decade. Solid phase protocols allow combinatorial
,2
3
preparation of compounds, automation of synthesis or simplicity of
handling and work-up during synthesis. The number of reactions for
which solid phase procedures exists has increased markedlyin recent
4
years. However, for reduction steps, such as the reduction of nitro com-
5
pounds, veryfew procedures are available.
Homogeneous reduction
*
Corresponding author. E-mail: Burkhard.Koenig@chemie.uni-regensburg.de
181
1
Copyright & 2002 byMarcel Dekker, Inc.
www.dekker.com

¨
RODEL ET AL.
1
182
6
reagents such as SnCl
7–12
13,14
or CrCl /Mn/TMSCl,
2
which have been
2
employed in solid phase synthesis, have significant disadvantages: The
procedures are not general and success stronglyvaries with substrate struc-
ture. Stoechiometric amounts of toxic metals are necessary, and the pro-
cedures are not easilyapplied in automated synthesis. The classical and well-
established methods for reduction in homogeneous solution with heteroge-
1
5,16
neous transition metal catalysts and a hydrogen source,
if used in solid
phase synthesis, lead to an unfavorable situation of two heterogeneous
reaction components. However, the problem might be resolved if the cata-
1
7
lytic site and polymer-bound substrate are brought in close contact. In this
paper we present our results in adapting a well known catalyzed heteroge-
neous reduction reaction to a solid phase protocol.
To make heterogeneous catalyzed reactions on polymer-bound sub-
strates possible, we deposit palladium as the active metal catalyst directly on
1
8
the polymer bead used for solid phase synthesis. Standard Merrifield resin
1a) was loaded with 4-nitro benzoic acid (2) using Cs CO and potassium
(
2
3
1
9
iodide in DMF (see Scheme 1 for conditions). The hydrogenation catalyst
was then precipitated on the polymer by heating the loaded bead with
palladium acetate in DMF for 1 h to 80 C. The beads turned dark black
ꢀ
indicating the precipitation of finelydivided palladium. From high resolu-
tion inductivelycoupled plasma mass spectrometry(HR-ICP-MS) a palla-
dium content of 9500 mg Pd per gram of resin was determined. Analysis of
DMF solutions in which the palladium loaded beads were stored for 24 h
gave a verylow palladium content of 2–3 mg Pd/ml, which indicates that the
palladium is stronglybound to the surface and not rapidlyreleased from the
bead into solution. In order to gain information about the structure of the
precipitated palladium, REM images of the beads with and without palla-
dium were recorded (see Figure 1). Even at high magnification no significant
differences of the surface structure were observed, from which we conclude a
2
0
fine distribution of the palladium over the whole surface.
The resin, now loaded with nitroarene substrate and palladium metal,
was treated with 20% (v/v) hydrazine hydrate solution in DMF at
room temperature. Instantaneous gas evolution indicates a spontaneous
reaction. To ensure complete conversion the beads were left in the solu-
tion overnight and washed with DMF several times. A positive bromo
2
1
phenol blue assay confirmed the presence of free amino groups on
the bead. 4-Amino benzoic acid methyl ester (8a) was cleaved from the
resin with sodium methoxide in methanol and isolated in 60% yield.
The presence of palladium as a catalyst is essential for the reaction.
Treatment of nitroarene-loaded Merrifield resin with hydrazine solution
without palladium deposition gave no conversion of starting material.
Palladium precipitation and the reduction step can be combined into one

REDUCTION OF POLYMER-BOUND NITROARENES
1183
Figure 1. REM images of Merrifield resins with (lower pictures) and without
upper pictures) precipitated palladium at low (left pictures) and high (right pictures)
magnification.
(
step, whereby palladium acetate and hydrazine hydrate solution are added
2
simultaneously. This allows a direct conversion of compound 3a and 5a.
2
Treatment of 5a with excess 4-nitro benzoyl chloride gave 6a, which was
treated with hydrazine hydrate solution for 12 h. Cleavage of the product
from the resin gave 9a, although in low yield of 28%. This shows that in
principle the deposited catalyst can be reused for subsequent catalytic steps
performed on the bead, but at the present stage loss of catalyst activity is
significant.
To prove the compatibilityof the method with more advanced
materials and techniques of solid phase synthesis, the procedure was per-
2
3
formed on TentaGel S RAM (1b), a TentaGel with rink amide linker
group. Using standard conditions, 4-nitro benzoic acid (2) was coupled to
the solid support. The loading capacityof the bead was verified bycleavage
of the bound substrate with TFA as amide, whereby99% of the compound

¨
RODEL ET AL.
1
184
was reisolated in analytical pure form. Palladium was precipitated on the
bead as described above, and treatment of the loaded bead with 20% (v/v)
hydrazine hydrate solution in DMF for 12 h at room temperature, washing
2
4
with DMF and cleavage of the product with TFA gave 8b in 94% isolated
ꢀ
Scheme 1. Reagents and conditions: (i) Cs CO , KI, DMF, 72 h, 80 C; (ii) DIC,
3
2
HOBt, Et
HOBt, Et
5 : 95); RT, 1 h.
3
N, DMF, RT, 12 h; (iii) 4-Nitrobenzoyl chloride, Et
3
N, DMF; (iv) 2, DIC,
Cl
2
3
N, DMF, RT, 12 h; (v) NaOMe, MeOH, RT, 12 h; (vi) TFA/CH
2
(

REDUCTION OF POLYMER-BOUND NITROARENES
1185
yield. A second coupling/reduction cycle of 5b via 6b and 7b gave 9b after
cleavage from the resin. However, again the isolated yield of 30% is not
satisfactoryand the stabilityof the catal ys t on the bean must be increased
before extended reaction sequences can be performed.
The scope of this method is limited bythe chemoselectivityto other
reduceable functional groups in the substrate, as in comparable reduction
reactions. In addition the reaction of 1-chloro-5-nitro benzoic acid was not
successful, most likelydue to the chemical reactivityof the chloroarene bond
in the presence of palladium. However, the method facilitates the used of the
large number of known and available aromatic and heteroaromatic nitro
compounds in librarys yn thesis on solid support.
In conclusion we have shown that polymer-bound 4-nitro benzoate
can be reduced to the corresponding aniline in 94% overall yield at room
temperature bytreatment with h yd razine solution if palladium as a catal ys t
2
5
is precipitated on the TentaGel bead. These experiments are first and
simple examples of catalytic beads that are loaded, in addition to the immo-
bilized substrate, with tools for catalytic and selective chemical transforma-
tions on their surface.
EXPERIMENTAL
Typical procedure for the reduction-coupling cycle on TentaGel S
RAM: A suspension of 500 mg resin-bound nitrobenzamide 3b in 5 ml of
ꢀ
DMF with 5 mg palladium (II) acetate was heated for 1 h to 80 C. The
resin was filtered off, washed with DMF and dichloromethane and dried in
vacuo. The palladium-loaded resin 4b was stirred in 5 ml of 20% (v/v)
hydrazine hydrate/DMF solution for 12 h at room temperature, the resin
was filtered off, washed with DMF, methanol and dichloromethane and
dried in vacuo. The reaction product was cleaved bytreatment with TFA
(5% in dichloromethane solution) to give 8b in 94% isolated yield or
coupled again with 2 to yield 9b after reduction and TFA cleavage from
the resin.
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deposit palladium from palladium salt solution using ultrasound
were not successful.

REDUCTION OF POLYMER-BOUND NITROARENES
1187
21. A sample of the beads was suspended in dichloromethane and a drop
of a 1% solution of bromo phenol blue in dimethylacetamide was
added. A deep blue staining of the beads indicates the presence of
free amino groups.
2
2. The palladium content of the beads and the solution was determined as
described before, which confirmed that under the reaction conditions
of the reduction the palladium is still present on the bead and is not
released into solution.
2
2
3. Purchased from Novabiochem.
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¨
Received in the Netherlands May10, 2001