PAPER
1657
Novel ZnX -Modulated Pd/C and Pt/C Catalysts for Chemoselective Hydro-
2
genation and Hydrogenolysis of Halogen–Substituted Nitroarenes, Alkenes,
Benzyl Ethers, and Aromatic Ketones
Z
G
nX -ModulatedC
e
hemoselec
o
tive
H
ydroge
r
nation ge Wu,* Mingsheng Huang, Monique Richards, Marc Poirier, Xin Wen, Richard W. Draper
2
Chemical Process Research and Development, Schering-Plough Research Institute, 1011 Morris Avenue, Union, New Jersey, 07083 USA
Fax +1(908)8206620; E-mail: george.wu@spcorp.com
Received 7 May 2003
zation or chromatography. Addition of a small amount of
acetic acid did not prevent the dechlorination. Addition of
Abstract: Novel ZnX -modulated Pd/C and Pt/C catalysts were de-
veloped to chemoselectively hydrogenate halogen-substituted ni-
troarenes, alkenes, benzyl ethers, and aromatic ketones.
2
0
.6 equivalent of ZnBr , however, completely blocked the
2
dechlorination pathway. The 0.6% of des-Cl in entry 3
originated from an impure Grignard reagent used for the
preparation of 1.
Key words: zinc halides, palladium, platinum, hydrogenation, ni-
troarenes
p-BnOC6H4
C6H4F-p
p-HOC H
6 4
C H F-p
6
4
10% Pd/C/H2
It is a challenging task to chemoselectively hydrogenate
functional groups in the presence of halogen substituents.
This issue is even more pronounced at the end of a synthe-
sis of a pharmaceutically active ingredient because of the
strict purity requirement. A number of methods have been
developed to minimize the undesired hydrodehalogena-
+
p-ClC H
6
4
O
p-ClC6H4
O
OH
OH
1
2
p-HOC6H4
C6H4F-p
p-HOC H
6 4
C H F-p
6
4
+
C6H5
O
6 4
p-ClC H
O
1
–3
tion of chloronitroarenes. However, the more expensive
platinum or toxic nickel-based catalysts are required. Var-
OH Des-Cl
Des-OH
Entry Pd/C ZnBr2
HOAc
Des-Cl, % Des-OH, % 2, % (isolated)
3
,4a
3,4
1
2
3
10%
10%
0
0
0
4.7
7.1
0.6
2.6
3.3
2.0
65%
n.a.
ious additives such as MgO,
morpholine,
3
5
2 drops
0
polyamines, amidine, phosphorous acid and its deriva-
tives, metal ions (salt), and a combination of inorgan-
ic/organic phosphorous with a vanadium compound have
3
,4b
6
1
0% 0.6 eq.
70%
7
Scheme 1 Chemoselective hydrogenolysis of chlorobenzyl ether 1
n.a. = not attempted)
been employed as catalyst modifiers over commercially
available catalysts. These additives often have their draw-
backs such as limited scope, low chemoselectivity, low re-
action rate, undesired side reactions, difficult separation
of the additives, cost, and toxicity. In addition, most of the
reported methods only inhibit hydrodechlorination. For
bromonitroarenes, the hydrodebromination is rarely sup-
(
We have now extended the scope of the ZnBr -modulated
2
palladium-catalyst to a number of other functional groups
including nitroarenes, alkenes and aromatic ketones. First,
we studied the hydrogenation of the chloronitroarene 3. In
the absence of ZnBr , the level of Des-Cl-4 varies from 2
8
2
pressed to below 2%. The chemoselective hydrogenation
to 12% depending on the amount of Pd/C used as shown
in Scheme 2. Addition of a mere 0.2 equivalent of ZnBr2
to the reaction mixture reduced the level of Des-Cl-4 to
between 0.1 and 0.3% with excellent isolated yield of 4.
The amount of Pd/C used has a small influence on the
chemoselectivity but has noticeable effect on the reaction
rate, particularly in the presence of ZnBr . This result sug-
gested that the palladium catalyst is poisoned or modulat-
ed by ZnBr . In contrast to the reported methods where the
more expensive platinum catalysts are required, our new
procedure only uses a small amount of palladium.
of iodonitroarenes is still very difficult to achieve.4 Fur-
thermore, most of the reported methods are restricted to
the reduction of halonitroarenes. There are few methods
for the chemoselective hydrogenation of haloaromatic
alkenes and ketones. We now report novel zinc halide-
modulated Pd/C and Pt/C catalysts that chemoselectively
hydrogenate chloro-, bromo-, and iodo-substituted ni-
troarenes, alkenes, benzyl ethers, and aromatic ketones.
b,9
2
2
Recently, we have reported the first example of a ZnBr2-
modulated chemoselective hydrogenolysis of a benzyl
ether in the total synthesis of a cholesterol absorption in-
Dichloronitrobenzene can also be chemoselectively re-
duced with ZnCl -modulated palladium catalyst as shown
in Scheme 3. In the absence of ZnBr , the 2,5-dichloroni-
trobenzene 5 was hydrogenated to give 96% of aniline
with 2% each of chloroaniline and aniline. It is worth not-
ing that the less hindered 5-chloro was reduced faster than
the 2-chloro derivative. Addition of 1 equivalent of ZnBr2
1
0
hibitor. As shown in Scheme 1, the use of 10% of com-
mercially available palladium on carbon resulted in 4.7%
2
2
(
HPLC normalization) of des-chloro by-product, an impu-
rity that was very difficult to purge out by either crystalli-
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1657,1660,ftx,en;C02903SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York