Transfer hydrogenation in ionic liquids under microwave irradiation

Article abstract of DOI:10.1055/s-2002-33349

Catalytic transfer hydrogenation (CTH) of different homo- or heteronuclear organic compounds was performed in a room temperature ionic liquid (RTIL) N-butyl-N′-methylimidazolium hexafluorophosphate, ([BMIM]⁺ [PF₆]^-) (1) as solvent heated by microwave irridiation. Formate salts such as ammonium formate and triethylammonium formate were used as a hydrogen source in the reaction catalyzed by palladium on carbon. Essentially pure products could be isolated in moderate to excellent yields by simple liquid-liquid extraction with methyl tert-butyl ether (MTBE). Recycling of the catalyst/solvent system was possible.

Full text of DOI:10.1055/s-2002-33349

SPECIAL TOPIC
1607
Transfer Hydrogenation in Ionic Liquids under Microwave Irradiation
ds ig Berthold,a,b Theo Schotten,* Helmut Hönigb
a
T
H
ransfer
H
ydrogen
e
ation in
I
on
r
ic Liqui
w
a
Lilly Forschung GmbH, 22419 Hamburg, Germany (a Division of Eli Lilly Research Laboratories)
Fax +49(40)52724614; E-mail: berthold_herwig@lilly.com ; E-mail: schotten_theo@lilly.com
b
Technical University Graz, Institute for Organic Chemistry, Stremayrgasse 16, 8010 Graz, Austria
Fax +43(316)8738740; E-mail: berthold@sbox.tu-graz.ac.at; helmut.hoenig@TUGraz.at
Received 7 June 2002
Dedicated to Jenny Berthold for her lifework.
sequently offering interesting options for workup and ex-
traction procedures.4 With regard to microwave-assisted
synthesis their extremely high dielectric constant makes
Abstract: Catalytic transfer hydrogenation (CTH) of different ho-
mo- or heteronuclear organic compounds was performed in a room
temperature ionic liquid (RTIL) N-butyl-N -methylimidazolium
a,b
+
–
hexafluorophosphate, ([BMIM] [PF ] ) (1) as solvent heated by them ideally suited to be rapidly heated in a microwave
6
microwave irridiation. Formate salts such as ammonium formate field.5 Catalytic transfer hydrogenation (CTH) is a ver-
a–d
and triethylammonium formate were used as a hydrogen source in
satile reaction for the reduction of homo or heteroatomic
the reaction catalyzed by palladium on carbon. Essentially pure
sp or sp2 bonds present in alkenes, alkynes, nitriles, nitro
products could be isolated in moderate to excellent yields by simple
and carbonyl compounds as well as for reductive dehalo-
liquid-liquid extraction with methyl tert-butyl ether (MTBE). Recy-
genation of haloarenes.6 The reactions have been con-
a–d
cling of the catalyst/solvent system was possible.
ducted preferably in a microwave field using a range of
Key words: microwaves, room temperature ionic liquid, catalytic
solvents like DMSO, ethylene glycol or propane-1,3-diol
transfer hydrogenation, unsaturated compounds, formate salts
and with different catalysts (i.e., palladium/carbon, Raney
nickel, and Wilkinson’s catalyst) using formic acid and its
salts as a hydrogen source.7 While ionic liquids have al-
a,b
The advantages of using microwave dielectric heating for
ready found broad application as solvent-cum-catalysts in
performing organic reactions has been realized by many
8a,5d
a wide range of synthetic transformations
including
1
a–e
different groups over the recent decade. The most com-
pelling features of microwave irradiation in chemical syn-
thesis are dramatically accelerated reaction rates and
improved yields, selectivity, and purity of the products in
many cases. Generally, the reaction can be run in a solvent
as a homogeneous or heterogeneous mixture or solvent-
free on solid supports like silica gel, alumina or clays. The
latter methodology has been developed originally to cir-
cumvent potential hazards of uncontrolled microwave
heating of flammable, toxic and volatile organic liquids
8b–j
catalytic hydrogenations with molecular hydrogen,
CTH with salts of formic acid in ionic liquids under mi-
crowave irradiation has not been reported to date. Herein,
we report our results using the ionic liquid (IL) N-butyl-
N -methylimidazolium hexafluorophosphate ([BMIM]
PF ] ) (1) (Figure) as a solvent and 10% palladium/car-
+
–
[
6
bon as a catalyst for the catalytic transfer hydrogenation
of various organic substrates. We have chosen 1 based on
its physicochemical properties (i.e., exceptionally high
thermal stability and immiscibility with organic as well as
aqueous solvents).
(
VOLs), especially when domestic microwave ovens have
2
a,b
been employed.
Nevertheless, avoiding or replacing VOLs in organic syn-
thesis is currently a major goal in designing ‘greener’ and
3
environmentally benign processes in industry. Very re-
cently room temperature ionic liquids (RTILs) have
drawn much attention to overcome many of these environ-
mental issues, due to their unique physicochemical prop-
Figure The structure of N-butyl-N -methylimidazolium hexa-
erties profile, as they are nonflammable, nontoxic (as far fluorophosphate.
as known), nonvolatile, recyclable, extremely high boil-
ing, and thermally and chemically stable. Their purely
In a first trial, we reduced 4-nitrobenzoic acid methyl ester
ionic character makes them excellent solubilizers for a
wide range of inorganic as well as organic substrates, thus
substituting polar aprotic solvents. RTILs are ‘tuneable’
concerning miscibility with other solvents (VOLs, water,
7a
(
1
2) applying the conditions reported by Bose et al. (i.e.,
0% Pd/C and ammonium formate at 120 °C using pro-
pane-1,3-diol as the solvent). A 70% yield of 4-aminoben-
zoic acid methyl ester (2a) was obtained after microwave
irradiation with 300 W for 7 minutes. In a second experi-
ment, propane-1,3-diol was replaced by the ionic liquid 1.
The yield of essentially pure product 2a increased to 92%
after simple liquid-liquid extraction. Encouraged by these
results, we applied the conditions to (E)-methyl cinnamate
scCO etc.) via a proper choice of the counter anion, con-
2
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1607,1610,ftx,en;C02802SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1
608
H. Berthold et al.
SPECIAL TOPIC
(
3). However, for complete conversion the reaction condi- ly, all solutions were freshly prepared. The unsatisfactory
tions had to be modified. Eventually a linear temperature results (Table 1, entries 4, 5, and 6) and loss of ammonium
gradient over 10 minutes to the final temperature of formate due to sublimation prompted us to replace ammo-
50 °C, subsequent heating over 70 minutes at 150 °C and nium formate by triethylamine formate6 by simply add-
b,7b
1
active cooling to 50 °C over 30 minutes was applied to the ing an equimolar cold mixture of Et N and formic acid in
3
reduction of various organic functionalities (Table 1).
a five fold excess. The results are shown in Table 2.
Interestingly, monitoring of the internal pressure allowed To test the recyclability of the ionic liquid/catalyst sys-
us to estimate the progress of the reaction. After having tem, five subsequent cycles of the reduction of 4 to 4a
reached a constant pressure of about 0.9 to 1.5 MPa the re- were performed. After each cycle, the ionic liquid phase
action was complete. According to the observations of was exhaustively extracted with MTBE and recharged
1
1
Sasson et al., gas evolution occurred when a stock solu- with 4 and a five molar excess of equimolar amounts of
tion of ammonium formate and Pd/C in 1 was warmed to triethylamine and formic acid. The results are shown in
5
0 °C in the absence of a hydrogen acceptor. Consequent- Table 3.
Table 1 CTH Route A with Ammonium Formate, 10% Pd/C, IL 1, 150 °C via Microwave Irradiation (Max. 300 Watt)
Entry
1
Substrate
Product
Yield (%)a
b
6b
92 (97)
2
a
2
3
2
3
99 (90)7b
3a
4a
84 (37)6d
4
5
4
5
byproducts
5
a
50% conversion
6
a:6b:6c = 6:1:1
6
7
8
6
7
0 of 7a
9
3
0 of 7b
67b,c
8
a
Synthesis 2002, No. 11, 1607–1610 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Transfer Hydrogenation in Ionic Liquids under Microwave Irridiation
1609
Table 2 CTH Route B with Triethylamine Formate, 10% Pd/C, IL 1, 150 °C via Microwave Irradiation (Max. 300 Watt)
Entry
1
Substrate
Product
Yield (%)a
83
2
a
2
b
6d
2
92 (48)
9
3
9a
c
6b
3
4
83 (90)
3
a
98 (37)6d
4
5
4a
5
6
97d
a:5b = 97:37b,6d
5
97
only 6c
6
7
7
no conversion
7
a
Table 3 Recyclability of the Catalytic System with Constant Reac- Similar results were obtained, when the reaction was ter-
tion Time
minated after reaching a constant pressure (Table 4).
In conclusion, various functional groups (i.e., nitro, alk-
ene, alkyne) have been cleanly reduced in ionic liquid 1
under microwave irradiation and conveniently isolated by
simple liquid/liquid extraction with MTBE in high yields
and purity. Alternatively, the aniline 9a could be isolated
by aqueous acidic extraction from 1, thus exploiting the
useful properties of 1 to form ternary phases with aqueous
and organic solvents. Yields were similar or better than
previously reported. Reductive dehalogenation of ha-
loarenes (results not shown) was successful, but occurred
Entry
Recovery (%)
Yield 4a (%)
1
99
99
100
91
68
56
59
75
2
3
102
96
4
5
100
99
Average
under partial de-methylation of 1, forming N-butylimida-
zole as a contaminant.5
b,12
In contrast to previous re-
Synthesis 2002, No. 11, 1607–1610 ISSN 0039-7881 © Thieme Stuttgart · New York

1
610
H. Berthold et al.
SPECIAL TOPIC
Table 4 Recyclability of the Catalytic System with Respect to Time
um formate was replaced by a freshly prepared, cold mixture of
Et N and 96% formic acid.
3
Entry
Time of Run
Recovery
(%)
4a
(%)
b
(
min)
Study of the Recycleability
The procedure was performed exactly as described in route B. After
extraction, traces of MTBE were removed by bubbling a gentle
stream of argon through the heated (80–100 °C) mixture of 1 and
the used catalyst (Tables 3 and 4).
1
2
3
4
5
32
50
60
72
90
61
43
98
100
100
101
100
100
100
100
90
79
67
59
79
92
Acknowledgment
We are indebted to Prof. Eric Carreira, ETH Zürich, and Drs. Gerd
Ruehter, Mark J. Tebbe and Macharri Vorndran-Jones, Eli Lilly Re-
search Laboratories for helpful discussions.
1
–5 averaged
6a
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®
equipped with Teflon coated stirring bars. IL 1 was handled pref-
erably with plastic lab ware.
Catalytic Tranfer Hydrogenation; General Procedures
Route A (Table 1, Entries 1–7): Substrates (3.27 mmol to 3.85
mmol) were dissolved in the ionic liquid 1 (3 mL) and 10% Pd/C
(50 mg/mmol substrate) was added. A five molar excess of finely
ground ammonium formate was added and the vessel sealed. The
vessel was irradiated with microwaves of max. 300 W with a tem-
perature ramp to reach 150 °C within 10 min, retaining this temper-
ature until the total time of 80 min had been expired. After cooling,
the reaction mixture was exhaustively extracted with MTBE and
checked by TLC (hexane–EtOAc, 80:20). The collected organic
phases were filtered through a short plug of silica gel to remove
traces of catalyst and evaporated. No further purification of the
products was required, since purity was typically >95% as checked
by NMR spectroscopy.
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Route B: (Table 2, Entries 1–7): The experiments were run under
identical conditions as described for route A, except that ammoni-
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Synthesis 2002, No. 11, 1607–1610 ISSN 0039-7881 © Thieme Stuttgart · New York