Simple and efficient microwave-assisted hydrogenation reactions at moderate temperature and pressure

Article abstract of DOI:10.1055/s-2006-958428

A generally applicable method for the introduction of gaseous hydrogen into a sealed reaction system to perform hydrogenation reactions under microwave irradiation has been developed. Several different types of substrates are easily reduced in short reaction times with moderate temperatures between 80 °C and 100 °C with 50 psi of hydrogen. The use of simultaneous cooling is also applied to the hydrogenation of more difficult substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958428

LETTER
131
Simple and Efficient Microwave-Assisted Hydrogenation Reactions at
Moderate Temperature and Pressure
M
icrowave-Assist
r
e
d
H
ydro
a
genations ce S. Vanier*
Life Science Division, CEM Corporation, P.O. Box 200, Matthews, NC 28106-0200, USA
Fax +1(704)8217894; E-mail: grace.vanier@cem.com
Received 15 August 2006
While these microwave-assisted hydrogenation reactions
give good yields of the reduced product, the additional
hydrogen donor reagent typically increases the purifica-
tion necessary for the reaction. Gaseous hydrogen is a
Abstract: A generally applicable method for the introduction of
gaseous hydrogen into a sealed reaction system to perform hydro-
genation reactions under microwave irradiation has been devel-
oped. Several different types of substrates are easily reduced in
short reaction times with moderate temperatures between 80 °C and more suitable hydrogen donor as it requires no additional
100 °C with 50 psi of hydrogen. The use of simultaneous cooling is
purification step for its removal, but getting the hydrogen
also applied to the hydrogenation of more difficult substrates.
gas into the reaction vessel can be challenging. There are
a few examples of dechlorination7 reactions and hydro-
Key words: hydrogenations, microwave, palladium, reductions,
simultaneous cooling
genation reactions8 performed in a microwave reactor that
use hydrogen gas, but these methods are not generally
applicable for introducing the gaseous reagent to the reac-
Hydrogenation is one of the most powerful transforma- tion vessel and for performing these reactions.
tions in synthetic chemistry. An astounding number of
A simple system has been developed for the introduction
natural product syntheses involve at least one hydro-
of hydrogen gas into a sealed microwave reaction system.
genation step. These reactions often require long reaction
The set-up provides both fiber optic temperature control
times to affect complete conversion to product. In
and pressure feedback control.9 As a model reaction, the
addition, hydrogenation reactions can also require harsh
hydrogenation of trans,trans-1,4-diphenyl-1,3-butadiene
reaction conditions such as high pressures and/or tem-
was performed with the gaseous reagent addition system.
peratures.
Using the ideal gas law, the amount of hydrogen neces-
Over the past 20 years, the area of microwave chemistry sary for complete conversion to product is about 45 psi.
has become a powerful method for performing challeng- Each of these reactions was performed by charging the
ing reactions in shorter amounts of time with higher yields reaction vessel to 50 psi to give only a slight excess of
and purity.1 As with several other types of metal-cata- hydrogen gas resulting in minimal waste.
lyzed reactions, hydrogenation reactions also benefit from
The hydrogenation of diene 1 was initially performed with
the use of microwave irradiation to accelerate the reaction
palladium on carbon in ethanol, a standard catalyst and
and improve yields. Unlike conventional hydrogenation
solvent system for hydrogenation reactions. When the
methods that rely on gaseous hydrogen, reactions per-
reaction was performed at 80 °C, 78% conversion to prod-
formed in a microwave typically require the addition of a
uct was obtained (Table 1). Increasing the temperature to
reagent that will generate the hydrogen gas in situ or will
100 °C neither increased nor decreased the conversion of
transfer hydrogen directly to the substrate. Ammonium
the reaction. Interestingly, a further increase in tempera-
formate is the most common hydrogen donor used for
ture to 120 °C saw a decrease in the conversion to 21%,
microwave-assisted hydrogenation reactions.2 The dis-
and increasing the temperature even further to 150 °C re-
advantages of using ammonium formate in a sealed
sulted in almost no conversion to product. This unusual
microwave reaction vessel are the development of high
temperature trend was unexpected and is an area of
pressures due to the generation of carbon dioxide and the
continued research.
sublimation of the ammonium formate at elevated tem-
With the optimized temperature, different solvents were
peratures. In addition, an excess of the ammonium for-
explored for the hydrogenation reaction. As previously
mate is typically necessary to drive the reaction to
discussed, when the reaction was performed in ethanol,
completion causing the need for additional purification.
78% conversion was observed. Changing the solvent to
Other hydrogen donors that have been reported in micro-
ethyl acetate, another common solvent for hydrogenation
wave-assisted hydrogenations include solid-supported
reactions, improved the conversion to >99% (Table 2).
The reaction was also performed with both tetrahydro-
furan and dichloromethane, but low conversions were
obtained. Toluene gave good conversion to product, but it
also presented some distinct disadvantages to the other
solvents. Toluene does not suspend the palladium on
carbon as well as the other solvents, and as a result small
formates,3 sodium formate,4 isopropanol for ketone reduc-
tions,5 and sodium borohydride for imine reductions.6
SYNLETT 2007, No. 1, pp 0131–0135
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Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958428; Art ID: S16106ST
© Georg Thieme Verlag Stuttgart · New York

132
G. S. Vanier
LETTER
Table 1 Temperature Studya
Table 3 Catalyst Concentration Studya
Pd/C, H2
EtOH, MW
Pd/C, H2
EtOAc
1
2
80 °C, MW
1
2
Temp (°C)
80
Conversion (%)b
Catalyst concentration (mol%) Conversion (%)b
78
78
21
2
10
5
>99
>99
>99
>99
100
120
2
150
1
a Conditions: 1 (0.5 mmol), Pd/C (10 mol%), H2 (50 psi), EtOH
a Conditions: 1 (0.5 mmol), H2 (50 psi), 80 °C, EtOAc (2 mL), 5 min.
(2 mL), 5 min.
b Determined by GC.
b Determined by GC.
same temperature, pressure, and time were used in the oil
bath experiment [1 (0.5 mmol), Pd/C (1 mol%), H2 (50
psi), 80 °C, EtOAc (2 mL), 5 min hold], and careful
control of the temperature profiles ensured accurate repro-
duction of the reaction conditions (Figure 1). The hydro-
genation performed in the microwave resulted in
complete conversion to product, while the reaction per-
formed in the oil bath resulted in only 55% conversion.
These results indicate that the microwave does indeed
accelerate the reaction and has an influence on the out-
come of the hydrogenation reaction.
amounts of the catalyst can stick to the sides of the reac-
tion vessel which can produce arcing in the microwave
field.10 This arcing will etch the glass vessel, and can
result in vessel failure. Therefore, toluene is not recom-
mended as a solvent for these hydrogenation reactions at
high concentrations of catalyst loading.
Table 2 Solvent Screena
Pd/C, H2
solvent
1
2
80 °C, MW
Solvent
EtOH
Conversion (%)b
78
>99
6
EtOAc
THF
Toluene
CH2Cl2
89
2
a Conditions: 1 (0.5 mmol), Pd/C (10 mol%), H2 (50 psi), 80 °C,
solvent (2 mL), 5 min.
b Determined by GC.
All of these initial studies were performed with high cata-
lyst concentrations. To make this a more environmentally
friendly and cost effective process, lower amounts of
catalyst were explored for the hydrogenation of diene 1.
As shown in Table 3, catalyst concentrations as low as 1
mol% can be used with no detrimental effect to the con-
versions. This catalyst concentration study was limited by
the small amounts of palladium on carbon required for the
1 mol% reaction, and even lower amounts of palladium
catalyst can likely be used.
Figure 1 Temperature profiles for the hydrogenation of diene 1 in
both the microwave and oil bath.
With the optimized conditions for the hydrogenation of
diene 1, the hydrogenation of various other unsaturated
compounds was explored (Table 4). Conjugated alkenes 3
and 4 were each hydrogenated in three minutes to give
better than 99% yield (entries 2 and 3). Non-conjugated
alkenes (entries 4 and 5) can also be reduced in short re-
action times to give excellent conversions.11 Trisubstitut-
ed olefins can be hydrogenated in five minutes as well at
80 °C to give 99% yield (entry 6). a,b-Unsaturated ketone
8 required slightly harsher conditions to give the desired
hydrogenated product, but none of the 1,2-reduced prod-
uct was observed (entry 7). In addition to olefins, alkynes
To ensure completeness of this microwave-assisted hy-
drogenation study, a direct comparison was made between
the microwave method and conventional heating. This
was achieved by performing the hydrogenation of diene 1
under reaction conditions, identical to those used in the
microwave reactions, in a preheated oil bath. The exact
Synlett 2007, No. 1, 131–135 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Hydrogenations
133
can be hydrogenated quickly and in high yield. Phenyl- moved in five minutes to give the deprotected proline in
acetylene (9) was hydrogenated to give ethylbenzene in excellent yield (entry 10). Lastly, a reductive amination
>99% conversion while diethylacetylene dicarboxylate between benzaldehyde and aniline gave 89% yield of the
(10) gave >99% yield of the desired product (entries 8 and desired N-benzylaniline (entry 11).
9). A carbobenzyloxy protecting group was easily re-
Table 4 Hydrogenation of Various Substratesa
Entry
1
Substrate
Temp (°C)
80
Time (min)
5
Yield (%)b
>99
1
3
2
3
80
80
3
3
>99
>99
O
OMe
4
5
4
5
80
80
5
>99c
>99c
10
6
6
7
80
5
99
89
Me
OH
Me
Me
O
7
100
20
Me
8
8
9
80
80
5
3
>99c
>99
9
O
EtO
OEt
O
O
10
HO
11
10
11
80
80
5
3
>99
98
O
Bn
N
O
O
H2N
12a
12b
a Conditions: substrate (0.5 mmol), Pd/C (1 mol%), H2 (50 psi), EtOAc (2 mL).
b Isolated yield.
c Conversion based on GC analysis.
Synlett 2007, No. 1, 131–135 © Thieme Stuttgart · New York

134
G. S. Vanier
LETTER
Each of the reactions described above proceeded smooth- also be used for the hydrogenation of pyridine derivatives
ly in as little as three minutes to give the desired products. as outlined in entry 4. The treatment of picolinic acid (16)
Unfortunately, when the same reaction conditions were with platinum oxide in the presence of hydrogen gas at
applied to the hydrogenation of nitrobenzene, only 70% 100 psi gave the desired pipecolic acid in excellent yield
yield could be obtained after 10 minutes at 80 °C. With after only 10 minutes. Lastly, the hydrogenation of cho-
these reaction conditions, only a small amount of power lesterol (17) was explored. The reaction was performed at
(<10 W) was required to maintain the temperature at 80 °C with simultaneous cooling for 5 minutes to give
80 °C. To get more energy into the reaction mixture, the high yield of the reduced product. When the exact same
use of simultaneous cooling was explored.12 When the reaction was performed in the previously described
same hydrogenation reaction of nitrobenzene was per- preheated oil bath at 80 °C, only 3% isolated yield was
formed at 80 °C with simultaneous cooling, ca. 100 W of obtained (entry 6). This clearly demonstrates that the rate
power was continuously added to the reaction mixture. enhancement for the hydrogenation of the cholesterol is
This increase in the amount of power in the reaction not solely based on the temperature of the reaction
resulted in complete conversion to product to give 85% mixture, and that the microwave is necessary to observe
isolated yield of the desired aniline (Table 5, entry 1).
complete hydrogenation.
Other nitrobenzene derivatives also benefited from the Several different examples have been presented that de-
use of simultaneous cooling. 4-Fluoronitrobenzene (14) monstrate the utility of microwave promoted hydrogena-
was hydrogenated using simultaneous cooling to give a tion reactions using a system designed for the use of
high yield of the corresponding aniline derivative. The hy- gaseous hydrogen. Each of the reported examples pro-
drogenation of hindered nitrobenzene 15 also proceeded ceeds in a short reaction time at moderate temperature and
in 15 minutes to give nearly quantitative yield of the de- pressure (80–100 °C and 50–100 psi). The chemistry also
sired aniline compound. The simultaneous cooling can can greatly benefit from the use of simultaneous cooling
Table 5 Hydrogenations with Simultaneous Coolinga
Entry
1
Substrate
Temp (°C)
80
Time (min)
10
Yield (%)b
85
NO2
13
2
3
80
80
15
15
>99
>99
NO2
F
14
Me
NO2
Me
15
4
5
80
80
10
5
>99c
>99
OH
N
O
16
Me
Me
Me
Me
H
Me
H
H
HO
17
6
80
5
3d
Me
Me
Me
Me
H
Me
H
H
HO
17
a Conditions: substrate (0.5 mmol), Pd/C (1 mol%), H2 (50 psi), EtOAc (2 mL), simultaneous cooling.
b Isolated yield.
c Conditions: 16 (0.5 mmol), PtO2 (10 mol%), H2 (100 psi), EtOH (2 mL).
d Performed in an oil bath at 80 °C.
Synlett 2007, No. 1, 131–135 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Hydrogenations
135
(7) (a) Wada, Y.; Yin, H.; Kitamura, T.; Yanagida, S. Chem.
Lett. 2000, 632. (b) Pillai, U. R.; Sahle-Demessie, E.;
Varma, R. S. Green Chem. 2004, 6, 295.
(8) (a) Heller, E.; Lautenschläger, W.; Holzgrabe, U.
Tetrahedron Lett. 2005, 46, 1247. (b) Gustafssön, T.;
Hedenstrom, M.; Kihlberg, J. J. Org. Chem. 2006, 71, 1911.
(9) Experimental Set-up.
in reactions that require higher power levels to achieve
complete hydrogenation. Work is in progress to apply this
system to other functional group hydrogenations as well
as to extend the method to more complex hydrogenation
reactions.
All reactions were performed with a CEM Discover single
mode microwave reactor equipped with a 300 W power
source. A 10 mL fiber optic accessory was equipped with a
gas inlet to allow introduction of hydrogen gas to the
reaction vessel, and each of the reactions was performed in a
CEM 10 mL microwave reaction vial. All temperature
measurements were performed with a fiber optic probe, and
2 mL of solvent was used for each reaction to ensure ample
submersion of the fiber optic probe.
Acknowledgment
The author gratefully acknowledges Dr. Perry Pellechia from the
University of South Carolina for collecting all of the NMR data.
References and Notes
(1) For reviews on microwave chemistry, see: (a) Hayes, B. L.
Microwave Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews, NC, 2002. (b) Loupy, A.
Microwaves in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2002. (c) Microwave Assisted Organic Synthesis;
Tierney, J. P.; Lidström, P., Eds.; Blackwell Publishing:
Oxford, UK, 2005. (d) Kappe, C. O.; Stadler, A.
Microwaves in Organic and Medicinal Chemistry; Wiley-
VCH: Weinheim, Germany, 2005.
(2) (a) Dayal, B.; Ertel, N. H.; Rapole, K. R.; Asgaonkar, A.;
Salen, G. Steroids 1997, 62, 451. (b) Banik, B. K.; Barakat,
K. J.; Wagle, D. R.; Manhas, M. S.; Bose, A. K. J. Org.
Chem. 1999, 64, 5746. (c) Daga, M. C.; Taddei, M.; Varchi,
G. Tetrahedron Lett. 2001, 42, 5191. (d) Berthold, H.;
Schotten, T.; Hönig, H. Synthesis 2002, 1607. (e) Stiasni,
N.; Kappe, C. O. ARKIVOC 2002, (viii), 71.
(3) (a) Desai, B.; Danks, T. N. Tetrahedron Lett. 2001, 42,
5963. (b) Danks, T. N.; Desai, B. Green Chem. 2002, 4, 179.
(4) Arcadi, A.; Cerichelli, G.; Chiarini, M.; Vico, R.; Zorzan, D.
Eur. J. Org. Chem. 2004, 3404.
(5) (a) Lutsenko, S.; Moberg, C. Tetrahedron: Asymmetry 2001,
12, 2529. (b) Reetz, M. T.; Li, X. J. Am. Chem. Soc. 2006,
128, 1044.
General Procedure.
To a solution of trans,trans-1,4-diphenyl-1,3-butadiene (1,
103 mg, 0.500 mmol) in 2.0 mL of EtOAc was added Pd/C
(10 wt%, 5 mg, 0.005 mmol). The reaction vessel was
purged three times with hydrogen, charged to 50 psi, and
then closed off to the source of hydrogen. The reaction was
heated under microwave irradiation to 80 °C with 100 W of
power and held for 5 min. Upon cooling to ambient
temperature, the reaction mixture was filtered through
Celite® and condensed to give 105 mg (>99%) of 1,4-
diphenylbutane. 1H NMR (400 MHz, CDCl3): d = 7.23–7.27
(m, 4 H), 7.14–7.17 (m, 6 H), 2.62 (t, J = 6.6 Hz, 4 H), 1.65
(dt, J = 7.2, 3.8 Hz, 4 H). 13C NMR (100 MHz, CDCl3): d =
142.66, 128.53, 128.38, 125.77, 35.93, 31.20.
Characterization data is consistent with that of commercially
available material.
(10) Whittaker, A. G.; Mingos, D. M. P. J. Chem. Soc., Dalton
Trans. 2000, 1521.
(11) Isolated yields were difficult due to the low volatility of the
products.
(12) (a) Katritzky, A. R.; Zhang, Y.; Singh, S. K.; Steel, P. J.
ARKIVOC 2003, (xv), 47. (b) Chen, J. J.; Deshpande, S. V.
Tetrahedron Lett. 2003, 44, 8873. (c) Arvela, R. K.;
Leadbeater, N. E. Org. Lett. 2005, 7, 2101.
(6) Akisanya, J.; Danks, T. N.; Garman, R. N. J. Organomet.
Chem. 2000, 603, 240.
Synlett 2007, No. 1, 131–135 © Thieme Stuttgart · New York

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