Palladium-catalyzed hydrogenation with use of ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] as a solvent and hydrogen source

Article abstract of DOI:10.1016/j.tet.2013.05.103

We designed ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO₂] for use as a solvent and hydrogen donor for hydrogenation. Catalytic hydrogenation of aromatic ketones, nitro groups, and olefins with PdCl₂ in [BHEA][HCO₂] generated the corresponding reduction products. Selective reduction of aromatic ketones over aliphatic ketones was observed. Hydrogenolysis of benzyl ethers and benzyl amines also proceeded. All these reactions were successfully carried out in good to excellent yields under mild and nonflammable conditions. In addition, the ionic liquid and Pd source can be reused several times.

Full text of DOI:10.1016/j.tet.2013.05.103

Tetrahedron 69 (2013) 6399e6403
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed hydrogenation with use of ionic liquid
bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] as
a solvent and hydrogen sourcey
,
Hideyuki Suzuki a, Seiki Yoshioka b, Ami Igesaka b, Hiromi Nishioka a, Yasuo Takeuchi a
*
a Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka,
Kita-ku, Okayama 700-8530, Japan
b Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2013
Received in revised form 20 May 2013
Accepted 23 May 2013
Available online 28 May 2013
We designed ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] for use as a solvent and
hydrogen donor for hydrogenation. Catalytic hydrogenation of aromatic ketones, nitro groups, and olefins
with PdCl2 in [BHEA][HCO2] generated the corresponding reduction products. Selective reduction of
aromatic ketones over aliphatic ketones was observed. Hydrogenolysis of benzyl ethers and benzyl amines
also proceeded. All these reactions were successfully carried out in good to excellent yields under mild
and nonflammable conditions. In addition, the ionic liquid and Pd source can be reused several times.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquids
Hydrogenation
Aromatic ketones
Nonflammability
Reuse
1. Introduction
of hydrogenation using Pd/C with H2 could be overcome if the
ionic liquid is used both as a solvent and as a reagent. That is, an
Ionic liquids are a new class of materials that have been
extensively studied since the last decade.2,3 Ionic liquids have
attracted increasing interest due to their unique properties, such
as negligible volatility, high thermal stability, low toxicity, and
reusability, which in turn makes them prominent candidates to
replace conventional organic solvents. Current research on ionic
liquids has shown that they support a large and diverse range of
organic reactions, such as Heck reaction,4 Suzuki cross-coupling
reaction,5 Stille cross-coupling reaction,5 homocoupling reaction,6
SonogashiraeHagihara reaction,6 Negishi cross-coupling reaction.7
The typical method for the synthesis of alcohols by hydroge-
nation of aromatic ketones using Pd and H2 is widely employed
even now because of the convenient experimental procedures
and/or because green reactions can be carried out.8e16 However,
problems related to flammability and reusability are encountered
in the method. While reduction with Pd and ammonium formate is
well known, there are only few examples of its application in the
reduction of aromatic ketones.17,18 We reasoned that the problems
ionic liquid that contains a formate counter anion should serve as
a hydrogen source (Fig. 1).
* Corresponding author. Tel./fax: þ81 86 251 7964; e-mail address: take@phar-
m.okayama-u.ac.jp (Y. Takeuchi).
y
See Ref. 1.
Fig. 1. Hydrogenation in ionic liquid with formate ions.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.103

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H. Suzuki et al. / Tetrahedron 69 (2013) 6399e6403
Table 2
Herein, we report the results of hydrogenation of various sub-
Effects of the quantity, temperature, and type of Pd source on yield
strates, including aromatic ketones, with a Pd source in an ionic
liquid.
Pd
O
OH
Me
[BHEA][HCO2] (40 eq.)
Ph
Me
Ph
r.t.
2. Results and discussion
1
2
Entry
Pd
Time (h)
Yielda (%)
Acetophenone (1) was selected as the substrate in order to
afford 1-phenylethanol (2) by hydrogenation using Pd/C with
H2 (Table 1, entry 5). Ionic liquids containing formate and
2-hydroxyethylammonium moiety were selected as the solvent and
reagent to facilitate convenient extraction of the product after the
reaction (Fig. 2).6,19e21
2
1
1
2
3
4
5
6
7
8
PdCl2 (1 mol %)
PdCl2 (5 mol %)
24
24
2
2
2
2
2
2
12
68
83 (81)
99
5
7
16
26
76
26
13 (5)
1
78
85
64
63
PdCl2 (10 mol %)
PdCl2 (20 mol %)
Pd(OAc)2 (10 mol %)
Pd(OCOCF3)2 (10 mol %)
Pd(NO3)2 (10 mol %)
PdSO4 (10 mol %)
a
Determined by 1H NMR analysis of the crude reaction mixture; isolated yields
Table 1
Screening of ionic liquids
are shown in parentheses.
PdCl2 (10 mol%)
ionic liquid (40 eq.)
O
OH
Me
r.t., 2 h
Ph
Me
Ph
Table 3
Reaction of various ketones
1
2
O
OH
R2
PdCl2 (20 mol%)
Entry
Ionic liquid
Yielda (%)
[BHEA][HCO2] (40 eq.)
R2
2
1
R1
R1
r.t.
1
2
3
[HEA][HCO2]
[HEPA][HCO2]
[BHEA][HCO2]
[DEHEA][HCO2]
d
57
73
81
20
80
21
19
5
56
0
3a-l
4a-l
Entry
R1
R2
Time (h)
Yielda (%)
4
5b
1
2
3
o-Me
m-Me
p-Me
p-OMe
p-CF3
Me
Me
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
24
24
24
24
2
8
85
40
10
94 (91)
96 (96)
76 (76)
a
Isolated yield.
b
Reaction was carried out with 10 wt % Pd/C (ca. 5 mol % of Pd metal) and H2 in
MeOH.
4b
5b
6b
7b
p-CO2Me
0.25
24
H
3g
O
O
8b
3h
24
9
[HEA][HCO2] : R1 = R2 = H
O
O
Me
Me
HCO2
HO
[HEPA][HCO2] : R1 = H, R2 = CH2CH2CH3
[BHEA][HCO2] : R1 = H, R2 = CH2CH2OH
[DEHEA][HCO2] : R1 = R2 = CH2CH3
H
N
R2
R1
9
3i
3j
8
92 (95)
67
Fig. 2. Selected ionic liquids.
O
10
24
Reactions of 1 with PdCl2 (10 mol %) for 2 h at rt in four types
of ionic liquids produced 2 in various yields. Ionic liquids [HEPA]
[HCO2] and [BHEA][HCO2] containing secondary ammonium ions
O
11b
3k
3l
24
72
88 (88)
0
Ph
Ph
Ph
afforded
2 in higher yields compared to [HEA][HCO2] and
O
[DEHEA][HCO2] (Table 1). The advantage in these reactions is the
use of stable PdII as the Pd source. Based on this result, we de-
cided to use [BHEA][HCO2] as the model ionic liquid for further
research.
The quantity of PdCl2 to afford a hydrogenation product in
good yield within a practical period should be more than 10 mol %
(Table 2, entries 1e4). Although we attempted this reaction using
various Pd sources, no other Pd source was found to give higher
yield than PdCl2 did (Table 2, entries 3 and 5e8).
The reductive ability of ketones in this method was strongly
dependent on the solubility of the substrate and the electronic
character of the substituent. Addition of the co-solvent (DMF) to
the ionic liquid system involving a solid substrate made the yield
increase (Table 3, entries 4e8 and 11). Ketones adjoining a ben-
zene ring that contained an electron donating group at the ortho
or para position afforded the reductive product in poor yield
(Table 3, entries 1, 3, 4, and 8). On the other hand, ketones
12
Me
Determined by 1H NMR analysis of the crude reaction mixture; isolated yields
are shown in parentheses.
a
b
Reactions were carried out with DMF (5 mL) as the co-solvent.
adjoining a benzene ring that contained an electron withdrawing
group afforded the corresponding alcohol in excellent yield
within a short span of reaction time (Table 3, entries 5 and 6).
Although the reduction of aryl ketone proceeded, dialkyl
ketone did not produce the corresponding alcohol (Table 3, en-
tries 11 and 12). These findings were applied to the selective
reduction among carbonyl groups, which cannot occur by the
conventional method (with H2 and Pd/C) and by NaBH4 reduction
(Scheme 1).

H. Suzuki et al. / Tetrahedron 69 (2013) 6399e6403
6401
We then explored the reusability of the ionic liquid in hydro-
genation of 1 to 2 (Table 5). The reusability of Pd and [BHEA][HCO2]
was tested without the addition of formic acid. Although the re-
action time was extended in order to obtain a yield higher than 70%,
the product was successfully obtained even in the fifth cycle of the
reaction. Recycling experiments were also attempted by adding
formic acid to the collected ionic liquid containing Pd. However, the
results in terms of yield and reaction time were not as remarkable
as those in the case of the reuse.
PdCl2 (10 mol%)
OH
[BHEA][HCO2] (40 eq.)
Me
Me
Ph
Ph
r.t., 24 h, 86%
O
O
6
O
H2, Pd/C, MeOH
r.t., 24 h, 74%
Me
Ph
O
7
5
Table 5
Experiment on reusability of acetophenone (1)
OH
NaBH4, MeOH
PdCl2 (20 mol%)
Me
O
OH
Me
Ph
[BHEA][HCO2]
r.t., 30 min, 97%
OH
Ph
Me
Ph
r.t.
1
2
8
Yielda (%)
Scheme 1. Selective hydrogenation.
Cycle
Time
1
2
3
4
5
6
2 h
6 h
36 h
6 d
18 d
92 d
93
96
70
Next, we investigated the scope of this reaction. Hydrogenation
of nitrobenzene (9), trans-stilbene (11a), cis-stilbene (11b), and
diphenylacetylene (13) proceeded in excellent yields (Table 4, entry
1e4). The aniline (10) was converted into acetanilide (22) for the
low boiling point. The dehalogenation of aryl halides proceeded in
good yields (Table 4, entries 5 and 6). The deprotection of the ar-
omatic amines and aromatic alcohols with a Cbz or a benzyl pro-
tecting group proceeded in good to excellent yields (Table 4, entries
7e9). However, the deprotection of aliphatic alcohols with a benzyl
protecting group did not proceed (Table 4, entry 10). Further, ex-
traction of aliphatic amines from the ionic liquid [BHEA][HCO2] was
difficult.
77
73
22b
Determined by 1H NMR analysis of the crude reaction mixture.
Isolated yield.
a
b
Additional reusability experiments were conducted using ni-
trobenzene (9), trans-stilbene (11a), and cis-stilbene (11b) as the
substrate (Tables 6e8). Until the fifth cycle, good yields were ob-
tained when using 9 as the substrate (Table 6). The reaction time
was extended as in the case of 1. When 11a and 11b were utilized as
substrates, the reaction proceeded in good yield until up to the
third cycle (Tables 7 and 8). Even when the co-solvent DMF was
used, the reusability experiments were successful.
Table 4
Reactions corresponding to various substratesa
Entry
Substrate
Product
PdCl2
(mol %) (h)
Time Yieldb
(%)
96c
95
9
10
12
1
1
5
12
NO2
Ph
NH2
Ph
Table 6
Experiment on reusability of nitrobenzene (9)
2d
24
11a
Ph
Ph
PdCl2 (10 mol%)
[BHEA][HCO2]
Ph
Ph
3
5
5
24
24
94e
98e
NO2
NH2
Ph
Ph
Ph 11b
12
12
Ph
Ph
r.t.
4d
9
10
Ph
13
Cycle
Time (h)
Yielda,b (%)
OH
OH
5
6
20
24
4
81e
1
2
3
4
5
1
4
8
16
65
87
86
81
84
84
14a
15
Cl
OH
14b
OH
15 20
90
a
Br
The two-step yield: aniline (10) was converted into acetanilide (22).
Isolated yield.
b
7
8
1
24
24
97c
76c
NHCbz
NH2
NH2
10
16
17
5
NHBn
OBn
10
Table 7
Experiment on reusability of trans-stilbene (11a)
OH
PdCl2 (20 mol%)
9d
10
12
93
0
[BHEA][HCO2], DMF
18
20
19
21
Ph
Ph
Ph
Ph
r.t.
11a
12
OBn
Me
OH
10
20
168
Cycle
Time [h]
Yield %a
Ph
Ph
Me
1
2
3
4
2
12
24
72
90
90
92
68
a
Reactions were carried out using PdCl2 and [BHEA][HCO2] at rt.
Isolated yield.
The two-step yield: aniline (10) was converted into acetanilide (22).
Reactions were carried out with DMF (5 mL) as the co-solvent.
Determined by 1H NMR analysis of the crude reaction mixture.
b
c
d
e
a
Determined by 1H NMR analysis of the crude reaction mixture.

6402
H. Suzuki et al. / Tetrahedron 69 (2013) 6399e6403
Table 8
f
¼2.0 cm, l¼13.0 cm; EtOAcehexane, 1:5) to give 1-phenylethanol
Experiment on reusability of cis-stilbene (11b)
(2) as colorless oil; yield: 99.5 mg (81%).
(Table 3, entry 5): To a solution of 40-(trifluoromethyl)aceto-
phenone (3e) (188 mg, 1.00 mmol) in DMF (5.00 mL) was added
[BHEA][HCO2] (5.00 mL, 39.7 mmol) and PdCl2 (35.5 mg,
20.0 mol %) at rt and the reaction mixture was stirred at the same
temperature for 2 h under argon atmosphere. The mixture was
poured into brine (10 mL) and extracted with Et2O (10ꢁ10 mL). The
organic layer was washed with brine (150 mL) and dried with
MgSO4. After removal of the solvent, the residue was subjected to
PdCl2 (20 mol%)
[BHEA][HCO2], DMF
Ph
Ph
Ph
Ph
r.t.
11b
12
Cycle
Time (h)
Yielda (%)
1
2
3
4
2
12
24
72
91
99
95
68
column chromatography (Merck Kieselgel 60,
f¼2.0 cm, l¼7.5 cm;
EtOAcehexane, 1:5) to give 1-(4-trifluoromethylphenyl)ethanol
(4e) as colorless oil; yield: 174 mg (91%).
Determined by 1H NMR analysis of the crude reaction mixture.
a
(Scheme 1): To a solution of 1-phenyl-1,4-pentanedione (5)
(176 mg, 1.00 mmol) in [BHEA][HCO2] (5.00 mL, 39.7 mmol) was
added PdCl2 (17.7 mg,10.0 mol %) at rt and the reaction mixture was
stirred at the same temperature for 24 h under argon atmosphere.
The mixture was poured into brine (10 mL) and extracted with
EtOAc (10ꢁ10 mL). The organic layer was washed with brine
(100 mL) and dried with MgSO4. After removal of the solvent, the
residue was subjected to column chromatography (Merck Kieselgel
Furthermore, this reaction solution did not ignite even when
PdCl2 was introduced in the middle of the reaction under a condition
that would have certainly caused the ignition of the reaction solu-
tion in the case of Pd/C with H2. Thus, a new nonflammable hy-
drogenation system with ionic liquid and catalyst was established.
3. Conclusion
60,
f
¼2.0 cm, l¼24.0 cm; EtOAcehexane, 1:3) to give 5-hydroxy-5-
phenylpentane-2-one (6) as colorless oil; yield: 152.9 mg (86%).
(Scheme 1): To a solution of 1-phenyl-1,4-pentanedione (5)
(176 mg, 1.00 mmol) in MeOH (5.00 mL) was added 10 wt % Pd/C
(53.2 mg) at rt and the reaction mixture was stirred at the same
temperature for 24 h under H2 atmosphere. After filtration and
removal of the solvent, the residue was subjected to column
We developed a new hydrogenation system using ionic liquids.
This method is more useful in terms of flammability and reusability
than the conventional method (with H2 and Pd/C). Since this
method has advantages in terms of the solvent, reagent, and cata-
lyst, it is certainly superior to the conventional system. In addition,
selective reduction of aromatic ketones over aliphatic ketones was
observed when this method was employed.
chromatography (Merck Kieselgel 60,
EtOAcehexane, 1:20) to give 5-phenyl-2-pentanone (7) as colorless
oil; yield: 120.6 mg (74%).
f
¼2.0 cm, l¼20.0 cm;
4. Experimental section
4.1. General
(Scheme 1): To a solution of 1-phenyl-1,4-pentanedione (5)
(176 mg, 1.00 mmol) in MeOH (5.00 mL) was added NaBH4
(83.2 mg, 2.20 mmol) at rt and the reaction mixture was stirred at
the same temperature for 30 min under argon atmosphere. The
mixture was poured into H2O (5 mL) and extracted with EtOAc
(3ꢁ10 mL). The organic layer was washed with brine (30 mL) and
dried with MgSO4. After removal of the solvent, the residue was
subjected to column chromatography (Merck Kieselgel 60,
IR spectra were recorded on a JASCO FT/IR 350 spectrometer. 1H
NMR and 13C NMR spectra were run on a Varian NMR System 600,
or a JEOL AL-300 spectrometer. Chemical shifts (d) are reported in
parts per million (ppm), and the signals are described as s (singlet),
d (doublet), t (triplet), q (quartet), br (broad), and m (multiple).
Coupling constants (J values) are given in Hertz. Merck silica gel 60
(230e400 mesh) was employed for column chromatography.
Compounds 2,22 4a,22 4b,23 4c,22 4d,22 4e,24 4f,25 4g,26 4h,27 4i,28
4j,22 4k,29 6,30 7,31 8,32 12,33 15,34 19, 21, 2235 are all known com-
pounds. These compounds were identified by comparing the
spectral data with an authentic sample or a commercially available.
f
¼2.0 cm, l¼13.0 cm; EtOAcehexane, 1:3) to give 1-phenyl-1,4-
pentanediol (8) as colorless oil; yield: 175.6 mg (97%).
(Table 4, entry 1): To a solution of nitrobenzene (9) (123 mg,
1.00 mmol) in [BHEA][HCO2] (5.00 mL, 39.7 mmol) was added PdCl2
(1.80 mg, 1.00 mol %) at rt and the reaction mixture was stirred at
the same temperature for 12 h under argon atmosphere. The
mixture was poured into brine (10 mL) and extracted with EtOAc
(10ꢁ10 mL). The organic layer was washed with brine (150 mL) and
dried with MgSO4. To a solution was added acetic anhydride
(2.84 mL, 30 mmol) at rt and the reaction mixture was stirred at the
same temperature for 30 min under argon atmosphere. The mix-
ture was washed with a saturated solution of sodium carbonate
(80 mL), brine (150 mL), and dried with MgSO4. After removal of the
solvent, the residue was subjected to column chromatography
4.2. Preparation of ionic liquids
[HEA][HCO2], [HEPA][HCO2], [BHEA][HCO2], and [DEHEA]
[HCO2] were prepared by dropping the stoichiometric amount of
formic acid to corresponding amino alcohol at 0 ꢀC. The reaction
mixture was stirred at rt for 2 h under argon atmosphere. After
completion of the reaction, the ionic liquid was washed with EtOAc
and Et2O. The ionic liquid was dried in vacuo at 40 ꢀC.
(Merck Kieselgel 60,
give acetanilide (22); yield: 130 mg (96%).
f
¼2.0 cm, l¼11.5 cm; EtOAcehexane, 1:3) to
4.3. Typical experimental procedure
4.4. Typical experimental procedure for the reuse
experiments
(Table 2, entry 3): To a solution of acetophenone (1) (120 mg,
1.00 mmol) in [BHEA][HCO2] (5.00 mL, 39.7 mmol) was added PdCl2
(17.7 mg, 10.0 mol %) at rt and the reaction mixture was stirred at
the same temperature for 2 h under argon atmosphere. The mixture
was poured into brine (10 mL) and extracted with EtOAc
(10ꢁ10 mL). The organic layer was washed with brine (150 mL) and
dried with MgSO4. After removal of the solvent, the residue was
subjected to column chromatography (Merck Kieselgel 60,
(Table 5): To a solution of acetophenone (1) (120 mg,1.00 mmol)
in [BHEA][HCO2] (5.00 mL, 39.7 mmol) was added PdCl2 (35.5 mg,
20.0 mol %) at rt and the reaction mixture was stirred at the same
temperature for 2 h under argon atmosphere. The mixture was
extracted with Et2O (20ꢁ10 mL). The organic layer was washed
with brine (200 mL) and dried with MgSO4. The solvent was re-
moved under reduced pressure to give crude reaction mixture.

H. Suzuki et al. / Tetrahedron 69 (2013) 6399e6403
6403
Yield was directly determined by 1H NMR spectroscopy. The
References and notes
remaining [BHEA][HCO2] was used in the next reaction without
further purification.
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Colorless liquid; 1H NMR (600 MHz, DMSO-d6):
d 8.37 (s, 1H,
CHO), 3.59 (t, J¼5.4 Hz, 2H, CH2CH2OH), 2.85 (t, J¼5.4 Hz, 2H,
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2830, 1595, 1365, 1080, 775 cmꢂ1
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yethylpropylammonium formate; [BHEA][HCO2] bis(2-hydroxyethyl)ammo-
nium formate; [DEHEA][HCO2] diethyl(2-hydroxyethyl)ammonium formate.
Colorless liquid; 1H NMR (600 MHz, DMSO-d6):
d 8.35 (s, 1H,
CHO), 6.33 (br s, 4H, NH, and OH), 3.59 (t, J¼5.4 Hz, 4H, CH2CH2OH),
2.87 (t, J¼5.4 Hz, 4H, CH2CH2OH); 13C NMR (150 MHz, DMSO-d6):
ꢀ
22. Castro, L. C. M.; Bezier, D.; Sortais, J.-B.; Darcel, C. Adv. Synth. Catal. 2011, 353,
d
167.3, 56.9, 49.4; IR (neat): 3330, 2830, 1590, 1450, 1350, 1070,
1279e1284.
945, 775 cmꢂ1
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76, 6452e6456.
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26. Findlay, N. J.; Park, S. R.; Schoenebeck, F.; Cahard, E.; Zhou, S.; Berlouis, L. E. A.;
Spicer, M. D.; Tuttle, T.; Murphy, J. A. J. Am. Chem. Soc. 2010, 132, 15462e15464.
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2007, 46, 7491e7494.
4.8. Diethyl(2-hydroxyethyl) ammonium formate [DEHEA]
[HCO2]
Colorless liquid; 1H NMR (600 MHz, DMSO-d6):
d 8.30 (s, 1H,
CHO), 3.59 (t, J¼6.0 Hz, 2H, CH2CH2OH), 2.85 (q, J¼7.2 Hz, 4H,
CH2CH3), 2.83 (t, J¼6.0 Hz, 2H, CH2CH2OH), 1.08 (t, J¼7.2 Hz, 6H,
CH2CH3); 13C NMR (150 MHz, DMSO-d6):
d 166.6, 56.1, 53.4, 46.7, 8.8;
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Jpn. 2003, 76, 2009e2026.
IR (neat): 3340, 2980, 2830, 2680, 1600, 1475, 1365, 1080, 775 cmꢂ1
31. Ochiai, M.; Tuchimoto, Y.; Higashiura, N. Org. Lett. 2004, 6, 1505e1508.
€
32. Martín-Matute, B.; Backvall, J.-E. J. Org. Chem. 2004, 69, 9191e9195.
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2006, 1981e1990.
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Acknowledgements
We are grateful to the SC-NMR Laboratory of Okayama Univer-
sity for the use of the facilities.