Non-flammable and reusable hydrogenation of aromatic ketones in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2012.05.066

A novel method of hydrogenation of aromatic ketones in the ionic liquid [BHEA][HCO₂] was developed; this method is more enhanced in terms of flammability and reusability as compared to the conventional method (H ₂ and Pd/C). The redu

Full text of DOI:10.1016/j.tetlet.2012.05.066

Tetrahedron Letters 53 (2012) 3686–3688
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Non-flammable and reusable hydrogenation of aromatic ketones in ionic liquid
⇑
Hideyuki Suzuki, Hiromi Nishioka, Yasuo Takeuchi
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
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method of hydrogenation of aromatic ketones in the ionic liquid [BHEA][HCO2] was developed;
this method is more enhanced in terms of flammability and reusability as compared to the conventional
method (H2 and Pd/C). The reductive selectivities of aromatic and aliphatic ketones in this method were
observed.
Received 6 April 2012
Revised 9 May 2012
Accepted 14 May 2012
Available online 17 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquid
Hydrogenation
Aromatic ketones
Non-flammability
Reuse
Typical method for the synthesis of alcohols by hydrogenation
of aromatic ketones using Pd and H2 is widely carried out even
now for convenient experimental procedures and/or to induce
green reactions.1–9 However, this method experiences unavoidable
problems with respect to flammability and reusability. While
reduction with Pd and ammonium formate is also known well,
there are few examples of application to aromatic ketones.10,11 In
order to solve these problems, we tried to use the ionic liquid.
Ionic liquid is a new type of compound that has been exten-
sively researched since the last decade.12,13 This compound is used
mainly as a solvent because of its unique polarity and solubility.14–
17 We think that the problems of hydrogenation using Pd/C with H2
can be solved if the ionic liquid is used not only as a solvent but
also as a reagent. That is, an ionic liquid that contains formate as
the counter anion can certainly serve as a hydrogen source (Fig. 1).
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 hydroxye-
thylammonium moiety were selected as the solvent and reagent
for a convenient extraction after the reaction (Fig. 2).15–18
All reactions of 1 with PdCl2 (10 mol %) for 2 h at room temper-
ature in four types of ionic liquids produced 2, whose yields in the
reaction in the ionic liquids [HEPA][HCO2] and [BHEA][HCO2] con-
taining secondary ammonium were high (Table 1). The advantage
in this reaction is use of PdII as a stable palladium source. We
decided to use [BHEA][HCO2] as the most suitable ionic liquid in
the next research.
Figure 1. Hydrogenation in ionic liquid with formate.
The quantity of PdCl2 to afford a hydrogenation product in good
yield within a practical time period should be more than 10 mol %
(Table 2, entries 1–4 and 14).19 However, the addition of heat in
this reaction decreased the yield (Table 2, entries 3 and 5–7). We
reason that this result can be attributed to the heat-induced degra-
dation of formate in the ionic liquid. Although we attempted this
reaction using various Pd sources, no other Pd source was found
to give a higher yield than PdCl2 (Table 2, entries 3 and 8–13).
The reuse reactions of Pd and the ionic liquid continued without
the addition of formic acid (Table 3).20 Although the reaction time
had to be extended in order to obtain a yield higher than 70%, the
product was successfully afforded even in the fifth cycle of the
reaction. 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 ignited the reaction solution
⇑
Corresponding author. Tel./fax: +81 86 251 7964.
E-mail address: take@pharm.okayama-u.ac.jp (Y. Takeuchi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.066

H. Suzuki et al. / Tetrahedron Letters 53 (2012) 3686–3688
3687
Table 1
Table 3
Screening of ionic liquid
Reuse experiments
PdCl2 (10 mol%)
PdCl2 (20 mol%)
ionic liquid (40 eq.)
O
OH
Me
O
[BHEA][HCO2] (40 eq.)
OH
Me
r.t., 2 h
Ph
Me
Ph
Ph
Me
Ph
r.t.
1
2
1
2
Yielda (%)
Entry
Ionic liquid
Yielda (%)
Cycle
Time
2
1
2
1
1
2
3
[HEA][HCO2]
[HEPA][HCO2]
[BHEA][HCO2]
[DEHEA][HCO2]
—
57
73
81
20
80
21
19
5
56
0
1
2
3
4
5
2 h
6 h
36 h
6 d
18 d
93
96
70
77
73
7
4
7
12
23
4
5b
a
a
Determined by 1H NMR analysis of the crude reaction mixture.
Isolated yield.
10 wt % Pd/C (ca. 5 mol % of Pd metal) in MeOH.
b
Table 4
Reaction of various substrates
[HEA][HCO2] : R1 = R2 = H
HCO2
HO
[HEPA][HCO2] : R1 = H, R2 = CH2CH2CH3
[BHEA][HCO2] : R1 = H, R2 = CH2CH2OH
[DEHEA][HCO2] : R1 = R2 = CH2CH3
H
N
R1
O
OH
R2
PdCl2 (20 mol%)
[BHEA][HCO2] (40 eq.)
R2
R2
R1
R1
co-solvent
r.t.
Figure 2. Selected ionic liquids.
Entry
R1
R2
Co-solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
o-Me
o-Me
m-Me
m-Me
p-Me
p-Me
p-OMe
p-OMe
p-CF3
p-CF3
p-CO2Me
p-CO2Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
—
DMF
—
DMF
—
DMF
—
DMF
—
DMF
—
DMF
—
DMF
24
24
24
24
24
24
24
24
24
2
8
0
85
71
40
27
4
10
10
94 (91)
86
96 (96)
36
76 (70)
in the case of Pd/C with H2. Herein, the new method of reusable
and non-flammable hydrogenation was thus established. Recycling
experiments were attempted by addition of formic acid to the col-
lected ionic liquid containing Pd. However, the remarkable effect of
the yield or reaction time was not observed as compared with the
case of reuse.
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 4, entries 7–18 and 21–24). Ketones adjoining a
benzene ring that contained an electron donating group at the
ortho or para position afforded the reductive product in poor yield
(Table 4, entries 1, 2, 5–8, 15 and 16). On the other hand, ketones
adjoining a benzene ring that contained an electron withdrawing
24
0.25
24
24
H
Ph
15
16
O
—
DMF
24
24
3
9
O
O
Me
17
18
O
—
DMF
8
8
92 (95)
>99 (>99)
Me
Table 2
Study on the quantity, temperature, and kind of Pd
19
20
O
—
DMF
24
24
67
31
Pd
O
OH
Me
[BHEA][HCO2] (40 eq.)
Ph
Me
Ph
21
22
O
—
DMF
24
24
20
88 (88)
1
2
Ph
Ph
Entry
Pd
Temp
Time (h)
Yielda (%)
23
24
O
—
DMF
72
72
0
0
2
1
Ph
Me
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PdCl2 (1 mol %)
PdCl2 (5 mol %)
rt
rt
rt
rt
60 °C
80 °C
100 °C
rt
rt
rt
24
24
2
2
2
2
2
2
2
2
2
2
2
12
68
83 (81)
98 (90)
35
76
26
13 (5)
2 (0)
55
Determined by 1H NMR analysis of the crude reaction mixture; isolated yields
are shown in parentheses.
a
PdCl2 (10 mol %)
PdCl2 (10 mol %)
PdCl2 (10 mol %)
PdCl2 (10 mol %)
PdBr2 (10 mol %)
PdI2 (10 mol %)
PdCl2 (10 mol %)
Pd(OAc)2 (10 mol %)
Pd(OCOCF3)2 (10 mol %)
Pd(NO3)2 (10 mol %)
PdSO4 (10 mol %)
PdCl2 (20 mol %)
29
20
13
—
5
7
16
26
49
71
77
71
78
85
64
63
group afforded the corresponding alcohol in excellent yield within
a short span of reaction time (Table 4, entries 10 and 12). Although
the reduction of aryl ketone proceeded, aliphatic ketone did not
produce the corresponding alcohol (Table 4, entry 23, 24). These
findings were applied to the selective reduction among carbonyl
groups, which cannot occur by NaBH4 reduction (Scheme 1).
We developed the new hydrogenation system of aromatic
ketones in the ionic liquid for giving alcohols with the regioselec-
tivity. Since this method includes the advantage in the solvent, the
rt
rt
rt
rt
2
99
1
Determined by 1H NMR analysis of the crude reaction mixture; isolated yields
are shown in parentheses.
a

3688
H. Suzuki et al. / Tetrahedron Letters 53 (2012) 3686–3688
8. Wang, C.; Yang, G.; Zhuang, J.; Zhang, W. Tetrahedron Lett. 2010, 51, 2044–2047.
PdCl2 (20 mol%)
[BHEA][HCO2] (40 eq.)
OH
9. Goulioukina, N. S.; Bondarenko, G. N.; Bogdanov, A. V.; Gavrilov, K. N.;
Beletskaya, I. P. Eur. J. Org. Chem. 2009, 510–515.
10. Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91–95.
11. Yu, J.-Q.; Wu, H.-C.; Ramarao, C.; Spencer, J. B.; Ley, S. V. Chem. Commun. 2003,
678–679.
Me
Ph
r.t., 2 h, 91%
O
O
4
12. Welton, T. Chem. Rev. 1999, 99, 2071–2083.
Me
Ph
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´
´
´
´
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2010, 327, 45–50.
O
3
OH
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5136–5143.
NaBH4, MeOH
Me
OH
Ph
r.t., 30 min, 97%
17. Pinkert, A.; Marsh, K. N.; Pang, S. Ind. Eng. Chem. Res. 2010, 49, 11809–11813.
18. [HEA][HCO2] 2-Hydroxyethylammonium formate; [HEPA][HCO2] 2-Hydroxy
ethylpropylammonium formate; [BHEA][HCO2] Bis(2-hydroxyethyl)ammo
nium formate; [DEHEA][HCO2] Diethyl(2-hydroxyethyl)ammonium formate.
19. (Table 2, entry 4): 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 mixture was stirred at the same temperature for 6 h under argon
atmosphere. The mixture was poured into brine (10 mL) and extracted with
EtOAc (10 Â 10 mL). The organic layer was washed with brine (100 mL) and
dried with MgSO4. After removal of the solvent, the residue was subjected to
5
Scheme 1. Selective hydrogenation.
reagent, and the catalyst, we are sure that the conventional system
has been improved.
References and notes
column chromatography (Merck kieselgel 60,
u = 2.0 cm, l = 11.5 cm; EtOAc–
hexane, 1:5) to give 1-phenylethanol (2) as colorless oil; yield: 110 mg (90%).
20. Typical experimental procedure for the reuse experiments (Table 3): To a
solution of acetophenone (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 mixture was
stirred at the same temperature for 2 h under argon atmosphere. The mixture
was extracted with Et2O (20 Â 10 mL). The organic layer was washed with
brine (200 mL) and dried with MgSO4. The solvent was removed under reduced
pressure to give crude reaction mixture. Yield was directly determined by 1H
NMR spectroscopy. The remaining [BHEA][HCO2] was used in the next reaction
without further purification.
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