Platinum-triethylamine-catalyzed hydrogenation of aldehydes and cyclohexanones

Article abstract of DOI:10.1016/j.tetlet.2009.07.006

The first hydrogenation of aldehydes and chemoselective hydrogenation of cyclohexanones catalyzed by PtO₂-Et₃N are presented. An additionally attractive feature of this hydrogenation is being applicable to the complicated molecules. Three equivalent of triethylamine and 0.05 equiv of PtO₂ in 95% ethanol are found to be the optimal condition.

Full text of DOI:10.1016/j.tetlet.2009.07.006

Tetrahedron Letters 50 (2009) 5270–5273
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Tetrahedron Letters
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Platinum–triethylamine-catalyzed hydrogenation of aldehydes
and cyclohexanones
*
Feng Gao, Qiao-Hong Chen, Feng-Peng Wang
Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, No. 17, Duan 3, Renmin Nan Road, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first hydrogenation of aldehydes and chemoselective hydrogenation of cyclohexanones catalyzed by
PtO2–Et3N are presented. An additionally attractive feature of this hydrogenation is being applicable to
the complicated molecules. Three equivalent of triethylamine and 0.05 equiv of PtO2 in 95% ethanol
are found to be the optimal condition.
Received 29 April 2009
Revised 23 June 2009
Accepted 3 July 2009
Available online 7 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
As part of our ongoing program on the modification of paclitaxel
analogs, D6,7 olefinic double bond in compound 1 was envisioned
to be reduced by PtO2-catalyzed hydrogenation, by analogy with
our successful reduction of the conjugated olefinic double bond
in diterpenoid alkaloid 2.1 Initially, we misjudged that the olefinic
double bond in compound 1 did not undergo the hydrogenation
catalyzed by platinum dioxide over 24 h barely based on the TLC
behavior (silica gel GF254; cyclohexane/acetone 2:1, and chloro-
form/methanol 98:2). At this point, we compared the structural
difference between 1 and 2, which indicated that the diterpenoid
alkaloid 2 possessed an additional tertiary amine substructure rel-
ative to compound 1. With the notion that the extra tertiary amine
substructure in 2 might promote the hydrogenation of olefinic
double bond, we next investigated on the hydrogenation of
compound 1 in the presence of platinum dioxide and triethyl-
amine. Very interestingly, not only D6,7 olefinic double bond but
also C-5 ketone group in compound 1 was hydrogenated in the
presence of platinum dioxide and triethylamine (Scheme 1). This
interesting experimental result spurred us to investigate the gener-
ality and the best reaction conditions of this catalytic hydrogena-
tion of aldehydes and ketones.
It is well known that reduction of C@O double bonds using
molecular hydrogen is a very important process in industrial or-
ganic synthesis due to its low cost and complete atom efficiency.2
Homogeneous Rh, Ru, and to a lesser degree Ir complexes are used
for the enantioselective hydrogenation with both hydrogen and
organic donors as reducing agent. Elegant work by Noyori and
co-workers has demonstrated the efficient synthesis of a variety
of chiral secondary alcohols via the Ru-binap-catalyzed hydroge-
nation of simple ketones.3 For the heterogeneous hydrogenation
of carbonyl groups, the preferred catalysts are Pd, Pt, and Ni. The
most interesting point was Orito’s catalytic system, platinum
catalysts modified with cinchona alkaloids, for the hydrogenation
of activated ketones.4 As summarized in a recent review,5 several
groups tried to improve catalyst performance by using different
supports or catalyst pre-treatments. For example, metal-supported
Pt,6 polysulfosiloxane–Pt complex,7 and platinum nanocatalyst8
have been applied to the hydrogenation of ketones. However, the
scope of this technology is still restricted to the hydrogenation of
ketones activated in
a or b position. It was reported in the litera-
ture9 that the substituted cyclohexanones could be hydrogenated
in the presence of PtO2. However, neither the PtO2/Et3N system
nor the hydrogenation of aldehydes and other ketones was men-
tioned. The PtO2/Et3N system has already been applied to the
hydrogenation of other functionalities, such as pyridinium salt,10a
nitryl group,10b,c and alkyne,10d but there was no detail explanation
on it. To the best of our knowledge, PtO2–Et3N-catalyzed hydroge-
nation of aldehydes and ketones has not been reported yet. It is
therefore significant to present herein the first example of catalytic
and chemoselective hydrogenation of aldehydes and cyclohexa-
nones catalyzed by platinum dioxide and triethylamine, proceed-
ing under room temperature and atmospheric pressure.
Our initial experiments demonstrated that treatment of com-
pound 1 with H2 in the presence of Pd/C at room temperature
afforded only D6,7 double bond reduced product 1a in 95% yield.
Further hydrogenation of 1a in the presence of platinum dioxide
and triethylamine provided the C-5 ketone-reduced product 1b
with high yield (95%), which suggested that both saturated and
unsaturated cyclohexanones could be reduced to the correspond-
ing cyclohexanols by the PtO2–Et3N-catalyzed hydrogenation
(Scheme 1).
The scope of this novel transformation was examined on a
series of aldehydes at room temperature and atmospheric pressure
of hydrogen in the presence of platinum dioxide and triethylamine
(Table 1). Aldehydes in either simple aliphatic compounds (entries
1–2), simple aromatic compounds (entries 3–4), or complicated
natural analogs (entries 5–6) were reduced uneventfully in
* Corresponding author. Tel./fax: +86 28 85501368.
E-mail address: wfp@scu.edu.cn (F.-P. Wang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.006

F. Gao et al. / Tetrahedron Letters 50 (2009) 5270–5273
5271
OH
OH
OCH3
OMs
OCH3
OMs
H2 (1 atm)/PtO2
95% EtOH/48h
N
N
OH
OH
OCH3
2a (95%)
O
O
H
H
OCH3
H3CO
H3CO
2
BocO
O
BocO
BocO
O
H
O
H
H2 (1 atm)
PtO2 /Et3N
BocO
BocO
BocO
+
O
OH
OAc
O
H
95% EtOH, 24 h
OAc
OAc
O
O
O
O
O
O
HO
O
O
HO
HO
1a
O
(35%)
1b (65%)
1
H2 (1 atm)/Pd-C/95% EtOH/24h
95% yield
H
2 (1 atm)/PtO2/Et3N
95% EtOH/24h, 95% yield
Scheme 1. Hydrogenation of compounds 1 and 2.
Table 1
PtO2–Et3N-catalyzed hydrogenation of aldehydesa
Entrya
Aldehydes
Alcoholsb
T (h)
Yield (%)
1
2
3
Propylaldehyde
Pivalaldehyde
Benzaldehyde
Propyl alcohol
2,2-Dimethylpropanol
Phenylmethanol
12
12
12
>99
>99
>99
CHO
CH2OH
4
16
>99
BocO
BocO
O
O
OBoc
OBoc
BocO
BocO
BocO
5
24
>99
OH
CHO
OH
OH
CH2OH
OH
H
H
O
O
O
O
O
O
O
BocO
BocO
O
O
BocO
6
24
98
OH
CHO
OH
OH
H
H
CH2OH
O
O
O
O
OH
O
a
Reaction conditions: PtO2 (5 mol %), Et3N (1 equiv), 95% EtOH (solvent) at 25 °C under an atmospheric pressure of H2.
b
Yields reported were calculated based on the 1H NMR data.
Table 2
12–24 h reaction time. Both carbonate and Boc protecting groups
(entries 5–6) were perfectly compatible with the reaction condi-
tions. All the corresponding alcohols were obtained in almost
quantitative yields after simple filtration and evaporation.
Base and solvent optimization for PtO2-catalyzed hydrogenation of cyclohexanonea
O
OH
H2 (1 atm) / PtO2
base, solvent, rt
Next, we began our optimization by testing the effect of several
different bases on the hydrogenation with cyclohexanone as model
substrate (Table 2). It was found that employment of other
commonly used inorganic and organic bases (such as Et2NH,
DBU, DIPEA, Pyridine, NaOH, and EtONa) in combination with plat-
inum dioxide also allowed hydrogenation of cyclohexanone, but
the conversion did not proceed to completion and thereby gave
relatively low yields. Moreover, the reaction was found to proceed
smoothly in excellent yield with not less than 3 equivalent of
triethylamine. Further optimization with platinum dioxide-trieth-
ylamine showed that 95% ethanol, instead of methanol and THF,
was the most suitable solvent for this hydrogenation. To this end,
3 equiv of triethylamine and 0.05 equiv of PtO2 in 95% ethanol
were found to be the optimal condition.
Entrya
Base (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Et3N (3.0)
Et3N (6.0)
Et3N (1.5)
Et3N (0.5)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et2NH (3.0)
DBU (3.0)
DIPEA (3.0)
Pyridine (3.0)
NaOH (3.0)
EtONa (3.0)
95% EtOH
95% EtOH
95% EtOH
95% EtOH
MeOH
THF
CH2Cl2
Toluene
DMF
95% EtOH
95% EtOH
95% EtOH
95% EtOH
95% EtOH
EtOH
97.5
97.5
75.0
65.0
85.0
70.0
25.0
20.0
65.0
90.0
45.0
25.0
45.0
40.0
50.0
The high activity of this catalytic hydrogenation of aldehydes
and cyclohexanones naturally led us to evaluate the possibility of
hydrogenation of other cyclic ketones and acyclic ketones. Many
cyclic ketones were prepared and treated with hydrogen in the
presence of PtO2–Et3N (Table 3). Notably, no (or with low yield)
reduction product was observed from the hydrogenation of five-,
a
Reaction conditions: cyclohexanone (10.0 mmol), PtO2 (5 mol %), base (5.0–
30.0 mmol), and solvent (5.0 ml) under H2 (1 atm) for 24 h.
b
Yields reported were calculated based on the 1H NMR data.
seven-, eight-, or ten-membered cyclic ketones. The only exception
is cyclohexanones, which could be hydrogenated in high yields

5272
F. Gao et al. / Tetrahedron Letters 50 (2009) 5270–5273
Table 3
PtO2–Et3N-catalyzed hydrogenation of cyclohexanones
Entry
1
Cyclohexanones
Alcohols
Yield (%)
95
O
OH
cis:trans = 3:1
OH
OH
O
O
O
O
O
O
2
3
a
:b = 1:3
95
90
O
HO
O
O
HO
O
O
O
a
:b = 1:3
HO
HO
O
OH
OMs
H3CO
H3CO
OMs
4
5
6
85
90
80
N
N
O
O
O
H
O
H
O
O
O
O
OH
O
O
O
OAc
OAc
O
O
H
H
OAc
OAc
BocO
BocO
O
O
OBoc
OBoc
BocO
BocO
OAc
OAc
H
H
OH
O
O
O
O
O
O
O
O
O
BocO
BocO
O
O
OBoc
OBoc
BocO
H3CO
BocO
H3CO
7
8
9
90
90
90
O
OH
OAc
H
H
O
O
O
O
OAc
OH
OH
OH
O
O
O
O
N
a:b = 4:6
N
O
O
O
O
H
O
H
O
O
BocO
BocO
O
O
BocO
BocO
O
OH
H
H
O
O
O
O
OAc
O
OAc
OH
O
OH
(Table 3). At this point, we paid our attention to the evaluation of
the chemoselective hydrogenation of simple cyclic ketones to
exclude the possibility of steric effect on the reaction. Accordingly,
cyclopentanone, cyclohexanone, and cycloheptanone were hydro-
genated under 1 atm H2 for 24 h, respectively. It was found that
only cyclohexanone was quantitatively converted to cyclohexanol,
and that almost all of cyclopentanone (85%) and cycloheptanone
(90%) were recovered from the hydrogenation (Supplementary
data). Several acyclic ketones (such as butan-2-one, 3-methylb-
cyclohexanones would be particularly useful in the synthesis and
structural modifications of complicated natural products.
Interestingly, the cyclohexanone in alkaloid 2a did not undergo
the hydrogenation under this condition. Consideration of the
possible influence of alkalinity, the nitrogen atom in alkaloid 2a
was deactivated by N-deethylation11 followed by acetylation to
give 2c (Scheme 2). Very happily, the N-deactivated compound
2c was readily hydrogenated to alcohol under our aforementioned
reaction condition (Scheme 2), which indicated that the alkalinity
of the nitrogen atom is detrimental to the hydrogenation reaction
catalyzed by PtO2–Et3N.
utan-2-one,
3,3-dimethylbutan-2-one,
acetophenone,
and
benzophenone) were treated with hydrogen in the presence of
PtO2–Et3N as well, which only furnished the corresponding alco-
hols in less than 30% yield. This chemoselective hydrogenation of
The mechanistic understanding of heterogeneous catalytic hydro-
genation of ketones is still relatively poor as compared with that of

F. Gao et al. / Tetrahedron Letters 50 (2009) 5270–5273
5273
greatly beneficial to the complicated natural product chemistry.
In addition, PtO2 and Et3N are commercially available, easy to han-
dle, and the products can be easily separated by filtration and
evaporation. An additionally attractive feature of this hydrogena-
tion is being applicable to the complicated molecules. Extension
of this work and investigation of its reaction mechanism are
currently in progress.
OH
OH
OCH3
OMs
OCH3
OMs
Ac2O/Pyr
NBS/HOAc
N
NH
H
H3CO
OH
40%
OH
O
85%
O
H
OCH3
OCH3
2b (95%)
H3CO
2a
OH
OH
OCH3
OMs
OCH3
OMs
Acknowledgment
O
O
H2 (1 atm)/PtO2/Et3
N
N
N
OH
95% EtOH/24h
yield 90%
OH
This research work was supported financially by the National
Science Foundation of China (No. 30672526).
O
HO
H
H
OCH3
OCH3
H3CO
H3CO
2c
2d
Supplementary data
Scheme 2. Preparation and hydrogenation of compound 2c.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.006.
homogeneous catalysts.4 Despite the impressive development in the
field of the hydrogenation of activated ketones by supported plati-
num catalyst (usually Pt/Al2O3) modified with cinchona alkaloids,
the mechanistic details at the base of the reaction are still under
debate.12 Several models have been developed, and the conflicting
opinions reflect the great scientific interest of this topic.
References and notes
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It was demonstrated that the bifunctional M–H/N–H motif, a
hydride and amine cis-coordinated on the metal center, plays an
important role for the hydrogenation of ketones.3e,12–17 Similarly,
we presumed that PtO2/Et3N has the bifunctional Pt–H/N–H motif,
which could enhance the catalytic ability of Platinum based on the
following observations: (i) when triethylamine was replaced by
other bases, such as NaOH, diisopropylethylamine, pyridine, and
isobutylamine, the conversion rate of the hydrogenation was
significantly decreased; (ii) Benzophenone (a ketone that cannot
be enolized) can be hydrogenated in about 25% yield under the
aforementioned condition; and (iii) Benzaldehyde (an aldehyde
that cannot be enolized) was hydrogenated in the presence of
PtO2/Et3N in quantitative yield. In addition, it was reported that
the enol form can also be the reactive species in the hydrogenation
of the activated ketone on modified platinum.12 The triethylamine
might lead to the formation of a protonated amine-enolate salt of
ketones and aldehydes. Accordingly, we surmised that the hydro-
genation of ketones and aldehydes catalyzed by PtO2/Et3N might
experience the enol form intermediate alternatively. In this case,
the different stability of the enol might elucidate the ring size-
selectivity hydrogenation observed in our experiments because
the cyclic six-membered enols are most stable among the cyclic
enols.
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K.; Terashima, S. Tetrahedron 1994, 50, 2793–2808; (d) Keenan, R. M.; Miller,
W. H.; Barton, L. S.; Bondinell, W. E.; Cousins, R. D.; Eppley, D. F.; Hwang, S.-M.;
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4048–4057. and the references cited therein.
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In summary, the first hydrogenation of aldehydes and chemose-
lective hydrogenation of cyclohexanones catalyzed by PtO2–Et3N
was presented. This novel method is quite general, and proceeds
efficiently at ambient temperature and under atmospheric H2
pressure. The aldehydes can be hydrogenated in high yields; and
cyclohexanones can be selectively reduced to the corresponding
alcohols in the presence of other cyclic ketones, which would be