Highly atom-efficient and chemoselective reduction of ketones in the presence of aldehydes using heterogeneous catalysts

Article abstract of DOI:10.1039/c3gc41322e

The first demonstration of a 100% atom-efficient selective reduction of less reactive ketones over aldehydes using heterogeneous catalysts is reported. Extremely high selectivities for intra- and intermolecular reductions of ketones over aldehydes were achieved. This system was also applicable to a column reactor, leading to a gram-scale synthesis.

Full text of DOI:10.1039/c3gc41322e

View Article Online
View Journal
Green Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Takahashi, T. Mitsudome, T. Mizugaki,
K. Jitsukawa and K. Kaneda, Green Chem., 2013, DOI: 10.1039/C3GC41322E.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
Volume 12 | Number 9 | September 2010 | Pages 1481–1676
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1463-9262
COMMUNICATION
CRITICAL REVIEW
Luque, Varma and Baruwati
Dumesic et al.
Magnetically seperable organocatalyst Catalytic conversion of biomass
for homocoupling of arylboronic acids to biofuels
1463-9262(2010)12:9;1-U
www.rsc.org/greenchem
Registered Charity Number 207890

Page 1 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C3GC41322E
The first demonstration of 100%-atom efficient ketone selective hydrogenation was
achieved using heterogeneous catalyst.

Green Chemistry
Page 2 of 5
Dynamic Article Links ►
Journal Name
View Article Online
DOI: 10.1039/C3GC41322E
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Highly Atom-Efficient and Chemoselective Reduction of Ketones in the
Presence of Aldehydes Using Heterogeneous Catalysts
Yusuke Takahashi,a Takato Mitsudome,a Tomoo Mizugaki,a Koichiro Jitsukawaa and
Kiyotomi Kaneda*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
50
The first demonstration of a 100% atom-efficient selective
(a) Previous Works
reduction of less reactive ketones over aldehydes using
heterogeneous catalysts is reported. Extremely high
10 selectivities for intra- and intermolecular reductions of
ketones over aldehydes were achieved. This system was also
applicable to a column reactor, leading to a gram-scale
synthesis.
Protecting method3-9
O
OH
R2
Protecting agent
Reducing agent
Deprotecting agent
Waste
R1
R3
R2
O
R1
R3
O
Waste
Tsuji et al.10
1. CuCl, bowl-shaped phosphine, Ph2SiH2, t-BuONa, -40 o
Waste
OH
O
55
60
65
C
R1
R3
R2
O
R1
R3
R2
O
2. HCl-MeOH
Waste
Selective reduction of a targeted functional group in the
15 presence of other reducible functionalities is of great interest in
organic synthesis.1 In this context, chemoselective reduction of a
ketone group in the presence of an aldehyde is an important
methodology to synthesize valuable intermediates for drugs and
natural products.2 However, the selective reduction of ketones
20 over aldehydes is highly challenging because ketones are
generally less reactive than aldehydes. Luche developed the
pioneering and strong method for the selective reduction of
ketones over aldehydes using the CeCl3ꢀEtOHꢀNaBH4 system
(Luche reduction), which included acetalization of aldehydes
25 followed by reduction of ketones and then deprotection of the
acetals.3 To date, several similar approaches have been
proposed.4ꢀ9 However, these methods have the fatal problem of
low atom efficiency due to the necessity of stoichiometric
protecting reagents, metal hydrides, and toxic acids for the
30 deprotection, producing large amounts of waste (Figure 1a). More
recently, Tsuji and coꢀworkers reported a wellꢀdesigned copper
catalyst with a bowlꢀshaped phosphine ligand, which showed
excellent selectivity toward ketones over aldehydes in the
reduction.10 Although this system avoids the protection and
35 deprotection steps for the aldehyde groups, a hydrosilane is
inevitably required as a reducing reagent, resulting in low atomꢀ
efficiency. This protocol also suffers from the lack of generality
due to the requirement of a complicated preparation method for
the special ligand and the strictly controlled conditions (ꢀ40 °C).
40 These above reported methods, furthermore, involve
(b) This Work
R'OH
H2
O
OH
R2
OR'
Mertal
nanoparticle
catalyst
O
OH
R2
Solid acid
catalyst
Solid acid
catalyst
R1
R3
R2
OR'
R1
R3
R1
R3
R2
O
R1
R3
(I) Acetalization
(II) Reduction
(III) Deacetalization
O
OR'
OR'
H2O
100% atom-efficiency
Fig. 1 Strategy for the wasteꢀfree ketoneꢀselective hydrogenation using
heterogeneous catalysts
homogeneous catalysts that are difficult to recover and reuse.
Therefore, the highly atomꢀefficient reduction of ketones in the
70 presence of aldehydes using heterogeneous catalysts is still the
subject of considerable interest.
Herein, we report the first demonstration of a 100% atomꢀ
efficient selective reduction of ketones in the presence of
aldehydes using reusable heterogeneous catalysts (Figure 1b).
75 This catalytic method is simple, and achieves extremely high
ketone selectivities over aldehydes in oneꢀpot reaction sequences
through (I) acetalization, (II) hydrogenation using H2 and (III)
deacetalization. The alcohols and water used are regenerated and
H2 is available as a wasteꢀfree reducing agent, providing 100%
80 atomꢀefficiency for the ketoneꢀselective hydrogenation.
Furthermore, the present wasteꢀfree heterogeneous catalyst
system was applicable to a flow column reactor, leading to the
success of a gramꢀscale synthesis.
To demonstrate the highly atomꢀefficient selective reduction of
85 2ꢀoctanone (2) over nꢀoctanal (1) as a model reaction, the
acetalization step of 1 was initially investigated in the presence of
2 using Ti4+ cationꢀexchanged montmorillonite (Tiꢀmont)
(Scheme 1). This is because that Tiꢀmont was found to act as an
efficient solid acid catalyst for acetalization.11 As expected, the
90 acetalization of 1 proceeded efficiently in the presence of 2 in
MeOH solvent at 30 °C under Ar atmosphere to afford the
——————————————————————————
a Department of Materials Engineering Science, Graduate School of
Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka,
Osaka, 560-8531, Japan. E-mail: kaneda@cheng.es.osaka-u.ac.jp; Fax:
45 +81 6-6850-6260; Tel: +81 6-6850-6260.
b Research Center for Solar Energy Chemistry, Osaka University, 1-3
Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
† Electronic Supplementary Information (ESI) available: Experimental
details, EXAFS analysis and TEM images. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Page 3 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C3GC41322E
50
5
Scheme 2 Successive oneꢀpot hydrogenation of ketone catalyzed by Tiꢀ
mont and RunanoHAP. Reaction conditions: (I) Tiꢀmont (0.05 g),
RunanoHAP (0.05 g), MeOH (2 mL), 30 oC, 0.5 h. (II) 40 oC, 1 h. (III) H2O
55 (4 mL), 80 oC, 0.5 h.
Scheme 1 Acetalization of carbonyl compounds catalyzed by Tiꢀmont
corresponding octanal dimethyl acetal (3) in >99% yield
accompanied by 20% yield of 2ꢀoctanone dimethyl ketal (4).12
Next, the hydrogenation of 2 in the presence of 3 was studied
using various supported metal nanoparticle catalysts under 1 atm
of H2 at 40 °C (Table 1). Interestingly, hydroxyapatite (HAP)ꢀ
supported Ru nanoparticle catalyst (RunanoHAP) showed excellent
10
the production of 2. Consequently, 2 was converted quantitatively
to afford 5. After the selective hydrogenation of 2, the addition of
water to the reaction mixture including Tiꢀmont and RunanoHAP
followed by heating at 80 °C promoted the smooth
activity for the selective hydrogenation of 2.13 The corresponding 60 deacetalization of 3 to recover 1 without any loss (Scheme 2
15 2ꢀoctanol (5) was quantitatively obtained while 3 was intact and
fully recovered after the reaction (entry 1). Among the organic
and inorganic supports for Ru nanoparticles tested, HAP was the
best (entries 1ꢀ5). HAPꢀsupported on other transition metal
Reaction B). The deprotection is due to the presence of the solid
acid catalyst of Tiꢀmont.15 Namely, Tiꢀmont was found to act as
an efficient dual catalyst for both the acetalization and
deacetalization steps in the oneꢀpot reaction. The combination
nanoparticles showed less catalytic activity than RunanoHAP 65 catalyst of Tiꢀmont with RunanoHAP enabled the successful
20 (entries 6ꢀ9 vs. 1). The use of Rh and Cu nanoparticles resulted in
lower yields of 5. Pt and Pd nanoparticles gave 5 in moderate
yields, but hydrogenolysis of 3 to methyl octyl ether occurred
simultaneously.14 These results revealed that the combination of
promotion of the successive acetalizationꢀhydrogenationꢀ
deacetalization sequence, leading to the 100% atomꢀefficient
selective reduction of 2 to 5 with quantitative recovery of 1.
The present TiꢀmontꢀRunanoHAP catalyst system could be
Ru nanoparticles with HAP support is effective for the selective 70 extended to various pairs of ketones and aldehydes in the oneꢀpot
25 hydrogenation of 2 to 5 in the presence of 3 under mild reaction
conditions.
Based on these results, we attempted the combination of these
two heterogeneous catalyst systems in a oneꢀpot hydrogenation of
selective hydrogenation of ketones (Table 2). Aliphatic and
alicyclic ketones such as 2ꢀoctanone, 4ꢀoctanone and
cyclopentanone were selectively hydrogenated to the
corresponding alcohols in excellent yields together with
2 in the presence of 1. Namely, the oneꢀpot chemoselective 75 quantitative recoveries of the original aldehydes (entries 1ꢀ4).
30 transformation of 2 to 5 through the acetalization of 1 followed
by the hydrogenation of 2 was investigated, employing both Tiꢀ
mont and RunanoHAP (Scheme 2). Notably, Tiꢀmont and
RunanoHAP worked independently without any mutual
Selective hydrogenation of cyclohexanone over nꢀoctanal was
also achieved when using 1,3ꢀpropanediol in place of MeOH
(entry 5).16 An aromatic ketone was also selectively hydrogenated
to the corresponding alcohol by the addition of DMSO without
deactivation to afford the desired product 5 in excellent yield 80 hydrogenation of the aromatic ring or hydrogenolysis of the
35 together with the quantitative recovery of 3 (Scheme 2 Reaction
A). As shown in Scheme 1, ketal 4 was also formed in the
acetalization step by the use of Tiꢀmont alone. In contrast, 4 was
not detected at all in the oneꢀpot sequence. This is because the
hydrogenation of 2 to 5 shifts the equilibrium between 2 and 4 to
benzyl hydroxyl group (entry 6).17 Furthermore, the present
catalyst system could be employed for the intramolecular
selective hydrogenation of ketones over aldehydes. Various
ketoaldehydes were efficiently hydrogenated to give the
85 corresponding hydroxyl aldehydes (entries 7ꢀ9). Interestingly, the
hydrogenation of
a
diketone to the corresponding
40 Table 1 Hydrogenation of 2 in the presence of 3 using various supported
metal nanoparticle catalystsa
hydroxycyclohexanone was also performed, and the lessꢀreactive
ketone moiety could be preferentially hydrogenated (entry 10).
A further advantage of the present heterogeneous catalyst
90 system is the applicability to a continuous flow reactor. A flow
reactor in which the first and third columns were filled with Tiꢀ
mont and the second column with RunanoHAP was designed as
shown in Scheme 3. When 8ꢀoxononanal (100 mmol, 15.6 g) in
MeOH (0.20 M) was introduced to the reactor, it flowed
95 continuously through the three columns and was transformed into
the desired 8ꢀhydroxynonanal in 94% isolated yield (14.7 g) via
the acetalizationꢀhydrogenationꢀdeacetalization sequence.
Furthermore, after the flow reaction, no Ru and Ti ions were
detected in the reaction mixture by ICP analysis, and the resulting
100 mixture of water and MeOH is easily recovered and separated.18
This demonstrates the success in simplifying the purification
process of the desired products with high efficiency. The
combination use of heterogeneous catalysts provides a powerful
method to replace the low atomꢀefficient chemical synthesis with
a
Reaction conditions: catalyst (metal: 10 mol%), MeOH (2 mL).
b
c
45 Determined by GC using an internal standard technique. 3 was
hydrogenolyzed to methyl octyl ether.
.
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Green Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C3GC41322E
Table 2 Selective hydrogenation of ketones over aldehydesa
This work was supported by a GrantꢀinꢀAid for Young
Scientists (A) (23686116) from the Japan Society for the
35 Promotion of Science (JSPS). We thank Dr. Uruga, Dr. Kato, Dr.
Nitta, Dr. Ina (SPringꢀ8) for XAFS measurements. The TEM
experiments were carried out by using a facility in the Research
Center for Ultrahigh Voltage Electron Microscopy, Osaka
University.
40 Notes and references
1
2
3
4
(a) B. M. Trost, Science, 1991, 254, 1471; (b) R. A. Sheldon, J. Mol.
Cat., 1996, 107, 75; (c) R. A. Sheldon, Pure Appl. Chem., 2000, 72,
1233.
Ketoneꢀselective reduction is useful to synthesize cyclic acetals.
Fujioka et al. applied this reaction to the asymmetric synthesis of (+)ꢀ
centrolobine with the highest reported overall yield. See ref. 8.
(a) J. L. Luche and A. L. Gemal, J. Am. Chem. Soc., 1979, 101, 5849;
(b) A. L. Gemal and J. L. Luche, J. Org. Chem., 1979, 44, 4187; (c)
A. L. Gemal and J. L. Luche, Tetrahedron Lett., 1981, 22, 4077.
(a) T. Chihara, T. Wakabayashi and K. Taya, Chem. Lett., 1981, 10,
1657; (b) T. Chihara, T. Wakabayashi, K. Taya and H. Ogawa, Can.
J. Chem., 1990, 68, 720.
M. P. Paradisi, G. P. Zecchini and G. Ortar, Tetrahedron Lett., 1980,
21, 5085.
J. H. An, T. B. Sim, J. Choi and N. M. Yoon, Bull. Korean Chem.
Soc., 1997, 18, 111.
45
50
55
60
65
70
75
5
6
7
8
A. Clerici, N. Pastori and O. Porta, Eur. J. Org. Chem., 2002, 3326.
H. Fujioka, K. Yahara, O. Kubo, Y. Sawama, T. Hamada and T.
Maegawa, Angew. Chem. Int. Ed., 2011, 50, 12232.
G. Bastug, S. Dierick, F. Lebreux, and I. E. Markó, Org. Lett., 2012,
14, 1306.
9
10 T. Fujihara, K. Semba, J. Terao and Y. Tsuji, Angew. Chem. Int. Ed.,
2010, 49, 1472.
11 Tiꢀmont acts as an efficient Brønsted acid catalyst for acetalization:
(a) T. Kawabata, T. Mizugaki, K. Ebitani and K. Kaneda,
Tetrahedron Lett., 2001, 42, 8329; (b) T. Mitsudome, T. Matsuno, S.
Sueoka, T. Mizugaki, K. Jitsukawa and K. Kaneda, Heterocycles,
2012, 84, 371.
12 Tiꢀmont showed higher catalytic activity than other solid acid
catalysts under the present reaction conditions, see Supporting
Information.
a
Reaction conditions: Tiꢀmont (0.05 g), RunanoHAP (0.05 g, Ru: 10
o
o
5
mol%), MeOH (2 mL), (I) 30 C, Ar, 0.5 h; (II) 40 C, H2 (1 atm); (III)
H2O (4 mL), 80 oC, Ar, 1 h. Determined by GC using an internal
b
c
standard technique. 1,4ꢀDioxane (2 mL) and 1,3ꢀpropanediol (2 mmol)
were used in place of MeOH. d RunanoHAP (0.1 g, Ru: 20 mol%), MeOH
(2 mL), DMSO (100 mol%), 60 oC. 1,4ꢀDioxane (2 mL) and
e
10 ethyleneglycol (2 mmol) were used in place of MeOH.
.
13 The preparation and characterization of RunanoHAP are described in
the Supporting Information.
14 It is well known that acetals are decomposed to ethers in H2
atmosphere with Pt or Pd catalysts: (a) M. Verzele, M. Acke and M.
Anteun, J. Chem. Soc., 1963, 5598; (b) V. Bethmont, F. Fache and
M. Lemaire, Tetrahedron Lett., 1995, 36, 4235; (c) Y. Fujii, H.
Furugaki, E. Tamura, S. Yano and K. Kita, Bull. Chem. Soc. Jpn.,
2005, 78, 456.
15
80 15 T. Kawabata, M. Kato, T. Mizugaki, K. Ebitani and K. Kaneda,
Chem. Lett., 2003, 32, 648; see also ref. 11(a) and 11(b).
16 When using MeOH solvent in entries 5 and 9, not only aldehydes but
also ketone moieties of cyclohexanones were protected, causing no
occurrence of the hydrogenation of cyclohexanones to cyclohexanols.
20
85
90
95
On the other hand, when choosing 1,3ꢀpropanediol in place of
MeOH, 1,3ꢀpropanediol could act as an efficient aldehydeꢀselective
protecting agent to promote the selective hydrogenation of
cyclohexanones to cyclohexanols in the presence of aldehyde groups.
17 We found that the addition of DMSO to the reaction mixture could
suppress the hydrogenation of the aromatic ring or hydrogenolysis of
the benzyl hydroxyl group. Similar effects of DMSO for the
semihydrogenation of alkynes have also been reported, see: (a) Y.
Takahashi, N. Hashimoto, T. Hara, S. Shimazu, T. Mitsudome, T.
Mizugaki, K. Jitsukawa and K. Kaneda, Chem. Lett., 2011, 40, 405;
(b) T. Mitsudome, Y. Takahashi, S. Ichikawa, T. Mizugaki, K.
Jitsukawa and K. Kaneda, Angew. Chem. Int. Ed., 2013, 52, 1481.
18 MeOH and water can be efficiently separated by rectification or
membrane separation: D. W. Green and R. H. Perry, Perry's
Scheme 3 Continuous flow reactor system consisting of Tiꢀmont and
RunanoHAP for ketoneꢀselective hydrogenation
a high atomꢀefficient one, leading to greener industrial production
of fine chemicals.
25
In conclusion, we developed
a
100% atomꢀefficient
heterogeneous catalyst system for the oneꢀpot selective
hydrogenation of less reactive ketones over aldehydes. This
catalyst system has great advantages such as (i) high selectivity
for various ketones over aldehydes in interꢀand intramolecular
30 hydrogenations, (ii) reusable catalysts and reagents, (iii) simple
and easy reaction method, and (iv) the applicability to flow
reactors.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Page 5 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C3GC41322E
Chemical Engineers' Handbook 6th edition 1984, Tokyo: McGrawꢀ
Hill.
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]