Ruthenium-catalyzed reduction of allylic alcohols: An efficient isomerization/transfer hydrogenation tandem process

Article abstract of DOI:10.1039/b618573h

A simple and highly efficient method for the selective reduction of the C=C bond in allylic alcohols has been developed using the ruthenium(ii) catalyst [{RuCl(μ-Cl)(η⁶-C₆Me₆)}₂]. The Royal Society of Chemistry.

Full text of DOI:10.1039/b618573h

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Ruthenium-catalyzed reduction of allylic alcohols: An efficient
isomerization/transfer hydrogenation tandem process
Victorio Cadierno,* Javier Francos, Jos e´ Gimeno* and Noel Nebra
Received (in Cambridge, UK) 3rd January 2007, Accepted 27th February 2007
First published as an Advance Article on the web 19th March 2007
DOI: 10.1039/b618573h
A simple and highly efficient method for the selective reduction
particular, the best results were obtained using the hexamethyl-
6
benzene-Ru(II) dimer [{RuCl(m-Cl)(g -C
of the CLC bond in allylic alcohols has been developed using
6 6 2
Me )} ], which lead to
6
the ruthenium(II) catalyst [{RuCl(m-Cl)(g -C
6
Me
6
)}
2
].
the almost quantitative formation of the desired saturated alcohol
21
after only 3.5 h (TOF = 28 h ; Table 1, entry 1). For the rest of
the catalysts, variable amounts of the intermediate carbonyl
compound, i.e. octan-3-one, were still detected in the reaction
media after 9 h (Table 1, entries 2–13).
Ruthenium-catalyzed processes have become one of the most
preferred methodologies in organic synthesis because of their
1
highly efficient performance and versatile applications. Among
6
their most innovative synthetic approaches, a number of one-pot
processes involving multiple chemical transformations (tandem
Remarkably, the efficiency shown by [{RuCl(m-Cl)(g -
C
6
Me
ofthebis(allyl)-ruthenium(IV)derivatives[RuCl
18 = dodeca-2,6,10-triene-1,12-diyl) and [{RuCl(m-Cl)-
6 2
)} ] in the reduction of 1-octen-3-ol is far higher than that
2,3
3
2
3
catalysis) have recently appeared.
2
(g :g :g -C12H18)]
Herein, we report a simple and highly efficient method for the
selective reduction of the CLC bond in allylic alcohols, based on a
novel ruthenium-catalyzed tandem process (Scheme 1). This one-
pot transformation involves the initial isomerization of the allylic
alcohol and subsequent transfer hydrogenation (TH) of the
resulting carbonyl compound. A series of ruthenium complexes
are well known catalysts for performing both individual steps with
12
(C H
3
3
(g :g -C H )} ] (C H = 2,7-dimethylocta-2,6-diene-1,8-diyl),
10 16 2 10 16
2 3
which, when associated with Cs CO , are among the most
active ruthenium catalysts reported to date for allylic alcohol
8
isomerization (Table 1: entry 1 vs. entries 12–13). This fact
clearly indicates that the transfer hydrogenation of the
intermediate carbonyl compound is the rate limiting step of
this tandem process. In accord with this, monitoring the
4
,5
high efficiency. The overall transformation, depicted in Scheme 1,
represents an appealing alternative to classical transition metal-
catalytic reduction of 1-octen-3-ol to octan-3-ol, catalyzed by
6
{RuCl(m-Cl)(g -C Me )} ], by GC (Fig. 1) shows that the
6
catalyzed CLC hydrogenations (Ru, Rh and Ir catalysts) since (i)
it takes place under relatively mild conditions and (ii) propan-2-ol
[
6
6
2
initial isomerization step takes place readily (ca. 15 min) to
is used as both the solvent and hydrogen source, avoiding the use
2
of H gas.
Table 1 Reduction of 1-octen-3-ol catalyzed by Ru in the presence of
Cs CO
2 3
a
Firstly, as a model reaction, we checked the catalytic activity of
several ruthenium complexes in the reduction of 1-octen-3-ol to
octan-3-ol (Table 1). Ru(II) (Table 1, entries 1–10), Ru(III) (Table 1,
entry 11) and Ru(IV) (Table 1, entries 12–13) derivatives were each
tested as catalyst precursors. Thus, we have found that, under
7
, 0.1 M
optimized conditions (1 mol% of Ru, 2 mol% of Cs CO
2
3
solution of the substrate in propan-2-ol, 82 uC), total consumption
of 1-octen-3-ol (.99% conversion, GC-determined) takes place
within 9 h, independent of the ruthenium source employed. In
Conversion Yield
b
Entry Catalyst
Time/h (%)
(%)
6
[{RuCl(m-Cl)(g -C
1
2
3
4
5
6
7
8
9
0
6
Me
6
)}
2
]
3.5
3 2
)} ] 6
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
99
95
91
75
92
35
26
16
1
4
3
94
86
6
[{RuCl(m-Cl)(g -1,3,5-C
6
H
3
Me
[{RuCl(m-Cl)(g -para-cymene)}
6
2
]
9
9
9
9
9
9
9
9
9
9
9
6
[{RuCl(m-Cl)(g -C
6
H
6
)}
2
]
[RuCl
2
(PPh
3
)
H
3
]
3
[Ru(g -2-C
[{RuCl
[RuCl (DMSO)
3
4
Me)
2
(COD)]
2 n
(COD)} ]
2
4
]
5
[RuCl(g -C
[RuCl(g -C
5
H
H
5
)(PPh
)(PPh
3
)
)
2
2
]
]
5
1
9
7
3
Scheme 1 Reduction of allylic alcohols through an isomerization/TH
11
RuCl
[RuCl
[{RuCl(m-Cl)(g :g -C10
3
?nH
2
O
3
2
3
1
1
a
2
3
2
(g :g :g -C12
H18)]
2
16)} ]
tandem process.
3
3
H
Reactions performed under a N
2
atmosphere at 82 uC using 2 mmol
CO
Departamento de Qu ´ı mica Org a´ nica e Inorg a´ nica, Instituto
Universitario de Qu ´ı mica Organomet a´ lica ‘‘Enrique Moles’’ (Unidad
Asociada al C.S.I.C.), Universidad de Oviedo, 33071, Oviedo, Spain.
E-mail: vcm@uniovi.es; jgh@uniovi.es; Fax: +34 985103446;
Tel: +34 985103461
of 1-octen-3-ol (0.1 M in propan-2-ol). [Substrate] : [Ru] : [Cs
2
3
]
b
ratio = 100 : 1 : 2. Yield of octan-3-ol determined by GC. The
difference between conversion and octan-3-ol yield corresponds to
the intermediate octan-3-one present in the reaction medium.
2
536 | Chem. Commun., 2007, 2536–2538
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6
Scheme 2 Reduction of 1 catalyzed by [{RuCl(m-Cl)(g -C
6
Me
6
)}
2
].
a ruthenium charge of 1 mol%. It is also interesting to note the
6
chemoselectivity shown by complex [{RuCl(m-Cl)(g -C Me )} ] in
6 6 2
the reduction of geraniol (Table 3, entry 13). Thus, although this
Fig. 1 Product distribution as a function of time for the reduction of
6
1
6 6 2
-octen-3-ol catalyzed by [{RuCl(m-Cl)(g -C Me )} ].
Table 3 Reduction of allylic alcohols containing substituted CLC
a
2 3
bonds catalyzed by Ru in the presence of Cs CO
afford octan-3-one, which slowly evolves into the final
saturated alcohol (quantitative yield after 3.5 h).
6
The dimeric Ru(II) complex [{RuCl(m-Cl)(g -C Me )} ] is also
6
6 2
very efficient in the reduction of a large number of allylic alcohols,
proving the scope and synthetic utility of this catalytic transforma-
tion.{ Nevertheless, its activity is strongly dependent on the
substitution of the carbon–carbon double bond of the substrate
Ru
(mol%) Time/h (%)
Conversion Yield
b
Entry Substrate
1
(%)
9
employed. Thus, as observed for 1-octen-3-ol, other monosub-
1
9
.99
97
stituted allylic alcohols can be also reduced in almost quantitative
yields using low ruthenium loadings (1–2 mol%, see entries 1–11 in
Table 2).{ Only when the coordinating furyl group was present in
the molecule was a higher catalyst charge (5 mol% of Ru) required
2
3
5
3
3
.99
.99
99
97
7.5
(Table 2, entry 12). Remarkably, the reduction of the two CLC
bonds of the bis(allylic alcohol) 1 could be also completely
achieved in 24 h, affording 1,3-bis(1-hydroxypropyl)benzene in
4
5
6
7
5
5
3
1
9
.99
.99
.99
.99
90
91
99
92
88% isolated yield (Scheme 2).
Di- and tri-substituted allylic alcohols are also reduced to the
corresponding saturated alcohols in .90% yield using higher ruth-
enium loadings (3–5 mol%, see Table 3). Only the disubstituted
species 3-penten-2-ol (Table 3, entry 1) and 2-methyl-2-propen-1-ol
22
25
9
(Table 3, entry 7), both containing the less sterically demanding
methyl group on the CLC bond, could be efficiently reduced using
Table 2 Reduction of monosubstituted allylic alcohols catalyzed by
Ru in the presence of Cs CO
a
8
9
5
5
5
5
9
6
.99
.99
.99
.99
98
96
93
93
2
3
Ru
(mol%)
Conversion
(%)
Yield
(%)
b
Entry
R
Time/h
1
1
1
0
1
9.5
1
2
3
4
5
6
7
H
1
1
1
1
1
1
1
1
2
2
2
5
5.5
5.5
3
3.5
3
22
10
22
15
24
24
5
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
.99
99
98
97
99
97
98
97
90
99
99
99
98
Me
Et
n
Pr
Bu
9
n
Bn
Ph
4-C
3-C
4-C
4-C
c
8
9
6
H
H
H
H
4
4
4
4
OMe
OMe
F
2
3
5
5
5
.99
.99
90
97
6
6
6
1
1
1
a
0
1
2
Cl
1
24
2-Furyl
Reactions performed under a N
2
atmosphere at 82 uC using 2 mmol
a
of the corresponding allylic alcohol (0.1 M in propan-2-ol). [Ru] :
[
Reactions performed under a N atmosphere at 82 uC using 2 mmol
of the corresponding allylic alcohol (0.1 M in propan-2-ol). [Ru] :
[Cs CO ] ratio = 1 : 2. Yield of the saturated alcohol determined
2 3
by GC. The difference between conversion and yield corresponds to
the intermediate carbonyl compound present in the reaction medium.
2
b
] ratio = 1 : 2. Yield of the saturated alcohol determined
Cs CO
2
3
b
by GC. The difference between conversion and yield corresponds to
the intermediate carbonyl compound present in the reaction medium.
ca. 8% of 1-methoxy-4-propylbenzene was also formed.
c
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Chem. Commun., 2007, 2536–2538 | 2537

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{
We note that these reactions can be performed on a preparative scale.
Representative example: Under a N
2
atmosphere, a-vinylbenzyl alcohol
Me )} ] (0.067 g, 0.1 mmol), Cs CO
0.132 g, 0.4 mmol) and propan-2-ol (200 mL) were introduced into a
6
(2.68 g, 20 mmol), [{RuCl(m-Cl)(g -C
6
6
2
2
3
(
Schlenk flask and the reaction mixture stirred at 82 uC for 15 h (almost
quantitative yield by GC). After removal of the solvent under vacuum,
flash chromatography (silica gel) of the residue using a mixture of EtOAc/
hexane (1 : 10) as eluent afforded 2.45 g (17.99 mmol) of analytically pure
1-phenyl-1-propanol (90% yield).
§
corresponding allylic alcohol (5 mmol), [{RuCl(m-Cl)(g -C
General procedure for the catalytic reactions in water: In a sealed tube, the
6
6 6 2
Me )} ] (0.025–
Scheme 3 Reduction of allylic alcohols using water as the solvent.
0.125 mmol, 1–5 mol% of Ru) and NaO CH (5.15 g, 75 mmol) were mixed
2
in water (10 mL) under an inert atmosphere. The reaction mixture was then
stirred at 100 uC for the indicated time.
compound presents two carbon–carbon double bonds, only
isomerization of the CLC in a-position with respect to the alcohol
group takes place, affording 3,7-dimethyl-6-octen-1-ol selectively.
Transition metal-catalyzed organic transformations in aqueous
media have attracted much attention in recent years since, from an
environmental perspective, water is the most benign and
1
(a) Ruthenium Catalysts and Fine Chemistry, ed. C. Bruneau and P. H.
Dixneuf, Springer-Verlag, Berlin, 2004; (b) Ruthenium in Organic
Synthesis, ed. S.-I. Murahashi, Wiley-VCH, Weinheim, 2004.
For a review on Ru-catalyzed tandem processes, see: C. Bruneau,
S. D e´ rien and P. H. Dixneuf, Top. Organomet. Chem., 2006, 19, 295.
For a highly formative review on tandem catalysis, see: D. E. Fogg and
E. N. dos Santos, Coord. Chem. Rev., 2004, 248, 2365.
2
3
10
inexpensive solvent known. This fact prompted us to explore
6
the ability of complex [{RuCl(m-Cl)(g -C
6
Me
6
)}
2
] to perform the
4 For general reviews on the catalytic isomerization of allylic alcohols, see:
a) R. Uma, C. Cr e´ visy and R. Gr e´ e, Chem. Rev., 2003, 103, 27; (b)
R. C. van der Drift, E. Bouwman and E. Drent, J. Organomet. Chem.,
002, 650, 1. A number of highly efficient Ru catalysts have recently
(
reduction of allylic alcohols in water using sodium formate as the
1
1
hydrogen source (Scheme 3). § The preliminary results seem to
indicate that, in spite of the insolubility of the catalyst in water, the
reduction of the substrates can also be efficiently performed in
2
been described: (c) V. Cadierno, S. E. Garc ´ı a-Garrido and J. Gimeno,
Chem. Commun., 2004, 232; (d) M. Ito, S. Kitahara and T. Ikariya,
J. Am. Chem. Soc., 2005, 127, 6172; (e) B. Mart ´ı n-Matute, K. Bog a´ r,
M. Edin, F. B. Kaynak and J.-E. B a¨ ckvall, Chem.–Eur. J., 2005, 11,
1
2
aqueous media. Close examination of the reaction mixtures
showed that they were emulsions rather than homogeneous solu-
tions, the catalytic reaction probably taking place at the interface.
In summary, an operationally simple and highly efficient
procedure for selective reduction of the CLC bond of allylic
alcohols has been developed. This one-pot catalytic transforma-
5832; (f) V. Cadierno, S. E. Garc ´ı a-Garrido, J. Gimeno, A. Varela-
A´ lvarez and J. A. Sordo, J. Am. Chem. Soc., 2006, 128, 1360; (g)
P. Crochet, M. A. Fern a´ ndez-Z u´ mel, J. Gimeno and M. Scheele,
Organometallics, 2006, 25, 4846.
5
6
TH of carbonyl compounds is one of the most studied Ru-catalyzed
transformations: (a) S. E. Clapman, A. Hadzovic and R. H. Morris,
Coord. Chem. Rev., 2004, 248, 2201; (b) S. Gladiali and A. Alberico,
Chem. Soc. Rev., 2006, 35, 226.
Examples of the metal-catalyzed hydrogenation of allylic alcohols can
be found in: (a) H. Takaya, T. Ohta, S. Inoue, M. Katimura and
R. Noyori, Org. Synth., 1995, 72, 74; (b) Y. Sun, C. Le Blond, J. Wang,
D. G. Blackmond, J. Laquidara and J. R. Sowa, Jr., J. Am. Chem. Soc.,
tion, using the readily available ruthenium(II) dimer
6
{RuCl(m-Cl)(g -C
[
6
Me
6
)}
2
], is based on an unprecedented tandem
process involving the initial isomerization of the allylic alcohol into
the corresponding carbonyl compound and subsequent transfer
hydrogenation of the latter. We are confident that this simple
methodology will be of interest to a wide range of synthetic
organic chemists since: (i) it represents an appealing alternative to
1995, 117, 12647; (c) D. G. Blackmond, A. Lightfoot, A. Pfaltz,
T. Rosner, P. Schnider and N. Zimmermann, Chirality, 2000, 12, 442.
Both individual steps, i.e. allylic alcohol isomerization and TH of the
carbonyl intermediate, require the use of a base as a co-catalyst to
promote the formation of the corresponding hydride–ruthenium
complexes, which are the real catalytically active species in both
7
6,12
classical CLC hydrogenation using H2(g)
and (ii) provides an
efficient synthetic approach that allows the use of aqueous reaction
media. Efforts to assess the scope, limitations and mechanism of
transformations (see ref. 4 and ref. 5). Several bases (Li
CO , Cs CO , LiOH?H O, NaOH, KOH, CsOH?H O, NaO Bu and
KO Bu) and [Ru] : [base] ratios (from 1 : 1 to 1 : 24) have been checked;
the best results being obtained when Cs CO was used as a co-catalyst
optimal [Ru] : [Cs CO ] ratios = 1 : 2, 1 : 3 and 1 : 4). As expected, low
conversions (,15%) were observed in all cases in the absence of base.
2 3 2 3
CO , Na CO ,
this catalytic reaction are now in progress. The intriguing ability of
6
the water-insoluble precatalyst [{RuCl(m-Cl)(g -C
t
K
2
3
2
3
2
2
t
6
Me
6
)}
2
] to
efficiently promote the tandem process in aqueous media deserves
a more detailed study.
2
3
(
2
3
This work was supported by the Spanish Ministerio de
Educaci o´ n y Ciencia (MEC, project BQU2003-00255) and
FICYT of Asturias (project IB05-035). N. N. and V. C. thank
MEC for the award of a PhD grant and a Ram o´ n y Cajal
contract, respectively.
3
2
3
3
3
8
9
2 2
Using [RuCl (g :g :g -C12H18)] and [{RuCl(m-Cl)(g :g -C10H16)} ] as
21 21
catalysts, TOF values of 429 h and 3000 h , respectively, were
attained in the isomerization of 1-octen-3-ol into octan-3-one in
refluxing THF (0.2 mol% Ru, 0.4 mol% of Cs CO
2
3
). Under the same
6
reaction conditions, [{RuCl(m-Cl)(g -C Me )} ] lead to a TOF value of
6 6 2
21
only 125 h . See ref. 4f.
It is well known that the isomerization of allylic alcohols becomes more
difficult as the number of substituents increases on the CLC double
bond, requiring longer reaction times and/or higher catalyst loadings.
See ref. 4.
Notes and references
{ General procedure for the catalytic reactions: In a Schlenk flask fitted with
a condenser, the corresponding allylic alcohol (2 mmol), the ruthenium
10 For recent reviews, see: (a) C.-J. Li, Chem. Rev., 2005, 105, 3095; (b)
C.-J. Li and L. Chen, Chem. Soc. Rev., 2006, 35, 68.
11 NaO CH is the most popular hydrogen source (it also acts as base) used
2
6
catalyst precursor [{RuCl(m-Cl)(g -C
of Ru) and Cs CO (0.04–0.2 mmol, 2–10 mol%) were dissolved in propan-
-ol (20 mL) under an inert atmosphere. The reaction mixture was then
6 6 2
Me )} ] (0.01–0.05 mmol, 1–5 mol%
2
3
2
in the aqueous TH of carbonyl compounds. See ref. 5.
stirred at 82 uC for the indicated time, the course of the reaction being
monitored by regular sampling and analysis by GC. The identity of the
resulting saturated alcohols, as well as the carbonyl intermediates, was
assessed by comparison with commercially available, or independently
synthesized (following reported procedures), pure samples and by their GC/
MS fragmentation.
12 (a) A related Ru-catalyzed isomerization/hydrogenation tandem process
in an aqueous medium has been reported: P. Csabai and F. Jo o´ ,
Organometallics, 2004, 23, 5640; (b) The Ru-catalyzed reduction of
4
alkenes using NaBH has been recently described: G. R. A. Adair,
K. K. Kapoor, A. L. B. Scolan and J. M. J. Williams, Tetrahedron Lett.,
2006, 47, 8943.
2
538 | Chem. Commun., 2007, 2536–2538
This journal is ß The Royal Society of Chemistry 2007