C-C Bond formation from alcohols using a Xantphos ruthenium complex

Article abstract of DOI:10.1016/j.tetlet.2006.07.069

A ruthenium complex of Xantphos has been shown to be a good catalyst for the alkylation of active methylene compounds with a range of alcohols.

Full text of DOI:10.1016/j.tetlet.2006.07.069

Tetrahedron Letters 47 (2006) 6787–6789
C–C Bond formation from alcohols using
a Xantphos ruthenium complex
Paul A. Slatford, Michael K. Whittlesey and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom
Received 19 June 2006; accepted 14 July 2006
Available online 4 August 2006
Abstract—A ruthenium complex of Xantphos has been shown to be a good catalyst for the alkylation of active methylene com-
pounds with a range of alcohols.
Ó 2006 Elsevier Ltd. All rights reserved.
The alkylation of activated methylene compounds is
commonly carried out with alkyl halides. Due to the
toxic and often mutagenic properties of these alkyl
halides, an attractive alternative is to use alcohols as
alkylating agents. We have recently demonstrated that
iridium and ruthenium catalysts can be used for the
formation of C–C bonds from alcohols via an indirect
Wittig reaction. In this chemistry, the metal catalyst bor-
rows hydrogen from the alcohol substrate 1, temporarily
forming an intermediate aldehyde 2, which undergoes a
transformation into alkene 3. The borrowed hydrogen is
then returned to the alkene to form the new C–C bond
in product 4, as shown in Scheme 1.
have alkylated nitriles4,5 and ketones6–8 using a similar
‘borrowing hydrogen’ strategy although there is often
a need for long reaction times, high catalyst loading,
or an excess of one of the coupling partners. We were
interested to find catalysts that would allow this ap-
proach to C–C bond-forming reactions to occur more
readily, and would avoid the formation of triphenyl-
phosphine oxide from the indirect Wittig chemistry.
1
2
We identified the reaction between benzyl alcohol 1a
and ketonitrile 5 as a model reaction for an oxidation-
Knoevenagel-reduction process to provide alkylated
product 6 (Scheme 2). As expected, the iridium catalysed
The conversion of the intermediate aldehyde into the
intermediate alkene can be achieved using methods
other than Wittig olefination. For example, we have
achieved an iridium catalysed alkylation of alcohols
O
O
catalyst, ligand
tBu
tBu
Ph
Ph
OH
toluene, reflux
CN
CN
1
a
5
6
3
using malonates and nitroalkanes. Other researchers
R'
R
OH
R
PPh2
PPh2
1
4
O
PR2
M
PPh2
PPh2
Fe
PR2
MH2
11
1
0
R = Ph, 7
R'
PPh3
i
R
O
R
Pr, 8
alkene
formation
OC
P
H
2
3
t
Bu, 9
Ru
O
H
P
Scheme 1. Borrowing hydrogen in the alkylation of alcohols.
PPh2
PPh2
1
2
13
*
Corresponding author. Tel.: +44 1225 383942; fax: +44 1225
86231; e-mail: j.m.j.williams@bath.ac.uk
3
Scheme 2. Reaction of benzyl alcohol 1a with ketonitrile 5.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.069

6788
P. A. Slatford et al. / Tetrahedron Letters 47 (2006) 6787–6789
a
a
Table 1. Comparison of ligands for C–C bond formation
Table 2. C–C bond formation using the Ru/Xantphos catalyst
Entry Metal
Ligand Time (h) Conversion (%)
Entry Alcohol Conversion (%) Yield (%)
(
loading, mol %)
1
2
3
4
5
6
7
8
PhCH
p-MeOC
p-FC
p-F CC
p-O NC
p-BrC
o-MeOC
Furfuryl alcohol, 1h
2
OH, 1a
CH
CH
CH
CH
CH OH, 1f
CH
100
OH, 1b 100
78
83
89
83
31
79
82
b
1
2
3
4
5
6
7
8
Ir (5)
Ru (5)
7
—
7
24
18
3
55
56
56
91
<1
22
8
6
H
4
2
6
H
4
2
OH, 1c
OH, 1d
OH, 1e
100
100
52
Ru (0.5)
Ru (0.5)
Ru (0.5)
Ru (0.5)
Ru (0.5)
Ru (0.5)
3
6
H
4
2
8
3
2
6
H
4
2
9
16
16
3
6
H
4
2
100
10
11
12
6
H
4
2
OH, 1g 100
11
Not isolated
3
100
a
Typical reaction conditions: Alcohol (1 equiv), ketonitrile 5 (1 equiv)
were treated with Ru(PPh (CO)H (0.5 mol %), ligand (0.5 mol %),
piperidinium acetate (5 mol %), PhMe, reflux, 4 h.
a
Typical reaction conditions: Benzyl alcohol 1a (1 equiv), ketonitrile 5
1 equiv) were treated with Ru(PPh
3
)
3
2
(
3 3 2
) (CO)H (0.5 mol %), ligand
(
0.5 mol %), piperidinium acetate (5 mol %), PhMe, reflux.
b
˚
2 2 3
(2.5 mol %), dppf 7 (5 mol %), K CO (5 mol %), 3 A
[
Ir(cod)Cl]
We chose to use 1 equiv of ligand with in situ generation
of catalyst as a convenient procedure for examining the
alkylation of other alcohols (Scheme 3). For benzylic
alcohols 1a–g, we allowed the reactions to run for 4 h,
to ensure complete reaction. As shown in Table 2, all
benzylic alcohols were fully converted into product with
the exception of p-nitrobenzyl alcohol 1e and furfuryl
alcohol 1h (entries 5 and 8, respectively). The oxidation
of p-nitrobenzyl alcohol 1e is retarded by the presence of
the electron-withdrawing nitro group, and we speculate
that the furyl ring may inhibit catalysis by chelation.
molecular sieves, piperidinium acetate (25 mol %), PhMe, reflux.
process that we had previously explored required high
catalyst loadings and long reaction times to achieve a
successful reaction (Table 1, entry 1). Variation of the
ligand with the iridium catalyst did not lead to any
improvement, and our attention turned to the use of
ruthenium-based complexes.
Whilst the use of Ru(PPh ) (CO)H offered no clear
3
3
2
improvement, we were pleased to find that the use of
dppf 7 as an additive provided a significantly more reac-
tive catalytic system. The more electron rich ferrocene-
based ligand 8 offered further improvement, but when
the tert-butyl analogue 9 was employed, the reaction
was very slow, presumably due to the steric require-
ments of this ligand. Application of other bidentate
ligands in this process identified the ligand Xantphos
We were pleased to find that this system could be ap-
plied to aliphatic alcohols (Table 3). Complete conver-
sion was achieved in 4 h, although a higher catalyst
loading was required, presumably due to the difficult
nature of these oxidations. Whilst 5 mol % catalyst
was routinely used, in the case of 2-phenylethanol we
have shown that complete conversion is still obtained
with a lower catalyst loading of 2.5 mol % (entry 3).
1
2 as an excellent choice for this reaction, and allowed
the alkylation process to occur within 3 h using only
.5 mol % of catalyst. Ligand 12 has been shown to en-
hance the reactivity of several transition metal catalysed
Other nucleophiles were examined for the alkylation of
benzyl alcohol (Scheme 4). Dibenzyl malonate 14a and
cyano ester 14b were alkylated in reasonable yields,
but required longer reaction times. Sulfone 14c afforded
product 16c along with the intermediate alkene 15c,
0
9
,10
reactions,
and is known to provide a wide bite angle
upon complexation. The addition of more than 1 equiv
of 12 to Ru(PPh ) (CO)H provided only a small bene-
3
3
2
1
4
15
which had not been hydrogenated. We and others
fit; 93% conversion was observed after 30 min using
equiv of ligand, whilst 98% conversion was obtained
have previously reported that alcohols can be oxidised
1
by a loss of H , and this may explain the oxidation
2
using 2 equiv of ligand under otherwise identical condi-
observed here.
tions. Ruthenium complex 13 was prepared by exchange
1
1
of phosphine ligands, and this pre-formed catalyst
gave 99% conversion in 30 min.
In summary, we have shown that the use of alcohols as
alkylating agents provides an attractive alternative to
conventional, often toxic, alkyl halides. Ketonitrile 5
has been alkylated with a range of alcohols giving excel-
Murahashi has reported that some ruthenium complexes
catalyse the condensation of activated nitriles with alde-
1
2
hydes, but in these reactions we found that piperidi-
nium acetate was needed to catalyse the condensation.
Other amines or ammonium acetates were found to be
a
Table 3. C–C bond formation using aliphatic alcohols
Entry Alcohol
Conversion (%) Yield (%)
1
3
inferior.
1
2
3
4
5
6
Furfuryl alcohol, 1h
100
100
100
100
72
—
87
85
69
76
PhCH
PhCH
2
CH
CH
2
OH, 1i
OH, 1i
b
2
2
O
O
Undecanol, 1j
Cyclopropyl methanol, 1k 100
Tryptophol, 1l 100
i
tBu
R
tBu
R
OH
CN
CN
a
Typical reaction conditions: Alcohol (1 equiv) and ketonitrile 5
1 equiv) were treated with Ru(PPh (CO)H (5 mol %), ligand
(5 mol %), piperidinium acetate (25 mol %), PhMe, reflux, 4 h.
1
5
6
(
3
)
3
2
Scheme 3. Alkylation of other alcohols with ketonitrile 5. Reagents
and conditions: (i) Ru(PPh (CO)H (0.5 mol %), Xantphos 12
0.5 mol %), piperidinium acetate (5 mol %), PhMe, reflux, 4 h.
b
3
)
3
2
3 3 2
Ru(PPh ) (CO)H (2.5 mol %), ligand (2.5 mol %), piperidinium
(
acetate (25 mol %), PhMe, reflux, 4 h.

P. A. Slatford et al. / Tetrahedron Letters 47 (2006) 6787–6789
6789
E'
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E'
Ph
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Ph
Ph
E
1
a
E
E
1
4a-c
1
5a-c
16a-c
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E = E' = CO Bn 14a
2
15a = 8%
15b = 19%
15c = 46%
16a = 78%
16b = 73%
16c = 45%
E = CN, E' = CO Et 14b
2
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Scheme 4. Use of other active methylene compounds in C–C bond
formation. Reagents and conditions: (i) Ru(PPh (CO)H (5 mol %),
Xantphos 12 (5 mol %), piperidinium acetate (25 mol %), PhMe,
reflux, 24 h. (ii) Ru(PPh (CO)H (2 mol %), Xantphos 12
2 mol %), piperidinium acetate (25 mol %), PhMe, reflux, 4 h.
3
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3
2
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3
)
3
2
(
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phosphine Xantphos 12 has a remarkable ligand acceler-
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Ru(P–P)(PAr )(CO)H complexes will be reported in due
course: Mahon, M. F.; Slatford, P. A.; Williams, J. M. J.;
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Acknowledgments
1
The authors wish to thank the EPSRC and Crystal
Faraday for funding.
1
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2