[Ru(DMSO)4] Cl2 catalyzes the α-alkylation of ketones by alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.03.158

The electrophilic α-alkylation of ketones with alcohols was accomplished by a [Ru(DMSO)₄]Cl₂ catalyzed process, water being the only wasted material. The reaction can be successfully governed to produce either the expected ketones or their related alcohols only by changing the reaction conditions. When 2-aminobenzyl alcohol was used, a cyclization process took place to yield 2,3-disubstituted quinolines.

Full text of DOI:10.1016/j.tetlet.2005.03.158

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3683–3686
[Ru(DMSO)4]Cl2 catalyzes the a-alkylation of ketones by alcohols
ꢀ
*
´ ´
Ricardo Martınez, Gabriel J. Brand, Diego J. Ramon and Miguel Yus
´ ´ ´ ´
Instituto de Sıntesis Organica y Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Alicante,
Apdo. 99, E-03080-Alicante, Spain
Received 14 February 2005; revised 21 March 2005; accepted 22 March 2005
Available online 6 April 2005
Abstract—The electrophilic a-alkylation of ketones with alcohols was accomplished by a [Ru(DMSO)4]Cl2 catalyzed process, water
being the only wasted material. The reaction can be successfully governed to produce either the expected ketones or their related
alcohols only by changing the reaction conditions. When 2-aminobenzyl alcohol was used, a cyclization process took place to yield
2,3-disubstituted quinolines.
Ó 2005 Elsevier Ltd. All rights reserved.
The carbon–carbon bond formation is placed, without
any doubt, as the pivotal method in organic synthesis,1
especially, the a-alkylation of carbonyl compounds with
different electrophiles (e.g., alkyl halides).2 However, the
classical protocols of this reaction create some problems
(e.g., LDA, dry THF, alkyl tosylate, etc., Scheme 1), not
only from a synthetic but also from an economic and an
environmental point of view. Among them, one of the
major drawbacks is the low atom economy or effi-
ciency,3 due to the use of strong bases with high molec-
ular weight and the loss of the leaving group of the
electrophile.
from the living group and base sometimes make the clas-
sical alkylation methods not very practical for industrial
use.
In the recent past, the realm of transition metal organic
chemistry has provided us with excellent reagents able to
overcome these classical problems. The ruthenium king-
dom is one of them. Its chemistry has a variety of useful
characteristics including high electron transfer ability,
high coordination levels, Lewis acid activity and low re-
dox potentials. Consequently, a large number of novel
and useful reactions are beginning to be developed using
both stoichiometric and catalytic amounts of different
complexes.4 Moreover, the relative low toxicity of ruthe-
nium salts,5 when they are compared with other heavy
metal salts,6 has permitted their use for the catalytic
elimination of organic toxics7 and as drugs for the treat-
ment of cancer.8 All these facts explain the great interest
of the organic chemistry community for ruthenium
chemistry.
On the other hand, the problems with the waste and, of
course, with the unavoidable inorganic salts derived
O
O
1) LiN(Pri)2, dry THF
2) R3OTs
R2
R2
R1
R1
R3
We present in this letter the use of [Ru(DMSO)4]Cl29 as
an efficient catalyst for the a-alkylation of ketones using
alcohols as electrophiles. The alcohols are generally not
used as electrophilic alkylating agents due to the high
energy of C–O bond (ꢀ90 kcal/mol). Moreover, under
the normal basic reaction conditions employed in enol-
ate alkylations, alcohols are transformed into alkoxide
reducing the normal poor leaving group character of
the oxygen. However, alcohols can be converted into
electrophilic systems by their transformation into the
corresponding sulfonic esters or halides.10 Another pos-
sibility is their transformation into the corresponding
Mw of final Product
(Mw of all reagents)i
Atom Efficiency =
Σ
i
Scheme 1.
Keywords: C–C bond forming; Alkylation; Ruthenium catalysis;
Ketones; Quinolines.
*
Corresponding author. Tel.: +35 965 90 35 48; fax: +35 965 90 35
49; e-mail: yus@ua.es
ꢀ Undergraduate student from Albert-Ludwigs-Universita¨t Freiburg.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.158

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R. Martınez et al. / Tetrahedron Letters 46 (2005) 3683–3686
3684
O
aldehydes, which have a clear electrophilic character.
With these considerations in mind, we mixed equimolec-
ular amounts of acetophenone, benzyl alcohol and
KOH in the presence of a catalytic amount of [Ru(DM-
Ar
Ar
HO
R
OH-
[Ru]
2
1
11
SO)4]Cl2 (2%) with the hope that ruthenium species
would oxidize the alcohol to the corresponding electro-
philic aldehyde12 and it could condense with the ketone
under the reaction conditions. To our delight, after a
few hours at dioxane reflux, the MS–GC analysis of
reaction mixture showed the presence of expected 1,3-di-
phenyl-1-propanone (3a), as well as the other by-products
in different amounts, such as 1,3-diphenyl-1-propanol,
benzaldehyde, 1-phenylethanol and chalcone.
H2O
O-
H
O
R
5
4
O
[Ru-H2]
OH-
Ar
R
6
3
The optimization of reaction conditions for the prepar-
ation of ketone 3a, such as base (KOH, CsOH, Et3N,
none), solvent (1,4-dioxane, THF, water, MeCN,
DMF, CH2Cl2), extra ligand (pyridinedicarboxylic acid)
and temperature showed a maximum under the condi-
tions depicted in Table 1. Other reaction conditions
either gave a very low yield or failed.
O
[Ru]
Ar
R
Scheme 2.
The reaction gave excellent results for methyl aryl ke-
tones 1 and arylmethanol derivatives 2, the correspond-
ing alkylated ketone 3 being in some cases the only
product detected. The results were very homogeneous
independently on functionalities on the aromatic ring.
In the case of using p-trifluoromethylacetophenone (Ta-
ble 1, entry 8), instead of obtaining the expected ketone,
the main product isolated (48%) was the corresponding
alcohol arising from the reduction of the expected ke-
tone 3, probably due to the higher electrophilic charac-
ter of this electron-withdrawing substituted ketone. For
this reason, the reaction was repeated with a double
amount of alcohol (which is at the same time the source
of reducing agents and the electrophile) giving the alco-
hol coming from the reduction of 3h with good yield.
The only by-product detected in the case of thiophene
derivatives 3j,k was the related alcohol coming from
the reduction of starting ketone 1.
All the above results, together with the observation of
different by-products of the reaction, drove us to pro-
pose the mechanism pathway depicted in Scheme 2, in
which the ruthenium species are able to oxidize the alco-
hol 2 to the corresponding aldehyde 4, yielding a hypo-
thetical ruthenium hydride. The aldol condensation
between this aldehyde and the enolate of ketone 5 (ob-
tained in turn by deprotonation of the ketone 1 by the
base or by reaction with the ruthenium hydride com-
plex)13 gave the a,b-unsaturated ketone 6, which is final-
ly reduced by the ruthenium hydride to yield alkylated
ketone 3, regenerating the starting ruthenium catalytic
species, which can start a new catalytic cycle. According
to this mechanistic pathway, the amount of KOH used
could be catalytic. However, when the reaction was per-
formed with lower amounts of base the yield dropped
drastically, showing that the base plays an extra un-
known role, probably, deprotonating the alcohol and/
or forcing the formation of alkoxy-ruthenium complex.
Table 1. Electrophilic a-alkylation of methyl aryl ketones using
alcohols
(2,1 eq)
R
HO
KOH (1 eq)
O
O
[Ru(DMSO)4]Cl2 (2 mol%)
Ar
Ar
R
Dioxane, 80 ºC
3
1
Entry
Ketone 3
No.
Ar
R
% Yielda
It should be pointed out that the waste material of the
reaction is water, which is a clear environmental friendly
compound and with a very low molecular weight. This
last fact makes the atom efficiency very high compared
with any other method of electrophilic alkylation, antici-
pating a very promising future for this strategy.14,15
1
a
b
c
d
e
f
Ph
Ph
Ph
2-BrC6H4
72
93
86
93
85
92
69
89b
87
45
41
2
3
Ph
3-BnOC6H4
4-MeOC6H4
4-ClC6H4
4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-(F3C)C6H4
2-C10H8
2-Thiophene
2-Thiophene
5
6
2-ClC6H4
3,4-(MeO)2C6H4
7
g
h
i
Another interesting point of this reaction appeared
when it was performed using 2-aminobenzyl alcohol
(2l). In this case, instead of the corresponding ketone
of type 3 quinolines 8 were isolated, which formally arise
from the internal condensation of the amine with the
carbonyl compound in the intermediate of type 6. The
first trial was performed using acetophenone and alco-
hol 2l, yielding the quinoline 8b in 70% yield. The
8
Ph
Ph
9
10
11
j
Ph
2-BrC6H4
k
a Isolated yields after column chromatography (silica gel: hexane/ethyl
acetate).
b Yield of the related alcohol when the reaction was performed using
2 equiv of benzyl alcohol.

´
R. Martınez et al. / Tetrahedron Letters 46 (2005) 3683–3686
3685
Table 2. Synthesis of quinolines 8 by condensation of ketones and
alochol 2l
Table 3. Sequential electrophilic a-alkylation and reduction of ketones
using alcohols
HO
R2
(2, 2 eq)
KOH (1 eq)
(2l, 1 eq)
PPh3 (2 mol%)
H2N
O
OH
[Ru(DMSO)4]Cl2 (2 mol%)
HO
R1
1, 7
R1
R2
KOH (1 eq)
Dioxane, 80 ºC
Ph2CO (1 eq)
R1
9
[Ru(DMSO)4]Cl2 (2 mol%)
O
N
Dioxane, 80 ºC
Entry
Alcohols 9
R2
R2
1, 7
R1
R2
No.
R1
% Yielda
8
1
2
3
4
a
b
c
But
Ph
Ph
Pri
Ph
25
35
45
78
Entry
Quinoline 8
n-C5H11
Ph
Ph
No.
R1
R2
% Yielda
d
1
2
3
4
5
6
7
a
b
c
d
e
f
–(CH2)4–
88
94
81
67
96
89
96
a Isolated yields after column chromatography (silica gel: hexane/ethyl
acetate).
Ph
Ph
Ph
H
Me
Et
H
4-MeC6H4
2-Furan
2-Thiophene
In this case, all kind of ketones can be used, although
the best results were obtained for alkyl aryl ketones, as
well as benzylic alcohols, yields are in general modest.
H
g
H
a Isolated yields after acid/base extraction.
In summary, the [Ru(DMSO)4]Cl2 is a very cheap, safe
and efficient catalyst to promote the unusual a-alkyl-
ation of ketones. This process constitutes a good exam-
ple of a very high atom efficiency reaction and provides
an alternative entry to the synthesis of quinolines.
analysis of the crude mixture showed the presence of 1-
phenylethanol, indicating that the in situ formed ruthe-
nium hydride is partially unable to restart the catalytic
cycle and should be oxidized. Different hydrogen scav-
enger systems, such as the own starting ketone, 1-hexene
or benzophenone were tested for avoiding this inconve-
nience. Similar results were obtained either using one
equivalent of benzophenone or a double amount of
the starting ketone, adopting the former scavenger
(Table 2).
Acknowledgements
This work was supported by Spanish Ministerio de
´
Educacion y Ciencia (project CTQ2004-01261) and by
the Ceneralitat Valenciana (project CTIDB/2002/318).
G.J.B. thanks the European Union for an Erasmus
fellowship (September 2003–February 2004).
The isolation of pure quinolines was very easy only
through an acid/base extraction. Under these new condi-
tions not only alkyl aryl ketones 1 but also a dialkyl
ketone 7 could be successfully used. Moreover, the reac-
tion can be performed with ketones with longer substitu-
ent than methyl, which could be evidence that the
condensation between the carbonyl group of the ketone
and the amine to form the corresponding imine takes
place prior to the aldol condensation and therefore
favouring it.
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