The α-alkylation of methyl ketones with primary alcohols promoted by nickel nanoparticles under mild and ligandless conditions

Article abstract of DOI:10.1055/s-2007-984522

Nickel nanoparticles have been found to promote the α-alkylation of ketones with primary alcohols in the absence of any added ligand or base, under mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984522

LETTER
1877
The a-Alkylation of Methyl Ketones with Primary Alcohols Promoted by
Nickel Nanoparticles under Mild and Ligandless Conditions
a-Alkylation
o
r
f
Methy
a
l
Ketones ncisco Alonso,* Paola Riente, Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Química Orgánica (ISO), Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain
Fax +34(96)5903549; E-mail: falonso@ua.es; E-mail: yus@ua.es
Received 25 April 2007
Dedicated to the memory of Professor Yoshihiko Ito
contributions and ideas that can broaden the knowledge
Abstract: Nickel nanoparticles have been found to promote the
and applications of this reaction are welcome. In this
sense, the search for new catalytic systems involving the
cheaper non-noble metals directed to larger-scale process-
es should be a priority.
a-alkylation of ketones with primary alcohols in the absence of any
added ligand or base, under mild reaction conditions.
Key words: a-alkylation, ketones, primary alcohols, nickel, nano-
particles
On the other hand, we have recently reported the fast syn-
thesis of nickel(0) nanoparticles from different nickel(II)
chloride containing systems by reduction with lithium
powder and a catalytic amount of an arene in THF at room
temperature.8 The high reactivity and versatility of these
nanoparticles was demonstrated in the reduction of a wide
variety of functional groups9 as well as in the highly selec-
tive semihydrogenation of alkynes and dienes,10 and in the
conjugate reduction of a,b-unsaturated carbonyl com-
pounds,11 in all the cases under mild reaction conditions.
In the two latter applications an alcohol was used as a
source of hydrogen, some experiments showing that, at
least in part, a transfer hydrogenation was involved in
these reductions. Therefore, we envisaged the possibility
of application of these nickel nanoparticles to the a-alky-
lation of ketones with primary alcohols.
Among the different methods available for the synthesis
of ketones, the a-alkylation of ketone enolates with alkyl
halides is probably the most frequently used one.1 In the
last five years, however, an increasing interest has been
devoted to the transition-metal-catalyzed a-alkylation of
ketones with primary alcohols, as an alternative strategy
that can improve the regioselectivity of the process at the
time that produces only water as a side product.2 This field
seems to be restricted to catalysts containing some noble
metals, such as ruthenium, iridium, and palladium. For in-
stance, Cho et al. successfully utilized RuCl2(PPh3)33a and
Pd/C3b for the a-alkylation of aromatic and aliphatic
ketones with primary alcohols under homogeneous and
heterogeneous conditions, respectively. However, the ad-
dition of a sacrificial hydrogen acceptor (1-dodecene or 1-
decene) was necessary in order to prevent the over-reduc-
tion of the alkylated ketone. Complex [RuCl2(DMSO)4]
did not require such an additive, but it is not commercially
available and its reactivity was limited to the a-alkylation
of aryl methyl ketones with benzylic alcohols.4 The hete-
rogeneous palladium catalysts Pd/AlO(OH)5 (composed
of palladium nanoparticles entrapped in aluminum hy-
droxide) and Pd/viologen6 (palladium nanoparticles en-
trapped in a viologen polymer) were more efficient
because of the wide substrate scope, excellent product
yields and recyclability. All the catalytic systems men-
tioned above were used together with stoichiometric
amounts of a base (1–3 equiv). The rather expensive
iridium complex [Ir(cod)Cl]2 in the presence of PPh3 is the
only catalyst that was used with catalytic amounts of a
base (0.1–0.3 equiv), showing a high performance in the
absence of solvent.7
Since no mention of the use of nickel for the title reaction
was made in any of the publications handled, we carried
out a deep bibliographic search in order to be sure about
whether it was or it was not previously used. As the only
result, a Japanese patent described the preparation of
ketones from alcohols and methyl ketones in a reactor
containing some nickel catalysts at 180 °C.12
We report herein the first explicit application of nickel, in
the form of nanoparticles, to promote the fast a-alkylation
of ketones with primary alcohols in the absence of any
added ligand, hydrogen acceptor or base, under mild reac-
tion conditions.
We first focused on the reaction of acetophenone with
ethanol (Table 1). It is noteworthy that, to the best of our
knowledge, ethanol has never been used as an alkylating
agent in this type of reaction, perhaps because of its low
reactivity or because the reaction temperature applied
exceeded that of its boiling point. The nickel(0) nanopar-
ticles were generated from anhydrous nickel(II) chloride,
lithium powder and a catalytic amount of DTBB (4,4¢-
di-tert-butylbiphenyl) in THF at room temperature. As
shown in Table 1, the progressive increase in the amount
of ethanol improved the yield of 3 (entries 1–3), the best
result being obtained when using a large excess of ethanol
Since the transition-metal-catalyzed a-alkylation of ke-
tones with primary alcohols is still in its infancy, new
SYNLETT 2007, No. 12, pp 1877–1880
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4
.0
7
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0
0
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Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984522; Art ID: D12807ST
© Georg Thieme Verlag Stuttgart · New York

1878
F. Alonso et al.
LETTER
Table 1 Reaction of Acetophenone with Ethanol Promoted by Nickel Nanoparticles in THF under Different Conditionsa
O
OH
O
Ni nanoparticles
THF
EtOH
+
+
Ph
Ph
Ph
1
2
3
4
Product (%)b
Entry
Ni (mmol)
Li (mmol)
EtOH
2 mmol
4 mmol
8 mmol
4 mL
Temp (° C)
Time (h)
3
4
1
1
2
3
4
5
6
7
8
1
1
1
1
1
2
2
2
2
4
2
2
2
76
76
76
76
76
76
76
r.t.
4
15
15
2
28
52
55
81
67
19
45
7
47
37
43
–
21
10
–
–
4 mL
2
23
–
–
0.1
4 mL
15
15
24
81
55
77
0.2
1
4 mL
–
4 mL
–
a Compounds 1 (1 mmol) and 2 were added to a suspension of the nickel(0) nanoparticles generated from NiCl2, lithium powder, and a catalytic
amount of DTBB (5%) in THF at r.t.
b GLC yield.
(entry 4) and stoichiometric amounts of nickel and lithium in addition could be recovered. Acetone alkylation gave a
at 76 °C. In this case, the reaction was completed in only mixture of the mono- and dialkylated ketones in 23% and
2 hours. A slight decrease in the yield was observed by 27% isolated yields, respectively (entry 11).
adding 2 mmol excess of lithium in order to generate the
In order to compare our ketone alkylation methodology
corresponding alkoxide (entry 5). The alkylation also pro-
with the other methods previously appeared in the litera-
ceeded with catalytic amounts of nickel but it was much
ture,3–7 we selected the alkylation of acetophenone with
slower and did no go to completion (entries 6 and 7, see
benzyl alcohol as the only example commonly studied in
the comments below). Product 3 was formed even at room
all these reports. As shown in Scheme 1, our procedure
temperature (entry 8) albeit with a low conversion. It is
provided a high isolated yield of dihydrochalcone under
worthwhile mentioning that the alcohol derived from the
the mildest reaction conditions and in a relatively short re-
reduction of 3 was not detected in any of the experiments.
action time. The fact that no over-reduced product was de-
With these results in hand, we tried to extend this method- tected, together with the absence of any added base and
ology to other ketones and alcohols (Table 2). Thus, ace- use of common THF as a solvent, are additional advantag-
tophenone could be also alkylated very rapidly with n- es. We are aware that the use of stoichiometric instead of
propanol (used for the first time as alkylating agent) under catalytic amounts of nickel is a weakness of this method-
the same reaction conditions used for ethanol (entry 1), ology. We have got some evidence that this requirement
giving valerophenone in good yield (entry 2). Ethanol and is because the nanoparticles suffer some agglomeration
n-propanol are cheap and volatile alcohols and can be upon prolonged heating. Nonetheless, we believe that this
used in excess, whereas 4 mmol was found to be the opti- problem can, very probably, be overcome by stabilization
mum amount for benzyl alcohols. The reaction of ace- of the nanoparticles on a solid support.
tophenone with benzyl alcohol furnished dihydrochalcone
in high yield (entry 3), while moderate to good yields
O
O
conditions
were obtained for differently substituted benzyl alcohols
(entries 4 and 5). Acetophenone derivatives bearing elec-
tron-withdrawing or electron-donating groups were also
alkylated with benzyl alcohol in moderate yields (entries
6 and 713). Interestingly, the alkylation reaction could also
be applied to alkyl methyl ketones, though the yields
were, in general, more modest under the described reac-
tion conditions. The reactions were relatively fast for
three of the ketones (entries 8, 9, and 11) and much slower
for pinacolone (entry 10). At any rate, the resulting ke-
tones could be separated from the starting ketones, which
+
Ph
OH
Ph
Ph
Ph
82%3a
RuCl2(PPh3)3, KOH, 1-dodecene, dioxane 80 °C, 20 h
[Ir(cod)Cl]2-PPh3, KOH, solvent-free
Pd/C, KOH, dioxane, 1-decene
Pd/AlO(OH), K3PO4, toluene
100 °C, 4 h
100 °C, 20 h
80 °C, 8 h
80 °C, 24 h
86%7
66%3b
92%5
72%4
82%6
85%
[Ru(DMSO)4]Cl2, KOH, dioxane
Pd/viologen, Ba(OH)2·H2O, 7 equiv H2O 100 °C, 24 h
Ni nanoparticles, no added base, THF 76 °C, 6 h
Scheme 1 Reaction of acetophenone and benzyl alcohol with
different catalytic systems
Synlett 2007, No. 12, 1877–1880 © Thieme Stuttgart · New York

LETTER
a-Alkylation of Methyl Ketones
1879
Table 2 Reaction of Ketones with Alcohols Promoted by Nickel Nanoparticlesa
Entry
1
Ketone
Alcohol
Time (h)
2
Product
Yield (%)b
O
O
c
EtOH
81 (66)
84 (68)
Ph
O
Ph
O
2
3
n-PrOHc
2
6
Ph
O
Ph
O
92 (85)
70 (41)
Ph
Cl
OH
Ph
O
Ph
Ph
O
OH
4
5
6
7
8
6
Ph
Ph
Cl
O
O
OH
84 (71)
77 (51)
71 (42)
Ph
Ph
MeO
Ph
OMe
Ph
O
O
OH
OH
MeO
F3C
MeO
F3C
O
O
7
3
Ph
Ph
O
O
8
9
8
6
(36)
Ph
Ph
OH
OH
Ph
Ph
O
O
52 (59)
n-C5H11
n-C5H11
O
O
10
11
24
4
56 (22)
(27)d
Ph
OH
Ph
O
O
Ph
OH
Ph
Ph
a Ketone (1 mmol), alcohol (4 mmol), Ni nanoparticles (1 mmol), THF, 76 °C.
b GLC yield, isolated yield in parenthesis.
c 4 mL of alcohol.
d The monoalkylation product 4-phenylbutan-2-one was isolated in 23% yield.
In conclusion, we have demonstrated for the first time that
nickel, in the form of nanoparticles, is a potential alterna-
tive to the use of noble-metal-based catalysts for the a-
alkylation of ketones with alcohols. The reaction proceeds
in short reaction times and in the absence of any added
ligand or base, under mild conditions.14 This discovery
opens up the possible application of nickel for this reac-
tion at an industrial scale. Further studies on the scope and
applications of this methodology and on the reaction
mechanism are under way.
Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC; grant no. CTQ2004-01261) and the
Generalitat Valenciana (GV; grants no. GRUPOS03/135 and
GV05/005). P.R. thanks the MEC for a predoctoral grant.
References and Notes
(1) (a) Caine, D. In Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M.; Fleming, I.; Pattenden, G., Eds.; Pergamon:
Oxford, 1991, 1–63. (b) Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000.
(2) For a recent review, see: Guillena, G.; Ramón, D. J.; Yus, M.
Angew. Chem. Int. Ed. 2007, 46, 2358.
Synlett 2007, No. 12, 1877–1880 © Thieme Stuttgart · New York

1880
F. Alonso et al.
LETTER
(3) (a) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C.
Tetrahedron Lett. 2002, 43, 7987. (b) Cho, C. S. J. Mol.
Catal. A: Chem. 2005, 240, 55.
(4) (a) Martínez, R.; Brand, G. J.; Ramón, D. J.; Yus, M.
Tetrahedron Lett. 2005, 46, 3683. (b) Martínez, R.; Ramón,
D. J.; Yus, M. Tetrahedron 2006, 62, 8988.
(5) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R.
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corresponding alcohol (4 mmol for benzyl alcohols, 4 mL
for EtOH and n-PrOH) and the ketone (1 mmol) were
consecutively added. The reaction mixture was warmed to
76 °C and monitored by GLC-MS until total or steady
conversion of the starting material. The resulting suspension
was filtered through a pad containing Celite®, the filtrate was
washed with 2 M HCl (2 × 20 mL) and dried over MgSO4.
The residue obtained after removal of the solvent (15 torr)
was purified by column chromatography (silica gel, hexane–
EtOAc) to give the pure alkylated ketone.
Butyrophenone and valerophenone were characterized by
comparison of their physical and spectroscopic data with
those of commercially available samples (Aldrich). 3-(4-
Methoxyphenyl)-1-phenylpropan-1-one,15 (4-chloro-
phenyl)-1-phenylpropan-1-one,15 1-(4-methoxyphenyl)-3-
phenylpropan-1-one,16 1-(4-trifluoromethylphenyl)-3-
phenylpropan-1-one,17 1-phenylhexan-3-one,18 1-phenyl-
octan-3-one,19 and 1-phenyl-4,4-dimethylpentan-3-one20
were characterized by comparison of their physical and
spectroscopic data with those described in the literature.
(15) Cho, C. S.; Shim, S. C. J. Organomet. Chem. 2006, 691,
4329.
(16) Goosen, L. J.; Ghosh, K. Eur. J. Org. Chem. 2002, 3254.
(17) Spogliarich, R.; Farnetti, E.; Graziani, M. Tetrahedron 1991,
47, 1965.
(18) Cabello, J. A.; Campelo, J. M.; García, A.; Luna, D.;
Marinas, J. M. J. Org. Chem. 1986, 51, 1786.
(13) It must be pointed out that the alkylated ketone in entry 7 was
not obtained (0% yield) by using the complex
[RuCl2(dmso)4].4
(14) General Procedure for the a-Alkylation of Ketones with
Primary Alcohols
Nickel(II) chloride (130 mg, 1 mmol) was added over a
suspension of lithium (14 mg, 2 mmol) and DTBB (13 mg,
0.05 mmol) in THF (2 mL) at r.t. under argon. The reaction
mixture, which was initially dark blue, changed to black
indicating that nickel(0) was formed. After 10 min, the
(19) Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002, 67,
935.
(20) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57,
4817.
Synlett 2007, No. 12, 1877–1880 © Thieme Stuttgart · New York

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