Alcohols for the α-alkylation of methyl ketones and indirect aza-wittig reaction promoted by nickel nanoparticles

Article abstract of DOI:10.1002/ejoc.200800729

Nickel nanoparticles have been found to activate primary alcohols used for the α-alkylation of ketones or in indirect aza-Wittig reactions. These processes involve hydrogen transfer from the alcohol to the intermediate α,β-unsaturated ketone or imine, respectively. All these reactions are carried out in the absence of any ligand, hydrogen acceptor or base under mild reaction conditions. For the first time nickel is employed as a potential alternative to noble-metal-based catalysts in both reactions. A reaction mechanism is proposed on the basis of some deuteration experiments. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800729

FULL PAPER
DOI: 10.1002/ejoc.200800729
Alcohols for the α-Alkylation of Methyl Ketones and Indirect Aza-Wittig
Reaction Promoted by Nickel Nanoparticles
Francisco Alonso,*[a] Paola Riente,[a] and Miguel Yus*[a]
Dedicated to Dr. Cecilio Márquez on the occasion of his retirement
Keywords: Alcohols / Ketone alkylation / Hydrogen transfer / Nickel nanoparticles / Aza-Wittig reactions
Nickel nanoparticles have been found to activate primary
alcohols used for the α-alkylation of ketones or in indirect
aza-Wittig reactions. These processes involve hydrogen
transfer from the alcohol to the intermediate α,β-unsaturated
ketone or imine, respectively. All these reactions are carried
out in the absence of any ligand, hydrogen acceptor or base
under mild reaction conditions. For the first time nickel is
employed as a potential alternative to noble-metal-based
catalysts in both reactions. A reaction mechanism is proposed
on the basis of some deuteration experiments.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
obtained in high yields. The presence of stoichiometric
amounts of a base (1–3 equiv.) was a common characteristic
for the catalytic systems mentioned above. As an exception,
however, catalytic amounts of a base (0.1–0.3 equiv.) to-
gether with PPh3 were used in the case of the rather expens-
ive iridium complex [Ir(COD)Cl]2. Interestingly, reactions
were performed at 100 °C in the absence of solvent with a
varied substrate scope.[7]
Introduction
The α-alkylation of ketone enolates with alkyl halides is
probably the most frequently used method for the synthesis
of ketones.[1] In recent years, however, alcohols have
emerged as potential alternative alkylating agents of
ketones by proper activation with a transition-metal cata-
lyst.[2] This strategy can improve both the atom efficiency
and the regioselectivity of the process producing only water
as a side product. Until recently, this research was carried
out only with catalysts containing some group-8 noble met-
als, such as ruthenium, iridium, and palladium. For in-
stance, the α-alkylation of aromatic and aliphatic ketones
with primary alcohols was successfully accomplished by
The aza-Wittig reaction is another important tool in or-
ganic synthesis directed towards the construction of acyclic
and cyclic compounds that has experienced a tremendous
development in recent years.[8] In this reaction, phosphaz-
enes (iminophosphoranes) react with carbonyl compounds,
in an analogous manner to phosphorus ylides in the Wittig
reaction, to give C=N bonds. To the best of our knowledge,
the conversion of alcohols into N-alkylanilines through an
indirect aza-Wittig reaction has been carried out only under
iridium catalysis by Williams et al.[9] In this research, sev-
eral benzylic alcohols reacted with N-(triphenylphosphor-
anylidene)aniline in the presence of 2 mol-% of [IrCl-
(COD)]2, 5 mol-% of 1,1Ј-bis(diphenylphosphanyl)ferro-
cene and K2CO3 at 110 °C for 24 h. Both the α-alkylation
of ketones and the indirect aza-Wittig reactions involve hy-
drogen transfer[10] from the starting alcohol to the interme-
diate α,β-unsaturated ketone and imine, respectively. This
process has been defined by some authors as a hydrogen
autotransfer process[2a] or a process in which hydrogen is
borrowed.[2b]
[3a]
Cho et al. with both RuCl2(PPh3)3 and Pd/C[3b] catalysts
at 80–100 °C in dioxane. The presence of a sacrificial hydro-
gen acceptor (1-dodecene or 1-decene) was, however, man-
datory in order to avoid the over-reduction of the alkylated
ketone. The non-commercially available complex
RuCl2(DMSO)4 was applied in the absence of a hydrogen
acceptor, albeit to the specific α-alkylation of aryl methyl
ketones with benzylic alcohols.[4] Wider substrate scope was
observed for the heterogeneous palladium catalysts Pd/
AlO(OH)[5] (composed of palladium nanoparticles en-
trapped in aluminum hydroxide) and Pd/viologen[6] (palla-
dium nanoparticles entrapped in a viologen polymer),
which could be recycled at the time that the products were
[a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
On the other hand, and due to our ongoing interest on
the study of active metals,[11] we have developed a mild
methodology for the fast synthesis of nickel(0) nanopar-
ticles, from different nickel(II) chloride-containing systems
Fax: +34-965903549
E-mail: falonso@ua.es
yus@ua.es
4908
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Reactions Promoted by Nickel Nanoparticles
in THF, using lithium powder and a catalytic amount of Table 1. Reaction of acetophenone with ethanol promoted by
NiNPs in THF under different conditions.[a]
an arene as reducing agent.[12] These nanoparticles found
application in many different functional group transforma-
tions, including the reduction of a wide variety of func-
tional groups,[13] the highly selective semihydrogenation of
alkynes and dienes,[14] conjugate reduction of α,β-unsatu-
rated carbonyl compounds,[15] homocoupling of aryl
iodides,[16] and more recently, in the hydrogen transfer re-
duction of carbonyl compounds[17] and reductive amination
of aldehydes.[18] Also recently, we communicated for the
first time that nickel, in the form of nanoparticles, can act
as a potential alternative to the use of noble-metal-based
catalysts for the α-alkylation of ketones with alcohols.[19]
These reactions proceed in short reaction times and in the
absence of any ligand, hydrogen acceptor or base, under
mild conditions.
Product [%][b]
En-
try
Ni
[mmol]
Li
[mmol]
EtOH
T
[°C]
t [h]
3
4
1
1
2
3
4
5
6
7
8
1
1
1
1
1
0.1
0.2
1
2
2
2
2
4
2
2
2
2 mmol 76
4 mmol 76
8 mmol 76
4
28
52
55
81
67
19
45
7
47
37
43
–
23
–
21
10
–
–
–
81
55
77
15
15
2
4 mL
4 mL
4 mL
4 mL
4 mL
76
76
76
76
r.t.
2
15
15
24
–
–
[a] 1 (1 mmol) and 2 were added to a suspension of the NiNPs
generated from NiCl2, lithium powder, and a catalytic amount of
DTBB (5%) in THF at room temp. [b] GLC yield.
We wish to report herein a more detailed study on the
α-alkylation of ketones with alcohols promoted by nickel
nanoparticles, including a mechanistic proposal based on
some deuterium labelling experiments, as well as the appli-
cation of these nanoparticles to the indirect aza-Wittig reac- their lower reactivity, compared to the benzylic alcohols, or
tion to give N-alkylated anilines.
in the reaction temperatures applied that exceeded those of
their boiling points. Ethanol and n-propanol were used in
large excess because they are cheap and volatile, 4 equiv.
was found to be the optimum amount for other alcohols.
Phenethyl alcohol was another aliphatic primary alcohol
Results and Discussion
The nickel(0) nanoparticles (NiNPs) were generated from tested in the alkylation of acetophenone to give 1,4-di-
anhydrous nickel(II) chloride, lithium powder and a cata- phenylbutan-1-one in moderate yield (entry 3). Acetophe-
lytic amount of DTBB (4,4Ј-di-tert-butylbiphenyl) in THF none was also subjected to the alkylation reaction with sev-
at room temperature, and used in the α-alkylation of aceto- eral benzylic alcohols. Thus, the reaction with benzyl
phenone with ethanol as a model reaction (Table 1). We alcohol furnished dihydrochalcone in high yield (entry 4),
first optimised the amount of ethanol, the yield of butyro- while moderate-to-good yields were obtained for 4-chlo-
phenone (3) increasing progressively with the amount of robenzyl alcohol, 4-methoxybenzyl alcohol, and furan-2-yl-
ethanol (entries 1–3). In these cases, however, important methanol (entries 5–7). Acetophenone derivatives bearing
amounts of 1-phenylethanol, from the reduction of the electron-donating or electron-withdrawing groups were also
starting ketone, were obtained. The best result was obtained alkylated with benzyl alcohol. 4-(Trifluoromethyl)acetophe-
with a large excess of ethanol (entry 4) and stoichiometric none reacted faster than 4-methoxyacetophenone due prob-
amounts of both nickel and lithium at 76 °C, the reaction ably to the higher acidity of the methyl hydrogens in the
being completed in only 2 h. In one of the experiments, former ketone (entries 8 and 9). It must be pointed out that
2 mmol excess of lithium were added in order to know 0% yield of the alkylated ketone in entry 8 was obtained
whether the lithium ethoxide in situ generated had any ef- by using the complex RuCl2(DMSO)4.[4] Interestingly, the
fect on the reaction course. A decrease in the yield was ob- alkylation reaction could be also applied to a variety of
served together with the formation of the reduced starting alkyl methyl ketones with benzyl alcohol, albeit the reaction
ketone (entry 5). Two attempts to use the NiNPs in catalytic with aliphatic non-benzylic alcohols failed. The reaction
amounts resulted in much slower reactions that did not go times and yields were shown to be dependent on the ketone
to completion (entries 6 and 7). Product 3 was formed even structure. Thus, the linear alkyl-substituted methyl ketones
at room temperature (entry 8) albeit with a low conversion (entries 10 and 11) reacted faster than the branched alkyl-
and long reaction time. It is worthy to note that, in contrast substituted (entries 12 and 13), the best yield being achieved
to other catalytic systems, we did not observe the formation in the case of 5-methylhexan-2-one (entry 12). In those
of the alcohol derived from the reduction of 3.
cases in which the yields were lower, the resulting ketones
We tried to extend this methodology to other ketones could be separated from the starting ketones by column
and alcohols (Table 2). Thus, valerophenone could be ob- chromatography, which, in addition, could be recovered. An
tained in a short reaction time and good yield by alkylation attempt to dialkylate acetone with benzyl alcohol gave a
of acetophenone with n-propanol (entry 2), under the same mixture of the mono- and dialkylated ketones in 23 and
reaction conditions used for ethanol (entry 1). It is note- 27% isolated yields, respectively (entry 14). Finally, the al-
worthy that, to the best of our knowledge, this is the first kylation of the α,β-unsaturated ketone (E)-non-3-en-2-one
time that both ethanol and n-propanol have been used as with benzyl alcohol afforded the corresponding saturated
alkylating agents of ketones. The reasons can be found in alkylated ketone in good yield (entry 15). In this case, the
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F. Alonso, P. Riente, M. Yus
FULL PAPER
Table 2. α-Alkylation of ketones with primary alcohols promoted by Ni nanoparticles.[a]
[a] Ketone (1 mmol), alcohol (4 mmol), NiNPs (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.
conjugate reduction in the expected product seems to be tions and in a relatively short reaction time. The fact that
very favoured since it was observed even when using an no over-reduced product was detected, together with the
equimolecular amount of the alcohol.
absence of any ligand, hydrogen acceptor, or added base, as
We tried to compare our ketone alkylation method with well as the use of common THF as a solvent, are additional
others previously reported in the literature.[3–7] The alky- advantages. The alkylation of alkyl methyl ketones with ali-
lation of acetophenone with benzyl alcohol was the only phatic non-benzylic alcohols is, however, better ac-
example commonly studied in all these reports. As it is complished with the palladium and iridium catalysts. Al-
shown in Scheme 1, our procedure led to a high isolated though the use of stoichiometric instead of catalytic
yield of dihydrochalcone under the mildest reaction condi- amounts of nickel is a weakness of this methodology, we
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Reactions Promoted by Nickel Nanoparticles
must take into account that nickel is 100-fold cheaper than
ruthenium (referred to the corresponding chlorides, Ald-
rich), the latter being the cheapest noble metals shown be-
low.
Scheme 3. Deuterium labelling experiments in the α-alkylation of
acetophenone with benzyl alcohol.
Scheme 1. Reaction of acetophenone with benzyl alcohol in dif-
ferent catalytic systems.
In the two first experiments, deuterium incorporation
was only observed at the α-position of the carbonyl group
in the product dihydrochalcone. Interestingly, the same deu-
terium percentage was obtained in both cases. From these
results in can be inferred that, in spite of the fact that no
external base was added, small amounts of the lithium
metal used for the generation of the NiNPs could react with
the alcohol, forming a catalytic amount of the correspond-
ing alkoxide. This alkoxide could generate the acetophe-
none enolate, which by a fast deuteration (protonation) and
deuterium-hydrogen scrambling would lead to an equilibra-
tion mixture. The fact that no deuterium incorporation was
observed at the beta position of dihydrochalcone in the ex-
periment with PhCH2OD is in agreement with the equili-
bration mixture being achieved for the starting ketone be-
fore the alkylation (see comments on the third experiment),
together with the possibility of a primary isotopic effect in
the scrambled alcohol dehydrogenation step.
The reaction mechanism of the herein described reac-
tions has been scarcely studied. In general, the α-alkylation
of ketones with primary alcohols is formally explained by
a sequence of reactions involving: (a) dehydrogenation of
the alcohol to give the aldehyde and the metal dihydride,
(b) base-promoted aldol condensation between the alde-
hyde and ketone, followed by dehydration, to furnish the
α,β-unsaturated ketone, and (c) chemoselective reduction of
the α,β-unsaturated ketone by hydrogen transfer from the
metal dihydride giving the alkylated ketone (Scheme 2).[3,7]
In a third experiment, the alkylation of acetophenone
with PhCD2OH yielded dihydrochalcone with 20 and 72%
D incorporation at the α- and β-positions, respectively. This
result is very much in agreement with the reaction mecha-
nism depicted in Scheme 4. According to this mechanism,
the oxidation of PhCD2OH would give the deuterated benz-
Scheme 2. Formal mechanism for the α-alkylation of ketones with
alcohols.
RuCl2(DMSO)4/KOH/dioxane is the only system for aldehyde PhCDO and nickel hydride-deuteride species. Al-
which the reaction mechanism has been studied in detail.[4b] dol condensation followed by dehydration would lead to β-
Thus, based on deuteration experiments, the authors con- deuterated chalcone, which would undergo reduction by
cluded that, after the aldol reaction, the reduction of the deuterium-hydrogen transfer from nickel. If we consider
carbon–carbon double bond in the α,β-unsaturated ketone that statistically the two modes of addition of D-H to the
occurred through a Michael-type process involving a ruthe- carbon–carbon double bond are equally possible, then a 1:1
nium enolate. In the case of our methodology with the mixture of the regioisomeric dideuterated products would
NiNPs the scenario is quite different since the reaction is be obtained. The overall deuterium incorporation at the α-
considered to take place under heterogeneous conditions, and β-positions of the product is very close to that observed
and consequently, it is more difficult to study. Nonetheless, experimentally. In view of these results, we can propose a
we carried out a series of experiments with different deute- general dihydride-type reaction mechanism in which the
rium-labelled components of the reaction that could pro- two hydrogen atoms of the alcohol (the α-C–H to the O
vide any evidence about the reaction mechanism. In par- atom and the O–H) become equivalent after being transfer-
ticular, we studied the reaction of acetophenone with benzyl red to the metal. This proposal is consistent with the results
alcohol-OD (PhCH2OD), α,α,α-trideuterioacetophenone obtained in the hydrogen-transfer reduction of carbonyl
(PhCOCD3) with benzyl alcohol, and acetophenone with compounds promoted by NiNPs using 2-propanol as hy-
α,α-dideuteriobenzyl alcohol (PhCD2OH) under the above drogen donor, where the same type of mechanism was pro-
reaction conditions (Scheme 3).
posed.[17a]
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F. Alonso, P. Riente, M. Yus
FULL PAPER
Table 3. Indirect aza-Wittig reaction of alcohols with N-(triphenyl-
phosphoranilidene)aniline.[a]
Scheme 4. Theoretical deuterium incorporation in the α-alkylation
of acetophenone with PhCD2OH based on a dihydride-type mecha-
nism.
[a] Alcohol (1 mmol), Ph3P=NPh (1.1 mmol), NiNPs (1 mmol),
THF, 76 °C. [b] Isolated yield. [c] 2 mmol of EtOH were used.
Based on a similar type of chemistry, we also studied the
reactivity of the NiNPs in the indirect aza-Wittig reaction.
In this case, a series of primary alcohols were treated with
commercially available N-(triphenylphosphoranylidene)ani-
line, under similar reaction conditions as those described
for the α-alkylation of ketones (Table 3). In general, longer
reaction times were needed to afford the corresponding N-
alkylanilines in modest yields. A variety of representative
primary alcohols were studied, benzyl alcohol reacting
faster probably due to the more favoured formation of the
intermediate benzaldehyde (entry 1). Other substrates such
as linear alkyl- (entries 2 and 3), branched alkyl- (entry 4),
or cycloalkyl-substituted (entry 5) alcohols gave the ex-
pected secondary amines in isolated yields around 50%. In
the case of 4-methylpent-3-en-1-ol, the saturated alkyl-sub-
stituted N-(4-methylpentyl)aniline was obtained (entry 6).
It is worthy of note that, so far, this type of reaction had
only been reported under iridium catalysis.[9] Although the
yields achieved with the NiNPs are lower than those with
complex [IrCl(COD)]2, the substrate scope is wider, the re-
action conditions are milder and the reaction system is sim-
pler.
Scheme 5. General reaction pathway for the indirect aza-Wittig re-
action of alcohols with N-(triphenylphosphoranylidene)aniline.
The starting materials were recovered unchanged in the al-
kylation reaction of acetophenone with benzyl alcohol,
either with Raney Ni or with Ni/Al2O3, under the reaction
conditions reported for the NiNPs (THF, 76 °C, 24 h). A
mixture of products, including aniline (8%), the starting
alcohol (56%), the corresponding imine (4%) and amine
(2%), was obtained in the indirect aza-Wittig reaction of
benzyl alcohol with N-(triphenylphosphoranylidene)aniline
using Raney Ni, whereas no reaction was observed with
Ni/Al2O3.
Based on the above mechanistic proposal, a similar reac-
tion pathway can be invoked for the indirect aza-Wittig re-
action (Scheme 5). In this case, the in situ generated alde-
hyde would undergo an aza-Wittig reaction with N-(tri-
phenylphosphoranylidene)aniline to give the corresponding
imine. Trace amounts of the imine have been detected in
Conclusions
We have reported, for the first time, the use of nickel
some of the experiments. Reduction of the imine by hydro- for the activation of primary alcohols in the α-alkylation of
gen transfer from the alcohol mediated by the NiNPs would ketones and in the indirect aza-Wittig reaction. The nickel
provide the expected N-alkylated aniline. The transfer hy- metal used, in the form of nanoparticles, has shown to be
drogenation of imines, generated in situ from amines and a potential alternative in these reactions to noble-metal cat-
aldehydes (reductive amination), has been recently reported alysts such as those derived from palladium, ruthenium, or
by us under the catalysis of NiNPs and using 2-propanol iridium. A variety of acetophenones have been successfully
as a hydrogen source.[18]
alkylated with aliphatic and benzylic alcohols to give the
Finally, we compared the reactivity of the NiNPs with corresponding products in moderate-to-high yields. It is
two common and commercially available nickel catalysts, noteworthy that ethanol and n-propanol have been used for
Raney Ni and Ni/Al2O3, in the above described reactions. the first time as alkylating agents in this reaction. The alky-
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Reactions Promoted by Nickel Nanoparticles
General Procedure for the Indirect Aza-Wittig Reaction of Alcohols
with N-(Triphenylphosphoranilidene)aniline: N-(Triphenylphos-
phoranilidene)aniline (389 mg, 1.1 mmol) and the corresponding
alcohol (1 mmol) were consecutively added to the NiNPs suspen-
sion, prepared as described for the α-alkylation of ketones. The
reaction mixture was warmed up to 76 °C and monitored by GLC-
MS until total or steady conversion of the starting material. The
resulting suspension was diluted with Et2O (20 mL), filtered
through a pad containing celite, and the filtrate was dried with
MgSO4. The residue obtained after removal of the solvent (15 Torr)
lation of alkyl methyl ketones was, in general, less efficient
and could only be applied to benzylic alcohols. The NiNPs
have also found application in the indirect aza-Wittig reac-
tion of alcohols with an iminophosphorane, leading to N-
alkylated anilines in moderate yields but with a wider sub-
strate scope, milder reaction conditions, and simpler reac-
tion system than under iridium catalysis. Deuterium label-
ling experiments have brought some evidence about a dihy-
dride-type reaction mechanism operating in these reactions.
Furthermore, the NiNPs have shown to be superior to was purified by column chromatography (silica gel, hexane/EtOAc)
to give the pure N-alkylaniline.
other common nickel catalysts in the two processes de-
scribed herein, which, in addition, proceed in the absence
of any hydrogen acceptor, ligand, or added base.
N-Benzylaniline, N-ethylaniline, N-hexylaniline, and N-isopentyl-
aniline were characterised by comparison of their physical and
spectroscopic data with those of commercially available samples
(Aldrich). N-(Cyclopentylmethyl)aniline[29] and N-(4-methylpentyl)-
aniline[30] were characterised by comparison of their physical and
spectroscopic data with those described in the literature.
Experimental Section
General Remarks: Anhydrous nickel(II) chloride (Aldrich), lithium
powder (MEDALCHEMY S. L.), and DTBB (4,4Ј-di-tert-butylbi-
phenyl, Aldrich) were commercially available. All the starting mate-
rials were commercially available of the best grade (Aldrich, Acros,
Alfa Aesar) and were used without further purification. THF was
directly used without any purification (Fluka, 99.9%). All reactions
were carried out under an Ar atmosphere. Benzyl alcohol-OD
(PhCH2OD) was prepared by stirring benzyl alcohol with an excess
of deuterium oxide for 1 h, followed by extraction with diethyl
ether, drying with anhydrous magnesium sulfate and solvent evapo-
ration. α,α,α-Trideuterioacetophenone (PhCOCD3) was prepared
by hydrogen-deuterium exchange with D2O in the presence of KOH
at room temperature.[20] α,α-Dideuteriobenzyl alcohol (PhCD2OH)
was prepared by reduction of methyl benzoate with lithium alumi-
num deuteride in THF at 0 °C.[21] Flash column chromatography
was performed using silica gel 60 of 40–60 microns.
Acknowledgments
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC) (grants no. CTQ2004-01261 and
CTQ2007-65218), Consolider Ingenio, (2010-CSD2007-00006),
and the Generalitat Valenciana (G. V.) (grants no. GRUPOS03/135
and GV05/005). P. R. thanks the MEC for a predoctoral grant.
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General Procedure for the α-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 room temperature under argon. The
reaction mixture, which was initially dark blue, changed to black
indicating that the NiNPs suspension was formed. After 10 min,
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EtOH and n-PrOH) and the ketone (1 mmol) were consecutively
added. The reaction mixture was warmed up to 76 °C and moni-
tored by GLC-MS until total or steady conversion of the starting
material. The resulting suspension was diluted with Et2O (20 mL),
filtered through a pad containing celite, and the filtrate was washed
with 2  HCl (2ϫ20 mL) and dried with MgSO4. The residue ob-
tained after removal of the solvent (15 Torr) was purified by col-
umn chromatography (silica gel, hexane/EtOAc) to give the pure
alkylated ketone.
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Butyrophenone, valerophenone, and 4-phenylbutyrophenone were
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Eur. J. Org. Chem. 2008, 4908–4914
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www.eurjoc.org
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Received: July 22, 2008
Published Online: September 4, 2008
4914
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4908–4914