Organic Letters
Letter
a
Scheme 1). Again, the Ph* group appeared to be crucial for the
favorable outcome of the strategy. Other ortho disubstituted
phenyl rings proved to be less successful, and almost no
alkylated product was isolated from the nonsubstituted aryl
ketones.7 Gunanathan explored a ruthenium-catalyzed cross-
coupling reaction of secondary alcohols, leading to β-
substituted aromatic ketones (Scheme 1).8 This methodology
allowed the synthesis of a variety of β-branched aromatic
ketones in moderate to excellent yield (30−90%) and was not
limited to the use of Ph* benzylic alcohol. Remarkably, the Ru-
Macho complex oxidized the alkyl alcohols faster than the
benzylic ones, and the aromatic enones were selectively formed
and reduced.
Even if these pioneer works open new opportunities in
sustainable chemistry, some limitations are still present. These
procedures are based on the use of platinum-based metal
complexes or of expensive phosphine ligands or required high
reaction temperatures.
We and Morrill have recently demonstrated that the
diaminocyclopentadienone iron tricarbonyl complex Fe1 was
an efficient catalyst for the alkylation of ketones, amines,
oxindoles, indoles, and alcohols with a large variety of primary
alcohols, including methanol.9,10 We have also showed that
Fe1 could catalyzed the chemoselective reduction of various
α,β-unsaturated ketones into saturated ketones under basic
conditions.11 Interestingly, trisubstituted alkenes were hydro-
genated under these hydride transfer conditions.11 These
precedents open the way to the alkylation of ketones with
secondary alcohols catalyzed by a phosphine-free cyclo-
pentadienone iron carbonyl complex (Scheme 2).
Table 1. Optimization of the Reaction Conditions
b
entry
Fe
base
alcohol (equiv)
solvent
conv. (%)
c
1
2
3
4
5
6
7
8
Fe1
Fe1
Fe1
Fe1
Fe1
Fe1
Fe1
Fe1
Fe1
Fe2
Fe3
Fe4
Cs2CO3
Cs2CO3
K3PO4
2
2
2
2
2
2
1.5
1.5
1.5
1.5
1.5
1.5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CPME
tBuOH
toluene
toluene
toluene
-
61
10
32
48
NaOMe
NaOH
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
98
d
98 (87)
76
79
78
80
84
9
10
11
12
a
General conditions: ketone (0.5 mmol), Fe (2 mol %), Me3NO (4
b
mol %), base (1 equiv), and toluene (1 mL). Conversions were
c
1
determined by H NMR analysis of the crude mixture. Base (0.1
d
equiv). Yield in bracket was based on isolated product.
and tert-butanol, could be introduced in this alkylation, but the
conversions were somewhat lower (76 and 79% conversion,
respectively, Table 1 entries 8 and 9). Whereas complex Fe1
was the sole efficient complex in the α-alkylation of ketones
with primary alcohols, β-branched ketones have been obtained
under these reaction conditions from secondary alcohols with
other cyclopentadienone iron tricarbonyl complexes (Fe2, Fe3,
and Fe4), albeit in lower conversions (Table 1 entries 10−12).
Finally the best conditions were as follows: 0.5 mmol of 2,4,6-
trimethylphenyl ketone underwent alkylation in the presence
of 2 mol % of Fe1 and 4 mol % of N-trimethylamine oxide, 1.5
equiv of 2-phenylethanol, and 1 equiv of NaOtBu in refluxing
toluene to give the β-branched ketone in 87% isolated yield
(entry 7, Table 1).
Scheme 2. Layout of the Iron-Catalyzed Hydrogen
Autotransfer with Secondary Alcohols
Having established an optimized protocol, we set out the
scope of the iron-catalyzed borrowing hydrogen alkylation with
secondary alcohols. First, the aryl group of the starting ketone
was modified. As previously stated by Donohoe and
Sundararaju,6,7 a substituted aromatic ring at the ortho,
ortho′ positions was a prerequisite for good overall reactivity
(Scheme 3), as it orientates the aromatic ring and the carbonyl
function orthogonally and consequently avoids competitive
reactions, such as dimerization and reduction. The alkylation
of various aromatic ketones with 2-phenyl ethanol illustrates
this precondition (Scheme 3). A complex mixture was
obtained when acetophenone or 1-(naphthalen-2-yl)ethan-1-
one was used as the enolate precursor, whereas the β,β′-
disubstituted ketones 1a−3a were isolated in good yield from
2,4,6-trimethylphenyl, pentamethyl, and 2,4,6-tris(iso-propyl)
acetophenone (73−87%, Scheme 3).
To promote the synthetic utility of our protocol, a gram-
scale alkylation of 1-mesitylethan-1-one was carried out. The
corresponding 1-mesityl-3-phenylbutan-1-one 1a was isolated
in 83% yield.
We then examined the Fe1-catalyzed alkylation of both
2,4,6-trimethylphenyl and pentamethyl ketone with a variety of
secondary benzylic type alcohols (Scheme 3). Various
electron-donating, electron-withdrawing substituents (such as
halides and ether) within the aromatic ring and naphthyl group
were tolerated, and the corresponding β,β′-disubstituted
The borrowing hydrogen reaction between 1-mesitylethan-
1-one and 1-phenylethan-1-ol was initially chosen as a model
reaction to define the optimized reaction conditions (Table 1
and Table S1). Me3NO was used to activate Fe1, Fe3, and Fe4
and liberate a vacant site,12,13 and Fe2 was thermally activated
at 70 °C.10d,11 A rapid examination of the temperature, in the
presence of Fe1 as a catalyst, 1 equiv of ketone, and 2 equiv of
alcohol in toluene, showed that almost no reaction occurred
below 110 °C (entries 1−3, Table S1). Apart from the
temperature, the key parameter was the base. NaOtBu gave a
full conversion when other bases such as Cs2CO3, NaOMe,
NaOH, or K3PO4 led to the alkylated ketone in a much lower
conversion (entries 2−6, Table 1). Moreover, a stoichiometric
amount of base has to be used to maintain a high activity
(entries 1 and 2, Table 1). Reducing the amount of alcohol to
1.5 equiv did not modify the activity (entries 6 and 7, Table 1).
Various solvents, such as cyclopentyl methyl ether (CPME)
B
Org. Lett. XXXX, XXX, XXX−XXX