Iron-Catalyzed Tandem Three-Component Alkylation: Access to α-Methylated Substituted Ketones

Article abstract of DOI:10.1021/acs.orglett.9b00630

The borrowing hydrogen strategy has been applied in the synthesis of α-branched methylated ketones via a tandem three-component reaction catalyzed by a diaminocyclopentadienone iron tricarbonyl complex. Various alkyl and aromatic methyl ketones underwent dialkylation with various primary alcohols and methanol as alkylating agents in mild reaction conditions and good yields. Deuterium labeling experiments suggested that the benzylic alcohol was the hydrogen source in this tandem process.

Full text of DOI:10.1021/acs.orglett.9b00630

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Iron-Catalyzed Tandem Three-Component Alkylation: Access to
α‑Methylated Substituted Ketones
Leo
́
Bettoni, Charlotte Seck, Mbaye Diagne Mbaye, Sylvain Gaillard, and Jean-Luc Renaud*,†
†
†,‡
†,‡
†
†
Normandie Universite,
‡Universite
Assane Seck de Ziguinchor, Ziguinchor BP 523, Sen
S Supporting Information
́
LCMT, ENSICAEN, UNICAEN, CNRS, 6 boulevard du Marec
́
hal Juin, Caen 14000, France
́
egal
́ ́
*
ABSTRACT: The borrowing hydrogen strategy has been applied in the synthesis
of α-branched methylated ketones via a tandem three-component reaction
catalyzed by a diaminocyclopentadienone iron tricarbonyl complex. Various alkyl
and aromatic methyl ketones underwent dialkylation with various primary alcohols
and methanol as alkylating agents in mild reaction conditions and good yields.
Deuterium labeling experiments suggested that the benzylic alcohol was the
hydrogen source in this tandem process.
mong the substituted ketones, α-branched methylated
However, all these methodologies are based either on the α-
10−16
A
ketones occupy a singular place. This motive is often
methylation of substituted ketones
double alkylation of methyl ketones, as demonstrated by
or on a sequential
1
,2
encountered in pharmaceutical compounds. The methyl
substituent can modify both physical and biological properties
10c
13
Donohoe and co-workers and Dang and Seayad. Another
approach to these α-methylated ketones could be a one-pot
multicomponent alkylation between a methyl ketone, meth-
anol, and a second alcohol. The challenge in such an approach
relies on the possible synthesis of three alkylated products: the
dimethylated ketone, the dialkylated ketone, and the target α-
methylated α-alkylated ketone. The success of such method-
ology relies on the difference in reactivity between methanol
and the second alcohol. The more energetic demanding
dehydrogenation step of methanol, compared to other alcohols
2
if incorporated in biologically active compounds. Methylation,
and more generally alkylation, of ketones is ubiquitous in
organic synthesis. Such a reaction usually involves, on
industrial and laboratory scale, the preparation of an enolate,
by deprotonation of the ketone with a strong base, followed by
trapping with an electrophile (alkyl halide or triflate
3
derivatives). edure is well studied and developed, such an
approach generates amounts of wastes and requires the
4
handling of hazardous and toxic chemicals. In recent years,
−
1
−1
(
ΔH = +84 kJmol for methanol vs ΔH = +68 kJmol for
in order to develop more eco-friendly methodologies, new
ethanol), might be one of the key steps for a successful
sequential double alkylation. However, a catalytic one pot
multicomponent reaction using two different alcohols and a
ketone remains underdeveloped and is still not explored with
Earth-abundant metals. To date, only one report by Kundu and
co-workers on such a three component alkylation has been
strategies have been proposed for the construction of C−C
5
,6
bonds. Among these approaches, the borrowing hydrogen
strategy or hydrogen autotransfer possesses several advantages
such as the use of easy-to-handle alcohols as alkylating agents
and the formation of water as a sole side product. Since the
7
pioneer work of Grigg et al., several complexes, including
17
disclosed in the literature. This coupling reaction between
8
,9
Earth-abundant ones, have been described (Scheme 1).
methanol, benzyl alcohols, and aromatic ketones delivered the
α-branched methylated ketones in moderate to good yields in
the presence of a ruthenium complex at 110 °C (Scheme 1).
While economic pressure and development of sustainable
methodologies urged the replacement of platinum complexes
by Earth-abundant ones, there is no report to date of such a
one-pot process with an earth abundant catalyst. Following our
Scheme 1. Previous Work in Hydrogen Autotransfer
Methylation of Substituted Ketones
18
ongoing interest on the borrowing hydrogen strategy, we
report the first three-component alkylation catalyzed by an iron
complex, allowing the synthesis of α-branched methylated
Received: February 19, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ketones from methanol, as C1 source, benzyl alcohols, and
aliphatic and aromatic ketones in mild reaction conditions
compound 1a accompanied by the dimethylated derivative
(entry 14, Table S1). A significant decrease of the conversion
in 1a was observed when a stoichiometric or substoichiometric
amount of base was used (entries 10−11, Table S1), and the
benzylated ketone was then the major compound. Gratifyingly,
(Scheme 2).
Scheme 2. Outline of the Fe-Catalyzed Tandem Three-
Component Alkylation
20
when complex Fe2 was introduced, the conversion was
improved to 91% in 1a, whatever the activation (entries 22−
23, Table S1). Any other alterations of the reaction conditions
hampered the yields (Table S1). Finally, other cyclo-
21
22
pentadienone iron carbonyl complexes (Fe3 and Fe4 )
led either to lower selectivity or to only monoalkylation
product (entries 25−26, Table S1).
The scope of this unprecedented iron-catalyzed multi-
component alkylation via the borrowing strategy was explored
first starting with various aromatic and aliphatic ketones,
methanol, and benzyl alcohol (Scheme 3). Various sub-
As a starting point for this multicomponent reaction, we
chose the alkylation of 4-methoxyacetophenone (1 equiv) with
benzyl alcohol and methanol as a model reaction for the
optimization of the reaction conditions (Table S1). Several
activation protocols can be used with cyclopentadienone iron
stituents, such as electron-withdrawing group (CF ), electron-
3
donating group (MeO), acetal, and halide, within the aromatic
fragment were tolerated and the corresponding alkylated
ketones were isolated in moderate to good yields (compounds
19a
20
carbonyl complexes: photolytic activation,
Me NO, or
3
19b
1
a−j, Scheme 3). Heteroaryl methyl ketones (2-furanyl, 2-
hydroxide base (Hieber’s method) for Fe2−4 and thermal
18a
pyridyl) also underwent the dialkylation, and compounds 1k
and 1n were isolated in 63% and 33% yield, respectively
activation for Fe1 (Temp. > 70 °C). A rapid screening of
the temperature, using complex Fe1, in a mixture of methanol
(
Scheme 3). The lower yield with 2-acetylpyridine might be
(
0.5 mL, 25 equiv) and benzyl alcohol (0.5 mL, 9.3 equiv),
revealed that a temperature of 90 °C furnished gratifyingly the
α-methylated ketone as a major compound with a good
selectivity (entries 1−3, Table S1). Decreasing the amount of
benzyl alcohol (0.265 mL, 5 equiv) did not impede the
selectivity in favor of the branched dialkyl ketone 1a, despite a
longer reaction time (entry 9, Table S1). An increase of the
amount of methanol (50 equiv) led to a mixture of the desired
due to some coordination of the pyridine moiety to the 16-
electron deficient iron center, which consequently decreased
the reaction rate. Sterically hindered and hindered extended
aromatic systems did not hamper the reactivity. Compounds 1l
and 1m have been isolated in 89% and 66% yield, respectively
(Scheme 3). Finally, to extend the scope in this tandem
sequence, some aliphatic ketones were scrutinized. Yields were
a
Scheme 3. Tandem Three-Component Alkylation of Ketones
a
General Conditions: ketone (0.5 mmol), Fe2 (2 mol %), KOH (10 mol %), K PO (2 equiv), benzyl type alcohol (2.5 mmol), MeOH (0.5 mL)
3
4
at 90 °C for 24 h. Yield was based on isolated product.
B
DOI: 10.1021/acs.orglett.9b00630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
4b
usually lower (1o−q and 1ad, 34−49%, Scheme 3) due to the
ation of ketones, higher chemoselectivity was observed with
Fe2 in this catalytic experiment as no deuteration of the
benzylic position was noticed. These experiments provided
some insight into the mechanism: (i) The benzyl alcohol is the
source of hydride in the overall process, explaining why an
excess of it is required. This result differs from the conclusion
lower reactivity of these ketones. The deprotonation is less
efficient (pK values are higher), and the monobenzylated
a
products were the major compounds in this cascade reaction.
To highlight the robustness of our protocol, the three
component alkylation between (2′-methyl)acetophenone,
methanol, and benzyl alcohol was carried out on a gram-
scale (5 mmol), and the corresponding α-methylated ketone 1f
was isolated in 90% yield (1.08 g).
17
reported in Kundu and co-workers’ work. (ii) There is no
hydrogen/deuterium exchange between deuterated methanol
and benzyl alcohol or deuterium scrambling.
Having explored the scope on the ketone fragment, we
delineated the limitation on the benzylic alcohols (Scheme 3).
In this work, acetophenone and 2-acetyl furan were used as
models for aromatic and heteroaromatic ketones. Again, a
variety of substituted benzylic alcohols were tolerated (1t−w
and 1z−ad) and the corresponding isolated yields were
reasonably good (50−64%). Higher yields were reached with
heteroaromatic alcohols. Compounds 1r−s and 1x−y were
obtained in 72−89% yield (Scheme 3).
To elucidate the possible reversibility of some steps and gain
more insights on this reaction, some complementary
stoichiometric experiments were conducted with acetophe-
none, benzaldehyde, and formaldehyde (Schemes S1 and S2).
By reacting both aldehydes with acetophenone in basic
conditions in methanol at 90 °C, chalcone was observed
quantitatively within 4 h while 40% of starting acetophenone
remained in the presence of formaldehyde (Scheme S2(i),(ii)).
On the basis of the more facile dehydrogenation of benzyl
alcohol and the faster condensation of benzaldehyde, the first
major intermediate is then the chalcone and not the
phenylpropenone (Scheme S1, k > k and k > k ). The
Finally, to increase the versatility of this protocol and
increase its potential in synthesis, two more functionalized
methyl ketones were engaged in the tandem three-component
reaction. These ketones were prepared by an iron-catalyzed
chemoselective reductive alkylation of N-methylaminoacetal-
dehyde dimethyl acetal and (S)-prolinol with 4-acetylbenzal-
2
1
4
3
second key step for a selective three-component reaction is the
second condensation. Two unsaturated ketones can be
expected, the first one by reaction between the dihydrochal-
24
dehyde in 79% and 99% yield, respectively. The ketones 2a−
d were isolated in good yields (42−73%, Scheme 3).
Gratifyingly, the catalytic system tolerated aliphatic acyclic
acetal (neither hydrolysis nor hydrogenolysis has been
observed), free alcohol, and benzylic amine.
cone and formaldehyde (k , Scheme S1) and the second one
9
by reaction with benzaldehyde (k , Scheme S1). Both
1
0
unsaturated ketones were fully obtained within 4 h as analyzed
1
by H NMR spectroscopy analysis (Scheme S2(iii),(iv)). By
adding two drops of water in the reaction medium, reversibility
of the aldol condensation was noticed with benzyledene
adduct, unlike with the methylene adduct (Scheme S2(v),
(vi)). Thus, this reversible aldol reaction drove the overall
equilibrium toward the methylene adduct. Surprisingly, when
the same sequence was realized with propiophenone, no
reversibility of the aldol adducts was noticed (Scheme S2(vi),
(viii)). However, a competitive alkylation of the propiophe-
none with methanol and benzyl alcohol provided the
dimethylated ketone as a major compound over the α-
methylated α-benzylated ketone in a 96/4 ratio (Scheme
S2(ix)).
To provide a mechanistic framework consistent with our
experiments, deuterium-labeling experiments and stoichiomet-
ric complementary experiments were undertaken (Scheme 4
and Schemes S1−S2).
Scheme 4. Mechanistic Studies, Deuterium-Labeling
Experiment
On the basis of all these results and on our previous works
on the borrowing hydrogen methodology and chemoselective
1
8,23
reduction of unsaturated enones,
following mechanism (Figure 1). On the basis of the seminal
work of Knolker on ligand exchange with sodium hydroxide
and our previous DFT calculations,
we proposed the
̈
1
8c,19b
the intermediate III
could be generated from Fe2 through first an initial Hieber’s
type activation (addition of the hydroxide on one CO ligand
When the dihydrochalcone was submitted to the methyl-
followed by the hydride formation and release of CO ) leading
2
ation conditions in deuterated methanol, the CD -labeled
to intermediate II and then the release of hydrogen after
reaction with methanol (Figure 1). After coordination of the
alcohol (intermediate IV), the first dehydrogenation step
furnished again the intermediate II and liberated the aromatic
aldehyde. The α,β-unsaturated ketone, resulting from the
condensation of the aldehyde and the enolate, could then be
reduced via intermediate V, and could furnish the mono-
alkylated ketone and the unsaturated iron species III (Figure
1). A similar sequence with methanol could lead to the exo-
methylene α-benzyl ketone, and its subsequent reduction via
intermediate VII would deliver the α-branched methylated
ketones (Figure 1).
3
ketone 1b was isolated in 76% yield (Scheme 4). This result is
comparable to that of the nondeuterated version (Scheme 3).
Full incorporation of deuterium on the methyl group was
obtained, and deuterium was also introduced in the α-carbonyl
position. The multicomponent reaction in the optimized
conditions with (2′-methyl)acetophenone and benzyl alcohol
(
5 equiv) in fully deuterated methanol (25 equiv) furnished
the CD -labeled ketone 1f-d2/1f-d3 in 81% yield (Scheme 4).
2
Compared to the previous experiment, first the α-carbonyl
position was not fully deuterated (H/D = 37/63) and, second,
no CD fragment was observed by NMR spectroscopy (Figures
3
S16 and S17). In sharp contrast with the recent report by
Rueping and co-workers on the manganese-catalyzed methyl-
In conclusion, we have developed the first iron-catalyzed
three-component alkylation procedure with various aliphatic
C
DOI: 10.1021/acs.orglett.9b00630
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Figure 1. Simplified mechanistic proposal.
and aromatic ketones using benzylic alcohols and methanol as
alkylating reagents in the presence of a well-defined bifunc-
tional iron complex. This alkylation process provided α-
methylated α-alkylated ketones in moderate to high yields in
the presence of other reducible functionalities. These results
open the route to an environmentally acceptable atom-efficient
procedure to functionalized ketones.
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