Iron-Catalyzed α-Alkylation of Ketones with Alcohols

Article abstract of DOI:10.1002/anie.201506698

A general and benign iron-catalyzed α-alkylation reaction of ketones with primary alcohols has been developed. The key to success of the reaction is the use of a Kn?lker-type complex as catalyst (2 mol %) in the presence of Cs₂CO₃ as base (10 mol %) under hydrogen-borrowing conditions. Using 2-aminobenzyl alcohol as alkylation reagent allows for the "green" synthesis of quinoline derivatives.

Full text of DOI:10.1002/anie.201506698

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506698
German Edition: DOI: 10.1002/ange.201506698
Green Chemistry
Iron-Catalyzed a-Alkylation of Ketones with Alcohols
Saravanakumar Elangovan, Jean-Baptiste Sortais,* Matthias Beller, and Christophe Darcel*
Abstract: A general and benign iron-catalyzed a-alkylation
reaction of ketones with primary alcohols has been developed.
The key to success of the reaction is the use of a Knçlker-type
complex as catalyst (2 mol%) in the presence of Cs2CO3 as
base (10 mol%) under hydrogen-borrowing conditions. Using
2-aminobenzyl alcohol as alkylation reagent allows for the
“green” synthesis of quinoline derivatives.
With respect to the catalyst, Knçlker-type complexes 1[11]
constitute convenient and stable precursors, which have
been used by us and others for hydrogenations and hydrogen
transfer reactions,[12] as well as for selective oxidations of
alcohols.[13] So far, such complexes have scarcely been used in
redox neutral processes. Meanwhile, acceptorless alcohol
dehydrogenation reactions were recently described with iron
pincer complexes using the so-called MACHO (PNP)
ligand.[14] Furthermore, the synthesis of substituted amines
by alkylation of the corresponding primary or secondary
amines by alcohols was also just reported.[15] Herein, we
demonstrate the first iron-catalyzed a-alkylation of ketones
with alcohols in the presence of the complex 1 using a hydro-
gen borrowing strategy (Scheme 1).
T
he selective a-functionalization of ketones with organo-
halides in the presence of a base is one of the most
fundamental reactions to build up carbon–carbon bonds.[1]
This method usually suffers from the use of stoichiometric
amount of base, and the use of halides which leads to the
formation of (over)stoichiometric amounts of waste. By
contrast, owing to their availability and often lower prices,
alcohols have emerged as interesting alternative alkylating
reagents in the presence of suitable catalysts.[2] More specif-
ically, using the so-called borrowing hydrogen or hydrogen
autotransfer strategy,[2,3] an alcohol is dehydrogenated to the
corresponding aldehyde or ketone, which in situ reacts with
an enolate to form after dehydration the a,b-unsaturated
ketone. Finally, this latter product is reduced to the desired
alkylated ketone. Notably, in the overall process, the catalyst
plays the role of a hydrogen shuttle.
Scheme 1. Iron-catalyzed a-alkylation of ketones with alcohols.
Pioneering results using alcohols as alkylation reagents
were reported by Guerbet more than one hundred years ago.
In those initial studies, the “self” b-alkylation of primary
alcohols proceeded in the presence of copper salts and base.[4]
Later on, related catalytic anaerobic dehydrogenative cou-
pling reactions starting from alcohols were reported using
different noble metals such as ruthenium,[5] iridium,[6] or
palladium.[7] Obviously, in terms of sustainability, such pre-
cious transition metals should be substituted by more eco-
friendly, inexpensive, and widely abundant first row-based
metals.
Based on the results using Knçlker-type catalysts for both
reduction and oxidation reactions, and for alkylation of
amines,[15] we envisioned that such complexes can promote
hydrogen transfer reactions using alcohols as alkylating
reagent in the a-functionalization of ketones (Table 1).
Indeed, in a preliminary experiment with acetophenone
(1 equiv) and benzylalcohol (1.5 equiv) in the presence of
5 mol% of the complex 1 as the pre-catalyst and 30 mol% of
K2CO3 at 1408C, 1,3-diphenylpropan-1-one 5a was obtained
in 55% GC-yield together with 1-phenylethanol 6a (32%
GC-yield), resulting from the reduction of acetophenone,
which indicates that hydrogen transfer did occur during the
reaction (Table 1, entry 1). When using Cs2CO3 (30 mol%) as
the base, the reactivity was increased and 62% of the desired
a-alkylated product 5a was obtained after 24 h with 38% of
6a (Table 1, entry 2; Supporting Information, Table S3).
Variation of the nature of the iron complex by substituting
one CO ligand by PPh3 (complex 2), and acetonitrile (com-
plex 3), or by modifying the cyclopentadienone ligand (com-
plex 4) led to active catalysts, but with lower chemoselectiv-
ities (yields 5a/6a from 33/18 to 45/30; Table 1, entries 3–5).
Notably, the cyclopentadienone motif is crucial for the
activity of the catalyst because when Fe2(CO)9 was used as
the precatalyst, no activity was observed even at prolonged
reaction time (48 h; Table 1, entry 6). Interestingly, when
Among these metals, iron attracts significant attention
and is considered as a valuable alternative.[8] In the last
À
decade, iron catalysts have increasingly been used in C C
cross coupling reactions,[9] and especially in reductions.[10]
[*] S. Elangovan, Dr. J.-B. Sortais, Prof. Dr. C. Darcel
UMR 6226 CNRS, UniversitØ de Rennes 1
Institut des Sciences Chimiques de Rennes,
Team “Organometallics: Materials and Catalysis,
Centre for Catalysis and Green Chemistry
campus de Beaulieu, 35042 Rennes, Cedex (France)
E-mail: jean-baptiste.sortais@univ-rennes1.fr
christophe.darcel@univ-rennes1.fr
S. Elangovan, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Strasse 29a, Rostock, 18059 (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506698.
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Table 1: Iron-catalyzed a-alkylation of acetophenone with benzylalcohol:
Table 2: Scope of the iron-catalyzed a-alkylation of ketones with
Variation of reaction parameters.[a]
alcohols.[a]
Entry
t [h] NMR-yield[b]
(Isolated)[c]
5 [%]
1
2
3
4
5
6
7
8
R=H, 5a
24
48
24
48
24
48
48
48
80 (60)
80 (57)
68 (58)
92 (72)
78 (71)
57 (36)
67 (52)
50 (38)
Entry Complex
(mol%)
Base
(mol%)
t [h]
Yield [%]
Yield [%]
R=p-OMe, 5b
R=p-Me, 5c
R=o-Me, 5d
R=p-Cl, 5e
R=p-Br, 5 f
R=p-F, 5g
5a[b]
6a[b]
1
1 (5)
K2CO3 (30)
36
55
62
46
33
45
0
61
74
44
80
0
32
38
24
18
30
0
29
20
10
6
2
1(5)
Cs2CO3 (30) 24
Cs2CO3 (10) 24
Cs2CO3 (10) 24
Cs2CO3 (10) 24
Cs2CO3 (10) 48
Cs2CO3 (10) 24
Cs2CO3 (10) 24
Cs2CO3 (10) 24
Cs2CO3 (10) 24
Cs2CO3 (10) 24
3
2 (2)
4
3 (2)
R=p-CF3, 5h
5
4 (2)
6
7
Fe2(CO)9 (5)
1(2)
1 (2)
9
10
Ar=2,4,6-Me3-C6H2, 5i
Ar=2-naphthyl, 5j
48
48
59 (51)
76 (60)
8[c]
9[c]
2 (2)
10[c,d] 1 (2)
11[c,e] 1 (2)
11
12
13
14
R=OMe, 5k
R=iPr, 5l
R=Cl, 5m
R=F, 5n
48
24
48
24
63 (51)
75 (59)
76 (55)
73 (62)
0
5
0
12
13
1 (10)
–
–
24
0
0
Cs2CO3 (15) 24
[a] acetophenone (0.5 mmol), benzyl alcohol (0.75 mmol, 1.5 equiv), [Fe]
(2–10 mol%), base (10–30 mol%), toluene (1 mL), 1408C. [b] Yields
determined by GC analysis. [c] 1.3 equiv of benzyl alcohol was used.
[d] 2 mol% of PPh3 was used as an additive. [e] Reaction under neat
conditions at 1408C.
15
16
R=p-Cl, R’=F, 5o
R=o-Me, R’=Me, 5p
24
48
80 (59)
70 (56)
17
24
48
0
18[d]
5q
72 (50)
19
20
R=Ph, 5r
R=Me, 5s
48
48
47 (42)
70 (55)
decreasing the catalytic amount of the iron complex 1
(2 mol%) and of the base Cs2CO3 (10 mol%) in the presence
of 1.5 equiv of benzyl alcohol, 61% of 5a and 29% of 6a was
obtained (Table 1, entry 7). When lowering the amount of
benzyl alcohol to 1.3 equiv, the chemoselectivity was
improved notably with a decrease of the amount of 1-
phenylethanol 6a: catalyst 1 (5a: 74% and 6a: 20%) and
catalyst 2 (5a: 44% and 6a: 10%) (Table 1, entries 8 and 9 vs
7 and 3, respectively).[16] Finally, a significant breakthrough
was obtained using a catalytic system generated in situ from
the Knçlker complex 1 (2 mol%) and PPh3 (2 mol%) under
similar conditions to those in the entry 8, and 80% of the a-
alkylated product 5a was obtained with only 6% of 6a
(Table 1, entry 10). Interestingly, the nature of the phosphine
is also important: with 2 mol% of P(o-Tol)3 or P(2-methyl-
furyl)3, similar results were achieved, whereas in the presence
of 2 mol% of PCy3, PPhMe2, or P(OPh)3, less active and
selective transformations were observed (Supporting Infor-
mation, Table S4).
Obviously, no coupling occurred in the absence of iron
catalyst or Cs2CO3 as the base, or when the reaction was
performed in neat conditions (Table 1, entries 11–13).
To demonstrate the general scope of this method,
reactions of various arylalkylketones with primary alcohols
were investigated using the optimized conditions (2 mol% of
complex 1, 2 mol% PPh3, 10 mol% Cs2CO3, 1 equiv of
ketone, and 1.3 equiv of alcohol in toluene at 1408C for
24 h) (Table 2; Supporting Information, Figure S5).
21
5t
48
54 (43)
22
R=Me, X=S, 5u
R=H, X=O, 5v
48
48
70 (46)
(19)
23[d]
[a] Reaction conditions: ketone (1 mmol), alcohol (1.3 mmol), com-
plex 1 (0.02 mmol, 2 mol%), PPh3 (0.02 mmol, 2 mol%), Cs2CO3
(0.1 mmol, 10 mol%), toluene (2 mL), 1408C. [b] 1H NMR-yields in the
crude mixture. [c] Yield of isolated product. [d] tBuOK (10 mol%) was
used as the base.
In all of these cases, the a-alkylated derivative 5 was
obtained as the major product with small amounts of the
alcohols resulting from the reduction of the starting material
and/or the formed ketones. The substitution on the aryl
ring Ar1 of arylmethylketones has no noticeable effect on the
efficiency of the reaction. With both electron-withdrawing
(Table 2, entries 5–8) and electron-donating substituents
(Table 2, entries 2–4,9), the a-alkylated ketones were
obtained in 50–92% 1H NMR-yields (36–72% yields of
isolated product) with 0–20% of the reduced compounds
from the starting and/or the formed ketones. a-Tetralone in
the presence of benzyl alcohol led specifically to the a-
alkylated-a-tetralone in 50% isolated yield after 48 h
(Table 2, entries 17,18). Similarly, there is no significant
effect of the substitution of the aryl ring R2 on the benzyl
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alcohol derivatives. Consequently, alcohols with both elec-
tron-donating (Table 2, entries 11,12,16) and electron-with-
drawing substituents (Table 2, entries 13–15,21) gave the
corresponding a-alkylated ketones in 51–62% yields of
isolated product. Furthermore, bio-based and synthetically
more interesting alcohols such as butan-1-ol and 3-phenyl-
propan-1-ol could be used, and led to the corresponding
ketones in 55 and 42% yields of isolated products, respec-
transformation is the use of a Knçlker-type iron complex as
catalyst. The optimized catalytic system permitted the devel-
opment of the first iron-catalyzed Friedländer annulation
reaction starting from 2-aminobenzyl alcohols. Notably, this
method is not only of interest for organic synthesis, but also
permits the green valorization of bio-based alcohols.
tively (Table 2, entries 19–20). Methanol was unfortunately Experimental Section
Typical procedure for Fe-catalyzed a-alkylation of ketones with
not suitable for this transformation, probably owing to the
more difficult dehydrogenation reaction of this alcohol. More
gratifyingly, heteroaromatic methylketones, such as 3-pyri-
dylmethylketone or heteroaromatic alcohols such as 2-
thienylethanol, performed well in this reaction (Table 2,
entries 21 and 22).[17]
primary alcohols: an oven-dried 10 mL Schlenk tube, equipped with
a stirring bar, was charged with acetophenone (120 mg, 1 mmol),
benzyl alcohol (1.3 mmol), iron complex 1 (8.4 mg, 0.02 mmol), PPh3
(5.2 mg, 0.02 mmol), Cs2CO3 (32.4 mg, 0.1 mmol), and toluene
(2 mL). Under argon, the mixture was stirred at RT for 2 min, then
was placed into a pre-heated oil bath at 1408C and stirred for 24–48 h.
The reaction mixture was cooled to RT, then diluted with ethyl
acetate and washed with brine solution. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (n-pentane/
diethylether).
Following the general hydrogen-borrowing concept, our
iron-catalyzed method allows also for the synthesis of
quinoline derivatives. Based on the classic Friedländer
annulation reaction, quinolines can be prepared in a straight-
forward manner from 2-aminobenzaldehyde and various
ketones.[18] In general, self-aldol condensation by-products
and the low stability of 2-aminobenzaldehyde are some of the
challenges of this reaction. Using the more stable 2-amino-
benzyl alcohol in the presence of a catalytic amount of base
under hydrogen-borrowing conditions is an advantage to
perform this reaction[19] compared to reactions in the presence
of stoichiometric amounts of base.[20] Using the optimal
conditions developed for a-alkylation described above, 2-
aminobenzylalcohol 7 (1.3 equiv) reacted with 1 equiv of
acetophenone to give the corresponding quinoline derivative
8a in 63% yield of isolated product. The only other product
detected in this sequence was 2-phenylethanol (Scheme 2).
Acknowledgements
J.B.S. and C.D. thank the CNRS, the University of Rennes
1 for financial support. S.E. acknowledges a PhD ARED
grant from The rØgion Bretagne.
Keywords: alkylation · borrowing hydrogen ·
homogeneous catalysis · Friedländer reaction · iron catalysts
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14483–14486
Angew. Chem. 2015, 127, 14691–14694
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[21] Even if we obtained comparable results in the case of
acetophenone with Cs2CO3 and KOtBu (10 mol%) [Cs2CO3:
quinoline 8a (68%), 1-phenylethanol 6a (32%); KOtBu: 8a
(66%), 6a (34%)], with substituted acetophenone derivatives,
KOtBu was more efficient [for example, 4-Cl-C6H4-COMe:
Cs2CO3, 8a (35%), 6a (20%); KOtBu, 8a (72%), 6a (28%)].
Received: July 20, 2015
Revised: August 21, 2015
Published online: September 25, 2015
14486 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14483 –14486