Cu(I)-catalyzed α-alkylation of ketones with styrene derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.06.019

α-Alkylation of ketones with styrene derivatives was developed using a mesitylcopper-dppp complex as a soft Bronsted base catalyst. No waste derived from the alkylating reagent was produced in this catalytic alkylation reaction. The bisphosphine ligand structure, as well as the reaction solvent, had profound effects on catalyst activity. The reaction proceeded under mild conditions from a range of ketones and styrene derivatives. The present catalysis is especially useful for the selective mono-alkylation of ketones.

Full text of DOI:10.1016/j.tetlet.2012.06.019

Tetrahedron Letters 53 (2012) 4381–4384
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu(I)-catalyzed
a-alkylation of ketones with styrene derivatives
Shohei Majima a, Yohei Shimizu a,b, , Motomu Kanai a,b,
⇑
⇑
a Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
b Kanai Life Science Catalysis Project, ERATO, Japan Science and Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Alkylation of ketones with styrene derivatives was developed using a mesitylcopper–dppp complex as
Received 9 May 2012
Revised 1 June 2012
Accepted 6 June 2012
Available online 12 June 2012
a soft Brønsted base catalyst. No waste derived from the alkylating reagent was produced in this catalytic
alkylation reaction. The bisphosphine ligand structure, as well as the reaction solvent, had profound
effects on catalyst activity. The reaction proceeded under mild conditions from a range of ketones and
styrene derivatives. The present catalysis is especially useful for the selective mono-alkylation of ketones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkylation
Ketone
Olefin
Catalyst
Addition
Carbon–carbon bond forming reactions are used to construct
main frameworks of organic molecules. -Alkylation of carbonyl
compounds is among the most important and widely used ap-
proaches for this purpose. Generally, -alkylation of carbonyl com-
a) radical
O
c) alkali metal enolate
a
M
O
+
+
a
pounds is accomplished through initial conversion to enolates
using stoichiometric amounts of base, followed by nucleophilic at-
tack of the thus-generated enolates to alkylating reagents, such as
alkyl halides and tosylates. This method is reliable, but the use of
more than 1 equiv of strong base limits compatible functional
groups in the substrates. In addition, the use of alkylating reagents
with leaving groups inevitably produces a stoichiometric amount of
metal salt waste, which is not favorable in terms of atom economy.1
Overalkylation is also problematic in some cases. Although, recent
catalytic allylic alkylation reactions have overcome these draw-
backs to some extent,2 the use of enolates containing a single car-
b) enol or silyl enol ester
d) transition metal enolate
:
OSilyl
OH
M
O
M
or
+
Figure 1. Activation of ketones and olefins.
has been less explored, however, despite the fact that ketones are
a common functional group in organic synthesis.7 The previously
reported catalytic methods of
vated unsaturated C–C bonds can be classified into the following
three types; (1) addition of -carbon radicals derived from ketones
to alkenes (Fig. 1a),8 (2) addition of enols or silyl enol ethers to
bonyl group as
a
nucleophile in allylic alkylation reactions
-alkylated car-
a-alkylation of ketones with unacti-
remains difficult. The Michael addition3 produces
a
bonyl compounds; however, the electrophiles require electron-
withdrawing groups.
a
On the other hand, there have been several reports of catalytic
alkenes or alkynes through the activation of
p-bonds by p-acidic
transition metals (Fig. 1b),9 and (3) addition of highly nucleophilic
a
-alkylation or alkenylation of carbonyl compounds using unacti-
vated alkenes and alkynes as electrophiles.4 These types of reac-
tions do not require leaving groups or electron-withdrawing
groups on the electrophiles. 1,3-Diketones, b-keto esters, and alde-
hydes have been used as common nucleophiles in these
alkali metal enolates to alkenes or alkynes (Fig. 1c).10
We envisioned that the addition of ketone-derived enolates to
unactivated alkenes in the third category is a potentially useful
alkylation method because the ketone-derived enolates are rather
stable and relatively easy to prepare using a Brønsted base catalyst.
All of the previously reported enolate addition reactions to unacti-
vated alkenes used potassium enolates as the active species. The
reaction conditions are highly basic, however, so application to
multifunctional substrates is difficult. In addition, overalkylation
reactions.5,6
a-Alkylation of ketones using olefins as electrophiles
⇑
Corresponding authors. Fax: +81 3 56845206.
E-mail addresses: y-shimizu@mol.f.u-tokyo.ac.jp (Y. Shimizu), kanai@mol.f.u-
tokyo.ac.jp (M. Kanai).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.019

4382
S. Majima et al. / Tetrahedron Letters 53 (2012) 4381–4384
Table 1
Initial screening
decreases the yield of the desired products. We hypothesized that
the reaction would proceed under milder basic conditions with the
use of a transition metal enolate due to the ability of transition
O
Base (10 mol%)
O
metals to activate
p-bonds (Fig. 1d), leading to higher functional
Additive (11 mol%)
Ph
group tolerance and the capacity for mono-alkylation.
Ph
+
Ph
Ph
Based on this idea, we began our investigation with the catalytic
Solvent
45 °C, 24 h
Me
Me
a-alkylation of propiophenone (1a) using styrene (2a). We first
1a
2a
(1 equiv)
3aa
studied various catalytic combinations of transition metal triflates
or halides (metal = nickel, rhodium, ruthenium, palladium, gold,
silver, etc.) with potassium tert-butoxide, expecting the formation
of transition metal enolates in situ. These combinations, however,
did not improve the reactivity compared to the use of potassium
tert-butoxide as a catalyst. Therefore, we next focused our atten-
tion on a copper(I) alkoxide11 catalyst. We previously reported that
a chiral copper alkoxide could be a Brønsted base catalyst for var-
ious asymmetric addition reactions.12,13 Thus, copper(I) alkoxides
should deprotonate ketones, generating a copper enolate species.
Furthermore, copper(I) could interact with olefins because cop-
(1 equiv)
Entry
Base
Additive
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
CuOiPr
MesCu
None
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
0
0
0
8
1,10-Phen
rac-Binap
Bu3Pb
dppe
dppp
dppb
dppp
dppp
dppp
dppp
21
88 (85)c
1<
0
0
0
THF
10
11
12
HMPA
DMF
DMSO
per(I) forms
p
-complexes with olefins.14 Together, we hypothe-
90
dppp
91 (84)c
sized that both enolate formation and
p-activation of olefins
would be possible with a copper(I) catalyst.15
a
Yields were determined by 1H NMR spectroscopy by using an internal standard.
21 mol% of Bu3P was added.
Isolated yields were shown in parentheses.
We first investigated copper isopropoxide, generated from com-
mercially available mesityl copper and 1 equiv of iPrOH,11,12 as a
catalyst in the reaction of 1a and 2a (Table 1). In the absence of
any ligands, copper isopropoxide formed a precipitate under the
b
c
Table 2
Substrate scopea
O
O
MesCu (10 mol%)
dppp (11 mol%)
R3
R1
R1
R3
+
R2
R2
DMSO, 45 °C
1
2
3
(1 equiv)
(1 equiv)
Entry
1
Ketones
Olefins
Ph
Time (h)
Yield (%)
85
O
2a
1a
24
24
Ph
Me
O
1b
2
3
2a
2a
70
92
Ph
Et
O
1c
Me
24
24
MeO
Fe
O
4
2a
71
1d
Me
O
78b
35
1e
5
6
2a
2a
24
48
O
1f
Me
Me
Br
7
8
1a
1a
35
26
85
89
2b
: 4-Br
2c
: 2-Br

S. Majima et al. / Tetrahedron Letters 53 (2012) 4381–4384
4383
Table 2 (continued)
Entry
Ketones
Olefins
Time (h)
42
Yield (%)
87
CO2tBu
9
1a
2d
CN
10
1a
42
61
2e
11
12
1a
1a
37
35
81
92
2f: 4-vinyl
N
2g: 2-vinyl
67c
Ph
2h
13
1a
24
a
Conditions: MesCu (10 mol%), dppp (11 mol%), DMSO (0.5 M), 45 °C. Yields are isolated yields.
Reaction temperature: 60 °C.
Yield was determined after hydrogenation by Pd/fibroin, H2, MeOH.
b
c
p-chloro substituent produced only trace amounts of the product.
This finding suggests that the addition of a copper enolate to
alkenes, rather than the deprotonation of ketones, was the rate-
determining step,16 which is consistent with the result using elec-
Ph
a)
Catalyst
(10 mol%)
O
1a
2a
3aa
+
+
Ph
(1 equiv)
(2 equiv)
DMSO
45 °C, 24 h
Ph
Me
tron-rich ferrocene-substituted ketone 1d (entry 4).
a-Tetralone
3aa'
(1e) also had a high reactivity (entry 5). The product yield from ali-
phatic ketone 1f was moderate because dialkylations proceeded as
side reactions (entry 6).
MesCu + dppp
KOtBu
96%
55%
4%
45%
b)
The scope of olefin substrates was then investigated. Both o- and
p-bromo styrene derivatives 2b and 2c afforded the corresponding
products in high yield (entries 7 and 8). The reaction proceeded
selectively at the C@C double bond, even when using olefins with
polar electron-withdrawing functional groups, such as an ester or
nitrile, on the aromatic ring (entries 9 and 10). However, the reac-
tion of an olefin possessing an electron-donating p-methoxy group
did not proceed at all under the optimized conditions. On the other
hand, it is noteworthy that vinyl pyridines 2f and 2g, which poten-
tially coordinate to the copper catalyst and deactivate its activity,
were excellent olefin substrates in this reaction (entries 11 and
12). Diene 2h was a competent substrate with the reaction proceed-
ing selectively at the terminal position of the diene (entry 13).
Although, the present catalysis is limited to the aryl-substituted
olefins, the requirement of just a 1:1 ratio of ketones and olefins
for high product yields is significant. In contrast, under the previous
conditions, excess amounts of ketones were always required.
An advantage of the current Cu(I)-catalyzed alkylation of ke-
tones is its excellent selectivity for mono-alkylation in the case
of aromatic ketones. Thus, we compared the current Cu(I)-cata-
lyzed reaction to the previous KOtBu-catalyzed reaction10 under
various conditions (Fig. 2). First, we performed the reaction be-
tween 1 equiv of 1a and 2 equiv of 2a (Fig. 2a). Using KOtBu as
the catalyst, 55% of mono-alkylated product 3aa and 45% of di-
alkylated product 3aa0 were obtained after 24 h. On the other hand,
use of the Cu(I)–dppp catalyst produced mono-alkylated product
3aa in 96% yield concomitant with only 4% of di-alkylated product
3aa0. In addition, a competitive experiment using 0.5 equiv of 1a
and 0.5 equiv of 1g in the presence of 1 equiv of 2a showed excel-
lent selectivity for mono-alkylation in the current catalysis
(Fig. 2b). In the KOtBu catalysis, 3aa was obtained in 49% along
with 3ga 29%. On the other hand, in the Cu(I)–dppp system, 3aa
was obtained selectively in 48% along with only 2% of 3ga. Thus,
the Cu(I)-catalyzed alkylation is especially suitable for selective
mono-alkylation of aromatic ketones.
1a
Catalyst
(10 mol%)
(0.5 equiv)
O
Ph
+
2a
(1 equiv)
3aa
+
Ph
O
H
DMSO
45 °C, 24 h
Me
3ga
Me
Me
Ph
Me
MesCu + dppp
KOtBu
48%
49%
2%
1g
(0.5 equiv)
29%
Figure 2. Comparison experiments of mono-alkylation.
reaction conditions (entry 1). To stabilize the active copper species,
we screened various ligands. Although, amine ligands and tri-aryl
phosphine ligands did not produce any desired alkylation products
(entries 2 and 3), 3aa was obtained in 8% yield when using tributyl-
phosphine (entry 4). Use of a 1,2-bis(diphenylphosphino)ethane li-
gand significantly improved the reactivity, and the yield of 3aa was
increased to 21% (entry 5). Encouraged by this result, we next stud-
ied the effects of the linker length between two phosphine moieties,
and found that 1,3-bis(diphenylphosphino)propane was the best li-
gand for this reaction (85% yield, entry 6). Catalyst activity was
sharply decreased, however, by increasing the linker by one carbon
using 1,4-bis(diphenylphosphino)butane as the ligand (entry 7).
These results suggest that both proper bite angle and flexibility of
the ligand backbone are keys for high catalyst activity. The solvent
effects were also large, and only DMSO and DMF were appropriate
solvents (entries 6 and 11). The use of other solvents, such as THF,
dichloroethane, and hexamethylphosphoramide resulted in nega-
tive effect on the product yields (entries 8–10). Finally, we found
that mesitylcopper catalyzed the a-alkylation with efficiency com-
parable to copper isopropoxide (entry 12). Due to the easier manip-
ulations, we considered the conditions of entry 12 to be optimal.
The substrate scope was investigated under the optimized con-
ditions (Table 2). The reaction of butyrophenone (1b) produced a
slightly lower yield than propiophenone, possibly due to the in-
creased steric bulkiness (entry 2). Propiophenone derivative 1c
with an electron-donating p-methoxy substituent on the aromatic
ring exhibited higher reactivity (entry 3) than propiophenone,
while a propiophenone derivative with an electron-withdrawing
In summary, we have demonstrated a catalytic
a-alkylation
reaction of ketones with styrene derivatives using a mesitylcop-
per–dppp complex. The reaction proceeded under mild conditions
from a range of ketones and styrenes. The present catalysis is espe-
cially suitable for mono-alkylation of ketones.

4384
S. Majima et al. / Tetrahedron Letters 53 (2012) 4381–4384
130, 15688; (d) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Angew. Chem.,
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This work was supported by Grant-in-Aid for Research Activity
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16. Consistent with this tendency, the corresponding
a-alkylation product was not
produced using acetophenone as the starting ketone.