Published on the web March 22, 2013
471
Copper-catalyzed 1,4-Addition Reaction of Grignard Reagent
to Enones Using Microflow System
Haruo Katayama and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyodai-Katsura, Nishikyo-ku, Kyoto 615-8510
(Received January 25, 2013; CL-130061; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp)
The copper-catalyzed conjugate addition of a Grignard
Φ = 1.0 mm) for the copper-catalyzed 1,4-addition of
a
reagent to an ¡,¢-unsaturated ketone was performed in a
microflow system. In the reaction using the microflow system, a
chemoselective 1,4-addition reaction to an enone in the presence
of a saturated ketone group proceeded successfully.
Grignard reagent. Optimization of the copper-catalyzed 1,4-
addition reaction was performed as shown in Table 1. A THF
solution of BuMgBr (1a, 1.0 M, 1.0 mL min¹1) and a THF
solution of CuCN¢2LiCl (0.26 mL min¹1) were introduced via a
syringe pump into the micromixer M1. The amount of copper
catalyst was controlled by the concentration of the solution
(x M). For maintenance of the reaction temperature, M1, M2,
R1, and R2 were immersed in a water bath with a temperature
controller. After 15 s at 25 °C in R1, a THF solution of
cyclohexenone (0.8 M, 1.26 mL min¹1) was introduced via M2.
The amount of cyclohexenone (2a) introduced was equimolar
with BuMgBr (1a). In some cases, 1.5 molar equivalents of
chlorotrimethylsilane were also introduced simultaneously.7
The resulting mixture was passed through R2 at 25 °C. The
residential period (t s) was varied by its length (y m). The results
are summarized in Table 1. As shown in Entry 6, the product 3a
was obtained in 94% yield even in the absence of chlorotrime-
thylsilane.
As shown in Table 2, a tandem reaction, that is, the trap of
an enolate with an aldehyde, was performed through connection
of the third micromixer M3. When cyclohexenone (2a) was
used as the starting enone, it was treated in M2 with a mixture of
an equimolar amount of Grignard reagent 1 and 1.0 mol %
CuCN¢2LiCl, premixed in M1. Continuous introduction of an
aldehyde to this system via M3 gave the corresponding aldol
adduct in good yield (Entries 1-5). In the reaction using
cyclopentenone as the enone, 3.0 mol % copper salt was
necessary to obtain the corresponding product in good yield
(Entries 6 and 7). In all cases, the products were obtained as a
mixture of two major diastereomers.
Organocopper reagents are one of the most prevalent
synthetic tools for performing conjugate addition to enones.1
Various types of organocopper species have been developed and
used in practical syntheses. Among them, the copper-catalyzed
reaction of a Grignard reagent is favored owing to its simple
procedure and the complete consumption of the Grignard reagent
as a nucleophile.1,2 Enantioselective addition by using a catalytic
amount of an optically active ligand is also beneficial.3 The
stoichiometric magnesiocuprates, however, are still the frequent
choice in natural-product synthesis, as they can be guaranteed to
be unreactive toward the coexisting saturated ketone moiety. For
extreme control of the stoichiometry of a reagent in organic
synthesis, the microflow system (space integration)4 has shown
several promising results.5 Application of the microflow system
to the copper-catalyzed 1,4-addition reaction of a Grignard
reagent may result in a chemoselective reaction, that is, the 1,4-
addition to an enone in the presence of a simple ketone, because
the microflow system can realize the accurate control of a
stoichiometric ratio between substrates and reagents. It will also
lead to an efficient method for the realization of a tandem
reaction (time and space integration), that is, an enone-derived
enolate trap with an intramolecular carbonyl group.6
As shown in Scheme 1, we constructed a microflow system
consisting of two T-shaped SUS micromixers (M1 and M2;
Φ = 0.5 mm) and two SUS microtube reactors (R1 and R2;
Table 1. Optimization of copper-catalyzed 1,4-addition of
BuMgBr (1a) with a microflow systema
Entry x/M mol %b TMSCl/equiv y/m t/sc 3a/%
O
Bu
NH4Claq
2a
O
BuMgBr + cat CuCN•2LiCl
THF
with/without
TMSCl
1
2
3
4
5
6
7
0.038
0.12
0.19
0.38
0.12
0.12
0.12
1.0
3.0
5.0
1.5
1.5
1.5
1.5
0
0.8
0.8
0.8
0.8
0.25
0.8
2.0
15
15
15
15
5.0
15
22
>99
>99
92
93
58
1a
3a
R1
R2
Φ = 1.0 mm
0.4 m
Time 15 s
25 °C
Φ = 1.0 mm
y m
10
BuMgBr (1a) in THF (1.0 M)
25 °C
1.0 mLmin−1
3.0
3.0
3.0
M1
Φ = 0.5 mm
NH4Cl aq
0
0
94
91
M2
Φ = 0.5 mm
aThe reaction was performed with the microflow system in
Scheme 1: T-shaped SUS micromixer: M1 (inner diameter:
0.5 mm) and M2 (inner diameter: 0.5 mm); SUS microtube
reactor: R1 (Φ = 1.0 mm, length = 1.0 m), R2 (Φ = 1.0 mm,
length = 0.25-2.0 m). bCalculated from the concentration of
CuCN•2LiCl in THF (xM)
0.26 mLmin−1
Cyclohexenone (2a) in THF (0.8 M)
1.26 mLmin−1 (1.0 equiv)
with/without TMSCl (1.5 equiv)
c
CuCN¢2LiCl (x M). Residential period: Calculated from the
length of R2 (y m).
Scheme 1. Copper-catalyzed 1,4-addition of BuMgBr (1a)
with a microflow system.
Chem. Lett. 2013, 42, 471-472
© 2013 The Chemical Society of Japan
Katayama, Haruo
