1118
M. Rachwalski et al. / Tetrahedron: Asymmetry 24 (2013) 1117–1119
O
Et
O
3. Conclusion
ligand 1, Ni(acac)2
Ph
Ph
+ Et2Zn
Ph
Ph
The chiral bidentate ligands of type 1 derived from (S)-(+)-man-
delic acid containing two stereogenic centers were found to be
highly effective catalysts for the enantioselective conjugate
Michael additions of diethylzinc to enones (chalcone and 2-cycloh-
exen-1-one, respectively). The stereogenic centers located at the
azirdine moieties had a decisive influence on the stereochemistry
of the reactions. It should be noted that each enantiomer of the
designed product should be available by the use of the respective
diastereomeric ligands.
toluene
3
2
Scheme 2. Asymmetric conjugate Michael addition of diethylzinc to chalcone.
O
O
ligand 1, Ni(acac)2
+ Et2Zn
toluene
Et
5
4
4. Experimental
4.1. General
Scheme 3. Asymmetric conjugate Michael addition of diethylzinc to 2-cyclohexen-
1-one.
Unless otherwise specified, all reagents were purchased from
commercial suppliers and used without further purification. Tolu-
ene was distilled from sodium benzophenone ketyl radical. 1H
NMR spectra were recorded on a Bruker instrument at 600 MHz
with CDCl3 as the solvent and relative to TMS as the internal stan-
dard. Data are reported as s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, b = broad. Optical rotations were mea-
sured on a Perkin–Elmer 241 MC polarimeter with a sodium lamp
at room temperature (c 1). Column chromatography was carried
out using Merck 60 silica gel. TLC was performed on Merck 60
experiments without Ni(acac)2 were also carried out. All of the re-
sults are collected in Table 1.
Table 1
Screening of ligands 1a–d
Entry Ligand
Product 3
Product 5
a
a
Yield
(%)
[a
]
D
eeb
(%)
Abs
config. (%)
Yield
[a
]
D
eeb
(%)
Abs
config.c
1
2
3
4
5
1a
1b
1c
42 À1.2 46
90 À2.3 89
93 À2.3 91
50 À1.2 53
(R)
(R)
(R)
(R)
(S)
39 À4.7 44
88 À9.5 89
92 À9.6 90
48 À4.9 46
(S)
(S)
(S)
(S)
(R)
F254 silica gel plates. Visualization was accomplished with UV light
(254 nm) or using iodine vapor. The enantiomeric excess (ee) val-
ues were determined by chiral HPLC (Knauer, Chiralcel AS). Aziri-
dines a–d were prepared according to the literature.24 Chiral
bidentate ligands were synthesized using the procedure previously
described.12
1cd
1d
91
+2.3 90
90
+9.4 88
a
b
c
In chloroform (c 1).
Determined using chiral HPLC.
According to the literature data.20
No Ni(acac)2 added.
d
4.2. General protocol for the conjugate Michael addition of dieth-
ylzinc to a,b-unsaturated enones using the chiral bidentate ligands
and Ni(acac)2
Table 1 shows some noteworthy findings. First, the formation of
enantiomerically enriched products 3 and 5 in the presence of cat-
alyst 1a, containing an achiral 2,2-dimethylaziridine, indicates that
the stereogenic center located in the aziridine moiety has a decisive
influence on the stereochemistry of the reaction. Second, the use of
both diastereomeric ligands 1c and 1d led to the formation of chiral
products 3 and 5 with opposite absolute configurations. The small
differences in their ee values may be explained in terms of ‘match‘
and ‘mismatch‘ interactions with the stereogenic center located in
the mandelic acid moiety. The same tendency was previously ob-
served using other heteroorganic ligands in asymmetric conjugate
additions of diethylzinc to enones.3 Finally, in the absence of a nick-
el catalyst (entry 4), the 1,4-addition took place, although chemical
yield and enantiomeric excess of 3 and 5 were significantly lower.
As a result, the use of a metal catalyst is crucial for both the effi-
ciency and high stereoselectivity of the title reaction. Additionally,
the high chemical yield and enantiomeric excess of the product of
the nickel-catalyzed addition of diethylzinc to 2-cyclohexen-1-
one [(S)-trans enone] were somewhat unexpected due to the usu-
ally accepted mechanism and previous literature findings18 that
only (S)-cis enones were good substrates for the title reaction. How-
ever, this unusual phenomenon was observed in our previous stud-
ies on the nickel-catalyzed addition of diethylzinc to (S)-cis and (S)-
trans enones using chiral heteroorganic aziridine alcohols.3 This fact
might be based on the extraordinary ability of aziridines to form
complexes with various zinc species,21–23 leading to the desired
chiral product 5 probably via another mechanistic pathway than re-
ported earlier.18 Further mechanistic studies into this process will
be undertaken.
A solution of Ni(acac)2 (0.018 g, 0.07 mmol) and chiral ligand
1a–d (0.11 mmol) in 5 mL of freshly distilled toluene was stirred
under a nitrogen atmosphere at room temperature for 1 h. After
this time, the corresponding substrate (1 mmol) was added, the
mixture was cooled to À20 °C, and a solution of diethylzinc in hex-
ane (1.0 M) (1.65 mL, 1.65 mmol) was added. The mixture was stir-
red at À20 °C for 1 h and at room temperature overnight. After
complete conversion (TLC), the reaction mixture was poured into
20 mL of 1 M HCl and extracted three times with diethyl ether.
The combined organic phases were washed with brine and dried
over anhydrous magnesium sulfate. Filtration and evaporation
yielded the crude products 3 and 5. After purification via column
chromatography on silica gel using hexane and ethyl acetate in
gradient as an eluent, pure products 3 and 5 were obtained. Chem-
ical yields, enantiomeric excesses (determined by chiral HPLC), and
specific rotation values are shown in Table 1.
4.2.1. (R)-(À)-1,3-Diphenyl-pentan-1-one 3
Colorless solid; 1H NMR (CDCl3): d = 0.75 (t, J = 7.3 Hz, 3H),
1.56–1.60 (m, 1H), 1.71–1.74 (m, 1H), 3.16–3.22 (m, 3H),
7.10–7.34 (m, 5H), 7.35–7.38 (m, 2H), 7.44–7.47 (m, 1H), 7.82–
7.83 (m, 2H). Other spectroscopic data of compound 3 are in agree-
ment with the literature.20
4.2.2. (S)-(À)-3-Ethylcyclohexanone 4
Colorless liquid; 1H NMR (CDCl3): d = 0.93 (t, J = 7.2 Hz, 3H),
1.28–1.41 (m, 3H), 1.67–1.74 (m, 2H), 1.94–2.39 (m, 6H). Other
Rachwalski, Michal
