Novel N,N,P-tridentate ligands for the highly enantioselective copper-catalyzed 1,4-addition of dialkylzincs to enones

Article abstract of DOI:10.1021/ol801259u

(Chemical Equation Presented) Use of 0.25 mol % of the N,N,P-tridentate ligand containing the 2-quinolyl moiety (1 and 2) and 0.1 mol % of Cu(OTf) ₂ enabled the enantioselective 1,4-addition of dialkylzincs to cyclic enones to produce 1,4-adduc

Full text of DOI:10.1021/ol801259u

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3509-3512
Novel N,N,P-Tridentate Ligands for the
Highly Enantioselective
Copper-Catalyzed 1,4-Addition of
Dialkylzincs to Enones
Kenjiro Kawamura, Hitomi Fukuzawa, and Masahiko Hayashi*
Department of Chemistry, Graduate School of Science, Kobe UniVersity,
Kobe 657-8501, Japan
mhayashi@kobe-u.ac.jp
Received June 4, 2008
ABSTRACT
Use of 0.25 mol % of the N,N,P-tridentate ligand containing the 2-quinolyl moiety (1 and 2) and 0.1 mol % of Cu(OTf)2 enabled the enantioselective
1,4-addition of dialkylzincs to cyclic enones to produce 1,4-adducts in up to 99% ee.
The enantioselective 1,4-addition of organometallic species
to enones is one of the most important asymmetric
carbon-carbon bond forming reactions in organic synthesis.1
Some reports on the enantioselective 1,4-addition of dialky-
lzincs to enones are available.2 Following the first report of
copper-catalyzed 1,4-addition of diethylzinc to enones by
Alexakis et al.,3 several reports of chiral phosphites,4
phosphoramidites,5 and other types of ligands, such as chiral
bis(oxazolines)6 and N-heterocyclic carbene ligands,7 have
emerged. For example, Escher and Pfaltz reported a new type
of chiral oxazoline-phosphate ligand,4a and Reiser and co-
workers reported bis(oxazoline) ligands6a for the asymmetric
1,4-addition of dialkylzinc to enones.8
We have developed O,N,O-tridentate ligands having the
Schiff base framework type I for use in various asymmetric
carbon-carbon bond forming reactions. Some examples
include the asymmetric silylcyanation of aldehydes,9 the
enantioselective addition of diketenes to aldehydes,10 and
(1) (a) Perlmutter, P. In Conjugate Addition Reaction in Organic
Synthesis, Tetrahedron Organic Chemistry Series No. 9; Pergamon Press:
Oxford, 1992. (b) Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Verlag,
Berlin, Heidelberg, 1999; Chapter 31.1. (c) Tomioka, K. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Verlag, Berlin, Heidelberg, NY, 2004; Supplement to Chapter
31.1.
(5) (a) Boeda, F.; Rix, D.; Clavier, H.; Cre´visy, C.; Mauduit, M.
Tetrahedron: Asymmetry 2006, 17, 2726–2729. (b) Ref 4b.
(6) (a) Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser, O. Org. Lett. 2001,
3, 4259–4262. (b) Barros, M. T.; Maycock, C. D.; Phillips, A. M. F.
Tetrahedron: Asymmetry 2005, 16, 2946–2953.
(2) For a review:(a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221–3236.
(3) Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry 1993,
4, 2427–2430.
(4) (a) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879–2888. (b)
Cramer, N.; Laschat, S.; Baro, A. Organometallics 2006, 25, 2284–2291.
(7) Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.; Mangeney, P.;
Alexakis, A. J. Organomet. Chem. 2005, 690, 5672–5695.
10.1021/ol801259u CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

the enantioselective addition of dialkylzincs to aldehydes.11
Considering the affinity to transition metal, we designed and
synthesized new chiral N,N,P-tridentate ligands (type II).
Here we report newly designed N,N,P-tridentate ligands
(Scheme 1) and their application to the copper-catalyzed
substituted aziridines in high yield. The thus obtained
aziridines were treated with KPPh2 to give the corresponding
amino phosphines.12 Condensation of 2-quinolylcarbaldehyde
with these amino phosphines gave the desired N,N,P-ligands
in high yield.
Table 1 lists the optimized reaction conditions, such as
Scheme 1
Table 1. Enantioselective 1,4-Addition of Diethylzinc to
2-Cyclohexene-1-one (3)
enantioselective addition of dialkylzincs to enones.
The N,N,P-ligands were simply prepared as follows
(Scheme 2): Starting from ꢀ-amino alcohols such as L-valinol
Cu(OTf)2/mol
a
entry
R
%
temp/°C time/h convn/%b ee/%b
1
2
3
4
5
6
7
8
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
1.0
0.5
0.2
0.2
0.2
0.1
0.1
1.0
0.2
0.1
0.1
0
0
0
5
5
5
5
5
5
24
5
5
5
>99
>99
>99
>99
66
97 (S)
97 (S)
97 (S)
98 (S)
99 (S)
96 (S)
98 (S)
99 (S)
95 (S)
95 (S)
96 (S)
Scheme 2
-20
-40
0
-40
0
0
0
-40
89
>99
>99
>99
95
9
10
11
24
>99
a Cu(OTf)2:ligand ) 1:2.5. b The conversions and ee values were
determined by GC analysis (Supelco γ-DEX-225).
the amount of catalyst (Cu(OTf)2 and ligand), the reaction
temperature, and the substituent effect on the ligand (1: R
) i-Pr, 2: R ) t-Bu), in the reaction of 2-cyclohexen-1-one
with diethylzinc. We observed high enantioselectivity in both
cases of R ) i-Pr and t-Bu in this reaction. Even if the
catalyst load was decreased to 0.1 mol % of Cu(OTf)2 and
0.25 mol % of ligand, the reaction proceeded to afford (S)-
3-alkylcyclohexanone in 98% ee at -40 °C. In most of the
previously reported reactions, 1 mol % or more of catalyst
was necessary to obtain high ee. Compared with those
reported methods,1,2 our present catalyst system exhibited
high catalytic activity and enantioselectivity.
Regarding the utility of the 2-quinolyl moiety, Pfaltz and
co-workers pointed out an asymmetric Heck reaction and
asymmetric hydrogenation.13 The ligand having the 2-quinolyl
moiety exhibited higher ee than the one having the pyridyl
moiety. That is, when the pyridyl moiety was used instead
of the 2-quinolyl moiety under the same reaction conditions,
only 55% ee of product was obtained even if 1 mol % of
(R ) i-Pr) and L-tert-leucinol (R ) t-Bu), ditosylation of
ꢀ-amino alcohols followed by the treatment of KOH afforded
(8) Other examples of use of N,P-ligands: (a) Hu, X.; Chen, H.; Zhang,
X Angew. Chem., Int. Ed. 1999, 38, 3518–3521. (b) Morimoto, T.;
Yamaguchi, Y.; Suzuki, M.; Saitoh, A. Tetrahedron Lett. 2000, 41, 10025–
10029. (c) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755–756. (d) Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5,
3201–3203. (e) Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8,
4153–4155. (f) Soeta, T.; Selim, K.; Kuriyama, M.; Tomioka, K. AdV. Synth.
Catal. 2007, 349, 629–635. (g) Morimoto, T.; Obara, N.; Yoshida, I.;
Tanaka, K.; Kan, T. Tetrahedron Lett. 2007, 44, 3093–3095. (h) Hatano,
M.; Asai, T.; Ishihara, K. Tetrahedron Lett. 2007, 48, 8590–8594.
(9) (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Chem. Soc.,
Chem. Commun. 1991, 1752–1753. (b) Hayashi, M.; Miyamoto, Y.; Inoue,
T.; Oguni, N. J. Org. Chem. 1993, 58, 1515–1522.
(10) (a) Hayashi, M.; Inoue, T.; Oguni, N. J. Chem. Soc., Chem.
Commun. 1994, 341–342. (b) Hayashi, M.; Inoue, T.; Miyamoto, Y.; Oguni,
N. Tetrahedron 1994, 50, 4385–4398. (c) Hayashi, M.; Yoshimoto, K.;
Hirata, N.; Tanaka, K.; Oguni, N.; Harada, K.; Matsushita, A.; Kawachi,
Y.; Sasaki, H. Isr. J. Chem. 2001, 41, 241–246.
(12) Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.;
Kumada, M. J. Org. Chem. 1983, 48, 2195–2202.
(13) (a) Loiseleur, O.; Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz,
A. J. Organomet. Chem. 1999, 576, 16–22. (b) Drury, W. J.; Zimmermann,
N.; Keenan, M.; Hayashi, M.; Kaiser, S.; Goddard, R.; Pfaltz, A. Angew.
Chem., Int. Ed. Engl. 2004, 43, 70–74.
(11) (a) Tanaka, T.; Yasuda, Y.; Hayashi, M. J. Org. Chem. 2006, 71,
7091–7093. (b) Tanaka, T.; Sano, Y.; Hayashi, M. Chem. Asian J. 2008,in
press.
3510
Org. Lett., Vol. 10, No. 16, 2008

Cu(OTf)2 and 2.5 mol % of chiral ligand were used.8b This
result clearly indicates that the 2-quinolyl moiety is essential
to achieve high enantioselectivity. It should be mentioned
that remarkable rate enhancement was observed by the
addition of N,N,P-ligands. That is, in the absence of ligands,
the product was obtained only in 31% conversion under the
same condition of entries 7 and 11 in Table 1 (>99%
conversion, 0.1 mol % of Cu(OTf)2, -40 °C, 24 h).
Under optimum conditions, that is, use of 0.1 mol % of
Cu(OTf)2 and 0.25 mol % of chiral ligand, we examined
the reaction of various cyclic enones, such as 2-cyclopenten-
1-one (4), 2-cyclohexene-1-one (3), 4,4-dimethyl-2-cyclo-
hexene-1-one (5), and 2-cyclohepten-1-one (6), with dime-
thylzinc and diethylzinc. Unfortunately, the reaction of
n-Bu2Zn with enones 3 and 4 gave n-butylated ketones in
low ee (12-36% ee) (entries 5, 6, 13, and 14, Table 2). We
the case of Me2Zn) and from 44% to 93% (in the case of
Et2Zn) (entries 1-4, Table 2). In the case of enones 3 and
5, the nature of R3 did not markedly influence reactivity and
selectivity. For the reaction of 2-cyclohepten-1-one (6), the
ligand having an i-Pr group gave higher ee than the one
having a t-Bu group, contrasting the results of the reaction
of 2-cyclopenten-1-one (4) (entries 17-20, Table 2).
The reaction of an acyclic enone, chalcone, with Et2Zn
using 0.1 mol % of Cu(OTf)2 and N,N,P-ligands 1 and 2
gave the 1,4-adduct in 8% ee (36% yield) and 63% ee (52%
yield), as shown in Scheme 3.
Scheme 3
Table 2. Enantioselective 1,4-Addition of Dialkylzinc to Cyclic
Enones
The combination of Ni(acac)2-N,N,P-ligands 1 and 2
afforded the 1,4-adduct in 78% ee (82% yield) and 90%
ee (77% yield), respectively, as shown in Scheme 4.
entry
n
R1
R2
R3
temp/°C convn/%a
ee/%a
1
2
3
4
5
6
7
8
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Et
i-Pr
t-Bu
i-Pr
t-Bu
-20
-20
-40
-40
-40
-40
-40
-40
-20
-20
-40
-40
-40
-40
-20
-20
-40
-40
-40
-40
74
88
70
85
64
67
59
35
88
77
>99
>99
58
66
9
58 (S)
92 (S)
44 (S)
93 (S)
36 (S)
14 (S)
99 (S)
97 (S)
98 (S)
98 (S)
98 (S)
96 (S)
12 (S)
18 (S)
86 (R)
82 (R)
88 (S)
83 (S)
79 (S)
68 (S)
Et
Scheme 4
n-Bu i-Pr
n-Bu t-Bu
Me
Me
Me
Me
Et
i-Pr
t-Bu
i-Pr
t-Bu
i-Pr
t-Bu
9
10
11
12
13
14
15
16
17
18
19
20
Et
n-Bu i-Pr
n-Bu t-Bu
Me Et
Me Et
H
H
H
H
i-Pr
t-Bu
i-Pr
t-Bu
i-Pr
t-Bu
6
Me
Me
Et
44
32
61
47
Although a large amount of catalyst is required in the Ni
system, compared with the Cu system, our newly devel-
oped ligands 1 and 2, particularly ligand 2, have high
enantioselectivity even in combination with Ni (Scheme
4). It should be noted that in hitherto reported studies of
the utility of the Ni catalyst system in the enantioselective
addition of dialkylzincs to enones most involved the
addition to acyclic enones, and reports on the addition to
cyclic enones are few. Thus, this Ni catalyst system proved
to be useful for cyclic enones.
Et
a The conversions and ee values were determined by GC analysis
(Supelco γ-DEX-225 for entries 1-16; Supelco ꢀ-DEX-225 for entries
17-20).
suppose the bulkiness of subtituents of ligands and dialky-
lzincs totally affects the structure of the transition state at
which stage the enantioselection will be determined. For
2-cyclopenten-1-one (4), the effect of substituents R3 in the
ligand was remarkable, and enantioselectivity was increased
dramatically; that is, ee was increased from 58% to 92% (in
In conclusion, we have revealed a new entry of chiral
N,N,P-tridentate ligands that promote the highly enantiose-
Org. Lett., Vol. 10, No. 16, 2008
3511

lective 1,4-addition of dialkylzinc to enones (up to 99% ee)
in combination with Cu(OTf)2.14
Acknowledgment. This paper is dedicated to Professor
Ryoji Noyori on the occasion of his 70th birthday. This work
was supported by Grants-in-Aid for Scientific Research on
Priority Areas “Advanced Molecular Transformations of
Carbon Resources” and No. B17340020 from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
(14) A typical experimental procedure for asymmetric 1,4-addition is
as follows (Table 1, entry 8): A solution of Cu(OTf)2 (3.6 mg, 0.01 mmol)
and ligand (10.6 mg, 0.025 mmol) in dichloromethane (1.5 mL) was stirred
under an argon atmosphere at room temperature for 0.5 h. To the solution
was added 2-cyclohexen-1-one (96 mg, 1 mmol) followed by dropwise
addition of Et2Zn (1.5 mmol, 1.5 mL of 1.0 M solution in hexane) at 0 °C.
After stirring for 5 h at 0 °C, the reaction mixture was quenched with 1 N
HCl solution (2 mL) and was extracted with Et2O (10 mL × 3). The
combined organic layer was washed with saturated aq NaHCO3 and dried
over Na2SO4. After the solvent was evaporated, an oily residue was purified
by silica gel column chromatography (hexane/Et2O ) 4/1) to afford 106
Supporting Information Available: Details of experi-
mental procedures and characterization data (1H and 13C
NMR, IR, mass spectrometry, and elementary analyses) for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
28
mg (84%) of 3-ethylcyclohexanone (99% ee (S)). [R]D -15.6° (c 1.0,
CHCl3) (lit.8e [R]D -8.8° (c 1.6, CHCl3) for 82% ee (S)). Data of the
26
conversion and the ee value of the product were determined by chiral-
phase GC analysis with a γ-DEX-225 (Supelco) column (30 m × 0.25 mm).
The absolute configuration was determined by comparison with literature
values.8e
OL801259U
3512
Org. Lett., Vol. 10, No. 16, 2008