Enantioselective copper-catalyzed conjugate addition of diethylzinc to enones using new chiral P,N ligands composed of (S)-2-alkyl-2-aminoethylphosphines and α-substituted pyridines

Article abstract of DOI:10.1016/S0040-4039(00)01789-5

New P,N ligands prepared from (S)-2-alkyl-2-aminoethylphosphines and α-substituted pyridines are efficient chiral ligands for the copper-catalyzed conjugate addition of diethylzinc to 2-cyclohexen-1-one and chalcone. The best result (90-91% ee) for the cy

Full text of DOI:10.1016/S0040-4039(00)01789-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10025–10029
Enantioselective copper-catalyzed conjugate addition of
diethylzinc to enones using new chiral P,N ligands
composed of (S)-2-alkyl-2-aminoethylphosphines and
a-substituted pyridines
Toshiaki Morimoto,* Yoichi Yamaguchi, Masato Suzuki and Akihito Saitoh
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka-shi 422-8526, Japan
Received 4 September 2000; revised 2 October 2000; accepted 6 October 2000
Abstract
New P,N ligands prepared from (S)-2-alkyl-2-aminoethylphosphines and a-substituted pyridines are
efficient chiral ligands for the copper-catalyzed conjugate addition of diethylzinc to 2-cyclohexen-1-one
and chalcone. The best result (90–91% ee) for the cyclohexenone was obtained with Cu(OTf)2 (0.7–1
mol%) and a P,N ligand 4 derived from (S)-1-(diphenylphosphino)-3-methyl-2-butanamine and 6-
methylpyridine-2-carboxaldehyde. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: copper catalysts; chiral ligands; asymmetric conjugate addition; enones.
The 1,4-addition of various organometallic reagents to a,b-unsaturated carbonyl or related
compounds is an important method for carbonꢀcarbon bond formation. Numerous chiral
auxiliaries or stoichiometric reagents have been reported for asymmetric conjugate additions,
while only a few chiral catalysts for the highly enantioselective conversions have been developed
recently.1
Among several metal-catalyzed 1,4-additions, chiral copper and nickel complexes have been
most widely investigated in the enantioselective addition of Grignard and dialkylzinc reagents to
enones.2–4 Since the first report on the enantioselective Cu-catalyzed 1,4-addition with diethyl-
zinc in 1993,5a a number of chiral phosphoramidites and phosphites have been developed as
ligands by several groups, namely, Alexakis,5 Feringa,6 Chan7 and Pfaltz;8 most of the highly
enantioselective ligands are constructed with chiral binaphthol, which is an important frame-
work for efficient enantioselection. Other new types of chiral ligands have been developed
recently for efficient Cu-catalyzed conjugate addition of diethylzinc to enones.9–12 Acyclic
* Corresponding author. E-mail: morimtt@ys2.u-shizuoka-ken.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01789-5

10026
enones, five-membered enones, and some other a,b-unsaturated compounds are relatively
difficult substrates to achieve high ee with diethylzinc and Cu catalysts in comparison with
six-membered enones.
Since there are few chiral ligands generally efficient for the asymmetric conjugate addition to
most a,b-unsaturated compounds, the development of other new types of chiral ligands is
greatly desired.
We have recently developed versatile chiral P,N-bidentate ligands, VALAP (1) and its
analogs, and C2-symmetric diphosphine ligands by employing (S)-2-alkyl-2-aminoethylphos-
phines as chiral units, which are readily accessible from chiral aminoalcohols obtained by
reduction of a-amino acids, and disclosed that the palladium complexes of these ligands are
efficient catalysts in enantioselective allylic substitution of acyclic and cyclic allyl esters.13 Since
the chiral unit, (S)-2-alkyl-2-aminoethylphosphine, was found to have an effective chiral
environment, we planned to employ it as a useful framework of new ligands for enantioselective
copper-catalyzed conjugate additions. In this paper we report the synthesis and application of a
series of P,N ligands consisting of the aminoethylphosphines and a-substituted pyridines in the
catalytic conjugate addition of diethylzinc to enones.
Chiral units, (S)-1-(diphenylphosphino)-3-methyl-2-butanamine and (S)-1-(diphenylphos-
phino)-2-propan-amine, were prepared from (S)-valinol and (S)-alaninol, respectively, according
to the reported procedure.13a,d,f Arylidene derivatives (2–5, 9)14 were obtained quantitatively by
condensation of the phosphinoalkanamines and the corresponding aromatic aldehydes. Reduc-
tion of 4 with lithium aluminum hydride gave 8. Picolinamide derivatives (6, 7) were prepared
by acylation with the corresponding acids and a condensing agent (EDCI, HOBT, NEt3).
N
PPh2
N
PPh2
N
PPh2
N
PPh2
N
PPh2
Me2N
N
N
N
VALAP (1)
2
3
5
4
O
O
NH PPh2
NH PPh2
NH PPh2
N
PPh2
N
N
N
S
6
8
9
7
Asymmetric copper-catalyzed conjugate addition of diethylzinc to a cyclic enone, 2-cyclo-
hexen-1-one, was chosen as a model reaction for evaluation of the P,N ligands (1–9). Typically,
the reaction was carried out with Cu(OTf)2 (1 mol%) and a ligand (2.5 mol%) at 0°C in
dichloromethane.15 The results are summarized in Table 1. Preliminary experiments with
P,N-bidentate ligands, VALAP (1) and a benzylidene derivative (2), gave only products with
disappointingly low ee. Then, we envisaged that the introduction of another coordinating group
to the ligand 2 might improve the enantioselectivity since the tridentate ligand can stabilize a
possible monoalkylcopper(I) intermediate, forming a more rigid chiral environment. As shown
in entry 3, a 2-pyridinomethylene derivative (3) gave a considerably improved enantioselectivity.
Introduction of a methyl group to the 6-position of the pyridine ring of 3 further increased the
enantioselectivity up to 91% ee (entry 4, ligand 4). With an analogous ligand 5 having an
(S)-2-methyl group in place of the isopropyl group, the enantioselectivity dropped seriously

10027
Table 1
Copper-catalyzed enantioselective conjugate addition of diethylzinc to 2-cyclohexen-1-one
O
O
Cu(OTf)2 (1 mol%)
ligand (2.5 mol%)
+
Et2Zn
Entry
Ligand
Solvent
Temp. (°C)
Time (h)
Conv. (%)
Ee (%)
Config.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
2
3
4
4
4
4
4
4
4a
4b
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
CH2Cl2
CH2Cl2
0
0
0
0
0
5
5
5
5
5
5
5
5
5
5
5
5
81
74
95
100
100
100
84
70
34
100
26
94
4
ꢀ0
55
91
85
81
80
70
27
90
53
36
52
40
30
ꢀ0
S
–
S
S
S
S
S
S
S
S
S
S
S
S
S
–
0
20
−20
−50
0
0
0
−20
−20
0
Overnight
Overnight
5
5
85
90
100
41
0
a Cu(OTf)2/ligand=0.7/1 (mol%).
b Cu(OTf)2/ligand=0.3/0.5 (mol%).
(entry 12). Use of other solvents such as toluene and THF slightly decreased the enantioselectiv-
ity of 4 (entries 5, 6). On the other hand, the reaction temperatures had considerable effect on
the enantioselectivity; the temperatures not only higher but lower than 0°C decreased the
selectivity (entries 7–9). The amounts of Cu(OTf)2 and ligand 4 could be reduced to 0.7 and 1
mol%, respectively, while keeping the conversion (100%) and the enantioselectivity (90% ee)
(entry 10). A further reduction of the Cu(OTf)2 amount to 0.3 mol% resulted in low conversion
with an inferior ee (entry 11). a-Pyridinecarboxamide derivatives (6,7) showed moderate
selectivity in toluene (entries 13, 14). The worse enantioselectivity of 7 and 8 (entries 14, 15) in
comparison with the corresponding imino ligand (4) indicates that the tridentate phosphino,
imino and pyridino groups play important roles in forming a desirable chiral pocket around the
Cu atom for alkylation with diethylzinc followed by coordination with cyclohexenone. The
importance of the pyridino nitrogen was also demonstrated by the use of a thiophene derivative
(9), which afforded only a racemic product in a lower yield (entry 16).
A representative acyclic enone, chalcone, was next examined with ligand 4 under typical
reaction conditions. The corresponding b-ethylation product was isolated in 90% yield with 71%
ee (R). It is rare to find highly efficient ligands for the asymmetric conjugate additions to both
cyclic and acyclic enones.9
Although the mechanism of copper-catalyzed conjugate addition of diethylzinc to enones has
not been sufficiently elucidated, a possible reaction path through a monoalkylcopper(I)–ligand
complex was postulated.6b A possible key intermediate involved in the enantioselection step with

10028
the copper complex of 4 is described later. Recently, we proposed a Pr/Mr chirality model to
classify most of the chiral bidentate ligands and clarified the correlation between the chirality of
the ligands and the absolute configurations of the products in Pd-catalyzed allylic alkylation.13d,f
According to these results, (S)-2-alkyl-2-aminoethylphosphine was elucidated to have Mr
chirality. On the basis of the present results and some other reported data,7,8,11 we deduced that
Mr chirality ligands afford the (S)-product in the Cu-catalyzed conjugate addition of diethylzinc
to 2-cyclohexen-1-one.
In conclusion, we have developed new tridentate chiral ligands bearing an aminoethylphos-
phine as a chiral unit and optimized their use in the enantioselective conjugate addition of
diethylzinc to enones. Extensive work is in progress to apply the ligands to other asymmetric
reactions and to search for related efficient chiral ligands.
Acknowledgements
This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science and Culture of Japan.
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10029
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14. Selected data for 4: [h]2D3 +66.7 (c 1.05, CHCl3); 1H NMR (270 MHz, CDCl3) l: 0.91 (d, 6H, J=6.6 Hz),
2.00–2.05 (m, 1H), 2.47–2.54 (m, 2H), 2.58 (s, 3H), 3.09–3.12 (m, 1H), 7.13–7.65 (m, 13H), 8.17 (s, 1H); IR
(CHCl3): 1647 cm−1; FAB-MS: m/z 375 (MH+).
15. Typical procedure for the conjugate addition reaction: a solution of Cu(OTf)2 (3.6 mg, 0.01 mmol) and 4 (9.4 mg,
0.025 mmol) in dichloromethane (1.5 ml) was stirred under Ar atmosphere at room temperature for 0.5 h. To the
solution was added 2-cyclohexen-1-one (98 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 a
1N HCl solution (1 ml) and was extracted with ether (2×20 ml). The combined organic layer was washed with
saturated aq. NaHCO3 and dried over MgSO4. The conversion yield was 100%. After the solvent was evaporated,
an oily residue was purified by flash column chromatography (SiO2, hexane/AcOEt=5/1) to afford 100 mg (79%)
of 3-ethylcyclohexanone (91% ee (S)). The data on conversion and the ee values of the product were determined
by GC with a SE-30 column and a g-DEX-225 (Supelco) column (30 m×0.25 mm (i.d.)),9 respectively. The
absolute configurations were determined by comparison of their GC retention times with that of an authentic
sample.
.
.