New phosphoramidite and phosphito-N chiral ligands based on 8-substituted quinolines and (S)-binaphthol; applications in the Cu-catalyzed enantioselective conjugate addition of diethylzinc to 2-cyclohexen-1-one

Article abstract of DOI:10.1016/S0957-4166(00)00188-9

The copper(II)-catalyzed enantioselective conjugate addition of diethylzinc to 2-cyclohexen-1-one, in the presence of phosphoramidite and of phosphito-N chiral ligands, derived from 8-chloroquinoline or 8-hydroxyquinoline and (S)-4-chloro-3,5-dioxa-4-phos

Full text of DOI:10.1016/S0957-4166(00)00188-9

Tetrahedron: Asymmetry 11 (2000) 2387±2392
New phosphoramidite and phosphito-N chiral ligands based
on 8-substituted quinolines and (S)-binaphthol; applications
in the Cu-catalyzed enantioselective conjugate addition of
diethylzinc to 2-cyclohexen-1-one
Carmela G. Arena, GianPiero Calabro, Giancarlo Francio and Felice Faraone*
Á Á
Dipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica dell'UniversitaÁ di Messina,
Salita Sperone 31, Villaggio S. Agata, 98166 Messina, Italy
Received 6 April 2000; accepted 9 May 2000
Abstract
The copper(II)-catalyzed enantioselective conjugate addition of diethylzinc to 2-cyclohexen-1-one, in the
presence of phosphoramidite, and of phosphito-N chiral ligands, derived from 8-chloroquinoline or 8-
0
hydroxyquinoline and (S)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a ]binaphthalene, resulted in
ee's of 70 and 51%, respectively. # 2000 Elsevier Science Ltd. All rights reserved.
1
. Introduction
The conjugate addition of dialkylzinc to a,b-unsaturated enones is a reliable method for the
1
synthesis of b-substituted carbonyl compounds. Although primary diorganozinc compounds do
2
not generally react with a,b-unsaturated cyclic and acyclic enones, these reactions occur in the
presence of catalytic amounts of Cu , Ni and Zn salts. The catalytic e€ect has been explained
either by alkyl transfer or by changes in the linear geometry and bond energy of the dialkylzinc
I
II
II
3
reagent upon coordination of the ligands.2 Recently, catalytic enantioselective conjugate addi-
�5
tion of organometallic reagents, particularly dialkylzinc, to enones has been achieved by chiral
I
II
II
4
Cu , Ni and Zn complexes. A variety of chiral ligands have been used in the metal-catalyzed
,6�8
,4-addition of dialkylzinc to enones.4
chiral ligands based on a chiral amine-moiety and on 3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a ]-
Feringa et al. have successfully used phosphoramidite
0
7
1
binaphthalene. With this ligand complete enantiocontrol in the Cu-catalyzed 1,4-additions of
8
dialkylzinc to cyclohexenone has been achieved. Several chiral-P,N ligands have also been developed.
Pfaltz et al.8 used chiral oxazoline-phosphite ligands in the Cu-catalyzed conjugate addition of
b
*
Corresponding author. E-mail: faraone@chem.unime.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00188-9

2
388
C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 2387±2392
8c
organometallic compounds to enones, while Stangeland and Sammakia employed chiral oxazoline-
phosphine ligands in the same type of reactions. Zhang et al.8 successfully used a chiral P,N
ligand that combines a diarylphosphine group and a substituted pyridine with a chiral binaphthyl
system.
d
We are interested in developing bulk mono- and bidentate-chiral ligands based on the rigid
quinoline backbone and in their applications in enantioselective homogeneous catalysis.9 Herein,
we wish to report the synthesis of new chiral phosphito-N ligands derived from the 8-hydroxy-
quinoline or on the 8-hydroxy-2-methyl-quinoline and (S)-4-chloro-3,5-dioxa-4-phosphacyclo-
,10
0
hepta[2,1-a;3,4-a ]binaphthalene, 1 and 2, and their applications in the enantioselective copper-
catalyzed conjugate addition of Et Zn to 2-cyclohexen-1-one, 4. The chiral phosphoramidite
ligand 3 was also tested in the same type of reaction.
2
2
. Results and discussion
The new chiral phosphito-P,N ligands 1 and 2 (Fig. 1) were obtained by adding equimolar
0
solutions of (S)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a ]binaphthalene to 8-hydroxy-
ꢀ
quinoline or 8-hydroxy-2-methyl-quinoline in the presence of NEt at 0 C in toluene. Compounds
3
1
and 2 are white moisture-sensitive solids that are soluble in most common solvents except
alkanes. The new compounds were fully characterized by elemental analysis and NMR spectro-
scopy. In the 31P{ H} NMR spectrum, in CDCl , they exhibit resonances at ꢀ 142.7 (1) and ꢀ
1
1
3
1
41.3 (2) respectively; in the H NMR spectrum of 2, in CDCl , the protons of the methyl group
3
in 2-position of the quinoline ring give rise to a signal at ꢀ 2.67.
Figure 1.
The phosphoramidite ligand 3 (BINAPHOSHQUIN) (Fig. 1) has been previously reported by
9
us together with its rhodium(III), palladium(II) and platinum(II) complexes. Compound 3 was
obtained by allowing 8-chloroquinoline to react with n-BuLi in a 1:1 molar ratio in tetra-
ꢀ
hydrofuran at ^78 C and subsequent addition of (S)-4-chloro-3,5-dioxa-4-phosphacyclohepta-
0
[
2,1-a;3,4-a ]binaphthalene. The (S S )-3 (3a) and (S R )-3 (3b) diastereomers of BINA-
a
C
a C
PHOSHQUIN were separated by means of their di€erent solubilities in hexane. Their absolute
con®gurations were derived from the crystal structure of a platinum(II) compound synthesized
using only one diastereomer.9

C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 2387±2392
2389
We selected 2-cyclohexen-1-one, 4, as a typical substrate to test the eciency of the catalytic
system formed by Cu(OTf) and the ligands 1, 2 and 3 in the enantioselective conjugate addition
2
of Et Zn to enones (Scheme 1).
2
Scheme 1.
The results are summarized in Table 1. Comparison of the experimental data obtained with the
ligands 1 and 2 (entries 1±7) clearly indicates that in the latter the methyl group in the ortho
position to the nitrogen atom exerts a bene®cial e€ect on the enantioselectivity of the process.
The Cu(OTf) :4 molar ratio and the solvent have a signi®cant e€ect on the reaction time and on
2
the enantioselectivity. The most promising result was obtained using ligand 2 with a Cu(OTf) :4
2
ꢀ
molar ratio of 0.03 at ^15 C, in CH Cl as a solvent. Under these conditions the conversion is
2
2
almost complete within 2 h and (S)-3-ethylcyclohexanone 5 was obtained in 51% ee (entry 7). In
toluene the corresponding ee value was lowered to 35% (entry 5). The reaction proceeded more
slowly and less selectively when the catalyst loading was reduced (entry 6).
Table 1
Cu-catalyzed enantioselective 1,4-addition of diethylzinc to cyclohex-2-enone 4
Using the phosphoramidite 3a as a ligand in the reaction under investigation, the addition is
ꢀ
very fast at ^15 C and 5 was obtained as a racemic mixture (entry 9). In contrast to 3a, employing
the diastereomer 3b as a ligand, 5 was obtained in more than 96% yield with an enantiomeric
ꢀ
excess of 70%. The reaction was run in toluene at ^15 C, in the presence of an excess of Et Zn,
2
and using a molar ratio 3b:Cu(OTf) =2 (entry 10). When the reaction temperature was lowered
ꢀ
2
ꢀ
from ^15 C to ^30 C the enantioselectivity decreased to 54% and a longer reaction time was

2
390
C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 2387±2392
needed to obtain quantitative conversion (entry 11). Similar e€ects of the reaction temperature on
related reactions have been reported. Toluene was found to be the solvent of choice if the
reactions were performed with ligand 3b, whereas higher ee's could be achieved with ligands 1 or
11
4e,f
2
version rate and the ee. Increasing the molar ratio of 3b: Cu(OTf) from 2:1 to 4:1 decreased the
if CH Cl was used instead.
The coordinating solvent acetonitrile diminishes both the con-
2
2
2
catalytic activity as well as the enantioselectivity (compare entries 10 and 12). The excess ligand
probably prevents the formation of open coordination sites required for the transfer of the ethyl-
group from Et Zn to the Cu-complex. A similar e€ect was observed by Chan et al. using chiral
2
aryl-diphosphites.12
The striking di€erence in the catalytic behaviour of the diastereomeric forms S S and S R of
a
C
a C
3 may be related to the di€erent orientation of the quinoline's chlorine atom in the intermediate
copper complex. It was demonstrated that the di€erent nature of the products obtained by
allowing the diastereomers (R R )-3 and (R S )-3 to react with [Rh(CO) Cl] is due to the posi-
2
a
C
a
C
2
tion assumed by the Cl atom relative to the metal. Only in the case of the diastereomer (R R )-3
a
C
9
was intramolecular redox addition of the C±Cl bond to the rhodium centre observed. Further-
more, the relative con®guration of the stereogenic centre in respect of the atropoisomeric moiety
was found to be a crucial factor in determining matching and mis-matching combinations in
enantioselective reactions for related bidentate ligands.10
Although the phosphoramidite ligand 3b allows acceptable enantioselectivity in copper-catalyzed
conjugate addition of Et Zn to 2-cyclohexen-1-one, the results are less satisfactory than those
2
obtained by Feringa et al. using similar ligands. The two ligand systems have an identical dioxa-
phosphepine unit but di€erent substituents on the nitrogen. The nitrogen atom is part of a C1-
symmetrical heterocycle in the new ligand 3b, whereas two chiral substituents at nitrogen lead to an
overall C symmetry for Feringa's ligand system. C -Symmetrical ligands are also usually more
2
2
e€ective chiral auxiliaries for other catalytic processes such as hydrogenation, although sig-
ni®cant exceptions are known.13
In summary, we reported on the synthesis of two new chiral-P,N ligands and on their application
in the Cu-catalyzed asymmetric conjugate addition of diethylzinc. Enantioselectivities up to 70%
were reached with phosphoramidite ligand BINAPHOSHQUIN. Further studies on other reac-
tions with these ligands are in progress.
3
. Experimental
A published method was used to prepare the compound (S)-4-chloro-3,5-dioxa-4-phosphacyclo-
0
9
hepta[2,1-a;3,4-a ]binaphthalene. All other reagents were purchased from Sigma±Aldrich and were
used as supplied. Solvents were dried by standard procedures. All experiments were performed
under puri®ed nitrogen. For column chromatography, silica gel 60 (220±440 mesh) purchased
from Fluka was used. NMR experiments were carried out using a Bruker AMX R300 spectrometer.
1
31
1
H NMR spectra were referenced to internal tetramethylsilane and P{ H} spectra to external
5% H PO . Elemental analyses were performed by Redox s.n.c., Cologno Monzese, Milano.
3 4
8
3
.1. General procedure for the synthesis of phosphite-quinoline ligands 1±2
A solution of the appropriate quinoline (8-hydroxyquinoline for 1 and 8-hydroxy-2-methyl-
quinoline for 2) (3.28 mmol) and Et N (0.653 g, 6.57 mmol) in toluene (10 mL) was added
3

C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 2387±2392
2391
0
dropwise to a solution of (S)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a ]binaphthalene
ꢀ
(1.390 g, 3.28 mmol) in the same solvent (15 mL) at 0 C. The reaction mixture was stirred over-
night at room temperature and then the precipitate of Et N HCl formed was removed by ®ltration.
.
3
The toluene was evaporated from the ®ltrate. The residue was washed with hexane (5 mL) and
dried. A white solid was obtained in 90% yield. Compound 1: anal. calcd for C H NO P: C,
29
18
3
1
7
CH), 9.01 (d, 1H, CH). P{ H} NMR (C D ) 142.7 (s). Compound 2: anal. calcd for
5.81; H, 3.95; N, 3.05. Found: C, 75.77; H, 3.91; N, 2.98. H NMR (C D ) ꢀ 7.15±8.15 (m, 17H,
6 6
31
1
6
6
1
C H NO P: C, 76.10; H, 4.26; N, 2.96. Found: C, 76.22; H, 4.30; N, 2.93. H NMR (C D ) ꢀ
3
0
20
3
6
6
31
1
2
.67 (s, 3H, CH ); 6.76±7.73 (m, 17H, CH). P{ H} NMR (C D ) 141.3 (s).
6
3
6
3
.2. General procedure for asymmetric 1,4-conjugate addition
A solution of Cu(OTf) (18.1 mg, 0.050 mmol) and 3b (53.8 mg, 0.100 mmol) in toluene (5 mL)
2
ꢀ
was stirred for 1 h. The dark-pink solution was cooled (^15 C) and 2-cyclohexen-1-one (159.6
mg, 1.666 mmol) and 1.6 mL of Et Zn (1.1 M solution in toluene) were added slowly. The
ꢀ
2
resulting mixture was stirred at ^15 C until the conversion was almost complete. Then HCl 1N
(
25 mL) was added and the mixture extracted with Et O (2Â20 mL). The organic phase was
2
washed with brine (20 mL), dried over MgSO , and concentrated under vacuum. The crude product
4
was puri®ed by column chromatography on silica gel (hexane:diethyl ether, 5:1) to a€ord the 1,4-
product. The ee values were determined by 13C NMR.
14
Acknowledgements
Financial support from MURST is gratefully acknowledged.
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