Grignard cross-coupling catalyzed by chiral phosphino-quincorine and phosphino-quincoridine derivatives

Article abstract of DOI:10.1016/S0957-4166(01)00342-1

New β-aminoalkylphosphines with a stereogenic nitrogen center have been synthesized from quincorine and quincoridine. Nickel catalysts were studied for their enantioselectivity in the asymmetric Kumada-Corriu reaction. The (2S,4S,5R)-2-diphenylphosphinomethyl-5-ethyl-quinuclidine-nickel complex led to e.e. of 85% for the cross-coupling of l-phenylethyl-magnesium chloride with vinyl bromide.

Full text of DOI:10.1016/S0957-4166(01)00342-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1983–1985
Grignard cross-coupling catalyzed by chiral phosphino–quincorine
and phosphino–quincoridine derivatives
Ste´phane Pellet-Rostaing,a Christine Saluzzo,a Rob Ter Halle,a Je´re´my Breuzard,a Laurent Vial,a
Fre´de´ric Le Guyaderb and Marc Lemairea,*
aLaboratoire de Catalyse et Synthe`se Organique, UMR 5622, UCBL, CPE, 43 bd du 11 novembre 1918,
69622 Villeurbanne Cedex, France
bRhodia, CR de Lyon, 85 av des Fre`res Perret, 69192 Saint Fons Cedex, France
Received 12 June 2001; accepted 30 July 2001
Abstract—New b-aminoalkylphosphines with a stereogenic nitrogen center have been synthesized from quincorine and quin-
coridine. Nickel catalysts were studied for their enantioselectivity in the asymmetric Kumada–Corriu reaction. The (2S,4S,5R)-2-
diphenylphosphinomethyl-5-ethyl-quinuclidine–nickel complex led to e.e. of 85% for the cross-coupling of 1-phenylethyl-
magnesium chloride with vinyl bromide. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
of numerous complexes of transition metals used in
asymmetric catalysis.1 A major interest in these ligands
was their use in the synthesis of nickel complexes used
for the Grignard cross-coupling reaction with aryl or
vinyl halides, which has met with an unprecedented
success using Kumada’s aminoalkylphosphines.2,3
The synthesis of optically pure isomers constitutes a
major goal in the field of fine chemistry. The improve-
ment of the enantioselectivity of asymmetric reactions
involves the development of new chiral ligands, the
chirality of which is carried by the carbon skeleton
and/or the electronic differentiation of coordination
atoms. In this latter case, the metallic center could be
coordinated, either by a hard nitrogen donor or by a
soft phosphorus donor. Thus amino-phosphine type
ligands have been developed to lead to the preparation
In our laboratory, we chose to illustrate this concept by
the synthesis of aminophosphine ligands bearing a
stereogenic nitrogen atom and to test their abilities as
catalysts for asymmetric Grignard cross-coupling, also
called the Kumada–Corriu reaction.4
ii
i
iii
H
H
H
N
.HCl
H
N
N
N
77%
24%
100%
3a
4a
4b
1a
2a
Cl
PPh2
OH
OH
ii
i
iii
N
N
.HCl
N
Ph2P
N
Cl
HO
HO
56%
100%
24%
H
H
H
H
1b
2b
3b
Scheme 1. (i) H2, Pd/C 10%, THF, rt, Ar; (ii) (a) HCl 33%, EtOH; (b) SOCl2, CHCl3, 0°C; (iii) HPPh2, tert-BuOK, THF, reflux,
Ar.
* Corresponding author. Tel.: 33-(0)4-72-43-14-07; fax: 33-(0)4-72-43-14-08; e-mail: marc.lemaire@univ-lyon1.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00342-1

1984
S. Pellet-Rostaing et al. / Tetrahedron: Asymmetry 12 (2001) 1983–1985
2. Results and discussion
better conversion than 4a (runs 1 and 3). At low
temperature, despite giving a lower yield (50%), 4a gave
the product with high e.e. of 85% (run 2), close to the
values obtained under the same conditions with
Kumada’s tert-leuphos (83%) or valphos (81%)2,3 and
Kellog’s homomethphos (88%)13 ligand. Thus, the
nickel-(2S,4S,5R)quinphos 4a complex is one of the
best systems described in the literature to date.
Quincorine 1a and quincoridine 1b are bicyclic b-amino
alcohols obtained by cleavage of the alkaloid analogues
quinine and quinidine.5,6 These fragments have four
stereogenic centers each, including the stereogenic (S)-
configured N-bridgehead.
Although several works focused on the transformation
of these building blocks to use them as novel medicinal
receptors,7–10 none mentioned their use as ligands for
asymmetric catalysis. Among these derivatives, vinylic
3. Experimental
analogues
of
(2S,4S,5R)-
and
(2R,4S,5R)-2-
3.1. Reduction of vinylic function of 1a and 1b
diphenylphosphino-5-ethyl-quinuclidine (quinphos 4a
and 4b) have been obtained by Hoffmann et al.9 via
mesylate intermediates. Using a modified synthetic
route, we prepared 4a and 4b in four steps via
chloromethyl intermediates (Scheme 1).
Under Ar, at room temperature, 1a (or 1b) (1 g, 6
mmol) and Pd/C 10% (1 g) were maintained under H2
(1 Bar) in THF (60 mL) for a period of 8 h. The
resulting solution was filtered through Celite and the
filtrate was evaporated to give pure 2a and 2b (100%
yield) (for characterization, see Ref. 9).
To avoid eventual side reactions with the vinyl func-
tionality and to prevent potential vinyl–metal interac-
tions during the preparation of catalysts, 1a and 1b
were firstly hydrogenated with a Pd/C catalyst afford-
ing dihydro derivatives 2a and 2b quantitatively.11 In
order to exclude the possible intramolecular aziridinium
ion formation,12 the amine hydrochloride analogues
were prepared with HCl in EtOH and converted into
chloromethyl compounds 3a and 3b with SOCl2 in good
yields. Finally, introduction of the diphenylphosphine
residue was carried out by the standard procedure using
tert-BuOK and HPPh2 in THF. Purification by chro-
matography afforded diastereomerically pure quinphos
(2S,4S,5R)-4a and (2R,4S,5R)-4b, both in 24% yield.
3.2. Synthesis of 3a and 3b
A solution of alcohol 2a or 2b (0.9 g, 5.3 mmol) in
ethanol (10 mL) was added to a solution of 37%
hydrochloric acid (4 mL) in ethanol (10 mL). After
stirring the mixture for 30 min, the solvent and the
excess acid were removed under reduced pressure. Thio-
nyl chloride (1 mL) was then added to a solution of the
amine hydrochloride in CHCl3 (10 mL) at 0°C. After
stirring the mixture for 2 h under reflux, the solvent was
removed and the residue dissolved in ethanol (2 mL).
Dropwise addition of Et2O provided white crystals
which were collected by filtration. Drying under vac-
uum at 50°C over P2O5 gave pure 3a or 3b in 56 and
81%, respectively. 3a: ES-MS (ES+): 188.0 ([M+H]+);
411.2 ([2M+HCl+H]+); (ES−): 258.0 ([M+Cl]−); 296.0
([M+HCl+Cl]−). 1H NMR (CDCl3): 0.82 (t, 3H, J=
7.1); 1.4–2.2 (m, 8H); 2.8–4.0 (m, 7H); 11.89 (s, 1H).
13C NMR (CDCl3): 11.5; 24.3; 24.6; 26.6; 34.9; 41.6;
43.5; 55.6; 57.4. 3b: ES-MS (ES+): 188.0 ([M+H]+);
411.2 ([2M+HCl+H]+); (ES−): 258.0 ([M+Cl]−); 296.0
([M+HCl+Cl]−). 1H NMR (CDCl3): 0.92 (t, 3H, J=
7.1); 1.3–2.2 (m, 8H); 2.7–4.4 (m, 7H); 12.28 (s, 1H).
13C NMR (CDCl3): 11.4; 23.9; 24.5; 24.8; 24.9; 35.2;
42.7; 48.5; 48.6; 57.5.
Quinphos 4a and 4b were examined for their enantiose-
lectivity in the cross-coupling of 1-phenylethylmagne-
sium chloride with vinyl bromide in the presence of
nickel chloride (Scheme 2). The chiral catalysts (0.5%)
were prepared in situ by mixing nickel chloride and the
ligand in a 1:1 ratio. Table 1 summarizes the reaction
conditions and results. At 25°C, catalyst 4a led to better
enantioselectivity than 4b, which nevertheless gave a
MgCl
NiCl2, L*, Et2O
*
3.3. Synthesis of quinphos 4a and 4b
, 12h
Br
To a suspension of tert-BuOK (11.5 mmol) in anhy-
drous THF (20 mL) was added diphenylphosphine (2.2
mmol). After stirring the mixture for 30 min at room
temperature, amine hydrochloride salts 3a or 3b (0.5 g,
2.2 mmol) were added to the red solution. The reaction
mixture was heated under reflux until the total disap-
pearance of the color. After evaporation of the solvent,
aqueous HCl (10%, 10 mL) was added to the residue.
The aqueous layer was extracted with toluene, neutral-
ized with 10% NaOH and then extracted with toluene.
The organic layer was rinsed with brine, dried with
Na2SO4 and evaporated. Purification by filtration
through alumina led to pure 4a and 4b as colorless oils
in 24% yield. 4a: [h]D25=+15.9 (c=1, THF). ES-MS
Scheme 2.
Table 1. Nickel-catalyzed cross-coupling of 1-phenylethyl-
magnesium chloride with vinyl bromide
Run
Ligand
Temperature
(°C)
Yielda
(%)
E.e.a
(%)
1
2
3
(2S,4S,5R)-4a
(2S,4S,5R)-4a
(2R,4S,5R)-4b
25
0
25
65
50
80
75 (+)
85 (+)
65 (−)
a Yield and enantioselectivity were determined on a b-dex (0.25
mm×60 m) column with styrene as internal standard.

S. Pellet-Rostaing et al. / Tetrahedron: Asymmetry 12 (2001) 1983–1985
1985
1
(ES+): 338.2.0 ([M+H]+). 31P (CDCl3): −22.0. H NMR
(CDCl3): 0.75 (t, br, 3H); 1.0–3.2 (m, 15H); 7.2–7.7 (m,
10H); 13C NMR (CDCl3): 11.9; 25.7; 26.9; (d, J=5); 29.2;
29.7 (d, J=7); 37.4 (d, J=12); 37.9; 48.7 (d, J=11); 48.9
(d, J=17); 128.4; 128.5; 128.6; 132.7; 132.9. 4b: [h]2D5=
Organometallics 2001, 20, 2570–2578 and references cited
therein.
2. Hayashi, T.; Fukushima, M.; Konishi, M.; Kumada, M.
Tetrahedron Lett. 1980, 21, 79–82.
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2202.
4. Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159–2231.
−16.2 (c=1, THF). ES-MS (ES+): 338.2.0 ([M+H]+). 31
P
1
(CDCl3): −22.0. H NMR (CDCl3): 0.87 (t, br, 3H);
1.0–1.8 (m, 9H); 2.0–3.0 (m, 6H); 7.2–7.6 (m, 10H); 13C
NMR (CDCl3): 12.1; 25.8; 26.5; (d, J=5); 27.3; 29.6 (d,
J=7); 35.1 (d, J=12); 37.9; 49.1 (d, J=11); 53.4 (d,
J=17); 128.3; 128.4; 128.5; 133.0; 133.1.
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3.4. Typical Kumada–Corriu reaction
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3982–3996.
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R. Tetrahedron 2000, 56, 4453–4465.
Under Ar, vinyl bromide (20 mmol) and 1-phenylethyl-
magnesium chloride (40 mmol) were successively added
to a solution of anhydrous NiCl2 (0.1 mmol) and chiral
quinphos (0.1 mmol) in ether (40 mL) at −78°C. The
mixture was kept at 0°C for 12 h and hydrolyzed with
aqueous HCl (10%). The organic layer was extracted with
ether, washed with saturated Na2CO3 solution and dried
over anhydrous Na2SO4.
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References
1. For a detailed bibliography of the use of P,N type ligands
for asymmetric reactions, see: Kwong, F. Y.; Chan, K. S.