New chiral phosphine-phosphites: A convenient synthesis based on the demethylation of o-anisyl phosphines and application in highly enantioselective catalytic hydrogenations

Article abstract of DOI:10.1016/S0957-4166(01)00464-5

An easy demethylation of o-anisyl phosphines provides a convenient access to a series of new chiral phosphine-phosphites. The screening of these derivatives as ligands in rhodium-catalyzed asymmetric hydrogenation of dimethyl itaconate has shown a profoun

Full text of DOI:10.1016/S0957-4166(01)00464-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2501–2504
New chiral phosphine–phosphites: a convenient synthesis based
on the demethylation of o-anisyl phosphines and application in
highly enantioselective catalytic hydrogenations
Andre´s Sua´rez and Antonio Pizzano*
Instituto de Investigaciones Qu´ımicas, Consejo Superior de Investigaciones Cient´ıficas-Universidad de Sevilla,
c/ Ame´rico Vespucio s/n, Isla de la Cartuja, E-41092 Seville, Spain
Received 9 October 2001; accepted 19 October 2001
Abstract—An easy demethylation of o-anisyl phosphines provides a convenient access to a series of new chiral phosphine–phos-
phites. The screening of these derivatives as ligands in rhodium-catalyzed asymmetric hydrogenation of dimethyl itaconate has
shown a profound influence of ligand structure on the enantioselectivity of the process. © 2001 Elsevier Science Ltd. All rights
reserved.
The need to expand the range of efficient asymmetric-
catalyzed transformations has generated an enormous
interest on the synthesis and screening of new chiral
ligands. An important strategy in the search for the
optimum catalyst relies upon the use of bifunctional
ligands that possess two chemically distinct coordinat-
ing atoms1 and are capable of inducing different reac-
tivity from that provided by the ubiquitous C2
symmetric ligands.2
R2
R2
R1
R1
P
P
P
+
O
Cl
P
O
O
OH
O
O
C
B
A
The desired phosphine–phosphites can be conveniently
prepared by condensation of a phenol–phosphine B
with the appropriate chlorophosphite C, in the presence
of a base.6 Therefore, a modular approach to the
synthesis of molecules A requires a range of reagents B
and C, either achiral or chiral in both enantiomeric
forms. Since a variety of chlorophosphites is readily
accessible from the corresponding diols, the difficulty of
the synthesis dwells in a flexible preparation of phos-
phines B.7 An adaptation to o-anisyl phosphines of the
well-known demethylation of aryl ethers8 proved suit-
able, and accordingly the reaction of phosphine 1a
(R=Ph) with 2.3 molar equivalents of BBr3,9 followed
by treatment with methanol, produced the phospho-
nium bromide 2a (Scheme 1). The corresponding phe-
nol–phosphine 3a was subsequently obtained by
deprotonation of the salt 2a with NEt3. The methyl 3b
and isopropyl 3c derivatives were prepared following
the same sequence of reactions, although on a practical
basis it is easier to isolate the corresponding phospho-
nium salts and to effect their deprotonation in situ,
before the condensation reaction. Compounds 2a and
Being aware of the unsurpassed performance of phos-
phine–phosphite ligands in asymmetric hydroformyla-
tion,3 as well as their utility in other enantioselective
catalytic reactions,4 we have undertaken a practical
synthesis of phosphine–phosphites with general struc-
ture A, and have made use of these ligands in rhodium-
catalyzed asymmetric hydrogenation. The possibility of
locating the stereogenic elements in either the phos-
phine or the phosphite sites provides considerable struc-
tural flexibility for ligand optimization. Moreover,
variable donating ability can be achieved by a proper
selection of the phosphine substituents, whereas the
rather rigid backbone of the bidentate ligand should
favor an efficient transfer of chirality when coordinated
to a metal center.5
* Corresponding author. Fax: int+954460565; e-mail: pizzano@
cica.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00464-5

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A. Sua´rez, A. Pizzano / Tetrahedron: Asymmetry 12 (2001) 2501–2504
R2
R2
H
R2
R1
R1
R1
P
P
P
(i) BBr3
NEt3
Br
(ii) MeOH
OMe
OH
OH
R1 = R2 = Ph (3a),
1a-1d
2a-2d
Me (3b), i-Pr (3c)
R1 = Me; R2 = Ph ((S)-3d)
Scheme 1.
2b can be readily purified by crystallization and they
are actually less air-sensitive than their phosphine
counterparts.
As briefly mentioned, the preparation of the desired
phosphine–phosphites can be achieved by the straight-
forward condensation of derivatives 3 with the appropri-
ate chlorophosphite, in the presence of a base. For the
sake of simplicity and cost effectiveness, we have pre-
pared a series of ligands with only one stereogenic
element (Scheme 2). Thus, phosphines 3a–c were com-
bined with (S)-3,3%-di-tert-butyl-5,5%,6,6%-tetramethyl-
2,2%-bisphenoxyphosphorus chloride 4a,14 while chiral
(S)-3d was reacted with conformationally flexible
3,3%,5,5% - tetra - tert - butyl - 2,2% - bisphenoxyphosphorus
chloride 4b.15
With the aim of generating a more challenging P-stereo-
genic phenol phosphine enantioselectively we next inves-
tigated the sequence of reactions in Scheme 1 on a chiral
anisyl phosphine. For this purpose, o-anisyl-
methylphenylphosphine (PAMP) was chosen, as both
enantiomers of this phosphine are available through
various known methods.10 Furthermore, its use would
lead to a phosphine–phosphite of type A, with R% groups
of different bulkiness, a situation potentially useful in
asymmetric catalysis. It is worth pointing out that
demethylation of (S)-PAMP produces the corresponding
phenol (S)-3d without observable racemization.11 To the
best of our knowledge, the above procedure constitutes
the first synthesis of this valuable building block in a
highly enantioenriched form.12 Considering in addition
the vast range of chiral o-anisyl phosphines described in
the literature13 this synthetic methodology should open
the way to other similar phenol–phosphines.
To check the utility of our ligand design, we have
examined the performance of ligands 5 in the rhodium-
catalyzed enantioselective dimethyl itaconate hydrogena-
tion. Previously, and to avoid an imprecise ligand to
metal ratio, we have synthesized complexes of formula-
tion [(COD)Rh(P-OP)]BF4 (6a–d; P-OP=5a–d) from
[(COD)2Rh]BF4 and an equimolar amount of the appro-
priate ligand. All compounds 6 generate active catalysts
(Scheme 3) and complete the reaction under our standard
R2
R1
P
R1= R2
R1= Me
R2 = Ph
OH
4a
4b
NEt3
3
NEt3
R1
R1
Ph
But
Me
P
P
But
But
But
O
O
P
O
O
O
O
P
But
5a-5c (R1 = Ph, Me, i-Pr)
But
5d
Scheme 2.
Scheme 3.
H2
[(COD)Rh(P-OP)]BF4
MeO2C
MeO2C
CO2Me
CO2Me

A. Sua´rez, A. Pizzano / Tetrahedron: Asymmetry 12 (2001) 2501–2504
2503
conditions (Table 1).16 Most noteworthy, the enantiose-
References
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employed. For instance, for compounds 6a–c, with
chirality based on the phosphite fragment, the nature of
the phosphine group has a profound effect on the
enantioselectivity of the reaction. Thus, the phenyl
derivative gives the product with an excellent enantiose-
lectivity (99.3%, entry 1), whereas the isopropyl com-
pound 6c produces an almost racemic product (entry 3)
and the methyl substituted complex 6b gives the methyl
succinate of opposite configuration, with a low enan-
tiomeric purity (30.8% ee, entry 2).17 Compound 6d,
which possesses a P-stereogenic phosphine fragment,
leads only to moderate enantioselectivity (49.2% ee,
entry 4). Remarkably, the best catalyst precursor 6a
shows also convenient reaction rates and it is able to
complete reactions at lower catalysts loadings (S/C=
3000–10000, entries 5 and 6) with excellent enantio-
selectivity (ee >99.5%).
1. A large variety of bifunctional ligands has been described
in the literature, but for the particular case of phosphines,
see for example: PꢀN ligands: (a) Alcock, N.; Hulmes, D.
I.; Brown, J. M. J. Chem. Soc., Chem. Commun. 1995,
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Org. Chem. 1993, 58, 1945; PꢀS ligands: (e) Hauptman,
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Wieser-Jeunesse, C.; Knochel, P. Angew. Chem., Int. Ed.
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In summary, we have described a convenient prepara-
tion of a series of new chiral phosphine–phosphites
based on the easy demethylation of o-anisyl phosphi-
nes, a methodology applied for the first time to the
highly enantioselective synthesis of a P-stereogenic phe-
nol phosphine. The simplicity and flexibility of this
synthetic protocol allows the application of these lig-
ands in asymmetric catalysis following a modular
approach. By using this strategy, a significant catalyst
optimization has been achieved in enantioselective
dimethyl itaconate hydrogenation. The application of
these ligands in other enantioselective metal-catalyzed
processes is currently under progress.
Table 1. Results of the asymmetric hydrogenationsa
Entry
Cat. precursor
S/C
% ee (Config.)
1
2
3
4
6a
6b
6c
6d
6a
6a
500
500
500
500
3000
10000
99.3 (S)
30.8 (R)
1.8 (R)
49.2 (S)
99.8 (S)
99.6 (S)
5. Control of conformational mobility is a critical parame-
ter on ligand design. For example, see: Burk, M. J.;
Pizzano, A.; Mart´ın, J. M.; Liable-Sands, L.; Rheingold,
A. L. Organometallics 2000, 19, 250.
6. (a) Baker, M. J.; Pringle, P. J. Chem. Soc., Chem. Com-
mun. 1993, 314; (b) Kranich, R.; Eis, K.; Geis, O.; Mu¨hle,
S.; Bats, J. W.; Schmalz, H.-G. Chem. Eur. J. 2000, 6,
2874.
7. (a) Rauchfuss, T. B. Inorg. Chem. 1977, 16, 2966; (b)
Heinicke, J.; Kadyrov, R.; Kindermann, M. K.; Koesling,
M.; Jones, P. G. Chem. Ber. 1996, 129, 1547; (c) Schmut-
zler, R.; Schomburg, D.; Bartsch, R.; Stelzer, O. Z.
Naturforsch. 1984, 39, 1177.
5b
6b,c
a All reactions were completed under the conditions specified. Reac-
tions were carried out at room temperature under an initial H2
pressure of 4 atm and 0.2 M dichloromethane solutions of substrate
using the appropriate catalyst precursor for 17 h.
b 0.5 M substrate concentration, 5 atm initial pressure.
c 24 h reaction time (95% conversion after 17 h).
8. Greene, T. W. Protective Groups in Organic Synthesis;
John Wiley and Sons: New York, 1991.
9. Sembiring, S. B.; Colbran, S. B.; Craig, D. C. Inorg.
Chem. 1995, 34, 761.
Acknowledgements
10. For example see: (a) Juge´, S.; Ste´phan, M.; Laffitte, J. A.;
Genet, J. P. Tetrahedron Lett. 1990, 31, 6357; (b) Vedejs,
E.; Donde, Y. J. Am. Chem. Soc. 1997, 119, 2993.
11. (S)-3d. To a stirred solution of (S)-PAMP (0.17 g, 0.74
mmol) in CH2Cl2 (5 mL) cooled at −78°C was added
BBr3 (0.16 mL, 1.7 mmol) via syringe. The resulting
mixture was allowed to warm to room temperature and
We deeply acknowledge Professor E. Carmona for his
invaluable help on the development of this work. We
also thank Drs. M. L. Poveda and N. Khiar and
Professor M. A. Perica`s for helpful comments. We
acknowledge financial support from DGES (Grant No.
PB97-0732) and Chirotech. A.S. thanks the Junta de
Andaluc´ıa for a fellowship.

2504
A. Sua´rez, A. Pizzano / Tetrahedron: Asymmetry 12 (2001) 2501–2504
13. Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 94,
stirred for additional 12 h. The mixture was carefully
1375.
evaporated to dryness. The residue was treated with
MeOH and the mixture refluxed for 5 h. After the solvent
and volatiles were removed, the resulting solid was sus-
pended in Et2O and NEt3 (0.25 mL, 1.8 mmol) added.
The suspension was stirred for 2 h and filtered. The
resulting solution was evaporated, redissolved in CH2Cl2
and filtered through a short pad of silica, yielding (S)-3d
as a white solid (0.13 g, 81%). [h]2D0=−15.4 (c 1.0, THF).
14. The new chlorophosphite 4a can be readily prepared
from the corresponding bisphenol. The latter reagent is
easily available on a multigram scale. See: Alexander, J.;
Schrock, R. R.; Davis, W. M.; Hultzsch, K. C.; Hoveyda,
A. H.; Houser, J. H. Organometallics 2000, 19, 3700.
15. Buisman, G. J. H.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M. Tetrahedron: Asymmetry 1993, 4, 1625.
16. Representative procedure for the enantioselective hydro-
genations. In a glove box, a Fischer–Porter tube (80 mL)
was charged with a solution of dimethyl itaconate (0.18 g,
1.1 mmol) and 6a (0.002 g, 0.0022 mmol) in CH2Cl2 (5
mL). The vessel was brought outside the glove box,
submitted to vacuum–hydrogen cycles and finally pres-
surized to 4 atm. The reaction mixture was stirred for 17
h, then the reactor was depressurized and the obtained
mixture was evaporated to dryness, redissolved in ethyl
acetate–hexanes (1:1) mixture and passed through a short
pad of silica. The resulting residue was analyzed by 1H
NMR to determine conversion and by chiral GC for
enantiomeric excess as follows: dimethyl methylsuccinate
(Supelco g-DEX 225, 70°C (5 min), then 10°C/min up to
130°C, 15.0 psi He) (S) t1=12.56 min, (R) t2=12.74 min.
17. The effect of the phosphine group can be due to its
donating properties. Substantial electronic effects on
rhodium enantioselective olefin hydrogenation with C1
symmetric ligands have been described before. See:
RajanBabu, T. V.; Radetich, B.; You, K. K.; Ayers, T.
A.; Casalnuovo, A. L.; Calabrese, J. C. J. Org. Chem.
1999, 64, 3429. Studies concerning this influence are
currently under way.
2
1H NMR (C6D6, 300 MHz): l 1.26 (d, J(H,P)=2.4 Hz,
3H, Me), 6.38 (brs, 1H, OH), 6.70 (m, 1H, CH arom.),
6.85 (m, 1H, CH arom.), 6.99–7.25 (m, 7H, CH arom.).
31P{1H} NMR (C6D6, 121 MHz): l −53.1. 13C{1H}
NMR (CD2Cl2, 75 MHz): l 10.9 (d, J(C,P)=10 Hz),
115.5, 121.4, 123.6 (d, J(C,P)=6 Hz), 128.6, 128.9 (d,
J(C,P)=6 Hz), 131.5 (d, J(C,P)=8 Hz), 131.7, 132.8,
139.1 (d, J(C,P)=7 Hz), 159.5 (d, J(C,P)=20 Hz).
HRMS (EI, direct insert): m/z 216.0704 ([M+] exact mass
cald for C13H13OP: 216.0701). The lack of racemization
along the demethylation reaction has been corroborated
by 31P{1H} NMR analysis of the phosphine–phosphites
obtained by condensation between chlorophosphite 4a
and phosphines rac-3d and (S)-3d. Configuration of the
product was confirmed by its conversion to the corre-
sponding known borane adduct.12
12. Very recently, Juge´ and co-workers have described the
first enantioselective synthesis of a P-stereogenic 2-
hydroxyaryl phosphine ((R)-o-anisyl-2-hydroxynaph-
thylphenyl phosphine) using an alternative procedure.
See: Moulin, D.; Bago, S.; Bauduin, C.; Darcel, C.; Juge´,
S. Tetrahedron: Asymmetry 2000, 11, 3939.