Chiral bidentate phosphabenzene-based ligands: Synthesis, coordination chemistry, and application in Rh-catalyzed asymmetric hydrogenations

Article abstract of DOI:10.1016/j.tetlet.2006.01.049

Novel hydroxy-functionalized phosphabenzenes were synthesized, which provide the possibility to prepare chiral phosphabenzene-phosphites. These systems act as bidentate ligands toward rhodium centers and the corresponding metal complexes were applied in t

Full text of DOI:10.1016/j.tetlet.2006.01.049

Tetrahedron Letters 47 (2006) 2017–2020
Chiral bidentate phosphabenzene-based ligands:
synthesis, coordination chemistry, and application in
Rh-catalyzed asymmetric hydrogenations
a
b
Christian Muller,a, Leire Guarrotxena Lopez, Huub Kooijman,
*
´
¨
Anthony L. Spekb and Dieter Vogta
aDepartment of Chemical Engineering and Chemistry, Schuit Institute of Catalysis, Laboratory of Homogeneous Catalysis,
Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
bDepartment of Crystal and Structural Chemistry, Utrecht University, Utrecht, The Netherlands
Received 29 November 2005; revised 2 January 2006; accepted 12 January 2006
Available online 7 February 2006
Dedicated to Professor Arthur J. Ashe, III on the occasion of his 65th birthday
Abstract—Novel hydroxy-functionalized phosphabenzenes were synthesized, which provide the possibility to prepare chiral phos-
phabenzene–phosphites. These systems act as bidentate ligands toward rhodium centers and the corresponding metal complexes
were applied in the rhodium-catalyzed asymmetric hydrogenation of prochiral substrates.
Ó 2006 Elsevier Ltd. All rights reserved.
Phosphabenzenes (phosphinines, phosphorines), the
higher homologues of pyridines, have been known for
many decades, due to the pioneering work of Ma¨rkl
and Ashe in the late 1960s.1,2 These heterocycles are pla-
nar, aromatic systems in which one –CH– group of the
aryl moiety is substituted by an isoelectronic phospho-
rus atom, thus exhibiting lone pair electrons suitable
for r-coordination to a metal center.3 In comparison
to aryl phosphines and aryl phosphites, which are fre-
quently applied as ligands in metal-catalyzed reactions
under homogeneous reaction conditions,4 phosphabenz-
enes act qualitatively as r-donor and p-acceptor ligands
with electronic properties somewhat more similar to
phosphites.5 However, their application in homoge-
neous catalysis is still limited or even neglected,5,6
despite the fact that very interesting results in terms of
activity and selectivity were obtained in the hydroformyl-
ation of alkenes, as reported by Breit and co-work-
ers.6a,b Even though a few examples of chiral bidentate
ligands based on phosphabenzenes have been reported
as well, no enantioselectivity in asymmetric catalytic
reactions has been observed so far.7
We report here a synthetic route to novel hydroxy-func-
tionalized phosphabenzenes, which can be easily con-
verted into chiral, bidentate ligands. Results on their
coordination chemistry and application in asymmetric
hydrogenations are presented, and demonstrate a promi-
sing step forward in developing these truly unique phos-
phines to their full potential.
Reaction of the methoxy-functionalized pyrylium salts
1a/b8 with an excess of BBr3 in CH2Cl29 gave, in a clean
and quantitative reaction, the corresponding hydroxy-
substituted compounds 2a/b after aqueous work-up
(Scheme 1).
The complete removal of the –CH3 groups was con-
1
firmed by H NMR spectroscopy. No resonances were
observed by 19F NMR spectroscopy, suggesting loss of
the BFꢀ4 anion during aqueous work-up. In fact, the
reaction with H2O produced substantial amounts of
HBr, which led to anion exchange of BFꢀ4 for Brꢀ, yield-
ing quantitatively the pyrylium salts 2a/b as red and yel-
low solids, respectively. Red crystals of 2a, suitable for
X-ray crystallography, were obtained by slow crystalli-
zation from methanol and the molecular structure is
Keywords: Phosphabenzenes; Phosphites; Homogeneous catalysis;
Asymmetric hydrogenation; Rhodium.
*
Corresponding author. Tel.: +31 40 2474679; fax: +31 40 2455054;
e-mail: c.mueller@tue.nl
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.049

2018
C. Mu¨ller et al. / Tetrahedron Letters 47 (2006) 2017–2020
R
R
1. BBr3 / CH2Cl2
2. H2O
O
O
O
R
R
O
H
R
R
CH3
Br
BF4
1a: R = H
1b: R = Me
2a: R = H
2b: R = Me
Scheme 1. Synthesis of hydroxy-functionalized pyrylium salts.
–O–CH3 group with BBr3/CH2Cl2 followed by aqueous
work-up gave the desired products 3a and 3b as yellow
and red solids. In the 31P NMR spectrum, compound
3a showed a resonance at d = 188.9 ppm (C6D6), and a
resonance at d = 197.6 ppm (C6D6) was observed for 3b.
Due to their phenolic –OH group, compounds 3a/b
could easily be transformed into the corresponding
chiral phosphabenzene–phosphites.13 Thus, reaction of
3a/b with (S)-BINOL-PCl14 in the presence of NEt3
gave the desired bidentate ligands 5a and 5b, respec-
tively (Scheme 3).
Figure 1. Crystal packing of 2a (displacement ellipsoid plot11 at 30%
probability level, H atoms excluded with exception of those involved in
hydrogen bonds). Superscript a denotes symmetry operation 1ꢀx,
1ꢀy, ꢀz. Interatomic distances (A) and angles (°): O2ꢁ ꢁ ꢁBr1a:
˚
3.1780(14), O1–C1: 1.349(2), O1–C5: 1.356(2), C1–O1–C5:
122.30(12); angles (°) between the central ring and the rings containing
O2, C15, and C21 are 23.97(8), 9.98(8), and 1.32(8), respectively.
Compounds 5a/b were obtained in quantitative yields as
yellow, air- and moisture-sensitive solids. Through-
space coupling between the two different phosphorus
nuclei was observed in the 31P NMR spectrum of 5a,
as indicated by two doublets at d = 190.3 ppm (phos-
phabenzene-P) and d = 145.4 ppm (phosphite-P) and a
coupling constant of JP–P = 5.9 Hz (5b: d = 197.6 ppm,
145.0 ppm, JP–P = 10.4 Hz).
illustrated in Figure 1. It confirms not only the stability
of the six-membered heterocycle under the applied harsh
reaction conditions and the formation of the hydroxy-
functionalized salt, but also the presence of a Brꢀ, rather
than a BFꢀ4 anion. Salt 2a crystallized in a layer-type
structure with hydrogen bonds between the –OH func-
tionalities and Brꢀ anions of different layers.10
Upon addition of 5a to 1 equiv of Rh(cod)2BF4, reac-
tion under loss of COD took place and the correspond-
ing rhodium complex (P1P2)Rh(cod)BF4 (5a/Rh+) was
formed quantitatively. The 31P NMR spectrum of
5a/Rh+ revealed that the phosphabenzene–phosphite
ligand was indeed coordinated to the metal center in a
The pyrylium salts 2a and 2b were further reacted with
P(SiMe3)3 and the corresponding hydroxy-functional-
ized phosphabenzenes 3a and 3b were obtained (Scheme
2).
12
Alternatively, 3a/b were synthesized from the methoxy-
functionalized phosphabenzenes 4a/b, which were
obtained from 1a/b and P(SiMe3)3.8 Cleavage of the
bidentate fashion:15 a doublet of doublets (JRh–P1
=
172.9 Hz, JP1–P2 = 68.8 Hz) at d = 160.5 ppm was
observed in the phosphabenzene region P1 as well as
R
R
1. BBr3 / CH2Cl2
P(SiMe3)3
2. H2O
2a / 2b
P
P
CH3CN
O
H
R
R
O
R
R
CH3
3a: R = H
3b: R = Me
4a: R = H
4b: R = Me
Scheme 2. Synthesis of hydroxy-functionalized phosphabenzenes.

C. Mu¨ller et al. / Tetrahedron Letters 47 (2006) 2017–2020
2019
R
R
R
(S)-Binol-PCl
5a: R = H
5b: R = Me
P
3a / 3b
O
O
NEt3
toluene
P
O
Scheme 3. Synthesis of chiral, bidentate phosphabenzene–phosphites.
tylamino)cinnamate in terms of activity, than any of
the two other systems [2,4,6-triphenylphosphinine]2Rh+
(6/Rh+) and [(S)-Binol-P-OPh]2Rh+ (7/Rh+): a very low
TOF of 55 hꢀ1 was found for 6/Rh+, while a TOF of
530 hꢀ1 was observed for 7/Rh+ (T = 40 °C, 10 bar
H2, 100 equiv substrate). Thus, the latter system showed
only half of the activity compared to the system based
on the bidentate ligand 5a. Concerning the selectivity,
the system 7/Rh+ showed only a slightly better perfor-
mance in the stereoselection process compared to 5a/
Rh+ under the applied reaction conditions (ee 70% vs
62%, R).
Figure 2. 31P NMR spectrum of 5a/Rh+ (CD2Cl2, T = 25 °C).
in the phosphite region P2 at d = 136.5 ppm (JRh–P2
243.2 Hz, JP2–P1 = 68.8 Hz) (Fig. 2).
=
The complexes 5a/Rh+ and 5b/Rh+ were further applied
in the rhodium-catalyzed asymmetric hydrogenation of
methyl 2-(N-acetylamino)cinnamate as well as dimethyl
itaconate3,16 (Eq. 1 and 2); the reactions were performed
simultaneously in a parallel reactor system (AMTEC
SPR16) under different reaction conditions.
At T = 25 °C and a hydrogen pressure of 10 bar, di-
methyl itaconate was quantitatively hydrogenated with
the system 5a/Rh+ (0.1 mol %) and a TOF of 2500 hꢀ1
(Fig. 3a).
Interestingly, an ee of 79% of the S-configured product
was found. Increasing the reaction temperature to
T = 40 °C led to a very active hydrogenation catalyst
with a TOF of 5300 hꢀ1, along with a slight drop in
ee to 68% (b). The system 5b/Rh+ showed reduced
activity, most likely due to the steric bulk of the substi-
tuted phenyl ring close to the metal center: while a TOF
of 60 hꢀ1 was observed at T = 25 °C (c), the activity of
the catalyst increased at T = 40 °C and a TOF of
COOCH3
COOCH3
*
L2Rh+
H2
NHCOCH3
NHCOCH3
ð1Þ
ð2Þ
L2Rh+
COOCH3
COOCH3
H3COOC
H3COOC
*
H2
At T = 25 °C and a hydrogen pressure of 5 bar, almost
no conversion of the enamide (100 equiv) to the hydro-
genated product was observed. However, by increasing
the temperature to T = 40 °C and p(H2) to 10 bar, a fast
and quantitative hydrogenation reaction with the system
5a/Rh+ took place (TOF = 1030 hꢀ1 at 20% conver-
sion). Analysis of the reaction product by GC revealed
an enantiomeric excess of 62% of the R product. Under
the same reaction conditions, the system 5b/Rh+ showed
a slightly reduced activity (TOF = 800 hꢀ1). However,
the CH3-substituents on the phenyl ring showed a dra-
matic effect on the stereoselection process: an ee of only
19% (R product) was found.
The bidentate system 5a/Rh+ was further compared
with Rh-complexes based on the two monodentate
ligands 2,4,6-triphenylphosphinine1,6b and (S)-BINOL-P-
OPh.17 Remarkably, the system 5a/Rh+ performed
much better in the hydrogenation of methyl 2-(N-ace-
Figure 3. Gas uptake curves for the hydrogenation of dimethyl
itaconate with 5a/b/Rh+ (p(H2) = 10 bar, Rh/S = 1:1000, cRh
=
1.25 mM). (a) 5a/Rh+, T = 25 °C; (b) 5a/Rh+, T = 40 °C; (c) 5b/
Rh+, T = 25 °C; (d) 5b/Rh+, T = 40 °C, CH2Cl2.

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C. Mu¨ller et al. / Tetrahedron Letters 47 (2006) 2017–2020
1050 hꢀ1 was found (d). Similar to the results mentioned
above, a decrease in the enantioselectivity (ee = 14.0%
at T = 25 °C; ee = 9.2% at T = 40 °C, S-product) was
observed for this system.
6. (a) Breit, B.; Winde, R.; Harms, K. J. Chem. Soc., Perkin
Trans. 1 1997, 18, 2681–2682; (b) Breit, B.; Winde, R.;
Mackewitz, T.; Paciello, R.; Harms, K. Chem. Eur. J.
2001, 7, 3106–3121; (c) Knoch, F.; Kremer, F.; Schmidt,
U.; Zenneck, U.; Le Floch, P.; Mathey, F. Organometal-
lics 1996, 15, 2713–2719; (d) Reetz, M. T.; Mehler, G.
Tetrahedron Lett. 2003, 44, 4593–4596; (e) Reetz, M. T.;
Li, X. Angew. Chem., Int. Ed. 2005, 44, 2962–2964.
7. Breit, B. J. Mol. Catal. A: Chem. 1999, 143, 143–154.
8. For the synthesis of 1a/4a see Ref. 6b, for 1b and 4b see
the Supplementary data.
In summary, phosphabenzenes should be regarded as far
more than laboratory curiosities. Subsequent work to
improve the activity and selectivity of chiral, bidentate
phosphabenzenes-based ligands, as well as investiga-
tions on their scope and limitations in other asymmetric
homogeneous catalytic reactions is currently being car-
ried out in our laboratories.
´
9. Suarez, A.; Pizzano, A. Tetrahedron: Asymmetry 2001, 12,
2501–2504.
10. Crystal structure of 2a: [C23H17O2]+Brꢀ, Mr =
405.27 g molꢀ1
c = 10.480(2) A,
,
triclinic, P1a ¼ 9:139ð2Þ, b = 9.805(2),
ꢀ
˚
a = 91.89(2),
b = 102.85(2),
c =
3
Acknowledgments
˚
106.51(2) deg, V = 873.2(3) A . 26,528 Reflections mea-
sured, 3979 unique, using MoKa radiation (k =
0.71073 A). Structure solved with direct methods
(SHELXS86), 238 parameters refined (SHELXL-97), including
˚
The authors wish to thank Umicore for generous gifts
of rhodium. This work was supported in part
(A.L.S.) by the Council for the Chemical Sciences of
the Netherlands Organization for Scientific Research
(CW-NWO).
hydroxyl
H coordinates. R1 = 0.0250, wR2 = 0.0625,
S = 1.049. Residual density in the range ꢀ0.57,
3
˚
0.33 e A . Crystallographic data (excluding structure fac-
tors) for the structure in this paper has been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 288639. Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
11. Spek, A. L. J. Appl. Cryst. 2003, 36, 7–13.
12. Nieke, E.; Westermann, H. Synthesis 1988, 4, 330.
13. For related phosphines–phosphites see for example: (a)
Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am.
Supplementary data
Electronic supplementary information (ESI) available:
A listing of experimental procedures and crystallo-
graphic data. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.01.049.
´
´
Chem. Soc. 1993, 115, 7033–7034; (b) Suarez, A.; Mendez-
Rojas, M. A.; Pizzano, A. Organometallics 2002, 21, 4611–
4621; (c) Baker, M. J.; Pringle, P. J. Chem. Soc., Chem.
Commun. 1993, 314–316; (d) Kranich, R.; Eis, K.; Geis,
References and notes
O.; Muhle, S.; Bats, J. W.; Schmalz, H.-G. Chem. Eur. J.
¨
1. Ma¨rkl, G. Angew. Chem. 1966, 78, 907–908.
2. Ashe, A. J., III. J. Am. Chem. Soc. 1971, 93, 3293–3295.
3. (a) Le Floch, P. In Phosphorus–Carbon Heterocyclic
Chemistry: The Rise of a New Domain; Mathey, F., Ed.;
Pergamon: Palaiseau, 2001; pp 485–533; (b) Mathey, F.
Angew. Chem., Int. Ed. 2003, 42, 1578–1604.
4. Van Leeuwen, P. W. N. M. In Homogeneous Catalysis—
Understanding the Art; Kluwer Academic, 2004.
5. DiMauro, E. F.; Kozlowski, M. C. J. Chem. Soc., Perkin
Trans. 1 2002, 439–444.
2000, 6, 2874–2894.
14. Huttenloch, O.; Laxman, E.; Waldmann, H. Chem. Eur. J.
2002, 8, 4767–4780.
15. The formation of polynuclear species with bridging
ligands cannot be excluded. However, the presence of
more than one species should be expected in this case.
16. See for example: Tang, W.; Zhang, X. Chem. Rev. 2003,
103, 3029–3069, and references cited therein.
17. Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39,
3889–3890.