Supported chiral monodentate ligands in rhodium-catalysed asymmetric hydrogenation and palladium-catalysed asymmetric allylic alkylation

Article abstract of DOI:10.1002/ejoc.200900911

A family of monodentate polystyrene-supported phosphites, phosphoramidites and phosphanes has been prepared and evaluated, as ligands in rhodium-catalysed asymmetric hydrogenation and palladium-catalysed asymmetric allylic alkylation. The supported ligands yielded active and enantioselective catalysts, which in selected cases match the performance of the nonsupported counterparts. As expected, the performance of the supported ligands in the rhodium-cata-lysed hydrogenation depends on the nature of the ligand, the type of polymeric support, as well as on the substrate. Ad-ditionally, the supported ligands have been applied in the monodentate ligand combination approach, by combining them, with nonsupported, monodentate ligands. The partially supported heteroligand combinations possess different catalytic properties than the related nonsupported combinations. The heteroligand species, however, are not formed selectively, and nonsupported homoleptic complexes also contribute to the overall activity.

Full text of DOI:10.1002/ejoc.200900911

FULL PAPER
DOI: 10.1002/ejoc.200900911
Supported Chiral Monodentate Ligands in Rhodium-Catalysed Asymmetric
Hydrogenation and Palladium-Catalysed Asymmetric Allylic Alkylation
Bert H. G. Swennenhuis,[a] Ruifang Chen,[a] Piet W. N. M. van Leeuwen,[a]
Johannes G. de Vries,[b] and Paul C. J. Kamer*[c]
Keywords: Supported catalysts / Asymmetric catalysis / Combinatorial chemistry / Hydrogenation / Heteroligand approach
A family of monodentate polystyrene-supported phosphites,
phosphoramidites and phosphanes has been prepared and
evaluated as ligands in rhodium-catalysed asymmetric hy-
drogenation and palladium-catalysed asymmetric allylic al-
ditionally, the supported ligands have been applied in the
monodentate ligand combination approach, by combining
them with nonsupported monodentate ligands. The partially
supported heteroligand combinations possess different cata-
kylation. The supported ligands yielded active and enantio- lytic properties than the related nonsupported combinations.
selective catalysts, which in selected cases match the per-
formance of the nonsupported counterparts. As expected, the
performance of the supported ligands in the rhodium-cata-
lysed hydrogenation depends on the nature of the ligand, the
type of polymeric support, as well as on the substrate. Ad-
The heteroligand species, however, are not formed selec-
tively, and nonsupported homoleptic complexes also contrib-
ute to the overall activity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
methods thus accelerates both the synthesis and the screen-
ing of ligand libraries. In addition, polymer-supported li-
gands allow recovery and reuse of both the transition metal
and the ligand, while due to the swelling properties of the
support, good mixing with the reactants can be main-
tained.[6–8] Illustrative are the good activities observed for a
number of resin-supported chiral monodentate ligands in
the rhodium-catalysed asymmetric hydrogenation.[9] The
supported phosphite and phosphoramidite ligands studied
so far, have been predominantly derived from the chiral BI-
NOL moiety (BINOL = 1,1Ј-binaphthalene-2,2Ј-diol). Re-
cently we synthesised a structurally diverse family of poly-
mer-supported monodentate ligands[3a] and here we report
their application in rhodium-catalysed asymmetric hydro-
genation and palladium-catalysed asymmetric allylic alky-
lation reactions.
Introduction
In the last decades chiral (monodentate) phosphorus li-
gands have proven their superiority in numerous transition-
metal-catalysed asymmetric transformations.[1–3] Subtle
changes in ligand structure can have a decisive influence
on the stability, activity and selectivity of a catalyst. Not
surprisingly, efficient (combinatorial) techniques for the
preparation and evaluation of catalyst libraries in a time
efficient manner are highly desirable.[2,4] The quest for ef-
ficient catalysts still relies heavily on the synthesis of ligand
libraries. Several groups have successfully applied solid-
phase techniques for the parallel and combinatorial synthe-
sis of (supported) ligands.[3,5] Phosphorus based ligands are
in general prone to oxidation and/or hydrolysis reactions
and the major advantage of this approach is the easy purifi-
cation, which can be achieved by a simple washing pro-
cedure. Waldmann and co-workers have shown that in cop-
per-catalysed enantioselective conjugate addition reactions,
polymer-bound phosphoramidites mirrored the perform-
ance of the soluble analogues.[5a] Application of solid-phase
Results and Discussion
Figure 1 shows the structures of the resin-supported
monodentate ligands studied. The immobilised ligands are
referred to by a code, in which the letters specify the type
[a] Van ’t Hoff Institute for Molecular Sciences, University of Am- of polymeric support, while the numbers indicate the sub-
sterdam,
stituents on the phosphorus atom.
Amsterdam, The Netherlands
Several resin-supported phosphites and phosphoramid-
ites had been synthesised previously.[3a] We synthesised ad-
ditional members by reaction of hydroxy-functionalised
polystyrene (1) with the appropriate phosphorus chloride
in the presence of a tertiary amine as a base (Scheme 1).
Elemental analysis and 31P gel-phase NMR[10] indicated
that the ligands were formed in good yield (100–91%) and
[b] DSM Pharmaceutical Products – Innovative Synthesis & Catal-
ysis,
P. O. Box 18, 6160 MD Geleen, The Netherlands
[c] EaStCHEM, Department of Chemistry, St. Andrews Univer-
sity,
St. Andrews, Scotland, U.K.
E-mail: pcjk@st-andrews.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900911.
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Supported Catalysts for Asymmetric Catalysis
allylic alkylation is often regarded as a standard test to de-
termine the efficiency of a ligand in asymmetric C–C bond
formations.[16] Palladium, in combination with bulky mono-
dentate phosphoramidite or phosphite ligands, yields highly
active and enantioselective allylic alkylation catalysts.[17] Al-
though a variety of polymer-supported chiral ligands have
been studied in this reaction,[8b,18] resin-bound phosphite
and phosphoramidite ligands have been largely neglected.
We evaluated our family of supported monodentate ligands
and chose the alkylation of 1,3-diphenyl-2-propenyl acetate
(5) with dimethyl malonate (6) as a model reaction
(Scheme 2). The results are summarised in Table 1.
Scheme 2. Palladium-catalysed alkylation of 1,3-diphenyl-2-pro-
penyl acetate.
Table 1. Chiral monodentate polymer-supported ligands in the pal-
ladium-catalysed allylic alkylation. Reaction conditions: Pd/ligand/
5/6/BSA = 1:2:100:300:300, [Pd] = 5 m, CH2Cl2, room temp.,
pinch of KOAc added, catalyst precursor: [Pd(allyl)Cl]2, catalyst
incubation time: 15 min, reaction time: 16 h.
Figure 1. Structures of the supported ligands used in this study.
purity, with small amounts (Ͻ1%) of hydrolysis products
as the major impurities. Chiral phosphoramidite A9 was
Entry
Ligand
Conversion[a]
ee[b]
synthesised
from
(2R,4S,5R)-2-chloro-3,4-dimethyl-5-
1
2
3
4
5
6
7
8
A1
A3
A9
A10
B4
B7
C2
C4
L1
L3
L3
100
100
100
100
84
87
100
85
14 (R)
31 (S)
7 (S)
phenyl-1,3,2-oxazaphospholidine (2) and displayed two sig-
nals in 31P gel-phase NMR (141 and 135 ppm, 1:1.8) which
has also been observed for nonsupported analogues[11,12]
and can be assigned to the formation of the different dia-
stereomers.[13] Chiral diamidophosphite A10 was synthe-
sised from (2R,5S)-2-chloro-3-phenyl-1,3-diaza-2-phos-
phabicyclo[3.3.0]octane (3).[14] It displayed a single reso-
nance in 31P gel-phase NMR at δ = 120 ppm, which, ac-
cording to the observed chemical shift, indicates that the
phosphorus stereocentre possesses an R-configuration.[15]
The achiral diphenylphosphinite A14 was prepared
straightforwardly by reaction of the hydroxy-functionalised
resin (1) with chlorodiphenylphosphane (4).
0[c]
58 (S)
2 (R)
32 (R)
52 (S)
89 (S)[d]
25 (S)[e,f]
29 (S)[e]
9
10
11
99
100
100
[a] Given in %, based on conversion of 5. Determined by GC with
n-decane as internal standard. [b] Given in %. Determined by
HPLC (Daicel OD). [c] Pd/ligand, 1:1, immobilised catalyst puri-
fied prior to the reaction. [d] Taken from ref.[17]. [e] Pd/ligand/5/6/
BSA = 1:2:20:60:60. [Pd] = 3.8 m. [f] Pd/ligand, 1:1.
Application of two equivalents of phosphites A1 and A3,
phosphoramidites A9, B7 and C2 and diamidophosphite
A10 resulted in active catalysts, giving the products in quan-
titative yields (Entries 1–4 and 6–7). The ligands do not
create an efficient chiral environment around the catalytic
centre, as the enantioselectivities were low (0–32%). Sup-
ported phosphoramidites B4 and C4, derived from the chi-
ral TADDOL moiety gave the product in somewhat higher
enantiomeric purities (58 and 52% ee, respectively), albeit
displaying lower activities (84 and 85% conversion, Entries
5 and 8, TADDOL = α,α,αЈ,αЈ-tetraaryl-1,3-dioxolane-4,5-
dimethanol).[19] Interestingly, the type of polymeric support
and the type of amido linker (B vs. C) appears to have a
Scheme 1. Synthesis of A9, A10 and A14.
Palladium-Catalysed Asymmetric Allylic Alkylation
Allylic substitution reactions are among the most widely limited influence on the performance, as both the activity
studied catalytic reactions in organic synthesis. Asymmetric and enantioselectivity of B4 and C4 are comparable. Never-
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P. C. J. Kamer et al.
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theless, the support does clearly influence the performance.
Compared to L1 (Figure 2), the supported analogues B4
and C4 are far less efficient ligands (Entries 5, 8 and 9).
Not only do they give the products in lower yields (84–
85% vs. 99%), the immobilised ligands display far lower
enantioselectivities (52–58% vs. 89% ee). Application of
A10 leads to racemic product (Entry 4) and its performance
is in contrast to the nonsupported analogue L2, which in-
duces up to 78% ee.[15] (R)-monophos (L3) and the related
polymer-supported C2, display similar enantioselectivities
(29 and 32% ee, Entries 7 and 10–11). Although only a
limited number of supported ligands have been compared
with their nonsupported analogues, it can be concluded that
the performances of the supported catalysts do not meet
those of their solution counterparts.
Scheme 3. Rhodium-catalysed asymmetric hydrogenation of di-
methyl itaconate and methyl 2-acetamidoacrylate.
Table 2. Performance of resin-supported ligands in the hydrogena-
tion of 7. Reaction conditions: Rh/7 1:40, [Rh] = 2.8 m, 5 bar H2,
CH2Cl2, room temp., catalyst formed in situ, catalyst precursor:
[(COD)Rh(MeCN)2]BF4, catalyst incubation time: 30 min, reac-
tion time: 20 h.
Entry
Ligand
Ligand/Rh
Conversion[a]
ee[b]
1
2
3
4
5
6
7
8
A1
A1
A3
A3
A9
A9
B1
B1
C1
C1
C1
C1
D2
L3
L3
L4
1
2
1
2
1
2
1
2
2
2
1
2
1
1
2
1
100
100
100
69
100
100
100
80
11 (R)
17 (R)
24 (R)
29 (R)
24 (R)
21 (R)
41 (R)
41 (R)
9
16
21
16 (R)[c,d,e]
24 (R)[c,d]
77 (R)[c]
70 (R)[c]
Ͼ 97 (S)
Ͼ 97 (R)
Ͼ 97 (R)
97 (S)[f]
10
11
12
13
14
15
16
100
100
98
100
100
100
[a] Based on conversion of 7, determined by GC with n-decane as
internal standard. [b] Determined by chiral GC. [c] Rh/substrate,
1:20, [Rh] = 5.0 m. Catalyst precursor: [Rh(COD)2]BF4. [d] 1 bar
H2. [e] Reaction mixture shaken. [f] From ref.[20b]; Rh/7 = 1:1000,
1.3 bar H2.
Figure 2. Nonsupported monodentate ligands applied in the stud-
ies.
Rhodium-Catalysed Hydrogenation
catalytic performance.[21] Generally the catalyst displayed
Chiral monodentate phosphites and phosphoramidites good activities, but gave the product in low to moderate
belong to the most efficient ligands known for rhodium- enantioselectivities. Illustrative is the results obtained with
catalysed asymmetric hydrogenation of alkenes and car- supported phosphite A1, which is derived from the chiral
bon–element double bonds.[1a,1b,20] Resin-bound chiral li- R-BINOL moiety. With a metal to ligand ratio of 1:1, the
gands have proven their efficiency in asymmetric hydrogen- ligand gave the product quantitatively in 11% ee (Entry 1).
ation, but mostly BINOL derived phosphites or P-chiral With a ligand to metal ratio of two, the enantiomeric excess
phosphanes have been studied.[9] We evaluated our family (ee) increased slightly to 17% (Entry 2).[22] The low enantio-
of supported monodentate phosphites and phosphoramid- selectivity is in sharp contrast to that observed for the re-
ites in the rhodium-catalysed hydrogenation of dimethyl ita- lated nonsupported phosphite L4 (Figure 2), as this gives
conate (7, Scheme 3) and methyl 2-acetamidoacrylate (8), the product in 97% ee (Entry 16). Similar drastic drops in
of which the results are summarised in Table 2.
enantioselectivity as a result of the immobilisation on a
First we studied in situ formed catalysts, for which we (polymeric) support have been reported for other ligands.[9d]
allowed the supported ligand and the catalyst precursor The low enantioselectivities induced by ephedrine derived
([(COD)Rh(MeCN)2]BF4) to react for 30 min in DCM phosphoramidite A9 (21–24% ee, Entries 5–6) is compar-
prior to the catalytic reaction (see Supporting Information able to related nonsupported oxazaphospholidines, for
for details). We applied both 1:1 and 1:2 metal to ligand which up to 40% ee has been reported.[12] Application of
ratios, as different coordination modes of the metal to the TADDOL-derived phosphite A3 resulted in active catalysts,
resin (e.g. monodentate vs. bidentate) may reflect on the but inducing only low enantioselectivities (Entries 3–4). Use
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Supported Catalysts for Asymmetric Catalysis
of two equivalents of A3 resulted in a considerable drop in dichloromethane (7–9% ee). The conversions showed some-
conversion (100 vs. 69%), while the ee increased slightly what more variation (54–71%). Surprisingly, the highest ac-
from 24 to 29% (Entry 3 vs. 4). We attribute this difference tivity (71% yield) was observed in methanol, a solvent in
in performance to a lower percentage of uncoordinated rho- which the resins swell poorly. The purified catalysts derived
dium as a result of the higher ligand to metal ratio. A com- from A10 displayed good activity in dichloromethane
parable behaviour was observed for phosphoramidite B1 (100% conversion), but gave the product as a racemate (En-
(Entries 7–8). Increasing the ligand to metal ratio to two try 4). Finally, we evaluated the performance of preformed
resulted in a drop in conversion (100 to 80%), although for catalysts in the hydrogenation of methyl 2-acetamidoacry-
this ligand the enantioselectivity was not affected (41% ee). late (8, Scheme 3). Again good activities were observed, giv-
Phosphoramidite C1 was studied under various conditions ing the product in almost all cases in quantitative yields
and the results indicate that the performance of the catalyst (Entries 5–9). The product was formed in good enantiopur-
is very sensitive to the reaction conditions (Entries 9–12).[23] ity when BINOL derived ligands A1 and C2 were applied
Under one bar of hydrogen pressure and with a ligand to (78 and 80% ee, Entries 5 and 7). Application of TADDOL
metal ratio of two the catalyst displayed a poor catalytic derived phosphite A3 gave nearly racemic product (5% ee,
performance; i.e. both conversion and enantioselectivity Entry 6).
were low (Entries 9–10). Increasing the hydrogen pressure
Table 3. Performance of purified resin-supported hydrogenation
to five bars resulted in a considerable increase of both ac-
catalysts. Reaction conditions: Rh/ligand/substrate = 1:1:62, [Rh] =
tivity and enantioselectivity (100% conversion, 70% ee, En-
2.8 m, 5 bar H2, CH2Cl2, room temp., catalyst precursor: [(COD)
try 11). The enantioselectivity increased even further to
Rh(MeCN)2]BF4, catalyst formed for 14 h prior to purification,
77% ee when the metal and ligand were applied in equi-
molar amounts (Entry 12). The nonsupported L3 is, com-
pared to C1, significantly more enantioselective (97% ee,
Entries 14–15). A direct comparison of the performances of
the related B1, C1 and L3 is, however, not possible, as the
structure of the amido moiety of phosphoramidites has a
profound influence on the catalytic performance.[24] With
ligand D2, derived from a primary amine-functionalised
resin,[23] the product was formed in nearly quantitative yield
and in excellent enantiomeric purity (Ͼ 97% ee, Entry 13).
This result is particularly interesting, as several groups have
observed that the N–H proton in primary amine derived
phosphoramidites has a crucial influence on both the sta-
bility of the ligand and the performance of the hydrogena-
tion catalyst.[9d,25,26] The latter effect has been attributed to
hydrogen bonds, but since phosphoramidite D2 is immobi-
lised on a polymeric support, which restricts the occurrence
of these interactions, our data indicate that other factors
also play a role.[26] Nonsupported rhodium species may
contribute to the activity of the in situ formed catalysts and
as a result will lower the overall enantioselectivity. We there-
fore determined the performance of purified resins. To this
purpose, the resin and the catalyst precursor (1:1) were al-
lowed to react in DCM for 14 h, followed by removal of the
solvent phase and washing of the resin. For ligand A1, the
purified catalyst displayed a considerably lower activity (54
vs. 100% conversion) and proved to be less enantioselective
(7 vs. 17% ee) than the in situ generated catalysts (Entry 1,
Table 3 vs. Entries 1–2, Table 2). This suggests that in the
purified and the in situ generated catalysts, the catalytic
centre is present in different environments.[27] Generally, the
solvent has a profound influence on the activity and
enantioselectivity of rhodium hydrogenation catalysts.[1a]
Furthermore the type of solvent determines the swelling of
polystyrene resins and thereby influences the accessibility
reaction time: 24 h.
Entry
Ligand
Substrate
Solvent Conversion[a] ee[b]
1
2
3
4
5
6
7
8
9
A1
A1
A1
A10
A1
A3
C2
L3
7
7
7
7
8
8
8
8
8
CH2Cl2
MeOH
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
54
71
67
100
100
100
96
100
100
7 (R)[c]
7 (R)[h]
9 (R)[h]
0
78 (S)[d]
5 (R)[d]
80 (R)[e]
Ͼ 97 (S)[e,f]
81 (R)[f,g]
L4
[a] Based on conversion of the substrate, determined by GC with
n-decane as internal standard. [b] Determined by chiral GC. [c]
[Rh] = 6.3 m. Reaction time = 14 h. [d] [Rh] = 8.8 m. [e] [Rh] =
1.3 m. [f] Catalyst formed in situ. [g] From ref.[20b]; Rh/8 = 1:1000,
1.3 bar H2. [h] Rh/ligand = 1:2, [Rh] = 6.3 m. Catalyst preformed
in CH2Cl2. Reaction time: 20 h.
Interestingly, for methyl 2-acetamidoacrylate the
enantioselectivities obtained with the supported A1 and the
related nonsupported L4 are comparable (78 vs. 81% ee),
while for dimethyl itaconate as the substrate the perform-
ances of the supported and nonsupported ligands are con-
siderably different (7% ee for A1 and 97% for L4). In con-
trast, for both substrates L3 induced considerably higher
ee values (roughly 97%) than C1 or C2 (roughly 80% ee).
Although only two substrates have been applied, the results
indicate that the complex relationship between the catalytic
properties of polymer-supported catalysts and their homo-
geneous analogues is also dependent on the type of sub-
strate.
Application of Polymer-Supported Ligands in the
Heterocombinations of Ligands
The discovery that heterocombinations of chiral mono-
of the catalytic centre.[8d,9a,28] We therefore studied the per- dentate ligands can yield more active and enantioselective
formance of preformed A1-based catalysts in methanol and catalysts than the homocombinations has been an impor-
toluene (Entries 2–3, Table 3). The enantioselectivities in tant breakthrough in asymmetric catalysis.[2] The methodol-
these solvents are very comparable to those observed for ogy allows the screening of very large libraries of ligand
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combinations, with only limited synthetic effort.[29] NMR
studies have revealed that homocombinations, e.g., (Pa)2M;
see Equation (1), are present in the mixture and these spe-
cies can lower the overall catalytic performance of the sys-
tem.[30]
Pa + Pb + M Ǟ (Pa)2M + PaPbM + (Pb)2M
(1)
The site isolation of polystyrene-bound monodentate li-
gands, as a result of the immobilisation on the support, can
inhibit the formation of bis-ligated species.[21,31] We antici-
pated that, as a result of the site isolation offered by the
polymeric support, resin-supported monodentate ligands
would lead to the selective formation of the desired hetero-
ligand complex (Scheme 4).
Scheme 5. Stepwise formation of a supported heteroligand palla-
dium complex. Chloride anions and charges have been omitted for
clarity.
Scheme 4. Selective formation of supported heteroligand com-
plexes.
Preliminary results indicate that the approach indeed
leads to the formation of supported palladium heteroligand
complexes. When a (tert-butyl)(benzyl)(phenyl)phosphane-
based resin (F15, Scheme 5)[32] was in situ reacted with
0.25 equiv. [Pd(allyl)Cl]2 (F15/Pd, 2:1, solvent = THF/
C6D6, 8:1), two broad signals were observed in the 31P gel-
phase NMR spectrum (Figure 3, spectrum I). The upfield
signal at roughly 9 ppm corresponds to the uncoordinated
∧
phosphane (marked in Figure 3 with ), while the palla-
Figure 3. NMR spectra corresponding to the stepwise formation
of a supported heteroligand palladium complex.
dium complex displays a signal at roughly 46 ppm (marked
with *). The integral corresponds to the involvement of ap-
proximately 50% of the phosphanes in coordination to the
metal centre, indicating that the metal is not coordinated in ligand combinations is given in Table 4 (see Exp. Section
a bis-ligated manner (Scheme 5). The resin was sub- for the full set of data). The performances of the combina-
sequently allowed to react with 0.25 equiv. [Pd(allyl)Cl]2 tion ranged from good (100% conversion and 73% ee for
and 1 equiv. PPh3 (F15:Pd:PPh3 1:1:1). In the 31P gel-phase the E14/L3 combination, Entry 8) to very poor (9% conver-
NMR spectrum (II), the signal corresponding to uncoordi- sion and 9% ee for the C2/L7 combination, Entry 5). The
nated F15 was virtually absent, indicating that all resin-sup- influence of the type of nonsupported ligand on the cata-
ported phosphanes are coordinated to the metal. No phos- lytic performance is particularly evident if the performances
phorus containing species were observed in the solution of the related C2/L7, C2/L8 and C2/L9 systems are com-
phase above the resin (spectrum III). This signifies that the pared (Entries 5–7). The most active system is formed by
PPh3 was immobilised on the resin as a result of coordina- combining C2 with L9 (88% yield), while C2/L7 is roughly
tion to the palladium centre, thus the formation of a sup- ten times less active (9%) and the activity of C2/L8 is in
ported heteroligand complex (Scheme 5).
between (50%). The enantioselectivity follows a different
Although supported heteroligand catalysts have been re- trend; with L8 inducing the highest ee (43%), while L9 re-
ported,[33] to the best of our knowledge the methodology sults in almost racemic product. Typical heteroligand effects
has not yet been applied in a combinatorial approach. For become evident by comparing the performance of a hetero-
the catalytic reactions, we turned our attention to the rho- system with the performances of the two parent ligands. For
dium-catalysed hydrogenation. This reaction has been ex- example, for A9 full conversion and 24% ee was observed
tensively studied in the heteroligand approach, giving vital (Entries 5–6, Table 2). For the A9/18 combination the con-
information on the performance and behaviour of (related) version drops to 80% and the ee increases to 40% (Entry
nonsupported heteroligand catalysts. We started by study- 1, Table 4). Thus, in the presence of the achiral tris-ortho-
ing in situ generated catalyst, formed by reaction of equi- tolylphosphane (L7) the ee observed for A9 increases, indi-
molar amounts of the resin (Pa), the nonsupported ligand cating that the supported heteroligand catalyst is formed
(Pb) and the catalyst precursor in DCM. The structures of successfully. Similarly, for B1/L5 the results indicate that the
the supported and nonsupported ligands are depicted in heteroligand catalyst is formed. Ligand B1 gives the prod-
Figures 1 and 2. The performance of a selection of hetero- uct in 41% ee (R) (Entries 7–8, Table 2). In combination
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Supported Catalysts for Asymmetric Catalysis
with the achiral phosphoramidite L5, the ee increases to of the E14/L3 system. Similarly, for the A2/L3 combination
53% (Entry 2, Table 4). Combining B1 with the achiral the product is formed quantitatively in Ͼ97% ee (Entry 1).
phosphane L7, results in 46% ee, but now predominately The solution phase, separated from the resin prior to the
as the S-isomer (Entry 3, Table 4). Thus, a switch in chiral- catalytic reaction, displays a similar activity; although the
ity of the product can be induced by addition of an appro- enantioselectivity is lower (67% ee, Entry 2). The resin
priate achiral monodentate phosphane. Similar effects have phase, which was also applied as a catalyst, proved equally
been observed by others for related nonsupported sys- active, but gives the product in only 5% ee (Entry 3). Thus,
tems.[29]
nonsupported species (of L3) are present in the solution
phase. The fact that the resin and solution phases do not
match the performance of the combined phases indicates
that in the in situ system the heteroligand catalyst is formed
and contributes to the overall activity. Thus, although the
polymeric support does influence the ratio of the homo-
and heteroligand species (and thereby the catalytic perform-
ance), the site isolation offered by the resin is not sufficient
for the selective formation of the immobilised heteroligand
rhodium complexes.[36,37]
Table 4. Performance of heteroligand combinations in the hydro-
genation of 7. Reaction conditions: Rh/7 = 1:40, [Rh] = 2.8 m,
5 bar H2, CH2Cl2, room temp., catalyst formed in situ, catalyst pre-
cursor: [(COD)Rh(MeCN)2]BF4, catalyst incubation time: 30 min,
reaction time: 20 h.
Entry
Pa
Pb
Conversion[a]
ee[b]
1
A9
B1
B1
C2
C2
C2
C2
E14
L6
L7
L5
L7
L5
L7
L8
L9
L3
L3
80
60
86
25
9
50
88
100
100
40 (R)
53 (R)
46 (S)
5 (R)
9 (S)
43 (S)
1 (R)
2
3[c]
4
Table 5. Catalytic performance of the solution and polymeric phase
of in situ generated heterocombinations in the hydrogenation of 7.
Reaction conditions: Rh/7 = 1:40, [Rh] = 2.8 m, 5 bar H2,
CH2Cl2, room temp., catalyst formed in situ, catalyst precursor:
[(COD)Rh(MeCN)2]BF4, catalyst incubation time: 30 min, reac-
tion time: 20 h.
5[c]
6[c]
7[c]
8
73 (R)
Ͼ 97 (R)
9
[a] Based on conversion of 7, determined by GC with n-decane as
internal standard. [b] Determined by chiral GC (Betadex 325). [c]
Reaction mixture was not stirred.
Entry
Pa
Pb
Phase
Conversion[a] ee[b]
1
2
3
4
5
A2
A2
A2
E14
E14
L3
L3
L3
L3
L3
both
solution
resin
both
solution
100
100
100
100
100
Ͼ 97 (R)
67 (R)[c]
5 (R)[c]
Interestingly, resin C2 in combination with the achiral
L5 and L7 displayed considerably lower activities and
enantioselectivities than the B1/L5 and B1/L7 combinations
(Entries 2 vs. 4 and 3 vs. 5). Because both resins are BI-
NOL-based, this fact indicates that the type of support
(resin B vs. C) has a decisive influence on the performance
of the heteroligand system. This can be attributed to the
differences in amido linker (proline vs. N-methylbenzyl-
amine), but the different microenvironments supplied by the
two polymeric supports may be equally important. The in-
fluence of the microenvironment is also evident from the
different performance of E14/L3 and L6/L3 (Entries 8–9).
73 (R)
Ͼ 97 (R)[d]
[a] Based on conversion of the substrate, determined by GC with
n-decane as internal standard. [b] Determined by chiral GC (Beta-
dex 325). [c] Solution and resin phase separated prior to catalysis
after incubation time of 14 h. [d] Solution and resin separated after
40 min reaction time. Solution phase returned to autoclave for an
additional 19 h reaction time.
Conclusions
In conclusion, polystyrene-supported (chiral) mono-
In these related systems, triphenylphosphane is either pres- dentate phosphites and phosphoramidites have been
ent in its supported form (E14) or as a nonsupported ligand studied as ligands for transition-metal-catalysed asymmet-
(L6). The immobilisation of the triphenylphosphane results ric reactions. In the palladium-catalysed asymmetric allylic
in a significant decrease in enantioselectivity (73% ee for alkylation, moderate to good activities and enantio-
E14/L3 vs. Ͼ 97% ee for L6/L3). We attribute this differ- selectivities were observed. In the rhodium-catalysed hydro-
ence to the site isolation offered by the polymer, influencing genation, the polymers yielded active and enantioselective
the ratios in which the various homo- and heteroligand catalysts. Several supported ligands induced lower activities
complexes are formed.[34] On the basis of this result, it can and enantioselectivities than their homogeneous analogues.
not be confirmed that the supported heteroligand species is A general correlation between the catalytic performance of
formed selectively. The presence of nonsupported species the supported and nonsupported analogues was not found.
was confirmed by experiments in which the activity of the Moreover, it turned out that the relationship between the
solution and resin phases were determined independently, catalytic properties of the two counterparts is highly de-
for which the data are given in Table 5.[35] When after pendent on the type of substrate. In addition, we applied
40 min reaction time the solution phase of E14/L3 was sep- the polymer-bound ligands in the heteroligand combination
arated from the polymeric phase and allowed to react for approach by combining them with nonsupported mono-
another 19 h, the product was obtained in Ͼ97% ee (Entry dentate ligands. We anticipated that the site isolation of-
5). For the heteroligand combination in which the phases fered by the polymeric support would yield the heteroligand
were not separated the product was obtained in a lower ee complex selectively. The results, however, indicate that the
of 73% ee (Entry 4). This indicates that (highly enantiose- systems consist of mixtures of supported and nonsupported
lective) L3-based species are present in the solution phase homo- and heteroligand species.
Eur. J. Org. Chem. 2009, 5796–5803
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5801

P. C. J. Kamer et al.
FULL PAPER
Experimental Section
[1]
a) M. van den Berg, A. J. Minnaard, R. M. Haak, M. Leeman,
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General Remarks: All reactions were carried out under strictly oxy-
gen and water free conditions, using standard Schlenk techniques
under an atmosphere of purified nitrogen or argon. Chemical were
purchased in highest commercially available purity from Acros Chi-
mica, Aldrich Chemical Co., Biosolve, Fluka and Merck and were
used as received, unless indicated otherwise. Toluene and C6D6 was
distilled from sodium, diethyl ether and THF from sodium/benzo-
phenone, tertiary amines, dichloromethane and methanol were dis-
tilled from calcium hydride. Chlorodiphenylphosphane was freshly
distilled prior to use. (2R,4S,5R)-2-chloro-3,4-dimethyl-5-phenyl-
1,3,2-oxazaphospholidine (2) was synthesised according to a litera-
ture procedure.[38] Dr. N. Vautravers and Prof. D. Cole-Hamilton
are greatly acknowledged for a generous gift of (2R,5S)-1,3-diaza-
2-chloro-3-phenyl-2-phosphabicyclo[3.3.0]octane
(3).
4-hy-
[2]
[3]
[4]
droxyphenol, polymer-bound (1, 1% DVB-PS, 50–100 mesh,
0.91 mmol/g) was purchased from Aldrich. Polymer-supported tri-
phenylphosphane (E14, 1% DVB-PS, 100–200 mesh, 1.2–
1.5 mmol/g) was purchased from Acros Chimica and with the exep-
tion of A9, A10, A11 and A14, all other resin-bound ligands were
synthesised according to literature procedures.[3a] The monodentate
phosphites were synthesised according to literature procedures.[3a]
NMR spectra were recorded at room temperature on a Bruker Av-
ance 300, a Bruker Avance 400 NMR, a Varian Mercury 300 or a
Varian Inova 500 spectrometer. Positive chemical shifts (δ) are
given (in ppm) for high-frequency shifts relative to an 85% H3PO4
in D2O reference (31P). Gel-phase 31P NMR spectra of the resins
suspended in THF (using a D2O inner tube) or THF/C6D6 (8:1)
were recorded using standard NMR techniques. Elemental analyses
were carried out by H. Kolbe Mikroanalytisches Laboratorium,
Mülheim an der Ruhr, Germany.
R.
den Heeten,
B. H. G.
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[5]
[6]
Preparation of A9: 545 mg (0.50 mmol) 4-hydroxyphenol polymer-
bound resin (1) was washed with THF (3 ϫ 5 mL) and suspended
in 10 mL toluene. After 1 h 1.0 mL iPr2NEt (3.8 mmol, 7.6 equiv.)
was added, followed by 236 mg (2R,4S,5R)-2-chloro-3,4-dimethyl-
5-phenyl-1,3,2-oxazaphospholidine (2; 1.03 mmol, 2.07 equiv.). A
gentle flow of argon was bubbled through the mixture for several
5 min periods within 3 h, after which the reaction was allowed to
proceed for an additional 14 h. The suspension was filtered and the
resin washed with subsequently toluene, THF, DCM, Et2O, DCM
and Et2O (5 mL each) and dried under a gentle flow of argon,
followed by drying under vacuum. 31P NMR (THF/C6D6, 8:1):
141 ppm (broad singlet), 135 ppm (broad singlet); (10:18). Microa-
nalysis: found P 2.17%.
[7]
[8]
A10, A11 and A14: Were prepared in a similar manner, replacing 2
with the appropriate phosphorus-chloride reagent. A10: 31P NMR
(THF): 120 ppm. A11: 31P NMR (THF/C6D6, 8:1): 128 ppm. Mi-
croanalysis: found P 1.14%. A14: 31P NMR (THF/C6D6, 8:1):
112 ppm. Microanalysis: found P 2.46%.
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Supporting Information (see also the footnote on the first page of
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Acknowledgments
This work was supported by the Nederlandse Organisatie voor
Wetenschappelijk Onderzoek (NWO), Combinatorial Chemistry
program and by DSM Pharmaceutical Products, Inc.
5802
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Bidentate formation has been observed for (highly crosslinked)
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[22] Generally it was observed that the rhodium black formation
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[37] Initial results with heteroligand combinations in the palladium-
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Received: August 12, 2009
Published Online: September 24, 2009
As a result of a technical error, the Early View version of this
paper contained the wrong Scheme 2; it has since been corrected.
[23] Note that, resins Cx and Dx contain at least two phosphorus
compounds; see ref.[3a] for details.
[24] See for instance: a) H. Bernsmann, M. van den Berg, R. Hoen,
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40, 1267–1277.
Eur. J. Org. Chem. 2009, 5796–5803
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5803