Polymer-supported phosphoramidites: Highly efficient and recyclable catalysts for asymmetric hydrogenation of dimethylitaconate and dehydroamino acids and esters

Article abstract of DOI:10.1016/S0957-4166(03)00253-2

Several novel phosphoramidites have been prepared by reaction of the primary amines para-vinylaniline, ortho-anisidine, 2-methoxyphenyl(4-vinylbenzyl)amine, 8-aminoquinoline and 3-vinyl-8-aminoquinoline with (S)-1,1′-bi-2-naphthylchlorophosphite, in the presence of base. Rhodium(I) complexes of these phosphoramidites catalyse the asymmetric hydrogenation of dimethylitaconate and dehydroamino acids and esters giving ee values up to 95%. Soluble non-cross linked polymers of the para-vinylaniline and 3-vinyl-8-aminoquinoline-based phosphoramidites have been prepared by free radical co-polymerisation with styrene in the presence of AIBN as initiator. The corresponding [Rh(COD)]⁺ complexes serve as recyclable catalysts for the asymmetric hydrogenation dimethylitaconate and dehydroamino acids and esters to give ee values up to 80%.

Full text of DOI:10.1016/S0957-4166(03)00253-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1517–1527
Polymer-supported phosphoramidites: highly efficient and
recyclable catalysts for asymmetric hydrogenation of
dimethylitaconate and dehydroamino acids and esters
a,
a,b
a
a
a
Simon Doherty, * Edward G. Robins, Ibolya P a´ l, Colin R. Newman, Christopher Hardacre,
b
b
David Rooney and Damian A. Mooney
a
School of Chemistry, David Keir Building, Queens University, Belfast BT9 5AG, UK
b
Department of Chemical Engineering, David Keir Building, Queens University, Belfast BT9 5AG, UK
Received 10 February 2003; accepted 12 March 2003
Abstract—Several novel phosphoramidites have been prepared by reaction of the primary amines para-vinylaniline, ortho-ani-
sidine, 2-methoxyphenyl(4-vinylbenzyl)amine, 8-aminoquinoline and 3-vinyl-8-aminoquinoline with (S)-1,1%-bi-2-naph-
thylchlorophosphite, in the presence of base. Rhodium(I) complexes of these phosphoramidites catalyse the asymmetric
hydrogenation of dimethylitaconate and dehydroamino acids and esters giving ee values up to 95%. Soluble non-cross linked
polymers of the para-vinylaniline and 3-vinyl-8-aminoquinoline-based phosphoramidites have been prepared by free radical
+
co-polymerisation with styrene in the presence of AIBN as initiator. The corresponding [Rh(COD)] complexes serve as recyclable
catalysts for the asymmetric hydrogenation dimethylitaconate and dehydroamino acids and esters to give ee values up to 80%.
©
2003 Elsevier Science Ltd. All rights reserved.
1
. Introduction
ligands have been prepared including the bidentate
5 6 7 8
phosphines Chiraphos, DuPHOS, BICP, BINAP,
9
10
Although the enantioselective hydrogenation of prochiral
alkenes hasbeen extensively studied, thedesignofefficient
chiralancillaryligandsforhomogeneoustransitionmetal-
catalysed hydrogenation still continues to receive much1
attention. Since the development of (R,R)-DIOP in 1971,
it has generally been accepted that a conformationally
rigid symmetric bidentate diphosphine is required to
Norphos TangPhos and various ferrocenyl-based lig-
11
ands such as Josiphos and FerroPHOS as well as
bidentate phosphites, phosphinites and phospho-
12
13
14
nites, many of which form highly enantioselective
hydrogenation catalysts. Despite encouraging perfor-
mances by many of these bidentate P-chelates, the past
few years have witnessed a renewed interest in the
development of chiral monodentate phosphorus-contain-
ing ligands for use in rhodium-catalysed asymmetric
2
achieve effective asymmetric induction, even though the
P-chiral monodentate phosphines phenyl-o-anisyl-
methylphosphine (PAMP) and cyclohexyl-o-anisyl-
methyl phosphine (CAMP) were shown to be highly
efficient ancillary ligands for the asymmetric hydrogena-
tion of dehydroamino acid derivatives, the former giving
15
hydrogenation reactions. Pringle was among the first to
demonstrate that monodentate phosphonites derived
from 2,2%-binaphthol and 9,9%-biphenanthrol can outper-
form their chelating analogues in the asymmetric hydro-
3
16
up to 90% ee. In fact, soon after the development of
genation of methyl-2-acetamido acrylate. Following
PAMP, Knowles prepared its diphosphine counterpart,
DIPAMP, which was more efficient as a chiral ancillary
ligand than its monophosphine equivalent. Since these
this, a number of closely related reports appeared which
17
detail the use of monodentate phosphine, phospho-
4
18
19
20
nite, phospholane, and phosphite ligands for the
rhodium-catalysed asymmetric hydrogenation of dehy-
pioneering studies, an immense number of P-chelate
*
0
Corresponding author. E-mail: s.doherty@qub.ac.uk
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00253-2

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S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
droamino acid derivatives. Among the most successful of
rhodium-catalysed asymmetric hydrogenation of dehy-
droamino acid derivatives, although polymer-bound
phosphoramidites have been successfully employed in
copper-mediated enantioselective conjugate addition
21
these are complexes of monodentate phosphites 1 and
2
2
phosphoramidites 2 based on axially chiral 2,2%-binaph-
23
thol and phosphoramidites 3 containing a 1,1%-spirobi-
indane backbone (SIPHOS), which gives ee values in
excess of 99%.
27
reactions. With the aim of preparing polymer-supported
phosphoramidites it was first necessary to identify, pre-
pare and evaluate the performance of monomers that can
either undergo direct co-polymerisation or be easily
modified to incorporate a polymerisable vinyl substituent.
Firstly, phosphoramidite 4 was chosen since it can be
prepared from commercially available 4-vinylaniline and
can be tethered to a polymer support by co-polymerisa-
tion with styrene. Phosphoramidite 5 was prepared as it
contains an ortho methoxy group similar to that present
in the chiral monodentate phosphines PAMP and
There is also considerable interest in the recycling and
reusability of chiral transition metal catalysts since the
metal is often relatively expensive and the ligand synthesis
often involves a multi-step procedure that requires expen-
sivereagents. Oneofthemoststraightforwardapproaches
to recycle a catalyst is immobilisation on an inert support.
Ideally, the immobilised catalyst should have an activity
and selectivity comparable to that of its homogeneous
counterpart and be easily recovered from the reaction
mixture by filtration. Unfortunately, loss of activity due
to leaching is a common problem for supported catalysts
and the selectivity is often lower than that obtained with
its unsupported homogeneous counterpart. Monodentate
phosphoramidites are ideal candidates for immobilisation
since they are highly efficient chiral ancillary ligands for
rhodium-catalysed asymmetric hydrogenations but are
relatively expensive in metal and ligand. Polymer resins
such as polystyrene are finding increasing use in organic
3
CAMP, which form highly efficient hydrogenation cat-
alysts. It has been suggested that the high selectivity of
these catalysts may result from the formation of a
hemilabile chelate via coordination of the methoxy group.
In this regard, 5 is also potentially capable of forming
a hemilabile six-membered chelate as is phosphoramidite
6
via coordination through phosphorus and the quinoline
nitrogen atom. Phosphoramidite 2, reported earlier by
22
Feringa and co-workers, was chosen as the benchmark
with which to compare ligands 4–6 since it is relatively
straightforward to prepare and is an excellent chiral
ancillary ligand for rhodium-catalysed hydrogenations.
2
4
synthesis and are rapidly becoming the support ofchoice
2
5
for catalyst immobilisation. Whilst insoluble cross-
linked polystyrene has been most commonly employed,
non-cross-linked polystyrene (NCPS) is often soluble and
combines the advantages of solution phase properties
Phosphoramidite 2 was prepared from (S)-1,1%-bi-2-
26
naphthol and hexamethylphosphorus triamide according
with ease of product purification and separation. Herein
we report the synthesis of novel phosphoramidites based
on the axially chiral 2,2%-binaphthol backbone and their
application to the homogenous and soluble polymer-sup-
ported rhodium-catalysed hydrogenation of dimethylita-
conate and dehydroamino acid derivatives.
22
to the literature procedure and phosphoramidites 4–6
were prepared according to the general procedure out-
lined in Scheme 1. The chiral chlorophosphite (S)-1,1%-bi-
2
-naphthyl chlorophosphite was prepared by slow
addition of a THF solution of phosphorus trichloride to
a solution of (S)-1,1%-bi-2-naphthol and triethylamine in
2
8
THF, according to the modified procedure of Osborne.
2
. Results and discussion
Dropwise addition of a toluene solution of the appropri-
ate primary amine to an ice-cooled toluene solution of
(S)-1,1%-bi-2-naphthyl chlorophosphite and base gave
high yields of the desired phosphoramidites 4–6, as
air-stable spectroscopically pure solids after purification
by flash column chromatography.
2
.1. Synthesis of phosphoramidites
To the best of our knowledge there have been no reports
of the use of polymer-supported phosphoramidites for the
Scheme 1. Synthesis of phosphoramidites 5 and 6.

S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
1519
Scheme 2. Synthesis of phosphoramidite 7.
Phosphoramidite 7, containing a p-styrenyl substituent
was identified as a monomer that could be converted
into a soluble non-cross linked polymer-supported ver-
sion of the ortho-methoxy substituted phosphoramidite
Under our conditions the rhodium-catalysed hydro-
genation of dimethylitaconate 8 proceeds to completion
for all catalysts studied with phosphoramidite 5 giving
an ee of 91% (entry 3), compared to that of 85% for the
benchmark phosphoramidite 2 (entry 2). While phos-
phoramidite 2 catalysed the hydrogenation of dehy-
droamino esters 9 and 11 to give ee’s in excess of 99%
(entries 5 and 13) reduction of the corresponding acids
10 and 12 was markedly less selective. Surprisingly, in
our hands the [Rh(2) (COD)][BF ] catalysed hydro-
5
. Although 7 could not be prepared using the proce-
dure outlined above for 4–6, reaction of (S)-1,1%-bi-2-
naphthyl chlorophosphite with lithium 2-methoxy-
phenyl(4-vinylbenzyl)amide, generated in situ by depro-
tonation of the corresponding secondary amine with
butyl lithium, gave the desired product in reasonable
yield. Purification of the crude reaction mixture by flash
chromatography on silica gel afforded phosphoramidite
2
4
genation of substrate 12 gave an ee value of 67% (entry
17), which is significantly lower than that reported
22
7
as an air-stable spectroscopically pure material
Scheme 2).
earlier by Feringa under similar conditions. Reassur-
ingly though, the enantioselectivities obtained for
hydrogenation of substrates 8–11 were comparable to
those reported for the benchmark phosphoramidite 2.
While phosphoramidite 5 was more selective for the
rhodium-catalysed hydrogenation of esters 10 and 12
than their corresponding acids, phosphoramidite 4 was
slightly more selective for the hydrogenation of acid 12
compared with its ester 11 (entries 14 and 18). In this
regard, Chan has noted on several occasions that the
rates and enantioselectivities of hydrogenation of (Z)-
acetamido-3-arylacrylic acids are lower than those
obtained for the hydrogenation of their corresponding
(
2
.2. Rhodium-catalysed enantioselective hydrogenation
of dimethylitaconate and dehydroamino acid derivatives
The efficiency of phosphoramidites 2, 4, 5 and 7 as
chiral ancillary ligands for rhodium-catalysed asymmet-
ric hydrogenations has been investigated. The cationic
rhodium catalysts [RhL (COD)][BF ] (L=2, 4, 5, 7)
2
4
were typically prepared in situ by reaction of 2 equiv. of
the appropriate phosphoramidite with [Rh(COD)2]-
[
BF ] in dichloromethane at room temperature. The
4
13e,f
results for the asymmetric hydrogenation of dimethyl-
esters.
Despite the promising selectivities obtained
itaconate 8 (Eq. (1)) and dehydroamino acid derivatives
for hydrogenations based on 5, introduction of an
additional p-vinylbenzyl group on nitrogen, i.e. phos-
phoramidite 7, resulted in a dramatic reduction in
catalyst performance. Indeed, for all substrates exam-
9
–12 (Eq. (2)) catalysed by [RhL (COD)][BF ] under
2
4
ambient conditions (rt, 1 bar H , 20 h), are given in
2
Table 1.
(
(
1)
2)

1
520
S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
ined, phosphoramidite 7 gave significantly lower ee’s
values (entries 4, 8, 12, 16 and 20) than those obtained
with 5 (entries 3, 7, 11, 15 and 19). Such a reduction in
enantioselectivity with increasing steric bulk at nitrogen
parallels closely the reduced selectivity observed in the
asymmetric hydrogenation of enamides with diethyl
and in this regard the high enantioselectivities for these
substrates is not surprising (Table 1).
In general, the performance of catalysts prepared in situ
from 2 equiv. of monodentate phosphoramidites 2, 4, 5
or 7 and [Rh(COD) ][BF ] were comparable to that
2
4
2
3
and diisopropyl spiro-phosphoramidites.
obtained with pre-formed complexes of the type
Rh(L) (COD)][BF ]. In contrast, precatalyst prepared
[
2
4
With regard to catalyst performance, Orpen and
Pringle have proposed that two sterically demanding
cis-coordinated binaphthol derived phosphonites adopt
a stable rigid conformation around the metal such that
the two biaryl fragments adopt an edge-on arrangement
which is highly effective for transfer of chiral informa-
by reaction of [Rh(COD) ][BF ] with 2 equiv. of phos-
2 4
phoramidite 6, showed no activity for hydrogenation of
substrates 8–12. Since phosphoramidite 6 is capable of
coordinating to rhodium in a bidentate manner, as a
P,N chelate, the absence of activity for catalyst mix-
tures based on a Rh:ligand ratio of 1:2 could be due to
formation of the inactive bischelate [Rh(6) ][BF ]. In
1
6
tion, in much the same manner as the alternating
edge/face arrangement of chiral diphosphines. The pre-
catalyst [Rh(1) (COD)][BF ] is also clearly capable of
2
4
this regard, bischelate complexes have previously been
4
a
reported to be inactive for olefin hydrogenation. The
bis(chelate) complex [Rh(6) ][BF ] (l 146.8 ppm, d,
2
4
forming a similar conformationally rigid framework
2
4
a
Table 1. Homogeneous rhodium-catalysed hydrogenation of dimethylitaconate 8 and dehydroamino acid derivatives 9–12

S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
1521
Table 2. Homogeneous rhodium-catalysed hydrogenation of dimethylitaconate 8 and dehydroamino acid derivatives 9–12
a
using phosphoramidite 6
JRhP=271 Hz) has been prepared by reaction of 2
rhodium complexes of phosphoramidite 6 are given in
Table 2. Under identical conditions, preformed catalyst
equiv. of phosphoramidite with [Rh(COD) ][BF ], iso-
2
4
lated by crystallisation from a dichloromethane solu-
tion layered with hexane, and shown to be catalytically
inactive. A molecular ion peak at 1020 amu in the
electrospray mass spectrum of [Ru(6) ][BF ] is consis-
[Rh(6)(COD)][BF ] showed a marked increase in enan-
4
tioselectivity to give an ee value of 84% for the same
substrate (entry 4). In an attempt to glean insight in to
3
1
the origin of these disparate enantioselectivities
P
2
4
tent with this bischelate formulation. Our suggestion
that 6 acts as a bidentate ligand is also supported by
the recent studies of Buono and co-workers who have
demonstrated that the related diastereomerically pure
NMR spectroscopy was used to examine the nature of
the solution species formed by mixing [Rh(COD) ][BF ]
2
1
4
3
1
and phosphoramidite 6 in a 1:1 ratio. The P{ H}
NMR spectrum of this reaction mixture revealed the
presence of two major phosphorus-containing species
[Rh(6) ][BF ] (l 146.8 ppm) and [Rh(6)(COD)][BF ] (l
(
2R,5S)-3-phenyl-2-(8-quinolinoxy)-1,3-diaza-2-phos-
phabicyclo-[3.3.0]octane (QUIPHOS) coordinates to
2
4
4
2
9
palladium in a bidentate chelating manner. Reduction
of the Rh:ligand combination to a ratio of 1:1 gave a
catalyst mixture that was active for the hydrogenation
of substrate 9, giving complete conversion and a mod-
est enantioselectivity of 69% (entry 2). Full details of
the asymmetric hydrogenation of dimethylitaconate 8
and dehydroamino acid derivatives 9–12 catalysed by
131.7 ppm, d, JRhP=247 Hz) in approximately 3:2
31
molar ratio, respectively. In comparison the P NMR
spectrum of isolated precatalyst, purified by crystallisa-
tion, showed one major component, a doublet at l
131.7 which corresponds to [Rh(6)(COD)][BF ]. Under
4
ambient conditions, [Rh(COD) ][BF ] is also active for
2
4
the hydrogenation of methyl-2-acetamidoacrylate 9 and

1
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S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
gives quantitative conversion to racemic product. Thus,
the most likely origin of the lower enantioselectivity
obtained during the hydrogenation of 9 with in situ
generated catalyst is competing hydrogenation by unre-
acted achiral [Rh(COD) ][BF ], which could account
phosphoramidite 13 by reaction with (S)-1,1%-bi-2-
naphthyl chlorophosphite in the presence of
triethylamine.
2
4
The objective of preparing soluble, non-cross-linked
styrene-based co-polymers of 4 and 13 was to generate
functionalised resins that combine the solubility of
homogeneous catalysts with the ease of separation of
for up to 40% of the reaction mixture.
Although hydrogenation of substrates 9 and 11–12 with
[
Rh(6)(COD)][BF ] gave conversions and enantioselec-
17
4
heterogeneous supports. Co-polymers 14 and 15 were
tivities similar to those obtained with phosphoramidites
and 5, dehydroamino acid 10 gave less than 50%
prepared by suspension co-polymerisation of styrene
with phosphoramidite monomers 4 and 13, respectively,
in toluene in the presence of 2,2%-azobis(2-
methyl)propionitrile (AIBN) as radical initiator
4
conversion, although the ee value of 63% was only
marginally lower. As expected the conversion improved
to 74% when the hydrogenation of 8 was conducted at
(
Scheme 4). The resulting co-polymers were isolated as
3
0°C, although the enantioselectivity was slightly lower
with an ee value of 54%. Encouragingly, [Rh(6)(COD)]-
BF ] showed excellent enantioselectivity for the hydro-
off-white powders by precipitation with methanol fol-
lowed by exhaustive drying to remove residual solvent.
The phosphorus content was obtained by elemental
analysis (C, H, N and P) and the polydispersities of 14
and 15 were measured by gel permeation chromatogra-
phy (GPC). Both polymers 14 and 15 were found to
have a unimodal molecular weight distribution with
similar polydispersities M /M =1.7 and 1.6, respec-
[
4
genation of
8 giving quantitative conversion to
dimethyl-(S)-methylsuccinate with an ee of 95%, a
marked improvement compared with the performance
of benchmark phosphoramidite 2, which gave an ee of
85% under identical conditions.
W
N
tively, although their average molecular weights (MW)
differed (M =20,100 Da. for 14 and M =10,200 Da.
2
.3. Polymer-supported catalysis
W
W
for 15). The supported complexes 14[Rh] and 15[Rh]
In order to synthesise a styrene co-polymer incorporat-
ing the same functionality as 6, phosphoramidite 13
was prepared from 3-bromoquinoline according to the
procedure outlined in Scheme 3. Nitration of 3-bromo-
quinoline followed by Fe-mediated reduction in 50%
acetic acid afforded a 9:1 mixture of 8-amino-3-bromo-
quinoline and 5-amino-3-bromoquinoline, which was
purified by crystallisation to give the desired 8-amino-
substituted product. The polymerisable vinyl sub-
stituent was introduced by a Pd(0) mediated Stille
cross-coupling reaction between 8-amino-3-bromo-
quinoline and tributylvinyltin to give 3-vinyl-8-amino-
quinoline, which was subsequently converted into
were prepared by stirring a dichloromethane solution of
1
4 and 15 with [Rh(COD) ][BF ] at room temperature
2
4
for 24 h and isolated as yellow/orange powders by
precipitation with dry methanol. The rhodium loading
in 14[Rh] and 15[Rh] was determined by inductively
coupled plasma atomic emission (ICP-AES) analysis of
a sample of polymer digested in refluxing aqua.
Rhodium-loaded polymers 14[Rh] and 15[Rh] catalyse
the enantioselective hydrogenation of dimethylitaconate
8 and dehydroamino acid derivatives 9–12 under the
same conditions as rhodium complexes of phospho-
Scheme 3. Synthesis of phosphoramidite 13.

S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
1523
Scheme 4. Polymerisation of phosphoramidite monomers 4 and 13.
Table 3. Hydrogenation results for metal-loaded phosphoramidite co-polymers 14[Rh] and 15[Rh]
ramidites 2 and 4–7 (ambient temperature, 1 bar H in
polymer that remained was redissolved in the minimum
volume of dichloromethane, precipitated with
methanol, filtered, dried and recycled (vide infra).
Hydrogenation of 8–12 in the presence of Rh[14] gave
quantitative conversions for all substrates and enantio-
2
dichloromethane, 5 mol% [Rh]), the results of which are
summarised in Table 3. Following the reaction, the
solvent was removed and the product isolated by
extracting the resulting residue with methanol. The

1
524
S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
selectivities that were comparable to those obtained
with phosphoramidite 4. In fact, Rh[14] gave slightly
higher enantioselectivities for the hydrogenation of
dehydroamino esters 9 and 11 than catalyst generated
from [Rh(COD) ][BF ] and 4. Specifically, 14[Rh] gave
ity, although a marked drop in conversion was noted
30
between the 1:2 and 1:1 Rh:ligand combination.
The major advantages of polymer-supported catalysts
are the ease of separation and product purification and
the ability to recycle and reuse expensive catalysts a
number of times. Rhodium-loaded phosphoramidite co-
polymer 14 was chosen for catalyst recycling studies
since the conversions and enantioselectivities achieved
with this catalyst were comparable to those of its
unsupported counterpart. The results for the hydro-
genation of methyl-2-acetamidocinnamate 11 catalysed
by 14[Rh] and recycled over four runs are given in
Table 4. After each run the dichloromethane solvent
was removed under reduced pressure and the polymer
precipitated by addition of methanol to give near quan-
titative recovery of orange-yellow catalyst (ca. 95%)
after filtering and drying, with less than 14% losses due
to manual transfer over four catalyst recycles. The
results shown in Table 4 clearly demonstrate that recy-
cling of 14[Rh] results in negligible loss of activity and
enantioselectivity over four recycles and ICP-AES anal-
ysis of the methanol washings showed no sign of
rhodium leaching after each run. However, significant
losses in activity and selectivity were observed for cata-
lysts requiring longer reaction times and for these sub-
strates only three catalyst recycles were possible.
2
4
ee’s of 75 and 80% for the hydrogenation of 9 and 11,
respectively, while [Rh(COD) ][BF ]/4 gave ee values of
2
4
7
2 and 79%, respectively. In contrast, [Rh(6)(COD)]-
[BF ] clearly outperforms its polymer-supported coun-
4
terpart 15[Rh] for the asymmetric hydrogenation of
substrates 8–12 with the most dramatic difference man-
ifested in the hydrogenation of dimethylitaconate 8,
which gave 100% conversion and an ee of 95% com-
pared with 57% conversion and 49% ee with 15[Rh].
The results listed in Table 3 clearly show that co-poly-
mer 14[Rh], containing the monodentate ligand 4, con-
sistently outperforms 15[Rh], which contains the P,N
chelating ligand 6. In the case of 14[Rh] the random
co-polymerisation and low phosphoramidite content
(
2.5–3.5%) is likely to preclude cis-coordination of two
phosphoramidites and thus 14[Rh] would be expected
to behave/perform in much the same manner as a 1:1
Rh:ligand combination. In this regard, while the
rhodium-catalysed hydrogenation of substrates 8–12
with the [Rh(COD) ][BF ]/4 combination were typically
2
4
run at a Rh:ligand ratio of 1:2, catalysts generated with
a Rh:ligand ratio of 1:1 gave comparable enantioselec-
tivities and conversions. Given that enantioselectivity
does not depend markedly on the Rh:ligand ratio it is
not surprising that the 14[Rh] catalysed hydrogenation
of substrates 8–12 (Table 3) gave ee values that were
either comparable to or higher than those achieved with
3. Conclusions
In summary, several phosphoramidite ligands have
been prepared which give ee values as high as 95% for
the asymmetric hydrogenation of prochiral olefins. We
have demonstrated the straightforward synthesis and
practical application of soluble non-cross-linked sty-
rene-phosphoramidite co-polymers as suitable supports
for the rhodium-catalysed asymmetric hydrogenation of
prochiral olefins. In some cases the performance of the
polymer-supported catalyst is comparable to or better
than that of the corresponding unsupported catalyst.
These catalysts have been successfully recycled with no
significant loss of activity or selectivity over short reac-
tion times. Investigations are currently underway in our
laboratory to improve and optimise catalyst perfor-
mance through ligand modification and determine the
nature of the active catalyst and the factors that deter-
[
Rh(4) (COD)][BF ]. Although efficient transfer of chi-
2
4
rality appears unlikely for a complex of a single
monophosphorus ligand, Reeetz and Mehler have
shown that simple BINOL-based monophosphites are
excellent ancillary ligands for the rhodium-catalysed
hydrogenation of dimethylitaconate giving ee values as
high as 99.6% with a Rh:ligand ratio of 1:1. Moreover,
this variable did not influence enantioselectivity over a
range of Rh:ligand combinations from 1:1 to 1:4. Simi-
larly, Chan has used monodentate phosphoramidites,
derived from enantiopure H -BINOL and dimethyl-
8
amine, for the rhodium-catalysed hydrogenation of
methyl (Z)-acetamidocinnaminate and found that the
Rh:L ratio does not significantly effect enantioselectiv-
Table 4. Asymmetric hydrogenation of 11 with recycling of polymer-supported catalyst 14[Rh]

S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
1525
mine selectivity. Ultimately, we intend to examine the
processibility and engineering properties of these poly-
mer-supported catalysts in order to identify polymers
suitable for fibre extrusion and/or coating of high sur-
face area substrates.
layer chromatography until all the 3-bromoquinoline
had been consumed (ca. 2 h). The mixture was diluted
with water (50 mL) and NaOH added until the solution
reached pH 10–11. The resulting solution was extracted
with diethyl ether (2×50 mL), the organic phase dried
over anhydrous magnesium sulfate and the solvent
removed under reduced pressure to give a 9:1 mixture
4
4
. Experimental
of
3-bromo-8-nitroquinoline
and
3-bromo-5-
nitroquinoline, respectively. Recrystallisation from
ethylacetate afforded 5.0 g of. 3-bromo-8-nitroquino-
line. H NMR (CDCl ): 3-bromo-8-nitroquinoline l
.1. General procedures
1
3
All manipulations involving air/moisture sensitive
materials were carried out using standard Schlenk tech-
niques under an inert atmosphere of nitrogen or argon.
Toluene was distilled from sodium metal, diethyl ether
and hexane were distilled from potassium/sodium alloy,
tetrahydrofuran was distilled from potassium, dimethyl-
formamide (DMF) and dichloromethane were distilled
from calcium hydride and methanol distilled from mag-
nesium methoxide. Deuteriochloroform was pre-dried
from calcium hydride, then vacuum transferred and
9.26 (dd, 1H, J=2.2 Hz, 0.7 Hz), 9.04 (d, 1H, J=6.5
Hz), 8.44 (m, 2H), 7.86 (pseudo t, 1H).
4.2.3. Synthesis of 3-vinyl-8-aminoquinoline. A DMF (15
mL) solution of 3-bromo-8-aminoquinoline (0.500 g,
2.24 mmol) and tetrakis(triphenylphosphine) palla-
dium(0) (0.129 g, 0.112 mmol, 5 mol%), shielded from
the light, was treated with 1.1 equiv. of tributyl-
(vinyl)tin (0.72 mL, 2.47 mmol) and the resulting mix-
ture heated to 60°C overnight, after which time it was
cooled to room temperature and quenched by addition
of saturated aqueous potassium fluoride (100 mL). The
organic phase was extracted with diethyl ether (4×50
mL), separated, dried over anhydrous magnesium sul-
fate and the solvent removed under reduced pressure to
afford the crude product as a pale orange solid. Purifi-
cation by chromatography over silica gel using diethyl
1
13
1
stored over 4 A
P{ H} NMR spectra were recorded on a Bruker 300
,
molecular sieves. H, C{ H} and
3
1
1
MHz spectrometer, gas chromatography was performed
using a Varian Gas Chromatograph CP-3800 with a
CP7495 Chirasil-
L
-Val column (25 m×0.25 mm id)
using He as
a
carrier gas. Bis(1,5-cyclooctadi-
3
1
ene)rhodium tetrafluoroborate,
3-bromo-8-amino-
3
2
22
quinoline and phosphoramidite 2 were prepared
ether as eluent afforded 3-vinyl-8-aminoquinoline as a
1
according to literature procedures.
pale orange/yellow solid in 66% yield (0.251 g).
H
NMR (CDCl ): l 9.00 (d, 1H, J=2.1 Hz), 8.07 (br. s,
1H), 7.50 (m, 2H), 6.85 (dd, 1H, J=17.7 Hz, 11.1 Hz),
3
4
4
.2. Synthesis of amines
6
.79 (m, 1H), 5.96 (d, 1H, J=17.7 Hz), 5.43 (d, 1H,
13
1
.2.1. Synthesis of 2-methoxyphenyl-(4-vinylbenzyl)-
J=11.1 Hz), 4.25 (br. s, 2H); C{ H} (CDCl ): l
3
amine. An ice-cooled solution of triethylamine (4.58
mL, 32.85 mmol) in toluene (20 mL) was treated with a
toluene (10 mL) solution of ortho-anisidine (1.85 mL,
149.2, 148.8, 142.8, 134.4, 130.3, 129.3, 126.7, 120.4,
118.7, 116.2, 110.9.
16.43 mmol) followed by a toluene (10 mL) solution of
4.3. Synthesis of phosphoramidites
para-vinylbenzyl chloride (2.32 mL, 16.43 mmol) before
being heated at reflux overnight. After this time, the
mixture was cooled to room temperature and diluted
with water (150 mL) and diethyl ether (150 mL). The
organic phase was separated, washed with water (3×50
mL) and the aqueous phase extracted with diethyl ether
4.3.1. Synthesis of phosphoramidite 4. A toluene (10 mL)
solution of triethylamine (0.69 mL, 4.95 mmol) and
(S)-1,1%-bi-2-naphthyl chlorophosphite (0.868 g, 2.48
mmol) was cooled to 0°C and treated dropwise with a
toluene (10 mL) solution of 4-aminostyrene (0.29 mL,
2.48 mmol). The resulting solution was heated at 80°C
overnight, cooled to room temperature, filtered through
celite and concentrated under vacuum. The crude
product was extracted into a minimum volume of
dichloromethane and purified by flash chromatography
over silica gel (60–120 mesh, 9:1 hexane/diethylether) to
(
3×50 mL). The organic phases were combined, dried
over anhydrous magnesium sulfate and the solvent
removed under vacuum to afford a crude orange solid
which was recrystallised from boiling hexane to give
2
-methoxyphenyl-(4-vinylbenzyl)amine as a white crys-
1
talline solid in 61% yield (2.40 g). H NMR (CDCl ): l
3
3
1
1
7
6
.36 (m, 4H, Ar), 6.81 (m, 2H, Ar), 6.69 (m, 2H, Ar),
.57 (dd, 1H, J=17.6 Hz, 10.9 Hz), 5.73 (d, 1H,
give 1 as a white, air stable solid (0.69 g, 55%). P{ H}
1
(CDCl ): l 148.2; H NMR (CDCl ): l 7.85 (m, 4H,
3
3
J=17.6 Hz), 5.22 (1H, J=10.9 Hz), 4.62 (br. s, 1H,
Ar), 7.46–7.16 (m, 10H, Ar), 6.86 (m, 2H, Ar), 6.57 (dd,
1H, J=17.6 Hz, 10.9 Hz), 5.53 (d, 1H, J=17.6 Hz),
5.03 (m, 2H, vinyl CH, NH). Anal. calcd for
C H NO P: C, 77.59; H, 4.65; N, 3.23. Found: C,
13
1
NH), 4.34 (s, 2H, -CH -), 3.84 (s, 3H, -OCH ); C{ H}
2
3
(
1
CDCl ): l 47.8, 55.4, 109.4, 110.1, 113.6, 116.7, 121.3,
26.4, 127.7, 136.6, 138.1, 139.3, 146.8.
3
28
20
2
7
8.01; H, 4.79; N, 3.51%. [h] =+7.52 (c 0.05, CHCl ).
D 3
4
.2.2. Synthesis of 3-bromo-8-nitroquinoline. To a solu-
tion of 3-bromoquinoline (5.0 g, 24.0 mmol) in conc.
4.3.2. Synthesis of phosphoramidite 5. A toluene solu-
tion of ortho-anisidine (0.26 mL, 2.31 mmol) was added
dropwise to an ice-cold solution of triethylamine (0.64
mL, 4.62 mmol) and (S)-1,1%-bi-2-naphthyl chlorophos-
phite (0.810 g, 2.31 mmol) in toluene (10 mL). The
H SO (10 mL) cooled in a water/ice bath was added
dropwise 8 mL of a conc. H SO /conc. HNO mixture
2
4
2
4
3
(
6:2). The reaction mixture was maintained at low
temperature, stirred rapidly and monitored by thin

1
526
S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
resulting reaction mixture was heated at 80°C and
stirred overnight after which time it was cooled to room
temperature and filtered through celite. The solvent was
removed and the crude product purified by column
chromatography over silica gel (1:1 hexane/
dichloromethane) to give 2 as a white air-stable solid in
and purified by flash chromatography over silica gel
(1:1 diethyl ether/hexane) to afford phosphoramidite 11
3
1
1
as an off-white solid in 61% yield (0.627 g). P{ H}
1
(CDCl ): l 147.3; H NMR (CDCl ): l 9.00 (d, 1H,
3
3
J=2.0 Hz), 7.92 (m, 6H), 7.52 (m, 7H), 7. 30 (m, 3H),
6.79 (dd, 1H, J=17.7 Hz, 11.1 Hz), 5.91 (d, 1H,
J=17.7 Hz), 5.70 (d, 1H, JPH=4.6 Hz), 5.42 (d, 1H,
J=11.1 Hz). Anal. calcd for C H N O P: C, 76.85; H,
3
1
1
1
5
9% yield (0.600 g). P{ H} (CDCl ): l 148.8; H
3
NMR (CDCl ): l 7.84 (m, 4H), 7.24 (m, 4H), 7.18 (m,
3
31 21
2
2
4
H), 6.78 (m, 4H), 5.89 (br s, 1H), 3.68 (s, 3H). Anal.
4.37; N, 5.78. Found: C, 77.10; H, 4.59; N, 5.97%.
calcd for C H NO P: C, 74.14; H, 4.61; N, 3.20.
[h] =−39.2 (c 0.05, CHCl ).
2
7
20
3
D
3
Found: C, 74.44; H, 4.91; N, 3.43%. [h] =+96.9 (c
D
0.05, CHCl3).
4.4. General procedure for co-polymerisation of phos-
phoramidite monomers with styrene
4
.3.3. Synthesis of phosphoramidite 6. A solution of
-aminoquinoline (597 g, 4.14 mmol) in toluene (10
8
A Schlenk flask was charged with phosphoramidite
monomer 4 or 13 (0.73 mmol, 2.5 mol%) and styrene
(28.47 mmol, 97.5 mol%). The mixture was degassed by
three vacuum/nitrogen cycles and diluted with toluene
(30 mL) before being treated with 2 mol% 2,2%-azobis(2-
methylpropionitrile (AIBN) and heated at 65°C
overnight. The solvent was concentrated under reduced
pressure to give a viscous paste, which was triturated
with hexane (60 mL) to yield the co-polymer as a fine
powder. The phosphoramidite–styrene co-polymers
were isolated by filtration and dried under reduced
mL) was added dropwise to an ice-cold toluene solution
containing triethylamine (1.15 mL, 8.27 mmol) and
(
S)-1,1%-bi-2-naphthyl chlorophosphite (1.450 g, 4.14
mmol) in toluene (10 mL). The reaction mixture was
heated at 80°C overnight then cooled to room tempera-
ture and filtered through celite. The solvent was
removed from the colourless filtrate to afford phospho-
ramidite 3 as a white solid, which needed no further
3
1
1
purification (1.365 g, 72%). P{ H} (CDCl ): l 147.2;
3
1
H NMR (CDCl ): l 8.55 (m, 1H), 7.83 (m, 6H),
3
3
1
1
7
.38–7.12 (m, 12H), 5.18 (br s, 1H). Anal. calcd for
pressure. Co-polymer 14: P{ H} (CDCl ): l 148.4;
3
C H N O P: C, 75.98; H, 4.18; N, 6.11. Found: C,
Polydispersity (M /M )=1.7, Average molecular
29
19
2
2
W
N
7
6.23; H, 4.29; N, 6.53%. [h] =−43.4 (c 0.05, CHCl ).
weight
(M )=20,100
2
Da.
Anal.
calcd
for
D
3
W
C340H332NO P: C, 90.84; H, 7.44; N, 0.31; P, 0.69.
4
.3.4. Synthesis of phosphoramidite 7. A THF (25 mL)
Found: C, 89.90; H, 7.72; N, 0.83; P, 0.68%. [h] =
D
1
3
1
solution of 2-methoxyphenyl-(4-vinylbenzyl)amine
+4.84 (c 0.10, CHCl ). Co-polymer 15:
P{ H}
3
(
1.100 g, 4.60 mmol) was cooled to −78°C and a 2.5 M
(CDCl ): l 147.0; Polydispersity (M /M )=1.6, Aver-
3
W
N
solution of butyllithium in hexanes (1.84 mL, 4.60
mmol) added carefully. The resulting mixture was
stirred for 30 min, after which time a THF (20 mL)
solution of (S)-1,1%-bi-2-naphthyl chlorophosphite
age molecular weight (M )=10,200 Da. Anal. calcd for
W
C343H333N O P: C, 90.62; H, 7.38; N, 0.62; P, 0.68.
2
2
Found: C, 89.33; H, 7.78; N, 0.92; P, 0.74%. [h] =
D
+13.72 (c 0.10, CHCl3).
(
1.612 g, 4.60 mmol) was added dropwise. The reaction
mixture was stirred at low temperature for a further
.5–2 h before being allowed to warm to room temper-
4.5. Synthesis of rhodium-loaded polymers
In a typical procedure, polymer 14 or 15 (0.087 mmol
1
ature. The solvent was removed under reduced pressure
and the resulting off-white solid purified by flash chro-
matography over silica gel (9:1 hexane/diethyl ether) to
give phosphoramidite 5 as a white solid in 63% yield
phosphoramidite) was added to
a
solution of
[Rh(COD) ][BF ] (0.031 g, 0.0764 mmol) in
2
4
dichloromethane (10 mL). The resulting solution was
allowed to stir for 1 h after which time the polymer was
precipitated by addition of methanol, filtered and
washed exhaustively with n-hexane. The rhodium load-
ings of 14[Rh] and 15[Rh] were determined as 0.32 and
0.26% Rh by wt, respectively, by inductively coupled
plasma atomic emission analysis.
3
1
1
1
(
1.60 g). P{ H} (CDCl ): l 142.2; H NMR (CDCl ):
3
3
l 7.93 (m, 4H), 7.63 (m, 2H), 7.40 (m, 4H), 7.27 (m,
2
1
H), 7.12 (m, 3H), 6.95 (m, 4H), 6.72 (m, 1H), 6.56 (dd,
H, J=17.6 Hz, 10.9 Hz), 5.59 (dd, 1H, J=17.6 Hz, 1.0
Hz), 5.11 (dd, 1H, J=10.9 Hz, 1.0 Hz), 4.33 (dd, 1H,
J=14.6 Hz, JHP=2.4 Hz), 3.98 (s, 3H), 3.95 (dd, 1H,
J=14.6 Hz, JHP=1.9 Hz). Anal. calcd for
C H NO P: C, 78.11; H, 5.10; N, 2.53. Found: C,
4.6. General hydrogenation procedure
36
28
3
78.38; H, 2.66; N, 2.61%. [h] =+96.9 (c 0.05, CHCl ).
D 3
Hydrogenation reactions were performed using stan-
dard Schlenk techniques and conducted under ambient
H pressure at room temperature for 20 h (4 h for the
2
4
.3.5. Synthesis of phosphoramidite 13. A toluene (10
mL) solution of triethylamine (0.59 mL, 4.23 mmol)
and (S)-1,1%-bi-2-naphthyl chlorophosphite (0.741 g,
hydrogenation
of
methyl-2-acetamidocinnamate).
2
.12 mmol) was cooled in an ice bath and treated with
Homogeneous catalytic reactions were performed with
0.2 mmol substrate in dichloromethane (5 mL, 0.04 M)
and a substrate:[Rh(COD) ]BF :phosphoramidite ratio
of 1:0.05:0.10. Polymer-supported reactions were per-
formed using 0.2 mmol substrate in dichloromethane (5
mL, 0.04 M) and a substrate:polymer ratio of 1:0.05.
Amino acids were converted to the corresponding
a solution of 3-vinyl-8-aminoquinoline (0.360 g, 2.12
mmol) in a THF/toluene (5 mL/15 mL) before being
heated 60°C overnight, after which the mixture was
filtered through celite and concentrated under reduced
pressure to yield a bright orange solid. The product was
extracted into a minimum volume of dichloromethane
2
4

S. Doherty et al. / Tetrahedron: Asymmetry 14 (2003) 1517–1527
1527
methyl esters by reaction with diazomethane prior to
analysis by gas chromatography with a CP7495 Chi-
rasil-L-Val column. Enantiomeric excesses were deter-
mined by gas chromatography for the hydrogenation of
amino acid derivatives as their methyl esters. For N-
acetylalanine methyl esters: initial T=80°C held for 4
min, ramping to 100°C at 4°C/min. For N-acetylphenyl-
alanine methyl esters: initial T=120°C, ramping to
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Acknowledgements
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4
We gratefully acknowledge the Queens University of
Belfast (SD) and the EPSRC (EGR) for financial sup-
port of this work and Johnson Matthey for loans of
palladium salts.
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(