Modular solid-phase synthesis, catalytic application and efficient recycling of supported phosphine-phosphite ligand libraries

Article abstract of DOI:10.1039/c5dt03226a

In spite of decades of research in the field of homogeneous asymmetric catalysis the discovery of new high performance catalysts still relies heavily on trial-and-error. There is still a lack of efficient combinatorial methods which enable the synthesis and screening of vast ligand libraries, especially for bidentate phosphorus ligands. Here we present a highly modular solid-phase synthetic approach which provides facile access to libraries of phosphine-phosphite ligands in quantitative yield requiring only minimal work-up. The obtained library of supported phosphine-phosphites was successfully applied in rhodium catalyzed asymmetric hydrogenation obtaining high enantioselectivities up to 98%. Also, these polymer supported ligands could be successfully recycled under batch conditions exhibiting only a small decline of activity and no loss of selectivity.

Full text of DOI:10.1039/c5dt03226a

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Modular solid-phase synthesis, catalytic
application and efficient recycling of supported
phosphine–phosphite ligand libraries†
Cite this: DOI: 10.1039/c5dt03226a
Frank J. L. Heutz and Paul C. J. Kamer*
In spite of decades of research in the field of homogeneous asymmetric catalysis the discovery of new
high performance catalysts still relies heavily on trial-and-error. There is still a lack of efficient combina-
torial methods which enable the synthesis and screening of vast ligand libraries, especially for bidentate
phosphorus ligands. Here we present a highly modular solid-phase synthetic approach which provides
facile access to libraries of phosphine–phosphite ligands in quantitative yield requiring only minimal
work-up. The obtained library of supported phosphine–phosphites was successfully applied in rhodium
catalyzed asymmetric hydrogenation obtaining high enantioselectivities up to 98%. Also, these polymer
supported ligands could be successfully recycled under batch conditions exhibiting only a small decline
of activity and no loss of selectivity.
Received 20th August 2015,
Accepted 9th October 2015
DOI: 10.1039/c5dt03226a
www.rsc.org/dalton
which can be attributed to the difficulty of introducing two
different phosphorus moieties onto the ligand backbone.
Introduction
Over the last few decades transition metal mediated asym-
Heterobidentate P-OP ligands such as phosphine–phos-
metric catalysis has evolved into an indispensable tool to both phites have received increased attention over the last years and
academia and industry, providing access to optically active have proven to be very efficient ligands for various asymmetric
compounds such as flavors and fragrances, pharmaceuticals transformations such as hydrogenation, hydroformylation and
and agrochemicals.1 Despite the fact that nowadays homo- allylic substitution.9 BINAPHOS, first reported by the group of
geneous asymmetric catalysis is a highly evolved field of Takaya and Nozaki,10 has been highly effective in a wide range
research, the discovery of high performance ligands for asym- of reactions and belongs to the small group of so-called privi-
metric transformations remains challenging.2 Although our leged ligands in asymmetric catalysis.2 The highly modular
knowledge of organometallic chemistry and ligand effects in structure of phosphine–phosphites and the fact they possess
catalysis is ever increasing and computational techniques play two electronically different phosphorus moieties, resulting in
an increasingly important role,3 the development of new cata- different trans-labilizing properties, makes them promising
lysts still relies heavily on trial-and-error.4
candidates for the combinatorial synthesis and high-through-
Combinatorial synthetic methodologies and high-through- put screening of structurally diverse ligand libraries.11 There
put screening have proven their value in asymmetric catalysis have been few reports of modular approaches towards phos-
and numerous successful approaches have been reported phine–phosphite ligand but so far the applications remain
using both covalent5 and supramolecular chemistry.6 For phos- fairly limited.12 The preparation of this class of ligands still
phorus donor ligands the focus has mainly been on standard relies on classical solution-phase methodologies and work-up
solution-phase techniques and mainly monodentate ligands.7 procedures and suffers from relatively low yields, thus hamper-
Large libraries of bidentate phosphorus ligands and efficient ing truly high-throughput synthesis and screening.
combinatorial methods for synthesizing these remain scarce
Solid-phase synthesis (SPS) provides a promising alternative
due to their intrinsically more complicated synthesis and approach towards ligand libraries and has already successfully
work-up procedures.8 This is even more the case for hetero- been employed for many years for the synthesis of large com-
bidentate phosphorus ligands like phosphine–phosphites, pound libraries such as polypeptides and oligosaccharides.13
Using solid-phase synthesis, ligand structures can be built up
step-by-step in a combinatorial fashion while being bound to a
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews
resin bead. Using a solid support has as main advantage that
KY16 9ST, UK. E-mail: pcjk@st-andrews.ac.uk
it can greatly simplify ligand purification procedures which in
turn allows the use of large excesses of reagents to drive
†Electronic supplementary information (ESI) available: Experimental and
characterisation data. See DOI: 10.1039/c5dt03226a
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reactions to completion. Often the work-up only comprises a supported diphosphines.17 Subsequently, the sulfate group is
simple filtration or decantation step as opposed to the labor- hydrolyzed and the resulting hydroxyalkyl phosphines are
ious work-up procedures employed in the solution-phase syn- reacted with chlorophosphite reagents yielding supported
thesis of phosphorus ligands.14 The facile work-up makes phosphine–phosphite ligands. A similar solution-phase pro-
solid-phase synthesis very suitable for automated synthesis cedure has been reported by the group of Bakos and one of
using high throughput equipment.
their homogeneous analogues of our supported P-OP ligands
An additional advantage of employing a solid support is is depicted in Fig. 1.18
that it can greatly facilitate catalyst recovery after the catalytic
Using our solid-phase synthetic approach this class of
reaction and potentially even lead to recyclable immobilized ligands is readily accessible under very mild conditions requir-
catalysts. There are numerous accounts of immobilized ing only a very minimal work-up procedure between each reac-
(chiral) phosphorus ligands addressing catalyst recovery, tion step. Moreover, the supported ligands were obtained in
which presents one of the major problems in homogeneous high purity with each reaction step proceeding quantitatively
catalysis. The vast majority however, are reports of non- as determined by gel-phase 31P NMR (see Fig. 2). Compara-
modular single ligands or catalysts anchored to a support.15
tively, when employing traditional solution-phase methodo-
Surprisingly, the application of solid-phase synthesis for logies laborious purification methods like column
the combinatorial synthesis of supported bidentate phos- chromatography and distillations under inert conditions are
phorus ligands remains fairly limited.8 However, there have often required and the overall yield for similar phosphine–
been reports on SPS of a small variety of aminophosphine– phosphites can be as low as 30%.19
phosphine and aminophosphine–phosphite libraries16 and
The starting synthon of the solid-phase synthesis are sup-
recently we reported on the solid-phase synthesis of diphos- ported phosphine–boranes 1a–b·BH3 which are readily accessi-
phine ligands.17 Using a similar methodology we now report ble by treating a choromethyl functionalized resin, in this case
on an efficient combinatorial solid-phase synthetic approach Merrifield resin, with various primary lithium phosphides
for libraries of highly modular and recyclable phosphine– having different substituents (R1). The introduction of the
phosphite ligands.
phosphine moiety takes place in a non-stereospecific fashion
and yields a racemic mixture. Subsequently the obtained sup-
ported secondary phosphines can be protected by treatment
with BH3·SMe2 to make them less prone to oxidation.
BH3·SMe2 was chosen as reagent over the THF adduct due to
its higher stability and solubility. Upon deprotonation using
lithium diisopropylamide (LDA, step I) the lithiated phos-
phine–boranes (Li·1a–b·BH3) can be reacted with a cyclic
sulfate which after ring opening, with full inversion at one of
the stereogenic centers,20 serves as the ligand backbone
(step II). Stronger bases such as n-butyl lithium resulted in
side products due to transmetallation at the benzylic position.
Diversity can be introduced by employing various cyclic sul-
fates having a varying backbone length (n) and bearing
different substituents (R2). All the above mentioned reaction
steps could be readily followed by 31P NMR confirming the for-
mation of the desired intermediates (see Fig. 2 for a represen-
tative example).
Results and discussion
Solid-phase synthesis of phosphine–phosphite ligands
A ligand library of 16 supported phosphine–phosphite (P-OP)
ligands was prepared of which the general structure is
depicted in Fig. 1. These ligands possess a highly modular
structure and by varying the three main building blocks in a
combinatorial fashion it is possible to quickly generate a
ligand library showing large structural diversity. The phos-
phine moiety can be altered by using phosphines bearing
different substituents (R1) and for the ligand backbone cyclic
sulfates with a varying backbone length (n) and different sub-
stituents (R2) can be used. Finally diversity in the –OP part of
the ligand can be created by employing various chlorophos-
phites to introduce the phosphite moiety giving in total 4
points of diversity.
Next step is the hydrolysis of the supported phosphine–
borane sulfates (3a–h·BH3) to the corresponding hydroxyalkyl
phosphines (4a–h·BH3). Bakos et al. have reported an analo-
gous homogeneous procedure18 but their conditions, 90 °C
using 2 M sulfuric acid, were found to be too harsh and led to
decomposition of the resin. Instead a very mild hydrolysis at
room temperature was applied, using a 1 : 1 mixture of THF
and 0.1 M sulfuric acid to ensure proper swelling of the resin
and to retain its structural integrity. The hydrolysis proceeded
relatively slow and proved difficult to monitor by 31P NMR as
there was no notable NMR shift observable, although the
hydrolysis products did exhibit slightly sharper peaks (Fig. 2).
Using 7Li NMR however, it was possible to follow the hydro-
lysis in time. The consumption of the lithium sulfate group,
exhibiting a peak around 1 ppm, could be readily monitored
We have developed a modular stepwise methodology for the
synthesis of P-OP ligands (see Scheme 1). The initial synthetic
steps for the preparation of the intermediate supported
phosphine–borane sulfates are identical to those reported for
Fig. 1 General structure of highly modular supported phosphine–
phosphite ligands (left), and a solution-phase analog reported by Bakos
et al. (L17, right).18
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Scheme 1 Solid-phase synthetic approach towards supported phosphine–phosphite ligands, all reactions were performed in THF at room temp-
erature unless stated otherwise.
It was decided to perform the removal of the BH3 group
prior to introduction of the –OP moiety as phosphites are
known to be more prone to hydrolysis under basic con-
ditions.21 The borane group was removed by treatment with an
excess of 1,4-diazabicyclo[2.2.2]octane (DABCO, 10 eq.) at
40 °C which could be readily followed by 31P NMR (Fig. 2).
Next the phosphite moieties were introduced by treating the
supported hydroxyalkyl phosphines (4a–h) with various
chlorophosphites in the presence of triethylamine. Both (S)-
binol and (R)-binol derived chlorophosphites were employed
as well as a slightly more bulky trimethylsilyl functionalized
binol-PCl. Moreover, also a t-butyl functionalized bisphenol
derived chlorophosphite was used, demonstrating the versati-
lity of this solid-phase synthetic approach. In all cases the
introduction of the –OP moiety proceeded smoothly although
for the more bulky phosphites a slightly larger excess, up to 3
equivalents of reagent, was required.
Fig. 2 Solid-phase synthesis of representative supported phosphine–
phosphite L1 as monitored by gel-phase 31P NMR spectroscopy.
Fig. 2 shows that this reaction step could be readily moni-
tored using 31P NMR and the appearance of a second peak in a
1 : 1 ratio could be observed confirming the formation of the
desired supported P-OP ligands in high purity. In some cases,
like for ligand L8, splitting into two 1 : 1 signals for the phos-
phine or phosphite group could be observed (Fig. 4). This is
due to the fact that all supported ligands are present as a
mixture of two epimers at the phosphine moiety. But for most
ligands only single broad peaks could be observed, probably
Fig. 3 Hydrolysis of representative supported phosphine–borane
sulfate 3a·BH3 monitored by 7Li NMR spectroscopy.
as seen in Fig. 3. Full hydrolysis was on average observed after
3 days and could also be confirmed using FT-IR and elemental
analysis, both showing full removal of the sulfate ester group.
Fig. 4 31P NMR spectrum of supported phosphine–phosphite L8 clearly
showing the presence of both epimers in a 1 : 1 ratio.
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Fig. 5 Complete Library of supported phosphine–phosphite ligands (L1–L16).
due to overlap of the two epimer signals. Deerenberg et al.
Table 1 Results of Rh-catalyzed asymmetric hydrogenation using
L1–L8
a
reported that for similar phosphine–phosphite systems the
P-stereogenic center has little influence on the chiral induc-
tion and that the selectivity is mainly determined by the
ligand backbone and the phosphite moiety.22 Finally the
actual phosphorus loading of the immobilized phosphine–
phosphites could be determined by elemental analysis. 1H and
13C NMR of the supported ligands was not very informative
due very broad peaks and overlap with signals of the Merrifield
resin (see ESI† for representative examples). The complete P-OP
ligand library (L1–L16) synthesized using this efficient solid- Entry
Substrate I
Substrate II
Substrate III
Ligand
eeb
eeb
eeb
phase synthetic approach is depicted in Fig. 5.
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L8
L2
L6
91 (R)
92 (R)
91 (S)
93 (S)
32 (R)
94 (R)
95 (S)
34 (S)
97 (R)
95 (R)
93 (R)
85 (R)
85 (S)
93 (S)
66 (R)
86 (R)
87 (S)
66 (S)
93 (R)
95 (R)
90 (R)
90 (R)
90 (S)
93 (S)
40 (R)
95 (R)
96 (S)
32 (S)
95 (R)
96 (R)
Rh-catalyzed asymmetric hydrogenation
The library of 16 supported phosphine–phosphite ligands was
employed in the asymmetric hydrogenation of several bench-
mark substrates. The complexation was performed prior to
catalysis by suspending the resin-bound ligands in
dichloromethane in the presence of 0.9 eq. of rhodium precur-
sor ([Rh(COD)2]X). After one hour the white resins had turned
bright yellow/orange and the now colorless supernatant was
removed. Subsequently the supported rhodium complexes conversion was determined by GC. b Enantiomeric excess of product
were washed with DCM and THF and filtered off. To confirm
full complexation, separate in situ NMR experiments were per-
8
9c
10c
a Reaction conditions: In a stainless steel autoclave, Rh/substrate =
1 : 30, p(H2) = 1.2 bar, T = 25 °C, t = 16 h, 0.5 mL of THF, all runs were
performed in duplicate, full conversion was obtained in all cases,
determined by chiral GC (absolute configuration drawn in
parenthesis). c Using [Rh(COD)2]SbF6 as metal precursor.
formed which indicated the expected bidentate coordination
to the metal center. Upon complexation very broad NMR
enantioselectivities up to 97% were observed. Interestingly it
was found that changing the counterion of the Rh-precursor
signals were observed, this phenomenon was already reported
for similar resin-supported systems.17,23
−
−
from BF4 to SbF6 (entries 9 and 10) seemed to have a bene-
ficial effect and led to an increase of ee of up to 9%.This
counterion effect has already been reported for similar homo-
geneous phosphite- and diamidophosphite-based systems.24
Looking at the ligand backbone length it can be seen that for
substrate II higher enantioselectivities were obtained for
Table 1 shows the results for the asymmetric hydrogenation
of substrates I–III using supported ligands L1–L8. These 8
ligands all bear the same substituents (R1 and R2) and differ
only in the number of carbon atoms in the ligand backbone
(n) and the configuration of the backbone and phosphite
moiety. In all cases full conversion was achieved and
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ligands having a C3 backbone, n = 1, (L1 and L4, entries 1 and 4) in this case changing R1 from a phenyl group to a cyclohexyl
while for substrates I and III better selectivities were observed group led to the opposite enantiomer with varying levels of
with supported phosphine–phosphites having a C4 backbone, selectivity for all three of the tested substrates. This nicely
n = 2, (L6–L7, entries 6–7).
showcases that small changes in ligand structure can have a
Also the influence of the configuration of the backbone and huge influence on the outcome of a catalytic reaction and
phosphite moiety was investigated for L1–L8. The (S)-Binol demonstrates the power of this effective modular approach
moiety always leads to the (R) enantiomer and an (R)-Binol towards the synthesis and screening of large supported P-OP
group yields the (S) product in the asymmetric hydrogenation ligand libraries.
of substrates I–III (see Table 1). For the supported ligands
Lastly different phosphite moieties and their influence on
bearing a C3 backbone (n = 1, L1–L4) a small matched/ the selectivity were investigated. Both a slightly more bulky
mismatched effect could be observed with the matched pairs SiMe3 substituted (S)-binol and an achiral t-butyl substituted
(RC,SC,Sax) and (SC,RC,Rax) achieving up to 8% higher selectiv- bisphenol derived phosphite were employed. From Table 2 it
ities in the case of substrate II (entries 1 and 4). Interestingly, can be concluded that changing to a SiMe3 substituted binol
for L5–L8 (n = 2) a much larger and inverse matched/mis- moiety (L13 and L14, entries 5 and 6) in most cases has a small
matched effect was observed. In this case the matched pairs but positive effect on the selectivity when compared to their
are (RC,SC,Rax) and (SC,RC,Sax) (entries 6 and 7) which exhibited non-substituted binol counterparts L2 and L6 (Table 1, entries
differences in enantioselectivity up to 62% when compared to 2 and 6). Going to the achiral t-butyl bisphenol phosphite did
their mismatched counterparts (entries 5 and 8).
seem to have
a
large influence resulting in lower
C3 ligand backbone
Moreover, the effect of altering the substituents R1 and R2 enantioselectivities. For L15 with
a
was studied (Table 2, entries 1–4). It was found that replacing (Table 2, entry 7) enantioselectivities up to 11% lower than for
the methyl group on the ligand backbone (R2) with a slightly the binol bearing counterpart L2 (Table 1, entry 2) were
more bulky ethyl group appeared to have a small positive effect observed. In the case of L16 bearing a C4 backbone (Table 2,
on the selectivity. When comparing L6 (Table 1, entry 6) with entry 8) the effect of changing to the achiral bisphenol moiety
L9 (Table 2, entry 1) it can be seen that the latter one bearing was much larger. For L16 a significant drop in selectivity of
an ethyl group achieves up to 5% higher enantioselectivities. respectively 48% and 80% was found for substrates I and III
Exchanging the phenyl substituent on the phosphine moiety when compared to the parent ligand L6 (Table 1, entry 6).
(R1) for a cyclohexyl group on the other hand seemed to have a Moreover for substrate II surprisingly, a complete loss of
detrimental effect. While L10 (Table 2, entry 2) exhibits similar selectivity was observed.
selectivity in the hydrogenation of I as its phenyl bearing
When compared to phosphine–phosphite L17 reported by
counterpart L1 (Table 1, entry 1) the selectivity for the other Bakos et al. (Table 2, entry 9),18 essentially the homogeneous
two substrates is up to 26% lower. Similarly, the enantio- counterpart of resin-bound ligand L2, it was found that some
selectivities achieved by L12 (Table 2, entry 4) are comparable of the supported ligands performed very well. For substrate I it
to those of its phenyl-bearing counterpart L9 (Table 2, entry 1) can be seen that comparable enantioselectivities were obtained
for two of the three substrates but for substrate II the selecti- (Table 1, entry 9) and for substrate III supported P-OP ligand
vity is much lower. More surprisingly, when comparing L11 L9 even outperforms it solution-phase analogue by 2%
(Table 2 entry 3) and L5 (Table 1, entry 5) it was observed that (Table 2, entry 1). This is quite remarkable as in most known
cases the immobilization of a homogeneous catalyst has a det-
rimental effect on the selectivity. This shows that the modular
solid-phase synthetic approach demonstrated here not only
Table 2 Results of Rh-catalyzed asymmetric hydrogenation using
L9–L17
enables the facile synthesis and screening of large P-OP ligand
libraries but can also actually lead to highly selective
a
supported catalysts.
Substrate I
Substrate II
Substrate III
Entry
Ligand
eeb
eeb
eeb
1
2
3
4
5
6
7
8
9c
L9
96 (R)
90 (R)
41 (S)
95 (R)
93 (R)
88 (R)
95 (R)
46 (R)
97 (R)
91 (R)
67 (R)
64 (S)
40 (R)
87 (R)
76 (R)
92 (R)
2 (R)
98 (R)
66 (R)
91 (S)
97 (R)
92 (R)
79 (R)
94 (R)
15 (R)
96 (R)
Supported catalysis recycling
L10
L11
L12
L13
L14
L15
L16
L17
To assess the reusability of these supported phosphine–phos-
phites the best performing member of the ligand library L9
was employed in the asymmetric hydrogenation of acetamido-
cinnamic acid methyl ester III. The catalyst recycling was per-
formed under batch conditions in a Schlenk vessel under a
flow of hydrogen. In between each reaction cycle the resin was
washed with substrate solution while maintaining a hydrogen
atmosphere to ensure catalyst stability. Finally the reaction
time was reduced in the recycling experiments to study re-
cycling at low conversion, which gives a better indication of
the actual catalyst stability.
—
a Reaction conditions: In a stainless steel autoclave, Rh/substrate =
1 : 30, p(H2) = 1.2 bar, T = 25 °C, t = 16 h, 0.5 mL of THF, all runs were
performed in duplicate, full conversion was obtained in all cases,
conversion was determined by GC. b Enantiomeric excess of product
determined by chiral GC (absolute configuration drawn in
parenthesis). c Data taken from ref. 18.
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similar ligands, often resulting in low yields. The supported
ligand library was successfully employed in Rh-catalyzed asym-
metric hydrogenation and three benchmark substrates were
screened. Very high enantioselectivities up to 98% were
achieved. Moreover some members of the ligand library even
outperformed a homogeneous counterpart showing that the
immobilization did not have a detrimental effect on the
selectivity. Finally supported ligand L9 was employed in cata-
lyst recycling under batch conditions. The ligand, immobilized
on Merrifield resin, could be successfully reused for 11 reac-
tion cycles showing only a very minor loss of activity. Moreover,
no decrease in selectivity was observed throughout the recy-
cling experiments. The exhibited recyclability is remarkably
high for these types of ligands and might make this system
highly suitable for catalysis under flow conditions.
Fig. 6 Results of catalyst recycling of supported ligand L9 in the Rh-
catalyzed asymmetric hydrogenation of substrate III. Reaction con-
ditions: In a Schlenk vessel under H2 atmosphere, Rh/substrate = 1 : 30,
p(H2) = 1 atm, T = 25 °C, t = 20 min, 1.5 mL of THF, all runs were per-
formed in duplicate.
The results of the catalyst recycling experiments are sum-
marized in Fig. 6. Merrifield supported ligand L9 could be
reused up to 7 times without any loss of activity. After 11 runs
only a very marginal drop in conversion of 3.3% was observed.
The loss of activity might have been caused by the possible
introduction of trace amounts of moisture or air during work-
up in between reaction cycles. Moreover the selectivity stayed
constant (average 97.2%) over the full extent of the recycling
experiments.
Also the metal leaching into solution after each reaction
cycle was analyzed using ICP-OES. After the first reaction cycle
an initial Rh leaching of 1.6 ppm was found and the metal
leaching appeared to stay constant after 3 recycling runs and
only a minimal leaching of on average 1.3 ppm was detected
(for full results see ESI, Table S-I†). The fact that no initial
decrease in catalytic activity was observed despite that some
metal leaching was detected, seems to indicate the leaching
might actually be caused by physically adsorbed rhodium resi-
dues residing in the pores of the resin. Moreover no phos-
phorus leaching could be observed after analyzing the reaction
solution with 31P NMR which also supports that the small
decrease in catalytic activity is probably caused by other de-
activation processes than leaching of active complex into solu-
tion. As phosphite-based ligands are prone to hydrolysis and
phosphines to oxidation L9 shows remarkable stability for a
phosphine–phosphite.25 Potentially this type of supported
P-OP ligands could provide promising candidates for catalysis
under flow conditions.
Experimental section
General experimental
All reactions and manipulations were carried out under inert
conditions using standard Schlenk techniques or in an
MBraun glovebox unless stated otherwise. All glassware was
dried prior to use to remove traces of water. All chemicals were
obtained from commercial suppliers and used as received
unless otherwise stated. Diethyl ether and THF were distilled
from sodium/benzophenone and triethylamine, dichloro-
methane and acetonitrile were distilled from calcium hydride.
Novabiochem™ Merrifield resin (100–200 mesh, 1.24 mmol
g−1 or 1.48 mmol g−1, 1% cross-linked) was obtained from
EMD Millipore.
General procedure for the synthesis of resin-bound
phosphine–boranes (1a–b·BH3)
Step 1. Merrifield resin (2.0 g, 1.24 mmol g−1, 2.48 mmol, 1.0
eq.), was swollen in THF (50 mL) and cooled to −78 °C. A
freshly prepared primary lithium phosphide solution (20 mL,
0.15 M, 1.2 eq.), also cooled to −78 °C was added under gentle
stirring to avoid mechanical abrasion of the resin. The reaction
mixture was allowed to warm up to room temperature and was
left overnight without stirring. The supernatant was removed
and the resin was washed subsequently with three 20 mL por-
tions of THF followed by three 20 mL portions of Et2O. The
product was directly used in the next step without additional
purification.
Step 2. A resin-bound phosphine, synthesized in the pre-
vious step, was swollen in THF (50 mL). Next, BH3·SMe2
(12.5 mL, 2.0 M in toluene, 10 eq.) was added under gentle
Conclusion
A new modular solid-phase synthetic procedure allowing the stirring to avoid mechanical abrasion of the resin. Upon
facile synthesis of large and diverse libraries of phosphine– addition the resin colored white and the reaction was stopped
phosphites was developed. Using this approach a library of 16 when full conversion was observed by 31P NMR. Next, the
phosphine–phosphite ligands could be obtained in very high supernatant was removed and the resin was washed sub-
yields. Moreover only a very minimal work-up was required sequently with three 20 mL portions of THF followed by three
between reaction steps as opposed to the laborious purifi- 20 mL of Et2O. The product was dried in vacuo yielding a white
cation methods employed in the solution-phase synthesis of resin-bound phosphine–borane.
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General procedure for the synthesis of resin-bound
phosphine–borane sulfates (3a–h·BH3)
Step 2. A deprotected resin-bound hydroxyalkyl phosphine
synthesized in the previous step was swollen in THF (10 mL)
and triethylamine (2.25 mmol, 9.0 eq.) was added. A chloro-
phosphite (0.75 mmol, 3.0 eq.) was dissolved in THF (5 mL)
and was added to the resin at 0 °C under gentle stirring to
avoid mechanical abrasion of the resin. Upon addition a pre-
cipitate was formed. The reaction was monitored using 31P
NMR and full conversion was reached when a 1 : 1 ratio of
phosphine to phosphite was observed (2–16 hours). Next, the
supernatant was removed and the resin was washed sub-
sequently with three 5 mL portions of DCM, three 5 mL por-
tions of THF and three 5 mL portions of Et2O. The product
was dried in vacuo yielding a white resin-bound phosphine–
phosphite.
Step 1. A resin-bound phosphine–borane (1a–b·BH3, 500 mg,
∼0.6 mmol) was swollen in THF (20 mL). Next, LDA (3 mL,
2.0 M in THF/heptane/ethylbenzene, 10 eq.) was added under
gentle stirring to avoid mechanical abrasion of the resin. Upon
addition the resin colored dark brown and was allowed to react
for 3 hours. Next, the supernatant was removed and the resin
was washed subsequently with three 10 mL portions of THF
followed by three 10 mL portions of Et2O. The product was
used in the next step without additional purification.
Step 2. A lithiated resin-bound phosphine–borane syn-
thesized in the previous step was swollen in THF (15 mL). A
cyclic sulfate (2a–e, 0.72 mmol, 1.2 eq.) was azeotropically
dried with toluene (3 times), dissolved in THF (5 mL) and sub-
sequently added to the resin under gentle stirring to avoid
mechanical abrasion. Upon addition the resin turned from
dark brown to yellow and was allowed to react overnight. Next,
the supernatant was removed and the resin was washed sub-
sequently with three 10 mL portions of THF and three 10 mL
portions of Et2O. The product was dried in vacuo yielding a
light yellow resin. The product was used in the next step
without additional purification.
General procedure for Rh-catalyzed asymmetric hydrogenation
The hydrogenation experiments were performed in a stainless
steel autoclave charged with an insert suitable for 10 reaction
vessels including Teflon mini stirring bars. In a typical experi-
ment, a reaction vessel was charged with a resin-bound phos-
phine–phosphite (5 mg, ∼4.0 μmol) and a solution of [Rh-
(COD)2]X (0.9 eq.) in CH2Cl2 (1 mL) was added and the hetero-
geneous mixture was allowed to stir gently for 4 h. The super-
natant was removed and the resulting orange resin was
washed subsequently with three 1 mL portions of THF fol-
lowed by three 1 mL portions of Et2O. Next, a solution of sub-
strate (0.5 mL, 0.24 M, 30 eq.) in THF was added to the
reaction vessel. Subsequently, the autoclave was purged three
times with 5 bar of H2 and then pressurized to 1.2 bar. The
reaction mixtures were gently stirred at 25 °C. After 16 h, the
autoclave was depressurized and the reaction mixtures were fil-
tered over a plug of silica. Prior to GC measurements substrate
II and its products were derivatized using (trimethylsilyl)diazo-
methane (2 M in diethyl ether), in essence yielding substrate
III. The conversion and the enantiomeric excess were deter-
mined by chiral GC, see ESI† for column and conditions.
General procedure for the synthesis of resin-bound hydroxyalkyl
phosphine–boranes (4a–h·BH3)
A resin-bound phosphine–borane sulfate (3a–h·BH3, 500 mg,
∼0.5 mmol) was swollen, under gentle stirring, in
1 : 1 mixture of THF and 0.1 M of degassed H2SO4 (20 mL).
The resin was left overnight without stirring to avoid mechan-
ical abrasion of the resin. Next the resin was washed with
three 5 mL portions of THF and resuspended in THF (10 mL).
a
7
The progress of the hydrolysis was monitored using Li NMR.
If no full consumption of Li was observed the resin was resus-
pended in a fresh mixture of THF and H2SO4 and left over-
night. This procedure was repeated until no lithium signal
could be observed anymore by 7Li NMR (on average 3 days).
Next, the supernatant was removed and the resin was washed
subsequently with five 10 mL portions of THF followed by
three 10 mL portions of Et2O. The product was dried in vacuo
affording a white resin which was used in the next step
without additional purification.
Acknowledgements
We thank the European Union (Marie Curie ITN SusPhos,
grant agreement no. 317404) for financial support.
General procedure for the synthesis of resin-bound
phosphine–phosphites (L1–L16)
Notes and references
Step 1. A resin-bound hydroxyalkyl phosphine–borane (4a–
h·BH3, 250 mg, ∼0.25 mmol) was suspended in THF (5 mL)
and a solution of 1,4-diazabicyclo[2.2.2]octane (5 mL, 0.5 M in
THF, 10 eq.) was added. The reaction was heated to 40 °C and
was left overnight without stirring. After complete deprotection
was confirmed by 31P NMR, the supernatant was removed and
the resin was washed subsequently with three 5 mL portions
of THF followed by three 5 mL portions of Et2O. The product
was used directly in the next step without further purification.
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