Rapid, in situ synthesis of bidentate ligands: Chromatography-free generation of catalyst libraries

Article abstract of DOI:10.1039/c1ob06180a

The parallel synthesis of chiral bidentate ligands and their subsequent use in situ for a catalytic process is described. The ligands thus prepared gave comparable results to those obtained when the ligands were synthesized and purified by conventional means. This includes oxazolines and other compounds of similar complexity, meaning that for the first time these valuable compounds have been brought into the field of combinatorial catalysis.

Full text of DOI:10.1039/c1ob06180a

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Organic &
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COMMUNICATION
Rapid, in situ synthesis of bidentate ligands: chromatography-free generation
of catalyst libraries†
Robin Frauenlob, Martha M. McCormack, Carolyn M. Walsh and Enda Bergin*
Received 15th July 2011, Accepted 24th August 2011
DOI: 10.1039/c1ob06180a
The parallel synthesis of chiral bidentate ligands and their
subsequent use in situ for a catalytic process is described.
The ligands thus prepared gave comparable results to those
obtained when the ligands were synthesized and purified
by conventional means. This includes oxazolines and other
compounds of similar complexity, meaning that for the first
time these valuable compounds have been brought into the
field of combinatorial catalysis.
stymied combinatorial asymmetric catalysis for some time,6i and
a general solution to this problem would represent a great step
forward.3g
Our initial approach to this problem is outlined in Fig. 1. We ex-
amined Schiff base formation as a route to P,N-ligands, reasoning
that the high yields normally obtained in these reactions would
make them ideal candidates for in situ generated libraries. Other
advantages of this system include the fact that both fragments
(aldehyde and amine) are readily available and independently
variable, and that the only side product (water) could easily be
removed by molecular sieves. This last point is important as it
opens up the possibility of direct screening of crude reaction
mixtures in catalytic reactions.
While asymmetric catalysis is a highly successful and still bur-
geoning field of study, one common difficulty is identifying a
suitable catalyst for a given reaction—a process that can be both
time-consuming and expensive. As has been noted by Knowles,
due to the fact that the energy differences between diastereomeric
transition states leading to antipodal products are often very small
(~2 kcal mol-1 for 95% ee), it is extremely difficult to predict
successful structures in advance.1
One attractive solution to this problem is the combinatorial
synthesis of ligands, especially when those ligands can subsequently
be used directly in a catalytic process without any purification.
A hugely successful example of this strategy is the MonoPhos
instant ligand libraries and related systems developed by de Vries
and others,2 where chiral phosphoramidites were synthesised in
parallel and used in situ for rapid screening. The ligands are
typically formed with purities between 90–95%, and give levels
of product enantiomeric excess only slightly reduced compared to
the purified ligands.
Bidentate ligands on the other hand have proven more difficult
to deal with, and this remains a problem today. While there
are methods for the modular and high throughput synthesis of
libraries of bidentate ligands, typically these methods require
manipulation and purification of the resulting ligands.3,4 Al-
ternative methods have been employed, including solid phase5
and supramolecular6 approaches, and one case where a single
tridentate ligand was synthesised in situ.7 However, in situ methods
for the generation of solution phase bidentate ligand libraries are
still lagging well behind the great strides taken for monodentate
ligands, partly due to the greater synthetic difficulties associated
with their synthesis.2b Indeed this has been a factor which has
Fig. 1 Imine formation as a route to in situ ligand libraries.
A preliminary experiment (see Fig. 1) indicated that by mixing
an equimolar amount of amine and aldehyde together in toluene
◦
˚
in the presence of 4 A molecular sieves at 70 C overnight, ligand
1 could be generated in pure form (as shown by 1H and 31P NMR).
This operationally simple route proved applicable to the synthesis
of many ligand types and very high purities were obtained (greater
than 95%). Unfortunately ketones did not prove amenable to this
process: when 2-acetylpyridine was used with the same amine
the corresponding ketimine was produced with a conversion of
30%, with significant amounts of unreacted amine and ketone
remaining.
The methodology could, however, easily be extended to sim-
ilar functional groups. Use of secondary diamines allowed the
generation of aminal-based ligands,8 while condensation using
secondary amino alcohols furnished oxazolidines,8 another highly
useful functionality in asymmetric catalysis.9 The only example we
found where pure ligands were not obtained was the condensation
of primary diamines with one equivalent of aldehyde: in this
particular case, as expected, a mixture of bis- and mono-imine
products was observed.8
School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.
E-mail: ebergin@tcd.ie; Fax: +353 1 6712826; Tel: +353 1 8962514
† Electronic supplementary information (ESI) available: Characterisation
and NMR spectra for all ligands. See DOI: 10.1039/c1ob06180a
Fig. 2 outlines some of the ligand structural diversity that
is easily achievable by this methodology. From a very simple
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indicated that we could synthesize not just oxazolines (7), but also
imidazolines (8) and thiazolines (9), in very high purities (>95%
as measured by 1H NMR spectroscopy).8
It was necessary to test if the in situ prepared ligands could be
directly applied in catalytic reactions and, if so, whether they would
exhibit similar efficacy to those associated with the corresponding
isolated, purified ligands. As a test reaction we investigated the
transfer hydrogenation of acetophenone in water (chosen due to
the fact that variants of this process employing imine ligands
are characterized by moderate levels of asymmetric induction,
with levels of product enantiomeric excess of up to 51% using
acetophenone as the electrophile).12 Thus, in the context of the
use of easily generated imine-based ligands, it represents a process
with considerable scope for development.13 Ligand 10 has been
employed in this reaction previously, and so we compared our
in situ results with those obtained with the purified compound
(see Fig. 3). Gratifyingly the level of performance of the in situ
prepared material was almost identical to that of the isolated,
purified version12 (48% vs. 52% ee, 98% vs. 99% conversion),
indicating that this methodology could provide a rapid method
for evaluating ligand performance.
Fig. 2 Rapid ligand generation for direct use in asymmetric catalysis.
condensation reaction, solutions of chiral imine (3), aminal (4)
and oxazolidine (5) ligands were accessible. Due to the ready avail-
ability of varied (and inexpensive) chiral amines, aminoalcohols
and diamines, combined with the easy variability of the aldehyde
fragment, we now possessed a methodology for the in situ synthesis
of structurally varied ligands in very high purities.
Fig. 3 Comparison of purified vs. in situ ligands.
While these ligands are useful and structurally diverse, an
even greater challenge is the synthesis of highly successful—and
complex—ligands such as oxazolines.10 To this end we examined
the use of pyridyl imidate 6 (Fig. 2), a known precursor of
oxazolines.11 This route has the advantage of being a one-step
process, again opening up the possibility of employing the ligands
in situ in high throughput screening. Normally such oxazoline
syntheses are carried out with an acid catalyst (e.g. HCl) and
purified by column chromatography or recrystallization; however,
we were keen to avoid the addition of any further additives or
purification steps. We were gratified to find that simply heating the
imidate with an aminoalcohol in the presence of molecular sieves
was sufficient. We posited that the side products (ammonia and
The behavior of ligands derived from imidates was also
evaluated. Ligand 14 was synthesized and purified by column
chromatography. The results obtained from the purified ligand
were again closely matched to the results of the ligand simply
formed by the condensation of L-phenylalaninol with imidate
6, followed by direct use in the reaction (13% ee in both cases,
12% conversion for in situ vs. 15% for purified). This was a
particularly important result, as it showed that we could now bring
the powerful and complex oxazoline ligands into combinatorial
catalysis.
Encouraged by these findings we made a small proof-of-concept
library and screened this in the reaction (see Table 1 and Fig. 4).
Generating each of the ligands was facile, and could be carried
out in parallel; a library of this size (or even larger) could easily be
produced in one day.
˚
methanol) could be absorbed by 4 A molecular sieves (or, if trace
ammonia was a problem, simple evaporation of the solvent would
yield pure compound). Initial tests supported this hypothesis, and
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Table 1 Asymmetric transfer hydrogenation in water with in situ gener-
ated ligands
Entry
Ligand
Conversion (%)
ee (%)
Config.
1
2
3
1
5
7
41
<5
8
(S)
—
5
8
79
98
99
11
18
8
12
15
29
2
(S)
(S)
(S)
(R)
(R)
(R)
(S)
(S)
(R)
—
4
10
10
11
12
13
14
14
15
16
17
18
19
20
21
22
23
24
25
26
48
51
51
68
26
13
13
40
<5
<5
43
<5
47
<5
15
<5
49
<5
9
5a
6
7
8
9
10a
11
12
13
14
15
16
17
18
19
20
21
22
6
—
25
15
7
4
6
5
58
5
(S)
(S)
(S)
—
(R)
—
(S)
—
(S)
10
a Ligands isolated and purified prior to use.
the simplicity of this system encourages the chemist to access
structures that would otherwise not be considered. It appears
likely that the most selective species is the major component
(ligand 12). While it was not possible to isolate this ligand in pure
form the other species in solution—bisimine 11 and cyclohexane
diamine starting material—both furnished the alcohol with lower
enantiomeric excess (51% and 43% respectively).
While none of the ligands in this library allowed the formation of
the product with outstanding levels of enantiomeric excess, even
using a small, rapidly generated library such as that described
above we were able to significantly improve upon the literature
benchmark for catalysis of this reaction using an imine-based
ligand. Much more importantly we demonstrated the ease with
which our methodology could be used to generate bidentate
ligand libraries of synthetically useful structures to test directly
in asymmetric reactions, and that the results obtained by the in
situ ligands were a reliable measure of the results obtained by the
purified ligands.
In conclusion, we have developed an operationally simple
method for the rapid generation of ligand libraries. A great
deal of structural diversity is easily achievable, not only P,N-,
N,N- and N,O-imine-based ligands, but also the more complex
oxazoline and imidazoline ligands have now been brought into
the repertoire of combinatorial catalysis. It is worth noting that
ligands of such complexity have previously been beyond the scope
of in situ synthesis, and the advantages this brings to the field are
clear. Finally, this methodology is not only time effective, but also
can reduce cost and waste—instead of synthesizing each ligand
on a reasonably large scale and subsequently purifying, simply
microlitre quantities of the two fragments can be heated together
Fig. 4 Ligands employed in this study. [(a) Compound 5 consisted of
a 5.6 : 1 ratio of the two diastereomers. Compound 12 consisted of an
equilibrium mixture of monoimine 12 (70%) with bis-imine 11 + unreacted
cyclohexane diamine (30%). See the ESI for details†].
(b)
Some trends could be observed in the results obtained. All of
the best results obtained were with imine ligands, in common
with the results reported by Himeda.12 P,N-ligands uniformly
gave low conversions, although the enantioselectivities were more
variable. Increasing the bulk on the aldehyde fragment had a
detrimental effect on both the conversion and selectivity (cf. 1
vs. 16, 10 vs. 19 and 17 vs. 20), perhaps by inhibiting binding at the
metal centre. The effect of increasing the steric bulk in the amine
fragment had a variable effect. In pyridine-based imine ligands it
appeared to reduce conversions but not selectivities (10 vs. 20),
whereas in the phosphine imine case it greatly reduced both (1
vs. 23). Electronic effects were somewhat more difficult to probe;
for instance compound 15 produced 1-phenylethanol in 40% ee,
but the addition of either electron withdrawing (21) or electron
donating (22) groups decreased this value.
The enantiomeric excess of the product obtained was moderate
(albeit it in a challenging system), with a maximum of 68%
achieved with ligand 12. As mentioned previously, in the case
of this type of ligand there were three species in equilibrium
(monoimine 12, bisimine 11 and cyclohexane diamine). Ordinarily
this would have lead to the rejection of 12 as a candidate; however,
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to generate sufficient ligand quantities for screening. Once a hit
has been found the ligand can either be synthesized and purified as
normal or subjected to a further round of combinatorial chemical
space exploration around that structure. Studies to further extend
this proof-of-concept to diverse ligand classes for application in
challenging asymmetric transformations are underway.
5 (a) R. den Heeten, B. H. G. Swennenhuis, P. W. N. M. van Leeuwen, J.
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2008, 3785; (c) T. Arai, N. Yokoyama and A. Yanagisawa, Chem.–Eur.
J., 2008, 14, 2052; (d) C. A. Christensen and M. Meldal, J. Comb.
Chem., 2007, 9, 79; (e) C. M. Sprout, M. L. Richmond and C. T. Seto,
J. Org. Chem., 2004, 69, 6666; (f) M. B. Francis and E. N. Jacobsen,
Angew. Chem., Int. Ed., 1999, 38, 937.
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N. H. Reek, Chem.–Eur. J., 2009, 15, 10272; (b) P.-A. R. Breuil, F. W.
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Acknowledgements
Financial support from Trinity College and from the Sci-
ence Foundation Ireland SURE program (MMcC) is gratefully
acknowledged.
Notes and references
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8 See the ESI for details†.
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13 The N-alkyl aldimines produced were tested for their stability under
these reaction conditions. Compound 10 was stirred in the reaction
buffer at 40 ◦C overnight, followed by neutralisation and extraction
with CH2Cl2. No hydrolysis products were observed.
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