chlorophosphites can be isolated as solids. To obtain a pure
phosphoramidite ligand, column chromatography and/or
recrystallization were typically performed prior to its use in
catalysis. This tedious workup represented an obstacle toward
a fully automated preparation of a large ligand library.
Considering Scheme 1, one realizes that as long as
stoichiometric amounts of reagents are used and the reaction
Scheme 1. Synthesis of Phosphoramidite Ligands
goes to completion, the main impurity present is the HCl
salt of the base. Thus, performing the reaction in a suitable
solvent followed by simple filtration of the precipitated HCl
salt should lead to sufficiently clean phosphoramidite ligands.
Figure 1. Protocol for the synthesis of the library.
To verify this idea, a known phosphoramidite (derived from
4
(
R)-2,2′-binaphthol and diethylamine) was synthesized ac-
fication. The absence of the purification step in the automated
procedure makes these primary amine based phosphoramid-
ites readily available.
Stock solutions of all the reagents were prepared in toluene
and dispensed directly into the 96-well microplate with a
liquid handling robot. The 32 reaction mixtures were
vortexed using an orbital shaker for 2 h followed by parallel
filtration giving 32 ligand solutions. A fraction of each
solution was transferred to two sets of 32 vials, which
cording to this simplified protocol and tested in the Rh-
catalyzed hydrogenation of methyl 2-acetamidocinnamate (1).
Remarkably, the conversion and the ee obtained (full
conversion, ee of 94%) were similar to the values obtained
5
with purified ligands (full conversion, ee of 97%). No
filtration led to an inactive catalyst. The simplified synthetic
protocol could then be easily automated by using a 96-well
oleophobic filterplate. Parallel filtration is performed upon
application of vacuum, and the filtrates are collected in a
second 96-well microplate that can be used for storage
contained Rh(COD)
substrate 1 in DCM and Z-methyl 3-acetamido-2-butenoate
2) in i-PrOH, respectively (substrate/Rh ) 50 mol/mol,
2 4
BF (L/Rh ratio ) 2 mol/mol) and
(Figure 1).
(
Our first library of ligands contained 32 members (Figure
). It was prepared by reacting (R)-2,2′-binaphthol-based
Figure 1). The 64 hydrogenation reactions were performed
2
6
in parallel in a Premex 96-Multi Reactor at room temper-
chlorophosphite with 32 different amines in the presence of
triethylamine as a base, thus generating 32 phosphoramidites
with a wide diversity in their amino moiety. This initial set
of amines was randomly assembled to validate the concept.
It contained 24 primary amines and 8 secondary amines.
Primary amines have not been used extensively as they lead
to phosphoramidites that partially decompose during puri-
ature and 6 bar of H
Figure 2.
2
for 1 h. The results are presented in
For the set using substrate 1, almost all of the members
of the library led to full conversions, indicating that most of
the ligands were formed with an acceptable degree of purity.
31
P NMR revealed the presence of trace amounts of other
phosphorus species that remarkably did not affect the
performance of the catalyst. The absence of reaction for the
phosphoramidites based on 4B and 6C was due to the
nonformation of the ligand, as observed by NMR. This gives
an acceptable cull rate (ratio of failed syntheses over the
total number of compounds) for the library of ∼10%. The
most enantioselective ligands for this reaction are based on
secondary amines, i.e., 7A, 7B, 7C, and 8A with ee’s of
94%, 95%, 91%, and 92%, respectively. The ee’s are slightly
lower than those obtained with fully purified ligands but the
(3) (a) de Vries, A. H. M.; Pineschi, M.; Arnold, L. A.; Imbos, R.;
Feringa, B. L. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (b) Feringa,
B. L. Acc. Chem. Res. 2002, 33, 346. (c) van den Berg, M.; Minnaard, A.
J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa,
B. L. J. Am. Chem. Soc. 2000, 122, 11539. (d) van den Berg, M.; Minnaard,
A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B.
L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers,
J. A. F.; Henderickx, H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003,
3
45, 308. (e) Pe n˜ a, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J.
Am. Chem. Soc. 2002, 124, 14552. (f) Boiteau, J. G.; Imbos, R.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681. (g) Imbos, R.; Minnaard, A.
J.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 184. (h) Jensen, J. F.;
Svendsen, Y.; la Cour, T. V.; Pedersen, H. L.; Johannsen, M. J. Am. Chem.
Soc. 2002, 124, 4558. (i) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc.
3
c,d,4,5
ranking is in agreement with previous results.
Results with the more challenging substrate 2 are far less
uniform. In terms of enantioselectivities, the best ligands are
all based on primary aliphatic amines branched on the
R-carbon (e.g., 1B, 92% ee; 1C, 92% ee; 2B, 94% ee; 5C,
2
002, 124, 15164. (j) Lopez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 3426. (k) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J.
F. J. Am. Chem. Soc. 2003, 125, 14272. (l) Bartels, B.; Helmchen, G. Chem.
Commun. 1999, 741. (m) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi,
M.; Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 930.
(
4) Jia, X.; Li, X.; Xu, L.; Shi, Q.; Yao, X.; Chan, A. S. C. J. Org.
Chem. 2003, 68, 4539.
5) See the Supporting Information.
(6) This reactor was developed by Premex in cooperation with DSM.
See: www.premex-reactorag.ch/e/spezialloesungen/produkteneuheiten/.
(
1734
Org. Lett., Vol. 6, No. 11, 2004