Development of a Benzimidazole-Derived Bidentate P,N-Ligand for Enantioselective Iridium-Catalyzed Hydrogenations

Article abstract of DOI:10.1002/ejoc.201301243

The development of a novel benzimidazole-derived bidentate P,N-ligand and its application in Ir-catalyzed hydrogenation is described. The ligand backbone was obtained through a one-pot tandem hydroformylation-cyclization sequence and the enantiomers of the generated alcohol were separated by chiral HPLC. By comparing the experimentally obtained CD spectra of the enantiomers with the simulated spectra generated from time-dependent DFT calculations, the absolute configuration could be obtained. The chiral alcohols could further be isolated on a larger scale after transesterification by using Candida Antarctica lipase B (Novozym 435) and could subsequently be converted into the corresponding chiral P,N-ligand by reaction with ClPPh₂. The coordination properties of the racemic P,N-ligand were investigated and the molecular structure of the Rh^I complex [(P,N)Rh(CO)Cl] was determined by X-ray crystal structure analysis. The corresponding chiral cationic Ir^I complex was used as catalyst for the enantioselective hydrogenation of prochiral N-phenyl-(1-phenylethylidene)amine and trans-α-methylstilbene. For the N-aryl-substituted imine, enantiomeric excesses of only 10 % were obtained, whereas the unfunctionalized olefin could be hydrogenated with enantiomeric excesses of up to 90 %. Interestingly, the modular synthetic access to the P,N-hybrid system described here allows facile modification of the ligand structure, which should extend the scope of such novel P,N-ligands for asymmetric catalytic conversions to a large extent in the future.

Full text of DOI:10.1002/ejoc.201301243

FULL PAPER
DOI: 10.1002/ejoc.201301243
Development of a Benzimidazole-Derived Bidentate P,N-Ligand for
Enantioselective Iridium-Catalyzed Hydrogenations
Jarno J. M. Weemers,[a] Fanni D. Sypaseuth,[a] Patrick S. Bäuerlein,[a]
William N. P. van der Graaff,[a] Ivo A. W. Filot,[a] Martin Lutz,[b] and Christian Müller*[a,c]
Keywords: Ligand design / N,P ligands / Asymmetric catalysis / Hydrogenation / Iridium / Nitrogen heterocycles / Kinetic
resolution
The development of a novel benzimidazole-derived biden-
tate P,N-ligand and its application in Ir-catalyzed hydrogena-
tion is described. The ligand backbone was obtained through
a one-pot tandem hydroformylation–cyclization sequence
and the enantiomers of the generated alcohol were separated
by chiral HPLC. By comparing the experimentally obtained
CD spectra of the enantiomers with the simulated spectra
generated from time-dependent DFT calculations, the abso-
lute configuration could be obtained. The chiral alcohols
could further be isolated on a larger scale after transesterifi-
cation by using Candida Antarctica lipase B (Novozym 435)
and could subsequently be converted into the corresponding
chiral P,N-ligand by reaction with ClPPh2. The coordination
properties of the racemic P,N-ligand were investigated and
the molecular structure of the RhI complex [(P,N)Rh(CO)Cl]
was determined by X-ray crystal structure analysis. The cor-
responding chiral cationic IrI complex was used as catalyst
for the enantioselective hydrogenation of prochiral N-
phenyl-(1-phenylethylidene)amine
and
trans-α-methyl-
stilbene. For the N-aryl-substituted imine, enantiomeric ex-
cesses of only 10% were obtained, whereas the unfunction-
alized olefin could be hydrogenated with enantiomeric ex-
cesses of up to 90%. Interestingly, the modular synthetic ac-
cess to the P,N-hybrid system described here allows facile
modification of the ligand structure, which should extend the
scope of such novel P,N-ligands for asymmetric catalytic con-
versions to a large extent in the future.
Crabtree was the first to describe the remarkable catalytic
activities of (pyridine)(phosphine)iridium complexes in the
hydrogenation of variously substituted olefins (Figure 1,
A).[4] Later, the application of chiral bidentate P,N-ligands
in iridium-catalyzed hydrogenation was pioneered by Pfaltz
and co-workers[5] (B and C). Since then, major contri-
butions in the areas of ligand design as well as the applica-
tion of more challenging substrate classes have been made
by the groups of Burgess,[6] Andersson (D),[7] and others.[8]
P,N-Hybrid ligands (Figure 1) consist of a phosphorus
atom, which acts as a “soft” donor towards a metal center
and is able to stabilize metals in lower oxidation states. The
nitrogen atom, on the other hand, stabilizes metals in
higher oxidation states due to its “hard” donor characteris-
tics. Such mixed donor ligands show a potentially hemilab-
ile behavior that depends on the oxidation state of the metal
center in the catalytic cycle, and one donor atom can be
more strongly bound than the other. Although mono-
dentate phosphines were the first chiral ligands to be pre-
pared and applied in the enantioselective catalytic hydro-
genation, the use of bidentate ligands resulted in far supe-
rior enantioselectivities. Research on monodentate ligands,
however, has increased over the last ten years. De Vries and
co-workers[9] demonstrated excellent enantioselectivities of
acyclic N-aryl imines with an iridium catalyst based on the
monodentate phosphoramidite PipPhos (Figure 1, E). The
Introduction
The enantioselective hydrogenation of prochiral sub-
strates is one of the most important and efficient asymmet-
ric catalytic transformations for the pharmaceutical indus-
try, the production of fine chemicals, as well as for acade-
mia.[1] Enantioselective hydrogenations of chelating prochi-
ral alkenes based on cationic rhodium systems have been
well-studied.[2] On the other hand, the hydrogenation of
C=N double bonds and nonfunctionalized prochiral alk-
enes, which lack polarized double bonds and bear func-
tional groups that do not coordinate to the metal center, is
currently of special interest but still remains a challenge.[3]
For this reaction, iridium complexes based on chiral P,N-
ligands are particularly well-suited, however, access to such
ligand systems is often not trivial.
[a] Chemical Engineering and Chemistry, Eindhoven University of
Technology,
Den Dolech 2, 5600 MB Eindhoven, The Netherlands
[b] Bijvoet Center for Biomolecular Research, Crystal and
Structural Chemistry, Utrecht University,
Padualaan 8, 3584 CH Utrecht, the Netherlands
[c] Institut für Chemie und Biochemie – Anorganische Chemie,
Freie Universität Berlin,
Fabeckstr. 34/36, 14195 Berlin, Germany
E-mail: c.mueller@fu-berlin.de
http://www.bcp-fu-berlin.de/ak-mueller
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301243.
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Enantioselective Iridium-Catalyzed Hydrogenations
Figure 1. Selected examples of ligands and complexes for iridium-catalyzed hydrogenation.
focus on new ligand classes was further extended by Burgess asymmetric iridium-catalyzed hydrogenation of an N-aryl
and co-workers, who successfully applied NHC carbene- imine and an unfunctionalized olefin substrate.
based C,N/Ir+ catalysts in the asymmetric hydrogenation of
aryl alkenes.[6c–6e]
Results and Discussion
Recently, we reported on the selective formation of hy-
droxy-functionalized bicyclic imidazole G through a tan-
dem type hydroformylation–cyclization sequence starting
from a methylallyl heteroaromatic substrate (Scheme 1).[10]
Stimulated by our recent results, we started to investigate
the scope of the hydroformylation–cyclization sequence and
synthesized the methylallyl-functionalized benzimidazole
derivative 1 (Scheme 2). This compound was prepared in a
one-step reaction starting from benzimidazole and commer-
cially available 3-chloro-2-methylpropene and was obtained
in good yield after workup. Substrate 1 was subsequently
hydroformylated in toluene as solvent at 120 °C in CO/H2
(1:1, 20 bar) in the presence of a catalytic system based on
[Rh(acac)(CO)2] and a phosphabarrelene (Scheme 2).[10]
After 45 h, 1 was almost completely converted and prod-
uct 3 was collected as a white solid after recrystallization
from hot tetrahydrofuran (THF) or toluene. Figure 2 shows
Scheme 1. Tandem type one-pot hydroformylation–cyclization se-
quence for the formation of chiral bicyclic methyl-substituted benz-
imidazole-based alcohol G.
Interestingly, the core structure of the generated hetero- the distribution-of-species plot generated during the hydro-
cycles is found in biologically active compounds such as formylation–cyclization sequence.
nagstatins. Moreover, we realized that they can also serve
The crystalline material was analyzed by means of chiral
as chiral building blocks for the preparation of a new class HPLC and it was possible to separate the four stereoiso-
of imidazole-based P,N-ligands (Figure 1, F) and are there- mers, resulting from the implementation of two stereogenic
fore potentially relevant for both pharmaceutical and fine centers during the formation of 3 from 1. From the integrals
chemistry applications. As a matter of fact, this new type of the signals, a diastereomeric ratio of 1:3 could be con-
of system has a striking resemblance to previously reported cluded (Figure 3).
(chiral) ligands;[4–8] they all contain both a phosphorus and
a nitrogen donor atom and form six-membered chelate- characteristic resonance of the proton adjacent to the OH-
rings upon coordination to an iridium metal center. functionality at δ = 5.0–5.3 ppm as well as the resonance of
Analysis of 3 by 1H NMR spectroscopy revealed the
Here, we report on the design, synthesis, and characteri- the proton of the OH group at δ = 5.9–6.3 ppm. The same
zation of a novel type of tricyclic benzimidazole-based P,N- ratio of diastereomers in the diastereomeric mixture was
ligand and present a first example of its application in the observed as determined by HPLC analysis (Figure 4).
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Scheme 2. Tandem hydroformylation–cyclization sequence for the formation of benzimidazole-based alcohol 3.
1
Figure 4. H NMR (400.16 MHz, CDCl3, 25 °C) spectrum of the
diastereomeric mixture of 3.
Figure 2. Distribution of species plot for the one-pot tandem hy-
droformylation-cyclization reaction of 1. Reaction conditions:
120 °C, 20 bar (CO/H2 = 1:1), THF, Vtot = 8.0 mL, Rh/L/S =
1:20:1500, substrate (12.0 mmol, 1.5 mL), [Rh(acac)(CO)2], phos-
phabarrelene.[10]
the OH group as donor and N(1) as acceptor, centrosym-
metric dimers were formed in the crystal (Figure 5, b).
From Figure 3 it is clear that a separation of all four stereo-
isomers into diastereomerically pure compounds by (semi)-
preparative HPLC would be difficult to achieve, even under
optimized conditions. We therefore decided to simplify the
target molecule by excluding the methyl group connected
to C(2) (Scheme 3), and thus reduce the number of possible
stereoisomers.
As a starting point for the one-pot tandem type hydro-
formylation–cyclization sequence, allyl-substituted benz-
imidazole 4 was chosen as substrate, which could be synthe-
sized in one step by reaction of benzimidazole with allyl
bromide. Because 4 lacks a methyl group on the β-position
of the double bond, in contrast to compound 1, the number
of stereoisomers is reduced from two enantiomeric pairs to
only one enantiomeric pair. Compound 4 was hydroformyl-
ated in the first step to the intermediate aldehyde 5 at
Figure 3. HPLC analysis of baseline separation of both dia- 120 °C with syngas (20 bar, CO/H2 = 1:1) by using
stereomeric pairs of 3 (ratio 1:1:3:3) by using analytical HPLC on
[Rh(acac)(CO)2] as metal precursor and Xantphos as ligand
(Scheme 3).
This chelating diphosphine is known to direct the hydro-
formylation reactions towards the desired linear product.[11]
We anticipated that the subsequent ring-closing reaction
a chiral stationary phase with n-hexane/2-propanol (98:2) as the
eluent (Chiralcel OJ-H; t1 = 8.70, t2 = 10.32, t3 = 16.98, t4
22.01 min; T = 25 °C; flow rate: 1.0 mL/min; λ = 254 nm).
=
Racemic single crystals of 3 that were suitable for X-ray would finally generate racemic alcohol 6, according to
diffraction were obtained by crystallization from hot THF; Scheme 3. From the distribution-of-species plot shown in
the molecular structure of the syn-stereoisomer in the crys- Figure 6 it became clear, however, that the hydrofor-
tal is depicted in Figure 5 (a). By hydrogen bonding with mylation–cyclization sequence in the case of substrate 4 was
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Enantioselective Iridium-Catalyzed Hydrogenations
Figure 6. Distribution-of-species plot for the one-pot tandem hy-
droformylation–cyclization reaction of 4. Reaction conditions:
120 °C, 20 bar (CO/H2 = 1:1), toluene, Vtot = 8.0 mL, Rh/L/S =
1:4:1500, substrate (12.0 mmol, 2.07 g), [Rh(acac)(CO)2],
Xantphos.
Figure 5. Molecular structure of 3 in the crystal. Displacement el-
lipsoids are shown at the 50% probability level. (a) Stereoisomer
(R,S)-3 (b) Hydrogen bonding between two adjacent molecules.
Symmetry operation i: 1 – x, 1 – y, 1 – z.
Figure 7. Additional byproducts formed during the one-pot tan-
dem hydroformylation–cyclization reaction of 4.
less selective than for 1. In addition to the formation of azole d, and another 9% was hydrogenated to give f. The
the desired benzimidazole-based secondary alcohol 6, three aldehyde was slowly converted into the ring-closed product.
additional byproducts d–f were observed.
This reaction, however, is in competition with the hydrogen-
Analysis of the product mixture by GC–MS revealed that ation of the aldehyde to the alcohol e. After 40 hours, the
not only had the hydrogenated product, N-propylbenzimid- aldehyde is almost fully converted, and the ring-closed
azole (f), formed but also the alcohol corresponding to the product 6 and alcohol f make up 51 and 14% of the reac-
linear aldehyde (e), and even benzimidazole (d) was de- tion mixture, respectively. The formation of benzimidazole
tected in relatively large amounts (ca. 21%) (Figure 7).
is remarkable; the reductive cleavage of the N–C bond is
From Figure 6 it is clear that consumption of substrate probably due to a deprotection reaction in which the allyl
4 is very fast, because almost full conversion was ac- group is cleaved, forming benzimidazole and propene. As a
complished within 30 minutes. At that time, the maximum matter of fact, compound d seems not to be generated from
concentration of aldehyde 5 was reached, accounting for aldehyde 5, but is instead formed rapidly at the very begin-
58% of the total composition. In the same period of time, ning of the substrate conversion, with its concentration sub-
about 20% of the substrate was converted into benzimid- sequently remaining constant during the course of the reac-
Scheme 3. Tandem hydroformylation–cyclization sequence for the formation of tricyclic benzimidazole-based alcohol 6. L = Xantphos,
Rh = [Rh(acac)(CO)2].
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C. Müller et al.
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tion. The deallylation process of allylamines is known to
be catalyzed by transition-metal complexes (most notably
rhodium and ruthenium).[12,13]
After cyclization of the linear aldehyde, a racemic mix-
ture of chiral tricyclic alcohol 6 was formed. Even though
a product mixture was generated during the hydrofor-
mylation–cyclization sequence, 6 could easily be isolated as
a highly pure, white solid or as colorless crystals after com-
bined flash column chromatography and recrystallization of
the mixture from hot THF or toluene. The racemic alcohol
Scheme 4. Synthesis of racemic P,N-ligand 7 from racemic tricyclic
alcohol 6.
able for X-ray diffraction could be obtained from [(rac-7)
Rh(CO)Cl] by slow diffusion of Et2O into a CH2Cl2 solu-
tion of the complex (Figure 9).
1
was analyzed by H and 13C{1H} NMR spectroscopy as
well as by chiral HPLC. The 1H NMR spectrum of 6 along
with the HPLC chromatogram is depicted in Figure 8.
We then considered whether it was possible to transform
compound 6 into a novel P,N-hybrid ligand, and found that
racemic tricyclic alcohol 6 could indeed be easily converted
into the corresponding racemic P,N-ligand 7 by reaction
with chlorodiphenylphosphine in the presence of NEt3.
Compound 7 was isolated as a white solid in 76% yield
after filtration (Scheme 4).
To verify the structure of this novel type of hemilabile
P,N-ligand, we investigated the coordination behavior of
rac-7 towards [Ir(COD)2]BF4 and [Ir(COD)2]BArF
(Scheme 5). Both reactions resulted in a single resonance in
Scheme 5. Synthesis of complex 8.
Rh complex 8 crystallized as a racemate in the triclinic
the 31P{1H} NMR spectra (δ = 102.7 ppm and δ = space group P1 (no. 2) and the molecular structure along
105.4 ppm, respectively). Unfortunately, all attempts to ob- with selected bond lengths and angles is shown in Figure 9.
tain crystals from the above mentioned complexes failed. The rhodium atom displays a square-planar geometry,
Nonetheless, reaction of rac-7 with the Rh-dimer [Rh- which is typical for a 16-electron complex. The planarity of
(CO)2Cl]2 was successful, and yellow crystals that were suit- the benzimidazole part is clearly visible as well as the non-
¯
1
Figure 8. H NMR spectroscopic analysis and HPLC chromatogram of both enantiomers of 6 obtained by using an analytical HPLC
column with a chiral stationary phase [Chiralpak IC; n-heptane/CH2Cl2/EtOH:diethylamine (75:25:3:0.1); t1 = 15.15 min, t2 = 16.24 min;
T = 25 °C; flow rate 1.0 mL/min].
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Enantioselective Iridium-Catalyzed Hydrogenations
planar, fused, six-membered ring. Moreover, the chlorine
atom occupies the trans-position relative to the phosphorus
atom, whereas the CO molecule is coordinated trans to the
benzimidazole moiety.
Scheme 6. Iridium-catalyzed hydrogenation of N-phenyl-(1-phenyl-
ethylidene)amine 9. Reaction conditions: 25 °C, H2 (10 bar),
CH2Cl2, Vtot
= 8.0 mL. Ir/L/S = 1:1.05:100. 9 (2.0 mmol),
[Ir(cod)2]BArF, cIr = 1.6ϫ10–4 molL–1. Ligand = rac-7 or 12.
Scheme 7. Iridium-catalyzed hydrogenation of trans-α-methylstil-
bene 10. Reaction conditions: 25 °C, H2 (10 bar), CH2Cl2, Vtot
=
=
8.0 mL. Ir/L/S = 1:1.05:50. 10 (1.0 mmol), [Ir(cod)2]BArF, cIr
1.6ϫ10–4 molL–1. Ligand = rac-7. For ligand = 12: Ir/L/S =
1:1.05:100.
crease in H2 gas consumption towards the end of the reac-
tion. Substrate 10 was hydrogenated under the same reac-
tion conditions, although only half of the concentration of
9 was used. The gas uptake plot for 10 (Figure 11) showed
a significantly reduced activity compared with 9, which
reached a conversion of 67% after 16 h (TOF = 20 h–1 at
10% conversion). Turnover frequencies were determined at
10% conversion because the reaction with substrate 10 was
no longer in the linear regime.
Figure 9. Molecular structure of 8 determined by X-ray crystal
structure determination. Only one enantiomer of the racemic crys-
tal structure is shown. Displacement ellipsoids are shown at the
50% probability level. Selected bond lengths (Å): Rh(1)–P(1):
2.1925(4); Rh(1)–N(1): 2.0982(12); P(1)–O(1): 1.6337(11); Rh(1)–
Cl(1): 2.3897(4); Rh(1)–C(24): 1.8192(16); O(2)–C(24): 1.147(2);
bond angle (°): P(1)–Rh(1)–N(1): 87.24(3).
Additional analysis revealed that complex 8 shows a
doublet in the 31P{1H} NMR spectrum at δ = 132.8 ppm
(J = 178.2 Hz) and a CO stretching frequency of ν =
˜
1992 cm–1 in the IR spectrum. In comparison to imidazole-
based Rh complexes analyzed by Field et al.,[14] ligand 7
has clearly more π-accepting characteristics than the re-
ported phosphine-based ligands.
To gain further insight into the applicability of the newly
developed P,N-ligand in homogeneous catalytic reactions,
we performed iridium-catalyzed hydrogenation reactions of
N-phenyl-(1-phenylethylidene)amine (9; Scheme 6) and
trans-α-methylstilbene (10; Scheme 7) in a parallel reactor
system (AMTEC SPR16). At 25 °C and a constant hydro-
Figure 10. Gas uptake curve for the hydrogenation of 9 with rac-7/
Ir+.
Because the preparation of the P,N-hybrid ligand was
gen pressure (10 bar), substrate 9 was quantitatively con- successful and its coordination chemistry as well as its ap-
verted into the hydrogenated product 9a within 16 h (TOF plicability in hydrogenation reactions had been explored, we
= 107 h–1 at 10% conversion).
then started to investigate the chiral resolution of the
From the gas uptake plot (Figure 10) it is clear that, enantiomers so that enantiopure 7 could be applied as li-
within the first two hours, approximately 90% of 9 was con- gand in asymmetric catalytic reactions. To this end, rac-6
verted into the product, which was followed by a sharp de- was dissolved in a mixture of n-heptane/CH2Cl2/EtOH/di-
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C. Müller et al.
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Figure 11. Gas uptake curve for the hydrogenation of 10 with rac-
7/Ir+.
ethylamine (75:25:3:0.1) and analyzed by means of chiral
HPLC. Baseline separation of 6-E1 (first eluted enantiomer)
and 6-E2 (second eluted enantiomer) was only achieved at
low concentrations by using an analytical HPLC with a chi-
ral stationary phase [Chiralpak IC; n-heptane/CH2Cl2/
EtOH-diethylamine (75:25:3:0.1); t1 = 15.15 min, t2
=
16.24 min; T = 25 °C; flow rate: 1.0 mL/min; see also Fig-
ure 8]. With the separation of the two enantiomers by chiral
HPLC achieved, we could obtain both fractions in high en-
antiopurity for further characterization.
To assign the absolute configurations of 6-E1 and 6-E2,
the optical properties of the separated enantiomers were de-
termined by circular dichroism (CD) in ClCH2CH2Cl; the
experimentally recorded spectra are shown in Figure 12
(top).
Figure 12. (Top) Experimental CD spectra of 6-E1 (solid line) and
6-E2 (dashed line) in ClCH2CH2Cl. The experimental CD spectra
(gray dots) have been smoothed (dashed line) to reduce the high
noise level. (Bottom) Theoretical CD spectra of enantiomers (S)-6
(solid line) and (R)-6 (dashed line).
The bisignate (–/+) CD curve of 6-E1 shows the presence
of an exciton split couplet with a relatively small amplitude
of ΣΔε ≈ 10, whereas the bisignate (+/–) CD curve of 6-E2
has a couplet with an amplitude of ΣΔε ≈ 12. The CD spec-
tra also display two Cotton effects for each enantiomer at
λ ≈ 290 and 255 nm. The deviation in ΣΔε values between
the two enantiomers can be attributed to a difference in ral, larger than those in the experimental spectra. For the
concentration as a result of the enrichment procedure. theoretical calculations, both conformers were structurally
To deduce the absolute configuration, the CD spectra for optimized and although the rotation of the hydroxyl group
both enantiomers were simulated by means of a time-de- as well as the fluxional chaired C4H7OH “bridge” have in-
pendent Density Functional Theory method at the B3LYP/ fluence on the shape of the theoretical CD spectrum, the
6-311+G(d,p) level. This technique has been shown to pro- overall bisignate character as seen in the theoretical and the
vide a reasonably accurate description of the photophysical experimental spectra remains unchanged. Furthermore, the
properties of various compounds, which include quite accu- spectra are independent of the conformations of these side
rate predictions of CD spectra.[15] The geometries for (R)-6 groups.
and (S)-6 were optimized at the B3LYP/6-311+G(d,p) level
By applying the Cahn–Ingold–Prelog priority rules,[16]
and their theoretical CD spectra were calculated as shown the absolute configuration of both enantiomers could be
in Figure 12 (bottom). The theoretical CD spectra of both determined. Because the calculated data are in such a close
enantiomers also display the same characteristic features as agreement with the experimental results, we are confident
the experimentally obtained spectra. The calculated spectra to assign unambiguously the (S)-6 configuration to the 6-
clearly show the bisignate shape as well as the sequence of E1 enantiomer and the (R)-6 configuration to the 6-E2
the negative/positive Cotton effects. Both the (–/+) pattern enantiomer (Figure 13).
and the (+/–) pattern are clearly visible, however, the peaks
Unfortunately, it turned out that at higher concentrations
show a redshift to higher wavelengths, and the intensity both peaks of 6 start to overlap significantly in the HPLC
maxima and minima of the theoretical spectra are, in gene- chromatogram, making separation on multimiligram scale
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Enantioselective Iridium-Catalyzed Hydrogenations
Figure 13. (Left) Enantiomer 6-E1 (first eluted compound) having
the S configuration. (Right) Enantiomer 6-E2 (second eluted com-
pound) having the R configuration.
very tedious and almost impossible. Therefore, the ap-
proach of separating the enantiomers of 6 on a larger scale
by using semipreparative HPLC was abandoned and we
shifted our focus to a different method. We chose the ki-
netic resolution of 6 by using a transesterification reaction
catalyzed by Candida Antarctica lipase B (CALB) immobi-
lized on acrylic resin (Novozym 435), and used vinyl but-
yrate as the acyl donor (Scheme 8). Lipases are the most
widely investigated enzymes due to their ease of handling
and because of their increased stability at high temperatures
and over a wide pH range.[17] Moreover, lipases are specific
towards the ester bond and, hence, the formation of unde-
sirable byproducts is eliminated.[18] Novozym 435 has been
applied in the synthesis of long-chain fatty acids and sugars,
in the preparation of long-chain acyl thioesters,[19] and in
the transesterification of several alcohols.[20]
The kinetic resolution of secondary alcohol 6 was investi-
gated under different reaction conditions. Novozym 435 has
been reported to be stable up to 90 °C, however, a tempera-
ture of 50 °C proved to be more efficient in our case. A
combination of toluene as solvent and Novozym 435 (25 w/
w-%) in the presence of vinyl butyrate (1.05 equiv.) gave the
best results within 23 h, as indicated by HPLC and 1H
NMR analysis after optimization of the enzymatic kinetic
resolution (Figure 14).
Figure 14. Front: HPLC analysis of baseline separation of both
enantiomers of 6 by using analytical HPLC on a chiral stationary
phase [Chiralpak IC; n-heptane/CH2Cl2/EtOH-diethylamine
(75:25:3:0.1); t1 = 16.06 min, t2 = 17.21 min; T = 25 °C; flow rate:
1.0 mL/min). Middle: Transesterification reaction after 23 h; tester
= 10.06 min and unreacted 6-E1. Background: First eluted enantio-
mer 6-E1 after column chromatography.
enantiomer had reacted completely towards the corre-
sponding ester 11 and that only a fraction of the slower
reacting (S)-enantiomer had also been converted. This reac-
tion profile indicated that the enzymatic transesterification
reaction followed Kazlauskas’ rule.[21]
Ester (R)-11 could easily be hydrolyzed to the corre-
sponding alcohol (R)-6 by stirring overnight in an aqueous
methanolic solution (MeOH/H2O, 4:1) in the presence of a
ten-fold excess of K2CO3 (Scheme 9).
Ester (R)-11 could easily be separated from alcohol (S)-
6 by column chromatography (Si; hexane/EtOAc, 1:1) and,
after subsequent washing of the column with MeOH,
alcohol (S)-6 was isolated in pure form with an enantio-
meric excess of more than 99% as determined by chiral
Scheme 9. Hydrolysis of ester (R)-11 to alcohol (R)-6.
1
HPLC analysis. The H NMR spectrum of the ester prod-
uct showed a downfield shift from 5.2 to 6.2 ppm for the
Chiral HPLC analysis indicated an enantiomeric excess
proton located at the carbon atom connected to the hy- of 96%. In subsequent reactions, as described in Scheme 4,
droxyl group, which allowed for an accurate determination both enantioenriched alcohols (S)-6 (Ͼ 99% ee) and (R)-6
of the conversion for each reaction. HPLC analysis of the (96% ee) were converted into their corresponding P,N-li-
reaction mixture over time clearly showed that the (R)- gands, (S)-12 and (R)-12, respectively (Figure 15).
Scheme 8. Kinetic resolution of rac-6 by using Candida Antarctica lipase B (Novozym 435) and vinyl butyrate as acyl donor.
Eur. J. Org. Chem. 2014, 350–362
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357

C. Müller et al.
FULL PAPER
that a small amount of enantiomeric purity could have been
lost during the reaction from 6 to 12. Table 1 also indicates
that performing the reaction at reduced pressure (5 bar) or
higher pressure (20 bar) both resulted in a significant re-
duction in conversion as well as a small decrease in enantio-
selectivity.
Figure 15. (Left) Bidentate P,N-ligand (S)-12. (Right) Bidentate
P,N-ligand (R)-12.
Conclusions
Our recently discovered tandem hydroformylation–cycli-
zation sequence of N-allyl-substituted imidazole-derivatives
towards OH-functionalized nitrogen heterocycles provides
the possibility of synthesizing novel chiral P,N-ligands.
Structure elucidation of the chiral ligand and the corre-
sponding metal complexes by means of CD spectroscopy
and X-ray crystal structure analysis provides valuable infor-
mation on their absolute configuration and coordination
behavior. Furthermore, the first enantiopure compound of
this type has been successfully used in the enantioselective
iridium-catalyzed hydrogenation of N-phenyl(1-phenyleth-
ylidene)amine and α-methylstilbene and enantiomeric ex-
cess values of up to 90% could be obtained. Interestingly,
the modular synthetic procedure used for the preparation
of the P,N-ligands provides the possibility to vary the sub-
stitution pattern of the ligand backbone in a facile way, so
that a wide variety of substituted chiral P,N-ligands are eas-
ily accessible. The scope of the hydroformylation–cycliza-
tion sequence and the preparation of the corresponding chi-
ral P,N-ligands as well as their application in asymmetric
homogeneous catalysis is being explored in our laboratories.
To investigate the enantioselectivity and activity of the
metal complexes based on the bidentate P,N-ligand 12, N-
phenyl-(1-phenylethylidene)amine (9; Scheme 6) and trans-
α-methylstilbene (10; Scheme 7) were chosen as model sub-
strates in the Ir-catalyzed asymmetric hydrogenation. The
catalytic reactions with (S)-12/Ir+ and (R)-12-R/Ir+ were
carried out by using a stainless steel 75-mL autoclave
equipped with a dropping funnel. The autoclave was first
charged with the iridium-based precatalyst solution fol-
lowed by the substrate solution, filled with H2 at the desired
pressure, and sealed. The substrates were hydrogenated at
25 °C and H2 (10 bar) for 20–24 h. From Table 1 it is clear
that imine 9 is quantitatively hydrogenated within 24 h as
determined by 1H NMR spectroscopy (entries 1 and 2).
Unfortunately, analysis of the reaction products by chiral
HPLC revealed an enantiomeric excess of only 10% for
both catalysts (S)-12/Ir+ (S product) and (R)-12/Ir+ (R
product). However, applying olefin 10 in the asymmetric
hydrogenation under the same conditions resulted in very
good enantioselectivities for both catalysts (S)-12/Ir+ and
(R)-12/Ir+ with enantiomeric excesses of 80 (R product) and
90% (S product), respectively (entries 3 and 4).
Experimental Section
Table 1. Asymmetric hydrogenation of N-phenyl-(1-phenyl-ethyl-
idene)amine and trans-α-methylstilbene.[a]
General: All manipulations were carried out under an argon atmo-
sphere by using modified Schlenk techniques, unless stated other-
wise. All glassware was dried prior to use by heating under vacuum.
All common chemicals were commercially available and purchased
from Aldrich Chemical Co., Merck or Strem Chemicals and used
as received. α-Methylstilbene was purchased from Merck and used
as received. N-Phenyl(1-phenylethylidene)amine was prepared ac-
cording to a modified literature procedure.[5a] Solvents were dried
and deoxygenated by using custom-made solvent purification col-
umns filled with Al2O3. Elemental analyses were recorded by
H. Kolbe, Mikroanalytisches Laboratorium, Mülheim a.d. Ruhr
(Germany). 1H, 13C{1H} and 31P{1H} NMR spectra were recorded
with a Varian Mercury 400 spectrometer and all chemical shifts are
reported relative to the residual proton resonance in the deuterated
solvents or referred to an 85% aqueous solution of H3PO4, respec-
tively.
Entry Ligand Substrate p [bar] Conv. [%][b]
ee [%][e]
1
2
3
4
5
6
(S)-12
(R)-12
(S)-12
(R)-12
(R)-12
(R)-12
9
9
10
10
10
10
10
10
10
10
5
100[c]
100[c]
91[d]
10 (S)
10 (R)
80 (R)
90 (S)
73 (S)
82 (S)
Ͼ99[d]
59[d]
20
41[d]
[a] Reaction conditions: [Ir(cod)2]BArF, Ir/L/S = 1:1.05:100, cRh
=
2.5 mm, Vtot = 12 mL, CH2Cl2, 25 °C. [b] Conversion was deter-
mined by 1H NMR spectroscopic analysis. [c] Determined after
24 h. [d] Determined after 20 h. [e] The ee was determined by ana-
lytical chiral HPLC.
Interestingly, these results clearly reveal that the less
enantiopure catalyst (R)-12/Ir+ (from (R)-6, having 96% ee)
obtained from the enzymatic kinetic resolution of the chiral
alcohol is slightly more enantioselective than (S)-12/Ir+
(from (S)-6, having Ͼ 99% ee). During the workup, after
the enzymatic kinetic resolution, only substantial amounts
of the unreacted alcohol (R)-6 could be eluted from the
column by using pure MeOH. During this procedure, min-
ute amounts of impurities could also be washed off the col-
umn, which could be the reason for the somewhat reduced
N-(2-Methylallyl)benzimidazole (1): Dimethyl sulfoxide (120 mL)
was added to KOH (19.0 g, 338.6 mmol, 4.0 equiv.) and the mixture
was stirred for 5 min, followed by the addition of benzimidazole
(10.03 g, 84.8 mmol, 1.0 equiv.). The mixture was stirred for an-
other 45 min, then cooled to a slurry using an ice-water bath. 3-
Bromo-1-propene (11.26 g, 93.1 mmol, 1.1 equiv.) was added drop-
wise and stirring was continued for 2 h under ice cooling, and for
a further 1.5 h without ice cooling. The reaction was quenched by
the addition of water (300 mL) and the aqueous phase was ex-
enantioselectivity. Furthermore, it might also by possible tracted with CH2Cl2 (3 ϫ 300 mL). The organic phase was back-
358
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Eur. J. Org. Chem. 2014, 350–362

Enantioselective Iridium-Catalyzed Hydrogenations
extracted with water (3 ϫ 300 mL), dried with anhydrous Na2SO4,
filtered, and all volatiles were removed in vacuo to give 1 (13.32 g,
77.3 mmol, 91.0%) as a white solid. 1H NMR (400.16 MHz,
8.2853(2), c = 10.3507(3) Å, α = 82.022(1), β = 77.139(1), γ =
79.627(1)°; V = 523.35(2) Å3; λ = 0.71073 Å; Z = 2; Dx
1.283 gcm–3; μ = 0.08 mm–1. 9024 Reflections were measured up
=
CDCl3, 25 °C): δ = 1.67 (s, 3 H, Me), 4.65 (s, 2 H, H2C=C), 4.79 to a resolution of (sinθ/λ)max = 0.65 Å–1. 2400 Reflections were
(br. s, 1 H), 4.96 (br. s, 1 H), 7.24–7.30 (m, 2 H), 7.32–7.38 (m, 1
unique (Rint = 0.029), of which 2022 were observed [IϾ2σ(I)]. 141
H), 7.78–7.84 (m, 1 H), 7.86 (s, 1 H) ppm. 13C NMR (100.62 MHz, Parameters were refined with no restraints. R1/wR2 [IϾ2σ(I)]:
CDCl3, 25 °C): δ = 19.9, 51.1, 110.1, 114.3, 120.2, 122.2, 123.1,
134.3, 139.5, 143.3, 143.7 ppm. MS: m/z = 171.10 [M]+.
0.0428/0.1114. R1/wR2 [all refl.]: 0.0515/0.1177. S = 1.036. Residual
electron density between –0.21 and 0.28 eÅ–3.
2-Methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-α]pyridin-4-ol (3):
A 75-mL stainless steel autoclave equipped with a sampling unit
and dropping funnel was charged with a solution of [Rh(acac)-
(CO)2] (2.1 mg, 8.0ϫ10–6 mmol, 1.0 equiv.) and phosphabarre-
lene[8] (20 equiv.) in THF (5 mL). To the dropping funnel was
added dropwise a solution of 1 (12.0 mmol, 1500 equiv.) in THF
(1.5 mL). The autoclave was sealed and pressurized with CO/H2
(1:1; 20 bar) and heated to preformation temperature and stirred
for 2 h. Subsequently, the substrate was added by using the drop-
ping funnel to the preformed catalyst solution initiating the start
of the reaction. When the reaction was complete, the autoclave was
cooled and the pressure was released. Crystallization from hot
THF gave the product as colorless crystals or as a white powder.
Compound 8: C24H21ClN2O2PRh; Fw = 538.76; yellow needle;
0.25ϫ0.12ϫ0.09 mm ; triclinic; P1 (no. 2); a = 10.1357(3), b =
3
¯
11.4360(3), c = 12.0375(4) Å, α = 62.2554(7), β = 65.1659(7), γ =
69.0578(7)°; V = 1097.68(6) Å3; λ = 0.71073 Å; Z = 2; Dx
=
1.630 gcm–3; μ = 1.00 mm–1. 23385 Reflections were measured up
to a resolution of (sinθ/λ)max = 0.65 Å-1. 5015 Reflections were
unique (Rint = 0.016), of which 4679 were observed [IϾ2σ(I)]. 280
Parameters were refined with no restraints. R1/wR2 [IϾ2σ(I)]:
0.0189/0.0485. R1/wR2 [all refl.]: 0.0213/0.0497. S = 1.037. Residual
electron density between –0.25 and 0.43 eÅ–3.
1-Allylbenzimidazole (4): A mixture of DMSO (120 mL) and KOH
pellets (19.0 g, 338.6 mmol, 4.0 equiv.) was stirred for 5 min, then
benzimidazole (10.0 g, 84.6 mmol, 1.0 equiv.) was added and stir-
ring was continued for 45 min. The mixture was ice-cooled to a
slurry and allyl bromide (11.3 g, 93.4 mmol, 1.1 equiv.) was added
dropwise. The ice bath was removed and the stirring was continued
for 45 min, then the mixture was poured onto ice-cooled water
(100 mL) and stirred for a further 30 min. The aqueous phase was
extracted with diethyl ether (3ϫ 100 mL) and the organic phase
was back-extracted with water (3ϫ 100 mL), dried with anhydrous
MgSO4, filtered, and all volatiles were removed in vacuo to give 4
(10.1 g, 63.8 mmol, 75%) as a pale-yellow oil. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 4.67–4.70 (dq, J = 5.5, 1.4 Hz, 2 H), 5.09–5.26
(m, 2 H), 5.88–5.98 (m, 1 H), 7.22–7.27 (m, 2 H), 7.29–7.34 (m, 1
H), 7.77–7.81 (m, 1 H), 7.83 (s, 1 H) ppm. 13C NMR (100.63 MHz,
CDCl3, 25 °C): δ = 47.4, 109.9, 118.6, 120.3, 122.2, 122.7, 131.9,
133.6, 142.9, 143.6 ppm; C10H10N2 (158.20): calcd. C 75.92, H 6.37,
N 17.71; found C 74.50 H 6.59 N 17.54.
1
Isomer anti-(S,S)-(3): H NMR (400.16 MHz, CDCl3, 25 °C): δ =
7.77–7.75 (m, 1 H), 7.35–7.25 (m, 3 H), 6.23 (br, 1 H), 5.25 (t, J =
3.5 Hz, 1 H), 4.29–4.24 (ddd, J = 11.9, 5.2, 0.8 Hz, 1 H), 3.55–3.49
(t, J = 11.3 Hz, 1 H), 2.82–2.78 (br, 1 H), 2.34–2.30 (m, 1 H), 1.90–
1.82 (ddd, J = 14.0, 12.0, 4.1 Hz, 1 H), 1.25–1.23 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (100.62 MHz, CDCl3, 25 °C): δ = 153.52,
142.25, 133.77, 122.44, 122.37, 119.19, 109.38, 61.14, 49.20, 37.58,
23.94, 18.71 ppm. MS: m/z = 201.11 [M]+.
1
Isomer syn-(S,R)-(3): H NMR (400.16 MHz, CDCl3, 25 °C): δ =
7.77–7.75 (m, 1 H), 7.35–7.25 (m, 3 H), 5.98 (br, 1 H), 5.08 (dd, J
= 11.0, 6.3 Hz, 1 H), 4.21–4.16 (ddd, J = 11.4, 5.2, 1.1 Hz, 1 H),
3.56–3.50 (t, J = 11.4 Hz, 1 H), 2.51–2.46 (m, 1 H), 2.36–2.29 (m,
1 H), 1.81–1.72 (dt, J = 12.6, 11.2 Hz, 1 H), 1.27–1.25 (d, J =
6.7 Hz, 3 H) ppm. 13C NMR (100.62 MHz, CDCl3, 25 °C): δ =
155.22, 142.64, 133.93, 122.44, 122.37, 119.19, 109.38, 63.98, 49.07,
38.65, 28.01, 18.89 ppm. MS: m/z = 201.11 [M]+. C12H14N2O
(202.25): calcd. C 71.26, H 6.98, N 13.85; found C 72.93, H 7.48,
N 13.13.
1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-4-ol (6): To
a
mixture of [Rh(acac)(CO)2] (5.4 mg, 2.1ϫ10–2 mmol, 1.0 equiv.)
and Xantphos (48.8 mg, 8.4ϫ10–2 mmol, 4 equiv.) was added tolu-
ene (13 mL). The reaction mixture was stirred for 15 min and trans-
ferred to a 75-mL stainless steel autoclave also equipped with a
dropping funnel. A mixture of 4 (5.0 g, 31.6 mmol, 1500 equiv.) and
toluene (4 mL) was added to the dropping funnel and the catalyst
solution was preformed at 140 °C and 20 bar (CO/H2) for 2 h. Af-
ter preformation, the substrate solution was added to the catalyst
solution by using the dropping funnel, which initiated the start of
the reaction. After 72 h, the autoclave was cooled and the pressure
was released. The reaction mixture was purified by flash column
chromatography (silica; n-hexane/EtOAc, 1:1, followed by MeOH)
to give the crude product mixture. Crystallization from a minimal
amount of toluene gave the 6 (2.26 g, 12.0 mmol, 38%) as colorless
crystals or as a white powder, m.p. 172 °C. 1H NMR (400.16 MHz,
CDCl3, 25 °C): δ = 2.04–2.14 (m, 1 H, CH2 next to chiral carbon),
2.16–2.32 (m, 2 H, CH2), 2.42–2.52 (m, 1 H, CH2 next to chiral
carbon), 3.99–4.16 (m, 2 H, CH2N), 5.17 (t, J = 5.6 Hz, 1 H, H on
the chiral carbon atom), 7.24–7.33 (m, 3 H), 7.49 (br. s, 1 H, –OH,
X-ray Crystal Structure Determination: X-ray intensities were mea-
sured with a Nonius KappaCCD diffractometer with a rotating
anode (compound 3) or with a Bruker Kappa ApexII dif-
fractometer with sealed tube (compound 8) at a temperature of
150(2) K. The intensities were integrated by using Eval15[22] (com-
pound 3) or Saint[23] (compound 8). Absorption correction and
scaling was performed with SADABS.[24] The structures were
solved by Direct Methods with the program SHELXS-97.[25] Least-
squares refinement was performed with SHELXL-97[25] against F2
of all reflections. Non-hydrogen atoms were refined with aniso-
tropic displacement parameters. All hydrogen atoms were located
in difference Fourier maps. The OH hydrogen atom in 3 was refined
freely with an isotropic displacement parameter, all other hydrogen
atoms were refined by using a riding model. Geometry calculations
and checking for higher symmetry was performed with the PLA-
TON program.[26]
position may vary), 7.73–7.78 (m,
1
H) ppm. 13C NMR
CCDC-948396 (for 3) and -948397 (for 8) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(100.63 MHz, CDCl3, 25 °C): δ = 18.99, 29.57, 42.51, 62.30, 109.46,
119.09, 122.47 (2C), 133.96, 142.04, 154.45 ppm. C11H12N2O
(188.23): C 70.19, H 6.43, N 14.88; found C 69.00, H 6.60, N 14.90.
Compound 3: C12H14N2O; Fw
0.42ϫ0.24ϫ0.12 mm ; triclinic; P1 (no. 2); a = 6.39757(16), b =
=
202.25; colorless plate;
4-[(Diphenylphosphanyl)oxy]-1,2,3,4-tetrahydrobenzimidazo[1,2-a]-
pyridine (7): A mixture of 6 (513.8 mg, 2.73 mmol, 1.0 equiv.), tri-
3
¯
Eur. J. Org. Chem. 2014, 350–362
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359

C. Müller et al.
ethylamine (690.5 mg, 6.83 mmol, 2.5 equiv.) and dichloromethane (R)-1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-4-yl Butyrate
FULL PAPER
1
(10 mL) under an argon atmosphere was cooled to –78 °C and sub-
sequently chlorodiphenylphosphine (602.2 mg, 2.73 mmol,
(11): M.p. 63 °C. H NMR (400.16 MHz, CDCl3, 25 °C): δ = 0.77
(t, J = 7.4 Hz, 3 H), 1.49 (q, J = 7.2 Hz, 2 H), 1.79–1.89 (m, 1 H),
1.91–1.98 (m, 2 H), 2.00–2.10 (m, 1 H), 2.16 (dt, J = 7.4, 2.9 Hz,
2 H), 2.62–2.72 (m, 1 H), 3.84–3.92 (m, 1 H), 5.98 (t, J = 4.7 Hz,
1 H), 7.00–7.10 (m, 3 H), 7.56–7.62 (m, 1 H) ppm. 13C NMR
(100.62 MHz, CDCl3, 25 °C): δ = 13.14, 17.87, 18.05, 26.70, 35.62,
41.73, 64.39, 109.01, 119.35, 122.09, 122.32, 133.64, 142.06, 147.86,
1.0 equiv.) in dichloromethane (3 mL) was added dropwise. The
mixture was warmed to room temperature overnight, then all vola-
tiles were removed in vacuo. The crude reaction mixture was redis-
solved in toluene and the triethylammonium chloride was filtered
off, washed with toluene and concentrated to give 7 (911.5 mg,
2.45 mmol, 90%) as a white solid. 1H NMR (400.16 MHz, CDCl3, 171.78 ppm. C15H18N2O2 (258.32): C 69.74, H 7.02, N 10.84; found
25 °C): δ = 1.99–2.12 (m, 2 H), 2.29–2.51 (m, 2 H), 3.89–4.26 (m,
2 H, CH2N), 5.35–5.39 (m, 1 H, H on the chiral carbon atom),
7.14–7.60 (m, 11 H), 7.56–7.60 (m, 2 H), 7.79–7.83 (m, 1 H) ppm.
13C NMR (100.62 MHz, CDCl3, 25 °C): δ = 18.07, 29.25, 29.30,
42.43, 42.61, 71.44, 71.67, 119.83, 122.14, 122.43, 127.99, 128.06,
128.25, 128.32, 128.85, 129.42, 129.81, 130.02, 130.39, 130.62,
142.08, 142.25, 142.51, 142.70, 142.90, 150.24, 150.31 ppm. 31P
NMR (161.98 MHz, CDCl3, 25 °C): δ = 114.6 ppm. C23H21N2OP
(372.40): C 74.18, H 5.68, N 7.52; found C 73.77, H 5.67, N 7.27.
C 69.73, H 7.03, N 10.83.
Deprotection of (R)-11: A solution of (R)-11 (605.4 mg, 2.3 mmol,
1.0 equiv.) and K2CO3 (3.21 g, 23.2 mmol, 10.0 equiv.) in MeOH/
H2O (20 mL, 4:1) was stirred for 20 h at room temperature. The
crude alcohol was filtered through a short pad of silica, washed
with MeOH, and subsequently dried with MgSO4, filtered, and
concentrated to give alcohol (R)-6 (397.0 mg, 2.11 mmol, 92%) as
a white solid (96% ee). The enantiomeric excess of the alcohol was
determined by chiral HPLC analysis.
[(4)Rh(CO)Cl] (8):
1.0 equiv.) in CH2Cl2 (4 mL) was added dropwise under argon to
solution of μ-dichlorotetracarbonyldirhodium (13.0 mg,
A solution of 7 (25.0 mg, 0.067 mmol,
HPLC Analysis: HPLC analysis and fraction collection were per-
formed with a Shimadzu LC-20AD pump, a Shimadzu SPD-20A
prominence UV/Vis detector, a Shimadzu SIL-20A HT prominence
autosampler, and a CTO-20AC prominence column oven. Column
and analysis specifications for the one-pot tandem hydrofor-
mylation–cyclization sequence: Chiralcel OJ-H (250ϫ4.6 mm, par-
ticle size: 5 μm, purchased from Daicel), eluent: n-hexane/2-prop-
anol (98:2), column temperature: 25 °C, flow rate: 1.0 mL/min, p =
39 bar, λ = 254 nm (UV detector), injection volume: 20 μL. Col-
umn and analysis specifications for the enzymatic kinetic resolu-
tion: Chiralpak IC (250ϫ4.6 mm, particle size: 5 μm, purchased
from Daicel), eluent: n-heptane/CH2Cl2/EtOH/diethylamine
(75:25:3:0.1), column temperature: 25 °C, flow rate: 1.0 mL/min, p
= 28 bar, λ = 254 nm (UV detector), injection volume: 5 μL. Col-
umn and analysis specifications for the iridium-catalyzed hydrogen-
ation reactions: Chiralcel OJ-H (250ϫ4.6 mm, particle size: 5 μm,
purchased from Daicel), eluent: n-hexane/2-propanol (99:1), col-
umn temperature: 25 °C, flow rate: 1.0 mL/min, p = 37 bar, λ =
254 nm (UV detector), injection volume: 3 μL.
a
0.034 mmol, 0.5 equiv.) in CH2Cl2 (4 mL). Upon addition the solu-
tion became bright-yellow and CO formation was observed. The
mixture was stirred for 1 h at r.t., then all volatiles were removed
in vacuo to give complex 8 (36.1 mg, 0.067 mmol, quant.) as a yel-
low solid. 1H NMR (400.16 Hz, CD2Cl2, 25 °C): δ = 2.03–2.15 (m,
2 H), 2.26–2.35 (m, 1 H), 2.46–2.57 (m, 1 H), 3.98–4.37 (m, 2 H),
5.30–5.32 (t, J = 3.6 Hz, 1 H), 7.43–7.53 (m, 11 H), 7.69–7.82 (m,
2 H), 7.99–8.01 (m, 1 H) ppm. 13C NMR (100.62 MHz, CD2Cl2,
25 °C): δ = 20.04, 28.39, 28.48, 43.31, 70.83, 110.59, 121.86, 124.09,
124.80, 128.74 (d, J = 11.7 Hz), 128.92 (d, J = 11.1 Hz), 131.58,
131.72, 131.85 (d, J = 1.8 Hz), 132.29, 132.44, 133.70, 135.84,
136.46, 138.03 (d, J = 4.6 Hz), 138.60 (d, J = 4.6 Hz), 140.12,
1
2
149.67 (d, J = 7.1 Hz), 189.04 (dd, JRh,C = 72.3 Hz, JP,C
=
17.5 Hz, CO) ppm. 31P NMR (161.98 MHz, CD2Cl2, 25 °C): δ =
132.76 (d, JRh,P = 178.2 Hz). IR (KBr): ν = 1992.12 cm–1.
1
˜
N-Phenyl(1-phenylethylidene)amine (9): To molecular sieves (4 Å,
50 g) under argon was added toluene (60 mL), acetophenone
(12.0 g, 100.0 mmol, 1.0 equiv.) and aniline (11.20 g, 120.0 mmol,
1.2 equiv.). The reaction mixture was heated to reflux for 48 h and
subsequently cooled to room temperature. The molecular sieves
were filtered off and all volatiles were removed on a rotavap and
the residual liquid was distilled under high vacuum (b.p. 125 °C/
0.04 mbar) affording 9 (17.11 g, 87.6 mmol, 88%) as a pale-yellow
CD Analysis: CD spectroscopic measurements were performed at
25 °C with a Jasco J-815 spectropolarimeter. Appropriate settings
were chosen for the sensitivity, time constant, and scan rate, and
10.00 mm cuvettes were used. Racemate 6 (10.0 mg, 5.3ϫ10–5 mol)
was dissolved in a mixture of n-heptane/CH2Cl2/EtOH/dieth-
ylamine (75:25:3:0.1, 1.5 mL) prior to HPLC separation. Enantio-
mers 6-E1 and 6-E2 were eluted [eluent: n-heptane/CH2Cl2/EtOH/
diethylamine (75:25:3:0.1)], collected and all volatiles were removed
in vacuo. This procedure was performed five times and the com-
bined residues of 6-E1 and 6-E2 were each redissolved in
ClCH2CH2Cl (1.5 mL) and diluted to give final concentrations of
approximately 10–6 M. The CD spectra were recorded immediately.
1
solid, m.p. 39 °C. H NMR (400.16 MHz, CDCl3, 25 °C): δ = 2.24
(s, 3 H), 6.78–6.83 (m, 2 H), 7.06–7.12 (m, 1 H), 7.33–7.38 (m, 2
H), 7.42–7.48 (m, 3 H), 7.95–8.01 (m, 2 H) ppm. 13C NMR
(100.62 MHz, CDCl3, 25 °C): δ = 17.47, 119.47 (2C), 123.31,
127.27 (2C), 128.47 (2C), 129.05 (2C), 130.55, 139.58, 151.79,
165.55 ppm.
General Procedure for the Enzymatic Kinetic Resolution of 6: A mix-
Computational Details: Quantum chemical calculations were car-
ture of Novozym 435 (482.5 mg, 25 w/w-%) and
6 (1.93 g, ried out by using Density Functional Theory (DFT) with the
10.25 mmol, 1 equiv.) in toluene (29 mL) was heated to 50 °C. Sub-
sequently, vinyl butyrate (1.23 g, 10.77 mmol, 1.05 equiv.) was
added dropwise and the mixture was stirred for 23 h. When the
reaction was complete, the enzyme beads were filtered off and all
volatiles were removed in vacuo. The ester was separated from the
unreacted alcohol by column chromatography (silica; n-hexane/
EtOAc, 1:1) to give ester (R)-11 (916.7 mg, 3.55 mmol, 35%) as a
white solid. The unreacted alcohol was washed from the column
with pure MeOH to give alcohol (S)-6 (417.9 mg, 2.22 mmol, 22%)
as a white solid (Ͼ 99% ee). The enantiomeric excess of the alcohol
was determined by chiral HPLC analysis.
Gaussian 09 suite of programs.[27] All calculations were performed
at the B3LYP/6-311G+(d,p) level of theory. Full geometry optimi-
zations were done for compounds (R)-6 and (S)-6. The nature of
the stationary points was tested by analyzing the analytically calcu-
lated harmonic normal modes. All structures were confirmed to
contain no imaginary frequencies. Theoretical CD spectra were cal-
culated by using the time-dependent DFT (TD-DFT) method as
implemented in the Gaussian 09 program.[27] The number of states
included in the TD-DFT calculations was set to 50. The CD spec-
tra were simulated by overlapping Gaussian functions for each
transition; the width of the band at half height was fixed at 0.8 eV.
360
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 350–362

Enantioselective Iridium-Catalyzed Hydrogenations
General Procedure for the Hydrogenation Experiments in a Stainless
hexane/2-propanol (99:1), tS = 6.3 min, tR = 8.5 min, tsubstrate =
Steel Autoclave (75 mL):
A
solution of 12 (11.7 mg,
13.7 min.
3.2ϫ10–2 mmol, 1.05 equiv.) in CH2Cl2 (3.0 mL) was added drop-
wise at room temperature to a solution of [Ir(cod)2]BArF (38.2 mg,
3.0ϫ10–2 mmol, 1.0 equiv.) in CH2Cl2 (3.0 mL), stirred for over-
night and subsequently transferred to the 75-mL stainless steel au-
toclave. A solution of substrate 9 or 10 (3.0 mmol, 100 equiv.) in
CH2Cl2 (6 mL) was added and the autoclave was sealed and filled
with hydrogen gas. When the reaction was complete, excess H2 pres-
sure was released, the reaction mixture was filtered through a short
pad of silica, and all volatiles were removed in vacuo. The conver-
Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C, and 31P NMR spectra, IR spectra, HPLC traces from
catalytic experiments.
Acknowledgments
The authors would like to thank Ing. Ton Staring (TU/e, Labora-
tory for Catalysis and Organometallic Chemistry) for technical as-
sistance with the HPLC equipment. Dr. Anja Palmans (TU/e, de-
partment of Macromolecular and Organic Chemistry) is kindly ac-
knowledged for a generous gift of Novozym 435. C. M. thanks The
Netherlands Organization for Scientific Research (NWO-CW) for
a personal grant (NWO Vidi and NWO Echo). The X-ray dif-
fractometers were financed by NWO-CW.
1
sions were determined by H NMR analysis and the enantiomeric
excess was determined by chiral HPLC: For the hydrogenation
product of N-phenyl-(1-phenylethylidene)amine[28] (9a): Chiralcel
OJ-H, n-hexane/2-propanol (99:1), tR = 31.7 min, tS = 40.7 min,
tsubstrate = 36.3 min. The absolute configuration was determined by
comparison of the optical rotation with literature.[5a] For the hydro-
genation product of trans-α-methylstilbene (10a): Chiral HPLC:[29]
Chiralcel OJ-H, n-hexane/2-propanol (99:1), tS = 6.3 min, tR
=
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obtained from hydrogenation of trans-α-methylstilbene with a
known catalyst.[5b]
Reaction in an AMTEC Slurry-Phase Reactor SPR16 Parallel Reac-
tor System: Catalysis experiments were performed in a parallel au-
toclave system AMTEC SPR16,[30] equipped with pressure sensors
and a mass-flow controller suitable for monitoring and recording
gas uptakes throughout the reaction.
General Procedure for the Catalysis Experiments: A stainless steel
autoclave of the AMTEC SPR16 was heated to 90 °C and flushed
with argon (15 bar) four times. Subsequently, the reactor was co-
oled to room temperature and flushing with argon was repeated
again four times. The reactor was charged with a solution of the
precatalyst in CH2Cl2 (4 mL, see below) as well as the substrate
solution under argon (CH2Cl2, 4 mL, see below). The atmosphere
was further exchanged with hydrogen gas and the reactor was pres-
surized with hydrogen to 3 bar. After heating to the desired tem-
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throughout the experiment. The gas uptake of hydrogen was moni-
tored and recorded automatically. At the end of the catalysis ex-
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contents of the autoclave was filtered through a short pad of silica,
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1
all volatiles were removed in vacuo, and analyzed by means of H
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7 (7.8 mg, 2.1ϫ10–2 mmol, 1.05 equiv.) in CH2Cl2 (2.0 mL) was
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stirred for 2 h and subsequently transferred to the 15 mL stainless
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Hydrogenation Product of N-Phenyl-(1-phenylethylidene)amine[28]
(9a): 1H NMR (400.16 MHz, CDCl3, 25 °C): δ = 1.54 (d, J =
6.8 Hz, 3 H), 4.24 (br. s, 1 H), 4.50 (q, J = 6.8 Hz, 1 H), 6.51–6.57
(m, 2 H), 6.66 (tt, J = 7.4, 1.0 Hz, 1 H), 7.08–7.10 (m, 2 H), 7.21–
7.26 (m, 1 H), 7.30–7.35 (m, 2 H), 7.36–7.40 (m, 2 H) ppm; HPLC:
Chiralcel OJ-H, n-hexane/2-propanol (99:1), tR = 31.7 min, tS
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=
Hydrogenation Product of trans-α-Methylstilbene (10a): 1H NMR
(400.16 MHz, CDCl3, 25 °C): δ = 1.26–1.24 (d, J = 6.8 Hz, 3 H),
2.15–2.80 (m, 1 H), 2.93–3.05 (m, 2 H), 7.08–7.10 (d, J = 7.2 Hz,
2 H), 7.17–7.30 (m, 8 H) ppm; Chiral HPLC:[29] Chiralcel OJ-H, n-
Eur. J. Org. Chem. 2014, 350–362
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: August 19, 2013
Published Online: November 19, 2013
362
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 350–362