Unsymmetrical Iron P-NH-P′ Catalysts for the Asymmetric Pressure Hydrogenation of Aryl Ketones

Article abstract of DOI:10.1002/chem.201701254

The reductive amination of α-dialkylphosphine acetaldehydes with enantiopure β-aminophosphines is a new, versatile route to unsymmetrical tridentate (pincer) ligands P-NH-P′. Four new ligands PR₂CH₂CH₂NHCHR′CHR′′PPh₂ (R=iPr, Cy, R′=Ph, CH(CH₃)₂, R′′=Ph, H) prepared in this way are used to make the iron(II) complexes mer-FeCl₂(CO)(P-NH-P′) and mer-FeCl(H)(CO)(P-NH-P′). The hydride complex with the rigid ligand with R′=R′′=Ph is an efficient and highly enantioselective homogeneous asymmetric pressure hydrogenation (APH) catalyst. Prochiral aryl ketones are reduced under mild conditions (THF, 0.1 mol % catalyst, 1 mol % KOtBu, 5–10 bar, 50 °C) to the (S)-alcohols, usually in enantiomeric excess (ee) greater than 90 %. DFT calculations provided transition-state structures for the enantiodetermining hydride-transfer step.

Full text of DOI:10.1002/chem.201701254

A Journal of
Accepted Article
Title: Unsymmetrical iron P-NH-P' catalysts for the asymmetric
pressure hydrogenation of aryl ketones
Authors: Robert Harold Morris, Samantha Alizabeth Michelle Smith,
Paraskevi Olympia Lagaditis, Alan J. Lough, and Anne Lüpke
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To be cited as: Chem. Eur. J. 10.1002/chem.201701254
Link to VoR: http://dx.doi.org/10.1002/chem.201701254
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Unsymmetrical Iron P-NH-P’ Catalysts for the Asymmetric
Pressure Hydrogenation of Aryl Ketones
Samantha A. M. Smith[+][a] Paraskevi O. Lagaditis[+][a], Anne Lüpke[b], Alan J, Lough[a], Robert H.
Morris*[a]
Celebrating 100 years of CSC conferences in Canada and 150 years of the GDCh in Germany.
Abstract: The reductive amination of -dialkylphosphine
acetaldehydes with enantiopure -aminophosphines is new,
and selectivity for the APH of ketones[7] but more promising results for
the APH of imines.[8]
a
versatile route to unsymmetrical tridentate (pincer) ligands P-NH-P’.
Four new ligands PR2CH2CH2NHCHR’CHR’’PPh2 (R = iPr, Cy, R’ =
Ph, CH(CH3)2, R’’ = Ph, H) prepared in this way are used to make the
iron(II) complexes mer-FeCl2(CO)(P-NH-P’) and mer-FeCl(H)(CO)(P-
NH-P’). The hydride complex with the rigid ligand with R’= R’’= Ph is
an efficient and highly enantioselective homogeneous asymmetric
pressure hydrogenation (APH) catalyst. Prochiral aryl ketones are
reduced under mild conditions (THF, 0.1 mol% catalyst, 1 mol%
KOtBu, 5-10 bar, 50 ºC) to the (S)-alcohols, usually in enantiomeric
excess (e.e.) greater than 90%. DFT calculations provide transition
state structures for the enantiodetermining hydride transfer step.
Pincer iron complexes Fe(CO)X(Y)(PNP) (A, Figure 1), X, Y
halide, hydride, borohydride, PNP achiral ligand with
=
trialkylphosphine and pyridyl donors, have excellent activity for
the pressure hydrogenation of ketones as discovered by Milstein
and coworkers.[9] Similar complexes with achiral PNP ligands with
trialkylphosphine and secondary amine donors (B) were shown
by several groups to efficiently catalyze other hydrogenation and
dehydrogenation applications.[10]
Our group reported the first such pincer complex (C) with an
enantiopure ligand as a precursor for the APH of ketones to
alcohols with e.e. up to 89% and an imine to amine in 90% e.e.[11]
The mixed phosphine imine-type PNP’ ligand of C, which forms in
an iron-templated reaction, requires LiAlH4 reduction while on the
metal to produce the N-H functionality required for ketone
activation and enantioselectivity.[12] Some decomposition
products were identified in this reaction including undesired
The homogeneous asymmetric pressure hydrogenation of prochiral
ketones provides an efficient route to valuable non-racemic
alcohols.[1] While the best catalysts are based on ruthenium, osmium
and iridium,[2] more sustainable iron-based systems show much
promise.[3] The most enantioselective reductions to date (over 95% e.e.
in the alcohol product) were reported by the Gao group who used a
mixture of Fe3(CO)12 and an enantiopure 22-membered –PNNPNN-
macrocycle to catalyze the complete reduction of several aryl
ketones.[4] Our group reported the first well defined Fe(II) precatalysts
for the APH of ketones, trans-[Fe(L)(CO)(PNNP)]n+ containing
enantiopure PNNP ligands but the e.e. and activity were low to
moderate;[5] such complexes are excellent for the asymmetric transfer
hydrogenation (ATH) of ketones[6] but cause a reduction in e.e. of the
product alcohol at reaching the conversion determined by the
equilibrium. An advantage of the irreversibility of the APH process is
that complete conversion can be obtained with no degradation in the
Fe(CO)2(PNP’) complexes as a consequence of the dicarbonyl
13]
precursor structure..[11,
Thus a monocarbonyl precursor
complex was targeted. We also found that ligands forming five
membered rings –Fe-NH-C-C-PR2 form more active complexes
than those that form 6-membered rings and that R = alkyl may
provide more active catalysts than R = aryl.[13] Zirakzadeh et al.
have recently described the synthesis of similar complexes with
enantiopure ferrocenylphosphine ligands; e.e. up to 81% were
observed for the APH of aryl ketones.[14] Kirchner’s group has also
prepared chiral iron complexes with unsymmetrical PNP’ ligands
for the hydrogenation of ketones but no e.e. was reported.[15]
Based on these developments, we targeted the synthesis of a
new family of chiral pincer ligands and their iron APH catalysts as
described here.
e.e. of the alcohol.
Iron complexes with functionalized
cyclopentadienyl and chiral ligands have so far displayed low activity
[a]
S. A. M. Smith[+], Dr. P. O. Lagaditis[+], Dr. A. J. Lough, Prof. R. H.
Morris
Department of Chemistry
University of Toronto
80 Saint George St., Toronto, Ontario, Canada M5S3H6
E-mail: rmorris@chem.utoronto.ca
A. Lüpke
[b]
[+]
Department of Chemistry
Johannes Gutenberg University, Mainz
Saarstraße 21, 55122, Mainz, Germany
These authors contributed equally.
Figure 1. Iron hydrogenation and dehydrogenation catalysts with pincer ligands.
Supporting information for this article is given via a link at the end of
the document. CCDC 1525651 (S-7), 1538240 (S-8) and 1525652
(S-10) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
Reductive amination has proven to be a successful method for the
synthesis of the new ligands 1 to 4 (Scheme 1).
www.ccdc.cam.ac.uk/data_request/cif.
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Scheme 1. Synthesis of new chiral P-NH-P’ ligands.
Two equivalents of the hydride reagent are added, the first to release
the -diisopropylphosphine acetaldehyde by deprotonation of the
phosphonium dimer,[16] and the second to reduce the imine formed by
the condensation of this aldehyde with the primary amino group of the
-aminophosphine. Normally this method would yield tertiary amine
products;[17] however we find that the substituent α to the amine of the
starting material lends enough steric bulk to protect the secondary
amine from further reaction. Due to the availability of a range of
enantiopure -aminophosphines[18] and our air- and moisture-stable
phosphonium dimers,[19] a large variety of these ligands can be
synthesized in this manner. The characterization of ligands 1-4 is
discussed in the Supporting Information.
Figure 2. Structure of (S)-7 (molecule A) with thermal ellipsoids set at 30%
probability. Selected bond lengths [Å] and angles [°]: Fe1-P1 2.279(1), Fe1-P2
2.254(1), Fe1-Cl1 2.329(1), Fe1-Cl2 2.316(1), Fe1-C29 1.757(5), Fe1-N1
2.081(4), N1-H 0.86(4), C29-O1 1.129(5); N1-Fe1-P1 85.2(1), N1-Fe1-P2
84.7(1), P2-Fe1-P1 169.99(5), Cl2-Fe1-Cl1 171.02(5), C29-Fe1-N1 177.8(2).
Ligands 1-4 were stirred with anhydrous iron dichloride in
tetrahydrofuran (THF) under CO gas to yield the complexes (S,S)-5,
(S,S)-6, (S)-7, and (S)-8 in high yields as purple solids (Scheme 2).
They are synthesized as a single trans-dichloro isomer as signalled
by a characteristic set of doublets with a large 2JPP coupling constant
(177 Hz) in the 31P{1H} NMR spectra. The crystal structures of (S)-7
(Figure 2) and (S)-8 (Supporting Information) shows that they have
the expected mer configuration with the C-H on the chiral carbon anti
with respect to the N-H group. A very similar structure with the
symmetrical (PiPr2CH2CH2)2NH ligand has been reported.[20]
The monohydride complexes are prepared by treating the dichloro
complexes with Superhydride (LiHBEt3) at -30° (Scheme 3). (S,S)-9
exists as predominantly (87%) one isomer in solution, with
characteristic 31P{1H} spectra displaying two doublets with a large
coupling constant 2JPP (138 Hz), again suggesting a mer configuration
of the complex. The major isomer has an associated doublet of
doublet pattern in the hydride region of the 1H NMR spectrum with a
chemical shift of -21.5 ppm. Minor amounts of two other isomers are
present (see SI). Complex (S,S)-6 was reacted with Superhydride,
however the reaction produced a mixture of free ligand and several
unidentified phosphorus-containing species. The spectra of (S)-10 are
complex because of the presence of four isomers with doublet of
doublet or triplet hydride resonances at -20.47 ppm (5%), -20.96
(22%), -21.40 (31%) and -22.05 ppm (42%). Clearly the extra phenyl
group in (S,S)-9 is needed to restrict the number of diastereomers.
One of the isomers of (S)-10 has been crystallographically
characterized as shown in Figure 3. The N-H and Fe-H bonds are
almost parallel with a dihedral angle H-N1-Fe1-H of 7.0°. In the crystal
structure with the symmetrical (PiPr2CH2CH2)2NH ligand, the N-H is
found instead parallel to the Fe-Cl unit.[20] The synthesis of (S)-11 was
not selective with a mixture of up to six hydride complexes shown in
the 1H NMR spectrum. This complex was not tested due to the
complicated mixture of isomers.
Scheme 2. Synthesis of Fe(Cl)2(CO)(P-NH-P’) complexes.
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Scheme 4. The APH of ketones
Table 1. Results of ketone APH as in Scheme 4 with catalyst (S,S)-9.[a]
Scheme 3. Synthesis of iron chloro(hydrido) complexes.
Entry
R
R’
Conversion
(%)[b]
Time
(min)
e.e.
(S)
(%)[b]
1
2
3
4
5
CH3
CH2CH3
CH3
H
H
>99
>99
>99
38
90
120
90
95
96
93
62
86
o-Cl
H
C6H11
CH3
90
m-
8
60
(CF3)2
6
7
CH3
CH3
p-Cl
>99
>99
60
60
90
94
p-CH3
[a] reaction conditions for (S,S)-9: 10 bar H2, 0.1 mol% catalyst, 1
mol% KOtBu, 50 °C, 10 mL THF; [b] conversion and e.e.
determined by chiral GC.
Figure 3 Crystal structure of (S)-10. Selected bond lengths [Å] and angles [°]:
Fe1-H 1.40(4), Fe1-C29 1.717(4), Fe1-N1 2.093(3), Fe1-P2 2.189(1), Fe1-P1
2.218(1), Fe1-Cl1 2.4116(1), O1-C29 1.164(5), N1-H 0.90(6); N1-Fe1-P1
85.8(1), N1-Fe1-P2 83.7(1), H-Fe1-N1 84.1(16), C29-Fe1-N1 171.89(2), P2-
Fe1-P1 164.79(5), H-Fe1-Cl1 170(1), C29-Fe1-Cl1 100.1(2), N1-Fe1-Cl1
87.7(1).
The APH of acetophenone (entry 1, Table 1) using (S,S)-9 produced
(S)-1-phenylethanol in much higher e.e. (95%) than our previously
reported system based on catalyst C (89%);[11] Gao’s system gave
97% e.e. but at longer reaction times, higher pressure, higher catalyst
and base loading. Similar results are obtained when acetophenone
is hydrogenated using (S,S)-9 with 5 bar H2. The hydrogenation of
propiophenone (entry 2) took longer than the standard 90 min.
reaction, but resulted in quantitative conversion at 120 min. with 96%
e.e. (S). The ortho-chloro substituted ketone (entry 3) is considered a
challenging substrate for asymmetric reduction [21] but it is efficiently
and selectively reduced by this catalyst system. The product, (S)-1-
The chloro(hydrido) complexes (S,S)-9 and (S)-10 were tested as
catalysts for the APH of selected ketones in THF in the presence of
base (Scheme 4). These systems were found to be very active under
the conditions of 10 bar of H2, 50° C, of ketone: catalyst: KOtBu =
1000:1:10; oxygen must be rigorously excluded in the preparation of
the catalyst solution and its injection into the purged pressure reactor.
The complex (S)-10 containing one substituent on the backbone of
the ligand when tested for the APH of acetophenone gave low to
moderate enantioselectivity depending on the reaction conditions (50-
80%). Fortunately (S,S)-9 with two phenyl groups on the backbone
yields excellent results, quantitatively reducing a variety of ketones to
the (S)-alcohols in high e.e. (Table 1, Figure 4). The second phenyl
substituent on the ligand backbone of this complex is clearly important
to lock the PPh2 group into a rigid, asymmetric structure; the complex
C (Figure 1) also has this feature, and both (S,S)-9 and C have similar
activity and are much more enantioselective than (S)-10 and other
complexes that just have one substituent next to the NH. [13]
(2-chlorophenyl)ethanol, has been identified as
a key chiral
intermediate in the synthesis of a new class of chemotherapeutic
drugs.[22] Cyclohexyl phenyl ketone (entry 4) proved to be a difficult
substrate to reduce, with less than 40% conversion and low e.e. The
APH of 3’,5’-bis(trifluoromethyl)acetophenone (entry 5) resulted in a
very low conversion, possibly because the acidic alcohol product
deactivates the catalyst. Para-methylacetophenone (entry 7) is
reduced with somewhat higher enantioselectivity (94% (S)) than para-
chloroacetophenone (90%, entry 6). This suggests that the
enantioselectivity can be influenced by the electronics of the ketone
substrate, perhaps by affecting the strength of the NH-O(ketone)
hydrogen bond which orients the ketone in the hydride transfer
step.[12]
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Figure 5. The transition state structure of the transfer of a hydride from the
dihydride of the (S,S)-9 system to acetophenone to give the (S) alcohol.
Hydrogens on the ketone and on the ligand other than the NH have been
deleted for clarity.
Figure 4. Other ketones reduced by the (S,S)-9 system (except 16).
The difference in position of the acetyl functionality in
acetylnaphthone substrates 12 and 13 affected the number of
turnovers in 90 min., 1000 TON for 12 vs 610 for 13, while both were
reduced in high e.e. (R)-1-(1-naphthyl)ethanol has been used to
desymmetrize prochiral 3-substituted glutaric anhydrides, giving the
chiral building blocks for (+)-compactin, an HMG-CoA-reductase
inhibitor.[23] 2-Acetylfuran (14) was reduced quantitatively to the
alcohol with 95% e.e. (S). This chiral product can be used for the
synthesis of macrosphelide B, shown to be a strong inhibitor for the
adhesion of human leukemia HL-60 cells to human umbilical-vein
cells.[24] 3-Methylbutan-2-one (15), a challenging aliphatic ketone, was
successfully reduced quantitatively but with low enantioselectivity,
and surprisingly, with the (R)-alcohol in excess. Oddly the very similar
system with catalyst C provided the (S)-alcohol in 46% e.e.[11] The
even more challenging 3,3-dimethylbutan-2-one (16) proved to be too
sterically crowded for (S,S)-9 to reduce. Further exploration of the
activity and enantioselectivity of (S,S)-9 is currently in progress.
In conclusion, a new method of ligand synthesis has been
successfully utilized to produce four new iron dichloride complexes
and four new iron hydride complexes, one of which shows great
promise for the enantioselective reduction of ketones. The use of the
well defined precatalyst (S,S)-9 allows the quantitative APH of a
variety of ketones to enantiomerically enriched alcohols in up to 96%
e.e. Ortho-chloroacetophenone, 1-acetylnaphthone, and 2-
acetylfuran have been reduced quantitatively with high
enantioselectivities to alcohols of interest to the pharmaceutical
industry. We have disclosed a versatile method that allows the
synthesis of a wide range of catalyst structures, a flexibility often
needed when matching the catalyst with the substrate to attain high
levels of enantioselection.
Previous work has provided strong evidence for
a mer
Experimental Section
FeH2(CO)L structure with trans dihydrides, where L is a P-NH-P ligand,
as the active catalyst that transfers a hydride to the ketone.[10b, 10e, 10g,
12c]
See the Supporting Information.
The transition state structure producing (S)-1-phenylethanol by
attack of a hydride in trans-FeH2(CO)((S,S)-1) on acetophenone was
calculated using DFT (Figure 5) and found to be 1.6 kcal/mol lower in
energy than that producing the (R) alcohol (Supporting information).
In this structure the phenyl group of the ketone lies over the isopropyl
groups while the smaller methyl group is against a phenyl of the PPh2,
that is locked into position by the adjacent asymmetric array of phenyl
groups which also lock the five-membered -PCHPhCHPhNHFe- ring
by taking the favourable equatorial positions.
Acknowledgements
R.H.M. thanks NSERC Canada for a Discovery grant and the
Canada Council for the Arts for a Killam Fellowship. This work
was also made possible by the SCICOMP NMR facilities provided
by the Canada Foundation for Innovation, project number 19119,
and the Ontario Ministry of Research, Innovation and Science.
The Deutscher Akademischer Austauschdienst (DAAD) is
thanked for support for A.P. Calculations were performed using
the facilities of SHARCNET and Scinet of Compute/Calcul
Canada.
Keywords: Homogeneous hydrogenation • asymmetric
synthesis • iron catalysts • ketone reduction • pincer ligand
synthesis
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10.1002/chem.201701254
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
Highly enantioselective and active
iron catalyst. The reductive
Samantha A. M. Smith, Paraskevi O.
Lagaditis, Anne Lüpke, Alan J, Lough,
Robert H. Morris*
amination of -dialkylphosphine
acetaldehydes with enantiopure -
aminophosphines is a new, versatile
route to unsymmetrical tridentate
(pincer) ligands P-NH-P’. Several
prochiral aryl ketones are reduced to
the (S)-alcohols, usually in e.e.
Page No. – Page No.
Unsymmetrical Iron P-NH-P’ Catalysts
for the Asymmetric Pressure
Hydrogenation of Aryl Ketones
greater than 90%, using 0.1 mol% of
an iron complex mer-FeCl(H)(CO)(P-
NH-P’) at 5 to 10 bar H2 and 50° C.
This article is protected by copyright. All rights reserved.