Asymmetric hydrogenation of imines with a recyclable chiral frustrated Lewis pair catalyst

Article abstract of DOI:10.1039/c2dt30536d

A camphor based chiral phosphonium hydrido borate zwitterion was synthesised and successfully applied in the enantioselective hydrogenation of imines with selectivities up to 76% ee. The high stability of the novel chiral FLP-system enables effective recy

Full text of DOI:10.1039/c2dt30536d

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This article is published as part of the Dalton Transactions themed
issue entitled:
Frustrated Lewis Pairs
Guest Editor: Douglas Stephan
Published in issue 30, 2012 of Dalton Transactions
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Communication
Hydrogen activation by 2-boryl-N,N-dialkylanilines: a revision of Piers’ ansa-aminoborane
Konstantin Chernichenko, Martin Nieger, Markku Leskelä and Timo Repo
Paper
Frustrated Lewis pair addition to conjugated diynes: Formation of zwitterionic 1,2,3-butatriene
derivatives
Philipp Feldhaus, Birgitta Schirmer, Birgit Wibbeling, Constantin G. Daniliuc, Roland Fröhlich,
Stefan Grimme, Gerald Kehr and Gerhard Erker
Paper
Fixation of carbon dioxide and related small molecules by a bifunctional frustrated pyrazolylborane
Lewis pair
Eileen Theuergarten, Janin Schlösser, Danny Schlüns, Matthias Freytag, Constantin G. Daniliuc,
Peter G. Jones and Matthias Tamm
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COMMUNICATION
Asymmetric hydrogenation of imines with a recyclable chiral frustrated Lewis
pair catalyst†
Ghazi Ghattas,a Dianjun Chen,a Fangfang Panb and Jürgen Klankermayer*a
Received 6th March 2012, Accepted 8th May 2012
DOI: 10.1039/c2dt30536d
A camphor based chiral phosphonium hydrido borate
zwitterion was synthesised and successfully applied in the
enantioselective hydrogenation of imines with selectivities up
to 76% ee. The high stability of the novel chiral FLP-system
enables effective recycling of the metal-free catalyst.
Combinations of sterically demanding electron pair donor and
acceptor compounds do not form the expected classical Lewis
acid–base adducts, but the special nature of this arrangement
enabled the unprecedented activation of small molecules and
Fig. 1 Frustrated Lewis pairs as effective metal-free catalysts.
paved the way towards effective metal-free catalytic transform-
ations.1 In 2006 Douglas W. Stephan demonstrated for the first
time that intramolecular combinations of strong Lewis acid and
these systems. This catalyst could be used in the enantioselective
hydrogenation of imines with a moderate catalytic loading
leading to an enantiomeric excess up to 37% ee.8 Herein we
base allow the heterolytic cleavage of molecular hydrogen via
the formation of a phosphonium borate zwitterion.2 This species
report on a novel efficient and highly stable chiral FLP, able to
was robust, air and moisture stable and only heating to 150 °C
easily activate hydrogen and to act as a catalyst for metal-free
prompted the elimination of hydrogen, regenerating the intra-
enantioselective hydrogenation of prochiral imines with high
selectivity.
molecular phosphine–borane frustrated Lewis pair (FLP).3 This
remarkable activation could subsequently be generalised and
The synthesis strategy of the FLP is based on the already
combinations of sterically hindered phosphines and boranes were
established chiral intermolecular FLP system 2, and the stability
not only able to activate hydrogen, but also emerged as effective
of this novel catalyst is expected to be strongly enhanced with
hydrogenation catalysts. However, these synthetically readily
retained activity and selectivity, due to the comparable Lewis
accessible intermolecular FLP systems demonstrated reduced
acidity of the borane fragment. The synthesis of the intramolecu-
lar phosphine–borane FLP catalyst is presented in Scheme 1.
Reaction of (1R)-(+)-camphor 4 with (4-bromophenyl) mag-
nesium bromide 5 gave the corresponding tertiary alcohol 6.
stability in the presence of air and moisture, thus complicating
the effective recycling of the metal-free catalysts.
Taking into consideration the uniqueness of intramolecular
frustrated Lewis pairs, the phosphine–borane 14 could be estab-
Subsequent dehydration using thionyl chloride/pyridine resulted
lished in 2007 as one of the most active metal-free dihydrogen
in (1R,4R)-2-(4-bromophenyl)-1,7,7-trimethyl-2-phenylbicyclo
[2.2.1]hept-2-ene 7 in 45% yield.9 Lithiation of compound 7
activators. Moreover, this metal-free system served as an effec-
tive catalyst for hydrogenation of various unsaturated substrates,5
using t-BuLi and nucleophilic substitution with di-tert-butyl-
chlorophosphine afforded di-tert-butyl(4-((1R,4R)-1,7,7-trimethyl-
bicyclo[2.2.1]hept-2-en-2yl)-phenyl)phosphine 8. Hydroboration
and adds to different organic carbonyl compounds (Fig. 1).6
In 2010 intermolecular frustrated Lewis pairs based on chiral
boranes could be synthesised and 2 was reported as a catalyst for
of the unsaturated compound 8 using Piers borane (bis(penta-
fluorophenyl)borane)10 in n-pentane at 100 °C provided diaster-
eomerically pure borane 9, which was used without further
enantioselective hydrogenation of imines with an enantiomeric
excess up to 83%.7 Recently, Bernhard Rieger and Timo Repo
described the chiral intramolecular FLP 3 with high air and
purification for hydrogen activation at room temperature and
moisture stability, foreshadowing the extended applicability of
ambient pressure. The resulting phosphonium hydrido borate
zwitterion 10 could be effectively purified using column chrom-
atography with dichloromethane as eluent, already indicating the
aInstitut für Technische und Makromolekulare Chemie, RWTH Aachen
expected increased stability of the chiral system in comparison to
the hitherto existing chiral metal free catalysts, which decom-
posed under these conditions. After the purification the solvent
was removed and compound 10 could be isolated as a colourless
powder in 40% yield. Phosphonium hydrido borate 10 could
be fully characterised by multinuclear NMR analysis. The
University, Worringerweg 1, 52074 Aachen, Germany.
E-mail: jklankermayer@itmc.rwth-aachen.de; Tel: +49 241 80-28137
bInstitut für Anorganische Chemie, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
†Electronic supplementary information (ESI) available. CCDC 880086.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2dt30536d
9026 | Dalton Trans., 2012, 41, 9026–9028
This journal is © The Royal Society of Chemistry 2012

Fig. 2 Molecular structure of catalyst 10 in the crystal. Hydrogen
atoms and solvent molecules were omitted for clarity except for the
hydrogen atoms bonded to boron and phosphorus.
Table 1 Enantioselective hydrogenation of imines using chiral
intramolecular FLPs 10
Scheme 1 Synthetic pathway to chiral FLP catalyst 9 and the phos-
phonium hydrido borate zwitterion 10.
31P{1H}-NMR spectrum of 10 reveals a singlet resonance at δ =
53.7 ppm, and the 19F{1H}-NMR spectrum shows two sets of
signals for the diastereotopic C6F5 rings [(ortho) δ = −132.36 (d,
J
F–F = 21.9 Hz, 2F), (ortho) −132.83 (dm, JF–F = 19.32 Hz, 2F),
Entrya
Substrate
Conversione [%]
Isolated yield [%]
eef [%]
(para) −165.73 (t, JF–F = 23.4 Hz, 1F), (para) −165.93 (t, JF–F
= 20.8 Hz, 1F), (meta) −167.61 (m, 2F), (meta) −167.82 (m,
2F)]. In the 1H-NMR spectrum a broad signal at 2.85 ppm corre-
sponding to BH, and a doublet at 5.71 ppm (JP–H = 477 Hz)
for PH could be observed. The 11B-NMR displays a doublet at
δ = −19.25 ppm (JB–H = 81.6 Hz).
Crystallisation of compound 10 in a mixture of dichloro-
methane and n-pentane resulted in crystals suitable for X-ray
crystallographic analysis. The unit cell contains two independent
molecules with identical absolute configuration (1R,2R,3R,4S)
and one of them is shown in Fig. 2.
Having this new chiral FLP in hand, catalytic transformations
with various prochiral imines as substrates were performed and
the results are summarised in Table 1. Using 2 mol% catalyst 10
at 65 °C and 25 bar hydrogen pressure, imines N-(1-phenylethy-
lidene)aniline 11a, N-(1-(2-naphthyl)ethylidene)aniline 11b, and
N-phenyl-(1-(4-chlorophenyl)ethylidene)aniline 11c were hydro-
genated at a conversion of 70%, 51%, and 33% (Table 1, entries
1–3). After two days of reaction time, 72% ee, 76% ee, and 72%
ee could be obtained for the chiral amine products. Extending
the reaction time from 2 to 3 days for imine 11a increased the
conversion to 90% with comparable enantioselectivity (Table 1,
entry 4). The more activated methoxy substituted imines N-(1-
phenylethylidene)-4-methoxyaniline 11d and N-(1-(2-naphthyl)-
ethylidene)-4-methoxyaniline 11e could be more easily hydro-
genated and full conversion was obtained within 2 days with a
selectivity from 73% ee to 76% ee (Table 1, entries 5 and 6).
1
2
11a
11b
11c
11a
11d
11e
11f
70
51
33
90
>99
>99
70
>99
>99
63
32
21
79
95
94
51
95
95
72 (R)
76 (−)
72 (−)
72 (R)
73 (R)
76 (+)
72 (+)
76 (+)
70 (−)
3
4b
5
6
7
8c
9d
11g
11h
a Reaction conditions: catalyst loading (2.0 mol%), imine (0.5 mmol),
H2 (25 bar), 1 mL toluene, T = 65 °C, 2 days. b Reaction time: 3 days.
c Reaction time: 1 day. d Reaction time: 5 days, catalyst loading (0.5 mol
%). e Yield was determined by 1H NMR analysis. f % ee was determined
by HPLC or GC methods using a chiral column, absolute configurations
assigned by comparison of retention times and optical rotations with
literature values.
Replacing one methoxy function with a chlorine group, the con-
version in the transformation of N-[1-(4-chlorophenyl)ethyl-
idene]-p-anisidine 11f decreased slightly to 70% within 2 days
with a selectivity of 72% ee (Table 1, entry 7).
Full conversion was achieved within only one day of reaction
time at a notable enantioselectivity of 76% ee with the substrate
incorporating two methoxy substituents (N-[1-(4-methoxy)-
phenyl]ethylidene-4-methoxyaniline 11g) (Table 1, entry 8). In
order to demonstrate the applicability of the catalytic system, the
catalyst loading was reduced to 0.5 mol% in the hydrogenation
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 9026–9028 | 9027

Table 2 Recycling experiments with catalyst 10 and imine 11g
hydrogenation mechanism of the chiral FLP catalyst is underway
and will be presented in the near future.
Entrya
Catalyst-run
Conversion [%]
ee [%]
1
2
3
4
5
1st
>99
>99
>99
>99
70
76 (+)
76 (+)
76 (+)
76 (+)
76 (+)
2nd
3rd
4th
5th
Acknowledgements
This work was performed as part of the Cluster of Excellence
“Tailor-Made Fuels from Biomass”, which is funded by the
Excellence Initiative of the German federal and state govern-
ments to promote science and research at German universities.
a Reaction conditions: catalyst loading (2.5 mol%), H2 (25 bar), imine
11g (1.42 mmol), 1 mL toluene, T = 65 °C. Reaction time: 24 h; yield
was determined by H NMR analysis; % ee was determined by HPLC,
1
absolute configurations assigned by comparison of retention times and
optical rotations with literature values.
Notes and references
1 (a) W. Tochtermann, Angew. Chem., 1966, 78, 355–375, (Angew. Chem.,
Int. Ed. Engl., 1966, 5, 351–371); (b) G. Wittig and E. Benz, Chem. Ber.,
1959, 92, 1999–2013; (c) G. Wittig and A. Rückert, Justus Liebigs Ann.
Chem., 1950, 566, 101–113.
2 (a) G. C. Welch, R. R. San Juan, J. D. Masuda and D. W. Stephan,
Science, 2006, 314, 1124–1126; (b) D. W. Stephan and G. Erker, Angew.
Chem., 2010, 122, 50–81, (Angew. Chem., Int. Ed., 2010, 49, 46–76).
3 (a) P. A. Chase, G. C. Welch, T. Jurca and D. W. Stephan, Angew. Chem.,
2007, 119, 8196–8199, (Angew. Chem., Int. Ed., 2007, 46, 8050–8053);
(b) P. A. Chase, G. C. Welch, T. Jurca and D. W. Stephan, Angew. Chem.,
2007, 119, 9296; (c) E. Otten, R. C. Neu and D. W. Stephan, J. Am.
Chem. Soc., 2009, 131, 9918–9919; (d) G. Menard and D. W. Stephan,
J. Am. Chem. Soc., 2010, 132, 1796–1797.
4 P. Spies, G. Erker, G. Kehr, K. Bergander, R. Fröhlich, S. Grimme and
D. W. Stephan, Chem. Commun., 2007, 5072–5074.
5 (a) P. Spies, S. Schwendemann, S. Lange, G. Kehr, R. Fröhlich and
G. Erker, Angew. Chem., 2008, 120, 7654–7657, (Angew. Chem., Int. Ed.,
2008, 47, 7543–7546).
6 (a) C. M. Mömming, G. Kehr, B. Wibbeling, R. Fröhlich and G. Erker,
Dalton Trans., 2010, 39, 7556–7564; (b) C. M. Mömming, E. Otten,
G. Kehr, R. Fröhlich, S. Grimme, D. W. Stephan and G. Erker, Angew.
Chem., 2009, 121, 6770–6773, (Angew. Chem., Int. Ed., 2009, 48, 6643–
6646); (c) C. M. Moemming, S. Froemel, G. Kehr, R. Froehlich,
S. Grimme and G. Erker, J. Am. Chem. Soc., 2009, 131, 12280–12289.
7 (a) D. Chen, Y. Wang and J. Klankermayer, Angew. Chem., 2010, 122,
9665–9668, (Angew. Chem., Int. Ed., 2010, 49, 9475–9478).
8 V. Sumerin, K. Chernichenko, M. Nieger, M. Leskelä, B. Rieger and
T. Repo, Adv. Synth. Catal., 2011, 353, 2093–2110.
of imine N-(1-(4-methoxyphenyl)ethylidene)aniline 11h and,
consequently, the amine could be obtained with an enantio-
selectivity of 70% ee in 95% yield. The recyclability of catalyst
10 was investigated in more detail in the hydrogenation of imine
11g (Table 2). After the first hydrogenation experiment catalyst
10 was precipitated under air with pentane, the supernatant solu-
tion was separated and analysed, showing full conversion and an
enantioselectivity of 76% ee (Table 2, entry 1). The recycled
solid catalyst 10 was subsequently retransferred to the autoclave,
mixed with toluene and substrate, and pressurized with 25 bar
hydrogen. Four consecutive runs demonstrated a constant
enantioselectivity of 76% ee and full conversion, confirming the
effectiveness and stability of the novel chiral FLP catalyst
(Table 2, entries 1–4).
Conclusions
In summary a novel chiral FLP salt was successfully synthesised
and fully characterised. The stable catalyst was able to selec-
tively hydrogenate prochiral imines with an enantioselectivity up
to 76% ee at low catalyst loading. Furthermore, the increased
recyclability in comparison to the related chiral intermolecular
system demonstrates the effectiveness of the modified catalyst
design. Further investigation regarding the scope and the
9 J. Coxon, M. Hartshorn and A. Lewis, Aust. J. Chem., 1971, 24,
1017–1026.
10 D. J. Parks, R. E. von H. Spence and W. E. Piers, Angew. Chem., Int. Ed.
Engl., 1995, 34, 809–811.
9028 | Dalton Trans., 2012, 41, 9026–9028
This journal is © The Royal Society of Chemistry 2012