Chemical Science: Edge Article
Chemical Science: Edge Article
Chemical Science: Edge Article
Introduction from lower yields and very long reaction times compared to
transition-metal catalyzed hydrogenations. Furthermore, they
Chiral amines play an important role as building blocks for the require hydride donors such as dihydropyridines that generate
synthesis of pharmaceuticals and agrochemicals. They are also stoichiometric waste products. So a practical readily accessible
of great importance as chiral auxiliaries, catalysts and resolving catalyst for the asymmetric hydrogenation of dialkyl ketimines
agents. Therefore, asymmetric hydrogenation of ketimines has remains elusive.
received much attention as an attractive, very direct route to We have recently begun to reinvestigate Ir–phosphinoox-
enantiomerically enriched amines.1 High yields, perfect atom azoline complexes that we originally introduced as catalysts for
economy and mild conditions make this approach ideal for imine hydrogenation in 1997.6a Aer evaluation of a wide range
industrial applications. This is impressively demonstrated by of phosphinooxazoline (PHOX) derivatives and careful optimi-
the multi-ton scale production of the herbicide metolachlor, zation of the reaction conditions, excellent enantioselectivities
based on an extremely active and productive Ir-diphosphine and high turnover numbers have been achieved in the hydro-
catalyst.2 genation of aryl alkyl N-arylketimines such as I1 (Scheme 1).6b
During the last two decades a wide range of chiral Ti, Rh, Ir, However, analogous dialkyl ketimines still gave disap-
Pd, Ru,1 and most recently Fe1,3 complexes have been developed pointing results. We therefore decided to conduct a mechanistic
that catalyze the hydrogenation of various imines with high study, in the hope that it would guide the development of
enantioselectivity. However, the scope of most catalysts is rather improved catalysts with broader substrate scope.
narrow and there are still important classes of imines that give
unsatisfactory results with the available catalysts. Especially the
hydrogenation of imines derived from dialkyl ketones remains a
Results and discussion
challenging problem. With the exception of the dual catalyst Here we report the outcome of this study that led to surprising
system reported by Xiao and co-workers,4 consisting of a chiral insights into the structure of the catalytic intermediates and,
Ir(Cp*)–diamine complex and an elaborate chiral binaphthol- ultimately, to a new catalyst system that gave promising results
derived phosphoric acid (TRIP), most catalysts give very low in the hydrogenation of dialkyl ketimines.
enantioselectivities with these substrates. Organocatalytic Experimental mechanistic studies of imine hydrogenation
asymmetric imine reduction and reductive amination has also with Ir-PHOX complexes have not been reported. However,
been developed to afford chiral aliphatic amines with high
enantioselectivities.5 However, these reactions generally suffer
2760 | Chem. Sci., 2013, 4, 2760–2766 This journal is ª The Royal Society of Chemistry 2013
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(Scheme 2). What are the possible conclusions that can be drawn from
When the dihydride complex, generated by reaction of 1a with these results? The iridacycle formed under hydrogenation
H2 in THF at 25 C, was treated with I1 at 0 C, rapid formation conditions could be an inactive species outside the catalytic
of an iridacycle 2 was observed. This complex proved to be very cycle that is in equilibrium with an active catalytic intermediate
sensitive and rapidly decomposed upon exposure to air. Attempts through reversible cyclometalation/reductive elimination,
to obtain suitable crystals for X-ray analysis failed and, therefore, similar to the reaction scheme proposed by Marcazzan and
the BArF (tetrakis[(3,5-triuoromethyl)phenyl]borate) counterion James.12
that, in our experience, oen impedes crystallization, was Alternatively, it could be directly involved in the catalytic
exchanged with chloride or hexauorophosphate. The chloride cycle. In this case, it could either react via reduction of the
complex 3 was readily obtained by treatment with LiCl and silica cyclometalated imine, followed by reductive elimination
gel in ethyl acetate and puried by ash chromatography on releasing the saturated amine, or the cyclometalated imine
silica gel. Ion exchange with NaBArF in THF led back to the BArF could serve as a stable ligand that remains bound throughout
complex 2. the catalytic cycle.
While crystallization attempts of 3 were unsuccessful, the To distinguish between these possibilities we carried out the
hexauorophosphate salt 5 furnished suitable crystals for X-ray cross-over experiment shown in Scheme 6. If a catalytic inter-
analysis (Scheme 3 and Fig. 1).9 Furthermore, a preliminary mediate derived from 3 would release the free imine I1, the
crystal structure of the analogous iridacycle 7 prepared from cyclometalation product of substrate I2 along with amine A1
SimplePHOX complex 6 (Scheme 4 and Fig. 2) could also be would be formed. However, we did not observe even traces of I1
determined.10 or A1 in the course of the hydrogenation reaction by GC anal-
An analogous cyclometalation reaction of [Ir(H)2(PPh3)2- ysis.13,14 These results are consistent with the hypothesis that
(acetone)2]PF6 with benzaldehyde N-benzylimine has been repor- cyclometalation is irreversible and the imine remains bound to
ted by James and co-workers.11 The resulting iridacycle was tested iridium throughout the catalytic reaction. The enantiomeric
in the hydrogenation of imines but showed no catalytic activity.11a excess of A2 remained constant throughout the reaction.13
When complex 3 was tested as catalyst for the hydrogenation We speculated that the cyclometalated complex formed
of I1, no reaction was observed. However, when the chloride was under hydrogenation conditions could be a superior catalyst
replaced with the non-coordinating anion BArF by addition of compared to complex 1a and that the poor results in the
an equimolar amount of NaBArF, an active catalyst was gener- hydrogenation of aliphatic ketimines could be a consequence of
ated that furnished the same enantiomer of amine A1 with the inability of these substrates to form cyclometalated
identical enantioselectivity as the reduction catalyzed by the complexes.
parent complex 1a (Scheme 5).
Scheme 2 Formation of cyclometalated imine complexes. Fig. 1 Crystal structure of 5 (PF6 counterion omitted for clarity).
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1 3 NaBArF 1 40 73 (R)
2 1a — 1 5 69 (R)
3 3 — 1 0 —
4 1a I1 (2 mol%) 1 50 73 (R)
5 1a I1 (2 mol%) 50 >99 71 (R)
6 1a — 50 27 35 (R)
a b
Scheme 6 Hydrogenation of imine I2 with iridacycle 3 in combination with Determined by GC analysis. Determined by HPLC analysis on a
NaBArF. chiral stationary phase.
2762 | Chem. Sci., 2013, 4, 2760–2766 This journal is ª The Royal Society of Chemistry 2013
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1 (S)-12 1 63 15 (S)
2 (S)-13 1 31 23 (R)
3 (S)-13 5 97 14 (R)
4 (R)-13 1 20 23 (S)
5 (R)-13 5 99 14 (S)
6 (R)-14 1 40 17 (S)
a b
Determined by GC analysis. Determined by HPLC analysis on a
Scheme 7 Preparation of chiral iridium complexes (S)-10 derived from achiral Ir- chiral stationary phase.
PHOX complex 8 and chiral imine 9. Upon addition of NaBArF, chloride abstrac-
tion results in the formation of one single hydride complex (S)-11 in solution.
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Table 4 Screening of different imines as additives Table 5 Asymmetric hydrogenation of N-phenyl aliphatic imines
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1 1a I1 23 >99 71 (R)
1 I1 H H >99 71 (R) 2 1a I1 5 >99 73 (R)
2 I4 2-Me H >99 69 (R) 3 1a I24 23 >99 85 (R)
3 I5 2-F H 90–95 71 (R) 4 1a I24 5 >99 92 (R)
4 I6 3-NO2 H 75–99 48 (R)
5 I7 3,5-(NO2)2 H 10 15 (R)
6 I8 3,5-Me2 H >99 3 (S)
7 I9 3,5-iPr2 H 34 42 (S)
8 I10 3,5-tBu2 H 11 10 (R) 5 1a I24 5 33 84 (R)
9 I2 4-MeO H >99 67 (R)
10 I11 4-tBu H >99 64 (R)
11 I12 4-Me H >99 63 (R)
12 I13 4-Cl H >99 56 (R) 6 1a I1 5 >99 49 ()
13 I14 4-F H >99 66 (R) 7 1a I24 5 >99 70 ()
14 I15 4-CF3 H 95 50 (R) 8 1b I24 5 >99 80 ()
15 I16 4-NO2 H 40 45 (R)
16 I17 4-Me 2-Br >99 68 (R)
9 1a I24 5 >99 62 (+)
17 I18 H 2-Me >99 78 (R)
10 1b I24 5 94 72 (+)
18 I19 H 2-MeO >99 71 (R)
19 I20 H 3-MeO >99 68 (R)
20 I21 H 4-MeO >99 69 (R)
21 I22 H 4-CF3 >99 59 (R)
22 I23 H 2-iPr >99 81 (R)
23 I24 H 2,6-Me2 >99 85 (R) 11 1b I24 5 >99 52 ()
a b
Determined by GC analysis. Determined by HPLC analysis on a
chiral stationary phase.
2764 | Chem. Sci., 2013, 4, 2760–2766 This journal is ª The Royal Society of Chemistry 2013
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type has not been reported yet apart from I33. As these substrates in an autoclave (60 mL) and purged with argon for 5 min.
proved to be less reactive, hydrogenations were conducted at Anhydrous CH2Cl2 (1 mL) was added by syringe under a stream
room temperature. Using imine I1 as additive the N-benzylimine of argon and the autoclave was closed. For reactions at low
I33 furnished a moderate ee of 44% (entry 1). An even lower temperature the autoclave was immersed in a cooling bath for
enantioselectivity is observed for the N-n-butylimine I34 (entry 2). 60 min before starting the reaction. The autoclave was pres-
On the other hand almost the same ee as for corresponding surized with hydrogen gas, hydrogen was released and the
N-phenylimine I3 was observed in the hydrogenation of I35 (entry autoclave pressurized again. It was then placed on a stirring
3). The N-cyclohexyl analogue I34 reacted with even higher plate for the time indicated. Aer releasing the pressure, the
enantioselectivity of 77% ee (entry 4), demonstrating that purely solvent was evaporated under a stream of nitrogen. The residue
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alkyl-substituted imines are suitable substrates for this catalyst was suspended in pentane–diethyl ether (5 : 1) and ltered
system. The more bulky complex 1b and the sterically demanding through a short elution plug (cotton bottom, 40 5 mm silica
Open Access Article. Published on 09 April 2013. Downloaded on 26/09/2016 16:16:25.
N-(2,6-dimethylphenyl)imine I24 afforded lower yields and gel). The crude ltrate was analysed by GC for conversion before
enantioselectivities with these substrates. being puried by ash chromatography (SiO2, pentane–diethyl
ether (20 : 1), 15 2 cm) and analysed by HPLC on a chiral
Conclusions stationary phase for determination of the enantiomeric excess.
We have found that the active catalyst in the hydrogenation of Preparative reaction
acetophenone-derived imines with Ir–PHOX precatalysts is an
Imine I3 (1.005 g, 5 mmol), 1a (0.1 mmol), I24 (0.1 mmol), and a
iridacycle generated under hydrogenation conditions by cyclo-
stir bar were added to a 25 mL Pyrex oven-dried glass vial that
metalation of the substrate. Cyclometalated complexes of this
had been placed in an autoclave (60 mL) and purged with argon
type, formed in situ by addition of an equimolar equivalent of
for 5 min. Anhydrous CH2Cl2 (5 mL) was added by syringe under
acetophenone imine, show higher reactivity and better enan-
a stream of argon and the autoclave was closed. The autoclave
tioselectivity in the hydrogenation of N-phenyl and N-alkyl
was immersed in a cooling bath for 60 min at 5 C before it
aliphatic ketimines than the corresponding Ir-PHOX complex
was pressurized with hydrogen gas. Hydrogen was released and
alone. Obviously, the reaction proceeds through a pathway that
the autoclave pressurized again before being placed on a stir-
differs from the catalytic cycles proposed in the literature.7
ring plate for 18 h. Aer pressure release the reaction mixture
Although at present the scope is still limited, our ndings
was transferred to a 50 mL round-bottom ask and solvents
indicate many opportunities for further improvement of this
removed under reduced pressure. The residue was suspended
catalyst system by structural variation of both the chiral P,N
in pentane–diethyl ether (20 : 1) and puried by ash chroma-
ligand and the cyclometalated imine.
tography (SiO2, pentane–diethyl ether (10 : 1), 21 3 cm).
Solvents were removed under reduced pressure and the residue
Experimental section was dried in vacuo to afford A3 (998 mg, 4.92 mmol, 98%).
Screening
Imine (0.1 mmol), catalyst (2 mmol), additive (2 mmol), and a stir Acknowledgements
bar were added to an oven-dried glass vial that had been placed Support of this work by the Swiss National Science Foundation
(SNF) and the Federal Commission for Technology and Innovation
Table 6 Asymmetric hydrogenation of N-alkyl aliphatic imines (KTI) is gratefully acknowledged. We thank Dr Markus
Neuburger for the crystal structure analysis, Robin Wehlauch
for synthetic contributions and Prof. Dr Klaus Dittrich from
BASF for generous gis of chemicals.
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2766 | Chem. Sci., 2013, 4, 2760–2766 This journal is ª The Royal Society of Chemistry 2013