Novel amido-complexes for the efficient asymmetric hydrogenation of imines

Article abstract of DOI:10.1002/adsc.201000733

Novel N,N,P ligand stabilized rhodium complexes exhibiting high activities and enantioselectivities in the asymmetric hydrogenation of N-aryl imines are introduced. The ligands were synthesized from inexpensive starting materials and their modular design

Full text of DOI:10.1002/adsc.201000733

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DOI: 10.1002/adsc.201000733
Novel Amido-Complexes for the Efficient Asymmetric
Hydrogenation of Imines
Kathrin Kutlescha,a Torsten Irrgang,a,b and Rhett Kempea,*
a
Lehrstuhl fꢀr Anorganische Chemie II, Universitꢁt Bayreuth, Universitꢁtsstraße 30, 95440 Bayreuth, Germany
Fax : (+49)-921-55-2157; phone: (+49)-921-55-2541; e-mail: kempe@uni-bayreuth.de
AIKAA-Chemicals GmbH, Kꢁmmereigasse 11, 95444 Bayreuth, Germany
b
Received: September 24, 2010; Published online: December 3, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000733.
Abstract: Novel N,N,P ligand stabilized rhodium
complexes exhibiting high activities and enantiose-
lectivities in the asymmetric hydrogenation of N-
aryl imines are introduced. The ligands were syn-
thesized from inexpensive starting materials and
their modular design allows for the introduction of
a broad variety of substitution patterns. Additional-
ly, a rather low catalyst loading could be employed.
followed by a cyclocondensation reaction with 1,3-di-
ketones (Scheme 1).
The resulting iridium amido-complexes exhibit
good activities and excellent enantioselectivities in
the asymmetric ketone hydrogenation.[9]
Herein, the synthesis of novel imidazo
ACHTUNGTREN[NUNG 1,5-b]pyrid-
AHCTUNGTREGaNNUN zine-substituted amines 3 is reported. Upon deproto-
nation they act as monoanionic tridentate amido-li-
gands and are suitable for the stabilization of group 9
metal complexes. The chiral amido-complexes 4 show
high efficiency and very good enantioselectivity in the
asymmetric hydrogenation of imines.[10]
Keywords: amido-ligands; asymmetric catalysis; hy-
drogenation; imines; rhodium
The novel amines 3 can be synthesized via P-func-
tionalization of 2 in good to excellent yields and high
purities (Scheme 2). Lithiation with n-BuLi selectively
Given that 80% of the pharmaceuticals in the prod- occurs at the O-atom of the hydroxy group. Subse-
uct-pipeline are chiral and that the launch of enantio- quently one equivalent of dialkylchlorophosphine, di-
pure drugs will be facilitated, there is an increasing arylchlorophosphine or ethylene chlorophosphite is
demand for chiral intermediates such as amines, alco- added, giving rise to 3a–h as orange viscous products.
hols or acids.[1] Asymmetric hydrogenation technolo-
The amido-complexes 4a–j can be obtained via an
[11]
gies, which are (atom) economic and easily up-scala- alcohol elimination route with [MOCH
ble, provide an excellent access to those substances.[2]
During the last decade various enantioselective imine
hydrogenation catalysts were introduced,[3–7] most of
them being cationic iridium complexes based on neu-
tral P,N ligands, for instance, phosphine oxazolines or
P,N ferrocenyls.[3] Neutral ligands might be easier re-
placed by strongly coordinating substrates like imines
and consequently we became interested in developing
anionic ligands for the enantioselective hydrogenation
of imines.
3ACHTUNGTNER(NUNG cod)]2
Recently, we introduced imidazoACTHNUTRGNEUNG[1,5-b]pyridazine-
substituted amido-ligands, which stabilize late and
early transition metal complexes.[8] Chiral imidazo-
ACHTUNGTRENNUNG[1,5-b]pyridazine-substituted amino alcohols 2 are of
special interest thereby. They can be synthesized in a
one-pot approach via the nucleophilic ring transfor-
mation of oxadiazolium halides 1 with amino alcohols
Scheme 1. One-pot synthesis of 2.
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Adv. Synth. Catal. 2010, 352, 3126 – 3130

Novel Amido-Complexes for the Efficient Asymmetric Hydrogenation of Imines
Scheme 2. Synthesis of 3a–h (3a: R2 =i-Bu, R5 =Ph; 3b:
_
R2 =i-Bu, R5 =i-Pr; 3c: R2 =i-Bu, R5R5 =OCH2CH2O; 3d:
R2 =Me, R5 =i-Pr; 3e: R2 =Bn, R5 =i-Pr; 3f: R2 =i-Bu, R5 =
Et; 3g: R2 =i-Bu, R5 =t-Bu; 3h: R2 =i-Bu, R5 =Cy).
Figure 1. Molecular structure of 4a; selected bond length
À
À
[ꢃ] and -angles [8]: N4 Rh1 2.233(2), N1 Rh1 2.349(2),
P1 Rh1 2.2423(8), O1 P1 1.608(2); N1 Rh1 N4 74.02(8),
À
À
À
À
À
À
À
À
À
À
N4 Rh1 P1 79.67(7), N2 N1 Rh1 107.84(16), C9 N4 Rh1
À
À
113.83(18), O1 P1 Rh1 112.30(8).
Scheme 3. Synthesis of amido-complexes 4a–j (M=Rh: 4a:
Table 1. Results of the asymmetric hydrogenation of 5a.[a]
R2 =i-Bu, R5 =Ph; 4b: R2 =i-Bu, R5 =i-Pr; 4c: R2 =i-Bu,
_
R5R5 =OCH2CH2O; 4d: R2 =Me, R5 =i-Pr; 4e: R2 =Bn,
R5 =i-Pr; 4f: R2 =i-Bu, R5 =Et; 4g: R2 =i-Bu, R5 =t-Bu; 4h:
Entry Pre-Catalyst Base
Conversion[b] [%] ee[c] [%]
R2 =i-Bu, R5 =Cy; M=Ir: 4i: R2 =i-Bu, R5 =i-Pr; 4j: R2 =i-
1
2
3
4
5
6
7
8
4b
4b
4c
4c
4i
4i
4j
4j
–
0
–
_
Bu, R5R5 =OCH2CH2O).
KO-t-Bu >99
46
KO-t-Bu 41
82
rac
21
–
17
–
–
–
0
(M=Ir, Rh) (Scheme 3). Addition of 0.5 equivalents
of the metal precursor to a solution of 3a–h in THF
gives rise to 4a–j, which is accompanied by a color
change to blue/green. The NMR spectra show a single
signal set for the deprotonated ligand and coordinated
1,5-cyclooctadiene. The Rh(I)-P coupling constant of
158.40 Hz (4a) is in accordance with the literature
value.[12]
KO-t-Bu 37
–
KO-t-Bu 98
0
30
[a]
[b]
[c]
Reaction conditions: 0.1 mol% 4, 24 h, 408C, 60 bar H2.
Determined via GC.
Determined via HPLC.
An X-ray crystal structure analysis of 4a was per-
formed to determine the molecular structure could be achieved in 24 h with a catalyst loading of
(Figure 1).
only 0.1 mol%.
The monoanionic ligand coordinates the Rh atom
The selectivity in the asymmetric hydrogenation of
via a five-membered chelate (Rh1, N4, C9, N2, N1). 5a with 4b could be increased from 82% (408C,
The complex is further stabilized by coordination of 60 bar) to 90% (room temperature, 20 bar) by optimi-
À
À
the P atom (P1 Rh1). Since the N4 Rh1 bond length zation of the reaction conditions. A pressure depend-
of 2.233 ꢃ is significantly shorter than the N1 Rh1 ence of the selectivity was not observed (5–60 bar).
À
bond length (2.350 ꢃ), the anionic charge of the The addition of an excess of KO-t-Bu (see Supporting
ligand is localized at the amido N atom. The phenyl Information) generates the best activity and enantio-
substituents of the P atom are orientated 93.168 to selectivity.
each other and point away from the imidazopyrid-
ACHTUNGTRENNUNGazine plane.
Due to the modular design of 4, the steric and elec-
tronic properties of the ligand can easily be fine-
Complexes 4b and c (Rh) and 4i and j (Ir) tuned towards the substrate. Hereby the influence of
(Scheme 3) were utilized for the asymmetric hydroge- amino alcohol and P substituents on the activity and
nation of N-(1-phenylethylidene)aniline 5a at 408C enantioselectivity was investigated (Table 2).
and 60 bar H2 pressure (Table 1). Hereby, the dialkyl-
The combination of electron-donating phosphine
phosphine-substituted rhodium amido-complex 4b substituents (i-Pr, Cy) and amino alcohols (i-Bu) gave
was the most promising catalyst system. Upon addi- the best results in the hydrogenation of 5a (Table 2,
tion of KO-t-Bu complete conversion and 82% ee entries 2 and 7).
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Kathrin Kutlescha et al.
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Table 2. Catalyst screening for the hydrogenation of 5a.[a]
High enantioselectivities, which are similar to the
best known literature systems[4d,e;3e,f], could be ob-
tained in the asymmetric hydrogenation of various N-
aryl imines 5 with 4b (Table 3).
Due to the anionic nature of the supporting ligand,
a higher hydrogenation efficiency in comparison to
most of these literature systems was observed. The
catalyst loading could be reduced to 0.1–0.2 mol%
(typically 1 mol% in the literature).
Entry
Pre-Catalyst
Conversion[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
4a
4b
4d
4e
4f
4g
4h
62
>99
79
63
85
70
90
81
84
85
86
90
88
96
The high efficiency and enantioselectivity could fur-
[a]
Reaction conditions: 0.1 mol% 4, KO-t-Bu, 24 h, 208C, thermore be verified in a preparative experiment.
20 bar H2.
Therein 2.5 g of N-(1-phenylethyl)aniline were isolat-
ed (83% yield and 89% ee).
In conclusion, the reported amido-complexes repre-
sent a novel class of efficient and easily accessible cat-
alysts for the asymmetric hydrogenation of imines.
[b]
[b]
Determined via GC.
Determined via HPLC.
Table 3. Hydrogenation of N-aryl imines with 4b.[a]
Entry
1#
Imine
Conversion[b] [%]
ee[c] [%]
Best literature[d] ee [%]
5a
>99
90
95[4e]
2
3
4
5b
5c
5d
97
86
82
89
94[3f]
97[4e]
91[3f]
>99
>99
5*#
5e
98
91
99[4d]
6
5f
5g
5h
5i
>99
>99
>99
>99
87
75
83
76
–
7#
8#
9
97[4e]
–
78[3e]
10*#
5j
>99
>99
74
57
–
–
11*
5k
[a]
Reaction conditions: 0.1 mol% (* 0.2 mol%) 4b, KO-t-Bu, 48 h (# 24 h), 208C, 20 bar H2.
Determined via GC.
[b]
[c]
[d]
Determined via HPLC.
[3f]
[4d]
Literature conditions:[3e] 0.5 mol% Ir complex, 258C, 20 bar H2;
1 mol% Ir complex, 108C, 1 bar H2.
1 mol% Ir-complex, 208C, 20 bar H2.
1 mol%
[4e]
[Ir
G
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Novel Amido-Complexes for the Efficient Asymmetric Hydrogenation of Imines
Angew. Chem. 2009, 121, 5449–5453; Angew. Chem.
Due to the modular ligand design, broad substitution
patterns can be realized. The high efficiency and good
selectivity combined with the novel structural motif
opens up new prospects for the enantioselective hy-
drogenation of imines.
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Experimental Section
General Procedure for the Asymmetric
Hydrogenation
Stock solutions of the pre-catalysts (3.01 mmol/mL) were
prepared in THF via alcohol elimination reaction of the
ligand (stock solution in THF) and 0.5 equiv. of [MOCH3
ACHTUNGTRENNUNG(cod)]2 (M=Rh, Ir). Stock solutions of the imines
(1.51 mmolmLÀ1) were prepared in THF. The solutions
were prepared and stored in a glove box. A high-pressure
steel autoclave (Parr Instruments; 300 mL, 200 bar, 3508C)
with an aluminum insert for multiple reaction tubes (5 or
20) was taken into a glove box. Then the reaction tube
(placed in a 20- or 5-well insert for the autoclave, equipped
with a magnetic stir bar) was loaded with additive (base if
required), the pre-catalyst-solution (e.g., 200 mL=0.1 mol%)
and 400 mL (0.60 mmol) of the substrate solution. Then the
autoclave was sealed and taken out of the glove box. The
autoclave was attached to a high-pressure hydrogen line and
purged with H2. The autoclave was sealed under the appro-
priate H2 pressure and the mixture was stirred for, for exam-
ple, 24 h at the appropriate pressure at room temperature or
at the appropriate temperature (external heating mantle). In
order to stop the hydrogenation reaction, the pressure was
released and water and dodecane (standard for GC) were
added to the reaction solution. The samples were extracted
with diethyl ether (3 mL) and the organic phase was centri-
fugalized at 12,000 rpm and filtered through 0.2 mm PTFE-
syringe filters. This solution was directly used for determina-
tion of the conversion (GC, Lipodex E or Chirasil-DEX
column). For HPLC (Chiralpak IB column) purposes the
samples were diluted (40ꢄ) with diethyl ether (determina-
tion of ee).
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Acknowledgements
This work was supported by NANOCAT, an international
graduate-program within the Elitenetzwerk Bayern. We thank
Germund Glatz for his support in the X-ray laboratories.
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