Identification of new catalysts for the asymmetric reduction of imines into chiral amines with polymethylhydrosiloxane using high-throughput screening

Article abstract of DOI:10.1016/j.tetlet.2004.03.159

The use of high-throughput techniques allowed the rapid identification of new catalysts for the enantioselective reduction of imines using polymethylhydrosiloxane (PMHS) as a reducing agent. By a simple modification of the chiral ligand structure that came out of the screening, the enantioselectivity of the reduction was increased from 40% ee to 60% ee.

Full text of DOI:10.1016/j.tetlet.2004.03.159

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4383–4387
Identification of new catalysts for the asymmetric reduction
of imines into chiral amines with polymethylhydrosiloxane
using high-throughput screening
Tania Ireland,* Franßcois Fontanet and Guen-Gnanh Tchao
Rhodia, Lyon Research Center, Catalysis Department, 69 192 St-Fons, France
Received 16 February 2004; revised 24 March 2004; accepted 29 March 2004
Abstract—The use of high-throughput techniques allowed the rapid identification of new catalysts for the enantioselective reduction
of imines using polymethylhydrosiloxane (PMHS) as a reducing agent. By a simple modification of the chiral ligand structure that
came out of the screening, the enantioselectivity of the reduction was increased from 40% ee to 60% ee.
Ó 2004 Elsevier Ltd. All rights reserved.
The use of polymethylhydrosiloxane (PMHS) as a
reducing agent is an interesting alternative to the use of
hydrogen since no pressure reactor is required. Fur-
thermore, PMHS is inexpensive, nontoxic and stable to
air and moisture co-product of the silicon industry.1 It
has already been used in many applications like reduc-
tion of ketones, esters, imines, halogen or phosphine
oxides but also asymmetric reductions.1;2 For example
ketones can be reduced into chiral alcohols with PMHS
in the presence of zinc-chiral diamines,3 cadmium/bis-
oxazoline catalysts4 or copper/chiral diphosphines.5 We
were interested in reducing imines into chiral amines
using PMHS as a reducing agent.6 Some catalysts are
already described for this reaction, particularly the tita-
nocene complex developed by Hansen and Buchwald
that leads to chiral amines with very high enantioselec-
tivities.7 However this method requires a catalyst pre-
activation and the addition of an amine in the course of
the reaction. Other examples of achiral imine reductions
with PMHS have also been published. Thus ZnCl2
(2 equiv)8 and Ti(OiPr)4 (1.25 equiv, in situ formation of
imine)9 were used as catalysts but in stoichiometric
amount. A convenient method was published by Fu and
Lopez that uses a catalytic amount of a tinIV complex to
perform the reaction.10 Recently Mortreux and
co-workers showed that a zinc–diamine complex could
be used in a catalytic amount to reduce effectively
ketones and imines.11
We wish to report herein the results obtained in a par-
allel screening of a large number of catalyst–chiral
ligand combinations for the enantioselective reduction
of imines into chiral amines using PMHS as a reducing
agent. Since the numerous type of catalysts that have
been described to activate PMHS, a diversified parallel
library was prepared by combining commercially avail-
able catalysts and chiral ligands.12 The chiral ligands
were chosen among acids, alcohols, aminoalcohols,
diamines or diphosphines in order to identify all types
of structures that could be able to induce chirality
(Scheme 1).
Two targets were identified as model substrates for the
parallel library screening, the ketimine 1 and the cyclic
imine 2 (Scheme 2).
The reactions were performed in 96-well microtiterplates
using reagents in solution (imine/PMHS: 1/1,2 mol % of
catalyst and 2 mol % of ligand in MeOH). The solutions
were delivered using a Gilson 215 robot inside a glove-
box. The reactions were quenched after 20 h with a
solution of MeONa in MeOH. The crude reaction
mixtures were directly analyzed by GC (conversion) and
by HPLC analysis (enantioselectivity). The results
obtained for the reduction of the ketimine 1 are shown
in Scheme 3 and those for the reduction of the cyclic
imine 2 in Scheme 4.
Keywords: Asymmetric imine reduction; PMHS; High-throughput
screening.
* Corresponding author. Tel.: +33-4-72-89-66-76; fax: +33-4-72-89-68-
90; e-mail: tania.ireland@eu.rhodia.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.159

4384
T.Ireland et al./ Tetrahedron Letters 45 (2004) 4383–4387
Ph
NHTos
Ph
Ph
NH
2
H
N
Ph
N
H
Ph
NH
NH
2
2
Ph
L1
L3
L2
OAc
CO H
NH
HN
O
O
N
2
N
N
O
O
N
N
iPr
iPr
L6
L4
L7
L5
PPh
Br
Ph P
2
OH
2
NH
HN
PPh
PPh
2
2
O O
NH
2
L9
L8
OH
OH
OH
OH
OH
OH
Br
L10
L11
L12
Scheme 1.
Catalyst 2 mol%
MeO
MeO
Ph
N
Ph
NH
Chiral ligand 2 mol%
N
Ph
CH
PMHS (1 eq), MeOH
Ph
CH
3
3
1: N-Benzylphenylethylimine
2: 1-Methyl-6,7-dimethoxy
-3,4-dihydroisoquinoline
Scheme 2. Asymmetric reduction of imines with PMHS.
Among the catalysts screened, Sn(OTf)2, Zn(OTf)2,
In(OTf)3, Cd(CHB)2 turned out to be active even in
2 mol % amount. Although different tin and zinc cata-
lysts were already known to perform the reaction cata-
lytically,10;11 indium and cadmium catalysts were not yet
described. Interestingly the addition of a ligand led in
most cases to an increase of the catalyst activity. The
best enantioselectivity was obtained with Sn(OTf)2/
binaphthol (L10) leading to the N-benzylphenylethyl-
amine with upto 40% ee. Chiral induction (upto 20%
ee) was also observed with binaphthol (L10) in combi-
nation with In(OTf)3 and with PyBox (L4) in combi-
nation with Zn(OTf)2 or Cd(CHB)2. Although Zn/L3
complex is known for the enantioselective reduction of
ketones,3 no enantioselectivity was observed for the
reduction of imine 1 in our screening conditions using
this catalyst. Surprisingly, even simple chiral carboxylic
acid like O-acetylmandelic acid (L6) led to some chiral
induction (upto 16% ee) in combination with Sn(OTf)
or In(OTf)3.
2
The substrate specificity often observed for enantio-
selective reactions was confirmed by performing a sim-
ilar screening for the enantioselective reduction of imine
2. The results are shown in Scheme 4.
The best result for the reduction of the cyclic imine 2
was obtained with Cd(CHB)2/PyBox (L4) leading to the
corresponding amine with 32% ee. Furthermore
In(OTf)3 that was active for the reduction of imine 1
turned out to be much less efficient for the reduction
of imine 2. CoCl2 showed some activity for the reduc-
tion but no chiral induction was observed. Simi-
lar activities were observed with ZnBr2 instead of
Zn(OTf)2.
To confirm the results obtained from parallel screening
the most promising catalysts were tested for the reduc-
tion of imine 1 and imine 2 on a lab scale. The results are
summarized in Table 1.
OTf: triflate; CHB: cyclohexanebutyrate.

T.Ireland et al./ Tetrahedron Letters 45 (2004) 4383–4387
4385
Conversion %
Iee I %
90
80
70
60
50
40
30
20
10
No ligand
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
0
Scheme 3. Screening of catalysts for the asymmetric reduction of the ketimine 1 with PMHS.
Conversion %
Iee I %
60
No ligand
L1
50
40
30
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
20
10
0
Scheme 4. Screening of catalysts for the asymmetric reduction of the cyclic imine 2 with PMHS.

4386
T.Ireland et al./ Tetrahedron Letters 45 (2004) 4383–4387
Table 1. Enantioselective reduction of imines with PMHSa
Entry
Imine
Catalyst
Catalyst amount (mol %)
Ligand
Time (h)
Conversion (%)b
Ee (%)c
1
1
1
1
1
1
1
1
2
1
1
1
Sn(OTf)2
In(OTf)3
Zn(OTf)2
Cd(CHB)2
Sn(OTf)2
Zn(OTf)2
In(OTf)3
Cd(CHB)2
Sn(OTf)2
Zn(OTf)2
In(OTf)3
10
10
2
––
––
4.5
22
6
82
67
––
––
2
3d
––
––
87
––
––
4
10
2
22
2
62
5
L10
L10
L10
L4
98 (90)e
>99
56
40 (R)
30 (R)
29 (R)
33
6
2
6
7
8f
2
6
2
20
6
60
85
9
2
L12
L12
L12
60 (R)
33 (R)
36 (R)
10
11
2
6
87
50
2
6
a Reactions were performed at room temperature with imine (1.0 mmol), PMHS (1.2 equiv), ligand (ꢀ mol %), catalyst (ꢀ mol %) in MeOH.
b Determined by GC using a c-DEX225 Supelco column.
c Determined by HPLC using a Daicel OD-H column.
d 2 equiv of PMHS was used.
e (Isolated yield%).
f Toluene was added to solubilize the amine.
The catalytic activity of Sn(OTf)2, In(OTf)3, Zn(OTf)2
and Cd(CHB)2 was confirmed. Thus Zn(OTf)2 can be
used in catalytic amount as low as 2 mol % but the use of
10 mol % of Sn(OTf)2, In(OTf)3 or Cd(CHB)2 is neces-
sary to obtain a good conversion (Table 1, entries 1–4).
Acknowledgements
We thank Prof. G. C. Fu for helpful discussions.
The use of an excess of alcohol is critical to run the
reaction catalytically. In the absence of methanol
no conversion was observed whereas the use of only
2 equiv led to a very sluggish reaction. Interestingly the
reduction could be performed under an air atmosphere.
References and notes
1. For a review on PMHS chemistry see: Lawrence, N. J.;
Drew, M. D.; Bushell, S. M. J.Chem.Soc,. Perkin Trans.
1 1999, 3381–3391.
2. Recent applications of PMHS in enantioselective reduc-
tions of conjugated double bonds: (a) Lipshutz, B. H.;
The addition of a ligand led in all cases to a catalyst acti-
vation and 2 mol % of catalyst is then enough to get a high
conversion (Table 1, entries 5 and 6). The best enantio-
selectivity observed in microtiterplate for the reduction of
imine 1 and 2 were confirmed (Table 1, entries 5 and 8).
Servesko, J. F. Angew.Chem,. Int.Ed.
2003, 42, 4789–
4792; (b) Czekelius, C.; Carreira, E. M. Angew.Chem., Int.
Ed. 2003, 42, 4793–4795.
3. Mimoun, H.; de Saint Laumer, J. Y.; Giannini, L.;
Scopelliti, R.; Floriani, C. J.Am.Chem.Soc.
6158–6166.
1999, 121,
Since the binaphthol ligand (L10) led to the best chiral
induction we tried to modify its structure. Thus the
enantioselectivity was increased to 60% ee for the
reduction of imine 1 simply by adding two bromo sub-
stituents in 3 and 30 positions of the binaphthol (see
ligand L12, Scheme 1 and Table 1, entry 9). However
this substituent effect was not as strong with Zn(OTf)2
and In(OTf)3 (Table 1, entries 10 and 11).
4. Lawrence, N. J.; Bushell, S. M. Tetrahedron Lett. 2000, 41,
4507–4512.
€
5. (a) Courmarcel, J.; Mostefaı, N.; Sirol, S.; Choppin, S.;
Riant, O. Isr.J.Chem. 2001, 41, 231; (b) Lipshutz, B. H.;
Noson, K.; Chrisman, W. J.Am.Chem.Soc.
2001, 123,
12917; (c) Lipshutz, B. H.; Noson, K.; Chrisman, W.;
Lower, A. J.Am.Chem.Soc. 2003, 125, 8779–9789.
6. For reviews on enantioselective imine reduction see: (a)
Kobayashi, S.; Ishitani, H. Chem.Rev. 1999, 99, 1069–
1094; (b) Spindler, F.; Blaser, H.-U. In Transition Metals
For Organic Synthesis; Belle, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 1998; pp 69–80.
7. (a) Hansen, M. C.; Buchwald, S. L. Org.Lett. 2000, 2(5),
713–715; (b) Verdaguer, X.; Lange, U. E. W.; Buchwald,
S. L. Angew.Chem,. Int.Ed. 1998, 37, 1103–1107.
8. Chandrasekhar, S.; Venkat Reddy, M.; Chandraiah, L.
Synth.Commun. 1999, 29(22), 3981–3987.
9. Chandrasekhar, S.; Raji Reddy, Ch.; Moinuddin Ahmed
Synlett 2000, 11, 1655–1657.
10. Lopez, R. M.; Fu, G. C. Tetrahedron 1997, 53, 16349–
16354.
11. Bette, V.; Mortreux, A.; Lehmann, C. W.; Carpentier,
J. F. Chem.Commun. 2003, 332–333.
12. For reviews on high-throughput screening in catalysis see:
(a) Reetz, M. T. Angew.Chem., Int.Ed. 2001, 40, 284–310;
(b) Maier, W. F. Angew.Chem,. Int.Ed. 1999, 38, 1216–
1223; (c) Jandeleit, B.; Shaefer, D. J.; Powers, T. S.;
In summary we have successfully used high throughput
techniques in order to identify new catalysts like In-
(OTf)3 and Cd(CHB)2 for the reduction of imines into
amines using PMHS as a reducing agent. Chiral induc-
tion was observed by simple combinations of catalysts
such as Sn(OTf)2, Zn(OTf)2, In(OTf)3 and Cd(CHB)2
with chiral ligands. The screening of various type of
chiral ligands allowed us to identify active structures.
Then a more focused ligand design strategy allowed us
to increase our best enantiomeric excess from 40% to
60% ee. The advantage of using high-throughput
screening was again demonstrated since the most effi-
cient catalyst was substrate depending. Further optimi-
zations of the chiral ligand structures in order to
increase the enantioselectivity of the reaction are in
progress in our laboratory.

T.Ireland et al./ Tetrahedron Letters 45 (2004) 4383–4387
4387
Turner, H. W.; Weinberg, W. H. Angew.Chem,. Int.Ed.
1999, 38, 2494–2532; (d) Shimizu, K. D.; Snapper, M. L.;
Hoveyda, A. H. Chem.Eur.J. 1998, 4, 1885–1889; see also
(e) Taran, F.; Gauchet, C.; Mohar, B.; Meunier, S.;
Wagner, A.; Miokowski, C. Angew.Chem,. Int.Ed. 2002,
41, 124–127; (f) Hoogenraag, M.; Klaus, G. M.; Elders,
N.; Hooijschuur, S. M.; McKay, B.; Smith, A. A.; Damen,
E. W. P. Tetrahedron: Asymmetry 2004, 15, 519, and
references cited therein.
ꢀ
Valleix, A.; Renard, P. Y.; Creminon, C.; Grassi, J.;