New P,N-ferrocenyl ligands for the asymmetric Ir-catalyzed hydrogenation of imines

Article abstract of DOI:10.1021/ol071168t

The Ir-catalyzed enantioselective hydrogenation of various N-3,5-dimethyl-4-methoxy)phenylimines was performed under mild conditions in the presence of new P,N-ferrocenyl iridium complexes leading to (R)-N-(3,5-dimethyl-4-methoxy)phenylamines in high yields and enantioselectivities (up to 99%). These chiral aryl amines can be readily deprotected using Ce(NH₄)₂(NO₃)₆.

Full text of DOI:10.1021/ol071168t

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3089-3092
New P,N-Ferrocenyl Ligands for the
Asymmetric Ir-Catalyzed Hydrogenation
of Imines
Murthy N. Cheemala and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received May 18, 2007
ABSTRACT
The Ir-catalyzed enantioselective hydrogenation of various N-(3,5-dimethyl-4-methoxy)phenylimines was performed under mild conditions in
the presence of new P,N-ferrocenyl iridium complexes leading to (R)-N-(3,5-dimethyl-4-methoxy)phenylamines in high yields and enantioselectivities
(up to 99%). These chiral aryl amines can be readily deprotected using Ce(NH4)2(NO3)6.
The asymmetric synthesis of chiral amines is an important
synthetic task since these structural units are part of numerous
biologically relevant compounds.1 In the past decade, the
synthesis of chiral benzylic amines through asymmetric
hydrogenation of imines received much attention.2 Although
many catalysts were developed for the asymmetric imine
hydrogenation, most of them are only suitable for cyclic
substrates. The reduction of acyclic imines with high
enantioselectivities is still a major challenge in this field.3
Recently, chiral Ir complexes have been successfully used
as catalysts for the highly enantioselective reduction of
imines.4 Recent results on the Ir-catalyzed reduction of (Z)-
R-methylacetamidocinnamate using chiral terpene-derived
ligands5 led us to study the use of readily available ferrocenyl
ligands6,7 for the Ir-catalyzed imine reduction. Herein, we
report a novel class of chiral P,N-ferrocenyl ligands and their
use for the enantioselective reduction of imines (up to 99%
ee). Thus, the treatment of (S)-ferrocenyl sulfoxide8 1 with
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10.1021/ol071168t CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/07/2007

Scheme 1
LDA (-78 °C, 0.5 h) followed by the addition of ClPPh2
(-78 °C, 1 h, then 25 °C, 1.5 h) led to an air-sensitive
72% yield. This inseparable mixture of alcohols was al-
kylated with MeI or PhCH2Br (KH, THF, 0 °C, 1 h then
Table 1. Asymmetric Hydrogenation of Imines 10a Using the
Catalysts 8a-9ba
entry
L*
solvent
toluene
Tol/MeOH (1:1)
MeOH
Tol/MeOH (4:1)
Tol/MeOH (4:1)
Tol/MeOH (4:1)
Tol/MeOH (4:1)
Tol/MeOH (4:1)
Tol/MeOH (4:1)
conversionb (%)
eec (%)
1
2
3
4
5
6
7
8d
9e
8b
8b
8b
8b
8a
9a
9b
8a
8a
96
63
23
11 (S)
56 (S)
39 (S)
67 (S)
84 (R)
84 (R)
65 (S)
84 (R)
80 (R)
72
100
100
75
100
100
a Reaction conditions: imine 10a (0.5 mmol), catalyst (1 mol %), 10
1
bar, H2, rt. b Conversion was measured by Chiral GC or H NMR after 2
h. c Enantioselectivity was determined by Chiral GC using a DEX-CB
column. The configuration of amine 11a is shown in parentheses. d Reaction
was performed using 0.5 mol % of the catalyst, and full conversion was
achieved in 3 h. e Reaction was performed using 0.25 mol % of the catalyst,
and full conversion was achieved in 12 h.
Figure 1. X-ray structure of the P,N-ligand 4b.
diphenylphosphine derivative which was protected in situ
with sulfur in BuNH2 (25 °C, 2-4 h) leading to the
phosphinothioylferrocene 2 in 88% yield. The performance
of a sulfoxide/lithium exchange8b using phenyllithium9 (THF,
-78 °C, 10 min) followed by the addition of 2-pyridinecar-
boxaldehyde (-78 °C, 1.5 h, then 25 °C, 1.5 h) leads to a
3:2 mixture of two diastereomeric ferrocenyl alcohols 3 in
MeI (25 °C, 0.5 h) or PhCH2Br (25 °C, 0.5 h)) leading to
readily separable ferrocenyl ethers 4a (54%) and 4b (35%)
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10, 375. (e) Lotz, M.; Ireland, T.; Almena-pera, J. J.; Knochel, P.
Tetrahedron: Asymmetry 1999, 10, 1839. (f) Klo¨tzing, R. J.; Lotz, M.;
Knochel, P. Tetrahedron: Asymmetry 2003, 14, 255. (g) Lotz, M.; Kramer,
G.; Knochel, P. Chem. Commun. 2002, 2546.
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3090
Org. Lett., Vol. 9, No. 16, 2007

Scheme 2
or 5a (56%) and 5b (36%), respectively (Scheme 1). The
relative stereochemistry of ferrocenes 4 and 5 was determined
by X-ray analysis (Figure 1).10
leading to the air stable P,N-derivatives 6a,b and 7a,b in
82-86% yield. Their reaction with [Ir(COD)Cl]2 in CH2Cl2
(25 °C, 1 h) followed by the addition of NaBARF12 in water
(25 °C, 0.5 h) led to the four chiral iridium complexes 8a,b
and 9a,b in 88-90% yield (Scheme 2).
We have investigated the use of these readily available Ir
catalysts 8a-9b for the asymmetric reduction of aromatic
imines using N-phenylethylideneamine 10a as the model
substrate. Preliminary studies indicate that catalysts 8a and
9a give the best enantioselectivities and reaction rates in the
mixture of toluene and methanol (4:1) (Table 1).
Table 2. Asymmetric Hydrogenation of Imines 10a-h and
12a Using the Ir Complex 8a
To improve the asymmetric imine hydrogenation further,
we have varied the aryl substituent attached to the imine
nitrogen (Table 2). Whereas the hydrogenation of the imine
10a (R ) H) led to the chiral phenethylamine 11a under
mild conditions (10 bar, 25 °C, 2 h) in quantitative yield
and 84% ee (entry 1 of Table 2), we noticed that the use of
electron-rich imine 10b (R ) 4-MeO) led to an improved
enantioselectivity of 85% ee (entry 2). Interestingly, hydro-
genation of the imine 10c (R ) 3,5-dimethyl) gives the
corresponding secondary amine 11c in 93-94% ee (entry
3). However, due to difficulties for performing the depro-
tection of the phenylethylamine 11c, we chose the second
best imine (12a : R ) 3,5-dimethyl-4-methoxy; entry 4),
which leads to the phenylethylamine derivative 13a in 92-
entry imine
R
timea (h) eeb,c (%)
1
2
3
4
10a
10b
10c
12a
H
4-MeO
2
2
2
2
84 (84)
85 (85)
94 (93)
94 (92)
3,5-dimethyl
3,5-dimethyl-4-methoxy
a Time to achieve full conversion. b Enantioselectivity was determined
by HPLC (Chiralcel OD-H) or by GC using a Chiral Dex-CB column.
c Enantioselectivities obtained by using the catalyst 9a are shown in
parentheses.
The four ferrocenyl derivatives 4a,b and 5a,b were
smoothly desulfurized (Raney Ni, MeOH, 25 °C, 12 h)11
Scheme 3
Org. Lett., Vol. 9, No. 16, 2007
3091

Scheme 4
94% ee. It was anticipated that the deprotection of com-
pounds like 13 would occur under mild conditions.
catalysts 8a and 9a to various kinds of imines bearing a side
chain at the R-position such as 12j and 12k led to the
corresponding secondary amines 13j and 13k in 94 and 95%
ee, respectively (entries 10 and 11). Interestingly, the
reduction of the imine 12l bearing a remote keto group
proceeded quantitatively, yielding the corresponding amine
13l in 99% ee (entry 12).
Table 3. Asymmetric Hydrogenation of Imines 12a-l Using
the Ir Complex 8a
The deprotection of the 3,5-dimethyl-4-methoxyphenyl
moiety of amines of type 13 occurs smoothly with cerium
ammonium nitrate (CAN; Ce(NH4)2(NO3)6)13 in a 6:1 MeOH/
H2O mixture, providing the corresponding primary amines
in good yields (Scheme 3).
Furthermore, we extended this protocol to the asymmetric
synthesis of chiral γ and δ-lactams.14,15 Thus, the imines 12m
and 12n bearing a remote ester group were subjected to the
asymmetric hydrogenation, and after subsequent deprotection
of the N-aromatic group, 5-phenyl-2-pyrrolidinone 16 and
6-phenyl-2-piperidinone 17 were obtained in 74% yield, 92%
ee and 78% yield, 97% ee, respectively (Scheme 4).
In summary, we have prepared new ferrocenyl P,N-ligands
which are effective for the Ir-catalyzed asymmetric hydro-
genation of acyclic N-arylimines, providing various chiral
phenylalkylamines with high enantioselectivities. This method
can be used to prepare γ- and δ-lactams in 92-97% ee.
Study of further applications of these ligands in asymmetric
catalysis is currently underway in our laboratories.
entry imine
Ar
R
timea (h) eeb,c (%)
1
2
3
4
5
12a Ph
Me
Me
Me
Me
Me
2
2
2
2
4
4
2
6
2
2
4
6
94 (92)
93 (92)
92 (90)
89 (88)
92 (92)
94 (92)
93 (91)
94 (93)
93 (93)
94 (92)
95 (94)
99 (98)
12b 3-MeC6H4
12c 4-PhC6H4
12d 4-CF3C6H4
12e 4-ClC6H4
6
12f
4-MeCO2C6H4 Me
7
12g 3-FC6H4
Me
Me
Me
Et
8
12h 2-MeC6H4
9
12i
12j
12k Ph
12l Ph
2-naphthyl
Ph
10
11
12
Pent
-(CH2)3COPh
a Time to achieve full conversion. b Enantioselectivity was determined
by HPLC using Chiracel OD-H or by Chiracel-AD column. c Enantio-
selectivities obtained by using the catalyst 9a are shown in parentheses.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for the financial support and Merck Research
Laboratories (MSD), Chemetall GmbH (Frankfurt), and
BASF AG (Ludwigshafen) for generous gift of chemicals.
We have prepared a range of imines of type 12 and have
obtained uniformly high enantioselectivities (89-99% ee;
Table 3) in asymmetric hydrogenation using the catalysts
8a and 9a. The catalyst 8a generally provides slightly better
results compared to the catalyst 9a (Table 3). Both electron-
donating (entries 2, 3, 8, and 9) as well as electron-
withdrawing substituents (entries 4, 5, 6 and 7) gave good
results. Extending this asymmetric imine hydrogenation with
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL071168T
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