Iridium-catalyzed asymmetric hydrogenation of unfunctionalized enamines

Article abstract of DOI:10.1002/chem.200802576

The application of cationic iridium catalysts with chiral oxazoline- or pyridine-based N,P ligands for the asymmetric hydrogenation of different unfunctionalized enamines was reported. N-methyl-N-phenyl- and N-methyl-N-benzly-(1-phynylvinly1)amine were hy

Full text of DOI:10.1002/chem.200802576

DOI: 10.1002/chem.200802576
Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized
Enamines
Alejandro Baeza and Andreas Pfaltz*[a]
Optically active amines are present in many natural prod-
ucts prompting the development of numerous different
strategies and methodologies to access these compounds.
Our group, among others, has already reported the synthesis
of enantioenriched secondary amines via catalytic asymmet-
ric hydrogenation of imines using cationic iridium com-
plexes with chiral N,P ligands.[1] In seeking to broaden the
utility of this class of catalysts, we studied the asymmetric
hydrogenation of unfunctionalized enamines as a route to
optically active tertiary amines. In contrast with the well
known hydrogenation of enamides or other functionalized
enamines,[2] there are only few examples of successful asym-
metric hydrogenations of unfunctionalized enamines: Buch-
wald and Lee employed an ansa-titanocene complex that
gave high enantioselectivities with various (1-arylvinyl)-
strates; hydrogenation of 1a proceeded well using Ir-phox
complexes such as 3, whereas Ir-threphox complexes such as
4 gave poor results, especially in terms of enantioselectivity,
while the reverse behavior was observed for 1b. Thus, after
an exhaustive screening of catalysts and reaction conditions
for the two enamines (see Supporting Information for de-
tails), two optimized methods were established, one for N-
aryl- and and one for N-benzyl-substituted enamines
(Table 1). Method A, which involves the use of 1 mol% of
phox catalyst 3, under 10 or 50 bar of hydrogen pressure
(depending on the substrate) in CH2Cl2, gave high conver-
sion and ee values of 90–91% for enamines 1a–c (Table 1,
entries 1–4). While the substituents at the N-phenyl group
had essentially no effect on the enantioselectivity, the para-
methoxy group in derivative 1b reduced the reactivity such
that 50 bar of hydrogen pressure were necessary to obtain
full conversion (Table 1, compare entries 2 and 3). Method
B, which involves the use of 0.5 mol% of commercially
available threphox complex 4[7] under 10 or 50 bar of hydro-
gen pressure in CH2Cl2 or TBME, gave poor results with
this class of enamine, but was more effective for the asym-
metric hydrogenation of enamines with a benzyl-substituted
nitrogen atom (Table 1, entries 5–10). Amine 2d was ob-
tained with full conversion and high enantioselectivity, com-
parable to the ee reported by Buchwald and Lee[3] for this
substrate, using either CH2Cl2 or TBME as solvent (Table 1,
entries 5 and 6). The presence of para substituents at the
phenyl ring attached to the double bond had a negative
effect on both reactivity and enantioselectivity. Although
full conversion could be obtained at 50 bar of H2 pressure,
enantioselectivities were only moderate (Table 1, entries 7–
10). The hydrogenation of enamines 1e and 1 f was found to
be very sensitive to the choice of solvent. While enamine 1e
gave higher conversion and better enantioselectivity in
TBME than in CH2Cl2, the opposite trend was observed for
enamine 1 f.
ACHTUNGTRENNUNGamines, although relatively high catalyst loadings (typically
5 mol%) were required.[3] Bçrner and co-workers, with a
rhodium–diphosphine catalyst, obtained moderate enantio-
meric excesses with a cyclic and an acyclic vinylamine,[4] and
more recently, the group of Zhou achieved enantioselectivi-
ties of 87 to >99% ee in the hydrogenation of 1-(1,2-diary-
lvinyl)pyrrolidines by using a rhodium catalyst derived from
a spiro phosphonite ligand.[5] Here we report the application
of cationic iridium catalysts with chiral oxazoline- or pyri-
dine-based N,P ligands for the asymmetric hydrogenation of
various unfunctionalized enamines.[6]
Initial studies were performed with enamines having a ter-
minal double bond. Thus, N-methyl-N-phenyl- (1a) and N-
methyl-N-benzyl-(1-phenylvinyl)amine (1d) were hydrogen-
ated by using a range of iridium complexes under 50 bar of
H2 in CH2Cl2 for 2 h. A brief catalyst screening revealed a
pronounced difference in behavior between the two sub-
[a] Dr. A. Baeza, Prof. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
The furyl-substituted enamine 1g proved to be much less
reactive than the phenyl-substituted analogue. It was neces-
sary to raise the reaction temperature to 08C to achieve full
conversion and the ee did not exceed 50% (Table 1,
E-mail: andreas.pfaltz@unibas.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802576.
2266
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2266 – 2269

COMMUNICATION
Table 1. Asymmetric hydrogenation of enamines 1a–j.
of the tert-butyl-substituted enamine 1 f was slow and unse-
lective (Table 1, entry 14). At room temperature the reac-
tion went to completion but led to racemic product.
The results show that iridium complexes 3 and 4 are
active catalysts for the hydrogenation of enamines giving
full conversion with catalyst loadings of 0.5–1 mol%. The
enantiomeric excesses strongly depend on the substitution
pattern at the C=C bond and the nitrogen atom. A N-aryl
or N-benzyl group seems to have a benficial effect on the
enantioselectivity. With enamines 1a–d the ee values were
comparable to those reported for the hydrogenation of anal-
ogous enamines using titanocene catalysts.[2] While titano-
cene catalysts have been successfully applied to a broader
range of enamines than catalysts 3 and 4, iridium complexes
are more active, which allows substantially lower catalyst
loadings.
Once the ability of iridium-P,N complexes for the asym-
metric hydrogenation of unfunctionalized enamines with a
terminal double bond was demonstrated, 1,2-disubstituted
enamines were the next objective. First, cyclic substrates,
such as 5a, were examined. The hydrogenation of enamines
of this type has not been reported yet. After an extensive
catalyst screening and optimization of the reaction condi-
tions (see Supporting Information for details), the threphox
catalyst 4 was found to provide the best results under condi-
tions similar to those of Method B, but with 50 bar of hydro-
gen pressure and 1 mol% catalyst loading (Scheme 1). In
this case, TBME proved to be the solvent of choice giving
up to 87% ee, whereas the ee in CH2Cl2 was only 80%.
Method A
Method B
Entry Enamine
1
Conv.
ee [%][c]
Conv.
ee
[%][b]
[%][b]
[%][c]
98
91 (+)
51
13(+)
2
3
70
>99
87 (+)
90 (+)
43
>99
20(+)
17(+)
G
ACHTUNGTRENNUNG
90.5 (+
4
>99
55(+)
)
5
6
>99
78 (+)
>99
92(À)
–
–
>99[d]
92.5(À)
>99
AHCTUNGTRENGN(UN 50 bar)
7
8
56 (+)
73
93
65(À)
74(À)[d]
–
–
AHCTUNGTRENGN(UN 50 bar)
9
10
88
98
(50 bar)
27 (+)
19 (+)
62
>99
ACHTUNGTRNE(NUNG 50 bar)
76(À)
75(À)
G
11
>99[e]
>99
7 (+)
98[e]
50(À)
12
13
14
44 (S)
18 (+)
21[f]
>99
8(R)
54(À)
n.d.[g]
Scheme 1. Asymmetric hydrogenation of cyclic enamines with catalyst 4.
>99
>99
53
(50 bar)
26
ACHTUNGTRNE(NUNG 50 bar)
When imines 5b and 5c (see Scheme 2) were subjected to
these conditions, low (<10%) or no conversion was ob-
tained, respectively. Therefore, the temperature was raised
G
[a] Reactions were carried out under 10 bar hydrogen pressure, in
CH2Cl2, and at À208C unless otherwise specified. [b] Determined by GC
analysis after removal of the catalyst (see Supporting Information for de-
tails). [c] Determined by HPLC analysis on a Daicel Chiralcel OJ column
(see supporting information for details). [d] TBME was used as solvent.
1
[e] The reaction was carried out at 08C. [f] Determined by H NMR anal-
ysis of the diasteromers resulting from addition of (R)- or (S)-O-methyl-
mandelic acid (see Supporting Information for details). [g] Not deter-
mined.
entry 11). Enamines bearing alkyl substituents on the nitro-
gen afforded low enantioselectivities with both methods, al-
though full conversions were obtained under 50 bar of hy-
drogen pressure (Table 1, entries 12 and 13). Hydrogenation
Scheme 2. Asymmetric hydrogenation of cyclic enamines with catalyst 7.
Chem. Eur. J. 2009, 15, 2266 – 2269
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2267

A. Pfaltz and A. Baeza
to 258C, resulting in full conversion and 59% ee for enam-
ine 5c when the reaction was carried out in TBME, but
again no reaction was observed with 5b. Therefore, other
catalysts were examined (see Supporting Information for de-
tails). Complex 7 derived from a pyridine–phosphinite
ligand, that had previously shown exceptionally high reactiv-
ity in the hydrogention of furans,[8] proved to be the most re-
active catalyst in this case. With 1 mol% of catalyst 7 under
50 bar hydrogen pressure at 08C in CH2Cl2, enamine 5c was
fully hydrogenated with 71% ee (Scheme 2). Attempts to in-
crease the enantioselectivity by decreasing the temperature
to À208C were unsuccessful. Although the enantioselectivity
raised to 76%, the conversion dropped to 47%. Unfortu-
nately, all attempts to hydrogenate enamine 5b, using vari-
ous catalysts and reaction conditions failed.
We next tested analogous acyclic enamines using 8a and
8b as substrates, the latter isolated as a 95:5 E/Z mixture.
Since the results obtained with catalyst 7 were unsatisfacto-
ry, additional catalysts were screened (see Supporting Infor-
mation for details). Among them, complex 10 was identified
as the most effective catalyst for the asymmetric hydrogena-
tion of substrate 8b. At 08C and 1 mol% catalyst loading
under 50 bar of hydrogen pressure it gave the corresponding
amine 9b with full conversion and 67% ee (Scheme 3). At
Scheme 4. Asymmetric hydrogenation of acyclic enamine 11.
with high conversion and 69% ee in CH2Cl2 at room temper-
ature under 50 bar hydrogen pressure (Scheme 4).
In summary, we have found that cationic iridium com-
plexes with chiral oxazoline- or pyridine-based N,P ligands
are active catalysts for the asymmetric hydrogenation of en-
amines. The best results were obtained with (1-phenylvinyl)-
amines bearing a phenyl or benzyl substituent on the nitro-
gen atom, which were hydrogenated with enantiomeric ex-
cesses of >90%. Enantioselectivities in the hydrogenation
of cyclic and acyclic 1,2-disubstituted enamines were lower.
Nevertheless, the cyclic enamine 6a was converted to the sa-
turated amine with 87% ee. With the exception of (1,2-dia-
rylvinyl)amines 11 the asymmetric hydrogenation of disub-
stituted enamines of this type has not been reported before.
These results show that iridium complexes with chiral N,P li-
gands[9] are useful catalysts for the asymmetric hydrogena-
tion of enamines that broaden the scope of this transforma-
tion.
Experimental Section
General procedure for the iridium-catalyzed asymmetric hydrogenation
of enamines: A solution of the enamine (0.2 mmol) and the iridium com-
plex (1 mol% or 0.5 mol%) in dry dichloromethane or TBME (1 mL)
under inert atmosphere was placed in an autoclave, which was sealed and
placed in cooling bath for one hour at the appropriate temperature.
After this time, the autoclave was purged with hydrogen, pressurized to
the desired hydrogen pressure, and stirred at the corresponding tempera-
ture for the indicated time. Then, the solvent was evaporated and the cat-
alyst removed by filtration through a short silica gel column (3ꢁ1 cm)
with a 1:1 mixture of pentane and diethyl ether as eluent, giving the
amine product as a pure compound after evaporation of the solvent. For
amines which still contained impurities after filtration, an extractive
acidic workup was carried out to obtain the pure compounds.
Scheme 3. Asymmetric hydrogenation of acyclic enamines with catalyst
10.
À208C the reaction still went to completion but disappoint-
ingly, the enantioselectivity did not improve. As observed
for the cyclic enamine 5b the N-phenyl derivative 8a did
not react under these conditions. With the more reactive
pyridine-based catalysts of type 7, partial hydrogenation was
observed at room temperature but the enantioselectivity
was low.
For catalyst screening, reactions were performed on a 0.1 mmol scale.
See Supporting Information for details and analytical data of compounds.
The pyrrolidine enamine 11 was also tested (Scheme 4).
The asymmetric hydrogenation of this substrate has been
previously reported by Zhou and co-workers, who obtained
full conversion and enantioselectivities of up to 87% ee
using 2 mol% of a rhodium spiro-phosphonite complex, and
2 mol% of iodine and 20 mol% of acetic acid as additives.[5]
Again complex 7 proved to be the most active catalyst,
giving full conversion even at À208C, although with poor
enantioselectivity (up to 41% ee; see Supporting Informa-
tion for details). Better results were obtained with the oxa-
zoline–phosphinite complex 13, which afforded amine 12
Acknowledgements
A. Baeza would like to thank the Spanish Ministerio de Educaciꢂn, Cien-
cia y Deporte (MECD) and Fundaciꢂn EspaÇola para la Ciencia y la
Tecnologꢃa (FECYT) for a Postdoctoral fellowship. Support of this work
by the Swiss National Science Foundation and the Federal Commission
for Technology and Innovation (KTI) is gratefully acknowledged.
2268
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2266 – 2269

Ir-Catalyzed Asymmetric Hydrogenation of Unfunctionalized Enamines
COMMUNICATION
[3] N. E. Lee, S. L. Buchwald, J. Am. Chem. Soc. 1994, 116, 5985.
[4] V. I. Tararov, R. Kadyrov, T. H. Riermeier, J. Holz, A. Bçrner, Tetra-
hedron Lett. 2000, 41, 2351.
Keywords: amines
hydrogenation · enamines · iridium
· asymmetric catalysis · asymmetric
[5] G.-H. Hou, J.-H Xie, L.-X. Wang, Q.-L. Zhou, J. Am. Chem. Soc.
2006, 128, 11774.
[1] a) P. Schnider, G. Koch, R. Prꢄtꢅt, G. Wang, F. M. Bohnen, C.
Krꢆger, A. Pfaltz, Chem. Eur. J. 1997, 3, 887; b) A. Trifonova, J. S.
Diesen, C. J. Chapman, P. G. Andersson, Org. Lett. 2004, 6, 3825;
c) A. Trifonova, J. S. Diesen, P. G. Andersson, Chem. Eur. J. 2006, 12,
2318; d) C. Moessner, C. Bolm, Angew. Chem. 2005, 117, 7736;
Angew. Chem. Int. Ed. 2005, 44, 7564; e) S. F. Zhu, J. B. Xie, Y. Z.
Zhang, S. Li, Q. L. Zhou, J. Am. Chem. Soc. 2006, 128, 12886;
f) M. N. Cheemala, P. Knochel, Org. Lett. 2007, 9, 3089.
[6] After completion of this manuscript, Andersson et al. reported the
hydrogenation of a-substituted vinylamines with up to 87% ee using
iridium catalysts derived from bicyclic aminophosphine–oxazoline li-
gands: P. Cheruku, T. L. Church, A. Trifonova, T. Wartmann, P. G.
Andersson, Tetrahedron Lett. 2008, 49, 7290.
[7] a) F. Menges, A. Pfaltz, Adv. Synth. Catal. 2002, 344, 40; b) S. McIn-
tyre, E. Hçrmann, F. Menges, S. P. Smidt, A. Pfaltz, Adv. Synth.
Catal. 2005, 347, 282.
[2] For reviews see: a) J. M. Brown in Comprehensive Asymmetric Catal-
ysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, p. 121; b) J. M. Brown in Handbook of Homogeneous
Hydrogenation, Vol. 2 (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-
VCH, Weinheim, 2007, p. 1073; c) F. Spindler, H. U. Blaser in Hand-
book of Homogeneous Hydrogenation, Vol. 2 (Eds.: J. G. de Vries,
C. J. Elsevier), Wiley-VCH, Weinheim, 2007, p. 1193; d) H. U. Blaser,
F. Spindler, M. Thommen in Handbook of Homogeneous Hydrogena-
tion, Vol. 2 (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH, Wein-
heim, 2007, p. 1279, and references therein.
[8] a) S. Bell, B. Wꢆstenberg, S. Kaiser, F. Menges, T. Netscher, A.
Pfaltz, Science 2006, 311, 642; b) S. Kaiser, S. P. Smidt, A. Pfaltz,
Angew. Chem. 2006, 118, 5318; Angew. Chem. Int. Ed. 2006, 45, 5194.
[9] For other applications of these catalysts, see: a) S. Roseblade, A.
Pfaltz, Acc. Chem. Res. 2007, 40, 1402; b) K. Kꢇllstrçm, I. Munslow,
P. G. Andersson, Chem. Eur. J. 2006, 12, 3194; c) X. Cui, K. Burgess,
Chem. Rev. 2005, 105, 3272.
Received: December 8, 2008
Published online: January 28, 2009
Chem. Eur. J. 2009, 15, 2266 – 2269
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2269