Access to chiral tertiary amines via the iridium-catalyzed asymmetric hydrogenation of enamines

Article abstract of DOI:10.1016/j.tetlet.2008.10.035

The asymmetric hydrogenation of N,N-dialkyl and N-alkyl-N-aryl enamines to chiral tertiary amines was studied. All the N,P-ligated iridium complexes investigated were active catalysts for the reaction, but only those with bicycle-supported oxazoline-phosp

Full text of DOI:10.1016/j.tetlet.2008.10.035

Tetrahedron Letters 49 (2008) 7290–7293
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Tetrahedron Letters
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Access to chiral tertiary amines via the iridium-catalyzed
asymmetric hydrogenation of enamines
*
Pradeep Cheruku, Tamara L. Church, Anna Trifonova, Thomas Wartmann, Pher G. Andersson
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S751-23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric hydrogenation of N,N-dialkyl and N-alkyl-N-aryl enamines to chiral tertiary amines was
studied. All the N,P-ligated iridium complexes investigated were active catalysts for the reaction, but only
those with bicycle-supported oxazoline-phosphine ligands gave reasonable stereoinduction. The best
catalyst produced a range of chiral tertiary amines in up to 87% ee.
Received 8 September 2008
Revised 29 September 2008
Accepted 8 October 2008
Available online 14 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Hydrogenation
Enamines
Chiral tertiary amines
The prevalence of chiral trialkyl and dialkylaryl tertiary amines
can hardly be overstated. They are present in myriad natural prod-
ucts, including Cinchona, tetrahydroisoquinoline, and tetrahydro-
b-carboline alkaloids. They are also used as enantioselective organ-
ocatalysts1 and as ligands for asymmetric transition metal cata-
lysts.2 Chiral tertiary amines have been synthesized by several
methods; however, the discovery and development of routes to
this class of compounds are ongoing. Turner and co-workers
recently developed a chemoenzymatic system for the dynamic
kinetic resolution of cyclic tertiary amines.3 Hartwig and co-
workers have reported the iridium-catalyzed, enantioselective
allylic amination of allyl acetates,4 carbonates4 and alcohols5 to
produce chiral tertiary amines in good or high yields and high ee
values. Asymmetric allylic amination has since been accomplished
with other palladium6 and iridium7 catalysts, though each was
applied to make only one or two tertiary amines. The copper-
catalyzed addition of terminal alkynes to isoquinoline iminium
ions has been shown to yield N-alkylated (i.e., tertiary) isoquino-
lines with chirality in the 1 position.8
R2
R2
Catalyst
Catalyst
N
HN
*
a
b
+ H2
R1
R1
Imine
2° Amine
R2
R2
+
R1
N
R3
R1
N
+
+
H2
*
R3 X-
Iminium
(R2, R3 = H)
3° Amine
R2
R2
Catalyst
R1
N
R3
R1
N
R3
H2
c
*
Enamine
(R2, R3 = H)
3° Amine
Scheme 1. Asymmetric hydrogenation as a route to chiral amines.
Catalytic enantioselective hydrogenation is currently a major
source of chiral materials, and can be envisioned as a route to chi-
ral tertiary amines. Considerable progress has been made in the
enantioselective hydrogenation of imines, which can produce chi-
ral secondary amines very selectively (Scheme 1a).9 Though ter-
tiary amines cannot be produced by imine hydrogenation, they
are accessible from the hydrogenation of iminium salts (Scheme
1b) and enamines (Scheme 1c). In 2001, Magee and Norton re-
ported the direct asymmetric hydrogenation of two iminium salts
to tertiary amines with modest ee values;10 in 2006, Zhu, Deng,
and co-workers used asymmetric transfer hydrogenation to con-
vert two iminium ions to tertiary amines very stereoselectively.11
The latter method has been applied to the synthesis of some
naturally occurring alkaloids.12 The asymmetric hydrogenation of
enamines has also been achieved. In the earliest report, Lee and
Buchwald used a titanocene catalyst to hydrogenate a range of
enamines to chiral tertiary amines with high ee values.13 Though
* Corresponding author. Tel.: +46 18 471 3801; fax: +46 18 471 3818.
E-mail address: pher.andersson@biorg.uu.se (P. G. Andersson).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.035

P. Cheruku et al. / Tetrahedron Letters 49 (2008) 7290–7293
7291
Table 1
5 mol % of catalyst was required, good yields were obtained. The
rhodium-catalyzed asymmetric hydrogenations of b-amino- ,b-
Screening of N,P ligands in the asymmetric hydrogenation of
a-(diethylamino)-
a
*
styrene, 1, by [(L )Ir(COD)]+[BArF]À
unsaturated esters and amides have also been reported, and can
be very stereoselective.14 However, only primary and secondary
amines have been synthesized this way; in one case, evidence sug-
gests that the reaction is actually a hydrogenation of the imine tau-
tomer of the substrate.14c Rhodium catalysts have also been
applied to the asymmetric hydrogenation of enamines without
additional coordinating groups. Börner and co-workers published
the hydrogenation of this type of enamine to tertiary amines in
up to 72% ee,15 whereas Zhou and co-workers obtained better
enantioselectivities using a rhodium catalyst in combination with
iodine and acetic acid.16 Kalck et al. recently described the
asymmetric hydrogenation of enamines by rhodium and iridium
catalysts in an ionic liquid; a wide range of ee values were
reported.17
The successes reported in the asymmetric hydrogenation of en-
amines suggest that it is a viable route to chiral tertiary amines,
and the reaction is especially attractive considering the straightfor-
ward substrate synthesis.18 However, very few asymmetric enam-
ine hydrogenations have been demonstrated. The promise showed
by this reaction, coupled with the need for further development in
the synthesis of chiral tertiary amines, led us to pursue enamines
as substrates in our iridium-catalyzed hydrogenation studies. Irid-
ium complexes with chiral N,P or N,C ligands have been used
extensively in the asymmetric hydrogenation of imines9 and of lar-
gely unfunctionalized olefins19,20 and have recently been applied to
the asymmetric hydrogenation of olefins with weakly coordinating
or non-coordinating functional groups21 such as vinyl fluorides,22
vinyl silanes,23 vinyl phosphonates24 and enol phosphinate es-
ters.25 Especially relevant to enamine reduction are the recent
asymmetric hydrogenations of their oxygen analogues, enol
ethers,20f,26 and of heteroaromatic rings.27 Lewis bases are known
to inhibit olefin hydrogenation by N,P-ligated iridium complexes,28
so the amine functionalities in both the starting material and prod-
uct pose potential threats to iridium-catalyzed enamine hydroge-
nation. However, such catalysts are active for the hydrogenation
of imines to secondary amines, so we were hopeful that they could
also produce tertiary amines through hydrogenation.
0.5 mol% [L*Ir(COD)]+[BArF]-
H2
+
NEt2
, 0.1 M
NEt2
*
CH2Cl2, r.t., 6 h
1
50 bar
Entry
1
L*
Conv.a (%)
>99
eeb (%)
64 (+)
PPh2
N
(A)
N
O
P(o-tol)2
N
N
N
2
3
4
5
>99
>99
>99
>99
>99
84 (+)
64 (+)
0
(
B)
N
O
PPh2
(C
)
N
O
Ph
Ph
PPh2
(D)
N
S
Ph
PPh2
N
(E)
14
Ph
S
6
0
a
Conversion to
a
-(diethylamino)ethylbenzene, as determined by 1H NMR.
ee of amine product, determined by 1H NMR after reaction with (R)-O-mandelic
acid.
b
We began by testing several of our chiral iridium complexes,
which have known activity for asymmetric olefin hydrogena-
tion,22a,29,30 in the reduction of a prochiral enamine (Table 1). We
chose a-(diethylamino)styrene, 1, as the substrate for these initial
reactions. The amine functionality of 1 did not inactivate the cata-
Most of the enamines examined in this study were synthesized
lysts tested; in fact, all the catalysts converted 1 completely to the
from the corresponding ketones and secondary amines using
White and Weingarten’s TiCl4-mediated method33 and were puri-
fied by distillation.34 The substrate scope of enamine hydrogena-
tion by [(B)Ir(COD)]+[BArF]À was evaluated using the same
conditions applied to the reduction of 1: 0.5 mol % catalyst and
50 bar H2 at room temperature for 6 h (Table 2). This was sufficient
to convert most enamines to the desired tertiary amine, though a
range of enantioselectivities were obtained. For example, replacing
the phenyl group of 1 with a 4-tolyl group (entry 2) produced a
small increase in stereoselectivity, returning the corresponding
amine in 87% ee. The related substrate 3, which has a more elec-
tron-donating 4-methoxy group, however, was reduced in only
64% ee (entry 3). Improved stereoselectivity was observed in the
hydrogenation of the electron-poor 4-trimethylfluoro derivative 4
(77% ee; entry 4), though this reaction was still slightly less selec-
tive than the reduction of 1. The 2-naphthyl-substituted enamine 5
was also hydrogenated in a moderate 64% ee (entry 5).
desired tertiary amine,
a-(diethylamino) ethylbenzene, after 6 h
under 50 bar H2 at room temperature.31,32 The structurally similar
thiazole-phosphine and imidazole-phosphine ligands E and F (en-
tries 5 and 6) produced active catalysts for enamine reduction, but
imparted little or no stereoselectivity. Bicycle-based oxazoline-
phosphine ligands A–C (entries 1–3) produced catalysts that com-
bined hydrogenation activity with much better stereoselectivity.
Among these three catalysts, the substituent(s) at the 4 position
of the oxazoline ring appeared to impact stereodiscrimination of
the catalyst less than the phosphine substituents did. Two catalysts
whose ligands differed only in the oxazoline moiety (A and C, en-
tries 1 and 3) hydrogenated 1 with identical ee values, whereas
changing the –PPh2 group of A to the –P(o-tol)2 group in B pro-
duced a sizeable increase in ee for the same reaction (84% vs
64%, entries 2 and 1, respectively). Nevertheless, the oxazoline
group clearly played an important role in stereoselectivity, as a
bicycle-based thiazole-phosphine ligand (D, entry 4) produced a
catalyst that completely hydrogenated 1 to a racemic mixture of
tertiary amine products. Overall, [(B)Ir(COD)]+[BArF]À was the
most stereoselective catalyst for the hydrogenation of the test
enamine, and was therefore used in further studies of this reaction.
At first, the nature of the amine group appeared to have much
less impact on the reaction than that of the aryl group, as a-(meth-
ylphenylamino)styrene (6, entry 6) was reduced in similar ee to
the dialkylamino substrate 1 (79% vs 84%). The reaction proved
more difficult when the amino group was cyclic (entries 7 and

7292
P. Cheruku et al. / Tetrahedron Letters 49 (2008) 7290–7293
Table 2
try 10). Though the hydrogenation of this substrate yields an achi-
ral product, we were encouraged by the ability of the catalyst to
reduce enamines bearing trisubstituted olefins, as this will cer-
tainly be important in the future development of asymmetric en-
amine hydrogenation. Based on the sensitivity of the conversion
to subtle changes on the enamine, in particular amongst the cyclic
substrates, we speculate that the tertiary amine products can inhi-
bit the catalyst if they are sufficiently basic and unhindered. This
would explain why an N,N-diethylamine-functionalized enamine
such as 1 is hydrogenated to completion despite the fact that the
pyrrolidine derivative 7, which has a more exposed electron pair,
is not. (The fact that the conversion of 8 to amine reached a plateau
suggests that it is the product, rather than the starting material,
that poisons the catalyst.) The other pyrrolidine-containing sub-
strate, 10, was hydrogenated to completion; in this case, the more
hindered amine produced in the reduction of the trisubstituted
olefin may be less capable of inhibiting the catalyst. Enamines 6
and 9, despite bearing small methyl groups on the nitrogen, are
also fully hydrogenated, perhaps because they form dialkyl aryl
amines, which are less basic than trialkyl amines.
The hydrogenation of various enamines using the catalyst [(B)Ir(COD)]+[BArF]À
0.5 mol% [(B
)Ir(COD)]+[BArF]-
R3
R3
R1
N
R2
R1
N
R2
H2
+
*
CH2Cl2, r.t., 6 h
0.1 M
50 bar
Entry
1
Substrate
Conv.a (%)
>99
eeb (%)
84 (+)
(1)
NEt2
2
3
4
5
>99
>99
>99
>99
87
64
77
64
(2)
NEt2
(3)
NEt2
MeO
F3C
+
À
(4)
*
NEt2
NEt2
Several complexes of the form [(L )Ir(COD)] [BArF] are active
catalysts for the hydrogenation of N,N-dialkyl and N-alkyl-N-aryl
*
enamines to tertiary amines. When L = B, a bicycle-supported
phosphine-oxazoline ligand, the catalyst produces chiral tertiary
amines in up to 87% ee. In most cases, 0.5 mol % of catalyst was suf-
ficient to completely reduce the substrate after 6 h at room tem-
perature, though a few interesting cases of lower catalyst activity
were observed. The asymmetric reductions of nine enamines are
reported. Future work on this topic will focus on understanding
the subtle effect of enamine structure on catalyst activity, improv-
ing stereoselectivity, and extending the reaction to include enam-
ines with trisubstituted double bonds.
(5)
6
>99
79 (+)
(6)
(7)
(8)
N
N
N
7
8
66
75
33 (R)c
Acknowledgments
30
The authors are grateful to Ms. P. Kaukoranta, Mr.
A. Paptchikhine, and Dr. J. S. Diesen for providing catalyst samples,
and to The Swedish Research Council (VR; Contract 2006-3611) for
funding. T.W. is grateful to the ERASMUS-Programme, and T.L.C. is
grateful to Wenner-Gren Stiftelserna for a postdoctoral fellowship.
O
(9)
N
N
9
>99
>99
20
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a
b
ee of amine product, determined by 1H NMR after reaction with (R)-O-mandelic
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Determined based on comparison of the 1H NMR spectrum of the (R)-O-man-
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d
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a-(4-morpholino)styrene (8),
which was hydrogenated to 75% conversion and in 30% ee after
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substrate (0.2 mmol) and Ir complex (0.5 mol %). Dry CH2Cl2 (2 mL) was
added and the vial was placed in a steel bomb. The bomb was purged three
times with hydrogen, then filled to 50 bar with H2 gas. After stirring for 6 h
at room temperature, the pressure was released and the solvent was
removed in vacuo. The crude product was chromatographed (EtOAc/
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(1-cyclohexen-1-yl)pyrrolidine (Table 2, entry 10) were purchased from
Aldrich and used as received.