New P, N ligands for asymmetric Ir-catalyzed reactions

Article abstract of DOI:10.1002/anie.200351936

Chiral Ir complexes such as 1 catalyze the hydrogenation of (E)-1, 2-diphenylpropene at 1 bar of H₂ to give (5)-1, 2-diphenylpropane with up to 95% ee and full conversion (see scheme). Methyl (Z)-α -(acetamido)cinnamate underwent enantioselective hydrogenation under similar conditions to the corresponding amino acid derivative with up to 96% ee. BARF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, cod = 1, 5-cyclooctadiene.

Full text of DOI:10.1002/anie.200351936

Angewandte
Chemie
The treatment of these unsaturated pyridines with di-
phenylphosphane (Ph2PH), dicyclohexylphosphane ((c-
C6H11)2PH), or diphenylphosphane oxide (Ph2P(O)H) in
dimethyl sulfoxide (DMSO) or N-methylpyrrolidinone
(NMP) in the presence of a catalytic amount of tBuOK
(20 mol%) provided the phosphane oxides 16a–d and 17a–b
in 55–93% yield.[2c] The phosphane oxides were reduced with
HSiCl3/Et3N in toluene[7] to give the desired P,N ligands 1–6 in
60–92% yield (Scheme 2). The relative stereochemistry of the
P,N ligands was established by NOESY NMR experiments
and by X-ray crystal-structure analysis (see Supporting
Information).[8]
Although a number of terpene-derived ligands have been
prepared and used in asymmetric catalysis,[9] these new
modular ligands, in which a broad range of pyridyl and
related heterocycles can be incorporated, display particularly
high enantioselectivities in asymmetric iridium-catalyzed
Asymmetric Hydrogenation
New P,N Ligands for Asymmetric Ir-Catalyzed
Reactions**
Tanasri Bunlaksananusorn, Kurt Polborn,
and Paul Knochel*
In memory of Alain Louis Rodriguez
The preparation of new ligands for asymmetric
metal catalysis has led in recent years to the
discovery of several new classes of chiral ligands.[1]
Recently, we reported tBuOK-catalyzed addition
reactions of nucleophiles (carbonyl derivatives
and phosphanes) to a variety of functionalized
alkenes.[2] Herein, we report the use of this
method for the preparation of the new chiral
P,N ligands[3] 1–6 (see Scheme 2) from readily
available chiral building blocks such as d-(+)-
camphor (7) and (R)-(+)-nopinone (8). We show
that these ligands can be used for highly enantio-
selective Ir-catalyzed hydrogenations.
Scheme 1. The synthesis of 2-alkenylpyridines 13–15: a) [Pd(dba)2] (2 mol%), dppf (2 mol%),
alkenyl triflate 9 or 10, THF, LiCl, reflux, overnight; b) [Pd(PPh3)4] (5 mol%), PhB(OH)2,
Na2CO3, toluene, MeOH, H2O, 858C, overnight. dba=dibenzylideneacetone, dppf=1,1’-bis-
(diphenylphosphanyl)ferrocene.
The known alkenyl triflate[4] 9 underwent
smooth Negishi cross-coupling reactions[5] to
afford the desired 2-alkenyl pyridines 13a–c in
35–78% yield[6] and the 2-alkenyl quinoline 14 in
65% yield. Similarly, the alkenyl triflate 10 was
converted into the 2-alkenyl pyridines 15a–c in
69–85% yield (Scheme 1).
[*] Prof. Dr. P. Knochel, T. Bunlaksananusorn,
Dr. K. Polborn
Department Chemie, Ludwig-Maximilians-Universität
Butenandtstrasse 5–13, Haus F,
81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie for
financial support. We thank BASF AG (Ludwigshafen),
Bayer AG (Leverkusen), and Chemetall GmbH
(Frankfurt) for the generous gift of chemicals.
Supporting information for this article is available on
the WWW under http://www.angewandte.org or from
the author.
Scheme 2. Preparation of the P,N ligands 1–6.
Angew. Chem. Int. Ed. 2003, 42, 3941 –3943
DOI: 10.1002/anie.200351936
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3941

Communications
hydrogenations.[10,11] Thus, the P,N ligands 1–6 were heated
Table 1: Iridium-catalyzed enantioselective hydrogenation of 19a and
19b in toluene at 258C.
with [{Ir(cod)Cl}2] in CH2Cl2 (408C, 1 h), and the reaction was
quenched with sodium tetrakis(3,5-bis(trifluoromethyl)phen-
yl)borate (NaBARF) or with NH4PF6 in water to give the
corresponding iridium complexes 18a–f in 75–89% yield,
according to the procedure of Pfaltzand co-workers
(Scheme 3).[11]
Entry
18 (mol%)
19
P [bar][a]
t [h]
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a (1.0)
a (1.0)
a (0.5)
a (1.0)
a (0.5)
b (1.0)
c (1.0)
d (1.0)
d (1.0)
d (1.0)
d (0.5)
d (0.1)
d (0.1)
e (1.0)
a (1.0)
d (1.0)
d (1.0)
d (1.0)
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
50
50
50
1
1
50
1
50
50
1
1
1
50
50
50
50
1
12
12
12
5
44
100
100
91
90
6
93.5[d]
95.0
95.0
95.0
95.0
–
80.0
95.0
94.0
95.0
96.0
–
95.0
80.0[e]
91.0
94.7
94.0
95.2[d]
2
12
12
12
2
5
2
12
12
2
2
2
80
100
100
100
96
1
92
26
87
100
76
75
2
2
50
[a] Reaction pressure. [b] Conversion. [c] The enantiomeric excess was
determined by HPLC on a chiral phase (Daicel Chiracel OJ column). The
products have the S configuration unless otherwise indicated. [d] This
reaction was performed in CH2Cl2. [e] R configuration.
We found that the hydrogenation of 24 under our
standard conditions (H2 (50 bar), room temperature,
12 h) in CH2Cl2/MeOH (10:1) in the presence of the
chiral Ir catalysts 18a and 18d provided the phenyl-
alanine derivative 25 in 100% conversion and with
95.4% ee and 95.3% ee, respectively. Moreover, when
the reaction was carried out the higher temperature of 508C
and at just 1 bar of H2, 100% conversion and an excellent
96.5% ee were observed (Scheme 4). These results show the
potential of Ir complexes for new applications in the
asymmetric synthesis of amino acids.
In summary, we have prepared a new type of P,N ligand,
which facilitates the Ir-catalyzed enantioselective hydrogena-
tion of unactivated stilbene derivatives and dehydroamino
acid derivatives. Because of the modular synthesis[12] of these
ligands, their stereochemical and electronic properties can be
tuned to optimize the enantioselectivity of a given asymmetric
reaction or for a particular substrate. Further applications in
new asymmetric reactions are currently underway in our
laboratories.[13]
Scheme 3. Preparation of the chiral Ir complexes 18a–f and their use in the asymmetric
hydrogenation of 19a and 19b. cod=1,5-cyclooctadiene.
The Ir-catalyzed hydrogenation of (E)-1,2-diphenylpro-
pene (19a) and 2-(4-methoxyphenyl)-1-phenyl-1-propene
(19b) was performed at room temperature in the presence
of complexes 18a–e (0.1–1 mol%; Table 1). A slower reaction
was observed in CH2Cl2, and excellent conversion was
observed in toluene (see Table 1, entries 1 and 2). Remark-
ably, the use of complex 18d, which contains a quinolyl group,
led to high conversions and high enantioselectivities (Table 1,
entries 8–13). As a result of the high activity of this catalyst,
the reaction can be carried out at 1 bar of hydrogen (Table 1,
entries 10, 11, and 12). Similar results were obtained with 19b
(Table 1, entries 15–18). Catalyst 18d was the most active of
those studied (see Table 1, entries 15 and 16). Other sub-
strates, such as ethyl 3-phenylbut-2-enoate (21), 2-methyl-3-
phenylallyl alcohol (22), and 2-methyl-3-phenylallyl acetate
(23), were also hydrogenated in the
presence of catalyst 18d (1 mol%; H2
(50 bar), room temperature, 12 h), and
the desired reduced products were
obtained with moderate to good enantio-
selectivities (58–80% ee; Scheme 4).
The hydrogenation of unsaturated
enamides such as 24 to amino acid
derivatives such as 25 is of special inter-
est. This enantioselective hydrogenation
has been studied extensively in the pres-
ence of Rh catalysts.[1] To our knowledge,
no enantioselective Ir-catalyzed hydro-
genation of this type has been reported.
Scheme 4. Ir-catalyzed hydrogenation of unsaturated substrates with catalysts 18a and 18d.
conv.=conversion.
3942
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Angewandte
Chemie
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Preparation of (S)-25: An autoclave was charged with 18a (4.7 mg,
3.0 mmol, 1 mol%), 24 (65 mg, 0.3 mmol), CH2Cl2 (3 mL), and MeOH
(0.3 mL). The autoclave was then sealed and pressurized to 1 bar of
H2, and the reaction mixture was stirred at 508C for 2 h. The CH2Cl2
and MeOH were then removed and the crude product was passed
through a short column of silica gel with diethyl ether as eluent. After
evaporation of the solvent, (S)-25 was obtained in quantitative yield
and with 96.5% ee. The ee value was determined by GC on a chiral
phase (Chiralsil L-Val); 1408C: tr = 10.5 (R), 11.5 min (S).
Received: May 20, 2003 [Z51936]
Keywords: asymmetric catalysis · cross-coupling ·
.
hydrogenation · iridium · N,P ligands
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