Angewandte
Communications
Chemie
the synthesis of a small library of MaxPHOX–Ir catalysts and
examined their performance in the asymmetric hydrogena-
tion of cyclic enamides.
Chiral iridium–N,P complexes have been developed into
the catalysts of choice for the hydrogenation of nonfunction-
alized and minimally functionalized alkenes.[10] However,
little attention has been paid to the use of such catalytic
systems for the hydrogenation of alkenes bearing a metal-
coordinating group.[11]
Herein we report the synthesis of a MaxPHOX–Ir catalyst
library. This library enabled us to identify the structural
features necessary for complete control of enantioselectivity
in the hydrogenation of enamides derived from b-tetralones.
Thus, we show how iridium-based catalysts outperform the
best Ru and Rh systems for the hydrogenation of this class of
alkenes.
The optimized synthesis of the MaxPHOX catalyst library
is shown in Scheme 3. The N-Boc-protected amino acid was
coupled to the corresponding amino alcohol by the use of
isobutyl chloroformate. Removal of the Boc group afforded
the corresponding amino alcohols 3a–h, which were sub-
sequently coupled to the chiral phosphinyl mesyl anhydride
derived from (S)-tert-butyl(methyl)phosphinous acid
borane[9,12,13] with inversion of configuration at the P center
to provide the open-chain borane-protected aminophosphine
alcohols 4a–h. This key coupling reaction in the synthetic
sequence is highly chemoselective for amine nucleophiles; no
reaction was observed at the alcohol position. Next, 4a–h
were subjected to alcohol activation and base-induced chain
cyclization to produce the corresponding borane-protected
phosphine–oxazoline ligands 5a–h. We found that the ligand
synthesis was more general and efficient when the oxazoline
cyclization was carried out at a later stage. Finally, removal of
the borane protecting group with neat pyrrolidine, treatment
with [{Ir(cod)Cl}2], and counterion exchange with NaBArF
afforded the corresponding MaxPHOX–Ir complexes 6a–h in
good to excellent yields.
Complexes 6a–h had the same S configuration at the
P center.[12] The four possible diastereomers with isopropyl
groups at the tail and the oxazoline positions were synthesized
((SP,R,S)-6b, (SP,S,S)-6d, (SP,R,R)-6e, (SP,S,R)-6 f)). We also
synthesized complexes 6a, 6c, 6g, and 6h to study the effect
of the substituent on the oxazoline heterocycle.
Scheme 3. Synthesis of MaxPHOX ligands and the corresponding
iridium complexes. cod=1,5-cyclooctadiene, DCM=dichloromethane,
Ms=methanesulfonyl.
We then studied the hydrogenation of N-(3,4-dihydro-
naphthalen-2-yl)acetamide (2) with this small library of
catalysts (Table 1). When the hydrogenation reaction was
carried out at a catalyst loading of 1 mol% under 50 bar of H2
in CH2Cl2 at room temperature with catalysts bearing the
same substituents but with different relative configurations
(6b, 6d, 6e, 6 f), matched–mismatched behavior with respect
to the configurations at the oxazoline and P center became
clear. With catalysts 6e (SP,R,R) and 6 f (SP,S,R) with the
matched configuration, the selectivity increased to 96 and
97% ee. Finally, when we changed the substituent on the
oxazoline ring to a tert-butyl group and kept the best relative
configuration found (SP,S,R; catalyst 6g), we obtained the
product of the hydrogenation of 2 with over 99% ee.
With the second-best catalyst 6 f, we next studied the
effect of the solvent and hydrogen pressure on the hydro-
genation of cyclic enamides. When DCM was used as the
solvent, a decrease in hydrogen pressure resulted in an
increase in selectivity (Table 2, entries 1–3). Reactions at 10
and 3 bar of hydrogen resulted in complete conversion and
total enantioselectivity (99% ee). Environmentally friendly
solvents, such as methanol and ethyl acetate, also proved
appropriate for the present catalytic system (Table 2,
entries 4–8). A similar dependence of selectivity on the
hydrogen pressure was found for these solvents. At 10 bar
of hydrogen, 99% ee was reached in MeOH (Table 2,
entry 5). Also in EtOAc, the pressure could be lowered to
3 bar to enable total conversion and selectivity (Table 2,
entry 8). Therefore, a catalyst with a tert-butyl-substituted
oxazoline group is not mandatory for complete stereocontrol
2
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!