.
Angewandte
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with more electron-rich doubly oxygenated ligand frame-
works. When the phosphole-containing MP2-SEGPHOS
(L12) was employed, the chiral piperidine 2 (Ar= Ph) was
obtained in 96% ee. High ee values were also observed for
two other structurally diverse N-benzylpyridinium bromides
(Ar= 2-MeCO2C6H4 and 4-MeOC6H4), thus suggesting that
a general protocol might be achievable. The size of the
phosphole substituents was found to be critical (L12 and L13),
as evidenced by the increased selectivity when a less sterically
encumbered phosphole was employed.
It is worth noting that to the best of our knowledge the
results obtained with L12 represent the first reported
examples of the use of MP2-SEGPHOS in a highly efficient
asymmetric reaction.[11] A number of unique features of
phospholes may contribute to the observed high efficiency
and enantioselectivity in the reactions employing MP2-
SEGPHOS as a ligand. Firstly, the previously noted relation-
ship between the selectivity of the asymmetric hydrogenation
and donor capacity of the ligand would be further enhanced
by the phosphole functionality of MP2-SEGPHOS
(Scheme 1).[12] Secondly, the rigidity[13] and planarity[14] of
the phosphole unit would be expected to provide a well-
defined chiral pocket[15] around the reactive site which is
substantially different from those seen with other C2-sym-
metric bis(phosphine) ligands.
Scheme 1. Order of electron-donating ability of phosphorus ligands.
[a] Infrared data for [LMo(CO)5] complexes.[12] Only the highest energy
u(CO) is given.
Figure 2. Selected results of ligand screen for asymmetric hydrogena-
tion of N-alkyl-2-phenylpyridium bromide substrates using iridium
catalysts. Reactions were carried out using 0.01 mmol of substrate in
0.12 mL of mixed solvent. Absolute enantiomeric excesses were
determined by SFC using a chiral stationary phase. Ar1=2-
MeCO2C6H4 and Ar2=4-MeOC6H4 for the Ar group in 1. cod=1,5-
cyclooctadiene.
Having identified MP2-SEGPHOS as the most selective
ligand of those examined, we next explored the influence of
solvent (Table 1). While many single solvents led to excellent
enantioselectivity for 1a, acceptable reactivity was only
observed for THF, acetone, and 1,2-dichloroethane (DCE)
with 2 mol% of the iridium catalyst. The combination of
acetone and DCE proved optimal (Table 1, entry 10), thus
allowing the iridium catalyst loading to be lowered to
0.5 mol%.
ing-group chemistry (Figure 2).[10] While simple N-benzylpyr-
idinium salts have been demonstrated to be very challenging
substrates in asymmetric hydrogenation, we envisioned that
an in depth evaluation of ligand architecture with respect to
reaction selectivity might result in the identification of an
efficient catalyst. A library of 240 chiral phosphine ligands
was evaluated. While the majority of phosphine ligands
screened gave less than 60% ee, several active and selective
ligands were discovered. Doubly oxygenated atropisomeric
C2-symmetric bis(phosphine) ligands, such as SynPhos, SEG-
PHOS, and GarPhos, in conjunction with [{Ir(cod)Cl}2] as
a precatalyst showed good enantioselectivities in the asym-
metric hydrogenation of 1a (L7–L11; Figure 2). The fine-
tuning of the GarPhos and SEGPHOS ligands structure also
had notable impact on their enantioselectivities, with more
sterically encumbered and electron-rich phosphine aryl sub-
stituents giving higher enantioselectivities (L8, L9, and L10,
L11). In addition, generally higher selectivities were observed
To explore the utility of the newly developed Ir/MP2-
SEGPHOS catalytic system, a range of N-benzyl-2-substi-
tuted pyridium bromide substrates were synthesized and
studied under the optimized reaction conditions. The results
are summarized in Table 2. For all chosen 2-arylpyridinium
substrates (entries 1–15), the chiral products 2a–m were
obtained in excellent yield and selectivity (90% to 96% ee).
The catalytic system worked well for ortho-substituted,
sterically hindered substrates such as 1d, 1k, and 1m
(entries 4, 12, and 15), thus highlighting the enhanced
reactivity of this system. The enantioselectivities in these
cases were only slightly less than those where the 2-aryl group
bore substituents in the meta or para positions. Significantly,
the electronic properties of the 2-aryl group did not exert any
noticeable effect on the reaction selectivity. Both the elec-
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 12761 –12764