Organic Letters
Letter
respectively.5a In 2008, Xiao and coworkers reported a
ruthenium-catalyzed asymmetric hydrogenation of cyclic
imines. When a methyl group was replaced by a large
isopropyl group, yields and enantioselectivities decreased
from 94% to 85% and from 99% to 83% ee.5b In 2012, the
Zhou group developed an iridium-catalyzed asymmetric
hydrogenation of cyclic imines using Siphos-PE as the chiral
ligand. A similar steric effect was found when the bulkier
substituents were introduced to the cyclic imines, and the
corresponding adducts were obtained with ee values of 99%,
98%, and 96%, with methyl, ethyl, and isopropyl substituents,
respectively (Figure 2a). Furthermore, the relatively bulkier 1-
with full conversions and different enantioselectivities (29−
91% ee, Scheme 1). tBu-ax-Josiphos was found to give the best
Scheme 1. Performance of Chiral Phosphines in the
Asymmetric Hydrogenation of 1a
Figure 2. Asymmetric hydrogenation of cyclic imine substrates for the
synthesis of chiral THIQs. (a) Previous asymmetric hydrogenation
research of less hindered substrates. (b) This work: Ir-catalyzed
enantioselective hydrogenation of sterically hindered DHIQs.
a
Reaction conditions: [Ir(COD)Cl]2/Siphos-PE/substrate/KI
t
0.5:2.2:100:10, 0.5 mmol in 2 mL of BuOMe under 50 atm H2
and 50 °C for 24 h.
phenyl-3,4-DHIQ was a less reactive substrate for Zhou’s
catalytic system, giving only 18% conversion.5d In fact, the
asymmetric hydrogenation of 1-aryl-DHIQs was once a
challenging subject for a long time in the past.6 As for the
bulkier 1-substituted DHIQs (such as t-butyl, t-amyl, and 1-
adamantyl), to the best of our knowledge, there has been no
report so far.
results (>99% conversion, 91% ee). Subsequently, a series of
reaction condition screenings for the additive, solvent,
temperature, and H2 pressure were conducted (Table S1).
The asymmetric transformation catalyzed by Ir-tBu-ax-Josiphos
in THF at 50 °C and 50 atm H2 in the presence of HBr (40%
aqueous solution) was proved to be optimal, producing (S)-2a
in high yield with up to 99% ee.
As part of our targets in developing highly efficient methods
for the convenient preparation of biologically relevant chiral
amines, we have developed a type of versatile catalyst, the Ir-
ax-Josiphos complex, that has shown excellent catalytic
activities and enantioselectivities for the iridium-catalyzed
asymmetric hydrogenation of acyclic and cyclic imine
substrates.6i,7 To our great delight, our previous studies on
this subject led us to find that this Ir/ax-Josiphos catalytic
system seemed to be compatible with some sterically hindered
substrates (such as 1-(2′-substituted-aryl)-3,4-DHIQs).6i We
wondered whether this efficient catalytic system could tolerate
bulkier DHIQs. Herein we report our primary results on the
enantioselective hydrogenation of sterically hindered 3,4-
DHIQs 1 catalyzed by an in situ catalyst generated by
Under the optimal reaction conditions, a variety of sterically
hindered 1-substituted 3,4-DHIQs 1a−m were hydrogenated
to chiral THIQs 2a−m with good to excellent enantioselectiv-
ities (77−99% ee, Scheme 2). The stereochemical results of the
substrates 1 seem to be insensitive to the bulk of the 1-
substituted group, affording adducts with similar enantiose-
lectivities. Increasing the bulk of the 1-substituted group has
nearly no effect on the enantioselectivity of the hydrogenation
reaction. For example, the hydrogenation of 1c, 1g, and 1k
with a 1-adamantyl group could also provide excellent
enantioselectivities (94%, 95%, and 91% ee). It is particularly
worth mentioning that this catalytic system displayed good
catalytic performance in the asymmetric preparation of some
intermediates of interesting biological active compounds 2h
and 2l. At the same time, this catalytic system showed good
reactivities for most of the substrates, providing >99%
conversion with a 1 mol % catalyst loading. Although the
hydrogenation reactions of 1h, 1l, and 1m have relatively low
reactivities, the transformations can still acquire full con-
versions by increasing the temperature and catalyst loading.
Simultaneously, we fortunately obtained the single-crystal X-
ray structure of the corresponding sulfonamide derived from
2c; then, the absolute configuration of the hydrogenation
adduct 2c was determined.
t
[Ir(COD)Cl]2 and Bu-ax-Josiphos (Figure 2b), providing
bulky 1-substituted THIQs 2 with up to excellent enantiose-
lectivity (up to 99% ee).
Initially, 1-(tert-butyl)-6,7-dimethoxy-3,4-DHIQ (1a) was
selected as the standard substrate to optimize the reaction
conditions in the iridium-catalyzed asymmetric hydrogenation.
Some commercial chiral ligands and ax-Josiphos were
evaluated. The reaction was carried out in the presences of
0.5 mol % [Ir(COD)Cl]2 and 1.1 mol % ligand under 50 atm
H2 at 50 °C in toluene for 24 h, using 40% HBr aqueous
solution as the additive. All chiral diphosphine ligands and
Zhou’s phosphoramidite Siphos-PE could catalyze this reaction
B
Org. Lett. XXXX, XXX, XXX−XXX