1
Tetrahedron Letters
Ir(I)-Catalyzed Enantioselective Hydrogenolysis of 3-Aryl-3-hydroxyisoindolin-1-
ones
Chen Ge, Ren-Xiao Liang, Ren-Rong Liu, Bin Xiang, and Yi-Xia Jia*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
ARTICLE INFO
ABSTRACT
An enantioselective hydrogenolysis of 3-aryl-3-hydroxyisoindolin-1-ones under H2 has been
developed by using Ir(I)/(R)-MeO-Biphep complex as a catalyst. Cyclic diaryl methylamides
were obtained in moderate to excellent yields and up to 92% ee.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Hemiaminal
Iridium
Asymmetric hydrogenolysis
As important class of organic compounds, chiral amines are
unique subunits occurring in natural and unnatural bioactive
molecules and widely used as chiral catalysts, chiral reagents,
and resolving reagents in organic synthesis.1 As a result,
considerable attention has been paid to the synthesis of chiral
amines and numerous reliable approaches have therefore been
developed. Amongst, the transition-metal-catalyzed asymmetric
hydrogenation of prochiral imines and enamines represents one
of the most efficient and convenient approaches toward chiral
amines and their derivatives.2 On the other hand, enantioselective
hydrogenolysis of hemiaminals, stable precursors of imines,3
enabled an alternative access to chiral amines. Zhou and co-
workers developed an attractive enantioselective hydrogenolysis
of 3-alkyl-3-hydroxyisoindolin-1-ones by employing chiral
phosphoric acid as catalyst and Hantzsch ester as hydride source,
efficiently achieving cyclic N-carbonyl chiral amides in modest
to excellent enantioselectivitis.4 Our group realized the
asymmetric hydrogenolysis of 3-aryl-3-hydroxyisoindolin-1-ones
based on the same type of chiral catalyst and with
benzothiazolines as hydride donors, which led to chiral 3-
arylisoindolinones, cyclic diaryl methylamides, in good to
excellent yields and modest to excellent enantioselectivities.5
Herein, we communicated a Ir(I)-catalyzed enantioselective
hydrogenolysis of 3-aryl-3-hydroxyisoindolin-1-ones, which
resulted in 3-arylisoindolinones, important building blocks in
biologically active molecules, in moderate to excellent yields and
moderate to good enantioselectivities (Scheme 1).
Scheme 1. Ir-catalyzed asymmetric hydrogenolysis of 3-aryl-3-
hydroxyisoindolin-1-ons.
Initially, 3-hydroxy-3-phenyl-isoindolin-1-one 1a was used as
model substrate to optimize reaction condition. Upon exposure to
30 atm H2 under the catalysis of [Ir(cod)Cl]2 with (S)-BINAP as a
ligand, the reaction underwent smoothly in the presence of 1.0
equiv CF3CO2H at 25 oC to afford the desired product 2a in 89%
isolated yield and 63% ee (Table 1, entry 1). Encouraged by this
primary result, solvent effect was then investigated. The reaction
in toluene led to product 2a in a slightly higher enantioselectivity
while the yield was decreased to 76% (entry 2). The yield and ee
were both increased in DCE solvent (entry 4), while no reaction
occurred in THF (entry 3). CHCl3 was finally determined to be
the best choice in terms of the obtained enantioselectivity (78%
ee, entry 5). Additives, such as 4Å molecular sieves, Na2SO4, and
MgSO4, were then introduced to remove the formed H2O during
the reaction (entries 6-8). To our delight, the product was
obtained in 91% yield and 80% ee when MgSO4 was added to the
reaction (entry 7). Other organic acids tested, such as TsOH•H2O
and CF3SO3H, resulted in inferior results (entries 9-10). To
further improve the enantioselectivity, other commercially
available chiral diphosphine ligands, such as (R)-Synphos, (R)-
Segphos, and (R)-MeO-Biphep, were examined in the reaction
You and co-workers
disclosed an enantioselective
hydrogenolysis of cyclic indolyl-substituted 3-hydroxyisoindolin-
1-ones to achieve chiral tetrahedron--carbolines in excellent
yields and enantioselectivities.6 Despite of these progress, the
aforementioned reports exclusively relied on the use of chiral
phosphoric acids as catalyst and organic molecules as hydride
donors. We noted that Pd-catalyzed asymmetric hydrogenolysis
reactions have been well developed through enantioselective C-O
or C-X bonds cleavage processes,7 while utilization of other
transition metals in homogenous enantioselective hydrogenolysis,
in particular for the synthesis of chiral amines, are still very rare.
So far, there has no example reported for the asymmetric
hydrogenolysis of hemiaminals employing chiral metal catalyst.