Chemistry Reference
In-Depth Information
lines could be hydrogenated using Ir complexes of a few atropisomeric biaryl ligands,
such as BIPHEP, SegPhos, and SynPhos. The addition of molecular iodine was critical
to generate the highly active catalyst for this transformation. A few other ferrocene-
based ligands were also examined in this transformation [391]. On the other hand,
chloroformates were used as the activating reagent to provide the secondary coordi-
nating group and to quench the free amine product [392]. A wide range of quinoline
substrates were examined and over 95% ee was observed. This method has been dem-
onstrated in the synthesis of a few tetrahydroquinoline alkaloids and drug molecules
[389,393]. The hydrogenation of isoquinolines was notably less selective and slower
than quinolines.
Catalytic asymmetric hydrogenation of substituted pyridines are signifi cantly more
challenging due to the high stability of the substrates. A few early attempts using Rh-
BINAP catalyst only resulted in poor selectivity [394]. Although some heterogeneous
catalysis [395] and chiral auxiliary methods [396] have been developed, the asymmet-
ric hydrogenation of the substituted pyridines in a homogeneous solution had
remained an unsolved problem for many years. Recently, an inspiring approach was
reported by the Charette group [397]. Asymmetric hydrogenation of pyridine deriva-
tives were successfully achieved after converting the substrates into
N
- benzoylimino-
pyridinium ylides. Using an electron-defi cient Ir - P,N - ligand catalyst, up to 90% ee was
obtained from a range of substrates in the presence of catalytic iodine (Eq. 7.58).
Despite of the high enantioselectivity and mild reaction condition of this method, the
deprotection of product requires strong reducing agents such as Raney nickel and
lithium-ammonia, which may limit the method from practical applications. The Zhang
group reported another approach involving a two-step hydrogenation process [398].
The aromaticity of pyridine derivatives was fi rst broken by a partial heterogeneous
hydrogenation catalyzed by Pd/C. The intermediate with a remaining hindered double
bond was protected and then subjected to the second asymmetric hydrogenation cata-
lyzed by the Rh-TangPhos catalyst. Over 99% ee was achieved with a limited sub-
strate scope (Scheme 7.17 ).
COOEt
COOEt
Pd/C. EtOH
H
2
, 100 psi
RCOX
n-BuLi
N
N
R
O
COOEt
Rh-TangPhos
CH
2
Cl
2
,80
o
C, H
2
100 atm
N
R
O
48-99% ee
Scheme 7.17.
Reduction of substituted pyridine.
