column I, a toluene solution of malonate 7, and triethylamine into a sequence of
column X and column II. The desired γ-nitro ester 10 was obtained in 84% yield with
94% enantiomeric excess at this step after workup. The crude solution of 10 eluted
from column II and atmospheric pressure H 2 was passed through column III, which
was packed with poly(dimethyl)silane-supported palladium/carbon, to afford
γ-lactam 11 in 74% yield with 94% enantiomeric excess. The final stage in the
synthesis of Rolipram involved the hydrolysis and decarboxylation of the ester part
of 11. This flow synthesis was conducted with column IV, which was packed with
silica-supported carboxylic acid (Chromatorex ACD, Fuji Silysia), passing through
the mixture of crude solution of 11 after separation of H 2 gas, water, and o-xylene,
from the top down at 120
C. Finally, (S)-Rolipram (12) was obtained in 50% yield
from 9 (997.8 mg/h, 96% enantiomeric excess). In this sequential continuous-flow
system, the hydrogenation step using a palladium nanoparticle catalyst was placed at
a later stage of the sequential transformation. This means that the crude mixture that
was introduced to the heterogeneous catalyst was potentially a mixture of various
compounds including remaining starting materials and small amounts of sideproducts. Therefore, robust catalysts that were not poisoned by other compounds
were required for this purpose. During the screening of the hydrogenation catalyst,
neither several commercially available Ni and Pd catalysts nor poly
(methylphenylsilane)-supported palladium/alumina catalyst worked at all.
3.3 Reductive Amination Through Hydrogenation Using
Metal Nanoparticle Catalysts Under Continuous-Flow
Conditions
C–N bond-formation reactions are among the most important transformations for the
synthesis of APIs and other biologically important compounds. Substitution reactions with alkyl halides are a common approach for this purpose; however, in
addition to overreaction issues, this reaction is not suitable from a green organic
synthesis point of view because of the massive amount of inorganic salts that are
generated as waste (Scheme 11a). On the other hand, reductive amination of
carbonyl compounds using H 2 is a promising approach because only water is
generated (Scheme 11b). This approach is not only recommended from a green
organic synthesis point of view but also offers the potential of application to
sequential continuous-flow systems because water is readily removed by phase
separation during flow. However, problems often arise due to reversibility, compound/functional group incompatibility, and overreduction. In particular, the reduction of aryl imines often gives secondary amines that are contaminated with the
corresponding primary amine, derived from overreduction and debenzylation of the
desired product. In 2005, Ley and co-workers realized continuous-flow hydrogenation of imines to the corresponding amines using a commercially available H-Cube
®
flow hydrogenator (Scheme 12) [18]. H-Cube
® mixes hydrogen gas with a flowing
Nanoparticle Catalysts in Flow Systems
225
column X and column II. The desired γ-nitro ester 10 was obtained in 84% yield with
94% enantiomeric excess at this step after workup. The crude solution of 10 eluted
from column II and atmospheric pressure H 2 was passed through column III, which
was packed with poly(dimethyl)silane-supported palladium/carbon, to afford
γ-lactam 11 in 74% yield with 94% enantiomeric excess. The final stage in the
synthesis of Rolipram involved the hydrolysis and decarboxylation of the ester part
of 11. This flow synthesis was conducted with column IV, which was packed with
silica-supported carboxylic acid (Chromatorex ACD, Fuji Silysia), passing through
the mixture of crude solution of 11 after separation of H 2 gas, water, and o-xylene,
from the top down at 120
C. Finally, (S)-Rolipram (12) was obtained in 50% yield
from 9 (997.8 mg/h, 96% enantiomeric excess). In this sequential continuous-flow
system, the hydrogenation step using a palladium nanoparticle catalyst was placed at
a later stage of the sequential transformation. This means that the crude mixture that
was introduced to the heterogeneous catalyst was potentially a mixture of various
compounds including remaining starting materials and small amounts of sideproducts. Therefore, robust catalysts that were not poisoned by other compounds
were required for this purpose. During the screening of the hydrogenation catalyst,
neither several commercially available Ni and Pd catalysts nor poly
(methylphenylsilane)-supported palladium/alumina catalyst worked at all.
3.3 Reductive Amination Through Hydrogenation Using
Metal Nanoparticle Catalysts Under Continuous-Flow
Conditions
C–N bond-formation reactions are among the most important transformations for the
synthesis of APIs and other biologically important compounds. Substitution reactions with alkyl halides are a common approach for this purpose; however, in
addition to overreaction issues, this reaction is not suitable from a green organic
synthesis point of view because of the massive amount of inorganic salts that are
generated as waste (Scheme 11a). On the other hand, reductive amination of
carbonyl compounds using H 2 is a promising approach because only water is
generated (Scheme 11b). This approach is not only recommended from a green
organic synthesis point of view but also offers the potential of application to
sequential continuous-flow systems because water is readily removed by phase
separation during flow. However, problems often arise due to reversibility, compound/functional group incompatibility, and overreduction. In particular, the reduction of aryl imines often gives secondary amines that are contaminated with the
corresponding primary amine, derived from overreduction and debenzylation of the
desired product. In 2005, Ley and co-workers realized continuous-flow hydrogenation of imines to the corresponding amines using a commercially available H-Cube
®
flow hydrogenator (Scheme 12) [18]. H-Cube
® mixes hydrogen gas with a flowing
Nanoparticle Catalysts in Flow Systems
225