Multistep Continuous Flow Synthesis of Fine Chemicals with Heterogeneous Catalysts

187 Pages·2023·4.773 MB·english

by  Saito Y.

Springer Theses
Recognizing Outstanding Ph.D. Research
Yuki Saito
Multistep
Continuous
Flow Synthesis
of Fine Chemicals
with Heterogeneous
Catalysts
Springer Theses
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Yuki Saito
Multistep Continuous Flow
Synthesis of Fine Chemicals
with Heterogeneous Catalysts
Doctoral Thesis accepted by
The University of Tokyo, Tokyo, Japan
Author Supervisor
Dr. Yuki Saito Prof. Shu¯ Kobayashi
Department of Chemistry, School Department of Chemistry
of Science The University of Tokyo
The University of Tokyo Tokyo, Japan
Tokyo, Japan
ISSN 2190-5053 ISSN 2190-5061 (electronic)
Springer Theses
ISBN 978-981-19-7257-7 ISBN 978-981-19-7258-4 (eBook)
https://doi.org/10.1007/978-981-19-7258-4
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Supervisor’s Foreword
Synthetic organic chemistry has been performed using batch methods for a long
time, but recently, attention has been focused on flow methods, which are excellent
in terms of environmental load, efficiency, and safety. On the basis of this back-
ground, Dr. Yuki Saito describes this thesis that covers five chapters on the develop-
ment of carbon–carbon bond forming reactions and hydrogenation reactions by the
continuous-flow method and multistep fine chemical synthesis using heterogeneous
catalysts.
First, Dr. Saito describes the synthesis of nitrogroup-containing compounds based
on a multistep continuous-flow method. Since organic compounds containing a
nitrogroup are versatile they can be converted to amino compounds by reducing the
nitrogroup. In addition, the proton at the α-position of the nitrogroup is highly acidic
and deprotonation proceeds easily, resulting in a carbanion and a nucleophilic reac-
tion to produce various compounds. Dr. Saito has clarified that various nitroalkenes
can be synthesized from aldehydes and nitromethane using silicaamine/calcium chlo-
ride as a catalyst. Furthermore, without isolating the nitroalkene obtained there, it
was discovered that various nitrogroup-containing compounds can be synthesized
by carrying out the second-step reaction using the sequential-flow method.
Next, Dr. Saito describes the hydrogenation of nitriles using polysilane-supported
palladium catalysts. The reaction to obtain primary amines by hydrogenation of
nitriles is the most efficient reaction type (addition reaction) that does not generate
waste, but secondary amines and tertiary amines are produced by overreaction of the
products. In this thesis, it was demonstrated that the target primary amine hydrochlo-
ride can be obtained in high yield simply by passing the reactant nitrile, hydrogen,
and hydrochloric acid through a column packed with a polysilane-supported palla-
dium catalyst. This flow reaction can be operated continuously for more than 300
hours while maintaining the activity of the catalyst, and the catalyst turnover rate at
that time exceeds 10,000.
Furthermore, Dr. Saito describes aldol-type reactions in a continuous-flow process
using strongly basic ion-exchange resins as catalysts. The effectiveness of flow reac-
tions using heterogeneous catalysts is well known, but at present there is a problem
that the number of applicable catalysts is still insufficient. Ion-exchange resins have
v
vi Supervisor’sForeword
been widely used for ion exchange of water, etc. In this thesis, it is clarified that these
ion-exchange resins can be used as heterogeneous catalysts for synthetic organic reac-
tions. That is, the desired aldol adduct can be obtained in high yield by passing a
ketone and an aldehyde through a column packed with a strongly basic ion-exchange
resin. In addition, it has also been clarified that the target adducts can be obtained
in high yields when esters and aldehydes as well as nitriles and aldehydes are,
respectively, circulated under similar conditions.
Finally, the hydrogenation reaction and the aldol-type reaction developed in
this thesis are used to synthesize active pharmaceutical ingredients by sequential-
flow reactions. Synthesis of Donepezil, an Alzheimer’s-type dementia inhibitor, by
connecting a column filled with a strongly basic ion-exchange resin and a polysilane-
supported palladium catalyst, circulating the raw materials aldehyde and ketone, and
then flowing hydrogen, has been successful. According to this flow synthesis, it is
possible to directly obtain the desired drug substance by simply flowing the raw
materials. It is clarified that the pure target product can be obtained simply by recrys-
tallizing the final crude product without any separation or purification during the
synthesis. Similarly, columns filled with a strongly basic ion-exchange resin and a
polysilane-supported palladium catalyst are connected, the raw materials nitrile and
aldehyde are circulated there, and hydrogen is further flowed to obtain a synthetic
intermediate of Venlafaxine, an antidepressant. Dr. Saito also succeeded in directly
synthesizing Venlafaxine from this synthetic intermediate in two steps. These results
demonstrate that the flow method, instead of the conventional batch method, can
be used to synthesize active pharmaceutical ingredients more efficiently and safely
with less environmental load. The academic significance of this thesis as well as its
impact on the industry is highly evaluated.
As described above, this thesis describes excellent results on the development of
continuous-flow reactions using heterogeneous catalysts and the synthesis of active
pharmaceutical ingredients by the continuous-flow method. Dr. Saito was highly
evaluated and received the Student Research Prize in March 2018 from the Graduate
School of Science, The University of Tokyo.
Tokyo, Japan Prof. Shu¯ Kobayashi
September 2022
Abstract
Development of Heterogeneous Catalysts for Continuous-Flow C–C Bond
Formation and Hydrogenation Reactions for Multistep Synthesis of Fine
Chemicals
Introduction
Continuous-flow synthesis has many advantages over conventional batch synthesis
from the viewpoint of efficiency, safety, environmental friendliness, and scalability.
Among several types of continuous-flow methods, flow reactions using heteroge-
neous catalysts are the most attractive and efficient system for multistep chemical
transformations, because the use of activated reagents can be avoided and catalysts
can be easily separated from products and used continuously. However, the appli-
cation of heterogeneous catalysts to continuous-flow reactions is still limited for
single-step reactions, and it has been regarded as a great challenge to synthesize
fine chemicals under continuous-flow conditions using heterogeneous catalysts. In
general, Active Pharmaceutical Ingredient (API) synthesis requires multistep chem-
ical transformations. To realize continuous-flow synthesis of APIs with heteroge-
neous catalysts, each reaction has to be “clean” without generating byproducts for
the next reaction. For this reason, the precise design of whole synthetic routes and the
development of catalysts to enable each transformation are essential and challenging
points. Previously, our group reported a multistep continuous-flow synthesis of chiral
API, Rolipram, without any quenching and purification operation. The whole process
involves six chemical transformations through four kinds of heterogeneous catalysts.
Although this example is the milestone of continuous-flow fine chemical synthesis,
the scope of reactions and catalysts is still limited and needs to be expanded for the
future development of this field.
In my Ph.D. thesis, I decided to focus on C–C bond formation and hydrogenation,
because these types of reactions generally take place with high atom economy and
vii
viii Abstract
generate water as a sole byproduct, which can be easily removed. To achieve a multi-
step continuous-flow synthesis, my strategy is a construction of backbone of a target
molecule at first by aldol-type reactions with substrates with high oxidation states,
which can potentially act as a nucleophile, followed by conversion of the functional
groups to final target by selective hydrogenation. I hypothesized that various kinds of
fine chemicals can be synthesized by connecting these two types of reactions under
continuous-flow conditions.
Synthesis of Nitro-Containing Compounds Through Multistep
Continuous Flow
Nitro alkenes are one of the most important, versatile, and frequently used inter-
mediates in organic synthesis. In the first step, I investigated the effect of flow
rates and concentrations on productivity and yield using nitromethane and benzalde-
hyde as substrates using amine-functionalized silica with CaaCsl a catalyst under
2
continuous-flow conditions. The reactions were performed with various flow rates
between 0.05 and 1.0 mL/min at 0.1 M concentration. With 0.05 ml/min flow rate,
the yield was kept >90% to supply 36 mmol of nitromethane. The yield was kept with
0.1 ml/min flow rate, resulting in an increase of productivity by double. However, a
further increase in flow rate from 0.25 to 1.0 ml/min resulted in a decrease in the yield.
Next, concentrations were changed between 0.1 M and 1.0 M with 0.05 ml/min flow
rate. Surprisingly, the yield was maintained >90% even with 1.0 M concentration,
resulting in an increase of productivity by 10 times. These results indicated that longer
residence time was the key to achieve high productivity. Under optimized reaction
conditions, the scope of aldehyde was examined. With five kinds of aromatic alde-
hydes, the yield was kept >80% to supply ~150 mmol of substrates. For the second
step, I investigated various types of acid–base heterogeneous catalysts such as metal
oxides, surface-functionalized SiO, and polystyrene-immobilized catalysts. Metal
2
oxides worked as heterogeneous base catalysts and promoted 1,4-addition of benzy-
lamine and 1,3-ketoester under continuous-flow conditions. During the investigation,
I found that fresh preparation of catalysts was the key to achieve >80% yield and
>48 h lifetime. DMAP-immobilized silica was employed as heterogeneous Lewis-
base catalyst for Morita–Baylis–Hillman reaction. Although the catalyst was effec-
tive under single continuous-flow conditions, the catalyst deactivation was observed
after 6 h when combined in the first nitroolefin synthesis. Such deactivation problem
was solved by changing the dehydrating agent in the first column from tCo aCl
2
MS 4A, indicating that the deactivation was caused by leached Ca species. Finally,
I could synthesize seven kinds of nitro-containing compounds in two steps under
continuous-flow conditions without any workup and purification (Sche1m).e
Abstract ix
CH3+N O2 CaCl2/S(2iO0.22-N gH) 2 = 3/1 Ph NO2 2nd Catalyst EtO2C OH NO2 PBhn NH NO2 PEh E NO2
Ph O 0.05 mL/møin1 0 x 300 mm Sus, 75 oC Ph
(1.2 eq.) 0.05 mL/min NH O2N OH * O
0.2 M in Toluene EtO2C CHO Ph NH2 EtO O O Ph NO2 Ph S Ph * NO2
S OH O
N
H HO S
Scheme 1 2-step synthesis of nitro–containing compounds
PS
O
R1 or N Ar O NMe3(OH) EWG = ketone, nitrie
Ar + EWG
0.1 M, Toluene/EtOH R2 R2
R1
or N (solvent) 0.2 ml/min rt-60 oC 85%-quant. yield
Me
Scheme 2 Aldol-type reactions using basic resin catalysts
Anion Exchange Resins as Catalysts for Direct Aldol-Type
Reactions
To establish a general method of aldol condensations under continuous-flow condi-
tions, I started the investigation of heterogeneous base catalysts. As a model reaction,
α-tetralone and benzaldehyde were used as substrates and various heterogeneous
catalysts were evaluated under batch conditions. Amine-functionalized silica cata-
lysts did not give any product, although they were effective for nitroalkene synthesis.
Common solid bases such as metal oxides, hydrotalcite, and KOF/Arlesulted in
2 3
low conversion and yield presumably due to low basicity and deactivation by gener-
ated water. On the other hand, a basic resin having ammonium hydroxide afforded
the desired α,β-unsaturated ketone in 90% yield. Because the physical properties of
these resins differ significantly depending on the solvent, I decided to investigate
the effect of solvent to catalyst activity. As a result, EtOH and Toluene gave supe-
rior results compared to THF. However, no conversion was observed using EtOAc or
DCM as a solvent. Although the origin of the solvent effect was still unclear, swelling
of resins seemed to be the one key factor to achieve high catalyst activity. Interest-
ingly, the aldol product could be obtained in >99% chemoselectivity by decreasing
reaction temperature from rt to −4oC0 using the same catalyst in moderate yield.
The catalyst efficiently worked even under continuous-flow conditions to obtain the
desire α,β-unsaturated compounds in >80% yield with >99% selectivity for >48 h.
Throughout the investigation of substrate scope, the catalyst was found to be effective
for other kinds of nucleophiles such as benzyl nitriles, and even acetonitrile could
be employed as nucleophile when using a solvent amount. Interestingly, a similar
solvent effect was observed for other nucleophiles (Sche2m).e