6 research outputs found
Lewis Acid-Catalyzed Addition of Benzophenone Imine to Epoxides Enables the Selective Synthesis and Derivatization of Primary 1,2-Amino Alcohols
Benzophenone imine was found to be
an effective ammonia surrogate
for the selective preparation of primary 1,2-amino alcohols from epoxides,
including enantiopure epichlorohydrin, in the presence of catalytic
YÂ(OTf)<sub>3</sub>. High-throughput screening of 48 Lewis acids quickly
identified YÂ(OTf)<sub>3</sub> as an effective mediator of the addition
reaction under mild conditions. Following acidic hydrolysis, the primary
amino alcohol salt is revealed and partitions into the aqueous solution,
while the benzophenone byproduct is easily removed by simple extraction
with ethyl acetate. These ammonium salts can be directly Boc-protected
or further derivatized without isolation to form benzamides and sulfonamides
under SchottenâBaumann-type conditions in up to 79% isolated
yield over three steps. This methodology has been used to prepare
key intermediates for the synthesis of PRMT5 inhibitors with high
enantiopurity as well as numerous other amide and sulfonamide derivatives
An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine
2,3-Dichlorobenzoyl cyanide is a
key intermediate in the synthesis
of Lamotrigine. An assessment of various catalytic systems for the
cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described.
High-throughput experimentation identified many conditions for effecting
the requisite chemistry, including amine bases and phase-transfer
catalysts, as well as catalyst-free conditions utilizing acetonitrile
as a polar cosolvent. A novel catalyst, CuBr<sub>2</sub>, was identified
by consideration of the possible oxidation of CuÂ(I) during high-throughput
screening experimentation. CuCN was found to be the best cyanide source
for achieving clean conversion; however, the solubility of CuCN was
the major factor limiting reaction rate under many conditions. Improving
CuCN solubility by using acetonitrile as solvent enhanced the reaction
rate even in the absence of the catalysts tested but significantly
complicated isolation of the product. With no acetonitrile cosolvent,
phase-transfer catalysts such as tetrabutylÂammonium bromide
(TBABr) are effective; however, use of TBABr led to inconsistent reaction
profiles from run-to-run, due to an unexpected clumping of the CuCN
solid. Switching to cetylÂtrimethylÂammonium bromide (CTAB)
alleviated this clumping behavior, leading to consistent reactivity.
This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichloroÂbenzoyl
cyanide in 77% isolated yield
Bis(amidate)bis(amido) Titanium Complex: A Regioselective Intermolecular Alkyne Hydroamination Catalyst
An
efficient and selective bisÂ(amidate)ÂbisÂ(amido) titanium precatalyst
for the anti-Markovnikov hydroamination of alkynes is reported. Hydroamination
of terminal and internal alkynes with primary alkylamines, arylamines,
and hydrazines is promoted by 5â10 mol % of Ti catalyst. Various
functional groups are tolerated including esters, protected alcohols,
and imines. The in situ generated complex shows comparable catalytic
activity, demonstrating its synthetic versatility for benchtop application.
Applications of this catalyst for the synthesis of amino alcohols
and a one-pot procedure for indole synthesis are described. A mechanistic
proposal that invokes turnover-limiting protonolysis is presented
to rationalize the observed regioselectivities
A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol
A combined
high-throughput screening and reaction profiling approach
to the telescoping of two reductions in the synthesis of Salbutamol
is described. Optimization studies revealed the beneficial effect
of mildly acidic conditions, and the use of water as a cosolvent.
Persistent formation of deoxygenated impurities using a Pd/C catalyst
led to the initiation of reaction profiling studies, which revealed
that the ketone intermediate formed after rapid debenzylation is the
sole source of deoxygenated impurities, indicating that more rapid
ketone hydrogenation should minimize this deoxygenation. A dual catalyst
approach based on these insights has been developed, with both Pd/Pt
and Ru/Pt catalyst systems as more selective than Pd-only systems.
Based on reaction profiles that indicate the deoxygenation side reaction
is first-order in the concentration of debenzylated ketone intermediate,
Pt catalysts for rapid and selective ketone hydrogenation were paired
with Pd and Ru catalysts known to perform selective debenzylation.
Optimization of these dual catalyst processes led to conditions that
were demonstrated on 20 g scale to prepare Salbutamol in 49% isolated
yield after recrystallization
Direct Heterocycle CâH Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation
One
of the major challenges in developing catalytic methods for
CâC bond formation is the identification of generally applicable
reaction conditions, particularly if multiple substrate structural
classes are involved. Pd-catalyzed direct arylation reactions are
powerful transformations that enable direct functionalization of CâH
bonds; however, the corresponding direct alkenylation reactions, using
vinyl (pseudo) halide electrophiles, are less well developed. Inspired
by process development efforts toward GSK3368715, an
investigational active pharmaceutical ingredient, we report that a
Pd(II) palladacycle derived from tri-tert-butylphosphine
and Pd(OAc)2 is an effective single-component precatalyst
for a variety of direct alkenylation reactions. High-throughput experimentation
identified optimal solvent/base combinations for a variety of HetArâH
substrate classes undergoing CâH activation without the need
for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative
catalytic mechanism, where in situ-generated Pd(0) supports a canonical
Pd(0)/(II) cross-coupling cycle and the palladacycle effects CâH
activation via CMD in a redox-neutral cycle. In all, 192 substrate
combinations were tested with a hit rate of approximately 40% and
24 isolated examples. Importantly, this method was applied to prepare
a key intermediate in the synthesis of GSK3368715 on
multigram scale
Direct Heterocycle CâH Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation
One
of the major challenges in developing catalytic methods for
CâC bond formation is the identification of generally applicable
reaction conditions, particularly if multiple substrate structural
classes are involved. Pd-catalyzed direct arylation reactions are
powerful transformations that enable direct functionalization of CâH
bonds; however, the corresponding direct alkenylation reactions, using
vinyl (pseudo) halide electrophiles, are less well developed. Inspired
by process development efforts toward GSK3368715, an
investigational active pharmaceutical ingredient, we report that a
Pd(II) palladacycle derived from tri-tert-butylphosphine
and Pd(OAc)2 is an effective single-component precatalyst
for a variety of direct alkenylation reactions. High-throughput experimentation
identified optimal solvent/base combinations for a variety of HetArâH
substrate classes undergoing CâH activation without the need
for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative
catalytic mechanism, where in situ-generated Pd(0) supports a canonical
Pd(0)/(II) cross-coupling cycle and the palladacycle effects CâH
activation via CMD in a redox-neutral cycle. In all, 192 substrate
combinations were tested with a hit rate of approximately 40% and
24 isolated examples. Importantly, this method was applied to prepare
a key intermediate in the synthesis of GSK3368715 on
multigram scale