Flow chemistry has unlocked a world of possibilities for the synthetic community, but the idea that it is a mysterious "black box" needs to go. In this review, we show...
Carbon–nitrogen
bonds are ubiquitous in biologically active
compounds, prompting synthetic chemists to design various methodologies
for their preparation. Arguably, the ideal synthetic approach is to
be able to directly convert omnipresent C–H bonds in organic
molecules, enabling even late-stage functionalization of complex organic
scaffolds. While this approach has been thoroughly investigated for
C(sp
2
)–H bonds, only few examples have been reported
for the direct amination of aliphatic C(sp
3
)–H bonds.
Herein, we report the use of a newly developed flow photoreactor equipped
with high intensity chip-on-board LED technology (144 W optical power)
to trigger the regioselective and scalable C(sp
3
)–H
amination via decatungstate photocatalysis. This high-intensity reactor
platform enables simultaneously fast results gathering and scalability
in a single device, thus bridging the gap between academic discovery
(mmol scale) and industrial production (>2 kg/day productivity).
The
photocatalytic transformation is amenable to the conversion of both
activated and nonactivated hydrocarbons, leading to protected hydrazine
products by reaction with azodicarboxylates. We further validated
the robustness of our manifold by designing telescoped flow approaches
for the synthesis of pyrazoles, phthalazinones and free amines.
In this work, continuous flow nitration
of trifluoromethoxybenzene
(TFMB) was conducted in a microchannel reactor. The effects of process
parameters, including temperature, residence time, sulfuric acid strength,
flow rate, and reactor structure, were systemically investigated.
It was found that the aforementioned process parameters had significant
effect on TFMB conversion, while the product selectivity was merely
sensitive to the reaction temperature. On the basis of the results
of process parameter optimization, a scale-up strategy combining microreactor
with distributed packed tubular reactor was presented. Consequently,
excellent performance was achieved in the combined reactor with a
kilogram-scale production.
Trifluoromethoxybenzene (TFMB) nitration was studied in a microreactor, furnishing kinetic data that promoted the process development of large-scale synthesis.
Tetrabutylammonium
decatungstate (TBADT) has emerged as an efficient
and versatile photocatalyst for hydrogen atom transfer (HAT) processes
that enables the cleavage of both activated and unactivated aliphatic
C–H bonds. Using a recently developed oscillatory millistructured
continuous-flow photoreactor, investigations of a decatungstate-catalyzed
C(sp
3
)–H alkylation protocol were carried out, and
the results are presented here. The performance of the reactor was
evaluated in correlation to several chemical and process parameters,
including residence time, light intensity, catalyst loading, and substrate/reagent
concentration. In comparison with previously reported batch and flow
protocols, conditions were found that led to considerably higher productivity,
achieving a throughput up to 36.7 mmol/h with a residence time of
only 7.5 min.
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