Three-Component Assembly of Multiply Substituted Homoallylic Alcohols and Amines Using a Flow Chemistry Photoreactor

Oxadiazolines are bench-stable diazo precursors, which are activated under UV radiation in the presence of vinylboronic acids and aldehydes to enable a one-step three-component assembly of densely functionalized homoallylic alcohols. Substitution on all positions of the homoallylic alcohol product were achieved with high functional group tolerance. No catalyst or other additive was required to effect the reaction, which proceeds at 20 °C over 40 min. Imines and indoles were also incorporated, giving access to homoallylic amines.

Comment: Interestingly, the progress of the reaction was monitored by using a FlowIR ® device, indicated by the C=O stretch signal of the formed byproduct MeOAc.

A Catalytic Hydrogenation of Arenes: Batch versus Flow
Significance: Kobayashi and co-workers report an efficient arene hydrogenation catalyzed by polysilane-immobilized Rh-Pt bimetallic nanoparticles. A wide selection of aromatic compounds were fully hydrogenated to the corresponding aliphatic products in good to excellent yields. The transformation is shown and compared under batch and flow conditions.

F . J A M I S O N * ( M A S S A C H U S E T T S I N S T I T U T E O F T E C H N O L O G Y , C A M B R I D G E , U S A ) Reconfigurable System for Automated Optimization of Diverse Chemical Reactions
Science 2018, 361, 1220-1225.

Versatile Flow-Based Automatic Reaction Optimization Platform
Significance: The use of automation to carry out labor-intensive synthesis tasks is of increasing interest, and several approaches have been developed for easing the often trial-and-error-based burden of reaction optimization (for example, see: D. Perera et al. Science 2018, 359, 429). The current report describes easy-to-use plug-and-play reaction modules that form a continuous-flow-based system that permits efficient optimization of a specified chemical transformation, as well as providing the ability to evaluate the scope of a reaction rapidly and to access synthetically useful quantities of a material through a scaling-out approach.
Comment: The described system features six bays that can be equipped with a selection of interchangeable modules, including heated, cooled, packed-bed, or LED reactors or liquid-liquid separators. Integrated continuous reaction monitoring through a series of techniques permits automatic optimization of the reaction under investigation by using an established algorithm. The initial model study investigated a Buchwald-Hartwig amination between 4-methoxyaniline and 1-bromo-4-methoxybenzene. The optimized conditions identified were then applied across eight more substrates, with scale-up also demonstrated. Similar case studies are reported for a Horner-Wadsworth-Emmons olefination, a reductive amination, a Suzuki-Miyaura coupling, an S N Ar reaction, a photoredox-mediated iminium ion formation/trapping, and a two-step sequence involving initial ketene generation followed by trapping in a [2+2] cycloaddition.

O . K A P P E * ( R E S E A R C H C E N T E R P H A R M A C E U T I C A L E N G I N E E R I N G , G R A Z , U N I V E R S I T Y O F G R A Z , A N D G R A Z U N I V E R S I T Y O F T E C H N O L O G Y , A U S T R I A ; L O N Z A , V I S P , S W I T Z E R L A N D ) Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source
Org. Process Res. Dev. 2018, 22, 1553-1563.

Continuous Flow Synthesis of Eflornithine
Significance: Eflornithine (Vaniqa ® , Ornidyl ® ) is an ornithine decarboxylase inhibitor that is used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth in women. It is also used to treat opportunistic infections with Pneumocystis carinii pneumonia, that affects people with a weak immune system such as those suffering from acquired immunodeficiency syndrome (AIDS). Eflornithine is on the WHO list of essential medicines.

Comment:
In the Lonza synthesis of eflornithine, the difluoromethyl group is installed by alkylation of malonate A with chlorodifluoromethane (5.0 equiv). Kappe and co-workers devised a flow synthesis of eflornithine that relies on the reaction of the enolate D with difluorocarbene generated in situ from fluoroform (1.05 equiv) and lithium hexamethyldisilazide followed by protonation of the adduct E. Fluoroform is non-toxic and ozone benign though it has global warming potential. The telescoped flow process was operated for four hours to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.

Continuous-Flow Synthesis of Amines and Hydroxylamines
Significance: The authors describe a continuousflow methodology for the chemoselective reaction of alkyl halides and ammonia or hydroxylamines. The primary ammonium salts and hydroxylamines were generated in good to excellent yields.
Comment: An in-line workup procedure to isolate the primary amine was developed. Subsequent Paal-Knorr pyrrole synthesis was performed in a one-pot process. An amide synthesis using an aroyl chloride is also described. A mono-substituted epoxide was a viable electrophile in lieu of an alkyl halide.

Chloroacetate Claisen Reactions in Continuous Flow
Significance: The mild homologation of esters using chloroacetate Claisen reactions in continuous flow is reported. Reaction of the dianion formed in situ with several esters gave the desired chloroketones in high yields, avoiding common chemoselectivity issues of previous chloroketone synthesis methods.

Comment:
The crude -chloro-and bis-,′chloroketones were suitable for cyclization reactions leading to various heterocycles. Functionalized 1,4-diketones were also obtained through the reaction of -chloroketones with zinc enolates.