The frustrations of precipitation, fouling and blockages of liquid-based flow reactors is familiar to all researchers that have worked with continuous flow equipment. There have been many innovative solutions to try and circumvent this issue. This short review will highlight the emerging technique of mechanochemistry and reactive extrusion as a continuous process that can directly work on solid (and liquid) materials and elicit chemical transformations.
All fluorochemicals-including elemental fluorine and nucleophilic, electrophilic, and radical fluorinating reagents-are prepared from hydrogen fluoride (HF). This highly toxic and corrosive gas is produced by the reaction of acid-grade fluorspar (>97% CaF2) with sulfuric acid under harsh conditions. The use of fluorspar to produce fluorochemicals via a process that bypasses HF is highly desirable but remains an unsolved problem because of the prohibitive insolubility of CaF2. Inspired by calcium phosphate biomineralization, we herein disclose a protocol of treating acid-grade fluorspar with dipotassium hydrogen phosphate (K2HPO4) under mechanochemical conditions. The process affords a solid composed of crystalline K3(HPO4)F and K2-xCay(PO3F)a(PO4)b, which is found suitable for forging sulfur-fluorine and carbon-fluorine bonds.
[This corrects the article DOI: 10.1021/acs.oprd.2c00226.].
The nickel catalyzed Suzuki-Miyaura-type coupling of aryl sulfamates and boronic acid derivatives enabled by temperature-controlled mechanochemistry via the development of a programmable PID-controlled jar heater is reported. This base-metal-catalyzed, solvent-free, all-under-air protocol was also scaled 200-fold using twin-screw extrusion technology affording decagram quantities of material.
Rapid and wide-ranging developments have established mechanochemistry as a powerful avenue in sustainable organic synthesis. This is primarily due to unique opportunities which have been offered in solvent-free - or highly solvent-minimised - reaction systems. Nevertheless, despite elegant advances in ball-milling technology, limitations in scale-up still remain. This tutorial review covers the first reports into the translation from "batch-mode" ball-milling to "flow-mode" reactive extrusion, using twin-screw extrusion.
Chemistry Techniques, Synthetic , Solvents
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.
A reagent-controlled stereodivergent carbocyclisation of aryl aldimine-derived, photocatalytically generated, α-amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α-amino radical species underwent a single stereoselective cyclisation to give trans-configured amino-indane structures in good yield, whereas using a substituted Hantzsch ester as a milder reductant afforded cis-fused tetracyclic tetrahydroquinoline frameworks, resulting from two consecutive radical cyclisations. Judicious choice of the reaction conditions allowed libraries of both single and dual cyclisation products to be synthesised with high selectivity, notable predictability, and good-to-excellent yields. Computational analysis employing DFT revealed the reaction pathway and mechanistic rationale behind this finely balanced yet readily controlled photocatalytic system.
The nickel-catalyzed cross-electrophile coupling of aryl halides and alkyl halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C-C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive setups, in reaction times of 2 h. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the nickel catalytic cycle, enabling the synthesis of 28 cross-electrophile coupled products.
The mechanochemical synthesis of 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile and related organic fluorophores/photocatalysts via a solvent-minimized four-fold SNAr pathway is herein described. Employing sodium tert-butoxide as base, and negating the need for any air/moisture-sensitive reaction set-ups, a selection of organic dyes was synthesized in just 1 h using this ball-milling technique. Furthermore, the transformation was then showcased on a multigram scale.
Solvents , Ionophores
Recent research endeavors have established that the mechanochemical activation of piezoelectric materials can open new avenues in redox chemistry. Impact forces, such as those imparted by a ball mill, have been shown to transform piezoelectric materials such as barium titanate (BaTiO3 ) into a highly polarized state, which can then donate an electron to a suitable oxidant and receive an electron from a suitable reductant, mimicking established photoredox catalytic cycles. Proof-of-concept studies have elucidated that mechanoredox chemistry holds great potential in sustainable and efficient radical-based synthesis.
Catalysis
The selective and efficient C-H methylation of sp2 and sp3 carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures.
Chemistry Techniques, Synthetic , Organic Chemicals/chemical synthesis , Methylation , Molecular Structure , Organic Chemicals/chemistry
The construction of diverse sp3 -rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7-diazabicyclo[3.2.1]octanes (bridged 1,3-diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4-substituted quinoline substrates, with subsequent Hantzsch ester-promoted reduction to a dihydropyridine intermediate which undergoes in situ two-electron ring closure to form the bridged diazepane architecture. A wide scope of N-arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all-carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.
Azepines/chemical synthesis , Imines/chemistry , Quinolines/chemistry , Azepines/chemistry , Catalysis , Cyclization , Molecular Structure , Oxidation-Reduction , Photochemical Processes , Stereoisomerism
The construction of enantioenriched azabicyclo[3.3.1]nonan-6-one heterocycles via an enantioselective desymmetrization of allene-linked cyclohexanones, enabled through a dual catalytic system, that provides synchronous activation of the cyclohexanone with a chiral prolinamide and the allene with a copper(i) co-catalyst to deliver the stereodefined bicyclic core, is described. Successful application to oxygen analogues was also achieved, thereby providing a new enantioselective synthetic entry to architecturally complex bicyclic ethereal frameworks. The mechanistic pathway and the origin of enantio- and diastereoselectivities has been uncovered using density functional theory (DFT) calculations.
The catalytic reductive transformation of carboxylic esters into α-branched ethers is described. The procedure pivots on the chemoselective iridium-catalyzed hydrosilylation of ester and lactone functionality to afford a silyl acetal intermediate. Upon treatment with a Lewis acid, these hemilabile intermediates dissociate to form reactive oxocarbenium ions, which can be intercepted by allyltributyltin nucleophiles, resulting in the formation of valuable α-branched alkyl-alkyl ether derivatives. This reductive allylation procedure was found to be amenable to a range of carboxylic ester starting materials, and good chemoselectivity for ethyl over tert-butyl esters was demonstrated. Furthermore, downstream synthetic manipulation of α-amino acid-derived products led to the efficient formation of pyrrolidine, piperidine, and azepane frameworks.
A quinone-mediated general synthetic platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles, via a nucleophilic α-amino radical intermediate. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the functionalization of drug molecules.
A visible light mediated iridium photocatalysed reverse polarity Povarov reaction of aryl imines and electron deficient alkenes is described. Operating via a putative nucleophilic α-amino radical, generated by a proton coupled electron transfer process, addition to a range of conjugated electron deficient alkene substrates affords substituted tetrahydroquinoline products in high yields and with typically good to excellent diastereoselectivity in favor of the trans diastereoisomer. Sub-stoichiometric quantities of Hantzsch ester were found to be key to initiate the overall redox-neutral, free radical cyclization cascade. This new reaction complements existing two electron Lewis acid mediated variants and expands the capabilities of imine umpolung chemistry to synthetically relevant cyclisation methodology.
A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivatives is described. Pivoting on a key nucleophilic addition of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliphatic chains. Application to biologically relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcohols is also demonstrated.
