Continuous flow based catch and release protocol for the synthesis of alpha-ketoesters

Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of α-ketoesters is reported

3D‐printed polypropylene continuous‐flow column reactors: exploration of reactor utility in SNAr reactions and the synthesis of bicyclic and tetracyclic heterocycles

3D printing has the potential to transform the way in which chemical reactions are carried out due to its low‐cost, ease‐of‐use as a technology and its capacity to expedite the development of iteratively enhanced prototypes. In this present study, we developed a novel, low‐cost polypropylene (PP) column reactor that was incorporated into an existing continuous‐flow reactor for the synthesis of heterocycles. The utility and solvent resistance of the printed devices were explored in SNAr reactions to produce substituted aniline derivatives and in the synthesis of bicyclic and tetracyclic heterocycles. Using this approach, a range of heterocyclic compounds was synthesised including the core structure of the natural product (±)‐γ‐lycorane and structurally complex compounds based on the tetracyclic core of the erythrina alkaloids

Complete functionalisation of small and large diameter bromopolystyrene beads; applications for solid-supported reagents, scavengers and diversity-oriented synthesis

Bromopolystyrene beads with diameters of up to 600 µm have been derivatized completely, via bromine-magnesium exchange and interception with electrophiles, to yield high quality solid-supported reagents, scavengers and solid supports for use in diversity-oriented synthesis. The operational efficiency of parallel, combinatorial and diversity-oriented syntheses 1 is greatly improved by the use of insoluble solid supports. 2 The functionalization of solid supports, such as cross-linked polystyrene, is therefore of enormous importance. 3 We and others have found that bead diameters greater than 150 µm possess optimum handling properties. 4 However, existing methodology used to generate a polystyrene aryl carbanion, which could be intercepted by a variety of electrophiles, is only applicable to smaller-sized beads. 5 This is presumably due to insufficient penetration by the reagent. Metallation of cross-linked polystyrene has been performed by the direct lithiation of polystyrene 6 or by halogen (usually bromine)-metal exchange. 8 We describe herein a reproducible method of derivatising bromopolystyrene using Oshima's trialkylmagnesate complex 9 i-Pr(n-Bu) 2 MgLi to form quantitatively a Grignard-like polymer (1), which can be intercepted with electrophiles to form derivatized polymer beads of any size up to at least 600 µm diameter beads. 10 Oshima and coworkers have used their magnesium ate complexes to metallate aryl bromides, but have not reported their use on polymeric starting materials. Triphenylphosphine polystyrene (aka diphenylphosphino polystyrene), which can be used as a replacement for triphenylphosphine, but avoids the need for troublesome post-synthesis purification to remove phosphine-derived products such as triphenylphosphine oxide, is a huge commercial success. Use of Ph 2 PCl as an electrophile generates high quality triphenylphosphine polystyrene (2) beads of any size (150-600 µm). Treatment with i-PrMgCl or n-BuLi alone fails to functionalize completely the beads Scheme 1 Strategy to derivatize bromopolystyrene. † Electronic supplementary information (ESI) available: experimental techniques, apparatus, characterisation and spectroscopic data. See http://www.rsc.org/suppdata/ob/b4/b406488g/ Bead sizes over 150 µm are more convenient to handle, and our resulting white beads Our procedure works successfully with many other electrophiles such as CO 2 , isocyanates, ketones, trimethyl borate, dimethylformamide (to give aldehyde derivatized polystyrene), thioisocyanates, allyl bromide, S 8 , or PhSSPh (Scheme 2). 6,7,10 The derivatised products can be used as reagents, scavengers and for solid-supported organic synthesis. Of particular interest to our efforts in solid-phase, diversityoriented synthesis is the efficient formation of a novel diisopropylsilane-derivatized polystyrene (3), 11 which could not be Scheme 2 Synthesis of functionalized polystyrene, which can be used as reagents, scavengers and for solid-supported synthesis

Site distribution in resin beads as determined by confocal Raman spectroscopy

Scanning confocal Raman spectroscopy was used to study the distribution of reactive sites within a resin bead used for solid-phase synthesis. The distribution of NH2 groups in aminomethylated polystyrene resin (APS) was determined by doping with varying amounts of 4-cyanobenzoic acid. The extent of loading was determined by both elemental analysis and ninhydrin assays. The spatial distribution of the coupled 4-cyanobenzamide within the bead was determined to an in-plane resolution of 1µm and depth resolution of about 4µm, using; the strong Raman CN stretching vibrational transition at 2230 cm(-1). Dry and swollen beads were studied and the distribution was found to be essentially uniform throughout the bead in all cases