Continuous flow processing as a tool for the generation of terpene-derived monomer libraries

We report the development of a continuous flow approach for the preparation of two bio-derived monomer libraries. A small range of terpenes (ocimene, myrcene, α-terpinene, α-phellandrene, isoprene, and farnesene) have been used as the base set for the library, with the first library derived from a Diels–Alder reaction with the platform chemical maleic anhydride. The second library requires the derivatization of the first through a hydrogenation reaction. The potential for scale-up of both libraries has been demonstrated, with the Diels–Alder process delivering 10.5 grams of the product in 3 hours and the hydrogenation process delivering 10 grams of the material in 16 hours

Exploring the generation and use of acylketenes with continuous flow processes

The generation and use of reactive intermediates is well suited to continuous flow processing owing to the ability to scale up reactions, contain hazards and heat solvents past their atmospheric temperature boiling points. Herein we explore the chemistry of acylketenes, generated from commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TMD, 10) under continuous flow conditions. The developed flow chemistry system is capable of permitting a wide range of applications of these acylketene intermediates, including access to equilibrating processes that result in ketone exchange. Some of the dioxinone products resulting from this study are destabilised towards acylketene generation, this is demonstrated through their ability to generate acylketene at lower reaction temperatures

Efficient Heck arylations of cyclic and acyclic acrylate derivatives using arenediazonium tetrafluoroborates. A new synthesis of the antidepressant drug (+/-)-paroxetine

The Heck arylation of acyclic- and cyclic-substituted acrylates using several arenediazonium tetrafluoroborates was investigated. Arylations were carried out under aerobic, ligand-free conditions to provide the corresponding substituted acrylates in moderate to high isolated yields. Heck arylations were usually completed in less than 2 h in refluxing methanol. The aza-endocyclic acrylate derivative 11a was converted into the antidepressant drug ((+)(-))-paroxetine in a concise new route in good overall yield.881657166

Non-occurrence of a Zincke-like process upon treatment of 1-(2,4-dinitrophenyl)-3-methylimidazolium chloride with a chiral primary amine

Huang's preparation of chiral imidazolium salts by means of a Zincke-like process was re-investigated. It was shown that treatment of 1-(2,4-dinitrophenyl)-3-methylimidazolium chloride with L-alaninol gives rise to complete decomposition of the starting salt via an S(N)Ar reaction and that the material described by Huang was not the claimed chiral imidazolium salt, thus questioning the occurrence of the ionic liquids reported in the original work.o TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE AGOSTO DE 2015.10888588

Research data supporting "Diastereoselective synthesis of functionalized indolines using in situ generated allyl boronic species"

NMR data and IR dat

Diastereoselective Synthesis of Functionalized Indolines Using in situ Generated Allyl Boronic Species

A new three-component coupling protocol for preparation of functionalized indolines, with a high degree of diastereoselectivity, has been developed. The protocol is based on the in situ homologation of vinyl boronic acids to allylboronic acids, using TMSCHN2 as carbon source, and subsequent coupling reaction with indoles to give 2-substituted indolines. The scope of the method was exemplified in several examples.São Paulo Research Foundation – FAPESP (awards No. 2014/26378-2 and 2014/25770-6 award No. 2016/05630-0), CNPq (award No. 453862/2014-4), Croucher Foundatio

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addition, addition-elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This Platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.17911921208EPSRC [EP/K009494/1]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)EPSRC [EP/K009494/1]FAPESP [2012/05909-4

Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin

An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor (16) (20.9 g prepared over 3 h), with a productivity of 7 g·h–1. An asymmetric Brown allylation protocol was also evaluated under continuous flow conditions. This approach employing (−)-Ipc2B(allyl) provided an (S)-goniothalamin intermediate in 98% yield and 91.5% enantiomeric excess (ee) with a productivity of 1.8 g·h–1. For the final step, a ring-closing metathesis reaction was explored under several conditions in both batch and flow regimes. In a batch operation, the Grubbs second-generation was shown to be effective and highly selective for the desired ring closure product over those arising from other modes of reactivity, and the reaction was complete in 1.5 h. In a flow operation, reactivity and selectivity were attenuated relative to the batch mode; however, after further optimization, the residence time could be reduced to 16 min with good selectivity and good yield of the target product. A tube-in-tube reactor was investigated for in-situ ethylene removal to favor ring-closing over cross-metathesis, in this context. These results provide further evidence of the utility of flow chemistry for organometallic processing and reaction telescoping. Using the developed integrated batch and flow methods, a total of 7.75 g of goniothalamin (1) was synthesized

Synthesis of methoxylated goniothalamin, aza-goniothalamin and gamma-pyrones and their in vitro evaluation against human cancer cells

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the gamma-pyrones and the azagoniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin ( 1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds. (C) 2012 Elsevier Ltd. All rights reserved.201136353651Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESP [10/16990-1, 2009/51602-5