Turning mustard gas chemistry into green chemistry: a new tool for pharmaceutical synthesis

N,N -dialkyl ethylamine moiety can be found in numerous scaffolds of macromolecules, catalysts and especiallypharmaceuticals such as Tamoxifen, Raloxifene, Amiodarone, Phenyltoloxamine, Trifenagrel and Trimethobenzamide.Common synthetic procedures for its incorporation in a substrate rely on the use of a nitrogen mustard gas or onmultistep syntheses featuring chlorine hazardous/toxic chemistry. Herein are reported our latest results on the one-potsynthetic approach for the introduction of the N,N -dialkyl ethylamine moiety in different phenolic substrates via dialkylcarbonate chemistry. In a typical reaction, 2-dimethylaminoethanol was reacted with a nucleophile (a phenolic scaffold)and dialkyl carbonate (DAC), i.e., diethyl carbonate (DEC), in the presence of a base. In particular, DEC was used for thein-situ formation of ß-aminocarbonate (mustard carbonate) that in turn acts as an alkylating agent via nitrogen nitrogenanchimeric assistance. Different substrates were investigated including precursors of commercially available drugsgiving the related alkylated compound in good to quantitative yields. This one-pot alkylation approach is a striking example of chlorine-free direct substitution of an alcohol, indicated as oneof the key Green Chemistry research areas for pharmaceuticals manufacturers. Furthermore, an in vitro toxicity studyhas been conducted on ß-aminocarbonate and its alcohol precursor, giving an insight into the cytotoxicity values of thereagents for the synthetic procedure proposed

5,5'(Oxy-bis(methylene)bis-2-furfural (OBMF) from 5-hydroxymethyl-2-furfural (HMF): a systematic study for the synthesis of a new platform molecule from renewable substances

The continued exploitation and depletion of fossil fuels has prompted the scientific community to search for more sustainable and environmentally friendly alternatives. In the last decade, the synthesis of biomass-derived chemicals has become a priority to boost the transition from refinery to biorefinery. Sugars are an extremely abundant bio-resource in nature; even today, one of the most studied reactions is the synthesis of 5-hydroxymethyl-2-furfural (HMF). This compound is considered extremely important for biorefinery because of its wide range of possible applications (pharmaceutical, biofuels, polymer precursors, surfactants). However, it has been observed, during the spontaneous degenerative process of HMF, the formation of a compound that could be equally important 5,5'-[oxybis(methylene)]bis-2-furfural (OBMF). The synthesis of OBMF is scarcely reported in the literature, only in recent years interest in this dimer of HMF has emerged for its possible applications in industry. Good yield values of OBMF are reported in the literature from HMF (Figure 1) in the presence of an acid catalyst; however, the solvents used are the most common halogenated and/or aromatic solvents, known to be toxic. The objective of this work was to find a viable synthetic route to access OBMF without having to resort to the use of such solvents and, in addition, utilize already commercially available and inexpensive acid catalysts. Through smallscale optimizations, the best solvent was found to be dimethyl carbonate;4 In addition, two heterogeneous acid catalysts - Purolite 269 and ferric sulfate (Fe2(SO4)3) - showed excellent efficiency in promoting the HMF etherification reaction with quantitative yields (> 90%). Subsequently, a scale-up of the reaction was carried out, obtaining OBMF with an isolated yield of 81%. Given the excellent results obtained, this work can be a starting point to undertake the study of new synthetic methodologies for this molecule such as continuous flow reactions of which the literature is lacking

Dimethyl isosorbide via organocatalyst N-methyl pyrrolidine: scaling up, purification and concurrent reaction pathways

Dimethyl isosorbide (DMI) is a green replacement for conventional dipolar solvents as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) that are toxic and dangerous for human and environmental health. DMI is one of the simplest derivatives well-known bio-based platform chemical isosorbide, an anhydro sugar readily synthesised by D-sorbitol dehydration reaction. [1] The synthesis of DMI is mainly based on the etherification of bio-based platform chemical isosorbide in the presence of basic or acid catalyst employing different alkylating agent. Among them, dimethyl carbonate (DMC) is relevant thanks to its haracteristics: good biodegradability and low toxicity. [2] In this work, we report an extensive investigation on highly yielding methylation of isosorbide via DMC chemistry promoted by several nitrogen organocatalyst. [3] Reaction conditions were performed and then applied for the methylation of isosorbide epimers - isomannide and isoidide - and for preliminary scale-up test (10 g of isosorbide). Pure DMI, starting from mixture reaction, was obtained by both column chromatography and distillation at reduced pressure. Between all nitrogen used, N-methyl pyrrolidine (NMPy) demonstrated excellent behaviour as catalyst also for the one-pot conversion of D-sorbitol into DMI. Furthermore, for the first time, all seven methyl and carboxymethyl intermediates - observed during the etherification of isosorbide - were synthetized, isolated and characterised. This study allowed us to know more deeply the concurrent reaction pathways (methylation, methyl carbonylation and decarboxylation) leading to DMI and on the role played by NMPy in the methylation of isosorbide and in this way to propose a mechanism of conversion into isosorbide into DMI via DMC chemistry

Alkyl Levulinates from Furfuryl Alcohol Using CT151 Purolite as Heterogenous Catalyst: Optimization, Purification, and Recycling

Commercially available Purolite CT151 demonstrated to be an efficient acid catalyst for the synthesis of alkyl levulinates via alcoholysis of furfuryl alcohol (FA) at mild temperatures (80–120 °C) and short reaction time (5 h). Reaction conditions were first optimized for the synthesis of ethyl levulinate and then tested for the preparation of methyl-, propyl-, isopropyl-, butyl, sec-butyl- and allyl levulinate. Preliminary scale-up tests were carried out for most of the alkyl levulinates (starting from 5.0 g of FA) and the resulting products were isolated as pure by distillation in good yields (up to 63%). Furthermore, recycling experiments, conducted for the preparation of ethyl levulinate, showed that both the Purolite CT151 and the exceeding ethanol can be recovered and reused for four consecutive runs without any noticeable loss in the catalyst activit

SUSTAINABLE GRAM-SCALE SYNTHESES OF FURANICS

Among the numerous bio-based platform chemicals - key molecules of the Biorefinery research field - a series of furan-based compounds easily synthetised from D-fructose has captured the scientists’ attention in consideration of their potential market applications. An archetype of these molecules is 5-hydroxymethylfurfural (HMF), a building block that has found numerous applications in the synthesis of chemicals, materials, bio-based polymers and fuels

5,5'(Oxy-bis(methylene)bis-2-furfural (OBMF) da 5-hydroxymethyl-2-furfural (HMF): studio sistematico per la sintesi di una nuova molecola piattaforma da sostanze rinnovabili

Il continuo sfruttamento e il progressivo esaurimento dei combustibili fossili, ha spinto la comunità scientifica a ricercare alternative più sostenibili e rispettose dell’ambiente. Negli ultimi dieci anni, la sintesi di prodotti chimici derivati dalla biomassa è diventata una priorità per incentivare la transizione da raffineria a bioraffineria. Gli zuccheri sono una biorisorsa estremamente abbondante in natura; ancora oggi, una delle reazioni più studiate è la sintesi del 5-hydroxymethyl-2-furfural (HMF). Questo composto è considerato estremamente importante per la bioraffineria per la sua vasta gamma di possibili applicazioni (farmaceutiche, biocarburanti, precursori polimerici, tensioattivi). Tuttavia è stata osservata, durante il processo spontaneo degenerativo del HMF, la formazione di un composto che potrebbe avere altrettanta rilevanza importante il 5,5’-[oxybis(methylene)]bis-2-furfural (OBMF). La sintesi del OBMF è scarsamente riportata in letteratura, soltanto negli ultimi anni l’interesse verso questo dimero del HMF è emerso per le sue possibili applicazioni in ambito industriale. Buoni valori di resa del OBMF vengono riportati in letteratura a partire dal HMF (Figura 1) in presenza di un catalizzatore acido; tuttavia, i solventi utilizzati sono i più comuni solventi alogenati e/o aromatici, noti per essere tossici. Obiettivo di questo lavoro è stato quello di trovare una valida via sintetica per poter accedere al OBMF senza dover ricorrere all’utilizzo di tali solventi e, in aggiunta, utilizzare catalizzatori acidi già disponibili commercialmente ed economici. Tramite le ottimizzazioni in piccola scala, il miglior solvente è risultato essere il dimetil carbonato; inoltre, due catalizzatori acidi eterogenei - Purolite 269 e solfato ferrico (Fe2(SO4)3) - hanno mostrato una ottima efficienza nel promuovere la reazione di eterificazione del HMF con rese quantitative (> 90%). Successivamente è stato effettuato uno scale-up della reazione, ottenendo l’OBMF con una resa isolata del 73%. Visti gli ottimi risultati ottenuti, questo lavoro può essere di spunto per intraprendere lo studio di nuove metodologie sintetiche per questa molecola come ad esempio reazioni in flusso continuo di cui la letteratura risulta essere assent

Sintesi del metil estere dell’acido furan dicarbossilico (FDME) a partire dall’acido galattarico tramite la chimica del dimetil carbonato

L’acido 2,5-furandicarbossilico (FDCA) è stato studiato estensivamente come monomero per per la produzione di poliesteri1 come il polietilene furanoato (PEF), considerato il più valido biosostituto del polietilene tereftalato (PET). Il PEF possiede notevoli proprietà meccaniche e termiche, una forte barriera ai gas, un basso carbon footprint e una ridotta produzione di gas serra durante la sua sintesi.2 La maggior parte dei processi sintetici per l’ FDCA utilizzano zuccheri edibili (glucosio e fruttosio) come substrati attraverso la produzione del 5-idrossimetilfurfurale (HMF) come intermedio.3 Il principale svantaggio di questo processo riguarda l’instabilità, il costo elevato e la difficile separazione e purificazione dell’HMF, che portano alla formazione di umine, abbassando notevolmente la resa della reazione.4 Pochi studi si sono invece concentrati sulla produzione di FDCA a partire da substrati differenti. Ad esempio questo composto può anche essere sintetizzato a partire dai cosiddetti acidi aldarici, i derivati dicarbossilici monosaccaridi (C6), che possono essere ottenuti sia tramite ossidazione degli stessi o direttamante dalla buccia di alcuni agrumi come cedro e arancia.5 Partendo da queste premesse, il seguente studio riporta una sintesi alternativa per la produzione del dimetil estere dell’acido 2,5-furandicarbossilico (FDME) a partire dall’acido galattarico (o mucico) tramite la chimica del dimetil carbonato (DMC). In una tipica reazione l’acido galattarico viene fatto reagire con DMC in presenza di Amberlyst-36 come catalizzatore acido. La reazione viene condotta in autocalve a 200 °C per 2 ore. Il prodotto può essere facilmente ottenuto come solido cristallino tramite purificazione con carbone attivo con resa del 70 %. Inoltre, sulla base dei diversi intermedi di reazione identificati, è stato ipotizzato un possibile meccanismo di reazione che evidenzia l’indispensabile contributo del dimetilcarbonato nella formazione del prodotto

Multi gram scale synthesis of HMF and comparative environmental evaluation

5-Hydroxymethylfurfural (HMF) is a bio-based platform chemical that can be used as building block to produce complex and useful compounds with diverse applicability, in particular, bio-based polymers, materials and fuels [1], [2]. Even though HMF synthesis holds promise for a greener future, with the current state of technology the high production cost limits its competitiveness at an industrial scale[1]. In this project our main goal is to develop an optimized procedure for the synthesis of HMF that will allow us to perform scale-up reactions with competitive yields with a green mindset. The synthesis of HMF from the dehydration of D-fructose, already investigated by our research group[2], was performed with a heterogeneous acid catalyst using various conditions in different settings: autoclave, sonificator and microwave oven. The best results were obtained employing a stainless-steel autoclave which allowed a large scale HMF production using up to forty grams of D-fructose as starting material. The final product was recovered from the crude mixture and purified by a custom-made crystallization procedure. Finally, green metrics were used to evaluate the greenness of the reaction in comparison with previously reported works[3]

Synthesis and derivatization of 2,5-bis(hydroxymethyl)furan (BHMF)

Biomass-derived C6-furanic platform chemicals are regarded as the most promising building blocks in biorefinery exploitation. 5-Hydroxymethylfurfural (HMF) is referred as a “sleeping giant” in consideration of its potential in bridging the gap from a fossil-based chemistry to a more sustainable one. HMF is a versatile substrate with enormous market potential as it can be easily converted into high value chemicals, materials and bio-based polymers.[1] However, there are some limitations in developing an efficient HMF-based chemistry, i.e., its preferred solubility in water rather than in organic solvents, the absence of a cost-efficient scale-up synthesis, and well know HMF stability issue partially solved by the addition of small amount of specific stabilizers. In our laboratory we have developed a new approach to HMF from D-Fructose using dimethyl carbonate as an extracting solvent in the presence of an acidic heterogenous catalyst. This synthesis is easily scalable up to 20 grams of D-fructose and allows to recover HMF in 70% isolated yield.[2] Quick reduction of HMF to the related 2,5-bis(hydroxymethyl)furan (BHMF) was also carried out using sodium borohydride as reducing agent. This latter approach led to prepare rapidly a rather large amount of BHMF. As a result, BHMF derivatization was also investigated. In particular we have focused on BHMF etherification reaction to achieve 2,5-bis(alkoxymethyl) furans (BAMFs) – well-known biofuel candidates. Several catalysts were investigated; (mild) reaction conditions were optimized and thus employed for the preparation of a library of BAMFs (10 compounds). Products isolation and purification were addressed for each BAMFs.[3] Two examples of etherification reactions were also conducted in gram-scale i.e. for the synthesis of 2,5-bis(methoxymethyl)furan and 2,5-bis(isopropoxymethyl) furan. Ongoing research on BHMF includes studying its reactivity with dialkyl carbonates. The idea is to develop a library of easy accessible bio-based monomers for polycarbonate, polyurethanes as well as potentially interesting intermediates for surfactants and detergents production.[4

Analoghi carbonati delle ipriti

I gas mostarda o ipriti, bis(2-cloroetil)solfuro e la bis(2-cloroetil)etilammina, sono tristemente conosciuti per il loro impiego come armi chimiche durante la Prima Guerra Mondiale.1 La tossicità delle ipriti è strettamente correlata alla loro elevata reattività. Infatti, questi composti sono in grado di eliminare lo ione cloruro attraverso una sostituzione nucleofila intramolecolare grazie all’effetto anchimerico dello zolfo o dell’azoto vicinale, generando uno ione episolfonico o aziridinico ciclico che è – a sua volta - estremamente reattivo.2 Nonostante la loro ben nota tossicità, questi composti trovano largo impiego nella preparazione di farmaci, nonché come reagenti per la sintesi di intermedi di reazione.3 Nello studio qui presentato, i dialchil carbonati (DAC)4 – noti reagenti e solventi Green – sono stati fatti reagire con alcoli/dioli precursori dei gas mostarda portando ad una nuova classe di composti: le mostarde carbonate. La reattività degli analoghi carbonati delle ipriti è stata successivamente investigata dimostrando che questi composti preservano l’effetto anchimerico dei gas mostarda, ma non presentano alcuna tossicità, nè pericolo per l’operatore o l’ambiente.5 Le reazioni di alchilazione favorite dall’effetto anchimerico delle mostarde carbonate sono state condotte impiegando diversi nucleofili e operando sia in autoclave ad alta temperatura (180 °C) che in neat a temperature inferiori (150 °C) e a pressione atmosferica. Inoltre, recentemente sono state studiate reazioni di alchilazione in one-pot dove la mostarda carbonata è sintetizzata in situ e reagisce immediatamente con il nucleofilo scelto. Riferimenti 1. a) J. C. Dacre, M. Goldman, Pharmacol. Rev. 1996, 48, 289–326; b) J. Liu, K. L. Powell, H. D. Thames, M. C. MacLeod, Chem. Res. Toxicol. 2010, 23, 488–496. 2. E. Block in Reactions of Organosulfur Compounds, Academic Press, New York, 1978, pp. 141–145. 3. M. C. S. Barnes, H. J. Dennison, S. S. Flack, J. A. Lumley, P. S. Pang, K. C. Spencer, WO2011/27156, 2011. 4. a) P. Tundo, M. Selva, Acc. Chem. Res. 2002, 35, 9, 706; b) Fabio Arico,̀ A. S. Aldoshin, and P. Tundo, ACS Sustainable Chem. Eng.2016, 4, 2843−2851 5. F. Aricò, M. Chiurato, J. Peltier, P. Tundo. Eur. J. Org. Chem. 2012, 3223–322