Renzo Luisi

Università degli Studi di Bari Aldo Moro | Università di Bari · Department of Pharmacy - Drug Sciences

Direct synthesis of NH-sulfoximines from sulfides has been achieved through O and NH transfer in the same reaction, occurring with complete selectivity. The reaction is mediated by bisacetoxyiodobenzene under simple conditions and employs inexpensive N-sources. Preliminary studies indicate that NH-transfer is likely to be first, followed by oxidati...

The almost unexplored four-membered heterocycles azetidines, represent a particularly interesting class of molecules, among the family of saturated nitrogen heterocycles. Although often challenging to synthesize, substituted azetidines strongly attract chemists because of their importance in catalysis, stereoselective synthesis and medicinal chemis...

Tertiary butyl esters find large applications in synthetic organic chemistry. A straightforward method for the direct introduction of the tert-butoxycarbonyl group into a variety of organic compounds has been developed using flow microreactor systems. The resultant flow process was more efficient, versatile and sustainable compared to the batch.

The transfer of nitrogen atoms is extremely valuable in the preparation of medicinal compounds. Here, a new system for NH transfer is developed to prepare sulfoximines, which are emerging as valuable motifs for drug discovery. This is achieved using readily available sources of nitrogen without the requirement for pre-activation or for metal cataly...

The reactivity profile of lithiated N-Boc-2-arylazetidines has been investigated filling a gap in the chemistry of this kind of four-membered heterocycles. Two unexpected and unprecedented results have been observed: an “ortho-effect” accounting for a regioselective functionalization of the azetidine ring, and a self-condensation leading to new and...

Aza‐S(VI) fluorides are crucial compounds in the synthesis of various S(VI) derivatives, which find broad applications in drug discovery. However, the synthesis of sulfonimidoyl and sulfondiimidoyl fluorides have been relatively underexplored, often requiring lengthy reaction sequences and/or the use of hazardous gaseous reagents. In this study, we...

Sulfur(VI)–fluoride exchange (SuFEx) is a second generation, metal-free click chemistry concept introduced by Sharpless in 2014. Since the introduction of the concept, a large variety of synthetic methodologies to S(VI)-SuFEx hubs, and their derivatization with oxygen-, nitrogen-, and carbon-based nucleophiles have been developed. Herein, we provid...

The development of novel strained spiro heterocycles (SSHs) as bioisosteres for aromatic or non‐strained aliphatic rings is highly sought after for improving drug design. Their high molecular rigidity and predictable vectorization can enhance drug‐likeness, target selectivity and clinical success. Towards this goal, 1‐oxa‐2,6‐diazaspiro[3.3]heptane...

This chapter presents the procedure for synthesis of NH‐sulfoximines from sulfides using ammonium carbamate and (diacetoxyiodo) benzene to transfer NH and O. Sulfoximines are emerging motifs in the life sciences and have shown application in asymmetric synthesis as chiral auxiliaries, ligands and catalysts. Their Lewis basic character has also made...

This chapter presents the procedure for synthesis of enantioenriched NH‐sulfoximines by NH transfer to sulfoxides using ammonium carbamate and (diacetoxyiodo) benzene. Sulfoximines are emerging motifs in the life sciences and have shown application in asymmetric synthesis as chiral auxiliaries, ligands and catalysts. Their Lewis basic character has...

Naturally occurring and readily available α-hydroxy carboxylic acids (AHAs) are utilized as platforms for visible light-mediated oxidative CO2-extrusion furnishing α-hydroxy radicals proved to be versatile C1 to Cn hydroxyalkylating agents. The direct decarboxylative Giese reaction (DDGR) is operationally simple, not requiring activator or sacrific...

This study explores the application of computer-aided retrosynthesis (CAR) for developing greener and more efficient synthetic routes for the active pharmaceutical ingredient (API) IM-204, a helicase primase inhibitor with potential against Herpes simplex virus (HSV) infections. Using various CAR tools, several total synthetic routes were identifie...

Naturally occurring and readily available α-hydroxy carboxylic acids (AHAs) are utilized as platforms for visible light-mediated oxidative CO2-extrusion furnishing α-hydroxy radicals proved to be versatile C1 to Cn hydroxyalkylating agents. The decarboxylative direct Giese reaction (DDGR) is operationally simple, not requiring activator or sacrific...

Significant advancements have been made in the synthesis of overlooked aza-S(IV) motifs. The accessibility of sulfinamidines and sulfinimidate esters has greatly improved through the recent development of efficient and complementary synthetic strategies. Intriguingly, new discoveries have emerged regarding the reactivity of these substances, highli...

A strategy for anti‐Markovnikov hydroalkyl/aryl thiolation and disulfidation of 2‐azetines under continuous flow conditions has been developed. Thiyl radicals are generated from thiols or disulfides and subsequently propagate into the azetine unsaturation to forge the C−S bond and shape a secondary radical intermediate. This carbon‐centered radical...

The development of NH transfer reactions using hypervalent iodine and simple sources of ammonia has facilitated the synthesis of sulfoximines and sulfonimidamides for applications across the chemical sciences. Perhaps most notably, the methods have been widely applied in medicinal chemistry and in the preparation of biologically active compounds, i...

A direct nucleophilic monofluoroalkylation strategy leveraging on lithium fluorocarbenoids has been developed. Flow microreactor technology allows capitalization of the synthetic potential of these scarcely explored short-lived intermediates - namely 1-fluoro-2-phenylethyllithium, 1-fluoro-3-phenylpropyllithium, and 1-fluorononyllithium - generated...

In this work we report a waste-minimized continuous flow process for the synthesis of β-aminocarbonyls through hydration of N- B oc-2-azetines promoted under acid-catalysed conditions.

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (R)-4-methylbenzenesulfonimidate was synthesized via the stereoselective NH-transfer to (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-4-methylbenzenesulfinate. The reaction employed diacetoxyiodobenzene (DIB) and ammonium carbamate, and occurred in acetonitrile at room temperature. The imidation of sulfur p...

The growing interest in novel sulfur pharmacophores led to recent advances in the synthesis of some S(IV) and S(VI) motifs. However, preparation and isolation of uncommon primary sulfinamidines, the aza‐analogues of sulfinamides, is highly desirable. Here we report a multistep continuous flow synthesis of poorly explored NH2‐sulfinamidines by nucle...

Two unprecedented transformations of 2-azetines are reported. Varied C2-functionalized 2-azetines, prepared under continuous flow conditions, acted as linchpin for the preparation of either -aminocarbonyls or C3-thiolated azetidines. Interestingly, the two transformations occurred following an ionic or radical pathway depending on the reaction con...

An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1H-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole ring, employing a base-catalysed Claisen–Schmidt condensation reaction, is described. Isomeric chalcones were further reacted with N-hydroxy-4-toluenesulfonamide and regioselective...

In recent years, fluoroiodomethane (CH2FI) has emerged as an easy-to-handle, non-ozone depleting agent and readily available platform for monofluoromethylation strategies. Recent applications in nucleophilic substitutions, lithiation reactions, transition-metal catalyzed transformations, radical processes, and 18F-radiolabelling chemistry showcase...

The use of flow technology as enabling tool for accessing to 1-azabicyclo[1.1.0]butanes bearing strained 3-, 4-, and 5-membered O-heterocycles with C3(N-het)-C2(O-het) connectivity is reported. Reactivity and chemoselectivity (N-ring vs O-ring)...

In this work it is demonstrated that enantiomerically enriched N-alkyl 2-oxazolinylazetidines undergo exclusive α-lithiation, and that the resulting lithiated intermediate is chemically stable but configurationally labile under the given experimental conditions that afford enantioenriched N-alkyl-2,2-disubstituted azetidines. Although this study re...

We report an improved approach for the integration of flow synthesis and continuous chromatography, for applications in the end-to-end preparation of pharmaceutically-relevant small molecules. It involves the combination of sequential...

Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This Review covers the most recent advances in the synthesis of NH‐sulfoximines, including extensive developments in both S−N and S−C bond formations. Moreover, flow chemistry processes for...

Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This has been prompted by both pioneering works taking sulfoximine containing compounds into clinical trials and the concurrent development of powerful synthetic methods. This review covers...

Strained compounds are privileged moieties in modern synthesis. In this context, 1‐azabicyclo[1.1.0]butanes are appealing structural motifs that can be employed as click reagents or precursors to azetidines. We herein report the first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1‐azabicyclo[1.1....

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologie...

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologie...

The reaction between configurably stable -lithiated oxiranes (and aziridines) and 3-substituted cyclobutanones allows to obtain enantiomerically enriched cyclobutanols (er > 98:2). These adducts, subjected to base-mediated Payne rearrangement lead to...

The reported flow-batch approach enables the easy preparation of 2 H -azirines and their stereoselective transformation into highly functionalized NH -aziridines, starting from vinyl azides and organolithium compounds. The protocol has been developed using cyclopentyl methyl ether (CPME) as an environmentally benign solvent, resulting into a sustai...

Organolithium compounds, first reported more than a century ago are still capturing the interests of synthetic chemists not only because are very useful reagents for the selective construction of CC and CX bonds, but also because lithiation chemistry can always reveal new and interesting aspects that stimulate creativity and design in modern synthe...

Nitrogen-containing four-membered heterocycles are extremely important in modern organic synthesis. The rigidity brought about by these heterocyclic scaffolds can be exploited in medicinal chemistry and modern drug discovery programs. In this chapter, recent advances on the synthesis and reactivity of azetidines, azetines, azetes, and azetidinones...

Strained….in Flow! The first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1‐azabicyclo[1.1.0]butane is reported. Several structurally unique C3‐functionalized 1‐azabicyclo[1.1.0]butanes were prepared using this strategy starting from readily available starting materials. Abstract Strained compou...

The reported flow-batch approach enables the easy preparation of 2 H -azirines and their stereoselective transformation into highly functionalized NH-aziridines, starting from vinyl azides and organolithiums. The protocol has been developed using cyclopentylmethylether (CPME) as an environmentally responsible solvent, resulting into a sustainable,...

The formation of hydrazinium salts by N−N bond formation has typically involved the use of hazardous and difficult to handle reagents. Here, mild and operationally simple conditions for the synthesis of hydrazinium salts are reported. Electrophilic nitrogen transfer to the nitrogen atom of tertiary amines is achieved using iodosylbenzene as oxidant...

In this work we report a new synthetic tactic for the straightforward preparation of hardly accessible sulfinamidines and sulfinamide esters, by using a simple metal-free protocol. The process is robust and uses readily available sulfenamides as the S-donor and sulfonyloxycarbamates as the N-source. The scope and mechanism have also been investigat...

Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selecte...

Since their discovery in the late 1960s, 1-azabicyclo[1.1.0]butanes have demonstrated to be interesting precursors of azetidines, because of the peculiar reactivity of the C3-N bond that allows the double functionalization in 1,3 positions. In particular, the recent advances reported by Baran, Lopchuck, Aggarwal, and others witnesses the synthetic...

A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several β-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucos...

Quenched: An external quenching method based on flow microreactors allows the generation and use of short‐lived fluoro‐substituted methyllithium agents, such as fluoromethyllithium, fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. Highly chemoselective reactions have been developed, opening new opportunities in the synthesis of fluorina...

A straightforward flow synthesis of α-chloro aldehydes has been developed. The strategy involves, for the first time, the thermal unstable chloroiodomethyllithium carbenoid and carbonyl compounds. A batch versus flow comparative study showcases the superb capability of flow technology in prolonging the lifetime of the lithiated carbenoid, even at -...

The external quenching method based on flow microreactors allows the generation and use of short‐lived fluoro‐substituted methyllithium reagents, such as fluoromethyllithium, fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. Highly chemoselective reactions have been developed, opening new opportunities in the synthesis of fluorinated mol...

In view of the expanding interest in fluorinated heterocycles, the installation of a fluoroalkyl group in a molecule represents a challenging task in organic synthesis. Nowadays, convenient strategies for introducing CF2X groups are still on demand because halodifluoromethylated compounds are useful synthetic intermediates in medicinal and agrochem...

Nuclear Magnetic Resonance (NMR) is an analytical technique extensively used in almost every chemical laboratory for structural identification. This technique provides statistically equivalent signals in spite of using spectrometer with different hardware features and is successfully used for the traceability and quantification of analytes in food...

In a flow microreactor, aryllithiums bearing a piperidylmethyl group were generated using nBuLi by precise residence time control and effective temperature control, and then selectively borylated with boronic esters such as 2‐isopropoxy‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (BpinOiPr) and trimethyl borate B(OMe)3 by fast mixing. Moreover, the dir...

In the field of organic synthesis, the advent of flow chemistry and flow microreactor technology represented a tremendous novelty in the way of thinking and performing chemical reactions. Just as the classical flask and glass connectors, are still in use, after centuries, in our synthetic laboratories; flow devices will need to conquer the bench of...

Flow chemistry and heterogenous catalysis hold incredible potential from a sustainability point of view and from a green perspective. In fact, if heterogenous catalysts are required by the chemical industry for their efficiency, on the other hand, heterogenous flow catalysis would allow performing greener and more efficient chemistry at an industri...

The production of biodiesel at the industrial level is mainly based on the use of basic catalysts. Otherwise, also acidic catalysis allowed high conversion and yields, as this method is not affected by the percentage of free fatty acids present in the starting sample. This work has been useful in assessing the possible catalytic pathways in the pro...

In the field of organic synthesis, the advent of flow chemistry and flow microreactor technology represented a tremendous novelty in the way of thinking and performing chemical reactions, opening the doors to poorly explored or even impossible transformations using batch methods. In this Concept article, we would like to highlight the impact of flo...

A facile microwave assisted three-component protocol allows the synthesis of chiral aryl-1,2-mercaptoamines in water in a few minutes with high yields, bypassing the use of toxic aziridine intermediates. The chiral...

A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a...

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH‐sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disul...

This work reports the preparation of propranolol according to a flow process. Propranolol has been prepared paying attention to tackle the formation of the by-product tertiary amine, resulting from an additional ring opening of the starting epoxide. Remarkably, the use of catalytic amount of water resulted beneficial for the yield and purity of the...

The use of graphene derivatives as supports improves the properties of heterogeneous catalysts, with graphene oxide (GO) being the most frequently employed. To explore greener possibilities as well as to get some insights into the role of the different graphenic supports (GO, rGO, carbon black, and graphite nanoplatelets), we prepared, under the sa...

NH‐ und O‐Transfer: Praktische Reagentien für den NH‐ und O‐Transfer ermöglichen die direkte Synthese von NH‐Sulfonimidamiden aus Sulfenamiden. In nur zwei Schritten wurden unterschiedlich funktionalisierten Sulfonimidamide aus kommerziell erhältlichen Substraten in hoher Ausbeute hergestellt. Zudem wurden Alkoxyamino‐λ⁶‐sulfannitrile isoliert, und...

Continuous flow chemistry is radically changing the way of performing chemical synthesis, and several chemical and pharmaceutical companies are now investing in this enabling technology [...]

An unprecedented direct fluorocyclopropanation of allylic alcohols is successfully achieved. This simple method involves the not so elusive fluoroiodomethyllithium, a carbenoidic intermediates, that under the developed conditions discloses its electrophilic...

The discovery of alternative fuels that can replace conventional fuels has become the goal of many scientific researches. Biodiesel is produced from vegetable oils through a transesterification reaction that converts triglycerides into fatty acid methyl esters (FAME), with the use of a low molecular weight alcohol, in different reaction conditions...

An expeditious, high-yielding synthesis of rare α-fluoroepoxides and α-fluoroaziridines through the addition of the unkown fluoroiodomethyllithium (LiCHIF) - formed via deprotonation the commercially available fluoroiodomethane with a lithium amide base - to carbonyl-like compounds is documented. The ring-closure reactions, leading to α-fluorinated...

We report herein a synthetic protocol for the preparation of 1,3-dibromo-1,1-difluoro-2-propanone, a new synthon used for the first time in a reaction with aromatic amines and sodium thiocyanate, leading to thiazoles which are useful candidates in drug discovery programs. The new synthon allows to introduce a bromodifluoromethyl group at the C4 of...

Flow chemistry and heterogenous catalysis hold incredible potential from a sustainability point of view and from a green perspective. In fact, if heterogenous catalysts are required by the chemical industry for their efficiency, on the other hand, heterogenous flow catalysis would allow performing greener and more efficient chemistry at an industri...

The development of a multistep continuous-flow process, consisting of a direct α-lithiation stage and subsequent hydroxylation by aerobic oxidation, is reported. The protocol is applied to the synthesis of cyclopentylmandelic acid (CPMA), the main building block for the anticholinergic glycopyrronium bromide (glycopyrrolate). We demonstrate the saf...