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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 sacrificial oxidants, and enables the synthesis of a diverse range of hydroxylated products, introducing connectivity typically precluded from conventional polar domains. Notably, the methodology has been extended to widely used glycolic acid resulting in a highly efficient and unprecedented C1 hydroxyhomologation tactic. The use of flow technology further facilitates scalability and adds green credentials to this synthetic methodology.
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The oxetane ring has evolved as a useful bioisostere for dimethyl and carbonyl groups for the improvement of physiochemical properties of drug candidates. Herein, we report the generation and utilization of highly unstable 3-oxetanyllithium as a hitherto unexplored nucleophile leveraging flash technology. A range of different electrophiles are suitable reaction partners in this protocol, and we demonstrate the utility of this protocol in late-stage pharmaceutical analogue synthesis.
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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, highlighting the electrophilic nature of sulfinimidate esters and the nucleophilic character of sulfinamidines. Moreover, sulfinamidines have been found to be prone to oxidation, leading to the formation of important aza-S(VI) derivatives. In this review, our aim is to present an almost comprehensive overview of the most relevant achievements in the preparation and structural characterization of these overlooked compounds.
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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 through lithium/iodine exchange reaction. This robust protocol was employed to prepare new fluorinated products, adopting various classes of electrophiles. The inherent advantages of microreactor technology contribute to rendering this approach a new valuable tool for direct fluoroalkylation chemistry.
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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 nucleophilic attack of organometallic reagents to inâ situ prepared N-(trimethylsilyl)-N-trityl-λ4 -sulfanediimine (Tr-N=S=N-TMS). The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen-lithium exchange of aryl bromides and iodides with n-butyllithium. Moreover, the synthetic potential of the methodology was assessed by exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas.
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Bromuros , Litio , Yoduros , Celecoxib , Halógenos , AzufreRESUMEN
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 reveals the configurational instability of the diastereomeric lithiated azetidines, it points out an interesting stereoconvergence of such lithiated intermediates towards the thermodynamically stable species, making the overall process highly stereoselective (er > 95:5, dr > 85:15) after trapping with electrophiles. This peculiar behavior has been rationalized by considering the dynamics at the azetidine nitrogen atom, the inversion at the C-Li center supported by in situ FT-IR experiments, and DFT calculations that suggested the presence of η3-coordinated species for diastereomeric lithiated azetidines. The described situation contrasted with the demonstrated stability of the smaller lithiated aziridine analogue. The capability of oxazolinylazetidines to undergo different reaction patterns with organolithium bases supports the model termed "dynamic control of reactivity" of relevance in organolithium chemistry. It has been demonstrated that only 2,2-substituted oxazolinylazetidines with suitable stereochemical requirements could undergo C=N addition of organolithiums in non-coordinating solvents, leading to useful precursors of chiral (er > 95:5) ketoazetidines.
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Azetidinas , Litio , Nitrógeno , Espectroscopía Infrarroja por Transformada de Fourier , EstereoisomerismoRESUMEN
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 potential of this reagent for the preparation of organofluorine compounds. In this minireview, we provide an update to the field covering the recent relevant literature on the use of CH2FI.
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Elementos de Transición , Indicadores y Reactivos , Elementos de Transición/químicaRESUMEN
The use of flow technology as an enabling tool for accessing 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) were also evaluated. New chemical space has been explored and new structural motifs such as ABB-aziridines or spiro azetidine-oxazetidines are also reported.
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Azetidinas , Aziridinas , Butanos , TecnologíaRESUMEN
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 recent developments in the synthesis of sulfoximines concentrating on developments since 2015. This includes extensive developments in both S-N and S-C bond formations. Flow chemistry processes for sulfoximine synthesis are also covered. Finally, subsequent transformations of sulfoximines, particularly in N-functionalization are reviewed, including N-S, N-P, N-C bond forming processes and cyclization reactions.
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Química Farmacéutica , Ciclización , Estructura MolecularRESUMEN
In this work we investigated, for the first time, the reactivity of sulfinimidate esters as an electrophilic sulfinimidoyl motif source. The reaction of such sulfinimidate esters with Grignard reagents enables the preparation of protected sulfilimines in high yields and with a remarkable structural variability. Moreover, the transformation can be performed in CPME (cyclopentyl methyl ether) as a green solvent under environmentally responsible conditions.
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The generation and functionalization, under continuous flow conditions, of two different lithiated four-membered aza-heterocycles is reported. N-Boc-3-iodoazetidine acts as a common synthetic platform for the genesis of C3-lithiated azetidine and C2-lithiated azetine depending on the lithiation agent. Flow technology enables easy handling of such lithiated intermediates at much higher temperatures compared to batch processing. Flow technology combined with cyclopentylmethyl ether as an environmentally responsible solvent allows us to address sustainability concerns.
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Azetidinas , AzetinasRESUMEN
The reaction between configurably stable α-lithiated oxiranes and 3-substituted cyclobutanones allows obtaining enantiomerically enriched cyclobutanols (er > 98 : 2). These adducts, subjected to base-mediated Payne rearrangement, lead to the synthesis of a new class of oxaspirohexanes, useful precursors of 2,4-disubstituted cyclopentanones.
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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[1.1.0]butanes. The flow method allows for exquisite control of the reaction parameters, and the process operates at higher temperatures and safer conditions with respect to batch mode. The efficiency of this intramolecular cyclization/C3-lithiation/electrophilic quenching flow sequence is documented with more than 20 examples.
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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 investigated.
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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. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds.
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Química Farmacéutica/tendencias , Compuestos Heterocíclicos/síntesis química , Indoles/síntesis química , Compuestos Heterocíclicos/química , Humanos , Indoles/químicaRESUMEN
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 double functionalization in the 1,3 positions. In particular, the recent advances reported by Baran, Lopchuk, Aggarwal, and others witness the synthetic relevance of such strained azabicycles in the synthesis of highly functionalized azetidines. However, the synthesis and reactivity of 1-azabicyclo[1.1.0]butanes remains a poorly explored topic in organic chemistry. This review aims to furnish a comprehensive knowledge on the preparation of 1-azabicyclo[1.1.0]butanes and the transformation into functionalized saturated four-membered azacycles.
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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 ß-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucose, mannose and galactose as glycosyl units. The process has been extended to a lactose derived thioglycoside and to a glucose derived sulfenamide. The process was chemo- and stereoselective, and X-ray analysis confirmed the structure and provided stereochemical information on the configuration at the sulfur atom. A model for the stereochemical outcome is proposed based on the steric environment of the sulfide.
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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 -20 °C. Remarkably, the high chemoselectivity realized in flow allowed for preparing polyfunctionalized α-chloro aldehydes not easily accessible with traditional batch procedures.
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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 molecules using fluorinated organometallics.
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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 non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines.