RESUMEN
Acylsilanes are able to react as nucleophilic carbene precursors, electrophiles, and directing groups in C-H functionalization. To date, some of the products reportedly formed during transition-metal-catalyzed and photochemical reactions involving acylsilanes have been incorrectly assigned. To provide clarity, we herein address these structural misassignments and detail the revised structures. New insights into the reactivity of acylsilanes were also afforded via the discovery that light-induced siloxy carbenes participate in intramolecular 1,2-carbonyl addition to proximal esters.
RESUMEN
Investigations into C-H amidation reactions catalysed by cationic half-sandwich d6 metal complexes revealed that the indenyl-derived catalyst [Ind*RhCl2 ]2 significantly accelerated the directed ortho C-H amidation of benzoyl silanes using 1,4,2-dioxazol-5-ones. Ring slippage involving a haptotropic η5 to η3 rearrangement of the indenyl complex proposedly enables ligand substitution at the metal centre to proceed via associative, rather than dissociative pathways, leading to significant rate and yield enhancements. Intriguingly, this phenomenon appears specific for C-H amidation reactions involving weakly coordinating carbonyl-based directing groups with no acceleration observed for the corresponding reactions involving strongly coordinating nitrogen-based directing groups.
RESUMEN
Polynucleotides, DNA and RNA (mRNA and non-coding RNAs) are critically involved in the molecular pathways of disease. Small molecule binding interactions with polynucleotides can modify functional polynucleotide topologies and/or their interactions with proteins. Current approaches to library design (lead-like or fragment-like libraries) are based on protein-ligand interactions and often include careful consideration of the 3-dimensional orientation of binding motifs and exclude π-rich compounds (polyfused aromatics) to avoid off-target R/DNA interactions. In contrast to proteins, where π,π-interactions are weak, polynucleotides can form strong π,π-interactions with suitable π-rich ligands. To assist in designing a polynucleotide-biased library, a scaffold-divergent synthesis approach to polyfused aromatic scaffolds has been undertaken. Initial screening hits that form moderately stable polynucleotide-ligand-protein ternary complexes can be further optimized through judicious incorporation of substituents on the scaffold to increase protein-ligand interactions. An example of this approach is given for topoisomerase-1 (TOP1), generating a novel TOP1 inhibitory chemotype.
Asunto(s)
Polinucleótidos , ARN , Polinucleótidos/química , Ligandos , ADN/química , ProteínasRESUMEN
Siloxy carbenes, formed thermally or photochemically from acyl silanes via a 1,2-Brook rearrangement, are intriguing reactive intermediates that partake in a range of chemical reactions. To gain further insight into the properties of this class of carbenes, the thermodynamic stabilities of a series of known siloxy carbenes were explored on the basis of hydrogenation enthalpies. Calculations were conducted at the B3LYP-D3(BJ) level (using dispersion-corrected DFT) on siloxy carbenes (X-C-OSiR3, singlet and triplet state), oxocarbenium ions (X-CH-OSiR3+), and their hydrogen addition products (X-CH2-OSiR3). Overall, strong correlation between singlet-triplet gaps and hydrogenation enthalpies was observed. Carbene stabilization enthalpy (CSE) values were also determined to provide additional insight into the structural features that influence the stability of siloxy carbenes.
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Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.
Asunto(s)
Antibacterianos/química , Antibacterianos/síntesis química , Técnicas de Química Sintética/métodos , Diarilquinolinas/química , Diarilquinolinas/síntesis química , Antibacterianos/farmacología , Ácidos Borónicos/química , Diarilquinolinas/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , SeguridadRESUMEN
A new method for the regioselective and stereoselective iodoacyloxylation of alkynes has been developed. This protocol utilizes a combination of an iodobenzene dicarboxylate and iodine to functionalize a series of activated and unactivated alkynes in an entirely selective and predictable fashion. The resultant iodo-enol esters were subsequently coupled with boronic acids to afford tetrasubstituted alkene derivatives, which could be further converted to the corresponding 1,1-disubstituted acetophenone.
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Alquinos/química , Hidrocarburos Yodados/síntesis química , Hidrocarburos Yodados/química , Estructura Molecular , EstereoisomerismoRESUMEN
Light-induced Brook rearrangements of acylsilanes facilitate silylacylation reactions of electron-deficient internal alkynes. A wide range of aromatic substituents on the acylsilane aryl group are tolerated, affording a series of functionalized enonyl silanes. The presence of electron-withdrawing substituents on the alkyne is crucial for the success of the addition process.
RESUMEN
The Willgerodt-Kindler reaction has, in recent years, received limited attention and application in synthetic organic chemistry. With the advent of new technology such as microwave-assisted heating, several new, high-yielding, practical, and more environmentally friendly reaction protocols have been developed. This review aims to once again draw attention to this relatively underutilised process by highlighting the recent developments in the Willgerodt-Kindler reaction in the synthesis of (thio)amides, carboxylic acids, and heterocycles.
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Ácidos Carboxílicos/síntesis química , Técnicas Químicas Combinatorias/métodos , Compuestos Heterocíclicos/síntesis química , Microondas , Tioamidas/síntesis química , Ácidos Carboxílicos/química , Tecnología Química Verde , Compuestos Heterocíclicos/química , Tioamidas/químicaRESUMEN
Acylsilanes are a fascinating class of compounds that display a number of distinctive chemical and physical properties. The unique reactivity pattern of the acylsilane functional group [R-C(O)Si] makes them an increasingly attractive moiety in modern organic synthesis, and as such, they have been utilised in a diverse range of transformations. This review provides an overview of the recent advances in the synthesis and application of acylsilanes in organic chemistry, with a particular focus on the progress made in the last two decades.
RESUMEN
Acylsilanes are known to undergo a 1,2-silicon-to-oxygen migration under thermal or photochemical conditions to form siloxycarbenes. However, there are few reports regarding the application of siloxycarbenes in organic synthesis and surprisingly, their reaction with CC double or triple bonds remains virtually unexplored. To facilitate such a study, previously inaccessible aromatic acylsilanes containing an ortho-tethered CC double bond were identified as suitable substrates. To access these key intermediates, we developed a new synthetic method utilizing a rhodium-catalyzed oxidative Heck-type olefination involving the application of an acylsilane moiety as a directing group. When exposed to visible-light irradiation, the ortho-olefinated acylsilanes underwent a smooth intramolecular cyclization process to afford valuable indanone derivatives in quantitative yields. This result paves the way for the development of new transformations involving siloxycarbene intermediates.
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CH(3)CN and O(2) do the trick! A copper-mediated direct oxidative cross-coupling of 2-(het)aryl-1,3,4-oxadiazoles with polyhaloarenes under mild reaction conditions has been developed (see scheme). The process provides a concise access to biaryl structures containing polyhaloarenes, which are of interest in the fields of pharmaceuticals and functional materials. Acetonitrile and oxygen play crucial roles.
RESUMEN
To date, the clinical use of the anti-tubercular therapy bedaquiline has been somewhat limited due to safety concerns. Recent investigations determined that modification of the B- and C-ring units of bedaquiline delivered new diarylquinolines (for example TBAJ-587) with potent anti-tubercular activity yet an improved safety profile due to reduced affinity for the hERG channel. Building on our recent discovery that substitution of the quinoline motif (the A-ring subunit) for C5-aryl pyridine groups within bedaquiline analogues led to retention of anti-tubercular activity, we investigated the concurrent modification of A-, B- and C-ring units within bedaquiline variants. This led to the discovery that 4-trifluoromethoxyphenyl and 4-chlorophenyl pyridyl analogues of TBAJ-587 retained relatively potent anti-tubercular activity and for the 4-chlorophenyl derivative in particular, a significant reduction in hERG inhibition relative to bedaquiline was achieved, demonstrating that modifications of the A-, B- and C-ring units within the bedaquiline structure is a viable strategy for the design of effective, yet safer (and less lipophilic) anti-tubercular compounds.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Diarilquinolinas/farmacología , Diarilquinolinas/química , Antituberculosos/farmacología , Antituberculosos/químicaRESUMEN
Despite their synthetic utility, practical methods to prepare diversely functionalized aromatic acyl silanes (benzoyl silanes) remain scarce. We herein report that cobalt complexes can successfully engage acyl silanes as weakly coordinating directing groups to catalyse the ortho C-H functionalisation of benzoyl silanes. Under Cp*Co(III) catalysis, installation of allyl or amido functionality at the 2-position of benzoyl silanes was achieved, while reaction with internal alkynes led to a desilylative annulation to afford indenone scaffolds. A Co(II)/dppp catalytic system was also investigated to achieve the acyl silane directed hydroarylative cyclisation of 1,6-enynes to access unique benzoyl silane derivatives.
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Cobalto , Silanos , Catálisis , Alquinos , CiclizaciónRESUMEN
Visible light induced singlet nucleophilic carbenes undergo rapid [2 + 1]-cycloaddition with tethered olefins to afford unique bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane scaffolds. This cyclopropanation process requires only visible light irradiation to proceed, circumventing the use of exogenous (photo)catalysts, sensitisers or additives and showcases a vastly underexplored mode of reactivity for nucleophilic carbenes in chemical synthesis. The discovery of additional transformations including a cyclopropanation/retro-Michael/Michael cascade process to afford chromanones and a photochemical C-H insertion reaction are also described.
RESUMEN
Palladium-catalyzed domino Heck-aza-Michael reactions for the synthesis of a series of C1-substituted tetrahydro-ß-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process involves the initial intermolecular Heck reaction of an aryl bromide with an electron deficient alkene, followed by an intramolecular aza-Michael reaction to form the new N-heterocycle in high yield.
RESUMEN
Studies into the Cp*Rh(iii)-catalysed hydroarylation of alkenes with aryl acyl silanes led to the discovery of a new synthetic strategy to access unique silicon derived indene frameworks. Rather than protodemetalation of the metal enolate formed following insertion of an alkene into the aryl C-H bond, intramolecular aldol condensation of the acyl silane occurred to generate a series of 2-formyl- and 2-acetyl-3-silyl indenes. This represents only the second example of rhodium-catalysed C-H functionalisation employing acyl silanes as weakly coordinating directing groups and the intramolecular aldol condensation strategy was extended to access analogous silicon derived benzofurans.
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Singlet nucleophilic carbenes (SNCs) containing only one heteroatom donor remain underutilized in chemical synthesis. We recently discovered that visible-light-induced SNC intermediates can be trapped by fluorinated ketones via 1,2-carbonyl addition to afford benzoin-type products. This discovery represents a rare example of nucleophilic carbenes reacting with ketones and delivers an efficient, user-friendly, and scalable process for accessing fluorinated tertiary alcohol derivatives driven only by light circumventing the use of exogenous catalysts or additives.
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Despite promising efficacy, the clinical use of the anti-tubercular therapeutic bedaquiline has been restricted due to safety concerns. To date, limited SAR studies have focused on the quinoline ring (A-ring), and as such, we set out to explore modifications within this region in an attempt to discover new bedaquiline variants with an improved safety profile. We herein report the development of unique synthetic strategies that facilitated access to novel bedaquiline analogues leading to the discovery that anti-tubercular activity could be retained following replacement of the quinoline motif with pyridine heterocycles. This discovery is anticipated to open up multiple new avenues for exploration in the design of improved anti-tubercular therapeutics.
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Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 µL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.
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Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Triazinas/uso terapéutico , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Células CACO-2 , Femenino , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacocinéticaRESUMEN
A simple and efficient palladium-catalyzed domino reaction for the synthesis of a series of C1-substituted tetrahydro-beta-carbolines is described. This domino process involves a Heck reaction at the indole 2-position of a halogenated tryptamine precursor, followed by intramolecular aza-Michael addition.