Late-stage Functionalization Research Articles

Cu(II)-NHC Catalyzed Insertion of Quinoid Carbenes into cis-Epoxides: Stereoselective Synthesis of trans-Dihydronaphthodioxine.

A straightforward synthesis of trans-dihydronaphthodioxine has been efficiently accomplished through Cu(II)-NHC catalysis, involving the stereoselective ring opening of cis-epoxides with quinoid-carbene. Intramolecular SN2-like substitution facilitates the inversion of stereochemistry during cis-epoxide ring opening. This reaction has been developed under simple conditions, demonstrating a broad substrate scope with a wide chemoselective profile. Additionally, late-stage functionalization of complex bioactive molecules has been successfully achieved.

Copper-Catalyzed Propargylation of Terminal Olefins to Skipped Enynes.

A highly efficient and easy to operate method for synthesizing skipped enynes catalyzed by copper has been reported for the first time. A wide variety of skipped enynes were obtained in acceptable to good yields employing nonactivated terminal olefins as nucleophiles under mild conditions. This protocol features broad substrate scope and high functional group tolerance, therefore enabling late-stage functionalization and a scale-up experiment further to highlight the synthetic utility.

Manganese-Catalyzed Electrochemical Amination of Activated Alkenes.

We have unveiled a new manganese-catalyzed electrochemical amination method to transform activated alkenes into a diverse array of vinyl amines harnessing sodium azide as the aminating reagent. The strategy claims notable versatility by accommodating a broad spectrum of substrates, demonstrating good compatibility with diverse functional groups, as well as delivering a moderate to good range of yields. The successful late-stage functionalization further underscores its practical utility. A radical mechanism is proposed based on experimental mechanistic studies.

Ex Situ Generation of D2 for Reductive Deuteration: Scope and Application to Late-Stage Functionalization.

An efficient deuteration method through the ex situ generation of D2 for the reductive deuteration of biologically significant α-substituted acrylic acids and enamide derivatives is reported. This method was successfully applied to the synthesis of deuterated analogs of marketed NSAIDs such as ibuprofen, flurbiprofen, and naproxen. Additionally, it facilitates late-stage deuteration of enamides and N-vinylated drugs. Moreover, the method was extended to N-viny azoles, cinnamic acid derivatives, and other unsaturated substrates toward deuteration reaction. This technique utilizes D2O as a safe and economical deuterium source. Notably, the reaction is performed in a standard fume hood setup, ensuring ease of handling and enhanced practicality.

3-Amino-1-methyl-1H-pyridin-2-one as Inbuilt Directing Group for Additive-Free Late-Stage ortho-Amination under Copper Catalysis towards Biologically Relevant Molecules

AbstractArylamines are essential building blocks that are found in biologically important substances, agrochemicals, and natural products. One of the C–N bond formation methods that is conveniently step- and atom-economical is the C–H bond activated amination process. We divulge an operationally simple and general method using 3-amino-1-methyl-1H-pyridin-2-one (AMP) as inbuilt directing group (DG) for additive-free, copper(II)-catalyzed ortho amination of β-C(sp2)–H bonds of arenes and heteroarenes. Notably, this cross dehydrogenative amination reaction exhibits a broad scope regarding amine coupling partners, including heterocyclic amines, secondary aliphatic amines, and cyclic amides, with exclusive site selectivity and excellent functional group tolerance. Moreover, implementing this methodology, we could also synthesize medicinally important compounds to showcase the suitability of this inbuilt DG for late-stage functionalization.

A Practical Synthetic Route to Cinnolines: Application to the Design and Synthesis of RSV NNI Inhibitor JNJ-8003 Analogues.

The manuscript describes the development of an efficient synthetic route to cinnolines, facilitating faster access to JNJ-8003 related Respiratory Syncytial Virus (RSV) non-nucleoside (NNI) inhibitors. Starting from correctly functionalized aryl halides, a Sonogashira reaction followed by SNAr reaction with hydrazine 1,2-dicabroxylate reagents provided dihydrocinnolines directly via in situ 6-endo-dig cyclization. The dihydrocinnolines were conveniently transformed to corresponding cinnolines in one step. Notably, this three-step route to cinnolines is more practical and safer than traditional methods that involve hazardous diazo intermediates. The methodology demonstrated a broad substrate scope. Strategic selection of a readily available aryl halide enabled the synthesis of diverse cinnolines that served as JNJ-8003 analogues through late-stage functionalization. Furthermore, by capitalizing the inherent reactivity of aryl halides toward SNAr reactions, we explored the synthesis of various heteroaromatic cinnolines. Given the extensive biological properties exhibited by cinnolines, our approach is poised to inspire further investigations in this field.

Direct β-C-H ketoalkylation of enaminoesters with cyclopropanols under metal-free conditions.

A TEMPO-mediated β-ketoalkylation of enaminoesters with cyclopropanols under metal-free conditions is herein described. This reaction provides a straightforward and highly efficient route to β-keto alkyl substituted enaminoesters for the first time, which could be rapidly and efficiently converted into synthetically useful 2-alkoxycarbonyl functionalized 1,5-diketones. Moreover, the practicability of this protocol is successfully demonstrated by scale-up experiments and the late-stage functionalization of natural products and pharmaceutically relevant molecules.

Visible-Light-Mediated Cascade 1,4-Hydrogen Atom Transfer versus Dearomative Spirocyclization of N-Benzylacrylamides: Divergent Access to Functionalized γ-Ketoamides and 2-Azaspiro[4.5]decanes.

Visible-light-driven metal- and photocatalyst-free cascade 1,4-HAT and dearomative spirocyclization of N-benzylacrylamides are described for sustainable synthesis of a variety of pharmaceutically important γ-ketoamides and 2-Azaspiro[4.5]decanes in one pot in good to excellent yields. Readily accessible and nontoxic materials, expensive Ir or Ru photocatalyst-free mild conditions, excellent functional group tolerance, operational simplicity, and scalability enhance the practical value of this protocol. Mechanistic studies reveal that acyl radicals generated from α-oxocarboxylic acids trigger the rare 1,4-HAT and dearomative spirocyclization. The synthetic potential of this environmentally benign method is further showcased by late-stage functionalization of drug molecules, amino acid, and peptides.

PIII/PV═O Redox Catalysis Mediated Thioesterification of Carboxylic Acids with Disulfides under Air Conditions.

An efficient organophosphorus-catalyzed thiocarbonylation reaction of disulfides with carboxylic acids under air conditions was described. Various functional groups on carboxylic acids and disulfides can be tolerated under the present reaction conditions, affording thioesters in good to excellent yields. This method exhibited excellent chemoselectivity and can be applied for the late-stage functionalization of drug molecules containing a carboxylic acid group.

Phthalimidine Synthesis via Iridium-Catalyzed Reductive Lactamization.

Herein, we report a sustainable and efficient method for the synthesis of structurally diverse phthalimidines from 2-formylbenzoic acid and primary amines using an iridium-catalyzed reductive lactamization strategy. The advantages of this method, such as the use of water-ethanol as a solvent, broad substrate scope, high catalyst efficiency (S/C up to 10000), good scalability, and easy purification, enable it to be a practical approach to phthalimidines. It is suggested that iridium hydride formation is involved in the rate-limiting step. Synthetic applications for the late-stage functionalization of medicinally relevant molecules are also demonstrated.

Cu-Catalyzed Relay Functionalization of Alkenes: Diverse Synthesis of Diazidated Quinazolinones and Polycyclic Imidazoles.

A Cu-catalyzed relay process for the preparation of diazidated quinazolinone and polycyclic imidazole derivatives in which readily available alkene-tethered substrates undergo an addition/cyclization/C(sp3)-H functionalization of alkene sequences with high efficiency is described. Various functionalized N-heteropolycyclic compounds were readily prepared in good yields with a broad substrate scope. Moreover, the direct azidation of the α-C(sp3)-H bond of the corresponding N-heterocycles has been demonstrated on the basis of mechanistic studies, which provide an alternative late-stage functionalization approach for the derivatization of N-heterocyclic scaffolds.

Merging Photoinduced Electron Transfer with Hydrogen Atom Transfer: Formal β-C(sp3)-H Pyridination of Carbonyls.

In this study, a novel approach that combines photoinduced electron transfer (ET) with hydrogen atom transfer (HAT) has been introduced for the selective β-C(sp3)-H pyridination of carbonyl compounds. This method is notable for its absence of transition metals and its ability to function under benign reaction conditions, resulting in a range of pyridinated carbonyl derivatives with consistently moderate to good yields. The significance of this technique is further underscored by its potential for the late-stage functionalization of pharmaceutically significant molecules. Mechanistic investigations confirmed that the reaction proceeds via a radical-mediated pathway.

Photoredox-Catalyzed Alkene Acylesterification with Acyloxime Esters via C-C and Tertiary C-O Bond Formation.

We describe an efficient acyl esterification method for alkenes utilizing acyloxime esters as bifunctional reagents featuring radical acylation and congested C-O bond formation. This approach is characterized by mild photoredox conditions, high step and atom economy, a broad substrate scope, and excellent regioselectivity. A variety of valuable α-acyl hindered alcohol esters, including those obtained via gram-scale synthesis and late-stage functionalization of pharmaceutical molecules, were presented, demonstrating its synthetic potential and practicability.

Visible-Light-Mediated Deaminative Alkylation of Primary Amines with Silacarboxylic Acids via Isonitrile Formation.

The functionalization of the C-N bond of amines is a straightforward strategy for the construction of complex scaffolds or for the late-stage functionalization of pharmaceuticals. Herein, we describe a photoredox-catalyzed strategy for the deaminative alkylation of primary amine-derived isonitriles that provides unnatural amino acid derivatives under mild conditions. The use of silacarboxylic acids as silyl radical precursors enables the generation of carbon-centered radicals that allow the construction of Csp3-Csp3 bonds via a Giese-type addition, avoiding the undesired hydrodeamination product.

Recent Advances of 3-Hetero-substituted 4H-pyrido[1,2-a]pyrimidin-4-one: A Review

Late-stage functionalization of pyrido[1,2-a]pyrimidin-4-one at pyrimidine ring structure is crucial to design pharmaceuticals, agrochemicals and materials for sustainable development. 4Hpyrido[ 1,2-a]pyrimidin-4-ones skeleton, a potent privileged scaffold, ubiquitously exists in numerous bioactive natural and pharmacologic products. Scope of different synthetic methods including their synthetic application to design new materials and biological activity of differently substituted 4Hpyrido[ 1,2-a]pyrimidin-4-ones are of main interest. Researchers are relentlessly working to develop more efficient and ecofriendly methods for their synthesis. This review provides, a comprehensive discussion of the recent advancements in the field of synthesis and application of 3-heterosubstituted 4H-pyrido[1,2-a]pyrimidin-4-one for sustainable development.

Photomediated controllable alkylation/nitrosoalkylation of N-heteroaromatics via nucleohomolytic substitution of alkylboronic esters with N-nitrosamines

The development of sustainable late-stage functionalization (LSF) methods has become a focal point of research in the field of organic synthesis.

Late-stage installation and functionalization of alkyl pyridiniums: a general HTE amenable strategy to access diverse aryl alanine containing macrocyclic peptides.

This manuscript describes a strategy to readily access diverse aryl and homoaryl alanine-containing pharmaceutically relevant macrocyclic peptides. A two-step sequence involving the late-stage installation of the pyridinium functionality on macrocyclic peptides followed by reductive couplings was implemented. These transformations are amenable to microscale high-throughput experimentation (HTE) and enable rapid access to aryl alanine-containing macrocyclic peptides that would otherwise be inaccessible via solid-phase peptide synthesis using commercially available amino acids. Numerous aryl and heteroaryl derivatives can be effectively used in these reactions. In addition, a systematic investigation was undertaken using an "informer" set of macrocyclic peptides which revealed the compatibility of the late-stage diversification with peptides containing diverse side chain functionalities.

Regioselective Late-stage Functionalization of Tetraphenylenes: Rapid Construction of Double Helical Architectures and Potential Hole Transport Materials

Herein we report a novel approach for diversification of tetraphenylene via regioselective late-stage iodination follow by atom(s) insertion to the resulted cyclic iodonium salts. Thus, steric hindrance effect of tert-butyl...

Defluorinative thio-functionalization: direct synthesis of methyl-dithioesters from trifluoromethylarenes.

A new functional group transformation allowing the synthesis of methyl-dithioesters from readily available trifluoromethyl arenes via defluorinative functionalization has been developed. This microwave-assisted method is operationally simple, rapid, and eliminates the need for pre-functionalization while accommodating a broad range of functional groups. In addition, it does not rely on highly odorous thiol sources, and utilizes the commercially available reagent BF3SMe2 complex as a multifunctional Lewis acid/sulfur source/defluorination and demethylation agent. Finally, this approach is suitable for late-stage functionalizations, as shown by the transformation of pharmaceuticals leflunomide, flufenamic acid and celecoxib into novel methyl-dithioester derivatives.

Selective Arene Photonitration via Iron-Complex β-Homolysis.

Nitroaromatics, as an important member and source of nitrogen-containing aromatics, is bringing enormous economic benefits in fields of pharmaceuticals, dyes, pesticides, functional materials, fertilizers, and explosives. Nonetheless, the notoriously polluting nitration industry, which suffers from excessive discharge of fumes and waste acids, poor functional group tolerance, and tremendous purification difficulty, renders mild, efficient, and environmentally friendly nitration a formidable challenge. Herein, we develop a visible-light-driven biocompatible arene C-H nitration strategy with good efficiency and regioselectivity, marvelous substrate applicability and functional group tolerance, and wide application in scale-up synthesis, total synthesis, and late-stage functionalization. A nitryl radical delivered through unusual β-homolysis of a photoexcited ferric-nitrate complex is proposed to be the key nitrification reagent in this system.