Minisci-type Reactions Research Articles

Self-assembly of decavanadate and Ni(HCO3)2 into nanoparticles anchored on carbon nitride for efficient photocatalytic Minisci-type alkylation

Photocatalysis Minisci-type reactions involving carbon-centered radicals (CCRs) have emerged as a hot and significant topic in the field of organic synthesis chemistry. Herein, we present a nickel-vanadium nanoparticle anchored on carbon nitride catalyst (NiV-CN) and persulfate as a hydrogen atom transfer (HAT) precursor. This catalyst enables the photocatalytic Minisci-type CCR alkylation. The nickel-vanadium nanoparticles are synthesized via electrostatic attraction between [V10O28]6− anions and Ni(HCO3)2, with in situ self-assembly occurring during the hydrothermal process. In the model reaction of 4-methylquinoline with cyclohexane, the NiV-CN catalyst showed high stability, without significant loss its catalytic activity after three cycles. The CCRs was extended to cycloalkanes, adamantanes, and cyclic ethers, which react with quinoline, isoquinoline, and benzothiazole to provide the corresponding products in moderate to excellent yields. Mechanism studies indicate that nickel-vanadium nanoparticles play a crucial role in the formation process of carbon-centered radicals by activating the persulfate precursor into sulfate radicals under visible-light irradiation.

Advances in Photoinduced Minisci-like Reactions

AbstractThe Minisci reaction, which has been around for more than five decades, is still the preferred tool for the straightforward alkylation of basic heteroarenes. The recent developments in photocatalysis have opened novel pathways for radical generation under milder and more sustainable conditions. Implementing this approach into the Minisci reaction has renewed interest in this transformation, which is attractive per se in Medicinal Chemistry. Aspects such as sacrificial oxidants, catalysts, and specific reaction conditions should be carefully examined to evaluate the practicability of the protocol. This short review focuses on recent advances (2020 to February 2024) in photoinduced Minisci-type reactions, emphasizing sustainability.1 Introduction2 Using Noble-Metal-Based Photocatalysts3 Noble-Metal-Free Methods Using Sacrificial Oxidants4 Noble-Metal-Free Methods Without Sacrificial Oxidants5 Conclusions and Perspectives

Minisci-Type Reactions Promoted by a Zirconium-Phenazine MOF

Minisci-Type Reactions Promoted by a Zirconium-Phenazine MOF

Direct C-H functionalisation of azoles via Minisci reactions.

Azoles have widespread applications in medicinal chemistry; for example, thiazoles, imidazoles, benzimidazoles, isoxazoles, tetrazoles and triazoles appear in the top 25 most frequently used N-heterocycles in FDA-approved drugs. Efficient routes for the late-stage C-H functionalisation of azole cores would therefore be highly desirable. The Minisci reaction, a nucleophilic radical addition reaction onto N-heterocyclic bases, is a direct C-H functionalisation reaction that has the potential to be a powerful method for C-H functionalisations of azole scaffolds. However, azoles have not been as widely studied as substrates for modern Minisci-type reactions as they are often more electron-rich and thus more challenging substrates compared to electron-poor 6-membered N-heterocycles such as quinolines, pyrazines and pyridines typically used in Minisci reactions. Nevertheless, with the prevalence of azole scaffolds in drug design, the Minisci reaction has the potential to be a transformative tool for late-stage C-H functionalisations to efficiently access decorated azole motifs. This review thus aims to give an overview of the C-H functionalisation of azoles via Minisci-type reactions, highlighting recent progress, existing limitations and potential areas for growth.

Photocatalyzed Minisci-type reactions for late-stage functionalization of pharmaceutically relevant compounds

The application of photocatalyzed Minisci-type reactions in LSF accelerates the discovery of drug candidates in a green way.

Recent developments in the photoredox catalyzed Minisci-type reactions under continuous flow.

The Minisci reaction constitutes a straightforward and convenient strategy to achieve the direct C-H functionalization of heterocyclic molecules. This radical-based reaction platform has received increasing attention due to the predictability of its outcome according to the nature of the radicals and heterocycles involved. Considering the importance of these heterocyclic scaffolds in the development and production of drug molecules, it is inevitable that scaling up this reaction manifold is of utmost importance. This review will present recent strategies to achieve the goal, which mostly involve implementing the reaction conditions under continuous flow.

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification.

Described herein are studies toward the core modification of cyclic aliphatic amines using either a riboflavin/photo-irradiation approach or Cu(I) and Ag(I) to mediate the process. Structural remodeling of cyclic amines is explored through oxidative C-N and C-C bond cleavage using peroxydisulfate (persulfate) as an oxidant. Ring-opening reactions to access linear aldehydes or carboxylic acids with flavin-derived photocatalysis or Cu salts, respectively, are demonstrated. A complementary ring-opening process mediated by Ag(I) facilitates decarboxylative Csp3-Csp2 coupling in Minisci-type reactions through a key alkyl radical intermediate. Heterocycle interconversion is demonstrated through the transformation of N-acyl cyclic amines to oxazines using Cu(II) oxidation of the alkyl radical. These transformations are investigated by computation to inform the proposed mechanistic pathways. Computational studies indicate that persulfate mediates oxidation of cyclic amines with concomitant reduction of riboflavin. Persulfate is subsequently reduced by formal hydride transfer from the reduced riboflavin catalyst. Oxidation of the cyclic aliphatic amines with a Cu(I) salt is proposed to be initiated by homolysis of the peroxy bond of persulfate followed by α-HAT from the cyclic amine and radical recombination to form an α-sulfate adduct, which is hydrolyzed to the hemiaminal. Investigation of the pathway to form oxazines indicates a kinetic preference for cyclization over more typical elimination pathways to form olefins through Cu(II) oxidation of alkyl radicals.

N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C-H Functionalization via Radical-Based Processes under Visible Light Irradiation.

The radical-mediated C-H functionalization of pyridines has attracted considerable attention as a powerful tool in synthetic chemistry for the direct functionalization of the C-H bonds of the pyridine scaffold. Classically, the synthetic methods for functionalized pyridines often involve radical-mediated Minisci-type reactions under strongly acidic conditions. However, the site-selective functionalization of pyridines in unbiased systems has been a long-standing challenge because the pyridine scaffold contains multiple competing reaction sites (C2 vs C4) to intercept free radicals. Therefore, prefunctionalization of the pyridine is required to avoid issues observed with the formation of a mixture of regioisomers and overalkylated side products.Recently, N-functionalized pyridinium salts have been attracting considerable attention in organic chemistry as promising radical precursors and pyridine surrogates. The notable advantage of N-functionalized pyridinium salts lies in their ability to enhance the reactivity and selectivity for synthetically useful reactions under acid-free conditions. This approach enables exquisite regiocontrol for nonclassical Minisci-type reactions at the C2 and C4 positions under mild reaction conditions, which are suitable for the late-stage functionalization of bioactive molecules with greater complexity and diversity. Over the past five years, a variety of fascinating synthetic applications have been developed using various types of pyridinium salts under visible light conditions. In addition, a new platform for alkene difunctionalization using appropriately designed N-substituted pyridinium salts as bifunctional reagents has been reported, offering an innovative assembly process for complex organic architectures. Intriguingly, strategies involving light-absorbing electron donor-acceptor (EDA) complexes between pyridinium salts and suitable electron-rich donors further open up new reactivity under photocatalyst-free conditions. Furthermore, we developed enantioselective reactions using pyridinium salts to afford enantioenriched molecules bearing pyridines through single-electron N-heterocyclic carbene (NHC) catalysis.Herein, we provide a broad overview of our recent contributions to the development of N-functionalized pyridinium salts and summarize the cornerstones of organic reactions that successfully employ these pyridinium salts under visible light conditions. The major advances in the field are systematically categorized on the basis of the pyridines' N-substituent, N-X (X = O, N, C, and SO2CF3), and its reactivity patterns. Furthermore, the identification of new activation modes and their mechanistic aspects are discussed by providing representative contributions to each paradigm. We hope that this Account will inspire broad interest in the continued innovation of N-functionalized pyridinium salts in the exploration of new transformations.

Recent Advances in Minisci-type Reactions and Applications in Organic Synthesis

Recent Advances in Minisci-type Reactions and Applications in Organic Synthesis

Recent Advances in Minisci-type Reactions and Applications in Organic Synthesis

Minisci-type reactions have been widely known as reactions that involve the addition of carbon-centered radicals to basic heteroarenes followed by formal hydrogen atom loss. While the originally developed protocols for radical generation remain in active use today, in recent years, the new array of radical generation strategies have allowed the use of a wider variety of radical precursors that often operate under milder and more benign conditions. New transformations based on free radical reactivity are now available to a synthetic chemist, to utilize a Minisci-type reaction. Radical-generation methods based on photoredox catalysis and electrochemistry, which utilize thermal cleavage or the in situ generation of reactive radical precursors, have become popular approaches. Our review will cover the remarkable literature that has been reported on this topic in recent 5 years, from 2015-01 to 2020-01, in an attempt to provide guidance to the synthetic chemist on both the challenges that need to be overcome and the applications in organic synthesis.

Hydrogen Atom Transfer-Driven Enantioselective Minisci Reaction of Amides.

Minisci-type reactions constitute one of the most powerful methods for building up complexity around basic heteroarenes. The most desirable variants involve formal oxidative coupling of a C–H bond on each partner, leading back to the simplest possible starting materials. We herein disclose a method that enables such a coupling of linear amides and heteroarenes with full control of enantioselectivity at the newly formed stereocenter as well as site selectivity on both the heteroarene and the amide. This is achieved by the use of a chiral phosphoric acid catalyst in conjunction with diacetyl as a combined hydrogen atom transfer reagent and oxidant. Diacetyl is directly photoexcitable, and thus, no extraneous photocatalyst is required: an added feature that contributes to the simplicity and practicality of the protocol.

Recent Advances in Minisci-type Reactions and Applications in Organic Synthesis

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Catalytic Enantioselective Minisci Reaction

Minisci-type reactions offer a direct and versatile approach to C–C bond formation on basic heteroarenes: molecules of importance in the pharmaceutical and agrochemical industries. In 2018, our group reported an enantioselective variant of this reaction, enabled by the use of a chiral phosphoric acid (CPA) catalyst. This allowed the addition of nucleophilic, prochiral N-Ac-α-amino radicals to quinolines and pyridines with high levels of regio- and enantiocontrol.

Regioselective Amidomethylation of 4-Chloro-3-fluoropyridine by Metalation and Minisci-Type Reactions.

The synthesis of a series of 2-amidomethylated pyridines (3-8) was investigated, starting from 4-chloro-3-fluoropyridine. Kinetic deprotonation at -75 °C followed by reaction with DMF gave 2-formyl-4-chloro-3-fluoropyridine 10 regioselectively, which was converted to 2-aminomethyl analogue 1 via sulfinamide 2. Alternatively, Minisci-type amidomethylation under Ag+/persulfate or photoredox-mediated conditions using a series of amino acid derivatives gave (3-8, 19, and 34) in 30-74% yield and isomer ratios in the range 6.7:1 to >50:1. The latter methods gave overall yields similar to that of the deprotonation approach, but were shorter and more amenable to scale-up. In particular, N-Boc analogue 8 was obtained in a single step. The amidomethylations of another six 3-fluoropyridines under the photoredox conditions were briefly examined.

Acid and Solvent Effects on the Regioselectivity of Minisci-Type Addition to Quinolines Using Amino Acid Derived Redox Active Esters

Minisci-type reactions comprise an important class of reactions for the direct functionalization of basic heterocyclic compounds. On certain heterocycles, such as quinolines, Minisci-type reactions face a regioselectivity choice which often results in mixtures of regioisomers at the C2 and C4 positions, limiting utility. We present a study of the effect of solvent and Brønsted acid catalyst on regioselectivity in the addition of N-acetyl-substituted, α-amino alkyl radicals to quinolines. By tuning the solvent and acid combination we identify conditions that strongly favour C2 and strongly favour C4 and present a small scope of compatible substrates.

Recent Advances in Minisci-type Reactions and Applications in Organic Synthesis

Recent Advances in Minisci-type Reactions and Applications in Organic Synthesis

Predictive Multivariate Linear Regression Analysis Guides Successful Catalytic Enantioselective Minisci Reactions of Diazines.

The Minisci reaction is one of the most direct and versatile methods for forging new carbon–carbon bonds onto basic heteroarenes: a broad subset of compounds ubiquitous in medicinal chemistry. While many Minisci-type reactions result in new stereocenters, control of the absolute stereochemistry has proved challenging. An asymmetric variant was recently realized using chiral phosphoric acid catalysis, although in that study the substrates were limited to quinolines and pyridines. Mechanistic uncertainties and nonobvious enantioselectivity trends made the task of extending the reaction to important new substrate classes challenging and time-intensive. Herein, we describe an approach to address this problem through rigorous analysis of the reaction landscape guided by a carefully designed reaction data set and facilitated through multivariate linear regression (MLR) analysis. These techniques permitted the development of mechanistically informative correlations providing the basis to transfer enantioselectivity outcomes to new reaction components, ultimately predicting pyrimidines to be particularly amenable to the protocol. The predictions of enantioselectivity outcomes for these valuable, pharmaceutically relevant motifs were remarkably accurate in most cases and resulted in a comprehensive exploration of scope, significantly expanding the utility and versatility of this methodology. This successful outcome is a powerful demonstration of the benefits of utilizing MLR analysis as a predictive platform for effective and efficient reaction scope exploration across substrate classes.

Decarboxylative Alkylation of Heteroarenes Using N-Hydroxybenzimidoyl Chloride Esters.

Functionalized N-heteroarenes are highly desired motifs in medicinal chemistry and pharmaceutical industry. Minisci-type reactions usually require a protonated N-heteroarene for the alkyl radical to attack. This work describes a leaving-group-assisted redox-active ester to enable direct coupling of an amino acid with N-heteroarenes. The efficient and sustainable photoredox strategy provides rapid access to an alkylated heterocyclic manifold.

Recent Advances in Minisci-Type Reactions.

Reactions that involve the addition of carbon-centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci-type reactions. First developed into a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci-type reaction. Radical-generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci-type reactions will also be discussed.

The Acid-Free Cyclopropanol-Minisci Reaction Reveals the Catalytic Role of Silver-Pyridine Complexes.

A well-defined homogeneous silver precatalyst can be utilized for the direct C-H functionalization of a wide range of aromatic nitrogen heterocycles with cyclopropanols under acid-free conditions. This reaction can be conducted on gram-scale and with low catalyst loadings (as low as 1%), which is rare for silver-catalyzed Minisci-type reactions. Moreover, reactivity trends, as well as steric and calculated electronic properties of the heterocycles, strongly suggest that silver-heterocycle complexes formed in situ behave as redox active catalysts and as Lewis acid activators of the heterocycle and that the electronic nature of the heterocyclic substrates tunes the reactivity of the resulting complexes.