Late-stage Functionalization Research Articles

Brønsted acid-mediated thiazole synthesis from sulfoxonium ylides.

A Brønsted acid-mediated insertion of thioureas/thioamides into sulfoxonium ylides to synthesise 40 thiazoles (34-95% yields) under mild, metal-free conditions is described. This process is scalable, substrate-tolerant (including both α-substituted and heterocyclic ylides/groups) and was successfully applied to the late-stage functionalisation of the complex chemical probe molecule (+)-JQ1.

Organocatalytic regio- and enantioselective C1-arylation of β,γ-alkynyl-α-imino esters with pyrrolo[2,1-a]isoquinolines.

We herein report regio- and enantioselective arylation of β,γ-alkynyl-α-imino esters with pyrroloisoquinolines. Using chiral phosphoric acid catalysts, a wide range of novel axially chiral tetrasubstituted α-amino allenoates were accessed in good yields with excellent enantioselectivities. Notably, this transformation occurred preferentially at the sterically more hindered C1-position of pyrroloisoquinolines. The potential scalability and late-stage functionalization demonstrated the utility of the current protocol.

Recent advances in photocatalytic and transition metal-catalyzed synthesis of disulfide compounds.

Disulfide bonds are essential in protein folding, cellular redox balance, materials science, and drug development. Despite existing synthetic methods, the efficient and selective synthesis of unsymmetrical disulfides remains challenging. This review highlights innovative approaches in visible light photocatalysis, including decarboxylation, deoxydisulfidation of alcohols, and direct C-H disulfidation, showcasing broad substrate applicability and functional group tolerance under mild conditions. Additionally, it explores transition metal-catalyzed systems with copper, nickel, palladium, chromium, Iridium, Rhodium molybdenum, and scandium, offering effective strategies for unsymmetrical disulfide bond formation and late-stage functionalization of complex molecules through reductive coupling, selective oxidation, and novel insertion reactions.

Photoinduced fluoroalkylation-peroxidation of alkenes enabled by ligand-to-iron charge transfer mediated decarboxylation.

We report here a photoinduced iron-catalyzed fluoroalkylation-peroxidation of activated and/or unactivated alkenes with fluoroalkyl carboxylic acids and hydroperoxide. The ligand-to-iron charge transfer strategy effectively overcomes the high redox potential of the fluoroalkyl carboxylic acids, facilitating the difunctionalization reaction to occur smoothly under mild reaction conditions. The late-stage functionalization of drug and natural product derivatives was also demonstrated.

Unravelling a bench-stable zinc-amide compound as highly active multitasking catalyst for radical-mediated selective alk(en)ylation of unactivated carbocycles under mild conditions.

The direct functionalization of unactivated organic moieties via C-C bond formation has long fascinated synthetic chemists. Although base-metal systems are steadily emerging in this area, achieving multitasking activity in a single catalyst to execute several such functionalizations under mild conditions is challenging. To address this, we herein report an effective protocol for the selective C-alk(en)ylation of indene/fluorene with alcohol as a green alkylating agent employing a naturally abundant and eco-friendly zinc-derived compound, for the first time. Notably, this study unveils the unique potential of a bench-stable Zn compound bearing an amidated imidazolium salt towards C-C bond-forming reactions utilizing an array of alcohols, ranging from aliphatic to aromatic and, attractively, even secondary alcohols. Moreover, this readily scalable protocol, which proceeds via an underdeveloped radical-mediated borrowing hydrogen protocol (an aldehyde is generated from an alcohol, and subsequent condensation with indene/fluorene provides the corresponding alkenylated products) established based on a range of control experiments, works effortlessly under mild conditions using a low catalyst loading. Notably, this approach affords remarkable selectivity towards alkylated or alkenylated products with a high level of functional group tolerance and chemoselectivity. Crucially, the catalytic activity of these Zn compounds can be attributed to their hydrogen atom transfer (HAT) capability, while their selectivity towards different products can be understood in terms of employed reaction conditions. Lastly, the synthetic utility of obtained products was showcased by their late-stage functionalization to access unsymmetrical 9,9-disubstituted fluorenes, which are potentially useful for various optoelectronic applications.

Para-Selective radical alkylation of pyridines with diacyl peroxides and peresters

A regioselective para-alkylation of pyridines using alkyl carboxylic acid-derived diacyl peroxides or peresters is reported. This reaction proceeds under mild conditions, and late-stage functionalization of complex pyridines can be realized.

Selective synthesis of functionalized linear aliphatic primary amines via decarboxylative radical-polar crossover

Organic photoredox-driven generation of distant primary radicals for the hydroaminoalkylation of styrenes or Michael acceptors, yielding linear aliphatic primary amines, including late-stage functionalisation and total synthesis of drug compounds.

Palladium-catalysed Tsuji-Trost-type vinyl epoxide cross-coupling with umpolung hydrazones.

Selective functionalisation of synthetically useful vinyl epoxides via carbon-carbon (C-C) bond formation has been a major challenge for many years due to its unique inherent chemical reactivity. Non-stabilised carbanions in the form of organometallic reagents have been shown to be robust and versatile reagents in C-C bond formation; however, they are employed in superstoichiometric quantities, require the protection of active functional groups, and generate copious amounts of metallic waste. Therefore, the development of mild carbanion sources as simple alternatives is highly desired. In this work, we report a highly chemo- and regioselective palladium-catalysed vinyl epoxide cross-coupling utilising hydrazones as organometallic equivalents (HOME). Hydrazones, generated from carbonyl-containing renewable feedstocks, enable a more sustainable reaction, and provide an alternative to highly reactive and sensitive unstabilized organometallic reagents. A broad substrate scope, with high functional group tolerance, is demonstrated along with the late-stage functionalisation of natural product derivatives.

Visible light-induced reductive aza-6π electrocyclization access to phenanthridines.

Visible light-induced aza-6π electrocyclization was developed for the synthesis of aza-arenes from nitroarenes with diverse aldehydes. This protocol allows the reduction of nitroarenes by B2nep2 and subsequent 6π-electrocyclization of the in situ formed imine under visible light. An array of 6- and multi-substituted phenanthridines were constructed in moderate to good yields under purple LEDs at room temperature. A wide scope of substrates with diverse functional groups were well tolerated. In addition, the synthetic utility of this methodology was further demonstrated in the late-stage functionalization of celecoxib.

Stereoselective benzylic C(sp3)-H alkenylation enabled by metallaphotoredox catalysis.

Selective activation of the benzylic C(sp3)-H bond is pivotal for the construction of complex organic frameworks. Achieving precise selectivity among C-H bonds with comparable energetic and steric profiles remains a profound synthetic challenge. Herein, we unveil a site- and stereoselective benzylic C(sp3)-H alkenylation utilizing metallaphotoredox catalysis. Various linear and cyclic (Z)-all-carbon tri- and tetrasubstituted olefins can be smoothly obtained. This strategy can be applied to complex substrates with multiple benzylic sites, previously deemed unsuitable due to the uncontrollable site-selectivity. In addition, sensitive functional groups such as terminal alkenyl and TMS groups are compatible under the mild conditions. The exceptional site-selectivity and broad substrate compatibility are attributed to the visible-light catalyzed relay electron transfer-proton transfer process. More importantly, we have extended this methodology to achieve enantioselective benzylic C(sp3)-H alkenylation, producing highly enantioenriched products. The applicability and scalability of our protocol are further validated through late-stage functionalization of complex structures and gram-scale operations, underscoring its practicality and robustness.

Synthesis of axially chiral diaryl ethers via NHC-catalyzed atroposelective esterification.

Axially chiral diaryl ethers bearing two potential axes find unique applications in bioactive molecules and catalysis. However, only very few catalytic methods have been developed to construct structurally diverse diaryl ethers. We herein describe an NHC-catalyzed atroposelective esterification of prochiral dialdehydes, leading to the construction of enantioenriched axially chiral diaryl ethers. Mechanistic studies indicate that the matched kinetic resolutions play an essential role in the challenging chiral induction of flexible dual-axial chirality by removing minor enantiomers via over-functionalization. This protocol features mild conditions, excellent enantioselectivity, broad substrate scope, and applicability to late-stage functionalization, and provides a modular platform for the synthesis of axially chiral diaryl ethers and their derivatives.

A visible-light-induced photosensitizer-free decarbonylative Minisci-type reaction.

This study presents a green and practical visible-light-induced photosensitizer-free decarbonylative Minisci-type reaction using aldehydes as alkyl radical precursors. The photocatalytic system exhibits a broad substrate scope and synthetically useful yields. Mechanistic experiments revealed that alkyl radicals could be generated through auto-oxidation of aldehydes under irradiation, which is a mild and effective method for achieving late-stage functionalization of N-heteroarenes. Some biologically active N-heteroarenes could be alkylated using this photocatalytic system smoothly.

Expedient, regioselective C-H chalcogenation of 3,4-dihydro-1,4-benzoxazines using a palladium-copper catalyst.

The palladium-catalysed regioselective C-H chalcogenation of benzoxazines with disulfides and diselenides in air has been described. In this protocol, palladium acetate serves as the catalyst in conjunction with copper as an oxidizing agent. Through this approach, a wide array of sulfenylation and selenylation reactions of benzomorpholines have been effected, yielding results ranging from good to excellent. Thus, the established procedure demonstrates superb regioselectivity and a strong tolerance towards various functional groups and is suitable for gram-scale synthesis. Additionally, this synthetic approach offers a practical and convenient pathway for late-stage functionalization leading to the Rosenmund-von Braun reaction.

Switching the regioselectivity of acid-catalyzed reactions of arylnaphtho[2,1-b]furans via a [1,2]-aryl shift.

The [1,2]-aryl shift reaction was used to synthesize naphtho[2,1-b]furans as promising fluorescent scaffolds for organic electronics. The target compounds are furan analogues of phenanthrene formally accessed by isosteric replacement of the CHCH moiety with an oxygen atom. The straightforward and robust approach involving a [1,2]-aryl shift as a key step provides easy access to a wide range of naphtho[2,1-b]furans with the possibility of late-stage functionalization. Efficient switching of the regioselectivity of acid-catalyzed reactions of arylnaphtho[2,1-b]furans via a [1,2]-aryl shift has been demonstrated. A one-pot protocol involving sequential intramolecular condensation/[1,2]-aryl shift/intermolecular oxidative aromatic coupling to provide access to binaphtho[2,1-b]furan analogues of BINOL was developed. The advantage of these compounds lies in the strong variation in chemical properties and spectral performance depending on the nature and position of the aryl substituent, which facilitates the synthesis of compounds with desired spectral characteristics and opens up prospects for their further use in electronics, biotechnologies and organic synthesis.

Metal-free synthesis of γ-ketosulfones through Brønsted acid-promoted conjugate addition of sulfinamides.

A straightforward and general metal-free method has been developed to add sufinamide-derived sulfone units on Michael acceptors under mild conditions. This reaction enables the preparation of a large variety of original γ-ketosulfones, of which only a few synthetic methods have been reported. The mild reaction conditions used tolerate a wide diversity of functional groups and empower the implementation of a late-stage functionalisation strategy.

Cr-catalyzed borylation of C(aryl)-F bonds using a terpyridine ligand.

The defluoroborylation of fluoroarenes by chromium-catalyzed cleavage of unactivated C-F bonds is described. The reaction uses HBpin as the boron source, low-cost and commercially available chromium salt as the precatalyst, and terpyridine as a crucial ligand, providing a protocol with atom-efficient benefits and a wide range of applicable substrates for the functionalization of aryl C-F bonds. Preliminary mechanistic studies indicate that an unprecedented Cr-catalyzed magnesiation of the unactivated C-F bond occurred. The generated arylmagnesium intermediates then participated in the subsequent borylation reaction. The application of the strategy in the preparation of valuable derivatives is demonstrated by the late-stage functionalization of boronate ester groups.

Photoinduced cerium-catalyzed C-H acylation of unactivated alkanes.

Ketones are ubiquitous motifs in the realm of pharmaceuticals and natural products. Traditional approaches to accessing these species involve the addition of metal reagents to carboxyl compounds under harsh conditions. Herein, we report a cerium-catalyzed acylation of unactivated C(sp3)-H bonds using bench-stable acyl azolium reagents under mild and operationally-friendly conditions. This reaction exhibits excellent generality, accommodating a wide range of feedstock chemicals such as cycloalkanes and acyclic compounds as well as facilitating the late-stage functionalization of pharmaceuticals. We demonstrate further applications of our strategy with a three-component radical relay reaction and an enantioselective N-heterocyclic carbene (NHC) and cerium dual-catalyzed reaction.

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.

Harnessing alcohols as sustainable reagents for late-stage functionalisation: synthesis of drugs and bio-inspired compounds.

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C-X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources.

Synthesis of alkynyl sulfides via base-promoted nucleophilic ring-opening of α-bromostyrene sulfonium salt.

An efficient method for the synthesis of alkynyl sulfides via a C(sp3)-S bond cleavage of α-bromostyrene sulfonium salts has been developed. This base-promoted nucleophilic ring-opening pathway allows the preparation of diverse alkynyl sulfide compounds using tetramethylene sulfoxide as the sulfur source. The reaction proceeds with good functional group tolerance and could be applied to the late-stage functionalization of bioactive molecules and drugs. Furthermore, the synthetic utility of this method was demonstrated by a one-pot synthesis, scale-up reaction and further modification of various alkynyl sulfide products.