Radical Decarboxylation Research Articles

Polymer End Group Control through a Decarboxylative Cobalt-Mediated Radical Polymerization: New Avenues for Synthesizing Peptide, Protein, and Nanomaterial Conjugates.

Cobalt-mediated radical polymerizations (CMRPs) have been initiated by the radical decarboxylation of tetrachlorophthalimide activated esters. This allows for the controlled radical polymerization of activated monomers across a broad temperature range with a single cobalt species, with the incorporation of polymer end groups derived from simple carboxylic acid derivatives and termination with an organozinc reagent. This method has been applied to the synthesis of a polymer/graphene conjugate and a water-soluble protein/polymer conjugate, demonstrating the first examples of CMRP in graphene and protein conjugation.

Decarboxylative Radical Addition to Methylideneoxazolidinones for Stereocontrolled Synthesis of Selectively Protected Diamino Diacids.

Syntheses of stereochemically pure and selectively protected diamino diacids can be achieved by redox decarboxylation of distal N-hydroxyphthalimide esters of protected aspartic, glutamic or α-aminoadipic acids via radical addition to methylideneoxazolidinones. The products are useful for solid-supported syntheses of robust bioactive carbocyclic peptide analogs. Yields of reactive primary radical addition are superior to those of more stabilized radicals, and the reaction fails if the alkylideneoxazolidinone has a methyl substituent on its terminus (i.e., 13a/13b).

Aromatic Ketone-Catalyzed Photochemical Synthesis of Imidazo-isoquinolinone Derivatives.

We have developed an efficient photocatalytic decarboxylative radical addition/cyclization strategy to synthesize imidazo-isoquinolinone derivatives using inexpensive aromatic ketone photocatalysts. This method not only tolerates a wide range of functional groups but also works well for both alkyl and aryl radicals.

Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition–Elimination–Oxa-Michael Reactions

A photocatalytic decarboxylative radical conjugate addition-elimination-oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones is developed to construct diverse cyclopentanonyl-fused functionalized 5-7 membered cyclic ethers. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC50 values.

Na2 Eosin Y Catalyzed Alkylation of Enol Acetates by Radical Decarboxylation of N‐Hydroxyphthalimide Esters

AbstractA novel, efficient and transition‐metal‐free alkylation of enol acetates by radical decarboxylation of N‐hydroxyphthalimide esters to synthesize α‐alkylated ketones in existence of Na2‐eosin Y at room temperature has been developed. This methodology features operational simplicity, mild reaction conditions, widely functional group tolerance, affording a diverse array of α‐alkylated ketones in moderate to good yields.

Radical Decarboxylative Fluorination of Aromatic Carboxylic Acids

Key words fluorination - decarboxylation - carboxylic acids - copper catalysis

Synthesis of Alkyl Fluorides by Silver‐Catalyzed Radical Decarboxylative Fluorination of Cesium Oxalates

AbstractA combination of silver nitrate (AgNO3) catalyst and Selectfluor® was found to perform radical deoxyfluorination of cesium oxalates derived from corresponding alcohols. The reaction tolerates a wide range of functional groups and provides preferentially access to tertiary alkyl fluorides.

Radical Decarboxylative Carbometalation of Benzoic Acids: A Solution to Aromatic Decarboxylative Fluorination.

Abundant aromatic carboxylic acids exist in great structural diversity from nature and synthesis. To date, the synthetically valuable decarboxylative functionalization of benzoic acids is realized mainly by transition-metal-catalyzed decarboxylative cross couplings. However, the high activation barrier for thermal decarboxylative carbometalation that often requires 140 °C reaction temperature limits both the substrate scope as well as the scope of suitable reactions that can sustain such conditions. Numerous reactions, for example, decarboxylative fluorination that is well developed for aliphatic carboxylic acids, are out of reach for the aromatic counterparts with current reaction chemistry. Here, we report a conceptually different approach through a low-barrier photoinduced ligand to metal charge transfer (LMCT)-enabled radical decarboxylative carbometalation strategy, which generates a putative high-valent arylcopper(III) complex, from which versatile facile reductive eliminations can occur. We demonstrate the suitability of our new approach to address previously unrealized general decarboxylative fluorination of benzoic acids.

Photoinduced Decarboxylative Radical Addition Reactions for Late Stage Functionalization of Peptide Substrates

AbstractPhotoredox chemistry has greatly stimulated the application of radical based transformations in medicinal chemistry and early drug discovery in recent years. Carboxylate groups have been identified as traceless leaving groups that can be converted into radical intermediates capable of undergoing 1,4‐conjugate addition reactions to Michael acceptors. Herein, we show the successful C‐terminal derivatization of small peptide substrates by using this methodology in a parallel synthesis setting. Finally, we outline a general strategy for the γ‐homologation of several drugs derived from α‐amino acids in a late stage functionalization (LSF) approach.

Visible-Light-Mediated Decarboxylative Radical Addition Bifunctionalization Cascade for the Production of 1,4-Amino Alcohols.

A photocatalytic decarboxylative radical addition bifunctionalization cascade for the synthesis of functionalized alcohols is described. The catalytic cycle is completed through single-electron transfer. The advantages of this reaction are the commercially available materials, wide functional group compatibility, and mild conditions. Notably, some amino acids and bioactive carboxylic acids can provide corresponding products in moderate to good yields, reflecting the potential value in drug development.

An in situ masking strategy enables radical monodecarboxylative C-C bond coupling of malonic acid derivatives.

The utilization of malonic acids in radical decarboxylative functionalization is still underexploited, and the few existing examples are primarily limited to bisdecarboxylative functionalization. While radical monodecarboxylative functionalization is highly desirable, it is challenging because of the difficulty in suppressing the second radical decarboxylation step. Herein, we report the successful radical monodecarboxylative C–C bond coupling of malonic acids with ethynylbenziodoxolone (EBX) reagents enabled by an in situ masking strategy, affording synthetically useful 2(3H)-furanones in satisfactory yields. The keys to the success of this transformation include (1) the dual role of a silver catalyst as a single-electron transfer catalyst to drive the radical decarboxylative alkynylation and as a Lewis acid catalyst to promote the 5-endo-dig cyclization and (2) the dual function of the alkynyl reagent as a radical trapper and as an in situ masking group. Notably, the latent carboxylate group in the furanones could be readily released, which could serve as a versatile synthetic handle for further elaborations. Thus, both carboxylic acid groups in malonic acid derivatives have been well utilized for the rapid construction of molecular complexity.

Photoinduced homolytic decarboxylative acylation/cyclization of unactivated alkenes with α-keto acid under external oxidant and photocatalyst free conditions: access to quinazolinone derivatives.

A novel and green strategy for the synthesis of acylated quinazolinone derivatives via photo-induced decarboxylative cascade radical acylation/cyclization of quinazolinone bearing unactivated alkenes has been developed. The protocol provides a novel route to access acyl radicals from α-keto acids through a self-catalyzed energy transfer process. Most importantly, the reaction proceeded smoothly without any external photocatalyst, additive or oxidant, and could be easily scaled-up in flow conditions with sunlight irradiation.

Access to benzene-modified 2nd generation strigolactams and GR24 by merging C-H olefination with decarboxylative Giese cyclization.

Herein, we reported an efficient and general synthetic route to assemble benzene-modified 2nd generation strigolactams and GR24. The key features of this synthesis include a palladium-catalyzed ortho-selective olefination of the commercially available substituted N-Boc phenylalanine and a decarboxylative Giese radical cyclization. The bioactivities of these compounds to stimulate the seed germination of Orobanche aegyptiaca parasitic weed were also analysed. 2nd generation strigolactam 15f derived from para-OMe phenylalanine showed superior bioactivity to the original unsubstituted 15b.

Metal free decarboxylative aminoxylation of carboxylic acids using a biphasic solvent system.

The smooth oxidative radical decarboxylation of carboxylic acids with TEMPO and other derivatives as radical scavengers is reported. The key to success was the use of a two-phase solvent system to avoid otherwise predominant side reactions such as the oxidation of TEMPO by persulfate and enabled the selective formation of synthetically useful alkoxyamines. The method does not require transition metals and was successfully used in a new synthetic approach for the antidepressant indatraline.

Photocatalyzed redox-neutral decarboxylative alkylation of heteroaryl methanamines

A redox-neutral decarboxylative radical–radical coupling reaction of heteroaryl methylamines with NHPI esters has been developed by employing a copper complex as a photocatalyst with blue LED irradiation.

A benzene-bridged divanadium complex-early transition metal catalyst for alkene alkylarylation with PhI(O2CR)2via decarboxylation.

The synthesis, structure and catalytic activity of a benzene-bridged divanadium complex were comprehensively studied. The reduction of (Nacnac)VCl2 (1) (Nacnac = (2,6-iPr2C6H3NCMe)2HC) supported by β-diketiminate with potassium graphite (KC8) by employing benzene as the solvent allows access to the benzene-bridged inverted-sandwich divanadium complex (μ-η6:η6-C6H6)[V(Nacnac)]2 (2a), which can catalyze alkene alkylarylation with hypervalent iodine(iii) reagents (HIRs) via decarboxylation to generate regioselectively diverse indolinones. Furthermore, the mild nature of this reaction was amenable to a wide range of functionalities on alkenes and HIRs. Mechanistic studies revealed a relay sequence of decarboxylative radical alkylation/radical arylation/oxidative re-aromatization.

Silver-catalyzed decarboxylative radical allylation of α,α-difluoroarylacetic acids for the construction of CF2-allyl bonds.

An efficient silver-catalyzed method of decarboxylative radical allylation of α,α-difluoroarylacetic acids to build CF2-allyl bonds has been developed. Using allylsulfone as an allyl donor, α,α-difluorine substituted arylacetic acids bearing various functional groups are successfully allylated to access a series of 3-(α,α-difluorobenzyl)-1-propylene compounds in moderate to excellent yields in aqueous CH3CN solution under the mild conditions. Experimental studies disclosed that the α-fluorine substitution of arylacetic acid has a great influence on free radical activity and reactivity.

Silver-catalyzed decarboxylative radical relay difluoroalkylation–carbocyclization: convenient access to CF2-containing quinolinones

A practical Ag-catalyzed formal decarboxylation and radical difluoroalkylation–carbocyclization–hydrolysis route is established to construct a series of structurally diverse CF2-containing N-heterocycles.

BiVO4 prepared by the sol–gel doped on graphite felt cathode for ciprofloxacin degradation and mechanism in solar-photo-electro-Fenton

In this research, bismuth vanadate-doped graphite felt (GF-BiVO4) was successfully prepared by sol–gel method, in which BiVO4 owned superior electro-Fenton (EF) and solar-photo-electro-Fenton (SPEF) performance. Combined with the analysis by X-ray diffractometer (XRD), field emission transmission electron microscopy (FE-TEM), nitrogen adsorption–desorption isotherms and cyclic voltammetry (CV), the changes of electrodes were reflected in structure and physicochemical properties. The doping of monoclinic BiVO4 endued GF with a higher surface area and more electro-active sites and better electrode activity in comparison to Raw-GF. Then, the GFs were used as cathodes to detect •OH concentration with coumarin (COU) as probe molecule and to evaluate photoelectric performance with ciprofloxacin (CIP) in photocatalysis, EF and SPEF processes. The results demonstrated that the concentration of •OH followed an order of SPEF> EF> photocatalysis, which was consistent with the removal rate of CIP (99.8%, 99.4% and 21.2%, respectively) on GF-BiVO4 at 5 min. Further, five degradation pathways of CIP in SPEF system were proposed including the attack on piperazine ring, oxidation on cyclopropyl group, decarboxylation and hydroxyl radical addition, oxidation on benzene group and defluorination. The study provides insights into the enhancement of EF and SPEF performance and the degradation pathway of CIP in SPEF.

Synthesis of Reverse Glycosyl Fluorides and Rare Glycosyl Fluorides Enabled by Radical Decarboxylative Fluorination of Uronic Acids.

An efficient protocol for synthesizing reverse glycosyl fluorides is described, relying on silver-promoted decarboxylative fluorination of structurally diverse pentofuran- and hexopyranuronic acids under the mild reaction conditions. The potential applications of the reaction are further demonstrated by converting readily available d-uronic acid derivatives into uncommon d-/l-glycosyl fluorides through a C1-to-C5 switch strategy. The reaction mechanism is corroborated by 5-exo-trig radical cyclization of allyl α-d-C-glucopyranuronic acid triggered by decarboxylative fluorination.