NHC and visible light-mediated photoredox co-catalyzed 1,4-sulfonylacylation of 1,3-enynes for tetrasubstituted allenyl ketones

The modulation of selectivity of highly reactive carbon radical cross-coupling for the construction of C–C bonds represents a challenging task in organic chemistry. N-Heterocyclic carbene (NHC) catalyzed radical transformations have opened a new avenue for acyl radical cross-coupling chemistry. With this method, highly selective cross-coupling of an acyl radical with an alkyl radical for efficient construction of C–C bonds was successfully realized. However, the cross-coupling reaction of acyl radicals with vinyl radicals has been much less investigated. We herein describe NHC and visible light-mediated photoredox co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes, providing structurally diversified valuable tetrasubstituted allenyl ketones. Mechanistic studies indicated that ketyl radicals are formed from aroyl fluorides via the oxidative quenching of the photocatalyst excited state, allenyl radicals are generated from chemo-specific sulfonyl radical addition to the 1,3-enynes, and finally, the key allenyl and ketyl radical cross-coupling provides tetrasubstituted allenyl ketones.

Unprecedented NHC and photocatalysis co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes has been realized, providing structurally diversified tetrasubstituted allenyl ketones via allenyl and ketyl radical cross-coupling.     

A Photoinduced,Nickel-Catalyzed Reaction for the Stereoselective Assembly of C-Linked Glycosides and Glycopeptides

C-Alkyl glycosides and glycoproteins exist in natural products and are prized for their role as carbohydrate mimics in drug design. However, a practical strategy that merges glycosyl donors with readily accessible reagents, derived from abundant carboxylic acid and amine feedstocks, is yet to be conceived. Herein, we show that a nickel catalyst promotes C−C coupling between glycosyl halides and aliphatic acids or primary amines (converted into redox-active electrophiles in one step), in the presence of Hantzsch ester and LiI (or Et₃N) under blue LED illumination to deliver C-alkyl glycosides with high diastereoselectivity. Mechanistic studies support the photoinduced formation of alkyl radicals that react with a glycosyl nickel species generated in situ to facilitate cross-coupling. Through this manifold, innate CO₂H and NH₂ motifs embedded within amino acids and oligopeptides are selectively capped and functionalized to afford glycopeptide conjugates through late-stage glycosylation.     

A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher''s attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

A non-classical ring opening radical clock reaction using the innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis has been demonstrated, providing a brand-new synthetic approach to access a variety of alkynyl derivatives.     

Suzuki-type cross-coupling of alkyl trifluoroborates with acid fluoride enabled by NHC/photoredox dual catalysis

The Suzuki–Miyaura cross-coupling of C(sp³)-hybridised boronic compounds still remains a challenging task, thereby hindering the broad application of alkyl boron substrates in carbon–carbon bond-forming reactions. Herein, we developed an NHC/photoredox dual catalytic cross-coupling of alkyl trifluoroborates with acid fluorides, providing an alternative solution to the classical acylative Suzuki coupling chemistry. With this protocol, various ketones could be rapidly synthesised from readily available materials under mild conditions. Preliminary mechanistic studies shed light on the unique radical reaction mechanism.

An acylative Suzuki-type cross-coupling of alkyl trifluoroborates and acid fluorides was developed by merging NHC organocatalysis with photoredox catalysis. A broad spectrum of ketones could be facilely synthesised under mild reaction conditions.     

Modular synthesis of α-arylated carboxylic acids,esters and amides via photocatalyzed triple C–F bond cleavage of methyltrifluorides

α-Arylated carboxylic acids, esters and amides are widespread motifs in bioactive molecules and important building blocks in chemical synthesis. Thus, straightforward and rapid access to such structures is highly desirable. Here we report an organophotocatalytic multicomponent synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles. This operationally simple strategy features a unified access to functionally diverse α-arylated carboxylic acids, esters, and primary, secondary, and tertiary amides through backbone assembly from simple starting materials enabled by consecutive C–F bond functionalization at room temperature. Preliminary mechanistic investigations reveal that the reaction operates through a radical-triggered three-step cascade process, which involves distinct mechanisms for each defluorinative functionalization of the C–F bond.

Here we report an organophotocatalytic synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles.     

Superacidic cyclization of higher terpenoid acids and their esters

The superacidic cyclization of aliphatic and partially cyclized C₁₅–C₂₅ terpenoid acids and their esters proceeds structure-selectively and stereospecifically, affording -isomers of completely cyclized epimeric ,-unsaturated acids or esters; the configuration of their carboxylic or ester groups is predetermined by the configuration of the double bond conjugated with the carboxyl or ester groups in the starting compounds.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2507–2513, December, 1995.     

A highly selective decarboxylative deuteration of carboxylic acids

In this paper, we report a mild and practical method for precise deuteration of aliphatic carboxylic acids by synergistic photoredox and HAT catalysis. The reaction delivers excellent D-incorporation (up to 99%) at predicted sites even in substrates bearing reactive C–H bonds or versatile functional groups. The use of a recirculation reactor with a peristaltic pump supports a scalable preparative ability (up to 50 mmol) under very mild reaction conditions. The practical and precise deuteration of readily available complex carboxylic acids makes this protocol promising for the preparation of deuterium-labelled compounds.

A scalable, practical and general method for precise deuteration of aliphatic carboxylic acids via synergistic photoredox and HAT catalysis has been developed. The use of recirculation reactor achieved the preparative scale deuteration.     

Diastereoselective and enantioselective photoredox pinacol coupling promoted by titanium complexes with a red-absorbing organic dye

The pinacol coupling reaction, a reductive coupling of carbonyl compounds that proceeds through the formation of ketyl radicals in the presence of an electron donor, affords the corresponding 1,2-diols in one single step. The photoredox version of this transformation has been accomplished using different organic dyes or photoactive metal complexes in the presence of sacrificial donors such as tertiary amines or Hantzsch''s ester. Normally, the homo-coupling of such reactive ketyl radicals is neither diastereo- nor enantio-selective. Herein, we report a highly diastereoselective pinacol coupling reaction of aromatic aldehydes promoted by 5 mol% of the non-toxic, inexpensive and available Cp₂TiCl₂ complex. The key feature that allows the complete control of diastereoselectivity is the employment of a red-absorbing organic dye in the presence of a redox-active titanium complex. Taking advantage of the well-tailored photoredox potential of this organic dye, the selective reduction of Ti(iv) to Ti(iii) is achieved. These conditions enable the formation of the d,l (syn) diastereoisomer as the favored product of the pinacol coupling (d.r. > 20 : 1 in most of the cases). Moreover, employing a simply prepared chiral SalenTi complex, the new photoredox reaction gave a complete diastereoselection for the d,l diastereoisomer, and high enantiocontrol (up to 92% of enantiomeric excess).

A metallaphotoredox, diastereoselective and enantioselective pinacol coupling reaction promoted by titanium complexes with the use of a red-absorbing organic dye was developed.     

Nanopatterns of molecular spoked wheels as giant homologues of benzene tricarboxylic acids

Molecular spoked wheels with D_3h and C_s symmetry are synthesized by Vollhardt trimerization of C_2v-symmetric dumbbell structures with central acetylene units and subsequent intramolecular ring closure. Scanning tunneling microscopy of the D_3h-symmetric species at the solid/liquid interface on graphite reveals triporous chiral honeycomb nanopatterns in which the alkoxy side chains dominate the packing over the carboxylic acid groups, which remain unpaired. In contrast, C_s-symmetric isomers partially allow for pairing of the carboxylic acids, which therefore act as a probe for the reduced alkoxy chain nanopattern stabilization. This observation also reflects the adsorbate substrate symmetry mismatch, which leads to an increase of nanopattern complexity and unexpected templating of alkoxy side chains along the graphite armchair directions. State-of-the-art GFN-FF calculations confirm the overall structure of this packing and attribute the unusual side-chain orientation to a steric constraint in a confined environment. These calculations go far beyond conventional simple space-filling models and are therefore particularly suitable for this special case of molecular packing.

Scanning tunneling microscopy investigations of phenylene-based molecular spoked wheels with D_3h and C_s symmetries on graphite show the competitive or complementary effects of carboxylic acid groups and alkoxy chains on the nanopattern formation.     

A visible-light-promoted cross-dehydrogenative-coupling reaction of N-arylglycine esters with imidazo[1,2-a]pyridines

A mild and convenient visible-light-promoted cross-dehydrogenative-coupling reaction between N-arylglycine esters and imidazo[1,2-a]pyridines for the construction of CC bond was developed. A range of N-arylglycine esters and imidazo[1,2-a]pyridines were able to undergo the CDC reaction readily to afford α-heteroaryl substituted α-amino acid derivatives in good to excellent yields. A tentative mechanism for the photoredox reaction was also proposed. Importantly, the use of copper(II) salt as the sole catalyst in this visible-light-promoted transformation makes this reaction sustainable and practical.     

Decarboxylative 1,4-carbocyanation of 1,3-enynes to access tetra-substituted allenes via copper/photoredox dual catalysis

We disclose herein the first example of merging photoredox catalysis and copper catalysis for radical 1,4-carbocyanations of 1,3-enynes. Alkyl N-hydroxyphthalimide esters are utilized as radical precursors, and the reported mild and redox-neutral protocol has broad substrate scope and remarkable functional group tolerance. This strategy allows for the synthesis of diverse multi-substituted allenes with high chemo- and regio-selectivities, also permitting late stage allenylation of natural products and drug molecules.

An efficient synthesis of multi-substituted allenes by metallaphotoredox-catalyzed decarboxylative 1,4-carbocyanation of 1,3-enynes is described.     

Photomediated core modification of organic photoredox catalysts in radical addition: mechanism and applications

Dihydrophenazines and their analogues have been widely used as strong reducing photoredox catalysts in radical chemistry, such as organocatalyzed atom transfer radical polymerization (O-ATRP). However, when dihydrophenazines were employed as organic photoredox catalysts (OPCs) to mediate O-ATRP, the initiator efficiency was nonquantitative due to cross-coupling between dihydrophenazines and radical species. Here, a new kind of core modification for dihydrophenazines, phenoxazines and phenothiazines was developed through this cross-coupling process. Mechanistic studies suggested that the radical species would be more likely to couple with OPC'' radical cations rather than the ground-state OPC. Core modification of OPCs could stabilize the radical ions in an oxidative quenching catalytic cycle. Significantly, core modifications of OPCs could lower the energy of light required for photoexcitation. Compared with their noncore-modified counterparts, all the core-modified dihydrophenazines and phenoxazines exhibited efficient performance in controlling O-ATRP for the synthesis of poly(methyl methacrylate) with higher initiator efficiencies under the irradiation of simulated sunlight.

Photomediated core modification of organic photocatalysts through a radical/radical cation cross-coupling process enables the ability to stabilize radical ions and prevent undesirable side reactions.     

Synthesis of Reversed C‐Acyl Glycosides through Ni/Photoredox Dual Catalysis

The incorporation of C‐glycosides in drug design has become a routine practice for medicinal chemists. These naturally occurring building blocks exhibit attractive pharmaceutical profiles, and have become an important target of synthetic efforts in recent decades. 1 Described herein is a practical, scalable, and versatile route for the synthesis of non‐anomeric and unexploited C‐acyl glycosides through a Ni/photoredox dual catalytic system. By utilizing an organic photocatalyst, a range of glycosyl‐based radicals are generated and efficiently coupled with highly functionalized carboxylic acids at room temperature. Distinctive features of this transformation include its mild conditions, impressive compatibility with a wide array of functional groups, and most significantly, preservation of the anomeric carbon: a handle for further, late‐stage derivatization.     

Radical-mediated vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes

The addition of sulfonyl radicals to alkenes and alkynes is a valuable method for constructing useful highly functionalized sulfonyl compounds. The underexplored alkoxy- and fluorosulfonyl radicals are easily accessed by CF₃ radical addition to readily available allylsulfonic acid derivatives and then β-fragmentation. These substituted sulfonyl radicals add to aryl alkyl alkynes to give vinyl radicals that are trapped by trifluoromethyl transfer to provide tetra-substituted alkenes bearing the privileged alkoxy- or fluorosulfonyl group on one carbon and a trifluoromethyl group on the other. This process exhibits broad functional group compatibility and allows for the late-stage functionalization of drug molecules, demonstrating its potential in drug discovery and chemical biology.

An unprecedented method for vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes has been developed to afford useful alkenylsulfonate esters and alkenylsulfonyl fluorides.     

Copper-catalysed photoinduced decarboxylative alkynylation: a combined experimental and computational study

Redox-active esters (RAEs) as alkyl radical precursors have demonstrated great advantages for C–C bond formation. A decarboxylative cross-coupling method is described to afford substituted alkynes from various carboxylic acids using copper catalysts CuCl and Cu(acac)₂. The photoexcitation of copper acetylides with electron-rich NEt₃ as a ligand provides a general strategy to generate a range of alkyl radicals from RAEs of carboxylic acids, which can be readily coupled with a variety of aromatic alkynes. The scope of this cross-coupling reaction can be further expanded to aliphatic alkynes and alkynyl silanes using a catalytic amount of preformed copper-phenylacetylide. In addition, DFT calculations revealed the favorable reaction pathway and that the bidentate acetylacetonate ligand of the copper intermediate plays an important role in inhibiting the homo-coupling of the alkyne.

Redox-active esters (RAEs) as alkyl radical precursors have demonstrated great advantages for Cu-catalysed C–C bond formation.     

Base-mediated reactions of N-alkyl-O-acyl hydroxamic acids: synthesis of 3-oxo-2,3-dihydro-4-isoxazole carboxylic ester derivatives

Treatment of malonyl derived O-acyl hydroxamic acid derivatives 10a-h with the phosphazene super base P-2-t-Bu 7 gives 2,3-dihydro-4-isoxazole carboxylic ester derivatives 11a-h. The rate and yield of the reaction is dependent upon the O-acyl substituent.     

Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids.     

Structure dependence in the solvolysis kinetics of amino acid esters

To better understand acyl transfer reactions of oligopeptides, seventeen N-acyl amino acid esters were solvolyzed in mildly basic methanol-d₄. All show pseudo-first-order kinetics by ¹H NMR. The rate constant varies up to 400-fold with the identity of the amino acid and up to 6200-fold with the identity of the N-acyl group. The impact of the N-acyl group on the rate constant is discussed in terms of crowding, amide conformation, and amide CO bond character.     

Radical boron migration of allylboronic esters

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The boron atom migration through the allylic carbon skeleton proceeds via consecutive 1,2-boron migrations and Smiles-type rearrangement to furnish a variety of terminally functionalized alkyl boronates. Several types of migrating variations of heteronuclei radicals and dearomatization processes are also tolerated, allowing for further elaboration of highly functionalized boron-containing frameworks.

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The atom-switch acrobatics proceeds via cascade 1,2-boron migrations and Smiles type rearrangement to furnish a variety of terminally functionalized alkyl boronates.     

α-Branched amines through radical coupling with 2-azaallyl anions,redox active esters and alkenes

α-Branched amines are fundamental building blocks in a variety of natural products and pharmaceuticals. Herein is reported a unique cascade reaction that enables the preparation of α-branched amines bearing aryl or alkyl groups at the β- or γ-positions. The cascade is initiated by reduction of redox active esters to alkyl radicals. The resulting alkyl radicals are trapped by styrene derivatives, leading to benzylic radicals. The persistent 2-azaallyl radicals and benzylic radicals are proposed to undergo a radical–radical coupling leading to functionalized amine products. Evidence is provided that the role of the nickel catalyst is to promote formation of the alkyl radical from the redox active ester and not promote the C–C bond formation. The synthetic method introduced herein tolerates a variety of imines and redox active esters, allowing for efficient construction of amine building blocks.

A mild method for the construction of α-branched amine derivatives is presented. SET processes between the Ni catalyst, redox active esters and 2-azaallyl anions generate azaallyl radicals and alkyl radicals that functionalize the alkenes.