Synthesis of novel pyranoquinones using an acyl radical cyclization strategy

The thiol-catalysed cyclization of acyl radicals generated directly from benzaldehyde precursors has been investigated. Hindered β-benzyloxyacrylates cyclize efficiently providing a tin-free radical cyclization approach to the serine/threonine kinase AKT inhibitor frenolicin B, whilst γ-aryloxy crotonates give good yields of benzopyran-4-ones. This method is applied to the synthesis of a novel tetracyclic analogue of the pyranonaphthoquinone antibiotics.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Radical cascade cyclizations and platinum(II)-catalyzed cycloisomerizations of ynamides

Ynamides are tested as new partners in radical and organometallic transformations. A radical cascade involving a 5-exo-dig cyclization followed by a 6-endo-trig radical trapping transforms ynamides into hetero-polycyclic compounds such as isoindoles, isoindolinones and pyrido-isoindolones. Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation, which provides cyclobutanones.     

Synthesis of five- to seven-membered polyfunctional terpenic carbocycles via Ti(III)-catalyzed radical cyclizations of epoxypolyprenes

Ring size on Ti(III)-mediated radical cyclization of monoepoxypolyprenoids can be controlled by varying the substitution pattern and/or the electronic distribution of the double bond involved in the ring closure. The feasibility of applying this idea to tandem cyclizations has also been proven. Besides, when a silyloxy function is located in α position to the oxirane ring of the acyclic polyprene, the cyclization leads to carbocyclic terpenoids doubly functionalized in the A ring with acceptable yields. These results widen significantly the scope of this methodology.     

Synthesis of aryl ring-fused benzimidazolequinones using 6-exo-trig radical cyclizations

The preparation of alicyclic ring-fused tetracyclic and pentacyclic benzimidazoles containing one and two fused aryl rings, respectively, is achieved conveniently in three steps, including Bu₃SnH-mediated 6-exo-trig cyclization of σ-aryl radicals generated from 1-allyl-2-(ω-bromoaryl)benzimidazoles. Inclusion of 4,7-dimethoxy substituents on the radical precursors allows access to aryl ring-fused benzimidazolequinones, a unique family of potential bioreductive anti-cancer agents.     

Initiating radical cyclizations by H transfer from transition metals

CpCr(CO)₃H and HV(CO)₄(P-P) (where P-P is a chelating diphosphine) can be used to initiate radical cyclizations by transferring H to activated terminal olefins. CpCr(CO)₃H can catalyze reductive cyclizations, with H₂ as the ultimate reductant. Appropriate substrates can be assembled by the Morita-Baylis-Hillman reaction of methyl acrylate with an aldehyde. Six- as well as five-membered rings can be formed, and a tandem cyclization to decalin can be effected.     

Iron(II)-catalyzed direct CH cyanoalkylation of 2H-indazoles and coumarins via radical CC bond cleavage

An iron-catalyzed C-3 cyanoalkylation of 2H-indazole and coumarin derivates with cyclobutanone oxime esters has been accomplished, which proceeds efficiently in a high regioselective manner to construct diverse alkylated 2H-indazole and coumarin derivates in moderate to good yields. Preliminary mechanistic studies reveal that a distal cyanosubstituted alkyl radicals intermediate would be formed through radical-involved CC bond cleavage of cyclobutanone oximes ester.     

Enhanced reactivity in radical cyclizations of hydrazones using the silicon-tethered 1-bromovinyl group

A silicon-tethered 1-bromovinyl group was shown to function as a radical precursor for tin-mediated vinyl additions to chiral α- or β-hydroxyhydrazone. In contrast to related thiyl-mediated methods, these vinyl bromides were not limited to the 5-exo cyclization mode. A series of Si-tethered 5-exo and 6-exo cyclizations formed the corresponding five- and six-membered exo-methylene-substituted oxasilacycles. Treatment with fluoride cleaved the Si-C and Si-O bonds to afford the corresponding allylic hydrazines. Diastereoselectivities ranged from 2:1 to 25:1 (anti:syn) for the 5-exo cyclizations, depending on the size of the exocyclic substituent, but 6-exo cyclization was not diastereoselective. A variant involving Tamao oxidation of the exo-methylene oxasilacyclopentane intermediate afforded a methyl ketone, a net process corresponding to addition of a radical acyl anion equivalent.     

Front Cover: Deoxygenative Intramolecular Minisci-Type Reaction to Access Fused Heterocyclic Scaffolds (Eur. J. Org. Chem. 7/2023)

Herein, we present a straightforward strategy for the synthesis of fused heterocycles through a deoxygenative, intramolecular Minisci-type reaction. This approach grants access to complex polycyclic scaffolds in three steps from readily available starting materials, such as chlorinated heteroarenes and 1,3-diols. The use of saccharide derivatives as the starting 1,3-diol motif allows for the synthesis of novel heterocyclic scaffolds with excellent diastereoselectivity and formal retention of configuration at the newly formed C−C bond.     

Polarity‐Reversal‐Catalyzed Hydrostannylation Reactions: Benzeneselenol‐Mediated Homolytic Hydrostannylation of Electron‐Rich Olefins

Addition of 10 mol‐% of diphenyl diselenide to hydrostannylation reactions involving electron‐rich olefins results in a dramatic improvement in yield. For example, reaction of α‐{[(tert‐butyl)dimethylsilyl]oxy}styrene ( 1 ) with triphenylstannane ( 2a ; 1.1 equiv.) in the presence of PhSeSePh and 2,2′‐azobis[2‐methylpropanenitrile] (AIBN) affords {2‐{[(tert‐butyl)dimethylsilyl]oxy}‐2‐phenylethyl}triphenylstannane ( 3a ) in 95% yield after 2 h. This reaction presumably benefits, by the increased rate of H‐atom transfer, from the in situ generated polarity‐reversal catalyst, benzeneselenol.     

Synthetic applications of aryl radical building blocks for cyclisation onto azoles

2-(2-Bromophenyl)ethyl groups have been used as building blocks in radical cyclisation reactions onto azoles to synthesise tri- and tetra-cyclic heterocycles. 2-(2-Bromophenyl)ethyl methanesulfonate was used to alkylate azoles (imidazoles, pyrroles, indoles and pyrazoles) for the synthesis of the radical precursors. Cyclisations of the intermediate aryl radicals yield new 6-membered rings attached to the azoles. The aryl radicals undergo intramolecular homolytic aromatic substitution onto the azole rings. Tributylgermanium hydride has been used with success to replace the toxic and troublesome tributyltin hydride. Initial studies show that the protocol can be used on solid phase resins. The molecular and crystal structures of methyl 5,6-dihydroimidazo[5,1-a]iso-quinoline-1-carboxylate and methyl 5,6-dihydroimidazo[2,1-a]isoquinoline-3-carboxylate were determined by X-ray crystallography.     

Synthesis of novel isoxazoline-fused cispentacin stereoisomers

New isoxazoline-fused cispentacins were prepared by the 1,3-dipolar cycloaddition of nitrile oxides to β-amino esters containing a cyclopentene skeleton. This synthetic procedure gave regio- and diastereoisomers of the cispentacins. The synthetic route was extended to the synthesis of these compounds in enantiomerically pure form.     

The synthesis of carbohydrate-derived acylsilanes and their intramolecular free radical cyclizations with the formation of polyoxygenated cyclopentanes

A convenient way for the synthesis of acylsilanes from arabinose, lyxose, and ribose is developed. All the chiral centers of the carbohydrate templates are conserved, and only the reducing end is transformed into the acylsilane functional group. The non-reducing end of the templates can be converted into a bromide. These bromo acylsilanes undergo efficient intramolecular radical cyclizations to give polyoxygenated cyclopentanes.     

ortho-Acidic aromatic thiols as efficient catalysts of intramolecular Morita-Baylis-Hillman and Rauhut-Currier reactions

ortho-Mercaptobenzoic acid and ortho-mercaptophenols were discovered as efficient thiol catalysts of both the intramolecular Morita-Baylis-Hillman (MBH) and Rauhut-Currier (RC) reaction. High reaction rates were achieved under mildly basic, aqueous conditions. The unprecedented catalytic activity of these protic nucleophiles could originate from a Brønsted acid induced destabilization of intermediate thioethers and thus represent a unique mechanism of multifunctional Lewis base catalysis.     

Ketenimine Complexes from Carbene Complexes and Isocyanides: Versatile Building Blocks for Carbocycles and N-Heterocycles [New Synthetic Methods (74)]

Ketenimine complexes are readily available in great variety by reaction of isocyanides with carbene complexes. They have proven to be useful building blocks in new synthetic approaches to carbocyclic and N-heterocyclic four-, five-, and six-membered rings. The reactions involve new metal-induced bond formation patterns of the ketenimine ligands, which can be influenced across a wide range by varying the following five parameters: the metal, the ligands, and the three substituents on the N?C?C unit.     

Copper-catalyzed radical oxytrifluoromethylation of alkenyl oximes at ambient temperature

A mild and efficient copper-catalyzed radical oxytrifluoromethylation reaction of alkenyl oximes was successfully developed. The method provides a straightforward access to a wide range of CF₃-containing isoxazolines in good to excellent yields.     

Copper-catalyzed radical cascade reaction of isocyanate and ethers

A novel copper-catalyzed amination of ethers using isocyanates and DTBP is developed. The reaction provides a unique approach to the synthesis of Boc-protected α-aminals through three-component radical cascade reactions. It provides an alternative method for the construction of this type of valuable motifs in high yield. Meanwhile, the method exhibits high tolerance of various functional groups, such as ether, halide, ester and acyl functionalities.     

Generation of alkyl radicals from alkylsilyl peroxides and their applications to C-N or C-O bond formations

This article describes a novel method for the generation of alkyl radicals from alkylsilyl peroxides and their applications to the Cu-catalyzed mono-N-alkylation of amides or arylamines, and to the O-alkylation of carboxylic acids. The use of alkylsilyl peroxides as alkyl radical sources includes the following synthetic advantages: i) various alkylsilyl peroxides can be readily synthesized from the corresponding alcohols and be stored at bench, and ii) a variety of alkyl radicals can be generated efficiently under mild conditions.     

Controlling the regiochemistry of radical cyclizations

This review describes the results of our recent studies on the control of the regiochemistry of radical cyclizations. N-vinylic alpha-chloroacetamides generally cyclized in a 5-endo-trig manner to give five-membered lactams, whereas 4-exo-trig cyclization occurred when the cyclized radical intermediates were highly stabilized by an adjacent phenyl or phenylthio group to afford beta-lactams. The 5-exo or 6-exo cyclization of aryl radicals onto the alkenic bond of enamides could be shifted to the corresponding 6-endo or 7-endo mode of cyclization by a positional change of the carbonyl group of enamides. The 6-endo- and 7-endo-selective aryl radical cyclizations were applied to radical cascades for the synthesis of alkaloids such as phenanthroindolizidine, cephalotaxine skeleton, and lennoxamine. The 5-exo-trig cyclization of an alkyl radical onto the alkenyl bond of enamides could also be shifted to the 6-endo mode by a positional change of the carbonyl group of enamides. The 6-endo- selective cyclization was applied to the radical cascade to afford a cylindricine skeleton. Other examples of controlling the regiochemistry of radical cyclizations and their applications to the synthesis of natural products are also discussed.