On the mechanism and kinetics of radical reactions of epoxyketones and epoxynitriles induced by titanocene chloride

The reactions of a series of epoxynitriles and epoxyketones induced by titanocene chloride have been studied. The kinetics of the decyanogenation of beta,gamma-epoxynitriles with Ti(III) corresponds to a radical reaction (k25 approximately 106 s-1), as demonstrated by competition experiments with H-transfer from 1,4-cyclohexadiene (1,4-CHD) or PhSH or conjugate addition to acrylonitrile. The 5-exo cyclization onto nitrile induced by Ti(III) is a radical reaction (k25 approximately 107 s-1) as seen in competition experiments with H-transfer from PhSH or the titanocene-water complex. The iminyl or alkoxyl radicals generated by 5-exo cyclization onto nitriles or ketones only undergo a reduction with Ti(III). This reaction overwhelms any alternative process, such as tandem cyclization onto alkenes or beta-scission. Iminyl radicals generated by 4-exo cyclizations onto nitriles undergo reduction with Ti(III) and beta-scission reaction in a ratio of 96:4 when the alpha-substituent is CN. Alkoxyl radicals from 4-exo cyclizations onto ketone carbonyls undergo reduction with Ti(III) and beta-scission in a ratio of 60:40 when the alpha-substituent is COOR. In nearly all the reactions studied, the role of Ti(III) is triple: a radical initiator (homolytic cleavage of oxirane), a Lewis acid (coordination to CN or C=O), and a terminator (reduction of iminyl or alkoxyl radicals).     

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.     

Silylboranes as new sources of silyl radicals for chain-transfer reactions

Various silylboranes, which were outfitted with a catecholborane moiety at one end and a (Me(3)Si)(3)Si moiety at the other end of a carbon chain, were prepared through the hydroboration of the corresponding unsaturated silanes. The C-centered radical species generated from these silylboranes efficiently cyclized to provide, through a 5-exo intramolecular homolytic substitution at the silicon center, the corresponding silacycle and a Me(3)Si radical that was subsequently trapped by sulfonyl acceptors. These cyclizations proceeded at unprecedented rates, due, in part, to a strong gem-dialkyl effect that was attributable to the presence of bulky substituents on a quaternary center located on the chain. In parallel, we designed arylsilylboranes that produced silyl radicals through a 1,5-hydrogen transfer. Such silyl radicals may be valuable radical chain carriers, for instance, in oximation reactions of alkyl halides. Finally, computational studies allowed calculation of activation barriers of the homolytic substitution step and additionally illustrated that the overall reaction mechanism involved a transition state in which the attacking carbon center, the central silicon atom, and the Me(3)Si leaving group were collinear.     

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone , mackinazolinone , tryptanthrin , luotonin A and rutaecarpine were synthesised by radical cyclisation onto 3H-quinazolin-4-one.     

Visible‐Light‐Promoted Iminyl‐Radical Formation from Acyl Oximes: A Unified Approach to Pyridines,Quinolines, and Phenanthridines

A unified strategy involving visible‐light‐induced iminyl‐radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac‐[Ir(ppy)₃] as a photoredox catalyst, the acyl oximes were converted by 1 e^? reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N‐containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible‐light‐induced iminyl‐radical formation was successfully applied to a five‐step concise synthesis of benzo[c]phenanthridine alkaloids.     

Visible‐Light‐Promoted Iminyl‐Radical Formation from Acyl Oximes: A Unified Approach to Pyridines,Quinolines, and Phenanthridines

A unified strategy involving visible‐light‐induced iminyl‐radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac‐[Ir(ppy)₃] as a photoredox catalyst, the acyl oximes were converted by 1 e⁻ reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N‐containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible‐light‐induced iminyl‐radical formation was successfully applied to a five‐step concise synthesis of benzo[c]phenanthridine alkaloids.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines via radical cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.     

Bu3SnH-mediated radical cyclisation onto azoles

Alkyl radicals have been cyclised onto pyrroles, imidazoles and pyrazoles, and acyl radicals cyclised onto pyrroles, using Bu₃SnH-, (TMS)₃SiH- and Bu₃GeH-mediated aromatic homolytic substitution for the synthesis of bicyclic N-heterocycles. The reactions yield intermediate π-radicals that lose hydrogen in the rearomatisation step of the aromatic homolytic substitution. Mechanistic studies of these rearomatisation steps indicate aromatic homolytic substitution in which the initiator or breakdown products from the inhibitor are responsible for the H-abstraction step.     

Preparation of polycyclic systems by sequential 5-exo-digonal radical cyclization, 1,5-hydrogen transfer from silicon, and 5-endo-trigonal cyclization

Radicals of type 1 undergo 5-exo diagonal cyclization, and the resulting vinyl radical abstracts hydrogen from silicon to afford a silicon-centered radical. This radical closes in a 5-endo trigonal manner to generate radicals of type 4, which are reduced (4 --> 5) by stannane, except when the starting acetylene carries a terminal trimethylstannyl group. In this case, radicals 4 expel trimethylstannyl radical to afford vinyl silanes 6. The stereochemical outcome of the radical cascade 1 --> 5 is controlled by the stereochemistry of the oxygen-bearing carbon in 1 (see starred atom). The sequence can be initiated by carbon-, alpha-substituted carbon-, oxyacyl-, and carbamoyl radicals and generates a silicon-containing ring fused onto a carbocycle or heterocycle. Numerous examples are described, as well as a number of transformations of the final cyclization products, especially their response to n-Bu(4)NF and to BF(3).OEt(2), reagents that cleave the newly formed carbon-silicon bond.     

Cyclizations of N-stannylaminyl radicals onto nitriles

[reaction: see text] Stannylaminyl radicals derived from radical reactions of Bu(3)SnH with azidoalkylmalononitriles exhibit highly efficient 5- and 6-exo cyclization onto either nitrile group to give aminoiminyl radicals that in turn are reduced to amidines or undergo successive 5-exo cyclization onto an internal alkene.     

Microwave-assisted syntheses of N-heterocycles using alkenone-, alkynone- and aryl-carbonyl O-phenyl oximes: formal synthesis of neocryptolepine

This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.     

Stereoselective synthesis of cyclic ethers using vinylogous sulfonates as radical acceptors: effect of E/Z geometry and temperature on diastereoselectivity

Treatment of the E-vinylogous sulfonates 1a-g with tris(trimethylsilyl)silane and triethylborane, in the presence of air, furnished the cyclic ethers 2/3a-g with good to excellent diastereoselectivity favoring the cis-isomer 2. This study demonstrated the level of stereocontrol in a 6-exo radical cyclization and may be attributed to the type of radical intermediate. Hence, the modest selectivity obtained for the cyclization of 1e may be a function of the acyl radical geometry (sp2) and high inversion barrier (29 kcal/mol) as compared to the alkyl (1 kcal/mol) and vinyl (2.9 kcal/mol) radicals. This is consistent with the acyl radical cyclization having an earlier transition state than the corresponding alkyl and vinyl radicals. The modest diastereoselectivity can be improved dramatically using the Z-vinylogous sulfonate (> or =34:1; R = Ph) to promote kinetic trapping of the s-trans rotamer I and III, respectively (Figure 1). The 5-exo alkyl radical cyclization reaction under nonreductive Keck-allylation conditions was also examined, in which 8 was formed in 91% overall yield. This transformation provides a convenient method for in situ homologation and should be applicable to target directed synthesis.     

Electrophilic properties of anodically generated polynitroalkyl radicals in homolytic aromatic substitution

Conclusions Arylpolynitromethanes, the products of the electrochemical oxidation of polynitrocarbanions in the presence of benzene and its substitution products, are formed by homolytic aromatic substitution. During this process the intermediate polynitroalkyl radicals show electrophilic properties. The yield of arylpolynitromethanes depends on radical structure and on the electron donor properties of the aromatic substrate.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 368–374, February, 1988.     

Synthese radicalaire d'analgesiques potentiels: aryl-4 piperidines substituees en 2 et benzomorphanes

The synthesis of a series of 3-aryl 5-hexenyl amines and the cyclisations of the corresponding N-chloroamines are described. When the ring closure results from the amino radical addition to the ethylenic double bond, 2-chloromethyl 4-phenyl piperidines are obtained. These compounds lead by intramolecular Friedel-Craft reaction to varied substituted 6,7-benzomorphanes. When the phenyl ring is substituted with a methoxyl group, the cyclisation proceeds via homolytic aromatic substitution and 4-allyl tetrahydroquinolines are formed.     

Isonitrile trapping reactions under thermolysis of alkoxyamines for the synthesis of quinolines

[reaction: see text] An efficient tandem radical process comprising a thermal alkoxyamine homolysis, an isonitrile trapping reaction, a 5-exo-trig cyclization, and a homolytic aromatic substitution leads to substituted dihydroquinolines. Depending on the substituent R(1), oxidation to dihydro-1H-cyclopenta[b]quinolines (for R(1) = aryl) or tautomerization to tetrahydro-1H-cyclopenta[b]quinolines (for R(1) = CO(2)Me, CN) occurs. The heterocycles are obtained in moderate to good yields. Upon using microwave-induced heating, the reaction time can be shortened from 3 days to 30 min.     

A new synthetic approach to (+)-lactacystin based on radical cyclisation of enantiopure alpha-ethynyl substituted serine derivatives to 4-methylenepyrrolidinones

Treatment of the acetylenic bromoamide 42c, derived from the enantiopure alpha-amino alcohol 40, with Bu(3)SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2:1). Cleavage of the alkene bond in 43/44, using O(3)-Me(2)S, next gave the corresponding 4-ketopyrrolidinone 45/46. Alpha-phenylsulfanylation of 45/46, using S-methyl-p-toluenethiosulfonate-Et(3)N, proceeded in a stereoselective manner and led to the methylsulfanyl derivative 48 (ca. 9:1 selectivity). Manipulation of the functionality in 48, using two separate sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29, i.e. 32 to 33 and/or 31 to 34.     

Reactivity of NBS towards N-allyl glycinyl derivatives

The reaction of precursors 3 with NBS in radical conditions does not yield any azetidine resulting from a 4-exo radical cyclisation with bromine atom transfer, or any brominated product at the glycinyl position. Instead, dibrominated adducts 4 and aminals 5 have been formed in good yields. We have investigated the mechanism of this puzzling transformation and shown that the homolytic abstraction of a hydrogen atom by a Br^• radical does not take place at the capto-dative position but at the allylic one. The resulting α-bromo derivative 8 would then evolve into an iminium intermediate with concomitant production of bromine and of a succinimidyl anion, which explains the formation of products 4 and 5. To cite this article: C. Koerber et al., C.R. Chimie 6 (2003).     

5-exo Radical cyclization onto 3-alkoxyketimino-1, 6-anhydromannopyranoses. Efficient preparation of synthetic intermediates for (-)-tetrodotoxin

Ketoxime ethers at C3 of 1,6-anhydro-beta-D-mannopyranose derivatives were found to be useful 5-exo radical traps of alkyl and vinyl radicals generated at a chain tethered to the C2 hydroxyl group, allowing advanced synthetic intermediates for (-)-tetrodotoxin to be prepared from D-mannose in good overall yield.     

Isonitriles as source and fate of imidoyl radicals: a novel homolytic α-fragmentation

Imidoyl radicals 4a-c react with phenylacetylene to give annulation products and nitrile 12, arising from β-scission of the intermediate iminyl radical that is involved in the rearrangement of azaspirocyclohexadienyl 8. In contrast, imidoyls 4d and 15 do not react with the alkyne and give good yields of the corresponding isonitriles through a novel example of homolytic α-fragmentation.     

Unprecedented aromatic homolytic substitutions and cyclization of amide-iminyl radicals: experimental and theoretical study

Amide-iminyl radicals are versatile and efficient intermediates in cascade radical cyclizations of N-acylcyanamides. They are easily trapped by alkenes or (hetero-)aromatic rings and cyclize into a series of new heterocyclic compounds which bear a pyrroloquinazoline moiety. As an illustration of the synthetic importance of these compounds, the total synthesis of the natural antitumor compound luotonin A was achieved through a tin-free radical cascade cyclization process. Not only do amide-iminyl radicals lead to new tetracyclic heterocycles but these nitrogen-centered radical species also react in aromatic homolytic substitutions. Indeed, the amide-iminyl radical moiety unprecedentedly displaces methyl, methoxy, and fluorine radicals from an aromatic carbon atom. This seminal reaction in the field of radical chemistry has been developed experimentally and its mechanism has additionally been investigated by a theoretical study.