Matteo Minozzi

From Azides to Nitrogen‐Centered Radicals: Applications of Azide Radical Chemistry to Organic Synthesis

Over the last thirty years organic azides have drawn a great deal of attention as radical traps for carbon- and heteroatom-centered radicals, both in intra- and in intermolecular processes. The resulting intermediates (nitrogen-centered radicals such as triazenyls, aminyls, or even iminyls) can be conveniently employed in the synthesis of a variety of cyclic and acyclic nitrogen-containing compounds.

An Insight into the Radical Thiol/Yne Coupling: The Emergence of Arylalkyne-Tagged Sugars for the Direct Photoinduced Glycosylation of Cysteine-Containing Peptides

An explorative study of the Thiol-Yne Coupling (TYC) reaction has been carried out using an aliphatic (1-octyne) and an aromatic alkyne (phenylacetylene) and two alkanethiols (methyl thioglycolate and N-acetyl-L-cysteine methyl ester). The outcomes of the TYC reactions strongly depend on the experimental conditions (e.g., temperature, solvent, and alkyne/thiol ratio), but these can be properly adjusted to achieve selective production of either mono- or bis-coupling products. With respect to 1-octyne, phenylacetylene undergoes notably easier radical hydrothiolation, further showing a notably higher aptitude for monohydrothiolation exclusive of bis-hydrothiolation. The overall findings were exploited in glycosylation of cysteine derivatives as well as of cysteine-containing peptides. A sugar featuring an arylacetylene moiety gave rise to a true click-reaction, that is, glycosylation of the tripeptide glutathione in its native form, by means of virtually equimolar amounts of reagents. This reaction was successfully applied, under physiological conditions, to a cysteine-containing nonapeptide with marked advantages over the analogous Thiol-Ene Coupling (TEC) derivatization. A TYC/TEC sequence affording bis-armed cysteine derivatives through dual functionalization of an alkynyl sugar was additionally devised.

Iminyl Radicals from α-Azido o-Iodoanilides via 1,5-H Transfer Reactions of Aryl Radicals: New Transformation of α-Azido Acids to Decarboxylated Nitriles

The radical reaction of tributyltin hydride with o-iodo- N-methylanilides derived from alpha-azido acids provides an excellent access to alpha-(aminocarbonyl)iminyl radicals through 1,5-hydrogen transfer reaction of initially formed aryl radicals followed by beta-elimination of dinitrogen from ensuing alpha-azido-alpha-(aminocarbonyl)alkyl radicals. The outcoming iminyls display a peculiar tendency to form corresponding nitriles by beta-elimination of aminocarbonyl radicals.

Tin-free generation of alkyl radicals from alkyl 4-pentynyl sulfides via homolytic substitution at the sulfur atom.

Homolytic substitution at the sulfur atom of beta-(phenylsulfanyl)vinyl radicals, obtained by radical reaction of benzenethiol with easily accessible alkyl 4-pentynyl sulfides, is a mild, effective, tin-free route for the generation of all types of alkyl radicals. This protocol can be employed in reductive defunctionalizations as well as cyclizations onto both electron-rich and electron-poor C-C double bonds.

Radical chain reactions of α-azido ketones with tributyltin hydride: reduction vs nitrogen insertion and 1,2-hydrogen shift in the intermediate N-stannylaminyl radicals

Abstract The radical chain reactions of a variety of acyclic and cyclic α-azido ketones with tributyltin hydride have been investigated. The derived N-(tributylstannyl)aminyl radicals normally undergo H-abstraction reaction yielding corresponding amines, and thence symmetrical pyrazines by subsequent self-condensation, in competition with 1,2-H-migration from the α-carbon to nitrogen leading to α-imino ketone decomposition products with loss of the chain-carrying tributyltin radical. The noteworthy occurrence of a quite uncommon radical 1,2-hydrogen-atom shift is considered to be largely due to consequent formation of a highly stable, captodative carbon-centred radical. In contrast with our previous N-stannylaminyl radicals produced from α-azido-β-keto esters, the present aminyl congeners give poor amounts (or even none) of nitrogen-inserted amides/lactams, which are envisaged to arise from intramolecular three-membered cyclisation onto the ketone moiety followed by β-scission of the resultant alkoxyl radical. It is inferred that adequate stabilisation of the eventual ring-opened carbon radical be a major factor for the successful outcome of the regiospecific nitrogen insertion process. Evidence is also presented that chemoselective attack of tris(trimethylsilyl)silyl radical to the ketone oxygen of an α-azido ketone gives rise to deazidation as a likely consequence of β-elimination of azidyl radical by the ensuing α-silyloxyalkyl radical. X-Ray crystal structure analyses of the bromo ketone 5a , the azido ketone 5b , the caprolactam 22 , and the pyrazine 26 have been performed.

Synthesis and X-ray characterisation of a new polycondensed heterocycle obtained by a novel Mn(III)-mediated cascade reaction of 2-cyanophenyl isothiocyanate

Abstract 2-Cyanophenyl isothiocyanate reacted with Mn(III) acetate in acetic acid or acetonitrile to give fair yields of a new polycondensed heterocycle arising from the joining together of two molecules of the starting isothiocyanate with loss of a CS moiety. The yields were close to 90% when the reaction was carried out in the presence of diethyl malonate. This compound was unambiguously identified by X-ray crystallography. Under the same conditions, 2-(methoxycarbonyl)phenyl isothiocyanate gave a quinazolinimine derivative instead which is likely to arise from cyclisation of an intermediate N,N′-diarylthiourea. The mechanism of formation of the former compound probably involves formation of a N,N′-bis(2-cyanophenyl)thiourea, followed by rearrangement and radical tandem ring closure of the corresponding cyclic imine derivative. This hypothesis is also supported by semiempirical calculations.

Thermal decomposition of tert-butyl ortho-(phenylsulfanyl)- and ortho-(phenylsulfonyl)phenyliminoxyperacetates: The reactivity of thio-substituted iminyl radicals

Some ortho-(phenylsulfanyl)- and ortho-(phenylsulfonyl)-substituted phenyliminyl radicals have been generated by thermal decomposition of suitable tert-butyl iminoxyperacetates. The sulfanyl-substituted iminyls showed no tendency to give either 1,7- or 1,6-ring closure onto the S-phenyl ring. They gave instead 1,5-cyclisation onto the sulfur atom with release of a phenyl radical and formation of benzoisothiazoles. This seems to be the first example of SHi reaction of a nitrogen-centred radical at a sulfide moiety. On the other hand, the sulfonyl-substituted iminyl underwent 1,6-cyclisation to a small extent, furnishing a phenanthridine through an unprecedented 1,5-aryl radical migration from sulfur to nitrogen followed by loss of sulfur dioxide and ring closure of an aryl radical.

Reactions of 1-(2-alkoxyphenyl)alkaniminyl radicals

Genereration of the iminyls 1d and 1e by standard methods in the gas-phase by flash vacuum pyrolysis (FVP), or in solution, respectively, gives rise to 1,3-benzoxazines 18 and 22 by a mechanism which probably involves a 1,6-hydrogen atom translocation. Under FVP conditions, 2-cyanophenol 14 is a major product from 2-alkoxyphenylalkaniminyls 1b–d; the dealkylation is an integral part of the reaction mechanism and not a subsequent reaction of 2-alkoxybenzonitriles, which themselves are only very minor products of the pyrolyses.