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.

Radical allylations by reaction of azides with allylindium dichloride.

Allylindium dichloride is an effective reagent for carrying out photolytically initiated radical allylation reactions, as also proved by EPR experiments. In the presence of suitable azides that can give rise to electrophilic radicals, a homolytic chain reaction occurs with formation of allylated compounds. With delta-azido esters and chlorides generation of primary indiumaminyl radicals is followed by a very efficient 1,5-H shift process that gives rise to electrophilic carbon-centred radicals, whose subsequent allylation by the starting indium reagent, followed by aqueous workup, eventually affords allylated nitrogen heterocycles in good yields. Some comparative theoretical calculations accounted for the observation that analogous reactions with an organoallyltin reagent did not work at all. The results show that the reaction with allylindium dichloride seems strongly favoured by both a lower BDE of the allyl-metal bond and a considerably faster, exothermic 1,5-H migration step.

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.

Iminyl radicals from alpha-azido o-iodoanilides via 1,5-H transfer reactions of aryl radicals: new transformation of alpha-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 reduction of aromatic azides to amines with triethylsilane.

Aromatic azides are inert toward triethylsilane under thermal conditions in the presence of a radical initiator, but in the presence of additional catalytic amounts of tert-dodecanethiol, they afford anilinosilanes and thence the corresponding anilines in virtually quantitative yields.

Reaction of azides with dichloroindium hydride: very mild production of amines and pyrrolidin-2-imines through possible indium-aminyl radicals.

Organic azides are easily reduced to the corresponding amines by reaction with dichloroindium hydride under very mild conditions and in a highly chemoselective fashion. Gamma-azidonitriles give rise to outstanding five-membered cyclizations affording pyrrolidin-2-imines. A rationalization of the overall experimental data cannot exclude the occurrence of competitive radical and nonradical pathways, but certain results are, however, soundly consistent with the intermediacy of indium-bound nitrogen-centered radicals. [reaction: see text]

Generation and cyclization of unsaturated carbamoyl radicals derived from S-4-pentynyl carbamothioates under tin-free conditions.

The radical reaction of benzenethiol with S-4-pentynyl carbamothioates provides a valuable protocol for the tin-free generation of carbamoyl radicals, which arise from intramolecular substitution at sulfur by the initial sulfanylvinyl radicals. This procedure can be usefully employed to achieve N-benzylcarbamoyl radical 5-exo and 4-exo cyclizations leading, respectively, to pyrrolidinones and azetidinones, although, for the latter, it seems of lesser utility. Novel evidence is presented that N-tosyl-substituted carbamoyl radicals display a peculiar tendency to yield the corresponding isocyanate by beta-elimination of the tosyl radical.

Radical reduction of aromatic azides to amines with tributylgermanium hydride.

[reaction: see text] Aromatic azides are inert toward tributylgermanium hydride under thermal conditions in the absence and in the presence of a radical initiator but in the presence of catalytic amounts of benzenethiol undergo fast reaction, yielding reduced anilines and 2-germylated derivatives in high overall yields.

Thermal reactions of tributyltin hydride with alpha-azido esters: unexpected intervention of tin triazene adducts under both nonradical and radical conditions.

Thermal reaction of various alpha-azido esters with Bu(3)SnH in refluxing benzene results in smooth production of 3-(tributylstannyl)-1-triazene adducts affording cyclized 1,2,3-triazol-4-ones in preference to reduced amines and thence provides a new useful method for the preparation of these triazole derivatives. In the presence of AIBN the occurrence of triazene products still remains important or even exclusive and, consequently, generation of the expected stannylaminyl radicals is seriously limited. With 2-azidomalonates and alpha-azido-beta-keto esters stannyltriazenes can similarly occur in the absence of the radical initiator, but in the latter cases the ensuing triazenes undergo preferential cyclization onto the ketone moiety to give reactive hydroxytriazolines. Contrary to alpha-azido esters, in the presence of AIBN alpha-azido-beta-keto esters as well as azidomalonates give rise only to the usual stannylaminyl radicals. A possible explanation for the different behavior of the mono- and dicarbonyl azides in the presence of AIBN is put forward.

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.

Generation and intramolecular reactivity of acyl radicals from alkynylthiol esters under reducing tin-free conditions.

[reaction: see text] The radical chain reaction of benzenethiol with alkynylthiol esters provides a new, valuable protocol for the tin-free generation of acyl radicals that arise from intramolecular substitution at sulfur by the initial sulfanylvinyl radicals.

Cascade radical reactions via alpha-(arylsulfanyl)imidoyl radicals: competitive [4 + 2] and [4 + 1] radical annulations of alkynyl isothiocyanates with aryl radicals.

Aryl radicals react with 2-(2-phenylethynyl)phenyl isothiocyanate through a novel radical cascade reaction entailing formation of alpha-(arylsulfanyl)imidoyl radicals and affording a new class of compounds, i.e. thiochromeno[2,3-b]indoles. These derivatives are formed as mixtures of substituted analogues arising from competitive [4 + 2] and [4 + 1] radical annulations. The isomer ratio is strongly dependent on the aryl substituent and is correlated to its capability to delocalize spin density. The presence of a methylsulfanyl group in the ortho-position of the initial aryl radical results in complete regioselectivity and better yields, as the consequence of both strong spin-delocalization effect, which promotes exclusive [4 + 1] annulation, and good radical leaving-group ability, which facilitates aromatization of the final cyclohexadienyl radical. Theoretical calculations support the hypothesis of competitive, independent [4 + 2] and [4 + 1] annulation pathways. They also suggest that rearrangement onto the sulfur atom of the [4 + 1] intermediate does not occur via a sulfuranyl radical but rather through either a transition state or a sulfur-centered (thioamidyl) radical; the latter is possibly the preferred route in the presence of an o-methylsulfanyl moiety that can act as a leaving group in the final ipso-cyclization process.

Intramolecular cyclization of acyl radicals onto the azido group: a new radical approach to cyclized lactams.

[reaction: see text] Aryl- and alkyl-derived azidoacyl radicals, generated from thiolesters by intramolecular homolytic substitution at the sulfur, can undergo five- and six-membered cyclization onto the azido moiety to give cyclized lactams.

Reactions of Benzocyclic ß-Keto Esters with Sulfonyl Azides. 2.1 Further Insight into the Influence of Azide Structure and Solvent on the Reaction Course.

The reactions of 2-ethoxycarbonyl-1-benzosuberone with 4-methoxybenzenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl, methanesulfonyl, and trifluoromethanesulfonyl azide, in the presence of triethylamine, have been investigated in N,N-dimethylformamide, acetonitrile, or tetrahydrofuran with the intent of clarifying the influence of both the azide electrophile and solvent on the reaction course. The present findings, in addition to those previously obtained with tosyl and 4-nitrobenzenesulfonyl azide, indicate that both the electronic features of the sulfonyl azide and the solvent polarity greatly affect the possible occurrence of azidation and/or Favorskii-type ring contraction at the expense of deacylating diazo transfer. Azidation is promoted by the less electrophilic azides, while it is virtually avoided by the more electrophilic ones. Ring contraction occurs to a limited extent with the less electrophilic azides, but it becomes the main process with those more electrophilic. Moreover, azidation is virtually unaffected by the solvent polarity, while ring contraction can markedly be enhanced by a highly polar solvent. Firm evidence has additionally been obtained that, in contrast to a previous claim, trifluoromethanesulfonyl azide can normally perform diazotization of acyclic ß-keto esters in preference to azidation.