Harry Heaney

Vilsmeier formylation and glyoxylation reactions of nucleophilic aromatic compounds using pyrophosphoryl chloride

Abstract Reactions of N,N-dimethylformamide and N-methylformanilide with pyrophosphoryl chloride lead to the formation of reagents that undergo reactions with a wide range of nucleophilic aromatic substrates, including indoles, pyrroles, thiophenes, furans, and methoxy-substituted carbocyclic arenes to afford, after hydrolysis of the initial products, good to excellent yields of the expected aldehydes; reactions with methyl oxamates allow the preparation of methyl arylglyoxylates.

Oxidation during reductive cyclisations using Bu3SnH

Abstract Reductive cyclisations using Bu 3 SnH include an “oxidation” step if the removal of an acidic proton from the intermediate cyclised radical, by Bu 3 SnH acting as a base, is favourable. A “pseudo” S RN 1 mechanism is proposed.

Experimental Evidence for the Involvement of Dinuclear Alkynylcopper(I) Complexes in Alkyne–Azide Chemistry

Dinuclear alkynylcopper(I) ladderane complexes are prepared by a robust and simple protocol involving the reduction of Cu(2)(OH)(3)OAc or Cu(OAc)(2) by easily oxidised alcohols in the presence of terminal alkynes; they function as efficient catalysts in copper-catalysed alkyne-azide cycloaddition reactions as predicted by the Ahlquist-Fokin calculations. The same copper(I) catalysts are formed during reactions by using the Sharpless-Fokin protocol. The experimental results also provide evidence that sodium ascorbate functions as a base to deprotonate terminal alkynes and additionally give a convincing alternative explanation for the fact that the Cu(I)-catalysed reactions of certain 1,3-diazides with phenylacetylene give bis(triazoles) as the major products. The same dinuclear alkynylcopper(I) complexes also function as catalysts in cycloaddition reactions of azides with 1-iodoalkynes.

3.3 – The Intramolecular Aromatic Friedel–Crafts Reaction

Most of the general features of the intermolecular Friedel–Crafts acylations that are the subject of Volume 2, Chapter 3.2 also apply to the intramolecular versions. The present chapter should be regarded as an extension to the earlier one. The intramolecular Friedel–Crafts reaction has been reviewed previously,1 including reactions specifically involving the use of polyphosphoric acid.1c We will concentrate our attention on more recent examples in order to exemplify the general principles that were also described in those reviews. There is no reason to suppose that the mechanistic considerations that we considered in the earlier chapter do not also apply in the present case. The thermodynamic problems associated with intermolecular reactions result in some important changes to those general features when we consider the intramolecular versions. The enthalpy effect relates to any ring or steric strain that may be present in the transition state leading to cyclization and the entropy effect relates to the ease or difficulty of making the two ends of the reacting system meet. As is the case with the majority of nonradical cyclization reactions, six-membered rings are formed most easily, followed by five- and seven-membered systems. Medium-sized rings are not easily obtained2 and large-sized rings are only obtained in reasonable yields using high dilution techniques. Thus the conversion of 6-phenylhexanoic acid into the acid chloride and cyclization using aluminum chloride in dichloromethane gave the benzocyclooctenone in only 38% yield (equation 1).2b Other reactions leading to the formation of, for example, an eightmembered heterocyclic ring (a benzazocinone),2c have also been reported using a procedure2d that involves the use of 3 equiv. of aluminum chloride. A reaction of 16-phenylhexadecanoyl chloride with aluminum bromide gave the 20-membered ring product shown in equation (2) in 70% yield using a high dilution procedure.3 In analogous reactions leading to the formation of 18-, 15- and 13-membered rings the products were obtained in 57%, 30% and 5% yields respectively. Rather surprisingly the cyclization of o-β-phenethylphenylacetic acid using polyphosphoric acid gave 2,3,6,7-dibenzocyclooctanone in 93% yield.4 Presumably this results from the presence of the four sp3 carbon atoms, which impart significant rigidity to the molecule and hence increase the chance that the two ends of the reacting system will meet. We will classify the remaining parts of this chapter according to the size of ring produced.

Alkynylcopper(I) polymers and their use in a mechanistic study of alkyne–azide click reactions

Polymeric dinuclear alkynylcopper(I) complexes, for example phenylethynylcopper(I), can be prepared by a robust method involving the interaction of terminal alkynes with copper(II) salts in acetonitrile. The use of the ladder polymers provides heterogeneous catalysts for copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions and provides important mechanistic information.

Copper(1) catalysed aromatic nucleophilic substitution: A mechanistic and synthetic comparison with the SRN1 reaction

Evidence is provided to support a mechanism for Cu(1) catalysed aromatic nucleophilic substitution via inner-sphere electron-transfer and a Cu(111) intermediate, and to show the synthetic potential for Cu(1) catalysis relative to the SRN1 reaction.

The oxidation of aromatic aldehydes by magnesium monoperoxyphthalate and urea–hydrogen peroxide

Magnesium monoperoxyphthalate and urea–hydrogen peroxide–acetic anhydride are effective reagents in the oxidation of benzaldehyde to benzoic acid and o- and p-methoxybenzaldehyde to the corresponding phenols. On the other hand, aromatic aldehydes, including the isomeric methoxybenzaldehydes, are oxidised to the corresponding benzoic acid derivatives in good to excellent yields by the hydroperoxide anion generated from urea–hydrogen peroxide.

Synthesis of oxindoles by radical cyclisation

Abstract Oxindoles are readily synthesised by intramolecular addition of aryl radicals to the α-position of α,β-unsaturated N -alkylamides.

Intramolecular aromatic substitution (SRN1) reactions; use of entrainment for the preparation of benzothiazoles

Abstract The process of entrainment (catalytic chain initiation) with the enolate-anion of acetone has been used in intramolecular aromatic S RN 1 subsitution for the preparation of 2-phenyl- and 2-methyl-1,3-benzothiazole in high yield from o -iodothiobenzanilide and o -iodothioacetanilide.

THE GENERATION OF IMINIUM IONS USING CHLOROSILANES AND THEIR REACTIONS WITH ELECTRON RICH AROMATIC HETEROCYCLES

Abstract Dichlorodimethylsilane and trichloromethylsilane have been used to generate iminium ions from aminals and aminol ethers derived from secondary alkylamines, including glycine derivatives, in aprotic media which were shown to undergo reactions with electron rich aromatic heterocycles, including furan, to give mono-aminoalkylation products in good yields. Whereas chlorotrimethylsilane has been shown to generate iminium ions from aminol ethers, no evidence was adduced for the involvement of iminium ions using aminals. 2,5-Disubstitution of N-methylpyrrole was the major result in reactions of N-methylpyrrole with aminals in the presence of chlorotrimethylsilane where no build up of hydrogen chloride occurs and where chlorotrimethylsilane can function catalytically. Experimental results, including the use of bis(trimethylsilyl)acetamide as a proton scavenger, and some relative rate data, are presented that allow possible mechanisms to be evaluated.