Frederick J. Swinbourne

Advances in Indolizine Chemistry

Publisher Summary This chapter discusses the synthetic routes, physical properties, and reactions of indolizines. One of the synthetic routes presented is Tschitschibabin reaction involving the quaternization of a 2-substituted pyridine, normally using an α -halo carbonyl compound, followed by intramolecular cyclization of the quaternary salt with a mild base, usually aqueous sodium bicarbonate. Another route is ring closure reactions providing indolizines unsubstituted in the five-membered ring. Several physical properties including electronic spectra, acid–base properties, mass spectra, infrared spectra, nuclear magnetic resonance (NMR) spectra and X-ray diffraction are described. The most widely investigated reaction of the indolizine nucleus is electrophilic substitution. The other reactions of indolizines discussed are cyclizations, reduction, oxidation, and polymerization. Cyclization is concerned with reactions that result in the fusion of one or more additional rings to the indolizine system. Various indolizines containing vinyl groups in the pyridine ring are synthesized by polymerization reactions.

CHLOROSULFONATION OF DIARYL AZINES

Abstract Benzaldehyde- and o-, m-, p-anisaldehyde azines; thiophene-2-carboxaldehyde, and biphenyl-4-carboxaldehyde azines (1-8) reacted with excess chlorosulfonic acid to give the disulphonyl chlorides (1a-8a). These were condensed with amines and hydrazine to give 27 derivatives, (Table 1) for biocidal evaluation. The orientation of sulfonation is discussed in relation to the stereoelectronic factors and the spectral data. Attempted chlorosulfonation of furan-2-carboxaldehyde azine (9) gave an impure product which could not be clearly characterized as the morpholidate derivative.

CHLOROSULFONATION OF SOME POLYNUCLEAR HETEROCYCLIC COMPOUNDS

Abstract Dibenzofuran (1), dibenzothiophen (20) and the 5,5-dioxide (29), carbazole (43) and fluorene (50) have been reacted with chlorosulfonic acid. The resultant sulfonyl chlorides (2, 12, 18, 21, 23, 27, 30, 37, 44, 46 and 51) were condensed with amines and hydrazine to afford 32 derivatives for biological screening. The orientation of chlorosulfonation has been determined by NMR spectral analysis and is compared with the chlorosulfonation of the analogous acyclic compounds. Selected compounds were tested as potential pest control agents.

A NOVEL REACTION OF BENZALACETONE WITH CHLOROSULFONIC ACID

Abstract Benzalacetone 1 with an excess of chlorosulfonic acid did not give the expected 4, ω-disulfonyl dichloride 2, but 4,β-dichlorosulfonylstyrene 3, which was identified by microanalytical and spectral data, and characterised as the bis-N,N-dimethylsulfonamide 4 and the bis-acetone hydrazone 5. A mechanism for the conversion of 1 into 3 is proposed.

THE REACTIONS OF SOME THIOPHENE SULFONYL DERIVATIVES

Abstract Thiophene-2-sulfonyl chloride has been allowed to react with 7 amines, hydrazine and sodium azide. The hydrazide was converted into 21 hydrazones. The azide reacts with cyclohexene, norbornene and triphenylphosphine. The sulfonyl chloride with chlorosulfonic acid gave a mixture of the 2,4- and 2,5-bis-sulfonyl chlorides (2:1). These were not separated by conversion to amides, azides, hydrazides, or hydrazones. 2-Carboxythiophene with chlorosulfonic acid gave a mixture of the 4- and 5-sulfonyl chlorides (9:1), conversion to amides and recrystallization gave the 4-sulfonamides. Chloro-sulfonation of 2-carboxamido- and 2-N,N-dimethylcarboxamidothiophene gave the 4-sulfonyl chlorides, characterized as amides, hydrazides and 18 hydrazones. Some N-arylthiophenesulfonamides were condensed with trichloromethylsulfonyl chloride. The i.r., n.m.r. and mass spectra of the various thiophenesulfonyl derivatives are discussed.

THE REACTION OF CHLOROSULFONIC ACID WITH BENZALACETONE AND BENZALPINACOLONE

Abstract Freshly prepared benzalacetone (1) can be converted into styrene-4,β-disulfonyl dichloride (3) on treatment with an excess of chlorosulfonic acid. The yield is influenced by the work-up conditions. A number of derivatives have been prepared from 3, by reaction with nitrogen nucleophiles. Benzalpinacolone (5). which precludes enolisation-a key step in the conversion of 1 into 3, was also converted into 3 on treatment with an excess of chlorosulfonic acid. The identity of the product was confirmed by reaction with dimethylamine and morpholine, which gave the bis-sulphonamides (4) and (16) respectively. A reaction mechanism for the conversion of (5) into (3) has been proposed.

SOME SULFONYL DERIVATIVES OF SALICYLIC ACID AND RELATED COMPOUNDS

Abstract o-Methoxybenzamide, salicyclic acid, salicylamide and N-acetylsalicylamide have been converted to the corresponding 5-sulfonyl chlorides, and p-hydroxybenzoic acid to the 3-sulfonyl chloride. The sulfonyl chlorides were characterized by the preparation of various derivatives, e.g. amides, hydrazides, hydrazones and azides. Chlorosulfonation of O-acetyl compounds showed either complete or partial deacetylation. O-Acetyl compounds were therefore obtained by subsequent acetylation. O-Acetylsalicylamide on heating was converted to the N-acetyl derivative and the isomerization was followed by h.p.l.c. In contrast both m-and p-acetoxybenzamides were relatively stable. Salicylanilide and O-methylsalicylanilide, with chlorosulfonic acid gave the 1,4′-disulfonyl chlorides. On the other hand, 4′-chloro- and 4′-chloro-O-methyl-salicylanilides afforded the corresponding monosulfonyl chlorides. The i.r., n.m.r. and mass spectra, together with the algaecidal and antibacterial results are briefly discussed.

THE REACTION OF SOME SUBSTITUTED BENZILS AND HETEROCYCLIC ANALOGS WITH CHLOROSULFONIC ACID

Abstract The chlorosulfonation of a number of unsymmetrical benzils gave substituted benzofurans. Ring closure is dependent upon the electronic character of the substituent groups and can be controlled by electron-withdrawing groups. The reaction of the 2-thienyl analog gave one product but the 3-thienyl compound gave a mixture of isomers. The previously proposed mechanism can be used to explain these results.

SALICYLIC ACID SULFONYL DERIVATIVES AND RELATED COMPOUNDS

Abstract Salicylic acid-5-sulfonohydrazide (3) has been condensed with β-dicarbonyl compounds to form pyrazoles (5). With ethyl acetoacetate, tri- and hexafluoropentane-2,4-dione the hydrazones (4) were obtained; although the former did cyclise in the presence of potassium carbonate-magnesium sulfate. With hexane-2,5-dione the pyrrole (7) was formed and not the pyridazine (8). Acylation of salicylic acid-5-and p-acetamidobenzene-sulfonohydrazides was examined; mono-acetates, benzoates and p-toleuenesulfonates and diacetates are described, but other pure diacyl derivatives could not be isolated. Reaction with succinic and maleic anhydrides gave the corresponding amic acids (9, 10), and their cylisation to pyridazines (11) was examined; only the maleamic acid (10)) was converted to the pyridazine (11). Maleic hydrazide (14) by condensation with p-acetamido-benzenesulfonyl chloride gave the O-sulfonyl pyridazine (15). 5-Chlorosalicylic acid-3-sulfonohydrazide (18) was prepared and characterized as the aceton...

Chlorosulfonation of some compounds containing two phenyl rings

Abstract Diphenylmethane (1) and dibenzyl (17) reacted with chlorosulphonic acid to give the corresponding p,p′-disulphonyl chlorides (2,18). However, attempted chlorosulfonations of α-chloro-, αα′-dichlorodiphenylmethane, stilbene and 1,4-diphenylbutadiene were unsuccessful. Diphenylacetic acid reacted with chlorosulfonic acid to give a mixture of 4,4′-dichlorosulfonyl-benzophenone (40) and α-chlorodiphenylmethane-4,4′-disulfonyl chloride (39). Benzilic acid (41) afforded 9-chlorofluorene-2,7-disulfonyl chloride (42), which with amines gave 3 different products according to the reaction conditions. Fluorene (53) and the 9-carboxylic acid (43) have been treated with chlorosulfonic acid. The various sulfonyl chlorides were converted into 43 derivatives for biocidal evaluation. Mechanistic interpretations for the reactions are included.