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The title compounds, required as models in spectrometric work, have been synthesised by a six-stage route from 3-bromofuran-2-carbaldehyde diethyl acetal and the corresponding thiophen acetal.

3β-Hydroxy-5α-androstan-16-one is conveniently prepared from the readily available 3-hydroxy-17-ketone by a simple sequence which gives an overall yield of 53%

The mechanisms of two reactions which give isomeric thiazol-5-yl ketones have been elucidated by work with substrates containing pairs of acyl groups and their deuterium-substituted analogues.

Incubation of certain dioxygenated 5α-androstanes, notably 3,6-hydroxy-ketones, with Leptoporus fissilis gives 16β, 18-dihydroxy- and 16β-monohydroxy-products in combined yields of over 50%.

A convenient procedure for preparing N-mono- and N,N-di-substituted cyanamides from cyanogen bromide has been developed. N,N-Disubstituted thioureas, obtained from the cyanamides, were condensed with α-bromo-α-cyano-ketones to give 5-cyano-2-(N,N-disubstituted amino)thiazoles and with α-bromo-ketones to give 2-(N,N-disubstituted amino)thiazoles. Substitution in the latter products afforded 5-trifluoroacetyl- and 5-nitro-2-(N,N-disubstitutedamino)thiazoles; nitration is greatly facilitated by the presence of a 4-aryl group.The average values of the barriers to rotation of the 2-NR2 groups (ΔG‡298) in the 5-substituted thiazoles were established by variable temperature 1H n.m.r. spectrometry to be 57.4 kJ mol-1(5-NO2), 56.2 (5-COCF3), and 51.5 (5-CN). I.r. examinations showed that the 5-trifluoroacetyl compounds adopt one rotational form preferentially; this is probably the carbonyl O,S-syn-conformation.

The conformational preferences of 2-(N,N-disubstituted amino)thiazoles having a 4-substituent (R1) and a 5-acyl group (R2CO) have been established by i.r. spectrometry and a crystallographic examination. In solution the compounds with R2= aryl and R1= Me or aryl exist predominantly or entirely in the carbonyl O,S-anti arrangement; for those with R1= aryl and R2= Me the syn rotamer is the main form but a small amount (ca. 15%) of the anti rotamer is present.Nitrosation of 4-aryl-2-dimethylaminothiazoles gives 5-nitroso derivatives, and these are probably the first authentic nitrosothiazoles. The barrier to rotation of the dimethylamino group is unexpectedly high (ΔG298‡= 69 kJ mol–1), exceeding even that of the 5-trifluoroacetyl analogues.

Hydroxy-ketones in the 5α-androstane series are converted into fluoro-ketones by diethylaminosulphur trifluoride under mild conditions; acetoxy-ketones give acetoxydifluorides under more vigorous conditions.

N-Imidoyl-N,N-disubstituted thioureas react with α-halogeno ketones in the presence of triethylamine to give the expected 2-(N,N-disubstituted amino) thiazol-5-yl ketones in high yield. The corresponding reactions of N-acyl-N,N-disubstituted thioureas lead to mixtures of these products and isomers which arise from rearrangement between cyclic intermediates. Mixtures of the isomeric thiazolyl ketones are also formed by treating N,N-disubstituted thioureas with 2-bromo 1,3-diketones. The mixtures from the second and third routes contain the same products but in significantly different proportions. A mechanistic scheme which accounts for the main findings was developed.During the work 40 new 2-(N,N-disubstituted amino)thiazol-5-yl ketones were prepared and their structures rigorously established; characteristic mass spectral fragmentation patterns were particularly useful in identifying the substituents at positions 4 and 5 of the thiazole ring.

Solutions of 66 alkyl furan-2-carboxylates in carbon tetrachloride and in acetonitrile have been examined at high dispersion in the i.r. CO region. In carbon tetrachloride one ester shows four bands, eight show single bands, and 57 show well separated doublets. With one exception, the doublets are the consequence of rotational isomerism between syn-s-trans- and anti-s-trans-forms. The higher wavenumber component of a doublet arises from the form with the higher dipole moment and the higher enthalpy: this form is very probably the syn-s-trans-rotamer. The failure of attempts to obtain reliable free energy and entropy differences reveals the shortcomings of standard approaches to the determination of energy differences between rotational isomers from i.r. data.

The NH and CO bands of solutions of pyrrole-2-carboxylates, pyrrole-2-carbaldehydes, and their N–Me analogues have been studied. Knowledge gained from the spectra of the aldehydes, which are known to adopt the N,O-syn-conformation, was applied in deducing the conformational preferences of the esters from their i.r. absorptions. The N-Me esters exist predominantly or exclusively in the N, carbonyl O-syn-arrangement. With the N–H esters both syn- and anti-rotamers are present, the former predominating, and in the case of t-butyl pyrrole-2-carboxylate the syn-form was shown to be thermochemically more stable than the anti-form by ca. 4.8 kJ mol–1. The intermolecular associations of pyrrole-2-carbaldehyde and of t-butyl pyrrole-2-carboxylate give species containing more than two molecules of the substrates and involve similar enthalpy changes (ca. 22 kJ mol–1).

Procedures are described for converting primary amines into their well-crystalline trichloroacetyl-derivatives by treatment with hexachloroacetone under mild conditions. Although secondary aromatic N-methylamines are unaffected by hexachloroacetone, saturated heterocyclic amines react vigorously.A mechanistic study using 2-amino-4-t-butylthiazole showed that the reaction is first order in hexachloroacetone, second order in amine, and base-catalysed; there is no appreciable kinetic isotope (H/D) effect nor accumulation of intermediates during the reaction. A sequence which accommodates these results is suggested.

The possible occurrence of rotational isomerism in 35 thiophen- and furan-2-carbonyl fluorides and chlorides has been investigated by n.m.r. and i.r. spectrometry. At room temperature, solutions of the fluorides in trichlorofluoromethane, carbon tetrachloride, and acetonitrile contain appreciable amounts of the syn- and anti-rotamers. With furan-2-carbonyl fluoride, the compound investigated in most detail, the rotamer giving the higher field 19F signal in non-polar solvents at low temperature corresponds to the rotamer of the 5-deuterio-analogue which has the higher wavenumber CO band; these are the predominant forms (ca. 70% in trichiorofluoromethane) and are thought to be the syn-rotamers. It is probable that the chlorides also exhibit rotational isomerism, but the absence of halogen n.m.r. evidence makes the interpretation less certain.

43 2-Oxofurans have been examined at high resoultion in the i.r. CO region. The CO doublets observed for furan-2-carbaldehyde (and six related aldehydes) originate in Fermi resonance and not rotational isomerism: the CO stretching bands of the two rotational isomers in these systems must have almost exactly equal wave-numbers.

Protection of a primary amine group against attack by organic or aqueous solutions of strong bases or nucleophiles is achieved by incoporation into an N- substituted 2,5-dimethylpyrrole system from which the amine group is regenerated by treatment with hydroxylamine hydrochloride.

The reaction between N-benzoyl-N′-methyl-N′-phenylthiourea and chloroacetone gives 5-benzoyl-4-methyl-2-(N-methyl-N-phenylamino)thiazole rather than the 5-acetyl-4-phenylisomer which would be predicted from previous work on this route to thiazoles.

Solutions of the methyl and t-butyl esters of o-, m-, and p-fluoro-, -chloro-, and -bromo-benzoates have been examined in the i.r. CO region. All but one of the o- and p-esters show doublets whereas the m-isomers give single bands. The doublets of the o-esters arise from rotational isomers, the thermochemically less stable syn-s-trans forms absorbing at higher wavenumbers than the anti-s-trans rotamers; those of the p-isomers are caused by the operation of Fermi resonance. It is probable that the rotamers of the m-esters have similar CO wavenumbers. A convenient, safe procedure for preparing t-butyl esters has been developed.

A study has been made of the condensations between N-acyl-N′,N′-disubstituted thioureas and α-halogeno ketones [reaction (I)], and between N,N-disubstituted thioureas and 2-bromo-1,3-diketones [reaction (II)]. The mechanistic details were elucidated by using substrates with pairs of (almost) equally reactive but spectrometrically distinguishable acyl groups, e.g., CH3CO and CD3CO. In the presence of added base (triethylamine) both reactions proceed through a common open-chain 1,3-diketone; from this, isomeric products are formed by nucleophilic attack at the alternative carbonyl groups to give cyclic intermediates which then undergo rate-limiting dehydration. If base is not added the media become acidic. Reaction (II) follows its previous course but the relative rates of the stages are reversed. In reaction (I) the initial cyclic intermediate is dehydrated so rapidly that the open-chain 1,3-diketone is not formed, and only one isomer is produced.Both reactions are useful preparatively. For example, by adding or omitting triethylamine a typical reaction (I) was induced to give 1-(5-p-methoxybenzoyl-4-p-nitrophenylthiazol-2-yl)hexahydroazepine (yield 79%) or the isomeric 4-p-methoxyphenyl-5-p-nitrophenyl compound (78%).

5-Acetyl-2-(N,N-disubstituted amino)thiazoles, unsubstituted or with Me, But, or Ph groups at position 4, have been prepared by unambiguous methods and examined spectrometrically; crystallographic studies have been carried out on four of the compounds and a related 4-aryl-5-trifluoroacetylthiazole. In solution the 4-H, 4-But, and 4-Ar compounds exist predominantly in one conformation but with the 4-Me compounds, two forms (carbonyl O,S-syn or anti, related by rotation of the 5-acetyl group) of approximately equal stability are present. The X-ray work establishes that for 5-acetylthiazoles, as solids, the 4-H and 4-Ph derivatives have the carbonyl O, S-syn stereochemistry whereas the 4-Me and 4-But derivatives have the anti arrangement; in contrast with the 5-acetyl-4-phenyl compound the 4-aryl-5-trifluoroacetylthiazole adopts the anti arrangement. These findings validate a correlatioh, for solutions, between the stereochemistry of the rotational isomers and the positions of their i.r. CO bands.The results confirm the operation of a strong mesomeric interaction between the 2-NR2 and 5-CH3(CF3)CO groups.

Efficient preparations of 4- and 5-phenyl-4,5-dihydropyridazin-3(2H)-ones have been developed, the main reactions of these compounds have been studied, and the synthetic routes have been used to give analogues with substituents in the phenyl rings.In the best synthesis of the 4-phenyldihydropyridazinone (72% overall yield) the product was obtained from phenylacetic acid by three simple stages. This approach was applied in preparations of the 2- and 4-hydroxyphenyl compounds and, in conjunction with a recent method for amine protection, the 4-aminophenyl analogue. A four stage synthesis starting from benzaldehyde gave the 5-phenyl-dihydropyridazinone in 47% overall yield; hydroxybenzaldehydes were similarly converted into 5-(allyloxyphenyl)dihydropyridazinones.Oxidation to phenylpyridazinones occurred more readily with the 4- and 5-phenyldihydropyridazin-ones than with the 6-phenyl isomer. The 4- and 5-dihydropyridazinones were smoothly reduced to tetrahydropyridazinones by hydrogenation over platinum but were unaffected by palladium in the presence of hydrazine or cyclohexene.

Series of new 4- and 5-substituted thiazoles with acetamido-, mono-, di-, and tri-chloroacetamido-, and trifluoroacetamido-groups at position 2 have been prepared. Amide-acylimine tautomerism in these compounds has been investigated by comparing their i.r. and u.v. spectra in carbon tetrachloride and in acetonitrile with those of related 2-N-methylacetamido- and 3-methyl-2-acetylimino-thiazoles. The trichloro- and trifluoro-acetamides exhibit tautomerism in both solvents; the acylimine-forms are most stable with the trifluoro-compounds in the more polar solvent.

Protection of a primary amine group is achieved by incorporating it into an N-substituted 2,5-dimethylpyrrole system. The method affords protection against strong bases and nucleophiles, heating with concentrated alkali, standard mineral acid work-up conditions, and various other reagents.Phenyl-, pyridyl-, thiazolyl-, and alkyl-amines have been studied. All give trisubstituted pyrroles in high yield (>80%) by reaction with hexane-2,5-dione. The pyrroles from the first three types are stable to storage; even the N-alkyl compounds can be used without difficulty. Regeneration of the amine group, by treatment with hydroxylamine hydrochloride, is efficient (ca. 80% yield) with the phenyl, pyridyl, and alkyl compounds but less satisfactory (60–65% generally but down to 25% in two cases) with the thiazolyl derivatives.

Solutions of α-mercapto-ketone anions, generated from O-ethyl S-2-oxoethyl dithiocarbonates and piperidine, react with cyanamides to give 2-aminothiazoles with substituents on the heterocycle or the exo-nitrogen atom.

Although α-mercapto ketones react with cyanamides to give substituted 2-aminothiazoles the yields are satisfactory in only the simplest cases. However, a range of 2-aminothiazoles with substitutents on the ring or the exo-nitrogen atom was obtained efficiently by the following one-pot procedure: a solution of an α-mercapto ketone anion was generated by treating an O-ethyl S-2-oxoethyl dithiocarbonate with piperidine at 20 °C, a cyanamide was added, and the solution was heated for 3–6 h.

Efficient methods for the preparation of the compounds listed in the title have been developed. Examination of their 1H n.m.r. spectra showed that in these substituted dihydronaphthalenes the ring containing the olefinic bond is conformationally mobile. Study of the deuteriated derivatives was useful in interpreting the gross spectrometric features of the parent compounds but did not simplify the detailed analysis.

The condensation of α-halogeno ketones with N-monosubstituted thioureas in neutral solvent leads exclusively to 2-(N-substituted amino)thiazoles. In the present work it was shown that under acidic conditions mixtures of 2-(N-substituted amino)thiazoles and 3-substituted 2-imino-2,3-dihydrothiazoles are formed. (The isomers were distinguished by characteristic differences between their 5-H 1H n.m.r. signals and the i.r. CO bands of their trifluoroacetate derivatives.) The proportions of the 2-imino-2,3-dihydrothiazoles in the mixtures are influenced by experimental features and by the structures of the starting materials. Reactions in 10M-HCl-EtOH (1 :2) at 80 °C for 20 min were found to be the most efficient for generating 2-imino-2,3-dihydrothiazoles; in the most favourable case 2-imino-3,4-dimethyl-2,3-dihydrothiazole was obtained in 73% yield.A possible explanation of the results is discussed.

Methods for preparing N,N-disubstituted 2-aminothiazoles have been investigated. 4-Substituted N,N-dimethyl-, N-benzyl-N-methyl-, and N-methyl-N-phenyl-amines were prepared and converted by Vilsmeier formylation into 2-amino-5-carbaldehydes which were examined by i.r. and 1H n.m.r. spectrometry. The aldehyde group adopts the carbonyl O,S-syn-conformation. With the N,N-dimethyl and N-benzyl-N-methyl compounds the barrier to rotation of the amine group (ΔG‡) is 50–55 kJ mol–1 and is insensitive to the nature of the 4-substituent. The amine group of the N-methyl-N-phenyl compounds has a marked preference for one orientation. This was shown by a crystallographic study of 4-t-butyl-2-(N-methyl-N-phenylamino)thiazole-5-carbaldehyde to have the phenyl group directed towards the sulphur atom of the thiazole ring.The results of the physical methods overlap in establishing the importance of a mesomeric interaction between the functional groups of 2-aminothiazole-5-carbaldehydes.

A series of alkyl thiazole-2-carboxylates containing a range of substituents at the 4- and 5-positions has been prepared. Solutions of these esters (mostly new compounds) show well resolved doublets in the i.r. CO region which arise from rotational isomers. The higher wavenumber components are assigned to the more polar carbonyl O,S-anti-s-trans-rotamers and the lower wavenumber components to the carbonyl O,S-syn-s-trans-forms. Small, but systematic, differences between the methyl esters are noted.

Methods have been developed for introducing deuterium at some or all of the furan and thiophen ring positions. The compounds prepared include all the mono-, di-, and tri-deuteriofuran-2-carbaldehydes and -2-carboxylic acids, 5-deuteriofuran-2-[2H]carbaldehyde, and the monodeuteriothiophen-2-carbaldehydes. Furyl- and thienyl-lithium compounds are the key intermediates for replacing hydrogen or halogen atoms by deuterium, and for carrying out selective reactions at the α- or β-positions of the heterocyclic rings.

A series of heterocyclic 2-carbaldehydes and 2-[2H]carbaldehydes have been prepared, most of them by Vilsmeier formylation of mono- and di-substituted furans and thiophens. Isopropylation of methyl furan-2-carboxylate was used to obtain the 4- and 5-monoisopropyl- and 4,5-di-isopropyl-furan-2-carboxylic acids. With different aryl 2-furyl ketones bromine may attack either the benzenoid ring or the heterocyclic ring preferentially.

The O–H stretching absorptions of aryldi-t-butylmethanols are composed of three symmetrical bands. These are assigned to antiperiplanar H–O–C–Ar arrangement, and two synclinal forms which are distinguished by the presence or absence of O–H ⋯π-electron interaction. N.m.r. evidence suggests that interconversion between the synclinal forms, involving only a partial rotation about the Ar–C axis, is rapid at 34 °C; complete rotation is more severely impeded.The measurement of enthalpy differences confirms the occurrence of intramolecular bonding in benzyl alcohol and dimethylphenylmethanol.

Convenient routes from readily available starting materials to furan- and thiophen-2-carboxylic acids with substituents (mainly halogen atoms) at various positions are described. A series of esters (methyl, ethyl, t-butyl, and 17-oxo-5α-androstan-3β-yl) have been prepared from these acids and from the unsubstituted heterocyclic 2-carb-oxylic acids.Methyl furan-2-carboxylate reacts with bromine in the presence of aluminium chloride to give the 4,5-dibromo-ester. The presence of 1,2-dichloroethane changes the course of the reaction, the product then being the 4-bromo-5-chloro-ester. Furan-2-carbaldehyde shows the opposite behaviour, giving as the main products the 4-bromo-5-chloro-aldehyde in the absence of a solvent and the 4,5-dibromoaldehyde when 1,2-dichloroethane is present. Careful control of conditions is necessary in the preparation of 4-bromothiophen-2-carbaldehyde from thiophen-2-carbaldehyde, bromine, and aluminium chloride.