Derek J. Chadwick

2,3-Dimethylene-2,3-Dihydrothiophene: The thiophene analogue of ortho-xylylene

Abstract The hitherto unknown 2,3-dimethylene-2,3-dihydrothiophene (the thiophene analogue of ortho-xylylene) and a substituted derivative have been prepared in solution and trapped as Diels-Alder adducts in good to excellent yields.

High-yield syntheses of 2,3-disubstituted furans and thiophenes

Abstract The course of lithiation of furan- and thiophene-2-carboxylic acids is critically dependent on the identity of the lithium base allowing high-yielding syntheses of 2,3- and 2,5-disubstituted thiophenes: the proposed use of a trimethylsilyl blocking group to control metallation in the furan acid provides a useful route to 2,3-disubstituted furans.

High-yielding syntheses of 4(5)-substituted imidazoles via organolithium intermediates. the utility of sulphonamide n-protection and silicon-containing blocking groups

Abstract N -Protection of imidazole as its N , N -dimethyl-sulphonamido derivative, and blocking of the 2-position with the triethylsilyl group permits regioselective 5-metallation with sec-butyl-lithium. The resulting organolithium intermediates react with a range of electrophiles and the products are easily deprotected to give the 4(5)-substituted NH-free imidazoles in good to excellent yields. Isolation of the silicon-blocked intermediate is unnecessary and, indeed, is disadvantageous to final yields, making the procedure attractively economical of time.

Conformational analysis—III: A lanthanide induced shift (LIS) NMR investigation of benzaldehyde, and thiophen- and furan-2-aldehyde

Abstract A rigorous error analysis of LIS is described which avoids the use of any normalising atom. This analysis is used to investigate the LIS of benzaldehyde and thiophen- and furan-2-aldehyde. The non pseudo-contact components of theYb(fod)3 induced shifts are isolated and found to be appreciable at the carbonyl carbon and the ortho and para carbons. Estimation of the diamagnetic contribution to these shifts withLa(fod)3 allows a precise analysis of the1H and13C LiS of these aldehydes without the need to invoke any contact shifts. The lanthanide-complex geometry found is essentially one-site, i.e. 100% population on the unhindered exo side of the carbonyl. The lanthanide is in the molecular plane of the aldehydes with Ln O and Ln.O.C. parameters ofca 2.5A˚and 140°, respectively. This procedure also gives the percent population of the O-cis conformer of furfural asca 70–75% in CDCl3 solution.

A lanthanide induced shift (LIS) investigation of the conformation of cyclohexanones in solution

Abstract The solution conformations of cyclohexanone 1 and 4- t -butyl cyclohexanone 2 have been obtained by the use of the LIS given by Yb(fod) 3 . A starting geometry for the substrates was obtained by molecular mechanics calculations. The use of a two-site model for lanthanide-substrate complexing, together with iteration on the 1 H and 13 C induced shifts allowed the angle of pucker of the cyclohexanone rings to be determined. In contrast, a one-site model gave no acceptable solutions. The cyclohexanone ring is somewhat flatter at the carbonyl end than cyclohexane, the angle of pucker (α) being reduced from 51° to 49° i.e. the dihedral angle (ω 12 ) is reduced trom 56 to 51°. In 4- t -butyl-cyclohexanone the angle of pucker at the carbonyl end is further reduced. The solution conformation of 1 agrees closely with that deduced by MM calculations; interestingly, the conformation of 2 is essentially identical with the geometry found in the crystal.

Conformational analysis-V.: A lanthanide induced shift (L.I.S.) N.M.R. investigation of conformational isomerism in aromatic aldehydes and ketones

Abstract An L.I.S. N.M.R. investigation of conformational isomerism in meta-nitrobenzaldehyde and furan- and thiophene-3-aldehydes, and of the conformation of acetophenone has been carried out. With the diamagnetic (complexation) contributions to the observed shifts removed by means of experiments with La (fod)3 and the application of our previously-described lanthanide ion complexing model, the pseudo-contact shifts have been used to obtain the precise conformational preferences of the aldehydes. They exist to the extent of 45%, 100% and 80% respectively in the O - trans conformation, findings which are good agreement with the previously-reported values. The L.I.S.s for acetophenone are in best agreement with a planar molecule, although the definition is not as good in this case. These examples suggest that the L.I.S. technique is of general applicability in the determination of conformer populations and the conformations of aromatic aldehydes and ketones.

The protecting–directing role of the trityl group in syntheses of pyrrole derivatives: efficient preparations of 1-H-pyrrole-3-carboxylic acid and 3-acyl-, 3-amino-, and 3-bromo-1-tritylpyrroles

Trifluoroacetylation, formylation, and bromination of 1-tritylpyrrole occur regioselectively at the 3-position in high yields. Quantitative hydrolysis of the 3-trifluoroacetyl derivative and removal of the trityl group from the resulting acid with sodium in liquid ammonia furnishes a new, short, high-yielding synthesis of the simple 1-H-pyrrole-3-carboxylic acid. 1-Tritylpyrrole-3-carboxylic acid has been converted efficiently into 3-aminopyrroles via Curtius rearrangement of the derived azide: 3-amino-1-tritylpyrrole appears to exist in solution exclusively as its imino-Δ4-pyrroline tautomer. 1-H-3-t-Butyloxycarbonylaminopyrrole undergoes trifluoroacetylation regioselectively at the 2-position. Metallation of 1-tritylpyrrole with butyl-lithium in hexamethylphosphoric triamide gives rise to the unexpected products 9-phenylfluorene, 1-methoxycarbonylpyrrole and methyl triphenylmethylacetate (after work-up of the lithiointermediates with carbon dioxide and methylation of the resulting acids).The mechanism proposed for the reductive cleavage of the trityl group in 1-tritylpyrrole is supported by the results of cyclic voltammetry experiments.

Conformational analysis—II1: A lanthanide-induced shift nmr and theoretical study of bicyclo [3.1.0] hexan-3-one and adamantanone

Abstract The solution conformation of bicyclo [3.1.0] hexan-3-one has been obtained by the use of the shifts induced in its 1H and 13C NMR by Yb(fod)3. Refinement of the angle of pucker, ∝, of the 5-membered ring indicates that the molecule adopts a flattened boat conformation with ∝ = 195°. This prediction is supported by ab initio, STO-3G, calculations on the isolated molecule. Use of a two- or four-site model for lanthanide-substrate complexing adequately reproduces the experimental data whereas a one-site binding model is unsatisfactory. The importance of multi-site binding is further emphasised by results for the C2v-symmetric ketone, adamantanone, where only a four-site model gives satisfactory agreement between observed and calculated lanthanide-induced shifts.

Regioselective α- and β-metallations of thiophene derivatives bearing the 4,4-dimethyloxazolin-2-yl group. Application of the method to syntheses of 2,3- and 2,5-disubstituted thiophene derivatives

The effects of change of solvent, metallating agent, reaction time and temperature, and of the presence or absence of agents capable of complex formation with either the lithium cation or the oxazoline moiety, on the lithiation of 4,4-dimethyl-2-(2-thienyl)oxazoline are explored. Conditions are thereby estab-lished for high-yielding syntheses of the 3- and 5-lithio-intermediates and for control of regioselectivity of metallation. The nucleophilicity of the 3-lithio-intermediate is profoundly solvent dependent, and appropriate conditions for reaction of both 3- and 5-lithiated species with a wide variety of electrophiles are presented. Syntheses of a range of 2,3- and 2,5-disubstituted thiophene derivatives have thereby been achieved, utilising, in addition, a new method for the transformation of oxazolino into carboxy functionality.The balance between basicity and nucleophilicity of the 3-lithio-intermediate in its reaction with [1H6]- and [2H6]-acetone is shown to be sensitive to isotope effects.

Regioselective β-metallations of 2-substituted furan and N-methylpyrrole derivatives employing the directing effect of the oxazolino group: syntheses of 2,3-disubstituted furans and N-methylpyrroles

The effects of change of solvent and reaction time, of addition of Li+-chelating agent, and, in some instances, of change of temperature and metallating agent, on the metallation of 2-(2-furyl)- and 2-(N-methylpyrrol-2-yl)oxazolines by alkyl-lithium reagents are explored. Conditions are thereby established for high-yielding syntheses of lithio-intermediates and for control of regioselectivity of metallation. Syntheses of pure samples of 2-(3-hydroxyphenylmethyl-2-furyl)-, 2-(5-hydroxyphenylmethyl-2-furyl)-, 2-(3-carboxy-N-methylpyrrol-2-yl)- and 2-(5-carboxy-N-methylpyrrol-2-yl)-4,4-dimethyloxazolines, based on the results of these investigations, are reported.