John B. Weston

Nitrone cycloadditions: synthesis of (±)-andrachamine

The usefulness of the cycloaddition of alkenes to 2-alkyl-2,3,4,5-tetrahydropyridine oxides for the preparation of trans-2,6-dialkylpiperidines is confirmed by a stereoselective synthesis of (±)-andrachamine. Peroxy acid oxidation of 9-oxa-1-azabicyclo[4.3.0]nonanes does not lead regioselectively to the corresponding 2-alkyl-2,3,4,5-tetrahydropyridine oxide, as had previously been claimed.

Nitrone cycloaddition: an approach to the cyclophane alkaloid (±)-lythranidine

The synthesis of (±)-lythranidine 1, a cyclophane alkaloid from Lythrum anceps Makino, involves three interesting problems. These are the construction of the 17-membered ring, the formation of the trans- 2,6-dialkylpiperidine and the establishment of the correct relative stereochemistry at the four asymmetric centres (C-3, C-5, C-9, C-11). In our approach to the synthesis of this alkaloid, the trans-dialkylpiperidine was formed via a nitrone cycloaddition reaction. Cyclisation to give the 17-membered ring was achieved using tris(triphenylphosphine)nickel(o), prepared in situ from bis(triphenylphosphine) nickel dichloride, and the di-iodide 9. Deprotection of macrocyclic biaryl 10 gave the (C-3, C-11) epimer of (±)-lythranidine.

Electrophilic aromatic substitution. Part XV. The kinetics, mechanism, and products of nitrodebromination in sulphuric acid

The kinetics of nitration in sulphuric acid of o- and p-dibromobenzene, p-bromo- and p-chloro-toluene, 2-bromo-m-xylene, and p-bromochlorobenzene are reported. For these compounds and for bromobenzene and p-bromofluorobenzene the yields of products formed over a range of acidities have been determined. Nitrodebromination was not detected with o-dibromobenzene and 2-bromo-m-xylene, but was a major outcome of nitrating p-dibromobenzene, p-bromotoluene, and p-bromochlorobenzene. The degree of nitrodebromination increased with increasing dilution of the sulphuric acid and evidence is provided to show that Wheland intermediates formed at brominated carbon atoms (WiBr) are either debrominated or rearranged by nitro-group migration. There is no intramolecular migration of bromine and little or no nucleophilic capture of the Wheland intermediates.When methyl groups are present ipso-nitration at C(Me) occurs and is followed by nucleophilic capture by water and by nitro-group migration in proportions which varied with the acidity. Nitrodechlorination was not observed, but even if attack at C(Cl) is assumed to occur a choice between subsequent decomposition of the Wheland intermediate to its components and nitro-group migration cannot be made. In p-dibromobenzene the C(Br) positions are at least as reactive as the C(H) positions.

Electrophilic aromatic substitution. Part 16. The nitration of anisole, o-methylanisole, and p-methylanisole in aqueous sulphuric acid

In the quantitative mononitration of anisole in 54–82% sulphuric acid at 25° the o : p ratio varies from 1.8 to 0.7. It is suggested that the rate-limiting step is the formation of an encounter pair between the nitronium ion and an anisole molecule which is hydrogen-bonded to a hydronium ion. The change in the o : p ratio may be due to competition between direct formation of Wheland intermediates from the hydrogen-bonded encounter pair, and loss of the hydronium ion to give a nitroniurn ion–anisole encounter pair, with subsequent formation of Wheland intermediates. With o- and p-methylanisole the products, and changes in product ratios with acidity are interpreted by considering the fates of the ipso-Wheland intermediates formed at C–Me. 4-Methyl-2-nitrophenol is an important product of the nitration of p-methylanisole, and results from ipso-attack by nitronium at C–Me, followed by attack of water and loss of methoxy.

Cycloaddition of 2,3,4,5-tetrahydropyridine N-oxide to vinyl ethers. Enantioselective synthesis of 2-(N-benzylpiperidin-2-yl)ethanol

The title compound has been obtained in high optical purity by cycloaddition of 2,3,4,5-tetrahydropyridine N-oxide and (R)-2,2-dimethyl-1-phenylpropyl vinyl ether followed by N-benzylation and reduction of the salt with lithium aluminium hydride.

Nitrone cycloaddition: peroxy acid oxidation of 2-phenyl-1-oxa-9-azabicyclo[4.3.0]nonane

Oxidation of 2-phenyl-1-oxa-9-azabicyclo[4.3.0]nonane (5) with m-chloroperoxybenzoic acid is not regioselective, in contrast to the case with the corresponding 1-oxa-8-azabicyclo[3.3.0]octane (2; n= 1, R1= H, R2= Ph), affording mainly the keto-nitrone (7). On reaction with styrene in boiling toluene the latter forms the oxabicyclononane (9).

Electrophilic aromatic substitution. Part XIII. Kinetics, isomer yields, and the consequences of ipso-attack in the nitration of toluene and polymethylbenzenes in aqueous sulphuric acid, and their significance for the mechanism of aromatic nitration

Toluene, o-xylene, m-xylene, 1,2,4-, and 1,2,3-trimethylbenzene give yields of mononitro-isomers which vary with the percentage of sulphuric acid in a way which depends on (a) the medium dependence of the relative reactivities of the various substituted and unsubstituted positions in the molecule and (b) the partitioning of Wheland intermediates formed at substituted (ipso) positions between rearrangement and nucleophilic capture. Nitration of all the polymethylbenzenes studied occurs at closely similar rates, the encounter rate between the aromatic compound and the nitronium ion, yet positional selectivity does not disappear under these conditions, showing the necessity of including in the kinetic scheme an intermediate preceding Wheland intermediate formation.

5-Thiorotenoids: a new synthesis of general applicability to rotenoids

A new synthesis of general utility for rotenoid structures is reported and applied to the specific case of 5-thiorotenoids.

Electrophilic aromatic substitution. Part 22. The nitration of some reactive aromatics in methanesulphonic acid, and the question of positional selectivity in encounter rate nitrations of substituted naphthalenes and 1,2-diphenylethanes

Nitrations in aqueous methanesulphonic acid are shown by the steep acidity dependence of the rate constants, the identification of a kinetic form zeroth-order in the concentration of the aromatic, and the existence of a limiting rate constant identified as the encounter rate constant, most probably to involve the nitronium ion.2-Methyl-, 2-methoxy-, and 2-methoxy-6-methyl-naphthalene react at the encounter rate. In the last compound the ratio of reactivities of C-1 and C-5 is 6.5 : 1 (smaller than that reported by other workers because of the suppression of nitrosation). Comparison amongst the three compounds suggests that in the nitration of 2-methoxy-6-methylnaphthalene the rate-controlling step is the irreversible formation of an encounter pair which is sufficiently long-lived and mobile to allow selection between positions of differing reactivities in the following product-controlling step of σ-complex formation. The case resembles that of the nitration of 1,2,4-trimethylbenzene reported earlier.Mesitylene, 3,5-dimethoxytoluene, and 1-(3,5-dimethoxyphenyl)-2-(3,5-dimethylphenyl)ethane react at the encounter rate (with the two methoxylated compounds account has to be taken of the effect upon their performances of ring protonation). In the unprotonated diarylethane the ratio of reactivities (1.8) of the methoxylated and and the methylated rings is very close to the ratio of reactivities (1.4–1.5) of the mononuclear compounds. The small selectivity between the two rings in the unprotonated diarylethane shows that the compound is nitrated by the formation of two non-interconverting encounter pairs, formation of which is both rate- and (so far as intranuclear behaviour is concerned) product-determining.Although 1-(3,5-dichlorophenyl)-2-(3,5-dimethylphenyl)ethane also reacts at the encounter rate (being nitrated only in the methylated ring), comparison with the previously mentioned diarylethane shows that a statistical factor (not exactly 2 because of the slightly differing efficiencies of the two rings in the dimethoxylated compound in forming productive ion pairs) has to be taken into account in comparing the two compounds.The behaviour of these various compounds in no way requires the assumption of bonding forces between electrophile and aromatic in the encounter pair, but the performance of 1-(3,5-dimethoxyphenyl)-2-(3,5-dimethylphenyl)-ethane could be very easily understood if the two encounter pairs were π-complexes, or involved some other kind of stabilisation.

Positional selectivity in aromatic nitration occurring at the diffusion rate

Nitration of pseudocumene (1,2,4-trimethyl-benzene) produces 5- and 6-nitropseudocumenes in the ratio 9:1 under conditions where there is evidence that both C-5 and C-6 are activated sufficiently to react upon encounter, showing the necessity for including in the kinetic scheme an intermediate preceding Wheland intermediate formation.