Francesco Del Cima

Stereochemistry of ring enlargements with bridged systems. Comparison of the nitrous acid deamination of endo- and exo-2-aminomethylbicyclo[3.2.1]octan-2-ol with the reaction between bicyclo[3.2.1]-octan-2-one and diazomethane

The synthesis and nitrous acid deamination of exo- and endo-2-aminomethylbicyclo[3.2.1]octan-2-ol are described. The product distribution is markedly dependent on the amino-alcohol stereochemistry and comparison with the product distribution for the diazomethane ring enlargement of bicyclo[3.2.1]octan-2-one suggests that diazomethane attacks the carbonyl group preferentially from the exo-side (equatorial direction). A similar study with bicyclo[2.2.1]heptane systems is also reported.

The reactivity of pseudoaromatic compounds. Part IV. Normal substitutions of 2-substituted tropones by secondary or tertiary amines; abnormal behaviour of 2-fluorotropone

2-Fluorotropone reacts with piperidine in benzene to give 2-piperidinotropone quantitatively. Experiments with 2-fluoro[3,5,7-2H3]tropone show normal substitution of fluorine by the nitrogen atom of piperidine. A kinetic investigation shows (i) that this reaction is of overall second-order (first-order with respect to both reagents) and (ii) that the free energy of activation is 4–5 kcal mol–1 lower than the corresponding values found for 2-chloro-, 2-bromo-, 2-iodo-, and 2-methoxy-tropone. Clearly, the reaction does not follow the isokinetic relationship observed for the other tropones. The behaviour of 2-fluorotropone towards quinuclidine depends on the solvent; in dimethyl sulphoxide, substitution of fluorine by quinuclidine gives 1-{2-[N-oxocyclohepta-1,3,5-trien-1-yl)-piperidin-4-yl]ethyl}-1-azoniabicyclo[2,2,2]octane fluoride at a rate comparable to that for similar reaction of 2-iodo- or 2-chloro-tropone, but in benzene at room temperature 2-fluorotropone does not react with quinuclidine unlike the chloro- or iodo-compound. Under reflux, only intractable tars are obtained.1-Halogeno-2,4-dinitrobenzenes behave similarly; they undergo clean substitution of the halogen atom by protic amines in both dimethyl sulphoxide and benzene. However, the fluoro-compound is unreactive towards quinuclidine whereas under similar conditions the chloro-compound gives 1-{2-[N-(2,4-dinitrophenyl)piperidin-4-yl]ethyl}-1-azoniabicyclo[2,2,2]octane chloride. Under forcing conditions piperidinium 2,4-dinitrophenolate is formed by hydrolysis (due to moisture) of 1-fluoro-2,4-dinitrobenzene. Intramolecular base catalysis by the ‘carbonyl’ oxygen atom is suggested as the basis of the isokinetic relationship in the reactions of the troponoid system with protic amines, and the observed data are consistent with this hypothesis.

On the stereochemistry of Grignard addition to bicyclo[3.3.1]nonan-2-one. Preferential axial attack on a cyclohexanone system by a bulky nucleophile

Bicyclo[3.3.1]nonan-2-one (1) reacts with methylmagnesium iodide to give, in a high overall yield, a 19:1 mixture of exo-2-methylbicyclo[3.3.1]nonan-2-ol (2) and the endo-epimer (3), respectively. The high propensity of compound (1) for axial attack by a bulky reagent, such as a Grignard reagent, is atypical of bridged cyclohexanones. Possibly, flattening of the bicyclo[3.3.1]nonan-2-one skeleton favours axial attack. Results of the oxymercuriation–demercuriation of related olefins is in accordance with this view.

A route to 6-functionalised 1,3-diaza-azulenes and aminotropones via hydride replacement from cycloheptatrienones

4-Methylthiotropone regiospecifically cyclises with toluamidine in benzene, but less readily in dimethyl sulphoxide, to give 6-methylthio-2-p-tolyl-1,3-diaza-azulene. With dimethylamine hydride replacement occurs in dimethyl sulphoxide (but not in benzene) at both C(7) and C(2)(ca. 1 : 1 ratio) to give the corresponding amino(methylthio)tropones which are slowly de(methylsulphenyl)ated in the reaction medium. This reaction is favoured by oxidising agents such as potassium ferricyanide. In contrast, 4-methoxy-, 4-dimethylamino-, and 2-dimethylamino-substituents inhibit reactions by both amidines and amines with the cycloheptatrienone nucleus. Further attempts directed at obtaining 4-functionalized 1,3-diaza-azulenes failed because both 2-ethylthiotropone and 2-dimethylsulphoniotropone tetrafluoroborate cyclise with benzamidine to give the corresponding 1,3-diazaazulene with loss of sulphur.

On the reactions of alkanedithiols with picryl halides

The reaction of picryl chloride with ethane-1,2-dithiol and base leads to a spiro-σ-adduct via the initially formed 2-picrylthioethanethiol. Similar behaviour has been found with propane-1,3-diol and picryl iodide. In contrast, with propane-1,3-dithiol in place of ethane-1,2-dithiol the initially formed 3-picrylthiopropane-1-thiol collapses via intramolecular displacement of an ortho-nitro-group; no spiro-σ-adduct was detected. With butane-1,4-dithiol or pentane-1,5-dithiol and picryl chloride only polymers were isolated.

Pseudoaromatic compounds. Part XXII. Reactions of 2-functionalized tropones with sodium toluene-p-thiolate

Relative rates for replacement, without rearrangement, of the X group of some 2-X-tropones by sodium toulene-p-thiolate in dimethyl sulphoxide are in the order 82,2.6,3.5,1.0,and ca. 29 000 for X = F,Cl,Br,I, and N[CH2CH2]3-CHI–, respectively, whilst with X = OCH3 slow demethylation occurs instead. The rate of replacement of the quinuclidinium group has been computed for the free reagents present in equilibrium with an adduct which lies off the reaction co-ordinate. These data give support to the idea that ready replacement of strongly bound X groups, such as fluorine or methoxy, of 2-X-tropones by primary or secondary amines is due to stabilisation of the transition state by proton bridging among the protonated nitrogen, the tropone carbonyl oxygen, and for fluorine, the leaving-group.

Ring enlargement of bicyclo[3.3.1]nonan-2-one with diazomethane

Bicyclo[3.3.1]nonan-2-one reacted with ethyl N-nitrosomethylcarbamate to give bicyclo[4.3.1]decan-2- and -3-one, reduction of which gave the parent bicyclodecane, and a small amount of bicyclo[3.3.1]nonan-2-spirooxiran.

Regiospecific amination of deactivated cycloheptatrienones via hydride replacement

3-Dialkylaminotropones and 3-alkoxytropones can be regiospecifically aminated at C-7 with either primary or secondary amines in benzene, whilst 3-alkyl-aminotropones resist amination.

The origin of high ortho:para-reactivity ratios in the reactions of fluoronitrobenzenes with potassium t-butoxide in t-butyl alcohol

Kinetic data for fluorine substitution of 1-fluoro-2- or 1-fluoro-4-nitrobenzene by potassium methoxide in methyl alcohol in the presence or absence of added dicyclohexyl-18-crown-6 or by potassium t-butoxide in t-butyl alcohol in the presence of the crown ether are reported. The crown ether has a negligible influence on the kinetics of the reactions of potassium methoxide where the ortho:para-activation ratio is around unity. In sharp contrast, comparison with previous data for the reactions of the same substrates with potassium t-butoxide in t-butyl alcohol shows that on addition of the crown ether (in equimolar quantities to the nucleophile, with consequent nearly total removal of potassium cation from the bulk system), the rate of reaction of the o-nitro-substituted substrate is increased by only a factor of three while that of the p-nitro-substituted substrate is increased by a factor of nearly 2000. Consequently, the ortho:para-ratio changes from 3·6 × 102 in the absence to ca. 1 in the presence of the crown ether. These results show that the high value of the ortho:para-ratio obtained in t-butyl alcohol in the absence of addenda can be attributed mainly to specific stabilization of the transition state of the reaction of the o-nitro-substituted substrate by potassium cation bridging between the nucleophile and nitro-group oxygen atoms. This intramolecular assistance is a consequence of the low polarity and low dissociating ability of the medium used, t-butyl alcohol, and does not appear when the medium is more polar and dissociating, like methyl alcohol.

Nucleophilic catalysis with rearrangement. The reactivity of pseudoaromatic compounds. Part VII. The 1-azabicyclo[2,2,2]octane-catalysed reaction of 2-iodocyclohepta-2,4,6-trien-1-one with piperidine

The reactions of either 2-chloro- or 2-iodo-cyclohepta-2,4,6-trien-1-one with piperidine give, in a variety of media, including benzene, 2-piperidinocyclohepta-2,4,6-trien-1-one in quantitative yield, no rearrangement being involved. An added tertiary amine, such as 1-azabicyclo[2,2,2]octane (quinuclidine), catalyses the reaction of the chloro-compound in benzene only to a negligible extent, while the reaction of the iodo-compound is appreciably catalysed. It can be excluded that this reflects base catalysis by quinuclidine since the same reactions are not catalysed by other bases such as piperidine or 2,4-dinitrophenolate (whereas they undergo efficient acid catalysis by compounds such as phenol). Rather, quinuclidine catalysis can be accounted for in terms of two consecutive nucleophilic displacements at the troponoid carbon atom which we have encountered in previous studies. The first, displacement of iodine by quinuclidine from 2-iodo-cyclohepta-2,4,6-trien-1-one to give the reactive intermediate 2-(1-azoniabicyclo[2,2,2]oct-1-yl)cyclohepta-2,4,6-trien-1-one iodide, is a substitution at the carbon occupied by iodine. The second, of quinuclidine by piperidine from the reactive intermediate, is a nucleophilic substitution with rearrangement [substitution at C(7)]. This mechanism, which could be termed ‘nucleophilic catalysis with rearrangement’ is proved by labelling experiments. Thus, in the case of 2-iodo[3,5,7-2H3]cyclohepta-2,4,6-trien-1-one, when quinuclidine is present, substitution by piperidine occurs at both C(2) and C(7) of the ring, substitution at C(7) occurring clearly via the reactive intermediate suggested above and substitution at C(2) occurring in a process in which quinuclidine does not take part.