Peter W. Hickmott

Enamine chemistry. Part XVII. Reaction of αβ-unsaturated acid chlorides with enamines. Further mechanistic investigations. Effect of triethylamine on the reaction path

αα′-Annulation of enamines of cyclic ketones occurs on treatment with αβ-unsaturated acid chlorides in boiling benzene, to give bridged bicyclic ketones. Further evidence supports the contention that this occurs by initial N-acylation of the enamine followed by a [3,3]sigmatropic rearrangement. In the presence of triethylamine the course of the reaction is changed. C-Acylation of the enamine occurs, leading to a tetrahydrochromanone. This reaction has been shown to involve a vinylketen intermediate. The evidence available indicates that vinylketens react with enamines by a two-stage mechanism to give a zwitterionic intermediate, rather than by concerted [2 + 2] or [4 + 2] cycloaddition.

Enamine chemistry. Part XIX. Stereochemistry of the transition state of the reaction of αβ-unsaturated acid chlorides with enamines: crystal structure of 1-methyl-7-exo-t-butylbicyclo[3.3.1]nonane-2,9-dione

Treatment of the morpholine enamine of 2-methyl-4-t-butylcyclohexanone with acryolyl chloride in boiling benzene gives 1-methyl-7-t-butylbicyclo[3.3.1]nonane-2,9-dione (VIII) as a mixture of two isomers (4 : 1). X-Ray analysis of the major isomer indicates that initial carbon–carbon bond formation occurs predominantly from the axial side of the enamine double bond. The molecular conformation is boat-chair.

Enamine chemistry. Part XX. Reactions of αβ-unsaturated acid chlorides. Synthesis of alkyl 2,6-dioxobicyclo[3.3.1]nonane-1-carboxylates, alkyl 2,9-dioxobicyclo[3.3.1]nonane-7-carboxylates, and 2,9-dioxobicyclo[3.3.1]nonane-7-carbonitriles

Reactions of the pyrrolidine enamines of dialkyl 4-oxocyclohexane-1,1-dicarboxylates with acryloyl chloride give alkyl 2,6-dioxobicyclo[3.3.1]nonane-1-carboxylates, whereas the pyrrolidine enamines of ethyl 4-oxocyclohexane-1-carboxylate and ethyl 1-cyano-4-oxocyclohexane-1-carboxylate give ethyl 2,9-dioxobicyclo[3.3.1]nonane-7-carboxylates and 2,9-dioxobicyclo[3.3.1]nonane-7-carbonitriles, respectively. The reasons for this change in the course of the reaction are discussed. Distillation of the proline enamine of diethyl 4-oxocyclohexane-1,1-dicarboxylate gives a pyrrolo[1,2-a]indole derivative.

Introduction of pharmacophoric groups into polycyclic systems. Part 3. Amine derivatives of adamantane and diaza-adamantane

Methods for introducing various pharmacophoric amine-containing substituents into the adamantane system have been investigated. These include β-and α-aminoalkyloxyimino, β-aminoalkylidene, β-hydroxyethylamino, and β-phenylethylamino. Aminoalkyloxyimines were prepared by alkylation of the anion of adamantanone oxime with the corresponding aminoalkyl chloride, and a 2-aminoethylidene derivative was prepared by Wittig reaction of 2-dimethylaminoethyltriphenylphosphonium bromide with adamantanone. The reaction of 6-hydroxy-7-methyl-6-phenyladamantane-2,4-dione with aqueous sodium cyanide has been shown to be both regio- and stereo-selective, only the C-2 carbonyl group reacting from the most hindered direction. This is possibly due to stabilisation of the cyanohydrin by hydrogen bonding between the hydroxy and C-4 carbonyl groups. When trimethylsilyl cyanide was used in place of sodium cyanide, the reaction remained regioselective but, in the absence of hydrogen bond stabilisation, the stereoselectivity was lost and two trimethylsilyloxy cyanides were isolated, epimeric at C-2. The stereochemistry of one epimer has been determined by X-ray crystallography, details of which are reported here. Hydrogenation of the trimethylsilyloxy cyanides then gave the corresponding β-hydroxyamine, isolated as the hydrochloride. Finally 5,7-diphenyl-1,3-diaza-adamantan-6-one was prepared by a literature method and converted, with difficulty, into the oxime which was reduced by RedAl to the corresponding amine.

ENAMINE CHEMISTRY. PART 27. THE EFFECT OF ADDITIONAL α‐ AND β‐HETEROATOMS ON THE PΠ‐CONJUGATION AND REACTIVITY OF ENAMINES. SUB OR SUPER ENAMINES?

Der Einflus der α- und β-Heteroatome in Enaminen wie z.B. (I)-(III) besteht in der Verminderung der p?-Konjugation zwischen einsamem N-Elektronenpaar und den rr-Elektronen der Doppelbindung.

Enamine chemistry. Part 25. Preparation and carbon-13 nuclear magnetic resonance spectra of N-alkyl-morpholines and -pyrrolidines. Comparison with the carbon-13 spectra of the corresponding acyclic enamines

The preparation and 13C chemical shifts of a series of N-alkyl-morpholines and -pyrrolidines are reported. The α-and β-effects of the amine moieties have been evaluated and compared with those operating in the corresponding enamines and with the α- and β-effects of an isopropyl group. The factors affecting the relative magnitude of these effects are discussed.

Enamine chemistry. Part 22. Carbon-13 nuclear magnetic resonance spectra of acyclic enamines

The 13C chemical shifts of a series of acyclic enamines derived from morpholine and pyrrolidine are reported. There is considerable variation in the contribution of the amine moiety to the chemical shift of the olefinic C-2, which is attributed principally to variation in the mesomeric contribution to the electron density. The amine contribution to the chemical shift of the olefinic C-1 is relatively constant if allowance is made for changes in the shift parameters of the alkyl substituents.

Enamine chemistry. Part 23. Synthesis, spectral properties, and relative stabilities of cyclic dienamine complexes of tricarbonyliron

Reaction of [Fe(CO)5] and the morpholine and pyrrolidine dienamines of 3,5,5-trimethylcyclohex-2-en-1-one gives a mixture of two tricarbonyl(dienamine)iron complexes. The complex in which the dienamine system is cross-conjugated has been shown to be more stable than that in which the dienamine is linearly conjugated. The reason for this, and the effect on the spectral properties, are discussed.

Enamine chemistry. Part XXI. Condensation of L-sodium or L-ethyl prolinate with ketones to give substituted polyhydropyrrolo[1,2a]-indoles and -pyrrolizines

The effect of substituents and ring size on the cyclization of enamines derives from L-ethyl pyrrolidine-2-carboxylate and cyclic ketones, to give 1,2,3,5,6,7,8,9a-octahydropyrrolo[1,2-a]indol-9-ones, has been investigated and the conversion of the parent system into the perhydropyrrolo[1,2-a]indol-9-one is reported. Application of the reaction to simple acyclic ketones, β-diketones, and β-oxo-esters gives the corresponding substituted pyrrolizines.

Enamine chemistry. Part 24. 2,2-versus 2,6-Disubstitution in 2-alkylcyclohexanone enamines. Factors affecting the regioselectivity and stereoselectivity of enamine alkylation and protonation

The factors affecting the reversibility and energetics of competing reaction pathways are discussed and shown to provide a rational explanation for the regioselectivity of reaction of 2-substituted cyclohexanone enamines.