Αβ-unsaturated Acid Chlorides Research Articles

Enamine chemistry. Part 29. Synthesis of adamantane derivatives from α,β-unsaturated acid chlorides and 4,4-disubstituted cyclohexanone enamines. Multiple [3,3] sigmatropic rearrangement transition state stereochemistry. X-Ray analysis

Chemical, spectroscopic and X-ray crystallographic evidence has confirmed that the three isomers of 6-hydroxy-7,9-dimethyl-6-phenyladamantane-2,4-dione, obtained by the reaction of crotonoyl chloride with the pyrrolidine enamine of 4-benzoyl-4-methylcyclohexanone, have the 9α-methyl-6α-phenyl (4), 9β-methyl-6α-phenyl (2), and 9β-methyl-6β-phenyl (3) configurations. The mechanism of their formation has been investigated and the evidence available indicates that the stereochemistry of the C-6 and C-9 chiral centres is determined largely by the stereochemistry of the [3,3] sigmatropic rearrangement leading to them. A chair-like transition state for the rearrangement, occurring from the same side of the cyclohexene ring as the benzoyl group (chair-syn) in the intermediate N-acylated enamine (9a) must lead to the 9α-Me,6α-Ph configuration as in (4), whereas the same process from the opposite side (chair-anti) followed by inversion of the substituted ring carbon could lead to the 9β-Me,6β-Ph configuration as in (2) and the 9β-Me,6α-Ph configuration as in (3). However, the main isomer (3), having the more crowded 9β-Me,6β-Ph configuration, is more likely to be derived by a [3,3] sigmatropic rearrangement having a boat-like transition state, but again occurring from the same side of the cyclohexene ring as the benzoyl group (boat-syn). An X-ray crystallographic analysis of 6β- hydroxy-7,9α-dimethyl-6α-phenyladamantane-2,4-dione (4) and of 3-(5-benzoyl-5-methyl-2-oxocyclohexyl)-butanoic acid (34), isolated at an intermediate stage in the above reaction, has been carried out. The corresponding reaction of αβ-unsaturated acid chlorides with enamines of 4-benzoyl-4-phenyl-cyclohexanone (9c) and ethyl 1 -benzoyl-4-oxocyclohexane-1 -carboxylate (9b) has been carried out and shown to lead to 6-hydroxy-6,7-diphenyladamantane-2,4-diones and ethyl 2-hydroxy-4,6-dioxo-2-phenyladamantane-1 -carboxylates respectively, as a mixture of stereoisomers. A similar multiplicity in the stereochemistry of the transition state of the [3,3] sigmatropic rearrangement is evident from the structures of the adamantane derivatives produced.

Enamine chemistry. Part 26. Preparation of substituted adamantane-2,4-diones and bicyclo[2.2.2]octan-2-ones

Reaction of αβ-unsaturated acid chlorides with the morpholine or pyrrolidine enamines derived from 4-benzoyl-4-methylcyclohexanone gives the corresponding 6-hydroxy-7-methyl-6-phenyladamantane-2, 4-dione in moderate to good yield. Enamines from 4-acetyl-4-phenyl (or 4-ethoxycarbonyl) cyclohexanone could not be isolated owing to their preferential cyclisation into 1 -phenyl (or 1 -ethoxycarbonyl) 4-substituted aminobicyclo[2.2.2]octan-2-ones.

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.

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 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 XIV. Reaction of αβ-unsaturated acid chlorides with tertiary enamino-ketones and -esters

4-Acetyl- and 4-benzoyl-3-(substituted amino)cyclohex-2-en-1-ones have been isolated from the reaction of acryloyl chloride with tertiary enamino-ketones. Tertiary enamino-ethyl esters give the corresponding 4-ethoxy-carbonylcyclohexenones. 2′,4′-Dimethyl-6′-morpholinoacetophenone has been obtained from the self-condensation of 4-morpholinopent-3-en-2-one and identified from spectral data.

Enamine chemistry. Part XIII. Reaction of αβ-unsaturated acid chlorides with primary and secondary enamines. Synthesis of tetrahydro-2-oxopyridines and octahydro-2-oxoquinolines

αβ-Unsaturated acid chlorides react with primary and secondary enamines, obtained by condensation of ammonia or primary amines with β-diketones or β-keto-esters, to give tetrahydro-2-oxopyridines or octahydro-2-oxoquinolines. The evidence available from this and previous work suggests that the reaction involves initial O- or N-acylation followed by a [3,3] sigmatropic rearrangement and cyclisation of the keten intermediate formed on to the nitrogen atom.

Hydrocyanation. Part VIII. Conjugate hydrocyanation of steroidal αβ-unsaturated carboxylic acid derivatives

Conjugate hydrocyanation of steroidal αβ-unsaturated carboxylic acid methyl esters with diethylaluminium cyanide, when carried out at about 100°, gives β-cyanocarboxylic esters in low yields. With more reactive αβ-unsaturated carboxylic acid derivatives, the hydrocyanation proceeds smoothly at room temperature to give β-cyanocarboxylic acid derivatives in excellent yields: an αβ-unsaturated acid cyanide and some αβ-unsaturated acid chlorides, on hydrocyanation followed by hydrolysis, are converted into β-cyanocarboxylic acids, and β-cyanothiocarboxylic S-esters are obtained by treating αβ-unsaturated thiocarboxylic S-esters with diethylaluminium cyanide. Stereochemistry and structure–reactivity relationships in these hydrocyanations are discussed.

The synthesis of 3,4-dihydrocarbostyril derivatives from αβ-unsaturated acid chlorides and the imines formed from ketones and primary amines

The reaction of αβ-unsaturated acid chlorides with the imines formed from ketones and primary amines, followed by photocyclization of the resultant αβ-unsaturated enamides, gives 3,4-dihydrocarbostyril derivatives.

Enamine chemistry. Part V. Reaction of αβ-unsaturated acid chlorides with enamines of medium and large ring ketones

The reaction of αβ-unsaturated acid chlorides with enamines of medium and large ring ketones gives bicyclic (n, 3, 1) products, the nature of which is governed by the ability of the bridge-head position to accommodate a double bond in the 1-carbon bridge. When this is not possible the product is the iminium salt which is readily hydrolysed to the bicylic dione. With larger rings proton-loss from the iminium salt becomes increasingly more favourable to give bicyclic enamino-ketones, the lowest member of this series which has been isolated being 11-morpholinobicyclo[5,3,1]undec-7(11)-en-8-one.

Enamine chemistry. Part II. Reaction of αβ-unsaturated acid chlorides with dienamines. Preparation of cyclohexeno(2′,1′:6,7)bicyclo[3,3,1]-non-6-ene-2,9-diones

Reaction of acryloyl chloride with dienamines derived from Δ1,8a-2-octalones gives mainly the corresponding cyclohexeno(2′,1′:6,7)bicyclo[3,3,1]-non-6-ene-2,9-dione (20—30%), by initial reaction at C-1 and cyclisation at C-3 of the octalone. Small amounts of 1,8- and 4a,8-bridged products were also isolated. The mechanism of the reaction is discussed.

Enamine chemistry. Part III. Reaction of αβ-unsaturated acid chlorides with enamines of acyclic ketones. Preparation of cyclohexane-1,3-diones

Reaction of acryloyl, crotonoyl, and methacryloyl chlorides with the morpholine enamine of diethyl ketone has been shown to give 2,4-dimethyl-, 2,4,5-trimethyl-, and 2,4,6-trimethyl-cyclohexane-1,3-diones respectively. The intermediate substituted 3-morpholinocyclohex-2-enones have been isolated and characterised as their perchlorates. Acryloyl chloride and the morpholine enamine of ethyl isopropyl ketone and the dimethylamine enamine of di-isopropyl ketone gave 2,2,4-trimethyl- and 2,2,4,4-tetramethyl-cyclohexane-1,3-diones respectively. The morpholine enamine of dibenzyl ketone gave 3-morpholino-2,4-diphenyl-cyclohex-2-enone which could not be hydrolysed to the cyclohexane-1,3-dione. The mechanism of the reaction is discussed.

Enamine chemistry. Part IV. Reaction of αβ-unsaturated acid chlorides with enamines of aldehydes

The reaction of acryloyl chloride with 2-methyl-1-piperidinopropene in boiling benzene gives 2,2,6,6-tetramethyl-3-oxoheptane-1,7-dial, whereas crotonoyl and cinnamoyl chlorides give mixtures of the corresponding unsaturated 2-acyl-2-methylpropanal and unsaturated carboxamide. 2-Methyl-1-(pyrrolidin-1-yl)propene and crotonoyl chloride react at room temperature to give an iminium salt which may be hydrolysed to a 2-dihydropyranyl-2-methylpropanal or be converted by heat into a second iminium salt which on hydrolysis gives 2,2,5,6,6-pentamethyl-3-oxoheptane-1,7-dial. The reaction mechanism is discussed.

171. Reaction of αβ-unsaturated acid chlorides with alcohols in the presence of tertiary amines

171. Reaction of αβ-unsaturated acid chlorides with alcohols in the presence of tertiary amines