Exocyclic unsaturated ketones

Steroidal a,j8-unsaturated ketones such as /l -3-ketones undergo a facile reaction with pyrrolidine to give the corresponding, d - -dienamines (111) (40,53). The reaction is much slower with morpholine and piperidine, which is undoubtedly due to the generation of the double bond exocyclic to the six-membered hetero rings in the step involving the dehydration of the intermediate carbinolamine (112) to the corresponding iminium ion (113). 

Chalcone dibromides are advantageous intermediates for the preparation of various nitrogen-containing heterocycles (refs. 1-4). In the case of exocyclic a,P-unsaturated ketones, however, only few examples are known concerning the utilization of their dibromides for such purposes (ref. 5). Our aim was, therefore, the synthesis of the dibromides of various exocyclic a,P-unsaturated ketones (ref. 6) and to study their chemical transformations. In our present paper the reaction of such dibromides with azide nucleophile is reported. 

The exocyclic a,P-unsaturated ketones la-h used for the preparation of dibromides 2a-h were E isomers synthesized by known procedures (refs. 7,8). Previously we reported the synthesis of some dibromides (2a,d,g) used here as starting materials, by the bromine addition of the appropriate a,P-unsaturated ketones (la,d,g) (ref. 6). In the case of our present study, compounds lb,c,e,f,h were allowed to react with a small excess of bromine in carbon tetrachloride solution at room temperature for approx. 20 min. to afford the dibromides 2b,c,e,f,h (Eqn. 1) (Table 1). 

Table 1. Yields of bromination of exocyclic a-p-unsaturated ketones...

This method provides a convenient synthesis of alkenes with the double bond in a relatively unstable position. Thus reduction of the p-toluenesulfonylhydrazones of a,(3-unsaturated aryl ketones and conjugated dienones gives rise to nonconjugated olefins. Unsaturated ketones with endocyclic double bonds produce olefins with double bonds in the exocyclic position. The reduction of p-toluenesulfonylhydrazones of conjugated alkynones furnishes a simple synthesis of 1,3-disubstituted allenes. ... 

Cyclic 0,y-unsaturated ketones undergo a photochemical rearrangement thought to involve a-cleavage and radical rearrangement. The products of these cyclic ketones are j8,y-unsaturated ketones possessing exocyclic olefinic linkages,<41,4a)... 

Table 8.17 shows the scope of the reaction of acetylcobalt tetracarbonyl with polyenes. The reactions are regiospecific with the acetyl group adding to the terminal unsaturated carbon atom of the ir-electron system to produce the E-a,p-unsaturated ketones [9]. In the reaction with fulvenes [10], only the 1-acetyl and 1,4-diacetyl derivatives are formed, with no evidence of the 2-isomer. This is an indication of the relative stabilities of the cyclic it-allyl complexes, compared with the exocyclic complex. It has been postulated that, in the reactions of conjugated systems, the initial o-allyl adduct proceeds to the products via the it-allyl complex (cf Scheme 8.1), whereas in the case of unconjugated tt-systems, the initial o-adduct is more stable and tends to undergo a further carbonylation reaction. 

Extending their earlier work on Vilsmeier formylation (c/. Vol. 7, p. 36), Traas et al. have formylated the a/S-unsaturated ketone isophorone almost exclusively at the more favoured exocyclic position to yield (190), which may be selectively... 

Similar equipment for applications on the laboratory scale has been reported (and has recently been commercialized) (69-72). Most of the reported applications had the aim of investigating kinetics of chemical reactions as indicated by changes in liquid-phase concentrations. The equipment can typically be used at elevated temperatures and pressures. Applications to heterogeneous catalytic reactions include investigations of the enantioselective hydrogenation of exocyclic a,p-unsaturated ketones catalyzed by Pd/C in the presence of (A)-proline (73) and the esterification of hexanoic acid with octanol catalyzed by a solid acid (the resin Nafion on silica) (74). 

A report of House, Respess and Whitesides (47) showed that the reaction of lithium dimethyl cuprate with the unsaturated ketone 135 gave exclusively the ketone J36 having the methyl trans to the t-butyl group. In this case where the double-bond is exocyclic, stereoelectronic effects allow equal attack from either face. Thus, the exclusive formation of 136 must be due to steric reasons only, the equatorial approach being favored. 

Alkyl vinyl ketones having the general structure 67 (X = H, Table 8) exhibit different reactive sites, depending on the nature of the substituents and the steric requirements. Vinyl ketobases (for the analogous styryl derivatives see Refs. 353 and 354) are obtained by attack of type A on acyclic or exocyclic unsaturated substrates in acidic medium, or with preformed methyleneimmonium salts. Vinylogous Mannieh bases are... 

To accomplish a quantitative treatment of the concentration-time plots it was first necessary to elucidate the reasons for the observed deviations after longer time intervals. A consecutive reaction of the a,jS-unsaturated ketones was expected. Because the cyclopentanone derivative 5, containing an exocyclic double bond, can undergo isomerization (Erskine and Waight, 1960) further attention was centred on phenyl vinyl ketone (7) formed in reaction (2b). In a separate study, reported on p. 25 it was found that phenyl vinyl ketone reacts imder the conditions used with hydroxide ions at a measurable rate at pH above about 9. Because the Mannich bases 4 and 6 have piT values of about 9-5 and 9-6, respectively, the rate of elimination was measurable with these compounds at pH > 8-5. Hence practically over the whole pH-range in which the elimination can be studied, the consecutive reaction of the phenyl vinyl ketone formed had to be taken into account. In preference to the development of a mathematical treatment for the system of consecutive reactions a more suitable Mannich base, for which such complications would be absent, was looked for. 

Cycloaddition of a,3-unsaturated ketones, acyl ketenes, acyl, thioacyl, imidoyl and vinyl isocyanates, as well as the corresponding isothiocyanates, to the C=C bond of vinylidenephosphoranes leads to the formation of six-membered heterocycles carrying an exocyclic ylide function e.g. equation 117). In some instances the mentioned thioisocyanates, however, may undergo [2 + 2] cycloaddition at the C=S bond. Interestingly N-aryliminovinylidenetriphenylphosphoranes dimerize in a [4 2] cycloaddition on heating alone. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

Syntheses of heterocyclic compounds by the reactions of exocyclic a,/ -unsaturated ketones 04JHC229. 

The Michael addition of secondary amines to veatchinone (31) occurs only in the presence of alumina of activity III, to afford adducts (32). This behaviour seems to be general for exocyclic cx3-unsaturated ketones, e.g 2-methylene-1-tetralone (Pelletier et al., ibid., 1980, 21, 809). 

Fogassy, G., Tangier, A., Levai, A., Toth, G. (2002) Enantioselective hydrogenation of exocyclic alpha,beta-unsaturated ketones. Part II. Hydrogenation in the presence of (S)-proline, J. Mol. Catal. A. Chem. 179, 101-106. 

Intramolecular acylations are also possible with unsaturated fatty compounds (2). The intramolecular reaction of petroselinic acid chloride and EtAlCl2 gave the cyclic product [20] with an exocyclic double bond (Scheme 9). The ring closure took place regioselectively at C-6. The pure ( )-adduct was isolated in a yield of 58%. The unsaturated ketone [20] could be easily hydrogenated to give 2-dodecylcyclohexanone [21]. 

The selective catalytic hydrogenation of exocyclic a,/3-unsaturated ketones was successfully utilized in the assymetric synthesis process of the chiral building blocks, a-hydroxy acids. The influence of the catalyst support, solvent and additives in the selective 1,4-reduction was studied in a series of exocyclic enone systems (Scheme The best conditions for the selective reduction of the exocyclic double bond were obtained in an apolar solvent like toluene over a range of Pd-supported catalysts (Pd black, Pd/Ti02, Pd/Al203, Pd/SiOa, Pd/C). The usage of polar solvents like methanol and DMF decreased the selectivity dramatically but addition of triethyl amine, pyridine or potassium acetate to the reaction mixtures revert this result successfully. 

A multistep sequence to guaiazulene may cover a hydroformylation step [150]. The sesquiterpene, which is found in nature in the guaiac and chamomile oil, is used as an anti-inflammatory compound in cosmetics. The starting point for the synthesis considered here was dehydrolinalool, which was converted into a cyclopentene-based unsaturated ketone (Scheme 6.53). The hydroformylation took place exclusively on the exocyclic double bound. Subsequent steps afforded guaiazulene. 

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