3-Ionone synthesis

Pseudoionones (PS) are valuable intermediate compounds for the synthesis of a and P-ionones, which are widely used as pharmaeeuticals and fragranees. In partieular, P-ionone is the preferred reactant for different synthesis proeesses leading to vitamin A (1). Pseudoionones are commercially produced via the aldol eondensation of eitral with acetone in a liquid-phase process involving the use of diluted bases, sueh as NaOH, Ba(OH)2, LiOH, which pose problems of high toxieity, eorrosion, and spent base disposal (2). The eonsecutive cyelization of pseudoionones to yield a and P-ionones is catalyzed by strong liquid aeids. The two-step proeess for ionone synthesis is depicted in equation (1). 

The ionones possess odours which are reminiscent of violet, sometimes also with woody notes. Each isomer has its own combination of violet and wood character and small variations in the composition can have relatively large effects on the odour. The most valued odour is that of (Z)-a-wu-methylionone (8.58). The exact composition of the product mixture from any ionone synthesis of this type depends very much on the nature of the catalysts and reaction conditions employed. A vast amount of development work has gone into each step of the synthesis in order to optimise yield and product isomer ratio. All the companies which produce ionones have their own signature blends of isomers and the mixtures are available under many different trade names. For obvious reasons, much of the detail of development work and reaction and distillation conditions are kept as company secrets. Citral and the ionones are very important commercially, not just in their own right but also as intermediates in the synthesis of vitamins. Consequently, there is a large volume of published academic and patent literature on their synthesis. This will be considered in more detail in Chapter 9, in the context of factors concerning synthesis on commercial production scale. 

The presence of the additional methyl group in the irone structure makes them more difficult synthetic targets than the ionones. Figure 8.29 shows Barton s 8 21 modification of Tiemann s ionone synthesis, in... 

One ofthe most elegant syntheses comes from Joseph A. Turpin and Leland O. Weigel. Starting material is 6-methylhept -6-en-2-one, which is as well an intermediate in the ionone synthesis, and can be accessed from isobutene, formaldehyde and acetone. By means of a Sharpless dihydroxylation and acid ring-closure, frontalin is obtained with an enantiomeric excess of60-70 %. [200]... 

Two molecules of vitamin A are formed from one molecule of -carotene. Vitamin A crystallizes in pale yellow needles m.p. 64 C. It is optically inactive. It is unstable in solution when heated in air, but comparatively stable without aeration. Vitamin A is manufactured by extraction from fish-liver oils and by synthesis from / -ionone. The role of vitamin A in vision seems to be different from its systemic function. See also relincne and rhodopsin. 

Enone formation-aromatization has been used for the synthesis of 7-hydro-xyalkavinone (716)[456]. The isotlavone 717 was prepared by the elimina-tion[457]. The unsaturated 5-keto allyl esters 718 and 719, obtained in two steps from myreene. were subjected to enone formation. The reaction can be carried out even at room temperature using dinitriles such as adiponitrile (720) or 1,6-dicyanohexane as a solvent and a weak ligand to give the pseudo-ionone isomers 721 and 722 without giving an allylated product(458]. 

Chloroacetate esters are usually made by removing water from a mixture of chloroacetic acid and the corresponding alcohol. Reaction of alcohol with chloroacetyl chloride is an anhydrous process which Hberates HCl. Chloroacetic acid will react with olefins in the presence of a catalyst to yield chloroacetate esters. Dichloroacetic and trichloroacetic acid esters are also known. These esters are usehil in synthesis. They are more reactive than the parent acids. Ethyl chloroacetate can be converted to sodium fluoroacetate by reaction with potassium fluoride (see Fluorine compounds, organic). Both methyl and ethyl chloroacetate are used as agricultural and pharmaceutical intermediates, specialty solvents, flavors, and fragrances. Methyl chloroacetate and P ionone undergo a Dar2ens reaction to form an intermediate in the synthesis of Vitamin A. Reaction of methyl chloroacetate with ammonia produces chloroacetamide [79-07-2] C2H ClNO (53). 

In the case of the synthesis of 10,19,19,19-2H4-vitamin A, the most useful for biological studies, three deuterium atoms were incorporated into /i-ionone 30, in >98% by deuterium exchange with excess D2O in the presence of Na02H (and pyridine). The tri-deuteriated 30, utilized in Wittig-Horner reaction with dideuterio triethyl phosphonate, provided tetradeuteriated ethyl /J-ionilidene acetate 31 with more than 98% 2H4 (by NMR). No deuterium loss in the subsequent synthetic steps was observed as evidenced by MS and NMR analysis. 

Reductive elimination of an allylic diol group. A new synthesis of vitamin A involves reduction of the allylic diol 1, prepared in several steps from JJ-ionone, with a low valent titanium formed from TiCl3 and LiAlH, in the ratio 2 1. Thus, the allylic diol group of 1 [either (E) or (Z)] is reduced to an (E,E)-1,3-diene group to form the silyl ether (2) of vitamin A.1 When the primary hydroxyl group is protected as an acetate, the reduction gives a mixture of (E)- and (Z)-2. 

S-Ionones, 1,2,4-trioxane synthesis, 291 IPCS (International Programme on Chemical Safety), 747... 

D-glucopyranosyl esters of abscisic acid and /3-ionylideneacetic acid (120) have been prepared by treatment of the acid with a-acetobromoglucose in the presence of triethylamine/ Two papers " describe a new synthesis of y-ionone (64) in which the key intermediate (121) is prepared from y-cyclocitral (122) and acetone in the presence of BU2BSO3CH2CF3. 

Uses. Because of its strong lemon odor, citral is very important for aroma compositions such as citrus flavors. In perfumery it can be used only in neutral media due to its tendency to undergo discoloration, oxidation, and polymerization. It is used as a starting material in the synthesis of ionones and methylionones, particularly /3-ionone, which is an intermediate in vitamin A synthesis. 

Methyl-5-hepten-2-one is an important intermediate in the synthesis of terpenoids. Its odor properties are not impressive. It occurs in nature as a decomposition product of terpenes. Tagetone [6752-80-3] is a major component of tagetes oil. Solanone [1937-45-8] and pseudoionone [141-10-6] are acyclic Cn ketones with a terpenoid skeleton. Solanone is one of the flavor-determining constituents of tobacco, pseudoionone is an intermediate in the synthesis of ionones. 

Ionone is converted into intermediates for vitamin A synthesis. The hydrogenation of ionones and methylionones is of some importance. Dihydro or tetrahydro derivatives or ionols can be obtained depending on reaction conditions. 

Ionone C13H20O [76-76-5] 192.30 82 (0.16) 0.9317 1.4985 violet-like with woody-resinous tonality (intermediate in the synthesis of 7-dihydro-ionone, a component of ambergris)... 

In the synthesis of vitamin A, the dependence on natural sources as well as steadily increasing production via /3-ionone as an intermediate have led to the development of a method for synthesizing citral from dehydrolinalool (see p. 37). More recent routes employ dehydrolinalool as the starting material for pseudoionone. Dehydrolinalool is converted into pseudoionone by using either diketene [92] or a suitably substituted acetoacetate (Carroll reaction) [93] ... 

C13H22O, Mr 194.32, 20 0.940-0.960, n 1.485-1.498, is a colorless to pale yellow liquid with an extremely powerful, amber, somewhat musty and animal odor. It is a constituent of ambergris (see p. 174). A synthesis starts with the thermolysis of /3-ionone (see p. 63) which leads to dehydroambrinol. The title compound is obtained by hydrogenation over Raney nickel in methanolic solution [115]. 

Terpenes important for both fragrances and flavours can be prepared from citral, such as citronellol, linalool, nerolidol, geraniol, farnesol and bisabolol. Citral is also an important starting material for the synthesis of vitamins A and E, carotenoids and other flavour and fragrance compounds like ionones. Most of the /3-ionone synthesised is probably used for vitamin A synthesis. 

SCHEME 81. Synthesis of (7 )-a-ionone using a stereoselective anti-8, 2 -substitution... 

A short synthesis of retinal was described by Taylor et al. [42] based on the addition of a C]3 vinylalane to a methylpyrylium salt. The 13Z-retinal (48%) was isomerised to all E retinal by a previous procedure [43]. P-Ionone was first converted into the alkyne and then into the vinylalane, using the Negishi methodology [44], Addition of an excess of this alane to 4-methylpyrilium tetrafluoroborate [45] gave 13Z-retinal, being isomerized to the all E isomer (L in benzene/ether), Fig. (18). 

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