2-acetoxy methyl ketones

This method for the synthesis of higher-carbon ketoses is based on the reaction of diazomethane with an acid chloride to give a diazomethyl ketone which, on hydrolysis (or acetolysis), furnishes a hydroxy (or acetoxy) methyl ketone. The reaction was first applied in the sugar field in 1938 and has since been widely used in the synthesis of ketoses by Wolfrom and coworkers. As developed by Wolfrom, the synthesis uses fully acety-lated derivatives in the following stages aldose — acetylated aldonic acid acetylated aldonyl chloride acetylated diazomethyl ketose — acetylated ketose — ketose. The method is illustrated in the synthesis of D-galacto-heptulose (10). ... 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

The reduction of hydroxy or acetoxy ketones by baker s yeast shows an interesting stereoselectivity. For the reduction of acetylbenzofuran derivatives with baker s yeast, the methyl ketones afforded (S)-alcohol in 20-68% ee. The hydroxyl derivatives afforded (S)-alcohol in 87-93% ee, and the acetoxy derivatives gave (R)-alcohols in 84-91% ee (Figure 8.33) [24bj. 

The most synthetically valuable method for converting alkynes to ketones is by mercuric ion-catalyzed hydration. Terminal alkynes give methyl ketones, in accordance with the Markovnikov rule. Internal alkynes give mixtures of ketones unless some structural feature promotes regioselectivity. Reactions with Hg(OAc)2 in other nucleophilic solvents such as acetic acid or methanol proceed to (3-acetoxy- or (3-methoxyalkenylmercury intermediates,152 which can be reduced or solvolyzed to ketones. The regiochemistry is indicative of a mercurinium ion intermediate that is opened by nucleophilic attack at the more positive carbon, that is, the additions follow the Markovnikov rule. Scheme 4.8 gives some examples of alkyne hydration reactions. 

Oxidation of allylic andhomallylic acetates (cf. 10,175-176).1 This system is an efficient catalyst for oxygenation of terminal alkenes to methyl ketones (Wacker process). Similar oxidation of internal olefins is not useful because it is not regioselective. However, this catalyst effects oxygenation of allylic ethers and acetates regioselectively to give the corresponding /i-alkoxy ketones in 40-75% yield. Under the same conditions, homoallylic acetates are oxidized to y-acetoxy ketones as the major products. 

The reaction is very slow in acetic acid alone, and accelerated as acetate by the addition of bases [59]. These two isomers undergo Pd-catalysed allylic rearrangement with each other. 3-Acetoxy-l,7-octadiene (139) is converted to the allylic alcohol 157 and to the enone 158, which is used as a bisannulation reagent [60], Thus Michael addition of 158 to 2-methylcyclopentanedione (159) and aldol condensation give 160. The terminal alkene is oxidized using PdCl2/CuCl/02 to the methyl ketone 161. After reduction of the double bond in 161, aldol condensation affords the tricyclic system 162. 

After Michael addition of 17 to 2-methyl-1,3-cyclohexanedione (19) and the first aldol condensation, the double bond in 20 is reduced to give 21. The acetoxy group in 21 is unmasked by hydrolysis and oxidation, and subsequent aldol condensation gives 22. Again, the terminal double bond in 22 is oxidized with PdCk to methyl ketone, and subsequent hydrogenation of the internal double bond affords the trione 23, from which the steroid A-ring 24 is formed by aldol condensation [34],... 

Oxidation of 3-acetoxy-l-nonene (14) at 50 C gave a mixture of the methyl ketone (15) and 1-ace-toxy-3-nonanone (16) in 33% and 17% yields. The latter was formed by regioselective oxidation of 1-acetoxy-2-nonene, itself formed by the allylic rearrangement of (14) promoted by Pd ions (equation 11). 

Auxiliary cleavage with concomitant carbon-carbon bond formation is a particularly attractive option, which has been demonstrated in a bimolecular sense using the dianion of methyl sulfone (giving a methyl ketone), and in an intramolecular sense using a Claisen-type condensation of a p-acetoxy enolate (giving a 5-lactone). An interesting halolactonization procedure has... 

Diels-Alder-based strategy (Scheme 18).90 An analogous route has also been explored by Miller et a/.91 who obtained the acetoxy-aldehyde (152) from the Diels-Alder reaction of 3-methylbuta-l,3-dienyl acetate with 2-methylprop-2-enal. Cyclization of (152) with sodium hydride gave the coumarin derivative (153). Unfortunately, cyclization of the corresponding methyl ketone (154) yielded the chromanone derivative (155) and not the methyl analogue of (153). 

The oxidation of manool has been re-examined with the aim of producing ambergris-type perfumes. Oxidation with potassium permanganate afforded the known s methyl ketone (6), the diether (7), and at 40 °C the lactone (8). Sodium dichromate gave the aldehyde (9) as a mixture of E- and Z-isomers. Further oxidation of the methyl ketone with hypobromite gave an a-hydroxy-acid (10) and an ether (11) which was also obtained from manoyl oxide. Oxidation of the ketone with per-acid gave an acetoxy-epoxide which on reduction with lithium aluminium hydride afforded a diol. This was converted into an odoriferous ether (12). The ready formation of 5- and 6-membered-ring ethers of this type is a characteristic feature of this area of diterpenoid chemistry. 

In striking contrast to the above observations is the finding that both reduction and reductive methylation of the tetrahydropyranyl ether of 17a-ace-toxypregnenolone (71) afford the expected products (72a, b) in 85-88 % yields by direct crystallization of the crude reaction products. Clearly, the complications in the reduction of the 16-en-20-one system are attributable primarily to reactions of the carbon-carbon double bond rather than to the a-carbanion (73), which is the final intermediate in both the reduction of the 16-dehydro compounds and the 17-acetoxy ketones. 

Reaction of 17j -acetoxy-3,3-ethylenedioxy-5a-androstan-l-one (1) with methylmagnesium bromide followed by treatment with acid and reacetylation affords the 1-methyl-A -3-ketone (3). The configuration of carbon-1 of the intermediate (2) has not been established/ ... 

In the androstane and pregnane series the 7-methyl-A -3-ketones (36) are produced from 3j -acetoxy-A -7-ketones (34) with methyllithium, and subsequent Oppenauer oxidation of (35). ° ... 

Schaub ° introduced methyl groups at both the 16a- and 17a-positions by 1,4-addition of methylmagnesium iodide to the A -20-ketone (8) followed by methylation of the intermediate 16a-methyl-17-enolate anion (9) with methyl iodide. After hydrolysis of the tetrahydropyranyl ether group a 40% yield of the 16,17-dimethyl derivative (10) was obtained. With the corresponding 3j -acetoxy derivative, the yield of (10) is only 20%. 

Acetoxy-4-chloroandrosta-l,4,6-trien-3-one and A -triene-3,l 1-di-ketones give analogous 1,4-additions to provide the la-methyl compounds. ... 

Thus, the model compound 5a, 6a-epoxy-6j -methyltigogenin acetate (103) affords 3)5-hydroxy-6)5-methyl-10(5 6)crZ)eo-(25S)-spirostan-5-one acetate (104) in 90 % yield. As expected, the j9-acetoxy ketone (104) loses the elements of acetic acid on passing through a column of alumina to give 6)5-methyl-10(5 -> 6)-flZ>eo-(25S)-spirost-3-en-5-one (105). 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

Addition of l,3-bis(methylthio)allyllithium to aldehydes, ketones, and epoxides followed by mercuric ion-promoted hydrolysis furnishes hydroxyalkyl derivatives of acrolein5 that are otherwise available in lower yield by multistep procedures. For example, addition of 1,3-bis-(methylthio)allyllithium to acetone proceeds in 97% yield to give a tertiary alcohol that is hydrolyzed with mercuric chloride and calcium carbonate to saturated aldehyde.8 Similarly, addition of l,3-bis(methylthio)allyl-lithium to an epoxide, acetylation of the hydroxyl group, and hydrolysis with mercuric chloride and calcium carbonate provides a 5-acetoxy-a,/ -unsaturatcd aldehyde,6 as indicated in Table I. Cyclic cis-epoxides give aldehydes in which the acetoxy group is trans to the 3-oxopropenyl group. 

Radioimmunoassay of Steroids. —6/8-Hydroxycortisol 21-acetate (29) reacted selectively in cold pyridine with carboxymethoxylamine, giving the 3-(0-carboxy-methyl)oxime the 21-acetoxy-group seemingly slows competing reaction with the 20-ketone. The BSA conjugate was used to raise an antibody for the RIA of 6/3 -hydroxycortisol. ... 

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