Methyl ketols

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

Alcoholic potassium hydroxide or sodium hydroxide are normally used to convert the halohydrins to oxiranes. Other bases have also been employed to effect ring closure in the presence of labile functional groups such as a-ketols, e.g., potassium acetate in ethanol, potassium acetate in acetone or potassium carbonate in methanol.However, weaker bases can lead to solvolytic side reactions. Ring closure under neutral conditions employing potassiunT fluoride in dimethyl sulfoxide, dimethylformamide or A-methyl-pyrrolidone has been reported in the patent literature. 

Reduction of 16-keto-17(0i)-hydroxyestratrienol-3-methyl to 16,17-dihydroxyestratrienol-3-methyl ether A solution of 800 mg of the alpha ketol methyl ether in 100 cc of ethanol and 10 cc of acetic acid was carefully maintained at 40°C (water bath), and 200 g of freshly prepared sodium amalgam (2%) were added in small pieces with efficient swirling. Before all of the amalgam had been added, a precipitation of sodium acetate occurred, and at this point an additional 100 cc of 50% acetic acid were added. After all the reducing agent had been added, the mixture was transferred to a separatory funnel with ether and water. 

The results indicate that the product ratio is determined by the competition between the various reaction steps. Under base-catalyzed conditions, 2-butanone reacts with benzaldehyde at the methyl group to give l-phenylpent-l-en-3-one. Under acid-catalyzed conditions, the product is the result of condensation at the methylene group, namely, 3-methyl-4-phenylbut-3-en-2-one. Under the reaction conditions used, it is not possible to isolate the intermediate ketols, because the addition step is rate-limiting. These intermediates can be... 

The very sensitive ether peroxide test strips (Merckoquant, Art. No. 10011), available from E. Merck, Darmstadt, are used. If the test is still positive at this point, an additional 0.2 ml. of N-methyl morpholine is added. Stirring and heating at 75° are continued for another 5 hours. Remaining peroxide renders the work-up and drying of the product potentially hazardous. N-Methylmorpholine N-oxide (1) and hydrogen peroxide form a strong 1 1 complex. In the reaction with osmium tetroxide, this complex produces conditions similar to those of the Milas reaction,7 and some ketol formation may result. 

Novel 3-aryl-2-imino-4-methyl-2,5-dihydrofurans have also been efficiently synthesised using focused microwave heating by a one-pot condensation from a-ketols and substituted phenylacetonitrile in the presence of sodium ethoxide in ethanol (Scheme 3.2)4. 

The structure of the phenylcoumarone (XXII) 26) was derived from analytical and spectral investigation and was confirmed by a synthesis 29) starting from dehydrodiconiferyl alcohol (XXVII). The latter compound (XXVII) was converted by monoperphthalic acid into an epoxide whose side chain was equivalent to that of an arylglycerol. By properly performed acidolysis, the epoxide side chain therefore was converted into the primary ketol structure, and at the same time the hydroxymethyl-substituted phenylcoumaran system see XXVII) was converted into the methyl-substituted phenylcoumarone system of XXII (Figure 8). 

Methyl gibberellate (VIII), the corresponding ketol (IX), and the keto acid methyl ester (X) are oxidized to a,/ -unsaturated ketones (XI) (5). The hydroxyl group is therefore allylic to the ring A double bond. Moreover the Xu. (228 to 229 mfx) of these a,/ -unsaturated ketones is such that the double bond must be disubstituted. A disubstituted double bond, allylic to C-2, can only be placed as shown in structure (VIII). 

On the basis of the success of these initial reports on the proline-catalyzed intramolecular aldol reaction several groups focused on extending this type of synthesis to bicyclic products bearing angular substituents other than methyl and ethyl reported earlier [97-101]. Preparation of bicyclic systems with protected hydroxymethyl substituents, e.g. 99, was reported by Uda et al. (Scheme 6.46, Eq. 1) [113, 114]. As a selected example, the aldol adduct 99 was formed in 70% yield and with 75% ee in the presence of one equivalent of L-proline. Synthesis of a related product with an angular phenylthio substituent, 101, was described by Watt and co-workers (Scheme 6.46, Eq. 2) [115]. After intramolecular proline-catalyzed aldol reaction, dehydration of the ketol intermediate, and subsequent recrystallization... 

The use of (R)-(+)-pro1ine in acetonitrile induced the asymmetric aldol cycllzation of the triketone to the enantiomeric ketol, (-)-(3aR,7aR)-2,3,3a,4,7,7a-hexahydro-3a-hydroxy-7a-methyl-lH-indene-1,5(6H)-dione.10... 

Circular dlchroism studies of the 7a-methyl bicyclic ketol suggested, and a single-crystal X-ray diffraction study of the racemic compound confirmed, the c1s conformation with an axial 7a-methyl and an equatorial 3a-hydroxy group in the six-membered ring of the bicyclic system. On the other hand, similar measurements of the 7a-ethyl bicycllc keto established the alternate possible cis conformation to avoid the 1,3-diaxial interactions between the angular ethyl group and the C-4 and C-6 axial hydrogens. 

Formyl-2-cyclohexenones (e.g. 129) react with 3-methyl-2-pyrrolidino-l-butene (130) to give, after hydrolysis, bicyclic ketols, e.g. 134, which on dehydration with trifluoroace-tic acid gave octaline diones such as 135 (equation 24)67. This type of [3 + 3] carbocyclization requires a molar ratio enamine enalone of 2 1 for optimum results, which is explained by the exchange of the enamine 130 with hydroxymethylene ketone 131 to form pyrrolidinomethylene ketone 132 and 3-methyl-2-butanone. 

Carbon-centered nucleophiles can also be used to advantage in the reaction with epoxides. For example, the lithium enolate of cyclohexanone 96 engages in nucleophilic attack of cyclohexene oxide 90 in the presence of boron trifluoride etherate to give the ketol 97 in 76% yield with predominant syn stereochemistry about the newly formed carbon-carbon bond <03JOC3049>. In addition, a novel trimethylaluminum / trialkylsilyl triflate system has been reported for the one-pot alkylation and silylation of epoxides, as exemplified by the conversion of alkenyl epoxide 98 to the homologous silyl ether 99. The methyl group is delivered via backside attack on the less substituted terminus of the epoxide <03OL3265>. 

SYNS ACETYL METHYL CARBINOL 2-BUTAN-OI 3-ONE 2,3-BUTANOLONE DIMETHYL-KETOL FEMA No. 2008 3-HYDROXY-2-BUTANONE 1-HYDROXYETHYL METHYL KETONE y-HYDROXY-P-OXOBUTANE... 

The condensation of methyl ketones and subsequent dehydration to olefinic ketones is frequently accomplished without isolation of the ketol. The course of the condensation of methyl -alkyl ketones depends upon the nature of the reagent. The methyl group is involved when a basic catalyst such as aluminum t-butoxide is employed. The unsaturated ketones are obtained in 70-80% yields branched ketones give somewhat lower yields. ... 

Methyl aryl ketones are converted smoothly to the olefinic ketones by aluminum /-butoxide. This reagent has the added advantage of removing the water formed by the dehydration of the ketols. The condensations are carried out at 60 140°, with the distillation of t-butyl alcohol from the reaction mixture if necessary. An example is the preparation of dypnone, CsH5C(CHj)=CHCOC H5, from acetophenone in 82% yield. ... 

The main feature is the preference for the C n) position for the 0X0 function. This avoids large syn diaxial interactions, especially with the Cmethyl group. Equilibration of C(i6),C i7) ketols favours the I7 0 hydroxy-i6-ketone (ii) for the same reason [44] ... 

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