Sodium hydride enones

The hydrogeh atom bound to the amide nitrogen in 15 is rather acidic and it can be easily removed as a proton in the presence of some competent base. Naturally, such an event would afford a delocalized anion, a nucleophilic species, which could attack the proximal epoxide at position 16 in an intramolecular fashion to give the desired azabicyclo[3.2.1]octanol framework. In the event, when a solution of 15 in benzene is treated with sodium hydride at 100 °C, the processes just outlined do in fact take place and intermediate 14 is obtained after hydrolytic cleavage of the trifluoroacetyl group with potassium hydroxide. The formation of azabi-cyclo[3.2.1]octanol 14 in an overall yield of 43% from enone 16 underscores the efficiency of Overman s route to this heavily functionalized bicycle. 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

Fig (14) Olefin (107) has been converted to cyclic ether (114) by standard reactions. Its transformation to enone (115) is accomplished by annelation with methyl vinyl ketone and heating the resulting diketone with sodium hydride in dimethoxyethane. The ketoester (116) is subjected to Grignard reaction with methyllithium, aromatization and methylation to obtain the cyclic ether (117). Its transformation to phenolic ester (119) has been achieved by reduction, oxidation and esterification and deoxygenation. 

Scheme 40 illustrates an interesting two-step selective reduction of an enone system, first with sodium hydride and NaAlH2(0CH2CH20Me)2 and then with the same reagent in the presence of 1,4-diazabicy-clo[2.2.2]octane. Specific reduction, however is not achieved with NaBH4, UBH4, LiBHBu s or 9-BBN-H.250... 

Any equilibrium will produce the thermodynamically most stable enolate. The most stable enolate will have the greatest charge delocalization. In the above example, the thermodynamically favored enolate is conjugated the kinetically favored enolate is not. Common conditions for thermodynamic control are to use average bases (like sodium ethoxide or potassium tert-butoxide, p abH 16 to 19) in alcohol solvents. Proton transfer equilibria rapidly occur among base, solvent, ketone, and enolate. Sodium hydride or potassium hydride in an ether solvent are also thermodynamic reaction conditions that allow equilibration between the ketone and the enolate. Enones have two possible enolates weaker bases give the thermodynamically more stable extended enolate, whereas kinetic conditions produce the cross-conjugated enolate. 

Acylketene dithioacetal 107 and the corresponding /3-methylthio-a,/3-enone 108 undergo self-condensation and aromatization in the presence of sodium hydride and methyl benzoates in refluxing xylene to give 2,6-bis(methylthio)-4-hydroxyacetophenone (109) and 4-hydroxyacetophenone (110), respectively, in good yields (equation 103) . The possible pathway for the formation of 109 and 110 could involve base-catalysed condensation of either 107 or 108 with methyl benzoates followed by successive inter-and intramolecular Michael additions and elimination of SMe. No reaction is observed in the absence of methyl benzoates. 

Sodium hydride. 14, 288 16, 307-308 Enol carbonates. D-Acylation is enolates, which are generated with NaH-esters at 0°C. Aryl and a,/3-enone ei o4 TMEDA at -78°. 

Alkylation of the enolate of (138) with methallyliodide gave the product (149) whose stereochemistry was assigned on the basis of equilibration experiment. It was converted to the dione (150) by oxidation with osmium tetrooxide and sodiumperiodate. The aldol cyclization of (150) effected with sodium hydride and trace of t-amyl alcohol in refluxing benzene afforded the enone (151) in 88% yield. Normal protic conditions (sodium hydroxide, ethanol) were not effective in this transformation. All attempts for its conversion to aphidicolin (148) by intermolecular additions proved fruitless and therefore were turned to intramolecular methods. Molecular models show clearly that the top face of the carbonyl group is less hindered to nucleophilic attack than is the bottom face. Thus the reduction of (151) with lithium aluminium hydride afforded the alcohol (152) whose vinyl ether (153) was subjected to pyrolysis for 2 hr at 360 C in toluene solution containing a small amount of sodium t-pentoxide to obtain the aldehyde (154) in 69% yield. Reduction and then tosylation afforded the alcohol (155) and tosylate (156) respectively. Treatment of this tosylate with Collman s reagent [67] (a reaction that failed in the model system) afforded the already reported ketoacetonide (145) whose conversion to aphidicolin (148) has been described in "Fig (12)". 

Monoalkylation of a., -unsaturated ketones see also 4, 300). Alkylation of enamines of enones usually gives low yields of C-alkylated products because of competing N-alkylation. An expedient is to convert the N,N-dimethylhydrazone of the enone into the metalloenamine by a strong base (sodium hydride or LDA... 

Starting from 3,4-dimethylcyclohex-2-enone, a methyl group and the ester function are introduced in a single step. Prior to the reduction of the ester with aluminium hydride, the keto-function is protected as an enolate by deprotonation with sodium hydride. The aluminate thus produced is protonated diastereose-... 

The sodium hydride abstracts a proton on mi allylic position on y to the enone, producing an anion with extended delocalization between positions a and y. 

Cyclohept-2-enone and cyclo-oct-2-enone undergo ring-contraction to 1-acetyl-cyclopentene and 1-acetylcyclohexene, respectively, in aqueous ethanol containing triethylamine at 140 Treatment of eucarvone with sodium hydride and methyl iodide gave a mixture of products including the bicyclic compounds 3-methylcar-4-en-2-one and l,3-dimethylcar-4-en-2-one. Attempts to dehydrate cycloheptene (237) gave mixtures of dimethylisopropylbenzenes. ... 

The selective reduction of enones may be achieved by use of the correct catalyst. Thus reduction of enones by sodium hydride-sodium alkoxide mixtures with zinc(ii) chloride as catalyst gives 1,2- whereas nickel(ii) acetate gives 1,4-reduction. Similarly, use of cobalt(ii) or nickel(ii) chlorides yields only saturated ketones from the borohydride reduction of /3-alkyl- or /3-aryl-thio-enones. ... 

Further studies of complex reducing agents based on sodium hydride have shown that a mixture of sodium hydride, sodium t-amylate, and zinc chloride (ZnCRA) gives regioselective 1,2-reduction of a, 8-enones to allylic alcohols, in contrast to the 1,4-reduction preference shown by the earlier developed NiCRA (3,135). The activity is enhanced by the addition of MgBr2. 

Optimum conditions for the reduction of saturated ketones by the complex reducing agent formed from sodium hydride, sodium t-amylate, and Ni" acetate (NiCRA) have been delineated.Reoxidation of the secondary alcohol products is dramatically postponed by the addition of alkali- or alkaline-earth-metal salts, and catalytic ketone reductions are achieved with NiCRA-MgBr2 mixtures. Full details of the reducing properties of various complex metal hydrides (12) of copper, formed by reaction of UAIH4 with appropriate lithium methylcuprates [equation (1)], have been published for example enones are reduced pre-... 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

The rest of the synthesis (Scheme 13) is completely stereospecific and most of the steps are known (20). The bicyclic acid was oxidatively decarboxylated with lead tetraacetate and copper acetate (21). The resulting enone was alkylated with methyllithium giving a single crystalline allylic tertiary alcohol. This compound was cleaved with osmium tetroxide and sodium periodate. Inverse addition of the Wittig reagent effected methylenation in 85% yield. Finally, the acid was reduced with lithium aluminum hydride to grandisol. 

Reductions. This hydride is a strong reducing agent comparable to other lithium trialkylhydrides. It is superior to DIBAH for selective 1,2-reduction of enones. Reduction of ketones, esters, acid chlorides, and anhydrides proceeds at -78°. However, ketones can be reduced selectively in the presence of an ester. Esters are reduced to a mixture of an alcohol and an aldehyde. Complete reduction to an alcohol can be effected by reduction at -78° with 2 equiv. of 1 and then with excess sodium borohydride. Tertiary amides are reduced by 1 equiv. of the reagent to aldehydes in generally high yield. Selective reduction of primary halides in the presence of secondary halides is possible. 

Na[AlH2(OCH2CH20CH3)2l (RED-AL) (sodium bis-[2-methoxyethoxy]-aluminium hydride) Ethers, toluene -78 to RT ester — alcohol ketone — alcohol aldehyde — alcohol alkyl halide — alkane epoxide — alcohol Dt,U-unsaturated enone —> allvlic alcohol... 

The first chiral aluminum catalyst for effecting asymmetric Michael addition reactions was reported by Shibasaki and coworkers in 1986 [82], The catalyst was prepared by addition of two equivalents of (i )-BINOL to lithium aluminum hydride which gave the heterobimetallic complex 394. The structure of 394 was supported by X-ray structure analysis of its complex with cyclohexenone in which it was found that the carbonyl oxygen of the enone is coordinated to the lithium. This catalyst was found to result in excellent induction in the Michael addition of malonic esters to cyclic enones, as indicated in Sch. 51. It had previously been reported that a heterobimetallic catalyst prepared from (i )-BINOL and sodium and lanthanum was also effective in similar Michael additions [83-85]. Although the LaNaBINOL catalyst was faster, the LiAlBINOL catalyst 394 (ALB) led to higher asymmetric induction. 

Correct reagent selection allowed reduction of steroidal enone (74) to either diastereoisomeric allylic alcohol, uncontaminated by its isomer. Sodium borohydride/cerium chloride in methanol-THF gave the equatorial alcohol (73), while L-selectride produced the axial isomer (75) via equatorial attack (Scheme 12). Unexpected axial attack on diketone (76) to give equatorial alcohol (77 equation 19) led to the proposition that for hydride additions to decalones two 1,3-diaxial interactions override one peri interaction which in turn takes precedence over a single 1,3-diaxial interaction. ... 

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