Cyclopentanone 2-methyl- enolization

Similarly, 144 has been obtained from the reaction of 1-trimethylsilylcyclopropyl methyl selenide with n-BuLi The a-bromosilane 147 underwent lithiation with n-BuLi in THF at —78 °C to provide 144 with superior efficiency to any other method, Eq. (46))81). 147 was prepared in large quantities by the Hunsdiecker degradation of the 1-trimethylsilylcyclopropanecarboxylic acid 146, obtained by successively reacting the commercially available cyclopropanecarboxylic acid with -BuLi (2 equivalents) and ClSiMe3 82). Uneventfully, 144 added to carbonyl compounds, except for cyclopentanone where enolate anion formation competed the 1-trimethylsilylcyclo-propylcarbinols 148 underwent acid-induced dehydration to the expected 1-trimethyl-silylvinylcyclopropanes 149 79-81) while base induced elimination (KH, diglyme, 90 °C) led to cyclopropylidenecycloalkanes 150 77), Eq. (47). 

Fig. 7.3. Crystal structures of some lithium etiolates of ketones. (A) Unsolvated hexameric enolate of methyl t-butyl ketone (B) tetrahydrofuran solvate of tetramer of enolate of methyl r-butyl ketone (C) tetrahydrofuran solvate of tetramer of enolate of cyclopentanone (D) dimeric enolate of 3,3-dimethyl-4-(r-butyldimethylsiloxy)-2-pentanone. (Structural diagrams are reproduced from Refs. 66-69.) by permission of the American Chemical Society and Verlag Helvetica Chimica Acta AG.

An important stage in the synthesis has been reached. It was anticipated that cleavage of the trimethylsilyl enol ether in 18 using the procedure of Binkley and Heathcock18 would regiospecifically furnish the thermodynamic (more substituted) cyclopentanone enolate, a nucleophilic species that could then be alkylated with iodo-diyne 17. To secure what is to become the trans CD ring junction of the steroid nucleus, the diastereoisomer in which the vinyl and methyl substituents have a cis relationship must be formed. In the... 

In a related study the adduct of the lithium enolate of methyl bis(trimethylsilyl)acetale and ( —)-(/J)-2-(4-methylphenylsulfinyl)-2-cyclopentanone was transformed to ( — )-methyl jasmonate in > 99% ee. In contrast to the previous study described in this section, addition of the enolate proceeded apparently through a chelated form of the enone15. 

The synthesis of the non-racemic cyclopentanone (+)-93 is outlined in Scheme 15. Starting with 2-methyl-cyclopent-2-enone (90), sequential cuprate addition and enolate alkylation afforded the racemic cyclopentanone rac-92 as a single diastereomer. The double bond was cleaved by ozonolysis, the resulting aldehyde chemoselectively reduced in the presence of the keto function and the primary hydroxyl function was subsequently protected as a silyl ether to provide racemic rac-93. This sequence has been applied fre-... 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

The procedure reported here provides a convenient method for the a-hydroxylation of ketones which form enolates under the reaction conditions. The reaction has been applied successfully to a series of para-substituted acetophenones, 1-phenyl-1-propanone, 3-pentanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclododecanone, 2-methyl cyclohexanone, 2-norbornanone and benzalacetone. In the case of a steroidal example it was shown that a carbon-carbon double bond and a secondary hydroxyl group are not oxidized. A primary amino function, as in the case of p-aminoacetophenone, is not affected.5 Similarly, a tertiary amino ketone such as tropinone undergoes the a-hydroxy at ion reaction.5... 

Michael addition.1 This ketene silyl acetal undergoes Michael addition to a,fl-enones in acetonitrile in the absence of a Lewis acid to afford the corresponding O-silylated Michael adduct in high yield. These O-silyl enolates undergo site-specific electrophilic substitution. This sequence was used for vicinal dialkylation of cyclohexanone (equation I) and of cyclopentanone. It is particularly useful for synthesis of methyl jasmonate and related compounds from cyclopentenone. 

Phenol annelation.1 This modified methyl vinyl ketone can be used for synthesis of 5,6,7,8-tetrahydro-2-naphthol or 5-indanol by reaction with the lithium enolate of cyclohexanone or cyclopentanone, respectively. The former reaction is formulated in equation (I). 

Iodobenzenesulfonamide (32) undergoes photostimulated SRN1 reactions in liquid ammonia, with the potassium enolates derived from acetone, pinacolone, 3-methyl-2-butanone, cyclopentanone, cyclohexanone and cyclooctanone, to give fair to good yields of 2H-l,2-benzothiazine-l, 1-dioxides (Scheme 10.59) [73],... 

The reductive dehalogenation predominates in the photoinduced reactions of 32 with 3-pentanone, 2-methyl-3-pentanone, and 2,4-dimethyl-3-pentanone. Although, substitution is favored over reduction in all of the reactions of 32 with cyclic ketone enolates, a competing reduction is responsible for the lower yields observed with cyclopentanone and cyclohexanone compared to cyclooctanone (Scheme 10.59) [73]. 

The rates for the methylation of cyclopentanone and for the proton abstraction from 2-methylcyclopentanone were significantly increased by a factor of 7500 and 5, respectively, when six equivalents of HMPA were added to the reaction. Using 31P, 7Li and 13C NMR spectroscopy, Suzuki and Noyori found that the tetrasolvated Dy dimer was exclusively generated from the tetrameric (T0,4) and dimeric (D0,4) tetrasolvated lithium amine-free enolate of cyclopentanone (0.16 M in THF, —100 °C, ratio 2/3)275. Kinetic analysis gave a first-order reaction in dimer and HMPA for the reaction with a modulation for free HMPA33, and a first-order reaction in dimer for deprotonation, independent of HMPA. Possible transition state structures for alkylation and proton abstraction are drawn in Scheme 85. 

Phosphinylation of the enolate anion obtained in situ by the 1,4-addition of the trimethyl trithioorthoformate anion to 2-cyclopentenone gives exclusively / w .v-2-(diphenylphosphino)-3-[tris(methylthio)methyl]cyclopentanone (1) which, after oxidation and methanolysis, produces methyl tranx-2-(diphenylphosphinyl)-3-oxocyclopentanecarboxylate (3)51. 

Exactly 10 years after the previous statement appeared, the first lithium enolate crystal structures were published as (5) and (6). Thus, structural information derived from X-ray diffraction analysis proved the tetrameric, cubic geometry for the THF-solvated, lithium enolates derived from r-butyl methyl ketone (pinacolone) and from cyclopentanone. Hence, the tetrameric aggregate characterized previously by NMR as (7) was now defined unambiguously. Moreover, the general tetrameric aggregate (7) now became embellished in (5) and (6) by the inclusion of coordinating solvent molecules, i.e. THE. A representative quotation from this 1981 crystal structure analysis is given below. 

Trapping of the Beckmann intermediates with enol silyl ethers affords facile entry to a variety of en-amino ketones. This condensation takes place with retention of regiochemical integrity in both oxime sulfonates and enol silyl ethers. Reaction of 6-methyl-l-(trimethylsiloxy)-l-cyclohexene (41) or 1-methyl-2-(trimethylsiloxy)-l-cyclohexene (42) with cyclohexanone oxime mesylate furnishes (43) or (44), respectively, as the sole isolable products (equation 25). Another striking feature of the reaction is the high chemospecificity. The condensation of the enol silyl ether (45), derived from p-acetoxyaceto-phenone, occurs in a chemospecific fashion with cyclododecanone oxime mesylate, the acetoxy moiety remaining intact (equation 26). Oxime sulfonates of aromatic ketones and cyclopentanones are not employable since complex reaction mixtures are formed. 

Problem 22.1 Draw structures for the enol lautoiners of the following compounds (a) Cyclopentanone (b) Methyl thioacetate (c) Ethyl acetate... 

Enolate equilibration and di- and poly-alkylation are the major side reactions, which lead to reduced yields of desired products in ketone alkylations. These processes occur as a result of equilibration of the starting enolate (or enolate mixture) with the neutral monoalkylation product(s) via proton transfer reactions. Polyalkylation may also occur when bases, in addition to the starting enolate, which are capable of deprotonating the monoalkylated ketone are present in the medium. With symmetrical ketones, e.g. cyclopentanone and cyclohexanone, the problem of regioselectivity does not arise. However, except under special conditions, polyalkylation occurs to a significant extent during enolate alkylations of more kinetically acidic ketones such as cyclobutanone, cyclopentanone and acyclic ketones, particularly methyl ketones. Polyalkylation is also a troublesome side reaction with less acidic ketones such as cyclohexanone. 

Scheme 2 shows the results of two studies on the methylation of the lithium enolate of cyclopentanone (10), which was prepared by deprotonation of the ketone with trityllithium in DME or by cleavage of the 1-trimethylsiloxycyclopentene with methyllithium in THF. A signiEcant quantity of over-alkylation occurred when the enolate was treated with methyl iodide, particularly when DME was employed as the solvent at room temperature. Also, as indicated in Scheme 2, Noyori and coworkers showed that by adding 3 equiv. of HMPA to the enolate (10) and reducing the temperature at which the reaction was conducted, the yield of 2-methylcyclopentanone was greatly improved.

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

The photocycloaddition of chloroprene to methyl 2,4-dioxopentanoate (4) has been reported. Only two de Mayo style products were obtained from this process and these were identified as the adducts (5) and (6) arising from the two paths of addition of the enol (7) to the diene. Precise kinetic data has been obtained for the photochemical dimerisation of the cyclopentanone derivative (8). ... 

Further reactions on these compounds lead to other oxidised products in which the lack of stereochemical control in the epoxidation is unimportant, so, for example isophorone oxide rearranges with various catalysts to the cyclopentanone 182 (80% yield) while both isomers of pulegone oxide 179 gives the cycloheptadione29 183 (78% yield). Exhaustive methylation of the extended enolate produced by reduction of 181 gives 184 in good yield.28... 

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