2-Cyclohexenone lithium enolates

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

The addition of the lithium enolates of methyl acetate and methyl (trimelhylsilyl)acetate to ( + )-(S)-2-(4-methylphenylsulfinyl)-2-cycloalkenones gives, after desulfurization, (/ -substituted cycloalkenones. A higher level of selectivity is observed with the a-silyl ester enolate and in the cyclohexenone series13. The stereochemical outcome is rationalized by assuming attack on a ground-state conformation analogous to that in Section 1.5.3.2.1. 

The final step in a recent synthesis of cannabichromene (2) is the aromatization of the cyclohexenone ring of 1. Reagents used for this purpose also attack the double bond in the side chain, but the desired reaction was effected by treatment of the lithium enolate of 1 with benzeneselenenyl chloride followed by selenoxide elimination in the presence of 3,5-dimethoxyaniline.5... 

Aromatization of cyclohexenonesf This reaction is possible by selenenylation of (lie lithium enolate of the cyclohexenone, followed by oxidation of the resulting xclcnide. To obtain satisfactory yields of the phenol, an aromatic amine is added in llu oxidation step to react selectively with the benzeneselenenic acid formed. For this pin pose, 3,5-dimethoxyaniline is the most satisfactory amine. 

Tandem inter- and intramolecular Michael addition using the enolates of aj3-unsa-turated ketones as Michael donors has also been successfully achieved [139]. For instance, treatment of cyclohexenone (133)-ATPH complex in toluene with a THF solution of the benzalacetone lithium enolate at -78 °C, then reflux for 13 h gave the stereochemically homogeneous annulation product 134 in 50 % yield (> 84 % de) as indicated in Sch. 102. 

Bicycloannelation.2 The a -enolate of an a,/J-cyclohexenone reacts with this phosphonium salt to form a tricyclo[3.2.1.02 7]octane in low to moderate yield. This reaction was used in a short synthesis of the pentacyclic diterpene trachyloban-19-oic acid (4). Reaction of the lithium enolate of 2, prepared from podocarpic acid, with I provided the pentacyclic ketone 3, which was reduced by the Wolff-Kishner reaction to 4. 

Cyclohexenone adds Bu2CuLi to give the lithium enolate 54 which is quenched with methyl iodide to give the anti disubstituted24 ketone 55. This could in principle be made from the ketone 56, but whatever regioselectivity 56 might show with LDA cannot be expected to favour 54. 

Kinetic enolisation and reaction at the a position are easy to control by lithium enolates. Hence cyclohexenone reacts with LDA to give the enolate 90 which is alkylated at the a position to give 91 but silylated on oxygen24 to give 92, much as expected for simple lithium enolates (chapter 2). 

Similarly, the simple lithium enolate 4.143 reacts with cyclohexenone at -78 °C to give the product 4.142 of direct attack, but warming the reaction mixture to room temperature allows this step to revert to the starting materials, and they then form the thermodynamically more stable product 4.144 of conjugate attack.374 /3-Dicarbonyl enolates, commonly used in Michael reactions, usually do not allow the isolation of the product of direct attack, since the first step is even more easily reversible in such cases. 

The lithium enolate of methyl trimethylsilyl acetate adds to cyclopentenone and cyclohexenone sulfoxides by the nonchelate model with good to excellent selectivity, as shown in Scheme 5.42a [210]. After the Michael addition, the sulfoxide and trimethylsilyl groups are removed, and the selectivity is assessed by determining the... 

Conjugate addition. Trialkylstannyllithium reagents prepared in ether solution undergo predominantly 1,2-addition to cyclohexenones, but solutions prepared in THF undergo conjugate addition to almost all enones, even hindered ones. The intermediate lithium enolates can be alkylated with reactive alkyl halides. These reactions are useful because secondary alkylstannanes are converted into the corresponding carbonyl compound by oxidation with Cr03-2Py. Tertiary alkylstannanes are also oxidized by CrOa-lPy, but mixtures of alcohols and products of dehydration are formed. 

Related Mannich reactions have been reported by Holy and Wang. These chemists generated the silyl enol ethers under either thermodynamic or kinetic control, but cleaved the ether with methyllithium to the same lithium enolate and then added the Mannich salt. Product distributions demonstrated that the addition reaction is regiospecific. They also found that the reaction can be conducted by the trapping technique of conjugate addition of dimethylcopper-lithium to cyclohexenone followed by addition of the immonium salt (equation I.)... 

Cyclohexenones and Related Derivatives. House and Wilkins have now demonstrated that addition of lithium dimethylcuprate to 3-methylcyclohex-3-enone in 1 1 molar equivalents results in a solution of the lithium enolate and a precipitate of (MeCu). Even when soluble cuprous species occur, there is no evidence to suggest that reaction with lithium enolates to give copper(i) enolates occurs. In a 1,4-addition reaction phenylithio[(a-diethoxymethyl)vinyl] cuprate with cyclohexenone at 233 K in Et20 gave ultimately 88% of the 3-allylcyclohexanone (38) (a-diethoxymethyl)-vinylcopper gave the 1,2-addition product. 

The conjugate addition of enolate anions to activated 3-trimethylsilyl-3-buten-2-one helped solve another long-standing problem in organic synthesis by permitting the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration is avoided. The annulation of thermodynamically unstable lithium enolates with MVK, where equilibration to the more stable enolate occurs prior to Michael addition, often yields a mixture of stractmal isomers. For exan le, Boeckman successfully employed 3-trimethylsilyl-3-buten-2-one in a Robinson annulation sequence (eq 2). Thus treatment of cyclohexenone with lithium dimethylcuprate in diethyl ether and then with 3-trimethylsilyl-3-buten-2-one gives the desired Michael adduct, which is converted into the functionalized octalone in 52% overall yield. ... 

The reaction between an aryl vinyl selenoxide and ketone lithium enolates provides a convenient preparation of cyclopropyl ketones/ Further details have appeared concerning the bicycloannulation of cyclohexenones by reaction of a -enolates with vinylphosphonium salts, to form tricyclo[3.2.1.0 ]octan-6-ones [equation (43)]/ The method has been used to synthesize the trachylobane carbon skeleton. The reaction can also be carried out with vinyl sulphones, but with this reagent HMPA is required for the cyclization to be successful. ... 

Notwithstanding a prior claim that methylthio esters react only sluggishly under these conditions, such a variant proved effective for a short synthesis of the 4-demethoxy-11-deoxyanthracycline skeleton (eq 72). This is especially significant because methylthio esters are available by an efficient C-C connective process involving C-acylation of ketone lithium enolates with Carbon Oxysulfide (COS) followed by S-methylation with lodomethane. For the deoxyanthracycline synthesis, the requisite enolate was generated by 1,4-addition of a silyl-stabilized benzyllithium derivative to 2-cyclohexenone. 

Ss2 reaction with a,fi-epoxy ketones.6 The enolate 1 of 2,3-epoxycyclohexanone reacts with methyllithium to give, after acidic work-up, 2-methy -2-cyclohexenone (3), the product of SN2 addition. Reaction of 1 with lithium dimethyl cuprate on the other hand results in 6-methyl-2-cyclohexcnonc (2), the product of Sv2 addition. 

The structure of catalyst 428 was proposed as a result of the several experiments shown in Sch. 60 and discussed below [89]. Firstly, it was observed that treatment of ALB catalyst 394 (Sch. 51) with methyllithium produced a solution from which the hexacoordinate aluminum species 434 (M = Li) could be crystallized in 43 % yield. The same compound could also be obtained from solutions prepared from 394 and nBuLi, and the sodium enolate of 425. Solid-state X-ray analysis of this compound revealed that it has the same structiu-e as the species 417 (Sch. 56) isolated by Feringa and coworkers during the preparation of ALB with excess BINOL (Sch. 55) [86]. The tris-BINOL(tris-lithium) alimunum complex 434 is not the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone because the use of this material as catalyst gave the Michael adduct 426 in 28 % yield and 57 % ee which is dramatically lower than obtained by use of catalyst 428 (Sch. 59). In addition, the use of catalyst 434 (M = Li) gave the alkene product 429 in 13 % yield, a product that was not seen with catalyst 428. Additional evidence comes from the reaction between 425 and cyclopentenone with catalyst 434 (M = Li) which gives the adduct 427 in 78 % yield and 12 % ee. 

A remarkably facile tandem 1,4-conjugate addition Claisen rearrangement is observed by utilizing the copper enolate derived by addition of lithium dimethylcop-per to 2-(allyloxy)-2-cyclohexenone. The resultant hydroxy ketone is obtained as a single stereoisomer in nearly quantitative yield. 

Lithium cyclohexadienolates, generated from the corresponding cyclohexenones with lithium diisopropylamide (method A) or produced without using amines from the trimethylsilyl enol ethers, undergo addition to 2-chloro-2-cyclopropyUdeneacetates at ambient temperature in an inert solvent to give y-oxo esters in good to excellent yield (see Table 5). These products can be readily transformed to multifunctional bicyclo[2.2.2]octanes 31 as well as bicyclo[3.2.1]octane derivatives 32. ... 

Many of the naturally occurring ochtodanes have a double bond in the ring, and the most direct way to 5,5-dimethyl-2-cyclohexenone (728) is from the enol ether of dimedone by lithium aluminum hydride reduction. " The cyclohexenone can then be used directly to introduce a C2 unit it was also reduced catalytically to the previously mentioned 3,3-dimethylcyclohexanone. Treatment of the ozonolysis product from 3-carene (277) with sodium ethoxide also led to a ketone, 729, that might be a useful starting material. ... 

Regiosp>ecific synthesis of enol silyl ethers can also be achieved from enones either by reductive silylation or by 1,4-addition of the conjugated system. Thus, Li/NH reduction of the decalone (27) and silylation give the enol silyl ether (28). Similarly, addition of lithium dimethylcuprate to cyclohexenone followed by silylation gives the enol silyl ether (29). Trimethylsilyl cyanide (30) normally adds 1,2 to conjugated ketones (e.g. carvone, 31). However, in the presence of trialkylaluminum, 1,4-addition bdces place to give the enol silyl ether (32 Scheme 9). The same overall transformation can be accomplished by diethylaluminum cyanide and trimethylchlorosilane. ... 

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