Cyclohexanones lithium salts

The unsaturated tetraoxaquaterene (accompanied by linear condensation products) was first synthesized in 18.5% yield by the acid-catalyzed condensation of furan with acetone in the absence of added lithium salts. Other ketones also condensed with furan to give analogous products in 6-12% yield.A corresponding macrocycle was also prepared in 9% yield from pyrrole and cyclohexanone. The macrocyclic ether products have also been obtained by condensation of short linear condensation products having 2, 3, or 4 furan rings with a carbonyl compound. ... 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

In addition to previously described syntheses4-5 by diazo group transfer with deformylation,6 2-diazocyclohexanone has been prepared by two variants of this method. In one, the reaction of 2-(hydroxymethylene)cyclohexanone with -toluene-sulfonyl azide is carried out in ether/diethylamine, and an enamine is assumed to be formed as an intermediate 7 in the other, the sodium salt of the hydroxymethylene compound was treated with the lithium salt of p-carboxybenzenesulfonyl azide... 

For conversion of ketones into a,/3-unsaturated aldehydes containing two additional carbon atoms, several multistep processes via ethynyl or vinyl carbinol intermediates have been reported.4-10 Although the overall yields obtained by these routes for the conversion of cyclohexanone into cyclohexylideneacetaldehyde have never exceeded 50%, they were the only useful methods for this type of conversion until the excellent process of Wittig11 appeared. This process consists of normal aldol condensations of ketones with the lithium salt of ethylidenecyclohexylamine and subsequent dehydration and hydrolysis. 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

This seemingly simple result may have far reaching consequences. For example, it may help to explain the effect of added lithium salts in nucleophilic additions to cyclohexanones as discussed earlier in this chapter. Thus, model (63) shown in Figure 472.135-137 explain the enhancement of rate and may also be relevant to the origins of stereoselectivity in this reaction. Of course, the exact location of the lithium atom and the aggregation state of the adding nucleophile are subject to speculation, since for lithium these parameters seem to be highly variable. 

Indeed, addition of alkali halides and particularly LiCl or LiBr allows the reduction of 4-tert butyl cyclohexanone with nearly quantitative yields20. Note that with other ketones, addition of lithium salt improves the reproducibility of their reduction by strongly postponing the reoxidation. 

The reaction of carbonyl groups produces the opposite regioselectivity. The reaction of (41c) with cyclohexanone gives predominantly the a-adduct (a y = 71 29). The lithium salt of the trimethylsilyl derivative (41d) in THF-HMPA produces the a-adduct in reactions with a variety of aldehydes and ketones (98-100% regioselectivity). Mild acid hydrolysis of the product monosilyl ethers affords 3,4-dihydroxy-... 

Regiospecific alkylation of ketones. This salt converts trimethylsHyl enol ethers into quaternary ammonium enolates that undergo regiospecific monoalkylation. This method is especially useful for alkylation at the less substituted position of a cyclohexanone lithium enolates are more useful for alkylation at... 

Nickon investigated the 1,2-hydrogen shifts in thermal and photic Bamford-Stevens reactions of cyclohexanones. Under eonditions known to favor the Shapiro reaction, tosylhydrazone 18a afforded the two expected alkenes 19 and 20 as well as an unexpected product (identified as 21) in a ratio of 15 60 25. Under conditions known to favor the Bamford-Stevens reaction, lithium salt 18b was subjected to thermolysis (neat, 170 °C) and also to photolysis (pentane suspension, -70 °C). Under both sets of conditions the three products 19, 20 and 21 were formed in approximately the same ratio (84 4 12 and 83 6 11), thus demonstrating the switching of major alkene product from 19 to 20 on moving from the Shapiro reaction to the Bamford-Stevens reaction. 

The method described here gives higher yields of the macrocyclic tetraethers and allows the product from furan and cyclohexanone to be formed directly in 5-10% yield, whereas this product was previously obtained only by an indirect route. The added lithium perchlorate undoubtedly accelerates the reaction, since after short reaction times the product was isolated in 20% yield when the salt was present and in only 5% yield when the salt was absent. The lithium cation is presumably acting as a template which coordinates with the oxygen atoms of... 

Common reagents such as lithium diisopropylamide (LDA see Chapter 11, Problem 5) react with carbonyl compounds to yield lithium enolate salts and diisopropylamine, e.g., for reaction with cyclohexanone. 

Addition of LiBr or LiCl to a solution of Sml2 in THF causes a color change from blue to purple. Oxidation potential of Sml2 in THF changes from —1.33 V to —1.98 0.01 V upon addition of I2 or LiBr (more than 1 equiv.), or to —2.11 0.01 V by addition of 12 or more equiv. of LiCl. In the presence of 4-12 equiv. of the bromide or chloride salt, the pinacol coupling reaction of cyclohexanone is accelerated. These salts should be dried before use otherwise, simple reduction to cyclohexanol occurs. The co-existing lithium cation can also act as a Lewis acid to activate the carbonyl group by coordination. ... 

Preparative Methods the most convenient preparation of (/ ,/ )-stilbenediamine is described in Organic Syntheses." Condensation of benzil and cyclohexanone in the presence of ammonium acetate and acetic acid (eq 1) produces a spirocyclic 2//-imidazole (mp 105-106 °C). Reduction with Lithium in THF/NH3 followed by an ethanol quench and hydrolysis with aqueous HCl (eq 2) affords the racemic diamine as a pale yellow solid (mp 81-82 °C). Resolution is achieved by multiple recrystallizations of the tartaric acid salts ifom water/ethanol. The sulfonamides are prepared by reaction of the enantiomeri-cally pure diamine with the appropriate anhydride or sulfonyl chloride in CH2CI2 in the presence of Triethylamine and a catalytic amount of 4-Dimethylaminopyridine (eq 3). 

Preparative Methods (i) preparation of racemic DPEN and its optical resolution Reaction of benzil and cyclohexanone in the presence of ammonium acetate and acetic acid at reflux temperature gives a cyclic bis-imine (1) (eq 1). Stereoselective reduction of the bis-imine with lithium in THF-liquid ammonia at —78 °C followed by addition of ethanol, then hydrolysis with hydrochloric acid and neutralization with sodium hydroxide produces the racemic diamine (2). Recrystallization of the l-tartaric acid salt from a 1 1 water-ethanol mixture followed by neutralization with sodium hydroxide, recrystallization from hexane results in (5,5)-DPEN (3) as colorless crystals. 

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