Grignard reagents cyclohexanones

Cyclohexanone shows most of the typical reactions of aUphatic ketones. It reacts with hydroxjiamine, phenyUiydrazine, semicarbazide, Grignard reagents, hydrogen cyanide, sodium bisulfite, etc, to form the usual addition products, and it undergoes the various condensation reactions that are typical of ketones having cx-methylene groups. Reduction converts cyclohexanone to cyclohexanol or cyclohexane, and oxidation with nitric acid converts cyclohexanone almost quantitatively to adipic acid. 

Grignard reagents undergo a general and very useful reaction with ketones. Melhylmagnesium bromide, for example, reacts with cyclohexanone to yield a product with the formula C7HuO. What is the structure of this product if it has an IR absorption at 3400 cm-1 ... 

The conjugate addition of Grignard reagents to 2-cyclohexenone was promoted by catalytic amounts (2-4 mol %) of alkylcopper(I) complexes of the lithium amide prepared from N- (R)-1 -phenylethyl]-2-[(/ )-l-phenylethyliminojcycloheptatrienamine, Li[CuR(CHIRAMT)]52,11. However, 3-substituted cyclohexanones were obtained in very low ee (4-14%). 

When cyclohexanone oxime 6e was used as amination reagent, primary amines were obtained from phenylmagnesium bromide. Reaction of 6e with alkyl Grignard reagents gave aziridines, whereas reaction with phenyllithium gave aziridine and the addition product of phenyllithium to the imine (Scheme 57) 24. 

This method is based on the procedure of Kazarin.2 The same substance has been prepared by the reaction of the dimagnesium halide of acetylene with cyclohexanone 3 and also by the reaction of cyclohexanone with acetylene in the presence of potassium /erZ-butoxide followed by the preparation of the Grignard reagent of this compound and further reaction again with cyclohexanone.4... 

Dibutylbenzene has been prepared from cyclohexanone by tedious, multistep procedures.3 4 The present one-step method is based on the selective cross-coupling of a Grignard reagent with an organic halide in the presence of a phosphine-nickel catalyst.3... 

Ketoacids with a 1,6-relationship are easily made from cyclohexanone 9 by addition of an organo-lithium or Grignard reagent, dehydration of the tertiary alcohol 10 and oxidation of the cyclohexene 11 to form 12. 

Equatorial, and Axial Addition of Classic Grignard Reagents and Reetz-Grignard Reagents to a Conformationally Fixed Cyclohexanone... 

Magnesium reacts with alkyl halides to form alkyl magnesium bromide salts known as Grignard reagents. As mentioned throughout this book, these species bear nucleophilic carbon atoms. As illustrated using arrow pushing, the alkyl anion adds to the carbonyl and subsequently eliminates methoxide. This addition-elimination process leads to the formation of cyclohexanone. 

Once again, the best choice is a Grignard reaction, but there are two possible reactions that give the methylcyclohexane skeleton. A cyclohexyl Grignard reagent can add to formaldehyde, or a methyl Grignard reagent can add to cyclohexanone. (There are other possibilities, but none that are more direct.)... 

If the aldehyde is protected as an acetal, however, it is unreactive toward a Grignard reagent. The masked aldehyde is converted to the Grignard reagent, which is allowed to react with cyclohexanone. Dilute aqueous acid both protonates the alkoxide to give the alcohol and hydrolyzes the acetal to give the deprotected aldehyde. 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

The most successful application of this method has been the synthesis of 2-substituted cyclohexanones by the action of either aliphatic or aromatic Grignard reagents on 2-chlorocyclohexanone. An example is the formation of 2-phenylcyclohexanone (R = CjH,) in 60% yield. The... 

Only a few cases of the reduction of alkyl enol ethers to the corresponding alkene have been reported. a-Ethoxystyrene and related derivatives are reduced to alkenes by treatment with Grignard reagents. In addition, enol ethers of cyclohexanone derivatives have been cleaved to the cyclohexene products using either DIBAL at elevated temperatures or diborane/boron trifluoride etherate. By analogy to the hy-droboration of silyl enol ethers, this latter method involves formation of an intermediate p-ethoxy or-ganoborane which undergoes acid-catalyzed elimination to afford the alkene. 

Application of the purified magnesium method to l,3-dibromo-2,2-dimethylpropane affords 15 18% of 1,3-di-Grignard reagent [23], which has been reacted with two molecules of cyclohexanone to afford the expected 1,3-diol [24]. However, the substitution pattern of the 1,3-di-Grignard reagent is limited one /i-alkyl substituent resulted in low yields and high decomposition rates owing to increased / -hydride mobility [25]. 

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