Reaction with Carbonyl Compounds 2 Imines

The deoxygenation of aldehydes and ketones to the corresponding hydrocarbons via the hydrazones is known as the Wolff-Kishner reduction. Various modifications of the original protocols have been suggested. One of the most useful is the Huang-Minlon modification, which substituted hydrazine hydrate as a safer and less expensive replacement of anhydrous hydrazine. In addition, diethylene glycol together with sodium hydroxide was used to increase the reaction 

Y(03SCF3)3 to afford a monoaminoalkylation product in good yield in aqueous media. Zinc tetrafluoroborate is also highly effective for such couplings in aqueous THF. Kobayashi also reported a Mannich-type reaction of imines with silyl enolates catalyzed by neutral salts such as sodium tiiflate in water as a suspension medium. Unusual kinetic behavior indicates that the presence of the Mannich adduct facilitates the rate of its formation. 

On the other hand, Kobayashi has developed a Bronsted acid-combined catalyst for aqueous Mannich-type reactions. Three-component Mannich-type reactions of aldehydes, amines, and ketones (e.g., benzaldehyde, p-anisidine, and cyclohexanone) were efficiently 

It has also been shown that dimethylsilyl enolates can be activated by diisopropylamine and water and exhibit a high reactivity toward A -tosyl imines to give Mannich-type reaction products in the absence of a Fewis acid or a Bronsted acid. For example, the reaction of [(1-cyclohexen-l-yl)oxy]dimethylsilane with 4-methyl-A/ -(phenylmethylene)benzene sulfonamide gave re/-4-methyl-N- (f )-[(15)-(2-oxocyclohexyl)phenyl-methyl] benzenesulfonamide (anri-isomer) in 91% yield stereoselectively (99 1 antvsyn) (Eq. 11.30). On the other hand, Fi and co-workers reported a mthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions by reacting allyl alcohol and imine in protic solvents. 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water ( 4 vol%). Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31). The diastereoselective Mannich-type reaction 

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In this section, reactions of zinc dienolates with carbonyl compounds, imines and conjugated enones will be considered all of these reactions have been proved to be reversible, and, hence, conditions favouring either kinetic or thermodynamic control will drive the reaction towards the formation of different regioisomers. Generally, equilibrating conditions lead to attack at the position of 190, as a thermodynamically more stable conjugated carbonyl or carboxylic compound is formed on the other hand, kinetic control leads to attack at the electron richer a-position. 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

In recent years, it has been shown that co-ordinated phosphines may also undergo reactions with carbonyl compounds. This is well exemplified in the reactions of [(MeHPCH2CH2PHMe)2Pd]2+ (Fig. 5-51). The reaction with formaldehyde yields a complex of an open-chain hydroxymethyl substituted ligand, the same species that is obtained from reaction of the free ligand. This is the phosphorus analogue of the aminol intermediate in imine formation. It is extremely unusual to obtain RP=CR2 systems in the absence of sterically demanding substituents. 

More general solutions come from the replacement of alkylations by reactions with carbonyl compounds. These generally occur once only and in many cases cannot occur twice as the products—amides 12 or imines 15 for example—are much less nucleophilic than the starting amine. The products are reduced to the target amines. The amide route is restricted to amines with a CH2 group next to nitrogen 13 but the imine route is very general and is known as reductive animation.1 It is the most important way to make amines and a recent survey showed that the majority of amines made in the pharmaceutical industry are made this way. 

Reaction with carbonyl compound 8 produced optically active imine 48 that could add cyanide to afford the chiral a-aminonitrile 49. 

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