Imines, preparation from ketones

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

Organomagnesium compounds react with imines, prepared from 3-methoxy-2-naphth-aldehydes by a 1.4-addition mechanism. This reaction can be performed with high diastere-oselectivity. The method was applied for the synthesis of optically pure S-tetralones . Vinyhnagnesium bromide reacts as an acceptor with a ketone dimethyl hydrazone zincate 207, yielding a 1,1-bimetallic species, which can be reacted sequentially with two different electrophiles (equations 131 and 132) . The reaction proceeds via a metalla-aza-Claisen rearrangement, where the dimethylhydrazone anion behaves as an aza-allylic system . 

Enantioselective alkylation of ketones. Chiral imines prepared from cyclic ketones and 1 on metalation and alkylation are converted to chiral 2-alkyleyclo-alkanones in 87-100% enantiomeric purity.1 The high cnantioselectivity is dependent on chelation of the lithium ion in the anion by the methoxyl group, which results in a rigid structure. 

Substituted 4,5-dihydroazepines 281 can be prepared in high yield by a rhodium-mediated hetero-[5 + 21-cycloaddition of the cyclopropyl imines derived from ketones 279 on reaction with the primary amines 280, with dimethyl acetylenedicarboxylate (Scheme 146) <2002JA15154>. 

Piperidones (19) have been prepared from ketones (MeCOCH2R) and aromatic imines (Ar -N=CHAr ) via a double Mannich reaction and tandem cyclization. The l2-induced room temperature reaction is highly stereoselective, giving only one of four possible isomers. Chelation and hydrogen-bonding effects have been invoked to explain the specificity(g)... 

Originally, a C-20 amine (prepared from a bisnorcholanic acid) was converted into its 7V-chloro derivative, dehydrohalogenated to the imine, converted into the A-acetylenanime, reacted with perbenzoic acid, then hydrolyzed to the 17a-hydroxy-20-ketone ... 

Imine formation from such reagents as hydroxylamine and 2,4-dinitro-phenylhydrazine is sometimes useful because the products of these reactions— oximes and 2,4-dinitrophenylhydrazones (2,4-DNPs), respectively—are often crystalline and easy to handle. Such crystalline derivatives are occasionally prepared as a means of purifying and characterizing liquid ketones or aldehydes. 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

For the preparation of enamines or imines from ketones, see Section 356 (Amine-Alkene). 0 1. CFsSOsSiMes, MeCN S... 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Amines can react with various carbonyl compounds and their derivatives in aqueous media to give the corresponding imine derivatives. These reactions have been discussed in related chapters. The synthetically most useful reaction of this type is the formation of imines and imine derivatives from the condensation of amines with aldehydes and ketones. Water is an excellent solvent for such condensation reactions. For example, water was found to be an ideal solvent for a high-yield, fast preparation of easily hydrolyzable 2-pyrrolecarbaldimines.23 In the presence of Cu2+, the reaction afforded the corresponding Cu(II) chelates (Eq. 11.19). 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

Preparation of enantiomerically pare secondary amines by catalytic asymmetric hydrogenation or hydrosilylation of imines is as important as the preparation of alcohols from ketones. However, asymmetric hydrogenation of prochiral ON double bonds has received relatively less attention despite the obvious preparative potential of this process.98... 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

In contrast to earlier known imines, those imines derived from a-(methoxymethyl)benzene-ethanamine, which allow formation of a rigid chelate by additional coordination of the lithium with the methoxy group, enabled the preparation of a-alkylated cyclic ketones in very high enantiomeric excesses (90-99% ee)7,8. However, alkylations of imines derived from medium ring ketones were accomplished in 30-82% ee9. The alkylation of acyclic ketones was performed with enantiomeric excesses of more than 75 % and, in the case of the imine derived from 4-heptanone, proceeded with complete asymmetric induction10. 

The most general method for synthesizing amines involves the reduction of oximes and imine derivatives obtained from aldehydes or ketones (see Sections 5.5.2 and 4.3.11). By catalytic hydrogenation or by LiAltLj reduction, while 1° amines are prepared from oxime or unsubstituted imine, 2° amines are obtained from substituted imine. Unsubstituted imines are relatively unstable, and are reduced in situ. 

However, these compounds are generally unstable. Most imines with a hydrogen on the nitrogen spontaneously polymerize.143 Stable hemiaminals can be prepared from polychlorinated and polyfluorinated aldehydes and ketones, and diaryl ketones do give stable imines Ar2C=NH.144 Aside from these, when stable compounds are prepared in this reaction, they are the result of combinations and condensations of one or more molecules of 12 and/or 13 with each other or with additional molecules of ammonia or carbonyl compound. The most important example of such a product is hexamethylenetetramine145 (11), prepared from ammonia and formaldehyde.146 Aromatic aldehydes give hydrobenzamides ArCH(N=CHAr)2 derived from three molecules of aldehyde and two of ammonia.147... 

Chiral 2,2-disubstituted cycloalkanones.1 The imine 2 prepared from racemic 2-methylcyclohexanone and (S)-( - )-l, reacts with methyl vinyl ketone to form an adduct that is hydrolyzed to the (R)-( + )-diketone 3 in 91% ee with recovery of 1 in almost quantitative yield. The reaction is described as a deracemizing alkylation. ... 

As shown in Scheme 1.95, the chiral titanocene catalyst 34 (see Scheme 1.10) prepared from 33, n-C4HgLi, andC6H5SiH3 shows a moderate-to-good enantioselectivity in the hydrogenation of /V-benzyl i mines of aryl methyl ketones, whereas the catalytic activity is rather low even at 137 atm [346]. The ketimine with R1 = 4-CH3OC6H4 is hydrogenated with (/ )-34 to give the R amine with 86% ee. The E Z of the imine substrate affects the enantioselection. The optical... 

The nucleophilic activation of hydrosilanes as HSi(OR)3 offers an opportunity to transfer one hydride on the carbon of ketones or imines [22]. The enantioselective organocatalytic hydrosilylation of ketones was first reported in 1999 by Matsu-mura et al. [23], the catalyst employed being a proline derivative 19 (Scheme 11.7). Amide 20 was also able to catalyze the hydrosilylation of ketimines, as indicated in Scheme 11.7 [24]. Improved results were recently reported by Kocovsky and Maikov [25], who prepared from valine some acyclic analogues of prolina-... 

Archer et al. obtained 3a-A-(2-diethylaminoethyl)aminotropane (4) in 85% yield by hydrogenation of the imine 3, prepared from the reaction of tropinone (1) with 2-diethylaminoethylamine (2), over platinum oxide in ethanol at room temperature (eq. 8.3).4 The same hydrogenation was also carried out over Raney Ni at 60°C and 6.9 MPa H2. The product was converted directly to the phenyl thioureide without isolating the amine. Compound 4 was also obtained in a 66% yield by hydrogenating the imine 3, which had been prepared in situ in ethanol by allowing a mixture of 1 and 2 to stand for 2 h, over prereduced platinum oxide mostly at room temperature and finally at 50°C to finish the reaction. In a large-scale run in methanol, a 77.8% yield of 4 was obtained (eq. 8.3). It was noticed that it was not necessary to prereduce Adams platinum oxide when the ketone and the amine were premixed, since the induction period could be eliminated by this procedure. 

Stereoselective reduction of cyclohexylimines. Imines of alkyl-substituted cyclohexyl ketones are reduced by this borohydride stereoselectively (>90%) to axial secondary amines. Axial primary cyclohexylamines are prepared conveniently by reduction of the imine derived from/ ,/) -dimethoxybenzhydrylamine and sub.scquent cleavage with formic acid (equation 1). 

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