Ketones, conversion amines

Enamidines (2). Lithiation of 1 followed by treatment with aldehydes or ketones results in Peterson olefination to give a mixture of isomeric enamidines (2) in good yield. These enamidines can be used to convert the carbonyl compounds used in (heir preparation to homologated amines, aldehydes, and ketones. Conversion to a mclhylaminc involves reduction with sodium borohydride (pH 6) to an aminal, which is then hydrolyzed by dilute acid. The sequence can be carried out from 1 without isolation of any intermediates (equation I). 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

Among the many reactions of these species is the conversion to chiral species such as 18-D-XIX. This compound can be obtained in enantiomerically pure form and can be converted to the CpRe(NO)PPh3 ion.69 This ion is a chiral Lewis base that binds a variety of prochiral molecules (olefins, ketones, aldehydes, amines). With these adducts one may conduct numerous reactions where enantiomeric excesses >98% are obtained. As an example, a prochiral methyl ketone will bind selectively, as in 18-D-XX and is then subject to attack by R X to produce only one enantiomer of the RR MeCO product. 

For the modified procedure, it was found that the relative amounts of TiCl4/ketone and amine /ketone which should be used to achieve a rapid conversion were highly dependent on the structure of the ketone.[7,8] In the example below, the formation of the morpholine enamine from methyl isobutyl ketone was studied. 

Figure 14.40 Celgene process for the conversion of ketones to amines using isopropylamine.

MORITA-BAYLIS-HILLMAN Vinyl Ketone Alkylation Amine catalyzed conversion of acrylates to a-(hydroxyalkyl) acrylates or of vinyl ketones to a-(hydroxyalkyl) vinyl ketones, also with chiral induction (see 1st edition). 

Transformation of 2,2 -dimethyl-l,3-propanediol yielded the corresponding diamine (70%) and the intermediate amino alcohol (7%) with 75% conversion (Figure 2). Temperatures above 210 °C were detrimental to diamine selectivity because of /5 o-butylamine formation by re/ro-aldol or retro-formylation reactions (Scheme 7). In the other two substrates, whieh have an H atom in C2 position, direct elimination of water to form a reactive allylic alcohol (or a,j0-unsaturated ketone or amine) was the major side-reaction which reduced selectivity. 

Conversion of Ketones. The hydroammonol rsis of ketones to amines can be carried out in either the vapor or the liquid phase. The technique employed depends on the ph rsiGal and chemical properties of the reactants and final products. 

Amides may also be prepared by conversion of ketones into amines followed by acylation. See section 102 (Amines from Ketones)... 

Leuckart reaction The conversion of ketones and aromatic aldehyde,s to primary amines by reaction with ammonium methanoale at a high temperature. 

The conversion of an aldehyde or ketone into the corresponding amine by heating with ammonium formate or with formamide and formic acid at about... 

Inspired by the work of Burk and Feaster ) we attempted to use (2-pyridyl)hydrazine (4.36) as a coordinating auxiliary (Scheme 4.10). Hydrazines generally react effidently with ketones and aldehydes. Hence, if satisfactory activation of the dienophile can be achieved through coordination of a Lewis acid to the (2-pyridyl)hydrazone moiety in water. Lewis-add catalysis of a large class of ketone- and aldehyde-activated dienophiles is antidpated Subsequent conversion of the hydrazone group into an amine functionality has been reported previously by Burk and Feaster ... 

The treatment of ketoximes with lithium aluminum hydride is usually a facile method for the conversion of ketones into primary amines, although in certain cases secondary amine side products are also obtained. Application of this reaction to steroidal ketoximes, by using lithium aluminum deuteride and anhydrous ether as solvent, leads to epimeric mixtures of monodeuterated primary amines the ratio of the epimers depends on the position of the oxime function. An illustrative example is the preparation of the 3(x-dj- and 3j5-di-aminoandrostane epimers (113 and 114, R = H) in isotopic purities equal to that of the reagent. 

Analogous to DPNH (144-146), 1,4-dihydropyridines (147) act as reducing agents. For instance, the conversion of aromatic nitro compounds to amines (148) and reduction of enones to ketones (749) has been achieved. 

The reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid in the presence of a strong acid is known as the Schmidt reaction A common application is the conversion of a carboxylic acid 1 into an amine 2 with concomitant chain degradation by one carbon atom. The reaction of hydrazoic acid with a ketone 3 does not lead to chain degradation, but rather to formation of an amide 4 by formal insertion of an NH-group. 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

TS-1 is a material that perfectly fits the definition of single-site catalyst discussed in the previous Section. It is an active and selective catalyst in a number of low-temperature oxidation reactions with aqueous H2O2 as the oxidant. Such reactions include phenol hydroxylation [9,17], olefin epoxida-tion [9,10,14,17,40], alkane oxidation [11,17,20], oxidation of ammonia to hydroxylamine [14,17,18], cyclohexanone ammoximation [8,17,18,41], conversion of secondary amines to dialkylhydroxylamines [8,17], and conversion of secondary alcohols to ketones [9,17], (see Fig. 1). Few oxidation reactions with ozone and oxygen as oxidants have been investigated. 

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