Amino ketones formation

Azirines react with alcohols in the presence of alkoxides to give alkoxyaziridines (67JA4456). Further treatment with alcohol and alkoxide results in the formation of amino ketone acetals. Alkoxyaziridines are not isolated in general from the acid-catalyzed addition of methanol to azirines. Azirines are also known to react with amines (66JOC1423). Frequently the initially produced adducts undergo subsequent transformations. 

Reaction of 2-alkyl- -pyrrolines and 2-alkyl- -piperideines with acid chlorides leads to ring-opening and formation of N-acylated amino ketones (131, = 1, 2) (211-213). Ketene reacts with J -piperideine to form a tricyclic derivative (132) (214). 

The intermediate formation of iminium salts is postulated in the reduction of (x-amino ketones by the Clemmensen method, occurring with concomitant ring enlargement or contraction (244-246). Reduction of l,2,2-trimethyl-3-piperidone (154) in this manner gave l-methyl-2-iso-propylpyrrolidine (155). 

Scheme 5.15. Lewis acid-catalyzed formation of an a-amino ketone.

The simple primary amines of the aliphatic series, then, do not form diazo-compounds because the reaction which would le, d to their formation only occurs at a temperature at which they are destroyed. The reactivity of the NH2-group can, however, be increased by a neighbouring carbonyl group. Thus we come to the case of the esters of the a-amino-carboxylic acids and of the a-amino-ketones. The ethyl ester of glycine can be diazotised even in the cold the diazo-compound which does not decompose under these conditions undergoes stabilisation by elimination of water and change into ethyl diazoacetate ... 

Electroreduction of aliphatic amides in the presence of chlorotrimethylsilane gives coupling products and this reaction is useful for the synthesis of a-amino ketones (Scheme 22) [41]. In this reaction, the formation of an Mg salt promotes the coupling of two anion radical centers. 

The electrolysis of asymmetric ketones 43 led to the formation of isomers and stereoisomers. Kinetic measurements for the formation of ketimine 43 in saturated ammoniacal methanol indicated that at least 12 h of the reaction time were required to reach the equilibrium in which approximately 40% of 42 was converted into the ketimine 43. However, the electrolysis was completed within 2.5 h and the products 44 were isolated in 50-76% yields. It seems that the sluggish equilibrium gives a significant concentration of ketimine 43 which is oxidized by the 1 generated at the anode, and the equilibrium is shifted towards formation of the product 44. 2,5-Dihydro-IH-imidazols of type 44, which were unsubstituted on nitrogen, are rare compounds. They can be hydrolyzed with hydrochloric acid to afford the corresponding a-amino ketones as versatile synthetic intermediates for a wide variety of heterocyclic compounds, that are otherwise difficult to prepare. 

Further research on intramolecular photocyclization of amino enones and amino ketones based on electron transfer has been made by Kraus and Chen [228]. In analogy to the earlier results of Roth and El Raie [229], Kraus and Chen obtain the cyclopropanol derivative 286 as single stereoisomer by direct irradiation of 285. Photolysis of the amino enone 287 does not lead to a three-membered ring product, but only to pyrrolidine 288. The irradiation of the unsaturated keto ester 289 results in the even more unexpected formation of a nine-membered ring product 290. Such remote photocyclizations have rarely been described so far. 

Two years later, Terada and coworkers described an asymmetric organocatalytic aza-ene-type reaction (Scheme 28) [50], BINOL phosphate (7 )-3m (0.1 mol%, R = 9-anthryl) bearing 9-anthryl substituents mediated the reaction of A-benzoylated aldimines 32 with enecarbamate 76 derived from acetophenone. Subsequent hydrolysis led to the formation of P-amino ketones 77 in good yields (53-97%) and excellent enantioselectivities (92-98% ee). A substrate/catalyst ratio of 1,000 1 has rarely been achieved in asymmetric Brpnsted acid catalysis before. 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Cyclic dimerization of the a-amino ketone, which is formed by reduction of a-azido ketone 149 with triphenylphosphine, leads to the formation of a pyrazine derivative 150 (Scheme 40) <1994JOC6828>. Reduced Te also dimerized a-keto azide 149 to give pyrazine 150 <2006JOG2797>. 

Thus, the N,N-dibenzyl-protected aminonitrile 55 was prepared via Swern oxidation of N,N-dibenzylaminoethanol 54 followed by treatment with the enantio-pure amine auxiliary (S,S)-53 and HCN, resulting in the formation of a 3 2 epimeric mixture of the aminonitriles 55 in 55% yield, from which the single dia-stereomers could be isolated by chromatography. After lithiation with LDA, addition to the requisite (E)-a, P-unsaturated esters and hydrolysis of the aminonitrile moiety with silver nitrate, the desired a-amino keto esters R)-S6 were obtained with yields of 65-81% and enantiomeric excesses ee of 78-98%, which could be improved to ee > 98% by a simple recrystallization. Since the amino ketone functionality can be cleaved oxidatively, the 5-amino-4-oxo-esters 56 could be transformed to the corresponding succinic half-esters 57 with hydrogen peroxide in methanol in good to excellent yields (68-90%) (Scheme 1.1.15). 

Photochemical excitation of cyclic a-amino ketones (41 and 43) leads to the formation of bicyclic azetidines and azetidinols by abstraction of a hydrogen y to the ketone followed by cyclization. Production of (42) (72CC1108) and (44) (75TL2463) is believed to occur as a singlet state reaction. 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

The hexahydropyrimidine (58), formed from l-phenylpropane-l,2-dione and propane-1,3-diamine, is an excellent precursor for the a-diimine macrocyclic complexes (60), presumably via the amino ketone (59) (Scheme 36).126 In this case, intramolecular cyclization of (59) to (58) is reversible, so that the metal ion can exert a thermodynamic template effect in formation of the complex (60). This represents a further example of a long-known phenomenon in which a metal ion can stabilize an a-diimine structure by virtue of the formation of stable five-membered chelate rings. Many 2-hydroxy- or 2-mercapto-amines undergo reaction with a-dicarbonyl compounds to yield heterocyclic compounds rather than a-diimines. However, in the presence of suitable metal... 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

In the reaction of /h/f-difluoro ketones with amines, a,/I-unsaturated / -amino ketones are formed, either by inline formation and imine enaminc tautomerization or via elimination of hydrogen fluoride and subsequent substitution of the other fluorine.22 Geminal sp2-bonded difluoridcs arc converted into ketenimines.12-49,89,90... 

Trifluoromethyl ketones can also be synthesized from 1-trifluoromethyl-substituted enol ethers, which are readily prepared from aldehydes via a Wittig reaction (Scheme 9). Similar to Ruppert s procedure (Section 15.1.4.3.4), this method has thus far only been used to prepare trifluoromethyl compounds. The a-amino trifluoromethyl ketones produced in the reaction scheme are much less stable than the corresponding a-amino ketones, which leads to the formation of byproducts (a-hydroxy ketones) during attempts to purify the a-amino trifluoromethyl ketones by chromatography on silica gel. 35 ... 

In contrast to these observations, reaction of 96 with primary alkylmagnesium halides leads to a mixture of the corresponding p-amino ketone and p-amino carbinols in variable amounts, depending upon the size of the alkyl moiety as well as the nature of the counterion. As shown in Scheme 33, almost exclusive formation of the corresponding ketones 99, 100, and 101 (ketonexarbinol ratio >99 1) takes place when lithium enolates and alkyl magnesium chlorides are the reagents employed [100]. 

When the amino ketone 1 was heated at 150-160°C for 15 minutes with the constant boiling liquid salt "trimethylammonium formate (TMAF, 5HCOOH.2NMe3), two products were obtained, the major of which (58%) was shown to be 2. 

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