A-Amino ketone hydrochlorides

SL 358 (1995) (a-keto lactone and amide, a-amino ketone hydrochloride)... 

This reaction has been modified by directly using a-amino ketone hydrochloride or reducing a-nitrosoketone or hydrazone via hydrogenation to form pyrrole derivatives. 

Later, these authors extended this methodology to the hydrogenation of substituted aromatic a-amino ketone hydrochlorides by using the same... 

Hydrogenation of substituted aromatic a-amino ketone hydrochlorides in the presence of an in situ generated nickel catalyst derived from a ferrocenylphosphine ligand. 

Cp,Cp-IndoNOP 18 [15 p], have provided excellent enantioselectivity and reactivity for the enantioseiective hydrogenation of a-, / -, and y-alkyl amino ketone hydrochloride salts. 

Amino Ketones Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Tab. 1.9). The rhodium precatalysts, combined with chiral phosphorous ligands such as BPPFOH [10b], MCCPM [24f-k], Cy,Cy-oxo-ProNOP [79c, e], Cp,Cp-oxoProNOP [79c, e], and IndoNOP [79g], have provided excellent enantioselectivity and reactivity for the asymmetric hydrogenation of a, yS, and y-al-kyl amino ketone hydrochloride salts. 

Pioneering studies on the asymmetric hydrogenation of a-amino ketones have been done by Kumada and Achiwa [3, 4]. Achiwa s MCCPM/Rh complex catalyzed the reaction of 2-(dimethylamino)acetophenone hydrochloride with an Si C of 100,000 under 20 atm of H2 to give the corresponding chiral amino alcohol in 96% ee [32], although the reactions of other amino ketones showed less satisfactory rates and enantioselectivity. 

The two-step one-pot total synthesis of Ro 22-1319, an antipsychotic agent featuring a rigid pyrrolo[2,3-g]isoquinoline skeleton, was accomplished by D.L. Coffen and co-workers. The cyclic 1,3-diketone precursor was prepared from arecoline and dimethyl malonate, and in the same reaction vessel an amino ketone hydrochloride was added. The pH of the reaction mixture was adjusted to 4 in order to initiate the formation of the pyrrole. 

Cyclic dimerization of an a-amino ketone also leads to the formation of a pyrazine derivative <92T7879>. Treatment of D-glucosamine hydrochloride under various conditions results in simultaneous formation of fructosazine (148) and deoxyfructosazine (149) in ratios of 1 28 to 100 1 <91CPB792>. Zinc chloride-promoted dimerization of 7V-arylaminoacetophenone (Scheme 35) gives... 

The intriguing structure of these steroids coupled with their potent biological activity and limited availability makes them an attractive challenge for the synthetic organic chemist. One of the key features of any attempted synthesis is the central heterocyclic ring. The classical method of pyrazine synthesis involves the dimerization of a-amino ketones. A steroidal example relevant to the cephalostatin problem was reported15 as early as 1968 (Scheme 4) androstanolone (1) was converted to a-oximino ketone 2, which was hydrogenated to afford the hydrochloride salt of a-amino ketone 3. The salt was neutralized to the free base, and condensed in situ to yield symmetrical dimer 4 in modest overall yields. 

Pictet and Gams (51) carried out the first complete synthesis of the alkaloid in 1909. Veratrol was acetylated in a Friedel-Crafts reaction, the acetoveratrone (XXX) was treated with nitrous acid, and the corresponding isonitroso derivative reduced to aminoacetoveratrone (XXXI) with tin and hydrochloric acid. The hydrochloride of this a-amino ketone was condensed with homoveratroyl chloride, and the resulting homovera-... 

Diethoxy a-hydroxy-benzylphosphonate has been reported to undergo nucleophilic substitution with primary amines to give a-aminophosphonates (Scheme 184) " Primary aromatic amines have been prepared from arylboronic acids in the presence of 0-(2,4-dinitrophenyl)hydroxylamine. " Reaction of iV-t-butanesulfinyl a-haloimines with alkoxides has been reported to give iV-t-butanesulfinyl 2-amino acetals that are precursors for TMSOTf-promoted synthesis of iV-protected a-amino aldehydes and ketones and for the HCl-promoted synthesis of 2-amino acetal hydrochlorides and a-amino ketone and a-amino aldehyde hydrochlorides (Scheme 185). " ... 

A solution of a 2-aminobenzophenone (0.1 mol) and an z-amino acid ethyl ester hydrochloride (0.15 mol) in pyridine (200 mL) was refluxed. During the first 4h, 20-50 mL of liquid was allowed to distill and was replaced by fresh pyridine. Heating was continued for a further 11 h, the mixture was evaporated under reduced pressure and H20 and Et20 were added. In most cases some of the reaction product remained undissolved and was filtered off. The aqueous layer was separated, made alkaline and extracted with Et20. The comhined F.t20 phases were washed with H20. dried and evaporated and the reaction product was separated from unchanged amino ketone by crystallization. 

The (2S,4S)-MCCPM-Rh(I) complex was found previously by Achiwa and colleagues to be an efficient catalyst for the enantioselective hydrogenation of /9-amino ketone derivatives, leading to a practical enantioselective synthesis of (F)-fluoxetine [N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine] hydrochloride [22 b]. Moreover, the use of AMPP ligands again proved to be efficient for these substrates, as exemplified in Table 33.6 [15 i],... 

The 1,3-proton shift reaction has also been applied to the synthesis of a-(perfluoroalkyl)-a-amino acids, specifically 3.3,3-trifluoroalanine.2 -26 Attempts to prepare the A-benzylimine of ethyl 3,3.3-trifluoro-2-oxopropanoate by direct condensation with benzylamine were very difficult due to the exceptionally high stability of the intermediate a-amino alcohol, which fails to dehydrate. By contrast, 1-phenylethanamine reacted with ethyl 3,3,3-trifluoro-2-oxo-propanoate to form ketimine 33 in 83 % yield.26 The 1,3-proton shift reaction of 33 is much faster than those of ketimines derived from perfluoroalkyl ketones or perfluoroaldehydes (see Table 5). Complete conversion in triethylamine required 6 hours at room temperature and afforded the isomeric Shiff base 34 in 92 % yield. Mild hydrolysis of Shifif base 34 gives a-amino ester 35, which in turn hydrolyzes to 3,3,3-trjfluoroalanine hydrochloride (36). 

Exercise 17-21 a. A useful modification of aldol addition to methanal, known as the Mannich reaction, uses a secondary amine (usually as its hydrochloride salt) to selectively introduce one carbon atom at the alpha position of an aldehyde or ketone. The actual product is the salt of an amino ketone. For example,... 

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