Of a-amino ketones

The enantioseiective hydrogenation of a-amino ketones has been applied extensively to the synthesis of chiral drugs such as the / -agonist SR 58611 (Sanofi Cie). m-Chlorstyreneoxide was obtained via carbene-induced ring closure of the amino alcohol. Epoxide-opening by a chiral amine obtained via a ruthenium-catalyzed hydrogenation of an enamide has led to the desired compound where... 

Scheme 33.13 Some applications of the enantioselective hydrogenation of a-amino ketones.

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

A simple synthesis of a-amino ketones and esters 231 (R1 = EtO or Ph R2 = H or CO2EE R3 = Me or CH2C02Et R4 = PhCH2 or CH2C02Et) proceeds from diazo ketones and esters, respectively, tertiary amines and copper powder. The intermediate... 

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. 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

Hendrickson and co-workers have used the reaction of a-amino-ketones with acetylenic esters for synthesizing pyrrole derivatives. Thus, in the reaction of a-aminopropiophenone with DMAD, an intermediate enamine adduct (56) is formed, which ultimately gives rise to the pyrrole 57 in presence of methanolic HCl [Eq. (16)]. Pandit and Huisman have shown the generality of this scheme in the synthesis of polycyclic pyrrole derivatives. 

This procedure may be used for the preparation of a variety of a-amino ketones as is indicated in Table I, which summarizes most of the submitters experience with this reaction. Principal deviations from the procedure wifi be in the time required for a negative starch-iodide test and the nature and amount of extraction and recrystallization solvent. It is strongly recommended that any one using the reaction for the first time carry out the preparation on a-phenylethylamine before attempting to use it on other more valuable amines. 

R Pyrrole substituents R3 R4 R5 Source of a-amino ketone Yield (%> Ref. 

The intermediates which are assumed to be involved in the Knorr cyclization can also be prepared by addition of a-amino ketones to electrophilic alkynes (equation 77). This methodology has found use primarily with dimethyl acetylenedicarboxylate to form pyrrole-2,3-dicarboxylate esters (equation 77), but methyl propiolate is also reactive (68T1567,69T527, 64JA107, 62JOC3346). 

The reaction of a-amino ketones (508d) with thiosemicarbazides (761) affords 3-amino-4,5-dihydro-l,2,4-triazines (762) and the dihydrotriazine-3-thiones (763) (57MI21900). 2,2-Dimethyl-3-dimethylamino-2i/-azirine (764) reacts with benzohydrazides (765 R = Ar) via the open-chain intermediates (766) to give 3-aryl-6-dimethyIamino-2,5-dihydro-l,2,4-triazines (767 R = Ar). With ethyl carbazidate (765 R = OEt) the corresponding triazin-3-one (768) is formed (78HCA2419,78C332). 

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. 

In a related contribution O Brien described the AA on styrenes and converted the amino alcohols into enantiopure diamines by using a reaction strategy similar to Janda s [83], Further synthetic applications of the AA include a new access to Evans chiral oxazolidinones [84], the enantioselective synthesis of a-amino ketones from silyl enol ethers [85], the stereoselective synthesis of cyclohexyl norstatine [86], and a route towards amino cyclitols by aminohydroxy-lation of dienylsilanes [87]. 

Asymmetric hydrogenation of a-amino ketones.1 A catalyst prepared from [Rh(COD)Cl]2 and (2S,4S)-1 effects highly enantioselective hydrogenation of ex-amino ketones. This reaction provides a ready route to (S)-propranolol (3) from a 3-aryloxy-2-oxo-1 -propylamine (2). A number of related a-amino ketones are hydrogenated under these conditions to the corresponding (2S)-alcohols in 85-96% ee, but 3-amino ketones are reduced with lower enantioselectivity. 

Esters of oxazole-4-carboxylic acids are easily hydrolyzed by hydrochloric acid to give salts of a-amino ketones (equation 5) the action of 2,4-dinitrophenjlhydrazine on the ester (133) in the presence of hydrochloric acid leads to the 2,4-dinitrophenylhydrazone (134). 

The use of N-sulphonyl oxaziridine allowed the isolation of either a-hydroxy ketones, when the enamine was trisubstituted, or of a-amino ketones, when the enamine was disubstituted78 (Scheme 55). 

The Marckwald synthesis116 employed the reaction of a-amino-ketones with cyanates, thiocyanates, and isothiocyanates to yield 3 -imidazol-2-ones or AH-imidazole-2-thiones which are readily converted into imidazoles. The chief limitation of this method, which has been discussed adequately in earlier reviews,1-3 is in the synthesis of the a-aminocarbonyl compounds. The most convenient procedure is by reduction with sodium amalgam of a-amino acids.117 Among recent applications of the method118 119 is the synthesis118 of 4,5-... 

Condensation of a-Amino Ketones and Carbonyl Compounds (Knorr) 841... 

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