Hydrogenation amino ketones

The use of primary amines instead of ammonia affords l,2-dialkyl-/l -pyrrolines or l,2-dialkyl-/l -piperideines. Amino ketones with a primary amino group are intermediates in the reduction of y-nitropropylalkyl ketones (14,15) or S-nitrobutylalkyl ketones (16-18) by catalytic hydrogenation over Raney nickel or with zinc and hydrochloric acid (Scheme 1). 

An unusual solvent system was chosen for the intramolecular reductive alkylation of the masked amino ketone (15). The purpose of the strongly acid system was to prevent cyclization of the deblocked amino ketone to 16, further hydrogenation of which gives the unwanted isomer 17 by attack at the convex face. The desired opposite isomer can be obtained by reduction of 16 with UAIH4 (52). 

Excellent asymmetric hydrogenation of amino ketones has been applied for the syntheses of many chiral drugs. For example, the enantioselective hydrogenation of 3-aryloxy-2-oxo-l-propylamine derivatives can directly afford the l-amino-3-aryloxy-2-propanol derivatives as chiral / -adrenergic blocking agents. This has been successfully accomplished with a neutral MCCPM-Rh complex as the catalyst. With 0.01 mol.% of an (A,A)-MCCPM-Rh complex,... 

Noyori and coworkers reported well-defined ruthenium(II) catalyst systems of the type RuH( 76-arene)(NH2CHPhCHPhNTs) for the asymmetric transfer hydrogenation of ketones and imines [94]. These also act via an outer-sphere hydride transfer mechanism shown in Scheme 3.12. The hydride transfer from ruthenium and proton transfer from the amino group to the C=0 bond of a ketone or C=N bond of an imine produces the alcohol or amine product, respectively. The amido complex that is produced is unreactive to H2 (except at high pressures), but readily reacts with iPrOH or formate to regenerate the hydride catalyst. 

Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Table 33.5). The rhodium precatalysts, when combined with chiral phosphorus ligands such as BPPFOH 4 [20b], hydroxyproline derivatives ligands [20-24], Cy,Cy-oxo-ProNOP 15, Cp,Cp-oxoProNOP 16, and... 

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. 

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 (R)-amino ketone is hydrogenated enantioselectively by a neutral complex [ (S)-(i )-BPPFOH RhCl]2 to give the (R,R)-isoproterenol analogue, a compound which has been shown to possess very potent /9-adrenoreceptor agonistic activity... 

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],... 

Zhang and colleagues [26] synthesized the Duanphos enantiomers 57 and 58, and reported on the Rh-Duanphos-catalyzed highly efficient hydrogenation of a series of /9-secondary-amino ketones with ee-values of up to >99%, and with turnover numbers (TONs) of more than 4500 (Table 33.7). This hydrogenation provides a potentially practical synthesis for key pharmaceutical intermediates. The y-secondary amino alcohols are of particular interest to synthetic chemists as they are key intermediates for the synthesis of an important class of antidepressants, 59-62 [32]. 

Table 33.6 Hydrogenation of a series of aromatic jS-and y-amino ketones 55a-b and 56 with [Rh-AMPP] catalysts.

Table 33.7 Hydrogenation of a series of -secondary-amino ketones with...

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... 

Recently, Zhang and coworkers [108] showed Rh-DuanPhos to be a very effective catalyst for the hydrogenation of a variety of aromatic y-amino ketones. In a... 

BINAP-ruthenium dicarboxylate complexes are also efficient catalysts for asymmetric hydrogenation of enamides, a,p- and p,y-unsatu rated carboxylic acids, a-amino ketones, and a-acylaminoacrylic acids.1 2 3 4 5... 

Palmer, M.J., Kenny, J.A., Walsgrove, T., Kawamoto, A.M. and Wills, M., Asymmetric transfer hydrogenation of ketones using amino alcohol and monotosylated diamine derivatives of indane. 

Amino acidate N,0-coordinated chiral complexes of Ru, Rh and Ir have found applications in the catalytic hydrogenations of ketones and unsaturated aldehydes... 

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. 

Ohkuma, T., Ishii, D., Takeno, H. and Noyori, R. Asymmetric Hydrogenation of Amino Ketones Using Chiral RuCl2(diphosphine)( 1,2-diamine) Complexes. J. Am. Chem. Soc. 2000, 122, 6510-6511. 

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