Hydroxy amines from amides

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Oxazolines.1 Hydroxy amides, prepared from p-hydroxy amines and acid chlorides, are converted into 2-oxazolines with the Mitsunobu reagent at 0 — 25° (equation I). 

The latter, on reaction with methylamine yielded via the P-epoxide 373, the trans-a aminoalcohol 374, which was N-acylated to the amide 375. Acid-catalysed dehydration of the tertiary alcohol 375, led to the olefin 375, from which the key radical precursor, the chlorothioether377 was secured in quantitative yield by reaction with N-chlorosuccinimide. In keeping with the earlier results recorded for structurally related compounds, 377 on heating in the presence of ruthenium dichloride and triphenylphosphine also underwent a 5-exo radical addition to generate the cyclohexyl radical 378 which recaptured the chlorine atom to furnish the a-chloro-c/5-hydroindolone 379. Oxidation of thioether 379 gave the corresponding sulfoxide 380, which on successive treatment with trifluoroacetic anhydride and aqueous bicarbonate led to the chloro-a-ketoamide 381. The olefin 382 resulting from base induced dehydrochlorination of 381, was reduced to the hydroxy-amine 383, which was obtained as the sole diastereoisomer... 

The oxyamination and diamination procedures described so far suffer from two important limitations. They require a stoichiometric quantity of osmium reagents and it is difficult to remove the tert-alkyl group from the product. Hence, procedures that employ catalytic amounts of osmium tetroxide for the preparation of vicinal hydroxy 4-methylbenzenesulfon-amides, precursors of /1-hydroxy amines, have been developed. 

A -methoxymethyl-amines or-amides A -acetyloxymethyl-amines or -amides or A/, iV-dimethylfonnamide acetals, all react with phosphorus(III) esters in non-classical Michaelis-Arbuzov fashion. From these and similar reactions, quaternary salts of the type 186 have been isolated. The A-methylated dervative may be preformed or produced in situ in mixtures containing amide, formaldehyde and phosphite ester. The products of the reactions are A-acylated (acetyl, benzoyl, phthaloyl, pyridinecarbonyl or benzyloxycarbonyl) when derived from amides, or A,A-dialkyl derivatives from hydroxy (or methoxy)methylamines the use of Me2NCH(OMe)2 leads to dimethylaminomethyl-enebisphosphonic esters. Ivanov and coworkers have made a detailed study of the reactions which occur between phosphorus(III) amides Et2NPYZ and the substrates, RCONHOAc (Scheme 16). The reagent can attack the substrate by virtue of the nucle-... 

Most methods for the formation of oxazolines from B-hydroxy-amines and -acids call for vigorous conditions often leading to polymeric side-products. However Roush and Patel have found that treatment of the easily obtained hydroxy-amides (123) with... 

Latentiation of ampicillin can also be achieved by tying up the proximate amino and amide functions as an acetone aminal. Inclusion of acetone in the reaction mixture allows 6-APA to be condensed directly with the acid chloride from 24. There is thus obtained directly the prodrug hetacillin (34). Although this compound has little antibiotic activity in its own right, it hydrolyzes to ampicillin in the body. The p-hydroxy derivative amoxycillin (35) shows somewhat better oral activity. A similar sequence using formaldehyde gives metampicillin (36). °... 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

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