Amino alcohols Morpholine

Further transformations of a-alkyl-3-oxazolidineacetonitriles are possible. Addition of methyllithium to the cyano group followed by acid hydrolysis gave a morpholine derivative, from which a /i-amino alcohol was obtained as a diastereomeric mixture (d.r. 80 20)69. 

Reaction products of poly(isobutenyl)succinic anhydrides (78) with morpholine and amino alcohols... 

Amino alcohols Azidotrimethylsilane, 24 Benzyl isocyanate, 30 Diethylamine, 312 Morpholine, 14 Pyrrolidine, 14... 

When amino alcohols are used as the amine components along with glyoxal or a-keto-aldehydes, this process generates 2-hydroxy-morpholines 128 (Scheme 7.17) [62, 63], According to Carboni [63], this reaction proceeds with variable diastereo-selectivities (e.g. 129-131), and we have found that certain chiral amino alcohols give modest asymmetric induction (e.g. 132) [62]. 

The intermediate lactol was to be subjected to a diastereoselective acetalization with (/ )-3,5-bistrifluoromethylphenyl ethanol. In order to probe this diastereoselective coupling, a variety of chiral iV-R lactols 76 was desired. In addition, since the ultimate success to aprepitant via this route depended on crystalline intermediates, numerous A -substituted lactols 76 needed to be prepared in order to investigate the crystalline properties of downstream intermediates. Accordingly, a versatile procedure to access a variety of A-substituted morpholine-2,3-diones 75 and 2-hydroxymorpholin-3-ones 76 was required. This was accomplished by the condensation of amino alcohols 74 with diethyl oxalate to afford diones 75, which could be selectively reduced to the corresponding lactols 76 (Scheme 22). A host of these substrates were synthesized however, none offered any significant advantage over the simple A-Bn lactol 69. Thus, the objective became the development of a concise synthesis for this substrate. 

Chiral morpholines and piperazines. The ring formation by tandem allylic substitutions of l,4-diacetoxy-2-butene with 1,2-amino alcohols and 1,2-diamines is promoted by Pd(0) complexes. In the presence of a chiral BINAP ligand this reaction gives optically active products. 

Substituted morpholines 65-68 have been used as chiral auxiliaries for the formation of chiral dienophiles after IV-acylation with acrylic acid (Section D. 1.6.1.1.1.1.2.1.). The auxiliaries are obtained from amino acids (especially valine) via benzyl amino alcohols by cyclization of the AMiydroxyethyl derivative40. 

The 3,5-disubstituted morpholine derivatives have been obtained in good yield and as a single stereoisomer using a carboamination reaction starting from a chiral a-amino alcohol precursor. In this approach, 2-subsituted (9-allyl ethanolamine 59 has been synthesized from A -Boc-pro-tected amino alcohol by simple (9-allylation, Boc-deprotec-tion, and Pd-catalyzed A -arylation reactions. For substrate 59 when treated with an external aryl bromide and Pd(OAc)2 catalyst in the presence of NaOt-Bu base and... 

SCHEME 40.13. Carboamination reaction of substituted chiral amino alcohol synthesis of disubstituted morpholines. 

R)-19 under the reaction conditions is a pre-requisite that is again fulfilled in this process. As shown in Scheme 13.13, enantiomeric excesses > 90% and almost quantitative yields were achieved for several aryl N-carboxy anhydrides. In these examples allyl alcohol was used as the nucleophile. The corresponding amino acids can be liberated quantitatively and with unchanged ee from the esters (R)-19 by Pd-catalyzed deallylation, using morpholine as the nucleophile (Scheme 13.13) [25]. 

The formation of unsubstituted quinoxaline 1,4-dioxide in the Beirut reaction has been observed using a number of substrates benzoylacetalde-hyde and its enamines,395 vinyl acetate (Et2NH),396 acetylene (NEt3)397,398 propargyl alcohol, propiolic acid, and phenylacetylene (various amines).398 Some of these are unexceptional, but the apparent dephenylation in the case of the phenylacetylene is surprising. However, recently the reaction of benzofuroxan with diethylamine was reinvestigated399 (see Section V,E), and quinoxaline dioxide was found to be one of the major products from a complex sequence of oxidation and reduction reactions. It seems probable with phenylacetylene, and possible in other cases too, that the amines play more than a catalytic role in quinoxaline dioxide production. The amino-quinoxalinone 175 was reported, using vinyl acetate and morpholine.396... 

While Wheland (91) suggests that 4-aminopyridine is an aromatic amine little success has been achieved in hydrogenation. Orthner (92) cites failure with platinum catalysts under a variety of conditions. Very low yield (16.5%) resulted from reduction of the hydrochloride salt with platinum catalyst under 80 atm pressure (93). In the reduction of A7-(4-pyridyl)morpholine where the 4-amino nitrogen atom is tertiary, hydrogenation in alcohol was successful with ruthenium (5), but unsuccessful with rhodium on alumina or platinum oxide in acetic acid. It is possible that the pressure conditions used for reduction with ruthenium catalysts may be conducive to conversion of 4-aminopyridine, since these catalysts are less inhibited by strong nitrogen bases. 

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