Morpholino compounds

The latter sequence, as reported by Overkleeft, van Boom and coworkers, employs substrates of type 9-42 containing both azide and aldehyde functionalities. Treatment of 9-42 with PMe3 in MeOH at room temperature forms a cyclic imine 9-43 via an intermediate phosphazene. Following the addition of an acid and an isocyanide 9-43, products of type 9-44 are obtained. According to this scheme, enan-tiopure carbohydrate-derived azido aldehydes 9-45 and 9-48 led to the morpholino compounds 9-46 and 9-47, as well as to the pipecolic acid scaffolds 9-49 and 9-50, re-... 

All primarily formed compounds were shown to be enJo-morpholino isomers. Derivatives marked with an asterisk isomerized to the corresponding xo-isomers upon heating or in the presence of acids. Starting from 258 pure endo- and xo-morpholino compounds could be obtained in the case of 263 and 266 (benzyltetrazole as the heterocycle) the diastereomers of 259 and 261 were synthesized more conveniently... 

The yields of isolated products varied from 45 to 95%. It is not totally proven whether an iminium ion is involved in the formation of 7-morpholinobicyclo[4.1. OJheptane 14. All primarily formed compounds were shown to be ent/o-morpholino isomers. Some derivatives isomerized to the corresponding ejfo-isomers on heating with acidic catalysts. Starting from 13 pure endo-and exo-morpholino compounds could be obtained in the case of the azide 14f and aminal 14k with benzotetrazole as the heterocycle. Reaction of potassium cyanate with 13 gave a trimer of 14e at ambient temperature or the exo-morphohno diastereomer of 14e at higher temperature. ... 

When the thiomorpholide 38 is heated, hydrogen sulfide is eliminated and the morpholino compound 39 is formed. " However acid treatment results in an alternative mode of decomposition to give the mercapto compound 40. Presumably protonation of the morpholine residue favors elimination of the amine rather than hydrogen sulfide. The morpholino derivative 39 may also be prepared by treatment of the dich-loroacetyl compound 41 with morpholine and sulfur. ... 

Nevertheless this can be circumvented if a silyl group (R = MesSi) is present in the enamine derived, in the example, from pyrrolidine (ref.90). The direction of cyclisatbn, in dichloromethane containing titanium(IV) chloride, is dependent on the structure of the co-reacting enamine so that enamines from symmetrical dialkylketones give 5-alkylaminophenols whereas those from cyclic ketones (in the example shown, a morpholino compound) afford the 5,6-cyclo series (n = 2-5). 

A range of deoxyadenosine bisphosphates with modified ribose units have been prepared and evaluated as ligands at the P2Yj receptor. The modications included deoxy-compounds, carbocyclic analogues, anhydrohexitol nucleosides, and morpholino-compounds. Improved routes have been reported to the... 

An unusual reaction course was observed in the reaction of dialkylamines with 4-nitrofurazan [163], Indeed, treatment of the latter with an excess of morpholine gave two products, one of them being derived from oxidative substitution of hydrogen in position 7, while the second, 6is-morpholino compound, proved to be the result of the redox process (Scheme 54). 

Treatment of l-morpholino-6-iminocyclohexene with hydrazine hydrate in the presence of ketones leads to 2,3,5,6,7,8-hexahydro-l,2,4-benzotriazine 4-oxides 156. In the absence of carbonyl compounds, this reaction affords the spirobicyclo compound 157 (75S794). 

However, exo-selective Diels-Alder reactions are found when a,/J-unsatu-rated exocyclic carbene complexes are used as dienophiles. The fixed s-cis conformation of the vinylcarbene moiety of the complex seems to be responsible for the exo selectivity observed in this reaction. Moreover, the reaction of optically active carbene complexes with 2-morpholino- 1,3-butadienes allows the asymmetric synthesis of spiro compounds [99] (Scheme 53). 

On this basis, a large number of piperazinylphenyl derivatives, such as PNU-97665 [52], PNU-100592 (eperezolid) [53], and their morpholino and thiomorpholino analogues PNU-100766 (linezolid) [53] and PNU-10048 [54], were synthesized. These compounds are either on the market or in the later stages of clinical trials for the treatment of infections caused by strains resistant to conventional antibacterials. See Fig. 4 for the corresponding structures. 

Quite recently, the same research group compared the electrophilicity of 6-nitro-tetrazolo[l,5- ]pyridine and 6,8-dini-trotetrazolo[l,5- ]pyridine 11 with a series of electron-deficient aromatic and heteroaromatic compounds <2005JOC6242>. As reference nucleophiles, fV-methylpyrrole, indole, fV-methylindole, and some morpholino enamines were used. The reactivity of the electrophiles studied followed the linear-free energy relationship defined by Mayr et al. <2003ACR66>. 

In Poland, various 5-cycloaminornetbyl-6-(p-chlorophenyl)-4,5-dihydro-3(2//)-pyridazinones (89, R1 = pyrrolidino, piperidino, morpholino, etc. R2 = H, substituted alkyl, aryl) have been prepared in search of biologically active pyridazines some of these compounds have been reported to exhibit immunosuppressive activity [180, 284, 285]. 

The first case presented is that of 2-[(acyloxy)methyl]benzamides of the general structure 8.187 (Fig. 8.22) [239]. Two model compounds were examined (NRR = MeNH or morpholino, R" = Me) they reacted, as expected, to give the secondary amine and phthalide in quantitative yields. At pH 9.3 and 60°, chemical hydrolysis was 2-10 times faster than the subsequent cyclization-elimination. At pH 7.4 and 37°, the chemical hydrolysis was slow (f1/2 ca. 400 h), while hydrolysis in human plasma was fast (tm 3.2 and 1.4 h, respectively). 

A benzotriazole-assisted synthesis of ethyl 5-aminoimidazo[2,l-h]thia-zole-6-carboxylate 65 has been developed (96TL1787). Traces of compound 63 were isolated from 2-aminothiazole 23 using benzotriazole and freshly distilled ethyl glyoxylate in benzene, whereas by application of a-benzotria-zolyl-a-morpholino acetate with methyl iodide in THF, 63 was isolated in 40% yield. Subsequent treatment of 63 with potassium cyanide in ethanol at rt involves substitution of the benzotriazole moiety. Intramolecular cycli-zation of 64 yields 65, albeit in 10% yield. a-Ketoester 66 is also obtained (Scheme 3). 

---