Cyclodehydration methodology

A cyclodehydration methodology has been developed, leading to the imidazole [2,l-fl]isoquinoline ring system (Scheme 16). The chemistry is thought to involve dicationic, superelectrophilic intermediates. For example, the ketone (65) provides the... 

The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene. A third very useful approach is cyclodehydration of 0-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate. However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfo-nyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point. 

Mesoionic oxazolones (munchnones) 297 can be generated by cyclodehydration of N-substituted a-amino acids 295 or by alkylation of oxazolones 296 (Scheme 7.98). These compounds are reactive and versatile 1,3-dipoles that undergo cycloaddition reactions with dipolarophiles to generate a variety of heterocyclic systems. In particular, this is an extremely versatile methodology to prepare pyrroles that result from elimination of carbon dioxide from the initial cycloadduct. Numerous examples have appeared in the literature in recent years and several have been selected for discussion. The reader should consult Part A, Chapter 4 for an extensive discussion and additional examples. 

Trifluoromethanesulfonic acid can mediate the condensation of alkenamides 275 with t-trioxane to afford 3,6-dihydropyrans 276. The reaction proceeds via two oxo-ene reactions to afford the intermediate diol 277, which undergoes cyclodehydration to form the desired dihydropyrans (Scheme 70). This methodology can provide a route to the regioisomeric dihydropyran 278 by simple modification of the starting alkenamide (Equation 127) <1997TL9057>. 

So as to expand the methodology by incorporating a cyclic amino acid, compound 53 was treated with sodium prolinate in hot DMSO to afford the crude substitution adduct 58 (Scheme 9). Subsequent cyclodehydration using acetic anhydride provided the pyrido[3,4-b]pyrrolizidin- 1-one S949 in high overall yield for the two steps. Following the protocol... 

Fukuyama and Xu" reported the first total synthesis of (—)-tantazole B 1188b (Ri = R2 = CH3) in 1993. This synthesis also corrected the originally assigned stereochemistry of the methyl group in ring E. The authors discovered a novel and versatile synthesis of thiazolines 1314 via cyclodehydration of ammonium thiol esters 1313 and adapted this methodology to prepare 1188b (Scheme 1.337). 

The methodology was extended to the synthesis of preclamol analogues bearing an alkyl substituent at the piperidine 2-position, starting from the appropriate a-arylketones instead of the aldehydes. Interestingly, the stereochemical outcome of these reactions differed from that observed in the cyclodehydrations from the aldehyde esters, since lactams with a cis S-CgHs/R relationship were now formed as the major isomers (Scheme 1.32). 

Pioneering work on this subject [8] reported the preparation of various perfluoro-alkylamidoxiines 11 (Rf=CF3, C2F5, C3F7, C7F15) and their acylation with perfluoro-acylchlorides (Rf COCI) followed by cyclodehydration to produce 3,5-bis(perfluoroalkyl)-l,2,4-oxadiazoles 12 either symmetrically (Rf=Rf ) or unsymmetrically substituted. By following the same methodology, bis-oxadiazoles 14 (n=3) could be obtained (Scheme 3) [8, 9],... 

---