Acyl bromides amino

The synthesis of small arrays of organic compounds derived from multicomponent condensations was recently reported by Studer et al. (119). A 10-member amino acid amide library L7 (Fig. 8.21) was prepared using the fluorous Ugi ( Flugi ) condensation, and another 10-member dihydropyrimidine library L8 (Fig. 8.21) was prepared using the Biginelli ( Fluginelli ) condensation adapted to the fluorous phase. The key intermediates for library preparation were the silyl bromide 8.36, prepared from a fluorous iodide (120), and the acyl bromide 8.37 and the acid 8.38, prepared from an orthothiobenzoate (121), as shown in Fig 8.21. The structure of the fluorous tag was... 

Under the influence of the triamine-Al catalyst, in situ generated ketene (formed from acyl bromide and diisopropylethy-lamine) reacted with aliphatic or aromatic aldehydes, affording -lactone in excellent yield and 88 96% ee (eq 5). AAC reactions deliver enatioeniiched -lactone acetate aldol surrogates, which are direct progenitors of numerous chiral building blocks (/S-amino acid, allene, and Q , -disubstituted carboxylic acids ). 

A synthesis of aspartic acid is based on this strategy. Disconnection (a) is attractive since acyl-amino malonate (7) is a reagent for synthon (6). Synthon (8) can be represented by allyl bromide. 

Most of the now synthetically used quantitative cascade reactions involve an initial substitution step. That is quite clear for the reactions of acyl hahdes with thioureas to give 2-aminothiazoliiun salts. The 3-cascade consists of substitution to form the thiuronium salt, specific cychzation with the more nucleophihc of the amino groups, and elimination of water. In all reported cases, the water of reaction is taken up by the product crystal and it can be removed by heating to about 80 °C in a vacuiun. For example, if the thioureas 162 and phenacyl bromide 217 are stoichiometrically ball-milled at room temperature for 30 min, quantitative yields of the pure products 428 are obtained in all cases after drying at 0.01 bar at 80 °C [ 10] (Scheme 67). The free bases 429 can be obtained by trituration of 428 with NaHCOj solution. Furthermore, the thioureido-acet-amides 275 react correspondingly with 217 to give quantitative yields of the salts 430 from which the free bases can be obtained by NaHCOj trituration [96]. 

The synthesis of valsartan (2) by Novartis/Ciba-Geigy chemists is highlighted in Scheme 9.5. Biphenylbenzyl bromide 18 is converted to biphenyl acetate 19 in the presence of sodium acetate in acetic acid. Hydrolysis of 19 followed by Swern oxidation delivered the biphenyl aldehyde 20, which underwent reductive amination with (L)-valine methyl ester (21) to give biphenyl amino acid 22. Acylation of 22 with penta-noyl chloride (23) afforded biphenyl nitrile 24, which is reacted with tributyltin azide to form the tetrazole followed by ester hydrolysis and acidihcation to provide valsartan (2). [See Biihlmayer et al. (1994, 1995).]... 

---