Biphasic amidation, with 3,5

The establishment of the stereocenter in efavirenz provides a challenging goal for the synthetic chemist (Pierce et al., 1998 Thompson et al., 1995). The synthesis starts by treating 4-chloroaniline with pivaloyl chloride under biphasic conditions to provide the desired amide 10 (Scheme 6.2). Ortho metallation as directed by the amide is accomplished with two equivalents of n-butyllithium (or w-hexyllithium) in tetramethylethylene diamine (TMEDA) and MTBE. The resulting dianion is quenched with ethyl trifluoroacetate to provide pivaloylamide ketone 11 (Euhrer and Gschwend, 1979). The amide is hydrolyzed in situ to provide the trifluoroketone hydrate hydrochloride 12, which crystallizes from the reaction mixture (>98% pure). 

Inductive activation of the amide by the adjacent fluorine atom allows for the basic hydrolysis of the amide bond under relatively mild conditions (warming to 75 °C in a biphasic solution of 2 N sodium hydroxide in a 2 2 1 mixture of water, terf-butyl alcohol, and methanol) to form carboxylic acids with high enantiomeric excess (eq 26). ... 

N-a-Amino acids (10 mg) were typically dissolved in 200 mM, pH 10 sodium metaborate buffer (1 ml), and methylated directly by the addition of a 1 1 v/v solution (20 gl) of [ C]iodomethane in acetonitrile, with rapid mixing of the sealed biphasic mixture at 37°C for 24 h. Cystine dimethyl ester, in particular, was first converted to the diamide at pH 9.5 using ammonia. Histidine amide was first acetylated prior to reaction with iodomethane. 

Multigram quantities of A-methoxycarbonyl-3-phenyloxaziridine (53a) and A-Boc-3-phenyl-oxaziridine (53b) are produced by carefully controling the oxidation of the corresponding imines with buffered Oxone in biphasic media (Equation (49)) <91CC435,93JOC4791). The principle product is amide (190) if the oxidation is carried out at room temperature or with MCPBA. 

As expected, 1 is more active than 4, and is recovered in quantitative yield by extraction with perfluoromethylcyclohexane. Although 2 and 3 are more active than 4, they cannot be recovered by extraction with any fluorous solvents. The amide condensation proceeds cleanly in the presence of 5 mol% of 1 the desirable amide has been obtained in 95% yield by azeotropic reflux for 15 h. In addition, the corresponding N-benzylamide has been obtained in quantitative yield by heating 4-phenylbutyric acid with benzylamine in the presence of 2 mol% of 1 under azeotropic reflux conditions for 4 h. Based on these results, the re-use of 1 has been examined for the direct amide condensation reaction of cyclohexanecarboxylic add and benzylamine in a 1 1 1 mixture of o-xylene, toluene, and perfluorodecalin under azeotropic reflux conditions with removal of water for 12 h [ Eq. (2) and Table 2] [5]. After the reaction has been completed, the homogeneous solution is cooled to ambient temperature to be separated in the biphase mode of o-xylene-toluene/ perfluorodecalin. The corresponding amide is obtained in quantitative yield from the organic phase. Catalyst 1 can be completely recovered from the fluorous phase and re-used in the recyclable fluorous immobilized phase. 

Finkelmann and Schafheutle studied monomeric and polymeric amphiphiles containing a monosaccharide headgroup [138]. The monomer, iV-D(-)-gluco-A-methyl-(12-acryloyloxy)-dodecane-1 -amide, exhibits Lj (>52°C) and L phases (65-88%, 57-87 °C), with a biphasic region separating the two. The polymer, poly-(A-D(-)-glu-co-A -methyl-( 12-acry loyloxy )-dodecane-1-amide) again exhibits Li and phases but these are formed at -0.1 °C. The lamellar phase exists between 37 and 100% polymer, and up to 184.8 °C. It is separated from... 

This reaction has been extended to the reaction between aldehydes and alkenyl complexes of boranes, silanes, and stannes to give allylic alcohols, " where the reaction with alkenyl complexes of silanes is known as the silyl-Prins reaction. In addition, several Lewis acids-mediated or -promoted Prins reactions have recently been developed, including the application of TMSI, hafnium (IV) bis(perfluorooctanesulfonyl)amides (in fluorous biphase system),iron (III) species," and 2,6-di-f rf-butylphenoxy(difluoro)borane. J... 

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