Pseudoephedrine carboxamides

From Ephedrine to Pseudoephedrine Carboxamide More than a decade after the seminal work of Larcheveque, Myers and coworkers described the alkylation of carboxamides derived from pseudoephedrine [33, 34]. Both enantiomers of pseudoephedrine are also readily available and quite inexpensive. The preparation of the carboxamides consists in the coupling between commercially available pseudoephedrine and an acyl chloride or an anhydride. The corresponding carboxamides are often crystalline and can be easily purified by recrystallization. Myers found slightly modified conditions in order to obtain high levels of diaste-reoselectivity in the alkylation process. The deprotonation occurs also with LDA but in the presence of 6 equivalents of anhydrous lithium chloride, which improve two crucial parameters (i) the global kinetics of the reaction (typically... 

REDUCTION TO THE CORRESPONDING ALDEHYDE Lithium triethoxyaluminum hydride [LiAlH(OEt)j] was found to readily convert pseudoephedrine carboxamides to the corresponding aldehyde with only limited erosion of the ees (Table 2.5). To do so, a solution of the pseudoephedrine carboxamide in THF is added at -78°C to a suspension of LiAlH(OEt)j (2.3 equiv) in hexanes. The reaction mixture is then warmed to 0°C before a dilute acidic aqueous solution (typically HCl 0.5 M) is added, resulting in the formation of the desired aldehyde along with the pseudoephedrine aminal 27. To avoid the formation of the byproduct, the quenching can be performed using a 1M aqueous solution of hydrochloric acid and 10 equivalents of trifluoroacetic add. 

TRANSFORMATION INTO KETONES BY THE ADDITION OF ORGANOLiTHiuM SPECIES It was shown that the addition of an excess of an organolithium species on a pseudoephedrine carboxamide affords the corresponding ketone. In practice, the reaction proceeds through the deprotonation of the free hydroxyl group followed by the addition of the... 

TABLE 2.5 Reduction of Pseudoephedrine Carboxamides into Aldehydes... 

TABLE 2.7 Conversion of Pseudoephedrine Carboxamides into Ketones... 

SCHEME 237 Transformation of pseudoephedrine carboxamides into cyclic iminium salt. 

Utilization of Myers Alkylation with Other Electrophiles Pseudoephedrine carboxamides were also used as pronucleophile with a wide variety of electrophiles. Rapidly after his seminal paper, Myers explored the possibihty of using epoxides as electrophiles [38], Surprisingly, the approach of the epoxide occurred from the opposite face of the enolate compared to alkyl halides (Scheme 2.38). 

In 2004, researchers from Merck laboratories explored Michael additions on pseudoephedrine carboxamide-derived enolates [41]. A singular salt effect was observed as the presence of LiCl in the reaction mixture led to the syn-adduct, while the absence of LiCl afforded the anti-adduct... 

Myers-Type Alkylations with Different Carboxamides In 2012, Myers described the diastereoselective alkylation of (1S,2S)- and (lR,2R)-2-methylamino-l,2-diphenylethanol carboxamides 29 and 30 [43] (Scheme 2.39). This study unveiled several advantages of these chiral auxiliaries over the more traditional pseudoephedrine carboxamides ... 

The preparation of the C11-C17 fragment involved a diastereoselective alkylation between pseudoephedrine carboxamide 25 and the elaborated primary alkyl iodide... 

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