Nitrile/alcohol coupling

Figure 12.5 Nitrile/alcohol coupling proposed mechanism.

Related to the intramolecular pinacolic coupling reactions in some respects is a ketone-nitrile reductive coupling process. This process also permits the construction of highly functionalized carbocycles, although the yields are sranewhat reduced owing to the reluctance of nitriles to undergo such radical addition reactions (equation 75). Presumably, simple reduction of the ketone to the alcohol c< npetes with the desired process. 

Cui X, Shi F, Deng Y et al (2011) Ruthenium-catalyzed nitro and nitrile compounds coupling with alcohols alternative route for Ai-substituted amine synthesis. Chem-Eur J 17(9) 2587-2591... 

The use of N-glycosyl amides as glycosyl donors was reported by Pleuss and Kunz [240]. These amides were activated by Ph3P and CBr4 to produce bromo-N-imidates, which were spontaneously converted into the corresponding bromide concomitant with releasing nitrile, and then coupled with alcohols by activation with AgOTf (Scheme 5.86). 

Chromium(II) sulfate is a versatile reagent for the mild reduction of a variety of bonds. Thus aqueous dimethylformamide solutions of this reagent at room temperature couple benzylic halides, reduce aliphatic monohalides to alkanes, convert vicinal dihalides to olefins, convert geminal halides to carben-oids, reduce acetylenes to /raw5-olefins, and reduce a,j3-unsatu-rated esters, acids, and nitriles to the corresponding saturated derivatives. These conditions also reduce aldehydes to alcohols. The reduction of diethyl fumarate described in this preparation illustrates the mildness of the reaction conditions for the reduction of acetylenes and o ,j8-unsaturated esters, acids, and nitriles. 

There are two problems. Enolates of primary amides are not very practical as the NH protons are more acidic than the CH protons. The solution is to use the nitrile and hydrolyse it later to the amide. A more serious problem is that the Sn2 reaction we want to use to couple the two together will go with inversion and that will give the biologically inactive enantiomer of darifenacin. The solution is a double inversion. Protection of the amine by tosylation 67 is followed by tosylation of the alcohol with inversion using a Mitsunobu-style reaction. This unusual esterification goes reliably with inversion.20... 

Oxazolines [1] can be synthesized by several routes two common methods are described below (Fig. 1). Readily available j5-amino alcohols 1 can be coupled with an acid chloride to yield the amide 2 which is then cyclized to the oxazoline 3 in the presence of zinc(II) chloride. Alternatively a one step synthesis of 3 can be achieved by reacting 1 with nitriles. Both methods are reliable... 

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