2- Hydroxypyridine, catalysis

The installation of the amine functionality at C5 is accomplished by mesylation of 41 followed by azide displacement to give 44 (71% yield over four steps). The P-aminopropanamide 13 is then introduced directly to the lactone under 2-hydroxypyridine catalysis to give the penultimate intermediate 45. Reduction of the azide and isolation as the hemifumarate salt provides aliskiren hemifiimarate (l).37 Based on the information disclosed to date, the synthesis of aliskiren is accomplished with an overall yield of 14% from iso vanillin 14 with a longest linear sequence of 15 steps. Given the complexity of aliskiren, this is a remarkably efficient process, and it should be noted that this analysis likely only establishes a lower limit of efficiency, as further optimization of the route on a manufacturing scale is expected. 

Scheme 2.5 Self-assembly through hydrogen bonding of the 2-pyridone/2-hydroxypyridine system 1 (6-DPPon) to generate bidentate ligand metal complexes 3 for homogeneous catalysis.

The reaction of ethyl 2-phenyl-4//-furo[3,2-/>]pyrrole-5-carboxylate (94) with 2-nitrobenzyl-oromide afforded ethyl 4-(2-nitrobenzyl)-2-phenylfuro[3,2-6]pyrrole-5-carboxylate (269) under conditions of phase transfer catalysis by utilization of sodium carbonate and tetrabutylammonium bromide. This product (269) was hydrogenated using palladium-on-charcoal catalyst to give the amine (270), which cyclized in the presence of 2-hydroxypyridine to give 2-phenylfuro[2, 3 4,5]pyrrolo[2,l-c]benzo[l,4]diazepin-l 1-one (271) <92CCC1487>. 

Decarboxylation. Acid chlorides react with the sodium salt of 1 (DMAP catalysis) to form esters (2) derived from N-hydroxypyridine-2-thione. These esters undergo radical chain decarboxylation to the noralkane on heating with tri-n-butyltin hydride (equation I). ... 

A polyfunctional catalyst possesses two or more reactive groups which interact with different parts of the substrate. The classical (and still most important) example of polyfunctional catalysis is the mutarotation of glucose in benzene solution under the action of 2-hydroxypyridine. According to the finding of Swain and Brown [275], the reaction is first-order in the substrate and first-order in the catalyst. A 10-3 M solution of the catalyst is 7000 times more active than a mixture of 10"3 M pyridine and 10"3 M phenol. 

The concept of bifunctional catalysis was first introduced to account for the unusually large catalytic efficiency of 2-hydroxypyridine in the mutarotation of tetramethylglucose (42). In this reaction, phenol acts as an acid catalyst and pyridine as a basic catalyst and it was, therefore, concluded that a compound with the phenolic hydroxyl and the basic nitrogen at the proper spacing should be able to produce a concerted attack on the sensitive bond of the reactive molecule, with a corresponding reduction of the required activation energy. A similar effect was invoked to explain the unusual pH dependence of the hydrolysis of p-nitrophenyl acetate in the presence of poly-4(5)-vinylimidazole (PVI) (43). 

Bifunctional catalysis. Some time ago Swain and Brown1 observed that 2-hydroxypyridine catalyzed the mutarotation of tetramethylglucose by a concerted base-acid catalysis and that it is more effective than pyridine plus phenol. A few years later Beyerman and van den Brink2 showed that 2-hydroxypyridine and other bifunctional compounds catalyze the reaction of amines with cyano-methyl esters (reactive esters) as well as low-energy esters in peptide synthesis. Pyrazole and 1,2,4-triazole (1,1188), were equally effective. 

A direct substitution mechanism was indicated for the 2-pyridone catalysis of aminolysis of methyl acetate by methylamine." This mechanism is represented in Figure 7.9. It avoids a tetrahedral intermediate and describes a concerted displacement process that is facilitated by proton transfer involving 2-pyridone. Two very closely related TSs involving either the 2-hydroxypyridine or 2-pyridone tautomers were found. These TSs show extensive cleavage of the C-0 bond (2.0-2.2 A) and formation... 

In order to understand the action of acid-base pair sites on solids, we can resort to analogies with homogeneous catalysis. Tanabe [288] gives a very illustrative example the mutarotation of tetramethylgiucose catalyzed by 2-hydroxypyridine (291 ]. 

Shinkai and Bruice (21, 22) recently have described the first example of a zinc-ion-catalyzed reduction of aldehyde by NADH and NADH analogs in aqueous solution. They found that 3-hydroxypyridine-4-carboxaldehyde derivatives are reduced by 1,4-dihydropyridines in aqueous methanol (52% by weight) at 30°. Furthermore, this reaction is subject to catalysis by divalent metal ions, including Zn(II), Eq. (9). The following apparent relative order for metal ion effectivenes was observed Ni2+>Co2+>Zn2+>Mn2+>Mg2+>control. 

Catalysis of the hydrolysis of an acetal by 2-hydroxypyridine. (Adapted from reference 157.)... 

The findings of Swain and Brown 55) support the ternary mechanism proposed by Lowry for the mutarotation of tetra-O-methylglucose. It was found that the mutarotation of tetra-O-methylglucose in benzene in the presence of both an acid (phenol) and a base (pyridine) followed third-order kinetics but was first-order with respect to each component tetra-O-methyl-glucose, pyridine, and phenol 55). 2-Hydroxypyridine was found to be a very effective bifunctional catalyst, and since both acid and base functions were in the same molecule, the mutarotation followed second-order kinetics. Its catalytic action was essentially independent of the other acid and base species present. Although it is a much weaker acid or base than either phenol or pyridine, its catalysis of the mutarotation of tetra-O-methylglucose in benzene was much greater than that of either pyridine or phenol, or a mixture of both 55). 

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