Hydroxypyridines amines

Rhenium(VI) complexes, 4,194 alkoxides, 4,196 amides, 4,194 amines, 4,199 carboxylates, 4,199 dimethylformamide, 4,199 dioxane, 4,198 halides, 4,195,199 2-hydroxypyridine, 4,199 imides, 4,194 magnetic behavior, 1,271 mixed sulfur-nitrogen compounds, 4,196 N heterocycles, 4,199 nitrides, 4,194 oxide halides, 4, 195 oxoanions,4,196 pyridine, 4,199 sulfates, 4,198 sulfur compounds, 4,196 tellurates, 4,198... 

Aminyl radicals are produced by the sequence outlined in equation 114. The action of phosgene on the sodium salt of A-hydroxypyridine-2-thione yields the salt 326, which reacts with amines to give 327. The latter decompose to the radicals 328 on heating or irradiation380. 

Other interesting data in these reactions concern the H/D isotopic effect of the nucleophile/catalyst, for example when [2-hydroxypyridine] = [2 — 02H] = 0.08, fcobsH/ obsD = 1-5. Since a very poor H/D effect is usual in SjvAr reactions with neutral nucleophiles (amines) in apolar solvents10, the authors conclude that the unusually high H/D effect should be due to a difference in the Xh/Xd = 1.75 of the molecular complex. Nevertheless, the same effect could be explained on the basis of an autoassociation of... 

The reaction of furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31 too). Substituted furan-2-carbaldehydes and 2-acylfurans on heating with ammonia and ammonium salts, often under pressure, yield 3-hydroxypyridines. The mechanism of this reaction is thought to involve nucleophilic attack of ammonia at the 2-position. Ring opening affords an amino aldehyde or ketone and thence, by reclosure, the 3-hydroxy-pyridine (Scheme 29). A wide range of substitutents is tolerated. Primary amines with furan-2-carbaldehydes yield A-substituted pyrroles, the closure of the intermediate... 

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. 

Newcomb and coworkers have very elegantly demonstrated that N-hydroxypyridine-2-thione carbamates lc (PTOC carbamates, X = NR2) are directly analogous to the A-hydroxy-pyridine-2-thione esters la. They can be prepared readily from primary and secondary amines. Reaction of these carbamates in a radical chain process gives carbamoyl radicals that decarboxylate to give aminyl radicals, Scheme 40.66 71 In the... 

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>. 

Azole approach. An important route for the synthesis of 3-hydroxypyridines is the reaction between a substituted furan and ammonia, or a primary amine. If the amino acid cysteine is used, the corresponding fused dihydrothiazole (479) can be obtained. Starting from optically active cysteine the corresponding cyclic enantiomer is obtained provided the fused product carries a 5-substituent, which for steric reasons prevents the otherwise ready racemization. A number of steps are involved in the overall reaction which may perhaps be rationalized by thiazolidine intermediates. The desired oxidation level in the substituted furan can either be reached by a-oxidation in an alkyl side-chain (499) or more generally by raising the furan ring itself to a higher oxidation level as in (500) (81H(15)1349). 

Protected derivatives of uridine and protected guanosine are activated by treatment with 2-mesitylenesulfonyl chloride, a tertiary base, and DMAP as the catalyst to the corresponding 4-0- or 6-0-mesitylenesul-fonyl derivatives, which react readily with hydroxypyridines or 0-nitrophenol to form the stable, reactive 143, as well as the 0-deprotected 144. These are readily aminated, especially after quaternization of the pyridyloxy moiety with methyliodide, by ammonia, methylamine, dimeth-... 

Alternative methods include deprotonation of the amine, to enhance its nucleophilicity, by one equivalent of sodium methoxide, sodium amide, metallic sodium,n-butyllithium, sodium hydride in dimethyl sulfoxide or Grignard reagent. Under less drastic basic conditions 2-hydroxypyridine catalyzes the reaction at elevated temperatures (130-170 °C). ... 

Certain aromatic amines may cause reduction of Fe(III) ions in the presence of Fer-roZine Iron reagent (125), according to equation 18, leading to the formation of a stable violet-colored complex with Fe(II) ions (126), the concentration of which is measured at 562 nm. At pH 5, the color develops in a few minutes at room temperature and the absorbance of 126 is proportional to the concentration of the analyte. Neither the oxidation products of the analyte nor the excess of Fe(III) or 125 affect the assay however, not all aromatic amines undergo this reaction. Thus, compounds such as 1,4-phenylenediamine, 2,4-diaminotoluene, 8-aminoquinoline and 2-amino-3-hydroxypyridine can be determined... 

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. 

More recently Openshaw and Whittaker3 in a synthesis of emetine alkaloids needed to effect condensation of an amine with a low-energy ester and in the particular case studied found that use of hydroxy pyridine raised the yield from 2% to 87%. Twelve other mono- or polyhydroxylated heterocyclics were examined, but 2-hydroxypyridine was clearly superior. 

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