O-Hydroxy-N-heterocyclics

Thionyl chloridejmethanesulfonic acid < -Chloro- from o-hydroxy-N-heterocyclics... 

On comparing the different modes of activation of a given hydroxy-N-heterocycle, one must realize that leaving groups such as O-sulfonates or O-phosphates can react in two different ways, as depicted in the following case of 2-sulfonyloxypyridine (36). 

To remove the water, which is formed on dimerization of trimethylsilanol, at least one additional equivalent of a silylating agent such as HMDS [boiling point = 126°C] must be used. Excess HMDS can then react with trimethylsilanol or water to give hexamethyldisiloxane and ammonia, but will also reconvert any hydrolyzed hydroxy-N-heterocycle into the corresponding activated O-silylated intermediates. Thus, sufficient HMDS should be used to silylate the hydroxy-N-heterocycle and all the alcoholic, phenolic, or other acidic hydroxy groups present in the heterocyclic or amine moiety. It should also be used to convert trimethylsilanol and water (or intruded humidity) from the reaction into hexamethyldisiloxane and ammonia (Eqs. 1-3). 

N-heterocyclic azafluoranthenes N,N-carbonyldi(azoles) cyano-N-heterocyclics dioxo-hydroxy-imines, cyclic o-imino-N-heterocyclics... 

Development of base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone and its application to synthesis of bioactive comporrrrds 99YGK84. Fluorination of O- and N-heterocycles with molecular fluorine in the synthesis of fluorine-containing bioactive compounds 98YGK107. 

Insertion of a C=0, C=S or S=0 group between an amino and a hydroxy function of a 1,2-aminoalcohol produces a five-membered heterocycle with O and N as ring heteroatoms linked by -CO-, -CS- and -SO-groups. Although the reaction proceeds in two steps, it can often be carried out as a one-pot process. 

This section deals with the reactions in which the formation of N-heterocycles proceeds through the Mannich-type cyclocondensations of anionic o-adducts of nitroarenes. The reactions of o-adducts with formaldehyde and primary amines result in 1,3-annelation of the piperidine ring to the core structure of nitroarenes. Depending on nitroarene structure, there are two main routes for these reactions to take (a) the o-adduct is formed via the addition of C-nucleophile to a nitroarene bearing the hydroxy group and (b) cyclocondensation of hydride adducts of nitroarenes, where the hydride ion acts as a nucleophile. At least two wcta-positioned nitro groups in aromatic ring are necessary for these reactions to proceed. Scheme 52 demonstrates both of these options. 

Under different reaction conditions, however, a 3-hydroxy-l,3-benzoxazin-2,4-dione is formed[122] (see also six-membered heterocycles containing an N—CO—O unit, Section 7.1.6) ... 

A strictly dehned region of chemical shifts of C2, C4, and C5 atoms in A-oxides of 4A-imidazoles allows to dehne clearly the position of the A-oxide oxygen atom (102). Chemical shifts of the a-C nitrone group in a-N-, O-, and S-substituted nitrones are located in the region of 137 to 150 ppm (388, 413). On the basis of 13C NMR analysis of 3-imidazoline-3-oxide derivatives, the position of tautomeric equilibria in amino-, hydroxy-, and mercapto- nitrones has been estimated. It is shown that tautomeric equilibria in OH- and SH-derivatives are shifted toward the oxo and thioxo forms (approximately 95%), while amino derivatives remain as amino nitrones (413). In the compounds with an intracyclic amino group, an aminonitrone (A) - A-hydroxyaminoimino (B) tautomeric equilibrium was observed (Scheme 2.76), depending on both, the nature of the solvent and the character of the substituent in position 2 of the heterocycle (414). 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

Like D-glucose and D-fructose, however, D-xylose can be utilized chemic ly or microbially—to generate a variety of interesting five-ca n c emica s o er than furfural (vide supra) or xylitol, a noncaloric sweetener, both being duectly produced from xylan hydrolysates, that is, without the actual isolation of the sugar. Other readily accessible intermediate products of high preparative utiUty (Scheme 2.14) are the open-chain fixed dithioacetal, the D-xylal, and D-hydroxy-xylal esters, or pyrazol or imidazol A -heterocycles with a hydrophilic trihydroxypropyl side chain. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

In the condensation of diols, halogenated alcohols, amino alcohols, cyclic hydroxy ethers, or other bifunctional hydroxy compounds with carbodiimides, 5-, 6-, and 7-membered 1,3-O-N- or l,3-7V,7V-heterocyclics are obtained [14]. 

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