A -Hydroxy compounds

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

The intermediacy of an aci-nitro compound has been proposed for the sulfuric acid cyclization of o-nitrophenylacetic acid to yield a mixture of 2,1-benzisoxazole and 2,1-benzisoxazole-3-carboxylic acid. The acid does not decarboxylate under the reaction conditions. The proposed aci-nitro intermediate cyclized to an A/ -hydroxy compound which decomposed to the products (Scheme 179) (70JCS(C)2660). 

An organic isocyanate (MDI or a pre-polymer) with a hydroxy compound. The isocyanates are potent respiratory sensitizers, the risk increasing with volatility... 

Recently, many investigators have extended the early observations that the ultraviolet spectra of - and y-hydroxypyridines resemble those of their A -methyl (not the 0-methyl) derivatives. This spectral resemblance is found both in aqueous solutions and in solutions of solvents with low dielectric constants, e.g., quinol-4-one in benzene, indicating that these compounds exist predominantly in the oxo form under all conditions. These data are summarized in Table I. In contrast, 4-hydroxyquinoline-3-carboxylic acid has been tentatively concluded to exist in the hydroxy form %- pjTid-2-one-4-carboxylic acid has also been formulated as a hydroxy compound, but this has been disputed. ... 

Heterocyclic compounds carrying hydroxyl groups may be compared with phenols. Thomson has reviewed the tautomeric behavior of phenols often both tautomeric forms of polycyclic compounds such as naphthols can be isolated. Early work on hydroxy-thiophenes and -furans was also reviewed by Thomsond but until recently their chemistry has been in a somewhat confused state. A pattern is now beginning to emerge, at least for the a-substituted compounds, which appear to exist as A -oxo derivatives and to attain equilibrium slowly with the corresponding A -oxo forms. For the a-hydroxy compounds, the equilibrium generally favors the A -oxo form. 

Less is known about the j8-hydroxypyrroles than about the isomeric a-hydroxy compounds. Originally ethyl 4-hydroxy-2-methylpyrrole-3-carboxylate was suggested, on the basis of chemical evidence, to exist as a mixture of the oxo and hydroxy forms, 64 and 65, respectively. 

It is now clear that the great majority of compounds containing potential amino groups exist in the amino form, although relatively little ciuantitative data are currently available and several discrepancies still await elucidation. As is always the case, the tendency for an amino compound to exist in the corresponding imino form is less than the tendency for a hydroxy compound to tautomerize to the 0X0 form. 

Cationic polymerization can terminate by adding a hydroxy compound such as water ... 

As explained in Chapter 1, the urethane group is the product of the reaction of a hydroxy compound with an isocyanate group (Reaction 4.8). This reaction occurs by step kinetics, yet is usually an addition process since no small molecule is lost as the reaction proceeds. 

This reaction illustrates the striking difference in behavior between carboxylic esters on the one hand and aldehydes and ketones on the other. When a carbanion such as an enolate ion is added to the carbonyl group of an aldehyde or ketone (16-41), the H or R is not lost, since these groups are much poorer leaving groups than OR. Instead the intermediate similar to 146 adds a proton at the oxygen to give a hydroxy compound. 

The more activated the ester, the less stable is the compound. All the esters mentioned above can be used as shelf-stable reagents except benzotriazolyl esters, which decompose too readily. In addition to their use as activated forms of the A - a I ko x y ca r bo n y I am i n o acids, the esters derived from hydroxamic acids are implicated as intermediates in coupling reactions in which the A-hydroxy compounds have been added to promote efficient coupling between an acid and a primary or secondary amine (see Section 2.10). It is pertinent to mention that the O-acylisourea generated from carbodiimides (see Section 2.02) is an activated ester but one of nature different than those alluded to above. 

Most activated esters are crystalline compounds that can be stored for subsequent use. A variety of properties are exhibited by the various esters. All esters mentioned in this monograph (see Section 2.9) except succinimido esters generate a hydroxy compound that is insoluble in water when aminolyzed. Elimination of this material can be a nuisance in some cases. Nitrophenols are not readily soluble in alkali a trace is sufficient to produce a yellow color in the solution of the reaction product. 

Early workers noted that electrochemical oxidation of N,N-dimethyl-amides in acetic acid gives the a-acetoxy compound [101]. Oxidation in acetic acid of amides derived from piperidine and pyrroUdine proceeds differently to yield a mixture of stereoisomers of the a,P-diacetoxy and p-acetoxy-a-hydroxy compounds [125]. 

HA was found to be mutagenic in bacteria, and it was reported that plant chromosomes break in the presence of HA, but it was found to be noncarcinogenic to mice. However, Gross did cite some A-hydroxy compounds (i.e. HA derivatives) as carcinogens . The mechanism of mutagenesis of HA was found to involve primarily interaction with the pyrimidine bases of the cytidine-guanosine pairs. 

Other procedures for a oxidation of ketones are based on prior generation of the enolate. The most useful oxidant in these procedures is a molybdenum compound, MoOs-pyridine-HMPA, which is prepared by dissolving M0O3 in hydrogen peroxide, followed by addition of HMPA. This reagent oxidizes the enolates of aldehydes, ketones, esters, and lactones to the corresponding a-hydroxy compound.189 190 191... 

Figure 2, Oxidation and other reactions of suljallate indicating mutagenic activities of the products in the S. typhimurium TA 100 assay (revertants/nmole without activation/with activation / designates no data available). All thio- and dithiocarbamates are formed from oxidations with MCPBA except for the a-hydroxy compound. 2-Chloroacrolein is a metabolite in the mouse liver microsome-NADPH system. The other compounds are potential metabolites. Several of the oxidized thio- and...

Kinetics of oxidation of toluene and cumene to the corresponding a-hydroxy compounds by stoich. trani-[Ru(0)(bpy)(tpy)] VCH3CN were reported a two-electron hydride-ion transfer step may be involved [672]. Electro-oxidation of side-chains in alkylaromatics by [Ru(0)(bpy)(tpy)] (generated electrochemicaUy in situ from [Ru(OH)(bpy)(tpy)] V BuOH/water pH 6.8/Pt electrodes/50°C) was effected toluene gave benzoic acid and ethylbenzene gave acetophenone (Table 4.1) [673]. 

Since the a -acetates should produce the corresponding a -hydroxy compounds by hydrolysis of the ester function (20), we investigated the stability of these acetates in aqueous solution by following the UV maximum in the range of 225-235 nm. The results are summarized in Table 5. 

The dione, 3, is a yellow crystalline solid that, despite its strained four-membered ring, is much less reactive than 1,2-benzenedione (ort/w-benzoquinone). It cannot be reduced to a cyclobutadienediol, does not undergo Diels-Alder reactions, and with bromine gives a substitution product rather than addition. The bromo compound so formed hydrolyzes rapidly to a hydroxy compound, 4, which is an extraordinarily strong acid having an ionization constant about 109 times that of benzenol ... 

A variety of activated carbonyls such as a-keto esters, benzils, cyclohexane-1,2-dione, and a-ketophosphonates have been reduced to the corresponding a-hydroxy compounds in THF at room temperature, using alkylphosphines (PMe3 or PPhMe2).335... 

Benzenedisulfonimide derivatives (147 X = H or Ar) are accessible via the bis sulfonyl chloride and NH3 (69JOC3434) or arylamines. The A-hydroxy compound (147 X = OH) is prepared by the action of HNQ2 on the disulfinic acid (81JOC2691). 

Explanation 70 is a big surprise. On heating for weeks at 90°C with a large excess of sodium salt of a hydroxy compound in A.iV -dimethyl-imidazolid-2-one, all fluorine atoms are replaced by the residues of the hydroxy compounds such as m-cresol, 2-naphthol, or 2-hydroxytetralin. Compound L is octakis(alkoxy)- or octakis(aryloxy)naphthalene [98]. 

The diols (97) from asymmetric dil droxylation are easily converted to cyclic sii e esters (98) and thence to cyclic sulfate esters (99).This two-step process, reaction of the diol (97) with thionyl chloride followed by ruthenium tetroxide catalyzed oxidation, can be done in one pot if desired and transforms the relatively unreactive diol into an epoxide mimic, ue. the 1,2-cyclic sulfate (99), which is an excellent electrophile. A survey of reactions shows that cyclic sulfates can be opened by hydride, azide, fluoride, thiocyanide, carboxylate and nitrate ions. Benzylmagnesium chloride and thie anion of dimethyl malonate can also be used to open the cyclic sulfates. Opening by a nucleophile leads to formation of an intermediate 3-sidfate aiuon (100) which is easily hydrolyzed to a -hydroxy compound (101). Conditions for cat ytic acid hydrolysis have been developed that allow for selective removal of the sulfate ester in the presence of other acid sensitive groups such as acetals, ketals and silyl ethers. 

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