Hydroxy reaction conditions

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Suggest reaction conditions suitable for the preparation of compound A from 5 hydroxy 2 hexynoic acid... 

The reaction conditions can be varied so that only one of those monomers is formed. 1-Hydroxy-methylurea and l,3-bis(hydroxymethyl)urea condense in the presence of an acid catalyst to produce urea formaldehyde resins. A wide variety of resins can be obtained by careful selection of the pH, reaction temperature, reactant ratio, amino monomer, and degree of polymerization. If the reaction is carried far enough, an infusible polymer network is produced. 

Reactions of the Aromatic Ring. The aromatic ring of hydroxybenzaldehydes participates in several typical aromatic electrophilic reactions. Ha.logena.tlon, Chlorination and bromination yield mono- and dihalo derivatives, depending on reaction conditions. Bromination of / -hydroxy-benzaldehyde in chloroform yields 65—75% of the product shown (39). 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

The tetracycline molecule (1) presents a special challenge with regard to the study of stmcture—activity relationships. The difficulty has been to devise chemical pathways that preserve the BCD ring chromophore and its antibacterial properties. The labiUty of the 6-hydroxy group to acid and base degradation (12,13), plus the ease of epimerization (23) at position 4, contribute to chemical instabiUty under many reaction conditions. 

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

Reaction of the A-nitrosoglycine (394) with acetic anhydride gave the anhydro-5-hydroxy-l,2,3-oxadiazolium hydroxide (395). Reaction with DMAD resulted in formation of the intermediate 1 1 cycloadduct (396) which was not isolated and which lost CO2 under the thermal reaction conditions to give dimethyl l-phenylpyrazole-3,4-dicarboxylate (397) (83MI40300). This reaction is capable of considerable variation in terms of the substituents... 

Using Reimer-Tiemann reaction conditions on 3-alkyl-6-hydroxy-1,2-benzisoxazoles results in formylation occurring at the 7-position (77UC(B)1056). 

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). 

If homolytic reaction conditions (heat and nonpolar solvents) can be avoided and if the reaction is conducted in the presence of a weak base, lead tetraacetate is an efficient oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The yield of product is in many cases better than that obtained by oxidation with chromium trioxide. The reaction in pyridine is moderately slow the intial red pyridine complex turns to a yellow solution as the reaction progresses, the color change thus serving as an indicator. The method is surprisingly mild and free of side reactions. Thus 17a-ethinyl-17jS-hydroxy steroids are not attacked and 5a-hydroxy-3-ket-ones are not dehydrated. 

Ehminations of HX to give double bonds offer considerable scope for selectivity and choice of reaction conditions. The dehydration of alcohols is the most common example of this class and may be achieved directly or through intermediate derivatives. In most cases, such derivatives are transient species formed in situ, but sometimes e.g. sulfonates, certain other esters and halides) they are isolated and characterized. Eliminations from jS-substituted ketones are very facile. The dehydration of jS-hydroxy ketones has been covered in section V. 

Extension of this reaction to other substrates, however, revealed that it is more complex, and that side products are formed depending on (1) the nature of the substrate, (2) the reaction conditions, e.g. temperature and solvent,and (3) the method of work-up." Thus, in addition to the desired substitution products, primary and secondary hydroxy steroids generally yield esters and ethers and undergo simple dehydration as well as dehydration accompanied by rearrangement. 

TABLE 8-1 Effect of Reaction Conditions on Product Composition in the Treatment of 3)S-Hydroxy-5a-androstan-l7-one (5,6 mmoles) with Diethyl(2-chloro-l,l,2-trifluoroethyl) amine (9 mmoles)... 

A 17a-methyl in the product of ring D homo-annulation of 17-hydroxy-20-keto steroids may limit the general synthetic utility of the reaction. On the other hand, the 17a-hydroxyl group gives additional flexibility in planning further transformations. Moreover, by adjusting reaction conditions, the stereochemistry of the products can be changed. 

Huonnations with DAST proceed with high chemoselectivity In general, under very mild reaction conditions usually required for the replacement of hydroxyl groups, other functional groups, including phenolic hydroxyl groups [112], remain intact This provides a method for selective conversion of hydroxy esters [95 97] (Table 6), hydroxy ketones [120, 121], hydroxy lactones [722, 123], hydroxy lactams [124] and hydroxy nitriles [725] into fluoro esters, fluoro ketones, fluoro lactones, fluoro lactams, and fluoro nitnles, respectively (equations 60-63)... 

Hydroxy- and 1-alkoxyindoles undergo characteristic reactions depending on their structures, reagents, and reaction conditions. At the beginning of this section, preparations of 1-alkoxyindoles and l-(Q -D-glucopyranosyl)indoles are discussed. 

Several reactions giving rise to hydroxy- and amino-isoxazoles have also been investigated. Thus the reaction of alkoxymethylene-cyanoacetates and hydroxylamine leading to 5-amino- or 5-hydroxy-isoxazoles proved to be rather useful.It is of particular interest that, by changing the reaction conditions, Bauer and Nambury succeeded in obtaining isomeric aminoisoxazolones (24 25 26). It is also possible to prepare isoxazol-3-ones from some /S-ketoesters. ... 

If the initially formed /3-hydroxy carbonyl compound 3 still has an a-hydrogen, a subsequent elimination of water can take place, leading to an o ,/3-unsaturated aldehyde or ketone 4. In some cases the dehydration occurs already under the aldol reaction conditions in general it can be carried out by heating in the presence of acid ... 

In a variation of the scheme above, alkylation of p-hydroxy-benzoic acid with cyclohexyl iodide affords the cyclohexyl ether, 55. (Under alkaline reaction conditions, the ester formed concurrently does not survive the reaction.) Acylation of the acid chloride obtained from 55 with the preformed side chain (56) gives cyclomethycaine (57). ... 

The reaction conditions needed for aldol dehydration are often only a bit more vigorous (slightly higher temperature, for instance) than the conditions needed for the aldol formation itself. As a result, conjugated enones are usually obtained directly from aldol reactions without isolating the intermediate jS-hydroxy carbonyl compounds. 

It is important to emphasize that the hydroxy dithioketal cyclization can be conducted under mild reaction conditions and can be successfully applied to a variety of substrates.15 However, the utility of this method for the synthesis of didehydrooxocane-contain-ing natural products requires the diastereoselective, reductive removal of the ethylthio group. Gratifyingly, treatment of 13 with triphenyltin hydride and a catalytic amount of the radical initiator, azobisisobutyronitrile (AIBN), accomplishes a homolytic cleavage of the C-S bond and furnishes didehydrooxocane 14 in diastereo-merically pure form (95 % yield), after hydrogen atom transfer. 

In chlorinations either a substitution or an addition process can occur with the ultimate reaction pathway(s) determined by a combination of factors, which include the reaction conditions, the positions and natures of any substituents present, and the catalyst used. Uncatalyzed chlorination of benzothiadiazole is an exothermic reaction that gives rise to a mixture of isomeric tetrachloro addition products. These are converted in basic medium into 4,7-dichloro-2,1,3-benzothiadiazole (70RCR923). When an iron(III) catalyst is present 4- and 7-chloro substitution becomes the dominant process. Chlorination of a number of 4-substituted 2,1,3-benzothiadiazoles (43) using an oxidative process gave a combination of chlorinated and oxidized products. The 4-hydroxy, 4-amino-, 4-methyl-amino, and 4-acetoxy derivatives of 43 all formed the chloroquinones (44) (40-61% yields). With the 4-aIkoxy substrates both 44 and some 5,7-dichlorinated product were obtained (88CHE96). 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

The cyclization of the homologous epoxide 36 under acidic conditions was also investigated (Table 9.5) [110]. As would be expected, compound 36a reacted by a 6-exo cyclization to give tetrahydropyran 38a (Entry 1). The a, 3-unsaturated hydroxy epoxide 36b gave a 1 3.5 mixture of oxepane 37b and tetrahydropyran 38b (Entry 2). Subjection of 36c and 36d, which both contain more electron-rich 71-systems, to the reaction conditions resulted in preferential 7-endo cyclization to give 37c and 37d, thus confirming the powerful regiodirecting effect of the vinyl moiety (Entries 3 and 4). 

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