Preparation of the Parent Compounds

From among the known isohexides (see Section II), isosorbide (3) is that of the highest importance, not least because of the pharmaceutical use of its nitrates and the good solvent properties of its dimethyl ether. 

Protonation occurs preferentially at the primary hydroxyl group. The first dehydration step can also take place between the 3- and 6-position, leading to the 3,6-monoanhydro derivative 41. The second water-elimination step from the 1,4-, as well as from the 3,6-, anhydro-D-glucitol, leads to the formation of D-isosorbide. However, kinetic studies showed94 that the proportion of the 3,6-anhydro isomer is low compared to that of the 1,4-anhydride. An investigation giving similar results is described in Ref. 95. 

For (15 )-l-2H-D-mannitol (42) as the starting material, it has been elucidated that, during dehydration to the 1,4-anhydro- (43) or 3,6-anhydro-mannitol (44), and, subsequently, to the (1 fl)-1 -2H-isomannide (45), an 

Important sources of side reactions during the dehydration processes are (1) formation of the 2,5-anhydro isomer, which cannot be converted into 

isoidide IM, isomannide IS, isosorbide. p-Toluenesulfonic acid. The exact amount was not determined. 

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This class of aziridine-forming reaction includes the first reaction reported to afford aziridines. In 1888 Gabriel reported that aziridines could be prepared in a two-step process, by chlorination of ethanolamines with thionyl chloride, followed by alkali-induced cyclization [75]. Wenker subsequently reported that heating of 600 g of ethanolamine with more than 1 kg of 96 % sulfuric acid at high temperature produced P-aminoethyl sulphuric acid 282 g of it was distilled from aqueous base to give 23 g of aziridine itself, the first preparation of the parent compound in a pure condition [76]. Though there is no evidence to substantiate the hypothesis, the intermediate in these reactions is perhaps a cyclic sulfamidate (Scheme 4.51). 

Several methods for the preparation of the parent compound in this system, tris(trimethylsilyl)phosphite, have been reported.114 118 The application of this and related reagents in reaction with alkyl halides has been reported and used for the preparation of a variety of phosphonic acid analogues of phospholipids.114119-124 Interestingly, alkyl chlorides appear to be more reactive with the silyl reagents than do alkyl iodides, a reversal of the normally observed trend with alkyl esters of the phosphorus acids. (The particular use of silyl phosphorus reagents for the synthesis of biologically significant compounds has... 

The A-hydroxycarboxamide group is a key fragment of many siderophores so that a convenient synthesis of this group is crucial for further progress. A variety of methods have been attempted for the preparation of hydroxamic acids starting from carboxylic acids. Although some of these methods are quite efficient for the preparation of substituted hydroxamic acids, the preparation of the parent compound is still a problem and yields are often moderately unacceptable, in part due to the low solubility of the parent hydroxylamine hydrochloride in organic solvents. 

This method was also applied to preparation of thieno[3,4-c]pyrroles, including the first preparation of the parent compound (Scheme 9.4) (5a,b). When treated with NaNs, the bromo compounds (12) underwent 1,3-dipolar cycloaddition to yield the triazolines 13. 1,3-Dipolar cycloreversion gave the salts of the thieno[3,4-c]pyrroles... 

They were formulated by him as anthranols. Also, von Pechmann described a monooxyphenylanthranol which presumably was a mixture of7f and 9-(/ -hydroxyphenyI)anthrone (see Section IV,A,4). Now many 1,3-diarylbenzo[c]furans are known (Section IV,A,6) the preparation of the parent compound (4) and of simple derivatives has also been described (Section III,B). 

Murray and Hauser 62 reported that the cyclization of the condensation product of 3-aminopyridine N-oxide and EMME affords the 1,7-naphthyridine derivative (54). This compound was converted into the chloro derivative (55) by the steps outlined below. Both Ikekawa9 and Albert11 converted compound 55 into the parent 1,7-naphthyridine (3) by oxidation of the hydrazino derivative. This synthetic route constituted the first preparation of the parent compound. 

However, at this stage the results of another area of our research of the benzoylphenyl ureas, i.e. the environmental studies, were going to have a vital influence on the further selection of the best compound. A preliminary study with a radioactive preparation of the "parent" compound Du 191 11> labeled with at the carbonyl group of the benzoyl... 

The synthesis of 1,2,5-thiadiazoles from a-diamines was studied as early as 1897 when Michaelis attempted the preparation of the parent compound by reaction of ethylenediamine with sulfur dioxide. The product, however, was bissulfimic acid (28) which readily lost sulfur dioxide to form the betaine (28a). Later Shew reported that 3,4-dicyano-l,2,5-thiadiazole (30) results from the reaction of cis-diaminomaleonitrile (29, HCN tetramer) with thionyl chloride, a reaction which is analogous to 2,1,3-benzothiadiazole formation from o-phenylenediamines. The synthesis of the parent 1,2,5-thiadiazole and some alkyl analogs (32) was accomplished by reaction of salts of... 

Attempted preparations of the parent compound, pyrazine, from halogeneoacetal-dehyde and ammonia were not very successful (23, 237). Tschitschibabin and Schtschukina (237) made a careful study of this reaction their best yield, after oxidation with mercuric salts, was not higher than 11%. Some pyrazines prepared by this method are listed in Table 11.3 (3,10, 23,31,166,193, 209,236-247). 

Because of the dipolar property and high strain, triafulvenes are susceptible to nucleophilic attack by bases at the cyclopropene moiety hence, the elimination method has limited utility except for the preparation of the parent compound methylenecyclopropene (1). 

Armed with these encouraging results, we attempted the preparation of the parent compounds in this series, a goal long sought by synthetic chemists. In the past, attempts to synthesize unsaturated dihydropyrimidines from the parent a,/ -unsaturated carbonyl compound acrolein failed,143,146 154 155 probably because of fast polymerization of acrolein in the presence of strong bases. Therefore, if one could interfere with this polymerization, the Michael-type addition, leading to the desired product, could then proceed unhindered. Hydroquinone was found to provide the best such protection against polymerization of acrolein.156... 

In addition to the classical allyl vinyl ether rearrangement, several variations have been developed which improve the synthetic value of the Claisen rearrangement with respect to the preparation of the parent compounds, reaction conditions and stereoselectivity. 

These reactions were referred to in Section II,A in connection with the preparation of the parent compound, but they have a much wider application and represent a valuable development in synthesis in this series. 

Again, the preparation of the parent compound has, as yet, not been achieved. However, numerous 1,2-diazetidines are known. 

Interest in the 1,3-dithiane system continues, with an improved procedure for the preparation of the parent compound (940PP377) and the preparation of new 2-substituted derivatives (94SL547). The carbanion derived from 2-trimethylsilane-l,3-dithiane is bisalkylated by chiral epoxides in the presence of... 

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