Alkoxy- and alkylthio-substituted

The reaction of 3,4-bis(benzenesulfonyl)furoxan with alcohols and thiols in basic media affords a variety of alkoxy-and alkylthio-substituted (benzenesulfonyl)furoxans. For these derivatives a paramount problem is to determine the position (3- or 4-) of the substitution in the furoxan ring. The structures of these derivatives were assigned on the basis of both chemical and NMR evidence. In particular, 13C NMR substituent constants were obtained by NMR study of suitable furoxan models. By assuming a complete additivity of the substituent effects at the furoxan ring, these values were used for structural determination <1997FES405>. 

Reaction of 3,4-bis(phenylsulfonyl)-l,2,5-oxadiazole oxide isomers with ethanol and ethanethiol in basic medium gave the expected alkoxy- and alkylthio-substituted (benzenesulfonyl)furoxans, respectively <1996JHC327, 1997FES405>. Nucleophilic substitution of the sulfonyl group of 3,4-bis-(benzenesulfonyl)furoxan 222 in the presence of aqueous NaOH in tetrahydrofuran (THF) furnished the corresponding 3 -0-(3-benzenesulfonylfur-oxan-4-yl) derivative 223 in 79-92% yield (Equation 44) <2004JME1840>. 

Alkoxy- and alkylthio-substituted aminothienopyrimidines 94 were prepared by cyclization of the corresponding isoureas and isothioureas 95. Isoureas are generated in situ from thiophenes 30 with cyanates in the presence of acids (1984INDP151496). Isothioureas are produced by alkylation of thioureas 33 (1991GEP287503). 

The cyclodehydrogenation of electron-rich alkoxy- and alkylthio-substituted hexaphenylbenzenes resulted in ether cleavage [62]. In addition, hexaphenyl-benzenes substituted with redox-active moieties, such as diarylamines or pyridine, do not provide the desired HBC derivatives, presumably due to the preferential formation of nitrogen-localized radical cations [63]. Thus, the hexaether 15 did not yield the desired hexaalkoxy-substituted HBC upon treatment with FeCh, but rather an unexpected indeno[l,2-b]fluorene derivative 16, the structure of which was confirmed using X-ray crystallography (Scheme 13.5) [64]. 

SftT 1 substitutions also proceed easily in compounds forming highly stabilized secondary carbocations such as benzyhydrol , ferrocene and analogous systems. A variety of leaving groups can be utilized in these reactions including halides, alkoxy and alkylthio in the presence of mercury salts and ethers. 

Other 7- substituents that have been introduced include the dialkylamino, acetamido, hydroxy, alkoxy and alkylthio groups (B-71MI11209). Acylation of the 7-amino group by heterocycles such as cyanuric chloride and its derivatives was inevitable, as was incorporation of a 7-triazole substitution pattern by diazotization of the 7-amino group and o-coupling with 2-naphthylamine followed by triazolization (94). 

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

Usually, 3- and 4-substituted thianes are prepared from the 3- and 4-oxothians by the common techniques applicable to alicyclic chemistry. Reduction affords alcohols which may be etherified or halogenated, while oximation and reduction produces the amino derivatives, which are also accessible via the halo compounds. 2-Alkoxy and 2-alkylthio compounds are made by acid catalyzed addition of alcohols and thiols to 3,4-dihydro-2H-thiopyran (75MI22502) in a reaction analogous to the use of dihydropyran for protection of alcohols as THP ethers. 

Other synthons for 1,3-dicarbonyl compounds that have been successfully applied include p-chloro-a,P-unsaturated ketones and aldehydes, P-dimethylamino-a,P-unsaturated ketones (easily obtained from ketones by reaction with DMFDMA), P-alkoxy-enones"" and vinyl-amidinium salts."" Alkynyl-ketones react with 5-alkyl-isothioureas, giving 2-alkylthio-pyrimidines" and propiolic acid reacts with urea to give uracil directly in about 50% yield. "" 1,3-Keto-esters with formamidine produce 4-pyrimidinones"" and C-substituted formamidines with ethyl cyanoacetate give 2-substituted-6-amino -pyrimidinones. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ortho-aminonitriles " and in general, from P-enamino esters. ... 

With few exceptions, derivatives of tervalent phosphorus acids are prepared from phosphorus trichloride by nucleophilic substitution of one or two of the chloro groups with organometallic compounds, followed by substitution of the remaining chloro groups with alkoxy, amino, alkylthio groups, etc., or vice versa (Scheme 1). Occasionally a tervalent compound is best obtained by reduction of a (thio)phosphoryl derivative which is prepared from (thio)phosphoryl chloride (Scheme 2), or from a P—H compound and an electrophilic reagent, e.g. Scheme 3. 

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