Sulfur-directed cyclization

A second example for a sulfur-directed cyclization, in which even two thio-phenyl groups were present as substituents on the target alkene 36, is shown in Scheme 14 [85]. This substitution pattern is capable of reversing the usual regios-electivity observed for aryl radical additions to enamides. In the presence of a fivefold excess of tributyltin hydride, one sulfur group is removed immediately after the cyclization step. The resulting tricyclic thioether 37 was further converted to mappicine ketone 38. 

The direct cyclization route So far, attempts at closing the lactam ring from an open-chain precursor carrying appropriate sulfur substituents have not been successful. These include efforts at building a lactam ring from the dithiazine (126) (73JA1989) or the open-chain compound (127) (73HCA1218). 

Recent work by Rault-Berthelot et al. considered an alternative pathway to 115 (Scheme 34) [33]. Diels-Alder cyclization with trans,tranr-l,4-diphenyl-1,3-butadiene (116) and dimethyl acetylenedicarboxylate (117) resulted in cyclohexadiene 118 where subsequent oxidation with Pd/C afforded terphenyl 119. Direct cyclization of 119 using concentrated sulfuric acid does afford 115, but only in 12% yield. Instead, saponification of 119 to diacid 120 followed by cyclization improves the yield of 115 to 38%. 

Syntheses of new 8,2 -0-anhydro and 8,5 -0-anhydro nucleosides of adenine and guanine, by cyclization of the appropriate 8-bromopurine nucleosides, were reported..Additional N-substituted-imino-bridged analogs and a new sulfur-bridged analog of 2,3 nhydrothymidine were synthesized. A novel method was reported for the direct cyclization of 2 -deoxynucleosides to the 2,3 -anhydro... 

This is illustrated by the reaction of enamine, 113 with sulfene to produce adduct 114 in an 80 % yield (146). The product 114 was also observed in an 18% yield from the reaction of diazomethane, sulfur dioxide, and enamine 113 (153). It was demonstrated that this cyclization reaction must involve sulfene adding to the enamine directly and not acylation of the enamine by... 

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

The phthalide 25, obtainable by condensation of 4,4 -bisdimethyl-aminobenzophenone-2-carboxylic acid with 3-dimethylaminoacetanilide and subsequent hydrolysis, was diazotized in sulfuric acid and the resultant diazonium salt treated with copper powder to yield 26. However, better yields are reportedly obtained by carrying out ring closure of the diazonium salt in phosphoric acid.103 A further synthetic route has also been described in which phthalides undergo intramolecular cyclization in the presence of aluminum chloride and urea.104,105 Thus, Crystal Violet lactone (2) has been directly converted into phthalide 26.106... 

Cyclizations at moderate to low dilution. A series of A-tosylated (tosyl = p-toluenesulphonyl Ts) macrocycles may be readily prepared by direct means starting from pre-tosylated reactants (Richman Atkins, 1974). Equation [2.3] summarizes an example of this useful reaction type. Reasonable yields (often considerably better than 50%) of such cyclic tosylated products may be achieved in spite of the fact that such reactions are usually performed at moderate dilution. A number of procedures exist for detosylation of these products to yield the corresponding rings containing only secondary nitrogens a common method has been to treat the tosylated intermediate with hot concentrated sulfuric acid for several days. 

The iV-oxide of 1,2,4-thiadiazole has been reported, but this compound was synthesized by cyclization of suitable substituted precursors as direct oxidation would favor oxidation on the sulfur atom <1999J(P1)2243> (see Section 5.08.5.5). 

Thiadiazole 1,1-dioxides are known they are not prepared by direct oxidation of the 1,2,4-thiadiazole ring, as ring cleavage occurs giving sulfate ion. They are only accessible by cyclization of precursors already incorporating the oxidized sulfur functions <1996CHEC-II(4)307>. 

Oxidation may be achieved in the presence of oxygen or air. Other suitable oxidants include sulfur, sodium polysulfide, iron (III) chloride, potassium ferro-cyanide (III) or potassium dichromate, peroxydisulfate or salts of aromatic nitro-sulfonic acids. An aqueous/alkaline medium is used in the presence of a high boiling organic solvent which is not miscible with water or which is almost immiscible with water. Cyclization with chlorosulfonic acid can be followed directly by oxidation with bromine to afford the thioindigo system, without separation of the intermediate. 

Ionic hydrogenation of the same bicyclic diene 382 by Et3SiH in the presence of CF3COOH at room temperature or at 80 °C via ions 387 and 388 is accompanied by transannular cyclizations (equation 139)192. The behavior of diene 382 under Ritter reaction conditions (MeCN, H2SO4) reveals new possibilities to control the transannular cyclizations (equation 140)193. Depending on the sulfuric acid concentration, the reaction temperature and the presence of a nucleophilic solvent, these transformations can be directed to the formation of either the bicyclic amides 389 and 390 having the precursor structure or the tricyclic products 391193. 

A direct aza-Wittig cyclization to triazolotriazine 176 (Scheme 67) takes place when triazinone 174 is treated with diphenylthiourea, the latter being substituted on the nitrogen. Elimination of triphenylphosphane sulfide from 175 makes 1,2,4-triazole accessible [86JCS(P1)2037]. When the nucleophilic attack continues on the sulfur, thiadiazoles are formed [86JCS(P1)2037]. 

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