By Means of Ring-Closure Reactions

Although the present rapid development of thiophene chemistry is owang to the commercial availability of thiophene, many thiophene derivatives can still advantageously be prepared by means of ring-closure reactions instead of by a complex series of substitution reactions starting with thiophene. 

The reaction of 1,2-dibenzoylethane with hydrogen sulfide and hydrogen chloride in chloroform, with zinc chloride as a catalyst, gives 2,5-diphenylthiophene in high yield and is claimed to be better than the classic P2S5 method.  

Substituted thiophenes, such as 2-iodo-, 2-bromo-, 2 chloromethyl-, and 2-acetyl-thiophene have been obtained by reacting crude, coal-tar benzene with the appropriate reagents.  

The reaction of olefins,alcohols,and epoxides with or at high temperatures over catalysts such as 

Al Os or CrzOg-AlgOg has been used for the preparation of simple thiophenes in moderate yields. 

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Ring Closure by Means of a Condensation Reaction a. Condensation with Elimination of Water. The starting materials are mono- and diacid hydrazides, acylsemicarbazides, and related compounds. The ring closure producing the oxadiazole proceeds as in Eq. (1). The well-known conversion of JV.A -diacid hydrazides to... 

Pyrimidine biosynthesis commences with a reaction between carbamyl phosphate and aspartic acid to give carbamyl aspartic acid which then nndergoes ring closure and oxidation to orotic acid. A reaction then occurs between orotic acid and 5-phosphoribosyl pyrophosphate to give orotidine-5-phosphate which on decarboxylation yields uridine-5-phosphate (UMP). By means of two successive reactions with ATP, UMP can then be converted into UTP and this by reaction with ammonia can give rise to cytidine triphosphate, CTP (11.126). 

A set of electrocyclic ring closures is the subject of recent controversy because their mechanism lies in the borderline between pericyclic and pseudopericyclic reactions [123-127], The mechanisms were clarified by means of ELF analyses [121,122]. As shown in Figure 28.4, connected patterns (C) are... 

The idea of the evidence is rather simple and can be elucidated by means of the following experiment. Let us consider, for example, a molecule of 2-methylpentane labeled in a branched position by 13C 2-methyl- 13C(2)-pentane. If the consecutive reactions in the adsorbed state are with a given metal of low extent, and this is certainly true for Pt or Pd, then the appearance, among the product, of 3-methyl-l3C(3)-pentane is very strong evidence of the operation of the 5C (cyclic) intermediates. Only via a ring closure at one place and an opening at another place of the molecule can a label move simultaneously with the branch. On the other hand, when the branch and labeled atom become separated by isomerization, this is evidence of the operation of the 3Cay complexes (see Fig. 5). 

The above synthetic methods for oxetane all involve formation of a new C—O bond. Cyclization by formation of a new C—C bond has been applied with compounds having benzylic or alkylic CH groups. Recent examples of this type of ring closure are the rearrangement of trans- 2,3-epoxycyclohexyl allyl ether by means of s-butyllithium and the dehydrochlorination of a-cyanobenzyl 2-chloroethyl ether with aqueous base and phase transfer catalyst (equation 86). Both reactions probably involve carbanion intermediates (76TL2115, 75MIP51300). 

The closure of the macrocyclic ring by means of an intramolecular 8 2 reaction is a straightforward approach, and sulfur-stabilized carbanion alkylation has been successfully applied in the synthesis of 14-membered cembranoids. The synthesis of nephthenol (40) and cembrene A (59) is an example of this methodology. In Li and Yue s report, the total synthesis of ( )-sarcophytol M (17) was achieved from ger-aniol (137) through 12 steps and in 8.9% overall yield with an intramolecular nucleophilic addition of a sulfur-stabilized carbanion to a ketone as a key step. This example is the first of the closure of a macrocyclic ring with the intramolecular nucleophihc addition of a sulfur-stabilized carbanion to a ketone (Scheme 6-7). 

The closure of the macrocyclic ring by means of an intramolecular Sn2 reaction is a straightforward approach. For example, an intramolecular nucleophilic addition of sulfur-stabilized carbanion to epoxide was used in the synthesis of nephthenol (40) and cembrene A (59) from trani.tran -geranylhanlool (144) (Scheme 6-10). ... 

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