Ring cyclization

Several 4-amino-2,5-disubstituted thiazoles (257) have been obtained recently (702, 756, 776, 814, 820) by a ring cyclization reaction of halogeno compounds with cyanamide derivatives (263) according to the general Scheme 135. 

Thiophene [110-02-1] and a number of its derivatives are significant in fine chemical industries as intermediates to many products for pharmaceutical, agrochemical, dyestuffs, and electronic appHcations. This article concentrates on the industrial, commercial, and economic aspects of the production and apphcations of thiophene and thiophene derivatives and details the main synthetic schemes to the parent ring system and simple alkyl and aryl derivatives. Functionalization of the ring and the synthesis of some functional derivatives that result, not from the parent ring system, but by direct ring cyclization reactions are also considered. Many good reviews on the chemistry of thiophene and thiophene derivatives are available (1 7). 

Electrophilic substitution of thiophene occurs largely at the 2-position and the reactivity of the ring is greater than that of benzene. 3-Substituted derivatives are generally prepared by indirect means or through ring cyclization reactions. 

Certain /3-hydroxyoximes, unsubstituted in the ortho position of an adjacent benzene ring, cyclize when treated with phosphoric acid to give styrylbenzoxazole (equation 60). 

The Pictet-Spengler reaction is an acid-catalyzed intramolecular cyclization of an intermediate imine of 2-arylethylamine, formed by condensation with a carbonyl compound, to give 1,2,3,4-tetrahydroisoquinoline derivatives. This condensation reaction has been studied under acid-catalyzed and superacid-catalyzed conditions, and a linear correlation had been found between the rate of the reaction and the acidity of the reaction medium. Substrates with electron-donating substituents on the aromatic ring cyclize faster than the corresponding unsubstituted compounds, supporting the idea that the cyclization process is involved in the rate-determining step of the reaction. 

In the synthesis of l,3-dithiole-2-thione derivatives as intermediates for electropolymerization precursors, the bicyclic 462 was found to be inert to normal cyclization conditions <1999JOC6418>. This is believed to be due to steric hindrance, from the boat conformation of the dithiin ring. Cyclization was achieved, albeit in only moderate yields, by heating with P2S3 to give the thiophene 463a or HBr/AcOH for the furan 463b (Equation 125). 

In a semimicro synthesis selenophene is prepared from bis(trimethylsilyl)-1,3-butadiyn and NaHSe generated in situ from Se and NaBH4 in aqueous dimethylformamide.52 Other ring cyclization reactions have been performed... 

In very small macrocycles (7- and 8-membered rings), cyclization is not expected, despite the very short c-d distance of of 2.5 and 2.6 A, respectively. The ring strain in the cyclized product would simply be too high... 

Besides ring cyclization reactions, reductive methods can also provide access to reduced forms of pyrimidines, quin-azolines, and perimidines. Both hydrogenation and metal hydride addition can be used <1994HC(52)1, 1996HC(55)1>. 

A pretty good diastereocontrol was achieved in the six-membered ring cyclization of 47, where diethylaluminium chloride and a catalytic amount of CuBr2 SMe2 were used to promote the internal attack of the Reformatsky centre to the sterically hindered carbonyl unit to give 48a and 48b (equation 32)108. 

The intramolecular nucleophilic attack of a nitrogen atom on an allylpalladium complex was also used to construct a five and a six membered heterocycle in the same step. TV-substituted 2-iodobenzamides bearing an allene function in the appropriate distance from the iodine underwent cyclization through the carbopalladation of the allene moiety by the arylpalladium complex, formed in the first step of the catalytic cycle. The intermediate allylpalladium complex, part of a nine membered ring, cyclized readily to give the pyrroloisoquinolone derivative in excellent yield (4.23.). The nature of the added ligand and the solvent both had a marked influence on the efficiency of the transformation.26... 

Several of the synthetic methods appropriate to these compounds have already been described as applicable to small rings (cyclization by metalloid hydride addition to alkenes and alkynes, and coupling through metal halide elimination). While much of the chemistry of these compounds is similar to that of acyclic derivatives, a few peculiarities are worthy... 

In the cases of -butylbenzene and 2-phenylpentane, there is an additional difference (other than ring size) between cyclization to naphthalenes and alkylindans. The reaction forming naphthalenes involves the addition of a primary carbon atom to the aromatic ring, while formation of alkylindans (and alkylindenes) involves secondary carbon atoms. With n-pentylbenzene, however, secondary carbon atoms are involved in both five- and six-ring cyclizations. 

The stability of the intermediate carbonium ion determines whether cyclization forms five- or six-membered rings. In the case of n-butylbenzene and 2-phenylpentane, acid-catalyzed six-ring cyclization would involve very unstable primary carbonium ions C6H5-CH2-CH2-CH2-CH2+ or C6H5-CH(CH3)-CH2-CH2-CH2 +. Therefore, only five-membered rings could be formed in acid-catalyzed cyclization from these two hydrocarbons. 

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