By the Thorpe-Ziegler reaction

The formation of tetracyclic thiophene (232) (via 231) by the Thorpe-Ziegler reaction in the presence of N-bromsuccinimide (NBS) represents a special case, because the pyrimidine-2-thione 229 also served as precursor for the CH-acidic alkylation agent 230 (95H2195) (Scheme 59). 

The Thorpe-Ziegler reaction has been employed in the synthesis of thieno[3,4-t4pyritnidines by providing the thiophene 421. Heating this compound under reflux in formic acid leads to a series of thienopyrimidines 422 (Equation 157) <2002IZK854>. 

Figure 15.6. Mechanisms of thiophene formation by the Thorpe-Ziegler and Gewald reactions. X leaving group Z electron-withdrawing group.

Substituted tetrahydrothieno[2,3-c][2,7]naphthyridines 342 were prepared by the reaction of naphthyridinethione 343 with derivatives of chloroacetic acid in ethanol in the presence of sodium ethoxide (the Thorpe-Ziegler reaction). Their properties were investigated (1995MI2, 1996KGS512, 1997MI2). 

There is an intramolecular version of the Thorpe reaction called the Thorpe-Ziegler reaction. 35 when an a,co-dinitrile is treated with base, formation of the enolate is followed by cyclization. When adiponitrile (210)... 

The use ort/io-cyanoanilines provides an effective means to prepare 4-aminoquinolines by base-catalyzed ring closure onto the cyano group <97BCJ 1697>. In one example the use of DMSO/KO-r-Bu offers a mild base system for the Thorpe-Ziegler reaction <97H(45)483>. 

The Thorpe-Ziegler reaction has also been used for the preparation of functionalized thienopyridines. Alkylation of 16 by chloroacetonitrile first results in the formation of 17. Treatment of 17 with sodium ethoxide results in a Thorpe-Ziegler reaction to produce 18 in excellent yield. Thienopyridine 18 can also be secured directly by treatment of 16 with chloroacetonitrile in the presence of ethoxide. ... 

An interesting rearrangement was observed in the Thorpe-Ziegler reaction of 19. Aimed at the synthesis of a benzothiazepine, treatment of 19 with sodium hydride resulted in the formation of intermediate 20. While protonation of 20 would have provided the desired benzothiazepine, instead, intramolecular attack by the enolate resulted in the formation of 21. Subsequent expulsion of sulfur and aromatization provided the 2-morpholinoquinoline 22 in good yield. 

The Thorpe-Ziegler reaction has been widely utilized in the synthesis of natural products. Deslongchamps and co-workers used the cyclization for construction of the D-ring of the stemodane skeleton in the natural product (-(-)-maritimol. (+)-Maritimol (36), isolated from Stemodia maritime was used as a Caribbean folk medicine for the treatment of venereal diseases. Cyclization of dinitrile 34 was followed by acidic hydrolysis to yield tetracycle 35, The synthesis of 35 represented a formal synthesis of the natural product, as this intermediate could be elaborated to 36 using conditions developed by Piers and co-workers. ... 

It is important to recognize that the reactions in Tables 9.6-9.10 (and the corresponding schemes) are provided only to allow anticipation of reactions not seen or discussed. That is, the principles are general. For example, combination of an acyloin-type process (Table 9.9, item 6, Scheme 9.145) with the chemistry of the nitriles adumbrated in Table 9.10, items 6 and 7, and Schemes 9.158 and 9.159 would lead to an understanding of the Thorpe-Ziegler reaction. Thus, as shown in Scheme 9.160, 2,6-dicyano-2-methylhexane on treatment with base, followed by acid... 

The reactions have been comprehensively reviewed in Organic Reactions-, the acylation of esters in Volume 1 (1942), the acylation of ketones in Volume 8 (1954) and the Dieckmann and Thorpe-Ziegler reactions in Volume 15 (1967). More recent reviews are provided by House and in a book on carbon-carbon bond-forming reactions. Specific examples of many of these reactions are given in Organic-Syntheses . 

The equilibrium character of the reactions described in this chapter means that the reverse processes also occur. The retro-Claisen, retro-Dieckmann and retro-Thorpe-Ziegler reactions are all known and can be synthetically useful. In some cases the substrate may have been formed by the same or similar forward reaction, whereas in others the substrate has to be formed by another process since the equilibrium lies completely on the side of the retro-reaction product. As in the case of the forward reaction, tandem reaction sequences can be constructed, often with the same types of preceding reaction as were described for the forward sequence. 

On the surface it would appear that the mechanism of 4 and 5 formation arises by generation of equal molar amounts of acetonitrile and propionitrile from 1 by a metal catalyzed retro Thorpe-Ziegler Reaction (5) to generate equal moles of the two alkyl nitriles. These, in turn, are in-situ hydrogenated to their respective alkylideneamine intermediate (8) which in turn adds 1 to form the N-(aminoalkyl)-... 

Piperidones, for example, 9/10, are important piperidine derivatives. Several methods can be used for their synthesis, thus (a) the Dieckmann cyclization of the diesters 7 followed by acid-cleavage of the condensation products (8 9) or the Thorpe-Ziegler cyclization of the corresponding dinitriles, (b) the cyclization of dialkyl ketones or acetonedicarboxylates with aldehydes and a primary amine in a twofold Mannich reaction 10) [227] ... 

This reaction was confirmed by isotopic labelling. When cyclo-butanecarbonitrile was in excess, the product, even under mild conditions, was dicyclobutyl ketone (v =q 1700 cm l) formed by a rapid reaction of carbanion with the CN group (Thorpe-Ziegler reaction). 

Highly substituted [l,6]naphthyridines have been prepared by the Michael addition and subsequent Thorpe-Ziegler cyclization of a series of chalcones with malononitrile in the presence of pyrrolidine, over extended periods of heating <1999SC3881>. Attempts to reduce the reaction times using microwave irradiation gave mixtures of products... 

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