By the Thorpe reaction

Until recently the products of all nitrile cyclizations by the Thorpe reaction had been formulated as imines, although the products were found in 1955 to be better written as the enamine structure. In order to verify the reaction mechanism of the Thorpe reaction, the solid-state reaction of 84 and Bu OK was monitored by measurement of IR spectra in Nujol mulls. As the reaction proceeds (Scheme 14), the CN absorption of 84 at 2250 cm" decreases and a new CN absorption of the imine intermediate (87) arises at 2143 cm As 87 is converted into 88 by a proton migration, the CN absorption of 87 at 2143 cm" disappears, and only the CN absorption of 88 at 2189 cm remains finally [13]. 

Based on the structures of the starting reagents, several main pathways of formation (A-C) of the thiophene ring by the Thorpe reaction can be... 

Recently, a method has been developed for the synthesis of thieno[2,3-Z>] indeno[2,l-< ]pyridine derivatives 23 by the Thorpe reaction starting from thiones 24 (2000SC3883). It should be noted that compounds 23 were synthesized according to the same procedure three years earlier (1997MI1). However, the latter study is... 

As mentioned above, amines of the thienopyridine series synthesized by the Thorpe reaction always contain an electron-withdrawing substituent (acyl, alkoxy-carbonyl, etc.) at position 2. The presence of the o-aminocarbonyl fragment in these compounds makes these compounds useful as synthons for pyridine ring construction in the Friedlaender synthesis. Generally, condensation occurs in the presence of a basic catalyst. The acid-promoted synthesis can be exemplified by the preparation of tetracyclic structure 59 from pyranothienopyridine 60 (1996RFP1417446). 

The successive condensation of compound (318) with tert-butyl cyanoacetate, hydrogen cyanide, and acrylonitrile, and pyrolysis to eliminate the tert-butoxycarbonyl grouping, led to the trinitrile (321). Its intramolecular condensation by the Thorpe reaction gave the bicyclic product (320) which was... 

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). 

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

In the anionic polymerization of rigorously purified acrylo-nitrile, studied in Du Pont Co. by Dr. E. F. Evans, there is apparently a termination if the reaction proceeds at higher temperatures (50°—70° C). This is shown by a decreasing yield at higher temperatures as compared with 100% conversion observed at lower temperatures. It has been proposed that the termination is due to an isomerization that resembles the Thorpe reaction, namely... 

B.iv. Nitrile Enolates. Nitrile enolates are formed by reaction of a nitrile with LDA or another suitable base. Both alkylation 30 and condensation reactions with aldehydes 3 or ketones are known. 32 in addition to alkyl halides and carbonyl derivatives, condensation can occur with another nitrile. The base-catalyzed condensation of two nitriles to give a cyano-ketone, via an intermediate cyano enolate, is known as the Thorpe reaction. 33.109e Reaction of butanenitrile with sodium ethoxide gave a nitrile enolate, which reacted with a second molecule of butanenitrile at the electrophilic cyano carbon to give 206. Hydrolysis gave an intermediate imine-nitrile (207), which is in equilibrium with the enamine form (208, sec. 9.6.A). Hydrolysis led to the final product of the Thorpe reaction, an a-cyano ketone, 209. 33 Mixed condensations are possible when LDA and kinetic conditions are used to generate the a-lithionitrile (a mixed Thorpe reaction). When pentanenitrile was treated with LDA and condensed with benzonitrile, 2-cyano-l-phenyl-1-pentanone was the isolated product after acid hydrolysis. Nitrile enolates can also be alkylated with a variety of alkyl halides. 34... 

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 Guareschi-Thorpe pyridine synthesis is closely related to the Hantzsch protocol. The primary point of difference lies in the use of cyanoacetic esters. This modification assembles pyridine 23 by the condensation of acetoacetic esters 21 with cyanoacetic esters 22 in the presence of ammonia. A second variation of this method involves reaction of cyanoacetic ester 22 with P-diketone 24 in the presence of ammonia to generate the 2-hydroxypyridine 25. 

Thorpe reaction org chem The reaction by which, in presence of lithium amides, a,(rt-dinitriles undergo base-catalyzed condensation to cyclic iminonitriles, which can be hydrolyzed and decarboxylated to cyclic ketones. thorp re,ak-shan TMPC See tetrakis(hydroxymethyl)phosphonium chloride, thulia See thulium oxide. thu-le-a ... 

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>. 

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... 

Problem 17.37 The C of the —C=N group is an electrophilic site capable of being attacked by a carbanion. Show how nitriles like CHjCH C N undergo an aldol-type condensation (Thorpe reaction) with hindered bases. M... 

Ring closure by conventional methods (Thorpe reaction) is given in equation (7) (730S(53)98). An important route to the appropriate starting material employs a Michael addition of PhPH2 or MeOP(0)H2 to an a,j8-unsaturated nitrile, carbonyl compound, etc., e.g. equations (8) and (9). 

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