Thorpe-Ziegler condensations

Thiocarbonates, synthesis of, 17, 3 Thiocyanation of aromatic amines, phenols, and polynuclear hydrocarbons, 3, 6 Thiophenes, synthesis of, 6, 9 Thorpe-Ziegler condensation, 15, 1 31 Tiemann reaction, 3, 9 Tiffeneau-Demjanov reaction, 11, 2 Tin(n) enolates, 46, 1 Tin hydride method to prepare radicals,... 

The well-known Thorpe-Ziegler condensation reaction (Ref. 2) involves the nucleophilic addition of a carbanion to an electrophilic center. Starting from adiponitrile, enamino nitrile 9 is recovered. Catalytic hydrogenation of this compound gives trans AMCPA as the major isomer (scheme 4) ... 

Hurd and Shah [147] found that the Dieckmann condensation is suitable for macrocyclization and superior to the parallel Thorpe-Ziegler condensation. For example, zearalanone 246) was prepared from diester 243 by using this method... 

Schaefer, J. P., Bloomfield, J. J. Dieckmann condensation. (Including the Thorpe-Ziegler condensation). Org. React. 1967,15, 1-203. 

For example, condensation of the 5-cyano ketone 146 with methyl [ C ]cyanoacetate gave (Figure 7.36) a-[ C]cyanobenzo[a]quinolizin-2-yUdeneacetate derivative 147 in 52% yield. Reduction of the double bond followed by selective de-methoxycarbonylation provided the dinitrile, a key intermediate in the synthesis of carbon-14-labeled 4a-hydroxy-allo-berbane (148) . Despite loss of half of the label during formation of the final ring by Thorpe-Ziegler condensation, this route was considered superior to the alternative longer route. 

The use of classical condensation reactions is important. Thus, the Dieckmann reaction (equation 38) and the Thorpe-Ziegler cyclization (equation 39) have been used for almost a century for the preparation of a wide range of monocyclic and benzo-fused heterocycles. The aldol condensation and related reactions have also been fairly widely exploited, especially for the synthesis of 4-quinolones (the Camps reaction, e.g. equation 40), and various extensions of this general approach are described in the monograph chapters. 

Thorpe-Ziegler synthesis of 3-aminoindoles with additional functional groups was used as part of the synthesis of condensed indoles [e.g., azepines (94) were obtained from 3-amino-2-benzoylindoles (93) (91JHC379) (Scheme 24)]. In these cases the nature of the substituent R is important for a smooth reaction (Ac < Bz < 2-N02-benzoyl, but no reaction when R = H). With 2-chloro-3-(/V-bromoacetyl-/V-methylamino)pyridine and o-benzoylaminobenzonitriles (95), the condensed pyridodiazepinones 97 and 99 (95H753) were obtained via intermediates 96 and 3-aminoindoles intermediate (via 98) 3-aminoindoles followed by substitution of the 2-chloro substituent by the resulting 3-amino group (Scheme 25). 

The base-catalysed intermolecular condensation of nitriles of the type RCH2CN is one of the oldest known methods for the preparation of / -enaminonitriles, and in the case of simple self-condensation it leads to aliphatic analogues of the cyclic / -ena-minonitriles formed in the classical Thorpe-Ziegler cyclization. For example, the base-catalysed dimerization of acetonitrile with sodium gives 3-amino-crotononitrile661. 

Thorpe-Ziegler cyclhation. Doombos and Strating used this reagent for effecting thccyclizationof(l) to (2), Acyloin condensation of analogous esters failed in this case. 

Generally, the synthesis of thienopyrimidines using the Claisen, Thorpe-Ziegler, and Friedlaender condensations can be represented by the following scheme ... 

The Dieckmann, Thorpe and Thorpe-Ziegler reactions all involve intramolecular cyclization of a stabilized anion to form a cyclic ketone. The Dieckmann reaction is the intramolecular equivalent of the Claisen condensation and yields cyclic 2-alkoxycarbonyl ketones as primary products, whereas the primary products of the Thorpe reaction are 2-cyanoenamines (Scheme 13). Sub quent hydrolysis affords cyclic ketones but the primary products, particularly those from the Dieckmann reaction, have a useful synthetic role (see Section 3.6.3.S.1). 

The condensation of thioglycolates or a-thioketones onto nitriles, known as the Thorpe-Ziegler cyelization, can be employed to synthesize p-aminothiophenes. This basic strategy was utilized to synthesize a-(methylthio)thiophene 38 , 2,4-diaminothiophene 39 , benzo[fc]thiophene 40 , thieno[2,3-c]pyridazine 41 , thieno[3",2" 5, 6 ]pyrido[2, 3 4,5]thieno[2,3-c]pyridazine 42 , thieno[2,3-i ]pyridine 43 , and thieno[3,2-c]pyran-4-one 44 . 

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

The Thorpe-Ziegler cyclization is the intramolecular condensation of dinitriles to yield imines which ultimately tautomerize to the corresponding enamine. The enamine can be hydrolyzed to yield the p-ketonitrile imder more harsh conditions, hydrolysis of the nitrile results in decarboxylation to yield the ketone. 

The Thorpe-Ziegler cyclization is characterized by a relatively straightforward mechanism. As demonstrated below, deprotonation of dinitrile 1 results in the formation of the anionic species 2. Intramolecular cyclization in a manner similar to the well-known Dieckmann condensation yields 3. Workup under aqueous conditions then produces imine 4, which immediately tautomerizes to the conjugated enamine 5. 

Although the Thorpe-Ziegler name is typically limited to the selfcondensation of nitriles, many other intramolecular condensation reactions are often referred to in the same maimer when a nitrile is the electrophile. While this review focuses specifically on the dinitrile variant of the reaction, the reader s attention is directed to a wealth of literature on these related... 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

Scheme 9.160. A Thorpe-Ziegler reaction of 2,6-dicyano-2-methylhexane. First, base treatment allows the dinitrile to undergo acyloin-type condensation (Scheme 9.145) to an imino-nitrile. Hydrolysis of the imine (Scheme 9.65) generates a P-ketonitrUe, which, on further hydrolysis (Scheme 9.46), produces a P-ketocarboxylic acid, which then undergoes decarboxylation (vide infra). Interestingly, the intermolecular version of this reaction is the Thorpe reaction, while the intramolecular version is the Thorpe-Ziegler reaction. See Baron, H. Remfry, F. G. P. Thorpe, J. F. /. Chem. Soc., 1904,85,1726, as well as Ziegler, K. Eberle, H. Ohlinger, H. Liebigs Ann. Chem., 1933,504, 94, and Ziegler, K. Chem. Ber., 1934,67,139.

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