Intramolecular Thorpe reaction

In the Thorpe reaction, the a carbon of one nitrile molecule is added to the CN carbon of another, so this reaction is analogous to the aldol reaction (16-38). The C=NH bond is, of course, hydrolyzable (16-2), so p-keto nitriles can be prepared in this manner. The Thorpe reaction can be done intramolecularly, in which case it is... 

The intramolecular Thorpe reaction can also be carried out under solvent-free conditions. When a mixture of powdered adiponitrile (80) and Bu OK was kept at room temperature for 3 h, cyclization product 81 was obtained as a... 

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). 

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 intramolecular version of the Thorpe reaction, which is base-catalyzed selfcondensation of nitriles to yield imines that tautomerize to enamine. 

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.

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... 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

The few thiophene syntheses reported in which the formation of the heterocycle is realized on an insoluble support (Entries 1-3, Table 15.10) are based on the intramolecular addition of C,H-acidic compounds to nitriles (Thorpe-Ziegler reaction), or on the Gewald thiophene synthesis. The mechanism of these cyclizations is outlined in Figure 15.6. In thiophene preparations performed on solid phase, the required a-(cya-... 

The intramolecular iron-catalyzed Alder-ene reaction of enynes in the carbocy-clization reaction was recently reported by Furstner et al. (Scheme 9.8) [20], A low-valent cyclopentadienyliron catalyst, specifically the [CpFe(C2H4)2][Li(tmeda)] complex, is a reactive catalyst for enyne cydoisomerization reactions. Bicyclic products, also incorporating large ring systems, are thereby accessible, and the Thorpe-Ingold effect seems to be helpful for these types of reactions. 

Several neutral titanium complexes have been shown to catalyse intramolecular hydroamination reactions of alkenes. The corresponding pyrrolidine and piperidine products were formed in up to 97% yields. However, only the geminally disubstituted aminoalkenes were successfully cyclized (Thorpe-Ingold effect).56... 

Triazines with C5-tethered dienophilic side chains are sterically constrained to undergo intramolecular Diels-Alder reactions across N2 and C5 of the 1,2,4-triazines. Elimination of a nitrile from the intermediate adduct (N1 and C6 of the starting 1,2,4-triazine) affords condensed pyrimidines. The reactivity of 5-(alkynyl substituted)-l,2,4-triazines in the intramolecular [4 -(- 2] cycloaddition reaction is highly dependent on the steric and electronic disposition in the dienophilic side chain. The cycloaddition is hindered when an electron-donating atom (N, O) is used to link the dienophilic side chain to the 1,2,4-triazine nucleus, while introduction of bulky groups into the side chain facilitates the process via the Thorpe-Ingold effect.183... 

The Thorpe-Ingold effect assists the intramolecular Diels-Alder reaction with inverse electron demand <86TL2107>. 

The intramolecular Thorpe-Ziegler reaction of hexadecadinitrile with lithium l -ethylanHide according to the Ruggli-Ziegler dilution principle provided a technical advancement. At a concentration of 0.067 mole/1 the yield ranged around 60-70%. 

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... 

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. 

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