Cyclization condensation

GENERATION AND CYCLIZATIVE CONDENSATION OF o-AMINOBENZYL ALDEHYDES AND KETONES... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

Diamines, aminothiols, and aminoalcohols are well suited for quantitative solid-state cyclizing condensations with simple aldehydes and ketones. As yet only quantitative gas-solid reactions with acetone and solid-solid reactions with paraformaldehyde (that will monomerize upon the milling) have been profited from. An early remarkable reaction type involving two molecules of... 

Reactions in this category correspond to construction of the pyrrole ring from ammonia or a substituted derivative and a preassembled carbon array. These can be subdivided into cyclizative condensations and metal-promoted processes. 

One of the most general pyrrole syntheses is the cyclizative condensation of 1,4-dicarbonyl compounds with ammonia, a primary amine or related compound. The mechanistic pattern involves formation of carbinolamine and imine intermediates followed by aromatization. This method is sometimes referred to as the Paal-Knorr pyrrole synthesis (equation 65) (B-77MI30601). Once the dicarbonyl compound is available, the cyclization normally proceeds in good yield, so ease of access to the diketone is of major importance in determining the applicability of this method to specific pyrroles. Pyrrole formation usually takes place on heating the diketone in a solvent such as benzene or toluene with a catalytic amount of acid. An alternative method involves heating the dicarbonyl compound and an amine salt... 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

Because substituted anilines are widely available, they are ideal starting materials for the synthesis of indoles. Although anilines are often the precursors of the hydrazones used in the Fischer cyclization, more direct methods for conversion of anilines to indoles would be highly desirable. Such a process would, in general, have to involve some method for specific o -substitution of the aniline derivative. In the most successful method of this type which has been developed to date, a specific rearrangement effecting o-substitution is the key to a synthetic scheme which constructs indoles from anilines via anilinosulfonium ions. The procedure, which in appropriate circumstances can be carried out without isolation of the intermediates, involves oxidation of the aniline to an A-chloroaniline, reaction with a thiomethylmethyl ketone and a weak base, followed by cyclizative condensation (equation... 

Cyclizative condensations based on aldol-type reactions which conform to the llbd pattern have also been developed. Condensation of bis(alkoxycarbonylmethyl)amines or bis(cyanomethyl)amines with benzil affords 3,4-diarylpyrrole-2,5-dicarboxylic add esters or nitriles. These reactions frequently lead to partial hydrolysis of at least one of the alkoxycarbonyl substituents and if the 3,4-diarylpyrrole is the ultimate objective, work-up involving complete hydrolytic decarboxylation is appropriate (equation 119) (6lLA(639)l02, 65JOC859). 

The cyclization steps are facilitated by the ready susceptibility of the pyrrole ring to electrophilic attack. Step-wise approaches such as these give much better yields than attempts at cyclizative annelation of pyrroles with potentially bifunctional reagents. For example, the cyclizative condensation of pyrrole with 2,5-hexanedione, which gives 4,7-dimethylindole (equation 138), is plagued with by-product formation to the extent that the indole is obtained in only 28% yield (68AJC2053). 

The carboxylic acid family of substituents is most often introduced at the stage of ring synthesis for both pyrroles and indoles. Many of the cyclizative condensation routes to pyrroles in fact rely on the presence of ester substituents. Indoles with 2-carboxy substituents are easily available from the adaptation of the Fisher synthesis, which provides the arylhy-... 

Pyrrolinones are best obtained by cyclizative condensation of y-keto esters with ammonia or a primary amine (reaction 195). Alternatively, the 2-pyrrolinones may be obtained by cyclization of preformed a-keto amides as shown in reaction (196) (71CC346). Preexisting lactones (2H- or 5H-furanones) also react with amines to give pyrrolinones (reaction 197). Jones and Bean give references to specific examples of these methods as well as to more specialized examples (B-77MI30610). 

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