Friedlander condensation reaction

Syntheses of heterocycles by the Friedlander condensation reaction 04MI10. 

The mechanistic pathway of the ordinary Friedlander synthesis is not rigorously known. Two steps are formulated. In a first step a condensation reaction, catalyzed by acid or base, takes place, that can lead to formation of two different types of products (a) an imine (Schiff base) 4, or (b) an o ,/3-unsaturated carbonyl compound 5 ... 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

The Friedlander condensation of 2,6-diaminopyridine-3,5-dicarbaldehyde (393) with various ketones has been reported (77JOC3410). Reaction of the aldehyde with acetophenone, with deoxybenzoin and with a-tetralone generates the 5,10-dihydro-l,9,10-anthyridine derivatives (394 R = H), (394 R = Ph) and (395) respectively, whilst with acenaphthenone the nonacyclic anthyridine (396) is obtained. The condensation between 2-amino-3-ethoxy-carbonyI-l,8-naphthyridine (225) and alkyl carboxylates under basic conditions produces 4-hydroxy-1,9,10-anthyridin-2-ones (397) (79BAP571). 

The camptothecin synthesis of Shen/Dani-shefsky [16] (Scheme 8) starts with the construction of the D ring reaction of 46 with 47 affords 48. The next step (48 49) introduces the C20 ethyl group. Hydroxymethylation of 49 delivers lactone SO. The B ring of the camptothecin precursor 52 should be accomplished by a Friedlander condensation of 10 with 11. For this purpose, a keto group at C2 of the C,D,E ring building block had to be installed. Shen and Danishefsky solved this problem by combination of an aldol condensation (50 —> 51) and a subsequent ozonolysis (51 11). Important for... 

Aminopyrimidine-5-carbaldehydes,24 prepared by Vilsmeier formylation, condense in a Friedlander-type reaction with a variety of active methylene partners such as ketones, j3-oxo esters, malonic add derivatives or arylacetonitriles, the latter preferably with electron-withdrawing substituents. 

The most commonly used ADA modules contain the pyrimidine-2,4-dione nucleus. Not surprisingly, N-alkylation of thymine or uracil with an alkyl halide provides a simple, one-step method of functionalizing this module. Other ADA units include simple imides (e.g., 10), heterocycle 13, which was used by Kelly in a bisubstrate reaction template [17], and the anthyridinone or anthyridan units in 15 and 18, respectively. The latter modules are synthesized by double Friedlander condensation of 2,6-diaminopyridine-3,5-dicarboxal-... 

The reaction of 148 with 10% HCl-MeOH afforded selective hydrolysis of the amide to form the 3-aminopyridine 149, in which the ring was subsequently closed after treatment with palladium(O) to give the /3-carboline 150. Friedlander condensation of 150 with 2-amino-3-benzyloxy-4-bromo-benzaldehyde (151), which was synthesized in four steps (5S), gave the 2-/3-carbolinequinoline 152. Hydrogen bromide gas debenzoylation of 152 was followed by oxidation with potassium nitrosodisulfonate (Fremy s salt) to obtain Kende s intermediate 131. 

A four-step synthesis of 8-amino-7-quinoline carbaldehyde (87) from 8-hydroxyquinoline (88) has been disclosed (Scheme 48) (94T(50) 10685). Major steps involved a Bucherer reaction followed by Claisen type rearrangement, isomerization and ozonolysis. Amino aldehyde (87) underwent Friedlander condensation with 2-acetylpyridine to form 2-pyridyl-l,10-phenanthroline (89). 

The great majority of quinolines and isoquinolines have been prepared by ring construction, instead of transformation of preexisting derivatives. They are obtained by variants of two main routes. The first route involves the cyclization of mono-substituted benzene rings, usually A-substituted anilines (Skraup, Doebner-von Miller, Knorr, Conrad-Limpach), and the second route involves the intramolecular condensation of o-disubstituted benzenes for the formation of the requisite pyridine ring (Friedlander, Pfitzinger reaction, etc.). 

The Friedlander reaction is quite versatile and can be used either by electron-rich or electron-poor aromatic components. The only limitation is the sustainability of the orf/ro-acylaniline for self condensation. In this logic, protected anilines and imines in some cases are used to avoid the undesired self condensation of the starting anilines. On the other hand, the Friedlander condensation is applicable to the aldehydes, ketones, carboxylic acids, esters, amides, nitriles, and aldoximines that have an adjacent enolizable group. In... 

This reaction is related to the Friedlander Condensation and Pfitzinger Reaction. 

Also known as the Friedlander condensation, it combines an a-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene a adjacent to the carbonyl to furnish a substituted quinoline. The reaction can be promoted by... 

Beier and Pastyrikova (13MI411) reported that reductive ring opening of SFs-substituted benzisoxazoles 78a, 79a using iron in aqueous AcOH resulted in excellent yields of ori/ o-aminobenzophenones 100, 101, which can be used as precursors for the synthesis of other SFs-substituted heterocycles such as quinazoHnes (see Section 2.8), as weU as for the synthesis of SFs-substituted quinolines. Thus 6-SFs-quinoline 102 was prepared in high yield by the Friedlander annulation reaction of 101 with excess ethyl acetoacetate in the presence of catalytic cerium (IV) ammonium nitrate (CAN). Similarly, aminoketone 100 was condensed in good yield with cyclohexanone to provide 7-SFs-quinoline 103 (Scheme 25). 

Synthesis of quinoline derivatives via the Friedlander coupling condensation reaction [116] was carried out under microwave inadiatioa The reactants were different acetophenones and 2-aminoacetophenones or benzophenones. The product was obtained in 4 min of irradiation (Scheme 11.59). 

In 2012, Gong and co-workers reported an enantioselective three-component reaction based on an asymmetric relay catalytic domino Friedlander condensation-transfer hydrogenation reaction of 2-aminophenyl ketones. 

Friedlander Reaction Friedlander condensation is one of the most used and cited reactions in organic synthesis and it is the method of choice for the synthesis of a large variety of nitrogen heterocyclic ring systems such as quinolines, naphthyridines, phenanthrolines, quindolines, or acridones [142]. 

Friedlander condensation is considered as an atom-economic reaction proceeding through double condensation between 2-aminoaryl carbonyl compoimds with other carbonyl components that show enolizable hydrogens. 

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