Friedlander reaction

Friedlander reaction FrieUnder synthesis Fries rearrangement Frigen... 

Synthesis and Properties. Polyquinolines are formed by the step-growth polymerization of o-aminophenyl (aryl) ketone monomers and ketone monomers with alpha hydrogens (mosdy acetophenone derivatives). Both AA—BB and AB-type polyquinolines are known as well as a number of copolymers. Polyquinolines have often been prepared by the Friedlander reaction (88), which involves either an acid- or a base-catalyzed condensation of an (9-amino aromatic aldehyde or ketone with a ketomethylene compound, producing quinoline. Surveys of monomers and their syntheses and properties have beenpubhshed (89—91). 

By 1922, the Friedlander reaction had been well enough established that it was being used to prepare derivatives for structure elucidation. ... 

Two possible mechanisms exist for the Friedlander reaction. The first involves initial imine formation followed by intramolecular Claisen condensation, while the second reverses the order of the steps. Evidence for both mechanisms has been found, both... 

The Friedlander reaction is quite versatile. The primary limitation on the o-aminobenzaldehyde component is preparation of the starting material as one might expect, these compounds are prone to self-condensation. Both electron rich and electron poor o-aminobenzocarbonyl compounds undergo the Friedlander reaction. When ketone partner 2 has only one available reactive methyl or methylene or is symmetrical, only one product is obtained. Even when two products can be formed, it is possible to choose reaction conditions such that only one product is isolated vide infra). The reaction can be promoted by acid catalysis, sometimes with improved results. 

Several variations of the Friedlander reaction exist and are well known enough to have their own names ... 

The Fehnel modification describes the Friedlander reaction in acetic acid with a... 

The Henegar modification of the Friedlander reaction has been recently reported. The A-Boc protected derivative of o-aminobenzaldehyde (25, in this case prepared via directed ortho metallation of 24) is a stable, crystalline compound that can be stored for extended periods (in contrast with 4, which typically is freshly prepared). Treatment of 25 with ketone 26 in acetic acid results in deprotection of the aniline in situ and subsequent formation of 27, an intermediate in the synthesis of mappicine. 

The Friedlander reaction originally was performed in ethanolic alkoxide. Amine bases, such as piperidine, have been used. Anion exchange resins have also been used. ... 

Alternatively, the Friedlander reaction can be promoted by thermolysis to ISO-ZOO °C in the absence of solvents. ... 

Merck chemists have done a detailed investigation on the effect of reaction conditions on the yield and selectivity of the Friedlander reaction. Initially, the... 

The Friedlander reaction makes available a wide variety of 1,10-phenanthrolines and other macrocyclic chelators (e.g. 33, 34 and 35). These polyaza-aromatic rings can bind a variety of metals or organic substrates. 

Since various substituents are tolerated, the Friedlander reaction is of preparative value for the synthesis of a large variety of quinoline derivatives. The benzene ring may bear for example alkyl, alkoxy, nitro or halogen substituents. Substituents R, R and R" also are variable. The reaction can be carried out with various carbonyl compounds, that contain an enolizable a-methylene group. The reactivity of that group is an important factor for a successful reaction. 

Indolizino-quinoline 250, the ring system present in camphotecine and mappicine, has been prepared using classical Friedlander reaction under microwave irradiation conditions [160]. The reaction was successfully carried out in AcOH as the solvent and gave good results even with unstable o-amino benzaldehydes 248 (Scheme 92). 

A way to introduce the primary amino group directly onto the selenophene ring is via the azido compound, obtained by nucleophilic substitution of the bromo derivative with sodium azide. Useful transformations of the azido group are shown in Scheme 12.117 The amino aldehyde (109) is a suitable starting material for the preparation of selenolo[3,2-b]pyridine (110) by the Friedlander reaction.138 Not only can the azido be reduced to an amino... 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

Polyquinolines (PQ) are obtained by the Friedlander reaction of a bis-o-aminoaromatic aldehyde (or ketone) with an aromatic hisketomethylene reactant [Concilio et al., 2001 Stille, 1981]. The quinoline ring is formed hy a combination of an aldol condensation and imine formation (Eq. 2-221). Polymerization is carried out at 135°C in m-cresol with poly (phosphoric acid) as the catalyst. The reaction also proceeds under base catalysis, but there... 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

The synthetic utility of these derivatives towards the preparation of condensed heterocycles has been demonstrated. Thus, treatment of 252 with cyclohexanone under acidic conditions (66JOC3852) (Friedlander reaction) and molten urea affords the naphthyridine 253 and pyridopy-rimidinone 251, respectively (Scheme 76) (89JHC105). Application of these reactions on the isomeric iV-pivaloylamino pyridine ketones affords analogue heterocycles 254-257. 

A general way to prepare furo[3,2-6]pyridines utilizes the Friedlander reaction applied to 3-amino-2-formylfuran (Scheme 17). It proved unnecessary to isolate these o-aminocar-bonyl compounds. Thus the reaction solutions obtained from the reduction of the azido compounds can be used directly after removal of the precipitated sulfur (75ACS(B)233, 75ACS(B)224). 

Thieno[3,2-fc]pyridines are obtained in 49-87% yield (74JPR169). Application of the Friedlander reaction to 3-amino-2-formylthiophene gives (261) in reasonable yield (Scheme 78) (75ACS(B)224,75 ACS(B)233). As in the case of the synthesis of furo[3,2- >]pyridines (Section 3.17.2.1.1(i)(d), Scheme 17), it was unnecessary to isolate the o-aminocarbonyl compounds. 6-Substituted 7-hydroxythieno[3,2-6]pyridin-5(4/7)-ones (e.g. 295) can be prepared by base-catalyzed cyclization of the amides (294), which were obtained in high yields from readily available 3-amino-2-alkoxycarbonylthiophenes (293 Scheme 79) (80JCR(S)6) for... 

Gronowitz and coworkers prepared (426) by application of the Friedlander reaction (75ACS(B)233). The Friedlander method utilizes the reaction in alkaline or acidic media between an o-aminocarbonyl compound and a carbonyl compound containing an active methylene group. The amino compound used is 3-amino-2-formylselenophene, which is... 

The Friedlander annulation is one of the most straightforward approaches towards poly-substituted quinolines. Thus, a 22-membered library of quinolines was synthesized in a TsOH-catalyzed cyclocondensation-dehydration of 2-aminoaryl ketones and 2-aminoarylaldehydes with ketones in a household microwave oven (with power control) under solvent-free conditions [112]. It was observed that the Friedlander reaction occurred readily also in an oil-bath (at 100 °C). To compare the conventional and dielectric heating conditions precisely, a purpose-built monomode microwave system with temperature control was employed instead of the household oven. The experiments at 100 °C under otherwise identical conditions demonstrated that the dielectric heating protocol was only slightly faster. Products were isolated by a simple precipitation-neutralization sequence (in the case of solid products) or neutralization-extraction for oily or low melting point products (Scheme 43). 

A series of 2,7-disubstituted pyrido[3,2- ]quinolines (24) were obtained by a double Friedlander reaction on 4,6-diamino-isophthalaldehyde (Equation (10)) <84LA133>. 

Using an environmentally benign Friedlander synthesis, Yang and co-workers synthesized 11 //-indeno[ l, 2,/)Jquinolincs in refluxing ethanol and a catalytic amount of sodium ethoxide <07T7654>. This method provided a very nice complement to quinoline synthesis through the Friedlander reaction while avoiding harsh reaction conditions. 

Camps, R Gomez, E. Munoz-Torrero, D. Amo, M. On the regioselectivity of the Friedlander reaction leading to huprines stereospecific acid-promoted isomerization of syn-huprines to their anti-regioisomers. Tetrahedron-Asymmetry, 2001, 12(20) 2909-2914. 

The synthesis of decahydropyrido [3,4-h] acridine 47, by a Friedlander reaction, and its opioid-antagonistic activity (IC50 = 54 nM) has been claimed [92JAP(K)92/275288]. 

A Friedliinder reaction (review [3017]) between a 2-aminobenzaIdehyde (2.3) and a 4-unsubstituted resorcinol in the presence of a base is a convenient method of synthesizing a fused pyridine, but the expected product (2.6) of a Friedlander reaction between 2-aminobenzaldehyde and A -acetyl-3-pyrrolidone in aqueous alkali was not obtained instead, a low yield of the isomeric ring system (2.S) was isolated. Both types of products were obtained when the pyrrolidone was replaced by ethyl 3-oxopyrrolidine-l-carboxylate, the [3,2-6] isomer predominating. A mixture of isomers was also obtained when the reaction was attempted under acidic conditions. 

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