TheFriedländer Synthesis of Quinolines

Abstract

Friedländer prepared quinoline in 1882 by the condensation of o ‐aminobenzaldehyde with acetaldehyde in the presence of sodium hydroxide. This type of reaction has since been extensively explored and, in its most general form, can be defined as an acid‐ or base‐catalyzed condensation followed by a cyclodehydration between an o ‐amino‐substituted aromatic aldehyde, ketone, or derivative thereof with an appropriately substituted aldehyde, ketone, or other carbonyl compound containing a reactive α‐methylene group. Some quinolines can also be prepared simply by heating a mixture of the reactants with or without a solvent. Because both reactants contain a carbonyl group, certain quinolines can be prepared from a single starting compound. Of historic interest is the formation of the dye flavaniline from acetanilide. When acetanilide is heated with zinc chloride, the acetyl group of some molecules migrates to the ortho position, and that of others migrates to the para position. The resulting mixture of o ‐acetylaniline and p ‐acetylaniline then undergoes Friedländer condensation to form flavaniline. Two related quinoline syntheses, the Pfitzinger reaction and the Niementowski reaction, can be considered as extensions of the Friedländer synthesis. The Pfitzinger reaction uses an isatic acid or isatin and the Niementowski reaction uses an anthranilic acid for condensation to form a 4‐quinolinecarboxylic acid and a 4‐hydroxyquinoline, respectively. Several other related reactions, such as the Combes quinoline synthesis, the Doebner–Miller quinoline synthesis, and the Skraup quinoline synthesis, use different types of starting compounds. It is of interest that all of the six aforementioned syntheses of quinolines were discovered within a period of 14 years in the latter part of the nineteenth century, undoubtedly reflecting many scientific interests and commercial activities at that time, including the isolation of quinolines from coal tar, the manufacture of dyes, and studies of natural products such as alkaloids.

Friedländer condensation of 5-aminopyrazole-4-carbaldehydes with reactive α-methylene ketones: Synthesis of pyrazolo[3,4-b]pyridines

“…under microwave irradiation) [10]. We obtained the best results when a mixture of the appropriate 5-aminopyrazole-4-carbaldehyde 3 and the corresponding ketone 4 or 6 were brought to reaction in refluxing ethanolic potassium hydroxide solution.…”

“…o-Aminoaldehydes are the key intermediates for the synthesis of various biologically active heterocycles e.g. [8,9] using the Friedländer reaction with ketones in a 4+2 cyclocondensation [10], which prompted us to investigate the reaction pathway of 5-aminopyrazole-4-carbaldehydes with α-methylene ketones to new 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo[3,4-b]pyridines, especially to 1,3,6-triarylpyrazolo[3,4-b]pyridines. A literature survey shows a few reports on the synthesis of pyrazolo [3,4-b]pyridines using the Friedländer condensation [11], however with substitution patterns different to ours.…”

“…As mentioned above, the Friedländer condensation can be catalyzed by various agents [10]. When we extended Scheme 2 Friedländer Condensation of 5-Aminopyrazole-4-carbaldehydes Nov-Dec 20051313 our synthetic investigations to CH-acidic compounds such as benzoylacetonitriles 9, β-ketoesters 11 or diethyl malonate 13 as keto-component, we found that already piperidine as base was sufficiently strong to catalyze the condensation reaction, which allowed also the preparation of sensitive substituents such as ester groups without decomposition.…”

A Modular Approach to Oxoindolizino Quinolines: Efficient Synthesis of Mappicine Ketone (Nothapodytine B)

“…A Friedländer condensation, which is ideal for accessing diversely substituted quinolines, was planned for the formation of the tetracyclic framework of the oxoindolizino quinolines. [5] The requisite ketones B were viewed as products of benzylic-type oxidation of pyridones C, which would originate from various Claisen and Stille/Suzuki transformations of hydroxypyridones D. [6] Hydroxypyridones D are easily available through cycloaddition of the isomünchnone dipoles derived from diazo imides E. [7] We now illustrate the feasibility of this general strategy by way of an effective synthesis of mappicine ketone (1 a). Mappicine ketone, present in small amounts in Nothapodytes foetida (a plant found in India), [1] and formed by thermolysis of camptothecin, [8] displays strong, selective activity against herpes viruses (HSV-1 and HSV-2, including Acyclovirresistant forms) and human cytomegalovirus.…”

Synthesis of novel 2‐aminoimidazo[4,5‐b]pyridines, including the thieno analogue of the cooked‐food mutagen IFP

“…We Jan-Feb 2006 101 Figure 1 The Friedländer reaction [23], studies on the mechanism of which were recently reported [24], have previously been used by our group to obtain the related imidazo-quinoline [18] 6 ( Figure 2) and -naphthyridines such as 7a-c [17,25] that are analogous to the IFP sulfur analogue 1, by simply heating creatinine (8, Scheme 2) or isocreatinine (12, Scheme 2) with an appropriate ortho-aminocarbaldehyde in ethylene glycol instead of using typical Friedländer conditions. Several other procedures have been described [23] for the Friedländer reaction, including bismuth triflates catalysis [26], solid state synthesis [27], tin chloride/zinc chloride conditions on the ortho-nitrocarbaldehyde [28] and microwave conditions [29]. In analogy with previous work [30], we found that it was necessary to transform creatinine to its enolic silyl ether with bis(trimethylsilyl)acetamide (BSA) for our condensation with the thiophene ortho-aminocarbaldehyde 11 (Scheme 1) and the benzothiophene analogues 21 and 24 (Scheme 4) used in this work.…”