Quinoline Friedlander synthesis

The Friedlander quinoline synthesis 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 acid, base, or heat. 

Friedlander, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572. Paul Friedlander (1857-1923), born in Kdnigsberg, Prussia, apprenticed under Carl Graebe and Adolf von Baeyer. He was interested in mnsic and was an accomplished pianist. 

Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed. Wiley Sons, New York, 1952, 4, Qninohne, Isoqninoline and Their Benzo Derivatives, 45-47. (Review). 

in Heterocyclic Compounds, Qninolines, vol. 32, 1977 Wiley Sons New York, 181-191. (Review). 

Shiozawa, A. Ichikawa, Y.-I. Komnro, C. Knrashige, S. Miyazaki, H. Yamanaka, H. Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 102, Springer-Verlag Berlin Heidelberg 2009 

Li Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 110, Springer International Publishing Switzerland 2014 

Example 5, Using propylphosphonic anhydride (T3P) as the coupling agent  

Condensation of o-aminobenzaldehydes with a-methylene carbonyl compounds 

Quinolines 3 can be obtained from reaction of orr/zo-aminobenzaldehydes or o-aminoarylketones 1 with a-methylene carbonyl compounds.Various modified procedures are known a related reaction is the Skraup quinoline synthesis. 

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  

Although that reaction has been known for more than one hundred years, it is not clear whether the reaction proceeds via pathway (a) or (b) or both. Since the reaction works with a large number of different substrates and under various 

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. 

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In 1886 Pfltzinger reported a formal extension of the known Friedlander protocol for the synthesis of quinolic acids. This new protocol relied on the use of isatin which is much more stable than the ort/io-aminoaryl intermediates that are required in the Friedlander quinoline synthesis. In this early paper, Pfitzinger reports that upon heating of isatin 3 in the presence of aqueous sodium hydroxide, the former is. hydrolyzed to the isatic acid 4 which then in the presence of acetone reacts to give aniluvitonic acid 6. ... 

The Friedlander quinoline synthesis is particular useful for the preparation of 3-substituted quinolines, which are less accessible by other routes. A drawback however is the fact that the required o-atninobenzaldehydes or o-aminoarylketones are not as easy to prepare as, e.g., the anilines that are required for the Skraup synthesis. 

By reaction of a primary aromatic amine—e.g. aniline 1—with glycerol 2, and a subsequent oxidation of the intermediate product 4, quinoline 5 or a quinoline derivative can be obtained.As in the case of the related Friedlander quinoline synthesis, there are also some variants known for the Skraup synthesis, where the quinoline skeleton is constructed in similar ways using different starting materials. ... 

Note These examples are extensions of the Friedlander quinoline synthesis. 3-Ammo-2-quinoxalinecarbaldehyde (183, R = H) and diethyl malonate (184) gave ethyl 2-oxo-l,2-dihydropyrido[2,3-fc]quinoxaline-3-carboxylate (185, R = H) (trace NaOH, trace H2O, EtOH, 10 min 60%). ... 

Wang et al. reported two different reaction conditions for a solvent free Friedlander quinoline synthesis. Initially, they reported the reaction of 2-acetyl anilines 73 with a variety of P-diketoesters 74 using / -Ts()H as the catalyst under microwave conditions to form substituted quinolines 75 <060BC104>. They also reported the same reaction using BiCl3 as the catalyst under thermal conditions <06LOC289>. Both sets of conditions afford high yields and simpler experimental procedures. 

In addition to their work with solvent free systems, Wang and co-workers reported a water mediated Friedlander quinoline synthesis using hydrochloric acid and conventional heating to synthesize a variety of substituted quinolines in high yields <06TL1059>. 

Pflum, D. A. Friedlander Quinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 411—415. (Review). 

The Borsche modification of the Friedlander quinoline synthesis has been shown to be of general use97 in the preparation of 1,7-naphthyridines (60). The preparative sequence involves the synthesis of compound 58 and its condensation with a carbonyl compound (59). 

Friedlander quinoline synthesis has been accomplished in ionic liquids with substoichiometric amounts of FeCl3-6H20 (Scheme 8.33) [101]. The substitution pattern of products 77 is, however, relatively limited to 2,4-diaryl-functionalized quinolines, as depicted in Scheme 8.33. 

Scheme 8.33 Iron-mediated Friedlander quinoline synthesis.

FRIEDLANDER Quinoline Synthesis Quinoline synthesis from condensation of o aminoaryi aldehydes (ketones) with c aldehydes (ketones)... 

FRIEDLANDER Quinoline synthesis t32 FRIES Phenol ester rearrangement 133 FRITSCH. BUTTENBERG - WIECHELL Acetylene synthesis 134... 

Additionally, Rivkin and co-workers synthesized a variety of 4-hydroxy-3-phenylquinolin-2-(l//)-ones under solvent free microwave conditions using an activated arylmalonate <06TL2395>. Reacting the desired substituted aniline with di-(2,4,6-trichlorophenyl)-2-phenyl-malonate at 250 °C with microwave irradiation for 15 min resulted in a variety of 4-hydroxy-3-phenylquinolin-2-(l//)-ones in good yields. They also demonstrated the utility of this method in the synthesis of type I fatty acid synthase inhibitors <06BMCL4620>. Kumar et al. have reported a variation of the Friedlander quinoline synthesis. They highlight the use of CeClj THjO as a reusable catalyst in the reaction of 2-... 

This reaction is particularly useful in the Friedlander quinoline synthesis, the use of which has been limited by the inaccessibility of o-aminobenzaldehydes. Thus a one-pot synthesis of quinolines is now possible by reduction of an o-nitrobenz-aldehyde with the reagent in the presence of an a-methylene ketone. 

Formylpyrazoles, 121 Fremy s sale, 42, 329-330 Friedel-Crafts acylation, 110 Friedel-Crafts alkylation, 217 Friedlander quinoline synthesis, 102 Frontalin, 201, 202... 

In their quest to synthesize quinolines without the need to involve metalated species as cross-coupling partners, Banwell and coworkers have devised a two-step procedure wherein the first step is the palladium[0]-mediated Ullmann cross-coupling of 1-bromo-2-nitroarenes (e.g. 173) with p-halo-cnals [74]. The resulting p-nitroaryl enal undergoes reductive cyclization, in the style of the Friedlander quinoline synthesis, to give the corresponding quinoline. A wide range of quinolines can be accessed by this method since many l-halo-2-nitroarenes are commercially available and p-halo-cnals such as 174 can be easily prepared by Vilsmeier haloformylation of the appropriate ketones. 

An alternative approach to the tetracyclic systan forms the heterocyclic ring by nucleophilic addition of an amine to a carbonyl group. Application of the Friedlander quinoline synthesis to various methoxy-1-tetralones yields the methoxy-5,6-dihydrobenz-[c]acridines, which are dehydrogenated to the aromatic compound by distillation from palladium-charcoal (M. Croisy-Delcey et al. J. med. Chem., 1983, 26, 303). 

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