What Is Friedländer Quinoline Synthesis?
The Friedländer reaction involves the acid- or base-catalyzed cyclocondensation of o-aminoaryl aldehydes or ketones with carbonyl compounds containing an α-methylene group to form quinoline scaffolds. First reported in 1882 by Paul Friedländer, this method has evolved to accommodate diverse substrates and catalytic systems, enabling the synthesis of highly functionalized quinolines.
- Catalysts: Acidic [e.g., trifluoromethanesulfonic acid (TFOH), H2SO4, sulfated polyborate, zeolites] or basic [e.g., potassium tert-butoxide (KOtBu), 1,8-diazabicycloundec-7-ene (DBU)].
- Solvents: Polar aprotic solvents (e.g., chlorobenzene, dichloromethane (DCM)) under acidic conditions; non-polar solvents (e.g., toluene) for base-mediated reactions.
- Reactants: o-Aminoaryl aldehydes or ketones; ketones containing α-methylene.
- Products: Substituted quinolines.
- Reaction Type: Cyclization reaction.
- Related Reactions: Combes quinoline synthesis, Knorr quinoline synthesis, Skraup reaction, Doebner-Miller reaction.
Fig 1. Friedländer quinoline synthesis and its mechanism. [1]
Mechanism of Friedländer Quinoline Synthesis
First, the two molecules undergo aldol condensation and dehydration to obtain α, β-unsaturated aldehydes and ketones. Subsequently, the amino group undergoes intramolecular condensation with the carbonyl group and undergoes acid- or base-catalyzed ring dehydration to obtain a quinoline ring.
Experimental Tips for Friedländer Quinoline Synthesis
- The traditional Friedländer quinoline synthesis method is suitable for small-scale preparation, but due to the relatively harsh reaction conditions (high temperature, acid, base catalysis, etc.), the yield decreases when the production is scaled up. Studies have reported that the use of catalytic amounts of gold catalysts can enable the reaction to proceed under milder conditions. In addition, the Friedländer quinoline synthesis catalyzed by p-toluenesulfonic acid and iodine has been achieved under solvent-free conditions. Friedländer quinoline synthesis can also be carried out under solid phase support.
- When using asymmetric ketones, regioselectivity is a problem in the Friedländer quinoline synthesis method. Introducing a phosphoryl group on the α-carbon of the ketone, or using an appropriate amine catalyst, or using an ionic liquid are effective ways to solve the regioselectivity problem.
- To avoid side reactions such as aldol condensation of ketones under alkaline conditions, the imine analogue of o-aniline can be used to replace o-aniline. This method has been verified for the synthesis of camptothecin.
Application Examples of Friedländer Quinoline Synthesis
- Example 1: You-Dong Shao et al. first developed a diastereoselective Friedländer heterocyclization reaction of 2-aminoaryl ketones with α-methylene carbonyl derivatives using chiral phosphoric acid as an efficient organic catalyst. The reaction prepared the desired enantiomer-enriched axial chiral multi-substituted 4-arylquinoline system with good to high yields and enantioselectivities (yield up to 94% and ee value up to 97%). In addition, the product is easy to derivatize to obtain a series of new quinoline-containing heteroenantiomers, which have great potential in asymmetric catalysis and drug development. [2]
- Example 2: The work of Ganesh Pandey et al. used the Friedländer quinoline synthesis method as a key step to achieve the enantiospecific synthesis of (+)-eucophylline. [3]
Fig 2. Synthetic examples via Friedländer quinoline synthesis.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 206-208.
- Shao, You-Dong, et al. Organic Letters, 2019, 21(12), 4831-4836.
- Pandey, Ganesh, et al. Organic Letters, 2017, 19(12), 3267-3270.
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