Paal-Knorr Synthesis

Paal-Knorr Furan Synthesis

In 1884, Paal and Knorr almost simultaneously reported that 1,4-diketones can be dehydrated to form polysubstituted furans under the action of strong acids. Any 1,4-dicarbonyl compound (mainly aldehydes, ketones) or their analogs can undergo such a transformation under the action of protic acids (HCl, HS₂O₄, p-TsOH, etc.) and Lewis acids (ZnBr₂, BF₃·Et₂O, etc.), or dehydrating agents (P₂O₅, Ac₂O, etc.). This synthetic method has been widely used and is called Paal-Knorr synthesis. Analogs of 1,4-dicarbonyl compounds can be in the form of acetals, ketals, or with one of the carbonyl groups replaced by an epoxide.

Reaction Mechanism

The first step of the Paal-Knorr furan synthesis reaction is the rapid protonation of one carbonyl group, while the other carbonyl group undergoes enolization and the hydroxyl group attacks to form a ring, which is the rate-determining step. The intermediate generated then receives a proton for dehydration and finally deprotonates to form a furan ring.

Fig 1. Paal-Knorr furan synthesis and its mechanism. [1]

Paal-Knorr Pyrrole Synthesis

Similarly, Paal also reported that 1,4-diketones react with concentrated ammonia or acetic acid solution of ammonium acetate to form multi-substituted pyrroles. Knor reported that 1,4-diketones react with primary amines to form pyrroles with substitutions on nitrogen. This reaction of preparing pyrroles by condensing 1,4-dicarbonyl compounds with ammonia or primary amines is called the Paal-Knorr pyrrole synthesis. Similarly, any 1,4-dicarbonyl compound (mainly 1,4-diketones) or their analogs can undergo such a transformation. For this reaction, the amine substrate is widely applicable, which can be ammonia, primary aliphatic amines, aromatic amines with electron-donating or electron-withdrawing groups on the aromatic ring, and heterocyclic amines. Both protonic acids and Lewis acids can catalyze this reaction. The choice of reaction solvent mainly depends on the type of amine.

Reaction Mechanism

The mechanism of Paal-Knorr pyrrole synthesis reaction is that amines attack two carbonyl groups in turn to form a ring, and then remove two molecules of water to form pyrrole. The ring formation step is also the rate-determining step.

Fig 2. Paal-Knorr pyrrole synthesis and its mechanism. [2]

Limitations and Improvements of Paal-Knorr Synthesis

Both Paal-Knorr furan synthesis and Paal-Knorr pyrrole synthesis are acid-catalyzed condensation reactions with 1,4-dicarbonyl compounds as precursors. The main difference lies in whether the second component amine is added. Therefore, the development and improvement of these two methodologies are usually intertwined. The disadvantages of Paal-Knorr furan/pyrrole synthesis are that 1,4-dicarbonyl compound precursors are difficult to prepare, and the cyclization usually requires a long time of reflux in acid solution, the conditions are more severe, and it is not applicable to substrates containing acid-sensitive functional groups.

Improvement of Reaction Conditions

Mild Lewis acids such as Sc(OTf)₃, Bi(NO₃)₃, layered α-Zr(KPO₄)₂, α-Zr(CH₃PO₃)_1.2(O₃PC₆H₄SO₃H)_0.8 are used for catalysis. I₂, clay, and montmorillonite can also promote the reaction. There are also many studies on the Paal-Knonr furan/pyrrole synthesis reaction under microwave conditions.

Ionic liquid [BMIm]BF₄ can be used as a reaction solvent, and the reaction can be carried out at room temperature without the addition of acid catalyst.

Multi-Component/Tandem Strategy

Muller et al. reported a three-step one-pot preparation of multi-substituted pyrroles by coupling isomerization/Stetter 1,4-addition/Paal-Knorr pyrrole synthesis of electron-withdrawing substituted aryl (heterocyclic) halides, terminal alkynols, aldehydes and primary amines.

Application Examples of Paal-Knorr Reaction

• Example 1: Bing Xu et al. achieved the total synthesis of Marineosin A with Paal-Knorr pyrrole synthesis as one of the key steps. [3]
• Example 2: Taddei et al. reported a two-step preparation of various ester-substituted 1,4-diketones from commercially available β-ketoesters, reacting with Et₂Zn, CH₂I₂, aldehydes and then oxidizing with PCC. It can cyclize to furan products under microwave conditions, or add amines and cyclize to the corresponding pyrrole products under microwave conditions. [4]

Fig 3. Synthetic examples via Paal-Knorr synthesis.

Related Products

CAS No.	Structure	Product
583-05-1		1-Phenyl-1,4-pentanedione
17515-66-1		3-CARBETHOXY-1,1,1-TRIFLUOROHEXANE-2,5-DIONE
495-71-6		1,2-Dibenzoylethane
13669-05-1		1,4-Di(2-thienyl)-1,4-butanedione
5027-32-7		3,4-Diacetyl-2,5-hexanedione
41892-81-3		ETHYL 2-ACETYL-4-OXOPENTANOATE
2955-65-9		3,6-Octanedione

References

1. Organic Chemistry Portal, Paal-Knorr Furan Synthesis.
2. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 418-420.
3. Xu, Bing, et al. Organic letters, 2016, 18(9), 2028-2031.
4. Minetto, Giacomo, et al. Organic Letters, 2004, 6(3), 389-392.