Paal-Knorr synthesis reaction with aldehydes

Paal-Knorr synthesis, 4, 118, 329 Pariser-Parr-Pople approach, 4, 157 PE spectroscopy, 4, 24, 188-189 photoaddition reactions with aliphatic aldehydes and ketones, 4, 232 photochemical reactions, 4, 67, 201-205 with aliphatic carbonyl compounds, 4, 268 with dimethyl acetylenedicarboxylate, 4, 268 Piloty synthesis, 4, 345 Piloty-Robinson synthesis, 4, 110-111 polymers, 273-274, 295, 301, 302 applications, 4, 376 polymethylation, 4, 224 N-protected, 4, 238 palladation, 4, 83 protonation, 4, 46, 47, 206 pyridazine synthesis from, 3, 52 pyridine complexes NMR, 4, 165... 

The Paal-Knorr Synthesis of Pyrroies. The Paal-Knorr method makes use of a 1,4-di-carbonyl compound (aldehyde or ketone) in reaction with primary amines or ammonia. Many pyrroles have been made by this general process. Alkyl and some other substituents are allowed on the dicarbonyl chain. Diketones, dialdehydes, and ketoalde-hydes all serve as reactants. Primary amines give rise to 1-alkylpyrroles. Examples of the overall process are shown in Scheme 4.2. 

In 1884, C. Paal and L. Knorr almost simultaneously reported that 1,4-diketones upon treatment with strong mineral acids underwent dehydration to form substituted furans. This transformation soon became widely used and now it is referred to as the Paal-Knorr furan synthesis. The general features of the method are 1) virtually any 1,4-dicarbonyl compound (mainly aldehydes and ketones) or their surrogates are suitable substrates 2) the dehydration is affected by strong mineral acids such as hydrochloric acid or sulfuric acid, but often Lewis acids and dehydrating agents (e.g., phosphorous pentoxide, acetic anhydride, etc.) can be used and 3) the yields are usually moderate to good. The two major drawbacks of the reaction are the relative difficulty to obtain the 1,4-dicarbonyl substrates, and the sensitivity of many functionalities to acidic conditions. 

Many other aromatic compounds have been prepared in two-component reactions mediated by L-Pro as Lewis base. Hence, benzimidazoles were obtained from a range of o-phenylenediamines and aldehydes in moderate to excellent yields.The reaction of aldimines with succinaldehyde or l,4-ketoaldehydes ° by means of L-Pro catalysis is a robust method for the direct synthesis of formylpyrroles and a sustainable alternative procedure to the Paal-Knorr reaction (Scheme 2.14). 

Furans are prepared by modification of the chemistry used to make pyrrole derivatives. Because furans have an oxygen atom rather than a nitrogen atom, a modification of the reactive partners is required. When 2,5-hexanedione (115) is treated with acid, the product is a furan, 124. This is called the Paal-Knorr furan synthesis, and it begins with protonation of one carbonyl and attack of the oxygen atom of the second carbonyl to close the ring. Elimination of water leads to the furan because it generates an aromatic system. The reaction of protonated ketones and aldehydes with oxygen nucleophiles was discussed in Chapter 18 (Section 18.6). The mechanism for formation of 124 is therefore related to the chemistry presented in Chapter 18. 

Minetto et al. (2004) carried out synthesis of tetrasubstituted pyrroles (and trisub-stituted furans) in a three-step reaction of P-ketoester with an aldehyde followed by oxidation to give number of substituted 1,4-dicarbonyl compounds, which is further cyclized by microwave-assisted with the Paal-Knorr reaction. 

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