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9.13.1.4.1.1 Method 1: Condensation Reactions of 1,4-Dicarbonyl Compounds or Equivalents with Amines (The Paal–Knorr Synthesis)

DOI: 10.1055/sos-SD-009-00542

Black, D. StC.Science of Synthesis, (20019455.

The classical cyclizative condensation of 1,4-dicarbonyl compounds with ammonia or primary amino compounds is still one of the most generally useful pyrrole syntheses. The reaction takes place in solvents such as ethanol, dimethylformamide, or acetic acid, and proceeds via carbinolamine and imine intermediates followed by dehydration to the aromatic ring.[‌53‌‌58‌] This method is referred to as the PaalKnorr synthesis. For example, hexane-2,5-dione (93) reacts with ammonia (from ammonium carbonate) to give 2,5-dimethyl-1H-pyrrole (94),[‌59‌] and with 4-bromoaniline (95) to give 1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrole (96) (Scheme 16).[‌60‌] Titanium(IV) chloride can be used as an effective Lewis acid catalyst and dehydrating agent for the formation of sterically hindered pyrroles.[‌61‌] The primary amines in this methodology can be replaced by hydrazines.[‌62‌] The use of alkoxycarbonylhydrazines, followed by removal of the nitrogen protecting group, has recently been developed as a very effective synthesis of pyrrol-1-amines. For example, hexane-2,5-dione (93) combines with the acylhydrazide 97 to give the pyrrole 98 in almost quantitative yield (Scheme 16).[‌63‌] In this case the protecting group was removed by tetrabutylammonium fluoride.

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8-(8-Meeeeeeeeee)-8,8-eeeeeeee-8M-eeeeeee (88):[‌88‌]

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References