Substituted pyrroles, Hantzsch pyrrole synthesis

A similar MW strategy has been used to synthesize a set of pyrimidinones (65-95%) via the Biginelli condensation reaction in a household MW oven and has been successfully applied to combinatorial synthesis [139]. More recent examples describe a convenient synthesis of highly substituted pyrroles (60-72%) on silica gel using readily available a, 3-unsaturated carbonyl compounds, amines, and ni-troalkanes [140], and the use of neat reactants under solvent-free conditions to generate Biginelli and Hantzsch reaction products with enhanced yields and shortened reaction times [141]. 

The Hantzsch pyrrole synthesis is the condensation of p-ketoesters with primary amines (or ammonia) and a-haloketones to give substituted pyrroles. 

The Hantzsch pyrrole synthesis remains useful for the preparation of A/-substituted pyrroles from primary amines for materials chemistry and medicine. However, for pyrroles where N is unsubstituted, the Hantzsch pyrrole synthesis has largely been replaced by the Knorr pyrrole synthesis because the latter generally leads to higher product yields. 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

Recently Cosford and co-workers used a one-step continuous flow Hantzsch synthesis to prepare a series of A -substituted pyrrole-3-carboxylic acids as part of their ongoing efforts to develop efficient and high-yielding flow chemistry methods for multistep transformations. Reaction of /-butyl acetoacetate 32 and a-bromoacetophenone 34 with amines 33,36,38,40,42, and 44 using diisopropylethyl amine (DIPEA) and DMF at 200 "C in a continuous flow reactor gave the corresponding A-substituted pyrroles in modest yields (40-62%). The authors found the optimal reaetion conditions were 2.2 equiv of /-butyl acetoacetate, 1 equiv of amine and 0.5 equiv of DIPEA in a 0.5M solution of a-bromoacetophenone predissolved in DMF. In addition, the authors noted that the HBr produced as a byproduct of the reaction simultaneously hydrolyzed the ester to give the free acid. Several additional P-ketoesters and a-bromoketones were explored in their report with similar success. 

At first, analogous to the 1,4-dihydropyridine synthesis, in the Hantzsch pyrrole synthesis, a p-ketocarbonyl compound reacts with ammonia or a secondary amine, forming an enamine II. This enamine II reacts with the a-haloketone I in a nucleophilic substitution and gives, after tautomerization and condensation, the pyrroles HI (Scheme 13.130). 

In the last years, only some examples of multicomponent pyrrole syntheses have been published, but those are highly interesting in terms of reaction conditions and substitution patterns of the obtained pyrroles. One example is the conversion of a-iodoketones 594 in a Hantzsch pyrrole synthesis under high-speed vibration milling conditions (HSVM) and CAN catalysis, with silver nitrate as scavenger for the produced hydroiodic acid (Scheme 13.149) [269]. 

In recent years, synthesis of pyrroles has drawn the attention of chemists. Traditional methods used for pyrrole synthesis include the Hantzsch reaction [45] and the Paal-Knorr condensation reaction [46,47], The latter is the most widely used method, which involves the cyclocondensation reaction of 1,4-dicarbonyl compounds with primary amines to produce substituted pyrroles. In addition, there are several methods such as 1,3-dipolar cydoaddition reaction, aza-Wittig reaction, reductive coupling, and titanium-catalyzed hydroamination of diynes. Scheme 1 shows several catalysts used in this type of reaction [44]. 

Pyrroles are the core unit of a wide variety of natural products [76]. Although many methods are available for the synthesis of these species, most are multi-step procedures resulting in low yields [77, 78]. However, Hantzsch made another important contribution to the progress of multicomponent chemistry. In his procedure pyrroles were successfully prepared from primary amines, j8-ketoesters, and a-halo-genated j5-ketoesters [79]. Only a few other one-step procedures have been reported for pyrroles but, because of to long reaction times and insufficient scope of substitution at the ring, these are not very satisfactory [80, 81]. 

In a three-component cyclocondensation, a-halocarbonyl compounds react with P-ketoesters (or P-diketones) and ammonia or primary amines to give pyrrole-3-carboxylates (or 3-acyIpyrroIes), which are substituted either in 1,2,4- or in 1,2,5-position, for example, 43/45 (Hantzsch synthesis) ... 

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