Hantzsch synthesis of pyrroles

Hantzsch and Feist Syntheses. The Hant2sch synthesis of pyrroles iavolves condensation of an a-haloketone (10) with a p-keto ester (6) ia the presence of ammonia or an amine (22). 

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]. 

Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

Hansa yellow org chem Group of organic azo pigments with strong tinting power, but poor opacity in paints used where nontoxIcIty Is Important. han-sa yel o ) Hantzsch synthesis org chem The reaction whereby a pyrrole compound is formed when a p-ketoester, chloroacetone, and a primary amine condense. hansh, sin-tha-sas ... 

Standard heterocyclic syntheses tend to have a name associated with them and it is simply not worth while learning these names. Few chemists use any but the most famous of them we will mention the Knorr pyrrole synthesis, the Hantzsch pyridine synthesis, and the Fischer and Reissert indole syntheses. We did not mention that the synthesis of furans from 1,4-dicarbonyl compounds is known as the Feist-Benary synthesis, and there are many more like this. If you are really interested in these other names we suggest you consult a specialist book on heterocyclic chemistry. 

Halo ketones react with enamines 177 to form pyrroles (the Hantzsch pyrrole synthesis, ) and with -keto esters 179 under basic conditions to give furans 180 (the FeistBenary furan synthesis, ). The orientation in the Hantzsch pyrrole synthesis 177 178 differs from that in the FeistBenary furan synthesis 179 180 (Scheme 99). In an example of a modified Hantzsch synthesis, the -aminoacrylonitrile 182 reacts with ketone 181 to give pyrrole 183 in a moderate yield (Scheme 100) a series of similar compounds can be synthesized using this approach <1997S530>. A solid-phase extension of the Hantzsch synthesis has also been reported <1998BML2381>. 

Enamines are also involved in the classical Hantzsch synthesis, which is usually performed by annulation of an enamine intermediate derived from ammonia and a suitable /3-ketoester or an equivalent 1,3-diketo synthon, with an a-haloketone. A new development is the adaptation of this reaction to solid-phase conditions <1998TL2381>. Heating of the /3-aminoacrylonitrile 276 with the ketone 277 gave a decent yield of the pyrrole 278 (Equation 85), a member of a series of similar compounds which were synthesized using this approach <1997S530>. An additional solid-phase variant of the Hantzsch synthesis provided a set of pyrrole-/3-carboxamide derivatives <1998BML2381>. 

Knoevenagel reactions are used in the synthesis of a wide variety of O- and N-heterocycles. In the typical Knorr pyrrole synthesis, a 1,3-dicarbonyl compound is condensed with an oximino- or azimino-1,3-dicarbonyl compound followed by reductive cyclization. Thus, catalytic hydrogenation of benzyl acetoacetate (243) and diethyl oximinoacetonedicarboxylate (242) affords pyrrole (244), which is transformed to (245) by another Knoevenagel reaction (Scheme 49). A rational synthesis of all four uropor-phyrines has been achieved by cyclization of appropriate pyrroles such as (245). ° Another typical preparation of a heterocycle that involves a Knoevenagel condensation is the Hantzsch 1,4-dihydro-pyridine synthesis. Here, an aldehyde and two molecules of a 1,3-dicarl30nyl compound react in the... 

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]. 

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]. 

This reaction was first reported by Hantzsch in 1890. It is the preparation of 2,5-dialkyl or 2,4,5-trialkylpyrrole derivatives from the condensation of of-halo-ketones, )0-ketoesters and ammonia or amines. Therefore, it is often known as the Hantzsch pyrrole synthesis or simply the Hantzsch synthesis. During this synthesis, ammonia or amine reacts quickly with y0-keto esters to form enamine esters or 3-amino crotonates that cyclize with of-halo-ketones to form pyrrole derivatives upon heating, and the regioselectivity strongly depends on the substituents on the starting materials. Thus, this reaction can directly start from 3-amino crotonates or enamines of 0-keto esters. Further extension of this reaction from aromatic amines results in the formation of indole derivatives, or carbazole derivatives if cyclized with a-halo-cyclohexanones. The synthesized pyrroles have wide application in medicinal chemistry, conducting polymers, molecular optics, sensors,etc. 

Hantzsch s first important research was the synthesis of pyridine from acetoacetic ester and aldehyde ammonia, a general method of synthesis of pyridine derivatives. Coumarone, discovered by Fittig and Ebert (see p. 768), was (with some derivatives) synthesised by Hantzsch, who called it the fur-furane of the naphthalene series . He synthesised thiazole, and benzene, pyridine, and thiophen derivatives from derivatives of pentamethylene, and pyrrole, investigated tetrazoles, and perthiocyanic acid C2N2S3H2 (discovered by Wohler), giving it a cyclic structure." ... 

The Hantzsch synthesis has been used to generate pyrroles, thiazoles and dihydropyridine derivatives. Pyrroles (3) are generated from the reaction of P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones (path A). Thiazoles (5) are generated from the reaction between a-haloketones and thiourea or thioamide derivatives (path B). Dihydropyridines (7) are generated from the reaction of aldehydes with p-ketoesters and ammonia or ammonia derivatives, or enamines derived from the reaction of ketones or P-ketoesters with amines (path C). Dihydropyridines can be readily converted to the corresponding pyridine derivatives and so this reaction is often termed the Hantzsch pyridine synthesis. 

The Hantzsch dihydropyridine synthesis was first reported by Arthur Rudolf Hantzsch in 1881. The Hantzsch pyrrole and thiazole reactions were reported in the years following Hantzsch s initial report on the synthesis of dihydropyridines. 

The traditional Hantzsch pyrrole synthesis consists of a one-pot reaction between P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones. This process, known as the three-component (3CP) Hantzsch pyrrole synthesis, has been largely replaced by a two component (2CP) Hantzsch synthesis using preformed enamines. Preformed enamines help provide better control over the regioselectivity of the reaction. In addition, the use of preformed enamines helps reduce the side products produced from the self condensation of P-ketoesters. 

The original Hantzsch 1,4-dihydropyridine synthesis is a one-pot reaction between an aldehyde, 2 equiv of a P-ketoester, and ammonia or an ammonia derivative. This process, known as the 3CP Hantzsch 1,4-dihydropyridine synthesis, is still useful for the synthesis of symmetrical 1,4-dihydropyridines. However, it is less successful for the synthesis of asymmetrical derivatives due to the number of side products formed when using mixed p-ketoesters in the reaction. Like the Hantzsch pyrrole... 

Skaddan and co-workers employed the Hantzsch synthesis in their preparation of isotopically labeled l- -pyrrole-2,3,5-tricarboxylic acid, a metabolic by-product of the breakdown of melatonin. Labeled -H-pyrrole-2,3,5-tricarboxylic acid is currently under investigation as a tool to study the effectiveness of new hyper pigmentation drugs. C-Labeled ethyl acetoacetate 19 and 2-chloroethanal 20, when treated with -labeled aqueous ammonium hydroxide, produced pyrrole 21 in 35% yield. The authors chose to use this approach due to the relatively low cost and availability of the reagents required to prepare this compound. 

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. 

Stetinova and co-workers used the Hantzsch synthesis to prepare 1,2,4-trisubstituted pyrroles as part of their ongoing efforts to produce novel pyrrole derivatives with antihypertensive activity. Reaction of aldehyde 274 with methyl acetoacetate 180 and glycine methyl ester hydrochloride 275 in sodium methoxide in methanol gave the corresponding 1,4-dihydropyridine 276 in 43% yield. 

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