Hantzsch reaction pyrrole

In the first step, Rink amide AM PS Resin was acetoacetylated with diketene. Treatment with primary amines resulted in polymer-bound enaminones which then underwent a Hantzsch reaction [30] with l,4-dibromo-2,3-butanedione under formation of 5-(2-bro-moacetyl)pyrroles which could be cleaved from the resin with 20 % TFA/CH2C12. 

Other vorkers have described convenient syntheses of highly substituted pyrroles (60-72%) on silica gel using readily available a,/i-unsaturated carbonyl compounds, amines, and nitroalkanes under the action of MW irradiation [191]. The neat reactants have been used under solvent-free conditions to generate Biginelli and Hantzsch reaction products vith enhanced yields and shortened reaction times (Scheme 8.79) [192]. 

A -iodosuccinimide (lequiv.) and p-toluenesulfonic acid (10mol%) for Ih, to form an a-iodoketone 153 in situ. In the second reaction step, to this milling vessel were added primary amine (2equiv.), 3-dicarbonyl compound 155 (1.5equiv.), cerium(IV) ammonium nitrate (5%), and silver nitrate (1 equiv.) and ball milled for another 1 h. The scope of this pyrrole synthesis was broader than the one described in the literature for previous variations of the Hantzsch reaction, since nitrogen-unsubstituted pyrroles and also double Hantzsch-like reactions based on the use of diamines as starting materials were successfully carried out. 

T. A. Moss, T. Nowak, Tetrahedron Lett. 2012, 53, 3056-3060. Synthesis of 2,3-dicarbonylated pyrroles and furans via the three-component Hantzsch reaction. 

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]. 

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

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 ... 

Several significant pyrrole syntheses involve the formal tricomponent cyclization of type III ace (equation 126). The Hantzsch pyrrole synthesis involves a dicarbonyl compound, an a -halo ketone and ammonia or an amine. The mechanistic pattern is similar to that involved in the Knorr synthesis (Section 3.06.3.4.1). In addition to a-halo ketones and a-haloal-dehydes, compounds such as 1,2-dichloroethyl acetate, 1,2-dibromoethyl acetate and 1,2-dichloroethyl ethyl ether can serve as a -haloaldehyde equivalents (equation 127) (70CJC1689, 70JCS(C)285>. It is believed that the initial step in these reactions is the formation of a stabilized enamine from the amine and the /3 -dicarbonyl compound. A structural ambiguity... 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

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>. 

In the following section we focus our attention on library analysis, and especially on libraries which are not related to oligomers. To demonstrate the possibilities and limits of this analysis, two typical compound libraries were chosen. The first group of libraries contains an aromatic scaffold, pyrroles, which were synthesized by the Hantzsch pyrrole synthesis. The second class of compounds are heterocyclic isoxazolines synthesized via a 1,3-dipolar cyclo-addition. In both cases the reaction conditions were first established on single compounds. Supporting mass spectrometric data are presented in Section 17.7 (Appendix). 

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]. 

In Scheme 1.8.5.4, three versions of the Hantzsch multicomponent one-pot reaction are shown leading to thiazoles, pyrroles and dihydropyridines.3 ... 

It is possible that the mechanism of the Hantzsch pyrrole synthesis commenced with the condensation between the amine and the ketoester. The resulting imine then undergoes an Sn2 replacement reaction with the a-haloketone via the intermediacy of an enamine. The adduct as an enamine ketone then undergoes an intramolecular C-N bond formation to deliver the final pyrrole after extrusion of a molecule of water. 

This reaction is related to the Hantzsch Pyrrole Synthesis. 

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. 

This reaction is related to the Fischer Indole Synthesis, Hantzsch Pyrrole Synthesis, Knorr Pyrrole Synthesis and Paal-Knorr Pyrrole Synthesis. 

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... 

---