Pyrroles Hantzsch

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. 

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. 

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). 

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 ... 

Ulace Hantzsch pyrrole synthesis from a-halocarbonyl compounds, /3-dicarbonyl 3.06.4.1... 

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]. 

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>. 

Formyl-l//-pyrroles have also been used as synthons for the preparation of polysubstituted 4-(l//-pyrrol-3-yl)-1,4-dihydropyridines 1307-1310 under the conditions of the standard and modified Hantzsch s dihydropyridine synthesis or by regioselective alkylation of the 1,4-dihydropyridine skeleton (Scheme 250) <2005ARK127>. 

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>. 

There are numerous variations in the Hantzsch protocol deriving from variations in the aldehydes, ammonia derivatives and active methylene compounds employed. The final products are 1,4-dihydropyridine and pyridine derivatives as well as pyrroles. 

The Hantzsch pyrrole synthesis foimd application in the preparation of a series of Cdc7 kinase inhibitors (Scheme 17) [41, 42]. Cdc7 is a key regulator of the S-phase of the cell cycle and its inhibition can cause tumor cell death. SAR studies of a series of 2-heteroaryl-pyrrolopyridinones 74 identified compound 75 (Fig. 11) as a potent ATP-competitive inhibitor of Cdc7. This compound had a Ki of 0.5 uM,... 

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. 

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). 

Figure 17.9. Hantzsch pyrrole synthesis on the solid phase.

Trautwein, A. W., StiBmuth, R. D. und Jung, G., Hantzsch pyrrole synthesis on solid support. Bi-oorg. Med. Chem. Lett. 1998, 8, 2381-2384. 

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... 

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