Pyrrole Hantzsch synthesis

Reaction of a-chloromethyl ketones with p-ketoesters and ammonia to assemble pyrroles. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 120, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 128, Springer International Publishing Switzerland 2014 

Estevez, Veronica Villacampa, M. Menendez, J. C. Chem. Commun. 2013, 49, 591-593. 

Anderson, L. R. Kirk-Othmer EncycL Chem. TechnoL 3rd Ed. 1982, 79, 499. (Review). 

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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]. 

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>. 

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 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. 

Another classic method is that known as the Hantzsch pyrrole synthesis (Scheme 9.4). The nitrogen starting material is an enamine (9.2), which is prepared from a beta-keto ester and ammonia. The beta-position of the enamine is electron-rich and is alkylated with an alpha-haloketone. The amino and the carbonyl groups interact in the familiar way to close the ring. 

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

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. 

The Hantzsch pyrrole synthesis was employed to prepare pyrrole-2-acetic acids as anti-inflammatory agents. A transient precipitate of a white crystalline solid was formed when diethyl acetone-dicarboxylate was mixed with aqueous methylamine. After chloroacetone was added rapidly with cooling before the disappearance of the precipitate, a good yield of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate was produced. Further functional group transformations then produced pyrrole-2-acetic acids as anti-inflammatory agents. 

Reproduced from Estdvez V, Villacampa M, Menpndez JC. Three-component access to pyrroles promoted by the CAN-silver nitrate system under high-speed vibration milling conditions a generalization of the hantzsch pyrrole synthesis. Chem Common 2013 49 591-3, with permission from the Royal Society of Chemistry. 

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. 

Other references related to the Hantzsch pyrrole synthesis are cited in the literature. 

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

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. 

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