Pyrrole synthesis, from 1,4-dicarbonyl compound

Dicarbonyl compounds pyridazine synthesis from, 3, 45 pyrrole synthesis from, 4, 329 reactions... 

Pyrrole synthesis from at-dicarbonyl compounds.15 A new approach to N-benzyl-pyrroles is formulated for biacetyl as starting material (equation I). The method is also suitable for annelation of a pyrrole group to an a-methylene carbonyl compound. 

Ilac Knorr pyrrole synthesis from a-amino ketones and /3-dicarbonyl compounds 3.06.3.4.1... 

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

Pyrrole synthesis from 1,3-dicarbonyl compounds (or enamino Ketones) and a-amino acids via cyclization of enamino acid intermediates. 

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

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... 

The 1,4-dicarbonyl compounds resulting from Stetter reactions have been used by Muller and colleagues [52] and by Bharadwaj and Scheidt [53] in efficient one-pot Stetter-Paal-Knorr protocols for the synthesis of highly substituted pyrroles. In an analogous fashion, Frantz et al. converted their a-ketoamides into the corresponding imidazoles by treatment with a primary amine [54]. 

Dioxins behave as masked cis y-hydroxy enones and as such are an excellent source of y-lactones, notably in an enantio-enriched form <02JOC5307>. Treatment of the dioxin with an amine base results in rearrangement to 1,4-dicarbonyl compounds from which pyrroles and thiophenes are available in a one-pot synthesis <02TL3199>. Stabilised phosphonates add to 1,2-dioxins to yield diastereo-pure substituted cyclopropanes <02JOC3142>. 

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. 

In planning the synthesis of a pyrrole or a pyridine from a dicarbonyl compound, considerable variation in oxidation state is possible Tire oxidation state is chosen to make further disconnection of the carbon skeleton as easy as possible. We can now see how these same principles can be applied to pyrazoles and pyridazines. 

A synthesis of a set of 2-pyridylpyrroles has been described, involving annulation of 1,3-dicarbonyl compounds with 2-(aminomethyl)pyridine under acidic conditions, as illustrated by the construction of compound 437 (Equation 121) <20020L435>. Likewise, pyrroles have also been obtained from reactions between 1,3-diaryl-l,3-dicarbonyl compounds and imines or oximes promoted by the TiCU/Zn-system <2004SL2239>. Yet another approach involves rhodium-catalyzed reactions of isonitriles with 1,3-dicarbonyl synthons, which enables for instance preparation of fluorinated pyrroles <20010L421>. 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

The ring synthesis of five-membered heterocycles has been extensively investigated, and many and subtle methods have been devised. Each of these three heterocyclic systems can be prepared from 1,4-dicarbonyl-compounds, for furans by acid-catalysed cyclising dehydration, and for pyrroles and thiophenes by interaction with ammonia or a primary amine, or a source of sulfur, respectively. 

Pyrroles.—Formation. A general synthesis of 2-aryl-pyrroles (112) is by cycliz-ation of the esters (111), which are obtained from unsaturated aldehydes and methyl azidoacetate. Thermolysis of the acetylene (113 Ar = p-MeC6H4) gives Al-(p-tolyl)pyrrole with the elimination of p-thiocresol. The pyrrole derivative (115) is the product of the action of benzylamine on tri-(t-butylthio)cyclopropenylium perchlorate (114). Azoalkenes combine with fi-dicarbonyl compounds or with enamines to yield derivatives of Al-aminopyrrole thus the ester (116) and ethyl acetoacetate form (117). The base-catalysed addition of methyl propiolate to toluene-p-sulphonylmethyl isocyanide, T0SCH2NC, gives the ester (118). The dipolar cyclo-adduct (120) of piperidinocyclopentene to the azo-compound (119) forms the A-(tosyl-amino)pyrrole derivative (121) and piperidine on heating. ... 

The Hantzch pyrrole synthesis is a variation of this reaction which is conducted as a three component synthesis from a j8-dicarbonyl compound, an a-haloketone or aldehyde and anunonia or an amine (Equation (38)). Yields for this procedure are typically 20-50% <7oaci689>. The regiochemistry is that resulting from N—C bond formation at the carbonyl carbon of the a-haloaldehyde. 

Construction of the phosphole ring, with one useful exception, is accomplished by methods that are quite different from those employed for the N, S, O ring systems. Because of fundamental differences in the chemistry of phosphines versus amines, none of the familiar carbonyl condensation processes are known to be applicable to phosphole synthesis. Thus an attempt to use the Paal-Knorr condensation of 1,4-dicarbonyl compounds with PhPH2 <65JCS2184> and with PH3 <88ZOB783> failed to give phospholes. The only successful method known to the present that is common to both the phosphole and pyrrole ring systems is the condensation of 1,3-diynes with primary phosphines... 

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