Pyrrole-2-carboxaldehyde derivatives

A Knoevenagel condensation followed by intramolecular aldol reaction provides an efficient route to the indolizine core (Scheme 10) (13JOC10395). Pyrrole-2-carboxaldehyde derivatives combined with a number of 1,3-dicarbonyl compounds to provide the indolizines in good yields. 

Various groups were tolerated on the pyrrole-2-carboxaldehyde derivatives (37 other examples, 51-100% yields). 

Condensation of tren with 2,3-dihydroxybenzaldehyde, sal (52) (or derivatives), acac, 2-hydroxy-acetophenone (or derivatives), pyridine carboxaldehydes, pyrrole carboxaldehydes and... 

The aziridine 101 derived from pyrrole-2-carboxaldehyde was found to undergo a further unusual transformation when treated with trifluoroacetic acid (TFA) at room temperature, giving the 5//-pyrrolo[l,2-r ]imidazole 102 in good yield. The cyclization is initiated by protonation of the carbonyl group (Scheme 10) <2000TL4991>. 

Condensation of A-protected pyrrole-2-carboxaldehyde with ethyl a-amino-/3, -diethoxypropionate followed by reduction and cyclization in the presence of TiCU afforded the pyrrolo[2,3-c]pyridine derivative 70 in excellent yield (93T8139). 

Pyrrole units form part of the coordinating entities of Schiff base ligands derived from pyrrole 2-carboxaldehyde, for example in the iron(II) complex of the ligand derived from pyrrole 2-carboxaldehyde and trien, which is low-spin despite the feeble coordinating properties of the pyrrole—CH=N— units. The synthesis, structure, and spectroscopic and electrochemical properties of tris-ligand iron(III) complexes of phenyldipyrromethenate (dipyrrin, (129)), and its... 

In an effort to explore the chemistry of pyrrolodiazines and their quatemized salts (see Section 6.2.2.2), Alvarez-Builla and co-workers prepared a series of pyrrolo[l,2-c]pyrimidines via methodology developed in their laboratory <99JOC7788>. Cyclocondensation of tosylmethyl isocyanide with substituted pyrrole-2-carboxaldehydes 17 produced pyrimidine derivatives 18 sifter removal of the tosyl group. The key to this procedure was the use of tosylmethyl isocyanide, which provided a relatively easily removed tosyl group in comparison to the more problematic decarboxylation of a carboxylic acid functionality. 

The situation appears decisively different in 3-formyl derivatives. Theoretical calculations (77JCS(P2)1601 79NJC473) reveal a small energy difference between X,0-cis and X,0-trans conformations in furan-3-carboxaldehyde (4, X = O), and pyrrole-3-carboxaldehyde (4, X = NH), and the X,0-cis form is... 

Pyrroles and furans also undergo the Gattermann aldehyde synthesis with HC1 and HCN, furan gives furfuraldehyde and 2-methylindole gives 2-methylindole-3-carboxaldehyde. The Houben-Hoesch ketone synthesis is also applicable to the preparation of acyl derivatives of furans and pyrroles, e.g. ethyl 2,4-dimethylpyrrole-3-carboxylate with MeCN and HC1 yields (81). 

Some pyrrole derivatives have pleasant flavor. For example, pyrrole-2-carboxaldehyde gives a sweet and corn-like odor and 2-acetylpyrrole has caramel-like flavor. However, some pyrroles have been found to contribute to off-flavor of food products (24). Pyrroles have not received as much attention as flavor components as other heterocyclic Maillard reaction products such as pyrazines and thiazoles even though the number of derivatives identified is almost the same as that of pyrazines (Figure 1). Proposed formation mechanisms of pyrroles in the Maillard reaction systems are similar to those of thiophenes (Figures 2). 

Irradiation of 3-methylthiophene in hexafluoropropan-2-ol with added methanesulfonic acid brings about single electron-transfer oxidation and this yields a species that has been identified as the Z>w-protonated radical-cation of (289). Irradiation of 2-acetyl-5-iodothiophene leads to cleavage of the C-I bond and the resultant radical adds to acrylonitrile to afford the adduct (290) in moderate yield. Reactions of this type have also been described for iodofuran and iodopyrrole derivatives and in the latter case 4,5-diiodo-l//-pyrrole-2-carboxaldehyde reacts photochemically with thiophene to give... 

The reaction of l-amino-l-deoxy-n-fructose with 2,4-pentanedione gives 3-acetyl-2-methyl-4-(D-araZ)mo-tetrahydroxybutyl)pyrrole (20). Acetylation of this compound yields a tetra-O-acetyl derivative, and periodate oxidation of (20) furnishes 4-acetyl-5-methylpyrrole-3-carboxaldehyde (24), which can be subsequently oxidized to 4-acetyl-5-methylpyrrole-3-carboxylic acid (26). 

Schiff base derived from pyrrole-2-carboxaldehyde and 3-amino-... 

The dibromo derivative of the dimeric pyrrole (39) is a useful precursor of 4-substituted pyrrole-2-carboxaldehydes (Equation (109)) <88TL3215>. 

Many substituted thiophenes are commercially available. Thus, the study of the effects of substituents on polythiophene is relatively straightforward in comparison with pyrrole, whose 3-monosubstituted and 3,4-substituted derivatives are not easily synthesized. Table 3 gives many substituted thiophenes that can be electrochemi-cally oxidized to produce conducting polymers. Some derivatives, such as 3-thiophene acetic acid, 3-thiophene malonic acid, 3-thiophene carboxylic acid, and 3-thiophene carboxaldehyde do not polymerize at all [205). 

Thus, condensation between pyrrole-3,4-dimethyl-2-carboxaldehyde and the 3-(2,4-dimethyl-3-yl)propanoic acid yields a dipyrrole fragment, and condensation between the same aldehyde and the 3-ethyl-2,4-dimethylpyrrole forms a second such dipyrrole. Bromination of the latter in the presence of iron(III) tribromide introduces a bromine into the only vacant 2-position as well as onto the only a-methyl available. This derivative can then be coupled to the only available a-position on the first fragment utilizing tin(II) chloride. Finally, heating in orf/io-dichlorobenzene (ODCB) at reflux (ISO C) in the presence of air for 5 min completes the cycUzation to the porphyrin. 

Kathiravan and Raghxmathan reported the synthesis of pyrrole-fused polycyclic heterocycles via intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides derived from pyrrole-2-carbaldehyde 28 and secondary amino acids in IL [BM1M][BF4]. The methodology involved the synthesis of N-alkenyl carboxaldehyde from 28 followed by freafment with sarcosine in [BM1M][BF4] as reaction medium at 85-95 C for about 3h to afford pyrrolo-pyrrolidines 29 in good yield (Scheme 3). The same reaction when carried out in organic solvents such as toluene, methanol, and acetonitrile, the reactions observed were slow, giving product in low yield [80]. 

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