Fluorinated pyrroles synthesis

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>. 

Synthesis of Fluorinated Pyrroles As described in the previous Section 3.2.1, the availability of hydroxypyrrolidines provided convenient functionality for introduction of fluorine, and many syntheses were based on either nucleophihc displacement of oxygen functionality by fluoride or deoxyfluorination with DAST or other such reagents. In contrast, many fundamentally different methods have been used to prepare fluorinated pyrroles. 

There have been several reports of the synthesis of p-fluorinated porphyrins by construction of the macrocyclic ring using fluorinated pyrrole precursors. For... 

Another possibility for the synthesis of fluorinated pyrroles is the use of their nonaromatic precursors. Thus, 3,3-difluoro-l-pyrrolines 30 were prepared via electrophilic fluorination of the corresponding 1-pyrrolines 29 by Selectfluor. Reaction of the difluoropyrrolines 30 with sodium aUcoxides yielded fluorinated 5-(alkoxymethyl) pyrroles 31 in good yields [18],... 

Direct fluorination/trifluoromethylation are very synthetically attractive approaches to prepare fluorinated pyrroles due to it is not necessary to construct the heterocyclic core. Especially this methods are convenient for the synthesis of fluoropyrroles. In contrast, synthesis of trifluoropyrroles is restricted by lower regioselectivity, moderate yields and the application of gaseous CF3I or quite unstable (bis(trifluoroacetyl)peroxides). 

Cycloaddition reactions open an access to both 2- and 3-trifluoromethylated pyrroles with wide range of additional substituents in pyrrole ring, therefore the method is very useful and general for synthesis of fluorinated pyrroles. 

The use of carbonyl function is classic approach in heterocyclic synthesis. In case of fluorinated pyrroles this approach was frequently used. Convenient method for synthesis of pyrroles 221 is based on the reaction of fluorinated 5-keto acid esters or amides 220 with ammonia. In case of methyl and ethyl esters amidolysis was... 

The Knorr pyrrole synthesis was also employed for the synthesis of 3-trifluoropyrroles [91]. Treatment of ethyl trifluoroacetoacetate 267 with sodium nitrite in acetic acid led to the oxime 268. Refluxing with zinc dust and addition of 1,3-dicarbonyl compounds 269 afforded the 3-trifluoromethylpyrroles 270 in moderate yields. Using more acidic trifluoroacetic acid allowed to lower the reaction temperature to 70 °C [92]. Using a similar approach, the tricarboxylic acid ester 273 was prepared starting from the acetone dicarboxylic acid ester 271 and the fluorinated keto ester 272 [93]. 

So, application of isocyanides is one of the best methods for synthesis of fluorinated pyrroles due to high yields, simplicity and mild reaction conditions. 

Trifluoromethylpyrroles were also used in the fluorinated porphyrins synthesis [121], Thus, porphyrin 475 was prepared in three steps starting from pyrrole 373a. At first step reduction of carboxyethyl group was performed. Next, intermolecular alkylation takes place to form CH2-bridged precursor of porphyrin under PTSA catalysis. The last step is aromatization under treatment with chloranile. 

Fluorinated pyrroles have been studied intensively in recent years. As a resnlt, a significant number of synthetic approaches to these compounds was elaborated. The most general methods involve direct fluorination/trifluoromethylation of the parent pyrroles, both the [3 -1- 2]- and the [4H-2]-cycloaddition reactions, the applications of carbonyl compounds as well as TOSMIC and isocyanoacetates. Thongh variety of methods are already known, the elaboration of novel preparative pathways towards fluorinated pyrrole derivatives is still ongoing, which is due to the manifold of biological activities of this structural motive and the use as precursors for porphyrins synthesis. It is no doubt, that this branch of synthetic organic chemistry will enjoy a much attention, giving rise to sustainable flow of novel convenient pathways to the synthesis of fluorinated pyrroles. 

Attanasi OA, FUippone P, Guidi B, Mantellini F, Santeusanio S (2001) Regioselective synthesis of stable 2-(trifluoromethyl)-2,3-dihydro-lH-pyrrol-2-ols and derived fluorinated heterocycles. Synthesis 1837-1845... 

Okada E, Masuda R, Hojo M, Inoue R (1992) A facile and convenient synthetic method for N-P-trifluoroacetylvinyl amino acid esters, a-aminoacetophenones and euninoacetonitriles as potentially useful precursors of fluorine-containing pyrroles. Synthesis 533-555... 

The first p-fluorinated pyrrole (1) used in the synthesis of the first partially... 

Liu and coworkers have recently published the synthesis of (3) and (4), as well as several other fluorinated pyrrole analogues (not shown), by aminofluorination of allenes the synthetic approach is shown in Scheme 3 [15], This strategy takes advantage of a selective, silver-catalyzed intramolecular fluorination reaction, but the approach works best with substrates that possess electron-withdrawing R -groups on the 3-position. Because of this limitation, the yield of (3) is significantly higher than (4), 80 % versus 28 %, respectively. 4-Fluoro-pyrrole-2-carboxylic acid (5a, Fig. 2), synthesized from a fluorinated proline, was explored as a potential intermediate on the route to (3), but only extensive decomposition products were observed when (5a) was subject to flash pyrolysis [16]. 

The early investigations [613-615] of N-vinylpyrroles trifluoroacetylation have been undertaken in order to assess the relative activity of two most probable nucleophilic sites (a-position of the pyrrole ring and p-position of the N-vinyl moiety) and to develop preparative methods for the synthesis of novel fluorinated pyrrole derivatives [614]. 

The next stage of synthesis was the replacement of pyrrole hydrogen atoms by fluorine atoms. The zinc complex was fluorinated by cobalt fluoride according to the appropriate technique [44, 46], The target product was extracted from reaction products by chromatographic separation in a column filled with neutral aluminum oxide. 

Much effort has been directed toward synthesis of fluorine-containing heterocycles, owing to their biological activity <2004MI357>. A 2-fluoro-substituted pyrrole 304 has been synthesized (ca. 40%) by a treatment of the 5-lithiated l-methyl-2-octyl-l//-pyrrole with iV-fluoro-iV-(phenylsulfonyl)benzenesulfonamide (Equation 69) <2003JFC(124)159>. At room temperature pyrrole 304 slowly undergoes a dimerization process. 

Rhodium acetate-catalyzed diazo decomposition has been used in a synthesis of the pyrrole 51, illustrating a route to several similar 3-oxypyrrole systems (Equation 11) <2002SL1913>. Similar annulations of some related fluorine containing substrates resulted in various unusual fluoropyrrole derivatives <20030L745>. 

Porphyrins can be conveniently assembled by condensation of simple pyrroles with aldehydes under Lewis acid catalysis (Lindsey conditions). Accordingly, 3-fluoro- and 3,4-difluoropyrroles have received much attention as precursors of fluorinated porphyrin derivatives. For example, in work on the synthesis of partially [3-fluorinated 5,10,15,20-tetraphenylporphyrins and derivatives, previously unreported 3-fluoro-1//-pyrrole (52) was required (see Fig. 3.24)." ... 

Fluorinated analogues of other pyrrolic macrocyclic systems are also receiving current attention. The recent development of a short and efficient synthesis of substituted corroles has facilitated the syntheses of several fluorinated and perfluori-nated analogues of this tetrapyrrolic macrocycle. " Gross and coworkers found that... 

In contrast to what is true in the case of the non-fluorinated calix[/2]pyrroles v/here it has proven difficult to isolate species with n> A. the synthesis of Compound 12 led to the two isolable and kinetically stable higher-order... 

Sessler. J.L. Anzenbacher, P., Jr. Shrives. J.A. Jursikova, 38. K. Lynch, V. Marquez, M. Direct synthesis of expanded fluorinated calix[/r]pyrroles Decafluorocalix[5]pyrrole... 

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