2.3.4- trisubstituted pyrroles

Benzofuranyl)pyrroles, 2-(2-thienyl)pyrroles , 2,2 -dipyrroles, 3-(2-pyr-rolyl)indoles , 2-(2-benzimidazolyl)pyrroles and2-(2-, 3- and4-pyridyl)pyrroles were prepared using this method. Reaction of alkynes (for example, propyne) or allene with ketoximes in a superbase system (MOH/DMSO) leads to 2,5-di- or 2,3,5-trisubstituted pyrroles Pyrroles and dipyrroles were synthesized also from corresponding dioximes and acetylene in a KOH/DMSO system It has also been shown that 1,2-dichloroeth-ane can serve as a source of acetylene in pyrrole synthesis. Oxime 52 in the system acetylene/RbOH/DMSO at 70 °C afforded a mixture of three pyrroles 53-55 in low yields (equation 23). The formation of product 53 occurred through recyclization of pyrrolopy-ridine intermediate. ... 

The acid-catalyzed addition of aliphatic ketones to 2,3,4- or 2,3,5-trisubstituted pyrroles generally produces bispyrrolylalkanes, analogous in structure to the products of the corresponding reactions with aldehydes, whereas 2,5-disubstituted pyrroles react with acetone to form a 2 3 adduct (113). Pyrrole and 3,4-disubstituted pyrroles react with aliphatic ketones to give porphyrinogens (114), which, unlike the macrocycles obtained from the... 

The reaction is mostly regioselective affording mainly or exclusively 2,5-di- and 2,3,5-trisubstituted pyrroles. The minor isomers in most cases were the corresponding 2,4-di- and 2,3,4-trisubstituted pyrroles, only in... 

Likewise, pyrroles are accessible if in the last cyclocondensation step a primary amine is applied. Therefore, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of primary amines 96 or ammonium chloride and glacial acetic acid, the 1,2,3,5-tetrasubstituted or 2,3,5-trisubstituted pyrroles 97 are obtained in good yields in a one-pot procedure (Scheme 52) [259, 260]. 

Scheme 52 Cl-Stetter addition-Paal-Knorr four-component synthesis of 1,2,3,5-tetrasubstituted and 2,3,5-trisubstituted pyrroles 97...

The regioselective synthesis of pyrroles via [3,3]- and [l,3]-sigmatropic rearrangements of 0-vinyl oximes formed by iridium-catalysed isomerization of 0-allyl oximes is such that when enolization is favoured, a [3,3]-rearrangement followed by a Paal-Knorr cyclization gives a 2,3,4-trisubstituted pyrrole and when enolization is disfavoured, a [l,3]-rearrangement occurs prior to enolization to give a 2,3,5-trisubstituted pyrrole after cyclization (Scheme 10). ... 

When formation of N-O-dvinyl hydroxylamine is favored, its [3,3]-rearrange-ment leads to 2,3,4-trisubstituted pyrroles while 1,3-prototropic shift to the O-l-propenyl oximes is hindered, [l,3]-sigmatropic rearrangement occurs to give 2,3,5-trisubstituted pyrrole (after cyclization of intermediate amino aldehyde) Scheme 1.143. 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

The addition of trithiazyl trichloride (NSC1)3 to 2,5-disubstituted furans and to N-2,5-trisubstituted pyrroles has led to the formation of isothiazole derivatives <96JHC1419>. 

A ring opening reaction of (1-lactams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles <06CC2616>. In the event, treatment of (3-lactam 3 with MeONa led to pyrrole-2-acetic ester 4 after cleavage of the amide bond, 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required. 

A thermal ring opening reaction of an imine-substituted cyclopropene led to a mixture of 2,3,4-trisubstituted and 3,4,5-trisubstituted pyrroles <06TL5793>. 

The second Had synthesis provided a route to 2,3,4-trisubstituted pyrroles <06CC2271>. Mixing cinnamaldehyde 27 with aminocarbene complex 28 in the presence of molecular sieves (MS) gave pyrrole 29. The authors proposed a mechanism that included a cyclopropane intermediate and subsequent fragmentation and intramolecular condensation. 

In Scheme 5 under the lukianol section, the Bullington synthesis [17] of 2,3,4-trisubstituted pyrroles was presented. Bullington has used this strategy to prepare ningalin B and the resulting steps in this route are presented in Scheme 17. This route also constitutes a very efficient method for the construction of the ningalin A and B scaffold. 

It should be noted that the 1 1 adducts of benzyne with pyrrylmag-nesium iodide, and A -methyl- and iV-benzylpyrrole were isolated and characterized only as the hydrobromide (113), the methiodide (115), and the picrate of 102, respectively. The low yields of all these derivatives are due in part to further reactions of thenaphthalen-l,4-imines with benzyne (see Section III, F and G). Yields are better where the starting pjnrole has an electron-withdrawing N-substituent. Some analogous naphthalen-l,4-imines expected from 1,2,5-trisubstituted pyrroles apparently rearrange spontaneously to j3-naphthylamine derivatives under the conditions for their formation (see Section III, F). The related adducts 107 and 108 are formed from tetrahalobenzynes and N-methy Ipyrrole. 

A more flexible approach to pyrroles has been developed (Tetrahedron Lett. 2004,45,9315) by Keiji Maruoka of Kyoto University. Rearrangement of 5 by the A1 complex 6 leads, by preferential benzyl migration, to the trisubstituted pyrrole 7. 

Vinylpyrroles and 3-(3-pyrrolyl)propenoic acids (366 X = H or C02H) react under acid catalysis with trisubstituted pyrroles to yield the bispyrrolylethanes (367) and (368). The formation of (367) arises from the direct nucleophilic attack on the 3-vinyl group, whereas (368) results from the dissociation of the initial adduct to produce the 2-vinylpyrrole, which reacts further (58LA(611)205). The structures of the bispyrrolylethanes were established... 

The 3-vinylpyrroles (366 X = H or C02H) also react with electrophiles. No products were isolated, but it was suggested that the blue colouration produced upon the acid-catalyzed reaction with Ehrlich s reagent was due to the formation of (370) and that it was identical with that of the product obtained from the reaction of the trisubstituted pyrrole and the cinnamaldehyde. Similarly, the red colouration obtained from the reaction of (366 X = H or C02H) with diazotized sulfanilic acid was ascribed to the formation of (371) <58LA(611)205). 

The [3 + 2] addition of type llbd is a significant method for synthesis of both simple and complex pyrrole derivatives. One manifestation of this pattern is seen in the base-catalyzed condensation of tosylmethyl isocyanide with alkenes having strong electron-accepting substituents. The aromatization by elimination of the arenesulfinic add occurs under the reaction conditions (equation 117) (72TL5337). This reaction can be applied to the synthesis of 2,3,4-trisubstituted pyrroles by using C-alkylated tosylmethyl isocyanides or AT-tosyl-methyl-S- methylthioimidates <77H(7)77, 81JHC1127). 

Similar reaction conditions as those by Bose were used for a range of other applications, for example, the synthesis of heterocycles. A combination of a microwave-assisted Paal-Knorr reaction15 with a transfer hydrogenation takes place in the preparation of 2,5-di- and 1,2,5-trisubstituted pyrroles from -l,4-diaryl-2-butene-l,4-diones in a one-pot operation. Hydrogenation was achieved with ammonium formates and 10% Pd/C as catalyst in PEG-200. Yields of up to 92% were obtained within 0.5-2 min (Scheme 4.2)16. 

Various 1,2,4-trisubstituted pyrroles 30 have been prepared using a palladium catalyzed reaction of the enones 31 with glycine ethyl ester as outlined in the example below, or benzylamine catalyzed by Pd(PPh3)4 to give the corresponding 1-benzylpyrroles <02SL619>. 

Subsequent reactions occur in the cytoplasm and they are irreversible. Two molecules of 8-aminolevulinate are condensed by the enzyme porphobilinogen synthase to form the trisubstituted pyrrole porphobilinogen. Two enzymes, uroporphyrinogen synthase and uroporphyrinogen cosynthase, condense four molecules of porphobilinogen to the porphyrin uroporphyrinogen III. 

---