Pyrrole aminomethylation

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

The enzymatic conversion of a-(aminomethyl)pyrroles is also used by nature to produce porphyrinogens like uroporphyrinogen III (see introduction, compound 8), which is the key building block in the biosynthesis of all known porphinoid natural products. This biomimetic method is a powerful tool for the synthesis of different porphyrins, e.g. for the preparation of JV,Af, V ,Ar"-tetramethylporphyrin-2,3,7,8,12,13,17,18-octaacetic acid dibromide 12.36... 

The tetramerization of suitable monopyrroles is one of the simplest and most effective approaches to prepare porphyrins (see Section 1.1.1.1.). This approach, which is best carried out with a-(hydroxymethyl)- or ot-(aminomethyl)pyrroles, can be designated as a biomimetic synthesis because nature also uses the x-(aminomethyl)pyrrole porphobilinogen to produce uroporphyrinogen III. the key intermediate in the biosynthesis of all kinds of naturally occurring porphyrins, hydroporphyrins and corrins. The only restriction of this tetramerization method is the fact that tnonopyrroles with different -substituents form a mixture of four constitutionally isomeric porphyrins named as porphyrins I, II, III, and IV. In the porphyrin biosynthesis starting from porphobilinogen, which has an acetic acid and a propionic acid side chain in the y6-positions, this tetramerization is enzymatically controlled so that only the type III constitutional isomer is formed. 

Die Reduktion cyclischer Schiff scher Basen mit Hydriden verlauft ahnlich den acycli-schen Verbindungen zu Aminen. Azirine werden durch Lithiumalanat zu den Aziridi-nen reduziert, mit Natriumboranat in Methanol erfolgt dagegen Solvolyse zum Me-thyl-aminomethyl-ather5. 4,5-Dihydro-3H-pyrrol-Derivate lassen sich mit Lithiumalanat6 und Natriumboranat7 zu Pyrrolidinen reduzieren. Ahnlich konnen auch Pipe-... 

Phenols, secondary and tertiary aromatic amines, pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-15). When phenols and other activated aromatic compounds are treated withA-hydroxymethylchloroacetamide, amidomethylation takes place " ... 

Tetrahydropyrrolo[3,2-f]pyridines, 61, undergo trifluoroacetylation and aminomethylation reactions at the a-position of the pyrrole <2004CHE1477>. The reactions occur in moderate to good yields (45-80%). 

Pyrrole is aminomethylated to give products of type (106). The intermediate immonium ion generated from formaldehyde, dimethylamine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethyl-thiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The... 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

The Mannich reaction on the thieno[3,2-6]pyrrole (47) gave the 6-substituted dialkyl-aminomethyl derivative (50 Scheme 10). The dialkylamino function in (50) was replaced by CN following standard procedures (64JOC2160). 

The benzene ring has been proposed as an isosteric replacement in a dipeptide to enforce either the tram l1 1 or the cis conformation 312>31 (Scheme 1). Similarly, 2-(amino-methyl)pyrrole-l-acetic acid (8, R = H) has been proposed as a cis peptide bond mimic,141 having the same number of atoms between the amino and carboxylic acid functions as in a dipeptide. Several other amino- and carboxy-substituted aromatic structures have been used as spacers in peptides 2-, 3-, and 4-aminobenzoic acids (Abz, e.g., 7), 2-, 3-, and 4-(amino-methyl)benzoic acids (Amb, e.g., 2), 2-, 3-, and 4-(aminophenyl)acetic acids (APha, e.g., 5), 2- (4), 3-, and 4-(aminomethylphenyl)acetic acid (Ampa), (aminomethyl)pyrrole-, -thiophene-, and -furancarboxylic acids 6, (aminomethyl)pyrrole- 8 and -thienylacetic acids, and aminobiphenylcarboxylic acids. 

Aminomethyl)pyrrole-2-carboxylic acid (85, Scheme 24) was used with good results as a spacer in the synthesis of cyclic peptide GPIIb/IIIa receptor antagonists.[74 The 1,2-sub-stituted pyrrole 8 represents a cis peptide bond surrogate in which the R1 side chain can easily be varied. However, no application in biologically relevant peptides have been reported to date. 

Aminomethyl)pyrrole-2-carboxylic acid (85) was prepared from methyl 5-formylpyrrole-2-carboxylate by conversion to the oxime and subsequent reduction, Boc protection, and saponificationJ74 ... 

Scheme 25 Preparation of 2-(Aminomethyl)pyrrole-l-acetic Acid Derivatives1"2-1141...

Like pyrrole, indole readily undergoes the Mannich reaction affording the aminomethyl derivative 7.26. A variety of nucleophiles can displace the amine via an elimination followed by a 1,4-addition reaction, as in the preparation of acetate 7.27. 

The use of lithiated /V-heterocyclic compounds, such as 2.4-1 his(/V. /V -dimethyl-aminomethyl)]-ALmethyl pyrrole, 1-methylimidazole and A. /V-dimethylaminomethyl pyrrole, gave access to novel W,W-dimethyl amino functionalised titanocenes 36-38 with promising IC50 values of 63 and 13 pM, and the very impressive value of 6.8 pM in 38, which is illustrated in Fig. 10 as well [29]. 

A pyrrole synthesis leading to 20 has been achieved by a CuBr catalyzed cyclization of the intermediate imine 21, which was prepared over several steps from 1,3-hexadiyne (22) in a one-pot operation <02CHE748>. Aminomethyl substituted allenes have also been used for the synthesis of pyrroles by a palladium catalyzed annulation with aryl iodides <02H(57)2261>. 

A reagent that will bring about aminomethylation of furans as well as pyrroles is the A-silyl-A,O-acetal 132, used with a Lewis acid, and this also gives primary amines, not available from the classical procedures, e.g., Scheme 61 <2003JOC483>. 

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>. 

Aminomethylation of furans that directly delivered primary furfurylamine products was realized using A -silyl-A)0-acetal 27 under Lewis acid-catalyzed conditions, as illustrated in Equation (19). However, furans are less nucleophilic toward 27 than pyrroles <2003JOC483>. 

Fig. 26. C-Aminomethyl derivative of pyrrole starting trom the eorresponding N-hydroxymethyl compound and amine.

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

Pyrrole is aminomethylated in position 2, that is, in the a position with respect to the heteroatom. - When the pyrrole ring is fused to another aromatic ring (e.g., indole d e -... 

The oximes of the 1-butyl and 1-phenyl aldehydes (148) were reduced with zinc and hydrochloric acid to give 1-butyl- and l-phenyl-3-aminomethyl-4-methyl-7-azaindole, in 63 and 65% yield, respectively. Reduction of the 1-phenyl oxime with lithium aluminum hydride, however, was accompanied by reduction of the pyrrole ring to give the corresponding 3-aminomethyl azaindoline in 80% yield. 9... 

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