Pyrrole reactions with nucleophiles

Although brominated derivatives of the five-membered heterocycles may be prepared by reactions of the co-ordinated ligands, these may then undergo further reactions with nucleophiles. As an example, the nucleophilic displacement of bromide from 8.15 by sulfide has been used to form new macrocyclic systems (Fig. 8-12). The palladium probably serves a dual function in this reaction. First, it organises the open-chain ligand such that the two reactive sites are held in proximity, so allowing the intramolecular formation of the sulfide and, second, it may activate the pyrrolic ring to nucleophilic displacement of bromide. 

The salts of methylene derivatives of 2H- and 3//-pyrroles and -indoles are produced in the Ehrlich reaction (Scheme 32, Section 3.05.1.2.8) and they are also intermediates in the Vilsmeier-Haack reaction (Scheme 24, Section 3.05.2.1.6). Although 6-fV,fV-dimethyl-amino-l-azafulvene, i.e. 2-(Ar,Ar-dimethylaminomethylene)-2//-pyrrole, dimerizes spontaneously (see Section 3.05.2.5), the 6-aryl-6-Ar)Ar-dimethylamino-l-azafulvenes (514 R = aryl) can be isolated (71JCS(B)1405) but, curiously, they are more susceptible to reactions with nucleophiles at the 6-position than are the corresponding salts (B-77MI30508). The benzo[6 ]-1 -azafulvenes, obtained from the reaction of 2-formylindoles with dialkylamines, also dimerize spontaneously, but the isomeric benzo[c]-2-azaf ulvenes, derived from 3-formylindoles, are thermally more stable, although they are extremely moisture sensitive... 

Just as electrophilic substitution is the characteristic reaction of benzene and electron-rich heteroaromatic compounds (pyrrole, furan etc.), so substitution reactions with nucleophiles can be looked on as characteristic of pyridines. 

The nucleophilic reaction with the solvent is of crucial importance. Monomers with lower oxidation potentials (aniline and pyrrole) can easily be polymerized even in aqueous electrolytes. For monomers with higher oxidation potentials, aprotic solvents must be used, such as acetonitrile... 

When forced, reactions with ammonia commonly lead to derivatives of pyrrole or pyridine, e.g., 2-furoic acid at 210r,C gives 2-amino-3-hydroxyri-dine.189 Hydrazine is a better nucleophile and attacks 3-acylfurans in hot ethanol if there is no group to be displaced the ring opens and a pyrazole is formed.190... 

Reactions with dialdehydes allow the introduction of two additional rings in one step. Thus, condensation of 1 -(2-aminoethyl)pyrrole with glutaraldehyde and benzotriazole gives tricyclic intermediate 627 in which the benzotriazolyl moiety can be readily substituted with nucleophiles to give products 628 (Scheme 97) <2002JOC8220>. Condensation of ethyl ester of L-tryptophan with 2,5-dimethoxytetrahydrofuran and benzotriazole in acetic acid gives tetracyclic intermediate 629 which upon treatment with nucleophiles (silyl derivatives) is converted to products 630 <1999T3489>. 

A different mode of cycloaddition occurs with 7-azabicyclo[2.2.1]-heptadiene derivatives, in which the nucleophilicity of the nitrogen atom determines the point of attachment of the electrophilic dienophile. The addition depicted in 87, which may occur in two steps via a zwitterionic intermediate rather than by a concerted mechanism, accounts for the structures (88) of 1 2 adducts obtained with A-methyl- or A-benzyl-pyrrole and dimethyl acetylenedicarboxylate. At a higher temperature the reaction with A-methylpyrrole also afforded the indole tetraester... 

We shall consider the sequence as firstly imine formation (an abbreviated form of this mechanism is shown), followed by imine-enamine tautomerism. This provides a nucleophilic centre and allows a subsequent aldol-type reaction with enamine plus ketone. The pyrrole ring is produced by proton loss and a dehydration. 

The 4- and 6-positions of pyrrolo[2,3-3]pyridines can be substituted via palladium-catalyzed cross-coupling reactions with the 4- or 6-halo-substituted derivatives (Scheme 3) <2001SL609>. Nucleophilic displacement of the 4-substituent of 6-chloro-4-nitro- and 4,6-dichloro-pyrrolo[2,3-/ ]pyridines takes place with phenols. Protection of the pyrrole nitrogen with a /3-trimethylsilylethoxymethyl (SEM) group affords good yields of the aryl ethers (Equation 3) <2006TL2069>. 

Nucleophilic aromatic substitutions 1,3-azoles are more reactive than pyrrole, furan or thiaphene towards nucleophilic attack. Some examples of nucleophilic aromatic substitutions of oxazole, imidazole and thiazoles and their derivatives are given below. In the reaction with imidazole, the presence of a nitro-group in the reactant can activate the reaction because the nitro-group can act as an electron acceptor. 

Vinyl ethers and amines disclose little tendency to revert to type thus, the intermediate formed by reaction with an electrophilic reagent reacts further by adding a nucleophilic species to yield an addition compound cf the sequence (8) — (11). Thiophene and pyrrole have a high degree of aromatic character consequently the initial product formed by reaction of thiophene or pyrrole with an electrophilic species subsequently loses a proton to give a substituted compound cf the reaction sequence (12) — (15). Furan has less aromatic character and often reacts by overall addition as well as by substitution. In electrophilic addition, the first step is the same as for substitution, i.e. the formation of a tr-complex (e.g. 13), but instead of losing a proton this now adds a nucleophile. 

The possible ambiguities that may arise in ring syntheses based upon nucleophilic reactions with a-halo ketones are also exemplified by the reactions with a-lithioaldimines leading to pyrrole formation, as shown in Scheme 73a (73TL3517). A similar problem could well arise in the related carbazole synthesis indicated in Scheme 73b if a less symmetrical substrate was employed (81TL1475). 

Although the hydroxy group is a relatively poor leaving group, its base-catalyzed nucleophilic substitution by the mechanism shown in Scheme 69 accounts not only for the hydrogenolysis of the 3-hydroxymethylindoles, but also for their SN reactions with ethoxide ions, cyanide ions and with piperidine. Nucleophilic substitution on 2-hydroxymethyl-pyrroles is generally precluded by the faster formation of the bis(2-pyrrolyl)methanes, but the synthesis of 2-cyano-2-(2,5-dimethyl-3-pyrroIyl) propanes from 2,5-dimethylpyrrole, propanone and potassium cyanide probably results from an SN reaction of the cyanide ion upon the initially formed 3-pyrrolylcarbinol (81USP4248784). The formation of (294)... 

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