Reactions of pyrroles

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

Reaction of pyrrole with carbenes yields enlarged ring systems as well as 2-formylpyrrole [1003-29-8] (40). 

The thermal reactions of pyrroles include the rearrangement of A-substituted pyrroles to C-substituted derivatives (Scheme 1). The rearrangement of A-acylpyrroles has also been reported to occur in the vapour phase on irradiation. 

Pyrroles react with the conjugate acids of aldehydes and ketones to give carbinols (e.g. 67) which cannot normally be isolated but which undergo proton-catalyzed loss of water to give reactive electrophiles (e.g. 68). Subsequent reaction may lead to polymeric products, but in the case of reaction of pyrrole and acetone a cyclic tetramer (69) is formed in high yield. 

Complex reactions occur on the autoxidation of pyrroles (see Section 3.05.1.4) predictably, susceptibility to autoxidation increases with increasing alkyl substitution, llie photosensitized reaction of pyrrole and oxygen yields 5-hydroxy-A -pyrrolin-2-one, probably by way of an intermediate cyclic peroxide (Scheme 28) (76JA802). 

Furan and thiophene undergo addition reactions with carbenes. Thus cyclopropane derivatives are obtained from these heterocycles on copper(I) bromide-catalyzed reaction with diazomethane and light-promoted reaction with diazoacetic acid ester (Scheme 41). The copper-catalyzed reaction of pyrrole with diazoacetic acid ester, however, gives a 2-substituted product (Scheme 42). 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

The reactions of pyrroles with dimethyl acetylenedicarboxylate (DMAD) have been extensively investigated. In the presence of a proton donor the Michael adducts (125) and (126) are formed. However, under aprotic conditions the reversible formation of the 1 1 Diels-Alder adduct (127) is an important reaction. In the case of the adduct from 1-methylpyrrole, reaction with a further molecule of DMAD can occur to give a dihydroindole (Scheme 48) (82H(19)1915). 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

Ciamician reported the formation of 3-halogenopyridines in low yield from the reaction of pyrryl potassium with chloroform, or bromo-form, in ether. Similar reactions of pyrrole with benzal chloride and methylene iodide gave 3-phenylpyridine and traces of pyridine, respectively. These reactions were later reinvestigated by Alexander... 

Last, N-vinylpyrrole can be obtained in good yield from the reaction of pyrrole and acetylene over soda lime at 265°C [237]. 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

A similar reaction of pyrroles 20 with acrylates provides the C-2 substituted a-alkenyl derivatives 21 in 24-91% yield [29]. The 2,6-dichlorobenzoyl protecting group is noteworthy as it prevents cyclization of the phenyl group onto the pyrrole ring (vide infra). 

As will be seen in this chapter and in the rest of the book, the Heck reaction and its numerous variations represent a fantastically powerful set of tools available to the heterocyclic chemist. Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, A-methylpyrrole, A-(phenylsulfonyl)pyrrole) react with 2-chloro-3,6-dialkylpyrazines under Heck conditions to give mixtures of C-2 and C-3 pyrrole-substituted pyrazines in low... 

The soliddiquid phase-transfer catalysed reaction of pyrrole with prop-2-ynyl bromide, in the presence of Aliquat, yields l-(prop-2-ynyl)pyrrole (20%), together... 

As with the reaction of pyrroles, diazoles and triazoles react with propargyl bromide to yield TV-substituted products and, depending upon the base strength, either TV-prop-2-ynylazoles or allenic derivatives are formed [30]. Generally, with potassium carbonate under soliddiquid two-phase conditions at room temperature in the absence of a solvent, the prop-2-ynyl compounds are formed as sole products, whereas with solid potassium hydroxide at elevated temperatures the allenes are obtained as the major products. Benztriazole produces a mixture of the N1- and N2-prop-2-ynyl, and N2-allenic derivatives, whereas with potassium hydroxide only the N -allenic derivative is obtained. The alkynes readily isomerize to the allenes in the presence of base and the quaternary ammonium salt, or upon treatment with methanolic sodium hydroxide. A series of l-(alk-2-ynyl)imidazoles have been prepared, as intermediates in the synthesis of imidazopyridines [31 ] and the reaction of 3-hydroxymethylpyrazoles with propargyl bromide leads to pyrazolooxazines [32]. 

Selected examples of the reaction of pyrroles and indoles with dihalocarbenes... 

Flouk has also considered the alkylation reactions of pyrroles and indoles using the same class of catalyst. The report addresses the fact that while catalyst 12 provides high ees in the alkylation of pyrroles (Scheme 15), the same is not true of indoles and catalyst 21 is required instead (Scheme 16). A thorough examination of the accessible transition states for the reaction of iminium ion 184 with pyrrole and with indole led to the conclusion that the two reactions occur through different transition states. Pyrrole adopts a closed transition state reminiscent of that of the Diels-Alder reaction whereas indole adopts an open transition state (Fig. 19) [233]. 

Technically important electrochemical reactions of pyrrole and thiophene involve oxidation in non-nucleophilic solvents when the radical-cation intermediates react with the neutral molecule causing polymer growth [169, 191], Under controlled conditions polymer films can be grown on the anode surface from acetonitrile. Tliese films exhibit redox properties and in the oxidised, or cation doped state, are electrically conducting. They can form the positive pole of a rechargeable battery system. Pyrroles with N-substituents are also polymerizable to form coherent films [192], Films have been constructed to support electroactive transition metal centres adjacent to the electrode surface fomiing a modified electrode,... 

Paulvannan K (2004) An atom-economical approach to conformationally constrained tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder reaction of pyrrole. J Org Chem 69 1207-1214... 

In addition to the protected pyrroles mentioned above, the 1-azafulvene dimer formed by Mannich reaction of pyrrole-2-carboxaldehyde with di-methylamine has also been successfully lithiated adjacent to both pyrrole nitrogens (Scheme 10). Reaction with electrophiles and subsequent hydrolysis leads to 5-substituted pyrrole-2-carboxaldehydes in good yield [88TL777 92JOM(423)173]. 

Fig. 13 Reaction of pyrrole with isatin to form 3,3-di(2-pyrrolyl)oxindole...

Ru(CO)(porph 0 (porpff ""=chiral poprphyrin from reaction of pyrrole with l,2,3,4,5,6,7,8-octahydro-l 4,5 8-dimethanothracene-9-carboxaldehyde) is made from (porph 0 and RUjCCO). As Ru(CO)(porpff )/(Cl2PyNO)/CgHg it catalysed the asymmetric epoxidation of alkenes with e.e. values up to 88% at room temperatures (better yields were obtained in sealed tubes up to 125°C) [878],... 

In an extension of atom-transfer radical reactions to heterocyclic systems, Byers has introduced a novel methodology for the addition of electron-deficient radicals to unprotected pyrroles and indoles in a stannane-fi ee, non-oxidative process <99TL2677>. For exanqrle, photochemical reaction of pyrrole (33) with etl l iodoacetate (34) in presence of thiosulfiite as an iodine reductant, phase transfer catalyst and propylene oxide led to high yields of the 2-alkylated pyrrole 35 <99TL2677>. 

Problem 20.15 Give the products of reaction of pyrrole with (a) in aqueous KI (6) CHjCN + HCi, followed by hydrolysis (c) CHjMgl. 

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