2- -5-methylpyrrole, reaction

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). 

N-Alkylpyrroles may be obtained by the Knorr synthesis or by the reaction of the pyrrolyl metallates, ie, Na, K, and Tl, with alkyl haUdes such as iodomethane, eg, 1-methylpyrrole [96-54-8]. Alkylation of pyrroles at the other ring positions can be carried out under mild conditions with allyhc or hensylic hahdes or under more stringent conditions (100—150°C) with CH I. However, unless most of the other ring positions are blocked, poly alkylation and polymerisation tend to occur. N-Alkylation of pyrroles is favored by polar solvents and weakly coordinating cations (Na", K" ). More strongly coordinating cations (Li", Mg " ) lead to more C-alkylation. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

The reaction can also be carried out using smaller amounts of 1-methylpyrrole (0.113 mol), butyraldehyde (0.113 mol) and a solvent (245 ml acetonitrile, ACS grade) 1n a somewhat larger reaction vessel. After 17 hr of photolysis, and after removal of the volatile material and distillation of the remaining oil under reduced pressure, 4-5 g of the alcohol 1s Isolated. 

Perfluoroalkylation of substituted benzenes and heterocyclic substrates has been accomplished through thermolysis of perfluoroalkyl iodides in the presence of the appropriate aromatic compound Isomeric mixtures are often obtained W-Methylpyrrole [143] and furan [148] yield only the a-substituted products (equation 128) Imidazoles are perfluoroalkylated under LTV irradiation [149] (equation 129). 4-Perfluoroalkylimidazoles are obtained regioselectively by SET reactions of an imidazole anion with fluoroalkyl iodides or bromides under mild conditions [150] (equation 130) (for the SET mechanism, see equation 57)... 

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

When the original reaction between the 1-methylpyrrole and dimethyl acetylenedicarboxylate was carried out on a larger scale with inadequate cooling, an exothermic reaction took place and none of the dihydroindole (48) could be detected among the products. However these included the mellitic ester (49) and the pyrrole (50), indicating that some of the dihydroindole (48) had formed and had combined with more of the acetylenic ester as already described. A decomposition product of the dihydroindole as yet unidentified, tetramethyl l-methylindole-2,3,6,7-tetracarboxylate (52), and tetramethyl prehnit-... 

A reaction of alkylpyrroles with hot aqueous sulfuric acid leading to indoles almost certainly involves the dimers as intermediates, thus 2-methylpyrrole gives 2,4-dimethylindole and 2-isopropyl-, 3-methyl-, and 2,3-dimethylpyrrole lead to indoles the structures of which have not yet been established. 

As can be seen from the survey, only a limited number of alkyl pyrroles are polymerized, actually dimerized, by acid in ether or in water. The dimerizable pyrroles include all those which have free adjacent a- and jS-positions, that is 2- and 3-methyl-, 2-isopropyl-, and 2,3-dimethyl-pyrrole. It must be repeated that no homogeneous product has yet been obtained from 3-methylpyrrole, and this reaction deserves more study. 

The use of pyrrole and N-methylpyrrole was found to be preferable. Through the addition of N-methylpyrrole, all cationic side reactions could be effectively suppressed, and only dimerization products produced by Ni-catalysis were obtained. In this case the dimer selectivity was as high as 98 %. Scheme 5.2-21 shows the catalytic system that allowed the first successful application of [(H-COD)Ni(hfacac)] in the biphasic linear dimerization of 1-butene. 

On the other hand, Doblhofer218 has pointed out that since conducting polymer films are solvated and contain mobile ions, the potential drop occurs primarily at the metal/polymer interface. As with a redox polymer, electrons move across the film because of concentration gradients of oxidized and reduced sites, and redox processes involving solution species occur as bimolecular reactions with polymer redox sites at the polymer/solution interface. This model was found to be consistent with data for the reduction and oxidation of a variety of species at poly(7V-methylpyrrole). This polymer has a relatively low maximum conductivity (10-6 - 10 5 S cm"1) and was only partially oxidized in the mediation experiments, which may explain why it behaved more like a redox polymer than a typical conducting polymer. 

For example, Mannich reaction of N-methylpyrrole affords the corresponding dimethylaminomethyl derivative (2) and treatment with methyl iodide affords the quaternary salt (3). Displacement of the quaternary amine by means of cyanide leads to the substituted... 

The reaction of tetrafluorobenzyne with iV-methylpyrrole leads to a good yield of the adduct (106), and with thiophen to tetrafluoro-naphtha-ene 56>. That this latter reaction was the first example of a Diels-Alder reaction of thiophen was shown by following the reaction by XH n.m.r. spectroscopy. Evidence for the intermediacy of the episulphide (107) was obtained. 

Aromaticity of 2,4,6-tri-fert-butylphenylphosphole (17d) was also revealed in chemical reactions phosphole 17d could undergo aromatic electrophilic substitution. In reaction with acetyl chloride, a mixture of 2-, 4-, and 5-acetyl phospholes (23a, 24a, and 25a, respectively), as well as a diacetyl derivative (26a) were formed (Scheme 6) [39], Interestingly, the most crowded 2-acetyl derivative (23a) was the main product of the Friedel-Crafts reaction. A similar situation was observed for 3-methylpyrrol [46],... 

The presence of a 2-substitutent in 3-phenylazirines (17, R —H in Scheme 21) modifies the mode of reaction with molybdenum carbonyl.47 In contrast to pyrazine formation for (17, R =H see Section V,C,2), the alkenyl azirine (18, Scheme 22) is transformed in excellent yield into 2-phenyl-5-carboxy-methylpyrrole. This product probably arises by intramolecular cyclization within an intermediate dienylnitrene intermediate, and related reactions have been devised to synthesize isoxazoles (see Section IV,E,2) and pyrazoles (see Section IV,D,1).47 The molybdenum carbonyl-promoted formation of 2,5-disubstituted pyrroles47 has analogy in uncatalyzed thermal, but not photochemical decomposition of 3-phenyl-2//-azirine 2-acrylate.49... 

New electrophilic substitution reaction methods for the preparation of dipyrromethanes have been reported. The condensation of IV-methylpyrrole with benzaldehyde leading to the corresponding dipyrromethane was promoted by the addition of the organic catalyst, pyrrolidinium tetrafluoroborate <06T12375>. The reaction between pyrrole and N-tosyl imines promoted by metal triflates gave dipyrromethanes whereas tripyrromethane byproducts were not observed <06T10130>. 

Reaction of l-Methylpyrrole-2-acetonitrile 43 with 6 New Efficient Synthesis of Highly Substituted Indoles (Type-IV, 4a Model)... 

The /3-electrophilic additions of pentaamineosmium(ll) complexes bearing various 4,5-tf -coordinated pyrroles to carbonyl compounds have been reported by Harman and co-workers (Scheme 78). 1 1-Methylpyrrole complex, when reacted with benzaldehyde or its dimethylacetal in the presence of /-butyldimethylsilyl triflate (TBSOTf), afforded the corresponding aldol adduct 177 as a 1 1 ratio of diastereoisomers. Pyrrole, 1-methylpyrrole, or 2,5-dimethylpyr-role osmium complexes reacted with an excess of acetone in the presence of TBSOTf to give the O-silylated 377-pyrrolium aldol adducts 178, which may serve as intermediates for various other reactions. 

Various iodinated pyiToles have been prepared by direct iodination [19,24] or via thallation [25]. For example, 3-iodo-V-TIPS-pyrrole is prepared in 61% yield from 6 [19], and 3,4-diiodo-2-formyl-l-methylpyrrole is available in 54% yield via a bis-thallation reaction [25]. 

Bailey described the first application of the Stille coupling to pyrroles, and one of the earliest examples of any such reaction involving heterocycles [66]. Lithiation of IV-methylpyrrole and quenching with trimethylstannyl chloride gives 2-(trimethylstannyl)pyrrole (76), and palladium-catalyzed coupling with iodobenzene affords l-methyl-2-phenylpyrrole (46) in good yield. 

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... 

---