2-Methylpyrrole

Methylpyrrole was obtained from Aldrich Chemical Company, Inc. and distilled before use, bp 112-112.5 C. 

Pyrolysis of the methylamine salt (produced by neutralising mucic acid with aqueous methylamlne) in the presence of glycerol yields JV-methylpyrrole ... 

Modifications iaclude the use of P-ketoaldehydes as acetals, eg (9), which leads to loss of the formyl group (21) the product ia this example is 5-ethoxycarbonyl-2-methylpyrrole [3284-51 -3]. 

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... 

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

The first proton to be removed from iV-methylpyrrole by w-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. The formation of a 2,4-dilithio derivative is noteworthy since in the case of both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(P1)887). iV-Methylindole, benzo[6]furan and benzo[6]thiophene are also deprotonated at C-2. Selenophene and benzo[6]selenophene and tellurophene and benzo[6]tellurophene similarly yield 2-lithio derivatives (77AHC(21)119). 

Competitive metallation experiments with IV-methylpyrrole and thiophene and with IV-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with H-butyllithium in ether. The comparative reactivity of thiophene and furan with butyllithium depends on the metallation conditions. In hexane, furan reacts more rapidly than thiophene but in ether, in the presence of tetramethylethylenediamine (TMEDA), the order of reactivity is reversed (77JCS(P1)887). Competitive metallation experiments have established that dibenzofuran is more easily lithiated than dibenzothiophene, which in turn is more easily lithiated than A-ethylcarbazole. These compounds lose the proton bound to carbon 4 in dibenzofuran and dibenzothiophene and the equivalent proton (bound to carbon 1) in the carbazole (64JOM(2)304). 

Directive effects on lithiation have also been studied. The regiospecific /3-metallation of A-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect of the oxazolino group (82JCs(Pl)1343). 2-Substituted furans and thiophenes are metallated in the 5-position. The formation of 2-lithio-3-bromofuran on treatment of... 

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). 

The benzyne adducts prepared from A -methylpyrrole (and A -methylisoindole) are deaminated conveniently by dichlorocarbene generated under phase-transfer conditions (81JOC1025 to give a convenient route to substituted naphthalenes (134) (and anthracenes) (Scheme 49). 

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... 

Aminofurans substituted with electron-withdrawing groups e.g. NO2) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Amino-3-acetylfurans are converted into 3-cyano-2-methylpyrroles on treatment with aqueous ammonia. This transformation is a further illustration of the relative instability of the amino derivatives of five-membered ring heterocycles compared with anilines (Scheme 67) (781003821). 

The reactivities of the isoxazoles are compared with those of benzene and some five-membered ring heterocycles in Table 7. Isoxazole is more reactive than benzene (by 4.3 log units) and isothiazole (0.8) and is less reactive than 1-methylpyrazole, furan, thiophene and 1-methylpyrrole. A 5-methyl substituent activates the nucleus more than does a... 

Pyrolysis mass spectrometry, which does not require a volatile derivative, has been applied to various penicillins (78MI51100). These spectra contained fragments arising from the bicyclic ring system (4,5-dihydro-5,5-dimethylthiazole at mje 115, 1- and 2-methylpyrrole at mje 81 and unidentified peaks at m/e 100 and 125) as well as a series of fragments characteristic of the C(6) side chain. 

The susceptibility of 3-(l-hydroxybutyl)-l-methylpyrrole to air oxidation and decomposition with acid requires that prolonged storage be done in tightly capped containers in a refrigerator. 

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. 

The precedent is strong for the involvement of oxetanes as Intermediates in carbonyl additions to pyrroles. " NMR evidence has been obtained far an oxetane adduct of acetone and N-methylpyrrole. The initial photoadduct was shown to rearrange readily on workup to the 3-(hydroxyalkyl)pyrrole derivative. 

Hydroxybutyl )-l-methylpyrrole 1 H-Pyrrole-3-methanol, l-methyl-o(-propyl- (IQ) 70702-66-8... 

Photochemical [2 + 2] cycloaddition is a powerful way to produce cyclobutanes, which, in turn, are reactive synthesis intermediates. N-Methylpyrrole adds aldehydes via [2 -I- 2] photocycloaddition to give transient oxetanes with high regioselectivity Ring-opening produces 3-(oi-hydroxyalkyl)pyrroles which are oxidized easily to 3-arylpyrroles, such as 3-BUTYROYL-l-METHYL-PYRROLE. With a special apparatus, ethylene is conveniently added to 3-methyl-... 

While the hydrolytic alkamines, aconine and delphonine, cannot be hydrogenated and have therefore been regarded as saturated, their ultra-violet absorption spectra as bases in solution and in common with those of heteratisine and tetrahydroatisine, show a strong absorption within the range 2,200 to 2,600 A, indicating unsaturation. With the bases in acid solution there is a reduction in intensity and a shift in the position of the absorption. It is assumed that these results arise from association of points of unsaturation with the nitrogen atom, A similar range of absorption is shown by iV-methylpyrrole, as base in solution, but in this case there is no shift in position on acidification. 

Fluorination of N-methylpyrrole over cobalt trifluoride gives six polyfluo-rinated Af-methylpyrrolidines The same compounds and two others and perfluoro-1-methylpyrrolidme are obtained by fluorination of N-methylpyrrolidine. The yields of the individual products are low [75] (equation 8)... 

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). 

An interesting rearrangement which is based on the intramolecular acylation of an enamine by an ester is found in the aromatization of the adduct derived from N-methylpyrrole and an acetylenedicarboxylic ester (407,408). 

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