Alkylations alkyl halides, pyrrole

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

Alkylation at nitrogen has been achieved by treating indole or pyrrole with alkyl halides in ionic solutions of potassium carbonate in l- -butyl-3-methylimidazolium tetrafluoroborate [bmim][BFJ <06TL2435>. Bis-protection of 3,3 -diiodo-2,2 -biindoles with Me, Boc, C02Et, or S02Ph has been described by Roy and Gribble <06SC3487>. 

Under microwave irradiation several azaheterocycles (i.e. pyrrole, imidazole, indole and carbazole) can react remarkably fast with alkyl halides to give, exclusively, N-al-kyl derivatives (Eqs. 32 and 33) [45, 46]. Such reactions have been performed simply by mixing an azaheterocycle compound with 50% excess alkyl halide and a catalytic amount of TBAB. The reactants were absorbed either on a mixture of potassium carbonate and potassium hydroxide or on potassium carbonate alone and then irradiated in a domestic microwave oven for 30 s-10 min. 

The use of dimethyl sulphoxide as a dipolar aprotic solvent is well known,7 and the present method can be regarded as a model procedure and has been applied to the preparation of a number of N-w-alkyl-pyrroles and N-w-alkyl indoles.8 The yield of N-benzylindole is considerably higher than in previously reported preparations and is as good as that reported for the preparation of N-methylindole in liquid ammonia.4 The present method is, however, less laborious and quicker to carry out. Very high yields are obtained in reactions using w-alkyl halides and moderately good yields with secondary alkyl halides. The reactions should be compared with those recently reported for pyrryl-thallium.9... 

Other pubKcations dealing with the catalytic ability of electrogenerated cobalt(I) species have appeared. Cob(I)alamin reacts with 1,4-dibromobutane to yield a tet-ramethylene-1,4-di-Co -cobalamin complex [138]. Alkyl radicals (which arise from the oxidative addition of cobalt(I) tetraphenyl porphyrin to an alkyl halide) have been found to migrate from the cobalt center to a nitrogen of a pyrrole ring [139]. 

Pyrrolethiols, readily obtained from the corresponding thiocyanates by reduction or treatment with alkali, rapidly oxidize to the corresponding disulfides. They are converted into thioethers by reaction with alkyl halides in the presence of base. Pyrrole-, furan- and thiophene-thiols exist predominantly as such rather than in tautomeric thione forms. 

The range of halides which are useful in the alkylation of pyrrole and indole can be predicted by reference to the well-known reactivity of halides and sulfonates towards SN2... 

Dioxacorroles are 18-7r-electron aromatic systems like corroles. They exhibit basicity intermediate between that of porphyrin and corrole, and require 1 h at 100 °C in TFA for complete deuteration of the meso positions. The furan protons are also substituted by deuterium under the same conditions after lOOh. Friedel-Crafts acylation occurs at C-5 while alkyl halides attack on the pyrrolic nitrogens to give a mixture of mono- and di-alkyl derivatives. 

Azalene salts 90 and 92 are obtained by quaternization of the corresponding heterocyclic bases with alkyl halides or tosylates. If the heterocyclic base contains several nitrogen atoms, alkylation can produce different quaternary salts. Quaternization, however, is surprisingly selective if certain conditions are met.205 Pyrrolo- and indolopyridines containing one pyridine-and one pyrrole-type nitrogen atom in their molecular lattice are (in aprotic solvents) almost exclusively alkylated at the nitrogen atom of the pyridine... 

Indoles can be 3-alkylated by allyl alcohols in the presence of lithium perchlorate and acetic acid 101 is an example (Scheme 42). Pyrrole -alkylation can be achieved with simple alkyl halides [1-bromopentadecane, l-(bromomethyl)-, l-(3-chloropropyl)- and l-(3-iodopropyl)benzenes, 2-(2-bromoethyl)- and 2-(3-bromopropyl)naphthalenes] and mesylates [3-phenylpropyl-, l-methyl-3-phenylpropyl-, 2-(2-naphthyl)ethyl- and 3-(2-naphthyl)propyl methanesulfonates] selectively at C(2) and C(5) positions via reaction in various ionic liquids (e.g., Scheme 43) <20050L1231>. 

C-Alkylation of pyrroles and indoles can be mediated by alumina in association with the appropriate halide. 3-Indolyl sugar derivatives have been obtained by alkylation reactions of indolylmagnesium bromide. This type of alkylation has been extended to ring-fused indoles 105 and yields 3//-indole derivatives 106 in good yields. 

In ionic liquids li/-pyrrole replaced the halogen atom of an alkyl halide to give the corresponding N-substituted pyrroles in excellent yields (Equation 11) <2004S1951>. 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

Alkylation of phenols, alcohols, amides, and acids. N-Alkylation of indoles and pyrroles by means of solid KOH in DMSO was reported a few years ago. Actually this method is applicable to a number of substrates. The substrate and alkyl halide are added to powdered KOH and stirred in DMSO, usually at 20°. Methyl-ation of phenols, alcohols, and amides occurs in high yield in about 5-30 minutes. Esterification of acids is slower. Dehydrohalogenation is a competing or predominating reaction when secondary or tertiary halides are used. Another limitation is that amino groups are converted into quaternary salts under these conditions. The general method can be used for permethylation of peptides. 

Alkylation ofindole and pyrrole. Indole and pyrrole can be N-alkylated in high yield by conversion to the potassium salt by KOH in DMSO followed by addition of an alkyl halide. l-Bcnzylindole(2) can be obtained from indole (I) by this procedure in 92 97%... 

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