Pyrroles, 3-alkyl-2-benzyl

Pyrroles give polyalkylated products on reaction with methyl iodide at elevated temperatures and the more reactive ally and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas A-alkylated pyrroles are obtained by alkylation of pyrrole alkali metal salts in ionizing solvents (see Section 3.3.1.3.1). Pyrrolenines are formed by the C-alkylation of the Grignard derivatives of polyalkylated pyrroles. Alkylation occurs at positions 2 and 3, although the former predominates. 

Trofimov, B.A., S.E. Korostova, L.N. Sobenina et al. 1982. Pyrroles from ketoximes and acetylene. XK. Regioselectivity of the reaction of alkyl benzyl ketoximes with acetylene. Khim Geterocicl 2 193-198. 

The related planar pyrrole analog 118 has also been prepared (2) from either ethyl or benzyl pyrrole-2-carboxylate 116. Direct alkylation with diethyl phosphonomethyl triflate (70) and base produced the N-phosphonomethylpyrrole 2-carboxylate 117, which was deprotected with trimethylsilyl bromide and saponified to the corresponding phosphonic acid 118. 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

Two other series of compounds which do not fall into other structural types are (165) and (166). The pyrrole (165) showed inhibition of human ISN (3.6 /iM) only a few other substituents on the ring nitrogen (benzyl, 2-bromophenyl but not 4-bromophenyl) were reported with similar activity [270]. A series of lactones (166), where R is small alkyl or benzylidene, inhib-... 

Using this information in conjunction with a study into the preferred conformations of iminium ions generated from catalysts 12 and 21, Houk suggests that the additional steric bulk of the ferf-butyl group causes the benzyl arm of the catalyst to shield better the Si face of the C=C double bond - a requirement for high ees in an open transition state. For both the Diels-Alder and pyrrole/indole alkylation... 

A novel tandem carbonyiation/cyclization radical process has been developed for the intramolecular acylation of l-(2-iodoethyl)indoles and pyrroles <99TL7153>. In this process, an acyl radical is formed when CO is trapped by an alkyl radical formed from the AIBN-induced radical reaction of l-(2-iodoethyl)indoles 104 with BusSnH. Intramolecular addition of the acyl radical to the C-2 position of the heteroaromatic system presumably affords a benzylic radical which undergoes in situ oxidative rearomatization to the bicycloketones 105. 

For example, during N-alkylation of pyrrole under conventional alkaline conditions C-alkylation also occurs at positions 2 and 3. Thus the Grignard derivative of pyrrole122 reacting with dimethyl sulfate in HMPA gives a mixture of mono- and dimethylation products. The first example of pyrrole benzylation under PT conditions was reported by Jonczyk and Makosza.123 The /V-benzyl compound was the major product. 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

Triflic acid is also efficient in the alkylation of electron-rich aromatics (anisole, 1,3-dimethoxybenzene, 2-methylfurane, pyrrole, benzofurane, indole) with secondary benzylic alcohols and 3-phenylallyl alcohols (50°C, 1-9 h, 66-95% yield).201 Benzene, toluene, and halobenzenes are also alkylated with hydroxy-biindantetraone 53 in triflic acid within 1-2h202 [Eq. (5.78)]. Suprisingly, however, the primary products (with the exception of the 4-methylphenyl-substituted compound) undergo rearrangement upon prolonged treatment to yield alkenes... 

Another advantage of this approach is that we can now use electrophilic substitution on the pyrrole to add the rest of the molecule. So the secondary benzylic alcohol 106 might well cyclise to 105 with Lewis acid catalysis as the cation will be reasonably stable and the reaction is intramolecular. But the Friedel-Crafts alkylation to give 107 will not succeed as the cation would be primary. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Many conditions for N-substitutions utilize partial conversion into anions, i.e., utilize equilibrium concentrations of the N-anion especially under phase-transfer conditions (e.g., <2004JOC8668> and Scheme 8 <1997CM644>), or in ionic liquids, [Bmim][PF6] or [Bmim][PF4] <2004S1951>, or using DMAP <1999TL2733>. Under phase-transfer conditions, the preference for N-alkylation in indoles ranges from 1.5 1 for benzyl bromide to 10 1 for benzyl chloride and -alkyl bromides, over 3-alkylation. Another variant is to use cesium fluoride/Celite as a solid base <2001T9951> which is convenient and efficient. N-Chlorination of pyrrole occurs when a solution of pyrrole in carbon tetrachloride is stirred at 0C with an aqueous solution of sodium hypochlorite. 

N-Alkylation of lf/-pyrrole, indole and carbazole can be accomplished with benzyl halides (chloride and bromide) in acetonitrile and cesium fluoride/Celite employed as a solid base (Equation 12) <2001T9951>. The procedure is convenient and efficient, and generally gives rise to the N-alkylated products exclusively, in high yields (78-93%). 

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). 

Arylpyrroles, substituted or unsubstituted at the nitrogen, undergo a much more drastic oxidation than alkyl derivatives by the action of hydrogen peroxide. In most cases opening of the heterocyclic ring occurs, both at the bond between the heteroatom and the a-carbon and between the a- and )8-carbon atoms. From 2,5-diphenylpyrrole in acetic medium benzoic acid and acetophenone are formed.51 From 2,3,5-triphenyl-pyrrole (58, R = H) the product is 59,61 while from 58 (R = benzyl) the compounds 60 (R = benzyl) and 61 are produced.62 Other pyrroles that were found to behave similarly are listed below. 

Other uses of cobalt(I) catalysts include the reductive intramolecular cyclization of bromocyclohexenones to form bicyclic ketones [391] and the radical cyclization of bro-moacetals [392,393]. Krautler and coworkers [394] found that 1,4-dibromobutane interacts with electrogenerated cob(I)alamin to afford a tetramethylene-l,4-di = Co -cobalamin species. In a recent study of the reactions of cobalt(I) tetraphenyl porphyrin with benzyl chloride or 1-chlorobutane, Zheng and coworkers [395] reported that alkyl radicals are transferred from the cobalt center to a nitrogen of a pyrrole ring, leading to formation of an A-alkyl cobalt porphyrin complex. 

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