Alkylation of heterocycles

The decomposition of diacyl peroxides provides a fairly clean method for the production of alkyl radicals and, therefore, it has been used in most quantitative and preparative studies of the alkylation of heterocyclic compounds,... 

The most accurate data on isomer distributions in alkylation of heterocycles have been obtained from the reaction of 3-n-butylpyridine with methyl radicals in acetic aeid. The ratio of the monomethyl products was determined by infrared spectroscopy and gas chromatography and is showm in (27). A small amount of 2,6-dimethyl-3-n-butylpyridine was also obtained. These ratios again show a high proportion of ortho substitution. 

The alkylation of heterocyclic nitrogen compounds with alkyllithium reagents is called Ziegler alkylation. Aryllithium reagents give arylation. The reaction occurs... 

Scheme 2.64 The clean and efficient N-alkylation of heterocyclic compounds.

This reaction resembles decarboxylation of carboxylates during electrode one-electron oxidation (Kolbe reaction). Kolbe reaction also consists of one-electron oxidation, decarboxylation, and culminates in dimerization of alkyl radicals just after their formation at the electrode surface. When the sulfate radical acts as a one-electron oxidant, the caboradical dimerization is hampered. The radicals can be used in preparative procedures. One typical example is alkylation of heterocyclic nitrogen bases (Minisci et al. 1983). This difference between Kolbe reaction and the reaction with the help of a dissolved electrode (the sulfate radical) deserves some explanation. The concentration of the one-electron oxidation products in the electrode vicinity is significantly higher than that in the bulk of the solution. Therefore, in the case of anode-impelled reactions, the dimerization of radicals produced from carboxylates proceeds easily. Noticeably, 864 secures the single electron nature of oxidation more strictly than an anode. In electrode reactions, radical intermediates can... 

Homolytic Alkylation of Heterocyclic Compounds in Acidic Medium... 

The ready alkylation of heterocyclic thiols lends this link to applications in solid-phase synthesis. Although much more work has been done in other heterocyclic systems, a prototype solid-phase synthesis has been described in which the pteridine is built from a 2- or 4-alkylthiopyrimidine attached to a cross-linked polystyrene support <20030BG1909, 2003TL1267> Oxidative cleavage was preferred using DMDO to avoid unwanted by-products... 

The insertions of PTC-generated dichlorocarbene into CH bonds of 1,3-dioxane and 1,3-dioxolane rings represent examples of C-alkylation of heterocyclic nucleophiles.119,120 The mechanism is different from those just considered because a carbanion on the heterocyclic ring probably is not formed during insertion. 

If the heterocyclic base contains several pyridine-type nitrogens select can also be observed. Indeno[l,2-b]quinoxalines, for example, are quaternized at the N-10 atom.110 The alkylation of heterocycles conta one pyrrole-type nitrogen and several pyridine-type nitrogens is appar selective (e.g., indolo[2,3-b]quinoxaline).201 The yields of quaternary however, are extremely low,201 even if phenacyl halides or a-halo ester used.207 Perhaps the resultant quaternary salts are dealkylated.200,207... 

In Reaction 1-100, the sulfate anion radical, and not the anode, acts as a one-electron oxidant. In this case, the caboradical dimerization is hampered. The radicals can be used in preparative procedures. One typical example is alkylation of heterocyclic nitrogen bases (Minisci et al. 1983). 

Intermolecular Michael addition, including alkylation of heterocyclic aromatics and aniline... 

Alkylation of heterocyclic enamines proceeds similarly to the alkylation of Fischer s base discussed above. Lukes and Dedek223 obtained on methylation of l-methyl-2-ethylidenepyrrolidine (51) a C-alkylation product, i.e. 1 -methyl-2-isopropyl-A2-pyrroline (52). Alkylation of the same enamine with ethyl bromoacetate 224 was the first synthetic step in the preparation of DL-pseudoheliotridane. 

Pyrroline is a desirable starting material for alkylation of heterocycles. 1-(Methoxycarbonyl)-3-pyrroline2 has been used to prepare 2,5-dialkylated pyrrolines,3 which resulted in the synthesis of the Pharaoh ant trail pheromone43 and gephyrotoxin 2 2 3.4b Alkylation of 3-pyrrolines has also led to the synthesis of 12-azaprostaglandins.5 The submitters have used a formamidine derived from 3-pyrroline to provide access to 2-substituted pyrrolines and pyrrolidines,6 which has led to the synthesis of the unnatural (+)-anisomycin.7... 

When the decomposition is carried out in an inert solvent, methyl acetate and ethane are formed, whereas in the gas-phase decomposition methyl acetate is completely absent and ethane is produced in much smaller quantity.85 It was suggested that the dimers in solution represent the recombination of methyl, and the combination of methyl and acetoxy radicals, within the solvent cage. 85 87 The decomposition of diacyl peroxides provides a fairly clean method for the production of alkyl radicals and, therefore, it has been used in most quantitative and preparative studies of the alkylation of heterocyclic compounds. 

Gotta MF, Mayr H (1998) Kinetics of the friedel-crafts alkylations of heterocyclic arenes comparisons of the nucleophilic reactivities of aromatic and nonaromatic tc-Systems. J Org Chem 63 9769-9775... 

A number of publications have appeared on the alkylation of heterocycles under phase-transfer conditions (see also pp. 295, 318, and 331) these reactions appear to proceed in high yield and with great selectivity. Alkylation of pyridazin-3-ones with primary and secondary alkyl bromides gives high yields of 2-A -alkyl derivatives electron-deficient olefins may also be used as the alkylating agents, thus acrylonitrile affords the cyanoethyl derivative (92). ... 

Scheme 18.16 Regioslective alkylation of heterocyclic allyl sulfides streamlines Mislow-Evans approach. Application to nuciferal S5mthesis. ...

On the basis of the previous results. Park, Jew, and co-workers [101] developed in 2009 an efficient synthetic methodology for enantiomerically pure a-alkyl-a,3-diaminopropionic acid. They described the asymmetric PTC alkylation of Af(l)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid /cr/-butyl esters (52) with propargyl, allyl, and substituted benzyl bromides under catalysis with the binaphthalene-derived PTC XXV (Scheme 8.19). Alkylated products were obtained in high yields with excellent enantioselectivities and their acidic hydrolysis furnished corresponding optically active a-alkyl-a,(3-diaminopropionic acids. Another example of PTC alkylation of heterocyclic compounds, namely 1-cyanotetrahydro-(3-carbolines using a binaphthyl-modified V-spiro-type catalyst L, was reported by Maruoka and co-workers [103]. 

In 2013, Singh and co-workers also reported an iron(II) phthalocyanine (FePc)-catalyzed /-alkylation of heterocyclic amines (Fq. 31) [129]. In most cases, the reactions of benzyl alcohols could give moderate to excellent yields, but aliphatic alcohols gave only poor yields of the products. 

Bala M, Verma PK, Singh B (2013) Iron phthalocyanine as an efficient and versatile catalyst for N-alkylation of heterocyclic amines with alcohols one-pot synthesis of 2-suhstituted benzimidazoles, benzothiazoles and benzoxazoles. Green Chem 15(6) 1687-1693... 

SCHEME 5.34 Nickel-catalyzed alkylation of heterocycles with grignard reagents. 

Calculations suggest that the diastereoselectivity found for electrophilic a-substitu-tion of the enolates of various 2-piperidine acetates on reaction with iodomethane or trisyl azide is a consequence of transition state alignment of the enolate C—C bond perpendicular to the C—N bond of the piperidine, and approach of the electrophile to the least hindered face of the enolate. A further study of alkylation of heterocyclic j8-amino esters has attributed the high diastereoselectivity to reaction of the transient lithium ( )-enolate in a conformation where the A - strain is minimized (Scheme 5). °... 

Guido, W, and Mathre, D. J., Phase-transfer alkylation of heterocycles in the presence of 18-crown-6 and potassium tert-butoxide, J. Org. Chem., 45, 3172, 1980. Mariani, G., Modena, G., Pizzo, G. E, and Scorrano, G., The effect of crown-ethers on the reactivity of alkoxides. Part 2. The reaction of potassium isopropoxide and 2,4-dinitrohalogenobutanes in propan-2-ol-benzene, J. Chem. Soc., Perkin Trans. 2, 1187, 1979. 

The alkylation of heterocyclic compounds such as furan and thiophene, which can not be alkylated by the conventional Friedel-Crafts, are also performed with this method. ... 

Sc 3, 4 gjjj lanthanides. " Very recently, even metal halides were shown to be effective for acylation and/or alkylation of heterocyclic compoimds if those have heavier transition or main-group metals as central metals, including Rh, Ir, In, 6, 7 pj 85,88 gj 89 weaker interaction of central... 

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