Useful Electrophiles

Among the most common and synthetically-usef electrophiles are nitronium and acyl cations, NO2+ at CH3CO+, respectively. The former is the active agent electrophilic nitration while the latter is the active reage in Friedel-Crafts acylation. 

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Alkylation can also be accomplished with electrophilic alkenes. There is a dichotomy between basic and acidic conditions. Under basic conditions, where the indole anion is the reactive nucleophile, A-alkylation occurs. Under acidic conditions C-alkylation is observed. The reaction of indole with 4-vinylpyri-dine is an interesting illustration. Good yields of the 3-alkylation product are obtained in refluxing acetic acid[18] whereas if the reaction is done in ethanol containing sodium ethoxide 1-alkylation occurs[19]. Table 11.2 gives some examples of 3-alkylation using electrophilic alkenes. 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the... 

Fluorinatton of graphite with fluorine gives graphite fluorides that have interesting properties, as recently reviewed [63]. Pyridine and its derivatives add elemental fluorine to form unstable N-fluoro adducts [14, 26, 64, 65]. These may decompose to 2-fluoropyndines [65] or be stabilized by treatment with inflate salts to form useful electrophilic fluonnating agents [64]... 

The bulk of enamine studies since Stork s original publication have focused on establishing the breadth and limitations of individual substitution reactions and on extending the list of useful electrophiles. In addition, auxiliary studies have enriched our knowledge about the ambident nature of the vinyl nitrogen system, stereoelectronic factors governing its reactivity, its stability and spectroscopic properties. An increasing number of synthetic applications of these fundamental studies can be expected in future years. 

Azafulvaleiies of type 7-10 constitute electron-poor compounds therefore, only a few reactions using electrophilic agents have been described. Tlius, heating 26a with methyl iodide or benzoyl chloride and subsequent treatment of the resulting products with FIBF4 gave the dithiolium salts... 

Among the most useful electrophilic aromatic substitution reactions In the laboratory is alkylation—the introduction of an alkyl group onto the benzene ring. Called the Friedel-Crafts reaction after its discoverers, the reaction is carried out... 

Most reactions of alkenyl and allylic silanes require strong carbon electrophiles and Lewis acid catalysts are often involved. The most useful electrophiles from a synthetic standpoint are carbonyl compounds, iminium ions, and electrophilic alkenes. 

Epoxides can also be converted to allylic alcohols using electrophilic reagents. The treatment of epoxides with trialkyl silyl iodides and an organic base gives the silyl ether of the corresponding allylic alcohols.154... 

Scheme 4.4 Some useful electrophilic substitution reactions of anthraquinone (52)...

More pertinent to the interests of fluoro-organic chemists, a number of compounds bearing a single N—F bond have become useful electrophilic fluorination reagents, i.e., behaving as effective sources of F+. The structures of some of them are given below, along with the chemical shifts for the N—F fluorine substituent. 

At present, the chemisty of selenophenes and tellurophenes is a relatively scantily studied area. Nevertheless, a number of new valuable contributions dealing with their chemistry have emerged. Electrophilic cyclization of l-(l-alkynyl)-2-(methylseleno)arenes provides a route to a variety of 2,3-disubstituted benzo[fe]selenophenes, as illustrated by the preparation of the system 88. Other useful electrophiles for similar reactions are E or NBS <06JOC2307>. Similar chemistry has also been employed in preparation of 2,3-disubstituted benzo[f>]selenophenes on solid phase <06JCC163>. In addition, syntheses of 2,3-dihydroselenolo[2,3- >]pyridines have been achieved using radical chemistry <06OBC466>. 

In addition to the silicon-based in situ activation of hemiacetal donors, there has been a significant body of work that uses electrophilic silicon activation of preformed C-l silyl hemiacetal donors [54—67]. However, this work is outside the scope of this discussion. 

It is generally believed that it was Ingold [1] in the early 1930s who proposed the first global electrophilicity scale to describe electron-deficient (electrophile) and electron-rich (nucleophile) species based on the valence electron theory of Lewis. Much has been accomplished since then. One of the widely used electrophilicity scales derived from experimental data was proposed by Mayr et al. [5-12] ... 

Among the many useful electrophiles, carbonyl compounds and their derivatives lead to products of the highest value for synthetic endeavors. First experiments with aldehydes and ketones were performed by Hoff, Brandsma and Arens (Scheme 8.15) [12b]. The primary allenyl adducts 60, which are isolable in moderate to excellent yields [12b, 47], serve as starting materials for subsequent cyclizations (see Section 8.2.2.2). 

The successful design of new synthetic sequences using electrophilic carbene complexes thus requires careful assessment of potential side-reactions. 

Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C-C and C-N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). 

Aldehydes constitute useful electrophilic partners in such nickel-catalyzed reactions because the condensation between alkynes, aldehydes and diorganozinc compounds can afford stereodefined cyclic or acyclic ally lie alcohols67-69, as illustrated by the stereoselective cyclization of 111 to the corresponding 3-hydroxypyrrolidine (equation 46). Allenes or 1,3-dienes instead of alkynes also lead to similar reactivity70. 

Substitutions may be electrophilic or nucleophilic according to the reagent used. Electrophilic chlorination or bromination usually takes place at position 3 and /or 5 where a relatively high 7t-electron density is located in all pyran-like heterocycles. In a second process, electrophilic attack occurs only after deprotonation of a starting substrate with a strong base substitution in the 2-, 4-, or 6-positions is typical. Nucleophilic substitution usually takes place if a pyran or thiopyran has in the 2-, 4-, or 6-position a chlorine, methoxy, or an amine leaving group. 

The oxazoles and their derivatives have played a variety of fascinating roles in the preparation of new molecular systems. Much of this chemistry stems from their ability to serve as diene components (azabutadiene equivalents) in reactions with a variety of dienophilic agents, to undergo nuclear metallation, to activate attached aryl or alkyl groups to deprotonation (thus functioning as masked aldehydes, ketones or carboxylic acid groups), and to serve as useful electrophiles on conversion to AT-alkylated salts. 

The popular approach to tetrahydrofurans involves an electrophilic process and the commonly used electrophiles for the cyclization are acids, oxygen, halogen, mercury (see Section 3.11.2.2.9) and selenium. The ionic hydrogenation of furans with excess triethyl-silane in trifluoroacetic acid affords high yields, e.g. 2-methylfuran is reduced to 2-methyl-tetrahydrofuran and 2-ethylfuran to 2-ethyltetrahydrofuran (see Section 3.11.2.5). The synthesis of several dihydro and tetrahydrofurans containing natural products by chirality transfer from carbohydrates has been used successfully for total synthesis, e.g. (-)-nonactic acid. A reasonable yield of 2-alkyltetrahydrofuran was prepared from 4-alkylbut-l-en-4-ol by hydroboration followed by cyclization with p-toluenesulfonic acid. 

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