Electrophilic substitution alkylation

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Bromination of 2-dialkylaminothiazoles has been reported to be successful by one author (415) and to fail by others (375. 385). If the mechanism of direct electrophilic substitution is accepted for these compounds, it is difficult to understand why alkyl substitution on such a remote position as exocyclic nitrogen may inhibit this reaction in the C-5 position. 

The most widely studied electrophilic substitution reactions are haloge-nation and nitration. Two main types of substrates are possible alkyl-thiazoles and arylthiazoles. 

Reactions. The CF O— group exerts predominant para orientation in electrophilic substitution reactions such as nitration, halogenation, acylation, and alkylation (350). 

A tertiary carbonium ion is more stable than a secondary carbonium ion, which is in turn more stable than a primary carbonium ion. Therefore, the alkylation of ben2ene with isobutylene is much easier than is alkylation with ethylene. The reactivity of substituted aromatics for electrophilic substitution is affected by the inductive and resonance effects of a substituent. An electron-donating group, such as the hydroxyl and methyl groups, activates the alkylation and an electron-withdrawing group, such as chloride, deactivates it. 

SuIfona.tlon, Sulfonation is a common reaction with dialkyl sulfates, either by slow decomposition on heating with the release of SO or by attack at the sulfur end of the O—S bond (63). Reaction products are usually the dimethyl ether, methanol, sulfonic acid, and methyl sulfonates, corresponding to both routes. Reactive aromatics are commonly those with higher reactivity to electrophilic substitution at temperatures > 100° C. Tn phenylamine, diphenylmethylamine, anisole, and diphenyl ether exhibit ring sulfonation at 150—160°C, 140°C, 155—160°C, and 180—190°C, respectively, but diphenyl ketone and benzyl methyl ether do not react up to 190°C. Diphenyl amine methylates and then sulfonates. Catalysis of sulfonation of anthraquinone by dimethyl sulfate occurs with thaHium(III) oxide or mercury(II) oxide at 170°C. Alkyl interchange also gives sulfation. 

Resonance effects are the primary influence on orientation and reactivity in electrophilic substitution. The common activating groups in electrophilic aromatic substitution, in approximate order of decreasing effectiveness, are —NR2, —NHR, —NH2, —OH, —OR, —NO, —NHCOR, —OCOR, alkyls, —F, —Cl, —Br, —1, aryls, —CH2COOH, and —CH=CH—COOH. Activating groups are ortho- and para-directing. Mixtures of ortho- and para-isomers are frequently produced the exact proportions are usually a function of steric effects and reaction conditions. 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

Polarization and dipole moment studies for alkyl-, aryl-, carbonyl- hydroxy- (keto-) and amino-isoxazoles have been compiled and likewise support the low electron nature of the ring 63AHC(2)365, 62HC(l7)l,p. 177). More recent studies predict the order of electrophilic substitution to be 5>4> 3 on frontier electron density values of 0.7831, 0.3721 and 0.0659, respectively 7lPMH(4)237,pp.245,247). This contrasts with earlier reports of 4>5>3 on density values of —0.09, -t-0.14 and -t-0.18 in that order 63AHC(2 365). 

Coumarin, 6-ethoxycarbonyl-4,5,7-trihydroxy-synthesis, 3, 805-806 Coumarin, 3-hydroxy-Mannich reaction, 3, 680 mass spectra, 3, 609 Coumarin, 4-hydroxy-alkylation, 3, 692 azo dyes from, I, 331 electrophilic substitution, 2, 30 IR spectra, 3, 596 Mannich reaction, 3, 680 mass spectra, 2, 23 3, 609 molecular structure, 3, 622 reactions... 

Beyer synthesis, 2, 474 electrolytic oxidation, 2, 325 7r-electron density calculations, 2, 316 1-electron reduction, 2, 282, 283 electrophilic halogenation, 2, 49 electrophilic substitution, 2, 49 Emmert reaction, 2, 276 food preservative, 1,411 free radical acylation, 2, 298 free radical alkylation, 2, 45, 295 free radical amidation, 2, 299 free radical arylation, 2, 295 Friedel-Crafts reactions, 2, 208 Friedlander synthesis, 2, 70, 443 fluorination, 2, 199 halogenation, 2, 40 hydrogenation, 2, 45, 284-285, 327 hydrogen-deuterium exchange, 2, 196, 286 hydroxylation, 2, 325 iodination, 2, 202, 320 ionization constants, 2, 172 IR spectra, 2, 18 lithiation, 2, 267... 

Quinolinium 2-dicyanomethylene-1,1,3,3-tetracyanopropanediide dimensions, 2, 110 Quinolinium iodide, 1-alkyl-Ladenburg rearrangement, 2, 300 Quinolinium iodide, 1-methyl-Ladenburg rearrangement, 2, 300, 335 Quinolinium iodide, [l-methyl-4-[3(5)-pyrazolyl]-blood sugar level and, 5, 291 Quinolinium perchlorate, 1-ethoxy-hydroxymethylation, 2, 300 Quinolinium perchlorate, 1-methyl-nitration, 2, 318 Quinolinium salts alkylation, 2, 293 Beyer synthesis, 2, 474 electrophilic substitution, 2, 317 free radical alkylation, 2, 45 nitration, 2, 188 reactions... 

Selenolopyrylium salts, 4, 1034—1036 Selenolo[2,3-c]pyrylium salts synthesis, 4, 969 Selenolo[3,2-b]pyrylium salts synthesis, 4, 1035 Selenolo[3,2-c]pyrylium salts synthesis, 4, 969 Selenoloseknophenes electrophilic substitution, 4, 1057 NMR, 4, 13 synthesis, 4, 135 UV spectra, 4, 1044 Selenoloselenophenes, alkyl-synthesis, 4, 967 Selenolo[2,3-b]selenophenes ionization potentials, 4, 1046 Selenolo[3,2- bjselenophenes dipole moments, 4, 1049 ionization potentials, 4, 1046 structure, 4, 1038, 1039 Selenolo 3,4-f)]selenophenes H NMR, 4, 1042 synthesis, 4, 1067 Selenolo[3,4-c]selenophenes non-classical reactions, 4, 1062 synthesis, 4, 1076 Selenolothiophenes electrophilic substitution, 4, 1057 H NMR, 4, 1041 UV spectra, 4, 1044 Selenolo[2,3- bjthiophenes... 

As electrophilic substitutes for peracids, the use of borate ester induced decomposition of alkyl hydroperoxides and molybdenum VI peroxy-complexes have been reported in the recent literature. Although these reagents have led to the epoxidation of olefins in greater than 90% yield there are no reports yet of their application to steroid olefins. 

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

Other typical electrophilic aromatic substitution reactions—nitration (second entr-y), sul-fonation (fourth entry), and Friedel-Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo electrophilic substitution reactions that are limited to only the most active aromatic compounds these include nitrosation (third entry) and coupling with diazonium salts (seventh entry). 

The most notable chemistry of the biscylopen-tadienyls results from the aromaticity of the cyclopentadienyl rings. This is now far too extensively documented to be described in full but an outline of some of its manifestations is in Fig. 25.14. Ferrocene resists catalytic hydrogenation and does not undergo the typical reactions of conjugated dienes, such as the Diels-Alder reaction. Nor are direct nitration and halogenation possible because of oxidation to the ferricinium ion. However, Friedel-Crafts acylation as well as alkylation and metallation reactions, are readily effected. Indeed, electrophilic substitution of ferrocene occurs with such facility compared to, say, benzene (3 x 10 faster) that some explanation is called for. It has been suggested that. 

The reaction involves an electrophilic attack into the 5-position of the pyrimidine ring and thus only those pyrimidines that are activated toward electrophilic substitution by the presence of electron-donating substituents at the 2- and 4-positions undergo cyclization. 2,4,6-Triaminopyrimidine, 6-aminouracil, 6-amino-2-thiouracil, 4-amino-2,4 dimercaptopyrimidine, 2,4-diaminopyrimidin-6(l/I)-one, and various 4-amino-vV-alkyl and aryl pyriinidones have all been converted into pyrido[2,3-[Pg.160]

Electrophilic substitution at ring nitrogen atoms has been limited to protonation and iV-alkylation of the anion derived from a pyrido-pyrimidinone.i - Thus, the sodium salt of pyrido-[2,3-d]pyrimidine-2,4-(l//,3ir)-dione and dimethylsulfate yield the 1,3-dimethy] derivative (176). 

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