Of electrophilic centers

Ritchie (1975) has found that the reactivity of nucleophiles toward a number of different types of electrophilic centers can be correlated remarkably well by a very simple equation (192), where kNu is the rate constant for reaction of a... 

Hydroxylamines, as potentially ambident nucleophiles, can utilize either the basic N atom or the O atom in nucleophilic reaction with a variety of electrophilic centers . This is illustrated in Scheme 2 through the box on the left hand side of the diagram. Also shown in Scheme 2 are the dissociation equilibria K,, K a, and K 2- The equilibrium denoted as... 

The above results clearly demonstrate that the reactivities of electrophilic centers can be enhanced by adjacent positive charge. We have also found several interesting exanq)les suggesting that positive charge centers can influence the regiochemistry of nucleophilic attack. There are two reported examples of superelectrophilic species undergoing nucleophilic attack at the... 

Catalysis of Intramolecular Sakurai Reactions. Et AICI2 has been extensively used as a catalyst for intramolecular Sakurai additions. Enones (eqs 12 and 13) have been most extensively explored. Different products are often obtained with fluoride or Lewis acid catalysis. EtAlCl2 is the Lewis acid used most often although TiCLi and BF3 have also been used. EtAlCl2 also catalyzes intramolecular Sakurai reactions with ketones and other electrophiles. The cyclization of electrophilic centers onto alkylstannanes and Prins-type additions to vinylsilanes are also catalyzed by EtAlCl2. 

The equation does not take into account such pertubation factors as steric effects, solvent effects, and ion-pair formation. These factors, however, may be neglected when experiments are carried out in the same solvent at the same temperature and concentration for an homogeneous set of substrates. So, for a given ambident nucleophile the rate ratio kj/kj will depend on A and B, which vary with (a) the attacked electrophilic center, (b) the solvent, and (c) the counterpart cationic species of the anion. The important point in this kind of study is to change only one parameter at a time. This simple rule has not always been followed, and little systematic work has been done in this field (12) stiH widely open after the discovery of the role played by single electron transfer mechanism in ambident reactivity (1689). 

This section is organized according to the electrophilic center presented to the nucleophilic nitrogen of the active species. This organization allow s a consistent treatment of the reactivity. However, a small drawback arises when ambident electrophilic centers are considered, and these cases are treated as if the more reactive center were known, which is not always the case. 

The amino group activates the thiazole ring toward electrophilic centers. This point is illustrated by the rate constants of the reaction between 2-dialkylaminothiazoles (32) and methyl iodide in nitromethane at 25 C (Scheme 23) (158). The steric effects of substituents on nitrogen are... 

Thus in neutral medium the reactivity of 2-aminothiazoles derivatives toward sp C electrophilic centers usually occurs through the ring nitrogen. A notable exception is provided by the reaction between 2-amino-thiazole and a solution (acetone-water, 1 1) of ethylene oxide (183) that yields 2-(2-hydroxyethylamino)thiazole (39) (Scheme 28), Structure 39... 

All the examples of reactivity in acidic medium (Scheme 40) involve a reagent with a sp C hybridized electrophilic center, but the actual reactive species generated bears a sp C electrophilic center. In this case, exocyclic N-alkylation is not surprising (see Section III.2). 

Thus the reactivity of 2-aminothiazole derivatives toward reactants bearing a sp C hybridized electrophilic center follows the general pattern ... 

In most of the following reactions the reagent possesses two electrophilic centers, one of them being a sp hybridized carbon however. 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

The problem is more complicated when the ambident nucleophile. 2-aminothiazole, reacts with an ambident electrophilic center. Such an example is provided by the reaction between 2-amino-5-R-thiazole and ethoxycarbonyl isothiocyanate (144), which has been thoroughly studied by Nagano et al. (64, 78, 264) the various possibilities are summarized in Scheme 95. At 5°C, in ethyl acetate, the only observed products were 145a, 148. and 150. Product 148 must be heated to 180°C for 5 hr to give in low yield (25%) the thiazolo[3.2-a]-s-tnazine-2-thio-4-one (148a) (102). This establishes that attack 1-B is probably not possible at -5°C. When R = H the percentages of 145a. 148. and 150 are 29, 50, and 7%, respectively. These results show that ... 

Nevertheless, the puzzling fact to be explained is that the harder ring nitrogen prefers the softer electrophilic center and that this preference is more pronounced than the one observed for the amino nitrogen. Much remains to be done to explain ambident heterocyclic reactivity it was shown recently by comparison between Photoelectrons Spectroscopy and kinetic data that not only the frontier densities but also the relative symmetries of nucleophilic occupied orbitals and electrophilic unoccupied orbitals must be taken into consideration (308). 

Ambident reactivity of the same nucleophilic species toward different nitrosation electrophilic centers. 

Aminothiazole in its neutral form seems to be able to react in 3 different positions according to the electrophilic center considered (Scheme 146). The question of C-5 reactivity for this neutral form remains open, however, because the observed product might also be formed from the protonated form of 2-aminothiazoles. A surprising... 

Diazo coupling involves the N exocyclic atom of the diazonium salt, which acts as an electrophilic center. The diazonium salts of thiazoles couple with a-naphthol (605). 2-nitroresorcinol (606), pyrocatechol (607-609), 2.6-dihydroxy 4-methyl-5-cyanopyridine (610). and other heteroaromatic compounds (404. 611) (Scheme 188). The rates of coupling between 2-diazothicizolium salts and 2-naphthol-3.6-disulfonic acid were measured spectrophotometrically and found to be slower than that of 2-diazopyridinium salts but faster than that of benzene diazonium salts (561 i. The bis-diazonium salt of bis(2-amino-4-methylthiazole) couples with /3-naphthol to give 333 (Scheme 189) (612). The products obtained from the diazo coupling are usuallv highly colored (234. 338. 339. 613-616). 

Data are lacking on the mechanisms of these reactions, but knowledge of other series suggests that the first step is attack of the exocyclic sulfur of 66 on the exocyclic sulfur of 67 converted into an electrophilic center by catalysis (Scheme 31). 

Acrylonitrile reacts with the sodium salt of 4.5-dimethvl-A-4-thiazoline-2-thione (73J (R4 = R5 = Me) to yield 3-(2-cyanoethyl)-4.5-dimethyl-A-4-thiazoline-2-thione (74) (R4 = R, = Me) (Scheme 35 (160). Humphlett s studies of this reaction showed that the size of the R4 substituent is a determinant factor for the S versus N ratio (161. 162). If R4 == H, 100% of the N-substituted product (74) is obtained this drops to 50% when R4 = methyl, and only the S-substituted product (75) is obtained when R4 = phenyl. The same trend is observed with various CH2 = CH-X (X = C00CH3. COCH3) reagents (149). The S/N ratio also depends on the electrophilic center for CH2 = CH-X systems thus S-reaction occurs predominantly with acrylonitrile, whereas N-substitution predominates with methvlvinvlketone (149). 

It is noteworthy that some catalysts convert thioethers to quaternary salts where the reactive electrophilic center is no longer one of the two C centers but the C sp center of the thiazolium salt (284. 285). Thus... 

Extension of the approach discussed above suggests several structural types which may be classified under this category, the main variable being the nature and hybridization of the electrophilic centers and the nature of the atoms joining these two centers. They may be conveniently divided into two groups ... 

The transition state for the rapid hydrolysis of the monoanion has been depicted as involving an intramolecular general acid catalysis by the carboxylic acid group, with participation by the anionic carboxylate group, which becomes bound at the developing electrophilic center... 

Reaction type 3 (equation 10), where the complete hetero-l,3-diene skeleton is incorporated into the newly formed ring system, occurs with compounds having both a nucleophilic center and an electrophilic center If these two functionalities are in positions 1 and 2, various types of six-membered ring systems become accessible 4,4-Bis(trifluoromethyl)-I,3-diaza-1,3-butadienes require only room temperature to react with acetyl cyanide to yield l,4,5,6-tetrahydropynmidin-6-ones [96] Likewise, certain open-chain 1,3-diketones (acetylacetone and acetoacetates) and the heterodiene form six-membered nng systems [97] (equation 19)... 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

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