Electrophilic nitrogen electrophiles

Various other heteroatom-substituted earbocations were also found to be activated by superacids. a-Nitro and a-cyanocarbenium ions, R2C N02 or R2C CN, for example, undergo O- or N-protonation, respectively, to dicationic species, decreasing neighboring nitrogen participation, which greatly enhances the electrophilicity of their carbo-... 

You will have noticed that, throughout this chapter, the heteroatom has always been hie nucleophile. There is one way to use nitrogen as an electrophile however and this provides a good synhion for ammo acid synthesis ... 

A completely different, important type of synthesis, which was developed more recently, takes advantage of the electrophilicity of nitrogen-containing 1,3-dipolar compounds rather than the nucleophilicity of amines or enamines. Such compounds add to multiple bonds, e.g. C—C, C C, C—O, in a [2 + 3 -cycioaddition to form five-membered heterocycles. 

The pyridine-like nitrogen of the 2H-pyrrol-2-yiidene unit tends to withdraw electrons from the conjugated system and deactivates it in reactions with electrophiles. The add-catalyzed condensations described above for pyrroles and dipyrromethanes therefore do not occur with dipyrromethenes. Vilsmeier formylation, for example, is only successful with pyrroles and dipyrromethanes but not with dipyrromethenes. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Because Pd(II) salts, like Hgtll) salts, can effect electrophilic metallation of the indole ring at C3, it is also possible to carry out vinylation on indoles without 3-substituents. These reactions usually require the use of an equiv. of the Pd(ll) salt and also a Cu(If) or Ag(I) salt to effect reoxidation of the Pd. As in the standard Heck conditions, an EW substitution on the indole nitrogen is usually necessary. Entry 8 of Table 11.3 is an interesting example. The oxidative vinylation was achieved in 87% yield by using one equiv. of PdfOAcfj and one equiv. of chloranil as a co-oxidant. This example is also noteworthy in that the 4-broino substituent was unreactive under these conditions. Part B of Table 11.3 lists some other representative procedures. 

Introduction of substituents on the carbocyclic ring relies primarily on electrophilic substitution and on organometallic reactions. The former reactions are not under strong regiochcmical control. The nitrogen atom can stabilize any of the C-nng o-complexes and both pyrrole and benzo ring substituents can influence the substitution pattern, so that the position of substitution tends to be dependent on the specific substitution pattern (Scheme 14.1). 

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... 

If the thiazole under consideration reacts in its neutral form, the ring nitrogen is expected to be reactive center. Exceptions could be expected for 2-araino-4-R thiazoies with bulky R groups and for electrophilic reactants able to generate a carbocation. 

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 exocyclic nitrogen is slightly more reactive toward the electrophilic center A than is its ring counterpart. 

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). 

Formamidinoyl isothiocyanates (157) combine with 2-aminothiazoles the ring nitrogen attacks the spC part of the electrophilic reagent (312) further reaction then yields aza-condensed thiazolo-s-triazines (158) (Scheme 99) (313). Mesoionic S-alkvlthiazolo[3.2-fl]-i-tria2ine-5,7-diones (159) are obtained when 2-alkylaminothiazoles react with phenoxycar-bonyl isocyanate (304). 

Zugravescu reports the isolation of ring nitrogen substitution products (195) (Scheme 124) (325). and it is not clear whether direct electrophilic substitution in the 5-position is the general case or if the finally observed product results from rearrangement. 

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. 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

Reactivity of A-4-thiazoline-2-thiones and derivatives involves four main possibilities nucleophilic reactivity of exocyclic sulfur atom or ring nitrogen, electrophilic reactivity of carbon 2 and electrophilic substitution on carbon 5. 

Reaction takes place on nitrogen when the electrophilic center is an sp carbon, particularly if it is charged. Thus Mannich reaction yields the N-substituted compound (71 and 72) (Scheme 34) (54. 157-159). The same reaction is reported with piperidine, o-toluidine. and methylaniline (158). 

A-2-Thiazoline-4-one possesses three nucleophilic centers (the C-5 atom, the oxygen, and the nitrogen) and two electrophilic centers (the C-4 and C-2 atOT.rs). In the literature all these reactive centers have been involved in autocondensation reactions. 

In conclusion, in terms of electrophilic reactivity a methyl group in the 2-position is equally reactive in the two categories of heterocycles (selenazole and thiazole). Of the two positions ortho to nitrogen, only the 2-position is activated. The 5-position is sensitive to electrophilic reagents and resembles more closely the para position of a benzene ring. 

Quaternarj salts are obtained by alkylation of selenazole bases, the heterocyclic nitrogen atom playing the role of nucleophile with regard to the electrophilic carbon of the alkylating, agent. 

Despite its V excessive character (340), thiazole, just as pyridine, is resistant to electrophilic substitution. In both cases the ring nitrogen deactivates the heterocyclic nucleus toward electrophilic attack. Moreover, most electrophilic substitutions, which are performed in acidic medium, involve the protonated form of thiazole or some quaternary thiazolium derivatives, whose reactivity toward electrophiles is still lower than that of the free base. 

The electrophile (E ) m this reaction is mtromum ion (0=N=0) The charge distn bution m mtromum ion is evident both m its Lewis structure and m the electrostatic potential map of Figure 12 2 There we see the complementary relationship between the electron poor region near nitrogen of NO, and the electron rich region associated with the TT electrons of benzene... 

One reason for the low reactivity of pyridine is that its nitrogen atom because it IS more electronegative than a CH in benzene causes the rr electrons to be held more tightly and raises the activation energy for attack by an electrophile Another is that the nitrogen of pyridine is protonated in sulfuric acid and the resulting pyndinium ion is even more deactivated than pyndine itself... 

The orbital and resonance models for bonding in arylamines are simply alternative ways of describing the same phenomenon Delocalization of the nitrogen lone pair decreases the electron density at nitrogen while increasing it m the rr system of the aro matic ring We ve already seen one chemical consequence of this m the high level of reactivity of aniline m electrophilic aromatic substitution reactions (Section 12 12) Other ways m which electron delocalization affects the properties of arylamines are described m later sections of this chapter... 

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