Reactions with nitrogen electrophiles

B. Monosubstituted Aromatic Amines I. Reaction with nitrogen electrophiles... 

Enamines have a three-atom tt system and are thus in principle capable of reaction with an electrophile on nitrogen or on carbon as shown by the mesomeric forms (1) and (2),... 

The mechanism of organolithium addition to naphthyl oxazolines is believed to occur via initial complexation of the alkyllithium reagent to the oxazoline nitrogen atom and the methyl ether to form chelated intermediate 17. Addition of the alkyl group to the arena 7t-system affords azaenolate 18, which undergoes reaction with an electrophile on the opposite face of the alkyl group to provide the observed product 4. The chelating methyl... 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Neutral pyrroles and indoles also are not susceptible to attack at the cyclic nitrogen. However, the pA d of carbazole and 9-methylcarbazole equal to — 6.0 and — 8.2, respectively, (in H2S04-Et0H, 4 1) refer to N-protonation (71JA5102). Pyrrole anions undergo easy reaction with various electrophiles. 

Phospha sugar nucleosides have not yet been shown to be naturally occurring. Some analogues of phospha sugar nucleosides (e.g., 118) are prepared from 2-bromo-3-hydroxyphospholanes 94 or 103 by nucleophilic substitution reaction with nitrogen nucleophiles (Schemes 35 and 36, and Table 8). However, the nucleophilic substitution reaction (or electrophilic substitution reaction in the presence of catalyst) of 2-bromo-3-hydroxyphospholanes 94... 

The reaction with 1-azabutadiene is also unfavorable for other reasons. To begin with, the 4 + 2 cyclization is inherently less exothermic than with 2-azabutadiene (see Exercise 20, p. 123). Furthermore, the enamine product will rapidly undergo side-reactions with adventitious electrophiles. An imine-enamine tautomerism which transforms R-N=CH-CH=CH-CH3 into RNH-CH=CH-CH=CH2 also contributes to lowering the yield. Finally, electron-poor dienophiles may undergo a competing reaction with the nitrogen lone pair. 

Furthermore, the amine part of the amide group is unlike any normal amine group. Most amines are easily protonated. However, since the lone pair on the amide s nitrogen is tied up in the 7t system, it is less available for protonation or, indeed, reaction with any electrophile. As a result, an amide is preferentially protonated on the oxygen atom but it is difficult to protonate even there (see next chapter, p. 201). Conjugation affects reactivity. 

Now for a reaction with nitrogen as an electrophile that illustrates enol reactivity and reminds us that tautomerism applies to functional groups other than the carbonyl. Let us suppose you have a... 

Extensive studies have revolved around the ability of alkyl substituents on benzotriazole nitrogen to be deprotonated for example, 1-methylbenzotriazole is lithiated readily with -BuLi or LDA at the methyl group and the subsequent reactions with various electrophiles provide 1-substituted benzotriazoles, e.g., 799 <1997JOC4142>. 1-Alkyl- and 1-benzylbenzotriazoles react with borane to give air- and water-stable complexes 800 these can also be deprotonated at the alkyl group removal of the borane unit is achieved by refluxing in ethanol <19980PP325>. 

The chirality of the phenylalanine derivative 10 is used for a direct, stereoselective a-alkylation (Scheme 2) [19]. After treatment with base and reaction with an electrophile the a-alkylated amino acid 11 is obtained in up to 88 % ee. It is not yet clear whether the deprotonated species is an enolate with a chiral nitrogen atom (12) or a chiral, a-metallated compound (13). The protecting groups on the nitrogen seem to play an important role. It is not yet possible to alkylate other phenylalanine derivatives by means of this reaction. 

The Darzens reaction of the oxazoline 360 with a series of aldimines has been shown to form aziridine 362 in good yields and with high diastereoselectivity <2005X3251>. Deprotonation of the aziridine to form the aziridinyl anion and subsequent reaction with an electrophile provide the highly substituted aziridines 363 in moderate yields. The diphenylphosphinyl group on the nitrogen provides optimal yields in the lithiation reaction (Scheme 94). 

Regioselective lithiation on the benzene moiety of 4-substituted quinazolines occurs at position peri to the N1 ring nitrogen. Thus, treatment of 4-methoxyquinazolines 8 with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at — 78 to 0 X followed by reaction with various electrophiles affords 8-substituted quinazoline derivatives 9. This regioselective lithiation provides easy access to a large range of substituted quinazolines which are not easily synthesized by other routes. ... 

The resulting anion can then carry out a nucleophilic reaction with the electrophilic nitrogen of the nitroso group of nitrosobenzene. 

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