Electrophilic Attack at Nitrogen

The azetidinium acetates 18 are suitable substrates for the synthesis of 1-arylazetidines 19 2000EJ01815 . The palladium-catalyzed coupling reaction of azetidines 18 with aryl bromides has led to the synthesis of 1-arylazetidines 19 (Equation 1). This reaction required the presence of a strong base such as /-butoxide. 

The reaction of azetidine-3-thiol hydrochloride 20 with 2-methylthio-l,3-thiazoline 21 in the presence of a catalytic amount of triphenylphosphine afforded 2-(3-mercaptoazetidin-l-yl)-l,3-thiazoline hydrochloride 22 (Equation 2), which is useful for the pendant moiety of new oral 1/3-methylcarbapenem antibiotic L-084 2002H(56)433 . 

Isoxazoles are weakly basic. Isoxazole has a pKa of -2.97 at 25 °C, and the values for its 3-methyl, 5-methyl and 3,5-dimethyl derivatives are -1.62, -2.01 and -1.61, respectively a 4-nitro group reduces the pKa of 3,5-dimethylisoxazole to -6.43. For 4-substituted 3,5-diphenylisoxazoles the pK values showed a good correlation with the Hammett crm constants for the substituents (79AHC(25)147) (see also Section 4.16.2.4.4, Tables 3 and 4). 

On the basis of UV studies, 1,2-benzisoxazoles are considered to be weaker bases than the above isoxazoles (8lAHC(29)l, p. 9) and the pKa values for l,2-benzisoxazole-3-carboxylic acids are comparable with those of o -nitrobenzoic acids. 

Although isolated salts of 2,1-benzisoxazoles have not been reported, spectral data in acidic media show evidence for protonation. 

Although isoxazoles are comparatively weak electron donors, complexes with numerous metal ions, notable metal (II) ions, have been reported. The ligands include isoxazole and its methyl, phenyl, amino and hydroxy derivatives. They are listed with references in Table 5. 

4- Amino-3,5-dimethylisoxazole 5 - Amino-3,4-dimethylisoxazole 3-Phenylisoxazole-5(4H)-one Dimethyldiisoxazolone 

The possibility of acetylating the pyrrole nitrogen atom of 9a was investigated. The reaction was performed in the presence of different bases, and the highest yield of the corresponding compound 9b was achieved for potassium tert-butoxide. As should be expected, even trace amounts of this compound are absent from the acylation products of thienopyrrole 9a under Friedel-Crafts conditions 20020L387 . 

As indicated in CHEC-I 84CHEC-I(5)167 , electrophilic attack at nitrogen is the most characteristic of the whole pyrazole reactivity. Several protecting groups have been used in pyrazole chemistry p-methoxybenzyl 88BSB573 , pyrrolidinomethyl 89PHCi , [2-(trimethylsilyl)ethoxy]methyl 92H(34)303 . 

Pyridazine and its benzo derivatives are electron-deficient ring systems. Nevertheless, many examples of successful reactions of electrophiles on one of the nitrogen atoms of these skeletons have been described. 

The (benzo)pyridazines are inherently electron deficient ring systems, more so than pyridine, and while there are many examples of electrophilic reaction of (benzo)pyridazines on nitrogen, reactions such as protonation and A-oxidation occur less readily than with pyridine. 

Pyridines and azines behave as tertiary amines in their reactions with a wide range of electrophiles  

The ease of such reactions depends on two major factors the nucleophilicity of the nitrogen atom, dominated by its charge density, and the degree of steric hindrance. A minor factor is the juxtaposition of nitrogen lone pairs (the a-effect), which increases the reactivity at nitrogen in pyridazines, but not sufficiently to overcome the unfavorable electronic effect (see below). 

The pKa of a nitrogen is a convenient measure of its nucleophilicity in proton addition steric effects are unimportant. All other types of electrophilic attack at nitrogen are sensitive in varying degrees to steric effects from a-substituents. (Exception certain ring formation reactions as in metal chelation.) 

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Electrophilic Attack at Nitrogen. The lone pair on pyridiae (1) = 5.22) reacts with electrophiles under mild conditions, with protonic... 

Complexation with metals has been observed with a variety of pyridopyridazinones, whilst electrophilic attack at nitrogen is involved in cyclizations to a variety of azolo and azino fused tricyclic systems, e.g. (65CPB586, 7UOC3812). 

Reactivity of Nonconjugated Rings 12.15.6.1 Electrophilic Attack at Nitrogen... 

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