Nitrogen nucleophiles formation

Buscemi, S., Vivona, N. and Caronna, T. (1996) Photoinduced molecular rearrangements. The photochemistry of some 1,2,4-oxadiazoles in the presence of nitrogen nucleophiles. Formation of 1,2,4-triazoles, indazoles, and benzimidazoles. Journal of Organic Chemistry, 61 (24), 8397-8401. 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

The principal reactions of this class of compounds are summarized in Scheme 172. In most of these reactions the reactive nucleophilic center is the terminal NHj group, although the other exocyclic nitrogen may also be involved, as shown by acetylation, which yields 284 and 285. However, the structure of compound 281 is not the one proposed in a recent report (1582) that attributes the attack to the other exocyclic nitrogen. The formation of osazones (287) from sugars, 2-hydrazinothiazoles, and hydrazine has been reported (525, 531). 

The polymerization of ethyleneimine (16,354—357) is started by a catalyticaHy active reagent (H or a Lewis acid), which converts the ethyleneimine into a highly electrophilic initiator molecule. The initiator then reacts with nitrogen nucleophiles, such as the ethyleneimine monomer and the subsequendy formed oligomers, to produce a branched polymer, which contains primary, secondary, and tertiary nitrogen atoms in random ratios. Termination takes place by intramolecular macrocycle formation. 

Formal replacement of one of the bulky halogens in polyhalogenofluoro-ethanes by nitrogen nucleophiles occurs through the intermediate formation of fluorinated olefins [91, 92] (see equation 47) (equation 79). 

An important variant for transition metal-catalyzed carbon-nitrogen bond formation is allylic substitution (for reviews, see1,la lh). Nucleophilic attack by an amine on an 7r-allyl intermediate, generated from either an allylic alcohol derivative,2 16,16a 16f an alkenyloxirane,17-19,19a-19d an alkenylaziridine19,19a 19d, or a propargyl alcohol derivative,21,21a 21d gives an allylic amine derivative. 

Palladium-catalyzed reactions of alkenes containing nitrogen nucleophiles have proven to be a powerful methodology for C—N bond formation leading to pyrroles. 

More generally, electrolytically formed electrophilic centers react with nucleophilic centers. For example, in Scheme 4 [7], an electrogenerated nitroso group leads to a nitrogen-nitrogen bond formation after reaction with an amino group. When the electrolysis is performed in a batch cell, a rapid cyclization... 

Carbon-Nitrogen Bond Formation A carbon-nitrogen bond can result either from the reaction between an anodically produced cationic center and an amino group or from the reaction between a nucleophilic center and an electrogenerated electrophilic nitrogen... 

Carbon-Nitrogen Bond Formation The cathodic reduction, in protic media, of aromatic nitro compounds produces nucleophilic centers, either... 

The factors involved in the attack of nitrogen nucleophiles on carbonyl compounds, e.g. the p/fa of the nitrogen, and the thermodynamics of the formation of neutral (T ) versus zwitterionic (T ) tetrahedral intermediates, have been discussed in terms of their influence on the form of the pH-rate profile. ... 

Neighboring group participation effects appear to play a crucial role in the nucleophilic substitution of chlorine in Michael adducts of 1-R, 2-R, 3-X. Thus, this substitution proceeds very easily in any of the adducts formed with an electron rich nitrogen, sulfur and oxygen Michael donor. For the adducts of nitrogen nucleophiles, the facile substitution of the chlorine has been suggested to occur via formation of intermediate aziridinium ions 103 [8] (Scheme 32), and this postulate was later supported by isolation of azaspiropentane derivatives under appropriate conditions in several reactions (see Sect. 3.2.2) [11b, 53,56]. It is most likely that alkylthio substituents in adducts of type 85 participate in the same way to first form spirocyclopropane-annelated thiiranium ion intermediates which are subsequently opened by attack of the incoming nucleophile. 

The kinetic and other evidence obtained suggest that the carbon-nitrogen bond formation is the consequence of a nucleophilic interaction of an Af-phenylchlorohydroxylamine intermediate 135, formed in the second reaction step from 134, and the acyl halide, which leads to an Af-acyl-Af-chlorophenylhydroxylamine cation intermediate 136. The latter loses chlorine with the formation of 137. 

There is one report of competitive nucleophilic attack at the amide carbonyl in an Ai-acyloxy-A-aUtoxyamide. Shtamburg and coworkers have reported that MeONa reacted with Ai-acetoxy-A-ethoxybenzamide (159) in DME giving methyl and ethyl benzoate (160 and 161) (Scheme 26) . They attributed the formation of methyl benzoate to the direct attack of methoxide ion at the amide carbonyl rather than at nitrogen. The formation of 161 was attributed to a HERON reaction. Though not mentioned by the authors, it seems likely that under these aprotic conditions, 162 could also have been formed by methoxide attack at the acetate carbonyl leading to an anion-induced HERON reaction, by analogy with the reaction of Ai-acyloxy-Ai-alkoxyamides and aqueous hydroxide discussed above (Section IV.C.3.c)... 

In the case of thiocyanogen chloride and thiocyanogen, the formal electrophile is [NCS]+. The presumed intermediate is a cyanosulfonium ion. The thiocyanate anion is an ambident nucleophile, and both carbon-sulfur and carbon-nitrogen bond formation can be observed, depending upon the reaction conditions (see entry 9 in Scheme 4.5). 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Treatment of the enol tosylate obtained with amines led to the formation of / -amino-a-fluoro acrylaldehydes (Eq. 90) when bifunctional nitrogen nucleophiles were used, pyrazoles and pyrimidines were obtained [267]. More recently the reaction has been used to prepare the alkyl- or arylthio congeners [268]. 

Cyclizations with nitrogen nucleophiles involving alkynes and allenes have received little attention until recently. The cyclizations of several a-aminoallenes to 3-pyrrolines with silver tetrafluoroborate was reported by Claesson and coworkers (equation 133).264 A similar cyclization to form A -carba-penems has been reported (equation 134).265 Diastereomeric allenes (R1 R2) were shown to cyclize with complete stereocontrol. Cyclization with palladium chloride in the presence of allyl bromide or electrophilic alkenes allowed for the intermediate vinylpalladium species to be trapped by the electrophile.2651 A related product was obtained by cyclization of an alkynic substrate (equation 13S).265 Other examples of 5-endo cyclization of p-aminoalkynes50 include the formation of indoles by cyclization of 2-alkynylanilines with mercury salts200 or palladium chloride,266a,266b,266c formation of 1-pyrrolines with catalytic palladium chloride (equation 136)198 and formation of pyrroles by cyclization of hydroxy-substituted p-aminoalkynes.198,2666... 

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