Nitrilium ion intermediate

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

Acetonitrile is another participating solvent, which in many cases leads to the formation of an equatorially linked glycoside [125-131], It has been proposed that these reactions proceed via an a-nitrilium ion intermediate. It is not well understood why the nitrilium ion adopts an axial orientation however, spectroscopic studies support the proposed anomeric configuration [130,131], It is known that nucleophilic substitution of the a-nitrilium ion by an alcohol leads to P-glycosidic bonds and the best P-selectivities are obtained when reactive alcohols at low reaction temperatures are employed. Unfortunately, mannosides give poor anomeric selec-tivities under these conditions. 

The carbenium ion adds to the nitrile nitrogen to give a nitrilium ion intermediate, which undergoes hydrolysis to the corresponding amide upon aqueous work-up. 

The Beckmann rearrangement of cyclic oximes results in lactams. This is exemplified in Figure 11.38 with the generation of e-caprolactam, the monomer of nylon-6. The nitrilium ion intermediate cannot adopt the preferred linear structure because it is embedded in a seven-membered ring. Therefore, in this case the intermediate might better be described as the resonance hybride of the resonance forms A (C=N+ triple bond) and B (C+=N double bond). The C,N multiple bond in this intermediate resembles the bond between the two C atoms in benzyne that do not carry H atoms. 

The Beckmann rearrangement is one of the typical reactions of oxime derivatives and the N-substituted nitrilium ion intermediates have been widely exploited as synthetic intermediates for the preparation of nitrogen-containing heterocycles, " while few examples have been reported for the nucleophilic substitution on the sp nitrogen atom of oximes. Even though, in some of them, carbon-nitrogen bond formation is realized, these reactions have not been well generalized as synthetic tools. ... 

A number of nitriles added to bicyclic alkenes after conversion into a nitrilium ion intermediate, generated by treatment with sulfuric acid. Thus, derivatives of 3-azatricyclo[5.3.1.04,9]undecene 30 were obtained starting from 2,6-dimethylenebicyclo[3.3.1]nonane 29 with total diastereose-lectivity187. 

If the rearrangement of oxime sulfonates is induced by organoaluminum reagents,the nitrilium ion intermediate 82 is captured by the nucleophile originally attached to the Al. By this means an oxime can be converted to an imine, an imino thioether (R-N=C-SR), or an imino nitrile (R-N=C-CN). " In the last case, the nucleophile comes from added trimethylsilyl cyanide. The imine-producing reaction can also be accomplished with a Grignard reagent in benzene or toluene. " ... 

Evidence supporting the involvement of nitrilium ion intermediates is available from the large number of heterocyclic derivatives obtained by intramolecular trapping reactions. Furthermore, independently generated nitrilium salts undergo hydrolysis to Ritter products (Scheme 3). 

The physical technique with the greatest potential for synthetic applications of Ritter-type reactions is electrochemistry. A selection only of examples is discussed here. Synthetic chemists unfamiliar with this technique will find the review by Eberson and Nyberg an informative and entertaining introduction to this area. Electrochemical Ritter reactions may be performed through anodic substitution of a hydrogen by the nitrile, followed by hydrolysis of the nitrilium ion intermediate, as shown in Scheme 42. The majority of reactions investigated have been anodic acetamidations using hydrocarbons, alkyl halides, esters or ketones as the substrate. In some cases, such as reaction of the adamantane derivatives (83), the yields of amide product are excellent (Scheme 43). 

Nitrilium ion intermediates have been shown to have synthetic utility. Addition of phosphate carbanion to 5-keto steroids could be controlled to yield either cis or trans olefin. " ... 

Amidooxazoles are produced from nitriles and C,A-diacylimines (161), which are formed in situ by the action of Lewis acids on A-(methoxyalkyl)amides <90JOC5225>. The later compounds are available by treatment of 2-aryloxazoles with bromine in methanol. A mixture of oxazole isomers is obtained in quantitative yield from acetonitrile, other nitriles also give diamide products (162). The reaction proceeds through a nitrilium ion intermediate (163) that may form the oxazoles by one of two pathways, one of which includes the diamides as intermediates (Scheme 76). 

The first step in the Ritter reaction is the formation of a carbenium ion 1. Thus any substrate capable of generating a stable carbenium ion is a suitable starting material. In the case of tertiary alcohols 5, the mechanism begins with an acid mediated El elimination of the hydroxyl to give the requisite carbenium ion 1. Nucleophilic attack by the nitrogen lone pair on the nitrile 2 leads to the formation of a nitrilium ion intermediate 7 and hydrolysis by simple aqueous workup then produces the amide 3. 

The protonation by the carboxylic acid moiety to give an imi-nium ion followed by a nucleophilic attack of the isonitrile leads to the formation of a nitrilium ion intermediate, which is subsequently intercepted by the corresponding carboxylate anion. The resulting imino anhydride typically undergoes an irreversible transacylation (Mumm rearrangement) to give a final Ugi product (Fig. Ic). For the construction of a 2D library array, only two of the four possible components involved in the Ugi reaction are varied. 

The two examples portrayed below, each occurring via different mechanistic pathways, give one a sense of the breadth of the chemistry. In the first (Eq. 2), different nucleophiles, viz., azide and methanol, add across a double bond [5]. The more nucleophilic of the pair adds to the less substituted carbon to afford a heteroatom-stabilized cation that is then intercepted by the second nucleophile, ultimately delivering the product (Eq. 3). The second example portrays the replacement of a C-H bond on anthracene with acetonitrile to afford the acetamide adduct after hydrolysis of the nitrilium ion intermediate (Eq. 4) [6]. 

In this example, water was nsed as a nucleophile instead of an organic acid. The yields of the obtained a-amino amides 2 ranged from moderate to good (Scheme 7.3). In order to explain the resnlts, a mechanistic proposal was envisaged by the anthors where the phenyl phosphinic acid (6) was proposed to have a dnal role, as Brpnsted acid by protonation of the imine intermediate and as a Lewis base by trapping the nitrilium ion intermediate formed between the aldehyde, the amine, and the isonitrile, forming intermediate 7. In the last step, the water released from the imine formation reacts with intermediate 7 to give 8, which was transformed into the componnd 2 and catalyst 6. 

Scheme 7.5). The released water molecule then reacts with BDMS (9) to generate HBr, dimethyl sulfide, and HOBr. Since there is no water in the system, the water can not attack the nitrilium ion intermediate 12. Therefore, a second molecule of amine could react with the nitrilium ion, generating the final product 10. 

The B-N reaction could have two other plausible mechanistic pathways. Path (a) involves the generation of a dichlorophosphoryl imine-ester intermediate, which upon cyclization, leads to elimination with imine formation (Scheme 7) (07MI290). Path (b) includes the formation of a nitrilium ion intermediate followed by cyclization to dihydroisoquino-line (97JCS(P1)2217) (Scheme 8).This mechanistic deviation is due to the ambiguity over the timing for the elimination of the carbonyl oxygen in the amide precursor. Presently, it is often assumed that different conditions affect the predominance of one mechanism over the other. Under certain... 

In a first proof-of-principle study, we chose benzhydryl bromide 21 as a test substrate, since this compound features a relatively weak C-Br bond. If the corresponding benzhydryl carbocation is formed (see Scheme 16) and no further nucleophiles are added, the solvent (acetonitrile) will attack the cation and form a nitrilium ion intermediate. Finally, traces of water in the solvent will hydrolyze this species to from W-benzhydryl acetamide 22 in an overall Ritter-like reaction. The formation of this product from benzhydryl bromide can easily be followed by H-NMR spectroscopy. 

Bischler-Napieralski Reaction. A widely used method for cyclization of iV-p-phenylethyl amides to form dihydroisoquino-lines and isoquinolines (eq 6) is the Bischler-Napieralski reaction. A nitrilium ion intermediate has been implicated in this reaction. ... 

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