Nucleophilic attack Ritter reaction

The preparation of amides by the addition of hydrogen cyanide or alkyl nitriles to alkenes in the presence of acids, known as the Ritter reaction, has been reviewed.229-232 The reaction may be considered simplistically as nucleophilic attack of a nitrile on a carbocation formed by the protonation of an alkene. Subsequent hydrolysis of the nitrilium intermediate gives the amide product (equation 164). The overall result is addition of a molecule of H—NHCOR to a C—C double bond. 

In 1952, Ritter and Murphy reported cases of intramolecular Ritter behavior resulting in formation of dihydroisoquinolines from reactions of methyleugenol with nitriles such as veratronitrile (equation 30). Such reactions involve nucleophilic attack by the aromatic ring on the nitrilium ion and are enhanced by... 

Cristol has earned out photochemical studies on a range of cyclic halogenated substrates which yield Ritter-type products.Irradiation of the dihalides (80) in acetonitrile normally affords a mixture of the isomeric piquets (81) and (82 X = halogen), plus polar material. However, when the solvent was switched to 3% aqueous acetonitrile, significant amounts of the additional products (81 X = OH 13%) and (81 X = NHAc 16%), plus traces of (82 X = NHAc) were isolated (equation 40). These new substances are believed to result from nucleophilic attack by water or acetonitrile on a ground state carbe-nium ion-like intermediate. A number of further, closely related reactions of this type have been described.These photolyses consistently yield amide products but, unfortunately from the synthetic viewpoint, mixtures are often produced, and overall yields of the amides are not generally high. 

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. 

In a report describing acid-promoted Ritter reactions involving a-methylene-)5-hydroxyesters, an I -type process was found to be the preferred mechanism. For compound (104), both Ritter reaction products (105 and 106) are obtained. In order to rule out 5 2 or Sf 2 mechanisms, kinetic analysis was performed, kinetic isotope effects were evaluated, and both Hammett and Eyring plots were done. The mechanistic studies were consistent with an I -type process being preferred with initial formation of the oxonium cation, loss of water, and formation of the allylic acarbocation (107). DFT calculations indicated nucleophilic attack at the terminal carbon (107b, 5 10 was favored by about 2.6kcalmol over attack at the benzylic position (107a, 5 1) (Scheme 23). 

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

The reaction starts with loss of two electrons from the aromatic system of 39a this is stabilized by loss of a 2-butyl carbonium ion, which reacts with acetonitrile in a Ritter-type reaction, and by attack by the nucleophile pyridine. The second loss of two electrons maj occur before or after the ring closure. Similar internal substitution reactions are of potential value for the synthesis of heterocyclic compounds. 

Bimolecular trapping of phenoxonium ions by nucleophilic yr-bonds can lead to cyclized products when attack occurs at the or /io-position. For instance, a Ritter-type reaction occurs when MeCN is used as solvent in the absence of other nucleophiles, leading to a useful synthesis of benzoxazoles (XLV) [48] ... 

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. 

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