Ritter reaction extensions

Extension of the Ritter reaction to conjugated dienes, however, has been less successful. The reaction is often met with competing Diels-Alder reactions or extensive polymerization. The polymerization that occurs during the reaction of 1,3-dienes and nitriles has been used in the synthesis of linear... 

Meyers and Garcia-Munoz64 assume that the cyclization of the -ketonitriles 67 by the action of concentrated sulfuric acid may be regarded as a still further extension of the Ritter reaction to the reactions of carbonyl compounds in the synthesis of nitrogen-containing heterocycles (equation 25). In this case the cyano-group reacts as a nucleophile with the positively charged center of the carboxonium intermediate J L... 

As an alternative to amide formation, intramolecular cyclizadons involving the nitrilium ion lead to a variety of heterocyclic systems (Section 1.9.2). Since carbenium ions, or their equivalents, may be produced by means other than strong acid, a number of valuable extensions of the original reaction are possible (Section 1.9.3). In addition, nitrilium and imidate species are also available through other processes, implying that the Ritter reaction has close mechanistic relationships with other well-established reactions and with the chemistry of the isonitriles. These aspects are explored in Section 1.9.4. 

A modified Ritter reaction was used by Y.L. Janin et al. for the preparation of electron rich 1-aryl-3-carboxylisoquinolines, which are considered to be the eiectron-rich anaiogues of PK 11195, a faicipain-2 inhibitor. interestingiy, the standard Ritter reaction conditions (strong acid) ied to extensive decomposition of both starting materiais, but the use of HBF4 in ether gave rise to the desired dihydroisoquinoiine, aibeit in poor yieid. 

The reaction of nitriles with aromatic aldehydes is carried out at heating the reactants to 50-70°C with a 1 -h 10 (v/v) mixture of concentrated sulfuric acid and glacial acetic acid. The cycloaddition reaction is regiospecific. The oxazines 21 (equation 10) are formed as diastereoisomeric pairs which are free from their regioisomeric products in the limit of the NMR analysis. Precursors used were benzonitrile and acetonitrile as well as acetaldehyde, benzaldehyde and its substituted derivatives, and a number of the olefins having various structures. Until now, the reaction of aldehydes with nitriles was interpreted as an extension of the Ritter reaction. The initial O-protonation of aldehyde 22 is postulated to form in the presence of acid the hydroxycarbenium ion 23 which then reacts as a cationoid electrophile with the nitrile (equation 11) giving the nitrilium ion 24. 

Additions of electrophilic carbon to cyanides are well known ". They occur in e.g. the Ritter reaction which has been reviewed extensively by BishopIn this reaction a carbenium ion, generated from e.g. r-butanol and sulphuric acid, attacks the nitrogen atom of a cyanide (equation 36). Sometimes, cyanides are applied to trap carbocations. An ex-... 

Other acid-catalysed addition reactions include reaction with nitriles (Ritter reaction), formaldehyde (Prins reaction) and carbon monoxide and water (Koch reaction). These reactions are normally catalysed by concentrated sulphuric acid. Extensive isomerization occurs and may even lead to quaternary compounds of the type RC(CH3)XR where X is the new functional group introduced into the molecule. Homogeneous catalysts have been developed which give simpler products without extensive isomerization. 

Other Sulfonic Acids. Extensive development work has been conducted on acrylic sulfonate-containing monomers. 2-Sulfoethyl methacrylate (SEM) monomer 5Ahas proved to be of limited commercial value owing to the hydrolytic instability of the ester linkage. However, recently well-defined homopolymers of 3-sulfopropyl methacrylate (SPMA) were prepared under aqueous RAFT conditions with 4-cyanopentanoic acid dithiobenzoate and V-501 as the CTA/initiator pair at 70°C (39). This same hydrolytic instability has been a serious problem with 3-sulfo-2-hydroxypropyl methacrylate. In contrast, 2-acrylamido-2-methylpropanesulfonic acid (AMPSA) 6A, prepared by the reactions of SO3 with isobutylene followed by the Ritter reaction with acrylonitrile (134), is quite hydrolytically stable. 

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