Ritter reaction intramolecular

DFT calculations on the Mg(L—H)(L) complex reveal how water and acetonitrile can be lost (Scheme 9). Thus intramolecular proton transfer tautomerizes the neutral acetamide ligand in 48 into the hydroxyrmine form in 49, which can then dissociate via another intramolecular proton transfer to yield the four-coordinate adduct 50, which now contains both water and acetonitrile ligands. It is this complex that is the direct precursor to water and acetonitrile loss. Note that the reaction shown in Scheme 9 is a retro-Ritter reaction and involves fragmentation of the neutral rather than the anionic acetamide ligand, which is a bidentate spectator ligand. 

The treatment of 3-cyano-4-styrylpyridine (109) with polyphos-phoric acid gave substance 110. This cyclization represents a rare example of an intramolecular Ritter reaction.128 This derivative was converted into compound 111 by the steps outlined. A similar condensation involving the treatment of compound 112 with polyphosphoric acid afforded l,8-dihydroxy-3,6-diphenyl-2,7-naph-thyridine (113) in 65% yield.129... 

Little attention seems to have been paid to this type of reaction involving intramolecular nitrilium salt formation. Typical experimental conditions of the Ritter reaction have always been employed in the few instances which have been studied. The reaction does not appear to be widely applicable and at least three exceptions have been recorded in the literature.75-77... 

A combination of the Pummerer rearrangement and the Ritter reaction occurs in the reaction of acetonitrile with methyl phenyl sulfoxide (equation 25) in a mixture of irifluoroacetic acid and its anhydride, although a substantial amount of the nonnal a-acetoxylation also occurs. Participation by amido groups is also possible, the interest here being largely in the construction of lactams via the intramolecular cycli-zation mode. Whereas Wolfe and his coworkers were unable to find conditions for the cyclization of S-phenylcysteinamide sulfoxides under Pummerer conditions, Kaneko found that variously substituted... 

Acid-catalyzed nucleophilic addition of a nitrile to a carbenium ion generated from alcohol (usually tertiary primary alcohols other than benzyl alcohol will not react), yielding an amide. Sanguigni, J.A. and Levine, R., Amides from nitriles and alcohols by the Ritter reaction, J. Med. Chem. 53, 573-574, 1964 Radzicka, A. and Konieczny, M., Studies on the Ritter reaction. I. Synthesis of 3-/5-bartbituryl/-Ipropanesulfonic acids with anti-inflammatory activity, ArcA Immunol. Ther. Exp. 30,421 32,1982 Van Emelen, K., De Wit, T., Hoomaert, G.J., and Compemolle, R, Diastereoselective intramolecular... 

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. 

The pathways by which nitrile groups can be utilized in the construction of heterocyclic systems have been reviewed by Meyers and Sircar. Two of these routes constitute intramolecular variants of the Ritter reaction and, therefore, are discussed here in detail. 

Until recently, the intramolecular cyclization procedure had been used only to synthesize fused heterocyclic structures. The first report of a bridged product, in 1978, involved only a minor amount (9%) of an azabicyclo[3.3.1]nonane derivative obtained from the reaction of ds-carveol with acetonitrile and BFj-EtiO. However, several effective examples are now known. These all involve reaction of the nitri-lium intermediate with an internal alkenic nucleophile to yield a 1-azacyclohexene ring and a new carbe-nium ion which undergoes conventional, but stereospecific, Ritter reaction fiom the least hindered face. Such reactions are typified by formation of the multicyclic structures (64 equation 38) 5<) and (65 equation 39), 5i considerable potential in the synthesis of complex nitrogen heterocyclic systems... 

Reports of five-membered ring formation involving this mechanism remain unauthenticated. Formation of an oxazolidinone product from Ritter reaction of cyclohexanone and cyclohexanone cyanohydrin has been shown by Ducker to result from an alternative pathway. Although 4-methyl-3-pentenonitrile did undergo intramolecular cyclization, this did not involve pyrrolidone formation. Rather a novel dimeric process took place, leading to formation of a monocyclic (74) and a bi-cyclic (75) product. The latter was readily ring opened to (74) using silver oxide and water (Scheme 37). 

Both nitronium and nitrosonium salts are effective initiators but with quite different results. Thus, propene and nitronium fluoroborate react to produce the secondary a-nitrocarbenium ion which undergoes Ritter reaction with acetonitrile to yield amide (118). Under similar conditions, nitrosonium fluoroborate leads to heterocyclic products. Intramolecular reaction of the nitroso and nitrilium groups, followed by prototropic shifts, affords the iV-hydroxy imidazolium salt (119). This may be either neutralized to produce the iV-oxide or reduced to the imidazole (120 Scheme SS). 

An alternative approach is to use the readily available P-hydroxy phenyl selenides as Ritter substrates. Amide formation occurs with retention of configuration, indicating that fission of the carbon-oxygen bond is assisted by the neighboring phenylseleno group (Scheme 61). Diphenyl diselenide and iodine react with 1,5-dienes to give carbocyclic products. Initial formation of the episelenonium ion is followed by intramolecular attack and subsequent Ritter reaction (Scheme 62). ... 

Retro-Ritter reaction amide into alkene reverse sequence to above SOCI2 or P4O10. Intramolecular Ritter reaction alkene (etc.) into heterocycle sequence (130) -> carbenium ion - (129) - (131) (where Y is a nucleophilic substituent) H2SO4 then H2O. 

The intramolecular Ritter reaction was utiiized by F. Compernoiie and co-workers for the synthesis of a potentiai dopamine receptor iigand." The six-membered iactam ring was formed upon treatment of the tertiary benzyiic aicohoi substrate with methansuifonic acid. The benzyiic carbocation was captured by the nitrogen of the cyano group. 

Van Emelen, K., De Wit, T., Hoornaert, G. J., Compernolle, F. Synthesis of cis-fused hexahydro-4aH-indeno[1,2-b]pyridines via intramolecular Ritter reaction and their conversion to tricyclic analogs of NK-1 and dopamine receptor ligands. Tetrahedron 2002, 58,4225-4236. 

However, a considerable difference should be noted between a-hydroxyalkyl nitrilium ions 24 which contain an intramolecular nucleophilic center (OH group), and N-alkylnitrilium ions 26 which are the intermediates of a Ritter reaction. The transformation of ions 24 into the A -acyliminium ions 25 (equation 11) is evidently an intramolecular rearrangement (see Sections V.B and V.C), while the nitrilium salts 26 can be converted into ions 25 only by an oxidative dehydrogenation of amides 27 (equation 12). 

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