Pyridinium salts addition reactions

Nucleophilic addition remains the most utilized reaction of pyridinium salts. Addition generally occurs at the 2- or 4-position giving rise to 2- or 4-dihydropyridines, respectively. Charette et al. observed nucleophilic addition of organometallic reagents to the 2-position of N-amidine pyridinium salts <050L5401>. This chemistry is illustrated in Scheme 19 with amide 71. 

The great significance of the later discovery, that exactly comparable additions to iV-aUcoxycarbonyl- or iV-aryloxycarbonyl-pyridinium cations, generated and reacted in situ, is that the dihydro-pyridines that resnlt are stable, and can be further manipulated. If re-aromatisation " is required, the iV-substituent can be easily removed to give a substituted pyridine. It is worth noting the contrast to the use of A-acyl-pyridinium salts for reaction with alcohol, amine nncleophiles (8.1.1.7), when attack is at the carbonyl carbon the nse of an iV-alkoxy/aryloxycarbonyl-pyridininm salt in the present context diverts attack to a ring carbon. 

Addition of an ammonia source to pyrylium salts readily affords pyridine derivatives and provides a good method for the preparation of the pyridine moiety if the corresponding pyrylium salt is accessible. The carbon oxygen double bond present in the pyrylium salt is an oxonium ion however, owing to aromatic stabilization they are easily formed by a variety of methods. The reactivity of pyrylium salts toward nucleophiles makes them useful reagents for the preparation of structurally diverse heterocyclic compounds. Thus pyrylium salts afford pyridines by reaction with ammonia, pyridine-A -oxides by reaction with hydroxylamine and pyridinium salts by reaction with primary amines. 

The Zincke reaction is an overall amine exchange process that converts N- 2,A-dinitrophenyl)pyridinium salts (e.g, 1), known as Zincke salts, to iV-aryl or iV-alkyl pyridiniums 2 upon treatment with the appropriate aniline or alkyl amine. The Zincke salts are produced by reaction of pyridine or its derivatives with 2,4-dinitrochlorobenzene. This venerable reaction, first reported in 1904 and independently explored by Konig, proceeds via nucleophilic addition, ring opening, amine exchange, and electrocyclic reclosure, a sequence that also requires a series of proton transfers. By... 

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

Another example with porphyrinic dipolar species uses pyridinium salt derivatives as precursors of porphyrinic pyridinium ylides (Scheme 18) <05TL5487>. The procedure involves the reaction of porphyrin 58 with methyl bromoacetate, in refluxing chloroform, to give pyridinium salt 59. The latter, in the presence of K2CO3, reacts with 1,4-benzoquinone to yield only the mono-addition compound 60. Notably, when the reaction was performed in the presence of DBU, bis-addition occurred and the porphyrinic dimer 61 was the only isolated addition product. 

Reactions of highly electron-rich organometalate salts (organocuprates, orga-noborates, Grignard reagents, etc.) and metal hydrides (trialkyltin hydride, triethylsilane, borohydrides, etc.) with cyano-substituted olefins, enones, ketones, carbocations, pyridinium cations, etc. are conventionally formulated as nucleophilic addition reactions. We illustrate the utility of donor/acceptor association and electron-transfer below. 

Thermolysis of 1-imidoyliminopyridinium N-ylides 109 gave the pyrido-triazines 110 in addition to 111 and 112 (76CL413 77JOC443). Compounds 109 were obtained by the reaction of pyridinium salts 107 with 108. 

The total synthesis of vallesiachotamine (9) and isovallesiachotamine (10) has been completed elegantly by Wenkert and Spitzner (393) by utilizing the addition of a silicon-stabilized anion to pyridinium salt 633 to achieve the properly substituted indoloquinolizidine 634 by cyclization, from which 9 and 10 could be prepared in racemic form by simple reaction steps. 

Attack on Unsaturated Carbon. The annual addition of phosphites to every variety of activated double bond continues. These include nitro-alkenes,9 a/S-unsaturated carboxylic acid derivatives,10 maleimides,11 fulvenes,12 and pyridinium salts.13 The reaction of diethyl phosphite with keten 0,N-, S,N, and Al,AT-acetals has been used to prepare the enamine phosphonates (19).14... 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

The reaction of nucleophiles with pyridinium salts leads to addition, giving dihydropyridines. Attack... 

The authors showed that the above reaction carried out in 7V-hexyl-pyridinium salts gave higher yields than imidazolium salts, that the addition of a phosphine ligand to Pd reduced the yield in pyridinium salts, and that higher reaction temperatures were required to obtain high yields. Howarth and Dallas studied the use of [bmimJpF ] as an IL solvent for the reaction of aryl halides and methyl acrylate. They found that the yields of the products were comparable with that obtained with DMF, and that the solvent and catalyst could be reused several times. 

Pyridinium salts are susceptible to addition reactions with nucleophiles and to reduction. 

Nucleophiles react particularly easily with quaternized azines and with pyrylium and thiopyrylium slats (cf. equation 23) typical examples, including the well-known reaction of pyridinium salts with hydroxide in the presence of potassium ferricyanide to give 2-pyridones, are summarized in equations (34)-(36) (note the rather unusual orientation of addition in the last case reaction normally occurs essentially exclusively a to the heteroatom if the position is free or occupied by a leaving group). 

A hydrogen attached to a pyridine or pyridine 1-oxide nucleus cannot be replaced directly by cyanide however, addition of cyanide to various quaternary salts constitutes an important class of reactions of synthetic importance. Before surveying these reactions in detail, the four main classes are outlined. In 1905, Reissert reported the first example, the reaction of quinoline with benzoyl chloride in aqueous potassium cyanide (Scheme 111) (05CB1603). This yielded a crystalline product, C17H12N2O, a Reissert compound (176) which afforded benzaldehyde and quinaldinic acid on acid hydrolysis (Scheme 111). Kaufmann (09CB3776) treated a 1 -methylquinolinium salt with aqueous potassium cyanide and observed 1,4-rather than 1,2-addition (Scheme 112), the Reissert-Kaufmann reaction. Reissert compounds are well known in the quinoline and isoquinoline series, but only rarely have even small yields been found in the pyridine series. On the other hand, cyanide ions add 1,4 with ease to pyridinium salts that have an electron withdrawing substituent at C-3. 

Thieno[2,3-f]pyridine derivatives, 51, undergo methylation at the ring nitrogen with methyl iodide however, the thieno[2,3-f]pyridinium salts that are produced are very labile and they are readily reduced by NaBH4. Additional reaction with methyl iodide leads to quaternary ammmonium salts <2005JME4972>. 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

The formation of activated iminium intermediates derived from nitrogen heterocycles has been reported by Comins . The activation of pyridine derivative such as 214 with phenyl chloroformate provides the pyridinium salt 215, which smoothly reacts with the zinc homoenolate 216 leading to the addition product 217 in 66% yield . The reaction... 

Dihydropyridines can be prepared on cross-linked polystyrene by the addition of organometallic reagents to pyridinium salts (Entry 6, Table 15.21). These reactions do not always give high yields because of several competing processes (e.g. cleavage of the linker, deacylation of the /V-acylpyridinium salt). 

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