A-Acylpyridinium salts

Heterocyclization of 4-(2-alkylaminobenzoyl)pyridazines 68 into diazaacridones 71 can be promoted either by ionization of their NH-group into more nucleophilic anions 69 or by converting them into A-acylpyridinium salts 70 possessing higher electrophilicity (Scheme 21) (89LAC481). The reactions are performed in the... 

A-Acylpyridinium salts are more reactive than the A-alkyl derivatives and afford more stable dihydropyridine products on addition of nucleophiles. Organocuprates are utilized for entry into 2-alkynyl-substituted quinoline systems (Equation 53) <2005TL8905>. They have the advantage of superior selectivity over Grignard reagents, which yield a mixture of the 2- and 4-substituted products. The reaction has been expanded to include isoquinolines and pyridines. 

The acylimidazoles (Table 6.1, entry 10) and the A-acylpyridinium salts (entry 12) occupy additional leading positions with respect to their acylation rates. In the acylimidazoles the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the 17-electron sextet, which makes the imidazole ring an aromatic compound. For a similar reason there is no resonance stabilization of the C=0 double bond in A-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

Orthoesters and carbonic acid derivatives can be employed in lieu of carbonyl compounds. For example, 2,2-diethoxy-2//-chromene (178) and mediyl cyanoacetate give the 2//-chromene derivative (179 Scheme 31). (Methylthio)alkylideniminium salts (180) react with active methylene compounds under basic conditions (K2CO3 or EtsN) to give the corresponding condensation products (181 Scheme 32) 240 jjjis method is an alternative to the Eschenmoser procedure for synthesizing vinylogous lactams and urethanes. A(-Alkyl and A(-acylpyridinium salts can also serve as electrophiles in the Knoevena-gel condensation with activated methylenes. " Suitably activated nitriles (R CN) such as trichloroacetonitrile or ethyl cyanoformate react with various 1,3-dicarbonyl compounds to afford (182) in the presence of catalytic amounts of metal acetylacetonates [M(acac)n]. In the presence of TiCU non-... 

Conjugate addition. Acceptors include nitroalkenes, (tropone)iron tricarbonyl, and A-acylpyridinium salts in the conjugate addition. It may be followed by a cycloacylation process. ... 

Organometallic reagents add very readily to A-alkyl-, A-aryl- and with important synthetic significance, A-acylpyridinium salts. In the simplest cases, addition is to an a-carbon the resulting 2-substituted-l,2-dihydropyridine can be handled and spectroscopically identified, with care, but more importantly can be easily oxidised to a 2-substituted pyridinium salt. ... 

Sodium borohydride reduction of 4-substituted isoquinolinium salts led to vinylogous cyanamides, ureas, and urethanes, as well as the corresponding tetrahydroquinolines (640). Hydrogenation of /8-acylpyridinium salts (641) to vinylogous ureas was exploited in syntheses of alkaloids (642), leading, for instance, to lupinine, epilupinine, and corynantheidine (643, 644). Similarly, syntheses of dasycarpidone and epidasycarpidone were achieved (645) through isomerization of an a,/0-unsaturated 2-acylindole and cyclization of the resultant enamine. 

A study on the effectiveness of various cyclohexyl-based chiral auxiliaries in the asynunetric addition of Grignard reagents to 1-acylpyridinium salts 45 has been published <96TL(37)3807>. 

Just as pyridine is a weaker base than piperidine, it is also a poorer nucleophile. Nevertheless, it reacts with electrophiles to form stable pyridinium salts. In the examples shown, primary alkyl halides form N-alkylpyridinium salts, whereas acyl halides and anhydrides react to give N-acylpyridinium salts. 

However, the salts can be used as valuable transacylating agents, particularly for alcohols, and in this application the salt is not isolated but reacted in situ with the alcohol. An excess of pyridine is needed and such reactions were carried out in pyridine both as reagent and as solvent. Unfortunately, pyridine is difficult to remove from the products, and its use has been superseded by DMAP [4-(A,A-dimethylamino)pyridine]. Now, after A-acylation the 4-A,A-dimethylamino group reinforces the nucleophilicity of the corresponding acylpyridinium salt (Scheme 2.6b), and this promotes the transfer of the acyl group from the salt to the alcohol in the next step. Only a catalytic amount of DMAP is used. 

In the case of the O-acylation of /3-keto esters with iV-acylpyridinium salts a mechanism as shown in Scheme 73 has been suggested (61JOC1684). 

More stable iV-acylpyridinium salts can be formed by using 4-(Ar,Ar-dialkyl-amino)pyridines. The salts are less readily hydrolyzed and are effective in the acylation of sterically hindered alcohols (72S619) and in the formation of iV-f-butoxycarbonyl derivatives of a-amino acids in aqueous alkali, for use in peptide synthesis (71CC267). 

It will be appreciated that iV-acylpyridinium salts are potentially ambident nucleophilic attack can occur at either the acyl carbonyl or by addition to a ring atom. Examples of the latter behaviour are discussed in the previous chapter. 

Acyl and sulfonyl halides and anhydrides react instantaneously with pyridine to form quaternary salts which are excellent acylating and sulfonylating agents. The familiar use of pyridine as a solvent in such reactions reflects this. While usually used in situ, stable A-acylpyridinium and N-acylisoquinolinium salts, e.g. (63), have been isolated and their structures confirmed by single crystal... 

A class of acylpyridinium salts that has been investigated quantitatively is the carbamoyl pyridinium compounds. Diphenylcarbamoyl-pyridinium chloride was synthesised in 1907277. l-(N,N-Dimethylcarbamoyl)-pyridinium chloride (XLVI) was found by Johnson and Rumon278 to decompose to its component parts in non-hydroxylic solvents, dielectric constants from 5 to 95, viz. 

Expanding on established chemistry using iV-acylpyridinium salts as intermediates for the preparation of iV-acyldihydropyridines and dihydropyridones, Wanner and co-workers examined a method using a bicyclolactone... 

With an amino acid-derived chiral auxiliary employed in the chloroformate, reaction of silyl enol ethers with isoquinolinium salts showed not only regiospecificity, but some stereoselectivity as well (Equation 61) <1999SL1154>. The addition of ketene silyl acetals to an W-acylpyridinium salt containing a chiral 2,2-dimethylox-azolidine at C-3 gave 1,4-dihydropyridines with excellent stereoselectivity <2002JA8184>. 

Porphobilinogen and Studies of Its Biosynthesis, ft. Neier. Synthesis and Cycloaddition Reactions of Iso-Condensed Heteroaromatic Pyrroles, C. K. Sha. Azacyclopentadienyl Metal Compounds Historical Background and Recent Advances, C. Janiak and N. Kuhn. Recent Developments in the Synthesis of Marine Pyridoacridine Alkaloids, A. M. Echavar-ren. Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates, D. L. Comins and S. P. Joseph. Index. S S... 

Another level of refinement regarding in situ acyl group activations is reached when the activated hydroxycarboxylic acid A is converted into the corresponding IV-acylpyridinium salt B with / ara-(dimethylamino)pyridine, (Figure 6.9). Under these conditions macrocyclizations routinely succeed in yields well above 50%. 

Cyclization occurs directly through catalysis by the acid liberated when a pyridine-2(lH)-thione is heated with an a-halo acid ester. The most convenient method for preparing the thiazole, however, seems to be the cyclization of (2-pyridinethio)acetic acids in acetic anhydride in the presence of pyridine. Without base catalysis the reaction is slow, which suggests a mixed anhydride intermediate. Mixed anhydride formation with ethyl chlorofor-mate in pyridine, or carboxyl activation by DCC in pyridine, gives the mesoionic product. The cyclization reaction and the chemical stability of the thiazole are adversely affected by a pyridine 6-substituent. The initially formed acylpyridinium salt (407) undergoes rapid tautomerization to the aromatic thiazole form equilibrium between the forms (407) and (408) is verified by rapid deuteration at C-2 (R1 = H) in AcOH-d (81H(15)1349). 

Allyl and benzyl bromides react with a,/ -unsaturated nitriles in the presence of indium(i) iodide under sonication to produce the corresponding allylated and benzylated imines, involving exclusive addition of the allyl/benzyl group to the nitrile moiety (Equation (63)).273 The reaction of allylindium reagents with methyl cyanoacetates affords the corresponding allylation-enamination products (Equation (64)).27 l-Acyl-l,2-dihydropyridines are prepared by indium-mediated allylation of 1-acylpyridinium salts (Equation (65)).275 Quinoline and isoquinoline activated by... 

Under acidic conditions secondary a,/ -unsubstituted enaminones undergo self-condensation to give 3-acylpyridinium salts in high yield241 (equation 171). The / -protonated enaminone acts with the intact enaminone in the same manner as the CH-acidic 1,3-dicarbonyls. 

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