Alkylpyridines reactions with

Alkylpyridines are aminated preferentially at the 2-position, but reaction is slower than in the parent system. Quinoline is difficult to aminate and only a low yield of 2-aminoquinoline (32%) is obtained from reaction with sodamide in toluene. When dimethylaniline is employed as solvent, 2-amino-3,4-dihydroquinoline (24%) becomes the major product, and the yield of 2-aminoquinoline drops to 7%. The best yields of 2-aminoquinoline (53-69%) have been obtained by using barium or potassium amide in liquid ammonia. Use of the potassium salt also produces a 10% yield of the 4-amino isomer. The... 

The amide ions are powerful bases and may be used (i) to dehydrohalogenate halo-compounds to alkenes and alkynes, and (ii) to generate reactive anions from terminal acetylenes, and compounds having reactive a-hydrogens (e.g. carbonyl compounds, nitriles, 2-alkylpyridines, etc.) these anions may then be used in a variety of synthetic procedures, e.g. alkylations, reactions with carbonyl components, etc. A further use of the metal amides in liquid ammonia is the formation of other important bases such as sodium triphenylmethide (from sodamide and triphenylmethane). 

Alkylpyridines.3 Highly selective alkylation of pyridine at C4 is possible by quatemization with this triflate followed by reaction with a Grignard reagent. Substitution occurs with almost complete regiospecificity ( > 99%) to give 4-alkyl-l, 4-dihydropyridines, which are oxidized by oxygen to 4-substituted pyridines (equation 1). 

Many 2-alkylpyridines were isolated and identified in roasted lamb fat (45). 2-Alkylpyridines were proposed to form from the corresponding unsaturated n-fatty aldehyde reacting with ammonia upon heat treatment. Ammonia, arising from glycine, can react with nonanal, arising from beef fat, produced 2-butylpyridine in a beef fat/glycine browning model system (6). The same phenomenon was observed in the formation of 2-pentylpyridine from 1-decanal. Maltol produced 2-ethyl-3-hydroxy-6-methylpyridine as a major product in a reaction with ammonia (12). 

There is no doubt that in these. reactions the nitrogen atom of the pyridine ring is complexed with either the lithium alkyl or aryl or with the lithium bromide which is usually present in many preparations of organolithium compounds. It has been established that, either in the presence of an excess of lithium bromide or in the total absence of this salt, phenyllithium still gives the same ortho .para ratio on reaction with 3-picoline.229 To account for the predominant formation of the 2,3-isomer in the reaction of CH3Li with 3-alkylpyridines, it was suggested261 that the transition states for these reactions were similar... 

And 4-alkylpyridines undergo reaction with ethylene under pressure at 140-1500 in the presence of sodium to form the corresponding 2-n-propyl- and (3-pentyl)-2- and 4-pyridines. Yields of 6-94 of monoethylated products are obtained from higher 2- and 4-alkylpyridines (28). The relative ethylation of 4-alkylpyridines is 3. 5 to 7.0 times greater than that of 2-alkylpyridines, and is associated with greater acidity of the 4 over the 2 isomers. 

A pathway leading to the formation of pyridines by aldolization of aldehydes, reaction with ammonia and intramolecular cyclization has been proposed by Vernin (1981). Mottram (1991) explained the formation of 2-alkylpyridines by reaction of ammonia on dienals. 

Therefore, alkylpyridines and A -alkylpyridinium ions undergo base- or acid-catalysed reactions with electrophilic reagents preferably at the 2- and 4- heterobenzylic positions. 

The ring synthesis of imidazo[l,2-a]pyridines is based on the Chichibabin route to indolizines (Section 25.1.2), but using 2-aminopyridines instead of 2-alkylpyridines. The initial reaction with the halo-ketone is regioselective for the ring nitrogen, so isomerically pure products are obtained. 2-Oxoimidazo[l,2-a]pyridines are the products when an o-bromo-ester is used instead of a ketone. 

Therefore, alkylpyridines and N-alkylpyridinium ions undergo base- or acid-catalyzed reactions with electrophilic reagents preferably at the 2- and 4- heterobenzylic positions. For instance, the CH3 group of 2- or 4-picohne can be alkylated (—> 71), carboxylated —> 72), and acylated (—> 74) by a CiAisEN-like condensation aldol addition 73), multiple aldol addition (—> 76), and aldol condensation 75) are also possible. 

In contrast, N-oxides of 2- and 4-alkylpyridines are functionalized in the side-chain (Boekelheide reaction) by acylation reagents (acid anhydrides [104] leading to acy-loxylation, sulfonyl chlorides, or POCI3 [105] leading to chlorination). For instance, 2-picoline-N-oxide on reaction with AC2O yields a mixture of acetoxy compounds (97-99), in which the methyl-acetoxylated product 97 dominates [106] ... 

Reactions of pyridine 1-oxide with Grignard reagents have been little studied. The reported cases give very poor yields of 2-alkylpyridines. Only one example of a Grignard reaction with a pyridone seems to have been recorded with benzyl magnesium chloride, l-methyl-2-pyridone gave 2-benzal-1 -methyl-1,2-dihydropyridine5 . 

Ziegler and Zeiser i were the first to use 2-picolyl lithium in this way, condensing it with benzyl chloride, and 3- and 4-picolyl lithium have since been employed in alkylations. 2-Picolyl lithium has also been used in reactions with a,a)-dihalogenoalkanes , and this and 4-picolyl lithium with o)-diethoxyalkyl halides 5-Alkoxy- c and 5-nitro-2-picolyl lithium have likewise been alkylated, and secondary alkylpyridines were obtained from the higher primary 2- and 4-alkylpyridinesi2 ... 

Competitive ethylations were carried out by using 2- and 4-alkyl-pyridines to study inductive effects. Results of a study on this subject made by Notari and Pines 52) are reported in Table V along with results for alkylbenzenes. The 4-alkylpyridines closely parallel the alkylbenzenes in their relative reaction rates, whereas the 2-alkylpyridines have a different order. A solvation effect of the nitrogen may be the reason. 

The results of some of the many aminations of pyridine and its derivatives that have been carried out appear in Table 14. Yields are quoted where possible but these should not be used for quantitative comparisons as reaction and work up conditions vary widely. 2-Alkylpyridines aminate at the vacant a-position, except when the substituent is very large. 2-f-Butylpyridine does not undergo the Chichibabin reaction, probably because the bulky 2-f-butyl group prevents adsorption on to the sodamide surface. In contrast, 2-phenylpyridine undergoes amination in very good yield. Aminations of 2- and 4-methyl-pyridines do not involve attack on the anhydrobases in aprotic solvents, but some ionization does take place in liquid ammonia. 4-Benzylpyridine forms a carbanion (148) which is only aminated with difficulty by a second mole of sodamide (equation 103). 

In the absence of the strong acid a different course ensues. The acetate ion attacks the A-acyloxypyridinium cation (127) at the a-position and elimination of acetic acid gives the product, 2-acetoxypyridine (128 Scheme 116) (65T1971,63JA958). The course of the reaction under these conditions with 2- and 4-alkylpyridine A-oxides has been discussed earlier (Section 2.06.3.1). 

In both reactions the yield of product is low. With PF3, some Cr(V-C5H5N)(PF3)5 is formed in addition to the complex, but the two compounds are easily separated by chromatography (78, 83). Conventional synthetic methods can form complexes of type Cr(alkylpyridine)(CO)3 but not the complexes of C5HSN or Cr(t)6-alkylpyridine)2 (81). 

The above reactions have been illustrated for 2- and 4-alkylpyridines. They generally fail if no heteroatom is a or 7, as in 3-alkylpyridines and 5-alkylpyrimidines. a- and [3-Alkyl groups in pyridine A-oxides are somewhat more reactive than those on the corresponding pyridines. In addition to the reactions already mentioned, 2-picoline 1-oxide undergoes Claisen condensation with ethyl oxalate to yield the pyruvic ester (630) (for the conversion of alkyl substituents in A-oxides into CH,OAc groups see Section 3.2.3.12.5.iv). 

Alkylpyridinium halides give mixtures of alkylpyridines on heating, e.g. (964) gives 2- and 4-picoline, with other minor products. This reaction is known as the Ladenburg rearrangement, and involves /V-alkyl bond homolysis. 

Selective o/t/io-acylation and orrfio-formylation of 2-alkyl pyridines is possible by [2,3] sigmatropic rearrangement (Sommelet-Hauser) of a-pyrrolidinyl-2-alkylpyridine sulfonates (268), prepared by treating the parent base with cyanomethyl benzenesulfonate (76JOC2658). Acid hydrolysis of the rearranged product (269 R = H) yields 3-formyl-2-methylpyridine (270). Methylation of (269 R = H) using NaH-Mel and acid hydrolysis of the reaction mixture gives 3-acetyl-2-methylpyridine (270 R = Me). 

The general process is shown in equation (3). The L unit in the [Cr(CO)3L3] can be CO (most common),15"20 MeCN,21 22 2-alkylpyridine,23 ammonia24-27 and other donor ligands. The rate (reaction temperature) is related to the nature of L the most reactive readily available source of Cr(CO)3 is [(q6-naphthalene)Cr(CO)3], which undergoes favorable arene exchange under mild conditions with many... 

A 1,3-dipolar cycloaddition of indanoneenamines and nitrilimines produces the indeno[2,1 -cjpyrazole (52).135 The yields of such cyclization reactions are high (60-80%). Reactions of A-alkylpyridine-3-ylides with picryl chloride involving cyclization give a mixture of pseudoazulenes 35 and 36.103 An additional preparation of pyrindine 26 is from 1,2- and 1,4-oxides of azonine.55... 

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