2- Benzylpyridine

The first three of a series of papers by Ridd and co-workers on Inductive and Field effects in Aromatic Substitution have appeared. Results of studies of the nitration of 4-phenylp5nidine and of 4-benzylpyridine in aqueous sulphuric acid were reported and use of the usual criteria (para 8.2) showed that in each case the conjugate acid was the species undergoing nitration. The values of where fm refers to the corresponding homocyclic compound (biphenyl or diphenylmethane) when plotted against r, the distance between the... 

Amination of the deactivated carbanion of 4-benzylpyridine formed with excess sodamide presumably proceeds because the strong indirect deactivation is overcome by electrophilic attack by Na+ at the partially anionic azine-nitrogen and by concerted nucleophilic attack by H2N at the 2-position via a 6-membered cyclic transition state (75). However, in simple nucleophilic displacement a carbanion will be more deactivating than the corresponding alkyl group, as is true in general for anionic substituents and their non-ionic counterparts. 

Relatively few pyridines with substituents other than alkyl groups have so far been examined, and with some of these the reaction has been carried out only in the presence of added solvent. A comparison of the reactivities of these pyridines is therefore difficult. It has, however, been established that the presence of benzoyl groups in the 3- and 4-positions causes a very marked drop in the yields of the corresponding 2,2 -bipyridines. The 3- and 4-benzylpyridines were found to be more reactive but even in the absence of solvent, and in vacuo, 4-benzylpyridine gave only about one-third of the yield of the 2,2 -bipyridine compared with pyridine itself. Ethyl nicotinate in the absence of solvent and under vacuum -- gave a similar yield of biaryl but 4-phenylpyridine was found to be less reactive. 

In the course of an investigation aimed at refining hypotensive leads, 4-benzylpyridine (45) was reduced with a platinum catalyst in acidic medium to the corresponding piperidine, and this was alkylated with dimethylaminoethyl chloride to give 46. This... 

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). 

The intermediacy of an anhydro base (57) was referred to in Scheme 46. Analogous anhydro bases (pyridone methides) can be formed by deprotonation of quaternary salts of 2- and 4-benzylpyridines and the like. The pyridone methides are usually highly reactive and not readily isolable some stable examples are shown in Scheme 49. Pyridine methides are intermediates in the base-catalyzed alkylation and acylation reactions of pyridinium salts at the exocyclic carbon. Compounds of type (60) have been estimated to have 25-30% dipolar character. Protonation of (60) occurs at the 2 - and 3 -positions in the ratio 4 1 respectively (70JCS(C)800). 

Electrophilic substitution of benzylpyridines occurs in the benzyl ring. Nitration of 4-benzylpyridine in ca. 85% sulfuric acid gives products in the ratio ortho 14%, meta 6% and para 80% (71JCS(B)712). Nitration of 1- and 4-benzylisoquinolines gives p-nitrobenzyl derivatives. 

The effective deprotonation of finorene (pATa = 22.6), 2-bromoflnorene (pATa = 20.0), 2,7-dibromofluorene (pA a 20.0), acetophenone (pATa = 24.7) and phenylacetonitrile (p a = 21.9) was shown, bnt not for weaker acids snch as 4-benzylpyridine (pATa = 26.7). The nsefulness of generated reagents 1 was Ulnstrated in reactions of nncleophihc addition to electrophiles, characteristic of the ordinary Grignard reagents (5, Tables 2 and 3), as will be reviewed in Section VI. 

Benzylpyridine [2116-65-6J M 169.2, b 110.0°/6mm, d 1.065, n 1.5814. Dried with NaOH for several days, then distd from CaO under reduced pressure, redistilling the middle fraction. 

Jensen et al.16 also studied the decomposition of 5-ethoxythiatriazole in dibutyl phthalate solution in the presence of trichloroacetic acid, tripentylamine, 4-benzylpyridine, anhydrous aluminum chloride, or trinitrobenzene, but practically no effect on the reaction rate was observed. However, later experiments have shown that the decomposition can indeed by enhanced catalytically by Lewis acids under conditions where the catalyst is not sequestered by complex formation with the solvent.19 Thus the addition of aluminum chloride to 5-phenylthiatriazole in benzene causes a brisk evolution of nitrogen at room temperature, and if instead boron tribromide is added, a rather violent reaction sets in. However, when esters or ethers are used as... 

Hands and Katritzky (58JCSI754) compared the nitration of the phenyl and benzylpyridines and their /V-oxides. The results are shown in Table VIII. The tentative conclusion was that 2-phenylpyridine and its N-oxide nitrated as the free base, but that benzylpyridines may be nitrated as conjugate acids. However, later work has shown that, in fact, both compounds react as their conjugate acids [68JCS(B)862]. Further work has shown that the same result occurs with 4-phenyl and 4-benzylpyridines [71 JCS(B)712]. 

As 4-benzylpyridine. ( )-8-Phenylmenthyl. de 82%. For another example, see procedure in text. rde 30%. Exclusive 2-addition to /V-benzyl-and /V-methyl-3-4-dimethylpyridinium halides has been reported [21]. Kde 91%. 

An acyl transfer agent which can be used for the synthesis of acid anhydrides is obtained from the reaction of an acid chloride with 4-benzylpyridine (equation 24). In this way benzoic acid anhydride and cinnamic acid anhydride were obtained in 72% and 57% yields, respectively. As the intermediate, 1-acyl-4-benzylidene-l,4-dihydropyridines, can be isolated, Ais procedure should be well suited for the preparation of mixed anhydrides. Mixed aromatic and aliphatic anhydrides can be prepared with 2-ben-zoylthio-l-methylpyridinium chloride and salts of carboxylic acids. These reactions are carried out in aqueous solution. Iliey make use of the high reactivity of esters of thiocarboxylic esters towards nucleophiles. The mixed anhydrides of benzoic acid with 3-phenylpropanoic acid, phenoxyacetic acid, isobu-tyric acid, p-toluic acid and cinnamic acid were formed in 82, 79,61,91 and 66% yields, respectively. 

In the case of the reaction of the benzyl (4-pyridyl)sulfoxide (53) with phenylmagnesium bromide, a similar reaction of ligand coupling took place easily to lead to 4-benzylpyridine (54)72... 

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