N-alkylation of pyridine

Evaluation of steric effects can also be made by separating electronic from steric effects with the help of linear free energy relationship and appropriate parameters. Applications of the Hammett equation to heterocycles have been reviewed (64AHC(3)209 76AHC(20)1) and the influence of substituent effects on the basicity and N-alkylation of pyridines, which have been by far the most widely studied, shows the difficulties in this approach. Jaffe and Jones (64AHC(3)209) reported a good correlation between pKA of 3- and 4-substituted pyridines and Hammett a parameters ([Pg.179]

Chiral pyridinium-based ionic liquids can be prepared by N-alkylation of pyridines with chloromethyl ()-menthyl ether <2006TA1728>. A room temperature ionic liquid brominating agent is obtained when A- -pcntylpyridinium bromide is reacted with bromine <2004SL1318>. 

Few other reactions of series of substituted pyridines have been investigated extensively. Dondoni, Modena, and Todesco have measured the rate of N-oxidation of a limited series of pyridines and found a good correlation with normal u-values with a p-value of — 2.23. The A-alkylation of pyridines with alkyl iodides in nitrobenzene has been studied by Brown and Cahn and by Clarke and Rothwell. Unfortunately, the only data available are for the parent compound and for alkyl derivatives, and, since the a-values for the various alkyl groups in a given position are substantially constant, this leaves a correlation of only three independent points. However, the rates of A-alkylation of the j8- and y-alkyl derivatives are so nearly equal that it appears as if no correlation existed. Clarke and Rothwell have also studied the alkylation with allyl bromide in nitromethane at various temperatures, and in this case a more extensive series is available. The authors state that no overall Hammett correlation is obtained however, the j8-substituted derivatives fall on one straight line and the y-derivatives on another one with a different slope. The data are shown in Fig. 2. The line for the j8-compounds, p = — 2.53 0.31, r = 0.95, is seen not to be very good the line for the y-derivatives, p = — 1.42 0.06, r = 0.99, is much more satisfactory. It does not seem likely that the discrepancy is due to the intervention of resonance effects, since in this case one would expect the correlation for the y-derivatives to be poorer than that for the j8-analogs. More extensive studies with a wider variety of substituents would seem very desirable. 

N-Alkylation of oxazolo[4,5-4]pyridines can be achieved in a number of ways. Viaud et al. have reported direct N-alkylation by reaction with alkyl halides (Equation 27 Table 23) or Michael condensation with a range of olefins (Equation 28 Table 24) <1996TL2409>, both methods affording the desired products in good yields. 

Table 23 N-Alkylation of oxazolo[4,5-b]pyridines (Equation 27) <1996TL2409> R Yield (%)...

Smiles rearrangement.1 Attempted N-alkylation of 3-(2,4,6-trichlorophen-oxyacetamido)pyridine (1) catalyzed by TDA-1 is accompanied by a Smiles rear-... 

Reductive amination, a suitable method for N-alkylation of amines, can be carried out using methanolic pyridine-borane under conventional conditions at room temperature for 3-16 h (95JOC5995). Under MWI, alkylation of hexahydroazepine 432 with paraformaldehyde and formic acid gave 70% of A -methylhexahydroazepine 433 after 4min of irradiation (Scheme 85) (01JCR(S)292). Similarly, A -alkyl and A -cycloalkylhydroazepines 434 and 435 were obtained in 28-81% yields. 

The first laboratory synthesis of (1) was carried out by N-alkylation of the 2-N-nitro-imidazolidine system (4) [31], obtained by cyclocondensation of N-nitro-guanidine (3) [32] and ethylenediamine, with 6-chloro-3-chloromethyl-pyridine (5, CCMP) (Scheme 29.2.2.1). 

The scope of various pyridine derivatives with 1-hexene was examined with L45c-Sc/[Ph3C][B(C6F5)4] as the catalyst (Table 5.8). The asymmetric alkylation of 2-Me, 2-Et, 2- Pr, 2- Bu, and 2-phenyl-substituted pyridines 188 could also be achieved similarly in high yields (83-94%) and enantioselectivity (up to 94 6 er) (entries 1-5). Notably, the C—H bond activation reaction occurred selectively at the pyridine unit rather than at the phenyl group in the case of 2-phenylpyridine, which is in contrast with the reactions catalyzed by late transition metal complexes. The iodo, bromo, and chloro substituents in the picoline substrates are well compatible (entries 6-8). No alkylation reaction was observed with unsubstituted pyridine or quinoline, probably due to the poisoning effect of the N atom of pyridine to the metal center. 

Selective C2-alkylation of pyridine N-oxides was successfully developed by Mai (26 —> 31) (2012SL938) (benzyl halides, Scheme 14a) and Fu (26 32) (2013JA616) (secondary and tertiary alkyl bromides (Scheme... 

The compound. [Co(II)(salen)(py)2], has not been well characterized, while a series of [Co(II)(N.R.sal)2(py)23 complexes have been obtained, R being n-alkyl and aryl groups, where py and salen denote a pyridine molecule and a bis(salicylaldehyde) ethylenediiminate anion, respectively, A number of new complexes, [Co(III)(salen)X ] have been synthesized, X being NH, n-alkyl amines, pyridine, H O, NCS , NO and CN", It seems that the Co(III) complexes of this type are obtained as crystals when X denotes one of those ligands which produce ligand field which is stronger than a certain value. 

The N-alkylation of N-substituted (e.g., A-methyl and Af-ethyl) perfluoroalkanesulfonamides with halogenated alcohols (e.g., chloroethanol) is an important reaction in organic chemistry and can be achieved with K2CO3, triethylamine, NaH, or with sodium methoxylate or eth-oxylate. Several patents claim that perfluoroalkanesulfonamidoethanols can be obtained by the reaction of a sulfonamide with ethylene carbonate, oxirane, and related compounds at elevated temperatures in the presence of a base, for example, potassium hydroxide, pyridine, triethylamine, or potassium carbonate. Industrially, the most important process is the alkylation of Af-methyl and A-ethyl perfluoroalkanesulfonamide with ethylene carbonate (see Figure 18.2). ... 

This reaction of MA with ylids has also been proposed by Thyagarajan and Rajagoplan in another case. During an attempt to determine the aromaticity of N-alkyl-2-pyridines such as 10, the condensation with MA was tried. The product that had two maleic acid residues was assigned the structure 11. The following scheme was proposed for the formation of 11, which decomposes on sublimation. 

In 2011, Driver and coworkers synthesized dimebolin by utilizing a ruthenium-catalyzed nitrenoid insertion reaction that they developed (Scheme 16.10) [21]. Azide 49 was readily prepared from 48 by a two-step sequence, consisting of treatment with sodium nitrite and sodium azide, and alkylation of pyridine. Addition of catalytic RuClg hydrate to 49 formed putative ruthenium nitrenoid 50 [22], which then underwent regioselective C-H amination at the C4 position of the pyridinium ion to give y-carbolinium salt 51 in 91% yield. Deprotonation of the N-H group of 51, followed by alkylation with 52, appended the requisite pyridine... 

The formation of N-acylpyridinium ions from acyl chlorides and pyridines is effectively promoted by (la) and i-Pr3SiOTf. The N-acylpyridinium ions are usable for the synthesis of dihydropyridines and their derivatives by alkylation with Grignard reagents [128]. This reaction sequence has been applied to asymmetric alkylation of pyridines using a chiral acyl chloride [129]. 

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