3-Alkylpyridine synthesis

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

In Baldwin s formal total synthesis of haliclamines A and B, a Suzuki coupling of 3-bromopyridine was the central operation [52], Chemoselective hydroboration of diene 66 employing 9-BBN occurred at the less hindered terminal olefin. Suzuki coupling of the resulting alkylborane with 3-bromopyridine then furnished alkylpyridine 67 as a common intermediate for the synthesis of haliclamines A and B. 

A few pyrolytic methods of synthesis are known, leading directly to the formation of pyridine rings by formation of the /3, y-bond. Alkylpyridines are obtained when unsaturated imines (116) or (117) are passed over heated zeolites (80IZV655) or alumina (72IZV2263). More dehydrogenation is achieved by the use of nickel or alumina, as in the synthesis of tetrahydroquinolines (118) or octahydrophenanthridine (119) (78IZV1446). 

Attack by phosphorus nucleophiles on pyridinium salts is well established, and is the basis for a method for the regioselective synthesis of 4-alkylpyridines,212 and of 1-alkylisoquinolines.213 Although the phosphonate adducts (67) were obtained in high yields in all cases examined (R = Me, Et, CH2=CHCH2, Bu, PI1CH2), the final step gave satisfactory yields only in the case R = Bu (Scheme 25). 

The greatest amount of work has been done on the oxidation of alkylpyridines and pyridine itself. However, this reported synthesis technology was neither modern nor necessarily optimum. 

Stamicarbon217> claims the use of anion exchange membranes in divided cells for the electrochemical oxidation of alkylpyridines to the corresponding pyridinecarboxylic acids. Finally, Takeda 218) has used the principle of paired synthesis in a divided cell for the simultaneous generation of synthetic intermediates. 

The gas phase acid-catalyzed synthesis of pyridines from formaldehyde, ammonia and an alkanal is a complex reaction sequence, comprising at least two aldol condensations, an imine formation, a cyclization and a dehydrogenation (9). With acetaldehyde as the alkanal, a mixture of pyridine and picolines (methylpyridines) is formed. In comparison with amorphous catalysts, zeolites display superior performance, particularly those with MFI or BEA topology. Because formation of higher alkylpyridines is impeded in the shape-selective environment, the lifetime of zeolites is much improved in comparison with that of amorphous materials. Moreover, the catalytic performance can be enhanced by doping the structure with metals such as Pb, Co or Tl, which assist in the dehydrogenation. 

A unique method for preparing 4-alkylpyridines consists in treatment of pyridine with aliphatic anhydrides in the presence of zinc dust. The intermediate l,4-diacyl-l,4-dihydropyridines are not isolated but are further reduced to the 4-alkylpyridlnes by the action of zinc dust and acetic acid. The procedure is illustrated by the synthesis of 4-ethyl-pyridine (38% over-all). ... 

This system may be recommended for the quick exploration of new synthetic applications in research laboratories which do not specialize in organometallic techniques because the cobalt salts can be used in the hydrated form under air, and no sophisticated ligands are necessary. Cobalt(I) halide complexes of the type [XC0L3] having a moderate activity in the synthesis of 2-alkylpyridines are also easily accessible (eq. (3)) [19]. 

The preferred catalysts for the one-step co-cyclization of acetylene and acetonitrile (or alkyl cyanides in general) to give a-picoline (or 2-alkylpyridines) are i/ -Cp-cobalt cod or / -trimethylsilyl-Cp-cobalt cod (eq. (2)). The a-picoline synthesis is best performed in pure nitrile without any additional solvent [5 d]. 

AKYLPYRIDINIUM AND 3-ALKYLPYRIDINE COMPOUNDS FROM MARINE SPONGES, THEIR SYNTHESIS, BIOLOGICAL ACTIVITIES AND POTENTIAL USE... 

We present an overview of the structures for 3-alkylpyridine and 3-alkylpyridinium compounds that have been isolated, taking into account the structural characterization of alkylpyridinium compounds and discussing the central role played by mass spectrometry. Concerning their synthesis, both the natural pathways and organic synthesis of pyridinium alkaloids are reviewed. Synthetic aspects of 3-alkylpyridines have been taken into account only where relevant for structural modifications or for the assignment of absolute configurations. Finally, biological activities of both 3-alkylpyridine and 3-alkylpyridinium compounds and the potential use of the latter are discussed. 

Later, Baldwin and co-workers reported an efficient synthesis of the whole series of cyclostellettamines A-F [44]. The appropriate monomeric 3-alkylpyridine was prepared, as illustrated in Fig. (28), from 3-methylpyridine (81), or from 3-pyridin-3-ylpropanal (82) when tridecan-1,13-diol was unavailable as a commercial reagent. 

The procedure can also be applied in the case of substrates 87 and 88 bearing different chains. This is the case for the synthesis of the asymmetrical bis-pyridinium macrocycle, a precursor of haliclamine A [50]. As illustrated in Fig. (34), the 3-alkylpyridine derivatives 93 and 94, obtained by the commercially available thiophene 92, lead to the dimeric macrocycle via the Zincke procedure, which affords obtaining haliclamine A (49) by reduction. 

The addition of nucleophiles to 1-acylpyridinium salts has surfaced as a powerful method for the synthesis of substituted pyridines. The 1-acylpyridinium salts are formed in situ by adding an acyl chloride to a pyridine in an aprotic solvent such as tetrahydrofuran. The formation of the 1-acylpyridinium salt is very rapid and will occur in the presence of various organometallics without significant competition from the reaction of the nucleophile and the acyl chloride. The addition of ethyl chloroformate to a mixture of pyridine and ethylmagnesium bromide gives 1,2- and 1-4-dihydropyridines 29 and 30 in a ratio of 64/36. Although these dihydropyridine intermediates can be aromatized with hot sulfur to 2- and 4-alkylpyridines, the poor regioselectivity makes this procedure unattractive. 

A novel method for the synthesis of 2-alkylpyridines and 2-pyridine-carbinols starts from pyridine and involves the pyridine Reissert analog 175. Anion formation with sodium hydride and alkylation with alkyl halides afford the 2-alkyl-l-ethoxycarbonyl-2-cyano-1,2-dihydropyridines 176, which on heating with HMPT/Nal (HMPT = hexamethylphosphorous triamide) give 2-alkylpyridines 177. Condensation of the anion with benzaldehyde or o-tolualdehyde leads to 2-pyridinecarbinols (85CI(L)125). The reaction of 1,4-bis(trimethylsilyl)-1,4-dihydropyridine (178) with aldehydes (and ketones) in... 

The reactions shown in this section illustrate the versatility of Af-substituted pyridines in the synthesis of condensed heterocycles containing pyrrole. Some of the cyclizations proceed without the need for externally applied heat [2419, 2422,2830,2980a], and for most of the cyclizations, the conditions are relatively mild. The preformed ylide is used in some of the reactions while in others, it is generated in situ. It is even possible to react a 2-methylpyridine with an Af-alkyl-ating agent, such as bromoacetone, and then cyclize the intermediate iV-alkyl derivative by heating with sodium acetate-acetic anhydride or carbonate without isolating either the intermediate. /V-alkylpyridine or the ylide [2157, 2295, 2393, 3512]. 

Many alkylpyridines are manufactured commercially by chemically complex processes which often produce them as mixtures. A good example is the extraordinary Chichibabin synthesis, in which paraldehyde and ammonium hydroxide react together at 230 °C under pressure to afford 52% of 5-ethyl-2-methylpyridine so here, four mol equivalents of acetaldehyde and one of ammonia combine. Also of commercial significance is the cobalt-catalysed interaction of a nitrile and acetylene. ... 

The most general approach to indolizines is the Chichibabin synthesis which involves quaternisation of a 2-alkylpyridine with an a-haloketone, followed by base-catalysed cyclisation via deprotonation of the pyridinium a-methyl which is of... 

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. 

Theonelladins A-D A novel alkylpyridines (15-18) were isolated from Theonella swinhoei and exhibit mild activities in vitro against murine lymphomas and epidermoid carcinoma [29]. Two stereoselective total syntheses of theonelladins A-D have been published to date. A general strategy was used involving the construction of a common carbon skeleton 15a (see Scheme 4). Although the successful completion of the synthesis of 15-18 was achieved, the final introduction of the amino group into the molecule was not a clean step. 

Synthesis of 3-alkylpyridines. Part 2. Synthesis of both enantiomers of Niphatesine C. Bracher, F. and Papke, T. J. Chem. Soc., Perkin Trans. 11995, 2323. 

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