Pyridines chloromethylation

Acidic hahde catalysts used in chloromethylation include (44) ZnCl, ZnCl2 + AlCl, SnCl, SnCl, AlCl +ketones, AlCl + pyridine, AlCl ... 

Etherification. The reaction of alkyl haUdes with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraaHyl ether is formed on reaction of D-mannitol with aHyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional aHyl bromide, leads to hexaaHyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trim ethyl chi oro s il an e in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

Cyanuric acid readily dissolves in aqueous formaldehyde forming tris(hydroxymethyl)isocyanurate [10471-40-6] (THMIC) which can be isolated by evaporation (11). THMIC in turn reacts with acetic anhydride to yield tris(acetoxymethyl)isocyanurate [54635-07-3], either thionyl chloride or phosphoms pentachloride to give tris(chloromethyl)isocyanurate [63579-00-0], and phenyl isocyanate in pyridine to yield tris(A/-phenylcarbamoxymethyl) isocyanurate [21253-39-4] in 87% yield (65). Reaction of CA with paraformaldehyde and 2,6-dicyclohexylphenol yields... 

Pyridine, 4-(chloromethyl)-l,4-dihydro-4ff-azepines from, 7, 524 ring expansion, 7, 543-544 Pyridine, 2-chloro-6-trichloromethyl-as bactericide, 2, 514 Pyridine, 2-cyano-ions... 

Chloromethyl)pyridine hydrochloride [1822-51-1] M 164.0, m 170-175°, 172-173°, pK , -5.6. Purified by recrystn from EtOH or EtOH-dry Et20. It melts between 171° and 175° and the clear melt resolidifies on further heating at 190° and turns red to black at 280° but does not melt again. The picrate-hydrochloride (prepared in EtOH) has m 146-147°. The free base is an oil, [Mosher and Tessieri J Am Chem Soc 73 4925 1951.]... 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

A solution of 82 parts by weight of 7-chloromethyl-pyridine-hydrochloride in 60 parts of water is added dropwise, at 0 to 5°C, to 250 parts by weight of a 50% aqueous ethyl amine solution. The mixture is stirred for 1 hour at 60°C, whereupon it is cooled down and separated in the cold with solid potassium hydroxide. The oil formed is separated off, dried over potassium hydroxide and distilled. The ethyl-(7-picolyl)-amine formed boils over at 103° to 104°C under a pressure of 13 mm Hg. Its dihydrochloride melts at 198° to 200°C. 

Curiously, 6-(chloromethyl)-4-methyl-2-methylene-3-phenyl-3-azabicyclo[4.1.0]hept-4-ene-l,5-dicarbonitrile (31), obtained from 4,4-bis(chloromethyl)-2,6-dimethyl-l-phenyl-1,4-dihydro-pyridine-3,5-dicarbonitrile, rearranges via 4-(chloromethyl)-7-methyl-2-methylene-l-phenyl-2, 5-dihydro-l//-azepine-3,6-dicarbonitrile (32) to yield the 4-(chloromethylene)-4,5-dihydro-1//-azepine 33 as the final product.127... 

Azepine-3,6-dicarboxvlates, e. g. 14, formed by solvolysis of 4-(chloromethyl)-l, 4-dihydro-pyridine-3,5-dicarboxylates(see Section 3.1.1.4.1.5.), readily undergo thermal and base-induced isomerizations to 3//-azepines, e.g. 15.29... 

Hoomaert has studied Diels-Alder reactions of pyridine oquinodimethane analogs generated from functionalized o-bis(chloromethyl)pyridines <96T(52)11889>. The photochemical cycloaddition of 2-alkoxy-3-cyano-4,6-dimethylpyridine with methacrylonitrile gives a bicyclic azetine, 6-alkoxy-3,5-dicyano-2,5,8-trimethyl-7-azabicyclo[4.2.0]octa-2,7-diene, in moderate yield <96CC1349>. Regiospecific hydroxylation of 3-(methylaminomethyl)pyridine to 5-(methylaminomethyl)-2-(17/)-pyridone by Arthrobacter ureafaciens has been reported <96MI173>. 

Iodide 48), As(OCH2)3CMe, S(t-Bu)2 (79), and pyridines 80) do not react with CpMo(CO)3Me in THE or MeCN. However, interaction between Na[CpMo(CO)3] and 2-(chloromethyl)pyridine has afforded (XIX) 144),... 

Some 2-(chloromethyl) derivatives of kojic acid form quaternary salts with tertiary aliphatic amines80-86 and with thiourea.83 Quaternary pyridin-ium salts (LXII) were obtained by Looker and Okamoto81 from LX and LXI in dry pyridine. Water-insoluble derivatives of kojic acid could be rendered water-soluble by these quaternizations. 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

Bromo substituents in the 6- and 6 -positions of 2,2 -bipyridines are particularly reactive, being readily converted to amino,cyano, ° al-koxyl, hydrazino, chloro, and hydrogen groups and by way of the corresponding lithio derivatives to carboxyl, methyl, aldehyde or alkylcarbonyl, and other groupings. 6,6 -Dibromo-2,2 -bi-pyridine also reacts with the disodium derivatives of polyethylene glycols to give crown ethers akin to 100, and 6,6 -bis(chloromethyl)-2,2 -bi-pyridine " and the derived 6,6 -bis(mercaptomethyl)-2,2 -bipyridine... 

H-Azepines are more rare than 1H- or 3H-azepines and only a few synthetic approaches have been developed. Of these the two main methods involve the ring expansion of six-membered heterocycles. Early studies revealed that highly substituted 4f/-azepines (269) result from the base-catalyzed ring expansion of 4-(chloromethyl)-l,4-dihydro-pyridines (267 Scheme 37). The reaction was found to be temperature and solvent sensitive, and azepines (268)-(270) have been isolated and characterized. However, later studies (68JCS(C)1675) on cyano derivatives (267 E = CN) show the reaction to be even more... 

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