Pyridine, 3-chloro-, synthesis

Additional pyrimido[4,5-f ]quinoline syntheses include one involving the action of cyanogen bromide on 2-chloro-3-cyanoquinoline similar to that described for pyridines (Section 2.15.5.5.1) (78JHC877), and a synthesis of pyrimido[4,5-fe]quinoline-2-carboxylic... 

Imidazo[4,5-6]pyridine, 7-chloro-l-(tri-0-acetyl-j3-D-ribofuranosyl)-synthesis, 5, 617... 

A third synthesis which has resulted in the preparation of rieinine and a number of its derivatives is due to Schroeter, Seidler, Sulzbacher and Kanitz,i2 who foimd that cyanoacetyl chloride polymerises spontaneously to 6-chloro-2 4-dihydroxy-3-cyano-pyridine. The di-sodium derivative of this with methyl sulphate produces A -methyl-6-chloro-4-hydroxy-3-cyano-2-pyridone (6-chlororicininic acid), the mono-sodium derivative of which, with methyl bromide or sulphate, is converted into 6-chlororicinine and the latter is reduced by zinc and sulphuric acid to rieinine. A fourth synthesis, starting from 3-nitro-4-pyridone, is due to Reitmann. ... 

The base-catalyzed Michael addition of 2-chlorocyanoacetate to a,p-unsaturated ketones or aldehydes affords 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and usefiil in the synthesis of 2,Xdisubstituted pyridines <95T(51)13177>. 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

The synthesis of the pyridine acid 3 is outlined in Scheme 9.3. The 2-chloro-5-trifluoromethylpyridine was coupled with hydroxybutyric acid in the presence of an excess of sodium hydride to afford acid 3 in around 35% yield after necessary purification. 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

The synthesis of diphenylmethylpyrimidotriazinones 243 was achieved (86MI2) by the reaction of 3-chloro-5,6-diphenyl[l,2,4]triazine with chlo-ro- or cyanoacetamides in pyridine to give 242, which cyclized with sodium acetate in acetic acid. 

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3-dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloro-iV,jV-dimethyl-armnotrimethinium hexafluorophosphate afforded 8 in 97% yield . Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. 

Another synthesis of halopyridines, unique to pyridine and other JV-containing heteroarenes, involves transformation of pyridine N-oxide into the corresponding pyridone followed by halogenation. In one case, treatment of 3-chloro-2,4 -bipyridine-l -oxide (8) with acetic anhydride produced the pyridone, which was then converted to dichloride 9 with POCls/DMF [7]. 

The one-pot synthesis of 4-azaindole is also initiated by photoirradiation 3-amino-2-chloro-pyridine and acetaldehyde are the starting materials (Fontan et al. 1981 Scheme 7.37). 

Pyrazine and pyrimidine heterocycles, like pyridine, are electron deficient and need the presence of an activating/electron-releasing group to allow efficient electrophilic nitration to occur. An example of this strategy is seen during the synthesis of 2,6-diamino-3,5-dinitropyrazine (ANPz) (183) where one of the chloro groups of 2,6-dichloropyrazine (180) is substituted for a... 

These reactions were applied to the preparation of macrocycles containing pyridine and other heterocycles as shown in Scheme 12 [84JCS(P1)1833]. The starting material for this synthesis is 2,6-dichloropy-ridine which was converted to 2-chloro-6-methylthiopyridine quantitatively when the reaction was carried out under a liquid-liquid binary phase... 

In 1972 Wright prepared 3-chlorothieno[3,2-6]thiophene-2-carbonyl chloride (94) in 11-13% yield by heating 3-(2-thienyl)acrylic acid, thionyl chloride, and pyridine, a method of synthesis of benzo[6]-thiophene-2-carbonyl chloride derivatives. " Methyl 3,5-dichloro-thieno[3,2-6]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When fte reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

In order to introduce substituent variation on the amino group at the pyrazolo[l,5- 7]pyridine 7-position, a modified procedure was investigated where a 7-chloro substituent was carried through the synthesis. However, this procedure was compromised by the fact that dimethylamine displacement of the chlorine also occurred during formation of the enamino ketone 1000, giving the dimethylamino compound 1001 as a major by-product <2003X9001, 2005BMC5346>. 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

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