Grignard reagents with pyridine oxides

The reaction of a Grignard reagent with quaternary salts obtained from. V-oxides of pyridine, quinoline, and their homologs has been utilized401,402 for the preparation of 2-alkylated compounds. 

Indeed, the addition of the Grignard reagents to pyridine M-oxides in THF at room temperature followed by treatment with acetic anhydride at 120 °C affords 2-substituted pyridines in good to high yields (Scheme 13) [35]. 

It is worth noting that the addition of the Grignard reagents to pyridine IV-oxides in THF at low temperature (from —78 to —20 °C) and treatment with trifluoroacetic anhydride (TFAA) provide an efficient general procedme for the synthesis of substituted pyridines (Scheme 14). The method is compatible with a range of functional groups, such as esters, halogens, and nitriles [36]. 

Similarly, the reaction of Grignard reagents with quaternary salts from pyridine 1-oxides promises to be of practical value i. Thus, 1-ethoxypyri-dinium bromide reacts with ethyl magnesium bromide to give 78 per cent of 2-ethylpyridine. The picoline 1-oxide quaternary salts react equally efficiently in the case of l-ethoxy-3-methylpyridinium bromide, the product is almost exclusively the 2-alky 1-3-methylpyridine. The reaction probably proceeds as shown, but a side-reaction always generates some of the parent base ... 

There are several reports that alkylated pyridine N-oxides react with Grignard reagents to give 2-alkylated pyridines (50,51). 

The synthesis of 4-substituted pyridines via 1,4-addition of Grignard reagents to pyridinecarboxamides has been studied. After addition of Grignard reagents to pyridinecarboxamides 32, oxidation of the dihydropyridine intermediates with NCS or oxygen provides the substituted pyridines 33 in good yields <95T(51)9531>. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Alkylpyridines.3 Highly selective alkylation of pyridine at C4 is possible by quatemization with this triflate followed by reaction with a Grignard reagent. Substitution occurs with almost complete regiospecificity ( > 99%) to give 4-alkyl-l, 4-dihydropyridines, which are oxidized by oxygen to 4-substituted pyridines (equation 1). 

An improved route to the key intermediate 326 was also developed (165). Namely, 322 was converted to the monoprotected 1,4-dione 327 by sequential addition of the Grignard reagent derived from 2-(2-bromoethyl)-2-methyl-l,3-dioxolane followed by oxidation of the resulting benzylic alcohol with pyridin-ium dichromate (PDC). The ketone 327 was then smoothly transformed to the 2-azadiene 328 by olefination with BAMP. The regioselective addition of n-butyllithium to 328 as before followed by alkylation of the resulting metalloenamine with benzyl A-(2-bromoethyl)-A-methylcarbamate and acid-catalyzed hydrolysis furnished 325, which was converted to the cyclohexenone 326 by base-induced cycloaldolization and dehydration. 

The starting compound 251 was reduced to 252 with sodium borohydride. The latter was heated under reflux in 6% sulfuric acid in methanol to afford compound 253. Treatment of the latter with maleic anhydride at 170° for 3 hr afforded compound 254. Bisdecarboxylation of 254 with dicarbonyl bistriphenylphosphinenickel in anhydrous diglyme under nitrogen at reflux temperature for 6 hr afforded the olefin 255 in 69% yield (171). The latter was reduced with lithium aluminium hydride to the primary alcohol 256, which was oxidized to the aldehyde 257 with Ar,A -dicyclohexylcarbodiimide, dimethyl sulfoxide and pyridine in dry benzene. Treatment of the aldehyde 257 with an excess of the Grignard reagent prepared from l-bromo-3-benzyloxybutane afforded a mixture of diastereoisomers represented by the structure 258. 

Certain pyridines react with Grignard reagents in the 1,4-manner when substituted by electron-withdrawing groups such as a carboxamide <2000J(P1)4245, 2005JOC2000>. The intermediate dihydropyridine can conveniently be oxidized to the pyridine structure. An example of this is seen in the reaction of 6-chloronicotinic acid derivative 125 with an excess of o-tolylmagnesium chloride, followed by oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone... 

Grignard reagents were said to give low yields of products with the A-oxides themselves. For example, phenylmagnesium bromide and pyridine A-oxide yielded a small amount of 2-phenylpyridine.335-337 Poor yields were also reported with sec-butyl and -butylmagnesium bromides.338 It has recently been reported, however, that pyridine... 

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