Grignard pyridine derivatives

Isoquinolinium 369 and [2,7]naphthyridin-2-ium 371 salts have also been used for the preparation of 2,3,8,8a-tetrahydro-57/-oxazolo[3,2-tf]pyridine derivatives (Scheme 98) addition of Grignard reagents to 369 is followed by a spontaneous cyclization to 370 <1998JOC1767> while an asymmetric version of the Bradsher cycloaddition between 371 and chiral enol ether 372 gives 373 in good yield and selectivities <1996TL7019>. 

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. 

Cyclizations of the type (156) - (151) include the conversion of (a) carboxylic acids (218 X = O, S) into diones (219) (34% yield) under acidic conditions <74MI 715-01) (b) pyridine derivative (220) into the pyrano[3,2-c]pyridine (221) (72% yield) via an intramolecular Grignard reaction <82JCS(P1)93> and (c) a 1 1 mixture of diastereoisomers (222) into a 1 1 mixture of diastereoisomeric pyranopyrans (223) via a HSnBu3-mediated free radical cyclization <93LA629>. The diethyl ethoxymethylenemalonate (EMME) synthesis of 3-ethoxycarbonyl-4-naphthyridone derivatives has been discussed in CHEC-I <84CHEC-i(2)58i>. 

This type of reaction could not be effected using alkyl-lithium or alkyl-Grignard reagents. Also, the products represented by 2.225 and 2.227 with presumed divalent cobalt centers as offered by Johnson and coworkers should be considered as being tentative only no conclusive data were actually given in support of the proposed formulations. There is also a discrepancy between the main textual body and the experimental section of the 1973 paper by Johnson and coworkers as to which Co(III) derivative was actually used in these reactions. In the main body, it is stated that the square planar (implying pyridine-free) Co(III) corrole is used, whereas in the experimental section, it is stated that the pyridine derivatives were used. 

Ethyl chloroformate added dropwise at 0° during 10 min. to a mixture of A-tert-butylpyridine and a soln. of er -butylmagnesium chloride in tetrahydrofuran, then treated at 0° with water -> l-ethoxycarbonyl-2,4-di-terr-butyl-l,2-dihydro-pyridine. Y 55%, - In the absence of ethyl chloroformate, pyridine derivs. react poorly with Grignard compds. F. e. s. G. Fraenkel, J. W. Cooper, and C. M. Fink, Ang. Ch. 82, 518 (1970). 

Similarly, thiazole reacts at —60°C with phenyllithium affording thiazol-2-yllithium (156) (13, 437). As in the case of the Grignard derivative, thiazolyllithium does not rearrange under heating as does the adduct of pyridine and butyllithium (438). 

Adition of Grignard reagents. Reaction of 2,3-O-isopropylidene-D-ribose (62) with ethynyl magnesium bromide gives l,2-dideoxy-4,5-0-iso-propylidene-D-a//o-hept-l-ynitol (63), which is then converted into its 7-O-trityl ether (64). Treatment of 64 with TsCl/pyridine provides 2,3-0-isopropylidene-5-0-trityl-a-D-ribofuranosylethyne (65) which upon deprotection affords derivative 66 (Scheme 22).89... 

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... 

A-Acylpyridinium salts are more reactive than the A-alkyl derivatives and afford more stable dihydropyridine products on addition of nucleophiles. Organocuprates are utilized for entry into 2-alkynyl-substituted quinoline systems (Equation 53) <2005TL8905>. They have the advantage of superior selectivity over Grignard reagents, which yield a mixture of the 2- and 4-substituted products. The reaction has been expanded to include isoquinolines and pyridines. 

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