Thieno-pyridines, halogenation

C led to metallation in the 2-position and not addition to the azomethine bond. Reaction with DMF gave the 2-formyl-derivative. The 3-lithio-derivative was obtained by halogen-metal exchange with 3-bromothieno[2,3-6]pyridine. Further studies of the chlorination and 5-oxidation of thieno[2,3-6]pyridine have been reported. The mass-spectral fragmentation patterns of a series of thieno-pyridine A -oxides, 5-oxides, and 55-dioxides have been elaborated. The reductive acetylation of nitro-thieno-pyridines has been studied. Polymethine... 

Nucleophilic halogenations tend to favor the pyridine moiety. The Meisenheimer reaction of thieno[3,2-6]pyridine N-oxide (125) gave only a 24% yield of a 1.4 1 mixture of the 5- and 7-chloro derivatives. Nucleophilic displacement of a 7-nitro group provided a more satisfactory route to the 7-chloro (73%) and 7-bromo (39%) derivatives (85JHC1249). 

A modification of the Pomeranz-Fritsch synthesis <1983JCXI3344> is used in the preparation of thieno[2,3- l-pyridine and its 2-substituted derivatives. An aryl aldehyde undergoes condensation with aminoacetaldehyde dimethyl acetal giving a Schiff base which cyclizes to form an imine product. The imine is treated with ethyl chloroformate followed by triethyl phosphate to form an intermediate carbonate-phosphonate, which then cyclizes to the thienopyr-idine product (Scheme 22) <2004S1935>. Very low product yields (2-17%) are obtained for alkyl- and phenyl-substituted thieno[2,3- ]pyridines however, the unsubstituted product and 2-halogenated derivatives give moderate yields (28-44%). 

Thieno[2,3-. ]pyridines, 115, form via a condensation reaction with halogenated carbonyl compounds, as shown in Scheme 35. Depending on the base strength of the reagent and reaction conditions, intermediate 114 may be isolated <2005CCA63>. 

Thieno[3,2-c]pyridin-4-one (277) has been prepared by thermal cyclization of 2-thienyl-vinyl isocyanate (Scheme 73) (70BSB301). The derived chloro compound (278) can either be reduced by zinc-acetic acid to (260) or be readily converted into other derivatives by nucleophilic substitution of the halogen. The formation of 4-thiomethyl-6,7-dihydro-thieno[3,2-c]pyridine (280) by cyclization of the isothiocyanate (279) has also been reported (equation 23) (73GEP2318399). 

Depending on the reaction conditions, halogenation of thieno[2,3-Z>]pyridine (20) can lead to a variety of products resulting from substitution, addition, and oxidation reactions. 2,3-Dibromo-thieno[2,3-/)]pyridine is produced by the reaction of compound (20) with bromine in an aqueous carbon tetrachloride system and the 2,3-dichloro-2,3-dihydro derivative is formed from the same starting material upon treatment with chlorine in chloroform/water or with iodobenzene dichloride in aqueous acetonitrile (70JHC81, 71JHC931). 

Similarly to the analogous reaction with furo[2,3-Z>]pyridines, metallation of compound (20) with n-butyllithium in TMEDA followed by the addition of DMF afforded the 2-formyl derivative in 66% yield. Likewise, metallation of the isomer (22) under the same conditions afforded the 2-formyl derivative in comparable yield <84JHC785>. Introduction of a carbonyl group at C-3 of compound (20) was accomplished by halogen-metal exchange between 3-bromothieno[2,3-6]pyridine and n-butyllithium. Table 45 lists some of the thieno[2,3-Z>]pyridine derivatives formed by this method <74JHC355>. 

Substitution (usually nitration or halogenation, but in a few cases other reactions) has been reported at the 3-position of compounds 8.110 that is, for furo[2,3-fj]pyridine (and for the corresponding 3,2-b, 2,3-c, and 3,2-c isomers) (75JHC705 84JHC725), 2-substituted furo- or thieno[2,3-6]-pyrazines (78RTC151), thieno[2,3-6]pyridine (and the 3,2-b, 2,3-c,... 

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