4- thiophene-3-carbaldehydes

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

Thiophene-2-carbaldehyde, 3-bromo-synthesis, 4, 81 Thiophenecarbaldehydes benzothiophene synthesis from, 4, 906 reactions, 4, 807 synthesis, 4, 148 Wittig reactions, 4, 807 Thiophene-2-carb aldehydes bromination, 4, 753 conformation, 4, 33 halogenation, 4, 753 reactions, 4, 72-73 reactivity, 4, 72-73 reduction, 4, 776 Thiophene-3-carb aldehydes conformation, 4, 33 reactivity, 4, 72... 

The reactions of substituted furo[3,2- ]pyrrole-5-carbohydrazides with 5-arylfuran-2-carbaldehydes, 4,5-disubsti-tuted furan-2-carbaldehydes, and thiophene-2-carbaldehyde have been studied <2005CEC622>. The advantage of microwave (MW) irradiation on some of these reactions was reflected in the reduced reaction time and increased yields (Table 8). The series of substituted hydrazones 241-246 was obtained from these... 

Compound 99 reacts with alkynes to generate thieno[2,3-f]thiopyranthiones and thieno[3,2-f]thiopyranthiones. The ratio of isomers is typically 1 1. The reaction proceeds via a cycloaddition reaction and an unprecedented molecular rearrangement (Equation 35) <20050L791>. Thieno[2,3-f]- and [3,2-f]thiopyrans can be prepared from thiophene-2-carbaldehyde in a multistep synthesis that leads to the thienothiopyrans in excellent yields <1999J(P1)2639>. 

Early work on the experimentally established conformational preferences in solution for a variety of other 2-substituted heterocycles is summarized in Table 30. Most of these conclusions have been deduced either from dipole moment measurements in benzene or by the use of lanthanide induced shifts for chloroform solutions. The aforementioned MO studies correctly predict the preferred conformations, (63, R = H) or (64, R = H), of pyrrole-2-carbaldehyde, thiophene-2-carbaldehyde and furfural in the gas phase. 

Chloromethylthiophene shows similar reactivity to benzyl chloride, in that it is readily converted into 2-cyanomethylthiophene, thiophene-2-carbaldehyde (by treatment with hexamethylenetetramine) and a Grignard reagent (345). The latter reacts with electrophiles to give 2-methyl-3-substituted thiophenes e.g. 346). 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of Af-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive to hydroxide addition at the carbonyl carbon than A-methylpyrrole-2-carbaldehyde (76JOC1952). Pyrrole-2-aldehydes fail to undergo Cannizzaro and benzoin reactions, which is attributed to mesomerism involving the ring nitrogen (see 366). They yield 2-hydroxymethylpyrroles (by NaBH4 reduction) and 2-methylpyrroles (Wolff-Kishner reduction). The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

Thiophene-2-carbaldehyde has become extremely cheap and easily available through the Vilsmeier formylation of thiophene. The reactions of thiophene substrates with several iminium salts have been investigated (B-76MI31400). 3-Phenylthiophene gives 4-phenylthiophene-2-carbaldehyde with chloromethylene iminium ion. In the case of 2-methoxy-5-methylthiophene, a dealkylation takes place above 50-70 °C. If the intermediate iminium salt (91) is formed at 20 °C and then hydrolyzed, the aldehyde (92) is obtained. 

Thiophene-2-carbaldehyde condenses easily with ethyl acetoacetate or ethyl nitroacetate in the presence of TiCU and a tertiary organic base (pyridine or N- methylmorpholine) at 0-22 °C, giving (361) (72T663). Base-catalyzed condensation of thiophene-2-carbaldehyde with methyl (methylthio)methyl sulfoxide followed by treatment with HC1 in alcohols gives (2-thienyl)acetic esters (Scheme 114) (79BCJ2013). 

Hydroxylamine-O-sulfonic acid converts thiophene-2-carbaldehyde into the nitrile in high yield under mild conditions. 3-Azidothiophene-2-carbonitrile has been prepared thus and used for synthesizing many types of fused thiophenes (80JHC1765). Vapour-phase ammoxidation of thiophene-2-carbaldehyde to the nitrile has also been described (78CPB2838) the Mo-Bi-Sb (molar ratio 3 5 2) mixed oxide catalyst was found most suitable. 

The C-thioacylation of l-alkyl-2-methyltetrahydropyrimidines and 1,2-dimethyl-dihydroimidazole has been achieved by reaction with thiophene-2-carbaldehydes in the presence of sulfur (Scheme 115) (82T1673). The yield of product is better with thiophene-2-carbaldehydes (30-40%) than with benzaldehyde. 

Wittig reactions on thiophenecarbaldehydes have been used to extend the side chain. Thus thiophene-2-carbaldehyde and its vinylogues (362) react with the alkyltriphenylphos-phonium bromides (363) in presence of NaOMe to form the vinylthiophenes (364) (70T1291). Similarly, thiophene-2,5-dicarbaIdehyde leads to (365). The Wittig reaction has also been... 

Benzo[6]thiophene-2-carbaldehyde can be converted to 2-(l, 2 -epoxyethyl)-benzo[6]-thiophene by reaction with trimethylsulfoxonium iodide and sodium hydride or with diazomethane. However, the 3-carbaldehyde is reported to give the 3-acetyl derivative on treatment with diazomethane (Scheme 120) (70AHC(ll)177). 

Thenaldehyde (thiophene-2-carbaldehyde) is readily available via the Vilsmeier-Haack reaction of DMF with thiophene catalyzed by phosphorus oxychloride. The Sommelet reaction with 2-chloromethylthiophene also gives reasonable yields (63AHC(l)l). Likewise, thiophene is readily acylated with acyl anhydrides or acid chlorides (equation 14), using mild Friedel-Crafts catalysts, such as tin(IV) chloride, zinc chloride, boron trifluoride, titanium tetrachloride, mercury(II) chloride, iodine and even silica-alumina gels or low-calcium-content montmorillonite clays (52HC(3)l). 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

Oxidation of the salt (125) with active manganese dioxide gives a high yield of thiophene-2-carbaldehyde (67G397). Amines, both primary and secondary, readily cleave the ring with expulsion of hydrogen sulfide and generation of the iminium species (128) in up to 90%... 

The addition of ZnBi 2 to die tandem 1,3-azaprotio cyclotransfer-cycloaddition of a ketoxime with divinyl ketone results in rate enhancement and the exclusive formation of l-aza-7-oxabicyclo[3.2.1]octan-3-ones.79 The 1,3-dipolar cycloaddition of 1-aza-l-cyclooctene 1-oxide with alkenes produces the corresponding isoxazolidines in high yields with a minimum of polymeric material.80 The cycloaddition of thiophene-2 -carbaldehyde oxime with acetonitrile and methyl acrylate produces the 1,3-dipolar adduct, substituted isoxazolidines, and not the previously reported 4 + 2-adducts.81 Density functional theory and semi-empirical methods have been used to investigate the 3 + 2-cycloaddition of azoxides with alkenes to produce 1,2,3-oxadiazolidines.82 The 3 + 2-cycloaddition of a-nitrosostyrenes (62) with 1,3-diazabuta-l,3-dienes (63) and imines produces functionalized cyclic nitrones (64) regioselectively (Scheme 22).83... 

Bromo-2-thienyl-thiophene-2-carbaldehyde (128), obtained from the photochemical coupling of 5-iodothiophene-2-carbaldehyde and 2-bro-mothiophene, can be reduced with NaBH4 129 was treated with propyne, copper iodide, and Pd(PPh3)4 under phase-transfer conditions to give a natural bithiophene 130 isolated from Arctium lappa (87JOC5243). 

The use of methyltriphenylphosphonium bromide and MeSOCH2 on 5-bromo-2-thienyl-thiophene-2-carbaldehyde (128) furnished the corresponding olefin 133. The reaction with propyne in this case furnished a natural bithiophene 134 isolated from Tagetes minuta (86G747). 

Catalytic reduction of thiopyrylium salts under forcing conditions yields tetrahy-drothiopyrans, but oxidation with manganese dioxide of the unsubstituted thiopyrylium cation (first obtained by Pettit [100]) affords thiophene-2-carbaldehyde in a reaction without analogy to pyrylium salts [101], Like a- and y-benzylic positions in pyrylium salts, methyl(ene) groups of alkyl substituents in thiopyrylium cations are usefully acidic and as such the corresponding anhydrobases may be trapped by various nucleophiles. 

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