Furan Vilsmeier formylation

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

In the case of 1,3-diphenylfuro[3,2-c]pyrazole (58) most electrophilic substitutions, e.g., Vilsmeier formylation, Friedel-Crafts acylation, and monobromination, take place in the furan ring. Excess bromine gives the second bromination in the 4-position of the 1-phenyl group, but nitration gives the l-(4-nitrophenyl) derivative and a second, uncharacterized, product (78YZ204). 

Partial rate factors, relative to pyrrole, for trifluoroacetylation at the 5-position of some 2-alkylpyrroles are Me, 23.8 Et, 24.8 r-Bu, 24.8 [72JCS(P2)71]. Thus, the activating effect of a 2-alkyl group is far lower than that found in furan and thiophene, and this is confirmed in Vilsmeier formylation and acetylation of pyrroles where 2-methyl activates by factors of 15 and 42, respectively [77G339, 77JCS(P2)1284],... 

Benzo[6]furan, when treated with nitric and acetic acids, yields 2-nitrobenzo[Z ]furan. When the ViLSMEiER formylation is used, 2-benzo[Z ]furaldehyde is obtained, and 2-lithiobenzo[Z ]furans are formed with butyllithium. 

Vilsmeier formylation of furans is a good route to formylfurans, though the ready availability of furfural as a starting material, and methods involving lithiated furans (section 15.4.1) are important. Formylation of substituted furans follows the rule that the strong tendency for a-substitution overrides other factors, thus both 2-methylfuran and methyl furan-3-carboxylate give the 5-aldehyde 3-methylfuran gives mainly the 2-aldehyde. ... 

Furthermore, fiirans are susceptible to Vilsmeier formylation (with POCI3/DMF (dimethylformamide)), which gives rise to furan aldehydes, for example, 11 from 2-methylfuran (via a-attack and hydrolysis of the primarily formed iminium ion) ... 

Electrophilic reactants attack benzo[b]furan preferentially at the 2-position. Thus, nitration with HNO3 in acetic acid yields 2-nitrobenzo[b]furan, while N2O4 in benzene leads to a 4 1-mixture of 3- and 2-substitution products. On Vilsmeier formylation (DMF/POCI3), benzo[b]furan-2-carbaldehyde (1) is obtained. Condensation with aldehydes in the presence of Bi(OTf)3 as catalyst leads to bis-(2-benzo[b]furyl)methanes (3) in... 

Acylation and metallation studies on monomers, dimers, trimers, and tetramers containing linked thiophen, pyridine, pyrimidine, furan, benzofuran, benzothiophen, and indole moieties have been published/ Deuteriation, halogenation, and diazo-coupling reactions of 2-oxo- and 2-thioxo-l,2-dihy-dropyrimidinium salts have been studied and compared with results for 2,2-dialkyl-1,2-dihydropyrimidinium and 2,3-dihydro-1,4-diazepinium salts in order to demonstrate the effect of an adjacent 0x0- or thioxo-group on the properties of a 1,5-diazopentadienium system/ Vilsmeier formylation of, and tautomerism in, 2-hydroxypyrazolo[5,l-h]quinazolone and l-phenylpyrazolo[5,l-A]-quinazoline-2,9-dione have been studied/ The pyrazolo[3,4-c]pyrazole (71) has been methylated and acetylated, the major products being (72)/ ... 

Vilsmeier reaction on the furopyrrole (52) led to formylation at C-5 to give aldehyde (53 Scheme 11). This result clearly shows greater reactivity at C-5 than at C-3 in the furo[3,2-6]pyrrole, although.the strongly electron-withdrawing 2-nitrophenyl substituent is probably involved in the total deactivation of the furan ring (78AHC(22)183). 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

The reaction proceeds by formation of the electrophilic Vilsmeier complex 2.30, followed by electrophilic substitution of the heterocycle. The formyl group is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all undergo this formylation which is highly selective for the C2 position. 

Regioselective formylation was also achieved by treatment of a 3-phenylbenzo[3]furan with AiACdimethylforma-mide and phosphoryl chloride (Vilsmeier reagent) at 0-25 °C to give 2-carbaldehyde derivative in 90% yield (Equation 61). In addition, a variety of interesting 2-acylbenzo[/ ]furan derivatives were described in the same article <2002T5125>. 

Thiophene is chlorinated by CI2 or SO2CI2. Bromination occurs by Br2 in acetic acid or with N-bromosuccinimide. Nitration is effected by concentrated nitric acid in acetic acid at 10°C. Further substitution predominantly yields 2,4-dinitrothiophene. Sulfonation with 96% H2SO4 occurs at 30°C within minutes. Benzene reacts extremely slowly under these conditions. This provides the basis for a method to remove thiophene from coal tar benzene (see p 77). Alkylation of thiophenes often gives only poor yields. However, more efficient procedures are the Vilsmeier-Haack formylation, which yields thiophene-2-carbaldehyde, and acylation with acyl chlorides in the presence of tin tetrachloride, to give 2-acylthiophenes. Like furan, thiophene is mercurated with mercury(II) chloride. 

Isoxazoles are quatemized by iodoalkanes or dialkyl sulfates. Electrophilic substitutions such as halo-genation, nitration, sulfonation, Vilsmeier-Haack formylation and acetoxymercuration, occur at the 4-position, provided this position is unsubstituted. As with oxazole, the pyridine-like N-atom impedes electrophilic substitution, so that isoxazoles are less reactive than furans but more reactive than benzene. 

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