Furan 2-formyl

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

A quantitative study has been made on the effect of a methyl group in the 2-position of five-membered heteroaromatic compounds on the reactivity of position 5 in the formylation and trifluoroacetylation reaction. The order of sensitivity to the activating effect of the substituent is furan > tellurophene >selenophene = thiophene (77AHC(2l)ll9). 

Timko and Cram were the first to prepare true crown ethers containing the furanyl subcyclic unit ° . Destructive distillation of sucrose yielded 2-hydroxymethyl-5-formyl-furan 7 in 41% yield. This could be reduced to the corresponding diol in 91% yield by treatment with sodium borohydride. Reaction of the diol with tetraethylene glycol dito-sylate, and potassium t-butoxide in THE solution afforded the crown in 36% yield. The approach is illustrated below as Eq. (3.26). 

It was reported that the eorresponding 2-hydroxy-3-aeetyl-benzofuran exists entirely in the enol form (73AJC1079 84H737 87CC1150) [produees deep blue eolor with ferrie ehloride (55JA1623)].This is in aeeordanee with AMI, PM3, and B3LYP/6-31G ealeulations for 3-formyl-2-hydroxybenzo [h]furan as model eompound (99UP1) (see Seheme 10, all values in keal/mol). 

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 ... 

This section deals with investigations specifically aimed at producing homopolymers and copolymers of furan carbonyl compounds by the selective opening of the carbonyl bond. The many reports on polymerization of 2-furaldehyde which in fact deal with complicated acid-catalysed resinification reactions which involve both the formyl group and the furan ring are reviewed in Chapter VI. 

The polymerization of 2-furaldehyde by sodium and sodium naphthalene reported by Kulakov and Kamenskii151 did not produce structure 32, but rather some resinous oligomeric materials formed through the interactions of the furan ring with the formyl group. 

However, the rate of substitution of pyrrole is too high and that of benzene too low to be followed by standard techniques, and consequently a kinetic study was limited to furan, thiophene, selenophene, and tellurophene. Activation entropies are constant for all four members of the series, indicating that the arrangement of the atoms around the reaction center is similar, i.e., the transition states of all four rings occur at similar positions along the reaction coordinate. The relative rates for the formylation are thus controlled by the activation enthalpies. At 30UC relative rates are furan (107), thiophene (1), selenophene (3.64), and tellurophene (36.8).68... 

Computer simulation of lanthanide-induced shifts in the 2-formyl and 2-acetyl derivatives of furan, thiophene, selenophene, and tellurophene108 indicate a nearly equipopulated mixture of trans and cis conformers of the furan, and a preponderance of the cis for the thiophene, selenophene, and tellurophene derivatives. This difference is due to an interaction between the ring heteroatom and the carbonyl oxygen lone pair electrons. 

Deprotection of 2,2-disubstituted-l,3-dithiolanes to give carbonyl compounds can be achieved using Oxone with KBr in aq. MeCN <06TL8559> and a review of silylated heterocycles as formyl anion equivalents includes reference to 64 <06CC4881>. A method for transformation of propargylic dithiolanes 43 into tetrasubstituted furans has been reported <06SL1209> and Michael addition of enolates to the chiral dithiolane dioxide 65 takes place... 

Formyl fluoride, 50, 2 Fremy s salt, 52, 86, 88 Furan, 3-aeety1-2,4-dimethyl-, 53, 1... 

The most stable O2 addition adduct below T = 1250 K is 6-peroxyoxepinone (route A in Fig. 12), which can cyclize to form a 1,4-peroxy intermediate which subsequently releases CO2 to form a 5-oxopentanalyl radical. This species can cyclize and fragment, yielding formyl radical, furan, and carbon dioxide. Above T = 1250 K, the... 

Thus, aside from furan-2-carboxaldehyde, where the equilibrium between conformers is rather sensitive to external effects, the 2-formyl derivatives of five-membered heterocycles are rather rigid from a conformational point of view. 

The situation appears decisively different in 3-formyl derivatives. Theoretical calculations (77JCS(P2)1601 79NJC473) reveal a small energy difference between X,0-cis and X,0-trans conformations in furan-3-carboxaldehyde (4, X = O), and pyrrole-3-carboxaldehyde (4, X = NH), and the X,0-cis form is... 

Substituents at C(4) do not appreciably modify the conformational equilibrium of the 2-formyl group in furan, pyrrole, thiophene, and selenophene derivatives (81RCR336). 

The energetics relative to the conformational problem of pyridine-2-carboxaldehyde thus appear qualitatively similar to that of furan-2-carbox-aldehyde the less polar conformer is more stable as an isolated molecule and polar media are likely to reverse the relative stability. Nevertheless, while the energy difference between cis and trans forms of 2-formyl derivative of furan becomes nearly zero in solvents of relatively low polarity (72T3015), the same seems to occur for pyridine derivative in more polar solvents. 

In acetyl and higher COAlk derivatives of furan (76ZN(A)1217 84JST(116)377 85JCS(P2)1839), for example, in the 2-formyl- and 7-formylbenzo[h]furans (84JCS(P2)1479), the conformational equilibrium was found to be solvent dependent. This behavior should characterize all situations in which the energy difference between cis- and trans-conformers is small (<8 kJ mol" ) and the more stable conformer in nonpolar media is the one with lower polarity. 

Viismeier reaction Formylation of pyrrole, furan or thiophene is carried out using a combination of phosphorus oxychloride (POCI3) and... 

The situation in 2-acetylfuran (63, R = Me) resembles qualitatively that of the 2-formyl (63, R = H). Accurate NMR measurements (85JCS(P2)1839) at low temperature and in dimethyl ether performed on 2-acyl derivatives of furan have enabled direct detection of the two conformers. At 173K the (E)-conformer population for 2-acetylfuran amounts to 53%. 

The reactivity of five-membered rings with one heteroatom to electrophilic reagents has been quantitatively compared. Table 1 shows that the rates of substitution for (a) formylation by phosgene and V,iV-dimethylformamide, (b) acetylation by acetic anhydride and tin(IV) chloride, and (c) trifluoroacetylation with trifluoroacetic anhydride (71AHC(13)235) are all in the sequence furan > tellurophene > selenophene > thiophene. Pyrrole is still more reactive as shown by the rate for trifluoroacetylation, by the relative rates of bromination of the 2-methoxycarbonyl derivatives (pyrrole > furan > selenophene > thiophene), and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3]+ (Scheme 5) (2-methylindole ss V-methylindole > indole > pyrrole > furan > thiophene (73CC540)). 

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