Para-formyl phenols

Duff reaction. The ortho-formylation of phenols or para-formylation of aromatic amines with hexamethylenetetramine in the presence of an acidic catalyst. 

Dehydrative condensation of benzofurazan oxide with phenolic enolates affords phenazine di-N-oxides (Scheme 7). The condensation proceeds under mild conditions (NaOH/H20, H2O, MeOH/RNH2, Si02/CHs-CN at room temperature) and can be applied to a broad range of substituted nucleophiles of varying oxidation levels (phenolates, resorcinolates, hydro-quinones, and benzoquinones). A few limitations have been encountered for the phenol, and these include insufficient reactivity of dioxalane-protected p-formyl phenol and decarboxylation of free carboxylates at even mild reaction conditions (NaOH/H20, 60 Nucleophilic attack on the benzofurazan will occur from the para position in ortho- and meta-substituted phenolates, whereas para-substituted phenols will attack from the ortho position. Subsequently, elimination of H2O or ROH will take place if possible otherwise, elimination of H2 will give the phena-... 

ABSTRACT. Selective formylation of phenol at the 4-position is achieved by using 3-cyclodextrin as catalyst in the reaction of phenol with chloroform in aqueous alkali. The reactions of 1,3-dihydroxybenzene and indol, respectively, in the place of phenol give 2,4-dihydroxybenz-aldehyde and indole-3-aldehyde in virtually 100% selectivies and high yields. The reactions of para-substituted phenols, 4-methylphenol and 5,6,7,8-tetrahydro-2-naphthol, instead of phenol, effect the selective dichloromethylation at the para-positions. Selective carboxylation of phenol at the 4-position is achieved in the reaction of phenol with carbon tetrachloride in aqueous alkali by using 3-cyclodextrin and copper powder as catalyst. 

The dependence of the selectivity for para-dichloromethylation on the initial molar ratio of 3-CyD to phenol was similar to that for para-formylation of phenol as shown in Fig. 1. The dropwise method required only a small amount of 3 CyD, i.e., 10 mol % to 4-methylphenol for 96 % selectivity [5]. 

The applicability of the Gattermann synthesis is limited to electron-rich aromatic substrates, such as phenols and phenolic ethers. The introduction of the formyl group occurs preferentially para to the activating substituent (compare Friedel-Crafts acylation). If the /jara-position is already substituted, then the ort/zo-derivative will be formed. 

The formylation of phenols with the electron-rich olefin to give imidazolidin-2-yl-phenols is very selective and avoids mixtures of o- and p-isomers which are frequently obtained by methods commonly employed for the synthesis of phenolaldehydes. Para substitution of the cyclic aminal group in the phenol is preferred. If the p-position is blocked or sterically hindered, the reaction proceeds via the ortho- aminals to salicylaldehydes. Incorporation of more than one aldehyde group in the benzene nucleus is often achieved with hydroxy- and aminophenols. 

Formylation.2 Reaction of (C6H5S)3CH (2) with 1 generates the carbocation (C6H5S)2C+H, which reacts with phenols or aromatic ethers to give the thioacetals (3), which are readily hydrolyzed to aldehydes. The formylation shows high para-preference. Example ... 

A formyl substituent, like a nitro group, is strongly electron-withdrawing and acidstrengthening, especially when ortho or para to the hydroxyl group. p-Hydroxy-benzaldehyde, with a of 2.4 x 10 , is a stronger acid than phenol. 

Increased selectivity has also been obtained using polyethylene glycol as complexing agent.Using toluene as solvent, the authors report a 1 10 para. ortho ratio in the formylation of phenol. 

Phenolic aldehydes can be obtained by the Duff reaction, in which the phenol is heated with urotropine, boric acid, and glycerol for 30 minutes at 150-160° 857 the yields are not high (15-20%), but the procedure is simpler and less time -consuming than the Reimer-Tiemann synthesis the products are the ortho-derivatives. Dialkylanilines can be formylated in the same way,858 but here the products are the para-aldehydes. 

Generally, the Vilsmeier reaction fails for benzene, alkylbenzenes and naphthalene. The reaction gives low yields in the case of phenol ethers if the para-position is already occupied and fails for highly substituted benzofurans, indicating that the presence of a sufficiently reactive (labile) hydrogen atom on the aromatic ring is necessary for successful application. However, Martinez et al. reported the formylation of 1,3,5-trimethylbenzene, naphthalene, acenaphthene, anthracene and phenanthrene in fair yield using the trifluoromethanesulphonic anhydride/dimethylformamide complex (Eq 1.29). 

Reaction of phenoxy-magnesium halides with orthoformates is an older method for regioselective ortho formylation and gives moderate yields (30-55%) with simple alkyl phenols, however yields are very low when bulky groups, halo, nitro or carboxy substituents are present (Eq 1.40). Contrary to this the formylation of free phenol with aluminum chloride-triethylorthoformate yields the para-isomer (Eq 1.40). ... 

A modern adaptation uses trifluoroacetic acid as catalyst. That allows for formylation of aromatics such as toluene and xylene and even electron deficient phenols such as 2,4-difluorophenol under mild conditions in good yields.A high order of para regioselectivity is exhibited even for phenols.The mechanism involves fast aminomethylation followed by a rate-determining dehydrogenation step to the imine similar to that observed in the Sommelet reaction hydrolysis then gives the aldehyde (Eq 1.42). ... 

With toluene as substrate formylation proceeded in a high yield (99%) with respect to aldehyde formation and with good para-selectivity (90%) in a reaction time of only 1 hour. The reaction was carried out on phenol under the same reaction conditions. Surprisingly, the reactivity of phenol proved to be much lower than that of toluene and a reaction time of more than 4 hours was required to obtain acceptable yields, albeit with reduced para-selectivity. When the reaction was extended to anisole, only small differences compared to phenol were observed within the first hour of the reaction, but at extended reaction times phenol proved to give better conversions. The results indicate that the reaction is sustained for a longer time with phenol than with anisole. 

Chloro-aluminate ionic liquids promote the carbonylation of alkylated aromatic compounds, but fails in the case of oxygenated aromatics. Aldehyde yields of formylation in the acidified neutral ionic liquids were generally similar compared to reactions conducted in HF as solvent/catalyst (cf Table 2.2). The increase in aldehyde yields with the use of extended alkyl chain lengths of the cationic part of the melt, may be due to improved CO solubility. HF/BFs-acidified neutral ionic liquids showed both increases in para-selectivity compared to HF as solvent and catalyst. Formylation of anisole and toluene, but not of phenol in the neutral ionic liquids resulted in increased secondary product formation in comparison with hydrogen fluoride used as solvent/catalyst. This difference in behaviour is not understood at present, but suggests that phenol is a good substrate for formylation in this medium, particularly with the development of a system catalytic with respect to HF/BF3 in mind. 

Targeted products include para-anisaldehyde, ortho- and para-hydroxybenzaldehyde which are important intermediates for the manufacture of chemicals used in the flavor and fragrance market and various other chemicals. The use of CO technology (HF/BF3) to produce these aldehydes in a two-step process from phenol as reagent is economically attractive due to the relative low cost and other benefits associated with syngas as reagent. The aim of the study was to evaluate and understand this relatively unexplored approach to the formylation of aromatic compounds. 

The reactivity of both phenol and anisole proved to be much lower than that of toluene. The main aldehyde isomer (para) produced in these HF/BF3/CO formylations as well as of other ortho-para directing mono-substituted benzenes tested in our laboratories were in accordance with published results. Efforts to increase substrate conversion resulted in substantial secondary product formation and mechanistic investigations showed this to be a consequence of the inherent high acidity of the reaction environment. 

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