Anisole formylation

In a final effort to establish CO formylation with heterogeneous catalysts, fluoridised silica-alumina (used effectively as an hydrofluoric acid alternative in the liquid phase alkylation of benzene ), was activated and investigated for catalytic anisole formylation (Table 2.6). As in the case of the other heterogeneous catalysts, no formylation was observed. 

The occurrence of p-methoxyacetophenone ( ) as secondary product in both of the mechanistic studies as well as with anisole formylation reaction was rather surprising. The same product was however reported by Saint-Jalmes et al. ° during the FIC02Me/FIF/BF3 formylation of anisole. These workers postulated the acid catalysed decomposition of methyl formate into methanol and CO as first step in the reaction. This is followed by dehydration of the liberated methanol with the formation of the methyl cation ( ), which is then carbonylated to produce the acylium ion (44). Subsequent nucleophilic attack of anisole on then produces the observed acetophenone (45) (Scheme 2.11). 

The formyl group is cleaved with HF/anisole/(CH2SH)2- It is also cleaved at pH 9-10. ... 

L-isoleucine methyl ester, N-formyl L-isoleucine methyl ester and N-acetyl L-isoleucine methyl ester. The major component of the male attractant pheromone of the scarab beetle, Holotrichia reynaudi, was identified as anisole. ... 

Formylation of the less reactive phenol and anisole with CO in HF-BF3 was found to require at least stoichiometric amount of the acid for effective transformation (50 equiv. of HF, 2 equiv. of BF3, 50 bar CO, 45°C).445 Conversion increases with increasing reaction time but results in decreasing paralortho ratios suggesting a change from kinetic control to thermodynamic control and the reversibility of formylation. Furthermore, the amount of byproducts (mainly diphenylmethane derivatives) originating from reactions between substrates and products also increases. Additional studies in ionic liquids showed that imidazolium cations with increased chain lengths—for example, l-octyl-3-methylimidazolium salts—are effective in the formylation process. This was attributed to the enhanced solubility of CO in the ionic liquid medium. Tris(dichloromethyl)amine, triformamide, and tris (diformylamino)methane have recently been applied in the formylation of activated aromatic compounds in the presence of triflic acid at low temperature (— 10 to 20°C) albeit yields are moderate.446... 

Isopropyl anisole (171) was converted to bromide (172) by metalation, formylation and bromination. Alkylation with cyclopropyl ketoester produced (173) whose transformation to alcohol (174) was achieved by saponification, decarboxylation and reduction.. Its conversion to homoallylic bromide (175) was accomplished by the method of Julia et al. [56]. Alkylation of ethyl acetoacetate with bromide (175) furnished p-ketoester (176). It was subjected to cyclization with stannic chloride in dichloromethane. The resulting tricyclic alcohol provided the olefinic ester (177) by treatment with mesylchloride and triethylamine. Epoxidation followed by elimination led to the previously reported intermediate (146) whose conversion to triptolide (149) has already been described. 

The major advantage of the seunpling technique developed, was that some trace chemicals could be trapped tind described for the first time as Black Truffle aroma constituents. In particular, some compounds, important flavor contributors, generally appearing in small concentrations, such as benzaldehyde, propanal, ethyl acetate, anisole or dimethyl disulfide - previously identified in Shiitake mushrooms (9) - could be characterized. This was also the case for three aromatic compounds, toluene, xylene and ethyl benzene, well known as raw vegetable constituents (1 ). In addition, two aliphatic esters, isopropyl and sec-butyl formates, and one cyclic sulfur compound (2-formyl thiophene) previously reported respectively in plums and apples (W) and in coffee and bread products (n) were identified. 

C solid-state NMR has been applied to study 4-acetyl-, formyl- and carboxy-benzo-9-crown-3 ether.Chemical shift differences of ca. 8.5 ppm have been observed between the two aryl-O-C carbons and are explained using results of ab initio calculations previously performed on anisole. Chemical shift assignments have been verified by the use of selectively deuterated derivatives. 

Acetylated products which are formed during formylation of guaiacol or anisol are difficult to explain. 

In 1922 Majima and Kotake reported that 3-formylindole (209) could be obtained in yields of up to 40% by the action of a fivefold excess of ethyl formate on indole magnesium iodide in anisole at low temperatures. However, they also claimed that only traces of the aldehyde were obtained when the reaction was carried out in ether.10 11 In 1927 Putochin studied the effect of temperature on the nature of the products formed when the formylation reaction was carried out in benzene and observed that 1-formyl derivatives were the major products obtained at low temperatures, whereas the 3-formyl derivatives predominated at higher temperatures.13 Britton et al. in 1947 claimed that the formation of the 3-formylindole derivative is probably favored, relative to the alternate 1-formylation process, by elevated temperatures and pressures.95 However, it was apparently not possible to suppress completely the formation of the 1-formyl derivatives and yields of the order of 40% of both products were usually obtained.96... 

Another industrial process uses electrochemical oxidation in the presence of lower aliphatic alcohols via the corresponding anisaldehyde dialkyl acetal [172]. Anisaldehyde may also be produced by methylation of 4-hydroxybenzaldehyde, which is easily obtained by oxidation of p-cresol [172a], or by Vilsmeier formylation of anisol [172b]. 

It thermally decomposes to IV -dimethylcarbamoyl chloride. Secondary formamides form similar adducts, which on heating afford isocyanates. Aromatic compounds such as anisole are not formylated by the DMF-SO2CI2 adduct but chlorosulfonated. This reaction was also performed with thiophenes 2-thiophenecarbaldehydes are formed as byproducts. The formation of triformaminomethane from form-amide and SO2CI2 has been reported. ... 

The presence of cyclodextrins in reaction mixtures often results in the alteration of well known chemical transformations, due either to their catalytic activities or by controlling the formation of certain reaction products. This latter may lead to the alteration of the ratio of products, formed, and to the improvement of the selectivities and yield of the reactions [1]. Characteristic examples are the selective chlorination of anisole [2] and the selective formylation of phenol [3]. 

Rahm et al. describes the formylation of anisole (50% isolated yield) and alkylated benzenes in fair yield using acetone cyanohydrin (Eq 1.19). Similar to the Gattermann reaction no formylation is obtained with pyrrole and only traces of aldehydes were observed with phenol and furane as substrates. 

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. 

Figure 2.4 Secondary products obtained during CO formylation reactions of toiuene, anisole and phenol using HF/BF3 as catalyst. (Yield ranges in brackets)...

In an effort to obtain augmented yields and selectivities in the CO formylation of phenol, anisole and toluene, a few reactions were initiated during which the type and amount of Lewis- and Brensted acid were varied. 

Freshly calcined catalyst was then utilised in CO formylation reactions using toluene and anisole as substrates respectively. However, no aldehyde products were observed (Runs 7 and 8). 

Table 2.6 Attempted CO formylation of anisole using fluoridised silica-alumina as acid catalyst... 

Understanding the CO/HF/BF3 formylation mechanism would be beneficial to the extend that it would facilitate reaction optimisation, minimisation of side-product formation and provide an indication of whether the reaction can be performed under catalytic conditions. As little is known in the literature of the reaction mechanism in the case of anisole, efforts were focused on this aspect. 

The dication concept can also be extended to the formation of the anisole- and phenol dication as reported by Takezaki " who isolated an anisole/FIF/BFs complex containing a 1 1 2 ratio of reactants (Scheme 2.3). Protonation of the pro-electrophile CO via the intracomplex mechanism is followed by electrophilic aromatic substitution with formation of the 71- and a -complex respectively followed by aldehyde formation through the loss of a proton and X. The corresponding rate of formylation is expected to be slower than in the case of toluene due to the lower nucleophilicity of the protonated anisole. 

Yet another possible formylation mechanism that needs to be considered, involve direct nucleophilic attack of CO on the protonated aromatic system. However, this mechanism (Scheme 2.5) can be discounted since it will result in mefa-substituted aldehydes in the case of toluene, phenol and anisole as substrates. 

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