4- Fluorobenzaldehyde, reaction with

Triisopropyl-1,3,5-dioxaphosphorinane (26) and its sulfide react with chloral, p-fluorobenzaldehyde, and acetaldehyde [Eq. (18)]. In the latter case, the hydroxymethyl derivative (29) (R = Me) was obtained. The reaction with chloral and p-fluorobenzaldehyde does not stop at the addition stage, but proceeds further to form the oxides (30) (R = CCI3,p-F-C6H4) (81IZV2776). 

Enders et al. (53) reported the use of chiral l,3-dioxan-5-ylamines in condensation reactions with aromatic aldehydes to form ylides in situ, which underwent thermal cycloaddition reactions with excellent yields. Treatment of 193 with benzaldehyde or p-fluorobenzaldehyde in the presence of excess dimethyl fumarate or fumaronitrile gave rise to the expected adducts in 85% yield with a >96% diastereomeric excess. For nitriles (R = CN), the endo/exo selectivity was higher at 70 30 than for the esters (R = C02Me) at 55 45 (Scheme 3.56). 

The aldehydes 3 were synthesized either by Vilsmeyer formyladon of 2 or by reaction of 4-fluorobenzaldehyde with a secondary amine (20). The stilbenes 4 were formed from the corresponding 4-dialkylamino-benzaldehydes either by the Homer-Emmons reaction with 4-nitrobenzyl-(diethyl)phosphonate (prepared by the Arbuzov reaction of a-bromo-4-nitrotoluene) or with 4-methylsulfonylbenzyl(diethyl)phosphonate (prepared in three steps from 4-methylthiobenzylaicohol) (21). A few nitrostilbene compounds were synthesized by heating aldehyde 3 with 4-nitrophenylacetic acid in the presence of piperidine. 

The title compound, 319, has been prepared311 in three steps starting with nucleophilic displacement of the nitro group of 4-nitrobenzaldehyde 321 with [18F]CsF, followed by reduction of the [18F]4-fluorobenzaldehyde 322 with LiAlH4 and treatment of crude alcohol with 47% HI. 320 has been obtained in the reaction of 319 with spiperone (equation 138). 

Reactions between aldehydes and alkynes to give propargyl alcohols are also described in Kitazume and Kasai s paper [55]. Here, various aldehydes such as benzaldehyde or 4-fluorobenzaldehyde were treated with alkynes such as phenylethyne or pent-l-yne in three ionic liquids [EDBU][OTf], [BMIM][PFg], and [BMIM][BF4] (Scheme 5.1-27). A base (DBU) and Zn(OTf)2 were required for the reaction to be effective the yields were in the 50-70 % range. The best ionic liquid for this reaction depended on the individual reaction. 

Hydantoin (5.2 g, 52 mmol) was added to piperidine (9.9 mL, 100 mmol) in a twonecked reaction flask equipped with a magnetic stirrer bar and heated to 130 °C under nitrogen flux. 4-Fluorobenzaldehyde (5 mL, 47 mmol) was added dropwise to the stirring mixture. The reaction was monitored by TLC (eluent ethyl acetate/cyclohex-ane, 1 4) and reached completion in 30 min. 

Transformation of [4- F]fluorobenzaldehydes into [4- F]fluorophenyl-alkenes using the Wittig reaction has been relatively unexplored. Examples are shown in Scheme 35. It requires the in situ generation of the ylid [171] by reaction of the phosphonium bromide with propylenoxide [172]. These conditions, successfully used in carbon-11 chemistry [173], have however the drawback of leading to a mixture of Z and E stereoisomers. 

In a subsequent study, Shudo and co-workers244 showed that benzaldehydes with electron-withdrawing groups (N02, CF3) react with 2 equivalents of benzene in the presence of triflic acid to give substituted triphenylmethanes in good yields [Eq. (5.90)]. They also observed that pura-fluorobenzaldehyde and biphenyl-4-carboxaldehyde yield diphenylmethane and triphenylmethanol under similar conditions, and the same products were also isolated in the reaction of triphenylmethane (Scheme 5.29). 

To 100 g of 2-(N-methyl-N-(2-pyridyl)amino)ethanol in 500 ml DMF was added 100 g of 4-fluorobenzaldehyde. The reaction mixture was stirred for 10 min at room temperature and 80 g of potassium tertiary butoxide was added to the reaction mixture. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 5-10°C and under the cold conditions, 1.5 L of water was added and stirred for 15 min. The mixture was extracted with ethyl acetate. The combined organic layer was washed with 3 times 1 L water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 148 g (88%) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzaldehyde. 

This potent [18F]-labelled muscarinic cholinergic receptor ligand 142182,183 has been synthesized184 by reductive amination of [2-18F]- and [4-18F]fluorobenzaldehyde with norben-zyldexetimide185a and sodium cyanoborohydride in a one-pot reaction (equation 92). Specific activities were 500-4000 mCi mmol-1 (142) (for the 2-fluoro compound) and 2400-8000 mCi mmol-1 (for the 4-fluoro compound). 

A process for the preparation of fluorobcnzencs comprises the heating of fluorobenzaldehydes in the presence of a catalyst. Suitable catalysts are transition metals from the B groups 1, 11. VI. VII and VIII. The best catalytical properties seem to be held by rhodium and the metals of the platinum group, e.g. formation of 1.3-difluorobenzene (5). The reaction maybe carried out in homogeneous solution with soluble rhodium catalysts (Wilkinson s catalyst) or in heterogeneous phase with the catalyst fixed on a carrier. ... 

Aluminum has exceedingly high affinity toward fluorine, as is evident from the bond strengtlis in several metal-fluorine diatomic molecules Al-F, 663.6 6.3 Li-F, 577 21 Ti-F, 569 34 Si-F, 552.7 2.1 Sn-F, 466.5 13 and Mg-F, 461.9 5.0 kJ mol [33]. This characteristic feature can be used for chelation-controlled aldol reaction of fluorinated aldehydes with KSA. Thus, in the presence of a stoichiometric amount of MesAl, 2-fluorobenzaldehyde reacts smoothly with KSA 10 to give aldol 11 with high anti selectivity. Other Lewis acids and non-fluorinated aldehydes lead to less stereoselectivity (Scheme 10.6) [34]. 

Acetic anhydride is added to 3-fluorobenzaldehyde, N-acetyl glycine, and anhydrous sodium acetate in ethyl acetate. The reaction mixture is heated to 80 °C. After completion of the reaction, the mixture is cooled, water is added, and the resultant precipitate is filtered and washed. The crude azlactone intermediate is then treated with aqueous sodium hydroxide followed by acidification. The resultant precipitate is filtered, washed, and dried to provide the N-acetyl dehydro-3-fluorophenylalanine in 70% yield from the aldehyde on a 50 kg scale. 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

The Heck reaction can also be used to prepare pharmaceutical intermediates for NSAID, e. g. suiindac and dehydronabumetone, from bromoaromatic precursors and commercially available alkenes. The central intermediate in the synthesis of suiindac, as developed by Merck [27], is p-fluoro-a-methylcinnamic acid ester condensation of p-fluorobenzaldehyde with propionic anhydride gives p-fluoro-a-methylcinnamic acid. The starting aldehyde is relatively expensive and unstable, and the yield of the Knoevenagel transformation is fairly low (Scheme 5). 

Styryl-functionalized vanadyl(lV) salen covalently anchored onto mercapto-modifled ACs and SWCNTs showed high catalytic activity in the cyanosilylation of benzaldehyde with substrate conversion of 83 and 93%, respectively [91]. The SWCNTs were shown to be more suitable support for the VO complex relative to the high-surface-area AC, because the latter support exhibited some adventitious activity. The asymmetric version of the reaction was also performed using the chiral vanadyl complex the SWCNTs also behaved as a better support, as the %ee was 66%, whereas for AC the %ee was 48% [91]. The VO(IV) complex immobilized onto SWCNTs was also tested in the catalytic cyanosilylation of hexanal and 4-fluorobenzaldehyde with high substrate conversions 97 and 96%, respectively. 

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