O-fluorobenzaldehyde

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 condensation of o-aminophenol wifh o-fluorobenzaldehyde in PEG 400 afforded dibenz[fi,/l[l,4]oxazepine (152) (Scheme 87) [120]. It was demonstrated that PEG 400 could be easily recycled in a series of runs. Using PEGs with lower (PEG 200 or PEG 300) or higher (PEG 1000) molecular weight as a medium resulted in similar product yields (87-88%). Using conventional organic solvents as cosolvents with PEG 400 also did not affect the reaction yield. 

Ferroglycine sulfate Ferrous fumarate Fluoranthene Flora ntyrone Fluoroacetyl chloride Afloqualone p-Fluorobenzaldehyde Sulindac Fluorobenzene Flubendazole o-Fluorobenzoyl chloride Flunitrazepam... 

Both [2- F] and [4- F]fluorobenzaldehydes are key intermediates in the synthesis of N-[ F]fluorobenzylamines via reductive aminations. This methodo o-gy has been successfully appHed to the preparation of a potential ace y -cholinesterase inhibitor [143] and of fluoro analogues of dexetimide, potent ligand of muscarinic cholinergic receptor [144] (Scheme 23). 

Gas-phase basicities of several substituted benzaldehydes (62 X = o-/m-/p-Me/F, o-j 77 -Cl) have been measured, relative to benzaldehyde or mesitylene as reference bases, over a range of temperatures.101 The tolualdehydes are more basic than benzaldehyde, the halobenzaldehydes less so, following classical aromatic substituent effects. The data also correlate well with solution-based linear-free-energy substituent constants, as well as with theoretical (MNDO) calculations. Some deviations are noteworthy (i) the o-halobenzaldehydes (especially chloro) have higher basicities than predicted, but calculations tend to rale out the hydrogen-bonded isomer (63), which is also contraindicated by a normal A,S value, inconsistent with the expected restriction of— hOH rotation in such a structure (ii) anomalies in the high-temperature behaviour of m-fluorobenzaldehyde in the presence of mesitylene reference base are consistent with a specific catalysed isomerization to the ortho- or para-isomer. 

In collaboration with Jim O Neil and Scott Taylor, the Francis group has also explored the use of MS2 in positron emission tomography (PET) imaging, whereby the positrons emitted by a radioactive isotope like F can be used to image low-abtmdant biomarkets with low bad oimd and exquisite sensitivity. To install these isotopes, the diazonium chemistry described in Section 9.14.3 was first used to modifyMS2 at Y85 with an aldehyde moiety. A bifimctional aminooxy linker was then used to attach [ F]fluorobenzaldehyde to the interior surface of the capsids. Additional molecules (to mimic dmg cargo) could be attached to tmmodified sites on the internal surface of MS2, and the biodistribution of the labeled capsids could be followed by PET after injection into rats. 

F]fluorobenzaldehyde ([ F]FBA) was prepared within about 30 min in preparative yields of about 50% using solid-phase extraction cartridges for purification. Conjugation of various oxyamine acetate conjugated peptides ( Figs. 42.25 and O 42.26) was carried out in H20/MeOH (pH 2) in 60-80% yield (10 min) and peptide concentrations of 0.5 mm. 

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