Benzaldehyde fluorinations

Sulfur tetrafluoride [7783-60-0] SF, replaces halogen in haloalkanes, haloalkenes, and aryl chlorides, but is only effective (even at elevated temperatures) in the presence of a Lewis acid catalyst. The reagent is most often used in the replacement of carbonyl oxygen with fluorine (15,16). Aldehydes and ketones react readily, particularly if no alpha-hydrogen atoms are present (eg, benzal fluoride [455-31-2] from benzaldehyde), but acids, esters, acid chlorides, and anhydrides are very sluggish. However, these reactions can be catalyzed by Lewis acids (HP, BF, etc). 

When tetrahydrothiophene is treated in a similar manner, ring opening occurs to give 4-methylthiobutyl fluoride. In the benzaldehyde dithioacetal, gem-di-fluorination takes place to form benzylidene fluoride, though in low yield [6] (equations 9 and 10). 

On the other hand, the fluorine-induced addition of the diastereomeric silyl-subsliluted sulfides 36 A and 36B to benzaldehyde proceeds without loss of stereochemical information and with retention of configuration32. Since, however, the anionic reagent 35A/35B is known to be configurationally labile, the observed retention of configuration in the fluorine-induced desi-lylative hydroxy alkylation lends experimental evidence to the notion that these reactions proceed via hypervalent silicon species rather than anionic reagents. 

Figure 6.25. Asymmetric allylation of benzaldehyde catalysed by a fluorinated Ti/BINOL complex under...

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

The preparation of fluorinated catechols and phenols and particularly fluori-nated derivatives of the catecholamines and aminoacids has led to the search for methods which do not induce racemization of chiral precursors. Benzaldehydes and alkoxybenzaldehydes are considered as latent phenols and catechols respec-... 

In related studies, it has been shown that a-fluorobenzylphosphonates ArCHFPO(OEt)2 (38) will undergo Wadsworth-Emmons-type olefination reactions with aldehydes and ketones [57]. 39 was prepared from benzaldehydes and HP(0) (OEt)2, which was fluorinated using diethylaminosulfur tiifluoride for example, diethyl [(3,5-dimethylphenyl)(fluoro)methyl]phosphonate (38) was formed in 91%. An 82% yield of Me 2-[(fluoro)(4-fluorophenyl)methylene]butanoate (1 1 E Z) (40) was obtained from 38 and methyl 2-oxobutanoate (Scheme 13). 

Several of the alpha-ethyl analogues of ARIADNE were N,N-dialky lated, and were target compounds for halogenation with radio-iodine or radio-fluorine, for evaluation as potential brain blood-flow indicators. In these studies, all examples followed a common flow diagram. The reaction of the appropriate benzaldehyde... 

A multistep solid phase synthesis of (3-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between -78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

High yields have been achieved via Schiff base condensation of 2-aminophenol 115 and fluorinated benzaldehyde... 

Another application of HNLs can be found in the chemoenzymatic synthesis of the broadband antibiotic thiamphenicol and its fluorinated derivative florfenicol [203]. The conversion of 4-methylsulfanyl-benzaldehyde to the mandelonitrile was catalyzed by a novel enzyme from a Chinese almond (Prunus communis L. var. dulcis Borkh). A concentrated powder from the kernels was prepared and a mixture of the cmde meal, aldehyde, and HCN was stirred in isopropyl ether at room temperature for 12 h, yielding the cyanohydrin with 99% ee after recrystallization. The building block formed was then successfully applied in the total synthesis of thiamphenicol and florfenicol (Fig. 41). 

Preparation of 3,7-Dimethyloctyloxy)Benzaldehyde-Terminated Poly[9,9-Dioctyl)2,7-Fluorine]... 

The reaction of hydrazones with elemental fluorine can also be used for the synthesis of gem-in ally difiuorinated compounds (Table 4). The procedure, however, can have severe limitations it is only applicable to aryl ketone hydrazones (no reaction is observed with the hydrazones of benzaldehyde, cyclohexanone, or cyclopentanone), and mixtures ofdi- and monolluorinated compounds are obtained. In some cases, monofiuorinated derivatives are the only reaction products (entries 4 and 5). 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic /3 lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (-)-lasubine (I). Tin tetrachloride mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be aUylated with high diastereoselectivity to give optically active homoaUyhc amines (Scheme 87). 

Soloshonok and Hayashi applied chiral ferrocenylphosphine-gold(I) complexes to asymmetric aldol-type reactions of fluorinated benzaldehydes with methyl isocyano-acetate (27) and A, A/-dimethyl-a-isocyanoacetamide (95). It is noteworthy that successive substitution of hydrogen atoms by fluorine in the phenyl ring of benzaldehyde causes gradual increase of both the cis selectivity and the ee of cw-oxazolines [53]. 

A versatile C4-building block, difluorinated Danishefsky s diene, was developed for the construction of fluorinated six-membered rings in the laboratory of K. Uneyama. The diene was prepared by the selective C-F bond cleavage of trifluoromethyl ketones. The reaction of this novel diene with benzaldehyde afforded the corresponding difluoro dihydropyrone in 92% ee in the presence of equimolar Ti(IV)-(R)-BINOL. ... 

With thin-film nickel reactors, Chambers and co-workers demonstrated the biphasic fluorination of numerous organic substrates including diketones [70], substituted toluenes [71], and more recently benzaldehyde derivatives [72], using... 

The condensation of fluorinated 3-oxoesters or 1,3-diketones with benzaldehyde and urea or thiourea result in the diastereoselective formation of 4-fluoroalkyl-4-hydroxy-2-oxo(thioxo)-6-phenylhexahydropyrimidine-5-carboxylates from which by dehydration under acetic conditions the corresponding 6-fluoroalkyl-2-oxo(thioxo)-4-phenyl-l,2,3,4-tetrahydropyrimidine-5-carboxylates were obtained (01ZOR915, 00JFC(103)17) (Scheme 55). 

Viehe and his co-workers86 carried out the addition of chloroform to carbonyl groups in liquid ammonia the yield depended on the structure of the acceptor their condensing agents were sodamide, sodium hydroxide, and sodium alkoxides acetone, ethyl methyl ketone, diethyl ketone, cyclo-pentanone, cyclohexanone, and benzaldehyde were treated in this way. It is also possible to add tribromomethane, but not fluorinated methanes. 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

Fluorinated methyl aryl ethers. The facile rearrangement of oxygenated benzyl derivatives effected by XeFa to give fluorinated methyl ethers, i.e., benzyl alcohols to fluoromethyl aryl ethers and benzaldehydes to difluoromethyl aryl ethers, may involve the formation of fluoroxy intermediates and thence oxaspirobenzenium ions. 

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