Boron fluorides substitution

Additional acylation studies were also reported (24), (26). In the first case it is claimed that acylation of thiophene is achieved by means of HC104 and acetic anhydride affording a 65 % yield of 2-acetylthiophene. In the second paper Levine and coworkers reported that while 2,5-dimethylthiophene could be readily acetylated, 2,5-dichlorothiophene acetylated sluggishly. This is, however, readily explained, since the presence of chlorine atoms on the thiophene ring decreased its reactivity in electrophilic substitution reactions. In the case of methyl substitution, however, the 3 and 4 positions of the ring are activated toward electrophilic substitution by the inductive and hyperconjugative effects. Thus 2,5-dimethylthiophene was successfully acylated by the boron fluoride etherate method in high yield with three aliphatic anhydrides. 

Fabre, B. Lehmann, U. Schliiter, A.D. Boronic ester-substituted terpyridine metal complex as a novel fluoride-sensitive redox receptor. Electrochim. Acta 2001, 46, 2855-2861 and references therein. 

Recently, Fabre et al. [31] and Freund et al. [7, 8] used electro-chemically deposited, self-doped, boronic-acid-substituted, conducting polymers for saccharide and fluoride detection. Freund et al. prepared a potentiometric sensor for saccharides using self-doped PABA [7, 8]. The transduction mechanism in that system is reportedly the change in pKa of polyaniline that accompanies complexation, and the resulting change in the electrochemical potential. Sensors produced with this approach exhibit reversible responses with selectivity to various saccharides and 1,2-diols (Figure 3.22) that reflect their binding constants with phenylboronic acid observed in bulk solutions. The sensitivity... 

The relative basicities of aromatic hydrocarbons, as represented by the equilibrium constants for their protonation in mixtures of hydrogen fluoride and boron trifluoride, have been measured. The effects of substituents upon these basicities resemble their effects upon the rates of electrophilic substitutions a linear relationship exists between the logarithms of the relative basicities and the logarithms of the relative rate constants for various substitutions, such as chlorination and... 

The cr-complexes (iv) are thus the intermediates corresponding to the substitution process of hydrogen exchange. Those for some other substitutions have also been isolated in particular, benzylidyne trifluoride reacts with nitryl fluoride and boron trifluoride at — ioo°C to give a yellow complex. Above — 50 °C the latter decomposes to hydrogen fluoride, boron trifluoride, and an almost quantitative yield of tn-nitrobenzylidyne trifluoride. The latter is the normal product of nitrating benzylidyne trifluoride, and the complex is formulated as... 

Table 3. Synthesis of ort/io-Substituted Fluoroaromatics from Nitrite Esters, Boron Trifluoride, and Hydrogen Fluoride [26]...

In order to achieve high yields, the reaction usually is conducted by application of high pressure. For laboratory use, the need for high-pressure equipment, together with the toxicity of carbon monoxide, makes that reaction less practicable. The scope of that reaction is limited to benzene, alkyl substituted and certain other electron-rich aromatic compounds. With mono-substituted benzenes, thepara-for-mylated product is formed preferentially. Super-acidic catalysts have been developed, for example generated from trifluoromethanesulfonic acid, hydrogen fluoride and boron trifluoride the application of elevated pressure is then not necessary. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Mechanistically there is ample evidence that the Balz-Schiemann reaction is heterolytic. This is shown by arylation trapping experiments. The added arene substrates are found to be arylated in isomer ratios which are typical for an electrophilic aromatic substitution by the aryl cation and not for a homolytic substitution by the aryl radical (Makarova et al., 1958). Swain and Rogers (1975) showed that the reaction takes place in the ion pair with the tetrafluoroborate, and not, as one might imagine, with a fluoride ion originating from the dissociation of the tetrafluoroborate into boron trifluoride and fluoride ions. This is demonstrated by the insensitivity of the ratio of products ArF/ArCl in methylene chloride solution at 25 °C to excess BF3 concentration. 

A rapid MW-assisted palladium-catalyzed coupling of heteroaryl and aryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored on TentaGel has been achieved [174]. An environmentally friendly Suzuki cross-coupling reaction has been developed that uses polyethylene glycol (PEG) as the reaction medium and palladium chloride as a catalyst [175]. A solventless Suzuki coupling has also been reported on palladium-doped alumina in the presence of potassium fluoride as a base [176], This approach has been extended to Sonogashira coupling reaction wherein terminal alkynes couple readily with aryl or alkenyl iodides on palladium-doped alumina in the presence of triphenylphosphine and cuprous iodide (Scheme 6.52) [177]. 

Fig. 6. Variation of enthalpies of boron and aluminum fluorides with chlorine substitution.

Attempts to prepare fluoro derivatives of (102) failed and resulted in the formation of the unusual /i-pyrazolyl fi-oxo dimer [ ReO HBF(pz)2-A,A 2(/i-pz)2(M-0)] (105)." An X-ray structural analysis shows that one pyrazolyl residue of each tridentate ligand has been substituted by fluoride. With the analogous complex containing hydridotris(3,5-dimethyl-l-pyrazolylborate), however, mixed Cl/F, I/F, or OSO2CF3/F derivatives of (102) are readily formed. The different reactivity of the hydridotris(pyrazolyl)borato rhenium complexes has been attributed to the greater steric protection of the boron atom afforded by the dimethyl-substituted ligand. 

In this procedure, the ketone is first converted to its enol acetate by reaction with acetic anhydride in the presence of a proton acid. Since this enol acetylation is performed under equilibrating conditions, the more stable enol acetate (usually the more highly substituted isomer) is produced. Acetylation of this enol acetate, catalyzed by the Lewis acid boron trifluoride, usually leads to the formation of the enol acetate of a /3-diketone which is cleaved by boron trifluoride to form acetyl fluoride and the borofluoride complex of the /3-diketone. Thus, this procedure offers a convenient and general synthetic route... 

A novel method for the convenient synthesis of alkenyl fluorides 15, as well as diflu-oromethyl-substituted alcohols 16 and amides 17, via electrophilic fluorination with one equivalent of F-Teda BF4 (6) of alkenyl boronic acids and trifluoroborates, has been reported.87 The alkenyl fluorides 15 are obtained as Z/E mixtures when the reaction is carried out with one equivalent of F-Teda BF4 in acetonitrile at room temperature. When the reaction is performed with two equivalents of F-Teda BF4 in water or a nitrile solvent the difluoromethyl-substituted alcohols 16 or amides 17, respectively, are obtained. 

Arsenic(III) fluoride, like antimony(III) fluoride (see Section 12.1.), is used to substitute fluorine for chlorine, bromine and iodine not only at carbon but also at other atoms, such as phosphorus, boron or metals. Chlorophosphanes undergo oxidative fluorination with arsenic(III) fluoride [or antimony(III) fluoride] to trifluoro-A5-phosphanes 1. 

Another interesting substitution reaction is the conversion of l-methoxybicyclo[2.2.2]octane (3a) and l-methoxy-4-methylbicyclo[2.2.2]octane (3b) with acetyl fluoride and boron trifluoride,9 but this has not yet been extended to other substrates. 

In substitution reactions of the carbonyl oxygen, boron trifluoride has been used as a reagent. 4-Fluorobenzoyl chloride (5) can be converted to the corresponding fluoride 6 in addition to remarkable amounts of l-fluoro-4-(trifluoromethyl)benzene (7),10 however, this conversion does not appear to be generally useful. 

Chlorine can be substituted by hydrogen fluoride and boron trifluoride to yield chlorofluorocarbon compounds. This process is applied for producing 1,1-dichloro-l-fluoroethane (14), which is considered as a replacement for trichlorofluoromethane as a blowing agent for plastic foam.18... 

Boron trifluoride complexes are also often applied. BF3 when used with acyl fluorides showed in some cases distinct differences compared to other catalyst-reagent combinations. For example, acylation of 2-methylnaphthalene with isoBuCOF and BF3 gives high yield (83%) of the 6-substituted isomer in contrast to AICI3 (30%).40 A similar example is shown here ... 

Evidence for the tetrahedral intermediate includes a Hammett p constant of+2.1 for the deacylation reaction of substituted benzoyl-chymotrypsins and the formation of tetrahedral complexes with many inhibitors, such as boronates, sulfonyl fluorides, peptide aldehydes, and peptidyl trifluoromethyl ketones. In these last the chemical shift of the imidazole proton is 18.9 ppm, indicating a good low-barrier H-bond, and the pJQ of the imidazolium is 12.1, indicating that it is stabilized by 7.3 kcal mol 1 compared to substrate-free chymotrypsin. The imidazole in effect is a much stronger base, facilitating proton removal from the serine. 

An efficient aqueous phase Suzuki-Miyaura reaction of activated aryl chlorides with aryl boronic acids has been reported. The method uses a new D-glucosamine-based dicyclohexylarylphosphine ligand for the palladium catalyst and works well with nitro-and cyano-activated chlorides.32 The aryl fluoride bond has been considered inert to palladium-catalysed substitution reactions. However, a computational study, backed up by experiment, shows that the presence of a carboxylate group ortho to fluorine will allow reaction both with phenylboronic acids in a Suzuki-type reaction and with organotin reagents in a Stille-type reaction the presence of the adjacent oxyanion stabilizes the transition state.33... 

Thus, for our present purposes a similar approach was followed using Suzuki cross-coupling reactions as the key steps in the synthesis of our target compounds. Symmetrically substituted compounds were synthesized in a twofold Suzuki crosscoupling reaction from commercially available p-substituted phenylboronic acids or esters and 4,4 -dibromobiphenyl or 4,4 -biphenyl-bis-boronic acid ester and a p-substituted arylhalide, respectively, using tetrakis (triphenylphosphino) palladium as catalyst together with cesium fluoride as base in dry tetrahydrofurane as shown in Scheme 8.1. The desired products were obtained in respectable yields after heating at reflux for 50 h. 

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