1.1.1- Trifluorides carboxylic acid

Olefins are carbonylated in concentrated sulfuric acid at moderate temperatures (0—40°C) and low pressures with formic acid, which serves as the source of carbon monoxide (Koch-Haaf reaction) (187). Liquid hydrogen fluoride, preferably in the presence of boron trifluoride, is an equally good catalyst and solvent system (see Carboxylic acids). 

Highly Branched Acids. These acids, called neoacids, are produced from highly branched olefins, carbon monoxide, and an acid catalyst such as sulfuric acid, hydrogen fluoride, or boron trifluoride. 2,2,2-Trimethylacetic acid (pivaUc acid) is made from isobutylene and neodecanoic acid is produced from propylene trimer (see Carboxylic Acids, trialkylacetic acids). 

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-... 

Many aldehydes and ketones have been converted to g m-difluoro compounds with sulfur tetrafluoride (SF4), " including quinones, which give 1,1,4,4-tetra-fluorocyclohexadiene derivatives. With ketones, yields can be raised and the reaction temperature lowered, by the addition of anhydrous HF. Carboxylic acids, acyl chlorides, and amides react with SF4 to give 1,1,1-trifluorides. In these cases the first product is the acyl fluoride, which then undergoes the ge i-difluorination reaction ... 

Displacement of the 3-hydroxyl group of 74 was carried out with Et2NSF3 (DAST) (DAST - diethylaminosulfur trifluoride) in dichloromethane. The expected fluorinated product 75 on treatment with aqueous perchloric acid led to regioselective epoxide ring opening to give 76, which on treatment with hydrazine hydrate at 100 °C for 18 h yielded 3,4-dihydroxy-8-oxo-octahydropyridazino[l,6-r/][l,2,4]triazine-l-carboxylic acid phenylamide 77 (Scheme 3) <1997T9357>. 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

Nakagome and co-workers effected the successful cyclization of N-ethyl-N-arylaminomethylenemalonates (749) in poly phosphoric acid, prepared from orthophosphoric acid and phosphorus pentoxide in polyphosphate ester (PPE), prepared from phosphorus pentoxide and anhydrous diethyl ether in chloroform in phosphoryl chloride on the action of boron trifluoride etherate on the action of acetic anhydride and concentrated sulfuric acid or on the action of phosphorus pentoxide in benzene [71GEP2033971, 71JHC357 76JAP(K) 18440]. Depending on the work-up process, l-ethyl-4-oxoquinoline-3-carboxylates (750, R1 = Et), l-ethyl-4-oxoquinoline-3-carboxylic acids (750, R2 = H) and 3-ethoxycarbonyl-4-chloroquinolinium iodides (751) were obtained. Only the cyclization of... 

The cyclization of the racemic methyl ester of 1727 (R = Me) and its (S) enantiomer by boron trifluoride gave 9,I0-difluoro-7-oxopyrido[l,2,3-carboxylic acid and its optically active form, respectively [89J AP( K)228974]. 

The ability of quaternary ammonium halides to form weakly H-bonded complex ion-pairs with acids is well established, as illustrated by the stability of quaternary ammonium hydrogen difluoride and dihydrogen trifluorides [e.g. 60] and the extractability of halogen acids [61]. It has also been shown that weaker acids, such as hypochlorous acid, carboxylic acids, phenols, alcohols and hydrogen peroxide [61-64] also form complex ion-pairs. Such ion-pairs can often be beneficial in phase-transfer reactions, but the lipophilic nature of H-bonded complex ion-pairs with oxy acids, e.g. [Q+X HOAr] or [Q+X HO.CO.R], inhibits O-alkylation reactions necessitating the maintenance of the aqueous phase at pH > 7.0 with sodium or potassium carbonate to ensure effective formation of ethers or esterification [49,64]. 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

Hydrolysis of the ethyl ester proceeded smoothly using hydrochloric acid in acetic acid to give carboxylic acid 69 in 88% yield (Scheme 4.9). Previously, amines were allowed to react with the carboxylic acid core in hot DMSO to deliver the C7 products however, the difluoroborate 70, derived from the carboxylic acid 69, greatly increased the reactivity of the C7 position. Consequently, the displacement of the C7-F with amines was accomplished at lower temperature (Baker et al., 2004 Cecchetti et al., 1996 Domalaga et al., 1993 Ellsworth et al., 2005a,b Hu et al., 2003). In this event, the carboxylic acid was allowed to react with boron trifluoride to deliver difluroboronate 70 in excellent yield. The thus afforded borate ester reacted with A -methylpiperidine in DMSO in the presence of triethylamine at ambient temperature to furnish ( —)-ofloxacin (1, levofloxacin) in 56% yield. 

The gas chromatographic separation of acids present in plasticizers, apart from identifying volatile aliphatic carboxylic acids up to Ce, deals mainly with methyl esters. Carboxylic acids, present either as free acids or as alkali salts after saponification of the plasticizers, must be esterified. Conversion with methanol in presence of boron trifluoride (2) is recommended. But even better suited for plasticizer analysis is direct re-esterification of the plasticizers writh methanolic hydrochloric acid (2). 

Tributyltin hydride, 316 Tributyltinlithium, 319 Trichloroacetonitrile, 321 Other carbohydrates (Diethylamino)sulfur trifluoride, 110 Triethyloxonium tetrafluoroborate, 44 Carbonates (see also Enol carbonates) Carbon dioxide, 65 Di-/-butyl dicarbonate, 94 Carboxylic acids (see also Dicarbonyl compounds, Unsaturated carbonyl compounds)... 

The addition of carboxylic acids to alkynes affords enol esters which are useful as intermediates in organic synthesis.470 As in the addition to alkenes, a catalyst is usually required for high conversions of alkynes to enol esters. Simple acid catalysis has been employed (equation 279),471 but the more common catalysts are Lewis acids, such as boron trifluoride etherate,472 silver nitrate,473 zinc acetate474 and zinc oxide (equations 280 and 281),47S-476... 

Mercury salts, such as mercury(II) acetate,521-525 mercury(II) oxide,524,526-528 metcury(II) trifluoroace-tate,529,530 mercury(II) sulfate524,531 and mercury(II) phosphate531 catalyze the addition of carboxylic acids to alkynes. Acetic anhydride in the presence of boron trifluoride etherate can also be effectively used in this reaction (equation 292).521,522 Alkynoic acids undergo mercury-catalyzed cyclization to lactones (equation 293).523,532,533... 

Methyl esters may be prepared by reaction of the aromatic carboxylic acid with diazomethane (cf. Section 4.2.25, p. 433) or, more conveniently, by reaction with a boron trifluoride-methanol reagent. The latter procedure is illustrated by the preparation of methyl m-chlorobenzoate and dimethyl terephthalate (Expt 6.164). t-Butyl esters may be prepared by conversion of the acid into an N-acylimidazole by reaction with N,N -carbonyldiimidazole, followed by reaction with t-butyl alcohol in the presence of DBU62 (Expt 6.165). 

We also found that ester functionality was compatible with this reduction sequence. Thus, treatment of the ester-lactone 81 with sodium borohydride and boron trifluoride etherate provided the tetrahydropyran 123 in 55% purified yield. Upon reaction with sodium hydroxide, 81 underwent simple ester hydrolysis to furnish the carboxylic acid 127 (see Table 3). 

O-tert-Butyl trichloroacetimidate, prepared in 70% yield by reacting potassium rerr-butoxide with trichloroacetonitrile, reacts with carboxylic acids and alcohols in the presence of a catalytic amount of boron trifluoride etherate at room temperature in cyclohexane-dichloromethane [Scheme 6.35], 7 The method also converts alcohols to ferr-butyl ethers (see section 4.3.2). A very similar reaction that allows /erf-butylation under essentially neutral conditions on a large scale involves reaction of a carboxylic acid with 3-4 equivalents of JV,N -di-isopropyl-Orerf-butylisourea88 [Scheme 6,36].56S9 The reaction proceeds via a tertiary carbocation ion intermediate and since capture of the cation is inefficient, excess isourea is required. The presence of alcohols is tolerated but not thiols or unhindered amines. The reaction conditions are compatible with a range of acid sensitive groups such as AMrityl derivatives and cydopentylidene acetals.90... 

Mixed carboxylic-carbonic anhydrides decompose in the presence of DMAP to give esters and carbon dioxide under mild conditions [Scheme 6,51], In the case of benzyl esters, the mixed car boxy lic-car bon ic anhydrides can be generated by reaction of the carboxylic acid with benzyl chloroformate in the presence of triethylamine (1.1 equiv) and DMAP (0.1 equiv)126 or more conveniently by reaction of the carboxylic acid with dibenzyl dicarbonate (dibenzyl pyrocarbo-nate) in THF or ferf-butyl alcohol in the presence of DMAP (0.1 equiv).127 The reactions generally work well except for hindered carboxylic acids. The method can also be used to make methyl, ethyl, ferf-butyl and ally esters. Carboxylic acids react with 2 equivalents of benzyl 2,2t2-trichloroacetimidate12s in the presence of a catalytic amount of boron trifluoride etherate to give the benzyl ester in modest to good yield,12g... 

Naturally, it is possible to synthesise a similar ligand system without central chirality and in fact without the unnecessary methylene linker unit. A suitable synthesis starts with planar chiral ferrocenyl aldehyde acetal (see Figure 5.30). Hydrolysis and oxidation of the acetal yields the corresponding carboxylic acid that is transformed into the azide and subsequently turned into the respective primary amine functionalised planar chiral ferrocene. A rather complex reaction sequence involving 5-triazine, bromoacetal-dehyde diethylacetal and boron trifluoride etherate eventually yields the desired doubly ferrocenyl substituted imidazolium salt that can be deprotonated with the usual potassium tert-butylate to the free carbene. The ligand was used to form a variety of palladium(II) carbene complexes with pyridine or a phosphane as coligand. 

On-column methylation of barbiturates, hydan-toins, and some carboxylic acids can be achieved by injecting the sample mixed with 0.2M trimethyl-anilinium hydroxide in methanol. For carboxylic acids, the sample can be dissolved in 14% boron trifluoride in methanol and heated at 60 to 100° for 30 minutes. After evaporation of the bulk of the methanol, the mixture is diluted with a few millilitres of water and the methyl derivative extracted with a small volume of hexane. 

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