Amides fluorination

As a noble metal, silver becomes one of the most important metals in the life of human beings, which has been used as currency and ornaments by humans for thousands of years. Nowadays, silver and its salts have been widely used in photography, electrical equipment, jewelry, as well as transition metal for catalysis in chemistry. In chemical research, silver complexes were usually thought to be low activity and used as either co-catalysts [1, 2] or Lewis acids [3] for decades. In recent years, a wide range of important organic transformation has been catalyzed by silver complexes, including C-H insertion, amination/amidation, fluorination, hydrosilylation, decarboxylation, and so on [4-12]. 

Particularly alkyl halides which have a perfluoroalkyl group at the /3-position undergo smooth carbonylation. Probably the coordination of fluorine to form a five-membered chelate ring accelerates the reaction. Double carbonylation to give the a-keto amide 915 is possible in Et NH with the fluorine-bearing alkyl iodide 914[769,770]. The ester 917 is obtained by the carbonylation of the /3-perfluoroalkyl iodide 916 in ethanol. 

A/-Chloro fatty acid amides have been synthesized from the direct halogenation of the amide in boiling water (28). They are useful as reactive intermediates for further synthesis. Fluorination has also been reported by treating the fatty amide with fluorine-containing acid reagents at 200 °C to reach a fluorinated amide with less reactivity toward fluorocarbon polymers (29). 

Fluorocarbon soHds are rare in defoamer compositions, presumably on account of their cost. SoHd fluorine-containing fatty alcohols and amides are known. The most familiar fluorocarbon soHd is polytetrafluoroethylene [9002-84-0]. Because it is more hydrophobic than siHcone-treated siHca, it might be expected to perform impressively as a defoamer component (14). However, in conventional hydrocarbon oil formulations it works poorly because the particles aggregate strongly together. In lower surface tension fluids such as siHcone and fluorocarbon oils, the powdered polytetrafluoroethylene particles are much better dispersed and the formulation performs weU as a defoamer. 

Beyer synthesis, 2, 474 electrolytic oxidation, 2, 325 7r-electron density calculations, 2, 316 1-electron reduction, 2, 282, 283 electrophilic halogenation, 2, 49 electrophilic substitution, 2, 49 Emmert reaction, 2, 276 food preservative, 1,411 free radical acylation, 2, 298 free radical alkylation, 2, 45, 295 free radical amidation, 2, 299 free radical arylation, 2, 295 Friedel-Crafts reactions, 2, 208 Friedlander synthesis, 2, 70, 443 fluorination, 2, 199 halogenation, 2, 40 hydrogenation, 2, 45, 284-285, 327 hydrogen-deuterium exchange, 2, 196, 286 hydroxylation, 2, 325 iodination, 2, 202, 320 ionization constants, 2, 172 IR spectra, 2, 18 lithiation, 2, 267... 

Electropositive fluorinating agents are categorized in distinct classes as (1) fluoroxy reagents, in which the fluorine is bound to an oxygen atom (for reviews, see references 1,2,3, 4, 5, and 6) (2) fluoraza reagents, in which the fluorine atom IS bound to the nitrogen atom of either an amide or ammonium ion structure (for a partial review, see reference 6), (3) xenon difluoride, in which the fluorine atoms are bound to xenon (for reviews, see references 5, 7, 8, and 114) and (4) perchloryl Iluoride, in which the fluorine atom is bound to the chlorine atom of the perchloryl function (for a review, see reference 9). 

Trimelhylsilyl enol ethers are effective substrates in fluorination with fluo-roxytrifluoromethanefor the preparation of a-fluoro esters, amides and aldehydes [J7] (equations 13-15)... 

The fluoraza reagents consist of two types of compounds one in which a fluorine atom is bound to the nitrogen atom of an amide or, more often, a sulfonamide and one in which a fluorine atom is bound to the nitrogen atom of a tertiary amine such as pyridine, quinuclidine, or triethylenediamine 1,4-diaza-bicyclo[2 2.2]octane. The positive charge on the nitrogen is counterbalanced by a non-nucleophilic anion such as triflate or tetrafluoroborate. 

The A -fluoroamide reactants were initially prepared by fluorination of amides with fluoroxytnfluoromethane [63 Current methods involve the direct fluorination of amide reagents with elemental fluorine under a variety of conditions [48. 64, 65, 66, 67, 68, 69, 71, 72, 73, 74, 76, 81. 82] (Tables 3a and 3b)... 

Amino groups bound to sulfur can be replaced by fluorine via diazotization. In contrast to carboxylic acid amides, fluorodediazoniation of aromatic sulfonamides IS readily accomplished to give sulfonyl fluorides in high yields [52, 7S (equation 16) Tetrazotization-fluorination of sulfanilamide can also be effected to give a 38% yield of p-fluorobenzenesulfonyl fluoride [52],... 

Fluorinated organosilicon compounds may be prepared from readUy available fluorohalocarbons by using phosphorous amides [84, 85, 86] or tetrakis(dimeth-ylamino)ethylene [57] for the generation of the fluoroorganic nucleophiles (equations 61-69). 

Compounds where fluorine is bound directly to silicon may be prepared duectly from sihcon tetrafluonde, obtamed by treatment of sihcon tetrachlonde with antimony tnfluonde and an alkyUithium or hthium amide base [99, 100] (equauon 80)... 

The reactions of fluorinated esters and amides to form, respectively, enol ethers [47] and enamines [4S] give high yields and are interesting synthetic transformations (equations 34 and 35) (Table 12)... 

Table 12. Fluorinated Esters and Amides in the Wittig Reaction to Form Enol Ethers [47 and Enamines 48 ...

In the Schmidt reaction of fluonnated dicarboxyhc acids, the appropnate amides can be obtained in fairly good yield [48] Complications arise from possible cychzation if the fluorine atom is in the 8 position relative to the newly formed amino group [/] Fluonnated aromatic ethers, upon heating in dimethylformamide, undergo Smiles rearrangement to give diarylamines [49, 50] (equation 11)... 

It is interesting to note that all the new aromatic systems, as described, undergo displacement polymerizations in DMAC solvent by the K2CO3 method, except perfluoroalkylene [10] and amide activated polymerization [9], which were performed in NMP solvent. The displacement polymerization in DMAC solvent was carried out at 155-164°C. poly(aryl ether ketones) require less reaction time (3-6 h) than other aromatic systems for synthesis of polyethers [15]. Synthesis of the fluorinated polyether as reported by Irvin et al. [16] was carried out at room temperature for 16 h (Mw = 75,000), whereas the same polymer by Mercer et al. [17] was synthesized at 120°C for 17 h (Mw = 78,970). 

Nitrogen- or Fluorine-Containing Phosphonates In N-containing phosphoric acid esters an >NH or >NR group is used instead of the bivalent >0. A typical reaction is the transformation of POCl3 with primary or secondary amines to the corresponding amides see Eq. (73) ... 

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

The 3-O-methyl derivative of methyl 2-acetamido-2-deoxy-/3-D-glucopyranoside has the same c.d. spectrum in water and in fluorinated alcohols. This confirms that solvent binding to the 3-hydroxyl group is important in determining the orientation of the amide relative to the 3-substituent. 

Surfactants used as lubricants are added to polymer resins to improve the flow characteristics of the plastic during processing they also stabilise the cells of polyurethane foams during the foaming process. Surfactants are either nonionic (e.g. fatty amides and alcohols), cationic, anionic (dominating class e.g. alkylbenzene sulfonates), zwitterionic, hetero-element or polymeric (e.g. EO-PO block copolymers). Fluorinated anionic surfactants or super surfactants enable a variety of surfaces normally regarded as difficult to wet. These include PE and PP any product required to wet the surface of these polymers will benefit from inclusion of fluorosurfactants. Surfactants are frequently multicomponent formulations, based on petro- or oleochemicals. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

The relative reactivity of a-haloacetates toward protein functional groups is sulfhydryl > imidazolyl > thioether > amine. Among halo derivatives the relative reactivity is I > Br > Cl > F, with fluorine being almost unreactive. The oc-haloacetamides have the same trend of relative reactivities, but will create a terminal amide group not a terminal carboxylate. 

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