Imines fluorination

Isocyanides react with fluorine [75 to yield difluoromethylene imines, which tend to dimerize In an inert solvent, imines accept fluorine fioin trifluoromethyl hypofluorite [76, 77] (equation 11)... 

However, when the addition is performed 111 a nucleopliilic solvent such as methanol, cleavage of the imine linkage occurs to give difliioroamino compounds [78] (equation 12) W, At-Difluorotrifluoromethylamine can be prepared from or from thiocyanates, as shown in equation 13 [79, 80] Another way to produce difluoroamino compounds is the addition of fluorine to nitriles by means of AgFj [Sf ] or C0F3 [S/]... 

Trifluoromethylisocyanide reacts with hydrogen fluoride to give a mixture of isomeric fluorinated imines [56] (equation 12)... 

Carbon-nitrogen multiple bonds in fluorinated imines and nitriles react with halogen fluoride reagents Imines provide 7V-chloroamine.s on reaction with chlo rme fluoride [62, 121, 122, 123] (equations 23 and 24) or with cesium fluoride and chlorine [124] and A -bromoammes on reaction with cesium fluoride and bromine (equation 24)... 

Deprotonation of / /-cyclohexylfluoroacetone imines by lithium hexamethyl-disilazide or tertiary butyl lithium at very low temperature allows a regioselective alkylation at the carbon carrying fluorine [773] (equation 98). 

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

Hexafluoroacetone and certain perfluorinated or partially fluorinated ketones, aldehydes, and imines react with a-functionalized carboxylic acids (e.g., a-amino, a-At-methylamino [S3, 84], a-hydroxy [S5], and a-mercapto [Sd] acids) to give five-membered heterocyclic systems (equation 13). 

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

The mechanism of attack of 1,3-dipolar reagents on fluoroalkenes can be considered to be either stepwise or concerted. Heteroaromatic N-imines react by a stepwise 1,3 addition to perfluoroalkenes and -alkynes to give fluorinated pyrazolo[l,5-a]pyridines [82JCS(P1)1593]. Pyridinium /-butoxycarbonylmethylide with fluoroalkenes gave pyrrolo[l,2-a]pyri-dines [86JCS(P 1) 1769] and indolizines (22) are obtained with pyridinium phenacylide [91JFC(51)407]. 

Pyrimidin-2-ones 43 with fluorinated substituents have been prepared by reaction of metallated imines with fluorinated nitriles, followed by cyclisation with triphosgene <06T1444>. 

Fluorinated triazole derivatives have been prepared by a somewhat deceptive route that starts with imine perfluoro(5-aza-4-nonene) 140 reaction of 140 with aromatic hydrazines gives 1,2,4-triazoles 141a-g in good yields (Equation 44 and Table 27) <2001RJ01621, 2001ZOR1693>. 

Racemic fluorinated tryptophan derivatives 31 were obtained from 3-methylene indole 29 and fluorinated imines 30 using the imino-ene reaction (Equation (18)).28 The highest yields were obtained for the more electrophilic imines (R2 = SC>2Ph, Ts, SC Me). Moreover, these reactions took place at ambient temperature. 

As well as the Bingel reaction and its modifications some more reactions that involve the addition-elimination mechanism have been discovered. 1,2-Methano-[60]fullerenes are obtainable in good yields by reaction with phosphorus- [44] or sulfur-ylides [45,46] or by fluorine-ion-mediated reaction with silylated nucleophiles [47]. The reaction with ylides requires stabilized sulfur or phosphorus ylides (Scheme 3.9). As well as representing a new route to l,2-methano[60]fullerenes, the synthesis of methanofullerenes with a formyl group at the bridgehead-carbon is possible. This formyl-group can be easily transformed into imines with various aromatic amines. 

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

Metabolism of the anti-malarial amodiaquine provides quinone-imine, which is an electrophilic metabolite responsible for hepatotoxicity and agranulocytosis. These side effects have severely restricted the clinical use of amodiaquine. The replacement of the phenolic hydroxyl by a fluorine prevents from oxidation process. Then, the A/-dealkylation becomes the major process. This has led to further refinements, with the preparation of the A/-f-butyl analogue, a compound which resists towards metabolic side-chain cleavage and has an excellent in vitro and in vivo profile (Fig. 15) [56]. 

Although the fluoride anion is not a good leaving group (because of the great strength of the C-F bond), ketones, imines and jS-fluoroesters easily afford this S-elimination reaction (Fig. 22) [77], The S-elimination process remains efficient for CF2 and CF3 compounds, while the C-F bond is stronger. Indeed, fluorine atoms render more acidic the a proton, which makes easier the formation of the anion. 

While nonracemic trifluoroalanines can easily undergo racemization or dehydro-fluorination, many asymmetric syntheses oftrifluoroalanines have been proposed. These syntheses generally involve an asymmetric reduction step of an imine or an enamine. This step can be performed by utilizing either chiral catalysts or chiral auxiliaries. 

Unique and versatile olefin polymerizations with group 4 bis(phenoxy-imine) complexes have been disclosed by scientists at Mitsui. " In a series of Ti complexes with fluorinated iV-phenyl groups (Figure 10, complexes FlO-7-FlO-14), Mitani et al. observed a substantial difference in ethylene polymerizations between complexes having... 

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