Anilines fluorination

Perfluorobenzene undergoes Sf Ar reactions readily with dimethylarmne, aniline, N methylaniline [AS], piperidine, A/-tnmethylsilyliminotnmcthylphos-phorane [69], and bthinm aniUde [70], but the reactions are often accompanied by sigmficant amounts of di- or polysubstitubon However, with the lithium salt of A -tnmethylsilylanilme, only one fluorine atom in pcrfluorobenzeneis replaced [71] (equation 36)... 

The electronic properties of the aniline are important in the Doebner reaction. The reaction works best with electronic donating groups. Anilines substituted with a chlorine at the meta position consistently give low yields, but fluorine at the meta position seems... 

Acetylated aniline 21 was reacted under Skraup/Doebner-von Miller conditions in the presence of an arsenic salt to yield quinoline 22 with concurrent displacement of fluorine. ... 

In hydroxyUc solvents, the reaction with aniline follows a bi-molecular course but is complicated by competing solvolysis. This is a striking result when compared with the behavior of picryl chloride, which is much more selective with regard to the same reagents (aniline and alcohol), and has been interpreted to mean that bond-breaking has made appreciable progress in the rate-determining step of the reaction of phosphonitrilic chloride. Furthermore, the same indication is obtained from the fact that in the reactions of the halides, the fluorine chlorine ratios are less than one. ... 

In the right-hand section, N-ethylation of the aniline nitrogen was optimal, while shifting the methyl to the 4-position increased activity. This, combined with fluorination at the m-position, afforded (23b) as the most potent compound of this series. Since the pharmacokinetic properties of (23b) were not disclosed, it is not clear if manipulation of the hit compound led, apart from an increase in potency, to a corresponding improvement of the pharmacological profile. 

Chlorine dioxide Copper Fluorine Hydrazine Hydrocarbons (benzene, butane, propane, gasoline, turpentine, etc) Hydrocyanic acid Hydrofluoric acid, anhydrous (hydrogen fluoride) Hydrogen peroxide Ammonia, methane, phosphine or hydrogen sulphide Acetylene, hydrogen peroxide Isolate from everything Hydrogen peroxide, nitric acid, or any other oxidant Fluorine, chlorine, bromine, chromic acid, peroxide Nitric acid, alkalis Ammonia, aqueous or anhydrous Copper, chromium, iron, most metals or their salts, any flammable liquid, combustible materials, aniline, nitromethane... 

Aniline, dimethylamine and pyridine incandesce on contact with fluorine. 

Ring transposition processes are well established in six-membered heteroaromatic systems. Recent studies have centered on perfluoro systems in which bicyclic and tricyclic intermediates are sufficiently stable to permit isolation or at least detection. Thus, on irradiation in CF2C1CFC12, the perfluoropyridine 207 is converted into the azabicyclo[2.2.0]hexa-2,5-diene 208 and the two azaprismanes 209 and 210.154 An azabicyclo[2.2.0]hexa-2,5-diene has also been shown to be an intermediate in the photorearrangement of substituted 2-methylpyridines to o-substituted anilines.155 Diaza-bicyclo[2.2.0]hexa-2,5-dienes have similarly been shown to be intermediates in the conversion of fluorinated pyridazines (211) into the corresponding pyrazines (212)156 the proposed pathway is outlined in Scheme 7. Photoproducts which are formally dimers of intermediate azetes have been obtained when analogous reactions are carried out in a flow system.157... 

As we have seen (pp. 50 et seq.) the reaction between phosphorus oxydichlorofluoride and alcohols, phenols and thiols, affords dialkyl, dicyctoalkyl, diaryl phosphorofluoridates and dialkyl phosphorodithiolates. In a Report1 to the Ministry of Supply on fluorophosphonates a description was given of a new type of nitrogen fluorophosphonate formed by the action of 4 mol. of aniline on 1 mol. of phosphorus oxydichlorofluoride, the fluorine atom being unaffected ... 

In the toluidines (methylanilines) the n MO is destabilized by 0.2-0.3 eV, while in the corresponding monofluoroanilines it is stabilized by about 0.1 eV75. The effect of several fluorine atoms seems to be additive, as indicated by the IP( n) value of pentafluoroaniline42,71 which is 0.7 eV greater than that of aniline. 

The SnCU-catalysed Claisen and Cope rearrangements of A -allylanilines and N-allylenamines, and the effect of meffl-substituents in the aromatic ring on the Claisen aromatic amino rearrangement of a series of fluorinated anilines, have been investigated. 

One of the earlier second-generation quinolones indeed includes fluorine at the 6 position and a basic function at the 7 position, characteristic of the more potent drugs that also feature a broader spectmm of antibacterial activity. The starting material (39-3) for one of these agents is prepared by application of the same scheme as above to the substituted aniline (39-1). Nucleophilic aromatic displacement with A-methylpiperazine (39-4) proceeds at the 7 position due to activation by the carbonyl group para to the chlorine (39-5). Saponification of the displacement product leads to pefloxacin (39-6) [46]. 

It is interesting to note that a number of researchers have attempted, more or less successfully, to construct reliable mathematical models which combine structural elements and experimental data to predict the toxicities of new substances not yet experimentally tested for humans and other species.110152 Furthermore pharmacology, toxicity, metabolism and enzyme-inhibiting effects of fluorine-containing aromatic systems (e.g., anilines, ben-zothiadiazines, butyrophenones, corticoids, phenothiazines, steroids, uracils) have been discussed in depth in the literature.153-156... 

In contrast, some substituted anilines, e.g. 2-nitroaniline,143 2-chIoro-4-(trifluoromethyI)ani-Iine,143 benzene-1,3-diamine,150 or 4-chlorobenzene-1,3-diamine,150 give only very low yields of product or formed tars under the fluorination conditions. The diazotization followed by in situ fluorodediazoniation of the corresponding diazonium salts have been systematically studied in hydrogen fluoridc/base solutions of different composition to ascertain the most important influences on the reaction.329 Besides numerous examples of substituted anilines, various derivatives of pyridine, pyrimidine, 1.3,5-triazine, and benzthiazole have been included in these investigations (yields 45—99%). 

The reactivity of aromatic molecules in fluorination reactions with trifluoromethyl hypofluorite has been studied in detail, and in the case of aniline derivatives the effect of the substituent on nitrogen on the relative reactivity and ortho/para ratio in various aprotic nonpolar, aprotic polar and protic solvents has been determined.5... 

---