Halogenated quinolines, directed

Fluoropyridines have been prepared by direct reaction of fluorine diluted in an inert gas and dissolved in a polyhalogenated solvent (91BCJ1081). Presumably these reactions involve attack by free halogen atoms as distinct from the ionic halogenation at lower temperatures which gives p-orientation (cf. Section 3.2.1.4.7). Under similar conditions (Br2,450°C) quinoline gives 2-bromoquinoline. 

The direct halogenation of furan is unsatisfactory on a preparative scale, and halofurans are more conveniently prepared by the following methods (B-79M131200). Decarboxylation of halofurancarboxylic acids is usually carried out with copper and quinoline at 150-230 °C to yield the corresponding halofuran, which can be removed by distillation. 

The preparation of fluorinated pyridine derivatives continues to be of considerable importance due to the effect that the fluorine atom can have on the physical, chemical, and biological properties of the heterocycle. Despite this, there are few reports on the direct electrophilic fluorination of pyridines. The treatment of various quinoline derivatives with elemental fluorine in acidic reaction media afforded mono- and difluorinated products where the halogenation occurred on the benzene ring of the heterocycles <2004JFC661>. 

To substantiate this mechanism, haloquinolines (75) were used. The strategy was to hinder sterically the addition of superoxide. In the case of 6-chloroquinoline, the products were the same as those formed from quinoline, except that they were chlorinated, which was expected because position 6 is not involved in either mechanism. Halogen substitution on the pyridine moiety in part directed oxygen addition to the benzene moiety, which was consistent with superoxide addition onto the more accessible positions on the benzene ring of the halogenated radical cation. This result supports the fact that a cycloaddition mechanism can take place in the photocatalytic degradation of quinoline. This mechanism has been proposed in the case of other aromatics, such as 4-chlorophenol (76) and 4-chloro-catechol (77). 

In some ylides photolytic conditions were necessary for their transylidation [30]. The conversion of iodonium ylides into a-halogeno derivatives of the parent carbonyl compound (or other precursor) with hydrogen halides is normally effected directly, without isolation of their iodonium salts. A similar reaction with halogens leads to the formation of a,a-bis halogenated products [31]. The reaction of pyridines with the non-isolable PhI=C(CN)2 is of interest, since it permits the ready transfer of the C(CN)2 functionality to the nitrogen of pyridine, quinoline, etc. the yields here were generally moderate but in some cases the products could not be obtained using other dicyanocarbene precursors [32],... 

Puschel and Stefanac use alkaline hydrogen peroxide in the oxygen flask method to oxidize arsenic to arsenate. The arsenate is titrated directly with standard lead nitrate solution with 4-(2-pyridylazo) resorcinol or 8-hydroxy-7-(4-sulpho-l-naphthylazo) quinoline-5-sulphonic acid as indicator. Phosphorus interferes in this method. The precision at the 99% confidence limit is within 0.67% for a 3-mg sample. In another variation, Stefanac used sodium acetate as the absorbing liquid, and arsenite and arsenate are precipitated with silver nitrate. The precipitate is dissolved in potassium nickel cyanide (K2Ni(CN)4) solution and the displaced nickel is titrated with EDTA solution, with murexide as indicator. The average error is within 0.19% for a 3-mg sample. Halogens and phosphate interfere in the procedure. 

The Pd-catalyzed oxidation of unfunctionalized C-H bonds has recently been described by Sanford. These reactions lead to the direct, regioselective installation of hydroxyl groups or halogen atoms onto aromatic and heteroaromatic ring systems. For example, benzo[//]quinoline is selectively converted to 10-chlorobenzo[A]quinoline upon treatment with catalytic Pd(OAc)2 and NCS [103]. As shown below, these transformations are also effective for the installation of oxygenated functional groups including acetates and alkyl ethers. The oxidative functionalization of. sy/ C-H bonds has also been achieved [104]. 

A limited use of direct electrophilic substitution combined with halogen/lithium exchange or orf/to-lithiation allows us to make a variety of pyridines and quinolines. When the N-oxides are used as well, the scope is even wider. Nucleophilic substitution extends this still further. In the next chapter (33) we shall see that electrophilic oxygen can also be added to pyridines. What is missing is the direct formation of 3-substituted pyridines this is dealt with in the next section. 

Direct deprotonation of quinolines or isoquinolines can only be succeeded via directed ort/io-metalation. Metal-halogen exchange can be used to produce organometallic nucleophiles from the halides located either on the benzene or the pyridine ring. ... 

On the other hand, quinolinyl nucleophiles as the quinolinylzinc derivatives presented in the following example have been prepared by the in situ transmetallation of quinolinyllithium salts realized by direct halogen-metal exchange of 6-bromo quinoline derivative. The zinc salt was allowed to react with several aryl bromides, affording clean Negishi reactions for the formation of 6-substituted derivatives, which are potent inhibitors of steroid 5a reductases of types 1 and 2 ... 

If the aromatic moiety of a cinnamylamine derivative has an ort/io-halogen substituent, 1,2-dihydroquinoline would be obtained yia the subsequent S Ar reaction. In the presence of catalytic amounts of tosylamide, MBH adduct 603 was rearranged to the thermodynamically more stable tosylamide derivative, which then could be easily subjected to nucleophilic aromatic substitution reaction at the ortho position, giving 1,2-dihydroquinoline 605 in 81% yield. Furthermore, using DBU as a base, elimination of p-toluenesulfinic acid afforded quinoline 606 in 69% yield (Scheme 4.178). However, interestingly, Xn-substituted MBH adducts 607 were directly converted into quinolines 608 in a one-pot reaction in moderate yields. The discrepancy between 604 and 607... 

Halogenation. Direct halogenation of quinoline proceeds at the 2-position. Fluorination and bromination are known, but they proceed using forcing conditions (eqs 24 and 25). lodination proceeds under milder conditions, but requires an additional titanium-based reagent (eq 26). Chlorination of quinoline without prior activation has not been reported. 

Abstract The data on the chemistry of fluorinated quinolines available in the literature of the last 10-15 years are presented. A variety of synthetic methods exploiting cyclization and cycloaddition reactions, displacements of halogen atoms or the diaza group, as well as direct fluorinations have been considered. Novel approaches to functionalization of polyfluorinated quinolines, including nucleophilic displacement of fluorine atoms, cross-coupling reactions, and synthesis on the basis of organome-tallic compounds are discussed. Selected representative examples of fluoroquinolines... 

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