Quinolone halogenation

The 5-position of quinolones can be substituted by small groups such as halogens, hydroxyl, or amino (54—56). The amino group at this position can be advantageous, particularly when appHed to 6,8-difluoro-7-piperazinyl or 6,8-difluoro-7-pyrrohdinyl quinolones. In contrast to 6,8-difluoro quinolones, when this replacement is appHed to ofloxacin, the resulting derivative has reduced antibacterial activity (57). Replacement of the 5-amino group with methylamine or dimethylamine causes activity to drop substantially. Sparfloxacin [110871-86-8] (21), a representative of 5-amino-6,8-difluoro quinolones, affords modest improvements in gram-positive activity as well as increased in vivo potency when compared with both ciprofloxacin and ofloxacin (54). 

In the general preparation of quinolones by forming the nitrogen aryl bond a in the ring closure, typical precursors are prepared as shown in Figure 2. The ring closure involves nucleophilic displacement of a halogen, usually a chlorine or fluorine (76) eg, (29) and (30) lead to (31) [86483-54-7] and (32) [123942-15-4] respectively. 

This coupling works best when the halogen at the 7-position is bromine rather than chlorine or fluorine. This represents the first appUcation of this coupling reaction to the intact quinoline nucleus and thus represents an important advance in quinolone chemistry. 

A popular method to prepare haloquinolines is the halogenation of quinolones using oxyphosphorus halides, most notably POCI3. The... 

Among the nucleophilic processes available for introduction of bromine to quinolines are reactions of the diazonium salts (87JHC181) and syntheses based on hydroxyquinolines or quinolones (91M935) (Scheme 36). The former processes are especially useful for making 5-, 6-, 7-, and 8-bromo derivatives. Halogen-halogen exchange reactions have also been reported, but they are not common. When perfluoroquinoline was heated... 

Coverage is restricted to halogenation of conjugated heterocycles. Although not all of these can be classified as aromatic (e.g., pyranones, fulvalenes), there are aspects of their reactivities that have parallels in the series traditionally classified as heteroaromatic. Processes that produce a halogenoaromatic product from a nonaromatic substrate (e.g., quinolone to chloroquinoline) are usually included. 

Another property of the quinolone class is phototoxicity, extreme sensitivity to sunlight. Quinoloncs pos.sessing a halogen atom at the 8 position (e.g., lomeiloxacin) have the highe.st incidence of phototoxicity, while those having an amino (e.g.. sparfloxacin) or methoxy group at either the S or the 8 position have the lowe.st incidence. ... 

Lomefloxacin reportedly causes the highest incidence of phototoxicity (photosensitivity) of the currently available quinolones. The presence of a halogen atom (fluorine, in this case) at the 8 position has been correlated with an increased chance of phototoxicity in the quinolone.s. ... 

A popular method to prepare haloquinolines is the halogenation of quinolones using oxyphosphorus halides, most notably POCI3. The carbonyl can be located either at the C(2) or the C(4) positions. As depicted in Scheme 1, the C(2) position of quinolone 4 was chlorinated with POCI3 to give 6-bromo-2-chloroquinoline (5) [1]. The subsequent S Ar displacement of the chlorine substituent on 5 with sodium methoxide led to 6-bromo-2-methoxyquinoline. Analogously, chlorination at the C(4) position of quinolones is exemplified by transformations 6 7 [2] and 8 9 [3]. 

Many quinoline derivatives are important biologically active agents. 8-Hydroxyquinoline and some of its halogenated derivatives are used as antiseptics. Chloroquine 111 is one of the older but still important antimalarials. A -Alkyl-4-quinolone-3-carboxylic acid and systems derived therefrom are constituents of antibacterials (gyrase inhibitors [112]) such as nalidixic acid 112, ciprofloxazin 113 and moxifloxazin 114. The quinoline-8-carboxylic acid derivative 115 (quinmerac) is employed as a herbicide for Galium aparine and other broad-leaved weeds. Methoxatin 116, known as coenzyme PQQ is a heterotricyclic mammalian cofactor for lysyl oxidase and dopamine P-hydroxylase [113]. 

Structure-activity relationships in both quinolone and naphthyridone series of compounds have shown that introduction of a C-6 substituent tends to enhance antibacterial activity [3, 5] and it is of particular interest that replacement of an hydrogen atom by an halogen atom especially fluorine results in an outstanding enhancement of the antibacterial activity. All the clinically useful new quinolones bear a fluorine at the C-6 position of the quinolone, naphthyridine, or benzoxazine ring system and consequently almost all the chemical modifications involved any position but C-6, the fluorine atom being always present. 

In the quinolone series when the halogen in position 7 is a chlorine atom, the condensation of amines is effective only on free carboxylic acids. If a fluorine atom is present at C-7, then the nucleophilic displacement can be realized on esters of carboxylic acids. 

In addition to reaction catalysts, a number of quinolines were described with valuable chemo-sensing properties. Even a simple quinolone, such as that shown in Scheme 1, can be used as a method for cyanide detection in aqueous environments (14TL1052).This quinoline-derived probe with an aldehyde forms a cyanohydrin with strong fluorescence. Another quinoline chemosensor, a quinoline tripodal thiourea, selectively binds with fluoride and no other halogens (14TL1467). A thioamide-based sensor with both... 

These are intermediary chemicals in the synthesis of halogenated quinolones and quinolines. A dermatitis on the face and wrist of a young woman was described by Rycroft in 1981. She had come into contact only once with the quinolone derivative and twice with the anilide compound. 

A Parham cyclization strategy has been used to synthesize a wide variety of isoquinolines. For example, iodide 66 is smoothly converted to 67, which can be reduced (sodium borohydride/trifluoroacetic acid, 99%) or treated with nucleophiles and a Lewis acid to effect a-amidoalkylation. Likewise, imidazo[4,3-a]isoquinolinones (68), ° thiazolo[4,3-a]isoquinolinones (69), ° pyrrolo[2,l-a]isoquinolines (70), pyrrolo[ 1,2-6] isoquinolines (71), pyrrolo[l,2-6]acridinones (72), ° pyirolo[l,2-g]quinolones (73), ° thieno[3,2-y]indolizinones (74), ° and furo[3,2-/lindolizinones (75). ° It should be noted that the latter ring system 63 was prepared by deprotonation (LDA) rather than halogen-lithium exchange. °... 

The triflate leaving group was introduced to coupling reactions as an alterative to halogens. They are particularly useful when there is no simple way to prepare the required halide partner. Aryl triflates can be prepared from phenols and pyridyl triflates can be prepared from pyridones. This transformation is usually achieved using triflic anhydride and an amine base. The coupling of a triflate 2.191, derived from quinolone 2.190, with stannane 2.192 was used in a short synthesis of dubamine 2.193 (Scheme 2.66). 

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