Arylation of quinolines

Phenylation of quinoline with benzoyl peroxide is easier (qpl,nR 5.0) than that of pyridine (71BSF2612). Substitution takes place at all carbons, and partial rate factors (F2 = 3.3, F3 = 1.8, F4 = 5.4, Fs = 6.6, F6 = 1.5, F7 = 1.6, F8 = 9.6) were obtained at 1% conversion. Homolytic arylation of quinoline is not of much synthetic value as reactions taken to higher conversion suffer not only from lack of selectivity, but di- and poly-substitution also take place. 

The immediate products of addition of alkyl and aryl Grignard reagents and alkyl- and aryllithiums are dihydro-quinolines and -isoquinolines and can be characterised as such, but can be oxidised to afford the C-substituted, re-aromatised heterocycles illustrated below is a 2-arylation of quinoline. ... 

A number of methods for the derivitazion of quinoline have been described in the literature many of them are complementary (Scheme 10.42). One example for regioselec-tive C2-arylation came from laboratories of Bergman and Ellman. °° In this method, a rhodium(I) complex was shown to catalyze the direct arylation of quinolines 126 with electron-deficient and electron-rich aryl bromides to afford products 127A-D. The... 

Arylation of Quinoline N-Oxides and Pyridines N-Oxides. An efficient protocol to directly arylate quinoline A-oxides was developed using palladium acetate as the catalyst and potassium carbonate as the hase. A survey of different phosphines demonstrated that the sterically less encumbered di-tert-butyl(methyl)phosphonium tetrafluoroborate provides higher yields relative to tri-iert-hutylphosphine. Using this protocol, 15 quinohne A-oxides were arylated in good to excellent yields (eq 1). ... 

Palladium and nickel catalysts can also be used to effect arylation of quinoline at the 2-position. Using Pd(OAc)2 and AgN03/02 as an oxidant system results in an oxidative arylation (eq 21). Similarly, using Ni(cod)2 and diarylzinc nucleophiles, it is possible to selectively arylate the 2-position (eq 22). ... 

The Lewis acid-catalyzed cyclization of 3-anaino-2-alkerLirnines (21) leads to a wide variety of alkyl- and aryl-substituted quinolines (59). The high regiospecificity and the excellent yields obtained make this process promising. 

Alteration of the relative reactivity of the ring-positions of quinoline is expected and observed when cyclic transition states can intervene. Quinoline plus phenylmagnesium bromide (Et20,150°, 3 hr) produces the 2-phenyl derivative (66% yield) phenyllithium gives predominantly the same product along with a little of the 4-phenylation product. Reaction of butyllithium (Et 0, —35°, 15 min) forms 2-butylquinoline directly in 94% yield. 2-Aryl- or 6-methoxy-quinolines give addition at the 2-position with aryllithium re-agents, and reaction there is so favored that appreciable substitution (35%) takes place at the 2-position even in the 4-chloroquinoline 414. Hydride reduction at the 2-position of quinoline predominates. Reaction of amide ion at the 2-position via a cyclic... 

Modifications of this method, such as the use of the more stable diazonium trifluoroacetates and the decomposition of benzenedia-zonium zincichloride with zinc dust, have been used as sources of aryl radicals, although not in the arylation of heterocyclic compounds. Pyridine, quinoline, and thiophene can be phenylated by treatment with benzenediazonium chloride and aluminum trichloride. ... 

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

The palladium-catalyzed arylation of alkenes by haloarenes, and applications in furan synthesis have been described earlier (see Eq. 14 in Section IV,B, 1). By employing o-aminoiodoarenes and appropriately substituted (Z)-alkenes it has proved possible to develop an efficient synthetic route to quinolin-2-ones (Scheme 140).213... 

Fig. 16 Summary of the best results obtained in the Ir-catalyzed hydrogenation of quinolines, quinoxalines, and Af-aryl imines using binol-derived phosphoroamidite PipPhos 19 ligand...

Synthesis of quinolines by nucleophilic substitution of nitrogen atom in oxime derivatives was described by Narasaka and coworkers. /3-Aryl ketone oximes 297 in the presence of trifluoroacetic anhydride and 4-chloranil afforded quinolines 298 in 72-82% yield (equation 128). However, interaction of oxime 299 with 48% HBr at 105 °C proceeded with elimination of hydroxyimino group and gave 2,3-dimethoxynaphtho[l,2-fc]quinolizinium bromide (300) in 45% yield (equation 129). ... 

Akiyama et al. extended this reaction to alkynylimines for the preparation of quinoline derivatives [28]. Treatment of N-aryl(alkynyl)imines 99 with 20 mol% W (CO)5(thf) in THF at reflux followed by oxidative work-up using NMO gave 2-arylquinolines 100 in reasonable yield through electrocydization of the vinylidene intermediate (Scheme 5.31). 

A preparation of quinoline-3-thiol from the diazonium salt, according to prior literature, and using potassium ethyl xanthate, abnormally threw down a solid during extraction of the product into ether. This solid, filtered and dried, exploded on prodding with a metal spatula. The solid had an nmr spectrum consistent with the expected product, an 5-aryl-O-ethyl xanthate. Although the author appears aware of only the arenediazosulfide hazard, this must have been the 5 -arenediazoxanthate. A misprint renders quinoline as quinine. 

The synthesis of derivatives of quinoline from isatins and carboxylic acid anhydrides can also be realized without isolating the intermediate N-acyl derivatives. Thus, unsubstituted 2-quinolonecarboxylic acid containing the 14C isotope at position 3 was synthesized by the condensation of isatin 7 with the anhydride (H314CC0)20 [172], The unsubstituted acid 168 [163] and its 3-aryl derivatives 195 [173, 174] were obtained by heating the isatin 7 directly with the respective anhydrides. 

Optically active pipecolic acid and its derivatives can be prepared via 4-phenylpyrido[2,l-c][l,4]oxazin-l-one derivatives. Representatives of the third generation of quinoline-3-carboxylic acid antibacterial agents ofloxacin (19), its levorotatory enantiomer, levofloxacin (20), and rufloxacin (21) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (22) is under development. Other 10-aryl-9-fluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzox-azine-6-carboxylic acids and 7//-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylic acids exhibit mammalian topoisomerase II inhibitory activity. 

In the course of an investigation on axial chirality in metal chelates [60], 4- and 5-aryl-substituted quinolin-8-ols were required. If, in the case of aryl groups bearing bulky sub-... 

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