Heteroarenes arylation

Desulfuration.1 This complex as such or in combination with 2,2 -bipyridyl (bpy) or triphenylphosphine (a NiCRAL) can effect desulfuration of heteroarenes. aryl thioethers, dithioketals, sulfoxides, or sulfones in DME or THF at 63° in 1.5-30 hours. NiCRA is sufficient for aryl thioethers, dithioketals, but NiCRALs are more efficient for desulfuration of heteroarenes. Yields can be comparable with those obtained with Raney nickel. 

Direct Arylation of Heteroarenes, Aryl silicon reagents were employed to directly arylate heteroarenes via a Pd-catalyzed, ligand-free process. Silver(I) fluoride was the most effective source of fluoride (93%) compared with FeFs, KF, wBu4NF-H20, and CsF, although CuF2 gave a comparable performance (82%). In addition to activating the arylsilanes, silver(I) fluoride acts as a co-oxidant with Cu(0Ac)2-H20 to oxidize Pd° to Pd. The electron-rich and electron-deficient aryl (trimethoxy)silanes could be coupled to access arylated benzothiazoles in excellent yields (83-93%) (eq 19). 

The alkaloid dubamine contains a single bond between the two heteroarene units. This lond was formed in 79% yield by the generally valuable palladium-catalyzed eoupling of an ryltrimethylstannane with an aryl triflate (see section 1.6). The requisite stannane was pre-ared from l,3-benzodioxol-5-yl triflate and hexamethyldistannane with the same palladium atalyst, the triflate ester was obtained from 2(1 f/)-quinolinone and trifluoromethanesulfonic jihydride (A.M. Echavarren, 1987). An earlier attempt to perform this aryl coupling by dassical means gave a yield of only 1 %. 

Under different conditions [PdfOAcj2, K2CO3, flu4NBr, NMP], the 1 3 coupling product 86 with 4-aryl-9,10-dihydrophenanthrene units was obtained. The product 86 was transformed into a variety of polycyclic aromatic compounds such as 87 and 88[83], The polycyclic heteroarene-annulated cyclopen-tadicnc 90 is prepared by the coupling of 3-iodopyridine and dicyclopentadiene (89), followed by retro-Diels Alder reaction on thermolysis[84]. 

The direct arylation of heteroaryls is particularly attractive due to the fact that these moieties are present in many biologically active compounds [58], Recently, etinkaya and co-workers reported the direct arylation of benzoxazoles and ben-zothiazoles with aryl bromides catalysed by a bis-NHC-palladium complex [59], Also, Sames and co-workers have described the C-H arylation of different SEM-protected heteroarenes, catalysed by NHC-Pd complex 28 (Scheme 7.12, pathway a) [60],... 

The arylation of electron-rich arenes, such as azulene (55)206 and heteroarenes, has been sporadically described. Under similar conditions phenols undergo arylation, which is preferably directed at the ort/zo-positions, probably due to the involvement of palladium phenolate intermediates.188,207 Polysubstitution occurs readily.208 The para-position can be attacked only with the sterically hindered 2,6-di-t-butylphenol.209 Similar ortho-diarylation of arenes bearing carbonyl groups (acetophenone, anthrone, benzanilide, etc.) shows that the or//zo-di reeling effect of the substituent is more important than its other electronic effects.189... 

A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 <030L3607>. According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAc)2/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication <06OL2899>. 

The arylation of common heteroarenes could be governed by the choice of conditions. Free (NH)-heteroarenes were C-arylated via selective catalytic C-H bond functionalizations. The key to these transformations was the use of MgO, which enabled the formation of a salt of the heteroarene, hence offering N-protection in situ (Equations (84) and (85)). a... 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

Autoxidation of secondary acetonitriles under phase-transfer catalytic conditions [2] avoids the use of hazardous and/or expensive materials required for the classical conversion of the nitriles into ketones. In the course of C-alkylation of secondary acetonitriles (see Chapter 6), it had been noted that oxidative cleavage of the nitrile group frequently occurred (Scheme 10.7) [3]. In both cases, oxidation of the anionic intermediate presumably proceeds via the peroxy derivative with the extrusion of the cyanate ion [2], Advantage of the direct oxidation reaction has been made in the synthesis of aryl ketones [3], particularly of benzoylheteroarenes. The cyanomethylheteroarenes, obtained by a photochemically induced reaction of halo-heteroarenes with phenylacetonitrile, are oxidized by air under the basic conditions. Oxidative coupling of bromoacetonitriles under basic catalytic conditions has been also observed (see Chapter 6). 

The direct borylation of arenes was catalyzed by iridium complexes [61-63]. Iridium complex generated from [lrCl(cod)]2 and 2,2 -bipyridine (bpy) showed the high catalytic activity of the reaction of bis (pinaco la to) diboron (B2Pin2) 138 with benzene 139 to afford phenylborane 140 (Equation 10.36) [61]. Various arenes and heteroarenes are allowed to react with B2Pin2 and pinacolborane (HBpin) in the presence of [lrCl(cod)]2/bipyridne or [lr(OMe)(cod)]2/bipyridine to produce corresponding aryl- and heteroarylboron compounds [62]. The reaction is considered to proceed via the formation of a tris(boryl)iridium(lll) species and its oxidative addition to an aromahc C—H bond. 

Betaines 375 and 376 could be isolated in the three-component reaction of carboxyclic iminophosphoranes (374) with aryl isocyanates and pyridines or quinolines as heteroarene components (93UP1). This route (Scheme 135) opens another broad range of novel heterocyclic systems. 

Heck in one of his first papers already demonstrated the feasibility of applying the palladium-catalyzed crosscoupling of aryl and alkenyl halides with alkenes repetitively on appropriate oligofunctional substrates. For example, twofold coupling of 1,4-diiodobenzene with styrene furnished 1,4-distyrylbenzene in 67% yield (Scheme 1). Since then, a large number of ortho-, meta-, and / r< -dihaloarenes and -heteroarenes have been subjected to twofold Heck reactions with various alkenes (Schemes 2-4). 

Some heteroarylamines have been prepared by aromatic nucleophilic substitution of suitable support-bound arylating agents with amines (Table 3.27). This technique has been successfully employed in the synthesis of 2-(alkylamino)pyrimidines [507,508], 2-(arylamino)pyrimidines [509], aminopurines [510-512], and 1,3,5-triazines [513]. When the heteroarene is bound to the support as a thioether, nucleophilic clea-... 

Reissert compounds (l-acyl-l,2-dihydro-2-quinolinecarbonitriles) have been prepared on cross-linked polystyrene and C-alkylated in the presence of strong bases (Entry 8, Table 15.25). Treatment of polystyrene-bound C-alkylated Reissert compounds with KOH leads to the release of isoquinolines into solution (Entry 9, Table 15.25). The reaction of support-bound quinoline- and isoquinoline /Y-oxides with acy-lating agents followed by treatment with electron-rich heteroarenes and enamines has been used to prepare alkylated and arylated derivatives of these heterocycles (Entry 10, Table 15.25 see also Table 15.26). 

Thiation of aromatic compounds is utilized both for the preparation of aryl sulfides and for the generation of sulfur heteroarenes. The diaryl thioether motif is found in the structure of several approved pharmaceuticals, such as antihistamines. In a recent letter, Wu and He disclosed that Cu(I) catalysis is very efficient for the coupling of thiophenols with aryl iodides (Scheme 39) [ 108]. The procedure is very similiar to the diaryl ether synthesis under microwave irradiation reported by the same authors. 

Palladium-Catalyzed Arylation of Heteroarenes 229 Masahiro Miura and Tetsuya Satoh... 

This reaction has been extended to other heteroarene carboxylates and to cycloalk-enones,leadingto conjugated aryl or heteroaryl enones ingood yields (Scheme 10.59).91... 

In contrast to the observed reactivity of phenoxide and aryl alkoxide ions, arene and heteroarene thiolate ions typically couple with aryl radical to generate C—S bonds. The only exception to this regioselective reaction is the addition of 1-naphthalene thiolate ion to p-anisyl radical to render both C- and S-substitutions in 14% and 65% yields, respectively, while with 1-naphthyl radical, 95% of C—S coupling is obtained. In general, PhS- ions react with Arl in liquid ammonia under photostimulation to afford good yields of ArSPh or heteroaryl-SAr (70-100%). Substitution of the less-reactive ArBr can be achieved under photochemical initiation in DMF, MeCN, or DM SO [1],... 

Amines, amides, and N-H containing heteroarenes smoothly react with Ar3Bi(OAc)2 in the presence of Cu(OAc)2 to give A-arylated products (Equation (128)). In general, primary amines are monoarylated, because the... 

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