Arylation of heterocycles

Some heterocycles undergo facile inter- and intramolecular arylations. Two mechanistic explanations of the arylation are possible. The Heck-type reaction is one of them. Carbopalladation of one of two double bonds with Ar-Pd-X gives la, which is stabilized by jr-allylpalladium formation. Pd and jS-H is anti in la and hence syn f-H elimination is not possible. Therefore, in stereoisomerization from anti la to syn lb a relationship between Pd and jS-hydrogen occurs, and syn y3-H elimination from lb affords the arylation product (path a). Another explanation is electrophilic substitution with Ar-Pd-X. Since arylations occur mainly at electron-rich carbons of heterocycles, they can be understood as electrophilic substitutions (path b). In some cases, a Heck-type mechanism seems to be more reasonable. Certainly arylations proceed by one of these mechanisms depending on the electronic nature of the substrates and reaction conditions, and hence further mechanistic studies are necessary. 

Furans, thiophenes, and pyrroles are arylated at the electron-rich C-2 positions. Further arylation occurs at C-5. Similarly, arylations at C-2 positions of benzofu-rans, benzothiophenes, and indoles take place preferentially. 

Ohta and co-workers carried out extensive studies on intermolecular arylation of various heterocycles (furan, thiophene, pyrrole, oxazole, thiazole, A-methylimi-dazole, benz[fe]oxazole, benzo[i ]furan, and benzo[ ]thiophene) with mainly chlo-ropyrazines as heteroaryl halides using Pd(PPh3)4 and AcOK [3]. 

Reaction of the chloropyrazine 2 with furan afforded the 2-arylfuran. 2-Arylation of benzo[ ]furan (4) occurs with o-bromonitrobenzene (3) [3b]. Regioselective 2-arylation of ethyl 3-furancarboxylate with 3 occurred to give 5 in 80 % yield when Pd(PPh3)4 and AcOK were used in toluene. 5-Arylation was the main path when ligandless Pd/C was used in the polar solvent NMP. The furo[3,2-c]quinolinone 6 was obtained after hydrogenation of the nitro group [4]. 

Intramolecular reaction of the vinyl triflate with benzo[ ]furan in 7 is a key step in the preparation of the synthetic intermediate 8 of (—)-frondosin A [5], Intramolecular reaction of the iodide with furan in 9 gave the tetracyclic jS-lactam 10 containing furan ring in the presence of TI2CO3 as a base. The rather unusual C-3 substitution occurs in the reactions of 7 and 9, because the C-2 positions are blocked [6], If the cyclizations of 7 and 9 proceed similar to Heck-type carbopalladation and f-H elimination, direct syn y3-H elimination is not possible, and isomerization from anti to syn, followed by syn y3-H elimination should occur. Therefore, direct electrophilic substitution may be a better explanation. 

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A number of methods are available for generating aryl radicals. They have been reviewed recently as has the evidence that the processes result in the generation of free aryl radicals, Those methods which have been used for the arylation of heterocyclic compounds are described here, and their applications to the arylation of specific heterocycles are discussed and tabulated in Section II,C,D and E. 

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. ... 

Phenyl radicals can be generated by the thermal decomposition of lead tctrabcnzoate, phenyl iodosobenzoate, and diphenyliodonium hydroxide,- - and by the electrolysis of benzoic acid.- These methods have been employed in the arylation of aromatic compounds, including heterocycles. A method of promise which has not been applied to the arylation of heterocycles is the formation of aryl radicals by the photolysis of aromatic iodides at 2537... 

There has been relatively little work on the mechanism of arylation of heterocyclic compounds, but the arylation of homocyclic compounds has been studied in great detail. Those mechanistic aspects of the reactions with heterocycles which have been examined parallel closely the corresponding aspects of the reactions of homocycles, and there is... 

Free-radical arylation of heterocyclic compounds is a relatively inefficient process in which yields of particular products greater than 50% are rare. This is the inevitable result of the high reactivity and low selectivity of aryl radicals not only is it usual for the heterocyclic compound to be attacked at each of its available positions, but, as shown in preceding sections, other by-products are numerous. Nevertheless, the method often presents the only short route to a given compound and it has been widely applied. Preparative uses are grouped in this section under the heading of the heterocyclic system concerned. 

In addition to palladium catalysts, Co(OAc)2 shows a catalytic activity for the arylation of heterocycles, including thiazole, oxazole, imidazole, benzothiazole, benzoxazole, and benzimidazole.78 As shown in Scheme 6, the catalytic system Co(OAc)2/9/Cs2C03 gives G5 phenylated thiazole, while the bimetallic system Co(OAc)2/CuI/9/Cs2C03 furnishes the G2 phenylated thiazole. The rhodium-catalyzed reaction of heterocycles such as benzimidazoles, benzoxazole, dihydroquinazoline, and oxazoline provides the arylation product with the aid of [RhCl(coe)]2/PCy3 catalyst.79 The intermediacy of an isolable A-heterocyle carbene complex is proposed. 

The reactions of the 5-oxazolanes 14 with aryllead triacetates are examples of the typical arylation of heterocycles by which products 15 are formed. After hydrolysis and decarboxylation, heterocyclic compounds 15 are converted to the arylglycines 16 in yields of 81-93% (Equation (5)).33... 

In 2005 and 2006, Mori et al. reported the arylation of heterocycles with aryl iodides using palladium dichloride complexes as catalysts and silver nitrate or fluoride as activators (Scheme 10.50). The best coupling conditions were obtained with a combination of silver nitrate and potassium fluoride.82... 

The reactions of arylation of heterocyclic /3-ketoesters were employed in the synthesis of a number of isoflavanones and isoflavones.27,28 cr-Methylene cr-arylketones can be easily and selectively obtained by arylation of allyl /3-ketoesters which are eventually deprotected by the Tsuji s procedures. a Deallyloxycarbonylation was performed by treatment of the allyl cr-aryl-/3-ketoesters with catalytic amounts of palladium(n) acetate, triethylammo-nium formate and triphenylphosphane in THF at room temperature and afforded the a-arylketones in 75-97% yield.27 Deallyloxycarbonylation-dehydrogenation can be realized with the same allyl esters by treatment with catalytic amounts of palladium(n) acetate and l,2-bis(diphenylphosphino)ethane (DPPE) in acetonitrile under reflux and affords the ct-aryl cr,/3-unsaturated ketones in 60-90% yield (Scheme 4).28 In particular, this reaction was used in a direct convergent synthesis of 2 -hydroxyisoflavones involving arylation of an appropriate allyl /3-ketoester with the MOM-protected (2-methoxymethoxyphenyl)lead triacetate derivative (Scheme 4). The reaction of the isomeric... 

Copper diacetate-catalyzed arylation of heterocyclic amines such as piperidine, tetrahydroisoquinoline 76101 or 1,6-diazacyclodecane 77104 by aryllead triacetates gave only modest to moderately good yields of the iV-aryl derivatives (Equation (76) and (77)). The reactions with aliphatic amines lead to particularly poor yields of the derived anilines101 (Equations (78) and (79)), although the arylation of cyclooctylamine 78 with an electron-rich aryllead triacetate afforded the aniline derivative 79 in a moderately good yield (52%) (Equation (80)).1O5 1O5a... 

Synthesis and arylation of heterocycles using copper catalyzed C-N-, C-O- and C-S-coupling reactions 03SL2428. 

Copper-catalysed arylation of heterocyclic amines such as piperidine,tetrahydroisoquinoline or l,6-diazacyclodecane204 ith aryllead triacetates gave only modest to moderately good yields of the A -aryl derivative, and the reaction with aliphatic amines led to particularly poor yields of the derived anilines. 

Scheme 14 First-generation Rh-catalyzed C-H arylation of heterocycles by Lewis et al. [102].

In a second report, the Bergman and Ellman groups improved on their original procedure for the arylation of heterocycles with aryl halides [103]. The key improvements over the previous method were three-fold (1) the use of the hindered tertiary amine base Pr.NBu in replacement of Et3N (2) microwave irradiation for rapid (<1 h), high temperature (250 °C) reactions in 1,2-dichlorobenzene (3) the use of bulky bicyclic trialkylphosphine ligands of the phobane family in replacement of PCy3 (Scheme 15). Under typical reaction conditions, the heterocycle... 

Structure-property relationship studies of bidentate phosphine-alkene ligands in the catalytic arylation of heterocycles were pursued with the synthesis of a... 

The use of (Z)-l-ferf-butyl-2,3,6,7-tetrahydrophosphepine ligand was thus identified as a superior catalytic system for the arylation of heterocycles with bromoarenes, with higher conversions and low incidence of hydrodehalogenation (Scheme 17). Under typical reaction conditions, the heterocycle (1 equiv.), ArBr... 

Lewis JC, Wiedemann SH, Bergman RG, EUman JA (2004) Arylation of heterocycles via rhodium-catalyzed C-H bond functionalization. Org Lett 6 35-38... 

Lewis JC, Wu JY, Bergman RG, EUman JA (2006) Microwave-promoted rhodium-catalyzed arylation of heterocycles through C-H bond activation. Angew Chem Int Ed 45 1589-1591... 

Lewis JC, Berman AM, Bergman RG, Ellman JA (2008) Rh(I)-catalyzed arylation of heterocycles via C-H bond activation expanded scope through mechanistic insight. J Am Chem Soc 130 2493-2500... 

N-Arylation. (5)-2-(Imidazolylmethyl)pyrrolidine 11 is yet another derivative of the series, and it functions as a catalyst for A -arylation of heterocyclic amines. 

The microwave-promoted arylation of heterocyclic compounds by C-H activation was also reported. It was found that the use of 9-cyclohexylbicyclo[4.2.1]-9-phosphanonane as a ligand was critical in obtaining high yields. With this ligand, aryl bromides were efficiently coupled to a variety of heterocyclic compounds as compared with other catalyst systems that are prone to cause hydrodehalogenation. 

Scheme 24 Fe-catalyzed ortfio-arylation of heterocycles directed by an imine group.

The rhodium-catalyzed arylation of heterocycles was also proposed to proceed by an electrophihc aromatic pathway [83]. When using [RhCl(CO) P[OCH(CF3)2]3 2... 

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