Heterocycles direct arylations

Abstract This chapter highlights the use of iV-heterocyclic carbenes as supporting ligands in arylation reactions different than the more common cross-coupling reactions, including C-F bond activation, catalytic arylation, homocoupling, direct arylation and oxidative Heck reactions. 

The direct catalytic carbonylation of halides to aldehydes is not readily achieved. Aryl, heterocyclic and vinyl halides, for example, in the presence of [Pd(PPh3)2Ch], a stoichiometric quantity of tertiary amine and synthesis gas (CO/H2), are converted to aldehydes, but the conditions are somewhat drastic (80-100 bar, 80-150 Alkyl halides are even less suitable for this reaction as they tend to undergo dehydrohalogenation to form alkenes, rather than carbonylation. However, using the platinum catalyst [PtCh(PPh3)2], primary alkyl iodides can be successfully carbonylated to aldehydes in good yield under moderate conditions (equation 5). °... 

Lautens has applied the direct arylation strategy to enable the coupling of a variety of heteroaromatics as the terminal step of the Catellani reaction sequence. A variety of /V-bromoalkyl nitrogen heterocycles including indoles [77-79], azaindoles [78], pyrroles [78, 80], pyrazoles [80, 81], and indazoles [81] have successfully undergone an ortfto-alkylation/direct arylation reaction to afford a wide variety of heterocyclic products in good to excellent yields (Scheme 33). The reaction conditions... 

Scheme 33 Nitrogen heterocycles synthesized via o/t/jo-alkylation/direct arylation sequence...

By synthesizing bromoalkyl-sulfur and -oxygen based heterocycles, Lautens was able to extend the strategy to include the synthesis of polycyclic thiophenes and furans [83, 84], Under similar reaction conditions to those used for nitrogen-based heterocycles, polycyclic products were obtained in good to excellent yields (Scheme 35). The electronic nature of the aryl iodide had a large impact on the observed yields, as electron-deficient aryl iodides worked well, while little to no product was obtained with electron-rich ones. Based upon these results, Lautens proposed that the mechanism of direct arylation of thiophenes occurs through an electrophilic metalation mechanism. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

The direct arylation, with substitution of hydrogen, mainly of electron-rich heterocycles, such as mono- and di-hetero 5-membered rings, by reaction with aryP or alkenyl halides, is a very useful supplement to cross coupling, eliminating the need for the preparation of an organometallic partner. 

In ruthenium-catalyzed direct arylations, the directing abilities of 2-oxazolinyl, 2-imidazolinyl, and 1-pyrazolyl groups turned out to be comparable to those observed for 2-pyridyl substituents [60]. As a consequence, a number of nitrogen-containing five-membered heterocycles have been employed as directing groups in intermo-lecular ortho-arylation reactions [60, 62], As an example, the 2-aryloxazoline 76 was... 

However, for the preparation of compounds with Ar-HetAr or HetAr-HetAr bonds bearing 3-, 4- or 5-substituted electron-deficient heterocyclic moieties, direct arylations using halogenated electron-deficient heteroarenes as electrophiles are usually superior. Selected examples of such couplings are summarized in Table 9.1. 

Palladium-catalyzed arylations of simple electron-rich five-membered heteroarenes with one heteroatom, such as furans, thiophenes, and pyrroles, with aryl iodides, bromides, or chlorides are among the most frequently studied direct arylation reactions [31, 39, 85]. These reactions usually afforded five-membered heterocycles, which were arylated at the position adjacent to the heteroatom in moderate to good yields. These reactions were mainly accomplished with electrophilic catalysts and proceeded more efficiently using aryl bromides with electron-withdrawing groups. This is in agreement with an electrophilic SEAr-type mechanism relying on a palladium(0)/palladium(ll) manifold [86]. Selected results of catalytic direct arylations of simple electron-rich five-membered heteroarenes (124—126) with aryl iodides, bromides, or chlorides are summarized in Table 9.2. 

This process is commonly known as the Sonogashira reaction and has proven extraordinarily useful for the synthesis of a wide variety of aryl alkynes or enynes. When neighboring functionality exists, Pd and Cu salts are well known to effect cyclization to the corresponding hetero- or carbocycle. Thus, the reaction of terminal alkynes and aryl or vinylic halides bearing neighboring functionality often leads directly to heterocycles or carbocycles, providing a particularly useful synthesis of benzofurans and indoles. 

Recent advances in intermolecular direct arylation reactions of heterocycles and arenas 07AA35. 

Regioselective (site-selective) functionalization of unsaturated haloge-nated nitrogen, oxygen, and sulfur heterocycles by Pd-catalyzed cross-couplings and direct arylation processes 07CSR1036. 

In 2010, Radi and coworkers reported the synthesis of isozaleplon, which is a regioisomer of the therapeutic drug Zaleplon to treat insomnia. The synthesis of isozaleplon featured the key C-C bond formation via direct arylation of the tautomerizable heterocycle with the arylboronic ester using PyBroP in the presence of PdCl2(PPh3)2 catalyst (10H1359). 

In 2012, Sharma and coworkers reported the direct arylation of tautom-erizable heterocycles with azoles under microwave conditions. This Pd/Cu catalyzed dehydrative phosphonium coupling via C—OH and C—H bond activation elegandy produced the diheteroaryl compounds via direct arylation of the tautomerizable heterocycle with boronic acids using PyBroP in the presence of Pd(OAc)2 and Cul catalysts (120L1854). 

Interestingly, during their studies on the direct arylation via dehydrative phosphonium coupling, the authors also discovered some side products, the homocoupled symmetrical biheterocycles in about 10-15% yields resulted from the tautomerizable heterocycles. This type of symmetrical biheterocycles have important applications in photochemistry... 

In 2013, Neres and coworkers reported the synthesis, biochemical, and microbiological evaluation of a series of pyrazolopyridine derivatives as nonnucleoside inhibitors of BasE, an adenylating enzyme in the sidero-phore biosynthetic pathway of the opportunistic pathogen Acinetobacter hau-mannii. Dozens of analogs on the aryl-pyrazolopyridine series were synthesized via direct arylation of the tautomerizable heterocycle with... 

Cross-coupling reactions of thiophenes by C-H functionalization have been extensively reviewed in the year 2014 (14ASC17). One important feature is a discussion of recent progress made in direct arylation and heteroarylation reactions involving thiophenes and other five-membered heterocycles containing one heteroatom. 

Intemiolecular direct arylation of five-membered ring heterocycles by nonactivated aryl chlorides 12KGS26. 

The palladium(II)-assisted alkenylation of aromatic compounds has also been applied to the synthesis of heterocycles. A novel synthesis of pyrido[3,4-d] pyrimidines, pyrido[2,3-d]pyrimidines and quinazolines was developed by Hirota et al. [18] employing the palladium(ll)-promoted oxidative coupling of uracil derivatives and alkenes. l,3-Dimethyluracil-6-carboxaldehyde dimethylhydrazone (22), 6-dimethylaminomethylenamino-l,3-dimethyluracil (24) and ( )-6-(2-dimethylaminovinyl) uracil (26) all reacted with methyl acrylate in the presence of stoichiometric Pd(OAc)2, producing pyrido[3,4-ii]pyrimidine 23, pyrido[2,3-if]pyrimidine 25 and quinazoline 27, each apparently arising from direct arylation, 6ti electrocycliza-tion, and elimination of dimethylamine, in 67%, 89% and 64% yields respectively (Scheme 9.3). 

Intermolecular direct arylations of heteroarenes, such as indoles, pyrroles or (benzo)furans, were, thus far, predominantly achieved with palladium catalysts (see Chapter 10). However, rhodium complexes proved also competent for the direct functionaUzations of various valuable heteroarenes with comparable or, in some cases, improved catalytic performance. Thus, rhodium-catalyzed C—H bond functionalizations of various N-heterocycles, were elegantly developed by Bergman, Ellman and coworkers. Here, the use of a catalytic system comprising [RhCl(coe)2]2 and PCys led to direct arylations of unprotected benzimidazoles with aryl iodides... 

The beneficial effect of copper salts in stoichiometric quantities for palladium-catalyzed direct arylations of N-heterocycles was reported by Miura and coworkers in 1998 [53,54]. However, it was only recently that catalytic amounts of inexpensive Cul were found to enable direct arylations of heteroarenes [55, 56]. Remarkably, a variety of N-heterocycles could be arylated in high yields of isolated products with aryl iodides as electrophiles (Scheme 9.40). Unfortunately, this ligand-free catalytic system required the use of a relatively strong base, thereby limiting its functional group tolerance. 

Many examples exist of synthetically useful intermolecular paUadium-catalyzed arylations of Jt-excessive heterocycles [4, 7, 50-56]. The reaction has also been extended to the direct arylation of pyridine, diazine and azole N-oxides with aryl halides [57]. Interestingly, tuning the ligand and base allows selective sp or sp activation of alkyl pyridine or pyrazine N-oxides [58], Palladium-catalyzed sp activation of alkylanines [59] and benzyUc arylation of benzoxazoles has also been described [60]. 

To overcome the ring closure of intermediate 10 giving rise to by-product 8 that was particularly encountered with secondary alkyl halides. Tautens and coworkers [22] developed conditions that favor the oxidative addition of alkyl hahdes. The methodology was widely applied to the intramolecular (Scheme 19.12) and intermolecular ortho alkylation of aromatic C-H bonds with secondary alkyl iodides and bromides [23]. Depending on the terminating reactions employed (the Heck reaction, direct arylation of heterocycles, and the Buchwald-Hartwig amination), a variety of valuable heterocydes were efficiently prepared. It should be pointed out that the reaction of enantioenriched substrates occurred with... 

While primary electrophiles proved successful, secondary alkyl halides proved troublesome. Alkyl iodides were the most efficient but bromides and chlorides could also be successfully employed by using a catalytic amount of Nal to promote halide exchange. Copper iodide proved to be a beneficial cocatalyst to achieve satisfactory yields. An array of experiments gave the conclusion that the reaction proceeds via in situ formation of the metallated heteroarene, as already suggested for nickel/copper- and copper-catalyzed direct arylation and alkynylation of aromatic heterocycles [44, 52]. It was also suggested that nickel nanoparticles play an important role in the catalysis. 

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