Copper catalysis arylation

Sulfur dioxide (see above) as well as S02, SO , and SOj have been used as building blocks in three-component sulfone syntheses. It has long been known that aromatic sulfinic acids are easily available from diazonium salts and sulfur dioxide under copper catalysis . Mechanistically, aryl radicals as reactive intermediates add to sulfur dioxide generating arenesulfonyl radicals, which either take up an electron (or hydrogen) yielding a sulfinic acid or add to an olefinic double bond yielding final y -halogenated alkyl aryl sulfones (equation 78). 

Scheme 11.6 gives some examples of the various substitution reactions of aryl diazonium ions. Entries 1 to 6 are examples of reductive dediazonization. Entry 1 is an older procedure that uses hydrogen abstraction from ethanol for reduction. Entry 2 involves reduction by hypophosphorous acid. Entry 3 illustrates use of copper catalysis in conjunction with hypophosphorous acid. Entries 4 and 5 are DMF-mediated reductions, with ferrous catalysis in the latter case. Entry 6 involves reduction by NaBH4. 

It has been found that a number of bidentate ligands greatly expand the scope of copper catalysis. Copper(I) iodide used in conjunction with a chelating diamine is a good catalyst for amidation of aryl bromides. Of several diamines that were examined, rra s-yV,yV -dimethylcyclohexane-l,2-diamine was among the best. These conditions are applicable to aryl bromides and iodides with either ERG or EWG substituents, as well as to relatively hindered halides. The nucleophiles that are reactive under these conditions include acyclic and cyclic amides.149... 

Rh2(OAc)4-catalyzed decomposition of 2-diazocyclohexane-l,3-dione 380a or its 5,5-dimethyl derivate 380b in the presence of an aryl iodide leads to an iodonium ylide 381 355). The mild reaction conditions unique to the rhodium catalyst are essential to the successful isolation of the ylide which rearranges to 382 under the more forcing conditions required upon copper catalysis (copper bronze, Cu(acac)2, CuCl2) 355). 

Figure 3.5. Chiral hgands that exhibit >90% ee in the reaction between P-aryl acyclic enones and diethylzinc under copper catalysis.

Although the preparation has been repeated, there have been no other reports of the type of reaction, (described in 1923) in which carbazole in the presence of excess potassium hydroxide and nitrobenzene at only 50°C gave a good yield of 9-(4-nitrophenyl)-carbazole, presumably via an adduct such as 43 subsequently oxidized by excess nitrobenzene and/or air. More recent examples of N-arylation of carbazoles have involved copper catalysis in reaction of aryl halides with carbazoles. Thus, copper bronze and potassium carbonate heated with the carbazole and the appropriate aromatic halide have produced 9-(4-methoxyphenyl)- and 9-(2-tolyl)carbazoles 9-(4-phenylphenyl)carbazole, l,4-di(carbazol-9-yl)benzene, 4,4 -di(carbazol-9-yl)biphenyl, and 9-(2-pyridyl)- and 9-(2-quinolyl)carbazoles 9-[2-(2-phenylphenyl)phenyl]- and 9-[2-(4-methylphenyl)phenyl] carbazoles 9-(3-bromo-6-nitrophenyl)-, 9-[3-(carbazol-9-yl]-, 9-(2-nitrophenyl)-, 9-(4-methyl-2-nitrophenyl)-, 9-(4-methoxycarbonyl)-l-nitro-, and l-nitro-9-(4-tolyl)carbazoles 9-(2-methoxycarbonylphenyl)carbazole 9-[2- 2-... 

Yamamoto and coworkers studied the substitution of ally lie phosphates by Grignard reagents in the presence of copper or iron salts. Only the Sn2 product is formed under copper catalysis whereas, in the presence of iron(III) acetylacetonate, the Sn2 product is generally obtained with an excellent selectivity (Scheme 49). It should be noted that aryl-, alkenyl-, aUcynyl- and aUcyhnagnesium halides can be used successfully. 

The Pschorr Reaction allows the preparation of biaryl tricyclics by intramolecular substitution of one arene by an aryl radical. This radical is generated in situ from an aryl diazonium salt by copper catalysis. Although excess copper salts are used, the yield is normally moderate. 

The arylation of nucleophiles by reaction with diaryliodonium salts can be greatly facilitated by copper catalysis. This effect was observed by Beringer et al in the thermal decomposition of diaryliodonium halides as well as by Caserio et al in the hydrolysis of diaryliodonium salts. 2 jhe thermal decomposition of diphenyliodonium chloride shows a reduced activation energy upon copper catalysis Ea = 19 kcal/mole in Methylene glycol in the presence of CuCl instead of 31 kcal/mole in the absence of catalyst.From the synthetic point of view, the copper-catalysed arylation with diaryliodonium salts has been particularly useful in the case of a number of reactions involving heteroatomic nucleophiles, in particular for 5-, 5e-, O- and N-arylation reactions. 

The 5-arylation of sulfides is greatly improved by copper catalysis. The uncatalysed reaction requires heating under reflux to afford modest to moderate yields of the 5-aryl sulfonium derivatives. By contrast, upon copper catalysis, the reaction proceeds at room temperature to afford good to high yields of the 5-aryl sulfonium derivatives. 2-146,151 Moreover, the reaction was extended to the double arylation of the more readily available aiylthiols.l Similarly, the reaction of areneselenolates with diaryliodonium salts led to diarylselenides and triarylselenonium salts were easily obtained by copper catalysed arylation of diarylselenides. 2... 

This review focuses on the synthetic applications of carbon-hydrogen bond arylation by aryl halides, concentrating on palladium and copper catalysis. Mechanistic issues will be covered only briefly. Some examples of carbon-hydrogen... 

The p/fa for benzimidazole is 12.3 and for indazole, the value is 13.9. The benzimidazolyl and indazolyl anions react straightforwardly on nitrogen with electrophiles, though mixtures of N-1- and N-2-substituted products can result in the latter case. For example, amination with hydroxylamine 0-suIfonic acid gives a 2 1 ratio of 1-amino-l//-indazole and 2-amino-2//-indazole ° or to take another example, the ratio of N-1-to N-2-ethylated products from methyl indazol-3-ylcarboxylate can vary from 1 1 to 18 1 depending on the base and the solvent. The N-arylation of benzimidazoles and indazoles can be achieved with palladium or copper catalysis (See 4.2.10). 

In order to compare the new nickel catalytic system with the classical copper catalysis used for the arylation of alcohols (ref. 16), several experiments were performed with various copper catalysts (eqn. 5) (Table 5). 

Accordingly the arylation of nucleophiles catalysed by the nickel(II) complex bipy2NiBr2 can be considered as a good synthetic tool and at least as an interesting alternative to the usual copper catalysis. 

The seminal work by the groups of Hartwig and Buchwald in 1994 on aryl amina-tion chemistry has spurred substantial research on C-N bond formation in general and aryl-nitrogen bond formation in particular [114]. Catalytic aryl amine couplings are usually slow processes, especially when copper catalysis is used, often... 

A cyclocondensation reaction between alkynes 29 and amines 28 to give arylated pyrroles 30 was developed using catalytic base to drive the reaction forward. This procedure was altered so that tri-substituted pyrroles can be synthesized by first dimerizing the alkyne under copper catalysis and then subjecting the product to KOH in the presence of amines (14T8252). 

Several reports of late have described aromatic C-N bond formations using aryl boronic acids and copper catalysis. Initial reports from DuPont on this topic in the late 1990s relied on stoichiometric Cu(OAc)2, but more recently, it has been shown that reduced levels of copper (5-10%) can be used, together with myristic acid (10-20 mol%), forming diarylamines (Eqn. 1-5). ° Representative products, and yields, are shown below (32-35). 

Another important class of reactions involves the introduction of a cyano group by substitution in an Ar-Z precursor. In fact, novel pathways leading to aromatic nitriles-for example, photosubstitution reactions-are desirable in view of the many applications of aryl cyanides as agrochemicals and pharmaceuticals. Today, the classical copper(l)-mediated Rosenmund-von Braun and Sandmeyer reactions, from aryl halides and aryldiazonium salts respectively, have been supplanted by reactions which employ palladium- or copper-catalysis [57]. The rather common use of excess cyanide anion may lead to a deactivation of the catalyst, and affect to a remarkable extent each of the key steps of the catalytic cycle [58aj. Although the use of complex iron cyanide has been shown to offer an effective solution to this limitation [58b,c], photocyanation provides an equally useful alternative [10],... 

There has been a review of the use of transition-metal catalysts in the formation of C—S, C—Se, and C—Te bonds." Copper catalysis enables the formation of unsymmetrical diaryl thioethers from two differently substituted aryl iodides using ethylxanthogenate as the source of sulfur. Initial formation of an aryl xanthate, such as (17), is followed by hydrolysis to the arenethiolate, which couples with the second aryl iodide." Copper catalysis has also been used in the methylthiolation of aryl halides by DMSO. The method requires the presence of a source of fluoride ions, such as zinc fluoride." In the presence of a palladium catalyst, the reaction of aryl and heteroaryl bromides with AgSCp3 gives the corresponding trifluoromethylsulfldes." ... 

Three reviews have detailed progress in the formation of biaryl systems using metal-catalysed substitutions of carbon—hydrogen bonds. The preferential arylation at the para-position of phenol and aniline derivatives with diaryl iodonium salts has been achieved using copper catalysis. Under similar reaction conditions, a-arylacetamides are selectively arylated at the meta-position. A mechanistic study, including DFT calculations, suggests that the meta-selectivity in the copper-catalysed arylation of anilides derives from a Heck-like four-membered transition state involving a Cu(III)-phenyl species (47). 

The prevalence of the aniline functional group in alkaloid natural products of medicinal interest has inspired a number of metal-catalyzed strategies for the preparation of substituted anilines. One classical method, a variation of the Ullman aryl ether synthesis, features copper catalysis. This method generally suffers from harsh reaction conditions and limited substrate scope. Nonetheless, the simplicity of the transformation and the inexpensiveness of copper catalysis has prompted additional development of this strategy. For instance, cyclohexylphenylamine is formed in excellent yield from the copper(I) iodide-catalyzed amination of iodobenzene. ... 

In 2005, Fu and co-workers developed an efficient method for the preparation of medium- and large-sized nitrogen heterocycles via copper-catalyzed intramoleeular Af-arylation of phosphoramidates and carbamates. Introduetion of the phosphoryl group or tert-butO q carbonyl at the iV-termini can improve intramolecular cyclization under copper catalysis, and the phosphoiyl (DIPP diisopropylphospho) and tert-butO q carbonyl can easily be removed under the mild conditions (Scheme 4.10). 

Over a century ago, Ullmann reported coupling reactions catalysed by metallic copper. ° ° The harsh conditions typically involved limited its applicability, but Ullmann s work ultimately stimulated the search for milder conditions using copper catalysis. Both copper(I) and copper(II) salts can catalyse the coupling of aryl halides with a range of heteroatom nucleophiles, including phenols (Scheme 2.168, 2.169), ° alcohols (Scheme 2.170),thiols (Scheme 2.171, 2.172), amines (Scheme 2.173), anilines (Scheme 2.174)2" and A/ -heterocycles (Scheme 2.175,2.176).2i2.2i3... 

In this vein, alkynyl-functionalized (hetero)arenes were utilized in Pd-catalyzed arylation and cyclization events to reach tetrasubstituted alkenes. This strategy proved successful with an iV-phenylpropiolamide (Scheme 18a) [240] and N-(2-alkynylbenzyl)indoles (Scheme 18b) [241]. Copper catalysis was also viable, as demonstrated in reactions with 2-ethynyl anilides to yield benzoxazines (Scheme 18c) [242]. A copper-catalyzed carboarylation of electron-rich alkynes... 

In 2014, Ohno and co-workers reported the synthesis of the more complex ynamides 68 based on the copper-catalyzed alkynylation of tosyl amide 66 using aryl EBX reagent 67 (Scheme 34) [158]. Interestingly, this constituted the first example of a copper-catalyzed reaction with an EBX reagent in which the alkyne group is kept in the product. Although alkynyl bromides have traditionally been used in copper catalysis for the synthesis of ynamides, they were not successful in this case. 

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