Mono- and binuclear palladacycles via regioselective C–H bond activation: syntheses, mechanistic insights and catalytic activity in direct arylation of azoles (original) (raw)
Palladium‐Catalyzed Regioselective C−H Arylation of 4‐Azaindazole at C3, C5 and C7 Positions
Advanced Synthesis & Catalysis, 2021
Direct and site-selective C5 and C7 palladiumcatalyzed C-H arylations of 4-azaindazole N-oxide have been achieved. A bidentate ligand and Pd(OAc)2 catalyst in toluene promoted the activation of C5 position, while a phosphine ligand and PdCl2 catalyst in DMA directed the arylation at C7 position. Using this new method, the synthesis of C5, C7-diarylated 4-azaindazole N-oxides as well as the C3, C5 C7 triarylated 4-azaindazoles was achieved towards future medicinal compound development.
Journal of the American Chemical Society, 2009
Palladium-catalyzed direct arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.
Molecules
The transition metal-catalyzed C–H bond functionalization of azoles has emerged as one of the most important strategies to decorate these biologically important scaffolds. Despite significant progress in the C–H functionalization of various heteroarenes, the regioselective alkylation and alkenylation of azoles are still arduous transformations in many cases. This review covers recent advances in the direct C–H alkenylation, alkylation and alkynylation of azoles utilizing transition metal-catalysis. Moreover, the limitations of different strategies, chemoselectivity and regioselectivity issues will be discussed in this review.
Chinese Journal of Chemistry, 2018
Herein, we report that a series of novel palladium(II)‐NHC complexes (NHC=N‐heterocyclic carbene) were synthesized. The structures of all novel complexes were characterized by 1H NMR, 13C NMR, FT‐IR spectroscopy and elemental analysis techniques. These palladium(II)‐NHC complexes were tested as efficient catalysts in the direct C—H bond activation of benzoxazole and benzothiazole with aryl bromides in the presence of 1 mol% catalyst loading at 150 °C for 4 h. Under the given conditions, various aryl bromides were successfully applied as the arylating reagents to achieve the 2‐arylbenzoxazoles and 2‐arylbenzothiazoles in acceptable to high yields.
Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds
Accounts of Chemical Research, 2009
The transition-metal-catalyzed functionalization of C-H bonds is a powerful method for generating carbon-carbon bonds. Although significant advances to this field have been reported during the last decade, many challenges remain. First, most of the methods are substrate-specific and thus cannot be generalized. Second, conversions of unactivated (i.e. not benzylic or alpha to heteroatom) sp 3 C-H bonds to C-C bonds are rare, with most examples limited to t-butyl groups-a conversion that is inherently simple because there are no β-hydrogens that can be eliminated. Finally, the palladium, rhodium, and ruthenium catalysts routinely used for the conversion of C-H bonds to C-C bonds are expensive. Catalytically active metals that are cheaper and less exotic (e.g. copper, iron, and manganese) are rarely used. This Account describes our attempts to provide solutions to these three problems. We have developed a general method for directing-group-containing arene arylation by aryl iodides. Using palladium acetate as the catalyst, we arylated anilides, benzamides, benzoic acids, benzylamines, and 2substituted pyridine derivatives under nearly identical conditions. We have also developed a method for the palladium-catalyzed auxiliary-assisted arylation of unactivated sp 3 C-H bonds. This procedure allows for the β-arylation of carboxylic acid derivatives and the γ-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C-H bonds (i.e. those with pKa values <35 in DMSO). Using a copper iodide catalyst in combination with a base and a phenanthroline ligand, we successfully arylated electron-rich and electron-deficient heterocycles and electron-poor arenes possessing at least two electron-withdrawing groups. The reaction exhibits unusual regioselectivity: arylation occurs at the most hindered position. This coppercatalyzed method supplements the well-known C-H activation/borylation methodology, in which functionalization usually occurs at the least hindered position.
C−H Bond Functionalization in the Synthesis of Fused 1,2,3-Triazoles
Organic Letters, 2010
A highly modular approach to fused 1,2,3-triazoles has been developed featuring a one-pot procedure combining copper(I) catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H bond functionalization. A class of structurally unique heterocycles was synthesized in good yields. Over the past decade, direct functionalization of C-H bonds has become a popular and sought after approach in CC bond forming reactions. 1 Using this strategy ensures more concise and less wasteful syntheses by foregoing the steps required to make activated starting materials necessary for conventional cross-coupling reactions. Although direct arylation of heteroaromatic compounds is widespread, 1 the use of halogenated heterocycles as electrophiles in C-H functionalizing reactions is less common. 2 Herein we discuss the use of 4-iodo-1,2,3-triazoles as electrophiles in a C-H functionalization. A common approach in the synthesis of 1,2,3-triazoles is the copper-catalyzed Huisgen cycloaddition of alkynes and azides (CuAAC). The efficacy and reliability of this reaction has demonstrated its utility in many areas of chemical science, and applications of both fused and linear triazoles in pharmaceutically relevant targets are common. 3-5 A drawback of this cycloaddition is the attenuated reactivity of disubstituted alkynes, which can limit the scope to the
Catalytic C–C coupling through C–H arylation of arenes or heteroarenes
Coordination Chemistry Reviews, 2010
with bromobenzene in the presence of Pd(OAc) 2 /PPh 3 as catalyst with Cs 2 CO 3 as a base in refluxing o-xylene for 32 h gave 2-biphenyl-6-terphenylphenol in 58% yield. One of the possible pathways is shown below in Scheme 11. Benzyl alcohols, acetophenones, benzyl phenyl ketones, anilides [9] and benzaldehydes [66] could be arylated analogously in ortho positions. Aliphatic carbons of acetophenones and benzyl phenyl ketones were also arylated. [9] Scheme 11. The mechanism seems to correspond to an electrophilic substitution assisted by chelation (Scheme 12). This is in accord with the transition state proposed for electrophilic attack on phenols. [67] Scheme 12. Two methods for direct o-arylation of benzoic acids with aryl iodides or bromides have been proposed by Daugulis: the first employs stoichiometric amounts of silver acetate for iodide 11 removal from aryl iodide in acetic acid at 130 °C; the second, suitable for aryl chlorides, uses n-butyl-di-1-adamantylphosphine ligand in DMF at 145 °C. [68] 4.2 Arene C-H Arylation Directed by Heteroatoms The attack of bromobenzene on the 2-position of furan has been recognized since 1985 [53] (Scheme 13) but only more recently a methodology of broader scope has been worked out. Scheme 13. A number of heterocycles can now be arylated selectively using palladium and rhodium catalysts. Beside furans, [69] several types of heterocycles such as pyrroles, [70] indoles, [70,71] thiophenes, [9] oxazoles, [72] thiazoles, [50] imidazoles, [73] indolizines [74] have been reported to undergo selective arylation. [9] Scheme 14 shows some examples using different heterocyclic substrates, aryl halides (iodides, bromides, chlorides), catalysts, bases and additives. Scheme 14. Indoles offer an interesting example of reactivity at two positions (C-2 and C-3). See for examples the first and second equation of Scheme 14. Reactivity at C-3 was obtained in the presence of phosphinous acids as ligands for palladium [71] while phenylation at the C-2 position occurred in the presence of Pd(OAc)2/PPh3. [75] Sames et al. rationalized this behavior 12 in the framework of the electrophilic substitution mechanism. Position C-3 is the preferred one, but if proton removal from the initial palladium complex is slow, there is time for a metal migration from C-3 to C-2 and arylation of the latter may occur exclusively. [75] Indole research has been reviewed. [76] In the presence of PdCl2(PPh3)2 and under the conditions reported in the third equation indolizine readily reacts with bromobenzene to afford the C-3 phenylated derivative in 71% yield. The reaction is compatible with a variety of substituents both on the indolizine and aryl halide. [74] The use of AgNO3/KF at 150°C allowed Pd-catalyzed arylation of 2-bromothiophenes with aryl iodides without affecting the Br-C bond. [74c] Aryl chlorides can arylate benzothiazole (fourth equation of Scheme 14) under the catalytic action of palladium in the presence of bulky, electron-rich phosphine ligands such as n-BuAd2P (Ad = adamantyl), which gives the best results. The methodology is applicable to a variety of electron-rich heterocycles and aryl chlorides. [72b] Selectivities in cross-coupling of azoles with two or more heteroatoms is discussed in a review. [77] Direct arylation of 1,2,3-triazole can be performed under palladium [78,79] and copper [80] catalysis. Selective arylations at the 2-and 5positions of azoles were achieved by varying the palladium-based catalytic system. For example CuI addition directed arylation towards position 2 of both N-methylimidazole and thiazole, while in the absence of CuI the 5-position was preferred. [81] Sames and coworkers found that some SEM-protected pyrazoles (SEM = 2-(trimethylsilyl)ethoxymethyl) could be arylated selectively at the 5-position and sequentially in the 3-position after SEM shift to the other nitrogen in the presence of palladium acetate, P(n-Bu)Ad2 and potassium pivalate at 140 °C in DMA. The deprotonation mechanism proposed by Fagnou [18,19,82] may be here at work to explain the preferential reactivity of the more acidic 5-position. [83] In some cases it has been shown that a deprotonation with ring opening is involved. Benzoxazoles open up the oxazole ring forming a palladium-coordinated isocyanophenolate. [84] The reaction occurs at 120 °C using Pd(OAc)2/PPh3, Cs2CO3 in DMF for 1 h. A proton abstraction mechanism has been suggested to be at work as shown in Scheme 15. A similar mechanism has been shown to be operative for 2-metalated thiazoles and imidazoles. [85] 13 Scheme 15. Thiophenes, furans, pyrroles and indoles could be arylated with a rhodium catalyst containing P[OCH(CF 3) 2 ] 3 as ligand. 3-Methoxythiophene was diarylated by iodobenzene selectively at carbons adjacent to sulfur to afford 2,5-diphenyl-3-methoxythiophene in 79% yield (Scheme 16). The reaction was over in 30 min when carried out in m-xylene at 200 °C under microwave irradiation. [86] The reaction was also extended to arene derivatives. Experimental data are consistent with an electrophilic mechanism. [87] Scheme 16. Rhodium-catalyzed arylation of benzimidazole in the presence of 9-cyclohexylbicyclo[4.2.1]-9-phosphanonane (cyclohexylphobane) was achieved by direct coupling of benzimidazole with aryl iodides and bromides bearing a wide variety of functional groups in good yields under microwave conditions (250 °C). [88] Miura and coworkers described several procedures in which arene and heteroarene C-H [6] and CC [9] activation are intertwined. We deem it useful to deal first with the general process of arene arylation reported in Scheme 17 for ,-disubstituted arylmethanols, which can be traced to both type of activation, the former product coming from OH assisted C-H arylation and the latter from CC bond cleavage with concomitant ketone formation (involving hydroxyl palladation). [89] 14 Scheme 17. The reaction of 2-phenyl-2-propanol with bromobenzene gave rise to mono-, di-and triphenylated products as shown in Scheme 18. The first two products result from arylation via CC bond cleavage, while the others from OH assisted C-H arylation. Selectivation towards the former products (essentially the monoarylated one) can be achieved using triphenylmethanol in place of 2-phenylpropanol and a bulky phosphine such as PCy 3. This also enables aryl chlorides to react efficiently. [89] Scheme 18. Passing to a heterocyclic substrate such as thiophene, the CR 2 OH group was readily removed from the 3-position and replaced by a phenyl group after aryl attack on position 2. A third phenyl group attacked position 5 more slowly. Thus, as reported in Scheme 19, ,-diphenyl-3-thiophenemethanol and bromobenzene were converted into 2,3-diphenylthiophene in 86% yield. Only a minor amount (10%) of 2,3,5-triphenylthiophene was formed. [90]
Efficient palladium-catalyzed direct arylation of azines and diazines using ligand-free conditions
Tetrahedron, 2009
The use of the palladium-catalyzed direct arylation was successfully tested on different electron-deficient heterocycles. The results demonstrate the effectiveness of the method based on the intramolecular coupling reaction providing polyazacyclic systems. This new application was obtained by using ligandfree conditions with the mixture of Pd(OAc) 2 and TBAC as catalytic system. With suitable substrates different products arising from regioselective coupling were observed.