Direct arylations triazoles

Consequently, ruthenium-catalyzed direct arylations with aryl halides in less coordinating apolar solvents, such as toluene, were probed. Notably, a catalytic system derived from SPO preligand 59 enabled regioselective C-H bond functionalizations at the aromatic moieties of /V-aryl substituted 1,2,3-triazoles (Scheme 32) [88],... 

Scheme 32 Ruthenium-catalyzed direct arylation of 1,2,3-triazole 84 in an apolar solvent...

Scheme 9.33 Ruthenium-catalyzed direct arylation of triazole 94.

As carboxylic acid additives increased the efficiency of palladium catalysts in direct arylations through a cooperative deprotonation/metallation mechanism (see Chapter 11) [45], their application to ruthenium catalysis was tested. Thus, it was found that a ruthenium complex modified with carboxylic acid MesC02H (96) displayed a broad scope and allowed for the efficient directed arylation of triazoles, pyridines, pyrazoles or oxazolines [44, 46). With respect to the electrophile, aryl bromides, chlorides and tosylates, including ortho-substituted derivatives, were found to be viable substrates. It should be noted here that these direct arylations could be performed at a lower reaction temperatures of 80 °C (Scheme 9.34). 

Recently, catalytic amounts of inexpensive Cul were employed for regioselective direct arylations of 1,2,3-triazoles (Scheme 9.42) [58]. 

As 1,4-disubstituted 1,2,3-triazoles are usually prepared through copper-catalyzed 1,3-dipolar cycloadditions of terminal alkynes with organic azides, the use of a single copper complex for a direct arylation-based sequential catalysis was probed. Thereby, a modular chemo- and regioselective synthesis of fully-substituted 1,2,3-triazoles was achieved (Scheme 9.43). Notably, the overall reaction involved the selective coupUng of four components through the formation of one C—C- and three C—N-bonds [58]. 

Direct arylations of indolizines 40 using aryl bromide 41 as electrophile was reported by Gevorgyan. These transformations proceeded selectively at position C-3 (42) and sensitive functionalities were tolerated (Scheme 9). Detailed mechanistic studies strongly supported an electrophilic aromatic substitution-type mechanism to be operative. Additionally, Gevorgyan developed a palladium-catalyzed direet arylation of 1,2,3-triazole 43 using aryl bromide 44 as electrophiles (Scheme 8). Experimental and theorical studies suggested that reactions are likely to proceed via electrophilic aromatic substitution-type mechanism. 

Ackermann probed carboxylic acids as cocatalysts in ruthenium-catalyzed direct arylations. Mesityl carboxylic acid was found to be a very active preligand, which displayed a broad scope for effective arylations of pyridine, 1,2,3-triazole, oxazoline or pyrazole derivatives. Regarding the electrophile, diversely functionalized aryl bromides, but, interestingly, also aryl chlorides were found to be practicable substrates (Scheme 23). These transformations were proposed to occur through a transition state like 90, where carboxylate assisted during CMD process. 

An efficient and simple tandem protocol for the synthesis of 1,2,3-triazole-fused imidazo-[l,2-a]pyridines was reported in 2013. The reactions followed a copper-catalyzed tandem azide-allq ne cycloaddition (CuAAC), Ullmann-type C-N coupling, and intramolecular direct arylation sequence and showed high generality and functional group tolerance. Good yields (59-77%) of 1,2,3-triazole-fused imidazo[l,2-a]pyridines were produced in a single step (Scheme 3.7). 

Substituted 1-N-alkyl- or l-N-aryl-1,2,3-triazoles can be subjected to direct arylation in the 5-position, for example, in Pd-catalyzed protocol using aryl chlorides in the presence of K2CO3 and P(cyclohexyl)3 to give the triazoles 14 [484] ... 

Triazoles undergo direct arylation with aryl chlorides in the presence of catalytic palladium and PCys as the ligand (eq 162). The reaction time can be reduced by employing a microwave. Other electron-rich phosphines can be employed for the functionalization of heterocycles with aryl chlorides under conventional heating. ... 

This Pd-mediated C-H activation can be exploited in a more synthetically oriented manner. Thus, a general access to 1,4,5-trisubstituted ttiazoles by a palladium-catalyzed direct arylation of 1,4-disubstituted triazoles 118 has been reported by the group of Gevorgyan [90], This methodology allows for the introduction of both electron-deficient and rich aryl groups, with a good fimctional group tolerance. It has been latter reported that a similar arylation can be conducted under aerobic conditions, with a recyclable palladium catalyst [91] (Scheme 36)... 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

The direction of MCR involving pyruvic acid, aldehyde, and l-aryl substituted l,2,4-triazole-3,5-diamine was different from the directions of all other processes that were discussed earher. It was established [53] that this treatment yielded 3-(5-ammo-lH-l,2,4-triazol-3-ylamino)furan-2(5H)-one 39 instead of triazolopyri-midine carboxylic acids 38 (Scheme 16). 

Reaction of 1-azidoadamantane with nitro and sulfoxy olefins (Scheme 77, R = H or Ph and X = N02 R = Ph and X = SOPh) leads directly to the triazoles two isomers are obtained from the /i-nitrostyrene reaction with the 5-phenyl-1-adamantyltriazole as the major product.155 Likewise, triazoles are the only products formed in the reaction of aryl azides with /J-nitrostyrene (Scheme 77)294,295 however, unlike the azidoadamantane reaction, a... 

The direct synthesis of aryl- or alkyl nitriles from cyanide and organohalide precursors is revered in synthetic chemistry, as the nitriles represent a flexible functionality that can easily be converted into (for example) carboxylic acids, esters, amides, amidines, amines and various hetero cycles [67], such as thiazoles, oxazolidones, triazoles and tetrazoles [68]. The tetrazole group... 

Several unique heterocyclic fused-1,2,4-triazole structures have been published. Pyridine amination of 216 with O-mesitylenesulfonylhydroxylamine followed by condensation with various aryl and heterocyclic aldehydes and subsequent cyclization and oxidation gave triazolopyridines 217 <03TL1675>. Triazolopyridines 217 were utilized in the direct conversion to the triazolopyridine amides 218 with methylaluminoxane premixed with amines in a combinatorial library synthesis. A convenient synthesis of novel 4-(l,2,4-triazol-l-yl)-2-pyrazolines and their derivatives has been reported <03SC1449>. A novel triheterocyclic ring system, thieno[2,3-y][l,2,4]triazolo[l,5-a]azepines, has been published <03S1231>. 

Triazolines have also been easily obtained in the reactions of azides with unsaturated nitriles with ethylenesulphonic acid derivatives and with maleimides . Steric hindrance caused by additional substitution by alkyl or aryl groups lowers the yields and also influences the orientation. The reaction of phenyl azide with j3-nitrostyrene proceeded only at 130° and yielded only 20% of the expected 1,5-diphenyl-4-nitrotriazoline (229), together with 1,4-diphenyl triazole (230), resulting from addition in the opposite direction ". ... 

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