Arylation of triazoles

Arylation of triazole by the Gomberg-Bachmann method (72M141200) has been described. 

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). 

To conclude this section, we report a patent application by Wyeth, the pharma company in 2009 that describes the arylation of triazol-l-yloxy and triazol-l-yl heterocycles with aryl boronic acids, using molecular oxygen and PdlPPhj) as the catalyst (Figure 2.16), giving molecules that are useful for the treatment of oncological diseases or disorders and for the treatment of inflammation [71]. The mechanism was not discussed. 

Figure 2.16 The arylation of triazol-1-yloxy and triazol-1-yl heterocycles with aryl boronic acids by a group...

Fig. 4 Mechanistic rational for the regioselective Pd-catalyzed arylation of triazoles...

Intramolecular arylation of triazoles by a palladium-catalyzed dehydrogenative pathway has also been reported. This closely related transformation enables efficient preparation of tricyclic triazoles without any prefunctionalization of arylating agents [97]. Under optimized conditions, this coupling can be conducted at ambient air pressure (Scheme 42). 

Finally, NHC complexes of copper, formed in situ from the hnidazolium salt and CuBr have been used in the monoarylation of aniline [167]. Trinuclear Cu(I) catalysts have been applied to the arylation of pyrazoles, triazoles, amides and phenols [168] (Scheme 6.50). 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

Nitration of triazole and its C-monoalkyl derivatives fails. Aryltriazoles are nitrated on the aryl ring in preference to the triazole, but 3-p-nitrophenyltriazole in which each ring is deactivated gives l-nitro-3-j7-nitrophenyltriazole which rearranges at 120°C to 3-nitro-5-p-nitrophenyltriazole <72CC37>. 

An alternate approach for the 1-arylation of pyrroles is offered by their copper catalyzed coupling with aryl bromides and iodides, as depicted in 6.68. The process, run in the presence of trans-N,N -dnnethyl-cyclohcxane-diamine, was also efficient in the A-arylation of pyrazole, imidazole, triazoles and indazole, giving a mixture of isomers in the latter case.100... 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

The similarity of the UV spectra of s-triazolo[3,2-c]-s-triazoles (see equation 44) and 3-aryl-s-triazoles indicates a lack of electronic interaction between the two fused s-triazole rings. In lH-2,6-diphenyl-s-triazolo[3,2-c]-1s-triazole, the UV spectrum exhibits the resultant effects of the two triazole rings each substituted with an aryl group (66JHC119). 

On oxidation of 1,2-cyclooctanedione dihydrazone with HgO, cyclooctyne and Hg derivatives of triazoles have been identified. The major product is C32H42NeHg, which was assigned the structure shown (68LA(716)ll). Cyclometallations of 2-aryl-4,5-dimethyl-l,2,3-triazoles occur with Pd(II), Pt(II), Rh(II) and Ir(III) chlorides (78MI4lio5). The triazole acts as an N—C-chelate ligand. 

The base-catalyzed condensation of azides with activated methylene compounds is a well-established route to 1/7-triazoles. This is a regiospecific method ideally suited for the synthesis of triazoles with a 5-amino or -hydroxy substituent, and an aryl or carbonyl function at C-4. The general scheme is shown in Scheme 8. The stepwise character of the reaction is best revealed by the anomerism of glycosyl azides during their reaction with... 

Activated aromatic halides and 2- or 4-pyridyl halides can be used for the N-arylation of 1,2,4-triazoles, best achieved by the Ullmann technique (70JCS(C)8s). Preference for annular arylation on N-1 rather than N-4 is observed but arylations of 3-aminotriazoles with picryl chloride are anomalous the parent triazole itself is substituted on N-1 but in... 

N-arylimidazoles, important compounds in medicinal research, have been synthesized by nucleophilic aromatic substitution and Ulmann-type coupling. Aromatic substitution is, however, limited by the need for substrates activated by electron-withdrawing groups. The arylation of diazoles and triazoles, e.g. imidazole, by p-tolyllead triacetate compares very favorably with the Ullmann and related methods in that the conditions employed are much milder and the yields are usually excellent and reproducible (Scheme 13.43) [64]. 

An efficient protocol for solvent-free N-arylation of N-heterocycles, including imidazoles and triazoles, by aryl trimethoxysilanes using FeCla/Cu as co-catalyst and TBAF as the base under air has been demonstrated by Li et al. Various imidazoles and triazoles are compatible with this procedure (Scheme 5.47). 

AAMonosubsti luted triazole arylation resulted in product mixture. Arylation of 1,5-disubstituted triazole afforded the product in low yield consistent with results reported by Yorimitsu. 

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

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