Direct Azole Amination: CH Functionalization as a New Approach to Biologically Important Heterocycles

Abstract

Angew. Chem. Int. Ed. 2010Ed. , 49, 2282Ed. -2285 for substoichiometric quantities of catalyst, with 20 mol % Cu(OAc) 2 delivering a reasonable yield and reaction time. These reaction conditions were extended to the amination of benzoxazole, N-methylbenzimidazole, and 4,5-dimethylthiazole, as well as for the use of secondary aliphatic amines and sulfonamides. The use of four equivalents of the amine nucleophile is necessary to prevent side reactions of the reactive organocopper intermediate, thus limiting the potential use of this method with amines that require significant synthetic investment in their preparation, and thereby diminishing the advantages in atom economy that favor the use of direct CÀH amination. Wang and Schreiber recently developed closely related reaction conditions for the amidation of various heterocyclic compounds.[11] The optimized conditions (Scheme 4) also use 20 mol % Cu(OAc) 2 with a simple ligand (pyridine), weak inorganic base (Na 2 CO 3 ), and nonpolar aromatic solvent (toluene). A range of amides (e.g. 8), ureas, carbamates, and sulfonamides were found to efficiently amidate the C2-position of 1-methyl-benzimidazole (7), although primary amides and sulfonamides required the use of two equivalents of Cu(OAc) 2 . Acyclic secondary amides were ineffective, reportedly as a result of steric hindrance. As before, a large excess of the nucleophile (five equivalents) was required to prevent a competing side reaction, which was identified in this case by Schreiber as the dimerization of benzimidazole.Interestingly, Schreiber reports that the use of amines in this reaction leads to significant dimerization in every case, and is attributed to strong electron-donation by the amine nucleophile and its unfavorable deprotonation. Alternatively, weak amide nucleophiles such as phthalimide were also unreactive, thus suggesting the need to find a balance between the opposing properties of nucleophilicity and NÀH acidity. The scope of the CÀH coupling partner was extended to similar acidic, fully substituted azoles. No examples were reported that tested the expected regioselectivity of the reaction. Modified reaction conditions also allowed the direct amidation of fluorobenzenes, albeit in low yields, in a direct parallel with the pK a -dependent copper-catalyzed CÀH arylation developed by Daugulis. [6] The mechanism proposed by both Mori and Schreiber (Scheme 5) is directly analogous to that proposed by Stahl for the amidation of alkynes; formation of organocopper intermediate 13 by deprotonation, coordination of the nucleophile (!14), and then reductive elimination with the catalyst regenerated by molecular oxygen.An alternative, noncatalytic approach to copper-mediated heterocycle CÀH amination has recently been reported by Knochel and co-workers, [12] essentially dividing the proposed catalytic cycle described above into its component steps by sequential addition of the reagents. Building on similar previous work, Knochels oxidative amination started with the formation of a heterocyclic anion ...

Cu-Catalyzed Direct Amidation of Aromatic C–H Bonds: An Access to Arylamines

“…12 In this context, Yu and co-workers first reported the stoichiometric Cu-mediated Ar–H amination of 2-arylpyridines. 13a Later, a similar work was reported by the Chatani group.…”

Cu(acac)2 catalyzed oxidative C–H bond amination of azoles with amines under base-free conditions

“…In particular, the oxidative C-H bond amination reaction of heteroarenes for the synthesis of various aminoheterocycles is important because of its wide range of applications in the synthesis of biologically active compounds and organic intermediates. 6,7 Selective oxidative functionalization of C-H bonds in heteroarenes with amines is one of the challenging transformations.…”

Regioselective CH Imidation of Five‐Membered Heterocyclic Compounds through a Metal Catalytic or Organocatalytic Approach

“…[4] The five-membered heterocycles pyrrole, furan, and thiophene with amine substituents are important synthetic intermediates and employed widely in medicinal chemistry. [12] However, in sharp contrast to those extensive studies, the CÀH/NÀH amination of five-membered heterocycles pyrrole, furan, and thiophene have rarely been reported because of their tendency to undergo homocoupling and, probably more importantly, because prior oxidation of the em-ployed amines before the desired amination step needs to be suppressed under the plausible oxidative conditions. Therefore, direct functionalization of these compounds is economically attractive and of important synthetic usage.…”

“…Therefore, direct functionalization of these compounds is economically attractive and of important synthetic usage. [12] However, in sharp contrast to those extensive studies, the CÀH/NÀH amination of five-membered heterocycles pyrrole, furan, and thiophene have rarely been reported because of their tendency to undergo homocoupling and, probably more importantly, because prior oxidation of the em-ployed amines before the desired amination step needs to be suppressed under the plausible oxidative conditions. [6] Over the past decades, a variety of elegant methods have been developed for the intermolecular C À H arylation, [7] alkylation, [8] olefination [9] and alkynylation [10] of azoles.…”

“…Transition-metal-catalyzed synthetic transformations have been considered as one of the most reliable and powerful tools for connection of such chemical bonds, giving complex molecular structures in an efficient and economical manner. [12] However, in sharp contrast to those extensive studies, the CÀH/NÀH amination of five-membered heterocycles pyrrole, furan, and thiophene have rarely been reported because of their tendency to undergo homocoupling and, probably more importantly, because prior oxidation of the em-ployed amines before the desired amination step needs to be suppressed under the plausible oxidative conditions. Meanwhile, significant advances on C À H/ N À H coupling, [11] including amination of azoles have been made.…”