Reductive Arylation of Nitroarenes with Chloroarenes: Reducing Conditions Enable New Reactivity from Palladium Catalysts
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Abstract:
Palladium-catalyzed C–N bond forming reactions are a key tool in modern synthetic organic chemistry. Despite advances in catalyst design enabling the use of a variety of aryl (pseudo)halides, the neces-sary aniline coupling partner is often synthesized in a discrete reduc-tion step from a nitroarene. An ideal synthetic sequence would avoid the necessity of this step while maintaining the reliable reactivity of palladium catalysis. Herein we describe how reducing conditions enable new chemical steps and reactivity from well-studied palladium catalysts, resulting in a new, useful transformation: the reductive arylation of nitroarenes with chloroarenes to form diarylamines. Mechanistic experiments suggest that under reducing conditions, BrettPhos-palladium complexes catalyze the dual N-arylation of typi-cally inert azoarenes—generated via the in situ reduction of ni-troarenes—via two distinct mechanisms. Initial N-arylation proceeds via a novel association-reductive palladation sequence followed by reductive elimination to yield an intermediate 1,1,2-triarylhydrazine. Arylation of this intermediate by the same catalyst via a traditional amine arylation sequence forms a transient tetraarylhydrazine, un-locking reductive N–N bond cleavage to liberate the desired product. The resulting reaction allows for the synthesis of diarylamines bearing a variety of synthetically valuable functionalities and heteroaryl cores in high yield.Keywords:
Reductive elimination
Reactivity
Aryl halide
Organic Synthesis
Kinetic studies conducted under both catalytic and stoichiometric conditions were employed to investigate the reductive elimination of RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl) based palladium amido complexes. These complexes were found to be the resting state in Pd-catalyzed cross-coupling reactions for a range of aryl halides and diarylamines. Hammett plots demonstrated that Pd(II) amido complexes derived from electron-deficient aryl halides or electron-rich diarylamines undergo faster rates of reductive elimination. A Hammett study employing SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) and analogues of SPhos demonstrated that electron donation of the "lower" aryl group is key to the stability of the amido complex with respect to reductive elimination. The rate of reductive elimination of an amido complex based on a BrettPhos-RuPhos hybrid ligand (2-(dicyclohexylphosphino)-3,6-dimethoxy-2',6'-diisopropoxybiphenyl) demonstrated that the presence of the 3-methoxy substituent on the "upper" ring of the ligand slows the rate of reductive elimination. These studies indicate that reductive elimination occurs readily for more nucleophilic amines such as N-alkyl anilines, N,N-dialkyl amines, and primary aliphatic amines using this class of ligands.
Reductive elimination
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The direct α-arylation of carbonyl compounds emerged over the last two decades as a straightforward method for the formation of C(sp3)–C(sp2) bonds. Mechanistic studies suggested a classical cross-coupling catalytic cycle. This consists of oxidative addition of the aryl halide (ArX) to the Pd(0)-catalyst, transmetallation of the Na- or K-enolate generated in situ, and subsequent reductive elimination. Even though the general reaction mechanism was thoroughly investigated, studies focusing on enantioselective variants of this transformation are rare. Here, the computational study of the [Pd(BINAP)]-catalyzed α-arylation of 2-methyltetralone with bromobenzene is reported. The whole reaction energy profile was computed and several mechanistic scenarios were investigated for the key steps of the reaction, which are the enolate transmetallation and the C–C bond-forming reductive elimination. Among the computed mechanisms, the reductive elimination from the C-bound enolate Pd complex was found to be the most favorable one, providing a good match with the stereoselectivity observed experimentally with different ligands and substrates. Detailed analysis of the stereodetermining transition structures allowed us to establish the origin of the reaction enantioselectivity.
Transmetalation
Reductive elimination
Bromobenzene
Oxidative addition
Aryl halide
Catalytic cycle
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Reductive elimination
Aryl halide
Oxidative addition
Elimination reaction
Reactive intermediate
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Oxidative addition
Reductive elimination
Aryl halide
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Upon the addition of Br2 to complexes (P−P)Pt(Ar)2, two different products were observed, depending on the bite angle of the bidentate phosphine ligand: a Pt(II) aryl bromide complex, the product of C−Br reductive elimination, and Pt(IV) oxidative addition complex. At high temperatures, the latter exclusively gave the product of the C−C reductive elimination.
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Oxidative addition
Aryl halide
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Density functional theory calculations were performed to understand the distinctly different reactivities of o-carboxylate-substituted aryl halides and pristine aryl halides toward the PdII-catalyzed γ-C(sp3)–H arylation of secondary alkylamines. It is found that, when 2-iodobenzoic acid (a representative of o-carboxylate-substituted aryl halides) is used as an aryl transfer agent, the arylation reaction is energetically favorable, while when the pristine aryl halide iodobenzene is used as the aryl transfer reagent, the reaction is kinetically difficult. Our calculations showed an operative PdII/PdIV/PdII redox cycle, which differs in the mechanistic details from the cycle proposed by the experimental authors. The improved mechanism emphasizes that (i) the intrinsic role of the o-carboxylate group is facilitating the C(sp3)−C(sp2) bond reductive elimination from PdIV rather than facilitating the oxidative addition of the aryl iodide on PdII, (ii) the decarboxylation occurs at the PdII species instead of the PdIV species, and (iii) the 1,2-arylpalladium migration proceeds via a stepwise mechanism where the reductive elimination occurs before decarboxylation, not via a concerted mechanism that merges the three processes decarboxylation, 1,2-arylpalladium migration, and C(sp3)–C(sp2) reductive elimination into one. The experimentally observed exclusive site selectivity of the reaction was also rationalized well.
Reductive elimination
Iodobenzene
Decarboxylation
Carboxylate
Oxidative addition
Aryl halide
Catalytic cycle
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CONSPECTUS: Transition metal-catalyzed organic transformations often reveal competing reaction pathways. Determining the factors that control the selectivity of such reactions is of extreme importance for the design of reliable synthetic protocols. Herein, we present the account of our studies over the past decade aimed at understanding the selectivity of reductive elimination chemistry of organotransition metal complexes under electrophilic halogenation conditions. Much of our effort has focused on finding the conditions for selective formation of carbon (aryl)-halogen bonds in the presence of competing C-C reductive elimination alternatives. In most cases, the latter was the thermodynamically preferred pathway; however, we found that the reactions could be diverted toward the formation of aryl-iodine and aryl-bromine bonds under kinetic conditions. Of particular importance was to maintain the complex geometry that prohibits C-C elimination while allowing for the elimination of carbon-halogen bonds. This was achieved by employing sterically rigid diphosphine ligands which prevented isomerization within a series of Pt(IV) complexes. It was also important to understand that the neutral M(IV) products often observed or isolated in the oxidative addition reactions are not necessarily the intermediates in the reductive elimination chemistry as it generally takes place from unsaturated species formed en route to relatively stable M(IV) complexes. While aryl-halide reductive elimination for heavier halogens can be competitive with aryl-aryl coupling in diaryl M(IV) complexes, the latter reaction always prevails over aryl-fluoride bond formation. Even when one of the aryl groups is a part of a rigid cyclometalated ligand C-C coupling is still the dominant reaction pathway. However, when one of the aryl groups is replaced with a phenolate donor aryl-F bond formation becomes preferred over C-O bond elimination. During our studies, other interesting reactions have been discovered. For example, the fluorination of the C(sp(3))-H bond can be very selective and compete favorably with C-C coupling. Also, in electron-poor complexes, metal oxidation can have higher energy than oxidation of the coordinated iodo ligand resulting in I-F elimination instead of the formation of aryl-I bond. Overall, electrophilic fluorination can lead to often very selective elimination reactions giving new C-C, C-I, C-F, or I-F bonds, with this selectivity dependent on the metal center, supporting ligands, complex geometry, and electrophilic fluorine source. Together with the many reports on the halogenation of organometallic compounds that appeared in recent years, our results contribute to understanding the requirements for selective transformations under electrophilic conditions and design of new synthetic methods for making organohalogen compounds.
Organopalladium
Reductive elimination
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Monomeric, three-coordinate arylpalladium(II) halide complexes undergo reductive elimination of aryl halide to form free haloarene and Pd(0). Reductive elimination of aryl chlorides, bromides, and iodides were observed upon the addition of P(t-Bu)3 to Pd[P(t-Bu)3](Ar)(X) (X = Cl, Br, I). Conditions to observe the equilibrium between reductive elimination and oxidative addition were established with five haloarenes. Reductive elimination of aryl chloride was most favored thermodynamically, and elimination of aryl iodide was the least favored. However, reductive elimination from the aryl chloride complex was the slowest, and reductive elimination from the aryl bromide complex was the fastest. These data show that the electronic properties of the halide, not the thermodynamic driving force for the addition of elimination reaction, control the rates for addition and elimination of haloarenes. Mechanistic data suggest that reversible reductive elimination of aryl bromide to form Pd[P(t-Bu)3] and free aryl bromide is followed by rate-limiting coordination of P(t-Bu)3 to form Pd[P(t-Bu)3]2.
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Oxidative addition
Aryl halide
Elimination reaction
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Well-defined aryl–CuIII–halide species undergo reductive elimination upon acid addition resulting in the formation of strong aryl–halide bonds. The computationally studied mechanism points towards ligand protonation as the rate-determining step, in agreement with previous experimental data.
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Aryl halide
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We report the reductive elimination of haloarene from {Pd[P(o-tol)3](Ar)(μ-X)}2 (X = Cl, Br, I) upon addition of the strongly electron-donating, but sterically hindered, phosphine P(t-Bu)3 and related ligands. Reductive elimination of aryl chlorides, bromides, and iodides from these dimeric arylpalladium(II) halide complexes was observed upon the addition of P(t-Bu)3. Conditions to observe the elimination and addition equilibria were established for all three halides, and values for these equilibrium constants were measured. Reductive elimination of aryl chlorides was most favored thermodynamically, and elimination of aryl iodide was the least favored. However, reactions of the aryl chloride complexes were the slowest. Detailed mechanistic data revealed that cleavage of the starting dimer, accompanied by ligand substitution either before or after cleavage, led to the formation of a three-coordinate arylpalladium(II) halide monomer that reductively eliminated haloarene.
Reductive elimination
Aryl halide
Elimination reaction
Oxidative addition
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