focused on the use of copper to mediate ipso-reactivity with aryl-halides. The first of his developments was described in 1901 and details the homocoupling of ortho-nitrobromobenzene (Scheme 20a).73 An analogous amination procedure was described two years later, coupling aniline to ortho-chlorobenzoic acid 110 (Scheme 20b).74 This amination process was further developed in 1906 by Goldberg, demonstrating that catalytic loadings of copper could give high product yields on addition to a basified mixture of bromobenzene and ortho-aminobenzoic acid in refluxing nitrobenzene (Scheme 20c).75
O 1.0 equiv. Me2CuLi•LiI
1.0 equiv. Me3SiCN OSiMe3
Me 1.
2.
THF-d8, –100 to –80 ºC
102 103
Me2CuLi•LiI
104
O
Cu Me Me
Li O
Cu Me MeLi Li I
+
105 106 107
Me Cu Me
CN Me3SiO
Li O
Me3SiCN
coordination oxidative attack
a)
b)
102
Scheme 20 – a) Ullmann’s copper(0)-mediated biaryl formation;73 b) Ullmann’s copper(0)-mediated amination procedure;74 Goldberg’s copper(0)-catalysed amination procedure75
The extreme conditions required for Ullmann and Goldberg’s processes meant that the use of copper catalysis for cross-coupling was comparatively under-researched for the next century.67,76 However, in 2001 and 2002, the Taillefer and Buchwald groups concurrently patented Ullmann-type processes employing ligands to enhance reactivity.77–79 These studies prompted a revival in the area and led to the development of a large number of carbon-heteroatom bond-forming processes.80,81 One such example can be seen in Buchwald’s N-/O-selective arylation of aminoalcohols, where the selective coupling of either the alcohol or amine portion of 113 is controlled by the ligand employed (Scheme 21).82 Diketone ligand 114 gives amine functionalisation, whilst the use of phenanthroline 116 leads to reaction through the alcohol. Whilst the differing chemoselectivity can be explained based on the native ligand charge and pKa differences, the wider mechanism of the process is disputed.
Scheme 21 – Buchwald’s N-/O-selective arylation of aminoalcohols82
Br
NO2 neat, >200 ºC
NO2
O2N 2.0 equiv. Cu(0)
108 (2.0 equiv.) 109
Cl
115 112 113 117
97% O O 86%
There are two generally proposed pathways for Ullmann-type reactivity. One such proposal invokes a Cu(I)-Cu(II) cycling mechanism and radical behaviour, whilst the second focuses on a Cu(I)-Cu(III) redox loop and employs oxidative addition and reductive elimination steps. Extensive kinetic investigations have been carried out to either confirm or disprove either of these mechanisms, but have yielded few conclusive results. Studies employing radical traps and radical clocks have, with the exception of a photoinduced process,83 demonstrated free-radical activity to not be mechanistically viable.84–86 These results can be rationalised by any radical activity occurring in a closed-shell manner but can also be taken as evidence for a Cu(I)/Cu(III) cycle. Unfortunately, this latter manifold has also proved very difficult to experimentally support, largely due the identification of the aryl-halide activation step as the turnover-limiting step in Ullmann couplings. Computational evaluation has therefore become the method of choice for the investigation of the behaviour of copper-catalysed heteroatom arylation reactions using iodoarenes.
Computational studies have been carried out on Buchwald’s N-/O-selective aminoalcohol arylation process (Scheme 21). In line with the disagreement regarding the behaviour of the copper catalyst, both Cu(I)-Cu(II) and Cu(I)-Cu(III) redox cycles have been investigated. Firstly, computing model systems with methanol and methylamine, Houk and Buchwald proposed distinct closed-shell radical mechanisms for N- and O-arylation (Scheme 22).87
Scheme 22 – Houk and Buchwald’s a) SET and b) IAT mechanistic rationale;87 bold red/blue quantities denote the relative energy of the system at that stage of the mechanism (kcal mol-1)
Cu I
N-arylation was computed to proceed through a single electron transfer (SET) process with the catalyst resting state the anionic ligand-bound copper(I) iodide adduct 118 (Scheme 22a). The first step of the reaction involves the displacement of the iodide with deprotonated amine, giving anionic copper(I) amide 119. This species then acts as a single-electron reductant, reducing iodobenzene to its corresponding radical anion and furnishing the copper(II) adduct 120. The radical anion then loses iodide to give a phenyl radical which rapidly attacks the copper-bound nitrogen to generate copper(I) amine complex 121. Displacement of the coupled amine with iodide regenerates the anionic adduct 118.
In contrast, O-arylation was determined to occur through an iodine atom transfer (IAT) mechanism (Scheme 22b). In this process, methanol displaces iodide from the neutral copper(I) species 123 and is concurrently deprotonated to give copper(I) methoxide 124. The intermediate then undergoes iodine atom transfer to give copper(II) intermediate 125 and phenyl radical. The radical then attacks the bound methoxide, formally reducing the copper centre to generate ether-bound copper(I) iodide 126.
Dissociation of the product aryl ether regenerates the catalyst.
Computing the reaction system employing the true substrate, the Fu group proposed alternative mechanisms for the observed N- and O-arylations (Scheme 23).88 Both of these processes proceed through a copper(I)/(III) redox manifold.
Scheme 23 – Yu’s a) nitrogen arylation and b) oxygen arylation with a Cu(I)/Cu(III) mechanistic rational;.88 bold red/blue quantities denote the relative energy of the system at that stage of the mechanism (kcal mol-1)
Cu
In the case of nitrogen arylation (Scheme 23a), the catalytic cycle rests at the copper(I)-aryl iodide adduct 128. Oxidative addition of 128 is observed to be relatively energetically favourable (ΔG‡ = +9.7 kcal mol-1), giving copper(III) intermediate 129. A rate-determining apical association of the aminoalcohol then gives nitrogen-bound adduct 130 (ΔG = +14.1 kcal mol-1). Subsequent elimination of iodide and concurrent deprotonation of the amine gives Cu(III) amide 131, which then undergoes reductive elimination to furnish the nitrogen-coupled adduct 132 and regenerate copper(I).
Oxygen arylation (Scheme 23b) proceeds from copper(I) iodide complex 123. Ligand association with the hydroxylamine gives metastable intermediate 133, which rapidly loses iodide with deprotonation of the alcohol to form copper(I) alkoxide 134. The oxy-anion-bound intermediate then undergoes the rate-limiting oxidative addition step (ΔG‡ = 22.7 kcal mol-1), giving apical-iodide bound Cu(III) adduct 135.
Reductive elimination furnishes the coupled product 136 and reforms the Cu(I) iodide catalyst.
Yu has also calculated the highest-energy points on Houk and Buchwald’s SET/IAT models when applied to the use of 5-amino-pentan-1-ol 113. It is shown that for nitrogen arylation, the highest point on the oxidative addition/reductive elimination energetic profile is substantially lower in energy than for the proposed SET pathway (ΔΔG‡ = 34.8 kcal mol-1). Similarly, the highest point on the Cu(I)/Cu(III) pathway towards oxygen arylation is lower in energy than that of the IAT mechanism (ΔΔG‡ > 16.2 kcal mol-1). These data indicate that a copper(I)-copper(III) cycling mechanism is generally more favourable than copper(I)-copper(II) radical processes.
Further support for a copper(I)-copper(III) reaction manifold can be seen in Ribas’ work on the generation and reaction of crystallographically characterised aryl-copper(III) adducts.89 Ribas’ crucial work builds on results published in 2002 from a collaboration between Hedman, Hodgson, Llobet and Stack.90 These early studies detail the generation of copper(III)-aryl adducts via disproportionation from copper(II) salts in the presence of triazamacrocylic ligand 137 (Scheme 24a). The products were verified by X-ray crystallography and the oxidation state of the metal centre was confirmed by K-edge absorption spectroscopy. Using an engineered ligand backbone (140) and basic conditions, Ribas directly demonstrated oxidative addition of copper(I) salts into C–Br bonds to occur (Scheme 24b), allowing the production of stable copper(III) adducts (141). Interestingly, the reaction could be reversed on the addition of acid to the system. Furthermore, macrocylic aryl bromide 142 has been observed to undergo coupling with nucleophile 143 in the presence of catalytic copper hexafluorophosphate (Scheme 24c), firmly supporting the role of Cu(III) in the Ullmann reaction. This result was reinforced by the production of aryl ethers on the exposure of copper(III) species such as 138 and 141 to oxygen nucleophiles.91
Scheme 24 – a) Hedman, Hodgson, Llobet and Stack’s product of copper(III)-aryl species by copper(II) disproportionation;90 Ribas’ b) reversible Cu(I) oxidative addition into aryl bromide 140 and c) catalytic coupling
of 142 to nucleophile 14389
Whilst other mechanistic pathways cannot be discounted, clear evidence has been provided to indicate that copper(I)-copper(III) redox cycling is possible. The accessibility of Cu(III) under this reaction manifold has implications beyond the Ullmann reaction as other processes have also been proposed to proceed through high-valent copper intermediates. Examples include the Hurtley reaction,92–94 the Chan-Lam coupling,95 and the aromatic Finkelstein reaction.96 Finally, the mechanistic studies carried out on the reactivity of copper salts with aryl halides has allowed understanding of copper-catalysed reactions employing diaryliodonium salts, the focus of the remainder of this chapter.
1.4.3. Generation and reactivity of electrophilic Cu(III) species with iodonium salts