Els nous sons dels anys seixanta.

As has been shown in previous chapters, ligands are important to transition metal catalyzed homogeneous reactions.167-169 A lot of work in optimizing reaction conditions are involved in the selection of ligands.170 Ligands stabilize the metal center, mediate the electronic and steric properties of the metal center as well as provide chemo-, regio- and stereoselectivity to chemical reactions.171 The proper selection of ligands is of crucial importance in Suzuki-Miyaura cross- coupling reactions as well as in borylation reactions. However, development of new ligands can be tedious and costly. To fully exploit the potential of existing ligands, we applied mixed-ligand strategy to develop nickel based catalytic systems for neopentyglycolborylations and Suzuki- Miyaura cross-coupling reactions.6,116,172

In this chapter, only mixed-ligand systems showing improved reactivity or selectivity compared to mono-ligand systems will be discussed. Tandem reactions applying mixed-ligands will not be discussed because essentially these reactions involve two sequential reactions utilizing two different ligands instead of applying mixed-ligand concept in a one-step reaction.173,174

42

In 2002-2003, the concept of mixed-ligand or ligand combination was developed.175-178 Reetz176 proposed to exploit the potential of existing ligands by combining different ligands in one reaction (MLnL’m) instead of inventing new ligands. Considering in most cases, multiple ligands bind to one reactive metal center (MLn, n=3-6).179 By mixing the ligands bound to the metal center, heterocombination metal ligand complexes (MLnL’m) can be formed. During reaction, ligands dissociate, exchange and associate.179,180 The mixed-ligand method greatly increases the amount of available catalytic systems. For example, given a library of 10 ligands, there are 45 heterocombinations, a five fold increase in the number of catalytic systems.

The Reetz group applied the idea on Rh catalyzed asymmetric hydrogenation of actamidoacrylate.176 With monodentate BINOL-based modular phosphonite ligand, the ee of hydrogenation of acetamidoacrylate ranges from 7.4 to 95.4. With combined phosphonite ligands, the ee of hydrogenation of acetamidoarylate increases to 98.0. (Scheme 1.38)

Scheme 1.38. Increase of ee of Rh Catalyzed Asymmetric Hydrogenation of Actamidoacrylate by Mixed-Ligand System176

The Feringa group demonstrated that improved ee and yield could be obtained for Rh catalyzed asymmetric C-C bond formation using the mixed ligand approach.

N H O R2 R1 H₂ [Rh(L)x]BF4 N H O R2 R1 R₁ = CO₂CH₃, Ph, p-Cl-C₆H₄, 2-naphthyl R2 = H, Ph Homocombination of ligand: ee 75.6 - 94.4 Mixed-ligand system: ee 96.4 - 98

43

Figure 1.3. Improved ee was obtained for Rh catalyzed asymmetric C-C bond formation by mixed-ligand approach.

(Reprinted with permission from reference 177 . Copyright (2003) American Chemical Society.177 ) Both Reetz’s and Feringa’s systems are built upon two basic features: 1) a metal center is bonded to multiple ligands; 2) ligand exchange happens easily in reaction. Thus with a mixed ligand, several catalytically active species, MLn, MLn-mL’m, ML’n coexist in reaction mixture. Due to the different binding affinity of ligands to the metal center, the ratio of each species in the mixture does not necessarily follow a statistical distribution. During the reaction, the most reactive and selective species will react fastest, hence increase the conversion and selectivity of the system. It is important to notice that mixed-ligand systems might not be necessarily more reactive or selective than monoligand systems. Thus, an optimization process is needed. For chiral systems, generally a combination of chiral ligands or a chiral ligand with an achiral ligand is applied. Achiral ligands can be used to improve the conversion or regioselectivity of an achiral reaction.170

The scenario is different for Ni or Pd based mixed-ligand catalyzed cross-coupling and borylation systems. In 2002, the Bedford178 group observed that using a mixture of PCy3 and triarylphosphite ligand, a turnover number (TON) of up to 1,000,000 was reported for palladium catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides with arylboronic acids (Scheme 1.39).178 For comparison, the TON of a single ligand system generally ranges from 3000 to 6000.178 The increase of TON comes from the increased longevity of catalyst life rather than higher reaction rate according to kinetic studies.178 The coligand (PCy3) decreases the reactivity

44

of Pd triarylphosphite complex but stabilizes the resting state of Pd by preventing the aggregation of Pd0.

Scheme 1.39. Suzuki-Miyaura Cross-Coupling of Aryl Chlorides with Mixed-Ligand Pd Catalytic System178

In the case of Buchwald precatalysts, due to the high steric hindrance of the Buchwald ligand, the metal center is only bonded to one ligand.167,174,181 The feature of a combination of ligands on one metal center does not apply. However, an increase of activity and selectivity of mixed-ligands in Pd catalyzed amination181 reactions was observed. The mixed-ligand system not only showed the merits of each mono ligand system but enabled the synthesis of asymmetric triarylamines. The catalysts based on BrettPhos (1 and 3, Scheme 1.40) are only efficient for monoarylation of primary amines but inefficient in amination reactions of secondary amines.181 On the other hand, the catalysts based on RuPhos (2 and 4, Scheme 1.40) are efficient for the arylation of secondary amines but produce low conversion for amination of primary amines due to the formation of significant quantities of undesired diarylation byproduct.174,181 Upon mixing the precatalysts based on BrettPhos (3, Scheme 1.40) with RuPhos (2, Scheme 1.40), the arylation of secondary amine was accomplished with comparable yields compared to precatalysts based on RuPhos alone (4, Scheme 1.40).181 When mixing the precatalysts based on RuPhos (2, Scheme 1.40) with BrettPhos (1, Scheme 1.40), the arylation of primary amines was accomplished with comparable yields compared to precatalysts based on RuPhos alone (4, Scheme 1.40) without undesired biarylation reaction.181 Most importantly, the synthesis of an

Cl R₁ + _B(OH) 2 R2 t-Bu t-Bu Pd O Cl Cl Pd O t-Bu t-Bu PAr2 Ar2P Ar = O t-Bu t-Bu 0.01 % PCy3, Cs2CO3, dioxane, 100 oC, 17 h 0.005% R1 R2 1 equiv 1.5 equiv

45

asymmetric triarylamine TPD was accomplished using this mixed-ligand system. (Scheme 1.40)181

Scheme 1.40. Mixed-Ligand Pd-Catalyzed C-N Cross-Coupling Reactions for Both Primary Amines and Secondary Amines181

Using crossover experiments, the mechanism of this enhanced reactivity of mixed-ligand Pd system was proposed. (Scheme 1.41)

i-Pr i-Pr i-PrPCy2 OMe MeO 1 (BrettPhos) PCy₂ Oi-Pr Oi-Pr 1 (RuPhos) PdNH2 L Cl 3: L = BrettPhos 4: L = RuPhos ArX + HN(R₁)R₂

mixture of 2 and 3 (0.005 - 1 mol%) Base, solvent, 80 - 110 o_{C, 16 - 24 h}

N Ar R1

R₂

ArX + H₂NR₃

mixture of 1 and 4 (0.005 - 1 mol%) Base, solvent, 80 - 110 o_{C, 16 - 24 h} N Ar R3 H H₂N NH₂ Br + Cl 0.2% 2, 0.2% 3

NaOt-Bu, dioxane, 110 o_{C, 24 h}

N N

46

Scheme 1.41. Proposed Mechanism of the Mixed-Ligand Pd Catalytic System for Arylation of Amines181 (Reprinted with permission from reference 181. Copyright (2010) American Chemical Society)

For the arylation of primary amines, the left catalytic cycle dominates. The right hand cycle proceeds for arylation of secondary amines. It indicates Pd preferably binds with BrettPhos, thus only small amount of RuPhos-Pd complex exists in the reaction mixture. Therefore, no biarylation of primary amine was observed. For secondary amines, since BrettPhos cannot catalyze the amination, a small amount of RuPhos-Pd complex from ligand exchange at PdII or Pd0 oxidation state catalyzes the amination. In the synthesis of asymmetric triarylamines, the Pd undergoes facile ligand exchange between the two cycles at both Pd0 and PdII state. The success of this mixed-ligand system is based on the rapid ligand exchange process on Pd as well as the higher rate of the desired reaction compared to undesired side reactions.181

The Peng group also observed the enhanced reactivity of mixed-ligand Pd catalyzed C-N and C- S coupling of N-arylaminotriazole nucleosides with anilines and thiols (Scheme 1.42), which is otherwise not achievable with single ligand systems.182,183 Both triazole and purine chlorides and bromides are aminated with a broad scope of anilines. Selective amination of bromo-triazole

1: BrettPhos 2: RuPhos

47

processes smoothly with 4-chloroaniline with 73% yield. Heteroaryl chlorides and bromides were thiolated with aromatic and aliphatic thiols. 182,183

Scheme 1.42. Pd Mixed-Ligand Catalyzed Amination and Thiolation of N-arylaminotriazole Nucleosides182,183

To study the mechanism underlining the mixed-ligand system, cyclic voltammetry and 31P NMR experiments were carried out. Peng concluded that the enhanced reactivity comes from the faster formation of desired (Synphos)Pd(dba)183 and [(CyPF-tBu)Pd(dba)]182 in the presence of Xantphos. While (Xantphos)Pd(dba) is not reactive for amination or thiolation, it is formed quickly in the reaction and exchanges rapidly with Synphos and CyPF-tBu. 182,183 During reaction, the Pd0 and PdII are stabilized by Xantphos, and facile ligand exchange happens on Pd0 and PdII states. Later, the Peng group concluded that Pd(dba)2 and Pd2(dba)3 offered equivalent catalytic efficiency in the reported Pd-catalyzed C-N and C-S cross-coupling reactions involving mixed ligand systems.184 (Scheme 1.43)

N N N O OAc OAc AcO O OCH₃ X X = Br, Cl + Ar-NH₂ [Pd2(dba)3] Synphos/Xantphos N N N O OAc OAc AcO O OCH3 Ar-HN N N N O OAc OAc AcO O OCH3 X X = Br, Cl + R-SH [Pd2(dba)3] CyPF-t-Bu/Xantphos N N N O OAc OAc AcO O OCH3 R-S K2CO3, toluene, 110 oC 3 h - 20 h, 70% - 92 % NEt3, toluene, 115 oC 24 h, 50% - 94 % 1 equiv 2 equiv 1 equiv 2 equiv

48

Scheme 1.43. Proposed Mechanism of Mixed-Bidentate-Ligand Pd Catalytic System (Reprinted with Permission from Reference 183 Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

A similar explanation was provided via DFT studies on the increased reactivity of mixed ligand systems in the PdII-Bronsted acid catalyzed migratory ring expansion reaction of an indenyl cyclobutanol to a spirocyclic indene compounds. The DFT studies showed that ligand exchange stabilizes the intermediate species, thus lowering the activation energy of the ring expansion reaction, 185 which is similar to the effect of a supporting ligand in Pd mixed-ligand catalyzed amination of halogenated nucleosides.183

Our group first noticed the mixed-ligand effects in both nickel catalyzed borylation and Suzuki- Miyaura cross-coupling reactions.

In 2004, we observed that a mixed-ligand NiCl2(dppe)/PPh3 system42 showed solvent- independent reactivity in nickel catalyzed Suzuki-Miyaura cross-coupling reactions of aryl mesylates, arenesulfonates and halides with arylboronic acids. Both electron-rich (-OMe substituted) or electron-deficient (COOMe substituted) aryl mesylates and chlorides are cross- coupled in good to excellent yields in toluene and dioxanes. As-received ACS reagent grade solvents were applied successfully as well (Scheme 1.44).42

49

Scheme 1.44. NiCl2(dppe)/PPh3 Mixed Ligand System Catalyzed Suzuki-Miyaura Cross- Coupling of Aryl Halides and Sulfonates

Later, we observed similar mixed-ligand effects in nickel catalyzed borylation of aryl sulfonates and halides (Scheme 1.45).114-116 With NiCl2(dppp)/dppf, the rate of borylation increased while side reactions such as dehalogenation and homocoupling were inhibited. A variety of functional groups including esters, ethers, imides and cyanides were tolerated. Halogenated thiophene was borylated but not pyridine derivatives. Zero valent metals accelerate the borylation reaction, which competes with side dehalogenation reactions.114-116

Scheme 1.45. NiCl2(dppp)/dppf Mixed-Ligand System Catalyzed Neopentylglycolborylation of Aryl Halides and Sulfonates114-116

Later, we applied mixed ligand6,172 Ni(COD)2/PCy3 and NiIICl(1-naphthyl)(PPh3)2/PCy3 system in the cross-coupling of aryl/heteraryl mesylates and sulfamates with aryl/heteroaryl neopentylglycolboronates in THF at room temperature.6,172 The reaction showed a great tolerance to functional groups. Without PCy3, neither Ni(COD)2 nor NiIICl(1-naphthyl)(PPh3)2 is capable of catalyzing the coupling reaction. We suspect the more electron rich PCy3 replaces

X R R = OMe, COOMe + B(OH)2 NiCl2(dppe)/PPh3 dioxane or toluene 80 o_{C, 14 h} R R = OMe, COOMe X = I, Br, Cl, OMs 1 equiv _{1.2 equiv} X R R = o, m, p -F, OMe, COOMe CN, CH₂CN + NiCl2(dppp)/dppf toluene 100 o_{C, 14 h R} B X = I, Br, Cl, OMs, OTs HB O O O O

50

COD and PPh3 in the catalyst activation step. Further study showed COD and PPh3 are deleterious to the reaction.

Scheme 1.46. Ni(COD)2/PCy3 and NiIICl(1-naphthyl)(PPh3)2/PCy3 Catalyzed Cross-Coupling of Aryl/Heteraryl Mesylates and Sulfamates with Aryl/Heteroaryl Neopentylglycolboronates6,172

The Lei group reported that the Ni(PPh3)4/dppp mixed-ligand system catalyzed the Heck reaction of terminal alkenes with secondary and tertiary α-carbonyl alkyl bromides.186 The reaction proceed by a SET mechanism in which Ni0(PPh3)4 serves as the electron donor. Reactions carried out with mixed-ligand Ni(PPh3)4/dppp showed higher activity compared to the Ni(PPh3)4/PPh3 system.

The difference in Ni mixed-ligand catalyzed reactions and Pd mixed-ligand catalyzed reactions lies in the rate of ligand exchange. While the ligand exchange in palladium mixed-ligand catalyzed reactions is facile,181 in nickel mixed-ligand catalyzed reactions, the exchange is relatively slow.115

To conclude, the mixed-ligand strategy has provided a powerful method in transition metal catalyzed reactions, including hydrogenation,176 asymmetric C-C bond formation,177 amination,183,187 thiolation,182 Suzuki-Miyaura cross-coupling,42 borylation114-116 and Heck reactions.186 Mixed-ligand systems provide superior activity by providing stable intermediates in the catalytic cycle,185 extending the lifetime of the zero oxidation state metal and facilitate the formation of active species. The mixed-ligand effect is expected to influence other transition metal

R₁ X + B

O O R₂

6 mol% Ni(COD)₂, 12 mol% PCy₃ or 5 mol% NiII_{Cl(1-naphthyl)(PPh}

3)2 10% PCy₃

K3PO4, THF, 23 oC

R₁ R₂

R₁ = OCH₃, CO₂CH₃, COCH₃,, CN; R₂ = OCH₃, CO₂CH₃ 1 equiv 1 - 1.2 equiv

51

catalytic systems with the development of high throughput technology. However, there is no guideline yet to predict the behavior of mixed-ligand systems.