Xavi Ribas is Professor Agregat of Inorganic Chemistry in the Chemistry Department of the Universitat de Girona since 2006. He graduated in Chemistry from the Universitat de Girona (1996) and in 2001 obtained PhD in Chemistry by the Universitat de Girona. His main research interests are bioinorganic Models of Cu and Fe No-Heme Oxygenases, molecular Oxygen Activation and C-H and C-C Bond Activation. Chemistry of Cu(III).

C–H and C–X Bond Functionalization

Transition Metal Mediation

By Xavi Ribas

The Royal Society of Chemistry

Copyright © 2013 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-570-4

Contents

Chapter 1 Cu-Catalyzed Ullmann-Type C – Heteroatom Bond Formation: The Key Role of Dinucleating Ancillary Ligands Yongwen Jiang, Lanting Xu, Chenggang Zhou and Dawei Ma, 1,
Chapter 2 Mechanistic Understanding of Copper-Catalyzed Aryl–Heteroatom Bond Formation: Dependence on Ancillary Ligands Alicia Casitas, 46,
Chapter 3 Fundamental Pd0/PdII Redox Steps in Cross-coupling Reactions: Homogeneous, Hybrid Homogeneous–Heterogeneous to Heterogeneous Mechanistic Pathways for C–C Couplings Ian J. S. Fairlamb and Adam F. Lee, 72,
Chapter 4 PdII/PdIV Redox Couple Mediated C–X Bond Formation Andrei N. Vedernikov, 108,
Chapter 5 Organometallic PdIII Complexes in C – C and C – Heteroatom Bond Formation Reactions Julia R. Khusnutdinova and Liviu M. Mirica, 122,
Chapter 6 Aromatic C – F Activation: Converting Fluoroarenes to Useful Building Blocks Lauren Keyes and Jennifer A. Love, 159,
Chapter 7 Strategies Towards Challenging Fluorination Reactions Charlotte Hollingworth and Véronique Gouverneur, 193,
Chapter 8 Coordination-Directed Metallation Strategy for C – H Functionalization Luciano Cuesta and Esteban P. Urriolabeitia, 262,
Chapter 9 Transition Metal-Catalysed Direct Arylation of Unactivated Arenes with Aryl Halides Aiwen Lei and Hua Zhang, 310,
Chapter 10 Double C–H Activation in Pd-Catalyzed Cross-Coupling Reactions of Non-Preactivated Arenes Weiping Su, Min Zhang and Ge Wu, 328,
Chapter 11 Dioxygen-Coupled Palladium and Copper-Catalyzed Csp2–H Functionalization: Reactions and Mechanisms Xin Mu and Guosheng Liu, 363,
Chapter 12 Catalytic C–H/C–X Bond Functionalisation of Nucleosides, Nucleotides, Nucleic Acids, Amino Acids, Peptides and Proteins Sara De Ornellas, Thomas J. Williams, Christoph G. Baumann and Ian J. S. Fairlamb, 409,
Subject Index, 448,

CHAPTER 1

Cu-Catalyzed Ullmann-Type C–Heteroatom Bond Formation: The Key Role of Dinucleating Ancillary Ligands

YONGWEN JIANG, LANTING XU, CHENGGANG ZHOU AND DAWEI MA

1.1 Introduction

Copper-catalyzed coupling reactions of aryl halides with nucleophiles, so called Ullmann-type reactions, are well-established methods for preparing pharmaceutically and materially important compounds. The traditional version of these coupling reactions normally requires harsh reaction conditions, and the reactions have a reputation for erratic yields. Since the late 1990s, a great number of ligands, particularly N,N-, N,O– and O,O-bidentate ligands, have been revealed to have the ability to promote Ullmann-type reactions. The combination of copper salts and these ligands allow the coupling reactions to be conducted in milder conditions and with dramatically enhanced yields. Under these mild reaction conditions, an increasing number of nucleophiles have been found to be applicable for copper-catalyzed arylation reactions, therefore leading to structural moieties that are prevalent in building blocks of functional molecules in the life sciences and material sciences.

As a general trend, ligand promoted Ullmann-type reactions are not too sensitive to the choice of the copper source, but the choice of ligands is often crucial for different coupling reactions. In most cases ligands play an essential role for obtaining improved results, speeding up cross-coupling under much milder conditions, widening the substrate scope, and enhancing chemoselectivity and enantioselectivity. These ligands were believed to coordinate with CuI, thereby changing the electronic nature of this active species. Some proposed intermediates formed from CuI and bidentate ligands are outlined in Figure 1.1. The complexes 1–4 are formed by coordinating with ionic ligands, while complexes 5–8 result from the coordination of CuI with nonionic ligands.

The structures of some useful N,O-,N,N-, O,O-bidentate ligands as well as copper-complexes are outlined in Figure 1.2. In this chapter we wish to summarize their applications in promoting Ullmann-type coupling reactions, which can be classified into C–N, C–O, C–S and C–P bond formation reactions.

1.2 C–N Bond Formation

1.2.1 Arylation of Amines

1.2.1.1 Arylation of Aliphatic Primary and Secondary Amines

Copper catalyzed coupling between aryl halides and aliphatic primary amines is a typical transformation for checking the efficiency of newly developed ligands. Many ligands have proven effective for this reaction. The reaction conditions employed with these ligands are summarized in Table 1.1. As a class of cheap and conveniently available N,O-bidentate ligands, amino acids have been revealed to have a strong accelerating effect for Ullmann arylation amination. L-Proline (L1) was shown to be applicable for both aryl iodides and bromides with a working temperature range from 60 to 90 °C. In some cases N-methylglycine (L4) gave similar results (entry 1). 2-N,N-dimethylaminoethanol (deanol, L7) was another useful N,O-bidentate ligand for the amination of aryl halides although excessive addition was required (entry 2). Notably, the coupling reaction works well in aqueous media, and various amines (including simple primary amines, amino acids, amino alcohols and even peptides) could couple with aryl iodides at 80–90 °C. Two other N,O-bidentate ligands, 2-hydroxylbenzaldehyde N-phenylhydrazone L17 and 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone L19 showed the powerful acceleration effect, which made the coupling reaction of aryliodides with primary amines proceed at room temperature (entries 3 and 4). However, in this case the higher reaction temperature was still required if aryl bromides were used (entry 4).

The first efficient O,O-bidentate ligand for this transformation was ethylene glycol (L57), which was reported by Buchwald and coworkers, but only aryl iodides were suitable for the coupling (entry 5). Subsequently, they found that diethylsalicylamide (L60) was a powerful ligand for accelerating the aryl amination of aryl bromides (entry 6). Some years later, 2-isobutyrylcyclohexanone (L51) was found to be another powerful ligand, leading to the coupling reaction of aryl iodides with amines occur at room temperature, and aryl amination with aryl bromides proceed at 90 °C (entry 7). Additionally, a combination of CuCl as the catalyst, ethyl 2-oxocyclohexanecarboxylate (L50) as the ligand, and tetramethylammonium hydroxide as the base has been showed effective for aryl amination (entry 8).

rac-BINOL (1,10-binaphthyl-2,20-diol, L58) is another important and interesting O,O-bidentate ligand for the amination of aryl halides. The copper source was found to have a marked influence to this coupling reaction. The combination of CuBr and rac-BINOL (entry 10) could make amination of aryl iodides work at room temperature, while the combination of other copper sources (Cu, CuI, CuO/FeCl3) and rac-BINOL was not so effective (entry 9, 11). Additionally, with the assistance of ortho-carbonyl acid, coupling of aryl bromides and amines could be carried out at room temperature (entry 12).

A few N,N-bidentate ligands have been used to promote the coupling of aryl halides and primary amines (entries 13 and 14). Using diimine-type ligand L44 ((1E,2E)-oxalaldehyde dioxime (OADO)) and phase-transfer catalyst made the reaction work well in water (entry 13). Two activated aryl chlorides, 2-chlorobenzoic acid and 2-chloronicotinic acid, could give good results in this case.

Some phosphine ligands were also efficient for the amination of aryl halides although the relatively high reaction temperatures were required (entries 14–17).

Unlike Pd-catalyzed aryl amination, ligand-promoted Ullmann amination is very sensitive to steric hindrance of the amines. For example, when secondary amines were employed, the reaction became sluggish and only less hindered cyclic amines could give satisfactory conversions. Some ligand-promoted arylation of cyclic secondary amines are indicated in Table 1.2.

When acyclic secondary amines were used as the coupling partners, low conversions were observed in most cases. Twieg and coworkers reported the first useful example for arylation of acyclic secondary amines (Scheme 1.1). When N,N-dimethylaminoethanol (L7) was used as both the ligand and the solvent, 2- and 3-bromothiophenes could be coupled with some acyclic secondary amines under the catalysis of Cu/CuI. In this case complete conversion was only observed when amino alcohols were employed, presumably because amino alcohol could also accelerate this coupling reaction.

Recently, Ma and coworkers discovered a very powerful ligand for the arylation of acyclic secondary amines (Scheme 1.2). They found that the combination of CuI and 2-(2,6-dimethylphenylamino)-2-oxoacetic acid (DMPAO, L61) could make the coupling reaction of aryl halides with various aliphatic acyclic secondary amines work well at 60–110 °C. Notably, for the coupling of aryl bromides with primary amines and cyclic secondary amines, the catalytic system was still very efficient even when decreasing the catalyst loading to 1 mol%.

1.2.1.2 Arylation of Aryl Amines

Due to poor reactivity, aryl amines normally required higher reaction temperatures to ensure good conversion compared with aliphatic amines. In early studies, phenanthroline as well as its CuI-complex (C1) were used in the arylation of aryl amines, but were only applicable for the synthesis of triarylamines from secondary aryl amines (Table 1.3, entry 1). Two other N,N-bidentate ligands, N,N’-bis(2,6-diisopropylphenyl)-1,4-diaza-1,3-butadiene (DAB) L38 and 9-azajulolidine L45, were also efficient for the arylation of diarylamines when a strong base like tBuOK and tBuONa was used (entries 2 and 3).29,30 DMEDA (L26) was found to be a better ligand for the N-arylation of heteroarylamines (entry 4).

For N,O-bidentate ligands, L-proline (L1) could promote CuI-catalyzed arylation of primary aryl amines and the working temperature was 90 °C (entry 5). But only electron-rich anilines gave complete conversions, while electron-deficient anilines provided low yields. Fu found that this drawback could be overcome by heating the reaction mixture at 110 °C and using pipecolinic acid (L9) as a ligand (entry 6). Widening the substrate scope was possible when pyrrole-2-carboxylic acid (L11) was used, as evident from the fact that various aryl amines and some hindered aryl halides could give satisfactory coupling yields (entry 7).

rac-BINOL was the only O,O-bidentate ligand that has been used for the monoarylation of anilines (entry 8). Additionally, pyrrolidine-2-phosphonic acid phenyl monoester (L21) and pyrrolidine-2-phosphonate (L22) were also effective for promoting Cu-catalyzed coupling of aryl halides with anilines (entries 9 and 10).

1.2.1.3 Arylation of ammonia

The first copper/ligand catalyzed coupling reaction of aryl halides with ammonia was reported by a Merck group (Scheme 1.3, eqn (1.1)). In this case ethylene glycol was believed to serve as both ligand and solvent, and the reaction worked at 80 °C under an elevated pressure. These reaction conditions are suitable for substituted pyridine bromides and aryl bromides (eqn (1.2)).

Subsequently, several more powerful ligands for promoting this special coupling reaction were discovered, and the results are summarized in Table 1.4. Mild conditions were discovered by Kim and Chang, in which L-proline (L1) was employed as the ligand (entry 1). Both NH4Cl and NH3xH2O could be used as the nitrogen source, and the reaction proceeded smoothly at room temperature in the case of aryl iodides. But for aryl bromides, only substrates with an electron-withdrawing group gave good yields even increasing reaction temperature to 80 °C. To solve this problem, another ligand, trans-4-hydroxy-L-proline L2, was tested. This promoter was found to be applicable for both electron-deficient and electron-rich aryl bromides, could make their coupling with ammonia complete at 50 °C (entry 2).

Taillefer and coworkers reported that some 1,3-diketones are powerful ligands for copper-catalyzed coupling of aryl halides with ammonia. The optimized combination was Cu(acac)2 and acetylacetone L52, which makes this transformation complete at 60–90 °C in DMF. Both aryl iodides and aryl bromides are suitable coupling partners (entry 3).

Copper-carbene complexes C4, 1-(5,6,7,8-tetrahydroquinolin-8-yl)-2-methylpropane-1-one L18, sulfonato-Cu(salen) complex C6 and D-gluco-samine L70 could also affect this reaction (entries 4–7). But in one case aqueous ammonia was not a suitable coupling partner and a saturated ammonia solution in MeOH/NMP had to be used.

Recently, Page and coworkers reported that amination of aryl iodides could work well in liquid ammonia at room temperature under the catalysis of 1 mol% CuI and 1 mol% ascorbic acid L71. Increasing the reaction temperature to 100 °C could lead to complete conversion in case of aryl bromides as substrates (entry 8).

By employing some synthetic equivalents of ammonia, other alternative methods for preparing primary aryl amines have been reported. During the studies on the CuI/L-proline catalyzed coupling of aryl halides with amidine hydrochlorides, Fu and coworkers discovered that primary anilines were directly isolated. This transformation was believed to undergo a coupling/ hydrolysis process as indicated in Scheme 1.4.

The CuI/L-proline or CuI/N,N’-dimethylethylenediamine (L26) catalyzed coupling of aryl halides with sodium azide generally provided the corresponding aryl azides. Surprisingly, the Helquist group observed that primary anilines could be produced exclusively if the reaction was carried out by using 100 mol% CuI, 130 mol% L-proline and 2 equiv. of sodium azide (Scheme 1.5). Although the detailed mechanism is not clear yet, this reaction provides an alternative approach for assembling primary anilines from aryl halides.

The CuI/N,N’-dimethylethylenediamine (L26)-catalyzed coupling of trifluoroacetamide with aryl halides could proceed smoothly in DMF (for aryl iodides) or dioxane (for aryl bromides) to deliver the corresponding amidation products, which could be easily converted into primary aryl amines via hydrolysis in a one-pot manner (Scheme 1.6).

1.2.2 Arylation and Vinylation of N-Heterocycles

1.2.2.1 Coupling of Aryl Halides and N-Heterocycles

N-Aryl heterocycles are frequently found in bioactive molecules and are useful precursors for material science. Therefore, method development for synthesis of N-aryl heterocycles has become a hot area in organic synthesis. Copper/ligand catalyzed cross-coupling of aryl halides with N-heterocycles has been proven to be one of the most powerful approaches for assembling these compounds. The suitable N-heterocycle coupling partners were outlined in Figure 1.3.

Although a stoichiometric quantity of ligand had to be used, 1,10-phenanthroline (L29) was the first ligand used for copper-catalyzed arylation of imidazole with aryl iodides (Table 1.5, entry 1). As an extension of this study, Cu2O/4,7-dimethoxy-1,10-phenanthroline (L30) was found to be more effective, leading to the coupling reaction occur at 80–110 °C in the presence of Cs2CO3 and using n-PrCN as a solvent (entry 2). For coupling of iodobenzene and imidazole, complete conversion could be achieved with only 0.05 mol% of copper(I) iodide and 0.075 mol% of ligand. Other improved procedures, including the use of KF/Al2O3 or TBAF as the base, have been reported for Cu/1,10-phenanthroline-catalyzed arylation of diazoles, benzoimidazoles and indoles (entries 3–5).

Diamine ligands, like trans-dicyclohexane-1,2-diamine L24 and trans-N,N’-dimethyl-dicyclohexane-1,2-diamine L25, are also useful promoters for copper catalyzed coupling of aryl halides with N-heterocycles (entries 6–8). A wide range of heterocycles, including indoles, pyrroles, pyrazoles, imidazoles and triazoles, were successfully employed in this case. Noteworthy is that optimized reaction conditions are slightly different for different N-heterocycles (entries 6–8).

Some other N,N-bidentate ligands have been demonstrated to be able to promote Cu-catalyzed arylation of N-heterocycles. Among them, (S)-pyrrolidinylimidazole (L48) could be used for coupling reaction of activated aryl chlorides with imidazoles (entry 9); N,N’-dimethyl-1,1′-binaphthyl-2,2′-diamine L36 and 2-(2′-pyridyl)benzimidazole L33 were more suitable for the coupling of aryl halides with indoles (entries 10–11); and (1E, 2E)-oxalaldehyde dioxime L44 was a suitable ligand for coupling in water (entry 12).

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