The formation of C-O, C-N, and C-S bonds is one of the most attractive methods for organic chemists. The successful Pd-mediated C-X bond formation provided a powerful tool to access a wide range of pharmaceutical molecules and bioactive natural products. However, costly palladium reagents and general air-sensitive system limited its applications in organic synthesis, process chemistry, and industrial manufacturing. These disadvantages required exploration of new metal-catalyzed reagents and systems to conduct these reactions. The inexpensive metal copper attracted increasing attention after the pioneering work of Buchwald and his group23, 41 in this area. The combination of copper salts and efficient ligands significantly improved the reaction yields and compatibilities, probably due to the increased solubility and decreased aggregation of copper salts in the presence of the ligands. These ligands could be mainly classified as O,O-, N,N-, and N,O-ligands according to their corresponding chemical structures (Figure 1).
Several copper complexes used in Ullmann coupling reactions are shown in Figure 2.
In addition, with the development of sustainable, environmentally benign, and cost-effective chemistry, “green” concept and techniques in organic synthesis have become widely accepted and applied in recent years.42,43 Recent and representative green synthetic methodologies, such as ligand-free systems, reusable catalysts, and microwave or ultrasound irradiation, will also be highlighted in this review.
1. New Development of Ligands and Copper Complexes
a. C-O Bond Formation
In 2009, Yang et al.44 reported an effective glyoxal bis(phenylhydrazone) ligand (L15) for the catalytic Ullmann O-arylation of various substituted phenols and aryl bromides under mild reaction conditions (Table 2, Entry 1).
Development of the Ullmann O-Arylation
(2-Pyridyl)acetone45 (L23), as a new supporting ligand, was used in the copper-catalyzed Ullmann O-arylation of diverse (hetero)aryl halides (X = I, Br, Cl) with different phenols (Table 2, Entry 2). Until then, there were only a few examples46–48 about the successful copper-catalyzed coupling of chlorobenzene with phenols. The electron-deficient aromatic chlorides gave diaryl ethers in moderate to excellent yields at high temperature (120°C); however, acceptable yields were obtained only with electron-rich aryl chlorides in the presence of excess substrates.
In 2010, Buchwald and Maiti49 described a simple and effective protocol for the Ullmann coupling between sterically hindered phenols and aryl halides (X = I; Br). Inexpensive picolinic acid (L25) was employed as the ligand in this method, which tolerated a variety of functional groups (Table 2, Entry 3).
An efficient Cu2O/1H-imidazole-4-carboxylic acid (L24) catalytic system for the O-arylation of phenols and iodoarenes was reported by Cheng and Hsieh.50 The reaction afforded an array of substituted diaryl ethers under mild conditions. The low catalytic loading (1 mol%) and economical copper source increased the possibility for the industrial application (Table 2, Entry 4).
In 2008, Buchwald et al.51 described mild conditions for the Ullmann O-arylation of aryl halides (X = I, Br) and aliphatic alcohols (Table 2, Entry 5). The relatively low catalyst loading and good functional group tolerance allowed easy access to a wide range of arylalkyl ethers.
Sekar et al.52 presented a simple and effective Cu(OTf)2/1,1′-binaphthyl-2,2′-diamine (BINAM, L16) catalytic system for the synthesis of a large number of diaryl ethers (Table 2, Entry 6).
Methenamine (L18), a commercially available and inexpensive material, was found to be efficient in the Ullmann etherification by Qian’s team.53 This methodology was applicable to a variety of phenols and aryl halides under mild conditions; twenty-eight compounds were obtained in moderate to excellent yields, except for p-acylphenol (Table 2, Entry 7). Notably, methenamine, a low molecular weight polymer of ammonia and formaldehyde, is also an antibiotic and undergoes acidic hydrolysis to give the active component formaldehyde with antimicrobial property.
Buchwald and Maiti54 described the selective formation of the C-O bond in the copper-catalyzed reaction of aryl halides with 3-amino- and 4-aminophenols by employing picolinic acid (L25) and trans-N,N′-dimethyl-1,2-cyclohexanediamine (CyDMEDA, L17), as the ligand, respectively (Table 2, Entry 8).
In 2011, commercially available potassium fluoride/clinoptilolite (KF/CP) was found to be an effective base in the Ullmann O-arylation of aryl iodide and phenols under the CuI/L10 or L29 catalytic system (Table 2, Entry 9).55 The base was also efficient in the SNAr reaction of activated aryl fluorides and phenols without catalyst.
In 2008, Hu et al.56 reported an air-stable copper(I)-bipyridyl complex, (C1, Figure 2) which exhibited high catalytic capability in the Ullmann O-arylation of both phenols and aliphatic alcohols with aryl halides (Table 2, Entry 10).
Taillefer and coworkers57 described a simple and efficient method for the copper-catalyzed synthesis of phenols by employing hydroxide salts (Table 2, Entry 11). The reaction solvent was essential to the selectivity between the phenol product and the diaryl ether side-product, which was formed by further Ullmann etherification of the in situ produced phenol with aryl iodide. The screened ligands dibenzoylmethane (L1) and N,N′-dimethylenediamine (L14) were found to be effective with aryl iodides and aryl bromides, respectively, but the ligand loading was high (up to 50 mol%).
In 2010, Fu and Yang58 reported a similar protocol for the synthesis of substituted phenols via copper-catalyzed, Ullmann-type reaction by employing pyridine-2-aldoxime (L28), as the ligand, and water, as the solvent (Table 2, Entry 12). Interestingly, the acid group of 2-chlorobenzoic acid greatly facilitated the hydroxylation process; while other aryl chlorides remained unreactive under this catalytic system. In 2010, Ma et al. also observed the ortho-effect in the ligand-free Ullmann O-arylation of o-chlorotrifluoroacetanilides with phenols;59 this CuBr/L22 catalytic system was also efficient with sterically hindered phenols.
Based on its previous work, the Taillefer group60 described a new protocol allowing the synthesis of symmetrical and unsymmetrical diaryl ethers from aryl halides and simple oxygen source, such as H2O or hydroxide salts (Scheme 1). The reaction proceeded to give phenols initially, followed by faster etherification of aryl halides with the formed phenols. The unsymmetrical coupling of different aryl halides accompanied the formation of symmetrical diaryl ethers, especially for the reactive aryl iodide.
In 2013, a highly efficient and regioselective Ullmann reaction of 2,x-dihalopyridines with phenols was described by Chen et al.61 The corresponding 2-aryloxypyridines were obtained in good to high yields under the CuI/TMEDA catalytic system (Scheme 2).
b. C-N Bond Formation
In 2009, the Wan group62 reported an efficient CuO/oxalyl dihydrazide/ketone system for the Ullmann amination of aryl halides in water. The most reliable ketone was found to be hexane-2,5-dione (Table 3, Entry 1). Both aryl bromides and iodides could be aminated by a variety of anilines, aliphatic amines, and imidazoles under microwave irradiation or conventional heating. The reaction could even proceed smoothly at room temperature by increasing the catalyst loading to 20 mol% and prolonging the reaction time to 96 h, except for the imidazole substrates. But this method required high loading of oxalyl dihydrazide (L34, 50 mol%) and hexane-2,5-dione (L4, 1 equiv.) additives.
Development of the Ullmann N-Arylation
On the basis of their previous work, Wan et al.63 subsequently developed a novel and improved ligand pyrrole-2-carbohydrazide (L32) for the Cu-catalyzed amination of aryl halides with amines in water (Table 3, Entry 2). The reaction time could be reduced to 5 min under microwave irradiation. Interestingly, the N2,N2′-disubstituted oxalic acid bishydrazide derivative (L35)64 was also an effective ligand, for the Ullmann reaction, which was then reported by the same group (Table 3, Entry 3).
In 2010, Wu et al.65 reported an Ullmann coupling reaction of 4-iodotoluene with pyrazole and 1,2,4-triazole by employing ligands L27 and L13 (Table 3, Entry 4).
The copper-catalyzed arylation of oxadiamines and polyamines for the synthesis of N,N′-diaryl derivatives was studied by Beletskaya and her students.72 The yields of the target products and the selectivity of the arylation of the amino groups were strongly dependent on the nature of oxadiamines, polyamines, and aryl halides, as well as on the reaction conditions, such as ligands, solvents, and bases. The best results were achieved by using CuI/proline/Cs2CO3/MeCN or EtCN system for the N,N′-diarylation of tetraamines and CuI/α-acetylcyclohexanone or α-isobutyrylcyclohexanone/Cs2CO3/DMF system for the N,N′-diarylation of oxadiamines.
In 2011, Wang et al.66 demonstrated an efficient Ullmann reaction of aryl bromides with N-heterocycles catalyzed by the combination of CuI and acylhydrazine- or acylhydrazone-type ligands. The facile access to the modifications of the acylhydrazine and acylhydrazone units allowed the optimization of catalytic activity and selectivity. The coupling reaction gave the corresponding products in moderate to high yields using L33, as the ligand (Table 3, Entry 5).
The CuCl/L30 catalytic system was found to be efficient in the Ullmann N-arylation of aryl halides with N-heterocycles and alkylamines (Table 3, Entry 6).67
The Ullmann reaction of aryl iodides and guanidine nitrate was successfully performed under the CuI/L31 catalytic system (Table 3, Entry 7).68 The desired N,N′-diarylguanidines were obtained in 19–92% yields.
The Ullmann coupling of aryl halides (X = I, Br) and substituted amidine hydrochlorides provided a practical methodology for the synthesis of substituted anilines (Table 3, Entry 8).69 The reaction gave the corresponding products in moderate to good yields under optimized conditions (CuI/L19/Cs2CO3/DMF).
In 2010, Qiao et al. reported a simple protocol for the copper-catalyzed synthesis of substituted aromatic amines using NaN3, as the amine source (Table 3, Entry 9).70 Control experiments showed ortho-functional groups (COOH, CONH2, NHCOR) played an important role in the catalytic cycles. Notably, the ortho-effect was also observed in the Ullmann coupling of o-halobenzoic acid and alkylamines;73 the reaction was carried out at ambient temperature, using CuI/L9 as the catalyst.
In 2009, Taillefer and Xia71 reported a practical and economical synthesis of anilines by employing aryl halides and ammonia, as the starting materials. The inexpensive ligands (L2/L3) and nitrogen source, together with the mild conditions, provided a possibility for industrial scale production (Table 3, Entry 10).
In a recent mini-review by Enthaler,74 several protocols using ammonia as the starting material for the synthesis of anilines via copper-mediated coupling reaction were discussed (Scheme 3). In general, these protocols could be performed at low reaction temperatures suitable for potential industrial applications, but the high catalyst loadings remain a challenge for use in commercial processes.
c. C-S Bond Formation
In 2009, Li et al.75 reported a simple and highly efficient copper-catalyzed S-arylation of thiophenols and aryl halides (X = I, Br). This method gave moderate to excellent yields of diaryl sulfides with a wide range of functional groups by using 1,2,3,4-tetrahydro-8-hydroxyquinoline (L26), as the ligand. The reactions of activated aryl iodides could be conducted even at room temperature (Table 4, Entry 1).
Development of the Ullmann S-Arylation
The combination of CuI and cis-1,2-cyclohexanediol76 (L8) was described as a general, mild, and efficient catalytic system for the synthesis of various sulfides bearing arylvinyl, diaryl, heteroaryl, and alkyl motifs. The notably mild reaction conditions enabled a wide range of functional groups to be present in both reaction substrates. However, vinyl chloride, vinyl tosylate, vinyl trifluoromethanesulfonate, and potassium vinyltrifluoroborate were found to be completely inert in this catalytic system. Notably, coupling reactions of E- and Z-vinyl iodides with RSH gave their corresponding products with the retention of the stereochemistry (Table 4, Entry 2).
The Cu(OTf)2/BINAM (L16) catalytic system, used in the Ullmann O-arylation, was also effective in the synthesis of a variety of diaryl and arylalkyl thioethers.77 Highly activated aryl chlorides and tosylates provided the corresponding thioether products without a catalyst, suggesting nucleophilic addition elimination mechanism (Table 4, Entry 3).
In 2009, Feng et al.78 reported a copper-catalyzed Ullmann coupling of various alkyl, aryl, and heteroaryl thiols with aryl and heteroaryl halides (X = I, Br, Cl). Notably, this catalytic system was also effective with highly activated aryl chlorides, such as p-acetyl, p-cyano, p-nitro, and p-trifluoromethylchlorobenzenes, although the yields were relatively low (52–82%) (Table 4, Entry 4).
Qi’s group79 recently described a general and economical one-pot synthesis of substituted thiophenols via copper-catalyzed C-S formation of aryl and heteroaryl iodides and thiourea, followed by the treatment of aqueous hydrochloric acid (Table 4, Entry 5).
In 2011, Ramaswamy et al.80 reported an Ullmann-type reaction of halothiophenecarboxylic acids and halobenzoic acid with sodium bisulfite (Scheme 4). The proposed oxidative addition and reductive elimination mechanism were supported by the following observations: 1) The reactivity order ArBr 〉〉 ArCl, and the cyclic voltammetric data on cathodic potential was consistent with the nucleofugicity of the halide; 2) Couplings were favored by the presence of electron-withdrawing groups; 3) Coupling did not occur without a copper catalyst; 4) Radical inhibitors, such as butylated hydroxytoluene (BHT) did not suppress the reaction, and the results showed that ortho-carboxylic acid groups accelerated significantly the rate of oxidative addition process of the copper complex to the C-Br bond.
d. More Than One-type Bond Formation
The ligands, mentioned above, are largely applicable to one specific type of bond formation (C-O, C-N, or C-S). As more novel and advanced ligands were explored and developed, several versatile catalytic systems for different bond formations were established over the past few years. This review highlights some recent examples of these highly active ligands.
In 2006, Fu et al.46 disclosed a new and efficient copper-catalyzed reaction for the formations of C-N, C-O, and C-P bonds (Table 5, Entry 1). A broad array of N-, O-, and P-arylated products was synthesized in good to excellent yields by using the CuI/pyrrolidine-2-phosphonic acid phenyl monoester (PPAPM, L21) catalytic system. The aryl chloride substrates gave lower yields due to decreased reactivity.
Versatile Ligands for the Ullmann Reaction
1,1,1-tris(Hydroxymethyl)ethane81 (L6) and ethyl 2-oxocyclohexanecarboxylate29 (L5) were then found to be efficient in the copper-catalyzed Ullmann reaction of aryl halides with O-, N-, and S-nucleophiles (Table 5, Entry 2–3).
A new and practical ligand, 2-pyridin-2-yl-1H-benzoimidazole82 (L12), was reported in the coupling reactions of vinyl halides (X = I, Br) with N-heterocycles and phenols (Table 5, Entry 4). A broad range of N-vinyl heterocycles and arylvinyl ethers was achieved in good to excellent yields with the retention of the stereochemistry under mild conditions.
In 2011, Chen et al.83 developed a novel type of N,N′-dioxide ligand (L36), which was efficient for the Ullmann coupling of aryl halides with diverse O-, N-, and S-nucleophilic reagents (Table 5, Entry 5).
2. Green Synthetic Methodology
In a simple term, the principles of green chemistry require low “cost” and high “benefit” in organic reactions. As for the Ullmann reaction, it means that less expensive ligands or ligand- or additive-free conditions, reusable catalysts, and shorter reaction time should be selected. In this context, great efforts have been devoted to developing greener and more sustainable synthetic methods for copper-mediated Ullmann coupling reactions.
a. Ligand- or Additive-free Conditions
Ligand-free, Ullmann-type coupling reactions attracted considerable attention due to the advantage of economical and green conditions.
Chan et al.84 developed a catalytic and efficient ligand-free condition (CuI, n-Bu4N+Br−, DMF, K3PO4, reflux, 22 h) for the Ullmann O-arylation of various substituted phenols and aliphatic alcohols with aryl iodides (Scheme 5). This reaction system was also found to be effective in the Ullmann S-arylation85 of aryl iodides with aromatic and aliphatic thiols.
In 2007, Correa and Bolm86 reported a catalytic and ligand-free Ullmann N-arylation (Scheme 6) of various N-heterocycles with aryl halides (X = I, Br, Cl). Cu2O was employed, as the catalyst. Unfortunately, aniline and benzylamine proved to be unsuccessful substrates for this protocol. A much milder ligand-free condition at 35–40°C and using 20 mol% CuI, as the catalyst, was established for a similar scope of substrates.87
Following on its previous work, in 2010, Bolm’s group88 further developed another Cu powder/CsOAc/DMSO system for the ligand-free Ullmann coupling reaction (Scheme 7). The heteroaryl chloride exhibited low reactivity under the same reaction condition. Interestingly, the reaction with electron-rich 3-bromothiophene gave a moderate yield of the desired product; in contrast, the use of 2-bromothiophene, as the substrate, was unsuccessful.
In 2011, the ligand- and solvent-free Ullmann reaction of aryl halides with alkyl amines was reported by Wei’s group.89 The reaction gave the corresponding anilines in moderate to excellent yields under the catalysis of 5 mol% copper powder (Scheme 8).
The CuCl/n-Bu4N+OH− (40% aq.) catalytic system was found to be an efficient ligand-free protocol for the Ullmann C-N bond formation of aryl halides (X = I, Br) and alkylamines or N-heterocycles,90 the yield was dramatically reduced when the reaction was not carried under an inert atmosphere.
In 2010, Punniyamurthy et al.91 revealed a ligand-free protocol of copper-catalyzed coupling of aryl iodides with amides or imidazoles (Scheme 9).
In 2011, Antilla et al.92 disclosed a ligand-free protocol for the Ullmann coupling reaction of aryl iodides with amidines or benzamidines (Scheme 10).
Punniyamurthy et al.93 reported the ligand-free synthesis of substituted 2-(arylthio)arylcyanamides via the cascade intra- and intermolecular Ullmann C-S coupling reaction of 2-(iodoaryl)thioureas with aryl iodides (Scheme 11).
In 2011, a novel method for the preparation of symmetric diaryl thioethers was developed by Zhao and coworkers94via double Ullmann S-arylation of aryl halides with thioacetamide under ligand-free conditions (Scheme 12).
Additional examples for the application of ligand-free Ullmann reaction in the synthesis of heterocycles will be discussed in the section II.1.
b. Recyclable Heterogeneous Catalysts
In most homogeneous catalytic systems, the copper catalysts are usually discarded following the reaction and the catalyst loading is high. Thus, the development of inexpensive, ligand-free, and recyclable catalysts remains a very active area of research. In addition, heterogeneous catalysts offer the advantage of easy separation from the organic solvents. The combination of polymers,95 charcoal,96 cellulose,97 zeolites,98 alumina,99 and silica gel100 with copper salt allowed facile access to heterogeneous catalysts.
In 2012, Jain et al.101 described a recyclable and efficient heterogeneous copper(II) trans-bis-(glycinato) complex catalyst for the synthesis of diaryl ethers via Ullmann-type reaction (Scheme 13). The catalyst could be easily prepared from copper(II) acetate and glycine.102 The reaction gave moderate to high yields of diaryl ethers under mild conditions. The presence of ortho-substituted and electron-withdrawing groups of the phenol substrates had a negative effect on this reaction. The authors also studied the reactivity of the recycled catalyst and found that it retained high activity for the coupling reaction, even after 7 runs.
A series of supported CuO catalysts were prepared and characterized by Li and coworkers.103 Among them, CuO/γ-Al2O3 proved to be the most effective catalyst for the Ullmann O-arylation of iodobenzene. The recycle experiment showed that the catalytic activity of the recycled catalyst remained the same after 3 cycles.
The combination of CuFe2O4 and 1,10-phenanthroline (L10) was determined to be an efficient catalytic system for the Ullmann alkoxylation of aryl halides and aliphatic alkyl alcohols.104 The recycle experiment suggested the used catalyst retained high activity by simple grinding with an agate mortar, even in the seventh run.
As reported by Mulla and coworkers,105 heterogeneous recyclable copper fluorapatite (CuFAP) could be used as an efficient catalyst for the Ullmann O-arylation of aryl halides (X = I, Br) with the potassium salt of substituted phenols in the presence of N-methyl 2-pyrrolidone (NMP), as the solvent, at 120°C.
In 2011, Rad and coworkers106 designed and synthesized a novel and efficient silica-supported heterogeneous catalyst (Scheme 14), namely, copper nanoparticle-doped silica cuprous sulfate (CN-DSCS) for the Ullmann N-arylation of nucleobases and N-heterocycles with aryl halides (X = I, Br). The screening of bases and solvents revealed that 1,8-diazabicycloundec-7-ene (DBU) and DMF were the most suitable conditions for this protocol. Subsequently, a series of N-aryl-nucleobases was achieved in moderate to good yields under the optimized conditions.
In 2011, a new polymer-supported copper(I) complex (Scheme 15) was synthesized and characterized by Islam et al.107 The Ullmann coupling of aryl halides and substituted anilines gave the triarylamine products. The catalyst could be easily recycled by filtration, washed, dried under vacuum, and then conducted in the next run under optimized conditions. The reused catalyst maintained its catalytic potency in this reaction.
Recently, an alumina-supported Cu(II) complex108 was synthesized from CuSO4 and basic alumina by stirring them in water followed by removal of the water under reduced pressure at 120°C (Scheme 16). This catalyst complex exhibited excellent catalytic activity in the Ullmann coupling of various aromatic and alkyl thiols, phenols, and aliphatic amines with aryl halides (X = I, Br). Interestingly, the coupling reaction of aryl iodides or bromides was controlled by the base selected, this protocol allowed facile access to unsymmetrical bis-thioethers. The recyclable CuO on alumina was found to be effective in the catalytic formation of aryl C-O bond.109
In 2012, Li et al.110 disclosed a newly developed heterogeneous catalytic system for the Ullmann O-arylation, using metal-organic framework (MOF) material-supported CuI as the catalyst. Very recently, the MOF-119111 was synthesized and used as a reusable catalyst in the Ullmann O-arylation.
Nanomaterials have been widely explored and used, as catalysts, for organic synthesis112–117 due to their high surface area. The use of copper nanoparticles, as catalysts for Ullmann reaction, were summarized in a recent review.118
Nano CuO particles48 demonstrated enhanced catalytic activity in the Ullmann coupling of aryl halides (X = I, Br, Cl) with phenols under ligand-free conditions than regular CuO powder.
Recently, a practical Ullmann C-O and C-S bond formation using CuO nanoparticles as catalysts, was described by Karvembu and Babu.119 (Scheme 17) The corresponding diaryl ethers and sulfides were easily obtained under mild conditions (3 mol% CuO nanoparticles/KOH/DMAc/27°C).
In 2009, the CuO nanoparticles were reported as an efficient catalyst for the formation of C-N, C-O, and C-S bonds.120 In this study, a broad range of amides, amines, imidazoles, phenols, alcohols, and thiols were used to react with aryl iodides under mild conditions; and to evaluate the scope and generality of this reaction system. Notably, the CuO nanoparticles retained high catalytic activity, even after 3 runs.
The CuFe2O4 nanoparticles were found to be an effective catalyst for the Ullmann reaction of aryl halides and N-heterocycles (Scheme 18).121 The catalyst could be easily removed from the reaction mixture by a magnetic separator due to its magnetic property. Similar catalytic behavior was observed, even after three consecutive cycles. This reusable catalyst was also found to be efficient in the catalysis of the Ullmann C-S bond formation.122
In 2012, the CuO nanoparticles-catalyzed ligand-free Ullmann reaction of indoline/indoline carboxylic acid with aryl/alkyl halides was disclosed by Nageswar and coworkers.123 The corresponding 1-substituted indole derivatives were easily achieved via aromatization under these catalytic conditions (Scheme 19).
With the catalysis of CuI nanoparticles, the Ullmann C-O and C-N bond formation of aryl chlorides with phenols, N-heterocycles, or alkylamines gave the desired products in good to excellent yields.124 The catalyst loading was reduced to 1.25 mol% and the catalyst could be reused for several runs without the loss of catalytic activity.
The Ullmann coupling reaction of phenols with aryl halides (X = I, Br, Cl) using Cu2O nanocubes as the catalyst was described by Park and coworkers.125 It is noteworthy that the catalyst loading was reduced to as low as 0.1 mol%.
In 2012, Obora et al. reported the preparation of single nano-sized Cu nanoparticles via the DMF reduction method.126 With the catalysis of these highly effective nanoparticles, the highest turnover number reached 2.2×104 when the catalyst loading was reduced to 1×10−3 mol% in the Ullmann O-arylation of aryl halides (X = I, Br) and phenols.
The nano-ferrite-dopamine-supported copper complex (nano-Fe3O4-DOPA-Cu) was reported as an efficient catalyst for the Ullmann S-arylation of aryl halides (X = I, Br) with thiolphenols (Scheme 20).127 The catalyst can be easily separated from the reaction mixture by a magnetic separator on the basis of its magnetic property.
c. Microwave/ultrasound-assisted Synthesis
The most notable advantages of microwave-assisted organic synthesis (MAOS)128–132 include faster and easier heating of the reaction, shorter reaction time, and high-throughput chemistry. In some cases, the reaction yields and selectivity can also be greatly improved under microwave irradiation.
Macrocyclic diaryl ether derivatives133 represent an important class of naturally occurring diarylheptanoids and show a wide range of biological activities. To improve the efficiency of macrocyclization, in 2012, Sun et al. developed an efficient and modular microwave-assisted macrocyclization of diaryl ethers via copper-catalyzed intra- and/or bimolecular Ullmann coupling; and investigated the scope and generality of a number of substrates with different linkers, ring sizes, and substitution patterns (Scheme 21).134 The structure of the intra- and bimolecular cyclic products was confirmed by X-ray crystallography.
In 2012, the intramolecular Ullmann macrocyclization was demonstrated by James and coworkers under high concentration conditions (up to 0.1 M).135 The highest macrocyclization efficiency (Emac) value136 for these reactions was 7.86, indicating that the macrocyclization process is highly efficient (Scheme 22).
In 2007, Müller and Baqi137 described the microwave-assisted Ullmann synthesis of anilinoanthraquinone derivatives. The reaction gave the corresponding products in moderate to good yields in 2–20 minutes (Scheme 23).
In 2011, Bolm et al.138 reported a solvent- and ligand-free Ullmann coupling of halopyridines with N-nucleophiles under microwave irradiation (Scheme 24). In this work, N-heterocycles such as pyrazole, imidazole, pyrrole, and indole reacted well with halopyridines to give the corresponding products in moderate to good yields; however, benzyl and arylamines were found to be poor substrates under the reported conditions.
In 2012, Su’s group139 described microwave-assisted Ullmann reaction of aryl halide (X = I, Br, Cl) with N-heterocycles by using calixarene [Emim][Pro] ionic liquid as both the ligand and surfactant (Scheme 25). A variety of N-heterocycle substrates were used in the reaction to give the corresponding products in good to excellent yields; among them, the π-electron-rich N-heterocycles showed lower reactivity in this catalytic system.
An efficient and ligand-free protocol for the Ullmann synthesis of N-aryl-1H-imidazoles was described by Zhang et al. (Scheme 26).140 The reaction of aryl bromides and imidazole or N,N′-carbonyldiimidazole gave the corresponding products in moderate to good yields, under microwave irradiation.
The PEG3400-Cu2O-Cs2CO3 was reported as a recyclable and ligand-free catalytic system for the Ullmann arylation of aryl halides with indole and benzimidazole under microwave irradiation.141
Microwave-assisted Ullmann C-S bond formation was reported by Bagley and coworkers (Scheme 27).142,143 The reaction of aryl-X (X = I, Br) and aryl/alkyl-SH gave the corresponding sulfide in moderate to good yields under the optimized conditions (CuI/L7/K2CO3/i-PrOH/microwave).
The base-free Ullmann O-arylation was reported by Schouten and coworkers.144 The combination of nano-Cu, -CuZn, and -CuSn as the catalysts and microwave heating led to improved turnovers and reaction yields. The additive 18-crown-6 ether also enhanced the reaction activity (Scheme 28). In 2012, the same group designed a continuous-flow milli-sized tubular reactor for the Ullmann O-arylation of phenol and 4-chloropyridine.145 Both low microwave power and Cu/ZnO-coated internal walls of the tubular milli-reactor were found to be beneficial to increase the yield.
Several additional examples62–64 related to microwave-assisted Ullmann C-N bond formation have been included in the section I.1.b (Table 3, Entry 1–3).
Ultrasonic irradiation was also found to be effective to improve the Ullmann reactions. For example, in 2012, Anandan et al.146 described the ultrasound-assisted Ullmann N-coupling of 2-halobenzoic acid with complex aryl- and alkylamines to give the corresponding products in good to excellent yields (Scheme 29).
3. Mechanistic Study
Although various efficient catalytic systems for Ullmann and Ullmann-type reactions have been developed over the last decade, the exact mechanism for these processes still remains elusive. In general, two potential routes have been proposed in the literature. One involves the Cu(III) intermediate via an oxidative addition and reductive elimination mechanism,147–151 while the other proceeds through the single-electron transfer (SET) mechanism.152–155 Overall, it appears that the reaction mechanism may depend mainly on the specific reaction conditions.
The copper(I) phenoxide complexes containing ancillary nitrogen-donor ligands were synthesized and structurally identified by Hartwig’s group151 in 2010 (Scheme 30). The crystal structure of the [(Me2phen)2Cu][Cu(OPh)2] complex revealed that this copper complex existed as an ionic form in the solid state. In this work, the status of the complexes in DMSO was also studied by the measurement of the molar conductivity of the solutions. The values of 1.0 mM solution containing complexes C2, C3, C4 were 37.1, 27.0, 31.9 Ω−1cm2mol−1, respectively. These data suggested the copper complexes exist mainly in an ionic form in a polar solvent.
The following study of the reactions using a stoichiometric amount of C2 (Figure 2) with o-(allyloxy)iodobenzene provided a supporting evidence for a redox route rather than a radical mechanism (Scheme 31). Typically, the corresponding aryl radical of o-(allyloxy)iodobenzene was recognized to undergo rapid cyclization to form a [3-(2,3-dihydrobenzofuran)]methyl radical, subsequently trapped by the aryloxide ion (ArO−) group. But none of the cyclized products was observed in this case.
Furthermore, several Cu(I)-amido complexes were synthesized and identified by Hartwig and Giri150 in the same year (Scheme 32). The reaction of C6 with o-(allyloxy)iodobenzene gave the N-arylated product in 60% yield, without the formation of the cyclization product. The subsequent DFT calculation also supported the mechanism proceeding through Cu(III) intermediates.
In contrast, Fu et al.156 recently presented evidence for the viability of a radical pathway (Scheme 33), which demonstrated the Ullmann C-N chemistry can proceed by the radical route following irradiation. In this report, reaction of the stoichiometric (t-Bu3P)2Cu(carbazolide) (C7) with iodobenzene gave the N-arylated product under the exposure to the 100-W mercury lamp at −40°C. Interestingly, the photoinduced coupling of C7 with o-(allyloxy)iodobenzene gave a cyclic product instead of the N-arylated product. The subsequent experimental data also indicated the formation of the aryl radical under this light-induced system.
The Ullmann reaction or Ullmann coupling is a coupling reaction between arylhalides and copper. The reaction is named after Fritz Ullmann.
A typical example is the coupling of 2 ortho-chloronitrobenzene reactants to form 2,2'-dinitrobiphenyl with a copper - bronze alloy.
The traditional version of the Ullmann reaction requires harsh reaction conditions, and the reaction has a reputation for erratic yields. Since its discovery some improvements and alternative procedures have been introduced.
The reaction mechanism of the Ullmann reaction is extensively studied. Electron spin resonance rules out a radical intermediate. The oxidative addition / reductive elimination sequence observed with palladium catalysts is unlikely for copper because copper(III) is rarely observed. The reaction probably involves the formation of an organocopper compound (RCuX) which reacts with the other aryl reactant in a nucleophilic aromatic substitution. Alternative mechanisms do exist such as σ-bondmetathesis.
The classical Ullmann reaction is limited to electron deficient aryl halides and requires harsh reaction conditions. Modern variants of the Ullman reaction employing palladium and nickel have widened the substrate scope of the reaction and rendered reaction conditions more mild. Yields are generally still moderate, however. In organic synthesis this reaction is often replaced by palladium coupling reactions such as the Heck reaction, the Hiyama coupling and the Sonogashira coupling.
In a variation of the Ullmann reaction, (2-bromovinyl)-benzene is reacted with imidazole in an ionic liquid, BMIMBF4*, to give N-(2-phenylvinyl)-imidazole. The reaction requires (L)-prolinecatalysis.
- * BMIMBF4 stands for the ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate
- ^P.E. Fanta (1974). "The Ullmann Synthesis of Biaryls". Synthesis. 1974: 9–21. doi:10.1055/s-1974-23219.
- ^F. Ullmann; Jean Bielecki (1901). "Ueber Synthesen in der Biphenylreihe". Chemische Berichte. 34 (2): 2174–2185. doi:10.1002/cber.190103402141.
- ^Reynold C. Fuson and E. A. Cleveland, "2,2'-dinitrobiphenyl", Organic Syntheses, Coll. Vol. 3, 339. Online article
- ^J. Hassan; M. Sevignon; C. Gozzi; E. Schulz; M. Lemaire (2002). "Aryl-Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction". Chemical Reviews. 102 (5): 1359–1470. doi:10.1021/cr000664r. PMID 11996540.
- ^Derek van Allen, PhD Thesis, University of Massachusetts Amherst2004. Electronic thesis
- ^Nelson, T. D.; Crouch, R. D. Org. React.2004, 63, 265. doi:10.1002/0471264180.or063.03
- ^Zhiming Wang, Weiliang Bao and Yong Jiang, "L-Proline promoted Ullmann-type reaction of vinyl bromides with imidazoles in ionic liquids", Chemical Communications, 2005, 2849-51 Abstract