Design and application of a novel and effective ligand for the Cu-catalyzed amination of aryl halides in water

ABSTRACT An effective ligand for the Ullmann-type C–N coupling reaction in water has been obtained using a novel tactic, namely, introducing a third group into the ligand to both improve the ligand’s water solubility and enhance the ligand’s coordinating ability. Applying this method, we have developed an effective ligand for the Cu-catalyzed amination of aryl halides, in particular, for aryl chlorides in water. The substrate diversity of the catalyst system, relatively less time required (6–12 h), and water as the reaction solvent make it attractive in both academia and industry. GRAPHICAL ABSTRACT


Introduction
The copper-catalyzed direct amination of aryl halides with amines is one of the most common methods to construct C(sp 2 )-N bond containing compounds (1-3), which often found in numerous bioactive natural products, active pharmaceutical agents, agricultural agents, and advanced materials (1,(3)(4)(5)(6).The Ullmann coupling reaction utilizing copper (Cu) as promoter, which is one of the foremost transition metal catalyzed coupling reactions, is a century-old reaction, but its brilliance has been overshadowed by the combination of the stoichiometric use of copper salts, utilization of polar solvents, and harsh reaction conditions.The combination of these reaction parameters often leads to poor functional group compatibility and poor reaction efficiency, which motivated the successful development of a Pd-catalyzed C-N coupling reaction as an alternative synthetic strategy (7).However, the intrinsic characteristics of copper, such as its higher abundance on Earth, lower cost and higher environmental friendliness than precious transition metals, together with its divergent chemical properties, destined the resurgence of Ullmann-type coupling reactions (7,8).Over the past three decades, many successful protocols for Cu-catalyzed Ullmann-type coupling reactions of amines and aryl halides have been established through ligand engineering after the landmark ligandaccelerating works by Buchwald (9), Ma (10,11) and Taillefer (12).In these protocols, the most common ligands are diamines, amino acids, pyridines, O,O-ligands and oxalic diamides.Oxalic diamides have been used for the amination of aryl chlorides with CuI as a catalyst in DMSO at 120 °C for 24 h (13,14).However, Ullmann type C-N coupling reactions are still much more challenging than Pd-based Buchwald-Hartwig amination in terms of reaction efficiency and the catalyst loading (13,15).Moreover, as environmental concerns about solvents have increased, chemists are now moving away from the use of toxic, volatile, environmentally harmful and biologically incompatible organic solvents to fulfill one or more criteria of sustainable chemistry (16).From this point of view, water is one of the most obvious replacements due to its low cost, ready availability, and low danger of exposure to researchers in the laboratory and operators in industry (17,18).Accordingly, several groups have successfully developed Ullmann-type C-N coupling protocols in pure water or aqueous media using following tactics: (1) enhancing the water solubility of hydrophobic counterparts (2,(19)(20)(21)(22)(23) to produce hydrophilic ligands.For example, pyridine N-oxides (21) and thiazolyl phosphines (19) were used as ligands to efficiently facilitate Cu-catalyzed amination of aryl bromides and iodides in aqueous media; (2) using newly developed water-soluble ligands, such as carbohydrates and their derivatives (24)(25)(26)(27)(28) and hydrazides and their derivatives (23,(29)(30)(31)(32) as ligands to carry out the Cu-catalyzed amination of aryl bromides and iodides in water or in aqueous media.Since aryl chlorides are less expensive, more abundant and more atom economy for industrial applications than their bromide and iodide counterparts, developing highly effective protocols for the Cu-catalyzed amination of aryl chlorides in water is highly desirable and attractive.However, the Cu-catalyzed amination of aryl chlorides in water is hitherto still rare (33) and challenging because of the less reactivity of chlorides (34).For example, the amination of aryl iodides in water was completed at 30 °C with oxalyldihydrazide/hexane-2,5-dione/CuO as a catalyst system (31).The Cu-catalyzed amination of aryl chlorides at 120 °C for 24 h also required high catalyst and additive loadings (31,33).Two problems remain unresolved in the ongoing development of effective ligands to promote Cu-catalyzed Ullmann-type C-N coupling reactions of aryl halides with amines in environmentally benign media.One is the necessity of using a relatively large quantity of ligands or additives in our previously reported Table 1.Effects of Cu-sources, ligands, bases, PTC and temperature on the coupling reaction of 4-chloroanisole with aniline.versatile method for the C-N coupling reaction in water (31)(32)(33)(35)(36)(37), and the other is the mechanism by which our ligands only work effectively in aqueous (31)(32)(33)(35)(36)(37) or alcoholic media (38)(39)(40) but do not work in normal organic solvents.Hence, we herein report the design and application of a novel and effective ligand to promote the Ullmann-type C-N coupling reaction of aryl halides with amines in water.(Figure 1).
Our previously reported catalytic system, namely CuI/ N',N'-diphenyl-1H-pyrrole-2-carbohydrazide (L), effectively performed the Ullmann-type C-N coupling reaction of aryl iodides and amines in diethylene glycol (DEG) at room-temperature (38) However, the above catalytic system did not work so effectively in water, and almost did not work at all in other common organic solvents, even aprotic solvents, such as DMSO and nitrile.We reasonably speculated that the differences in reactivity may have resulted from both the solubility and the coordination ability of protic solvents.Namely, the characteristics of tricoordinate copper(I) complexes (41) may be one of the mechanistic causes leading to protic solvent selectivity.

Result and discussion
Hence, we modified L by adding a hydroxymethyl group to the phenyl ring to introduce a third coordinating atom to produce the ortho-, meta-and para-substituted analogs (L1, L2 and L3, respectively), which showed improved solubility in water and/or coordination contributions (Figure 2).
Interesting, when 5 mol% of CuI and 5 mol% of L1 were applied, the model reaction of 4-chloroanisole with aniline yielded the desired product, 4-methoxy-Nphenylaniline, with a normalized GC yield of 24% (Table 1, Entry 2).In comparison, applying L2 only resulted in a 3% normalized GC yield of desired product (Table 1, Entry 3), while L3, like L, did not yield any the desired product (Table 1, Entry 1 and Entry 4).These results might be due to the differences in coordinating ability among the tested ligands.Actually, the theoretical modeling solubilities (42) of all three ligands were almost the same (log S: −3.911, Figure 3. Products and isolated yields for the amination of aryl chlorides with amines.Scheme 1.The plausible structure of the dinuclear cuprous complex of L1. −3.858, and −3.851 for L1, L2 and L3, respectively), although their solubilities obviously improved in comparison to that of L (log S: −4.515); the LC-MS (MeOH as a mobile phase, in ESI ionization mode) analysis (Figure S1) of the aqueous phase of the reaction mixture indicated that a novel dinuclear cuprous complex of L1 would be formed in the reaction process.As can be seen from the MS spectrum, an interesting copper isotope cluster of peaks (564 (97), 565 (32), 566 (100), 567 (34)) was observed (Figures S2 and S3), which could speculate the corresponding structure as Scheme 1.
Hence, this interesting result encouraged us to optimize the reaction conditions related to the copper sources, bases, solvents, and ratios of substrates, catalysts, and ligands (Table 1).As presented in Table 1, the best-performing ligand was L1, which performed the model reaction (Figure 3(a)) under the optimized conditions with 80% isolated yield.
To exclude the possibility that other transition metal contaminants (i.e.Ru, Rh, Pd and Pt) played a real catalytic role rather than copper.Two confirmative experiments have been carried out.Initially, the ICP-MS analysis (Table S1) of our reaction mixture showed that the amounts of the tested transition metals were all below 1 ppm molar ratio relative to 4 chloroanisole.In addition, the model reaction was run at almost the same condition except using 1 mol% Pd(OAc) 2 instead of 10 mol% CuO.As a result, no Buchwald-Hartwig type reaction being observed by GC-MS analysis (Table 1, Entry 37).
A wide range of aryl chlorides were aminated with amines under the optimized conditions to explore the scope of this catalyst system.As shown in Figure 3, both activated and unactivated aryl chlorides reacted with anilines to afford the desired products in good to excellent isolated yields (Figure 3(a-g)); the aryl chlorides reacted smoothly with the more nucleophilic  anilines with no surprises (Figure 3(h-i)).For aliphatic amines, the expected results were obtained (Figure 3 (j-q)) due to the stronger nucleophilicities of benzylamine and cyclohexanamine than those of the anilines.Pyrrolidine, which is a secondary cyclic amine, reacted well with aryl chlorides and produced fair to good yields, although higher amine hindrance decreased the rate of the conversion of the aryl chlorides (Figure 3(ru)).
Unfortunately, when applying our protocol to the arylation of heteroarylamines, such as imidazole and pyrazole, only a small quantity of 4-chloroanisole was converted into the desired products in trace and 10% isolated yields (Figure 3(w)), respectively.This intriguing phenomenon compelled us to investigate further, and we found that the decomposition of L1 into D1 with the promotion of azoles ceased the desired reaction.Notably, this side reaction would be an alternative way to produce N-substituted 1H-indazole (Figure 4).
It is well documented that aryl bromides and iodides have higher reactivity for Ullmann-type C-N coupling reactions than their chloride counterparts.The reaction conditions required to carry out the corresponding reactions were expected to be milder.All tested aryl bromides smoothly reacted with various amines at 60 °C within 6 h with good to excellent yields, as shown in Figure 5.In addition, the less reactive azoles, such as 1H-pyrazole and imidazole, also reacted well with 4-bromoanisole to afford the desired products within 6 h in 84% and 42% isolated yields, respectively (Figure 5, Figure 3(w-x)), at an elevated temperature (100 °C).Moreover, all tested aryl iodides reacted with all tested amines except the more hindered amine as well as expected at room-temperature within 12 h to provide the desired products except the more hindered amine (Figure 5, Figure 3(a-r)).

Conclusion
In conclusion, we have established a new method for designing effective ligands for Ullmann-type C-N reactions in water, namely, introducing a third group into the a previously identified ligand to both improve the ligand's water solubility and enhance the ligand's coordinating ability.Applying this method, we developed a general and effective approach for the Cu-catalyzed amination of aryl halides, in particular, for aryl chlorides in water.The advantages of this procedure are summarized as follows: (1) the general Ullmann type C-N coupling reaction is performed in water, especially for the amination of aryl chlorides, making it more economical, safer and more practical, especially for large-scale processes in industry; (2) the shorter time requirement makes it more effective and more controllable in the lab; (3) the lower loadings of the catalyst and the ligand makes it greener and more economical; and (4) room-temperature copper-catalyzed amination of aryl iodides makes it attractive in industry.These results will encourage us to discover and develop more effective ligands for Ullmann-type C-N coupling reactions in water by improving the solubility and coordinating capacity.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Figure 1 .
Figure 1.Cu-catalyzed amination of aryl chlorides in water by our group.

Figure 2 .
Figure 2. Ligands used in this work.

Figure 4 .
Figure 4.The decomposition of L1 into D1 with the promotion of imidazole under the optimized condition.

Figure 5 .
Figure 5. Products and isolated yields for the amination of aryl bromides or iodides with amines.
b Relative to 4-chloroanisole.c Normalized GC conversation and yield.d Without nitrogen.e 2 mmol of aniline was added.f 3 mmol of aniline was added.g Not detected.h Trimethylphenyl ammonium chloride.