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Research ArticleNovember 30, 2017

Mechanistic and Performance Studies on the Ligand-Promoted Ullmann Amination Reaction
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ACS Catalysis

Cite this: ACS Catal. 2018, 8, 1, 101–109

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https://doi.org/10.1021/acscatal.7b03664

Published November 30, 2017

Abstract

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Over the last two decades many different auxiliary ligand systems have been utilized in the copper-catalyzed Ullmann amination reaction. However, there has been little consensus on the relative merits of the varied ligands and the exact role they might play in the catalytic process. Accordingly, in this work some of the most commonly employed auxiliary ligands have been evaluated for C–N coupling using reaction progress kinetic analysis (RPKA) methodology. The results reveal not only the relative kinetic competencies of the different auxiliary ligands but also their markedly different influences on catalyst degradation rates. For the model Ullmann reaction between piperidine and iodobenzene using the soluble organic base bis(tetra-n-butylphosphonium) malonate (TBPM) at room temperature, N-methylglycine was shown to give the best performance in terms of high catalytic rate of reaction and comparatively low catalyst deactivation rates. Further experimental and rate data indicate a common catalytic cycle for all auxiliary ligands studied, although additional off-cycle processes are observed for some of the ligands (notably phenanthroline). The ability of the auxiliary ligand, base (malonate dianion), and substrate (amine) to all act competitively as ligands for the copper center is also demonstrated. On the basis of these results an improved protocol for room-temperature copper-catalyzed C–N couplings is presented with 27 different examples reported.

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1 Introduction

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The Ullmann C–N cross-coupling reaction dates back to the early 1900s, where the use of stoichiometric amounts of copper and high reaction temperatures allowed for the coupling of aryl halides and amines. (1) However, there were several drawbacks to this classical Ullmann reaction, where strong bases, long reaction times, and electron-deficient aryl substrates were required for the reaction to proceed. More recent developments include the use of bidentate ligands, such as 1,10-phenanthroline (phen), which allowed the cross-coupling reaction to be carried out catalytically under milder reaction conditions (Scheme 1). (2-12) Today, the modified Ullmann reaction is an important component in the toolbox of a synthetic organic chemist and has been employed in the synthesis of numerous bioactive compounds, natural products, and organic materials containing C–N bonds. (2-6, 13-17)

Scheme 1. Modified Ullmann Amination Reaction

The low cost and toxicity of copper coupled with the use of cheap and readily available auxiliary ligands based on N and O atoms makes it an attractive alternative to the otherwise successful palladium-catalyzed Buchwald–Hartwig reaction. (18-21) Historically, the mechanism of the Ullmann reaction has been the subject of much debate, with often contradictory interpretations of experimental and computational data in the literature. (22-25) This lack of understanding has hindered the development of more robust catalytic systems and the improvement of existing systems.

However, recent studies have all pointed toward the copper catalyst playing an important role in the activation of the aryl halide substrate, (22, 23) with spectroscopic evidence for an oxidative addition/reductive elimination pathway via a copper(III) intermediate. (26-28) Despite these advances the role of the auxiliary ligand in the catalytic cycle remains relatively unexplored, with ligand optimization studies predominately based solely upon empirical final-yield figures, rather than any deeper kinetic or mechanistic insights.

Reaction progress kinetic analysis (RPKA) is a powerful methodology which can allow a simplified mechanism to be developed, taking into account catalyst inhibition/deactivation pathways and other reaction steps. (29, 30) However, commonly used inorganic bases in the Ullmann reaction such as K₂CO₃, K₃PO₄, and Cs₂CO₃ can obfuscate RPKA measurements due to their poor solubility in the polar aprotic solvents commonly used in this reaction. (13, 25) This prevents the collection of accurate kinetic data due to mass transfer effects of the base. Therefore, kinetic studies on copper-mediated coupling reactions have been limited in the past to reactions involving low-pK_a substrates such as the Goldberg reaction. (31, 32) However, we have recently shown that using soluble organic bases, such as bis(tetra-n-butylphosphonium) malonate (TBPM), can mitigate any base mass-transfer effects and thus enable the collection of much more accurate kinetic data in these systems. (9, 33) In addition, using TBPM gave excellent yields of cross-coupled products at temperatures as low as 0 °C with aryl iodides. (9, 33) Studies on the TBPM-promoted ligand-free Ullmann reaction using the RPKA methodology carried out previously in our group have allowed us to recently propose a modified catalytic cycle (Scheme 2) and simplified steady-state rate law (eq 1 in Scheme 2) for this reaction and to explore in more depth possible catalyst deactivation pathways. First-order kinetics were observed with respect to [1], [2], and [Cu]_total, coupled with negative dependence on [TBPM]. (33) This negative dependence on base was attributed to the formation of off-cycle copper(I) species. The key role of the base in Ullmann and Goldberg reactions and its ability to competitively bind to the copper(I/III) metal center, has also been highlighted in recent studies by Sharma (27) and Nguyen. (34)

Scheme 2. Proposed Reaction Mechanism for the Cu-Catalyzed Cross Coupling Reaction between 1 and 2 under Ligand-Free Conditions (33)

In this work, we extend our studies on the mechanism of the catalytic Ullmann reaction by kinetically profiling a wide range of commonly used auxiliary ligands in the cross-coupling of piperidine and iodobenzene using TBPM as the base. These results allow us to move beyond just looking at product yields and compare for the first time the influence of the auxiliary ligand on the rate of reaction, rate dependence in substrates, and catalyst deactivation/inhibition pathways.

2 Results and Discussion

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2.1 Ligand Screening

In continuation of our earlier work, the reaction between piperidine (1) and iodobenzene (2) was chosen as the model system for kinetic study. Vigorous air- and moisture-free conditions were employed. Piperidine is of particular interest, as it has been cited as one of the most frequently used nitrogen heterocycles in U.S. FDA approved drugs. (35) Under auxiliary-ligand-free conditions, we observed TBPM to give good reactivity (98% yield) at room temperature relative to inorganic bases such as K₂CO₃, K₃PO₄, and Cs₂CO₃ (all <6% yield). This can be attributed to the solubility of and dissociation of TBPM in DMSO at room temperature (9) in comparison to inorganic bases and the ability of the malonate component of TBPM to serve as a ligand as well as a base. (33) Initial screenings were carried out using a diverse range of auxiliary ligands, many of which are taken from successful Ullmann coupling protocols in the literature (Scheme 3). Although Ma and co-workers have recently reported a series of oxalic diamide ligands that can activate aryl bromides and chloride substrates in the Ullmann reaction, (36-41) these had to be omitted from this study due to their very poor solubility in DMSO at room temperature.

Scheme 3. Kinetic Studies on the Ullmann Amination Reaction between 1 and 2 Using Various Auxiliary Ligands^a

The rate of reaction was monitored for each auxiliary ligand using reaction calorimetry. To verify that the calorimetric data do correctly correlate with the progress of the reaction, a sample reaction (using ethylene glycol, L14) was monitored using ¹H NMR spectroscopy and the product yield directly compared against that determined using heat flow experiments. Close agreement between heat flow and NMR conversions was observed (see Figure 1).

Figure 1. Comparison between heat flow and ¹H NMR conversions.

The determined enthalpy of reaction ΔH_rxn for all experiments in this study was consistent within ±5% (ΔH_rxn = 170.5 ± 8.5 kJ mol^–1). Varying the initial substrate concentrations did not influence the calculated enthalpy of reaction ΔH_rxn. These experiments therefore validate the use of reaction calorimetry as a tool to study the ligand-promoted Ullmann reaction.

Complete (100%) conversion of iodobenzene was obtained for all reactions. The yield of the desired cross-coupled product 3 in each case was in excess of 98% with approximately 2% yield of benzene side product also observed. In no cases were any aryl iodide to ligand couplings observed (even with ligands containing NH functionalities). The benzene is most likely formed from hydrodehalogenation of the iodobenzene, with similar hydrodehalogenation side products already reported in the literature for other copper(I)-catalyzed protocols. (33, 42-44) Variation in the type of auxiliary ligand had no effect on the amount of benzene formed, and the auxiliary ligand can thus be ruled out as a source of the hydrogen atom, with the piperidine NH (33) or the mono- or diprotonated base byproduct (34) being a likely source. The consistent value of ΔH_rxn means that any heat flow from the hydrodehalogenation side reaction is negligible relative to the C–N cross-coupling reaction and can thus be ignored.

Heat flow vs time plots were collected using reaction calorimetry in the presence of each auxiliary ligand as well as under auxiliary-ligand-free conditions (Figure S2 in the Supporting Information). These highlight the difference in reactivity as seen by the variations in maximum heat flow. The heat flow plots were processed to give the initial rate of reaction for each studied auxiliary ligand (Scheme 3). Triphenylphosphine (L16) and the tetradentate Salen ligand (L17) were also studied but furnished product yields of only 13 and 48%, respectively; this led to large potential errors in their calorimetrically determined reaction rates, and hence they have not been included in Scheme 3.

Most of the auxiliary ligands studied gave a faster initial rate of reaction relative to the auxiliary-ligand-free reaction. However, L4 and L13 exhibited slower initial reaction rates and L3, L5, L12, and L15 had no observable effect on the reaction rate. Changing the ligand loadings of this latter set of ligands also had no effect on the initial reaction rates (Figure S3 in the Supporting Information). These results reflect the competitive nature of the binding of the auxiliary ligand and the malonate dianion for copper(I), with the equilibrium sitting far on the side of the malonate-coordinated species for L3, L5, L12, and L15.

Overall the ligand screening results show that auxiliary ligands containing secondary amine functionalities give the best reactivity. Tertiary amines are less active in promoting the reaction, as can be seen from the comparisons of L1 with L5 and of L6 with L7. A key factor in these observations is likely to be the steric bulk of the ligand. (23) In addition, auxiliary ligands with pyridine or alcohol/phenol functionalities display little or no ligand-based acceleration effect. While some similar patterns in ligand preferences have been reported in the literature, (8-10, 45-48) these have been based on final yield measurements and as far as we are aware have not incorporated any kinetic measurements.

2.2 Catalyst Deactivation

The collection of experimental rate data continuously over the course of a reaction combined with RPKA methods allows additional mechanistic insights over and above the initial rate calculations to be made. (29, 30) All reactions reported herein were monitored in situ using reaction calorimetry to produce “graphical rate equations”. (29, 30) Only data between 20 and 80% conversions are displayed to limit any inaccuracies as the limiting substrate (2) approaches zero and to eliminate any heat transfer effects. Representative examples of these plots are shown in Figure 2 (see the Supporting Information for all plots over all conversion values). It is immediately apparent that, in addition to differing initial rates, the curvature of these plots varies. Plots of auxiliary ligands with two NH groups (L1 and L2) have a higher curvature than the other plots. Thus, although L2 exhibits an initial rate identical with that of L6 (Scheme 3), this rate drops off far more quickly as the reaction progresses. This is indicative of differences in the mechanisms or the presence of alternative reaction pathways such as catalyst deactivation or inhibition. In order to probe these differences, information regarding catalyst deactivation and the rate dependence in substrates was sought through different and same excess experiments. For all experiments reported herein, 1 is in excess while 2 is the limiting substrate.

Figure 2. Graphical rate equations for experiments using L1, L2, L4, L6, and auxiliary-ligand-free reactions using the conditions shown in Scheme 3.

Same excess experiments were carried out in the presence of ligands L1, L4, and L6 to determine if catalyst deactivation occurs over the course of the reaction (Figure 3). These ligands were chosen as they differed the most from the auxiliary-ligand-free reaction, exhibiting either faster or slower reaction rates or, in the case of L1, a different reaction profile. The same excess experiment involved a reduction in [1]₀, [2]₀, and [TBPM]₀, while keeping their difference in concentration the same (i.e., [e] = 0.0500 M). This is equivalent to starting the same reaction but at different starting points. Therefore, the lack of overlap between the same excess experiment (orange, Figure 3) and the standard experiment (blue, Figure 3) confirms that catalyst deactivation or product inhibition does indeed occur. Product inhibition was ruled out by carrying out an extra same excess experiment involving the addition of product 3 and byproducts 4 and 5 into the reaction mixture (green, Figure 3). Overlap between the second (green) and first (blue) same excess experiment curves shows that any catalyst inhibition caused by product coordination, solution conductivity changes caused by the formation of tetra-n-butylphosphonium iodide, or protonation of piperidine by monoanionic malonic acid are all negligible in this reaction regardless of the ligand used. Thus, catalyst decomposition is the most likely deactivation process.

Figure 3. Graphical rate equations for experiments carried out using the same excess protocol with L1 (top), L4 (middle), and L6 (bottom). See the Supporting Information for full plots.

The gap between the same excess experiment and the standard experiment in Figure 3 is noticeably larger for L1 than for L4, L6, and auxiliary-ligand-free reactions. At the arbitrary value of [2] = 0.4 M, the reaction rate was 60% lower with L1 in comparison to 30% lower with L6 and 12% lower with L4. Significantly increased catalyst deactivation is therefore occurring in the presence of L1, while a reduction in catalyst deactivation occurs with L4. On the basis of these studies, L6 would seem to provide the best balance with high rate of reaction and comparatively low catalyst deactivation.

A multiple substrate addition protocol was carried out to further verify the presence of catalyst deactivation: 0.1000 M of [1]₀ and 0.0500 M of [2]₀ in the presence of 10 mol % of ligand (L1, L2, L4, or L6) was initiated with 5 mol % of CuI. Once this first reaction had reached completion (i.e., negligible heat flow was detected by the calorimeter), a further solution of 1 and 2 (0.500 mmol each in 200 μL of DMSO) was added to the reaction mixture to restart the reaction. A third reaction was subsequently started once the second reaction had ended. If no catalyst deactivation occurs, each subsequent reaction should be marginally faster than the previous one owing to lower [TBPM]. This is due to the negative dependence in [TBPM] caused by the formation of off-cycle copper(I) dimalonate species (Scheme 2) as determined previously. (33) However, this was not the case, as each subsequent reaction was significantly slower than the previous one. An example of this with L1 is shown in Figure 4 (for other ligands see Figure S5 in the Supporting Information). Therefore, catalyst deactivation is indeed occurring. The change in catalyst concentration due to an increase in reaction volume is negligible, as it is much smaller than the change in rate of reaction. Due to catalyst deactivation, the third and final reaction gave only 75% yield of 3 for all four auxiliary ligands studied.

Figure 4. Graphical rate equations for each sequential reaction with L1.

The stability of the prospective copper(I) intermediates in the presence of these ligands was also investigated by addition of the respective ligand to freshly prepared copper(I) piperidide (49) in [D₆]DMSO at room temperature under an inert atmosphere. Thus, addition of L1 to copper(I) piperidide resulted in total decomposition of the copper piperidide complex within 2 h (determined using ¹H NMR with mesitylene as an internal standard). However, when L4 was added (or under auxiliary-ligand-free conditions), less than 1% complex decomposition was observed over a similar time period. Finally, addition of L6 gave approximately 60% copper(I) piperidide decomposition after 2 h. For each of these above reactions, an equivalence of iodobenzene was subsequently added to the resultant solution, and the mixture was stirred for 24 h at 80 °C. Conversion to the C–N coupled product 3 was determined using ¹H NMR and found to be 0% for L1 and L2, 15% for L4, and 43% for L6. These results are consistent with the calorimetric data, showing L6 to confer the best balance between high rate of reaction and low rate of catalyst deactivation. The lack of any conversion at all for the L1- and L2-treated samples suggests that catalyst deactivation under these conditions is irreversible. However, a reversible catalyst deactivation process cannot be ruled out under the catalytic conditions and further studies are still required to clarify the exact mechanism of catalyst deactivation.

2.3 Rate Dependence in Substrates

Rate dependence in substrates was determined using RPKA methods for both L4 and L6. Reactions with these two auxiliary ligands both showed reasonable catalyst stability (vide supra) and allowed comparison between a ligand that gives a faster (L6) and slower (L4) rate of reaction relative to that of the auxiliary-ligand-free reaction. A series of different excess experiments were carried out to determine the rate dependence of [1]₀, [2]₀, [TBPM]₀, and [Cu]_total.

Decreasing [2]₀ from 0.1000 to 0.0500 M while keeping the concentrations of other substrates and catalyst the same led to a corresponding decrease in the reaction rate (Figure 5; for full plots refer to Figure S6 in the Supporting Information) in the presence of either L4 and L6. Moderately good overlap between the normalized rate equations when the reaction rate was normalized by [2] is indicative of first-order dependence with respect to [2] (Figure 5). This is consistent with what was observed with the auxiliary-ligand-free reaction. (33)

Figure 5. Normalized graphical rate equations indicating first order in [2] for L4 (top) and L6 (bottom). [e] = “excess” = [1]₀ – [2]_0. See the Supporting Information for full graphical rate plots.

The rate dependence in [Cu]_total was probed next. Lowering [Cu]_total from 10 to 5 mol % gave a corresponding decrease in the reaction rate regardless of the auxiliary ligand used (Figure 6; for full plots refer to Figure S7 in the Supporting Information). Normalized rate equations revealed a first-order dependence in [Cu]_total with either L4 or L6 (Figure 6).

Figure 6. Normalized graphical rate equations indicating first order in [Cu]_total for L4 (top) and L6 (bottom). Full graphical rate plots are available in the Supporting Information.

Negative dependence in [TBPM] was observed in the presence of both L4 and L6, with increasing [TBPM]₀ leading to slower reaction rates (Figure S8 in the Supporting Information). Negative dependence in [TBPM] can be attributed to the formation of off-cycle copper(I) dimalonate species which in turn can undergo disproportionation to copper(0) and copper(II) at room temperature even under inert atmospheres (see Scheme 2). (33, 50, 51)

Positive noninteger dependence on [1] was observed using the difference excess protocol with L4 or L6 (Figure S11 in the Supporting Information). In comparison, a first-order dependence on [1] was observed under ligand-free conditions. (33) This can be rationalized by the presence of off-cycle equilibria involving the auxiliary ligand (vide infra). However, reactions involving a large excess of [1]₀ move toward first order in [1] with observed rate values that are independent of the auxiliary ligand employed (see Figures S12 and S13 in the Supporting Information). We believe this is due to displacement of the auxiliary ligand at very high [1] to give an on-cycle [Cu(C₅H₁₀N)(C₅H₁₀NH)] species. This behavior is indicative of competitive ligand binding at the copper center.

Taken together, these different excess experiments with L4 or L6 showed that, at ≤0.3 M of [1]₀, [2]₀, [TBPM]₀, and [Cu]_total, all reaction components influence the reaction rate. First-order dependence on [2] and [Cu]_total, a positive dependence on [1], and a negative dependence on [TBPM] were observed.

2.4 Rate Dependence in Ligand

The effect of auxiliary ligand loading on the initial rate of reaction for several of the ligands is illustrated in Figure 7. The bar chart illustrates how positive dependence on L1, L2, and L6 was observed in the range of 5–20 mol %. (52)

Figure 7. Bar chart illustrating the reaction rate at different auxiliary ligand loadings.

Variation in L3 loadings did not influence the reaction rate, which remained essentially identical with that of the auxiliary-ligand-free reaction (Figure 7). This can be explained by the presence of an excess of malonate dianion from the base which acts competitively as a ligand for the copper center with L3, with the equilibrium siting predominately on the side of the malonate coordinated species.

Increasing L4 loadings led to a slower rate of reaction, which can be attributed to its higher binding affinity toward copper(I) (in comparison to L3), (53) combined with a tendency to form the unreactive separated ion-pair complexes [Cu(L4)₂]⁺[Cu(piperidide)₂]⁻ as shown in section 2.5. The formation of such an off-cycle species is already well-known for similar L4-ligated Cu(I) species (2, 32, 34, 43, 49, 54) and explains the observed negative dependence on L4 and slower rate of reaction in comparison to the auxiliary-ligand-free system.

2.5 Catalyst Speciation with Auxiliary Ligand

Attempts were made to study the catalyst speciation in the presence of auxiliary ligands L1, L2, L4, and L6. However, on addition of L1, L2, or L6 to copper(I) complexes (piperidide, iodide, or tert-butoxide) in [D₆]DMSO, in all cases decomposition of the resultant species was observed (to copper(0) and copper(II) salts) even under vigorous air- and moisture-free conditions. However, similar studies with L4 proved more successful, giving stable complexes amenable to characterization by ¹H NMR spectroscopy.

Thus, a series of NMR experiments were carried out with L4 to probe the formation and stability of the potential ion-separated species [Cu(L4)₂]⁺[Cu(piperidide)₂]⁻. Lithium bis(piperidido)cuprate(I) was prepared from copper(I) iodide and lithium piperidide, (49) and its ¹H NMR spectrum directly compared to that of a mixture of copper(I) piperidide and L4 (1:1 ratio). In both cases, identical shifts were observed for the piperidide resonances (Figure S16 in the Supporting Information). Moreover, addition of L4 and piperidine to [CuO^tBu]₄ in THF gave a waxy red solid (see the Supporting Information), which was analyzed by ¹H NMR spectroscopy in [D₆]DMSO (Figure S16) to give once more an identical spectrum, again supporting the formation of [Cu(L4)₂]⁺[Cu(piperidide)₂]⁻ during the cross-coupling reaction. These findings are consistent with previous literature reports for this ligand. (31, 32, 43, 54)

Addition of iodobenzene (2) to either lithium bis(piperidido)cuprate(I) or [Cu(L4)₂]⁺[Cu(piperidide)₂]⁻ gave no further reaction, and no N-phenylpiperidine (3) was observed. This supports the notion that these ion-pair species are unreactive in the Ullmann coupling reaction. In addition, all these cuprate species were observed to be stable at room temperature under inert atmospheres for approximately 2 days.

2.6 Aryl Halide Activation

The aryl halide activation step was investigated using 2-(allyloxy)iodobenzene as a radical probe to determine if radical intermediates are present under the reaction conditions used in this study. The presence of radical intermediates will cause the radical probe to undergo rapid ring closure via a 5-exo-trig process (k = 9.6 × 10⁹ s^–1 in DMSO), and the resulting methyl radical generated will subsequently react with the nucleophile. (55) However, in the absence of such radical intermediates C–N bond formation would be observed. The reaction between piperidine and the radical probe with L1, L2, L4, or L6 gave only the C–N coupled product (Scheme 4), suggesting that aryl halide activation proceeds via oxidative addition/reductive elimination through a copper(I)/copper(III) mechanism. This is consistent with previous work carried out by Hartwig et al. (54)

Scheme 4. Reaction between 2-(Allyloxy)iodobenzene and Piperidine in the Presence of L1, L2, L4, or L6 To Determine if the Aryl Halide Activation Step Proceeds via Radical Intermediates

2.7 Reaction Design toward Improved Performance

One of the aims of this work is to allow a more systematic and informed quality-by-design approach to catalyst and auxiliary ligand selection in copper-catalyzed protocols. Hence, we sought to apply our findings to room-temperature C–N couplings using common inorganic bases which are currently very challenging with existing systems.

Initially several inorganic bases were tested for the cross-coupling of a model system (benzylamine and iodobenzene), and K₃PO₄ was shown to give excellent yields using a higher catalyst loading of 10% (Table S1 in the Supporting Information). Although TBPM is a significantly superior base under these conditions, it was thought that its lack of commercial availability would make it less attractive to the academic and industrial communities at present. Unfortunately, we have been unable to carry out a full kinetic evaluation of the reaction using K₃PO₄ due to mass transfer effects of the base. However, auxiliary ligand screening showed a good correlation between the achieved product yield with K₃PO₄ (Table S2 in the Supporting Information) and the observed reaction rates with TBPM (section 2.1). In addition, mechanisms equivalent to Scheme 2 have been proposed for Ullmann couplings employing K₃PO₄, and recent studies have shown that phosphonate ions can act as both a ligand and a base in the catalytic cycle (thus being analogous to the observed behavior of the malonate anion in TBPM). (26, 27)

On the basis of the RPKA results N-methylglycine (L6) was chosen as the auxiliary ligand, showing the best balance between fast initial rate of reaction and low levels of catalyst deactivation. A slight excess of amine (1.5 equiv) was employed to drive the reaction forward to the catalyst resting state (LCuNR₂) and prevent catalyst deactivation (Scheme 2). (33)

The reaction scope was extended to a variety of amines and aryl iodides: 27 examples in total (Table 1). The product yields obtained all compare favorably with those of room-temperature copper(I) protocols (where known (11, 56)). Most substrate combinations gave high yields (75%+), although electron-deficient (11g–i) and sterically bulky (11j,k) amines gave poorer conversions. In addition, ortho-substituted aryl iodides (11u–x) gave no or little conversion, showing that the system is highly sensitive to steric bulk at this position. In no case was any coupling of the N-methylglycine with the aryl iodide observed.

Table 1. Coupling Reaction between Amines and Aryl Iodides with K₃PO₄ and L6^a

^{Table a}

Reaction conditions: HNRR′ (1.5 mmol), ArI (1 mmol), CuI (0.1 mmol), N-methylglycine (0.2 mmol), K₃PO₄ (2 mmol), DMSO (1 mL). Isolated yields are reported.

Given the mildness of the reaction conditions and its efficiency, the reaction was also carried out on a larger scale to test its scalability. No significant effects on the product yields were observed on scale-up (10 mmol scale): 85% yield for 11a and 70% for 11b.

3 Conclusions

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An evaluation of some of the most commonly employed auxiliary ligands for application in the copper(I)-catalyzed Ullmann amination reaction has been undertaken. The model reaction between piperidine and iodobenzene in the presence of the soluble organic base bis(tetra-n-butylphosphonium) malonate (TBPM) has been adopted due to its high performance at room temperature and the absence of any mass transfer effects of the base. Kinetic studies using reaction calorimetry and RPKA methodology have revealed the relative catalytic reaction rates for each of these ligand systems as well as their different influences on catalyst deactivation. The rates of catalyst deactivation in particular are reported to vary considerably among the different auxiliary ligands. Together these data provide a much better insight into the relative merits of the different ligands in comparison to the final yield measurements which are usually cited.

Further kinetic, spectroscopic, and experimental studies strongly suggest that the on-cycle mechanism of C–N bond formation (namely, coordination of the amine to the copper(I), deprotonation of the amine, oxidative addition of the aryl iodide, and finally reductive elimination) is consistent across all auxiliary ligand systems. However, additional off-cycle processes have been observed for some auxiliary ligands, most notably phenanthroline (L4), which readily forms a very stable but dormant diionic species. In addition, kinetic rate experiments reveal the ability of the auxiliary ligand, base (malonate dianion), and substrate (amine) to all act competitively as ligands for the copper center. This adds significantly to the complexity of these systems, making optimization and modeling all the more challenging.

Nevertheless, on the basis of our studies N-methylglycine (L6) was identified to possess the best balance of high catalytic reaction rates and low catalyst deactivation for room-temperature C–N couplings. Hence, a new and efficient room-temperature Ullmann amination reaction system was designed where the combination of K₃PO₄ and N-methylglycine (L6) gave excellent reactivity with high room-temperature yields reported for a variety of amines and aryl iodides (27 examples in total). We are currently using a similar methodology to explore other copper-catalyzed aminations involving more challenging substrates with lower catalyst and auxiliary ligand loadings.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b03664.

Experimental procedures, experimental and spectroscopic data, full graphs related to the kinetic studies, and details of the kinetic modeling using COPASI (PDF)

cs7b03664_si_001.pdf (10.84 MB)

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Author Information

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Corresponding Author
- Robert P. Davies - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom; http://orcid.org/0000-0003-1503-0969; Email: [email protected]
Authors
- Quintin A. Lo - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
- David Sale - Process Studies Group, Jealott’s Hill Research Centre, Syngenta, Bracknell, Berkshire RG42 6EY, United Kingdom
- D. Christopher Braddock - Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom; http://orcid.org/0000-0002-4161-7256
Notes
The authors declare no competing financial interest.

Acknowledgment

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This work was supported by Syngenta and the UK EPSRC (Grant EP/M507878/1).

References

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This article references 56 other publications.

1
Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382– 2384 DOI: 10.1002/cber.190303602174
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On a new formation of diphenylamine derivatives. [machine translation]
Ullmann, F.
Berichte der Deutschen Chemischen Gesellschaft (1903), 36 (), 2382-84CODEN: BDCGAS ISSN:.
[Machine Translation of Descriptors]. Provisional Report. Author tried with the help of the indicated reaction, (Ber. Dtsch. Chem. Ges. vo. 34, pg. 2174; C. vo. 1901, II. pg. 478) to transform o-chlorobenzoic acid into diphenic acid. There with merging at the first with copper no favorable result was obtained, the conversion to aniline solution to implement was tried. When a boiling solution was shifted of o-chlorobenzoic acid in aniline gradually with cu powder, then dissolved; after short boiling up the aniline with diluted HCl, whereby a dark-colored, crystalline mass stayed, those into diluted NH3 mostly soluble was away-dissolved and from the solution after acidifying in weakly yellow crystals of the melting point 181° again-received. They proved in all characteristics identically to of GRAEBE and LAGODZINSKI, (LIEBIG's Ann. vo. 276, pg. 45), represented Phenylanthranilic acid. Those surprisingly easy formation of these acid takes place only at presence of copper; all other condensation means examined up to now did not cause the formation. The reaction is applicable also to other aromatic amines; o-toluidine supplied in an yield of 90% o-tolylanthranilic acid, m-nitraniline, best to o-Nitrobenzene solution, m-Nitrodiphenylamin-o-carbonic acid, C13H10O4N2; yellow needles of the melting point 215°; easily soluble in alcohol, insoluble in water; a yellow forms at 340° when short warming up with concentrated H2SO4; melting at nitroacridone.
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Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670– 674 DOI: 10.1021/jo981804o
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Ligand-Accelerated Catalysis of the Ullmann Condensation: Application to Hole Conducting Triarylamines
Goodbrand, H. Bruce; Hu, Nan-Xing
Journal of Organic Chemistry (1999), 64 (2), 670-674CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
High-purity triarylamines, useful in xerog. photoreceptors as concd. solid solns. in polymeric transport layers functioning as efficient hole conductors, were prepd. via Ullmann condensations of aryl amines and aryl iodides modified by the addn. of copper-binding ligand 1,10-phenanthroline. The new procedure moderates the severity of the conditions required to effect these reactions, and produces rapid and clean reactions at temps. 50-100° lower than previously required. The new catalyst system is applicable to bis(arylation) reactions and to large scale work. Thus, reaction of PhNH2 with 4-IC6H4Me in refluxing toluene contg. CuCl, KOH flakes, and 1,10-phenanthroline for 5 h gave 73% PhN(C6H4Me-4)2.
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Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164– 5173 DOI: 10.1021/jo0504464
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Amino Acid Promoted CuI-Catalyzed C-N Bond Formation between Aryl Halides and Amines or N-Containing Heterocycles
Zhang, Hui; Cai, Qian; Ma, Dawei
Journal of Organic Chemistry (2005), 70 (13), 5164-5173CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
CuI-catalyzed coupling reaction of electron-deficient aryl iodides with aliph. primary amines occurred under the promotion of N-methylglycine. Using L-proline as the promoter, coupling reaction of aryl iodides or aryl bromides with aliph. primary amines, aliph. cyclic secondary amines, or electron-rich primary arylamines proceeded. Also, an intramol. coupling reaction between aryl chloride and primary amine moieties gave indoline. Coupling reaction of aryl iodides with indole, pyrrole, carbazole, imidazole, or pyrazole was also carried out. And, finally, coupling of electron-deficient aryl bromides with imidazole or pyrazole occurred. The corresponding N-aryl products were obtained in good to excellent yields. N,N-dimethylglycine promoted the coupling reaction of electron-rich aryl bromides with imidazole or pyrazole to afford the corresponding N-aryl imidazoles. The possible action of amino acids in these coupling reactions is discussed.
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Lin, H.; Sun, D. Org. Prep. Proced. Int. 2013, 45, 341– 394 DOI: 10.1080/00304948.2013.816208
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Recent Synthetic Developments and Applications of the Ullmann Reaction. A Review
Lin, Hao; Sun, Dianqing
Organic Preparations and Procedures International (2013), 45 (5), 341-394CODEN: OPPIAK; ISSN:0030-4948. (Taylor & Francis Ltd.)
There is no expanded citation for this reference.
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Fischer, C.; Koenig, B. Beilstein J. Org. Chem. 2011, 7, 59– 74 DOI: 10.3762/bjoc.7.10
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Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds
Fischer, Carolin; Koenig, Burkhard
Beilstein Journal of Organic Chemistry (2011), 7 (), 59-74, No. 10CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
A review. The authors discussed and compare in this review the three main N-arylation methods in their application to the synthesis of biol. active compds.: Palladium-catalyzed Buchwald-Hartwig-type reactions, copper-mediated Ullmann-type and Chan-Lam-type N-arylation reactions. The discussed examples show that palladium-catalyzed reactions are favored for large-scale applications and tolerate sterically demanding substituents on the coupling partners better than Chan-Lam reactions. Chan-Lam N-arylations are particularly mild and do not require addnl. ligands, which facilitates the work-up. However, reaction times can be very long. Ullmann- and Buchwald-Hartwig-type methods were used in intramol. reactions, giving access to complex ring structures. All three N-arylation methods have specific advantages and disadvantages that should be considered when selecting the reaction conditions for a desired C-N bond formation in the course of a total synthesis or drug synthesis.
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Bedos-Belval, F.; Rouch, A.; Vanucci-Bacqué, C.; Baltas, M. MedChemComm 2012, 3, 1356– 1372 DOI: 10.1039/c2md20199b
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7
Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190– 6199 DOI: 10.1021/jo070807a
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Copper-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
Altman, Ryan A.; Koval, Erica D.; Buchwald, Stephen L.
Journal of Organic Chemistry (2007), 72 (16), 6190-6199CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
4,7-Dimethoxy-1,10-phenanthroline (L1c) was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazoles and benzimidazoles with both aryl iodides and bromides under mild conditions. Further optimization of the system has revealed that the addn. of poly(ethylene glycol) accelerates this reaction. A variety of hindered and functionalized imidazoles, benzimidazoles, and aryl halides were transformed in good to excellent yields. Heteroaryl halides were also coupled in moderate to good yields. We also present the results obtained from a series of coupling reactions, which directly compare the use of L1c with other recently reported ligands.
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Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453– 2455 DOI: 10.1021/ol0346584
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Mild Method for Ullmann Coupling Reaction of Amines and Aryl Halides
Ma, Dawei; Cai, Qian; Zhang, Hui
Organic Letters (2003), 5 (14), 2453-2455CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
Copper(I)-catalyzed Ullmann-type arom. amination of aryl iodides and aryl bromides in DMSO at 40-90° gave the corresponding N-aryl or N,N-diaryl amines in good to excellent yields by using either N-methylglycine or L-proline as a ligand.
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Yang, C.-T.; Fu, Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L. Angew. Chem., Int. Ed. 2009, 48, 7398– 7401 DOI: 10.1002/anie.200903158
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Ma, D.; Liu, F. Chem. Commun. 2004, 3, 1934– 1935 DOI: 10.1039/b407090a
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Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742– 8743 DOI: 10.1021/ja063063b
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Highly Selective Room-Temperature Copper-Catalyzed C-N Coupling Reactions
Shafir, Alexandr; Buchwald, Stephen L.
Journal of the American Chemical Society (2006), 128 (27), 8742-8743CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Through the use of cyclic β-diketones as supporting ligands, the copper-catalyzed coupling of aryl iodides with aliph. amines occurs at room temp. in as little as 1 h. These high reaction rates allow for the coupling of a wide range of aryl and heteroaryl iodides at room temp. This method is highly tolerant of a no. of reactive functional groups, including -Br and arom. -NH2 as well as phenolic and aliph. -OH. The high selectivity of the CuI-β-diketone catalyst for aliph. amines represents a useful complement to the palladium-based methods.
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Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490– 3491 DOI: 10.1021/ja068926f
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N- versus O-Arylation of Aminoalcohols: Orthogonal Selectivity in Copper-Based Catalysts
Shafir, Alexandr; Lichtor, Phillip A.; Buchwald, Stephen L.
Journal of the American Chemical Society (2007), 129 (12), 3490-3491CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Two complementary protocols for copper-catalyzed arylation of amino alcs. were developed. Selective N-arylation was accomplished at room temp. using 2-isobutyrylcyclohexanone (a β-diketone) as supporting ligand, while selective O-arylation required the use of 3,4,7,8-tetramethylphenanthroline at 80-110 °C. Systematic examn. of the reaction scope revealed that high levels of selectivity are achieved for a variety of substrates, provided that nonchelating (or weakly chelating) amino alcs. are used. The generality of the method was highlighted by the synthesis, in a pairwise fashion, of a no. of functionalized N- and O-arylated amino alcs.
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Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054– 3131 DOI: 10.1021/cr8002505
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Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis
Evano, Gwilherm; Blanchard, Nicolas; Toumi, Mathieu
Chemical Reviews (Washington, DC, United States) (2008), 108 (8), 3054-3131CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. Copper-catalyzed coupling reactions and their applications in natural products and designed biomols. synthesis were reviewed.
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Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166– 4175 DOI: 10.1039/b905601g
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Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442– 451 DOI: 10.1021/jo026125z
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16
Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459– 12467 DOI: 10.1021/ja981662f
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Accelerating effect induced by the structure of α-amino acid in the copper-catalyzed coupling reaction of aryl halides with α-amino acids. Synthesis of benzolactam-V8
Ma, Dawei; Zhang, Yongda; Yao, Jiangchao; Wu, Shihui; Tao, Fenggang
Journal of the American Chemical Society (1998), 120 (48), 12459-12467CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The coupling of optically pure α-amino acids with aryl halides produces enantiopure N-aryl-α-amino acids with retention of configuration under the catalysis of CuI. This reaction can complete at much lower temp. than typical Ullmann condensation even for electron-rich aryl halides, which indicates that an accelerating effect induced by the structure of the α-amino acid exists in this reaction. α-Amino acids with larger hydrophobic groups give higher coupling yields, while those with smaller hydrophobic groups only deliver lower yields and no coupling products were detected for those with hydrophilic groups. No racemization was obsd. in most cases of this coupling reaction. After some controlled expts., a possible mechanism including the π-complex and the intramol. substitution reaction is proposed. Based on this catalyzed reaction, a facile and stereoselective synthesis of benzolactam-V8 (I), a new PKC activator, is achieved.
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Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189– 2191 DOI: 10.1021/ol016043h
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First Total Synthesis of Martinellic Acid, a Naturally Occurring Bradykinin Receptor Antagonist
Ma, Dawei; Xia, Chengfeng; Jiang, Jiqing; Zhang, Jianhua
Organic Letters (2001), 3 (14), 2189-2191CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The first total synthesis of martinellic acid (I), a naturally occurring bradykinin receptor antagonist, via a CuI-catalyzed coupling reaction of β-amino ester (S)-HO(CH2)3CH(NH2)CH2CO2Et with 1,4-diiodobenzene and a guanylation reaction of secondary amine (II) under mild conditions as key steps, is described.
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Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852– 860 DOI: 10.1021/ar970282g
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Carbon-Heteroatom Bond-Forming Reductive Eliminations of Amines, Ethers, and Sulfides
Hartwig, John F.
Accounts of Chemical Research (1998), 31 (12), 852-860CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review contg. 58 refs.
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Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805– 818 DOI: 10.1021/ar9600650
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Rational Development of Practical Catalysts for Aromatic Carbon-Nitrogen Bond Formation
Wolfe, John P.; Wagaw, Seble; Marcoux, Jean-Francois; Buchwald, Stephen L.
Accounts of Chemical Research (1998), 31 (12), 805-818CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review with 42 refs.
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Hartwig, J. F. Pure Appl. Chem. 1999, 71, 1417– 1423 DOI: 10.1351/pac199971081417
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21
Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125– 146 DOI: 10.1016/S0022-328X(98)01054-7
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Palladium-catalyzed amination of aryl halides and sulfonates
Yang, Bryant H.; Buchwald, Stephen L.
Journal of Organometallic Chemistry (1999), 576 (1-2), 125-146CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science S.A.)
In this review, with 96 refs., the progress made in the Pd-catalyzed amination of aryl halides and sulfonates is described with particular attention given to applications in synthetic org. chem.
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Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries, J. G. Dalt. Trans. 2010, 39, 10338– 10351 DOI: 10.1039/c0dt00674b
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The mechanism of the modified Ullmann reaction
Sperotto, Elena; van Klink, Gerard P. M.; van Koten, Gerard; de Vries, Johannes G.
Dalton Transactions (2010), 39 (43), 10338-10351CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
A review. The copper-mediated arom. nucleophilic substitution reactions developed by Fritz Ullmann and Irma Goldberg required stoichiometric amts. of copper and very high reaction temps. Recently, it was found that addn. of relatively cheap ligands (diamines, amino alcs., diketones, diols) made these reactions truly catalytic, with catalyst amts. as low as 1 mol% or even lower. Since these catalysts are homogeneous, it has opened up the possibility to investigate the mechanism of these modified Ullmann reactions. Most authors agree that Cu(I) is the true catalyst even though Cu(0) and Cu(II) catalysts have also shown to be active. It should be noted however that Cu(I) is capable of reversible disproportionation into Cu(0) and Cu(II). In the first step, the nucleophile displaces the halide in the LnCu(I)X complex forming LnCu(I)ZR (Z = O, NR', S). Quite a no. of mechanisms have been proposed for the actual reaction of this complex with the aryl halide: 1. Oxidative addn. of ArX forming a Cu(III) intermediate followed by reductive elimination; 2. Sigma bond metathesis; in this mechanism copper remains in the Cu(II) oxidn. state; 3. Single electron transfer (SET) in which a radical anion of the aryl halide is formed (Cu(I)/Cu(II)); 4. Iodine atom transfer (IAT) to give the aryl radical (Cu(I)/Cu(II)); 5. π-complexation of the aryl halide with the Cu(I) complex, which is thought to enable the nucleophilic substitution reaction. Initially, the radical type mechanisms 3 and 4 where discounted based on the fact that radical clock-type expts. with ortho-allyl aryl halides failed to give the cyclised products. However, a recent DFT study by Houk, Buchwald and co-workers shows that the modified Ullmann reaction between aryl iodide and amines or primary alcs. proceeds either via an SET or an IAT mechanism. Van Koten has shown that stalled aminations can be rejuvenated by the addn. of Cu(0), which serves to reduce the formed Cu(II) to Cu(I); this also corroborates a Cu(I)/Cu(II) mechanism. Thus the use of radical clock type expts. in these metal catalyzed reactions is not reliable. DFT calcns. from Hartwig seem to confirm a Cu(I)/Cu(III) type mechanism for the amidation (Goldberg) reaction, although not all possible mechanisms were calcd.
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Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Chem. Soc. Rev. 2014, 43, 3525– 3520 DOI: 10.1039/C3CS60289C
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Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development
Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C.
Chemical Society Reviews (2014), 43 (10), 3525-3550CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. The history and development of copper catalyzed Ullmann type coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years was covered. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalc. arylation were discussed. Recent developments in green chem. for these reactions, such as reactions in aq. media and heterogeneous catalysis were also covered.
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Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096– 3099 DOI: 10.1002/anie.200703209
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Catalytic C-C, C-N, and C-O Ullmann-type coupling reactions: copper makes a difference
Monnier, Florian; Taillefer, Marc
Angewandte Chemie, International Edition (2008), 47 (17), 3096-3099CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review on significant advances recently made in carrying out enantioselective and chemoselective arylation of nucleophiles (Nu) by using a copper catalyst.
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Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954– 6971 DOI: 10.1002/anie.200804497
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Catalytic C-C, C-N, and C-O Ullmann-Type Coupling Reactions
Monnier, Florian; Taillefer, Marc
Angewandte Chemie, International Edition (2009), 48 (38), 6954-6971CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The copper-catalyzed Ullmann condensations are the key reactions for the formation of carbon-heteroatom and carbon-carbon bonds in org. synthesis. These reactions can lead to structural moieties that are prevalent in building blocks of active mols. in the life sciences and in many material precursors. An increasing no. of publications have appeared concerning Ullmann-type intermol. reactions for the coupling of aryl and vinyl halides with N-, O-, and C-nucleophiles, and this Minireview highlights recent and major developments in this topic since 2004.
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Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301– 2318 DOI: 10.1039/c3sc21818j
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The role of organometallic copper(III) complexes in homogeneous catalysis
Casitas, Alicia; Ribas, Xavi
Chemical Science (2013), 4 (6), 2301-2318CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
A review; organometallic CuIII species have been invoked in many copper-catalyzed reactions, but until recently, exptl. evidences were lacking. The advent of new spectroscopic techniques and the characterization of simple and stable catalyst models have been key to gain clear mechanistic insights into these important reactions. In this perspective, we will discuss these discoveries and the corresponding mechanistic proposals that derive from important reactions such as nucleophilic organocuprate chem. for C-C bond formation, C-heteroatom cross-coupling reactions (Ullmann condensation reactions and halide-exchange processes) and direct C-H bond functionalizations catalyzed by copper.
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Gurjar, K. K.; Sharma, R. K. ChemCatChem 2017, 9, 862– 869 DOI: 10.1002/cctc.201601174
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Mechanistic Studies of Ullmann-Type C-N Coupling Reactions: Carbonate-Ligated Copper(III) Intermediates
Gurjar, Kamlesh K.; Sharma, Rajendra K.
ChemCatChem (2017), 9 (5), 862-869CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
In Ullmann-type C-N coupling reactions, the involvement of CuIII species has been proposed many times on the basis of the oxidative addn.-reductive elimination (OA-RE) path for these reactions, but actual species could not be traced in exptl. studies. In the C-N coupling reactions, carbonate and phosphate were considered widely as bases. In the present study, Cu-mediated C-N coupling reactions of aryl halides and NuNH (amide and imide) were investigated extensively, and we provide direct spectroscopic evidence of actual CuIII species. For the first time, we reveal that carbonate and phosphate ions act as bidentate ligands as well as a base in the catalytic cycle, and thus the actual intermediate species is a carbonate- or phosphate-ligated, distorted octahedral CuIII complex. Our exptl. and computational studies have strengthened the hypothesis that these reactions follow an OA-RE path.
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Exptl. studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the org. base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic anal. (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concn. range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, neg. first-order kinetics in [TBPM] was obsd. This neg. rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examn. of the aryl halide activation mechanism using radical probes was undertaken, which is consistent with an oxidative addn. pathway. On the basis of these findings, a more detailed mechanistic cycle for the C-N coupling is proposed, including catalyst deactivation pathways.
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ACS Catalysis

Cite this: ACS Catal. 2018, 8, 1, 101–109

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https://doi.org/10.1021/acscatal.7b03664

Published November 30, 2017

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Abstract
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Scheme 1
Scheme 1. Modified Ullmann Amination Reaction
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Scheme 2
Scheme 2. Proposed Reaction Mechanism for the Cu-Catalyzed Cross Coupling Reaction between 1 and 2 under Ligand-Free Conditions (33)
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Scheme 3
Scheme 3. Kinetic Studies on the Ullmann Amination Reaction between 1 and 2 Using Various Auxiliary Ligands^a
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Scheme aInitial reaction rates are shown in red. The initial rate of the auxiliary-ligand-free reaction was 5.2 × 10^–3 M min^–1.
Figure 1
Figure 1. Comparison between heat flow and ¹H NMR conversions.
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Figure 2
Figure 2. Graphical rate equations for experiments using L1, L2, L4, L6, and auxiliary-ligand-free reactions using the conditions shown in Scheme 3.
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Figure 3
Figure 3. Graphical rate equations for experiments carried out using the same excess protocol with L1 (top), L4 (middle), and L6 (bottom). See the Supporting Information for full plots.
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Figure 4
Figure 4. Graphical rate equations for each sequential reaction with L1.
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Figure 5
Figure 5. Normalized graphical rate equations indicating first order in [2] for L4 (top) and L6 (bottom). [e] = “excess” = [1]₀ – [2]_0. See the Supporting Information for full graphical rate plots.
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Figure 6
Figure 6. Normalized graphical rate equations indicating first order in [Cu]_total for L4 (top) and L6 (bottom). Full graphical rate plots are available in the Supporting Information.
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Figure 7
Figure 7. Bar chart illustrating the reaction rate at different auxiliary ligand loadings.
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Scheme 4
Scheme 4. Reaction between 2-(Allyloxy)iodobenzene and Piperidine in the Presence of L1, L2, L4, or L6 To Determine if the Aryl Halide Activation Step Proceeds via Radical Intermediates
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References
This article references 56 other publications.
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  In this review, with 96 refs., the progress made in the Pd-catalyzed amination of aryl halides and sulfonates is described with particular attention given to applications in synthetic org. chem.
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22. 22
  Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries, J. G. Dalt. Trans. 2010, 39, 10338– 10351 DOI: 10.1039/c0dt00674b
  22
  The mechanism of the modified Ullmann reaction
  Sperotto, Elena; van Klink, Gerard P. M.; van Koten, Gerard; de Vries, Johannes G.
  Dalton Transactions (2010), 39 (43), 10338-10351CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  A review. The copper-mediated arom. nucleophilic substitution reactions developed by Fritz Ullmann and Irma Goldberg required stoichiometric amts. of copper and very high reaction temps. Recently, it was found that addn. of relatively cheap ligands (diamines, amino alcs., diketones, diols) made these reactions truly catalytic, with catalyst amts. as low as 1 mol% or even lower. Since these catalysts are homogeneous, it has opened up the possibility to investigate the mechanism of these modified Ullmann reactions. Most authors agree that Cu(I) is the true catalyst even though Cu(0) and Cu(II) catalysts have also shown to be active. It should be noted however that Cu(I) is capable of reversible disproportionation into Cu(0) and Cu(II). In the first step, the nucleophile displaces the halide in the LnCu(I)X complex forming LnCu(I)ZR (Z = O, NR', S). Quite a no. of mechanisms have been proposed for the actual reaction of this complex with the aryl halide: 1. Oxidative addn. of ArX forming a Cu(III) intermediate followed by reductive elimination; 2. Sigma bond metathesis; in this mechanism copper remains in the Cu(II) oxidn. state; 3. Single electron transfer (SET) in which a radical anion of the aryl halide is formed (Cu(I)/Cu(II)); 4. Iodine atom transfer (IAT) to give the aryl radical (Cu(I)/Cu(II)); 5. π-complexation of the aryl halide with the Cu(I) complex, which is thought to enable the nucleophilic substitution reaction. Initially, the radical type mechanisms 3 and 4 where discounted based on the fact that radical clock-type expts. with ortho-allyl aryl halides failed to give the cyclised products. However, a recent DFT study by Houk, Buchwald and co-workers shows that the modified Ullmann reaction between aryl iodide and amines or primary alcs. proceeds either via an SET or an IAT mechanism. Van Koten has shown that stalled aminations can be rejuvenated by the addn. of Cu(0), which serves to reduce the formed Cu(II) to Cu(I); this also corroborates a Cu(I)/Cu(II) mechanism. Thus the use of radical clock type expts. in these metal catalyzed reactions is not reliable. DFT calcns. from Hartwig seem to confirm a Cu(I)/Cu(III) type mechanism for the amidation (Goldberg) reaction, although not all possible mechanisms were calcd.
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23. 23
  Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Chem. Soc. Rev. 2014, 43, 3525– 3520 DOI: 10.1039/C3CS60289C
  23
  Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development
  Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C.
  Chemical Society Reviews (2014), 43 (10), 3525-3550CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. The history and development of copper catalyzed Ullmann type coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years was covered. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalc. arylation were discussed. Recent developments in green chem. for these reactions, such as reactions in aq. media and heterogeneous catalysis were also covered.
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24. 24
  Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096– 3099 DOI: 10.1002/anie.200703209
  24
  Catalytic C-C, C-N, and C-O Ullmann-type coupling reactions: copper makes a difference
  Monnier, Florian; Taillefer, Marc
  Angewandte Chemie, International Edition (2008), 47 (17), 3096-3099CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review on significant advances recently made in carrying out enantioselective and chemoselective arylation of nucleophiles (Nu) by using a copper catalyst.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlvVWqt74%253D&md5=7f7371bb53d6611c04339db0f605b5dc
25. 25
  Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954– 6971 DOI: 10.1002/anie.200804497
  25
  Catalytic C-C, C-N, and C-O Ullmann-Type Coupling Reactions
  Monnier, Florian; Taillefer, Marc
  Angewandte Chemie, International Edition (2009), 48 (38), 6954-6971CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The copper-catalyzed Ullmann condensations are the key reactions for the formation of carbon-heteroatom and carbon-carbon bonds in org. synthesis. These reactions can lead to structural moieties that are prevalent in building blocks of active mols. in the life sciences and in many material precursors. An increasing no. of publications have appeared concerning Ullmann-type intermol. reactions for the coupling of aryl and vinyl halides with N-, O-, and C-nucleophiles, and this Minireview highlights recent and major developments in this topic since 2004.
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26. 26
  Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301– 2318 DOI: 10.1039/c3sc21818j
  26
  The role of organometallic copper(III) complexes in homogeneous catalysis
  Casitas, Alicia; Ribas, Xavi
  Chemical Science (2013), 4 (6), 2301-2318CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  A review; organometallic CuIII species have been invoked in many copper-catalyzed reactions, but until recently, exptl. evidences were lacking. The advent of new spectroscopic techniques and the characterization of simple and stable catalyst models have been key to gain clear mechanistic insights into these important reactions. In this perspective, we will discuss these discoveries and the corresponding mechanistic proposals that derive from important reactions such as nucleophilic organocuprate chem. for C-C bond formation, C-heteroatom cross-coupling reactions (Ullmann condensation reactions and halide-exchange processes) and direct C-H bond functionalizations catalyzed by copper.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntV2js70%253D&md5=ee0d13b3248520f1b075f3d72d0c1eba
27. 27
  Gurjar, K. K.; Sharma, R. K. ChemCatChem 2017, 9, 862– 869 DOI: 10.1002/cctc.201601174
  27
  Mechanistic Studies of Ullmann-Type C-N Coupling Reactions: Carbonate-Ligated Copper(III) Intermediates
  Gurjar, Kamlesh K.; Sharma, Rajendra K.
  ChemCatChem (2017), 9 (5), 862-869CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
  In Ullmann-type C-N coupling reactions, the involvement of CuIII species has been proposed many times on the basis of the oxidative addn.-reductive elimination (OA-RE) path for these reactions, but actual species could not be traced in exptl. studies. In the C-N coupling reactions, carbonate and phosphate were considered widely as bases. In the present study, Cu-mediated C-N coupling reactions of aryl halides and NuNH (amide and imide) were investigated extensively, and we provide direct spectroscopic evidence of actual CuIII species. For the first time, we reveal that carbonate and phosphate ions act as bidentate ligands as well as a base in the catalytic cycle, and thus the actual intermediate species is a carbonate- or phosphate-ligated, distorted octahedral CuIII complex. Our exptl. and computational studies have strengthened the hypothesis that these reactions follow an OA-RE path.
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28. 28
  Rovira, M.; Jašíková, L.; Andris, E.; Acuña-Parés, F.; Soler, M.; Güell, I.; Wang, M.-Z.; Gómez, L.; Luis, J. M.; Roithová, J.; Ribas, X. Chem. Commun. 2017, 53, 8786– 8789 DOI: 10.1039/C7CC04491G
  There is no corresponding record for this reference.
29. 29
  Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44, 4302– 4320 DOI: 10.1002/anie.200462544
  29
  Reaction progress kinetic analysis: A powerful methodology for mechanistic studies of complex catalytic reactions
  Blackmond, Donna G.
  Angewandte Chemie, International Edition (2005), 44 (28), 4302-4320CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Reaction progress kinetic anal. to obtain a comprehensive picture of complex catalytic reaction behavior is described. This methodol. employs in situ measurements and simple manipulations to construct a series of graphical rate equations that enable anal. of the reaction to be accomplished from a minimal no. of expts. Such an anal. helps to describe the driving forces of a reaction and may be used to help distinguish between different proposed mechanistic models. This Review describes the procedure for undertaking such anal. for any new reaction under study.
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30. 30
  Blackmond, D. G. J. Am. Chem. Soc. 2015, 137, 10852– 10866 DOI: 10.1021/jacs.5b05841
  There is no corresponding record for this reference.
31. 31
  Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120– 4121 DOI: 10.1021/ja050120c
  There is no corresponding record for this reference.
32. 32
  Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78– 88 DOI: 10.1021/ja0781893
  There is no corresponding record for this reference.
33. 33
  Sung, S.; Sale, D.; Braddock, D. C.; Armstrong, A.; Brennan, C.; Davies, R. P. ACS Catal. 2016, 6, 3965– 3974 DOI: 10.1021/acscatal.6b00504
  33
  Mechanistic studies on the copper-catalyzed N-arylation of alkylamines promoted by organic soluble ionic bases
  Sung, Simon; Sale, David; Braddock, D. Christopher; Armstrong, Alan; Brennan, Colin; Davies, Robert P.
  ACS Catalysis (2016), 6 (6), 3965-3974CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  Exptl. studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the org. base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic anal. (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concn. range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, neg. first-order kinetics in [TBPM] was obsd. This neg. rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examn. of the aryl halide activation mechanism using radical probes was undertaken, which is consistent with an oxidative addn. pathway. On the basis of these findings, a more detailed mechanistic cycle for the C-N coupling is proposed, including catalyst deactivation pathways.
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34. 34
  Sherborne, G. J.; Adomeit, S.; Menzel, R.; Rabeah, J.; Brückner, A.; Fielding, M. R.; Willans, C. E.; Nguyen, B. N. Chem. Sci. 2017, 8, 7203– 7210 DOI: 10.1039/C7SC02859H
  34
  Origins of high catalyst loading in copper(I)-catalyzed Ullmann-Goldberg C-N coupling reactions
  Sherborne, Grant J.; Adomeit, Sven; Menzel, Robert; Rabeah, Jabor; Bruckner, Angelika; Fielding, Mark R.; Willans, Charlotte E.; Nguyen, Bao N.
  Chemical Science (2017), 8 (10), 7203-7210CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  A mechanistic investigation of Ullmann-Goldberg reactions using sol. and partially sol. bases led to the identification of various pathways for catalyst deactivation through (i) product inhibition with amine products, (ii) byproduct inhibition with inorg. halide salts, and (iii) ligand exchange by sol. carboxylate bases. The reactions using partially sol. inorg. bases showed variable induction periods, which are responsible for the reproducibility issues in these reactions. Surprisingly, more finely milled Cs2CO3 resulted in a longer induction period due to the higher concn. of the deprotonated amine/amide, leading to suppressed catalytic activity. These results have significant implications on future ligand development for the Ullmann-Goldberg reaction and on the solid form of the inorg. base as an important variable with mechanistic ramifications in many catalytic reactions.
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35. 35
  Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564– 12649 DOI: 10.1021/acs.chemrev.6b00512
  35
  Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions
  Ruiz-Castillo, Paula; Buchwald, Stephen L.
  Chemical Reviews (Washington, DC, United States) (2016), 116 (19), 12564-12649CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. Pd-catalyzed cross-coupling reactions that form C-N bonds have become useful methods to synthesize anilines and aniline derivs., an important class of compds. throughout chem. research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chem. research from 2008 to the present. Selected examples of C-N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compds., natural products, org. materials, and catalysts.
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36. 36
  Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. J. Am. Chem. Soc. 2015, 137, 11942– 11945 DOI: 10.1021/jacs.5b08411
  36
  CuI/Oxalic Diamide Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amines
  Zhou, Wei; Fan, Mengyang; Yin, Junli; Jiang, Yongwen; Ma, Dawei
  Journal of the American Chemical Society (2015), 137 (37), 11942-11945CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A class of oxalic diamides are found to be effective ligands for promoting CuI-catalyzed aryl amination with less reactive (hetero)aryl chlorides. The reaction proceeds at 120 °C with K3PO4 as the base in DMSO to afford a wide range of (hetero)aryl amines in good to excellent yields. The bis(N-aryl) substituted oxalamides are superior ligands to N-aryl-N'-alkyl substituted or bis(N-alkyl) substituted oxalamides. Both the electronic nature and the steric property of the arom. rings in ligands are important for their efficiency.
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37. 37
  Fan, M.; Zhou, W.; Jiang, Y.; Ma, D. Org. Lett. 2015, 17, 5934– 5937 DOI: 10.1021/acs.orglett.5b03230
  37
  Assembly of Primary (Hetero)Arylamines via CuI/Oxalic Diamide-Catalyzed Coupling of Aryl Chlorides and Ammonia
  Fan, Mengyang; Zhou, Wei; Jiang, Yongwen; Ma, Dawei
  Organic Letters (2015), 17 (23), 5934-5937CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A general and practical catalytic system for aryl amination of aryl chlorides with aq. or gaseous ammonia has been developed, with CuI as the catalyst and bisaryl oxalic diamides as the ligands. The reaction proceeds at 105-120 °C to provide a diverse set of primary (hetero)aryl amines in high yields with various functional groups.
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38. 38
  Fan, M.; Zhou, W.; Jiang, Y.; Ma, D. Angew. Chem., Int. Ed. 2016, 55, 6211– 6215 DOI: 10.1002/anie.201601035
  There is no corresponding record for this reference.
39. 39
  Xia, S.; Gan, L.; Wang, K.; Li, Z.; Ma, D. J. Am. Chem. Soc. 2016, 138, 13493– 13496 DOI: 10.1021/jacs.6b08114
  There is no corresponding record for this reference.
40. 40
  Gao, J.; Bhunia, S.; Wang, K.; Gan, L.; Xia, S.; Ma, D. Org. Lett. 2017, 19, 2809– 2812 DOI: 10.1021/acs.orglett.7b00901
  40
  Discovery of N-(Naphthalen-1-yl)-N'-alkyl Oxalamide Ligands Enables Cu-Catalyzed Aryl Amination with High Turnovers
  Gao, Jie; Bhunia, Subhajit; Wang, Kailiang; Gan, Lu; Xia, Shanghua; Ma, Dawei
  Organic Letters (2017), 19 (11), 2809-2812CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  In the presence of Cu2O and the oxalamide I, aryl- and heteroaryl bromides and iodides were aminated chemoselectively with primary amines (alkyl favored over aryl), ammonium hydroxide, and secondary cyclic amines and N-methylbenzylamine using KOH in EtOH at 50-80° to yield aryl- and heteroarylamines such as N-benzyl-p-anisidine in 35-98% yields using 0.1-0.5 mol% of Cu2O.
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41. 41
  Pawar, G. G.; Wu, H.; De, S.; Ma, D. Adv. Synth. Catal. 2017, 359, 1631– 1636 DOI: 10.1002/adsc.201700026
  There is no corresponding record for this reference.
42. 42
  Rovira, M.; Soler, M.; Güell, I.; Wang, M.-Z.; Gomez, L.; Ribas, X. J. Org. Chem. 2016, 81, 7315– 7325 DOI: 10.1021/acs.joc.6b01035
  There is no corresponding record for this reference.
43. 43
  Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 9971– 9983 DOI: 10.1021/ja076668w
  There is no corresponding record for this reference.
44. 44
  Tye, J. W.; Weng, Z.; Giri, R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49, 2185– 2189 DOI: 10.1002/anie.200902245
  There is no corresponding record for this reference.
45. 45
  Cai, Q.; Zhang, H.; Zou, B.; Xie, X.; Zhu, W.; He, G.; Wang, J.; Pan, X.; Chen, Y.; Yuan, Q.; Liu, F.; Lu, B.; Ma, D. Pure Appl. Chem. 2009, 81, 227– 234 DOI: 10.1351/PAC-CON-08-08-19
  There is no corresponding record for this reference.
46. 46
  Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581– 584 DOI: 10.1021/ol0171867
  46
  Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides: An Efficient System Even in an Air Atmosphere
  Kwong, Fuk Yee; Klapars, Artis; Buchwald, Stephen L.
  Organic Letters (2002), 4 (4), 581-584CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  A mild method for the copper-catalyzed amination of aryl iodides is reported. This operationally simple C-N bond-forming protocol uses CuI as the catalyst and ethylene glycol as ligand in 2-propanol. A variety of functionalized aryl iodides as well as several amines were efficiently coupled using this method. This catalytic amination procedure is relatively insensitive to moisture and can be performed under an air atm. with comparable yield. Preliminary results on the amination of aryl bromides are also described.
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47. 47
  Otto, N.; Opatz, T. Beilstein J. Org. Chem. 2012, 8, 1105– 1111 DOI: 10.3762/bjoc.8.122
  47
  Screening of ligands for the Ullmann synthesis of electron-rich diaryl ethers
  Otto, Nicola; Opatz, Till
  Beilstein Journal of Organic Chemistry (2012), 8 (), 1105-1111, No. 122CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  In the search for ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at relatively low temps., 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural class could be identified.
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48. 48
  Uma Maheswar Reddy, K.; Santosh Kumar, K.; Panasa Reddy, A. Asian J. Chem. 2014, 26, 4747– 4751 DOI: 10.14233/ajchem.2014.16194
  There is no corresponding record for this reference.
49. 49
  Sung, S.; Braddock, D. C.; Armstrong, A.; Brennan, C.; Sale, D.; White, A. J. P.; Davies, R. P. Chem. - Eur. J. 2015, 21, 7179– 7192 DOI: 10.1002/chem.201405699
  49
  Synthesis, Characterisation and Reactivity of Copper(I) Amide Complexes and Studies on Their Role in the Modified Ullmann Amination Reaction
  Sung, Simon; Braddock, D. Christopher; Armstrong, Alan; Brennan, Colin; Sale, David; White, Andrew J. P.; Davies, Robert P.
  Chemistry - A European Journal (2015), 21 (19), 7179-7192CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Copper(I) alkylamide complexes were synthesized; copper(I) dicyclohexylamide (1), copper(I) 2,2,6,6-tetramethylpiperidide (2), copper(I) pyrrolidide (3), copper(I) piperidide (4), and copper(I) benzylamide (5). Their solid-state structures and structures in [D6]benzene soln. are characterized, with the aggregation state in soln. detd. by a combination of DOSY NMR spectroscopy and DFT calcns. Complexes 1, 2 and 4 exist as tetramers in the solid state by x-ray crystallog. In [D6]benzene soln., complexes 1, 2 and 5 were found by using 1H DOSY NMR to exist in rapid equil. between aggregates with av. aggregation nos. of 2.5, 2.4 and 3.3, resp., at 0.05M concn. Conversely, distinct trimeric, tetrameric and pentameric forms of 3 and 4 were distinguishable by one-dimensional 1H and 1H DOSY NMR spectroscopy. Complexes 3-5 react stoichiometrically with iodobenzene, in the presence or absence of 1,10-phenanthroline as an ancillary ligand, to give arylamine products indicative of their role as potential intermediates in the modified Ullmann reaction. The role of phenanthroline also was explored both in the stoichiometric reaction and in the catalytic Ullmann protocol.
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50. 50
  He, C.; Zhang, G.; Ke, J.; Zhang, H.; Miller, J. T.; Kropf, A. J.; Lei, A. J. Am. Chem. Soc. 2013, 135, 488– 493 DOI: 10.1021/ja310111p
  There is no corresponding record for this reference.
51. 51
  Cheng, B.; Yi, H.; He, C.; Liu, C.; Lei, A. Organometallics 2015, 34, 206– 211 DOI: 10.1021/om501053k
  There is no corresponding record for this reference.
52. 52
  Experiments involving higher ligand loadings could not be carried out owing to the poor solubility of amino acids in DMSO at concentrations above 20 mol % at room temperature.
  There is no corresponding record for this reference.
53. 53
  Rannulu, N. S.; Rodgers, M. T. J. Phys. Chem. A 2007, 111, 3465– 3479 DOI: 10.1021/jp066903h
  There is no corresponding record for this reference.
54. 54
  Giri, R.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 15860– 15863 DOI: 10.1021/ja105695s
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55. 55
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Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b03664.
- Experimental procedures, experimental and spectroscopic data, full graphs related to the kinetic studies, and details of the kinetic modeling using COPASI (PDF)
- cs7b03664_si_001.pdf (10.84 MB)
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Mechanistic and Performance Studies on the Ligand-Promoted Ullmann Amination ReactionClick to copy article linkArticle link copied!

ACS Catalysis

Abstract

1 Introduction

Scheme 1

Scheme 2

2 Results and Discussion

2.1 Ligand Screening

Scheme 3

Figure 1

2.2 Catalyst Deactivation

Figure 2

Figure 3

Figure 4

2.3 Rate Dependence in Substrates

Figure 5

Figure 6

2.4 Rate Dependence in Ligand

Figure 7

2.5 Catalyst Speciation with Auxiliary Ligand

2.6 Aryl Halide Activation

Scheme 4

2.7 Reaction Design toward Improved Performance

3 Conclusions

Supporting Information

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Acknowledgment

References

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ACS Catalysis

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Abstract

Scheme 1

Scheme 2

Scheme 3

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Scheme 4

References

Supporting Information

Supporting Information

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Mechanistic and Performance Studies on the Ligand-Promoted Ullmann Amination Reaction
Click to copy article linkArticle link copied!