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Copper-Mediated Amination of Aryl C–H Bonds with the Direct Use of Aqueous Ammonia via a Disproportionation Pathway Hyunwoo Kim, Joon Heo, Junho Kim, Mu-Hyun Baik, and Sukbok Chang J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Oct 2018 Downloaded from http://pubs.acs.org on October 12, 2018

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Journal of the American Chemical Society

Copper-Mediated Amination of Aryl C− −H Bonds with the Direct Use of Aqueous Ammonia via a Disproportionation Pathway Hyunwoo Kim,2,1 Joon Heo,1,2 Junho Kim,1 Mu-Hyun Baik2,1* and Sukbok Chang2,1* 1

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea 2

Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon 34141, South Korea

Supporting Information Placeholder ABSTRACT: The direct amination of C–H bonds with ammonia is a challenge in synthetic chemistry. Herein, we present a copper-mediated approach that enables a chelation-assisted aromatic C–H bond amination using aqueous ammonia. A key strategy was to use soft low-valent Cu(I) species to avoid the strong coordination of ammonia. Mechanistic investigations suggest that the catalysis is initiated by a facile deprotonation of bound ammonia and the C–N coupling is achieved by subsequent reductive elimination of the resultant copper-amido intermediate from a Cu(III)-intermediate that is readily generated by disproportionation of low-valent copper analogues. This mechanistic postulate was supported by a preliminary kinetic isotope effect (KIE) study and computations. This new chelation assisted, copper mediated C–H bond amination with aqueous ammonia was successfully applied to a broad range of substrates to deliver primary anilines. Moreover, the mild conditions required for this transformation allowed the reaction to operate even under substoichiometric conditions to enable a late-stage application for the preparation of pharmaceutical agents.

cules;2d and (ii) once a well-defined metal-ammine complexes is formed, the amido transfer to the arene substrate upon deprotonation is fundamentally difficult, because the M–NH2 bond is strong due to good σ- and πdonor abilities of the amido group.2e,6 In this context, the precedent routes to primary anilines often employ a detour via an array of ammonia surrogates (Scheme 1A).7 In particular, one recent advance showed a promising organophotocatalytic method,8 but there is room for improvement in the regioselectivty. Thus, a more conventional catalytic method for the direct and selective amination of C–H bonds using ammonia under mild conditions was an unmet challenge at large. Herein, we report a Cu-mediated procedure that enables a chelation assisted aromatic C−H amination directly using aqueous ammonia (Scheme 1B). Key to this new approach is that a low-valent copper precursor is employed, which we propose to be an ideal metal to suppress catalyst poisoning. We propose that a Cu(III) intermediate is involved, that is formed in situ by disproportionation of low-valent copper species. The newly developed amination method was successfully applied to a range of aromatic C–H bonds of benzamides to deliver primary anilines. With a compatible and mild oxidant system, the

Introduction The conversion of highly abundant feedstock chemicals to value-added products is a central theme in synthetic chemistry. For instance, procedures that utilize ammonia (NH3) as an amino source are attractive because nitrogencontaining molecules are crucial in pharmaceuticals and in material science.1 Although the intrinsic value of such transformation is widely recognized, there are only a handful methods that use ammonia directly in synthesis.2 While certain transition metal complexes and singlet carbene were shown to activate ammonia homolytically,2d,3 these promising studies did not yield a catalytic process, which ideally would install a primary amino (−NH2) group on a molecular target. Cross-coupling prefunctionalized substrates like aryl halides with heterolytically activated ammonia proved a much more efficient strategy and was recently demonstrated using transition metal catalysts.4 Despite these advances, C–H amination of arenes5 with ammonia remains underdeveloped and the challenges are mainly linked to the following difficulties: (i) ammonia is an excellent ligand for various metals and rapidly forms stable Werner-type complexes leading to inhibition of the prerequisite C−H bond activation of substrate mole-

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copper loading could be reduced to sub-stoichiometric amounts (down to 25 mol %). The synthetic utility of the developed procedure was illustrated by applying it to the direct amination of bio-relevant molecules such as Bexarotene and Probenecid.

inal study on Cu(III)-aryl species that can facilitate the reductive elimination to form C–N bonds with a variety of nitrogen-based nucleophiles with pKa values ranging from 13.4 to 23.5 in DMSO (Scheme 2A).11a Subsequently, Wang also revealed that the C−N bond formation was more plausible with Cu(III)-aryl complexes, while Cu(II)-aryl analogues were considered to be less feasible (Scheme 2B). In both cases, it was found that the disproportionation of copper produces a Cu(III)-aryl species after C–H bond activation from a Cu(II) precursor.11b,c,g

Scheme 1. C− −H Amination Approaches to Primary Anilines A ammonia (NH3) surrogates O

chelator R

R

O

NH2

BnO

O NH S

R'O

OAc

N

Chang

Wu & Tung

NH4CO2NH2

NH3

Scheme 2. Well-defined High-valent Cu-aryl Systems Mediating C− −H Amidation

Ph Yu

Bolm

H

Nicewicz

up to 36% yield

Ph

N3

or H

Glorius

O

(EDG)n

NH2

Hirano & Uchiyama

H

NH2

PC

R organophotocatalyst

via [Rh], [Ir] and [Cu] catalysis

H

Long-standing

R

Challenge LxM(NH3)

prohibitively slow C H activation R

M(NH3)xn+ + NH3 excess

transition-metal catalyst poisoning

B. This work Disproportionation chelator R

Cu OAc + NH3 (aq)

H

chelator

I

CuI/CuIII

R

DMSO

NH2

Chelation-assisted C H amination of arenes with aqueous NH3

Inspired by these studies, we initially sought to establish a copper-mediated system that is capable of both N−H bond cleavage and C−N reductive elimination with ammonia as a nucleophile. A variety of directing groups as supporting ligand was considered. We hypothesized that the coordination of the copper to the aromatic substrate carrying a bidentate chelating group should be helpful. Such process is entropically favored because two ammine ligands are replaced by a single bidentate chelate.12 To verify the hypothesis, our initial evaluation focused on the direct use of tetraammine complex Cu(NH3)4SO4 as a reaction mediator as well as an ammonia source. At the outset, substrate 1a derived from 2-(4,5dihydrooxazol-2-yl)aniline, which was initially explored by Yu,7a,10a,13 was selected to examine the desired reactivity (Table 1, Y1). When 1a was treated with stoichiometric amount of Cu(NH3)4SO4 and 2.0 equiv of t-BuOK, a promising result was observed in that 12% of the desired orthoaminated product 2a was obtained. Interestingly, a regioisomeric product 2a’ was not observed, presenting a highly regioselective reactivity toward the sterically less demanding C–H bond. Chelating groups other than Y1 failed to deliver C–H amination products (Y2–6, and also see the Supporting Information (SI) for full data).14 The use of Cu(OAc)2 (1.0 equiv) with an aqueous ammonia solution instead of Cu(NH3)4SO4 gave a comparable level of reaction efficiency (entry 2). We postulated that the low reactivity with a Cu(II) precursor is mainly

Intermediacy of Cu(III) that enables facile deprotonation & reductive elimination A key disproportionation of copper precursor accelerates the reaction Copper loading can be lowered down sub-stoichiometric amounts

Result and Discussion Because of their versatility in mediating C–N bond forming reactions, palladium and copper species were first envisaged to be plausible choices for developing an ammonia-based amination reaction.9 In particular, a copper-based system has been shown to be promising toward C–H amination and, interestingly, under some conditions it was capable of maintaining activity even when anilines or alkylamines were added.10 This finding was remarkable as these substrates are known to often cause catalyst poisoning in other catalytic procedures. Although the details about how copper outperforms other metals were unclear initially, we hypothesized that understanding the general mechanistic trends for copper-mediated C–H amination reactions will be helpful for exploring a catalyst system that can use ammonia as the nitrogen source. Although isolable copper-aryl species where the oxidation state of copper is higher than +1 are largely unexplored owing to their intrinsic instability, recent model studies on the high-valent derivatives provided a central tool for understanding Cu-mediated C–H functionalization reactions (Scheme 2).11 In 2008, Stahl reported a sem-

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Journal of the American Chemical Society CuOAc (0.25) NH3·H2O 90 71 + AgOAc (2.0) (13.5) CuOAc (0.25) NH3·H2O 16 + TEMPO (2.0) (13.5) 90 32 + O2 (1.0 atm) CuOAc (0.25) NH3·H2O 17 90 63 + NMO (3.0) (13.5) CuOAc (0.25) NH3·H2O 18 100 73 (70) + NMO (3.0) (13.5) a 1a (0.10 mmol), NH3 source (1.35 mmol), catalyst system and base additive in DMSO (0.0125 M) for 12 h. bYield based on 1H NMR analysis of the crude reaction mixture using CH2Br2 as the internal standard (isolated yield in parentheses). cReaction conducted in a 100 mL Parr reactor.; TEMPO, 2,2,6,6-Tetramethylpiperidine 1-oxyl.

due to the strong dative bonds with excessive amounts of hard Lewis basic ammonia, which retards the interaction between metal and substrate. Seeking to improve on this result, we hypothesized that the low-valent Cu(I) would offer a practical solution to the aforementioned problem, since it is a soft and low-coordinating metal with d10configuration.15,16 Indeed, it was found that the calculated binding energy of Cu(I)−NH3 is smaller than that of Cu(II)−NH3 in general, highlighted by an energy decomposition analysis (EDA) shown in the Supporting Information.17 Accordingly, we ventured to employ Cu(I) precursors (2.0 equiv) to ultimately deliver an equimolar amount of Cu(II) by disproportionation after engaging with the bidentate directing group. In accordance with our hypothesis, the use of Cu(I)OAc increased the reaction efficiency notably (entries 2 and 3).

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Investigating the effect of base additives, which we initially deemed important for the deprotonation of the ammonia bound to copper, we were surprised to find that the amination was most efficient when CuOAc was solely employed as a reaction mediator without any auxiliary base (entries 4–7, see SI for full data). We found that excellent efficiency can be achieved to deliver 2a in 89% isolated yield even when the reaction temperature was lowered to 60 oC (entry 8). Consistent to our initial hypothesis on the disproportionation of Cu(I) precursor, the reaction efficiency was dropped to 43% when 1.0 equiv of CuOAc was employed (entry 9). This result suggests that 2.0 equiv of Cu(I) is requisite amount in mediating the desired reaction via a disproportionation pathway. A significant decrease in yield was observed when Cu(I) precursors with less-basic counteranions such as halides or triflate were employed instead of CuOAc, validating that an acetate ion plays a role as a base additive (entry 10, see also SI). To verify our hypothesis on catalyst poisoning, an equimolar or even an excess amount of Cu(OAc)2 was evaluated again as a precursor under identical conditions, the reaction efficiency was significantly reduced as anticipated (entry 11, see also SI). Notably, the reaction was observed to be sluggish when gaseous ammonia was offered under high-pressure or ammonium salts were employed as surrogates of the ammonia solution (entries 12–13). Finally, it was found that the model reaction was compatible with a variety of external oxidants under reduced copper loading (25 mol %) to turn the initially optimized reaction catalytic (entries 14–17, see SI for full data). Among them, a mild catalytic system that utilizes N-methyl morpholine N-oxide (NMO)10b,18 as a single organic oxidant under slightly elevated temperature gave the most promising result (entry 18). It was noteworthy that other transition metal-based systems such as Pd, Pt, Co, Rh and Ir, were totally ineffective for mediating C–H amination with ammonia (see SI for full data). To better understand the mechanism of the present amination reaction, we carried out density functional theory (DFT) calculations and Figure 1 shows the reaction energy profile of the proposed mechanism (see SI for details).11b Two mechanistic possibilities were considered denoted as Path A and B. We assumed that after initial coordination of the Cu(I) ion to the bidentate ligand, the

Table 1. Optimization of Aromatic C− −H Amination Using a Ammonia

Entry 1 2

Catalyst Base additive (equiv) system (equiv)

Cu(NH3)4SO4 ·H2O (1.0)

KOt-Bu (2.0)

Cu(OAc)2 (1.0) KOt-Bu (2.0)

NH3 source (equiv)

Temp Yield (%)b (oC)

-

90

12

NH3·H2O (13.5)

90

8

3

CuOAc (2.0)

KOt-Bu (2.0)

NH3·H2O (13.5)

90

25

4

CuOAc (2.0)

Na2CO3 (2.0)

NH3·H2O (13.5)

90

55

5

CuOAc (2.0)

K2CO3 (2.0)

NH3·H2O (13.5)

90

45

6

CuOAc (2.0)

SrCO3 (2.0)

90

70

7

CuOAc (2.0)

-

90

90

8

CuOAc (2.0)

-

60

92 (89)

9

CuOAc (1.0)

-

60

43

10

CuI (2.0)

-

60

15

11

Cu(OAc)2 (1.0)

-

90

35

12

CuOAc (2.0)

-

60

34

13

CuOAc (2.0)

-

60

16

14

CuOAc (0.25) + AgOAc (2.0)

-

60

40

NH3·H2O (13.5) NH3·H2O (13.5) NH3·H2O (13.5) NH3·H2O (13.5) NH3·H2O (13.5) NH3·H2O (13.5) NH3 (5.0 bar)c NH4OAc (13.5) NH3·H2O (13.5)

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copper center must be oxidized to give a Cu(II)intermediate I, which can be furnished by a disproportionation reaction.11h Once intermediate I is formed, it was calculated to be more energetically stable than any other Cu(II) species that are formed by ligand exchange of acetate with one or more ammonia molecules (see Table S4 in Supporting Information for computational details). As anticipated, the reaction proceeds via a concerted metalation deprotonation (CMD)19 assisted by an acetate ion to afford the cyclometalated intermediate II. The calculations suggest a CMD barrier of 25.4 kcal/mol, which is the highest barrier computed for the reaction, in good

agreement with the experimentally measured primary KIE (kH/kD = 5.62, see SI page S16) indicating that the C–H bond cleavage step is rate-determining. This slow C−H activation step would compete with the formation of copper-ammine species under the employed reaction conditions with exceedingly high molar concentration of ammonia, eventually decreasing the reaction efficiency. Indeed, a significant decrease in reaction efficiency was observed when high atmospheric pressure of gaseous ammonia was employed as shown above in Table 1.

Figure 1. Calculated free energy profiles for the Cu-mediated aromatic C−H bond amination using ammonia.

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Journal of the American Chemical Society Next, the transient intermediate II binds an equivalent of ammonia via ligand exchange to give intermediate III at 8.3 kcal/mol. Interestingly, our calculations indicate that the deprotonation of ammonia from intermediate III is thermodynamically not feasible with complex IVa being 22.8 kcal/mol higher in energy. And even if the deprotonation could be achieved, the following reductive elimination was calculated to traverse transition state IVa-TS associated with an unrealistic barrier of 62.1 kcal/mol. Therefore, Path A is unlikely to be operative. Path B is much more reasonable energetically. Instead of undergoing deprotonation, the Cu(II)-center in intermediate III consumes an equivalent of [Cu(II)OAc]+ to disproportionate and produce intermediate IVb, which consists of a Cu(III)-center and was found at –13.5 kcal/mol (see SI page S24). The deprotonation of ammonia bound to the Cu(III)-center is much easier and our calculations estimated the deprotonation product Vb to be only 2.3 kcal/mol higher in energy. Although the possibility of a concerted proton-coupled electron-transfer cannot be ruled out, the proposed stepwise oxidation and deprotonation mechanism is consistent to our current calculation results. Finally, the reductive elimination via Vb-TS to give the product complex VIb was computed to be fast with a barrier of only 12.9 kcal/mol and highly exergonic. Interestingly, a significant increase in this barrier was observed when substrates with other directing groups were employed to a computation model.20 This result implies that the poor reactivity of other bidentate chelators are mainly attributed to the slowed reductive elimination step.

trolling the oxidation states of the copper center. The hardness of the Lewis acidic Cu(III) is a critical feature, because it strengthens the metal-ligand interactions and lowers the energy of intermediate IVb compared to III, while at the same time lowering the pKa of the metalbound ammine by 13.4 pKa units (Figure 2, see also SI page S27). But the Cu(III)-center must be formed at the right time during the reaction to avoid catalyst poisoning, as explained above. Since the present C–H amination was found to be operative under both Cu-mediated and Cucatalyzed conditions, the external oxidant employed in the catalytic reaction is not responsible for the oxidation of Cu(II)-intermediate to Cu(III). Instead, the role of NMO oxidant is likely involved in the reoxidation of inactive copper(0), which is produced by disproportionation in the early stage of the reaction. As summarized in Table 2, this newly developed method is capable of aminating C–H bonds in a wide range of benzamide substrates. Two sets of reaction conditions shown as stoichiometric and sub-stoichiometric (25 mol % of Cu) were examined to establish general synthetic options upon choosing a substrate. Substrates bearing electron-withdrawing substituents at the meta-position smoothly participated in the amination under both conditions, exclusively on sterically less demanding C–H bonds (2a–d). The scalability of this process was also successfully evaluated delivering 1.08g (62%) of 2a by conducting a 5.0 mmol scale reaction under sub-stoichiometric conditions. Benzamides with para-substituents including halogens could also be aminated without difficulty (2e–h), while ortho-substituted substrate showed somewhat diminished yield (2i). Notably, the reactivity of particular substrates which contains labile functional groups was also tested to give rise to satisfactory results (2d, 2f–j). It was also found that a highly functionalized primary aniline could be accessed by the present method (2j). The reaction efficiency was slightly diminished with benzamides that possess electronically rich substituents (2k– o). Interestingly, the current amination protocol was found to be compatible with heteroaromatic substrate as well, in which a quinolyl (1p) or a pyridyl (1q) C–H bonds could smoothly be engaged furnishing heteroaromatic primary amine products (2p–q). For such challenging substrates (1k, 1o–q), slightly revised reaction conditions were employed utilizing two equivalents of Na2CO3 or SrCO3 as base additives at increased temperature. Finally, the reactivity toward C–H bonds of bio-relevant structures was examined (1r–s). Using the newly developed C– H amination reaction, we were able to illustrate the installation of an amino group (–NH2) as a late-stage of synthesis directly from aqueous ammonia followed by simple transformation of the chelating group, furnishing amino (–NH2) derivatives of Bexarotene (6) and Probenecid (7). Conclusion In conclusion, we have developed a copper-mediated, chelation assisted arene C–H amination using aqueous ammonia as the nitrogen source. The use of soft, low-

Figure 2. ∆pKa calculation between aryl-Cu(II)-ammine and aryl-Cu(III)-ammine complexes.

The single-electron transfer (SET) mechanism where the oxidation of arene occurs prior to the nucleophilic attack of ammonia can also be envisioned as an alternative reaction pathway.11b However, considering the fact that the well-known radical scavenger TEMPO did not deteriorate the present amination and the significant primary kinetic isotope effect was observed (vide supra), the SET mechanism was considered to be less likely at the present stage. The dramatically different energy demands highlighted in Figure 1 emphasize the importance of con-

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valent copper(I) species to avoid the strong coordination of ammonia was critical for rendering the active species immune to poisoning. Based on precedent literature that the high-valent Cu(III)-aryl species could mediate C–N bond formation with various nitrogen nucleophiles, the challenging deprotonation and reductive elimination step with ammonia was conceivable with Cu(III) intermediate that is formed in situ. Indeed, our DFT calculations suggested that barriers of deprotonation of the ammine substrate can be lowered by ~13 pKa units when the Cu(II) center is oxidized to Cu(III). The developed C–H bond amination was successfully applied to a broad range of

aromatic substrates equipped with a properly optimized chelation group to directly deliver primary aniline products. As an additional benefit, a mild oxidant system was able to render the present Cu-mediated C–H amination into sub-stoichiometric conditions (25 mol % Cu loading), allowing a late-stage modification of pharmaceutical agents. We anticipate that the principles of facilitating disproportionation of copper to accelerate the deprotonation and reductive elimination of ammonia is generally valid and can be widely applied to develop various synthetic methods.

Table 2. Scope of the Direct (hetero)Aromatic C− −H Amination Using Ammonia

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Journal of the American Chemical Society Substrate (1, 0.1 mmol), aqueous ammonia solution (28 wt % in H2O, 1.35 mmol) and CuOAc (0.2 mmol) in DMSO (8.0 mL) at 60 oC for 12 h. Substrate (1, 0.1 mmol), aqueous ammonia solution (28 wt % in H2O, 1.35 mmol), CuOAc (0.025 mmol), NaOAc (0.2 mmol) and NMO (0.3 mmol) in DMSO (8.0 mL) at 100 oC for 12 h. cThe reaction was conducted on a 5.0 mmol scale. dSubstrate (1, 0.1 mmol), aqueous ammonia solution (28 wt % in H2O, 1.35 mmol) and CuOAc (0.2 mmol) in DMSO (8.0 mL) at 30 oC for 24 h. eSubstrate (1, 0.1 mmol), aqueous ammonia solution (28 wt % in H2O, 1.35 mmol), CuOAc (0.025 mmol), NaOAc (0.2 mmol) and NMO (0.3 mmol) in DMSO (8.0 mL) at 70 oC for 24 h. fSubstrate (1, 0.1 mmol), aqueous ammonia solution (28 wt % in H2O, 1.35 mmol), CuOAc (0.2 mmol) and SrCO3 (0.2 mmol) in DMSO (8.0 mL) at 110 oC for 2 h. gSubstrate (1, 0.1 mmol), aqueous ammonia solution (28 wt % in H2O, 1.35 mmol), CuOAc (0.2 mmol) and Na2CO3 (0.2 mmol) in DMSO (8.0 mL) at 130 oC for 2 h. hAminated products (2r or 2s, 0.03 mmol) and KOH (1.2 mmol) in EtOH (0.5 mL) at 80 oC for 18 h. Yields shown are isolated yields. The structure of the 2d was confirmed by X-ray diffraction of a single crystal. a

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ASSOCIATED CONTENT Supporting Information The following file is available free of charge on the ACS Publications website at http://pubs.acs.org. Experimental procedures, characterization data, spectroscopic data, crystallographic data, Cartesian coordinates of all computed structures and energy components (PDF). Crystal data (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank the Institute for Basic Science in Korea for financial support (IBS-R010-D1) and Mr. Jinwoo Kim for his help with the computational modeling studies. Single crystal Xray diffraction experiments with synchrotron radiation were performed at the BL2D-SMC in Pohang Accelerator Laboratory.

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(12) Tang, H.; Huang, X.-R.; Yao, J.; Chen, H. J. Org. Chem. 2015, 80, 4672. (13) Shang, M.; Wang, M.-M.; Saint-Denis, T. G.; Li, M.-H.; Dai, H.-X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 5317. (14) When an arene substrate without bearing a bidentate directing group such as N,N-dimethylbenzamide was employed as a substrate, neither an ortho- nor meta-aminated product was observed even after prolonged reaction time, recovering 98% of starting material. (15) Mukherjee, R. Comprehensive Coordination Chemistry: Vol. 6; Elsevier, 2003, 747.

(16) Pavelka, M.; Burda, J. V. Chem. Phys. 2005, 312, 193. (17) See Table S3 and Figure S2 in Supporting Information for details. (18) Roane, J.; Daugulis, O. J. Am. Chem. Soc. 2016, 138, 4601. (19) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848. (b) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. (20) See Figure S5 in Supporting Information for the calculations on reductive elimination step with other bidentate directing groups (Y2 and Y5).

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Copper-Mediated Amination of Aryl CH Bonds with the Di - American

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