Acceleration of Pd-Catalyzed Amide N-Arylations Using Cocatalytic

Aug 8, 2017 - Department of Chemistry, Temple University, Philadelphia, Pennsylvania ... Derek I. WozniakWilliam A. SabbersKushan C. WeerasiriLuckym V...
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Research Article pubs.acs.org/acscatalysis

Acceleration of Pd-Catalyzed Amide N‑Arylations Using Cocatalytic Metal Triflates: Substrate Scope and Mechanistic Study Joseph Becica and Graham E. Dobereiner* Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States S Supporting Information *

ABSTRACT: The Pd/xantphos-catalyzed cross-coupling of amides and aryl halides is accelerated by cocatalytic metal triflate additives. A survey of nitrogen nucleophiles reveals improved yields for a variety of N-aryl amide products when Al(OTf)3 is employed as a catalytic additive, with some exceptions. Initial rates of catalysis indicate that the Lewis acid acceleration is more pronounced when bromobenzene (PhBr) is used in comparison with iodobenzene (PhI). The observation of an aryl halide dependence on rate and various qualitative kinetic experiments are consistent with a mechanism in which ligand exchange of halide for amide (“transmetalation”) is turnover limiting. The mechanism may be different depending on whether PhBr or PhI is used as a coupling partner. Oxidative addition complexes (xantphos)Pd(Ph)(X) (X = Br, I; xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), likely intermediates in catalysis, have been prepared; their differing interactions with Yb(OTf)3 in solution resemble the halide dependence of the catalytic mechanism, which we propose originates from a reversible Lewis acid mediated halide abstraction during catalysis. KEYWORDS: palladium, cross coupling, amides, aryl halides, metal triflates, Lewis acids, transmetalation



INTRODUCTION Pd-catalyzed C−N bond formation has had a major effect on organic synthesis, and efforts to improve Pd couplings have continued to yield increasingly valuable methods for synthetic chemists.1−4 The coupling of primary and secondary amide, sulfonamide, carbamate, and urea nucleophiles has found important applications in the small- and large-scale synthesis of bioactive molecules including drug candidates, medicinally relevant heterocycles, and natural products, as well as valuable products for materials science (photoswitches and fluorescent probes, among others).5 Few methodologies broadly enable the coupling of amide nucleophiles,6 and there is interest in the development of more efficient protocols for couplings of these substrates, given the prevalence of amide linkages in biological and functional molecules.7 Advances in amide N-arylation have been largely made possible by the design of novel phosphine ligands with special properties, including wide bite angle bisphosphines8−11 and sterically hindered12−15 or electron-deficient6,16 phosphines. However, weakly nucleophilic amides and hindered amides (such as secondary acyclic amides) remain challenging substrates for conventional N-arylation methods. Pd catalysts featuring electron-deficient ligands enable efficient coupling of challenging amide substrates, but only with a limited scope of electrophiles.6 Therefore, more generalized protocols for Pd amide couplings continue to be sought. The mechanism of amide N-arylation17−21 (Figure 1) is believed to proceed via oxidative addition of an aryl halide or sulfonate (PhX) to Pd0 (A). Next, ligand exchange of the X ligand for an amidate ligandcommonly referred to as “transmetalation”involves amide coordination to B and base-mediated dehydrohalogenation to generate D. Subsequent © XXXX American Chemical Society

Figure 1. Proposed mechanism of Pd-catalyzed cross-coupling of amides and aryl halides.

C−N bond-forming reductive elimination from D generates the N-arylated amide product. Bidentate or sterically hindered phosphines have been shown to prevent catalytically inactive κ2 coordination of the amidate ligand (E),22 and the chelating 4,5Received: April 24, 2017 Revised: July 19, 2017

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evaluate possible Lewis acid effects in catalysis. Initial observations in our laboratory indicated that Lewis acid acceleration is general for Pd-catalyzed amide N-arylation, including heteroaromatic and homocyclic aryl halide substrates. We discovered that the yields within 2 h of reaction time for the coupling of bromobenzene (PhBr) or iodobenzene (PhI) with pyrrolidin-2-one (1) to generate N-phenylpyrrolidin-2-one (2) using 2 mol % Pd/xantphos catalyst and K3PO4 base in refluxing toluene (PhMe) are improved by the addition of 5 mol % of Lewis acids.31 A screen of additives yielded optimized reaction conditions (Scheme 1).

bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) is commonly employed for this class of reactions.23,24 The turnover-limiting step of amide N-arylation is often transmetalation,6,13 most likely due to the weak binding of amides to Pd. In contrast to ligand effects, amide coordination to Pd could instead be encouraged by increasing the electrophilicity of key intermediates in situ through secondary coordination sphere interactions.25 Related effects shown in several notable reports demonstrate that Lewis acid additives enable challenging transition-metal-mediated reactions, particularly reductive elimination (Figure 2).26−29 Nolan and

Scheme 1. Initial Screen of Lewis Acids in the Pd-Catalyzed Coupling of Aryl Halides and Pyrrolidin-2-onea

a Reaction conditions: 1.0 equiv of pyrrolidin-2-one (0.2 M [1]), 1.1 equiv of aryl halide, 1.2−1.5 equiv of K3PO4, 2 mol % of Pd(dba)2, 2 mol % of xantphos, 5 mol % of M(OTf)3, 2 mL of anhydrous toluene, 110 °C, 2 h. The yield was quantified by 1H NMR of the amide product versus an internal standard (1,3,5-trimethoxybenzene).

Figure 2. Key examples of Lewis acid enabled reductive elimination reactions.26−28

Moloy26 reported that adducts of a Lewis acid to PdII cyanide complexes accelerate the reductive elimination of nitriles, while Hartwig and Shen27 reported that adducts of Lewis acids to PdII amidate complexes accelerate the reductive elimination of Nheteroarylamides. In both cases, the rate of reductive elimination from Pd increases with the electrophilicity of the Lewis acid, where adduct formation apparently encourages reductive elimination by forming a more electrophilic metal intermediate. Similarly, Bergman and Tilley28,29 demonstrated that remote binding of a Lewis acid dramatically increases the rate of reductive elimination of electron-deficient biaryls from PtII. Efforts in our laboratory have focused on understanding how these stoichiometric effects, among others, may benefit the catalytic coupling of amides and aryl halides or heteroaryl halides, similar to the Lewis acid effects identified by Hartwig and Shen.27 The Hartwig−Shen study identified a stoichiometric Lewis acid induced reductive elimination reaction, as well as a Lewis acid cocatalytic effect in amide Nheteroarylation reactions using a Pd/xantphos catalyst. Several heteroaryl halides were coupled with lactams, benzamides, and secondary sulfonamides in significantly higher yields when triethylboron (BEt3) was added to the reaction mixture. We report here that metal triflate additives accelerate amide N-arylation using a Pd/xantphos catalyst. The acceleration effect is general for a wide variety of N-aryl amide products. On the basis of a mechanistic study, Lewis acids appear to accelerate the reaction by lowering the barriers to turnoverlimiting transmetalation.

A range of nitrogen nucleophiles were evaluated, including primary benzamides, primary aliphatic amides, secondary anilides, secondary acyclic amides, carbamates, and indoles (Chart 1). The following sections describe the yield enhancements observed upon adding Lewis acids to N-arylation reactions of various amide substrates. Al(OTf)3 was primarily employed as the Lewis acid, being the most inexpensive metal triflate and effective in accelerating the formation of 2 (Scheme 1). In general, adding 5 mol % of Al(OTf)3 provided significant increases in reaction yield (20 examples, as much as a 45% yield increase). In our survey of amides, the Pd to Lewis acid ratio was not individually optimized for each substrate. K3PO4 was found to be a suitable base for the coupling of primary benzamides or lactams, while reactions of other substrates required Cs2CO3. In select cases where the addition of 5 mol % of Al(OTf)3 to a 2 mol % Pd/xantphos catalyst mixture resulted in a decrease in yield, an increase in yield could be observed when a lower 1:1 Al:Pd ratio was employed. This is in concert with our mechanistic findings: significantly higher Lewis acid concentrations result in a reduced rate of catalysis (vide infra). Cyclic Amides. Despite the reduced nucleophilicity of the cyclic carbamate oxazolidin-2-one in comparison to the analogous lactam 1, this substrate (and variants) have been successfully employed in Pd-catalyzed N-arylation reactions with various ligands and a range of electrophiles.22,32,33 Under our conditions, the reaction of oxazolidin-2-one and PhBr with 2 mol % of Pd/xantphos and 5 mol % of Al(OTf)3 generates Nphenyloxazolidin-2-one (3) in quantitative yielda 41% increase in yield versus the reaction without added Lewis acid. The performance of our catalyst without Lewis acid (58% yield) is similar to that of reported catalyst systems.32 The reaction of 3-bromopyridine with oxazolidin-2-one generated N-3-pyridyloxazolidin-2-one (5) in reduced yield



RESULTS AND DISCUSSION Optimization of Catalysis and Substrate Scope. To yield the broadest and most accessible synthetic protocol, we chose widely available phenyl halides, the relatively inexpensive xantphos ligand, and moisture-tolerant metal triflate salts30 to 5863

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ACS Catalysis Chart 1. Survey of Lewis Acid Effect in Pd-Catalyzed N-Arylation with Various Nitrogen Nucleophilesf

a

K3PO4 was used rather than Cs2CO3. bIsolated yield. c5 mol % of Pd(dba)2 and 5 mol % of xantphos were used. d5 mol % of Pd(dba)2, 5 mol % of xantphos, and 5 mol % of Al(OTf)3 were used. e2.5 equiv of aryl halide and 3 equiv of Cs2CO3 were used. fReaction conditions: 1.0 equiv of amide, 1.1 equiv of aryl halide, 1.2−1.5 equiv of Cs2CO3, 2 mol % of Pd(dba)2, 2 mol % of xantphos, 5 mol % of M(OTf)3, 2 mL of anhydrous toluene, 110 °C, 18 h. Unless otherwise noted, the yield was quantified by 1H NMR of the amide product versus an internal standard (1,3,5-trimethoxybenzene). The bold bond indicates the C−N bond(s) formed.

when a Lewis acid was used, in contrast to increased yields in the N-heteroarylation of 1 with 3-bromopyridine. Consistent with Hartwig and Shen’s study of amide N-heteroarylation,27 increased yields of N-3-pyridylpyrrolidin-2-one (7, 81% yield with 5 mol % Sc(OTf)3, 39% yield increase) are observed. 4-Methylbenzamide. Various protocols have been developed to selectively N-arylate primary benzamides using Pd catalysts.15,21,23,34,35 Under our conditions, the N-arylation of 4methylbenzamide proceeded to a 50% yield of N-phenyl-4methylbenzamide (4) using 2 mol % Pd/xantphos and improved to 64% of 4 using 2 mol % of Pd/xantphos and 5 mol % of Al(OTf)3. A larger increase in yield was observed in the case of coupling 4-methylbenzamide with 3-bromopyridine. Addition of Al(OTf)3 afforded 5 in 94% yield (44% yield increase), again consistent with the Lewis acid acceleration observed by Hartwig and Shen.27 N-Methyl-p-toluenesulfonamide. Buchwald reports that the reaction of N-methyl-p-toluenesulfonamide is successfully coupled with the electron-rich 3,5-dimethylbromobenzene using 1 mol % of Pd/xantphos in refluxing PhMe (0.125 M) with Cs2CO3 base with long reaction times (38 h).24 In our hands, the reaction of N-methyl-p-toluenesulfonamide with the less electron rich PhBr yields N-methyl-N-phenyl-p-toluene-

sulfonamide (7, 8% yield) using 2 mol % of Pd/xantphos in refluxing PhMe (0.2 M) with Cs2CO3. At different catalyst and Lewis acid loadings (5 mol % of Pd/xantphos/Al(OTf)3), 8 was formed in 72% yield (20% increase with respect to 5 mol % Pd/xantphos). Additionally, N-methyl-N-3-pyridyl-p-toluenesulfonamide was formed in 54% yield (5 mol % Pd/ xantphos/Al(OTf)3, 29% yield increase with respect to 5 mol % Pd/xantphos). α-4-Fluorophenylacetamide. Carbonyl substrates with α hydrogens are susceptible to α-arylation,36 yet primary αphenylacetamide substrates have been employed in Pd coupling cascade reactions to prepare naphthyridinones and quinolinones under weakly basic conditions.37 Here, N-phenyl-α-4fluorophenylacetamide (10) and N-3-pyridyl-α-4-fluorophenylacetamide (11) required a higher catalyst loading (5% of Pd/ xantphos) to achieve good yields. Yields of 10 and 11 were comparable when Al(OTf)3 was employed (61% and 64%, respectively). Indeed, the N,α-diarylation product (11b) was observed as a byproduct in reactions which generated 11 (∼2% yield) and the formation of 11b was greater (10%) in the presence of 5 mol % of Al(OTf)3 (Scheme 2). The analogous N,α-diarylation product was not observed in reactions which generated 10, nor were N,N-diarylation products. 5864

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ACS Catalysis Scheme 2. N-Arylation and α-Arylation Products Observed in Reactions with α-4-Fluorophenylacetamide

diarylation (12c), and N,N,α-triarylation (12d) products (the minor products could not be isolated), and the yields of these products were determined by 19F NMR.38 When this reaction was repeated with 5 mol % of Al(OTf)3, 12 was selectively formed (72% yield). The reaction of levetiracetam, a primary aliphatic amide substrate with a hindered CH bond α to the amide carbonyl, with 3-bromopyridine selectively produced the mono-N-arylation product 13 (66% yield, 2 mol % of Pd/ xantphos and 5 mol % of Al(OTf)3, 22% yield increase). Secondary Acyclic Amides. To the best of our knowledge, only Pd catalysts featuring the ligand JackiePhos are broadly competent for N-arylation of secondary acyclic amides.6 Coupling of secondary acyclic amides is otherwise sluggish unless strongly activated aryl halides (such as 4-cyanobromobenzene and 4-nitroiodobenzene) are used.24,39,40 In the absence of these features, Buchwald reports the N-arylation of N-methylacetamide with PhBr, generating N-methyl-Nphenylacetamide (14, 73% yield) over 37 h using 4 mol % of Pd/xantphos with 1,4-dioxane solvent (0.25 M) and Cs2CO3 base.24 Under our conditions, 14 is produced in 48% yield over 18 h (5 mol % of Pd/xantphos/Al(OTf)3, PhMe solventa 22% yield increase with respect to 5 mol % of Pd/xantphos). The reaction of N-methylacetamide with methyl 4-bromobenzoate generates 15 in 89% yield (2 mol % of Pd/xantphos and 5

The reaction of α-4-fluorophenylacetamide with 2.5 equiv of methyl 4-bromobenzoate using 2 mol % of Pd/xantphos, on the other hand, produced a roughly 2:1:1:1 distribution of four products, the major product of which is the N-monoarylated product 12 (41% yield; Scheme 2). The minor products are tentatively identified as the N,α-diarylation (12b), N,N-

Figure 3. Comparison of selected catalytic reaction profiles: (A) N-arylation of 1 as a function of aryl halide; (B) N-arylation (PhBr) of 1 as a function of Lewis acid (1.5 mol %) or NBu4Br (1 equiv); (C) N-arylation (PhI) of 1 as a function of Lewis acid; (D) N-arylation (PhBr) of 1 as a function of Lewis acid concentration. Trend lines representing initial rates for selected trials are superimposed. 5865

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suggested by Hartwig and Shen.27 When pyridyl halide electrophiles are used, a Lewis acid/base adduct of the pyridyl nitrogen in LPd(Py)(NR2) is possible (as in Figure 2b); however, such an adduct is not possible with phenyl halide electrophiles. This suggests that the triflate salt has various potential roles in the catalyst system. With unsubstituted aryl halides, turnover-limiting transmetalation in amide N-arylation via Pd has been invoked,6,13 and our data are consistent with a turnover-limiting transmetalation step. The universal Pd intermediate involved in reductive elimination for electrophiles PhBr, PhI, and PhOTf(xant)Pd(Ph)(NR2)should in principle undergo a unimolecular reductive elimination at the same rate regardless of which electrophile were used; however, the differences in rate behavior in Figure 3A suggest a halide influence in the turnover-limiting step.13 Further, 31P NMR spectra of the catalytic reaction mixtures reveal (xant)Pd(Ph)(X) (22, X = Br; 23, X = I) to be the major phosphoruscontaining component of the resting state mixture of complexes. Finally, a mechanism in which oxidative addition of electrophile is rate-limiting for this catalyst system is possible but would be inconsistent with extensive literature precedent.4,6,13,16,23,24,27 The catalysis was then repeated with metal triflate additives (Figure 3B) using a 1:1 Lewis acid:Pd ratio. Initial rates were indeed increased in the reaction of PhBr with 1. The most dramatic increase in reactivity was observed upon the addition of 1.5 mol % of Sc(OTf)3 (ν = (36 ± 21) × 10−4 M min−1) and 1.5 mol % Yb(OTf)3 (ν = (36 ± 6.4) × 10−4 M min−1) (Table 1).41 In contrast, the addition of metal triflates did not produce

mol % of Al(OTf)3, 45% yield increase with respect to 2 mol % of Pd/xantphos) while the reaction of N-methylacetamide with 3-bromopyridine generated 16 in 54% yield (5 mol % of Pd/ xantphos/Al(OTf)3, 18% yield increase with respect to 5 mol % of Pd/xantphos). For 16, adding a metal triflate allows for reduced Pd loadings (and comparable conversion) in comparison to the Lewis acid free reactions. 16 is generated in 34% yield with 2 mol % of Pd/xantphos and 5 mol % of Al(OTf)3roughly the same yield as when the reaction is performed with 5 mol % of Pd/xantphos and no Lewis acid. The reaction of N-butylpropionamide and N-phenylpropionamide (larger secondary acyclic amides) with methyl 4bromobenzoate, forming 17 and 18, shows a decrease in yield when 5 mol % of Al(OTf)3 was employed. No N-arylation product was observed in the reaction of N-butylpropionamide or N-phenylpropionamide with PhBr. Melatonin, a Substrate with Multiple Functional Groups. Melatonin has two secondary nitrogens: an indole and a secondary acyclic amide site, both of which could potentially undergo N-arylation. We note that indole N-arylation via Pd or Cu is another area of cross-coupling with practical limitations.15 In our case, the reaction of melatonin with PhBr results in selective N-arylation at the indole nitrogen (19) and proceeds to higher yield in the presence of 5 mol % of Al(OTf)3 (60% yield, 30% increase), indicating that Lewis acid additives can accelerate coupling rates for nitrogen nucleophiles beyond amide substrates. No N-arylation products at the amide site on melatonin were observed by 1H NMR when using PhBr, even with excess PhBr (3 equiv) or after long reaction times (48 h). However, the reaction of melatonin with the more electrophilic methyl 4-bromobenzoate (2.5 equiv) resulted in diarylation at both nitrogen positions. Without Lewis acid, the indole Narylation product (20) and the N,N′-diarylation product (21) are formed in roughly 1:1 yield (20, 42%; 21, 38%). However, when the reaction is performed with 5 mol % of Al(OTf)3, moderate selectivity for 20 is observed (20, 67%; 21, 27%). In summary, we observe that metal triflate additives can improve yields and selectivity for various N-arylation reactions or allow for reduced Pd loadings. Use of a heteroaryl halide is not a requirement for an apparent accelerating effect, although various N-3-pyridylamide products have particularly significant increases in yield when Al(OTf)3 is employed. The influence of Al(OTf)3 is general for a variety of substrates, but additives reduce the overall reaction yield in some cases. Mechanistic Investigation. To quantify the effect of Lewis acids, we first performed kinetic measurements of crosscoupling under various conditions. Given the difference in reactivity between PhBr and PhI in our system (represented in Scheme 1), we first determined the relative initial rates of catalysis in the absence of Lewis acids using PhBr, PhI, and phenyl triflate (PhOTf) as substrates (Figure 3a). The reaction of 1 and PhBr (1.1 equiv) using Pd(dba)2 (1.5 mol %), xantphos (1.5 mol %), and K3PO4 (1.2 equiv) in PhMe (5.5 mL) proceeded to completion in approximately 9 h at 110 °C. The initial reaction profile shows that the concentration of the amide product 2 increases linearly with time, consistent with pseudo-zero-order kinetics with an observed initial rate of (14 ± 1.3) × 10−4 M min−1. The analogous reactions employing PhI and PhOTf are slower (ν = (9.5 ± 2.4) × 10−4 and (4.7 ± 1.6) × 10−4 M min−1, respectively) and begin to decrease in rate within 1 h. In cases where strongly deactivated heteroaryl halides are used, reductive elimination may be turnover-limiting, as

Table 1. Observed Initial Rates of Catalysis for Pd-Catalyzed Coupling of Aryl Halides and 1a entry

aryl halide

Lewis acid

1 2 3 4 5 6 7 8 9 10 11

PhBr PhI PhOTf PhBr PhBr PhBr PhBr PhBr PhI PhI PhI

N/A N/A N/A In(OTf)3 Sc(OTf)3 Al(OTf)3 Yb(OTf)3 Zn(OTf)2 In(OTf)3 Zn(OTf)2 Yb(OTf)3

initial rate (10−4 M min−1) 14 9.5 4.7 18 36 32 36 26 6.2 12 16

± ± ± ± ± ± ± ± ± ± ±

1.3 2.4 1.6 5.5 21 21 6.4 4.5 2.6 4.4 3.0

a Reaction conditions: 1.0 equiv of pyrrolidin-2-one (0.2 M [1]), 1.0 equiv of aryl halide, 1.2 equiv of K3PO4, 1.5 mol % of Pd(dba)2, 1.5 mol % of xantphos, 1.5 mol % of M(OTf)3, 5.5 mL of anhydrous toluene, 110 °C. Values given are averages and standard deviations of three trials.

a significant increase in rate for arylations using PhI (Figure 3C). The addition of 1.5 mol % of Yb(OTf)3 increased the initial rate slightly to (16 ± 3.0) × 10−4 M min−1 (from (9.5 ± 2.4) × 10−4 M min−1); however, the addition of 1.5 mol % of In(OTf)3 produced a decrease in initial rate (ν = (6.2 ± 2.6) × 10−4 M min−1). In general, further increases in the Lewis acid:Pd ratios resulted in a decrease in rate (Figure 3D). The observed differences in Lewis acid acceleration effects (PhBr vs PhI) lead us to believe that the transmetalation mechanism may vary as a function of halide in the LPdPhX intermediate. X− to NR2− ligand substitution may begin by amide association to LPd(Ph)(X), forming the five-membered 5866

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irreproducible, but when [1] was reduced, a slight decrease in rate was observed (ν = (8.7 ± 2.5) × 10−4 M min−1 (0.5:1 1:PhI)). Additional experiments involving exogenous salts (NBu4I or NBu4OTf) resulted in biphasic reaction mixtures, which precluded a quantitative kinetic analysis. These observations support a mechanism in which transmetalation is turnover-limiting, given (1) the rate of catalysis is dependent on the identity of aryl halide, (2) Lewis acid acceleration is pronounced for PhBr reactions, but not PhI reactions, (3) catalysis is inhibited by exogenous halide ions, and (4) reactions using PhBr are zero order in [PhBr] and [1], whereas reactions using PhI are more complex. In principle, the sequence of amide coordination and dehydrohalogenation steps is terminated by irreversible deprotonation of Pd-bound 1. Therefore, the efficiency at which this step occurs would be dependent on a number of pre-equilibria, which include dissociation of X− from (xant)Pd(Ph)(X), coordination of 1, dissociation of base, deprotonation of Pd-bound 1, and precipitation of a HX:base complex. (Figure 5).

intermediate LPd(Ph)(X)(HNR2), or by a dissociative ligand exchange via halide abstraction from LPd(Ph)(X), forming a cationic LPd(Ph)+ species.6 (Figure 4) Assuming trans-

Figure 4. Two possible mechanisms for transmetalation: rate-limiting amide coordination and rate-limiting halide dissociation.

metalation is turnover-limiting, the mechanisms could be distinguished by determining the catalytic rate dependence upon concentration of amide and of exogenous halide. An associative mechanism would be promoted by increased [amide], while a mechanism initiated by reversible halide dissociation would be inhibited by increased [X−]. The initial rate of catalysis was then determined under various conditions to establish reaction orders (Table 2). In the Table 2. Observed Initial Rates of Catalysis for Pd-Catalyzed Coupling of Aryl Halides and 1a entry

aryl halide

1 2 3 4 5 6 7 8 9

PhBr PhBr PhBr PhBr PhBr PhI PhI PhI PhI

modifications to std conditionsa 2 2 1 1

equiv cquiv equiv equiv

PhBr 1 NBu4Br KOTf

2 equiv PhI 2 equiv 1 0.5 equiv 1

initial rate (10−4 M min−1) 14 13 13 7.5 13 9.5 12 16 8.7

± ± ± ± ± ± ± ± ±

1.3 5.0 2.0 2.5 3.9 2.4 3.6 5.0 2.5

Figure 5. Pre-equilibria potentially relevant to turnover-limiting transmetalation.

Inhibition of PhBr catalysis by exogenous NBu4Br is consistent with dissociation of Br− from (xant)Pd(Ph)(Br) as a key step and may precede coordination of 1. For the case of PhI the observed rate dependence on [1] is complicated by the influence of [1] on the polarity of the reaction medium, a known factor in amide N-arylation couplings.42 Nonetheless, it is evident from our investigation that the halide identity influences the various transmetalation equilibria and it is possible that reactions employing PhI are more sensitive to solution polarity than those employing PhBr (Table 2, entries 7 and 8). Additionally, the yields of reactions employing PhI are also more variable in a screen of bases in comparison to those of PhBr.43 We note that it is possible a Lewis acid adduct of 1 would be activated toward transmetalation (such as a metal amidate complex), but we do not presently have experimental evidence to support this claim, and such an effect should be halide independent. Furthermore, increasing the Lewis acid loading beyond 1:1 LA:Pd to 3:1 and 6:1 decreases the rate of catalysis, where LA activation of 1 should further improve with increased [LA]. Interaction of Oxidative Addition Complexes with Metal Triflates. To better understand the interactions of metal triflates with Pd intermediates prior to transmetalation, we prepared (xant)Pd(Ph)(X) (22, X = Br; 23, X = I)22,44−49 and studied their solution behavior with Lewis acids. Complexes of the general structure (xant)Pd(Ar)(X) are known to be fluxional,22,44,45 exhibiting rapid cis−trans isomerization at room temperature (Figure 6), and the cis, trans, and ionized forms of (xant)Pd(Ph)(X) represented in Figure 6 may have different reactivities toward transmetalation in a catalytic setting. If Lewis acids affect the kinetics and/or thermodynamics of the isomerization pathway, the concentration of the ionized intermediate and rates of formation and consumption

a

Standard reaction conditions: 1.0−2.0 equiv of 1 (0.2−0.4 M [1]), 1.0−2.0 equiv of aryl halide, 1.2 equiv of K3PO4, 0−1 equiv of NBu4Br. 1.5 mol % of Pd(dba)2, 1.5 mol % of xantphos, 5.5 mL of anhydrous toluene, 110 °C. Values given are averages and standard deviations of three trials.

Lewis acid free coupling of amide 1 and PhBr with either 2:1 1:PhBr or 1:2 1:PhBr ratio, the rate of catalysis was unaffected (ν = (13 ± 5.0) × 10−4 M min−1 (2:1 1:PhBr), (13 ± 2.0) × 10−4 M min−1 (1:2 1:PhBr)), indicating that under our reaction conditions N-arylations using PhBr are zero order in [1] and in [PhBr]. Indeed, exogenous halide inhibits catalysis; the rate of coupling of 1 and PhBr with tetrabutylammonium bromide (NBu4Br, 1 equiv relative to amide) was reduced to (7.5 ± 2.5) × 10−4 M min−1. The rate of coupling of 1 and PhBr with potassium triflate (KOTf, 1 equiv to amide) is roughly the same as that without any additive (ν = (13.0 ± 3.9) × 10−4 M min−1). The latter experiment indicates that triflate anion itself does not independently increase the rate. Further, rate enhancements are not solely the consequence of an increase of the ionic strength of the reaction medium. The coupling of amide 1 and PhI exhibited different kinetic behavior, accelerating when the concentration of PhI was doubled (ν = (12 ± 3.6) × 10−4 M min−1 (1:2 1:PhI), (9.5 ± 2.4) × 10−4 M min−1 (1:1 1:PhI)) and when [1] was doubled (ν = (16 ± 5.0) × 10−4 M min−1). The nonlinear kinetic profile of the PhI catalytic reaction suggests complex reaction orders. Kinetic experiments with larger concentrations of [1] proved 5867

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κ3-P,O,P pincer-like bonding mode of xantphos44,45 can also promote halide exchange. The 31P resonance of 22 and 23 shifts downfield in the presence of increasing amounts of [(xant)Pd(Ph)][BArF4] (25), suggesting that bromide ligands exchange between Pd centers on the NMR time scale. At large mole fractions of 25 (X25 > 0.35), a single broad peak in the 31P spectrum (13.4 ppm, 292 K) is observed (Figure 8); this shift is Figure 6. Proposed pathway of cis−trans isomerization in (xant)Pd(Ph)(X) complexes.

could changethereby influencing the reaction rate of our catalytic reaction of interest. Variable-temperature NMR experiments were therefore conducted to probe the interaction of 22 and 23 with Lewis acids, with the understanding that our experiments would be at temperatures and conditions different from those of the catalytic reaction. The 31P NMR spectrum of 22 at 273 K in CD2Cl2 features a single resonance (singlet, 9.6 ppm) that broadens upon cooling to 260 K and at 195 K decoalesces to two signals (10.2 ppm, 22-trans; 8.6 ppm, 22-cis; 13:1 trans:cis ratio) (Figure 7A). In

Figure 8. 31P NMR spectra (0.02M, CDCl3) at 292 K of mixtures of 22 and 25. X corresponds to the mole fraction of 25.

identical to the 31P NMR resonance of 25 in the absence of 22. Similar behavior was observed for mixtures of 23 and 25. The 31 P resonances of 22 and 23 therefore depend upon the concentration of the dissociated (xant)Pd(Ph) fragment in solution. To confirm the competency of Yb(OTf)3 to generate a (xant)Pd(Ph) cation, 22 was combined with 5 equiv of Yb(OTf)3 and 100 equiv of 1 in CDCl3. The 31P spectrum revealed a single sharp resonance at 13.4 ppm, identical with that of the 31P resonance of 25 (Figure 9). In a solvent mixture akin to our catalytic conditions (0.4 M 1 in C7D8), the addition of Yb(OTf)3 resulted in a broadening and downfield shift of the 31 P resonance of the respective oxidative addition complex, suggesting that Yb(OTf)3 is competent to reversibly abstract halide ions from 22 and 23 in the catalytic reaction medium. The combination of 22, 5 equiv of Yb(OTf)3, and 100 equiv of 1 in C7D8 results in a very broad 31P resonance centered at 8.82 ppm; while this is indicative of fluxional behavior, decoalescence was not observed under cryogenic conditions (220 K).

Figure 7. 31P NMR spectra (0.02M, CD2Cl2) at 273 and 195 K: (A) 22; (B) 22 and 1 equiv of Yb(OTf)3; (C) 23; (D) 23 and 1 equiv of Yb(OTf)3.

the presence of 1 equiv of Yb(OTf)3 (the most soluble metal triflate explored in our study) in CD2Cl2 at 273 K, 22 resonates further downfield (11.5 ppm) and at 195 K is broadened and unresolved, without reaching a decoalescence point (Figure 7B)consistent with a change in cis−trans isomerization behavior upon addition of Lewis acid. Like 22, the 31P NMR spectrum of 23 is a singlet (10.6 ppm, 273 K, CD2Cl2) that broadens upon cooling. At 195 K, the peak resolves into two signals resonating at 11.9 (23-trans) and 8.7 (23-cis) ppm (∼15:1 trans:cis ratio) (Figure 7C). Two additional sharp singlets at 17 (24a) and 4.9 (24b) ppm are evident in the spectrum at 260 K, corresponding to the cis and trans isomers of Pd(xant)(I)2, formed as a decomposition product.48,50 In the presence of 1 equiv of Yb(OTf)3 at 195 K, only a single sharp resonance corresponding to 23-trans is observed (Figure 7D). Figure 7 demonstrates that the interaction of Yb(OTf)3 with 22 and 23 results in different effects on the fluxional behavior of either complex, showing that the effect of Lewis acid additive depends on the identity of halide X in the putative catalytic intermediate (xant)Pd(Ar)(X). One plausible role of metal triflate additives M(OTf)3 in catalysis is the facilitation of halide exchange in the first step of transmetalation, perhaps forming [(xant)Pd(Ph)][OTf]. Like M(OTf)3, cationic xantphos-ligated Pd complexes featuring a



CONCLUSION Co-catalytic metal triflate Lewis acids accelerate Pd/xantphoscatalyzed amide N-arylation using PhBr by as much as a factor of 3, while the acceleration of N-arylations using PhI is less significant. The effect is general for several classes of amide nucleophiles, and in several cases, improved selectivity for a single N-arylamide product is obtained. Reduced rates are observed at Lewis acid loadings beyond 1:1 LA:Pd. Various observations suggest that different mechanisms may occur depending on the aryl halide employed. For reactions with PhBr, pseudo-zero-order kinetics are observed in both [PhBr] and [1], as well as inhibition of catalysis by NBu4Br. For 5868

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE-1565721). Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund for partial support of this research. Support for the NMR facility at Temple University by a CURE grant from the Pennsylvania Department of Health is gratefully acknowledged. The authors thank Boulder Scientific for a gift of B(C6F5)3, Dr. Charles W. DeBrosse for assistance with variable-temperature NMR, and Prof. Nilay Hazari for helpful discussions.



Figure 9. 31P NMR spectra (0.6 mM, C7D8) at 292 K: (A) mixture of 22, 100 equiv of 1, and x equiv of Yb(OTf)3; (B) mixture of 23, 100 equiv of 1, and x equiv of Yb(OTf)3; (C) 22, 100 equiv of 1, and varying equivalents (x = 5, 1, 0.5, and 0) of Yb(OTf)3 (the spectrum of pure 25 (bottom; CDCl3, 292 K) is shown for comparison).

reactions with PhI, the rate of catalysis is lower and somewhat dependent on [PhI] and [1]. The rate of reaction of PhBr and 1 is not affected by KOTf, suggesting that acceleration effects are not necessarily due to ionic strength or the triflate anion. Transmetalation requires, at the very least, dissociation of X− from (xant)Pd(Ph)(X), coordination of 1, dissociation of base, deprotonation of Pd-bound 1, and precipitation of a HX:base complex. One or more of these steps are evidently dependent on whether X = Br or X = I. Complexes 22 and 23catalyst resting state complexesundergo halide abstraction with addition of Yb(OTf)3, forming [(xant)Pd(Ph)]+ as evidenced by stoichiometric 31P NMR studies. We propose that metal triflate additives facilitate halide abstraction in turnover-limiting transmetalation, thereby accelerating the overall catalytic process. Other productive influences of M(OTf)3 additives are possible, and further study in our laboratory aims to better understand additive effects across Pd catalysis.



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b01317. Experimental procedures, characterization, spectral data, and kinetic data (PDF)



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AUTHOR INFORMATION

Corresponding Author

*E-mail for G.E.D.: [email protected]. ORCID

Graham E. Dobereiner: 0000-0001-6885-2021 Notes

The authors declare no competing financial interest. 5869

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