Dialkylterphenyl Phosphine-Based Palladium Precatalysts for Efficient Aryl Amination of N-Nucleophiles

FULL PAPER Dialkylterphenyl Phosphine-Based Palladium Precatalysts for Efficient Aryl Amination of N-nucleophiles Raquel J. Rama,[a] Celia Maya[b] and M. Carmen Nicasio*[a] Dedicated to Professor Pablo Espinet on the occasion of his 70th birthday Abstract: A series of 2-aminobiphenyl palladacycles supported by dialkylterphenyl phosphines, PR2Ar’ (R = Me, Et, iPr, Cyp; Ar’ = ArDipp2, ArXyl2) have been prepared and structurally characterized. Neutral palladacycles were obtained with less bulky terphenyl phosphines (i.e. Me and Et substituents) while the largest phosphines provided cationic palladacycles in which the phosphines adopted a bidentate hemilabile k1-P,1-Carene coordination mode. The influence of the ligand structure on the catalytic performance of these Pd precatalysts was evaluated in aryl amination reactions. Cationic complexes bearing phosphines PiPr2ArXyl2 and PCyp2ArXyl2 were the most active of the series. These precatalysts have demonstrated a high versatility and efficiency in the coupling of a variety of N-nucleophiles, including secondary amines, alkyl amines, anilines and indoles, with electronically deactivated and ortho-substituted aryl chlorides at low catalyst loadings (0.25-0.75 mol% Pd) and without excess ligand. Introduction At present, palladium-catalyzed aryl amination is a general, versatile and reliable synthetic protocol for the formation of C(sp2)-N bonds, which finds applications both in academic and industrial contexts.[1] Since its introduction, almost 25 years ago by the groups of Buchwald[2] and Hartwig,[3] the rapid evolution experienced by this catalytic transformation has been largely driven by the development of new ancillary ligands, leading to increasingly challenging couplings under milder conditions.1d,[4] Not surprisingly, the most widely employed supporting ligands in Pd-catalyzed cross-coupling reactions are tertiary phosphines,[5] since their electronic and steric properties can be conveniently tuned by changing the nature of the substituents attached to the phosphorous atom. Actually, phosphines that combine both electron-richness and bulkiness produce remarkably active Pd catalytic species for Buchwald-Hartwig aminations.[6] Examples include bisphosphines like Xantphos[7] or Josiphos,[8] hemilabile P,N-ligands[9] and Buchwald’s biaryl monophosphines.[10] The mentioned dialkylbiaryl phosphines constitute a broad family of ligands, with an outstandingly extensive applicability,[1e] as their modular synthesis enables the customization of the ligand for a particular coupling.[11] Besides, most of these ligands feature fair air-stability both in solution and in the solid state, facilitating their manipulation. Furthermore, these ligands adopt different coordination modes, where P-bonding is complemented by weak M···Carene interactions with the non-phosphine-containing aryl ring.[10a,12] In the last decade, the use of well-defined Pd(II) precatalysts in cross-coupling reactions has been extended.[13] Precatalysts ensure a better control over the composition and stoichiometry of the catalytic species throughout the catalytic cycle, improving the efficiency and the economy of the process.[13b] In this regard, 2-aminobiphenyl palladacycles bearing larger dialkylbiaryl phosphine ligands have emerged as extremely powerful catalytic systems for aryl amination reactions.[14] Figure 1. Structural formula, abbreviated names and numbering scheme for terphenyl phosphines employed in this work. Contrary to Buchwald’s biaryl phosphines, dialkylterphenyl phosphines, PR2Ar’ with Ar’ = terphenyl radical, have been far less studied (Figure 1).[15] With the aim of investigating the properties of this type of ligands, we prepared a series of dialkylterphenyl phosphines with a variety of substituents both on the phosphorus and on the terphenyl moiety and evaluated their electronic and steric parameters.[16] These studies highlighted their strong basicity and their superior steric protection when compared to dicyclohexylbiaryl phosphines.[16b,c] Moreover, the coordination properties of terphenyl phosphines towards a variety of late transition metals including Rh, Ir, Ni, Pt and Au proved their ability to adopt different coordination modes involving the P atom [a] R. J. Rama, Prof. M. C. Nicasio Departamento de Química Inorgánica, Universidad de Sevilla Aptdo 1203, 41071 Sevilla (Spain) E-mail: [email protected]s [b] Dr. C. Maya Instituto de Investigaciones Químicas (IIQ), Departamento de Química Inorgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Sevilla Avda. Américo Vespucio 49, 41092 Sevilla, Spain Supporting information for this article is given via a link at the end of the document. FULL PAPER and one of the flanking aryl rings of the terphenyl fragment.[16,17] Herein, we describe the first application of terphenyl phosphines in Pd-catalyzed aryl amination reactions. With this aim, a series of 2-aminobiphenyl palladacycles stabilized by the ligands depicted in Figure 1 have been synthesized and structurally characterized. Their catalytic activities in the arylation of a variety of N-nucleophiles, including alkyl primary and secondary amines, anilines and indoles, with electronically deactivated methoxysubstituted aryl chlorides have been examined. Results and Discussion Synthesis and structural characterization of terphenyl phosphine-stabilized palladacycles Palladacycles 1a-1c were prepared in good yields following the procedure shown in Scheme 1,[14a,b] which involves the equimolar reaction between the 2-aminobiphenyl-Pd chloridebridged dimer with the less bulky terphenyl phosphine ligands L1- L3 in dichloromethane at room temperature. Whereas the reactions with PMe2Ar’ phosphines L1-L2 were achieved in 2 h, that involving PEt2ArXyl2, L3, required a considerably longer reaction time (24 h) to reach completion. Scheme 1. General synthesis of complexes 1a-1c. Complexes 1a-1c were isolated as air-stable colorless crystals and were fully characterized by microanalysis and NMR spectroscopy. As opposed to those described for analogous palladacycles bearing bulky monophosphine ligands,[14a,18] the room temperature 31P{1H} NMR spectra of compounds 1a-1c display single resonances at  1.7, 1.9 and 29.1, respectively, revealing shifts of about 40 ppm to higher frequencies with respect to the free phosphine ligands. The 1H NMR spectrum of 1a is consistent with a fast rotation of the phosphine ligand around the P-Cipso bond at 25 ºC, since the four methyl substituents of the xylyl rings originate only one resonance at 2.25 ppm and the two methyl groups directly bound to the P atom appear as a doublet at 1.00 ppm (JHP = 9 Hz). In addition, a broad singlet centered at 4.50 ppm is observed for the two protons of the amino group of the 2-aminobiphenyl moiety. Conversely, 1H NMR spectra for 1b and 1c show broad resonances in the aliphatic region, indicating that for both species the above-mentioned fluxional process is somewhat slower at room temperature. Upon cooling at -30 °C, these signals resolve into the distinct pattern of resonances expected for non-equivalent substituents both on the aryl rings and on the phosphorus atom, indicating a hindered process of exchange of the flaking aryl rings (see Figs. S1 and S2). Furthermore, for the PEt2ArXyl2 derivative 1c, the resonance due to the NH2 group splits into two signals at low temperature ( 4.62 and 4.56). The 1H-31P heteronuclear correlation experiment recorded at 0 ºC for 1c provides clear evidence of the coupling between the NH2 protons and the phosphorus atom, supporting a mutually trans arrangement between the phosphine and the amino group in these molecules. The solid-state structures of complexes 1a and 1c were confirmed by X-ray diffraction studies (Figures 2 and S3). In both complexes the PdII center is bonded to the 2-aminobiphenyl moiety, the phosphine and the chloride ligands in a slightly distorted square-planar geometry, with cis bond angles varying from ca. 83 to 95º. As in the cases of the solid-state structures reported for other 2-aminobiphenyl palladacycles,[18,19] the phosphorus atom in 1a and 1c is coordinated in trans position relative to the nitrogen atom of the amino group. The Pd-P distances of 2.2763(7) and 2.2596(7) Å for 1a and 1c, respectively, compare well with those found in similar complexes.[18,19] Figure 2. Molecular structure of 1a. Hydrogen atoms are omitted for clarity. Thermal ellipsoids are shown at 50% probability. Selected bond lengths [Å] and angles [º]: Pd-P 2.2763(7), Pd-N 2.107(2), Pd-C1 2.005(2), Pd-Cl 2.4151(6); N- Pd-P 170.37(6), C1-Pd-Cl 171.36(7), C1-Pd-P 94.64(7), P-Pd-Cl 92.69(2). Treatment of dichloromethane solutions of 1a and 1b with NaBArF promoted the abstraction of the chloride ligand and the quantitative formation of cationic species 2. As outlined in Scheme 2, the resulting free coordination site in these complexes was occupied by one of the flanking aryl rings of the terphenyl group. The structures proposed for complexes 2 were based on analytical and spectroscopic data, as well as on molar conductivity measurements. The resonance due to the phosphorus nucleus in the cationic derivatives 2 experiences a shift to higher frequency (∆ ≈ 13 ppm) with respect to that of the neutral complexes 1a and 1b. Such a shift may be indicative of a bidentate coordination mode of the phosphine ligand involving the P atom and one of the flanking aryl ring of terphenyl moiety.[16b] The complexity of 1H and 13C{1H} NMR spectra of 2a and 2b at 25 ºC attests for the low symmetry exhibited by these compounds. Thus taking 2a as an example, its 1H NMR spectrum shows separate signals for each of the methyl groups of the xylyl FULL PAPER fragments. The methyl groups attached to the P atom give rise to two doublets at 1.47 and 0.87 (JHP = 11 Hz). In addition, the two diasterotopic protons of the amino group resonate as a doublet of doublets at 4.37 (JHH = 5.1 and JHP = 9 Hz) and as broad doublet centered at 1.55 ppm. To confirm the cationic nature of complexes 2, conductivity measurements were undertaken in nitromethane as the solvent. The molar conductivities of 1.0 mM solutions of 2a and 2b in nitromethane were measured at 46.8 and 36.0 -1 cm2 mol-1, respectively. Both values are significantly lower than that of 82.2 -1 cm2 mol-1 gauged for [nBu]4NI, a 1:1 electrolyte, in this solvent.[20] However, although low, they are comparable to that measured for tetraphenyl borate salts (i.e. 59.4 for [(iC5H11)N][BPh4])[20,21] in nitromethane, for which this anomalous conductivity behavior has been attributed to a low mobility of the tetraphenyl borate anion.[20] Scheme 2. Synthesis of complex 2a and 2b. The general reaction conditions depicted in Scheme 1 were applied to the bulkier terphenyl phosphines, namely PiPr2ArXyl2, L4 and PCyp2ArXyl2, L5. The monitoring of these reactions by 31P{1H} NMR revealed the formation of new species ( 61.4 and 53.4, respectively) together with considerable amounts of free ligands. We found that reactions were completed when 3:1 Pd/phosphine molar ratios were used (Scheme 3). Scheme 3. General synthesis of complexes 3d and 3e. Complexes 3d and 3e were obtained as yellow crystalline solids by slow diffusion crystallization techniques. As stated above, their 31P{1H} NMR spectra contain only one 31P resonance, which is shifted by ca. 47 ppm to higher frequencies relative to the uncoordinated phosphines. Again, such a change in 31P  seems to indicate that terphenyl phosphines in these compounds could be coordinated in a bidentate fashion.[16b] In fact, the NMR features of the phosphine ligands in complexes 3 seem to support this hypothesis, since, in both instances, the two flanking xylyl rings of the terphenyl fragment and the two P-R groups appear inequivalent at room temperature. On the other hand, the integration of the resonances in the aromatic region of their 1H NMR spectra evidences the presence of three 2-aminobiphenyl units in these species. In light of the above and taking into account the stoichiometry of the reaction, it seems plausible that complexes 3 are not neutral compounds but salt-like derivatives, composed of a cationic palladacycle analogous to 2a and a dinuclear aminobiphenyl-palladium anionic species containing no phosphine ligands; however, its structure could not be ascertained from the NMR data. To validate this proposal, HRMS experiments were undertaken, confirming the presence of the mentioned cationic palladacycles in compounds 3. However, no information could be gathered from these experiments regarding the nature of the counterion. Additionally, the molar conductivities of 3d and 3e were gauged in nitromethane, obtaining values (47.3 and 45.8 -1 cm2 mol-1, respectively) very close to that of the ionic compound 2a. The postulated ionic nature of 3d and 3e was further confirmed by X-ray diffraction analyses. As illustrated in Figures 3 and S4, both species consist of a [Pd(2- aminobiphenyl)(PR2Ar’)]+ cation and a dinuclear {[Pd(2- aminobiphenyl)Cl]2(-Cl)}– anionic species. In the cations, the metal ion exhibits a distorted square-planar geometry with bond angles varying from the ideal value by as much as ca. 10º. As anticipated by the analysis of the NMR data, one of the coordination sites on the Pd(II) center is occupied by a weak Pd···Cipso interaction with the closer xylyl ring of the terphenyl fragment. These interactions are characterized by Pd···Cipso bond lengths (Pd-C(19)) of ca. 2.41 Å, within the range of 2.22-2.45 Å found for the 1-coordination of an arene moiety to a d8-ML3 fragment,[23] and comparable to those reported for analogous biaryl phosphine derivatives (ver comment).[14b] Additionally, in the case of complex 3d, the Pd-C distance to the ortho carbon of the proximal ring is about 2.57 Å, significantly longer than that to the ipso carbon, but shorter than the sum of the van der Waals radii of the atoms involved (3.06 Å).[22] To facilitate these interactions, the central aryl ring of the terphenyl moiety bends in both cases towards the metal, resulting in a narrowing of the corresponding P-Cipso-Cortho angle (115.4(3)° and 116.3(4)º for 3d and 3e, respectively) at the expense of the other (127.0(4)° and 125.4(5)º for 3d and 3e, respectively). Moreover, the bulky P-R groups are located on opposite sides of the plane defined by the central aryl ring of the terphenyl moiety. The Pd-P bond distances in both cationic species (2.26 and 2.28 Å, respectively, for 3d and 3e) match the value found in the analogous the BrettPhos complex (2.266 Å),[14b] but are substantially shorter than that of the bulkier tBuXPhos derivative (2.323 Å).[14b] The structure of the counterion consists of two almost square-planar [Pd(2-aminobiphenyl)Cl] units linked together by a single bridging chlorine atom, with the two terminal chloride ions in pseudo-trans disposition. The coordination planes of the two Pd atoms cross with a dihedral angle of ca. 64º. The Pd-Cl-Pd angle (ca. 119º) is significantly deviated from the 90º expected for a single M-X-M bridge,[24] but falls within the range found for other FULL PAPER complexes containing the Pd-ClPd fragment supported by bidentate o -coordinated ligands.[25] Consequently, the two metal centers are too far apart for any metal-metal interaction (Pd···Pd mean value ca. 4.28 Å). The Pd--Cl bond lengths are nearly identical (mean value: 2.49 Å) but somewhat longer than those of terminal Pd-Cl bonds (mean value: 2.32 Å). Though rare, homo and heteronuclear systems with a single unsupported halide bridge have been structurally described for various d8 transition metal ions.[23-26] Figure 3. Molecular structure of 3e. Hydrogen atoms are omitted for clarity. Thermal ellipsoids are shown at 50% probability. Selected bond lengths [Å] and angles [º]: Pd1-P 2.2646(15), Pd1-N1 2.144(5), Pd1-C1 2.024(6), Pd1-C19 2.422(6), Pd1-C20 2.617(6), Pd2-Cl1 2.4731(15), Pd2-Cl2 2.3101(15), Pd2-N2 2.052(5), Pd2-C45 1.977(6), Pd3-Cl1 2.4684(16), Pd3-Cl3 2.3232(15), Pd3-N3 2.053(5), Pd3-C57 1.980(6); N1-Pd1-P 163.02(14), C1-Pd1-C19 170.9(2), C1- Pd1-P 90.12(17), P-Pd1-C19 83.92(15), Pd2-Cl1-Pd3 118.34(6). These results underline that, as was the case of larger biaryl phosphines,[14b] sterically demanding ligands L4 and L5 do not favor the formation of neutral 2-aminobiphenyl palladacycles but instead promote the isolation of cationic [Pd(2- aminobiphenyl)(PR2Ar’)]+ species. The cationic palladacycles described above could be easily isolated as methanesulfonate (mesylate) salts from the reaction of the 2-aminobiphenyl-Pd mesylate-bridged dimer with phosphines L4 and L5 in dichloromethane at room temperature[28] (Scheme 4). This method was also applied for the synthesis of complex 4b with the less bulky ligand PMe2ArDipp2, L2. Scheme 4. General synthesis of complexes 4b, 4d-4e. Compounds 4 were obtained in quantitative yields as airstable, pale-yellow solids. They were characterized by microanalysis and NMR spectroscopy. Since the phosphine L2 facilitates the formation of both neutral and cationic 2- aminobiphenyl palladacycles (1b and 4b, respectively), it is interesting to comment the most significant differences in the NMR spectra of these two species. The 31P resonance for the ligated phosphine in 4b is shifted by ca. 11 ppm to higher frequency with respect to that of complex 1b due to the change in the coordination mode of the phosphine from monodentate to bidentate. Accordingly, the 1H and 13C{1H} NMR spectra of 4b evidence the lack of exchange between the two flanking aryl rings of the terphenyl moiety at room temperature, giving rise to a distinct set of signals for each of the iPr substituents on the Dipp rings and two different doublets for the methyl groups on the P atom. The solid-state structures of 4b, 4d and 4e were determined by X-ray diffraction studies (Figures 4, S5 and S6), confirming in all three cases the expected bidentate coordination mode of the terphenyl phosphines. Structural parameters (bond lengths and angles) obtained for the three complexes are essentially identical to those found for the cations of the salt-like compounds 3d and 3e. Figure 4. Molecular structure of 4b. Hydrogen atoms and OMscounterion are omitted for clarity. Thermal ellipsoids are shown at 50% probability. Selected bond lengths [Å] and angles [º]: Pd-P 2.2577(9), Pd-N 2.113(3), Pd-C1 2.018(3), Pd-C19 2.406(3), Pd-C20 2.555(3); N-Pd-P 167.56(8), C1-Pd-C19 168.32(13), C1-Pd-P 88.80(11), P-Pd-C19 81.66(9). Catalytic activity of terphenyl phosphine-stabilized palladacycles in C-N cross-coupling reactions With a series of neutral and cationic Pd(II) precatalysts in hand, we analyzed their performance in aryl aminations reactions using a variety of N-nucleophiles. Protocols for the N-arylation of secondary amines based on Pd are scarce.[29] On that basis, we evaluated complexes 1a-1c, 2a, 2b and 4b-4d as precatalysts in the coupling of 4- chlorotoluene with morpholine applying the conditions already reported for Pd catalyst systems based on RuPhos,[14b] an outstanding ligand for the arylation of secondary amines (Fig. 5). Indeed, for comparative purposes, the RuPhos-based 2- aminobiphenyl palladacycle was prepared and also tested in this study. As shown in Fig. 5, all terphenyl phosphine-stabilized precatalysts were active in the arylation of morpholine, observing FULL PAPER a direct correlation between the bulkiness of the substituents on the P atom and the catalytic efficiency of the resulting palladium complexes. Remarkably, precatalysts bearing PMe2-containing phosphines, 1a, 1b, 2a, 2b and 4b, afforded the coupling product in modest (30% for 1a) to high (82% for 4b) yields. This finding is particularly interesting considering that methyl-substituted phosphines are rarely used as ancillary ligands in cross-coupling reactions,[30] particularly those catalyzed by palladium, and emphasizes the significant steric encumbrance conferred by the terphenyl fragment.[31] We observed an interesting anion effect when compared the catalytic activity of 1b, 2b and 4b. Precatalyst 2b, with the weakly coordinating BArF anion, was the less efficient. Probably, the large size of BArF brings it close enough to the Pd(II) cationic species to slow the intermolecular interaction with the base rendering the LPd(0) catalytic species.[12b,14c] Overall, the best performances were obtained with palladacycles 4d and 4e bearing the bulkiest ligands L4 and L5, which provided the highest yields of product at 0.5 mol% catalyst loading without using any excess phosphine ligand.[32] In our hands, under the same reaction conditions, Buchwald’s RuPhos precatalysts resulted equally effective. Figure 5. Catalytic performance of 1, 2 and 4 in the N-arylation of morpholine with 4-chlorotoluene. Reaction conditions: 4-chlorotoluene (1 mmol), morpholine (1.2 mmol), [Pd] (0.005 mmol), NaOtBu (1.2 mmol), THF (1 mL), T = 80 ºC, reaction time = 19 h (unoptimized). Yields of isolated products. Having identified 4d and 4e as the most efficient Pd precatalysts of the series, we investigated their versatility in the N-arylation of secondary amines with various challenging aryl chlorides, e.g. electronically deactivated or sterically hindered substrates. Generally, both precatalysts displayed comparable activities in the studied reactions (Table 1). Thus, morpholine, pyrrolidine and indoline were effectively coupled with unactivated 4-chloroanisole with yields ranging from 80 to 98% (5aa, 5ag, 5al). Particularly, when 4-bromoanisole was used as the electrophilic coupling partner, the coupling with morpholine could be attained at even lower catalyst loading (0.25 mol%). ortho-Substituted aryl chlorides were successfully used as coupling partners under the standard reaction conditions (5ab-5ad, 5ah, 5ai, 5am). Similarly, the coupling of 2-chloropyridine with pyrrolidine proceeded satisfactorily, with catalyst 4e providing the corresponding products in high yields (5ak). However, the arylation of acyclic secondary amines proved more challenging with these two precatalysts and positive results could only be obtained in the reaction of N-methyl aniline with 3-chloroanisol (5an). Table 1. Scope of N-arylation of secondary amines with aryl chlorides catalyzed by 4d and 4e.[a] [a] Reaction conditions: aryl chloride (1 mmol), amine (1.2 mmol), [Pd] (0.005 mmol), NaOtBu (1.2 mmol), THF (1 mL), T = 80 ºC, 19 h (unoptimized). Yields of isolated products. [b] Aryl bromide (1 mmol). [c] Reaction time: 1 h. [d] tBuOH (1 mL) as the solvent. [e] [Pd] 0.0025 mmol. Next, we focused on primary amines as nucleophiles. Aniline and n-hexylamine were the model substrates for testing the reactivity of 4d and 4e. As in the previous case, the performance of our complexes was compared to that of the BrettPhos-based palladacycle, a highly efficient precatalyst for the N-arylation of primary amines.[14b] Applying the same reaction conditions as in the previous couplings, the three complexes produced quantitative yields of the product of the model reaction (Fig. 6). However, in the coupling of n-hexylamine with 3- chloroanisol the catalytic activity of 4d was significantly lower than that of the precatalyst bearing PCyp2ArXyl2, 4e. Under these conditions, Buchwald’s BrettPhos precatalyst delivered the coupling product in almost quantitative yield. Increasing the FULL PAPER temperature up to 100 ºC enhanced the reaction yield achieved with precatalyst 4e, matching that of the BrettPhos system. Figure 6. Catalytic performance of precatalysts 4d and 4e in the N-arylation of aniline with 4-chloroanisol and 3-chloroanisol, respectively. Reaction conditions: aryl chloride (1 mmol), amine (1.2 mmol), [Pd] (0.005 mmol), NaOtBu (1.2 mmol), THF (1 mL), T = 80 ºC or 100 ºC, reaction time = 19 h (unoptimized). Yields of isolated products. Under the standard conditions, the coupling of a variety of anilines with methoxy-substituted aryl chlorides proceeded well, providing products in good to high yields (Table 2). Steric hindrance in one or both of the coupling partners seemed not to be a major problem, particularly with precatalyst 4e, leading to the corresponding products in good to quantitative yields (6ab-6af). The N-arylation of 4-aminophenol, a structural motif in compounds with potential biological activities,[33] was selectively achieved with both precatalysts (6ag). Using the modified reaction conditions (reaction temperature = 100 ºC) precatalyst 4e effectively accomplished the coupling of an array of aliphatic primary amines with electron-rich (7ab, 7ak), electron neutral (7aa, 7ad, 7af, 7ai) or orthosubstituted methoxy-chloroarenes (7ac, 7ag, 7aj) providing the products in high yields (Table 2). Interestingly, heteroaryl chlorides were also tolerated affording moderate to good yields of the coupling products (7ae, 7ah). Cyclopropylamine, a substrate hardly used as cross-coupling partner, was efficiently coupled with 3-chloroanisol at 0.75 mol% catalyst loading, affording selectively the monoarylated product (7al). This result compares well with those reported by Colacot and co-workers using the [(BrettPhos)Pd(crotyl)]OTf] precatalyst.[34] The coupling reactions involving bulky adamantyl amine or 2-aminopyridine appeared to be more difficult and required an increase of the catalyst loading (1 mol% or 2 mol% Pd, respectively) to obtain reasonably good yields of N-arylated products (7am, 7an). To further expand the scope of N-nucleophiles, we gauged the activity of precatalyst 4e in the N-arylation of indoles (Table 3). Indole motifs are present in compounds with interesting medicinal applications.[35] However, scarce Pd-based catalytic systems exist which are able to effectively perform this challenging transformation.[36] As shown in Table 3, 4e was a competent precatalyst for the N-arylation of indoles with simple aryl chlorides at 110 ºC with 0.5 mol% catalyst loading and without adding excess ligand (8aa-8ah). Even the presence of a methyl substituent at the 2 position of the indole ring was tolerated, obtaining the coupling products in moderate yields (8ag, 8ah). It is interesting to note that competing C-arylation products were not observed in these reactions.[36c] Table 2. Scope of N-arylation of anilines and primary alkylamines with aryl chlorides catalyzed by 4d and 4e.[a],[b] [[a] Reaction conditions for anilines: aryl chloride (1 mmol), aniline (1.2 mmol), [Pd] (0.005 mmol), NaOtBu (1.2 mmol), THF (1 mL), T = 80 ºC, 19 h (unoptimized). [b] Reaction conditions for primary alkyl amines: aryl chloride (1 mmol), primary amine (1.2 mmol), 4e (0.005 mmol), NaOtBu (1.2 mmol), dioxane (1 mL), T = 100 ºC, 19 h (unoptimized). Yields of isolated products. [c] Reaction time: 1 h. [d] Aryl bromide (1 mmol), [Pd] 0.0025 mmol. [e] [Pd] 0.0075 mmol, T = 80 ºC. [f] [Pd] 0.01 mmol. [g] [Pd] 0.02 mmol. FULL PAPER Table 3. Scope of N-arylation of indoles with aryl chlorides catalyzed by 4e.[a] [a] Reaction conditions: aryl chloride (0.50 mmol), indole (0.53 mmol), [Pd] (0.0025 mmol), NaOtBu (0.7 mmol), toluene (1 mL), T = 110 ºC, 18 h. Yields of isolated products. [b] 1 mol% Pd. To assess the substrate preference of the more general precatalyst 4e, competition experiments between the different N- nucleophiles used in this survey were undertaken. These experiments were conducted under the reaction conditions collected in Tables 1-3, using 3-chloroanisole as the electrophilic coupling partner. As illustrated in Table 4, precatalyst 4e showed a clear preference for the arylation of the primary alkyl amine over the aromatic and the secondary amines. A striking result was found in the competition reaction between n-hexylamine and indole. When the experiment was carried out in toluene, a very low conversion of 3-chloroanisole was observed[37] (15%, entry 4), although with a high selectivity towards the N-arylation of indole over n-hexylamine. Since the arylation of indole proceeded efficiently in toluene (see Table 3), the coupling of n-hexylamine with 3-chloroanisole was examined in this solvent. Only 20% yield of the cross-coupling product was attained (110 ºC, 19 h), evincing an important solvent effect in this transformation. Complete conversion was observed when the reaction between these two competing N-nucleophiles was performed in dioxane, exhibiting a marked selectivity towards the product of the N- arylation of indole. Finally, we examined the coupling between aniline and 3- chloroanisole using precatalyst 4e in the presence of metallic mercury (see SI for details). No effect on the rate or product selectivity was observed during catalysis, suggestive evidence of homogenous catalysis.38 However, to rule out the participation of nanoparticles or Pd clusters as the active catalyst species in the coupling processes described here, a detailed mechanistic study, involving synthetic studies to generate key intermediates and kinetic experiments, is presently under way in our laboratory. Table 4. Amine competition experiments using precatalyst 4e.[a] [a] Reaction conditions: 3-chloroanisol (0.5 mmol), N-nucleophile (0.6 mmol), [Pd] (0.0025 mmol), NaOtBu (0.6 mmol), solvent (1 mL), 19 h. Conversions were determined by GC analysis of the reaction mixtures using dodecane as internal standard. [b] The arylation of n-hexylamine with 3-chloroanisole proceeded in toluene, at 110 ºC, with only 20% yield. Conclusions In summary, we have described the first catalytic application of terphenyl phosphine ligands, PR2Ar’, a new family of electron-rich, sterically encumbered monophosphines, in cross-coupling chemistry. In this study, we have developed two classes of air- and moisture-stable neutral and cationic 2-aminobiphenyl-derived palladacycles bearing dialkylterphenyl phosphines. In the neutral Pd(2-aminobiphenyl)Cl(PR2Ar’) complexes, stabilized by the less bulky ligands (i.e. those with Me and Et substituents on the P atom), the phosphine adopts a classical, 1-P, coordination mode. However, in cationic [Pd(2-aminobiphenyl)(PR2Ar’)]+ species, isolated with the most sterically hindered ligands, the phosphine is coordinated in a bidentate hemilabile fashion (1-P, -Carene), featuring a weak M···Carene interaction with one of the flanking aryl rings of the terphenyl fragment. These complexes have been evaluated as precatalysts in Pd-catalyzed aryl amination reactions, the most active being cationic 4d and, notably, 4e, bearing the phosphine PCyp2ArXyl2. Utilizing these two precatalysts, we have developed a practical, versatile and efficient protocol for the arylation of a variety of challenging N- nucleophiles, including secondary amines, primary alkyl amines and indoles, with problematic aryl chlorides, like those electronically deactivated or sterically encumbered. The couplings are conducted with low catalyst loading (0.25-0.75 mol% Pd) and without ligand excess. Experimental Section All preparations and manipulations were carried out under oxygen-free nitrogen, using conventional Schlenk. Solvents were rigorously dried and degassed before use. Ligands L1-L5,16a-b and [Pd(2-aminobiphenyl)X]2 (X = Cl,[39a] OMs[39b]) were synthesized by following previously reported FULL PAPER procedures. Reagents were purchased from commercial suppliers and used without further purification. Solution NMR spectra were recorded on Bruker Avance DPX-300, Avance DRX-400, Avance DRX-500, and 400 Ascend/R spectrometers. The 1H and 13C resonances of the solvent were used as the internal standard and the chemical shifts are reported relative to TMS while 31P was referenced to external H3PO4. Elemental analyses were performed by the Servicio de Microanálisis of the Instituto de Investigaciones Químicas (IIQ). High resolution mass spectra were registered on Orbitrap Elite Mass Spectrometer at the Centro de Investigación Tecnología e Innovación, CITIUS (Universidad de Sevilla). CITIUS. X-ray diffraction studies were accomplished at CITIUS and Centro de Investigación en Química Sostenible, CIQSO (Universidad de Huelva). Complete synthetic and catalytic procedures and characterization data for new compounds are provided in the Supporting Information. A selection of representative syntheses of Pd(II) complexes and catalytic reactions are reported below. Synthesis of Pd(2-aminobiphenyl)Cl(PMe2ArXyl2), 1a. CH2Cl2 (6 mL) was added to a mixture of 2-aminobiphenyl-Pd chloride-bridged dimer (35.8 mg, 0.058 mmol) and PMe2ArXyl2 (40 mg, 0.115 mmol). The reaction mixture was stirred at room temperature for 2 h. After removal of volatiles under vacuum, the white solid residue was extracted in CH2Cl2, filtered through a Celite plug and the solution was taken to dryness. The complex was purified by crystallization at -20 ºC from a diethyl ether: CH2Cl2 (2:1) mixture. Yield: 70 mg (93%). Elemental analysis calculated (found) for C36H37ClNPPd: C, 65.86 (65.74); H, 5.68 (5.86); N, 2.13 (2.22). Synthesis of [Pd(2-aminobiphenyl)(PMe2ArDipp2)]OMs, 4b. CH2Cl2 (6 mL) was added to a mixture of 2-aminobiphenyl-Pd mesylate-bridged dimer (44.4 mg, 0.06 mmol), PMe2ArDipp₂ (55.0 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 1 h. After removal of volatiles under vacuum, the orange solid residue was extracted in CH2Cl2, filtered through a Celite plug and the solution was taken to dryness. The complex was purified by crystallization at -0 ºC from a petroleum ether: CH2Cl2 (2:1) mixture. Yield: 89.0 mg (90%). Elemental analysis calculated (found) for C45H56NO3PPdS: C, 65.25 (65.15); H, 6.81 (6.45); N, 1.69 (1.61); S, 3.87 (3.77). General catalytic procedure for aryl amination reactions. The precatalyst (0.5-1 mol%), the base NaOtBu (1.2 mmol) and the solvent (1 mL) were added in turn to a vial equipped with a J Young tap and containing a magnetic bar. The N-nucleophile (1.2 mmol) and the aryl chloride (1 mmol) were added under a nitrogen atmosphere. The mixture was stirred at certain temperature (80 to 110 ºC) for 19 h in an oil bath. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (10 mL) and filtered through Celite. 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