Research will be limited to:
- Reaction: Buchwald-Hartwig C-N Coupling
- Substrate: Aryl Halide (Chloride or Bromide)
- Focus: Ligand Screening (XPhos, RuPhos, BINAP, BrettPhos)
- Troubleshooting

Strategy: I will investigate optimized protocols and troubleshooting guides for Buchwald-Hartwig C-N coupling specifically involving aryl chlorides and bromides. The focus will be on comparative ligand performance (XPhos, RuPhos, BINAP, BrettPhos) across different base/solvent combinations and identifying common failure modes (dehalogenation, catalyst inhibition, or base incompatibility) to provide a robust screening framework.
Queries:
- Buchwald-Hartwig C-N coupling ligand screening XPhos RuPhos BINAP BrettPhos aryl chloride bromide
- optimized protocol Buchwald-Hartwig aryl chloride base solvent compatibility troubleshooting
- comparison of XPhos vs RuPhos vs BrettPhos in amination of aryl halides
- Buchwald-Hartwig coupling troubleshooting guide catalyst deactivation aryl chloride
- high-throughput screening Buchwald-Hartwig amination ligand base solvent effects

Executing 5 concurrent searches:
- Buchwald-Hartwig C-N coupling ligand screening XPhos RuPhos BINAP BrettPhos aryl chloride bromide
- optimized protocol Buchwald-Hartwig aryl chloride base solvent compatibility troubleshooting
- comparison of XPhos vs RuPhos vs BrettPhos in amination of aryl halides
- Buchwald-Hartwig coupling troubleshooting guide catalyst deactivation aryl chloride
- high-throughput screening Buchwald-Hartwig amination ligand base solvent effects

Found 10 papers. Key excerpts:

Ligand Effects of BrettPhos and RuPhos on Rate-Limiting Steps in Buchwald–Hartwig Amination Reaction Due to the Modulation of Steric Hindrance and Electronic Structure — Jiaqi Tian et al., 2020

1 Introduction The
C–N bond is one of the most common chemical bonds in
nature. Cross-coupling reactions involving the formation of C–N
bonds have been widely used in the fabrications of chemicals, materials,
and medicines. 1 The palladium-catalyzed
C–N cross-coupling reactions discovered by Buchwald et al. 2 and Hartwig et al. 3 are the most representative reactions. Since the discovery of the
reaction in 1995, there have been many reports in the field of experiments,
mainly focusing on modification of the catalyst ligands, aiming to
increase the reaction yield to improve the functional group tolerance
of substrate and to realize the reaction under milder conditions.
As shown in Figure 1 a, some well-known ligands such as XPhos, 4 SPhos, 5 RuPhos, 6 and BrettPhos 7 have been demonstrated
to have high catalytic activities for specific substrates and have
been branded and now put into practical use. In recent years, improvements
in ligands have still been in progress. 8 − 10 Figure 1 (a) Buchwald–Hartwig
amination reactions and widely used
ligand catalysts Pd-L 1 –Pd-L 11 . (b) Difference
in catalyst activity between Pd-BrettPhos and Pd-RuPhos. Theoretical calculations have been carried out by several
research
groups to study the reaction pathways of Buchwald–Hartwig amination
reactions, mainly focused on certain steps such as C–Br bond
cleavage and C–N bond formation, 11 influence of solvents and bases, 12 and
differences in structures of intermediates formed by different ligand
catalysts. 13 − 15 It is worth mentioning that Ke and Liu et al. 16 calculated the potential energy curve of Buchwald–Hartwig
amination reaction, which contained two key steps: ligand exchange
and debromination. However, the difference in catalytic activity
between two kinds
of widely used catalyst ligands, BrettPhos and RuPhos, 17 − 20 has not been understood well. As shown in Figure 1 b, the following question arises: why does
BrettPhos have high catalytic activity for primary amines, while Ru

Phos
has high catalytic activity for secondary amines? Herein, we
aim to answer these questions through theoretical studies
on the Buchwald–Hartwig amination reaction pathway with different
Pd 0 ligand catalysts. It will be revealed that the catalytic
systems of the two ligands, BrettPhos and RuPhos, have different rate-limiting
steps. The effects of steric hindrance and electronic structure properties
of substituents also play an important role in the reaction systems.
Our research results would contribute to the knowledge of the Buchwald–Hartwig
amination reaction mechanism, and hence, can provide useful information
for the screening of catalysts or a rational design for new types
of ligands. 2 Computational Details All of the quantum
chemical calculations were carried out with
the Gaussian 16 21 software package. The
B3LYP functional 22 − 24 of density functional theory (DFT) method was used
in this work. We adopted two basis sets, i.e., basis set 1, B3LYP-D3
6-31G(d,p)//Lanl2dz, 25 which was used for
structural optimization, frequency analysis, and intrinsic reaction
coordinate (IRC) analysis in SMD 26 implicit
solvation model and basis sets 2, B3LYP-D3 6-311++ G(d,p) 27 //SDD, 28 which was
used to calculate the single point energy. The population analysis
was performed using the natural bond orbital (NBO) method. 29 , 30 The thermodynamic parameters were calculated at 298.15 K and 1.00
atm. The three-dimensional (3D) model was presented using CYLview 31 software. The molecular dynamics (MD)
simulations of intermediates in toluene
solvent molecules were also carried out with the Materials Studio
8.0 software. The atomic charges were obtained by the CHelpG 32 method with Multiwfn 33 software. All of the other parameters were generated from the consistent
valence force field (CVFF). 34 3 Results and Discussion We start from the study of Group 1 , in which bromobenzene
( A 1 ) reacts with aniline ( B 1 ) to form diphenylamine ( C

1 ) via catalyst Pd-BrettPhos or Pd-RuPhos,
respectively. The whole reaction pathway can be divided into three
parts: oxidative addition, deprotonation, and reductive elimination
( Figure 2 a). Configurations
of intermediates in the reaction pathway are shown in Figure S1a . Considering the associations of sodium
ions in intermediates 1 and 5 , we run molecular
dynamics simulations for the two intermediates in toluene. The MD
snapshots in Figure 2 b indicate that intermediates 1 and 5 have
sufficient stabilities in toluene (detailed data are shown in Figure S4 ). Figure 2 (a) Illustration of the reaction pathway.
(b) Potential energy
surfaces. Snapshots of molecular dynamics simulations for intermediates 1 and 5 at 50 ps are shown in the insets. 3.1 Oxidative Addition Initially, the
active Pd-BrettPhos/Pd-RuPhos is combined with the base sodium tert-butoxide
to form intermediate 1 , i.e., G 1 -Brett-1 / G 1 -Ru-1 (G 1 refers to Group 1 system; “Brett” and “Ru” represent BrettPhos
and RuPhos, respectively); then, intermediate 1 , G 1 -Brett-1 / G 1 -Ru-1 , would coordinate with
substrate A 1 by ligand exchange,
and the base is removed to form intermediate 2 , G 1 -Brett-2/G 1 -Ru-2 . In the following step, the cleavage
of C–Br bond of intermediate 2 , G 1 -Brett-2/G 1 -Ru-2 , occurs via the transition state TS 1 , G 1 -Brett-TS 1 / G 1 -Ru-TS 1 ,
to form intermediate 3 , G 1 -Brett-3 / G 1 -Ru-3 . Among them, the combination of Pd-BrettPhos/Pd-RuPhos
and base in the first step is indispensable because it lies in the
energy basin on the potential energy surface ( Figure 2 b). The activation energy

Optimisation of a Key Cross-Coupling Reaction Towards the Synthesis of a Promising Antileishmanial Compound — Raul F. Velasco et al., 2019

Introduction During the course of a research program aimed at identifying novel antileishmanial compounds, we discovered a series of N1-(1 H -pyrazolo[3,4d ]pyrimidin-6-yl)cyclohexyl-1,4trans -diamine compounds that led to GSK3186899/DDD853651 being selected as a pre-clinical development candidate for the treatment of visceral leishmaniasis ( Scheme 1 ) [1] , [2] . During the lead optimisation process, the chemistry team became interested in compound ( R ) -1 due to the orientation of a 4-methoxypyrimidyl substituent alongside a 3-methylmorpholine in the 3-position of the pyrazole ring. Whilst these groups could be introduced individually in a relatively straightforward manner ( e.g. 3-methylmorpholine with no methoxy ( R ) -2 or a methoxy substituent and an unsubstituted morpholine 3 , Scheme 1 ) incorporating both substituents into a single compound proved to be synthetically challenging. Scheme 1 A selection of N -1-(1 H -pyrazolo[3,4d ]pyrimidin-6-yl)cyclohexyl-1,4trans -diamine compounds of interest. The synthetic strategy chosen is highlighted in Scheme 2 , starting from 3-bromo-4,6-dichloro-1 H -pyrazolo[3,4d ]pyrimidine 8 ; which involved protection of the pyrazole N —H followed by sequential displacement of the three halides of 8 . The next step required a Buchwald-Hartwig coupling using 3-methylmorpholine, where there are few examples in the literature [3] , particularly when coupled with a sterically hindered partner such as 4 . Herein, we describe the development of the Buchwald-Hartwig coupling which enabled the delivery of multi-gram quantities of ( R ) -1 , with sufficiently high purity for 7 day rodent toxicology evaluation. Scheme 2 Retrosynthesis of ( R ) -1 . Within the medicinal chemistry program, analogues with less sterically hindered morpholines, such as 10a and 11a ( Scheme 3 ), were synthesised via standard Buch

wald-Hartwig coupling conditions in reasonable yields (48–75%) [2] , [4] . However, when these conditions were applied to the more sterically hindered 3-methylmorpholine of interest (working initially on the racemate), only around 20% of product was visible by LCMS in the reaction mixture after heating at reflux overnight, and pure compound could not be isolated from the crude reaction mixture. Scheme 3 Synthesis of less sterically hindered analogues 10a and 11a . Because of this poor yield, an alternative route to the more sterically hindered compounds was investigated. This was based on the alternative retrosynthesis in Scheme 4 . The key step would be to construct the pyrazole ring via activation and cyclisation of an appropriate amide such as 13 , avoiding the need for the challenging Buchwald-Hartwig coupling. This cyclisation was successfully used for the synthesis of analogues without a 4-methoxypyrimidyl substituent through generation and cyclisation of the thioamide [2] . However in this case, cyclisation did not occur even under forcing conditions, with demethylation of the methoxy groups being observed. Scheme 4 Alternative retrosynthesis of 1 . Because the alternative route proved unsuccessful, we returned to the initial Buchwald-Hartwig coupling route ( Scheme 2 ) and undertook an examination of all the components of the reaction: palladium source, ligand, base and solvent. The intent was to identify a set of conditions that could deliver at least 100 mg of final compound. Table 1 highlights a selection of the conditions tested, demonstrating the range of variables assessed and that the majority of conditions gave poor results. Starting material 4a was detected by liquid chromatography–mass spectrometry (LCMS) in most cases, alongside two major byproducts: debrominated starting material 17a and demethylated starting material 18a (particularly when using sodium tert -butoxide or potassium triphosphate as a base). Where product 16a was detected, the conversion was generally poor (0–23%). The choice of base appeared to be a key factor, as potassium hexamethyldisilazide (KHMDS, a strong non-nucleophilic base) gave significant improvements in conversion (52% by LCMS) with no evidence of remaining

4a or the byproducts 17a and 18a . Cesium fluoride (a non-nucleophilic and less sterically hindered base) gave no conversion to product with only starting material detected, presumably due to its lower base strength compared to KHMDS. Table 1 Effect of alternative conditions on the Buchwald-Hartwig coupling to give 16a . Catalyst Solvent Base Phosphine 16a e 4a e 17a e 18a e Pd 2 dba 3 Dioxane Cs 2 CO 3 Xantphos 5 16 50 – Xantphos a 7 45 30 – RuPhos 4 52 27 – KHMDS Ruphos 54 – – – DME Cs 2 CO 3 Xantphos 6 23 49 – RuPhos 19 21 40 – t BuONa BINAP 0 – – 53 DPEPhos 0 – – 45 Toluene Cs 2 CO 3 RuPhos 9 60 25 – 

 Pd(OAc) 2 Dioxane Cs 2 CO 3 Xantphos b 22 – 51 – Xantphos a 17 43 – – t BuOK Xantphos a 21 24 33 – KHMDS Ruphos c 52 – – – DME t BuONa SPhos 0 50 5 25 tBuXPhos 0 34 – 25 2-(dicyclohexylphosphino)biphenyl 0 20 – 56 K 3 PO 4 SPhos 0 68 17 8 Brettphos 0 58 30 10 Cs 2 CO 3 Ruphos 0 16 40 – Toluene Cs 2 CO 3 Xantphos 0 23 18 – RuPhos 0 15 9 – t BuONa BINAP d 0 28 – 39 Reactions were carried out on 50 mg scale using 4a , 5 mol% catalyst, 3.5 eq. base, 5 eq. racemic 3-methylmorpholine and 10 mol% ligand. a 10 mol% catalyst, 2.8 eq. base, 10 eq. racemic 3-methylmorpholine and 12 mol% ligand. b 10 mol% catalyst, 2.8 eq. base, 5 eq. racemic 3-methylmorpholine and 12 mol% ligand. c 5�

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry — Balaram S. Takale et al., 2022

1. IntroductionMetal catalyzed cross couplings have played a crucial role in different stages of drug development. For example, the drug discovery stage requires multiple compounds to be tested for the best biological activity, wherein rapid access to the chemical matter is very important. The ability of cross-coupling reactions to quickly derivatize the core compound results in the multiple compounds available for biological studies. The aim at this stage remains to get the compound in milligrams scale. This scenario changes rapidly as the compound moves to the next stage of development, where only a few out of many compounds are selected for toxicology and animal studies. The required amount of compound then increases to 10–100 g, and most of the time, the chemistry used to make the compound in milligram scale will be replicated in this case. Once the compound enters the development phase, several factors need to be considered. At this stage, “how” instead of “what” is important—how to make the compounds efficiently, quickly, and safely with the best quality is given prime importance. Nevertheless, process chemists were quite hesitant to use Pd-catalyzed reactions given the high toxicity of residual Pd content in the final drug substance. According to Food Drug Administration (FDA), ≤10 ppm Pd is allowed per dose [1,2]. This suggests that the old practice of cross-coupling reactions done using 5–10 mol% (50,000–100,000 ppm) Pd catalyst would most probably lead to very high residual Pd. Hence, a tedious and costly downstream Pd cleaning process would be required. The recent advances both in the actual development of efficient Pd catalysts [3,4] and Pd scavenging processes [5] have mostly solved this issue. How these two pathbreaking coupling reactions, Suzuki–Miyaura and Buchwald–Hartwig, are becoming the essence of drug development is discussed in this review. The detailed structure of ligands and catalysts used in the work described in this review is also given in Figure 1. 2. Suzuki–Miyaura CouplingThe Suzuki–Miyaura coupling remains a matured technology widely used in industrial synthesis. Although the initial discovery happened in 1979, the coupling’s real applicability was realized most recently, owing to the discovery of new metal catalysts and bulky ligands that could couple complex starting materials. This success led to the Nobel prize in 2010 [

6]. This reaction is so fundamentally and mechanistically well understood that it is possible to forge any complex C-C bond from the respective aryl halide and aryl boron reagents. The Suzuki–Miyaura coupling is one of the widely used reactions in pharmaceutical synthesis. For example, St-Jean and coworkers [7] from Genentech developed an efficient late-stage synthetic method for PI3K β-Sparing Inhibitor taselisib 6 [8], which has been demonstrated to have increased activity against PIK3CA mutant breast cancer. A one-pot Miyaura borylation, Suzuki–Miyaura coupling, and saponification to produce 5 from 1 were described. Extensive palladium catalyst screening indicated only the Buchwald XPhos G1 and G2 pre-catalysts [9] were able to achieve full conversion to boronate ester 2, with G2 selected after further optimization; 90 mol% of 3, which was synthesized on a kilogram scale through four steps, and 200 mol% of 1 M LiOH were added directly to the reaction vessel following borylation to carry out the Suzuki–Miyaura coupling. Remarkably, only 0.3 mol% of Pd catalyst was used to perform these two steps. After full conversion to 4, more LiOH was added to carry out saponification. Acidification with the addition of aqueous HCl provided 5 as a solid. An 88% yield and >98 A% purity was achieved for 5 on a kilogram scale (Scheme 1). Overall, the development of this one-pot synthesis of 5 lowered the process mass intensity (PMI) of the entire route significantly from previous reports. Due to the corrosivity of HCl and foaming issues during acidification, the plant scale acidification was run in n-propanol and H2SO4. The use of n-propanol also helped to purge Pd to <40 ppm vs. ~400 ppm.Akin and coworkers [10] from Pfizer designed a new synthetic method for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor PF-06815345 (13) [11], a potential treatment for decreasing serum LDL-cholesterol levels and reducing the risk of coronary heart disease. The precursor to 13•HCl is formed through a Suzuki–Miy

aura coupling of intermediates 10 and 11. A Buchwald–Hartwig amination is involved in the first step towards synthesizing 9, and a yield of 77% was achieved for the amination product. Optimization of the Suzuki–Miyaura coupling focused on minimizing various side products formed. The most attention was paid to a homodimer side product that was caused by higher oxygen levels of the reaction solution. Additional precautions and adaptations were made to the reaction protocol, including nitrogen purging, installing oxygen sensors, and ordering palladium catalysts from vendors in presubdivided ampules, to minimize the formation of the side product. Extensive screening also indicated that Pd(0) catalysts, in general, performed better than their Pd(II) counterparts, with Pd(PCy3)2 achieving the best results. This reaction scaled up well, achieving >99% conversion on a kilogram scale (Scheme 2).Goundry and coworkers [12] from AstraZeneca developed a large-scale synthetic route to ATR Inhibitor AZD6738 17 [13], a potential drug candidate in Phase I/II trials for treating both solid and hematological cancers. Due to time pressure, major changes were not made to the discovery route. Rather, the conditions for each chemical transformation were optimized and scaled up. The penultimate step in the synthesis of 17, which became the ultimate step in the new route due to the elimination of a deprotection step, is a Suzuki–Miyaura coupling to install the azaindole structure from boronate ester 16. On a kilogram scale, the catalyst system of (DTBPPS) palladium was tested as DTBPPS is a water-soluble ligand that would allow the palladium to be largely removed via aqueous washes. However, at 0.5 mol% of the catalyst, the reaction stalled at 5% conversion and could not be restarted by adding more catalyst or base. Therefore, the team reverted to Pd(PPh)3Cl2 conditions. On a plant scale, a screening of catalyst and ligands showed Pd(dppf)Cl2 to be a superior catalyst. The HCl salt of 15 was used, which necessitated the addition of an extra equivalent of the base. The reaction used ethanol as a solvent and achieved complete conversion in 2 h, with an average yield of 88% between

Third Generation Buchwald Precatalysts with XPhos and RuPhos: Multigram Scale Synthesis, Solvent-Dependent Isomerization of XPhos Pd G3 and Quality Control by — Svitlana O. Sotnik et al., 2021

1. IntroductionPalladium complexes with phosphine ligands are widely used catalysts in fine organic synthesis, particularly for C–C [1,2,3] and C–heteroatom [4,5] cross-coupling, homocoupling [6,7] and metathesis [8,9] reactions. During the last two decades, significant advances were achieved in the development of precatalysts of this type, and at present, several generations of the precatalysts are distinguished [1,2,4]. Among them, Buchwald precatalysts based on dialkylbiaryl phosphines of the third generation (G3)—so-called “Phos Pd G3 precatalysts” of composition Pd(ABP)(Phos)(OMs) (where ABP is the residue of 2-aminobiphenyl after one H atom elimination, Phos is specially designed phosphine, OMs− = CH3SO3−, Figure 1)—are of special interest due to their high catalytic activity compared to complexes of more “simple” structures, such as classical Pd(PPh3)4 [1,4,10]. The advantages of PdG3(Phos) systems include high activity along with stability in solutions and reasonable tolerance to air and moisture [11,12,13]. In the reaction mixture, Pd(ABP)(Phos)(OMs) complexes undergo reductive transformation producing active PhosPd(0) species, which directly participate in the catalytic cycle [3,4] (for this reason, the complexes Pd(ABP)(Phos)(OMs) are usually referred to as “the precatalysts”, which form “the catalysts” in situ).Catalyst quality plays an important role in the success of the catalytic transformations. From our own experience, there are several reasons to control the quality of the Pd(ABP)(Phos)(OMs) precatalyst when it is purchased from a commercial source or synthesized in laboratory for in-house scientific research purposes [14]. First, the sample may contain unreacted starting materials, such as [Pd(ABP)(OMs)]2, or other nonidentified coordination compounds, such as phosphine oxide, that, in the best case, play a role of inert �

�ballast” but can also induce unwanted side reactions. Second, the sample may contain residues of solvents used in its synthesis, especially solvents such as CH2Cl2, which appear to introduce unwanted reactive impurity for some processes. Third, partial decomposition of the complex may take place if the storage conditions are not complied with, leading to reduced catalytic performance of the sample. In all these cases, different samples may have significantly different catalytic activity, which cannot be foreseen. It is important to note that common methods for the purification of coordination compounds are not efficient in this case, because the complexes of the Pd(ABP)(Phos)(OMs) family are sensitive to air and heating. For example, our multiple attempts to purify such compounds by recrystallization usually gave the samples a similar purity (presumably due to formation of new impurities during the process); drying of the solids in vacuo to remove residues of the solvent almost never gave the desired result, but sometimes led to the partial decomposition of the sample. For these reasons, in-house production of the precatalysts for research purposes can be a more simple alternative compared to the analysis of commercially available samples or the elimination of the residues of specific solvents which are not desired for a certain application (instead, other solvent can be used for synthesis, the residues of which are not harmful for further stages of the catalyst use).Therefore, the development of a simple method for estimating the purity of the precatalysts, which can be used for their rapid everyday quality control (QC), is an important task. The problem of QC in this case cannot be effectively solved using many physical and physicochemical methods, because they are not sensitive enough to detect even 12% of impurities (elemental analysis, infrared or electronic spectroscopy) or do not provide reliable information on the impurities (single crystal XRD analysis of an arbitrarily chosen crystal; powder X-ray diffraction of bulk sample, since the impurity may be noncrystalline or chromatography with mass spectrometry, since the impurity may decompose on the column, giving fragments with high volatility that merge with the solvent or do not give distinct patterns in the MS). Thus, the determination of the impurities by many methods can be labour- and time-consuming and require complex equipment, while not giving reliable results.In order to develop a simple and reliable method

for the QC, we examined the NMR spectra of the Phos Pd G3 precatalysts. A similar approach was previously proposed to analyse the purity of Pd(II) acetate [15,16,17] and the complex of Pd(0) with dibenzylideneacetone [18], and in our experience, these methods appeared to be very efficient for the regular QC of these compounds.In the present study, the possibility of estimating the purity of the G3 precatalysts Pd(ABP)(Phos)(OMs) with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) by 1H- and 31P-NMR was demonstrated, and equations to determine the percentage of impurities in these compounds on the basis of their 1H-NMR spectra were derived. For this aim, the majority of signals in NMR spectra were assigned to certain nuclei using various techniques of 1D and 2D NMR spectroscopy. The reversible isomerization of Pd(ABP)(Phos)(OMs) upon solvent change was studied. Taking in mind the high importance and wide use of the Buchwald precatalysts in modern organic chemistry, we also isolated and identified several impurities in the precatalysts. The knowledge of the structure of such impurities can be helpful for the analysis of possible side reactions in fine organic synthesis. 2. Results and Discussion 2.1. Synthesis and X-ray Structures of the ComplexesThe third generation Buchwald precatalysts Pd(ABP)(XPhos)(OMs) are commonly prepared in three steps [11]. At the first step, 2-ammoniumbiphenyl mesylate is obtained from 2-aminobiphenyl and methanesulfonic acid [11]. Then, dimeric palladacycle [Pd(ABP)(Oms)]2 (1) is synthesized from palladium acetate and 2-ammoniumbiphenyl mesylate.From the solution remaining after crystallization of 1, we obtained complex 2, isolated as two sol

Pd-indenyl-diphosphine: an effective catalyst for the preparation of triarylamines. — Meng-Qi Yan et al., 2016

Scheme 1. Syntheses of Phosphine Ligands 1 and 2

Ligands 1 and 2 were applied in the palladium-catalyzed Buchwald-Hartwig coupling reaction of diphenyl amine with aryl chloride. The cross-coupling reaction between diphenyl amine and chlorobenzene was chosen as the model system (Scheme 2). Besides ligands 1 and 2, various structural monophosphine ligands were also examined for comparison. The reactions were carried out at 90 degC in DME for 24 h with Pd(dba) 2 as the catalyst precursor. Whereas low conversions were generally observed in this challenging crosscoupling reaction with ligands such as (2-mesityl-1H-inden-3-yl) dicyclohexylphosphine (6), CyJohnPhos (7) BrettPhos (10) and RuPhos (11), it is gratifying to report that ligand 2 and XPhos (9) provided a rapid conversion and excellent yields (81 % and 85 %, respectively). Since ligand 1, 2, and 8 possess the same lower aryl ring, their dramatic difference in reactivity clearly demonstrates the influence of the steric and electronic properties of the upper ring on their reactivity. We hypothesized that the bulky sterically hindered and relatively electron-rich nature of 2 compared to DavePhos (8) facilitates the key transmetallation step of this reaction. 5

Scheme 2. Ligand Screening for Buchwald-Hartwig Coupling of Chlorobenzene and Diphenylamine

Deprotonation of indene by base has been well-documented. We believe that the reaction of 1 and 2 with tBuONa in DME can generate the anionic ligand in situ, and the strong electron-donor ability of the indene anion may increase the electron density at phosphorus and improve the reaction rate as a result. To provide support for this finding, we undertook a series of 31 P NMR studies. When two equivalents of tBuONa was added to a solution of ligand 1 in DME, a red solution was formed immediately, the resonance for the ligand (d = -15.65 ppm) disappeared, and another new signal appeared ( d = -19.65 ppm), corresponding to anionic phosphine

ligand. Whereas, when two equivalents of tBuONa was added to a solution of ligand 2 in DME, a black-red solution was formed immediately, the two resonances for the ligand (d = 9.19 ppm and d = -20.18 ppm) disappeared, and another new signal appeared (d = - 15.79 ppm) corresponding to the anionic diphosphine ligand (See Supporting Information).
Many researchers have proved that the Pd-arene interaction is very important in Pd-catalyzed cross-coupling reactions. Despite numerous attempts employing various conditions, we have not been able to obtain structural information on the 1(anion)/2(anion)-Pd oxidative addition complex using X-ray crystallography. Thus, we turned to DFT calculations in order to gather insight into the structural framework of the oxidative addition complexes based upon 1(anion)-Pd(Ph)Cl, 2(anion)- Pd(Ph)Cl, and 8-Pd(Ph)Cl. The starting structure of 8-Pd(Ph)Cl was obtained from Buchwald et al. 6 In this case, we located two possible complexes by performing ground-state energy optimization on the oxidative addition product of 1-Pd and chlorobenzene (Figure 1). Complex 2 (anion)-Pd(Ph)Cl possesses two Pd-arene interactions with the non-phosphinecontaining ring of the ligand: Pd-C (2.85 A) and Pd-N (2.61 A). On the contrary, complex 1(anion)-Pd(Ph)Cl only possesses Pd-C (2.83 A) and/or Pd-N (3.33 A) interactions with the nonphosphine-containing ring of the ligand and complex 8-Pd(Ph)Cl only shows a Pd-N (2.59 A) interaction with the non-phosphinecontaining ring of the ligand. The larger the distance between Pd-arene, the lower the catalyst rate. Therefore, 2 took on the largest catalyst rate (81%) compared to 1 (47%) and 8 (68%). We believe that the ability of anionic 2 to stabilize the Pd(II) center of the oxidative addition complex through labile Pd-C and Pd-N interactions was

mainly responsible for the effectiveness of 2 as a supporting ligand in Pd-catalyzed cross-coupling reactions. The high effectiveness of ligand 2 observed in the coupling reaction between chlorobenzene and diphenyl amine encouraged us to study the substrate scope in the Buchwald-Hartwig coupling reaction of substituted aryl chlorides and the results summarized in Scheme 3. In most cases, different aryl chlorides reacted with diphenyl amine leading to their corresponding products in good yield. For example, the reaction of chlorobenzene with diphenyl amine gave rise to the corresponding tertiary amine in 81 % yield (10), coupling reactions of aryl chlorides bearing electron-donating substituents such as -Me and -OMe at the para and meta positions with diphenyl amine went smoothly, providing moderate to high yields of the expected products (70 %-80 % yield) (11, 12, 13, 14). The reaction of aryl chlorides bearing electronwithdrawing groups such as -CF 3 and -F at the para position also permit the coupling reaction with diphenyl amine, giving the required products in moderate to good yields (15, 16). Moreover, the base-sensitive -CN group was tolerated using our catalytic system and the corresponding triarylamine (17) was obtained in 62 % yield. In addition, 2-chloronaphthalene underwent the desired coupling reaction with diphenylamine, giving the triarylamine product in 65 % yield (18).

Scheme 3. Synthesis of Triarylamines from Chlorides and Diphenyl amine

To further demonstrate the general applicability of our catalyst system, we studied the Buchwald-Hartwig amination reaction with substituted aryl bromides (Scheme 4). We adopted the optimized reaction conditions to the amination of various aryl bromides with diphenylamine. 1-Bromo-4-butylbenzene, 1-bromo-3, 4, 5trimethoxybenzene, 1, 3-dibromobenzene and 4-bromostyrene could be aminated smoothly to give the triarylamine products in satisfactory yields (Scheme 4, 19, 20, 21, 22). In addition, sterically hindered aryl bromides

Buchwald–Hartwig Amination of Nitroarenes — Fumiyoshi Inoue et al., 2017

COMMUNICATION

Subsequently, we studied the scope of the nitroarenes in this reaction, using 2a as the amine-coupling partner under the previously established optimized reaction conditions (Table 2). The amination of 1a, nitrobenzene (1b), 4-nitrobiphenyl (1c), 4methoxynitrobenzene (1d), and 3,5-xylylnitrobenzene (1e) on a 0.60 mmol scale afforded the corresponding aryldiphenylamines in good yields (entries 1-5). An acetal-protected acetyl group was tolerated (entry 6), and the nitro group of 4fluoronitrobenzene (1g) was substituted exclusively by 2a (entry 7). It should be noted here that classical aromatic nucleophilic substitution reactions usually convert the fluoro group of 1g to an amino functionality as in 9-(4-nitrophenyl)-9H-carbazole (1h), which would subsequently react with 2a under modified reaction conditions (entry 8). Modifications of the aminations, i.e., choice of ligands and/or base, allowed nitroarenes bearing sterically demanding substituents 1i and 1j (entries 9 and 10) or a Lewisbasic functional group 1k and 1l (entries 11 and 12) to participate in the transformation. Nitronaphthalenes 1m and 1n can be cross-coupled with bis(4-tert-butylphenyl)amine (2b) to give the corresponding diarylnaphthylamines (3mb and 3nb; entries 13 and 14). Heteroaromatic nitro compounds such as 3nitropyridine and 2-nitrothiophene did not afford the corresponding triarylamines, whereas 1-methyl-5-nitroindole (1o) furnished the corresponding amination product in 52% (entry 15). Thereafter, we examined the scope of amines using 4nitroanisole (1d) as an electrophile, K3PO4*nH2O, and 1,4dioxane as a reaction solvent, which gave superior yields in these cases (Table 3). We discovered that polar solvents were necessary due to the limited solubility of the

amines in other solvents, and that K3PO4nH2O performed better than K3PO4 in polar solvents. Indeed, the reaction of aniline (2c) afforded the corresponding diarylamine 3dc, while the corresponding triarylamine was not detected, i.e., 3dc was not consumed as a nucleophile, probably on account of steric reasons (entry 1). NMethylaniline (2d) participated in the amination albeit in modest yield (entry 2). Piperidine (2e) can also be used in this transformation and furnish the corresponding tertiary amine in 61% yield (entry 3). 3,5-Xylylnitrobenzne (1e) was efficiently aminated by benzylamine (2f) (entry 4), whereas simple alkylamines such as hexylamine (2g) were also suitable for this reaction (entry 5). In both cases, tertiary amines were not obtained. A plausible reaction mechanism for the amination of nitroarenes is described in Scheme 1. As previously demonstrated, nitroarenes react with palladium(0) comlex A to form e 2 -arene-palladium(0) complexes such as B. This step is followed by oxidative addition the C-NO2 bond to afford C. Subsequently, an amine nucleophile could react with C in the presence of a base to afford arylpalladium amide D, which could reductively eliminate arylamine 3 and concomitantly exchange the arene ligands to regenerate A. Oxidative adduct 4 was prepared according to our previous report and was reacted with 2f at 50 degC in the presence of K3PO4nH2O to furnish Nbenzylaniline in 53% yield (eq. 1). This result supports the proposed catalytic cycle, in which the oxidative addition is turnover-limiting. In summary, we have developed the Pd-catalyzed Buchwald-Hartwig amination of nitroarenes. Using conventional Buchwald-Hartwig ligands allowed us to transform a range of substituted nitrobenzenes into triarylamines, diarylamines, alkylarylamines, and dialkylarylamines in moderate to good yields. Further efforts to develop novel coupling

processes through Ar-NO2 bond cleavage are currently underway in our laboratories and will be reported in due course.

Experimental Section

A 15-mL vial was charged with Pd(acac)2 (9.1 mg, 0.030 mmol), BrettPhos (0.090 mmol), 1 (0.60 mmol), and brought into a nitrogen-filled glovebox. In the glovebox, to the vial K3PO4 (382 mg, 1.8 mmol), 2 (0.90 mmol or 1.8 mmol), and n-heptane 3.0 mL) were added. The vial was sealed with a Teflon screw cap and taken out of the glovebox. The resulting mixture was stirred for 24 h at 130 degC. After the reaction, the mixture was filtered through a pad of Celite (r) . All volatiles were removed in vacuo and the residue was purified by medium pressure liquid chromatography (MPLC) using Biotage (r) SNAP Ultra to give the corresponding product. The following manipulations were performed before purification in some cases: To the crude, Et2O (10 mL) and H2O2 (30 wt% in H2O, 1.5 mL) were added and the resulting mixture was stirred for 10 minutes at room temperature. H2O (10 mL) was added and the organic layer was separated. The remained aqueous layer was washed with EtOAc (10 mL) and the organic layer was combined, dried over MgSO4, and filtered.

Enantioselective Synthesis of Arylglycines via Pd-Catalyzed Coupling of Schöllkopf Bis-Lactim Ethers with Aryl Chlorides — Daniel Sowa Prendes et al., 2023

Optically active arylglycine derivatives are common motifs in bioactive compounds, such as the penicillin derivative amoxicillin, the metabotropic glutamate receptor antagonist α-methyl-4-carboxyphenylglycine (MCPG) and the antiplatelet drug clopidogrel (Figure 1).

              Figure 1Open in figure viewerPowerPoint


                 Pharmaceutical relevant chiral arylglycine derivatives.




     Enantioenriched arylglycines are usually synthesized from (dynamic) kinetic resolution of racemic esters,1 amides,2 or hydantoins.3 They are also accessible via asymmetric variants of the Strecker4 and the Petasis-Borono Mannich reaction,5 via asymmetric hydrogenations of N-aryl α-amino esters,6 asymmetric N−H insertions,7 α-amination of carboxylic acids8 or Tayama's variant of the asymmetric Sommelet-Hauser rearrangement (Scheme 1a).9




              Scheme 1Open in figure viewerPowerPoint




                 Stereoselective arylation of glycine synthons.




     In the context of drug-discovery, it is desirable to couple functionalized arenes with chiral synthons to introduce the entire amino acid functionality within one step. This can be achieved in a diastereoselective manner starting from arylboronic acids and chiral N-tert-butanesulfinyl imino esters using the protocols by Ellman10 or Lu11 (Scheme 1b). Catalysts with chiral bis-oxazoline allow enantioselective arylations of prochiral α-imino esters (Scheme 1c).12 Similar additions of aryl nucleophiles to in situ prepared imine derivatives have also been achieved using redox chemistry13 or via three-component reactions.14 However, all of these methods suffer from the high price and limited availability of nucleophilic aryl sources.

     In contrast to arylglycines, aliphatic amino acids can easily be generated from glycine synthons and electrophilic substrates. The Schöllkopf synthesis, in which bis-lactim ethers react in a highly diastereoselective manner with abundant alkyl halides, is a widely used protocol for accessing non-natural alkylamino acids.15 Its popularity arises from the straightforward synthesis of enantioenriched bis-lactim ethers from glycine and a chiral-pool amino acid, its high diastereoselectivity, and the easy deprotection of the amino acid products. Unfortunately, this attractive synthetic concept does not extend to most arylglycines, as arylations of this chiral glycine synthon are only possible via (non-reg

iospecific) Friedel–Crafts or aryne pathways or using stoichiometric arene-manganese complexes.16

     A catalytic variant of the Schöllkopf reaction, in which the aryl halide substrates are coupled with bis-lactim ethers at customized palladium catalyst would be of high synthetic value (Scheme 1e). It would compare favorably to the few known Pd-catalyzed diastereoselective arylations of amino acid synthons, i.e., the Pd-catalyzed arylation of environmentally problematic nickel glycinates by Xu and Sun (Scheme 1d)17 and the arylation of chiral nitrones by Blandin.18 Both require high temperatures and reactive aryl bromides. The latter is furthermore restricted to quaternary products, which are more easily accessible than arylglycines, e.g. via asymmetric rearrangements,19 chiral aldehyde catalysis20 or phase-transfer catalysis.21

     Our mechanistic blueprint of the target reaction is outlined in Scheme 2. The initiating oxidative addition of the aryl chloride 1 to the Pd-catalyst calls for bulky, electron-rich ligands. The metalation of the bis-lactim ether 2 with formation of the organozinc reagent ZnCl-2 is likely to proceed in a diastereoselective fashion. However, the diastereomeric ratio (dr) of the product is unlikely to be fixed prior to the transmetalation of ZnCl-2 to the palladium center. Bulky ligands should be advantageous in this step, as these would favor—or preserve—an anti-configuration of the metal center and the amino acid residue R. The C-palladated species III should be set up for the desired C−C bond formation via a reductive elimination step. However, when probing the validity of this reaction design, we observed mainly the formation of pyrazine 4 and dehalogenated arene 5. This suggested that III is in equilibrium with η3-heteroallyl complex IV, and the η1

Phenylboronic Ester-Activated Aryl Iodide-Selective Buchwald-Hartwig-Type Amination toward Bioactivity Assay. — Raghu N Dhital et al., 2022

Carbon–nitrogen
bond-forming aminations are one of the most
important research topics in modern synthetic organic chemistry. 1 Among the various C–N bond-forming reactions,
the Buchwald–Hartwig reaction is a well-known palladium-catalyzed
C–N bond-forming cross-coupling reaction. 2 However, palladium is expensive and not an earth-abundant
metal; therefore, the replacement of palladium with nickel, an inexpensive
earth-abundant metal, is desirable for this reaction. Indeed, many
nickel-catalyzed carbon–nitrogen bond-forming reactions have
been reported. 3 Nickel-catalyzed cross-coupling
reactions usually require a bulky ligand bearing a large bite angle,
which assists the reductive elimination step. 3a − 3e Recently, a ligand-free nickel-photocatalyst dual-catalyzed
amination reaction was also reported. 4 Here,
the photocatalyst assists nickel to undergo reductive elimination.
In both cases, reductive elimination is the rate-determining step. 4a
We recently reported a nickel-iodide-catalyzed
activator-promoted
halogen-dependent chemoselective cross-coupling reaction of aryl halides. 5a In this reaction, the aryl chlorides undergo
the Suzuki–Miyaura-type coupling, which is activated by the
aryl amines ( Scheme 1 a, bottom). In contrast, aryl iodides undergo a C–N bond-forming
Buchwald–Hartwig-type amination, which is activated by phenylboronic
acids/esters ( Scheme 1 a, top). A boron-amine ate complex ( Scheme 1 a) appears to be a common intermediate in
both reactions. Although these phenomena are interesting in terms
of catalytic selectivity, reactions with multi-halide-containing substrates,
such as 4-iodo-1-bromobenzene or 4-iodo-1-chlorobenzene, produce a
complex reaction mixture, indicating the nonselective nature of the
nickel iodide catalyst toward aryl halide species ( Scheme 1 b). Because halogen-containing N -aryl aniline derivatives exhibit pharmaceutical and biological
activities, 6 a

ryl iodide-selective nickel
catalysis should provide straightforward access to bromo- or chloro-containing
biologically active molecules. In this study, a highly aryl iodide-selective
C–N bond-forming cross-coupling reaction was developed using
Ni(acac) 2 as the catalyst ( Scheme 1 c). Moreover, mechanistic studies and biochemical
assay screening of the synthesized C–N bond-forming cross-coupling
products were performed.
Nickel catalysts were screened for the aryl iodide-selective C–N
bond-forming amination ( Table 1 , entries 1–8; for more details, see the Supporting Information (Section 2)). When the
reaction of 1-chloro-4-iodobenzene ( 1b ) and toluidine
( 2a ) was carried out with phenylboronic ester ( 3a ) and 0.5 mol % Ni in the form of Ni(acac) 2 ,
the C–I bond selectively reacted with 2a to give
the corresponding amination product 4b with 94% yield.
Here, the C–Cl bond was almost intact (entry 1). The same reaction
did not proceed in the absence of 3a (entry 2). These
results suggest that phenylboronic ester acts as an activator. The
reaction of nickel iodide (NiI 2 ), which provided halogen-dependent
chemoselective cross-coupling, 5a afforded
a 21% yield of 4b , where the C–I and C–Cl
bonds underwent the reaction (entry 3). While NiI 2 reacts
with both aryl iodides and chlorides unselectively, Ni(acac) 2 does only with aryl iodides (for more details, see the Supporting Information (Section 2.4)). NiCl 2 and NiCl 2 (dme) produced 59 and 72% yields of 4b , respectively (entries 4 and 5). Nickel(0) catalysts, Ni(PPh 3 ) 4 and Ni(cod) 2 , promoted the formation
of 4b in 19 and 11% yields, respectively (entries 6 and
7). The chemical yield of the Ni(acac) 2 ·2H 2 O-catalyzed reaction was significantly lower than

that of the anhydrous
Ni(acac) 2 -catalyzed reaction (entries 1 and 8). Palladium
catalysts were found to be ineffective for this transformation because
they promoted the corresponding C–C bond-forming Suzuki–Miyaura-type
reaction (entries 9–11).
Reaction conditions: 1b (1.0 mmol), 2a (3.0 mmol), 3a (1.3 mmol),
and K 3 PO 4 (3 mmol). The yield was determined
by GC analysis using mesitylene as an external standard.
Without 3a .
After optimizing the reaction conditions,
we investigated the substrate
scope of several aryl iodides ( Table 2 ). The reactions of the multi-halide-substituted aryl
iodides exhibited high selectivity for the C–I bond. When 1-bromo-4-iodobenzene 1a was reacted with toluidine ( 2a ) under the
optimized reaction conditions, a 78% yield of 4-bromo- N -( p -tolyl)aniline 4a was obtained.
Similarly, p -chloro-, 1,3-dichloro-, and p -fluoro-substituted aryl iodides also selectively underwent
the desired amination reaction to afford 4b – 4d in 80–91% yield. The steric perturbations of the
benzene ring of the aryl iodide had no significant effect on the product
outcome. The reaction of 1-iodo-3,5-dimethyl benzene ( 1e ) generated the desired amination product 4e in 97%
yield. Substrates bearing electron-donating groups, such as p -methoxy ( 1f ) or p -ethoxy
( 1g ) groups, furnished the desired products in 95% yield.
However, electron-withdrawing groups such as p -CF 3 ( 1h ) had no significant effect on the product
outcome and provided the desired 4h in 96% yield. The
substrate with the bulky butyl group at the para -position
furnished the product with a 95% yield ( 4i ). The reaction
with o -, p -, and m -tolyliodides afforded amination products

Concatenating Suzuki Arylation and Buchwald–Hartwig Amination by A Sequentially Pd-Catalyzed One-Pot Process—Consecutive Three-Component Synthesis of C,N-Diarylated Heterocycles — Laura Mayer et al., 2020

Pd-catalyzed carbon–carbon and carbon–nitrogen bond formations by Suzuki arylation and Buchwald–Hartwig amination currently represent the most versatile and powerful synthetic tools for providing complex molecules in fundamental and applied research due to the easy availability of starting materials, the simplicity and generality of the methods, and the broad tolerance.1 Continuous tuning of ligands and precatalysts has set the stage for rich applications in the preparation of pharmaceuticals, agrochemicals, as well as advanced multifunctional materials.2 Among numerous C,N-bis(hetero)-arylated heterocycles, di(hetero)arylated indoles and carbazoles are interesting targets as privileged scaffolds in anticancer research (Figure 1). While 2,3-bisarylmaleimides bearing N-aryl indole moieties were identified as potent and selective inhibitors of protein kinases C (PKC),3 a simple N-(ortho-anisyl)-3-biphenylindole shows lower micromolar inhibition of the hedgehog signaling pathway,4 which represents a novel therapeutic principle in the treatment of certain cancers. In addition, N-phenylindolylanilines were found to inhibit the proliferation of HCT-116 human colon carcinoma cells at nanomolar concentrations.5 Non-canonical DNA i-motif selective ligands based on N-aryl-3-triazolyl carbazole have just recently been shown to modulate the transcription of cellular oncogenes.6

              Figure 1Open in figure viewerPowerPoint


                 C,N-Di(hetero)arylated indoles and carbazoles with considerable anticancer activity.






     The contemporary increasing relevance of sustainability and environmental awareness has posed the challenge of high catalyst efficiency and efficacy. Therefore, the catalyst economical use of a single metal catalyst for several organometallic catalytic processes in a single reaction vessel as a one-pot sequence enables simultaneously operational simplicity, generation of molecular complexity as well as saving of resources.7 Implementation of one catalyst for two or more mechanistically related reactions leads to sequential or tandem catalysis.8 Indeed, by the nature of the sequences distinctions are made between metal-catalyzed domino, tandem or cascade processes.9 Based upon the concept of sequentially metal-catalyzed processes employing simple starting materials structural complexity is quickly reached for diversity-oriented synthesis of functional molecules.10 Identifying suitable catalysts for concatenation of different reactions in a one-pot fashion as well as determination of matching reaction conditions remains a major challenge in devising highly practical sequentially catalyzed processes.7c, 11 Herein, we communicate our first findings on a novel sequentially Pd-catalyzed consecutive multicomponent synthesis of C,N-diaryl substituted heterocycles, for example, phenothiazines, carbazoles and indoles.

     Conceptually, this novel one-pot approach relies on the Pd-catalyzed Suzuki coupling of NH-bearing heteroaryl bromides with (hetero)arylboronic acids or esters, where the catalyst source en route catalyzes a Buchwald-Hartwig amination without further catalyst addition. Based upon the general interest in diversely substituted phenothiazines potent versatile donor units in diverse organic electronics12 for application in organic light-emitting diodes,13 organic photovoltaics,14 and as photoredox catalysts15 we were inspired to devise a consecutive three-component synthesis of 3,10-diaryl 10H-phenothiazines by sequential arylation with boronates and arylhalides. According to our findings N-unsubstituted 3-bromo phenothiazines uneventfully undergo Suzuki arylations

with aryl boronic acids in boiling aqueous DME or 1,4-dioxane.16

     For preventing undesired side reactions, such as homocoupling in the first reaction step, we reasoned that Suzuki coupling should be performed prior to Buchwald–Hartwig amination. By choosing cesium fluoride as a weak base for the Suzuki step, deprotonation of the NH-bond and the resulting homocoupling of the 3-bromo-10H-phenothiazine (1) can be efficiently excluded. For Buchwald-Hartwig reactions alkoxide bases are common17 for deprotonation of the aryl-palladium-amine complex.18 In particular, NaOtBu has been shown to be appropriate for primary and secondary aliphatic and aromatic amines and phenothiazines.19 As a corollary, water-free conditions for the Suzuki coupling must be ensured since trace amounts of water will convert any strong base into relatively weak hydroxides, reducing the efficiency in the Buchwald-Hartwig reaction of secondary amines.18

     After a thorough optimization of this novel sequentially Pd-catalyzed one-pot arylation-amination process (for details see Supporting Information), 3-bromo-10H-phenothiazine (1) and arylboronic acids and esters 2 can be transformed in the presence of catalytic amounts of Pd(dba)2 and [tBu3PH]BF4 and cesium fluoride as a base at 120 °C for 16 h, with subsequent addition of aryl bromide 3 and NaOtBu to give 3,10-diaryl 10H-phenothiazines 4 in moderate to very good yields (Scheme 1).




              Scheme 1Open in figure viewerPower

Role of the base in Buchwald-Hartwig amination — Ylva Sunesson et al., 2014

INTRODUCTION

Aryl amines are ubiquitous in natural products and druglike substances. As a consequence, the development of metalmediated protocols for their synthesis has been of immense importance in both industry and academia. A key example of this, the palladium-catalyzed Buchwald-Hartwig aryl amination (Scheme 1), 1 is now regarded as a vital tool in the organic chemist's synthesis toolbox. 2 Because of extensive experimental 3-5 and theoretical 4-7 investigations, we know much about the mechanism and special requirements of the Buchwald-Hartwig reaction. 8 A simplified catalytic cycle summarizing the more important findings is depicted in Figure 1. The precatalyst forms a Pd(0)-ligand complex that undergoes oxidative addition with the aryl electrophile, in common with most palladium-catalyzed coupling mechanisms. In the next step, the amine nucleophile is coordinated to the metal and deprotonated by the base. The catalytic cycle is closed by reductive elimination, yielding the final arylated amine product while regenerating the active catalyst.
Only certain ligands function well in this cycle. Among the most widely used are the Buchwald family of electron-rich monophosphine ligands. 9 Their mode of binding to the Pd center does in fact display some bidentate character through pcoordination from the second aryl ring, as has been shown both experimentally 10 and by crystallization of the intermediate complexes. 11 In Pd(II) complexes with hindered monodentate or hemilabile ligands like the biaryl phosphines, the strong trans effect of the aryl group allows the formation of T-shaped complexes where the position trans to the aryl group is empty, 12 opening a facile entry path for the amine substrate. The hemilabile behavior can also be displayed with some bisphosphine ligands, such as BINAP, allowing this class of ligand to also result in effective catalysis of the reaction (vide inf ra).
The detailed order of the coordination and deprotonation steps is still unclear, with several complexes in rapid and not easily studied equilibrium. 8 It is obvious from relative pK a values that the amine can be deprotonated by commonly used bases like alkoxides only if the amine has already been activated by coordination

to the metal. However, it is not known whether the base always has to coordinate first, expelling the leaving group X, or whether an external base can deprotonate the amine in a coordinatively saturated square planar palladium complex. The details of this part of the catalytic cycle may be important in determining which bases can be competent in the overall reaction.
Experimentally, it is necessary to distinguish between different types of amine nucleophiles. Anilines and other moderately acidic nitrogen functionalities like amides are easily arylated even when the base is relatively mild and/or unhindered (e.g., hydroxide and substituted phenolates). 13 On the other hand, dialkyl amines are more resistant to deprotonation and seem to require tert-butoxide or other alkoxide bases of similar basicity. 1c As a corollary, dialkyl amine arylation requires more rigorous drying than the corresponding aniline arylation, because trace water will convert any strong base to relatively weak hydroxide, reducing the efficiency in the reaction of alkyl amines.
This work stems from a project in which Buchwald-Hartwig amination is performed in flow. Successful implementations have already been reported by others 14,15 for the relatively simple and water-tolerant case of aniline arylation. For the purpose of this study, we wish to focus on a pharmaceutically relevant reaction between an aryl bromide and a dialkyl amine. Under these circumstances, bases such as t-BuOK or t-BuONa in combination with an aryl bromide will lead to production of KBr or NaBr, respectively, each of which has a low solubility in solvents that are compatible with arylation of alkyl amines 15 and are therefore incompatible with most flow reactors. In this work, we were interested in investigating whether it is possible to use an alternative, neutral base that will avoid precipitation in a relevant solvent (i.e., a solvent that will not react with strong bases).
We investigated our chosen reaction both experimentally and computationally. To facilitate the theoretical study, we chose experimentally relevant, small model systems to avoid extensive conformational equilibrations (Figure 2). As a starting point, we selected the simplest possible electrophile, phenyl b

romide, and a pharmaceutically relevant yet simple amine, morpholine. Of the experimentally competent ligands, the simplest is t-Bu 3 P, introduced into Buchwald-Hartwig amination by Nishiyama et al. 16 and shortly thereafter demonstrated to allow coupling at room temperature when Hartwig and co-workers used a 1:1 ratio of ligand to palladium. 17 The same model system was recently studied by McMullin et al., using similar computational methods. 6 Most of our computational studies have been performed with this small model system. On the basis of the results from the smaller system, we have also extended our study to include the BINAP ligand, as well as an alternative substrate, N-methylpiperazine. We have also challenged our predictions about reactivity under different conditions by experimental testing.
The most frequently used bases in the arylation of alkyl amines are tert-alkoxides; therefore, we chose the simplest representative of this class of base, t-BuO - , for our computational study. a Experimentally, both sodium and potassium salts work well. In the theoretical study, the counterion gives intractable problems with solvent coordination and conformation sampling. 18 Thus, we did not include the counterion in any of our calculations. We note that charge separation leads to high uncertainties in energies calculated with continuum solvation models and therefore avoid drawing conclusions from small calculated energy differences between complexes with different overall charges.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been demonstrated to function well in the arylation of anilines under microwave irradiation 19 and was therefore our primary candidate in the computational study. We were also interested in solvents with different polarities and how they would affect the preference for different mechanistic pathways with both types of bases. We therefore selected two solvents with ample experimental precedent, nonpolar toluene (simulated by continuum parameters for benzene) and polar aprotic DMF. Computationally, these were represented by continuum models.
DFT calculations were conducted at the B3LYP/LACVP* level, with corrections for dispersion as specified in the computational details. Geometries were determined in the gas phase, with thermodynamic and solvation corrections calculated at the final converged geometries. Only final free