Ligated Pd-Catalyzed Aminations of Aryl/Heteroaryl Halides with Aliphatic Amines under Sustainable Aqueous Micellar Conditions

Sustainable technology for constructing Pd-catalyzed C–N bonds involving aliphatic amines is reported. A catalytic system that relies on low levels of recyclable precious metal, a known and commercially available ligand, and a recyclable aqueous medium are combined, leading to a newly developed procedure. This new technology can be used in ocean water with equal effectiveness. Applications involving highly challenging reaction partners constituting late-stage functionalization are documented, as is a short but efficient synthesis of the drug naftopidil. Comparisons with existing aminations highlight the many advances being offered.


■ INTRODUCTION
−10 Given the ubiquitous nature of aliphatic amines in compounds of synthetic interest and the lack of alternative methodologies for their synthesis that are both mild and generally applicable, Pdcatalyzed aminations remain an important methodology in both academia and industrial laboratories. 11However, with the changing times, sustainability concerns associated with these reactions have spurred the need for methods that are both versatile and economical.Perhaps equally important have become the principles of green chemistry 12 that focus on safety, conservation of planetary resources, and the impact that C−N bond formations have on the environment.
Within the landscape of metal-catalyzed aminations featuring numerous methodologies, various approaches including group 10 transition metal-catalyzed aryl and heteroaryl aminations 13,14 and to a lesser extent Cu-catalyzed Ullmann couplings 15−18 have garnered extensive recognition for their applicability as well as their ability to accommodate a diverse array of functional groups. 19,20Considerable progress has also been made of late insofar as Chan−Evans−Lam couplings are concerned, 21 along with catalysts developed by Ma and coworkers 22 that have allowed a significant reduction in catalyst loadings and reaction temperatures.
−33 Additionally, N-heterocyclic carbene (NHC)-based precatalysts 26,29,34 have also shown promising activity in the coupling of secondary amines with unfunctionalized aryl halides.Notwithstanding their demonstrated potential, the applicability of most methods has generally been limited to relatively simple amines and coupling partners.Moreover, all are conducted in organic solvents, with some solvents being already prohibited, 35 and that additional significant drawbacks including generation of organic waste raise environmental concerns as it contributes to the depletion of our limited planetary petroleum resources.Furthermore, combustion of organic solvents leads to the generation of extensive levels of carbon dioxide being released into the atmosphere, thereby exacerbating climate change.
Adding to these concerns, amination reactions as practiced over the past 25 years 36 have required palladium catalysts used at loadings typically ranging from 1 to 10 mol %, which is both costly and consumes finite platinum group metal reserves.Moreover, rarely is the level of residual metal to be found in each coupled product evaluated when catalysts are utilized at these levels.Given the intricate interplay of these circumstances, it is becoming more obvious that alternative processes that are environmentally respectful (i.e., sustainable) are needed to affect traditional palladium-catalyzed aminations so vital to the fine chemicals industry in general, and the pharmaceutical industry, in particular.
−43 In cases involving primary aliphatic amines, the reaction can follow an undesired pathway, resulting in β-hydride elimination of a Pd amide species, ultimately affording the corresponding hydrodehalogenated arene.Efforts to minimize this undesired outcome have led to the development of numerous precatalysts, 25−33 such as sterically demanding bidentate phosphine (JosiPhos) ligands 14 and bipyrazole-based bulky monodentate phosphine ligands (e.g., BippyPhos; Scheme 1B). 44,45−48 In a big picture sense, however, obtaining catalysts in the GPhos series containing oxidative addition complexes entails a series of intricate and resource-intensive synthetic steps.This complexity is manifested in their elevated costs, and thus far, such species are not readily available and hence pose logistical challenges for widespread adoption. 47Furthermore, they have been designed for use exclusively in organic solvents, without recycling or any other metrics associated with environmental considerations in mind (e.g., E Factors 49−51 or process mass intensity (PMI) 52,53 values).These parameters, yet again, highlight the pressing need for an alternative, far more environmentally attractive, and sustainable process for aminations.
One potential solution for aminations involving homogeneous catalysis employing aliphatic amines employs micellar catalysis, 54−58 where the presence of a designer surfactant leads to nanomicelles that function as nanoreactors in which waterinsoluble coupling partners and catalyst interact, leading to the desired product under both aqueous and mild conditions.Our most recent amphiphile is Savie, 59 in which the MPEG hydrophilic portion (as in TPGS-750-M) is replaced with a polypeptoid derived from polysarcosine (Scheme 2A). 59,60We, and others, have previously identified ligand scaffolds that complex Pd forming catalysts that mediate aminations under micellar conditions in water (Scheme 2B). 61−67 However, the limited substrate scope and lack of late-stage functionalization may hinder applications of these methods at scale.Hence, we have developed a new protocol that (1) maintains or reduces the loadings of the Pd catalyst; (2) utilizes a commercially available ligand; (3) can be run in water and even ocean water; (4) is applicable to a large array of functionalized halides; (5) leads to products that contain low levels of residual Pd, thereby avoiding additional time and effort to meet FDA standards; (6) allows for recycling of the reaction medium and catalyst; and (7) can be used as part of a telescoped sequence en route to a known pharmaceutical, all being done in a single pot operation (Scheme 2C).

Optimization of Aminations between Aromatic Bromides and Aliphatic Amines
Amination with aliphatic amines is oftentimes highly sensitive to the nature of the ligand involved, 68,69 where it has been designed to (1) promote the formation of a monoligated Pd(0) complex; (2) activate palladium toward oxidative addition; (3) provide steric protection to the coordination sphere of the ligated palladium as a means of promoting selectivity; and (4) encourage C−N bond formation via facilitated reductive elimination.These features may necessitate that the ligand be both electron-rich and sterically Scheme 1. Various Aspects Associated with Pd-Catalyzed Aminations Scheme 2. Efforts To Develop a More Sustainable Amination Protocol demanding.The coupling between 1-bromo-3-(methylsulfonyl)benzene (1a) and 3,4-dimethoxyphenethylamine (1b) to afford 1 (Table 1) was specifically chosen as a representative model reaction to test the potential for a primary aliphatic amine to undergo the desired cross coupling, versus β-hydride elimination to the undesired imine along with the hydrodehalogenated arene.Since many known aryl aminations utilize alkoxide bases, 70−73 potassium t-butoxide (KOtBu) was initially selected for this purpose.

Representative Examples of C−N Couplings
The scope of the C−N bond construction using the combination of [Pd(crotyl)Cl] 2 and BippyPhos was examined under aqueous micellar conditions.As illustrated in Scheme 3, a variety of aryl/heteroaryl bromides undergo amination with an array of aliphatic amines to provide the desired aminated products.Primary aliphatic amines, including 3,4-dimethoxyphenethylamine, n-butylamine, cyclohexylamine, and cyclopropylmethylamine, all participated in couplings with various aryl/heteroaryl bromides in good-to-excellent isolated yields.Moreover, complete selectivity for monoarylation products (2−5) was seen.Likewise, benzylic amines reacted efficiently, affording the desired arylamines in good yields (products 6− 8).Cyclic amines of varying sizes and nucleophilicity, being among the most prevalent nitrogen-containing heterocycles in FDA-approved drugs, 1 include products containing four- (19), five-(10, 22, and 23), and six-membered rings (9, 11−18, 20,  21).It is also noteworthy that in addition to N-containing heterocycles, other heteroatom-containing heterocycles, such as 1,1'-difluorobenzodioxole (leading to product 17) and benzothiophene (affording 19), were amenable to these coupling conditions.In general, most amines are waterinsoluble, whether primary of secondary, since, as examined previously under very different conditions and in only a few cases, 66 those that are water-soluble can be quite challenging (see products 9, 10, and 20).

C−N Bond Formation in Ocean Water
The remarkable impact of added salts on the properties of aqueous micelles has previously been evaluated in terms of their effects on selected Pd-catalyzed C−C bond forming crosscoupling reactions. 77Thus, the potential for using ocean water for aminations, 76 rather than more expensive and potentially less readily available purified water, was briefly examined (Scheme 4).Two amination reactions led to products 12 and 24 in excellent isolated yields.Hence, the prospects for carrying out C−N bond formation under such conditions look encouraging, although these are likely to be done early in a sequence where ocean-derived impurities can be removed and the cost of the reaction medium may be a factor.

Recycling Studies
A commonly utilized metric for rapidly assessing the environmental friendliness of a reaction is Sheldon's E Factor, 49−51 which has stood the test of time although others are certainly becoming more prevalent, such as PMI 52,53 and especially a life cycle assessment (LCA). 78,79The latter, however, is far more accessible within industrial circles.Recycling of an aqueous reaction mixture can have a significant impact on these values, highlighting the major advantage of conducting various processes in water.Thus, following an initial reaction between 1-bromo-3-nitrobenzene 25a and a functionalized piperazine 25b (a precursor to the calcium channel blocker Flunarizine (Sibelium; Scheme 5), the desired product can be readily isolated via an in-flask extraction with recyclable amounts of MTBE (see SI, section 5).Reuse of the aqueous layer remaining in the same vessel for three additional cycles led to excellent results in terms of product formation and isolation.Only additional catalyst, ligand, base, and starting materials need to be added, preferably under an inert atmosphere, after each coupling.Overall, therefore, these four Table 1.Screening of Reaction Conditions for the Coupling of Aliphatic Amines a,b,c,d,e,f a Reactions were carried our at 0.25 mL scale.b NMR yields using 1,3,5,trimethoxybenzene as internal standard.c N/R = no reaction.reactions involved a total investment of only 1.1 mol % Pd or 0.275 mol % per amination.After the fourth reaction (i.e., the third recycle), salt buildup leading to increased viscosity precluded additional recycling.Associated E Factors were calculated to be only 1.51 (when recyclable MTBE is not Scheme 3. Representative Examples of Aliphatic Amines Used in Pd-Catalyzed C−N Bond Formation a Aryl halide (0.25 mmol), R"NHR' (0.375 mmol), [Pd(crotyl)Cl] 2 (0.5 mol % Pd; 0.25 mol % of the dimer), BippyPhos (2 mol %), KOtBu (0.5 mmol), 2 wt % Savie/H 2 O (0.45 mL), THF (0.05 mL), 60 °C.b [Pd] (0.75 mol %, 0.375 mol % dimer).c HCl salt of the amine was used.

Scheme 4. Comparisons of Reactions Run in Ocean Water
Scheme 5. Recycling Studies considered waste; see SI, section 5) and 10.5 (when MTBE is considered waste).ICP-MS analysis of a product isolated from amination after standard workup and purification showed a residual metal level of 0.78 ppm Pd, unlike levels to be expected for aminations run with far higher loadings of Pd in organic solvents. 36Since values on this order are far below those allowed by the FDA (10 ppm Pd per dose per day), 80 no additional processing to remove residual Pd is needed, which can otherwise be costly and time-consuming.

Late-Stage Aminations with Pharmaceutically Relevant Substrates
Both medicinal and process chemistry place significant value on Pd-catalyzed C−N coupling reactions, 81−86 given the large number of nitrogen-containing biologically active compounds.Several structurally challenging, free-amine-containing pharmaceuticals were coupled with aryl or heteroaryl halides, including complex cases selected from the Merck Informer library (e.g., product 35; Scheme 6) 87 in efforts to examine the true limits of this new technology.Highly functionalized reaction products, including derivatives of antidepressants such as Duloxetine (26; Cymbalta), Paroxetine (27; Paxil), Fluoxetine (28; Prozac), and Amoxapine (29; Asendin), were formed in good-to-excellent yields.Additionally, Narylation of (i) Desloratadine (Clarinex), an antihistamine medication (leading to product 30); (ii) a bicyclic 2°amine precursor to the antiemetic drug Granisetron (Sancuso; affording product 31); (iii) Fenofibrate (Lipofen), which which is an FDA-approved drug for the treatment of hypertriglyceridemia and hypercholesterolemia (leading to 32); (iv) Etoricoxib (Arcoxia), a selective COX-2 inhibitor for the treatment of osteoarthritis (giving product 33), and (v) the highly functionalized aryl chloride Glibenclamide (Diabeta) used for the treatment of type 2 diabetes (producing product 34); all gave the anticipated aminated derivatives.
Particularly noteworthy is the rate of these aminations, a key factor especially for those in pharma, which in most cases requires only an hour or less notwithstanding relatively low catalyst loadings.Collectively, C−N couplings of this nature involving complex pharmaceuticals used under environmentally responsible conditions further establish generality but also attest to the additional elements of sustainability involved, as a new and important tool based on chemistry in water can now be added to the growing toolbox.

Comparison Aminations with Existing Literature
Direct comparisons with state-of-the-art procedures were also made, focusing for the most part on the realization of intermediates associated with pharmaceutically relevant compounds (Scheme 7). 18,88Aminations arriving at products 36−39 indicate that by using this catalytic aqueous micellar system (i.e., [Pd(crotyl)Cl] 2 −BippyPhos), enhanced rates of couplings versus the corresponding reactions in organic solvents are to be expected.Moreover, yields tend to be comparable to, if not higher than, those reported previously.Lastly, and from the perspective of sheer convenience, the commercial availability of the Pd dimer and associated ligands that avoid pre-catalyst formation 89 suggests that this new catalytic combination offers several advantages to the practitioner previously unavailable.

Synthesis of Naftopidil
To further illustrate the potential of this technology, several effective and greener syntheses of naftopidil (43; Flivas), a selective α 1-adrenergic receptor antagonist used in the treatment of benign prostatic hypertrophy, were undertaken. 90ne route shown in Scheme 8 (see SI, section 6 for optimization) calls for an initial amination of 2-bromoanisole with N-Boc piperazine leading to the coupled product 40, 91 which can be isolated in 89% yield (see SI, section 6).Its N-Boc deprotection was accomplished using HCl giving isolable (of desired) amine 41 as the HCl salt.Alternatively, a streamlined 2-step, one-pot sequence was also developed where, following initial amination to 40, after which lowering the pH to ∼2 with conc.aq.HCl, intermediate 41 could be generated in freebase form and isolated in 86% overall yield (see SI, section 6.3).In parallel, epoxide 42 was prepared in 85% yield using 1-naphthol and epichlorohydrin in 95% EtOH.Epoxide opening by intermediate secondary amine 41 under aqueous micellar conditions afforded naftopidil (43) in 83% isolated yield (see SI, section 6.5).However, and perhaps

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even more attractive, is a 3-step, one-pot sequence (considering the longest linear sequence), starting with a Pdcatalyzed amination to give intermediate 40, which was used without isolation for its N-Boc deprotection to afford 41.Again, without isolation, epoxide opening by secondary amine 41 ultimately afforded racemic naftopidil (Flivas; 43) in 67% isolated overall yield.ICP−MS analysis of this material revealed no detectable levels of Pd, while the FDA-approved limit is 10 ppm per dose per day. 47

■ CONCLUSIONS
In summary, a protocol has been developed for aminations of aryl halides in water, employing homogeneous catalysis that utilizes sustainable loadings of precious metal.Thus, in addition to several aspects associated with sustainability, this work brings to the chemistry community a number of novel and timely advances, including the following: • the application of BippyPhos for C−N bond formation employing aliphatic amines in an aqueous micellar medium; • reliance on only commercially available catalyst precursors; • use of Pd at low catalyst loadings in recyclable water in multiple steps within a sequence, thereby documenting a rare case of "metal economy"; • reactions that can be in ocean water, addressing potential limitations due to availability of fresh water; • applications to aminations of structurally diverse aryl and heteroaryl halides together with aliphatic amines, which include highly functionalized, complex pharmaceuticals, and related species.Furthermore, aminations via continuous flow have also been carried out successfully not only using aliphatic amines but also with aromatic amines on aromatic/heteroaromatic halides. 92

■ EXPERIMENTAL PROCEDURES Preparation of a Stock Solution of [Pd(crotyl)Cl] 2 in THF
To a 1 dram vial with a PTFE-coated magnetic stir bar was added [Pd(crotyl)Cl] 2 (5 mg, 0.012 mmol).The vial was sealed with a rubber septum and evacuated and backfilled with argon three times using an argon/vacuum manifold.This was followed by the addition of anhydrous THF (obtained from a solvent purification system; 1 mL).The vial was stirred gently at rt until [Pd(crotyl)Cl] 2 dissolved completely.For a 0.25 mmol scale reaction, 50 μL of the stock solution contained 0.25 mol % of the dimer (0.5 mol % Pd), which was used directly for further optimization.

General Procedure for the Coupling of Aryl Halides with Aliphatic Amines
To a 1 dram vial equipped with a PTF-coated magnetic stir bar was added the aryl halide (1 equiv, 0.25 mmol, if solid), followed by the addition of the amine (0.375 mmol, 1.5 equiv, if solid).The vial was sealed with a rubber septum, evacuated, and backfilled with argon three times using an argon/vacuum manifold and then taken into an argon-filled glovebox, where BippyPhos (2 mol %, 2.5 mg) and KOtBu (2 equiv, 56 mg) were then added.The vial was taken out of the glovebox, and aryl bromide was added (if liquid), followed by the addition of the amine (if liquid) under an atmosphere of argon.Subsequently, a solution of 2 wt % Savie/H 2 O (0.45 mL) was added, followed by the addition of [Pd(crotyl)Cl] 2 (0.5−0.75 mol % Pd, 0.25−0.375mol % of dimer) as a stock solution in THF (50 μL, see SI, section 2).The reaction mixture was allowed to stir at 60 °C for the designated amount of time.Upon completion (as monitored by TLC), the reaction mixture was extracted with EtOAc (4 × 1 mL).The combined extracts were dried over anhydrous Na 2 SO 4 , filtered, concentrated in vacuo, and subjected to flash chromatography using the desired eluent (EtOAc/hexanes or MeOH/CH 2 Cl 2 , see analytical section for choice of eluents) to obtain the desired coupled products.

■ ASSOCIATED CONTENT
Irvine Mass Spectrometry Facility staff, Dr. Felix Grun, is warmly acknowledged with thanks.

d
Reaction was run at 70 °C for 24 h.e Isolated yield.f Reaction was run for 1.5 h.

Scheme 6 .
Scheme 6. Representative Examples of Late-Stage C−N Bond Formation

Scheme 7 .
Scheme 7. Comparisons with Recent Examples of Late-Stage C−N Bond Constructions