Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2024 Feb 12;4(2):680–689. doi: 10.1021/jacsau.3c00742

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

Karthik S Iyer 1, Rahul D Kavthe 1, Robert M Lammert 1, Jordan R Yirak 1, Bruce H Lipshutz 1,*
PMCID: PMC10900223  PMID: 38425930

Abstract

graphic file with name au3c00742_0010.jpg

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.

Keywords: aminations, aliphatic amines, BippyPhos, pharmaceutical diversification, API synthesis, micellar catalysis

Introduction

Palladium-catalyzed aminations of aryl/heteroaryl halides and pseudohalides are indispensable tools in synthesis, finding particularly extensive use in the synthesis of pharmaceuticals,1−4 natural products,1,5−7 and various materials.8−10 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, Pd-catalyzed aminations remain an important methodology in both academia and industrial laboratories.11 However, 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 chemistry12 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 aminations13,14 and to a lesser extent Cu-catalyzed Ullmann couplings15−18 have garnered extensive recognition for their applicability as well as their ability to accommodate a diverse array of functional groups.19,20 Considerable progress has also been made of late insofar as Chan–Evans–Lam couplings are concerned,21 along with catalysts developed by Ma and co-workers22 that have allowed a significant reduction in catalyst loadings and reaction temperatures.

Notable examples of effective ligands for aminations include various dialkylbiarylphosphanes23,24 and palladacycles incorporating these ligands.25−33 Additionally, N-heterocyclic carbene (NHC)-based precatalysts26,29,34 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 years36 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.

The mechanism of Pd-catalyzed C–N cross-coupling reactions is well documented (Scheme 1A).37−43 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) ligands14 and bipyrazole-based bulky monodentate phosphine ligands (e.g., BippyPhos; Scheme 1B).44,45 Recently, oxidative addition complexes have been introduced that exhibit noteworthy reactivity across a wide spectrum of aryl and pseudohalide electrophiles, including those featuring base-sensitive 5-membered heterocycles.46−48 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.47 Furthermore, 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 Factors49−51 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.

Scheme 1. Various Aspects Associated with Pd-Catalyzed Aminations.

Scheme 1

Open in a new tab

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 water-insoluble 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).59,60 We, 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).

Scheme 2. Efforts To Develop a More Sustainable Amination Protocol.

Scheme 2

Open in a new tab

Results and Discussion

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 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.

Table 1. Screening of Reaction Conditions for the Coupling of Aliphatic Aminesa,b,c,d,e,f.

graphic file with name au3c00742_0009.jpg

Open in a new tab
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.

d

Reaction was run at 70 °C for 24 h.

e

Isolated yield.

f

Reaction was run for 1.5 h.

With the Pd loading maintained at 0.5 mol % (i.e., 0.25 mol % of the dimer; Table 1), screening for the optimal ligand was carried out for this coupling under aqueous micellar conditions. To circumvent β-hydride elimination, bidentate ligands such as 1,1’-bis(di-t-butylphosphino)ferrocene (DtBPF) and tBuXantphos were evaluated (entries 6, 7) but without success. The Buchwald ligand, tBuBrettPhos, known to efficiently catalyze aminations of aryl (pseudo) halides with 1° amines74 afforded only trace amounts of 1 (entry 2). Only BippyPhos44,45 shown by Stradiotto et al. to couple aryl/heteroaryl chlorides with relatively simple amine nucleophiles in organic solvent proved to be effective (92% isolated yield, entry 3). An investigation of bases indicated that KOtBu performed the best (entries 9–12, also see SI, Table S2). Alternatively, use of KOH and t-BuOH (2 equiv) afforded identical results, indicative of the equilibration taking place in water.76 Unfortunately, lowering the Pd loading to 0.1 mol % of the dimer significantly reduced the yields (see SI, Table S3). Reducing the reaction time to 1.5 h from 8 h afforded 1 reproducibly in 90% isolated yield (entry 12). Optimized conditions for aminations of aryl halides, therefore, were determined to be Colacot’s pre-catalyst: [Pd(crotyl)Cl]2 (0.25 mol %);75 ligand: BippyPhos (2 mol %); base: KOtBu (2 equiv); and reaction medium: 2 wt % Savie/H2O, at 60 °C.

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 water-insoluble, 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).

Scheme 3. Representative Examples of Aliphatic Amines Used in Pd-Catalyzed C–N Bond Formation.

Scheme 3

Open in a new tab

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/H2O (0.45 mL), THF (0.05 mL), 60 °C.

[Pd] (0.75 mol %, 0.375 mol % dimer).

HCl salt of the amine was used.

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 cross-coupling reactions.77 Thus, 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.

Scheme 4. Comparisons of Reactions Run in Ocean Water.

Scheme 4

Open in a new tab

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 PMI52,53 and especially a life cycle assessment (LCA).78,79 The 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 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 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),80no additional processing to remove residual Pd is needed, which can otherwise be costly and time-consuming.

Scheme 5. Recycling Studies.

Scheme 5

Open in a new tab

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, N-arylation 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.

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

Scheme 6

Open in a new tab

Aryl halide (0.25 mmol), R″NHR′ (0.375 mmol), [Pd(crotyl)Cl]2 (0.25 mol %; 0.5 mol % [Pd]), BippyPhos (2 mol %), KOtBu (0.5 mmol), 2 wt % Savie/H2O (0.45 mL), THF (0.05 mL), 70 °C.

[Pd(crotyl)Cl]2 (0.375 mol %, 0.75 mol % [Pd]).

HCl salt of the amine was used.

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).18,88 Aminations 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 formation89 suggests that this new catalytic combination offers several advantages to the practitioner previously unavailable.

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

Scheme 7

Open in a new tab

Synthesis of Naftopidil

To further illustrate the potential of this technology, several effective and greener syntheses of naftopidil (43; Flivas), a selective α1-adrenergic receptor antagonist used in the treatment of benign prostatic hypertrophy, were undertaken.90 One 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.

Scheme 8. Compounds Formed En Route to Naftopidil.

Scheme 8

Open in a new tab

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 even more attractive, is a 3-step, one-pot sequence (considering the longest linear sequence), starting with a Pd-catalyzed 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/H2O (0.45 mL) was added, followed by the addition of [Pd(crotyl)Cl]2 (0.5–0.75 mol % Pd, 0.25–0.375 mol % 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 Na2SO4, filtered, concentrated in vacuo, and subjected to flash chromatography using the desired eluent (EtOAc/hexanes or MeOH/CH2Cl2, see analytical section for choice of eluents) to obtain the desired coupled products.

Acknowledgments

Assistance in collecting HRMS data from the UCSB Mass Spectrometry Facility staff, Dr. Dezmond Bishop, and from UC Irvine Mass Spectrometry Facility staff, Dr. Felix Grun, is warmly acknowledged with thanks.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.3c00742.

  • Experimental procedures, optimization details, and analytical data of isolated materials (NMR, HRMS) (PDF)

Author Contributions

⊥ K.S.I. and R.D.K. contributed equally. All authors have given approval to the final version of the manuscript. K.S.I. conceived the project and drafted the manuscript. R.D.K. performed experiments and contributed to the manuscript. R.M.L.Jr. and J.R.Y. assisted in experimental work. B.H.L. oversaw the work and aided in drafting the final manuscript. CRediT: Karthik Iyer conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing-original draft, writing-review & editing; Rahul Kavthe data curation, investigation, methodology, validation, writing-review & editing; Robert M. Lammert methodology, validation, visualization; Jordan R. Yirak methodology, validation, writing-review & editing.

Financial support provided by the NSF (CHE-2152566) is warmly acknowledged.

The authors declare no competing financial interest.

Supplementary Material

au3c00742_si_001.pdf (6.2MB, pdf)

References

  1. Vitaku E.; Smith D. T.; Njardarson J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]
  2. Sperry J. B.; Price Wiglesworth K. E.; Edmonds I.; Fiore P.; Boyles D. C.; Damon D. B.; Dorow R. L.; Piatnitski Chekler E. L.; Langille J.; Coe J. W. Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base–Sensitive 6–Bromoisoquinoline–1–carbonitrile with (S)–3–Amino–2–methylpropan–1–ol. Org. Process Res. Dev. 2014, 18, 1752–1758. 10.1021/op5002319. [DOI] [Google Scholar]
  3. Affouard C.; Crockett R. D.; Diker K.; Farrell R. P.; Gorins G.; Huckins J. R.; Caille S. Multi–Kilo Delivery of AMG 925 Featuring a Buchwald–Hartwig Amination and Processing with Insoluble Synthetic Intermediates. Org. Process Res. Dev. 2015, 19, 476–485. 10.1021/op500367p. [DOI] [Google Scholar]
  4. Ku Y.-Y.; Chan V. S.; Christesen A.; Grieme T.; Mulhern M.; Pu Y.-M.; Wendt M. D. Development of a Convergent Large–Scale Synthesis for Venetoclax, a First–in–Class BCL–2 Selective Inhibitor. J. Org. Chem. 2019, 84, 4814–4829. 10.1021/acs.joc.8b02750. [DOI] [PubMed] [Google Scholar]
  5. Mari M.; Bartoccini F.; Piersanti G. Synthesis of (−)–Epi–Indolactam V by an Intramolecular Buchwald–Hartwig C–N Coupling Cyclization Reaction. J. Org. Chem. 2013, 78, 7727–7734. 10.1021/jo4013767. [DOI] [PubMed] [Google Scholar]
  6. Foo K.; Newhouse T.; Mori I.; Takayama H.; Baran P. S. Total Synthesis Guided Structure Elucidation of (+)–Psychotetramine. Angew. Chem., Int. Ed. 2011, 50, 2716–2719. 10.1002/anie.201008048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Konkol L. C.; Guo F.; Sarjeant A. A.; Thomson R. J. Enantioselective Total Synthesis and Studies into the Configurational Stability of Bismurrayaquinone A. Angew. Chem., Int. Ed. 2011, 50, 9931–9934. 10.1002/anie.201104726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Shukla J.; Ajayakumar M. R.; Mukhopadhyay P. Buchwald Hartwig Coupling at the Naphthalenediimide Core:Access to Dendritic, Panchromatic NIR Absorbers with Exceptionally Low Band Gap. Org. Lett. 2018, 20, 7864–7868. 10.1021/acs.orglett.8b03408. [DOI] [PubMed] [Google Scholar]
  9. Astridge D. D.; Hoffman J. B.; Zhang F.; Park S. Y.; Zhu K.; Sellinger A. Polymer Hole Transport Materials for Perovskite Solar Cells via Buchwald–Hartwig Amination. ACS Appl. Polym. Mater. 2021, 3, 5578–5587. 10.1021/acsapm.1c00891. [DOI] [Google Scholar]
  10. Chen J.; Yan W.; Townsend E. J.; Feng J.; Pan L.; Del Angel Hernandez V.; Faul C. F. J. Tunable Surface Area, Porosity, and Function in Conjugated Microporous Polymers. Angew. Chem., Int. Ed. 2019, 58, 11715–11719. 10.1002/anie.201905488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Buchwald S. L.; Mauger C.; Mignani G.; Scholz U. Industrial-Scale Palladium-Catalyzed Coupling of Aryl Halides and Amines–A Personal Account. Adv. Synth.Catal. 2006, 348, 23–39. 10.1002/adsc.200505158. [DOI] [Google Scholar]; Torborg C.; Beller M. Recent applications of palladium-catalyzed coupling reactions in the pharmaceutical, agrochemical, and fine chemical industries. Adv. Synth. Catal. 2009, 351, 3027–3043. 10.1002/adsc.200900587. [DOI] [Google Scholar]
  12. Anastas P. T.; Warner J. C.. Principles of green chemistry. In Green chemistry: Theory and practice; Oxford University Press, 1998; Vol. 29, pp. 14821–14842.. [Google Scholar]
  13. Ruiz-Castillo P.; Buchwald S. L. Applications of Palladium Catalyzed C–N Cross–Coupling Reactions. Chem. Rev. 2016, 116, 12564–12649. 10.1021/acs.chemrev.6b00512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hartwig J. F. Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides. Acc. Chem. Res. 2008, 41, 1534–1544. 10.1021/ar800098p. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Yang Q.; Zhao Y.; Ma D. Cu–Mediated Ullmann–Type Cross–Coupling and Industrial Applications in Route Design, Process Development, and Scale–up of Pharmaceutical and Agrochemical Processes. Org. Process Res. Dev. 2022, 26, 1690–1750. 10.1021/acs.oprd.2c00050. [DOI] [Google Scholar]
  16. Ullmann F.; Bielecki J. Ueber Synthesen in der Biphenylreihe. Ber. Dtsch. Chem. Ges. 1901, 34, 2174–2185. 10.1002/cber.190103402141. [DOI] [Google Scholar]
  17. Ullmann F. Ueber eine neue Bildungsweise von Diphenylaminderivaten. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384. 10.1002/cber.190303602174. [DOI] [Google Scholar]
  18. Kim S. T.; Strauss M. J.; Cabré A.; Buchwald S. L. Room Temperature Cu–Catalyzed Amination of Aryl Bromides Enabled by DFT–Guided Ligand Design. J. Am. Chem. Soc. 2023, 145, 6966–6975. 10.1021/jacs.3c00500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Brown D. G.; Boström J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?. J. Med. Chem. 2016, 59, 4443–4458. 10.1021/acs.jmedchem.5b01409. [DOI] [PubMed] [Google Scholar]
  20. Wang Q.; Su Y.; Li L.; Huang H. Transition–metal catalyzed C–N bond activation. Chem. Soc. Rev. 2016, 45, 1257–1272. 10.1039/C5CS00534E. [DOI] [PubMed] [Google Scholar]
  21. Okano K.; Tokuyama H.; Fukuyama T. Copper-mediated aromatic amination reaction and its application to the total synthesis of natural products. Chem. Commun. 2014, 50, 13650–13663. 10.1039/C4CC03895A. [DOI] [PubMed] [Google Scholar]
  22. Bhunia S.; Pawar G. G.; Kumar S. V.; Jiang Y.; Ma D. Selected Copper–Based Reactions for C–N, C–O, C–S, and C–C Bond Formation. Angew. Chem., Int. Ed. 2017, 56, 16136–16179. 10.1002/anie.201701690. [DOI] [PubMed] [Google Scholar]
  23. Surry D. S.; Buchwald S. L. Dialkylbiaryl phosphines in Pd catalyzed amination: a user’s guide. Chem. Sci. 2011, 2, 27–50. 10.1039/C0SC00331J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ingoglia B. T.; Wagen C. C.; Buchwald S. L. Biaryl monophosphine ligands in palladium–catalyzed C–N coupling: An updated User’s guide. Tetrahedron 2019, 75, 4199–4211. 10.1016/j.tet.2019.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zim D.; Buchwald S. L. An air and thermally stable one–component catalyst for the amination of aryl chlorides. Org. Lett. 2003, 5, 2413–2415. 10.1021/ol034561h. [DOI] [PubMed] [Google Scholar]
  26. Marion N.; Nolan S. P. Well–defined N–heterocyclic carbenes– palladium (II) precatalysts for cross–coupling reactions. Acc. Chem. Res. 2008, 41, 1440–1449. 10.1021/ar800020y. [DOI] [PubMed] [Google Scholar]
  27. Biscoe N. R.; Fors B. P.; Buchwald S. L. A new class of easily activated palladium precatalysts for facile C– N cross–coupling reactions and the low temperature oxidative addition of aryl chlorides. J. Am. Chem. Soc. 2008, 130, 6686–6687. 10.1021/ja801137k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Johansson Seechurn C. C. C.; Parisel S. L.; Colacot T. J. Air–stable Pd (R–allyl) LCl (L= Q–Phos, P (t–Bu) 3, etc.) systems for C–C/N couplings: insight into the structure–activity relationship and catalyst activation pathway. J. Org. Chem. 2011, 76, 7918–7932. 10.1021/jo2013324. [DOI] [PubMed] [Google Scholar]
  29. Valente C.; Pompeo M.; Sayah M.; Organ M. G. Carbon–Heteroatom Coupling Using Pd–PEPPSI Complexes. Org. Process Res. Dev. 2014, 18, 180–190. 10.1021/op400278d. [DOI] [Google Scholar]
  30. DeAngelis A. J.; Gildner P. G.; Chow R.; Colacot T. J. Generating active “L–Pd (0)” via neutral or cationic π–allylpalladium complexes featuring biaryl/bipyrazolylphosphines: synthetic, mechanistic, and structure–activity studies in challenging cross–coupling reactions. J. Org. Chem. 2015, 80, 6794–6813. 10.1021/acs.joc.5b01005. [DOI] [PubMed] [Google Scholar]
  31. Bruno N. C.; Tudge M. T.; Buchwald S. L. Design and preparation of new palladium precatalysts for C–C and C–N cross–coupling reactions. Chem. Sci. 2013, 4, 916–920. 10.1039/C2SC20903A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Bruno N. C.; Buchwald S. L. Synthesis and application of palladium precatalysts that accommodate extremely bulky di–tert–butylphosphino biaryl ligands. Org. Lett. 2013, 15, 2876–2879. 10.1021/ol401208t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Bruno N. C.; Niljianskul N.; Buchwald S. L. Substituted 2–aminobiphenylpalladium methanesulfonate precatalysts and their use in C–C and C–N cross–couplings. J. Org. Chem. 2014, 79, 4161–4166. 10.1021/jo500355k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ouyang J. S.; Liu S.; Pan B.; Zhang Y.; Liang H.; Chen B.; He X.; Chan W. T. K.; Chan A. S.; Sun T. Y.; Wu Y. D.; Qiu L. A Bulky and Electron–Rich N–Heterocyclic Carbene–Palladium Complex (SIPr) Ph2Pd (cin) Cl: Highly Efficient and Versatile for the Buchwald–Hartwig Amination of (Hetero) aryl Chlorides with (Hetero) aryl Amines at Room Temperature. ACS Catal. 2021, 11, 9252–9261. 10.1021/acscatal.1c01929. [DOI] [Google Scholar]
  35. a https://cen.acs.org/policy/chemical-regulation/EPA-proposes-ban-uses-methylene/101/web/2023/04 (accessed 11–15–23);.; b https://oehha.ca.gov/proposition-65/chemicals/nn-dimethylformamide (accessed 12–29–23).
  36. Forero-Cortés P. A.; Haydl A. M. The 25th anniversary of the Buchwald–Hartwig amination: development, applications, and outlook. Org. Process Res. Dev. 2019, 23, 1478–1483. 10.1021/acs.oprd.9b00161. [DOI] [Google Scholar]
  37. Hartwig J. F. Carbon–Heteroatom Bond–Forming Reductive Eliminations of Amines, Ethers, and Sulfides. Acc. Chem. Res. 1998, 31, 852–860. 10.1021/ar970282g. [DOI] [Google Scholar]
  38. Hartwig J. F. Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism. Angew. Chem., Int. Ed. 1998, 37, 2046–2067. . [DOI] [PubMed] [Google Scholar]
  39. Shekhar S.; Ryberg P.; Hartwig J. F.; Mathew J. S.; Blackmond D. G.; Strieter E. R.; Buchwald S. L. Reevaluation of the Mechanism of the Amination of Aryl Halides Catalyzed by BINAP Ligated Palladium Complexes. J. Am. Chem. Soc. 2006, 128, 3584–3591. 10.1021/ja045533c. [DOI] [PubMed] [Google Scholar]
  40. Wagschal S.; Perego L. A.; Simon A.; Franco-Espejo A.; Tocqueville C.; Albaneze-Walker J.; Jutand A.; Grimaud L. Formation of XPhos–Ligated Palladium(0) Complexes and Reactivity in Oxidative Additions. Chem.—Eur. J. 2019, 25, 6980–6987. 10.1002/chem.201900451. [DOI] [PubMed] [Google Scholar]
  41. Biscoe M. R.; Barder T. E.; Buchwald S. L. Electronic Effects on the Selectivity of Pd–Catalyzed C–N Bond–Forming Reactions Using Biarylphosphine Ligands: The Competitive Roles of Amine Binding and Acidity. Angew. Chem., Int. Ed. 2007, 46, 7232–7235. 10.1002/anie.200702122. [DOI] [PubMed] [Google Scholar]
  42. Tatsumi K.; Hoffmann R.; Yamamoto A.; Stille J. K. Reductive Elimination of d8–Organotransition Metal Complexes. Bull. Chem. Soc. Jpn. 1981, 54, 1857–1867. 10.1246/bcsj.54.1857. [DOI] [Google Scholar]
  43. Arrechea P. L.; Buchwald S. L. Biaryl Phosphine Based Pd(II) Amido Complexes: The Effect of Ligand Structure on Reductive Elimination. J. Am. Chem. Soc. 2016, 138, 12486–12493. 10.1021/jacs.6b05990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Withbroe G. J.; Singer R. A.; Sieser J. E. Streamlined synthesis of the Bippyphos family of ligands and cross–coupling applications. Org. Process Res. Dev. 2008, 12, 480–489. 10.1021/op7002858. [DOI] [Google Scholar]
  45. Singer R. A. BippyPhos: A Highly Versatile Ligand for Pd-Catalyzed C– N, C– O and C– C Couplings. Isr. J. Chem. 2020, 60, 294–302. 10.1002/ijch.201900170. [DOI] [Google Scholar]
  46. Uehling M. R.; King R. P.; Krska S. W.; Cernak T.; Buchwald S. L. Pharmaceutical diversification via palladium oxidative addition complexes. Science 2019, 363, 405–408. 10.1126/science.aac6153. [DOI] [PubMed] [Google Scholar]
  47. GPhos Pd G6 TES is available on Sigma Aldrich (catalog no. 922900), in 100 mg quantities ($508 for 100 mg)McCann S. D.; Reichert E. C.; Arrechea P. L.; Buchwald S. L. Development of an Aryl Amination Catalyst with Broad Scope Guided by Consideration of Catalyst Stability. J. Am. Chem. Soc. 2020, 142, 15027–15037. 10.1021/jacs.0c06139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Reichert E. C.; Feng K.; Sather A. C.; Buchwald S. L. Pd–Catalyzed Amination of Base–Sensitive Five–Membered Heteroaryl Halides with Aliphatic Amines. J. Am. Chem. Soc. 2023, 145, 3323–3329. 10.1021/jacs.2c13520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sheldon R. A. The E Factor: Fifteen Years On. Green Chem. 2007, 9, 1273–1283. 10.1039/b713736m. [DOI] [Google Scholar]
  50. Sheldon R. A. The E Factor 25 years on: the Rise of Green Chemistry and Sustainability. Green Chem. 2017, 19, 18–43. 10.1039/C6GC02157C. [DOI] [Google Scholar]
  51. Sheldon R. A. The E factor at 30: a passion for pollution prevention. Green Chem. 2023, 25, 1704–1728. 10.1039/D2GC04747K. [DOI] [Google Scholar]
  52. Kowtharapu L. P.; Katari N. K.; Muchakayala S. K.; Marisetti V. M. Green metric tools for analytical methods assessment critical review, case studies and crucify.Trends. Analyt. Chem. 2023, 166, 117196 10.1016/j.trac.2023.117196. [DOI] [Google Scholar]
  53. Tamboli Y.; Kilbile J. T.; Merwade A. Y. Large-Scale Amide Coupling in Aqueous Media: Process for the Production of Diazabicyclooctane β-Lactamase Inhibitors. Org. Process Res. Dev. 2023, 27, 120–128. 10.1021/acs.oprd.2c00299. [DOI] [Google Scholar]
  54. For recent reviews on micellar catalysis, see references 54 - 56:Shen T.; Zhou S.; Ruan J.; Chen X.; Liu X.; Ge X.; Qian C. Recent Advances on Micellar Catalysis in Water. Adv. Colloid Interface Sci. 2021, 287, 102299 10.1016/j.cis.2020.102299. [DOI] [PubMed] [Google Scholar]
  55. LaSorella G.; Strukul G.; Scarso A. Recent Advances in Catalysis in Micellar Media. Green Chem. 2015, 17, 644–683. 10.1039/C4GC01368A. [DOI] [Google Scholar]
  56. Kitanosono T.; Masuda K.; Xu P.; Kobayashi S. Catalytic Organic Reactions in Water toward Sustainable Society. Chem. Rev. 2018, 118, 679–746. 10.1021/acs.chemrev.7b00417. [DOI] [PubMed] [Google Scholar]
  57. Ansari T. N.; Gallou F.; Handa S. Palladium-catalyzed micellar cross-couplings: An outlook. Coord. Chem. Rev. 2023, 488, 215158 10.1016/j.ccr.2023.215158. [DOI] [Google Scholar]
  58. Adamik R.; Herczegh A. R.; Varga I.; May Z.; Novák Z. Gate to a parallel universe: Utilization of biosurfactants in micellar catalysis. Green Chem. 2023, 25, 3462–3468. 10.1039/D3GC00365E. [DOI] [Google Scholar]
  59. Kincaid J. R. A.; Wong M. J.; Akporji N.; Gallou F.; Fialho D. M.; Lipshutz B. H. Introducing Savie: A Biodegradable Surfactant Enabling Chemo–and Biocatalysis and Related Reactions in Recyclable Water. J. Am. Chem. Soc. 2023, 145, 4266–4278. 10.1021/jacs.2c13444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Lipshutz B. H.; Ghorai S.; Abela A. R.; Moser R.; Nishikata T.; Duplais C.; Krasovskiy A.; Gaston R. D.; Gadwood R. C. TPGS–750–M: A Second–Generation Amphiphile for Metal–Catalyzed Cross Couplings in Water at Room Temperature. J. Org. Chem. 2011, 76, 4379–4391. 10.1021/jo101974u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Lipshutz B. H.; Chung D. W.; Rich B. Aminations of aryl bromides in water at room temperature. Adv. Synth. Catal. 2009, 351, 1717–1721. 10.1002/adsc.200900323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Tardiff B. J.; Stradiotto M. Buchwald–Hartwig Amination of (Hetero) aryl Chlorides by Employing Mor-DalPhos under Aqueous and Solvent-Free Conditions. Eur. J. Org. Chem. 2012, 21, 3972–3977. 10.1002/ejoc.201200510. [DOI] [PubMed] [Google Scholar]
  63. Isley N. A.; Dobarco S.; Lipshutz B. H. Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis. Green Chem. 2014, 16, 1480–1488. 10.1039/c3gc42188k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Salom′e C.; Wagner P.; Bollenbach M.; Bihel F.; Bourguignon J. J.; Schmitt M. Buchwald–Hartwig reactions in water using surfactants. Tetrahedron 2014, 70, 3413. 10.1016/j.tet.2014.03.083. [DOI] [Google Scholar]
  65. Wagner P.; Bollenbach M.; Doebelin C.; Bihel F.; Bourguignon J.-J.; Salome C.; Schmitt M. t–BuXPhos: a highly efficient ligand for Buchwald–Hartwig coupling in water. Green Chem. 2014, 16, 4170–4178. 10.1039/C4GC00853G. [DOI] [Google Scholar]
  66. Zhang Y.; Takale B. S.; Gallou F.; Reilly J.; Lipshutz B. H. Sustainable ppm level palladium-catalyzed aminations in nanoreactors under mild, aqueous conditions. Chem. Sci. 2019, 10, 10556–10561. 10.1039/C9SC03710A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Ansari T. N.; Taussat A.; Clark A. H.; Nachtegaal M.; Plummer S.; Gallou F.; Handa S. Insights on Bimetallic Micellar Nanocatalysis for Buchwald–Hartwig Aminations. ACS Catal. 2019, 9, 10389–10397. 10.1021/acscatal.9b02622. [DOI] [Google Scholar]
  68. Beletskaya I. P.; Cheprakov A. V. The complementary competitors: palladium and copper in C–N cross–coupling reactions. Organometallics 2012, 31, 7753–7808. 10.1021/om300683c. [DOI] [Google Scholar]
  69. Lundgren R. J.; Stradiotto M. Addressing Challenges in Palladium-Catalyzed Cross-Coupling Reactions Through Ligand Design. Chem.—Eur. J. 2012, 18, 9758–9769. 10.1002/chem.201201195. [DOI] [PubMed] [Google Scholar]
  70. Old D. W.; Wolfe J. P.; Buchwald S. L. A Highly Active Catalyst for Palladium–Catalyzed Cross–Coupling Reactions: Room Temperature Suzuki Couplings and Amination of Unactivated Aryl Chlorides. J. Am. Chem. Soc. 1998, 120, 9722–9723. 10.1021/ja982250+. [DOI] [Google Scholar]
  71. Wolfe J. P.; Tomori H.; Sadighi J. P.; Yin J.; Buchwald S. L. Simple, Efficient Catalyst System for the Palladium–Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates. J. Org. Chem. 2000, 65, 1158–1174. 10.1021/jo991699y. [DOI] [PubMed] [Google Scholar]
  72. Hartwig J. F.; Kawatsura M.; Hauck S. I.; Shaughnessy K. H.; Alcazar-Roman L. M. Room Temperature Palladium–Catalyzed Amination of Aryl Bromides and Chlorides and Extended Scope of Aromatic C–N Bond Formation with a Commercial Ligand. J. Org. Chem. 1999, 64, 5575–5580. 10.1021/jo990408i. [DOI] [PubMed] [Google Scholar]
  73. Lavoie C. M.; MacQueen P. M.; Rotta-Loria N. L.; Sawatzky R. S.; Borzenko A.; Chisholm A. J.; Hargreaves B. K. V.; McDonald R.; Ferguson M. J.; Stradiotto M. Challenging nickel catalysed amine arylations enabled by tailored ancillary ligand design. Nat. Commun. 2016, 7, 11073. 10.1038/ncomms11073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. a Maiti D.; Fors B. P.; Henderson J. L.; Nakamura Y.; Buchwald S. L. Palladium–catalyzed coupling of functionalized primary and secondary amines with aryl and heteroaryl halides: two ligands suffice in most cases. Chem. Sci. 2011, 2, 57–68. 10.1039/C0SC00330A. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Crawford S. M.; Lavery C. B.; Stradiotto M. BippyPhos: A single ligand with unprecedented scope in the Buchwald-Hartwig amination of (hetero) aryl chlorides.. Chem. Eur. J. 2013, 19, 16760–16771. 10.1002/chem.201302453. [DOI] [PubMed] [Google Scholar]
  75. a MacQueen P. M.; Holley R.; Ghorai S.; Colacot T. J. Convenient One-Pot Synthesis of L2Pd(O)- Complexes for Cross-Coupling Catalysis. Orgonomet 2023, 42, 2644–2650. 10.1021/acs.organomet.3c00059. [DOI] [Google Scholar]; b Firsan S. J.; Sivakumar V.; Colacot T. J. Twelve-Electron-Based LLPd(0) Catalysts, Their Mechanism of Action' and Selected Applications. Chem. Rev. 2022, 122, 16983–17027. 10.1021/acs.chemrev.2c00204. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Ansari T. N.; Taussat A.; Clark A. H.; Nachtegaal M.; Plummer S.; Gallou F.; Handa S. lnsights on Bimetallic Micellar Nanocatalysis for Buchwa|d-Hartwig Aminations. ACS Catal. 2019, 9, 10389–10397. 10.1021/acscatal.9b02622. [DOI] [Google Scholar]
  76. Iyer K. S.; Kavthe R. D.; Hu Y.; Lipshutz B. H. Nanoparticles as heterogeneous catalysts for ppm Pd–catalyzed aminations in water. ACS Sustainable Chem. Eng. 2023, 10.1021/acssuschemeng.3c06527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Lipshutz B. H.; Ghorai S.; Leong W. W. Y.; Taft B. R.; Krogstad D. V. Manipulating micellar environments for enhancing transition metal–catalyzed cross–couplings in water at room temperature. J. Org. Chem. 2011, 76, 5061–5073. 10.1021/jo200746y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Sabour M. R.; Zarrabi H.; Hajbabaie M. A systematic analysis of research trends on the utilization of life cycle assessment in pharmaceutical applications. Int. J. Environ. Sci. 2023, 20, 10921–10942. 10.1007/s13762-023-05103-4. [DOI] [Google Scholar]
  79. a Osorio-Tejada J. L.; Ferlin F.; Vaccaro L.; Hessel V. The sustainability impact of Nobel Prize Chemistry: life cycle assessment of C–C cross-coupling reactions. Green Chem. 2023, 25, 9760. 10.1039/D3GC01896B. [DOI] [Google Scholar]; b Mercer S. M.; Andraos J.; Jessop P. G. Choosing the Greenest Synthesis: A Multivariate Metric reen Chemistry Exercise. J. Chem. Ed. 2012, 89, 215–220. 10.1021/ed200249v. [DOI] [Google Scholar]
  80. Phillips S.; Holdsworth D.; Kauppinen P.; MacNamara C. Palladium impurity removal from active pharmaceutical ingredient process streams. Johns. Matthey Technol. Rev. 2016, 60, 277–286. 10.1595/205651316X693247. [DOI] [Google Scholar]
  81. Tasler S.; Mies J.; Lang M. Applicability Aspects of Transition Metal-Catalyzed Aromatic Amination Protocols in Medicinal Chemistry. Adv. Synth. Catal. 2007, 349, 2286–2300. 10.1002/adsc.200700133. [DOI] [Google Scholar]
  82. Roughley S. D.; Jordan A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451–3479. 10.1021/jm200187y. [DOI] [PubMed] [Google Scholar]
  83. Cooper T. W. J.; Campbell I. B.; Macdonald S. J. F. Factors Determining the Selection of Organic Reactions by Medicinal Chemists and the Use of These Reactions in Arrays (Small Focused Libraries). Angew. Chem., Int. Ed. 2010, 49, 8082–8091. 10.1002/anie.201002238. [DOI] [PubMed] [Google Scholar]
  84. Magano J.; Dunetz J. R. Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177–2250. 10.1021/cr100346g. [DOI] [PubMed] [Google Scholar]
  85. Buchwald S. L.; Mauger C.; Mignani G.; Scholz U. Industrial-Scale Palladium-Catalyzed Coupling of Aryl Halides and Amines–A Personal Account. Adv. Synth. Catal. 2006, 348, 23–39. 10.1002/adsc.200505158. [DOI] [Google Scholar]
  86. Carey J. S.; Laffan D.; Thomson C.; Williams M. T. Analysis of the Reactions Used for the Preparation of Drug Candidate Molecules. Org. Biomol. Chem. 2006, 4, 2337–2347. 10.1039/b602413k. [DOI] [PubMed] [Google Scholar]
  87. Kutchukian P. S.; Dropinski J. F.; Dykstra K. D.; Li B.; DiRocco D. A.; Streckfuss E. C.; Campeau L. C.; Cernak T.; Vachal P.; Davies I. W.; Krska S. W.; Dreher S. D. Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods. Chem. Sci. 2016, 7, 2604–2613. 10.1039/C5SC04751J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Li C.; Kawamata Y.; Nakamura H.; Vantourout J. C.; Liu Z.; Hou Q.; Bao D.; Starr J. T.; Chen J.; Yan M.; Baran P. S. Electrochemically enabled, nickel-catalyzed amination. Angew. Chem., Int. Ed. 2017, 129, 13268–13273. 10.1002/ange.201707906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. [Pd(crotyl)Cl)]2-(2-butenyl)chloropalladium dimer can be purchased from Sigma Aldrich; CAS No: 12081-22-0; Catalog No: 700045; BippyPhos can be purchased from Sigma Aldrich; CAS No: 894086-00-1; catalog no: 676632; from AK Scientific; catalog no: 4796AC.
  90. Kanno T.; Tanaka A.; Shimizu T.; Nakano T.; Nishizaki T.. Novel anticancer agent. U.S. Patent Application No. 14/298,400.
  91. For a procedure leading to compound 40 at the gram scale, see SI, page S16.
  92. Wong M. J.; Oftadeh E.; Saunders J. M.; Wood A. B.; Lipshutz B. H. ppm Pd–catalyzed aminations in Flow ... on water. ACS Catal. 2023, 14, 1545. 10.1021/acscatal.3c05257. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au3c00742_si_001.pdf (6.2MB, pdf)

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES