A Monophosphine Ligand Derived from Anthracene Photodimer

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

A Monophosphine Ligand Derived from Anthracene Photodimer: Synthetic Applications for Palladium-Catalyzed Coupling Reactions Xin Wang, Wei-Gang Liu, Chen-Ho Tung, Li-Zhu Wu, and Huan Cong* Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry & School of Future Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100190, China

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S Supporting Information *

ABSTRACT: Herein, we present an air-stable dianthracenyl monophosphine ligand (diAnthPhos) which can be prepared in two steps from commercially available anthracene derivatives. The ligand exhibits excellent efficiency for palladium-catalyzed coupling reactions. In particular, Miyaura borylation of heterocycle-containing electrophiles can be facilitated employing the diAnthPhos ligand with a broad substrate scope and low catalyst loading. The valuable synthetic utility of the new ligand is further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol for heteroaryl-containing substrates.

N

Scheme 1. Monophosphine Ligand diAnthPhos (1) and Its Preparationa

ew ligand design is one of the long-lasting research themes in the development of transition metal-catalyzed reactions, since ligands can tune the properties of metal centers by coordination, thereby enabling efficient catalyst turnover with desirable selectivity and substrate scope.1 Among the successful ligands known to date, the family of monophosphine ligands is particularly effective for palladium-catalyzed coupling reactions,2 featuring sterically demanding substituents on phosphine to increase catalyst durability as well as to facilitate reductive elimination steps (Scheme 1a).3 We speculate that the unique structure of the anthracene [4 + 4] photodimer4 not only could serve as useful synthetic building blocks5 but also provide an attractive opportunity for new monophosphine ligand design because of its rigid and bulky scaffold. Here we report a dianthracenyl monophosphine ligand, diAnthPhos (1), which exhibits versatile applications for a number of palladium-catalyzed coupling reactions of a broad range of heterocycle-containing substrates with a low catalyst loading. Designing and synthesizing ligands by means of photochemical approaches is an important strategy to establish distinct properties, but remains underdeveloped in the literature.6 We expect that the introduction and utility of ligand 1 would open the door toward the development of the dianthracene core as a new type of privileged scaffold for new ligand/reaction discovery. The ligand 1 features concise preparation, with two steps from the commercially available 1-bromoanthracene (2) and an overall 42% isolated yield. The [4 + 4] photocycloaddition between 2 and excess unsubstituted anthracene under ultraviolet light furnished the heterodimer 3. Treatment of 3 with n-butyllithium provided an aryl lithium intermediate which then reacted with diphenylphosphine chloride, affording the diAnthPhos (1) as an air-stable, free-flowing solid (Scheme © XXXX American Chemical Society

a

Reagents and conditions: (i) 2 (1.0 equiv), anthracene (10 equiv), toluene, xenon lamp, 110 °C, 24 h; (ii) 3 (1.0 equiv), n-BuLi (1.25 equiv), THF, −78 °C, 1.5 h; then PPh2Cl (2.0 equiv), 25 °C, 15 h.

1b). The all-aryl substitutions on the phosphine endow the ligand with good stability and ease of use in air. By design, the placement of the phosphine moiety next to the bridge-head position should maximize the steric effects of the dianthracene Received: July 12, 2019

A

DOI: 10.1021/acs.orglett.9b02414 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters scaffold7 when ligand 1 coordinates with a transition metal catalyst (cf. Figure 1).

Notably, compound 4y contains an unprotected labile amino group that may complicate transition-metal-catalyzed reactions. As summarized in Scheme 2, we were delighted to identify that the monophosphine ligand 1, when complexed with the Pd G4 dimer,10 could efficiently promote the borylation of all three substrates with excellent yields under a low catalyst loading (0.5 mol % Pd). Control experiments showed that the absence of 1 led to much less product formation. Inferior results to various extents were obtained when replacing 1 with a series of phosphine-based ligands, including simple triaryl- or trialkylphosphine ligands, Buchwald monophosphine ligands,11 AntPhos,9b and chelating bis(phosphine) ligands.8,12 It should be noted that compared with the diphenylphosphine moiety of 1, many of the above ligands contain more electron-donating and sterically demanding alkyl substituents on phosphines. Indeed, these results highlighted the effectiveness of ligand design based on the unique dianthracene scaffold. In order to unambiguously characterize the Pd precatalyst containing ligand 1, single crystals suitable for X-ray crystallographic analysis were obtained by slow diffusion of n-pentane into a dichloromethane solution of the 1-Pd G4 complex at −20 °C (Figure 1).13 The solid-state structure of 1-Pd G4 exhibits some similar features (e.g., bond lengths and bond angles surrounding the Pd center) compared to the previously reported structure of XPhos-Pd G4.10 The tetracoordinated Pd(II) center is observed with a slightly distorted square planar geometry, and the phosphine is bound to the palladium trans to the Pd−N bond. Additionally, when complexed with Pd G4, ligand 1 adopts a conformation that lays the two phenyl substituents on the phosphine away from the bulky dianthracene core. Employing the standard conditions, we explored the reaction scope with regard to the heterocycle-containing electrophiles (Scheme 3a) and observed excellent method generality and functional group tolerance.14 More than a dozen (hetero)aryl moieties, which are frequently used pharmacophores, prove to be suitable substrates with good efficiency and compatibility regardless of the electronic effects, including pyrazole, thiophene, isoxazole, pyridine, pyrimidine, indole, benzofuran, benzothiophene, 7-azaindole, benzo[1,3]dioxoles, benzoxazole, benzothiazole, benzothiadiazole, carbazole, dibenzothiophene, quinoline, and dihydropyrimidinone (5a−5t). Notably, substrates with steric hindrance (5c) or in the absence of protecting groups (5f, 5j, and 5p) smoothly afforded the desired products, showcasing the reaction robustness using the monophosphine 1 as the ligand. Since some of the boronic ester products (such as 5c, 5d, 5e, and 5r) are either unstable during silica gel chromatography or difficult to separate from minor impurities, we have further devised a one-pot Miyaura borylation/Suzuki coupling protocol (see Scheme 7) to isolate the corresponding C−C bond coupling products. To highlight the reaction utility featuring heterocyclecontaining substrates, late-stage borylations of pharmaceutical derivatives were investigated (Scheme 3b). Starting from the corresponding bromides or iodides, Celecoxib- and Trametinib-derived boronic esters (5u and 5v, respectively) were obtained with good to excellent yields, indicating profound potential for applications in medicinal chemistry. Heterocyclic boronic esters are highly important synthetic building blocks which can serve as linchpin compounds to access a variety of functionalized heterocycles.15 We next applied the standard conditions to access the key synthetic

Figure 1. X-ray crystallographic structure (ORTEP) of the precatalyst 1-Pd G4 with the thermal ellipsoids shown at a 50% probability. Hydrogen atoms were omitted for clarity.

Pd-catalyzed Miyaura borylation is a widely used methodology with numerous important applications in medicinal and material chemistry.8 In particular, general methods to convert heterocycle-containing electrophiles to the corresponding boronic esters are highly desirable, but remain challenging likely due to the nucleophilicity and/or side reactions originated from the heterocycles.9 In order to establish the utility of ligand 1, we set out with a comprehensive evaluation of three selected heteroaryl substrates to develop a generalized condition (Scheme 2 and Supporting Information (SI) Tables S1−S4). Specifically, 1-benzylpyrazole (4a), 4-bromoquinoline (4r), and 5-bromo-2-aminopyrimidine (4y) represent structural diversity with regard to heterocycle scaffolds and electron density. Scheme 2. Reaction Optimization by Evaluation of Ligandsa

a

The yields were determined by 1H NMR using an internal standard. B

DOI: 10.1021/acs.orglett.9b02414 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Substrate Scope

Scheme 4. Synthetic Applications toward Pharmacologically Active Molecules

a With 0.5 mol % Pd G4 dimer and 1.2 mol % ligand 1. bWith 1.0 mol % Pd G4 dimer and 2.4 mol % ligand 1. cThe yield was determined by 1 H NMR using an internal standard. See Scheme 7 for the isolated yield of the corresponding C−C bond coupling product employing the one-pot Miyaura borylation/Suzuki coupling protocol. dThe crude boronic ester 5l was further oxidized to the corresponding hydroxy-containing product prior to purification, with the yield referring to the final product (over two steps). See SI for details. e With 0.5 mol % Pd2dba3 and 1.2 mol % ligand 1. fStarting from aryl iodide.

a

The reaction was conducted using THF as solvent at 80 °C.

inhibitor19 and a five-lipoxygenase activating protein (FLAP) inhibitor.20 The Miyaura borylation reaction of heteroaryl substrates also shows good potential for scaling-up under an even lower catalyst loading. As shown in Scheme 5, the boronic ester product 5i can be isolated in gram scale using a 0.05 mol % loading of Pd G4 dimer and 0.12 mol % loading of ligand 1. Encouraged by the successful Miyaura borylation reactions, we then sought to expand the use of ligand 1 in a broader

precursors of pharmacologically active molecules (Scheme 4). Pleasingly, 5-bromopyrimidine derivative 4w could be converted into product 5w, an intermediate toward a GPR 119 agonist.16 Pyrazolyl bromide 4x proceeded smoothly to furnish the boronic ester 5x, which can be further carried through the synthetic routes to access the anticancer drug Crizotinib17 and a c-Met kinase inhibitor.18 Moreover, excellent yield could be obtained for unprotected aminopyrimidine substrate 4y with the desired boronic ester 5y being an key precursor en route to a phosphoinositide-3-kinase

Scheme 5. Gram-Scale Reaction

C

DOI: 10.1021/acs.orglett.9b02414 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters range of Pd-catalyzed couplings. It was revealed that the same combination of Pd G4 dimer and ligand 1 is a versatile and effective catalyst. With minor alternations from the aforementioned standard conditions (cf. Scheme 2), productive applications included Suzuki−Miyaura coupling3a,21 between 1-nathphyl boronic acid and sterically demanding aryl electrophiles (Scheme 6a, products 6a−6c), Negishi arylation22 of 2-bromopyrazine (Scheme 6b, product 7), and the arylation of a 1-indanone derivative23 affording the tertiary fluoride 8 (Scheme 6c).

Scheme 7. Applications of diAnthPhos (1) in One-Pot Miyaura Borylation/Suzuki Coupling Reactionsa

Scheme 6. Applications of diAnthPhos (1) in Pd-Catalyzed Coupling Reactions

a

All yields refer to the overall isolated yields over two steps. bReaction time for the Suzuki coupling step was 48 h.

The utility of ligand 1 is further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol11a,24 for heteroaryl-containing substrates, affording various C−C coupling products with high yields in an operation-efficient manner (Scheme 7). After the Pd-catalyzed borylation step, base, deoxygenated water, and the second electrophile were added to the crude reaction mixture. Then the Suzuki coupling step could proceed smoothly at elevated temperature, without the need for workup procedures or any additional Pd catalyst/ ligand. On one hand, this one-pot protocol could enable facile synthesis of heterocycle-derived coupling products from two distinct electrophiles without the isolation of boronic esters which may be unstable or time-consuming to separate (Scheme 7a). On the other hand, the productive formation of various heteroaryl-heteroaryl coupling products opens a new pathway for the rapid construction of functionalized heterocycle-rich compounds, and concurrently establishes the robustness of the Pd/ligand 1 catalyst (Scheme 7b). In summary, a novel anthracene photodimer-derived monophosphine diAnthPhos (1) has been prepared in two steps as an effective ligand for Pd-catalyzed coupling reactions. In particular, the combination of Pd G4 dimer and ligand 1 is a highly efficient catalyst to facilitate Miyaura borylation and one-pot Miyaura borylation/Suzuki coupling of heterocycle-

containing electrophiles at a low catalyst loading, among other versatile applications. The straightforward two-step synthesis of 1 should allow scalable access and diverse derivatizations for new ligand development. Considering the productive chemistry involving phosphine-based ligands and reagents, we expect a profound opportunity to explore the unique dianthracene core as the key feature for new molecule designs. Continuing investigation in this direction is currently underway and will be reported in due course.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02414. Experimental procedures and spectroscopic data for new compounds (PDF) D

DOI: 10.1021/acs.orglett.9b02414 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Accession Codes

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CCDC 1919887 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chen-Ho Tung: 0000-0001-9999-9755 Li-Zhu Wu: 0000-0002-5561-9922 Huan Cong: 0000-0003-1687-2404 Author Contributions

X.W. and W.-G.L. contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Strategic Priority Research Program of Chinese Academy of Sciences (XDB17000000), the National Key Research and Development Program of China (2017YFA0206903), the National Natural Science Foundation of China (21672227), the Recruitment Program of Global Experts, K. C. Wong Education Foundation, and the TIPC Director’s Fund is gratefully acknowledged. We thank Dr. Chong Han (Genentech) for helpful discussions. Prof. Congyang Wang (Institute of Chemistry, CAS) and Drs. Xiaodi Yang (Shanghai University of Traditional Chinese Medicine), Jie Su, and Wen Zhou (Peking University) are acknowledged for assistance with compound characterizations.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b02414 Org. Lett. XXXX, XXX, XXX−XXX