Letter pubs.acs.org/OrgLett
Palladium-Catalyzed C−H Bond Activation by Using Iminoquinone as a Directing Group and an Internal Oxidant or a Co-oxidant: Production of Dihydrophenanthridines, Phenanthridines, and Carbazoles Selvam Raju,† Pratheepkumar Annamalai,† Pei-Ling Chen,‡ Yi-Hung Liu,§ and Shih-Ching Chuang*,† †
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan § Instrumentation Center, National Taiwan University, Taipei 30010, Taiwan ‡
S Supporting Information *
ABSTRACT: A palladium-catalyzed C−H bond activation reaction, via a redox-neutral pathway, for the preparation of dihydrophenanthridine, phenanthridine, and carbazole derivatives from biaryl 2-iminoquinones is developed. The preinstalled iminoquinone was designed to act as a directing group for ortho C−H activation and an internal oxidant or a cooxidant. This catalysis proceeded through the following sequence: C−H bond activation, coordination and insertion of activated olefins, β-hydride elimination, H-shift, insertion, and protonation or β-hydride elimination. In addition, carbazoles can be prepared efficiently by using this method without the addition of external oxidants.
P
Scheme 1. Previous Work and Our Findings
henanthridine is a versatile scaffold and a critical building block for crucial heteroaromatic compounds. It is present in various naturally occurring compounds such as phenanthridine alkaloids,1 fluorescent chromophores,2 biologically active substances,3 and organic materials.4 In the past decades, C−H bond functionalization reactions catalyzed by transition metals have become atom-economic and eco-friendly reactions and provide a new and useful approach in synthetic organic chemistry for applications in the syntheses of bioactive heterocyclic compounds and material molecular structures.5 Such reactions differ from conventional methods, which use halogenated species as reactants. Phenanthridines and carbazoles can be synthesized from common starting materials, 2-arylanilines, through C−H bond activation.6 Miura reported the first synthesis of dihydrophenanthridines (Scheme 1a)7 from the reaction of N-tosyl-2-arylanilines with activated olefins under palladium catalysis, and Youn and co-workers followed this method.8 Li and co-workers reported a one-pot preparation of phenanthridines via oxidative C−C bond cleavage cyclization of biaryl-2-amines with olefins using palladium as the catalyst.9 Furthermore, phenanthridines were synthesized efficiently from 2-isocyanobiaryls with appropriate oxidants as initiators.10 We achieved palladium-catalyzed C2′−H activation of N-substituted 2-aminobiaryls followed by the insertion of [60]fullerene,11 CO,12 and diphenylacetylene13 to yield fullerobenzoazepines, phenanthridinones, and highly substituted naphthalenes, respectively. Gaunt14 and Miura15 developed a method for synthesizing carbazoles from N-substituted 2aminobiphenyls through Pd(II)- and copper(II)-catalyzed intramolecular coupling, respectively (Scheme 1b). Iminoquinone is a vital functionality in antineoplastic drugs and © 2017 American Chemical Society
actinomycin antibiotics.16 Recently, poloxin-2, an ester carrying the iminoquinone moiety, was found to induce mitotic arrest and apoptosis in cultured human tumor cells in a study elucidating the function of the Polo-like kinase 1 polo-box domain in living cells.17 Notably, N-acetyl p-benzoquinone imine is a cytochrome P-450-mediated oxidation product of acetaminophen.18 Metal-catalyzed redox-neutral C−H bond activation has attracted the interest of scientists because no exotic oxidants are Received: June 26, 2017 Published: July 18, 2017 4134
DOI: 10.1021/acs.orglett.7b01956 Org. Lett. 2017, 19, 4134−4137
Letter
Organic Letters Scheme 2. Substrate Scope Studya
required to perform these reactions. Generally, these reactions involve the cleavage of N−N or N−O bonds, and the cleaved residue is released as a byproduct. These redox-neutral reactions are found in ruthenium-, cobalt-, and rhodiumcatalyzed C−H bond functionalization.19 Benzoquinone has been frequently used as an oxidant in C−H functionalization, but it is not tolerated in all metal-catalysis reactions.20 Here, we propose using a new iminoquinone as a directing group, through a combination of biaryl-2-amines and substituted pbenzoquinones, and demonstrate that the substrates that are provided with an iminoquinone moiety undergo imine groupdirected C−H bond activation with iminoquinone as an internal oxidant or co-oxidant (Scheme 1c). This typical reaction rendered the syntheses of dihydrophenanthridine, phenanthridin-6(5H)-ylidenes, and carbazoles efficient. First, we studied the reaction of iminoquinone 2a with methyl acrylate (3a) in the presence of Pd(OAc)2 (10 mol %) in 1 mL of t-AmOH with 0.5 mL of acetic acid as a cosolvent at 120 °C for 24 h. It produced dihydrophenanthridine 4a and carbazole 7a in 61% with a molar ratio of 91:9 (Table 1, entry Table 1. Optimization of Reaction Conditionsa
a
All reactions were carried out with 2 (0.1 mmol), 3 (0.3 mmol), and Pd(OAc)2 (10 mol %) in 2 mL of PivOH under N2 at 120 °C for 24 h. b With 2 equiv of (vinylsulfonyl)benzene at 120 °C. entry
solvent (mL)
cosolvent (mL)
4a/7a
yielde (%)
1 2 3 4 5 6b 7c 8d 9 10
t-AmOH (1) HFIP (1) TFE (1) t-AmOH (1) t-AmOH (1) t-AmOH (1) t-AmOH (1) t-AmOH (1)
AcOH (0.5) AcOH (0.5) AcOH (0.5) PivOH (0.5) PivOH (1.0) PivOH (1.0) PivOH (1.0) PivOH (1.0) PivOH (2.0)
91:9 87:13
61 63 NDf 63 87 71 88 82 94 NDf
t-AmOH (2)
100:0 100:0 100:0 100:0 100:0 100:0
acrylates without external oxidants under palladium catalysis proceeded smoothly, affording their corresponding cyclization products 4a−f in good to excellent yields (78%−94%), whereas the reaction with phenyl acrylate produced product 4g in moderate yield 66%. Besides acrylates, alkenyl substrates, such as N,N-dimethyl acrylamide, (vinylsulfonyl)benzene and diethyl vinyl phosphonates, also reacted with iminoquinones to give cyclized products in moderate to good yields 64−88% (4h−j). Furthermore, the reactions using other substituted iminoquinones, such as R3 = 2,6-dimethyl and 2-tert-butyl, with methyl acrylate (3a) afforded their corresponding desired products 4k,l in 84−85% yields. Last, the interplay of the electronic effect (R1 and R2) on both the aryl rings also provided acceptable yields. We noticed that the electronic effect from the top ring R1 did not exert much impact on the reaction yields (4m and 4n, 80% and 77%, respectively), but that from the bottom ring R2 did influence yields drastically (4o and 4p, 63% and 92%, respectively). In short, dihydrophenanthridine can be efficiently synthesized in a redox-neutral system with iminoquinone as a directing group and an internal oxidant under palladium catalysis. We further evaluated other conditions for preparation of phenanthridin-6(5H)-ylidenes (see the Table S1 in the Supporting Information) and substrate scope with a variety of substituted iminoquinone 2-aminobiaryls (2a−w) and activated alkenes (3a−k), as shown in Scheme 3. As expected, a series of acrylates, such as Me, Et, nBu, cyclohexyl, and benzyl acrylates, were compatible with this protocol and produced good yields of phenanthridin-6(5H)-ylidenes (5a−e) at 72%−83%. However, unexpectedly, reactions with (vinylsulfonyl)benzene (3i) and acrylonitrile (3k) produced 5f−g in only moderate yields, 51% and 40%, respectively. Furthermore, reactions of substituted iminoquinones, R3 = 2,6-dimethyl (2b), 2-methyl (2c), and 2-tert-butyl (2d) with methyl acrylate afforded the phenanthridin-6(5H)-ylidenes 5h−j in 56−92% yields. We found that the substrate 2 with an electron-donating (methyl)
a
All of the reactions were performed with 2a (25.9 mg, 0.1 mmol), 3a (25.8 mg, 0.3 mmol), and 10 mol % of Pd(OAc)2 as a catalyst under N2 at 120 °C for 24 h unless otherwise stated. b100 °C. c110 °C. d130 °C. eYields were measured using 1H NMR spectroscopy with mesitylene as an internal standard. fND = not detected.
1). This reaction was examined with different alcoholic solvents such as hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE), but it only produced 63% of 4a and 7a in HFIP/ AcOH and gave no products in TFE/AcOH, respectively (entries 2 and 3). However, we found it more effective with use of pivalic acid as a cosolvent. The reaction generated up to 87% yield of product 4a with excellent selectivity; no carbazole was observed under these conditions (entries 4 and 5). Furthermore, we surveyed the reaction at temperatures of 100, 110, and 130 °C and noted that the reaction yield and product selectivity did not change much, providing 71%, 88%, and 82% yields, respectively (entries 6−8). To our delight, a remarkable increase of reaction yield to 94% was observed when pivalic acid was used as a sole solvent (entry 9). However, a control experiment with t-AmOH as a sole solvent did not produce 4a and 7a (entry 10). The scope of the cyclization reaction was examined with various iminoquinones (2a−w) and olefins (3a−j), as shown in Scheme 2. The reactions of iminoquinone 2a with alkyl 4135
DOI: 10.1021/acs.orglett.7b01956 Org. Lett. 2017, 19, 4134−4137
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Organic Letters Scheme 3. Substrate Scope Studya
iminoquinone as a directing group and an internal oxidant. With Cu(OAc)2/O2 as oxidants, however, compound 5a can be produced in 36% yield accompanied by 29% of iminoquinone (Scheme S1c). Furthermore, with only oxygen as the oxidant, it produced 5a in only 28% yield (Scheme S1d). Furthermore, we observed that Cu(OAc)2 can oxidize 6 to produce iminoquinone 2a in 86% yield (Scheme S1e). Based on the results of the above-mentioned experiments, we concluded that Cu(OAc)2 is a key oxidant for converting 6 to iminoquinone 2a, whereas the N-4-hydroxylphenyl functionality poorly directed C−H activation. The mechanism of the iminoquinone-directed ortho C−H activation was investigated through deuterium-labeling experiments (Scheme S2). A kinetic isotope effect study revealed kH/ kD values of 3.0 and 1.26 for formation of 4a and 5a in a 10 min reaction, indicating primary and secondary kinetic isotopic effects, respectively. The reaction is initiated by an iminoquinone-directed ortho C−H bond activation with palladium(II), which gives rise to the ortho-metalated complex I (Scheme 4). Palladacycle intermediate I undergoes insertion Scheme 4. Proposed Catalytic Cycle
a
All reactions were carried out with 2a (0.1 mmol), 3 (0.3 mmol), Pd(OAc)2 (10 mol %), and Cu(OAc)2 (0.5 equiv) in 1 mL of TFE at 120 °C for 24 h. b2 equiv of (vinylsulfonyl)benzene at 70 °C.
or -withdrawing group (trifluoromethoxy, fluoro, and chloro) on the upper aryl ring reacted smoothly to deliver the corresponding phenanthridin-6(5H)-ylidenes 5k−o in good yields (80−94%). However, substrates bearing electrondonating groups, such as methyl and methoxy groups, on the bottom aryl ring afforded their corresponding product 5p at 58%, accompanied by a transesterification product 5p′ at 24% as well as 5q at 60%. Substrates with electron-withdrawing groups such as chloro and difluoro moieties afforded the desired products (5r,s) in slightly low chemical yields (53%− 74%). Surprisingly, electronic effects between the aromatic rings of 2-aminobiaryls (2) afforded the desired products (5t− w) in moderate to good yields (58−92%) and with transesterification products as minor products (5t′ and 5u′). Only trace amounts of the trans-esterification products 5a′, 5k′, 5l′, 5r′, and 5v′ were observed in other cases. Finally, a substrate with the thienyl group produced 5x in a 66% yield. Thus, the present redox-neutral reaction with Cu(OAc)2 as a co-oxidant provided an efficient approach to accessing phenanthridin6(5H)-ylidenes under the optimal reaction conditions with a broad range of substrates. In the control experiments, the reduced substrate 6 underwent this developed palladium-catalyzed reaction with methyl acrylates to produce only trace amounts of 4a under the optimized conditions (Scheme S1a). Similarly, compound 5a was produced in only trace amounts from substrate 6 under the standard condition (Scheme S1b). These two experiments indicated that the reactions barely proceeded without
and protonation to give carbazoles 7a through intermediate VII. When palladacycle intermediate I reacts with activated olefins, it undergoes insertion to form an eight-membered palladacycle III. Subsequently, β-hydride elimination occurs and results in an ortho-alkenylated hydride complex IV. The putative palladium hydride complex undergoes an internal hydride shift, reducing the iminoquinone moiety to furnish complex V. Migratory insertion, a Michael-type nucleophilic addition, then occurs, causing the formation of an intermediate VI. Until this step, the valence charge of palladium is considered to be +2. Further, the intermediate VI was protonated by acidic solvent to give compound 4a. Thus, compounds 4a and 7a were formed through a redox-neutral pathway, and Pd(II) was regenerated to be involved in the next cycle. In the absence of acidic solvent, intermediate VI went through β-hydride elimination and removal of AcOH. It produced phenanthridin-6(5H)-ylidenes (5a) and generated Pd(0).21 Finally, Pd(0) was oxidized to Pd(II) by Cu(II), which furnished the catalytic cycle. We found that the iminoquinone 2 can be transformed to the N-4-hydroxyphenyl carbazoles 7a−e with 82−95% yields on treatment with 10 mol % of Pd(OAc)2 in TFE at 120 °C. This carbazole formation was tolerated with both electron-donating 4136
DOI: 10.1021/acs.orglett.7b01956 Org. Lett. 2017, 19, 4134−4137
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Organic Letters
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and -withdrawing functionalities on both aryl rings of 2 (Scheme 5). Finally, we attempted to remove the N-4Scheme 5. Substrate Scope Study
hydroxylphenyl moiety, even though the present method is limited to removing the protecting aryl group from amines. However, the prepared phenanthridin-6(5H)-ylidene 5a can be oxidized to produce 65% of deprotected phenanthridin-6(5H)one22 with 4 equiv of [bis(trifluoroacetoxy)iodo]benzene (PIFA) at 0 °C. In conclusion, we have demonstrated a strategy for the preparation of dihydrophenanthridines, phenanthridin-6(5H)ylidenes, and carbazoles with preinstalled iminoquinones as a directing group and an internal oxidant or co-oxidant using palladium catalysis.
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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.7b01956. Full experimental procedures, characterization data, and NMR spectra data (PDF) Crystallographic data for 2e (CIF) Crystallographic data for 4h (CIF) Crystallographic data for 5a (CIF) Crystallographic data for 5l′ (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shih-Ching Chuang: 0000-0002-6926-9812 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Ministry of Science and Technology of Taiwan for supporting this research financially (MOST104-2113-M009-014-MY3 and MOST105-2628-M-009-002-MY3).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01956 Org. Lett. 2017, 19, 4134−4137
