[[journaltype]]國外[[incitationindex]]SCI[[ispeerreviewed]]

謝仁傑

An efficient and concise procedure for the ligand-free copper-catalyzed cascade reaction of C–O and
C–N bond coupling was developed, which afforded various (NH)-phenanthridinones in moderate to
good yields with tolerance of a wide variety of substrates. This method could be useful for the syntheses
of natural alkaloids.補正完

Chen, Yan-Fu

Tamkang University Institutional Repository

Organic Chemistry Frontiers

An Efficient Synthesis of (NH)-Phenanthridinones via Ligand-Free Copper-Catalyzed Annulation

ORGANIC CHEMISTRYFRONTIERSRESEARCH ARTICLECite this: Org. Chem. Front., 2014, 1,253Received 25th December 2013,Accepted 2nd February 2014DOI: 10.1039/c3qo00082frsc.li/frontiers-organicAn eﬃcient synthesis of (NH)-phenanthridinonesvia ligand-free copper-catalyzed annulation†Yan-Fu Chen, Yi-Sheng Wu, Yu-Huei Jhan and Jen-Chieh Hsieh*An eﬃcient and concise procedure for the ligand-free copper-catalyzed cascade reaction of C–O andC–N bond coupling was developed, which aﬀorded various (NH)-phenanthridinones in moderate togood yields with tolerance of a wide variety of substrates. This method could be useful for the synthesesof natural alkaloids.IntroductionPhenanthridinone is an important building block for organicsynthesis because it has been frequently discovered in a widevariety of natural alkaloids1 and in addition possesses severaltypes of bioactivity such as antilymphoma, antileukemia, anti-tumor, antiviral and inhibitor of HIV-1 integrase etc.2 Tra-ditional approaches for the syntheses of phenanthridinonesare via intramolecular annulation of the corresponding amino-carboxylatebiphenyls3 or the reductive cyclization of nitro-carbonylbiphenyls.4 Other common strategies include radicalcyclization,5 Schmidt reaction/electrophilic aromatic substi-tution of biphenylcarboxylic acids,6 Beckmann rearrangementof fluorenones,7 microwave-assisted anionic ring closure reac-tion,8 anionic cycloaromatization of 1-aryl-3-hexen-1,5-diynes,9oxidative coupling reaction of N-arylbenzamide10 and Pd-cata-lyzed annulation of aryne with o-halobenzamides.11In recent years, palladium-catalyzed C–H functionalizationhas been well developed and used as a powerful method forcarbon–carbon12 and carbon–heteroatom13 bond formation.Development toward the syntheses of phenanthridinones hasalso turned to palladium-catalyzed C–H bond activation. Inparticular, the palladium catalytic cyclization reactions ofN-aryl-2-bromobenzamide14 and N-arylbenzamide15 are oftenreported. Domino processes for multiple C–H bond activationswere also carried out by Wang16 and Cheng’s17 researchgroups. However, these domino reactions were restricted to thesynthesis of N-methoxyphenanthridinones and further photo-chemical reaction was required to provide the corresponding(NH)-phenanthridinones for other synthetic applications.Very recently, novel procedures for the synthesis of phenan-thridinones through an oxidative insertion of carbon monox-ide to 2-aminobiaryls were disclosed independently by Orito,Zhu and Chuang.18 Their protocols selectively provide diﬀerentsort of phenanthridinones. However, only one case amongthese reports is related to the synthesis of (NH)-phenanthridi-nones. Therefore, the development of novel methods toaddress this issue is still desirable. Our experience in catalyticcoupling reactions involving nitriles19 encouraged us toexplore the possibility of the synthesis of free (NH)-phenanthri-dinones by a coupling reaction involving a nitrile. Herein, wereport the first example of an eﬃcient and convenient syn-thetic pathway to form (NH)-phenanthridinones through acopper-catalyzed cyclization reaction involving C–O and C–Nbond coupling of a nitrile.Results and discussionOur initial studies used 2′-bromo-[1,1′-biphenyl]-2-carbonitrile(1a) as a model substrate (Table 1, entry 1), which was treatedwith 5 mol% CuI and 3 equiv. of NaOH in 1.0 mL tBuOH at120 °C for 24 h; and the corresponding phenanthridinone (2a)was obtained in 69% NMR yield. Product 2a was confirmed by1H NMR, 13C NMR and HRMS analysis. We also observed asmall amount of undefined side products and biphenylamideafter working up the reaction.To optimize the reaction conditions, the eﬀect of solvent,base, reaction temperature and copper source were investi-gated (Table 1). We first examined the copper source for thisreaction (entries 2–4). Among the various copper sourcesemployed, CuI was found to be the most eﬀective catalyst, pro-viding the desired product 2a in 69% NMR yield (entry 1).Screening of the base revealed that NaOH and KOH gavesimilar results (entries 1 and 5). The cyclization reaction couldnot be completed within 24 h when using LiOH as base (entry6). The use of a NaOtBu–H2O system (entry 7) also aﬀorded the†Electronic supplementary information (ESI) available: Experimental procedure,characterization data, spectral data and copies of all compounds. See DOI:10.1039/c3qo00082fDepartment of Chemistry, Tamkang University, New Taipei City, 25137 Taiwan,Republic of China. E-mail: jchsieh@mail.tku.edu.tw; Fax: +886-2-26209924;Tel: +886-2-26215656 ext 2545This journal is © the Partner Organisations 2014 Org. Chem. Front., 2014, 1, 253–257 | 253desired product 2a in lower yield. It was found that theamount of base significantly aﬀected the yield of 2a, and 4.0equiv. of NaOH provided the best yield for this cyclization reac-tion (entry 8). Some unidentified compounds and biphenyl-amide were detected when the temperature was increased to140 °C (entry 9). However, only desired product 2a wasobtained when the reaction temperature was decreased to100 °C (entry 10).The eﬀect of solvent was investigated as well, and it wasfound that only highly polar solvents such as DMF and DMSOallowed the reaction to proceed successfully (entries 12 and13). However, the substrate 1a could be fully converted onlywhen using tBuOH as solvent. In addition, there was no sig-nificant diﬀerence when running the reaction under nitrogenatmosphere or under air (entry 14). Moreover, the present cycli-zation reaction could not aﬀord any desired product 2awithout a copper source (entry 15).The copper-catalyzed cyclization reaction was successfullyextended to various substrates (1), and the results are listed inTable 2. The reaction required at least 24 h to fully consumethe substrates (1). As indicated, the reaction worked well forvarious substrates and both electron-donating and electron-withdrawing substituents on the aryl bromide moiety were welltolerated to give the corresponding products in moderate togood yields (2a–2j). Substituents para to the bromide (2h–2j)dramatically aﬀected cyclization. Thus, a substrate with anelectron-withdrawing group provided a higher yield of thecorresponding product (2h) than those with an electron-donat-ing group (2i, 2j). We frequently detected a small amount ofthe corresponding 2-bromobiarylamide for substrates with anelectron-donating group on the aryl bromide moiety, whichcaused lower yields of the desired products (2c, 2d, 2i and 2j).Substituents on the benzonitrile moiety were also well toler-ated (2k–2y); however, the yields of the desired products werenot only decided by the substituents on the benzonitrilemoiety but also by the substituents on the aryl bromidemoiety. When hydrophilic substituents such as methoxygroup, chloride or fluoride were introduced into the phenan-thridinones, the yields of the desired products were generallyTable 1 Optimization of reaction conditionsaEntry [Cu] Base (n) Solvent Temp (°C)Yieldb (%)1a 2a1 CuI NaOH (3) tBuOH 120 0 692 CuBr NaOH (3) tBuOH 120 0 543 Cu2O NaOH (3) tBuOH 120 0 624 Cu(OAc)2 NaOH (3) tBuOH 120 0 495 CuI KOH (3) tBuOH 120 0 666 CuI LiOH (3) tBuOH 120 6 527 CuI NaOtBu (4)–H2O (1.1) tBuOH 120 23 358 CuI NaOH (4) tBuOH 120 0 879 CuI NaOH (4) tBuOH 140 0 6510 CuI NaOH (4) tBuOH 100 0 9611 CuI NaOH (4) tBuOH 80 17 7312 CuI NaOH (4) DMF 100 39 3213 CuI NaOH (4) DMSO 100 21 2514c CuI NaOH (4) tBuOH 100 0 9315 None NaOH (4) tBuOH 100 47 0a Reactions were carried out using 0.1 mmol (1.0 equiv.) 2′-bromo-[1,1′-biphenyl]-2-carbonitrile (1a) with 5 mol% [Cu] and base (n equiv.)in 1.0 mL solvent at T °C for 24 h. b 1H NMR yield based on internalstandard mesitylene. cUnder N2.Table 2 Scope of phenanthridinonesa,ba Reactions were carried out using 0.5 mmol (1.0 equiv.) substrate 1with 5 mol% CuI, 4.0 equiv. NaOH in 5.0 mL tBuOH at 100 °C for24 h. b Isolated yield. c 36 h.Research Article Organic Chemistry Frontiers254 | Org. Chem. Front., 2014, 1, 253–257 This journal is © the Partner Organisations 2014lower (2n, 2o, 2p, 2q and 2r). This is probably due to thepartial solubility of the products in water during the extraction.It is noteworthy that product 2k is a natural alkaloid known asphenaglydon, which has been isolated from the lipophilic leafextract of Glycosmis cyanocarpa (Rutaceae).20Reactions for substrates with a substituent ortho to thenitrile group (2t, 2u, 2v and 2w) did not go to completion evenafter a longer reaction time. The ortho substituents wouldretard the addition of hydroxide to nitrile and reduce theyields of the corresponding products. Substrates with a metaCF3 group on the benzonitrile moiety and with a naphthyl-nitrile moiety were also well tolerated to aﬀord the corres-ponding products 2x and 2y in excellent yields. Substratescontaining a picolinonitrile moiety or an electrophile such as aketone group were not tolerated and the reactions providedmessy crude spectra.In order to extend the application of the present method,we selectively synthesized two natural alkaloids crinasiadineand trisphaeridine by using our developed protocol as the keystep (Scheme 1). These two natural alkaloids represent thebasic skeletons of the Amaryllidaceae alkaloids, which appearin a wide range of natural alkaloids and bioactive compounds.Our synthetic route began from a commercially available com-pound 6k. Transformation of the aldehyde to nitrile and thesubsequent Suzuki coupling reaction provided the substrate1z. Under the standard conditions of the present copper cataly-sis, 1z was then converted to crinasiadine 2z in 4 steps with36% overall yield. Further transformation of 2z to its corres-ponding phenanthridine aﬀorded another natural alkaloid tri-sphaeridine 3b with two more steps and 25% overall yield.Conversion of 2z or 3b to other natural alkaloids can be easilyachieved by N-alkylation. For example, N-methylation of 2zand 3b can lead to other two natural alkaloids N-methylcrina-siadine21 and bicolorine.22 In addition, more complicatedcrinasiadine analogues (C1, C2, C3 and C4) could be syn-thesized by this pathway in moderate to good yields.The present methodology could be conducted for gram-scale synthesis as well. As shown in Scheme 2, conversion of1x to 2x under the standard conditions was carried out on a5 mmol scale with 76% isolated yield, which implied thepotential applications in industry. We also synthesized var-iously poly-substituted phenanthridine derivatives via for-mation of the corresponding triflate compound 3c as animportant building block in excellent yield, and various 6-sub-stituents could be introduced into the phenanthridinethrough palladium or nickel catalytic coupling reactions. 6-Aryland 6-alkyl phenanthridines could be respectively aﬀorded bySuzuki and Kumada type coupling reactions, and 6-H-phenan-thridine could be provided by palladium catalyzed reductionwith formic acid. Thus, the 6-phenylphenanthridine (3d),6-ethylphenanthridine (3e) and 6-H-phenanthridine (3f) weresuccessfully generated in 74%, 28% and 81% yields, respectively.Although a more detailed study might be required to fullyunderstand the mechanism of this copper-catalyzed annula-tion, a tentative pathway can be proposed according to theabove results and previous report (Scheme 3).19b Thus, theScheme 1 Syntheses of crinasiadine, trisphaeridine and analogues ofcrinasiadine.Scheme 2 Application to large-scale synthesis and syntheses ofvarious phenanthridines.Scheme 3 Proposed mechanism.Organic Chemistry Frontiers Research ArticleThis journal is © the Partner Organisations 2014 Org. Chem. Front., 2014, 1, 253–257 | 255catalytic reaction is likely to be initiated by the coordination ofthe nitrile on compound 1 to a Cu(I) complex, which acceler-ates the following nucleophilic addition by hydroxide to formcomplex A. The oxidative addition of complex A in an intra-molecular manner then occurred to generate Cu(III) species(complex B). The subsequent reductive elimination providescompound 3 and regenerates the Cu(I) species. Tautomeriza-tion of 3 aﬀords the desired product 2.ConclusionsIn conclusion, we have developed a novel method for thecopper-catalyzed cascade reaction of C–O and C–N bond coup-ling. This method eﬃciently provides poly-substituted (NH)-phenanthridinones in moderate to good yields with toleranceof a wide variety of substrates. In addition, this method couldbe also applied to synthesize three natural alkaloids in a shortnumber of steps with good overall yields. Moreover, conversionof the (NH)-phenanthridinone to the corresponding phenan-thridines with various 6-substituents was carried out as well.Further studies to explore the possibility to extend the appli-cations of this catalytic system are currently underway.ExperimentalGeneral procedure for the copper-catalyzed cyclizationTo a screw-capped vial (10 mL) were added CuI (0.025 mmol,4.8 mg, 5 mol%), NaOH (2.0 mmol, 80 mg, 4.0 equiv.), andsubstrate 1 (0.5 mmol, 1.0 equiv.) in tBuOH (5 mL). The vialwas then sealed with a cap and allowed to stir at 100 °C for24 h. The crude reaction mixture was diluted with ethyl acetate(20 mL) and H2O (10 mL). The mixture was then kept stirringat 70 °C for 30 min then the aqueous layer was removed andthe organic layer was concentrated in vacuo. The residue wasallowed to quickly flow through a short flash column chrom-atography by using ethyl acetate as eluent and then concen-trated in vacuo, following washed by CH2Cl2 to provide thepure product. 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An Efficient Synthesis of (NH)-Phenanthridinones via Ligand-Free Copper-Catalyzed Annulation

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