Oxygenation Approach to Functionalized

Nov 27, 2017 - The prevalence of phenanthridines as an important core structure among natural products, pharmaceutical molecules, and other functional...
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Crossover-Annulation/Oxygenation Approach to Functionalized Phenanthridines by Palladium−Copper Relay Catalysis Xiang Liu, Renjie Mao, and Cheng Ma* Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, China S Supporting Information *

ABSTRACT: A tandem crossover-annulation and oxygenation process of conjugated enediyne-acids and orthoalkynylanilines was achieved by palladium−copper relay catalysis under an oxygen atmosphere, giving access to the three-component assembly of 9-acylphenanthridine compounds.

T

Scheme 1. Palladium-Catalyzed Intermolecular Cascade Polycyclization of Internal Alkynes

he prevalence of phenanthridines as an important core structure among natural products, pharmaceutical molecules, and other functional materials has evoked considerable interest of chemists in the preparation of this structural motif over the past decades.1 In this content, the transition-metalcatalyzed intermolecular cascade annulations of benzenoid compounds provides an attractive strategy for the synthesis of densely substituted penanthridine derivatives because of the accessibility of diverse benzenoid substrates comparing with conventional ortho-functionalized biaryls.2 For example, Zhu,3a Lautens,3b and Malacria and co-workers3c independently established a set of palladium-catalyzed formal [4 + 2] annulation processes to construct phenanthridine frameworks.3 A few formal [3 + 3] cyclization routes through sequential C−N formation and C−C coupling reactions have also been exploited.4 In addition, the Ru- or Rh-catalyzed [2 + 2 + 2] cyclotrimerizations of preorganized diynes with alkynes could provide an elegant bicyclization route to this cyclic skeleton, albeit with tremendous difficulty in performing a regioselective cyclization with unsymmetrically substituted alkynes.5 Despite impressive progress, there remains a demand of conceptually novel and efficient cyclization protocols for functionalized penanthridine synthesis. However, palladium-catalyzed cascade cyclizations of alkynes are among the most versatile methods for the direct construction of polycycle skeletons.6 The development of atom-economical elementary reactions, such as nucleophilic reactions, direct arylation/C−H functionalization, and oxidative carbocyclizations, highlights the recent advance in this field.7 Some intermolecular reactions between ortho-alkynylanilines and other functionalized aryl alkynes were exploited to deliver Ncontaining aromatic compounds,8 such as the Pd(0)-initiated biscyclizations of aryl bromides and ortho-alkynylanilines to benzocyclopentene-fused quinolines (Scheme 1a)8a and the challenging oxidative heterodimerizations of two nucleophilebearing internal alkynes to conjugated indoles (Scheme 1b).8b Inspired by these studies and our recent results on the tandem formal dimerization/oxygenative carbonylation of enediyne scaffolds to naphthalene frameworks (Scheme 1c),9 we have envisioned that the readily accessible enediyne compounds 110 © 2017 American Chemical Society

may partake in novel transition-metal-catalyzed cascade polycyclizations with other nucleophile-containing internal alkynes and thereby provide a general synthetic strategy for fused heterocyclic compounds. 11 Herein, we report an unprecedented tandem crossover-annulation/oxygenation process of enediyne acids with ortho-alkynylanilines by palladium− copper relay catalysis under an oxygen atmosphere,12 giving Received: November 3, 2017 Published: November 27, 2017 6704

DOI: 10.1021/acs.orglett.7b03427 Org. Lett. 2017, 19, 6704−6707

Letter

Organic Letters Scheme 2. Reactions of 1a and 2-Alkynylanilines 2a

access to the expeditious synthesis of 9-acylphenanthridines (Scheme 1d). Our initial studies were performed with (E)-5-phenyl-2(phenylethynyl)pent-2-en-4-ynoic acid (1a) and aniline 2a in DMF at 30 °C (Table 1). While no productive conversions were Table 1. Optimization of Reaction Conditionsa

entry

Cu salt (equiv)

temp (°C)

time (h)

3aa/1a dimerb (%)

c

none none CuBr2 CuBr CuCl2 Cu(OAc)2 CuI CuI (0.1) CuI (0.5) CuI CuI CuI

30 30 30 30 30 30 30 30 30 0 60 30

24 24 24 24 24 24 24 24 15 48 6 24

−/− 15/trace 65/13 25/trace 21/trace 35/trace 78/12 70/15 72/13 70/8 69/23 93/trace

1 2 3 4 5 6 7 8 9 10 11 12d a

Unless otherwise noted, the reaction was carried out using 1a (0.2 mmol), 2a (0.3 mmol), PdCl2 (5 mol %), and Cu salt (0.2 equiv) in anhydrous DMF (1.5 mL) under O2 (1 atm). bIsolated yield. cWithout PdCl2. dWith MS 3 Å (50 mg).

a

Reagents and conditions: 1a (0.2 mmol), 2 (0.3 mmol), PdCl2 (5 mol %), CuI (0.2 equiv), and MS 3 Å (50 mg) in DMF (2.0 mL) under O2 (1 atm) at 30 °C, 24 h; then CH3I (0.4 mmol), K2CO3 (0.4 mmol), 2 h, N2. The yields are of the isolated products.

observed in the absence of any catalysts, the mixture of 1a and 2a furnished 9-acylphenanthridine 3aa in 15% isolated yield upon treatment with 5 mol % of PdCl2 under O2 (1 atm) after 24 h (Table 1, entries 1 and 2). The addition of 0.2 equiv of CuBr2 facilitated this palladium-catalyzed aerobic conversion13 to give 3aa in 65% yield, however, along with the dimer of 1a (13%) and some undetermined byproducts deriving from aniline 2a (Table 1, entry 3). Nevertheless, when CuBr2 was switched to CuBr, CuCl, or Cu(OAc)2, respectively, complex conversions occurred and led to a sharply decreasing yield (Table 1, entries 4−6). Among those copper catalysts examined, CuI proved to be optimal and afforded 3aa in 78% yield (Table 1, entry 7). Reducing the amounts of CuI from 0.2 to 0.1 equiv had little effect on the formation of 3aa, and the use of 0.5 equiv of CuI accelerated the conversion but in a similar yield (Table 1, entries 8 and 9). It was also found that the yield of 3aa dropped with variation of reaction temperature, and a higher temperature would prompt the homodimerization of 1a (Table 1, entries 10 and 11). The use of 3 Å molecular sieves to remove in situ generated H2O14 could almost completely inhibit the dimerization of 1a and cleanly delivered 3aa in 93% isolated yield (Table 1, entry 12), and the structure of 3aa was unambiguously determined by single-crystal X-ray analysis. The functional group tolerance of this tandem crossoverannulation/oxygenation process was screened with the reactions of acid 1a and a scope of 2-alkynylanilines 2 (Scheme 2). Due to the poor solubility of phenanthridine acids 3, their corresponding ester derivatives 4 were produced as products. Accordingly, after in situ methylation with CH3I under basic conditions, ester 4aa was isolated in 91% yield. A wide variety of functional groups including a halogen group (−Br and −Cl), electron-withdrawing

groups (−CN and − CF3), and electron-donating groups (−OMe and − CH3) could be installed at the aniline moiety of 2 to deliver the targeted esters 4 in good yield. Nevertheless, it was found that the nitrile-containing product 4ac was forged in a relatively low yield (76%), probably because of some competing conversions such as cycloadditions5d originating from the coordination between nitrile groups with transition-metal catalysts. However, a set of diaryl alkynes 2 (R4 = aryl) also worked well with 1a, rendering 4ai, 4aj, and 4ak in 80−85% yield. Next, the scope of enediyne acids 1 was examined (Scheme 3). A set of acids 1 was able to react with aniline 2a selectively to furnish phenanthridine compounds 4. Generally, good yields and high selectivity were observed for a variety of diaryl-substituted enediynes 1 possessing different electronic properties on the benzene rings. Electron-donating groups (−Me and −OMe) and electron-withdrawing groups (−NO2 and −Cl) were wholly tolerated. Other aromatic substituents including 1-naphthyl and benzo[d][1,3]dioxol-5-yl were also effective to deliver phenanthridines 4ea and 4ga in 77% and 81% yields, respectively. Moreover, diverse alkyl-substituted substrates 1 could be introduced to this reaction for the formation of products 4ha, 4ia, 4ja, 4ka, and 4la in 82−90% yield. As shown in Scheme 4, this three-component transformation could be readily manipulated on a multigram scale to form acid 3ai in 87% isolated yield. While the copper-catalyzed protodecarboxylation of 3ai delivered ketone 5ai in good yield, the Wolff−Kishner reduction of 3ai gave rise to diarylmethane 6705

DOI: 10.1021/acs.orglett.7b03427 Org. Lett. 2017, 19, 6704−6707

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Organic Letters Scheme 3. Scope of Enediyne Acids 1a

Scheme 5. Proposed Reaction Pathway

a

Reagents and conditions: 1 (0.2 mmol), 2 (0.3 mmol), PdCl2 (5 mol %), CuI (0.2 equiv), and MS 3 Å (50 mg) in DMF (2.0 mL) under O2 (1 atm) at 30 °C, 24 h; then CH3I (0.4 mmol), K2CO3 (0.4 mmol), 2 h, N2. The yields are of the isolated products.

alkyne unit.8a Next, the formal intramolecular syn-aminoalkenylation of alkyne leads to the bicyclization of intermediate II to enamine III and its tautomer III′, along with the release of a Pd(0) species, which could be oxidized to the palladium(II) catalyst using dioxygen as the terminal oxidant. Subsequent Cucatalyzed oxygenation12 of intermediates III and/or III′ with O2 would produce product 3, most likely through the spontaneous ring−chain tautomerism of hemiacetal V, arising from fragmentation of putative peroxide species IV.16 However, when TEMPO is used instead of O2 in the presence of stoichiometric amounts of palladium catalysts, adduct 8 would be furnished. In summary, we have reported the tandem crossoverannulation and oxygenation reaction of accessible enediyne acids and 2-alkynylanilines by palladium−copper relay catalysis under oxygen atmosphere. Taking advantage of a carboxyldirected coupling and decoupling strategy,17 this unprecedented process provides an efficient three-component approach to the regio- and chemoselective preparation of densely substituted phenanthridines.

Scheme 4. Synthesis of Phenanthridine Derivatives

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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.7b03427. Experimental procedures and characterization data of new compounds (PDF)

6ai. Treated by H2SO4, the intramolecular Friedel−Crafts acylation of 6ai furnished polycyclic ketone 7ai. As expected, the control experiment using a radical scavenger 2,2,6,6tetramethyl-1-piperidine-1-oxyl (TEMPO) allowed the formation of adduct 8aa upon treatment with 100 mol % of PdCl2 and CuI (0.2 equiv) under N2. These results hinted that a benzyl radical was probably generated in this process and would be responsible for the subsequent conversion. A mechanistic proposal is outlined in Scheme 5. Thus, initial intramolecular cyclization of enediyne acid 1 through a 5-endodig anti-oxypalladation15 delivers vinylpalladium species I, which conducts the syn-carbopalladation of unsymmetrically substituted alkyne 2 to forge II with excellent regioselectivity enabled by the coordination effects of an adjacent amino group and

Accession Codes

CCDC 1583796 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 data_ [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]. 6706

DOI: 10.1021/acs.orglett.7b03427 Org. Lett. 2017, 19, 6704−6707

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Organic Letters ORCID

(10) For palladium-catalyzed enediyne synthesis, see: (a) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Tetrahedron 2013, 69, 7869. For other recent examples, see: (b) Li, Z.; Ling, F.; Cheng, D.; Ma, C. Org. Lett. 2014, 16, 1822. (c) Danilkina, N. A.; Kulyashova, A. E.; Khlebnikov, A. F.; Bräse, S.; Balova, I. A. J. Org. Chem. 2014, 79, 9018. (d) Lee, J. T. D.; Zhao, Y. Angew. Chem., Int. Ed. 2016, 55, 13872. (11) For recent reviews of metal-catalyzed annulation reactions of conjugated enediynes, see: (a) Raviola, C.; Protti, S.; Ravelli, D.; Fagnoni, M. Chem. Soc. Rev. 2016, 45, 4364. (b) Asiri, A. M.; Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 4471. (c) Hashmi, A. S. K. Acc. Chem. Res. 2014, 47, 864. (d) Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. Chem. Rev. 2013, 113, 7089. (12) For reviews of Cu-catalyzed aerobic oxygenation, see: (a) McCann, S. D.; Stahl, S. S. Acc. Chem. Res. 2015, 48, 1756. (b) Liang, Y.-F.; Jiao, N. Acc. Chem. Res. 2017, 50, 1640. For aerobic carbo- and amino-oxygenation of alkynes, see: (c) Zheng, J.; Li, Z.; Wu, W.; Jiang, H. Org. Lett. 2016, 18, 6232. (d) Wang, Q.; Huang, L.; Wu, X.; Jiang, H. Org. Lett. 2013, 15, 5940. (e) Toh, K. K.; Sanjaya, S.; Sahnoun, S.; Chong, S. Y.; Chiba, S. Org. Lett. 2012, 14, 2290. (f) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 28. (13) For reviews of Pd-catalyzed aerobic oxidation reactions, see: (a) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (b) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736. (c) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854. (d) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (14) For a discussion on molecular sieves in palladium-catalyzed aerobic alcohol oxidation, see: Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org. Chem. 2006, 71, 1861. (15) For a discussion on the Baldwin’s ring closure rules, see: Alabugin, I. V.; Gilmore, K. Chem. Commun. 2013, 49, 11246. (16) Given the distinct role of CuI in the present conversion, it was proposed that hemiacetal V might be generated from peroxide species IV through Landolt reaction. (17) For selected reviews, see: (a) Bielski, R.; Witczak, Z. Chem. Rev. 2013, 113, 2205. (b) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.

Cheng Ma: 0000-0002-2456-6725 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21372196 and 21572199) for financial support

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DOI: 10.1021/acs.orglett.7b03427 Org. Lett. 2017, 19, 6704−6707