Letter pubs.acs.org/acscatalysis
Electrochemical Synthesis of Polycyclic N‑Heteroaromatics through Cascade Radical Cyclization of Diynes Zhong-Wei Hou,†,§ Zhong-Yi Mao,†,§ Jinshuai Song,‡ and Hai-Chao Xu*,† †
iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P.R. China ‡ Fujian Institute of Research on Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P.R. China S Supporting Information *
ABSTRACT: An electrochemical cyclization reaction of easily available urea-tethered diynes has been developed for the synthesis of nitrogendoped polycyclic aromatic hydrocarbons (PAHs). The employment of ferrocene as a mild and selective redox catalyst allows access to a variety of electron-rich PAHs including helicene-like structures without overoxidation. The electrosynthetic method involves an unprecedented amidyl radical cascade cyclization process to form three rings in a single operation. KEYWORDS: polycyclic aromatic hydrocarbon, radicals, cascade cyclization, organic electrochemistry, oxidation
P
Scheme 1. Synthesis of PAHs Through Cascade Radical Cyclization
olycyclic aromatic hydrocarbons (PAHs) are drawing increasing research interest because of their wide utility in material sciences.1 Heteroatom doping in the aromatic framework of PAHs is a useful technique to modulate their electronic structures and physicochemical characteristics, which can create novel material properties required for emerging applications.2 Currently, nitrogen is the most commonly used dopant among the various heteroatoms employed in the construction of polycyclic heteroaromatic molecules.2,3 Oxidative ring-fusion approaches are frequently employed for the assembling of PAHs.1c However, PAHs containing electronreleasing nitrogen atoms are prone to oxidative decomposition. Probably due to the difficulty in their synthesis, structuraldefined π-systems that possess electron-releasing nitrogens are limited, with pyrrole-based structures being most common.4 In contrast, various heteroaromatics containing electron-withdrawing pyridine-type nitrogens have been reported.2,3 The polyalkynes are attractive building blocks for the modular preparation of PAHs with defined structural and substitution patterns due to the high carbon ratios in these compounds and the availability of well-established crosscoupling reactions that can be used for their synthesis.5 However, there is considerable challenge in achieving chemoselective cyclization of polyalkynes consisting of alkyne structural units that carry similar substituents. In this regard, Alabugin has reported elegant tin-mediated radical-based processes that employed a tethered initiator6 or a traceless directing group7 to pinpoint the initial radical attack on the polyalkyne substrates (Scheme 1a). The development of tinfree technologies for promoting radical reactions, especially in a catalytic fashion, is of great importance for achieving green radical chemistry.8 We9 have been involved in developing electrochemical methods10,11 for promoting radical reactions and have recently established an amidyl radical cyclization of © XXXX American Chemical Society
monoalkynes for the synthesis of indoles.9b In inspired by both Alabugin’s and our own results, we speculated that cascade amidyl radical cyclization12,13 of polyalkynes could lead to novel PAHs. Herein, we report an unprecedented ferrocene (Cp2Fe)catalyzed electrochemical reaction to convert urea-tethered Received: June 28, 2017 Revised: July 27, 2017
5810
DOI: 10.1021/acscatal.7b02105 ACS Catal. 2017, 7, 5810−5813
Letter
ACS Catalysis Scheme 2. Substrate Scope¶
diynes to nitrogen-doped PAHs (Scheme 1b). Despite that the diynes are prone to base-promoted hydroamidation (Scheme S1) and the products are sensitive to overoxidation, the use of ferrocene as a mild redox catalyst in combination of continuous generation of the requisite base at the cathode (Scheme S2) ensure efficient access to a variety of electron-rich PAHs including helical structures.14 Unlike the tin-mediated reactions, the final five-membered ring remains conjugated. We started our investigation by identifying the optimal electrolysis conditions for the synthesis of the model PAH 2 from diyne 1 (R1 = Ph, R2 = R3 = R4 = H, Scheme 2). To avoid overoxidation of the electron-rich polyaromatic product, our previously developed conditions employing Cp2Fe as a catalyst were employed (see Table S1 of the Supporting Information for details of reaction optimization).9a,b After testing a range of reaction systems, the best results were obtained when the electrolysis was conducted under a constant current of 7.5 mA in an undivided cell equipped with a reticulated vitreous carbon (RVC) anode and a Pt plate cathode, using 5 mol % of Cp2Fe (Ep/2 = 0.45 V vs SCE in 1:1 THF/MeOH) as a redox catalyst, 1 equiv of Na2CO3 as an additive, and an electrolyte solution of nBu4NBF4 in refluxing THF/MeOH (1:1). Under these conditions, the desired product 2 was isolated in 78% yield. The use of a mild catalyst to promote the cascade cyclization instead of direct electrolysis15 was important to avoid overoxidation of the PAH product as the diyne 1 (Ep/2 = 1.43 V vs SCE) was oxidized at a potential much higher than that of 2 (Ep/2 = 0.89 V vs SCE). Consistent with our previous studies on Cp2Fe-catalyzed amidyl radical reactions,9a,b THF, Cp2Fe16 and the base additive were all crucial components of the reaction system. Replacing the electrolyte of nBu4NBF4 with other organic ammonium salts, such as Et4NBF4, nBu4NPF6 or Et4NOTs, also negatively affected product formation, albeit to lesser degrees (50−70% yields). On the other hand, performing the electrolysis reaction on a Pt- or graphite-based anode under different current densities all resulted in a substantial drop in yield. Increasing the current to 10 mA (54% yield) was found to have a more significant detrimental effect on reaction efficiency than lowering the current to 5 mA (76% yield). When the current was raised to 10 mA, the redox catalyst might not turn over fast enough to sustain the higher current and competitive oxidation of the product might happen leading to a reduced yield. It is noteworthy that the radical cyclization reaction showed no obvious sensitivity to oxygen as the product 2 was formed in 74% yield under air. We next explored the substrate scope of this electrolytic cascade cyclization reaction by varying the substituents on different positions of the diyne substrate (Scheme 2). Our results indicated that functional groups with different electronic properties, including the electron-donating Me group (3), halogens [F (4), Cl (5), Br (6)], as well as electronwithdrawing groups such as CF3 (7) and an ester (8), were all well tolerated on the phenyl ring A. Replacing phenyl ring A with a pyridyl ring was also tolerated (9). The reaction was compatible with various diyne substrates in which the phenyl ring B was substituted with Me (10), F (11), Cl (12) or a naphthyl group (13). Similarly, no significant impact on product formation was observed when the alkyne was capped with phenyl rings of diverse electronic properties (14−19), a naphthyl group (20), a pyridyl ring (21), different alkyl groups (23,24), or even a hydrogen (25). Diyne substrates carrying a complex steroid estrone (22)- or estradiol (26)-derived
¶
Reaction conditions: RVC anode (100 PPI, 1.2 cm × 1.2 cm × 0.6 cm), Pt cathode (1 cm × 1 cm), janode = 0.13 mA cm−2, diyne (0.2 mmol), solvent (6 mL), 2 h (2.8 F). aYield of isolated product. bA monocyclization (hydroamidation) product was isolated in 62% yield.
substituent were also tolerated. Meanwhile, the terminal phenyl ring C could be modified with OMe (27), Me (28), F (29), or Cl (30), but not with the highly electron-withdrawing CN (31), which triggered base-promoted alkyne hydroamidation leading to monocyclization (see Supporting Information, Scheme S1)17 Simultaneous installation of ortho- or parasubstituted phenyl rings on both alkyne moieties was also possible (32−35). More extended PHAs could be accessed by replacing phenyl ring C with fused bicyclic ring systems such as naphthalene (36,37), benzothiophene (38) and benzoxazole (39). 5811
DOI: 10.1021/acscatal.7b02105 ACS Catal. 2017, 7, 5810−5813
Letter
ACS Catalysis X-ray crystallography revealed that compound 37 crystallized as a racemic mixture in the solid state and assumed a nonplanar screw-shaped structure characterized with helical chirality (Figure 1). Significant molecular twisting was observed at the
Scheme 4. DFT-Derived Energy Profile for the Cascade Radical Transformation of Diyne 1a
Figure 1. ORTEP Representation for PAH 37 (CCDC 1546186). (A) Top view. (B) Side view.
cyclic urea ring with a dihedral angle C15−C1−C3−C8 of 32.5°. In comparison, the other side of the helix was largely planar, with the dihedral angle C6−C4−C14−C8 being only 1°. The current electrochemical cascade reaction provides a speedy and modular entry into helicene-like structures.18 To further explore the practical utility of the electrochemical cyclization reaction, we performed the synthesis of 2 on gram and decagram scale (Scheme 3). Higher current of 187 or 900
a
All energies are given relative to radical I except for the numbers highlighted in red that correspond to the activation barrier heights.
Scheme 3. Gram-Scale Synthesis stituted diynes. The employment of Cp2Fe as a mild and selective catalyst allows efficient cyclization while avoiding overoxidation of the PAH products. This transformation boasts broad substrate scope and compatibility with different functional groups, employs easily available substrates, and allows facile synthetic access to structurally defined polyaromatics with diverse substitution patterns. Exploration of applications of the nitrogen-doped PAHs in material sciences is ongoing in our laboratory.
■
mA was used to finish the reactions in 2−3 h.19 Under these conditions, the desired 2 was obtained in 57−69% yield, slightly lower than that of the milligram-scale reaction. We next performed thermodynamic and kinetic analyses of the cyclization of the amidyl radical intermediate I using density functional theory (DFT) calculations (Scheme 4).20 The results suggested that the cascade cyclization of I into IV is a descending and thermodynamically favorable process. Interestingly, the (cis-trans)-urea conformation of the nitrogencentered radical as show for I that is suitable for the amidyl radical cyclization to occur is preferred over the unproductive (trans, trans)-conformation I′ as suggested by the DFT calculation (Scheme 4) and the crystal structure of diyne 39s (Supporting Information, Figure S4), the starting material used for the synthesis of 39.21 The carbonyl group increases the electrophilicity22 of the nitrogen radical I making it reactive toward the rare 6-exo-dig cyclizations.9b,13b The 6-exo-dig process of II to give III is favored over the alternative formation of V probably because the latter disrupts aromaticity and forms a strained five-membered ring while the former increases πconjugation and forms a less strained six-membered ring. DFT calculation suggests that 6-exo-dig cyclization is favored kinetically and thermodynamically.6 In summary, we have developed an electrochemical cascade cyclization reaction that can be used to efficiently prepare nitrogen-doped polyaromatic compounds from various sub-
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b02105. Experimental procedure, characterization data, computational studies, and copies of 1H and 13C NMR spectra (PDF) (CIF) (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hai-Chao Xu: 0000-0002-3008-5143 Author Contributions §
Z.-W.H. and Z.-Y.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Financial support of this research from NSFC (Nos. 21672178, 21402164, and 21603227), MOST (No. 2016YFA0204100), and the “Thousand Youth Talents Plan”. 5812
DOI: 10.1021/acscatal.7b02105 ACS Catal. 2017, 7, 5810−5813
Letter
ACS Catalysis
■
Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2016, 55, 10872− 10876. (f) Ding, H.; DeRoy, P. L.; Perreault, C.; Larivee, A.; Siddiqui, A.; Caldwell, C. G.; Harran, S.; Harran, P. G. Angew. Chem., Int. Ed. 2015, 54, 4818−4822. (g) Broese, T.; Francke, R. Org. Lett. 2016, 18, 5896−5899. (h) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77−81. (i) Yang, Q.-L.; Li, Y.-Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S. J. Am. Chem. Soc. 2017, 139, 3293−3298. (j) Wang, P.; Tang, S.; Huang, P.; Lei, A. Angew. Chem., Int. Ed. 2017, 56, 3009−3013. (k) Schulz, L.; Enders, M.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2017, 56, 4877−4881. (12) Selected reviews on nitrogen-centered radicals: (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603−1618. (b) Chen, J. R.; Hu, X. Q.; Lu, L. Q.; Xiao, W. J. Chem. Soc. Rev. 2016, 45, 2044−2056. (c) Xiong, T.; Zhang, Q. Chem. Soc. Rev. 2016, 45, 3069−3087. (d) Baralle, A.; Baroudi, A.; Daniel, M.; Fensterbank, L.; Goddard, J.-P.; Lacôte, E.; Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C. In Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; Wiley: Chichester, U.K., 2012; p 767. (13) For examples of amidyl radical cascade cyclizations, see refs 9a, b, and (a) Callier-Dublanchet, A. C.; Cassayre, J.; Gagosz, F.; QuicletSire, B.; Sharp, L. A.; Zard, S. Z. Tetrahedron 2008, 64, 4803−4816. (b) Fuentes, N.; Kong, W. Q.; Fernandez-Sanchez, L.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 964−973. (c) Xiong, P.; Xu, F.; Qian, X.-Y.; Yohannes, Y.; Song, J.; Lu, X.; Xu, H.-C. Chem. - Eur. J. 2016, 22, 4379−4383. (d) Wang, X.; Xia, D.; Qin, W.; Zhou, R.; Zhou, X.; Zhou, Q.; Liu, W.; Dai, X.; Wang, H.; Wang, S.; Tan, L.; Zhang, D.; Song, H.; Liu, X.-Y.; Qin, Y. Chem. 2017, 2, 803−816. (14) Wu reported a Pd-catalyzed redox-neutral aminative dimerization of alkynes to access 5H-indeno[1,2-c] quinolines: Luo, Y.; Pan, X.; Wu, J. Org. Lett. 2011, 13, 1150−1153. (15) (a) Gieshoff, T.; Schollmeyer, D.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2016, 55, 9437−9440. (b) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.; Waldvogel, S. R. Chem. Commun. 2017, 53, 2974−2977. (c) Xu, H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2010, 132, 2839−2844. (16) The role of Cp2Fe as a mediator was confirmed by observing a catalytic current; see Figure S1 for details. (17) Ramesh, R.; Chandrasekaran, Y.; Megha, R.; Chandrasekaran, S. Tetrahedron 2007, 63, 9153−9162. (18) Selected recent reviews on helicenes: (a) Shen, Y.; Chen, C.-F. Chem. Rev. 2012, 112, 1463−1535. (b) Gingras, M. Chem. Soc. Rev. 2013, 42, 1051−1095. (c) Gingras, M. Chem. Soc. Rev. 2013, 42, 968− 1006. (19) Larger electrodes were employed to keep the current density of the anode as the same with that of the small-scale reaction. Please see the Supporting Information for details. (20) Please see Scheme S2 of the Supporting Information for a complete mechanistic proposal. (21) The barrier for the conversion of I to I′ was computed to be 19.0 kcal mol−1, higher than that of the 6-exo-dig cyclization (12.8 kcal mol−1). (22) (a) Davies, J.; Svejstrup, T. D.; Reina, D. F.; Sheikh, N. S.; Leonori, D. J. Am. Chem. Soc. 2016, 138, 8092−8095. (b) Reina, D. F.; Dauncey, E. M.; Morcillo, S. P.; Svejstrup, T. D.; Popescu, M. V.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Eur. J. Org. Chem. 2017, 2017, 2108−2111.
REFERENCES
(1) For selected reviews, see: (a) Anthony, J. E. Chem. Rev. 2006, 106, 5028−5048. (b) Feng, X.; Pisula, W.; Müllen, K. Pure Appl. Chem. 2009, 81, 2203−2224. (c) Narita, A.; Wang, X.-Y.; Feng, X.; Müllen, K. Chem. Soc. Rev. 2015, 44, 6616−6643. (2) (a) Stępień, M.; Gońka, E.; Ż yła, M.; Sprutta, N. Chem. Rev. 2017, 117, 3479−3716. (b) Jiang, W.; Li, Y.; Wang, Z. Chem. Soc. Rev. 2013, 42, 6113−6127. (3) Lin, T.; Chen, I. W.; Liu, F.; Yang, C.; Bi, H.; Xu, F.; Huang, F. Science 2015, 350, 1508−1513. (b) Bunz, U. H. F.; Engelhart, J. U.; Lindner, B. D.; Schaffroth, M. Angew. Chem., Int. Ed. 2013, 52, 3810− 3821. (c) Mateo-Alonso, A. Chem. Soc. Rev. 2014, 43, 6311−6324. (4) (a) Takase, M.; Narita, T.; Fujita, W.; Asano, M. S.; Nishinaga, T.; Benten, H.; Yoza, K.; Müllen, K. J. Am. Chem. Soc. 2013, 135, 8031−8040. (b) Berger, R.; Wagner, M.; Feng, X. L.; Müllen, K. Chem. Sci. 2015, 6, 436−441. (c) Yokoi, H.; Hiraoka, Y.; Hiroto, S.; Sakamaki, D.; Seki, S.; Shinokubo, H. Nat. Commun. 2015, 6, 8215− 8233. (5) Selected examples: (a) Yang, W.; Lucotti, A.; Tommasini, M.; Chalifoux, W. A. J. Am. Chem. Soc. 2016, 138, 9137−9144. (b) Riss, A.; Wickenburg, S.; Gorman, P.; Tan, L. Z.; Tsai, H.-Z.; de Oteyza, D. G.; Chen, Y.-C.; Bradley, A. J.; Ugeda, M. M.; Etkin, G.; Louie, S. G.; Fischer, F. R.; Crommie, M. F. Nano Lett. 2014, 14, 2251−2255. (c) Hibi, D.; Kitabayashi, K.; Fujita, K.; Takeda, T.; Tobe, Y. J. Org. Chem. 2016, 81, 3735−3743. (d) Bucher, J.; Wurm, T.; Taschinski, S.; Sachs, E.; Ascough, D.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2017, 359, 225−233. (6) (a) Pati, K.; Hughes, A. M.; Phan, H.; Alabugin, I. V. Chem. - Eur. J. 2014, 20, 390−393. (b) Byers, P. M.; Alabugin, I. V. J. Am. Chem. Soc. 2012, 134, 9609−9614. (c) Alabugin, I. V.; Gold, B. J. Org. Chem. 2013, 78, 7777−7784. (7) (a) Pati, K.; dos Passos Gomes, G.; Alabugin, I. V. Angew. Chem., Int. Ed. 2016, 55, 11633−11637. (b) Pati, K.; Dos Passos Gomes, G.; Harris, T.; Hughes, A.; Phan, H.; Banerjee, T.; Hanson, K.; Alabugin, I. V. J. Am. Chem. Soc. 2015, 137, 1165−1180. (8) (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072−3082. (b) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411−420. (c) Streamlining Free Radical Green Chemistry; Perchyonok, T., Lykakis, I. N., Postigo, A.; Eds., RSC Publishing: Thomas Graham House, Cambridge, U.K., 2011. (d) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58−106. (9) (a) Zhu, L.; Xiong, P.; Mao, Z.-Y.; Wang, Y.-H.; Yan, X.; Lu, X.; Xu, H.-C. Angew. Chem., Int. Ed. 2016, 55, 2226−2229. (b) Hou, Z.W.; Mao, Z.-Y.; Zhao, H.-B.; Melcamu, Y. Y.; Lu, X.; Song, J.; Xu, H.C. Angew. Chem., Int. Ed. 2016, 55, 9168−9172. (c) Zhao, H.-B.; Hou, Z.-W.; Liu, Z.-J.; Zhou, Z.-F.; Song, J.; Xu, H.-C. Angew. Chem., Int. Ed. 2017, 56, 587−590. (d) Xiong, P.; Xu, H.-H.; Xu, H.-C. J. Am. Chem. Soc. 2017, 139, 2956−2959. (e) Wu, Z.-J.; Xu, H.-C. Angew. Chem., Int. Ed. 2017, 56, 4734−4738. (10) Recent reviews on electroorganic synthesis: (a) Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265− 2299. (b) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492− 2521. (c) Waldvogel, S. R.; Janza, B. Angew. Chem., Int. Ed. 2014, 53, 7122−7123. (d) Francke, R. Beilstein J. Org. Chem. 2014, 10, 2858− 2873. (e) Waldvogel, S. R.; Möhle, S. Angew. Chem., Int. Ed. 2015, 54, 6398−6399. (f) Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605−621. (g) Ogawa, K. A.; Boydston, A. J. Chem. Lett. 2015, 44, 10− 16. (h) Horn, E. J.; Rosen, B. R.; Baran, P. S. ACS Cent. Sci. 2016, 2, 302−3098. (i) Schäfer, H. J. C. R. Chim. 2011, 14, 745−765. (11) Selected recent examples of electrochemical C−H functionalization: (a) Hayashi, R.; Shimizu, A.; Yoshida, J. J. Am. Chem. Soc. 2016, 138, 8400−8403. (b) Hayashi, R.; Shimizu, A.; Song, Y.; Ashikari, Y.; Nokami, T.; Yoshida, J. Chem. - Eur. J. 2017, 23, 61−64. (c) Yoo, S. J.; Li, L. J.; Zeng, C. C.; Little, R. D. Angew. Chem., Int. Ed. 2015, 54, 3744−3747. (d) Wiebe, A.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2016, 55, 11801−11805. (e) Lips, S.; Wiebe, A.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; 5813
DOI: 10.1021/acscatal.7b02105 ACS Catal. 2017, 7, 5810−5813
