Letter Cite This: Org. Lett. 2018, 20, 1324−1327
pubs.acs.org/OrgLett
Electrochemical Generation of Diaza-oxyallyl Cation for Cycloaddition in an All-Green Electrolytic System Longji Li†,‡ and Sanzhong Luo*,†,‡,§ †
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China § Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *
ABSTRACT: The electro-oxidative generation of diaza-oxyallyl cation and its application to the synthesis of diamine motifs has been explored. Because of the synergistic combination of anodic and cathodic reactions, the current electrochemical method not only avoids the use of a stoichiometric amount of chemical oxidant but also eliminates the need for supporting electrolyte and external base required for effective oxidation.
T
addition, the supporting electrolytes are mostly unrecyclable. In view of the increased attention on designing environmentally benign methods for oxidative transformations,6 an all-green electrolytic system was explored and presented. The current electrochemical process not only eliminates the use of equivalent oxidants but also any added electrolyte. Even better, the cathodic reduction can be utilized to in situ form a catalytic amount of methoxide anion base that is required for the reaction, thus eliminating the need for externally added base and allowing for good chemoselectivity. Cyclic voltammetry (CV) analysis of N,N′-dibenzyloxyurea 1a were carried out first. As shown in Figure 1, the Eox of 1a decreased significantly from 1.6 to 0.6 V (vs Ag/AgCl, Figure 1, left) after base (MeONa) was added, indicating the oxidation of urea was quite facile under its anionic status.7 We then investigated the electrochemical oxidative coupling 1a and indole 2a, a straightforward approach to access medicinally interesting 2,3-diaminoindolines. When the reaction was performed under controlled current electrolysis (undivided cell, graphite plates as anode and cathode) at 3 mA in LiClO4/ MeOH in the presence Na2CO3, only a trace of the desired cycloadduct was detected after 4F of charge. TLC analysis indicated complete consumption of indole 2a. The low yield was likely due to the overoxidation of the product. The use of redox mediator was then explored in order to prevent overoxidation. To our delight, the addition of organic mediators such as ferrocene, TEMPO, and nBu4NI all led to smooth conversion with moderate yields. It was also found that the addition of base was unnecessary as the reaction in its absence showed comparable activity in methanol (Scheme 2, 50% vs 43% with ferrocene). Ferrocene was then selected for further
he diaza-oxyallyl cation is an important reactive intermediate for synthetic organic chemistry.1 In particular, the cycloaddition between diaza-oxyallyl cation and carbon−carbon double bonds or dienes provides a promising route to the biologically important diamine motifs.2 The generation of diaza-oxyallyl involves base-mediated dehydrohalogenation of N-chloroureas,3 but it suffers from limited substrate scope and poor regioselectivity. Recently, Jeffrey reported the generation of the diaza-oxyallylic cation by direct oxidation of N,N′-dibenzyloxyurea with PhI(OAc)2. In this case, a smooth conversion requires slow addition of oxidant in fluoro solvent in the presence of a stoichiometric amount of solvent conjugated base.4 Herein, we report a straightforward electrochemical approach for the generation of diaza-oxylallyl cation without any added chemical oxidant and base (Scheme 1). Scheme 1. Electrochemical Generation of Diaza-oxyallyl Cation Intermediates
Electroorganic synthesis has recently experienced a renaissance as electrons are inherently environmentally friendly reagents compared with conventional oxidizing and reducing reagents.5 However, large amounts of supporting electrolytes are required in order to provide sufficient electrical conductivity for electrolysis. As a result, one can be faced with a tedious workup procedure to separate product from electrolyte. In © 2018 American Chemical Society
Received: January 5, 2018 Published: February 9, 2018 1324
DOI: 10.1021/acs.orglett.8b00057 Org. Lett. 2018, 20, 1324−1327
Letter
Organic Letters
Figure 1. Cyclic voltammograms in 0.1 M LiClO4/MeOH. Left: (a) 1a (1 mM); (b) 1a (1 mM), MeONa (5 mM). Right: (a′) Fc (1 mM), (b′) Fc (1 mM), 1a (5 mM); (c′) Fc (1 mM), 1a (5 mM), MeONa (10 mM).
Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Initial Experimental Finding
optimization. CV analysis demonstrated distinctively a catalytic current8 between 1a and ferrocene (Figure 1, right), indicating a rapid electron transfer occurring between [Cp2Fe]+ and 1a. In further optimization, it was found methanol as solvent was essential under base-free conditions (Table 1, entries 1−4) and the reaction in other solvents led to inferior results or even no desired product (entry 4). In particular, expensive fluoro alcoholic solvents such as TFP and HFIP, essential reaction media for chemically oxidation of 1a, gave poor yields (entries 2 and 3). The screening of different electrolytes in methanol did not lead to any improvement (Table 1, entries 5−8). Unexpectedly, it was found that a supporting electrolyte free reaction setting gave a comparable 48% yield under otherwise identical conditions (entry 9 vs entry 1). It was noted that the cell potential was increased from 0.9 to 3.5 V in the absent of supporting electrolyte, but the reactivity and chemoselectivity were maintained due to the presence of redox mediator ferrocene. Most delightfully, the productivity could be readily improved under these electrolyte-free conditions (Supporting Information for details). The desired cycloadduct could be obtained in 89% yield with platinum cathode and 2:1 molar ratio of 1a/2a (entry 12). Screening the electrode materials demonstrates that the platinum plate is the best choice for the cathode because of the low overpotential for proton reduction (Table 1, entries 11−13). The anode materials such as glassy carbon, RVC, or platinum plate were found to be less efficient than graphite plate (Table 1, entries 14−16). Previously, Fuchigami reported an electrolyte-free system in the presence of solid-supported base, and it was proposed that the solid base would dissociate methanol into methoxide anions and proton, serving as a supporting electrolyte.9 In our case, an external base is not required, and methoxide anion is generated
entry
1a/2a (equiv)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 2:1 2:1 2:1 2:1 2:1 2:1
electrolyte
solvent
anode/ cathode
yieldb (%)
LiClO4 LiClO4 LiClO4 LiClO4 nBu4NBF4 nEt4NPF6 nBu4NClO4 NaClO4
MeOH TFP HFIP MeCN MeOH MeOH MeOH MeOH MeOH EtOH MeOH MeOH MeOH MeOH MeOH MeOH
C/C C/C C/C C/C C/C C/C C/C C/C C/C C/C C/C C/Pt C/Cu GC/Pt Pt/Pt RVC/Pt
50 33 47 trace 40 41 46 51 48 45 73 89 56 49 53 53
a General conditions: 1a, 2a (0.10 mmol), ferrocene (5 mol %) in methanol (2.0 mL) at room temperature. bDetermined by 1H NMR analysis with an internal standard. TFP: 2,2,3,3-Tetrafluoro-1propanol. HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol.
in situ from cathode reaction. In addition, the methoxide anion also serves as base to deprotonate urea 1a for subsequent oxidation. The steady and slow generation of transient methoxide anion under electrolytic conditions provides a controllable approach for the generation of highly active diaza-oxylallyl cation and slow addition of oxidants required under chemically oxidative conditions4 can thus be avoided. Ethanol as solvent also worked in the absent of supporting electrolyte, albeit with a slightly inferior yield of 3a (Table 1, entry 10). When TFP or HFIP was used, the electric conduction was too low to process the electrolysis without the supporting electrolyte (Table S2, entries 9 and 10). With the optimized conditions in hand, we sought to delineate the scope of the reaction. Alkylation on the indole 1325
DOI: 10.1021/acs.orglett.8b00057 Org. Lett. 2018, 20, 1324−1327
Letter
Organic Letters nitrogen could be methyl, ethyl, propyl, isopropyl, n-butyl, allyl, or benzyl (Scheme 3, 3a−g). The substitution at C2 position of indoles also gave good yields (Scheme 3, 3h−k). Electronwithdrawing groups at C5 of indole were well tolerated (Scheme 3, 3l). The reaction was also compatible with a wide
range of functional groups at the C3 position of indole. These include cyclohexyl, benzyl, ether, ester, and isopropyl (Scheme 3, 3m−r). The reactions with nitriles, phthalimides or silyl ether substituted indoles gave only trace products. 1-Methyl1H-indole and pyrrole have also been examined in the reactions, showing unfortunately no desired product.10 To explore the synthetic potential of electro-generated diazaoxyallyl cationic intermediate, [4 + 3] coupling with furan, 2methylfuran, 2,5-dimethylfuran, and 1,3-cyclopentadiene were examined; in all these cases, the desired [4 + 3] adducts were obtained with moderate to good yields (Scheme 3, 3s−v). To examine the practical feasibility of this cycloaddition electrochemical process, the present electrochemical reaction was conducted on a large scale by using inexpensive carbon plates as electrodes. As shown in Scheme 4, reaction on a 2.5 mmol scale afforded 80% yield after constant electrolysis of 4.5 h (Scheme 4).
Scheme 3. Substrate Scopea
Scheme 4. Large-Scale Reactiona
a
General conditions: 1a (5.00 mmol), 2a (2.5 mmol), and ferrocene (0.12 mmol) in CH3OH (25 mL) at room temperature; constant current of 15 mA.
To gain additional insight into the reaction mechanism, a series of controlled experiments were performed. When the reaction was conducted in a divided cell where the anodic and the cathodic reaction are separated, no desired product was detected after the charge of 4F (Scheme 5, a). On the other Scheme 5. Control Experiments
hand, the addition of MeONa to the anodic cell led to 30% yield of the desired adducts. This result suggests both the anodic and anodic electrochemical processed are required for effective [3 + 2] cycloaddition reaction. Such a synergistic paired electrolysis is distinctive from the known parallel paired electrolysis, which involves two noninterfering half reactions.11 To further verify the role of methanol, we examined the additive effect for the reactions in aprotic solvent MeCN. When MeONa or MeOH was added, the then inert reaction could be activated to produce the desired adduct in decent yields (Scheme 5, b).
a Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), ferrocene (5 mol %) in methanol (2.0 mL) at room temperature. b1a (0.10 mmol), 2a (0.5 mmol), ferrocene (5 mol %) in ethanol (2 mL) at 0 °C.
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DOI: 10.1021/acs.orglett.8b00057 Org. Lett. 2018, 20, 1324−1327
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Organic Letters
L. L. Angew. Chem., Int. Ed. 2013, 52, 5061−5064. (c) Barnes, K. L.; Koster, A. K.; Jeffrey, C. S. Tetrahedron Lett. 2014, 55, 4690−4696. (2) (a) Xu, L.; Liu, H.; Murray, B. P.; Callebaut, C.; Lee, M. S.; Hong, A.; Strickley, R. G.; Tsai, L. K.; Stray, K. M.; Wang, Y. ACS Med. Chem. Lett. 2010, 1, 209−213. (b) Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; et al. Science 1994, 263, 380− 385. (c) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580−2627. (d) Saibabu Kotti, S. R.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101−114. (3) Jeffrey, C. S.; Anumandla, D.; Carson, C. R. Org. Lett. 2012, 14, 5764−5767. (4) (a) Anumandla, D.; Littlefield, R.; Jeffrey, C. S. Org. Lett. 2014, 16, 5112−5115. (b) Anumandla, D.; Acharya, A.; Jeffrey, C. S. Org. Lett. 2016, 18, 476−479. (5) For reviews, see: (a) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R. Green Chem. 2010, 12, 2099− 2119. (b) Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605− 621. (c) Waldvogel, S. R.; Janza, B. Angew. Chem., Int. Ed. 2014, 53, 7122−7123. (d) Moeller, K. D. Tetrahedron 2000, 56, 9527−9554. (e) Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605−621. (f) Yoshida, J. I.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265−2299. (g) Horn, E. J.; Rosen, B. R.; Baran, P. S. ACS Cent. Sci. 2016, 2, 302−308. (h) Jiang, Y.; Xu, K.; Zeng, C. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00271. (i) Zhang, S.; Li, L. J.; Wang, H. Q.; Li, Q.; Liu, W. M.; Xu, K.; Zeng, C. C. Org. Lett. 2018, 20, 252−255. (j) Sauermann, N.; Meyer, T. H.; Tian, C.; Ackermann, L. J. Am. Chem. Soc. 2017, 139, 18452−18455. (6) (a) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Chem. Rev. 2017, 117, 9016. (b) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433. (7) 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. (8) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492−2521. (9) (a) Tajima, T.; Fuchigami, T. J. Am. Chem. Soc. 2005, 127, 2848− 2849. (b) Tajima, T.; Fuchigami, T. Chem. - Eur. J. 2005, 11, 6192− 6196. (10) Other alkyl ureas such as N,N′-di-tert-butylurea have also been examined and show no reactivity. (11) (a) Ibanez, J. G.; Frontana-Uribe, B. A.; Vasquez-Medeano, R. J. Mex. Chem. Soc. 2016, 60, 247−260. (b) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230−13319. (c) Llorente, M. J.; Nguyen, B. H.; Kubiak, C. P.; Moeller, K. D. J. Am. Chem. Soc. 2016, 138, 15110−15113.
On the basis of the CV analysis and the control experiments described above, we proposed a synergistic paired electrolytic cycle (Scheme 6). The process was initialized by simultaneous Scheme 6. Proposed Mechanism
anodic oxidation of Cp2Fe to [Cp2Fe]+ and cathodic reduction to MeO− and H2. The two in situ generated solution species then worked in concert to facilitate the oxidation of urea 1 to diaza-oxyallyl cation 4. Subsequently, [3 + 2] or [4 + 3] cycloaddition with 4 proceeded to afford the expected cycloadducts in solution. In conclusion, we have developed an all-green electrolytic system to facilitate the oxidative generation of diaza-oxyallyl cation intermediate for cycloaddition reactions. The paired electrolysis synergistically combines both anodic and cathodic half reaction for effective oxidation, not only eliminating the use of chemical oxidant but also avoiding the need of external base and electrolyte.
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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.8b00057. Experimental procedures, characterization data, and 1H and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sanzhong Luo: 0000-0001-8714-4047 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Natural Science Foundation of China (21390400, 21202170, and 21472193) for financial support. S.L. is supported by the National Program of Top-notch Young Professionals, CAS One-hundred Talents Program, and CAS Youth Innovation Promotion Association.
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REFERENCES
(1) (a) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J. Am. Chem. Soc. 2011, 133, 7688−7691. (b) Fishman, J. M.; Kiessling, 1327
DOI: 10.1021/acs.orglett.8b00057 Org. Lett. 2018, 20, 1324−1327
