Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Electrosynthesis of Trisubstituted 2‑Oxazolines via Dehydrogenative Cyclization of β‑Amino Arylketones Huiqiao Wang,† Jinjin Zhang,† Jiajing Tan,*,‡ Lilan Xin,† Yaping Li,† Sheng Zhang,*,† and Kun Xu*,† †
Engineering Technology Research Center of Henan Province for Solar Catalysis, College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, P. R. China ‡ Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China S Supporting Information *
ABSTRACT: An electrochemically intramolecular functionalization of C(sp3)−H bonds with masked oxygen nucleophiles was developed. With KI as the catalyst and electrolyte, diverse trisubstituted 2-oxazolines were constructed in good to excellent yields. This newly developed electrochemical dehydrogenative approach features external oxidant-free and additive-free conditions.
(Figure 1b).4,5 The most common cyclization reagents include DAST/Deoxo-Fluor,4 and PPh3/DIPEA/CCl4.5 Recently, I2/ TBHP/K2CO3,6 or PhI(OAc)2/BF3·Et2O7 promoted oxidative cyclizations for trisubstituted 2-oxazolines synthesis with high efficiency were also reported. The aforementioned protocols led to new reactivity pathways and solved many problems associated with trisubstituted 2-oxazolines synthesis. However, these reported methods still suffered from drastic conditions and usage of expensive and toxic reagents, all of which make scale-up synthesis unpractical due to the high cost and byproduct formation. The use of excess amounts of chemical oxidants also leads to decreased atom economy. Given the significance of trisubstituted 2-oxazoline in natural and synthetic substances, a practical method for the synthesis of trisubstituted 2-oxazoline would be highly desirable. Organic electrosynthesis, enabling the replacement of dangerous and toxic chemicals by electrons, has received great attention as a powerful tool for green synthesis.8,9 Encouraged by the recent notable accomplishments in organic electrosynthesis, we conceived that green synthesis of trisubstituted 2-oxazoline could be achieved via an electrochemically induced intramolecular C−O bond formation process, if a masked oxygen nucleophile is embedded properly within the substrate. From an atom economy point of view, direct C(sp3)−H functionalization for C−O bonds formation would be attractive since it obviates prefunctionalization steps.10 However, current studies on electrochemically intramolecular C−O bonds formation are still limited to the C(sp2)−H functionalization.11 The direct intramolecular C(sp3)−H functionalization for C− O bonds formation under electrochemical conditions is less explored.12 Recently, the Zeng,13 Wang,14 and Lei groups15 independently reported halide was an efficient electrochemical
2-Oxazolines represent one of the most important classes of five-membered heterocycles, being ubiquitous in both chemical and biological entities.1 As such, the construction of 2oxazolines remains a significant research area in organic synthesis.2 In particular, trisubstituted 2-oxazolines are widely present in many medicinally active compounds and natural products of biological significance (Figure 1a).3 In addition, trisubstituted 2-oxazolines are valuable precursors for the preparation of highly functionalized oxazoles.4 Compared with other substitution patterns, the synthesis of trisubstituted 2-oxazolines is still less explored.4−7 Typical synthetic approaches for trisubstituted 2-oxazolines involved the preparation of a β-hydroxy amide followed by cyclization
Figure 1. Trisubstituted 2-oxazoline structural motifs exist in biologically active molecules and their synthetic approaches. © XXXX American Chemical Society
Received: January 16, 2018
A
DOI: 10.1021/acs.orglett.8b00165 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
reaction (Scheme 1). First, the substituents with electron-rich and electron-withdrawing natures on the Ar1 moiety were
mediator for C−C and C−N bonds formation. Inspired by these elegant works and our interest in developing electrochemical C−O bonds formation,16 we herein report an electrochemical dehydrogenative C(sp3)−H functionalization for C−O bonds formation with KI as the catalyst and electrolyte (Figure 1c). With this electrochemical approach, diverse trisubstituted 2-oxazolines were prepared efficiently from readily available β-amino arylketones with H2 evolution. We commenced our experimentation by testing the intramolecular C(sp3)−H functionalization of β-amino ketone 1a in an undivided cell equipped with a Pt anode and a Pt cathode, using 0.06 M KI in CH3CN as a supporting electrolyte under constant current conditions (Table 1). Gratifyingly, the
Scheme 1. Investigation of the Substrate Scopea
Table 1. Optimization Conditionsa
entry
[X]
solvent
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12b 13c 14d
KI KI KI KI KI KI NaI n-Bu4NI KBr LiBr n-Bu4NBr KI KI none
CH3CN THF MeOH CH3CN/THF CH3CN/DCM CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH CH3CN/MeOH
47 trace 36 59 51 85 79 55 67 72 44 52 49 trace
a
Reaction conditions: 1a (0.3 mmol), KI (0.6 mmol) in solvent (10 mL), Pt (1.5 × 1.5 cm2) anode and cathode, undivided cell, J = 4 mA/ cm2, rt, 2 h; isolated yield. bGraphite was used as the anode. cKI (0.09 mmol) in 0.1 M LiClO4 in CH3CN/MeOH (8/2 v/v) as the supporting electrolyte. d0.1 M LiClO4 in CH3CN/MeOH (8/2 v/v) as the supporting electrolyte.
a Reaction conditions: 1 (0.3 mmol), KI (0.6 mmol) in CH3CN/ MeOH (10 mL, 8/2, v/v), Pt (1.5 × 1.5 cm2) anode and cathode, undivided cell, J = 4 mA/cm2, rt, 2 h; isolated yield.
corresponding trisubstituted 2-oxazoline 2a was isolated in 47% yield (entry 1). However, the usage of THF or MeOH as the solvent gave 2a in trace or low yield (entries 2−3). Further optimization revealed that the yield could be improved to 85% with CH3CN/MeOH (8/2 v/v) as the mixed solvent (entry 6), while other mixed solvents gave inferior results (entries 4−5). Next, a series of halides as the electrolyte were optimized. The results showed that iodides exhibit better performance regarding the chemical yield than bromides (entries 4 and 7− 8 vs 9−11). Among the iodides screened, cheap KI as the electrolyte gave the best yield (entries 4 vs 7−8). Replacing the Pt anode by a graphite plate afforded 2a in lower yield (entry 12). Finally, two control experiments to probe the role of KI were carried out (entries 13−14). The usage of 0.3 equiv of KI with 0.1 M LiClO4 in CH3CN/MeOH as a supporting electrolyte gave 2a in 49% yield (entry 13), while only a trace amount of 2a was observed in the absence of KI (entry 14). These results revealed that KI may act as a catalyst to furnish the electrochemical C−O bonds formation. With the optimized conditions established, we next investigated the scope of this electrochemical cyclization
examined (2a−2m). In general, the reaction proceeded efficiently with various substituents attached to the Ar1 moiety and gave the products in 64% to 85% yields. As expected, more electron-rich substituents on the Ar1 moiety led to slightly lower yields due to the lower α-C−H reactivity (2f vs 2b−2d). When the aromatic ring was replaced by the 2-naphthyl group, the reaction also proceeded smoothly to give the corresponding product 2k in 71% yield. It is noteworthy that heteroaromatic rings such as furyl and thienyl groups were also well-tolerated, as evidenced by isolation of products 2l and 2m in 64% and 67% yields, respectively. For the substituent groups on the Ar2 moiety, electronic modification had a moderate effect on the chemical yields. Substrates with electron-withdrawing substitutions perform better than those substituted with an electron-rich group (2n− 2q vs 2r). Substrates possessing an ortho substituent were also well-tolerated, affording products 2s and 2t in 69% and 65% yields, respectively. When the chloro and bromo groups were altered to the meta position of the Ar2 moiety, the reactions also B
DOI: 10.1021/acs.orglett.8b00165 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Next, cyclic voltammetric (CV) experiments were carried out to determine the role of KI. As shown in curve b of Figure 2, no
proceeded smoothly, albeit with diminished yields (2u and 2v). However, the reaction did not occur when the Ar1 or Ar2 groups were replaced by aliphatic chains due to the lower α-C− H reactivity. It is noteworthy that single diastereoisomers of the products were detected for the present transformations, and the relative stereochemistry of the products was determined by the comparison of the coupling constant between the two sp3 methine protons with previous reports.6,7,17 To demonstrate the synthetic utility of this newly developed electrochemical approach for trisubstituted 2-oxazolines synthesis, a gram-scale synthesis was carried out. As shown in Scheme 2, the cyclization can be easily scaled up to gram scale as demonstrated by affording 2a in 69% yield on a 10 mmol scale. Scheme 2. Gram-Scale Synthesis
Figure 2. Cyclic voltammograms of KI and related compounds in 0.1 M LiClO4/CH3CN/MeOH (8/2 v/v) using Pt wire working electrode, Pt disk, and Ag/AgCl (0.1 M in CH3CN) as counter and reference electrodes at 100 mV/s scan rate: (a) background, (b) 1a (8 mmol/L), (c) KI (3 mmol/L) and 1a (8 mmol/L), and (d) KI (3 mmol/L).
To gain a better understanding of the reaction mechanism, some control experiments were carried out (Scheme 3). To
obvious oxidation peak of 1a was observed in the absence of KI in the range 0.0−2.0 V vs Ag/AgCl, which suggested that compound 1a could not be oxidized within the examined potential window. The CV of KI (curve d) exhibits two pairs of reversible redox waves, with the oxidation peaks at 0.42 V (Ox1) and 0.66 V (Ox2) vs Ag/AgCl, which correspond to the oxidation of I− to form I3− and I3− to form I2, respectively. The CV of the mixture of KI (3 mmol/L) and 1a (8 mmol/L) displayed an obvious catalytic current (curve c), while the peak currents of Ox1 and Ox2 increase dramatically from 8.9 to 18.5 μA and 7.8 to 16 μA, respectively. The increase of oxidation current suggests that KI is the catalyst for this electrochemical process, in which iodide is regenerated on the time scale of the CV scan.19 On the basis of the above-mentioned experiments, a plausible reaction mechanism for the generation of 2a was proposed, as shown in Scheme 5. First, the anodic oxidation of iodide
Scheme 3. Control Experiments
determine whether I2 was the active species for this reaction, 1 equiv of I2 was added to the reaction mixture without electrolysis. However, no reaction occurred and the starting material 1a was recovered, which revealed that I2 was not the active species for this reaction. As the electro-generated base (MeO−) could be efficiently formed at the cathode during the electrolysis, we next turned our attention to determine the role of MeO−. When MeOLi and I2 were added to the reaction mixture without electrolysis, product 2a was obtained in 42% yield. The results suggested that the in situ generated methyl hypoiodite may be the active species for this reaction.18 When a radical scavenger such as 1,1-diphenylethylene or 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was subjected to the reaction mixture, the yield of 2a only decreased slightly, which suggested that a radical intermediate may not be involved in the rate-determining step (Scheme 4).
Scheme 5. A Plausible Mechanism for the Formation of 2a
Scheme 4. Radical Trapping Experiment
generates molecular iodine, which reacts with electro-generated MeO− to give methyl hypoiodite 3. The reaction between 3 and 1a gives iodinated intermediate 4.20 Next, intermediate 4 is deprotonated by the electro-generated methoxide ion to give intermediate 5. Subsequent cyclization of 5 affords product 2a, while releasing one molecule of iodide. Meanwhile, cathodic C
DOI: 10.1021/acs.orglett.8b00165 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(6) Gao, W.-C.; Hu, F.; Huo, Y.-M.; Chang, H.-H.; Li, X.; Wei, W.-L. Org. Lett. 2015, 17, 3914. (7) Chavan, S. S.; Rupanawar, B. D.; Kamble, R. B.; Shelke, A. M.; Suryavanshi, G. Org. Chem. Front. 2018, 5, 544. (8) Recent reviews on organic electrosynthesis, see: (a) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492. (b) Francke, R. Beilstein J. Org. Chem. 2014, 10, 2858. (c) Tang, S.; Liu, Y. C.; Lei, A. Chem. 2018, 4, 27. (d) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230. (e) Cardoso, D. S. P.; Šljukić, B.; Santos, D. M. F.; Sequeira, C. A. C. Org. Process Res. Dev. 2017, 21, 1213. (f) Yoshida, J.i.; Shimizu, A.; Hayashi, R. Chem. Rev. 2017, DOI: 10.1021/ acs.chemrev.7b00475. (g) Jiang, Y.-Y.; Xu, K.; Zeng, C.-C. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00271. (h) Okada, Y.; Chiba, K. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00400. (i) Moeller, K. D. Chem. Rev. 2018, DOI: 10.1021/acs.chemrev.7b00656. (9) Selected recent reports on organic electrosynthesis, see: (a) Morofuji, T.; Shimizu, A.; Yoshida, J. J. Am. Chem. Soc. 2015, 137, 9816. (b) Broese, T.; Francke, R. Org. Lett. 2016, 18, 5896. (c) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.-Z.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77. (d) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.; Waldvogel, S. R. J. Am. Chem. Soc. 2017, 139, 12317. (e) Fu, N.-K.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Science 2017, 357, 575. (f) Wang, P.; Tang, S.; Huang, P.-F.; Lei, A.-W. Angew. Chem., Int. Ed. 2017, 56, 3009. (g) Yang, Q.-L.; Li, Y.-Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S. J. Am. Chem. Soc. 2017, 139, 3293. (h) Zhao, H.-B.; Hou, Z.-W.; Liu, Z.-J.; Zhou, Z.-F.; Song, J.-S.; Xu, H.-C. Angew. Chem., Int. Ed. 2017, 56, 587. (i) Kawamata, Y.; Yan, M.; Liu, Z.; Bao, D.-H.; Chen, J.; Starr, J. T.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 7448. (j) Sauermann, N.; Meyer, T. H.; Tian, C.; Ackermann, L. J. Am. Chem. Soc. 2017, 139, 18452. (k) Rafiee, M.; Wang, F.; Hruszkewycz, D. P.; Stahl, S. S. J. Am. Chem. Soc. 2018, 140, 22. (10) (a) Dohi, T.; Takenaga, N.; Goto, A.; Maruyama, A.; Kita, Y. Org. Lett. 2007, 9, 3129. (b) Sathyamoorthi, S.; Du Bois, J. Org. Lett. 2016, 18, 6308. (c) Wang, H.; Wang, Z.; Huang, H.; Tan, J.; Xu, K. Org. Lett. 2016, 18, 5680. (11) Selected examples, see: (a) Sutterer, A.; Moeller, K. D. J. Am. Chem. Soc. 2000, 122, 5636. (b) Redden, A.; Perkins, R. J.; Moeller, K. D. Angew. Chem., Int. Ed. 2013, 52, 12865. (c) Xu, F.; Zhu, L.; Zhu, S.; Yan, X.; Xu, H.-C. Chem. - Eur. J. 2014, 20, 12740. (d) Röse, P.; Emge, S.; Yoshida, J.-i.; Hilt, G. Beilstein J. Org. Chem. 2015, 11, 174. (e) Ding, H.; DeRoy, P. L.; Perreault, C.; Larivée, A.; Siddiqui, A.; Caldwell, C. G.; Harran, S.; Harran, P. G. Angew. Chem., Int. Ed. 2015, 54, 4818. (f) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.; Waldvogel, S. R. Chem. Commun. 2017, 53, 2974. (12) (a) Lee, D.-S. Tetrahedron: Asymmetry 2009, 20, 2014. (b) Okimoto, M.; Ohashi, K.; Yamamori, H.; Nishikawa, S.; Hoshi, M.; Yoshida, T. Synthesis 2012, 44, 1315. (13) (a) Jiang, Y.-Y.; Liang, S.; Zeng, C.-C.; Hu, L.-M.; Sun, B.-G. Green Chem. 2016, 18, 6311. (b) Wang, Q.-Q.; Xu, K.; Jiang, Y.-Y.; Liu, Y.-G.; Sun, B.-G.; Zeng, C.-C. Org. Lett. 2017, 19, 5517. (14) (a) Gao, H.-H.; Zha, Z.-G.; Zhang, Z.-L.; Ma, H.-Y.; Wang, Z.-Y. Chem. Commun. 2014, 50, 5034. (b) Xu, K.; Zhang, Z.; Qian, P.; Zha, Z.-G.; Wang, Z.-Y. Chem. Commun. 2015, 51, 11108. (c) Li, Y.-N.; Gao, H.-H.; Zhang, Z.-L.; Qian, P.; Bi, M.-X.; Zha, Z.-G.; Wang, Z.-Y. Chem. Commun. 2016, 52, 8600. (15) Tang, S.; Gao, X.-L.; Lei, A.-W. Chem. Commun. 2017, 53, 3354. (16) (a) Zhang, S.; Li, L.; Wang, H.-Q.; Li, Q.; Liu, W.; Xu, K.; Zeng, C. Org. Lett. 2018, 20, 252. (b) Zhang, S.; Lian, F.; Xue, M.; Qin, T.; Li, L.; Zhang, X.; Xu, K. Org. Lett. 2017, 19, 6622. (17) Hajra, S.; Bar, S.; Sinha, D.; Maji, B. J. Org. Chem. 2008, 73, 4320. (18) For selected example on in situ generation of methyl hypododite (CAS: 26466-04-6) from MeO− and I2, see: Howell, J.-L.; Muzzi, B.-J.; Rider, N.-L.; Aly, E.-M.; Abouelmagd, M.-K. J. Fluorine Chem. 1995, 72, 61. (19) Costentin, C.; Savéant, J.-M. ChemElectroChem 2014, 1, 1226. (20) Alkyl hypoiodite could be used as an efficient iodination reagent; see: Montoro, R.; Wirth, T. Org. Lett. 2003, 5, 4729.
reduction of MeOH generates a methoxide ion and hydrogen gas. In conclusion, we have developed an electrochemically induced intramolecular functionalization of C(sp3)−H bonds with masked oxygen nucleophiles using KI as the catalyst and electrolyte. With this electrochemical dehydrogenative approach, trisubstituted 2-oxazolines were prepared from readily available β-amino arylketones in good to excellent yields. As this protocol avoids employing an external oxidant, a transitionmetal catalyst, and additives, it provides an appealing approach to construct trisubstituted 2-oxazolines.
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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.8b00165. Experimental procedures, characterization data, and 1H and 13C NMR of new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Sheng Zhang: 0000-0002-9686-3921 Kun Xu: 0000-0002-0419-8822 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the Natural Science Foundation of China (U1504208, 21602119, 21702113, and 21702013). This project was funded by China Postdoctoral Science Foundation and the Fundamental Research Funds from the Central Universities (buctrc201721, PYCC1707).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00165 Org. Lett. XXXX, XXX, XXX−XXX
