Electrochemical Deoxygenation of N-Heteroaromatic N-Oxides

Published as part of the Cluster Electrochemical Synthesis and Catalysis

Abstract

An electrochemical method for the deoxygenation of N-heteroaromatic N-oxide to give the corresponding N-heteroaromatics has been developed. Several classes of N-heterocycles such as pyridine, quinoline, isoquinoline, and phenanthridine are tolerated. The electrochemical reactions proceed efficiently in aqueous solution without the need for transition-metal catalysts and waste-generating reducing reagents.

The N–O bond in aromatic N-oxides serves as an excellent directing group in C–H activation reactions, conferring enhanced reactivity and regioselectivity over their oxygen-free counterparts.[1] However, the deoxygenation of N-oxides generally requires Pd-catalyzed hydrogenation or a stoichiometric amount of a chemical reductant (Scheme [1], top),[1b] [c] [2] the latter of which are not only uneconomical, but also pose an environmental hazard. The development of more sustainable synthetic methods requires the reduction in use of sacrificial reagents. Organic electrosynthesis employs electricity to promote redox reactions and have been attracting increasing attention among chemists.[3] We have been interested in electrochemical synthesis and functionalization of N-heterocycles[4] and recently developed an electrochemical dehydrative cyclization reaction of oximes for the synthesis of N-heteroaromatics.[4a] The reactions proceed through dehydrogenative cyclization to form an N-heteroaromatic N-oxide followed by deoxygenation to give the final product. Herein we report the detailed studies on the electrochemical deoxygenation of N-heteroaromatic N-oxides (Scheme [1], bottom).

N-Oxide 1a was chosen as a model substrate for reaction optimization (Table [1]). The best conditions for the deoxygenation reaction involve running the electrolysis in MeCN/H₂O (4:1) at 80 °C employing reticulated vitreous carbon (RVC) as anode, Pb as cathode, and a constant current of 10 mA. Et₄NPF₆ (0.2 equiv) was added as a supporting electrolyte to increase conductivity of the reaction mixture. Under these conditions, the deoxygenated quinoline 2a was obtained in 76% yield after the consumption of 2 F mol^–1 of charge. Control experiments showed that H₂O (entry 2) and heating (entry 3) were needed for optimal results. Replacing MeCN with MeOH also led to yield reduction (entry 4). Pb was the optimal material for cathode as other materials such as Pt (entry 5), Fe (entry 6), graphite (entry 7), red brass (entry 8), and Ni (entry 9) were all less efficient for promoting the deoxygenation reaction. In addition, replacing RVC with graphite plate also reduced the yield of 2a slightly.

Table 1 Optimization of Reaction Conditions^a

Entry	Deviation from standard conditions	Yield (%)b
1	none	76c
2	no H2O	71
3	reaction at RT	55 (25)
4	MeOH/H2O (4:1)	60 (13)
5	Pt plate as cathode	35 (47)
6	Fe plate as cathode	37 (44)
7	graphite plate as cathode	69 (10)
8	red brass as cathode	65 (12)
9	Ni plate as cathode	58 (19)
10	graphite plate as anode	70 (<5)

^a Reaction conditions: 1a (0.3 mmol), MeCN (8 mL), H₂O (2 mL), Et₄NPF₆ (0.06 mmol), argon, RVC anode, Pb cathode, 10 mA, 1.6 h (2.0 F mol^–1).

^b Yield determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. Unreacted 1a is shown in parentheses.

^c Isolated yield.

The scope of the electrochemical deoxygenation reaction was explored (Scheme [2]).[5] 2-Methylquinoline N-oxide (1b) and quinoline N-oxide (1c) reacted to give the corresponding deoxygenated products (2b,[6] 2c [7]) in good yields. A brominated quinoline N-oxide (1d) underwent decomposition and failed to afford the desired product 2d. Pyridine N-oxides bearing at the 4-position an OMe (2e [8]), tBu (2f), Ph (2g), or CN (2h) group reacted smoothly. The relative low yield of the electron-deficient 2h might be caused by its overreduction at the cathode. 2-Substitued pyridine N-oxides were also suitable substrates (2i and 2j). The reaction tolerated other N-heteroaromatic N-oxides derived from isoquinoline (2k and 2l), phenanthridine (2m), and benzophenanthridine (2n). Acridine N-oxide (1o) reacted to give acridine (2o) in a low yield of 28%.

A possible mechanism for the electrochemical deoxygenation process was illustrated in Scheme [3]. The aromatic N-oxide is reduced at the cathode through a 2e^– process with the assistance of H₂O to give the corresponding deoxygenated product. At the anode, H₂O is probably oxidized to generate O₂. Since the same amount of H⁺ and OH⁻ are generated at the anode and cathode, respectively, H₂O is not consumed, and the net results are that the N-oxide reacts to give the deoxygenated product and O₂.

In summary, an electrochemical method for the deoxygenation of N-heteroaromatic N-oxide has been developed. The reactions are compatible with several classes of N-heterocycles and proceed efficiently in aqueous solution in the absence of transition-metal catalysts and waste-generating reducing reagents.

• References and Notes

• 1a Liu J, Xie Y, Zeng W, Lin D, Deng Y, Lu X. J. Org. Chem. 2015; 80: 4618
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• 1f Zhang LB, Hao XQ, Zhang SK, Liu K, Ren B, Gong JF, Niu JL, Song MP. J. Org. Chem. 2014; 79: 10399
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• 1g Yan G, Borah AJ, Yang M. Adv. Synth. Catal. 2014; 356: 2375
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• 2a Campeau L.-C, Rousseaux S, Fagnou K. J. Am. Chem. Soc. 2005; 127: 18020
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• 2d Wenkert D, Woodward RB. J. Org. Chem. 1983; 48: 283
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• 4a Zhao H.-B, Xu P, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2018; 57: 15153
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• 4b Hou Z.-W, Yan H, Song J.-S, Xu H.-C. Chin. J. Chem. 2018; 36: 909
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• 4c Yan H, Hou ZW, Xu HC. Angew. Chem. Int. Ed. 2019; 58: 4592
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• 4d Zhao H.-B, Liu Z.-J, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2017; 56: 12732
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• 4e Zhao H.-B, Hou Z.-W, Liu Z.-J, Zhou Z.-F, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2017; 56: 587
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• 5 General Procedure for the Electrochemical Deoxygenation Reactions A 10 mL three-necked round-bottomed flask was charged with the N-heteroaromatic N-oxide (0.30 mmol, 1.0 equiv) and Et₄NPF₆ (0.06 mmol, 0.2 equiv). The flask was then equipped with a condenser, a reticulated vitreous carbon (100 PPI, ca. 65 cm² cm⁻³, 1.2 cm × 1.0 cm × 0.8 cm) anode, and a Pb plate (1.0 cm × 1.0 cm) cathode and flushed with argon. MeCN and H₂O (4:1, 10.0 mL) were added. The electrolysis was carried out at 80 °C using a constant current of 10 mA until complete consumption of the substrate (monitored by TLC or ¹H NMR). The reaction mixture was concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with ethyl acetate/hexane to give the desired product.
• 6 Spectral Data for 2b Colorless oil; yield 70%; 2.4 F mol^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.04–7.95 (m, 2 H), 7.73 (dt, J = 8.3, 1.6 Hz, 1 H), 7.65 (ddt, J = 8.5, 6.9, 1.6 Hz, 1 H), 7.45 (ddt, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.26–7.21 (m, 1 H), 2.72 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.1, 148.0, 136.2, 129.5, 128.7, 127.6, 126.6, 125.7, 122.1, 25.5.
• 7 Spectral Data for 2c Colorless oil; yield 65%; 2.2 F mol^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.94–8.83 (m, 1 H), 8.10 (d, J = 8.2 Hz, 2 H), 7.82–7.63 (m, 2 H), 7.56–7.45 (m, 1 H), 7.35 (dq, J = 7.5, 3.8 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 150.5, 148.4, 136.1, 129.6, 129.5, 128.4, 127.9, 126.6, 121.2.
• 8 Spectral Data for 2e Colorless oil; yield 77%; 4.0 F mol^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.45–8.37 (m, 2 H), 6.85–6.68 (m, 2 H), 3.82 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.7, 151.2, 110.0, 55.2.

• References and Notes

• 1a Liu J, Xie Y, Zeng W, Lin D, Deng Y, Lu X. J. Org. Chem. 2015; 80: 4618
  CrossrefPubMedSearch in Google Scholar
• 1b Xiao B, Liu ZJ, Liu L, Fu Y. J. Am. Chem. Soc. 2013; 135: 616
  CrossrefPubMedSearch in Google Scholar
• 1c Cho SH, Hwang SJ, Chang S. J. Am. Chem. Soc. 2008; 130: 9254
  CrossrefPubMedSearch in Google Scholar
• 1d Wu J, Cui X, Chen L, Jiang G, Wu Y. J. Am. Chem. Soc. 2009; 131: 13888
  CrossrefPubMedSearch in Google Scholar
• 1e Tan Y, Barrios-Landeros F, Hartwig JF. J. Am. Chem. Soc. 2012; 134: 3683
  CrossrefPubMedSearch in Google Scholar
• 1f Zhang LB, Hao XQ, Zhang SK, Liu K, Ren B, Gong JF, Niu JL, Song MP. J. Org. Chem. 2014; 79: 10399
  CrossrefPubMedSearch in Google Scholar
• 1g Yan G, Borah AJ, Yang M. Adv. Synth. Catal. 2014; 356: 2375
  CrossrefSearch in Google Scholar
• 2a Campeau L.-C, Rousseaux S, Fagnou K. J. Am. Chem. Soc. 2005; 127: 18020
  CrossrefPubMedSearch in Google Scholar
• 2b Reis PM, Royo B. Tetrahedron Lett. 2009; 50: 949
  CrossrefSearch in Google Scholar
• 2c Singh SK, Reddy MS, Mangle M, Ganesh KR. Tetrahedron 2007; 63: 126
  CrossrefSearch in Google Scholar
• 2d Wenkert D, Woodward RB. J. Org. Chem. 1983; 48: 283
  CrossrefSearch in Google Scholar
• 2e Kim KD, Lee JH. Org. Lett. 2018; 20: 7712
  CrossrefPubMedSearch in Google Scholar
• 2f Wang Y, Espenson JH. Org. Lett. 2000; 2: 3525
  CrossrefPubMedSearch in Google Scholar
• 2g Kokatla HP, Thomson PF, Bae S, Doddi VR, Lakshman MK. J. Org. Chem. 2011; 76: 7842
  CrossrefPubMedSearch in Google Scholar
• 3a Francke R, Little RD. Chem. Soc. Rev. 2014; 43: 2492
  CrossrefPubMedSearch in Google Scholar
• 3b Yan M, Kawamata Y, Baran PS. Chem. Rev. 2017; 117: 13230
  CrossrefPubMedSearch in Google Scholar
• 3c Horn EJ, Rosen BR, Baran PS. ACS Cent. Sci. 2016; 2: 302
  CrossrefPubMedSearch in Google Scholar
• 3d Wiebe A, Gieshoff T, Möhle S, Rodrigo E, Zirbes M, Waldvogel SR. Angew. Chem. Int. Ed. 2018; 57: 5594
  CrossrefPubMedSearch in Google Scholar
• 3e Möhle S, Zirbes M, Rodrigo E, Gieshoff T, Wiebe A, Waldvogel SR. Angew. Chem. Int. Ed. 2018; 57: 6018
  CrossrefPubMedSearch in Google Scholar
• 3f Tang S, Liu Y, Lei A. Chem. 2018; 4: 27
  CrossrefSearch in Google Scholar
• 3g Feng R, Smith JA, Moeller KD. Acc. Chem. Res. 2017; 50: 2346
  CrossrefPubMedSearch in Google Scholar
• 3h Yang QL, Fang P, Mei TS. Chin. J. Chem. 2018; 36: 338
  CrossrefSearch in Google Scholar
• 3i Jiang Y, Xu K, Zeng C. Chem. Rev. 2018; 118: 4485
  CrossrefPubMedSearch in Google Scholar
• 3j Moeller KD. Chem. Rev. 2018; 118: 4817
  CrossrefPubMedSearch in Google Scholar
• 4a Zhao H.-B, Xu P, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2018; 57: 15153
  CrossrefPubMedSearch in Google Scholar
• 4b Hou Z.-W, Yan H, Song J.-S, Xu H.-C. Chin. J. Chem. 2018; 36: 909
  CrossrefSearch in Google Scholar
• 4c Yan H, Hou ZW, Xu HC. Angew. Chem. Int. Ed. 2019; 58: 4592
  CrossrefPubMedSearch in Google Scholar
• 4d Zhao H.-B, Liu Z.-J, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2017; 56: 12732
  CrossrefPubMedSearch in Google Scholar
• 4e Zhao H.-B, Hou Z.-W, Liu Z.-J, Zhou Z.-F, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2017; 56: 587
  CrossrefPubMedSearch in Google Scholar
• 5 General Procedure for the Electrochemical Deoxygenation Reactions A 10 mL three-necked round-bottomed flask was charged with the N-heteroaromatic N-oxide (0.30 mmol, 1.0 equiv) and Et₄NPF₆ (0.06 mmol, 0.2 equiv). The flask was then equipped with a condenser, a reticulated vitreous carbon (100 PPI, ca. 65 cm² cm⁻³, 1.2 cm × 1.0 cm × 0.8 cm) anode, and a Pb plate (1.0 cm × 1.0 cm) cathode and flushed with argon. MeCN and H₂O (4:1, 10.0 mL) were added. The electrolysis was carried out at 80 °C using a constant current of 10 mA until complete consumption of the substrate (monitored by TLC or ¹H NMR). The reaction mixture was concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with ethyl acetate/hexane to give the desired product.
• 6 Spectral Data for 2b Colorless oil; yield 70%; 2.4 F mol^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.04–7.95 (m, 2 H), 7.73 (dt, J = 8.3, 1.6 Hz, 1 H), 7.65 (ddt, J = 8.5, 6.9, 1.6 Hz, 1 H), 7.45 (ddt, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.26–7.21 (m, 1 H), 2.72 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.1, 148.0, 136.2, 129.5, 128.7, 127.6, 126.6, 125.7, 122.1, 25.5.
• 7 Spectral Data for 2c Colorless oil; yield 65%; 2.2 F mol^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.94–8.83 (m, 1 H), 8.10 (d, J = 8.2 Hz, 2 H), 7.82–7.63 (m, 2 H), 7.56–7.45 (m, 1 H), 7.35 (dq, J = 7.5, 3.8 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 150.5, 148.4, 136.1, 129.6, 129.5, 128.4, 127.9, 126.6, 121.2.
• 8 Spectral Data for 2e Colorless oil; yield 77%; 4.0 F mol^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.45–8.37 (m, 2 H), 6.85–6.68 (m, 2 H), 3.82 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.7, 151.2, 110.0, 55.2.

• Supplementary Material