Vanadium-Catalyzed Dehydrogenation of N

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Vanadium-Catalyzed Dehydrogenation of N‑Heterocycles in Water Nadine Zumbrägel,†,‡ Makoto Sako,‡ Shinobu Takizawa,‡ Hiroaki Sasai,*,‡ and Harald Gröger*,† †

Chair of Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan

‡

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S Supporting Information *

ABSTRACT: In this paper, the dehydrogenation of tetrahydroquinolines using oxovanadium(V) catalysts under mild conditions in water and oxygen atmosphere is described. This catalytic technology was successfully applied to a range of other structurally related N-heterocycles, and a reaction mechanism is proposed.

N

V2O5).16 On the other hand, vanadium represents a very attractive metal component for catalysts due to its abundant availability in nature and corresponding low costs, as well as low toxicity compared to other heavy metals.17 Attracted by these advantageous properties and the successful use of mono- and dinuclear oxovanadium catalysts for oxidative reactions under mild conditions,17c,18 we were interested in examining the dehydrogenation of N-heterocycles using mono- and dinuclear vanadium complexes, allowing a fine-tuning of their catalytic properties by modification of the ligands. In the following paper, we report the dehydrogenation of tetrahydroquinolines in the presence of vanadium catalysts under mild conditions in aqueous media using oxygen as oxidant. Furthermore, we demonstrate that this catalytic technology can be applied successfully toward dehydrogenation of other N-heterocycles and a reaction mechanism is proposed. In our initial experiments, we screened three commercially available vanadium catalysts and seven oxovanadium(V)-type catalysts (comprising mono- as well as dinuclear vanadium complexes) A−G (Scheme 1) against 1,2,3,4-tetrahydroquinaldine (1a), which was chosen as model substrate due to the importance of the resulting product as a key structural motif in pharmaceuticals.2 The screening was performed at 70 and 50 °C under ambient air atmosphere in distilled water for 17 h using 5 mol % (in case of dinuclear vanadium complexes) or 10 mol % (in case of mononuclear vanadium complexes) (Scheme 1). Among the three applied commercially available vanadium catalysts, only VO(OEt)3 showed a conversion toward quinaldine (2a) albeit being very low with only 3% after

itrogen-containing aromatic compounds play an important role in nature and medicine.1 Among other Nheteroaromatic compounds, 2-methylquinoline (quinaldine) is of particular importance, as it represents a key structural motif in a range of pharmaceuticals.2 Examples for pharmaceuticals bearing quinaldine as a key structural motif are, among others, montelukast2a and mefloquine.2b Dehydrogenation of the corresponding tetrahydroquinolines represents an atom-efficient access toward quinolines and has been studied extensively in the last years. As the dehydrogenation of N-heterocycles represents a thermodynamically “uphill process”, even though the nitrogen atom decreases the endothermicity compared to cycloalkanes,3 harsh reaction conditions are required in many cases. Yamaguchi et al. pioneered the dehydrogenation/hydrogenation of N-heterocycles using an iridium complex in p-xylene (under reflux conditions for the dehydrogenation reaction).4 In the past years, dehydrogenation reactions were studied using other iridium catalysts5 as well as metal complexes based on iron,6 cobalt,7 nickel,8 ruthenium,9 and copper.10 In addition, the Stahl group developed a method for the dehydrogenation of cyclohexanones toward phenols using palladium catalysts.11 Furthermore, a method using Pd/C12 was developed for the dehydrogenation of N-heterocycles and, recently, the successful use of palladium nanoparticles13,14 as well as platinum and rhodium nanoparticles14 for the dehydrogenation of Nheterocycles was also reported. Furthermore, the Stahl group succeeded in applying bioinspired o-quinone-based catalysts in combination with zinc,15 ruthenium,9b and cobalt7b for the dehydrogenation of N-heterocycles. However, until now, there has been only one report on a vanadium-catalyzed dehydrogenation of tetrahydroquinolines and other N-heterocycles, which is based on the utilization of vanadium pentoxide. This reaction suffers from harsh reaction conditions and high catalyst loading (up to 2.0 equiv of © XXXX American Chemical Society

Received: May 10, 2018

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DOI: 10.1021/acs.orglett.8b01484 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

optimization is the simple access to this catalyst via a one-step synthesis from commercially available starting materials (see Supporting Information (SI)). All optimization experiments were performed under ambient air atmosphere and at a reaction temperature of 60 °C (determined as optimal temperature) for 24 h (Table 2). It is noteworthy that in the

Scheme 1. Screening of Mono- and Dinuclear Vanadium Complexes for Dehydrogenation of 1,2,3,4Tetrahydroquinaldine (1a)

Table 2. Optimization of Reaction Conditions for Dehydrogenation of 1,2,3,4-Tetrahydroquinaldine (1a)

entry

cat. (mol %)

substrate (M)

1a 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a 12a 13a 14b 15c

2.5 5 10 20 10 10 10 10 10 10 10 10 10 10 10

0.4 0.4 0.4 0.4 0.1 1.0 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4

Table 1. Screening Results for the Dehydrogenation of 1,2,3,4-Tetrahydroquinaldine (1a) entry

cat. (mol %)

temp (°C)

conva (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

VOSO4 NaVO3 VO(OEt)3 (Ra,S,S)-A (5) (Ra,S)-B (10) rac-C (10) (S)-D (10) (S)-E (10) (R*,R*)-/(R,S)-F (5) (S)-G (10) (Ra,S,S)-A (5) (Ra,S)-B (10) rac-C (10) (S)-D (10) (S)-E (10) (R*,R*)-/(R,S)-F (5) (S)-G (10)

70 70 70 70 70 70 70 70 70 70 50 50 50 50 50 50 50

0 0 3 41 26 30 50 20 44 28 39 13 26 36 16 24 23

additive (5 mol %)

cosolvent (% v/v)

SDS Triton X-100 TBAB MeOH MeOH DMSO DMSO

(10) (20) (10) (20)

conv (%)d 14 30 44 60 35 53 41 44 37 30 30 39 40 63 90

a

Variation of reaction time: 24 h. bVariation of reaction time: 48 h. Variation of reaction time: 72 h. dDetermined by 1H NMR spectroscopy via comparison of substrate and product integrals.

c

initial experiments of the process optimization, we found a significant effect of the type of reaction vessel on the reaction course. Accordingly, all reactions were performed in Schlenk tubes (see the SI). Toward an optimization of the dehydrogenation of 1,2,3,4tetrahydroquinaldine (1a), the optimal catalyst loading was examined in the first step (Table 2, entries 1−4). As expected, the conversion of substrate 1a is higher with increased catalyst loading. As a compromise between high conversion and an economic use of the catalyst, 10 mol % catalyst loading was chosen for further optimization, leading to 44% conversion of the starting material 1a (Table 2, entry 3). Afterward, the optimal substrate concentration for the dehydrogenation of 1a was studied: Interestingly, while keeping the catalyst to substrate ratio constant, a higher substrate concentration leads to higher conversions (Table 2, entries 3, 5, and 6). A substrate concentration of 0.4 M (Table 2, entry 3) was chosen as optimal and applied in further optimization reactions. Due to the low solubility of the mononuclear vanadium complex (S)-D as well as the substrate 1a in water, the effect of a catalytic amount of surfactants was examined: Therefore, we added either anionic surfactant sodium dodecyl sulfate (SDS), neutral surfactant polyoxyethylene p-tert-octylphenyl ether (Triton X-100) or cationic surfactant tetrabutylammonium bromide (TBAB). However, addition of surfactants had no beneficial impact on the conversion of 1a (Table 2, entries 7− 9). Furthermore, addition of water-miscible cosolvents such as methanol and dimethyl sulfoxide, did not give higher

a

Determined by 1H NMR spectroscopy via comparison of substrate and product integrals.

17 h reaction time at 70 °C (Table 1, entries 1−3). For the examined vanadium complexes A−G bearing a chelating ligand backbone we were pleased to observe successful transformations of substrate 1a to quinaldine (2a) proceeding without any side reaction under nonoptimized reaction conditions (Table 1, entries 4−17). It should be noted that a differentiation of the enantiomers of substrate 1a in the dehydrogenation process (leading to a kinetic resolution) was not observed, thus enabling theoretically a quantitative conversion of tetrahydroquinaldine 1a to the desired product 2a under mild conditions. For further optimization of this reaction, mononuclear vanadium complex (S)-D was chosen, which showed 36% conversion already in the initial experiments under nonoptimized conditions (17 h at 50 °C; Table 1, entry 14). A further reason for our decision to use catalyst (S)-D for process B


Letter

Organic Letters

Inspired by these encouraging results on the dehydrogenation of 1,2,3,4-tetrahydroquinaldine (1a), we were interested in proposing a plausible reaction mechanism for the dehydrogenation of 1a using oxovanadium catalysts (S)-D. When the dehydrogenation of 1a was performed under inert atmosphere, nearly no conversion to quinaldine (2a) was observed (see the SI). This result is in accordance with our further finding that the progress of the reaction under ambient air is effected by the reaction vessel (see the SI). This indicates that oxygen is needed as cosubstrate to accept hydrogen and H2O2/H2O is formed as coupling product, being in accordance with previous reports.3,9b In the first step of the proposed mechanism, the amine is coordinated by vanadium to give I, followed by a single-electron transfer (SET) from the electronrich nitrogen center to the vanadium complex yielding II. Subsequent homolytic C−H bond cleavage gives an imine which is released from the oxovanadium complex prior to isomerization via a 1,4-dihydroquinaldine to 1,2-dihydroquinaldine. In addition, oxidation of the oxovanadium species with O2 furnishes regeneration of the catalyst (S)-D, which then can coordinate the formed 1,2-dihydroquinaldine leading to complex III. Such steps are in accordance with computational calculations by Sun et al.13 A further SET then gives IV, which is converted in the final step to the (regenerated) vanadium complex (S)-D under consumption of O2 and release of quinaldine (2a) (Scheme 3). The single-electron transfer hypothesis for the vanadium-amine complexes is in accordance with the hypothesis by Zhu et al.19 for the related vanadiumcatalyzed oxidative Strecker reaction. In order to explore the substrate scope of this methodology, we studied dehydrogenations of other tetrahydroquinolines, tetrahydroquinoxalines, 9,10-dihydroacridine, 1,2,3,4-tetrahydroisoquinoline, and 2-methylpiperidine (Scheme 4). We were pleased to find that 1,2,3,4-tetrahydroquinoline (1b) as well as tetrahydroquinolines 1c and 1d, which contain different electron-donating substituents at position 6, were dehydrogenated by the vanadium complex (S)-D efficiently, leading to excellent conversions under the optimized reaction conditions. The electron-deficient tetrahydroquinoline 1e was also dehydrogenated by (S)-D with quantitative conversion. In contrast, conversion was lower for tetrahydroquinolines 1f, which contained an electron-withdrawing and sterically demanding substituent at position 6, giving 89% conversion after 48 h of reaction time (Scheme 4). Encouraged by the promising results for the dehydrogenation of other tetrahydroquinoline derivatives, we tested two different tetrahydroquinoxalines 3a and 3b bearing different substituents at position 2. In these cases, both quinoxalines were obtained in quantitative conversion under the optimized reaction conditions for the dehydrogenation with the vanadium complex (S)-D. In addition, 9,10-dihydroacridine (4a) was dehydrogenated by this vanadium catalyst with good conversion of 82%, thus further underlining the value and applicability of this catalytic methodology (Scheme 4). Furthermore, we tested if 1,2,3,4-tetrahydroisoquinoline and 2-methylpiperidine are substrates for the dehydrogenation using vanadium complex (S)-D: Unfortunately for both substrates no product formation was observed (Scheme 4). Based on these results, we concluded that an aryl-substituted amine moiety is required as a structural prerequisite for the dehydrogenation using vanadium complex (S)-D (Scheme 4). In conclusion, we developed an efficient catalytic technology for the dehydrogenation of a range of N-heterocycles based on

conversions of the starting material 1a (Table 2, entries 10− 13). In order to gain high to quantitative conversions for the dehydrogenation of substrate 1a, the impact of the reaction time was studied: longer reaction times of 48 h (Table 2, entry 14) or 72 h (Table 2, entry 15) showed higher conversions of the starting material 1a to quinaldine 2a (up to 90% conversion after 72 h) (Table 2, entry 13), indicating a high stability of the catalyst as well. Encouraged by these results on the dehydrogenation of 1,2,3,4-tetrahydroquinaldine (1a), we further investigated the effect of oxidants on the dehydrogenation using vanadium complex (S)-D (Table 3): the addition of 1.5 equiv of Table 3. Effect of Oxidants on the Dehydrogenation of 1,2,3,4-Tetrahydroquinaldine (1a)

entry a

1 2a 3a 4a 5a 6b

oxidant (equiv/atm)

temp (°C)

convc (%)

ambient air (1 atm) ambient air (1 atm) H2O2 (1.5 equiv) TBHP (1.5 equiv) O2 (1 atm) O2 (1 atm)

60 rt rt rt 60 60

44 10 51 15 76 91

a

Variation of reaction time: 24 h. bVariation of reaction time: 48 h. Determined by 1H NMR spectroscopy via comparison of substrate and product integrals.

c

hydrogen peroxide increased the conversion of substrate 1a from 10% to 51% (Table 3, entries 2, 3). In contrast, the addition of 1.5 equiv of tert-butyl hydroperoxide showed almost no improvement (Table 3, entry 4). When performing the dehydrogenation reaction under 1 atm of oxygen at 60 °C, we were pleased to find that the conversion increased significantly to 76% after 24 h (Table 3, entry 5). As oxygen represents a mild, environmentally friendly, and easy-to-handle oxidant, we chose oxygen as oxidant for further experiments. When extending the reaction time to 48 h, 1,2,3,4-tetrahydroquinaldine (1a) was converted under oxygen atmosphere with a further improved conversion of 91% (Table 3, entry 6). With these optimized reaction conditions in hand, we performed the dehydrogenation of 1,2,3,4-tetrahydroquinaldine (1a) on an elevated laboratory scale of 1 mmol (Scheme 2). After 48 h of reaction time under oxygen atmosphere, the starting martial 1a was dehydrogenated with 86% conversion and quinaldine (2a) was isolated in 66% yield by flash column chromatography (Scheme 2). These results underline the applicability of the dehydrogenation of tetrahydroquinaldine (1a) by vanadium complex (S)-D. Scheme 2. Dehydrogenation of 1,2,3,4Tetrahydroquinaldine (1a) on a 1 mmol Scale

C


Letter

Organic Letters Scheme 3. Proposed Reaction Mechanism for the Dehydrogenation of 1,2,3,4-Tetrahydroquinaldine (1a)

ORCID

Scheme 4. Substrate Scope for the Dehydrogenation of NHeterocycles using Vanadium Complex (S)-Da

Shinobu Takizawa: 0000-0002-9668-1888 Harald Gröger: 0000-0001-8582-2107 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge generous support from the German Federal Ministry of Education and Research (BMBF) within the project “Biotechnologie 2020+, Nächste Generation biotechnologischer Verfahren” (Grant No. 031A184A), as well as from the German Academic Exchange Service (DAAD) and Japan Society for the Promotion of Science (JSPS) within the joint DAAD-JSPS funding program “DAAD PPP Japan 2017/2018” (DAAD Grant No. 57345562).

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a Conversions were determined by 1H NMR spectroscopy via comparison of substrate and product integrals.

the use of vanadium as an abundantly available, cheap, and low-toxic metal, which operates under mild conditions in water as a safe and cheap reaction medium. Furthermore, a reaction mechanism for the dehydrogenation using the vanadium complex was proposed. This technology was successfully applied for the dehydrogenation of tetrahydroquinolines, tetrahydroquinoxalines, and 9,10-dihydroacridine.

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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.8b01484. Experimental procedures, characterization data and NMR spectra for new compounds (PDF)

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REFERENCES

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Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. D


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Organic Letters Scalone, M.; Surkus, A.-E.; Junge, K.; Topf, C.; Beller, M. J. Am. Chem. Soc. 2015, 137, 10652. (7) (a) He, K.-H.; Tan, F.-F.; Zhou, C.-Z.; Zhou, G.-J.; Yang, X.-L.; Li, Y. Angew. Chem., Int. Ed. 2017, 56, 3080; Angew. Chem. 2017, 129, 3126. (b) Iosub, A. V.; Stahl, S. S. Org. Lett. 2015, 17, 4404. (c) Lee, S.; Di Vece, M.; Lee, B.; Seifert, S.; Winans, R. E.; Vajda, S. ChemCatChem 2012, 4, 1632. (d) Xu, R.; Chakraborty, S.; Yuan, H.; Jones, W. D. ACS Catal. 2015, 5, 6350. (8) (a) Ombaka, L. M.; Ndungu, P.; Nyamori, V. O. Catal. Today 2013, 217, 65. (b) Shimizu, K.-i.; Kon, K.; Shimura, K.; Hakim, S. S.M.A. J. Catal. 2013, 300, 242. (9) (a) Muthaiah, S.; Hong, S. H. Adv. Synth. Catal. 2012, 354, 3045. (b) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136, 11910. (10) Jung, D.; Kim, M. H.; Kim, J. Org. Lett. 2016, 18, 6300. (11) (a) Izawa, Y.; Zheng, C.; Stahl, S. S. Angew. Chem., Int. Ed. 2013, 52, 3672; Angew. Chem. 2013, 125, 3760. (b) Pun, D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8213. (12) Tanaka, T.; Okunaga, K.-i.; Hayashi, M. Tetrahedron Lett. 2010, 51, 4633. (13) Sun, X.-T.; Zhu, J.; Xia, Y.-T.; Wu, L. ChemCatChem 2017, 9, 2463. (14) Deraedt, C.; Ye, R.; Ralston, W. T.; Toste, F. D.; Somorjai, G. A. J. Am. Chem. Soc. 2017, 139, 18084. (15) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136, 506. (16) Karki, M.; Araujo, H.; Magolan, J. Synlett 2013, 24, 1675. (17) (a) Bauer, G.; Güther, V.; Hess, H.; Otto, A.; Roidl, O.; Roller, H.; Sattelberger, S. Vanadium and Vanadium Compounds, Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2000. (b) Review: Rehder, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 148; Angew. Chem. 1991, 103, 152. (c) Takizawa, S.; Gröger, H.; Sasai, H. Chem. - Eur. J. 2015, 21, 8992. (18) (a) Review: Takizawa, S. Chem. Pharm. Bull. 2009, 57, 1179. Selected examples: (b) Sako, M.; Ichinose, K.; Takizawa, S.; Sasai, H. Chem. - Asian J. 2017, 12, 1305. (c) Sako, M.; Sugizaki, A.; Takizawa, S. Bioorg. Med. Chem. Lett. 2018, DOI: 10.1016/j.bmcl.2018.02.033. (d) Sako, M.; Takeuchi, Y.; Tsujihara, T.; Kodera, J.; Kawano, T.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2016, 138, 11481. (e) Takizawa, S.; Rajesh, D.; Katayama, T.; Sasai, H. Synlett 2009, 2009, 1667. (f) Sako, M.; Takizawa, S.; Yoshida, Y.; Sasai, H. Tetrahedron: Asymmetry 2015, 26, 613. (19) Zhu, C.; Xia, J.-B.; Chen, C. Tetrahedron Lett. 2014, 55, 232.

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Vanadium-Catalyzed Dehydrogenation of N

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