Letter Cite This: Org. Lett. 2019, 21, 114−119
pubs.acs.org/OrgLett
Combining Flavin Photocatalysis and Organocatalysis: Metal-Free Aerobic Oxidation of Unactivated Benzylic Substrates Jan Zelenka,†,§ Eva Svobodova,́ † Jań Tarab́ ek,∥ Irena Hoskovcova,́ ‡ Veronika Boguschova,́ † Sarah Bailly,† Marek Sikorski,⊥ Jana Roithova,́ § and Radek Cibulka*,†
Org. Lett. 2019.21:114-119. Downloaded from pubs.acs.org by WESTERN SYDNEY UNIV on 01/11/19. For personal use only.
†
Department of Organic Chemistry and ‡Department of Inorganic Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague, Czech Republic § Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands ∥ Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Flemingovo náměstí 542/2, 16610 Prague, Czech Republic ⊥ Faculty of Chemistry; Adam Mickiewicz University in Poznan, Umultowska 89b, 61614 Poznan, Poland S Supporting Information *
ABSTRACT: We report a system with ethylene-bridged flavinium salt 2b which catalyzes the aerobic oxidation of toluenes and benzyl alcohols with high oxidation potential (Eox > +2.5 V vs SCE) to give the corresponding benzoic acids under visible light irradiation. This is caused by the high oxidizing power of excited 2b (E(2b*) = +2.67 V vs SCE) involved in photooxidation and by the accompanying dark organocatalytic oxygenation provided by the in situ formed flavin hydroperoxide 2b-OOH.
Scheme 1. Modes of Activation of Flavin “Co-Factors” for Oxidations in Natural and Artificial Systemsa
D
irect C−H (sp3) oxidation reactions are among the recent challenges in organic chemistry. Despite the rapid progress in this area, the number of mild oxidative procedures that do not need a stoichiometric or at least a catalytic amount of toxic metals is still limited.1 Nature uses oxygen as a stoichiometric oxidant employing incredibly efficient tools for its activation - monooxygenases.2 Mimicking their action seems to be a suitable way toward novel environmentally friendly oxidative methodologies. Flavin-dependent monooxygenases (FMOs) are the most important metal-free oxidative enzymes.2a,3 FMOs catalyze oxidations using FMN or FAD cofactors (Fl) derived from riboflavin 1a via flavin hydroperoxide (FlOOH, Scheme 1A), which transfers an oxygen atom from itself to the substrate.4 Many artificial systems for oxidation and oxygenation reactions with molecular oxygen are inspired by flavoenzymes.5,6 Most of these systems are based on flavinium salts and their hydroperoxides (e.g., ethylene-bridged salts 26g,7 and their hydroperoxides 2-OOH in Scheme 1B; see refs 5 and 8 for alternatives). However, like with the flavin-dependent and the other metal-free monooxygenases, the reactions catalyzed by flavins are limited to heteroatom oxygenations and Baeyer− Villiger oxidations.2a,5,8 The exception is the oxidation of benzylamine to its corresponding imine with flavin monoamine oxidase models7a,e and the aerobic oxidations of electron-poor benzaldehydes to benzoic acids catalyzed by 2.6g Photoexcitation represents an effective way to “stimulate” flavins toward benzylic oxidation reactions.9,10 This approach profits from the photochemical properties of riboflavin derivatives which are significantly stronger oxidants upon excitation.9 For example, the redox potential of a prominent © 2018 American Chemical Society
a
Ground state (E) and excited state (E*) redox potentials (vs SCE) are given for illustration.
flavin photooxidation catalyst, riboflavin tetraacetate 1b (Scheme 1C), shifts from −0.88 to +1.67 V vs SCE after irradiation with visible light (∼450 nm).11 Nevertheless, despite this improvement, irradiated 1b only oxidizes activated Received: November 7, 2018 Published: December 24, 2018 114
DOI: 10.1021/acs.orglett.8b03547 Org. Lett. 2019, 21, 114−119
Letter
Organic Letters substrates, such as 4-methoxybenzyl alcohol (Eox = +1.43 V vs SCE),12 or heteroatoms.13 Further enhancement of the oxidizing properties of 1b can be achieved by combining its co-ordination to Sc3+ ions with irradiation (E*(1b-Sc3+) = +2.45 V vs SCE).14 This system allows the oxidation of electron-poor benzyl alcohols and the oxidation of some toluenes to aldehydes.15 However, it does not oxidize the most difficult substrates like 4-trifluoromethyl- or 4-nitrotoluene. Moreover, it requires a rare-earth metal. With the aim to design a strongly oxidative metal-free artificial “flavoenzyme”, we have used a novel approach to activate flavin on the basis of the combination of (i) “quaternization” and (ii) photoexcitation (Scheme 1D).16 Herein, we report a system using flavinium salt 2b17 and visible light irradiation which allows the oxidation of challenging substrates with high oxidation potentials (Eox > +2.5 V vs SCE) including 4-trifluoromethyl or 4-nitrotoluene. Notably, our system has been proven to work as the first co-operative enzyme model employing flavin (in our case 2b) in both visible-light-promoted oxidation and dark monooxygenation. Spectral properties and high redox potential in an excited state (up to +2.67 V vs SCE) predict flavin 2b might be an excellent visible-light photooxidation agent (see Figure 1 and
Scheme 3. Equilibria between Salt 2b and Its Adducts with Hydrogen Peroxide (A) and Water (B)
With the optimized conditions using 2b (5 mol %) and 448 nm light,21 we explored the substrate scope with a special focus on substrates deactivated by an electron-withdrawing group (Table 1). When selecting substrates, we were also inspired by a few reported photocatalytic processes for benzylic oxidations, specifically oxidation of toluenes,22a diarylmethanes,22b and primary 22c and secondary22d benzyl alcohols with an acridinium salt, oxidation provided by excited fluorenone, and previously reported photooxidations with flavins.9−15,20 Benzyl alcohols 3 bearing various substituents afforded acids 5 in quantitative conversion after 16 h of irradiation, albeit 10% of 2b was necessary for the trifluoromethyl derivative (entries 1−4). Interestingly, the oxidation of 4-nitrobenzyl alcohol 3NO2 led to the selective formation of the aldehyde (entry 5). Secondary alcohols 6 afforded ketones 7 in moderate to high conversions and yields (entries 6 and 7). We also demonstrated that methyl (entry 13) and alkoxymethyl and acetal groups (entries 15 and 16) could be converted to the carboxylic function using our system. The oxidation of methylene in 10 and 12 (entries 12 and 14) afforded the ketones; in 10, methylene was selectively oxidized keeping the methyl group untouched. As expected, oxidation of the methyl and ethyl groups of electron-poor alkylbenzenes 8 and 9 was a more difficult task. Chloro derivatives 8-Cl and 9-Cl afforded the acid/ketone in moderate conversions and yields. However, the trifluoromethyl analogues 8-CF3 and 9-CF3 gave only a small amount of the desired oxidation products (entries 8−11). These results reflect the corresponding redox potentials. Chloro-substituted toluene 8-Cl (Eox = +2.21 V vs SCE), benzyl alcohol 3-Cl (Eox = +2.16 V vs SCE), and benzaldehyde 4-Cl (Eox = +2.65 V vs SCE) have lower potentials when compared to 2b*, which suggests that the electron transfer from chloro-substrates to 2b* is exergonic and thus feasible.24 On the other hand, electron transfer from the trifluoromethyl substrates to 2b* was almost at or even behind the limit of an exergonic process because of their high oxidation potential (Eox(8-CF3) = +2.61 V, Eox(3-CF3) = +2.70 V, Eox(4-CF3) > +2.8 V25 vs SCE). To our delight, we observed that 4-trifluoromethyltoluene (8-CF3) could be oxidized by 2b using 400 nm instead of 448 nm light (Table 2, cf. entries 1 and 2), i.e., at the absorption maximum of 2b. More interestingly, the system was significantly more efficient when omitting the molecular sieves (entry 3). Under these conditions, the transformation from aldehyde 4-CF3 to acid 5-CF3 was much easier. We hypothesize that, in the absence of MS, hydrogen peroxide (byproduct of photooxidation pathway, Scheme 4A) remains in the mixture and allows the transformation of 2b to hydroperoxide 2b-OOH (Scheme 3A), which provides the dark “nucleophilic” oxidation of aldehyde 4-CF3 to acid 5-CF3 as described by Carbery6g for electron-poor aldehydes (cf. Scheme 4B). In accordance with our hypothesis, we detected hydrogen peroxide (in an equal amount to the oxidation product) in the reaction mixtures in the absence of MS.26 Only a negligible amount of 2b was expected to be transformed into 2b-OOH in the presence of a strong acid
Figure 1. Spectral and electrochemical characteristics of 2b in acetonitrile.
the Supporting Information). Indeed, initial screening (see the Supporting Information) of the conditions for photocatalytic aerobic oxidation reaction resulted in a system transforming 4chlorobenzyl alcohol18 3-Cl (Eox = +2.16 V vs SCE) almost quantitatively to the corresponding benzoic acid 5-Cl (Scheme 2). An acidic medium (CF3COOH) keeps the flavin species in Scheme 2. Optimized Conditions for Photocatalytic Oxidations with 2b
the form of the photoactive salt 2b, preventing its transformation to adducts 2b-OOH or 2b-OH caused by a reaction of 2b with hydrogen peroxide (formed by the catalyst’s regeneration by oxygen) or water (Scheme 3). Molecular sieves (MSs) were added to facilitate H2O2 decomposition to water,19 as the removal of H2O2 extends the flavin’s lifetime in aerobic oxidation reactions.20 It should be noted that blank experiments excluded oxidation in the absence of 2b, light and oxygen and the effect of anion (Cl−)6b (see the Supporting Information). 115
DOI: 10.1021/acs.orglett.8b03547 Org. Lett. 2019, 21, 114−119
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Organic Letters Table 1. Scope of Photooxidation with 2ba
Table 2. Optimizing Conditions for Photooxidations of 8CF3a
yieldb (%) entry
catalyst
additive
8-CF3
3-CF3
4-CF3
5-CF3
1c 2 3 4 5c
2b 2b 2b 2b 16
CF3COOH + MS CF3COOH + MS CF3COOH HCOOH
100 47 33 26 80
0 9 3 9 traces
0 26 15 0 11
0 18 49 65 9
a
Conditions: 8 (0.14 mmol), 2b (5 mol %), CF3COOH (0.14 mmol) if mentioned, MS 4 Å (15 mg) if mentioned, acetonitrile (250 μL), 400 nm, 45 °C, oxygen (balloon), 8 h. bDetermined by 1H NMR. c 448 nm.
Scheme 4. Proposed Mechanism of Oxygenation of Toluenes Mediated by Flavinium Salt 2b (=Fl+ in the Scheme)a
a
The mechanism consists of a radical process (cycle A) giving aldehyde and its oxygenation with 2b-OOH (FlOOH in the scheme) (cycle B) or photooxidation (cycle C).
noted that the oxidation of 8-CF3 was not effectively catalyzed using 9-mesityl-10-methylacridinium perchlorate 16, a prominent photooxidation catalyst (Table 2, entry 5).27 The contribution of the organocatalytic monooxygenation of aldehyde to acid by 2b-OOH to the overall oxidation process (see Scheme 4B where 2b = Fl+) was verified by independent experiments. We performed the oxidation of aldehydes 4-CF3 and 4-NO2 in the dark in the presence of 2b (5%), HCOOH, and hydrogen peroxide (1 equiv), thus simulating the hypothetical reaction mixture during the photooxidation reaction. Under these conditions, we observed that a substantial amount of acid was formed after 8 h at 45 °C (50% of 5-CF3 and 67% of 5-NO2). Only a negligible amount (≤6%) of acid was observed in a control dark experiment without 2b. No oxidation of 4-NO2 to 5-NO2 was observed by the photocatalytic procedure using 2b (5%), HCOOH, and oxygen (for photocatalytic conditions, see Table 2), indicating
a
Conditions: substrate (1 mmol), 2b (5 mol %), CF3COOH (1 mmol), MS 4 Å (125−150 mg), solvent (2 mL), 448 nm, 40 °C, oxygen (balloon), 16 h. b10% cat. c24 h. dIn the absence of MS, HCOOH instead of CF3COOH. e400 nm. fNo acid formed. g45% aldehyde formed.
(CF3COOH). Using a weaker formic acid instead, approximately 15% of 2b was present in the form of 2b-OOH, as evident from the UV−vis and 1H NMR spectrum (see the Supporting Information), and thus, both reaction pathways, photocatalysis with 2b and organocatalysis with 2b-OOH, were possible. The improved system provided a significantly higher conversion of 8-CF3 to 5-CF3 with no aldehyde observed (entry 4) and even quantitative conversion on a preparative scale (Table 1, entry 9 in parentheses). It should be 116
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Organic Letters
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that the dark oxidation with 2b-OOH is the only process transforming aldehyde to acid in the case of the nitro derivative. On the other hand, some contribution of the photocatalytic pathway (Scheme 4c) can be expected for oxidation of 4-CF3. It is based on the observation that 24% of acid 5-CF3 was formed from 4-CF3 under photocatalytic conditions. Finally, a major contribution of the photooxidation pathway for transformation of 4-Cl to 5-Cl is expected. It is based on the observation that 5-Cl is formed quantitatively from 4-Cl under photocatalytic conditions while only 16% conversion was observed under organocatalytic conditions. Previous mechanistic studies on benzylic oxidations with flavins12b,d,15 have shown that the photooxidation starts by an electron transfer to provide a benzyl radical. We trapped the benzyl radical intermediate in an irradiated acetonitrile solution of 2b and toluene in the presence of TEMPO acting as a radical scavenger28 and detected the TEMPO−benzyl adduct using ESI-MS (see the Supporting Information), which supports that electron transfer is also involved in the oxidation reaction with 2b (Scheme 4A). It is also supported by observed suppression of oxidation in the presence of TEMPO and BHT and by effective quenching of 2b fluorescence with all substrates (see the Supporting Information). Complementary data were obtained using EPR spectroscopy. The EPR spectrum of a 2b−toluene (1:1) mixture in acetonitrile irradiated by a 448 nm diode was very similar to that reported previously under aerobic conditions7a in the presence of Me2S, pointing to the high content of the protonated flavinium radical cation (FlH•+).29 Finally, we present the oxidation of 4-nitrobenzyl alcohol 3NO2 as an example of a chemoselective reaction controlled by the reaction conditions, specifically depending on the involvement or absence of the organocatalytic pathway. With MS preventing the formation of 2b-OOH, the aldehyde is formed exclusively. In contrast, without MS, the oxidation reaction affords the carboxylic acid in an almost quantitative conversion (Scheme 5).
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03547. Methods description; synthesis and characterization of the catalysts 2; photocatalytic procedures and substrate scope studies; details on mechanistic studies; and hardcopy of NMR data for 2b and for oxidation products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ján Tarábek: 0000-0003-0116-3824 Jana Roithová: 0000-0001-5144-0688 Radek Cibulka: 0000-0002-8584-7715 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was supported by the Czech Science Foundation (Grant No. 18-15175S). M.S. would like to thank the National Science Centre, Poland (NCN), for the support (research grant 2017/27/B/ST4/02494).
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REFERENCES
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Scheme 5. Chemoselective Aerobic Oxidation of 3-NO2 Provided by Photocatalytic (A) and Coupled Photo/ Organocatalytic Systems (B) with 2b
In conclusion, we have demonstrated that excited flavinium salt 2b significantly overcomes oxidation properties of still used excited flavins and can serve as a strong oxidizing agent in visible light photoredox catalysis. Moreover, 2b retains its ability to form corresponding flavin hydroperoxides and act as an artificial monooxygenase. Combining both properties, a unique system was developed employing one flavin species in both the photocatalytic and organocatalytic cycles, which cooperate in an oxidation cascade.30 This allows the system to provide the transformation of strongly electron-deficient benzylic substrates to benzoic acids, which was not feasible by the previously reported photooxidation catalysts.12,22,27 117
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DOI: 10.1021/acs.orglett.8b03547 Org. Lett. 2019, 21, 114−119
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Organic Letters conditions using O2. Chem. Commun. 2015, 51, 14046−14049. (c) Ohkubo, K.; Suga, K.; Fukuzumi, S. Solvent-Free Selective Photocatalytic Oxidation of Benzyl Alcohol to Benzaldehyde by Molecular Oxygen Using 9-Phenyl-10-Methylacridinium. Chem. Commun. 2006, 42, 2018−2020. (d) Xu, H. J.; Xu, X. L.; Fu, Y.; Feng, Y. S. Photocatalytic Oxidation of Primary and Secondary Benzyl Alcohol Catalyzed by Two Coenzyme NAD+ Models. Chin. Chem. Lett. 2007, 18, 1471−1475. (e) Schilling, W.; Riemer, D.; Zhang, Y.; Hatami, N.; Das, S. Metal-Free Catalyst for Visible-Light-Induced Oxidation of Unactivated Alcohols Using Air/Oxygen as an Oxidant. ACS Catal. 2018, 8, 5425−5430. (23) The pKR+ value represents the pH where both forms, 2b and 2b-OH, are in a 1:1 ratio. See: Bunting, J. W. pKR+ values for pyridinium cations. Tetrahedron 1987, 43, 4277−4286. (24) The elatively high potential of aldehyde 4-Cl explains the kinetic profile of 6-Cl and 3-Cl oxidation corresponding to subsequent reactions with fast alcohol and slow aldehyde oxidation (see the Supporting Information). (25) No oxidation signal was observed within the range of potentials (up to 2.8 V) available under the experimental conditions of cyclic voltammetry measurements. (26) No H2O2 was detected in the reaction mixture with MS by iodometry. (27) (a) Sideri, I. K.; Voutyritsa, E.; Kokotos, C. G. Photoorganocatalysis, small organic molecules and light in the service of organic synthesis: the awakening of a sleeping giant. Org. Biomol. Chem. 2018, 16, 4596−4614. (b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075−10166. (c) Fukuzumi, S.; Ohkubo, K. Selective photocatalytic reactions with organic photocatalysts. Chem. Sci. 2013, 4, 561−574. (28) Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Glorius, F. Multicomponent Oxyalkylation of Styrenes Enabled by Hydrogen-BondAssisted Photoinduced Electron Transfer. Angew. Chem., Int. Ed. 2017, 56, 3708−3711. (29) We could not completely exclude the presence of the neutral flavin radical Fl• (see the Supporting Information for the detailed analysis of the EPR spectra). (30) Using usual taxonomy (see ref 31), our two-cycle flavin system belongs to the area of autotandem catalysis. There are several coupled photocatalytic−organocatalytic systems. Usually they involve two catalysts in two separated cooperating catalytic cycles (see examples in ref 32). (31) (a) Fogg, D. E.; dos Santos, E. N. Tandem catalysis: a taxonomy and illustrative review. Coord. Chem. Rev. 2004, 248, 2365− 2379. (b) Lohr, T. L.; Marks, T. J. Orthogonal tandem catalysis. Nat. Chem. 2015, 7, 477. (32) (a) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical Synthesis. Chem. Rev. 2016, 116, 10035− 74. (b) Hopkinson, M. N.; Sahoo, B.; Li, J. L.; Glorius, F. Dual catalysis sees the light: combining photoredox with organo-, acid, and transition-metal catalysis. Chem. - Eur. J. 2014, 20, 3874−86.
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DOI: 10.1021/acs.orglett.8b03547 Org. Lett. 2019, 21, 114−119
