Development of a Flow Photochemical Aerobic Oxidation of Benzylic

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

pubs.acs.org/OrgLett

Development of a Flow Photochemical Aerobic Oxidation of Benzylic C−H Bonds Mathieu Lesieur,† Christophe Genicot,† and Patrick Pasau*,† †

UCB Biopharma, Avenue de l’industrie, 1420 Braine l’Alleud, Belgium S Supporting Information *

ABSTRACT: A continuous mesofluidic process has been developed for benzylic C−H oxidation with moderate to good yields using a photocatalyst (riboflavin tetraacetate, RFT) activated by a UV lamp and an iron additive [Fe(ClO4)2] via incorporation of singlet oxygen (1O2) for the direct formation of oxidized CO or CH−OH compounds.

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of catalyst systems, and use of hazardous reagents.4 Therefore, the development of a more sustainable and cost-effective process is of critical interest for the industry in order to reduce safety risks and afford improved synthetic routes for larger scale reactions.5 Traditionally, the preparation of benzylic ketones has been achieved via a Friedel−Crafts acylation or by oxidation of the corresponding alcohols. 6 Other approaches have been developed, such as the direct oxidation of benzylic C−H bonds using transition metals (Fe, Mn, Ru) in combination with strong oxidants (H2O2, hypervalent iodide, Oxone, NHPI).7 An interesting and emerging strategy for direct oxidative C− H functionalization via a photoredox catalysis reaction has been gaining importance. Among these oxidative processes, the use of oxygen as a sustainable oxidant has attracted attention due to its high atom-economical, abundant, and environmentally friendly characteristics.8 A number of reports also describe oxidation methods using organic photocatalysts9 such as 1,4dicyanonaphthalene,10 a 10-phenyl-9-methylacridinium ion,11 or several heterogeneous catalysts.12 Recently, the natural riboflavin tetraacetate13 (1, RFT) has been highlighted as a photocatalyst for C−H oxidation of alkyl benzenes.14 However, these procedures are performed on a small scale with a limited substrate scope. In recent years, continuous-flow reactors have emerged as powerful tools to process photochemical transformations as a result of the efficient energy transfer between light and the reaction mixture.15 Additionally, other advantages, such as faster reaction time, high-pressure reaction, enhanced mass and heat transfer are making procedures more reproducible and scalable.16 Therefore, flow chemistry is ideally suited for photocatalytic C−H oxygenation reactions using molecular oxygen.17

ate-stage functionalization of unreactive C−H bonds has recently attracted broad interest in the pharmaceutical industry, as it offers the potential to build sophisticated molecular scaffolds in an innovative fashion.1 This approach offers the opportunity to manipulate highly functionalized molecules in ways that were previously difficult or inaccessible by traditional methods. The general concept involves a single preparative operation with the potential to quickly give access to a broad panel of new compounds.2 In particular, hydroxylation of the aliphatic C−H bond in a chemo-, regio-, and stereoselective manner can provide significant benefits in terms of metabolite properties and lead to compound diversification. Currently, a large range of commercially available pharmaceutical drugs contain one or more oxidized benzylic positions as part of their structural skeleton (Figure 1,

Figure 1. Benzylic C−H oxygenated pharmaceutical compounds.

highlighted in red). In many cases, the benzylic position is not fully functionalized and could represent a possible metabolic site, such as in donepezil and ketoprofen (Figure 1, highlighted in green). The usual approach in drug discovery relies on oxidation of these positions by cytochrome P450 or biomimetic metal complexes and strong oxidants.3 Limitations of these methods include the exquisite bioselectivity, scale-up, high cost © XXXX American Chemical Society

Received: February 13, 2018

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DOI: 10.1021/acs.orglett.8b00540 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

conversion (32%, Table 1, entry 10) of the desired products. Conducting the reaction in the absence of light or the photocatalyst (1, RFT) did not afford any desired product (Table 1, entries 11 and 12). Finally, the best result was achieved with an optimal flow rate of 0.1 mL·min−1 for the substrate solution and 1.0 mL·min−1 for oxygen gas, leading to oxidized products in 1 h with a good 69% conversion (59% isolated yield) (Table 1, entry 9). Under the optimized conditions, we subsequently investigated the substrate scope for the benzylic C−H oxidation catalysis (Scheme 2). We surveyed a series of other Indane

Herein, we report a C−H oxidation mesofluidic process using a combination of riboflavin tetraacetate (1, RFT) as the photocatalyst, iron perchlorate [Fe(ClO4)2] as an additive to avoid photocatalyst bleaching, and an oxygen source (1O2) for the direct formation of a CO or CH−OH bond. The flow chemistry protocol used for photocatalytic reaction studies is described in Scheme 1. 5-Fluoroindane (2a) was Scheme 1. Flow Setup for the Benzylic Oxidation of 5Fluoroindane (2a)

Scheme 2. Scope of the Benzylic C−H Oxidation

selected as a benchmark substrate and was diluted in 1.0 mL of a solution of 1 (RFT) and iron catalysts in an acetonitrile− water (9/1) mixture. Pure oxygen was bubbled through the solution with irradiation with a light source (UV lamp (106 W) or a LED lamp (450 nm)) at 50 °C. In all cases, one regioisomer product (3a) was predominantly obtained. We screened our system with different iron additives (Table 1, Table 1. Optimization for the Benzylic C−H Oxidation of 5Fluoroindane (2a)a entry

[Fe]

MeCN (mL·min−1)

O2 (mL·min−1)

3a convb (%)

1 2 3 4 5 6 7 8 9 10c 11d 12e

Chen−White Fe(ClO4)2 Fe(acac)2 Fe(OAc)2

0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.5 0.1 0.3 0.3 0.3

1 1 1 1 1 2 3 1 1 1 1 1

64 62 56 49 49 64 49 41 69 (59)f 32 0 0

Fe(ClO4)2 Fe(ClO4)2 Fe(ClO4)2 Fe(ClO4)2 Fe(ClO4)2 Fe(ClO4)2 Fe(ClO4)2

a

(a) Reaction conditions: 2 (0.5 mmol), 1 (10 mol %), [Fe(ClO4)2] (5 mol %), 50 °C, UV lamp (106 W), MeCN (0.1 mL.min−1), O2 (1.0 mL.min−1). Residence time: 25 min. Isolated yield. Conversion based on starting material 2. (b) 2 mmol scale reaction. Isolated yield.

substrates. Indanes with different substituents in the C4 position on the aromatic ring have been oxidized to the corresponding ketones in moderate to good yields (Scheme 2, 3a-3d). Products (3a, 3c and 3d) were preferentially obtained with good regioselectivity. Selective oxidation has been observed for azaindane derivatives (2e, 2f and 2n), and the three desired C−H oxygenated products were obtained with low to moderate isolated yields (3e, 30%), (3f, 18%) and (3n, 57%) without formation of N-oxide products. Similar regioselectivity occurred on Indane-1-carboxylic acid (2g) with the formation of a tertiary alcohol (3g), regardless of the existence of benzylic methylene. Increasing the size of the cycloalkyl chain resulted in a slight increase of the conversion with the formation of 1-tetralone (3h, 66%) and anthraquinone (3i, 72%). Remarkably, no overoxidation was observed on the 4,5,6,7-tetrahydrobenzothiophene compound (2j), affording regioselectively the ketone derivative (3j). Para-substituted ethylbenzene was oxidized into the corresponding acetophenone (3k) with lower yield. 1-(4-Chlorophenyl)ethanol (3l) was converted to the corresponding ketone with 69% isolated yield. Alkyl chain containing nitrile functionality can be

a Conditions: 5-fluoroindane (0.1 mmol), 1 (10 mol %), [Fe] (5 mol %), 50 °C, UV lamp (106 W), MeCN (mL·min−1), O2 (mL·min−1). b Conversion based on the 5-fluoroindane. cReaction irradiated with a 450 nm LED lamp (24 W). dReaction without irradiation. eReaction without photocatalyst. fIsolated yield.

entries 1−5). Similar conversions were observed in combination with [Fe(ClO4)2] or the White−Chen catalyst [2R,2′R(+)-[N,N′-bis(2-pyridylmethyl)]-2,2′-bipyrrolidine-bis-acetonitrile iron(II) hexafluoroantimonate] (Table 1, entry 1 vs entry 2). The absence of an iron source was deleterious for the reaction (Table 1, entry 5). Increasing the flow rate of O2 or the substrate mixture did not show a beneficial impact on the conversion (Table 1, entry 2 vs entries 6−8). Exchanging the UV lamp to a 450 nm LED lamp (24 W) gave a lower B

DOI: 10.1021/acs.orglett.8b00540 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Proposed mechanism for the photocatalysis benzylic oxidation

Figure 3. C−H oxidation of drug and natural compounds. Reaction conditions: 9 or 12 (0.5 mmol), 1 (10 mol %), [Fe(ClO4)2] (5 mol %), 50 °C, UV lamp (106 W), MeCN (0.1 mL min−1), O2 (1.0 mL· min−1). Residence time: 25 min.

triplet state (RFT*, 14) and can undergo consecutive electron reduction and protonation, leading concomitantly to the formation of RFTH2 (15) and the radical (R•, 16). At this stage, the 1O2 singlet will react with the radical species to generate the peroxo-radical (ROO•, 17) intermediate, affording the ketone or alcohol precursor of the desired products. The 1 O2 will then oxidize the intermediate RFTH2 in order to regenerate the catalyst 1 and form the H2O2 side product. Finally, hydrogen peroxide is reduced to O2 and H2O in the presence of an iron additive. In summary, this work describes the development of a new mesofluidic flow oxygenation process for benzylic C−H oxidation. The photocatalyst (1, RFT) was activated by a UV lamp and allowed the formation of a radical on the benzylic position of the substrate. The formation of ketone or alcohol was achieved via incorporation of singlet oxygen on the radical intermediate. This method is efficient and applicable to a broad range of substrates. Notably, oxidation occurs selectively on benzylic sites without overoxidation on the heterocyclic atoms, leading to the desired carbonyl or hydroxyl derivatives. The flow process allows a more sustainable protocol with good productivity. The time reduction and the higher concentration of the substrate achieved in flow allows its scalability to reach amounts of compound that could be difficult to achieve in batch. Application to the synthesis and late-stage modification of bioactive molecules were successfully demonstrated. Ongoing work in our laboratory is focused on further applications of this flow process on unreactive C−H bonds.

tolerated and product (3m) was obtained with an isolated yield of 29%. The C−H oxidation on ibuprofen methylester (2o) occurred on the less hindered benzylic position with the formation of the ketone (3o, 19%). Lastly, the scalability of our C−H oxidation methodology was evaluated on a 2 mmol scale and a good 77% isolated yield was obtained for the compound (3j). Finally, we demonstrated the broad applicability of the process for late-stage oxidation of drug/natural compounds. Using the standard protocol, we were able to oxidize ibuprofen (4, a nonsteroidal anti-inflammatory analgesic drug) in good yield (55%) of a single hydroxyl regioisomer (5). Interestingly, this compound oxygenated at position C 1′ is not the conventional metabolite produced by cytochrome P450 in the human liver (compared to 6−8, Figure 2).18

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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.8b00540. General procedures; 1H and 13C NMR spectra (PDF)

Figure 2. Cytochrome oxidation vs chemical C−H oxidation. Reaction conditions: 4 (0.5 mmol), 1 (10 mol %), [Fe(ClO4)2] (5 mol %), 50 °C, UV lamp (106 W), MeCN (0.1 mL min−1), O2 (1.0 mL·min−1). Residence time: 25 min. Isolated yield.

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The anti-inflamatory drug cycloprofen19 9 showed a similar result with the formation of the alcohol product 10 preferentially on the tertiary carbon with an isolated yield of 56%. Traces of the dioxidized product 11 were also observed by LC−MS but not isolated (Figure 3). Unfortunately, oxidation of the natural product celestolide 12 gave the desired ketoindane product 13 with a poor isolated yield (7%), presumably due to steric hindrance (Figure 3). A proposed mechanism for the process is depicted in Scheme 3. The photocatalyst (RFT, 1), after irradiation, is excited to its

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mathieu Lesieur: 0000-0002-7848-5111 Patrick Pasau: 0000-0002-1777-7911 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b00540 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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ACKNOWLEDGMENTS The authors gratefully acknowledge the Walloon region (Belgium) − DG06 (Convention n°7240) for funding.

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DOI: 10.1021/acs.orglett.8b00540 Org. Lett. XXXX, XXX, XXX−XXX