Radical Carbonylation Mediated by Continuous-Flow Visible-Light

Letter Cite This: Org. Lett. 2018, 20, 4663−4666

pubs.acs.org/OrgLett

Radical Carbonylation Mediated by Continuous-Flow Visible-Light Photocatalysis: Access to 2,3-Dihydrobenzofurans Nenad Micic† and Anastasios Polyzos*,‡ †

School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia CSIRO Manufacturing, Research Way, Clayton, Victoria 3168, Australia

‡

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S Supporting Information *

ABSTRACT: The annulative carbonylation of alkenyltethered arenediazonium salts using visible-light photocatalysis in continuous flow is described. The method furnishes a diverse series of novel acetate-functionalized 2,3dihydrobenzofurans at room temperature and moderate CO pressure (25 atm), delivering these products in a short time with straightforward scale-up. This continuous flow and freeradical approach overcomes the limitation of traditional Pd-catalyzed annulative carbonylation, giving valuable 2,3dihydrobenzofurans in a predictable and regioselective manner.

A

has been applied to the synthesis of acetaldehyde-functionalized O-heterocycles using organostannane reagents (Scheme 1b).6 The limitations of traditional free-radical carbonylation methods relate to the low regioselective control over the cyclization pathway, the requirement for high-pressure CO (>80 bar), and a strong radical acceptor coupling partner. These factors have encouraged the development of improved methods for radical carbonylation. In 2015, Xiao reported a single example of free-radical annulative alkoxycarbonylation of 2-allyloxybenzenediazonium salt mediated by organophotoredox catalysis.7 This marked a notably different reactivity manifold to previous radical methods, as simple nucleophiles could be engaged as coupling partners. Despite this milestone, the photoredox-mediated carbonylative cyclization of alkenyltethered aryl(pseudo)halides has not been developed. This is likely due to the practical and safety implications arising from the use of CO gas at high pressures (≥80 atm) and the requirement of specialized autoclave photoreactors, impairing accessibility and scalability. In this letter we report a method for the annulative carbonylation of alkenyl-tethered arenediazonium salts using visible-light photocatalysis in continuous flow processing (Scheme 1c). Our approach provides access to 3-acetatesubstituted 2,3-dihydrobenzofurans under mild reaction conditions with significant chemo- and regioselectivity. The application of continuous flow processing permits short reaction times (200 s), low partial pressure of gaseous CO (25 atm), and straightforward scale-up. We proposed that the 3-acetate-functionalized 2,3-dihydrobenzofurans could be generated from allyloxy-tethered benzenediazonium tetrafluoroborate (I) via a photoredox catalysis manifold (Scheme 2). Diazonium tetrafluoroborates

nnulative carbonylation is an attractive strategy for the synthesis of carbonyl-containing N- or O-heterocycles.1 The intramolecular Heck-type annulative carbonylation of allyl-2-iodophenyl ethers and amines provides a direct route to acetaldehyde-functionalized benzofuran, benzopyran, indoline, and tetrahydroisoquinoline derivatives.2 A limitation of this approach relates to multiple product distribution derived from competitive biscarbonylation, carbometalation, and β-hydride elimination pathways following oxidative addition.3 This protocol is particularly challenging for the synthesis of pharmaceutically relevant 2,3-dihydrobenzofurans (Scheme 1a).4 Free-radical carbonylation offers an advantageous alternative to Pd-catalyzed carbonylation of aryl (pseudo)halides.5 The radical-mediated carbonylation of alkenyl-tethered aryl halides Scheme 1. Synthesis of Acetate-Functionalized 2,3Dihydrobenzofurans via Annulation/Alkoxycarbonylation Cascade

Received: June 24, 2018 Published: July 20, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b01971 Org. Lett. 2018, 20, 4663−4666

Letter

Organic Letters

time in the photoreactor was set to 200 s. High dilution conditions were necessary to decrease unwanted intermolecular radical addition, particularly for intermediates III and IV.11 We embarked on our investigation by screening a selection of organic and transition metal photoredox catalysts (Table 1).

Scheme 2. Reaction Design for the Radical Annulation/ Alkoxycarbonylation under Photoredox Conditions

Table 1. Selected Optimization Experimentsa

are attractive aryl (pseudo)halide radical precursors due to their mild reduction potential (E° ∼ 0 V vs SCE)8 and convenient preparation. Single electron reduction from the excited state photocatalyst (PC*) to the allyloxy-tethered arenediazonium salt I induces homolytic cleavage of a C−N bond, generating the aryl radical II and oxidized photocatalyst (PC•+). Intramolecular radical alkene addition furnishes the primary alkyl radical intermediate III. Trapping of the alkyl radical with CO gives the acyl radical IV. Single electron oxidation of the acyl radical by the oxidized photocatalyst (PC•+) results in the regeneration of the photocatalyst (PC) and the formation of the acylium ion V. Reaction of the acylium ion with an alcohol affords the 3-acetate 2,3dihydrobenzofuran VI. The application of flow processing was anticipated to reduce reaction time and mediate carbonylation at reduced partial pressures of CO relative to the batch reaction. Moreover, continuous flow photochemistry has been established as a viable tool to improve the efficiency of photochemical transformations.9 Accordingly, a flow chemistry platform was developed to comprise a CO gas delivery system and tubular flow photoreactor. The flow configuration was comprised of a commercially available Teflon AF-2400 tube-in-tube reactor operating as a gas addition module (GAM) and was connected to a tubular flow photoreactor (Figure 1) (see Supporting Information (SI)). The AF-2400 GAM continuously delivers CO gas to a reaction stream in a controlled, safe, and reproducible manner.10

entry

deviation from scheme conditions

yield (%)b

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

no deviation Ru(bpy)3Cl2·6H2O (1 mol %) fluorescein (1 mol %) eosin Y (1 mol %), green 14 W LEDs 0.04 M concentration MeCN/MeOH (95:5) 10 equiv of MeOH 100 s photoreactor residence time 0.5 mol % [Ir] 0.5 mol % [Ir], CO (35 atm) no catalyst no light

74 67 65 8 53 64 47 69 85 (73) 85 trace n.d.

a

Unless otherwise noted, reactions were carried out with 1a (0.2 mmol), [Ir(dtbbpy)(ppy)2]PF6 (1 mol %), MeOH (10 mL), CO (25 atm), irradiation (450 nm LED, 14 W), room temperature, 200 s. bpy = 2,2′-bipyridine; ppy = 2-phenylpyridine; dtbbpy = 4,4′-di-tert-butyl2,2′-bipyridine. b1H NMR yields determined with maleic acid as the internal standard. Isolated yields in parentheses.

In the latter, Ru and Ir photocatalysts form stable complexes with CO, leading to catalyst deactivation under high pressures of CO.12 We anticipated that the lower CO pressures engaged under flow conditions potentially alleviate this unwanted deactivation pathway for transition metal photocatalysts. Accordingly, [Ir(dtbbpy)(ppy)2]PF6 was initially screened, and the catalyst afforded the desired methoxycarbonylated product 2a in good yield (entry 1). The archetypal ruthenium photocatalyst, Ru(bpy)3Cl2·6H2O, provided 2a in a slightly lower yield of 67%. In contrast, organophotocatalysts (entries 3−4, refer to SI for comprehensive catalyst screen) furnish 2a in lower yields relative to the transition metal dyes, suggesting that the Ir and Rh photocatalysts were not deactivated by CO under the flow conditions. Increasing the concentration of 1a resulted in polymerized byproducts (entry 5). The concentration of nucleophile (methanol) was reduced to 5% (v/v) with only a slight reduction in yield. However, stoichiometric quantities of alcohol resulted in poor yields (entries 6−7). Volumetric flow rates higher than 0.15 mL/min afforded complete conversion of the arenediazonium salt with a reduction in alkoxycarbonylated product, suggesting that the increased flow rate through the GAM did not result in saturation of the liquid phase with CO (entry 8). Longer residence times did not lead to an appreciable increase in yield. Reducing the catalyst loading to 0.5 mol % proved beneficial, affording the desired ester 2a in excellent yield (entry 9). The pressure of CO was modulated, and increasing the pressure of CO gas to 35 atm did not result in an increase in carbonylated products, implying intermolecular alkene addition of inter-

Figure 1. Schematic of the continuous flow platform with gas−liquid photoreactor.

The initial conditions for method development required methanolic solutions of 2-allyloxybenzenediazonium tetrafluoroborate (1a) and photocatalyst to be pumped through the GAM (0.15 mL/min), enriched with CO at 25 atm, then irradiated with blue light at room temperature to give methyl 2-(2,3-dihydrobenzofuran-3-yl)acetate (2a). The residence 4664

DOI: 10.1021/acs.orglett.8b01971 Org. Lett. 2018, 20, 4663−4666

Letter

Organic Letters mediate III was no longer a significant competing reaction pathway (entry 10). Control reactions showed that both irradiation and photocatalyst are required (entries 11−12). Notably, full conversion of 1a was observed for the [Ir(dtbbpy)(ppy)2]PF6, Ru(bpy)3Cl2·6H2O, and fluoresceincatalyzed reactions. 1H NMR analysis of the crude reaction mixtures identified trace amounts 3-methyl-2,3-dihydrobenzofuran, suggesting the competitive reduction of 1a may be occurring under the reaction conditions. With the optimal reaction conditions established, the scope of the developed transformation was explored (Scheme 3).

Scheme 4. Scope of Arenediazonium Tetrafluoroborate Allyloxy Ethersa

Scheme 3. Reaction Scope of Alcohol Coupling Partnera

a

Reaction conditions: 1m−u (0.2 mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.5 mol %), nBuOH/MeCN 1:1 v/v (10 mL), CO (25 atm), irradiation (450 nm LED, 14 W), room temperature, 200 s, isolated yields.

at the C5 position did not furnish the carbocyclized products in appreciable quantities (see SI). The generality of the reaction was further demonstrated through the compatibility of unsaturated ortho-tethered arenediazonium salts with the standard reaction conditions (Figure 2).

a Reaction conditions: 1a (0.2 mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.5 mol %), ROH/MeCN (10 mL), CO (25 atm), irradiation (450 nm LED, 14 W), room temperature, 200 s, isolated yields. bNo MeCN v/ v as cosolvent. c50% v/v MeCN used as cosolvent. d95% v/v MeCN used as cosolvent.

First, primary, secondary, and tertiary alkyl alcohol coupling partners were investigated, and each class of alcohol yielded the corresponding ester in excellent yield, regardless of steric bulk (2a−2f). Phenol, known to form azo compounds with addition to arenediazonium salts,13 formed the corresponding ester product 2h in a satisfactory yield. Alcohols with C−H bonds susceptible to radical abstraction were tolerated without quenching of the alkyl radical (2h−k).14 Alcohols with internal alkenes furnished unsaturated ester 2k with retention of double bond stereochemical configuration, and halogenated alcohols were compatible with the reaction conditions (2l), permitting further functionalization. We next turned our attention to evaluating the scope of the arenediazonium allyl ethers (Scheme 4). Weakly donating and electron-withdrawing substituents afforded the desired radical annulation/carbonylation product in good to excellent yields (2m−2t). In contrast to Pd-catalyzed carbonylation, bromo, chloro, and fluoro substituents were compatible, with no observable competitive biscarbonylation or dehalohydrogenated products detected by 1H NMR. Methoxy substitution at the C6 position (2u) was achieved in acceptable yield; unfortunately, methoxy, phenoxy, and acetamide substitution

Figure 2. Extension of the annulation/alkoxycarbonylation reaction to ortho-tethered arenediazonium salts. Reaction conditions: 3a−c (0.2 mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.5 mol %), nBuOH/MeCN 1:1 v/v (10 mL), CO (25 atm), irradiation (450 nm LED, 14 W), room temperature, 200 s, isolated yields are given.

The use of methallyloxy derivative 3a furnished the 3acetate-functionalized 2,3-dihydrobenzofuran 4a, with an allcarbon quaternary center at the C3 position, in good yield. Access to acetate-functionalized benzofuran 4b and chromane 4c could be realized through the use of propargyloxy and 1butenyloxy substitution, respectively. The scale up of high-pressure dilute photochemical multiphase reactions in batch presents significant challenges. To demonstrate the facile scalability of the developed flow 4665

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(5) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050− 1066. (6) Ryu, I.; Niguma, T.; Minakata, S.; Komatsu, M.; Hadida, S.; Curran, D. P. Tetrahedron Lett. 1997, 38, 7883−7886. (7) (a) Guo, W.; Lu, L.; Wang, Y.; Wang, Y.; Chen, J.; Xiao, W. Angew. Chem., Int. Ed. 2015, 54, 2265−2269. For reviews on visible light photoredox catalysis: (b) Peng, J. B.; Qi, X.; Wu, X. F. ChemSusChem 2016, 9, 2279−2283. (c) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102−113. (d) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322− 5363. (8) Elofson, R. M.; Edsberg, R. L.; Mecherly, P. A. J. Electrochem. Soc. 1950, 97, 166. (9) (a) Su, Y.; Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. - Eur. J. 2014, 20, 10562−10589. (b) Gilmore, K.; Seeberger, P. H. Chem. Rec. 2014, 14, 410−418. (c) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796−11893. (d) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. Rev. 2016, 116, 10276−10341. (e) Su, Y.; Kuijpers, K.; Hessel, V.; Noël, T. React. Chem. Eng. 2016, 1, 73−81. (f) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Beilstein J. Org. Chem. 2012, 8, 2025−2052. (10) (a) Koos, P.; Gross, U.; Polyzos, A.; O’Brien, M.; Baxendale, I.; Ley, S. V. Org. Biomol. Chem. 2011, 9, 6903−6908. (b) Gross, U.; Koos, P.; O’Brien, M.; Polyzos, A.; Ley, S. V. Eur. J. Org. Chem. 2014, 2014, 6418−6430. (c) Brzozowski, M.; O’Brien, M.; Ley, S. V.; Polyzos. Acc. Chem. Res. 2015, 48, 349−362. (11) Nagahara, K.; Ryu, I.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1997, 119, 5465−5466. (12) Deacon, G. B.; Patrick, J. M.; Skelton, B. W.; Thomas, N. C.; White, A. H. Aust. J. Chem. 1984, 37, 929. (13) Haghbeen, K.; Tan, E. W. J. Org. Chem. 1998, 63, 4503−4505. (14) Luo, Y. Comprehensive Handbook Of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.

protocol, the reaction was scaled by a factor of 20. To facilitate a preparative scale reaction, the GAM and photoreactor volumes were increased by a factor of 3 (see SI). Operating in the continuous flow regime, 4.0 mmol of 1a was processed to afford the ethyl ester 2b in 72% isolated yield. In summary, we have developed a continuous-flow, visiblelight photoredox catalytic approach for the annulative alkoxycarbonylation of alkenyl-tethered arenediazonium salts. Continuous-flow processing enabled significant process intensification compared to batch and facile scale-up. The developed method was applied to the synthesis of a diverse library of 3-acetate-functionalized 2,3-dihydrobenzofurans. This work exemplifies our strategy to overcome the challenges associated with Pd-catalyzed annulative carbonylation through a free-radical approach under mild reaction conditions. Work is currently underway in our laboratory to expand the general scope of visible-light photocatalytic carbonylation reactions using the continuous-flow platform.

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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.8b01971. Experimental procedures, compound characterization data, and NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Anastasios Polyzos: 0000-0003-1063-4990 Author Contributions

The manuscript was written through contributions of all authors. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS N. Micic acknowledges the University of Melbourne, Melbourne Research Scholarship (MRS). A. Polyzos acknowledges the University of Melbourne and CSIRO for the joint Establishment Grant.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01971 Org. Lett. 2018, 20, 4663−4666