Bräse, Stefan

Hassan, Zahid

Nieger, Martin

Oßwald, Simon

Zippel, Christoph

English

KITopen

RSC AdvancesPAPEROpen Access Article. Published on 25 January 2022. Downloaded on 8/15/2022 11:43:48 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal  | View IssueC–P bond formaaInstitute of Organic Chemistry, KarlsFritz-Haber-Weg 6, 76131 Karlsruhe, Gebraese@kit.edubDepartment of Chemistry, University of HFinlandcInstitute of Biological and Chemical SKarlsruhe Institute of Technology (KIT),Eggenstein-Leopoldshafen, Germany† Electronic supplementary information (Eanalytical data, crystallographic data andand crystallographic data in CIF or10.1039/d2ra00094f‡ These authors contributed equally to thCite this: RSC Adv., 2022, 12, 3309Received 6th January 2022Accepted 17th January 2022DOI: 10.1039/d2ra00094frsc.li/rsc-advances© 2022 The Author(s). Published bytion of cyclophanyl-, and arylhalides via a UV-induced photo Arbuzov reaction:a versatile portal to phosphonate-graftedscaffolds†Simon Oßwald, ‡a Christoph Zippel, ‡a Zahid Hassan, *a Martin Niegerband Stefan Bräse *acA new versatile method for the C–P bond formation of (hetero)aryl halides with trimethyl phosphite viaa UV-induced photo-Arbuzov reaction, accessing diverse phosphonate-grafted arenes, heteroarenes andco-facially stacked cyclophanes under mild reaction conditions without the need for catalyst, additives,or base is developed. The UV-induced photo-Arbuzov protocol has a wide synthetic scope with largefunctional group compatibility exemplified by over 30 derivatives. Besides mono-phosphonates, di- andtri-phosphonates are accessible in good to excellent yields. Mild and transition metal-free reactionconditions consolidate this method's potential for synthesizing pharmaceutically relevant compoundsand precursors of supramolecular nanostructured materials.Aryl phosphonates and phosphonic acids, as an important classof organophosphorus products, have elicited enormous interestin pharmaceutical science for their biological application,1–5 incatalysis as precursors of privileged phosphine ligands,6–8 andin materials science as supramolecular tectons.9–11 For thesynthesis of aryl phosphonates, besides conventional Grignardor organolithium protocols, the development of the palladium-catalyzed Hirao cross-coupling of H-phosphonates with arylhalides is a convenient method,12 and several modied proto-cols have been reported in recent years.13,14Development of new and generally useful C–P bond forma-tion methods with controlled selectivity that are widely appli-cable, cheap, and operationally simple have been anoutstanding objective since phosphonylated products havea broad spectrum of applications. For instance, phosphono-uoresceins due to the inuence of the phosphoryl moietyinsertion, show an almost 70-fold increase in intracellularruhe Institute of Technology (KIT),rmany. E-mail: zahid.hassan@kit.edu;elsinki, P.O. Box 55, 00014, Helsinki,ystems–Functional Molecular Systems,Herman-von-Helmholtz-Platz 1, 76344SI) available: Experimental procedures,kinetic data. CCDC 2103359 (4). For ESIother electronic format see DOI:is work.the Royal Society of Chemistrybrightness, compared to the analogous sulfono-, and carboxy-uorescein, as recently reported by Miller and co-workers.2Recent trends to realize C–P bond formation are focused onvisible-light-driven reactions, where Toste and co-workers rstdeveloped a dual catalytic strategy by combining gold andruthenium photoredox catalysis for the oxidative P-arylation ofH-phosphonates.15 Similarly, König and co-workers reportedthe ruthenium-catalyzed phosphonylation of electron-rich are-nes mediated by CAr–H activation employing trialkyl phos-phites.16 Metal-free variants using either organic dyes,17–20hypervalent iodine reagents,21 or strong base22 are additionallyemerged as a useful tool to promote C–P bond formation(Fig. 1).Strategies that employ trialkyl phosphites have the drawbackof expensive reagents, transition metal catalysts, or large cata-lyst loadings. The UV-induced photo-Arbuzov reaction hasmostly been neglected, even though it is more than 50 yearsold.23–25 The original publication by Griffin and coworkersdescribes the reaction of aryl iodides with trialkyl phosphites atlow temperatures (8 to 0 C).24 The phosphonylation of aryltriates with trialkyl phosphites via photo-induced Arbuzov-type reaction, using UV light in combination with a base asadditive has recently been realized.26 The need for aryl iodidesand poor substrate scope foreclosed this reaction to becomebroadly applicable. Advancing the UV-induced photo-Arbuzovreaction for the preparation of aryl phosphonates, in thiswork, we report a new and more effective method for C–P bondformation under mild conditions without the need for catalysts,additives, or a base employing a wide array of functionalizedaryl-, heteroaryl and thiacyclophanyl halides. The P-arylationRSC Adv., 2022, 12, 3309–3312 | 3309Fig. 1 Selected methods previously reported for light-induced C–Pbond formation.Scheme 1 Unprecedented domino-type de-sulfurization/phospho-nylation of dibromo-dithia[3.3]paracyclophane 3 towards para-bisphosphonylated-PCP 4. Crystal structure of product 4. Displace-ment parameters are drawn at a 50% probability level: top view(bottom left) and side view (bottom right).RSC Advances PaperOpen Access Article. Published on 25 January 2022. Downloaded on 8/15/2022 11:43:48 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Onlineproceeds with excellent functional group tolerance regardless ofthe steric hindrance and represents an important step forwardin enabling C–P bond formation. Multiple and dominoapproach was investigated under the optimized conditionsform the application perspective of the phosphonates asmolecular tectons in nanostructured materials.Scheme 2 Optimized phosphonylation reaction conditions. 6a (1.0 m,1.00 mmol), P(OMe)3 (5.00 mmol), UV light (245 nm, 224 W).Results and discussionWe commenced our studies by reacting dibromo-dithia[3.3]paracyclophane 3 (Scheme 1, top), with trimethyl phosphiteunder UV irradiation at room temperature. The phosphonylated[2.2]paracyclophane 4 was exclusively obtained by domino-typede-sulfurization/phosphonylation, whereas the bromo-substituted [2.2]paracyclophane derivative 5 was not detectedduring our investigations. The C–P coupling of the bromo-substituted dithia[3.3]paracyclophane 3 is unprecedentedcompared to uorinated-analogs, which under similar reactionconditions solely undergo sulphur-extrusion and no C–P bondformation occurs.27 Photolytic sulphur extrusion of [3.3]dithia-cyclophanes is a known high yielding synthesis method of thecorresponding PCP derivatives, an intriguing co-facially stackedscaffold, which is widely utilized in asymmetric catalysis, p-stacked conjugated polymers and other emerging optoelec-tronic materials.28–31 The para-bisphosphonylated [2.2]para-cyclophane 4, obtained by this domino-type reaction, wasanalyzed by detailed spectroscopic techniques, and unambig-uously conrmed by single-crystal X-ray diffraction analysis(Scheme 1, bottom). The precursor dithia[3.3]cyclophane 3 was3310 | RSC Adv., 2022, 12, 3309–3312prepared by cyclization of 1,4-bis(mercaptomethyl)benzene (1)and dibromo-2,5-dibromo-p-xylene (2) under dilution. Alterna-tively, enantiomerically pure planar-chiral dithia[3.3]para-cyclophane derivatives can also be obtained by rhodium-catalyzed cyclization of the same two precursors.32The phosphonylation reaction conditions were optimizedusing bromobenzene as test substrate (Scheme 2 and ESI, TableS1†). With 1,4-dioxane as the solvent and 5.00 equiv. trimethylphosphite, phosphonate 7a was isolated in 96% yield. Otherlight sources were examined, but neither blacklight (368 nm,160W) nor LED UV lamps (385 nm, 64W) or blue LEDs (471 nm,30W) led to any conversion, and staring material was recovered.To evaluate the synthetic scope and its limitations wereexplored based on the optimized reaction conditions (Scheme3). Both chloro- and iodobenzene led to the phosphonylatedproduct 7a, whereas phenyl triate led to a complex mixture. Ingeneral, the reaction proceeds in good to excellent yieldregardless of the steric hindrance (7b–7d) and electronic effects.Chloro-substituted bromobenzenes 6e led to a mixture ofmono- and di-phosphonylated products except for the ortho-chlorinated substrate 6e-o, which exclusively led to the di-© 2022 The Author(s). Published by the Royal Society of ChemistryScheme 3 Synthetic scope of the photo-Arbuzov reaction. Arylbromide 6 (1.0 m, 1.00 mmol), P(OMe)3 (5.00 mmol), UV light (245 nm,224 W). All yields refer to the isolated yield. Yield in parentheses refersto the corresponding di-phosphonylated products. a conducted ona 0.1 mol scale. b conducted in neat P(OMe)3 (20.0 mmol).Scheme 4 Multiple C–P bond formation. 6 (1.00 mmol), P(OMe)3(20.0 mmol), UV light (245 nm, 224 W). All yields refer to the isolatedyield. Yield in parentheses refers to the corresponding mono-phos-phonylated products. aConducted with 5.00 equiv. P(OMe)3 indioxane.Paper RSC AdvancesOpen Access Article. Published on 25 January 2022. Downloaded on 8/15/2022 11:43:48 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Onlinephosphonylated product. The uorinated bromobenzenes 6fgave the corresponding mono-phosphonates with a C–F bondintact, reecting its more negative reduction potential than a C–Cl bond.33 The exception here is para-uoro substituted bro-mobenzene 6f-p, where the di-phosphonate 6f0-p was isolated in37% yield. A similar result was observed in the case of bro-moanisole derivatives 6g. The ortho- and meta-substitutedcompounds were isolated as mono-phosphonylated products,as was the para-substituted derivative under the optimizedconditions. Instead, when the reaction was conducted withoutsolvent and 20 equiv. of trimethyl phosphite, the di-phosphonate 7g0-p was obtained in a 48% yield. In terms offunctional group tolerance, products bearing triuoromethyl,nitrile, hydroxy, amino, and ester substituents were all isolatedin very good yield. The highly reactive nitro- and aldehydefunctionality did not lead to any product formation, as did thecarboxylic acid 6n due to its low solubility in the solvents testedin this work.© 2022 The Author(s). Published by the Royal Society of ChemistryFor further diversication studies, benzofused system ofhalogenated heterocycles as reaction partners to achieve thedesired C–P transformation were demonstrated. Conversiontowards the pyridine derivatives 7t was observed, but the nalproduct could not be puried. The pyrazine 7u and the fusedheterocycles 7v and 7x were all obtained in moderate yield. Wealso pursued multiple-substituted C–P coupling variants, thearylphosphonates with multiple phosphonate groups hasapplications as molecular tectons to constitute a series ofunconventional nanostructured frameworks (MOFs and COFs)with unique properties.34,35Under modied reaction conditions,i.e., in neat trimethyl phosphite (20.0 equiv.), di- and tri-phosphonylation of the corresponding bromides were success-fully achieved in good yield (Scheme 4).The phosphonates 7p0–7s0 can be hydrolyzed to the corre-sponding phosphonic acids and can serve as potentially usefultectons. Under acidic hydrolysis, compounds 8a–c were ob-tained in quantitative yield without further purication(Scheme 5). The phosphonic moiety can coordinate withmetals,which offers a useful library of tectons for constructing supra-molecular nanostructured materials, e.g., proton-conductingframeworks.10In summary, we have established a UV-induced photo-Arbuzov reaction to synthesize skeletally diverse (hetero)arylphosphonates, which avoids the use of catalysts, additives, orbases. This synthetic methodology tolerates a wide spectrum offunctional groups and has been applied to a variety of aryl andheteroaryl halides. Dithia[3.3]cyclophanyl bromide, undergoesa domino-type de-sulfurization/phosphonylation. Besides,selective mono-phosphonates, di- and tri-phosphonates wereprepared, and readily converted to their corresponding phos-phonic acids. This transition metal-free methodology willRSC Adv., 2022, 12, 3309–3312 | 3311Scheme 5 Acidic hydrolysis of the di-phosphonylated substrates.RSC Advances PaperOpen Access Article. Published on 25 January 2022. Downloaded on 8/15/2022 11:43:48 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Onlinefurther advance the implication of phosphonates and phos-phonic acids scaffolds to construct supramolecular nano-structured materials with unique properties as well astransforming pharmaceutically relevant compounds.Conflicts of interestNo conicts of interest to declare.AcknowledgementsThe authors acknowledge the support provided by the DeutscheForschungsgemeinscha (DFG) under Germany's ExcellenceStrategy – 3DMM2O – EXC-2082/1–390761711. We thank thetechnical and analytical staff at IOC (KIT) for their assistance.Notes and references1 C. Queffelec, M. Petit, P. Janvier, D. A. Knight and B. Bujoli,Chem. Rev., 2012, 112, 3777–3807.2 J. L. Turnbull, B. R. Benlian, R. P. Golden and E. W. Miller, J.Am. Chem. Soc., 2021, 143, 6194–6201.3 C. S. Demmer, N. Krogsgaard-Larsen and L. Bunch, Chem.Rev., 2011, 111, 7981–8006.4 M. Sawa, T. Kiyoi, K. Kurokawa, H. Kumihara, M. Yamamoto,T. 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C–P bond formation of cyclophanyl-, and aryl halides a UV-induced photo Arbuzov reaction: a versatile portal to phosphonate-grafted scaffolds

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C–P bond formation of cyclophanyl-, and aryl halides a UV-induced photo Arbuzov reaction: a versatile portal to phosphonate-grafted scaffolds

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