A method for the metal-free synthesis of benzotriazoles in flow is reported. Using azides and in situ generated arynes, benzotriazoles are formed in a [3+2] cycloaddition within minutes. Employing different substitution patterns of the azide and aryne coupling partners, a modular access to benzotriazoles is provided. Thermal strain of hazardous azides and accumulation of reactive intermediates is minimized by short reaction times in flow, improving the safety profile of the process. The scalability of the reaction is demonstrated

Baranyi, Linda

Boeser, Lisa

Heretsch, Philipp

Kleoff, Merlin

English

Institutional Repository of the Freie Universität Berlin

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657Scalable Synthesis of Benzotriazoles via [3+2]Cycloaddition of Azides and Arynes in FlowMerlin Kleoff,[a] Lisa Boeser,[a] Linda Baranyi,[a] and Philipp Heretsch*[a]A method for the metal-free synthesis of benzotriazoles in flowis reported. Using azides and in situ generated arynes, benzo-triazoles are formed in a [3 + 2] cycloaddition within minutes.Employing different substitution patterns of the azide and arynecoupling partners, a modular access to benzotriazoles isprovided. Thermal strain of hazardous azides and accumulationof reactive intermediates is minimized by short reaction timesin flow, improving the safety profile of the process. Thescalability of the reaction is demonstrated.The copper(I)-catalyzed [3 + 2] cycloaddition of azides andalkynes (CuAAC) has affected chemistry, biology, and medicinalresearch alike.[1] In biological systems, azides and alkynes serveas bioorthogonal linkers allowing conjugation between twomolecules by the formation of 1,2,3-triazoles.[1f,h,2] Owing to thetoxicity of copper for living cells, copper-free [3 + 2] cyclo-additions are of great interest.[3] Thus, the metal-free reaction ofazides with arynes to substituted 1,2,3-benzotriazoles couldallow further applications.[4,5]With the appearance of pathogens resistant to commonazole-based pharmaceuticals, benzotriazoles emerged as valua-ble substitutes and since have been employed for antibacterial,antifungal, and antiviral agents with remarkable potency.[4c–f,6]Therefore, rapid and scalable access to a broad range offunctionalized benzotriazoles could further support medicinalstudies.As described by Larock[7a] and others,[7b–f] reaction of ortho-trimethylsilyl triflates with fluoride ions generates arynes whichundergo [3 + 2] cycloaddition with azides (Scheme 1A). Theresulting benzotriazoles were obtained after reaction times ofup to 24 hours. To accelerate the reaction, a microwaveprotocol was developed for the synthesis of benzyl substitutedbenzotriazoles but required a reaction temperature of 125 °C(Scheme 1B).[8]As heating of organic azides and highly reactive aryneintermediates poses the danger of an explosion, upscaling isproblematic.[9] In recent years, flow chemistry has evolved as analternative to overcome these limitations.[10] Given the superiorheat and mass transfer in microreactors, various reactions canbe significantly accelerated while offering an improved safetyand sustainability profile.[10–12]We have recently developed a flow platform for thesynthesis of natural products and their analogs. Reagents aredriven with argon instead of solvent to reduce solvent andreagent waste from drying and equilibration procedures.[13,14]Using this flow platform, we here describe a scalable methodfor the efficient preparation of benzotriazoles by [3 + 2] cyclo-addition of arynes and azides in flow (Scheme 1C).At the outset, we screened conditions for the reaction ofbenzyne precursor 1a with benzyl azide (2a) leading tobenzotriazole 3a (Table 1). To streamline the process andminimize thermal strain of organic azides, we aimed for a shortresidence time in a heated tube reactor.Initially, tetrabutylammonium fluoride (TBAF) was used as afluoride source since the limited solubility of cesium fluoride in[a] M. Kleoff, L. Boeser, L. Baranyi, Prof. Dr. P. HeretschInstitut für Chemie und BiochemieFreie Universität BerlinTakustraße 3, 14195 Berlin, GermanyE-mail: philipp.heretsch@fu-berlin.dewww.chemie.fu-berlin.de/heretschSupporting information for this article is available on the WWW underhttps://doi.org/10.1002/ejoc.202001543Part of the “YourJOC Talents” Special Collection.© 2020 The Authors. European Journal of Organic Chemistry published byWiley-VCH GmbH. This is an open access article under the terms of theCreative Commons Attribution Non-Commercial NoDerivs License, whichpermits use and distribution in any medium, provided the original work isproperly cited, the use is non-commercial and no modifications or adap-tations are made.Scheme 1. A) Synthesis of benzotriazoles via [3 + 2] cycloaddition of arynesand azides in batch at room temperature. B) Microwave-assisted reaction ofarynes with in situ formed benzyl azides. C) Expedient and scalable synthesisof benzotriazoles in flow. TBAT: tetrabutylammonium triphenyldifluorosili-cate; Tf: trifluoromethanesulfonyl; TMS: trimethylsilyl.Communicationsdoi.org/10.1002/ejoc.202001543979Eur. J. Org. Chem. 2021, 979 – 982 © 2020 The Authors. European Journal of Organic Chemistrypublished by Wiley-VCH GmbHWiley VCH Freitag, 05.02.20212106 / 190683 [S. 979/982] 1123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657acetonitrile precluded its use in our flow process. At 50 °C andwith a residence time of 8 minutes, different solvents(entries 1–3) were screened. While tetrahydrofuran (THF) andbenzotrifluoride resulted in low yields, employing acetonitrile assolvent, 3a was isolated with a moderate yield of 53 %. Whenpotassium fluoride and 18-crown-6 were used, almost noproduct was obtained (entry 4). Switching to tetrabutylammo-nium triphenyldifluorosilicate (TBAT) as a fluoride source gavesmooth conversion to benzotriazole 3a and an improved yieldof 74 % (entry 5). Further investigation of parameters revealed aresidence time of 8 min at 40 °C led to an incomplete reaction(68 % yield, entry 6). At higher temperatures, complete con-sumption of starting material was observed, but lower yieldswere obtained (entries 7 and 8).Employing higher flow rates and a shorter residence time of4 minutes at 50 °C, incomplete conversion of starting materialwas observed along with a lower yield of 64 % (entry 9).Eventually, when 1.7 equivalents of benzyne precursor 1a and1.8 equivalents of TBAT were used, the yield of benzotriazole3a could be increased to 87 % (entry 10). In accordance withour previous studies, the reaction could be performed withoutexclusion of air and moisture.[13a]With the optimized flow protocol in hand, the scope of the[3 + 2] cycloaddition of benzyne with various azides wasinvestigated (Scheme 2). Despite the intriguing properties offerrocenyl benzotriazoles,[4d] they have not been prepared fromarynes and ferrocenyl azides, thus far.[13b] This may be attributedMerlin Kleoff was born in Berlin, Germany, in1994 and studied chemistry at Freie Universi-tät Berlin where he received his B.Sc. in 2015.During his Master studies, he worked withProf. Dr. H.-U. Reißig on the preparation ofsuper Lewis basic terpyridine ligands. In 2018,he completed his M.Sc. with a thesis on thesynthesis of new ferrocene building blocks inthe group of Prof. Dr. B. Sarkar. He then joinedthe group of Prof. Dr. P. Heretsch for his PhDwhere he is currently working on syntheticapplications of flow chemistry.Lisa Boeser was born in Berlin, Germany, in1998 and studied chemistry at Freie Universi-tät Berlin. She completed her B. Sc. with athesis on the scalable synthesis of ferrocenylazides in flow in the group of Prof. Dr. P.Heretsch in 2019. Currently, she is conductingher master studies at Freie Universität Berlin.Linda Baranyi was born in 1993 in Furth imWald, Germany. She studied chemistry at theHumboldt-Universität zu Berlin where shereceived her B.Sc. in 2018. Currently, she isconducting her master studies in chemistry atFreie Universität Berlin.Philipp Heretsch was born in Lippstadt, Ger-many, in 1982. He obtained his PhD degreefrom Universität Leipzig (supervisor: Prof. Dr.A. Giannis) in 2009. After a postdoctoral staywith K.C. Nicolaou at The Scripps ResearchInstitute, La Jolla, California, and at RiceUniversity, Houston, Texas, he was appointedassistant professor at Freie Universität Berlinin 2015. His group is interested in frameworkmanipulation strategies in the context ofabeo-steroid and alkaloid synthesis as well asapplication of flow chemistry in natural prod-uct synthesis.Table 1. Optimization of the [3 + 2] cycloaddition of benzyne and benzylazide in a flow reactor.[a]Entry Fluoride source Solvent T [°C] Yield [%]1 TBAF THF 50 302 TBAF PhCF3 50 333 TBAF MeCN 50 534 KF/18-c-6 MeCN 50 35 TBAT MeCN 50 746 TBAT MeCN 40 687 TBAT MeCN 55 728 TBAT MeCN 60 669[b] TBAT MeCN 50 6410[c] TBAT MeCN 50 87[a] Yields of isolated product are given. Reaction conditions: 1a (0.3 mmol,0.15 m, 1.5 equiv), 2a (0.2 mmol, 0.1 m, 1.0 equiv), TBAT (0.32 mmol,0.16 m, 1.6 equiv); flow rate: 0.4 mL, 8 min. [b] Performed with a residencetime of 4 min. [c] Performed with 1.7 equiv. of 1a and 1.8 equiv. of TBAT.18-c-6: 1,4,7,10,13,16-hexaoxacyclooctadecane; THF: tetrahydrofuran.Communicationsdoi.org/10.1002/ejoc.202001543980Eur. J. Org. Chem. 2021, 979 – 982 www.eurjoc.org © 2020 The Authors. European Journal of Organic Chemistry publishedby Wiley-VCH GmbHWiley VCH Freitag, 05.02.20212106 / 190683 [S. 980/982] 1123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657to the potential explosiveness and thermal lability of ferrocenylazides, hampering their use in reactions at elevatedtemperatures.[15]Employing our flow protocol, the reaction of azidoferrocene2b provided the corresponding ferrocenyl benzotriazole 3b ina good yield of 81 %. Also, the bromo- (3c, 80 % yield) and theester-functionalized ferrocenyl benzotriazoles (3d, 68 % yield)could be obtained.1,1’-Diazidoferrocene 2e is a valuable building block forredox-switchable catalysts and sensors.[15,16] Due to the explo-siveness of 2e at temperatures above 56 °C,[15] syntheticapplications are limited, especially on a larger scale. However, inflow, azide 2e could be used without safety concerns. When 1.7equivalents of benzyne precursor 1a were employed, mono-benzotriazole 3e was isolated in a moderate yield of 37 %.Using 3.4 equivalents of benzyne precursor 1a and 3.6equivalents of TBAT, dibenzotriazole 3f was obtained in 38 %yield. The alkynyl substituted ferrocenyl benzotriazole 3g wasisolated in 67 % yield. Although, alcohols can react asnucleophiles with arynes, the [3 + 2] cycloaddition of alcoholsubstituted azide 2h gave benzotriazole 3h with a good yieldof 72 %. The enantioenriched benzotriazole 3 i (51 % yield) wasderived from the corresponding menthyl azide under retentionof the stereoconfiguration.Eventually, heterocyclic azides were tested as substrates.The 5,6-dihydro-2-oxazine 2 j was prepared by aza-Michaeladdition of 6H-1,2-oxazine with sodium azide in protic solvents(see the supporting information).[17] Cycloaddition with benzynegave the corresponding benzotriazole 3 j in a yield of 55 %.As benzotriazole substituted piperidone 3k shows promis-ing antibacterial and antifungal activity,[6] we aimed for its rapidand scalable synthesis. Employing our method, we prepared 3kin a yield of 66 %. To demonstrate the scalability of our flowprotocol, we synthesized 3k also on a gram scale correspond-ing to a theoretical productivity of 0.33 g/h in a similar yield of69 % with the same reactor setup.Finally, we investigated the scope of arynes by usingfunctionalized aryne precursors 1b–g (Scheme 3). When elec-tron-deficient aryne precursor 1b was employed, difluorinatedbenzotriazole 4a was isolated in 56 % yield. The sesamol-derived aryne precursor 1c reacted smoothly to benzotriazole4b in a good yield of 75 %. Using fluorinated aryne precursor1d, an inseparable mixture of the 5- and 6-fluoro isomers ofbenzotriazole 4c (61 % yield) was obtained in a 3 : 1 ratio. Incontrast, reaction with ortho-substituted precursors 1e–gselectively gave the 4-functionalized benzotriazoles 4d–f(60  71 % yield), as assigned by nOe spectroscopic analysis.In conclusion, we have developed a flow protocol for themetal-free synthesis of benzotriazoles by [3 + 2] cycloadditionof azides and in situ generated arynes. Due to the shortresidence time of 8 minutes, thermal strain is minimizedScheme 2. Scope of benzotriazoles 3a–k for the reaction of benzyne withorganic azides 2. Yields of isolated product are given. Reaction conditions:1a (0.34 mmol, 0.17 m, 1.7 equiv), 2a–k (0.2 mmol, 0.1 m, 1.0 equiv), TBAT(0.36 mmol, 0.18 m, 1.8 equiv), 50 °C, 8 min. For further details, see thesupporting information. [a] Employing 1a (0.34 mmol, 0.17 m, 3.4 equiv ), 2e(0.1 mmol, 0.05 m, 1.0 equiv), and TBAT (0.36 mmol, 0.18 m, 3.6 equiv).Scheme 3. Scope of benzotriazoles 4a–f for the reaction of various arynes1b–g with benzyl azide 2a. Yields of isolated product are given. Reactionconditions: 1b–g (0.34 mmol, 0.17 m, 1.7 equiv), 2a (0.2 mmol, 0.1 m,1.0 equiv), TBAT (0.36 mmol, 0.18 m, 1.8 equiv), 50 °C, residence time: 8 min.Communicationsdoi.org/10.1002/ejoc.202001543981Eur. J. Org. Chem. 2021, 979 – 982 www.eurjoc.org © 2020 The Authors. European Journal of Organic Chemistry publishedby Wiley-VCH GmbHWiley VCH Freitag, 05.02.20212106 / 190683 [S. 981/982] 1123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657enhancing the safety and efficiency of this protocol. A variety offunctionalized azides and arynes have been employed toprovide the corresponding benzotriazoles, including the gram-scale preparation of an antibacterial benzotriazole.AcknowledgementsFinancial support for this work was provided by the BoehringerIngelheim Stiftung. We are grateful to Dr. Johannes Schwan, Dr.Reinhold Zimmer, and Nicole Fouquet (all Freie Universität Berlin)for preparative support. We acknowledge the assistance of theCore Facility BioSupraMol supported by the DFG. Open accessfunding enabled and organized by Projekt DEAL.Conflict of InterestThe authors declare no conflict of interest.Keywords: Arynes · Click chemistry · Cycloaddition · Flowchemistry · Nitrogen heterocycles[1] a) H. C. 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Scalable Synthesis of Benzotriazoles via [3+2] Cycloaddition of Azides and Arynes in Flow

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Scalable Synthesis of Benzotriazoles via [3+2] Cycloaddition of Azides and Arynes in Flow

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