Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon-carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2 )-C(sp3 ) cross-coupling processes, with excellent functional-group tolerance.Pfizer
The Cambridge Home and EU Scholarship Scheme
UCB Biopharma SPR

Applequist

Bagutski

Barluenga

Battilocchio

Bomio

Bonet

Brackmann

Cambié

Davies

Deadman

Doyle

Gillingham

Gutmann

Kabalka

Kockmann

Kupracz

Lebel

Lima

Majchrzak

Movsisyan

Müller

Nakagawa

Peng

Plutschack

Regitz

Tran

Yoshifuji

Zollinger

Greb, Andreas

Poh, Jian-Siang

Greed, Stephanie

Battilocchio, Claudio

Pasau, Patrick

Blakemore, David C

Ley, Steven V

Apollo (Cambridge)

German Edition: DOI: 10.1002/ange.201710445Photochemistry Hot PaperInternational Edition: DOI: 10.1002/anie.201710445AVersatile Route to Unstable Diazo Compounds via Oxadiazolinesand their Use in Aryl–Alkyl Cross-Coupling ReactionsAndreas Greb+, Jian-Siang Poh+, Stephanie Greed, Claudio Battilocchio, Patrick Pasau,David C. Blakemore, and Steven V. Ley*Abstract: Coupling of readily available boronic acids anddiazo compounds has emerged recently as a powerful metal-free carbon–carbon bond forming method. However, thedifficulty in forming the unstable diazo compound partner ina mild fashion has hitherto limited their general use and thescope of the transformation. Here, we report the application ofoxadiazolines as precursors for the generation of an unstablefamily of diazo compounds using flow UV photolysis and theirfirst use in divergent protodeboronative and oxidative C(sp2)@C(sp3) cross-coupling processes, with excellent functional-group tolerance.Diazo compounds represent a highly useful class ofcompounds in organic synthesis,[1] for example in cyclopropa-nation,[2] and heteroatom@H[3] and C@H insertion[4] reactions.In particular, the reaction of diazo compounds with organo-boron species has attracted considerable interest over the pastfew years, such as in C(sp2)@C(sp3) cross-coupling reactions.[5]Our previous studies on the flow oxidation of hydra-zones,[6] showed the effectiveness of utilizing mild conditionsto generate and react diazo compounds with boronic acid. Inparticular, this allowed us to intercept the putative unstableboronic species and thereby enable access to alcohols[6] andpowerful iterative bond-forming processes.[7] Nevertheless,these studies were limited to the generation of “semi-stabilized diazo compounds”, bearing either an aryl or vinylgroup adjacent to the diazo moiety. To truly generalize thisconcept would require expansion into the elusive realm of“non-stabilized diazo compounds”, a class of compoundsnotorious for their intrinsic instability, toxic/hazardousnature, and difficulty of preparation (Scheme 1).[1b] Withinthis class of reactive intermediates, dialkyl-substituted diazocompounds pose a major challenge to both access and safelyutilize these reactive species. If a mild method to generatethese non-stabilized diazo compounds could therefore berealized, a more general method to enable aryl–alkyl cross-coupling may become possible, along with potential inter-ception of the intermediate boron species to afford newreactions.While a multitude of methods have been developed toaccess diazo compounds, few allow the generation of the non-stabilizedmembers of the family with sufficient generality. Aninteresting report byWarkentin et al. in 1989 showed that UVphotolysis of 1,3,4-oxadiazolines at around 300 nm led todiazoalkanes.[8] Surprisingly, this approach has been largelyoverlooked by chemists as a potential route to formingunstable diazo compounds, and has never before beenengaged in the development of new synthetic methods.Oxadiazolines are available by a two-step, one-pot procedurefrom readily available ketones through condensation of acetichydrazide and subsequent PhI(OAc)2-mediated oxidation. Incontrast to alternative diazo precursors such as hydrazonesand nitrosoamides, oxadiazolines were found to be bench-stable over many months (also see Supporting Informationfor differential scanning calorimetry data).At the outset of our investigation, we decided to exploitenabling flow technologies to achieve more efficient irradi-ation compared with a batch reactor,[9] and to avoid the build-up of hazardous quantities of any unstable diazo com-pounds.[10–12] Initial studies began with the generation ofoxadiazoline 1, a potential precursor for the cyclic, non-stabilized diazo compound, 4-diazotetrahydropyran (2 ;Scheme 2). Passage of an ethereal solution of 1 througha 10 mL reactor coil held at 10 8C and irradiated at 310 nmwith a 9 WUV lamp, at a 0.125 mLmin@1 flow rate (residenceScheme 1. Families of diazo compounds.[*] Dr. A. Greb,[+] J.-S. Poh,[+] S. Greed, Dr. C. Battilocchio, Prof. S. V. LeyDepartment of Chemistry, University of CambridgeLensfield Road, Cambridge, CB2 1EW (UK)E-mail: svl1000@cam.ac.ukDr. P. PasauUCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest1420 Braine-L’Alleud (Belgium)Dr. D. C. BlakemoreMedicine Design, Pfizer Inc.Eastern Point Road, Groton, CT 06340 (USA)[+] These authors contributed equally to this work.Supporting information and the ORCID identification number(s) forthe author(s) of this article can be found under:https://doi.org/10.1002/anie.201710445. Raw spectra may be foundathttps://doi.org/10.17863/CAM.12635.T 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co.KGaA. This is an open access article under the terms of the CreativeCommons Attribution License, which permits use, distribution andreproduction in any medium, provided the original work is properlycited.AngewandteChemieCommunications16602 T 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2017, 56, 16602 –16605time= 80 min) led to the generation of a distinctively redsolution. In-line IR spectroscopic analysis revealed twoimportant features: a peak at 2040 cm@1 corresponding tothe stretch of a diazo group confirmed the presence of diazocompound 2 ; in addition, a peak at 1746 cm@1 correspondingto the C=O stretch of methyl acetate was observed, a usefulgauge of assessing photolytic conversion of the oxadiazolines.Consequently, we could now efficiently access non-stabilizeddiazo compounds using a flow method and then study theiruse in C(sp2)@C(sp3) cross-coupling (see the SupportingInformation for optimization results). This procedure isdivergent depending upon the “workup” conditions of theintermediate boron species.Using a number of oxadiazolines and readily availableboronic acids (forming boroxines in situ),[13] we were able todemonstrate a remarkably broad reaction scope and unusu-ally high functional-group compatibility (Table 1). Withrespect to the oxadiazoline component, a variety of pharma-ceutically relevant 4-, 5- and 6-membered saturated hetero-cyclic examples were viable coupling partners, includingpyran (3a), tetrahydrofuran (3b), tetrahydrothiopyran (3c),tetrahydrothiophene (3d), thietane (3e), N-Boc piperidine(3 f), N-Boc pyrrolidine (3g), and N-Boc azetidine (3h) rings,providing moderate to excellent yields of the desired C(sp2)@C(sp3) cross-coupling products. It is particularly notable thatthe 4-membered rings were viable examples given theinstability of 4-membered cyclic diazo compounds,[14] whicharises from the relief of ring strain when moving from an sp2to an sp3 carbon center on reaction with electrophiles.Furthermore, tolerance of the tetrahydrothiophene andthietane moieties highlights examples where approachesusing a tosylhydrazone route or carbon-centered radicalapproaches would fail, due to the tendency of these systemsto undergo elimination/ring-opening. A number of carbocy-clic examples containing cycloalkyl groups (3 i–3 l) were alsopermissible substrates, along with a highly hindered adaman-tane substituent (3m). Tolerance of a cyclopropyl group (3n)is not only indicative of a non-radical based process for thisC(sp2)@C(sp3) cross-coupling, but also further exemplifies theadvantages of this procedure over methods utilizing carbon-centered radicals (where cyclopropane ring-opened productswould be obtained instead). In terms of functional-groupcompatibility for the oxadiazoline component, olefins (3o),alkynes (3p), acetals (3q), phosphonates (3r), sulfones (3s),furans (3v), and pyrimidines (3w) were all viable substrates.Remarkably, both an epoxide (3t) and an alkyl bromide (3u)could participate in this coupling process, products that wouldbe intractable to access using metal-catalyzed methods orharsh basic conditions. With respect to the boronic acidcomponent, a variety of electron-deficient aromatic ringsharboring various functional groups were suitable substrates,including those with 4-bromo (3x), 4-trifluoromethyl (3y), 4-Table 1: Metal-free protodeboronative and oxidative C(sp2)@C(sp3)cross-coupling.Yields stated are of isolated product. Protodeboronation: 0.5 mmol ofboronic acid, 1.0 mmol of oxadiazoline and 1.0 mmol of DIPEA, thenworkup using TBAF (3 equiv.) and stirred further at RT for 16 h. *protodeboronation was conducted at 75 8C for 16 h. Oxidation:0.5 mmol of boronic acid, 1.0 mmol of oxadiazoline and 1.0 mmol ofDIPEA, then workup by stirring further under air at RT for 16 h.Scheme 2. Oxadiazolines as diazo precursors and access to non-stabilized diazo compound 2.AngewandteChemieCommunications16603Angew. Chem. Int. Ed. 2017, 56, 16602 –16605 T 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.orgcyano (3z), and 4-methoxycarbonyl (3aa) substituents. Elec-tron-rich groups were also tolerated, including 3-acetamide(3ab), 4-methoxy (3ac), and o-methyl (3ad) substituents,although for the two latter cases, a higher temperature wasrequired to achieve protodeboronation. Although lower-yielding, heterocyclic boronic acids could also be employedin this method to provide useful amounts of desired cross-coupled product, for example, 3-pyridyl (3ae) and 2-thienyl(3af) substituents.A simple switch in the workup procedure to stirring underair provided the oxidized C(sp2)@C(sp3) cross-coupled prod-ucts, and this reaction exhibited a similar broad scope andhigh functional-group compatibility (Table 1).Again, a varietyof 4-, 5- and 6-membered saturated heterocyclic oxadiazolinescould be coupled with 4-chlorophenylboronic acid to generatea variety of tertiary alcohols (4a–4h) in generally similaryields to the protodeboronative method. Similar yields wereobtained for carbocyclic examples (4 i–4 l, 4n), with theexception of adamantane derivative 4m, where oxidationappeared to be extremely slow. In terms of functional-groupcompatibility, olefins (4o), alkynes (4p), acetals (4q), phos-phonates (4r), sulfones (4s), furans (4v) and pyrimidines(4w) all proceeded smoothly. A particular highlight was thetolerance of highly reactive functionalities such as an epoxide(4t) and alkyl bromide (4u). Electron-poor boronic acids (4x,4y) and electron-rich boronic acids (4ab) were also viablecoupling partners, although in the case of 4aa, protodeboro-nation appeared to be facile and 30% of the protodebor-onative C(sp2)@C(sp3) cross-coupled product 3aa was alsoobtained. This overall method is complementary to conven-tional Grignard addition but in many cases afforded productsthat are not compatible with organometallic species.To illustrate the utility of our newly developed method,we first turned to the trapping of the tertiary boronic acidderived from the coupling of 4-chlorophenylboronic acid andthe cyclobutane oxadiazoline precursor, using excess pinacolas the final workup quench, which provided the valuable Bpinproduct 5 in 74% yield (Scheme 3a). General methods toaccess and assess the reactivity of these tertiary alkylboronpinacol esters are vastly underdeveloped, so these examplesserve as testament to this versatile cross-coupling route, forthe synthesis of highly valued organoboron intermediates.Utilization of 5 for the generation of valuable and pharma-ceutically relevant tertiary cyclobutylamines was successfullydemonstrated, providing the benzyl protected derivative 6 in70% yield over two steps.[15] Furthermore, we were also ableto construct quaternary carbon centers using two recentlydeveloped methodologies for C(sp2)@C(sp3) cross-coupling ofboronic esters: reaction of 5 with 2-lithiofuran and a subse-quent quench with N-bromosuccinimide (NBS) led to cyclo-butylated furan derivative 7 in 47% yield;[16] whereas aniridium-catalyzed photoredox flow process[17] allowed us tocouple 1-isoquinolinecarbonitrile to 5, leading to cyclobuty-lated isoquinoline derivative 8 in 49% yield. Finally, we werefurther able to apply this process to the short three-stepsynthesis of the GABA receptor agonist drug, baclofen (10 ;Scheme 3b).[18]In summary, this work clearly demonstrates how oxadia-zolines may be used as efficient, bench-stable precursors fornon-stabilized diazo compounds. Indeed, with these improve-ments in metal-free C(sp2)@C(sp3) cross-coupling, this processcomplements the well-established organometallic and orga-nohalide cross-coupling procedures. In combination withreadily available arylboronic acids, this newly developedflow method allows a myriad of potent, divergent, metal-freeC(sp2)@C(sp3) cross-coupling processes exhibiting a verygeneral reaction scope and unparalleled functional-grouptolerance, as well as access to new tertiary alkyl boronicpinacol ester derivatives. Further applications of theseunstable diazo compounds are currently ongoing in ourlaboratories.AcknowledgementsThe authors are grateful to Pfizer (A.G. and D.C.B.), theCambridge Home and EU Scholarship Scheme (J.S.P.), UCBBiopharma SPRL (J.S.P., S.G. and P.P.), the EPSRC (S.V.L.,grant nos. EP/K009494/1, EP/K039520/1 and EP/M004120/1)and ECH2020 (S.V.L., Future & Emerging Technologies(FET) Sponsor Ref. - 737266) for financial support. We arealso grateful to David J. OQRourke at UCB for conductingdifferential scanning calorimetry analysis and DuncanGuthrie at Vapourtec for the generous loan of a UV photo-reactor.Scheme 3. Applications of the divergent C(sp2)@C(sp3) cross-couplingprocess.AngewandteChemieCommunications16604 www.angewandte.org T 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2017, 56, 16602 –16605Conflict of interestP.P. is an employee of UCB Biopharma SPRL. D.C.B. is anemployee and stockholder of Pfizer Inc.Keywords: boronic acids · cross-coupling · diazo compounds ·flow chemistry · photochemistryHow to cite: Angew. Chem. Int. Ed. 2017, 56, 16602–16605Angew. Chem. 2017, 129, 16829–16832[1] a) H. Zollinger, Diazo Chemistry I and II, Wiley-WCH, Wein-heim, 1995 ; b) M. Regitz, G.Maas,Diazo Compounds Propertiesand Synthesis, Academic Press, Orlando, 1986 ; c) M. P. Doyle,M. A. McKervey, T. Ye, Modern Catalytic Methods for OrganicSynthesis with Diazo Compounds, Wiley, New York, 1998.[2] a) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem.Rev. 2003, 103, 977 – 1050; b) F. Brackmann, A. de Meijere,Chem. Rev. 2007, 107, 4493 – 4497; c) S. Nakagawa, K. A.Bainbridge, K. Butcher, D. Ellis, W. Klute, T. Ryckmans,ChemMedChem 2012, 7, 233 – 236.[3] D. Gillingham, N. Fei, Chem. Soc. Rev. 2013, 42, 4918 – 4931.[4] H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417 – 424.[5] For a general overview, see: a) M. Paraja, M. Plaza, C. 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Ley, Angew.Chem. Int. Ed. 2016, 55, 14085 – 14089; Angew. Chem. 2016,128, 14291 – 14295.[18] S. Yoshifuji, M. Kaname, Chem. Pharm. Bull. 1995, 43, 1302 –1306.Manuscript received: October 10, 2017Accepted manuscript online: October 31, 2017Version of record online: December 5, 2017AngewandteChemieCommunications16605Angew. Chem. Int. Ed. 2017, 56, 16602 –16605 T 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions.

Andreas Greb

Jian-Siang Poh

Stephanie Greed

Claudio Battilocchio

Patrick Pasau

David C. Blakemore

Steven V. Ley

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Angewandte Chemie International Edition

A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions

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A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions.

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