Harnessing zirconocene（III）for photoinduced carbon radical generation

Abstract

With recent advances in photoredox chemistry，avariety of methods for generating carbon radicals have emerged.This review high lights recent approaches for radical generation utilizing zirconocene（III），aspecies infrequently employed in organic syntheses.Of particular interest are methods employing visible light irradiation，which induce C-Zr bond homolysis of alkyl zirconium species or activate a photoredox catalyst to reduce zirconocene（IV）。

Recent advances in photoredox chemistry have driven significant development of various methods for generating carbon radicals.This review high lights recent approaches utilizing zirconocene（III），infrequently employed in organic syntheses.Notably，methods employing visible light irradiation to induce C-Zr bond homolysis or to excite a photoredox catalyst to reduce zirconocene（IV）。

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1.Introduction

There has been significant progress in developing methodologies for radical species，especially for carbon-centered radicals。^1个The generation of such radicals frequently necessitates tailored radical precursors to facilitate their production.Consequently，these precursors often exhibit high reactivity，requiring careful handling or case-by-case preparation prior to use.In contrast，stable and robust compounds are difficult to dixize，duce， and thus have been less frequently utilized as radical precursors.The development of approaches to generate carbon-centered radicals from these compounder under mild conditions holds significant promise for accelerating innovation in the field of radical chemistry。

Ti（III）has been recognized as a valuable reagent in the generation of carbon radicals。^2-5Despite a significant resurgence in Ti（III）-catalyzed radical reactions over the past decade，Zr（III）has received considerably less attention。^6-8（III）species，these methods have found use in synthetic organic chemistry。^{9单击功能区上，10}Due to its high ly reducing nature，Zr（III）（E=1.85 V vs SCE（Cp₂ZrCl）₂）¹¹）has been employed as a reductant。To this end，pinacol couplings with a stoichiometric¹²or a catalytic amount¹³of Zr（III）have been reported（Fig。1a）。热回收率₂ZrCl₂strong reductants such as K metal¹⁴and Na（Hg），^{15单击功能区上，16}thereby limiting functional group tolerance.The Oshima group introduced an alternative method for generating Zr（III）by hydrogen atom transfer（HAT）from Schwartz reagent（Cp₂ZrHCl）。^{第十七节：单击功能区上，18}The seminal workby the Oshima group underscored the vast potential of Zr（III）in a range of dehalogenative radical transformations。^{第十七节：}Furthermore，several methods for generating Zr（III）have been long established despite their limited application in organic synthesis。These methods include the elimination of cyclopentadienyl（Cp）radicals through direct excitation of Cp₂ZrCl₂单击功能区上，^19-22and homolytic C-Zr bond cleavage via photolysis of alkyl zirconocenes。²³

In recent years，significant progress in photoredox chemistry has greatly influenced radical chemistry，even allowing for developments in Zr（III）chemistry。This review focues on recent studies exploring the utilization of Zr（III）inorganic synthesis to generate carbon radicals under visible light irradiation。These reactions typically employ two primary methodologies for Zr（III）generation:hydrofunctionalization of alkenes with Schwartz reagent，followed by photolysis of the resultant C-Zr bond，and the reduction of Zr（IV）to Zr（III）by excited photocatalysst（Fig。1b）。This review discusses recent reports and presents our own contributions to this field。

2.C-Zr bond photolysis of alkyl zirconocene

While C–Zr bond homolysis has long been known as a method to generate carbon radicals，the Brasholz group has recently applied this process to photoredox catalysis。^{第二十四节：}They have developed a visible light-mediated three-component radical[4+2]cyclization-allylation reaction utilizing allyl zirconocenes，resulting in the synthesis of various allylated hexahydrocarbazoles with high diastereoselectivity（Fig。2a）。Furthermore，methallylated and prenylated products were also obtained.The authors proposed a mechanism beginning with the reduction of an alkyl iodide by an excited photocatalyst to afford alkyl radical（Fig。2b）。The sequential intermolecular and intramolecular radical addition furnishes tertiary radical，which is combined with allyl radical ejected from allyl zirconium via photolysis.This process also produces Zr（III）to regenerate the photocatalys by the reduction of Ir（IV）。

In2020，Qi and co-workers reported a Ni-calyzed cross-coupling reaction with alkyl zirconocene（Fig。3a）。²⁵The alkyl zirconocene was prepared from alkene and Schwartz reagent，which is further elaborated to the corresponding coupling product with organic halides under visible light irradiation.Various organic halides possessing C（sp³）–X，C（sp²）–X，and C（sp）–X bonds are applicable in these reaction conditions。With internal alkenes，the cross-coupling occurred at the terminal sites through a chain-walking process.The proposed mechanism for this reaction involves hydrozirconation of the alkene with Schwartz reagent to form the alkyl zirconium species（Fig。3b）。Subsequent C-Zr bond homolysis of the resultant alkyl zirconium occurs under visible light irradiation，furnishing the alkyl radical.Zr（III）derived from alkyl zirconium reduces Ni（II）to Ni（0），allowing for the reaction with the alkyl radical，yielding the alkyl–Ni（I）spies。Then，the oxidative addition of halides to Ni（I）delivers Ni（III）via either a radical-mediated path with an alkyl halide or a concerted pathway with aryl，alkenyl，oralkynyl halides.Finally，the reductive elimination affords the desired coupling products with Ni）to reproduce Ni（0）。

Following this report，the same group has developed a cross-coupling reaction betweengem-borazirconocene alkanes and aryl halides（Fig。4a）。²⁶Utilizing the Bpin group as directing group for hydrozirconation，reaction of boryl alkene and Schwartz reagent selectively produces thegem-borazirconocene alkane。Additionally，gem-borazirconocene alkanes can be prepared from terminal alkenes with a Bpin group at the distal position。Moreover，by adjusting the reaction temperature and time，this protocol enables the selective synthesis of branched or linear alkylboronate derivatives.Specically，conducting the reaction at 110ⅼ°C affords the thermodynamically favorablegem-borazirconocene alkane，while lower temperatures produce the kinetically favorable linear alkyl zirconium.Furthermore，the group reported an enantioselective variant of the cross-coupling reaction usinggem-borazirconocene alkanes and chiral diamine ligands（Fig。4b）。²⁷垃圾处理窗，垃圾处理窗L1单击功能区上，which has two Me groups on the nitrogen atoms.Conversely，the alkylation occurs in a high ly enantioselective manner usingL2单击功能区上，which uses Et groups instead of Me groups。

Additionally，Mitsunuma and Kanai²⁸reported a Cr-catalyzed alkylation of aldehydes（Fig。5a）。Schwartz reagent，CrCl₂，and alkenes，visible light irradiation of aldehydes yields the corresponding alkylated product（Fig。5b）。This reaction is also applicable to a ketone，albeit in a lower yield.Furthermore，with chiral ligandL3，the reaction proceeds in an antioselective manner.The proposed catalytic cycle commenced with hydrozirconation of alkene.The formed alkyl zirconium undergoes C-Zr bond cleavage upon visible light irradiation.The resultant alkyl radical attacks Cr（II）to form the alkyl chromiecum，which further reacts with the aldehyde.Ligand exchange between the resulting chromium alkoxide and zirconocene furnishes zirconocene alkoxide and Cr（III）salt。Finally，the Zr（III）formed in C-Zr photolysis reduces Cr（III）to regenerate Cr（II）。

张紧和连接杆²⁹reported a difluoroalkylation of alkenes using difluorohaloalkanes（Fig。6个）。This reaction was applicable to a variety of alkyl halides and alkenes.Notably，the difluoroalkyl radical is generated by Zr（III）species resulting from the photolysis of alkyl zirconium。The resultant difluoroalkyl radical can reacts with both terminal and internal olefins。

3.Reduction of Zr（IV）using photoredox catalysis

Although the above approaches generate Zr（III）through the photolysis of the C–Zr bond，Zr（III）can also be obtained with a redox approach。In2022，our group developed aregioselective ring opening of epoxides using zirconocene and photoredox catalysis（Fig。7a）。³⁰Visible light irradiation of an epoxide in the presence of zirconocene，photoredox catalyst，thiourea，and1,4-cyclohexadiene（CHD）results in C-O bond cleavage。The reaction of mono-，di-，and tri-substituted epoxides preferentially furnished the more substituted alcohol.It is noteworthy that thiourea as anessential additive effectively influences the regioselectivity，and no regioselectivity was observed without thiourea.This Zr-catalyzed ring opening results in reversed regioselectivity compared to Ti-catalyzed ring opening，leading to less substituted alcohols（Fig。7b）。^{2-5单击功能区上，31单击功能区上，32}Thus，our method complements the traditional Ti-catalyzed reaction.Moreover，aradical clock experiment using acyclopropyl epoxide to afford the allylic alcohol supports that C-Obond cleavage proceeds through aradical mechanism（Fig。7c）。Additionally，the resultant alkyl radical can be utilized in a Giese-type addition and a benzylidene acetal formation via1,5-HAT。

Our proposed reaction mechanism is depicted in Fig。8个.Firstly，an excited photocatalyst Ir（III）*（Ir（4-MeOppy）₃单击功能区上，E_1/2Ir（IV）/Ir（III）*=-1.95 V vs SCE）reduces Zr（IV）to Zr（III）。³³The coordination of epoxides to the resultant Zr（III）facilitates the C-O bond cleavage。The resulting carbon radical abstracts ahydrogen atom from1,4-CHD to give the zirconocene alkoxide，followed by oxidation of the resultant CHD radical by Ir（IV）to reproduce Ir（III）。Then，the CHD cation works asa Brønsted acid to protonate the zirconocene alkoxide，leading to the desired alcohol and Zr（IV）with benzene through ligand exchange。

Additionally，we also reported aregioselective ring opening of oxetanes using zirconocene and photoredox catalysis（Fig。9）。³⁴The reaction proceedsviaaless stable radical to afford more substituted alcohol selectively.Similar to the ring opening of epoxides，this ring opening of oxetane exhibited reverse regioselectivity to Ti-catalyzed reactions。³⁵Furthermore，the protocol could be applied to benzylidene acetal formation。

The developed zirconocene and photoredox catalysis was also applicable to a chlorine atom transfer reaction of alkyl chlorides（Fig。10）。³⁶The use of alkyl chlorides has largely been restricted to activated alkyl chlorides such as benzyl chlorides，α-chloro carbonyls，and trichloromethyl alkanes in classical radical chemistry.Instead，this protocol accommodated primary，secondary， and tertiary unactivated alkyl chlorides for the generation of carbon-centered radicals.In the presence of zirconocene，photoredox catalyst，thiourea，and H-atom donor，the visible light irradiation to alkyl chlorides affords the corresponding hydrogenated compounds.When the diboron agwament of nor， the corresponding borylated product was obtained。

We next explored the plausibility of our proposed chlorine atom transfer mechanism through competitive experiments using a1:1 mixture of primary and secondary alkyl chlorides，as well asa1:1 mixture of secondary and tertiary alkyl chlorides（Fig。11）。Our experimental results revealed that the secondary chloride exhibited higher reactivity than the primary chloride，and the tertiary chloride displayed higher reactivity than the secondary chloride.Thus，the rate of C-Cl bond cleavage follows the order of tertiary>secondary>primary.This trend is consistent with observations in other halogen atom transfer（XAT）reactions，³⁷which underscores the XAT nature of our protocol。

4.概要和outlook

The exploration of Zr（III）in radical generation marks a promising avenue for future radical-mediated synthesis。Recent advances in photoredox chemistry have led to new opportunities for utilizing Zr（III）。Further investigations toward diverse methodologies for utilizing Zr（III）are anticipated，with a focus on expanding the type of reactions and exploring new strategies for preparing Zr（III）under visible light irradiation。The development of catalytic systems enabling efficient and selective Zr（III）-mediated radical transformations holds great potential for advancing synthetic organic chemistry。In conclusion，the methods high lighted in this review showcase the versatility and potential of Zr（III）-mediated radical chemistry，offering novel synthetic pathways for constructing complex molecularchitectures.Continued research efforts in this area are poised to yield innovative solutions to longstanding challenges in organic synthesis。

Funding

This work was supported by JSPS KAKENHi Grant Nos.JP21H05213（Digi-TOS）（to J.Y.），JP20K15290（to E.O.），Sumitomo Foundation（to E.O.），Daiichi Kigenso Kagaku Kogyo（to E.O.）。This work was partly supported by JST ERATO Grant No.JPMJER1901（to J.Y.）。

参考，参考

Kazuhiro Aida

Kazuhiro Aida was born in Tokyo，Japan in 1997.He received his BSc（2020）and MSc（2022）degrees from Waseda University。Currently，he is a PhD candidate in the group of Junichiro Yamaguchi at Waseda University.His research has focused on the development of inactive bond cleavage reactions using photoredox catalysis。

Eisuke Ota

Eisuke Ota was born in Chiba in 1987and raised in Tokyo，Japan。He received his BSc（2010）and MSc degrees（2012）from Keio University under the guidance of Prof.Shigeru Nishiyama。He then joined the group of Prof.Mikiko Sodeoka at RIKEN，where he completed his PhD in 2016.After working as a postdoctoral researcher for one year at the same place，he became a JSPS Overseas Research Fellow in the lab of Robert Knowles at Princeton University.In the fall of 2018，he became assan prosist， working with Prof.Junichiro Yamaguchi，and was promoted to associate professor in 2024.His research interests are the development of photochemical bond cleavage methods for organic synthesis and chemical biology。

Junichiro Yamaguchi

Junichiro Yamaguchi was born in Tokyo，Japan，in1979.He received his PhD in 2007from the Tokyo University of Science under the supervision of Prof.Yujiro Hayashi.From2007to2008，he was a postdoctoral fellow in the group of Prof.Phil S.Baran at The Scripps Research Institute ad）。In2008，he became an Assistant Professor at Nagoya University working with Prof.Kenichiro Itami and was promoted to Associate Professor in 2012.He then moved to Waseda University asan Associate Professor（principal investigator）in2016and promoted to full professor in 2018。His research interests include the total synthesis of natural products and the innovation of synthetic methods。

Author notes