Bimetallic Radical Redox-Relay Catalysis for the Isomerization of Epox- ides to Allylic Alcohols Ke-Yin Ye†‡§, Terry McCallum‡§, and Song Lin*‡ †College of Chemistry, Fuzhou University, Fuzhou, 350116, P.R. China ‡Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States ABSTRACT: Organic radicals are generally short-lived intermediates Scheme 1. Radical redox-relay applied to allylic alcohol synthesis A. General principle of radical redox-relay catalysis with exceptionally high reactivity. Strategically, achieving synthetically X useful transformations mediated by organic radicals requires both X TiIV TiIV TiIII –TiIII efficient initiation and selective termination events. Here, we report a X X new catalytic strategy, namely bimetallic radical redox-relay, in the regio- sub rad1 rad2 pdt and stereoselective rearrangement of epoxides to allylic alcohols. This reductive radical oxidative approach exploits the rich redox chemistry of Ti and Co complexes and initiation transformation termination merges reductive epoxide ring opening (initiation) with hydrogen atom B. An example of Ti-catalyzed radical redox-relay (ref 7) transfer (termination). Critically, upon effecting key bond-forming and O catalytic Ti R -breaking events, Ti and Co catalysts undergo proton-transfer/electron- R O R R transfer with one another to achieve turnover, thus constituting a truly Me Me Me synergistic dual catalytic system. Me TiIV TiIV R O O TiIII R –TiIII R Me R Epoxides are among the most important synthons in organic chemis- Me try.1 From canonical nucleophilic substitution2 to transition-metal cata- Me Me 3 lyzed cross coupling, a myriad of powerful transformations has been C. This work: Ti/Co bimetallic radical redox-relay for epoxide discovered that exploit the rich reactivity of these strained electrophiles. isomerization—design principle O Among the reactions of epoxides, their rearrangement into allylic alco- catalytic Ti/Co OH hols represents an attractive transformation, as it grants access to a class of highly useful synthetic intermediates in an efficient and atom-eco- 44–99% yield; 48–94% ee nomical fashion. This transformation can be carried out under base-me- 4 O III diated conditions (e.g., with LiNR2). The requirement for a strong base TiIV TiIV –Ti III II II inevitably subjects the substrate to various side reactions (e.g., nucleo- Ti H O Co –Co 5 γ β α I + philic ring opening and reactions from ⍺-deprotonation ) as well as nar- ERO HAT Co →H PT/ET rowing functional group compatibility. Furthermore, methods for the (formally CoIII–H) 6 synthesis of chiral allylic alcohols from epoxides are limited. Against this We envision that this radical redox-relay strategy could be extended backdrop, we disclose a radical redox-relay strategy for the isomerization to the synthesis of allylic alcohols with the introduction of a Co co-cata- of epoxides to allylic alcohols under mild conditions using Ti and Co lyst. In the proposed reaction, we exploit the well-established reactivity dual catalysis. of TiIII to induce homolytic epoxide ring opening (ERO; Scheme 1C).10 The rearrangement of epoxides to form allylic alcohols is a net redox- The developing radical character at the β-C induces significant weaken- neutral transformation. To circumvent the use of a base promoter, we ing of the C–H bond at the γ-position,11,12 and this enables hydrogen envision that this reaction could be achieved by combining a pair of sin- atom transfer (HAT) with a CoII catalyst to furnish the desired alkene gle-electron oxidation and reduction events in the same catalytic cycle. functionality. The resultant CoIII–H, depending on the ligand, can be 13 I + This strategy, which we named radical redox-relay (Scheme 1A), has acidic (pKa 10–15) and may be viewed as Co coordinated to H . This been demonstrated in the [3+2] cycloaddition of epoxides (Scheme catalytic intermediate could then undergo proton-transfer/electron- 1B),7 N-acylaziridines,8 or cyclopropyl ketones9 with alkenes. In these transfer (PT/ET)14 with the TiIV-alkoxide to deliver the desired allylic reactions, a TiIII catalyst reductively activates a functional group in the alcohol and regenerate both TiIII and CoII catalysts. Implementation of substrate to form a transient organic radical. Upon subsequent radical this proposed reaction thus relies on identifying catalysts that would ac- transformations to cleave and construct desired chemical bonds, TiIV ox- commodate the thermodynamics and kinetics of the key ERO, HAT, idatively terminates the resultant radical in a way akin to atom transfer and PT/ET steps in the same catalytic cycle. and completes the catalytic cycle. We note that our reaction design was constructed with immense in- spiration from prior art on the redox reactions of Ti10,15,16 and Co12,17,18 complexes in methodologically related contexts. In particular, recent re- ports have detailed Ti-catalyzed epoxide isomerization mediated by Ti– H intermediates.19 The scope of this reaction, however, is generally re- offers access to these synthetically useful epoxides in diastereomerically stricted to ⍺-methyl epoxides and precludes the formation of endo-ole- pure form, which are challenging via direct olefin epoxidation. fins (vide infra). Moreover, a super-stoichiometric metal reductant (Mn Table 1. Reaction optimization or Zn, >6 equiv with respect to epoxide) is necessary to achieve high Cp TiCl (cat.), [Co] (cat.) OBz OBz III 0 O 2 2 yields. Recently, Weix disclosed an elegant Ti /Ni dual catalysis for the Zn (cat.), Et3N•HCl (2.0 equiv) arylation of epoxides.3b,c In this setting, both catalytic species crucial for + reactivity were regenerated using stoichiometric Mn reductant. There- Et2O, 22 °C, 20 h Followed by Bz protection fore, these precedent systems are net reductive and mechanistically dis- 1a 2a 3a tinct from our reaction design. Entry mol% Ti [Co] mol% Zn 2a (%) 3a (%) We set out to evaluate various combinations of Ti and Co catalysts, which led to the discovery that Cp2TiCl2 (10 mol%) and [Co] 4 (5 1 10 4 (5 mol%) 20 65 11 mol%) in the presence of Zn (20 mol%) and Et3N•HCl (2 equiv) pro- 2 10 None 40 — (25) moted the conversion of epoxide 1a to the desired product 2a in 65% 3 10 4 (10 mol%) 20 82 7 yield (Table 1, entry 1). However, 11% byproduct 3a was also formed 4 10 4 (15 mol%) 20 82 — concurrently, which arose from reductive ring opening of 1a. The allylic 5 10 5 (5 mol%) 20 99 — alcohol product was in situ protected with benzoyl chloride to minimize 6 10 5 (1 mol%) 20 71 4 the loss of volatile products and facilitate product analysis. Notably, Ti 7b 10 5 (5 mol%) 20 — — alone without Co—conditions synonymous to related previously re- 8c 10 5 (5 mol%) 20 (40) — ports19e—led only to byproduct 3a (entry 2). This undesired side reac- tion could be mitigated at the expense of increased Co loading (entries 9 0 5 (5 mol%) 40 or 200 — — 3, 4). Alternatively, elaboration of the electronic profile of Co(salen) to 10 10 5 (5 mol%) 0 — — include electron-withdrawing CF3 groups ([Co] 5) furnished 2a in Me Me 4, R1 = R2 = Me Me Me 1 2 t quantitative yield and complete chemoselectivity (entry 5). This more 5, R = CF3, R = Bu 1 2 reactive HAT agent allowed us to decrease catalyst loading to 1 mol% N N 6, R = CF3, R = H II 1 2 while maintaining synthetically useful yield and selectivity (entry 6). De- Co 7, R = CF3, R = Me R1 O O R1 8, R1 = Cl, R2 = Me creasing the equivalents of Et3N•HCl, however, proved detrimental (en- 9, R1 = Br, R2 = Me tries 7, 8). Importantly, Co(salen) alone could not affect the isomeriza- R2 R2 10, R1 = Cl, R2 = Cl 18 tion (entry 9). Finally, control experiments demonstrated that cata- aIsolated yields are reported; yields in parentheses are determined by IV III 1 b c lytic Zn, which is proposed to reduce Ti precatalyst to Ti to kick start H NMR using mesitylene as internal standard. No Et3N•HCl. With the catalytic cycle, was vital to the formation of 2a (entry 10). We note 0.5 equiv Et3N•HCl. that the regioselectivity of the HAT process is practically exclusive and The intermediacy of organic radicals was confirmed using epoxides cyclohexanone, which would arise from H-atom abstraction ⍺-to the – 1aa and 1ab (Scheme 2C). [Co] 4 gave a mixture of uncyclized 2aa and OTiIV motif, was not observed. We hypothesize that this selectivity cyclized 2aa’ in 57:43 ratio. [Co] 5 instead gave an 80:20 mixture of stems from both electronic and steric reasons: the ⍺-H is both hydridic20 2aa/2aa’. These results are indicative of the HAT process occurring at (polarity mismatched with electron-rich CoII) and sterically encum- a faster rate with the electron deficient [Co] 5 over [Co] 4 and is com- 4 –1 22 bered by the pendant Ti catalyst. petitive with the transannular cyclization (kc ≈ 3.3 x 10 s ). Increasing Under optimal conditions, a variety of epoxides underwent the isom- the loading of [Co] 5 led to nearly complete suppression of cyclization, erization reaction to furnish desired allylic alcohols in good to excellent giving 2aa in 75% yield. Pinene derivative 1ab was converted to a 33:67 efficiency (Scheme 2A). Trisubstituted epoxide 1k gave varying ratios mixture of 2ab/2y using [Co] 4 and a 64:36 mixture using [Co] 5. of regioisomeric alkenes with [Co] 4 favoring the endo product (71:29) These data again indicate a facile HAT process with both Co catalysts 23 and [Co] 5 favoring the exo (39:61). Although the endo/exo selectivity that is comparable to the radical-induced fragmentation of pinene.