Bimetallic Radical Redox-Relay Catalysis for the Isomerization of Epoxides to Allylic Alcohols

Article abstract of DOI:10.1021/jacs.9b04993

Organic radicals are generally short-lived intermediates with exceptionally high reactivity. Strategically, achieving synthetically useful transformations mediated by organic radicals requires both efficient initiation and selective termination events. Here, we report a new catalytic strategy, namely, bimetallic radical redox-relay, in the regio- and stereoselective rearrangement of epoxides to allylic alcohols. This approach exploits the rich redox chemistry of Ti and Co complexes and merges reductive epoxide ring opening (initiation) with hydrogen atom transfer (termination). Critically, upon effecting key bond-forming and -breaking events, Ti and Co catalysts undergo proton transfer/electron transfer with one another to achieve turnover, thus constituting a truly synergistic dual catalytic system.

Full text of DOI:10.1021/jacs.9b04993

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Communication
Bimetallic Radical Redox-Relay Catalysis for the
Isomerization of Epoxides to Allylic Alcohols
Ke-Yin Ye, Terry McCallum, and Song Lin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04993 • Publication Date (Web): 02 Jun 2019
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Bimetallic Radical Redox-Relay Catalysis for the Isomerization of Epoxides to Allylic Alcohols
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Ke-Yin Ye†‡§, Terry McCallum‡§, and Song Lin*‡
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†College of Chemistry, Fuzhou University, Fuzhou, 350116, P.R. China
‡Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
Supporting Information Placeholder
cycloaddition of epoxides (Scheme 1B),7 N-acylaziridines,8 or
ABSTRACT: Organic radicals are generally short-lived
cyclopropyl ketones9 with alkenes. In these reactions, a TiIII
intermediates with exceptionally high reactivity. Strategically,
catalyst reductively activates a functional group in the
substrate to form
subsequent radical transformations to cleave and construct
desired chemical bonds, TiIV oxidatively terminates the
resultant radical in a way akin to atom transfer and completes
the catalytic cycle.
achieving synthetically useful transformations mediated by
organic radicals requires both efficient initiation and selective
termination events. Here, we report a new catalytic strategy,
namely bimetallic radical redox-relay, in the regio- and
stereoselective rearrangement of epoxides to allylic alcohols.
This approach exploits the rich redox chemistry of Ti and Co
complexes and merges reductive epoxide ring opening
(initiation) with hydrogen atom transfer (termination).
Critically, upon effecting key bond-forming and -breaking
events, Ti and Co catalysts undergo proton-transfer/electron-
transfer with one another to achieve turnover, thus
constituting a truly synergistic dual catalytic system.
a transient organic radical. Upon
Scheme 1. Literature precedent and working hypothesis
Epoxides are among the most important synthons in organic
chemistry.1 From nucleophilic substitution2 to transition-
metal catalyzed cross coupling,3 a myriad of powerful
transformations has been discovered that exploit the rich
reactivity of these strained electrophiles. Among the
reactions of epoxides, their rearrangement into allylic
alcohols represents an attractive transformation, as it grants
access to a class of highly useful synthetic intermediates in an
efficient and atom-economical fashion. This transformation
can be carried out under base-mediated conditions (e.g., with
LiNR2).4 The requirement for a strong base inevitably subjects
the substrate to various side reactions (e.g., nucleophilic ring
opening and reactions from ⍺-deprotonation5) as well as
narrowing functional-group compatibility. Furthermore,
methods for the synthesis of chiral allylic alcohols from
epoxides are limited.6 Against this backdrop, we disclose a
radical redox-relay strategy for the isomerization of epoxides
to allylic alcohols under mild conditions using Ti and Co dual
catalysis.
We envision that this radical redox-relay strategy could be
extended to the synthesis of allylic alcohols with the
introduction of a Co co-catalyst. In the proposed reaction, we
exploit the well-established reactivity of TiIII to induce
homolytic epoxide ring opening (ERO; Scheme 1C).10 The
developing radical character at the β-C induces weakening of
the C–H bond at the γ-position,11,12 which enables hydrogen
The rearrangement of epoxides to form allylic alcohols is net
redox-neutral. To circumvent the use of a base promoter, we
envision that this reaction could be achieved by combining a
pair of single-electron oxidation and reduction events in the
same catalytic cycle. This strategy, which we named radical
redox-relay (Scheme 1A), has been demonstrated in the [3+2]
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atom transfer (HAT) with a CoII catalyst to furnish the desired
selectivity likely stems from both electronic and steric
reasons: the ⍺-H is both hydridic20 (polarity mismatched with
electron-rich CoII) and sterically encumbered by the pendant
Ti catalyst.
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alkene functionality. This event generates a formal CoIII–H
intermediate, which is acidic (pKa 10–15)13a,b and may be
viewed as CoI with H+ bound to either the metal center or the
ligand [denoted as CoI(H+)].13b–d This catalytic intermediate
could then undergo proton-transfer/electron-transfer
(PT/ET)14 with the TiIV-alkoxide to deliver the desired allylic
alcohol and regenerate both TiIII and CoII catalysts.
Implementation of this proposed reaction thus relies on
identifying catalysts that would accommodate the
thermodynamics and kinetics of the key ERO, HAT, and PT/ET
steps in the same catalytic cycle.
Table 1. Reaction optimizationa
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Our reaction design was constructed with immense
inspiration from prior art on the redox reactions of Ti10,15,16
and Co12,17,18 complexes in methodologically related
contexts. In particular, recent reports have detailed Ti-
catalyzed epoxide isomerization mediated by Ti–H.19 The
scope of this reaction, however, is generally restricted to ⍺-
methyl epoxides and precludes the formation of endo-olefins.
Moreover, a super-stoichiometric metal reductant (Mn or Zn,
>6 equiv with respect to epoxide) is necessary to achieve high
yields. Recently, Weix disclosed elegant TiIII/Ni0 dual catalysis
for the arylation of epoxides.3b,c In this setting, both catalytic
species crucial for reactivity were regenerated using
stoichiometric Mn. Therefore, these precedent systems are
net reductive and mechanistically distinct from our reaction
design.
We set out to evaluate various combinations of Ti and Co
catalysts and discovered that Cp2TiCl2 (10 mol%) and [Co] 4
(5 mol%) in the presence of Zn (20 mol%) and Et3N•HCl (2
equiv) promoted the conversion of epoxide 1a to desired
product 2a in 65% yield (Table 1, entry 1). However, 11%
byproduct 3a was also formed, which arose from reductive
ring opening of 1a. The alcohol products were in situ
protected with benzoyl chloride to minimize the loss of
volatile products during workup. Notably, Ti alone without
Co—conditions synonymous to related previously
reports19e—led only to byproduct 3a (entry 2). This undesired
side reaction could be mitigated at the expense of increased
Co loading (entries 3, 4). Alternatively, elaboration of the
electronic profile of Co(salen) to include electron-
withdrawing CF3 groups ([Co] 5) furnished 2a quantitatively
in complete chemoselectivity (entry 5). This more reactive
HAT agent allowed us to decrease catalyst loading to 1 mol%
while maintaining useful yield and selectivity (entry 6).
Decreasing the equivalents of Et3N•HCl, however, proved
detrimental (entries 7, 8). Importantly, Co(salen) alone could
not affect the isomerization (entry 9).18 Finally, control
experiments demonstrated that catalytic Zn, which is
proposed to reduce TiIV precatalyst to TiIII to kick start the
catalytic cycle, was vital to the reaction (entry 10). We note
that the regioselectivity of the HAT process is practically
exclusive and cyclohexanone, which would arise from H-
abstraction ⍺-to the –OTiIV motif, was not observed. This
Scheme 2. Reaction scopea
Under optimal conditions, a variety of epoxides underwent
isomerization to furnish desired allylic alcohols in good to
excellent efficiency (Scheme 2A). Trisubstituted epoxide 1k
gave varying ratios of regioisomeric alkenes with [Co] 4
favoring the endo product (71:29) and [Co] 5 favoring the exo
(39:61). Although the endo/exo selectivity remains moderate
at this stage, the capability of steric/electronic tuning of
reaction regioselectivity is intriguing. Notably, our base-free
conditions allowed formation of 21–o without epimerization
of the acidic C–H. Enantioenriched epoxides 1s and 1t were
converted to the corresponding alcohols with complete
retention of configuration. In the case of 2t, only one
regioisomer was observed presumably because the β-H
adjacent to the OBz group in 1t is hydridic and polarity-
mismatched with CoII. Reaction of 1w gave a mixture of 2w
and bicyclic 2w’ in 53% and 31% yield, respectively; 2w was
readily converted to 2w’ under acidic conditions. Currently,
mono- and tetrasubstituted epoxides are challenging
substrates.21
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The Ti/Co dual catalytic system was also successfully applied
enantioselectivity and functional-group tolerance.25 Elegant
base-mediated strategies require a strong base and a chiral
amine catalyst;4,26 the former precludes base-sensitive
substrates and the latter often requires multistep synthesis.
The Corey-Bakshi-Shibata reduction also falls short when
considering conjugated enones.27
to the kinetic resolution of diastereomeric mixtures of several
epoxides (Scheme 2B). For example, 1,2-epoxycyclododecane
(1x, cis/trans = 69:31) delivered 2x in 78% yield with 17%
recovered trans-1x, indicating that cis-1x reacts at a faster
rate. Limonene oxide (1y) reacted to furnish 2y in 44% yield
alongside recovered trans-1y (40% yield). Reactions with
epoxy-cholesterol (1z) with varying ratios of α- and β-
anomers were also diastereoselective. For this substrate, [Co]
5 gave substantial amounts of reduced byproducts (3z)
presumably due to the poor steric accessibility of the γ-H in
this complex substrate. Thus, [Co] 8 (R1 = Cl, R2 = Me) with a
smaller size and similar electronic property was employed. α
-Predominant mixture of 1z (α/β 72:28) gave 28% 2z (α/β
6:94) with full recovery of α-1z whereas β-predominant
mixture (α/β 5:95) produced β-2z as a single diastereomer.22
This reaction thus offers access to these synthetically valuable
epoxides in diastereomerically pure form, which are
challenging via direct olefin epoxidation.
Scheme 3. Enantioselective rearrangementa
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The intermediacy of organic radicals was confirmed using
epoxides 1aa and 1ab (Scheme 2C). [Co] 4 gave a mixture of
uncyclized 2aa and cyclized 2aa’ in 57:43 ratio. [Co] 5 instead
gave an 80:20 mixture of 2aa/2aa’. These results indicate that
the HAT process occurring at a faster rate with the electron
deficient [Co] 5 over [Co] 4 and is competitive with the
transannular cyclization (kc ≈ 3.3 x 104 s–1).23 Increasing the
loading of [Co] 5 led to nearly complete suppression of
cyclization, giving 2aa in 75% yield. Pinene derivative 1ab
was converted to a 33:67 mixture of 2ab/2y using [Co] 4 and
a 64:36 mixture using [Co] 5. These data again indicate a
facile HAT process with both Co catalysts that is comparable
to the radical-induced fragmentation of pinene.24
Comparing with previous work on Ti-mediated epoxide
isomerization,19b–d our dual catalytic system exhibits
complementary chemoselectivity with several substrates
tested (Scheme 2D). For example, 1,2-epoxycyclododecane
(1x), which was converted smoothly to allylic alcohol 2x
under Ti/Co co-catalysis, underwent deoxygenation to yield
cyclododecene under solely Ti-mediated conditions (2x’).19b
In addition, the isomerization of epoxycyclohexane (1a) to 2a
was not observed using Ti only, with cyclohexanol (3a’)
formed as the major product. Notably, farnesol-derived
epoxide 1ac underwent cascade cyclization to 2ac’ using Ti
but was converted to linear product 2ac quantitatively using
Ti/Co.19d Lastly, the desired rearrangement of carvone-
derived 1ad were observed using Ti/Co, producing 2ad
without observation of Ti-mediated acetate elimination
(2ad’).19c To demonstrate the scalability of our method, we
synthesized β-2z and 2ac on 1-mmol scale and obtained
good to excellent yields.
Using epoxycyclohexene (1a), Kagan’s complex3c,28,29 11
along with [Co] 4 promoted the reaction with high
enantioselectivity albeit with the formation of byproduct 14a
in 10% (Scheme 3A, entry 1). Unexpectedly, [Co] 5, a more
reactive HAT catalyst, gave minimal conversion to desired
13a likely due to steric interactions with encumbered 11
(entry 3). Removing the tBu groups on [Co] 5 (i.e., [Co] 6), low
reactivity was observed due to low catalyst solubility (entry
4). Owing to the difficulty in synthesizing the (CF3,Me)-
substituted [Co] 7, we prepared halogenated derivatives ([Co]
Finally, we developed an enantioselective protocol using
chiral Ti complexes. Few methods are available for the
synthesis of enantioenriched cyclic allylic alcohols. The
Kharasch-Sosnovsky reaction enables the functionalization of
allylic C–H bonds but often suffers from low
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8–10) with similar electronic properties to 5 (see SI for cyclic
Specifically, Et3N•HCl protonates IB to liberate product 2a and
Cp2TiIVCl2. The resultant Et3N then deprotonates CoI(H+) to
furnish anionic CoI.17d The incipient CoI and TiIV will then
undergo ET to close both catalytic cycles. This step is
favorable on thermodynamic grounds given the highly
reducing character of CoI [Ep/2(CoII/I) = –1.65 V vs Ep/2(TiIV/III) =
–1.06 V; see SI].
The proposed reaction mechanism does not account for
the requirement for stoichiometric Et3N•HCl. However,
Et3N•HCl has been postulated to also play critical roles in
activating Zn dust and stabilizing TiIII catalytic species10d,31
and it has a very low solubility in the reaction medium. In this
reaction, the solely Ti-mediated pathway was not operative,
as GC analysis of the reaction headspace showed no evidence
of H2 formation, which would be expected if TiIV–H
intermediates are present.19e
In summary, the redox-neutral epoxide isomerization was
achieved using Ti/Co redox-relay catalysis. The optimized
process showed the intricacy in balancing steric and
electronic characteristics of the CoII catalyst. The reaction
scope includes a wide range of cyclic and acyclic epoxides
using readily available catalysts. The resolution of
diastereomeric epoxides and desymmetrization of meso-
epoxides were also discovered. This work represents a rare
example of Ti redox catalysis in the absence of stoichiometric
reductants, where turnover was achieved through redox-
relay with a Co co-catalyst. Further understanding the
mechanism of each elementary step of the reaction and
applications to new organic transformations are underway.
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voltammograms) but a smaller steric profile. Indeed, [Co] 8
proved optimal, producing 13a in 81% yield and 83% ee.
The scope of the enantioselective isomerization was
expanded to various meso-epoxides (Scheme 3B). With
simple cyclic systems, the products (13a–d, x) formed in
excellent yields and high enantioselectivity. 1w was smoothly
converted to 2w, which was further converted to bicyclic 2w’
with two bridge-head stereocenters in 88% ee. Dienol 13aa
was obtained from 1aa in 91% ee alongside traces of
transannular cyclization products. While linear meso-epoxide
1ae was not compatible with this transformation, 1af and
1ag led to desired products 2af and 2ag in high ee. Several
polysubstituted cyclic epoxides were transformed to the
corresponding products with multiple new stereocenters (2l–
o). Although the enantioselectivities in some of these cases
are moderate, our methodology provides access to these
interesting molecules that are challenging with base-
mediated isomerization due to competing epimerization.26
Given the synthetic accessibility of menthol derivatives, the
optimization of these systems by ligand modification is
promising.
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Scheme 4. Proposed mechanism
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data (PDF) and
crystallography data (CIF). The Supporting Information is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
songlin@cornell.edu
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interests.
We propose a synergistic dual catalytic cycle for the
epoxide isomerization (Scheme 4). The formation of Cp2TiIIICl
(monomer or dimer)10d via Zn reduction of Cp2TiIVCl2 triggers
1e– reduction of epoxide 1a to TiIV-bound β-alkoxyl radical IA.
Subsequently, IA is transformed into IB via either direct HAT
with CoII or a ligand-assisted, proton-coupled electron
transfer (PCET)13d to produce CoI(H+) intermediate.30 Finally,
IB undergoes PT/ET with CoI(H+) to regenerate CoII and TiIII.
We propose this PT/ET process is mediated by Et3N.
ACKNOWLEDGMENT
Financial support was provided by Cornell University. S.L.
thanks the NSF for a CAREER Award (CHE-1751839) and the
Alfred P. Sloan Foundation for a Sloan Fellowship. This study
made use of the NMR facility supported by the NSF (CHE-
1531632). We thank Dr. Samantha MacMillan for help with X-
ray crystallography, Dr. Ivan Keresztes for help with NMR
spectral analysis, Rileigh Casebolt for assistance with GC
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(11) Zhang, X.-M. Homolytic Bond Dissociation Enthalpies of the
C-H Bonds Adjacent to Radical Centers. J. Org. Chem. 1998, 63, 1872–
1877.
(12) West, J., Huang, D.; Sorensen, E. J. Acceptorless
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catalysis. Nat. Commun. 2015, 6, 10093.
measurements, and Zhidong Song, Jinjian Liu, Tom Schang,
Devin Wood, and Maria Congenie for experimental
assistance. We thank one reviewer for their feedback on the
nature of the cobalt hydride intermediate.
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A Catalytic Enantioselective Electron Transfer
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a cis-coordination site to
accommodate the β-H elimination unless the ligand sphere
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