Ketyl radical reactivity via atom transfer catalysis

Article abstract of DOI:10.1126/science.aau1777

Single-electron reduction of a carbonyl to a ketyl enables access to a polarity-reversed platform of reactivity for this cornerstone functional group. However, the synthetic utility of the ketyl radical is hindered by the strong reductants necessary for its generation, which also limit its reactivity to net reductive mechanisms.We report a strategy for net redox-neutral generation and reaction of ketyl radicals.The in situ conversion of aldehydes to a-acetoxy iodides lowers their reduction potential by more than 1 volt, allowing for milder access to the corresponding ketyl radicals and an oxidative termination event. Upon subjecting these iodides to a dimanganese decacarbonyl precatalyst and visible light irradiation, an atom transfer radical addition (ATRA) mechanism affords a broad scope of vinyl iodide products with high Z-selectivity.

Full text of DOI:10.1126/science.aau1777

RESEARCH
in a streamlined approach that obviates an
alkynylation–Al reduction–iodination sequence.
Among the atom transfer catalysts investigated,
several photocatalysts afforded new, redox-
neutral coupling adduct 3 preferentially over
the classic, reduced coupling product 4. These
catalysts included complexes of earth-abundant,
first-row metals (e.g., Mn, Fe) as well as more
reducing photocatalysts (e.g., Ru, Ir; see table
S1 for further details). Ultimately, a Mn2(CO)10
catalyst was found to provide excellent selec-
tivity for redox-neutral coupling (3:4, >20:1)
along with high Z:E diastereoselectivity (>20:1).
The latter feature is notable, as there are few
methods to access vinyl iodides with high Z-
selectivity (27). Although Mn-mediated reactions
are typically associated with oxidative mech-
anisms, atom transfer pathways are accessible
via Mn2(CO)10 (28–30). Unlike typical photo-
catalysts, a photon is not necessary for turnover
of the Mn catalyst. However, we observed that
continual irradiation is necessary to access high
efficiency and selectivity, likely due to an equi-
librium between the precatalyst dimer and the
active catalyst. Given the high chemo- and stereo-
selectivity afforded by the Mn catalyst, we de-
cided to further explore its synthetic potential
in this redox-neutral mechanism.
In our mechanistic proposal, shown in Fig. 1D,
Mn2(CO)10 precatalyst is homolyzed to Mn(CO)5
(5, Mn•) by irradiation with a blue LED. This 17-
electron species is a competent ATRA catalyst
that can abstract I• from the weak C-I bond
[bond dissociation energy (BDE), 58 kcal/mol]
(31) of in situ–generated a-acetoxy iodide 6.
Combination of the resultant ketyl radical 7
with alkyne 8 affords vinyl radical 9. This
open-shell intermediate is formally oxidized by
Mn(CO)5I (10, [Mn]-I) via atom transfer to re-
generate the Mn• catalyst (5), while also forming
vinyl iodide 3′ in a redox-neutral mechanism
(32). The net conversion of 6 to 3′ is exothermic
because of the formation of a strong vinyl C-I
bond (BDE, 61 to 68 kcal/mol). An observed
post-reaction isomerization of the vinyl iodide
products—from 1:1 to >20:1 Z:E selectivity—is
also thermodynamically favored by up to 3 kcal/
mol (33). This Mn-catalyzed isomerization likely
occurs via an intermediate vinyl radical, which is
consistent with reports of photoinduced, single-
electron reduction of aryl iodides for sp2 radical
generation (34, 35). This Mn-catalyzed ATRA
mechanism precludes an alternate pathway, in
which vinyl radical 9 is further reduced to vinyl
anion 11 [Ep,c = –0.1 V (36), which is at least 2 V
more favorable than carbonyl to ketyl reduction]
to afford allyl ester 4. Instead, by coupling cat-
alyst turnover with product formation, the classic
reductive mechanism can be overridden by this
redox-neutral pathway.
ORGANIC CHEMISTRY
Ketyl radical reactivity
via atom transfer catalysis
Lu Wang, Jeremy M. Lear, Sean M. Rafferty, Stacy C. Fosu, David A. Nagib*
Single-electron reduction of a carbonyl to a ketyl enables access to a polarity-reversed
platform of reactivity for this cornerstone functional group. However, the synthetic utility of
the ketyl radical is hindered by the strong reductants necessary for its generation, which also
limit its reactivity to net reductive mechanisms. We report a strategy for net redox-neutral
generation and reaction of ketyl radicals. The in situ conversion of aldehydes to a-acetoxy
iodides lowers their reduction potential by more than 1 volt, allowing for milder access to the
corresponding ketyl radicals and an oxidative termination event. Upon subjecting these
iodides to a dimanganese decacarbonyl precatalyst and visible light irradiation, an atom
transfer radical addition (ATRA) mechanism affords a broad scope of vinyl iodide products
with high Z-selectivity.
he ketyl coupling of carbonyls offers a
mechanistically inverted approach to con-
structing C-C bonds versus classic, polar
mechanisms (1). However, a major limita-
tion of this valuable method is its reliance
promotes mild ketyl radical formation from an
in situ–generated intermediate containing a
weak C-I bond. The resulting radical is capable
of coupling with a range of alkynes. Catalyst
turnover occurs (via formal oxidation of the
ensuing vinyl radical intermediate) by atom
transfer (19, 20) with Mn-I, in a net redox-neutral
mechanism that enables access to synthetically
versatile (21) Z-vinyl halides.
T
on strong, stoichiometric reductants (e.g., Na, K,
Ti) (2–4) to overcome the large reduction poten-
tial of carbonyls (peak cathodic potential Ep,c
>
–2 V versus SCE) (5, 6). As shown in Fig. 1A,
a powerful tool used to overcome the thermo-
dynamic barrier for ketyl generation is Kagan’s
reagent (SmI2) (7, 8). This single-electron re-
ductant can even be used catalytically when
coupled with strong, stoichiometric reductants
(e.g., Zn/Hg) (9). Recently, photochemical ap-
proaches have been applied to address this
fundamental thermodynamic challenge in a
complementary manner. For example, Knowles
and co-workers developed a proton-coupled
electron transfer strategy to reduce ketones
to ketyl radicals using Ir or Ru photocatalysts
(< –1.5 V), Brønsted acids, and a milder stoi-
chiometric reductant (e.g., Hantzsch ester)
(10, 11). The groups of Yoon, Ngai, and Huang
(12–15) have also shown that concerted use of
Lewis acids enables photocatalytic reduction
of carbonyls to access ketyl radicals and their
vinylogous analogs. Additional metal-catalyzed
strategies for carbonyl-alkyne coupling promote
complementary reactivity (by Ni, Ru, or Ir) with
alternate reductants (e.g., Et3B, Mg, H2) (16–18).
However, in each of the ketyl-based strategies,
a redox-neutral approach remains mechanis-
tically unfeasible because catalysts capable of
overcoming the high reduction potential of a
carbonyl are necessarily also prone to reducing
the resulting ketyl-coupling adduct.
In our synthetic design, we focused on ad-
dressing the challenge of ketyl radical gener-
ation from aliphatic aldehydes. We envisioned
that their conversion to a-oxy iodides would
benefit from hyperconjugative donation of the
nonbonding oxygen electrons into the C-I anti-
bonding orbital (n → s*) to further weaken
this bond. Among several a-iodo radical precur-
sors we investigated, the a-acetoxy derivative
proved simplest to generate under mild condi-
tions. This in situ activation is performed by
combining AcI (AcCl, NaI) with carbonyls [5%
Zn(OTf)2, 0°C, 15 min] in a modified version
of Adams’ nearly century-old procedure (22).
The resulting aldehyde derivatives are conve-
niently handled in an aerobic atmosphere at
room temperature and are stable to basic, aque-
ous washes without elimination. This practical
synthetic accessibility allowed us to electro-
chemically validate our hypothesis that a-acetoxy
iodides (Ep,c = –1.1 V; fig. S2) are more easily
reduced than their aldehyde precursors (> –2.2 V)
(5) as well as other alkyl iodides (23–26). Next,
we explored the generation of ketyl radicals—
and their redox-neutral coupling with alkynes—
by using a variety of atom transfer catalysts.
In accordance with our design plan, we ob-
served that several photocatalysts promote this
redox-neutral alkyne coupling with ketyl radi-
cals derived from aliphatic aldehydes (1), as
illustrated in Fig. 1C. Expecting the nucleo-
philicity of a-OAc ketyl radicals to be atten-
uated, we explored their combination with
several alkynes of varying electronic character.
In particular, coupling of silyl acetylene 2 af-
fords silyl vinyl iodide 3 (containing orthog-
onal handles for further synthetic manipulation)
Our complementary strategy, outlined in Fig. 1,
addresses this challenge by replacing the car-
bonyl reduction step with a halogen abstraction
event via an atom transfer radical addition
(ATRA) mechanism. In this case, a Mn catalyst
In probing the synthetic utility of this strat-
egy, we were pleased to find that aliphatic
aldehydes, which are challenging to reduce to
ketyls (Ep,c > –2 V) (5), efficiently combine with
a range of alkynes, as shown in Fig. 2. Alkynes
with broad electronic character are coupled to
the stabilized ketyl radicals, providing Z-vinyl
Department of Chemistry and Biochemistry, The Ohio State
University, Columbus, OH, USA.
*Corresponding author. Email: nagib.1@osu.edu
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Fig. 1. Discovery of a redox-neutral ketyl radical coupling. (A) Current
synthetic approaches to ketyl radicals rely on strong reductants that reduce
both the carbonyl and subsequent radical intermediates. (B) An alternate
strategy based on atom transfer of an a-acetoxy iodide enables milder
reductive initiation, coupled with oxidative termination, to provide a redox-
neutral ketyl coupling mechanism. (C) Several catalysts enable this atom
transfer strategy, including [CpFe(CO)2]2, Ru(bpy)3Cl2, Ir(ppy)2(dtbbpy)PF6,
and Mn2(CO)10, which provide a range of chemo- and stereoselectivities.
(D) Proposed mechanism: Photoinitiated homolysis of Mn2(CO)10 occurs with
visible light (blue LED). The Mn(CO)5 catalyst then formally reduces the in situ
formed a-acetoxy iodide via inner-sphere atom transfer. The resulting
ketyl radical combines with an alkyne to form a vinyl radical, which is oxidized by
the Mn catalyst to form the vinyl iodide product and regenerate Mn(CO)5.
This catalyst turnover step precludes an alternate reductive pathway, wherein a
second reduction of the vinyl radical affords the classic, non-iodo product.
i
nBu, n-butyl; Me, methyl; Pr, isopropyl; Et, ethyl; Ac, acetyl; Zn(OTf)2,
zinc trifluoromethylsulfonate; Cp, cyclopentadienyl; bpy, 2,2′-bipyridine; ppy,
2-phenylpyridine; dtbbpy, 4,4′-di-tert-butyl-2,2′-bipyridyl.
iodides in up to 20:1 diastereomeric ratio. For
example, alkynes with highly electron-releasing
substituents, such as SiEt3 or BPin, are com-
petent partners (12, 13), affording versatile
vinyl silanes or boronates (37, 38). Aryl alkynes
and 1,3-enynes afford valuable styrene and diene
adducts (14, 15), and electron-deficient propio-
lates also undergo ketyl coupling to merge these
electrophiles (16, 17).
In addition to conjugated alkynes, we found
propargyl esters to be suitable ketyl radical ac-
ceptors that afford Z-vinyl iodide 18, which
contains orthogonal allyl esters. An internal com-
petition between alkynes (alkyl- versus ester-
substituted) selectively converts the propiolate
alkyne to vinyl iodide 19, leaving the unsub-
stituted alkyne intact. The mild, radical addition
conditions are also tolerant of alcohols (20) and
ketones (21, 22), illustrating the orthogonality
and synthetic utility of this ATRA-based strategy.
To further demonstrate the functional group
compatibility of this ketyl-alkyne coupling, we
also explored a wide range of aliphatic aldehydes.
Aldehyde-derived ketyl radical precursors with
both small (23) and large (24) steric footprints
provide Z-vinyl iodides in >20:1 selectivity. The
tolerated functionality on the aldehyde com-
12 and 16 over the reaction course (Fig. 3A).
In each case, we observed rapid product for-
mation (>70% yield) within 15 min, albeit with
modest Z:E selectivity (7:1, 1:1). For the first
2 hours, product yields remained within 5 to
10% of their 15-min values, but Z:E selectivity
increased markedly (>20:1, 14:1), suggesting a
product isomerization mechanism. Additional
evidence of post-reaction epimerization was
found when a 1:1 mixture of vinyl iodide 16 was
resubjected to the Mn photocatalyst for 2 hours,
affording the Z-isomer selectively: 4:1 (10% cat-
alyst) or >20:1 (20% catalyst) (Fig. 3B).
Further insights were obtained for each ele-
mentary step of the atom transfer radical addi-
tion via the mechanistic experiments shown
in Fig. 3. First, a competition experiment be-
tween an electron-poor and an electron-rich
alkyne resulted in exclusive ketyl radical cou-
pling to the electron-deficient propiolate al-
kyne (16 versus 12), indicating that the a-OAc
radical has nucleophilic character (Fig. 3C).
Next, we validated the viability of the key oxi-
dation step required for catalyst turnover by
stoichiometric trapping of an aryl radical with
ponent includes arenes of varying electronic
character (25–27), ethers (28–29), and amides
(30–32). Alkyl halides (e.g., Cl, 33; I, 34) are
also tolerated in the reaction, illustrating selec-
tive reaction of the Mn catalyst with the hyper-
conjugatively activated a-acetoxy iodides.
Finally, although some ketone-derived ketyl
radicals are too hindered for efficient cross-
coupling, we found that trifluoroacetone provides
efficient access to Z-vinyl iodide 35 bearing an
adjacent tertiary ester. Electron-rich alkenes are
also capable of ketyl radical coupling, including
those substituted with Si (36) or B (37). An an-
tioxidant, vitamin E, was also incorporated in
the alkyne acceptor (38) without inhibiting this
mild ketyl radical coupling.
Our mechanistic hypothesis for the redox-
neutral catalytic reaction described above is
supported by reaction intermediate isolation
and resubjection, competition experiments, and
kinetic measurements (Fig. 3). To probe the or-
igin of the high Z:E diastereoselectivity, we
monitored product formation of vinyl iodides
Wang et al., Science 362, 225–229 (2018)
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i
Fig. 2. Synthetic scope of redox-neutral ketyl radical coupling. See
supplementary materials for experimental details. Isolated yield and Z:E ratio
are indicated below each entry. *20% Mn2(CO)10, 1 equiv KOAc. †5%
Mn2(CO)10, 0.5 equiv Pr2NEt. ‡10% Mn2(CO)10. Abbreviations: Ac, acyl;
Pin, pinacol; Piv, pivaloyl; TBDPS, tert-butyldiphenylsilyl; Phth, phthalyl;
Ts, toluenesulfonyl; BPin, bis(pinacolato)diboron.
[Mn]-I to form Ar-I (Fig. 3D). The sp2 C• radical
alkene 46 selectively combines with Et3Si-alkyne
to afford three-component coupling product 47.
and selectively combining them with an elec-
tronically diverse range of p-acceptors—through
the use of earth-abundant metal catalysts will
have broad utility in various synthetic arenas.
precursor, diazonium 39, affords aryl iodide 40 in
70% yield when combined with Mn(CO)5I and
eosin Y photocatalyst (3% without light, 68% with
only thermal initiation). Next, the rate of atom
transfer was compared to known radical clocks
(39) appended to propiolate (Fig. 3E). For each of
the three intramolecular traps investigated, only
atom transfer (i.e., vinyl C-I termination, 41–43)
was observed, in lieu of radical cyclization, which
occurs rapidly with these acceptors (>1 × 108 s–1).
Finally, cascade reactions were facilitated by in-
corporation of intramolecular traps within the
ketyl radical precursors (Fig. 3F). Unlike the rad-
ical clock experiments that did not manifest cy-
clization, these ring closures occurred selectively,
albeit with divergent outcomes dependent on the
hybridization of the coupled radical intermediate.
For example, alkyne 44, which forms an sp2 C•,
selectively traps iodine, affording two-component
coupling product 45, even in the presence of
alkyne traps (e.g., –CO2Et, –SiEt3). Alternatively,
an sp3 C• formed by ketyl radical cyclization of
In this case, intramolecular sp3 to sp3 transloca-
tion of the carbon radicals (a-OAc to a-CO2Et)
precedes intermolecular trapping of the alkyne.
The resultant sp3 C• is long-lived enough (or exists
as a living radical) (40) to then combine with an
alkyne, forming an sp2 C• that is rapidly trapped
as the vinyl iodide.
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ACKNOWLEDGMENTS
designing, performing, and analyzing experiments, as well as to
the writing of this manuscript. Competing interests: Authors declare
no competing interests. Data and materials availability: All data are
available in the main text or the supplementary materials.
Figs. S1 to S9
Tables S1 to S4
NMR Spectra
We thank M. He and A. Chen for assistance with cyclic voltammetry
experiments and density functional theory studies. Funding:
Supported by NSF CAREER award 1654656, NIH grant R35 GM119812,
and the American Chemical Society Petroleum Research Fund. S.C.F.
is grateful for an HHMI Gilliam Fellowship. Author contributions:
L.W. and D.A.N. designed this strategy. All authors contributed to
References (41–60)
SUPPLEMENTARY MATERIALS
15 May 2018; accepted 13 August 2018
10.1126/science.aau1777
www.sciencemag.org/content/362/6411/225/suppl/DC1
Wang et al., Science 362, 225–229 (2018)
12 October 2018
5 of 5

Ketyl radical reactivity via atom transfer catalysis
Lu Wang, Jeremy M. Lear, Sean M. Rafferty, Stacy C. Fosu and David A. Nagib
Science 362 (6411), 225-229.
DOI: 10.1126/science.aau1777
Iodine smooths the way to ketyl radicals
Chemists typically transform carbonyl compounds through polar two-electron reactions. It is also possible to
pursue radical coupling strategies by adding just one electron to form a ketyl group. However, the strong reductant
supplying that electron often limits the reaction's versatility. Wang et al. report a mild means of forming ketyls by first
adding acetyl iodides across the C=O bond (see the Perspective by Blackburn and Roizen). A photoactivated
manganese catalyst then temporarily pulls the iodine away, leaving a ketyl to couple with alkynes. The iodine then
returns to one of the alkyne's carbons, stabilizing the product but remaining poised for further transformations.
Science, this issue p. 225; see also p. 157
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