Radical-polar crossover reactions of vinylboron ate complexes

Article abstract of DOI:10.1126/science.aal3803

Vinyl boronic esters are valuable substrates for Suzuki-Miyaura cross-coupling reactions. However, boron-substituted alkenes have drawn little attention as radical acceptors, and the radical chemistry of vinylboron ate complexes is underexplored. We show here that carbon radicals add efficiently to vinylboron ate complexes and that their adduct radical anions undergo radical-polar crossover: A 1,2-alkyl/aryl shift from boron to the α-carbon sp² center provides secondary or tertiary alkyl boronic esters. In contrast to the Suzuki-Miyaura coupling, a transition metal is not required, and two carbon-carbon bonds are formed. The valuable boronic ester moiety remains in the product and can be used in follow-up chemistry, enlarging the chemical space of the method. The cascade uses commercial starting materials and provides access to perfluoroalkylated alcohols, γ-lactones, γ-hydroxy alkylnitriles, and compounds bearing quaternary carbon centers.

Full text of DOI:10.1126/science.aal3803

RESEARCH
◥
chemical research (9–11), we also focus here on
the use of perfluoroalkyl radicals (12).
REPORT
The reaction sequence required that the electron-
rich double bond in the starting vinylboron ate
complex react readily with electrophilic C rad-
icals. We therefore planned to use perfluoroalkyl
iodides (Rf–I) as C radical precursors in our ini-
tial studies. C radical generation can either be
achieved by I abstraction from Rf–I or by single-
electron reduction of Rf–I. Addition of the electro-
philic perfluoroalkyl radical Rf· to the vinylboron
ate complex would generate the corresponding
adduct radical anion I that could further react
via two different pathways (Fig. 2). In an electron-
catalyzed process (13), single-electron oxidation of
the adduct radical I by the perfluoroalkyl iodide
would lead in a radical-polar crossover step to
zwitterion II, along with the perfluoroalkyl rad-
ical, thereby sustaining the radical chain. Ionic
1,2-alkyl/aryl migration would eventually provide
the target boronic ester III (Fig. 2A). Alternatively,
adduct radical I could abstract the I atom of Rf–I
to give the atom transfer product IV, which could
further react in an ionic 1,2-alkyl/aryl migration
substituting the iodide, likely assisted by the counter
cation M+, to give III (Fig. 2B). Whether reactions
proceed by outer-sphere (I to II) or inner-sphere
(I to IV) electron transfer depends on the reduc-
tion potential of the alkyl radical precursor and
on the halogen atom transfer efficiency (14).
ORGANIC CHEMISTRY
Radical-polar crossover reactions of
vinylboron ate complexes
Marvin Kischkewitz,1 Kazuhiro Okamoto,2 Christian Mück-Lichtenfeld,1 Armido Studer1*
Vinyl boronic esters are valuable substrates for Suzuki-Miyaura cross-coupling reactions.
However, boron-substituted alkenes have drawn little attention as radical acceptors, and
the radical chemistry of vinylboron ate complexes is underexplored. We show here that
carbon radicals add efficiently to vinylboron ate complexes and that their adduct radical
anions undergo radical-polar crossover: A 1,2-alkyl/aryl shift from boron to the a-carbon
sp2 center provides secondary or tertiary alkyl boronic esters. In contrast to the Suzuki-
Miyaura coupling, a transition metal is not required, and two carbon-carbon bonds are
formed. The valuable boronic ester moiety remains in the product and can be used in
follow-up chemistry, enlarging the chemical space of the method. The cascade uses
commercial starting materials and provides access to perfluoroalkylated alcohols,
g-lactones, g-hydroxy alkylnitriles, and compounds bearing quaternary carbon centers.
inylboronic acid derivatives and their cor-
responding boron ate complexes are highly
valuable substrates in organic synthesis.
They are readily accessed at low cost, and
some of them are commercially available.
esters has been investigated (6–8); however, the
corresponding boron ate complexes have not been
applied as radical acceptors. Given the importance
of fluorine substituents in medicinal and agro-
V
Such boron compounds have been intensively
used in C–C bond formations. The most prom-
inent such reaction is the Nobel prize–winning
Suzuki-Miyaura coupling, in which the boron ate
complexes engage in transition metal (initially
palladium)–catalyzed cross-couplings with aryl,
alkenyl, alkynyl, and alkyl halides (Fig. 1A) (1, 2).
The Suzuki-Miyaura coupling is a two-component
process. Very recently, Morken and co-workers
elegantly used in situ–generated vinylboron ate
complexes in Pd-catalyzed three-component con-
junctive cross-coupling reactions (Fig. 1B) (3).
Electrophilic palladation of the vinyl group in-
duces a 1,2-R migration (where R is an alkyl or
aryl). Similar reactivity was noted in the Zweifel
reaction, in which the 1,2-R shift is induced by
initial electrophilic halogenation of the vinyl
group (Fig. 1C) (4). That approach was recently
extended further by Aggarwal and co-workers to
the stereospecific alkylation of lithiated hetero-
arenes with boronic esters (5). Here we report the
reaction of vinylboron ate complexes with alkyl
radicals to induce 1,2-R shifts (Fig. 1D). Our ap-
proach is complementary to the Morken reac-
tion: Whereas in the Pd variant, b-arylation of
the vinyl group is achieved, the radical approach
allows for b-alkylation of the alkene moiety. The
radical process proceeds without transition metal
catalysis, reducing the costs of the overall se-
quence. Radical chemistry on alkenyl boronic
Fig. 1.Vinylboron ate complexes show diverse reactivity. (A) Transition metal–catalyzed Suzuki-Miyaura
cross-coupling forms a single C–C bond. (B) Transition metal–catalyzed conjunctive cross-coupling forms
two C–C bonds. (C) The Zweifel reaction forms a C–halogen and a C–C bond in the absence of transition
metals. (D) Vinylboron ate complexes act as radical acceptors to form two C–C bonds in the absence of
transition metals, via radical addition and a subsequent 1,2-R shift; as in (B) and (C), the valuable boron
ester functionality remains in the product. An R indicates an alkyl or aryl group; X is a halogen. Red, first
C–C or C–X bond formed; blue, second C–C bond formed via 1,2-R migration.
1Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität, Corrensstraße 40, 48149 Münster, Germany.
2Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan.
*Corresponding author. Email: studer@uni-muenster.de
Kischkewitz et al., Science 355, 936–938 (2017) 3 March 2017
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for the radical sequence without any further pu-
rification. We combined the boron ate complex
with perfluorobutyl iodide in acetonitrile at 80°C
for 24 hours, using BEt3 (5 mol %) as a radical
initiator. For convenience, the resulting product
boronic ester was directly oxidized by treatment
with NaOH-H2O2 mixture. We found that the
target sequence proceeded smoothly, and the
desired alcohol 1a was obtained in 68% isolated
yield. Chain initiation can occur via reaction of
BEt3 with traces of air or via single-electron oxida-
tion of the vinylboron ate complex. As a side pro-
duct, phenol was obtained, derived from NaOOH
oxidation of PhBpin, which was generated by di-
rect oxidation of the boron ate complex. These
conditions were applied to all other experiments
in this series. Organolithium compounds that are
not commercially available were readily generated
in situ by Br-Li exchange from the corresponding
bromides (supplementary materials). Other vinyl
boronic esters that we tested provided lower yields
(supplementary materials), and replacing PhLi
with PhMgBr led to nearly complete suppres-
sion of the target three-component reaction. In
these reactions, phenol was formed as the major
product.
Fig. 2. Reaction design and mechanistic considerations. (A) Addition of the perfluoroalkyl radical
Rf· generates radical anion I that further reacts with Rf–I via single-electron oxidation to give Rf· and
zwitterion II. Ionic 1,2-alkyl/aryl migration leads to III. (B) Rf–I reacts in an atom transfer addition via I to
iodide IV that undergoes M+-mediated 1,2-alkyl/aryl migration to III. M, Li or MgBr.
The aryl group in the product alcohol is readily
varied by changing the aryl lithium component,
as documented by the successful preparation of
1b to 1e (41 to 75%). The modest yields obtained
in some transformations of this series and in
subsequent reactions can be explained by prob-
lems encountered during product isolation re-
lated to the volatility of the fluorinated alcohols.
In addition, side products were formed by direct
oxidation of the vinylboron ate complex. Keep-
ing PhLi as the aryl donor and vinylBpin as
the acceptor, we also demonstrated that other
perfluoroalkyl iodides (F2n+1CnI) perform well in
this three-component reaction (1f to 1j; 56 to
65%). The cascade also works efficiently when
using alkyl lithium reagents, as documented by
the successful preparation of secondary alcohols
1m to 1p (36 to 66%). We further varied both
the perfluoroalkyl iodide and the alkyl lithium
component to access alcohols 1q to 1s. The method
can also be used for the preparation of tertiary
alcohols. To this end, we switched to isopropenyl-
boronic acid pinacol ester (R1 = Me, methyl) as a
precursor of the radical acceptor. Reaction with
perfluoroalkyl iodides in combination with several
different organolithium compounds provided the
corresponding tertiary alcohols 1t to 1w.
We next investigated whether the a-fluoro
substituent in the C radical was essential for
the radical-polar crossover reaction and found
a-iodoesters to be suitable substrates for the
three-component cascade (Fig. 4A). Reaction of
vinylboronic acid pinacol ester with PhLi and
subsequent radical-polar crossover reaction with
ethyl a-iodoacetate provided g-butyrolactone
2a after oxidation of the boronic ester and acid-
catalyzed lactonization. In analogy, the g-lactones
2b to 2f were obtained in 40 to 94% isolated
yield. Furthermore, iodoacetonitrile could be
used in the radical-polar crossover sequence to
prepare the g-hydroxy nitriles 3a and 3b (Fig.
Fig. 3. Scope of the radical-polar crossover reaction of vinylboron ate complexes. The vinylboronic acid
pinacol ester, organolithium compound, and perfluoroalkyl iodide were varied. Isolated yields are given in
parentheses, and newly formed bonds are highlighted in bold. rt, room temperature; h, hours; dr, diastereo-
meric ratio. *Organolithium compound generated in situ from aryl bromide [1.3 equivalents (equiv)] by Br-Li
exchange (supplementary materials). †Boron ate complex generated in THF. ‡Radical cascade run with 10
equiv of the perfluoroalkyl iodide and 20 mol % of BEt3 at 60°C. §Radical cascade run with 20 mol % of BEt3.
We commenced our investigations by using
vinylboronic acid pinacol ester (vinylBpin), per-
fluorobutyl iodide, and phenyl lithium as the
three reaction components. All these reagents
are commercially available. Optimization studies
revealed that generation of the boron ate complex
is best achieved by treatment of vinylBpin in
Et2O (Et, ethyl) with PhLi (Ph, phenyl) at 0°C
(Fig. 3). Complete formation of the boron ate
complex under these conditions was unambig-
uously confirmed by 11B nuclear magnetic reso-
nance spectroscopy [in deuterated tetrahydrofuran
(THF–d8)], in which only one characteristic bo-
ron ate signal at d = 9.6 parts per million was
identified. The boron ate complex can be iso-
lated by simple removal of the solvent and used
Kischkewitz et al., Science 355, 936–938 (2017) 3 March 2017
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could be obtained with 52% enantiomeric excess
by running the reaction with the commercially
available chiral (+)-vinylboronic acid pinanediol
ester as starting material (see the supplementary
materials).
To shed light on the possible mechanism of
the radical cascade, we also tested Togni’s re-
agent (15) as a CF3 radical precursor. This re-
agent cannot react via iodine atom transfer but
cleanly provides a CF3 radical upon single-electron
reduction. We combined Togni’s reagent with
vinyl phenyl pinacolboronate in acetonitrile at
room temperature in the presence of tetrabu-
tylammonium iodide as an initiator and obtained
(after NaOOH oxidation) alcohol 1k in 41% yield
(Fig. 4D). Thus, at least for this process, it is
highly likely that the radical-polar crossover
proceeds via an outer-sphere electron transfer
according to the mechanism in Fig. 2A. We also
favor the outer-sphere process for the reactions
conducted with the alkyl iodides for the follow-
ing reasons. Successful transformations were
observed with electron-poor alkyl halides that
are readily reduced via a single-electron transfer
process. Moreover, cyclohexyl iodide and 1-
iodoadamantane, which are generally reactive
substrates in atom transfer reactions, did not
engage in the three-component reaction, although
in these two cases, reactivity of the sec- and tert-
alkyl radical toward the vinylboron ate complex
might also be lowered. In addition, we compu-
tationally investigated the reaction between a rad-
ical anion of type I (Rf = CF3, R = Ph, R' = CH3;
Fig. 2) and CF3I (supplementary materials). Elec-
tron removal from I directly leads to the phenyl
migration product III in a strongly exothermic
process. However, formation of the correspond-
ing I atom transfer product IV is also kinetically
viable, and IV has a low free-energy barrier for
1,2-phenyl migration (formation of III). We are
confident that readily generated alkenylboron
ate complexes have great potential as radical
acceptors in radical-polar crossover reactions.
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highlighted in bold. (A) a-Iodoesters act as radical precursors for the preparation of g-butyrolactones.
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reaction sequence is stopped after the radical-
polar crossover process, as documented by the
successful preparation of 4a to 4d (Fig. 4C).
Product 4d showed that radical addition also
works on b-substituted vinylboron ate complexes.
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strates for diverse follow-up chemistry. Along
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agreement no. 692640) for supporting this work. Additional data
supporting the conclusions are in the supplementary materials.
M.K., K.O., and A.S. conceived and designed the experiments and
analyzed the data. M.K. and K.O. performed the experiments, C.M.-L.
conducted all computations, and A.S. wrote the manuscript.
Materials and Methods
Figs. S1 to S3
Tables S1 to S3
Spectral Data
References (16–30)
ACKNOWLEDGMENTS
SUPPLEMENTARY MATERIALS
10 November 2016; accepted 31 January 2017
10.1126/science.aal3803
We thank the Naito Foundation (fellowship to K.O.), the University
of Münster, and the European Research Council (advanced grant
www.sciencemag.org/content/355/6328/936/suppl/DC1
Kischkewitz et al., Science 355, 936–938 (2017) 3 March 2017
4 of 4

Radical-polar crossover reactions of vinylboron ate complexes
Marvin Kischkewitz, Kazuhiro Okamoto, Christian
Mück-Lichtenfeld and Armido Studer (March 2, 2017)
Science 355 (6328), 936-938. [doi: 10.1126/science.aal3803]
Editor's Summary
Boron choreographs a double reaction
In the widely used Suzuki coupling reaction, boron surrenders an olefinic substituent to a metal
catalyst en route to carbon-carbon bond formation. Kischkewitz et al. report a metal-free alternative
pathway, wherein the boron stays bound to one end of the olefin while a carbon radical attacks the other
end. Charge transfer then prompts migration of an alkyl or aryl group from the boron to form a second
carbon-carbon bond. The boron can subsequently be displaced, generating a versatile array of alcohols,
lactones, and quaternary carbon centers from simple precursors.
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