Generation of α-Boryl Radicals and Their Conjugate Addition to Enones: Transition-Metal-Free Alkylation of gem-Diborylalkanes

Article abstract of DOI:10.1002/chem.202004581

A transition-metal-free method for the alkylation of gem-diborylalkanes with α,β-unsaturated ketones has been developed. It is demonstrated that the α-boryl radicals can be generated efficiently from gem-diborylalkanes with the aid of catechol and oxidants. The α-boryl radicals formed through such process can be engaged in conjugate addition reaction with α,β-unsaturated ketones. This transformation is a straightforward method for the synthesis of γ-borylketones.

Full text of DOI:10.1002/chem.202004581

Accepted Article
Accepted Article
Title: Generation of α-Boryl Radicals and Their Conjugate Addition to
Enones: Transition-Metal-Free Alkylation of gem-Diborylalkanes
Authors: Chaoqiang Wu, Zhicheng Bao, Bowen Dou, and Jianbo Wang
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To be cited as: Chem. Eur. J. 10.1002/chem.202004581
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Chemistry - A European Journal
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RESEARCH ARTICLE
Generation of -Boryl Radicals and Their Conjugate Addition to
Enones: Transition-Metal-Free Alkylation of gem-Diborylalkanes
Chaoqiang Wu, Zhicheng Bao, Bowen Dou, and Jianbo Wang*
C. Wu, Z. Bao, B. Dou, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry
Peking University
Beijing 100871, China
E-mail: wangjb@pku.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: A transition-metal-free method for the alkylation of gem-
diborylalkanes with -unsaturated ketones has been developed. It
is demonstrated that the -boryl radicals can be generated efficiently
from gem-diborylalkanes with the aid of catechol and oxidants. The
-boryl radicals formed through such process can be engaged in
conjugate addition reaction with -unsaturated ketones. This
transformation is a straightforward method for the synthesis of -
borylketones.
Organic molecules containing multiple boryl groups at the same
3
sp carbon center are highly versatile intermediates in organic
synthesis. Particularly, gem-diborylalkanes as novel alkylboronic
nucleophiles have recently attracted considerable attentions as
they can be applied in versatile C–C bonds forming reactions for
the construction of diverse and complex molecular structures.[1,2]
gem-Diborylalkanes are readily available and they are generally
air- and moisture-stable. From gem-diborylalkanes diverse
substituted derivatives can be easily accessed, making them
attractive and practical for structure diversifications. Typically,
there are two reaction modes for the functionalization of gem-
diborylalkanes. First, in the presence of metal alkoxide bases, -
boryl carbanion species can be generated via deborylative
pathway, which can be subsequently trapped by various
electrophiles, leading to the formation of diverse alkyl boronates
Scheme 1. General reaction modes of gem-diborylalkanes.
deborylative process.[9] In this context, alkylboronic acids and
alkyl trifluoroborates have been widely explored as the alkyl
radical precursors. However, the corresponding alkyl
pinacolboronates as alkyl radical precursors are rare due to their
high oxidation potentials. In 2014, Aggarwarl and co-workers
developed a protocol for the radical protodeboronation of alkyl
pinacolboronates by the activation of the boron moiety with n-
butyl lithium or TBAF (Scheme 2a).[10] Ley and co-workers later
[3]
(
Scheme 1a). Alternatively, with the aid of lithium amide bases,
demonstrated
that
the
Lewis
base-activated
alkyl
diborylalkane carbanion species can be obtained via
deprotonative pathway and react with various electrophiles for
the synthesis of complex gem-diborylalkane derivatives
pinacolboronates can be transformed into the corresponding
alkyl radicals via single electron oxidation by photoredox
catalysts (Scheme 2b).[11]
Scheme 1b).[ However, to the best of our knowledge the
4]
(
While Lewis bases are essential activating reagents for the
generation of alkyl radicals from the alkyl pinacolboronates
through single-electron oxidation, it is known that alkyl radicals
can be readily generated from alkyl catecholboronates with
suitable radical initiators, such as alkoxy radicals. The high
reaction mode of gem-diborylalkanes based on radical process,
such as the radical deborylative pathway shown in Scheme 1c,
remains unknown in the literature. We have conceived that a
radical process would significantly expand the diversity of the
reaction modes of gem-diborylalkanes.
reactivity
of
B-alkylcatecholboranes
toward
homolytic
The carbon radicals bearing -boronate substituents,
substitution by oxygen-centered radical is attributed to the
delocalization of the radical onto the benzene ring of the
perboryl radical intermediate, which is generated from the
complexation of B-alkylcatecholborane with the alkoxyl
radical.[ Inspired by this process, we considered that the gem-
diborylalkanes may be transformed into the corresponding
namely the -boryl radicals, have attracted significant attentions
attributed to their unique characters.[5] These radical species are
stabilized by the delocalization of the spin density onto the
empty -orbital of the adjacent boron atom.[6] The -boryl
12]
radicals of alkylboronate esters have been typically generated
by the addition of carbon-centered radicals to vinylboronates.
Other methods include iodine-atom-transfer of -iodoboronic
catecholboronate
intermediates
via
transesterification
esters[ and xanthate method using boryl xanthate. On the
7]
[8]
equilibrium in the presence of catechol and acid, which can be
further converted into -boryl radicals with suitable radical
initiators. The -boryl radicals thus generated may be subjected
other hand, organoboron compounds have been demonstrated
as efficient carbon-centered radical precursors through radical
1
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RESEARCH ARTICLE
Table 1. Optimization of the reaction conditions.[a]
o
Yield (%)[b]
Entry
Oxidant
Acid
1a:2a
T ( C)
Solvent
1
2
3
4
5
6
7
DTBP
TBHP
TFA
TFA
1:1
1:1
80
80
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
34
65
40
66
71
TBHP
TBHP
TBHP
TBHP
TBHP
AcOH
TFA
TFA
TFA
TFA
1:1
2:1
1:2
1:3
1:3
80
80
80
80
80
100
86 (85)[c]
PhMe
DCE
8
9
TBHP
TBHP
TBHP
TBHP
TFA
TFA
TFA
TFA
1:3
1:3
1:3
1:3
100
100
100
100
68
25
0
MeCN
10
1,4-dioxane
PhMe
1 [
1
d]
0
Scheme 2. Transition-metal-catalyzed thia-Sommelet-Hauser rearrangement.
[
a] The reaction was carried out with 1a and 2a in 3 mL toluene (0.3 mmol, 0.1
1
M) for 15 h. [b] Yield determined by H NMR spectroscopy analysis using
to the reaction with suitable radical acceptors, such as
2 2
CH Br as an internal standard. [c] Yield in the bracket refers to isolated
product. [d] Catechol was not added. DTBP: di-t-butyl peroxide; TBHP: tert-
butyl hydroperoxide; DCE: 1,2-dichloromethane.

−unsaturated ketones. While our study was ongoing, Renaud
and co-workers reported their study on a deboronative radical
reactions with pinacol alkylboronic esters based on
transesterification strategy using catechol (Scheme 2c).[
a
13]
Herein we report our study on a transition-metal-free alkylation
method of gem-diborylalkanes via -boryl radical species
(
Scheme 2d).
At the outset of our study, we chose gem-diborylalkane 1a
as the substrate and enone 2a as the radical acceptor for the
optimization of the reaction conditions (Table 1). With DTBP (di-
t-butyl peroxide) as the radical initiator and TFA (trifluoroacetic
acid) as the acidic additive, the desired product 3a could be
obtained at 80 oC with toluene as solvent, albeit in low yield
(
Table 1, entry 1). While TBHP (tert-butyl hydroperoxide) was
used as radical initiator instead of DTBP, the reaction was
significantly improved to 65% yield (Table 1, entry 2). The
reaction yield was diminished when acetic acid was used as the
additive due to its weaker acidity (Table 1, entry 3). Then the
effect of the 1a to 2a ratio was examined and 3.0 equiv of 2a
offered better result (Table 1, entries 4-6). A higher yield was
obtained when the temperature was increased to 100 oC, with
the desired product 3a obtained with 85% isolated yield (Table 1,
entry 7). For solvent effects, other solvents such as DCE (1,2-
dichloromethane), MeCN and 1,4-dioxane, were screened but
the reaction yields could not be improved (Table 1, entries 8-10).
Finally, control experiment indicated that catechol is
indispensable for the reaction (Table 1, entry 11).
With the optimized reaction conditions in hand, we next
proceeded to investigate the scope of the reaction with various
gem-diborylalkanes. As shown in Scheme 3, the reaction
worked well with a series of gem-diborylalkanes (1a-r), affording
the corresponding products (3a-r) in moderate to excellent yields.
Secondary alkyl groups substituted gem-diborylalkanes,
Scheme 3. Substrate scope of the gem-diborylalkanes. The reaction was
carried out with 1 and 2a in toluene (0.3 mmol, 0.1 M) at 100 oC for 15 h. All
the yields refer to isolated yields if not otherwise noted. [a] DTBP was used
instead of TBHP.
2
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RESEARCH ARTICLE
including cyclohexyl, cyclopentyl, isopropyl, isobutyl, all can be
converted into the corresponding products (3a-e) under standard
reaction conditions successfully with good yields. For gem-
diborylalkanes with simple long chain alkyl groups, DTBP should
be used instead of TBHP for efficient transformations (3f-m).
Furthermore, dialkyl groups substituted gem-diborylalkanes (3n,
diborylalkane 1a under the standard reaction conditions,
presumably due to steric effect. However, when less bulky gem-
diborylalkane 1f was used, the reaction occurred to afforded the
product 4n in 83% yield.
To gain insight into the reaction mechanism, several
control experiments were carried out (Scheme 5). Firstly, 5-vinyl-
substituted gem-diborylalkane 5 was treated under standard
reaction conditions and cyclization product 6 was obtained,
which indicated that 5-exo-trig ring-closing of -boryl radical is
involved in the reaction process (Scheme 5a). Next, diphenyl
diselenide 7 was added as radical trapping agent instead of
enones under the standard reaction conditions, and -boryl
radical trapped product 8 was indeed obtained (Scheme 5b).
When cyclopropyl-substituted gem-diborylalkane 9 was treated
with radical trapping agent diphenyl diselenide 7, vinyl boronate
10 was obtained due to the ring-opening of -boryl radical
followed by the trapping with diphenyl diselenide (Scheme 5c).
Finally, using allyl sulfone 11 as the radical trapping agent, the
corresponding product 12 could be obtained (Scheme 5d). Thus,
these control experiments support the involvement of -boryl
radical intermediate in the reaction.
3o) and cyclic gem-diborylalkanes with five-membered ring, six-
membered ring and seven-membered ring (3p, 3q, 3r) could
also afford the corresponding products with good yields under
the same reaction conditions.
Next, the scope of enones was also investigated under the
standard conditions. As shown in Scheme 4, the reaction
worked well with a series of enones (2a-n), affording the
corresponding products (4a-n) in moderate to good yields with
good functional group tolerance. Aryl enones bearing electron-
donating groups such as alkyl (2a, 2e, 2g) and alkoxy (2b, 2h,
2j), all can be converted into the corresponding products
successfully. Notably, the reaction tolerates halogen
substituents on the aromatic rings, including fluoro (2c), chloro
(
2i) and bromo (2f), which provides the possibility for additional
transformations through transition-metal-catalyzed coupling
reactions. For electron-withdrawing group substituted aryl enone,
such as methoxycarbonyl (2d), the corresponding product (4d)
could also be obtained albeit with lower yield. In addition,
heteroaryl enone (2l) and alkyl enone (2m) could also afford the
desired product with moderate yield. However, -methyl
substitutued aryl enone (2n) could not react with gem-
Scheme 5. Experiments for mechanistic understanding.
Based on the result of control experiments and previous
report,[14] a plausible mechanism was proposed as shown in
Scheme 6. Initially, gem-diborylalkane can be transferred into
the corresponding catecholboronate intermediate
A
via
transesterification equilibrium in the presence of catechol and
TFA. With DTBP or TBHP, -boryl radical species B can be
generated
from
the
corresponding
catecholboronate
intermediate A through the interaction of the catecholboronate
moiety with alkoxy radical. With enone as the radical acceptor,

-boryl radical species B can undergo radical conjugation
addition reaction to generate radical species C (C'). Finally, the
ultimate product D is formed from the radical species C (C') via
HAT (hydrogen atom transfer) process with hydrogen atom
source in the reaction system.[ An alternative pathway from
radical species C (C') follows a radical chain mechanism. The
radical species C (C') reacts with catecholboronate intermediate
A to generate -boryl radical species B and boron enolate E.[
The latter is hydrolyzed to afford the final product.
15]
16]
Scheme 4. Substrate scope of the enones. The reaction was carried out with
a and 2 in toluene (0.3 mmol, 0.1 M) at 100 oC for 15 h. All the yields refer to
1
To demonstrate the practical usefulness of this reaction, a
gram-scale experiment was performed with gem-diborylalkane
isolated yields if not otherwise noted. [a] gem-diborylalkane 1f was used
instead of gem-diborylalkane 1a.
1a and enone 2a under the standard reaction conditions. As
3
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Chemistry - A European Journal
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RESEARCH ARTICLE
show in Scheme 7, the reaction proceeded to afford the
corresponding boronate product 3a with 80% isolated yield,
trifluoroborate can also be formed in the presence of potassium
fluoride, which may undergo various subsequent transformations
(
Scheme 7b). Moreover, the cyclic gem-diborylalkane 16 was
subjected to the reaction with allyl sulfone 11, the corresponding
product 17 could be obtained in 77% yield (Scheme 7c).
In summary, we have developed a transition-metal-free
method for the alkylation of gem-diborylalkanes with -
unsaturated ketones. This transformation represents the first
example of generating -boryl radicals from gem-diborylalkanes,
which open new possibilities to expand the reaction modes of
gem-diborylalkanes. It is also demonstrated that the -boryl
radicals generated in this way undergo conjugate addition to
enones to afford -borylketones. The reaction has wide
substrate scope and can be scaled up efficiently, showing its
potential applications in organic synthesis for the preparation of
complex alkyl boronates.
Experimental Section
General procedure for the conjugate addition reaction
A 10 mL Schlenk tube equipped with a stir bar was charged with
1
,1-diborylalkane (0.3 mmol, 1.0 equiv) and catechol (33 mg, 0.3
mmol, 1.0 equiv). The tube was evacuated and filled with N2
three cycles). Toluene (3 mL), vinyl ketone (0.9 mmol, 3.0
Scheme 6. Proposed reaction mechanism.
(
which is similar to the corresponding small-scale experiment,
demonstrating the potential of this reaction for the preparation of
complex alkyl boronates in organic synthesis (Scheme 7a).
Further, several functional group transformations were also
performed with the alkyl boronate product 3a. The product 3a
can be oxidized to the corresponding alcohol with hydrogen
peroxide or reduced to alkane following the reported
procedure.[ Furthermore, the corresponding potassium
equiv), TBHP (82 μL, 70% aq. solution, 0.6 mmol, 2.0 equiv) or
DTBP (110 μL, 0.6 mmol, 2.0 equiv) and TFA (22 μL, 0.3 mmol,
1.0 equiv) were added via syringe successively. The reaction
mixture was stirred at 100 ºC for 15 h. Then the solution was
cooled down to room temperature and filtered through a short
plug of silica gel, eluting with ethyl acetate. The solvent was then
removed in vacuo to leave a crude mixture, which was purified
on a silica gel column to afford the pure product.
10]
Acknowledgements
This research is supported by NSFC (21871010).
Keywords: diborylalkane • boryl radical • conjugate addition •
-unsaturated ketone • alkylboronate
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[
2
5
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Entry for the Table of Contents
-Boryl radicals are generated with the aid of catechol and oxidant from gem-diborylalkanes The -boryl radicals are subsequently
engaged in conjugate addition reaction with -unsaturated ketones to afford -borylketones.
6
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