Generation of Alkyl Radical through Direct Excitation of Boracene-Based Alkylborate

Article abstract of DOI:10.1021/jacs.0c04456

The generation of tertiary, secondary, and primary alkyl radicals has been achieved by the direct visible-light excitation of a boracene-based alkylborate. This system is based on the photophysical properties of the organoboron molecule. The protocol is applicable to decyanoalkylation, Giese addition, and nickel-catalyzed carbon-carbon bond formations such as alkyl-aryl cross-coupling or vicinal alkylarylation of alkenes, enabling the introduction of various C(sp3) fragments to organic molecules.

Full text of DOI:10.1021/jacs.0c04456

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Communication
Generation of Alkyl Radical through Direct
Excitation of Boracene-based Alkylborate
Yukiya Sato, Kei Nakamura, Yuto Sumida, Daisuke Hashizume, Takamitsu Hosoya, and Hirohisa Ohmiya
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04456 • Publication Date (Web): 12 May 2020
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Generation of Alkyl Radical through Direct Excitation of Boracene-
based Alkylborate
†
†
†‡
§
‡
∥
⊥
⊥
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Yukiya Sato , Kei Nakamura , Yuto Sumida *, Daisuke Hashizume , Takamitsu Hosoya *, and Hiro-
hisa Ohmiya†#*
†
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kana-
zawa 920-1192, Japan
‡
Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research (BDR), 6-7-3 Minatojima-mina-
mimachi, Chuo-ku, Kobe 650-0047, Japan
§ RIKEN Center for Emergent Matter Science (CEMS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
∥
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
(TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
# JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
Supporting Information Placeholder
organoborates is applicable to decyanoalkylation, Giese addition,
and nickel-catalyzed carbon-carbon bond formations such as alkyl–
ABSTRACT: The generation of tertiary, secondary, and
primary alkyl radicals has been achieved by the direct visi-
ble-light excitation of a boracene-based alkylborate. This
system is based on the photophysical properties of the or-
ganoboron molecule. The protocol is applicable to decy-
anoalkylation, Giese addition, and nickel-catalyzed carbon-
carbon bond formations such as alkyl–aryl cross-coupling or
aryl cross-coupling or three-component vicinal alkylarylation of al-
kenes, thus enabling the introduction of various C(sp3) fragments
to organic molecules. Notably, the boracene is recovered after these
reactions and can be reused.
A. Generation of Alkyl Radical in Photoredox Catalysis
vicinal alkylarylation of alkenes, enabling the introduction
of various C(sp3) fragments to organic molecules.
(= electron acceptor)
A
[PC]
visible
light
–
A
–
[PC]*
[PC]
R
2 R3
X
R
2 R3
various
transformations
Recently, visible-light-driven generation of C(sp3)-centered rad-
icals under mild conditions has emerged as a powerful tool for
chemical reactions.1 The process proceeds through a single electron
transfer (SET) event between the excited-state photoredox catalyst
and radical precursors such as carboxylic acids,2 oxalates,3 or-
ganoborates,4 organosilicates,5 Katritzky salts,6 and 4-alkyl-1,4-di-
hydropyridines (alkyl-DHPs)7 (Figure 1A). This photochemical re-
action exploits the nature of C(sp3)-centered radicals, thus allowing
for the introduction of sterically hindered C(sp3) fragments such as
tertiary or secondary alkyl groups to organic molecules. Despite
remarkable progress achieved in this area, the oxidation/reduction
steps of the photoredox catalyst often complicate the reaction. In
this context, the direct excitation of a radical precursor, which ena-
bles circumventing the redox cycle of the photocatalyst, has
emerged as an alternative approach for the generation of a C(sp3)-
centered radical.8d Specifically, Melchiorre and co-workers demon-
strated the visible-light-mediated excitation of alkyl-DHPs and its
application to the nickel-catalyzed carbon–carbon bond forming
process.8a–c,e The excited state of the alkyl-DHPs acts simultane-
ously as a strong SET reductant, which modulates the nickel oxi-
dation state, and as an alkyl radical source. However, the generation
of a sterically hindered tertiary alkyl radical by direct visible-light
excitation remains underdeveloped (Figure 1B).
R1
R1
SET reduction
alkyl radical
radical precursor
B. Alkyl Radical from Direct Excitation of Alkyl-DHPs (Melchiorre)
R2
R1 R2
✽
R1 R2
direct
excitation
SET
reduction
R1
+
RO2C
Me
CO2R
Me
RO2C
Me
CO2R
Me
visible light
RO2C
Me
CO2R
Me
N
H
N
H
N
C. tertiary-Alkyl Radical from Direct Excitation of Boron-based Precursor (this work)
boracene-based alkylborate
R2
2 R3
R3
• excited by visible light
R
Li+
R1
O
(λ = > 370 nm)
– O
O
O
R1
Li
B
• alkyl radical source
B
• stable under air/moisture
2
1
direct
excitation
boracene
visible light (440 nm)
2 R3
Giese addition
R
+
1
R1
Ni-catalyzed
C–C bond fomations
Herein, we report that the direct visible-light excitation of bora-
cene 1-derived organoborate complex 2 generates tertiary, second-
ary, and primary alkyl radicals without the need for an external
photoredox catalyst (Figure 1C). The photoexcitation of
recyclable
alkyl
radical
Figure 1. Photoredox chemistry and direct excitation of radical precursors.
ACS Paragon Plus Environment

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In the pioneering work related to the photochemistry of or-
Page 2 of 7
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ganoborates, the intra-ion pair of alkyltriphenyl borate and cyanine
dye was described.9 The SET oxidation of the borate from the pho-
toexcited counter cation, cyanine dye, generated the alkyl radical
by carbon–boron bond cleavage. This SET of an intra-ion pair im-
plied that direct excitation of an organoborate under visible-light
irradiation to generate an alkyl radical would be feasible by appro-
priately designing the organoboron skeleton.
We are interested in the photosensitivity of tertiary alkylborates
prepared from 8,9-dioxa-8a-borabenzo[fg]tetracene (1),10 which
we refer to as boracene (Figure 1C). The boracene 1 has a highly
planar and robust structure based on the benzo[fg]tetracene skele-
ton partially replaced by O–B–O bonds, which provide extremely
high chemical stability. The corresponding tert-Bu-substituted bo-
rate 2a was easily prepared as a white solid in quantitative yield
from equimolar amounts of 1 and tert-butyllithium, and applicable
for the next transformation without any further purification. Fortu-
nately, the borate 2a was fairly stable to air/moisture,11 and the
structure was unambiguously confirmed by X-ray crystal structure
analysis (Figure 2A). The X-ray structure showed the tetrahedral
boron center, confirming the formation of the borate complex,
which deviated from the plane of boracene. The lithium cation is
coordinated to the two oxygen atoms of the borate in addition to
two or three THFs, which seem to contribute to the stability of the
complex (for details, see Supporting Information).
A. X-ray structure of 2a
Li+
9
O
– O
B
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2a
B. Photophysical property
Top view
Side view
UV/Vis
Fluorescence
0.35
0.3
4000
3500
3000
2500
2000
1500
1000
500
emission
absorption
We then investigated the photophysical properties of the alkyl-
borate 2a to evaluate the feasibility of the ideal photochemical re-
action. While the UV/Vis spectrum of boracene showed a maxi-
mum absorption wavelength at 335 nm (20 μM in DMA), the borate
2a afforded a red-shifted UV/Vis spectrum (Figure 2B). The ab-
sorption wavelength of the borate was observed at around 370 nm,
for which the tail reached over 400 nm. The corresponding fluores-
cence spectrum (excited at 370 nm) was also obtained. We meas-
ured the cyclic voltammetry (CV) of 2a, and the redox potential
(+0.78 V vs. SCE in MeCN) showed a relatively high value com-
pared to widely used alkyltrifluoroborate salt (e.g., t-BuBF3K =
+1.26 V vs. SCE in MeCN4e). Based on these UV/Vis, fluorescence,
and CV data, the redox potential of the excited alkylborate
[E(2a•+/2a*)] could be estimated as –2.2 V according to the Rehm–
Weller approximation.12
0.25
0.2
0.15
0.1
0.05
0
0
300 350 400 450
300 350 400 450 500
wavelength (nm)
wavelength (nm)
C. Radical trap experiment
O
N
O
N
+
+
1
2a
MeCN, 14 h
Blue LED
3a, 64%
TEMPO
50%
Next, several experiments using the boracene-based alkylborates
were performed to assess the generation manner of an alkyl radical
from the borate (Figures 2C and 2D). For example, the reaction of
tert-butylborate 2a in the presence of TEMPO, a common radical
scavenger, gave tert-butyl radical-trapped adduct in 64% yield un-
der visible-light irradiation (Figure 2C).13 Additionally, the borate
2b prepared from benzyl magnesium chloride was subjected to the
simple photo-irradiation conditions without additives. The reaction
afforded dibenzyl, dimerization product, in quantitative yield via
radical–radical coupling (Figure 2D).13 These results indicated that
simple photo-irradiation could trigger the generation of alkyl radi-
cals.
D. Dimerization via direct excitation
Ph MgCl
Ph
B(O2Ar)1/2Mg
1
Ph
Ph
THF, –78 ˚C to rt
1 h, then dried
THF, 14 h
Blue LED
quant.
2b
quant.
E. Decyanoalkylation of 4-cyanopyridine
NC
N
4
t-BuLi
1
+
1
B(O2Ar)Li
THF, –78 ˚C to rt
1 h, then dried
MeCN, 14 h
Blue LED
N
2a
quant.
5a, 80%
quant.
The subsequent attempt was a reaction using 4-cyanopyridine
(3)8a,14 amenable to test the redox process of 2a (Figure 2E).13 The
photo-mediated reaction of 2a with 4 in MeCN proceeded to give
the decyanoalkylated product 5a in 80% with quantitative recovery
of boracene 1.15 The estimated reduction potential of 2a would en-
able the SET reduction event between the photo-excited borate
[E(2a•+/2a*)] and 4 (E1/2 = –1.75 V vs. SCE in MeCN).16 Thus, the
SET reduction forms a persistent cyanopyridyl radical anion and
the tert-butyl radical, and then radical–radical coupling between the
two radicals delivers the carbon–carbon bond.17 Alternatively, the
simple photo-irradiation would directly give tert-butyl radical via
homolytic cleavage from an excited borate.
Following application of the alkylborate was the Giese addition18
to gain further supportive information on the radical process (Fig-
ure 2F).13 The reaction of tert- (2a), sec- (2c), and normal-butyl-
borate (2d) with dimethylfumarate (6a) under blue LED irradiation
afforded the corresponding 1,4-adducts in good yields with the re-
covery of 1. Both SET reduction and simple photo-irradiation
would enable to trigger the generation of alkyl radical.19 The reac-
tion using alkyltrifluoroborate salt, t-BuBF3K and 6a didn’t afford
the corresponding addition product (data not shown).
F. Giese addition
MeO2C
CO2Me
R
6a
R
CO2Me
CO2Me
7aa, 69%
+
1
B(O2Ar)Li
MeCN/MeOH (10/1)
14 h
Blue LED
78%
85%
57%
R = t-Bu (2a)
s-Bu (2c)
n-Bu (2d)
7ca, 56% (d.r. = 1:1)
7da, 31%
G. Ni-catalyzed alkyl–aryl coupling
Br
Ni(acac)2 (5 mol %)
+
2a
+
1
DMA, 14 h
Blue LED
Ph
Ph
8a
9aa, 76%
65%
Figure 2. (A) ORTEP diagrams of 2a (CCDC 1871613). Ellipsoids are
drawn at 50% probability. Hydrogen atoms and coordinated solvent THF
are omitted for clarity. (B) UV/Vis spectra of 2a (yellow line, 20 μM in
DMA). Fluorescence spectra of 2a (20 μM in DMA). Blue line: excitation
spectra; red line: emission spectra (excitation at 370 nm). (C) Radical trap
experiment. (D) Dimerization of benzyl radical via direct excitation. (E)
Decyanoalkylation of 4-cyanopyridine (3) under visible-light irradiation.
(F) Giese addition experiments under visible-light irradiation. (G) Ni-cata-
lyzed cross-coupling of 2a and 8a under visible-light irradiation.
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Based on these results, we turned our attention to the visible-
We next prepared various alkylborates and investigated their re-
activities for the nickel-catalyzed cross-coupling (Table 1, right).
The complexation of organolithium reagents with boracene 1 ena-
bled the preparation of organoborates, including tertiary, second-
ary, and primary alkyl groups. Alternatively, in situ lithiation of
alkyl halides using lithium di-tert-butylbiphenylide (LiDBB)21 in
the presence of 1 facilitated the preparation of tert-alkylborates.
The direct excitation of isolated or in situ prepared tert-alkylborates
allowed for the introduction of acyclic or cyclic tertiary carbon
fragments to the arene (9ed–9hd). As well as Figure 2F, the treat-
ment of 1 with secondary and primary alkyl Grignard reagents suc-
cessfully provided the corresponding borates. These secondary and
primary alkylborates were found to be competent alkyl reagents
(9ca–9bi). The catalytic system using the combination of NiBr2(di-
glyme) and 4,4'-di-tert-butyl-2,2'-bipyridyl in THF was effective.
This boracene-based nickel catalytic system permitted the installa-
tion of a methyl group, which is a medicinally important unit (Ta-
ble 1, bottom).22 The methylation was efficiently achieved to access
methylated (hetero)arenes, including the fluorophore and the phar-
maceutical, such as coumarin and indomethacin methyl ester (9oi–
9oq).
1
2
3
4
5
6
7
8
light-mediated nickel-catalyzed cross-coupling using an aryl halide
(Figure 2G). Specifically, the reaction between tert-butylborate 2a
(0.3 mmol) and 4-bromobiphenyl (8a) (0.2 mmol) proceeded with
a catalytic amount of Ni(acac)2 (5 mol %) in DMA under blue LED
irradiation at ambient temperature to afford the tert-alkylated arene
9aa in 76% isolated yield (the recovery of 1 was 65%).
With the nickel-catalyzed reaction conditions in hand, we inves-
tigated the scope of aryl halides (Table 1, left). In this case,
Ni(acac)2 or Ni(TMHD)2 were used as the nickel source. Electron-
rich and electron-deficient aryl halides were used successfully. In
some cases, isobutyl group-installed arene products via isomeriza-
tion were observed.20 Our protocol permitted the alkylation of elec-
tron-rich aryl bromides, which provided poor results under Ni/Ir
photoredox co-catalysis developed by Molander and co-workers
(9ab–9ae).2e The cross-coupling of pinacolato boryl group-pendant
bromoarene proceeded selectively at the C–Br bond (9al). β-Bro-
mostyrene and π-conjugated bromoarenes were also compatible
(9am and 9an).
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Table 1. Substrate scope
Scope of Aryl-X with 2aa
Scope of alkylborates
tertiary
Ni(TMHD)2 or Ni(acac)2
Ni(TMHD)2
(5 mol %)
8d
R
2 R3
X
(5 mol %)
OMe
R
2 R3
+
Ar
R1
RLi
Ar
B(O2Ar)Li
DMA, 14 h
Blue LED
1
or
R1
B(O2Ar)Li
9
DMA, 24 h
Blue LED
8
2a
RX / LiDBB
9
2
OMe
electron-rich
D3C CD3
D3C
Ar
9gd, 41%
t-Bu
OMe
Ar
Ar
Ar
Ar
9ad, 80%b (trace)
9ed, 73%
9fd, 53%
9hd, 64%e
NEt2
OMe
t-Bu
OMe
secondary
9ab, 73%b (8%)
9ac, 61%b (12%)
9ad, 80%b (trace)
9ae, 70%c (10%)
X = Br
X = Br
X = Br
X = Br
R2
NiBr2·diglyme (5 mol %)
dtbpy (6 mol %)
8a
R2
RLi
electron-deficient
R1
R1
or
B(O2Ar)M
1
THF, 14–24 h
Blue LED
Ph
RMgBr
2
9
(M = Li or 1/2Mg)
H
O
9ah, 40%b (5%)
X = Cl
OCF3
9af, 69%c,d
CN
9ag, 42%c
Ar
Ar
Ar
Ar
Ar
X = Br
X = Br
9ca, 59%f
9ia, 63%f
9ja, 35%f
9ka, 49%f
9la, 69%f
primary
Me
OMe
S
NiBr2·diglyme (5 mol %)
O
O O
O
dtbpy (6 mol %)
9ai, 72%b (10%)
RLi
9aj, 57%c
X = Br
9ak, 61%c (trace)
R1
8i
X = Cl
or
B(O2Ar)M
X = Br
R1
(M = Li or 1/2Mg)
1
THF, 14–24 h
Blue LED
RMgBr
2
π-conjugated
chemoselective
9
O
Ar
9bi, 88%g
O
Ar
Ar
B
Ar
O
9di, 51%g
9mi, 42%g
9ni 31%g
9al, 52%b (4%)
9am, 65%c,d
9an, 57%b
X = Br
X = Br
X = Br
Scope of methylation
Me
CO2Me
NiBr2·diglyme (5 mol %)
dtbpy (6 mol %)
Me
O
Me
Ac
Me
O
Me
8a, 8o, 8p or 8q
N
MeLi
Me
N
B(O2Ar)Li
Ar
1
OMe
THF, 24–40 h
Blue LED
9op, 76%
9oq, 80%
O
9oi, 73%
9oo, 56%
X = Cl
X = Br
X = Br
2o
X = Cl
9
c
a Number in parentheses is NMR yield of isobutylated arenes. b Ni(TMHD)2 was used as a catalyst. TMHD = 2,2,6,6-tetramethyl-3,5-heptanedionate.
Ni(acac)2 was used as a catalyst. d NMR yield. e NiBr2·diglyme (5 mol %), 4,4'-di-tert-butyl-2,2'-bipyridyl (dtbpy) (6 mol %) and THF solvent were used. f Ar
= 4-biphenyl. g Ar = 4-acetylphenyl.
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Page 4 of 7
1
A reaction pathway for the nickel-catalyzed alkyl–aryl cross-
2
3
4
5
6
7
8
9
coupling via direct visible-light excitation of alkylborates 2 is out-
lined in Scheme 1.23 The excited alkylborate 2* could play dual
roles as the actual radical precursor and a strong single electron re-
ductant. As predicted from the photophysical properties of 2a
([E(2a•+/2a*)] = –2.2 V vs. SCE in MeCN), the potential of the ex-
cited alkylborate 2* is high enough to reduce the NiII precatalyst
and NiI–Br D.24,25 Thus, active catalyst Ni0 is generated and is in-
volved in the catalytic cycle. The radical cation 2•+ from SET re-
duction generates an alkyl radical E with the recovery of boracene
1. For the nickel-catalyzed cycle, two types of pathways are con-
ceivable. One involves an oxidative addition of ArBr 8 to Ni0 A to
give Ar-NiII-Br B followed by combination with the alkyl radical
E. Another pathway proceeds in reversed order via alkyl NiI F.
Both pathways lead to the NiIII intermediate C, and reductive elim-
ination affords the cross-coupling product 9 and D.
With the Giese addition results shown in Figure 2F, we examined
the three-component vicinal alkylarylation of alkenes (Table 2).4f,26
The reaction of alkylborates 2, alkenes 6, and aryl bromides 8 oc-
curred in the presence of the nickel complex and THF solvent under
blue LED irradiation at ambient temperature to give three-compo-
nent coupling product 10. This protocol enabled the introduction of
tert- or sec-alkyl groups and aryl groups into carbon−carbon double
bonds with complete regioselectivity to produce complex carbon
frameworks. This process involves the generation of an alkyl radi-
cal and subsequent radical addition to an alkene followed by radical
recombination. For example, the reaction initiated by Giese-type
addition using tert-butyl acrylate gave the corresponding alkylary-
lation products (10aba, 10cba, 10abd, and 10abi). Moreover, the
alkylarylation of vinylboronic acid pinacol ester produced the ben-
zylboronate compounds (10aca and 10acd), probably because the
α-boryl radical intermediate was stabilized by hyperconjugation.
Similarly, an electron-rich olefin, vinyl pivalate, was also applica-
ble to the three-component coupling without β-alkoxy elimination
(10ada, 10add, 10adi, and 10eda). Unfortunately, the use of nor-
mal-alkylborate almost inhibited the transformation (data not
shown).
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ArBr
8
Ni0
Br
Ar
Blue
LED
NiII
R2 R3
B(O2Ar)Li
R2 R3
B(O2Ar)Li
E
ꢀ
A
B
R1
R1
In summary, we developed a photoredox catalyst-free method
for generating tertiary, secondary, and primary alkyl radicals by
the direct visible-light excitation of alkylborates derived from a π-
conjugated organoboron compound, boracene. This photoexcita-
tion protocol could be applied to decyanoalkylation, Giese addition,
and nickel-catalyzed carbon-carbon bond formations such as alkyl–
aryl cross-coupling or three-component vicinal alkylarylation of al-
kenes, via SET reduction or simple photo-irradiation. As a result,
various C(sp3) fragments could be introduced to organic molecules.
The recovery and reusability of boracene after the reaction illus-
trated the synthetic usefulness of this system. Our boracene-based
photochemical reaction system presents a new platform for carbon–
carbon bond formation in organic synthesis.
E
2
2*
R2 R3
R1 NiI
F
SET
8
+
R2 R3
B(O2Ar)Li
2 +
R2 R3
R2 R3
Br–
R1
R1
Br
NiI–Br
R1 NiIII
Ar
E
+
1
LiBr
D
C
R2 R3
Ar
R1
9
Scheme 1. Possible pathways
ASSOCIATED CONTENT
Table 2. Three-component alkylarylation of alkenes.
Supporting Information. Experimental details and characteriza-
tion data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Ar
Br
R
2 R3
Ni cat.
+
+
R
2 R3
Ar
R
R1
B(O2Ar)Li
THF, 14 h
Blue LED
R1
R
2a or 2e
6
8
10
AUTHOR INFORMATION
Ac
Ph
MeO
OMe
Corresponding Authors
Yuto Sumida: sumida@p.kanazawa-u.ac.jp
Takamitsu Hosoya: thosoya.cb@tmd.ac.jp
Hirohisa Ohmiya: ohmiya@p.kanazawa-u.ac.jp
Ot-Bu
Ot-Bu
R
Ot-Bu
O
O
O
R = t-Bu (10aba), 35%a
R = s-Bu (10cba), 64%b,c
10abd, 26%a
10abi, 56%a
ORCID
Ph
Ph
MeO
OMe
Yuto Sumida: 0000-0002-6524-5952
Takamitsu Hosoya: 0000-0002-7270-351X
Hirohisa Ohmiya: 0000-0002-1374-1137
O
Bpin
Bpin
O
t-Bu
Author Contributions
10aca, 67%a
10acd, 38%a
10ada, 72%d
⊥Y. S. and K. N. contributed equally.
Ac
Ph
MeO
OMe
O
ACKNOWLEDGMENT
O
O
O
t-Bu
This work was supported by JSPS KAKENHI Grant Number
JP18H01971 to Scientific Research (B), JSPS KAKENHI Grant
Number JP17H06449 (Hybrid Catalysis), Kanazawa University
SAKIGAKE project 2018, JST, PRESTO Grant Number
JPMJPR19T2 (to H.O.), JSPS KAKENHI Grant Number
JP18K05135 to Scientific Research (C), Tokyo Biochemical
O
t-Bu
O
t-Bu
10add, 52%d
10adi, 52%d,e
10eda, 40%d
a
b
NiBr2 (5 mol %) and bipyridine (6 mol %) were used as catalysts.
c
NiBr2·diglyme (5 mol %) and dtbpy (6 mol %) were used as catalysts.
Diastereomeric ratio (1:1). d Ni(cod)2 (5 mol %) and 1,10-phenanthroline (6
mol %) were used as catalysts. e 4'-Chloroacetophenone was used.
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