Visible Light-Induced Borylation of C-O, C-N, and C-X Bonds

Article abstract of DOI:10.1021/jacs.9b12519

Boronic acids are centrally important functional motifs and synthetic precursors. Visible light-induced borylation may provide access to structurally diverse boronates, but a broadly efficient photocatalytic borylation method that can effect borylation of a wide range of substrates, including strong C-O bonds, remains elusive. Herein, we report a general, metal-free visible light-induced photocatalytic borylation platform that enables borylation of electron-rich derivatives of phenols and anilines, chloroarenes, as well as other haloarenes. The reaction exhibits excellent functional group tolerance, as demonstrated by the borylation of a range of structurally complex substrates. Remarkably, the reaction is catalyzed by phenothiazine, a simple organic photocatalyst with MW < 200 that mediates the previously unachievable visible light-induced single electron reduction of phenol derivatives with reduction potentials as negative as approximately - 3 V versus SCE by a proton-coupled electron transfer mechanism. Mechanistic studies point to the crucial role of the photocatalyst-base interaction.

Full text of DOI:10.1021/jacs.9b12519

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Article
Visible Light-Induced Borylation of C-O, C-N, and C-X Bonds
Shengfei Jin, Hang T. Dang, Graham C. Haug, Ru He, Viet D Nguyen,
Vu T. Nguyen, Hadi D. Arman, Kirk S. Schanze, and Oleg V. Larionov
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12519 • Publication Date (Web): 03 Jan 2020
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Journal of the American Chemical Society
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Visible Light-Induced Borylation of C−O, C−N, and C−X Bonds
Shengfei Jin,a Hang. T. Dang,a Graham C. Haug,a Ru He,a,b Viet D. Nguyen,a Vu T. Nguyen,a Hadi D. Arman,a Kirk S. Schanze,a and Oleg
V. Larionov*a
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a Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249, United States
b Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
Supporting Information Placeholder
iodoarenes under visible light. Development of such a broad,
visible light-mediated, photocatalytic platform is a major chal-
ABSTRACT: Boronic acids are centrally important functional
motifs and synthetic precursors. Visible light-induced boryla-
lenge, because of the wide spectrum of reactivities of the aro-
tion may provide access to structurally diverse boronates, but
matic precursors.
a broadly-efficient photocatalytic borylation method that can
effect borylation of a wide range of substrates, including
strong C‒O bonds, remains elusive. Herein, we report a gen-
eral, metal-free visible light-induced photocatalytic borylation
platform that enables borylation of electron rich derivatives of
phenols and anilines, chloroarenes, as well as other
haloarenes. The reaction exhibits excellent functional group
tolerance, as demonstrated by the borylation of a range of
structurally complex substrates. Remarkably, the reaction is
catalyzed by phenothiazine, - a simple organic photocatalyst
with MW<200 that mediates the previously unachievable
visible light-induced single electron reduction of phenol de-
rivatives with reduction potentials as negative as ~ −3 V vs
SCE by a proton-coupled electron transfer mechanism. Mech-
anistic studies point to the crucial role of the photocatalyst–
base interaction.
Introduction
The importance of boronic acids continues to grow, as new
applications emerge in the areas of organic synthesis,1 cataly-
sis,2 materials science,3 drug discovery,4 and analytical chem-
istry.5 Although significant advances have recently been made
in synthetic approaches to boronic acids based on transition
metal catalysis,6 main group chemistry7 and photochemistry,8-
13
various challenges persist and efforts to expand the scope,
structural diversity, functional group tolerance, and catalyst
availability of emerging organoboron methodologies remain
at the forefront of several areas of chemistry. Given the im-
portance of aromatic boronic acids, it is desirable to have a
single catalytic platform that enables borylation of all com-
mon carbon−heteroatom bonds, including C−O, C−N, and C−X
(Cl, Br, I) bonds.
Since the initial reports on the UV light-induced Ar−X and
Ar−N borylation,8 a number of methods were developed that
allow for borylation of some of the aryl−heteroatom bonds, in
particular, by the groups of Li,9 Jiao,10 Schelter,11 and Studer.12
Despite the impressive progress, further work is needed to
develop a broad photocatalytic platform that encompasses a
wide array of diverse C−O, C−N, and C−X bonds and is pow-
ered by visible light as a more sustainable and functional
group-tolerant source of energy. A desirable photocatalytic
platform that can address these limitations would be based on
Figure 1. Visible light-induced phenothiazine-catalyzed
a single, readily available organic photocatalyst that enables
borylation of substrates with low reduction potentials.
borylations of phenols, anilines, as well as chloro-, bromo- and
1
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Page 2 of 10
For example, phenols with their strong C−O bond (BDE(C−O) reduction potential, PTH1 photocatalysis can inspire the de-
= 110.8 kcal/mol),14 present a particularly challenging prob-
lem for visible light-induced C−O-functionalization. Conver-
sion of phenols to sulfonates (e.g., triflates) is commonly used
in transition metal catalysis to facilitate the C−O bond cleav-
age, but this activation method may be of limited value in pho-
toinduced reactions, because sulfonates tend to undergo the
competing S−O bond scission upon photoexcitation or pho-
toinduced single electron transfer, regenerating phenols.15 In
addition, they have low reduction potentials, placing them
outside the range of typical photoredox catalysts and requir-
ing exceptionally strongly reducing photocatalysts with suita-
ble photophysical properties that remain to be developed. As
a result, a visible light-mediated C−O-borylation has remained
elusive, despite its high potential synthetic value. Given these
challenges, a conceptually distinct approach to activation and
cleavage of the Ar−O bond is required to achieve the C−O-
borylation under visible light, even before any progress is
made towards a general photocatalytic borylation platform.
On the other hand, in the haloarene series, iodoarenes have
relatively weak C−I bonds and less negative reduction poten-
tials (e.g., Ered= −2.39 V vs SCE for p-iodotoluene),16 while
chloroarenes, like derivatives of phenols, are much more diffi-
cult to reduce (e.g., Ered = −2.84 V for p-chlorotoluene). Hence,
the development of a single photocatalytic system that can
avoid excessively fast production of aryl radicals from aryl
iodides, while also being capable of efficient borylation of
chlorides is a significant hurdle.
velopment of other catalytic systems based on this concept.
1
2
3
4
5
6
7
8
9
Table 1. Influence of the Substituents in PTH1-4 on the
Catalyst Performance. a
·
1
+
Catalyst
Eox
/ PTH*), V
Yield,
%
(PTH
(SCE)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
−2.60
64
12
10
68
−2.58
−2.51
−2.71
Addressing the C−O borylation problem ꢀirst, we turned our
attention to aryl phosphate esters as a platform for visible
light-mediated activation of the C−O bond in phenols, hypoth-
esizing that they are less likely to undergo a SET-induced P−O
bond scission, due to the stronger P−O bond. However, aryl
phosphate esters have very negative reduction potentials
(Ered= −2.97 V vs SCE for p-tolyl diethyl phosphate), necessi-
tating a design of a new photocatalytic system with an en-
hanced reduction scope. We, therefore, hypothesized that a
reductive ability of an appropriately selected organic photo-
catalyst can be enhanced by a proton-coupled electron trans-
fer (PCET), enabling a photoinduced single electron transfer
to substrates with very negative reduction potentials, includ-
ing electron-rich aryl phosphate esters and chloroarenes
(Figure 1). Recent work by Knowles and other groups on pro-
ton-coupled electron transfer in photocatalysis has led to the
development of new synthetic methods for functionalization
of strong bonds.17 In search of a suitable photocatalyst, we
turned our attention to phenothiazine PTH1 − a common and
inexpensive commodity chemical. Although phenothiazine has
not been used as a photocatalyst, N-alkyl and aryl substituted
phenothiazines (e.g., PTH2 and PTH3, Table 1) have recently
attracted attention as efficient metal-free photocatalysts in
polymer chemistry and organic synthesis.18 N-Substituted
phenothiazines PTH2 and PTH3 have relatively strongly re-
ducing singlet excited states (Table 1) that allow for produc-
tion of alkyl and aryl radicals from more easily reducible C−X
bonds (e.g, electron deficient haloarenes and -haloesters).
Although phenothiazine PTH1 and the N-substituted ana-
logues PTH2 and PTH3 have very close excited state reduc-
tion potentials (Table 1), we hypothesized that phenothiazine
PTH1 can engage in a photoinduced PCET process with aryl
phosphates in the presence of an appropriate base, effectively
enhancing its reduction strength via this distinctly different
photoactivation mechanism, and enabling the downstream
borylation via a homolytic substitution with a diboron rea-
gent. Given the potentially broad utility of a visible light-
driven metal-free photocatalytic system with an adjustable
a
Reaction conditions: phosphate 1 (0.2 mmol), PTH1-4 (10
mol%), B2Pin2 (0.6 mmol), Cs2CO3 (0.6 mmol), MeCN (2 mL),
LED light (400 nm), 20 h. Yields were determined by 1H NMR
spectroscopy with 1,4-dimethoxybezene as an internal stand-
ard.
Table 2. Reaction Conditions for the Visible Light-
Driven C−O Borylation. a
Entry
Variations from standard condi-
tions
Yield, %
1
2
3
4
5
6
7
8
9
none
no light
64 (78b, 83c)
0
0
no PTH1
no Cs2CO3
0
with water (1 equiv.), 10 h
with 18-crown-6 (1 equiv.), 10 h
K3PO4 instead of Cs2CO3
2 equiv. B2pin2
63
60
30
52
37d
Tolyl triflate instead of 1
a Reaction conditions: see footnote for Table 1. b Isolated yield
c
for a reaction in the presence of water (1 equiv.). Isolated
yield after 36 h. d p-Cresol was also formed in 54% yield.
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Results and Discussion
Journal of the American Chemical Society
bility and phase transfer of the base would accelerate the
1
borylation, we tested water and 18-crown-6 and observed a
faster reaction (Table 2, entries 5 and 6, also see SI) and a
higher yield (Table 3, product 2), pointing to the important
role of the base in the catalytic process. Other bases were also
able to mediate the borylation (entry 7), with cesium car-
bonate showing an optimal performance. The borylation can
be carried out a lower loading of B2Pin2, albeit with a reduced
conversion (entry 8). As anticipated, replacing phosphate 1
with the corresponding triflate led to a substantially reduced
yield and a predominant S–O bond scission (entry 9).
Our studies revealed that the unsubstituted catalyst PTH1
was uniquely active as a photocatalyst for the borylation of
aryl phosphate 1, with Cs2CO3 as a base (Table 1), while a
mere substitution of the N-hydrogen atom with a methyl or
phenyl group (PTH2 and PTH3) led to a substantial decrease
in the catalytic activity. This result is striking, given the com-
parable excited state redox properties of the N-substituted
phenothiazines (Table 1). The structurally similar NH-
phenothiazine PTH4 showed a slightly improved perfor-
mance, likely due to the stronger reducing character of the
more electron rich core. Notably, none of the photocatalysts
PTH1-4 has a sufficiently strongly reducing singlet excited
state to effect the reduction of the electron-rich phosphate 1
(Ered = −2.97 V). The borylation product 2 was not formed in
the absence of light, PTH1, or cesium carbonate (Table 2).
Hypothesizing that addition of reagents that improved solu-
2
3
4
5
6
7
8
9
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We further proceeded with the evaluation of the scope of the
photocatalytic C−O borylation of phosphate esters (Table 3).
Electron-rich phosphates, e.g., 2-11 were readily borylated,
including those bearing strongly donating alkoxy groups. Me-
dicinally relevant fluoro group (12 and 13), as well as amide
(14) and carbamate (15) were also tolerated.
Table 3. Scope of the Visible Light-Induced C−O Borylation Reaction.a
PTH1 PTH4
(2-12 mol%)
or
BPin
BF3K
OP(O)(OEt)2
or
B2Pin2, Cs2CO3
MeCN, LED light
(then KHF2 or KF)
BPin
BPin
BPin
BPin
Me
BPin
BPin
BPin
tBu
BPin
Me
Me
tBu
MeO
b
c
c
b
d
c
3
4
5
2
, 84% (80% )
, 80%
, 84%
, 83% (64% )
6
7
8
9
, 74%
, 60%
, 57%
, 57%
1.4 g, 73%
Me Me
BPin
AcHN
BPin
F
BPin
F
BPin
O
O
Me
BPin
MeO
d
d
14
, 60%
12
, 52%
13
, 50%
10
, 65%
11
, 52%
BPin
BPin
BPin
BPin
BF3K
BPin
MeO2C
BocHN
NC
PinB
EtOOC
CO2Me
15
, 73%
(60%b)
16
, 68%
17
, 79%
1.6 g, 61%
d
e
d
19
18
, 56%
, 81% (56% )
20
, 70%
BF3K
BF3K
BF3K
O
BPin
O
O
O
N
N
N
N
O
21
, 80%
24
, 70%
22
, 65%
23
, 85%
BF3K
BPin
BPin
BPin
BPin
BF3K
H
N
N
BocN
O
N
N
O
Boc
Boc
27
b
g
25
, 62%
26
, 52%
28
29
30
, 50%
, 65%
, 50%
, 70% (68% )
O
OTBS
BF3K
BF3K
H
H
BF3K
H
N
AcHN
N
H
H
H
H
BocHN
EtOOC
from tyrosine
33
O
O
KF3B
PinB
from estrone
from estradiol
from tyramine
34
, 80%
moclobemide derivative
35
c,f
c
31
, 52%
32
, 42%
, 56%
, 47%
a
Reaction conditions: phosphate ester (0.2 mmol), B2Pin2 (0.6 mmol), Cs2CO3 (0.6 mmol), PTH1 or PTH4 (2−12 mol%), MeCN (2
mL), LED light (400 or 420 nm). b B2Pin2 (0.4 mmol). c In the presence of water (1 equiv.). d PTH4 was used. e B2Pin2 (0.3 mmol). f
The keto group in the phosphate ester was protected as an acetal that was removed concomitantly with conversion to trifluorobo-
rate 31. g 450 nm.
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Page 4 of 10
loading was in the 10−12 mol% range, but a lower (2 mol%)
Table 4. Scope of the Visible Light-Induced C−N Boryla-
tion Reaction of Quaternary Ammonium Salts.a
1
2
3
4
loading is possible for more reactive substrates (e.g., 16). Fur-
thermore, the borylation products can be isolated as or-
ganotrifluoroborate salts19 as a part of the work-up proce-
dure, further enhancing the practicality of the method.
PTH1
(1-10 mol%)
B2Pin2, Cs2CO3
or
BPin
BF3K
NR3X
MeCN
LED (400-450 nm)
(then KHF2 or KF)
With the C−O borylation optimized, we were curious to test
the performance of the new photocatalytic method on other
strong carbon−heteroatom bonds. In particular, functionaliza-
tion of the strong Ar−N bonds has remained a challenge. Our
previous work showed that the C−N-borylation of quaternary
arylammonium salts is feasible under UV light irradiation.8
However, a visible light-mediated C−N-borylation of quater-
nary arylammonium salts has remained elusive. Initial exper-
iments with phenyltrimethylammonium halides (chlorides,
bromides and iodides) demonstrated that the PTH1-
photocatalyzed C−N-borylation proceeds smoothly (3, Table
4). Furthermore, in contrast to the UV light-induced reaction
that required iodide and bromide as counteranions, the visi-
ble light-mediated reaction is insensitive to the counteranion,
and proceeds equally well with all halide salts, as well as tri-
flates and methylsulfates. Other N-alkyl groups were also tol-
erated in the ammonium residue. We further investigated the
scope of the reaction with a variety of quaternary arylammo-
nium salts. Substituents in the ortho, meta, and para positions
were well-tolerated (4, 9, 37-41). Substrates bearing medici-
nally-relevant fluorine-containing groups (CF3, CF3O, F2HCO)
were readily borylated (39-41), in addition to ester and sul-
fone groups (42, 43), as well as a naphthalene salt (30). Het-
erocycle-containing products 44-46 were obtained in good
yields. Furthermore, the C−N-borylation performed well in
the molecular setting of active pharmaceutical ingredients
(API), allowing for preparation of borylated derivatives of
aminoglutethimide (Cytadren, 47) and neostigmine (Prostig-
min, 48). The prerequisite quaternary arylammonium salts
can be prepared in situ by brief pretreatment of the corre-
sponding aniline or N-alkylaniline with MeOTf. The reaction
can be readily performed on gram scale (e.g., boronates 4 and
30). As with the C−O-borylation, the products can be isolated
as organotrifluoroborate salts or boronic acids. Quaternary
arylammonium salts were generally more reactive than phos-
phate esters, and 1−5 mol% PTH1 was sufficient to effect the
borylation for most of the substrates. On the mechanistic lev-
el, the insensitivity of the visible light-mediated borylation of
the quaternary ammonium salts to the counteranion indicated
that the reaction does not proceed by the charge transfer from
the anion, as it was observed in the UV light-induced reac-
tion.8
5
6
7
8
9
BPin
BPin
BPin
BPin
Me
(NMe3I),
89%
37
(NMe3I), 75%
36
(NMe3I),
78%
3
4
(NMe3I), 88%
(NMe3Br), 76%
(NMe3Cl), 71%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.7 g
, 78%
(
), 83%
N+
Me
OTf-
BPin
BPin
BPin
BPin
CF3O
Me
Me
MeO
F2HCO
39
9
(NMe3I),
85% (73%b)
40
38
(NMe3OTf),
73%c
(NMe3OTf),
72%c
(NMe3I),
90%
BPin
BPin
CF3
BF3K
MeO2S
MeOOC
41
42
43
(NMe3I),
49%
(NMe3OTf),
82%b
(NMe3I),
68%
BPin
BPin
N
H
30
44
(NMe3OTf), 82%
(NMe3I), 85%
1.6 g
, 60%
BF3K
O
BF3K
S
N
O
N
H
45
46
(NMe3OTf),
76%
45
-BPin
(NMe3OTf),
73%
BPin
B(OH)2
Me2N
O
O
N
H
O
O
from aminoglutethimide
47
from neostigmine
(NMe3OTf), 84%
48
(NMe3O3SOMe), 74%
a
b
Reaction conditions: see footnote for Table 3. B2Pin2 (0.3
mmol). c The salt was prepared in situ by stirring with MeOTf
(3.2 equiv.) for 20 min at rt before adding B2Pin2 and PTH1.
Haloarenes are the most commonly used and readily accessi-
ble precursors to boronic acids, and it is important to have a
broadly synthetically useful borylation method that can effect
the borylation of the three most abundant classes of
haloarenes, − chloro-, bromo- , and iodoarenes, in addition to
phenols and anilines. We, therefore, tested the performance of
the new visible light-mediated PTH1-photocatalyzed boryla-
tion reaction with chlorobenzene, as well as para-chloro-
bromo- and iodotoluene (Table 5). Remarkably, an efficient
borylation was observed with as little as 0.2−2 mol% PTH1
for all three classes of halides. Chlorobenzene and para-
chlorotoluene were converted to the corresponding boronic
esters 3 and 2 in good yields, despite their very negative re-
duction potentials (−2.83 and −2.84 V, respectively). Other
alkyl-substituted aryl chlorides, bromides, and iodides were
also borylated efficiently (4-6, 38, 49, 50), including the elec-
Phosphates with electron-withdrawing groups (e.g., cyano,
boryl, ester groups, 16-18) were equally suitable substrates.
All substitution patterns (o-, m-, p-) were tolerated (18-20),
and gram-scale syntheses were readily performed (3 and 17).
Similarly, phosphates bearing various N-heterocyclic substit-
uents were converted to the corresponding boronic esters 21-
28 in good yields. Furthermore, biphenyl and naphthalene-
derived phosphates were readily borylated (29-30), suggest-
ing that the reaction can be applicable to polyaromatic sys-
tems. Derivatives of estrone, estradiol, tyrosine, tyramine and
moclobemide were subjected to the photoinduced C−O
borylation and afforded boronates 31-35, indicating that the
new method can be used for borylation of naturally-occurring
and medicinally-relevant phenols. Catalysts PTH1 and PTH4
both performed well, and longer wavelength LED light (420
and 450 nm) was also used with success. The optimal catalyst
tron-rich ortho,para-substituted 4-chloro-m-xylene (Ered
=
−2.92 V, boronate 50). The reaction allows for production of
fluorinated boronic esters (12, 13, 39, 40, 51-57), as well as
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Journal of the American Chemical Society
Table 5. Scope of the Visible Light-Induced C−X Borylation Reaction.a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
c
d
Reaction conditions: see footnote for Table 3 with 2 equiv. B2Pin2. In the presence of water (1 equiv.). 3 equiv. B2Pin2. 1.2
equiv. B2Pin2. e 1.5 equiv. B2Pin2.
for selective borylation of a more readily reduced C−X bond
(58). Electron-rich 4-chloroanisole was readily reacted, as
well as other alkoxy group-containing haloarenes (9, 10, 59).
Boryl, thio, unprotected amino, amido, ester, and other elec-
tron-withdrawing groups (16, 17, 60-67) were well-
tolerated. A variety of biaryl and polycyclic haloarenes (29,
30, 68-74) were converted to the corresponding boronic es-
ters in good yields, independently of the halogen leaving
group. Some reactive haloarenes required as little as 0.2
mol% of PTH1, and most of the reactions were performed
with 1.2–2 equiv. B2Pin2. The reaction can be readily carried
out on a gram scale (16, 61).
Heterocyclic boronates are key precursors for many cross-
coupling reactions that are difficult to produce by convention-
al borylation strategies, due to the interference of electro-
philic or coordinating heteroatom-centered residues. We,
therefore, evaluated the performance of the new catalytic
system with a wide range of heterocyclic precursors (Table 6).
A wide range of substituted pyridineboronates (75-84), in-
cluding those bearing unprotected amino group (75), fluoro
(78 and 79), ester, cyano, trifluoromethyl and amido groups
(80-84) were readily accessed. Borylated quinolines (85-87),
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Table 6. Scope of the Visible Light-Induced C−X Borylation Reaction of Haloheteroarenes.a
1
2
3
4
Z
Z
Z
PTH1
(1-5 mol%)
or
BPin
BF3K
X
X
X
X
B2Pin2, Cs2CO3
Y
Y
Y
MeCN, LED (400 nm)
(then KHF2 or KF)
5
6
BF3K
Me
BPin
BF3K
BF3K
KF3B
F
COOMe
BF3K
7
8
9
in
Me
H2N
N
N
F
N
N
N
N
b
75
76
76
-H
77
78
79
80
, 62%
, 99%
, 70%
, 70%
, 85%
, 69%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BF3K
KF3B
(HO)2B
BF3K
BF3K
BF3K
CF3
KF3B
O
N
COOMe
N
CN
N
Me
N
N
N
N
N
H
81
, 44%
82
83
84
, 85%
85
, 73%
86
(X = Cl), 58%
, 78%
, 62%
87
, 53%
BF3K
KF3B
H2N
N
Me
N
N
BF3K
N
N
H
N
H
b
N
H
N
PinB
KF3B
BPin
BF3K
93
, 85%
H
b
b
88
(X = Cl), 55%
89
90
91
, 70%
, 70%
, 76%
92
, 71%
BPin
Me
MeO
N
Bpin
BPin
BPin
S
N
N
N
BF3K
, 80%
N
Me
S
BPin
H
O
O
S
b
b
b
94
95
96
97
98
, 70%
99
100
, 52%
, 71%
, 72%
, 80%
, 57%
a Reaction conditions: see footnote for Table 3 with 2 equiv. B2Pin2, X = Br unless otherwise specified. b 3 equiv. B2Pin2.
Table 7. Scope of the Visible Light-Induced C−X Borylation Reaction of APIs and Natural Products. a
a Reaction conditions: see footnote for Table 3 with 2 equiv. B2Pin2. b 3 equiv. B2Pin2.
indoles, and carbazoles (88-91) were also synthesized in
good yields. Since heterocycles that contain multiple nitrogen
atoms present a challenge for conventional borylation meth-
ods, we evaluated the reaction performance with borylated
heterocycles 92-95 and observed smooth conversion. Oxy-
gen- and sulfur-containing heterocycles were also tolerated
(96-100).
Boronates derived from salicine (101), strychnine (102), as
well as a variety of APIs and estrone (35, 103-110) bearing
basic heteroatoms, polar groups, and heterocyclic frameworks
were readily synthesized, confirming versatility of the new
method. The ability of the new catalytic system to effect the
borylation of all five major classes of C−X bonds can be ex-
ploited for the simultaneous introduction of two boryl groups,
en route to diborylarenes that have found applications as
linchpins and phosphors in materials science.3 Thus, various
combinations of C−O, C−Cl, C−Br, C−I, and C−N bonds were
The new borylation preformed equally well in the more com-
plex structural settings of natural products and APIs (Table 7).
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Journal of the American Chemical Society
A.
Table 8. Scope of the Visible Light-Induced Dual Boryla-
tion. a
BPin
PTH1
B2Pin
(10 mol%)
2, Cs2CO3
1
OP(O)(OEt)2
BPin
+
2
3
4
MeCN
LED light (400 nm)
119
120
31% (
121
: 1:14.5)
120 121
/
5
6
7
8
-1 -1
BPin
.
.
k = 1.1 10
M
s
+
BPin
B2Pin2
8
9
B.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*
a
b
c
d
e
f
PTH1
PTH1
PTH1
PTH1
PTH1
PTH1
PTH1
PTH1
-K
+ Cs2CO3
+ B2Pin2
+ 18-crown-6
*
*
*
*
+ 12-crown-4 + Cs2CO3
+ 18-crown-6 + Cs2CO3
+ B2Pin2 + Cs2CO3
g
h
*
*
a
b
Reaction conditions: see footnote for Table 3. The salt was
prepared in situ by stirring the aniline precursor with MeOTf
for 30 min at rt before adding B2Pin2 and PTH1.
Figure 2. Mechanistic studies of the PTH1 photoredox cata-
lyzed borylation reaction. A. Radical clock experiments with
phosphate ester 119. B. 1H NMR spectra of PTH1 (a), potassi-
um salt of PTH1 (PTH1-K, b), as well as PTH1 in the presence
of Cs2CO3, B2Pin2, and crown ethers (c-h), in acetonitrile with
a sealed coaxial capillary containing d12-cyclohexane.
simultaneously borylated, providing a straightforward access
to regioisomeric diborylarenes from a variety of halogenated
phenols, anilines, as well as dihaloarenes, by-passing inter-
mediates (Table 8, 17, 111-113). Additionally, we tested the
performance of the catalytic system with a range of diboron
esters (Table 9), since generation of various boryl esters using
a single borylation protocol presents remains a challenge and
is generally available only with UV-induced protocols. In all
cases, a uniformly smooth performance was observed, and the
corresponding products (18, 114-118) were obtained in good
yields. In contrast, B2(OH)4 proved to be unsuitable, due to
insolubility in acetonitrile. Boronic acids can still be prepared
using the present method, as exemplified by product 48, by a
simple modification in the workup procedure (See SI).
Initial experimental observations of the pronounced N-
substitution effects on the catalytic performance of phenothi-
azines PTH1-3 provided a strong indication of the crucial role
of the N−H group for the photoredox catalysis by PTH1 (Table
1) that was also previously observed for other PCET-enabled
catalytic systems.3f,g Furthermore, the acceleration observed
with reagents that improve solubility and phase transfer of
cesium carbonate also points to the equally important role of
the base. We, therefore, conducted a series of experiments in
order to clarify the mechanistic details of the photocatalysis.
First, the aryl radical intermediacy was confirmed in radical
clock experiments with phosphate 119 that produced boro-
nates 120 and 121 (Figure 2.A). The bimolecular rate con-
stant of the reaction of the aryl radical with B2pin2 (k = 1.1·108
M-1·s-1) was comparable with the value reported by Studer
(7.4·107 M-1·s-1) for the reaction of the catechol-derived dibo-
ron reagent B2Cat2 with the aryl radical produced from the
corresponding iodoarene.12 We next examined the roles of
cesium carbonate and the diboron reagent in the photoredox
catalysis by PTH1 by means of 1H NMR spectroscopy. First,
formation of the phenothiazine anion from PTH1 in the pres-
ence of cesium carbonate was ruled out (Figure 2.B, PTH1-K,
potassium salt of phenothiazine was used, cf. traces a-c, h),
indicating that the reaction does not proceed by a stepwise
mechanism with the phenothiazine anion acting as an elec-
tron donor in a photoinduced electron transfer. This conclu-
sion was independently corroborated by UV/Vis studies of the
PTH1/Cs2CO3/B2Pin2 system (see SI). Further, no significant
changes in the 1H NMR spectrum of PTH1 were observed in
the presence of B2Pin2, and only a minor shift of the N‒H sig-
nal was observed in the PTH1‒Cs2CO3 system, as expected
from the poor solubility of Cs2CO3 in acetonitrile (cf. traces a,c,
d). Significantly, addition of B2Pin2 to the PTH1‒Cs2CO3
Table 9. Scope of the Boronate Esters.a
B(OR)2
X
PTH1
(1 mol%)
B2(OR)4, Cs2CO3
MeCN, LED light
EtO2C
EtO2C
O
O
O
B
B
B
O
O
O
EtO2C
EtO2C
EtO2C
b
18
114
115
(X = Br), 82%
(X = OPO(OEt)2),
(X = Br), 73%
60%
(X = Br), 82%
O
B
O
B
O
B
O
H
O
O
EtO2C
EtO2C
EtO2C
118
(X = Br), 76%
116
117
(X = Br), 72%
(X = OPO(OEt)2), 53%
(X = Br), 90%
a
Reaction conditions: see footnote for Table 3 with 2 equiv.
B2Pin2. b Isolated as boronic acid.
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122
)
p-BocHNC6H5O2P(OEt)2
(
p-Chlorotoluene
PTH1‒carbonate-driven PCET process, stronger quenching
was observed in the PTH1‒Cs2CO3−crown ether system. The
PTH1
PTH1
PTH1
PTH1
1
2
3
4
5
6
7
8
+ Cs2CO3
+ Cs2CO3
same quenching behavior was observed for phenyltrime-
thylammonium iodide, as anticipated for the more readily
reducible substrate. Taken together, the pronounced N-
1
substitution effects combined with the results of the H NMR
and fluorescence quenching studies suggest that the photore-
dox catalysis by PTH1 is enabled by a proton-coupled elec-
tron transfer process arising from the PTH1‒carbonate inter-
action exemplified by complex 123 (Figure 4), resulting in the
borylation of substrates that have previously not been suita-
ble for visible light-induced photoredox catalysis.
p-Bromotoluene
p-Iodotoluene
PTH1
PTH1
PTH1
PTH1
9
+ Cs2CO3
+ Cs2CO3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Thermodynamic
and
kinetic
feasibility
of
the
PTH1‒carbonate photocatalytic borylation was further as-
sessed computationally. (TD)DFT calculations show that the
photoinduced proton-coupled electron transfer renders the
one-electron reduction of aryl phosphate esters thermody-
namically favorable from the singlet excited state of complex
123 (Figure 4, modelled with phosphate ester 124). Further-
more, Marcus theory-based estimations suggest that the re-
duction may occur by a stepwise dissociative process,
Phenyltrimethylammonium iodide
PTH1
PTH1
+ Cs2CO3
proceeding with a low activation barrier (2.1 kcal/mol) via
radical anion intermediate 124·-. The subsequent homolytic
substitution reaction of the generated aryl radical with B2Pin2
also proceeds with a low barrier of 4.4 kcal/mol. Importantly,
the ensuing barrierless and exergonic reaction of the inter-
mediate boryl radical with the oxidized photocatalyst complex
125 (i.e., phenothiazinyl radical – hydrogen carbonate com-
plex) provides a pathway for the regeneration of catalytically
active complex 123. The computational conclusions are con-
sistent with the experimental observations and provide fur-
ther support to the borylation mechanism.
Figure 3. Fluorescence quenching experiments for PTH1 in
the presence and in the absence of cesium carbonate and 18-
crown-6 with representative borylation substrates.
system led to a downfield shift of the N‒H signal (cf. traces c
and h). The same shift was observed for the PTH1‒Cs2CO3
system in the presence of crown ethers (cf. traces f, g, and h).
No interaction between PTH1 and B2Pin2 or crown ethers was
observed in the absence of Cs2CO3 (cf. traces d, e and g, h).
These observations suggest that, in addition to the primary
role as a borylation reagent, B2Pin2 also serves as a phase
transfer mediator for cesium carbonate, mimicking the behav-
ior of crown ethers. In support of this conclusion, the
B2Pin2−Cs+ species was detected in the solution of PTH1 in
the presence of Cs2CO3 and B2Pin2 by HRMS (MW = 387.0920),
while no signals corresponding to the sp3-adduct of B2Pin2 and
Cs2CO3 were detected by 11B NMR spectroscopy, indicating
that B2Pin2 primarily interacts with the base via the cesium
ions. Taken together, these results suggest a hydrogen bond-
ing interaction of PTH1 and Cs2CO3 that is assisted by B2Pin2.
The role of the PTH1‒Cs2CO3 interaction in the borylation
was further probed by fluorescence quenching experiments
with representative substrates (Ar−LG, LG = O2P(OEt)2, Cl, Br,
I, NMe3I) (Figure 3). For the purpose of the fluorescence
quenching experiments, 18-crown-6 was used as a phase
transfer mediator in place of B2Pin2 to ensure that the quench-
ing is not affected by the concomitant borylation, and given
the similar behavior of the crown ester and B2Pin2 (vide su-
pra). As expected, no PTH1 fluorescence quenching was ob-
served with phosphate ester 12220 in the absence of Cs2CO3
and the crown ether.21 However, the fluorescence was
quenched in the PTH1‒Cs2CO3−18-crown-6 system, pointing
to the involvement of a PTH1‒carbonate-enabled PCET pro-
cess in the borylation. p-Chlorotoluene and p-bromotoluene
exhibited similar quenching behavior, consistent with their
low reduction potentials. Iodoarenes and arylammonium
salts, on the other hand, have less negative reduction poten-
tials, and direct photoinduced electron transfer from excited
PTH1 was anticipated to contribute to the borylation process.
Indeed, PTH1 fluorescence quenching was observed with p-
iodotoluene. In line with the expected contribution of the
Figure 4. Computed Gibbs free energy profile of the PTH1-
photoredox catalyzed borylation reaction of phosphate esters,
G, kcal/mol.
Conclusion
In conclusion, we have developed a metal-free, visible light-
induced photocatalytic borylation platform that enables
borylation of a range of carbon‒heteroatom bonds, including,
for the first time, C‒O borylation of electron rich phenol de-
rivatives, chloroarenes, and C‒N borylation of aniline-derived
quaternary ammonium salts. The scope and functional group
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Journal of the American Chemical Society
tolerance of the method were further demonstrated on a
Borylation of Aryl Ethers via Ni-Catalyzed C–OMe Cleavage. J. Am.
1
2
3
4
5
6
7
8
number of representative carbocyclic and heterocyclic sub-
strates, as well as natural products and medicinally relevant
compounds. The photocatalysis is enabled by the simple,
abundant and low molecular weight heterocyclic commodity
chemical phenothiazine PTH1 that effects single electron re-
duction of substrates with strong bonds and low reduction
potentials by a proton-coupled electron transfer mechanism.
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ASSOCIATED CONTENT
Supporting Information
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Experimental and spectral details for all new compounds and
all reactions reported. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
oleg.larionov@utsa.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support by the Welch Foundation (AX-1788), NSF
(CHE-1455061) and NIGMS (GM134371) is gratefully
acknowledged. UTSA NMR and X-ray crystallography facilities
were supported by NSF (CHE-1625963 and CHE-1920057).
The authors acknowledge the Texas Advanced Computing
Center (TACC) at UT Austin for providing computational re-
sources.
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TOC graphic
e-
O
O
P(O)(OEt)2
P(O)(OEt)2
PC*
h
R
EDG
EDG
+
B(OR)2
B2(OR)4
e-
EDG
PC*
B-
H
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Small, abundant organic
photocatalyst with MW <200
Borylation of electron-rich substrates with strong
C-O, C-N, C-Cl bonds and Ered ~ -3 V vs SCE
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(21) No quenching was observed when either Cs2CO3 or 18-crown-
6 was absent.
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