Visible-light-promoted oxidative halogenation of (hetero)arenes

Article abstract of DOI:10.1039/d0gc02091e

Organic halides are critical building blocks that participate in various cross-coupling reactions. Furthermore, they widely exist as natural products and artificial molecules in drugs with important physiological activities. Although halogenation has been well studied, to the best of our knowledge, studies focussing on sensitive systems (e.g.aryl amines) have not been reported. Herein, we describe a compatible oxidative halogenation of (hetero)arenes with air as the oxidant and halide ions as halide sources under ambient conditions (visible light, air, aqueous system, room temperature, and normal pressure). Moreover, this protocol is practically feasible for gram-scale synthesis, showing potential for industrial application.

Full text of DOI:10.1039/d0gc02091e

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DOI: 10.1039/D0GC02091E
COMMUNICATION
Visible-Light-Promoted Oxidative Halogenation of (Hetero)Arenes
a
a
a,b,c
Lingling Lu, Yiming Li, Xuefeng Jiang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
O
Organic halides are critical building blocks, which participate in
various cross-coupling reactions. Furthermore, they widely exist as
natural products and artificial molecules in drug with important
physiological activities. Although halogenation has been well
studied, to the best of our knowledge, studies focus on sensitive
systems (e.g. aryl amines) have not been reported. Herein, we
describe a compatible oxidative halogenation of (hetero)arenes
with air as oxidant and halide ions as halide sources under ambient
conditions (visible light, air, aqueous system, room temperature,
and normal pressure). Moreover, this protocol is practically feasible
to gram-scale synthesis, which shows potential for industrial
application.
H
O
N
NH
HO
N
O
O
N
F
H
N
N
N
N
HN
F
Br
N
Me
F
Br
Me
N
Br
Bromazepam
Antianxiety
Binimetinib
BRAF/MEK inhibitors
Vandetanib
Antithyroid cancer
H2N
Br
Br
O
N
O
N
O
I
F
H
N
H
N
NH2
Me
N
HO
Me
N
Me
O
I
I
Me
Me
I
O
Bromhexine
Expectorant
Trametinib
MEK inhibitor
Iopanoic acid
Cholecystography
Figure 1. Representative halide-containing drugs.
Aryl halides, especially bromo- and iodoarenes, are classes of
significant compounds due to their irreplaceable roles in transition-
metal-catalyzed cross-coupling reactions,1 which serve as both
starting materials and the precursors of organometallic reagents,
Conventionally, aromatic halides are prepared through
electrophilic aromatic substitution with molecular halogens (Cl
Br , and I
).12 However, they suffer from limitations of hazardous
2
,
2
2
2
3
such as organolithium and Grignard reagents. Beyond synthesis
applications, they are widespread in nature as well. More than 1700
and corrosive conditions, poor tolerance and regioselectivity, as
well as over-halogenations (Figure 2A, Method 1). Subsequently,
various mild and easily-handled halogenating reagents,
represented by NXS (X = Br and I) prepared from molecular halogen
were developed under transition-metal-catalyzed conditions,13
albeit with lower atom-efficiency (Figure 2A, Method 2).
4
bromo- and iodoarenes have been isolated, which inspire their
prevalence in medicinal studies. Until now, there are more than 60
4
bromo- and iodoarenes approved as clinic drugs, such as antianxiety
5
6
drug Bomazepam, BRAF/MEK inhibitors Binimetinib, antineoplastic
7
drug Vandetanib, treatment of respiratory disease drug
+
Alternatively, electrophilic halide X (X = Br and I) can be generated
8
9
Bromhexine, MEK inhibitor drug Trametinib, and cholecystography
Iopanoic acid10 as shown in Figure 1. Furthermore, among the most
popular prefunctionalization in the process of drug synthesis,
bromination and iodination have occupied 46%, according to
Schneider group’s statistics.11
from halide ions14 with stoichiometric amounts of strong oxidants,
however, functional groups sensitive to oxidative conditions are
not well tolerated (Figure 2A, Method 3). Therefore, it is of great
demand for developing green oxygenation method for synthetic
aryl halides.
1
5
Recently, halogenation of arenes has been achieved via visible-
1
6
light photocatalysis . The first selective bromination of electron-
rich aromatics with oxygen gas was reported by Fukuzumi group in
2011,17 with 9-mesityl-10-methylacridinium perchlorate (Acr+–
Mes) as photocatalyst and aqueous HBr as Br source (Figure 2B),
which prefer electron strong donor (poly)methoxy-substituted
arenes. Kӧnig group15d established an excellent photocatalytic
a. Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China
Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: xfjiang@chem.ecnu.edu.cn
b.
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin,
3
00071, P. R. China.
c.
State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic
Chemistry Chinese Academy of Sciences, Shanghai, 200032, P. R. China.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
bromination method utilizing protonated sodium anthraquinone well as excellent crop selectivity , as the model substraVtieewwAirtthiclseoOunrlicnee
sulfonate (SAS)
of bromine, acid and water. Initially, differenDtObI:ro10m.1i0n3e9a/Dn0ioGnCs0w20e9r1eE
A) Conventional synthesis of aryl halides
Table 1: Conditions optimizationa
Method 1
Method 2
Method 3
'
Br ' (1.5 equiv.)
X2
H
NXS + Cat.
X- + oxidant
Br
NH2
NH2
Br
Acid (2.0 equiv.)
H2O (20 equiv.)
Ar
Ar
CO2Me
CO2Me
Me
HX
HCl, Me S,
2
X = Br, I
O
O
N
Inorganic salt, etc.
CH CN, Air, RT
Me
3
H
hazardous
corrosive
non-selectivity
H
low atom-efficiency
transition-metal-catalyst
amounts of oxidants
incompatible sensitive group
1
a
2a
blue LEDs
Me
Yield (%)b
Entry
' Br ' Source
Acid
B) Fukuzumi's work
HBr O2
Me
Me
1
2
3
4
5
6
7
8
9
LiBr
NaBr
KBr
.
58
+
NaHSO4 H2O
Acr - Mes
H
Br
Ar
R
Ar
R
.
89 (85)c
NaHSO4 H2O
N
blue LEDs
Me
R = OMe
NaHSO4.H O
2
83
42
+
(Acr - Mes)
NH4Br
TBAB
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
.
NaHSO4 H2O
C) KÖnig's work
.
85
O
NaHSO4 H2O
NaBr Air
TFA, SAS
NHPG
SO3Na
NHPG
KHSO4
AcOH
H3PO4
CSA
77
Ar
Ar
Br
H
Trace
36
blue LEDs
O
PG= protecting groups
(SAS)
TFA
SAS-H+
66
400 nm
TFA-H
10
H2SO4
74
SAS
O2
SAS-H+*
NHPG
Br
NHPG
11d
2e
.
76
+
H2O2
NaHSO4 H2O
HO2
Br
SAS-H
NaBr
.
63
1
NaHSO4 H2O
NHPG
HO2
aThe reaction condictions: 1a (0.2 mmol), H
O (4.0 mmol), NaBr (0.3 mmol),
2
D) This work
NaHSO
15 h. NMR yields with CH
4
.H
2
O (0.4 mmol), CH
3
CN (2.0 mL), room temperature, air, 2*3 W blue LEDs,
NaX Air
.
b
as internal standard. c isolated yields. c = 0.05 M,
d
NaHSO4 H2O
2
Br
2
NH2
NH2
e
Ar
H
Ar
CN
0.1 mmol scale. c = 0.3 M, 0.3 mmol scale, 36 h.
blue LEDs
X
Photocatalyst
Photocatalyst or not
X = Br, I
tested, such as LiBr, NaBr, KBr, NH
were detected with good to excellent yields (Table 1, entries 1-5),
and NaBr is the best (Table 1, entry 2). When KHSO was used instead
of NaHSO .H O, the desired product 2a can be obtained in 77% yield
(Table 1, entry 6). However, other BrØnsted acids failed to perform
better (Table 1, entries 7-10). The desired product 2a was obtained
in 76% yield when the concentration of the system decreased to 0.05
M (Table 1, entry 11), while yield dropped sharply when increased to
4
Br, and TBAB. Desired product 2a
Figure 2. Construction of aryl halides.
4
as an oxidizing photocatalyst (Eox = 1.8-2.3 V), in which long-lived
4
2
+
triplet state SAS-H * under visible light irradiation conditions was
critical for oxidizing arenes (Figure 2C). Despite with a broader
functional group compatibility, until now, halogenation of
unprotected primary arylamine has never been realized since of
paradoxical challenges: 1) aromatic amines are susceptible to
oxidation; 2) acids conditions are incompatible with amines with
ammonium salts generation.
0
.3 M (Table 1, entry 12). Thus, the reaction with 0.1 M at room
temperature under blue LEDs irradiation was found to be the optimal
conditions. Moreover, control experiment displays that no desired
product 2a was detected in the absence of acid, light, or air (Table
Inspiring from photocatalysis18 in our group, we tried to establish S1).
mild ambient conditions for the bromination and iodization with
great compatiblity, in which strategy accomplished the electron
With the optimized conditions in hand, we investigated the related
compatibility of halogenation based on anilines and heteroarenes, as
shown in Table 2. In general, anilines with different substituents can
be well compatible. Originally, the product 2a can be obtained from
polysubstituted aniline 1a with 85% yield, which used to serve as a
pivotal intermediate for synthesis of triketone herbicides 2ad.19
Aniline and ortho- or para-substituted aromatic amines with
transfer between oxygen and halide anions via substrate as both
catalyst and reactant controlling releasing rate of active halogen.
Herein we describe the oxyhalogenation under inorganic halide
sources, air, water, visible-light, room temperature, and normal
pressure for primary arylamine and (hetero)arenes (Figure 2D).
We commenced our studies with
methylbenzoate 1a，an intermediate19 of 4-hydroxyphenylpyruvate with moderate to good yields (2b-2j). It is note worthy that they are
methyl 2-amino-6- transformable halogens and different electron-deficient were tested
dioxygenase inhibitors which with broad-spectrum weed control as the
key skelecton of pharmacoactive molecules, such as
This journal is © The Royal Society of Chemistry 20xx
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
7
equiv.) instead of NaBr;
e
acetone as solvent;
f
10 mmol scale;
g
4
NH I instead of NaI;
View Article Online
antineoplastic drug Vandetanib 2bd, treating respiratory disease
8
yields of the isolated products are given.
DOI: 10.1039/D0GC02091E
drug Bromhexine (Figure 1). Among them, 2c can be used as the
starting material for the synthesis of MEK inhibitor Selumetinib
2
0
2
cd , which was granted orphan drug status by European medicines
Table 2: Aryl halides synthesisa
agency (EMA) for the treatment of neurofibromatosis type 1 (NF1) in
2
018. Moreover, 2j as an intermediates for synthesis of anti-HIV
blue LEDs
activities molecules 2jd. 21 In addition, the oxidatively sensitive
NaBr/NaI
H
X
phenylthioaniline is also tolerated (2k). Other polysubstituted
anilines (2l and 2m), even within condensed aromatic systems (2n)
can also be well transformed. In addition, tertiary aryl amine (2o) and
other electron-rich aromatics (2p and 2q) also experienced efficient
bromination. More importantly, late-stage modification of natrual
products, such as Coumarin 151 (2r) and Xanthotoxin (2s), delieverd
desired products in good yields. Beyond arylamines, transformations
with heterocyclics,22 such as midazo[1,2-a]pyrazine and unprotected
azaindole, presented successful results as well (2t-2v). Meanwhile,
5,5'-dibromo-2,2'-bithiophene (2w), an important intermediate of
organic optoelectronic materials,23 was successfully constructed
under standard conditions with dual bromination. Subsequently,
related iodination was also studied with sodium iodide instead of
sodium bromide. Generally, substituted anilines and heteroaromatic
amines can be well transformed (3a-3d). 3d can be used in the
synthesis of triketone herbicides.19 Furthermore, unprotected ethyl
.
NaHSO4 H2O
Ar
1
Ar
CH3CN/H2O, Air, RT
X = Br, I
2/3
bromination
NH2
Br
O
N
NH2
Br
OH
O
O
Me
O
N
F
CO2Me
R
N
ref. 20
ref. 7d
N
HN
F
Me
O
N
Me
Me
Br
2b, 48%b
85%a, f
2ad
2bd
2a
herbicides
Vandetanib
antineoplastic drug
Me
O
NH2
N
O
NH2
NH2
Br
N
OH
Cl
H
R
ref. 25b
N
NH
F
Cl
Br
Br
R
Br
2cd
2d R =
H, 44%c
Br, 53%b
Ph, 70%b
c, Cl, 85%b
2h R = Cl, 60%b
2
2
e
Selumetinib
MEK inhibitor
neurofibromatosis Type 1 drug
CF3, 80%b
2
f
2i
2g
CO2Et, 68%b
N
N
NH2
Br
O
S
N
N
S
ref. 23
HN
R
N
Br
Cl
CO2Et
j, 58%b
1
H-indole-2-carboxylate and 4 or 7- N-hetero indole could afford the
2
CO2Et
jd
anti-HIV activities
Cl
related products (3e-3g) in excellent yields. And 1,3,5-
trimethoxybenzene came into being corresponding iodinated
product in excellent yields (3h). Futhermore, gram-scale reaction
demonstrated the possibility of industrial synthesis, accomplished
with 2a (74%, 1.793 g) and 3f (63%, 1.538 g) yields, as shown figure
2
NH2
NH2
NH2
Br
S
Me
Me
NH2
Br
MeO
Br
Br
CO2Me
71%b
2l 65%b
2m 79%b
2n 52%a,e
2k
3
.
CF3
Br
OMe
OMe
Br
OMe
O
N
Br
H2N
O
O
NH2
NH2
Br
NH2
Br
NaI (2.0 eq.)
H2O (40 eq.)
NaHSO4.H2O (2.5 eq.)
CO2Me
Me
CO2Me Br
CO2Me
Me
I
MeO
(48 %) HBr (1.5 eq.)
N
N
Br
+
CH3CN (50 mL), O2, RT, blue LEDs
conv. = 97%
Me
N
N
H
H
CH3CN (50 mL), O2, RT, blue LEDs
conv. = 79%
50%b
Br
2p 63%b
2q 83%b
2r 81%a
1.5382 g
(63%)
2o
10 mmol (1.6519 g)
1
0 mmol
(1.1814 g)
1
.7937 g (74%)
0.214 g (6.6 %)
Br
Br
N
Br
N
N
N
N
NH
O
O
O
N
N
N
H
H
CH3CN aqueous
OMe
dropwiseing HBr
65%a
s
2t 86%a
2u 81%a
2v 81%a
2
iodination
NH2
NH2
I
NH2
Br
S
R
CO2Me
Figure 3. Gram-scale reactions.
ref. 20
S
Br
2ad
MeO
Me
I
CO2Me
I
Further mechanistic studies were carried out to figure out the
intrinsic mechanism of this transformation. First, according to
ultraviolet-visible absorption spectrums, aniline instead of other
species was found to be photosensitizer, absorbing light energy and
providing energy for the subsequent electron transfer (SI, Section III-
57%a
3a R = Cl, 51%d
3c 73%d
3d 50%d
2w
Ph, 42%d
3b
I
I
I
OMe
N
I
CO2Et
N
N
H
N
N
H
H
MeO
OMe
1
). Then, fluorescent quenching experiments disclosed NaBr can
86%d,g
3f 79%d, f
3g 86%d
3h 92%d
3e
quench the active aryl amine efficiently (SI, Section III-2). Radical
trapping experiment with 1,1-diphenylethylene suggested the
existence of bromo radical through the detection of trapping product
a
.H
Conditions: 1 (0.2 mmol, 1.0 equiv.), H
2
O (4.0 mmol, 20 equiv.), NaHSO
4
2
O (0.4
mmol, 2.0 equiv.), NaBr (0.3 mmol, 1.5 equiv.), CH
air, 2*3 W blue LEDs; with 4-(phenylethynyl)benzonitrile (0.04 mmol, 20 mol%);
cwith 2-(phenylethynyl)thiophene (0.04 mmol, 20 mol%); dNaI (0.6 mmol, 3.0
3
CN (2.0 mL), room temperature,
4
by GCMS, which further proved the electron-transferring process
b
between bromide anion and photosensor (SI, Section III-3).
Subsequently, active oxygen species were explored. Electron
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
paramagnetic resonance (EPR) study with 5,5-dimethyl-1-pyrroline- extracted with dichloromethane for three times. Then, organic layers
View Article Online
DOI: 10.1039/D0GC02091E
1
-oxide (DMPO) did not show apparent radical signals, indicating were combined, dried over sodium sulfate and filtration After
-•
2
neither superoxide radicals (O ) nor hydroxyl radicals (HO•) were evaporation of solvent, the residue was purified by column
crucial species (SI, Section III-4). Simultaneously, the above results chromatography (PE/EA) to give the corresponding products 2 or 3.
were further corroborated by experiments with various active
1
oxygen species inhibitors, such as singlet oxygen ( O
2
) inhibitors Conflicts of interest
-•
3
(NaN ,
2
1,3-diphenylisobenzofuran), superoxide radical (O )
inhibitors (1,3-diphenylisobenzofuran), and hydroxy radical (HO•) There are no conflicts to declare.
t
inhibitor ( BuOH) (SI, Section III-5). Finally, another important active
oxygen species—hydrogen peroxide (0.0109 mmol) was found in
standard system via quantitative iodometric experiments (SI, Section
III-6) , which might be helpful to oxidize bromo anion to radical
Acknowledgements
We are grateful for financial support provided by National Key
Research and Development Program of China (2017YFD0200500),
NSFC (21971065, 21722202, 21672069), the S&TCSM of Shanghai
According to the above results, a postulated reaction
mechanism is displayed in Figure 4. Initially, arylamine were excited
to generate an excited state (SM*) under blue light. Then, electron
transfer between SM* and halogen anion formed aromatic amine
(Grant 18JC1415600), Professor of Special Appointment (Eastern
Scholar) at Shanghai Institutions of Higher Learning, and the National
Program for Support of Top-notch Young Professionals.
-•
-•
radical anion (SM ) and halogen radical. The oxidation of SM by air
assisted by a proton, generating active oxidant hydrogen peroxide
Notes and references
and regenerated ground-state arylamine (SM). Then, X
generated from halide radical, followed by subsequent electrophilic
aromatic substitution (EArS) between X and SM producing P.
2
might be
1
. (a) R. F. Heck, J. P. Nolley, J. Org. Chem., 1972, 37, 2320-2322.
(b) A. S. Guram, S. L. Buchwald, J. Am. Chem. Soc., 1994, 116,
2
7
2
901-7902. (c) N. Miyaura, A. Suzuki, Chem. Rev., 1995, 95,
Controlled release and oxidization helped to prompt the
regioselectivity.
457-2483. (d) J. P. Wolfe, S. Wagaw, J. -F. Marcoux, S.
Buchwald, Acc. Chem. Res., 1998, 31, 805-818. (e) J. F.
Hartwig, Acc. Chem. Res., 1998, 31, 852-860. (f) F. Bellina, R.
Rossi, Chem. Rev., 2010, 110, 1082-1146. (g) S. Song, X. Li, J.
Wei, W. Wang, Y. Zhang, L. Ai, Y. Zhu, X. Shi, X. Zhang, N. Jiao,
Nat. Catal. 2020, 3, 107-115.

path b
NH2
2 2
H O
X
CO2Me
Me
path a
X
X2
NH2
2. N. Sotomayor, E. Lete, Curr. Org. Chem., 2003, 7, 275-300.
3. The Handbook of Grignard Reagents, G. S. Silverman, P. E.
Rakita, Eds. Dekker: New York, 1996.
SM*
CO2Me
Me
NH2
HBr
CO2Me
Me
4. The data were collected via Reaxy up to 25th December 2019.
SM
5
. (a) L. M. Sonne, P. Holm, Int. Pharmacopsychiat, 1975, 10,
1
25-128. (b) R. Fontaine, P. Mercier, P. Beaudry, L. Annable,
NH2
SM
NH2
G. Chouinard, Acta psychiatr. scand., 1986, 74, 451-458. (c) P.
K. Sorensen, P. Holm, C. Fynboe, E. Schaumburg, B. Andersen,
P. Bech, J. Pichard, Psychopharmacology, 1990, 100, 383-386.
CO2Me
Me
CO2Me
Me
H2O2
H+
O2
6. (a) H. R. Keller, X. Zhang, L. Li, H. Schaider, J. W. Wells,
Oncotarget, 2017, 8, 75675-75686. (b) P. Cheng, M. P.
Levesque, R. Dummer, J. Mangana, Cancer Treat. Rev., 2020,
SM
X
P
8
6, 101997-102003. (c) P. Tétu, B. Baroudjian, C. Lebbe, Curr.
Opin.
Oncol.,
2020,
32,
Figure 4 Proposed mechanism.
DOI:10.1097/CCO.0000000000000614.
7
. (a) S. A. Wells Jr, J. E. Gosnell, R. F. Gagel, J. Moley, D. Pfister,
J. A. Sosa, M. Skinner, A. Krebs, J. Vasselli, M. Schlumberger, J.
Clin., Oncol., 2010, 28, 767-772. (b) R. B. Natale, S.
Thongprasert, F. A. Greco, M. Thomas, C. -M. Tsai, P.
Sunpaweravong, D. Ferry, C. Mulatero, R. Whorf, J. Thomp-
son, F Barlesi, P. Langmuir, S. Gogov, J. A. Rowbottom, G. D.
Goss, J. Clin., Oncol., 2011, 29, 1059-1066. (c) M. Gao, C. M.
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Robinson, R. F. Gagel, H. Dralle, J. A. Fagin, Ma. Santoro, E.
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A. J. Ryan, M. J. Schlumberger, J. Clin., Oncol., 2012, 30, 134-
Conclusions
In summary, an easily-handled method for constructing
hetero)arenes bromide and iodide have been developed at room
(
temprature and normal pressure under blue light, employing
abundant halide anions in water as halide source, air as oxidant. This
strategy provided green methodology for constructing important
phamaceutical intermediates and modifing valuable molecules.
Gram-scale reactions proved its practicability. Further explorations
of industrial applications via this protocol are underway in our
laboratory.
1
41. (e) K. L. Brocklesby, J. S. Waby, C. Cawthorne, G. Smith.
Tetrahedron Lett., 2017, 58, 1467-1469.
8
9
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M. Delvita, Respiration, 1991, 58, 117-121. (b) K Felixl, M.
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General Procedure
In a 25 mL Schlenk tube, 1 (0.2 mmol, 1.0 equiv.), NaBr (0.3 mmol,
1
.5 equiv.), NaHSO
4
.H
2
O (0.4 mmol, 3.5 equiv.), H
2
O (72.0 mg, 20.0
CN (2.0 mL), and the reaction mixture
equiv.) were added into CH
3
was stirred at room temperature irradiated with 2*3 W blue LEDs,
which is opened to air. After the reaction completed, the reaction
mixture was neutralized with saturated sodium bicarbonate and
4
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