Visible-light-mediated radical cascade reaction: Synthesis of 3-bromocoumarins from alkynoates

Article abstract of DOI:10.1039/c7ob02199b

A visible-light-mediated radical addition of alkynoates to generate 3-bromocoumarins by using N-bromosuccinimide as the bromo source has been accomplished. This procedure provides a bromo radical addition/spirocyclization/ester migration cascade reaction

Full text of DOI:10.1039/c7ob02199b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Feng, J. Li, Z.
Liu, H. Sun, H. Shi, X. Wang, X. Xie and X. G. She, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB02199B.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 7
View Article Online
DOI: 10.1039/C7OB02199B
Journal Name
ARTICLE
Visible-light-mediated radical cascade reaction: synthesis of 3-
bromocoumarins from alkynoates
Received 00th January 20xx,
Accepted 00th January 20xx
Shangbiao Feng,a Jinlai Li,a Zaimin Liu,a Haiyu Sun,a Hongliang Shi,a Xiaolei Wang,a Xingang Xie,a
and Xuegong She*,a,b
DOI: 10.1039/x0xx00000x
A visible-light-mediated radical addition of alkynoates to generate 3-bromocoumarins by using of N-bromosuccinimide as
the bromo source has been accomplished. This procedure provides a bromo radical addition/spirocyclization/ester
migration cascade reaction under very mild reaction conditions without using of any catalyst or strong oxidant and does
not need high reaction temperature. Furthermore, the reaction can also be enlarged to gram scale, and the product 3-
www.rsc.org/
bromocoumarins can be further applied in the synthesis of complex compounds.
.
Introduction
The bromo group has undoubtedly occupied a unique position
in organic chemistry, as shown by its wide applications in
elaborating into other versatile building blocks through
transitional metal catalyzed coupling reactions, like Heck,1
Suzuki2 and Negishi,3 and it also presents in many natural
products.4 Therefore, extensive efforts for constructing
carbon-bromo bond have been pursued by chemists.5 The
direct bromination using bromine has a rich history, however,
it’s toxic, hazardous and less selective.6 Transition metal
catalyzed carbon–bromo bond formation is one of the most
research in this field. Nevertheless, an initial organic halide7 or
sterically hindered ligands8 are required in such
transformations. Thus, it is still in great demand to develop an
environmentally friendly, maneuverable strategy to construct
carbon-bromo bond.
Over the past few years, visible-light mediated photoredox
catalysis has emerged as a powerful synthetic tool in organic
synthesis.9 For its intrinsic characteristics of sustainability and
green chemistry, the direct bromination via photoredox
catalysis ever-grow interest from chemists.10 On the other
hand, readily available alkynoates have become fascinating
Scheme 1 Functionalization of alkynoates with bromo radical.
and powerful intermediates in organic synthesis for they are reasons, some groups have tried bromination to alkynoates. In
good radical receptors and often along with a cascade 2016, Pan's group demonstrated a novel bromination initiated
cyclization reaction to construct 3-functionalized coumarins,11 decarboxylation and trifunctioalization of alkynoate (Scheme
which have many pharmacological activities and widely found 1a).13 Ding's group also reported an elegant work on a radical
in the structures of natural or unnatural products.12 For these
brominative addition of alkynoates, oxidative spirocyclization
and 1,2-migration of esters for the synthesis of 3-
bromocoumarins (Scheme 1b).14 However, these reported
reactions needed high reaction temperatures (160 or 90°C) or
strong oxidant to generate the bromo radical which highly
limited their applications in complex molecule synthesis and
large scale preparation. Enlightened and encouraged by these
brilliant works and aiming to synthesize coumarins under mild
reaction conditions, herein we report a visible-light-mediated
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 7
ARTICLE
Journal Name
Table 2
Reaction scope of alkynoates[a]
bromo radical addition / spirocyclization / ester migration
cascade reaction to generate 3-bromocoumarins by using of N-
bromosuccinimide as the bromo source under very mild
reaction conditions without using photocatalyst or strong
oxidant and the reaction can also be enlarged to gram scale.
View Article Online
DOI: 10.1039/C7OB02199B
Results and discussion
Initially, the reaction between tolyl alkynoate 1a and NBS
2
was investigated. Using an 18 W blue LED strip as the visible
light source, MeCN as solvent, this reaction was performed at
room temperature in the air for 18 h. We were gratified to find
that the desired 3-bromocoumarin 3a was produced without
using photocatalyst , although only in 11% isolated yield (Table
1, entry 1). After screening of solvents, we were delight to find
that the reaction was implemented well in ethers solvent, and
THF proved to be optimal (Table 1, entries 2–7). Changing light
source into an 18 W fluorescent lamp, gave no better result
(Table 1, entry 8). Furthermore, when the reaction was
performed under argon atmosphere, it could give a better
yield than in the air (Table 1, entry 9). Subsequently, the yield
of 3a could be further increased to 72% when we increased
the amount of
2 to 3.0 equiv (Table 1, entry 10) and reduced 2
to 1.5 equiv led a lower yield (Table 1, entry 11). Finally, the
control experiment proved that the yield of 3a decreased
significantly and had low conversion even prolonged reaction
time to 48 h in the absence of light (Table 1, entry 12).
Table 1 Optimization of the reaction conditions[a]
[a] Reaction conditions:
1
(0.2 mmol),
2
(3.0 equiv), THF (2.0
mL), 18 W blue LED strip, at room temperature under argon
for 18-20 h. [b] Isolated yields. [c] The desired 3l was not
detected.
Entry
1
NBS (equiv)
Solvent
CH3CN
DCM
Yield b (%)
donating groups, such as Me, Et, i-Pr, and t-Bu on the para-
position of phenyl rings reacted with N-bromosuccinimide 2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
1.5
3.0
11
9
generating the corresponding 3-bromocoumarins (3a−e) in
moderate yields (63−75%). If there was a strong electron-
donating substituent (MeO), the yield would decrease to 52%.
The electron-withdrawing groups (F, Cl, Br and I) could also be
well tolerated, giving the desired coumarins (3g–j) in 51–59%
yields. To investigate the regioselectivity of the cyclization, a
meta-substituted substrate 1k was investigated and a mixture
of two regioisomers 3k and 3k' were obtained in 70% total
yield with a ratio of 1.12 : 1, respectively. However, the
reaction became complex when 1l was evaluated and the
desired product 3l was not detected, which could be
attributed to the steric hindrance of the ortho-substituent. On
the other hand, some R2-substituted alkynoates were also
2
3
DMSO
DMF
n.r.
trace
51
4
5
1,4-dioxane
DME
6
43
7
THF
63
8c
THF
41
9d
THF
68
10d
11d
12d,e
THF
72
THF
44
THF
< 5
[a] Reaction conditions: tolyl alkynoate
(
1a
,
0.2 mmol),
solvent (2.0 mL) at room temperature in the air for 18 h. [b]
Isolated yield. [c] A 18 W Fluorescent lamp was used. [d]
Under argon atmosphere. [e] Without visible light irradiation.
evaluated. All of them (1m
reposefully and gave the corresponding products (3m
−
p
) underwent the desired reaction
) in
–p
65–70% yields regardless of electron-donating or -withdrawing
groups. Moreover, when R2 was a 3-thienyl group 1q, it was
also found to be suitable for the transformation with a
moderate yield (3q, 50%). Furthermore, aliphatic substrate,
with a cyclopropane group at the alkyne site 1r was tested
under the standard conditions. We were gratified to get the
desired product 3r in acceptable yield.
To examine the substrate scope and limitations of this
approach, various alkynoates were prepared and reacted with
2
under the optimized reaction conditions (Table 2). Some
representative R1-substituted alkynoates were first evaluated
under the standard reaction conditions. When electron-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 7
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C7OB02199B
Scheme 4 Mechanism study.
Scheme 2 Distinctive reaction of substrate 1s
.
significant promoting effects of natural killer cell (a class of
lymphocytes which have spontaneous cytotoxic activity)
activity, and hold potential as immunomodulating agents
(Scheme 3b).16 Our strategy began with visible-light-mediated
An interesting discovery should be noted that substrate 1s
with a naphthyl group was also evaluated under the standard
reaction conditions. The desired product 3s was obtained in 32%
yield and a distinctive spirocyclization product 3s' was also
observed in moderate yield (scheme 2). This result was caused
by the bromo radical captured spirocyclization intermediate
again and it also provided us with a glimpse into the reaction
mechanism.
bromination and cyclization of
reaction, to give 3,4-biphenyl coumarin derivative
6
followed by Suzuki coupling
and the
8
synthesis of compounds 9a-9e should be possible followed by
three steps as published in the literature.17
In order to gain an insight into this transformation, we
conducted radical inhibition experiment for the mechanistic
study. When 3.0 equiv well-known radical scavenger 2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was added under the
standard conditions, the reaction was obviously inhibited
(Scheme 4), and this result indicates that the transformation
may proceed via a radical pathway.
On the basis of the above-mentioned experimental
observations and previous literatures,11 a plausible mechanism
for this cascade reaction is depicted in Scheme 5. First, the
bromo radical is generated from NBS through irradiation by
the blue LED. In this process, THF may form halogen bonding
adduct with NBS and facilitate the N-Br bond cleavage.18 Then
this bromo radical undergoes intermolecular selective addition
To demonstrate the synthetic potential of this reaction, we
enlarged 1a to 1.058 g scale. To our delight, decreasing the
amount of NBS to 2.0 equiv did not affect this transformation
and 3a was obtained in 70% isolated yield. We also wanted to
demonstrate further applications of these derivatives
3 in the
synthesis. Suzuki coupling reaction of 3a with 4-
Methylphenylboronic acid 4a catalyzed by Pd(OAc)2 and PCy3
afforded the corresponding 3-tolylcoumarin 5a in 92% yield
(Scheme 3a).15 For the 3-aminocoumarin core is a ubiquitous
subunit in many natural products with great biological
activities,17 Buchwald-Hartwig amination of 3a with p-anisidine
in the presence of Pd2(dba)3 and Xantphos provided the 3-
aminocoumarin 5b in 69% yield (Scheme 3a).15 we next sought
to demonstrate the utility of this method in rapid syntheses of
to the
intermediate
spirocyclization to provide intermediate
undergoes cleavage of the C–O bond to generate the carboxyl
radical , which can cyclize to form compound . The
abstraction a H-atom of by succinimide radical would give
the product . If 1s is employed to this transformation, for the
benzyl radical is stable, intermediate can provide by
spirocyclization, and intermediate is captured by another
bromo radical to form 3s'

-position of the C=O bond in alkynoate
which goes through intramolecular
. Subsequently, it
1 leads to vinyl
the 3,4-biphenyl coumarin derivatives 9a-9e, which had
A
,
B
C
D
D
F
3
A
E
E
.
Scheme 3 Applications of this method in synthesis.
Scheme 5 Possible reaction mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 7
ARTICLE
Journal Name
Compound 3a was obtained as a white solid in 72% yield
according to the general procedure. Mp: 191−193°C . H NMR
Conclusions
View Article Online
1
DOI: 10.1039/C7OB02199B
In summary, we have demonstrated a new approach for the
synthesis of the pharmacological activity attractive coumarins
core structure in moderate to good yields under catalyst and
strong oxidant free conditions. And it can also be enlarged to
gram scale, the product 3-bromocoumarins can be further
applied in the synthesis.
(400 MHz, CDCl3) δ 7.59 – 7.49 (m, 3H), 7.32 – 7.27 (m, 2H),
7.20 (s, 1H), 6.98 (dt, J = 18.7, 4.5 Hz, 2H), 2.43 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 157.6, 154.6, 152.5, 143.5, 135.4, 129.2,
128.8, 128.0, 127.3, 125.9, 117.9, 116.9, 111.2, 21.6. HRMS
(ESI): m/z [M+H]+ calculated for C16H12BrO2: 315.0015, found:
315.0014.
3-bromo-7-ethyl-4-phenyl-2H-chromen-2-one (3b).
Compound 3b was obtained as a white solid in 75% yield
according to the general procedure. Mp: 157−158°C . 1H NMR
(400 MHz, CDCl3) δ 7.61 – 7.49 (m, 3H), 7.32 – 7.27 (m, 2H),
7.23 (s, 1H), 7.01 (dt, J = 19.1, 4.8 Hz, 2H), 2.73 (q, J = 7.6 Hz,
2H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 157.6,
154.6, 152.6, 149.7, 135.4, 129.2, 128.8, 128.1, 127.4, 124.7,
118.1, 115.7, 111.3, 28.8, 15.0. HRMS (ESI): m/z [M+H]+
calculated for C17H14BrO2: 329.0172, found: 329.0171.
3-bromo-7-isopropyl-4-phenyl-2H-chromen-2-one (3c).
Compound 3c was obtained as a white solid in 71% yield
according to the general procedure. Mp: 118−120°C . 1H NMR
(400 MHz, CDCl3) δ 7.61 – 7.49 (m, 3H), 7.33 – 7.27 (m, 2H),
7.26 (s, 1H), 7.06 (dd, J = 8.3, 1.5 Hz, 1H), 6.99 (d, J = 8.3 Hz,
1H), 2.99 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H). 13C NMR
(100 MHz, CDCl3) δ 157.6, 154.6, 154.4, 152.7, 135.5, 129.2,
128.8, 128.1, 127.5, 123.4, 118.3, 114.4, 111.3, 34.2, 23.5.
HRMS (ESI): m/z [M+H]+ calculated for C18H16BrO2: 343.0328,
found: 343.0326.
Experimental section
General information.
Solvents were purified and dried by standard methods prior to
use. All commercially available reagents were used without
further purification unless otherwise noted. All syntheses of
complex were carried out under argon atmosphere on Wattecs
Parallel Reactor. Column chromatography was generally
performed on silica gel (200-300 mesh) and reactions were
monitored by thin layer chromatography (TLC) using silica gel
GF254 plates with UV light to visualize the course of reaction.
Melting points were determined with
a digital Koffer
apparatus and were uncorrected after recrystallized with
petroleum ether and ethyl acetate. 1H and 13C NMR data were
recorded on a 400 MHz or 300 MHz spectrometer using CDCl3
as solvent at room temperature. The chemical shifts (δ) are
reported in ppm and coupling constants (J) in Hz. High-
resolution mass spectra (HRMS) were obtained on a FT-ICR
spectrometer.
General procedure for the visible-light-promoted cascade
reaction.
To a reaction tube equipped with a magnetic stir bar was
3-bromo-7-(tert-butyl)-4-phenyl-2H-chromen-2-one (3d).
Compound 3d was obtained as ropy oil in 68% yield according
to the general procedure. 1H NMR (400 MHz, CDCl3) δ 7.59 –
7.50 (m, 3H), 7.41 (d, J = 1.8 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.22
(dd, J = 8.5, 1.9 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 1.34 (s, 9H). 13
C
added phenyl 3-phenylpropiolate
1 (0.2 mmol, 1.0 equiv), NBS
2
(N-bromosuccinimide, 0.6 mmol, 3.0 equiv). The reaction
NMR (100 MHz, CDCl3) δ 157.7, 156.7, 154.5, 152.5, 135.4,
129.3, 128.8, 128.1, 127.1, 122.2, 117.9, 113.6, 111.5, 35.3,
31.0. HRMS (ESI): m/z [M+H]+ calculated for C19H18BrO2:
357.0485, found: 357.0484.
tube was then filled with dry argon. After that, THF (2.0 mL)
was injected into the tube via a syringe. Then the reaction was
irradiated with an 18 W blue LED strip and stirred at room
temperature from 18-20 h. The reaction was monitored by TLC
to establish the consumption of starting material. After it was
complete, the reaction mixture was concentrated under
reduced pressure to give a residue which was purified by silica
gel column chromatography to afford the desired coumarin
product.
3-bromo-4-phenyl-2H-chromen-2-one (3e).
Compound 3e was obtained as a white solid in 63% yield
1
according to the general procedure. Mp: 154−155°C . H NMR
(400 MHz, CDCl3) δ 7.61 – 7.51 (m, 4H), 7.41 (dd, J = 8.3, 0.8 Hz,
1H), 7.33 – 7.28 (m, 2H), 7.22 – 7.16 (m, 1H), 7.08 (dd, J = 8.0,
1.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.34, 154.62,
152.48, 135.29, 132.02, 129.34, 128.85, 128.07, 127.60, 124.69,
120.35, 116.82, 112.65. HRMS (ESI): m/z [M+H]+ calculated for
C15H10BrO2: 300.9859, found: 300.9863.
3-bromo-7-methoxy-4-phenyl-2H-chromen-2-one (3f).
Compound 3f was obtained as a white solid in 52% yield
according to the general procedure. Mp: 153−155°C . 1H NMR
(400 MHz, CDCl3) δ 7.59 – 7.49 (m, 3H), 7.31 – 7.27 (m, 2H),
6.97 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.9,
2.5 Hz, 1H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.9,
157.8, 154.8, 154.3, 135.6, 129.3, 128.8, 128.6, 128.1, 114.0,
112.9, 108.8, 100.6, 55.9. HRMS (ESI): m/z [M+H]+ calculated
for C16H12BrO3: 330.9964, found: 330.9963.
Gram Scale Preparation of 3a.
To a reaction tube equipped with a magnetic stir bar was
added tolyl alkynoate 1a (1.058 g, 4.483 mmol, 1.0 equiv), NBS
2
(N-bromosuccinimide, 1.596 g, 8.966 mmol, 2.0 equiv). The
reaction tube was then filled with dry argon. After that, THF
(15.0 mL) was injected into the tube via a syringe. Then the
reaction was irradiated with an 18 W blue LED strip and stirred
at room temperature for 24 h. After it was complete, the
reaction mixture was concentrated under reduced pressure to
give a residue which was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 50:1 to 20:1)
to afford the desired 3a in 70% yield (0.933 g).
3-bromo-7-fluoro-4-phenyl-2H-chromen-2-one (3g).
3-bromo-7-methyl-4-phenyl-2H-chromen-2-one (3a).
Compound 3g was obtained as a white solid in 52% yield
according to the general procedure. Mp: 206−207°C . 1H NMR
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 7
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
(400 MHz, CDCl3) δ 7.61 – 7.52 (m, 3H), 7.32 – 7.27 (m, 2H), 7.37 (d, J = 7.9 Hz, 2H), 7.22 –7.10 (m, 4H), 2.4V7iew(sA,rt3icHle )O.n1li3ne
C
7.10 (ddd, J = 14.9, 8.8, 4.2 Hz, 2H), 6.92 (ddd, J = 8.9, 8.1, 2.5 NMR (100 MHz, CDCl3) δ 157.4, 154.8,DO15I:210.5.1,03193/9C.74O,B0123129.93B,
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ (165.67, 163.13, d, J = 254 131.9, 129.5, 128.1, 127.7, 124.6, 120.5, 116.8, 112.6, 21.4.
Hz), 157.01, 154.15, (153.55, 153.42, d, J = 13 Hz), 135.10, HRMS (ESI): m/z [M+H]+ calculated for C16H12BrO2: 315.0015,
129.52, (129.43, 129.33, d, J = 10 Hz), 128.96, 127.99, (117.15, found: 315.0017.
117.12, d, J = 3 Hz), (112.93, 112.70, d, J = 23 Hz), (111.42, 3-bromo-7-(tert-butyl)-4-(p-tolyl)-2H-chromen-2-one (3n).
111.39, d, J = 3 Hz), (104.49, 104.23, d, J = 26 Hz). HRMS (ESI): Compound 3n was obtained as ropy oil in 65% yield according
1
m/z [M+NH4]+ calculated for C15H12BrFNO2: 336.0030, found: to the general procedure. H NMR (400 MHz, CDCl3) δ 7.40 (d,
336.0031.
J = 1.8 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.24 – 7.16 (m, 3H), 7.04
3-bromo-7-chloro-4-phenyl-2H-chromen-2-one (3h).
(d, J = 8.5 Hz, 1H), 2.47 (s, 3H), 1.34 (s, 9H). 13C NMR (100 MHz,
Compound 3h was obtained as a white solid in 59% yield CDCl3) δ 157.7, 156.6, 154.7, 152.5, 139.3, 132.4, 129.4, 128.0,
according to the general procedure. Mp: 204−205°C . 1H NMR 127.2, 122.1, 118.0, 113.5, 111.4, 35.2, 30.9, 21.4. HRMS (ESI):
(400 MHz, CDCl3) δ 7.61 – 7.52 (m, 3H), 7.42 (d, J = 1.9 Hz, 1H), m/z [M+H]+ calculated for C20H20BrO2:371.0641, found:
7.31 – 7.27 (m, 2H), 7.16 (dd, J = 8.6, 1.9 Hz, 1H), 7.01 (d, J = 371.0651.
8.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 156.7, 154.0, 152.6, 3-bromo-7-(tert-butyl)-4-(4-methoxyphenyl)-2H-chromen-2-
138.0, 134.9, 129.6, 129.0, 128.5, 128.0, 125.3, 119.0, 117.1, one (3o).
112.6. HRMS (ESI): m/z [M+H]+ calculated for C15H9BrClO2: Compound 3o was obtained as ropy oil in 66% yield according
334.9469, found: 334.9468.
3,7-dibromo-4-phenyl-2H-chromen-2-one (3i).
to the general procedure. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J
= 1.8 Hz, 1H), 7.28 – 7.21 (m, 3H), 7.11 – 7.04 (m, 3H), 3.91 (s,
Compound 3i was obtained as a white solid in 51% yield 3H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 160.2, 157.8,
according to the general procedure. Mp: 204−206°C . 1H NMR 156.6, 154.4, 152.5, 129.7, 127.5, 127.2, 122.2, 118.1, 114.1,
(400 MHz, CDCl3) δ 7.62 – 7.52 (m, 4H), 7.33 – 7.27 (m, 3H), 113.6, 111.6, 55.4, 35.2, 30.9. HRMS (ESI): m/z [M+H]+
6.94 (d, J = 8.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 156.7, calculated for C20H20BrO3: 387.0590, found: 387.0592.
154.0, 152.5, 134.8, 129.6, 129.0, 128.6, 128.1, 128.0, 126.0, 3-bromo-7-(tert-butyl)-4-(4-chlorophenyl)-2H-chromen-2-one
120.0, 119.3, 112.8. HRMS (ESI): m/z [M+H]+ calculated for (3p).
C15H9Br2O2: 378.8964, found: 378.378.8962.
3-bromo-7-iodo-4-phenyl-2H-chromen-2-one (3j).
Compound 3p was obtained as a white solid in 68% yield
according to the general procedure. Mp: 195−196°C . 1H NMR
Compound 3j was obtained as a white solid in 52% yield (400 MHz, CDCl3) δ 7.57 – 7.52 (m, 2H), 7.41 (d, J = 1.8 Hz, 1H),
according to the general procedure. Mp: 204−206°C . 1H NMR 7.28 – 7.22 (m, 3H), 6.98 (d, J = 8.5 Hz, 1H), 1.34 (s, 9H). 13
C
(400 MHz, CDCl3) δ 7.78 (d, J = 1.6 Hz, 1H), 7.60 – 7.54 (m, 3H), NMR (100 MHz, CDCl3) δ 157.4, 157.0, 153.3, 152.5, 135.5,
7.51 (dd, J = 8.4, 1.6 Hz, 1H), 7.30 – 7.26 (m, 2H), 6.77 (d, J = 133.7, 129.6, 129.2, 126.8, 122.4, 117.6, 113.7, 111.7, 35.3,
8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 156.5, 154.1, 152.2, 30.9. HRMS (ESI): m/z [M+H]+ calculated for C19H17BrClO2:
134.8, 134.0, 129.6, 129.0, 128.5, 128.0, 125.9, 119.9, 113.1, 391.0095, found: 391.0094.
97.5. HRMS (ESI): m/z [M+H]+ calculated for C15H9BrIO2: 3-bromo-7-(tert-butyl)-4-(thiophen-3-yl)-2H-chromen-2-one
462.8825, found: 462.8837.
(3q).
3-bromo-6,7-dimethyl-4-phenyl-2H-chromen-2-one (3k).
Compound 3q was obtained as a white solid in 50% yield
Compound 3k was obtained as a white solid in 37% yield according to the general procedure. Mp: 98−100°C . 1H NMR
according to the general procedure. Mp: 181−183°C . 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 5.0, 3.0 Hz, 1H), 7.45 (dd, J =
(400 MHz, CDCl3) δ 7.60 – 7.51 (m, 3H), 7.31 – 7.27 (m, 2H), 2.9, 1.2 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.27 – 7.24 (m, 2H),
7.18 (s, 1H), 6.77 (s, 1H), 2.33 (s, 3H), 2.18 (s, 3H). 13C NMR 7.19 (s, 1H), 7.18 – 7.14 (m, 1H), 1.34 (s, 9H). 13C NMR (100
(100 MHz, CDCl3) δ 157.8, 154.6, 150.9, 142.3, 135.6, 133.6, MHz, CDCl3) δ 157.6, 156.8, 152.4, 150.3, 134.8, 127.8, 126.9,
129.2, 128.8, 128.1, 127.5, 118.1, 117.3, 111.3, 20.2, 19.3. 126.5, 126.0, 122.3, 117.8, 113.6, 111.8, 35.3, 31.0. HRMS (ESI):
HRMS (ESI): m/z [M+H]+ calculated for C17H14BrO2: 329.0172, m/z [M+H]+ calculated for C17H16BrO2S: 363.0049, found:
found: 329.0171.
363.0048.
3-bromo-7,8-dimethyl-4-phenyl-2H-chromen-2-one (3k’).
3-bromo-7-(tert-butyl)-4-cyclopropyl-2H-chromen-2-one (3r).
Compound 3k’ was obtained as a white solid in 33% yield Compound 3r was obtained as ropy oil in 66% yield according
according to the general procedure. Mp: 186−189°C . 1H NMR to the general procedure. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J
(400 MHz, CDCl3) δ 7.58 – 7.48 (m, 3H), 7.30 – 7.26 (m, 2H), = 8.4 Hz, 1H), 7.39 – 7.31 (m, 2H), 1.89 (tt, J = 8.6, 5.9 Hz, 1H),
6.98 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 2.43 (s, 3H), 1.35 (s, 9H), 1.34 – 1.31 (m, 2H), 0.93 – 0.86 (m, 2H). 13C NMR
2.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.8, 155.1, 150.8, (100 MHz, CDCl3) δ 157.8, 156.2, 153.5, 152.0, 125.1, 121.9,
142.0, 135.8, 129.1, 128.7, 128.1, 126.1, 124.7, 124.5, 118.3, 118.2, 114.5, 113.6, 35.2, 31.0, 14.4, 9.3. HRMS (ESI): m/z
111.0, 20.4, 11.6. HRMS (ESI): m/z [M+H]+ calculated for [M+H]+ calculated for C16H18BrO2: 321.0485, found: 321.0487.
C17H14BrO2: 329.0172, found: 329.0174.
3-bromo-4-phenyl-2H-benzo[g]chromen-2-one (3s).
3-bromo-4-(p-tolyl)-2H-chromen-2-one (3m).
Compound 3s was obtained as a white solid in 32% yield
Compound 3m was obtained as a white solid in 70% yield according to the general procedure. Mp: 183−186°C . 1H NMR
according to the general procedure. Mp: 161−164°C . 1H NMR (400 MHz, CDCl3) δ 8.66 – 8.60 (m, 1H), 7.89 – 7.81 (m, 1H),
(400 MHz, CDCl3) δ 7.59 – 7.52 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.71 – 7.64 (m, 2H), 7.61 – 7.55 (m, 4H), 7.40 – 7.31 (m, 2H),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 7
ARTICLE
Journal Name
7.06 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.6, (75 MHz, CDCl3) δ 160.2, 157.4, 154.5, 152.4, 131.9, 129.7,
View Article Online
DOI: 10.1039/C7OB02199B
155.5, 149.7, 135.7, 134.8, 129.3, 129.1, 128.9, 128.1, 127.8, 127.7, 127.2, 124.6, 120.5, 116.7, 114.1, 112.7, 55.3. HRMS
127.5, 124.6, 122.9, 122.5, 115.6, 112.1, 100.0. HRMS (ESI): (ESI): m/z [M+H]+ calculated for C16H12BrO3: 330.9964, found:
m/z [M+H]+ calculated for C19H12BrO2: 351.0015, found: 330.9966.
351.0017.
1',4-dibromo-3-phenyl-1'H,5H-spiro[furan-2,2'-naphthalen]-5- K2HPO4 3H2O (0.90 mmol, 3.0 equiv) was added to a mixture of
one (3s’). compound (66.0 mg, 0.2 mmol, 1.0 equiv), phenylboronic
4-(4-methoxyphenyl)-3-phenyl-2H-chromen-2-one (8).

7
Compound 3s’ was obtained as a white solid in 50% yield acid (36.6 mg, 0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5.0
according to the general procedure. Mp: 182−185°C . 1H NMR mol %), and PCy3 (5.6 mg, 10.0 mol %) in methanol (2.0 mL).
(400 MHz, CDCl3) δ 7.68 – 7.63 (m, 2H), 7.60 – 7.56 (m, 1H), The reaction mixture was stirred at 60°C for 1 h. After
7.45 – 7.39 (m, 3H), 7.29 – 7.26 (m, 2H), 7.16 – 7.11 (m, 1H), completion of the reaction as indicated by TLC, the mixture
6.93 (d, J = 9.5 Hz, 1H), 6.09 (d, J = 9.5 Hz, 1H), 5.36 (s, 1H). 13
C
was cooled to room temperature and purified directly by flash
NMR (100 MHz, CDCl3) δ 166.7, 161.9, 134.1, 132.0, 130.7, column chromatography on silica gel (petroleum ether/ethyl
130.2, 129.5, 129.4, 129.2, 128.9, 128.8, 128.5, 127.7, 121.8, acetate = 10:1 to 5:1) to afford the product as a faint yellow
112.1, 87.6, 53.4. HRMS (ESI): m/z [M+H]+ calculated for solid in 90% yield (59.0 mg). Mp: 226−228°C . 1H NMR (300
8
C19H13Br2O2: 430.9277, found: 430.9270.
MHz, CDCl3) δ 7.52 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.41 (dd, J =
8.3, 0.9 Hz, 1H), 7.32 – 7.25 (m, 1H), 7.24 – 7.11 (m, 6H), 7.08 –
7-methyl-4-phenyl-3-(p-tolyl)-2H-chromen-2-one (5a).
K2HPO4 3H2O (0.90 mmol, 3.0 equiv) was added to a mixture of 7.00 (m, 2H), 6.87 – 6.79 (m, 2H), 3.78 (s, 3H). 13C NMR (75
compound 3a (63.0 mg, 0.2 mmol, 1.0 equiv), 4- MHz, CDCl3) δ 161.3, 159.4, 153.2, 151.4, 134.1, 131.3, 130.77,

Methylphenylboronic acid
4 (41.0 mg, 0.3 mmol, 1.5 equiv), 130.5, 127.8, 127.7, 127.5, 126.8, 126.5, 124.0, 120.7, 116.7,
Pd(OAc)2 (2.2 mg, 5.0 mol %), and PCy3 (5.6 mg, 10.0 mol %) in 113.7, 55.1. HRMS (ESI): m/z [M+H]+ calculated for C22H17O3:
methanol (2.0 mL). The reaction mixture was stirred at 60°C 329.1172, found: 329.1173.
for 1 h. After completion of the reaction as indicated by TLC,
the mixture was cooled to room temperature and purified
directly by flash column chromatography on silica gel
Conflicts of interest
(petroleum ether/ethyl acetate = 10:1 to 5:1) to afford the
product 5a as a white solid in 92% yield (60.0 mg). Mp:
232−234°C . 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m, 3H),
7.22 (s, 1H), 7.14 – 7.09 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 7.04 –
6.95 (m, 5H), 2.45 (s, 3H), 2.25 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 161.7, 153.2, 151.3, 142.5, 137.2, 134.9, 131.0, 130.4,
129.4, 128.5, 128.2, 128.1, 127.4, 125.9, 125.2, 118.2, 116.9,
21.6, 21.2. HRMS (ESI): m/z [M+H]+ calculated for C23H19O2:
327.1380, found: 327.1381.
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Science Foundation
of China (21125207, 21372103, 21472079 and 21572088),
PCSIRT (IRT_15R28) and the Fundamental Research Funds for
the Central Universities (lzujbky-2016-ct02).
3-((4-methoxyphenyl)amino)-7-methyl-4-phenyl-2H-
chromen-2-one (5b).
A mixture of compound 3a (63.0 mg, 0.2 mmol, 1.0 equiv), p-
anisidine 4b (29.5 mg, 0.24 mmol, 1.2 equiv), Pd2(dba)3 (4.6 mg,
2.5 mol %), Xantphos (5.8 mg, 5 mol %), and K2CO3 (55.2 mg,
0.4 mmol, 2.0 equiv) in toluene (2.0 mL) was stirred at 80°C for
18 h. After completion of the reaction as indicated by TLC, the
mixture was cooled to room temperature and purified directly
by flash column chromatography on silica gel (petroleum
ether/ethyl acetate = 20:1 to 10:1) to afford the product 5b as
a yellow solid in 69% yield (49.0 mg). Mp: 148−150°C . 1H NMR
(400 MHz, CDCl3) δ 7.28 – 7.21 (m, 3H), 7.20 – 7.14 (m, 3H),
7.05 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.8
Hz, 2H), 6.56 – 6.48 (m, 2H), 6.04 (s, 1H), 3.68 (s, 3H), 2.42 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 160.5, 155.4, 149.6, 138.7,
134.7, 133.4, 129.4, 128.4, 128.1, 126.4, 125.5, 124.9, 122.7,
119.1, 116.6, 113.6, 55.5, 21.3. HRMS (ESI): m/z [M+H]+
calculated for C23H20NO3: 358.1438, found: 358.1439.
Notes and references
1
2
3
4
(a) R. F. Heck, Acc. Chem. Res., 1979, 12, 146; (b) R. F. Heck,
Org. React., 1982, 27, 345.
(a) A. Suzuki, Acc. Chem. Res., 1982, 15, 178; (b) N. Miyaura
and A. Suzuki, Chem. Rev., 1995, 95, 2457.
(a) E. Negishi, Acc. Chem. Res., 1982, 15, 340; (b) E. Negishi,
and L. Anastasia, Chem. Rev., 2003, 103, 1979.
(a) C. S. Neumann, D. G. Fujimori and C. T. Walsh, Chem. Biol.,
2008, 15, 99; (b) P. M. Pauletti, L. S. Cintra, C. G. Braguine, A.
A. D. S. Filho, M. L. A. E. Silva, W. R. Cunha and A. H. Januário,
Mar. Drugs, 2010,
2013, 11, 1370.
8, 1526; (c) K. Benkendorff, Mar. Drugs,
5
For selected reviews, see: (a) P. S. Skell and J. G. Traynham,
Acc. Chem. Res., 1984, 15, 160; (b) M. F. Ruass, Acc. Chem.
Res., 1990, 23, 87; (c) C. J. Easton and C. A. Hutton, Synlett,
1998, 457; (d) W. Liu and J. T. Groves, Acc. Chem. Res., 2015,
48, 1727.
6
7
P. B. De la Mare, Electrophilic Halogenation, Cambridge
University Press, Cambridge, 1997, Chapter 5.
3-bromo-4-(4-methoxyphenyl)-2H-chromen-2-one (7).
(a) T. D. Sheppard, Org. Biomol. Chem., 2009, 7, 1043; (b) H.
Compound
7 was obtained as a white solid in 65% yield
Kuniyasu, A. Sanagawa, D. Nakane, T. Iwasaki, N. Kambe, K.
1
according to the general procedure. Mp: 154−156°C . H NMR
(300 MHz, CDCl3) δ 7.60 – 7.52 (m, 1H), 7.43 – 7.36 (m, 1H),
7.29 – 7.14 (m, 4H), 7.12 – 7.05 (m, 2H), 3.91 (s, 3H). 13C NMR
Bobuatong, Y. Lu and M. Ehara, Organometallics, 2013, 32
,
2026.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 7
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
8
9
(a) R. D. Grigg, R. Van Hoveln and J. M. Schomaker, J. Am.
View Article Online
DOI: 10.1039/C7OB02199B
Chem. Soc., 2012, 134, 16131; (b) R. Van Hoveln, B. M.
Hudson, H. B. Wedler, D. M. Bates, G. Le Gros, D. J. Tantillo
and J. M. Schomaker, J. Am. Chem. Soc., 2015, 137, 5346; (c)
C. M. Le, P. J. C. Menzies, D. A. Petrone and M. Lautens,
Angew. Chem., Int. Ed., 2015, 54, 254.
For partial reviews, see: (a) J. M. R. Narayanam and C. R. J.
Stephenson, Chem. Soc. Rev., 2011, 40, 102; (b) J. Xuan and
W. Xiao, Angew. Chem. Int. Ed., 2012, 51, 6828; (c) C. K. Prier,
D. A. Rankic and D. W. C. Macmillan, Chem. Rev., 2013, 113
5322; (d) Y. Xi, H. Yi and A. Lei, Org. Biomol. Chem., 2013, 11
,
,
,
2387; (e) S. Fukuzumi and K. Ohkubo, Chem. Sci., 2013,
4
561; (f) J. Xuan, Z. Zhang and W. Xiao, Angew. Chem. Int. Ed.,
2015, 54, 15632; (g) N. A. Romero and D. A. Nicewicz, Chem.
Rev., 2016, 116, 10075; (h) J. Chen, X. Hu, L. Lu and W. Xiao,
Chem. Soc. Rev., 2016, 45, 2044; (i) M. H. Shaw, J. Twilton
and D. W. C. MacMillan, J. Org. Chem., 2016, 81, 6898.
10 (a) K. Ohkubo, K. Mizushima, R. Iwata and S. Fukuzumi, Chem.
Sci., 2011, , 715; (b) T. Hou, P. Lu and P. Li, Tetrahedron
2
Lett., 2016. 57. 2273; (c) Q. Lin, Y. Ran, X. Xu and F. Qing, Org.
Lett., 2016, 18, 2419.
11 (a) X. Mi, C. Wang, M. Huang, J. Zhang, Y. Wu and Y. Wu, Org.
Lett., 2014, 16, 3356; (b) Y. Li, Y. Lu, G. Qiu and Q. Ding, Org.
Lett., 2014, 16, 4240; (c) A. C. Mantovani, T. A. C. Goulart, D.
F. Back, P. H. Menezes and G. Zeni, J. Org. Chem., 2014, 79
10526; (d) T. Liu, Q. Ding, Q. Zong and G. Qiu, Org. Chem.
Front., 2015, , 670; (e) K. Yan, D. Yang, W. Wei, F. Wang, F.
,
2
Shuai, Q. Li and H. Wang, J. Org. Chem., 2015, 80, 1550; (f) W.
Fu, M. Zhu, G. Zou, C. Xu, Z. Wang and B. Ji, J. Org. Chem.,
2015, 80, 4766; (g) X. Mi, C. Wang, M. Huang, Y. Wu and Y.
Wu, J. Org. Chem., 2015, 80, 148; (h) W. Wei, J. Wen, D. Yang,
M. Guo, Y. Wang, J. You and H. Wang, Chem. Commun., 2015,
51, 768; (i) W. Yang, S. Yang, P. Li and L. Wang, Chem.
Commun., 2015, 51, 7520; (j) S. Feng, X. Xie, W. Zhang, L. Liu,
Z. Zhong, D. Xu and X. She, Org. Lett., 2016, 18, 3846; (k) S.
Ni, J. Cao, H. Mei, J. Han, S. Li and Y. Pan, Green Chem., 2016,
18, 3935; (l) D. Zheng, J. Yu and J. Wu, Angew. Chem., Int. Ed.,
2016, 55, 11925; (m) S. Yang, H. Tan, W. Ji, X. Zhang, P. Li and
L. Wang, Adv. Synth. Catal., 2017, 359, 443.
12 (a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev.,
2003, 103, 893; (b) T. Taechowisan, C. Lu, Y. Shen and S. J.
Lumyong, Cancer Res. Ther., 2007, 3, 86; (c) X. Huang, Z.
Shan, H. Zhai, L. Su and X. Zhang, Chem. Biol. Drug Des., 2011,
78, 651; (d) E. B. B. Ong, N. Watanabe, A. Saito, Y. Futamura,
K. H. Abd El Galil, A. Koito, N. Najimudin and H. J. Osada, Biol.
Chem., 2011, 286, 14049.
13 (a) S. Ni, W. Sha, L. Zhang, C. Xie, H. Mei, J. Han and Y. Pan,
Org. Lett., 2016, 18, 712.
14 G. Qiu, T. Liu and Q. Ding, Org. Chem. Front., 2016, 3, 510.
15 L. Zhang, T. Meng, R. Fan and J. Wu, J. Org. Chem., 2007, 72
,
7279.
16 (a) T. Yamaguchi, T. Fukuda, F. Ishibashi and M. Iwao,
Tetrahedron Lett., 2006, 47, 3755; (b) L. Santana, E. Uriarte,
H. Gonzalez-Diaz, G. Zagotto, R. Soto-Otero and E. Mendez-
Alvarez, J. Med. Chem., 2006, 49, 1149.
17 H. Chen, L. Zhou, S. Li, Y. Yao, Y. Gu, C. Li, N. Li, M. Meng and
X. Li, Chin. J. Org. Chem., 2013, 33, 164.
18 (a) Y. Wei, S. Lin and F. Liang, Org. Lett., 2012, 14, 4202; (b) Y.
Wei, F. Liang and X. Zhang, Org. Lett., 2013, 15, 5186.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins