Synthesis of Flavone Derivatives through Versatile Palladium-Catalyzed Cross-Coupling Reactions of Tosyloxy- and Mesyloxyflavones

Article abstract of DOI:10.1055/s-0037-1611742

Tosyloxy- and mesyloxyflavones derived from abundant and biologically important hydroxyflavones were used to synthesize a series of functionalized flavones through versatile palladium-catalyzed cross-coupling reactions. A Pd(OAc) ₂ /2-[2-(dicyclohexylphosphino)phenyl]-1-methyl-1 H -indole system effectively catalyzed the reactions of a broad range of tosyloxy- and mesyloxyflavones as electrophilic coupling partners with various nucleophiles to give the corresponding products in good to excellent yields. Catalyst loadings of as little as 0.1 mol% Pd were successfully used. Importantly, we demonstrated that this protocol provided a significantly improved efficiency in the synthesis of a potential chromen-4-one-based analogue of a potent inhibitor of DNA-dependent protein kinase.

Full text of DOI:10.1055/s-0037-1611742

SYNLETT
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1
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-
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0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–G
letter
A
en
O. Y. Yuen et al.
Letter
Synlett
Synthesis of Flavone Derivatives through Versatile Palladium-Cata-
lyzed Cross-Coupling Reactions of Tosyloxy- and Mesyloxyflavones
On Ying Yuena
O
O
Wai Hang Panga
Xiangmeng Chena
Zicong Chena
Pd(OAc)2/CM-Phos
Nu
X
Cy2P
O
R
O
R
29 examples
up to 99% yield
Fuk Yee Kwonga
Chau Ming So*a,b
N
0
0
0
0-0
0
0
1-6
2
6
8-6
5
1
X
Nu
Me
CM-Phos
X = OTs, OMs
a Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong
SAR, P. R. of China
R = Ph, 2-morpholin-4-yl
Nu = ArB(OH)2, HNR1R2,H
R1
b The Hong Kong Polytechnic University, Shen-
zhen Research Institute, No. 18 Yuexing 1st Rd,
South Area, Hi-tech Park, Nanshan, Shenzhen
518057, P. R. of China
bccmso@polyu.edu.hk
Received: 22.01.2019
Accepted after revision: 05.02.2019
Published online: 04.03.2019
OH
O
O
OH
O
O
DOI: 10.1055/s-0037-1611742; Art ID: st-2019-u0040-l
OH
HO
HO
Abstract Tosyloxy- and mesyloxyflavones derived from abundant and
biologically important hydroxyflavones were used to synthesize a series
of functionalized flavones through versatile palladium-catalyzed cross-
coupling reactions. A Pd(OAc)2/2-[2-(dicyclohexylphosphino)phenyl]-1-
methyl-1H-indole system effectively catalyzed the reactions of a broad
range of tosyloxy- and mesyloxyflavones as electrophilic coupling part-
ners with various nucleophiles to give the corresponding products in
good to excellent yields. Catalyst loadings of as little as 0.1 mol% Pd
were successfully used. Importantly, we demonstrated that this proto-
col provided a significantly improved efficiency in the synthesis of a po-
tential chromen-4-one-based analogue of a potent inhibitor of DNA-de-
pendent protein kinase.
OMe
Diosmetin
(Diabetes)
Chrysin
(Antioxidant)
OH
O
O
HO
HO
Cl
N
Flavopiridol
Me
(Cancer)
Figure 1 Some flavones with therapeutic activities
Key words palladium catalysis, phosphine ligands, cross-coupling re-
actions, tosylates, mesylates, flavones
Conventional organic synthesis methods, such as the
Claisen–Schmidt condensation,3 the Baker–Venkataraman
rearrangement,4 ionic-liquid-promoted synthesis,5 the
Allan–Robinson reaction,6 the Vilsmeier–Haack reaction,7
and the Wittig reaction8 have been developed for the syn-
thesis of flavones. However, these reactions tend to give low
yields because they are conducted under strongly basic
and/or acidic conditions with prolonged reaction times.
Palladium-catalyzed cross-coupling reactions provide a
versatile technology in organic synthesis for the rapid con-
nection of electrophilic and organometallic fragments
through the formation of either carbon–carbon or carbon–
heteroatom bonds; they therefore offer a platform for the
rapid synthesis of functionalized flavones (Scheme 1).9 An
appropriate choice of palladium catalysts and fine-tuning of
Flavones are a class of flavonoids with a 2-phenyl-
chromen-4-one backbone. Their scaffold can be considered
a ‘skeleton key’, as it is an important motif in many com-
pounds with various substitution patterns that show versa-
tile biological activities. For example, some flavones have
antioxidant, antiinflammation, antiulcer, and antimicrobial
properties or can be used in the treatment of asthma, car-
diovascular disease, and cancers or in neuroprotection
therapy (Figure 1).1 Because of the wide range of biological
activities of flavones, medicinal chemists have focused con-
siderable attention on their structure–activity relation-
ships.2 Consequently, the design of synthetic strategies is
crucial for dealing with large libraries of flavones.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

B
O. Y. Yuen et al.
Letter
Synlett
R1
O
R2
O
O
R1
N
O
O
O
Ph
Bpin
Ph
R1O
R1O
O
Suzuki
O
O
Ph
P
Amination
Borylation
O
O
Ph
R1
X
O
O
Phosphination
Ph
Sonogashira
Fn
Ph
O
O
α-Arylation
Direct C–H Arylation
O
O
R1
O
Cyanation
Ph
NC
O
Ph
O
Ph
Scheme 1 Rapid syntheses of functionalized flavones through cross-coupling reactions
reaction conditions are necessary for the transformation of
halo- and sulfonyloxyflavones into the appropriate target
compounds.
We initially chose the palladium-catalyzed Suzuki–
Miyaura cross-coupling reaction of tosyloxy- and mesyl-
oxyflavones to synthesize functionalized flavones. To inves-
tigate the effect of various phosphine ligands, we chose 6-
tosyloxyflavone and 4-anisylboronic acid as benchmark
substrates (Scheme 2). The indolylphosphine ligand 2-[2-
(dicyclohexylphosphino)phenyl]-1-methyl-1H-indole (CM-
Phos) was first examined. CM-Phos showed excellent cata-
lytic activity toward the coupling reaction, and an 88% yield
In the past few years, Lemière,10 Pal,11 Caddick,12 and
Langer, Kónya, and Patonay13 and their corresponding co-
workers have reported several palladium-catalyzed cross-
coupling reactions (the Suzuki–Miyaura reaction, Stille cou-
pling, the Sonogashira reaction, and amination) of iodo-,
bromo-, and triflyloxyflavones. However, these reactions
tend to have several shortcomings, in particular the need
for high catalyst loadings (3–10 mol% of the Pd catalyst is
commonly used) and the limitation of their scope to halo-
or triflyloxyflavones. Flavones containing hydroxy groups
are common in nature and, despite the availability of halo-
flavones, many flavones are more generally available in
their phenolic form.14 Consequently, sulfonyloxyflavones
are desirable complements to haloflavones. They can be
prepared from a variety of commercially available hydroxy-
flavones, but are not accessible from their halide counter-
parts. Although triflating agents provide a means for trans-
forming hydroxyflavones into electrophiles, triflyloxyfla-
vones have a high cost and a low hydrolytic stability.
Indeed, the use of tosyloxy- and mesyloxyflavones is much
more desirable, due to their cost-effectiveness15 and their
high stability.16 Hence, we surmised that the use of tosy-
loxy- and mesyloxyflavones through advanced cross-cou-
pling technology might provide the key to success in tack-
ling existing limitations and might offer an efficient route
for medicinal chemistry. In view of our reported synthesis
and application of phosphine ligands,17 we aimed to devel-
op an efficient catalyst system to diversify the range of syn-
thesized functionalized flavones by using tosyloxy- and
mesyloxyflavones.
MeO
B(OH)2
O
O
O
O
1 mol% Pd(OAc)2
4 mol% Ligand
TsO
+
•
K3PO4 H2O, t-BuOH
Ph
Ph
OMe
110 °C, 2 h
Ligands:
Cy2P
Cy2P
N
P(1-Ad)2
N
N
N
O
Me
Me
CM-Phos
88%
PhMezolePhos
MorDalphos
8%
80%
PCy2
PCy2
i-Pr
i-Pr
P(1-Ad)2
MeO
OMe
i-Pr
XPhos
68%
SPhos
cataCXium A
20%
0%
Scheme 2 Evaluation of ligand efficacy. Reaction conditions: Ar1OTs
(0.5 mmol), Ar2B(OH)2 (1.0 mmol), Pd(OAc)2 (1 mol%), ligand (4 mol%),
K3PO4·H2O (1.5 mmol), t-BuOH (1.5 mL), stirring, 110 °C, 2 h, under N2.
The reported yields were determined by GC with dodecane as an inter-
nal standard.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

C
O. Y. Yuen et al.
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of the coupled product was obtained. The analogous ben-
zimidazolyl phosphine PhMezolePhos provided a slightly
lower product yield (80%). Several other commercially
available and well-recognized ligands (MorDalphos, XPhos,
SPhos, and cataCXium A) gave moderate product yields.
Using the identified Pd(OAc)2/CM-Phos catalyst system,
we next evaluated the efficacy of this catalyst system in the
palladium-catalyzed Suzuki–Miyaura cross-coupling reac-
tion of various tosyloxy- and mesyloxyflavones (Scheme 3).
A diverse set of arylboronic acids were successfully coupled
R1
Cy2P
O
O
O
B(OH)2
X
Pd(OAc)2/CM-Phos
R1
•
K3PO4 H2O, t-BuOH
N
O
Ph
Ph
110 °C, 2–18 h
Me
1
2
3
CM-Phos
X = OTs, OMs
OMe
MeO
CH2OH
O
O
O
O
O
Ph
O
Ph
Ph
3a
X = OTs
3b
X = OTs
3c
X = OTs
99% (2 mol% Pd, 2 h)
82% (1 mol% Pd, 2 h)
75% (2 mol% Pd, 2 h)
OMe
99% (2 mol% Pd, 2 h)
O
O
MeO
MeO
O
O
Ph
O
Ph
CH2OH
MeO
O
Ph
3d
3e
3f
X = OTs
X = OTs
X = OTs
99% (2 mol% Pd, 2 h)
99% (0.1 mol% Pd, 2 h)
94% (2 mol% Pd, 2 h)
83% (0.1 mol% Pd, 2 h)
73% (2 mol% Pd, 2 h)
O
O
O
O
Ph
O
Ph
N
O
Ph
O
F
3g
3h
3i
X = OTs
87% (2 mol% Pd, 2 h)
X = OTs
99% (2 mol% Pd, 2 h)
O
X = OTs
99% (2 mol% Pd, 2 h)
O
Me
O
O
O
Ph
O
Ph
Ph
F3C
CF3
3j
3k
3l
X = OTs
98% (2 mol% Pd, 2 h)
X = OTs
68% (2 mol% Pd, 2 h)
X = OMs
74% (2 mol% Pd, 18 h)a
Me
OH
O
O
O
Ph
Me
O
Me
3m
X = OTs
92% (2 mol% Pd, 2 h)
3n
X = OTs
90% (2 mol% Pd, 2 h)
Scheme 3 Palladium-catalyzed Suzuki–Miyaura reactions of tosyloxy and mesyloxyflavones. Reaction conditions: Ar1OTs/Ar1OMs (0.5 mmol), Ar2B(OH)2
(1.0 mmol), Pd(OAc)2/CM-Phos (1:4), K3PO4·H2O (1.5 mmol), t-BuOH (1.5 mL), stirring, 110 °C, under N2. Isolated yields are reported.a Anhyd K3PO4
was used instead of K3PO4·H2O.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

D
O. Y. Yuen et al.
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with tosyloxyflavones. The free hydroxy group in 2-(hy-
droxymethyl)phenylboronic acid was compatible with
these reaction conditions, giving products 3a and 3e an ex-
cellent yields (Scheme 3). Electron-rich (4-OMe), neutral
(3-OMe), and electron-deficient (4-F, 4-CF3 and 3-CF3) aryl-
boronic acids were suitable reactants, and afforded the cor-
responding products 3b, 3c, 3f, 3i, 3j, and 3k in good to ex-
cellent yields. (3,4,5-Trimethoxyphenyl)boronic acid was
also successfully converted into the corresponding product
3d. Moreover,biphenyl-4-ylboronic acid underwent the
transformation smoothly to give the terphenyl-containing
flavone 3g. [3-(Morpholin-4-ylmethyl)phenyl]boronic acid
also coupled readily with 7-tosyloxyflavone to give product
3h in excellent yield. Aryl mesylates are more challenging
substrates than aryl tosylates, because they are less suscep-
tible to oxidative addition. By using our catalyst system, 6-
mesyloxyflavone coupled smoothly to give product 3l in
good yield. The free hydroxy group in 5-hydroxy-7-tosy-
loxyflavone was found to be compatible with the reaction
conditions, giving product 3m. Particular noteworthy is
that this tolerance of hydroxy groups offers an avenue for
further versatile functionalization by conventional cross-
coupling protocols.9 Diarylation of chrysin (5,7-dihydroxy-
flavone) also proceeded smoothly to give the 5,7-diarylfla-
vone 3n in excellent yield.
To examine the site selectivity of our catalyst system to-
ward flavones containing multiple hydroxy groups, we used
ditosylated chrysin in a Suzuki–Miyaura reaction (Scheme
4). With only 1.0 equivalent of 3-tolylboronic acid, the reac-
tion rate was slightly reduced and some starting material
remained after one hour. However, an excellent selectivity
was observed, and the 7-arylated chrysin 3o was isolated in
70% yield. Next, when 4-anisylboronic acid was employed
as a second coupling partner, the 5,7-diarylated product 3p
with different aryl groups was obtained in 97% yield. A one-
pot addition of 2.5 equivalents of 3-tolylboronic acid gave
the 5,7-diarylated product 3p in 80% yield.
To further explore the effectiveness of our catalyst sys-
tem in coupling reactions of tosyloxyflavones, we next
turned our attention to the use of amines as nucleophilic
coupling partners (Scheme 5). Arylamines such as aniline
and or N-methylaniline coupled smoothly with tosyloxyfla-
OTs
O
OMe
MeO
B(OH)2
OTs
O
O
4 mol% Pd(OAc)2
16 mol% CM-Phos
2 mol% Pd(OAc)2
8 mol% CM-Phos
Me
TsO
O
Ph
O
O
Ph
Me
Me
K3PO4 • H2O, t-BuOH
K3PO4 • H2O, t-BuOH
110 °C, 1 h
110 °C, 3 h
Ph
B(OH)2
3o
3p
70%
97%
Scheme 4 Site-selective Suzuki–Miyaura reactions of ditosylated chrysin. Reaction conditions: (Step 1) Ar1OTs (0.5 mmol), Ar2B(OH)2 (0.5 mmol),
Pd(OAc)2 (4 mol%), CM-Phos (16 mol%), K3PO4·H2O (1.5 mmol), t-BuOH (1.5 mL), stirring, 110 °C, 1 h, N2; (Step 2) Ar1OTs (0.5 mmol), Ar2B(OH)2 (1.0
mmol), Pd(OAc)2 (2 mol%), CM-Phos (8 mol%), K3PO4·H2O (1.5 mmol), t-BuOH (1.5 mL), stirring, 110 °C, 3 h, N2. Isolated yields are reported.
Cy2P
R1
O
O
R1
R2
Pd(OAc)2/CM-Phos
N
R2
TsO
H
N
N
K2CO3, t-BuOH
Me
O
Ph
O
Ph
110 °C
CM-Phos
1
4
5
O
O
O
O
Me
N
O
O
O
O
O
H
N
N
Bu
N
Ph
Ph
Ph
Ph
Me
5a
5b
5c
5d
93% (2 mol% Pd, 24 h)
93% (2 mol% Pd, 24 h)
83% (2 mol% Pd, 24 h)
75% (2 mol% Pd, 18 h)
O
O
O
O
N
O
Ph
N
O
Ph
N
O
Ph
N
O
Ph
H
N
O
Me
Me
5e
85% (2 mol% Pd, 18 h)
5f
99% (2 mol% Pd, 18 h)
5g
95% (2 mol% Pd, 18 h)
5h
94% (2 mol% Pd, 18 h)
Scheme 5 Palladium-catalyzed amination of tosyloxyflavones. Reaction conditions: ArOTs (0.5 mmol), amines (0.75 mmol), Pd(OAc)2:CM-Phos (1:4),
PhB(OH)2 (0.02 mmol), K2CO3 (1.25 mmol), t-BuOH (1.5 mL), stirring, 110 °C, under N2. Isolated yields are reported.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

E
O. Y. Yuen et al.
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Synlett
vones to give the corresponding products 5a, 5b, 5f, and 5g
in excellent yields (Scheme 5). Secondary cyclic amines
(morpholine or 1-methylpiperazine) gave the correspond-
ing products 5c, 5e, and 5h in a good to excellent yields. A
secondary acyclic amine (N-methylbutylamine) was also
found to be a suitable cross-coupling partner, but gave
product 5d in a lower yield.
ciency of our catalyst system, we achieved an overall 30%
yield after a similar four-step synthesis; this corresponds to
a hundred-fold improvement compared with the original
synthesis (See the Supporting Information; Scheme S1).
This promising result suggests a convenient pathway for the
rapid and effective synthesis of flavone derivatives so as to
accelerate investigations of their biological activity.
Encouraged by these successes, we decided to further
expand the scope of our reaction. We synthesized another
functionalized flavone to demonstrate the applicability of
our system. 7-Tosyloxyflavone coupled smoothly under
mild conditions with hept-1-yne to give the corresponding
coupling product 6 (Scheme 6).
In summary, we have developed the first general and ef-
ficient protocol for the rapid synthesis of functionalized fla-
vones through palladium-catalyzed cross-coupling reac-
tions using tosyloxy- and mesyloxyflavones as electro-
philes.19–21 The combination of Pd(OAc)2 and the CM-Phos
ligand exhibited good compatibility with a wide range of
tosyloxy- and mesyloxyflavones with various types of nuc-
leophiles, including arylboronic acids, amines, and an
alkyne. Excellent product yields and a catalyst loading of as
little as 0.1 mol% Pd were achieved. This protocol permits
straightforward, rapid, and diversified modification of bio-
logically active flavones. We believe that this palladium-
catalyzed cross-coupling technology using the Pd(OAc)2–
CM-Phos catalyst system should be a useful tool for the de-
velopment of a drug library for lead optimizations and for
fine-tuning the biological properties of chromen-4-one-
based compounds.
H
O
2 mol% Pd(OAc)2
O
8 mol% CM-Phos
K3PO4, t-BuOH
100 °C, 18 h
n-C5H11
TsO
O
Ph
O
Ph
n-C5H11
6, 60%
Scheme 6 Palladium-catalyzed Sonogashira coupling of 7-tosyloxyfla-
vone Reaction conditions: ArOTs (0.5 mmol), hept-1-yne (1.0 mmol),
Pd(OAc)2 (2 mol%), CM-Phos (8 mol%), K3PO4 (1.5 mmol), t-BuOH (1.0
mL), stirring, 100 °C, 18 h, under N2. The isolated yield is reported.
To demonstrate the advantages of using tosylates and
our current catalyst system, we selected 7-diben-
zo[b,d]thien-4-yl-2-morpholin-4-yl-4H-chromen-4-one
(7), an analogue of a potent inhibitor of DNA-dependent
protein kinase as our example (Scheme 7).18 In the original-
ly reported synthesis, an extremely poor overall product
yield (as low as 0.26%) was obtained after the four-step syn-
thesis. This might be due to the poor stability and low toler-
ance of the triflate group. By taking advantage of the great-
er stability of the tosylate group, as well as the high effi-
Funding Information
We thank the Hong Kong Polytechnic University Start-up Fund (1-
BE0Z) for financial support.()
Acknowledgment
We are grateful to Dr. Pui Kin So (University research facilities in Life
Science, PolyU) for HRMS analyses.
Reported Synthesis
O
O
TfO
OH
O
HO
OH
O
S
Tf2O
OMe
OMe
O
N
TfO
O
N
O
O
7
Suzuki reaction: 7–38%yield
46%
3.7% yield after 3 steps
Overall yield: 0.26–1.4%
Our Synthesis
O
O
TsO
OH
OMe
HO
OH
O
S
TsCl
OMe
O
N
TsO
O
N
O
O
O
7
75%
31% yield after 3 steps
Suzuki reaction: 98% yield
Overall yield: 30%
Scheme 7 Synthesis of an analogue of a potent inhibitor of DNA-dependent protein kinase. Reaction condition: Ar1OTs (0.5 mmol), Ar2B(OH)2 (1.0
mmol), Pd(OAc)2 (2 mol%), CM-Phos (8 mol%), K3PO4·H2O (1.5 mmol), t-BuOH (1.5 mL), stirring, 110 °C, 3 h, under N2. Isolated yields are reported.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

F
O. Y. Yuen et al.
Letter
Synlett
Supporting Information
(16) (a) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486.
(b) Kozhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci.
Technol. 2013, 3, 562. (c) Zeng, H.; Qiu, Z.; Domínguez-Huerta,
A.; Hearne, Z.; Chen, Z.; Li, C.-J. ACS Catal. 2017, 7, 510.
(17) (a) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795.
(b) So, C. M.; Yeung, C. C.; Lau, C. P.; Kwong, F. Y. J. Org. Chem.
2008, 73, 7803. (c) So, C. M.; Chow, W. K.; Choy, P. Y.; Lau, C. P.;
Kwong, F. Y. Chem. Eur. J. 2010, 16, 7996. (d) So, C. M.; Kwong, F.
Y. Chem. Soc. Rev. 2011, 40, 4963. (e) Chung, K. H.; So, C. M.;
Wong, S. M.; Luk, C. H.; Zhou, Z.; Lau, C. P.; Kwong, F. Y. Chem.
Commun. 2012, 48, 1967. (f) Fu, W. C.; So, C. M.; Chow, W. K.;
Yuen, O. Y.; Kwong, F. Y. Org. Lett. 2015, 17, 4612. (g) Yuen, O. Y.;
So, C. M.; Man, H. W. Kwong F. Y. Chem. Eur. J. 2016, 22, 6471.
(18) Hardcastle, I. R.; Cockcroft, X.; Curtin, N. J.; Dessage El-Murr, M.;
Leahy, J. J. J.; Stockley, M.; Golding, B. T.; Rigoreau, L.;
Richardson, C.; Smith, G. C. M.; Griffin, R. J. J. Med. Chem. 2005,
48, 7829.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611742.
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References and Notes
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32, e22002.
(19) Suzuki–Miyaura Coupling of Tosyloxy- or Mesyloxyflavones;
General Procedure
A Schlenk tube containing a Teflon-coated magnetic stirrer bar
was charged with Pd(OAc)2 (2.24 mg, 0.010 mmol) and CM-
Phos (Pd/L = 1:4). The tube was then evacuated and flushed
with N2 three times. Precomplexation was conducted by adding
freshly distilled CH2Cl2 (1.0 mL) and Et3N (0.1 mL) to the tube.
The solution was stirred and placed in a preheated oil bath at
50 °C for 1–2 min until the solvent started boiling. The solvent
was then evaporated under high vacuum.
(2) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Burker, M. D.;
Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43, 46.
(c) Shimokawa, J. Tetrahedron Lett. 2014, 55, 6156.
(3) Climent, M. J.; Corma, A.; Iborra, S.; Primo, J. J. Catal. 1995, 151,
60.
(4) (a) Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767.
(b) Baker, W. J. Chem. Soc. 1933, 1381.
The appropriate tosyloxy- or mesyloxyflavone (0.5 mmol), aryl-
boronic acid (1.0 mmol), and K3PO4·H2O (345 mg, 1.5 mmol) or
K3PO4 (318 mg, 1.5 mmol) were then added to the tube, which
was evacuated and flushed with N2three times. t-BuOH (1.5 mL)
was added, the tube was sealed, and the mixture was stirred at
r.t. for 1 min. The tube was then placed in a preheated oil bath at
110 °C for the time shown in Table 2. When the reaction was
complete, the tube was allowed to cool to r.t. and EtOAc or
CH2Cl2 (~10 mL) and H2O (~3 mL) were added. The organic layer
was subjected to GC analysis. The filtrate was concentrated
under reduced pressure to give a crude product that was puri-
fied by flash column chromatography [silica gel (230–400
mesh)].
(5) Sarda, S. R.; Pathan, M. Y.; Paike, V. V.; Pachmase, P. R.; Jadhav,
W. N.; Pawar, R. P. ARKIVOC 2006, (xvi), 43.
(6) Allan, J.; Robinson, R. J. Chem. Soc., Trans. 1924, 125, 2192.
(7) Su, W. K.; Zhu, X. Y.; Li, Z. H. Org. Prep. Proced. Int. 2009, 41, 69.
(8) Das, J.; Ghosh, S. Tetrahedron Lett. 2011, 52, 7189.
(9) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (b) Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A.; Diederich, F., Ed.; Wiley-VCH: Wein-
heim, 2004, 2nd ed., Vols. 1 and 2. (c) Corbet, J.-P.; Mignani, G.
Chem. Rev. 2006, 106, 2651. (d) Palladium-Catalyzed Coupling
Reactions: Practical Aspects and Future Developments; Molnár,
Á., Ed.; Wiley-VCH: Weinheim, 2013. (e) Metal-Catalyzed Cross-
Coupling Reactions and More;
V
o
l
s.1
–
3
de Meijere, A.; Bräse, S.; Oestreich,
6-[2-(Hydroxymethyl)phenyl]-2-phenyl-4H-chromen-4-one
(3a)
M., Ed.; Wiley-VCH: Weinheim, 2014. (f) New Trends in Cross-
Coupling: Theory and Applications; Calacot, T. J., Ed.; RSC: Cam-
bridge, 2015.
White solid; yield: 123 mg (75%); mp 157.6–161.5 °C; Rf = 0.10
(EtOAc–hexane, 1:4). 1H NMR (400 MHz, CD2Cl2):  = 2.17 (br s,
1 H), 4.64 (s, 2 H), 6.85 (s, 1 H), 7.35–7.48 (m, 3 H), 7.57–7.63
(m, 4 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.80–7.82 (m, 1 H), 8.00–8.03
(m, 2 H), 8.20 (d, J = 2.2 Hz, 1 H). 13C NMR (100 MHz, CD2Cl2):
 = 62.7, 107.4, 118.0, 123.6, 125.6, 126.3, 127.7, 128.1, 128.8,
129.0, 130.1, 131.6, 131.8, 135.0, 138.0, 138.5, 139.7, 155.5,
163.5, 178.1. MS (EI): m/z (%) = 326.4 (M+, 100), 298.3 (81),
196.2 (65), 168.2 (18), 139.2 (44). HRMS: m/z [M + H]+ calcd for
(10) Deng, B.-L.; Lepoivre, J. A.; Lemière, G. Eur. J. Org. Chem. 1999,
2683.
(11) Pal, M.; Dakarapu, R.; Parasuraman, K.; Subramania, V.;
Yeleswarapu, K. R. J. Org. Chem. 2005, 70, 7179.
(12) Fitzmaurice, R. J.; Etheridge, Z. C.; Jumel, E.; Woolfson, D. N.;
Caddick, S. Chem. Commun. 2006, 4814.
(13) (a) Eleya, N.; Malik, I.; Reimann, S.; Wittler, K.; Hein, M.;
Patonay, T.; Villinger, A.; Ludwig, R.; Langer, P. Eur. J. Org. Chem.
2012, 1639. (b) Akrawi, O. A.; Patonay, T.; Kónya, K.; Langer, P.
Synlett 2013, 24, 860. (c) Kónya, K.; Paitás, D.; Kiss-Szikszai, A.;
Patonay, T. Eur. J. Org. Chem. 2015, 828. (d) Paitás, D.; Kónya, K.;
Kiss-Szikszai, A.; Džubák, P.; Pethő, Z.; Varga, Z.; Panyi, G.;
Patonay, T. J. Org. Chem. 2017, 82, 4578. (e) Jordán, S.; Paitás, D.;
Patonay, T.; Langer, P.; Kónya, K. Synthesis 2017, 49, 1983.
(14) The commercial availability of 7-bromoflavone is far less than
that of 7-hydroxyflavone.
C
22H17O3: 329.1172; found: 329.1181.
(20) Palladium-Catalyzed Amination of Tosyloxy- and Mesyloxy-
flavones: General Procedure
The Pd(OAc)2–CM-Phos complex was prepared in a Schlenk
tube as described above. The appropriate tosyloxy- or mesyl-
oxyflavone (0.5 mmol), K2CO3 (172.5 mg, 1.25 mmol), and, if
solid, the appropriate amine (0.75 mmol) and phenylboronic
acid (2.44 mg, 0.02 mmol) were added to the tube, which was
evacuated and flushed with N2 three times again. t-BuOH (1.5
mL) and, if liquid, the appropriate amine (0.75 mmol) were
added finally. The tube was sealed and the mixture was stirred
at r.t. for 1 min. The tube was then placed in a preheated oil bath
(15) According to the 2018 Aldrich Catalog: mesyl chloride ($173.5/1
L), tosyl chloride ($85.1/1 kg), triflic anhydride ($1620/1 kg).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

G
O. Y. Yuen et al.
Letter
Synlett
(110 °C) for the time indicated in Table 3. When the reaction
was complete, the tube was allowed to cool to r.t. and EtOAc or
CH2Cl2 (~10 mL) and H2O (~3 mL) were added. The organic layer
was subjected to GC analysis. The filtrate was concentrated
under reduced pressure to give a crude product that was puri-
fied by flash column chromatography [silica gel (230–400
mesh)].
2-Phenyl-6-(phenylamino)-4H-chromen-4-one (5a)
Orange solid; yield: 146 mg (93%); This is a known compound.
Melting point was not measured; Rf = 0.80 (EtOAc–CH2Cl2, 1:4).
1H NMR (400 MHz, CDCl3):  = 6.80 (s, 1 H), 6.99 (t, J = 7.3 Hz, 1
H), 7.13 (d, J = 7.6 Hz, 2 H), 7.28–7.32 (m, 2 H), 7.41–7.53 (m, 5
H), 7.81 (s, 1 H), 7.90–7.92 (m, 2 H). 13C NMR (100 MHz, CDCl3):
 = 106.8, 110.7, 118.5, 119.1, 122.0, 124.1, 124.8, 126.2, 129.0,
129.5, 131.4, 132.0, 141.2, 142.3, 151.0, 163.1, 178.2. MS (EI):
m/z (%) = 312.4 (M+, 100), 207.2 (6), 154.2 (25), 128.2 (4), 78.2
(5).
tube, which was evacuated and flushed with N2 three times.
Hept-1-yne (131.2 L, 1.0 mmol) and t-BuOH (1.0 mL) were
added, the tube was sealed, and the mixture was stirred at r.t.
for 1 min then placed in a preheated oil bath (100 °C) for 18 h.
When the reaction was complete, the tube was allowed to reach
r.t., and EtOAc or CH2Cl2 (~10 mL) and H2O (~3 mL) were added.
The organic layer was subjected to GC analysis. The filtrate was
concentrated under reduced pressure, and the crude product
was purified by flash column chromatography [silica gel (230–
400 mesh), EtOAc–hexane (1:4)] to give a light-orange solid;
yield: 95 mg (60%); mp 105.4–106.4 °C; (Rf = 0.5). 1H NMR (500
MHz, CDCl3):  = 0.94 (t, J =7.3 Hz, 3 H), 1.35–1.41 (m, 2 H),
1.42–1.48 (m, 2 H), 1.61–1.67 (m, 2 H), 2.45 (t, J = 7.2 Hz, 2 H),
6.79 (s, 1 H), 7.39 (d, J = 8.2 Hz, 1 H), 7.49–7.53 (m, 3 H), 7.57 (s,
1 H), 7.89 (d, J = 7.0 Hz, 2 H), 8.11 (d, J = 8.2 Hz, 1 H).13C NMR
(1205 MHz, CDCl3):  = 13.9, 19.5, 22.2, 28.1, 31.1, 79.4, 95.1,
107.7, 120.7, 122.8, 125.4, 126.2, 128.5, 129.0, 129.9, 131.6,
155.9, 163.4, 177.9. MS (EI): m/z (%) = 316.1 (M+, 64), 301.1 (14),
287.1 (100), 273.1 (56), 261.1 (74), 231.1 (35). HRMS: m/z [M +
H]+ calcd for C22H21O2: 317.1536; found: 317.1539.
(21) 7-Hept-1-yn-1-yl-2-phenyl-4H-chromen-4-one (6)
The Pd(OAc)2–CM-Phos complex was prepared in a Schlenk
tube as described above. 7-Tosyloxyflavone (196.0 mg, 0.5
mmol) and K3PO4 (318.0 mg, 1.50 mmol) were added to the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G