Photoinduced Generation of Acyl Radicals from Simple Aldehydes, Access to 3-Acyl-4-arylcoumarin Derivatives, and Evaluation of Their Antiandrogenic Activities

Article abstract of DOI:10.1021/acs.joc.7b02933

A novel photocatalysis to construct the 3-acyl-4-arylcoumarin framework from simple aldehyde with ynoate is described. The reaction proceeded through an acyl radical intermediate generated by hydrogen atom abstraction from aldehyde, followed by reaction with ynoate and then cyclization to afford coumarins. This valuable radical cyclization reaction gave over 20 coumarin derivatives in moderate to good yields with inexpensive 2-^tBu-anthraquinone as a catalyst. In addition, synthetic coumarins were investigated for 5α-dihydrotestosterone (DHT)-induced secretion of prostate-specific antigen (PSA) levels and cell proliferation of androgen-dependent CWR22Rv1 cells.

Full text of DOI:10.1021/acs.joc.7b02933

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Article
Photoinduced generation of acyl radicals from simple
aldehydes, access to 3-acyl-4-arylcoumarin derivatives,
and evaluation of their antiandrogenic activities
Kazuki Kawaai, Tomoaki Yamaguchi, Eiji Yamaguchi,
Satoshi Endo, Norihiro Tada, Akira Ikari, and Akichika Itoh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02933 • Publication Date (Web): 12 Jan 2018
Downloaded from http://pubs.acs.org on January 12, 2018
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The Journal of Organic Chemistry
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Photoinduced generation of acyl radicals from simple alde-
hydes, access to 3-acyl-4-arylcoumarin derivatives, and eval-
uation of their antiandrogenic activities
1
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†
†
,†
‡
†
‡
Kazuki Kawaai, Tomoaki Yamaguchi, Eiji Yamaguchi,* Satoshi Endo, Norihiro Tada, Akira Ikari,
,
†
and Akichika Itoh*
†
‡
Laboratory of Pharmaceutical Synthetic Chemistry and Laboratory of Biochemistry, Gifu Pharmaceutical University, 1ꢀ25ꢀ
4
, Daigakuꢀnishi, Gifu 501ꢀ1196, Japan
AQN (10 mol%)
Ar1
Ar1
BPO (200 mol%)
O
O
2 3
K CO (50 mol%)
Ar2
+
Ar2
tamyl alcohol, 20 h
H
Ar, visible light
O
O
O
O
over 20 examples
moderate to good yields
ABSTRACT: A novel photocatalysis to construct the 3ꢀacylꢀ4ꢀarylcoumarin framework from simple aldehyde with ynoate is deꢀ
scribed. The reaction proceeded through an acyl radical intermediate generated by hydrogen atom abstraction from aldehyde folꢀ
lowed by reaction with ynoate and then cyclization to afford coumarins. This valuable radical cyclization reaction gave over 20
t
coumarin derivatives in moderate to good yields with inexpensive 2ꢀ Buꢀanthraquinone as a catalyst. In addition, synthetic coumaꢀ
rins were investigated for 5αꢀdihydrotestosterone (DHT)ꢀinduced secretion of prostateꢀspecific antigen (PSA) levels and cell prolifꢀ
eration of androgenꢀdependent CWR22Rv1 cells.
13
biologically attractive 3ꢀacylcoumarins. According to this
scenario, Wu and coꢀworkers reported metalꢀfree tandem oxiꢀ
dative acylation/cyclization between alkynoates and aldeꢀ
■
INTRODUCTION
Coumarin and its derivatives contain a common framework
widely found in naturally occurring products and commercialꢀ
ly available pharmaceuticals. For instance, 3ꢀacylcoumarins
exhibit interesting biological activities as selective and reꢀ
12g
hydes, leading to 3ꢀacylꢀ4ꢀarylcoumarins. The method inꢀ
volves C–H abstraction to generate an acyl radical from an
aldehyde using a combined K S O /TBAB system under therꢀ
2
2
8
1
versible MAOꢀB (monoamine oxidaseꢀB) inhibitors, and 3ꢀ
mal reaction conditions.
acylꢀ4ꢀarylcoumarins exhibit anticancer activity through
On the other hand, photoinduced reactions with organic phoꢀ
tocatalysts have been explored in our laboratory, and we
2
caspaseꢀindependent apoptosis. They are potential drug canꢀ
14
3
4
didates for Parkinson’s disease and anticancer agents. In adꢀ
dition to medicinal applications, functionalized molecules
bearing coumarin moieties have been used as fluorescent
have already reported that anthraquinone derivatives (AQNs)
are effective in the oxidation of toluenes and benzyl alcohols
15
to benzoates and benzoic acids. Plausible mechanisms of
5
probes for biothiols.
these reactions include the generation of benzyl radical species
Besides traditional methods such as the Perkin/Knoevenagel
via hydrogen atom abstraction by the excited triplet state of
AQN . Thus, an Oꢀcentered radical of AQN can act as a
6
7
3
*
3
*
condensation,
Pechmann
reaction,
Mizorogiꢀ
8
9
Heck/lactonization, Kostanecki reaction, and Wittig reacꢀ
hydrogen atom scavenger. We envisioned that acyl radicals
can be generated by applying this catalytic system to benzalꢀ
dehydes if cleavage of the C–H bond of the aldehyde occurred
10
tion, several efficient synthetic methods have been docuꢀ
mented under the promotion of transition or heavy metal reaꢀ
11
3
*
gents (Scheme 1). The controlled generation of highly reacꢀ
tive chemical species is a fundamental strategy for constructꢀ
ing molecules in a straightforward fashion. The addition of in
situ generated radicals to a C−C triple bond affords highly
reactive vinyl radicals, and subsequent addition of these to
other C−C unsaturated bonds affords cyclic compounds. Based
on this strategy, various methods leading to coumarins, using
via AQN . In addition, 3ꢀacylꢀ4ꢀarylcoumarins can be syntheꢀ
sized by photocatalytic acyl radical addition to the ynoate in a
metalꢀfree fashion. Herein, we describe a metalꢀfree organoꢀ
photocatalystꢀinduced
oxidative
sequential
addiꢀ
tion/cyclization reaction of alkynoates with aldehyde under
mild reaction conditions to furnish biologically active 3ꢀ acylꢀ
4ꢀarylcoumarins (Scheme 3). We also investigated the effects
of 3ꢀacylꢀ4ꢀarylcoumarins on 5αꢀdihydrotestosterone (DHT)ꢀ
induced secretion of prostateꢀspecific antigen (PSA) levels and
cell proliferation of androgenꢀdependent CWR22Rv1 cells.
aryl alkynoates with a radical precursor, were developed
12
(
Scheme 2). Especially, employing acyl radicals in coumarin
synthesis under this strategy is a fundamental way to produce
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Page 2 of 9
Traditional coumarin synthesis
1
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3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
3
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3
4
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Perkin/Knoevenagel condensation
MizorogiꢀHeck/lactonization reaction
Kostanecki reaction
R1
R1
R2
O
Z
O
X
O
+
Z
+
O
+
O
O
R
OEt
OH
OH
OH
R3
Z = CN, CO
2
R, CO
2
H, Ar..
ref. 6
ref. 7
ref. 8
ref. 9
Pechmann reaction
Wittig synthesis
R2
R1
O
ref. 10
O
O
O
O
O
+
O
+
PPh3
OH
Br
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OR
Scheme 1. Synthesis of coumarin through classical transformation.
Coumarin synthesis: tandem C-centered radical addition/cyclization of ynoate
R
R
R
O
C
C
C
radical addition
cyclization
O
O
O
O
O
Yu, J.ꢀT. et al.
Sun, P. et al.
Zhang, X.; Wang, L. et al.
Adv. Synth. Catal. (2016)
Xie, X. et al.
Ding, Q.; Qiu, G. et al.
Tetrahedron (2016)
Org. Bio. Chem. (2016)
J. Org. Chem. (2016)
Org. Lett. (2016)
O
S
n
O
O
HO
R
CN
EtO
S
EWG
X
Me
Me
O
DLP
DCE, 85 ºC
TBPB, Na
130 ºC
2
CO
3
BIꢀOH, KPF
6
Ru(bpy)
3
Cl
2
, TBHP
K
2
S
2
O
8
/TBAB
toluene, blue LED
MeCN, blue LED
2
DCE, H O, 70 ºC
Liu, L. et al.
Fu, W. et al.
Tang, D.; Wang, H. et al.
J. Org. Chem. (2015)
Wu, Y.; Wu, Y. et al.
J. Org. Chem. (2015)
Ding, Q.; Qiu, G. et al.
Org. Chem. Front. (2015)
Org. Bio. Chem. (2016)
J. Org. Chem. (2015)
F
Br
O
O
n
X
O
OEt
F
HO
R
HO
R
H
R
O
O
O
CuBr, DTBP
facꢀIr(ppy)
3
, K
2
CO
3
3
AgNO , K
2
S
2
O
3
K
2
S
2
O
8
, TBAB
Ag
NaOAc
2
MeCN, H O, 80 ºC
2 3 2 2 3
CO , K S O
125 ºC
DMF, 78 ºC
DCE, H
2
O, 60 ºC
DCE, 90 ºC
5 W blue LED
Scheme 2. Synthesis of coumarin through in situ generated C-centered radical addition/cyclization of ynoate.
Direct oxidation of toluene to benzoate
dant, and potassium carbonate with visible light irradiation,
O
the desired product 3aa was obtained in 76% isolated yield,
along with complete regioselectivity (Table 1, entry 1). As
regards the photocatalysts, eosin Y was found to give the
product in moderate yield, but a commonly used photocatalyst,
tris(bipyridine)ruthenium(II) chloride, was found to be inefꢀ
fective (entries 2 and 3). Other oxidants, such as K S O , hyꢀ
drogen peroxide, and diꢀtertꢀbutyl peroxide (DTBP), led to a
decrease in the product yield (entries 4–6). Various bases were
also investigated, revealing that K CO is the most efficient
base compared to other bases (entries 7–9). On the other hand,
the desired product was observed in low yield without an oxiꢀ
dant (entry 10). These results suggest that the combination of a
photocatalyst with an oxidant is crucial for the reaction. Conꢀ
trol exper iments revealed that visible light irradiation is necꢀ
essary for the reaction to progress (entry 11). With the optimal
reaction conditions in hand (Table 1, entry 1), we investigated
the generality of the photocatalytic reaction. Initially, the
scope of aldehydes bearing various substituents (2) was
demonstrated using ynoate 1a as the model substrate (Table
2). The desired coumarins were obtained in good yield when
electronꢀrich benzaldehydes were employed as acyl radical
precursors (entries 2 and 3). Unsubstituted benzaldehyde was
also suitable for the reaction (entry 4). A radical precursor
such as benzaldehyde bearing an electronꢀwithdrawing group
at the para position also worked well, albeit with moderate
AQN cat.
Me
OMe
OH
visible light
O , MeOH
2
Direct oxidation of alcohol to benzoic acid
OH
O
2
2
8
AQN cat.
visible light
air, EtOAc
2
3
Working hypothesis for coumarin synthesis
O
R1
O
O
O
AQN
oxidant
O
O
R1
R2
R2
R2
H
visible light
O
Scheme 3. Working hypothesis and this work
■RESULT AND DISCUSSION
We examined the radical addition/cyclization of phenyl 3ꢀ
phenylꢀ2ꢀpropynate (1a) with pꢀtolualdehyde (2a) as model
substrate, using photocatalyst to optimize the reaction condiꢀ
tions. Key results are summarized in Table 1 (See Supporting
Information for more details). Fortunately, when we carried
out the reaction using 10 mol% 2ꢀtertꢀbutylanthraquinone (2ꢀ
t
BuꢀAQN) as the catalyst, benzoyl peroxide (BPO) as an oxiꢀ
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yield (entries 5–7). Functional groups substituted at the meta-
We then proceeded to examine the scope and generality of the
reaction of substituted ynoate 1 with aldehyde 2d. To our surꢀ
prise, when p-substituted alkynoate 1c was employed as the
substrate, the reaction gave the unexpected product 3cd, but an
anticipated one 3cd’ (Scheme 4). The result indicated that the
radical acylation, 5-exo-trig cyclization and 1,2ꢀester migraꢀ
tion, which was consisted with previous related report, should
1
2
3
4
5
6
7
8
9
and orthoꢀposition of the benzene ring were also tolerated,
with the annulation products furnished in 47–77% isolated
yield (entries 8–11).
Table 1. Optimization of the reaction conditions
catalyst (10 mol%)
Ph
12
oxidant (200 mol%)
additive (50 mol%)
tamyl alcohol, 20 h
Ph
O
O
a
take place in the reaction to furnish the product.
+
ArCHO
Ar
Ph
O
Ar = 4ꢀMeꢀC
6
H
4
5-exo-trig
Ph
O
O
a
O
Ar, visible light
1
2a
3aa
Ph
MeO
MeO
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
optimized
condition
MeO
3cd
33% yield
entry catalyst
oxidant
BPO
additive
K CO
3aa (%)
(74)
68
+ 2d
t
O
O
1
2
3
4
5
6
7
8
9
1
1
2ꢀ BuꢀAQN
Ph
O
2
3
3
3
3
3
1c
Eosin Y
BPO
K CO
2
Ph
6-endo-trig
O
O
Ru(bpy) Cl
BPO
K CO
2
38
3
2
t
3cd'
not detected
2ꢀ BuꢀAQN
K S O
K CO
2
15
2
2
8
t
2ꢀ BuꢀAQN
H O
K CO
2
24
2
2
Scheme 4. Acylation/cyclization/migration of 2d with p-
methyl alkynoate 1c
t
2ꢀ BuꢀAQN
DTBP
BPO
BPO
BPO
ꢀ
K CO
30
2
3
t
2ꢀ BuꢀAQN
Na CO
43
2
3
Based on the result, pꢀsubstituted ynoate 1b-g was employed
as substrates for the acylation/cyclization/migration reaction
(Table 3). A para-substituted phenoxy ring with either elecꢀ
tronꢀdonating groups (methylꢀ, methoxy) or electronꢀ
withdrawing groups (iodo, ester, acetyl, and acetoxy) attached
to the benzene ring gave the corresponding 1,2ꢀesrer migration
products (3ba–3ga) in moderate to good yields specifically
(entries 1–6).
t
2ꢀ BuꢀAQN
KOH
35
t
2ꢀ BuꢀAQN
Et N
3
43
t
0
1
2ꢀ BuꢀAQN
K CO
2
16
3
3
t
b
2ꢀ BuꢀAQN
BPO
K CO
2
0
a
1
Yields were determined by H NMR analysis of crude reaction
mixture using 1,1,2,2ꢀtetrachloroethane as an internal standard.
b
Number in parentheses refer to isolated yield. Reaction perꢀ
Table 3. Acylation/cyclization/migration of 2a with various
alkynoate 1
formed under the dark.
Table 2. Acylation/cyclization of 1a with various aldehydes
2
ꢀtBuꢀAQN (10 mol%)
BPO (200 mol%)
Ph
Ph
O
O
2
ꢀtBuꢀAQN (10 mol%)
BPO (200 mol%)
R
O
2 3
K CO (50 mol%)
p-tol
Ph
Ph
O
O
+
tamyl alcohol, 20 h
Ar, visible light
O
K
2
CO
3
(50 mol%)
O
O
p-tol
H
R
O
+
Ar
Ar
H
tamyl alcohol, 20 h
Ar, visible light
1
2a (10 equiv)
3
O
O
O
1a
2 (10 equiv)
3
a
entry
product
3
yield (%)
a
b
Ph
O
O
O
entry
2
Ar
3
yield (%)
74
1
3ba
70
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
4ꢀMeꢀC H
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
6
4
t
Me
Me
4ꢀ BuꢀC H
74
6
4
Ph
O
2
3
4
3ca
3da
3ea
58
61
79
4ꢀMeOꢀC H
67
6
4
C H
6
71
5
MeO
O
O
Me
4ꢀFꢀC H
66
6
4
Ph
O
O
O
4ꢀClꢀC H
58
6
4
b
7
2g
2h
2i
4ꢀCF ꢀC H
58
3
6
4
I
Me
Ph
O
8
3ꢀMeꢀC H
77
6
4
b
9
3ꢀMeOꢀC H
47
6
4
b
AcO
O
O
Me
10
2j
3ꢀClꢀC H
3aj
3ak
52
6
4
c
c
Ph
O
b
5
6
3fa
62
11
2k
2ꢀMeꢀC H
70
6
4
Reaction conditions: mixture of 1a (0.10 mmol), 2 (1.0 mmol), 2ꢀ
t
Ac
O
O
Me
BuꢀAQN (10 mol%), benzoyl peroxide (200 mol%), and K CO
50 mol%) in amyl alcohol (1 mL) was stirred for 20 h under an
2
3
c
t
Ph
O
76
(
3ga
argon atmosphere irradiated with four of 23 W fluorescent lamps.
a
b
t
Isolated yields. EtOAc was used as solvent instead of amyl alꢀ
cohol.
MeO2C
O
O
Me
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a
b
t
Me
N
Isolated yields. EtOAc was used as solvent instead of amyl
Me
O
c
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
alcohol. The reaction performed for 40 h.
standard
condition
CHO
1a
+
3
aa
Me (1)
We further explored the scope of the reaction by using mꢀ
substituted ynoate 1 as a substrate (Table 4).
Me
Me
2
Me
a (10 equiv)
2aꢀTEMPO
observed by GCꢀMS
Table 4. Acylation/cyclization/migration of 2a with various
m-substituted alkynoate 1
With TEMPO (300 mol %) : 0%
With BHT (100 mol %)
: 0%
ꢀtBuꢀAQN (10 mol %)
2
Ph
O
O
BPO (200 mol %)
K CO (50 mol %)
R
2
3
p-tol
2
ꢀtBuꢀAQN (10 mol%)
BPO (200 mol%)
1a
+
+
H
3ac
(2)
(3)
Ph
tamyl alcohol, 20 h
Ar, visible light
R
O
O
O
MeO
57%
O
K
CO
3
(50 mol%)
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
+
2c (10 equiv)
p-tol
H
EtOAc, 20 h
Ph
O
O
2ꢀ
t
BuꢀAQN (10 mol %)
BPO (200 mol %)
CO (50 mol %)
Ar, visible light
p-tol
O
1
2a (10 equiv)
K
2
3
1a
D
3ac
O
O
tamyl alcohol, 10 h
Ar, visible light
R
3'
MeO
31%
a
entry
1
3
yield (%)
1
2c-d (10 equiv)
KIE = 1.84
Ph
O
O
3ha
50
t
2ꢀ BuAQN (10 mol %)
MeO
2
c
3ac
BPO (200 mol %)
(
5 equiv)
56%
2 3
K CO (50 mol %)
O
Me
1a
1a
+
+
(4)
(5)
tamyl alcohol, 20 h
Ar, visible light
Ph
O
O
2
3ia
18
2e
3ae
(5 equiv)
28%
O
Me
BPO (200 mol %)
Br
2 3
K CO (50 mol %)
2a
Ph
O
O
3aa
3
ia’
29
23
(
10 equiv)
tamyl alcohol, 20 h
Ar, dark, temp.
Br
rt : 0% yield
0 ºC : 54% yield
8
O
O
Me
Scheme 6. Control experiments
Ph
O
3
3ja
To gain insight into the reaction mechanism, several control
experiments were conducted, as shown in Scheme 6. For the
first control experiment, we added radicalꢀtrapping reagents,
TEMPO and BHT, into the reaction mixture. The reaction was
found to be completely suppressed with no desired product
being obtained, and a radicalꢀtrapping product 2aꢀTEMPO
was detected by GCꢀMS (equation 1). This result suggested
that our strategy involved acyl radical generation. We assumed
that AQN was initially affected by benzaldehydes due to alꢀ
kynoates 2a but was completely recovered when the reaction
was conducted without aldehydes. We then investigated the
kinetic isotope effect (equations 2 and 3). The parallel kinetic
O
Me
Me
Ph
O
3
ja’
45
Me
O
O
Me
a
Isolated yields.
The desired coumarin (3ha) was obtained as the sole product
when the alkynoate with methoxy at the meta position of the
phenoxy ring was employed (entry 1). By contrast, with other
substituents, such as Br or Me, on the phenoxy ring, two regiꢀ
oisomers were furnished and the major compounds were reꢀ
acted at less sterically hindered positions compared to the miꢀ
nor products (3ia, 3ia’, 3ja, and 3ja’).
isotope effect (KIE) (k
/k = 1.84) was measured by using 2c
and 2c–d , and this value implies that cleavage of the C–H
H
D
1
bond is not the rateꢀdetermining step in the reaction mechaꢀ
nism. Moreover, the KIE rate observed is similar to two previꢀ
ously reported parallel KIE rates (k /k = 1.84), which were
ꢀtBuꢀAQN (10 mol%)
H
D
2
Ph
Ph
O
measured for the reaction of an Oꢀcentered radical such as
BPO (200 mol%)
t
16
O
K
CO
(50 mol%)
butoxyl with benzaldehyde/d ꢀbenzaldehyde. Competing
2
3
p-tol
6
+
experiments with pꢀanisaldehyde 2c and 4ꢀfluorobenzaldehyde
e were performed to reveal the electronic effect of the aldeꢀ
hyde. As a result, coumarin 3ac, which was generated by reacꢀ
tion with 2c, was observed as a major product, and the elecꢀ
tronꢀrich aldehyde was superior to the electronꢀpoor aldehyde,
p-tol
H
tamyl alcohol, 20 h
Ar, visible light
70% yield
O
O
O
O
2
OMe
1
k
2a (10 equiv)
3aa
Scheme 5. Acylation/cyclization/migration of 2a with o-
MeO alkynoate 1k
17
as reported previously. To evaluate the role of BPO, the reacꢀ
tion was performed without catalyst (equation 5). Although
the yield of 3aa was significantly decreased to 0% at room
temperature, the corresponding product was obtained in 54%
yield under thermal conditions. This result indicated that BPO
was decomposed under thermal conditions and that the benzoꢀ
yloxy radical generated acted as a hydrogen atom abstraction
agent.
Although the desired coumarin was not confirmed when emꢀ
ploying an ortho substituted alkynoate with methoxy on the
phenoxy moiety 1k, reaction at the ipso position of the methꢀ
oxy group proceeded to afford 3aa in 70% yield (Scheme 5).
ACS Paragon Plus Environment

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From both the overall results above and previously published
literature, two plausible mechanisms are depicted in Scheme
7.
compounds with less bulky 3ba or without substituent 3aa, the
bulky substituents of 3fa and 3ga might diminish the antiproꢀ
liferative potency of the compounds against CWR22Rv1 cells.
The results imply that all the compounds except for 3fa and
3ga inhibited androgenꢀinduced prostate cancer cell proliferaꢀ
tion through antagonistic activity against androgen receptors.
1
2
3
4
5
6
7
8
9
12
route 1
Ph
O
O
O
Ar
Ar
H
Ar
O
II
O
Ph
2
I
3AQN*
AQH
R
(
A)
BPO
O
O
##
AQN
250
1
2
PhCO H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
BPO
PhCO
2
or
2
00
50
00
*
Ph
O
Ph
1
1
O
O
**
*
*
O
O
Ar
Ar
*
*
**
PhCO ꢀ
ꢀ
O
**
2
PhCO2
III'
**
**
+
III
1,2 ester migration
PhCO2
5
0
0
**
H
O
O
O
O
O
aromatization
-
-
3aa 3ab 3ad 3af 3ag 3ah 3ak 3ba 3fa 3ga 3ja
Ar
H+
Ar
ꢀ
1 nM 5αꢀDHT
Ph
O
Ph
(
B)
IV
3
##
route2
200
Ph
O
O
O
O
Ar
*
Ar
H
Ar
1
50
O
II
2
I
**
PhCO
2
PhCO H
1
2
*
*
**
**
*
*
thermal or photo
decomposition
100
50
0
**
**
**
Ph
O
BPO
Ar
O
O
3
-
-
3aa 3ab 3ad 3af 3ag3ah 3ak 3ba 3fa 3ga 3ja
nM 5αꢀDHT
Scheme 7. Plausible reaction mechanisms
1
Initially, acyl radical I was generated through hydrogen atom
abstraction from the parent aldehyde by photogenerated
Figure 1. Inhibitory effects of the compounds on proliferation
of androgen-dependent prostate cancer CWR22Rv1 cells. (A)
PSA mRNA level. The cells were pretreated for 2 h with the indiꢀ
cated 50 ꢁM of 3 or the vehicle, DMSO, and then treated with 1
nM 5αꢀDHT for 24 h. The expression level of PSA in the cells
was analyzed by quantitative RTꢀPCR analysis. (B) Cell proliferaꢀ
tion. The cells were pretreated for 2 h with the indicated 50 ꢁM of
or the vehicle, DMSO, and then treated with 1 nM 5αꢀDHT for
2 h. The viability is expressed as a percentage of the value in the
control cells. p < 0.01, significantly different from the control
cells that were treated with vehicle alone. **p < 0.01, *p < 0.05,
significantly different from the cells that were treated with 5αꢀ
DHT alone.
3
*
·
AQN . The resultant AQH was reoxidized with BPO to reꢀ
generate AQN and form a benzoyloxy radical. Then, reaction
of I with ynoate 1 leads to vinyl radical intermediate II, which
undergoes 5-exo-trig cyclization to afford spirocyclic intermeꢀ
diate III. The generated III was readily oxidized to form carꢀ
bocation intermediate III’ under the reaction condition. 1,2ꢀ
ester migration of III’ could proceed to form IV, and the proꢀ
cess is able to explain the formation of unexpected cyclization
product 3ba-3ja’ (Table 3 and 4). Finally, aromatization of IV
furnishes the corresponding 3ꢀacylꢀ4ꢀarylcoumarin 3 (route 1).
The other possible mechanism is acyl radical generation mediꢀ
ated by a benzoyloxy radical, which is generated by photo or
thermal decomposition of BPO (route 2).
3
7
##
■
CONCLUSTION
The biological efficacies of synthetic 3ꢀacylꢀ4ꢀarylcoumarins 3
were investigated by analyzing their effects on cellular PSA
levels and the proliferation of androgenꢀdependent prostate
cancer CWR22Rv1 cells. Among the 11 compounds, all exꢀ
cept for 3fa and 3ga significantly inhibited PSA secretion and
cell growth induced by 1 nM 5αꢀDHT, and 3ja produced the
largest decrease in PSA levels (Figure 1). As 3fa and 3ga,
with a bulky substituent on the 4ꢀphenylcoumarine moiety at
the 7ꢀposition, showed significantly less inhibitory potency in
androgenꢀdependent PSA secretion and proliferation than
In conclusion, we have achieved the novel formation of acyl
radicals and access to coumarin derivatives under visible light
irradiation. Our methodology uses harmless visible light, a
cheap and commercially available photocatalyst, and simple
aldehydes as radical sources. Further applications of the radiꢀ
cals for other substrates is being studied at our laboratory.
In future work, we will aim to further understand the mechanisms
involved in the antiproliferative activity against androgenꢀ
dependent prostate cancer cells; our synthesis and evaluation reꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
2
0
sults for the coumarins studied indicate their efficacy as potential
candidates for new therapeutics.
3-(4-Methoxybenzoyl)-4-phenyl-2H-chromen-2-one (3ac) :
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Purification by flash chromatography on silica gel (R = 0.23 in nꢀ
f
hexane : toluene : ethyl acetate : acetic acid = 7 : 7 : 1 : 0.15). 3ac
ꢀ
2
■
EXPERIMENTAL SECTION
General Methods. Unless otherwise noted, all reactants or reꢀ
was obtained as a yellow solid (23.7 mg, 67% yield, 6.7 × 10
1
mmol). H NMR (500 MHz, CDCl ) δ 7.78 (d, J = 8.6 Hz, 2H),
3
7
7
.61 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H),
.35–7.23 (m, 7H), 6.83 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H).
agents including dry solvents were obtained from commercial
suppliers and used as received. Flash column chromatography was
performed with YMCꢀGEL SIL 8 nm Sꢀ25 um (SLF 08S25). Anaꢀ
lytical thinꢀlayer chromatography (TLC) was carried out using
13
C
NMR (100 MHz, CDCl ) δ 190.6, 164.2, 159.0, 153.7, 152.5,
3
1
32.6, 132.5, 131.8, 129.5, 129.4, 128.7, 128.6, 127.9, 126.2,
124.6, 119.5, 117.2, 113.9, 55.5. HRMS: m/z (DART) calcd for
0
.25 mm commercial silica gel plates (Merck silica gel 60 F254).
+
C H O (M+H) 357.1121, found 357.1108.
23 17
4
The developed chromatogram was analyzed by UV lamp (254
nm). H NMR, C NMR and F NMR spectra were obtained on
a JEOL ECA 500 spectrometer (500 MHz for H NMR, 125 MHz
for C NMR, and 470 MHz for F NMR) and a JEOL AL 400
spectrometer (400 MHz for H NMR, 100 MHz for C NMR).
Chemical shifts (δ) are expressed in parts per million and are inꢀ
ternally referenced [0.00 ppm (tetramethylsilane) for H NMR and
20
1
13
19
3-Benzoyl-4-phenyl-2H-chromen-2-one (3ad) : Purification
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
by flash chromatography on silica gel (R = 0.16 in nꢀhexane :
f
1
3
19
toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.3). 3ad was
ꢀ2
1
13
obtained as a yellow solid (23.0 mg, 71% yield, 7.1 × 10 mmol).
1
H NMR (500 MHz, CDCl ) δ 7.80 (d, J = 8.0 Hz, 2H), 7.62 (ddd,
3
1
J = 8.0, 7.5, 1.7 Hz, 1H), 7.52–7.46 (m, 2H), 7.38–7.24 (m, 9H).
13
13
C NMR (125 MHz, CDCl ) δ 192.1, 158.8, 153.7, 152.9, 136.1,
3
7
7.0 ppm (CDCl ) for C NMR]. Highꢀresolution mass spectra
3
1
1
33.8, 132.7, 132.3, 129.5, 129.2, 128.7, 128.6, 128.6, 127.9,
(HRMS) were obtained on a JEOL JMSꢀT100TD and are reported
as m/z (relative intensity). Melting points were measured on a
Yanaco micro melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin Elmer Spectrum 100 FTIR
25.9, 124.6, 119.4, 117.2. HRMS: m/z (DART) calcd for
+
C H O (M+H) 327.1016, found 327.1008.
22
15
3
2
0
3
-(4-Fluorobenzoyl)-4-phenyl-2H-chromen-2-one
(3ae) :
Purification by flash chromatography on silica gel (R = 0.16 in nꢀ
spectrometer and are reported in terms of frequency of absorption
f
–1
hexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.31).
(cm ).
ꢀ
3ae was obtained as a yellow solid (22.7 mg, 66% yield, 6.6 × 10
Preparation of Substrates. Alkynoates (1a, 1b, 1c, 1d, 1e, 1f,
2
1
18
mmol). H NMR (400 MHz, CDCl ) δ 7.84–7.81 (m, 2H), 7.63
ddd, J = 8.2, 6.8, 1.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.37–7.24
m, 7H), 7.03 (t, J = 8.7 Hz, 2H). C NMR (125 MHz, CDCl3)
1
g) were prepared using modified literature procedures.
General Procedure for synthesis of 3. To a pyrex test tube
(1.5 cm × 14.5 cm) was added ynoate (1) (0.10 mmol), aldehyde
3
(
(
13
ꢀ
2
δ 190.5, 166.1 (d, J = 255.5 Hz), 158.7, 153.7, 153.1, 132.8, 132.7
d, J = 2.4 Hz), 132.2, 132.0 (d, J = 9.6 Hz), 129.6, 128.6, 128.0,
25.6, 124.7, 119.3, 117.2, 115.9 (d, J = 21.6 Hz). (one carbon
(
2) (1.0 mmol, 10 equiv), 2ꢀtertꢀbutylꢀanthraquinone (1.0 × 10
(
mmol, 10 mol%), benzoyl peroxide (0.2 mmol), potassium carꢀ
ꢀ
2
1
bonate (5.0 × 10 mmol, 50 mol%) and tertꢀamyl alcohol (1.0
mL). The reaction tube was degassed through the freezeꢀpumpꢀ
thaw cycles for three times, then it was backfilled with argon. The
mixture was stirred at ambient temperature for 20 h irradiated
with four of 23 W fluorescent lamps placed at ca. 7.0 cm form the
test tube. The reaction was quenched with saturated aqueous Naꢀ
HCO and extracted with Et O (20 mL × 3). The combined organꢀ
ic layer was dried over MgSO , filtered and concentrated in vac-
uo. The residue was purified by flash column chromatography on
silica gel to furnish the desired product.
19
merged to others) F NMR (470 MHz, CDCl ) δ −103.2. HRMS:
3
+
m/z (DART) calcd for C22H O F (M+H) 345.0921, found
14 3
345.0909.
2
0
3-(4-Chlorobenzoyl)-4-phenyl-2H-chromen-2-one
Purification by flash chromatography on silica gel (R
(3af) :
= 0.23 in nꢀ
f
hexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.3).
3
2
ꢀ2
3af was obtained as a yellow solid (20.8 mg, 58% yield, 5.8 × 10
4
1
mmol). H NMR (400 MHz, CDCl
) δ 7.74 (d, J = 8.7 Hz, 2H),
7.63 (ddd, J = 8.2, 6.8, 1.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H),
7.37–7.24 (m, 9H). C NMR (100 MHz, CDCl ) δ 191.0, 158.8,
153.8, 153.4, 140.4, 134.6, 132.9, 132.2, 130.6, 129.7, 129.0,
3
1
9
13
3-(4-Methylbenzoyl)-4-phenyl-2H-chromen-2-one
(3aa) :
3
Purification by flash chromatography on silica gel (R = 0.21 in nꢀ
hexane : toluene : ethyl acetate : acetic acid = 7 : 7 : 1 : 0.15). 3aa
was obtained as a yellow solid (25.0 mg, 74% yield, 7.4 × 10
mmol). H NMR (500 MHz, CDCl ) δ 7.71 (d, J = 8.0 Hz, 2H),
f
128.7, 128.7, 128.1, 125.5, 124.8, 119.3, 117.3. HRMS: m/z
ꢀ
2
+
(DART) calcd for C H O Cl (M+H) 361.0626, found
22
14
3
1
361.0633.
3
7
7
.61 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.47 (dd, J = 8.6, 1.2 Hz, 1H),
.35–7.23 (m, 7H), 7.16 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H).
4-Phenyl-3-(4-trifluoromethylbenzoyl)-2H-chromen-2-one
13
20
C
(3ag) : Purification by flash chromatography on silica gel (R
f
=
NMR (125 MHz, CDCl ) δ 191.6, 158.8, 153.7, 152.7, 144.9,
133.7, 132.6, 132.3, 129.4, 129.3, 128.7, 128.5, 127.9, 126.1,
124.6, 119.5, 117.1, 21.8. (one carbon merged to others) HRMS:
0.19 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
: 0.31). 3ag was obtained as a yellow solid (22.8 mg, 58% yield,
3
ꢀ
2
1
5.8 × 10 mmol). H NMR (400 MHz, CDCl
Hz, 2H), 7.68–7.63 (m, 3H), 7.50 (d, J = 8.2 Hz, 1H), 7.38–7.25
) δ 7.91 (d, J = 8.2
3
+
m/z (DART) calcd for C H O (M+H) 341.1172, found
23 17
3
13
3
41.1173.
-[4-(1,1-Dimethylethyl)benzoyl]-4-phenyl-2H-chromen-2-
one (3ab): Purification by flash chromatography on silica gel (Rf
(m, 7H). C NMR (125 MHz, CDCl ) δ 191.2, 158.6, 153.9,
153.7, 138.8, 134.7 (q, J = 32.4 Hz), 133.1, 132.0, 129.7, 129.4,
3
3
128.7, 128.6, 128.1, 125.6, 125.1, 124.8, 123.4 (q, J = 272.3 Hz),
19
=
1
0.17 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 :
: 0.3). 3ab was obtained as a yellow solid (28.4 mg, 74% yield,
119.2, 117.2. F NMR (470 MHz, CDCl ) δ −63.1. HRMS: m/z
3
+
(DART) calcd for C H O F (M+H) 395.0890, found 395.0901.
3-(3-Methylbenzoyl)-4-phenyl-2H-chromen-2-one
23
14
3 3
ꢀ
2
1
21
7.4 × 10 mmol). H NMR (500 MHz, CDCl ) δ 7.74 (d, J = 8.6
Hz, 2H), 7.61 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.47 (dd, J = 8.6, 1.2
Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.35–7.34 (m, 3H), 7.30–7.23
(3ah) :
3
Purification by flash chromatography on silica gel (R = 0.14 in nꢀ
f
hexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.3).
1
3
ꢀ
(m, 4H), 1.29 (s, 9H). C NMR (125 MHz, CDCl ) δ 191.7,
3ah was obtained as a yellow solid (26.3 mg, 77% yield, 7.7 × 10
3
2
1
1
1
58.9, 157.6, 153.6, 152.8, 133.6, 132.6, 132.3, 129.4, 129.2,
28.7, 128.5, 127.9, 126.2, 125.6, 124.6, 119.5, 117.1, 35.2, 30.9.
mmol). H NMR (500 MHz, CDCl ) δ 7.62–7.56 (m, 2H), 7.46
(d, J = 8.6 Hz, 1H), 7.34–7.28 (m, 4H), 7.25–7.20 (m, 4H), 7.15–
7.10 (m, 2H), 2.39 (s, 3H). C NMR (125 MHz, CDCl ) δ 193.7,
3
13
m.p.: 178.0–178.6 °C. HRMS: m/z (DART) calcd for C H O
26
23
3
3
+
(M+H) 383.1642, found 383.1644. FTIR: (ATR) 3062, 2964,
158.8, 153.6, 152.3, 140.1, 135.8, 132.6, 132.4, 132.4, 131.9,
131.1, 129.3, 128.5, 128.4, 127.9, 127.4, 125.5, 124.6, 119.5,
ꢀ
1
2869, 1713, 1668, 1604, 1564, 1356, 1266 cm .
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
+
1
17.1, 21.3. HRMS: m/z (DART) calcd for C H O (M+H)
7.18 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.81 (dd, J =
2
3
17
3
13
1
2
3
4
5
6
7
8
9
341.1172, found 341.1181.
8.6, 2.9 Hz, 1H), 3.91 (s, 3H). C NMR (125 MHz, CDCl3)
δ 192.5, 163.5, 159.2, 155.6, 153.5, 136.5, 133.6, 132.7, 129.4,
129.2, 129.0, 128.6, 128.5, 122.6, 112.9, 112.8, 100.9, 55.9.
2
0
3
-(3-Methoxybenzoyl)-4-phenyl-2H-chromen-2-one (3ai) :
Purification by flash chromatography on silica gel (R = 0.18 in nꢀ
f
+
hexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.3). 3ai
HRMS: m/z (DART) calcd for C H O (M+H) 357.1121, found
2
3
16
4
ꢀ2
was obtained as a yellow solid (16.7 mg, 47% yield, 4.7 × 10
357.1122.
1
mmol). H NMR (500 MHz, CDCl ) δ 7.62 (ddd, J = 8.6, 6.9, 1.7
Hz, 1H), 7.47 (dd, J = 8.0, 1.2 Hz, 1H), 7.38–7.34 (m, 5H), 7.30–
7.24 (m, 5H), 7.06 (ddd, J = 8.0, 2.3, 1.2 Hz, 1H), 3.78 (s, 3H).
C NMR (125 MHz, CDCl ) δ 192.0, 159.7, 158.8, 153.7, 152.9,
37.4, 132.7, 132.3, 129.6, 129.5, 128.7, 128.6, 128.0, 126.0,
6-Iodo-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one
3
(3da): Purification by flash chromatography on silica gel (R =
f
0.25 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
: 0.3). 3da was obtained as a yellow solid (16.8 mg, 36% yield,
1
3
3
ꢀ
2
1
1
1
3.6 × 10 mmol). H NMR (400 MHz, CDCl ) δ 7.84 (d, J = 1.5
3
24.6, 122.5, 120.7, 119.4, 117.2, 112.6, 55.4. HRMS: m/z
Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.57 (dd, J = 8.2, 1.5 Hz, 1H),
7.35–7.33 (m, 3H), 7.25–7.23 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(DART) calcd for C H O (M+H) 357.1172, found 357.1167.
23
17
4
20
13
3
-(3-Chlorobenzoyl)-4-phenyl-2H-chromen-2-one
(3aj) :
6.97 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H). C NMR (125 MHz,
Purification by flash chromatography on silica gel (R = 0.20 in nꢀ
hexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.3).
CDCl ) δ 191.3, 158.0, 153.4, 152.2, 145.1, 133.9, 133.6, 131.9,
f
3
129.6, 129.4, 128.8, 128.7, 128.6, 126.6, 126.2, 119.0, 98.5, 21.8.
ꢀ
2
3aj was obtained as a yellow solid (18.7 mg, 52% yield, 5.2 × 10
(one carbon merged to others) m.p.: 219.9–221.2 °C. HRMS: m/z
1
+
mmol). H NMR (500 MHz, CDCl ) δ 7.74 (t, J = 1.7 Hz, 1H),
.68–7.62 (m, 2H), 7.49–7.46 (m, 2H), 7.38–7.35 (m, 3H), 7.33–
.25 (m, 5H). C NMR (125 MHz, CDCl ) δ 190.9, 158.6, 153.7,
53.6, 137.6, 134.9, 133.7, 133.0, 132.1, 129.9, 129.7, 129.0,
28.7, 128.6, 128.1, 127.3, 125.2, 124.8, 119.2, 117.3. HRMS:
m/z (DART) calcd for C H O Cl (M+H) 361.0626, found
(DART) calcd for C H O I (M+H) 467.0139, found 467.0156.
3
23 16
3
7
7
1
1
FTIR: (ATR) 3325, 2964, 2916, 2848, 1714, 1665, 1603, 1552,
13
ꢀ1
1372, 1209, 1029 cm .
3
6-Acetoxy-3-(4-Methylbenzoyl)-4-phenyl-2H-chromen-2-one
(3ea): Purification by flash chromatography on silica gel (R =
f
+
0.37 in nꢀhexane : toluene : ethyl acetate : acetic acid = 7 : 7 : 1 :
0.1). 3ea was obtained as a white solid (31.4 mg, 79% yield, 7.9 ×
2
2
14
3
3
61.0639.
3-(2-Methylbenzoyl)-4-phenyl-2H-chromen-2-one
2
0
ꢀ2
1
(3ak) :
10 mmol). H NMR (500 MHz, CDCl ) δ 7.69 (d, J = 8.6 Hz,
3
Purification by flash chromatography on silica gel (R = 0.23 in nꢀ
2H), 7.34–7.33 (m, 3H), 7.29 (d, J = 8.6 Hz, 1H), 7.26–7.24 (m,
f
hexane : toluene : ethyl acetate : acetic acid = 7 : 7 : 1 : 0.15). 3ak
3H),7.17 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 2.3 Hz, 1H), 2.36 (s,
ꢀ
2
13
was obtained as a yellow solid (24.0 mg, 70% yield, 7.0 × 10
6H). C NMR (125 MHz, CDCl ) δ 191.4, 168.7, 158.6, 154.2,
3
1
mmol). H NMR (500 MHz, CDCl ) δ 7.64–7.59 (m, 3H), 7.47
153.6, 152.3, 145.0, 133.7, 132.2, 129.5, 129.4, 129.4, 128.8,
128.6, 125.5, 118.6, 117.3, 110.6, 21.7, 21.1. (one carbon merged
3
13
(
dd, J = 8.6, 1.2 Hz, 1H), 7.35–7.23 (m, 9H), 2.33 (s, 3H).
C
NMR (125 MHz, CDCl ) δ 192.3, 158.8, 153.7, 152.8, 138.4,
to others) m.p.: 198.2–198.6 °C. HRMS: m/z (DART) calcd for
3
+
1
36.1, 134.7, 132.6, 132.3, 129.6, 129.4, 128.6, 128.5, 128.5,
C
25
H
18
O
5
(M+H) 399.1154, found 399.1160. FTIR: (ATR) 3061,
ꢀ
128.0, 126.7, 126.1, 124.6, 119.4, 117.2, 21.2. HRMS: m/z
2916, 2857, 1767, 1718, 1670, 1605, 1563, 1361, 1280, 1195 cm
+
1
(DART) calcd for C H O (M+H) 341.1172, found 341.1168.
.
23
17
3
3
-(4-Methylbenzoyl)-6-methyl-4-phenyl-2H-chromen-2-one
6-Acetyl-3-(4-Methylbenzoyl)-4-phenyl-2H-chromen-2-one
(
3ba): Purification by flash chromatography on silica gel (R =
(3fa): Purification by flash chromatography on silica gel (R =
f
f
0
0
×
.16 in nꢀhexane : toluene : ethyl acetate : acetic acid = 5 : 5 : 1 :
0.37 in nꢀhexane : toluene : ethyl acetate : acetic acid = 5 : 5 : 1 :
0.1). 3fa was obtained as a white solid (23.7 mg, 62% yield, 6.2 ×
.1). 3ba was obtained as a yellow solid (24.7 mg, 70% yield, 7.0
ꢀ2
1
ꢀ2
1
10 mmol). H NMR (400 MHz, CDCl ) δ 7.70 (d, J = 8.2 Hz,
10 mmol). H NMR (400 MHz, CDCl
1H), 7.80 (dd, J = 8.0 Hz, J = 1.7 Hz, 1H), 7.70 (d, J = 8.6 Hz,
2H), 7.40–7.36 (m, 4H), 7.27–7.26 (m, 2H), 7.18 (d, J = 8.0 Hz,
3
) δ 7.98 (d, J = 1.7 Hz,
3
2
H), 7.34–7.31 (m, 3H), 7.27–7.25 (m, 3H), 7.17–7.15 (m, 3H),
1
2
1
3
7.06 (d, J = 8.2 Hz, 1H), 2.49 (s, 3H), 2.35 (s, 3H). C NMR (125
MHz, CDCl ) δ 192.0, 163.4, 159.2, 155.6, 153.2, 144.7, 134.1,
13
2H), 2.68 (s, 3H), 2.36 (s, 3H). C NMR (125 MHz,
3
1
1
1
3
1
32.8, 129.4, 129.3, 129.3, 129.0, 128.6, 128.5, 122.8, 112.9,
00.8, 55.9, 21.8. (one carbon merged to others) m.p.: 194.1–
95.2 °C. HRMS: m/z (DART) calcd for C H O (M+H)
55.1334, found 355.1327. FTIR: (ATR) 3060, 2922, 1715, 1670,
605, 1555, 1361, 1262 cm .
CDCl
) δ 196.4, 191.1, 158.4, 153.5, 151.6, 145.2, 139.7, 133.4,
3
131.8, 129.7, 129.4, 129.4, 128.7, 128.6, 128.3, 128.0, 123.7,
+
122.9, 117.0, 26.9, 21.8. m.p.: 213.5–214.1 °C. HRMS: m/z
2
4
19
3
+
(DART) calcd for C25
H
18
O
4
(M+H) 383.1205, found 383.1205.
ꢀ1
ꢀ1
FTIR: (ATR) 2928, 1721, 1670, 1605, 1355, 1267 cm .
3-(4-Methylbenzoyl)-6-methylester-4-phenyl-2H-chromen-2-
one (3ga): Purification by flash chromatography on silica gel (R
6
-Methoxy-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one
(3ca): Purification by flash chromatography on silica gel (R =
f
f
0
0
×
.35 in nꢀhexane : toluene : ethyl acetate : acetic acid = 5 : 5 : 1 :
= 0.35 in nꢀhexane : toluene : ethyl acetate : acetic acid = 5 : 5 : 1
: 0.1). 3ga was obtained as a white solid (30.2 mg, 76% yield, 7.6
.1). 3ca was obtained as a yellow solid (21.5 mg, 58% yield, 5.8
ꢀ
2
1
ꢀ2
1
10 mmol). H NMR (400 MHz, CDCl ) δ 7.70 (d, J = 8.0 Hz,
× 10 mmol). H NMR (400 MHz, CDCl ) δ 8.08 (s, 1H), 7.88 (d,
3
3
2
6
3
H), 7.33–7.31 (m, 3H), 7.26–7.24 (m, 2H), 7.19–7.15 (m, 3H),
.94 (d, J = 2.9 Hz, 1H), 6.81 (dd, J = 8.6 Hz, J = 2.9 Hz, 1H),
.91 (s, 3H), 2.35 (s, 3H). C NMR (125 MHz, CDCl ) δ 192.0,
J = 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.37–7.35 (m, 4H),
7.28ꢀ7.27 (m, 2H), 7.17 (d, J = 7.7 Hz, 2H), 3.99 (s, 3H), 2.36 (s,
1
2
13
13
3H). C NMR (125 MHz, CDCl
) δ 191.2, 165.5, 158.3, 153.2,
3
3
163.4, 159.2, 155.6, 153.2, 144.7, 134.0, 132.8, 129.4, 129.3,
129.3, 129.2, 129.0, 128.6, 128.5, 122.8, 112.9, 112.8, 100.9,
151.6, 145.2, 133.6, 133.4, 131.8, 129.7, 129.4, 128.7, 128.6,
128.0, 127.9, 125.1, 122.9, 118.2, 52.8, 21.8. (one carbon merged
5
5.9, 21.7. m.p.: 199.9–201.0 °C. HRMS: m/z (DART) calcd for
to others) m.p.: 169.0–170.8 °C. HRMS: m/z (DART) calcd for
+
+
C H O (M+H) 371.1205, found 355.1219. FTIR: (ATR) 3062,
2
C
25
H
18
O
5
(M+H) 399.1154, found 399.1156. FTIR: (ATR) 3390,
2
4
18
4
ꢀ
1
922, 1721, 1668, 1605, 1588, 1356, 1279, 964 cm .
-Benzoyl-7-methoxy-4-phenyl-2H-chromen-2-one (3cd)
2953, 1717, 1671, 1606, 1557, 1435, 1420, 1359, 1277, 1230,
12i
ꢀ1
3
:
1095 cm .
Purification by flash chromatography on silica gel (R = 0.10 in nꢀ
3-(4-Methylbenzoyl)-7-methoxyl-4-phenyl-2H-chromen-2-one
f
hexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1 : 0.3).
(3ha): Purification by flash chromatography on silica gel (R =
f
ꢀ
3cd was obtained as a yellow solid (11.0 mg, 31% yield, 3.1 × 10
0.15 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
: 0.3). 3ha was obtained as a yellow solid (18.5 mg, 50% yield,
2
1
mmol). H NMR (500 MHz, CDCl ) δ 7.80 (d, J = 7.5 Hz, 2H),
3
ꢀ
2
1
7
.49 (t, J = 7.5 Hz, 1H), 7.37–7.30 (m, 5H), 7.26–7.24 (m, 2H),
5.0 × 10 mmol). H NMR (400 MHz, CDCl ) δ 7.70 (d, J = 8.2
3
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Page 8 of 9
Hz, 2H), 7.41 (d, J = 9.2 Hz, 1H), 7.35–7.33 (m, 3H), 7.28–7.27
(m, 2H), 7.20–7.15 (m, 3H), 6.71 (d, J = 2.9 Hz, 1H), 3.71 (s,
tography. An adduct of aldehyde with radical scavenger was deꢀ
tected as shown in Figures S1, Supporting Information. H NMR
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
3H), 2.36 (s, 3H). C NMR (125 MHz, CDCl ) δ 191.8, 159.0,
(500 MHz, CDCl ) δ 7.97 (d, J = 8.6 Hz, 2H), 7.25ꢀ7.27 (m, 2H),
3
3
1
1
56.1, 152.4, 148.1, 144.9, 133.7, 132.4, 129.5, 129.4, 129.3,
28.6, 126.5, 120.0, 119.7, 118.1, 110.7, 55.8, 21.8. (one carbon
2.42 (s, 3H), 1.57–1.81 (m, 5H), 1.44ꢀ1.48 (m, 1H), 1.27 (s, 6H),
1
3
1.11 (s, 6H). C NMR (125 MHz, CDCl ) δ 166.5, 143.5, 129.6,
3
merged to others) m.p.: 154.7–155.4 °C. HRMS: m/z (DART)
129.1, 126.9, 60.4, 39.0, 31.9, 21.7, 20.8, 17.0.
+
calcd for C H O (M+H) 371.1278, found 371.1268. FTIR:
Cell culture Experiment CWR22Rv1 cells were obtained
from American Type Culture Collection (Manassas, VA), and
grown in RPMI medium supplemented with 5% fetal bovine seꢀ
rum, penicillin (100 U/ml) and streptomycin (100 µg/ml) at 37 °C
24
19
4
(
ATR) 3060, 2924, 2853, 1711, 1670, 1604, 1566, 1359, 1267,
ꢀ
1
1235, 1037 cm .
5-Bromo-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one
(
3ia): Purification by flash chromatography on silica gel (R =
in a humidified incubator containing 5% CO2.
f
0
:
×
.17 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
0.3). 3ia was obtained as a yellow solid (7.4 mg, 18% yield, 1.8
Reverse transcription and quantitative PCR (qPCR) Total
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
RNA was isolated from the cells using the TRI reagent (Cosmo
Bio, Tokyo, Japan), and reverse transcription was performed usꢀ
ing a ReverTra Ace qPCR RT kit (TOYOBO, Osaka, Japan) acꢀ
cording to the manufacturer’s instructions. qPCR was performed
on a TaKaRa Thermal Cycler Dice RealꢀTime PCR System
(Takara Bio Inc, Otsu, Japan) using the KOD SYBR qPCR Mix
(TOYOBO). Expression levels of PSA mRNA in the cells were
normalized relative to that of βꢀactin using 5’ꢀ
ꢀ2
1
10 mmol). H NMR (500 MHz, CDCl ) δ 7.84 (dd, J = 8.0, 1.7
3
Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.35–7.32 (m, 3H), 7.25–7.21
m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 1H), 2.36 (s,
(
13
3H). C NMR (125 MHz, CDCl ) δ 191.1, 157.7, 152.3, 150.4,
3
145.1, 136.0, 133.5, 132.1, 129.6, 129.5, 129.4, 128.6, 127.2,
1
26.9, 125.1, 121.0, 110.9, 21.8. (one carbon merged to others)
m.p.: 201.6–202.2 °C. HRMS: m/z (DART) calcd for C H O Br
2
3
16
3
+
(
2
M+H) 419.0277, found 419.0925. FTIR: (ATR) 3062, 2923,
CCTCCTGAAGAATCGATTCCTꢀ3’
GAGGTCCACACACTGAAGTTꢀ3’
CAAGAGATGGCCGCTGCTꢀ3’
and
PSA
and
5’ꢀ
5’ꢀ
5’ꢀ
ꢀ1
854, 1725, 1669, 1605, 1555, 1442, 1348, 1056, 975 cm .
-Bromo-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one
3ia’): Purification by flash chromatography on silica gel (R =
for
and
7
(
TCCTTCTGCATCCTGTCGGCAꢀ3’ for βꢀactin as a primer set,
f
2
1
0.27 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
which was served as an internal control using 2ꢀꢂꢂCtꢀmethod.
:
×
7
2
1
1
0.3). 3ia’ was obtained as a white solid (12.3 mg, 29% yield, 2.9
Cell growth assay The cells were plated into a 96ꢀwell microꢀ
ꢀ
2
1
3
10 mmol). H NMR (400 MHz, CDCl ) δ 7.71–7.67 (m, 3H),
plate at a density of 3 x 10 cells/well into phenolꢀred deficient
3
.39–7.34 (m, 5H), 7.26–7.24 (m, 2H), 7.17 (d, J = 8.7 Hz, 2H),
RPMI medium supplemented with 5% charcoalꢀstripped FBS plus
antibiotics. The cells were then treated for 72 h with compounds
or DMSO. The number of viable CWR22Rv1 cells was measured
by the MTT method using 2ꢀ(4ꢀiodophenyl)ꢀ3ꢀ(4ꢀnitrophenyl)ꢀ5ꢀ
13
.36 (s, 3H). C NMR (125 MHz, CDCl ) δ 191.2, 158.3, 152.6,
3
51.6, 145.3, 135.5, 133.6, 131.7, 130.2, 129.9, 129.5, 128.9,
28.7, 127.2, 121.3, 119.0, 117.6, 21.9. (one carbon merged to
22
(2,4ꢀdisulfophenyl)ꢀ2Hꢀtetrazolium.
Data are expressed as
others) m.p.: 219.8–220.1 °C. HRMS: m/z (DART) calcd for
+
means ± SD of at least three independent experiments.
C H O Br (M+H) 419.0277, found 419.0282. FTIR: (ATR)
2
3
16
3
Statistical analysis Data are expressed as the means ± SD of at
least three independent experiments, unless otherwise noted. Staꢀ
tistical evaluation of the data was performed by using the unꢀ
paired Student’s tꢀtest and ANOVA followed by Fisher’s test.
3
1
425, 3062, 2919, 2850, 2121, 1898, 1713, 1667, 1603, 1557,
ꢀ
1
352, 1259, 1060, 968 cm .
-(4-Methylbenzoyl)-5-methyl-4-phenyl-2H-chromen-2-one
3ja): Purification by flash chromatography on silica gel (R =
3
(
f
0
:
.16 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
0.3). 3ja was obtained as a yellow solid (8.3 mg, 23% yield, 2.3
■
ASSOCIATED CONTENT
ꢀ
2
1
× 10 mmol). H NMR (500 MHz, CDCl ) δ 7.71 (d, J = 8.6 Hz,
2H), 7.46 (dd, J = 7.5, 1.2 Hz, 1H), 7.33–7.31 (m, 3H), 7.26–7.24
3
Supporting Information
13
The Supporting Information is available free of charge on the
ACS Publications website.
(m, 2H), 7.17–7.09 (m, 4H), 2.55 (s, 3H), 2.36 (s, 3H). C NMR
(
125 MHz, CDCl ) δ 191.8, 158.9, 153.0, 152.0, 144.8, 133.9,
3
1
13
Copies of H and C NMR spectra of all pure products
1
1
6
3
33.8, 132.7, 129.4, 129.3, 128.7, 128.4, 126.6, 125.9, 125.7,
24.0, 119.2, 21.8, 15.7. (one carbon merged to others) m.p.:
(PDF).
+
3.1–64.0 °C. HRMS: m/z (DART) calcd for C H O (M+H)
2
4
19
3
■
AUTHOR INFORMATION
55.1334, found 355.1325. FTIR: (ATR) 3061, 2924, 1716, 1670,
ꢀ
1
1604, 1571, 1353, 1263 cm .
Corresponding Author
3-(4-Methylbenzoyl)-7-methyl-4-phenyl-2H-chromen-2-one
Eꢀmail: yamaguchi@gifuꢀpu.ac.jp
Eꢀmail: itoha@gifuꢀpu.ac
(
3ja’): Purification by flash chromatography on silica gel (R =
f
0
:
×
.14 in nꢀhexane : toluene : ethyl acetate : acetic acid = 15 : 15 : 1
0.3). 3ja’ was obtained as a white solid (15.8 mg, 45% yield, 4.5
Notes
ꢀ2
1
10 mmol). H NMR (500 MHz, CDCl ) δ 7.70 (d, J = 8.0 Hz,
3
The authors declare no competing financial interest.
2
H), 7.42 (dd, J = 8.6, 1.7 Hz, 1H), 7.37–7.33 (m, 4H), 7.27–7.26
(
m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 2.36 (s, 3H), 2.32
ORCID
13
(s, 3H). C NMR (125 MHz, CDCl ) δ 191.8, 159.0, 152.7,
151.9, 144.8, 134.4, 133.8, 133.6, 132.5, 129.4, 129.3, 129.3,
3
Eiji Yamaguchi: 0000ꢀ0002ꢀ1167ꢀ8832
Satoshi Endo:0000-0003-0578-9672
Akira Ikari:0000-0003-2696-0897
1
1
3
1
28.7, 128.5, 127.5, 126.1, 119.1, 116.9, 21.8, 20.9. m.p.: 175.7–
+
76.9 °C. HRMS: m/z (DART) calcd for C H O (M+H)
2
4
19
3
55.1334, found 355.1335. FTIR: (ATR) 3058, 2923, 1714, 1670,
ꢀ1
REFERENCES
604, 1566, 1361, 1268 cm .
(1) (a) Ruan, B.ꢀF.; Cheng, H.ꢀJ.; Ren, J.; Li, H.ꢀL.; Guo, L.ꢀL.;
Zhang, X.ꢀX.; Liao, C. Eur. J. Med. Chem. 2015, 103, 185. (b)
Sandhu, S.; Bansal, Y.; Silakari, O.; Bansal, G. Bioorg. Med.
Chem. 2014, 22, 3806. (c) Carradori, S.; Secci, D.; Bolasco, A.;
The Radical Trapping Experiments. Following the general
procedure, except TEMPO (46.9 mg, 0.30 mmol.) was added, the
reaction of 1a (22.7 mg, 0.10 mmol) and 2a (118.0 ꢁl, 1.0 mmol)
for 20
h
afforded 2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl 4ꢀ
methylbenzoate (5) as a colerless oil (3.1mg) after flash chromaꢀ
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
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