Palladium-Catalyzed, Copper(I)-Promoted Methoxycarbonylation of Arylboronic Acids with O-Methyl S-Aryl Thiocarbonates

Article abstract of DOI:10.1021/acs.joc.0c00198

Here, we report O-methyl S-aryl thiocarbonates as a versatile esterification reagent for palladium-catalyzed methoxycarbonylation of arylboronic acid in the presence of copper(I) thiophene-2-carboxylate (CuTC). The reaction condition is mild, and a variety of substituents including sensitive-Cl,-Br, and free-NH₂ could be tolerated. Further applications in the late-stage esterification of some pharmaceutical drugs demonstrate the broad utility of this method.

Full text of DOI:10.1021/acs.joc.0c00198

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Article
Palladium-catalyzed, Copper(I)-promoted Methoxycarbonylation
of Arylboronic Acids with O-methyl S-aryl thiocarbonates
Ya-Fang Cao, Ling-Jun Li, Min Liu, Hui Xu, and Hui-Xiong Dai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00198 • Publication Date (Web): 20 Feb 2020
Downloaded from pubs.acs.org on February 20, 2020
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The Journal of Organic Chemistry
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Palladium-catalyzed, Copper(I)-promoted Methoxycarbonylation of
Arylboronic Acids with O-methyl S-aryl thiocarbonates
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Ya-Fang Cao, Ling-Jun Li, Min Liu, †, ‡ Hui Xu,* Hui-Xiong Dai*
§
†, ‡
, †
,†, ‡
†Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai
01203, China
2
‡University of Chinese Academy of Sciences, Beijing, China
§Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu 215123, China
.
.
.
.
.
Mild reaction conditions
Gram-scale synthesis
O
B(OH)2
+
O
Pd2dba3,CuTC
,4-dioxane, 60 o
OMe
Broad substrate scope
Compatible with -Br and free -NH2
Late-state of esterification of drugs
R
R
ArS
OMe
1
C
O
Me
H
O
O
OEt
H
H
H
MeO
MeO
O
MeO
H
H
NH2 MeO
Me Me
O
O
O
O
Me O
from unprotected amine
from clofibrate
from epiandrosterone
from estrone
ABSTRACT: Here we report O-methyl S-aryl thiocarbonates as a versatile esterification reagent for palladium-catalyzed
methoxycarbonylation of arylboronic acid in the presence of copper(I) thiophene-2-carboxylate (CuTC). The reaction condition is
2
mild, and a variety of substituents including sensitive -Cl, -Br, and free -NH could be tolerated. Further applications in the late-
stage esterification of some pharmaceutical drugs demonstrate the broad utility of this method.
INTRODUCTION
oxidative esterifications initiate the catalytic circle from Pd(II),
and terminate with Pd(0) species. Thus stoichiometric amount
external oxidant are required to regenerate the Pd(II) for
catalytic turnover (Scheme 1a). In 2010, Lei developed a
novel palladium-catalyzed aerobic oxidative carbonylation of
Aryl carboxylate esters are important structural motifs
found in pharmaceuticals, agrochemicals, and organic
materials.1 Many synthetic methods have been developed,
including traditional condensation of carboxylic acids with
alcohol, substitution of carbonate derivatives with Grignard
5
arylboronate esters by using air as the sole oxidant. Recently,
2
3
Ge and coworkers successfully applied potassium oxalate
reagents, and carbonylation of aryl (pseudo)halides with CO.
monoesters
in
the
esterification
of
potassium
.6 To
Recently, Pd-catalyzed oxidative esterification from broadly
accessible organometallic reagent has become a powerful
phenyltrifluoroborate in the present of 2 equiv. of K
2 2 8
S O
4
obviate the need for external oxidant, redox-neutral coupling
alternative to traditional synthetic methods. Conventionally,
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The Journal of Organic Chemistry
of Ar–M with internally oxidative reagent would be an
have been widely applied in the ketone synthesis.14 Fukuzawa
reported the palladium-catalyzed C-formylation of arylzincs
by utilizing the S-phenyl thioformate as versatile
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appealing strategy. However, this synthetic strategy is plagued
by the limited repertoire of compatible esterification reagent.
Jousseaume and Deng reported the Pd(0)-catalyzed oxidant-
free esterification of arylorganotins and arylboronic acids with
chloroformate (Scheme 1b).7,8 Wu elegantly utilized the
dialkyldicarbonates as esterification agents to furnish the
arylboronic acids.9 Recently, Kakiuchi, 10 Shi,11 and Xu12
reported Ru- and Pd-catalyzed C–H esterification with
a
formylating agent.15 Very recently, Kambe, 16 Hosoya, 17
Sanford18 reported Pd-, Rh-, Ni-catalyzed decarbonylative
thioetherification and borylation of aromatic thioesters.
Prompted by these reports, we questioned whether we could
realize the palladium-catalyzed C-esterification of arylmetallic
compounds with S-aryl thiocarbonate. Boronic acids are low
toxic, relatively stable to air and moisture, commercially
available, and broadly tolerant for functional group.
Considering these practical advantages, we reported here the
palladium-catalyzed methoxycarbonylation of aryl boronic
acids with O-methyl S-aryl thiocarbonate under mild and
redox-neutral conditions (Scheme 1c).
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chloroformate and Boc O. Although these protocols are often
effective, both chloroformate and dialkyldicarbonate are very
reactive and susceptible to nucleophiles, such as free amines.
Thus, the development of
a
practical and versatile
esterification reagent would be highly desirable.
Scheme 1. Esterification of Organometallic Reagent
RESULTS AND DISCUSSION
a: Oxidative esterification of ArM
O
M
Pd(OAc)2
R1
OMe
We commenced our studies by treating aryl boronic acids 1a,
+
CO
R1
Oxidant, base, MeOH
O-methyl S-p-toluenyl thiocarbonate 2 with 5 mol% Pd
at 60 oC (Table 1).
.16 mmol CuTc, 20 mol% PCy
2 3
(dba) ,
b: Redox-neutral esterification of ArM via C-Cl or C-O cleavage
O
0
3
O
Cl
OR
O
M
Pd(OAc)2/PPh3
Dioxane, base
R2
+
or
R2
OR
Gratifyingly, methoxycarbonylation of aryl boronic acids 1
occurred smoothly, giving the desired product 3a in 10%
yields (entry 1). Further screening of various phosphine
O
RO
O
OR
c: Redox-neutral esterification of ArB(OH)2 via C-S cleavage
O
Pd2dba3, CuTC
B(OH)2
O
OMe
R3
R3
+
This work
ArS
OMe
ligands showed that PPh and TFP could also promote the
3
1
2
3
esterification reagent
reaction, and TFP was the optimal choice (entry 2-5). Cu salts
Thioesters are versatile building blocks in organic synthesis.
Due to the feasibility of oxidative addition into the C(O)–S
bond of thioester, transition-metal-catalyzed C–S bond
activations of thioester have being one of the most important
tools for the construction of carbon-carbon and carbon-
heteroatom bonds.13 For example, palladium-catalyzed C-
acylations of organozinc and organoboronic reagents with
thioester, namely Fukuyama and Liebeskind–Srogl reaction,
are proposed to form strong Cu–S bound with thioester, thus
facilitating the transmetalation in Liebeskind-Srogl cross-
coupling reaction. However, the yields decreased when we
replaced CuTC with other Cu salts (entries 6-8). Lowering or
increasing the reaction temperature lead to the decreased yield
of esterated products (entries 9-11). The yield could be further
improved to 80% by using 1,4-dioxane as the reaction solvent
(Table 1, entry 12-17). For further investigation the effect of
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different S-substituents, we screened
The Journal of Organic Chemistry
a
variety of
further functionalization. 3,5-, 2,4-dimethoxy phenylboronic
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electronically and sterically diverse O-methyl S-phenyl
acid gave the corresponding disubstituted methyl benzoate 3x
thiocarbonates,
and
found
O-methyl
S-p-toluenyl
Table 2. Substrate Scope of Arylboronic Acidsa
thiocarbonate 2 was the optimal esterification agent (see
supporting information).
O
B(OH)2
+
O
2 3
Pd dba , TFP, CuTC
OMe
O
R
R
p-TolS
OMe
,4-dioxane, 60 o
C
1
Table 1.Optimization of the Reaction Conditionsa
1a-1aj
2
3a-3aj
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O
Me
O
OMe O
F
OMe
OMe
OMe
OMe
O
B(OH)2
+
O
Pd dba , Ligand, [Cu]
2
3
OMe
3a, 80%
3b, 65%
3c, 70%
3d, 40%
p-TolS
OMe
Solvent, Temp
Ph
O
O
O
O
1a
2
3a
Me
MeO
F3C
F
OMe
OMe
OMe
OMe
OMe
o
Yield/%c
Entry
Ligand
[Cu]
Temp/ C
Solvent
1
2
3
4
5
6
7
8
9
PCy3
PPh3
TFP
CuTC
CuTC
CuTC
CuTC
CuTC
CuOAC
CuMeSal
CuCl
60
60
60
60
60
60
60
60
rt
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
DCE
10
47
50
trace
18
24
29
trace
22
45
40
17
15
21
9
3e, 50%
3f, 81%
3g, 70%
3h, 65%
O
O
O
O
Cl
Br
NC
OMe
OMe
OMe
OMe
OMe
OMe
dppe
Johnphos
TFP
3i, 67%
3j, 62%
3k, 53%
3l, 60%
O
O
O
O
TFP
Ph
H2N
OMe
OMe
TFP
TFP
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
Me
Cl
MeO
3m, 80%
3n, 65%b
3o, 80%
3p, 82%
10
11
12
TFP
40
80
60
60
60
60
60
60
O
O
O
O
TFP
TFP
OMe
OMe
OMe
OMe
OMe
13
TFP
F3CO
F
Br
14
15
16
TFP
Acetonitrile
DMSO
3
q, 53%
3r, 70%
3s, 63%
3t, 60%
TFP
O
TFP
Dioxane
Dioxane
75
80
O
O
O
MeO
17b
TFP
OMe
OMe
a
Reaction conditions: 1a (0.12 mmol), 2 (0.1 mmol), Pd2(dba)3 (5 mol%), Ligand (20
mol%), [Cu] (1.6 equiv.), Solvent (1 mL), temp, N2, 16 h. TFP = Tri(2-furyl)phosphine.
dppe 1,2-Bis(diphenylphosphino)ethane, JohnPhos (2-biphenyl)di-tert-
F3C
Ph
TMS
OMe
=
=
3u, 60%
3v, 85%
3w, 70%b
3x, 70%c
O
b
c
1
butylphosphine. 1a (0.1 mmol), 2 (0.12 mmol). The yield was determined by H NMR
analysis of crude product using CH2Br2 as internal standard.
O
O
OMe
O
OMe
OMe
OMe
MeO
OMe
With the optimized reaction conditions in hand, we examined
the scope of various aryl boronic acids. As shown in Table 2,
y, 53%c
3aa,70%
3ab,70%
OMe
3
3z, 80%
O
O
OMe
O
O
OMe
OMe
N
under the optimized conditions (5 mol% Pd
2
(dba)
3
, 20 mol%
N
3ad, 50%b
3ae, 45%c
3af, 44%c
3ac, 81%
o
O
O
O
O
TFP, 0.16 mmol CuTc, 60 C), the methoxycarbonylation of
aryl boronic acid 1 with esterification agent 2 appeared to be
quite general with respect to the substituents. Aryl boronic
acid bearing electron-donating and -withdrawing groups (-Me,
OMe
MeO
OMe
OMe
OMe
N
MeO
N
N
H
O
3
ag, 49%c
3ah, 50%c
3ai, 65%c
3aj, 60%c
a
Arylboronic acid 1 (0.1 mmol), 2 (0.12 mmol), Pd (dba) (5 mol%), TFP (20 mol%), CuTC
2
3
0.16 mmol), 1,4-dioxane (1 mL), 60 oC, N2,16 h. b2 (0.2 mmol). c 2 (0.15 mmol).
(
3 3
-OMe, -OCF , -Ph, -F, -Cl, -Br, -CN, -CF ) were smoothly
and 3y in 70% and 53% yields, respectively. It is worth noting
that the substrates containing unprotected amine (3n, 3ai)
could be tolerated with the esterification reagents 2. For
polycyclic arene substrates, including naphthyl, phenanthrenyl,
and pyrenylboronic acid, esterificated products 3z-3ac were
obtained in yields of 70-80%. When alkenyl boronic acid 1ad
esterificated, giving the desired product 3a-3w in moderate to
good yields. Due to the mild and base-free reaction conditions,
very sensitive -Br (3j, 3t) and -TMS (3w) could be tolerated in
the presence of Pd(0), thus offering additional opportunity for
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Page 4 of 14
was employed in the reaction, the methyl cinnamate 3ad could The coordinated copper salts were proposed to act as an
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1
1
1
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1
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be obtained in 50% yield. To our delight, the protocol could be
extended to heterocycle compounds, including quinolone,
pyridine, unprotected indole, and benzofuran, giving the
esterated products (3ae-3aj) in 44-65% yields.
activator to enhance the reactivity of II in the cross coupling.
The subsequent transmetallation of arylboronic acid with
intermediate II afforded the complex III, which then
underwent the reductive elimination to furnish the final
product 3a with the regeneration of Pd(0) species.
To demonstrate the broad utility of this method, we further
applied this protocol in the late-stage esterification of some
drugs and bioactive molecules, including estrone, clofibrate,
and epiandrosterone, furnishing the corresponding derivatives
0
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3
4
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Scheme 3. Possible Mechanism
CuTC
MeO
S
Pd(0)
MeO
O
I
Me
O
3
ak-3am in 61-70% yields (Table 3).
3a
Oxidative
addition
Reductive
elimination
Table 3. Late-stage Esterification of Drugs Moleculesa
Me
O
MeO
Pd
B(OH)2
MeO Pd S
O
Pd2dba3, TFP, CuTC
R
OMe
O
+
R
1,4-dioxane, 60 o
C
III
O
CuTC
p-TolS
OMe
II
1
ak-1am
2
3ak-3am
Transmetallation
O
Me
Me
H
H
Me
B(OH)2
O
TC-B(OH)2
H
H
4-Me-PhSCu
EtO
O
H
O Me
O
H
from Clofibrate
from Estrone
from Epiandrosterone
3ak,70%
3al, 61%
3am, 64%
a
CONCLUSIONS
Reaction conditions: Arylboronic acid 1 (0.1 mmol), 2 (0.12 mmol), Pd2(dba)3 (5 mol%), TFP
20 mol%), CuTC (0.16 mmol), 1,4-dioxane (1 mL), 60 oC, N2,16 h.
(
In summary, we developed a palladium-catalyzed, copper-
promoted methoxycarbonylation of aryl boronic acid with O-
methyl S-p-toluenyl thiocarbonate. The reaction condition was
mild and the substrate scope was broad. A variety of
To illustrate the feasibility of this transformation for gram-
scale reaction, we carried out the reaction of substrate 1o with
2 on a 8.0 mmol scale. The desired product 3o was isolated in
73% yields (Scheme 2).
2
substituents including sensitive -Cl, -Br, and free -NH groups
Scheme 2. Gram-scale Synthesis
could be tolerated. The protocol could also be applied to the
late-stage esterification of some drugs, illustrating the broad
utility of this method.
O
B(OH)2
O
Pd2dba3, TFP, CuTC
OMe
+
p-TolS
OMe 1,4-dioxane, 60 oC, 34 h
Me
Me
1o
2
3o
0.88 g, 73% yield
8.0 mmol, 1.09 g
EXPERIMENTAL SECTION
General Information.
Based on the previous reports,13,14d a plausible mechanism
for the methoxycarbonylation of aryl boronic acid is depicted
in Scheme 3. First, O-methyl S-p-toluenyl thiocarbonate 2
coordinated with CuTC, forming the CuTC-bound thiolester
complex I. Then palladium species II was formed by
oxidative addition of Pd(0) into C(O)–S bond of thiolester.
All commercial reagents were purchased from TCI,
Sigma-Aldrich, Adamas-beta, and Energy Chemical of the
highest purity grade. They were used without further
purification unless specified. H and 13C NMR spectra were
1
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The Journal of Organic Chemistry
NH ·H O and saturated NaCl (aq). The organic fraction was
recorded on Bruker AVANCE III 400, Bruker AVANCE III
3
2
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
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
500 instruments. The peaks were internally referenced to
TMS (0.00 ppm) or residual undeuterated solvent signal. EI-
dried over anhydrous Na SO The solvent was evaporated
2 4
and the residue was purified by a silica gel packed flash
chromatography column using ethyl acetate/hexane as the
eluent.
double focus magnetic-sector high resolution MS
(EI-DFS-
HRMS) were recorded on a DFS-Thermofischer instrument at
the Center for Mass Spectrometry, Shanghai Institute of
Methyl benzoate (3a).22 Following the general procedure, the
reaction was conducted with 1a (12.2 mg, 0.1 mmol). The
product was obtained through silica gel chromatography (ethyl
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3
4
5
6
7
8
9
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1
2
3
4
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9
0
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3
4
5
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7
8
9
0
19
20
21
Material Medica. S-p-toluenyl thiocarbonate 2 , 1ak , 1al ,
1am20 are known products and synthesized according to the
literature.
1
acetate/hexane 1/100) as a light yellow oil (10.9 mg, 80%). H
General
Methoxycarbonylation.
To a 25 mL sealed tube was added substrates 1a (0.1
mmol), Pd dba (4.6 mg, 0.005 mmol, 5 mol%), CuTC (30.5
Procedure
for
Palladium-Catalyzed
NMR (400 MHz, CDCl ) δ 8.10-8.00 (m, 2H), 7.59-7.48 (m,
3
1H), 7.44-7.40 (m, 2H), 3.90 (s, 3H).
Methyl 2-methylbenzoate (3b).23 Following the general
procedure, the reaction was conducted with 1b (13.6 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a colorless oil
2
3
mg, 0.16 mmol, 1.6 equiv.), 2 (21.8 mg, 0.12 mmol, 1.2
equiv.) and 1,4-dioxane (1 mL). The reaction vessel was
purged with nitrogen three times. Then the tube was placed in a
1
(9.8 mg, 65%). H NMR (400 MHz, CDCl ) δ 7.93 (dd, J =
3
o
preheated oil bath at 60 C for 16 h. Upon completion, EtOAc
8.0, 1.6 Hz, 1H), 7.42 (td, J = 8.0, 1.6 Hz, 1H), 7.33-7.18 (m,
was added to dilute the mixture and washed with NH ·H O
2H), 3.92 (s, 3H), 2.63 (s, 3H).
3
2
and saturated NaCl (aq). The organic fraction was dried over
anhydrous Na SO . Then the solvent was evaporated and
Methyl 2-methoxybenzoate (3c).22 Following the general
procedure, the reaction was conducted with 1c (15.2 mg, 0.1
mmol). The product was obtained through silica gel
2
4
the residue was purified by a silica gel packed flash
chromatography column using ethyl acetate/hexane as the
eluent.
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
oil (11.6 mg, 70%). H NMR (400 MHz, CDCl
3
) δ 7.82 (dd, J
Procedure for Gram-scale Synthesis
= 8.0, 2.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.06-6.92 (m, 2H), 3.93
s, 3H), 3.91 (s, 3H).
Methyl 2-fluorobenzoate (3d). Following the general
(
To a 250 mL round-bottomed flask was added substrates 1o
3
2
(
(
(
1.09 g, 8 mmol), Pd
2
dba
3
(0.37 g, 0.4 mmol, 5 mol%), CuTC
2.44 g, 12.8 mmol, 1.6 equiv.), 1,4-dioxane (80 mL) and 2
procedure, the reaction was conducted with 1d (14.0 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1.75 g, 9.6 mmol, 1.2 equiv.). The reaction vessel was purged
with nitrogen three times. Then the flask was placed in a
preheated oil bath at 60 oC for 34 h. Upon completion,
EtOAc was added to dilute the mixture and washed with
1
oil (6.2 mg, 40%). H NMR (400 MHz, CDCl ) δ 7.96-7.92 (m,
3
1H), 7.59-7.43 (m, 1H), 7.25-7.07 (m, 2H), 3.94 (s, 3H).
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Methyl (1,1’-biphenyl)-2-carboxylate (3e).24 Following the
general procedure, the reaction was conducted with 1e (19.8
mg, 0.1 mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
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
1
3
oil (11.4 mg, 67%). H NMR (400 MHz, CDCl ) δ 8.03 (t, J =
2.0 Hz, 1H), 7.94 (dt, J = 8.0, 1.2 Hz, 1H), 7.54 (ddd, J = 8.0,
2.0, 1.2 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 3.94 (s, 3H).
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
oil (10.6 mg, 50%). H NMR (400 MHz, CDCl
3
) δ 7.85 (dd, J
Methyl 3-bromobenzoate (3j).22 Following the general
procedure, the reaction was conducted with 1j (20.1 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
=
7.6, 1.2 Hz, 1H), 7.56 (td, J = 7.6, 1.6 Hz, 1H), 7.48-7.37 (m,
5H), 7.37-7.32 (m, 2H), 3.66 (s, 3H).
-Methoxycarbonyl-3-methylbenzene (3f).23 Following the
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
1
general procedure, the reaction was conducted with 1f (13.6 mg,
3
oil (13.3 mg, 62%). H NMR (400 MHz, CDCl ) δ 8.20 (t, J =
0.1 mmol). The product was obtained through silica gel
1.6 Hz, 1H), 7.99 (dt, J = 8.0, 1.2 Hz, 1H), 7.70 (ddd, J = 8.0,
2.0, 1.2 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H).
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
oil (12.2 mg, 81%). H NMR (400 MHz, CDCl
3
) δ 7.96-7.79
Methyl 3-(trifluoromethyl) benzoate (3k).26 Following the
(m, 2H), 7.46-7.18 (m, 2H), 3.93 (s, 3H), 2.47-2.34 (m, 3H).
general procedure, the reaction was conducted with 1k (19.0
Methyl 3-methoxybenzoate (3g).23 Following the general
procedure, the reaction was conducted with 1g (15.2 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
mg, 0.1 mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
oil (10.8 mg, 53%). H NMR (400 MHz, CDCl
3
) δ 8.32 (d, J =
1.6 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.89-7.73 (m, 1H), 7.67-
1
oil (11.6 mg, 70%). H NMR (400 MHz, CDCl
3
) δ 7.66 (dt, J
7.53 (m, 1H), 3.97 (s, 3H).
= 7.6, 1.2 Hz, 1H), 7.58 (dd, J = 2.8, 1.6 Hz, 1H), 7.37 (t, J =
Methyl 3-cyanobenzoate (3l).27 Following the general
procedure, the reaction was conducted with 1l (14.7 mg, 0.1
mmol). The product was obtained through silica gel
8
3
.0 Hz, 1H), 7.12 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H), 3.94 (s, 3H),
.88 (s, 3H).
Methyl 3-fluorobenzoate (3h).25 Following the general
procedure, the reaction was conducted with 1h (14.0 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
chromatography (ethyl acetate/hexane 1/100) as a white solid
1
(9.7 mg, 60%). H NMR (400 MHz, CDCl
3
) δ 8.34-8.33 (m,
1H), 8.28 (dt, J = 8.0, 1.2 Hz, 1H), 7.85 (dt, J = 8.0, 1.2 Hz,
1H), 7.60 (td, J = 8.0, 0.8 Hz, 1H), 3.97 (s, 3H).
1
oil (10.1 mg, 65%). H NMR (400 MHz, CDCl
= 8.0, 1.2 Hz,1H), 7.74 (ddd, J = 9.2, 2.8, 1.6 Hz, 1H), 7.46-
.41 (m, 1H), 7.33-7.21 (m, 1H), 3.95 (s, 3H).
3
) δ 7.85 (dt, J
Methyl 3-phenylbenzoate (3m).28 Following the general
procedure, the reaction was conducted with 1m (15.6 mg, 0.1
mmol). The product was obtained through silica gel
7
Methyl 3-chlorobenzoate (3i).25 Following the general
procedure, the reaction was conducted with 1i (15.6 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
oil (17.0 mg, 80%). H NMR (400 MHz, CDCl
3
) δ 8.32 (d, J =
2.0 Hz, 1H), 8.09-8.00 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65
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The Journal of Organic Chemistry
(dd, J = 7.2, 2.0 Hz, 2H), 7.56-7.47 (m, 3H), 7.43-7.39 (m,
mmol). The product was obtained through silica gel
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
1H), 3.97 (s, 3H).
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
oil (10.8 mg, 70%). H NMR (500 MHz, CDCl
3
) δ 8.11-7.99
Methyl 3-aminobenzoate (3n).29 Following the general
procedure, the reaction was conducted with 1n (13.7 mg, 0.1
mmol). The product was obtained through silica gel
(m, 2H), 7.16-7.06 (m, 2H), 3.91 (s, 3H).
Methyl 4-chlorobenzoate (3s).22 Following the general
procedure, the reaction was conducted with 1s (15.6 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
chromatography (ethyl acetate/hexane 1/100) as a light yellow
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
oil (9.8 mg, 65%). H NMR (400 MHz, CDCl
3
) δ 7.45 (dt, J =
7
.6, 1.2 Hz, 1H), 7.37 (t, J = 2.0 Hz, 1H), 7.24 (t, J = 7.8 Hz,
H), 6.88 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H), 3.91 (s, 3H), 3.80 (s,
1
1
oil (10.7 mg, 63%). H NMR (400 MHz, CDCl
3
) δ 8.05-7.93
2H).
(m, 2H), 7.48-7.37 (m, 2H), 3.94 (s, 3H).
Methyl 4-methylbenzoate (3o).22 Following the general
procedure, the reaction was conducted with 1o (13.6 mg, 0.1
mmol). The product was obtained through silica gel
Methyl 4-bromobenzoate (3t).23 Following the general
procedure, the reaction was conducted with 1t (20.0 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
1
oil (12.0 mg, 80%). H NMR (400 MHz, CDCl
3
) δ 7.94 (d, J =
oil (12.9 mg, 60%). H NMR (400 MHz, CDCl
3
) δ 8.01-7.80
8
3
.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 3.91 (s, 3H), 2.41 (s,
(m, 2H), 7.71-7.49 (m, 2H), 3.94 (s, 3H).
H).
Methyl 4-(trifluoromethyl) benzoate (3u).31 Following the
general procedure, the reaction was conducted with 1u (19.0
mg, 0.1 mmol). The product was obtained through silica gel
2
2
4
-Methoxymethylbenzoate (3p).
Following the general
procedure, the reaction was conducted with 1p (15.2 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
chromatography (ethyl acetate/hexane 1/100) as a light yellow
oil (12.2 mg, 60%). H NMR (400 MHz, CDCl
3
) δ 8.18-8.03
1
oil (13.6 mg, 82%). H NMR (400 MHz, CDCl
3
) δ 8.07-7.95
(m, 2H), 7.30-7.27 (m, 2H), 3.95 (s, 3H).
(m, 2H), 7.01-6.87 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
Methyl 4-phenylbenzoate (3v).31 Following the general
Methyl 4-(trifluoromethoxy) benzoate (3q).30 Following the
general procedure, the reaction was conducted with 1q (20.6
mg, 0.1 mmol). The product was obtained through silica gel
procedure, the reaction was conducted with 1v (19.8 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
1
chromatography (ethyl acetate/hexane 1/100) as a light yellow
oil (18.0 mg, 85%). H NMR (400 MHz, CDCl
3
) δ 8.17-8.09
1
oil (11.7 mg, 53%). H NMR (400 MHz, CDCl
3
) δ 8.18-8.03
(m, 2H), 7.72-7.62 (m, 4H), 7.49 (t, J = 7.6 Hz, 2H), 7.45-7.39
(m, 2H), 7.30-7.27 (m, 2H), 3.95 (s, 3H).
(m, 1H), 3.97 (s, 3H).
Methyl 4-flurobenzoate (3r).23 Following the general
procedure, the reaction was conducted with 1r (14.0 mg, 0.1
Methyl 4-(trimethylsilyl) benzoate (3w).32 Following the
general procedure, the reaction was conducted with 1w (19.4
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1
mg, 0.1 mmol). The product was obtained through silica gel
oil (13.0 mg, 70%). H NMR (400 MHz, CDCl ) δ 8.66-8.62
3
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
chromatography (ethyl acetate/hexane 1/100) as a light yellow
(m, 1H), 8.09 (dd, J = 8.4, 1.6 Hz, 1H), 8.02-7.95 (m, 1H),
1
oil (14.6 mg, 70%). H NMR (400 MHz, CDCl
3
) δ 8.02 (d, J =
7.94-7.88 (m, 2H), 7.64-7.55 (m, 2H), 4.01 (s, 3H).
8
.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 0.31 (s,
H).
Methyl phenanthrene-9-carboxylate (3ab).34 Following the
9
general procedure, the reaction was conducted with 1ab (22.2
Methyl methyl 3,5-dimethoxybenzoate (3x).33 Following the
general procedure, the reaction was conducted with 1x (18.2
mg, 0.1 mmol). The product was obtained through silica gel
mg, 0.1 mmol). The product was obtained through silica gel
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
chromatography (ethyl acetate/hexane 1/100) as an amorphous
1
solid (16.5 mg, 70%). H NMR (400 MHz, CDCl
3
) δ 8.99-8.91
chromatography (ethyl acetate/hexane 1/100) as a white solid
(m, 1H), 8.80-8.68 (m, 2H), 8.51 (s, 1H), 8.04-7.96 (m, 1H),
7.82-7.60 (m, 4H), 4.08 (s, 3H).
1
(13.7 mg, 70%). H NMR (400 MHz, CDCl
3
) δ 7.20 (d, J = 2.4
Hz, 2H), 6.66 (t, J = 2.4 Hz, 1H), 3.92 (s, 3H), 3.84 (d, J = 0.8
1
-Pyrenecarboxylic acid methyl ester (3ac).35 Following the
Hz, 6H).
general procedure, the reaction was conducted with 1ac (24.6
Methyl 2, 4-dimethoxybenzoate (3y).33 Following the general
procedure, the reaction was conducted with 1y (18.2 mg, 0.1
mmol). The product was obtained through silica gel
mg, 0.1 mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as an amorphous
1
solid (21.1 mg, 81%). H NMR (500 MHz, CDCl
3
) δ 9.29 (d, J
chromatography (ethyl acetate/hexane 1/100) as a light yellow
= 9.5 Hz, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.30-8.22 (m, 3H),
8.17 (dd, J = 8.0, 3.2 Hz, 2H), 8.07 (dd, J = 8.0, 7.2 Hz, 2H),
4.14 (s, 3H).
1
oil (10.4 mg, 53%). H NMR (400 MHz, CDCl
3
) δ 7.91-7.84
(m, 1H), 6.51 (d, J = 8.0 Hz, 2H), 3.91 (s, 3H), 3.87 (d, J = 1.2
Hz, 6H).
1
-Phenylcclohexene (3ad).22 Following the general procedure,
Methyl 1-naphthoate (3z).33 Following the general procedure,
the reaction was conducted with 1z (17.2 mg, 0.1 mmol). The
product was obtained through silica gel chromatography (ethyl
the reaction was conducted with 1ad (14.8 mg, 0.1 mmol). The
product was obtained through silica gel chromatography (ethyl
1
acetate/hexane 1/100) as a light yellow oil (8.1 mg, 50%). H
1
acetate/hexane 1/100) as a light yellow oil (14.9 mg, 80%). H
3
NMR (400 MHz, CDCl ) δ 7.72 (d, J = 16.0 Hz, 1H), 7.56-
NMR (400 MHz, CDCl
3
) δ 8.98 (dd, J = 8.8, 1.2 Hz, 1H), 8.22
7.54 (m, 2H), 7.45-7.36 (m, 3H), 6.47 (d, J = 16.0 Hz, 1H),
(dd, J = 7.2, 1.2 Hz, 1H), 8.04 (dt, J = 8.2, 1.2 Hz, 1H), 7.94-
3.83 (s, 3H).
7
.85 (m, 1H), 7.68-7.64 (m, 1H), 7.60-7.47 (m, 2H), 4.04 (s,
Methyl qunoline-5-carboxylate (3ae).36 Following the general
procedure, the reaction was conducted with 1ae (17.3 mg, 0.1
mmol). The product was obtained through silica gel
3H).
Naphthalene-2-carboxylate (3aa).33 Following the general
procedure, the reaction was conducted with 1aa (17.2 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/100) as a light yellow
chromatography (ethyl acetate/hexane 1/40) as a light yellow
1
oil (8.4 mg, 45%). H NMR (400 MHz, CDCl
3
) δ 9.36 (d, J =
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.0 Hz, 1H), 8.98 (d, J = 4.0 Hz, 1H), 8.39-8.2 (m, 2H), 7.78- 7.43 (d, J = 4.0 Hz, 1H), 7.35-7.22 (m, 1H), 6.68-6.67 (m, 1H),
6
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
7.74 (m, 1H), 7.54 (dd, J = 8.8, 4.0 Hz, 1H), 4.03 (s, 3H).
3.96 (s, 3H).
Methyl quinoline-4-carboxylate (3af).37 Following the general
Benzofuran-3-carboxylic acid methyl ester (3aj).40 Following
procedure, the reaction was conducted with 1af (17.3 mg, 0.1
the general procedure, the reaction was conducted with 1aj
mmol). The product was obtained through silica gel
(16.2 mg, 0.1 mmol). The product was obtained through silica
chromatography (ethyl acetate/hexane 1/40) as a light yellow
gel chromatography (ethyl acetate/hexane 1/40) as light yellow
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
1
oil (8.2 mg, 44%). H NMR (500 MHz, CDCl
3
) δ 9.03 (d, J =
oil (10.6 mg, 60%). H NMR (400 MHz, CDCl
3
) δ 8.29 (s, 1H),
4
.5 Hz, 1H), δ 8.77 (dd, J = 8.5, 0.8 Hz, 1H), 8.18 (dd, J = 8.5,
.0 Hz, 1H), 7.91 (d, J = 4.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.68-
8.14-8.04 (m, 1H), 7.60-7.51 (m, 1H), 7.43-7.34 (m, 2H), 3.97
(s, 3H).
1
7.65 (m, 1H), 4.05 (s, 3H).
Methyl
4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)
oxy)
Methyl 2-methoxypyridine-5-carboxylate (3ag).38 Following
the general procedure, the reaction was conducted with 1ag
(15.3 mg, 0.1 mmol). The product was obtained through silica
benzoate (3ak). Following the general procedure, the reaction
was conducted with 1ak (25.2 mg, 0.1 mmol). The product was
obtained through silica gel chromatography (ethyl acetate/hex-
1
gel chromatography (ethyl acetate/hexane 1/40) as a light
ane 1/100) as light yellow oil (18.6 mg, 70%). H NMR (400
1
yellow oil (8.2 mg, 49%). H NMR (400 MHz, CDCl
3
) δ 8.85
3
MHz, CDCl ) δ 7.99-7.91 (m, 2H), 6.83 (d, J = 8.8 Hz, 2H),
(
dd, J = 2.4, 0.8 Hz, 1H), 8.17 (dd, J = 8.8, 2.4 Hz, 1H), 6.78
dd, J = 8.8, 0.8 Hz, 1H), 4.02 (s, 3H), 3.93 (s, 3H).
4.24 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.66 (s, 6H), 1.23 (t, J =
13
1
(
7.2 Hz, 3H). C{ H} NMR (125 MHz, CDCl
3
) δ 173.8, 166.8,
1
59.6, 131.2, 123.3, 117.3, 79.3, 61.7, 51.9, 25.4, 14.0. HRMS
Methyl 5-methoxypyridine-3-carboxylate (3ah).39 Following
the general procedure, the reaction was conducted with 1ah
(EI) m/z: [M]+ Calcd for C14
H
O
+
266.1149; Found
18
5
2
66.1150.
(15.3 mg, 0.1 mmol). The product was obtained through silica
gel chromatography (ethyl acetate/hexane 1/40) as a light
Methyl (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,
15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-
1
yellow oil (8.4 mg, 50%). H NMR (400 MHz, CDCl
3
) δ 8.84
(d, J = 1.6 Hz, 1H), 8.49 (d, J = 3.2 Hz, 1H), 7.78 (dd, J = 3.2,
carboxylate(3al).41 Following the general procedure, the
reaction was conducted with 1al (29.8 mg, 0.1 mmol). The
product was obtained through silica gel chromatography (ethyl
acetate/hexane 1/40) as an amorphous solid (19.0 mg, 61%).
1
.6 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H).
Methyl indole-5-carboxylate (3ai).30 Following the general
procedure, the reaction was conducted with 1ai (16.1 mg, 0.1
mmol). The product was obtained through silica gel
chromatography (ethyl acetate/hexane 1/40) as a white solid
1H NMR (400 MHz, CDCl
) δ 7.85-7.77 (m, 2H), 7.38 (d, J =
3
8
2
0
.0 Hz, 1H), 3.92 (s, 3H), 3.02-2.93 (m, 2H), 2.60-2.43 (m,
H), 2.39-2.33 (m, 1H), 2.26-1.96 (m, 4H), 1.71-1.47 (m, 6H),
.94 (s, 3H).
1
(
11.4 mg, 65%). H NMR (400 MHz, CDCl
3
) δ 8.55 (brs, 1H)
8.45 (dd, J = 1.6, 0.8 Hz, 1H), 7.94 (dd, J = 8.6, 1.6 Hz, 1H),
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Methyl
4-(((3R,8R,9S,10S,13S,14S)-10,13-dimethyl-17- CAS (No. 2014229 and 2018293), the Science and
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oxohexadecahydro-1H-cyclo penta[a]phenanthren-3-yl)oxy)
benzoate(3am) Following the general procedure, the reaction
was conducted with 1am (41.0 mg, 0.1 mmol). The product
was obtained through silica gel chromatography (ethyl
Technology Commission of Shanghai Municipality
(17JC1405000), the Program of Shanghai Academic Research
Leader (19XD1424600), the National Science & Technology
Major Project “Key New Drug Creation and Manufacturing
Program”, China (2018ZX09711002-006) for financial
support.
1
acetate/hexane 1/40) as a brown solid (27.2 mg, 64%). H
0
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NMR (400 MHz, CDCl
3
) δ 8.04-7.93 (m, 2H), 6.96-6.87 (m,
2H), 4.64 (t, J = 2.8 Hz, 1H), 3.89 (s, 3H), 2.49-2.42 (m, 1H),
REFERENCES
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1
.14-2.04 (m, 1H), 2.01-1.87 (m, 2H), 1.83-1.78 (m, 2H),
.76-1.40 (m, 9H), 1.40-1.19 (m, 5H), 1.12-0.96 (m, 1H), 0.88
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1
3
1
(
d, J = 3.2 Hz, 7H). C{ H} NMR (125 MHz, CDCl
3
) δ 166.9,
1
61.6, 131.6, 122.0, 115.2, 72.1, 54.2, 51.8, 51.4, 47.8, 39.6,
35.9, 35.8, 35.0, 32.5, 32.4, 31.5, 30.7, 28.1, 25.6, 21.7, 20.1,
+
1
3.8, 11.4. HRMS (EI) m/z: [M]+ Calcd for C27
24.2608; Found 424.2609.
H
36
O
4
4
ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
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*
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E-mail for Hui Xu: xuhui2018@simm.ac.cn
E-mail for Hui-Xiong Dai: hxdai@simm.ac.cn
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Notes
The authors declare no competing financial interest.
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