Aryne Precursors for Selective Generation of 3-Haloarynes: Preparation and Application to Synthetic Reactions

Article abstract of DOI:10.1021/acs.joc.0c01669

The synthesis and reaction of new 3-haloaryne precursors 2a-2h were studied. The ortho-(trimethylsilyl)aryl triflate precursors 2a-2h were prepared by a simple procedure involving O-trimethylsilylation and migration of a trimethylsilyl group followed by triflation. The remarkable feature of new precursors is the selective generation of 3-haloarynes by suppressing the competitive thia-Fries rearrangement, which is the problem in the reaction using the well-known 3-haloaryne precursors. The advantage of new precursor 2a over a typical precursor 1 was confirmed by the direct comparisons in several reactions. The application of precursors 2a-2h to the syntheses of heterocycles was also reported.

Full text of DOI:10.1021/acs.joc.0c01669

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Article
Aryne Precursors for Selective Generation of 3-Haloarynes:
Preparation and Application to Synthetic Reactions
Eito Yoshioka, Kengo Kakigi, Shouta Miyoshi, Yuichi Kawasaki, and Hideto Miyabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01669 • Publication Date (Web): 28 Sep 2020
Downloaded from pubs.acs.org on September 28, 2020
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Aryne Precursors for Selective Generation of 3-Haloarynes: Preparation and Application to Synthetic Reactions
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Eito Yoshioka, Kengo Kakigi, Shouta Miyoshi, Yuichi Kawasaki and Hideto Miyabe*
School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Chuo-ku, Kobe 650-8530, Japan.
miyabe@huhs.ac.jp
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ABSTRACT: The synthesis and reaction of new 3-haloaryne precursors 2a-h were studied. The ortho-(trimethylsilyl)aryl triflate precursors 2a-h
were prepared by the simple procedure involving O-trimethylsilylation and migration of trimethylsilyl group followed by triflation. The
remarkable feature of new precursors is the selective generation of 3-haloarynes by suppressing the competitive thia-Fries rearrangement, which is
the problem in the reaction using the well-known 3-haloaryne precursors. The advantage of new precursor 2a over a typical precursor 1 was
confirmed by the direct comparisons in several reactions. The application of precursors 2a-h to the synthesis of heterocycles was also reported.
Cl
Cl
Cl
TMS
OTf
OTf
F
F
TMS
R
R
selective
R
Cl
OH
Tf
competitive
thia-Fries
rearrangement
R
INTRODUCTION
Aryne chemistry has made great advances in organic synthesis,1-4 particularly by the development of ortho-(trimethylsilyl)aryl
triflates as easily activatable aryne precursors.5,6 In recent years, various precursors bearing functional groups have been explored to increase the
diversity in aryne-based products.7-13 However, the use of unsymmetrically substituted arynes is frequency constrained by the low regioselectivity;
thus, the regiocontrol using functional groups is an important task.14,15 As a novel method controlling the regioselectivity, the introduction of silyl
or boryl group at 3-position of arynes has been studied.7,8 The inductively electron-withdrawing groups such as 3-alkoxy9 and 3-triflyloxy10-12 are
known to direct the regioselectivity.13
Sufficient regiocontrol can be achieved by 3-haloarynes.14,16 The precursor 1 is a typical precursor for generating 3-chloroaryne C
(Figure 1). However, the generation of 3-chloroaryne C from 1 is plagued by the competitive thia-Fries rearrangement leading to B.17 In the
method using precursor 1, we presume that the steric repulsion in anion A would promote thia-Fries rearrangement. We assumed that the competitive
thia-Fries rearrangement could be suppressed by simply swapping the position of the triflate and trimethylsilyl (TMS) groups on the precursor.
Therefore, we have started to study the viability of new precursor 2a. Some preliminary results were reported in our patent.18 In this paper, we
report in detail the simple and practical method for preparing new 3-haloaryne precursors such as 2a and the selective aryne generation from the
sterically stable anions such as D. When a new precursor 2a is used, thia-Fries rearrangement of anion D leading to the sterically unfavorable anion
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E is completely suppressed. A method for synthesizing heterocycles using our new 3-haloaryne precursors is also reported.
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Cl
Cl
Cl
thia-Fries
rearrangement
CF3
O
OTf
O
S
O
F
S
CF3
O
O
competitive
TMS
A
B
O
9
1
Precursor
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Cl
3
selective
C
Cl
O
S
Cl
Cl
O
TMS
F
CF3
SO2CF3
OTf
O
O
thia-Fries
2a
New precursor
E
rearrangement
D
Figure 1. New precursor 2a for selective generation of 3-chloroaryne C.
RESULTS AND DISCUSSION
The well-known 3-chloroaryne precursor 1 was generally prepared from the particular substrate 2-bromo-6-chlorophenol 3 via the
bromine-lithium exchange reaction (Scheme 1).19 Garg and Houk’s group developed an alternative method starting from the readily available
substrate 2-chlorophenol 4, in which N-isopropylcarbamate was used as a directing group for ortho-metalation.20
Cl
Cl
Cl
OLi
OH
Br
OTMS
Br
i) BuLi
ii) Tf2O
1
TMS
3
Cl
Cl
Cl
i) TMEDA, TBSOTf
ii) TMEDA, BuLi
OH
O
NH
O
O
NH
1
O
TMS
iii) TMSCl
4
Scheme 1. Two methods for preparing the known precursor 1.
As the simple and practical approach to new precursor 2a, we examined the direct ortho-metalation procedure starting from the
readily available 3-chlorophenol 5a (Figure 1). The key requirement for our method is assumed to be the selective deprotonation (metalation) of
O-trimethylsilylated intermediate 7a in situ generated by the reaction of 5a with hexamethyldisilazane (HMDS).21 Another problem is that the
competitive elimination of chlorine atom on anion F giving aryne H might impede the expected migration of trimethylsilyl group leading to G.22
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Cl
Cl
Cl
i) HMDS
ii) Base
TMS
OH
TMS
Tf2O, (i-Pr)2NEt
CH2Cl2, –40 °C
OTf
THF
OH
5a
6a
2a
(87%)
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9
5a
Cl
HMDS
H
SiMe3
O
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Cl
Cl
selective
deprotonation
H
H
G
H
OSiMe3
OSiMe3
F
H
OSiMe3
7a
Figure 2. Synthetic approach to new precursor 2a.
The effect of several bases on TMS-migration leading to 6a is summarized in Table 1.23 To prepare the O-trimethylsilylated
intermediate 7a, we initially allowed 3-chlorophenol 5a to react with 1.5 equivalents of HMDS in THF at 0 °C. After being stirred at 50 °C for 5
hours, several bases were next added to this reaction mixture at –80 °C. Treatment with t-BuLi from –80 °C to 0 °C did not lead to the formation
of the desired C-trimethylsilylated phenol 6a (entry 1). O-Silylated intermediate 7a and the recovered starting material 5a were obtained in 50%
and 15% yields, respectively. In contrast, the desired TMS-migration product 6a was obtained in reasonable chemical yields when LiN(i-Pr)2 or
Li(TMP) was employed as a base (entries 2 and 3). Furthermore, the use of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride
complex24 Mg(TMP)2∙2LiCl led to an enhancement in chemical yield of TMS-migration product to give 6a in 86% yield (entry 4).
Mg(TMP)2∙2LiCl was used in the aryne generation by Tokuyama’s group;25 thus, it is important to note that Mg(TMP)2∙2LiCl can be used for the
selective deprotonation of 7a without the aryne generation. The conversion of C-silylated phenol 6a to new precursor 2a was achieved in 87%
yield by treatment of phenol 6a with Tf2O in the presence of (i-Pr)2NEt in CH2Cl2 at –40 °C for 5 hours (Figure 2). In fact, this procedure
facilitated the gram-scale synthesis of precursor 2a.
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Table 1. Effect of base on TMS-migration leading to 6a.a
Entry
Base (equiv.)
6a (% Yield)b
1
2
3
4
t-BuLi (1.2)
Not detected [7a (50), 5a (15)]
LiN(i-Pr)2 (1.2)
Li(TMP) (1.2)
Mg(TMP)2·2LiCl (1.2)
6a (57)
6a (44)
6a (86)
a
After treatment of 3-chlorophenol 5a with HMDS (1.5 equiv.) in THF at 50 °C for 5 h,
base (1.2 equiv.) was added to the reaction mixture at –80 °C. The reaction mixture was
stirred at –80 °C for 1 h and at –80 °C to 0 °C for 3 h. b Isolated yields.
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With these results in mind, we next synthesized the various precursors 2b-h from easily available 3-halophenol derivatives 5b-h
(Table 2). In the case of 3-fluorophenol 5b, O-trimethylsilylation and TMS-migration proceeded effectively to give the C-trimethylsilylated
phenol 6b in 81% (entry 1). 3-Fluoroaryne precursor 2b was synthesized by the triflation of 6b with Tf2O. Under the similar reaction conditions
using Mg(TMP)2·2LiCl, TMS-migration of 3-bromophenol 5c did not take place effectively owing to the competitive generation of several
unidentified by-products. Therefore, this transformation was re-examined by changing a base form Mg(TMP)2·2LiCl to LiN(i-Pr)2 (entry 2). The
use of LiN(i-Pr)2 led to the formation of C-silylated phenol 6c in 34% yield, which was converted to 3-bromoaryne precursor 2c in 75% yield.
When 3-chloro-4-methylphenol 5d was employed, the corresponding precursor 2d was prepared with the reasonable chemical efficiency (entry 3).
The use of 3,5-dichlorophenol 5e as a substrate led to a decrease in the chemical yield of C-silylated phenol 6e (entry 4). In the case of
3,5-dichlorophenol 5e, the deprotonation at C4 position may compete with the desired deprotonation at C2 position. In contrast,
O-trimethylsilylation and TMS-migration of 3-chloro-5-trifluorometylphenol 5f proceeded effectively to give the C-silylated phenol 6f in 69%
(entry 5). 3,4,5-Trifluorophenol 5g was converted into precursor 2g without any problems (entry 6). Additionally, the precursor 2h bearing a
methoxy group at C6 position was synthesized with good chemical efficiencies, allowing facile incorporation of structural variety (entry 7).
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Table 2. Synthesis of precursor 2b-h.
X
X
X
3
i) HMDS
Tf2O
TMS
OH
TMS
OTf
ii) Mg(TMP)2·2LiCl
(i-Pr)2NEt
1
5
THF
CH2Cl2
OH
R
R
R
5b-h
6b-h
2b-h
Entry
1 b
Substrate
Phenol (% Yield)a
Precursor (% Yield)a
F
F
F
TMS
TMS
OH
OH
OTf
5b
Br
6b (81)
2b (73)
2 c
3 b
4 b
Br
Br
TMS
TMS
OH
OH
6c (34)
Cl
OTf
2c (75)
Cl
5c
Cl
Me
Me
TMS
Me
TMS
OH
OH
OTf
5d
6d (53)
2d (76)
Cl
Cl
Cl
TMS
OH
TMS
OTf
Cl
OH
Cl
Cl
5e
6e (30)
2e (60)
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5 b
6 b
7 b
Cl
Cl
Cl
TMS
TMS
OTf
F3C
OH
F3C
OH
F3C
5f
6f (69)
2f (92)
F
F
F
F
F
F
F
TMS
OH
F
F
TMS
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OH
OTf
2g (76)
5g
6g (69)
F
F
F
TMS
OH
TMS
OTf
OH
MeO
MeO
MeO
5h
6h (91)
2h (97)
a Isolated yields. b After treatment of 3-halophenol 5b-h with HMDS (1.5 equiv.) in THF at 50 °C for 5 h,
Mg(TMP)2·2LiCl (1.2 equiv.) was added to the reaction mixture at –80 °C. The reaction mixture was stirred
c
at –80 °C for 1 h and at –80 °C to 0 °C for 3 h. Instead of Mg(TMP)2·2LiCl, LiN(i-Pr)2 (1.2 equiv.) was
used as a base under the same reaction conditions.
1
Greaney's study using precursor
Cl
Cl
Cl
O
O
CsF
OTf
CH3CN/toluene
rt
S
SO2CF3
thia-Fries
TMS
O2
Cl
Cl
1
8
(60%)
rearrangement
2
Our study using precursor
Cl
Cl
Cl
Cl
O
O
NC CH3
OH
OH
CH3
TMS
CsF
+
N
CH3
N
CH3
CH3CN/toluene
rt
H
OTf
10
(15%)
2a
N
Cl
I
9
2a
)
(43% based on 2 equiv. of
1
Re-experiment of Yoshida's study using precursor
Cl
Cl
Cl
n-Bu3SnF, KF
18-crown-6
OTf
OH
Tf
SnBu3
F
thia-Fries
+
rearrangement
DME, 0 °C
TMS
1
11
12
(14%)
(36%)
2
Our study using precursor
Cl
n-Bu3SnF, KF
18-crown-6
TMS
11
(92%)
DME, 0 °C
OTf
2a
Scheme 2. Direct comparisons between well-known precursor 1 and new precursor 2a.
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We next sought to explore the utility of our novel aryne precursor 2a by comparing its reactivity to that of 1 (Scheme 2). Tandem
thia-Fries rearrangement–cyclization of 1 giving phenoxathiindioxide 8 was reported by Greaney’s group.17b When aryltriflate 2a was used as an
aryne precursor under the same reaction conditions, thia-Fries rearrangement was completely suppressed and the formation of the corresponding
phenoxathiindioxide was not observed. In marked contrast, the N,N-bis(3-chlorophenyl)acetamide 9 and N-(3-chlorophenyl)acetamide 10 were
newly obtained as a result of the selective generation of 3-chloroaryne from 2a followed by the reaction of 3-chloroaryne with acetonitrile. Hu’s
group reported the reaction of aryne with acetonitrile in the diphenyliodonium-catalyzed fluorination of arynes using ortho-(trimethylsilyl)aryl
triflates in acetonitrile. They propose that aryne reacts with anion I generated from acetonitrile and hydroxide.26 Yoshida’s group reported that the
insertion of n-Bu3SnF into 3-chloroaryne generated from 1 proceeded in 1,2-dimethoxyethane (DME) with the moderated chemical efficiency to
give the insertion product 11 in 41% yield.27 In fact, we repeated this reaction and observed the competitive formation of the desired product 11 in
36% yield and thia-Fries rearrangement product 12 in 14% yield. The dramatic improvement in the chemical efficiency of this insertion reaction
was achieved by changing a precursor from 1 into 2a. The insertion product 11 was obtained in 92% yield by using new precursor 2a. It is also
noteworthy that a chlorine atom on new precursor 2a worked well for controlling the regioselectivities of these reactions.
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Cl
Cl
Br
2-bromofuran
CsF
+
2a
O
O
CH3CN, rt
5
Br
6
7
8
9
13
(30%)
14
(46%)
X
O
N
X
Ph
t-Bu
CHPh
O
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CsF
N
t-Bu
N
t-Bu
2a-c
+
O
CH3CN, rt
Ph
16a, 16c
15a-c
15a 16a
X = Cl (84%,
X = F (95%,
X = Br (82%,
:
= 89:11)
15b
)
15c 16c
:
= 86:14)
X
Ph
Regioselectivity
2a
2c
(X = Cl)
(X = Br)
2b
(X = F)
N
O
t-Bu
Cl
BnN3
CsF
N
N
2a
N
CH3CN, rt
Bn
17
17
(91%)
Cl
BnN3
CsF
OH
(46%)
1
+
CH3CN, rt
Tf
12
(12%)
Scheme 3. The utility of new precursor 2a in cycloaddition reactions.
We next studied the ability of new precursor 2a for controlling the regioselectivities in cycloaddition reactions (Scheme 3). Diels–
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Alder-type reaction of 2a with 2-bromofuran proceeded effectively, although it has shown the low regioselectivity. The regioisomers 13 and 14
were obtained in about 4:6 ratio. Good regioselectivities were observed in 1,3-dipolar cycloadditions using N-tert-butyl-α-phenylnitrone.
3-Chloroaryne precursor 2a, 3-fluoroaryne precursor 2b and 3-bromoaryne precursor 2c were employed. The [3+2] reaction of 3-chloroaryne,
generated from 2a, proceeded regioselectively to give the regioisomers 15a and 16a in 89:11 ratio. The use of precursor 2b having a fluorine
atom led to an enhancement in the regioselectivity to give the adduct 15b in 95% yield without the formation of regioisomer, while the ratio of
regioisomers 15c and 16c decreased to 86:14 by using 3-bromoaryne precursor 2c. The effect of halogen atom on directing the regioselectivity (F
> Cl > Br) consists with the distortion/interaction model propounded by Garg and Houk.14 The advantage of new precursor 2a over a typical
precursor 1 was again confirmed by the [3+2] cycloaddition using benzylazide. The Huisgen-type reaction of 2a with benzylazide proceeded
regioselectively under the copper metal-free reaction conditions to give the cyclic product 17 in 91% yield. In contrast, the use of a precursor 1
led to the competitive formation of the desired product 17 and thia-Fries rearrangement product 12.
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Next, the regiocontrolling effect of new precursors 2a on [2+2]-type reaction of aryne and N,N-dimethylformamide (DMF) was
examined by using three-component coupling reaction developed by our group (Scheme 4).28,29 In the presence of CsF, treatment of 2a with
diethyl malonate in DMF gave the coumarin derivative 18a in 85% yield without the formation of regioisomer. This reaction proceeded via a
route involving the highly regioselective insertion of 3-chloroaryne into C=O π-bond of DMF and the subsecent trapping of intermediate K with
anion L of diethyl malonate.30 When a precursor 1 was employed, the competitive formation of thia-Fries rearrangement product 12 was observed.
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Cl
Cl
CH2(CO2Et)2
CsF
NMe2
NMe2
2a
O
O
DMF, rt
J
Cl
NMe2
Cl
CO2Et
CO2Et
O EtO
O
O
O
K
L
18a
(85%)
Cl
Cl
CH2(CO2Et)2
CsF
CO2Et
O
OH
Tf
1
+
DMF, rt
O
12
18a
(17%)
(47%)
Scheme 4. Three-component coupling reaction using precursor 2a.
The synthesis of various coumarin derivatives using new precursors is shown in Scheme 5. High regioselectivities were achieved in
the reaction using 3-fluoroaryne precursor 2b and 3-bromoaryne precursor 2c to give the coumarin derivatives 18b and 18c in 80% and 76%
yields, respectively. The 3-chloro-4-methylaryne precursor 2d, 3,5-dichloroaryne precursor 2e and 3-chloro-5-trifluoromethylaryne precursor 2f
worked well. Next, the ability of a fluorine atom on aryne for directing the regioselectivity was investigated by using the 3,6-disubstituted aryne
M derived from precursor 2h. The directing ability of a fluorine atom on aryne M decreased by the effect of methoxy group as an inductively
electron-withdrawing group to give the regioisomers 18h and 19 in 63:37 ratio.
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X
X
CH2(CO2Et)2
CsF
CO2Et
TMS
OTf
DMF, rt
O
O
R
R
2b-f, 2h
18b-f, 18h
7
8
9
F
Br
Cl
CO2Et
O
CO2Et
O
Me
CO2Et
O
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O
O
O
18b
18c
18d
(81%)
(80%)
(76%)
Cl
Cl
CO2Et
CO2Et
Cl
O
O
F3C
O
O
18e
18f
(62%)
(61%)
F
F
F
minor
CO2Et
O
O
O
Nu
major
O
CO2Et
MeO
MeO
MeO
18h
19
M
18h 19
73% (
:
= 63:37)
Scheme 5. The synthesis of coumarin derivatives using new precursors.
The synthesis of tetrahydrobenzodiazepine derivatives based on the insertion of arynes into C–N σ-bond is shown in Scheme 6.31 In
the presence of CsF, new precursor 2a regioselectively reacted with 1,3-dimethyl-2-imidazolidinone (DMI) to give the benzodiazepine derivative
20a in 93% yield. Notably, the reaction of 2a with DMI was performed in gram scale. As expected, the use of 3-chloro-5-trifluorometylaryne
precursor 2f and 3,4,5-trifluoroaryne precursor 2g led to the formation of the corresponding product 20f and 20g in good yields.
O
X
X
O
TMS
OTf
NMe
CsF
MeN
NMe
DMI, rt
N
R
R
Me
DMI
2a, 2f, 6g
20a, 20f, 20g
O
O
O
F
Cl
Cl
F
F
NMe
NMe
NMe
F3C
N
N
N
Me
Me
Me
20g
20f
(75%)
20a
(76%)
(93%)
in gram-scale
Scheme 6. The synthesis of benzodiazepine derivatives.
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The chlorine atom on precursors can be used as a removable directing group. We finally show the method for reductive dechlorination
(Scheme 7). In the presence of Pd(OH)2/C, the hydrogenation of benzodiazepine derivative 20f with ammonium formate gave the dechlorinated
product 21 in 77% yield.
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9
O
O
Cl
HCO2NH4
Pd(OH)2/C
NMe
NMe
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F3C
MeOH, reflux
F3C
N
N
Me
Me
20f
21
(77%)
Scheme 7. Dechlorination of benzodiazepine derivative 20f.
CONCLUSION
We have developed the convenient method for preparing new 3-haloaryne precursors via O-trimethylsilylation and migration of
trimethylsilyl group followed by triflation. The use of new precursors suppresses the problematic thia-Fries rearrangement as a competitive
side-reaction, leading to the selective generation of 3-haloarynes. New 3-haloaryne precursors were successfully applied to the regioselective
synthesis of various heterocycles based on Diels-Alder-type reaction, 1,3-dipolar cycloaddition, π-bond insertion and σ-bond insertion of arynes
EXPERIMENTAL SECTION
General. Melting points were taken on a Yanaco MP-J3 and are uncorrected. Infrared spectra were measured on a JASCO FT/IR-4100. 1H-NMR
spectra were measured on a JEOL ECX-400 PSK (400 MHz) or Varian NMRS 600 (600 MHz) with CDCl3 as an internal standard (7.26 ppm) or
CD3CN as an internal standard (1.94 ppm). 13C-NMR spectra were measured on a JEOL ECX-400 PSK (100 MHz) or Varian NMRS 600 (151
MHz) with CDCl3 as an internal standard (77.0 ppm) or CD3CN as an internal standard (118.0 ppm). 19F-NMR spectra were measured on a JEOL
ECX-400 PSK (376 MHz) with C6F6 as an internal standard (–162.2 ppm). High-resolution mass spectra were recorded on a time-of-flight (TOF)
mass spectrometer by use of Thermo Fisher Scientific Exactive LC/MS spectrometer. For silica gel column chromatography, SiliCycle Inc.
SiliaFlash F60 was used. Preparative TLC separations were carried out on precoated silica gel plates (E. Merck 60F254). Products 6e,32 7a,33 10,34
11,27 1217b, 1714a and 18a35 are known compounds.
.
Procedure for preparing Mg(TMP)2 2LiCl: To a suspension of magnesium metal (turning, 535 mg, 22.0 mmol) in freshly distilled THF (55
mL) was added 1,2-dichloroethane (1.72 mL, 22.0 mmol) under argon atmosphere at room temperature and stirred at the same temperature for an
hour. In another two neck flask, n-BuLi (1.6 M in hexane, 27.5 mL, 44.0 mmol) was added dropwise to a solution of
2,2,6,6-tetramethylpiperidine (TMPH, 7.43 mL, 44.0 mmol) in freshly distilled THF (22 mL) under argon atmosphere at –80 °C. After being
warmed to 0 °C, this mixture was stirred at the same temperature for 30 min. To Li(TMP) solution in two neck flask was added dropwise the
MgCl2 solution at 0 °C and the reaction mixture was stirred at the same temperature for an hour.
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General procedure for TMS-migration reaction using Mg(TMP)2 2LiCl: To a solution of phenol derivatives 5a, 5b or 5d-h (20.0 mmol) in
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freshly distilled THF (20 mL) was added 1,1,1,3,3,3-hexamethyldisilazane (HMDS, 6.26 mL, 30.0 mmol) under argon atmosphere at room
temperature. After being stirred at 50 °C the same temperature for 5 hours, the reaction mixture was concentrated at reduced pressure. The
obtained O-trimethylsilylated intermediates were used next TMS-migration reaction without purification. To a solution of O-trimethylsilylated
intermediates (20.0 mmol) in freshly distilled THF (20 mL) was added dropwise Mg(TMP)2·2LiCl solution (22.0 mmol) under argon atmosphere
at –80 °C. After being stirred at the same temperature for an hour, the reaction mixture was stirred at –80 °C to 0 °C for 3 hours. The reaction
mixture was diluted with iced 0.5 M sodium (+)-tartrate solution and then extracted with hexanes. The organic phase was dried over Na2SO4 and
concentrated at reduced pressure. Purification of the residue by flash silica gel column chromatography afforded the products 6a, 6b or 6d-h.
Procedure for preparing LiN(i-Pr)2: To a solution of diisopropylamine ((i-Pr)2NH, 3.37 mL, 24.0 mmol) in freshly distilled THF (12 mL) was
added n-BuLi (1.6 M in hexane, 15.0 mL, 24.0 mmol) under argon atmosphere at –80 °C. After being warmed to 0 °C, this mixture was stirred at
the same temperature for 30 min.
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General procedure for TMS-migration reaction using LiN(i-Pr)2: To a solution of phenol derivatives 5a or 5c (20.0 mmol) in freshly distilled
THF (20 mL) was added 1,1,1,3,3,3-hexamethyldisilazane (HMDS, 6.26 mL, 30.0 mmol) under argon atmosphere at room temperature. After
being stirred at 50 °C the same temperature for 5 hours, the reaction mixture was concentrated at reduced pressure. The obtained
O-trimethylsilylated intermediates were used next TMS-migration reaction without purification. To a solution of O-trimethylsilylated
intermediates (20.0 mmol) in freshly distilled THF (20 mL) was added dropwise LiN(i-Pr)2 solution (24.0 mmol) under argon atmosphere at –
80 °C. After being stirred at the same temperature for an hour, the reaction temperature was raised to 0 °C and the reaction mixture was stirred at
the same temperature for 3 hours. The reaction mixture was diluted with iced water and then extracted with AcOEt. The organic phase was dried
over Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica gel column chromatography -afforded the products
6a or 6c.
.
3-Chloro-2-(trimethylsilyl)phenol (6a) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5a was carried out. Purification
of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6a (3.44 g, 86%) as colorless oil.
Following the general procedure using LiN(i-Pr)2, the reaction of 5a was carried out. Purification of the residue by flash silica gel column
chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6a (2.28 g, 57%) as colorless oil. IR (KBr) 3572 (br), 2954, 1582, 1423 cm-1.
1H NMR (400 MHz, CDCl3)  7.11 (1H, br t, J = 8.0 Hz), 6.91 (1H, d, J = 8.0 Hz), 6.60 (1H, d, J = 8.0 Hz), 5.20 (1H, br s), 0.45 (9H, s). 13C{1H}
NMR (100 MHz, CDCl3)  161.4, 141.6, 131.1, 123.2, 122.4, 113.7, 1.8. HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C9H1235ClOSi 199.0351;
Found: 199.0352; Calcd for C9H1237ClOSi 201.0324; Found: 201.0310.
.
3-Fluoro-2-(trimethylsilyl)phenol (6b) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5b was carried out. Purification
of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6b (2.97 g, 81%) as colorless oil. IR
(KBr) 3302 (br), 2924, 1605, 1441 cm-1. 1H NMR (400 MHz, CDCl3)  7.16 (1H, td, J = 8.2, 6.9 Hz), 6.57 (1H, td, J = 8.2, 1.0 Hz), 6.48 (1H, dd,
J = 8.2, 1.0 Hz), 5.15 (1H, br s), 0.37 (9H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  168.0 (d, J = 243 Hz), 161.3 (d, J = 15 Hz), 131.5
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(d, J = 11 Hz), 111.7 (d, J = 33 Hz), 110.7 (d, J = 3 Hz), 107.5 (d, J = 27 Hz), 0.5 (d, J = 3 Hz). 19F NMR (376 MHz, CDCl3)  −98.2 (1F, s).
HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C9H12FOSi 183.0647; Found: 183.0651.
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3-Bromo-2-(trimethylsilyl)phenol (6c) Following the general procedure using LiN(i-Pr)2, the reaction of 5c was carried out. Purification of the
residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6c (1.68 g, 34%) as colorless oil. IR (KBr)
3567 (br), 2954, 1583, 1564, 1418, 1251 cm-1. 1H NMR (400 MHz, CDCl3)  7.13 (1H, dd, J = 7.8, 1.0 Hz), 7.03 (1H, br t, J = 7.8 Hz), 6.64 (1H,
dd, J = 7.8, 1.0 Hz), 5.30 (1H, br s), 0.48 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  161.4, 131.3, 130.9, 126.1, 125.2, 114.3, 2.1. HRMS
(ESI−/TOF) m/z: [M − H]− Calcd for C9H1279BrOSi 242.9846; Found: 242.9841; Calcd for C9H1281BrOSi 244.9826; Found: 244.9819.
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3-Chloro-4-methyl-2-(trimethylsilyl)phenol (6d) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5d was carried out.
Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6d (2.29 g, 53%) as
colorless oil. IR (KBr) 3584 (br), 2953, 1574, 1452, 1368, 1251 cm-1. 1H NMR (400 MHz, CDCl3)  7.07 (1H, d, J = 8.2 Hz), 6.55 (1H, d, J = 8.2
Hz), 5.19 (1H, br s), 2.27 (3H, s), 0.46 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  159.4, 141.4, 132.4, 128.5, 123.0, 113.9, 20.3, 2.0. HRMS
(ESI−/TOF) m/z: [M − H]− Calcd for C10H1435ClOSi 213.0508; Found: 213.0509; Calcd for C10H1437ClOSi 215.0481; Found: 215.0470.
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3,5-Dichloro-2-(trimethylsilyl)phenol (6e) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5e was carried out.
Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6e (1.42 g, 30%) as
colorless oil. IR (KBr) 3307 (br), 2956, 1575, 1377, 1251 cm-1. 1H NMR (400 MHz, CDCl3)  6.93 (1H, d, J = 1.8 Hz), 6.64 (1H, d, J = 1.8 Hz),
5.77 (1H, br s), 0.43 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  161.7, 142.1, 136.0, 122.4, 114.8, 114.2, 1.6. HRMS (ESI−/TOF) m/z: [M −
TMS]− Calcd for C6H335Cl2O 160.9566; Found: 160.9567; Calcd for C6H335Cl37ClO 162.9537; Found: 162.9535; Calcd for C6H337Cl2O 164.9509;
Found: 164.9509.
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3-Chloro-5-trifluoromethyl-2-(trimethylsilyl)phenol (6f) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5f was
carried out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6f (3.70 g,
69%) as colorless oil. IR (KBr) 3601 (br), 2957, 1565, 1469, 1400, 1329 cm-1. 1H NMR (400 MHz, CDCl3)  7.16 (1H, br s), 6.84 (1H, br s), 5.78
(1H, br s), 0.46 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  161.6, 142.3, 133.2 (q, J = 33 Hz), 127.9, 123.0 (q, J = 274 Hz), 119.0 (q, J = 4 Hz),
110.4 (q, J = 4 Hz), 1.5. 19F NMR (376 MHz, CDCl3)  −63.9 (3F, s). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C10H1135ClF3OSi 267.0225;
Found: 267.0223; Calcd for C10H1137ClF3OSi 269.0198; Found: 269.0192.
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3,4,5-Trifluoro-2-(trimethylsilyl)phenol (6g) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5g was carried out.
Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:6) afforded the product 6g (3.02 g, 69%) as
colorless oil. IR (KBr) 3284 (br), 2926, 1614, 1513, 1435 cm-1. 1H NMR (400 MHz, CDCl3)  6.34 (1H, ddd, J = 11.0, 5.0, 2.3 Hz), 5.52 (1H, br
s), 0.36 (9H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  155.3 (ddd, J = 243, 10, 6 Hz), 155.2 (d, J = 14 Hz), 151.7 (ddd, J = 249, 11, 6
Hz), 134.5 (ddd, J = 247, 20, 15 Hz), 109.0 (m), 99.7 (dd, J = 19, 2 Hz), 0.3 (d, J = 3 Hz). 19F NMR (376 MHz, CDCl3)  −121.8 (1F, d, J = 23
Hz), −133.9 (1F, m), −172.5 (1F, m). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C9H10F3OSi 219.0459; Found: 219.0460.
.
3-Fluoro-6-methoxy-2-(trimethylsilyl)phenol (6h) Following the general procedure using Mg(TMP)2 2LiCl, the reaction of 5h was carried out.
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Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 20:1–1:4) afforded the product 6h (3.88 g, 91%) as
colorless oil. IR (KBr) 3529 (br), 2957, 1615, 1460, 1433, 1227 cm-1. 1H NMR (400 MHz, CDCl3)  6.77 (1H, dd, J = 8.7, 5.0 Hz), 6.47 (1H, t, J
= 8.7 Hz), 5.97 (1H, br d, J = 1.4 Hz), 3.85 (3H, s), 0.35 (9H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  161.4 (d, J = 235 Hz), 150.5 (d,
J = 16 Hz), 142.3 (d, J = 3 Hz), 112.0 (d, J = 12 Hz), 111.5 (d, J = 36 Hz), 105.2 (d, J = 29 Hz), 56.4, 0.3 (d, J = 3 Hz). 19F NMR (376 MHz,
CDCl3)  −108.7 (1F, s). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C10H14FO2Si 213.0753; Found: 213.0750.
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General procedure for the synthesis of precursor using Tf2O: To a solution of 6a-h (6.0 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.9
mmol) in anhydrous dichloromethane (15 mL) was added dropwise trifluoromethanesulfonic anhydride (1.11 mL, 6.6 mmol) under argon
atmosphere at –40 °C. After being stirred at the same temperature for 5 hours, the reaction mixture was diluted with iced water and then extracted
with dichloromethane. The organic phase was dried over Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica
gel column chromatography afforded the products 2a-h.
3-Chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) Following the general procedure using Tf2O, the reaction of 6a was carried
out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2a (1.67 g, 87%) as
colorless oil. IR (KBr) 2959, 1586, 1422, 1361 cm-1. 1H NMR (600 MHz, CDCl3)  7.37 (1H, dd, J = 7.9, 1.5 Hz), 7.34 (1H, t, J = 7.9 Hz), 7.26
(1H, dd, J = 7.9, 1.5 Hz), 0.49 (9H, s). 13C{1H} NMR (151 MHz, CDCl3)  154.5, 142.4, 131.9, 131.2, 129.8, 118.9, 118.6 (q, J = 321 Hz), 1.3.
19F NMR (376 MHz, CDCl3)  −73.1 (3F, s). HRMS (ESI−/TOF) m/z: [M − TMS]− Calcd for C7H335ClF3O3S 258.9449; Found: 258.9445; Calcd
for C7H337ClF3O3S 260.9420; Found: 260.9405.
3-Fluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2b) Following the general procedure using Tf2O, the reaction of 6b was carried
out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2b (1.38 g, 73%) as
colorless oil. IR (KBr) 2960, 1606, 1440 cm-1. 1H NMR (400 MHz, CDCl3)  7.41 (1H, td, J = 8.2, 6.4 Hz), 7.16 (1H, br m), 7.03 (1H, dd, J =
8.2, 1.0 Hz), 0.42 (9H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  167.3 (d, J = 247 Hz), 154.1 (d, J = 15 Hz), 131.9 (d, J = 11 Hz),
120.3 (d, J = 35 Hz), 118.5 (q, J = 322 Hz), 116.1 (br s), 115.1 (d, J = 27 Hz), 0.3 (d, J = 4 Hz). 19F NMR (376 MHz, CDCl3)  −73.5 (3F, s).
−94.1 (1F, m). HRMS (ESI−/TOF) m/z: [M − TMS]− Calcd for C7H3F4O3S 242.9745; Found: 242.9745.
3-Bromo-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2c) Following the general procedure using Tf2O, the reaction of 6c was carried
out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2c (1.70 g, 75%) as
colorless oil. IR (KBr) 2960, 1583, 1552, 1421 cm-1. 1H NMR (400 MHz, CDCl3)  7.58 (1H, dd, J = 7.8, 1.4 Hz), 7.34−7.23 (2H, m), 0.52 (9H,
s). 13C{1H} NMR (100 MHz, CDCl3) 154.4, 134.0, 133.5, 131.4 (2C), 119.5 (d, J = 2 Hz), 118.5 (q, J = 323 Hz), 1.7.. 19F NMR (376 MHz,
CDCl3)  −73.1 (3F, s). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C10H1179BrF3O3SSi 374.9339; Found: 374.9343; Calcd for
C10H1181BrF3O3SSi 376.9319; Found: 376.9344.
3-Chloro-4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2d) Following the general procedure using Tf2O, the reaction of 6d
was carried out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2d (1.59
g, 76%) as colorless oil. IR (KBr) 2959, 1575, 1422 cm-1. 1H NMR (400 MHz, CDCl3)  7.28 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 8.2 Hz), 2.38
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(3H, s), 0.49 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  152.4, 142.2, 136.9, 132.5, 131.9, 118.8, 118.5 (q, J = 323 Hz), 20.7, 1.5. 19F NMR
(376 MHz, CDCl3)  −73.0 (3F, s). HRMS (ESI−/TOF) m/z: [M − TMS]− Calcd for C8H535ClF3O3S 272.9605; Found: 272.9601; Calcd for
C8H537ClF3O3S 274.9577; Found: 274.9554.
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3,5-Dichloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2e) Following the general procedure using Tf2O, the reaction of 6e was
carried out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2e (1.32 g,
60%) as colorless crystals. Mp ca. 20 °C (hexanes). IR (KBr) 2959, 1579, 1538, 1429, 1368 cm-1. 1H NMR (400 MHz, CDCl3)  7.39 (1H, d, J =
1.8 Hz), 7.28 (1H, d, J = 1.8 Hz), 0.48 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  154.1, 142.9, 136.4, 130.5, 129.8, 119.6, 118.5 (q, J = 322
Hz), 1.2. 19F NMR (376 MHz, CDCl3)  −73.0 (3F, s). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C10H1035Cl2F3O3SSi 364.9455; Found:
364.9451; Calcd for C10H1035Cl37ClF3O3SSi 366.9426; Found: 366.9417; Calcd for C10H1037Cl2F3O3SSi 368.9399; Found: 368.9400. HRMS
(ESI−/TOF) m/z: [M − TMS]− Calcd for C7H235Cl2F3O3S 292.9055; Found: 292.9055; Calcd for C7H235Cl37ClF3O3S 294.9030; Found: 294.9026;
Calcd for C7H237Cl2F3O3S 296.9001; Found: 296.9000.
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3-Chloro-5-trifluoromethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2f) Following the general procedure using Tf2O, the reaction
of 6f was carried out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2f
(2.22 g, 92%) as colorless oil. IR (KBr) 2961, 1554, 1449, 1431 cm-1. 1H NMR (400 MHz, CDCl3)  7.62 (1H, br d, J = 1.0 Hz), 7.48 (1H, br s),
0.51 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  154.1, 143.3, 136.9, 133.6 (q, J = 35 Hz), 126.5 (q, J = 4 Hz), 122.2 (q, J = 273 Hz), 118.5 (q, J
= 322 Hz), 116.1, 1.1. 19F NMR (376 MHz, CDCl3)  −63.9 (3F, s), −72.9 (3F, s). HRMS (ESI−/TOF) m/z: [M − TMS]− Calcd for
C8H235ClF6O3S 326.9323; Found: 326.9303; Calcd for C8H237ClF6O3S 328.9294; Found: 328.9269.
3,4,5-Trifluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2g) Following the general procedure using Tf2O, the reaction of 6g was
carried out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:1–1:10) afforded the product 2g (1.61 g,
76%) as colorless oil. IR (KBr) 2963, 1626, 1496, 1430 cm-1. 1H NMR (400 MHz, CDCl3)  7.06 (1H, ddd, J = 9.6, 5.0, 2.3 Hz), 0.43 (9H, d, J =
1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  155.0 (ddd, J = 247, 10, 5 Hz), 151.3 (ddd, J = 255, 12, 6 Hz), 147.1 (ddd, J = 16, 12, 5 Hz), 139.3
(ddd, J = 257, 20, 14 Hz), 118.4 (q, J = 322 Hz), 118.3 (dt, J = 31, 4 Hz), 106.5 (d, J = 21 Hz), 0.2 (d, J = 4 Hz). 19F NMR (376 MHz, CDCl3) 
−73.4 (3F, s), −117.4 (1F, m), −129.6 (1F, m), −160.1 (1F, m). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C10H9F6O3SSi 350.9951; Found:
350.9949. HRMS (ESI−/TOF) m/z: [M − TMS]− Calcd for C7HF6O3S 278.9556; Found: 278.9560.
3-Fluoro-6-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2h) Following the general procedure using Tf2O, the reaction of 6h
was carried out. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 1:20–1:6) afforded the product 2h (2.01
g, 97%) as colorless crystals. Mp 21−23 °C (hexanes). IR (KBr) 2960, 1578, 1464, 1417 cm-1. 1H NMR (400 MHz, CDCl3)  7.03−6.93 (2H, m),
3.84 (3H, s), 0.43 (9H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  160.1 (d, J = 239 Hz), 147.3 (d, J = 3 Hz), 141.6 (d, J = 15 Hz), 122.8
(d, 35 Hz), 118.8 (q, J = 323 Hz), 115.2 (d, J = 29 Hz), 114.3 (d, J = 10 Hz), 56.1, 0.3 (d, J = 4 Hz). 19F NMR (376 MHz, CDCl3)  −71.9 (3F,
m), −105.9 (1F, m). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C11H13F4O4SSi 345.0245; Found: 345.0246. HRMS (ESI−/TOF) m/z: [M −
TMS]− Calcd for C8H5F4O4S 272.9850; Found: 272.9847.
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Reaction of new precursor 2a with acetonitrile: To a suspension of CsF (91 mg, 0.60 mmol) in anhydrous acetonitrile-toluene (3:1, v/v, 0.40
mL) was added precursor 2a (67 mg, 0.20 mmol) under argon atmosphere at room temperature. After being stirred at the same temperature for 12
hours, the reaction mixture was diluted with water and then extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated at
reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 1:2) afforded the products 9 (12 mg,
43% based on 2 equiv. of 2a) as colorless oil and 10 (5 mg, 15%) as colorless oil.
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N,N-Bis(3-chlorophenyl)acetamide (9) IR (KBr) 3066, 2928, 1682, 1588, 1474 cm-1. 1H NMR (400 MHz, CD3CN at 50 °C)  7.41 (2H, t, J =
2.1 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.33 (2H, m), 7.26 (2H, m), 1.99 (3H, s). 13C{1H} NMR (100 MHz, CD3CN at 50 °C) 170.7, 145.2, 135.1,
131.6, 128.8, 128.1, 127.3, 23.7. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C14H1135Cl2NONa 302.0110; Found: 302.0123; Calcd for
C14H1135Cl37ClNONa 304.0082; Found: 304.0087.
N-(3-chlorophenyl)acetamide (10) IR (KBr) 3303 (br), 3080, 2927, 1673, 1594, 1540, 1481, 1421 cm-1. 1H NMR (400 MHz, CDCl3)  7.62 (1H,
s), 7.34 (1H, d, J = 7.8 Hz), 7.27 (1H, br s), 7.23 (1H, t, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz), 2.18 (3H, s). 13C{1H} NMR (100 MHz, CDCl3) 
168.3, 139.0, 134.6, 130.0, 124.3, 119.8, 117.7, 24.6. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C8H835ClNONa 192.0187; Found: 192.0191;
Calcd for C8H837ClNONa 194.0159; Found: 194.0169.
Reaction of precursor 1 with n-Bu3SnF: To a suspension of KF (55 mg, 0.96 mmol) and 18-crown-6 (254 mg, 0.96 mmol) in anhydrous 1,2‐
dimethoxyethane (DME, 4.0 mL) were added tributyltin fluoride (124 mg, 0.40 mmol) and precursor 1 (160 mg, 0.48 mg) under argon
atmosphere at 0 °C. After being stirred at the same temperature for 7 hours, the reaction mixture was diluted with water and then extracted with
AcOEt. The organic phase was dried over Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica gel column
chromatography (AcOEt:hexanes = 0:11:10) afforded the product 11 (60 mg, 36%) as colorless oil and 12 (15 mg, 14%) as yellow solid.
Reaction of new precursor 2a with n-Bu3SnF: To a suspension of KF (55 mg, 0.96 mmol) and 18-crown-6 (254 mg, 0.96 mmol) in anhydrous
1,2‐dimethoxyethane (DME, 4.0 mL) were added tributyltin fluoride (124 mg, 0.40 mmol) and precursor 2a (160 mg, 0.48 mg) under argon
atmosphere at 0 °C. After being stirred at the same temperature for 7 hours, the reaction mixture was diluted with water and then extracted with
AcOEt. The organic phase was dried over Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica gel column
chromatography (AcOEt:hexanes = 0:11:10) afforded the product 11 (154 mg, 92%) as colorless oil.
Tributyl(2-chloro-6-fluorophenyl)stannane (11) IR (KBr) 2958, 1587, 1556, 1461, 1428 cm-1. 1H NMR (400 MHz, CDCl3)  7.20 (1H, m),
7.13 (1H, d, J = 7.8 Hz), 6.88 (1H, br t, J = 7.8 Hz), 1.58−1.48 (6H, m), 1.38−1.29 (6H, m), 1.28−1.12 (6H, m), 0.89 (9H, t, J = 7.3 Hz). 13C{1H}
NMR (100 MHz, CDCl3)  167.3 (d, J = 240 Hz), 142.7 (d, J = 17 Hz), 130.9 (d, J = 9 Hz), 128.6 (d, J = 50 Hz), 124.8 (d, J = 3 Hz), 112.7 (d, J
= 30 Hz), 28.9 (t, J = 10 Hz), 27.2 (t, J = 33 Hz), 13.6, 12.0 (d, J = 3 Hz). 19F NMR (376 MHz, CDCl3)  −91.0 (1F, t, J = 7 Hz). HRMS
(ESI−/TOF) m/z: [M − Bu]− Calcd for C14H2135ClF120Sn 363.0339; Found: 363.0352; Calcd for C14H2135ClF118Sn 361.0337; Found: 361.0366.
2-Chloro-6-(trifluoromethylsulfonyl)phenol (12) IR (KBr) 3408 (br), 2926, 1666, 1591, 1685, 1204 cm-1. 1H NMR (400 MHz, CDCl3)  7.71
(1H, dd, J = 7.8, 1.4 Hz), 7.65 (1H, br d, J = 7.8 Hz), 6.87 (1H, t, J = 7.8 Hz). An exchangeable proton peak of OH group was not clearly
detected. 13C{1H} NMR (100 MHz, CDCl3)  162.7, 137.8, 131.2, 126.7, 120.0 (q, J = 326 Hz), 114.8, 113.9. 19F NMR (376 MHz, CDCl3) 
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−79.1 (3F, s). HRMS (ESI−/TOF) m/z: [M − H]− Calcd for C7H335ClF3O3S 258.9449; Found: 258.9446; Calcd for C7H337ClF3O3S 260.9420;
Found: 260.9411.
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Diels-Alder-type reaction of new precursor 2a with 2-bromofuran: To a suspension of CsF (91 mg, 0.60 mmol) in anhydrous acetonitrile (4.0
mL) were added 2-bromofuran (35 L, 0.60 mmol) and precursor 2a (67 mg, 0.20 mmol) under argon atmosphere at room temperature. After
being stirred at the same temperature for 3 hours, the reaction mixture was filtrated with folded filter paper. The filtrate was concentrated at
reduced pressure. The purification by preparative TLC (AcOEt:hexanes = 1:10, 2-fold development) afforded the isomeric products 13 (16 mg,
30%) as colorless crystals and 14 (24 mg, 46%) as colorless oil.
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1-Bromo-5-chloro-1,4-dihydro-1,4-epoxynaphthalene (13) Mp 118−120 °C (CH2Cl2-hexanes). IR (KBr) 3019, 1587, 1448 cm-1. 1H NMR (400
MHz, CDCl3)  7.13 (1H, dd, J = 6.4, 1.8 Hz), 7.04−6.94 (4H, m), 5.68 (1H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  150.5, 145.9,
144.3, 143.8, 128.4, 127.9, 118.5, 90.5, 81.9. One carbon peak was missing due to overlapping. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for
C10H679Br35ClONa 278.9183; Found: 278.9198; Calcd for C10H681Br37ClONa 282.9135; Found: 282.9153.
1-Bromo-8-chloro-1,4-dihydro-1,4-epoxynaphthalene (14) IR (KBr) 3097, 3025, 1591, 1451 cm-1. 1H NMR (400 MHz, CDCl3)  7.24 (1H, br
d, J = 6.9 Hz), 7.10−6.97 (4H, m), 5.86 (1H, d, J = 1.8 Hz). 13C{1H} NMR (100 MHz, CDCl3)  151.4, 146.4, 145.7, 143.6, 127.5, 126.7, 126.3,
118.9, 91.9, 80.9. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C10H679Br35ClONa 278.9183; Found: 278.9202; Calcd for C10H681Br37ClONa
282.9135; Found: 282.9154.
General procedure for 1,3-Dipolar cycloaddition reaction of new precursors 2a-c with nitrone: To a suspension of CsF (182 mg, 1.2 mmol)
in anhydrous acetonitrile (4.0 mL) were added N-tert-butyl-α-phenylnitrone (142 mg, 0.80 mmol) and precursor 2a, 2b or 2c (0.40 mmol) under
argon atmosphere at room temperature. After being stirred at the same temperature for 3 hours, the reaction mixture was filtrated with folded
filter paper. The filtrate was concentrated at reduced pressure. Purification by flash silica gel column chromatography afforded the products 15a-c,
16a and 16c.
2-(tert-Butyl)-4-chloro-3-phenyl-2,3-dihydrobenzo[d]isoxazole (15a) Following the general procedure for 1,3-Dipolar cycloaddition, the
reaction of 2a was carried out. First purification by flash silica gel column chromatography (AcOEt:hexanes = 1:20) afforded the isomeric
products 15a and 16a (97 mg, 84%) as a mixture of 89:11. The isomers 15a and 16a were separated by second purification by preparative TLC
(AcOEt:hexanes = 1:1, 2-fold development), leading to 15a as colorless crystals and 16a as colorless oil. Mp 66−68 °C (hexanes). IR (KBr) 2974,
1591, 1449, 1365 cm-1. 1H NMR (400 MHz, CDCl3)  7.34−7.24 (5H, m), 7.13 (1H, br t, J = 8.2 Hz), 6.81 (1H, br d, J = 8.2 Hz), 6.75 (1H, br d, J
= 8.2 Hz), 5.60 (1H, s), 1.18 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  158.5, 141.7, 130.2, 129.6, 128.5, 128.0, 127.6, 127.5, 121.4, 105.3,
66.6, 61.6, 25.3. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C17H1835ClNONa 310.0969; Found: 310.0962; Calcd for C17H1837ClNONa
312.0945; Found: 312.0938.
2-(tert-Butyl)-7-chloro-3-phenyl-2,3-dihydrobenzo[d]isoxazole (16a) IR (KBr) 2975, 1594, 1456, 1365 cm-1. 1H NMR (400 MHz, CDCl3) 
7.41 (2H, dd, J = 7.3, 1.6 Hz), 7.34 (2H, m), 7.26 (1H, m), 7.13 (1H, dd, J = 7.3, 1.8 Hz), 6.77 (1H, dd, J = 7.3, 1.8 Hz), 6.73 (1H, br t, J = 7.3
Hz), 5.64 (1H, s), 1.20 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  152.3, 143.2, 131.7, 128.9, 128.7, 127.6, 127.2, 121.8 (2C), 112.8, 67.7, 61.3,
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25.4. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C17H1835ClNONa 310.0969; Found: 310.0993; Calcd for C17H1837ClNONa 312.0945; Found:
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2-(tert-Butyl)-4-fluoro-3-phenyl-2,3-dihydrobenzo[d]isoxazole (15b) Following the general procedure for 1,3-Dipolar cycloaddition, the
reaction of 2b was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes = 1:20) afforded the single product 15b
(102 mg, 95%) as white solid. IR (KBr) 2975, 1624, 1607, 1485, 1459, 1365 cm-1. 1H NMR (400 MHz, CDCl3)  7.40 (2H, br d, J = 7.3 Hz), 7.33
(2H, m), 7.26 (1H, m), 7.13 (1H, m), 6.61 (1H, br d, J = 8.2 Hz), 6.52 (1H, br t, J = 8.2 Hz), 5.72 (1H, s), 1.18 (9H, s). 13C{1H} NMR (100 MHz,
CDCl3)  159.4 (d, J = 8 Hz), 158.0 (d, J = 249 Hz), 142.2, 130.5 (d, J = 8 Hz), 128.5, 127.6, 127.2, 116.3 (d, J = 20 Hz), 107.8 (d, J = 20 Hz),
102.8 (d, J = 4 Hz), 64.4 (d, J = 3 Hz), 61.4, 25.3. 19F NMR (376 MHz, CDCl3)  −118.3 (1F, dd, J = 9, 6 Hz). HRMS (ESI+/TOF) m/z: [M +
Na]+ Calcd for C17H18FNONa 294.1265; Found: 294.1269.
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4-Bromo-2-(tert-butyl)-3-phenyl-2,3-dihydrobenzo[d]isoxazole (15c) Following the general procedure for 1,3-Dipolar cycloaddition, the
reaction of 2c was carried out. First purification by flash silica gel column chromatography (AcOEt:hexanes = 1:20) afforded the isomeric
products 15c and 16c (109 mg, 82%) as a mixture of 86:14. The isomers 15c and 16c were separated by second purification by preparative TLC
(CHCl3:hexane = 1:1, 2-fold development), leading to 15c as white solid and 16c as colorless oil. IR (KBr) 2974, 1585, 1444, 1365 cm-1. 1H
NMR (400 MHz, CDCl3)  7.34−7.24 (5H, m), 7.07 (1H, br t, J = 7.8 Hz), 6.98 (1H, br d, J = 7.8 Hz), 6.80 (1H, br d, J = 7.8 Hz), 5.53 (1H, s),
1.18 (9H, s). 13C{1H} NMR (100 MHz, CDCl3)  158.3, 141.6, 130.4, 129.4, 128.5, 128.2, 127.6, 124.3, 117.9, 105.8, 67.8, 61.7, 25.3. HRMS
(ESI+/TOF) m/z: [M + Na]+ Calcd for C17H1879BrNONa 354.0464; Found: 354.0465; Calcd for C17H1881BrNONa 356.0445; Found: 356.0441.
7-Bromo-2-(tert-butyl)-3-phenyl-2,3-dihydrobenzo[d]isoxazole (16c) IR (KBr) 2974, 1589, 1452, 1365 cm-1. 1H NMR (400 MHz, CDCl3) 
7.41 (2H, br d, J = 7.3 Hz), 7.36−7.31 (2H, m), 7.29−7.24 (2H, m), 6.82 (1H, br d, J = 7.3 Hz), 6.68 (1H, br t, J = 7.3 Hz), 5.67 (1H, s), 1.20 (9H,
s). 13C{1H} NMR (100 MHz, CDCl3)  153.8, 143.3, 131.7, 131.2, 128.7, 127.6, 127.2, 122.5, 122.1, 99.9, 67.9, 61.4, 25.4. HRMS (ESI+/TOF)
m/z: [M + Na]+ Calcd for C17H1879BrNONa 354.0464; Found: 354.0462; Calcd for C17H1881BrNONa 356.0445; Found: 356.0446.
1-Benzyl-4-chloro-1,2,3-benzotriazole (17) To a suspension of CsF (182 mg, 1.2 mmol) in anhydrous acetonitrile (4.0 mL) were added
benzylazide (50 L, 0.40 mmol) and precursor 2a (133 mg, 0.40 mmol) under argon atmosphere at room temperature. After being stirred at the
same temperature for 3 hours, the reaction mixture was diluted with water and then extracted with AcOEt. The organic phase was dried over
Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 0:11:10)
afforded the product 17 (89 mg, 91%) as colorless crystals. Mp 78−80 °C (AcOEt-hexanes). IR (KBr) 3067, 3033, 1609, 1581, 1494, 1454, 1424
cm-1. 1H NMR (400 MHz, CDCl3)  7.37−7.23 (8H, m), 5.86 (2H, s). 13C{1H} NMR (100 MHz, CDCl3)  144.0, 134.2, 134.1, 129.1, 128.6,
127.9, 127.6, 125.5, 123.8, 108.5, 52.7. HRMS (ESI+/TOF) m/z: [M + H]+ Calcd for C13H1135ClN3 244.0636; Found: 244.0637; Calcd for
C13H1137ClN3 246.0609; Found: 246.0610.
Procedure for three-component coupling reaction using precursor 1: To a suspension of CsF (91 mg, 0.60 mmol) and diethyl malonate (46
L, 0.30 mmol) in anhydrous N,N-dimethylformamide (DMF, 2.0 mL) was added precursor 1 (67 mg, 0.20 mmol) under argon atmosphere at
room temperature. After being stirred at the same temperature for 12 hours, silica gel (0.50 g) was added to the reaction mixture, which was
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concentrated under reduced pressure. The purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with
2% CH2Cl2) afforded the products 18a (24 mg, 47%) as colorless crystals and 12 (9 mg, 17%) as yellow solid.
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malonate (46 L, 0.30 mmol) in anhydrous N,N-dimethylformamide (DMF, 2.0 mL) was added precursors 2a-f or 2h (0.20 mmol) under argon
atmosphere at room temperature. After being stirred at the same temperature for 12 hours, silica gel (0.50 g) was added to the reaction mixture,
which was concentrated under reduced pressure. The purification of the residue by flash silica gel column chromatography afforded the products
18a-f, 18h and 19.
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5-Chloro-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18a) Following the general procedure for three-component coupling reaction,
the reaction of 2a was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with 2% CH2Cl2) afforded
the product 18a (43 mg, 85%) as colorless crystals. Mp 140−143 °C (AcOEt-hexanes). IR (KBr) 3087, 2980, 1766, 1719, 1595, 1562, 1451 cm-1.
1H NMR (400 MHz, CDCl3)  8.84 (1H, s), 7.55 (1H, br t, J = 8.2 Hz), 7.37 (1H, dd, J = 8.2, 1.0 Hz), 7.26 (1H, br d, J = 8.2 Hz), 4.43 (2H, q, J =
7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.7, 155.9, 155.8, 144.6, 134.2, 134.0, 125.4, 119.0, 116.6, 115.6, 62.2,
14.2. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C12H935ClO4Na 275.0082; Found: 275.0082; Calcd for C12H937ClO4Na 277.0056; Found:
277.0058.
5-Fluoro-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18b) Following the general procedure for three-component coupling reaction,
the reaction of 2b was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with 2% CH2Cl2) afforded
the product 18b (38 mg, 80%) as colorless crystals. Mp 124−126 °C (CH2Cl2-hexanes). IR (KBr) 3065, 2988, 1766, 1718, 1623, 1570, 1471,
1373 cm-1. 1H NMR (400 MHz, CDCl3)  8.73 (1H, s), 7.60 (1H, br m), 7.16 (1H, br d, J = 8.4 Hz), 7.04 (1H, br t, J = 8.4 Hz), 4.43 (2H, q, J =
7.2 Hz), 1.41 (3H, t, J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.6, 159.3 (d, J = 260 Hz), 155.9, 155.4 (d, J = 5 Hz), 141.4 (d, J = 4
Hz), 134.9 (d, J = 11 Hz), 118.4, 112.6 (d, J = 4 Hz), 110.6 (d, J = 19 Hz), 108.3 (d, J = 18 Hz), 62.2, 14.2. 19F NMR (376 MHz, CDCl3) 
−117.0 (1F, dd, J = 9, 6 Hz). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C12H9FO4Na 259.0377; Found: 259.0372.
5-Bromo-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18c) Following the general procedure for three-component coupling reaction,
the reaction of 2c was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with 2% CH2Cl2) afforded
the product 18c (45 mg, 76%) as colorless crystals. Mp 113−114 °C (CH2Cl2-hexanes). IR (KBr) 3084, 2980, 1766, 1718, 1611, 1446, 1372 cm-1.
1H NMR (400 MHz, CDCl3)  8.82 (1H, s), 7.56 (1H, br d, J = 8.2 Hz), 7.48 (1H, br t, J = 8.2 Hz), 7.32 (1H, br d, J = 8.2 Hz), 4.44 (2H, q, J =
7.2 Hz), 1.42 (3H, t, J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.7, 156.0, 155.8, 147.1, 134.5, 128.9, 123.9, 119.5, 118.1, 116.3, 62.3,
14.2. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C12H979BrO4Na 318.9576; Found: 318.9597; Calcd for C12H981BrO4Na 320.9557; Found:
320.9584.
5-Chloro-6-methyl-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18d) Following the general procedure for three-component
coupling reaction, the reaction of 2d was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with 2%
CH2Cl2) afforded the product 18d (43 mg, 81%) as colorless crystals. Mp 91−92 °C (CH2Cl2-hexanes). IR (KBr) 2985, 1766, 1714, 1615, 1572,
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1471 cm-1. 1H NMR (400 MHz, CDCl3)  8.90 (1H, s), 7.49 (1H, d, J = 8.2 Hz), 7.18 (1H, d, J = 8.2 Hz), 4.43 (2H, q, J = 7.2 Hz), 2.45 (3H, s),
1.42 (3H, t, J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.9, 156.2, 154.0, 145.3, 135.9, 133.1 (2C), 118.6, 116.5, 114.9, 62.2, 20.0, 14.2.
HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C13H1135ClO4Na 289.0238; Found: 289.0236; Calcd for C13H1137ClO4Na 291.0213; Found:
291.0212.
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5,7-Dichloro-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18e) Following the general procedure for three-component coupling
reaction, the reaction of 2e was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with 2% CH2Cl2)
afforded the product 18e (35 mg, 61%) as colorless crystals. Mp 72−74 °C (CH2Cl2-hexanes). IR (KBr) 3085, 2984, 1775, 1712, 1594, 1551,
1413 cm-1. 1H NMR (400 MHz, CDCl3)  8.78 (1H, s), 7.39 (1H, d, J = 1.8 Hz), 7.28 (1H, d, J = 1.8 Hz), 4.43 (2H, q, J = 7.2 Hz), 1.41 (3H, t, J =
7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.5, 155.7, 155.3, 144.0, 140.3, 134.6, 125.9, 118.7, 116.0, 115.2, 62.4, 14.2. HRMS (ESI+/TOF)
m/z: [M + Na]+ Calcd for C12H835Cl2O4Na 308.9692; Found: 308.9715; Calcd for C12H835Cl37ClO4Na 310.9664; Found: 310.9684.
5-Chloro-7-trifluoromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18f) Following the general procedure for
three-component coupling reaction, the reaction of 2f was carried out. Purification by flash silica gel column chromatography (AcOEt:hexanes =
1:81:0 with 2% CH2Cl2) afforded the product 18f (40mg, 62%) as colorless crystals. Mp 77−79 °C (hexanes). IR (KBr) 3090, 2989, 1777, 1710,
1622, 1564, 1423, 1349 cm-1. 1H NMR (400 MHz, CDCl3)  8.82 (1H, s), 7.61 (1H, d, J = 1.0 Hz), 7.51 (1H, br s), 4.45 (2H, q, J = 7.2 Hz), 1.43
(3H, t, J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.2, 155.4, 154.9, 143.2, 135.5 (q, J = 35 Hz), 135.0, 122.2 (q, J = 275 Hz), 122.0 (q, J
= 4 Hz), 121.2, 119.0, 113.0 (q, J = 4 Hz), 62.6, 14.2. 19F NMR (376 MHz, CDCl3)  −63.9 (3F, s). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for
C13H835ClF3O4Na 342.9955; Found: 342.9954; Calcd for C13H837ClF3O4Na 344.9930; Found: 344.9929.
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5-Fluoro-8-methoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (18h) Following the general procedure for three-component
coupling reaction, the reaction of 2h was carried out. First purification by flash silica gel column chromatography (AcOEt:hexanes = 1:81:0 with
2% CH2Cl2) afforded the isomeric products 18h and 19 (39 mg, 73%) as a mixture of 63:37. The isomers 18h and 19 were separated by second
purification by preparative TLC (CHCl3:Et2O = 15:1, 2-fold development), leading to 18h as pale yellow crystals and 19 as pale yellow crystals.
Mp 125−128 °C (i-Pr2O-CH2Cl2). IR (KBr) 3089, 2981, 1765, 1711, 1624, 1580, 1494, 1442 cm-1. 1H NMR (400 MHz, CDCl3)  8.67 (1H, s),
7.10 (1H, dd, J = 8.7, 4.8 Hz), 6.95 (1H, t, J = 8.7 Hz), 4.40 (2H, q, J = 7.2 Hz), 3.93 (3H, s), 1.39 (3H, t, J = 7.2 Hz). 13C{1H} NMR (100 MHz,
CDCl3)  162.5, 155.3, 152.5 (d, J = 253 Hz), 144.4 (d, J = 5 Hz), 143.4 (d, J = 4 Hz), 141.8 (d, J = 4 Hz), 118.4, 116.0 (d, J = 9 Hz), 109.4 (d, J
= 21 Hz), 108.7 (d, J = 21 Hz), 62.1 56.7, 14.1. 19F NMR (376 MHz, CDCl3)  −128.3 (1F, m). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for
C13H11FO5Na 289.0483; Found: 289.0486.
8-Fluoro-5-methoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester (19) Mp 158−159 °C (hexanes). IR (KBr) 2984, 2950, 1766,
1715, 1618, 1581, 1496, 1461 cm-1. 1H NMR (400 MHz, CDCl3)  8.85 (1H, d, J = 1.4 Hz), 7.34 (1H, t, J = 9.2 Hz), 6.63 (1H, dd, J = 9.2, 3.2
Hz), 4.41 (2H, q, J = 7.2 Hz), 3.95 (3H, s), 1.41 (3H, t, J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)  162.9, 155.3, 152.9 (d, J = 3 Hz), 143.8
(d, J = 2 Hz), 143.6 (d, J = 13 Hz), 143.4 (d, J = 247 Hz), 120.8 (d, J = 18 Hz), 116.8, 109.9, 104.3 (d, J = 6 Hz), 62.0, 56.3, 14.2. 19F NMR (376
MHz, CDCl3)  −143.6 (1F, m). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C13H11FO5Na 289.0483; Found: 289.0482.
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6-Chloro-1,2,3,4-tetrahydro-1,4-dimethyl-5H-1,4-benzodiazepin-5-one (20a) To a suspension of CsF (2.73 g, 18 mmol) and in distilled
1,3-dimethyl-2-imidazolidinone (DMI, 30 mL) was added precursors 2a (2.00 g, 6.0 mmol) under argon atmosphere at room temperature. After
being stirred at the same temperature for 12 hours, the reaction mixture was diluted with AcOEt and then filtrated with folded filter paper. The
filtrate was concentrated at reduced pressure. The purification of the residue by flash silica gel column chromatography (AcOEt:hexanes =
1:11:0) afforded the product 20a (1.25 g, 93%) as colorless crystals. Mp 166−168 °C (CH2Cl2-hexanes). IR (KBr) 3074, 2943, 2815, 1652,
1587, 1480, 1450, 1397 cm-1. 1H NMR (400 MHz, CDCl3)  7.23 (1H, br t, J = 7.8 Hz), 7.06 (1H, dd, J = 7.8, 1.0 Hz), 6.81 (1H, br d, J = 7.8 Hz),
3.41 (2H, br m), 3.22 (3H, s), 3.18 (2H, br m), 2.79 (3H, s). 13C{1H} NMR (100 MHz, CDCl3)  167.1, 148.1, 132.7, 131.0, 128.8, 124.1, 116.2,
57.1, 47.8, 40.1, 33.4. HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C11H1335ClN2ONa 247.0609; Found: 247.0612; Calcd for C11H1337ClN2ONa
249.0582; Found: 249.0586.
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6-Chloro-8-trifluoromethyl-1,2,3,4-tetrahydro-1,4-dimethyl-5H-1,4-benzodiazepin-5-one (20f) To a suspension of CsF (182 mg, 1.2 mmol)
and in distilled 1,3-dimethyl-2-imidazolidinone (DMI, 2.0 mL) was added precursors 2f (160 mg, 0.40 mmol) under argon atmosphere at room
temperature. After being stirred at the same temperature for 12 hours, the reaction mixture was diluted with AcOEt and then filtrated with folded
filter paper. The filtrate was concentrated at reduced pressure. The purification of the residue by flash silica gel column chromatography
(AcOEt:hexanes = 1:11:0) afforded the product 20f (89 mg, 76%) as colorless crystals. Mp 139−140 °C (CH2Cl2-hexanes). IR (KBr) 2949,
1660, 1566, 1487, 1415 cm-1. 1H NMR (400 MHz, CDCl3)  7.31 (1H, d, J = 1.0 Hz), 7.01 (1H, s) 3.44 (2H, br m), 3.24 (2H, br m), 3.22 (3H, s),
2.84 (3H, s). 13C{1H} NMR (100 MHz, CDCl3)  165.9, 148.4, 133.7, 133.2 (q, J = 33 Hz), 131.5, 123.1 (q, J = 274 Hz), 120.6 (q, J = 4 Hz),
113.1 (q, J = 4 Hz), 56.9, 47.6, 40.1, 33.5. 19F NMR (376 MHz, CDCl3)  −63.7 (3F, s). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for
C12H1235ClF3N2ONa 315.0482; Found: 315.0502; Calcd for C12H1237ClF3N2ONa 317.0456; Found: 317.0473.
6,7,8-Trifluoro-1,2,3,4-tetrahydro-1,4-dimethyl-5H-1,4-benzodiazepin-5-one (20g) To a suspension of CsF (182 mg, 1.2 mmol) and in
distilled 1,3-dimethyl-2-imidazolidinone (DMI, 2.0 mL) was added precursors 2g (141 mg, 0.40 mmol) under argon atmosphere at room
temperature. After being stirred at the same temperature for 12 hours, the reaction mixture was diluted with AcOEt and then filtrated with folded
filter paper. The filtrate was concentrated at reduced pressure. The purification of the residue by flash silica gel column chromatography
(AcOEt:hexanes = 1:11:0) afforded the product 20g (73 mg, 75%) as colorless crystals. Mp 93−94 °C (hexanes). IR (KBr) 2948, 1656, 1599,
1505, 1455 cm-1. 1H NMR (400 MHz, CDCl3)  6.45 (1H, ddd, J = 11.9, 6.0, 2.3 Hz), 3.44 (2H, br t, J = 5.7 Hz), 3.23 (2H, br t, J = 5.7 Hz), 3.16
(3H, s), 2.74 (3H, s). 13C{1H} NMR (100 MHz, CDCl3)  164.0, 152.4 (ddd, J = 252, 10, 6 Hz), 150.0 (ddd, J = 256, 12, 6 Hz), 142.9 (ddd, J =
10, 7, 3 Hz), 135.3 (dt, J = 247, 16 Hz), 114.6 (dt, J = 12, 2 Hz), 101.6 (dd, J = 20, 3 Hz), 57.2, 47.5, 40.2, 33.6. 19F NMR (376 MHz, CDCl3) 
−131.3 (1F, m), −134.1, (1F, m), −169.2, (1F, m). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for C11H11F3N2ONa 267.0716; Found: 267.0738.
8-Trifluoromethyl-1,2,3,4-tetrahydro-1,4-dimethyl-5H-1,4-benzodiazepin-5-one (21) To a solution of coumarin 20f (29 mg, 0.10 mmol) in
distilled MeOH (1.0 mL) were added ammonium formate (17 mg, 0.25 mmol) and Pd(OH)2/C (20%, 15 mg, 0.020 mmol) under argon
atmosphere at room temperature. After being stirred for 12 hours under the reflux conditions, the reaction mixture was filtrated with folded filter
paper. The filtrate was concentrated at reduced pressure. The purification of the residue by flash silica gel column chromatography
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(AcOEt:hexanes = 1:2) afforded the product 21 (20 mg, 77%) as colorless oil. IR (KBr) 2941, 1647, 1488, 1329 cm-1. H NMR (400 MHz,
CDCl3)  7.72 (1H, d, J = 7.8 Hz), 7.19 (1H, d, J = 7.8 Hz), 7.05 (1H, s), 3.44 (2H, dd, J = 6.4, 5.3 Hz), 3.37 (2H, dd, J = 6.4, 5.3 Hz), 3.20 (3H,
s), 2.87 (3H, s). 13C{1H} NMR (100 MHz, CDCl3)  169.2, 147.1, 133.5 (q, J = 32 Hz), 131.8, 131.0, 123.8 (q, J = 274 Hz), 117.4 (q, J = 4 Hz),
114.2 (q, J = 4 Hz), 57.8, 47.9, 40.0, 34.6. 19F NMR (376 MHz, CDCl3)  −63.5 (3F, s). HRMS (ESI+/TOF) m/z: [M + Na]+ Calcd for
C12H13F3N2ONa 281.0872; Found: 281.0866.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1H, 13C and 19F NMR spectra for obtained products.
AUTHOR INFORMATION
Corresponding Author
* E-mail: miyabe@huhs.ac.jp. Fax: (+81) 78-304-2794.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was partially supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) Grant Number 15K07879 (to E.Y.).
Notes and References
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(35) Compound 18a is commercially available.
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