Simple Photo-Induced Trifluoromethylation of Aromatic Rings

Article abstract of DOI:10.1055/s-0037-1609759

The trifluoromethylation of various aromatic compounds with Umemoto reagent II (2,8-difluoro-5-(trifluoromethyl)-5 H -dibenzo[ b, d ]thiophen-5-ium triflate) proceeded in moderate to good yields under simple photo-irradiation conditions without any cataly

Full text of DOI:10.1055/s-0037-1609759

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
special topic
A
en
H. Egami et al.
Special Topic
Synthesis
Simple Photo-Induced Trifluoromethylation of Aromatic Rings
Hiromichi Egami*
F
F
Yuta Ito
Takafumi Ide
S+
Shuya Masuda
Yoshitaka Hamashima*
TfO–
X
CF3
X
R
R
School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
hamashima@u-shizuoka-ken.ac.jp
•CF3
CF3
R
R
R2
R2
X
X
CF3
DMSO, r.t., 1 h
hegami@u-shizuoka-ken.ac.jp
CF3
N
N
N
Published as part of the Special Topic Modern Radical
Methods and their Strategic Applications in Synthesis
N
R1
R1
Received: 28.03.2018
Accepted after revision: 23.04.2018
Published online: 26.06.2018
group.9 Another reliable approach for C–H trifluoromethyl-
ation of aromatic rings is the use of the trifluoromethyl rad-
ical, and many reactions have been reported,10 including
some that employ trifluoromethylating reagents under
photoredox catalysis.11,12 For example, Li and co-workers
reported the C–H trifluoromethylation of aromatic rings us-
ing a trifluoromethyl radical generated by the reaction be-
tween Langlois reagent and a sacrificial photo-excited ke-
tone.13
We have been studying fluoro-functionalizations of C–C
multiple bonds14 as well as C–H bonds.15 During the course
of our program on benzylic C–H trifluoromethylation via
photo-enol formation [Scheme 1 (a)],15b we noticed that a
trifluoromethyl radical could be generated from an electro-
philic trifluoromethylating reagent, Togni reagent II, by
simple photo-irradiation in the presence of appropriate
substrates. In this report, we describe the C–H trifluoro-
methylation of aromatic rings under photo-irradiation con-
ditions in the absence of any catalyst or additive [Scheme 1
(b)].
DOI: 10.1055/s-0037-1609759; Art ID: ss-2018-c0214-st
Abstract The trifluoromethylation of various aromatic compounds
with Umemoto reagent II (2,8-difluoro-5-(trifluoromethyl)-5H-diben-
zo[b,d]thiophen-5-ium triflate) proceeded in moderate to good yields
under simple photo-irradiation conditions without any catalyst, addi-
tive, or activator. UV-Vis and NMR spectral analyses indicated that pre-
formation of an electron donor-acceptor complex between the trifluo-
romethylating reagent and the substrate, as proposed in previous stud-
ies, is not essential for generation of the trifluoromethyl radical. In-
stead, the radical appears to be formed by simple photo-activation of
the Umemoto reagent.
Key words trifluoromethylation, radical, photo-irradiation, Umemoto
reagent, aromatic substitution
The trifluoromethyl group is one of the most widely
used fluorine-containing functional groups in pharmaceu-
ticals, agrochemicals, and functional materials,1,2 and great
efforts have been made to develop effective methods for its
introduction into organic frameworks.3 Various methodolo-
gies are available, depending on the chemical structure of
the target compounds. In particular, trifluoromethylations
of C–C multiple bonds and aromatic rings have been inten-
sively studied for the last decade,3 and various trifluoro-
methylating reagents such as Togni reagent,4 Umemoto re-
agent,5 and Langlois reagent6,7 have been developed for this
purpose. Activation of the trifluoromethylating reagents
plays a crucial role in such reactions.
Direct functionalization of C–H bonds is extremely im-
portant from the viewpoint of atom- and step-economy,8
and therefore C–H trifluoromethylation has attracted con-
siderable interest. Indeed, transition-metal catalysis for C–H
activation has played a key role in developing trifluoro-
methylation reactions of aromatic rings bearing a directing
(a) Previous work: Trifluoromethylation via photo-enol
O
F3C
I
O
O
hν (365 nm)
R'
R'
+
R
O
R
DMSO, r.t., 1 h
OH
CF3
Ar
via
(b) This work
R
R
hν
+
CF3
+
[CF3
]
n
n
X
X
[CF3+] = electrophilic trifluoromethylating reagent
Scheme 1 Trifluoromethylation under photo-irradiation conditions
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
H. Egami et al.
Special Topic
Synthesis
Initially, 1,3,5-trimethoxybenzene (1a) was selected as a
test material (Table 1). Based on our previous work,15b Togni
reagent II (3) was examined as a trifluoromethylating re-
agent under irradiation at 365 nm with an LED device (en-
try 1). As expected, we obtained the desired product 2a in
28% yield. Togni reagent I (4) also provided 2a in 48% yield
(entry 2). Interestingly, Umemoto reagent (5) and Umemo-
to reagent II (6) were also found to be effective, and 2a was
obtained in 46% and 63% yields, respectively (entries 3 and
4). Among the solvents tested, DMSO was the solvent of
choice (entries 4–8). Polar solvents could be used, but less
polar solvents including CH2Cl2, did not work due to the low
solubility of 6 (entry 8). The irradiation wavelength affected
the reaction efficiency (entries 9–11), and the best result
was observed when a 375 nm LED was used (entry 9). To
our surprise, a blue LED (425 nm) also provided the desired
product in 42% yield (entry 11). Compound 2a was not de-
tected when the reaction was run in the dark (entry 12).
We tried adding K2CO3 to trap TfOH, which is considered to
form during this trifluoromethylation reaction (entry 13),
but the yield of 2a was not improved, suggesting that TfOH
did not affect the reaction.16 When we used three equiva-
lents of 1a, 2a was obtained in 95% yield (entry 15).
The substrate scope was next investigated under the op-
timized conditions (Scheme 2). The reaction with phenol
derivatives proceeded selectively on the aromatic ring.17
2,6-Disubstituted phenol provided 4-trifluoromethylated
product 2b in 43% yield, and 4-substituted phenol provided
2-trifluoromethylated product 2c in 56% yield. As in the
case of the phenols, aniline 2d was obtained selectively in
57% yield. While simple pyridine did not react, pyridines
having electron-donating groups underwent the reaction,
affording the desired products 2e and 2f in 46% and 60%
yields, respectively. The reaction of 8-aminoquinoline (1g)
proceeded smoothly to give both 5-trifluoromethylated and
7-trifluoromethylated products, together with a small
amount of the ditrifluoromethylated product. When 1-phe-
nyl-1H-pyrrole (1h) was used as a substrate, 2 equivalents
of 1h were enough to afford a high yield of 2h. Methyl 1H-
pyrrole-2-carboxylate (1i), which is relatively electron-defi-
cient, decreased the reaction efficiency, but 2i was obtained
in 45% yield. As expected, indole derivatives were good sub-
strates, and 2j and 2k were obtained in good yield.18 Mela-
tonin (1l) and tryptophan derivative 1m were trifluoro-
methylated without difficulty. Additionally, the reaction of
caffeine (1n) gave the desired product 2n in 59% yield.
To investigate the reaction mechanism, we measured
the UV-Vis and 19F NMR spectra of Umemoto reagent II (6)
and a mixture of 6 and 1a.19 The UV-Vis spectra and 19F
peaks of 6 did not change in the presence of the substrate
1a. In accord with this observation, DMSO solutions of 6
and the mixture of 6 and 1a were colorless, and the absorp-
tion band of 6 was detected at 379 nm in the UV-Vis spec-
Table 1 Optimization of the Reaction Conditionsa
OMe
OMe
[CF3+], hν
CF3
r.t., 1 h
MeO
F3C
OMe
MeO
OMe
1a
2a
F
F
I
O
F3C
I
O
O
S+
CF3
5
S+
–
TfO–
CF3
BF4
3
4
6
Entry
[CF3]
Solvent
hν (nm)
Yieldb (%)
1
2
3
4
5
6
6
6
6
6
6
6
6
6
6
6
6
DMSO
DMSO
DMSO
DMSO
MeCN
MeOH
DMF
365
365
365
365
365
365
365
365
375
395
425
–
28
48
46
63
40
38
44
4
3
4
5
6
7
8
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
70
67
42
0
10
11
12
13c
14d
15e
375
375
375
70
89
95 (92)f
a Reaction conditions: 1a (0.1 mmol, 1 equiv), trifluoromethylating reagent
(0.1 mmol, 1 equiv), photo-irradiation (3 W LED), unless otherwise men-
tioned.
b Determined by NMR using PhCF3 as an internal standard.
c Using 1 equiv of K2CO3.
d Using 2 equiv of 1a.
e Using 3 equiv of 1a.
f Isolated yield.
tra. In addition, decomposition of 6 to give a complex mix-
ture was observed by NMR when 6 was photo-irradiated in
the absence of the aromatic substrate. On the other hand,
the reaction of 6 with TEMPO provided TEMPO-CF3 7 and
the corresponding thiocarbazole 8 [Scheme 3 (a)].19 Com-
pound 2a was not formed in the presence of TEMPO, while
7 and 8 were observed [Scheme 3 (b)]. These results sup-
port the idea that the present reaction proceeds via addi-
tion of a trifluoromethyl radical. In other words, a trifluoro-
methyl radical could be generated by simple photo-activa-
tion of 6, and direct interaction between 6 and 1a is not
necessary for the reaction to proceed. Ragains and Xiao in-
dependently reported the generation of a trifluoromethyl
radical from the Umemoto reagent in the absence of any
photo-redox catalyst under simple visible light irradiation
conditions,20 and proposed that formation of an electron
donor-acceptor (EDA) complex between the Umemoto re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
H. Egami et al.
Special Topic
Synthesis
F
F
(a) Reaction of 6 with TEMPO under photo-irradiation
6 (0.1 mmol)
hν (375 nm)
F
F
+
S+
N
N
O·
TfO–
r.t., 1 h
X
CF3
OCF3
S
8
X
R
R
TEMPO (1 equiv)
7: 31%
(b) Reaction of 1a in the presence of TEMPO
6 (0.1 mmol)
•CF3
CF3
R
R2
R2
OMe
TEMPO (1 equiv)
X
X
R
CF3
DMSO, r.t., 1 h
hν (375 nm)
CF3
2a: not detected
N
N
N
N
r.t., 1 h
N
R1
R1
OCF3
MeO
OMe
1a (3 equiv)
7: 33%
OH
NH2
OH
t-Bu
t-Bu
CF3
Scheme 3 Results of mechanistic studies
CF3
CF3
t-Bu
2c: 56% (51%)
F
F
2b: 43% (37%)
2d: 57% (57%)
F
F
hν
sub.
S•+
TfO–
R
6
NH2
N
CF3
S+
CF3
N
CF3
•CF3
TfO–
7
MeO
N
OMe
N
CF3
5
F
F
F
CF3
F
2e: 46% (38%)
2f: 60% (51%)
2g, 5-CF3: 60% (59%)
2g’, 7-CF3: 30% (21%)
+
S•+
R
TfO–
CF3
TfOH
S
R
CF3
CF3
CF3
CF3
MeO2C
H
N
N
H
N
N
Ph
H
Scheme 4 Proposed mechanism of the trifluoromethylation
2h: 82% (72%)a
2i: 45% (43%)
2j: 78% (77%)
2k: 57% (54%)
NHBoc
O
consider that either an EDA complex or an exciplex may
also be involved as a reaction intermediate, depending on
the nature of the substrate.21
N
NHAc
CF3
CO2Me
CF3
MeO
N
CF3
N
O
N
N
N
In summary, we have achieved photo-induced C–H tri-
fluoromethylation of aromatic rings using Umemoto re-
agent II without the need for any additive or catalyst. Spec-
troscopic analyses and control experiments suggested that
interaction between Umemoto reagent II and a substrate is
not essential for this reaction; instead, the trifluoromethyl
radical is generated directly via photo-excitation of
Umemoto reagent II. Further investigations of this system
are underway in our laboratory.
H
H
2l: 66% (64%)
2m: 55% (44%)
2n: 59% (58%)
Scheme 2 Scope of the trifluoromethylation. Reagents and conditions:
substrate (3 equiv), 6 (0.1 mmol), DMSO, photo-irradiation (λ = 375
nm, 3-W LED), 1 h. Yields determined by 19F NMR analysis using PhCF3
as an internal standard; the values in parentheses are isolated yields. a
Run with 2 equiv of substrate.
agent and an electron-rich material is required to generate
the trifluoromethyl radical. In contrast to those reports, our
experiments clearly show that trifluoromethylation using
Umemoto reagents can be promoted by photo-irradiation
alone.
Based on the above results, the proposed mechanism is
illustrated in Scheme 4. Upon photo-activation of Umemoto
reagent II (6), a trifluoromethyl radical is released, and at-
tacks the aromatic ring of the substrate. Then, deprotona-
tion and single-electron transfer occur to afford the trifluo-
romethylated product. On the other hand, when more elec-
tron-rich substrates, such as anilines and indoles, were
treated with Umemoto reagent 6, we observed that the re-
action mixture turned reddish or yellowish. Therefore, we
1H and 19F NMR spectra were measured on a JEOL ECX-500 spectrom-
eter at 500 and 470 MHz, respectively. 13C NMR spectra were recorded
on a JEOL ECX-500 spectrometer at 125 MHz. Chemical shifts were
referenced to TMS (δ = 0) or CDCl3 for 1H NMR, CDCl3 for 13C NMR, and
to a CFCl3 external standard (δ = 0) for 19F NMR. Melting points were
measured on a Yanaco MP-J3. Column chromatography was per-
formed with silica gel N-60 (40–100 μm) purchased from Kanto
Chemical Co., Inc. TLC analysis was performed on Silica gel 60 F254
-
coated glass plates (Merck). Visualization of bands was carried out by
means of UV irradiation at 254 nm and/or by spraying with ethanolic
phosphomolybdic acid solution. Purification was also carried out us-
ing a Shimadzu recycling preparative HPLC system [LC-20AR; column,
YMC-GPC T-2000; CHCl3] as necessary. Light irradiation was per-
formed with a Relyon LED lamp (3 W, λ = 365, 375, 395, or 425 nm).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
H. Egami et al.
Special Topic
Synthesis
Anhyd MeCN, MeOH, and DMSO were purchased from KANTO Chem-
ical Co., Inc. Anhyd DMF and CH2Cl2 were purchased from Wako Pure
Chemical Industries, Ltd. Umemoto reagent II (6) was purchased from
TCI. Umemoto reagent (5) was purchased from Sigma-Aldrich. Togni
reagents 3 and 4 were synthesized according to the literature.4
4-(Dimethylamino)-3-(trifluoromethyl)pyridine (2e)22
[CAS Reg. No. 1643374-18-8]
Colorless oil; yield: 7.3 mg (38%).
1H NMR (CDCl3, 500 MHz): δ = 8.60 (s, 1 H), 8.35 (d, J = 5.7 Hz, 1 H),
6.74 (d, J = 5.7 Hz, 1 H), 3.01 (s, 6 H).
13C NMR (CDCl3, 125 MHz): δ = 155.6, 152.1, 149.9 (q, J = 6.4 Hz),
124.6 (q, J = 272.3 Hz), 113.4 (q, J = 30.0 Hz), 111.7, 42.7, 42.7.
1,3,5-Trimethoxy-2-(trifluoromethyl)benzene (2a);13 Typical Pro-
cedure
[CAS Reg. No. 1365122-33-3]
19F NMR (CDCl3, 470 MHz): δ = –56.0 (s, 3 F).
1,3,5-Trimethoxybenzene (1a; 50.5 mg, 0.3 mmol) and Umemoto re-
agent II (6; 43.8 mg, 0.1 mmol) were charged into a reaction tube (bo-
rosilicate glass JR-1, thickness = 1.8 mm), which was flame-dried un-
der vacuum. The tube was evacuated and back-filled with argon.
DMSO (1 mL) was then added to the tube. The mixture was stirred for
1 h under photo-irradiation (375 nm, 3-W LED × 1, 1.5 cm away from
the tube) at r.t. The solution was diluted with EtOAc, and the resulting
organic layer was washed with sat. aq NaHCO3. After extraction with
EtOAc, the combined organic layers were dried (Na2SO4). After filtra-
tion, the filtrate was concentrated in vacuo and the residue was sub-
mitted to 19F NMR analysis to determine the NMR yield with α,α,α-
trifluorotoluene as an internal standard. After evaporation of CDCl3,
the residue was purified by column chromatography (silica gel, n-
hexane/EtOAc 9:1) to provide 2a (21.8 mg, 92%) as a colorless solid;
mp 58–61 °C.
2,6-Dimethoxy-3-(trifluoromethyl)pyridine (2f)10d
[CAS Reg. No. 1365122-59-3]
Colorless oil; yield: 10.5 mg (51%).
1H NMR (CDCl3, 500 MHz): δ = 7.72 (d, J = 8.6 Hz, 1 H), 6.33 (d, J = 8.6
Hz, 1 H), 4.02 (s, 3 H), 3.96 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.1, 160.4, 138.8 (q, J = 4.8 Hz),
123.7 (q, J = 269.9 Hz), 104.4 (q, J = 33.6 Hz), 100.8, 53.9, 53.8.
19F NMR (CDCl3, 470 MHz): δ = –61.8 (s, 3 F).
5-(Trifluoromethyl)quinolin-8-amine (2g)10a
[CAS Reg. No. 483-69-2]
Colorless solid; yield: 12.5 mg (59%); mp 82–85 °C.
1H NMR (CDCl3, 500 MHz): δ = 6.13 (s, 2 H), 3.84 (s, 9 H).
13C NMR (CDCl3, 125 MHz): δ = 163.5, 160.4, 124.3 (q, J = 272.3 Hz),
100.3 (q, J = 30.0 Hz), 91.2, 56.2, 55.3.
1H NMR (CDCl3, 500 MHz): δ = 8.81 (dd, J = 1.7, 4.0 Hz, 1 H), 8.42–8.40
(m, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.50 (dd, J = 4.0, 8.6 Hz, 1 H), 6.83 (d,
J = 8.0 Hz, 1 H), 5.39 (br s, 2 H).
13C NMR (CDCl3, 125 MHz): δ = 147.6, 147.6, 137.8, 132.7, 126.7 (q, J =
6.0 Hz), 125.2, 125.0 (q, J = 271.1 Hz), 122.6, 113.4 (q, J = 31.2 Hz),
106.6.
19F NMR (CDCl3, 470 MHz): δ = –54.0 (s, 3 F).
2,6-Di-tert-butyl-4-(trifluoromethyl)phenol (2b)20
[CAS Reg. No. 120120-40-3]
19F NMR (CDCl3, 470 MHz): δ = –57.9 (s, 3 F).
Colorless solid; yield: 10.1 mg (37%); mp 70–72 °C.
1H NMR (CDCl3, 500 MHz): δ = 7.41 (s, 2 H), 5.55 (s, 1 H), 1.45 (s, 18
H).
13C NMR (CDCl3, 125 MHz): δ = 156.5, 136.2, 124.9 (q, J = 271.1 Hz),
122.2 (q, J = 3.6 Hz), 121.5 (q, J = 31.2 Hz), 34.4, 30.0.
19F NMR (CDCl3, 470 MHz): δ = –61.0 (s, 3 F).
7-(Trifluoromethyl)quinolin-8-amine (2g′)10a
[CAS Reg. No. 313-16-6]
Colorless solid; yield: 4.5 mg (21%); mp 62–64 °C.
1H NMR (CDCl3, 500 MHz): δ = 8.80 (dd, J = 1.4, 4.3 Hz, 1 H), 8.07 (dd,
J = 1.4, 8.3 Hz, 1 H), 7.50–7.46 (m, 2 H), 7.10 (d, J = 8.6 Hz, 1 H), 5.80
(br s, 2 H).
13C NMR (CDCl3, 125 MHz): δ = 148.0, 142.9, 138.2, 136.0, 129.9, 125.5
(q, J = 271.3 Hz), 123.5 (q, J = 4.8 Hz), 123.1, 114.4, 107.7 (q, J = 30.0
Hz).
4-tert-Butyl-2-(trifluoromethyl)phenol (2c)20
[CAS Reg. No. 57477-80-2]
Colorless solid; yield: 11.2 mg (51%); mp 57–59 °C.
1H NMR (CDCl3, 500 MHz): δ = 7.48 (d, J = 2.3 Hz, 1 H), 7.44 (dd, J = 2.3,
19F NMR (CDCl3, 470 MHz): δ = –61.4 (s, 3 F).
1-Phenyl-2-(trifluoromethyl)-1H-pyrrole (2h)13a
[CAS Reg. No. 1246178-37-9]
8.6 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 5.46 (q, J = 2.3 Hz, 1 H), 1.30 (s, 9
H).
13C NMR (CDCl3, 125 MHz): δ = 151.1, 143.6, 130.5, 124.4 (q, J = 272.3
Hz), 123.3 (q, J = 4.8 Hz), 117.4, 115.6 (q, J = 30.0 Hz), 34.2, 31.3.
19F NMR (CDCl3, 470 MHz): δ = –60.5 (s, 3 F).
Colorless oil; yield: 15.3 mg (72%).
1H NMR (CDCl3, 500 MHz): δ = 7.47–7.43 (m, 3 H), 7.39–7.37 (m, 2 H),
6.89–6.88 (m, 1 H), 6.73 (m, 1 H), 6.28–6.27 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 139.1, 129.0, 128.5, 127.2, 126.5,
122.2 (q, J = 38.4 Hz), 121.1 (q, J = 266.1 Hz), 112.7 (q, J = 3.6 Hz),
108.2.
2,6-Dimethyl-4-(trifluoromethyl)aniline (2d)10a
[CAS Reg. No. 144991-53-7]
Colorless oil; yield: 10.8 mg (57%).
1H NMR (CDCl3, 500 MHz): δ = 7.19 (s, 2 H), 3.84 (br s, 2 H), 2.20 (s, 6
19F NMR (CDCl3, 470 MHz): δ = –55.8 (s, 3 F).
Methyl 5-(Trifluoromethyl)-1H-pyrrole-2-carboxylate (2i)12e
[CAS Reg. No. 952182-25-1]
H).
13C NMR (CDCl3, 125 MHz): δ = 145.7, 125.1 (q, J = 3.6 Hz), 125.0 (q, J =
271.1 Hz), 121.1, 119.4 (q, J = 32.4 Hz), 17.5.
19F NMR (CDCl3, 470 MHz): δ = –60.9 (s, 3 F).
Colorless solid; yield: 8.3 mg (43%); mp 86–89 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
H. Egami et al.
Special Topic
Synthesis
1H NMR (CDCl3, 500 MHz): δ = 9.67 (br s, 1 H), 6.89–6.88 (m, 1 H),
6.60–6.59 (m, 1 H), 3.91 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 155.4, 151.3, 146.5, 138.9 (q, J = 40.8
Hz), 118.2 (q, J = 271.1 Hz), 109.6, 33.2, 29.9, 28.2.
13C NMR (CDCl3, 125 MHz): δ =160.9, 124.9, 124.5 (q, J = 39.6 Hz),
120.3 (q, J = 267.5 Hz), 114.9, 111.0 (q, J = 2.4 Hz), 52.1.
19F NMR (CDCl3, 470 MHz): δ = –62.3 (s, 3 F).
19F NMR (CDCl3, 470 MHz): δ = –60.3 (s, 3 F).
Funding Information
3-Methyl-2-(trifluoromethyl)-1H-indole (2j)13a
[CAS Reg. No. 913955-35-8]
This work was supported by a Grant-in-Aid for Scientific Research (B)
(No. 16H05077) from JSPS, and a grant under Basis for Supporting In-
novative Drug Discovering and Life Science Research (BINDS) from
Colorless solid; yield: 15.4 mg (77%); mp 70–72 °C.
1H NMR (CDCl3, 500 MHz): δ = 8.17 (br s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H),
7.39 (d, J = 8.0 Hz, 1 H), 7.33 (dd, J = 7.2, 8.0 Hz, 1 H), 7.20 (dd, J = 7.2,
8.0 Hz, 1 H), 7.45–7.44 (m, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 135.2, 128.0, 124.8, 122.1 (q, J = 268.7
Hz), 121.5 (q, J = 36.0 Hz), 120.4, 120.1, 114.1 (q, J = 3.6 Hz), 111.5, 8.3.
AMED.
a
Jp
a
n
S
o
ecity
o
f
r
ht
e
P
or
m
o
itn
of
S
ecince
1(
6
H
0
5
0
7
7)
Acknowledgment
We thank TOSOH F-TECH, Inc. for a generous gift of Ruppert-Prakash
reagent.
19F NMR (CDCl3, 470 MHz): δ = –58.5 (s, 3 F).
1,3-Dimethyl-2-(trifluoromethyl)-1H-indole (2k)9d
[CAS Reg. No. 1257268-91-9]
Supporting Information
Supporting information for this article is available online at
Colorless oil; yield: 11.6 mg (54%).
https://doi.org/10.1055/s-0037-1609759.
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1H NMR (CDCl3, 500 MHz): δ = 7.65 (d, J = 8.0 Hz, 1 H), 7.38–7.33 (m, 2
H), 7.19–7.16 (m, 1 H), 3.81 (s, 3 H), 2.46 (q, J = 2.3 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 137.7, 126.9, 124.5, 122.7 (q, J = 34.8
Hz), 122.7 (q, J = 269.9 Hz), 120.2, 119.8, 114.2, 109.5, 30.8, 8.9.
References
19F NMR (CDCl3, 470 MHz): δ = –55.8 (s, 3 F).
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2-(Trifluoromethyl)melatonine (2l)10c
[CAS Reg. No. 205675-33-8]
Colorless solid; yield: 19.1 mg (64%); mp 109–111 °C.
1H NMR (CDCl3, 500 MHz): δ = 8.69 (br s, 1 H), 7.30 (d, J = 9.2 Hz, 1 H),
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19F NMR (CDCl3, 470 MHz): δ = –57.8 (s, 3 F).
N-(tert-Butoxycarbonyl)-2-(trifluoromethyl)-L-tryptophan Meth-
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yl Ester (2m)10g
[CAS Reg. No. 1455451-07-6]
Colorless solid; yield: 17.1 mg (44%); mp 128–132 °C.
1H NMR (CDCl3, 500 MHz): δ = 8.42 (br s, 1 H), 7.70 (d, J = 8.0 Hz, 1 H),
7.39 (d, J = 8.0 Hz, 1 H), 7.32 (dd, J = 7.5, 8.0 Hz, 1 H), 7.20 (dd, J = 7.5,
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[CAS Reg. No. 413568-94-1]
Colorless solid; yield: 15.1 mg (58%); mp 135–137 °C.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
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Special Topic
Synthesis
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(19) See Supporting Information.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F