Synthesis of 1-substituted 2-(trifluoromethyl)indoles via a palladium-catalyzed double animation reaction

Article abstract of DOI:10.1055/S-0029-1218686

A new, selective protocol for the synthesis of 1-substituted 2-(trifluoromethyl)indoles has been developed by palladium-catalyzed double amination reaction of 2-chloro-1-(2-halophenyl)-3,3,3-trifluoroprop-1-enes with primary amines. This route allows the formation of two C-N bonds in one pot from the reaction between 2-chloro-1-(2-halophenyl)-3,3,3-trifluoroprop-1-enes and primary amines using the Pd₂(dba)₃/L₄/t-BuONa system. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218686

PAPER
1521
Synthesis of 1-Substituted 2-(Trifluoromethyl)indoles via a Palladium-
Catalyzed Double Amination Reaction
Synthesis of
1h
u
-
e
thyl)in
X
dole
s
iang Dong,a Xing-Guo Zhang,*a,b Qiong Liu,a Ri-Yuan Tang,a Ping Zhong,a Jin-Heng Li*a,b
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, P. R. of China
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research, Hunan Normal University, Changsha 410081,
P. R. of China
b
Fax +86(577)86689615; E-mail: zxg@wzu.edu.cn; E-mail: jhli@hunnu.edu.cn
Received 21 December 2009; revised 18 January 2010
ment of a direct and concise method for the synthesis of 2-
(trifluoromethyl)indoles using inexpensive and readily
available materials remains a challenging area for explo-
ration. Recently, the double amination reaction of 1,4-di-
Abstract: A new, selective protocol for the synthesis of 1-substitut-
ed 2-(trifluoromethyl)indoles has been developed by palladium-cat-
alyzed double amination reaction of 2-chloro-1-(2-halophenyl)-
3,3,3-trifluoroprop-1-enes with primary amines. This route allows
the formation of two C–N bonds in one pot from the reaction halides has been identified as one of the most direct and
between 2-chloro-1-(2-halophenyl)-3,3,3-trifluoroprop-1-enes and
efficient methods for the synthesis of indoles or pyr-
roles.11 To the best of our knowledge, the synthesis of in-
primary amines using the Pd2(dba)3/L4/t-BuONa system.
Key words: palladium, double amination, 2-chloro-1-(2-halophe-
nyl)-3,3,3-trifluoroprop-1-enes, 2-(trifluoromethyl)indoles
doles bearing a strong electron-withdrawing substituent at
the 2-position by the double amination process has not
been reported. 1-Aryl-2-chloro-3,3,3-trifluoroprop-1-
enes, which can be readily prepared from the reaction
A fluorine atom or a fluoroalkyl group presented in an or- of 2-halobenzaldehyde and Freon-113a in one step
ganic molecule produces profound changes in its chemi- (Scheme 1),12 are versatile trifluoromethyl-containing
cal, physical, and pharmacological properties.1 building blocks.13 We envisioned that these compounds
Particularly, incorporation of a trifluoromethyl group into could participate in a similar double amination reaction.
lead molecules has been employed as one of the most ef- Herein, we report a simple and efficient protocol for the
ficient methods in drug discovery2 because the resultant selective synthesis of 1-substituted 2-(trifluoromethyl)in-
products can both retain their original biological activity doles via palladium-catalyzed double amination reaction
and have improved pharmacokinetic properties, owing to of 2-chloro-1-(2-halophenyl)-3,3,3-trifluoroprop-1-enes
the unique chemical and physiological stability of the tri- with primary amines (Scheme 1).
fluoromethyl group.3,4 For example, 2-(trifluorometh-
yl)indoles have been widely employed as core structures
The reaction between 2-chloro-1-(2-bromophenyl)-3,3,3-
trifluoroprop-1-ene (1a) and aniline (2a) was initially
for developing pharmaceuticals, such as a general anes-
screened to optimize the reaction conditions (Table 1).14
thesia inducer,5 a tyrosine kinase inhibitor,6 and antitumor
The results demonstrated that the reaction temperature has
compounds.7 Several methods for the assembly of 2-(tri-
a fundamental influence on this tandem reaction (entries
fluoromethyl)indoles have been developed including tran-
1–4). While treatment of substrate 1a with aniline 2a af-
forded a trace amount of the target product 3 in the pres-
ence of Pd2(dba)3, tricyclohexylphosphine (L1) and
sodium tert-butoxide at 80 °C (entry 1), the yield of 3 in-
sition-metal-catalyzed coupling,8 thermolysis,9 and
Grignard cyclization reactions.10 Among them, the transi-
tion-metal-catalyzed coupling reaction is particularly effi-
cient for this purpose, However, a restriction of these
creased to 64% yield at 140 °C (entry 4). Prompted by
procedures is the use of expensive and unavailable 2-ha-
these results, the effect of ligands was subsequently exam-
loanilines as starting materials,8 Therefore, the develop-
RNH2 (2)
Pd2(dba)3/L4
CHO
CF3
CF3CCl3
CF3
t-BuONa
toluene, 140 °C
Cl
N
X
X
R
X = Br, Cl
1
NMe2
L4:
Cy2P
Scheme 1 Preparation and double amination of 2-chloro-1-(2-halophenyl)-3,3,3-trifluoroprop-1-enes 1
SYNTHESIS 2010, No. 9, pp 1521–1525
x
x
.
x
x
.2
0
1
0
Advanced online publication: 24.02.2010
DOI: 10.1055/s-0029-1218686; Art ID: F24509SS
© Georg Thieme Verlag Stuttgart · New York

1522
S.-X. Dong et al.
PAPER
Table 1 Screening Optimal Conditionsa
Table 2 Palladium-Catalyzed Double Amination Reactionsa
CF3
CF3
Pd2(dba)3/L4
[Pd], ligand
CF3
+
RNH2
CF3
+
NH2
t-BuONa
toluene, 140 °C
Cl
Cl
N
N
Br
1a
X
R
Ph
1a X = Br
1b X = Cl
2
2a
3
i-Pr
Entry Substrate 1 RNH2
Time Product Yieldb
PCy3
PPh3
L2
i-Pr
(h)
(%)
L1
2
R
PCy2 i-Pr
L3
1
2
3c
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
2b 1-naphthyl 16
4
67
94
96
76
62
84
87
64
41
68
24
44
36
trace
83
71
76
72
87
57
32
2c
2c
4-Tol
4-Tol
18
26
12
5
PCy2
5
Me2N
2d 2-Tol
6
N
N
2e
2f
2,6-Me2C6H3 6
7
L4
L5
4-MeOC6H4 10
8
Entry [Pd]
Ligand Base
Solvent Temp Yieldb
(°C)
(%)
trace
33
45
64
<5
76
82
36
42
28
62
57
64
52
54
80
2g 4-FC6H4
2h 4-ClC6H4
14
32
9
1
2
Pd2(dba)3 L1
Pd2(dba)3 L1
Pd2(dba)3 L1
Pd2(dba)3 L1
Pd2(dba)3 L2
Pd2(dba)3 L3
Pd2(dba)3 L4
Pd2(dba)3 L5
Pd2(dba)3 L4
Pd2(dba)3 L4
Pd2(dba)3 L4
Pd2(dba)3 L4
Pd(OAc)2 L4
Pd(PPh3)4 L4
Pd2(dba)3 L4
Pd2(dba)3 L4
t-BuONa toluene 80
10
11
12
13
14
15
trace
3
t-BuONa toluene 100
t-BuONa toluene 120
t-BuONa toluene 140
t-BuONa toluene 140
t-BuONa toluene 140
t-BuONa toluene 140
t-BuONa toluene 140
2i
2j
4-O2NC6H4 36
4-F3CC6H4 16
3
10
4
11
12
13
14
15
16
17
18
19
20
21
2k 4-pyridyl
24
5
2l CH2CH2Ph 10
6
2m Bu
2n Bz
2a Ph
26
48
18
7
8
9
Cs2CO3
K3PO4
toluene 140
toluene 140
2b 1-naphthyl 36
4
10
11
12
13
14
15c
16d
2c
4-Tol
16
18
12
5
t-BuONa DMF
140
2d 2-Tol
6
t-BuONa DMSO 140
t-BuONa toluene 140
t-BuONa toluene 140
t-BuONa toluene 140
t-BuONa toluene 140
2g 4-FC6H4
9
2j
4-F3CC6H4 24
14
12
2m Bu
15
a Reaction conditions: 1 (0.2 mmol), 2 (1.2 equiv), Pd2(dba)3
(5 mol%), L4 (10 mol%), t-BuONa (4.0 equiv), toluene (2.5 mL),
140 °C.
b Isolated yield.
c 1 mmol of 1a was used.
a Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), [Pd] (5 mol%),
ligand (10 mol%), base (4.0 equiv), solvent (2.5 mL), 12 h.
b Isolated yield.
c Pd2(dba)3 (2 mol%) and L4 (4 mol%).
d Pd2(dba)3 (10 mol%) and L4 (20 mol%).
nally, the amount of the catalytic system was evaluated
(entries 15 and 16). The results showed that identical re-
sults were observed in the presence of 10 mol% Pd2(dba)3
and 20 mol% of L4 (entry 16), but the yield decreased us-
ing 2 mol% Pd2(dba)3 combined with 4 mol% of L4 (entry
15). It is noteworthy that the yield of indole 3 did not de-
pend on the Z/E ratio of 1a; the same yield was observed
when using either the mixtures of 1a (Z/E 82:18)12b or 1a
(Z/E 96:4).12c
ined (entries 4–8). We were pleased to observe that ligand
L4 was the most efficient for the reaction, affording the
desired product 3 in 82% yield (entry 7). Examining the
bases and solvents (entries 9–12), it turned out that sodi-
um tert-butoxide combined with toluene was the most ef-
fective (entry 7). Two other palladium catalysts,
Pd(OAc)2 and Pd(PPh3)4, were also examined, and they
were less efficient than Pd2(dba)3 (entries 13 and 14). Fi-
Synthesis 2010, No. 9, 1521–1525 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Substituted 2-(Trifluoromethyl)indoles
1523
The combined organic layers were washed with sat. Na2CO3 soln
and brine, dried (Na2SO4), and evaporated under vacuum. The resi-
due was purified by flash column chromatography (hexane–EtOAc)
to afford 1a (67%, Z/E 82:18) or 1b (72%, Z/E 83:17).
With the optimal conditions in hand, we explored the
scope of the double amination reactions (Table 2). Initial-
ly, the reactions of substrate 1a with various primary
amines were investigated (entries 1–13). The results dem-
onstrated that the reaction conditions were compatible
with a wide range of primary arylamines (entries 1–10),
but less efficiency was displayed for heteroaryl amines
and aliphatic amines (entries 11–13). Moreover, several
functional groups, such as methyl, methoxy, fluoro, chlo-
ro, nitro, and trifluoromethyl groups, on the aryl moiety
were tolerated, and the properties of the functional groups
affected the reaction to some extent. Amine 2c bearing a
4-methylphenyl group, for instance, successfully under-
Palladium-Catalyzed Double Amination Reaction; General
Procedure
A mixture of 1-(2-bromophenyl)-2-chloro-3,3,3-trifluoroprop-1-
ene (1a, 57 mg, 0.2 mmol) or 2-chloro-1-(2-chlorophenyl)-3,3,3-tri-
fluoroprop-1-ene (1b, 48 mg, 0.2 mmol), aniline 2 (0.24 mmol),
Pd2(dba)3 (8.1 mg, 0.01 mmol), L4 (7.9 mg, 0.02 mmol), and t-
BuONa (7.7 mg, 0.8 mmol) in toluene (2.5 mL) was stirred at 140
°C for 6–36 h until complete consumption of the starting material
(TLC and GC-MS analysis). The mixture was poured into Et2O and
this was washed with brine. The aqueous layer was extracted with
went the reaction with substrate 1a, Pd2(dba)3, L4, and so- Et2O and the combined organic layers were dried (anhyd Na2SO4)
and evaporated under vacuum. The residue was purified by flash
column chromatography (hexane–EtOAc) to afford 3–15.
dium tert-butoxide to give 5 in 94% yield (entry 2), but
bulky amines 2d and 2e provided the corresponding prod-
ucts 6 and 7 in moderate yields under the same conditions
(entries 4 and 5). Arylamines 2i, bearing a strong electron-
withdrawing nitro group, also reduced the yield of 11 to
41% (entry 9). We found that low yields of 14 and 15 were
obtained from the reaction between substrate 1a with ali-
phatic amines 2l or 2m, respectively, under the standard
conditions, partly because of electronic effect (entries 12
and 13). Unfortunately, attempted amination of substrate
1a with amide 2n failed (entry 14). Subsequently, another
1,4-dichloride, 2-chloro-1-(2-chlorophenyl)-3,3,3-trifluo-
roprop-1-ene (1b), was examined in this reaction under
optimized conditions (entries 15–21). It was found that
1-Phenyl-2-(trifluoromethyl)-1H-indole (3)
Pale solid; mp 52.9–53.8 °C.
IR (KBr): 1498, 1267, 1193, 1163, 1115 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 7.4 Hz, 1 H), 7.57–
7.55 (m, 3 H), 7.46–7.44 (m, 2 H), 7.31–7.25 (m, 2 H), 7.14–7.10
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 139.8, 136.7, 129.0, 128.5, 127.9,
125.5, 124.8, 122.4 (q, JC-F = 266.8 Hz), 122.0, 121.3, 112.2, 105.7,
105.6.
19F NMR (283 MHz): d = –57.45.
LRMS (EI, 70 eV): m/z (%) = 261 (M+, 100), 240 (16), 222 (17), 77
(13), 51 (16).
moderate to good yields were achieved from the reactions
of substrate 1b with arylamines 2b–d, 1g, and 2j (entries HRMS (EI): m/z [M]+ calcd for C15H11F3N: 261.0760; found:
261.0763.
15–20). However, 15 was isolated in only 32% yield from
the reaction between 1b and butylamine (2m) (entry 21).
1-(Naphthalen-1-yl)-2-(trifluoromethyl)-1H-indole (4)
In summary, we have developed a new, practical protocol
for the preparation of 1-substituted 2-(trifluoromethyl)in-
doles by a Pd2(dba)3-catalyzed double amination reaction.
In the presence of Pd2(dba)3, L4, and sodium tert-butox-
ide, 2-chloro-1-(2-halophenyl)-3,3,3-trifluoroprop-1-enes
smoothly underwent the double amination reaction with a
wide range of primary amines to afford the desired 2-(tri-
fluoromethyl)indoles in moderate to good yields. Impor-
tantly, this new route allows the use of the less active 1,4-
dichloride as the starting substrate. Work to extend the re-
action in organic synthesis is currently underway.
Yellow oil.
IR (KBr): 1271, 1202, 1163, 1120, 773 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.97 (m, 1 H), 7.94 (m, 1 H), 7.78
(d, J = 7.2 Hz, 1 H), 7.60–7.58 (m, 2 H), 7.50 (m, 1 H), 7.23 (m, 1
H), 7.23–7.20 (m, 3 H), 7.03 (m, 1 H), 6.76 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 140.4, 134.2, 133.0, 129.9, 127.4,
127.3, 126.7, 126.6 (q, JC-F = 253.5 Hz), 125.3, 125.2, 122.9, 122.8,
122.0, 111.5, 105.7, 105.6, 105.5.
19F NMR (283 MHz): d = –58.64.
LRMS (EI, 70 eV): m/z (%) = 311 (M+, 20), 242 (12), 120 (38), 77
(9), 51 (3).
HRMS (EI): m/z [M]+ calcd for C19H12F3N: 311.0916; found:
311.0917.
Chemicals were either purchased or purified by standard tech-
niques. 1H NMR and 13C NMR were determined in CDCl3 soln with
a Bruker Avance 300 (300 MHz) spectrometer using TMS as the in-
ternal standard. 19F NMR spectra also were obtained in a CDCl3
soln on a Bruker Avance 300 (282.2 MHz) spectrometer using TFA
as external standard. All reactions under an N2 atmosphere were
conducted using standard Schlenk techniques. Column chromatog-
raphy was performed using EM silica gel 60 (300–400 mesh). Melt-
ing points are uncorrected.
1-(4-Tolyl)-2-(trifluoromethyl)-1H-indole (5)
A mixture of 1-(2-bromophenyl)-2-chloro-3,3,3-trifluoroprop-1-
ene (1a, 284 mg, 1 mmol), 4-methylaniline (2c, 128 mg, 1.2 mmol),
Pd2(dba)3 (46 mg, 0.05 mmol), L4 (39.4 mg, 0.1 mol), and t-BuONa
(384 mg, 4 mmol) in toluene (10 mL) was stirred at 140 °C for 26 h
until complete consumption of the starting material (TLC and GC-
MS analysis). The mixture was poured into Et2O and this was
washed with brine. The aqueous layer was extracted with Et2O and
the combined organic layers were dried (anhyd Na2SO4) and evap-
orated under vacuum. The residue was purified by flash column
chromatography (hexane–EtOAc) to afford 5 (96% yield) as a pale
yellow oil.
2-Chloro-3,3,3-trifluoro-1-(2-halophenyl)prop-1-enes 1a,b12b
A mixture of 2-chlorobenzaldehyde or 2-bromobenzaldehyde (1
mmol), CC13CF3 (2 mmol), Zn powder (5 mmol), and Ac2O (1.5
mmol) in DMF (2 mL) was stirred at 50 °C for 7 h until complete
consumption of the starting material (TLC). 5% HCl (10 mL) was
then added and the mixture was extracted with Et2O (3 × 10 mL).
IR (KBr): 1268, 1193, 1162, 1121, 1098 cm–1.
Synthesis 2010, No. 9, 1521–1525 © Thieme Stuttgart · New York

1524
S.-X. Dong et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.74 (d, J = 7.3 Hz, 1 H), 7.36–
13C NMR (75 MHz, CDCl3): d = 162.6 (d, JC-F = 247.5 Hz), 139.9,
132.5, 130.4, 125.4, 125.0, 124.8 (q, JC-F = 266.9 Hz), 122.0, 121.4,
116.5, 116.2, 111.0, 105.8.
19F NMR (283 MHz): d = –57.58 (3 F), –111.73 (1 F).
LRMS (EI, 70 eV): m/z (%) = 279 (M+, 17), 258 (12), 240 (3), 183
(4), 139 (5), 75 (12).
7.26 (m, 3 H), 7.25–7.10 (m, 3 H), 7.07 (m, 2 H), 2.48 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 139.9, 138.9, 134.0, 129.9, 128.4,
128.2, 125.4, 124.7, 124.6 (q, JC-F = 266.3 Hz), 121.9, 121.1, 111.2,
105.4, 21.2.
19F NMR (283 MHz): d = –57.58.
LRMS (EI, 70 eV): m/z (%) = 275 (M+, 17), 240 (3), 206 (3), 165
HRMS (EI): m/z [M]+ calcd for C15H9F4N: 279.0666; found:
(5), 91 (8), 65 (12).
279.0667.
HRMS (EI): m/z [M]+ calcd for C16H12F3N: 275.0916; found:
275.0919.
1-(4-Chlorophenyl)-2-(trifluoromethyl)-1H-indole (10)
Yellow oil.
1-(2-Tolyl)-2-(trifluoromethyl)-1H-indole (6)
IR (KBr): 2159, 1269, 1194, 1165, 1122 cm–1.
Yellow oil.
IR (KBr): 1266, 1190, 1163, 1120 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.74 (m, 1 H), 7.53–7.47 (m, 3 H),
7.33–7.14 (m, 3 H), 7.12 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 7.1 Hz, 1 H), 7.41–
7.20 (m, 6 H), 7.10 (s, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 1.89 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 139.2, 137.7, 135.3, 130.9, 128.0,
127.5, 125.4, 124.9, 124.4 (q, JC-F = 266.9 Hz), 122.1, 121.1, 111.0,
105.2, 16.9.
13C NMR (75 MHz, CDCl3): d = 139.6, 137.8, 135.0, 130.3, 129.3,
128.2, 126.9 (q, JC-F = 268.6 Hz), 126.8, 125.5, 122.7, 122.1, 110.9,
106.2.
19F NMR (283 MHz): d = –57.38.
LRMS (EI, 70 eV): m/z (%) = 295 (M+, 17), 240 (10), 191 (3), 120
(1), 75 (16).
19F NMR (283 MHz): d = –59.01.
LRMS (EI, 70 eV): m/z (%) = 275 (M+, 12), 206 (16), 204 (16), 102
HRMS (EI): m/z [M]+ calcd for C15H9ClF3N: 295.0370; found:
(14), 65 (16).
295.0370.
HRMS (EI): m/z [M]+ calcd for C16H12F3N: 275.0916; found:
275.0919.
1-(4-Nitrophenyl)-2-(trifluoromethyl)-1H-indole (11)
Yellow oil.
1-(2,6-Dimethylphenyl)-2-(trifluoromethyl)-1H-indole (7)
IR (KBr): 1271, 1201, 1162, 1119, 772 cm–1.
Yellow oil.
1H NMR (300 MHz,CDCl3): d = 8.43 (d, J = 8.8 Hz, 2 H), 7.75 (m,
1 H), 7.64 (d, J = 8.8 Hz, 2 H), 7.34–7.19 (m, 2 H), 7.19 (s, 1 H),
7.10 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 147.7, 142.4, 139.2, 129.2, 125.8,
125.6, 124.9, 124.2 (q, JC-F = 253.1 Hz), 122.4, 122.1, 110.6, 107.5,
107.4.
IR (KBr): 1201, 1162, 1119, 1120, 798 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76–7.73 (m, 1 H), 7.32–7.18 (m,
5 H), 7.13 (s, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 1.88 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.2, 138.1, 134.3, 129.2, 128.3,
127.5, 127.0, 125.5, 124.9, 124.3 (q, JC-F = 249.0 Hz), 122.1, 110.6,
105.2, 17.0.
19F NMR (283 MHz): d = –56.98.
19F NMR (283 MHz): d = –60.62.
LRMS (EI, 70 eV): m/z (%) = 289 (M+, 16), 220 (18), 204 (28), 102
LRMS (EI, 70 eV): m/z (%) = 306 (M+, 16), 276 (4), 240 (4), 191
(10), 120 (8), 50 (9).
HRMS (EI): m/z [M]+ calcd for C15H9F3N2O2: 306.0611; found:
(13), 77 (5).
306.0615.
HRMS (EI): m/z [M]+ calcd for C17H14F3N: 289.1073; found:
289.1077.
2-(Trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole
(12)
Yellow oil.
IR (KBr): 1271, 1202, 1163, 1120, 773 cm–1.
1-(4-Methoxyphenyl)-2-(trifluoromethyl)-1H-indole (8)
Yellow solid; mp 99.3–102.9 °C.
IR (KBr): 1271, 1202, 1162, 1119, 798 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 7.8 Hz, 1 H), 7.37–
7.27 (m, 2 H), 7.27–7.21 (m, 2 H), 7.11–7.04 (m, 4 H), 3.92 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.8, 140.1, 129.6, 128.5, 128.0,
125.3, 124.7, 124.3 (q, JC-F = 266.7 Hz), 121.9, 121.1, 114.4, 111.2,
105.3, 55.5.
19F NMR (283 MHz): d = –57.71.
LRMS (EI, 70 eV): m/z (%) = 291 (M+, 18), 276 (7), 222 (2), 178
(6).
HRMS (EI): m/z [M]+ calcd for C16H12F3NO: 291.0866; found:
291.0868.
1H NMR (300 MHz, CDCl3): d = 7.84 (d, J = 8.2 Hz, 2 H), 7.76 (d,
J = 7.4 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 2 H), 7.33–7.27 (m, 2 H), 7.17
(s, 1 H), 7.09 (d, J = 8.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 140.0, 139.6, 130.1, 127.7, 127.1
(q, JC-F = 269.3 Hz), 126.7, 125.7, 125.5, 124.7 (q, JC-F = 277.4 Hz),
122.3, 121.9, 115.7, 110.9, 106.7.
19F NMR (283 MHz): d = –57.24, –62.58.
LRMS (EI, 70 eV): m/z (%) = 329 (M+, 19), 260 (2), 240 (7), 191
(1), 95 (4).
HRMS(EI): m/z [M]+ calcd for C16H9F6N: 329.0634; found:
329.0638.
1-(4-Fluorophenyl)-2-(trifluoromethyl)-1H-indole (9)
Yellow oil.
IR (KBr): 1512, 1269, 1194, 1165, 1120 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 7.6 Hz, 1 H), 7.74–
7.39 (m, 2 H), 7.32–7.21 (m, 4 H), 7.13 (s, 1 H), 7.1 (m, 1 H).
1-(Pyridin-4-yl)-2-(trifluoromethyl)-1H-indole (13)
Yellow oil.
IR (KBr): 2159, 2028, 1979, 1163, 1122 cm–1.
Synthesis 2010, No. 9, 1521–1525 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Substituted 2-(Trifluoromethyl)indoles
1525
1H NMR (300 MHz,CDCl3): d = 8.83 (d, J = 5.8 Hz, 2 H), 7.75 (d,
J = 7.8 Hz, 1 H), 7.42 (d, J = 5.8 Hz, 2 H), 7.36–7.24 (m, 2 H),
7.18–7.15 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 151.4, 150.1, 144.6, 138.7, 127.8,
125.6, 124.3 (q, JC-F = 267.0 Hz), 122.7, 122.4, 122.0, 110.7, 107.6.
19F NMR (283 MHz): d = –56.89.
LRMS (EI, 70 eV): m/z (%) = 262 (M+, 16), 241 (10), 193 (2), 165
(2) (a) O’Hagen, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
(b) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedical
Aspects of Fluorine Chemistry; Elsevier: Amsterdam, 1993.
(c) Mann, J. Chem. Soc. Rev. 1987, 381. (d) Welch, J. T.
Tetrahedron 1987, 43, 3123. (e) Konno, T.; Chae, J.;
Ishihara, T.; Yamanaka, H. J. Org. Chem. 2004, 69, 8258.
(3) For reviews, see: (a) Yale, H. L. J. Med. Chem. 1958, 1,
121. (b) Hutson, P. H. J. Med. Chem. 2001, 44, 477.
(c) Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10,
625.
(4) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432.
(5) (a) Baker, M. T.; Attala, M. N. WO 2003,070,177, 2003.
(b) Akanmu M. A., Songkram C., Kagechika H., Honda K.;
Neurosci. Lett., 2004, 364: 199.
(6) Romines, W. H.; Kania, R. S.; Lou, J.; Collins, M. R.;
Cripps, S. J.; He, M.; Zhou, R.; Palmer, C. L.; Deal, J. G.
WO 2003,106,462, 2003.
(7) (a) Fukuda, Y.; Furuta, H.; Kusama, Y.; Ebisu, H.; Oomori,
Y.; Terashima, S. J. Med. Chem. 1999, 42, 1448.
(b) Fukuda, Y.; Furuta, H.; Shiga, F.; Oomori, Y.; Kusama,
Y.; Ebisu, H.; Terashima, S. Bioorg. Med. Chem. Lett. 1997,
7, 1683.
(8) (a) Dan-oh, Y.; Matta, H.; Uemura, J.; Watanabe, H.;
Uneyama, K. Bull. Chem. Soc. Jpn. 1995, 68, 1497.
(b) Furstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117,
4468. (c) Latham, E. J.; Stanforth, S. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 2059. (d) Larock, R. C.; Yum, E. K.;
Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (e) Konno, T.;
Chae, J.-H.; Ishihara, T.; Yamanaka, H. J. Org. Chem. 2004,
69, 8258. (f) Yu, C.; Wang, Y.-J.; Sun, Z.-M.; Ma, D.-W.
Org. Lett. 2008, 10, 625. (g) Tatsuhito, K.; Yu, N.;
Yoshikazu, H.; Tetsu, Y. J. Mol. Catal. A: Chem. 2008, 282,
34.
(9) Miyashita, K.; Kondoh, K.; Tsuchiya, K.; Miyabe, H.;
Imanishi, T. J. Chem. Soc., Perkin Trans. 1 1996, 1261.
(10) (a) Wang, Z.-X.; Ge, F.-L.; Wan, W.; Jiang, H.-Z.; Hao, J.
J. Fluorine Chem. 2007, 128, 1143. (b) Ge, F.-L.; Wang,
Z.-X.; Wan, W.; Hao, J. Synlett 2007, 447.
(11) (a) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem.
Int. Ed. 2005, 44, 403. (b) Willis, M. C.; Brace, G. N.;
Findlay, T. J. K.; Holmes, I. P. Adv. Synth. Catal. 2006, 348,
851. (c) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem.
Commun. 2007, 4764. (d) Nozaki, K.; Takahashi, K.;
Nakano, K.; Hiyama, T.; Tang, H.-Z.; Fujiki, M.;
Yamaguchi, S.; Tamao, K. Angew. Chem. Int. Ed. 2003, 42,
2051. (e) Martín, R.; Larsen, C. H.; Cuenca, A.; Buchwald,
S. L. Org. Lett. 2007, 9, 3379. (f) Hodgkinson, R. C.;
Schulz, J.; Willis, M. C. Org. Biomol. Chem. 2009, 7, 432.
(12) (a) Makoto, F.; Tamejiro, H. Bull. Chem. Soc. Jpn. 1987, 60,
4377. (b) Fujita, M.; Hiyama, T. Tetrahedron Lett. 1986, 27,
3655. (c) Chen, M.-W.; Zhang, X.-G.; Zhong, P.; Hu, M.-L.
Synth. Commun. 2009, 39, 756. (d) Korotchenko, V. N.;
Shastin, A. V.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2001, 57, 7519.
(7), 78 (12), 51 (33).
HRMS (EI): m/z [M]+ calcd for C14H9F3N2: 262.0712; found:
262.0713.
1-Phenethyl-2-(trifluoromethyl)-1H-indole (14)
Yellow oil.
IR (KBr): 1267, 1193, 1162, 1118, 1096 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55–7.18 (m, 8 H), 6.66–6.61 (m,
2 H), 3.49–3.41 (m, 2 H), 2.95 (t, J = 6.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 138.5, 133.3, 130.4, 128.8,
126.7, 125.1 (q, JC-F = 279.2 Hz), 122.4, 116.7, 116.4, 113.3, 110.1,
102.1, 44.4, 36.3.
19F NMR (283 MHz): d = –58.4.
LRMS (EI, 70 eV): m/z (%) = 289 (M+, 22), 198 (100), 178 (34),
128 (20), 91 (12).
HRMS (EI): m/z [M]+ calcd for C17H14F3N: 289.1073; found:
289.1075.
1-Butyl-2-(trifluoromethyl)-1H-indole (15)
Yellow oil.
IR (KBr): 1266, 1190, 1164, 1121, 752 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 8.0 Hz, 1 H), 7.38–
7.29 (m, 2 H), 7.18–7.13 (m, 1 H), 6.90 (s, 1 H), 4.22–4.16 (m, 2 H),
1.84–1.74 (m, 2 H), 1.44–1.36 (m, 2 H), 0.95 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.8, 127.0, 125.8, 124.9 (q,
JC-F = 266.5 Hz), 124.2, 122.3, 120.6, 110.3, 104.4, 44.7, 32.0, 20.2,
13.7.
19F NMR (283 MHz): d = –56.82.
LRMS (EI, 70 eV): m/z (%) = 241 (M+, 7), 198 (24), 172 (24), 128
(24), 77 (4), 57 (3).
HRMS (EI): m/z [M]+ calcd for C13H14F3N: 241.1073; found:
241.1075.
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20872112), Zhejiang Provincial Natural Science Foundation of
China (Nos. Y407116 and Y4080169), and Wenzhou University
(No. 2007L004) for financial support.
(13) (a) Meazza, G.; Capuzzi, L.; Piccardi, P. Synthesis 1989,
331. (b) Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A.
V.; Balenkova, E. S.; Haufe, G. J. Fluorine Chem. 2008,
129, 1052. (c) Sun, C.; Zhang, X.; Huang, H.; Zhou, P.
Bioorg. Med. Chem. 2006, 14, 8574. (d) Chambers, R. D.;
Edwards, A. R. J. Chem. Soc., Perkin Trans. 1 1997, 3623.
(e) Zhang, M.; Scott, J. G. J. Agric. Food Chem. 1994, 42,
1779.
References
(1) For recent reviews, see: (a) Smart, B. E. J. Fluorine Chem.
2001, 109, 3. (b) Maienfisch, P.; Hall, R. G. Chimia 2004,
58, 93. (c) For a recent special issue on ‘Fluorine in the Life
Sciences’, see: ChemBioChem 2004, 5, 557. (d) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320. (e) Chu, L.; Zhang, X.; Qing, F.-L. Org. Lett.
2009, 11, 2197.
(14) The structure of the products was determined according to
the single-crystal X-ray structure of the product 8.
Synthesis 2010, No. 9, 1521–1525 © Thieme Stuttgart · New York