Bromotriphenylphosphonium salt promoted one-pot cyclization to 2-fluoroalkyl-substituted indoles

Article abstract of DOI:10.1055/s-0034-1379030

2-Fluoroalkyl-substituted indoles were prepared in moderate to excellent yields through bromotriphenylphosphonium salt promoted ring formation with fluorine-containing carboxylic acids in the presence of triethylamine in toluene at reflux temperature. A range of 2-fluoroalkyl-substituted indole derivatives can be conveniently prepared.

Full text of DOI:10.1055/s-0034-1379030

PAPER
▌3309
paper
Bromotriphenylphosphonium Salt Promoted One-Pot Cyclization to 2-Fluoro-
alkyl-Substituted Indoles
2-Fluoroalkyl-Substituted Indoles
Zeng-xue Wang,* Tai-feng Zhang, Qing-wen Ma, Wei-gui Ni
Lunan Pharmaceutical Group Corporation, No. 209, Hongqi Rd, Linyi, Shandong, 276005, P. R. of China
E-mail: wangzx0912@126.com
Received: 19.06.2014; Accepted after revision: 05.08.2014
at reflux temperature. This process provides a convenient
Abstract: 2-Fluoroalkyl-substituted indoles were prepared in mod-
modular, scalable, and well-suited approach for the direct
erate to excellent yields through bromotriphenylphosphonium salt
synthesis of various 2-fluoroalkyl-substituted indole com-
pounds in one step (Scheme 1).
promoted ring formation with fluorine-containing carboxylic acids
in the presence of triethylamine in toluene at reflux temperature. A
range of 2-fluoroalkyl-substituted indole derivatives can be conve-
niently prepared.
R1
R1
Key words: cyclization, fluoroalkyl, indole, one-pot reaction,
ylides
–
OH
+
[Ph3P-Br]CBr3
R2
R2
Rf
toluene, Et3N, reflux
NH2
N
H
1
8
R1 = H, Me
Indole has been known for thousands of years, and the in-
dole group has been found in many natural products, and
employed as a synthetic intermediate for the preparation
of numerous heterocyclic compounds. Molecules contain-
ing the heterocyclic indole group constitute one of the
most important classes of compounds in organic chemis-
try.1 Among those, the fluoroalkyl-substituted indole de-
rivatives have received wide attention from both synthetic
and pharmaceutical viewpoints for a long time because of
the wide potential bioactivities of such derivatives.2 Until
now, a number of synthetic methods have been estab-
lished for the construction of the indole ring skeleton.3 Al-
though these approaches are efficient, most of the
cyclization conditions have drawbacks in that they use
harmful solvents, involve complex reaction systems, or
produce low yields.
+
R2 = H, 4-OMe, 5-OMe, 5-F, 5-Cl, 5-NO2
Rf = CF2H, CF3, C3F7
RfCO2H
2
Scheme 1 Synthesis of 2-fluoroalkyl-substituted indoles
Hao and co-workers reported the synthesis of 2-fluoroal-
kyl-substituted indoles through Grignard cyclization of
either fluorinated N-[2-(bromoalkyl)phenyl]imidoyl chlo-
rides or N-[2-(chloroalkyl)phenyl]imidoyl chlorides,6
which were simply prepared according to Uneyama’s pro-
cedure.7 By using this method, they also reported the syn-
8
thesis of fluorine-containing benzoxazole and indoline
derivatives9 from 2-aminophenol or 2-aminophenethyl al-
cohol. In this case, we wondered whether the fluoroalkyl-
substituted benzene-fused six-membered-ring compound
2-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (7) could
be obtained by using 2-aminobenzyl alcohol in the above
procedure. However, the cyclized 2-trifluoromethylindole
(8a) was instead obtained in 55% yield (Scheme 2).
Chlorotriphenylphosphonium
carbon
trichloride
–
([Ph3P+Cl]CCl3 ), which is easily generated in situ by the
reaction of triphenylphosphane with carbon tetrachloride,
serves as a chlorination reagent that can be used to trans-
form alcohols and carboxylic acid derivatives into the cor-
responding chlorides,4 acyl chlorides, or imidoyl
chlorides.5 However, the overuse of carbon tetrachloride
in these processes raised great environmental concern.
Therefore, the development of a general, reliable, and en-
vironmentally friendly method for the construction of
such nitrogen-containing bicyclic systems remains an im-
portant issue in organic synthesis.
OH
OH
NH2
Ph3P, Et3N
CCl4
Cl
N
CF3
1
3a
+
X
CF3COOH
O
2a
CF3
N
CF3
N
H
7
Herein, we disclose a one-pot cyclization of 2-aminoben-
zyl alcohols with fluorine-containing carboxylic acids in
the presence of triethylamine and bromotriphenylphos-
phonium salt, which is generated in situ by the reaction of
triphenylphosphane with carbon tetrabromide in toluene
8a
Scheme 2 Synthesis of 8a instead of 7
Carbon tetrachloride was used in this process as both the
reactant and solvent, and although it was evident that the
overuse of carbon tetrachloride represents a serious envi-
ronmental problem, the reactions provided reasonable re-
sults. To overcome this problem, carbon tetrabromide was
SYNTHESIS 2014, 46, 3309–3314
Advanced online publication: 08.09.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1379030; Art ID: ss2014-h0380-op
© Georg Thieme Verlag Stuttgart · New York

3310
Z.-x. Wang et al.
PAPER
used as a substitute for carbon tetrachloride as the reactant achieved when these compounds were treated with an
with the use of toluene as the solvent. The reaction went equivalent of base, such as triethylamine, 1,8-diazabicy-
to completion in the presence of carbon tetrabromide clo[5.4.0]undec-7-ene (DBU), or potassium carbonate, in
(3 equiv) in toluene. Furthermore, the reactant performed dichloromethane or carbon tetrachloride at ambient tem-
better and the yield reached 65%.
perature or at reflux temperature. In contrast to previous
reports, the further cyclization of 3a or 4a could be
achieved only in the presence of triphenylphosphine, car-
bon tetrachloride or carbon tetrabromide, and triethyl-
amine.8,9
It was clear that during the model reaction with trifluoro-
acetic acid, the imidoyl halide intermediate N-[2-(hy-
droxymethyl)phenyl]-2,2,2-trifluoroacetimidoyl halide
3a or 4a was formed at the initial stage, the intermediate
gradually disappeared and the cyclized product 8a was All imidoyl halide intermediates, such as 3a or 4a, were
obtained as the final product (Scheme 3).
clearly detected in all examined cases and formed indole
compounds except using 1-(2-aminophenyl)ethanol (1j)
as the starting material, which formed N-[2-(1-haloeth-
yl)phenyl]-2,2,2-trifluoroacetimidoyl halide 5j or 6j in-
stead of the corresponding indole compound (Scheme 4).
OH
X
–
+
OH
[Ph3P-X]CX3
N
solvent, Et3N, reflux
NH2
CF3
1
The intermediate N-[2-(hydroxymethyl)phenyl]-2,2,2-tri-
fluoroacetimidoyl halide 3 or 4, which could be detected,
formed the intermediate N-[2-(halomethyl)phenyl]-2,2,2-
trifluoroacetimidoyl halide 5 or 6 in the presence of
3a or 4a
+
3a, X = Cl, solvent = CCl4
4a, X = Br, solvent = toluene
CF3CO2H
CF3
2a
N
H
8a
–
[Ph3P+X]CX3 and triethylamine. We reasoned that the
excess triphenylphosphine attacked 5 or 6 and formed a
phosphonium salt I, which then reacted with triethylamine
to give ylide II. The latter was very active and unstable
and, once formed, can undergo immediate cyclization to
form 8 (Scheme 5). Because 3j is a secondary alkyl halide,
formation of the phosphonium salt intermediate I is diffi-
cult, which is presumably why we failed to obtain the cor-
responding indole.
Scheme 3 Synthesis of the intermediate 3a or 4a and 2-trifluoro-
methylindole (8a)
X
+
–
[Ph3P-X]CX3
OH
NH2
X
solvent, Et3N, reflux
N
1j
CF3
5j or 6j
Although details of the mechanism of the reaction remain
to be fully clarified, a range of 2-fluoroalkyl-substituted
indoles with different fluorine-containing carboxylic
acids and 2-aminobenzyl alcohols (Table 1) were pre-
pared in moderate to excellent yields by using this proce-
dure. Most of the starting 2-aminobenzyl alcohols are
commercially available. For specific structure demands,
the desired product can also be simply prepared by the re-
duction of 2-aminobenzoic acid or 2-nitrobenzoic acid.10
+
5j, X = Cl, solvent = CCl4, yield = 52%
6j, X = Br, solvent = toluene, yield = 59%
CF3CO2H
2a
Scheme 4 Synthesis of 5j or 6j
Further study of the mechanism revealed that decreasing
the quantity of triethylamine that was used in this reaction
to one-third of normal dosage could effectively prevent
the subsequent cyclization from reaching completion.
Thus, the intermediate 3a or 4a was successfully isolated
as a major and stable compound from the reaction mix-
ture. The further cyclization of 3a or 4a could not be
It was found that the yields of 8 were affected by the elec-
tronic nature of the substituent group R2 on the benzene
ring. Without substituent group (R2 = H) or with an elec-
tron-donating group, such as a methoxy group, the prod-
R1
R1
R1
N
–
+
+
–
OH
X
OH
Rf
[Ph3P-X]CX3
[Ph3P-X]CX3
R2
R2
R2
RfCO2H
+
NH2
Et3N
Et3N
N
X
X
2
1
Rf
5 or 6
3 or 4
R1
R1
R1
PPh3X
PPh3
R2
R2
Et3N
Ph3P
Et3N
R2
Rf
–
N
X
N
X
+
– [Ph3P-X]CX3
N
H
Rf
Rf
X3C
8
H
I
II
Scheme 5 Postulated mechanisms for the transformation of 2-aminobenzyl alcohols 1 into indoles 8
Synthesis 2014, 46, 3309–3314
© Georg Thieme Verlag Stuttgart · New York

PAPER
2-Fluoroalkyl-Substituted Indoles
3311
was complete, the reaction mixture was heated to reflux for 2 h. Af-
ter cooling, the solvent was removed by rotary evaporator, the resi-
due was carefully washed three times with hexane–EtOAc (10:1),
and the precipitate was removed by filtration. The filtrate was com-
bined and concentrated by rotary evaporator. The residue was then
purified by column chromatography (hexane–EtOAc, 10:1), to give
the product 3a.
Table 1 Synthesis of 2-Fluoroalkyl-Substituted Indole
R1
R1
–
+
OH
[Ph3P-X]CX3
R2
RfCO2H
+
R2
Rf
solvent, Et3N
reflux
N
2
NH2
H
1
8
Yield: 1.26 g (53%); off-white solid; mp 100–101 °C.
Entry R1
R2
Rf
8
Yield of 8 (%)a
X = Clb X = Brc
1H NMR (500 MHz): δ = 8.43 (br, 1 H), 7.91 (d, J = 8.0 Hz, 1 H,
Ar-H), 7.45 (m, 1 H), 7.37 (dd, J = 7.5, 1.5 Hz, 1 H), 7.27 (m, 1 H),
4.63 (s, 2 H).
13C NMR (125 MHz): δ = 155.2 (q, 2JC–F = 37.5 Hz, C-CF3), 133.7,
130.7, 130.3, 128.6, 127.6, 124.1, 115.8 (q, 1JC–F = 286.7 Hz, CF3),
43.7 (Ar-CH2OH).
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
CF3
8a
8b
8c
8d
8e
8f
55
47
62
73
55
49
41
66
67
65
56
72
80
64
55
51
77
76
CF2 H
C3F7
CF3
19F NMR (470 MHz): δ = 75.86 (s, 3 F).
4-OMe
4-F
Synthesis of N-[2-(Hydroxymethyl)phenyl]-2,2,2-trifluoro-
acetimidoyl Bromide (4a); General Procedure
CF3
A 100-mL, three-necked flask equipped with a condenser was
charged with Ph3P (2.20 g, 8.4 mmol), Et3N (0.28 g, 2.8 mmol),
CBr4 (2.79 g, 8.4 mmol), and fluorine-containing carboxylic acid
(2.8 mmol) in toluene (25.0 mL) at 0 °C under a nitrogen atmo-
sphere and the solution was stirred for 10 min. 2-Aminobenzyl al-
cohol 1a (2.8 mmol) was then added to the reaction mixture. Once
the addition was complete, the reaction mixture was heated to reflux
for 2 h. After cooling, the solvent was removed by rotary evapora-
tor, the residue was then carefully washed three times with hexane–
EtOAc (10:1), and the precipitate was removed by filtration. The
filtrate was combined and concentrated by rotary evaporator. The
residue was then purified by column chromatography (hexane–
EtOAc, 10:1) to offer the product 4a.
4-Cl
CF3
4-NO2
5-OMe
5-OMe
CF3
8g
8h
8i
CF3
C3F7
a Isolated yield.
b CCl4 as solvent.
c Toluene as solvent.
ucts are obtained in good yields, whereas with an electron-
deficient substituent, such as NO2, the yields decreased to
moderate. When the side-chain contained a substituent
group, such as R1 = Me, the reaction did not occur. The
bromotriphenylphosphonium salt system was, in all cases,
more efficient.
Yield: 442 mg (56%); off-white solid; mp 112–113 °C.
1H NMR (500 MHz): δ = 8.75 (br, 1 H), 7.92 (d, J = 8.0 Hz, 1 H,
Ar-H), 7.44 (m, 1 H), 7.37 (dd, J = 7.5, 1.5 Hz, 1 H), 7.26 (m, 1 H),
4.65 (s, 2 H).
13C NMR (125 MHz): δ = 154.5 (q, 2JC–F = 37.5 Hz, C-CF3), 133.8,
130.6, 130.3, 128.7, 127.1, 124.3, 114.7 (q, 1JC–F = 286.7 Hz, CF3),
43.5 (Ar-CH2OH).
In conclusion, a unique and concise one-pot synthesis of
2-fluoroalkyl-substituted indoles from 2-aminobenzyl al-
19F NMR (470 MHz): δ = 75.15 (s, 3 F).
cohols and fluorine-containing carboxylic acids has been MS (EI, 70 eV): m/z (%) = 281.0 (100) [M+], 283.0 (98), 263.9 (76),
265.9 (74), 196.0 (50), 198.0 (48), 106 (25).
HRMS: m/z [M+] calcd for C9H7BrF3NO: 280.9663; found:
280.9659.
developed. This new approach provides an efficient, scal-
able, low-cost, and direct access to the biologically im-
portant indoles.
Synthesis of 2-Fluoroalkyl-Substituted Indoles
All reagents were of analytical grade and were used without further
purification. All melting points were recorded with a WRS-1A or
WRS-1B digital melting-point apparatus without correction. H,
General Procedure 1
To a 200-mL three-necked, round-bottomed flask equipped with a
condenser was added Ph3P (7.86 g, 30 mmol), Et3N (4.2 mL, 30
mmol), CCl4 (40 mL, 419 mmol), and carboxylic acid (10 mmol) at
0 °C under a nitrogen atmosphere and the solution was then stirred
for 10 min. 2-Aminobenzyl alcohol 1 (10 mmol) was added to the
reaction mixture. Once the addition was complete, the reaction mix-
ture was heated to reflux for 3–12 h. After cooling, the solvent was
removed by rotary evaporator, the residue was then carefully
washed three times with hexane–EtOAc (4:1), and the precipitate
was removed by filtration. The filtrate was combined and concen-
trated by rotary evaporator. The residue was then purified by col-
umn chromatography (hexane–EtOAc, 4:1) to give the product.
1
13C, and 19F NMR spectra were recorded in CDCl3 with a Bruker
AV-500 spectrometer. Chemical shifts for lH NMR spectra are re-
ported in ppm downfield from TMS; chemical shifts for 13C NMR
spectra are reported in ppm relative to internal CDCl3 (δ = 77.0 ppm
for 13C), and chemical shifts for 19F NMR spectra are reported in
ppm downfield from external fluorotrichloromethane (CFCl3). In-
frared spectra (IR) were recorded with a VATAR 370 FT-IR spec-
trophotometer. Elemental analyses were carried out with a VARIO
EL111 elemental analyzer.
N-[2-(Hydroxymethyl)phenyl]-2,2,2-trifluoroacetimidoyl Chlo-
ride (3a); Typical Procedure6
General Procedure 2
To a 200-mL three-necked, round-bottomed flask equipped with a
condenser and a magnetic stir bar was added Ph3P (7.86 g, 30
mmol), Et3N (1.4 mL, 10 mmol), CCl4 (40 mL, 419 mmol), and car-
boxylic acid (10 mmol) at 0 °C under a nitrogen atmosphere and the
solution was then stirred for 10 min. 2-Aminobenzyl alcohol 1a (10
mmol) was then added to the reaction mixture. Once the addition
A 100-mL, three-necked flask equipped with a condenser was
charged with Ph3P (2.20 g, 8.4 mmol), Et3N (0.85 g, 8.4 mmol),
CBr4 (2.79 g, 8.4 mmol), and fluorine-containing carboxylic acid
(2.8 mmol) in toluene (25.0 mL) at 0 °C under a nitrogen atmo-
sphere and the solution was then stirred for 10 min. 2-Aminobenzyl
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3309–3314

3312
Z.-x. Wang et al.
PAPER
alcohol 1 (2.8 mmol) was added to the reaction mixture. Once the
addition was complete, the reaction mixture was heated to reflux for
1–3 h. After cooling, the solvent was removed by rotary evaporator,
the residue was then carefully washed three times with hexane–
EtOAc (4:1), and the precipitate was removed by filtration. The fil-
trate was combined and concentrated by rotary evaporator. The res-
idue was then purified by column chromatography (hexane–EtOAc,
4:1) to give the product.
19F NMR (470 MHz): δ = –60.50 (s, 3 F).
Anal. Calcd for C9H6F3N: C, 58.38; H, 3.27; N, 7.57. Found: C,
58.40; H, 3.31; N, 7.55.
2-Difluoromethylindole (8b)6
Obtained by following Procedure 1 from 2-aminobenzyl alcohol
(1.23 g, 10 mmol) and 2,2-difluoroacetic acid (0.96 g, 10 mmol) or
by following Procedure 2 from 2-aminobenzyl alcohol (345 mg, 2.8
mmol) and 2,2-difluoroacetic acid (269 mg, 2.8 mmol).
N-[2-(1-Chloroethyl)phenyl]-2,2,2-trifluoroacetimidoyl Chlo-
ride (5j)
Obtained by following Procedure 1 from 1-(2-aminophenyl)ethanol
(1.37 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14 g, 10 mmol).
Yield: 0.78 g (47%; Procedure 1), 262 mg (56%; Procedure 2); yel-
low solid; mp 56–58 °C.
IR (neat): 3395 (NH), 2924, 1621, 1371, 1069, 1015, 810, 750 cm–1.
1H NMR (500 MHz): δ = 8.31 (br, 1 H, NH), 7.65 (d, J = 8.0 Hz,
1 H, Ar-H), 7.35 (d, J = 8.0 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.17
(t, J = 7.5 Hz, 1 H), 6.82 (t, JH–F = 54.5 Hz, 1 H, CF2H), 6.73 (d,
JH–F = 2.0 Hz, 1 H, CH=C-CF2H).
13C NMR (125 MHz): δ = 136.2, 130.0 (t, 2JC–F = 24.2 Hz, C-CF2H),
126.9, 124.1, 121.6, 120.6, 111.6, 110.5 (t, 1JC–F = 233.4 Hz, CF2H),
103.9 (t, 3JC–F = 6.9 Hz, CH=C-CF2H).
Yield: 1.40 g (52%); colorless oil.
IR (neat): 2980, 1697 (C=N), 1486, 1288, 1209, 1165, 951, 765 cm–1.
1H NMR (500 MHz): δ = 7.65 (dd, J = 7.5, 2.0 Hz, 1 H), 7.40–7.31
(m, 2 H, Ar-H), 6.95 (dd, J = 7.5, 1.2 Hz, 1 H), 5.29 (q, J = 7.0 Hz,
1 H), 2.15 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz): δ = 141.1, 134.9, 134.2 (q, JC–F = 42.9 Hz,
C-CF3), 128.8, 127.7, 126.5, 119.2, 116.7 (q, JC–F = 275.8 Hz,
CF3), 43.1, 26.1 (Ar-CHBrCH3).
2
1
19F NMR (470 MHz): δ = –109.83 (d, JF–H = 54.9 Hz, 2 F).
19F NMR (470 MHz): δ = –71.60 (s, 3 F).
MS (EI, 70 eV): m/z (%) = 269.0 (100) [M+], 271.0 (63), 201.0 (68),
Anal. Calcd for C9H7F2N: C, 64.67; H, 4.22; N, 8.38. Found: C,
64.66; H, 4.19; N, 8.35.
2-Heptafluoropropylindole (8c)11
203.0 (43), 131 (45).
HRMS: m/z [M+] calcd for C10H8Cl2F3N: 268.9986; found:
268.9982.
Obtained by following Procedure 1 from 2-aminobenzyl alcohol
(1.23 g, 10 mmol) and heptafluorobutyric acid (2.14 g, 10 mmol) or
by following Procedure 2 from 2-aminobenzyl alcohol (345 mg, 2.8
mmol) and heptafluorobutyric acid (600 mg, 2.8 mmol).
Anal. Calcd for C10H8Cl2F3N: C, 44.47; H, 2.99; N, 5.19. Found: C,
44.50; H, 3.01; N, 5.21.
Yield: 1.77 g (62%; Procedure 1); 575 mg (72%; Procedure 2); yel-
low solid; mp 63–64 °C.
N-[2-(1-Bromoethyl)phenyl]-2,2,2-trifluoroacetimidoyl Bro-
mide (6j)
Obtained by following Procedure 2 from 1-(2-aminophenyl)ethanol
(384 mg, 2.8 mmol) and 2,2,2-trifluoroacetic acid (320 mg, 2.8
mmol).
IR (neat): 3308, 2953, 1628, 1548, 1459, 1343, 1232, 1080, 814,
760 cm–1.
1H NMR (500 MHz): δ = 8.32 (br, 1 H), 7.64 (d, J = 8.0 Hz, 1 H),
7.35 (m, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H),
6.87 (s, 1 H).
13C NMR (125 MHz): δ = 136.1, 127.5, 124.9, 121.5, 120.1, 119.3
(t, JC–C–F = 28.1 Hz), 117.9 (qt, JC–F = 286.2 Hz, JC–C–F = 33.8 Hz),
116.6 (m), 114.1 (tt, JC–F = 253.1 Hz, JC–C–F = 31.9 Hz), 111.5,
109.0 (m).
Yield: 593 mg (59%).
IR (neat): 2960, 1689, 1488, 1278, 1215, 1150, 953, 778 cm–1.
1H NMR (500 MHz): δ = 7.65 (dd, J = 7.5, 2.0 Hz, 1 H), 7.41–7.31
(m, 2 H, Ar-H), 6.94 (dd, J = 7.5, 1.2 Hz, 1 H), 5.38 (q, J = 7.0 Hz,
1 H), 2.34 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz): δ = 141.3, 134.8, 134.1 (q, JC–F = 42.9 Hz,
C-CF3), 128.7, 127.5, 126.5, 119.2, 116.7 (q, JC–F = 275.8 Hz,
CF3), 46.2, 27.0.
19F NMR (470 MHz): δ = –71.70 (s, 3 F).
MS (EI, 70 eV): m/z (%) = 358.9 [M+] (100.0), 356.8 (51), 360.9
(49), 290.9 (57), 288.9 (30), 292.9 (29), 131 (45).
HRMS: m/z [M+] calcd for C10H8Br2F3N: 356.8976; found:
356.8965.
2
19F NMR (470 MHz): δ = –80.20 (t, J = 9.4 Hz, 3 F), –109.60 (q, J =
9.4 Hz, 2 F), –126.70 (s, 2 F).
1
Anal. Calcd for C11H6F7N: C, 46.33; H, 2.12; N, 4.91. Found: C,
46.36; H, 2.09; N, 4.85.
6-Methoxy-2-trifluoromethylindole (8d)12
Obtained by following Procedure 1 from 2-amino-4-methoxyphe-
nyl methanol (1.53 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14
g, 10 mmol) or by following Procedure 2 from 2-amino-4-methoxy-
phenyl methanol (428 mg, 2.8 mmol) and 2,2,2-trifluoroacetic acid
(320 mg, 2.8 mmol).
2-Trifluoromethylindole (8a)6
Obtained by following Procedure 1 from 2-aminobenzyl alcohol
(1.23 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14 g, 10 mmol),
or by following Procedure 2 from 2-aminobenzyl alcohol (345 mg,
2.8 mmol) and 2,2,2-trifluoroacetic acid (320 mg, 2.8 mmol).
Yield: 1.57 g (73%; Procedure 1), 482 mg (80%; Procedure 2); col-
orless solid; mp 88–90 °C.
IR (neat): 3302 (NH), 2959, 1599, 1560, 1254, 1174, 1117,
1001 cm–1.
1H NMR (500 MHz): δ = 8.28 (br, 1 H, NH), 7.48 (d, J = 8.5 Hz,
1 H), 7.10 (d, J = 2.5 Hz, 1 H), 6.89 (dd, J = 9.0, 2.5 Hz, 1 H), 6.86
(s, 1 H, CH=C-CF3), 3.85 (s, 3 H).
Yield: 1.02 g (55%; Procedure 1), 337 mg (65%; Procedure 2);
light-yellow solid; mp 107–108 °C.
IR (neat): 3389 (NH), 2921, 1375, 1306, 1168, 1103, 940, 818,
754 cm–1.
13C NMR (125 MHz): δ = 158.2, 137.3, 126.2 (q, 2JC–F = 38.4 Hz,
C-CF3), 122.7, 121.2 (q, 1JC–F = 265.9 Hz, CF3), 119.7, 111.6, 104.3
(q, 3JC–F = 3.3 Hz, CH=C-CF3), 94.8, 55.7 (Ar-OCH3).
1H NMR (500 MHz): δ = 8.31 (br, 1 H, NH), 7.66 (d, J = 8.0 Hz,
1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.20 (t, J =
7.5 Hz, 1 H), 6.92 (s, 1 H).
19F NMR (470 MHz): δ = –60.45 (s, 3 F).
2
13C NMR (125 MHz): δ = 136.1, 126.5, 125.7 (q, JC–F = 38.8 Hz,
1
C-CF3), 124.8, 122.1, 121.2 (q, JC–F = 266.2 Hz, CF3), 121.1,
111.7, 104.3 (q, 3JC–F = 3.3 Hz, CH=C-CF3).
Synthesis 2014, 46, 3309–3314
© Georg Thieme Verlag Stuttgart · New York

PAPER
2-Fluoroalkyl-Substituted Indoles
5-Methoxy-2-trifluoromethyl Indole (8h)6
Obtained by following Procedure 1 from 2-amino-5-methoxyphe-
nyl methanol (1.53 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14
g, 10 mmol) or by following Procedure 2 from 2-amino-5-methoxy-
phenyl methanol (428 mg, 2.8 mmol) and 2,2,2-trifluoroacetic acid
(320 mg, 2.8 mmol).
3313
Anal. Calcd for C10H8F3NO: C, 55.82; H, 3.75; N, 6.51; O, 7.44.
Found: C, 55.86; H, 3.77; N, 6.45; O, 7.46.
6-Fluoro-2-trifluoromethylindole (8e)6
Obtained by following Procedure 1 from 2-amino-4-fluorophenyl
methanol (1.41 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14 g,
10 mmol) or by following Procedure 2 from 2-amino-4-fluorophe-
nyl methanol (395 mg, 2.8 mmol) and 2,2,2-trifluoroacetic acid
(320 mg, 2.8 mmol).
Yield: 1.42 g (66%; Procedure 1), 464 mg (77%; Procedure 2); yel-
low solid; mp 50–51 °C.
IR (neat): 3402 (NH), 2949, 1559, 1461, 1224, 1174, 1117, 801 cm–1.
Yield: 1.12 g (55%; Procedure 1), 364 mg (64%; Procedure 2); yel-
low viscous liquid; mp 125 °C (dec.).
IR (neat): 3457 (NH), 2938, 1566, 1305, 1249, 1169, 831 cm–1.
1H NMR (500 MHz): δ = 8.38 (br, 1 H, NH), 7.57 (dd, J = 8.8,
5.2 Hz, 1 H), 7.06 (m, 1 H), 6.96 (m, 1 H), 6.88 (s, 1 H, CH=C-
CF3).
1H NMR (500 MHz): δ = 8.30 (br, 1 H, NH), 7.33 (d, J = 8.5 Hz,
1 H), 7.11 (d, J = 2.5 Hz, 1 H), 7.00 (dd, J = 9.0, 2.5 Hz, 1 H), 6.84
(s, 1 H, CH=C-CF3), 3.86 (s, 3 H, Ar-OCH3).
2
13C NMR (125 MHz): δ = 154.7, 131.3, 127.1, 126.2 (q, JC–F
=
1
38.4 Hz, C-CF3), 121.2 (q, JC–F = 265.9 Hz, CF3), 115.6, 112.4,
103.8 (q, 3JC–F = 3.3 Hz, CH=C-CF3), 102.7, 55.5 (Ar-OCH3).
13C NMR (125 MHz): δ = 161.1 (d, 1JC–F = 240.0 Hz), 136.2 (d, 3JC–F
=
=
=
=
19F NMR (470 MHz): δ = –60.45 (s, 3 F).
2
3
12.5 Hz), 126.2 (q, JC–F = 39.2 Hz, C-CF3), 123.2 (d, JC–F
10.0 Hz), 122.9, 121.1 (q, 1JC–F = 265.8 Hz, CF3), 110.2 (d, 2JC–F
Anal. Calcd for C10H8F3NO: C, 55.82; H, 3.75; N, 6.51; O, 7.44.
Found: C, 55.85; H, 3.76; N, 6.48; O, 7.56.
3
2
25.0 Hz), 104.3 (q, JC–F = 3.3 Hz, CH=C-CF3), 97.8 (d, JC–F
26.2 Hz).
5-Methoxy-2-heptafluoropropylindole (8i)6
19F NMR (470 MHz): δ = –60.56 (s, 3 F, CF3), –116.7 (m, 1 F, Ar-
F).
Obtained by following Procedure 1 from 2-amino-5-methoxyphe-
nyl methanol (1.53 g, 10 mmol) and heptafluorobutyric acid (2.14
g, 10 mmol) or by following Procedure 2 from 2-amino-5-methoxy-
phenyl methanol (428 mg, 2.8 mmol) and heptafluorobutyric acid
(600 mg, 2.8 mmol).
Anal. Calcd for C9H5F4N: C, 53.21; H, 2.48; N, 6.90. Found: C,
53.17; H, 2.50; N, 6.91.
6-Chloro-2-trifluoromethylindole (8f)6
Yield: 2.11 g (67%; Procedure 1), 670 mg (76%; Procedure 1); yel-
low solid; mp 44–45 °C.
Obtained by following Procedure 1 from 2-amino-4-chlorophenyl
methanol (1.58 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14 g,
10 mmol) or by following Procedure 2 from 2-amino-4-chlorophe-
nyl methanol (441 mg, 2.8 mmol) and 2,2,2-trifluoroacetic acid
(320 mg, 2.8 mmol).
IR (neat): 3318 (NH), 2956, 1545, 1450, 1345, 1232, 1181, 967,
790 cm–1.
1H NMR (500 MHz): δ = 8.52 (br, 1 H, NH), 7.27 (d, J = 9.0 Hz,
1 H), 7.10 (d, J = 2.0 Hz, 1 H), 6.99 (dd, J = 8.8, 2.3 Hz, 1 H), 6.87
(s, 1 H, CH=C-C3F7), 3.84 (s, 3 H).
Yield: 1.08 g (49%; Procedure 1), 338 mg (55%; Procedure 2); yel-
low viscous liquid; mp 147 °C (dec.).
2
IR (neat): 3425 (NH), 1554, 1416, 1357, 1310, 1125, 922, 826 cm–1.
1H NMR (500 MHz): δ = 8.40 (br, 1 H, NH), 7.56 (d, J = 8.5 Hz,
13C NMR (125 MHz): δ = 155.1, 132.0, 127.5, 124.4 (t, JC–F
=
1
2
29.4 Hz, C-C3F7), 118.0 (qt, JC–F = 286.2 Hz, JC–F = 33.8 Hz,
1
2
CF2CF2CF3), 116.1, 112.8 (tt, JC–F = 251.9 Hz, JC–F = 31.2 Hz,
CF2CF2CF3), 112.7, 108.8 (m, CF2CF2-CF3), 106.0 (t, 3J = 5.0 Hz,
CH=C-C3F7), 102.7, 55.8 (Ar-OCH3).
19F NMR (470 MHz): δ = –80.20 (t, J = 9.4 Hz, 3 F, CF2CF2CF3),
–109.47 (q, J = 9.4 Hz, 2 F, CF2CF2CF3), –126.70 (s, 2 F,
CF2CF2CF3).
1 H), 7.43–7.16 (m, 2 H, Ar-H), 6.91 (s, 1 H, CH=C-CF3).
2
13C NMR (125 MHz): δ = 136.3, 130.8, 126.2 (q, JC–F = 38.8 Hz,
1
C-CF3), 124.8, 122.7, 122.1, 120.6 (q, JC–F = 266.3 Hz, CF3),
111.5, 103.8 (q, 3JC–F = 3.5 Hz, CH=C-CF3).
19F NMR (470 MHz): δ = –60.61 (s, 3 F).
Anal. Calcd for C9H5ClF3N: C, 49.23; H, 2.30; N, 6.38. Found: C,
49.35; H, 2.28; N, 6.40.
Anal. Calcd for C12H8F7NO: C, 45.73; H, 2.56; N, 4.44; O, 5.08.
Found: C, 45.75; H, 2. 60; N, 4.42; O, 5.11.
6-Nitro-2-trifluoromethylindole (8g)13
Obtained by following Procedure 1 from 2-amino-4-nitrophenyl
methanol (1.68 g, 10 mmol) and 2,2,2-trifluoroacetic acid (1.14 g,
10 mmol) or by following Procedure 2 from 2-amino-4-nitrophenyl
methanol (470 mg, 2.8 mmol) and 2,2,2-trifluoroacetic acid (320
mg, 2.8 mmol).
Acknowledgment
The authors thank Dr. J. Hao and The Instrumental Analysis &
Research Center of Shanghai University for structural analysis.
Yield: 943 mg (41%; Procedure 1), 328 mg (51%; Procedure 2);
yellow solid; mp 143–144 °C.
References
IR (neat): 3380 (NH), 1654, 1515, 1456, 1300, 1025, 927, 835 cm–1.
1H NMR (500 MHz): δ = 8.45 (br, 1 H, NH), 8.26 (d, J = 8.5 Hz,
1 H), 7.50–7.55 (m, 2 H), 6.95 (s, 1 H, CH=C-CF3).
(1) (a) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
(b) Shiri, M. Chem. Rev. 2012, 112, 3508.
(2) For leading references on the biological activities of indoles,
see: (a) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci,
L. S.; Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.;
Dicioccio, A. T.; Petrova, T.; Mitschler, A.; Podjarny, A. D.
J. Med. Chem. 2005, 48, 3141. (b) Granchi, C.; Roy, S.;
Giacomelli, C.; Macchia, M.; Tuccinardi, T.; Martinelli, A.;
Lanza, M.; Betti, L.; Giannaccini, G.; Lucacchini, A.; Funel,
N.; Leon, L. G.; Giovannetti, E.; Peters, G. J.; Palchaudhuri,
R.; Calvaresi, E. C.; Hergenrother, P. J.; Minutolo, F. J. Med.
Chem. 2011, 54, 1599. (c) Granchi, C.; Roy, S.; Mottinelli,
M.; Nardini, E.; Campinoti, F.; Tuccinardi, T.; Lanza, M.;
2
13C NMR (125 MHz): δ = 140.3, 138.8, 127.9 (q, JC–F = 38.6 Hz,
1
C-CF3), 123.7, 122.7, 122.1, 120.8 (q, JC–F = 266.3 Hz, CF3),
118.5, 102.4 (q, 3JC–F = 3.5 Hz, CH=C-CF3).
19F NMR (470 MHz): δ = –60.81 (s, 3 F).
Anal. Calcd for C9H5F3N2O2: C, 46.97; H, 2.19; N, 12.17; O, 13.90.
Found: C, 46.92; H, 2.17; N, 12.18; O, 13.93.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3309–3314

3314
Z.-x. Wang et al.
PAPER
Betti, L.; Giannaccini, G.; Lucacchini, A.; Martinelli, A.;
Macchia, M.; Minutolo, F. Bioorg. Med. Chem. Lett. 2011,
21, 7331.
Chem. Soc. 1962, 84, 1745. (c) Gadogan, J. I. G.; Mackie, R.
K. Chem. Soc. Rev. 1974, 3, 87.
(6) Wang, Z.; Ge, F.; Wan, W.; Jiang, H.; Hao, J. J. Fluorine
Chem. 2007, 128, 1143.
(7) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32.
(8) Ge, F.; Wang, Z.; Wan, W.; Lu, W.; Hao, J. Tetrahedron
Lett. 2007, 48, 3251.
(9) Wang, Z.; Wan, W.; Jiang, H.; Hao, J. J. Org. Chem. 2007,
72, 9364.
(3) For recent reviews on the synthesis of indoles, see:
(a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875. (b) Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E.
S.; Haufe, G.; Nenajdenko, V. G. Synthesis 2009, 3905.
(c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215.
(d) Gonzalo, B.; Isabel, F.; Pedro, J. R.; Carlos, V. Synthesis
2012, 44, 3590.
(4) (a) Kraxner, J.; Hübner, H.; Gmeiner, P. Arch. Pharm.
Pharm. Med. Chem. 2000, 333, 287. (b) Pichota, A.;
Gramlich, V.; Beck, A. K.; Seebach, D. Helv. Chim. Acta
2012, 95, 1239. (c) Liao, S.; Alfaro-Lopez, J.; Shenderovich,
M. D.; Hosohata, K.; Lin, J.; Li, X.; Stropova, D.; Davis, P.;
Jernigan, K. A.; Porreca, F.; Yamamura, H. I.; Hruby, V. J.
J. Med. Chem. 1998, 41, 4767. (d) Romanov-Michailidis, F.;
Guénée, L.; Alexakis, A. Org. Lett. 2013, 15, 5890.
(5) (a) Rabinowitz, R.; Marcus, R. J. Am. Chem. Soc. 1962, 84,
1312. (b) Ramirez, F.; Desai, N. B.; Mckelvie, N. J. Am.
(10) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.;
Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63,
4541.
(11) Yoshida, M.; Yoshida, T.; Kobayashi, M.; Kamigata, N.
J. Chem. Soc., Perkin Trans. 1 1989, 909.
(12) Miyashita, K.; Tsuchiya, K.; Kondoh, K.; Miyabe, H.;
Imanishi, T. J. Chem. Soc., Perkin Trans. 1 1996, 1261.
(13) Bujok, R.; Wróbel, Z.; Wojciechowski, K. Synlett 2012, 23,
1315.
Synthesis 2014, 46, 3309–3314
© Georg Thieme Verlag Stuttgart · New York