Cs2CO3-catalyzed alkylation of indoles with trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tet.2017.03.012

A Cs₂CO₃-catalyzed alkylation reaction of indoles with trifluoromethyl ketones was presented. Both alicyclic and aromatic trifluoromethyl ketones as well as various substituted indoles are compatible with the methodology. Good to excellent yields of the corresponding trifluoromethyl substituted tertiary alcohols 2,2,2-tritrifluoro-1-(1H-indol-3-yl)-ethan-1-ols were acquired as the sole products.

Full text of DOI:10.1016/j.tet.2017.03.012

Accepted Manuscript
Cs CO -catalyzed alkylation of indoles with trifluoromethyl ketones
2
3
Xiao-Dong Liu, Yi Wang, Hai-Yan Ma, Chun-Hui Xing, Yu Yuan, Long Lu
PII:
S0040-4020(17)30237-5
10.1016/j.tet.2017.03.012
TET 28518
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 December 2016
Revised Date: 4 March 2017
Accepted Date: 6 March 2017
Please cite this article as: Liu X-D, Wang Y, Ma H-Y, Xing C-H, Yuan Y, Lu L, Cs CO -catalyzed
2
3
alkylation of indoles with trifluoromethyl ketones, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.012.
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ACCEPTED MANUSCRIPT
Graphical abstract
HO CF3
R'
R
O
Cs2CO3 (1~10 mol%)
R
MeCN, r.t.
R'
CF3
N
HN
H
1
2
4
1

ACCEPTED MANUSCRIPT
Cs2CO3-Catalyzed Alkylation of Indoles with
Trifluoromethyl Ketones
Xiao-Dong Liua, Yi Wangb, Hai-Yan Maa,*, Chun-Hui Xingc,*, Yu Yuanb, Long Luc
a
School of Chemistry and Molecular Engineering, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, P.R. China
Phone: +86(21) 64253519; fax: +86(21) 64253519; haiyanma@ecust.edu.cn
b
c
College of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu Province,
225002, P. R. China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, 200032, Shanghai, P. R. China
Phone: +86(21)54925485; fax: +86(21)64166128; e-mail: xingch@sioc.ac.cn
Abstract
A Cs2CO3-catalyzed alkylation reaction of indoles with trifluoromethyl ketones
was presented. Both alicyclic and aromatic trifluoromethyl ketones as well as various
substituted indoles are compatible with the methodology. Good to excellent yields of
the
corresponding
trifluoromethyl
substituted
tertiary
alcohols
2,2,2-tritrifluoro-1-(1H-indol-3-yl)-ethan-1-ols were acquired as the sole products.
Keywords: 3-Indolylmethanol, Trifluoromethyl ketone, Indole, Cesium carbonate，
Alkylation
1. Introduction
Indole derivatives widely exist in natural and artificial synthetic compounds.
Extensive studies indicated that these compounds possess a wide range of
bioactivities such as antibacterial, antifungal, cytotoxic and insecticidal properties.1-2
Therefore, the syntheses of these valuable compounds are always the hotspot in
1

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organic chemistry, and numerous methods have been developed.3-5
Recently, 3-indolylmethanols has attracted more and more attentions because of not
only its potential bioactivities2b but also the versatility for the preparation of various
complex indole derivatives.5 Nevertheless, the syntheses of 3-indolylmethanols are
challenging due to their labile properties.3a-b,6 The most straightforward way for
constructing these useful materials is the direct alkylation of indoles with carbonyl
compounds. Several catalysis systems including enantioselective versions based on
this strategy have been reported.6b-c,7
On the other hand, organofluorine compounds are significant to medicinal and
agricultural sciences. Many pharmaceuticals and agrochemicals developed in the last
few decades contain either a fluorine atom or a trifluoromethyl group.8 Introducing
fluorinated groups into indole derivatives has been considered in drug-design. For
example, Zhang, Jiang and coworkers had demonstrated that
a
few
trifluoromethyl-substituted 3-indolylmethanol derivatives exhibited extremely
promising activities against wild-type HIV-1.2b
Trifluoromethyl-substituted 3-indolylmethanol derivatives could be synthesized
from the reactions of indoles with trifluoromethyl ketones under the catalysis of either
Lewis/Brønsted acids or cinchona alkaloids.7b-g Recently, base-promoted alkylation
reactions were also developed.6b,7a Bandini and coworker discovered TMG
(1,1,3,3-tetramethylguanidine) type organic bases were excellent catalysts for the
alkylation reaction of indoles with aromatic fluoromethyl ketones.6b Base-catalysis
owns unique advantage because it may avoid the formation of bisindolylation
byproducts. In view of this advantage, TMG was also widely used to synthesize
3-indolylmethanols from aromatic aldehydes.5d,5g
As our continuous effort of studying the chemical transformation of fluorinated
synthetic building blocks,9 we keep on investigating the reactions of trifluoromethyl
ketones with indoles and synthesizing of fluorine-containing indole derivatives with
potential bioactivities. We had lately described a trifluoromethanesulfonic
acid-catalyzed bisindolylation reaction of indoles with both alkyl and aryl
trifluoromethyl ketones.9b The bisindolylalkane derivatives were generated in
moderate to excellent yields (Scheme 1). Due to strong acid condition and high
reaction temperature, this reaction could not be terminated at the first indolylation
2

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stage, and therefore was unable to provide the trifluoromethyl-substituted
3-indolylmethanols as the products.
Scheme 1. Acid-catalyzed bisindolylation of trifluoromethyl ketone.
However, during our continuing study on the reactions of the fluorinated building
block-trifluoromethyl cyclopropyl ketone 2a, we found inorganic bases, especially
cesium carbonate could catalyze the alkylation reaction of indoles with 2a as well as
aromatic trifluoromethyl ketones, which provides an efficient method for the
syntheses of trifluoromethyl-substituted 3-indolylmethanols. Here, we would like to
report our results.
2. Results and discussion
The initial study was carried out with the examination of the model reaction of
indole 1a with alicyclic trifluoromethyl cyclopropyl ketone 2a. Various base species,
which serve as catalysts (20 mol% loading), were first investigated (Table 1).
Table 1
Screening of base catalysts a
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a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), base (0.04mmol, 20 mol%), 0.5 mmol
1a/mL solvent, stirred at room temperature for 3 h in a vial.
b Conversions were determined by 1H NMR.
c N.R. : No reaction.
As shown in Table 1, organic bases such as TMG, Et3N, DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene), quinine, and DIPEA (ethyldiisopropylamine)
exhibited poor catalytic activities for the reaction between 1a and 2a (Table1, entries
1~5). Noticeably, TMG, which was an excellent catalyst for the alkylation reaction of
indoles with aromatic fluoromethyl ketones,6b didn’t work well on this model reaction,
and only 6% conversion of 1a was obtained (Table1, entry 1). The result indicated
that TMG catalyst was not suitable for the reaction with alicyclic substrate. However,
inorganic bases displayed quite different catalytic abilities (Table1, entries 6~16).
Generally, cesium and potassium bases were superior to sodium and lithium bases
(Table1, entry 6 vs entry 8, entry 9 vs entry 10, entry 11 vs entries 12 ~13, entry 14 vs
entry 15) for promoting the alkylation of 1a with 2a. Cs2CO3, KOH and t-BuOK
exhibited almost equally high efficiencies, and 73%, 74% and 68% conversions of 1a
were observed respectively (Table 1, entries 6, 11 and 14). Considering the relative
weaker basicity of Cs2CO3, which might be more compatible with base-sensitive
substrates, it was thus selected as the optimal catalyst for the following studies.
The reaction conditions were further optimized with Cs2CO3 as catalyst. Solvents
were screened next (Table 2, entries 1~ 12). Acetonitrile was the best solvent of the
reaction (Table 2, entry 12). On the other hand, the reaction still proceeded smoothly
even with reduced catalyst loading (Table 2, entry 13). Concentration of substrates
4

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also played an important role. Higher conversions were obtained in more concentrated
reaction mixtures (Table 2, entries 13~16). A complete conversion of 1a was observed
at 2M concentration just in 3.5 hours with 10 mol% of base catalyst (Table 2, entry
18). Actually, the excess of substrate 2a was not necessary. The reaction could still
reach the complete conversion with equal equivalent of 1a and 2a under the same
conditions (Table 2, entry 19). Finally, the optimal reaction conditions were
determined as equal equivalent of both substrates of 2M concentration in acetonitrile
with 10 mol% of Cs2CO3 as catalyst at room temperature.
Table 2
Optimization of the reaction a
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a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Cs2CO3(5~20 mol%), 0.2~2 mmol
1a/mL solvent, stirred at room temperature for 3 h in a vial.
b Conversions were determined by 1H NMR .
c N.R. : No reaction; N.P. : No desired product.
d The reaction mixture was stirred at room temperature for 3.5 h.
e
Equal equivalent of 2a (0.2 mmol) was used and the reaction mixture was stirred at room
temperature for 3.5 h.
Table 3.
Substrate scope of indoles for Cs2CO3-catalyzed alkylation a
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), Cs2CO3 (10 mol%), 2 mmol 1a/mL
6

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MeCN, stirred at room temperature in a vial.
b Isolated yield.
c 30 mol% of Cs2CO3 was used and no reaction occurred.
Under the established optimal conditions, the scope of the reaction was then
explored. A wide range of substituted indoles were tested and the results are listed in
table 3. It appears that this inorganic base-catalyzed reaction was not sensitive to
electrical property of indole substrates. Both electron-donating and
electron-withdrawing substituents on indolyl-ring are well tolerated, and the
corresponding substituted 1-cyclopropyl-2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol
were isolated in good to excellent yields (Table 3, entries 1~15). On the other hand,
the size and steric hindrance of substituents are more important factors for the
reaction. For instance, 2-methyl-1H-indole reacted with 2a to afford the desired
product in very high yield. Replacing 2-methyl with 2-phenyl group, as a sharp
contrast, no reaction happened at all even with 30 mol% catalyst loading for 5 hours
(Table 3, entry 17 vs entry 19). Even though away from reaction centre, a large size
substituent such as 5-benzyloxy group would still retard the reaction (Table 3, entry
16).
Naturally, Cs2CO3-catalyzed alkylation reaction could also apply to aromatic
trifluoromethyl ketones and pyruvate (Table 4). A range of substituted aromatic
trifluoromethyl ketones were employed to react with indole and thus good to excellent
yields were obtained (Table 4, entries 1~4). Meanwhile, heteroaromatic ketones also
worked well (Table 4, entries 5~6). Actually, aromatic ketones are more active
substrates. For example, the reaction of phenyl trifluoromethyl ketone 2b with indole
proceeded smoothly and afforded product 4t in comparable yield even with 2 mol%
catalyst-loading (Table 4, entry 9).
Table 4.
Substrate scope of aryl trifluoromethyl ketones for Cs2CO3-catalyzed alkylation a
7

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Yield (%)b
Entry
2
Ar
Cs2CO3 (mol%)
Time (h)
4
4t
1
2
2b
2c
2d
2e
2f
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
Thiophen-2-yl
Pyridin-2-yl
MeOCO
C6H5
10
10
10
10
10
10
10
5
3
3
3
3
3
3
3
3
7
7
95
93
93
95
95
76
91
95
94
61
4u
4v
4w
4x
4y
4z
4t
3
4
5
6
2g
2h
2b
2b
2b
7
8
9
C6H5
2
4t
10
C6H5
1
4t
a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), Cs2CO3 (1~10 mol%), 2 mmol 1a/mL
MeCN, stirred at room temperature in a vial.
b Isolated yield.
3. Conclusions
In conclusion, a highly efficient Cs2CO3-catalyzed alkylation reaction of indoles
with trifluoromethyl ketones has been presented. Both alicyclic and aromatic
trifluoromethyl ketones as well as a wide range of substituted indoles are suitable for
this
methodology,
and
the
corresponding
products
2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ols were obtained in good to excellent yields.
The inorganic base-catalyzed enantioselective alkylation reaction as well as the
further transformations of the corresponding products will be explored in the near
future.
4. Experimental section
4.1 General information
19
1H NMR and F NMR spectra were obtained with an Agilent AM-400 instrument
with TMS as the internal standard and CFCl3 as the external standard, respectively.
13C NMR spectra were recorded on an Agilent AM-400 or AM-500 instrument with
TMS as the internal standard. Chemical shifts (δ) are reported in ppm, and coupling
constants (J) are in Hertz (Hz). FT-IR spectra were obtained with a Nicolet AV-360
spectrophotometer. Mass spectra were obtained on an Agilent 5973 Network or a
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Waters Micromass GCT Premier instrument. All melting points were determined on a
Büchi B-545 melting point apparatus and are uncorrected. Trifluoromethyl
cyclopropyl ketone was synthesized according to the literature (see Ref. 8b). All other
commercially available reagents were purchased from commercial sources and used
19
1
directly. All reactions were monitored by TLC, F NMR or H NMR. Flash column
chromatograph was carried out using 300-400 mesh silica gel at medium pressure.
4.2 General procedure for the alkylation of indoles with trifluoromethyl ketones
A 4mL vial was charged with indole or its derivative (1mmol) and cesium
carbonate (0.1 mmol), then 1-cyclopropyl-2,2,2-trifluoroethanone (1mmol) and
MeCN (0.5 mL) was added rapidly. The reaction mixture was stirred at room
temperature for appropriate time. The completeness of the reaction was monitored by
TLC. When the reaction was completed, the reaction mixture was filtered to remove
cesium carbonate and then purified by column chromatography on silica gel to afford
the desire product.
4.3 Data of products 4a-z
4.3.1. 1-Cyclopropyl-2,2,2-trifluoro-1-(1H-indol-3-yl)ethanol (4a)
o
1
Isolated yield: 93%, white solid, mp: 109-110 C. H NMR (400 MHz, CDCl3) δ
8.23 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 1.6 Hz,
1H), 7.24 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 2.31 (s, 1H), 1.71-1.64 (m, 1H),
19
0.79-0.73 (m, 1H), 0.69-0.54 (m, 2H), 0.46-0.40 (m, 1H) ppm; F NMR (375 MHz,
13
CDCl3) δ -79.09 (s, 3F) ppm; C NMR (100.7 MHz, CDCl3) δ 136.3, 126.3 (q, J =
284.7 Hz), 125.4, 123.8, 122.5, 121.3 (q, J = 2.3 Hz), 120.3, 113.4, 111.4, 74.8 (q, J =
29.6 Hz), 15.1 (q, J = 1.5 Hz), 1.2 ppm. IR (KBr): νmax = 3549, 3483, 3409, 3140,
3090, 3063, 3013, 1615, 1491, 1457, 1273, 1237, 1183, 1104, 824, 753 cm-1. MS (EI):
m/z (%) 255(M+, 47.5), 186(100), 158, 144, 130, 69; HRMS: Calculated for
C13H12NOF3: 255.0871, Found: 255.0874.
4.3.2. 1-Cyclopropyl-2,2,2-trifluoro-1-(5-methyl-1H-indol-3-yl)ethanol (4b)
Isolated yield: 93%, pale yellow solid, mp: 89-90 oC. 1H NMR (400 MHz, CDCl3) δ
9

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8.11 (s, 1H), 7.74 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 2.47 (s,
3H), 2.34 (s, 1H), 1.69-1.63 (m, 1H), 0.77-0.72 (m, 1H), 0.68-0.53 (m, 2H), 0.44-0.37
19
13
(m, 1H) ppm; F NMR (375 MHz, CDCl3) δ -79.00 (s, 3F) ppm; C NMR (100.7
MHz, CDCl3) δ 134.6, 129.6, 126.3 (q, J = 285.4 Hz), 125.6, 124.1, 123.9, 120.8 (q, J
= 1.5 Hz), 112.8, 111.1, 74.9 (q, J = 28.8 Hz), 21.6, 15.0 (q, J = 1.5 Hz), 1.1 ppm. IR
(KBr): νmax = 3512, 3460, 3416, 3308, 3035, 2925, 1585, 1542, 1484, 1421, 1393,
1182, 1066, 1036, 984, 797 cm-1. MS (EI): m/z (%) 269(M+, 44.21), 200(100), 172,
158, 144, 130, 69; HRMS: Calculated for C14H14NOF3: 269.1027; Found: 269.1026.
4.3.3. 1-Cyclopropyl-2,2,2-trifluoro-1-(6-methyl-1H-indol-3-yl)ethanol (4c)
o
1
Isolated yield: 94%, white solid, mp: 120-121 C. H NMR (400 MHz, CDCl3) δ
8.10 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 7.00 (d, J = 8.0 Hz,
1H), 2.46 (s, 3H), 2.29 (s, 1H), 1.69-1.62 (m, 1H), 0.77-0.71 (m, 1H), 0.67-0.52 (m,
19
13
2H), 0.44-0.38 (m, 1H) ppm; F NMR (375 MHz, CDCl3) δ -79.13 (s, 3F) ppm; C
NMR (100.7 MHz, CDCl3) δ 136.8, 132.4, 126.3 (q, J = 285.5 Hz), 123.2, 123.1 (q, J
= 1.5 Hz), 122.2, 120.8 (q, J = 2.3 Hz), 113.3, 111.3, 74.9 (q, J = 28.8 Hz), 21.5, 15.0
(q, J = 1.5 Hz), 1.2 ppm. IR (KBr): νmax = 3517, 3344, 3080, 3018, 2920, 1542, 1452,
1180, 1150, 1125, 1027, 980, 805 cm-1. MS (EI): m/z (%) 269(M+, 45.34), 200(100),
172, 158, 144, 130, 69. HRMS: Calculated for C14H14NOF3: 269.1027; Found:
269.1030.
4.3.4. 1-Cyclopropyl-2,2,2-trifluoro-1-(7-methyl-1H-indol-3-yl)ethanol (4d)
o
1
Isolated yield: 93%, white solid, mp: 68-69 C. H NMR (400 MHz, DMSO-d6) δ
11.15 (s, 1H), 7.63 (d, J = 6.8Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 6.91 (q, J = 7.2 Hz,
1H), 6.89 (s, 1H), 5.76 (s, 1H), 2.45 (s, 3H), 1.76-1.69 (m, 1H), 0.76-0.70 (m, 1H),
0.53-0.46 (m, 1H), 0.44-0.35 (m, 2H) ppm; 19F NMR (375 MHz, DMSO-d6) δ -77.71
(s, 3F) ppm; 13C NMR (100.7 MHz, DMSO-d6) δ 136.0, 127.0 (q, J = 285.9 Hz),
125.5, 124.6, 121.4, 120.6, 119.2, 119.0, 114.1, 73.1 (q, J = 27.7 Hz), 16.7, 14.8, 0.7
ppm. IR (KBr): νmax = 3541, 3478, 3438, 3142, 3059, 3086, 3008, 2924, 1550, 1497,
1455, 1383, 1194, 1153, 1096, 1031, 986, 789 cm-1. MS (EI): m/z (%) 269 (M+, 37.94),
10

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200 (100), 172, 158, 144, 130, 69, 43. HRMS: Calculated for C14H14NOF3: 269.1027;
Found: 269.1030.
4.3.5. 1-Cyclopropyl-2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)ethanol (4e)
o
1
Isolated yield: 94%, pale yellow solid, mp: 167-169 C. H NMR (400 MHz,
DMSO-d6) δ 11.06 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.29 (s, 1H), 7.28 (d, J = 8.8 Hz,
1H), 6.76 (dd, J = 8.8, 2.0 Hz, 1H), 5.79 (s, 1H), 3.73 (s, 3H), 1.72-1.66 (m, 1H),
19
0.75-0.70 (m, 1H), 0.54-0.46 (m, 1H), 0.46-0.38 (m, 2H) ppm; F NMR (375 MHz,
13
DMSO-d6) δ -77.68 (s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 153.0, 131.7,
127.1 (q, J = 285.2 Hz), 126.3, 125.6, 113.3, 112.1, 111.2, 103.6, 73.0 (q, J = 28.1
Hz), 55.4, 14.8, 0.7 ppm. IR (KBr): νmax = 3276, 3004, 2972, 2946, 2906, 2837, 1629,
1586, 1537, 1491, 1466, 1442, 1216, 1168, 1148, 1025, 990, 804 cm-1. MS (EI): m/z
(%) 285 (M+, 45.83), 216 (100), 188, 174, 160, 147, 132, 69. HRMS: Calculated for
C14H14NO2F3: 285.0977; Found: 285.0974
4.3.6. 1-Cyclopropyl-2,2,2-trifluoro-1-(5-fluoro-1H-indol-3-yl)ethanol (4f)
o
1
Isolated yield: 95%, pale yellow solid, mp: 82-86 C. H NMR (400 MHz,
DMSO-d6) δ 11.33 (s, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 11.2 Hz, 1H), 7.38
(dd, J = 9.2, 4.8 Hz, 1H), 6.94 (dt, J = 8.8, 2.8 Hz , 1H), 5.84 (s, 1H), 1.73-1.66 (m,
19
1H), 0.75-0.67 (m, 1H), 0.54-0.44 (m, 1H), 0.46-0.35 (m, 2H) ppm; F NMR (375
MHz, DMSO-d6) δ -77.90 (s, 3F), -125.06--125.13 (m, 1F) ppm; 13C NMR (100.7
MHz, DMSO-d6) δ 156.7 (d, J = 229.2 Hz), 133.2, 127.0, 126.9 (q, J = 285.4 Hz),
126.1 (d, J = 10.8 Hz), 113.9 (d, J = 4.5 Hz), 112.5 (d, J = 9.9 Hz), 109.3 (d, J = 26.5
Hz), 106.1 (d, J = 23.6 Hz), 73.0 (q, J = 28.2 Hz), 14.7, 0.7 ppm; IR (KBr): νmax
=
3559, 3354, 3136, 3017, 1633, 1582, 1541, 1488, 1464, 1435, 1165, 1127, 1107, 1060,
989, 833 cm-1; MS (EI): m/z (%) 273 (M+, 42.57), 204 (100), 176, 162, 148, 135, 107,
69; HRMS: Calculated for C13H11NOF4: 273.0777; Found: 273.0782.
4.3.7. 1-Cyclopropyl-2,2,2-trifluoro-1-(6-fluoro-1H-indol-3-yl)ethanol (4g)
o
1
Isolated yield: 95%, pale yellow solid, mp: 102-105 C. H NMR (400 MHz,
11

ACCEPTED MANUSCRIPT
DMSO-d6) δ 11.28 (s, 1H), 7.78 (dd, J = 8.4, 6.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H),
7.16 (dd, J = 10.0, 2.0 Hz, 1H), 6.88 (dt, J = 9.6, 2.4 Hz, 1H), 5.85 (s, 1H), 1.72-1.65
(m, 1H), 0.74-0.71 (m, 1H), 0.54-0.44 (m, 1H), 0.45-0.38 (m, 2H) ppm; 19F NMR
(375 MHz, DMSO-d6) δ -77.82 (s, 3F), -122.22--122.28 (m, 1F) ppm; 13C NMR
(100.7 MHz, DMSO-d6) δ 158.7 (d, J = 227.8 Hz), 136.4 (d, J = 12.0 Hz), 126.9 (q, J
= 286.2 Hz), 125.6 (d, J = 2.3 Hz), 122.7, 113.6 (d, J = 9.9 Hz), 114.0, 107.4 (d, J =
23.6 Hz), 97.4 (d, J = 25.1 Hz), 73.0 (q, J = 28.1 Hz), 14.8, 0.7 ppm; IR (KBr): νmax
=
3559, 3463, 3143, 3092, 3012, 1621, 1590, 1550, 1500, 1454, 1408, 1177, 1157, 1138,
987, 957, 852, 813 cm-1; MS (EI): m/z (%) 273 (M+, 45.02), 204 (100), 176, 162, 148,
135, 107, 69; HRMS: Calculated for C13H11NOF4: 273.0777; Found: 273.0774.
4.3.8. 1-(5-Chloro-1H-indol-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (4h)
o
1
Isolated yield: 96%, pale yellow solid, mp: 90-93 C. H NMR (400 MHz,
DMSO-d6) δ 11.43 (s, 1H), 7.78 (s, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.40 (d, J = 8.8 Hz,
1H), 7.10 (dd, J = 8.8, 2 Hz, 1H), 5.89 (s, 1H), 1.71-1.67 (m, 1H), 0.74-0.68 (m, 1H),
0.54-0.48 (m, 1H), 0.45-0.34 (m, 2H) ppm; 19F NMR (375 MHz, DMSO-d6) δ -77.94
13
(s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 134.9, 127.0, 126.8 (q, J = 285.2
Hz), 126.7, 123.5, 121.0, 120.6, 113.5, 113.1, 73.0 (q, J = 27.7 Hz), 14.7, 0.7 ppm; IR
(KBr): νmax = 3530, 3454, 3433, 3317, 1571, 1543, 1465, 1449, 1186, 1173, 1163, 986,
835, 798, 698 cm-1; MS (EI): m/z (%) 289 (M+, 33.93), 220 (100), 204, 178, 164, 151,
69; HRMS: Calculated for C13H11NOF3Cl: 289.0481; Found: 289.0485.
4.3.9. 1-(6-Chloro-1H-indol-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (4i)
o
Isolated yield: 95%, light red solid, mp: 93-95 C. 1H NMR (400 MHz, DMSO-d6)
δ 11.35 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 2 Hz,
1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 5.87 (s, 1H), 1.72-1.65 (m, 1H), 0.75-0.70 (m,
19
1H), 0.53-0.46 (m, 1H), 0.45-0.36 (m, 2H) ppm; F NMR (375 MHz, DMSO-d6) δ
13
-77.88 (s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 136.9, 126.8 (q, J = 285.9
Hz), 126.0, 125.8, 124.6, 122.8, 119.2, 114.0, 111.1, 73.0 (q, J = 28.5 Hz), 14.7, 0.7
ppm; IR (KBr): νmax = 3545, 3333, 3076, 3018, 1619, 1540, 1458, 1413, 1290, 1177,
12

ACCEPTED MANUSCRIPT
1150, 1128, 974, 811, 699 cm-1; MS (EI): m/z (%) 289 (M+, 37.24), 220 (100), 178,
164, 151, 69; HRMS: Calculated for C13H11NOF3Cl: 289.0481; Found: 289.0482.
4.3.10. 1-(7-Chloro-1H-indol-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (4j)
Isolated yield: 96%, pink thick liquid. 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s,
1H), 7.78 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.02
(t, J = 7.6 Hz, 1H), 5.92 (s, 1H), 1.78-1.71 (m, 1H), 0.77-0.70 (m, 1H), 0.54-0.48 (m,
19
1H), 0.48-0.34 (m, 2H) ppm; F NMR (375 MHz, DMSO-d6) δ -77.85 (s, 3F) ppm;
13C NMR (100.7 MHz, DMSO-d6) δ 133.3, 127.7, 126.7 (q, J = 285.9 Hz), 126.2,
122.4, 120.6, 119.9, 115.9, 115.2, 72.9 (q, J = 27.8 Hz), 14.7, 0.7 ppm; IR (KBr): νmax
= 3566, 3432, 3139, 3091, 3017, 2927, 1565, 1494, 1436, 1339, 1281, 1207, 1169,
1088, 1030, 989, 882, 837, 784, 596 cm-1; MS (EI): m/z (%) 289 (M+, 35.97), 220
(100), 178, 164, 151, 84, 69, 43; HRMS: Calculated for C13H11NOF3Cl: 289.0481;
Found: 289.0482.
4.3.11. 1-(5-Bromo-1H-indol-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (4k)
o
1
Isolated yield: 93%, light green solid, mp: 89-90 C. H NMR (400 MHz,
DMSO-d6) δ 11.44 (s, 1H), 7.93 (s, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.4 Hz,
1H), 7.21 (dd, J = 8.4, 2 Hz, 1H), 5.90 (s, 1H), 1.72-1.65 (m, 1H), 0.73-0.69 (m, 1H),
0.54-0.48 (m, 1H), 0.47-0.34 (m, 2H) ppm; 19F NMR (375 MHz, DMSO-d6) δ -77.95
13
(s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 135.1, 127.7, 126.8 (q, J = 285.9
Hz), 126.5, 123.6, 123.5, 113.6, 113.4, 111.6, 73.0 (q, J = 27.7 Hz), 14.7, 0.7 ppm; IR
(KBr): νmax = 3528, 3449, 3316, 1564, 1542, 1460, 1446, 1084, 985, 794, 583 cm-1;
MS (EI): m/z (%) 335, 333 (M+), 266, 264 (100), 222, 222, 210, 208, 144, 69; HRMS:
Calculated for C13H11NOF3Br: 332.9976; Found:332.9974.
4.3.12. 3-(1-Cyclopropyl-2,2,2-trifluoro-1-hydroxyethyl)-1H-indole-5-carbonitrile (4l)
Isolated yield: 93%, white solid, mp: 154-156 oC. 1H NMR (400 MHz, DMSO-d6) δ
11.82 (s, 1H), 8.21 (s, 1H), 7.72 (d, J = 2 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.46 (d, J
= 8 Hz, 1H), 6.02 (s, 1H), 1.78-1.71 (m, 1H), 0.75-0.71 (m, 1H), 0.54-0.49 (m, 1H),
13

ACCEPTED MANUSCRIPT
19
13
0.48-0.34 (m, 2H) ppm; F NMR (375 MHz, DMSO-d6) δ -78.07 (s, 3F) ppm; C
NMR (100.7 MHz, DMSO-d6) δ 138.3, 127.7, 127.0, 126.7 (q, J = 285.9 Hz), 125.7,
123.7, 120.7, 114.8, 113.1, 101.2, 73.1 (q, J = 28.3 Hz), 14.8, 0.7 ppm; IR (KBr): νmax
= 3627, 3593, 3333, 3018, 2925, 2225, 1619, 1541, 1472, 1433, 1274, 1072, 1029,
989, 809 cm-1; MS (EI): m/z (%) 280 (M+, 30.41), 211 (100), 183, 169, 155, 142, 114,
69; HRMS: Calculated for C14H11 N2OF3: 280.0823; Found: 280.0822.
4.3.13. 3-(1-Cyclopropyl-2,2,2-trifluoro-1-hydroxyethyl)-1H-indole-6-carbonitrile
(4m)
o
1
Isolated yield: 95%, white solid, mp: 164-167 C. H NMR (400 MHz, DMSO-d6)
δ 11.80 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.35
(dd, J = 8.4, 1.2 Hz, 1H), 5.97 (s, 1H), 1.75-1.71 (m, 1H), 0.75-0.71 (m, 1H),
0.53-0.48 (m, 1H), 0.47-0.34 (m, 2H) ppm; 19F NMR (375 MHz, DMSO-d6) δ -78.00
13
(s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 135.8, 129.8, 129.4, 127.2 (q, J =
285.4 Hz), 123.0, 121.9, 121.0, 117.1, 115.2, 103.0, 73.4 (q, J = 28.1 Hz), 15.2, 1.2
ppm; IR (KBr): νmax = 3280, 3120, 3015, 2227, 1625, 1537, 1507, 1463, 1420, 1350,
1239, 1186, 1151, 1031, 987, 815 cm-1; MS (EI): m/z (%) 280 (M+, 30.64), 211 (100),
183, 169, 155, 142, 114, 69; HRMS: Calculated for C14H11 N2OF3: 280.0823; Found:
280.0821.
4.3.14. 1-Cyclopropyl-2,2,2-trifluoro-1-(5-nitro-1H-indol-3-yl)ethanol (4n)
Isolated yield: 95%, yellow solid, mp: 156-158 oC. 1H NMR (400 MHz, DMSO-d6)
δ 11.99 (s, 1H), 8.78 (s, 1H), 8.01 (dd, J = 8.2, 2.4 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H),
7.57 (d, J = 9.2 Hz, 1H), 6.13 (s, 1H), 1.74-1.70 (m, 1H), 0.76-0.70 (m, 1H),
0.58-0.52 (m, 1H), 0.48-0.36 (m, 2H) ppm; 19F NMR (375 MHz, DMSO-d6) δ -78.05
13
(s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 140.6, 139.6, 128.8, 125.6 (q, J =
284.4 Hz), 125.2, 118.5, 116.5, 116.3, 112.2, 73.0 (q, J = 27.7 Hz), 14.7, 0.7 ppm; IR
(KBr): νmax = 3487, 3346, 3131, 3094, 3017, 1578, 1541, 1516, 1471, 1341, 1164,
1150, 1075, 990, 814 cm-1; MS (EI): m/z (%) 300 (M+, 21.13), 231, 203, 189, 175,
144, 69; HRMS: Calculated for C13H11N2O3F3: 300.0722; Found: 300.0724.
14

ACCEPTED MANUSCRIPT
4.3.15. 1-Cyclopropyl-2,2,2-trifluoro-1-(6-nitro-1H-indol-3-yl)ethanol (4o)
Isolated yield: 93%, yellow solid, mp: 187-190 oC. 1H NMR (400 MHz, DMSO-d6)
δ 12.00 (s, 1H), 8.34 (d, J = 2 Hz, 1H), 7.99-7.90 (m, 3H), 6.05 (s, 1H), 1.77-1.72 (m,
19
1H), 0.78-0.72 (m, 1H), 0.57-0.50 (m, 1H), 0.48-0.35 (m, 2H) ppm; F NMR (375
13
MHz, DMSO-d6) δ -78.03 (s, 3F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 141.8,
134.9, 131.6, 130.6, 126.6 (q, J = 285.5 Hz), 121.7, 115.1, 113.9, 108.4, 72.9 (q, J =
27.7 Hz), 14.7, 0.7 ppm; IR (KBr): νmax = 3433, 3258, 3132, 3072, 3031, 2919, 2852,
1589, 1500, 1459, 1431, 1374, 1348, 1282, 1178, 1147, 1133, 1058, 998, 882 cm-1;
MS (EI): m/z (%) 300 (M+, 22.99), 231 (100), 203, 189, 175, 144, 178, 69; HRMS:
Calculated for C13H11N2O3F3: 300.0722; Found: 300.0721.
4.3.16. 1-(5-(Benzyloxy)-1H-indol-3-yl)-1-cyclopropyl-2,2,2-trifluoroethanol (4p)
o
1
Isolated yield: 55%, white solid, mp: 155-156 C. H NMR (400 MHz, DMSO-d6)
δ 11.48 (s, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 6.8 Hz, 2H), 7.44-7.34 (m, 3H),
7.11-7.04 (m, 2H), 6.76 (dd, J = 7.2, 1.2 Hz, 1H), 6.14 (d, J = 1.6 Hz, 1H), 5.31 (q, J
= 15.2 Hz, 2H), 1.85-1.78 (m, 1H), 0.75-0.69 (m, 1H), 0.50-0.43(m, 1H), 0.42-0.35
(m, 1H), 0.28-0.22 (m, 1H) ppm; 19F NMR (375 MHz, DMSO-d6) δ -78.34 (s, 3F)
13
ppm; C NMR (100.7 MHz, DMSO-d6) δ 149.8, 138.3, 135.9, 128.5, 128.3, 128.1,
126.5 (q, J = 286.6 Hz), 124.9, 122.1, 115.5, 113.4, 106.3, 101.6, 71.3 (q, J = 27.7
Hz), 70.4, 14.5, 1.2 ppm. IR (KBr): νmax = 3306, 3128, 3032, 2933, 2879, 1577, 1538,
1508, 1470, 1375, 1329, 1274, 1241, 1169, 1152, 1096, 1080, 990, 739, 721 cm-1. MS
(EI): m/z (%) 361(M+), 253, 231, 201, 189, 160, 91(100), 69. HRMS: Calculated for
C20H18NO2F3: 361.1290; Found: 361.1288.
4.3.17. 1-Cyclopropyl-2,2,2-trifluoro-1-(2-methyl-1H-indol-3-yl)ethanol (4q)
o
1
Isolated yield: 90%, brown solid, mp: 83-86 C. H NMR (400 MHz, DMSO-d6) δ
11.05 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.2 Hz,
1H), 6.92 (t, J = 7.2 Hz, 1H), 5.56 (s, 1H), 2.53 (s, 3H), 1.91-1.84 (m, 1H), 0.92-0.86
(m, 1H), 0.59-0.52 (m, 1H), 0.45-0.39 (m, 2H) ppm; 19F NMR (375 MHz, DMSO-d6)
15

ACCEPTED MANUSCRIPT
δ -78.13 (s, 3 F) ppm; 13C NMR (100.7 MHz, DMSO-d6) δ 134.74, 134.68, 127.7,
127.3 (q, J = 286.6 Hz), 121.1, 119.9, 118.6, 110.4, 108.6, 74.2 (q, J = 28.5 Hz), 15.5,
14.4, 1.6 ppm. IR (KBr): νmax = 3558, 3487, 3396, 3095, 3064, 2998, 1618, 1550,
1490, 1458, 1429, 1383, 1272, 1232, 1192, 1147, 1134, 1041, 1027, 985, 955, 753
cm-1. MS (EI): m/z (%) 269(M+, 42.07), 200(100), 172, 158, 144, 130, 69. HRMS:
Calculated for C14H14NOF3: 269.1027; Found: 269.1031.
4.3.18. 1-Cyclopropyl-2,2,2-trifluoro-1-(5-methoxy-2-methyl-1H-indol-3-yl)ethanol
(4r)
o
1
Isolated yield: 81%, pale yellow solid, mp: 179-180 C. H NMR (400 MHz,
DMSO-d6) δ 10.89 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.65 (dd,
J = 8.4, 2.4 Hz, 1H), 5.55 (s, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 1.85-1.78 (m, 1H),
19
0.89-0.84 (m, 1H), 0.58-0.51 (m, 1H), 0.47-0.38 (m, 2H) ppm; F NMR (375 MHz,
13
DMSO-d6) δ -78.11 (s, 3 F) ppm; C NMR (100.7 MHz, DMSO-d6) δ 152.8, 135.2,
129.8, 128.2, 127.4 (q, J = 286.6 Hz), 110.7, 109.5, 108.4, 103.9, 74.1 (q, J = 27.7
Hz), 55.3, 15.4, 14.5, 1.6 ppm. IR (KBr): νmax = 3315, 3002, 2967, 2942, 1587, 1492,
1442, 1427, 1380, 1347, 1296, 1217, 1152, 1131, 1039, 1026, 991, 959, 834 cm-1. MS
(EI): m/z (%) 299(M+, 36.64), 230(100), 200, 188, 174, 158, 69. HRMS: Calculated
for C15H16NO2F3: 299.1133; Found: 299.1132.
4.3.19. 2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-phenylethanol (4t) 6b
1
Isolated yield: 95%, white solid. H NMR (400 MHz, CD3CN) δ 9.46 (s, 1H),
7.59-7.54 (m, 2H), 7.52-7.48 (m, 1H), 7.44 (dd, J = 8.2, 0.7 Hz, 1H), 7.38-7.34 (m,
3H), 7.10 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 8.0, 7.2 Hz, 1H),
4.66 (s, 1H) ppm. 19F NMR (375 MHz, CD3CN) δ -77.05 (s, 3F) ppm. 13C NMR
(100.7 MHz, CD3CN) δ 140.0, 137.6, 129.3, 128.8, 128.5, 126.9 (q, J = 286.0 Hz),
126.5, 124.6 (q, J = 2.7 Hz), 123.0, 121.6, 120.4, 114.3, 112.6), 77.5 (q, J = 29.0 Hz)
ppm.
4.3.20. 2,2,2-trifluoro-1-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanol (4u) 6b
16

ACCEPTED MANUSCRIPT
Isolated yield: 93%, white solid. 1H NMR (400 MHz, CD3CN) δ 9.48 (s, 1H), 7.56
(dd, J = 8.5, 5.5 Hz, 2H), 7.51-7.48 (m, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.14-7.05 (m,
3H), 7.03 (d, J = 8.0 Hz, 1H), 6.88 (ddd, J = 8.1, 7.1, 0.9 Hz, 1H), 4.73 (s, 1H) ppm.
13
19F NMR (375 MHz, CD3CN) δ -77.31 (s, 3F), -115.62– -116.18 (m, 1F) ppm. C
NMR (100.7 MHz, CD3CN) δ 163.6 (d, J = 245.2 Hz), 137.6, 136.1 (d, J = 3.1 Hz),
130.7 (dd, J = 8.4, 1.0 Hz), 126.7 (q, J = 286.8 Hz), 126.4, 124.7 (dd, J = 5.9, 2.9 Hz),
123.1, 121.5, 120.5, 115.5 (d, J = 21.8 Hz), 113.9, 112.6, 77.2 (q, J = 29.3 Hz) ppm.
4.3.21. 1-(4-chlorophenyl)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethanol (4v) 6b
Isolated yield: 93%, white solid. 1H NMR (400 MHz, CD3CN) δ 9.49 (s, 1H), 7.53
(d, J = 8.5 Hz, 2H), 7.51-7.48 (m, 1H), 7.44 (dd, J = 8.2, 0.6 Hz, 1H), 7.38-7.33 (m,
2H), 7.14-7.08 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.91-6.86 (m, 1H), 4.76 (s, 1H) ppm.
19F NMR (375 MHz, CD3CN) δ -77.21 (s, 3F) ppm. 13C NMR (100.7 MHz, CD3CN)
δ 138.9, 137.6, 134.9, 130.3, 128.9, 126.6 (q, J = 286.0 Hz), 126.3, 124.7 (dd, J = 5.6,
2.8 Hz), 123.1, 121.4, 120.5, 113.6, 112.6, 77.2 (q, J = 29.2 Hz) ppm.
4.3.22. 1-(4-bromophenyl)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethanol (4w) 6b
1
Isolated yield: 95%, white solid. H NMR (400 MHz, CD3CN) δ 9.49 (s, 1H),
7.54-7.42 (m, 7H), 7.11 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.89 (t, J = 7.5
19
13
Hz, 1H), 4.76 (s, 1H) ppm. F NMR (375 MHz, CD3CN) δ -77.19 (s, 3F) ppm. C
NMR (100.7 MHz, CD3CN) δ 139.4, 137.6, 131.9, 130.7, 126.6 (q, J = 286.1 Hz),
126.3, 124.7 (d, J = 2.9 Hz), 123.1 121.4, 120.5, 118.3, 113.6, 112.6, 77.3 (q, J = 29.1
Hz) ppm.
4.3.23. 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-(thiophen-2-yl)ethanol (4x) 6b
Isolated yield: 95%, white solid. 1H NMR (400 MHz, CD3CN) δ 9.53 (s, 1H), 7.48
(dd, J = 4.4, 3.1 Hz, 2H), 7.44 (dd, J = 5.1, 1.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.17
(t, J = 7.6 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 7.02 (d, J = 3.7 Hz, 1H), 7.01-6.97 (m,
1H), 5.07 (s, 1H) ppm. 19F NMR (375 MHz, CD3CN) δ -77.75 (s, 3F) ppm. 13C NMR
(100.7 MHz, CD3CN) δ 144.4, 137.6, 128.0 (d, J = 1.3 Hz), 127.8, 127.6, 126.6,
17

ACCEPTED MANUSCRIPT
126.5 (q, J = 285.9 Hz), 124.9 (dd, J = 5.0, 2.5 Hz), 123.1, 121.7, 120.6, 114.1, 112.7,
76.7 (q, J = 30.8 Hz) ppm.
4.3.24. 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-(pyridin-2-yl)ethanol (4y)
1
Isolated yield: 76%, white solid, mp: 159-161 oC. H NMR (400 MHz, CD3CN) δ
9.49 (s, 1H), 8.69 (ddd, J = 4.9, 1.6, 1.0 Hz, 1H), 7.76 (td, J = 7.8, 1.7 Hz, 1H), 7.51
(dq, J = 3.8, 1.8 Hz, 1H), 7.46-7.39 (m, 3H), 7.10 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.04
19
(d, J = 8.1 Hz, 1H), 6.87 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.78 (s, 1H) ppm. F NMR
13
(375 MHz, CD3CN) δ -76.86 (s, 3F) ppm. C NMR (100.7 MHz, CD3CN) δ 156.4,
148.3, 138.9, 137.5, 126.50 (q, J = 285.8 Hz), 126.49, 125.3, 125.0 (dd, J = 5.6, 2.7
Hz), 124.0 (dd, J = 3.3, 1.6 Hz), 123.1, 121.1, 120.5, 112.9, 112.6, 77.1 (q, J = 29.1
Hz) ppm. IR (KBr): νmax = 3340, 3133, 3061, 1595, 1572, 1549, 1459, 1470, 1434,
1401, 1277, 1256, 1241, 1208, 1170, 1152, 1108, 1088, 1072, 1046, 750 cm-1. MS
(EI): m/s (%) 292 (M+, 49.96), 223 (100), 224, 144, 117, 106, 79, 78. HRMS (EI):
Calculated for C15H11ON2F3: 292.0826; Found: 292.0823.
4.3.25. Methyl 3,3,3-trifluoro-2-hydroxy-2-(1H-indol-3-yl)propanoate (4z)10
Isolated yield: 91%, white solid. 1H NMR (400 MHz, CD3CN) δ 9.55 (s, 1H), 7.78
(d, J = 8.1 Hz, 1H), 7.46 (dd, J = 5.5, 1.9 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (dd, J
19
= 8.1, 7.1 Hz, 1H), 5.09 (d, J = 1.3 Hz, 1H), 3.87 (s, 3H) ppm. F NMR (375 MHz,
CD3CN) δ -77.18 (s, 3F) ppm. 13C NMR (100.7 MHz, CD3CN) δ 167.0, 137.6, 126.1,
126.0 (d, J = 1.4 Hz), 125.1 (q, J = 285.3 Hz), 123.3, 121.5 (d, J = 1.2 Hz), 121.1,
112.8, 109.2, 78.1 (q, J = 30.6 Hz), 54.5 ppm.
Acknowledgments
Supports from the National Natural Science Foundation of China (21272257,
21274041 and 21474028) are gratefully acknowledged.
Supplementary data: Supplementary data associated with this article can be found in
the online version.
18

ACCEPTED MANUSCRIPT
References and notes
1. Pozharskii, A. F.; Katritzky, A. R.; Soldatenkov, A. T. Heterocycles in Life and
Society: An Introduction to Heterocyclic Chemistry, Biochemistry and
Applications, Wiley, Chichester, 2011.
2. (a) Lebée, C.; Kataja, A. O.; Blanchard, F.; Masson, G. Chem. Eur. J. 2015, 21,
8399; (b) Jiang, H.-X.; Zhuang, D.-M.; Huang, Y.; Cao, X.-X.; Yao, J.-H.; Li,
J.-Y.; Wang, J.-Y.; Zhang, C.; Jiang, B. Org. Biomol. Chem. 2014, 12, 3446; (c)
Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev. 2010,
110, 2250; (d) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
110, 4489; (e) Ramesh, C.; Kavala, V.; Kuo, C. W.; Rama, R. B.; Yao, C. F. Eur. J.
Org. Chem. 2010, 3796; (f) Usami, Y.; Yamaguchi, J.; Numata, A. Heterocycles
2004, 63, 1123; (g) Veluri, R.; Oka, I.; Wagner-Dçbler, I.; Laatsch, H. J. Nat. Prod.
2003, 66, 1520; (h) Hibino, S.; Chozi, T. Nat. Prod. Rep. 2001, 18, 66; (i)
Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175; (j) Bennasar, M.-L.;
Vidal, B.; Bosch, J. J. Org. Chem. 1997, 62, 3597.
3. Some reviews about the preparation of indole derivatives, see: (a) Sundberg, R. J.
Indoles; Academic Press: London, 1996; (b) Remers, W. A. In Indoles,
Heterocyclic Compounds; Houlihan, W. J., Ed.; John Wiley & Sons: London,
1972; (c) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903; (d) Cacchi,
S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (e) Sheng, Y.-F.; Zhang, A.-J.; Zheng
X.-J.; You, S.-L. Chin. J. Org. Chem., 2008, 28, 605; (f) Bandini, M.; Melloni, A.;
Tommasi, S.; Umani-Ronchi, A. Synlett. 2005, 1199; (g) Bandini, M.; Melloni, A.;
Tommasi, S.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550; (h)
Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi A. Synlett. 2005, 1199.
4. A few selected examples about the preparation of indoles derivatives, see: (a) Gao,
X.; Wu, B.; Huang, W.-X.; Chen, M.-W.; Zhou, Y.-G. Angew. Chem. Int. Ed.
2015, 54, 11956; (b) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi,
S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424; (c) Shen, Z.-L.; Ji, S.-J.;
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Wang, S.-Y.; Zeng, X.-F. Tetrahedron 2005, 61, 10552; (d) Gribble, G. W.; Silva,
R. A.; Saulnier, M. G. Synth. Commun. 1999, 29, 729.
5. Reviews and some examples for preparation of indole derivatives from
3-indolylmethanols, see: (a) Zhu, S.; Xu, L.; Wang, L.; Xiao, J. Chin. J. Org.
Chem. 2016, 36, 1229; (b) Kasztelan, A.; Biedrzycki, M.; Kwiatkowskia, P. Adv.
Synth. Catal. 2016, 358, 2962; (c) Zhang, C.; Zhang, L.-X.; Qiu, Y.; Xu, B.; Zong
Y.; Guo Q.-X. RSC Adv., 2014 4, 6916; (d) Guo, Z.-L.; Xue, J.-H.; Fu, L.-N.;
,
Zhang, S.-E.; Guo Q.-X. Org. Lett., 2014, 16, 6472; (e) Xu, B.; Shi, L.-L.; Zhang,
Y.-Z.; Wu, Z.-J.; Fu, L.-N.; Luo, C.-Q.; Zhang, L.-X.; Peng, Y.-G.; Guo, Q.-X.
Chem. Sci., 2014, 5, 1988; (f) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng,
Y.-G.; Guo Q.-X. Angew. Chem. Int. Ed., 2012, 51, 1059; (g) Guo, Q.-X.; Peng,
Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett., 2009, 11, 4620;
(h) Zeng, X.-F.; Ji, S.-J.; Wang, S.-Y.; Tetrahedron 2005, 61, 10235.
6. (a) Fu, A.; Meng, W.; Li, H.; Nie, J.; Ma, J.-A. Org. Biomol. Chem., 2014, 12,
1908; (b) Bandini, M.; Sinisi, R. Org. Lett. 2009, 11, 2093; (c) Li, H.; Wang,
Y.-Q.; Deng, L. Org. Lett., 2006, 8, 4063; (d) Deb, M. L.; Bhuyan, P. J.
Tetrahedron Lett. 2006, 47, 1441.
7. A few examples of direct alkylation of indoles with carbonyl compounds, see: (a)
Elayaraja, R.; Karunakaran, R. J.; Tetrahedron Lett. 2012, 53, 6901; (b) Sasaki, S.;
Ikekame, Y.; Tanayama, M. Yamauchi, T.; Higashiyama, K. SynLett 2012, 23,
2699; (c) Borkin, D. A.; Landge, S. M.; Török, B. Chirality 2011, 23, 612; (d) Nie,
J.; Zhang, G.-W.; Wang, L.; Fu, A.; Zheng, Y.; Ma, J.-A. Chem. Commun. 2009,
2356; (e) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M.; Mhadgut, S.
C.; Yan, P.; Prakash, G. K. S. Angew. Chem. Int. Ed. 2005, 44, 3086; (f) Abid, M.;
Török, B. Adv. Synth. Catal. 2005, 347, 1797; (g) Zhuang, W.; Gathergood, N.;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009; (h)Zhou, P.; Li, Y.;
Meagher, K. L.; Mewshaw, R. G.; Harrison, B. L. Tetrahedron Lett. 2001, 42,
7333.
8. (a) Prakash Reddy, V. Organofluorine Compounds in Biology and Medicine,
Elsevier, 2015; (b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications, Second Edition. Wiley-VCH GmbH & Co. KGaA. 2013;
(c) Uneyama, K. Organofluorine Chemistry Wiley-Blackwell: Oxford, 2006; (d)
O’Hagan, D.; J. Fluorine Chem. 2010, 131, 1071.
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9. (a) Li, C.; Cai, L.-Z.; Liu, X.-D.; Zhu, S.-Z.; Xing, C.-H.; Lu, L. Tetrahedron Lett.
2016, 57, 2171; (b) Wang, Y.; Yuan, Y.; Xing, C.-H.; Lu, L. Tetrahedron Lett.
2014, 55, 1045; (c) Xing, C.; Li, X.; Zhu, S.; Zhao, J.; Zhu, S. Tetrahedron Lett.
2006, 47, 4951; (d) Xing, C.; Zhu, S. J. Org. Chem. 2004, 69, 6486.
10. Carmona, D.; Lamata, M. P.; Sánchez, A.; Viguri, F.; Rodríguez, R.; Oro, L. A.;
Liu, C.; Díez-Gonzálezb, S.; Maseras, F. Dalton Trans., 2014, 43, 11260.
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