p-TsOH promoted Fischer indole synthesis of multi-substituted 2-trifluoromethyl indole derivatives

Article abstract of DOI:10.1016/j.tet.2010.01.080

A p-TsOH promoted one-pot synthesis of multi-substituted 2-trifluoromethyl indole derivatives, for instance, 2-trifluoromethyl-3-phenylindoles, 2-trifluoromethyl-indole-3-propanoates, and 2-trifluoromethyl-indole-3-butanoates from reactions of 1,1,1-trifluoro-3-phenylacetone and simply prepared ω-trifluoromethyl substituted δ and ε-ketoesters with arylhydrazines via Fischer indole synthesis has been developed.

Full text of DOI:10.1016/j.tet.2010.01.080

Tetrahedron 66 (2010) 2746–2751
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
p-TsOH promoted Fischer indole synthesis of multi-substituted
2-trifluoromethyl indole derivatives
,
,b,
*
Haizhen Jiang a, Yangli Wang a, Wen Wan a b, Jian Hao a
a Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A p-TsOH promoted one-pot synthesis of multi-substituted 2-trifluoromethyl indole derivatives, for instance,
Received 20 November 2009
Received in revised form 8 January 2010
Accepted 22 January 2010
2-trifluoromethyl-3-phenylindoles, 2-trifluoromethyl-indole-3-propanoates, and 2-trifluoromethyl-indole-
3-butanoates from reactions of 1,1,1-trifluoro-3-phenylacetone and simply prepared
u-trifluoromethyl
substituted and -ketoesters with arylhydrazines via Fischer indole synthesis has been developed.
d
3
Available online 10 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fluorinated indoles
Fluorinated ketoesters
Fischer indole synthesis
1. Introduction
fluorinated indole skeletons via traditional Fischer indole synthesis
by using fluorinated ketone substrates.2f,9
The replacement of hydrogen or halogen atom or alkyl group in
organic molecules by CF3 group has received wide attention in
pharmaceuticals, agrochemicals, and material sciences due to the
specific properties of the trifluoromethyl group.1 Recent results
showed that the introduction of CF3 group at specific position in
organic skeletons could enhance the relatively physiological
stability, modulate the physical, chemical, and biological properties,
and improve the pharmacokinetic properties as well.2,3 Indole
scaffold exists in variety of natural products with biological
significance and was widely employed as pharmaceutical and
agrochemical intermediate.4 Indoles that have functional sub-
stituents at the C-2 and C-3 positions are capable of binding to
many receptors with high affinity especially for electron-
withdrawing substituent at C-2 position,3,5 in addition, indole-3-
carboxylates also have potential biological activities.6 Therefore,
simultaneously having both trifluoromethyl group at C-2 position
and carboxylate group at C-3 position of indole skeleton is well
worth to be expected to be a core structure in pharmaceutically and
agrochemically important molecules.7
In this paper, we wish to reveal the p-TsOH promoted Fischer
indole synthesis toward the biologically interesting multi-
substituted 2-trifluoromethyl indole derivatives including 2-tri-
fluoromethyl-3-carboxylates in one-pot manner directly from the
reaction of 1,1,1-trifluoro-3-phenylacetone and simply prepared
u
-trifluoromethyl d and 3-ketoesters building blocks with arylhy-
drazines.10 This synthesis is facile, scalable, and transition metal
free process. The reaction is typically passing through the hydra-
zone intermediate 3 followed by indolization to generate indole
product 4 (Scheme 1).
2. Results and discussion
Our previous results about the synthesis of trifluoromethyl
substituted 1,2-diaza-3-one heterocycles from
ketoesters has revealed that the reactions of arylhydrazines with
-trifluoromethyl ketoesters that have shorter chain length, such
as and -ketoesters provided a major formation of 1,2-diaza-3-
u-fluoroalkylated
u
b
g
one heterocycle compounds by a tandem condensation/ring-clo-
sure reaction, but our preliminary result showed that the reaction
with ketoesters that have longer chain length, such as d-ketoester,
Construction of such indole skeleton, however, still remains
a challenge due to the lack of sources of fluorinated substrates or
efficient ways to install both CF3 group and carboxylate group to
indole skeleton in one process.2a,8 To the best of our knowledge,
there was even no report in literature regarding to the synthesis of
could go through Fischer indolization.10 To reveal in-depth cover-
age of 2-trifluoromethyl indole derivatives via Fischer indole syn-
thesis, 1,1,1-trifluoro-3-phenylacetone (1a) was initially tested in
this process and 2-trifluoromethyl 3-phenylindole (4aa) could be
obtained successfully via Fischer indole synthesis under the catal-
* Corresponding author. Fax: þ86 21 66133380.
E-mail address: jhao@staff.shu.edu.cn (J. Hao).
ysis of ZnCl2. However, the reaction of trifluoromethyl d-ketoester
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.080

H. Jiang et al. / Tetrahedron 66 (2010) 2746–2751
2747
O
The Fischer indolizations of trifluoromethyl
d
and
3
-ketoesters
NHAr
R
N
(1d and 1e) with phenylhydrazine (2a) were successfully carried
out to form 2-trifluoromethyl indole-3-carboxylates (4da, 4ea)
under the promotion of stoichiometric p-TsOH in toluene (entries 7
R
ArNHNH (2)
2
( )
CF
3
n
0.1eq p-TsOH/ toluene
1
( )
CF
n
3
o
90 C
1a, n=1, R=Ph
3
and 18, Table 2). However, the reaction of g-ketoester with phe-
1b, n=1, R=CO Me
2
1c, n=2, R=CO Me
nylhydrazine under the same reaction conditions provided 4,5-
dihydro-6-trifluoromethyl pyridazinone as dominated product
rather than the formation of indole product, only trace amount of
indole product could be detected by 19F NMR. It’s clear that the final
2
1d, n=3, R=CO Me
2
1e, n=4, R=CO Me
2
R
( )
n-1
1.0 eq p-TsOH
59% - 88%
Fischer Indole Synthesis
products from the reactions of
g-ketoester and phenylhydrazines
R'
CF
3
were dominated by the chain length of
ketoesters. The formation of five-membered pyrazol-3-ols and six-
membered pyridazinones via condensation/ring-closure reaction of
u
-trifluoromethyl
N
H
4
n=1, R=Ph, R'=H, F, CH , NO
3
2
trifluoromethyl
hydrazine are thermodynamically favored. Whereas, to longer
chain length -ketoesters, the reactions with phenylhydrazines
b,g-ketoesters (shorter chain length) with phenyl-
n=3, 4, R= CO Me,
2
R'=H, F, Cl, NO , CH , OCH
3
2
3
d,3
Scheme 1. p-TsOH promoted one-pot synthesis of 2-trifluoromethyl indole derivatives.
were preferred to undergo the typical Fisher indolization process
(1d) with phenylhydrazine (2a) under the catalysis of ZnCl2 mainly
resulted in the formation of hydrazone (3da), only trace amount of
indole product was detected by 19F NMR even using excess amount
of ZnCl2 (entry 1, Table 1). Other Lewis acids, such as Ti(OEt)4
showed ability to catalyze the same condensations of ketoester 1
with hydrazine 2, and obtained hydrazones 3 in high ratios (entry 2,
Table 1). However, both of them encountered a great difficulty to
achieve the subsequential indolization. Protonic acids, such as
H2SO4, HCl, AcOH, and TFA were also able to promote such
condensation in water, MeOH, or toluene media, and provided
arylhydrazone intermediates in good ratios (Table 1). However,
they also weren’t suitable to carry out the Fischer indole synthesis
properly. Reactions under such conditions only yielded indole-3-
carboxylates 4 in lower yields or a complex mixture if reaction
temperature was raised. Instead, p-TsOH was found to be a proper
promoter to push the indolization to form desired 2-tri-
fluoromethyl indole-3-carboxylate (4da) in excellent ratios (entry
5, Table 1). The condensation of arylhydrazine with ketoester could
be terminated at stage of formation of hydrazone if catalytic
amount of p-TsOH was employed (entry 3, Table 1). Reaction
promoted by stoichiometric p-TsOH resulted in the formation of
corresponding indole-3-carboxylate (4da) as major products
(entries 5–7, Table 1). After screening and optimizing the reaction
conditions, stoichiometric p-TsOH in toluene at 90 ꢀC was selected
to be a prior condition for this one-pot synthesis of indole de-
rivatives (4).
Table 2
Synthesis of trifluoromethylated indole derivatives
ketones or ketoesters
4
from
u
-trifluoromethyl
Entry 1 CF3CO(CH2)nR
2 ArNHNH2
Temp/time
(ꢀC/h)
4
Yielda
(%)
1
2
3
4
5
6
7
8
1a (n¼1, R¼Ph)
2a (R0¼H)
80/8
80/8
80/8
4aa
4ab
4ac
4ad
4ba
4ca
4da
4db
4dc
4dd
4de
4df
4dg
4dh (4-F) 15
4dh0(6-F) 44
4di (4-Cl) 25
4di0(6-Cl) 40
3dj
4ea
4eb
83
79
88
71
0b
1a
1a
1a
2b(R0¼4-F)
2c (R0¼4-CH3)
2d (R0¼4-NO2) 80/8
1b (n¼1, R¼COOMe) 2a
1c (n¼2, R¼COOMe) 2a
1d (n¼3, R¼COOMe) 2a
Reflux/12
Reflux/12
90/12
0.01b
79
75
81
60
71
20
61
1d
1d
1d
1d
1d
1d
1d
2b (R0¼4-F)
90/12
90/12
9
2c (R0¼4-CH3)
10
11
12
13
14
2d (R0¼4-NO2) 90/15
2e (R0¼4-Cl)
90/12
2f (R0¼4-OCH3) 70/20
2g (R0¼2-F)
2h (R0¼3-F)
90/18
90/15
15
1d
2i (R0¼3-Cl)
90/15
16
17
18
1d
2j (R0¼2,4-NO2) 90/20
87c
68
1e (n¼4, R¼COOMe) 2a
1e 2b
90/15
90/15
70
a
Isolated yield.
b
c
Determined by 19F NMR analysis to the crude reaction mixtures.
Only hydrazone 3dj was obtained.
Table 1
Optimization of reaction conditions for the synthesis of 2-trifluoromethy 3-indole carboxylic ester 4da
NHPh
COOMe
CF3
O
N
PhNHNH2 (2a)
Acid Solvent
COOMe
COOMe
( )3
1d
CF3
( )3
CF3
N
H
3da
4da
Entry
Solvent
Acid
ZnCl2 (0.2 equiv)
Temp (ꢀC)
3da:4daa
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
MeOH
Reflux
Reflux
Reflux
Reflux
90
Reflux
90
Reflux
Reflux
Reflux
Reflux
99b:1
93b:0
82:16
75:22
1:95
Ti(OEt)4 (0.2 equiv)
p-TsOH (0.1 equiv)
p-TsOH (0.2 equiv)
p-TsOH (1.1 equiv)
p-TsOH (1.1 equiv)
p-TsOH (1.5 equiv)
CF3COOH (0.2 equiv)
98% H2SO4
1:86
1:93
94b:0
67:28
100:0
65:13
9
10
11
AcOH
MeOH
AcOH/AcONa
HCl
a
Ratio determined by 19F NMR analysis to the crude reaction mixtures after stirring 12 h.
b
Indole product 4da was only detected by 19F NMR as a minor product even using excess amount of acid.

2748
H. Jiang et al. / Tetrahedron 66 (2010) 2746–2751
through tautomerization, [3,3]-sigmatropic rearrangement, cycli-
zation, and aromatization. Moreover, the reactions of or
-ketoesters with aliphatic hydrazines only resulted in the
d
3
formations of cyclic trifluoromethylated dihydrodiazepinone or
1,2-diazocinone.10
The reactions of 1,1,1-trifluoro-3-phenylacetone with arylhy-
drazines could provide higher yield of 2-trifluoromethyl 3-phe-
nylindoles under the promotion of stoichiometric p-TsOH than the
reactions catalyzed by ZnCl2 (entries 1–4, Table 2).
Reactions toward methyl 2-trifluoromethyl-indole-3-prop-
anoates and methyl 2-trifluoromethyl-indole-3-butanoates from
u
-trifluoromethyl d-ketoester and 3-ketoester were carried out via
typical Fischer indole synthesis mechanism (Scheme 2). In general,
para- and ortho-electron releasing group substituted arylhy-
drazines exhibited higher reactivities and provided better yields of
products in comparison with those electron-withdrawing group
substituted hydrazines (entries 10 and 11). p-Methoxyphenylhy-
drazine (2f), however, is unstable,11 the condensation of 2f with
ketoester 1d was quite difficult to be controlled and resulted in
complex mixture, thus, the isolated yield of indole product 4df was
low. Regioisomers caused by stronger electronegative effect of
substituent group on phenyl ring of hydrazines was also observed
in the cases of using m-F and m-Cl-phenylhydrazines (entries 14
and 15, Table 2). Products (4dh0 and 4di0) from electron richer
position of phenylhydrazines were much favored. Moreover, m-F-
phenylhydrazines provided relatively higher regioselectivities
(4dh/4dh0) than m-Cl-phenylhydrazines (4di/4di0) due to stronger
electronegativity of fluorine atom.
Figure 1. An ORTEP plot of 4dc and its packing diagram.
Table 3
Hydrogen-bond geometry
D–H/A
D–H
H/A
D/A
D–H/A
N1–H1/O4
N2–H2/O1
C25–H25A/F6
0.86
0.86
0.97
2.07
2.07
2.35
2.925(5)
2.925(5)
2.958(6)
170.0
170.4
120
Symmetry codes: (i) ꢁxþ1, ꢁy, ꢁz; (ii) xþ1/2, ꢁyþ1/2, zþ1/2.
process from the reactions of 1,1,1-trifluoro-3-phenylacetone and
simply prepared -trifluoromethyl substituted and -ketoesters
u
d
3
with hydrazines via p-TsOH promoted Fischer indole synthesis.
Variation of the arylhydrazines and suitable fluorinated ketoester
or ketone can provide the desired 2-trifluoromethyl indole
derivatives.
+OH
Ar
NH
O
H+
R
-H2O
Condensation
R
N
( )n
F3C
( )n
F3C
1
R
..
4. Experimental section
4.1. General
( )n
F3C
1a, n=1, R=Ph
1d,1e, n= 3, 4, R=CO2Me
ArNHNH2
2
3
H+
R'
H
N
Reactions were conducted in an appropriate round bottom flask
equipped with magnetic stirring bar and condenser under nitrogen
protection. Thin layer chromatography (TLC) was performed on
a silica gel. All melting points were taken on WRS-1 digital melting
point apparatus made by Shanghai physical instrument factory
(SPOIF), China, and were uncorrected. 1H, 13C, and 19F NMR spectra
were recorded on Bruker AV-500 spectrometer. Chemical shifts for
1H NMR spectra are reported in parts per million downfield from
TMS, chemical shifts for 13C NMR spectra are reported in parts per
R
( )n-1
N
C
H
CF3
R
( )n-1
R
( )n-1
C
CF3
C
CF3
R'
R'
+
+
NH2
NH2
N
H
NH2
R
( )n-1
R
( )n-1
million relative to internal chloroform (d
77.2 ppm for 13C), and
H
C
CF3
chemical shifts for 19F NMR spectra are reported in parts per million
downfield from internal fluorotrichloromethane (CFCl3). Coupling
constants (J) are given in hertz (Hz). The terms m, s, d, t, q refer to
multiplet, singlet, doublet, triplet, quartet, respectively, br refers to
a broad signal. Infrared spectra (IR) were recorded on AVATAR 370
FT-IR spectrometer, absorbance frequencies are given at maximum
of intensity in cmꢁ1. Elemental analyses were performed with
Elemental Vario EL III instrument.
CF3
R'
R'
+
N
NH2
-NH3
NH
H
4
Scheme 2. Plausible reaction mechanism from ketones or ketoesters to indoles 4.
The structure of the product 4dc was confirmed by X-ray
diffraction studies (Fig. 1). In the diagram of crystal structure of 4dc,
crystal structure is stabilized by intermolecular and intramolecular
hydrogen bonds (Table 3). The supramolecular aggregation is
4.2. General procedure for the 2-trifluoromethyl indoles 4
completed by the presence of
p–p interactions, intermolecular
hydrogen bonds, and intermolecular van der Waals.
A 25 mL three-necked flask equipped with a condenser and
magnetic stir bar was charged with hydrazine (10 mmol), ketone or
ketoester (10 mmol), toluene-4-sulfonic acid (11 mmol), and tolu-
ene (10 mL) at 90 ꢀC under nitrogen atmosphere. After the solution
stirring for about 0.5 h, phenylhydrazone was produced. The mix-
ture was maintained for 3–18 h. Solvent was evaporated under
reduced pressure, and the residue was then purified by flash
column chromatography on silica gel to yield the product 4.
3. Conclusion
In conclusion, multi-substituted biologically significant 2-tri-
fluoromethyl indole derivatives, such as 2-trifluoromethyl-3-phe-
nylindoles, 2-trifluoromethyl-indole-3-propanoates, and 2-trifluo
romethyl-indole-3-butanoates, were synthesized through one-pot

H. Jiang et al. / Tetrahedron 66 (2010) 2746–2751
2749
4.2.1. 3-Phenyl-2-(trifluoromethyl)-1H-indole (4aa). Pale yellow
859, 807, 730. Anal. Calcd for C13H11F4NO2: C, 53.99; H, 3.83; N, 4.84.
Found: C, 53.94; H, 3.71; N, 4.90.
crystal (5:1 petroleum ether/acetone); mp 63–64 ꢀC (lit.12 63–
64 ꢀC); 1H NMR (500 MHz, CDCl3):
d 8.52 (br s, 1H), 7.65 (d, 1H,
J¼8.0 Hz), 7.54–7.53 (m, 2H), 7.49–7.46 (m, 3H), 7.42–7.36 (m, 2H),
4.2.7. Methyl 3-(5-methyl-2-(trifluoromethyl)-1H-indol-3-yl)propa-
7.22–7.19 (m, 1H); 13C NMR (125 MHz, CDCl3):
d
135.1, 132.3, 130.0,
noate (4dc). Yellow solid (5:1 petroleum ether/acetone); mp 156–
1
128.5, 127.7, 127.4, 125.3, 121.8 (q, JC–F¼267.5 Hz), 121.4, 121.3 (q,
158 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.23 (br s,1H), 7.43 (s,1H), 7.28
3
2JC–F¼37.5 Hz), 121.2, 119.9 (q, JC–F¼2.5 Hz), 111.8; 19F NMR
(d, 1H, J¼8.0 Hz), 7.15 (dd, 1H, J¼8.0, 1.0 Hz), 3.69 (s, 3H), 3.20 (td,
(470 MHz, CDCl3):
1495, 1448, 1325, 1130, 1109, 749, 703. Anal. Calcd for C15H10F3N: C,
68.96; H, 3.86; N, 5.36. Found: C, 69.25; H, 4.32; N, 5.05.
d
ꢁ56.80 (s, 3F). IR (cmꢁ1):
n 3450, 3058, 1606,
2H, J¼8.0, 1.0 Hz), 2.66 (t, 2H, J¼8.0 Hz), 2.46 (s, 3H); 13C NMR
(125 MHz, CDCl3):
d
173.7, 133.8, 130.1, 127.2, 126.7, 122.1 (q, 1JC–F
¼
2
3
267.5 Hz), 121.8 (q, JC–F¼37.5 Hz), 119.4, 116.0 (q, JC–F¼2.5 Hz),
111.7, 51.8, 35.4, 21.5, 19.5; 19F NMR (470 MHz, CDCl3):
ꢁ58.42 (s,
3F); IR (cmꢁ1):
3346, 3035, 1725, 1570, 1472, 1208, 1155, 1109, 794.
d
4.2.2. 5-Fluoro-3-phenyl-2-(trifluoromethyl)-1H-indole
n
(4ab). White solid (5:1 petroleum ether/acetone); mp 85–87 ꢀC;
Anal. Calcd for C14H14F3NO2: C, 58.95; H, 4.95; N, 4.91. Found: C,
58.75; H, 4.84; N, 4.80.
1H NMR (500 MHz, CDCl3):
d 8.53 (br s,1H), 7.55–7.50 (m, 4H), 7.46–
7.43 (m, 1H), 7.41–7.38 (m, 1H), 7.32 (dd, 1H, J¼9.0, 2.0 Hz), 7.14 (td,
1
1H, J¼9.0, 2.0 Hz); 13C NMR (125 MHz, CDCl3):
d
158.8 (d, JC–F
¼
¼
4.2.8. Methyl 3-(5-nitro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
2
236.3 Hz), 131.8, 131.6, 129.9, 129.8, 128.7, 127.9, 122.9 (q, JC–F
anoate (4dd). White solid (5:1 petroleum ether/acetone); mp 178–
3
36.3 Hz), 121.5 (q, 1JC–F¼267.5 Hz), 119.9 (q, JC–F¼2.5 Hz), 114.3 (d,
180 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.75 (br s, 1H), 8.69 (d, 1H,
3
2
2JC–F¼27.5 Hz), 112.9 (d, JC–F¼9.5 Hz), 105.9 (d, JC–F¼23.9 Hz); 19F
J¼2.0 Hz), 8.23 (dd, 1H, J¼9.0, 2.0 Hz), 7.47 (d, 1H, J¼9.0 Hz), 3.70 (s,
NMR (470 MHz, CDCl3):
d
ꢁ57.03 (s, 3F), ꢁ121.84 to ꢁ121.89 (m,1F);
3H), 3.29 (td, 2H, J¼8.0, 1.0 Hz), 2.70 (t, 2H, J¼8.0 Hz); 13C NMR
IR (cmꢁ1):
767, 703.
n
3453, 3063, 1609, 1570, 1457,1250,1164, 1123, 863, 800,
(125 MHz, (CD3)2CO):
d
173.0, 143.2, 139.6, 127.1, 125.6 (q, JC–F
¼
2
1
3
37.5 Hz), 122.6 (q, JC–F¼267.5 Hz), 120.5, 119.9 (q, JC–F¼2.5 Hz),
118.6, 113.8, 51.8, 35.8, 19.8; 19F NMR (470 MHz, CDCl3):
ꢁ59.07 (s,
3F); IR (cmꢁ1):
3349, 3080, 1725, 1587, 1520, 1355, 1181, 1150, 741.
d
4.2.3. 5-Methyl-3-phenyl-2-(trifluoromethyl)-1H-indole
n
(4ac). White solid (5:1 petroleum ether/acetone); mp 74–76 ꢀC; 1H
Anal. Calcd for C13H11F3N2O4: C, 49.37; H, 3.51; N, 8.86. Found: C,
49.15; H, 3.34; N, 8.73.
NMR (500 MHz, CDCl3):
d 8.40 (br s, 1H), 7.54–7.48 (m, 4H), 7.43–
7.40 (m, 2H), 7.36 (d, 1H, J¼8.5 Hz), 7.20 (d, 1H, J¼8.5 Hz), 2.44 (s,
3H); 13C NMR (125 MHz, CDCl3):
d
133.4, 132.4, 130.9, 130.1, 128.5,
4.2.9. Methyl 3-(5-chloro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
127.6, 127.1, 121.8 (q, 1JC–F¼267.5 Hz), 121.4 (q, 2JC–F¼37.5 Hz), 120.5,
anoate (4de). White solid (5:1 petroleum ether/acetone); mp 153–
119.5 (q, 3JC–F¼2.5 Hz), 118.6, 111.5, 21.6; 19F NMR (470 MHz, CDCl3):
156 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.53 (br s, 1H), 7.64 (d, 1H,
d
ꢁ56.76 (s, 3F); IR (cmꢁ1):
n
3381, 3086,1609,1568,1326,1171,1111,
J¼1.5 Hz), 7.33 (d, 1H, J¼8.0 Hz), 7.27 (dd, 1H, J¼8.0, 1.5 Hz), 3.69 (s,
699. Anal. Calcd for C16H12F3N: C, 69.81; H, 4.39; N, 5.09. Found: C,
69.72; H, 4.58; N, 4.99.
3H), 3.19 (td, 2H, J¼8.0, 1.0 Hz), 2.65 (t, 2H, J¼8.0 Hz); 13C NMR
(125 MHz, CDCl3):
d
173.1, 133.6, 128.2, 126.7, 125.6, 123.2 (q, 2JC–F
¼
1
3
37.5 Hz), 121.7 (q, JC–F¼267.5 Hz), 119.7, 116.5 (q, JC–F¼2.5 Hz),
113.1, 51.9, 35.2,19.4; 19F NMR (470 MHz, CDCl3):
ꢁ58.71 (s, 3F); IR
(cmꢁ1):
3324, 3063, 1725, 1588, 1456, 1148, 1114, 900, 797, 721.
4.2.4. 5-Nitro-3-phenyl-2-(trifluoromethyl)-1H-indole (4ad). Yellow
d
solid (4:1 hexane/ethyl acetate); mp 108–110 ꢀC; 1H NMR (500 MHz,
n
CDCl3):
d
8.95 (br s, 1H), 8.60 (d, 1H, J¼2.0 Hz), 8.28 (dd, 1H, J¼9.0,
Anal. Calcd for C13H11ClF3NO2: C, 51.08; H, 3.63; N, 4.58. Found: C,
51.16; H, 3.77; N, 4.31.
2.0 Hz), 7.57–7.49 (m, 6H); 13C NMR (125 MHz, CDCl3):
d 143.2, 137.8,
130.5,129.9,129.0,128.6,127.0,124.3(q,2JC–F¼37.5 Hz),122.2 (q, 3JC–F
¼
2.5 Hz), 121.0 (q, JC–F¼267.5 Hz), 120.6, 118.9, 112.4; 19F NMR
4.2.10. Methyl 3-(5-methoxy-2-(trifluoromethyl)-1H-indol-3-yl) pro
1
(470 MHz, CDCl3):
d
ꢁ57.41 (s, 3F); IR (cmꢁ1):
n
3360, 3090,1525,1478,
panoate (4df). Brown oil (4:1 hexane/ethyl acetate); 1H NMR
1337, 1173, 1129, 818, 750, 704. Anal. Calcd for C15H9F3N2O2: C, 58.83;
H, 2.96; N, 9.15. Found: C, 58.57; H, 3.24; N, 8.95.
(500 MHz, CDCl3):
d
8.21 (br s, 1H), 7.29 (d, 1H, J¼9.0 Hz), 7.05 (d, 1H,
J¼2.0 Hz), 6.99 (dd, 1H, J¼9.0, 2.0 Hz), 3.87 (s, 3H), 3.69 (s, 3H), 3.20
(td, 2H, J¼8.0, 1.0 Hz), 2.66 (t, 2H, J¼8.0 Hz); 13C NMR (125 MHz,
4.2.5. Methyl 3-(2-(trifluoromethyl)-1H-indol-3-yl) porpanoate
CDCl3):
d
173.4, 154.9, 129.8, 127.5, 122.4 (q, 2JC–F¼37.5 Hz), 122.0 (q,
(4da). White solid (5:1 petroleum ether/acetone); mp 151–154 ꢀC;
1JC–F¼267.5 Hz), 116.4 (q, 3JC–F¼2.5 Hz), 115.4, 112.9, 100.9, 56.0, 51.9,
1H NMR (500 MHz, CDCl3):
d
8.38 (br s, 1H), 7.68 (d, 1H, J¼8.0 Hz),
35.2, 19.5; 19F NMR (470 MHz, CDCl3):
d
ꢁ58.47 (s, 3F); IR (cmꢁ1):
n
7.41 (d, 1H, J¼8.0 Hz), 7.33 (dd, 1H, J¼8.0, 8.0 Hz), 7.20 (ddd, 1H,
J¼8.0, 8.0, 1.0 Hz), 3.68 (s, 3H), 3.24 (td, 2H, J¼8.0, 1.0 Hz), 2.67 (t,
3408, 1718, 1610, 1513, 1470, 1217, 1159, 1113, 804, 727.
2H, J¼8.0 Hz); 13C NMR (125 MHz, CDCl3):
d
2
173.8, 135.5, 127.0,
4.2.11. Methyl 3-(7-fluoro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
1
124.8, 122.1 (q, JC–F¼266.3 Hz), 121.8 (q, JC–F¼37.5 Hz), 120.6,
anoate (4dg). White solid (5:1 petroleum ether/acetone); mp 110–
120.0, 116.4 (q, JC–F¼2.5 Hz), 112.0, 51.9, 35.4, 19.4; 19F NMR
113 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.63 (br s, 1H), 7.44 (dd, 1H,
3
(470 MHz, CDCl3):
d
ꢁ58.44 (s, 3F); IR (cmꢁ1):
n
3363, 3044, 1718,
J¼8.0, 5.0 Hz), 7.10 (ddd, 1H, J¼8.0, 8.0, 5.0 Hz), 7.02 (dd, 1H, J¼11.0,
1592, 1458, 1201, 1155, 742. Anal. Calcd for C13H12F3NO2: C, 57.57; H,
4.46; N, 5.16. Found: C, 57.34; H, 4.70; N, 5.07.
8.0 Hz), 3.68 (s, 3H), 3.22 (td, 2H, J¼8.0, 1.0 Hz), 2.66 (t, 2H,
1
J¼8.0 Hz); 13C NMR (125 MHz, CDCl3):
d
173.3, 149.8 (d, JC–F
¼
2
2
243.8 Hz), 130.6, 124.1 (d, JC–F¼13.8 Hz), 122.8 (q, JC–F¼37.5 Hz),
1
3
3
4.2.6. Methyl 3-(5-fluoro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
121.7 (q, JC–F¼267.5 Hz), 121.1 (d, JC–F¼5.0 Hz), 117.5 (q, JC–F¼
3 2
anoate (4db). White solid (5:1 petroleum ether/acetone); mp 98–
2.5 Hz), 115.9 (d, JC–F¼5.0 Hz), 109.5 (d, JC–F¼16.3 Hz), 51.9, 35.2,
100 ꢀC; 1H NMR (500 MHz, CDCl3):
d
8.43 (br s, 1H), 7.35–7.30 (m,
19.5; 19F NMR (470 MHz, CDCl3):
d
ꢁ58.71 (s, 3F), ꢁ134.22 (dd, 1F,
2H), 7.10–7.06 (m,1H), 3.69 (s, 3H), 3.18 (td, 2H, J¼8.0,1.0 Hz), 2.65 (t,
J¼11.0, 5.0 Hz); IR (cmꢁ1):
n 3342, 3026, 1722, 1578, 1424, 1200,
2H, J¼8.0 Hz); 13C NMR (125 MHz, CDCl3):
d
173.5, 158.2 (d, 1JC–F
¼
1146, 1112, 800, 746. Anal. Calcd for C13H11F4NO2: C, 53.99; H, 3.83;
N, 4.84. Found: C, 53.83; H, 3.91; N, 4.78.
3
2
235.0 Hz), 131.9, 127.4 (d, JC–F¼10.0 Hz), 123.5 (q, JC–F¼37.5 Hz),
1
3
2
121.8 (q, JC–F¼267.5 Hz), 116.4 (q, JC–F¼2.5 Hz), 113.8 (d, JC–F
¼
25.0 Hz), 113.0 (d, 3JC–F¼10.0 Hz), 104.8 (d, 2JC–F¼25.0 Hz), 51.9, 35.2,
4.2.12. Methyl 3-(4-fluoro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
19.5; 19F NMR (470 MHz, CDCl3):
d
ꢁ58.73 (s, 3F), ꢁ122.22 to
anoate (4dh). White solid (5:1 petroleum ether/acetone); mp
ꢁ122.31 (m, 1F). IR (cmꢁ1):
n
3359, 3017, 1713, 1571, 1465, 1200, 1115,
105–108 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.47 (br s, 1H), 7.20–7.26

2750
H. Jiang et al. / Tetrahedron 66 (2010) 2746–2751
3
2
3
(m, 1H), 7.16 (d, 1H, J¼8.0 Hz), 6.82 (ddd, 1H, J¼11.0, 8.0, 0.5 Hz),
3.70 (s, 3H), 3.28 (td, 2H, J¼8.0, 1.0 Hz), 2.72–2.69 (m, 2H); 13C NMR
117.8 (q, JC–F¼2.5 Hz), 113.9 (d, JC–F¼26.3 Hz), 112.8 (d, JC–F
¼
10.0 Hz), 105.2 (d, JC–F¼22.5 Hz), 51.7, 33.5, 25.7, 23.2; 19F NMR
2
(125 MHz, CDCl3):
d
173.3, 157.7 (d, 1JC–F¼247.5 Hz), 137.8 (d, 3JC–F
¼
(470 MHz, CDCl3):
d
ꢁ58.47 (s, 3F), ꢁ122.51 to ꢁ122.53 (m, 1F); IR
3
2
10.0 Hz), 125.6 (d, JC–F¼7.5 Hz), 122.1 (q, JC–F¼37.5 Hz), 121.7 (q,
(cmꢁ1):
n 3357, 3010, 1723, 1568, 1470, 1208, 1147, 1103, 895, 803,
1JC–F¼267.5 Hz), 116.3 (d, JC–F¼20.0 Hz), 115.6 (q, JC–F¼2.5 Hz),
690. Anal. Calcd for C14H13F4NO2: C, 55.45; H, 4.32; N, 4.62. Found:
C, 55.57; H, 4.21; N, 4.57.
2
3
108.0 (d, 4JC–F¼3.8 Hz), 105.9 (d, 2JC–F¼20.0 Hz), 51.8, 35.8, 20.6; 19
F
NMR (470 MHz, CDCl3):
d
ꢁ58.38 (s, 3F), ꢁ122.53 (dd, 1F, J¼11.0,
5.0 Hz); IR (cmꢁ1):
1119, 785, 734.
n
3309, 3051, 1724, 1643, 1581, 1439, 1207, 1165,
4.2.18. Methyl 5-(2-(2,4-dinitrophenyl)hydrazono)-6,6,6-trifluorohex
anoate (3dj). Yellow solid (4:1 petroleum ether/ethyl acetate); mp
114–116 ꢀC; 1H NMR (500 MHz, CDCl3):
d 11.33 (br s, 1H), 9.15 (d,
4.2.13. Methyl 3-(6-fluoro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
J¼2.5 Hz, 2H), 8.44–8.42 (m, 1H), 8.06 (d, J¼9.5 Hz, 1H), 3.74 (s, 3H),
anoate (4dh0). Pale yellow solid (5:1 petroleum ether/acetone); mp
2.70–2.67 (m, 2H), 2.52 (t, J¼7.0 Hz, 2H), 2.07–2.01 (m, 2H); 13C
117–118 ꢀC; 1H NMR (500 MHz, CDCl3):
d
8.65 (br s, 1H), 7.59 (dd,
NMR (125 MHz, CDCl3):
d
172.7, 144.4, 143.2 (q, JC–F¼33.8 Hz),
2
1H, J¼9.0, 5.0 Hz), 7.02 (dd, 1H, J¼9.0, 2.0 Hz), 6.95 (td, 1H, J¼9.0,
140.2, 131.4, 130.5, 123.1 120.9 (q, 1JC–F¼272.5 Hz), 117.4, 52.2, 33.3,
2.0 Hz), 3.68 (s, 3H), 3.21 (td, 2H, J¼8.0, 1.0 Hz), 2.67 (t, 2H,
24.9, 20.2; 19F NMR (470 MHz, CDCl3):
d
ꢁ69.8 (s, 3F); IR (cmꢁ1):
n
1
J¼8.0 Hz); 13C NMR (125 MHz, CDCl3):
d
173.5, 161.4 (d, JC–F
¼
3313, 3094, 1725, 1616, 1594, 1335, 1196, 1132, 849, 743.
3
2
241.3 Hz), 135.5 (d, JC–F¼12.5 Hz), 123.7, 122.2 (q, JC–F¼37.5 Hz),
1
3
3
121.8 (q, JC–F¼267.5 Hz), 121.3 (d, JC–F¼10.0 Hz), 116.8 (q, JC–F
¼
4.3. X-ray crystal structure data of compound 4dc
2
2
2.5 Hz), 110.1 (d, JC–F¼25.0 Hz), 98.1 (d, JC–F¼25.0 Hz), 51.9, 35.4,
19.4; 19F NMR (470 MHz, CDCl3):
d
ꢁ58.56 (s, 3F), ꢁ116.76 (dd, 1F,
Single-crystal XRD was performed with graphite-monochromatic
Mo K radiation (
J¼11.0, 5.0 Hz); IR (cmꢁ1):
n 3319, 1715, 1631, 1576, 1442, 1268, 1157,
a
l
¼0.71073 Å) on a Bruker Smart ApexII CCD
1114, 847, 805, 730. Anal. Calcd for C13H11F4NO2: C, 53.99; H, 3.83;
N, 4.84. Found: C, 53.81; H, 3.85; N, 4.91.
diffractometer at T¼273(2) K. The structures were solved by direct
method with SHELXS-97 program and refined by full matrix least-
squares on F2 with SHELXL-97 program. All non-hydrogen atoms
were refined anisotropically, and hydrogen atoms were located and
included at their calculated position.
4.2.14. Methyl 3-(4-chloro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
anoate (4di). White solid (5:1 petroleum ether/acetone); mp 91–
93 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.57 (br s, 1H), 7.30 (dd, 1H,
CCDC 755245 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_-
request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: þ44 1223 336033.
J¼8.0,1.0 Hz), 7.20 (dd,1H, J¼8.0, 8.0 Hz), 7.15 (dd,1H, J¼8.0,1.0 Hz),
3.72 (s, 3H), 3.43 (td, 2H, J¼8.5, 1.0 Hz), 2.75–2.71 (m, 2H); 13C NMR
2
(125 MHz, CDCl3):
d
173.3, 136.7, 127.5, 125.4, 123.5 (q, JC–F
¼
¼
1
3
37.5 Hz), 122.8, 122.1, 121.7 (q, JC–F¼267.5 Hz), 117.1 (q, JC–F
2.5 Hz), 110.8, 51.8, 36.6, 20.0; 19F NMR (470 MHz, CDCl3):
(s, 3F); IR (cmꢁ1):
d
ꢁ58.41
n
3323, 3071, 1719, 1583, 1458, 1265, 1161, 1120,
780, 744, 684. Anal. Calcd for C13H11ClF3NO2: C, 51.08; H, 3.63; N,
4.58. Found: C, 51.01; H, 3.72; N, 4.47.
Acknowledgements
This work was financially supported by National Natural Science
Foundation of China (20772079), Science and Technology Com-
mission of Shanghai Municipality (07JC14020, 07ZR14040,
08JC1409900) and Shanghai Municipal Education Commission.
4.2.15. Methyl 3-(6-chloro-2-(trifluoromethyl)-1H-indol-3-yl) prop-
anoate (4di0). White solid (5:1 petroleum ether/acetone); mp 78–
79 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.47 (br s, 1H), 7.58 (d, 1H,
J¼8.5 Hz), 7.36 (d, 1H, J¼2.0 Hz), 7.15 (dd, 1H, J¼8.5, 2.0 Hz), 3.67 (s,
3H), 3.21 (td, 2H, J¼8.0, 1.0 Hz), 2.65 (t, 2H, J¼8.0 Hz); 13C NMR
References and notes
2
(125 MHz, CDCl3):
d
173.3, 135.6, 131.0, 125.7, 122.5 (q, JC–F
¼
¼
1
3
37.5 Hz), 121.8, 121.7 (q, JC–F¼267.5 Hz), 121.2, 117.0 (q, JC–F
2.5 Hz), 111.8, 51.9, 35.3, 19.4; 19F NMR (470 MHz, CDCl3):
(s, 3F); IR (cmꢁ1):
1. (a) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008, 41, 817–829; (b)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
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d
ꢁ58.66
n
3323, 3035, 1723, 1589, 1441, 1201, 1160, 1112,
920, 802, 716. Anal. Calcd for C13H11ClF3NO2: C, 51.08; H, 3.63; N,
4.58. Found: C, 51.06; H, 3.62; N, 4.59.
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4.2.16. Methyl 4-(2-(trifluoromethyl)-1H-indol-3-yl)butanoate
(4ea). White solid (5:1 petroleum ether/acetone); mp 156–159 ꢀC;
1H NMR (500 MHz, CDCl3):
d
8.43 (br s, 1H), 7.68 (d, 1H, J¼8.0 Hz),
7.38 (d,1H, J¼8.0 Hz), 7.31 (ddd, 1H, J¼8.0, 8.0,1.0 Hz), 7.18 (ddd, 1H,
J¼8.0, 8.0, 1.0 Hz), 3.67 (s, 3H), 2.94 (t, 2H, J¼7.5 Hz), 2.38 (td, 2H,
J¼7.5, 1.0 Hz), 2.03 (t, 2H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3):
d
174.3, 135.5, 127.4, 124.8, 122.2 (q, 1JC–F¼267.5 Hz), 121.8 (q, 2JC–F
¼
3
37.5 Hz), 120.6, 120.3, 117.6 (q, JC–F¼2.5 Hz), 111.9, 51.7, 33.6, 25.8,
23.1; 19F NMR (470 MHz, CDCl3):
d
ꢁ58.15 (s, 3F); IR (cmꢁ1):
n 3341,
3062, 1720, 1590, 1454, 1382, 1200, 1161, 1115, 746.
4.2.17. Methyl 4-(5-fluoro-2-(trifluoromethyl)-1H-indol-3-yl) buta-
noate (4eb). White solid (5:1 petroleum ether/acetone); mp 110–
6. (a) Yang, Y.; Xu, R.; Ma, C.; Vlot, A. C.; Klessig, D. F.; Pichersky, E. Plant Physiol.
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112 ꢀC; 1H NMR (500 MHz, CDCl3):
d 8.49 (br s, 1H), 7.33–7.29 (m,
2H), 7.07 (dd, 1H, J¼9.0, 2.5 Hz), 3.68 (s, 3H), 2.89 (td, 2H, J¼7.5,
1.0 Hz), 2.38 (t, 2H, J¼7.5 Hz), 2.00 (t, 2H, J¼7.5 Hz); 13C NMR
(125 MHz, CDCl3):
d
173.9, 158.2 (d, 1JC–F¼235.0 Hz), 131.9, 127.9 (d,
2
1
3JC–F¼10.0 Hz), 123.4 (q, JC–F¼37.5 Hz), 121.9 (q, JC–F¼267.5 Hz),

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