Construction of pyrrole- and indole-fused CF3-piperazine derivatives

Article abstract of DOI:10.1016/j.jfluchem.2019.109361

A series of pyrrole- and indole-fused trifluoromethyl-functionalized piperazine derivatives were constructed in moderate to good yields with excellent chemoselectivities via a Pictet-Spengler reaction under mild and operationally simple conditions. The synthetic utility of this protocol was further extended by the facile preparation of indole-fused CF₃-1,4-diazocane and enantioenriched CF₃-piperazines via a vinylogous Pictet-Spengler reaction and an asymmetric Pictet-Spengler reaction, respectively.

Full text of DOI:10.1016/j.jfluchem.2019.109361

JournalofFluorineChemistry226(2019)109361
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short Communication
Construction of pyrrole- and indole-fused CF3-piperazine derivatives
⁎
⁎
Yu-Ting Tiana,b, Yu-Wei Zonga,b, Jing Niea,b, Fa-Guang Zhanga,b, , Jun-An Maa,b,
a Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Centre of Chemical Science & Engineering,
Tianjin University, Tianjin 300072, PR China
b Joint School of NUS & TJU, International Campus of Tianjin University, Fuzhou 350207, PR China
A B S T R A C T
A series of pyrrole- and indole-fused trifluoromethyl-functionalized piperazine derivatives were constructed in moderate to good yields with excellent chemos-
electivities via a Pictet-Spengler reaction under mild and operationally simple conditions. The synthetic utility of this protocol was further extended by the facile
preparation of indole-fused CF3-1,4-diazocane and enantioenriched CF3-piperazines via a vinylogous Pictet-Spengler reaction and an asymmetric Pictet-Spengler
reaction, respectively.
1. Introduction
2. Results and discussion
Piperzines are frequently found N-heterocyclic motifs within many
biologically active natural products and medicinally relevant com-
pounds [1]. As a result, significant attention has been devoted on the
preparation of various structurally diversified paperzine derivatives in
the past few decades [2]. In this context, the trifluoromethyl-functio-
nalized piperzines have emerged as an attractive type of useful scaffolds
in drug discovery owing to the unique CF3 effect on the physicochem-
ical and pharmaceutical properties of organic molecules [3–4]. For
instance, it has been demonstrated that the introduction of a CF3 group
at amine’s vicinal positions can potentially result in lower basicity,
higher metabolic stability, and decreased acute toxicity [5]. However,
the synthesis of CF3-piperazine derivatives with increased molecular
complexity, such as the fused variants, has remained as an unmet
challenge. Indeed, to the best of our knowledge, only Nenajdenko and
coworkers have reported the preparation of pyrrole-fused CF3-piper-
azines via a Pictet-Spengler reaction (Scheme 1a) [6–7]. Despite the
advance, the practicality of this method is largely restricted due to the
length synthesis of starting materials, long reaction time, and limited
substrate scope. Therefore, with our continuing interest in the chem-
istry of CF3-containing heterocycles [8], herein we report the facile
construction of both pyrrole- and indole-fused CF3-piperazine deriva-
tives via a Pictet-Spengler reaction under mild and operationally simple
conditions (Scheme 1b). Furthermore, this approach has also been
successfully extended to provide indole-fused CF3-1,4-diazocane and
enantioenriched CF3-piperazines via a novel vinylogous Pictet-Spengler
reaction and an asymmetric Pictet-Spengler reaction, respectively [9].
On the basis of our precedent studies on the reaction development
of trifluoroacetaldehyde methyl hemiacetal (TFMH 1) [10], N-ami-
noethylpyrrole 2a was chosen as the model substrate to react with
TFMH under acidic conditions. Pleasingly, the desired CF3-piperazine
3a was obtained in 40% yield when acetic acid was employed as the
catalyst at room temperature (Table 1, entry 1). Encouraged by this
result, a series of Brønsted acids were then evaluated in this Pictet-
Spengler reaction (entries 2–4), among which the best result was
identified with trifluoroacetic acid (75% yield, entry 3) [11]. It should
be noted that Lewis acids such as aluminium chloride or boron tri-
fluoride diethyl etherate could also catalyze this transformation, albeit
with low yields (entries 5 and 6). Further optimizations including
changing the additive, solvent, catalyst loadings, or reaction tempera-
ture, resulted in no significant improvements (entries 7–17). Finally,
gram-scale experiment was also conducted and smoothly produced 3a
in 70% yield (entry 18), thus illustrating the robust nature of this
protocol.
With the optimized conditions in hand, the generality of this reac-
tion was examined by varying substituents on the pyrrole ring. As
shown in Scheme 2, 2-methyl, 2-ethyl, and 2,4-dimethyl-substituted N-
aminoethylpyrroles all underwent the Pictet − Spengler reaction with
TFMH uneventfully, thus giving rise to the corresponding CF3-piper-
azines 3b−3d in 63 − 77% yields. It should be noted that no formation
of the undesired Friedel–Crafts side-product was observed for all the
pyrrole-derived substrates. Notably, the indole core represents a privi-
leged type of hetreocycles in natural products, pharmaceuticals, and
materials [12]. However, the synthesis of indole-fused CF3-piperazines
⁎ Corresponding authors at: Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Centre of
Chemical Science & Engineering, Tianjin University, Tianjin 300072, PR China.
E-mail addresses: zhangfg1987@tju.edu.cn (F.-G. Zhang), majun_an68@tju.edu.cn (J.-A. Ma).
https://doi.org/10.1016/j.jfluchem.2019.109361
Received 26 June 2019; Received in revised form 15 August 2019; Accepted 16 August 2019
Availableonline23August2019
0022-1139/©2019ElsevierB.V.Allrightsreserved.

Y.-T. Tian, et al.
JournalofFluorineChemistry226(2019)109361
Scheme 1. Construction of CF3-piperazine derivatives via the Pictet-Spengler reaction.
Table 1
a
Optimizations for the Pictet − Spengler reaction between N-aminoethylpyrrole 2a and TFMH 1
.
Entry
Catalyst
Solvent
Additive
Yield (%)b
1
CH3COOH
H3PO4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
Na2SO4
3 Å MS
5 Å MS
–
40
70
75
39
29
28
66
56
63
55
55
59
55
59
66
60
55
70
2
3
CF3COOH
p-MeC6H4SO3H
AlCl3
4
5
6
BF3•Et2O
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
7
8
9
10
11
12
13
14
15c
16d
17e
18f
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
toluene
THF
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a
Reaction conditions: 1 (1 mmol, 2 equiv), 2a (0.5 mmol, 1 equiv), catalyst (10 mol%), and additive (250 mg) in indicated solvent (3 mL) at rt for 24 h.
b
c
d
e
f
Isolated yield.
catalyst (5 mol%).
catalyst (20 mol%).
50 °C.
5 mmol scale of 2a was employed.
Scheme 2. Synthesis of pyrrole-fused CF3-piperazine derivatives.
2

Y.-T. Tian, et al.
JournalofFluorineChemistry226(2019)109361
Scheme 3. Synthesis of indole-fused CF3-piperazine derivatives.
haven’t been reported until now. With this concern in mind, a series of
N-aminoethylindoles were subsequently subjected to the aforemen-
tioned Pictet − Spengler reaction under otherwise identical conditions.
To our great delight, a broad range of CF3-containing indole-fused pi-
perazine derivatives 5a−5 j were obtained in 47 − 95% yields (Scheme
3). For instance, electron-donating groups on the 3-methylindole motif
at different positions rendered cyclization products in high yields with
exclusive chemoselectivities (5b−5e). The halogen-substituted sub-
strates are also compatible in this transformation and produced com-
pounds 5f and 5 g in 90% and 86% yield, respectively, thereby may
offering new possibilities for downstream cross-coupling-type manip-
ulations [13]. Furthermore, the indole partners bearing different sub-
stitution patterns at the 3-positions, including ethyl, benzyl, and
phenyl, all proved to be viable substrates and delivered 5 h−5 j in
decent to good yields with excellent chemoselectivities.
plain yield. The molecular structure of this compound was un-
ambiguously confirmed by X-ray crystallographic analysis [15].
Finally, a preliminary optimization on the enantioselective variant
of this intramolecular Pictet-Spengler reaction was also conducted. To
our delight, enantioenriched pyrrole-fused CF3-piperazine 3a could be
afforded with 72% ee in an improved yield compared with the racemic
version (86% vs 75%, Scheme 5) when 3,3′-bis(2,4,6-triisopropyl-
phenyl)-substituted spirocyclic phosphoric acid (STRIP) was employed
as the chiral Brønsted acid. The extension of this asymmetric protocol to
the generation of enantioenriched indole-fused CF3-piperazine 5a was
found to be with limited success (95%, 48% ee, Scheme 5), thus de-
serving further systematic evaluations. Nevertheless, these promising
initial results highlight the high potential of this approach for the rapid
construction of chiral CF3-piperazine derivatives.
In conclusion, we have developed an efficient method for the con-
struction of both pyrrole and indole-fused CF3-piperazines from tri-
fluoroacetaldehyde methyl hemiacetal and N-aminoethyl heterocyclic
components. This facile protocol takes advantages of trifluoroacetic acid
as a practical catalyst for the Pictet-Spengler reaction, featuring broad
substrate scope and operational convenience. Notably, a novel vinylo-
gous Pictet-Spengler reaction also proved workable and generated the
Subsequently, the synthetic utility of this method was further de-
monstrated by a novel vinylogous Pictet-Spengler reaction (Scheme 4).
The N-aminoethyl-2-vinylindole 6 was prepared in a few steps from 3-
methylindole according to know procedures [14]. Treatment of com-
pound 6 with TFMH and trifluoroacetic acid at room temperature could
smoothly furnish the indole-fused CF3-1,4-diazocane 7, albeit with
Scheme 4. Synthesis of indole-fused CF3-1,4-diazocane via the vinylogous Pictet-Spengler reaction.
3

Y.-T. Tian, et al.
JournalofFluorineChemistry226(2019)109361
Scheme 5. Synthesis of enantioenriched CF3-piperazine derivatives via enantioselective Pictet-Spengler reaction.
corresponding indole-fused CF3-1,4-diazocane. Furthermore, two re-
presentative enantioenriched CF3-piperazines were obtained via the
chiral phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction.
Further investigations including the substrate scope expansion and me-
chanistic studies are ongoing in our laboratory, the results of which will
be reported in due course.
2 H), 2.85 (q, J =7.5 Hz, 2 H), 1.40 (t, J =7.5 Hz, 3 H), 1.10 (s, 2 H).
13C NMR (101 MHz, CDCl3) δ 136.6, 128.1, 124.6, 121.6, 119.3, 118.7,
117.7, 109.3, 49.4, 42.3, 18.3, 14.7. HRMS (ESI) found m/z 189.1386
[M+H]+, calcd for C12H17N2 189.1392. IR (cm−1): 2962, 2361, 1597,
1466, 1370, 1077, 737, 693 cm-1.
3.2.2. 2-(1H-pyrrol-1-yl) ethan-1-amine (4i)
yellow oil; 0.86 g; 89% yield; 1H NMR (400 MHz, CDCl3) δ 7.59 (d,
J =7.9 Hz, 1 H), 7.40 – 7.30 (m, 5 H), 7.30 – 7.19 (m, 3 H), 7.14 (t, J
=7.4 Hz, 1 H), 6.88 (s, 1 H), 4.17 (s, 2 H), 4.12 (t, J =5.9 Hz, 3 H), 3.09
(t, J =5.9 Hz, 2 H), 1.08 (s, 2 H). 13C NMR (101 MHz, CDCl3) δ 141.4,
136.7, 128.8, 128.4, 128.2, 126.4, 126.0, 121.8, 119.5, 119.1, 114.7,
3. Experimental section
3.1. General information
1H, 13C and 19F were recorded on Bruker AV 400 MHz instrument at
109.4, 49.5, 42.3, 31.6. HRMS (ESI) found m/z 251.1549 [M+H]+
,
400 MHz (1H NMR), 101 MHz (13C NMR), as well as 376 MHz (19
F
calcd for C17H9N2 251.1548. IR (cm−1): 2902, 2361, 1466, 1331, 1074,
NMR). Chemical shifts were reported in ppm down field from internal
Me4Si and external CCl3F, respectively. Multiplicity was indicated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublet), br (broad). Coupling constants were reported in
Hertz (Hz). MS were recorded on a VG ZABHS spectrometer with the
ESI resource. High resolution mass spectrometry (HRMS) spectra were
obtained on a Bruker miorOTOF-QII instrument. X-ray structural ana-
lysis was conducted on the Bruker APEX-II CCD instrument. Optical
rotations were determined using an Autopol IV-T. HPLC analyses were
carried out on a HewlettPackard Model HP 1200 instrument. Infrared
spectroscopies (IR) were conducted on a bruker vertex70 instrument.
Tetrahydrofuran (THF), diethyl ether, and toluene were distilled
from sodium/benzophenone prior to use; CH2Cl2 was distilled from
CaH2; All purchased reagents were used without further purification.
Analytical thin layer chromatography was performed on 0.20 mm
Qingdao Haiyang silica gel plates. Silica gel (200–300 mesh) (from
Qingdao Haiyang Chem. Company, Ltd.) was used for flash chromato-
graphy. Various substituted 3-methyl-1H-indoles, 3-ethyl-1H-indole, 3-
phenyl-1H-indole, 3-benzyl-1H-indole, aminoethyl pyrroles [16][7i]
were prepared according to the reported procedures.
735, 699 cm-1.
3.3. General procedure for the synthesis of pyrrole- and indole-fused CF3-
piperazine derivatives 3 and 5
To a 10 mL Schlenk flask equipped with a stirring bar was added
aminoethyl pyrroles 2 or 4 (0.5 mmol, 1.0 equiv), trifluoroacetaldehyde
methyl hemiacetal 1 (95 μL, 1.0 mmol, 2.0 equiv), 4 Å molecular sieves
(250 mg), and CH2Cl2 (3.0 mL). Then, trifluoroacetic acid (7.4 μL,
0.05 mmol, unless otherwise noted) was added to the mixture. The
resulting mixture was stirred at room temperature until the completion
of the reaction (monitored by TLC). The mixture was concentrated
under vacuum, and the residue was purified by flash column chroma-
tography on silica gel (eluted with petroleum ether / ethyl acetate = 10
/ 1) to give the desired product 3 or 5.
3.3.1. 1-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine (3a)
white solid; 71.3 mg; 75% yield; m.p.: 76−78 °C; 1H NMR
(400 MHz, CDCl3) δ 6.64 (t, J =2.4 Hz, 1 H), 6.21 – 6.18 (m, 1 H), 6.17
– 6.16 (m, 1 H), 4.62 (q, J =7.6 Hz, 1 H), 4.03 – 3.89 (m, 1 H), 3.45 –
3.39 (m, 1 H), 3.23 – 3.13 (m, 1 H), 1.97 (s, 1 H). 19F NMR (376 MHz,
CDCl3) δ -75.56 (d, J =7.6 Hz). 13C NMR (101 MHz, CDCl3) δ 125.5 (q,
J =281.9 Hz), 120.6, 119.5, 108.4, 106.8, 54.3 (q, J =30.4 Hz), 45.4,
41.1. HRMS (ESI) found m/z 191.0800 [M+H]+, calcd for C8H10N2F3
191.0796. IR (cm−1): 2360, 1267, 1158, 1115, 1076, 847, 755, 725,
3.2. General Procedure for Synthesis of N-aminoethyl pyrroles 2 and N-
aminoethyl indoles 4
To a solution of the corresponding pyrrole or indole derivative
(10 mmol) in MeCN (30 ml) was added sodium hydroxide (2.00 g,
50 mmol) and tetrabutylamonium hydrogen sulfate (0.17 g, 0.5 mmol).
After the solution was stirred at room temperature for 30 min, 2-
chloroethylamine hydrochloride (1.39 g, 12 mmol) was added. Then
the reaction mixture was refluxed for 24 h. The mixture was poured into
water (100 mL), extracted with diethyl ether, dried under MgSO4, and
concentrated under reduced pressure to give a crude product. The crude
was then purified by flash column chromatography on silica gel (eluted
with petroleum ether / ethyl acetate = 1 : 1) to give the pure product.
675 cm−1
.
3.3.2. 6-methyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine
(3b)
yellow solid; 68.4 mg; 67% yield; m.p.: 52–53 °C; 1H NMR (400 MHz,
CDCl3) δ 6.10 – 6.06 (m, 1 H), 5.91 (d, J =3.5 Hz, 1 H), 4.60 (q, J
=7.6 Hz, 1 H), 3.85 – 3.79 (m, 1 H), 3.77 – 3.69 (m, 1 H), 3.47 – 3.37 (m,
1 H), 3.24 – 3.13 (m, 1 H), 2.20 (s, 3 H), 2.04 (s, 1 H). 19F NMR
(376 MHz, CDCl3) δ -75.51 (d, J =7.6 Hz). 13C NMR (101 MHz, CDCl3) δ
128.5, 125.6 (q, J =282.4 Hz), 118.4, 106.33, 106.0 (d, J =1.5 Hz), 54.4
(q, J =30.4 Hz), 42.6, 40.9, 11.6. HRMS (ESI) found m/z 205.0951 [M
+H]+, calcd for C9H12N2F3 205.0953. IR (cm−1): 2361, 1266, 1156,
3.2.1. 2-(3-ethyl-1H-inden-1-yl) ethan-1-amine (4 h)
yellow oil; 4.76 g; 85% yield; 1H NMR (400 MHz, CDCl3) δ 7.67 (d,
J =7.9 Hz, 1 H), 7.36 (d, J =8.2 Hz, 1 H), 7.29 – 7.21 (m, 1 H), 7.21 –
7.09 (m, 1 H), 6.95 (s, 1 H), 4.14 (t, J =5.9 Hz, 2 H), 3.10 (t, J =5.9 Hz,
1115, 1086, 1060, 1026, 912, 852, 754, 722, 682, 625 cm−1
.
4

Y.-T. Tian, et al.
JournalofFluorineChemistry226(2019)109361
3.3.3. 6-ethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo
[1,2-a]
3.3.8. 7,10-dimethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino [1,2-
pyrazine (3c)
a] indole (5d)
yellow solid; 84.0 mg; 77% yield; m.p.: 39–40 °C; 1H NMR
(400 MHz, CDCl3) δ 6.13 (s, 1 H), 5.96 (d, J =2.9 Hz, 1 H), 4.63 (q, J
=7.5 Hz, 1 H), 3.90 – 3.80 (m, 1 H), 3.80 – 3.72 (m, 1 H), 3.49 – 3.35
(m, 1 H), 3.26 – 3.14 (m, 1 H), 2.57 (q, J =7.4 Hz, 2 H), 2.10 (s, 1 H),
1.28 (t, J =7.4 Hz, 3 H). 19F NMR (376 MHz, CDCl3) δ -75.47 (d, J
=7.5 Hz). 13C NMR (101 MHz, CDCl3) δ 134.8, 125.6 (q, J =282.0 Hz),
118.5, 105.9 (d, J =1.4 Hz), 104.5, 54.4 (q, J =30.2 Hz), 42.6, 40.9,
19.2, 12.7. HRMS (ESI) found m/z 219.1119 [M+H]+, calcd for
white solid; 119.4 mg; 89% yield; m.p.: 71–72 °C; 1H NMR
(400 MHz, CDCl3) δ 7.47 (d, J =8.0 Hz, 1 H), 7.09 (s, 1 H), 6.99 (d, J
=7.5 Hz, 1 H), 4.72 (q, J =8.1 Hz, 1 H), 4.20 – 4.12 (m, 1 H), 3.84 –
3.75 (m, 1 H), 3.68 – 3.57 (m, 1 H), 3.28 – 3.20 (m, 1 H), 2.50 (s, 3 H),
2.26 (s, 3 H), 1.57 (s, 1 H). 19F NMR (376 MHz, CDCl3) δ -71.54 (d, J
=8.1 Hz). 13C NMR (101 MHz, CDCl3) δ 137.6, 132.1, 126.4 (q, J
=286.7 Hz), 126.5, 122.4, 121.6, 118.8, 110.0, 109.2, 52.7 (q, J
=30.0 Hz), 42.5, 39.4, 22.0, 9.0 (q, J =2.3 Hz). HRMS (ESI) found m/z
269.1276 [M+H]+, calcd for C14H16N2F3 269.1266. IR (cm−1): 2360,
C
10H14N2F3 219.1109. IR (cm−1): 2360, 1265, 1157, 1130, 1090,
1061, 1040, 910, 854, 754, 723, 682, 625 cm−1
.
1456, 1343, 1303, 1247, 1116, 793, 634, 576 cm−1
.
3.3.9. 8-(benzyloxy)-10-methyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino
[1,2-a] indole (5e)
3.3.4. 6,8-dimethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo [1,2-a]
pyrazine (3d)
white solid; 138.7 mg; 77% yield; m.p.: 72–74 °C; 1H NMR
(400 MHz, CDCl3) δ 7.54 (d, J =7.3 Hz, 2 H), 7.44 (t, J =7.4 Hz, 2 H),
7.37 (t, J =7.2 Hz, 1 H), 7.22 (d, J =8.8 Hz, 1 H), 7.17 (d, J =1.9 Hz,
1 H), 7.03 (dd, J = 8.7, 2.1 Hz, 1 H), 5.17 (s, 2 H), 4.72 (q, J =8.1 Hz,
1 H), 4.20 – 4.05 (m, 1 H), 3.83 – 3.70 (m, 1 H), 3.69 – 3.56 (m, 1 H),
3.22 (d, J =12.3 Hz, 1 H), 2.29 (s, 3 H), 2.24 (s, 1 H). 19F NMR
(376 MHz, CDCl3) δ -71.32 (d, J =8.1 Hz). 13C NMR (101 MHz, CDCl3)
yellow solid; 68.7 mg; 63% yield; m.p.: 39–40 °C; 1H NMR
(400 MHz, CDCl3) δ 5.76 (s, 1 H), 4.50 (q, J =8.0 Hz, 1 H), 3.85 – 3.79
(m, 1 H), 3.69 – 3.59 (m, 1 H), 3.52 – 3.43 (m, 1 H), 2.16 (s, 3 H), 2.01
(s, 3 H), 0.83 (s, 1 H). 19F NMR (376 MHz, CDCl3) δ -72.58 (d, J
=7.9 Hz). 13C NMR (101 MHz, CDCl3) δ 128.7, 126.5 (q, J =285.8 Hz),
116.7, 114.9, 112.4, 108.5, 52.5 (q, J =29.9 Hz), 42.5, 39.6, 11.5.
HRMS (ESI) found m/z 219.1117 [M+H]+, calcd for C10H14N2F3
219.1109. IR (cm−1): 2360, 1266, 1115, 1085, 1059, 1026, 911, 852,
δ
153.7, 137.8, 132.7, 128.8, 128.7, 127.9, 127.7, 126.3 (q, J
=287.2 Hz), 123.9, 113.0, 109.9, 109.7, 102.7, 71.2, 52.6 (q, J
=30.0 Hz), 42.5, 39.2, 9.0 (q, J =2.3 Hz). HRMS (ESI) found m/z
361.1534 [M+H]+, calcd for C20H20N2OF3 361.1528. IR (cm−1):
755,721, 682, 625 cm−1
.
2360, 1453, 1344, 1255, 1118, 1023, 933, 832, 796, 731, 695 cm−1
.
3.3.5. 10-methyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino [1,2-a]
indole (5a)
3.3.10. 8-chloro-10-methyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino
[1,2-a] indole (5f)
white solid; 114.4 mg; 90% yield; m.p.: 97–98 °C; 1H NMR
(400 MHz, CDCl3) δ 7.52 (d, J =7.9 Hz, 1 H), 7.23 (d, J =8.1 Hz, 1 H),
7.20 – 7.14 (m, 1 H), 7.12 – 7.04 (m, 1 H), 4.67 (q, J =8.1 Hz, 1 H),
4.18 – 4.10 (m, 1 H), 3.81 – 3.71 (m, 1 H), 3.65 – 3.42 (m, 1 H), 3.27 –
3.09 (m, 1 H), 2.22 (s, 3 H), 1.97 (s, 1 H). 19F NMR (376 MHz, CDCl3) δ
-71.42 (d, J =8.1 Hz). 13C NMR (101 MHz, CDCl3) δ 137.1, 128.6,
126.3 (q, J =286.5 Hz), 123.2, 122.2, 119.9, 119.1, 110.2, 109.1, 52.7
(q, J =29.9 Hz), 42.5, 39.3, 9.0. HRMS (ESI) found m/z 255.1120 [M
+H]+, calcd for C13H14N2F3 255.1109. IR (cm−1): 2360, 1451, 1319,
0.5 equivalent of trifluoroacetic acid (18 μL, 0.25 mmol) was em-
ployed for the preparation of this compound; white solid; 129.9 mg;
90% yield; m.p.: 121–122 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1 H),
7.22 – 7.13 (m, 2 H), 4.73 (q, J =7.8 Hz, 1 H), 4.18 – 4.11 (m, 1 H),
3.88 – 3.72 (m, 1 H), 3.69 – 3.57 (m, 1 H), 3.26 (d, J =11.9 Hz, 1 H),
2.30 (s, 1 H), 2.25 (s, 3 H). 19F NMR (376 MHz, CDCl3) δ -71.32 (d, J
=8.0 Hz). 13C NMR (101 MHz, CDCl3) δ 135.5, 129.6, 126.2 (q, J
=286.6 Hz), 125.6, 124.6, 122.5, 118.7, 110.1, 109.8, 52.7 (q, J
=30.1 Hz), 42.6, 39.1, 8.9 (q, J =2.3 Hz). HRMS (ESI) found m/z
289.0733 [M+H]+, calcd for C13H13N2F3Cl 289.0719. IR (cm−1):
1255, 1136, 1082, 1011, 966, 883, 748, 684, 624, 543 cm−1
.
2361, 1452, 1247, 1117, 865, 792, 668 cm−1
.
3.3.6. 9,10-dimethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino [1,2-
a] indole (5b)
white solid; 124.8 mg; 93% yield; m.p.: 136–137 °C; 1H NMR
(400 MHz, CDCl3) δ 7.16 – 7.07 (m, 2 H), 6.90 – 6.82 (m, 1 H), 4.74 (q,
J =8.1 Hz, 1 H), 4.21 – 4.13 (m, 1 H), 3.84 – 3.74 (m, 1 H), 3.71 – 3.57
(m, 1 H), 3.29 – 3.20 (m, 1 H), 2.74 (s, 3 H), 2.47 (s, 2 H), 2.27 (s, 1 H).
19F NMR (376 MHz, CDCl3) δ -71.30 (d, J =7.7 Hz). 13C NMR
(101 MHz, CDCl3) δ 137.7, 131.8, 129.2 (q, J =286.5 Hz), 126.9,
123.1, 122.3, 121.6, 111.1, 107.1, 52.4 (q, J =29.8 Hz), 42.5, 39.3,
3.3.11. 8-bromo-10-methyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino
[1,2-a] indole (5 g)
0.5 equivalent of trifluoroacetic acid (18 μL, 0.25 mmol) was em-
ployed for the preparation of this compound; white solid; 143.3 mg;
86% yield; m.p.: 114–115 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J
=1.5 Hz, 1 H), 7.31 (dd, J = 8.6, 1.8 Hz, 1 H), 7.16 (d, J =8.6 Hz, 1 H),
4.73 (q, J =8.1 Hz, 1 H), 4.24 – 4.09 (m, 1 H), 3.87 – 3.76 (m, 1 H),
3.68 – 3.57 (m, 1 H), 3.26 (d, J =12.3 Hz, 1 H), 2.30 (s, 1 H), 2.24 (s,
3 H). 19F NMR (376 MHz, CDCl3) δ -71.33 (d, J =7.8 Hz). 13C NMR
(101 MHz, CDCl3) δ 135.7, 130.2, 126.2 (q, J =287.9 Hz). 125.0,
124.4, 121.8, 113.1, 110.6, 109.8, 52.7 (q, J =30.1 Hz), 42.6, 39.1, 8.9
(q, J =2.2 Hz). HRMS (ESI) found m/z 355.0035 [M + Na]+, calcd for
20.6, 12.0 (q, J =2.2 Hz). HRMS (ESI) found m/z 269.1277 [M+H]+
,
calcd for C14H16N2F3 269.1266. IR (cm−1): 2361, 1307, 1255, 1165,
1128, 1084, 861, 774, 748, 699, 649 cm−1
.
3.3.7. 8,10-dimethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino [1,2-
a] indole (5c)
C
13H12BrN2F3 Na 355.0028. IR (cm−1): 2967, 2360, 1450, 1337, 1244,
1115, 1092, 913, 867, 824, 791, 717, 657, 605 cm−1
.
white solid; 127.4 mg; 95% yield; m.p.: 84–86 °C; 1H NMR
(400 MHz, CDCl3) δ 7.37 (s, 1 H), 7.19 (d, J =8.3 Hz, 1 H), 7.07 (dd,
J = 8.3, 1.2 Hz, 1 H), 4.73 (q, J =8.2 Hz, 1 H), 4.21 – 4.14 (m, 1 H),
3.86 – 3.75 (m, 1 H), 3.68 – 3.58 (m, 1 H), 3.29 – 3.18 (m, 1 H), 2.47 (s,
3 H), 2.26 (s, 3 H), 1.57 (s, 1 H). 19F NMR (376 MHz, CDCl3) δ -71.46
(d, J =8.1 Hz). 13C NMR (101 MHz, CDCl3) δ 135.7, 129.2, 128.8,
126.4 (q, J =286.4 Hz), 123.8, 123.3, 118.8, 109.7, 108.9, 52.7 (q, J
=30.0 Hz), 42.6, 39.4, 21.7, 9.0 (q, J =2.2 Hz). HRMS (ESI) found m/z
269.1278 [M+H]+, calcd for C14H16N2F3 269.1266. IR (cm−1): 2969,
3.3.12. 10-ethyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino [1,2-a]
indole (5 h)
0.5 equivalent of trifluoroacetic acid (18 μL, 0.25 mmol) was em-
ployed for the preparation of this compound; yellow oil; 63.0 mg; 47%
yield; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J =7.9 Hz, 1 H), 7.33 –
7.19 (m, 2 H), 7.18 – 7.10 (m, 1 H), 4.75 (q, J =8.2 Hz, 1 H), 4.23 –
4.11 (m, 1 H), 3.87 – 3.76 (m, 1 H), 3.70 – 3.50 (m, 1 H), 3.22 (d, J
=12.6 Hz, 1 H), 2.92 – 2.63 (m, 2 H), 2.37 (s, 1 H), 1.28 (t, J =7.5 Hz,
3 H). 19F NMR (376 MHz, CDCl3) δ -71.52 (d, J =8.2 Hz). 13C NMR
2360, 1343, 1247, 1116, 794, 702, 575 cm−1
.
5

Y.-T. Tian, et al.
JournalofFluorineChemistry226(2019)109361
(101 MHz, CDCl3) δ 137.5, 127.7, 126.0 (q, J =286.5 Hz), 122.5,
122.2, 119.8, 119.7, 116.8, 109.3, 52.7 (q, J =29.9 Hz), 42.5, 39.2,
17.9, 14.9. HRMS (ESI) found m/z 291.1085 [M + Na]+, calcd for
(9.5 g, 35 mmol) in THF (60 mL) under ice cooling. The mixture was
stirred at room temperature for 1 h and then a solution of benzoic an-
hydride (9.5 g, 42 mmol) in THF (60–100 mL) was added at −78 °C.
The mixture was gradually warmed to room temperature. After the
stirring had been continued at the same temperature for 10–14 h, the
mixture was poured into water and extracted with ethyl acetate. The
extract was washed with water, dried over Na2SO4, and evaporated to
give (3-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)(phenyl)-methanone I-
2 (52% yield).
C
14H15F3N2Na 291.1080. IR (cm−1): 2968, 2360, 1453, 1350, 1255,
1119, 741 cm−1
.
3.3.13. 10-benzyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino [1,2-a]
indole (5i)
white solid; 92.5 mg; 56% yield; m.p.: 90–92 °C; 1H NMR
(400 MHz, CDCl3) δ 7.38 (d, J =7.9 Hz, 1 H), 7.33 (d, J =8.2 Hz, 1 H),
7.26 – 7.21 (m, 3 H), 7.21 – 7.14 (m, 3 H), 7.10 – 7.03 (m, 1 H), 4.67 (q,
J =8.1 Hz, 1 H), 4.31 – 4.21 (m, 1 H), 4.19 – 4.08 (m, 2 H), 3.96 – 3.87
(m, 1 H), 3.70 – 3.58 (m, 1 H), 3.29 – 3.21 (m, 1 H), 2.27 (s, 1 H). 19F
NMR (376 MHz, CDCl3) δ -70.94 (d, J =8.1 Hz). 13C NMR (101 MHz,
A mixture of the obtained material I-2, 10% NaOH (30 mL), and
ethanol (100 mL) was refluxed for 14 h. The solvent was evaporated
and the resulting residue was extracted with ethyl acetate. The extract
was washed with water, dried over Na2SO4, and evaporated to give (3-
methyl-1H-indol-2-yl) (phenyl) methanone I-3 (67% yield).
To a stirred solution of methylenetriphenylphosphorane [prepared
from methyltriphenylphosphonium bromide (3.93 g, 11 mmol) and
LiHMDS (10.67 mL of 1.0 M hexane solution, 11 mmol) in THF under
ice cooling] was added a solution of I-3 (9.4 mmol) in THF (30–60 mL)
under ice cooling. The mixture was warmed to room temperature and
kept under stirring for 14 h at the same temperature. The mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with water, dried over Na2SO4. The solvent was evaporated to
give I-4 (32% yield).
CDCl3)
δ
140.6, 137.3, 128.6, 128.5, 128.1, 126.2 (q,
J
=286.6 Hz).126.1, 124.2, 122.3, 120.1, 119.9, 113.1, 109.2, 52.7 (q, J
=30.0 Hz), 42.5, 39.1, 30.2 (q, J =2.2 Hz). HRMS (ESI) found m/z
331.1429 [M+H]+, calcd for C19H18N2F3 331.1422. IR (cm−1): 2361,
1307, 1255, 1165, 1128, 1084, 861, 774, 748, 699, 649 cm−1
.
3.3.14. -phenyl-1-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino
[1,2-a]
indole (5 j)
0.5 equivalent of trifluoroacetic acid (18 μL, 0.25 mmol) was em-
ployed for the preparation of this compound; white solid; 139.2 mg;
88% yield; m.p.: 195–196 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J
=7.9 Hz, 1 H), 7.46 (d, J =4.2 Hz, 4 H), 7.42 – 7.27 (m, 3 H), 7.18 (t, J
=7.4 Hz, 1 H), 5.08 (q, J =7.9 Hz, 1 H), 4.35 – 4.26 (m, 1 H), 4.09 –
3.97 (m, 1 H), 3.74 – 3.62 (m, 1 H), 3.32 (d, J =12.5 Hz, 1 H), 2.27 (s,
1 H). 19F NMR (376 MHz, CDCl3) δ -71.36 (d, J =7.9 Hz). 13C NMR
(101 MHz, CDCl3) δ 136.9, 134.7, 129.7, 128.9, 127.7, 126.8, 126.0 (q,
J =286.5 Hz). 123.2, 122.7, 120.7, 119.9, 117.12, 109.2, 52.6 (q, J
To a solution of previously prepared 3-methyl-2-(1-phenylvinyl)-
1H-indole I-4 (3 mmol) in MeCN (10 mL) was added sodium hydroxide
(0.60 g, 15 mmol) and tetrabutylamonium hydrogen sulfate (TBAS,
51 mg, 0.15 mmol). After the solution was stirred at room temperature
for 30 min, 2-chloroethylamine hydrochloride (0.42 g, 3.6 mmol) was
added. Then the reaction mixture was refluxed for 24 h. The mixture
was poured into water (100 mL), then extracted with ether, dried under
MgSO4 and concentrated under reduced pressure to give a crude pro-
duct. The crude was then purified by flash column chromatography on
silica gel (eluted with petroleum ether / ethyl acetate = 1 : 1) to give
the pure product 2-(3-methyl-2-(1-phenylvinyl)-1H-indol-1-yl)ethan-1-
amine 6 (93% yield).
=30.1 Hz), 42.5, 39.3. HRMS (ESI) found m/z 317.1274 [M+H]+
,
calcd for C18H16N2F3 317.1266. IR (cm−1): 2361, 1452, 1323, 1255,
1178, 1150, 1121, 1011, 889, 766, 750, 628, 565 cm−1
.
To a 10 mL Schlenk flask equipped with a stirring bar was added 2-(3-
methyl-2-(1-phenylvinyl)-1H-indol-1-yl) ethan-1-amine 6 (0.5 mmol, 1.0
equiv), trifluoroacetaldehyde methyl hemiacetal 1 (95 μL, 1.0 mmol, 2.0
equiv), 4 Å molecular sieves (250 mg), and CH2Cl2 (3.0 mL). Then, tri-
fluoroacetic acid (22 μL, 0.5 mmol) was added to the mixture. The re-
sulting mixture was stirred at room temperature until the completion of
the reaction (monitored by TLC, 24 h). Concentration under vacuum, and
the residue was purified by flash column chromatography on silica gel
(eluted with petroleum ether / ethyl acetate = 10 / 1) to give the desired
product 7.
3.4. Synthesis of indole-fused CF3-1,4-diazocane 7
3.4.1. 2-(3-methyl-2-(1-phenylvinyl)-1H-indol-1-yl) ethan-1-amine (6)
yellow solid; 0.8 g; 93% yield; m.p.: 64–65 °C; 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, J =7.7 Hz, 1 H), 7.49 – 7.36 (m, 7 H), 7.35 – 7.28 (m,
1 H), 6.21 (d, J =1.4 Hz, 1 H), 5.59 (d, J =1.4 Hz, 1 H), 3.97 (t, J
=6.6 Hz, 2 H), 2.92 (t, J =6.6 Hz, 2 H), 2.49 (s, 3 H), 0.93 (s, 2 H). 13
C
Sodium hydride (60% dispersion in mineral oil, 1.3 g, 33 mmol) was
added portionwise to a solution of 3-methylindole (4 g, 30 mmol) in
DMF (50 mL), keeping the temperature below 30 °C. After stirring for
15 min at room temperature, a solution of phenylsulphonyl chloride
(4.7 mL, 37 mmol) in DMF (20 mL) was added dropwise. The mixture
was stirred at room temperature for 2 h, then the solvent was evapo-
rated under vacuo. The residue was quenched with water and extracted
exhaustively over methylene dichloride. The combined organic layer
was dried over sodium sulphate, then the solvent was removed under
reduced pressure. The crude residue was purified by column chroma-
tograph on silica gel (eluted with methylene dichloride / hexane = 1 /
1) to give the pure product 1-(phenylsulphonyl)-3 methylindole I-1
(86% yield).
NMR (101 MHz, CDCl3) δ 140.1, 139.7, 136.6, 136.6, 128.6, 128.5,
128.2, 126.4, 121.8, 119.4, 119.1, 119.0, 110.2, 109.4, 47.2, 42.0, 9.3.
HRMS (ESI) found m/z 277.1696 [M+H]+
,
calcd for C19H20N2
.
277.1699. IR (cm−1): 2360, 1680, 669, 755 cm−1
3.4.2. (Z)-7-methyl-6-phenyl-4-(trifluoromethyl)-1,2,3,4-tetrahydro- [1,4]
diazocino [1,8-a] indole (7)
white solid; 55.0 mg; 30% yield; m.p.: 167–168 °C; 1H NMR
(400 MHz, CDCl3) δ 7.62 (d, J =7.9 Hz, 1 H), 7.41 – 7.27 (m, 7 H), 7.24
– 7.18 (m, 1 H), 6.42 (d, J =9.2 Hz, 1 H), 4.52 (dd, J = 15.3, 4.0 Hz,
1 H), 3.97 (dd, J = 15.4, 10.5 Hz, 1 H), 3.46 (dd, J = 14.9, 4.1 Hz, 1 H),
3.39 – 3.26 (m, 1 H), 3.00 (dd, J = 14.8, 10.6 Hz, 1 H), 1.94 (s, 3 H),
1.61 (s, 1 H). 19F NMR (376 MHz, CDCl3) δ -76.65 (d, J =7.6 Hz). 13C
NMR (101 MHz, CDCl3) δ 139.2, 137.7, 135.9, 133.4, 128.6, 128.3,
127.1, 125.3 (q, J =280.8 Hz), 125.0, 122.3, 119.7, 119.1, 110.1,
To a solution of LDA [prepared from diisopropylamine (3.89 g,
38.5 mmol) and nBuLi (25.7 mL of 1.5 M hexane solution, 38.5 mmol) in
THF] was added a solution of 1-(phenylsulphonyl)-3 methylindole I-1
6

Y.-T. Tian, et al.
JournalofFluorineChemistry226(2019)109361
109.0, 57.9 (q, J =30.3 Hz), 48.6, 47.8, 9.3. HRMS (ESI) found m/z
357.1576 [M+H]+, calcd for C21H20F3N2 357.1573. IR (cm−1): 2919,
2360, 1444, 1349, 1258, 1166, 1121, 1088, 967, 878, 792, 747, 720,
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3.5. Synthesis of enantioenriched pyrrole- and indole-fused CF3-piperazine
3a and 5a
To
a 10 mL Schlenk flask equipped with a stirring bar was
added aminoethyl pyrroles 2a or 4a (0.5 mmol, 1.0 equiv), tri-
fluoroacetaldehyde methyl hemiacetal 1 (95 μL, 1.0 mmol, 2.0 equiv),
5 Å molecular sieves (250 mg), STRIP (36 mg, 0.05 mmol). Then, THF
or CH2Cl2 (3.0 mL) was added to the mixture. The resulting mixture was
stirred at room temperature until the completion of the reaction
(monitored by TLC). The mixture was concentrated under vacuum, and
the residue was purified by flash column chromatography on silica gel
(eluted with petroleum ether / ethyl acetate = 10 / 1) to give the de-
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yellow solid; 81.8 mg; 86% yield; 72% ee; [determined by HPLC
analysis Daicel Chirapak AD-H, n-hexane/i-PrOH = 80/20, 254 nm UV
detector, 1.0 mL/min, t1 = 8.2 min (major) and t2 = 11.3 min (minor)].
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20
[α]D –29.6 (c 1.0, CH2Cl2).
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yellow solid; 120.8 mg; 95% yield; 48% ee; [determined by HPLC
analysis Daicel Chirapak AD-H, n-hexane/i-PrOH = 80/20, 254 nm UV
detector, 1.0 mL/min, t1 = 7.2 min (major) and t2 = 10.2 min (minor)].
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Acknowledgments
[11] Although 2 equivalents of trifluoroacetaldehyde methyl hemiacetal was employed,
the competitive reaction of fluoral into 5-position of pyrrole was not observed
throughout our study. Moreover, no conversion was observed when compound 3a
was treated with trifluoroacetaldehyde methyl hemiacetal under otherwise iden-
tical conditions.
This work was supported by the National Natural Science
Foundation of China (Nos. 21472137, 21532008, and 21772142) and
the National Basic Research Program of China (973 Program,
2014CB745100).
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Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.jfluchem.2019.
109361.
[14] 0.5 equivalent of trifluoroacetic acid was employed for the smooth formation of
compounds 5f-5h and 5j.
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[16] CCDC 1935476 contains the supplementary crystallographic data for compound 7.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(c) W.-Y. Siau, J.W. Bode, J. Am. Chem. Soc. 136 (2014) 17726–17729.
[4] (a) J.-A. Ma, D. Cahard, Chem. Rev. 104 (2004) 6119–6146;
7