Convenient preparation of 1-(indol-3-yl)-2,2,2-trifluoroethylamines via Friedel-Crafts reaction of α-trifluoroacetaldehyde hemiaminal

Article abstract of DOI:10.1016/S0022-1139(00)00407-3

Electrophilic substitution of indole with trifluoroacetaldehyde hemiaminals 1a-f, prepared from primary amines and trifluoroacetaldehyde ethyl hemiacetal (TFAE), proceeds readily in the presence of Lewis acids. Formation of N-alkyl 1-(indol-3-yl)-2,2,2-trifluoroethylamines (2) is preferred in the presence of BF₃, but yield of 2,2,2-trifluoroethyl alcohol (3) markedly increases when ZnI₂ is used. A stereochemistry study clearly showed that ethylamines 2e and 2f are produced with high diastereoselective excess when the optically active hemiaminals 1e and 1f are used.

Full text of DOI:10.1016/S0022-1139(00)00407-3

Journal of Fluorine Chemistry 108 (2001) 83±86
Convenient preparation of 1-(indol-3-yl)-2,2,2-tri¯uoroethylamines via
Friedel±Crafts reaction of a-tri¯uoroacetaldehyde hemiaminal
Yuefa Gong*, Katsuya Kato
National Industrial Research Institute of Nagoya, Hirate-cho, Kita-ku, Nagoya 462-8510, Japan
Received 28 August 2000; received in revised form 17 October 2000; accepted 27 November 2000
Abstract
Electrophilic substitution of indole with tri¯uoroacetaldehyde hemiaminals 1a±f, prepared from primary amines and tri¯uoroacetalde-
hyde ethyl hemiacetal (TFAE), proceeds readily in the presence of Lewis acids. Formation of N-alkyl 1-(indol-3-yl)-2,2,2-
tri¯uoroethylamines (2) is preferred in the presence of BF3, but yield of 2,2,2-tri¯uoroethyl alcohol (3) markedly increases when ZnI2
is used. A stereochemistry study clearly showed that ethylamines 2e and 2f are produced with high diastereoselective excess when the
optically active hemiaminals 1e and 1f are used. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: a-Tri¯uoromethyl hemiaminal; Friedel±Crafts reaction; Indole; a-Tri¯uoromethyl amine
1. Introduction
TFAE. The reaction of isopropylamine with TFAE was ®rst
done at room temperature for 4 h, N-isopropyl hemiaminal
1
Much attention has been devoted to the preparation of new
tri¯uoromethylated compounds because of their potential
important applications in the pharmaceutical, agrochemical
and material sciences. Many methods and reagents, e.g.
CF3SiMe3, the hemiacetal and other derivatives of tri¯uor-
oacetaldehyde [1±3], have been developed over past decades
for the preparation of a-tri¯uoromethyl carbinols. In con-
trast, little has been reported on the synthesis of a-tri¯uor-
omethyl amines [4±6].
We found that the reaction of electron-rich heteroarenes
with tri¯uoroacetaldehyde ethyl hemiacetal (TFAE) is an
ef®cient way to prepare 1-heteroaryl-2,2,2-tri¯uoroethyl
alcohols [7]. Recently, we have turned to the synthesis of
a-tri¯uoromethyl amines and investigated the possibility of
obtaining 1-heteroaryl-2,2,2-tri¯uoroethyl amines via the
Mannich-like reaction done with indole, isopropylamine
and TFAE. Here, we report a convenient way of preparing
1-(indol-3-yl)-2,2,2-tri¯uoroethyl amines by the Friedel±
Crafts reaction of indole with tri¯uoroacetaldehyde hemi-
aminals.
(1b) being formed in good yield as shown by H and 19F
NMR. This means the following equilibrium (1) lies mark-
edly to the right.
An equivalent amount of indole dissolved in glacial acetic
acid was added to this solution, and the mixture heated at
60±708C for 6 h. Final product analysis clearly showed that
the reaction only afforded about 20% of the a-tri¯uoro-
methyl amine (2b) and considerable amounts of other
compounds characterized as the a-tri¯uoromethyl alcohol
(3) and its condensation products [8]. We, therefore, looked
for conditions more appropriate to the preparation of com-
pound 2b by purifying hemiaminal 1b and by choosing an
ef®cient agent which would catalyze the substitution reac-
tion at a lower temperature.
The attempt to separate the hemiaminal 1b from the
ethanol by fractional distillation failed because of its facile
decomposition above 708C. Fortunately, ethanol could be
easily removed by evaporation under reduced pressure at
room temperature. By this means, a variety of N-alkyl
hemiaminals 1a±f have been prepared in excellent yields.
This method appears to be more convenient than that using
gaseous tri¯uoroacetaldehyde [9].
2. Results and discussion
The reactions of three N-alkyl hemiaminals, 1a±c, with
indole were done with one of the two typical Lewis acids,
BF3Et2O or ZnI2, as the catalyst. In the presence of
BF3ÁEt2O, the reaction went smoothly at 108C and was
completed in 1 h. The N-alkyl a-tri¯uoromethyl amines
2a±c were formed in moderate and excellent yields. In
The general procedure of Mannich reaction was alterna-
tively used to avoid the direct reaction between indole and
* Corresponding author. Tel.: ‡81-52-911-3296; fax: ‡81-52-911-2428.
E-mail address: gong@nirin.go.jp (Y. Gong).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 4 0 7 - 3

84
Y. Gong, K. Kato / Journal of Fluorine Chemistry 108 (2001) 83±86
Scheme 1.
addition, a-tri¯uoromethyl alcohol 3 and bisindole alkane 4
[8] were also generated (Scheme 1). The product distribution
was easily determined according to the distinguishable
chemical shifts (d 2a: 87.86, 3: 83.99, 4: 93.79) of their
¯uorine atoms. Details are given in Table 1 (runs 1±6).
In contrast, the yield of a-tri¯uoromethyl alcohol (3)
increased markedly when ZnI2 was used instead of
BF3ÁEt2O. This means that cleavage of the C±O bond of
the N-alkyl hemiaminal (path a) was promoted preferably by
BF3, whereas that of the C±N bond (path b) was obviously
favored in the presence of ZnI2 (Scheme 2). A reasonable
explanation for the great different behavior can be deduced
from the HSAB theory.
We then attempted to prepare 1-(indol-3-yl)-2,2,2-tri-
¯uoroethylamines (5). As reported in the literature, removal
of the N-diphenylmethyl group from the amines can be
achieved by re¯ux in aqueous hydrochloric acid [10,11].
Thus, a high yield of N-diphenylmethyl a-tri¯uoromethyl
amine (2d) was prepared using N-diphenylmethyl hemiam-
inal (1d) (run 7). Unfortunately, no detectable amount of the
target amine 5 was formed, however, when subsequent
hydrolysis of 2d was done in 6N aqueous hydrochloric acid.
For this reason, we tried to prepare the compound 5 using an
amine such as trimethylsilyl amine, because trimethylsilyl
group is easily removed in acidic aqueous media. In practice,
1,1,1,3,3,3-hexamethyldisilazane, a commercially available
reagent, has been used for this purpose.
The reaction of 1,1,1,3,3,3-hexamethyldisilazane with
TFAE was done at 508C. 1H, 19F NMR and GC/MS analyses
clearly showed that only little amount of N,N-bis(trimethyl-
silyl) hemiaminal was generated, and three main compo-
nents were assigned to be compounds 6±8 as illustrated in
Scheme 3. The mixture was used without further isolation to
react with equivalent amounts of indole in the presence of
BF3 at 108C. Product analysis showed that 5 was afforded in
62%, and 4 in 12% yields.
The stereochemistry of the substitution reaction was also
investigated. Two commonly used optically active amines,
(S)-( )-1-phenylethylamine [12] and (R)-(‡)-1-(1-naphthy-
l)ethylamine, reacted with TFAE, yielding the correspond-
ing optically active N-(1-aryl)ethyl hemiaminals 1e and 1f
almost quantitatively. The reaction with indole took place at
108C. High yields of the a-tri¯uoromethyl amines 2e and 2f
were isolated by silica-gel column chromatography. The
diastereomer ratio (runs 8 and 9) was determined by HPLC
and 19F NMR. The high diastereomeric excess clearly
showed that asymmetric substitution really did occur when
a chiral auxiliary was introduced into the N-alkyl hemiam-
inals. The steric effect may be the main factor because the de
value for the bulkier 1-naphthyl derivative is higher than that
of the phenyl derivative.
Table 1
Reaction of the hemiaminal 1a±c with indole at 108C
Run
Hemiaminal
Lewis acid Yields of 2 (%)a 2/3/4b
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1e
1f
BF3
ZnI2
BF3
ZnI2
BF3
ZnI2
BF3
BF3
BF3
2a: 56.1 (46)c
2a: 55.5
63.0/4.4/32.6
61.1/37.7/1.2
90.3/5.1/4.6
0.6/75.3/24.0
96.2/1.3/2.5
19.7/62.1/18.1
2b: 83.0 (78)c
2b: 0.6
2c: 88.5 (82)c
2c: 18.1
2d: (67)c
2e: (76)c
88.8 (de)d
99.0 (de)d
2f: (82)c
a Determined by HPLC.
b Determined by 19F NMR.
c Isolated yield in parentheses.
d Determined by 19F NMR, and confirmed by HPLC.
Scheme 2.

Y. Gong, K. Kato / Journal of Fluorine Chemistry 108 (2001) 83±86
85
Scheme 3.
In conclusion, the N-alkyl hemiaminals of tri¯uoroace-
taldehyde can be conveniently prepared from primary
amines and tri¯uoroacetaldehyde ethyl hemiacetal. More-
over, the reaction with electron-rich heteroarenes is an
ef®cient way to prepare 1-heteroaryl-2,2,2-tri¯uoroethyla-
mine in the presence of BF3.
3.3. Reactions of 1a±f with indole in the presence of boron
trifluoride
A solution of N-methyl hemiaminal (1a) (3.0 mmol,
0.39 g) and indole (3.0 mmol, 0.35 g) in dichloromethane
(10 ml) was cooled to 0±58C by an ice bath. To this solution,
boron tri¯uoride diethyl ether complex (3.0 mmol, 0.43 g)
was added with vigorous stirring. The mixture was then
stirred for 1 h at about 108C. To the reaction mixture, 10 ml
of distilled water was added. The mixture was then neu-
tralized (pH 8±9) with aqueous sodium bicarbonate,
extracted with ethyl acetate three times. The organic layer,
dried over sodium sulfate, was evaporated under reduced
pressure. The residue was analyzed by 1H and 19F NMR, and
puri®ed (eluted with 5:1 to 2:1 hexane/ethyl acetate) by
silica-gel column chromatography to give 0.32 g (46%) of
N-methyl 1-(indol-3-yl)-2,2,2-tri¯uoroethyl amine (2a).
The corresponding reactions of 1b±f with indole were
performed in the same way. The spectroscopic data for the
compounds 2a±f are given below.
3. Experimental details
3.1. General
1H NMR spectra were recorded with tetramethylsilane
(TMS) as an internal standard at 90 MHz on a Hitachi R-
90H FT spectrometer. 19F NMR spectra were recorded with
hexa¯uorobenzene as an internal standard at 84.7 MHz on
the same spectrometer. Mass spectra (70 eV) were measured
on a Hitachi M-80 instrument. High-resolution mass spectra
were measured on a JEOL JMS-SX102A MS spectrometer.
2a: A white needle, mp 102±1038C. 1H NMR (CDCl3) d
8.42 (1H, br), 7.70 (1H, m), 7.15±7.44 (4H, m), 4.39 (1H, q,
J ˆ 7:7 Hz), 2.50 (3H, s), 1.78 (1H, s, br). 19F NMR
3.2. Preparation of N-alkyl hemiaminal of
trifluoroacetaldehyde 1a±f
‡
In a typical procedure, 2.95 g (50 mmol) of isopropyla-
mine was added dropwise to 7.20 g (50 mmol) of TFAE over
30 min with continuous stirring at 5±108C. After being
stirred for 4 more hours, the mixture was evaporated below
258C under reduced pressure until most of the ethanol
evolved had been removed. The residue was dried in a
vacuum desiccator, giving 7.70 g (98%) of N-isopropyl
(CDCl3) 87.90 (3F, d, J ˆ 7:7 Hz). MS m/e 228 (M ,
39.8), 198 (18.9), 159 (100.0), 117 (33.6). HRMS calcd:
228.0874, found: 228.0870.
2b: Awhite solid, 73±748C. 1H NMR (CDCl3) d 8.26 (1H,
m), 7.72 (1H, m), 7.18±7.44 (4H, m), 4.55 (1H, q,
J ˆ 6:4 Hz), 2.91 (1H, m, J ˆ 6:3 Hz), 1.55 (1H, s), 1.06
(6H, d, J ˆ 6:3 Hz). 19F NMR (CDCl3) 87.55 (3F, d,
1
‡
hemiaminal (1b) as white crystals. 1b: H NMR (CDCl3)
d 4.65 (1H, q, J ˆ 6:4 Hz), 3.22, 3.16 (1H, q, J ˆ 5:5 Hz),
J ˆ 6:4 Hz). MS m/e 256 (M , 39.6), 198 (38.3), 187
(100.0), 145 (72.3), 60 (76.6). HRMS calcd: 256.1187,
found: 256.1175.
2.17 (2H, s, w), 1.14, 1.08 (6H, d, J ˆ 5:5 Hz). 19F NMR
‡
2c: A colorless liquid. 1H NMR (CDCl3) d 8.20 (1H, br),
7.10±7.70 (5H, m), 7.28 (5H, s), 4.42 (1H, q, J ˆ 7:7 Hz),
3.83, 3.73 (2H, s), 1.76 (1H, s, br). 19F NMR (CDCl3) 87.79
(CDCl3) 79.42 (3F, d, J ˆ 6:4 Hz). MS m/e 157 (M , 12.4),
142 (100.0), 124 (89.5), 88 (56.9), 60 (58.6). HRMS calcd:
157.0715, found: 157.0715.
‡
Other hemiaminals 1c±f was obtained according to the
same procedure. 1a was prepared by bubbling methylamine
into TFAE at room temperature. 1a, 1b and 1e are white
crystals, but decompose over 408C. 1c, 1d and 1f are
colorless liquid. 1a: 1H NMR (CDCl3) d 4.51 (1H, q,
J ˆ 4:6 Hz), 2.57 (3H, s), 2.50 (2H, br). 19F NMR (CDCl3)
79.86 (3F, d, J ˆ 4:6 Hz).
(3F, d, J ˆ 7:7 Hz). MS m/e 304 (M , 35.6), 235 (100.0),
198 (6.6), 117 (33.6), 91 (96.2). HRMS calcd: 304.1187,
found: 304.1177.
2d: A colorless liquid. 1H NMR (CDCl3) d 8.18 (1H, br),
7.10±7.69 (15H, m), 4.88, 4.80 (1H, s), 4.40 (1H, q,
J ˆ 7:7 Hz), 1.53 (1H, br). 19F NMR (CDCl3) 88.21 (3F,
‡
d, J ˆ 7:7 Hz). MS m/e 380 (M , 4.9), 311 (19.6), 263

86
Y. Gong, K. Kato / Journal of Fluorine Chemistry 108 (2001) 83±86
(28.3), 182 (100.0), 198 (6.6), 167 (93.8). HRMS calcd:
380.1500, found: 380.1497.
stirred for 30 min, then neutralized with saturated aqueous
sodium bicarbonate, extracted with ethyl acetate. The
organic layer was dried over sodium sulfate, and evaporated
under reduced pressure. The residue was puri®ed by silica-
gel column chromatography using 5:1 and 1:1 (v/v) of
hexane-ethyl acetate as the elution, giving 1.33 g (62%)
of the amine 5, a colorless needle. mp 130±1318C. 1H NMR
(acetone-d6) d 10.35 (1H, br), 7.75 (1H, m), 7.10±7.60 (4H,
m), 4.84 (1H, q, J ˆ 7:7 Hz), 2.30 (2H, s, br). 19F NMR
(acetone-d6) 87.42 (3F, d, J ˆ 7:7 Hz). Anal. found: C,
56.34; H, 4.25; N, 12.82. Calcd for C10H9F3N2: C, 56.06;
H, 4.24; N, 13.08.
2e: A colorless liquid. 1H NMR (CDCl3) d 8.20 (1H, br),
7.13±7.65 (5H, m), 7.28 (5H, s), 4.20 (1H, q, J ˆ 7:7 Hz),
3.71 (1H, q, J ˆ 6:8 Hz), 1.92 (1H, br), 1.31 (3H, d,
J ˆ 6:8 Hz). 19F NMR (CDCl3) 87.64 (3F, d, J ˆ
‡
7:7 Hz). MS m/e 318 (M , 31.3), 249 (68.2), 198 (43.6),
145 (46.5), 117 (100.0), 106 (76.3). HRMS calcd: 318.1344,
found: 318.1343.
1
2f: A white needle, mp 116±1178C. H NMR (CDCl3) d
6.88±8.10 (13H, m), 4.58 (1H, q, J ˆ 6:4 Hz), 4.26 (1H, q,
J ˆ 6:4 Hz), 2.03 (1H, s, w), 1.40 (3H, d, J ˆ 6:4 Hz). 19F
‡
NMR (CDCl3) 88.30 (3F, d, J ˆ 6:4 Hz). MS m/e 368 (M ,
50.3), 299 (36.2), 198 (39.6), 170 (68.9), 156 (100.0).
HRMS calcd: 368.1500, found: 368.1500.
Acknowledgements
3.4. Reactions of hemiaminal 1a±c with indole in the
presence of zinc iodide
Y.G. thanks for the Science and Technology Agency of
Japan (STA) for the award of Fellowship Program, which is
managed by the Research Development Corporation of
Japan (JRDC) in cooperation with Japan International
Science and Technology Exchange Center (JISTEC).
A mixture of indole (0.35 g, 3.0 mmol), N-methyl hemi-
aminal (1a) (0.39 g, 3.0 mmol), zinc iodide (0.48 g,
1.5 mmol) and dichloromethane (10 ml) was stirred for
24 h at room temperature. The mixture was transferred into
a separating funnel, and the ¯ask was washed with ethyl
acetate (20 ml). The combined organic layer was washed
with aqueous sodium bicarbonate and brine, dried over
sodium sulfate. After removing the solvents under reduced
References
[1] G.K.S. Prakash, R. Krishnamurti, G.A. Olah, J. Am. Chem. Soc. 111
(1989) 393±395.
[2] Y. Xu Jr., W.R. Dolbier, Tetrahedron Lett. (1998) 9151±9154.
[3] T. Kubota, M. Iijima, T. Tanaka, Tetrahedron Lett. 33 (1992) 1351±
1354.
1
pressure, the residue was analyzed by H and 19F NMR.
[4] S. Watanabe, T. Fujita, M. Sakamoto, H. Hamano, T. Kitazume, T.
Yamazaki, J. Fluorine Chem. 83 (1997) 15±19.
3.5. Preparation of 1-(indol-3-yl)-2,2,2-trifluoroethyl
amine (5)
[5] V.A. Soloshonok, T. Ono, J. Org. Chem. 62 (1997) 3030±3031.
[6] P. Bravo, M. Guidetti, F. Viani, M. Zanda, A.L. Markovsky, A.E.
SorochinskyIrina, V. Soloshonok, V.A. Soloshonok, Tetrahedron 54
(1998) 12789.
Tri¯uoroacetaldehyde ethyl hemiacetal (10.0 mmol,
1.44 g) was mixed with 1,1,1,3,3,3-hexamethyldisilazane
(10.0 mmol, 1.61 g) at 0±58C. The mixture was heated
and stirred at 508C for 2 h. After cooled, a solution of indole
(10.0 mmol, 1.17 g) in dichloromethane (20 ml) was added
into the mixture. Into the solution, chilled by an ice bath to
0±58C, boron tri¯uoride diethyl ether complex (10.0 mmol,
1.42 g) was dropped slowly to keep the reaction tempera-
ture. The mixture was continued to stir for 2 h at 108C. The
mixture was then poured into 20 ml of distilled water and
[7] Y. Gong, K. Kato, H. Kimoto, Bull. Chem. Soc. Jpn. 73 (2000)
249±250.
[8] Y. Maki, H. Kimoto, S. Fujii, J. Fluorine Chem. 39 (1988) 47±59.
[9] C. Mispelaere, N. Roques, Tetrahedron Lett. 40 (1999) 6411±6414.
[10] E.J. Corey, M. Grogan, J. Org. Lett. 1 (1999) 157.
[11] C.A. Krueger, K.W. Kuntz, C.D. Dzierba, W.G. Wirschun, J.D.
Gleason, M.L. Snapper, A.H. Hoveyda, J. Am. Chem. Soc. 121
(1999) 4284.
[12] E. Juaristi, J.L. Leon-Romo, A. Reyes, J. Escalante, Tetrahedron:
Asymm. 10 (1999) 2441±2495.