A facile synthesis of isomeric C -(2,2,2-trifluoroethyl)anilines

Article abstract of DOI:10.1055/s-0031-1290295

Three isomers of C-(2,2,2-trifluoroethyl)aniline were prepared on a multigram scale from readily available nitrophenylacetic acids in two steps. First, the carboxy groups of the latter were converted into the trifluoromethyl moieties by treatment with sul

Full text of DOI:10.1055/s-0031-1290295

1974▌
PRACTICAL SYNTHETIC PROCEDURES
pAracFticaal csyinltehetSic yprnocetdhureessis of Isomeric C-(2,2,2-Trifluoroethyl)anilines
Isomeric (2,2,2-Trifluoroethyl)anilines
Sergii Trofymchuk,a Andrii V. Bezdudny,a,b Yurii M. Pustovit,a,b Oleg Lukin,*c Alexander N. Boyko,c
Alexey Chekotylo,c Andrei A. Tolmachev,b,c Pavel K. Mykhailiuk*d
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska St. 5, 02660 Kiev-94, Ukraine
b
Enamine Ltd., Alexander Matrosov St. 23, 01103 Kiev, Ukraine
c
ChemBioCenter, Kiev National Taras Shevchenko University, Volodymyrska St. 62, 01033 Kiev, Ukraine
Fax +380(44)2351273; E-Mail: oleg.lukin@univ.kiev.ua
d
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska St. 64,
01033 Kiev, Ukraine
E-mail: pavel.mykhailiuk@gmail.com
PSP
Received: 04.01.2012; Accepted after revision: 25.01.2012
In memory of Prof. L. M. Yagupolskii - a father of modern fluoroorganic chemistry
No225
Abstract: Three isomers of C-(2,2,2-trifluoroethyl)aniline were prepared on a multigram scale from readily available nitrophenylacetic
acids in two steps. First, the carboxy groups of the latter were converted into the trifluoromethyl moieties by treatment with sulfur tetra-
fluoride. The obtained 2,2,2-trifluoroethyl-substituted nitrobenzenes were reduced catalytically into the corresponding anilines.
Key words: amines, trifluoromethyl group, fluorine, sulfur tetrafluoride, hydrogenation
COOH
NO2
CF3
CF3
SF4
H2, Pd/C
NO2
NH2
1
2
3
a: ortho
b: meta
c: para
Scheme 1 The synthesis of isomeric (2,2,2-trifluoroethyl)anilines
2-, 3-, and 4-(2,2,2-Trifluoroethyl)anilines (3a–c) bearing fluoromethyl)mercury (Yagupolskii et al.6) or
the privileged trifluoromethyl group1,2 are presently ac- (trifluoromethyl)zinc bromide (Kremlev et al.7) resulting
tively being used as building blocks in many drug discov- in 2c. Similarly, one-gram scale syntheses of 1-nitro-3-
ery programs.3 These compounds are usually prepared (2,2,2-trifluoroethyl)benzene (2b) and 1-nitro-4-(2,2,2-
through reduction of the corresponding (2,2,2-trifluoro- trifluoroethyl)benzene (2c) were reported by Nguyen et
ethyl)nitrobenzenes 2a–c.3c,d To our knowledge there is al.8 and Duan et al.9 starting from (difluoroethenyl)nitro-
only one report of an alternative preparation of 2-(2,2,2- benzenes and nitrobenzyl chlorodifluoroacetates, respec-
trifluoroethyl)aniline (3a) from aniline and 1-bromo- tively. Milligram-scale syntheses of 2b and 2c,
2,2,2-trifluoroethane.4 Since the reduction of the majority contaminated by mono- and difluoroethyl derivatives,
of nitroaromatic compounds can easily be performed on a from the corresponding nitrobenzyl alcohols and (2,2,2-
large scale, it is the limited synthetic access to 2a–c that trichloroethyl)nitrobenzenes were described by Clark et
hampers the multigram production of the title anilines. al.10 and Ando et al.,11 respectively. Very recently Kawai
There are several reports in the literature describing the et al.12 demonstrated a clean and high-yielding transform-
preparation of 2a–c on a one-gram or milligram scale. For ation of all three nitrobenzyl bromides into (2,2,2-trifluo-
example, Fuqua et al.5 described a gram-scale synthesis of roethyl)nitrobenzenes 2a–c by treatment with
1-nitro-4-(2,2,2-trifluoroethyl)benzene (2c) from 4-nitro- trifluoromethylsulfonium salts. Nevertheless, like in pre-
benzaldehyde and sodium chlorodifluoroacetate. Another ceding reports, the latter procedure was performed on a
small-scale approach involved copper(I)-catalyzed tri- milligram scale.
fluoromethylation of 4-nitrobenzyl bromide with bis(tri-
In this work we report a straightforward two-step prepara-
tion of (2,2,2-trifluoromethyl)anilines 3a–c on a multi-
gram scale. As shown in Scheme 1, the synthesis starts
from readily available nitrophenylacetic acids 1a–c.
SYNTHESIS 2012, 44, 1974–1976
Advanced online publication: 03.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Treatment of the latter with three equivalents of sulfur
DOI: 10.1055/s-0031-1290295; Art ID: SS-2012-T0012-PSP
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Isomeric (2,2,2-Trifluoroethyl)anilines
1975
tetrafluoride13,14 at room temperature for three days
afforded (2,2,2-trifluoroethyl)nitrobenzenes 2a–c in good
to high yields. Finally, palladium-on-carbon mediated hy-
drogenation of the nitro groups in 2a–c furnished the tar-
get (2,2,2-trifluoroethyl)anilines 3a–c in near quantitative
yields. Both synthetic steps were carried out with batch
sizes of 50–100 grams.
1-Nitro-4-(2,2,2-trifluoroethyl)benzene (2c)
Yield: 92.3 g (90%); mp 66–67 °C; bp 95–97 °C/0.2 mbar.
3
1H NMR (500 MHz): δ = 3.49 (q, JHF = 10.4 Hz, 2 H), 7.48 (d,
3JHH = 8.4 Hz, 2 H), 8.22 (d, 3JHH = 8.4 Hz, 2 H).
13C NMR (125 MHz): δ = 39.97 (q, 2JCF = 30.3 Hz), 123.82, 125.12
(q, 1JCF = 277 Hz), 131.16, 137.26 (q, 3JCF = 2.7 Hz), 147.96.
19F NMR (376 MHz): δ = –66.00 (t, 3JFH = 10.4 Hz).
LC-MS: m/z = 205 (M+).
To conclude, we have developed a reliable two-step pro-
cedure for the multigram-scale preparation of isomeric C- Anal. Calcd for C8H6F3NO2: C, 46.84; H, 2.95; N, 6.83. Found: C,
46.70; H, 3.07; N, 6.68.
(2,2,2-trifluoroethyl)anilines. Inasmuch as the latter are
important building blocks in medical research, our meth-
od would stimulate a more active involvement of the title
compounds in ongoing drug discovery programs.
C-(2,2,2-Trifluoroethyl)anilines 3a–c; General Procedure
A soln of nitro compound 2 (97 g, 0.473 mol) in MeOH (500 mL)
was stirred under atmosphere of H2 at r.t. and ambient pressure in
the presence of 10% Pd/C (10 g) until consumption of H2 ceased.
The catalyst was filtered off and the filtrate was concentrated and
distilled under vacuum.
Solvents were purified according to standard procedures. 2-Nitro-
phenylacetic acid (1a) and 4-nitrophenylacetic acid (1c) were pur-
chased from Linsai Trade; 3-nitrophenylacetic acid was purchased
from Daming Ruiheng Chemical Co, Ltd. All other materials were
purchased from Aldrich and Enamine. Melting points are uncorrect-
ed. 1H, 13C, and 19F NMR spectra were recorded on a Bruker Avance
500 spectrometer at 499.9 MHz, 124.9 MHz and 376 MHz, respec-
tively. Chemical shifts are reported downfield from TMS (1H, 13C)
and CFCl3 (19F) as internal standards. Mass spectra were recorded
on an Agilent 1100 LC MSD SL instrument with chemical ioniza-
tion (APCI) mode. Elemental analyses were carried out on a LECO
CHN-900 analyzer.
2-(2,2,2-Trifluoroethyl)aniline (3a)
Yield: 78.7 g (95%); mp 46–47 °C; bp 73–75 °C/16 mbar.
1H NMR (500 MHz): δ = 3.34 (q, 3JHF = 11.0 Hz, 2 H), 3.69 (br s, 2
H), 6.74 (d, 3JHH = 7.9 Hz, 1 H), 6.80 (t, 3JHH = 7.4 Hz, 1 H), 7.15
(m, 2 H).
2
13C NMR (125 MHz): δ = 35.94 (q, JCF = 30.0 Hz), 115.51 (q,
3JCF = 3 Hz), 117.09, 119.42, 126.48 (q, 1JCF = 277.7 Hz), 129.42,
132.42, 145.41.
19F NMR (376 MHz): δ = –65.62 (t, 3JFH = 10.4 Hz).
LC-MS: m/z = 176 (M + H+).
(2,2,2-Trifluoroethyl)nitrobenzenes 2a–c; General Procedure
Nitrophenylacetic acid (90.5 g, 0.5 mol) was placed in 500-mL
stainless steel autoclave, which was then evacuated, cooled with liq-
uid N2, and charged with SF4 (162 g, 1.5 mol). The autoclave was
kept at r.t. for 72 h. The gaseous products were vented off, the resi-
due was dissolved in CH2Cl2, poured onto ice and triturated with
concd NH4OH (200 mL). After 2 h the mixture was filtered, the or-
ganic phase was separated, dried (Na2SO4), and concentrated on a
rotary evaporator. The crude product was subjected to vacuum dis-
tillation.
Anal. Calcd for C8H8F3N: C, 54.86; H, 4.60; N, 8.00. Found: C,
54.74; H, 4.75; N, 7.69.
3-(2,2,2-Trifluoroethyl)aniline (3b)
Yellowish oil; yield: 75.4 g (91%); bp 91–92 °C/16 mbar.
1H NMR (500 MHz): δ = 3.29 (q, 3JHF = 11.0 Hz, 2 H), 3.71 (br s, 2
3
3
H), 6.63 (s, 1 H), 6.68 (d, JHH = 7.8 Hz, 1 H), 6.71 (d, JHH = 7.8
Hz, 1 H), 7.16 (t, 3JHH = 7.8 Hz, 1 H).
13C NMR (125 MHz): δ = 40.10 (q, 2JCF = 29.3 Hz), 114.71, 116.62,
120.23, 125.89 (q, 1JCF = 277 Hz), 129.50, 131.19 (q, 3JCF = 3 Hz),
146.69.
1-Nitro-2-(2,2,2-trifluoroethyl)benzene (2a)
Yield: 43.1 g (42%); mp 21–22 °C; bp 63–65 °C/0.13 mbar.
3
1H NMR (500 MHz): δ = 3.91 (q, JHF = 10.4 Hz, 2 H), 7.47 (d,
19F NMR (376 MHz): δ = –66.15 (t, 3JFH = 11.0 Hz).
LC-MS: m/z = 176 (M + H+).
3JHH = 7.6 Hz, 1 H), 7.52 (t, 3JHH = 8.2 Hz, 1 H), 7.62 (t, 3JHH = 7.6
Hz, 1 H), 8.00 (d, 3JHH = 8.2 Hz, 1 H).
Anal. Calcd for C8H8F3N: C, 54.86; H, 4.60; N, 8.00. Found: C,
54.70; H, 4.78; N, 7.86.
13C NMR (125 MHz): δ = 36.25 (q, JCF = 30.7 Hz), 124.67 (q,
2
3JCF = 3 Hz), 125.21 (q, JCF = 277.7 Hz), 125.34, 129.55, 133.23,
1
133.4, 149.93.
4-(2,2,2-Trifluoroethyl)aniline (3c)
19F NMR (376 MHz): δ = –65.58 (t, 3JFH = 10.4 Hz).
LC-MS: m/z = 205 (M+).
Yield: 80.3 g (97%); mp 45–46 °C; bp 108–110 °C/18.6 mbar.
1H NMR (500 MHz): δ = 3.23 (q, 3JHF = 10.9 Hz, 2 H), 3.55 (br s, 2
H), 6.65 (d, 3JHH = 8.3 Hz, 2 H), 7.06 (d, 3JHH = 8.3 Hz, 2 H).
Anal. Calcd for C8H6F3NO2: C, 46.84; H, 2.95; N, 6.83. Found: C,
46.56; H, 3.18; N, 6.64.
13C NMR (125 MHz): δ = 39.44 (q, 2JCF = 29.7 Hz), 115.16, 119.85
(q, 3JCF = 2.7 Hz), 126.08 (q, 1JCF = 276.3 Hz), 131.11, 146.33.
1-Nitro-3-(2,2,2-trifluoroethyl)benzene (2b)
19F NMR (376 MHz): δ = –66.99 (t, 3JFH = 10.9 Hz).
LC-MS: m/z = 176 (M + H+).
Yield: 79.4 g (78%); mp 45–46 °C; bp 90–92 °C/0.2 mbar.
3
1H NMR (500 MHz): δ = 3.48 (q, JHF = 10.4 Hz, 2 H), 7.55 (t,
3JHH = 7.9 Hz, 1 H), 7.63 (d, 3JHH = 7.9 Hz, 1 H), 8.18 (s, 1 H), 8.21
(d, 3JHH = 7.9 Hz, 1 H).
Anal. Calcd for C8H8F3N: C, 54.86; H, 4.60; N, 8.00. Found: C,
54.67; H, 4.73; N, 7.82.
13C NMR (125 MHz): δ = 39.86 (q, 2JCF = 30.7 Hz), 123.29, 125.10,
125.19 (q, 1JCF = 277 Hz), 129.77, 132.05 (q, 3JCF = 3 Hz), 136.20,
148.46.
19F NMR (376 MHz): δ = –66.29 (t, 3JFH = 10.4 Hz).
LC-MS: m/z = 205 (M+).
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© Georg Thieme Verlag Stuttgart · New York
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© Georg Thieme Verlag Stuttgart · New York