An improved synthesis of 2-, 3-, and 4-(trifluoromethyl)cyclohexylamines

Article abstract of DOI:10.1055/s-0032-1316985

An improved synthesis of 2-, 3-, and 4-trifluoromethylcyclohexylamines on a multigram scale via PtO₂-mediated hydrogenation of the corresponding trifluoromethylanilines in trifluoroacetic acid at room temperature under atmospheric pressure is reported. The hydrogenation occurred with a remarkable stereoselectivity favoring the formation of cis-isomers. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1316985

PAPER
▌2739
paper
An Improved Synthesis of 2-, 3-, and 4-(Trifluoromethyl)cyclohexylamines
An Improved Synthesis of (Trifluoromethyl)cyclohexylamines
Anatoliy N. Alekseenko,a Klukovsky Denis,a Oleg Lukin,*b Pavel K. Mykhailiuk,*c,d Oleg V. Shishkin,e
Yurii M. Pustovita
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02660 Kiev-94, Murmanska St. 5, Ukraine
b
ChemBioCenter, Kiev National Taras Shevchenko University, Volodymyrska St. 62, Kiev 01033, Ukraine
Fax +380(44)2351273; E-mail: oleg.lukin@gmail.com
c
Enamine Ltd., Aleksandr Matrosov St. 23, Kiev 01103, Ukraine
d
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska St. 64, Kiev 01033, Ukraine
E-mail: pavel.mykhailiuk@gmail.com
e
STC, Institute for Single Crystals, National Academy of Science of Ukraine, Lenin Ave. 60, Kharkov 61001, Ukraine
Received: 12.06.2012; Accepted after revision: 08.07.2012
mentioned the synthesis of compound 5 by hydrogenation
Abstract: An improved synthesis of 2-, 3-, and 4-trifluoromethyl-
of the corresponding aniline 2 in acetic acid using Rh as
cyclohexylamines on a multigram scale via PtO2-mediated hydro-
the catalyst at 50 °C and 4 bar.8 Further studies on the ap-
plicability of this procedure for the preparation of other
genation of the corresponding trifluoromethylanilines in
trifluoroacetic acid at room temperature under atmospheric pressure
is reported. The hydrogenation occurred with a remarkable stereo- isomeric (trifluoromethyl)cyclohexylamines were not re-
ported.9 Therefore, additional optimization of the reaction
selectivity favoring the formation of cis-isomers.
conditions is necessary. There are several reports in the
literature on the reduction of aromatic systems bearing
groups or ring heteroatoms capable of protonation in tri-
fluoroacetic acid (TFA) over PtO2 as the catalyst at atmo-
spheric pressure of hydrogen and ambient temperature.5,10
The reduction of aniline 1 in trifluoroacetic acid over PtO2
proceeded smoothly at room temperature and atmospheric
pressure of hydrogen. The product 42a was isolated from
the reaction mixture by distillation in 70% yield (Scheme 1).
Key words: trifluoromethyl group, amines, cyclohexyl group, hy-
drogenation, trifluoroacetic acid
Aminocyclohexane is a pharmacologically potent build-
ing block that plays an important role in drug design.1
Combination of the aminocyclohexane with another priv-
ileged substructure, that is, trifluoromethyl group, gives
isomeric (trifluoromethyl)cyclohexylamines 4, 5, and 6 as
shown in Scheme 1. These compounds are presently in-
volved in a number of drug discovery projects.2 This ap-
plication resulted in an increase of demand for compounds
4–6.3 Therefore, the development of an efficient synthetic
approach to these isomeric amines is of importance.
NH2
NH2
NH2
CF3
CF3
CF3
One of the most straightforward routes to saturated cycles,
such as cyclohexanes, is heterogeneous catalytic hydroge-
nation.4 Significant progress has been made in heteroge-
neous hydrogenation of mono-, bis-, and tricyclic
aromatic systems. High-yielding regioselective5 heteroge-
neous hydrogenations have been achieved in the case of
some bicyclic heteroaromatic compounds. Consequently,
the hydrogenation of readily available trifluoromethylan-
ilines 1–36 should be a convenient method to the target
compounds 4–6. This transformation was mentioned pre-
viously in two patents by Bayer and DuPont.7 The de-
scribed procedures, however, required the use of 5%
Ru/Al2O3 as the catalyst and proceeded under extremely
harsh conditions (150–175 °C/150–350 bar). On account
of such a high reaction temperature and the hydrogen
pressure, and hence an increased risk of explosion, the re-
ported protocols cannot be considered as convenient
large-scale methods to amines 4–6. A patent by Eli Lilly
1
2
3
70%
i
77%
i
73%
i
NH2
NH2
NH2
CF3
CF3
CF3
4
cis
5
6
cis/trans = 1.0:0.4
cis/trans = 1.0:0.7
ii
ii
ii
NHBoc
NHBoc
NHBoc
CF3
CF3
CF3
7
8
9
SYNTHESIS 2012, 44, 2739–2742
Advanced online publication: 08.08.2012
DOI: 10.1055/s-0032-1316985; Art ID: SS-2012-Z0513-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Preparation of (trifluoromethyl)cyclohexylamines 4–6 and
their N-Boc derivatives 7–9. Reagents and conditions: (i) PtO2, TFA,
H2 (1.05 bar), r.t.; (ii) a) Boc-anhydride, r.t.; b) crystallization.
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2740
A. N. Alekseenko et al.
PAPER
The reaction was easily scaled up without a decrease in while the position of the amide group can vary dependent-
the yield, so that 100 g of the product was conveniently ly on the substitution pattern as well as cis- or trans-
obtained in one synthetic run. Noteworthy, along with configuration. Subsequent repeated crystallization of
product 4, the formation of side products 4a and 4b (Fig- compounds 8 and 9 from cyclohexane allowed the isola-
ure 1) was also observed. Alcohol 4a was isolated from tion of their pure cis-isomers, which were fully character-
the reaction mixture in 10% yield. GS-MS analysis of the ized.
residue after distillation revealed the presence of the mix-
ture of stereoisomeric dicyclohexylamines 4b. However,
compound 4b was not isolated in its individual state.
OH
NH
CF3
F3C
CF3
4a
4b
m/z = 317
Figure 1 Side products of the hydrogenation of 1
Reduction of anilines 2 and 3 under the above-mentioned
reaction conditions proceeded in a similar manner to af-
ford products 5 and 6 in 77% and 73% isolated yield, re-
spectively.2c,d,f,11 Like in the case of compound 4, the
formation of the side dicyclohexylamines was observed,
while no traces of the corresponding alcohols were detect-
ed. Similarly to amine 4, the scaled up synthesis of both 5
and 6 was subsequently performed to obtain larger quan-
tities (>50 g) of the products in a single batch.
Figure 2 The molecular structure of compound 7 obtained by the
single crystal X-ray analysis
In summary, we have optimized the synthesis of isomeric
2-, 3-, and 4-(trifluoromethyl)cyclohexylamines via mild
PtO2 catalyzed hydrogenation of corresponding trifluoro-
methylanilines. The mild hydrogenation conditions favor
the formation of cis-isomers of all three trifluorocyclo-
hexylamines. The stereoselectivity, however, decreases
from 1,2-substituted 4 to 1,4-substituted 6 isomers. Given
the rapid access and scalability of the synthesis, the title
compounds can be used as versatile building blocks in or-
ganic and medicinal chemistry.
Notably, the reduction of aniline 1 afforded only the cis-
isomer 4, as judged by 1H, 13C, 19F NMR, and LC-MS of
the product. The cis-configuration of amine 4 was unam-
biguously proved by single crystal X-ray analysis of its
Boc derivative 7 (Scheme 1, Figure 2). In contrast to 4,
compounds 5 and 6 were isolated as mixtures of two ste-
reoisomers with cis/trans ratio of 2.7:1 and 1.4:1, respec-
tively. The stereoisomer ratios were obtained from HPLC
analyses while the configuration of the major components
Trifluoromethylanilines 1–3 were purchased from commercial
1
was figured out from H NMR spectra of N-Boc deriva-
1
sources. H, 13C and 19F NMR spectra were recorded on a Bruker
tives 8 and 9 (Scheme 1). 1H NMR spectra of crude 8 and
9 recorded in CDCl3 contain two sets of broad singlets
corresponding to axial and equatorial NCH protons at
about 3.4 and 3.9 ppm, respectively, and axial and equa-
torial amide protons at about 4.4 and 4.6 ppm, respective-
ly. The relative integral intensities of these sets of singlets
fit well with the stereoisomeric ratios obtained for parent
Avance 500 spectrometer at 499.9 MHz, 124.9 MHz, and 470.3
MHz, respectively. Chemical shifts are reported in ppm downfield
from TMS (1H, 13C) or CFCl3 (19F) as internal standards. Mass spec-
tra were recorded on a GC/MS instrument by electronic ionization
(EI).
Catalytic Hydrogenation of Trifluoromethylanilines; General
Procedure
1
PtO2 (6 g) was added portionwise to a degassed solution of the cor-
responding trifluoromethylaniline 1–3 (80.1 g, 0.5 mol) in TFA
(200 mL). A H2 pressure of ca. 1.05 bar was applied; and the reac-
tion mixture was shaken at r.t. After ca. 60–80 h, the reaction was
stopped. The catalyst was filtered off, and the solvent and 4a (in the
case of 1) were removed under reduced pressure. The residue was
triturated 5–10 min with hot 40% aq NaOH (200 mL) and the organ-
ic fraction was extracted with Et2O (3 × 100 mL). The Et2O solution
was dried over NaOH plates and the solvent was removed under re-
duced pressure. The crude products were purified by distillation un-
der atmospheric pressure.
amines 5 and 6 by HPLC. The CDCl3 H NMR spectrum
of compound 7, that is, the pure cis-isomer, contains only
one set of broad singlets for its equatorial NCH proton and
axial amide proton at 4.1 and 4.7 ppm, respectively. At the
same time F3CCH protons of compounds 7–9 are repre-
sented as one broad singlet at about 2.3–2.5 ppm. There-
fore, it appears that in compounds 7–9 chair-chair
transition is slow on the NMR timescale; the bulky triflu-
oromethyl group always assumes the equatorial position
Synthesis 2012, 44, 2739–2742
© Georg Thieme Verlag Stuttgart · New York

PAPER
An Improved Synthesis of (Trifluoromethyl)cyclohexylamines
2741
2-(Trifluoromethyl)cyclohexylamine (4)
Isolated as a pure cis-isomer; yield 58.2 g (70%); yellow oil; bp
150–151 °C/760 Torr.
13C NMR (125 MHz, DMSO-d6): δ = 19.71, 19.98, 24.32, 28.70,
2
31.30, 43.39 (q, JCF = 24 Hz), 44.17, 78.19, 127.74 (q, 1JCF = 279
Hz), 155.37.
1H NMR (500 MHz, CDCl3): δ = 1.07 (br s, 2 H, NH2), 1.15–1.21
(m, 1 H, CH), 1.38–1.73 (m, 7 H, CH), 1.89–2.20 (m, 1 H, CH),
3.36–3.38 (br s, 1 H, CH).
19F NMR (376 MHz, CDCl3): δ = –69.09 (s, CF3).
GS-MS: m/z = 267 (M+).
X-ray Diffraction Study12
13C NMR (125 MHz, CDCl3): δ = 18.89, 18.89, 24.81, 33.23, 44.44
3
2
1
The crystals suitable for an X-ray diffractional study were obtained
by a slow evaporation of a diluted solution of 7 in cyclohexane. Sin-
gle crystal X-ray analysis was performed on the Xcalibur-3 diffrac-
tometer (graphite monochromated MoKα radiation, CCD detector,
ω-scanning, 2Θmax = 60°). The structure was solved by direct meth-
od using SHELXTL package.
(q, JCF = 2.5 Hz), 45.70 (q, JCF = 24 Hz), 127.53 (q, JCF = 279
Hz).
19F NMR (376 MHz, CDCl3): δ = –70.08 (br s, CF3).
GS-MS: m/z = 167 (M+).
2-(Trifluoromethyl)cyclohexanol (4a)
Crystal data for 7: C12H20F3NO2, colorless crystals, crystal dimen-
sions 0.20 × 0.30 × 0.30 mm, Mr = 267.29; monoclinic, space
group P21/c, a = 32.732(1), b = 12.2259(4), c = 21.7756(8) Å,
β = 96.211(3)°, V = 8662.8(5) Å3, ρ = 1.230 g·cm–1, Z = 24,
μ(MoKα) = 0.108 MM–1, T = 198(2) K, F(000) = 3408. 67750 reflec-
tions collected, of which 15225 were unique, Rint = 0.058;
wR2 = 0.259 (14809 reflections), R1 = 0.085 [8316 reflections,
F>4σ(F), S = 1.033].
The compound was obtained as a side product during the synthesis
of amine 4. After the hydrogenation had been stopped, the catalyst
was filtered off, the solvent and 4a were collected under vacuum at
10 mm Hg in a trap cooled down to –10 °C. An excess of H2O was
added and the formed suspension was extracted with Et2O (3 × 50
mL). The combined Et2O extracts were washed with aq NaHCO3
(100 mL), dried (MgSO4), and the solvent was removed under re-
duced pressure. The crude product was subjected to distillation un-
der atmospheric pressure to provide pure alcohol 4a as a 95:5
mixture of stereoisomers; yield: 8.3 g (10%); colorless oil; bp 157–
158 °C/760 Torr. Signals of the main isomer are listed below.
3-(Trifluoromethyl)cyclohexylcarbamic Acid tert-Butyl Ester
(8)
Yield 48 g (60%); colorless solid; mp 96–97 °C.
1H NMR (500 MHz, CDCl3): δ = 1.16–1.36 (m, 1 H, CH), 1.37–
1.55 (m, 2 H, CH), 1.59–1.95 (m, 5 H, CH), 1.99–2.17 (m, 2 H, CH
+ OH), 4.23–4.36 (br m, 1 H, CH).
1H NMR (500 MHz, DMSO-d6): δ = 1.05–1.15 (m, 2 H, CH), 1.20–
1.25 (m, 1 H, CH), 1.33–1.39 (m, 1 H, CH), 1.41 (s, 9 H, CH3),
1.89–1.92 (m, 2 H, CH), 1.98–2.03 (m, 1 H, CH), 2.04–2.15 (m, 1
H, CH), 2.23–2.26 (m, 1 H, CH), 3.48 (br s, 1 H, CH), 4.44 (br s, 1
H, NH).
3
13C NMR (125 MHz, CDCl3): δ = 18.88, 19.15 (q, JCF = 2 Hz),
24.63, 32.58, 45.95 (q, 2JCF = 24 Hz), 63.91 (q, 3JCF = 3 Hz), 128.52
(q, 1JCF = 280 Hz).
13C NMR (125 MHz, CDCl3): δ = 23.56, 24.15, 32.11, 32.72, 41.25
(q, 2JCF = 26 Hz), 48.56, 127.11 (q, 1JCF = 278 Hz), 155.03.
19F NMR (376 MHz, CDCl3): δ = –70.22 (br s, CF3).
GS-MS: m/z = 168 (M+).
19F NMR (376 MHz, CDCl3): δ = –74.21 (d, 3JHF = 11 Hz, CF3).
GS-MS: m/z = 267 (M+).
3-(Trifluoromethyl)cyclohexylamine (5)
Isolated as a mixture of cis- and trans-isomers (cis/trans ratio 2.7:1
as revealed by HPLC and 19F NMR); yield: 64 g (77%); yellowish
oil; bp 158–159 °C/760 Torr.
19F NMR (376 MHz, CDCl3): δ = –74.10 (br s, CF3, major), –73.40
(br s, CF3, minor).
GS-MS: m/z = 167 (M+).
4-(Trifluoromethyl)cyclohexylcarbamic Acid tert-Butyl Ester
(9)
Yield 33 g (42%); colorless solid; mp 126–127 °C.
1H NMR (500 MHz, CDCl3): δ = 1.08–1.51 (m, 1 H, CH), 1.40 (s,
9 H, CH3), 1.44–1.62 (m, 3 H, CH), 1.78–1.82 (m, 2 H, CH), 1.85–
1.88 (m, 1 H, CH), 1.97–2.00 (m, 1 H, CH), 2.11–2.14 (m, 1 H, CH),
3.83 (br s, 1 H, CH), 4.65 (br s, 1 H, NH).
4-(Trifluoromethyl)cyclohexylamine (6)
13C NMR (125 MHz, DMSO-d6): δ = 20.05, 24.03, 28.42, 28.85,
31.89, 41.09 (q, JCF = 26 Hz), 48.96, 127.15 (q, JCF = 278 Hz),
155.20.
19F NMR (376 MHz, DMSO-d6): δ = –74.09 (d, 3JHF = 11 Hz, CF3).
GS-MS: m/z = 267 (M+).
Isolated as a mixture of cis- and trans-isomers (cis/trans ratio 1.4:1
as revealed by HPLC and 19F NMR); yield: 60.7 g (73%); yellowish
oil; bp 158–160 °C/760 Torr.
2
1
19F NMR (376 MHz, CDCl3): δ = –74.10 (br s, CF3, major), –73.40
(br s, CF3, minor).
GS-MS: m/z = 167 (M+).
References
Amides 7–9; General Procedure
Boc2O (65.4 g, 0.3 mol) was added to a solution of amine 4–6 (50
g, 0.3 mol) in CH2Cl2 (500 mL) at 0 °C. The mixture was stirred at
r.t. for 4 h and then triturated with 5% aq HCl (300 mL). The organ-
ic phase was separated, washed with H2O (2 × 300 mL), and dried
(Na2SO4). Evaporation of the solvent provided the residue, which
was recrystallized (repeatedly, if necessary) from cyclohexane to
afford pure products.
(1) There are 1148 N-substituted derivatives of
cyclohexanamine in the ‘MDL Drug Data Report’ database.
(2) For the use of amines 4, 5, and 6 within contemporary drug
discovery programs, see: (a) Inoue, T.; Hatanaka, K.; Sasaki,
H.; Takahashi, F.; Higashi, Y.; Hondo, T.; Sawada, H.;
Okimoto, A.; Mukoyoshi, K.; Tanaka, A.; Shirakami, S.;
Nakajima, Y.; Tojo, T.; Morita, M. Patent WO2007/7919
A2, 2007. (b) Weigand, S.; Bischoff, H.; Dittrich-
2-(Trifluoromethyl)cyclohexylcarbamic Acid tert-Butyl Ester
Wengenroth, E.; Heckroth, H.; Lang, D.; Vaupel, A.;
Woltering, M. Bioorg. Med. Chem. Lett. 2005, 15, 4619.
(c) Aquila, B.; Lyne, P.; Pontz, T. US Patent 2009/170849,
2009. (d) Rehwinkel, H.; Hoelscher, P.; Jaroch, S.; Suelzle,
D.; Hillmann, M.; Burton, G. A.; Macdougall, F. US Patent
2004/6075 A1, 2004. (e) Priepke, H.; Doods, H.; Kuelzer,
R.; Pfau, R.; Stenkamp, D.; Roenn, R.; Pelcman, B. Patent
(7)
Yield: 68 g (85%); colorless solid; mp 84–86 °C.
1H NMR (500 MHz, DMSO-d6): δ = 1.22–1.29 (m, 1 H, HCH),
1.35–1.43 (m, 1 H, HCH), 1.41 (s, 9 H, CH3), 1.46–1.49 (m, 1 H,
HCH), 1.52–1.59 (m, 3 H, HCH), 1.65–1.68 (m, 1 H, HCH), 1.75–
1.84 (m, 1 H, HCH), 2.42 (m, 1 H, F3CCH), 4.13 (m, 1 H, HNCH),
6.97 (d, 3JHH = 10 Hz, 1 H, NH).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2739–2742

2742
A. N. Alekseenko et al.
PAPER
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Crystallographic Data Centre, 12 Union Road, CB2 1EZ,
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They are available on request quoting the deposition number
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(3) Since 2006 Enamine Ltd. has received 46 requests for
providing amine 4, 59 for 5, and 119 for 6.
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Synthesis 2012, 44, 2739–2742
© Georg Thieme Verlag Stuttgart · New York