An expedient synthesis of 2,4,6-tris(trifluoromethyl)aniline

Article abstract of DOI:10.1055/s-0032-1316809

A simple two-step synthetic route leads to 2,4,6-tris(trifluoromethyl) aniline. It proceeds through deprotonation and iodination of 1,3,5-tris(trifluoromethyl)benzene, followed by copper-catalyzed amination. Georg Thieme Verlag KG Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1316809

SHORT PAPER
▌3595
short paper
An Expedient Synthesis of 2,4,6-Tris(trifluoromethyl)aniline
Fluorinated Aniline
Brian L. Edelbach,a Blaze M. Pharoah,a Sarina M. Bellows,b Peter R. Thayer,a Charles N. Fennie,a Ryan E. Cowley,b
Patrick L. Holland*b
a
Monroe Community College, 1000 East Henrietta Rd., Rochester, NY 14623, USA
b
Department of Chemistry, University of Rochester, Rochester, NY 14627, USA
Fax +1(585)2760205; E-mail: holland@chem.rochester.edu
Received: 25.09.2012; Accepted after revision: 23.10.2012
The addition of a strong base such as n-butyllithium to
Abstract: A simple two-step synthetic route leads to 2,4,6-tris(tri-
1,3,5-tris(trifluoromethyl)benzene is known to give 2,4,6-
fluoromethyl)aniline. It proceeds through deprotonation and iodin-
tris(trifluoromethyl)phenyllithium, which can be handled
ation of 1,3,5-tris(trifluoromethyl)benzene, followed by copper-
catalyzed amination.
in situ at 0 °C.6 The addition of Cl2 and Br2 to the lithio
derivative results in the formation of 1-chloro-2,4,6-
tris(trifluoromethyl)benzene and 1-bromo-2,4,6-tris(tri-
fluoromethyl)benzene, respectively, in low to moderate
Key words: fluorination, aniline, ligand precursor
yields.6a Our initial experiments indicated that butyl
Fluorinated substituents have become a valuable tool in
groups from n-butyllithium had replaced fluorines on the
medicinal chemistry.1 Strong and inert C–F bonds can
substituents in the predominant by-products. In order to
also give robust supporting ligands for catalysis.2 An easy
avoid this side reaction, we used the bulky base lithium di-
method for the introduction of fluorinated substituents is
isopropylamide (LDA). We also used I2 as the electro-
through condensation with a fluorinated amine, particu-
phile, due to the greater ease of handling.
larly with formation of a Schiff base (imine). In this work,
Under optimized conditions of 2 equivalents of LDA and
I2, this method generates a 63–75% yield of the aryl iodide
1. The superstoichiometric amounts of LDA and I2 were
necessary to achieve a high level of conversion to 1, and
~15% of the starting material remains even under opti-
mized conditions. The product 1 can be purified by subli-
mation. Singly sublimed 1 has an unidentified impurity
peak at δ = 4.1 in the 1H NMR spectrum though it passed
elemental analysis, and this material was sufficiently pure
for continuing into the subsequent reaction below. Addi-
tion of a few drops of water and resublimation from CaO
as a drying agent led to material with no detectable impu-
rities by NMR spectroscopy, which was suitable for com-
plete characterization. Compound 1 is a solid at room
temperature (mp 34 °C), but is quite volatile and thus pre-
cautions must be taken to avoid loss during rotary evapo-
ration.
we target 2,4,6-tris(trifluoromethyl)aniline (2), a hindered
aniline that shows great promise as a modular component
for synthesis.
One previously reported synthesis of 2 starts with 1,2,3,5-
benzenetetracarboxylic acid, which reacts with SF4 to
give 2,4,6-tris(trifluoromethyl)benzoyl fluoride. Addition
of ammonia generates the corresponding amide, and a
Hoffman rearrangement gives 2.3 While the overall reac-
tion sequence provides a 56% total yield of 2, specialized
equipment is required for the reaction. Another literature
route to compound 2 involves a five-step reaction
sequence with an overall yield of 43%.4 Another recently
reported synthesis involved electrophilic trifluoromethyl-
ation of 2-(trifluoromethyl)aniline using CF3I in the pres-
ence of an iron(II) catalyst, H2O2, and DMSO.5 They
reported a 55% yield for 2, but 2,4-bis(trifluoromethyl)an-
iline was also formed in 28% yield, and experimental de-
tails were not provided. In order to provide an easier
alternative, we have developed a synthesis leading to
compound 2 from the commercially available 1,3,5-
tris(trifluoromethyl)benzene (Scheme 1).
For the transformation of 1 to the aniline 2, a protocol de-
veloped by Helquist and co-workers7 for the conversion of
an aryl iodide into an arylamine was used. Compound 1
was combined with proline (1.3 equiv), NaN3 (2 equiv),
1) LDA
2) I2
Cu2O, NaN3
proline, DMSO
F3C
CF3
F3C
CF3
I
F3C
CF3
NH2
75%
55%
CF3
CF3
CF3
1
2
Scheme 1
SYNTHESIS 2012, 44, 3595–3597
Advanced online publication: 13.11.2012
0
0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316809; Art ID: SS-2012-M0747-OP
© Georg Thieme Verlag Stuttgart · New York

3596
B. L. Edelbach et al.
SHORT PAPER
Lithium Diisopropylamide (LDA)
and Cu2O (1 equiv) in DMSO, and stirred at 80 °C for one
hour. Again the major by-product was 1,3,5-tris(trifluoro-
methyl)benzene (~20% relative to 2). An aqueous workup
was used to remove ionic by-products, which should be
handled with care (quenched with sodium nitrite and han-
dled in a fume hood) due to the potentially explosive and
toxic nature of any remaining azide salts. After extraction,
the aniline was sublimed to give 2 as a white powder in
55% isolated yield. The 1H NMR spectrum of 2 shows a
singlet of the aromatic protons at δ = 7.86 and a broad sin-
glet at δ = 5.06 corresponding to the NH protons. The
19F{1H} NMR spectrum consists of a singlet at δ = –64.5
for the o-CF3 groups, and a singlet at δ = –63.0 for the
p-CF3 group.
This synthesis and workup were performed in an inert-atmosphere
glove box. To a solution of i-Pr2NH (8.6 mL, 0.061 mol) in pentane
(200 mL) at –78 °C was added a solution of n-BuLi (2.5 M in hex-
ane, 24.4 mL, 0.0609 mol) slowly with stirring. The solution was
stirred at –78 °C for 1 h, warmed to r.t., and stirred overnight. A
white solid (4.03 g, 0.038 mol, 62%) was collected on a medium frit
and washed with cold pentane (2 × 20 mL). The solid LDA was
dried under vacuum and stored in a –40 °C glovebox freezer.
1-Iodo-2,4,6-tris(trifluoromethyl)benzene (1)
LDA (0.806 g, 7.52 mmol, 2.0 equiv) was dissolved in Et2O (50
mL) in a 500 mL round-bottomed flask and cooled to 0 °C under N2.
1,3,5-Tris(trifluoromethyl)benzene (1.06 g, 0.7 mL, 3.76 mmol)
was dissolved in Et2O (2 mL) and the resulting solution was slowly
added to the LDA solution. The LDA turned dark as the addition
proceeded. This mixture was stirred at 0 °C for 1.25 h. I2 (1.91 g,
7.52 mmol, 2 equiv) was added all at once to the mixture and stirred
at 0 °C for 5 min and then at r.t. for 15 min. The mixture was ex-
posed to air, poured into a separatory funnel, and rinsed with Et2O
(2 × 20 mL). The mixture was washed with 10% aq Na2S2O3
(4 × 100 mL) in order to remove excess I2. A small amount of dark
solid persists throughout the Na2S2O3 washings. The organic layer
was then washed with brine (2 × 75 mL). The combined aqueous
layers were extracted with Et2O (30 mL), which was combined with
the other organic layers. The organic solution was then washed with
1 M aq HCl (3 × 75 mL) to remove i-Pr2NH. The aqueous acid
washes were extracted with Et2O (65 mL). The Et2O layer was
passed through filter paper and combined with the other Et2O layer.
The combined Et2O layers were dried (MgSO4) and the orange so-
lution was filtered through a pad of Celite. The majority of the sol-
vent was removed with a rotary evaporator until a viscous oil
remained (the product readily sublimed). The oil was transferred to
a sublimator with a minimum amount of Et2O and the solvent was
evaporated with a stream of N2. The resulting solid was sublimed at
20 °C under a static vacuum with dry ice/acetone in the cold finger
to give 1 as an orange solid that is suitable for further reactions;
yield: 1.1556 g (75%);8 mp 34–35 °C.
Thus, a simple two-step procedure leads to 2,4,6-tris(tri-
fluoromethyl)aniline on a gram scale. Detailed experi-
mental details are given here, to facilitate the
incorporation of this fragment into various useful mole-
cules by other chemists.
Unless otherwise specified, all manipulations were performed un-
der an inert atmosphere by standard Schlenk techniques or in an M.
Braun Unilab N2-filled glove box maintained at or below 1 ppm of
O2 and H2O. Glassware was dried at 150 °C overnight. The 1,3,5-
tris(trifluoromethyl)benzene (97% purity) was purchased from
Oakwood Products, dried over molecular sieves, and degassed be-
fore use. NaN3 and proline (99% purity) were purchased from Al-
drich Chemical Co. and used without further purification. Cu2O
(97% purity) was purchased from Alfa Aesar and used without fur-
ther purification. 1H NMR, 19F{1H} NMR, and 13C{1H} NMR spec-
tra were recorded on a Bruker Avance 400 spectrometer at r.t. (400
1
MHz for H NMR, 376 MHz for 19F NMR, and 100 MHz for 13C
1
NMR). All resonances in the H NMR spectra were reported in
ppm, relative to residual protiated solvent CHCl3 (δ = 7.26). All res-
onances in the 19F NMR spectra were referenced to α,α,α-trifluoro-
toluene (δ = –63.72) and were reported relative to CFCl3 (δ = 0). All
resonances in the 13C NMR spectra were referenced to CDCl3 (δ =
77.0). Pentane and Et2O were purified by passage through activated
alumina and ‘deoxygenizer’ columns from Glass Contour Co. (La-
guna Beach, CA, USA). DMSO was degassed by applying vacuum
for 4 min and refilling with N2 for a total of three cycles. i-Pr2NH
was distilled under nitrogen and dried over 4 Å MS three times. IR
spectra were recorded on a Shimadzu FT-IR Prestige 21 spectro-
meter equipped with a Pike diamond ATR. The CENTC Elemental
Analysis Facility at the University of Rochester determined elemental
analyses. Microanalysis samples were weighed with a PerkinElmer
model AD-6 Autobalance, and their compositions were determined
with a PerkinElmer 2400 Series II Analyzer. GC–MS was carried
out on a Shimadzu GCMS-QP2010 instrument.
IR (neat): 3102 (w), 1620 (m), 1584 (w), 1379 (w), 1269 (s), 1188
(s), 1043 (s), 1013 (s), 919 (s), 853 (m), 838 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 8.04 (s, 2 H, Harom).
13C{1H} NMR (100 MHz, CDCl3): δ = 138.1 (q, J = 31 Hz, C-2),
131.3 (q, J = 35 Hz, C-5), 127.2 (br s, C-4), 122.5 (q, J = 273 Hz,
C-6), 122.0 (q, J = 275 Hz, C-3), 94.7 (s, C-1).
19F{1H} NMR (376 MHz, CDCl3): δ = –63.3 (s, o-CF3), –64.4 (s, p-
CF3).
MS (EI+): m/z (%) = 408 (100), 281 (85), 212 (45) 162 (67), 143
(43).
Anal. Calcd for C9H2F9I: C, 26.49; H, 0.49. Found: C, 26.32; H,
0.63.
2,4,6-Tris(trifluoromethyl)aniline (2)
The numbering of carbon atoms used for 13C NMR peak assignment
is presented in Figure 1.
Caution! Although no problems were encountered, the following
procedure was carried out behind a shatter-resistant shield. The cop-
per and azide starting materials should not be mixed before the other
reagents, in order to avoid potential formation of explosive azide
complexes.
X = I, NH2
X
3
1
3
Under N2, a 125 mL resealable flask with a stir bar was charged with
proline (559 mg, 4.86 mmol, 1.3 equiv), NaN3 (447 mg, 7.34 mmol,
2.0 equiv), Cu2O (531 mg, 3.71 mmol, 1.0 equiv), the iodo com-
pound 1 (1.49 g, 3.64 mmol, 1.0 equiv), and DMSO (10 mL). This
mixture was heated at 80 °C for 1 h. An aliquot of the sample was
removed under N2, and 19F{1H} NMR spectroscopy (DMSO-d6) in-
dicated the complete consumption of the starting material [the prod-
uct 2 and ~20% of 1,3,5-tris(trifluoromethyl)benzene were
observed]. In a fume hood, the reaction mixture was cooled to r.t.
2
4
2
4
5
6
Figure 1 Atom-numbering used for 13C NMR spectra
Synthesis 2012, 44, 3595–3597
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Fluorinated Aniline
3597
and quenched by the addition of sat. aq NH4Cl (15 mL) and EtOAc
(12 mL). This biphasic mixture was stirred at r.t. for 1 h. The result-
ing dark green solution was filtered through a pad of Celite that was
subsequently washed with EtOAc (70 mL) and H2O (20 mL) (the
solid should be quenched with NaNO2 and disposed with care be-
cause of the possible presence of metal-azide salts). The filtrate was
transferred to a separatory funnel, the aqueous layer was removed,
and the organic phase was washed with sat. aq NaHCO3 (3 × 55
mL). The aqueous layer became less blue with each wash. After the
third wash, the aqueous layer was still slightly blue, so the organic
layer was washed with brine (2 × 55 mL), followed by a final wash-
ing with sat. aq NaHCO3 (55 mL), which was now colorless. To re-
move DMSO, the organic phase was washed with deionized H2O (4
× 100 mL). An emulsion formed after each wash but cleared up
more rapidly after each wash.9 The organic layer was washed a final
time with brine (80 mL).10 The combined organic layers were dried
(MgSO4) and the orange solution was filtered through filter paper
into a 250 mL round-bottom flask. The majority of the solvent was
removed with a rotary evaporator until a viscous oil remained (the
aniline product readily sublimed). The oil was transferred to a sub-
limator with a minimum amount of Et2O and the residual solvent
was evaporated with a stream of N2. The resulting solid was sub-
limed at 20 °C under a static vacuum with dry ice/acetone in the
cold finger, to give 2 as a white solid; yield: 0.5958 g (55%); mp 54–
55 °C (Lit.4 mp 58–59 °C).
References
(1) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320.
(2) (a) Bennett, B. L.; Hoerter, J. M.; Houlis, J. F.; Roddick, D.
M. Organometallics 2000, 19, 615. (b) Sadighi, J. P.;
Henling, L. M.; Labinger, J. A.; Bercaw, J. E. Tetrahedron
Lett. 2003, 44, 8073. (c) Hamilton, C. W.; Laitar, D. S.;
Sadighi, J. P. Chem. Commun. 2004, 1628. (d) Dias, H. V.
R.; Singh, S. Inorg. Chem. 2004, 43, 5786. (e) Despagnet-
Ayoub, E.; Jacob, K.; Vendier, L.; Etienne, M.; Álvarez, E.;
Caballero, A.; Díaz-Requejo, M. M.; Pérez, P. J.
Organometallics 2008, 27, 4779.
(3) (a) Burmakov, A. I.; Alekseeva, L. A.; Yagupolskii, L. M.
Zh. Org. Khim. 1970, 6, 144; Chem. Abstr. 1970, 89975.
(b) Synthesis of Fluoroorganic Compounds; Knunyants, I.
L.; Yacobson, G. G., Eds.; Springer: Berlin, 1985.
(4) Ahlemann, J.-T.; Roesky, H. W.; Noltemeyer, M.; Schmidt,
H.-G.; Markovsky, L. N.; Shermolovich, Y. G. J. Fluorine
Chem. 1998, 87, 87.
(5) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.;
Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine
Chem. 2010, 131, 98.
(6) (a) Carr, G. E.; Chambers, R. D.; Holmes, T. F.
J. Organomet. Chem. 1987, 325, 13. (b) Cornet, S. M.;
Dillon, K. B.; Entwistle, C. D.; Fox, M. A.; Goeta, A. E.;
Goodwin, H. P.; Marder, T. B.; Thompson, A. L. Dalton
Trans. 2003, 4395.
IR (neat): 3559 (w), 3465 (m), 1655 (m), 1507 (m), 1378 (m), 1254
(s), 1093 (s), 920 (s), 884 (m), 830 cm–1 (w).
1H NMR (400 MHz, CDCl3): δ = 7.86 (s, 2 H, Harom), 5.06 (br s, 2
(7) Markiewicz, J. T.; Wiest, O.; Helquist, P. J. Org. Chem.
2010, 75, 4887.
(8) This solid can be used in the synthesis of compound 2
directly, and passes elemental analysis. It can also be
resublimed from CaO after adding a few drops of water, to
give a white solid.
H, NH).
13C{1H} NMR (100 MHz, CDCl3): δ = 148.1 (s, C-1), 128.0 (br s,
C-4), 123.5 (q, J = 273 Hz, C-3), 123.3 (q, J = 271 Hz, C-6), 118.6
(q, J = 35 Hz, C-5), 115.3 (q, J = 31 Hz, C-2).
19F{1H} NMR (376 MHz, CDCl3): δ = –63.0 (s, p-CF3), –64.5 (s, o-
(9) If the emulsion after the first wash with water does not clear
up, 20 mL of brine can be added to the separatory funnel and
the mixture can be reshaken. It may take some time (~40
min) for the first emulsion to clear.
(10) When the aqueous layers and the brine layers were combined
and extracted with Et2O, no aniline 2 was observed in the
organic extracts, indicating that the desired product was not
water soluble.
CF3).
MS (EI+): m/z (%) = 297 (100), 278 (55), 277 (63), 257 (56), 238
(45), 207 (41), 188 (54), 181 (23), 69 (19).
Anal. Calcd for C9H4F9N: C, 36.38; H, 1.36; N, 4.71. Found: C,
36.14; H, 1.37; N, 4.58. Elemental analysis was also performed af-
ter the sample was resublimed over CaO. Found: C, 36.32; H, 1.32;
N, 4.62.
Acknowledgment
This work was supported by the National Science Foundation
(CHE-0911314).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3595–3597