A convenient synthesis of N,N-bis(trifluoromethyl)anilines

Article abstract of DOI:10.1016/j.jfluchem.2011.10.014

A convenient synthesis of N,N-bis(trifluoromethyl)anilines by means of dediazotation reactions of previously unknown aryldiazoniumbis(trifluoromethyl) imides in the presence of Cu^I salts are described. Properties and applications of N,N-bis(trifluoromethyl)anilines in syntheses of aromatic compounds containing the (CF₃)₂N group are presented.

Full text of DOI:10.1016/j.jfluchem.2011.10.014

Journal of Fluorine Chemistry 135 (2012) 176–182
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A convenient synthesis of N,N-bis(trifluoromethyl)anilines
a
c
a
M.E. Hirschberg a, , N.V. Ignat’ev
, A. Wenda , H.-J. Frohn , H. Willner
*
b,**
a Inorganic Chemistry, Bergische Universita¨t Wuppertal, Gaußstr. 20, D-42097 Wuppertal, Germany
b PM-ABE, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany
c Inorganic Chemistry, Universita¨t Duisburg-Essen, D-47048 Duisburg, Lotharstr. 1, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient synthesis of N,N-bis(trifluoromethyl)anilines by means of dediazotation reactions of
previously unknown aryldiazoniumbis(trifluoromethyl)imides in the presence of CuI salts are described.
Properties and applications of N,N-bis(trifluoromethyl)anilines in syntheses of aromatic compounds
containing the (CF3)2N group are presented.
Received 25 August 2011
Received in revised form 19 October 2011
Accepted 20 October 2011
Available online 25 October 2011
ß 2011 Elsevier B.V. All rights reserved.
Dedicated to the memory of
Prof. L.M. Yagupolskii.
Keywords:
Dediazotation
Bi(aryl)coupling
N,N-bis(trifluoromethyl)aniline
1. Introduction
The myocardial contractile activity of these synthesised com-
pounds in comparison to Nifedipine (ß, 2-nitrophenyl derivate)
The N(CF3)2 group is an ‘‘exceptional’’ group in organic
chemistry. In spite of its structural analogy to the dimethylamino
group, N(CH3)2, aromatic compounds containing the N(CF3)2
group, show significantly different properties. For instance, N,N-
dimethylaniline C6H5N(CH3)2 is in contrast to N,N-bis(trifluoro-
methyl)aniline C6H5N(CF3)2 a strong base, and C6H5N(CF3)2 does
not dissolve in concentrated hydrochloric acid [1]. The electronic
nature of both substituents differs strongly as can be seen from the
Hammett constants N(CH3)2 (ꢀ0.44) and N(CF3)2 (+0.50) [1,2].
The N(CF3)2 group bonded to aryl compounds is stable against
acids, bases, oxidants and reductants [1]. All these properties
makes the N(CF3)2 group a valuable substituent to tune the
properties of aromatic compounds. Various aromatic substances
containing the N(CF3)2 group have been synthesised and tested for
possible practical applications.
was studied. The most active substance had the N(CF3)2 group in
the ortho position of the benzene ring.
p-Bromo-N,N-bis(trifluoromethyl)aminobenzene was applied
in the synthesis of amphetamine 2-amino-1-[(4-N,N,-bis(trifluor-
omethylamino)phenyl]propane [4] and p-iodo-N,N-bis(trifluoro-
methyl)aminobenzene was used as the starting material in the
preparation of a series of triphenylmethane dyes [5]. Carbocyanine
dyes having the (CF3)2N group in the benzene ring were prepared
from 3-nitro-4-amino-N,N-bis(trifluoromethyl)aniline [6].
All these examples demonstrate that aromatic compounds
containing the N(CF3)2 substituent can serve as useful starting
materials in the preparation of a variety of compounds with
potential application.
The first aromatic compounds containing the N(CF3)2 group
were synthesised at the beginning of the 60 s last century by the
group of Yagupolskii (Kiev, Ukraine) [1] and Sheppard (Central
Research Department, E.I. du Pont de Nemours and Company,
Delaware, USA) [7].
Yagupolskii et al. have prepared ortho-, meta-, and para-N,N-
bis(trifluoromethyl)amino benzaldehydes and used these com-
pounds for the synthesis of 4-aryl-1,4-dihydropyridines containing
the N(CF3)2 group by means of a modified Hantzsch method [3].
The method of Yagupolskii is based on chlorination/fluorination
reactions of aromatic compounds containing the N(CF3)(CH3)
group (Scheme 1) [8].
The starting material, compound (I), can be synthesised by the
reaction of N-methyl-N-arylthiuramdisulphides (II) with SF4
(Scheme 2) [8].
This method has many disadvantages, for instance: low yield,
multistep procedure, use of expensive and toxic reagents.
* Corresponding author. Tel.: +49 202 439 3460; fax: +49 32121 109129.
** Corresponding author. Tel.: +49 151 1454 3102; fax: +49 (0)6151 728587.
E-mail addresses: Markus.Hirschberg@uniwuppertal.de,
Markus.Hirschberg@gmx.de (M.E. Hirschberg), Nikolai.Ignatiev@merckgroup.com
(N.V. Ignat’ev).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.10.014

M.E. Hirschberg et al. / Journal of Fluorine Chemistry 135 (2012) 176–182
177
Scheme 5.
Scheme 6.
Scheme 1.
Scheme 2.
Scheme 7.
The Sheppard method is based on the fluorination of N,N-
bis(fluoroformyl)anilines (III) with SF4 in aHF [7]. The starting
compounds (III) can be prepared by addition of COF2 to aryl
isocyanates (Scheme 3).
The disadvantages of this method are: the low yield of the
reaction with SF4 (2–12%), the use of toxic reagents like COF2, SF4,
HF and the required pressure vessels made of Hastelloy for the
reaction with SF4.
A further synthesis of N,N-bis(trifluoromethyl)aniline was
claimed by thermal decarboxylation of the oxy-carbonyl com-
pound (IV) (Scheme 4) [9].
However, this method could not be reproduced [10–12].
Another method is based on the interaction of benzene or
substituted benzenes with (CF3)2NON(CF3)2 (not commercial
available) yielding the corresponding ArN(CF3)2 compounds in
mixtures with by-products [11]. This reaction proceeds at room
temperature within several days and a radical mechanism has
been postulated [11].
Recently Merck KGaA (Darmstadt, Germany) has developed a
convenient method to generate the [(CF3)2N]ꢀ anion by the
reaction of metal fluorides or tetramethylammonium fluoride with
N,N-bis(trifluoromethyl)trifluoromethansulfonamide
CF3SO2N(CF3)2 (Scheme 7) [15].
The side product CF3SO2F can be trapped together with
dimethylamine in an organic solvent or in an ionic liquid media
yielding CF3SO2N(CH3)2 (Scheme 8).
CF3SO2N(CH3)2 can be easily converted into N,N-bis(trifluor-
omethyl)trifluoromethansulfonamide CF3SO2N(CF3)2 by means of
electrochemical fluorination in anhydrous HF (Simons process)
(Scheme 9) [16]:
In practice, the combination of those three steps (described
above) allows converting the cheap dimethylamine into the
[N(CF3)2]ꢀ anion (Scheme 10).
We have successfully applied the substitution of halogens by
the [N(CF3)2]ꢀ anion, for example (see Schemes 11–14) [15].
However, we failed to substitute activated halogens in aromatic
compounds by [N(CF3)2]ꢀ. For example, in the reaction of 2,4-
dinitrochloro benzene with the [N(CF3)2]ꢀ anion the replacement
of Cl by F preferably took place. To our knowledge, no examples of a
nucleophilic substitution of halogen in a phenyl moiety with
[N(CF3)2]ꢀ anion has been reported.
The
addition
of
N-halogenobis(trifluoromethyl)amines
(CF3)2NX (X = Cl, Br, or I) to cyclohexa-1,3-diene at ꢀ78 8C followed
by treatment of the reaction mixture with KOH and dehydrogena-
tion by means of Pd/C at 180–190 8C resulted in the formation of
N,N-bis(trifluoromethyl)aniline in overall yield of 48% in the case
X = Br [13]. It was difficult to scale up that method which need a
reaction time of 3 days.
The [N(CF3)2]ꢀ anion can be generated by addition of CsF to
perfluoroazopropene CF3–N55CF2 and used to substitute a halogen
atom in an activated position, for example Cl in cyanurchloride
(Scheme 5) [14].
In this contribution we are presenting a new and convenient
method for the syntheses of N,N-bis(trifluoro methyl)anilines by
dediazotation reactions of the hitherto unknown diazonium salts
This method to generate the [N(CF3)2]ꢀ anion is not convenient
for practical application because CF3–N55CF2 is highly toxic and
commercially not available. Furthermore the reaction is not
selective and results also in the formation of the dimeric product
(V) (Scheme 6).
Scheme 8.
Scheme 3.
Scheme 9.
Schemes 10.
Scheme 4.

178
M.E. Hirschberg et al. / Journal of Fluorine Chemistry 135 (2012) 176–182
Schemes 11–14.
Schemes 15 and 16.
[4-XC6H4N2][N(CF3)2] in the presence of copper(I) salts with
weakly coordinating anions.
18% yield; addition of elemental copper to the reaction mixture
increased the yield of para-iodobis(trifluoromethyl)aniline to 49%.
The decomposition of p-fluoro- and p-bromo phenyldiazonium
bis(trifluoromethyl)imide at 20 8C in the absence of Cu0 did not
result in the corresponding N,N-bis(trifluoromethyl)anilines at all.
The replacement of the system CuI[WCA]/Cu0 by CuII[WCA]
salts led to the complete decomposition of the [XC6H4N2][N(CF3)2]
salts without forming the desired products but mainly (CF3)2N–
C(F)55N–CF3 (V). It seems that the Cu(II) cation acted as a fluoride
scavenger triggering the formation of dimeric product (V).
While m- and p-bromo-N,N-bis(trifluoromethyl)anilines were
accessible from the corresponding phenyldiazonium imides, only
traces of the ortho-derivate could be observed in the reaction
mixture by NMR-spectroscopy. Decomposition of [2-
XC6H4N2][N(CF3)2] (X = Br, CF3) in the presence of CuI[WCA]/Cu0
resulted in the formation of 2-XC6H4F and (CF3)2N–C(F)55N–CF3 (V)
as major products. Probably, the halogen atom or the CF3 group in
the ortho-position positivates the ipso-C-atom and therefore
increases its fluoride affinity.
2. Results and discussion
2.1. Syntheses and properties of the N,N-bis(trifluoromethyl)anilines
The starting compound Rb[N(CF3)2] [15] was synthesised from
CF3SO2N(CF3)2 [16] according to the described procedure. The
aryldiazonium tetrafluoroborates were prepared by diazotation of
anilines with NaNO2 in HBF4 (50%) at 3–20 8C. The reaction of
Rb[N(CF3)2] with aryldiazonium tetrafluoroborates gave the
hitherto unknown aryldiazonium bis(trifluoromethyl)imides in
good yields (Schemes 15 and 16).
The desired N,N-bis(trifluoromethyl)anilines were prepared by
decomposition of the aryldiazonium bis(trifluoromethyl)imides in
the presence of CuI[WCA]ꢁ4 CH3CN salts (WCA = BF4, PF6,
P(C2F5)3F3, CF3SO3). The yield of the N,N-bis(trifluoromethyl)ani-
lines was improved by using CuI[WCA] salts with an additional
equimolar amount of Cu0 (Scheme 17).
While the methods mentioned in the introduction have many
disadvantages (for instance: not always reproducible, low yield,
multistep procedure, expensive and toxic reagents), the here
presented method strikes out as a new and reproducible one
combined with good yields.
The influence of Cu0 on the yield of N,N-bis(trifluoromethyl)a-
nilines was demonstrated as following: the thermal decomposition
of the p-iodo-phenyldiazonium bis(trifluoro methyl)imide at 20 8C
without addition of elemental copper resulted in p-IC6H4N(CF3)2 in
Scheme 17.

M.E. Hirschberg et al. / Journal of Fluorine Chemistry 135 (2012) 176–182
179
Scheme 18.
Scheme 19.
Scheme 20.
p-Halogen-N,N-bis(trifluoromethyl)anilines,
in
particular
(CF3)2NC6H4C(O)OH acid over P4O10 under reflux allowed access to
the corresponding anhydride.
4-BrC6H4N(CF3)2, offer variety of possibilities for further
a
derivatisation of these compounds. We successfully involved
4-BrC6H4N(CF3)2 in Heck and Suzuki coupling reactions (Schemes
18–20).
As already mentioned the bis(trifluoromethyl)amino group
attached to the aromatic ring is chemically very inert. Thus, 4-
BrC6H4N(CF3)2 did not react with H2SO4(conc.) (98%), HCl (36%),
CF3SO3CH3 or (CH3)3SiCN at 20 8C within 24 h.
The Suzuki coupling reactions (Schemes 19 and 20) with
different boronic acids were successfully carried out in polyethyl-
ene glycol 2000. PEG 2000 served in that case as well as solvent and
as ligand for Palladium(0), which was generated in situ.
Similar to p-substituted N,N-bis(trifluoromethyl)anilines, the
reaction of 3-BrC6H4N(CF3)2 with C6H5B(OH)2 in PEG 2000 resulted
in the formation of N,N-bis(trifluoromethyl)biphenyl-3-amine
(isolated yield: 69%).
4-IC6H4N(CF3)2 was treatedwithdiluted elementalF2 to form the
previously unknown 4-(difluoro-l3-iodanyl)-N,N-bis(trifluoro-
methyl)aniline (Scheme 21). To avoid the fluorination of the
aromatic ring, the reaction was carried out at ꢀ70 8C in the inert
solvent CCl3F.
The reductive bi(aryl) coupling of the 4-IC6H4N(CF3)2 was
carried out in water in the presence of Pd/C, 18-C-6 and Zn (Scheme
22).
The precursor 4-BrC6H4N(CF3)2 provided a convenient access to
the Grignard reagent (CF3)2NC6H4MgBr which reacted with CO2
forming the 4-[bis(trifluoromethyl)amino] benzoic acid, (CF3)2
NC6H4C(O)OH [5,8]. This benzoic acid is a useful compound for the
preparation of derivates, for example esters by the reaction with
MeOH or EtOH in presence of H2SO4(conc.) as catalyst. Heating of the
2.2. Multinuclear magnetic resonance spectroscopy of N,N-
bis(trifluoromethyl)anilines and their derivates
In contrast to the bis(trifluoromethyl)imide anion (chemical
shift
d
F = ꢀ37 ppm) the covalently bonded (CF3)2N group showed
resonance at about ꢀ56 ppm (singlet). The same tendency was
observed in the 13C NMR spectra. The signals of covalently bonded
bis(trifluoromethyl)amino groups appeared at 120 ppm whereas
the signal of the bis(trifluoromethyl)imide anion was observed
1
at 125 ppm. Differences in the JC,F coupling constants of the
bis(trifluoromethyl)amino group (1JC,F = 262 Hz, quartet) and
the bis(trifluoromethyl)imide anion (1JC,F = 243 Hz, quartet;
3JC,F = 11 Hz) reflect the distinction in the geometry and electronic
nature of covalently bonded (CF3)2N group and the [(CF3)2N]ꢀ anion.
In the case of the 4-(CF3)2NC6H4IF2 compound, the bis(tri-
fluoromethyl)amino group showed the typical chemical shift in the
19F and 13C NMR mode and the IF2 group appeared as a singlet at
ꢀ176 ppm in the 19F NMR spectrum.
3. Experimental part
All moisture sensitive compounds were handled under an
atmosphere of dry argon. Reactions were carried out in glass
vessels or in traps made from FEP tubes (o.d. = 4.1 mm,
i.d. = 3.5 mm or o.d. = 9.0 mm, i.d = 8.0 mm). CH3CN (supplier:
KMF) was purified by reflux and distillation in sequence over
KMnO4 and P4O10, respectively.
NMR spectra were recorded on a Bruker NMR spectrometer
AVANCE 300 (13C at 75.47 MHz, 19F at 282.40 MHz, and 1H at
300.13 MHz) and a Bruker spectrometer AVANCE 400 (13C at
100.61 MHz, 19F at 376.50 MHz, and 1H at 400.13 MHz). The
chemical shifts were referenced to TMS (13C, 1H), CCl3F (19F) (C6F6
Scheme 21.
as a secondary reference,
d
= ꢀ162.9). The ratio of 19F and 1H nuclei
in the products was determined by NMR spectroscopy after
addition of 1,3,5-trifluorbenzene or benzotrifluoride. Raman
Scheme 22.

180
M.E. Hirschberg et al. / Journal of Fluorine Chemistry 135 (2012) 176–182
spectra were recorded on the Bruker FT-Raman spectrometers RFS
100/S and FRA 106/S using the 1064 nm line of a Nd/YAG laser. The
back-scattered (1808) radiation was sampled and analysed (stoke
range: 50–4000 cmꢀ1). The samples were placed in glass
capillaries or FEP tubes.
4-IC6H4N(CF3)2: B.p. 94 8C at 46 hPa. Yield 49% (4.02 g,
11.32 mmol). 19F NMR (CH2Cl2, 24 8C)
d
, ppm: ꢀ56.1 (s, 6F,
, ppm: 7.82 (d, 2H, 3JH,H = 9 Hz),
, ppm:
N(CF3)2). 1H NMR (CH2Cl2, 24 8C)
d
7.13 (d, JH,H = 9 Hz, 2H). 13C{1H} NMR (CH2Cl2, 24 8C)
d
3
139.0 s, 132.3 s, 131.4 s, 119.6 (q, 1JC,F = 263 Hz, N(CF3)2), 96.3 (s).
19F NMR (CD3CN, 24 8C)
(CD3CN, 24 8C)
d
, ppm: ꢀ54.5 (s, 6F, N(CF3)2). 1H NMR
3
3.1. Syntheses of aryldiazonium tetrafluoroborates
d
,
ppm: 7.86 (d, JH,H = 9 Hz, 2H), 7.20 (d,
3JH,H = 9 Hz, 2H). 13C NMR (CD3CN, 24 8C)
d, ppm: 138.4 (dd,
2
2
3
Aryldiazonium tetrafluoroborates were prepared according to
the described methods [17].
1JC,H = 168 Hz, JC,H = 7 Hz), 132.1 (tt, JC,H = 9 Hz, JC,H = 3 Hz),
1
2
1
130.9 (dd, JC,H = 165 Hz, JC,H = 5 Hz), 119.2 (q, JC,F = 262 Hz,
(N(CF3)2), 95.8 (tt, JC,H = 10 Hz, JC,H = 3 Hz). Raman spectrum
(20 8C)
, cmꢀ1: 83 [72], 142 [47], 231 [30], 321 [13], 364 [8], 621
2
3
3.2. Syntheses of aryldiazonium bis(trifluoromethyl)imides
n
[13], 692 [23], 773 [100], 944 [11], 1014 [6], 1060 [24], 1179 [20],
1218 [23], 1585 [21], 3072 [56].
Aryldiazonium bis(trifluoromethyl)imides were prepared as
described previously [18].
3-BrC6H4N(CF3)2: B.p. 92 8C at 101 hPa. Yield 50% (3.06 g,
9.93 mmol). 19F NMR (CDCl3, 24 8C)
d
,
ppm: ꢀ56.1 (s, 6F,
, ppm: 7.66 (m, two overlapping
signals, 2H), 7.36 (m, two overlapping signals, 2H). 13C{1H} NMR
(CDCl3, 24 8C) , ppm: 134.4 (s), 134.0 (s), 133.6 (s), 131.1 (s), 129.0
3.3. Syntheses of arylbis(trifluoromethyl)amines
N(CF3)2). 1H NMR (CDCl3, 24 8C)
d
Synthesis of 4-FC6H4N(CF3)2 as an example: CF3SO2N(CF3)2
(5.12 g, 17.83 mmol) was added to a cold suspension (0 8C) of
RbF (1.61 g, 15.41 mmol) in CH3CN (7 mL). After 20 min the solid
was dissolved and the solution was added to a stirred cold solution
(0 8C) of [4-FC6H4N2][BF4] (2.8 g, 13.3 mmol) in CH3CN (9 mL). A
precipitate was formed. After 15 min of stirring the suspension was
degassed in vacuum (0.05 hPa, ꢀ25 8C, 7 min) and added dropwise
to a suspension (ꢀ30 8C) of Cu[PF6]ꢁ4 CH3CN (1.67 g, 4.48 mmol)/
Cu(0) (0.86 g, 13.56 mmol) in CH3CN (5 mL). The supernatant
became green. The reaction mixture was warmed to ꢀ20 8C and to
0 8C within 30 min, respectively. Finally, when the suspension was
stirred at 20 8C the supernatant became orange. The product 4-
FC6H4N(CF3)2 was distilled in vacuum with CH3CN. By azeotropic
distillation with n-pentane CH3CN could be removed and the
product was purified by repeated distillation. A colorless liquid
was obtained in 43% yield (1.41 g, 5.71 mmol).
d
1
(s), 123.3 (s), 120.2 (q, JC,F = 262 Hz, N(CF3)2). 19F NMR (CD3CN,
24 8C)
d
, ppm: ꢀ56.6 (s, 6F, N(CF3)2). 1H NMR (CD3CN, 24 8C)
d,
ppm: 7.72 (m, 1H), 7.67 (m, 1H), 7.45 (m, two overlapping signals,
2H). 13C{1H} NMR (CD3CN, 24 8C)
(s), 132.5 (s), 129.9 (s), 123.5 (s), 120.9 (q, 1JC,F = 262 Hz, N(CF3)2).
Raman spectrum (20 8C)
, cmꢀ1: 94 [22], 160 [6], 181 [12], 265 [7],
d, ppm: 135.1 (s), 134.6 (s), 134.0
n
297 [32], 327 [4], 374 [3], 557 [1], 645 [5], 713 [6], 784 [24], 1003
[100], 1073 [6], 1170 [3], 1216 [11], 1578 [5], 1592 [7], 3079 [37].
3.4. Heck coupling of 4-BrC6H4N(CF3)2 with styrene
A
suspension of Pd(OAc)2 (0.005 g, 0.022 mmol), K2CO3
(0.822 g, 5.948 mmol), styrene (0.476 g, 4.570 mmol), acetylace-
tone (5 L, 0.049 mmol), DMF (6 mL) and 4-BrC6H4N(CF3)2 (1.01 g,
m
3.25 mmol) was heated for 1 h at 130 8C under inert atmosphere
(Ar or N2). The suspension was cooled to 20 8C and H2O (50 mL)
was added. The solid was separated, dissolved in Et2O (50 mL) and
filtrated. The solvent was removed in vacuum (0.05 hPa, 20 8C, 2 h)
and the solid product was obtained in 83% yield (0.897 g,
2.707 mmol).
B.p. 115 8C (DSC: endothermic; TOnset) [Lit. 118–119 8C] [8]. 19
NMR (CH2Cl2, 24 8C)
, ppm: ꢀ57.1 (s, 6F, N(CF3)2), ꢀ111.4 (m, 1F,
F
d
4-FC6H4). 1H NMR (CH2Cl2, 24 8C) , ppm: 7.47 (m, 2H, H2,6), 7.18
d
(m, 2H, H3,5). 13C{1H} NMR (CH2Cl2, 24 8C)
d, ppm: 163.4 (d,
3
4
1JC,F = 251 Hz, C4), 131.6 (d, JC,F = 9 Hz, C2,6), 128.6 (d, JC,F = 3 Hz,
C1), 119.8 (q, JC,F = 262 Hz, N(CF3)2), 116.1 (d, JC,F = 23 Hz, C3,5).
M.p. 119 8C (DSC: endothermic, TOnset). 19F NMR (CH2Cl2, 24 8C)
1
2
19F NMR (CH3CN, 24 8C)
d
, ppm: ꢀ55.9 (s, 6F, N(CF3)2), ꢀ110.5 (tt,
d
, ppm: ꢀ56.0 (s, 6F, N(CF3)2). 1H NMR (CH2Cl2, 24 8C)
d, ppm:
3JF,H = 8 Hz, JF,H = 4 Hz, 1F, 4-FC6H4). 1H NMR (CH3CN, 24 8C)
d
,
overlapping signals from 7.7 to 7.0. 13C{1H} NMR (CH2Cl2, 24 8C)
d,
4
ppm: 7.47 (m, 2H, H2,6), 7.19 (m, 2H, H3,5). 13C{1H} NMR (CH3CN,
ppm: 139.4 (s), 136.6 (s), 131.3 (s), 130.9 (s), 129.9 (s), 128.6 (s),
1
3
1
24 8C)
d
, ppm: 163.7 (d, JC,F = 250 Hz, C4), 132.0 (d, JC,F = 9 Hz,
128.1 (s), 127.3 (s), 126.7 (s), 126.6 (s), 119.8 (q, JC,F = 262 Hz,
C2,6), 128.7 (d, JC,F = 3 Hz, C1), 120.0 (q, JC,F = 261 Hz, N(CF3)2),
(N(CF3)2). 19F NMR (CD3CN, 24 8C)
d
, ppm: ꢀ54.4 (s, 6F, N(CF3)2). 1H
4
1
116.6 (d, JC,F = 23 Hz, C3,5). Raman spectrum (20 8C)
n
, cmꢀ1: 83
NMR (CD3CN, 24 8C)
d, ppm: overlapping signals from 7.8 to
2
[84], 178 [7], 190 [7], 302 [21], 339 [7], 349 [7], 368 [10], 395 [13],
626 [10], 736 [3], 764 [44], 821 [100], 849 [6], 949 [9], 1157 [16],
1212 [8], 1257 [19], 1609 [14], 3010 [3], 3089 [63]. Elementary
analysis: calculated for C8H4F7N, %: C 38.88%, H 1.63%, N 5.67%;
found, %: C 38.42, H 1.59, N 6.03.
7.2 ppm. 13C{1H} NMR (CD3CN, 24 8C)
d, ppm: 140.8 (s), 137.7 (s),
131.9 (s), 131.8 (s), 131.0 (s), 129.7 (s), 129.1 (s), 128.5 (s), 127.6 (s,
two overlapping signals), 120.8 (q, 1JC,F = 261 Hz, N(CF3)2). Raman
spectrum (20 8C) n
, cmꢀ1: 106 [88], 203 [9], 618 [6], 668 [6], 769
[26], 825 [5], 867 [22], 949 [5], 1000 [36], 1029 [9], 1158 [6], 1182
[46], 1191 [67], 1225 [6], 1291 [5], 1306 [5], 1324 [14], 1417 [5],
1450 [4], 1494 [4], 1571 [11], 1597 [11], 1633 [100], 2997 [7], 3042
[6], 3066 [30].
4-BrC6H4N(CF3)2: B.p. 162 8C (DSC: endothermic; TOnset) [Lit.
84–87 8C at 50 mm] [8]. Yield 65% (8 g, 26 mmol). 19F NMR (CD2Cl2,
24 8C)
d
, ppm: ꢀ56.0 (s, 6F, N(CF3)2). 1H NMR (CD2Cl2, 24 8C)
d,
3
3
ppm: 7.63 (d, JH,H = 9 Hz, 2H), 7.29 (d, JH,H = 9 Hz, 2H). 13C NMR
(CH2Cl2, 24 8C)
d
, ppm: 132.7 (dd, 1JC,H = 168 Hz, 2JC,H = 6 Hz), 131.4
3.5. Suzuki coupling of 4-Br- and 3-BrC6H4N(CF3)2 with arylboranes
(tt, 2JC,H = 10 Hz, 3JC,H = 3 Hz), 131.2 (dd, 1JC,H = 165 Hz,
2JC,H = 5 Hz), 124.5 (tt, JC,H = 11 Hz, JC,H = 3 Hz), 119.5 (q,
Synthesis of 4-[N,N-bis(trifluoromethyl)amino]biphenyl as an
example: A suspension of Pd(OAc)2 (0.005 g, 0.022 mmol), K2CO3
(0.792 g, 5.731 mmol), C6H5B(OH)2 (0.564 g, 4.626 mmol),
2
3
1JC,F = 262 Hz, N(CF3)2). 13C NMR (CH3CN, 24 8C)
d
, ppm: 133.7
(dd, 1JC,H = 168 Hz, 2JC,H = 6 Hz), 132.2 (dd, 1JC,H = 165 Hz,
2JC,H = 5 Hz), 132.0 (tt, JC,H = 10 Hz, JC,H = 3 Hz), 125.1 (tt,
acetylacetone (5 mL, 0.049 mmol), DMF/H2O (5 mL/5 mL), and 4-
2
3
2JC,H = 11 Hz, 3JC,H = 3 Hz), 120.2 (q, 1JC,F = 262 Hz, N(CF3)2). Raman
BrC6H4N(CF3)2 (0.9 g, 2.9 mmol) was heated for 2 h at 90 8C under
inert atmosphere (Ar or N2). The suspension was cooled to 20 8C
and H2O (60 mL) was added. The solid was separated, dissolved in
Et2O (25 mL) and filtrated. The solvent was removed in vacuum
(0.05 hPa, 20 8C, 2 h). The product 4-[N,N-bis(trifluoromethyl)a-
spectrum (20 8C) n
, cmꢀ1: 82 [79], 156 [34], 248 [32], 290 [9], 327
[11], 366 [8], 562 [3], 621 [12], 673 [3], 704 [18], 732 [9], 774 [100],
811 [7], 956 [8], 1001 [10], 1019 [6], 1072 [30], 1175 [15], 1218
[23], 1589 [24], 3077 [74], 3177 [3].

M.E. Hirschberg et al. / Journal of Fluorine Chemistry 135 (2012) 176–182
181
mino]biphenyl was obtained in 88% yield (0.783 g, 2.565 mmol)
and could be sublimated (1.4 hPa, 55 8C).
were suspended in H2O (7 mL). The suspension was stirred for 48 h
at 20 8C and extracted with Et2O (20 mL). The combined organic
phases were dried over MgSO4. The solvent was removed in
vacuum (0.05 hPa, 20 8C, 2 h). The product 4,40-[N,N,N0,N0-Tetra-
kis(trifluoromethyl)diamino]biphenyl could be isolated as white
solid in 47% yield (0.181 g, 0.397 mmol).
M.p. 85 8C (DSC: endothermic, TOnset). 19F NMR (CH2Cl2,
24 8C)
d
, ppm: ꢀ56.0 (s, 6F, N(CF3)2). 1H NMR (CH2Cl2, 24 8C)
d,
3
3
ppm: 7.72 (d, JH,H = 8 Hz, 2H), 7.64 (d, JH,H = 8 Hz, 2H), 7.6–7.4
(m, 5H, five overlapping signals). 13C{1H} NMR (CH2Cl2, 24 8C)
d,
ppm: 143.2 (s), 139.4 (s), 131.5 (s), 129.9 (s), 128.8 (s), 128.1 (s),
M.p. 64.2 8C (DSC: endothermic, TOnset). 19F NMR (n-pentane,
1
127.9 (s), 127.0 (s), 119.9 (q, JC,F = 262 Hz, N(CF3)2). Raman
24 8C)
d
, ppm: ꢀ56.4 (s, 6F, N(CF3)2). 1H NMR (n-pentane, 24 8C)
d,
3
3
spectrum (20 8C)
n
, cmꢀ1: 95 [100], 218 [6], 256 [9], 333 [4], 614
ppm: 7.56 (d, JH,H = 9 Hz, 4H), 7.43 (d, JH,H = 9 Hz, 4H). 13C{19F}
[11], 643 [5], 741 [17], 779 [61], 951 [6], 997 [38], 1039 [17],
1162 [5], 1198 [13], 1256 [15], 1278 [51], 1598 [38], 1608 [55],
3070 [32], 3080 [43].
NMR (n-pentane, 24 8C)
pentane, 24 8C) , ppm: 142.2 (s), 133.5 (s), 130.7 (s), 128.4 (s).
Raman spectrum (20 8C)
, cmꢀ1: 84 [57], 234 [5], 367 [4], 419 [8],
d
, ppm: 120.4 (s, N(CF3)2). 13C{1H} NMR (n-
d
n
Instead of DMF and acetylacetone, PEG 2000 could be used.
446 [3], 569 [3], 622 [8], 756 [3], 786 [47], 828 [3], 950 [4], 1191
[14], 1225 [5], 1289 [44], 1527 [3], 1612 [100], 3085 [15].
3-[N,N-bis(trifluoromethylamino]biphenyl
19F NMR (n-pentane, 24 8C)
d
, ppm: ꢀ57.1 (s, 6F, N(CF3)2). 1H
3.8. Reduction of 4-BrC6H4N(CF3)2 to C6H5N(CF3)2
NMR (n-pentane, 24 8C) d, ppm: overlapping signals from 7.1 to
7.6 ppm. 13C NMR (n-pentane, 24 8C)
d
, ppm: 143.6 (m), 139.7 (m),
Cu (0.10 g, 1.57 mmol), Zn (0.10 g, 1.53 mmol) and 4-
BrC6H4N(CF3)2 (0.25 g, 0.81 mmol) were suspended in a mixture
of H2O and acetone (each 3 mL). After 24 h of stirring at 20 8C, the
complete reduction of 4-BrC6H4N(CF3)2 to C6H5N(CF3)2 was
observed.
1
1
133.8 (m), 129.6 (dm, JC,H = 162 Hz), 128.8 (dm, JC,H = 160 Hz),
1
1
128.7 (dm JC,H = 162 Hz), 128.5 (dm, JC,H = 160 Hz), 128.2 (dm,
1JC,H = 164 Hz), 127.9 (dm, 1JC,H = 160 Hz), 127.0 (dm,
1
1JC,H = 160 Hz), 120.3 (q, JC,F = 262 Hz, N(CF3)2).
40-Methoxy-4-[N,N-bis(trifluoromethyl)amino]biphenyl: Subli-
mation: 1.4 hPa, 60 8C. Yield 61% (0.415 g, 1.238 mmol). 19F
19F NMR (CH2Cl2, 24 8C)
(CH2Cl2, 24 8C)
d
, ppm: ꢀ55.4 (s, 6F, N(CF3)2). 1H NMR
d
, ppm: 7.77 (m, 2H), 7.46 (m, 3H).
NMR (CH2Cl2, 24 8C)
(CH2Cl2, 24 8C)
d
, ppm: ꢀ56.0 (s, 6F, N(CF3)2). 1H NMR
3
d
,
ppm: 7.66 (d, JH,H = 8 Hz, 2H), 7.56 (d,
3.9. Reaction of 4-(CF3)2NC6H4MgBr with CO2 to 4-
(CF3)2NC6H4C(O)OH
3JH,H = 9 Hz, 2H), 7.46 (d, JH,H = 8 Hz, 2H), 7.02 (d, JH,H = 9 Hz,
2H), 3.85 (s, 3H, OCH3). 13C NMR (CH2Cl2, 24 8C)
, ppm: 159.8 (m),
142.8 (tt, JC,H = 7 Hz, JC,H = 4 Hz), 131.6 (m), 130.8 (tt, 2JC,H = 10 Hz,
3
3
d
The Grignard reagent prepared from 4-BrC6H4N(CF3)2 (2.00 g,
6.49 mmol) and Mg turnings (0.16 g, 6.58 mmol) in ether (4 mL)
was treated with dry carbon dioxide at 0 8C. After 20 min the
reaction mixture was hydrolysed by ice and diluted HCl and was
extracted with Et2O (twice 5 mL). The combined organic phases
were dried over MgSO4, filtrated and the solvent was removed in
vacuum (0.05 hPa, 20 8C, 4 h). The solid was purified by
crystallisation from n-hexane and by sublimation (0.05 hPa,
80–90 8C, 24 h). The product 4-[bis(trifluoro methyl)amino]ben-
zoic acid was isolated as a white solid in 46% yield (2.31 g,
8.46 mmol).
3JC,H = 2 Hz), 129.9 (dm, JC,H = 164 Hz), 128.1 (dd, JC,H = 158 Hz,
1
1
2JC,H = 7 Hz), 127.5 (dd, JC,H = 161 Hz, JC,H = 7 Hz), 119.9 (q,
1
2
1JC,F = 262 Hz, N(CF3)2), 114.2 (dm JC,H = 160 Hz), 55.0 (q,
1
1JC,H = 144 Hz, OCH3). Raman spectrum (20 8C) , cmꢀ1: 84 [94],
n
231 [6], 350 [4], 408 [7], 624 [9], 717 [4], 748 [5], 774 [22], 807 [36],
950 [5], 1038 [3], 1193 [26], 1256 [19], 1282 [50], 1459 [5], 1533
[5], 1603 [100], 2844 [11], 2945 [8], 3021 [8], 3080 [40].
3.6. Fluorination of 4-IC6H4N(CF3)2 to 4-F2IC6H4N(CF3)2
4-IC6H4N(CF3)2 (0.50 g, 1.41 mmol) was dissolved in CCl3F
(2 mL) and a mixture of fluorine in nitrogen (5 vol%; precooled by a
copper helix at ꢀ70 8C) was bubbled into the stirred solution.
During the reaction, a solid precipitated. After addition of one
equivalent of fluorine, the fluorination was stopped. The superna-
tant was separated and the white solid was crystallised from n-
pentane. After separation the solid was dried in vacuum (0.05 hPa,
20 8C, 30 min). The product 4-(difluoro-l3-iodanyl)-N,N-bis(tri-
fluoromethyl)aniline was isolated as a white solid in 85% yield
(0.468 g, 1.191 mmol).
M.p. 136.2 8C (DSC: endothermic; TMax), lit. 139–139.4 8C [8].
19F NMR (CDCl3, 27 8C)
d
, ppm: ꢀ55.6 (s, 6F, N(CF3)2). 1H NMR
(CDCl3, 27 8C) d
, ppm: 12.65 (s, CO2H) 8.21 (m, 1JC,H = 168 Hz, 2H),
7.51 (m, 1JC,H = 165 Hz, 2H). 13C NMR (CDCl3, 27 8C)
d
, ppm: 171.6
1
(m), 137.9 (m), 132.0 (dd, JC,H = 167 Hz, JC,H = 7 Hz), 131.4 (m),
1
1
130.2 (dd, JC,H = 166 Hz, JC,H = 5 Hz), 120.0 (q, JC,F = 263 Hz,
N(CF3)2). 19F NMR (CD3CN, 27 8C)
, ppm: ꢀ56.3 (s, 6F, N(CF3)2).
1H NMR (CD3CN, 27 8C)
ppm: 9.27 (s, CO2H) 8.14 (m,
1JC,H = 167 Hz, 2H), 7.57 (m, JC,H = 165 Hz, 2H). 13C{1H} NMR
(CD3CN, 27 8C) , ppm: 166.8 (s), 137.0 (s), 133.1 (s), 132.1 (s),
130.8 (s), 120.6 (q, 1JC,F = 263 Hz, N(CF3)2). Raman spectrum (20 8C)
, cmꢀ1: 86 [83], 261 [4], 292 [16], 319 [12], 369 [10], 570 [3], 627
d
d
,
1
d
M.p. 70 8C (DSC: endothermic; TOnset). Dec. 187.6 8C (DSC:
exothermic, TOnset). 19F NMR (CH2Cl2, 24 8C)
d
, ppm: ꢀ55.9 (s, 6F,
n
N(CF3)2), ꢀ176.0 (s, 2F, IF2). 1H NMR (CH2Cl2, 24 8C)
d
, ppm: 8.05 (d,
[28], 672 [4], 767 [25], 783 [5], 806 [100], 828 [8], 952 [14], 1134
[14], 1180 [13], 1220 [14], 1285 [22], 1360 [6], 1418 [5], 1612 [69],
3
3JH,H = 9 Hz, 2H), 7.64 (d, JH,H = 9 Hz, 2H). 13C{19F} NMR (CH2Cl2,
24 8C)
d
, ppm: 119.6 (s, N(CF3)2). 13C{1H} NMR (CH2Cl2, 24 8C)
d
,
1642 [33] (
n .
s(C55O)), 3021 [5], 3092 [38] cmꢀ1
3
ppm: 135.2 (s), 132.3 (s), 130.8 (t, JC,IF2 = 5 Hz, C3,5), 124.6 (t,
2JC,IF2 = 10 Hz, C4), 119.6 (q, JC,F = 262 Hz, N(CF3)2). Raman
spectrum (20 8C) n
, cmꢀ1: 84 [100], 139 [65], 234 [29], 291 [15],
3.10. Esterification of 4-(CF3)2NC6H4C(O)OH
1
325 [14], 364 [11], 386 [17], 457 [27], 509 [66], 558 [9], 620 [20],
691 [21], 774 [77], 948 [6], 1009 [14], 1047 [11], 1183 [13], 1223
[21], 1379 [13], 1489 [4], 1582 [21], 3082 [42], 3164 [6].
Synthesis of 4-EtO(O)CC6H4N(CF3)2 as an example: 4-
HO2CC6H4N(CF3)2 (0.14 g, 0.51 mmol) was dissolved in EtOH
(0.2 mL) and H2SO4(conc.) (10
mL, 0.02 g, 0.19 mmol) was added.
The reaction mixture was heated for 5 h at 85 8C and cooled to
20 8C. The solvent was removed in vacuum (0.05 hPa, 20 8C,
30 min) and a pale orange solution remained. Ice water was added
and the solution was extracted with Et2O (three times 1 mL). The
combined organic extracts were washed with a Na2CO3 solution
(1 mL) and with H2O (1 mL) and dried over MgSO4. The organic layer
3.7. Reductive coupling of 4-IC6H4N(CF3)2 to 4,40-(CF3)2NC6H4–
C6H4N(CF3)2
Pd/C (0.39 g, 0.36 mmol), 18-C-6 (0.102 g, 0.386 mmol), Zn
(0.364 g, 5.494 mmol), and 4-IC6H4N(CF3)2 (0.30 g, 0.85 mmol)

182
M.E. Hirschberg et al. / Journal of Fluorine Chemistry 135 (2012) 176–182
was filtrated and the solvent was removed in vacuum (0.05 hPa,
20 8C, 2 h). The product ethyl 4-[bis(trifluoro methyl)amino]benzo-
ate was isolated as a colorless oil in 73% yield (0.11 g, 0.37 mmol).
Acknowledgement
We thank Dr. Jane Hubner (Bergische Universitat Wuppertal,
Germany) for analytical measurements.
¨
¨
19F NMR (CDCl3, 24 8C)
d
, ppm: ꢀ55.8 (s, 6F, N(CF3)2). 1H NMR
1
(CDCl3, 27 8C)
d
, ppm: 8.10 (m, JC,H = 165 Hz, 2H), 7.43 (m,
1JC,H = 164 Hz, 2H), 4.37 (q, 1JC,H = 148 Hz, 3JH,H = 7 Hz, CH2), 1.36 (t,
References
1JC,H = 127 Hz, JH,H = 7 Hz, CH3). 13C{1H} NMR (CDCl3, 27 8C)
d,
3
[1] L.M. Yagupolskii, Aromatic and Heterocyclic Compounds with Fluoro-containing
Substituents, Naukova Dumka, Kiev, 1988.
[2] P. Kirsch, Modern Fluoroorganic Chemistry. Synthesis, Reactivity, Applications,
2004.
[3] L.M. Yagupolsky, S.S. Shavaran, B.M. Klebanov, A.N. Rechitsky, I.I. Maletina, Khim.
Farm. Zh. 28 (1994) 28–31.
[4] R.N. Haszeldine, A.E. Tipping, R.H. Valentine, J. Fluorine Chem. 21 (1982) 329–334.
[5] M.I. Dronkina, L.M. Yagupol’skii, Zh. Org. Khim. 9 (1973) 2167–2172.
[6] M.I. Dronkina, S.P. Makarov, N.V. Kondratenko, L.M. Yagupol’skii, Ukr. Khim. Zh.
35 (1969) 535–540.
[7] F.S. Fawcett, W.A. Sheppard, J. Am. Chem. Soc. 87 (1965) 4341–4346.
[8] L.M. Yagupol’skii, M.I. Dronkina, Zh. Obshch. Khim. 36 (1966) 1343–1344.
[9] V.A. Ginsberg, N. Mirabekova, V. Grishina, U.S.S.R. Patent 360339 (1972).
[10] C.M. Irvin, Ph.D. Thesis, University of Manchester, 1980.
[11] G.D. Connelly, R.N. Haszeldine, A. Kenny, C.M. Irvin, A.E. Tipping, J. Fluorine Chem.
17 (1981) 191–195.
[12] M.S. Falou, C.M. Irvin, D. Jackson, A.E. Tipping, J. Fluorine Chem. 34 (1986) 259–264.
[13] T.W. Hart, R.N. Haszeldine, A.E. Tipping, J. Chem. Soc., Perkin Trans. I (1980) 1544–
1550.
[14] A.F. Gontar, E.G. Bykhovskaya, I.L. Knunyants, Izv. Akad. Nauk SSSR, Ser. Khim.
(1975) 2279–2282.
[15] (a) U. Heider, M. Schmidt, P. Sartori, N, Ignatyev, A. Kucheryna, EP 1 081 129 B1,
Merck Patent GmbH, Darmstadt, Germany.;
ppm: 165.6 (s), 136.9 (s), 132.7 (s), 131.2 (s), 130.0 (s), 120.1 (q,
1JC,F = 262 Hz, N(CF3)2), 61.8 (s, CH2), 14.5 (s, CH3).
4-(CF3)2NC6H4C(O)OCH3: 19F NMR (CDCl3, 27 8C)
d
, ppm: ꢀ55.8
(s, 6F, N(CF3)2). 1H NMR (CDCl3, 27 8C)
d, ppm: 8.09 (d,
1JC,H = 166 Hz, 3JH,H = 8 Hz, 2H), 7.43 (d, 1JC,H = 166 Hz, 3JH,H = 8 Hz,
1
2H), 3.90 (s, JC,H = 147 Hz, CH3). 13C{1H} NMR (CDCl3, 27 8C)
d
,
ppm: 166.1 (s), 137.0 (s), 132.4 (s), 131.3 (s), 130.1 (s), 120.0 (q,
1JC,F = 263 Hz, N(CF3)2), 52.7 (s, CH3).
3.11. Synthesis of [(CF3)2NC6H4C(O)]2O
4-(CF3)2NC6H4C(O)OH (0.40 g, 1.46 mmol) was dissolved in
CH2Cl2 (6 mL) and P4O10 (0.3 g, 0.1 mmol) was added. The
suspension was heated for 4 h under reflux and cooled to 20 8C.
After extraction with Et2O (3 mL), the extract was evaporated in
vacuum (0,05 hPa, 20 8C, 2 h). A solid remained, which was
crystallised from CH2Cl2 at ꢀ40 8C. The product 4-[bis(trifluoro-
methyl)amino]benzoic acid anhydride was dried in vacuum
(0.05 hPa, 20 8C, 2 h) to give 36% yield (0.28 g, 0.53 mmol).
(b) V. Hilarius, H. Buchholz, N. Ignatiev, P. Sartori, A. Kucherina, S. Datsenko, WO
2000/046180, Merck Patent GmbH, Darmstadt, Germany.;
(c) N. Ignatyev, U. Welz-Biermann, M. Schmidt, H. Willner, A. Kucheryna, WO
2004/054991, Merck Patent GmbH, Darmstadt, Germany.
[16] P. Sartori, N. Ignat’ev, S. Datsenko, J. Fluorine Chem. 75 (1995) 157–161.
[17] P. Hanson, J.R. Jones, A.B. Taylor, P.H. Walton, A.W. Timms, J. Chem. Soc., Perkin
Trans. 2 (2002) 1135–1150.
M.p. 78 8C (DSC: endothermic; TOnset). 19F NMR (CDCl3, 27 8C)
d,
ppm: ꢀ55.5 (s, 12F, 2 N(CF3)2). 1H NMR (CDCl3, 27 8C)
d
, ppm: 8.23
(m, 4H), 7.56 (m, 4H). 13C{1H} NMR (CDCl3, 27 8C)
d, ppm: 161.0 (s),
1
138.6 (s), 132.2 (s), 130.64 (s), 130.63 (s), 119.9 (q, JC,F = 263 Hz,
N(CF3)2).
[18] M.E. Hirschberg, N.V. Ignat’ev, A. Wenda, H.-J. Frohn, H. Willner, J. Fluorine Chem.
135 (2012) 176–182.