Convenient synthesis of aliphatic (CF3)2N-compounds

Article abstract of DOI:10.1016/j.jfluchem.2017.11.007

Convenient syntheses of organic compounds bearing the (CF₃)₂N group by means of nucleophilic substitution reactions with the [N(CF₃)₂]^? anion were developed. The syntheses and properties of previously

Full text of DOI:10.1016/j.jfluchem.2017.11.007

Accepted Manuscript
Title: Convenient synthesis of aliphatic (CF ) N-compounds
3
2
Authors: Christoph Breitenstein, Nikolai Ignat’ev, Walter
Frank
PII:
S0022-1139(17)30384-6
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2017.11.007
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Convenient synthesis of aliphatic (CF
3
2
) N-compounds
1
2*
Walter Frank1
Christoph Breitenstein , Nikolai Ignat‘ev
,
1
Institut für Anorganische Chemie und Strukturchemie, Material- und
Strukturforschung, Heinrich-Heine-Universität, Düsseldorf, Germany
2
Consultant, Merck KGaA, Darmstadt, Germany; Dr. Ignatiev – Chemistry
Consultancy, Duisburg, Germany; nikolai.ignatiev@external.merckgroup.com;
ignatiev@web.de
th
Dedicated to Professor Helge Willner on the occasion of his 70 birthday.
Keywords: nucleophilic substitution; [N(CF
3
)
]- anion; N,N-bis(trifluoromethyl)glycine;
2
fluorinated amino acids; acidity; ionic liquids in organic synthesis
Graphical Abstract
Highlights
1
. [N(CF
3
)
2
]- anion can be easily generated from CF
3
SO
2
N(CF
3
)2.
3 2
2. (CF )
N-derivatieves are accessible via nucleophilic substitution.
3
. Previously unknown N,N-bis(trifluoromethyl)glycine is prepared in high yield.
Abstract.
1

Convenient syntheses of organic compounds bearing the (CF
nucleophilic substitution reactions with the [N(CF
]- anion were developed. The
syntheses and properties of previously unknown N,N-bis(trifluoromethyl)glycine
CF NCH C(O)OH and its derivatives are described.
3
)
2
N group by means of
)
3 2
(
3
)
2
2
1. Introduction
The [N(CF
3
)
2
]- anion can be regarded as an analogue to well-known
-
bis(trifluoromethylsulfonyl)imide anion, [(CF
3
SO
2
)
2
N] (DesMarteau anion [1]). Both
anions are conjugated bases of the corresponding acids, namely
bis(trifluoromethyl)amine, (CF NH (1), and bis(trifluoromethylsulfonyl)imide,
CF SO NH. Although the (CF
)
3 2
(
3
2
)
2
3
SO
2
)
2
NH [1,2] was synthesised much later than
-
bis(trifluoromethyl)amine (1) [3,4], the chemistry of the [(CF
better developed in comparison to the chemistry of the [N(CF
the bis(trifluoromethylsulfonyl)imide, (CF SO NH, and its salts are available from
various companies or can be prepared from trifluoromethylsulfonyl fluoride,
CF SO F, by previously reported protocols [1,2]. The acid (CF SO NH and its alkali
metal salts (CF SO NM (M = Li, Na, K) [5] are convenient starting materials for the
3
SO
2
)
2
N] anion is far
)
]- anion. Currently,
3
2
3
)
2 2
3
2
3
)
2 2
3
)
2 2
preparation of hydrophobic ionic liquids with the bis(trifluoromethylsulfonyl)imide
anion [6].
Apparently, (CF
However, bis(trifluoromethyl)amine (1) can be protonated by the action of super
acids, like anhydrous HF (aHF) acidified with AsF [7,8].
The acidity of (CF SO NH (pKa = 1.7 [1]) is much higher than the acidity of
NH. Nevertheless, (CF NH can be deprotonated by action of strong bases,
for instance by triethylamine (Scheme 1) [9]. Salt 2 was isolated and characterized by
3
)
2
NH (1) is a much weaker base in comparison to (CH
3
2
) NH.
5
3
)
2 2
(CF
3
)
2
)
3 2
1
19
H and F NMR and elemental analysis [9].
Scheme 1. Deprotonation of the (CF
3
2
) NH with triethylamine [9].
2

The reactions of salt 2 with allylbromide or α-bromo-ethylacetate resulted in the
formation of the corresponding substituted products 3 and 4 (Scheme 2) [9].
Presumably, these reactions proceeded via a S 1 mechanism.
N
Scheme 2. Nucleophilic substitution reactions of the (CF
3
2
) N-anion [9].
Bis(trifluoromethyl)amine (I) can be prepared by various methods as described in the
literature [3, 4, 10]. (CF NH is a gas with a b.p. of -6.7 °C and it is extremely
moisture sensitive [4]. Due to these properties, compound 1 is not an ideal starting
material for the generation of the [N(CF
]- anion. More conveniently, the salts
CF NM (M = Cs, K) can be prepared by addition of CsF or KF to
perfluoroazapropene, CF -N=CF (5) [11,12]. Cs[N(CF ] was isolated as a solid and
characterized by NMR, infrared and Raman spectroscopy [13]. Cs[N(CF ] reacts
with allylbromide or α-bromoethylacetate similarly to the salt 2 giving access to the
compounds 3 and 4 [11,12]. Gaseous 5 does not react with NaF [14]. The CF
N=CF (5) has a b.p. of -33.7 °C [15]. It hydrolyses upon contact with moisture
Scheme 3) [4, 16]. The final products of the hydrolysis of CF -N=CF (5) are carbon
dioxide, ammonium fluoride, and HF (Scheme 3, A) [4]. Controlled hydrolysis of 5
gave trifluoromethylisocyanate, CF NCO (Scheme 3, B) [16].
)
3 2
)
3 2
(
)
3 2
3
2
)
3 2
)
3 2
3
-
2
(
3
2
3
Scheme 3. Hydrolysis of the CF
3
-N=CF (5) [4, 16].
2
3

Perfluoroazapropene (5) undergoes dimerization in the presence of fluoride anions
Scheme 4) [7,13,14].
(
Scheme 4. Dimerization of the CF
3
-N=CF (5) [7,13,14].
2
This reaction is reversible, that enables the usage of the dimer 6 (b.p. 39 °C) [17]
instead of gaseous 5 for the generation of the [N(CF
]- anion [13].
)
3 2
Perfluoroazapropene (5) is not commercially available, but it can be prepared by
various methods as described in the literature. The synthesis and chemistry of
perfluoroazapropene (5) and fluorinated aza-methines were reviewed several times
[
18 – 20].
Due to its properties and difficulties in the preparation, perfluoroazapropene
5) and dimer 6 are not convenient starting materials for the generation of the
CF N-anion.
More than 20 years ago, we have described the synthesis of (CF
starting from CF SO N(CF (7) [21]. N,N-Bis(trifluoromethyl)trifluoromethane
sulfonamide (7); b.p. 55-56 °C) is a convenient reagent for the preparation of organic
and inorganic salts with the [N(CF
]- anion (Scheme 5) [22 – 25]. Compound 7 is
stable at ambient conditions and can be stored for a long time.
(
(
)
3 2
3
2
) N-salts
3
2
)
3 2
)
3 2
Scheme 5. Preparation of the (CF
3
)
2
N-salts starting from N,N-bis(trifluoromethyl)-
SO N(CF (7) [22-25].
trifluoromethanesulfonamide, CF
3
2
)
3 2
The gaseous by-product, CF
produce CF SO N(CH , which is the starting material for the preparation of the
CF SO N(CF (7) by electrochemical fluorination (Simons process) [21]. This
technology offers a convenient route to use inexpensive dimethylamine for the
synthesis of (CF N-compounds [26].
Various organic salts of the [N(CF
reactions of tetrafluoroborates with Rb[N(CF
salts are sources of the nucleophilic [N(CF
3
SO
2
F, can be trapped with solution of dimethyl amine to
3
2
)
3 2
3
2
)
3 2
)
3 2
)
]- anion were prepared by metathesis
] [22-24]. These organic and inorganic
3 2
3 2
)
3
)
2
]- anion. For example, aromatic (CF
3
)
2
N-
4

compounds were prepared in one-step procedure starting from the corresponding
diazonium salts [27]. Decomposition of these salts in the presence of a suitable Cu(I)
catalyst resulted in the formation of the corresponding (CF
in reasonable to good yields (Scheme 6) [28].
3
2
) N-aromatic compounds
Scheme 6. Synthesis of Ar-N(CF
3
2
) compounds via diazonium salts [28].
Halogen containing N,N-bis(trifluoromethyl)anilines are useful starting material for
further derivatisations of the aromatic ring.
However, only a limited number of aliphatic (CF
3
)
2
N-compounds prepared by
]- anion have been
means of nucleophilic substitution reactions with the [N(CF
reported in the literature [11,12,22,23,29].
)
3 2
Here, we present the convenient synthesis of previously unknown N,N-
bis(trifluoromethyl)-α-aminoacetic acid (8), (CF NCH C(O)OH (N,N-
bis(trifluoromethyl)glycine) and its derivatives. With this contribution, we demonstrate
a practical methodology to introduce the (CF N group at primary and secondary
carbon atoms by nucleophilic substitution reactions. Furthermore, the synthesized
CF N-compounds are useful building blocks providing access to a variety of key
synthons for organic synthesis.
3
)
2
2
)
3 2
(
)
3 2
2. Results & Discussion
Despite the structural similarity to the dimethylamino group N(CH
bis(trifluoromethyl)amino group N(CF , differs strongly in its electronic properties
and sterically. The Hammett constant σ is -0.83 for N(CH ) [30] and +0.50 for
N(CF [31] reflects higher electronegativity of bis(trifluoromethyl)amino group. This
strongly influences the acid-base properties of the compounds bearing the (CF
group. For instance, N,N-dimethylaniline C N(CH is a fairly strong base. In
contrast, N,N-bis(trifluoromethyl)aniline, C N(CF , is not a base, at all. Moreover,
3
2
) , the
)
3 2
p
)
3 2
)
3 2
3
2
) N
6
H
5
)
3 2
6
H
5
)
3 2
it does not dissolve even in concentrated hydrochloric acid [31]. Another example is
5

the acidity of N,N-dimethylglycine (CH
bis(trifluoromethyl)glycine (CF NCH C(O)OH (8). While the amino acid
dimethylglycine exhibits two pK values (pK 1 = 2.04, pK 2 = 10.47) [32], titration of
3
)
2
NCH
2
C(O)OH, in comparison to N,N-
3
)
2
2
a
a
a
N,N-bis(trifluoromethyl)glycine revealed only one deprotonation step (pK = 2.94; this
a
study).
2
.1. Introduction of the (CF
3
2
) N group into aliphatic carbonyl compounds
Ethyl-N,N-bis(trifluoromethyl)glycine (4) was prepared by the interaction of (CF
salts with ethyl-α-bromoacetate (Scheme 7).
3
2
) N-
Scheme 7. Syntheses of ethyl- (4) and methyl N,N-bis(trifluoromethyl)glycine (9).
The reaction of K[N(CF
bromoacetate results in the formation of the compound 4 in 90% yield. The yield was
increased up to 96% by changing the (CF N-reagent to [(CH N][N(CF
TMA[N(CF ]) and using the ionic liquid bmpl FAP (bmpl = N-butyl-N-
3
2
) ] generated in dimethylacetamide (DMA) with ethyl-α-
3
)
2
3
)
4
3
2
) ]
(
)
3 2
methylpyrrolidinium; FAP = tris(pentafluoroethyl)trifluorophosphate) as reaction
media. The ionic liquid was recycled by washing of used bmpl FAP with water
followed by drying in vacuo. It was reused several times (>10) without loss in the
yield of 4. In a similar manner, the reaction of methyl-α-bromoacetate with K[N(CF
3
2
) ]
in DMA gave the N,N-bis(trifluoromethyl)-α-aminoacetic acid methyl ester 9 in 91 %
isolated yield. The above described procedures are more convenient and largely
improve the yield of the compounds 4 and 9 in comparison to previously reported
methods [22,25,29].
The essential drawback in the use of [(CH
3
)
4
N][N(CF
3
)
2
] and Rb[N(CF
3
2
) ] as
reagents [22,29] for the syntheses of the compounds 4 and 9 is the formation of small
quantities of mono-fluoroacetic acid esters as side products (Caution! mono-
fluoroacetic acid esters are volatile compounds and should be considered as
highly toxic substances, similar to mono-fluoroacetic acid, and must be
6

handled with all necessary safety measures). However, the formation of mono-
fluoroacetic acid esters was not observed, when K[N(CF ] was used as reagent for
)
3 2
the syntheses of 4 and 9. This finding is an important increase in reaction safety
without loss in yield.
α-Bromoketones are possessing similar reactivity as ethyl-α-bromoacetate
towards the [N(CF
3
)
2
]- anion. Various (CF
3
2
) N-substituted ketones were prepared by
this protocol (Scheme 8).
Scheme 8. Synthesis of N(CF
3
2
) substituted ketones.
The yield of α-bis(trifluoromethyl)aminoacetophenone (11a) in the reaction of
bromoacetophenone (10a) with in situ generated K[N(CF ] is 92%. It can be
increased to 96% by using TMA[N(CF ]. Bis(trifluoromethyl)aminomethyl-
trimethoxyphenyl ketone (11b) was synthesised in 92% yield by the reaction of 10b
with K[N(CF ], and (CF N-pinacolone (11c) was prepared in 72% yield by reaction
of bromomethyl-tert-butyl ketone 10c with TMA[N(CF ].
For a successful substitution at secondary carbon atoms, the reactivity of
bromide as a leaving group is not sufficient. Since the [N(CF
]- anion can act as a
)
3 2
)
3 2
3
)
2
)
3 2
)
3 2
)
3 2
weak base, elimination of HBr and formation of a double bond becomes the
predominant reaction in this case. To overcome this problem, we used starting
compounds having the better leaving triflate group, TfO. The corresponding triflates
were prepared by literature known methods [33]. This approach allowed the
preparation of compounds 13a,b having the (CF
3
2
) N group bonded to secondary
carbon atom (Scheme 9). The main drawback of this method is the inherent instability
of the triflates 12a,b above 0 °C due to their tendency to split off the triflate group.
This is the main reason for the moderate yields achieved for 13a (40%) and 13b
(44%). The elimination reaction and formation of ethyl acrylate was still a noticeable
side reaction in the case of 12a, but nevertheless, the main product in this reaction
was the desired ethyl N,N-bis(trifluoromethyl)alanine (13a).
7

Scheme 9. Synthesis of α-N(CF
3
2
) substituted carboxylates.
The substitution at a tertiary carbon atom was investigated with the examples ethyl-2-
methyl-2-bromopropanoate (CH CBrC(O)OEt, and ethyl-2-methyl-2-
mesylpropanoate (CH C(OSO CH )C(O)OEt. However, only elimination of HBr and
CH SO OH resulting in the formation of ethyl methacrylate could be observed during
the substitution reactions with the [N(CF
]- anion. Replacement of the mesyl group
with the triflate group as a leaving group did not give encouraging results. It appears,
that ethyl-2-methyl-2-triflylpropanoate (CH C(OSO CF )C(O)OEt, is not stable
)
3 2
3
)
2
2
3
3
2
)
3 2
3
)
2
2
3
under the reaction conditions. Ethyl methacrylate was the only product in this
reaction.
However, the “triflate-route” was successfully used for the introduction of the
N(CF
3
)
2
group into a non-activated position. For instance, methyl--N(CF
3
2
) -
hexanoate
(14)
was
prepared
SO
in
92%
yield
from
methyl-6-
(trifluoromethylsulfoxy)hexanoate CF
3
2
O(CH
2
)
5
C(O)OCH
3
, by reaction with in situ
generated Rb[N(CF
3
)
2
] (Table 3).
2
.2. Derivatisation of the initial building blocks
Ethyl 2-bis(trifluoromethyl)aminoacetate (4)
ethanol/NaOH to give the sodium salt 15 (Scheme 10).
undergoes
saponification
in
Scheme 10. Synthesis of N,N-bis(trifluoromethyl)glycine (8) and its sodium salt 15.
The sodium salt 15 can be protonated with dry gaseous HCl in diethyl ether to form
the highly volatile acid 8 as colourless solid in 86% yield over two steps (Scheme 10).
A pK
a
value of 2.94 was determined for 2-bis(trifluoromethyl)aminoacetic acid (8) by
8

potentiometric titration in water at 25 °C (Table 1). As expected, 2-
bis(trifluoromethyl)aminoacetic acid (8) is a stronger acid than acetic acid, but it is
weaker as monofluoro- and trifluoro-acetic acids. The pK
comparable to values determined for chloroacetic acid (pK
trifluoropropionic acid (pK = 3.02) [36, 37] (Table 1). It is interesting to compare the
acidity of N,N-bis(trifluoromethyl)glycine (8), N,N-dimethylglycine and glycine. The
pK value of 8 is higher than the pK of glycine (2.31) [32,34] and of dimethylglycine
2.04) [32]. Hence, N,N-bis(trifluoromethyl)glycine (8) is a weaker acid than N,N-
a
value of 2.94 is
a
= 2.87) [34,35] and
a
a
a
(
dimethylglycine. The higher acidity of glycine and N,N-dimethylglycine is due to the
formation of zwitterions. The positively charged amino functionality increases the
acidity of the adjacent carboxylic acid function. On the contrary, N,N-
bis(trifluoromethyl)glycine is not able to form a zwitterion due to the low basicity of the
(
CF
nitrogen atom restricting protonation of the (CF
formation of a zwitterionic structure. Thus, during the titration of N,N-
bis(trifluoromethyl)glycine (8) only one deprotonation step was observed (pK = 2.94;
this study), while the amino acid N,N-dimethylglycine exhibits two pK values (pKa1
.04, pKa2 = 10.47) [32]. This observation proves the differences in the properties of
the N(CH and the N(CF group. The comparison of the acidity of the N,N-
bis(trifluoromethyl)glycine (8) and trifluoropropionic acid (Table 1) shows that the
CF N group in the aliphatic chain exerts a similar electron withdrawing effect like a
CF group or a Cl atom. This similarity is also evident from the comparison of
inductive 
constants: 0.49, 0.49 and 0.40 (determined by 19F NMR spectroscopic
method) for N(CF , CF , and Cl, respectively [31].
3
)
2
N group. Two CF
3
groups efficiently withdraw electron density from the
)
3 2
N-group, which hinders the
a
a
=
2
3
)
2
)
3 2
(
)
3 2
3
I
3
)
2
3
Table 1. Acidity of acetic acid and its substituted analogues
Acid
HCH C(O)OH
ClCH C(O)OH
CF NCH
CF
FCH
CH NCH
pK
a
(in water at 25° C)
Ref.
[34, 35]
[34, 35]
this study
[36, 37]
[34]
2
4.76
2.87
2.94
3.02
2.59
2.04
2
(
3
)
2
2
C(O)OH
3
CH
2
C(O)OH
2
C(O)OH
C(O)OH
(
3
)
2
2
[32]
9

CF
3
C(O)OH
0.23
[35, 37]
in
N,N-bis(trifluoromethyl)glycine
(8)
was
prepared
its
protic
form,
(
CF NCH C(O)OH, and in its deuterated form, (CF
3
)
2
2
3
)
2
NCH C(O)OD. The IR spectra
2
of these two forms of the compound 8 are presented in the Figure 1. The H form of
the acid shows a broad absorption around 3000 cm-1 as expected for dimeric
carboxylic acids. The spectrum is dominated by the strong νas (C=O) at 1724 cm-1
-1
followed by strong C-F and C-O absorptions at 1100–1400 cm . Isotopic labelling
with deuterium strongly affected some bands, e.g. 1425 (νCOH), 1254 (νC-O), and 889
-1
-1
(
ν
OH·· ). Two new broad bands arise at 2257 cm and 2086 cm upon deuteration
O
and are clearly associated with OD vibrations. It is known that, strength of the H
bonded network is in most cases associated with the acidity of the investigated
compound [38]. Strong acids show a strong H bonded network, whereas medium
strong acids show
H
bonded networks of medium strength. N,N-
bis(trifluoromethyl)glycine cannot form a zwitterion due to the low basicity of the
nitrogen atom. This explains the differences of the IR spectra (Table 2) compared to
IR spectra of non-fluorinated amino acids. The IR spectrum (Fig. 1) of the N,N-
bis(trifluoromethyl)aminoacetic acid (8) is more closely correlated to IR spectra of
aliphatic carboxylic acids.
1
0

Figure 1. IR spectra of N,N-bis(trifluoromethyl)aminoacetic acid (8) as H (red) and D
black) isotopologue. For a better visibility, the spectra were scaled to similar
transmission values.
(
Table 2.
IR frequencies of deuterated and non-deuterated N,N-
bis(trifluoromethyl)acetic acid (8). Frequencies marked with asterisks are strongly
affected by the isotope effect.
ν (CF
3
)
2
NCH
2
C(O)OH, cm-1
ν (CF
3
)
2
NCH
C(O)OD, cm-1
2
3
2
1
1
1
8
070*m, 3005m, 2973m, 2904*m, 3006w, 2977w, 2906w, 2769vw, 2683vw,
772w, 2691w, 2581w, 1724st, 2572w, 2257*m, 2086*m, 1730st, 1446m,
451w, 1425*w, 1359st, 1336*sh, 1355st, 1286*m, 1219st, 1158st, 1122sh,
254*m, 1218st, 1202st, 1142st, 1061*vw, 1044*m, 1013st, 922m, 861w,
119st, 1011st, 921sh, 889*m br, 802w, 728m, 699m, 672*sh, 652m,
02w, 731w, 698m, 652m, 544w
644*m, 633*m, 538w
Reaction of the ester 4 with hydrazine hydrate to give the corresponding
N-acetyl hydrazide (16) proceeds very slow in organic solvents typically used
3 2
(CF )
for this reaction, e.g. isopropanol (yield 31 % after 72 h boiling), DMF (yield 41 % in
6.5 h at RT), and DMSO (yield 78 % after 40 h at RT) (Scheme 11). Isolation of the
2
hydrazide 16 from these solvents was difficult and resulted in loss of product due to
its volatility. The use of the ionic liquid, N-butyl-N-methylpyrrolidinium triflate (bmpl
OTf) as a solvent in this reaction increased the yield to 93 % after 24 h reaction time
at room temperature. The product 16 was separated from the ionic liquid by
sublimation. This procedure lets to avoid the time-consuming removal of organic
solvents from the reaction mixture and enhances the isolation of the product 16,
significantly. The ionic liquid bmpl OTf can be recycled and reused without
purification and loss in product yield.
1
1

O
O
O
NaOH
HCl(g)
(
F C) N
(F C) N
(F C) N
3 2
3
2
3
2
C H OH
2
5
(C H ) O
OC H
ONa
2
5 2
OH
2
5
90%
86%
4
15
8
ClC(O)C(O)Cl
in Et O
aq. H NNH2
P O
2
4
10
2
O
O
O
(
F C) N
(F C) N
(F C) N
3 2
3
2
3
2
NHNH2
Cl
2O
18 Yield: 93%
1
6 Yield: 93%
17
Used in situ for further derivatization
Scheme 11. Syntheses of N,N-bis(trifluoromethyl)amino acetic acid hydrazide (16),
chloride 17, and anhydride 18.
The sodium salt 15 reacted with oxalyl dichloride in diethyl ether to the acid chloride
1
1
7, which was not fully separated from residual solvent by distillation. According to H
and 19F NMR data, the conversion of 15 to 17 was quantitative (Scheme 11). A
solution of the acid chloride 17 in diethyl ether was stored and used for further
derivatisations without separation from Et O. The acid chloride 17 has been
2
described in the literature previously [39]. It was detected as a side product of the
decomposition of compound 19 according to the following equation (Scheme 12).
Scheme 12. Formation of the N,N-bis(trifluoromethyl)amino acetic acid chloride (17)
as a side product, according to the literature [39].
The literature procedure depicted in Scheme 12 is not the method of choice for the
preparation of compound 17. The synthesis of the N,N-bis(trifluoromethyl)amino
acetic acid chloride (17) starting from the sodium salt of N,N-
bis(trifluoromethyl)glycine (8) according to Scheme 11 is much more practical and
convenient. This remarkable example demonstrates the advantages of the new
methodology based on the use of (CF
3
2
) N-salts for nucleophilic substitution reactions
in the syntheses of (CF N containing aliphatic organic compounds.
3 2
)
1
2

The N,N-bis(trifluoromethyl)glycine (8) was dehydrated by phosphorous(V)-
oxide under solvent free condition to the corresponding acid anhydride 13, which can
be easily separated by sublimation under reduced pressure (Scheme 11). The
anhydride 13 is a very reactive compound. We obtained single crystals of the N,N-
bis(trifluoromethyl)glycine (8) by slow hydrolysis of the anhydride (18).
The ethyl ester of N,N-bis(trifluoromethyl)glycine (4) reacts not only with
hydrazine hydrate, but in the presence of ammonia it is converted to (CF
3
2
) N-
substituted acetamide 20 in 95 % yield (Scheme 13).
Scheme 13. Preparation of the N,N-bis(trifluoromethyl)amino acetamide (20),
-(bis(trifluoromethyl)amino)acetonitrile (21), and 2-(bis(trifluoromethyl)amino)ethanol
22).
2
(
The subsequent dehydration of compound 20 with P
-(bis(trifluoromethyl)amino)acetonitrile (21) as a colourless liquid in 76% yield
Scheme 13). The alcohol 22 was synthesized in 64 % yield by reduction of ester (IV)
4
O10 results in the formation of
2
(
at 0 °C using LiAlH
4
(Scheme 13). In a similar reaction, methyl--N(CF
3
)
2
-hexanoate
Cl to the
(
14), (CF N(CH
3
)
2
2
)
5
C(O)OCH , can be reduced by DIBAl-H in CH
3
2
2
corresponding aldehyde 24 in a very good yield. The obtained aldehyde 24 was
found to be highly sensitive against oxygen (air) and it is easily oxidized to (CF N-
substituted hexanoic acid 25. This acid was independently obtained in 86 % yield by
)
3 2
saponification of the methyl--N(CF
3
2
) -hexanoate (14) with aqueous NaOH followed
by acidic workup.
1
3

Scheme 14. Preparation of the methyl--N(CF
3
)
2
-hexanoate (14) and (CF
3
2
) N-
substituted hexanoic acid (25).
The reduction of the amide 20 or the nitrile 21 to the amine 23 (Scheme 13)
was investigated by different reactions including reduction with LiAlH , BH , NaBH
, but no pure product 23 was isolated in these experiments. Several side
were observed in the reaction mixtures. The desired
4
3
4
,
and Pd/C/H
2
products
2-[bis(trifluoromethyl)amino]ethylamine (23) was detected in the NMR-spectra of the
reaction mixtures as a minor species. The difficulties in synthesizing this simple
amine remain up to now unclear. A synthetic route to compound 23 by the Gabriel-
synthesis was attempted, but it was also unsuccessful.
Hydrazide 16 was converted to the corresponding azide 26, which was not
isolated due to its instability above 0 °C. NMR spectroscopy showed full conversion
of the hydrazide 16 within 30 min at 0 °C. Formation of any side products was not
detected during this reaction. The carbamate 27 was synthesised in 47% yield by the
Curtius rearrangement from azide 26 in the presence of ethanol (Scheme 14) by a
method adapted from the literature [40].
Scheme 15. Preparation of the N,N-bis(trifluoromethyl)amino acetazide (26) and its
conversion to carbamate 27.
When the Curtius rearrangement was performed in tert-butanol instead of ethanol,
the Boc-protected (CF
3
2
) N-methylamine (28) was obtained. However, despite all
efforts the deprotected amine was not isolated as pure compound.
1
4

The product yields and the properties of the compounds synthesised, including
their NMR spectra are presented in the Table 3.
Table 3. Syntheses and characterization of N(CF
3
)
2
containing compounds
Boiling
Melting)
point, °C
Product
Yield
%
NMR (Solvent),
(
δ, ppm
(
Pressure)
1H NMR (CD
O-CH CH ), 4.13 (sept, J = 1.6 Hz, 2H,
CH ), 1.25 (t, J = 7 Hz, 3H, CH ).
19F-NMR (CD
CN): -57.70 (t, J = 1.6 Hz).
C{ H} NMR (CD CN): 167.24 (s, C=O),
20.30 (q, 1JC,F = 263 Hz, CF
), 61.76 (s, -
O-CH CH ), 44.41 (s, CH ), 13.23 (s, -O-
CH CH ).
1H NMR (CD
.12 (sept, 2H, 4JF,H = 1.5 Hz, CH
CN): 4.22 (q, J = 7 Hz, 2H, -
3
2
3
a
9
9
0 ,
125-126
2
3
b
9
3
1
3
1
3
1
3
2
3
2
2
3
3
CN): 9.63 (br. s, 1H, OH),
4
2
)
19F NMR (CD
CN): -57.69 (t, 4JF,H = 1.5
3
8
6
low melting
solid
Hz).
1
3
1
C{ H} NMR (CD
20.3 (q, 1JC,F = 261 Hz, CF
CH ).
1H-NMR (CDCl
H, CH ), 3.79 (s, 3H, O-CH
19F-NMR (CDCl
): -57.35 (t, J = 1.4 Hz).
3
CN): 167.8 (s, C=O),
1
3
), 43.9 (s,
2
3
): 3.96 (sept, J = 1.4 Hz,
2
2
3
)
9
1c
114-115
3
1H NMR (CD
3
CN): 7.98 (d, J = 7.6 Hz,
2
6
4
2
H, H +H ), 7.69 (t, J = 7.6 Hz, 1H, H ),
k
9
9
2 ,
33-34
3
5
7
.56 (t, J = 7.6 Hz, 2H, H +H ), 4.94 (sept,
).
CN): -57.06 (t, 4JF,H = 1.6
l
6
(0.2 Pa;
4JF,H = 1.6 Hz, 2H, CH
-
3
2
1.5·10
19F NMR (CD
mm Hg)
3
Hz).
1
3
1
C{ H} NMR (CDCl
34.3 (s), 129.0 (s), 127.8 (s), 120.2 (q,
1JC,F = 262 Hz, CF
), 49.3 (s).
3
): 190.7 (C=O),
1
3
1
5

1H NMR (CD
CH), 4.94 (sept, 4JF,H = 1.7 Hz, 2H, CH
.89 (s, 6H, 2OCH ), 3.82 (s, 3H, OCH
CN): -57.05 (t, 4JF,H = 1.7
CN): 7.26 (s, 2H, arom.
3
2
),
low melting
solid
3
3
3
),
9
2m
19F NMR (CD
3
Hz).
1H NMR (CDCl
): 4.20 (sept, 4JF,H = 1.5
).
): -56.88 (t, 4JF,H = 1.5
3
Hz, 2H, CH ), 1.2 (s, 9H, 3CH
2
3
7
2n
19F NMR (CDCl
3
Hz).
1H NMR (CDCl
CH CH + CH
CHC=O), 1.56 (d, 3H, 3JH,H
7 Hz, CH
CHC=O), 1.25 (t, 3H, 3JH,H = 7
Hz, O-CH CH
19F NMR (CDCl
1H NMR (CDCl
br. s, 1H, CHC=O) 3.89 (s, 3H, OCH
19F NMR (CDCl
): -53.58 (br. s).
): 4.21 (m, 2H+1H, O-
3
2
3
3
4
0d
132-135
=
3
2
3
)
3
): -53,63 (br. s).
): 7.39 (m, 5H arom), 5.45
).
3
26-30 (0.5
(
3
4e
Pa; 3.8·10
-
4
3
3
mm Hg)
1H NMR (CD
.30 (br t, J = 7.6 Hz, 2H, 6-CH
J = 7.4 Hz, 2H, 2-CH ), 1.61 (m, 4H, 3-,5-
CH ), 1.33 (m, 2H, 4-CH ).
19F NMR (CD
CN): -57.83 (br. s).
C{ H} NMR (CD CN): 174.7 (s), 122.3
q, 1JC,F = 261 Hz, CF
), 52.0 (s), 45.8 (s),
4.5 (s), 30.2 (s), 26.7 (s), 25.4 (s).
CN): 3.61 (s, 3H, OCH
),
3
3
3
2
), 2.30 (t,
2
2i
2
2
9
60.5-62.0
(500 Pa;
3
13
1
3
.75 mm
Hg)
3
(
3
3
1H NMR (DMSO-d
): 3.58 (sept, 2H, 4JF,H
6
=
1.7 Hz, CH )
2
19F NMR (DMSO-d
): -53.41 (t, 4JF,H = 1.7
6
90
Hz).
1
3
1
C{ H} NMR (DMSO-d
q, 1JC,F = 257 Hz, CF
), 47.2 (s).
1H NMR (CD
CN): 7.81 (br. s, 1H, NH),
.93 (sept, 2H, 4JF,H = 1.5 Hz, CH
), 3.86
br. s, 2H, NH ).
6
): 170.1 (s), 121.0
(
3
3
f
3
1 ,
3
2
g
78
,
(98-100)
(
2
h
9
3
19F NMR (CD
CN): -58.08 (t, 4JF,H = 1.5
3
Hz).
13
1
C{ H} NMR (CD
3
CN): 166.1 (s), 120.5
(q, J = 262 Hz, CF
3
), 44.6 (s).
1
6

19F NMR (CD
CN): -58.6 (t, J = 1.3 Hz).
3
1H NMR (CD
.6 Hz, 2x CH
CN): 4.37 (sept, 4H, 4JF,H
).
=
3
1
2
6
5
5
19F NMR (CD
CN): -56.05 (t, 4JF,H = 1.6
3
Hz)
1H NMR (CD
CN): 6.46 (br. s, 1H, NH
.09 (br. s, 1H, NH
), 3.96 (sept, 2H, 4JF,H
1.5 Hz, CH ).
3
a
),
6
=
b
2
19F NMR (CD
CN): -58.13 (t, 4JF,H = 1.5
3
9
(119.7)
DSC)
Hz).
(
1
3
1
C{ H} NMR (CD
q, 1JC,F = 260 Hz, CF
1H NMR (CD CN): 4.42 (sept, 2H, 4JF,H
.0 Hz).
3
CN): 168.0 (s), 120.5
(
3
), 45.4 (s),
3
=
1
19F NMR (CD
CN): -59.09 (t, 4JF,H = 1.0
3
7
6
4
108-112
117-118
Hz).
13
1
C{ H} NMR (CD
Hz, CF ), 115.5 (s, CN), 32.8 (s, CH
1H NMR (CD CN): 3.61 (dt, 2H, 3JH,H
.0, 3JH,OH = 6.0 Hz, CH
H, 3JH,H = 6.0, 4JF,H = 1.4 Hz, CH
3
CN): 121.1 (q, J = 262
3
2
),
3
=
6
2
2
OH), 3.40 (t sept,
2
), 3.10
(
t, 1H, 3JH,OH = 6.0 Hz, OH).
6
19F NMR (CD
CN): -57.77 (t, 4JF,H = 1.4
3
Hz).
1
3
1
CN): 120.9 (q, 1JC,F
), 46.3 (s,
C{ H} NMR (CD
61 Hz, CF ), 59.6 (s, CH
CH OH).
1H NMR (CD
C(O)H), 3.30 (t hept, J = 7.6, 1.5 Hz, 2H,
6-CH ), 2.42 (td, J = 7.3, 1.6 Hz, 2H, 2-
3
=
2
3
2
2
3
CN): 9.69 (t, J = 1.6 Hz, 1H,
6
9.5-70
8
5j
(1500 Pa;
(
CF ) N(CH ) C(O)H
3 2 2 5
2
1
1.25 mm
Hg)
CH
H, 2-CH
19F NMR (CD
2
), 1.62 (m, 4H, 3-, 5-CH
2
), 1.33 (m,
2
4
2
2
).
3
CN): -57.92 (br. s).
C{ H} NMR (CD CN): 203.6, 122.1 (q,
1JC,F = 261 Hz, CF
), 45.6 (s), 44.2 (s),
0.1 (s), 26.5 (s), 22.2 (s).
13
1
3
3
3
1H NMR (CD
CN): 9.49 (s, 1H, OH), 3.30
), 2.30
3
(t hept, J = 7.7, 1.5 Hz, 2H, 6-CH
2
1
7

(
t, J = 7.4 Hz, 2H, 2-CH
-CH ), 1.35 (m, 2H, 4-CH
19F NMR (CD
CN): -57.88 (br. s).
C{ H} NMR (CD CN): 176.5 (s), 122.1
q, 1JC,F = 261 Hz, CF
), 45.6 (s), 34.1 (s),
0.0 (s), 26.4 (s), 25.0 (s).
2
), 1.62 (m, 4H, 3-,
5
2
2
).
86
67.5-68.5
20 Pa;
3
(
1
3
1
3
0
.15 mm
Hg)
(
3
3
1H NMR (CD
CN): 4.23 (sept, 2H, 4JF,H
=
3
Caution!
Compound
may be
1
.7 Hz, CH ).
2
19F NMR (CD
CN): -57.49 (t, 4JF,H = 1.7
3
Hz).
explosive
1H NMR (CDCl
3
): 5.33 (br. s, 1H, NH),
4
2
.80 (d, 2H, 3JN,H = 5.7 Hz, CH
2
), 4.14 (q,
O
H, 3JH,H = 7.2 Hz, OCH
2
), 1.23 (t, 3H,
3JH,H = 7.2 Hz, CH
19F NMR (CDCl
): -56.62 (br. s).
C{ H} NMR (CDCl ): 155.3 (C=O),
20.4 (q, 1JC,F = 262 Hz, CF
), 61.7 (s,
OCH ), 50.6 (s, CH ), 14.3 (s, CH ).
1H NMR (CD
CN): 6.18 (br. s, 1H, NH),
.76 (d sept, 2H, 3JN,H = 7.0 Hz, 4JF,H = 1.3
Hz, CH ), 1.42 (s, 9H, t-Bu).
19F NMR (CD
CN): -56.71 (br. s).
C{ H} NMR (CD CN): 155.9 (s), 121.7
q, 1JC,F = 263 Hz, CF
), 80.9 (s), 51.9 (s,
CH ), 28.5 (s).
).
3
4
7
colourless
oil
(
F C) N
N
OC H
2 5
3
2
3
H
1
3
1
3
2
7
1
3
2
2
3
3
4
2
3
low melting
solid
13
1
53
3
(
3
2
Conditions: a BrCH
C, 16 h); c BrCH
C(O)OMe + KF/7 in DMA (RT, 19 h); 12a + RbF/7 in CH
Et N][N(CF ] in CH
DMSO (RT, 40 h); 4 + NH
C(O)OEt + KF/7 in DMA (RT, 19 h); BrCH C(O)OEt + TMAF/8 in bmpl FAP (80
b
2
2
d
e
°
[
2
3
CN (RT, 18 h); 12b +
f
g
4
)
3 2
Cl
2 2
(RT, 24 h); 4 + NH
NH ·H O in bmpl OTf (RT, 24 h); CF
CN (RT, 15 min); 14 + Di-i-BuAlH in CH
2
NH
·H
2 2
O in i-PrOH (82 °C, 72h); 4 + NH
2
NH
2
·H O in
2
h
i
2
2
2
3
SO
2
O(CH
2
5
) C(O)OCH
3
+ RbF/7 in
j
k
l
CH
TMAF/7 in bmpl FAP (50 °C, 18 h); 10b + KF/7 in DMA (50 °C, 5 h); 10c + TMAF/7 in bmpl FAP
70 °C, 20 h).
3
Cl
2 2
(-50 °C, 3 h); 10a + KF/7 in DMA (RT, 10 h); 10a +
m
n
(
Summary
Organic compounds having the (CF
3
2
) N group are accessible by nucleophilic
substitution reactions of (CF
Aliphatic compounds, carboxylic acid esters, and ketones bearing the (CF
at primary and secondary carbon atoms were prepared in good to excellent yields. A
convenient method for the efficient introduction of the N(CF group using potassium
fluoride for in situ generation of (CF N-anion was developed. This method restricts
3
)
2
N-salts with readily available starting materials.
)
3 2
N group
)
3 2
)
3 2
1
8

the formation of monofluorinated side products and thus increases the safety in the
described syntheses. Syntheses of (CF N-containig building blocks having various
)
3 2
functional groups like carboxylic acids and its esters, acid hydrazide, acid anhydride,
acid chloride and amide, ketone, and aldehyde functionalities, primary nitriles and
alcohols are described. Derivatization of these new building blocks provide access to
a variety of organic compounds using well-known chemical reactions. The
remarkable stability of the (CF
3
)
2
N group against strong acids (H
2
SO ), reducing
4
agents (Di-i-BuAlH), and strong bases (NaOH) was demonstrated.
Acknowledgments
Financial support of this work by Merck KGaA (Darmstadt, Germany) is gratefully
acknowledged. The authors thank Dr. A. Wenda (AK Prof. Helge Wilner, Bergische
Universität Wuppertal, Germany) and Dr. M. Drisch (AK Prof. Maik Finze, Julius-
Maximilians-Universität Würzburg, Germany) for providing samples of crude N,N-
bis(trifluoromethyl)trifluoromethanesulfonamide (4) prepared by electrochemical
fluorination method [21]. Dr. J. Hübner (Bergische Universität Wuppertal, Germany)
is gratefully acknowledged for the potentiometric titration of N,N-
bis(trifluoromethyl)glycine (8). The authors thank Mr. P. Roloff (Institute of Inorganic
Chemistry and Structural Chemistry, Heinrich-Heine-University of Düsseldorf,
Germany) for elemental analyses of the compounds synthesized. C. Breitenstein
thanks Dr. P. Barthen (Institute of Inorganic Chemistry and Structural Chemistry,
Heinrich-Heine-University of Düsseldorf, Germany) for discussion of some
experimental results. N. Ignat’ev thanks Dr. Michael Schulte (Merck KGaA,
Darmstadt, Germany) for his support of this project and appreciates fruitful
discussions with Prof. Maik Finze (Julius-Maximilians-Universität Würzburg,
Germany) on the topic of (CF
3
2
) N chemistry.
3. Experimental Part
3.1. Materials and methods
All reactions were performed in a dry and inert atmosphere. All solvents were
dried with 3 Å molecular sieve before using. Ionic liquids, 1-butyl-1-
methylpyrrolidinium tris(pentafluoroethyl)trifluorophosphate (bmpl FAP) and 1-butyl-1-
1
9

methylpyrrolidinium trifluoromethanesulfonate (bmpl OTf), were dried in vacuo at 40 -
0 °C for several hours prior to use.
Anhydrous potassium ω-
6
fluoride,
dimethylformamide
(DMF),
bromoacetophenone, methyl bromoacetate, ethyl bromoacetate, bromopinacolone
and toluene have been purchased from Sigma-Aldrich. Dimethylacetamide (DMA),
ethanol, methanol, sodium nitrite, LiAlH , and hydrazine hydrate have been
4
purchased from Merck / VWR. Gaseous ammonia (3.8) was delivered by Air Liquide
and methyl mandelate, phosphorous(V)-oxide and sodium azide by Acros Organics.
Oxalylchloride was purchased from Fluka. All chemicals were used as received
unless otherwise noted. ω-Bromoacetophenone was purified by sublimation prior to
use. Tetramethylammonium fluoride (TMAF) was synthesized by a known method
[
41] from tetramethylammonium tetrafluoroborate and sodium fluoride in methanol.
Commercial potassium and rubidium fluorides were dried additionally in high vacuum
at 80 – 100 °C for several hours and stored in the glovebox. Ionic liquid bmpl OTf
was provided by Merck KGaA (Darmstadt, Germany) free of charge. Ionic liquid bmpl
FAP was prepared according to literature known procedure [42] from 1-butyl-1-
methylpyrrolidinium chloride and potassium tris(pentafluoroethyl)trifluorophosphate
(KFAP) in water. Currently, bmpl OTf and bmpl FAP can be bought from Merck
Millipore company; product Nrs. are 491029 and 491084 correspondingly.
1H, 13C, and 19F NMR spectra were recorded at 25 °C either in CD
3
CN,
(CD
3
)
2
SO, or in CDCl
3
on a Bruker Avance III 400 MHz spectrometer operating at
00.17, 100.62, 376.54 for H, 13C, 19F nuclei, respectively. NMR signals were
1
4
referenced against TMS ( H, C), and CFCl
(19F) as external standards.
1
13
3
Elemental analysis (C, H, N, S) were performed with a Euro EA3000
instrument (HEKA-Tech, Germany).
Infrared spectra were measured on crystalline samples at room temperature
on an Excalibur FTS 3500 spectrometer (Digilab, Germany) with a resolution of 4 cm-
1.
region of 4000–530 cm .
Potentiometric titration of N,N-bis(trifluoromethyl)glycine (8) was carried out for
IR spectra were recorded in the attenuated total reflection (ATR) mode in the
-1
a 0.018 M solution in bidistilled water at 25 °C using 0.1 M KOH as titrant. The pH
values during the titration experiment were measured with a Metrohm 780 pH-Meter
using a glass electrode. The pK
a
value of the N,N-bis(trifluoromethyl)glycine (8) was
calculated using the Henderson-Hasselbalch equation.
2
0

Caution! Highly volatile mono-fluoroacetic acid esters can undergo hydrolysis
resulting in the formation of volatile (5300 Pa; 39.75 mm Hg, 36°C) and highly toxic
mono-fluoroacetic acid (LD50 = 7 mg/kg, oral/mouse; source: the National Institute for
Occupational Safety and Health
-
NIOSH, https://www.cdc.gov/nioshrtecs/
AH5ACA30.html). By this reason mono-fluoroacetic acid esters should be considered
as toxic as mono-fluoroacetic acid itself.
3
.2. Introduction of the bis(trifluoromethyl)amino, (CF
3
2
) N group
Melting, boiling points, and the NMR spectroscopic data for the products described
below are given in the Table 3.
Ethyl 2-bis(trifluoromethyl)aminoacetate; ethyl N,N-bis(trifluoromethyl)glycine,
(CF
3
)
2
NCH C(O)OEt (4)
2
Method A.
Anhydrous tetramethylammonium fluoride (5.82 g, 62.5 mmol) was suspended in 30
mL bmpl FAP in a two-neck flask equipped with a dry-ice/ethanol reflux-condenser.
Under
CF SO
temperature, resulting in evolution of trifluoromethylsulfonylfluoride, CF
reaction mixture was stirred for 1 hour and then dry-ice/ethanol reflux-condenser was
let to warm up to room temperature to release the rest of the CF SO F (b.p. -21.5
C). Trifluoromethylsulfonyl fluoride, CF SO F can be trapped as a side product with
dry-ice condenser and converted to CF SO N(CH by reaction with dimethylamine.
CF SO N(CH is the starting material for the production of CF SO N(CF by
means of electrochemical fluorination process [21]. After removal of the CF SO
from the reaction mixture, ethyl-α-bromoacetate, BrCH C(O)OEt (8.22 g, 49.2 mmol)
vigorous
N(CF (7) (18.84 g, 66.1 mmol) was slowly added within 10 minutes at room
SO F. The
stirring,
N,N-bis(trifluoromethyl)trifluoromethanesulfonamide,
3
2
)
3 2
3
2
3
2
°
3
2
3
2
)
3 2
3
2
3
)
2
3
2
)
3 2
3
2
F
2
was added and the mixture was heated for 16 hours to 80 °C. The product was
isolated by condensation into a trap, cooled with liquid nitrogen, at 0.1 Pa (0.75·10-3
mm Hg) at 80 °C as a clear colourless liquid in 99 % yield (11.7 g). The composition
of the product is 97 mol% ethyl-2-bis(trifluoromethyl)aminoacetate and 3 mol% ethyl-
2
-fluoroacetate.
Method B.
2
1

Anhydrous potassium fluoride (10.0 g, 172 mmol) was suspended in 100 mL of dry
DMA in a two-neck flask equipped with a dry-ice/ethanol reflux-condenser. Under
vigorous stirring, N,N-bis(trifluoromethyl)trifluoromethanesulfonamide (7) (52.0 g, 182
mmol) was slowly added at room temperature, which resulted in evolution of
trifluoromethylsulfonylfluoride, CF
the reaction vessel. The reaction mixture was stirred 4 hours. After evaporation of the
CF SO F (dry-ice/ethanol reflux-condenser was let to warm up to room temperature),
3
SO
2
F, and the formation of a biphasic mixture in
3
2
ethyl-α-bromoacetate (23.0 g, 138 mmol) was added at room temperature resulting in
the formation of KBr precipitate. The mixture was stirred for 19 h at room temperature
and the slurry was poured into 300 mL of ice water. The lower organic phase was
separated, extracted two times with 100 mL of ice-cooled water, and dried with
magnesium sulfate yielding the product in high purity as colourless liquid. The volatile
product was over-condensed in vacuo onto calcium hydride and distilled. Yield: 29.7
g (90%). Elemental analysis: Calcd. for C
6
H
7
6
F NO2, %: C 30.14, H 2.95, N 5.86,
Found, %: C 29.38, H 2.90, N 5.97.
Methyl 2-bis(trifluoromethyl)aminoacetate, (CF
3
)
2
NCH C(O)OMe (9) was obtained
2
in 91 % yield as colourless liquid from methyl-α-bromoacetate as starting material.
1
-Bis(trifluoromethyl)amino-2-phenyl-ethan-2-one, (CF
3
)
2
NCH C(O)Ph (11a)
2
Method A.
In a two-neck flask equipped with a dry-ice/ethanol reflux-condenser, anhydrous
tetramethylammonium fluoride (6.65 g, 71.4 mmol) was suspended in 30 mL of dry
bmpl FAP. In twenty minutes, CF
3
SO
2
N(CF
3
)
2
(7) (22.6 g, 79.2 mmol) was added,
SO F. The reaction mixture was
that resulted in a strong evolution of gaseous CF
3
2
stirred for two hours under constant cooling, and then dry-ice/ethanol reflux-
condenser was let to warm up to room temperature to release the rest of the
CF
3
SO
2
F (b.p. -21.5 °C). After removal of the CF
3
SO
2
F from the reaction mixture, 1-
bromo-2-phenyl-ethan-2-one, BrCH
2
C(O)Ph (10a) (11.4 g, 57.5 mmol) was added as
a solid and the reaction mixture was heated at 50 °C for 18 h. The product was
isolated by condensation into a trap, cooled with liquid nitrogen, at 0.1 Pa (0.75·10-3
mm Hg) and 80 °C as a colourless liquid in 99% (15.5 g,) yield. The isolated
(CF
3
)
2
NCH
2
C(O)Ph (11a) contained 3 mol% of 1-fluoro-2-phenyl-ethan-2-one,
FCH
2
C(O)Ph as a by-product.
2
2

Method B.
Anhydrous potassium fluoride (0.92 g, 15.9 mmol) was suspended in 10 mL of dry
DMA in a two-neck flask equipped with a dry-ice/ethanol reflux-condenser. Under
vigorous stirring, N,N-bis(trifluoromethyl)trifluoromethanesulfonamide (7) (4.59 g,
1
6.1 mmol) was slowly added at room temperature, that resulted in evolution of
CF SO F and the formation of a biphasic mixture in the reaction vessel. The reaction
mixture was stirred for 1 hour and after evaporation of the CF SO F (the dry-
3
2
3
2
ice/ethanol reflux condenser was let to warm up to room temperature), 1-bromo-2-
phenyl-ethan-2-one (10a) (2.59 g, 13.0 mmol) was added at room temperature
resulting in the precipitation of KBr. The mixture was stirred for 10 h at room
temperature and the slurry was poured into 50 mL of ice water. After addition of 30
mL of dichloromethane, the lower organic phase was separated, extracted two times
with 50 mL of ice water, and dried with magnesium sulphate. Evaporation of the
solvent under reduced pressure yielded the product as a pale yellow, oily liquid that
solidified upon standing. (CF
g).
3
)
2
NCH C(O)Ph (11a) was obtained in 92% yield (3.25
2
Elemental analysis: Calcd. for C10
H
7
6
F NO, %: C 44.29, H 2.60, N 5.17, Found, %: C
44.44, H 2.48, N 5.17.
1
-Bis(trifluoromethyl)amino-2-(3,4,5-trimethoxyphenyl)-ethan-2-one (11b)
Anhydrous potassium fluoride (0.66 g, 11.4 mmol) was suspended in 10 mL of dry
DMA in a two-neck flask equipped with a dry-ice/ethanol reflux-condenser. Under
vigorous stirring, N,N-bis(trifluoromethyl)trifluoromethanesulfonamide (7) (3.58 g,
1
2.6 mmol) was added slowly at room temperature resulting in the evolution of
trifluoromethylsulfonylfluoride. The reaction mixture was stirred for 1 hour. After
evaporation of the CF SO F (the dry-ice/ethanol reflux condenser was let to warm up
to room temperature), 1-bromo-2-(3,4,5-trimethoxyphenyl)-ethan-2-one (10b) (2.59 g,
3.0 mmol) was added at room temperature resulting in the formation of KBr
precipitate. The mixture was stirred for 5 h at 50°C and the slurry was poured into
3
2
1
1
50 mL of ice water. The resulting precipitate was isolated by filtration, dissolved in
0 mL dichloromethane, and dried with magnesium sulphate. Evaporation of the
2
solvent under reduced pressure yielded the product 11b (3.8 g, 92% yield) as a pale-
yellow oil that solidified upon standing.
2
3

1
-Bis(trifluoromethyl)amino-3,3-dimethylbutan-2-one (11c)
In a two-neck flask equipped with a dry-ice/ethanol reflux-condenser, anhydrous
tetramethylammonium fluoride (1.01 g, 10.9 mmol) was suspended in 7 mL of dry
bmpl FAP. CF
strong gas (CF
cooling and then dry-ice/ethanol reflux-condenser was let to warm up to room
temperature to remove the rest of the CF SO F. 1-Bromo-3,3-dimethylbutan-2-one
10c) (1.48 g, 8.26 mmol) was added and the reaction mixture was heated to 70 °C
for 20 h. NMR analysis of the reaction mixture indicated full conversion of the starting
3
SO
2
N(CF
3
)
2
(7) (3.49 g, 12.25 mmol) was added, that resulted in a
3
SO
2
F) evolution. The mixture was stirred for 1 hour with constant
3
2
(
-3
material. The product was isolated by condensation at 0.3 Pa (2.25·10 mm Hg) and
0 °C into a trap cooled with liquid nitrogen. The obtained colourless liquid (2.0 g)
contained 86 mol% of 1-bis(trifluoromethyl)amino-3,3-dimethylbutan-2-one (11c) and
4 mol% of 1-fluoro-3,3-dimethylbutan-2-one, FCH C(O)C(CH , as a by-product.
The yield of 1-bis(trifluoromethyl)amino-3,3-dimethylbutan-2-one,
CF C(O)C(CH (11c) is 72%.
8
1
2
)
3 3
(
3
)
2
NCH
2
)
3 3
Ethyl 2-[N,N-bis(trifluoromethyl)amino]propanoate (13a)
Step 1.
Pyridine (7.26 g, 92.0 mmol) was dissolved in 200 mL of dry dichloromethane, cooled
to 0 °C, and triflic anhydride (25.0 g, 88.7 mmol) was added. After stirring of the
resulting suspension for 1 h at 0 °C, ethyl 2-hydroxypropanoate (10.0 g, 84.7 mmol)
was added. The initially formed precipitate dissolved and finally a fine, less
voluminous solid formed. After stirring the reaction mixture for 1h at 0 °C the solvent
was removed under reduced pressure (1200 Pa; 9.0 mm Hg) and the residue was
extracted with dry pentane (5 x 20 mL). The pentane phases were combined and the
solvent was distilled off. The product, ethyl-2-(trifluoromethylsulfoxy)propanoate,
CF
3
SO
2
OCH(CH )C(O)OEt, was purified by fractional condensation at 50 °C under
3
-
2
reduced pressure (2 Pa; 1.5·10 mm Hg) into two traps, at –10 °C and –196 °C.
Ethyl-2-(trifluoromethylsulfoxy)propanoate (12a) was isolated as a colourless clear
1
) δ, ppm: 5.19 (q, 3JH,H = 7.0 Hz, 1H,
CH
), 1.66 (d, 3JH,H = 7.0 Hz, 3H,
CH , 25 °C) δ,
). 19F NMR (CDCl
liquid in 87 % yield (18.45 g). H NMR (CDCl
3
CH
3
CHC=O), 4.26 (q, 3JH,H = 7.0 Hz, 2H, O-CH
CHC=O), 1.28 (t, 3JH,H = 7.1 Hz, 3H, -O-CH
).
2
3
CH
3
2
3
3
ppm: -74.05 (s, CF
3
2
4

Step 2.
Dry rubidium fluoride (4.58 g, 43.8 mmol) was suspended in 46 mL of dry acetonitrile
in a two-neck flask equipped with a dry-ice/ethanol reflux-condenser. Under vigorous
stirring, N,N-bis(trifluoromethyl)trifluoromethanesulfonamide (7) (14.5 g, 50.8 mmol)
was added slowly at room temperature, that resulted in evolution of gaseous
CF
3
3
SO
SO
2
2
F. The reaction mixture was stirred for 1 hour and after evaporation of the
F (dry-ice/ethanol reflux-condenser was let to warm up to room temperature),
CF
ethyl-2-(trifluoromethylsulfoxy)propanoate (12a) (10.1 g 40.5 mmol) was added. After
stirring for 18 h at room temperature, all volatile compounds were condensed into a
trap cooled with liquid nitrogen. The condensate was poured into 150 mL of water,
the organic phase was separated, and distilled to yield 4.05 g (40%) of ethyl-2-
bis(trifluoromethyl)aminopropanoate, (CF
3
)
2
NCH(CH )C(O)OEt (13a).
3
Methyl 2-bis(trifluoromethyl)amino-2-phenylacetate (13b)
Step 1.
Triflic anhydride (20.11 g, 71.3 mmol) was added to a solution of collidine (9.48 g,
78.3 mmol) and methyl 2-hydroxy-2-phenylacetate (10.78 g, 64.8 mmol) in 100 mL of
dry dichloromethane at –78 °C. The mixture was stirred for 90 minutes at –78 °C and
the solvent was removed under reduced pressure. A slightly yellow residue was
extracted at 0 °C 10 times with each of 20 mL pentane. After evaporation of the
solvent from the combined pentane phases, 13.2 g of methyl 2-phenyl-2-
(
trifluoromethylsulfoxy)acetate (12b) was isolated as a colourless solid (yield 68 %).
The solid slowly decomposes at temperatures above 0 °C.
1H NMR (CDCl
) δ, ppm 7.50 (s, 5H, arom. H), 6.06 (s, 1H, CHC=O), 3.87 (s, 3H,
). F NMR (CDCl ) δ, ppm: -75.49 (s, CF ).
3
1
9
OCH
3
3
3
Step 2.
A solution of methyl 2-phenyl-2-(trifluoromethylsulfoxy)acetate (12b) (3.12 g, 10.5
mmol) in 5 mL of dry dichloromethane was added to a solution of [Et N][N(CF
3.30 g, 11.8 mmol) in 10 mL of dry dichloromethane at room temperature. After
4
3
2
) ]
(
stirring for 24 h at room temperature, the solvent was removed under reduced
pressure. The residue, a yellow to brown oil, was extracted with pentane. After
2
5

evaporation of the pentane, methyl 2-bis(trifluoromethyl)amino-2-phenylacetate (13b)
was isolated by distillation as a colourless liquid in 44% yield.
Sodium 2-bis(trifluoromethyl)aminoacetate, (CF
3
)
2
NCH C(O)ONa (15)
2
Sodium hydroxide (2.14 g, 53.5 mmol) was dissolved in 30 mL of dry ethanol and
ethyl 2-bis(trifluoromethyl)aminoacetate (4) (13.28 g, 55.5 mmol) was added. The
mixture was heated to 60 °C for 20 h. After removal of the solvent in vacuo, the
product 15 was obtained as a colourless solid, which was purified by recrystallization
from ethyl acetate/hexane (3:4). Yield: 11.3 g (90%).
Elemental analysis: Calcd. for C
4
H
2
F
6
NNaO , %: C 20.62, H 0.87, N 6.01, Found, %:
2
C 20.75, H 0.80, N 6.06.
2
-Bis(trifluoromethyl)aminoacetic
CF NCH C(O)OH (8)
Sodium 2-bis(trifluoromethyl)aminoacetate (15) (4.4 g, 18.9 mmol) was suspended in
0 mL of dry diethyl ether and dry gaseous HCl was bubbled through the mixture.
acid;
N,N-bis(trifluoromethyl)glycine,
(
3
)
2
2
2
The resulting slurry was stirred for one hour at room temperature. The solvent was
removed in vacuo. After purification by sublimation, the product 8 was obtained as a
colourless solid. Yield: 3.4 g (86 %).
Elemental analysis: Calcd. for C
4
H
3
F
6
NO , %: C 22.76, H 1.43, N 6.64, Found, %: C
2
22.78, H 1.55, N 6.68.
The deuterated form of N,N-bis(trifluoromethyl)glycine (8) was synthesized by
interaction of the sodium salt with gaseous DCl in diethyl ether.
2
-N,N-Bis(trifluoromethyl)aminoacethydrazide, (CF
Method A.
Ethyl 2-N,N-bis(trifluoromethyl)aminoacetate (4) (2.75 g, 11.5 mmol) was dissolved in
0 mL of dry, degassed 2-propanol. Distilled hydrazine hydrate (0.89 g, 17.8 mmol)
3
)
2
NCH
2
C(O)NHNH
2
(16)
1
was added to this solution and the reaction mixture was refluxed for 72 hours. The
solvent was removed under reduced pressure. The residue was recrystallized twice
from 10 mL of benzene yielding 2-N,N-bis(trifluoromethyl)aminoacethydrazide (16)
(0.80 g, 31%) as thin, crystalline plates.
Method B.
2
6

Ethyl 2-N,N-bis(trifluoromethyl)aminoacetate (4) (5.06 g, 21.2 mmol) was dissolved
in 25 mL of DMSO and distilled hydrazine hydrate (2.46 g, 49.2 mmol) was added to
the solution. The reaction mixture was stirred for 40 h at room temperature and the
solvent was removed under reduced pressure. The resulting orange to yellow solid
was recrystallized from 30 mL of benzene. The product, 2-N,N-
bis(trifluoromethyl)aminoacethydrazide (16) was isolated as thin crystalline plates in
78% (4.0 g) yield.
Method C.
Ethyl-2-N,N-bis(trifluoromethyl)aminoacetate (4) (10.2 g, 42.8 mmol) was added to
dry bmpl OTf followed by addition of distilled hydrazine hydrate (5.8 g, 117 mmol).
The initially biphasic reaction mixture was stirred for 24 h at room temperature and
excess of hydrazine hydrate was removed in vacuo. The product,
(
CF
by sublimation.
Elemental analysis: Calcd. for C
3
)
2
NCH
2
C(O)NHNH (16), was isolated in 93% (8.9 g) yield as a colourless solid
2
4
H
5
F
6
3
N O, %: C 21.34, H 2.24, N 18.67, Found, %: C
21.34, H 2.08, N 18.67.
2
-N,N-Bis(trifluoromethyl)aminoacetyl chloride, (CF
3
)
2
NCH C(O)Cl (17)
2
Sodium 2-N,N-bis(trifluoromethyl)aminoacetate (15) (1.2 g, 5 mmol) was suspended
in 10 mL of dry diethylether and oxalyl dichloride (0.8 g, 6.4 mmol) was added
dropwise. The resulting slurry was refluxed for 1h, filtrated and used after filtration for
further experiments without additional purification.
1
The protons of the CH
diethyl ether.
2
-group in the H NMR-spectrum overlap with the signal of the
2
-N,N-Bis(trifluoromethyl)aminoacetic acid anhydride, [(CF
3
)
2
NCH
2
C(O)] O (18)
2
Solid 2-N,N-bis(trifluoromethyl)aminoacetic acid (8) (0.9 g, 4.4 mmol) was mixed with
phosphorous(V)-oxide (0.8 g, 5.5 mmol). The reaction mixture was stirred and heated
at 50 °C in a sealed flask for 3 h. The product 18 was isolated in 65 % yield (0.58 g)
as a colourless solid by sublimation.
2
-N,N-Bis(trifluoromethyl)amino-acetamide, (CF
3
)
2
NCH
2
C(O)NH (20)
2
2
7

Ethyl 2-N,N-bis(trifluoromethyl)aminoacetate (4) (9.5 g, 39.8 mmol) was dissolved in
0 mL of a 3 M solution of NH in methanol. The reaction mixture was stirred at 40 °C
for 45 h. The solvent was removed yielding the product (20) as a colourless solid in
5% (7.9 g); m.p. 119.7 °C (DSC).
Elemental analysis: Calcd. for C
5
3
9
4
H
4
F
6
2
N O, %: C 22.87, H 1.92, N 13.33, Found, %: C
22.83, H 1.94, N 13.51.
2-N,N-Bis(trifluoromethyl)amino-acetonitrile, (CF
3
)
2
NCH
2
CΞN (21)
2-N,N-Bis(trifluoromethyl)aminoacetamide (20) (5.6 g, 26.6 mmol) was heated with
phosphorous(V)-oxide (1.9 g, 13.4 mmol) at 160 °C for 1h. The product was isolated
in 76% (3.9 g) yield as a colourless liquid by distillation.
2
-N,N-Bis(trifluoromethyl)amino-ethanol, (CF
Ethyl-2-N,N-bis(trifluoromethyl)aminoacetate (4) (14.7 g, 61 mmol) was added
dropwise within 30 min to 40 mL of a 1 M solution of LiAlH in diethyl ether cooled to
°C. The reaction mixture was stirred for 40 min at 0 °C and then slowly poured into
3
)
2
NCH
2
CH
2
OH (22)
4
0
ice-cold water. The organic phase was separated, dried and the product was isolated
in 64% (7.7 g) yield by distillation.
Elemental analysis: Calcd. for C
4.35, H 2.62, N 6.93.
4
H
5
6
F NO,%: C 24.38, H 2.56, N 7.11, Found, %: C
2
Ethyl-N,N-bis(trifluoromethyl)aminomethyl carbamate, (CF
27)
Step 1.
3
)
2
NCH NHC(O)OEt
2
(
Safety note: The intermediate 2-N,N-bis(trifluoromethyl)aminoacetyl azide was not
isolated and kept constantly at 0 °C or below. Although above 0 °C we observed only
slow decomposition, azides have the tendency to undergo spontaneous violent
decomposition. The reaction should be performed only after application of additional
safety precautions, for instance protecting shield.
2
-N,N-bis(trifluoromethyl)aminoacethydrazide (16) (1.1 g, 5.1 mmol) was dissolved in
ice-cooled water by adding concentrated hydrochloric acid until a final pH = 1 was
reached. A solution of NaNO (0.4 g, 6.1 mmol) in 2 mL of water was added dropwise
2
to the solution of the hydrazide 16 and the reaction mixture was stirred at 0 °C in an
ice bath until the formed precipitate had dissolved (ca. 10 min). The reaction mixture
2
8

separated into two phases; the product 2-N,N-bis(trifluoromethyl)aminoacetyl azide
16) had concentrated in the bottom phase. For NMR spectra see Table 3.
(
Step 2.
The bottom phase was separated at 0 °C and mixed with 15 mL of dry ethanol. The
reaction mixture was refluxed for 10 h. The solvent was removed and the product 17
was isolated as colourless oil in 47% (0.6 g) yield.
Elemental analysis: Calcd. for C
6
H
8
F
6
N
2
2
O , %: C 28.36, H 3.17, N 11.02, Found, %:
C 28.44, H 3.06, N 10.85.
tert-Butyl-N,N-bis(trifluoromethyl)aminomethyl carbamate,
CF NCH NHC(O)O-t-Bu (28)
-N,N-bis(trifluoromethyl)aminoacethydrazide (16) (2.7 g, 12 mmol) was dissolved in
ice-cold water by adding concentrated hydrochloric acid to reach a final pH of 1 and
0 mL of toluene was added. NaNO (0.89 g, 12.9 mmol) in 5 mL of water was added
dropwise to the solution of the hydrazide 16 and the reaction mixture was stirred at 0
C in an ice bath until the formed precipitate had dissolved again. The lower phase
(
3
)
2
2
2
1
2
°
was separated, tert-butanol (1.16 g, 15.7 mmol) was added and the mixture was
refluxed for one hour. The solvent was removed under reduced pressure yielding 1.8
g (53%) of the product 28 as a slightly yellow oil that solidifies to give colourless
needles.
ε-N,N-Bis(trifluoromethyl)aminohexanoic acid, (CF
3
)
2
N(CH
2
5
) C(O)OH (25),
Step 1.
ε-Caprolacton (19.5 g, 171 mmol) was dissolved in 200 of methanol and 11 drops of
concentrated H SO were added from a Pasteur pipette. The mixture was stirred for
0 minutes at room temperature and 200 mL water were added. The reaction mixture
was extracted with CH Cl (3 x 50 mL). The organic phases were combined, dried
with MgSO , and concentrated in vacuo. The product, methyl-ε-hydroxyhexanoate,
2
4
4
2
2
4
was isolated in 78% (19.5 g) yield after distillation (b.p. 67.5-68.5 °C at 50 Pa; 0.38
mm Hg).
Step 2.
Triflic anhydride (20.6 g, 73 mmol) was added dropwise to an ice-cold solution of
pyridine (5.46 g, 69 mmol) in 100 mL of dry CH
2
Cl . A colourless solid formed. The
2
2
9