Methyl fluoroalkanoate as methyl-transferring reagent. Unexpected participation of BAl2 (SN2) mechanism in the reaction of methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate with amines

Article abstract of DOI:10.1016/j.jfluchem.2016.02.012

In the reaction of methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate with arylamines or arylmethylamines, an unexpected methyl transfer from the ester to the amine by the B_Al2 (S_N2) mechanism was observed leading to the corresponding N-methylamines under specific conditions. The reaction was accompanied by the formation of amides via B_Ac2 mechanism. The unexpected methyl transfer is highly dependent on the structure of the starting amine and is supported by the absence of solvent and high temperature.

Full text of DOI:10.1016/j.jfluchem.2016.02.012

Journal of Fluorine Chemistry 185 (2016) 31–35
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Methyl fluoroalkanoate as methyl-transferring reagent. Unexpected
participation of BAl2 (SN2) mechanism in the reaction of methyl 2,3,3,3-
tetrafluoro-2-methoxypropanoate with amines
b
b
Bohumil Dolenskýa, , Jaroslav Kvíc9ala , Oldrich Paleta
ꢀ
*
a
Department of Analytical Chemistry, University of Chemistry and Technology, Technická 5, Prague 6, Prague 166 28, Czech Republic
Department of Organic Chemistry, University of Chemistry and Technology, Technická 5, Prague 6, Prague 166 28, Czech Republic
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 6 January 2016
Received in revised form 25 February 2016
Accepted 27 February 2016
Available online 2 March 2016
In the reaction of methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate with arylamines or arylmethyl-
amines, an unexpected methyl transfer from the ester to the amine by the BAl2 (SN2) mechanism was
observed leading to the corresponding N-methylamines under specific conditions. The reaction was
accompanied by the formation of amides via BAc2 mechanism. The unexpected methyl transfer is highly
dependent on the structure of the starting amine and is supported by the absence of solvent and high
temperature.
Keywords:
Methyl tetrafluoropropanoate
Methyl transfer
ã 2016 Elsevier B.V. All rights reserved.
Amine methylation
BAl2 mechanism
SN2 mechanism
1. Introduction
pyridinecarboxylates [9], or ring-closure during gas-phase pyroly-
sis [10] can be considered.
The transfer of methyl group from ester to amine is a well
established reaction. It proceeds as the SN2 reaction at the methyl
group and is characteristic for methyl alkyl- or aryl-sulfonates, the
presence of excellent sulfonate or sulfate leaving group being the
key factor [1]. In contrast, this type of mechanism is quite rare for
methyl alkanoates, where nucleophiles usually react at the
carbonyl carbon to substitute the methoxy group by tetrahedral
In this article, we report unexpected methyl transfer from
methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate (TFMP, 1) to
amines by the BAl2 mechanism, depending both on the nature
of the amine and the reaction conditions. In general, the alternative
BAl1 mechanism is not accounted as it requires an unlikely
formation of methyl cation in solution.
BAc2 mechanism [2]. The reaction analogous to sulfonate chemis-
2. Results and discussion
try (assigned as BAl2) is limited to derivatives of highly acidic acids:
the methyl transfer from ester to amine was observed for methyl
salicylate [3],o-nitrobenzoate [4] and dimethyl oxalate or fumarate
[4]. The methyl transfer was also accomplished with dimethyl
carbonate [5]. Heating of 2-amino-20-hydroxy-30-(methoxycar-
bonyl)binaphthol gave intermolecular methyl transfer in solid
state [6]. As other examples of a BAl mechanism, ring-opening of
lactones [7], N-allylation under nickel catalysis [8],
formation of N-methyl-pyridiniumcarboxylic acid from methyl
During our study of chemistry of TFMP, we found that the
reaction of the TFMP with amines 2a–2c leads to the corresponding
amides 3 (Scheme 1), however, under specific conditions the TFMP
can act as a methylation agent. The transferring of one or two
methyl groups to the nitrogen atom thus yielded unexpected
products, namely N-methyl- and N,N-dimethylalkylammonium
fluoroalkanoates 4 and 5 (Scheme 1).
In the first set of qualitative experiments, we studied the role of
substrate, solvent and reaction temperature. The ratio of products
in the crude reaction mixtures was determined by 19F NMR
spectroscopy (the signal of CF group of amides 3 can be observed at
ꢀ136 ppm, for the salts 4 and 5 it can be found at ꢀ132 ppm), while
* Corresponding author.
E-mail address: dolenskb@vscht.cz (B. Dolenský).
http://dx.doi.org/10.1016/j.jfluchem.2016.02.012
0022-1139/ã 2016 Elsevier B.V. All rights reserved.

32
B. Dolenský et al. / Journal of Fluorine Chemistry 185 (2016) 31–35
Scheme 1. Reaction of TFMP (1) with amines 2a–2c.
Table 1
Screening of amidation/methyl transfer in the reaction of TFMP (1) with amines 2.
Entry
Amine
Temp. (ꢁC)
Time (h)
Solvent
Conversion
3:(4 + 5) ratio
2:6:7a ratio
of 1 (%)
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2b
2b
2b
2c
2c
Reflux
100
rt
rt
rt
Reflux
Reflux
Reflux
115
24
72
48
16
336
26
72
THF
None
Heptane
Methanol
THF
THF
1,4-Dioxane
THF
0
100
95
100
100
100
73
No reaction
15:85
98:2
>99:1
89:11
69:31
56:44
No reaction
36:64
No reaction
59:31:10
n.d.
n.d.
n.d.
n.d.
n.d.
No reaction
85:7:8
10
24
<1
81
None
a
6 and 7 are the corresponding N-methyl and N,N-dimethyl derivatives of amine 2, resp.
the degree of methylation of the amines 2 was obtained by GC–MS
analysis of the amine mixture formed after alkalization of the
crude reaction mixture with sodium hydroxide. The results are
listed in Table 1.
and N-benzylammonium salt 4b in a 89:11 ratio (Table 1, entry 5).
Raising the temperature to reflux increased the content of salt 4b
to a 69:31 ratio (Table 1, entry 6) and further enhancement of the
temperature to 100 ꢁC (refluxing 1,4-dioxane as the solvent) led to
the ratio of 45:55 (Table 1, entry 7). This identifies the reaction
temperature as the key factor in the competition between
Thus, aniline (2a) as the least nucleophilic amine did not react
with TFMP in refluxing THF (Table 1, entry 1). Similarly, the
reactivity of benzhydrylamine (2c) was negligible under these
conditions probably due to steric hindrance of the amino group
(Table 1, entry 8). The reactivity dramatically changed when the
solvent was omitted and the reaction temperature was raised.
Thus, the reaction of aniline (2a) with 8-fold excess of TFMP at
100 ꢁC for 9 h gave after alkalization a mixture of starting aniline
(2a), N-methylaniline (6a) and N,N-dimethylaniline (7a) in a
59:31:10 ratio. Small amount of amide 3a in the crude reaction
product was also detected (Table 1, entry 2). Analogous reaction of
TFMP with equivalent of benzhydrylamine (2c) at 115 ꢁC gave after
alkalization a mixture of starting amine 2c, N-methylbenzhydryl-
amine (6c) and N,N-dimethylbenzhydrylamine (7c) in a 85:7:8 ratio
(Table 1, entry 9). About one third of starting TFMP was converted
to the corresponding amide 3c.
amidation by the BAc
Ac1 mechanism is unlikely) and the methyl transfer by the
BAl2 mechanism.
2
mechanism (the alternative
B
In the preparative experiments (Table 2), conditions of entry 2
(110 ꢁC, no solvent) using the excess of aniline to minimize double
methylation were employed for the synthesis of N-methylanili-
nium salt 4a, which was isolated in a 55% yield, along with 5% of
amide 3a. Analogously, conditions of entry 9 (115 ꢁC, no solvent)
allowed the isolation of the corresponding salt 4c in a 64% yield
and of the corresponding benzhydrylamide 3c in a 23% yield.
Unfortunately, neither crystallization nor column chromatography
gave the salt 4c of good purity. Similarly, the conditions of entry 4
(MeOH as solvent, r.t.) were employed for the synthesis of N-
benzylamide 3b, which was isolated in an excellent 92% yield,
while the conditions of entry 7 (refluxing 1,4-dioxane) allowed the
isolation of the corresponding salt 4b in a 29% yield and N-
benzylamide 3b in 37% yield.
Benzylamine (2b) as a highly nucleophilic amine proved to be
most sensitive to the reaction conditions and hence its reactivity
was studied in detail. The amide 3b was formed almost exclusively
at room temperature, even when non-polar heptane or polar
methanol as the solvent was used (Table 1, entries 3 and 4).
However, the same reaction in THF afforded a mixture of amide 3b
Finally, the diamine containing both arylamino and arylme-
thylamino group, 2-(aminomethyl) aniline (2d), was employed in
the reaction with TFMP. In analogy to the reaction of benzylamine
Table 2
Preparation of amides 3 and salts 4 by the reaction of TFMP (1) with amines 2.
Entry
Amine
Temp. (ꢁC)
Time (h)
Solvent
yield of 3 (%)
yield of 4 (%)
1
2
3
4
2a
2b
2b
2c
110
rt
Reflux
115
24
16
72
24
None
5
55
Traces
29
Methanol
1,4-Dioxane
None
92
37
23
64

B. Dolenský et al. / Journal of Fluorine Chemistry 185 (2016) 31–35
33
Scheme 2. Reactions of 2-(aminomethyl) aniline with TFMP (1).
(Table 1, entries
3
and 4), N-benzylamide 3d was formed
All reactions were performed in a dry argon atmosphere in an
oven-dried flasks. All reagents were purchased from Sigma–
Aldrich and used without additional purifications with the
exception of aniline. The solvents were purified and dried
according to standard procedures.
exclusively in heptane or methanol in 94% yield with only traces
of the methyl transfer detected by 19F NMR spectroscopy
(Scheme 2). Interestingly, the reaction of the amine 2d with TFMP
in acetone as the solvent did give neither the expected N-
benzylamide 3d nor the salt 4 or 5 but tetrahydroquinazolinium
salt 8 in a 65% preparative yield. We explain the formation of the
salt 8 as a result of primary reaction of diamine 2d with acetone to
give tetrahydroquinazoline 9, accompanied by the release of one
molecule of water. TFMP is subsequently hydrolyzed to 2,3,3,3-
tetrafluoro-2-methoxypropanoic acid (10), which in turn forms the
final salt 8 with the compound 9 (Scheme 2).
4.2. Liberation of the acid 10 and the amines 2a–2c, 6a–6c, 7a, 7c and
11 from the salts 4a–4c, 5a, 5c and 8
About 50 mg of a salt was diluted in 1 mL of water, and 1 mL of
conc. HCl was added. After 30 min of stirring, the mixture was
extracted by 2 ꢂ 2 mL of diethyl ether. The organic part was dried
over MgSO4 and analysed by GC–MS. In all cases, only propionic
acid 10 was detected. The aqueous part was neutralized with solid
K2CO3 and basified to pH 10 with conc. aqueous KOH. The mixture
was extracted with 2 ꢂ 2 mL of diethyl ether, combined organic
fractions were dried over MgSO4 and analysed by GC–MS to
identify the base parts of the salts (the spectral characteristics were
in accord with database values).
3. Conclusion
During the study of aminolysis of methyl 2,3,3,3-tetrafluoro-2-
methoxypropanoate (TFMP, 1) with aromatic and aliphatic amines
by common BAc2 mechanism giving amides 3, we disclosed that
aromatic or hindered aliphatic amines underwent an unexpected
methylation to N-methyl and N,N-dimethylamines salts 4 and 5,
caused by a rare BAl2 mechanism. This side-reaction proceeds
preferably at higher temperatures in solvents of medium polarity
or without solvent. We believe the products of BAl2 mechanism are
often overlooked due to their low content or improper isolation,
which targets the expected neutral amide not an ionic salt. We
hope that our observation will increase the attention on the BAl
mechanisms and its products in the field of electron-deficient
carboxylates, particularly the fluorinated ones.
Aniline (2a): MS (EI+): 93 (100) [M+], 66 (44), 65 (26), 39 (18).
N-methylaniline (6a): MS (EI+): 107 (75) [M+],106 (100), 77 (24),
65 (8), 51 (14), 39 (8).
N,N-dimethylaniline (7a): MS (EI+): 121 (67) [M+],120 (100),104
(16), 91 (4), 77 (25), 51 (16), 42 (10).
Benzylamine (2b): MS (EI+): 108 (2) [M + H+], 107 (65) [M+], 106
(100), 91 (15), 79 (44), 78 (17), 77 (31), 65 (7), 63 (7), 51 (24), 50
(14).
N-methylbenzylamine (6b): MS (EI+): 122 (5) [M + H+], 121 (59)
[M+], 120 (100), 106 (9), 104 (5), 92 (12), 91 (64), 79 (6), 78 (9), 77
(15), 65 (24), 63 (10), 51 (17), 44 (100), 42 (59).
4. Experimental
Benzhydrylamine (2c): MS (EI+): 183 (5) [M+], 182 (35), 181 (6),
152 (3), 106 (8), 105 (100), 77 (66), 63 (2), 51 (28), 50 (9).
N-methylbenzhydrylamine (6c): MS (EI+): 197 (5) [M+], 196 (3),
182 (1), 167 (12), 165 (12), 152 (6), 139 (1), 121 (9), 120 (100), 119
(10), 106 (4), 105 (3), 104 (13), 91 (3), 77 (13), 63 (3), 51 (7), 42 (27).
N,N-dimethylbenzhydrylamine (7c): MS (EI+): 212 (2) [M + H+],
211 (12) [M+], 210 (1), 168 (9), 167 (64), 166 (10), 165 (28), 152 (16),
135 (10), 134 (100), 118 (6), 106 (1), 91 (8), 77 (8), 65 (4), 63 (4), 51
(6), 42 (11).
4.1. General description of methods and materials
Temperature data were uncorrected. NMR spectra were
recorded with a Varian Gemini 300 HC Spectrometer, 1H NMR
spectra at 300 MHz and 13C NMR spectra at 75 MHz using residual
signals of deuterated solvent as the internal standards and 19F NMR
spectra at 282 MHz using CCl3F as the internal standard. Chemical
shifts are given in parts per million, coupling constants in hertz.
Mass spectra (ESI, APCI) were measured with
a LCQ Fleet
2,2-Dimethyl-1,2,3,4-tetrahydroquinazoline (11): MS (EI+): 162
(16) [M+], 147 (77), 130 (4), 118 (3), 106 (100), 104 (100), 91 (3), 79
(7), 78 (11), 77 (20), 65 (4), 51 (9), 42 (12).
(Finnigan) instrument and GC-MW spectra (EI) with Hewlett-
Packard MSD 5971A instrument. Infrared spectra in KBr pellets
were scanned on a NICOLET 740 USA apparatus.

34
B. Dolenský et al. / Journal of Fluorine Chemistry 185 (2016) 31–35
4.3. Screening reactions of TFMP (1) with amines 2
0.70 g, 55%, white crystals). The filtrate was mixed with of aq.
solution of NaOH (10%, 10 mL) and extracted with chloroform.
The organic layer was dried over MgSO4, evaporated to dryness
and the residue was purified by column chromatography (30 g
of silica, eluent petroleum ether/CH2Cl2 1:1) to give N-phenyl-
2,3,3,3-tetrafluoro-2-methoxypropanamide (3a, 64 mg, 5%,
white crystals). N-phenyl-2,3,3,3-tetrafluoro-2-methoxypropa-
namide (3a): 1H NMR (CDCl3): 8.18 (1H, bs), 7.60 (2H, d,
JHH = 7.7 Hz), 7.39 (2H, t, JHH = 7.7 Hz), 7.22 (1H, t, JHH = 7.4 Hz),
3.67 (3H, s) ppm. 13C NMR (CDCl3): 158.20 (d, JCF = 30.3 Hz),
135.72, 129.26 (2C), 125.98, 120.24 (2C), 119.21 (qd, JCF = 286.9
Hz, JCF = 36.1 Hz), 105.68 (dq, JCF = 246.2 Hz, JCF = 35.5 Hz),
53.84 ppm. 19F NMR (CDCl3): ꢀ81.5 (3F, d, JFF = 3.4 Hz), -135.6
(1F, m) ppm. IR (KBr): 3321 w, 1689 s, 1601 w, 1538 wcmꢀ1. T.
subl. ꢃ75 ꢁC at 132 Pa. For C10H9F4NO2 (251.18): calcd. C 47.82, H
3.61, N 5.58; found C 47.65, H 3.73, N 5.55. Anilinium 2,3,3,3-
tetrafluoro-2-methoxypropanoate (4a): 1H NMR (DMSO-d6):
7.34 (3H, bs), 7.23 (2H, t, JHH = 7.1 Hz), 6.98–6.88 (3H, m, temp.),
3.51 (3H, s, temp.) ppm. 13C NMR (DMSO-d6): 161.75 (d,
JCF = 33.7 Hz), 141.27, 129.18 (2C), 121.15, 119.81 (qd, JCF = 285.6
Hz, JCF = 35.7 Hz), 118.00 (2C), ꢃ104.8 (dm, JCF = ꢃ243 Hz),
53.46 ppm. 19F NMR (DMSO-d6): ꢀ76.2 (3F, d, JFF = 3.0 Hz),
ꢀ126.3 (1F, m) ppm. 19F NMR (CDCl3): ꢀ81.4 (3F, d, JFF = 3.0 Hz),
ꢀ132.8 (1F, m). IR (KBr): 3416 w, 3000–2500 w, 1665–1550 s,
1500 s, 1410 m, 1325 m, 1194 s, 1159 s, 1068 s, 1159 s, 827 s, 751 s,
718 m, 691 m cmꢀ1. T. subl. 80 ꢁC at 264 Pa. M.p. 123-127 ꢁC. For
a) TFMP (1, 0.44 g, 2.3 mmol), aniline (2a, 0.22 g, 2.3 mmol) and
THF (6 mL) were heated to reflux (66 ꢁC) for 24 h. No reaction
was observed by 19F NMR spectroscopy.
b) TFMP (1, 2.02 g, 10.6 mmol) and aniline (2a, 0.39 g, 4.2 mmol)
were heated without solvent to 100 ꢁC for 3 days. Crude reaction
mixture was diluted with aq. solution of NaOH (10%, 20 mL) and
stirred at r.t. for 30 min. The mixture was extracted with
chloroform (2 ꢂ 2 mL) and combined organic fractions were
dried over MgSO4. By GC–MS analysis, 59:31:10 ratio of aniline
(2a), N-methylaniline (6a) and N,N-dimethylaniline (7a) was
found.
c) TFMP (1, 0.51 g, 2.7 mmol), benzylamine (2b, 0.28 g, 2.6 mmol)
and heptane (10 mL) were stirred at r.t. for 2 days. According to
analysis by 19F NMR spectroscopy, N-benzyl-2,3,3,3-tetrafluoro-
2-methoxypropanamide (3b) and N-methylbenzylammonium
2,3,3,3-tetrafluoro-2-methoxypropanoate (4b) were formed in
a 98:2 ratio at 95% conversion of TFMP.
d) TFMP (1, 0.44 g, 2.3 mmol), benzylamine (2b, 1.14 g, 10.7 mmol)
and methanol (10 mL) were stirred at r.t. for 16 h. According to
analysis by 19F NMR spectroscopy, N-benzyl-2,3,3,3-tetrafluoro-
2-methoxypropanamide (3b) was formed quantitatively with
only traces of N-methylbenzylammonium 2,3,3,3-tetrafluoro-
2-methoxypropanoate (4b) present.
e) TFMP (1, 0.43 g, 2.2 mmol), benzylamine (2b, 0.27 g, 2.5 mmol)
and THF (6 mL) were stirred at r.t. for 14 days. According to
analysis by 19F NMR spectroscopy, N-benzyl-2,3,3,3-tetrafluoro-
2-methoxypropanamide (3b) and N-methylbenzylammonium
2,3,3,3-tetrafluoro-2-methoxypropanoate (4b) were formed in
a 89:11 ratio at 100% conversion of TFMP.
f) TFMP (1, 0.60 g, 3.2 mmol), benzylamine (2b, 1.24 g, 11.5 mmol)
and THF (8 mL) were heated to reflux (66 ꢁC) for 26 h. According
to analysis by 19F NMR spectroscopy, N-benzyl-2,3,3,3-tetra-
fluoro-2-methoxypropanamide (3b) and N-methylbenzylam-
monium 2,3,3,3-tetrafluoro-2-methoxypropanoate (4b) were
formed in a 69:31 ratio at 100% conversion of TFMP.
g) TFMP (1, 3.50 g,18.4 mmol), benzylamine (2b,1.96 g,18.3 mmol)
and 1,4-dioxane (50 mL) were heated to reflux (101 ꢁC) for
3 days. According to analysis by 19F NMR spectroscopy, N-
benzyl-2,3,3,3-tetrafluoro-2-methoxypropanamide (3b) and N-
methylbenzylammonium 2,3,3,3-tetrafluoro-2-methoxypropa-
noate (4b) were formed in a 56:44 ratio at 73% conversion of
TFMP.
h) TFMP (1, 0.40 g, 2.1 mmol), benzhydrylamine (2c, 0.39 g,
2.1 mmol) and THF (5 mL) were heated to reflux (66 ꢁC) for
10 h. According to analysis by 19F NMR spectroscopy, only traces
of N-(diphenylmethyl)-2,3,3,3-tetrafluoro-2-methoxypropana-
mide (3c) were detected in the reaction mixture.
i) TFMP (1, 0.50 g, 2.7 mmol) and benzhydrylamine (2c, 0.47 g,
2.6 mmol) were heated without solvent to 115 ꢁC for 24 h.
According to analysis by 19F NMR spectroscopy, N-(diphenyl-
methyl)-2,3,3,3-tetrafluoro-2-methoxypropanamide (3b) and
N-methylbenzhydrylammonium 2,3,3,3-tetrafluoro-2-methox-
ypropionate (4c) were formed in a 36:64 ratio at 81% conversion
of TFMP.
C10H11F4NO3 (269.20): calcd. C 44.62, H 4.12, N 5.20; found C
44.83, H 4.23, N 5.09.
b) N-benzyl-2,3,3,3-tetrafluoro-2-methoxypropanamide
(3b).
TFMP (1, 0.44 g, 2.3 mmol), benzylamine (2b, 1.14 g, 10.7 mmol)
and methanol (10 mL) were stirred at r.t. for 16 h. Reaction
mixture was diluted with 10 mL of CH2Cl2, extracted with aq.
HCl (1:1) and water. The organic part was dried over MgSO4,
filtered and evaporated to dryness. Purification by column
chromatography (15 g of silica, eluent petroleum ether/CH2Cl2
1:1) gave N-benzyl-2,3,3,3-tetrafluoro-2-methoxypropana-
mide (3b, 0.56 g, 92% yield, oil, which solidified after several
weeks). 1H NMR (CDCl3): 7.44 (1H, bs, temp.), 7.33–7.22 (5H, m),
4.47 (2H, d, JHH = 6.0 Hz), 3.50 (3H, d, JHF = 1.2 Hz) ppm. 13C NMR
(CDCl3): 160.46 (d, JCF = 31.4 Hz), 136.76, 128.65 (2C), 127.70,
127.47 (2C), 119.21 (qd, JCF = 286.5 Hz, JCF = 35.2 Hz), 105.64 (dq,
JCF = 245.6 Hz, JCF = 35.1 Hz), 53.32, 43.54 ppm. 19F NMR (CDCl3):
-81.7 (3F, d, JFF = 3.7 Hz), ꢀ136.6 (1F, bs) ppm. MS (EI+): 265 (22)
[M+], 245 (2), 230 (2), 202 (2),190 (2),164 (2),131 (9),104 (6), 97
(5), 91 (100), 77 (8), 69 (10), 65 (16), 51 (8). M.p. 39–40.5 ꢁC. Bꢀ.p1.
110-115 ꢁC/396 Pa. IR (KBr): 3333 w, 1684 s,1607 w, 1537 wcm
.
For C11H11F4NO2 (265.21): calcd. C 49.82, H 4.18, N 5.28; found C
50.38, H 4.22, N 5.32.
c) N-methylbenzylammonium 2,3,3,3-tetrafluoro-2-methoxypro-
panoate (4b). TFMP (1, 3.50 g, 18.4 mmol), benzylamine (2b,
1.96 g, 18.3 mmol) and 1,4-dioxane (50 mL) were heated to
reflux (101 ꢁC) for 3 days. The reaction mixture was evaporated
to dryness and anchored on 10 g of silica. Elution with CH2Cl2
gave 1.72 g (37% yield) of crude amide 3b. The next elution with
methanol gave 1.53 g (29% yield) of crude salt 4b, whose
purification by crystallization was unsuccessful. N-benzylamo-
nium 2,3,3,3-tetrafluoro-2-methoxypropanoate (4b impure):
1H NMR (DMSO-d6): 8.71 (2.5H, bs), 7.36–7.28 (2H, m), 7.23–7.17
(3H, m), 3.87 (2H, s), 3.35 (3H, s) ppm. 19F NMR (CDCl3/DMSO-d6
4:1): ꢀ81.4 (3F, d, JFF = 3.7 Hz), ꢀ131.9 (1F, m, JFF = 3.7 Hz). IR
(KBr): 3432 w, 3020–2000 w, 1660 s, 1496 m, 1459 m, 1383 m,
1325 m, 1200 s, 1175 s, 1155 s, 1061 s, 1042 s, 808 m, 762 m,
4.4. Preparative reactions of TFMP (1) with amines 2
a) N-phenyl-2,3,3,3-tetrafluoro-2-methoxypropanamide (3a) and
anilinium 2,3,3,3-tetrafluoro-2-methoxypropanoate (4a). TFMP
(1, 0.90 g, 4.7 mmol) 1 and aniline (2a, 3.14 g, 33.7 mmol) were
heated to 110 ꢁC for 9 h. The reaction mixture was diluted with
chloroform (10 mL) and precipitated white solid was filtered off
to give anilinium 2,3,3,3-tetrafluoro-2-methoxypropanoate (4a,
746 m, 706 m cmꢀ1
.
d) N-(diphenylmethyl)-2,3,3,3-tetrafluor-2-methoxypropanamide
(3c) and N-(benzhydryl)-ammonium 2,3,3,3-tetrafluoro-2-
methoxypropanoate (4c): TFMP (1, 0.50 g, 2.7 mmol) 1 and

B. Dolenský et al. / Journal of Fluorine Chemistry 185 (2016) 31–35
35
benzhydrylamine (2c, 0.47 g, 2.6 mmol) were heated to 115 ꢁC
for 24 h. The reaction mixture was evaporated to dryness,
anchored on silica (2 g), and separated by chromatography (5 g
of silica, eluent ethyl acetate) to give 0.20 g (23% yield) of crude
amide 3c, which was purified by vacuum distillation. The next
elution by methanol gave 0.60 g (64% yield) of crude salt 4c,
whose purification by crystallization or chromatography was
1610 w, 1542 wcmꢀ1. M.p. 69.5–71.5 ꢁC. For C11H12F4N2O2
(280.22): calcd. C 47.15, H 4.32, N 10.00; found C 47.00, H
4.49, N 9.82.
f) 2,2-Dimethyl-1,2,3,4-tetrahydroquinazolinium
2,3,3,3-tetra-
fluoro-2-methoxypropanoate (8). TFMP (1, 1.37 g, 11.2 mmol),
2-(aminomethyl) aniline (2d, 2.69 g, 14.1 mmol) and acetone
(10 mL) were stirred at r.t. for 45 days. The reaction mixture was
evaporated to dryness to obtain 3.32 g of the mixture of crystals
and oil. The crystals were washed with CH2Cl2 to give 2.36 g
(65% yield) of white crystals of salt 8, which was purified by
recrystallization from ethanol. 1H NMR (DMSO-d6): 10.01 (2H,
bs), 6.76 (1H, bs), 6.73–6.66 (2H, m), 4.25 (2H, s), 3.40 (3H, s),
1.49 (6H, s) ppm. 13C NMR (DMSO-d6): 161.73 (d, JCF = 30.3 Hz),
140.4, 128.16, 126.94, 120.6 (qd, JCF = 285.1 Hz, JCF = 37.2 Hz),
117.69, 115.27, 112.87, 105.59 (dq, JCF = 245.3 Hz, JCF = 32.6 Hz),
66.17, 52.93 (d, JCF = 1.1 Hz), 24.52 (2C) ppm. 19F NMR (DMSO-
d6): ꢀ79.6 (3F, d, JFF = 3.9 Hz), ꢀ126.9 (1F, qq, JFF = 3.9 Hz,
JHF = 1.7 Hz). For C14H18N2O3F4 (338.31): calcd.. C 49.71, H
5.36, N 8.28; found C 49.50, H 5.28, N 8.25.
unsuccessful.
N-(diphenyl-methyl)-2,3,3,3-tetrafluor-2-
methoxypropanamide (3c): 1H NMR (CDCl3): 7.39–7.27 (6H,
m), 7.26–7.18 (4H, m), 7.09 (1H, bs), 6.31 (1H, d, JHH = 8.2 Hz),
3.56 (3H, s) ppm. 19F NMR (CDCl3): ꢀ81.6 (3F, d, JFF = 3.0 Hz),
ꢀ136.3 (1F, m) ppm. 13C NMR (CDCl3): 159.52 (d, JCF = 31.5 Hz),
140.09, 139.85, 128.91 (2C), 128.86 (2C), 128.01, 127.96, 127.28
(2C), 127.18 (2C), 119.22 (qd, JCF = 286.5 Hz, JCF = 35.2 Hz), 105.78
(dq, JCF = 245.2 Hz, JCF = 35.2 Hz), 57.43, 53.66 ppm. IR (KBr):
3317 w, 1686 s, 1604 w, 1525 wcmꢀ1. B.p. ꢃ150 ꢁC/132 Pa. For
C17H15F4NO2 (341.31): calcd. C 59.83, H 4.43, N 4.10, F 22.27;
found C 59.72, H 4.52, N 4.03, F 22.61. MS (EI+): 341 (25) [M+],
306 (12), 290 (1), 278 (1), 264 (1), 240 (1), 216 (4), 210 (11), 180
(5), 168 (15), 167 (100), 166 (16), 165 (43), 152 (19), 131 (22), 115
(4), 105 (7), 104 (18), 97 (7), 83 (6), 77 (21), 69 (13), 63 (4), 51
(12), 42 (6). N-(benzhydryl) amonium 2,3,3,3-tetrafluoro-2-
methoxypropanoate (4c impure): 1H NMR (DMSO-d6): 7.83 (4H,
d, JHH = 7.2 Hz), 7.72 (0.7H, d, JHH = 7.0 Hz), 7.45–7.32 (7H, m),
5.54 (0.1H, s), 5.34 (0.9H, s), 3.56 (3.4H, d, J = 1.3 Hz), 2.81 (6.1H,
s), 2.68 (0.5H, s) ppm. 19F NMR (CDCl3): ꢀ81.6 (3F, d, JFF = 3.8 Hz),
ꢀ131.8 (1F, m) ppm. 13C NMR (DMSO-d6): 165.01 (d, JCF = 31.3
Hz), 138.92, 138.48 (impurity), 130.81, 130.54 (impurity),
130.28, 130.16 (impurity), 129.64, 129.44 (impurity), 122.42
(qd, JCF = 284.5, JCF = 36.1 Hz), 107.44 (dq, JCF = 244.4 Hz, JCF = 33.3
Hz), 77.66, 68.38 (impurity), 54.40 (impurity), 43.73, 32.80
(impurity). For C17H17F4NO3 (359.32): calcd. C 56.83, H 4.77, N
3.90, F 21.15; found C 58.39, H 5.48, N 3.49, F 19.98.
Acknowledgement
We thank the Ministry of Education, Youth and Sports (Research
Project No. 6046137301) for financial support.
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115.83, 105.53 (dq, JCF = 245.7 Hz, JCF = 35.5 Hz), 53.31 (d, JCF
=
675–678.
2.3 Hz), 40.57 ppm. IR (KBr): 3483 w, 3377 w, 3328 w, 1672 s,