Key words
trifluoroacetyl - aromatic amines - bactericidal activity - transition-metal free
- dibromotrifluoroacetone
The synthesis of fluorinated organic molecules has become one of the most active and
dynamic areas in chemistry.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10] In fact, the fields of modern pharmaceuticals and plant protection agents as well
as advanced materials, for example, energy technologies (batteries, etc.), would be
impossible without appropriate organofluorine compounds. In this respect, the development
of new synthetic methodologies for the preparation of fluorinated molecules is crucial.
Although many elegant protocols for the introduction of fluorine atoms or fluoroalkyl
groups directly into a given organic substrate have been disclosed in the past decades,[11–27] there remains a continuing interest in complementary and improved procedures, particularly
in the development of new methods that can be applied on a practical scale.[28–34]
In the past few decades, many synthetic methods have been reported for the synthesis
of trifluoroacetylaniline, for example, from N-formylaniline and trifluoromethane, which can be synthesized under the action of
strong bases (Scheme [1a]).[35] Nitrobenzene substrates can also undergo reduction reactions with ethyl trifluoroacetate
under hydrogenation conditions with supported nickel catalysts (Scheme [1b]).[36] Direct dehydration of aniline and trifluoroacetic acid under iron catalysis can
be used to synthesize trifluoroacetylaniline (Scheme [1c]).[37] Heating 1,1,1-tribromo-3,3,3-trifluoropropanone with freshly distilled aniline also
leads to the formation of trifluoroacetanilide (Scheme [1d]).[38] Indeed, there are many other reports of similar methods.[39]
[40]
[41]
[42]
[43]
[44] However, there are still relatively few coupling reaction methods that do not use
transition metals, especially in pharmaceutical chemistry where strict control of
metal residues is required. This has driven researchers to develop new coupling reactions
that do not require the participation of transition metals to achieve the synthesis
of bioactive molecules. Based on this, we designed a coupling reaction between dibromotrifluoroacetone
and aniline that proceeds under alkaline conditions to efficiently synthesize such
compounds (Scheme [1e]).
Scheme 1 Synthesis strategy of trifluoroacetyl aniline
As shown in Table [1], O-hydroxyphenylamine (1a) was initially selected to react with 3,3-dibromo-1,1-trifluoroacetone (2) as a template. In the presence of sodium carbonate with 1,4-dioxane as the solvent,
the reaction was carried out at 100 °C for 10 hours, and the target compound was generated
with a yield of 39% (entry 1). We then screened the conditions of the reaction. First,
we examined different types of bases and found that the reaction yield increased to
65% when sodium bicarbonate was used (entries 1–10). Next, we investigated the solvent
used in the reaction. When 1,4-dioxane was used, the isolated yield of the reaction
was optimal, reaching 65% (entries 10–17). Subsequently, we investigated the temperature
required for the reaction (entries 18–21) and found that increasing or decreasing
the temperature decreased the reaction yield. When the temperature was 120 °C, the
yield was highest (78%; entry 20). Finally, we investigated the reaction time and
found that after 12 hours reaction, the yield increased to 83% (entries 22–24). Thus,
it was found that the optimal conditions for this reaction were 1a (1 mmol), 2 (2 mmol), sodium bicarbonate (2 mmol), 1,4-dioxane (2 mL), 120 °C, 12 h, which gave
a reaction yield of 83% (entry 24).
Table 1 Optimization of Reaction Conditionsa
 
|
|
Entry
|
Base
|
Solvent
|
Temp (°C)
|
Time (h)
|
Yield (%)b
|
|
1
|
Na2CO3
|
1,4-dioxane
|
100
|
10
|
39
|
|
2
|
Et3N
|
1,4-dioxane
|
100
|
10
|
49
|
|
3
|
K2CO3
|
1,4-dioxane
|
100
|
10
|
20
|
|
4
|
KHCO3
|
1,4-dioxane
|
100
|
10
|
59
|
|
5
|
DMAP
|
1,4-dioxane
|
100
|
10
|
39
|
|
6
|
DBU
|
1,4-dioxane
|
100
|
10
|
20
|
|
7
|
DIPEA
|
1,4-dioxane
|
100
|
10
|
10
|
|
8
|
t-BuOK
|
1,4-dioxane
|
100
|
10
|
7
|
|
9
|
t-BuONa
|
1,4-dioxane
|
100
|
10
|
12
|
|
10
|
NaHCO3
|
1,4-dioxane
|
100
|
10
|
65
|
|
11
|
NaHCO3
|
MeCN
|
100
|
10
|
59
|
|
12
|
NaHCO3
|
hexane
|
100
|
10
|
0
|
|
13
|
NaHCO3
|
DMF
|
100
|
10
|
54
|
|
14
|
NaHCO3
|
MOE
|
100
|
10
|
7
|
|
15
|
NaHCO3
|
MePh
|
100
|
10
|
10
|
|
16
|
NaHCO3
|
THF
|
100
|
10
|
0
|
|
17
|
NaHCO3
|
IPA
|
100
|
10
|
<5
|
|
18
|
NaHCO3
|
1,4-dioxane
|
60
|
10
|
29
|
|
19
|
NaHCO3
|
1,4-dioxane
|
80
|
10
|
34
|
|
20
|
NaHCO3
|
1,4-dioxane
|
120
|
10
|
78
|
|
21
|
NaHCO3
|
1,4-dioxane
|
140
|
10
|
49
|
|
22
|
NaHCO3
|
1,4-dioxane
|
120
|
6
|
20
|
|
23
|
NaHCO3
|
1,4-dioxane
|
120
|
8
|
44
|
|
24
|
NaHCO3
|
1,4-dioxane
|
120
|
12
|
83
|
a Reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), base (2.0 equiv), solvent (2.0 mL), 6–12 h, 60–140 °C. Note: IPA = isopropanol,
MOE = 2-methoxyethanol, DMF = N,N-dimethylformamide.
b Isolated yield.
In order to investigate the generality of this reaction, aniline derivatives with
different substituents were studied. The results indicate that, irrespective of whether
the substituents on aniline were electron-rich or electron-deficient, the corresponding
target compounds were generated under the optimal reaction conditions (Table [2]). With electron-rich substituents on aniline, such as alkyl, methoxy, ethoxy, and
hydroxyl groups, most of the corresponding target products 3a–j were obtained with high yields. When electron-deficient substituents were present
on the aniline, such as fluorine, chlorine, bromine, iodine, and cyanide, the corresponding
target products 3k–q were also obtained with good yields. At the same time, we also investigated compounds
with multiple substituents on aniline, and the corresponding target products 3r–ab were obtained with moderate to high yields.
Finally, we also conducted biological activity tests on the synthesized trifluoromethylaniline
derivatives and found that compounds 3z and 3aa have different bactericidal effects on different bacterial strains (Table [3]), especially on Staphylococcus aureus, Salmonella enteritidis, Pseudomonas aeruginosa, and Bacillus subtilis. For Bacillus subtilis, compound 3z exhibited a sterilization rate of over 99% (entry 4). These biological activity experimental
results provide a scientific basis for future drug screening.
Table 3 Biological Sterilization Studies
|
Entry
|
Strain
|
Bactericidal molecule
|
Sterilization conc. (CFU/mL)
|
Sterilization rate (%)
|
|
1
|
Staphylococcus aureus
|
3z
|
9 × 106
|
95.86
|
|
Staphylococcus aureus
|
3aa
|
5 × 106
|
62.28
|
|
2
|
Salmonella enteritidis
|
3z
|
2 × 106
|
78.52
|
|
Salmonella enteritidis
|
3aa
|
2 × 106
|
84.65
|
|
3
|
Pseudomonas aeruginosa
|
3z
|
1 × 106
|
30.33
|
|
Pseudomonas aeruginosa
|
3aa
|
1 × 106
|
48.87
|
|
4
|
Bacillus subtilis
|
3z
|
1 × 104
|
99.89
|
|
Bacillus subtilis
|
3aa
|
4 × 105
|
93.77
|
|
Scheme 2 Possible reaction mechanism.
To summarize, we have developed a transition-metal-free coupling reaction for the
efficient synthesis of trifluoroacetylaniline compounds. This method features mild
conditions and does not require transition-metal catalysts or ligands. Only a base
is needed to achieve this chemical conversion process, and the substrate range is
wide. More importantly, we conducted biological sterilization experiments and found
that two compounds had very good bactericidal effects, especially against Bacillus subtilis. This provides a technical basis for future biological activity research.
