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Tetrahedron
2
12
13
14
15
16
2.0
2.0
2.0
2.0
2.0
NaOH(5.
5)
KOH(11. MeCN/H2O
0)
LiOH(11
.0)
NaOH(1
1.0)
MeCN/H2O
(10/1)
rt
rt
rt
rt
rt
10min
10min
10min
10min
10min
52
75
62
77
77
mediated triclassification reaction, which produced one of the
following three substances: N-CF2H derivatives, formamides or
the starting secondary amines. The corresponding classification
tree model and its application in pharmaceutical chemistry
research had been investigated in this work.
(10/1)
MeCN/H2O
(10/1)
MeCN/H2O
(5/1)
2. Results and discussion
NaOH(1
1.0)
MeCN/H2O
(20/1)
Our initial study was the optimization of the reaction
condition of benzimidazole 1a with iododifluoroacetophenone 2
(Table 1). Firstly, a variety of reaction systems were screened
a Isolated yields.
b No reaction, and after 12h, compound 2 and it’s decomposition product
(PhCO2CF2H) were monitored by TLC.
Table 2. Difluoromethylation of 1a with different
(Table 1, entries 1-6), and only entry
6 furnished the
corresponding product 3a in 50% yield (entry 6). While
increasing the reaction temperature, the yield of 3a was not
improved obviously (Table 1, entry 7). Gratifyingly, increasing
the amount of 2 led to the improvement of the yield (Table 1,
entries 8-10). Using 2.0 equiv. of compound 2 gave a good yield
(77%)(entry 9), but when the amount of compound 2 was
increased to 2.5 equiv.(entry 10), the yield of 3a (76%) was not
promoted. When anhydrous acetonitrile was used as solvent, the
yield decreased to 48% (Table 1, entry 11). In addition, only 52%
yield was achieved when the amount of NaOH was reduced to
5.5 equiv. (Table 1, entry 12). Further optimization studies
revealed that the yield of 3a decreased slightly when the KOH or
LiOH was used as alkali source. It is worth noting that this
reaction takes only 10 minutes according to the monitoring of
TLC. The reaction condition of different ratio of the solvent
mixture (MeCN/H2O = 5/1, 10/1 and 20/1, v/v)( entries 15, 9 and
16) was validated here with same product and the similar yield.
Therefore, the ratio of the solvent mixture had no great influence.
Here, the option MeCN/H2O(10/1, v/v)was selected to form a
certain concentration of aqueous NaOH (65 wt%).
difluoroacetophenones
Entr
ya
X
Base
(equiv.)
Solvent
Temp
(oC)
rt
Time
10min
10min
10min
Yield
(%)b
72
1
Cl(4) NaOH(11.0) MeCN/H2O
(10/1)
Br(5) NaOH(11.0) MeCN/H2O
(10/1)O
2
3
rt
rt
70
77
I(2)
NaOH(11.0) MeCN/H2O
(10/1)
a For all cases, the reactant conditions were similar to those of entry 9 in
Table 1.
b Isolated yields.
With the optimum conditions in hand (Table 1, entry 9), the
scope of the secondary amines was examined and the results
were summarized in Table 3. Multifarious secondary amines,
such as benzimidazoles, indoles, indazoles, benzotriazoles,
imides, aliphatic secondary amines, imidazoles and N-
methylanilines, were investigated. The results showed that the
reaction of secondary amines with 2 under this optimized
conditions, furnished different products, falling into three main
categories: N-CF2H products, formamides and recovered starting
materials.
Thereafter, the reactivity of reagent 2 and the similar potential
difluorocarbene reagents, including PhCOCF2Cl (4), PhCOCF2Br
(5), were compared (Table 2). It was found that compounds 4 and
5 were also able to act as difluorocarbene reagents, but slightly
worse yields of 3a were received. So, as shown in Table 2,
compound 2 showed the best reaction effect among these three
difluoroacetophenones.
(i)
First of all, stable N-CF2H products were generated
(Table 3, entries 1-12). All benzimidazoles derivatives were
successfully N-difluoromethylated under the optimized reaction
condition. So, the corresponding N-difluoromethyl tertiary
amines were obtained good yield (up to 87%) by
difluoromethylation of the substrates with electron donating
groups such as methyl, benzyl, mercapto and pyridine (Table 3,
entries 2-4), while the yield of the substrates with strong electron
withdraw group, such as nitro group, decreased obviously (Table
3, entry 6). For indoles derivatives, the N-difluoromethylation
could smoothly implement with good yields for the substrates
substituted at their -3 or -6 site with meta-positioning group of
aromatic electrophilic substitution reaction (Table 3, entries 7, 9-
10). Besides, the optimum condition of the reaction was applied
in the N-difluoromethylation of 5-bromo substituted indazole 1k,
and product 3k was achieved in moderate yield (Table 3, entry
11). To examine the reactivity further, the unsubstituted
benzotriazole 1l was subjected to the reaction conditions
furnishing the corresponding product 3l in 87% isolated yield
(Table 3, entry 12).
Table 1. Optimization of reaction conditions for the
difluoromethylation of 1a
En
try
2
Base
(equiv.)
Solvent
Temp
(oC)
Time
Yield
(%)a
(equiv.)
1
2
1.0
1.0
Et3N(2.0
)
NaH(1.2
5)
THF
rt
rt
12h
12h
0b
0b
DMSO
3
4
1.0
1.0
NaH(1.0)
THF
THF
rt
rt
10min
10min
39
38
NaH(1.2
5)
5
6
1.0
1.0
NaH(2.0)
THF
rt
rt
10min
10min
32
50
NaOH(1
1.0)
MeCN/H2O
(10/1)
7
8
1.0
1.5
2.0
2.5
2.0
NaOH(1
1.0)
NaOH(1
1.0)
NaOH(1
1.0)
NaOH(1
1.0)
MeCN/H2O
(10/1)
MeCN/H2O
(10/1)
MeCN/H2O
(10/1)
MeCN/H2O
(10/1)
50
rt
10min
10min
10min
10min
10min
52
65
77
76
48
(ii) In addition, it was found that the N-methylanilines were
converted into N-formamides in good yields (82-89%) without
any N-CF2H derivatives (Table 3, entries 13-16), similar to the
work of song and other groups [40]. As shown in Table 3, the
phenyl substituted N-methylaniline (1o) formed formamide 6o
with 89% yield (Table 3, entry 15). When the substituent was
naphthyl, the yield of 6m was 88%, which was similar to that of
9
rt
10
11
rt
NaOH(1
1.0)
MeCN
rt
Chen, Xiu-Ping
