Communications
doi.org/10.1002/ejoc.202100580
nature of the base was studied (Table 1, entries 6–8) and when
NaOH was used, 2a was isolated in 40% yield. The efficiency of
the reaction was fine-tuned by decreasing the reaction temper-
ature (Table 1, entries 8–11), and the best yield was obtained
°
when the reaction was carried out at 0 C for 24 h (Table 1,
entry 10). Extension of the reaction time to 48 h gave a similar
result (Table 1, entry 12). Note that in absence of base, 2a was
obtained in only 19% yield (Table 1, entry 13).
Figure 1. 2,2,2-Trifluoroethoxylated Drugs.
With the best reaction conditions in hand, the scope of the
transition metal-free 2,2,2-trifluoroethoxylation reaction was
studied (Scheme 2). A panel of benzamide derivatives from the
8-aminoquinoline was functionalized. Note that decent yields
were obtained taking into consideration tedious purifications.
Not only para-substituted amides with a methyl or a methoxy
group (1a and 1b) were functionalized but also amides bearing
a phenyl or a naphthyl group (1c and 1d) were suitable
substrates. The 2,2,2-trifluoroethoxylaton of different para-
substituted benzamides with an electron withdrawing group
(CF3, 1e) or a halogen (Br, 1f) went smoothly. The reaction was
scaled up 10-fold and 2b was isolated in 47% yield. The
transformation turned out to be sensitive to the substitution
pattern and compounds 2g and 2h were isolated in low to
moderate yields, probably due to a less conjugated system in
case of meta substituted ones. Pleasingly, the amide derived
from the vanillin 1h was functionalized, leading to the expected
product 2h in 45% yield. The reaction was not restricted to
benzamide derivatives as amides derived from furan and
thiophene provided the corresponding 2,2,2-trifluoroeth-
oxylated products 2i and 2j in 50% yield in both cases. Finally,
2,2,2-trifluoroethoxylated quinolines would be of high interest
for pharmaceutical and agrochemical industries. Herein, the
unprecedented transition metal-free remote CÀ H bond 2,2,2-
trifluoroethoxylation of amide derived from 8-aminoquinoline
at the C5 position using the 2,2,2-trifluoroethanol as the
fluorinated source is reported.
We embarked on this project using the derivative 1a as the
model substrate. Initially, the copper-catalyzed 2,2,2-
trifluoroethoxylation of the amide 1a was first investigated in
the presence of Na2CO3 and PIDA in 2,2,2-trifluoroethanol at
°
25 C.
Pleasingly, 2a was isolated in a modest 14% yield (Table 1,
entry 1) and the reaction was completely selective towards the
functionalization at the C5 position of the 8-aminoquinoline
part, as no functionalization at the ortho position of the amide
part was observed.[16] Interestingly, a control experiment in the
absence of the copper catalyst showed that 2a was obtained in
18% yield (Table 1, entry 2). We then pursued our investigations
to further optimize this transition metal-free process. Several
oxidants were tested (table 1, entries 2–4) and PIDA turned out
to be the most efficient one. Note that no reaction occurred in
the absence of oxidant, highlighting hence its key role in the
depicted process (Table 1, entry 5). Then, the influence of the
Table 1. Optimization of the 2,2,2-trifluoroethoxylation reaction.[a]
Entry[b]
Oxidant
Base
T ( C)
Yield (%)
°
1[b]
2
3
4
5
6
7
8
PIDA
PIDA
PIFA
K2S2O8
/
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
CsOPiv
KOH
NaOH
NaOH
NaOH
NaOH
NaOH
/
25
25
25
25
25
25
25
25
10
0
14
18 (29)
(16)
NR
NR
20
25
40
36
55 (78)
31
9[c]
10[c]
11[c]
12[d]
13[c]
À 10
0
0
53
19
[a] Reaction conditions: amide 1a (0.2 mmol, 1 equiv.), base (2 equiv.),
oxidant (2 equiv.), TFE (0.1 M), Argon, T ( C), 2 h. 19F NMR yields were
Scheme 2. Scope of the 2,2,2-trifluoroethoxylation reaction. Reaction con-
ditions: amide 1 (0.2 mmol, 1 equiv.), NaOH (2 equiv.), PIDA (2 equiv.), TFE
°
determined using the α,α,α-trifluoroacetophenone as the internal standard
and were given in parenthesis. [b] Cu(OAc)2 (5 mol%) was used. [c] 24 h. [d]
48 h. PIDA=(Diacetoxyiodo)benzene. PIFA=[Bis(trifluoroacetoxy)iodo]
benzene. NR: no reaction.
(0.1 M), 0 C, 24 h. Isolated yields were given. 19F NMR yields were given in
°
parenthesis and were determined using the α,α,α-trifluoroacetophenone as
the internal standard. [a] The reaction was carried out on a 2 mmol scale.
Eur. J. Org. Chem. 2021, 3407–3410
3408
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