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10.1002/adsc.201800006
Advanced Synthesis & Catalysis
corresponding hemiaminal ether compounds, some
drawbacks such as the use of excess amounts of
peroxide, expensive oxidation reagent, low
conversions or yields and the limited substrate scopes
are still the issues limiting their further applications.
Moreover, to the best of our knowledge, the
transition-metal-free direct C(sp3)-H amination for
the synthesis of hydrazone hemiaminal ethers has not
been disclosed. In this regard, the development of a
novel, mild and environmental friendly metal-free
system to synthesize the hemi-amino ether
compounds remains highly desirable.
and 3). Although polyhaloalkanes, such as C2Cl6,
BrCCl3, CCl4, and CBr4 have been reported to form
EDA complexes with amines,16h,16i they were less
effective than C4F9I in this case (Table 1, entries 4-7).
Replacement of Cs2CO3 with other bases, such as
K2CO3, Na2CO3, NaH, or t-BuOK led to diminished
yields (Table 1, entries 8-11). Attempts to reduce the
amount of THF failed, reactions carried out in PhCH3,
CH3CN, DMF or DMSO using 10 equiv. of THF as
the coupling reagent was noneffective (Table 1,
entries 12-15). Finally, careful optimization of other
reaction parameters revealed that the amination
product could be afforded in 85% yield with 1.5
Perfluoroalkyl iodides (RFI) are known as
important perfluoroalkylating reagents through the
cleavage of C-I bonds and generation of
perfluoroalkyl radicals.[12] The reactive and strongly
o
equiv. of Cs2CO3 and 1.5 equiv. of n-C4F9I at 65 C
for 12h (Table 1, entries 16-19).
Table 1. Screening of the optimal reaction conditions.a)
•
electrophilic RF are prone to abstract hydrogen atoms
to afford hydrodehalogenation products.[13] Given the
low cost, less toxicity and ready availability, the
possible applications of RFI as H-abstraction reagents
for the hemiaminal ether synthesis are particularly
appealing. Furthermore, due to the small reduction
potential (E0 CF3I = −1.22 V vs SCE, in DMF)
red
Entry Oxidant
Base
Solvent Yield (%)b)
compared with hypervalent iodide (E0 Ph2I+ = −0.2
red
•
V vs SCE, in H2O) or peroxide (E0 t-BuO2 = 0.71
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
C4F9I
C4F9I
-
C2Cl6
BrCCl3
CCl4
Cs2CO3
-
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
PhCH3
67
NR
NR
43
27
24
45
23
NR
36
48
NR
NR
trace
trace
87
85
55
54
red
V vs NHE, in H2O),[14] the sensitive functional group
could be well tolerated. Nonetheless, the generation
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
NaH
•
of RF generally required environmentally unfriendly
reagents or harsh reaction conditions, such as
•
transition metals or UV irradiation. Generation of RF
CBr4
without initiators under mild conditions represent a
further stage of development. Recently, our group has
been interested in the reactions involving
perfluoroalkyl iodides,[15] we report herein an
unprecedented example of a halogen-bond-promoted
transition metal-free C-N bond formation reaction for
the hemiaminal ether (especially hydrazone
hemiaminal ether) synthesis. The active halogen-
bond adduct (one kind of electron donor-acceptor
complexes, EDA complexes)[16] could be formed
through a transiently generated amidyl anion with
perfluoroalkyl halide. Thermal or visible-light
irradiation of the halogen-bond adduct induced a
single electron transfer (SET),[17] thus allowing easy
access to radical species. The hydrogen atom transfer
C4F9I
C4F9I
C4F9I
C4F9I
C4F9I
C4F9I
C4F9I
C4F9I
C4F9I
C4F9Id)
C4F9Ie)
C4F9Id)
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c)
CH3CNc)
DMFc)
DMSOc)
THF
d)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
d)
d)
e)
THF
THF
THF
a)
Reaction conditions: under N2, 1a (0.3 mmol), base (0.6
o
mmol) and oxidant (0.6 mmol) in THF (3.0 mL) at 65 C
for 12 h. Isolated yield. THF (3.0 mmol) in 3.0 mL of
solvent. 1.5 equiv. of base or oxidant was added. 1.0
equiv. of oxidant or base was used.
b)
c)
•
(HAT) of the ether with RF would generate an alkyl
d)
e)
radical to finally afford the amination product
(Scheme 1c).[18] This approach could overcome the
difficulty of the previously reported methods and
feature synthetic simplicity, broad substrate scope,
and good functional-group compatibility.
With the optimal reaction conditions (Table 1,
entry 17) in hand, we proceeded to explore the
generality of this methodology. The reaction protocol
was first applied to the -C(sp3)-H amination of ether
2 with a wide range of hydrazone sulfonamides 1
(Table 2). Generally, acetophenone hydrazone
containing either electron-donating or electron-
withdrawing groups on the phenyl moiety were well
tolerated and reacted smoothly to aff ord the
corresponding products in good to excellent yields
(3b-3g). Extension of the chain length from the
methyl group to the ethyl or n-propyl group was
found to have only small impact on the reactivity (3h
To begin our study, the commercially available
acetophenone hydrazone 1a and tetrahydrofuran
(THF) 2a were chosen as the model substrates. The
feasibility of the transformation was then tested by
exposing the substrates to a mixture of n-C4F9I and
Cs2CO3. Gratifyingly, the desired amination product
was obtained in 67% isolated yield when the reaction
o
was performed at 65 C for 12h (Table 1, entry 1).
Then, several control experiments were conducted
and the results showed that both C4F9I and Cs2CO3
were indispensable for the reaction (Table 1, entries 2
2
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