Efficient imidation of C(sp3)-H bonds adjacent to oxygen atoms of aryl ethers under metal-free conditions

Article abstract of DOI:10.1039/c4cc06003b

An intermolecular oxidative C-N formation reaction of aryl ethers with pharmacological saccharins was realized under metal-free conditions for the first time. The understanding of the intrinsic characteristics between C(sp³)-H and C(sp²

Full text of DOI:10.1039/c4cc06003b

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Efficient imidation of C(sp3)–H bonds adjacent to
oxygen atoms of aryl ethers under metal-free
conditions†
Cite this: Chem. Commun., 2014,
50, 12880
Received 1st August 2014,
Accepted 30th August 2014
Kai Sun,* Xin Wang, Gang Li, Zhonghong Zhu, Yongqing Jiang and Beibei Xiao
DOI: 10.1039/c4cc06003b
www.rsc.org/chemcomm
An intermolecular oxidative C–N formation reaction of aryl ethers Through the development of novel catalyst systems, much progress
with pharmacological saccharins was realized under metal-free has been achieved in the direct transformation of aryl ethers (O-based
conditions for the first time. The understanding of the intrinsic electrophiles) through C(sp2)–O activation and offers a new pathway
characteristics between C(sp3)–H and C(sp2)–O bonds of aryl ethers to construct diverse compounds.10 Selective activation and direct
and their potential for application might promote more research functionalization of C(sp3)–H bonds adjacent to oxygen atoms with
interest in this area.
aryl ethers is also a highly appealing process but remains an elusive
goal. Hence, a rapid, efficient and practical access to selective
Nitrogen containing compounds are extremely important because activation of C(sp3)–H bonds in common aryl ethers is urgent and
of their abundance in various natural products as well as in highly desirable. As part of our continuing interest in the construction
synthetic organic compounds.1 Accordingly, the construction of of C–N bonds,11 we report in this communication an efficient and
the C–N bond is of significant importance as it opens avenues for highly regioselective protocol for oxidative imidation of C(sp3)–H
the introduction of nitrogen into organic molecules. The area of bonds adjacent to oxygen atoms with aryl ethers. In addition, cyclic
catalytic C–H amination has led to significant results arising both and chain alkyl ethers can also give the coupling products at C(sp3)–H
from the discovery of nitrene transfers and the combination of a to the ethereal oxygen. More importantly, this study contributed to
transition-metal-catalyzed C–H activation.2,3 Thus far, sustainable the understanding of the intrinsic nature of C(sp3)–H bonds adjacent
progress has been made in the area of oxidative C(sp)–H and C(sp2)–H to oxygen atoms of aromatic ethers, which are traditionally consid-
couplings for various C–N bond forming reactions. In addition, ered ‘‘inert’’ but show a mysterious and attractive synthetic potential
several excellent examples of the amination/functionalization of the upon the use of appropriate catalyst systems.
relatively active benzylic C(sp3)–H bonds, allylic C(sp3)–H bonds and
Our initial efforts focused on the direct coupling of anisole 1a
C(sp3)–H bonds adjacent to nitrogen atoms have been described.4–6 with saccharin 2 using a combination of di-tert-butyl peroxide
Direct amination of C(sp3)–H bonds adjacent to oxygen atoms is also (DTBP; tBuOOtBu) and Bu4NI, which was usually used in radical
a valuable goal; however, owing to the lack of reactivity under many oxidation coupling systems.12 In the presence of DTBP (4 equiv.) at
reaction conditions, most of the current research mainly focuses on 120 1C with stirring for 12 h, we obtained the desired product 3a in
the metal-catalyzed amination of such C(sp3)–H bonds.7
35% yield (Table 1, entry 1). The yield of 3a could be increased to
Direct functionalization of C(sp3)–H bonds adjacent to oxygen 88% by employing TBHP (70% in water) as the oxidant (Table 1,
atoms with tetrahydrofuran and 1,4-dioxane derivatives represents entry 2). Other oxidants such as TBHP (5–6 M in decane), K2S2O8,
one of the hot topics in the research studies of C(sp3)–H bond and H2O2 (30% aqueous solution) were less effective (Table 1,
activation, and recently, direct alkylation, alkenylation, arylation, ester- entries 3–5). When we decreased the amount of TBHP to 2 equiv.,
ification, thiolation and amination of such C(sp3)–H bonds have been with EtOAc as the solvent, the desired product 3a was obtained
demonstrated.8 However, to the best of our knowledge, no examples of in 64% yield (Table 1, entry 6). Further screening revealed that
the oxidative amidation of C(sp3)–H bonds adjacent to oxygen atoms of Bu4NI was the best choice for this reaction. Bu4NCl, Bu4NBr,
methyl aryl ethers have been reported to date. Aryl ethers are structural Bu4ONAc, and I2 afforded 3a in 79%, 54%, 59% and 0% yields,
components of natural products, pharmaceuticals, and agrochemicals.9 respectively (Table 1, entries 7–10). And no product was observed
when either Bu4NI or TBHP was absent (Table 1, entries 11 and 12).
It should be noted that this facile product was obtained under
environmentally benign conditions (with tert-butyl alcohol and
College of Chemistry and Chemical Engineering, Anyang Normal University,
Anyang 455000, P. R. China. E-mail: sunk468@nenu.edu.cn
water as by-products), as it did not require a metal catalyst and
the rigorous exclusion of air.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc06003b
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Table 1 Screening of reaction conditionsa
Table 2 Imidation of various aryl ethers with pharmacological saccharin
and its derivativesa,b
Entry
Catalyst
Oxidant
Yieldb [%]
1
2
3
4
5
6
7
8
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NCl
Bu4NBr
Bu4NAc
I2
DTBP
TBHP
TBHP
K2S2O8
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
35
88
53c
0
21
64d
79
54
59
0
9
10
11
12
Bu4NI
0
0
TBHP
a
Reaction conditions: 1a (0.5 mmol) and saccharin 2 (1.0 mmol) at
b
c
120 1C for 12 h. Yield of isolated product. TBHP (5–6 M in decane).
d
TBHP (70% in water) 2 equiv., EtOAc (1 mL) as the solvent.
With the optimized conditions in hand (Table 1, entry 2), the
substrate scope of the imidation reaction was investigated for sub-
stituted aryl ethers. As shown in Table 2, functional group compat-
ibility was good as those demonstrated for both electron-rich MeO,
and t-Bu and electron-deficient F, Cl, Br and CN groups which were
obtained in good to excellent yields (3b–3l). 4-Nitroanisole gave a
moderate yield in 47% (3m). The results of this work are significant
considering that Cl, Br and CN can be converted into various
functional groups under ambient conditions. It is noteworthy that
1-methoxy-4-methylbenzene gave the methyl imidated product (3g),
while the methoxy group remained intact, consistent with a previous
report by Zhu’s group.13 Similarly a smooth coupling was observed
for aryl ethers bearing substitution groups at different positions such
as 2-Cl, 3-Cl and 4-Cl and no previous yield disparity was observed
(3d, 3e and 3f). The fused bicyclic 1-methoxynaphthalene (3n) was
inert during the reaction. To our delight, methyl(phenyl)sulfane
was also compatible with this system and gave the desired product
in 64% yield.
a
Reaction conditions: 1 (0.5 mmol), saccharin 2 (1.0 mmol), Bu4NI
b
(0.05 mmol) and TBHP (2.0 mmol) at 120 1C for 8–12 h. Yield of
isolated product.
summarized in Table 3. Chain alkyl ethers 1,2-dimethoxyethane 4a
In fact, the saccharin moiety has been identified as an important provided the imidation products as a mixture at the methyl and
molecular component in various classes of biologically active com- methane adjacent to oxygen atoms (5a and 5a0). Cyclic alkyl ethers
pounds.14 The synthetic route to achieving saccharin derivatives tetrahydrofuran 4b and 1,4-dioxane 4c were also tested to give
generally start from ortho-difunctional arenes.15 The methodology of the corresponding imidation products with saccharin (5b and 5c).
the formation of C–N bonds directly from the C(sp3)–H bonds of In contrast to previous reports about metal-catalyzed imination of
aryl ethers and the N–H bond of saccharin will provide an attracting alkyl ethers, it is highlighted that this product is obtained under
alternative way for the synthesis of saccharin derivatives. Therefore, environmentally benign metal-free conditions.
other saccharin derivatives with substituents on the isothiazol-
To probe the reaction mechanism, several control experi-
3(2H)-one 1,1-dioxide were also tested and some representative ments were conducted. Intermolecular kinetic isotope effects
results are summarized in Table 2. Substrates bearing methyl (KIE, KH/KD) were obtained using equimolar amounts of tetra-
and aryl groups at the 4- and 5-positions of isothiazol-3(2H)-one hydrofuran/tetrahydrofuran-d8 and a KIE of 4.0 was observed,
1,1-dioxide occurred efficiently to deliver 3p to 3r in 82–87% suggesting that C(sp3)–H bond cleavage may be involved in the
yields, respectively. The desired products 3s were also obtained rate-determining step [eqn (1)]. Unexpectedly, when the radical
in good yield when the 4- and 5-positions of isothiazol-3(2H)-one inhibitor BHT (2,6-di-tert-butyl-4-methylphenol) and TEMPO
1,1-dioxide were alkyl groups.
(2,2,6,6-tetra-methyl-piperidine-N-oxyl) were introduced into
The reaction conditions that had been optimized for aryl ether the reaction mixture, respectively, the reaction progress was
derivatives were also suitable for the imidation of cyclic and chain completely suppressed even after longer times, and a methyl imidated
alkyl ethers. We select some typical compounds and the results are product H derived from BHT was isolated in 89% yield [eqn (2)].
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Table 3 Imidation of various alkyl ethers with saccharina,b
and chain alkyl ethers also reacted smoothly and afforded the
desired imidation products. Considering the excellent reaction
efficiency, and wide substrate scope, the strategy would be highly
desirable for the intermolecular oxidative C–N bond formation of
ether derivatives. Further investigation into the detailed mechanism
and application of this protocol is currently underway in our lab.
Notes and references
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a
Reaction conditions: 4 (0.5 mmol), saccharin 2 (1.0 mmol), Bu4NI
b
(0.05 mmol) and TBHP (2.0 mmol) at 120 1C for 11–12 h. Yield of
isolated product.
Based on the experimental results and considering previous
literatures about various types of functionalization of ether deri-
vatives,12c,e,k a possible mechanism is proposed for the present
catalytic reaction using tetrahydrofuran 4b as the model substrate
in Scheme 1, although further studies on the reaction mechanism
are needed. The first step is likely to be the carbon-centered radical
A adjacent to the oxygen of tetrahydrofuran that can be generated
by H-abstraction with a tert-butoxyl radical formed by the Bu4NI
initiated decomposition of peroxide. This radical could be further
oxidized to a cation B through a SET (single-electron-transfer) step,
whereas TBHP could react with Bu4NI and further undergo homo-
lytic cleavage to afford a tert-butoxyl radical. Finally, the coupling of B
with the nucleophile nitrogen source delivers the desired product 5b.
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In summary, we have developed a metal-free intermolecular
oxidative C–N formation reaction of aryl ethers using cheap and
pharmacological saccharin and its derivatives and TBHP as an
environmentally benign oxidant for the first time. The understand-
ing of the intrinsic characteristics between C(sp2)–O bonds and
C(sp3)–H of aryl ethers and their potential for application might
promote more research interest in this fertile area. In addition, cyclic
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Scheme 1 Proposed reaction mechanism.
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