DOI: 10.1002/anie.201106112
Synthetic Methods
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Iron-Catalyzed C H and C C Bond Cleavage: A Direct Approach to
Amides from Simple Hydrocarbons**
Chong Qin, Wang Zhou, Feng Chen, Yang Ou, and Ning Jiao*
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The direct transformation of hydrocarbons by transition-
nitrogen-containing molecules through C H or C C bond
cleavage, we investigated the FeCl2-catalyzed oxidative
reaction of bis(4-methoxyphenyl)methane (1a) in the pres-
ence of DDQ and sodium azide in acetic acid (see Table 1 for
structures). Interestingly, 4-methoxy-N-(4-methoxyphenyl)-
benzamide (2a) was obtained in 47% yield (GC; see entry 1
of Table S1 in the Supporting Information). Other azide
regents such as diphenylphosphoryl azide (DPPA),
(nBu)4NN3, and p-tosyl azide gave low yields (Table S1,
entries 2–4). Intriguingly, the amide product 2a was directly
produced in 90% yield when TMSN3 was employed as the
aminating agent (Table S1, entry 5). It is interesting that the
reaction of 1a under the metal-free conditions could also
produce 2a in 73% yield (Table S1, entry 13), probably
because the substrates containing electron-donating groups
can be easily oxidized by DDQ. The reactions in the presence
of other transition metals such as Pd, Cu, Mn, Co, and Ni did
not significantly affect the transformation (Table S1,
entries 6–12). Hence, it was concluded that the iron salt can
efficiently promote the reaction (Table S1, entries 5 and 13).
The reactions using BQ, CAN, TBHP, or Cu(OAc)2 as the
oxidant did not perform well (Table S1, entries 17–20). The
yield decreased to 35% when MeCN was employed as the
solvent (Table S1, entry 16). After extensive screening of
different parameters (Table S1), the optimal reaction con-
ditions were determined to be those labeled conditions A
(FeCl2 (10 mol%), TMSN3 (2.0 equiv), DDQ (2.2 equiv),
H2O (2.0 equiv), HOAc (2 mL), 608C, under argon). Under
these reaction conditions 2a was obtained in 90% yield
(Table S1, entry 5).
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metal-catalyzed selective C H and C C bond activation
(cleavage) has attracted considerable attention. The attention
arises not only from its fundamental scientific interest but also
from its potential utility in organic synthesis.[1,2] Recently, the
development of more atom-efficient, novel catalytic methods
for the preparation of amides under mild reaction conditions
has been one of the most exciting topics in organic synthesis.
Amides are essential for sustaining life, and they are
important moieties in organic chemistry, biological, and
pharmaceutical compounds.[3,4] Although the preparation of
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functionalized compounds by direct C H or C C bond
activation has been the focus of a significant number of
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studies, the amide bond formation through C H or C C bond
cleavage is still an extremely attractive yet challenging
goal.[5,6] Herein, we report a novel iron-catalyzed C H and
C C bond cleavage of benzyl hydrocarbons for the synthesis
of amides and enamides under mild reaction conditions
[Eq. (1)].
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Azides have been widely used in organic synthesis,[7]
including the click reaction.[8] Recently, some novel trans-
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formations of an azide species involving C H bond activation
for the synthesis of nitrogen-containing compounds have
been developed.[9] By employing azides as the aminating
agents, the direct synthesis of nitriles and tetrazoles has also
been disclosed.[10] A stabilized azide cation is reported as the
key intermediate in these transformations. To additionally
validate the utility of azide methodologies for the synthesis
The scope of the substrates was investigated under the
conditions A (Table 1). Diphenylmethanes bearing electron-
donating substituents (OMe, NMe2 and OEt) afforded the
desired products 2a, 2c, and 2d in good to excellent yields
(Table 1, entries 1, 3, and 4). However, when diphenyl-
methane (1b) was tested under conditions A, no product
was detected (see entry 1 of Table S2 in the Supporting
Information). Gratifyingly, when 1b was treated with DPPA,
instead of TMSN3, 41% yield of 2b was obtained (Table S2,
entry 2). Inspired by this, we additionally optimized the
reaction conditions by employing 1b as the model substrate
(Table S2, entries 3–20). The reaction did not work in the
absence of iron catalysts (Table S2, entries 3). Dramatically,
the efficiency is improved by the combination of azides
(DPPA/TMSN3 1:2) in the mixed solvent (HOAc/TFA 1:1).
Mn, Co, and Ni can also independently catalyze this trans-
formation but with low yields (Table S2, entries 16–20).
Under these alternate reaction conditions (conditions B) 1b
was converted into the desired amide 2b in 92% yield
(Table 1, entry 2). When unsymmetric diphenylmethanes,
[*] C. Qin, W. Zhou, F. Chen, Y. Ou, Dr. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Rd. 38, Beijing 100191 (China)
E-mail: jiaoning@bjmu.edu.cn
Dr. N. Jiao
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
[**] Financial support from Peking University, the National Science
Foundation of China (20872003), and the National Basic Research
Program of China (973 Program 2009CB825300) are greatly
appreciated. We thank Peng Feng in this group for reproducing the
results for 2e and 4c.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 12595 –12599
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12595