Rh-Catalyzed N-O Bond Cleavage of Anthranil: A C-H Amination Reagent for Simultaneous Incorporation of Amine and a Functional Group

Article abstract of DOI:10.1021/acs.orglett.6b01459

A novel Rh(III)-catalyzed C-H bond amination with the simultaneous release of a formyl group at distal positions is realized employing anthranil as a new type of C-H amination reagent. This chemistry provides an efficient protocol for the synthesis of 2-a

Full text of DOI:10.1021/acs.orglett.6b01459

Letter
pubs.acs.org/OrgLett
Rh-Catalyzed N−O Bond Cleavage of Anthranil: A C−H Amination
Reagent for Simultaneous Incorporation of Amine and a Functional
Group
Miancheng Zou,† Jianzhong Liu,† Conghui Tang,† and Ning Jiao*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191,
China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A novel Rh(III)-catalyzed C−H bond amination
with the simultaneous release of a formyl group at distal
positions is realized employing anthranil as a new type of C−H
amination reagent. This chemistry provides an efficient
protocol for the synthesis of 2-acyl diarylamines, which are
important structural motifs in many bioactive compounds. This
new type of C−H amination reagent possesses the advantages
of high atom economy, avoids the use of external oxidants, and enables further transformation of the amination products.
aryl aminations can be achieved with N-halo-substituted amine
rylamines are frequently found in numerous natural
Aproducts, pharmaceuticals, and functional materials. and N-alkyl hydroxylamines.6 This protocol is also suitable for
1
amidation with N-fluorobenzenesulfonimides and N-acetoxycar-
bamates.7 From the view of atom economy, commercially
available amines are ideal partners to form a C−N bond by dual
C−H and N−H bond cleavage in the presence of external
oxidants (Scheme 1a).8
Despite the significance of these protocols, amination
precursors that could enable the generation of amine with the
release of a functional group are rarely reported9 but are very
attractive because they offer the feasibility for further various
transformations using simultaneously incorporated amine and
functional groups (Scheme 1b). An elegant example was recently
disclosed by Yoshida and co-workers with an electro-oxidative
coupling process (Scheme 1c).9
Significant methodologies toward arylamine preparation have
been developed through C−N bond formation.2 In recent years,
considerable improvements have been achieved via direct C−H
amination.3 Among them, the nitrogen sources could be
generally categorized into three parts (Scheme 1a). C−H
activation with nitrenes has been widely used in C−N bond
formations employing iminoiodinanes or relative precursors4
and azide reagents.5 In addition, by using the umpolung strategy,
Scheme 1. Reagents for Direct C−H Amination
Herein, we report a novel transition-metal-catalyzed C−H
amination protocol for the synthesis of 2-acyl diarylamines,
which are important structural motifs and useful building blocks
(Scheme 1d). Various important bioactive compounds could be
prepared from 2-acyl diarylamine products (Figure 1). For
instance, transformation of aldehyde to an acid or amide group
could afford important drugs or inhibitors (Figure 1).10
Moreover, 2-(phenylamino)benzaldehyde could serve as a
precursor for the synthesis of various heterocycles, such as
indoles, indazoles, and acridines (Figure 1).11
Discovery of new N-containing reagents for C−H amination
has received much attention in recent years.12 Ideally, the new
amination reagents should be readily available, enabling high
atom economy13 and also serving as an internal oxidant.14 Given
the significance of the 2-acyl diarylamine skeleton (Figure 1), we
Received: May 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01459
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Organic Letters
Letter
system and the PivOH additive are indispensable in this
transformation (entries 2−4). 3a was obtained in slightly lower
yield when the loading of PivOH, 2a, or catalyst was decreased
(entries 5−7). Further, we found that the reaction did not
proceed at all under other transition metal catalysts such as Pd,
Ru, Co, and Ir (entries 8−11).
The scope of this Rh-catalyzed C−H amination reaction was
demonstrated with a series of oxime ether derivatives (Scheme
2). A variety of electron-neutral and electron-rich acetophenone
a
Scheme 2. Rh-Catalyzed Amination of Oxime Ethers
Figure 1. Transformation of 2-aminobenzaldehydes.
were eager to develop direct C(sp2)−H amination by installing 2-
amino benzaldehyde in one step, but it is a challenging issue
because the aldehyde group either is oxidized or undergoes side
reactions in conventional methods.15 Anthranil is a N,O-
containing heterocyclic compound and is commercially available.
It has been used in ring-opening reactions with organozinc
reagents and ring expansion reactions with aryldiazoacetates.16
Recently, Hashmi and co-workers reported a Au-catalyzed
cyclization of anthranil with alkyne to form 7-acyl indoles.17
However, it was not used in a direct C−H bond amination
reaction until Li’s work18 and this work (Scheme 1c). Employing
anthranil as an amination reagent would have the following
advantages: (1) 100% atom efficiency without atom waste, (2)
no requirement for an external oxidant, (3) direct C−H
amination with simultaneous release of amine and a formyl
group, and (4) production of high-value products as versatile
building blocks for further transformation, especially for
heterocycle synthesis.
a
Reaction conditions: 1 (0.2 mmol), 2a (2.5 equiv), [{Cp*RhCl2}2]
(4 mol %), AgNTf2 (16 mol %), PivOH (1.0 equiv), DCE (2 mL),
stirred at 85 °C under air for 24 h. Reaction was carried out with 2a
(0.2 mmol) and 1 (0.4 mmol) at 100 °C.
b
oximes were readily converted to the corresponding products
(3a−d,h) in excellent yields. Notably, halogen-substituted
substrates can be smoothly transformed to the corresponding
amination products (3e−g), which offer opportunities for further
coupling reactions. Oxime ethers derived from phenyl alkyl
ketones or diaryl ketones are also suitable substrates to achieve
C(sp2)−H amination products in high yields (3i−k). In addition,
cyclic oxime ether is well-tolerated in this transformation,
producing 3l in 82% yield.
Furthermore, other N-containing directing groups were
investigated (Scheme 3). Various substituents at the para
position of 2-phenylpyridine were tolerated and showed little
effect on the efficiency (5a−d). A methyl substituent attached to
the pyridine ring also showed satisfactory efficiency (5e). Other
N-containing heterocycles such as quinoline, purine, and
pyrazole derivatives could also act as directing groups for this
C−H amination reaction with high performance (5f−h).
The scope of the anthranils was then examined with oxime
ether 1a (Scheme 4). Several substituted anthranils performed
well and delivered the unprotected 2-acyl diarylamines in
moderate yields. Some functional groups, such as F (3m,q), Cl
(3n), Br (3o), or OAc (3p), could be contained in the substrates,
leading to various 2-acyl diarylamine products.
Based on the above assumptions, we commenced our
investigation using acetophenone O-methyl oxime (1a) as the
model substrate. After screening, we found that when 1a and 2a
were treated with [{Cp*RhCl2}2], AgNTf2, PivOH at 85 °C in
DCE, target product 3a was obtained in 77% yield (Table 1, entry
1). Controlled experiments revealed that the Rh/Ag catalyst
a
Table 1. Rh-Catalyzed Amination of Oxime 1a
b
entry
change from the standard conditions
yield (%)
1
2
none
77
no [{Cp*RhCl2}2]
no AgNTf2
NR
NR
<5
3
4
no PivOH
5
60 mol % of PivOH
64
6
2.0 equiv of 2a
70
7
[{Cp*RhCl2}2] (2.5 mol %), AgNTf2 (10 mol %)
Pd(OAc)2 instead of [{Cp*RhCl2}2]
[Ru(p-cym)Cl2]2 instead of [{Cp*RhCl2}2]
[Cp*Co(CO)l2 instead of [{Cp*RhCl2}2]
[Cp*lrCl2]2 instead of [{Cp*RhCl2}2]
60
As mentioned above, diarylamines are versatile intermediates
and flexible scaffolds in organic synthesis. After this pratical
intermolecular ortho-functional amination protocol was estab-
lished, we were eager to apply the products in other
transformations. Polycyclic aza-aromatic compounds are basic
skeletons in organic molecules, which can be constructed by
In(OTf)3 catalysis in 54% yield from 3a (eq 1). Meanwhile,
indoles are important structural motifs in bioactive compounds
8
NR
NR
NR
NR
9
10
11
a
Reaction conditions: 1a (0.2 mmol), 2a (2.5 equiv), catalyst,
b
additives, DCE (1 mL), stirred at 85 °C under air for 24 h. Isolated
yields.
B
DOI: 10.1021/acs.orglett.6b01459
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Heteroarylarenes
Scheme 5. Mechanistic Studies
a
Reaction conditions: 4 (0.2 mmol), 2a (2.5 equiv), [{Cp*RhCl2}2]
(4 mol %), AgNTf2 (16 mol %), PivOH (1.0 equiv), DCE (2 mL),
stirred at 100 °C under air for 24 h.
On the basis of the above results and previous reports, a
tentative mechanism is depicted as follows (Scheme 6). The
a
Scheme 4. Substrate Scope of Anthranils
Scheme 6. Proposed Mechanism
a
Reaction conditions: 1a (0.2 mmol), 2 (2.5 equiv), [{Cp*RhCl2}2]
(4 mol %), AgNTf2 (16 mol %), PivOH (1.0 equiv), DCE (2 mL),
stirred at 85 °C under air for 24 h.
active rhodium species reacts with 1a via C−H activation to form
cyclometalated intermediate I.20 Anthranil 2a coordinates to I
due to the nucleophilicity of nitrogen and delivers intermediate
II. Subsequent ring opening produces a Rh(V)N intermediate
III, and the amino group is inserted into the C−Rh bond to get
intermediate IV. Finally, protonolysis occurs to give the desired
product 3a with regeneration of the Rh catalyst.
In conclusion, a novel Rh-catalyzed ortho-C−H amination of
arenes was developed with anthranil as a new type of C−H
amination reagent. This chemistry provides an efficient protocol
to 2-acyl diarylamines, which are important structural motifs in
many bioactive compounds and could be used as versatile
building blocks for further heterocyclic compound construction.
The present C−H amination protocol possesses the advantages
of high atom economy without the addition of external oxidants,
which shows a bright future in C−H amination reactions. Further
studies to clarify the reaction mechanism and the synthetic
applications are ongoing in our laboratory.
and alkaloids. When 3a was treated with ethyl diazoacetate, N-
aryl indole 7 was produced in 52% yield (eq 2). Notably, 3a could
undergo a one-pot reaction to generate N-aryl indazole 8 in 60%
yield (eq 3), which is the core structure of anti-inflammatory
drugs and Hedgehog pathway antagonists.19
To further understand the mechanism, intermolecular kinetic
isotope effect (KIE) experiments were conducted in both parallel
and one-pot measurement (Scheme 5a,b), and large KIE values
of 3.8 and 2.7 indicated that the C−H/C−D dissociation might
be involved in the rate-determining step.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01459.
■
S
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DOI: 10.1021/acs.orglett.6b01459
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, analytical data, and NMR
Letter
2015, 17, 1513. (f) Kawakami, T.; Murakami, K.; Itami, K. J. Am. Chem.
Soc. 2015, 137, 2460.
spectra (PDF)
(8) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J.
Am. Chem. Soc. 2006, 128, 6790. (c) Uemura, T.; Imoto, S.; Chatani, N.
Chem. Lett. 2006, 35, 842. (d) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am.
Chem. Soc. 2006, 128, 9048. (e) Shang, M.; Sun, S. Z.; Dai, H. X.; Yu, J.-
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Am. Chem. Soc. 2014, 136, 5904. (g) Xiao, B.; Gong, T. J.; Xu, J.; Liu, Z.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiaoning@pku.edu.cn.
Notes
The authors declare no competing financial interest.
(9) Morofuji, T.; Shimizu, A.; Yoshida, J. J. Am. Chem. Soc. 2015, 137,
9816.
ACKNOWLEDGMENTS
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C.; Cocco, M. T.; Lilliu, V.; Onnis, V. J. Med. Chem. 2005, 48, 8245.
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■
Financial support from National Basic Research Program of
China (973 Program) (No. 2015CB856600), National Natural
Science Foundation of China (No. 21325206), and National
Young Top-notch Talent Support Program is greatly appre-
ciated. We thank Yeerlan Adeli in this group for reproducing the
results of 3m and 5h.
Devarajan, D.; Ess, D. H.; Kurti, L.; Falck, J. R. Science 2014, 343, 61.
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