Cobalt-Catalyzed Ortho-C(sp2)-H Amidation of Benzaldehydes with Dioxazolones Using Transient Directing Groups

Article abstract of DOI:10.1021/acs.orglett.9b02632

An efficient and convenient cobalt-catalyzed ortho-C(sp²)-H amidation of benzaldehydes employing dioxazolones as the aminating reagent has been developed. The key feature of this protocol is the use of green and economic earth-abundant metals c

Full text of DOI:10.1021/acs.orglett.9b02632

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Ortho-C(sp2)−H Amidation of Benzaldehydes with
Dioxazolones Using Transient Directing Groups
Jie Huang,† Jun Ding,‡ Tong-Mei Ding,‡ Shuiyi Zhang,† Yaqiu Wang,† Feng Sha,† Shu-Yu Zhang,‡
Xin-Yan Wu,*,† and Qiong Li*,†
†School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
‡Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs and School of Chemistry and Chemical Engineering, Shanghai
Jiao Tong University, Shanghai 200240, China
S
* Supporting Information
ABSTRACT: An efficient and convenient cobalt-catalyzed
ortho-C(sp2)−H amidation of benzaldehydes employing
dioxazolones as the aminating reagent has been developed.
The key feature of this protocol is the use of green and
economic earth-abundant metals cobalt as the catalyst with the
p-chloroaniline as the transient directing group. Further
application of our approach was demonstrated by the synthesis
of C1r serine protease inhibitor 45 and elastase inhibitor 49.
which poses a major challenge regarding its relatively weak
coordination ability and the instability of the aldehyde group.5
To overcome this deficiency, Shi,6a Yu,6b and Chen and
He6c independently developed more direct and efficient Ir-
catalyzed ortho-C−H amidations of benzaldehydes employing
substituted anilines as transient directing groups (TDGs) with
TsN3 as the aminating reagent (Scheme 1A). In 2018, Jiao7a
described the Rh-catalyzed ortho-C−H amidations of benzal-
dehydes with dioxazolones using p-trifluoromethylaniline (T3)
he highly efficient C−N bond formation has been a focus
Tof synthetic chemistry because nitrogen-containing
molecules are very important and widely present in
pharmaceutical agents, natural products, and synthetic
intermediates.1 Among these extensively explored C−N
bond-forming methods, the direct and high selective
conversion of an unactivated C−H bond to the corresponding
C−N bond has emerged as an ideal and attractive strategy with
great atom and step economy.
o-Aminobenzaldehyde and its derivatives can be used to
construct plentiful skeletons of biologically active molecules
(Figure 1)2 and organic materials; thus, the development of
new C−H amination procedures for the synthesis of 2-
aminobenzaldehydes has attracted a lot of attention in recent
years. In the past decade, transition-metal-catalyzed, directing
group mediated intermolecular regioselectivity C(sp2)−H
amination of arenes has been well documented.3 However,
the aldehyde-assisted ortho-C−H amination is relatively rare,4
Scheme 1. Transition-Metal-Catalyzed Ortho-C−H
Amination of Benzaldehydes
Received: July 26, 2019
Figure 1. Skeletons of some bioactive 2-formylaniline.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as TDG. Dong7b reported Rh-catalyzed direct ortho-C(sp2)−H
amidation of benzaldehydes with additives of Zn(OAc)2·
2H2O/PhCOOH. Zhang7c reported an efficient Rh-catalyzed
ortho-C−H amidation method employing H2O as the key
promoter, and the detailed mechanistic studies indicated that
the catalyst precursor interacted with dioxazolones and H2O to
generate the active catalytic species (Scheme 1B).
44% isolated yield (T5). Although the product 3 was obtained
in 38% yield using m-trifluoromethylaniline as TDG (T6), the
cheaper p-chloroaniline (T5) motivated us to use it as the
transient directing group in these Co-catalyzed C−H
amidation reactions. After varying the loading amounts of p-
chloroaniline (T5), we found that an 84% isolated yield of
desired products 3 was obtained under the optimized reaction
conditions: 10 mol % of Cp*Co(CH3CN)3[SbF6]2 (Cat. A)
and 1.0 equiv of p-chloroaniline (T5) in DCE at 120 °C under
Ar for 6 h.
Although the precious metal catalysts Rh and Ir have been
successfully used for the direct ortho-C−H amination of
benzaldehyde via the TDG strategy, their high cost and toxicity
limit their application and potential pharmaceutical chemical
studies;8 to date, using inexpensive or earth-abundant metals as
catalysts in this protocol has not been reported. In our ongoing
efforts to develop effective inexpensive metal-catalyzed C−H
activation and amination methods,9 in this paper, we report the
first Co-catalyzed direct ortho-C(sp2)−H amidation of
benzaldehydes using dioxazolones as the aminating source
with p-chloroaniline as the TDG. This protocol provides a
green and convenient strategy for the efficient synthesis of
diversely functionalized ortho-aminobenzaldehydes. Further
applications were demonstrated by the successful synthesis of
C1r serine protease inhibitor (45) and elastase inhibitor (49)10
We have carried out our investigation employing 4-
fluorobenzaldehyde 1 and dioxazolone11 2 in the presence of
10 mol % of Cp*Co(CH3CN)3[SbF6]2 (Cat. A) in DCE under
argon for 12 h. After an initial screening of the reaction
conditions, we found that a TDG was essential for the C−H
amidation, and just a trace desired product 3 was detected in
the absence of arylamine (see the Supporting Information).
Thus, we further screened a series of arylamines as TDG
additives to test this C−H amidation reaction (Table 1).
Interestingly, the previously reported TDGs in precious metal
Rh (T10 and T11) and Ir (T3) catalytic systems were not
suitable for our cobalt-catalyzed C−H amidation catalytic
system. To our delight, p-chloroaniline (T5) was found to be
the most effective TDG to afford the amidation product 3 in
After establishing the optimized conditions, we probed the
scope of benzaldehydes with dioxazolone 2 (Table 2). A wide
range of benzaldehydes were well-tolerated in our Co-catalyzed
system and gave the ortho-amidated benzaldehydes in good to
excellent yields. Subsequently, the ortho-, meta-, and para-
substituted benzaldehyde substrates (Table 2A−C) were used
to examine the effects of sterics hindrance and electrons on the
benzenes. The results indicate that the benzaldehydes with
halogen substitution and electron-donating groups (alkyl,
OMe, etc.) were found to be well-tolerated and gave the
amidation products in good to excellent yields. Comparatively,
the benzaldehydes with the strong electron-withdrawing
groups (CN, NO2, etc.) notably reduce the reactivity of C−
H amidations. Moreover, when the meta-substituted benzalde-
hydes (Table 2B) demonstrated high regioselectivity, less
hindered ortho-C−H was activated and the sole regioisomers
11−15 were obtained. In addition, this process shows high
monoselectivity, and the monoamidated products 17−25 were
obtained in 46−81% isolated yield. No diamidated products
were observed in the reaction system (Table 2C). Multi-
substituted benzaldehydes also gave the desired C−H
amidation product 27−35 in good to excellent yields (Table
2D), and the high regioselectivity was confirmed by X-ray
crystallographic analysis of compound 34. Furthermore, we
investigated the generality of dioxazolones. The results showed
that the aryl dioxazolones both with electron-donating and
electron-withdrawing substituents on the phenyl ring reacted
smoothly to give the corresponding amidated products 36−41
in good yields (Table 2E).
a,b
Table 1. Evaluation of Aniline Promoters
To elucidate the reaction mechanism, a series of preliminary
deuteration experiments were carried. The kinetic isotope
effect (KIE) was determined to be 2.15, which indicated that
the C−H activation might be the rate-limiting step. The radical
capture experiments suggested that the radical mechanism was
unlikely to be involved in our reaction (see the Supporting
Information).
On the basis of the results and previous reported
studies,7,11b,d,12 a possible mechanism was proposed (Scheme
2). Initially, condensation between 42 and arylamine generates
imine A. Subsequently, the combination of Co catalyst with
imine undergoes C−H bond activation via an acetate-assisted
intramolecular C−H concerted metalation−deprotonation
(CMD) to generate intermediate II. Next, coordination of
the dioxazolones B forms the intermediate III, which
undergoes the intermolecular migration insertion to afford
intermediate IV with the extrusion of CO2. Finally, the
protonation of intermediate IV by formed HSbF6 regenerates
the Co catalysts I and C.
To demonstrate the application of our earth-abundant metal
Co-catalyzed C−H amidation method as an efficient and
versatile synthetic strategy, two active molecules C1r serine
protease inhibitor 4510a and elastase Inhibitor 4910b were
synthesized under our mild conditions with good yield, which
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Cat. A (10 mol
%), and TDG (0.4 equiv) in DCE (1 mL) at 120 °C under Ar for 12
b
c
d
h. Isolated yield. 0.6 equiv of p-chloroaniline. 0.8 equiv of p-
chloroaniline. 1.0 equiv of p-chloroaniline for 6 h.
e
B
DOI: 10.1021/acs.orglett.9b02632
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Letter
a,b
Table 2. Substrate Scope of Benzaldehydes
Scheme 2. Proposed Mechanism
Scheme 3. Synthetic Applicability
by the synthesis of C1r serine protease inhibitor 45 and
elastase Inhibitor 49. Further applications of this C−H
amidation methodology in the synthesis of complex products
are currently under investigation.
a
Reaction conditions: benzaldehyde (0.2 mmol), dioxazolone (0.4
ASSOCIATED CONTENT
* Supporting Information
■
mmol), Cat. A (10 mol %), and T5 (0.2 mmol) in DCE (1 mL) at
120 °C under Ar for 6 h. Isolated yield. NR = no reaction.
S
b
c
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02632.
provides a more efficient synthetic route for the synthesis of
drug molecules and constructs scaffolds with bioactive
molecules (Scheme 3).
Experimental procedures, analytical data of products,
1
and copies of H and 13C spectra (PDF)
In summary, we have developed the first direct and
convenient Co-catalyzed ortho-C−H amidation of benzalde-
hydes using p-chloroaniline as the transient directing group.
These reactions are operationally simple and robust, and the
cobalt catalyst system avoids the use of expensive noble metals
Rh and Ir. In addition, the reaction produced broad and
structurally diverse ortho-amidated benzaldehydes in good to
high yield. The practicality of our approach was demonstrated
Accession Codes
CCDC 1940485 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.9b02632
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Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xinyanwu@ecust.edu.cn.
*E-mail: qul16@ecust.edu.cn.
ORCID
Shu-Yu Zhang: 0000-0002-1811-4159
Xin-Yan Wu: 0000-0002-6942-7067
Qiong Li: 0000-0002-0692-1877
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Fundamental Research Funds
for the Central Universities (222201814019, 201910251027),
NSFC (21672145, 51733007), and Natural Science Founda-
tion of Shanghai (19ZR1412300, 17JC1403700).
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