Cu-Catalyzed Direct Amination of Cyclic Amides via C-OH Bond Activation Using DMF

Article abstract of DOI:10.1021/acs.orglett.0c02320

Herein, we describe a Cu-catalyzed approach to directly accessing aromatic heterocyclic amines from cyclic amides. The most-reported methods for cyclic amide conversions to aromatic heterocyclic amines use an activating group, such as a halogen atom or a

Full text of DOI:10.1021/acs.orglett.0c02320

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Letter
Cu-Catalyzed Direct Amination of Cyclic Amides via C−OH Bond
Activation Using DMF
Peng Chen,† Kaixiu Luo,† Xianglin Yu, Xu Yuan, Xiaoyu Liu, Jun Lin,* and Yi Jin*
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ABSTRACT: Herein, we describe a Cu-catalyzed approach to directly
accessing aromatic heterocyclic amines from cyclic amides. The most-
reported methods for cyclic amide conversions to aromatic heterocyclic
amines use an activating group, such as a halogen atom or a trifluoromethane
sulfonyl group. However, subsequent elimination of activating groups during
the amination process results in significant waste. This copper-catalyzed
direct amination of cyclic amides in DMF forms aromatic heterocyclic amines
with environmental friendliness and readily available reagents. A plausible
radical mechanism has been proposed for the reaction. Meanwhile, the
coordinating effect of the N1 atom is key to the success of this reaction, which
provides assistance to the copper ions for the activation and amination of C−
O bonds.
necessary.2 In recent years, although direct amination via C−
H/N−H oxidative cross-dehydrogenative coupling (CDC) has
been developed as an alternative approach to the formation of
a C−N bond (Scheme 1a, route d),3 direct amination of
C(Arhet)−OH via C−OH bond activation, either catalytically
or stoichiometrically, has remained largely unknown (Scheme
1a, route e). An advantage of the direct amination of
C(Arhet)−OH is that C−OH bond activation and functional-
ization is regiospecific. Although, both Kang4a,b and Wan4c et
al. disclosed that phosphonium salts showed excellent
reactivity in the coupling C−N bond formations of cyclic
amides (Scheme 1b). The toxicity and cost of phosphonium
salts reagents limit the widespread use of this methodology.
The development of novel, environmentally friendly, and
efficient routes for rapid access to 2-amino-substituted
heterocycles under mild conditions is still in high demand.
Herein, we describe the metal-catalyzed direct amination of
cyclic amides via C−OH bond activation (Scheme 1c).
Transition-metal-catalyzed (e.g., Pd or Ni) transformation of
aryl carbamates into aromatic amines has been previously
achieved,5 and few examples of synergistic reactions using
directing groups or ligands have been reported to obtain aryl
carbamates from the corresponding phenol.
mino-substituted heterocycles with generic structure 3 are
Acommon structural moieties in natural products and
biologically active molecules.1 Transformation of cyclic amides
1 to 2-amino-substituted heterocycle 3 via C−N bond
formation has been a basic and reliable approach utilized
over recent times.
Traditional amino-substituted heterocycle synthesis involves
a multiple-step process that includes activation via halogen-
ation or sulfoylation (Scheme 1a, route a, or route b), which is
followed by amination via SNAr displacement (Scheme 1a,
route c). For these reactions, harsh conditions are typically
Scheme 1. Amination of Cyclic Amides
Received: July 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02320
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A

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a,b
Direct metal-catalyzed amination from C−OH bonds of
cyclic amides is highly challenging due to the high bond
dissociation energy of the C(Arhet)−O bond.6 Copper-
mediated C−N bond formation is a significant transformation
and has been developed to include a wide range of substrates.7
We hypothesize that the N1 atom of the cyclic amides can
coordinate with copper(III) and promote the metal to be
inserted into the C(Arhet)−O bond, thereby realizing the
activation of the C−OH bond, and using this feature to
complete the subsequent amination reaction.
Scheme 2. Substrate Scope of Quinazolines and Amines
To examine the feasibility of this hypothesis, copper-
catalyzed oxidative amination from quinazolinone (1a) with
piperidine (2a) was initially studied in the presence of a series
of copper catalysts by using t-butyl hydroperoxide (TBHP) as
an oxidant in DMF. Systematic copper catalyst screening
identified that monovalent copper afforded the expected
amination product (3a) in low yields (Table 1, entries 1 and
a b
,
Table 1. Reaction Condition Optimization
entry
catalyst
CuCl
CuI
CuCl2
CuI2
oxidant
solvent
base
yield (%)
1
2
3
4
5
6
7
8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
m-CPBA
DTBP
BPO
DTBP
DTBP
DTBP
DTBP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DEF
18
23
52
58
60
54
63
35
16
87
34
80
a
Cu(OAc)2
Cu(hfacac)2
Reaction conditions: In a 10 mL reaction tube, quinazolinone 1 (0.5
mmol), amine 2 (0.6 mmol), DTBP (2.0 mmol), Cu(acac)2 (5 mol
d
e
b
Cu(acac)2
%), DMF 5 mL, under air (1 atm), at 100 °C. Isolated yield based on
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
1.
9
10
11
12
13
14
15
hexanamine, and linear and branched alkylamines were
successfully tolerated in the reaction, resulting in moderate
to excellent yields (3a−3j, 68−94% yield). When we turned
our attention to substituted quinazolin-4(3H)-one, substrates
bearing either an electron-donating group (3k, 3s) or electron-
withdrawing group (3l−3o) also smoothly reacted to afford
the desired products in good to excellent yields. Additionally,
6-bromoquinazolinone and 6-iodoquinazolinone selectively
reacted to give the desired products (3p and 3q, respectively)
but not the Ullmann coupling products. The result shows that
the reaction is compatible with halogens.8 Thieno[2,3-
d]pyrimidin-4-ol and electron-rich 6,7-diether substituted
quinazolinones also serve as excellent substrates, affording
the corresponding 4-aminated products (3r−3u), which are
prevalent motifs in medicinal chemistry.9 Unfortunately,
quinazolinones reacted with aromatic amines failed to undergo
direct amination under these conditions. These results may be
due to the low activities of aromatic amines and the possibility
of being easily oxidized under oxidative conditions.
This direct amination also allowed the introduction of a
range of other cyclic amides, such as pyrimidin-4-ol,
substituted pyridin-2-ol, pyrimidin-2-ol, and pyrimidine-2,4-
diol (Scheme 3). 5-Nitropyridin-2-ol substituted with various
functional groups, such as Me, NH2, F, Cl, and Br (4c−4i) was
well-tolerated in the reaction system and provided the
possibility of further functionalization of the polysubstituted
pyridin-2-amine, enabling these products as core structures for
drugs. Additionally, pyrimidin-2-ol-bearing esters, trifluoro-
c
DMAC
DMF
DMF
nr
CsCO3
NaOAc
76
71
a
Reaction conditions: In a 10 mL reaction tube, quinazolinone 1a
(0.5 mmol), piperidine 2a (0.6 mmol), oxidant (2.0 mmol), catalyst
(5 mol %), base (0.6 mmol), solvent 5 mL, under air (1 atm), stirred
b
c
for 10 h at 100 °C. Isolated yield based on 1a. nr: no reaction.
d
e
hfacac = hexafluoroacetylacetone. acac = acetylacetone.
2), while divalent copper increased the product yield (Table 1,
entries 3−7) and using Cu(acac)2 achieved moderate yields.
Subsequent screening of oxidants found that the use of di-t-
butyl peroxide (DTBP) further increased the yield (Table 1,
entries 8−11). Solvent screening found that the amino-
formaldehyde group is necessary for the reaction to proceed
(Table 1, entry 13). Additionally, increasing the DTBP
concentration is conducive to the increased yield, but after
4.0 equiv., the change in yield is not obvious. Finally, the
addition of base is not conducive to the reaction (Table 1,
entries 14−15).
The scope of the direct amination of quinazolinones with
amines was next investigated using a Cu(acac)2 catalyst system
(Scheme 2). Amine substrates bearing a variety of secondary
alkylamine and primary alkylamines, including piperidine,
methyl-substituted piperidines, pyrrolidine, azepane, cyclo-
B
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a,b
Scheme 3. Substrate Scope of Heterocycles
Scheme 4. Mechanistic Studies
oxidant resulted in no products (Scheme 4, eq 3). This
indicates that the copper atom and DTBP oxidant are involved
in the activation of C−O bonds and the formation of C−N
bonds. To further understand the mechanism of C−N bond
coupling in the reaction, the effect of the N1 atom adjacent to
the C−O bond was comparatively investigated using quinolin-
4-ol as the reaction substrate (Scheme 4, eq 4). As expected,
no desired 4-aminated product was generated, and this result
points to the neighboring group participation effect of the N1
atom.
a
Reaction conditions: In a 10 mL reaction tube, heterocycle 1 (0.5
mmol), amine 2 (0.6 mmol), DTBP (2.0 mmol), Cu(acac)2 (5 mol
b
%), DMF 5 mL, under air (1 atm), at 100 °C. Isolated yield based on
1.
methyl, amides, and phenyl groups also generated the desired
products (4j−4q) in good to excellent yields. Pyrimidine-2,4-
diol bearing nitro, methyl, or ester groups directly obtained the
bifunctionalized aminated products (4r−4t). To verify the
structure of the aminated products, compounds 4c and 4l were
selected as representative compounds and characterized by X-
ray crystallography (Scheme 3).
Taking into consideration the above results and literature
precedents,5f,7b,c the possible reaction routes for the direct
amination of cyclic amides are depicted in Scheme 5. A four-
membered copper complex (A) may be first formed via
chelation of Cu(II) with (1a) through O-binding and N1-
binding of the substrate. Simultaneously, a butoxy radical
generated by the dissociation of DTBP abstracts a hydrogen
atom from DMF to produce an aminoacyl radical, which reacts
with complex (A) to form a Cu(III) intermediate (B).
Reductive elimination of the intermediate (B) results in the
formation of the carbamate (5a) and releases a Cu(I) species,
which may be reoxidized to Cu(II) by the DTBP oxidant or
oxidatively inserted into the C−O bond of the carbamate (5a)
assisted by N1 atom to generate the copper complexes (C).10
Subsequently, due to the strong basicity of the N atom of the
alkylamine, coordination exchange between the N1 atom of
quinazolinone and the N atom of the alkylamine may be
occurred to obtain a new copper complex intermediate (D).
This intermediate further underwent ligand exchange for
obtaining intermediate (E) by removing dimethylcarbamic
acid. Lastly, reductive elimination of intermediate (E) resulted
in the formation of amination product (3) and, again, released
a Cu(I) species. Based on this postulated mechanism, the
possible reason for the low yield of substrates containing
electron-donating substituents may be that when copper is
oxidized to insert the C−O bond, if the substrate is electron-
rich, which would reduce the activity of the insertion, thus
reducing the reaction yield.
To obtain mechanistic insights, a radical-trapping experi-
ment was carried out. Two different radical trapping reagents,
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and BHT (2,6-
di-tert-butyl-4-methylphenol), were introduced into the stand-
ard reaction system (Scheme 4, eq 1), respectively. After the
introduction of these reagents, the reactions were completely
suppressed. These results point to the involvement of radicals
in the reaction. Additionally, in the deuterated dimethylforma-
mide-1-d solvent, the presence of the molecular ion peak of
tert-butyl hydroxide-d (9) was detected by HRMS after
substrate 1a was treated with Cu catalyst and DTPB (Scheme
4, eq 1). During the early stages of the reaction (about 1 h), we
detected the presence of an intermediate (5a), which then
gradually disappeared as the reaction time progressed. We
isolated this intermediate and confirmed it as the carbamate
product of quinazolinone via NMR analysis. Interestingly, this
single intermediate can still be wholly converted into the final
aminated product (3a) under standard conditions (Scheme 4,
eq 2). It should also be noted that in the reaction mixture
solution, the molecular ion peak of the dimethylcarbamic acid
byproduct (8) was detected by HRMS. Subsequently, with
quinazolin-4-yl dimethylcarbamate (5a) as the substrate, both
control experiments without Cu(acac)2 catalyst or DTBP
C
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Scheme 5. Postulated Mechanism
To test the robustness of this Cu-catalyzed direct amination
of cyclic amides via C−OH bond activation, a multigram-scale
experiment was performed (Scheme 6). 5-Nitropyridin-2-ol
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02320.
Scheme 6. Synthetic Application
Experimental methods; X-ray crystallography data of
compounds: 4c, 4l; characterization data and copies of
1H and 13C NMR spectra for all new compounds (PDF)
Accession Codes
CCDC 2015298−2015299 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
(10 mmol) and of piperidine (12 mmol) were subjected to
standard conditions, and product 4c was isolated at 93% yield
(1.9 g). As a comparison, the methods reported in the
literature using a two-step method to obtain 4c only yielded
55%.11 Using 4c as the substrate with subsequent nitro
reduction and amide bond condensation, the analogue (7) of
anticancer compound NVP-LDE225 was obtained in almost
quantitative yields.
We have developed a copper-catalyzed direct amination of
cyclic amides as a conceptually complementary protocol for
the synthesis of aromatic heterocyclic amines. The required
activation of the C(Arhet)−O bond and the oxidative addition
of the C−O bond were both effectively promoted by the use of
a Cu(II) complex and the neighboring group participation
effect of the N1 atom. In addition, this strategy allows
amination to occur in the presence of active halogen atoms,
resulting in more extensive functional group compatibility.
Although this type of direct amination has been limited to alkyl
amines, this work demonstrates the viability of the direct
amination strategy in cyclic amides systems. We anticipate that
a broader range of substrates can be used in metal-catalyzed
direct amination by developing suitable catalysts, which are the
subjects of our ongoing studies.
Corresponding Authors
Jun Lin − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education and Yunnan Province, School of
Chemical Science and Technology, Yunnan University, Kunming
650091, P.R. China; orcid.org/0000-0002-2087-6013;
Email: linjun@ynu.edu.cn
Yi Jin − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education and Yunnan Province, School of
Chemical Science and Technology, Yunnan University, Kunming
650091, P.R. China; orcid.org/0000-0003-1348-2486;
Email: jinyi@ynu.edu.cn
Authors
Peng Chen − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming 650091, P.R. China
Kaixiu Luo − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming 650091, P.R. China
Xianglin Yu − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming 650091, P.R. China
D
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Xu Yuan − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education and Yunnan Province, School
of Chemical Science and Technology, Yunnan University,
Kunming 650091, P.R. China
Xiaoyu Liu − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming 650091, P.R. China
Complete contact information is available at:
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Author Contributions
†P.C. and K.L. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(b) Romagnoli, R.; Prencipe, F.; Oliva, P.; Baraldi, S.; Baraldi, P. G.
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■
The authors gratefully acknowledge the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT17R94), the NSFC (Nos. 21662044,
21262043, and 81760621), the Foundation of “Yunling
Scholar” Program of Yunnan Province (C6183005), the
Training Program for Young and Middle-aged Academic and
Technical Leaders in Yunnan Province (2015HB004), and the
Program for Excellent Young Talents,Yunnan University for
financial support.
(10) Metal insertion into aromatic C−O bond: (a) Berkefeld, A.;
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