Copper-Catalyzed Oxalamide-Directed ortho-C-H Amination of Anilines with Alkylamines

Article abstract of DOI:10.1021/acs.orglett.0c01632

A copper-catalyzed oxalamide-directed ortho-C-H amination of anilines has been developed by using 1 atm of air as the sole oxidant. The protocol shows excellent functional group tolerance, and some heterocyclic amines including indole, benzothiophene, benzothiazole, quinoline, isoquinoline, and quinoxaline could be compatible in the reaction. The late-stage diversification of medicinal drugs demonstrates the synthetic utility of this protocol.

Full text of DOI:10.1021/acs.orglett.0c01632

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Letter
Copper-Catalyzed Oxalamide-Directed ortho-C−H Amination of
Anilines with Alkylamines
Peng Wu, Wei Huang, Tai-Jin Cheng, Hai-Xia Lin, Hui Xu, and Hui-Xiong Dai*
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ABSTRACT: A copper-catalyzed oxalamide-directed ortho-C−H
amination of anilines has been developed by using 1 atm of air as
the sole oxidant. The protocol shows excellent functional group
tolerance, and some heterocyclic amines including indole,
benzothiophene, benzothiazole, quinoline, isoquinoline, and
quinoxaline could be compatible in the reaction. The late-stage
diversification of medicinal drugs demonstrates the synthetic utility
of this protocol.
ver the past decade, transition-metal-catalyzed, such as
catalyst. Strong coordination can form a more stable
ORu-, Rh-, Pd-, and Ir-catalyzed, C−H functionalization metallacycle and thus cause less reactivity in the subsequent
has emerged as a novel synthetic tool in organic synthesis.1
Compared with these precious metals, Cu salts are earth-
abundant and have low toxicity. Recently, directing-group-
assisted copper-mediated C−H functionalization has become a
hot research field (Scheme 1A).2 In 2006, Yu and coworkers
reported the first directed copper-catalyzed C−H functional-
ization of 2-phenylpyridine and proposed the single electron
transfer (SET) pathway mediated by a Cu(II) intermediate.3
However, the nonremovability of the pyridyl group limits the
further application in organic synthesis. An elegant work about
the copper-promoted ortho-C−H sulfenylation of benzoic acid
derivatives by using 8-aminoquinoline as the removable
directing group was developed by the Daugulis in 2012.4
Subsequently, they and other research groups exploited this
directing group to achieve biaryl coupling,5 amination,6
fluorination,7 etherification,8 and so on. Later on, we
developed amide-tethered oxazoline as the directing group to
realize Cu-catalyzed or -mediated C−H amination, trifluor-
omethylation, alkynylation, hydroxylation, arylation, and
thiolation.9 Meanwhile, Chen and Carretero independently
developed the copper-catalyzed picolinamide-directed ortho-
C−H amination of anilines with good functional group
tolerance.10 However, it was not sufficiently active for acyclic
amines, and a stoichiometric amount of the expensive
PhI(OAc)2 was required as an oxidant. Furthermore, Shi and
Song, respectively, developed the 2-(pyridin-2-yl)-isopropyl-
amine (PIP)-directing group and the 2-aminopyridine 1-oxide
directing group for copper-catalyzed or -mediated C−H
functionalization.11
C−H functionalization step. As a consequence, adding a
stoichiometric copper catalyst is required. In contrast, weak
coordination could kinetically facilitate the functionalization
step by forming the less thermodynamically stable metallacycle
and thus could theoretically achieve the catalytic cycle of the
copper catalyst.12 In 2017, we demonstrated that the use of a
weakly coordinating monodentate directing group in combi-
nation with an oxazoline ligand could achieve the copper-
promoted C−H amination and hydroxylation (Scheme 1B).13
The downside is that the reaction system requires stoichio-
metric amounts of Cu(I) and Cu(II) to obtain the moderate
yields. Therefore, how to realize C−H functionalization
effectively by using weakly coordinated directing groups
remains a challenge.
Recently, Ma and coworkers elegantly developed the oxalic
diamide as an efficient ligand in the copper-catalyzed
Ullmann−Goldberg-type coupling reactions of the less reactive
(hetero)aryl chloride with the nucleophilic reagent.14 The
oxalic diamide ligand was so efficient that only 0.01 mol % of
Cu2O and ligand could catalyze the cross-coupling of
(hetero)aryl iodides with primary amines in good yields.14d
Inspired by these works, we hypothesized that we could
convert this powerful Cu/oxalamide catalytic system into Cu-
catalyzed oxalamide-directed C−H functionalization (Scheme
1C). Herein we report a copper-catalyzed ortho-C−H
Received: May 13, 2020
Despite undisputable advances, copper-mediated C−H
functionalization reactions inevitably rely on strongly coordi-
nating directing groups due to the low reactivity of the copper
https://dx.doi.org/10.1021/acs.orglett.0c01632
© XXXX American Chemical Society
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A

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a b c
, ,
Scheme 1. Directing Groups for Copper-Catalyzed or
Table 1. Optimization of the Reaction Conditions
-Mediated C−H Functionalization
entry
variations from the standard conditions
yield (%) of 3b
c
1
none
72 (70)
2
no Cu
0
3
4
5
6
7
8
9
10
11
12
13
14
15
CuCl (10 mol %)
DMSO instead of PhMe
THF instead of PhMe
PhI(OAc)2 (2 equiv)
at N2 atmosphere
at O2 atmosphere
at 80 °C
1-DG1 instead of 1b
1-DG2 instead of 1b
1-DG3 instead of 1b
1-DG4 instead of 1b
1-DG5 instead of 1b
1-DG6 instead of 1b
56
trace
6
d
0
trace
71
29
0
47
62
0
0
trace
a
Reaction conditions: 1b (0.1 mmol), 2a (0.2 mmol), CuCl (20 mol
amination of aniline by using oxamide as a weakly coordinating
directing group.
b
%), PhMe (2.0 mL), air, 110 °C, 12 h. 1H NMR yields were
determined by using 1,1,2,2-tetrachloroethane as the internal
standard. Isolated yield. N2 atmosphere.
We commenced our studies by choosing N1,N1-diisopropyl-
N2-(p-tolyl) oxalamide 1b and morpholine 2a as the model
substrates. The optimized reaction conditions for the copper-
catalyzed ortho-C−H amination of anilines are shown in Table
1. A series of control experiments were carried out to better
understand this reaction. As expected, removing Cu from the
reaction mixture resulted in no detectable formation of
amination product 3b (entry 2). The yield was slightly
reduced when we lowered the loading of CuCl to 10 mol %
(entry 3). Toluene was the optimal solvent, and the yields
significantly decreased when THF or DMSO was used (entries
4 and 5). No desired product was observed when PhI(OAc)2
was added as the oxidant (entry 6). As expected, the yield
decreased to trace under the N2 atmosphere, which showed
that air was indispensable to oxidize Cu(I) to Cu(II) (entry 7).
Moreover, when the reaction was carried out under the O2
atmosphere, the result was consistent with that under air
(entry 8). Decreasing the temperature to 80 °C resulted in
lower conversion (entry 9). No reaction occurred when the
amino acid skeleton was used instead of oxalamide, presumably
due to the flexibility of the amino acid skeleton (entry 10). We
further modulated the substituents on the amide nitrogen and
found that the diisopropyl-substituted substrate showed the
best results (entries 11 and 12). The N-methylaniline substrate
was totally unreactive, indicating that the covalent bond
formed with copper was essential for the reaction (entry 13).
In addition, ester is not stable enough due to the aminolysis
with alkylamine (entry 14). Although 1-DG6 could form a five-
membered bis-dentate complex with Cu(II), no desired
product was observed (entry 15).
c
d
With the optimal conditions in hand, we proceeded to
explore the substrate scope with the corresponding anilines. As
shown in Scheme 2, electron-donating substrates showed
better reactivity than electron-withdrawing substrates. Weak
electron-donating groups, such as t-Bu, Ph, CF3O, and NHBoc
at the para position were well tolerated (1a, 1b, 1c, 1d, 1i, 1o),
giving the desired products in 40−70% yields. A variety of
electron-rich groups such as MeO, PhO, BnO, TBSO, and
MeS groups (1h, 1j, 1k, 1l, 1m) at the same position provided
good yields. Substitutes including fluoro, chloro, and very
sensitive iodo substitutions could be well tolerated, leaving a
functional handle for further elaboration (3e−g). When we
increased the catalyst loading of CuCl to 1 equiv, electron-
withdrawing ester and keto substitutions were found to be
tolerable (3p, 3q). N,N-Dimethyl-1,4-phenylenediamine (1n)
and 2-naphthylamine (1w) gave poor yields under the
standard conditions, and most of starting materials were
decomposed due to the amine exchange with morpholine 2a.
Luckily, when we reduced the temperature to 90 and 80 °C,
both of them showed high reactivity, giving the corresponding
products in 75 and 85% yields respectively (3n, 3w). meta-
Methyl- and methoxy-substituted anilines furnished moderate
to good yields, with the less sterically hindered six-position-
aminated product as the major product (3r, 3s). 1-Naphthyl-
amine (1v) gave a much lower yield than 2-naphthylamine
(1w), probably due to the steric hindrance. Multisubstituted
substrates such as 3,5-dimethoxy and 3,4-(methylenedioxy)
B
https://dx.doi.org/10.1021/acs.orglett.0c01632
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a b
,
a b
,
Scheme 2. Substrate Scope of Aromatic Anilines
Scheme 3. Substrate Scope of Alkylamines
a
Reaction conditions: 1i (0.1 mmol), 2 (0.2 mmol), CuCl (20 mol
b
c
%). PhMe (2 mL), air, 110 °C, 12 h. Isolated yield. CuCl (0.1
mmol).
medicinal drugs Aminoglutethimide (1af), Mesalazine (1ag),
Chlorphenesin (1ah), Aphotalide (1ai), and Anileridine (1aj),
which furnished the amination products in moderate to good
yields (Scheme 4).
a b
,
Scheme 4. Late-Stage Diversification of Medicinal Drugs
a
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), CuCl (20 mol
b
c
%). PhMe (2 mL), air, 110 °C, 12 h. Isolated yield. 1 mmol scale.
d
e
f
g
90 °C. CuCl (100 mol %). 80 °C. 100 °C, 3 h.
anilines gave excellent yields (3t, 3u). Remarkably, this
protocol could be well applied to heterocyclic amines (1x−
ae). Substrates containing pyridine (1x), indole (1y), and
quinoline (1ab, 1ac) provided moderated yields. To our
delight, this protocol could be extended to substrates
containing benzothiophene, benzothiazole, isoquinoline, and
quinoxaline, which had not been reported in previous work,10
providing the desired products in excellent yields (3z, 3aa, 3ad,
3ae).
a
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), CuCl (20 mol
b
%). PhMe (2 mL), air, 110 °C, 12 h. Isolated yield.
For a better understanding of the mechanism of copper-
catalyzed C−H amination, control experiments were carried
out, as shown in Scheme 5. Intermolecular kinetic isotope
competition experiments between 1a and 1a-d5 produced a
kinetic isotope effect (KIE) value of 1.0, indicating that C−H
cleavage was not the rate-limiting step. The addition of radical
scavenger TEMPO or BHT completely inhibited the reaction
under the standard conditions, which indicated that a SET)
pathway might be involved in the reaction.
On the basis of the previously described control experiments
and previous reports, a possible mechanism is proposed, as
shown in Scheme 6. Initially, Cu(I) is oxidized in situ under air
to form the Cu(II) species.11d Because of the two isopropyl
Next, we began to explore the scope of alkylamines. As
shown in Scheme 3, regardless of steric hindrance, amines such
as piperazine, piperidine, and morpholine were well compatible
in the reaction (4a−h). In addition, the reaction gave better
results for acyclic amines than that with picolinic amide-
embodied substrates,10 providing the amination products in
moderate to good yields (4i−o).
To demonstrate the synthetic utility of this protocol, we
applied this protocol to the late-stage diversification of
C
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giving the corresponding products in good to excellent yields.
We further demonstrate the synthetic utility of this protocol in
the late-stage diversification of medicinal drugs.
Scheme 5. Mechanistic Experiments
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01632.
Experimental procedures, characterizations of new
compounds, and NMR spectra data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Scheme 6. Proposed Mechanism of Copper-Catalyzed C−H
Amination of Anilines
Hui-Xiong Dai − Chinese Academy of Sciences Key Laboratory
of Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China; State Key Laboratory of Natural and
Biomimetic Drugs, Peking University, Beijing 100191, China;
University of Chinese Academy of Sciences, Beijing 100049,
China; orcid.org/0000-0002-2937-6146; Email: hxdai@
simm.ac.cn
Authors
Peng Wu − Department of Chemistry, Innovative Drug Research
Center, Shanghai University, Shanghai 200444, China
Wei Huang − School of Pharmacy, Nanchang University,
Nanchang 330006, China
Tai-Jin Cheng − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China; University of Chinese Academy of
Sciences, Beijing 100049, China
Hai-Xia Lin − Department of Chemistry, Innovative Drug
Research Center, Shanghai University, Shanghai 200444, China
Hui Xu − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China
substituents on the amide nitrogen, we proposed that Cu(II)
species coordinate with N and O of substrate 1a to form the
five-membered ring metal species I. The coordination mode of
OA has been demonstrated to be palladium-catalyzed
intramolecular amination by Zhao.15 Then, ligand exchange
with alkylamine 2a forms intermediate II. Subsequently,
intermediate III is formed via the SET process from the aryl
ring to the coordinated Cu(II). Finally, amine transfers to the
arene, followed by deprotonation to provide 3a with the
regeneration of Cu(I) species for the next catalytic cycle.3,10d
The directing group OA in the amination product could be
easily removed. For example, treatment of 3a with NaOH in
MeOH−THF at 100 °C gave the aniline derivative 5a in 85%
yield (Scheme 7).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01632
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, National Natural
Science Foundation of China (no. 21772211), Youth
Innovation Promotion Association CAS (nos. 2014229 and
2018293), Institutes for Drug Discovery and Development,
Chinese Academy of Sciences (no. CASIMM0120163006),
Science and Technology Commission of Shanghai Municipal-
ity (no. 17JC1405000), Program of Shanghai Academic
Research Leader (no. 19XD1424600), National Science &
Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (no. 2018ZX09711002-006),
and the State Key Laboratory of Natural and Biomimetic
Drugs for financial support.
Scheme 7. Removal of the Directing Group
In summary, we have developed a copper-catalyzed ortho-
C−H amination by using oxalamide as a weakly coordinating
directing group. By using 1 atm of air as the sole oxidant, the
reaction could smoothly proceed with good functional group
tolerance. Notably, a variety of heterocyclic amines such as
indole, benzothiophene, benzothiazole, quinoline, isoquinoline,
and quinoxaline could be well compatible in the reaction,
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