Copper-Catalyzed Cascade Cycloamination of α-Csp3-H Bond of N-Aryl Ketimines with Azides: Access to Quinoxalines

Article abstract of DOI:10.1021/acs.orglett.6b00709

A copper-catalyzed cycloamination of α-Csp³-H bond of N-aryl ketimines with sodium azide has been developed. This methodology provides an efficient access to quinoxalines and features mild reaction conditions and readily available ketimines with diverse functional group tolerance.

Full text of DOI:10.1021/acs.orglett.6b00709

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cascade Cycloamination of α‑Csp3−H Bond of
N‑Aryl Ketimines with Azides: Access to Quinoxalines
Tengfei Chen, Xun Chen, Jun Wei, Dongen Lin,* Ying Xie, and Wei Zeng*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed cycloamination of α-Csp3−H
bond of N-aryl ketimines with sodium azide has been developed.
This methodology provides an efficient access to quinoxalines and
features mild reaction conditions and readily available ketimines
with diverse functional group tolerance.
ransition-metal-catalyzed C−N bond-forming reactions
group also developed a copper-catalyzed α-Csp3−H bond
1
Tare widely used in organic synthesis. Among the various amination of N-alkyl ketimines involving free radical
intermediates to construct multifunctional imidazo[1,5-a]-
pyridines using N-heteroarenes as amine sources (Scheme
1b).9 These results imply that the α-Csp3−H bond of ketimines
instead of the imino bond (CN bond) easily suffers from a
free radical attack to form methylene radical intermediates
under oxidative conditions. Previously, our group focused on
developing novel organic reactions starting from imines to
construct different nitrogen-containing compounds.6c−e,9,10
Inspired by the above-mentioned works and due to the
versatile biological activities of quinoxalines (Figure 1),11 we
methodologies, direct C−H amination represents one of the
most efficient transformations for atom-economical construc-
tion of C−N bonds without the need for a prefunctionalized
site. In this regard, nitrene insertion into the C−H bond2 and
chelation-assisted C−H bond aminations have been well-
established for assembling nitrogen-containing compounds.3
Neverthless, in view of the fact that N-heterocycles are
commonly encountered in many natural products, pharma-
ceuticals, and others, the exploration of versatile C−H
amination approaches for constructing particular complex
molecules still remains challenging and important.4
On the other hand, as versatile synthetic units, imines and
their corresponding CN bond addition reactions with
organometallic reagents, Mannich donors, etc. provide a
powerful method for preparing various nitrogen-containing
compounds.5 In comparison, α-Csp3−H bond functionalization
of ketimines,6 especially for the α-Csp3−H bond amination, has
rarely been reported. To date, Jiao described that metal-free α-
Csp3−H bond aminations of N-aryl ketimines could efficiently
convert ketoimines to α-iminonitriles7 and quinoxaline N-
oxides8 through multiple single-electron transfer (SET)
processes using TMSN3 and tert-butyl nitrite (TBN) as the
nitrogen source, respectively (Scheme 1a). Moreover, our
Figure 1. Selected examples of bioactive quinoxalines.
Scheme 1. α-Csp3−H Bond Functionalizations of Ketimines
expected that quinoxalines could be furnished from ketoimines
and azides when transition-metal salts are employed as
catalysts. Herein we describe a copper-catalyzed α-Csp3−H
bond cycloamination of N-aryl ketimines for the synthesis of a
quinoxaline skeleton using sodium azide as the nitrogen source
(Scheme 1c).
The α-Csp3−H bond cycloamination cascade of N-phenyl-
ketoimine (1a) with tosyl azide (TsN3) was initially chosen as a
model reaction to screen various copper catalysts in the
presence of PhI(OAc)2 and AcOH in ethyl acetate at 25 °C
under an Ar atmosphere for 16 h (Table 1, entries 1−7). As
Received: March 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00709
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Letter
a
the more details). Also, when a large-scale reaction was
performed, we could still obtain a 57% yield of 2a (entry 21).
With the optimized conditions in hand, we then turned our
attention to explore the generality of the current procedure by
testing various N-arylketoimines (1) employing sodium azide as
the nitrogen source. As shown in Scheme 2, the cycloamination
Table 1. Optimization of the Reaction Parameters
b
entry
catalyst
azide
TsN3
oxidant
additive
yield (%)
1
Cu(OAc)2
CuCl2
CuBr2
CuSO4
CuI
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
PhCO2H
TsOH
iPrOH
PivOH
PivOH
PivOH
PivOH
9
a b
,
Scheme 2. Substrate Scope
2
TsN3
5
3
TsN3
trace
14
5
4
TsN3
5
TsN3
6
CuBr
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
TsN3
trace
19
39
0
7
TsN3
8
TMSN3
PhCON3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
9
10
11
12
13
14
15
16
17
18
19
20
21
49
0
c
BQ
Ag2CO3
0
PhIO
0
AgOAc
19
29
0
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
0
71
d
63
e
49
f
57
a
Unless otherwise noted, all the reactions were carried out using
ketoimine (1a) (0.10 mmol) and azide (0.30 mmol) with a copper
catalyst (10 mol %) in the presence of an oxidant (3.0 equiv) and
additive (2.0 equiv) in ethyl acetate (2.0 mL) at 25 °C for 16 h under
Ar in a sealed reaction tube, followed by flash chromatography on
b
c
d
SiO2. Isolated yield. BQ refers to 1,4-benzoquinone. The reaction
e
f
temperature is 10 °C. The reaction temperature is 45 °C. 2.0 mmol
of 1a and 6.0 mmol of sodium azide were used.
a
Unless otherwise noted, all the reactions were carried out using
ketoimine (1) (0.10 mmol) and sodium azide (0.30 mmol) with CuO
(10 mol %) in the presence of PIDA (3.0 equiv) and PivOH (2.0
equiv) in ethyl acetate (2.0 mL) at 25 °C for 16 h under Ar in a sealed
reaction tube, and then followed by flash chromatography on SiO2.
expected, we quickly found that copper salts, such as
Cu(OAc)2, CuCl2, CuSO4, CuI, and CuO, could furnish the
desired 2-phenylquinoxaline 2a in 5−19% isolated yields. CuO
was slightly superior to others and proved to be the best copper
catalyst (entry 7). Subsequently, we continued to evaluate
various azides including PhCON3, TMSN3, and NaN3 for
further improvement of the cycloamination conversion using
CuO as the catalyst. After the extensive screening, NaN3 was
found to be a good candidate which could moderately increase
the yield of 2a from 19% to 49% (compare entries 7−9 with
10), whereas PhCON3 was ineffective (entry 9). Moreover, to
render the reaction catalytic in CuO, we then tested a variety of
oxidants in the NaN3/CuO/AcOH system and found the
oxidant also played a crucial role in this transformation (entries
10−14). Among them, PhI(OAc)2 could effectively enhance
the α-imino Csp3−H bond cycloamination and afford a 49%
yield of 2a (entry 10). Finally, several proton-donor additives
including pivalic acid (PivOH), acetic acid, isopropyl alcohol,
and benzoic acid were further investigated in the NaN3/CuO/
PhI(OAc)2 system (entries 14−18), and PivOH was found to
be the most efficient in the formation of product 2a (entries 18,
71% yield) possibly due to the fact that PivOH could improve
the solubility of CuO in the reaction system. Additionally
notable is that lowering or increasing the reaction temperature
could not further improve the reaction yields (compare entries
19 and 20 with 18) (see the Supporting Information (SI) for
b
c
d
Isolated yield. The reaction time is 24 h. The reaction temperature
is 50 °C.
reactivity of N-arylketoimines (1) was obviously dependent on
the electronic and steric properties of the substituents. We first
evaluated substitution effects on the C-ketoimino phenyl rings
(Ar). The α-imino Csp3−H bond cycloamination cascade was
compatible with electronically diverse functional groups at the
4′-position of Ar, and 4-substitution on the phenyl rings with
electron-donating group (Me, MeO) afforded excellent yields
of 2b (77% yield) and 2c (80% yield), respectively. In contrast,
electron-withdrawing halide, nitro, nitrile, and ethoxylcarbonyl
groups moderately decreased the reaction conversion and
produced 52−68% yields of 2d−2i. Notably, a similar
substitution effect was also observed in the N-ketoimino
phenyl rings (2o−2s, 35−85% yields). Subsequently, we
prepared the C-(2- or 3- substituted phenyl)ketoimines and
found their corresponding cycloamination efficiency was
maintained irrespective of the type of substituent and the
substituted position in C-imino phenyl rings (2j−2n). For
examples, C-(2-methoxyl)phenyl, C-(3-methoxylphenyl, C-(2-
B
DOI: 10.1021/acs.orglett.6b00709
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Scheme 3. Preliminary Mechanistic Studies
chloro)phenyl, and C-(3-chloro)phenyl-substituted ketoimines
all allowed for this transformation and afforded the desired
quinoxalines with 50−68% yields (2j−2m). More importantly,
C-heteroaryl ketoimines were also tolerated under our reaction
conditions to assemble 2-(4-pyridyl)quinoxaline (2u, 53%
yield), 2-(3-pyridyl)quinoxaline (2v, 57% yield), 2-(2-furyl)-
quinoxaline (2w, 51% yield), and 2-(2-thienyl)quinoxaline (2x,
47% yield). Finally, when we introduced the chloro, methyl,
phenyl, and benzyl group to the α-imino Csp3 position, the
cycloamination reaction still worked and produced the
corresponding 2,3-substituted quinoxalines (2y−2−2z) in
acceptable yields (33−62%). Unfortunately, when bisalkyl-
substituted ketoimines were subjected to the standard reaction
conditions, no desired quinoxaline 2−3z was observed.
Scheme 4. Proposed Mechanism
Several control experiments were performed to investigate
the possible mechanism of this Csp3−H bond cycloamination.
First, the α-Csp3−H bond cycloamination of ketimine (1c)
with sodium azide was conducted in the absence of CuO under
the PIDA/PivOH/EtOAc/Ar reaction conditions at 25 °C for
16 h; no desired quinoxaline (2c) was observed, and most of
the starting material 1c was decomposed under our reaction
system. This result suggested that the CuO catalysts played a
key role in the formation of quinoxalines; Moreover, PIDA also
could not furnish a nitrile intermediate6 (3) under metal-free
conditions (Scheme 3a). Next, further subjection of α-
iminonitrile intermediate 3 to the CuO/PIDA/PivOH system
under Ar could still not result in the formation of the desired
product 2c, and the substrate 3 was recovered in 87% isolated
yield (Scheme 3b). This fact ruled out the possibility that α-
iminonitrile intermediates were involved in this cycloamination
process. Finally, addition of 2.0 equiv of TEMPO to the CuO/
PIDA/PivOH/Ar reaction system of 1c remarkably inhibited
the α-Csp3−H bond cycloamination of ketimines (Scheme 3c),
which revealed that a SET process and radical intermediates
were possibly involved in this reaction.
Based on the above-mentioned control experiments, a
plausible mechanism is proposed in Scheme 4. The initial
reaction of PhI(OAc)2 with sodium azide (NaN3) afforded
PhI(N3)2,12 and then PhI(N3)2 decomposed to produce azide
radical A and iodine radical B via the N−I(III) bond
homolysis.13 Next, the regioselective hydrogen abstraction of
the α-Csp3−H bond from 1a by azide radical A afforded the
methylene radical C, which could be cross-coupled with radical
intermediate B to give α-imino azide D. Once again, azide
radical A would abstract the α-Csp3−H bond of azide D to
furnish the α-imino methylene radical E.13a Subsequently,
denitrogenation and isomerization of E was followed by radical
cyclization to generate the intermediate H. Finallly, H could be
converted into the target quinoxaline 2a via a single-electron
transfer14 and aromatization process.
In conclusion, we have developed a novel and simple efficient
copper-catalyzed cycloamination cascade of the α-Csp3−H
bond of N-aryl ketimines, in conjunction with sodium azide as
the nitrogen source, for the rapid assembly of quinoxalines
under mild reaction conditions. This method tolerates a wide
range of readily available ketoimines with diverse functional
groups. Further investigations to elucidate the reaction
mechanism and extend the synthetic applications of this
transformation are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00709.
Detailed experimental procedures, characterization data,
copies of 1H and 13C NMR spectra for all isolated
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: denlin@scut.edu.cn.
*E-mail: zengwei@scut.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b00709
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ACKNOWLEDGMENTS
■
The authors thank the NSFC (No. 21372085) and Science and
Technology Program of Guangzhou (No. 156300075) for
financial support.
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