Copper-catalyzed three-component reaction of: N-heteroaryl aldehydes, nitriles, and water

Article abstract of DOI:10.1039/c9ob00599d

An efficient and straightforward method for the synthesis of N-heteroaroyl imides has been successfully developed involving a copper-catalyzed radical-triggered three-component reaction of N-heteroaryl aldehydes, nitriles, and water. Mechanistic studies indicate that the reaction may undergo a radical-triggered Ritter-type reaction in which water serves as the oxygen source for the formation of the C-O bond. The reaction has advantages such as a broad substrate scope for the N-heteroaryl aldehydes, atom economy, and simple operation.

Full text of DOI:10.1039/c9ob00599d

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DOI: 10.1039/C9OB00599D
ARTICLE
Copper-catalyzed three-component reaction of N-heteroaryl
aldehydes, nitriles, and water
Hanyang Bao, Bingwei Zhou, Hongwei Jin* and Yunkui Liu *
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and straightforward method for the synthesis of N-heteroaroyl imides has been successfully developed involving
a copper-catalyzed radical-triggered three-component reaction of N-heteroaryl aldehydes, nitriles, and water. Mechanistic
studies indicate that the reaction may undergo a radical-triggered Ritter-type reaction in which water serves as the oxygen
source for the C-O bond. The reaction has advantages of broad substrate scope for the N-heteroaryl aldehydes, atom
economy, and simple operation.
DOI: 10.1039/x0xx00000x
(a) Radical-triggered difunctionalization of C=C and CC bonds (intra- and intermolecular)
FG1
Introduction
FG2
FG1
FG1
+
+
FG2
FG2
FG2
FG2
In the past few decades, the radical-triggered inter- and
intramolecular difunctionalizations of the C=C or C≡C bonds
have received considerable attention because such reactions
usually provide a highly efficient strategy for the construction of
complex molecules in a simple operation and step-economy
manner.1-4 Up to now, a variety of C-C/C-C, C-C/C-X, or even C-
X/C-Xʹ (X, Xʹ = heteroatoms) structural units can be efficiently
constructed from the C=C or C≡C moieties based on various
carbon-centered or heteroatom-centered radical species
(Scheme 1a).1-4
extensively studied!
FG1
FG2
FG1: C-, O-, N-, S-, P-, halogen-centered radicals, etc.
(b) Radical-triggered difunctionalization of CN bond (C-addition of radicals)
FG1
C
FG2
only several examples!
N
FG2
R
C
N
+
FG1
R
(c) Radical-triggered difunctionalization of CN bond (N-addition of radicals)
O
The C≡N bond, structurally similar to the C=C and C≡C bond,
is also a useful and versatile building block in various organic
transformations.5-7 As far as the difunctionalization of the C≡N
bond is concerned, a lot of examples have been reported in
recent years.6,7 However, among them, examples involving the
radical-triggered difunctionalizations are still limited in
comparison with those examples in domains of the C=C and C≡C
bond (Scheme 1b).7 Among these limited examples, the
Malacria’s group reported an AIBN/n-Bu3SnH-mediated radical
cascade cyclization of N-(2-iodobenzyl)-N-acylcyanamides to
construct tetracyclic quinazolinones.7a,b Later, Yu and co-
workers further realized the same reaction by employing
photoredox strategy to initiate radicals.7c In recent years, Sun’s
H2O
only one literature!
Ph
R
C
N
+
Ph
R
N
H
(d) Our previous work: generation of N-heteroaromatic benzyl radicals under oxidative conditions
NO2
[ox]
R1, R2 = alkyl
H+
R2
NO2
R2
R2
R2
N
N
N
N
ref. 8a
+
R1
R1
OH
R1
R1
R1 = H; R2 = OH
H+
OMe
OMe
N
N
ref. 8b
(e) This work: Radical-triggered difunctionalization of CN bond (N-addition of aromatic acyl radicals)
N
R
+
H
[ox]
H2O
cat. Cu(OTf)2
H
N
R
H
N
N
N
N
H+
+
O
O
O
O
O
N-Heteroaryl aldehydes
Scheme 1 The radical-triggered difunctionalization of the C=C,
C≡C, and C≡N bonds.
group developed
a
convenient approach to prepare
phenanthridine derivatives involving several photocatalyst-
induced
radical
cascade
reactions
of
N-(2-
cyanoaryl)acrylamides.7d-f All the aforementioned radical-
triggered difunctionalizations of the C≡N bond proceed through
the addition of radical species to the carbon atom of the cyano
group as the initial step, while the radical-triggered direct N-
addition reactions are relatively rare. To the best of our
knowledge, there only one literature has been reported on this
type of reaction, which involves an N-addition of phenyl radicals
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology, Hangzhou, 310014, P. R. China.
E-mail: jhwei828@zjut.edu.cn; ykuiliu@zjut.edu.cn.
Electronic Supplementary Information (ESI) available: General reaction procedures,
characterization data, mechanic experiments, and copies of NMR spectra. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
to the C≡N bond leading to the synthesis of N-phenyl amides In view of the potential application of quinoxaline VdieewriAvratictlievOenslinine
12
(Scheme 1c).7g From the synthetic point of view, it is still highly chemical, pharmaceutical, and materials science fields, our
DOI: 10.1039/C9OB00599D
desirable to develop efficient methods for the construction of study commenced with the three-component reaction of 3-
molecule diversity via the difunctionalization of the C≡N bond phenylquinoxaline-2-carbaldehyde (1a), acetonitrile (2a), and
involving the radical-triggered direct N-addition reactions.
water as the model reaction for the optimization of the reaction
In our previous work, we disclosed that N-heteroaromatics conditions (Table 1). When 1a was treated with NCS (2.0 equiv)
having a benzyl C-H bond at the -position to the N-atom in N- in acetonitrile-water media (500/1, V/V) at 100 ºC for 18 h, N-
heteroaromatics may easily generate N-heteroaromatic benzyl acetyl-3-phenylquinoxaline-2-carboxamide 3aa was obtained in
radicals under oxidative conditions, which may further undergo 38% yield along with the formation of 4a and 5a as side products
radical tandem reactions (Scheme 1d).8 On the basis of this (entry 1, Table 1). Among several oxidants screened, K2S2O8
founding, we envision that N-heteroaryl aldehydes might showed the most effectiveness for the formation of 3aa (entry
similarly generate N-heteroaromatic acyl radicals under 2 vs 1, 3, and 4, Table 1). It was found that decreasing the
oxidative conditions (Scheme 1e). As part of our ongoing amount of K2S2O8 resulted in a low yield of 3aa (entry 5, Table
research interests in radical reactions8 and copper-catalyzed 1), and none of 3aa was obtained in the absence of K2S2O8 (entry
efficient tandem reactions,9,10 we herein describe a copper- 6, Table 1). In order to further improve the yield of 3aa, a series
catalyzed three-component reaction11 of N-heteroaryl of copper salts were screened as additives (entries 7-10, Table
aldehydes, nitriles, and water for the preparation of N- 1). Gratifyingly, when Cu(OTf)2 (20 mol %) was added, the
heteroaroyl imides involving a radical-triggered direct N- reaction could afford 3aa in 79% yield even with a less
addition as the key step (Scheme 1e).
consumption of K2S2O8
Results and discussion
Table 1 Optimization of the reaction conditionsa
oxidant
additive
N
N
Ph
O
N
N
Ph
O
N
N
Ph
O
N
N
Ph
+
H
+
H
N
NH2
2a
MeCN ( )/ H2O = 500: 1 (V/V)
temperature
reaction time, air
O
3aa
4a
5a
1a
Yield (%)b
3aa/4a/5a
38/6/17
63/12/28
59/10/23
34/40/trace
39/trace/11
N.R.
79/trace/10
39/trace/10
--/--/--
Copper salt
(mol %)
Oxidant
(equiv)
NCS (2.0)
Temp
(ºC)
100
100
100
100
100
100
60
60
60
60
60
60
60
60
60
60
60
60
60
Entry
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
--
--
--
--
--
--
18
18
18
18
18
18
6
6
6
6
6
6
6
6
6
6
6
6
6
K2S2O8 (2.0)
(NH4)2S2O8 (2.0)
TBHP (2.0)
K2S2O8 (1.0)
--
Cu(OTf)2 (20)
CuCl2 (20)
Cu(acac)2 (20)
Cu(OAc)2 (20)
--
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
TBHP (2.0)
(NH4)2S2O8 (1.0)
PhI(OAc)2 (1.0)
(NH4)2S2O8 (1.2)
(NH4)2S2O8 (0.8)
(NH4)2S2O8 (1.0)
(NH4)2S2O8 (1.0)
(NH4)2S2O8 (1.0)
15/--/--
23/--/--
66/trace/trace
63/trace/trace
47/13/trace
87/trace/trace
18/--/--
85/trace/trace
82/trace/trace
85/trace/trace
75/trace/14
53/trace/19
60
60
6
6
aReaction conditions: 1a (0.3 mmol), additive (n mol % based on 1a), oxidant (m equiv based on 1a), MeCN/H2O = 500:1 (V/V, 3.0
mL), at T oC unless otherwise noted. bIsolated yield. cSolvent: MeCN/H2O = 250:1 (V/V, 3.0 mL). dSolvent: MeCN/H2O = 100:1 (V/V,
3.0 mL). eSolvent: MeCN/H2O = 50:1 (V/V, 3.0 mL).
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB00599D
ARTICLE
R2
R2
N
N
R1
O
R2
R2
N
N
3
R1
O
Cu(OTf)2 (20 mol %)
(NH4)2S2O8 (1 equiv)
H
N
H
2a
MeCN ( )/H2O = 500: 1 (V/V)
60 oC, 6 h
O
1
3'
(1.0 equiv), with a shorter reaction time (6 h), andunder a lower
temperature (60 ºC) (entry 7 vs 2, Table 1). Note that the use of
20 mol % of Cu(OTf)2 was necessary to get a satisfactory yield of
3aa (entries 11-13 vs 7, Table 1). In the case of Cu(OTf)2 as an
additive, the reaction could give an even better yield of 3aa
when (NH4)2S2O8 was used as the oxidant instead of K2S2O8
(entry 15 vs 7, Table 1). Either increasing or decreasing the
amount of (NH4)2S2O8 resulted in a lower yield of 3aa (entries
17-18, Table 1). Finally, the influence of water content on the
reaction was also evaluated by the extra addition of water into
the reaction mixture. Unfortunately, decreased yields of 3aa
were obtained which suggested a subtle reaction condition
requiring an existence of trace amount of water in this reaction
system (entries 19-21 vs 15, Table 1).
Under the established reaction conditions, the scope of
quinoxaline-2-carbaldehydes 1 was investigated (Table 2). We
first examined the generality of 1 with various aryl groups at the
3-position of the quinoxaline scaffold (R1 = Ar, 3aa-na and 3ra-
va, Table 2). As seen from Table 2, quinoxaline-2-carbaldehydes
1 containing a range of aryl rings with various substitution
patterns (para-, meta- or ortho-) were able to undergo the
three-component reaction and the desired products could be
obtained in moderate to excellent yields (3ba-ha and 3ra-va,
Table 2). Generally, substrates 1 bearing electron-deficient
phenyl rings reacted more smoothly and delivered higher yields
of products than those possessing electron-rich ones (3ba-da vs
3ea-ha; 3ia, 3ja vs 3ka, Table 2). In addition, substrates with R1
as non-aryl groups (for example, R1 = H, Me, or Cl) were also
workable for the reaction albeit in lower yields of products in
several cases (3pa, 3qa, Table 2). Furthermore, quinoxaline-2-
carbaldehydes with different R2 groups including Cl, Br, and
methyl were also investigated, in which cases the desired
products could be obtained in moderate to good yields (3ra-va,
Table 2). A 3 mmol-scale
4'
R
N
N
N
N
Cl
O
N
N
2'
1'
H
H
H
N
N
N
N
N
H
N
O
O
O
O
O
O
O
3qa
: 63%
3oa
: 85%
3pa
: 45%
R1 = Ar
3aa
3ba
3ca
3da
3ea
: R = H, 87%
: R = 4'- Br, 95%
: R = 4'- Cl, 97%
: R = 4'- F, 98%
: R = 4'- Me, 67%
: R= 4'- Et, 63%
N
N
Br
Br
N
N
Cl
Cl
N
N
H
H
H
N
N
N
O
O
O
O
O
O
O
3fa
3ga
3ha
3ta: 63%
: R = 4'- OMe, 66%
: R = 4'- OBn, 86%
: R = 3'- Br, 88%
: R = 3'- Cl, 95%
3sa
: 73%
3ra
: 91%
OMe
3ia
3ja
N
N
N
N
H
N
H
3ka: R = 3'- OMe, 78%
3la
N
: R = 2'- F, 86%
O
O
O
3ma
: R = 2'- OMe, 85%
: R = 2'- Br, 89%
3ua
: 58%
3va
: 58%
3na
aReaction conditions: 1 (0.3 mmol), Cu(OTf)2 (20 mol % based
on 1), (NH4)2S2O8 (1.0 equiv), MeCN/H2O = 500:1 (V/V, 3.0 mL),
at 60 ºC for 6 h unless otherwise noted.
synthesis of 3aa was also investigated, and 3aa could be
obtained in 70% yield (see eq. 1S in ESI). A dialdehyde
(quinoxaline-2,3-dicarbaldehyde 1w) was used to react with
acetonitrile and water under the optimal conditions.
Unexpectedly, a concomitant deformylation also occurred and
imide 3oa was obtained in 65% yield.
Next, the scope of different nitriles 2 was investigated by
reacting with quinoxaline-2-carbaldehyde 1a under the
optimized reaction conditions (Table 3). It was found that the
yield of the desired imides depended heavily on the structure of
nitriles. For instance, n-butyronitrile, iso-butyronitrile,
benzonitrile, or 4-methoxybenzonitrile reacted with 1a and
water smoothly, and the desired products could be obtained in
moderate to good yields (54-83%, 3ab, 3ac, 3af, 3ag, Table 3).
In contrast, 3-methoxypropionitrile, acrylonitrile or 4-
nitrobenzonitrile gave a much lower yields of the products (3ad,
3ae, 3ah, Table 3). An attempt to use a stoichiometric amount
of benzonitrile for the reaction was also carried out by using the
DCE-water mixture as the solvent, and the reaction could still
afford 3af in 51% yield albeit in a prolonged reaction time.
Table 2 Substrate scope of quinoxaline-2-carbaldehydes 1.a
Table 3 Substrate scope of nitriles.a
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ARTICLE
Journal Name
2
R1
R
Cu(OTf)2 (20 mol %)
(NH4)2S2O8 (1 equiv)
View Article Online
N
N
N
N
Cu(OTf)2 (20 mol %)
K2S2O8 (1 equiv)
DOI: 10.1039/C9OB00599D
H
N
R1 CN
R1
R1
+
R1
H
N
2
/H2O = 500: 1 (V/V)
H
CHO

60 oC, 6 h
N
N
2a
MeCN ( )/ H2O = 500:1 (V/V)
O
O
O
O

O
O
O
2
1a
3
90 oC, 6 h
7
6
N
N
N
N
N
H
H
N
H
R3
N
OMe
N
H
N
H
N
H
N
N
O
O
O
O
O
F3C
N
N
N
3ac
: 54%
3ad
: 30%
3ab
: 81%
O
O
Br
O
O
O
O
O
O
7ga
: 35%
7ha
: 31%
b
7aa
7ba
7ca
7da
7ea
: R = H, 81%, 45%
: R = Me, 72%
: R = OMe, 71%
: R = F, 92%
N
N
N
N
N
N
R
H
N
H
N
H
N
H
N
H
O
O
b
O
O
O
N
N
b
c
c
N
3ae
: 27%
3af
: 83% ; 51%
3ag
3ah
: R = OMe,59%
: R = NO2, trace
: R = Br, 70%
: R = I, 71%
O
O
O
c
O
7fa
7ia
: 62%
7ja
: 70%
aReaction conditions: 1a (0.3 mmol), 2/ H2O = 500:1 (V/V, 3.0
mL), Cu(OTf)2 (20 mol % based on 1a), (NH4)2S2O8 (0.3 mmol), at
60 ºC for 6 h unless otherwise noted. bThe reaction was carried
out in 90 oC, and the reaction time was 12 h. cReaction
conditions: 1a (0.3 mmol), 2f-h (3.0 equiv based on 1a), Cu(OTf)2
(20 mol % based on 1a), (NH4)2S2O8 (1.0 equiv based on 1a) in
1,2-dichloroethane at 100 ºC for 18 h.
H
H
N
H
N
N
Cl
N
N
N
O
O
O
O
7ka
: 55%
7ma
: 63%
7la
: 61%

N

N
HN
O
S
N
H
H
N
O

N
N
Cl
To make the reaction synthetically valuable, we further set
out to investigate the scope of different N-heteroaryl
benzaldehydes 6 by treatment of 6 with acetonitrile 2a and
O
O
O
O
7na
: 55%
8a
: 45%
9a
: <10%
water (Table 4). First, a range of quinoline-2-carbaldehydes aReaction conditions: 6 (0.3 mmol), Cu(OTf)2 (20 mol % based
were investigated. Note that in these cases K2S2O8 is a more on 6), K2S2O8 (0.3 mmol), MeCN (2a)/H2O = 500:1 (V/V, 3.0 mL),
suitable oxidant and 90 C is a more suitable temperature for at 90 ºC for 6 h unless otherwise noted. b(NH4)2S2O8 (1.0 equiv)
o
getting a satisfactory yield of the target product. Under the was used at 90 oC.
modified reaction conditions, a series of substituted quinoline-
2-carbaldehydes underwent the three-component reaction
To gain insight into the mechanism of the present three-
smoothly to furnish the corresponding N-acetyl-quinoline-2- component reaction, several mechanistic experiments were
carboxamide in synthetically acceptable yields (7aa-ia, Table 4). carried out (Scheme 2). First, isotope labeling experiment was
Next, phenanthridine-6-carbaldehydes were also proven to be conducted to figure out the oxygen source for the product
suitable substrates for the present reaction and the desired formation. H2O18 was added to the model reaction in anhydrous
imides could be obtained in moderate yields (7ja-ma, Table 4). acetonitrile under the nitrogen atmosphere (Scheme 2a). To our
When 2-pincolinaldehyde was used, the desired product 7na expectation, the 18O-incorporated product 3aa-O18 was
was obtained in 55%. In addition, a benzo[d]thiazole-2- detected by LRMS analysis, which suggested that water served
carbaldehyde (8) was able to convert into the desired imide in as the oxygen source for the formation of the C-O bond in 3aa
45% yield (8a, Table 4). Finally, a pyrazole-4-carbaldehyde (9) (see in the ESI). Next, a radical scavenger (TEMPO or BHT) was
having a γ-N to the formyl group was tested for the reaction. subjected to the standard reaction conditions. As a result, the
Unfortunately, the reaction afforded the desired product in only reaction was thoroughly suppressed by employing 2.0
lower than 10% yield (9a, Table 4).
equivalents of TEMPO (Scheme 2b); a similar result was
obtained from the reaction using BHT (butylated
hydroxytoluene) as a radical scavenger (Scheme 2c). These
results supported that a radical process might be involved in this
reaction.13 Furthermore, a competitive reaction between 1a
and 1a-d (96%-D enrichment) for the measurement of
intermolecular KIE was carried out (Scheme 2d). The
intermolecular kH/kD of 1a to 1a-d was calculated to be 1.0
(Figure S2 in the Supporting Information), suggesting that the
cleavage of the C-H bond is not the rate-determining step.
Finally, quinoline-3-carbaldehyde 10, benzaldehyde 11, or
butyraldehyde 12 was investigated for the reaction (Scheme 2e).
Unfortunately, these substrates failed to give the desired
products while the starting materials were almost recovered.
These results suggest that substrates containing an N-atom at
Table 4 Substrate Scope of Other N-Heteroaryl Aldehydes 6.a
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
the β-position of the formyl group are very essential for the heteroaryl aldehydes, nitriles and water in theVipewreAsrteicnlecOenlionef
DOI: 10.1039/C9OB00599D
reaction.
persulfate salts. Thus a variety of N-(hetero)aroyl-containing
imides could be prepared in moderate to excellent yield under
simple reaction conditions. Mechanistic studies indicated that
the formation of N-(hetero)aromatic acyl radicals is the key step
for the present three-component reaction.
Cu(OTf)2 (20 mol %)
(NH4)2S2O8 (1 equiv)
3aa + 3aa-O18
a)
1a
1a
2a
MeCN ( , 3 mL)
H2O18 (5 equiv)
60 oC, 6 h, N2
total yield: 81%
Standard conditions
TEMPO (x equiv)
b)
c)
3aa
Experimental
General experimental methods
x = 0.5
2.0
yield: 53%
N.R.
Standard conditions
1a
3aa
BHT (x equiv)
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without purification. Melting
x = 0.5
2.0
yield: 64%
trace
1
points were uncorrected. The H and 13C NMR spectra were
Cu(OTf)2 (20 mol%)
(NH)4S2O8 (1 equiv)
N
N
N
N
N
recorded on a spectrometer at 25 C in CDCl3 at 500 MHz and
125 MHz (or at 400 MHz and 100 MHz), respectively. Proton
chemical shifts (δ) are relative to tetramethylsilane (TMS, δ =
0.00) as internal standard and expressed in ppm. Chemical shifts
of 13C NMR were reported relative to the solvent signal (CDCl3:
δ = 77.16 ppm). GC-MS experiments were performed with EI
source; high resolution mass spectra (HRMS) were obtained on
a TOF MS instrument with EI or ESI source. Acetonitrile is
dehydrated by CaH2 before preparation of the combined
MeCN/H2O solvent system. Flash column chromatography was
performed on silica gel (100-200 mesh) with the indicated
solvent mixtures.
+
d)
H
D
H
N
MeCN/ H2O = 500:1 (V/V)
60 oC, 70 min
N
O
O
O
O
1a
1a-
d (96%-D enrichment)
1a
1a
and -d were recovered
totally 33% of
kH/kD = 1.0
(calculated by 1H NMR analysis)
0.144 mmol
0.156 mmol
O
H
N
10
or
Cu(OTf)2 (20 mol %)
K2S2O8 (1 equiv)
O
10a 11a
, or
12a
,
H
e)
2a
MeCN ( )/ H2O = 500:1 (V/V)

90 oC, 6 h
11
or
O
H
12
Scheme 2 Mechanistic experiments.
Preparation of quinoxaline-2-carbaldehydes 1, quinoline-2-
carbaldehydes (6a-i), phenanthridine-6-carbaldehydes (6j-m),
8, and 9
On the basis of the above experiments and previous
literature,7g,8,14-19 a proposed mechanism for the radical-
triggered three-component reaction of 1a, 2a, and water is
described in Scheme 3. Initially, 1a might be oxidized into
All quinoxaline-2-carbaldehydes (1) and 8 were synthesized
according to the reported literature.8b Substrates 1a-1e,8b 1g,8b
1k,8b 1m,8b 1o,8b 1p,19 1r,8b 1t,8b 1v,8b and 88b are known
compounds and their NMR spectra were consistent with those
reported data. Quinoline-2-carbaldehydes (6a-i) and
phenanthridine-6-carbaldehydes (6j-m) were synthesized from
the oxidation of corresponding 2-methylquinoline and 6-methyl
phenanthridine with SeO2 according to the literature
procedure.20,21 For a typical procedure: 2-methylquinoline 19
(1.4 g, 10 mmol), selenium dioxide (2.0 g, 18 mmol) was added
to a mixture of dioxane (80 mL) and H2O (5 mL) and the mixture
was stirred and heated to reflux for 5 h. Upon completion, the
solvent was removed under vacuum. Then the residue was
dissolved in CH2Cl2 (80 mL), and filtered through Celite.
The filtrate extracted with H2O (80 mL) for three times to
remove redundant selenium dioxide and the organic phase was
collected. After evaporation of the solvent under vacuum, the
residue was purified by column chromatography on silica gel
(100-200 mesh) using petroleum ether-EtOAc (20:1-6:1) as
eluent to give pure 6a (1.3g, 80%). Substrates 6a-6d,21a 6e,21b
6f,21c 6h,21d 6j22 are known compounds and their NMR spectra
were consistent with those reported data. 9 was synthesized
according to the reported procedure, and its spectra were
consistent with the reported one.24 Substrates 1w, 10-12 are
commercially available.
2-
intermediate 13 by the Cu(II)/S2O8 system through a single-
electron-tranfer process (SET).8,14 13 released a proton to form
acyl radical species 14.8 Then the oxidation of 14 via a SET
process followed by the N-addition of the resulting acyl cation
species 16 to 2a leading to intermediate 17.14-16 The cationic
intermediate 17 was trapped by water followed by
a
tautomerization to give the final product 3aa (Path I).15,16 In
addition, a mechanism involved in first N-addition of 14 to the
C≡N triple bond of 1a followed by the formation of intermediate
17 might be also possible (Path II).7g,14,17,18
N
N
Ph
H
N
Ph
4a
N
CO
Protonation
O
15
N
Ph
O
N
Ph
O
N
N
Ph
N
N
Ph
-e
H
H
2-
Cu2+/1/2 S2O8
N
N
+
13
+
H+
Path I
O
Cu(II)
Cu(I)
O
1a
14
16
2-
2O8
S
1/2
2-
MeCN (2a) Path II
MeCN (2a)
Ritter-type reaction
SO4
N
Ph
O
N
Ph
H2O
-e
N
3aa
tautomerization
2-
Cu2+/1/2 S2O8
N
N
N
O
18
17
Scheme 3 Proposed mechanism for the formation of 3aa.
Conclusions
In summary, a copper-catalyzed radical-triggered Ritter-type
reaction has been achieved in a three-component reaction of N-
Typical experimental procedure for the synthesis of N-acetyl-
quinoxaline-2-carboxamides 3
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1 (0.3 mmol), Cu(OTf)2 (21.7 mg, 20 mol % based on 1), 2-carboxamides (7ja-ma) and N-acetylbenzo[d]thiazole-2-
View Article Online
DOI: 10.1039/C9OB00599D
(NH4)2S2O8 (68.5 mg, 0.3 mmol), and CH3CN/H2O = 500:1 (V/V, carboxamide (8a)
3 mL) were added to a 35-mL reaction tube. Then the reaction 6 (0.3 mmol), Cu(OTf)2 (21.7 mg, 20 mol % based on 6), K2S2O8
mixture was stirred at 60 ºC for 6 h. Upon completion, the (81.1 mg, 0.3 mmol, 1 equiv), and CH3CN/H2O = 500:1 were
resulting mixture was diluted with CH2Cl2 (10 mL) and filtered added to a 35-mL reaction tube. Then the reaction mixture was
through Celite. After evaporation of the solvent under vacuum, stirred at 90 ºC for 6 h. Upon completion, the resulting mixture
the residue was purified by column chromatography on silica was diluted with CH2Cl2 (10 mL) and filtered through Celite.
gel (100-200 mesh) using petroleum ether-EtOAc (6:1-3:1) as After evaporation of the solvent under vacuum, the residue was
eluent to give pure product 3.
purified by column chromatography on silica gel (100-200
N-acetyl-3-phenylquinoxaline-2-carboxamide (3aa): Purified mesh) using petroleum ether-EtOAc (10:1-6:1) as eluent to give
by column chromatography (petroleum ether/EtOAc, 6/1-3/1) pure product 7.
1
as a white solid (76.0 mg, 87%). m.p. 116.5168.7 ºC. H NMR
N-acetylquinoline-2-carboxamide (7aa): Purified by column
(500 MHz, CDCl3): δ 10.26 (s, 1H), 8.23 (dd, J1 = 8.5 Hz, J2 = 1.0 chromatography (petroleum ether/EtOAc, 10/1-6/1) as a white
1
Hz, 1H), 8.19 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz, 1H), 7.96–7.93 (m, 1H), solid (52.3 mg, 81%). m.p. 139.2140.8 ºC. H NMR (500 MHz,
7.91–7.87 (m, 1H), 7.68–7.66 (m, 2H), 7.54–7.53 (m, 3H), 2.55 CDCl3): δ 10.69 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.5 Hz,
(s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.2, 162.9, 154.4, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.82–7.78
143.1, 142.0, 138.9, 138.3, 132.9, 131.1, 129.42, 129.37, 129.3, (m, 1H), 7.68–7.65 (m, 1H), 2.66 (s, 3H). 13C{1H} NMR (125 MHz,
128.9, 128.3, 25.3; IR (potassium bromide) (ν, cm-1): 3234 (N-H), CDCl3): δ 172.1, 163.0, 147.6, 146.2, 138.0, 130.7, 129.9, 129.7,
1786 (C=O). HRMS (ESI) for C17H14N3O2 [M + H]+: calcd: 128.9, 127.7, 118.6, 25.3. IR (potassium bromide) (ν, cm-1): 3330
292.1081, found: 292.1090.
(N-H), 1710 (C=O). HRMS (ESI) for C12H11N2O2 [M + H]+: calcd:
215.0815, found: 215.0820.
Typical experimental procedure for the oxidative amidation of
quinoxaline-2-carbaldehyde 1a with different nitriles 2
N-acetylbenzo[d]thiazole-2-carboxamide (8a): Purified by
column chromatography (petroleum ether/EtOAc, 10/1-6/1) as
1
1a (0.3 mmol), Cu(OTf)2 (21.7 mg, 20 mol % base on 1a), and a yellow solid (29.5, 45%). m.p. 155.3158.6 ºC. H NMR (500
(NH4)2S2O8 (68.5 mg, 0.3 mmol, 1 equiv), and the 2/H2O mixture MHz, CDCl3): δ 9.78 (s, 1H), 8.15–8.13 (m, 1H), 8.02–8.00 (m,
(500:1, V/V, 3 mL) were added to a 35-mL tube. Then the 1H), 7.63–7.56 (m, 2H), 2.65 (s, 3H). 13C{1H} NMR (125 MHz,
reaction mixture was stirred at 60 ºC for 6 h. Upon completion, CDCl3): δ 171.2, 161.4, 158.4, 152.4, 137.8, 127.8, 127.4, 125.1,
the resulting mixture was diluted with CH2Cl2 (10 mL) and 122.5, 25.4. IR (potassium bromide) (ν, cm-1): 3348 (N-H), 1711
filtered through Celite. After evaporation of the solvent under (C=O). HRMS (ESI) for C10H9N2O2S [M + H]+: calcd: 221.0379,
vacuum, the residue was purified by column chromatography found: 221.0383.
on silica gel (100-200 mesh) using petroleum ether-EtOAc (6:1-
3:1) as eluent to give pure 3ab-3ag.
N-butyryl-3-phenylquinoxaline-2-carboxamide
Mechanistic studies
(3ab): Reaction of 1a in the Medium of CH3CN-H2O18
Purified by column chromatography (petroleum ether/EtOAc, 1a (70.2 mg, 0.3 mmol), Cu(OTf)2 (21.7 mg, 20 mol % based on
6/1-3/1) as a white solid (78.0 mg, 81%). m.p. 153.5–154.7 ºC. 1a), (NH4)2S2O8 (68.5 mg, 0.3 mmol, 1 equiv.), anhydrous CH3CN
1H NMR (500 MHz, CDCl3): δ 10.14 (s, 1H), 8.23 (dd, J1 = 8.5 Hz, (3 mL), and H2O18 (5 equiv based on 1a) were added to a 35-mL
J2 = 1.0 Hz, 1H), 8.19 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.96–7.87 tube under N2 atmosphere. Then the reaction mixture was
(m, 2H), 7.69–7.66 (m, 2H), 7.54–7.53 (m, 3H), 2.88 (t, J = 7.5 Hz, stirred at 60 ºC for 6 h. Upon completion, the resulting mixture
2H), 1.77–1.69 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125 was diluted with CH2Cl2 (10 mL) and filtered through Celite.
MHz, CDCl3): δ 174.9, 162.9, 154.2, 143.0, 142.4, 138.9, 138.3, After evaporation of the solvent under vacuum, the residue was
132.8, 131.1, 129.41, 129.38, 129.3, 128.9, 128.3, 39.3, 17.4, purified by column chromatography on silica gel (100-200
13.6. IR (potassium bromide) (ν, cm-1): 3235 (N-H), 1735 (C=O). mesh) using petroleum ether-EtOAc (6:1-3:1) as eluent to give
HRMS (ESI) for C19H18N3O2 [M + H]+: calcd: 320.1394, found: pure product. The resulting product 3aa/3aa-O18 sampled for
320.1386.
LRMS analysis (see Figure S1 in ESI).
N-isobutyryl-3-phenylquinoxaline-2-carboxamide
(3ac): Effect of Radical Scavenger TEMPO or BHT on the Model
Purified by column chromatography (petroleum ether/EtOAc, Reaction
6/1-3/1) as a white solid (48.9 mg, 51%). m.p. 209.8210.1 ºC. Procedure (take TEMPO as an example): 1a (70.2 mg, 0.3 mmol),
1H NMR (500 MHz, CDCl3): δ 9.91 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), Cu(OTf)2 (21.7 mg, 20 mol % based on 1a), (NH4)2S2O8 (68.5 mg,
8.19 (d, J = 7.9 Hz, 1H), 7.94-7.91 (m, 1H), 7.89-7.86 (m, 1H), 0.3 mmol, 1 equiv), TEMPO (0.5 equiv; or 2 equiv), and the
7.70-7.69 (m, 2H), 7.53-7.52 (m, 3H), 3.41-3.21 (m, 1H), 1.19 (s, CH3CN/H2O mixture (500:1, V/V, 3 mL) were added to 35-mL
3H), 1.18 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 178.3, 163.4, tube. Then the reaction mixture was stirred at 60 ºC for 6 h.
153.9, 143.4, 142.9, 139.1, 138.2, 132.5, 130.9, 129.46, 129.43, Upon completion, the resulting mixture was diluted with CH2Cl2
129.36, 128.9, 128.4, 35.1, 18.6. IR (potassium bromide) (ν, cm- (10 mL) and filtered through Celite. After evaporation of the
1): 3229 (N-H), 1733 (C=O). HRMS (ESI) for C19H18N3O2 [M + H]+: solvent under vacuum, the residue was purified by column
calcd: 320.1394, found: 320.1391.
chromatography on silica gel (100-200 mesh) using petroleum
Typical experimental procedure for the synthesis of N-acetyl- ether-EtOAc (6:1-3:1) as eluent to give pure product. In the
quinoline-2-carboxamides (7aa-ia), N-acetyl-phenanthridine- presence of 0.5 and 2.0 equiv of TEMPO, 3aa was obtained in
6 | J. Name., 2012, 00, 1-3
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5821; l) X. Wu, S. Wu and C. Zhu, Tetrahedron Lett., 2018, 59,
53% and 0% yield, respectively. In the presence of 0.5 equiv of
BHT, 3aa was obtained in 64% yield. In the presence of 2.0 equiv
of BHT, only trace amount of 3aa was obtained.
View Article Online
1328.
DOI: 10.1039/C9OB00599D
2
Selected recent examples for the radical-triggered
difunctionalization of alkenes, see: a) L. Huang, S.-C. Zheng,
B. Tan and X.-Y. Liu, Org. Lett., 2015, 17, 1589; b) Z.-Q. Xu, C.
Wang, L. Li, L. Duan and Y.-M. Li, J. Org. Chem., 2018, 83, 9718;
c) G. S. Sauer and S. Lin, ACS Catal., 2018, 8, 5175; d) L. Li, Q.-
S. Gu, N. Wang, P. Song, Z.-L. Li, X.-H. Li, F.-L. Wang and X.-Y.
Liu, Chem. Commun., 2017, 53, 4038; e) W.-T. Wei, W.-W. Ying,
W.-H. Bao, L.-H. Gao, X.-D. Xu, Y.-N. Wang and X.-X. Meng, ACS
Sustainable Chem. Eng., 2018, 6, 15301.
Review articles for radical-triggered difunctionalization of
alkynes, see: a) P. Gao, X.-R. Song, X.-Y. Liu and Y.-M. Liang,
Chem. Eur. J., 2015, 21, 7648; b) T. Besset, T. Poisson and X.
Pannecoucke, Eur. J. Org. Chem., 2015, 2765; c) S. R. Chemler,
M. T. Bovino, ACS Catal., 2013, 3, 1076; d) J. Xu and Q. Song,
Chin. J. Org. Chem., 2016, 36, 1151.
Selected recent examples for the radical-triggered
difunctionalization of alkynes, see: a) H. Sahoo, S. Singh and
M. Baidya, Org. Lett., 2018, 20, 3678; b) S. Ni, Y. Zhang, C. Xie,
H. Mei, J. Han and Y. Pan, Org. Lett., 2015, 17, 5524; c) D. P.
Jin, P. Gao, D.-Q. Chen, S. Chen, J. Wang, X.-Y. Liu and Y.-M.
Liang, Org. Lett., 2016, 18, 3486; d) Y. Liu, Q.-L. Wang, C.-S.
Zhou, B.-Q. Xiong, P.-L. Zhang, C.-A. Yang and K.-W. Tang, J.
Org. Chem., 2018, 83, 2210; e) W. Wei, H. Cui, D. Yang, H. Yue,
C. He, Y. Zhang and H. Wang, Green Chem., 2017, 19, 5608; f)
Q. Lu, J. Zhang, G. Zhao, Y. Qi, H. Wang and A. Lei, J. Am. Chem.
Soc., 2013, 135, 11482; g) K. Yan, D. Yang, W. Wei, F. Wang, Y.
Shuai, Q. Li and H. Wang, J. Org. Chem., 2015, 80, 1550.
a) Z. Rappoport, Chemistry of the Cyano Group, John Wiley &
Sons: London, 1970; (b) M.-X. Wang, Acc. Chem. Res., 2015,
48, 602; c) P. Anbarasan, T. Schareina and M. Beller, Chem.
Soc. Rev., 2011, 40, 5049.
Selected examples for the non-radical involved
difunctionalization of the C≡N bond, see: a) Y. Wang, L. Chen,
S. Zhang, Z. Lou, X. Su, L. Wen and M. Li, Org. Lett., 2013, 15,
4794; b) Y. Wang, C. Chen, J. Peng and M. Li, Angew. Chem.,
Int. Ed., 2013, 52, 5323; c) X. Sun, C. Chen, Y. Wang, J. Chen,
Z. Lou and M. Li, Chem. Commun., 2013, 40, 6752; d) L. Zhang,
G. Y. Ang, S. Chiba, Org. Lett., 2010, 12, 3682.
Intermolecular Competition Experiment on 1a and 1a-d
1a-d was synthesized according to the reported procedure.8b
1a-d was obtained in 96%-D enrichment. Analytical data for 1a-
1
d/1a (96/4): H NMR (CDCl3, 400 MHz): δ 10.33 (s, 0.04H, 1a),
8.33 (dd, J1 = 8.4 Hz, J2 = 1.0 Hz, 1H), 8.22 (dd, J1 = 8.4 Hz, J2 =
1.0 Hz, 1H), 7.97-7.86 (m, 2H), 7.74-7,67 (m, 2H), 7.59-7.55 (m,
3H). Procedure: A mixture of 1a (33.7 mg, 0.144 mmol), 1a-d
(96%-D enrichment) (36.7 mg, 0.155 mmol), Cu(OTf)2 (21.7 mg,
20 mol %), (NH4)2S2O8 (68.5 mg, 0.3 mmol), and CH3CN/H2O =
500:1 (V/V, 3 mL) were added to a 35-mL reaction tube. Then
the reaction mixture was stirred at 60 ºC for 70 min. Upon
completion, the resulting mixture was diluted with CH2Cl2 (10
mL) and filtered through Celite. After evaporation of the solvent
under vacuum, the residue was purified by column
chromatography on silica gel (100-200 mesh) using petroleum
ether-EtOAc (10:1-6:1) as eluent to give pure recovered mixture
3
4
1
of 1a and 1a-d. On the basis of H NMR analysis, 1a and 1a-d
were almost equally recovered. Therefore, the kH/kD was
calculated to be 1.0 (Figure S2 in ESI).
Quinoline-3-carbaldehyde 10, benzaldehyde 11, or
butyraldehyde 12 reacted with 2a and water
8 (or 9, 10) (0.3 mmol), Cu(OTf)2 (21.7 mg, 20 mol %), K2S2O8
(81.1 mg, 0.3 mmol, 1 equiv), and CH3CN/H2O = 500:1 were
added to a 35-mL reaction tube. Then the reaction mixture was
stirred at 90 ºC for 6 h. Upon completion, the resulting mixture
was diluted with CH2Cl2 (10 mL) and filtered through Celite.
After evaporation of the solvent under vacuum, samples were
taken for GC-MS analysis. It was found that no desired products
were detected while the starting materials were almost
recovered.
5
6
7
For radical-triggered difunctionalization of the C≡N bond, see:
a) A. Servais, M. Azzouz, D. Lopes, C. Courillon and M. Malacria,
Angew. Chem., Int. Ed., 2007, 46, 576; b) A. Beaume, C.
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P. Sun, J. Org. Chem., 2017, 82, 8148; f) X. Liu, Z. Wu, Z. Zhang,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the Natural Science Foundation of China (No.
21772176 and 21372201) for financial support.
8
9
a) D. Wu, J. Zhang, J. Cui, W. Zhang and Y. Liu, Chem. Commun.,
2014, 50,10857; b) Y. Liu, B. Jiang, W. Zhang and Z. Xu, J. Org.
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Notes and references
1
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