Copper-catalyzed tandem aerobic oxidative cyclization for the synthesis of 4-cyanoalkylpyrrolo[1,2-a]quinoxalines from 1-(2-aminophenyl)pyrroles and cyclobutanone oxime esters

Article abstract of DOI:10.1039/C8CC06256K

A copper-catalyzed tandem ring-opening/cyclization reaction for the synthesis of 4-cyanoalkylpyrrolo[1,2-a]quinoxalines from 1-(2-aminophenyl)pyrroles and cyclobutanone oxime esters has been developed. This reaction involves C-C bond cleavage and C-C and C-N bond constructions with good functional group tolerance. A wide range of products are obtained in moderate to good yields under mild conditions.

Full text of DOI:10.1039/C8CC06256K

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Copper-Catalyzed Tandem Aerobic Oxidative Cyclization for the
Synthesis of the 4-Cyanoalkylpyrrolo[1,2-a]quinoxalines from 1-
(2-Aminophenyl)pyrroles and Cyclobutanone Oxime Esters
Received 00th January 20xx,
Accepted 00th January 20xx
Zhenyu An,a Yong Jiang,b Xin Guan,a Rulong Yan*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) The pr evious wor ks of the reactions of alkenes and cyclobutanone oximes
A copper-catalyzed tandem ring-opening/cyclization reaction for
the synthesis of 4-cyanoalkylpyrrolo[1,2-a]quinoxalines from 1-(2-
aminophenyl)pyrroles and cyclobutanone oxime esters has been
developed. This reaction undergoes the C-C bond cleavage and C-C
and C-N bond constructions with good functional group tolerance.
A wide range of products are obtained in moderate to good yields
under mild conditions.
OBz
R
N
R
coupling reaction
NC
FG
b) Our group's pr evious work
FeCl3, 70% TBHP
n
Y
N
N
Y
N
X
CF3SO3H, tBuOH, rt
R
R
Pyrrolo[1,2-a]quinoxaline derivatives as versatile chemical
structures appear in a series of biologically significant
compounds, which are received particular attentions in the
XH
n
NH2
X = O, S
C
N
,
Y =
pharmaceutical
industry.1
For
instance,
4-
c) T his work
OBz
N
alkapolyenylpyrrolo[1,2-a]quinoxaline has been served as
central 5-HT3 receptor agonists.2 Many excellent
pharmacological compounds with pyrrolo[1,2-a]quinoxaline
scaffolds have also been proven, such as 5-HTR affinities,3 in
vitro antiparasitic,4 anticancer agents,5 and human protein
kinase CK2 inhibitors.6
X
N
X
N
N
Cu(OPiv)2 (10 mol %)
NMP, 80 °C, O2
R1
R1
NH2
CN
R2
R2
X = C, N
Scheme 1 Reactions of cyclobutanone oxime esters.
different molecules through ring-opening of cyclobutanone
oxime esters.11 For example, a direct C−H cyanoalkylaꢀon of
heteroaromatic N-oxides and quinones with cyclobutanone
oxime esters is reported by their group.12 Obviously, almost all
reports about cyclobutanone oxime esters are focusing on the
ring-opening and coupling reaction. The cyclization reaction
for the synthesis of new heterocyclic compounds using
cyclobutanone oxime esters as substrate is rarely investigated.
Recently, our group has successfully synthesized alkylol-
pyrrolo[1,2-a]quinoxalines from 1-(2-aminophenyl)pyrroles
and cyclic ethers via the cleavage of cyclic ethers.13 Thus, we
hypothesize that it is possible to introduce cyanoalkyl moieties
In the past decade, catalytic C-C and C-heteroatom bond
formations have been developed as important protocol for the
synthesis of heterocycles.7 In this field, the C-C bond cleavage
of cyclobutanone oxime esters has attracted considerable
interests, which introduces cyanoalkyl moieties to different
alkenes or alkynes.8 In 2017, the group of Shi reports the
copper-catalyzed intermolecular olefination of cyclobutanone
oxime esters with alkenes initiated by selective C-C bond
cleavage.9 Subsequently, Zhou discloses
a photoredox
approach to generate distal cyano-substituted alkyl radicals
through the C-C bond cleavage of cyclobutanone oxime
esters.10 Recently, the group of Guo and Duan has developed
many strategies to install diverse cyanoalkyl moieties into
into
pyrrolo[1,2-a]quinoxalines
from
1-(2-
aminophenyl)pyrroles and cyclobutanone oxime esters
through the cleavage of cyclobutanone oxime esters. Herein,
we report a new method to build cyanoalkyl-substituted
pyrrolo[1,2-a]quinoxalines from 1-(2-aminophenyl)pyrroles
and cyclobutanone oxime esters through the copper-catalyzed
ring-opening and cyclization reaction.
a.State Key Laboratory of Applied Organic Chemistry, Key laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou, Gansu, China.
Fax: 0931-8912596 E-mail: yanrl@lzu.edu.cn
b.School of Chemistry and Chemical Engineering, Yangtze Normal University,
Chongqing, China.
To identify the best reaction conditions, we started our
investigation from the reaction of 1-(2-aminophenyl)pyrrole
(
1a) with various cyclobutanone O-acyloximes (2) in NMP using
† Electronic Supplementary Information (ESI) available: Experimental procedures
spectroscopic data and X-Ray data. CCDC 1842652. See DOI: 10.1039/c000000x/
Cu(OPiv)2 as catalyst at 80 °C under O2 atmosphere. Various
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Table 2 Scope of substituted 1-(2-aminophenyl)pyrroles a
Table 1 Optimization of the reaction conditions a
Oxidant
(equiv)
Temp Yield
(°C)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
(%) b
Entry 2
Catalyst
Solvent
2a-1
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Pd(OAc)2
FeCl3
O2
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
64
1
2
3
4
2a-2
2a-3
2a-4
2a
O2
68
O2
74
O2
70
O2
80
5
6
2a
O2
0
7
2a
O2
40
8
2a
Cu(OAc)2
CuCl2
O2
61
9
2a
O2
48
10
2a
Cu(OTf)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
O2
65
11 c 2a
12 d 2a
13 e 2a
TBHP (2) NMP
DTBP (2) NMP
50
32
PhIO (2)
air
NMP
NMP
DMF
PhCl
0
14
15
16
17
2a
2a
2a
2a
2a
2a
2a
2a
68
a Reaction conditions: 1 (0.30 mmol), 2a (0.36 mmol), Cu(OPiv)2 (10
O2
69
mol %) in NMP (2 mL) at 80 °C under O2 (balloon) for 8 h.
O2
50
cyclobutanone O-benzoyl oxime 2a as substrate gave the best
result in 80% yield (Table 1, entry 5). Then, several transition-
metal catalysts were examined and the Cu(OPiv)2 was proved
to be the most effective catalyst (Table 1, entries 5-10).
Further investigation revealed that O2 was a better oxidant
than other oxidants (Table 1, entries 11-13). It's worth
mentioning that the desired product was obtained with 68%
yield under air condition. Subsequently, a screening of solvents
was operated and the results indicate that NMP should be
more effective for this reaction than DMSO, DMF, and PhCl
(Table 1, entries 15-17). Meanwhile, increasing the loading of
the Cu(OPiv)2 to 15 mol % or 20 mol % furnished lower yields
than Cu(OPiv)2 (10 mol %) (Table 1, entry 18). Furthermore,
the yield of 2a couldn’t be raised with an increase in the
reaction time (Table 1, entry 19). It was found that lower yields
were obtained when reactions were conducted at 100 °C and
60 °C, respectively (Table 1, entries 20-21). So the optimized
reaction system was established as Table 1, entry 5.
O2
DMSO 80
50
O2
NMP
NMP
NMP
NMP
80
78 f, 75 g
79 h
60
18
O2
80
19
20
O2
100
60
21
O2
75
a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), catalyst (10
mol %), solvent (2 mL) at 80 °C under O2 (balloon) for 8 h. b Yields
of isolated products. c 5.5 M TBHP in decane. d DTBP = di-tert-butyl
e
f
g
peroxide, PhIO = iodosobenzene. Cu(OPiv)2 (15 mol %).
Cu(OPiv)2 (20 mol %). h for 12 h. Entry in bold highlights optimized
reaction conditions, and the reaction time was monitored by TLC.
cyclobutanone O-acyloximes were tested firstly for this
process and all kinds of cyclobutanone O-acyloximes led to the
desired products in good yields (Table 1, entries 1-5). Notably,
With the optimized reaction conditions in hand, we first
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Table 3 Scope of substituted cyclobutanone oxime esters a
OBz
N
N
N
Cu(OPiv)2 (10 mol %)
NMP, 80 oC, O2
NH2
N
CN
R2
2
R2
1a
3
Scheme 3 Proposed mechanism.
scope of cyclobutanone O-benzoyl oximes 2. As shown in Table
3, cyclobutanone O-benzoyl oximes containing benzyl and 4-
methoxybenzyl groups at the C-3 position gave corresponding
products 3ab and 3ac in 65% and 52% yields, respectively.
What’s more, the reaction of 2d and 1a provided product 3ad
in 42% yield. Unfortunately, the method could not be
extended to 2-benzyl cyclobutanone O-benzoyl oxime 2e, only
a Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), Cu(OPiv)2
(10 mol %) in NMP (2 mL) at 80 °C under O2 (balloon) for 8 h;
yields of isolated products.
examined the scope of 1-(2-aminophenyl)pyrroles and the
a
trace amount of 3ae was detected. Meanwhile,
cyclopentanone O-benzoyl oxime 2f failed to give the target
product 3af
results are summarized in Table 2. In general, substrates
1
bearing electron-withdrawing or electron-donating groups
participated well in the reaction to generate the corresponding
.
To probe the mechanism of this transformation, some
control experiments were carried out in Scheme 2. When 1.0
equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added to the reaction system, no desired product was
products. Substrates 1b
-
1g bearing electron-donating groups
3ga in
reacted with 2a, giving corresponding products 3ba
-
moderate to good yields. Notably, 3-methyl- and 3-methoxy-
substituted 1-(2-aminophenyl)pyrroles were compatible with
the reaction conditions better than other electron-donating
groups, furnishing products 3da and 3ga in 74% and 69% yields,
respectively. On the other hand, electron-withdrawing groups,
such as halogen atoms, CF3, and pyrrolyl group, were also
suitable for the optimal condition, providing target products
observed and the alkylated TEMPO 4 was isolated in 63% yield.
As expected, submitting 2,6-di-tert-butyl-4-methyl-phenol
(BHT) to the standard conditions, only 10% yield 3aa was
afforded. The above results indicate that a radical process
should be involved in this transformation. The compound
5
was also prepared and examined under the standard
3ha
-
3sa in 47-80% yields. To our delight, substituted 2-(1H-
1u, and 1v reacted smoothly
conditions. However, no desired product 3aa was detected.
C
([M+H]+ 226.1330)
pyrrol-1-yl)pyridin-3-amines 1t
,
Moreover, the important intermediate
and
([M+H]+ 240.1116) were detected by HRMS analysis
with 2a and the yields were obtained in 46-54%. In addition,
1w as appropriate substrate delivered the product 3wa in 70%
yield.
E
(Figure S1, see the Supporting Information).
Based on preliminary results and literature reports,9,10,11,14
a
Encouraged by above results, we next investigated the
possible mechanism is displayed in Scheme 3. First,
cyclobutanone O-benzoyl oxime 2a undergoes N-O bond
cleavage in the presence of Cun, giving the imino radical
A.
Then, radical
to form radical
proposed. In path a, radical
intermediate . Subsequently, the peroxide intermediate
which is afforded from compound with Cu-promoted
oxidation, generates the intermediate through
decomposition. Finally, intramolecular nucleophilic attack of
the intermediate leads to the product 3aa. In path b, radical
would react with 1a to generate intermediate . But the
cannot transform to the desired product 3aa
A
releases the ring strain of cyclobutane skeleton
. Next, two possible reaction pathways are
reacts with 1a to produce
B
B
C
D,
C
E
E
B
5
intermediate
5
under optimized conditions based on the control experiment.
So the reaction would operated following the path a of
proposed mechanism.
Scheme 2 Control experiments.
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5
(a) V. Desplat, A. Geneste, M.-A. Begorre, S. B. Fabre, S.
Brajot, S. Massip, D. Thiolat, D. Mossalayi, C. Jarry, and J.
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In summary, we have developed
a copper-catalyzed
protocol to introduce cyanoalkyl groups into pyrrolo[1,2-
a]quinoxalines directly via a tandem ring-opening/cyclization
reaction of 1-(2-aminophenyl)pyrroles and cyclobutanone
oxime esters. This transformation presents a good functional
6
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group tolerance and
a series of cyanoalkyl-substituted
pyrrolo[1,2-a]quinoxalines are obtained in moderate to good
yields.
This work was supported by National Natural Science
Foundation of China (21672086), Gansu Province Science
Foundation for Youths (1606RJYA260) and the Fundamental
Research Funds for the Central Universities (lzujbky-2018-81).
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Conflicts of interest
There are no conflicts to declare.
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