Synthesis of pyrrolo[1,2-: A] quinoxalines via copper or iron-catalyzed aerobic oxidative carboamination of sp3C-H bonds

Article abstract of DOI:10.1039/c7ra09214h

An aerobic oxidative carboamination of sp³C-H bonds with 2-(1H-pyrrol-1-yl)anilines has been developed. The oxidative carboamination processes utilized simple and readily available starting materials to produce pyrrolo[1,2-a]quinoxalines in good to moderate yields. The transformations also featured inexpensive metal catalysts (copper or iron) and a green oxidant (O₂).

Full text of DOI:10.1039/c7ra09214h

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Synthesis of pyrrolo[1,2-a]quinoxalines via copper
or iron-catalyzed aerobic oxidative carboamination
of sp C–H bonds†
Cite this: RSC Adv., 2017, 7, 44132
3
Chenshu Dai, Siqi Deng, Qiuhua Zhu * and Xiaodong Tang
*
Received 21st August 2017
Accepted 6th September 2017
3
An aerobic oxidative carboamination of sp C–H bonds with 2-(1H-pyrrol-1-yl)anilines has been developed.
The oxidative carboamination processes utilized simple and readily available starting materials to produce
pyrrolo[1,2-a]quinoxalines in good to moderate yields. The transformations also featured inexpensive metal
DOI: 10.1039/c7ra09214h
rsc.li/rsc-advances
2
catalysts (copper or iron) and a green oxidant (O ).
The pyrrolo[1,2-a]quinoxalines are an important class of was just suitable for alkyl alcohols, and required alcohols as
heterocyclic compounds which are present in various biologi- solvents and high reaction temperature. Subsequently,
cally active agents. For example, some substituted pyrrolo[1,2-a] a method which utilized DMSO not only as solvent but also as
quinoxaline derivatives promised utilization for novel and the substrate for the synthesis of pyrrolo[1,2-a]quinoxalines was
1
11i
highly potent 5-HT receptor agonists. And 4-substituted pyr- reported by Ma (Scheme 1d). This was a good transformation
3
rolo[1,2-a]quinoxalines could specically inhibit the D-loop but only C4 no-substituted products were obtained. Therefore,
2a
activity of RAD51. Recently, Mai, Steegborn et al. presented it is highly desirable to develop new method for the construc-
a good work about using pyrrolo[1,2-a]quinoxaline derivatives tion of this important skeleton.
2
b
as Sirt6 activators. Furthermore, many pyrrolo[1,2-a]quinoxa-
On the other hand, direct transformations of inert chemical
3
line derivatives have been proven to possess other biological bonds especially sp C–H bonds play an important role in
activities, including antimalarial activity, antitumor activity,
HIV-1 reverse transcriptase inhibitors, human protein kinase an ideal reaction system for carbon–carbon and carbon–
CK2 inhibitors, PARP-1 inhibitors, non-peptide glucagon heteroatom bonds formation because copper catalysts are
receptor antagonists, and so on. They are also used as uo- inexpensive and low-toxic and molecular oxygen as an oxidant is
rescent probes for amyloid bril. In 1965, Cheesman and Tuck
3
4
12
sustainable chemistry. A copper/O system could be viewed as
2
5
6
7
8
9
groups rstly presented the method for the synthesis of pyrrolo
[1,2-a]quinoxaline compounds via the reactions between 2-(1H-
pyrrol-1-yl)anilines and formic acid under reux conditions
10
(
Scheme 1a). Aerward, many protocols for the preparation of
pyrrolo[1,2-a]quinoxalines have been developed one aer
11
another. Among them, the cyclization reactions involving 2-
1H-pyrrol-1-yl)anilines have always been the most active part.
And it was most reported to utilize 2-(1H-pyrrol-1-yl)anilines
(
11e–g
and aldehydes as the starting materials (Scheme 1b).
However, these methods suffered from some drawbacks such as
tedious procedure, strong oxidant, poor substrate applicability,
and so on. In 2017, Jiang and co-workers reported a green
aerobic oxidative synthesis of pyrrolo[1,2-a]quinoxalines from
11h
simple alcohols (Scheme 1c). However, the transformation
Guangdong Provincial Key Laboratory of New Drug Screening, School of
Pharmaceutical Sciences, Southern Medical University, 1023 South Shatai Road,
Baiyun District, Guangzhou 510515, P. R. China. E-mail: zhuqh@smu.edu.cn;
tangxdong@smu.edu.cn
†
Electronic supplementary information (ESI) available: Experimental section,
1
13
characterization of all compounds, Fig. S1, copies of H and C NMR spectra
for all target compounds. See DOI: 10.1039/c7ra09214h
Scheme 1 Synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-amino-
phenyl)pyrrole.
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easily available and environment friendly. Recently, the DMSO, PhCl, and toluene (entries 10–12). Different acids, such
aerobic copper-catalyzed transformations of methylhetarenes as AcOH, Ph PO H and TfOH were investigated, and the results
2
2
1
4a
have attracted increasing attention, such as esterication,
indicated that they were no better than TFA (entries 13–15).
When the reaction was carried out in the absence of a copper
14b,c
14d,e
14f–h
amidation,
oxygenation,
oxidative cross-coupling.
However, it remains scarce that applying these reactions to catalyst, no product was formed and if the reaction proceeded
14i,j
construct N-heterocycles.
Herein, we disclose a new aerobic without the acid, the yield of the desired heterocyclic product
copper-catalyzed cyclization reaction of 2-methylpyridine/ was very low (entries 16–17). The increase or decrease of reac-
quinoline with 2-(1H-pyrrol-1-yl)anilines for synthesis of pyr- tion temperature led to a diminished yield (entries 18–19).
rolo[1,2-a]quinoxalines (Scheme 1e).
Lower yield was obtained when the reaction was conducted in
Initially, the reaction of 2-(1H-pyrrol-1-yl)aniline 1a (0.3 the oper air (entry 20). Furthermore, no product was obtained
mmol) with 2-methylpyridine 2a (0.6 mmol) in 3 mL solvent for under N atmosphere (entry 21). Thus, the optimized reaction
2
1
2 h under a O atmosphere was chosen as the model reaction system for this aerobic oxidative carboamination reaction was:
2
to examine various reaction parameters and the results were 1a (0.3 mmol), 2a (0.6 mmol), Cu(OAc)
2
(0.06 mmol), TFA (0.3
ꢀ
summarized in Table 1. Our experiment began by reacting 1a mmol), and DMF (3 mL) under O
2
atmosphere at 120 C for
ꢀ
and 2a in DMF at 120 C in the presence of Cu(OTf)
2
(0.06 12 h.
With the optimal conditions established (Table 1, entry 2),
pyridin-2-yl)pyrrolo[1,2-a]quinoxaline (3a) was obtained in 48% we started to examine the reaction scope of the present trans-
mmol) and TFA (0.3 mmol). To our delight, the target product 4-
(
yield (entry 1). Several other copper salts were then screened, formation and the results were summarized in Table 2. Various
including Cu(OAc) , CuCl , CuBr , Cu(NO ) , CuCl, CuI, CuBr 2-methylpyridine reacted with 2-(1H-pyrrol-1-yl)aniline were
2
2
2
3 2
and CuCN. Our experimental results showed that all copper rstly examined and all of the reactions afforded the corre-
catalysts could catalyze the transformation to some extent and sponding pyrrolo[1,2-a]quinoxalines in moderate yields (Table
Cu(OAc) was most efficient (entries 2–9). Among the solvents 2, 3a–3e). When 2-methylquinoline was used as substrate, the
2
tested, DMF was found to be the most effective in comparison to yield of product was up to 85% (Table 2, 3f). Similarly, 2,6-
dimethylquinoline, 6-uoro-2-methylquinoline and 7-uoro-2-
methylquinoline also gave the expected cyclization products
a
Table 1 Optimization of the reaction conditions
3g, 3h and 3i in 72%, 58% and 54% yields, respectively. Finally,
the reaction of 5-methyl-2-(1H-pyrrol-1-yl)aniline with 2-meth-
ylquinoline could produce 7-methyl-4-(quinolin-2-yl)pyrrolo
[1,2-a]quinoxaline in 67% yield (Table 2, 3j).
It was amazing that the product pyrrolo[1,2-a]quinoxaline 4a
was formed when we treated 1a with Fe catalyst in DMSO, which
Entry
[Cu]
Additive
Solvent
Yield (%)
Table 2 Substrate scope of pyrrolo[1,2-a]quinoxalines via copper-
catalyzed cyclization reaction
a
1
2
3
4
5
6
7
8
9
Cu(OTf)
2
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
PhCl
Toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
48
78
64
67
70
65
45
54
52
63
n.d.
n.d.
37
41
56
n.d.
15
68
Cu(OAc)
CuCl
CuBr
Cu(NO
CuCl
CuI
2
2
2
3
)
2
CuBr
CuCN
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
—
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
Ph
2
PO
2
H
TfOH
TFA
—
TFA
TFA
TFA
TFA
2
2
2
2
2
b
c
59
64
n.d.
d
e
a
Reaction were performed with 1a (0.3 mmol), 2a (0.6 mmol), [Cu] (0.06
mmol), acid (0.3 mmol) in solvent (3.0 mL) under O
2
atmosphere for
b
1
2
h. Isolated yield. n.d.
¼
not determined.
The reaction
ꢀ
c
ꢀ
d
a
temperature was 110 C. The reaction temperature was 130 C. The
Reactions were performed with 1 (0.3 mmol), 2 (0.6 mmol), Cu(OAc)
2
2
e
ꢀ
reaction was under air. The reaction was under N
2
atmosphere.
(20 mol%), TFA (0.3 mmol) and DMF (3 mL) at 120 C under O
atmosphere for 12 h. Yields referred to isolated yields.
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Table 3 Substrate scope of pyrrolo[1,2-a]quinoxalines via iron-cata-
a
lyzed cyclization reaction
a
Reaction conditions: 1 (0.3 mmol), Fe(0) (20 mol%), AcOH (0.3 mmol), Scheme 3 Possible reaction mechanism.
ꢀ
and DMSO (3 mL) at 100 C under air atmosphere for 12 h. Yields
referred to isolated yields.
(1)). Except for the generation of the product 3a (32% yield), 2-
pyridinecarboxaldehyde 5a was obtained in 10% yield. When 2-
pyridinecarboxaldehyde 5a was allowed to react with 1a, the
pyrrolo[1,2-a]quinoxalins 3a was formed in 81% yield (Scheme
revealed that DMSO also served as C1 source in the oxidative
11i
cyclization reaction. Compared with previous work,
our
reaction proceeded with lower reaction temperature. Where
aer, we optimized the reaction conditions based on Fe catalyst
and the best reaction condition were as follows: 1a (0.3 mmol),
2, eqn (2)). These results indicated that 5a perhaps served as the
key intermediate in the cyclization reaction. When we added
a radical-trapping reagent (TEMPO) or a radical inhibitor (BHT)
to the reaction system, no product was detected. These obser-
vations demonstrated that there should be a radical pathway in
ꢀ
Fe(0) (20 mol%), AcOH (0.3 mmol) in DMSO (3 mL) at 100 C for
12 h (see the ESI† for details). Then, various 2-(1H-pyrrol-1-yl)
aniline 1 were examined in the cyclization reaction and the
results were summarized in Table 3. Different substituted 2-(1H-
pyrrol-1-yl)aniline could be converted into the corresponding
pyrrolo[1,2-a]quinoxaline in moderate to good yields, and
electron-withdrawing groups did not show a positive effect on
our reaction (Table 3, 4a–4e).
To gain more insight into the mechanism, some control
experiments shown in Scheme 2 were carried out. Firstly, the
reaction of 1a and 2a under standard conditions was inter-
rupted aer 1.0 h to analyze the intermediates (Scheme 2, eqn
this reaction.
11,14
According to previous studies
results above, we proposed the mechanism shown in Scheme 3.
Initially, 1a isomerizes to a nonaromatic enamine intermediate
A in the presence of acid.
reacts with the copper species to afford intermediate B and
further combines with the oxygen to generates peroxycopper
intermediate C.
and our experimental
14a,b,i,j
Where aer, intermediate A
14b,j
Intermediate C transforms to intermediate
n
D and subsequent elimination of Cu OH produces aldehyde
14b,j
5
a.
presence of Fe catalyst with O
or G is formed by dehydration condensation of 5a or CH O with
DMSO could decompose and produce CH
2
O in the
1
1i,14k,14l
2
.
The imine intermediate E
2
1
a, which cyclize to generate intermediate F or H through
11g
intramolecular Mannich reaction. Finally, oxidation of inter-
mediate F or H provides the nal product 3a or 4a.
11e–g
In conclusion, we have developed a copper or iron-catalyzed
3
direct aerobic oxidative carboamination of sp C–H bonds with
2
-(1H-pyrrol-1-yl)aniline. These methods afforded a novel
approach for the construction of biologically important pyrrolo
1,2-a]quinoxaline skeleton from readily available materials
[
using inexpensive metal catalysts and green oxidant (O2).
Further research for the mechanism and the synthetic appli-
cations are ongoing in our laboratory.
Conflicts of interest
Scheme 2 Control experiments.
There are no conicts to declare.
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