Controllable synthesis of pyrido[2,3-: b] indol-4-ones or indolo[3,2- b] quinolines via formal intramolecular C(sp2)-H functionalization

Article abstract of DOI:10.1039/c9ob02108f

A novel Fe-catalyzed protocol for the controllable synthesis of pyrido[2,3-b]indol-4-ones or indolo[3,2-b]quinolines has been developed by using indole-2-carboxylic derivatives as starting materials. Indole-2-carboxenamines were transformed into pyrido[2,3-b]indol-4-ones through intramolecular N-H/C-H coupling, in which a carbonyl 1,2-migration was involved. Whereas, when indole-2-carboxarylamines were employed, indolo[3,2-b]quinolones were produced through direct N-H/C-H coupling. The desired products were obtained under mild reaction conditions in moderate to good yields with wide substrate scope. The natural product quindolinone was conveniently prepared by this reaction.

Full text of DOI:10.1039/c9ob02108f

Organic &
Biomolecular Chemistry
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Controllable synthesis of pyrido[2,3-b]indol-4-
ones or indolo[3,2-b]quinolines via formal
intramolecular C(sp )–H functionalization†
Cite this: Org. Biomol. Chem., 2019,
7, 9960
2
1
a
a
a
a
a
Bo Song,
Mengdan Wang, Murong Xu,
Lingkai Kong,
Huihui Xie,
b
a
Chengyu Wang * and Yanzhong Li
*
A novel Fe-catalyzed protocol for the controllable synthesis of pyrido[2,3-b]indol-4-ones or indolo[3,2-b]
quinolines has been developed by using indole-2-carboxylic derivatives as starting materials. Indole-2-
carboxenamines were transformed into pyrido[2,3-b]indol-4-ones through intramolecular N–H/C–H
coupling, in which a carbonyl 1,2-migration was involved. Whereas, when indole-2-carboxarylamines
were employed, indolo[3,2-b]quinolones were produced through direct N–H/C–H coupling. The desired
products were obtained under mild reaction conditions in moderate to good yields with wide substrate
scope. The natural product quindolinone was conveniently prepared by this reaction.
Received 29th September 2019,
Accepted 8th November 2019
DOI: 10.1039/c9ob02108f
rsc.li/obc
sively studied β- and γ-carbolinones, synthesis procedures for
α-carbolinones are less exploited. Li et al. described the stereo-
Introduction
Transition-metal catalyzed C–H bond functionalization has selective synthesis of α-carbolinones through [4 + 2] annulations
1
1
drawn great attention in synthetic organic chemistry due to its (Scheme 2a). Ye and co-workers disclosed an efficient pro-
atom- and step-economic features. Indole structures have been cedure to obtain α-carbolinones via N-heterocyclic carbene-cata-
1
2
widely used in selective C–H bond functionalization reactions lyzed [3 + 3] annulation reactions (Scheme 2b). Though these
because of their utility in the syntheses of bioactive com- methods were effective, they focused on the synthesis of
1
pounds with an array of pharmaceutical properties. On the α-carbolinones of pyrido[2,3-b]indol-2-ones. Joule and co-
13
other hand, the combination of two biologically active motifs workers disclosed the base-promoted synthesis of indolo[3,2-
2
into one molecule is highly appealing in drug discovery.
b]quinolones using amide nitrogen as a nucleophile, in which
Indole-fused pyridones (including α-, β-, and γ-carbolinones) the indole N should be protected with a phenylsulfonyl group
and indole-fused quinolinones are high-profile skeletons in a (Scheme 2c). A transition-metal mediated or catalyzed synthesis
wide range of indole alkaloids with remarkable biological and procedure for isomeric pyrido[2,3-b]indol-4-one derivatives has
3
pharmacological activities (Scheme 1). Many elegant method- never been reported, to the best of our knowledge. Thus, the
ologies have been developed for the syntheses of development of straightforward and facile procedures for the
β-carbolinones, such as intramolecular Heck reactions of 2- synthesis of pyrido[2,3-b]indol-4-ones or indolo[3,2-b]quinolines
4
5
and 3-iodoindoles, intramolecular C–H activation, Au-cata- from easily accessible starting materials is highly desirable.
6
lyzed cycloismerization, and cation-mediated [3 + 3] cycliza-
tion; the synthesis approaches toward γ-carbolinones are also γ-carbolinones via Pd-catalyzed dual C(sp )–H functionali-
Recently, we have developed an efficient procedure to
7
2
well established, including Pd-catalyzed intramolecular dehy-
8
drogenative annulation, acid catalyzed intramolecular acyla-
9
tion of 2-substituted indole derivatives, and amination of
1
0
indole-3carboxylic acid. However, compared with the inten-
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of
Chemistry and Molecular Engineering, East China Normal University, 500
Dongchuan Road, Shanghai, 200241, China. E-mail: yzli@chem.ecnu.edu.cn
b
School of Chemistry and Chemical Engineering, Linyi University, Shuangling Road,
Linyi, Shandong, 276000, China
†
Electronic supplementary information (ESI) available. CCDC 1943909 and
943920. For ESI and crystallographic data in CIF or other electronic format see
1
DOI: 10.1039/c9ob02108f
Scheme 1 Some bioactive compounds with indole-fused heterocycles.
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a
Table 1 Optimization studies for the formation of 2a
b
Catalyst
Yield
Entry
(mol %)
[O] (equiv.)
(NH
Solvent
T (°C)
(%)
1
2
3
4
5
6
7
8
9
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
3
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
4 2
) S
O
2 8
(5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMAc
Toluene
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
80
60
60
60
60
60
60
60
60
30
3
3
3
3
3
TBHP
(5)
DDQ (5)
Ag CO
Trace
Trace
—
—
70
53
44
56
47
59
41
21
34
Trace
—
H O
2 2
2
3
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(3)
(4)
(6)
(4)
(4)
(4)
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
8
Cu(OAc)
Cu(OTf)
Fe (SO
FeSO (10)
Sc(OTf) (10)
AgOTf (10)
ZnCl (10)
2
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
2
2
4
)
3
(10)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4
3
2
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
—
3
3
3
3
3
3
3
3
3
3
3
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(5)
—
48
57
c
d
49
74
55
58
63
47
—
68
Scheme 2 Synthesis of indole-fused heterocycles.
(15)
Fe(OTf)
Fe(OTf)
3
(10)
(10)
—
e
1
4
27
3
K
2
S O
2 8
(4)
zation of indole-2-carboxamides involving 1,2-acyl migration.
a
We have also reported novel methodologies for the synthesis
Unless otherwise noted, all reactions were carried out under nitrogen
b
1
5
on a 0.2 mmol scale in the solvent (2 mL) at 60 °C. Isolated yields.
heterocycles based on enaminone chemistry. We envisioned
that pyrido[2,3-b]indol-4-one derivatives might be generated
via 1,2-acyl migration using 2-substituted indoles tethered to
an enaminone moiety. Due to continuous interest in the C–H
c
d
The reaction was carried out at 40 °C. The reaction was carried out
e
at 80 °C. The reaction was carried out in air.
1
6
functionalization chemistry of substituted indole derivatives,
(2a) was formed in 30% yield in the presence of 10 mol% of Fe
(OTf) and 5.0 equiv. of (NH as an oxidant in DMSO
(dimethyl sulfoxide) at 60 °C (entry 1). The structure of this
we herein report an efficient protocol for the selective syn-
thesis of pyrido[2,3-b]indol-4-one through C3-H/N–H
functionalization involving the 1,2-acyl migration from indole-
3
4 2 2 8
) S O
product was further confirmed by X-ray crystal analysis (see
the ESI†), and it meant that a rearrangement of the acyl group
from C-2 to the C-3 position of the indole ring did occur as we
expected. When the reaction was carried out using TBHP or
2
-enaminones. Furthermore, substrates of this methodology
could be applied to indole-2-carboxarylamines, which afforded
indolo[3,2-b]quinolones through the direct N–H/C–H coupling
reaction (Scheme 2d). These compounds contain the same
molecular skeleton as that of alkaloid quindolinone
H
(
(
2
O
2
as the oxidant, only a trace amount of 2a was detected
entries 2 and 3). DDQ or Ag CO also gave no products
entries 4 and 5). Interestingly, K S O resulted in a much
2
3
(Scheme 1, I), which could be converted into the cryptolepine
2
2 8
alkaloid analogs showing antimalarial activities and strong
higher yield of 2a (entry 6). Other catalysts, such as Cu(OAc)
Cu(OTf) Fe (SO FeSO Sc(OTf) AgOTf and ZnCl
afforded slightly lower yields (entries 7–13). Based on the
2
,
3
i–k
antiplasmodial activities.
2
,
2
4
)
3
,
4
,
3
,
2
optimal catalyst of Fe(OTf)
N-dimethylformamide),
3
, other solvents including DMF (N,
DMAc (N,N-dimethylacetamide),
Results and discussion
toluene and dioxane were screened, and no better results were
We commenced feasibility studies with indole-2-carboxena- obtained (entries 14–17). Decreasing or increasing the reaction
mine 1a as a model substrate (Table 1). It should be noted that temperature in DMSO gave lower yields of the desired product,
1
4a
when 1a was subjected to our previous system
10 mol%), Cu(OAc)
(3.0 equiv.), and PivOH (6.0 equiv.) in the corresponding 2a in only 49% yield (entry 20). To our
DMF at 140 °C for 9 hours), no reaction occurred. We were delight, the desired product 2a was formed in 74% yield with
(Pd(OAc)2 respectively (entries 18 and 19). 3.0 equiv. of K S O rendered
2 2 8
(
2
encouraged to find that the desired pyrido[2,3,b]indol-4-one 4.0 equiv. of K
S O (entry 21). Further increasing the amount
2 2 8
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of K
2
S
2
O
8
to 6.0 equiv. provided 55% yield (entry 22). When Fe as benzyl and n-butyl, no desired products could be obtained.
3
(OTf) was reduced to 5 mol%, the corresponding 2a was furn- Then, the effect of different groups (R ) on the alkene moiety
3
ished in a lower yield of 58%. Whereas, increasing the catalyst was investigated. It was found that the electron-donating aryl
loading to 15 mol% did not result in a better yield (entry 24 vs. groups (4-Me, 4-OMe) worked well under the standard con-
entry 21). Surprisingly, 2a could be obtained in the absence of ditions, affording the desired products 2p and 2q in 53% and
Fe(OTf)
3
, albeit in a low yield (entry 25). However, no reaction 46% yields, respectively. The electron-withdrawing aryl group
(entry 26). When the 4-Cl gave a low yield of 2r. For alkyl groups, a methyl substi-
occurred without the addition of K
2 2 8
S O
reaction was carried out in air, a lower yield of the desired tuted substrate resulted in only 22% of the carbolinone 2s.
1
product was observed (entry 27). Finally, the optimized reac- Finally, we investigated the substituent (R ) effect on the
tion conditions were concluded to be 10 mol% Fe(OTf)
.0 equiv. K S O in DMSO at 60 °C under N (entry 21).
3
and indole ring. Substrates with electron-rich (7-Me, 5-OMe) and
electron-deficient (5-Cl) groups all gave the desired products
4
2
2
8
2
With the optimal conditions established, we explored the 2u–2w in moderate yields. However, no desired product could
scope of this N-arylation reaction for the synthesis of pyrido be detected when N-methyl was replaced with Ts, Boc or H. A
2,3-b]indol-4-ones using a series of indole-2-carboxenamines gram-scale reaction for the synthesis of 2a could be conducted
Table 2). Firstly, we examined the electronic effects of various as well, delivering the desired product in 58% yield (610 mg),
[
(
2
N-aryl substituents (R ). The electron-donating aryl substitu- which nicely demonstrated the practical utility of this method-
ents (4-Me, 4-Et, 4- Bu, 3,4-diMe, 3,5-diMe, and 4-OMe) were ology (see the ESI†).
n
efficiently converted to the desired products 2b–2f in good
Next, we tried to further explore the substrate scope of this
yields. The –OMe group could even be conveniently incorpor- C–H/N–H coupling reaction. We reasoned that the replacement
ated at the 3- and/or 4-position of the aryl ring (2g–2i). The of the vinyl moiety in 1 with aryl groups might result in the for-
electron-withdrawing aryl groups (4-F or 4-Cl) smoothly mation of tetracyclic compounds, which contain a similar
resulted in the corresponding products in good yields (2j, 2k). molecular skeleton to alkaloid quindolinone (Scheme 1, I).
Other aryl substituents including the bulky 1-naphthyl and Then, substrate 3a was prepared and subjected to the optimal
5
-dihydro-indenyl also afforded the desired 2n and 2o in 53% reaction conditions. It is surprising that the corresponding
2
17
and 59% yields, respectively. When R were alkyl groups, such product 4a has exactly the same molecular skeleton as that
of alkaloid quindolinone (Scheme 1, I). This indicated that the
direct C–H/N–H coupling occurred without acyl migration in
a
Table 2 Scope of the indolyl enaminone 1
this reaction. The substrate feasibility was also examined, and
1
the results are shown in Table 3. R substituents either with
electron-donating (7-Me, 5-OMe) or electron-withdrawing
(
6-Cl) groups were suitable for the reaction, offering the corres-
ponding indolo[3,2-b]quinolones in 67% to 85% yields (4a–4d)
among which electron-rich aryl groups gave slightly higher
yields (4b, 77% yield; 4c, 85%) than those with electron-poor
a
Table 3 Synthesis of indolo[3,2-b]quinolones
a
a
Reaction conditions: 1 (0.3 mmol), Fe(OTf)
3
(10 mol%), K
2
2
S O
8
3 2 2 8
Reaction conditions: 1 (0.2 mmol), Fe(OTf) (10 mol%), K S O
(
1.2 mmol) in DMSO (3 mL) at 60 °C under nitrogen unless otherwise (0.8 mmol) in DMSO (2 mL) at 60 °C under nitrogen unless otherwise
noted. Isolated yields.
noted. Isolated yields.
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4
aryl groups (4d, 67% yield). For the R substituents, good
yields were obtained with either electron-rich or -poor aryl
2
groups (4e–4i). It is noteworthy when R is H, the reaction
could also proceed smoothly, affording the desired products in
1
8
high yields (4k, 4l). The natural product quindolinone (4k)
was conveniently prepared in 76% yield in this reaction. Even
3
when R is a methyl group, the corresponding 4m was
obtained in 27% yield. However, no desired product could be
3
detected when R is a Ts group.
In order to gain further insight into the reaction mecha- Scheme 5 Possible reaction pathway to 4a.
nism, radical trapping experiments were employed using
indole-2-carboxenamine 1a as the substrate. The reaction was
not inhibited by the addition of 2,2,6,6-tetramethyl-
piperidinoxy (TEMPO, 3.0 equiv.) or butylated hydroxytoluene
(
(
BHT, 2.0 equiv.), and 2a was still obtained in moderate yields
Scheme 3).
The results suggested that a radical pathway might not be
involved in this reaction.
Based on the above observations and the reported litera-
14
ture, a plausible reaction mechanism for the formation of 2a
is proposed (Scheme 4). Initially, substrate 1a reacts with Fe
(
3
OTf) to generate the iminium intermediate A, which may tau-
Scheme 6 Further modification of pyrido[2,3,b]indol-4-one.
tomerize to intermediate B. Then, a nucleophilic attack of the
vinyl amine to the iminium moiety results in the spiro inter-
mediate C, which is further converted to the intermediate D
through nucleophilic addition. Subsequently, intermediate D
undergoes 1,2-acyl migration to give intermediate E. Finally,
the desired product 2a is generated through protonation fol-
lowed by oxidative aromatization.
pathway to 4a is shown in Scheme 6. It is interesting that inter-
mediate A was formed from 1a (Scheme 4), whereas, inter-
mediate G was achieved through 3a (Scheme 5) at the begin-
ning of these reactions. We could see clearly from the H NMR
1
of 1a that there is hydrogen bonding between the carbonyl
oxygen and the hydrogen of amine (δ N–H 12.47 ppm), which
prevents the coordination of carbonyl oxygen to the Fe catalyst,
facilitating the formation of A from 1a. On the other hand,
there is no intramolecular hydrogen bonding between the car-
bonyl oxygen and the hydrogen of amine in 3a (δ N–H
1
9
A proposed reaction
5.87 ppm). Thus, coordination of carbonyl oxygen to the Fe
catalyst may occur to form intermediate G, which facilitates
the next intramolecular Michael addition reaction (Scheme 5).
To demonstrate the versatility of this C–H/N–H coupling
reaction, transformations of the thus formed pyrido[2,3,b]
indol-4-ones were performed. As shown in Scheme 6, 2a could
be easily converted to the corresponding 3-trifluoromethyl
derivative 5a in 53% yield. It also reacted readily with NBS to
give 3-bromo derivative 5b in 78% yield. X-ray crystal analysis
confirms the structure of 5b (see the ESI†). Moreover, 5b
underwent Suzuki coupling smoothly to give the phenylated
product 5c.
Scheme 3 Control experiment.
Conclusions
In summary, we have developed an atom-economical Fe-cata-
lyzed protocol for the controllable synthesis of pyrido[2,3-b]
indol-4-ones or indolo[3,2-b]quinolines through C–H/N–H
coupling reactions. The intramolecular hydrogen bonding
between the carbonyl oxygen and the hydrogen of amine in
the starting materials may account for the selectivity of the
outcomes.
Scheme 4 Proposed reaction mechanism for 2a.
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3
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1
,9-dihydro-4H-pyrido[2,3-b]indol-4-one
A typical procedure for the synthesis of 2a is as follows: indolyl
enaminone 1a (0.2 mmol, 70.5 mg), Fe(OTf) (0.02 mmol,
0.1 mg), K (0.8 mmol, 216.3 mg) and DMSO (2.0 mL)
3
1
2 2 8
S O
were placed in an Schlenk tube under N . Then the reaction
2
mixture was allowed to react at 60 °C for 4 h. After the reaction
was completed as monitored by thin-layer chromatography,
the reaction mixture was then quenched with water, and the
water layers were extracted with ethyl acetate (20 mL × 3). The
combined organic layers were washed with brine, dried over
anhydrous Na SO , filtered, and concentrated under reduced
pressure. Purification by chromatography on silica gel (di-
chloromethane/ethyl acetate = 1 : 1) afforded the desired com-
pound 2a.
2
4
1
5, 6353; (k) C. W. Wright, J. Addae-Kyereme, A. G. Breen,
General procedure for the synthesis of 10-methyl-5,10-dihydro-
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1
1H-indolo[3,2-b]quinolin-11-one
A typical procedure for the synthesis of 4a is as follows: the
substrate 3a (0.2 mmol, 50.1 mg), Fe(OTf) (0.02 mmol,
0.1 mg), K S O (0.8 mmol, 216.3 mg) and DMSO (2.0 mL)
3
1
2
2 8
were placed in a Schlenk tube under N
2
. Then the reaction
5 L. Li, B. Zhou, Y.-H. Wang, C. Shu, Y.-F. Pan, X. Lu and
L.-W. Ye, Angew. Chem., Int. Ed., 2015, 54, 8245.
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mixture was allowed to react at 60 °C for 2 h. After the reaction
was completed as monitored by thin-layer chromatography,
the reaction mixture was then quenched with water, and the
water layers were extracted with ethyl acetate (20 mL × 3). The
combined organic layers were washed with brine, dried over
2 4
anhydrous Na SO , filtered, and concentrated under reduced
pressure. Purification by chromatography on silica gel (pet-
roleum ether/ethyl acetate = 4 : 1) afforded the desired com-
pound 4a.
9 L. Li, X. Zhou, B. Yu and H. Huang, Org. Lett., 2017, 19,
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Conflicts of interest
11 K.-C. Yang, Q.-Z. Li, Y. Liu, Q.-Q. He, Y. Liu, H.-J. Leng,
A.-Q. Jia, S. Ramachandran and J.-L. Li, Org. Lett., 2018, 20,
There are no conflicts to declare.
7
518.
2 L. Yi, Y. Zhang, Z.-F. Zhang, D. Sun and S. Ye, Org. Lett.,
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1
1
1
2
Acknowledgements
1
We thank the National Natural Science Foundation of China
(
grant no. 21272074, 21871087, and 21702088) for financial
support.
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