Cobalt-Catalyzed Direct C-H Carbonylative Synthesis of Free (NH)-Indolo[1,2- a]quinoxalin-6(5 H)-ones

Article abstract of DOI:10.1021/acs.orglett.0c03900

A cobalt-catalyzed direct C-H carbonylative reaction of N-(2-(1H-indol-1-yl)phenyl)picolinamides for the synthesis of (NH)-indolo[1,2-a]quinoxalin-6(5H)-one skeletons has been developed. Using benzene-1,3,5-triyl triformate (TFBen) as the CO source and picolinamide as the traceless directing group, various free (NH)-indolo[1,2-a]quinoxalin-6(5H)-ones were obtained in good yields (up to 88%). Additionally, a series of product derivatizations were demonstrated, and the core fragment of PARP-1 inhibitor C can be readily constructed by this protocol.

Full text of DOI:10.1021/acs.orglett.0c03900

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Letter
Cobalt-Catalyzed Direct C−H Carbonylative Synthesis of Free
(NH)‑Indolo[1,2‑a]quinoxalin-6(5H)‑ones
Qian Gao, Jia-Ming Lu, Lingyun Yao, Siqi Wang, Jun Ying,* and Xiao-Feng Wu*
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ABSTRACT: A cobalt-catalyzed direct C−H carbonylative reaction of N-(2-(1H-indol-1-yl)phenyl)picolinamides for the synthesis
of (NH)-indolo[1,2-a]quinoxalin-6(5H)-one skeletons has been developed. Using benzene-1,3,5-triyl triformate (TFBen) as the CO
source and picolinamide as the traceless directing group, various free (NH)-indolo[1,2-a]quinoxalin-6(5H)-ones were obtained in
good yields (up to 88%). Additionally, a series of product derivatizations were demonstrated, and the core fragment of PARP-1
inhibitor C can be readily constructed by this protocol.
Scheme 2. C−H Carbonylative Synthesis of Indolo[1,2-
a]quinoxalin-6(5H)-ones
yrrolo[1,2-a]quinoxalin-4(5H)-ones have been considered
Pas a class of privileged scaffolds that are ubiquitous in a
wide range of pharmaceuticals and bioactive compounds.1−3
For instance, as shown in Scheme 1, compound A represents a
type of anti-HIV agent by inhibiting the non-nucleoside
reverse transcriptase.1 Compound B was found to exhibit
remarkable cytotoxic activity against a broad range of human
tumor cell lines as a potent tubulin polymerization and
topoisomerase I inhibitor.2 Compound C serves as a
poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor with
good enzymatic and cellular potency for cancer therapy.3
Moreover, indolo[1,2-a]quinoxalin-6(5H)-ones comprise the
core framework of pyrrolo[1,2-a]quinoxalin-4(5H)-ones and
have also attracted the interests of many scientists due to their
diverse biological activities.4 To assemble the complicated
indolo[1,2-a]quinoxalin-6(5H)-one scaffolds, a few synthetic
methods have been realized.5−8 The common methods involve
the intramolecular condensation of amino carboxylates in
multiple steps.5
On the contrary, transition-metal-catalyzed C−H bond
activation and carbonylation offer a direct and efficient
Scheme 1. Representative Pharmaceuticals and Bioactive
Compounds of Pyrrolo[1,2-a]quinoxalin-4(5H)-ones
Received: November 25, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03900
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Table 1. Screening of the Reaction Conditions
Scheme 3. Scope of N-(2-(1H-Indol-1-
a
yl)phenyl)picolinamides
entry
[Co]
CoCl2
Co(acac)2
Co(OAc)2·4H2O
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
9
PhCOOH
PhCOOH
PhCOOH
AcOH
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
DMSO
dioxane
dioxane
dioxane
dioxane
30
25
11
31
n.r.
45
42
40
trace
60
66
85
53
TFA
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
b
10
11
12
13
b c
,
b cd
,
,
b cde
,
, ,
CoCl2
a
Reaction conditions: 1a (0.2 mmol), Co catalyst (30 mol %),
Ag2CO3 (2.5 equiv), TFBen (3.0 equiv), additive (2.0 equiv), solvent
b
c
(2.0 mL), 130 °C, 20 h, isolated yield. Ag2CO3 (4.0 equiv). Et3N
d
e
(0.5 equiv). PivOH (4.0 equiv). CoCl2 (20 mol %).
approach to access carbonyl-containing compounds.9,10 There
are very limited reports on the direct C−H carbonylative
synthesis of indolo[1,2-a]quinoxalin-6(5H)-ones.11,12 In 2019,
Xu and coworkers developed a palladium/copper-cocatalyzed
C−H activation/N-dealkylative carbonylation of o-indolyl-
N,N-dimethylarylamines under 1 atm (CO/O2 = 1/3) mixed
gas of CO and oxygen for the synthesis of various N-methyl
indolo[1,2-a]quinoxalin-6(5H)-ones (Scheme 2, eq a).11a
Recently, Sankararaman disclosed a palladium-catalyzed C−
H carbonylation of N-substituted 2-(1H-indol-1-yl)anilines
that proceeded well under a CO atmosphere to give N-
substituted indolo[1,2-a]quinoxalin-6(5H)-ones (Scheme 2,
eq b).11b It is important to mention that although oxygen or air
is an ideal oxidant from an atom efficiency and sustainability
point of view, the risk of explosion when combining CO and
O2 gases at a certain ratio should be kept in mind.13 As a part
of our continued interest in C−H carbonylation,14 we now
report a cobalt-catalyzed C−H bond carbonylative synthesis of
free (NH)-indolo[1,2-a]quinoxalin-6(5H)-ones from N-(2-
(1H-indol-1-yl)phenyl)picolinamides and TFBen (Scheme 2,
eq c).
a
At the outset, the N-(2-(1H-indol-1-yl)phenyl)picolinamide
1a was chosen as the model substrate and was reacted with
TFBen (3.0 equiv) in the presence of CoCl2 (30 mol %) as the
catalyst, Ag2CO3 (2.5 equiv) as the oxidant, and PhCOOH
(2.0 equiv) as the additive at 130 °C for 20 h. To our delight,
the desired product 2a was achieved in 30% yield (Table 1,
entry 1). The reaction with Co(acac)2 and Co(OAc)2·4H2O as
the catalyst gave lower yields of 2a (Table 1, entries 2 and 3).
Then, a couple of additives were examined (Table 1, entries
4−6), and the yield was increased to 45% when PivOH was
employed (Table 1, entry 6). Furthermore, using other
solvents such as toluene, DMF, and DMSO gave reduced
yields of 2a (Table 1, entries 7−9). Notably, the reaction yield
was enhanced to 60% when the amount of Ag2CO3 was
increased (Table 1, entry 10). It was found that the addition of
Et3N could slightly promote the reaction to furnish 2a in 66%
Reaction condition: 1 (0.2 mmol), CoCl2 (30 mol %), Ag2CO3 (4.0
equiv), TFBen (3.0 equiv), PivOH (4.0 equiv), Et3N (0.5 equiv),
b
c
dioxane (2.0 mL), 130 °C, 20 h, isolated yield. 150 °C, 20 h. 130
°C, 30 h.
yield (Table 1, entry 11). Gratifyingly, utilizing an increased
loading of PivOH (4.0 equiv) significantly improved the yield
of 2a to 85% (Table 1, entry 12). Finally, a lower reaction yield
(53%) was obtained when the catalyst loading was reduced
(Table 1, entry 13). It is important to mention that Cu(OAc)2,
TBHP, and Mn(OAc)3 were tested as oxidants in place of
Ag2CO3 as well, but no target product could be detected from
these tests.
Next, a series of N-(2-(1H-indol-1-yl)phenyl)picolinamides
1 were investigated under optimal reaction conditions, and the
B
https://dx.doi.org/10.1021/acs.orglett.0c03900
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Scheme 4. Scale-up Reaction and Derivatization of the
Product 2a
Scheme 6. Plausible Mechanism
Scheme 5. Construction of the Core Skeleton 9 of PARP-1
a
Inhibitor C
compound 1s was successfully transformed to the product 2s
in 76% yield. However, the reaction failed when the C3
position of the indole ring was substituted with a phenyl ring.
Notably, the substrate 1t containing a 6-azaindole unit could
be converted to the expected product 2t in 58% yield as well.
Then, a scale-up reaction and a series of derivatization of the
product 2a were performed to demonstrate the utility of this
method (Scheme 4). When the N-(2-(1H-indol-1-yl)phenyl)-
picolinamide 1a (1.0 mmol) was subjected to the standard
reaction conditions, a 72% yield of the product 2a was
achieved smoothly. The treatment of 2a with NaH at 0 °C
followed by the addition of alkyl halides could provide various
N-alkyl-substituted indolo[1,2-a]quinoxalin-6(5H)-ones 3.
The reaction of 2a with methyl iodide gave a good yield
(77%) of compound 3a. When 2a was reacted with allyl
bromide and propargyl bromide, compounds 3b and 3c were
obtained in 62 and 65% yield, respectively.
a
Reagents and conditions: (a) Cs2CO3, DMF, 60 °C, 4 h. (b) Fe,
NH4Cl, H2O, 4 h. (c) DMAP, picolinic acid, EDCI, DCM, 12 h. (d)
CoCl2, Ag2CO3, PivOH, TFBen, Et3N, dioxane, 130 °C, 20 h.
results are shown in Scheme 3. For compounds bearing either
electron-donating or -withdrawing substituents at the C4
position of the benzene ring, the reaction afforded the desired
products 2b−d in 57−65% yields. It was found that the
reaction of compounds with substituents at the C5 position
proceeded well to give the products 2e−f in high yields.
Surprisingly, only trace product 2g was observed when the
substrate 1g with a methyl group at the C6 position was tested.
Here one possible reason for this phenomenon is the steric
effect from the ortho-methyl group, which makes the indole
ring and the aniline not in the same plane and leads to
difficulty in forming a new C−N bond. In addition, when
compounds had substituents such as Me, OMe, Cl, and
COOMe at the C6 position of the indole ring, the reaction
gave the corresponding products 2h−k in moderate to good
yields (48−88%). It was shown that good yields (65−88%) of
the products 2l−o were obtained when substrates with
functional groups at the C5 position were subjected to the
reaction system. Also, C4-substituted compounds could
undergo the reaction smoothly to give the products 2p−r in
high yields (56−82%). Furthermore, the C3-Me-substituted
Furthermore, the core skeleton of PARP-1 inhibitor C can
be easily established by this protocol as well (Scheme 5). The
coupling reaction of pyrrole 4 and the fluoride 5 led to the
formation of the nitro compound 6 in 65% yield. The
subsequent reduction of 6 with iron gave an excellent yield
(90%) of the amine 7, which was then reacted with picolinic
acid to access the picolinamide 8 in 75% yield. Gratifyingly, the
direct C−H carbonylative reaction of 8 under our standard
conditions could successfully construct the crucial pyrrolo[1,2-
a]quinoxalin-4(5H)-one skeleton 9 in 63% yield. Finally,
according to the known procedures,3 PARP-1 inhibitor C can
be synthesized via the reduction of 9 followed by amination.
On the basis of our results and previous reports,14,15
a
plausible mechanism for this cobalt-catalyzed C−H carbon-
ylation of N-(2-(1H-indol-1-yl)phenyl)picolinamides is pro-
posed as shown in Scheme 6. Initially, the coordination of the
Co(II) catalyst with the N-(2-(1H-indol-1-yl)phenyl)-
picolinamide 1a followed by the oxidation of the Ag(I) salt
forms the Co(III) species A′. Then, C−H bond activation at
the C2 position of A′ generates the Co(III) complex B′.
Subsequently, the insertion of CO that is released from TFBen
C
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Letter
(2) Diana, P.; Martorana, A.; Barraja, P.; Montalbano, A.; Dattolo,
G.; Cirrincione, G.; Dall’ Acqua, F.; Salvador, A.; Vedaldi, D.; Basso,
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to the Co(I) complex D′ via reductive elimination. Finally, the
hydrolysis of D′ leads to the formation of the target product 2a
and releases the Co(I) species. The Co(I) species is then
oxidized by the Ag(I) salt to regenerate the active Co(II)
catalyst for the next catalytic cycle.
In conclusion, we have developed a facile and convenient
approach to access free (NH)-indolo[1,2-a]quinoxalin-6(5H)-
ones via a cobalt-catalyzed C−H carbonylation of N-(2-(1H-
indol-1-yl)phenyl)picolinamides with TFBen as the CO source
and picolinamide as the traceless directing group. This method
also provides an efficient alternative for the establishment of
the core skeleton of PARP-1 inhibitor C.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Authors
■
(6) Kong, L.; Sun, Y.; Zheng, Z.; Tang, R.; Wang, M.; Li, Y.
Chemoselective N-H or C-2 arylation of indole-2-carboxamides:
controllable synthesis of indolo[1,2-a]quinoxalin-6-ones and 2,3′-
spirobi[indolin]-2′-ones. Org. Lett. 2018, 20, 5251−5255.
Jun Ying − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China;
Email: yingjun@zstu.edu.cn
Xiao-Feng Wu − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China;
Leibniz-Institut für Katalyse e. V. an der Universität Rostock,
18059 Rostock, Germany; orcid.org/0000-0001-6622-
3328; Email: xiao-feng.wu@catalysis.de
(7) Gogoi, A.; Sau, P.; Ali, W.; Guin, S.; Patel, B. K. Copper(II)-
catalyzed synthesis of indoloquinoxalin-6-ones through oxidative
Mannich reaction. Eur. J. Org. Chem. 2016, 2016, 1449−1453.
(8) Balalaie, S.; Bararjanian, M.; Hosseinzadeh, S.; Rominger, F.;
Bijanzadeh, H. R.; Wolf, E. Designing a sequential Ugi/Ullmann type
reaction for the synthesis of indolo[1,2-a]quinoxalinones catalyzed by
CuI/L-proline. Tetrahedron 2011, 67, 7294−7300.
Authors
(9) For selected reviews on oxidative carbonylation, see: (a) Liu, Q.;
Zhang, H.; Lei, A. Oxidative carbonylation reactions: organometallic
compounds (R-M) or hydrocarbons (R-H) as nucleophiles. Angew.
Chem., Int. Ed. 2011, 50, 10788−10799. (b) Wu, X.-F.; Neumann, H.;
Beller, M. Palladium-catalyzed oxidative carbonylation reactions.
ChemSusChem 2013, 6, 229−241. (c) Gabriele, B.; Mancuso, R.;
Salerno, G. Oxidative carbonylation as a powerful tool for the direct
synthesis of carbonylated heterocycles. Eur. J. Org. Chem. 2012, 2012,
6825−6839. (d) Díaz, D. J.; Darko, A. K.; McElwee-White, L.
Transition metal-catalyzed oxidative carbonylation of amines to ureas.
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G.; Mancuso, R.; Costa, M. Efficient synthesis of ureas by direct
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2004, 69, 4741−4750.
Qian Gao − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Jia-Ming Lu − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Lingyun Yao − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Siqi Wang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03900
Notes
(10) For selected examples of carbonylative C−H activation, see:
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copper Co-catalyzed oxidative C-H/C-H carbonylation of diphenyl-
amines: a way to access acridones. Org. Lett. 2017, 19, 94−97.
(c) Willcox, D.; Chappell, B. G. N.; Hogg, K. F.; Calleja, J.; Smalley,
A. P.; Gaunt, M. J. A general catalytic β-C-H carbonylation of
aliphatic amines to β-lactams. Science 2016, 354, 851−857.
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Li, L.; Xia, C.-G.; Xu, L.-W. Tertiary amine-directed and involved
carbonylative cyclizations through Pd/Cu-cocatalyzed multiple C-X
(X = H or N) bond cleavage. Chem. Sci. 2019, 10, 9292−9301.
(b) Chandrasekhar, A.; Sankararaman, S. Synthesis of indolo- and
pyrrolo[1,2-a]quinoxalinones through a palladium-catalyzed oxidative
carbonylation of the C2 position of indole. Org. Biomol. Chem. 2020,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Joint Funds of
Zhejiang Natural Science Foundation and Taizhou
(LTY21B020001) and the National Natural Science Founda-
tion of China (21772177).
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