Rh(iii)-Catalyzed C(sp2)-H functionalization/cyclization cascade of: N -carboxamide indole and iodonium reagents for access to indoloquinazolinone derivatives

Article abstract of DOI:10.1039/d1gc01820e

A rhodium-catalyzed synthesis of indoloquinazolinone from a readily available hypervalent iodonium reagent and N-carboxamide indole was developed. The protocol features broad functional group tolerance, mild conditions, and excellent yields. The target products were obtained simply by filtration, without tedious column chromatography. Notably, the noble metal catalyst system can be recycled effectively at least ten times. The strategy may be amenable to industrial production.

Full text of DOI:10.1039/d1gc01820e

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2
Rh(III)-Catalyzed C(sp )–H functionalization/
cyclization cascade of N-carboxamide indole
and iodonium reagents for access to
indoloquinazolinone derivatives†
Cite this: Green Chem., 2021, 23,
337
6
Received 23rd May 2021,
Accepted 30th July 2021
DOI: 10.1039/d1gc01820e
a
a
a
a,b
Zhi-Peng Han, Meng-Meng Xu, Rui-Ying Zhang, Xiao-Ping Xu
Shun-Jun Ji
*
and
a
rsc.li/greenchem
*
A rhodium-catalyzed synthesis of indoloquinazolinone from a bond formation from O-aminoacetophenones and aryl isocya-
readily available hypervalent iodonium reagent and N-carb- nates, however, 1.5 equiv. of Ag CO was required as an
2
3
9
oxamide indole was developed. The protocol features broad func- oxidant. Zhang’s group established the Rh(III)-catalyzed
tional group tolerance, mild conditions, and excellent yields. The C(sp )–H activation of N-carboxamide indoles with sulfoxo-
2
target products were obtained simply by filtration, without tedious nium ylides for the preparation of [1,3]oxazino[3,4-a] indol-1-
1
0
6
column chromatography. Notably, the noble metal catalyst system ones, wherein 10.0 mol% AgSbF was required (Scheme 2).
can be recycled effectively at least ten times. The strategy may be
Thus, the discovery of new routes that meet green synthesis
goals from readily available raw materials is still desirable.
From this point of view, we look forward to simpler workup
procedures and efficient catalyst recycling when noble metal
catalysts are used.
amenable to industrial production.
1
2
The quinazolinone and indole skeletons widely exist in
natural products and drug molecules, compounds which
display a wide range of biological activities, such as antibacter-
Iodonium ylides, inexpensive and readily available high-
valent iodine reagents, have been widely used in organic syn-
3
4
5
ial, anticancer, and antifungal activity. Derivatives such as
those shown in Scheme 1 can be applied as a 5-HT3 receptor
11
thesis. Under light, heat or metal catalysis conditions, iodo-
6
a
6b
antagonist, topoisomerase II inhibitor
and fluorescent
12
nium ylides are readily converted into carbenoid species.
6
c
nucleoside. Considering its wide biological activities, devel-
oping an efficient strategy for assembling the indoloquinazoli-
none core is highly desired.
Sometimes, iodonium ylides bearing an ortho carbonyl group
13
can be attacked by nucleophiles or tautomerize to form a
14
nucleophilic site. Iodonium ylides can also generate an
Many strategies with readily accessible indoloquinazolinone
have been reported so far; nevertheless, these existing
methods inevitably have limits, including the use of more
than one noble metal, low reaction efficiency, non-readily avail-
iodine radical in situ to promote a cascade cyclization reac-
15
tion. Compared to dangerous and explosive diazonium com-
16
pounds, iodonium ylides are safe and stable.
Recently, we found that in the presence of [Cp*RhCl ] and
2
2
7
able substrates or tedious workup. For example, Bao and co-
base, a cascade reaction of N-methoxyamide indole and iodo-
nium ylide reagent occurs facilely to produce an indoloquina-
zolinone. This reaction requires no noble metal oxidant and
the pure product can be directly obtained via only simple fil-
tration. The Rh(III) catalyst can be recycled more than 10 times
8
workers reported a nucleophilic addition/N-arylation/C–H
activation sequential process between ortho-gem-dibromovinyl
isocyanates and N-alkylanilines through Cu/Pd relay catalysis
in the synthesis of pyrimido[1,6-a]indol-1(2H)-one derivatives.
Recently, Ma’s group presented the assembly of indolo[1,2-c]-
quinazolinones via palladium catalyzed intramolecular C–C
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science & Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, China.
E-mail: xuxp@suda.edu.cn, shunjun@suda.edu.cn
b
Innovation Center for Chemical Science, Soochow University, China
†
Electronic supplementary information (ESI) available. CCDC 2070972. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1gc01820e
Scheme 1 Bio-active molecules bearing an indoloquinazolinone
skeleton.
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3 2 3 4
lysts such as RhCl , Co(OAc) and Pd(PPh ) were proven to be
inert in this reaction (Table 1, entries 2–4). Other solvents were
subsequently tested, but no better results than methanol were
observed (Table 1, entries 5–7). After screening a series of
bases (Table 1, entries 8–13), we found that the desired
product could be isolated in 82% yield when CsOAc was uti-
lized. Moreover, increasing the amount of CsOAc to 3 equiva-
lents resulted in a 91% yield of the product (Table 1, entries
1
4–16). Later, it was found that 1.2 equivalents of 2a was
sufficient to give the target product 3aa in 92% isolated yield
Table 1, entry 17). Based on the above results, we determined
the optimal conditions to be 1a (0.2 mmol) and 2a
(
(
0.24 mmol) in the presence of [Cp*RhCl
2 2
] (3.0 mol%), CsOAc
(
0.6 mmol) and methanol (2 mL) under an air atmosphere at
room temperature for 1 h.
With the optimal conditions established, examination of
the scope of indoles and iodonium ylides was carried out
(
Scheme 3). It was found that the reaction ran smoothly,
Scheme 2 Synthesis of the indoloquinazolinone skeleton.
with no obvious decrease in its catalytic activity (Scheme 2,
this work). Herein, we report the results.
Our research started with the model reaction of N-methoxy-
1
H-indole-1-carboxamides 1a and iodonium ylide 2a (2 equiv.).
Treatment of the above reaction with [Cp*RhCl ] (3.0 mol%),
2
2
NaOAc (1 equiv.), in acetonitrile under an air atmosphere gave
the product 3aa in 44% LC yield (Table 1, entry 1). Other cata-
a
Table 1 Optimization of the reaction conditions
b
Entry
Catalyst
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
[Cp*RhCl
2
]
2
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
CH
CH
CH
CH
DCE
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
3
3
3
3
CN
CN
CN
CN
44
0
0
RhCl
Co(OAc)
Pd(PPh
3
2
)
3 4
0
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
2
2
2
2
2
2
2
2
2
2
2
2
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
29
17
50
89
74
75
97 (82 )
33
47
99 (82 )
97 (86 )
99 (91 )
99 (94 , 92 )
Na
NaHCO
Cs CO
CsOAc
DABCO
Et
2
CO
3
3
10
11
12
13
14
15
16
17
2
3
c
3
N
d
e
f
c
CsOAc
CsOAc
CsOAc
CsOAc
c
c
g
c
h
]
2
a
Standard conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst
(
3.0 mol%), base (0.2 mmol) was dissolved in solvent (1 mL), the
b
mixture was stirred at rt for 1 h. Liquid chromatography (LC) yield
using biphenyl as an internal standard. Isolated yield by column
chromatography. CsOAc (1.0 equiv.). CsOAc (2.0 equiv.). CsOAc (3.0
equiv.). 1a (0.2 mmol), 2a (0.24 mmol), CsOAc (3.0 equiv.). Simply (2 mL), rt, 1 h, under air. Suction filtration yield (without purification by
c
Scheme 3 Substrate scope study. Reaction conditions: 1a (0.2 mmol),
a (0.24 mmol), [Cp*RhCl (3.0 mol%), CsOAc (0.6 mmol), MeOH
d
e
f
2
2 2
]
g
h
a
purified by filtration.
column chromatography). Isolated yields by column chromatography.
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regardless of whether electron-donating (methyl, methoxy) or After being recycled ten times, no obvious decrease in catalytic
withdrawing (cyano, nitro) groups were attached to the activity was observed.
-
benzene ring of the indole. A slight decrease in the yields was
observed when 3-phenyl and 3-methoxycarbonyl indoles were
introduced respectively, which may be mainly due to steric hin-
drance effects (Scheme 3, 3ar–3as). The introduction of
Conclusions
2
In conclusion, we developed a C(sp )–H functionalization/cycli-
zation cascade for the efficient synthesis of indoloquinazoli-
none derivatives from N-methoxycarbamoyl indoles and iodo-
nium ylides under mild conditions. The reaction has the
characteristics of the wide tolerance of functional groups and
high yields. The target products were obtained simply by fil-
tration, without the need for purification by tedious column
chromatography. Notably, the noble metal catalyst system can
be recycled effectively at least ten times meaning that the strat-
egy may be amenable to being used in industrial production.
4
-cyano- and 5-nitroindole led to poor yields of less than 50%
of the filtered products (Scheme 3, 3ak, 3au). However, higher
yields (70% for 3ak and 80% for 3au) could also be afforded
when the products were purified by column chromatography.
These results may demonstrate that the products are relatively
dissolvable in methanol. It was also found that
N-benzyloxyamidoindole was well tolerated in the reaction
(
Scheme 3, 3av), but no product was detected when
N-methoxycarbamoyl was replaced by phenylcarbamoyl
Scheme 3, 3aw). Finally, the compatibility of the iodonium
(
ylides was tested. The selected five iodonium ylides were suc-
cessfully reacted with 1a to furnish products 3bb–3be in
8
2–85% yields (Scheme 3, 3bb–3be).
In order to verify the potent application of the protocol, we
Author contributions
Zhi-Peng Han: investigation, methodology, formal analysis and
writing – original draft. Meng-Meng Xu: methodology. Rui-
Ying Zhang: validation. Xiao-Ping Xu: funding acquisition,
writing – review and editing, and project administration. Shun-
Jun Ji: project administration and supervision.
performed a model reaction on the gram scale. When 4 mmol
of substrate 1a was introduced, 1.11 g of the target product 3aa
was obtained in 90% yield via simple filtration. It was thus
found that this strategy may be amenable to industrial pro-
duction (Scheme 4).
The recyclability of the rhodium catalyst in methanol was
tested under the standard conditions (for details, see the ESI,†
Fig. 1). It was found that the catalytic system in organic phase
can be reused in the next cycle after the product was filtered.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (No. 21772138, 21672157), the project of
Scheme 4 Gram-scale synthesis. Reaction conditions: 1a (4 mmol), 2a the Scientific and Technologic Infrastructure of Suzhou
(
4.8 mmol), [Cp*RhCl
2
]
2
(3.0 mol%), CsOAc (12 mmol), MeOH (40 mL) at (SZS201708) and PAPD. We thank Nan-Quan Jiang in our
group for reproducing the results of 3ac, 3al, 3be, and the re-
rt for 1 h.
usability of the Rh catalyst in the organic phase.
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