CuH-Catalyzed Synthesis of 3-Hydroxyindolines and 2-Aryl-3H-indol-3-ones from o-Alkynylnitroarenes, Using Nitro as Both the Nitrogen and Oxygen Source

Article abstract of DOI:10.1021/acs.orglett.9b01849

CuH-catalyzed diasterospecific synthesis of 3-hydroxyindolines and 2-aryl-3H-indol-3-ones have been developed from o-alkynylnitroarenes in the presence of hydrosilane as the reductant. The protocol employs nitro as both nitrogen and oxygen sources for the

Full text of DOI:10.1021/acs.orglett.9b01849

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
CuH-Catalyzed Synthesis of 3‑Hydroxyindolines and 2‑Aryl-3H-
indol-3-ones from o‑Alkynylnitroarenes, Using Nitro as Both the
Nitrogen and Oxygen Source
Hui Peng,† Jinhui Ma,‡ Lingfei Duan,† Guangwen Zhang,‡ and Biaolin Yin*,†
†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou, People’s Republic of China, 510640
‡Department of Food Science and Engineering, Jinan University, Guangzhou 510632, China
S
* Supporting Information
ABSTRACT: CuH-catalyzed diasterospecific synthesis of 3-
hydroxyindolines and 2-aryl-3H-indol-3-ones have been developed
from o-alkynylnitroarenes in the presence of hydrosilane as the
reductant. The protocol employs nitro as both nitrogen and oxygen
sources for the intramolecular simultaneous construction of C−N
and C−O bonds.
Indolines are of considerable significance in both synthetic and
medicinal chemistry, because of a large quantity of naturally
occurring bioactive compounds and drugs whose structures
incorporate this heterocyclic framework (Figure 1).1 Accord-
source via reduction. Nevertheless, given that the N atom in
the nitro group has a high oxidation state, it is ideal to explore
more redox-economic reactions for further functionalization.
Despite the obvious advantages in step economy, cost
efficiency, and orthogonality, currently, only a few methods
have recently been developed for directly transforming nitro
compounds without the detour into the fully reduced anilines.9
Considering that CuH species has been demonstrated as a
versatile catalyst in a range of reductive couplings,10 and our
continuous interest in the development of new methods for
synthesizing indole derivatives,11,2h we herein wish to report a
diasterospecific access to 3-hydroxyindolines from o-alkynylni-
troarenes with the nitro group serving as both the nitrogen and
oxygen source of 3-hydroxylindolines, via an intramolecular
CuH-catalyzed reductive coupling of a nitro group with
alkynes.
Initially, we used 1-nitro-2-(p-tolylethynyl)benzene (1a) as
the substrate for the optimization of the reaction conditions. In
the presence of CuCl (10 mol %), dppf (10 mol %), and LiOt-
Bu (400 mol %), the reaction of 1a with Me(EtO)2SiH (400
mol %) for 12 h afforded 3-hydroxyindoline 2a in 27% yield as
a single diasteroisomer, along with a large amount of 1a (see
Table 1). The structure of 2a was ambiguously assigned via
single-crystal X-ray analysis (see the Supporting Information
(SI)). The hydroxyl and tolyl groups are located on the
opposite sides of the indoline ring. A range of other copper
catalysts, including CuBr, CuI, CuCl2, and CuF2 were
evaluated (Table 1, entries 2−5), and only CuCl2 gave a
higher yield (35%) than CuCl. Screening of bases demon-
strated LiOMe to be optimal, giving 2a in 62% yield (Table 1,
entries 6−8). Several other ligands were examined, but proved
to have no better yield than dppf (Table 1, entries 9−15).
Figure 1. Representative bioactive indolines.
ingly, numerous synthetic methods have been developed for
indolines and their derivatives bearing synthetically valuable
functional groups.2 Especially noteworthy among those are
indole ring’s dearomatic hydrogenation3 or cyclization,4 an
intramolecular coupling of imine and styrene catalyzed by
CuH species,5 and a Pd-catalyzed C−C coupling procedure
involving unactivated methylenes, etc.6 Despite its attractive-
ness, most of them required multiple steps using aryl amine
functionality as the nitrogen source of the indoline rings. Thus,
it is highly desirable to develop more-efficient nitrogen source,
such as a nitro group, for the synthesis of indoline rings with
step economy.
Nitroarenes, directly obtained from the nitration of the
parent arenes, are highly versatile and common aromatic
building blocks for access to the corresponding aryl amine,7
and indole8 involving the use of the nitro group as the nitrogen
Received: May 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01849
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Conditions Optimization
Scheme 1. Substrate Scope
b
entry
[Cu]
ligand
base
yield (%)
1
2
3
4
5
6
7
8
9
CuCl
CuBr
CuI
CuCl2
CuF2
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppe
BINAP
PPh2Cy
L1
L2
L3
L4
dppf
dppf
dppf
dppf
dppf
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOMe
NaOMe
KOt-Bu
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
27
30
19
35
18
62
19
trace
17
15
24
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
10
11
12
13
14
15
16
20
16
15
c
d
16
NR
e
17
trace
f
g
a
18
h
ND
All reactions were performed on a 0.5 mmol scale. Yields of isolated
products are given.
19
26
trace
i
20
furnishing reduction product 2u in 52% yield. When R2 was
4-Cl-Ph and R1 was 5-Cl or 5-Me, products 2v and 2w were
obtained in yields of 53% and 70%, respectively. The failure to
obtain 2x may be due to the strong coordination of pyridine
ring with the catalyst, leading to no reaction. When the
substrate possessing a thiophene framework was subjected to
the standard reaction conditions, the desired product (2y) was
not observed but a complex mixture was produced.
Encouraged by the above outcomes and, given that 2-aryl-
3H-indol-3-ones were widely used in organic and medicinal
chemistry, further exploration into the one-pot conversion of o-
alkynylnitroarenes to 2-aryl-3H-indol-3-ones, which represent
a class of important compounds with potent antiplasmodial
activities and have application as useful building blocks, was
attempted.12 As shown in Scheme 2, a range of 2-aryl-3H-
indol-3-ones 3 were produced in moderate yields (43%−68%)
upon treatment of 1 with Cu(OAc)2 (10 mol %), dppf (10
mol %), and Me(EtO)2SiH (400 mol %) in THF at room
temperature overnight, followed by treatment with silica gel at
80 °C for 12 h under O2. Note that before the treatment with
silica gel, the formed product was not stable enough to be
isolated by using silica chromatography.
Some control experiments were conducted to gain insight
into the mechanism for the formation of 2 (Scheme 3). First,
subjecting 1-nitro-2-styrylbenzene (4) to the standard
conditions did not afford 2b, indicating that 4 was not the
intermediate (see Scheme 3a). Second, the triple bond of
diphenylacetylene was not hydrogenated under the standard
conditions (Scheme 3b). Third, the isatogen 5b, prepared via
the known method,13 was transformed to 2b in 58% yield
under the standard conditions, indicating that 5b was a
possible intermediate (Scheme 3c). Fourth, subjecting 3a to
the standard conditions afforded 2a in 50% yield (Scheme 3d).
Fifth, the reaction of 3a with Me(EtO)2SiH and LiOMe
a
Reaction conditions: 1a (1 mmol), THF (2 mL), N2 atmosphere,
b
1
room temperature (rt). Yields were determined by H NMR using
c
d
CH2Br2 as the internal standard. [Si−H] = Et3SiH. NR = no
e
f
reaction. [Si−H]
= [(CH3)3SiO]2CH3SiH. [Si−H] =
g
h
[(CH3)2SiH]2NH. ND = not detected. [Si−H] = (EtO)3SiH.
i
[Si−H] = (CH3O)3SiH.
Evaluation of hydrosilanes revealed that Me(EtO)2SiH was
superior to all others tested (Table 1, entry 8 vs entry 16). On
the basis of the above observations, we concluded that the
optimized conditions for this transformation involved the use
of Me(EtO)2SiH as the reductant, CuCl2 as the catalyst, dppf
as the ligand, and LiOMe as the base at room temperature
(Table 1, entry 6; see the SI for details).
With the optimal reaction conditions in hand, we examined
the scope of substrates 1 with variable R1 and R2 groups for
this transformation (see Scheme 1). For R1 = H, R2 can be a
phenyl group, or phenyl groups substituted with electron-
donating groups of Me, Et, t-Bu, MeO, and with electron-
withdrawing groups of chlorides, CF3. The corresponding
products were afforded in yields of 40%−63% (4a−4l). R2 can
also be 1-naphthyl, 2-naphthyl, and thienyl, giving the desired
products in yields of 41%, 51%, and 60%, respectively (2m−
2o). Notably alkyl groups of R2 (1p and 1q) were also suitable
to this reaction, producing the corresponding products 2p and
2q, albeit in low yields (30% and 25%, respectively). When R2
was 4-Me-Ph, R1 was an electron-rich or electron-deficient
group, products (2r−2t) were obtained in yields of 40%−62%.
Substrate 1u, carrying both electron-rich substitutes of R1 and
R2, was also a good candidate for this transformation,
B
DOI: 10.1021/acs.orglett.9b01849
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. One-Pot Conversion of Nitroarenes to 2-Aryl-
3H-indol-3-ones
Scheme 4. Possible Mechanism for the Formation of 2
a
a
All reactions were performed on a 0.5 mmol scale. Silica (0.06 g).
Yields of isolated products are given.
Scheme 3. Control Experiments
likely by the oxidation of reduced species of E in the crude
products, using O2 as the oxidant (for the detailed formation
mechansim of 3, see the SI).
In summary, we have developed a diasterospecific and step-
economic method for the synthesis of 3-hydroxyindolines and
2-aryl-3H-indol-3-ones by CuH-catalyzed reductive coupling
of readily available o-alkynylnitroarene under mild conditions
with simple experimental procedure. In this protocol, the nitro
group serves as the nitrogen and oxygen source of indolines
and 2-aryl-3H-indol-3-ones with the simultaneous formation of
C−N and C−O bonds. Further studies on the reaction scope,
enantioselectivity control, and its application in synthesizing
bioactive products are underway, and the results will be
reported in due course.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01849.
■
afforded 2a in 51% yield. (Scheme 3e). The two control
experiments (Schemes 3d and 3e) indicate that 3a is likely the
intermediate and can be reduced into 2a using silane and (or)
LCuH as the reductant (see the SI for details of the control
experiments).
S
On the basis of the above observations and previous reports
on transition-metal-catalyzed cycloisomerizations of o-alkynyl-
nitroarene into isatogens,13,14 and hydrosilylation of imines15
and carbonyl functionalities,16 a possible reaction mechanism
for the formation of 2 involving the intermediates of isatogens
5 and 2-aryl-3H-indol-3-ones 3 is described in Scheme 4.
Specifically, LCuH species is initially formed after the reaction
of CuCl2 with a ligand and a stoichiometric amount of
hydrosilane.17 LCuH coordinates with substrate 1 to give
species A. The addition of nitroxide to the triple bond of A led
to B that isomerizes to copper-carbene C, which is then
transformed to D via intramolecular trapping of the nitroso
group in the 5-exo annulation. The dissociation of D delivers
isatogen 5,14c,f which is reduced by hydrosilane to generate E.
Subsequent reductive elimination of E with the aid of LiOMe
delivers the product 3. Finally, 3 is diasterospecifically reduced
by silane and (or) LCuH to furnish the thermodynamically
more stable indoline 2.18 According to the control experiments
(see control experiments (j) and (k) in the SI),19 we
speculated that 3 might be mainly produced by the elimination
of E with the assistance of silica gel. The minor way for 3 is
Details about experimental conditions, characterization
1
data, copies of H and 13C NMR spectra of all new
compounds (PDF)
Accession Codes
CCDC 1878765 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: blyin@scut.edu.cn.
ORCID
Biaolin Yin: 0000-0002-2547-0231
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b01849
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759. (b) Nakanishi,
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Program
on Key Research Project (No. 2016YFA0602900), the
National Natural Science Foundation of China (Nos.
21572068 and 21871094), the Science and Technology
Program of Guangzhou, China (No. 201707010057),
Guangdong Natural Science Foundation (No.
2017A030312005), and the Science and Technology Planning
Project of Guangdong Province, China (No.
2017A020216021). We greatly appreciate Prof. Fayang Qiu
(Guangzhou Institute of Biomedicine and Health, CAS), for
his helpful discussion on the reaction mechanism.
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DOI: 10.1021/acs.orglett.9b01849
Org. Lett. XXXX, XXX, XXX−XXX