C-H alkenylation/cyclization and sulfamidation of 2-phenylisatogens using: N -oxide as a directing group

Article abstract of DOI:10.1039/c9cc05719f

The first example of transition-metal-catalyzed C-H activations of 2-phenylisatogens with alkynes and sulfonyl azides has been developed using N-oxide as the directing group. Ru(ii)-Catalyzed C-H alkenylation/cyclization and Ir(iii)-catalyzed direct C-H sulfamidation proceeded with good yields and excellent functional group tolerance. Importantly, these two transformations provided straightforward routes for the synthesis of indol-3-one derivatives and sulfamidated 2-phenylisatogens respectively, which might be of considerable bioactivities.

Full text of DOI:10.1039/c9cc05719f

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C-H Alkenylation/Cyclization and Sulfamidation of 2-
Phenylisatogens Using N‑Oxide as a Directing Group†
Lingmei Guo,a Baolan Tang,a Ruifang Nie,a Yanzhao Liu,a Shan Lv,a Huijing Wang,b Li Guo,a Li Hai*a
Received 00th January 20xx,
Accepted 00th January 20xx
and Yong Wu*a
DOI: 10.1039/x0xx00000x
The first example of transition-metal-catalyzed C−H activations of
2-phenylisatogens with alkynes and sulfonyl azides has been
developed using N-oxide as the directing group. Ru(II)-catalyzed C-
H
alkenylation/cyclization and Ir(III)-catalyzed direct C−H
sulfamidation proceeded with good yields and excellent functional
group tolerance. Importantly, these two transformations provided
straightforward ways for the synthesis of indol-3-one derivatives
and sulfamidated 2-phenylisatogens respectively, which might be
of considerable bioactivities.
In contemporary organic chemistry, transition-metal-catalyzed
C-H activation, featuring efficiency, has been considered as a
powerful and atom-economic method to construct C-C, C-
heteroatom bonds and heterocyclic scaffolds1. In site-selective
C-H activation, the introduction of multifunctional directing
groups into the parent molecules is a unique and useful
strategy, which has been attractive in long term for chemists. In
this regard, a large number of nitrogen and oxygen directing
groups have been developed1, including amide2a, imine2b,
ester2c, ketone2d, N-oxide3-5, etc. Among them, heteroaromatic
N-oxides3, such as pyridine N-oxides3b-3c, quinoline N-oxides4
and arylnitrones5, exhibit excellent regioselectivity in ortho C-H
Scheme 1 Examples of C-H activation with N-containing or N-oxide directing groups
functionalizations and remote C-H bond activations by
transition-metal-catalyzed C-H activation.
2-Substituted-3-H-indol-3-one N-oxides, commonly known
as isatogens, have been well investigated due to their wide
applications in medicinal and pharmaceutical fields6. For
example, 2-phenylisatogens and their derivatives (Figure 1a)
show excellent antimalarial activity, while the phenol group
serves as the active essential group6g. Spiro 1,2-dihydro-3H-
indol-3-one, namely pseudo-indoxyl, is a further cyclization
product of 2-phenylisatogen. Pseudo-indoxyl is widespread in a
variety of natural products and biologically active molecules7
(Figure 1b). To enrich the library of 2-phenylisatogen derivatives
for their promising bioactivities, the current synthetic methods
typically rely on the intramolecular cyclization of 2-
nitrophenylacetylenes8. The necessarity of prefunctionalization
of the precursors limited their applications in academic
research and drug discovery. Aiming for better chemical
efficiency, we seek for
phenylisatogen derivatives.
a method to obtain more 2-
Figure 1 Selected examples of bioactive 2-phenylistongens and indole-3-ones
To the best of our knowledge, 2-phenylisatogens have not
been used for transition-metal-catalyzed C-H function. On the
basis of our previous works of C-H activation with N-containing
directing groups9 (Schem 1a) and the published works about the
N-oxide as directing groups3-5 (Schem 1b), we hypothesized that
N-oxide moiety in 2-phenylisatogen can serve as the directing
group for direct C-H functions, though it is important for its
a. Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
University, No.17, 3th Section, South Renmin Road, Chengdu, 610041, P. R. China.
E-mail: smile@scu.edu.cn; wyong@scu.edu.cn.
b.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California
San Diego, 9500 Gilman Drive, La Jolla, California 92093-0934 United States.
†Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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Table 2 C-H alkenylation/cyclization of 2-phenylisatogensa
unique bioactivities. Herein, we report the first transition-
metal-catalyzed C-H function reactions of 2-phenylisatogens
with alkynes and azides with N-oxide as directing group, leading
to indol-3-one derivatives and sulfamidated 2-phenylisatogens
respectively. The efficient and scalable Ru(II)-catalyzed C-H
alkenylation/cyclization of 2-phenylisatogens with internal
alkynes and Ir(III)-catalyzed C–H sulfamidation of 2-
phenylisatogens with sulfonyl azides were developed with
satisfying functional groups tolerance (Scheme 1c). Notably,
compared to other synthetic methods of indol-3-one
derivatives10, the Ru(II)-catalyzed C-H alkenylation/cyclization
of 2-phenylisatogens with unsymmetrical alkynes provided
better regioselectivity.
View Article Online
DOI: 10.1039/C9CC05719F
We commenced our investigation by examining of the
reaction between 2-phenylisatogen (1a) and 1-phenyl-1-hexyne
(2a) in the presence of [CoCp*(CO)I2]2/AgSbF6 catalyst, AgOAc
as additive, and DCE as solvent, under argon atmosphere at 80
°C. Unfortunately, the product was not observed (Table 1, entry
1). Optimization with other catalytic systems, including
[Cp*IrCl2]2/AgSbF6, [RuCl2(p-cymene)]2/AgSbF6, [RhCp*Cl2]2/
AgSbF6, gave the comparatively better results (Table 1, entries
2-4). The better yield of 76% was observed in the case of
[RuCl2(p-cymene)]2/AgSbF6 (Table 1, entry 2). With this
encouraging result, we then screened the sliver salts, such as
AgNTf2, AgBF4 and AgOTf. However, none of them improved the
yield (Table 1, entries 6-7). To our surprise, after extensive
additive screening (Table 1, entries 8-11), Cu(OAc)2 led to an
excellent yield of 81%. Thus the optimal reaction conditions
were determined as following: 1a (0.1 mmol), 2a (0.2 mmol),
[RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2 (1.0
equiv), DCE (1.0 mL), argon atmosphere, 80 °C, 28 h.
aReaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), [Ru(p-cymene)Cl2]2 (5 mol%),
AgSbF6 (20 mol%), Cu(OAc)2 (0.1 mmol) and DCE (1.0 mL) at 80°C for 28 h under
argon. Isolated yields are given by chromatography. b[Ru(p-cymene)Cl2]2 (10
mol%), at 100°C for 48 h. c2 (0.4 mmol)
summarized in Table 2. A series of 2-phenylisatogens bearing
various substituents at 2-phenyl moiety reacted with internal
alkyne 2a, providing desired products in moderate to high yield
(3aa-3ja). It was notable that the electron-withdrawing groups
on the phenyl ring slightly inhibited the transformation (3ea-
3ha and 3ja), whereas electron-donating groups dramatically
promoted the reaction (3ba-3da, 3ia). In addition, the reaction
performed smoothly with 6-substituted of 3-oxo-indolin-3-ones
in moderate yields (3ka-3ma). After successfully exploring the
substrate scope with 2-phenylisatogens, various alkynes were
tested. 1-Phenyl-1-hexynes bearing various substituents at
phenyl moiety reacted smoothly with 1a, affording the
corresponding products in good yields with excellent
regioselectivity (3ab-3ai). Replacing the phenyl moiety of 1-
phenyl-1-hexyne with thiophene, product 3aj was provided in
moderate yield. Also, unsymmetrical alkynes, including 1-
phenyl-1-propyne, cyclopropyl-substituted phenylacetylene
and methyl phenylpropiolate, worked well to generate the
corresponding products (3ak, 3al and 3an) in moderate to high
yields (56-79%). Moreover, symmetrical alkynes, such as
diphenylacetylene and dimethyl acetylenedicarboxylate, could
readily be reacted with 2-phenylisatogens 1 to generate the
desired products (3am and 3ao) in moderate yields. It should be
noted that dialkyl alkynes including hex-3-yne and oct-2-yne,
did not afford the corresponding products (3ap and 3aq).
Then, we turned our attention to investigate the C−N bond
formation to directly introduce the N-containing groups into 2-
phenylisatogens. In our preliminary investigation, 2-
phenylisatogen (1a) and TsN3 (4a) were used as model
substrates. After screening various reaction conditions (see the
Supporting Information, Table S1), the optimal conditions for
the reaction was determined as following: 1a (0.1 mmol), 4a
With the optimized conditions in hand, we moved on to
extend the scope of 2-phenylisatogens 1 and alkynes 2 as
Table 1 Optimization of the C-H alkenylation/cyclizationa
Entry
1
Catalyst
[CoCp*(CO)I2]2
Sliver salt
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgNTf2
AgBF4
Additive
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2
HOAc
Yieldb (%)
N.R.
76
2
[RuCl2(p-cymene)]2
[RhCp*Cl2]2
3
15
4
[Cp*IrCl2]2
10
5
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
73
6
N.R.
N.R.
81
7
AgOTf
8
AgSbF6
AgSbF6
AgSbF6
AgSbF6
9
35
10
11
PivOH
45
Ag2CO3
32
aReaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), catalyst (5 mol%), sliver salt
(20 mol%), additive (1.0 eq) and DCE (1.0 mL) at 80 °C for 28 h under
argon.bIsolated yields by chromatography on silica gel.
2 | J. Name., 2012, 00, 1-3
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(0.2 mmol), [Cp*IrCl2]2 (5 mol%), AgNTf2 (20 mol%), HOAc (2.0
eq), TFE (1.0 mL), argon atmosphere, at room temperature, 5 h.
View Article Online
DOI: 10.1039/C9CC05719F
Table 3 C−H sulfamidation reaction of 2-phenylisatogensa
Scheme 3 Proposed mechanism
involved in the turnover limiting step (see the Supporting
Information, Scheme S2).
On the basis of the experimental results and reported
studies4h,5g-5i,11, we propose a plausible reaction mechanism as
Scheme 3. The [Ru(p-cymene)Cl2]2-catalyst or [Cp*IrCl2]2-
catalyst in the presence of silver salt reacts with 1a via C−H
activation, forming six-membered metallacyclic intermediates I
or IV respectively. Intermediate I reacts with alkyne 2 through
coordination and subsequent insertion, leading to an eight-
membered ruthenacyclic intermediate II. As reported5i,11,12, this
insertion is assumed to be controlled by electronic as well as
steric effect, favoring II with highly regioselective. Then, an
intramolecular insertion of the C=N group by the Ru–alkenyl
bond of II afforded the intermediate III. Reductive elimination
in the next step provided product 3 along with the generation
of Ru(0) which is oxidized by Cu(OAc)2 further to Ru(II). In a
similar manner, intermediate V is generated by the interaction
of azide with the cationic metal center. Then, the nitrenoid
species inserts into the iridacycle, forming a new C−N bond in
VI. Finally, compound VI is protodemetalated, delivering the
sulfamidated product 5.
a Reaction conditions: 1a (0.1 mmol), 4a (0.2 mmol), [Cp*IrCl2]2 (5 mol%), AgNTf2
(20 mol%), HOAc (0.2 mmol) in TFE (1.0 mL) at room temperature for 5 h under Ar.
Isolated yields are given by chromatography on silica gel.
Using the optimized conditions, we explored the scope of
2-phenylisatogens 1 and sulfonyl azides 4 for this C-N bond-
forming reaction. To our delight, various 2-phenylisatogens
substituted with electron-donating and electron-withdrawing
groups at para- or meta-positions of the 2-phenyl moiety were
compatible with Ir(III)/AgNTf2 catalytic system, affording the
desired products (5aa-5ja). Other 6-position substituted 2-
phenylisatogens were also compatible with this transformation
(5ka-5ma). Reacted with 1a, aryl and alkyl substituted sulfonyl
azides 4 produced the corresponding products in high yields
(5ab-5af).
Next, experiments were performed to investigate the
reaction mechanism. As shown in Scheme 2a, 2-phenyl-3H-
indol-3-one (6), being lack of the N-oxide functionality as
directing group, and 1-phenyl-1-propyne (2a) were subjected to
the standard condition. However, none of products were
observed, which confirms the importance of this directing
group in C-H activation. In addition, when the reaction was
conducted in the presence of DCE/CH3COOD (9:1), H/D
exchange at the ortho-position of 1a was observed. It suggests,
in our case, the C−H activation is a reversible process (Scheme
2b). Furthermore, as shown in Scheme 2c, a significant kinetic
isotope effect (KIE) was observed (KH/KD = 2.3) in the
intermolecular competition assay, indicates that the C−H bond
cleavage is likely to be involved in the turnover limiting step.
Mechanistic studies of the C-H sulfamidation also suggests that
the C−H activation is a reversible process using N-oxide as
guiding group and cleavage of the C−H bond is likely to be
In conclusion, we have developed the first transition-
metal-catalyzed C−H functionalization of 2-phenylisatogens
with internal alkynes and sulfonyl azides for the synthesis of
indol-3-one derivatives and sulfamidated 2-phenylisatogens,
where N-oxide behaved as an efficient directing group.
Importantly,
[RuCl2(p-cymene)]2/AgSbF6 catalyzed
C-H
alkenylation/cyclization reaction of 2-phenylisatogens with
unsymmetrical alkynes showed excellent regioselectivity. In
addition, both reactions were proceed efficiently with the
advantages of broad substrate scope and excellent functional
group tolerance. Further studies on the C−H activation of 2-
phenylisatogens that highlight the unique role of C-H activation
in drug synthesis are currently underway in our laboratories.
We are grateful for the support from the National Natural
Science Foundation of China (NSFC) (grant number 81373259
and 81773577).
Conflicts of interest
There are no conflicts to declare.
Notes and references
Scheme 2 Mechanistic studies
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/C9CC05719F
Ru(II)-catalyzed C-H alkenylation/cyclization and Ir(III)-catalyzed C−H sulfamidation
provided indol-3-one derivatives and sulfamidated 2-phenylisatogens respectively, with good
yields and excellent functional group tolerance.
O
O
R2
O
O
S
O
O
H
R3
S
O
N
HN
N3
R3
R1
N
N
R1
IrIII
RuII
H
R2
O
O