RhIII-catalyzed redox-neutral C-H activation of pyrazolones: An economical approach for the synthesis of N-substituted indoles

Article abstract of DOI:10.1021/ol503404p

A new strategy is reported for the economical synthesis of indoles bearing an N-(3-aminobut-2-enoyl) substituent through Rh^III-catalyzed redox-neutral C-H activation of pyrazolones and alkynes. This approach utilizes cheap substrates and mild reaction conditions to access a unique class of indoles via a N-N bond oxidative cleavage without loss of the N-terminus, therefore meeting all the atom/step/redox economy principles.

Full text of DOI:10.1021/ol503404p

Letter
pubs.acs.org/OrgLett
RhIII-Catalyzed Redox-Neutral C−H Activation of Pyrazolones: An
Economical Approach for the Synthesis of N‑Substituted Indoles
Zhoulong Fan,†,∥ Shanshan Song,‡,∥ Wei Li,§,∥ Kaijun Geng,† Youjun Xu,§ Ze-Hong Miao,*,‡
and Ao Zhang*,†
‡
†CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica
(SIMM), Chinese Academy of Sciences, Shanghai 201203, China
§School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
S
* Supporting Information
ABSTRACT: A new strategy is reported for the economical
synthesis of indoles bearing an N-(3-aminobut-2-enoyl)
substituent through RhIII-catalyzed redox-neutral C−H
activation of pyrazolones and alkynes. This approach utilizes
cheap substrates and mild reaction conditions to access a
unique class of indoles via a N−N bond oxidative cleavage
without loss of the N-terminus, therefore meeting all the
atom/step/redox economy principles.
Scheme 1. Representative Strategies of Indole Synthesis
he indole backbone is commonly embedded in various
1
Tnatural products and synthetic congeners possessing a
wide spectrum of biological properties, including anticancer,
antiviral, and antidiabetic.2 In the past decades, preparation of
indoles 3 mainly depended on three synthetic strategies: [3,3]-
sigmatropic rearrangements (Fischer and Bartoli synthesis),3i,j
nucleophilic cyclization (Madelung and Smith reactions),3a and
transition-metal-catalyzed cross-coupling (Larock and Mori-Ban
synthesis).3d,f,g However, drawbacks such as the instability of
Grignard reagents, the utilization of strong bases, and additional
procedures for preactivating reagents restricted the practicality of
these reactions. Therefore, development of new methods to
assemble indoles readily, especially polycyclic or multisubstituted
variants, is rather daunting.
Recently, directing group (DG)-assisted C−H activation has
revolutionized the traditional design concept to the synthesis of
many complex molecules.4 Based on Larock-type Pd-catalyzed
cross-coupling indole synthesis (Scheme 1a),5 many DG-assisted
oxidative couplings toward substituted indoles have been
reported by Fagnou,6a,b Ackermann,6c and others6 (Scheme
1b). More recently, the redox-neutral coupling with an oxidizing
directing group (DGox) as an internal oxidant has emerged as an
attractive strategy in C−H activation (Scheme 1c).7 In such
external oxidant-free protocols, a DGox bearing a N−O bond is
generally used and the catalytic process is reinitiated by the
cleavage of the N−O bond.8 Compared to the N−O DGox
protocols, nevertheless, C−H activations utilizing a DGox
containing a N−N bond have been scarcely described.9
reaction proceeded with assistance of the DGox via a redox-
neutral C−H activation. In addition, Glorius,9c Hua,9h and
Cheng9j also reported additional examples to access indoles using
acetamido or imino as the NT (Scheme 2). Despite the progress,
however, judging by the three economy principles, atom/step/
redox,7,10 these reactions only fulfilled the redox economy and
lacked atom/step economy. All of these approaches suffered
from two major defects: (1) the DGox-containing substrates need
to be prepared in advance; (2) the N−N bond cleavage led to loss
of the N-terminus in the products.
In 2013, Huang9b reported a synthesis of indoles through a Rh-
catalyzed alkyne annulation using a triazene as the DG. In this
reaction, the NN double bond was successfully cleaved to
release the catalyst. However, an external oxidant was needed.
Using a nitroso as the N-terminus (NT) of the N−N bond in the
DGox was reported by Zhu9d and Huang.9e In this approach, the
Received: November 24, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503404p
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. RhIII-Catalyzed Redox-Neutral Coupling through
Table 1. Reaction Optimization for the Synthesis of 7aa
N−N Bond Cleavage (NT = N-Terminus)
b
entry
base
solvent
temp (°C)
yield (%)
1
2
3
CsOAc
NaOAc
Li2CO3
CsF
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
dioxane
m-xylene
mesitylene
DME
100
100
100
100
100
100
100
100
100
100
100
80
0
6
0
c
4
0
5
NaH2PO4
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
0
d
6
14
20
28
21
44
26
30
50
57
75
45
43
d
7
d
8
d
9
e
10
PhCl
d
11
toluene
e
12
PhCl
13
14
15
16
17
PhCl
120
130
130
130
100
PhCl
PhBr
PhI
We recently reported a rhodium-catalyzed oxidative coupling
of N-aryl-1H-pyrazol-5(4H)-one 6 with internal alkynes 211b
using the pyrazolone function as an intrinsic directing group.11
As a continuation of this work, we envisaged that the N−N bond
in the pyrazolone substrate might also be used as a DGox and
undergo a redox-neutral C−H activation that would lead to
products with a different structural scaffold. While our paper was
in preparation, the Huang group reported a ruthenium-catalyzed
redox-neutral C−H activation reaction of 1-phenylpyrazolidin-3-
one (phenidone) with alkynes, leading to the synthesis of N-
substituted indoles.12 Herein, we report that the RhIII-catalyzed
redox-neutral C−H activation of pyrazolones 6 with alkynes 2
occurred smoothly, yielding a unique class of indoles 7 bearing a
3-aminobut-2-enoyl substituent, which cannot be conveniently
prepared through the above-mentioned methods. In addition,
this reaction represents a novel Rh-catalyzed redox-neutral C−H
activation via N−N cleavage, satisfying all the atom/step/redox
economy principles.
Our initial investigation was carried out by treating pyrazolone
6a with diphenylacetylene 2a using [RhCp*Cl2]2 (2.5 mol %)
and CsOAc (2 equiv) in ClCH2CH2Cl at 100 °C for 6 h,9c but
the desired product 7aa was not obtained (Table 1, entry 1). We
then investigated a variety of bases instead of CsOAc in this
reaction (Table 1, entries 2−5). It was found that product 7aa
was obtained in 6% yield using NaOAc as the base, and the
structure was confirmed by the X-ray crystallography (see the
Supporting Information). Compound 8 was obtained as a side
product that was formed by alkylation of 6a with the solvent
ClCH2CH2Cl in the presence of CsF as the base (Table 1, entry
4). This reminded us that changing the solvent was urgent.
Among the solvents we tested (entries 6−11 of Table 1),
chlorobenzene led to an improved yield of 44%. Screening the
reaction temperature from 80 to 130 °C (Table 1, entries 12−
14), we found that the yield of 7aa was slightly improved (57%)
at 130 °C. In addition, other halogenated arenes were
investigated as the solvent, and we were surprised to find that
bromobenzene gave a high yield of 75% (Table 1, entry 15). The
exact reason why bromobenzene is superior to chlorobenzene as
the solvent is unclear at this moment. Therefore, the best
reaction condition was concluded as follows: pyrazolones 6,
PhF
a
Reaction conditions: 6a (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2
b
(2.5 mol %), base (0.2 mmol), solvent (1 mL), 2 h. Yields
determined by H NMR analysis using 1,2-dibromoethane as internal
standard. Compound 8 as the only product. 6 h. 4 h.
1
c
d
e
alkynes 2, [RhCp*Cl2]2 (catalyst), NaOAc (base) in PhBr
(solvent) at 130 °C in a sealed tube.
With the optimized reaction conditions in hand, the scope and
limitations were assessed with different pyrazolones and various
internal alkynes (Scheme 3). Except for the ortho-substituted
phenyl substrates, all monosubstituted, disubstituted, or fused
phenyl pyrazolones went through the reaction smoothly and
afforded the corresponding products in moderate to excellent
yields. For the para-substituted phenyl pyrazolones, both
electron-withdrawing and electron-donating groups, such as
chloro, methyl, and methoxyl, were tolerant under the reaction
conditions, and the corresponding products 7ca, 7ba, and 7da
were obtained in 76, 81, and 65% yields, respectively. The meta-
substituted phenyl substrates gave varying yields ranging
between 61 and 85% (7ea−7ha). Substrates with electron-
withdrawing and strong electron-donating groups afforded
slightly lower yields (61−68%). The ring-fused pyrazolone 6n
also participated in this reaction and afforded product 7na in 62%
yield. In the case of 1-(3-fluorophenyl)-3-methyl-1H-pyrazol-
5(4H)-one, a mixture of regioisomers 7ia and 7ia′ was observed.
A low yield of 36% was obtained for indole derivative 7ma, likely
due to the steric hindrance of the isopropyl group. Symmetric
diaryl acetylenes were also efficiently converted to the desired
indole derivatives (7ab−7ah) in 48−74% yields. However,
alkyl−alkyl (2i) and aryl−alkyl (2j) disubstituted alkynes
underwent a cyclization process11b and generated pyrazolo[1,2-
a]cinnolines (7ai and 7aj) and the tautomers (7ai′ and 7aj′),
with the former products in slightly higher yields. In addition, we
also investigated diheteroaryl alkynes, including 1,2-di(thiophen-
2-yl)ethyne and 1,2-di(pyridin-4-yl)ethyne, as well as phenyl
acetylene; unfortunately, no products were obtained.
A plausible mechanism is presented in Scheme 4 (based on the
model reaction of 6a and 2a). The active catalyst [RhCp*-
B
DOI: 10.1021/ol503404p
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
migration, accompanied by the N−N bond cleavage.9c,14 The
intermediate C then underwent a reductive elimination and
protonation to form the complex D, which was subsequently
protonated by acetic acid to afford the target product 7aa and
regenerate the RhIII catalyst.
Scheme 3. Reaction Scope for the Synthesis of N-Substituted
Indoles 7
a
Since the unique structure of the N-(3-aminobut-2-enoyl)-
substituted indoles in the current protocol is distinctly different
from the ones in other methods, we evaluated the inhibitory
effects of these compounds against the proliferation of several
cancer cells, including squamous carcinoma KB cells and
vincristine (VCR)-resistant KB/VCR cells. Tanshinone-1,
which is equally potent against KB and KB/VCR cells, and
VCR, which is highly potent and selective against KB cells, were
used as positive controls. The results are summarized in Table 2.
Table 2. Cytotoxicity of Selected Compounds Against Cancer
Cells
IC50 (μM)
compound
7ba
KB
KB/VCR
16.7
15.8
17.6
>20
>20
0.83
2.75
2.59
17.9
>20
15.0
>20
>20
2.47
7ka
7na
7ac
9
VCR
Tanshinone-1
Compared to Tanshinone-1 and VCR, most of our selected
compounds showed much less potency against the two cancer
cell lines. However, compound 7ba exhibited good potency
against KB/VCR with an IC50 value of 2.59 μM, which is equally
potent as that of Tanshinone-1. Meanwhile, 7ba is nearly inactive
against KB cells (16.7 μM), indicating that this compound might
have potential use to overcome tumor resistance to vincristine
selectively upon further structure optimization. Further, removal
of the indole N-substituent by treating 7aa with aqueous NaOH
(20%) provided 2,3-diphenyl-1H-indole (9) in 85% yield (see
the Supporting Information). Compound 9 was inactive in our
biological assay, indicating the importance of the N-(3-
aminobut-2-enoyl) side chain in our compounds.
a
Reaction conditions: [RhCp*Cl2]2 (2.5 mol %), NaOAc (1 mmol),
pyrazolones 6 (0.5 mmol), and alkynes 2 (0.5 mmol) in PhBr (2.5
mL) for 2−3 h under 130 °C. Isolated yields are given.
Scheme 4. Proposed Mechanism
In summary, we have established an economical synthesis of a
unique class of indoles bearing an N-(3-aminobut-2-enoyl)
substituent from pyrazolones and alkynes through RhIII-
catalyzed redox-neutral C−H activation. This reaction is
proposed to undergo a 1,2-rhodium shift/oxidation via N−N
bond cleavage without loss of the N-terminus in one step.
Biological assay showed that compound 7ba was potent and
selective against vincristine-resistant KB/VCR cell lines and may
be used as a hit/lead for further structure optimization.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data of all compounds,
and CIF file for compound 7aa (CCDC 1033339). This material
is available free of charge via the Internet at http://pubs.acs.org.
(OAc)2]2 was first formed from [RhCp*Cl2]2 and NaOAc.9h,13
A
directed C−H bond cleavage process then occurred to form a
rhodacycle A,11b,c which was followed by insertion of alkyne 2a,
affording the seven-membered intermediate B. The [5,7]-
bicyclic Rh complex B (RhIII) was then converted to a more
stable [6,6]-bicyclic metallacycle C (RhV) via a 1,2-rhodium
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhmiao@simm.ac.cn.
*E-mail: aozhang@simm.ac.cn.
C
DOI: 10.1021/ol503404p
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Author Contributions
∥Z.F., S.S., and W.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by Chinese National Natural Science
Foundation (81430080, 81125021, 81373277) and by the Major
State Basic Research Development Program (2015CB910603).
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