Ruthenium-catalyzed redox-neutral C-H activation via N-N cleavage: Synthesis of N-substituted indoles

Article abstract of DOI:10.1021/ol502998n

The first Ru-catalyzed redox-neutral C-H activation reaction via N-N bond cleavage is reported. Pyrazolidin-3-one is demonstrated as an internally oxidative directing group that enables C-H annulation reactions with a broad scope of alkynes, including previously incompetent terminal alkynes. Pharmacologically privileged 3-(1H-indol-1-yl)propanamides were synthesized in high yields.

Full text of DOI:10.1021/ol502998n

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Redox-Neutral C−H Activation via N−N
Cleavage: Synthesis of N‑Substituted Indoles
Zhenxing Zhang, Hao Jiang, and Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen Graduate
School, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: The first Ru-catalyzed redox-neutral C−H activation
reaction via N−N bond cleavage is reported. Pyrazolidin-3-one is
demonstrated as an internally oxidative directing group that enables C−
H annulation reactions with a broad scope of alkynes, including
previously incompetent terminal alkynes. Pharmacologically privileged 3-
(1H-indol-1-yl)propanamides were synthesized in high yields.
Scheme 1. Indole Synthesis via C−H Activation and N−N
Cleavage
n the past decade, transition-metal-catalyzed functionalization
Iof inert C−H bonds emerged as the new center stage for
synthetic innovations.1 Its unparalleled advantages over existing
methods of chemical bond formation have spurred intensive
studies in an effort to make it a general strategy for late-stage
functionalization of complex scaffolds. Because of the oxidative
nature of these dehydrogenative C−H bond coupling reactions,
stoichiometric amounts of sacrificing oxidants are often required
in order to turn over the precious transition-metal catalysts. An
overwhelming majority of external oxidants reported in the
literature are toxic metal salts that are unsuitable for large-scale
production. More recently, development of redox-neutral C−H
activation reactions has received much attention in which an
oxidative functional group serves as both a directing group (DG)
and an internal oxidant.2 This strategy eliminates the need for an
external oxidant.
Among reported oxidative DGs, the N−O bond is the most
frequently used, which has been demonstrated to successfully
turn over Rh, Pd, Ru, etc.3 On the other hand, redox-neutral C−
H activation reactions using N−N cleavage have been limited to
Rh catalysis owing to the relatively low oxidative potential of N−
N vs N−O (Scheme 1). Recently, Glorius reported the use of
hydrazide as the first oxidative N−N DG for the synthesis of
indoles.4 Zhu and we reported that nitrous amide was also a
competent group to turn over Rh(III).5 Subsequently,
hydrazones were also reported, independently by Zheng,
Matsuda, and Hua, as an internally oxidative N−N DG for
Rh(III).6 However, a major limitation for the Rh-catalyzed
alkyne annulation reaction is the requisite use of disubstituted
acetylenes. Terminal alkynes are known to be notorious
substrates for Rh catalysis due to serious homocoupling and
other side reactions.3d,o In contrast, the N−N bond has not been
demonstrated in C−H activation reactions using Ru, a
significantly cheaper metal, despite its catalytic versatility in
C−H activation reactions demonstrated extensively by Acker-
mann and others.7 Herein, we report our progress on the
development of Ru-catalyzed redox-neutral alkyne annulation
reactions via N−N cleavage with substrate scope beyond
previous methods using Rh.
In the past few years, our group has been interested in the
synthesis of polysubstituted indole scaffolds using redox-neutral
C−H annulation reactions with alkynes.5a,8 Despite the
aforementioned progress on Rh-catalyzed indole synthesis,
only internal alkynes were tolerated in the literature. Our own
experience showed that terminal alkynes were incompatible with
Rh(III) due to homocoupling of alkynes. It would be intuitively
wiser to employ an alternative metal, preferably cheaper, for the
Received: October 12, 2014
© XXXX American Chemical Society
A
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Letter
synthesis of indoles with terminal alkynes.9 Ru has been shown to
undergo directed olefination and subsequent cyclization using
alkynes. However, two questions need to be answered: (1) can
we identify an oxidative DG to make the reaction redox neutral;
(2) can terminal alkyne be tolerated? We initially examined
arenes bearing various functional groups with diphenylacetylene
using Ru catalysts. Unfortunately, most reactions resulted very
low yields of the desired 2,3-diphenylindole. For example, N′-
phenylacetohydrazide, previously used by Glorius in Rh
catalysis,4 only resulted in a small amount of the indole product.
Increasing the amount of Ru increased the yield of the indole
product. Nevertheless, the reaction was rather messy, and the
corresponding N−NAc indole was isolated as the major product.
This result suggested that the N−N bond of N−Ac hydrazine
was not oxidative enough to turn over the Ru(II) catalyst. In
order to further increase the oxidative potential of the N−N
bond, we decided to examine cyclic hydrazides in which the N−
N might be further activated by ring strain. Gratifyingly, we
quickly identified that pyrazolidin-3-one, which possesses a
slightly longer N−N bond than their acyclic counterpart,10 was
able to accomplish redox neutral synthesis of indoles using Ru
(Table 1)!
a
Scheme 2. Substrate Scope of Phenylpyrazolidin-3-ones
a
Reactions were carried out on 0.2 mmol scales. Isolated yield.
Table 1. Condition Investigation Using Pyrazolidin-3-one as
a
an Oxidative DG
was particularly effective for a broad range of substituents on the
arene. Ortho-, meta- and para-substituents were well tolerated.
Halgenated substrates afforded the indole products in good
yields. High yields were uniformly obtained regardless of the
electronic nature of the substituents. A substrate bearing a strong
electron-withdrawing nitro group resulted in 93% yield of the
desired product.
b
entry
catalyst
additive
solvent
yield (%)
1
2
3
4
5
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
t-AmOH
t-AmOH
t-AmOH
Ph-Cl
Cu(OAc)2
NaOAc
70 (67)
83 (87)
89 (91)
90 (90)
We next studied the scope of alkynes, especially asymmetrical
ones (Scheme 3). The standard reaction conditions accom-
modated both aryl,aryl-, alkyl,aryl-, and alkyl,alkyl-disubstituted
alkynes without affecting yield. For asymmetrical alkyl,aryl
substrates, single regioisomers (2-aryl-3-alkylindoles) were
obtained exclusively (Scheme 3, 3o−q). Since one major goal
of this work was to expand the scope of the triple bond to the
uncharted terminal alkynes, various 1-substituted acetylenes
were tested using the standard conditions. We were very pleased
to find that terminal alkynes not only reacted smoothly, but also
generated single regioisomers of the indole products (2-
substituted). Due to the redox-neutral nature of this chemistry,
very little dimerization of the alkynes were observed. It should be
noted that halogen substituted phenylacetylenes were efficiently
converted, despite the strong tendency of these substrates to
undergo self Sonogashira coupling reactions (Scheme 3, 3v−
x).11 In addition, cyano (Scheme 3, 3y), ester (Scheme 3, 3z),
and ether (Scheme 3, 3ac) groups were also suitable substituents.
1-Alkyl-substituted acetylenes were also effective with slightly
lower yields. The broad scope of alkynes represents a major
advance for the indole synthesis via C−H annulation reactions.
The product 3-(1H-indol-1-yl)propanamides were demon-
strated for their pharmacological relevance (Scheme 4). As a
matter of a fact, a number of products from Schemes 1 and 2,
along with their nitrile and acid derivatives, were studied for
antibacterial and antifungal activities.12 Very recently, they were
disclosed as potent inhibitors for aP2 (adipocyte protein 2), a
carrier protein for fatty acids that is a potential target for heart
disease, diabetes, asthma, obesity, and fatty liver disease.13 The
primary amides were hydrolyzed using KOH/EtOH to give the
corresponding acids that were further transformed to several
NaOAc
Na2CO3
Ph-Cl
a
Unless specified, the reactions were carried out using 1.5 equiv of
diphenylacetylene and 2 equiv of additive at 110 °C under argon for
18 h. Yields were determined by NMR integration. Numbers in the
b
parentheses are isolated yield.
Further, a condition survey was carried out by treating
substrate 1a and diphenylacetylene 2a with 2.5 mol % of Ru
catalyst and an additive in various solvents under an argon
atmosphere at 110 °C. Although RuCl3 was ineffective even in
the presence of a stoichiometric amount of copper, the
commercially available [RuCl2(p-cymene)]2 was a competent
catalyst for the C−H indole formation. The desired product 3a
was isolated in 67% yield when 2 equiv of Cu(OAc)2 was used
(Table 1, entry 1). Although the reaction did not proceed in the
absence of Cu(OAc)2, we quickly found out that the key missing
component was the OAc anion, not Cu, that would assist the C−
H insertion by Ru. Common carboxylate salts, i.e., NaOAc,
KOAc, and Na2CO3, were equally effective as their copper
counterparts (Table 1, entries 3−5). This reaction worked in
various solvents, with chlorobenzene affording the highest yields.
Although cheaper Na2CO3 promoted this redox neutral C−H
annulation smoothly, NaOAc was eventually chosen for substrate
scope survey considering its mild basicity that tolerates a broader
range of functional groups (vide infra).
The scope of the phenylpyrazolidin-3-one was examined using
diphenylacetylene (Scheme 2). The pyrazolidin-3-one tolerated
substitutions α- to the cyclic hydrazide carbonyl. This protocol
B
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Letter
a
modification of glyoxyl- and formylglycine-functionalized
proteins.17
Scheme 3. Scope of Alkynes
On the basis of the related mechanistic discussions on redox-
neutral Rh catalysis in the literature,4,18 we propose a preliminary
Ru(II)−Ru(IV)−Ru(II) catalytic cycle (Scheme 5). The active
Scheme 5. Proposed Catalytic Cycle for the Indole Synthesis
Ru(II) acetate first inserts into the NH bond of the pyrazolidin-3-
one to give the Ru(II) amido complex A, which undergoes
carboxylate-assisted concerted metalation−deprotonation to
give B. Subsequent alkyne insertion generates intermediate C
that is further oxidized to the Ru(IV) species D by the cleavage of
the cyclic N−N bond. Final reductive elimination releases the
product and the Ru(II) acetate.
a
Reactions were carried out on 0.2 mmol scales. Isolated yield.
In summary, we have developed a general regioselective
synthesis of polysubstituted indoles. This protocol demonstrates
several important advances over existing methods: (1) redox
neutral using a cheap Ru catalyst; (2) unprecedented Ru
turnover via N−N bond cleavage; (3) suitable for previously
incompatible terminal alkynes with excellent regioselectivity; and
(4) in situ installation of a pharmacologically significant N-
propanamide functionality via internal cleavage of the directing
group.
Scheme 4. Derivatization of the Primary Indole Products
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, condition screening table, product
characterizations, and copies of all NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: huangyong@pkusz.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
valuable pharmacophores. Amidation using primary and
secondary amines led to inhibitors for ZipA−FtsZ protein−
protein interaction that is a potential target for antibacterial
therapy.14 Upon treatment with PPA, the resulting acids
underwent Friedel−Crafts cyclization to give a fused [6,6,5]
tricyclic scaffold that was reported as a SIRT1 activator for the
treatment of type II diabetes and other metabolic disorders.15
The acids also cyclized onto the appending 2-aryl to give a
[6,5,7,6]-tetercyclic skeleton that resembles MK-3281, an NS5B
inhibitor for HCV.16 Product 3ac was easily transformed into a
useful Pictet−Spengler ligation reagent for site-specific chemical
■
This work is financially supported by the National Natural
Science Foundation of China (21372013), the Shenzhen
Peacock Program (KQTD201103), and the Shenzhen innova-
tion funds (CXZZ20130517152257071). Y.H. thanks the MOE
for the Program for New Century Excellent Talents in
University.
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