Ruthenium(II)-Catalyzed Traceless C?H Functionalization Using an N?N Bond as an Internal Oxidant

Article abstract of DOI:10.1002/chem.201602936

A previously elusive Ru^II-catalyzed N?N bond-based traceless C?H functionalization strategy is reported. An N-amino (i.e., hydrazine) group is used for the directed C?H functionalization with either an alkyne or an alkene, affording an indole derivative or olefination product. The synthesis features a broad substrate scope, superior atom and step economy, as well as mild reaction conditions.

Full text of DOI:10.1002/chem.201602936

A Journal of
Accepted Article
Title: Ruthenium(II)-Catalyzed Traceless C-H Functionalization Using N-N Bond as
an Internal Oxidant
Authors: Shuguang Zhou; Jinhu Wang; Pei Chen; Kehao Chen; Jin Zhu
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Ruthenium(II)-Catalyzed Traceless C-H Functionalization Using N-
N Bond as an Internal Oxidant
Shuguang Zhou, Jinhu Wang, Pei Chen, Kehao Chen, and Jin Zhu*
Abstract:
A
hitherto elusive Ru(II)-catalyzed N-N bond-based
still remain with respect to the accessibility of starting materials,
substrate scope, atom and step economy, reaction condition and
suitability of specific route-synthesized target compounds for
intended applications. Alkenylanilines are a class of versatile
synthetic intermediates that prove useful in the synthesis of
biologically active heterocyclic scaffolds through annulation with
various π-systems.[11] Despite their great synthetic potential, no
general, concise method that allows convenient incorporation of
various easily transformable substituents has been developed.[12]
We have recently developed a Rh(III)-catalyzed traceless C-H
functionalization protocol, based on the use of an N-amino
(hydrazine) directing group/internal oxidant,[8] for coupling with
alkynes and alkenes. That protocol has allowed high-yield
synthesis of both indoles and alkenylanilines. A generally
observed phenomenon is that Rh(III)-based catalytic systems
can exhibit higher synthetic versatility compared to Ru(II)-based
catalytic systems. Many of the C-H functionalization reactions
achievable with Rh(III)-based catalytic systems cannot be simply
extended to Ru(II)-based catalytic systems. There are many
determining factors, with the choice of directing groups as an
important one. Given the remarkable directing and oxidative
reactivity imparted by the N-amino (hydrazine) group, we
envisioned that a similar synthetic scheme could be likewise
achieved with the less expensive Ru(II) catalyst, and its
traceless C-H functionalization strategy is reported herein. An N-
amino (hydrazine) group is used for directed C-H functionalization
with either an alkyne or an alkene, affording indole derivative or
olefination product. The synthesis features a broad substrate scope,
superior atom and step economy, and mild reaction condition.
Transition-metal-catalyzed oxidative C-H functionalization
has received considerable attention in recent years due to the
superior atom and step economy this approach can offer to the
synthetic community.[1] An external oxidant is typically used to
turnover the catalyst and maintain the catalytic cycle.[2] The last
few years have witnessed the emergence and growing
popularity of an alternative approach, where a built-in internal
oxidant acts as the handle for catalyst turnover.[3] The internal
oxidant approach not only allows the elimination of necessity for
an external oxidant, but also offers, in many cases, enhanced
reactivity, selectivity, mild reaction condition and reduced
amount of waste product.[4] In this synthetic context, the proof-of-
concept protocols are primarily developed based on Rh(III) and
Co(III) catalytic systems, where a diversity of bonds (e.g., O-O,
N-O, N-N, C-N, S-O) can be employed to effect target
transformations.[5] For the second-row Ru(II) catalytic system,
except for one N-N-bond-derived protocol,[6] all reactions are
accomplished through oxidative N-O bond.[7] In that N-N bond-
based synthetic approach, although an internal oxidation
pathway is achieved, the overall reaction is not traceless
because the cleavage of originally cyclized directing group
leaves the linearized portion retained in the final indole product.
Traceless synthesis is desired in organic community as it can
prevent the incorporation of undesired functional groups in target
products. Indeed, the retention of directing group, in part or as a
whole, will in many cases negatively impact their suitability for
intended target applications. As part of our ongoing efforts to
develop traceless synthetic protocols,[3a,8] herein we wish to
report a hitherto elusive Ru(II)-catalyzed N-N bond-based
traceless internal oxidant system for C-H functionalization
(Scheme 1).
successful application in
a Ru(II)-based catalytic system
represents another important advance rather than a trivial
extension in the field of directed C-H functionalization. Detailed
experimental investigations have confirmed our conjecture and
N-amino group can indeed serve as a synthetically useful handle
across the transition metal series.
Indoles and alkenylanilines are two disparate classes of
molecules from structural standpoint, but can share a common
type of synthetic precursor and a similar synthetic pathway if a
suitable reaction scheme is devised. The privileged skeletons of
indoles are the focus of study for both organic and medicinal
chemists.[9] Although a plethora of methods, conventional and
newly developed,[10] have existed for their synthesis, challenges
[a]
Dr. S. Zhou, J. Wang, P. Chen, K. Chen, J. Zhu
Department of Polymer Science and Engineering
School of Chemistry and Chemical Engineering
State Key Laboratory of Coordination Chemistry
Nanjing National Laboratory of Microstructures
Nanjing University, Nanjing 210093 (P. R. China)
E-mail: jinz@nju.edu.cn
Scheme 1. Schematic of Ru(II)-catalyzed C-H bond alkenylation by internal
oxidant
We commenced our study on N-amino-directed C-H
functionalization by examining a coupling reaction with alkynes.
An arylhydrazine substrate 1a and an alkyne substrate 2a were
Supporting information for this article is given via a link at the end of
the document.

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COMMUNICATION
employed as the model starting materials and [RuCl2(p-
cymene)]2 (3 mol%) was tested as the catalyst (Table 1).
Screening of additives indicated that the reaction could indeed
proceed under both basic and acidic conditions, affording 3a as
the product. But no satisfactory yield was achieved for all the
acetate salts initially tested. A change of additive to 1.0 equiv
Zn(OTf)2 boosted the yield to 78% in MeOH. The yield can be
further increased to 91% through the adjustment of temperature
substituted substrates (1o-1q), regioisomeric products were
invariably produced, although steric effect allowed preferred
functionalization at the para position. Besides, in the reaction
involving 1-phenylpropyne, we have only observed the formation
of one regioisomer. The regioselectivity is caused by favored
coupling of arylhydrazine with 1-phenylpropyne at the less
hindered site (methyl-containing carbon) during the migratory
insertion process. Notably, alkynes containing a diversified set
of Ph/alkyl, alkyl/alkyl substituents were also competent
substrates for the transformation (1r-1x). Importantly, a terminal
o
to 60 C and amount of Zn(OTf)2 to 1.2 equiv. In addition, if the
overall atom economy is of paramount importance, one can also
lower the amount of Zn(OTf)2 to 0.05 equivalent to achieve a 47% alkyne equivalent incorporation can be achieved through the use
yield for the indole synthesis reaction (Table S3). A further test
on Ru(II)-based catalysts with different coordination
environments indicated that aromatic ligand was critical for the
creation of a catalytically competent Ru(II) species. The reaction
can be effected by the employment of a cationic Ru complex,
Ru(p-cymene)(OTf)2, as the catalyst. Control experiment
indicates that simple phenylhydrazine cannot undergo the
coupling reaction under the reaction conditions reported herein.
It is speculated that the co-planarity of the 4 atoms (two N-atoms
and two C-atoms) involved in the Ru(II) chelation dictates the
reaction outcome. Preliminary inspection by ChemDraw
indicates that 4 atoms are co-planar in 1a but are not co-planar
in simple phenylhydrazine.
of surrogate substrate containing a Me3Si substituent. To further
confirm the structure assignment reported herein, the structure
of 3l was solved by X-ray crystallographic analysis. The
remarkable reactivity offered by the N-amino directing group is
demonstrated by the scale-up reaction (Scheme 3).
Table 1.Optimization of reaction conditionsa,b
Scheme 2. Ru(II)-catalyzed C-H functionalization for the formation of indolesa,b
With optimal reaction conditions (3 mol% [RuCl2(p-
cymene)]2, 1.2 equiv Zn(OTf)2, MeOH as solvent, 60 oC) in hand,
the substrate scope for both arylhydrazines and alkynes was
explored (Scheme 2). High reaction yields were obtained for the
majority of tested substrates. The reaction is negatively
impacted by an increase of the bulkiness of the substituent on
the N atom (1a-1c). The reaction works efficiently for substrates
containing both electron-donating groups (1d, 1f-1i, 1o) and
electron-withdrawing groups (1e, 1j-1n, 1p, 1q) on the phenyl
ring. A change of substituent position from ortho (1d, 1e) to para
(1h, 1i) leads to a slight reduction of product yield. For meta-
Scheme 3. Gram-scale indole synthesis at a very low catalyst loading
Encouraged by the above results, we next examined the
possibility of replacing alkynes by other coupling reagents. An
obvious choice is alkene (Scheme 4), considering the typical
migratory insertion reaction observed for both types of structures.

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COMMUNICATION
Our extensive screening (Supporting Information) revealed that
the replacement of Zn(OTf)2 with KOAc (0.05 equiv) allowed the
smooth coupling of 1a and 4a and generation of olefination
product 5a in good yield (81%) at 40 C. The reaction yield can
be further improved to 90% with the slight adjustment of
temperature (to 70 oC). And a similar yield can be achieved with
compared to the preceding Ru(II)-catalyzed N-N bond-based
approach (110 oC).[6] It also avoids the acidic additive as
described in our recent Rh(III)-based system,[8] with the reaction
condition for the Ru(II)-based system reported herein being
neutral (Zn(OTf)2) or slightly basic (0.05 equivalent of KOAc).
Moreover, the ability to incorporate dialkyl-substituted alkynes
into indole skeleton and to perform olefination reaction
demonstrates the superior versatility of our Ru(II)-based system
as compared with that described before.[6]
o
the employment of
a
electrophilic Ru complex, Ru(p-
cymene)(OAc)2, as the catalyst. By adopting the optimized
reaction condition, the arylhydrazine substrate scope of the
reaction was next explored. A similar effect of steric hindrance
on the reaction yield was observed for an N-substitution. The
reaction proceeded also well for substrates bearing both
electron-donating (1d, 1f-1i, 1o) and electron-withdrawing (1e,
1j-1n, 1p, 1q) groups on the phenyl ring. For meta substitution,
a
single regioisomer was obtained for methyl-substituted
substrate (1o), whereas regioselectivity was not observed for
either floro- or chloro-substituted substrate (1p, 1q). The
examination of alkene substrate scope revealed the tolerance of
a wide range of electron-withdrawing groups (4r-4y). No reaction
was observed for a non-activated alkene. A single-crystal X-ray
diffraction study for 5l verified the olefination product structure
described herein. Again, the remarkable reactivity offered by the
N-amino directing group is manifested by the scale-up reaction
(Scheme 5).
Scheme 5. Gram-scale olefination reaction at a very low catalyst loading
We then conducted a series of experiments to unveil the
reaction mechanism of these redox-neutral processes. First, a
reaction between substrate 1a and CD3OD was monitored in the
absence of coupling partners (alkynes and alkenes).
A
deuterium labeling percentage of 6% and 11% was observed at
the ortho positions 1a under two respective conditions
(Supporting Information).
Next, two competition reactions were performed to
examine the electronic preference for these transformations
(Supporting Information). A one-pot reaction between 1h/1n and
2a revealed preferred reaction for substrate bearing the
electron-donating group, with the product distributed in a
0.63:0.27 ratio. Similarly, competing coupling of 1h and 1n with
4a indicated favored formation of olefination product for
substrate bearing the electron-donating group (product ratio
0.48:0.14). These results suggest that the C-H activation step
occurs through an electrophilic aromatic substitution pathway
(Supporting Information).
Scheme 6. Determination of intermolecular kinetic isotope effect
To gain further mechanistic insight into the indole
synthesis and olefination processes, two kinetic isotope effect
(KIE) experiments were performed with the participation of 1a
and 1a-d3. A high KIE value was observed for the coupling with
both alkyne (2a, kH/kD=6.1) (Scheme 6) and alkene (4a,
kH/kD=4.3) (Supporting Information), suggesting that the C-H
bond activation was the turnover-limiting step and occurred
through an electrophilic aromatic substitution pathway, and a
electrophilic Ru(II) species was proposed to be catalytically
active.[13] The role of Zn(OTf)2 is to induce anion exchange and
Scheme 4. Synthetic scope of Ru(II)-catalyzed olefination reactiona,b
The reactions reported herein are important from synthetic
condition and substrate scope perspectives. Our Ru(II)-based
catalytic system can proceed at a much lower temperature 60 oC

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COMMUNICATION
generate Ru(p-cymene)(OTf)2. Although OAc- can coordinate
more strongly to Ru(II), Ru(II) is still electrophilic enough to react
with the C-H bond. In addition, OAc- might act as an
intramolecular base for deprotonation. Taken together,
generation of the cationic species is not required for the reaction,
but the electrohilicity of the Ru(II) center is important for
activating the C-H bond. Since the anionic exchange process
involving Zn(OTf)2 is an equilibrium reaction (no precipitate
formation to push the reaction far to the cationic Ru(II) species
side), the role of extra amount of Zn(OTf)2 is proposed to drive
the equilibrium to the cationic Ru(II) species side.
mechanism enables the generation of indoles and olefination
products with a broad range of substitution patterns.
Acknowledgements
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
Keywords: Ru(II)-catalyzed • traceless C-H functionalization •
N-N bond cleavage • indole derivative • olefination product
Based on above mechanistic studies and literature
precedents, the following catalytic sequence was proposed
(Scheme 7, and Supporting Information): reaction of [RuCl2(p-
cymene)]2 with Zn(OTf)2 to generate catalytically competent
[Ru(p-cymene)]2+ species, coordination to N-amino group,
turnover-limiting C-H activation, migratory insertion of either
alkyne or alkene, generation of final product (ring closure for
coupling with alkyne, β-hydride elimination for coupling with
alkene) via internal oxidation mechanism (for indole synthesis:
nucleophilic attack of alkenylruthemium species on aryl-linked N
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Scheme 7. Proposed catalytic cycle for the formation of indoles
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Synthesis of Heterocycles: We
report herein a hitherto elusive Ru(II)-
catalyzed N-N bond-based traceless
C-H functionalization strategy. An N-
amino (hydrazine) group is used for
directed C-H functionalization with
either an alkyne or alkene, affording
Shuguang Zhou, Jinhu Wang, Pei Chen,
Kehao Chen, and Jin Zhu*
Page No. – Page No.
Ruthenium(II)-Catalyzed Traceless C-
H Functionalization Using N-N Bond
as an Internal Oxidant
indole
derivative
or
olefination
product. The synthesis features
a
broad substrate scope, superior atom
and step economy, and mild reaction
condition.