Rh(III)-catalyzed intermolecular C-H amination of 1-aryl-1 H -pyrazol-5(4 H)-ones with alkylamines

Article abstract of DOI:10.1021/ol402965d

An intermolecular C-H amination of 1-aryl-1H-pyrazol-5(4H)-ones was achieved under mild reaction conditions, using a low catalyst loading and with a broad scope of aminating reagents. This protocol not only provides the first example of rhodium(III)-catal

Full text of DOI:10.1021/ol402965d

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Intermolecular C−H Amination of
1‑Aryl‑1H‑pyrazol-5(4H)‑ones with Alkylamines
Kui Wu,†,‡ Zhoulong Fan,‡ Yu Xue,† Qizheng Yao,*,† and Ao Zhang*,‡
†Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
‡CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute
of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
S
* Supporting Information
ABSTRACT: An intermolecular C−H amination of 1-aryl-1H-pyrazol-5(4H)-ones was achieved under mild reaction conditions,
using a low catalyst loading and with a broad scope of aminating reagents. This protocol not only provides the first example of
rhodium(III)-catalyzed intermolecular aromatic C−H amination directed by an intrinsic functionality of the substrate/product
but also features aminating an existing drug with either primary or secondary N-benzoate alkylamines as the coupling partners.
ryl amines are essential structural fragments that widely
exist in both natural products and synthetic pharmaceut-
coordinating amide auxiliary with O-benzoyl hydroxylamines
were also reported.
A
icals.1 Conventional preparation of functional aryl amines is
largely dependent on Pd- or Cu-catalyzed C−N couplings2a−f
that generally require prefunctionalization of arenes (halides or
their equivalents). Recently, advances in the transition-metal-
catalyzed C−H activation/amination of inactivated simple
arenes have greatly revolutionalized the design concept and
disconnection strategy in the synthesis of aryl amines, especially
those complexes with multiple functionalities.3,4 However,
compared to the achievements in the intramolecular C−N
bond formation,5 the intermolecular arene C−H activation/
amination has received limited success.6−8 One of the earliest
examples of Pd-catalyzed intermolecular C−H activation/
amination was reported by Yu8a who used N-(4-CF3-C6F4)-
benzamides as the arene substrates and O-benzoyl hydroxyl-
amines as the coupling partners (N-source) under the
Pd(OAC)2/AgOAc/CsF system. With the assistance of
CONH-(4-CF3)C6F4 as the directing group, a series of
secondary amino groups were successfully introduced (eq a,
Scheme 1). Similarly, with N-pivaloyloxy benzamides as the
substrates and N-chloroamines as the coupling partners, a
Rh(III)-catalyzed intermolecular electrophilic C−H amination
was also reported recently by Glorius8b (eq b, Scheme 1).
Meanwhile, with the O-methyloxime moiety as the directing
group, Rh(III)-catalyzed intermolecular C−H amination of
acetophenone O-methyloximes with either secondary or
primary N-chloroalkylamines was achieved by Yu et al. (eq c,
Scheme 1).9 Very recently, Cu(OAc)2-catalyzed10a intermolec-
ular C−H amination using benzamides bearing an 8-amino-
quinoline moiety as the directing group and Ru(II)-catalyzed10b
C−H amination of various heterocycles directed by a weakly
Notably, all the pioneering work was limited to simple
benzamides, acetophenone O-methyloximes, or their equiv-
alents as the arene substrates, and the directing group needs to
be pre-built-in and removed afterward. It would be desirable to
develop new intermolecular C−H aminations on arene
substrates bearing an intrinsic functionality capable of directing
the position selectivity of the C−H amination. To this end, we
recently found that 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(1a) is an optimal arene substrate for Rh(III)-catalyzed
intermolecular electrophilic C−H amination (Scheme 1).
With the pyrazol-5(4H)-one fragment in 1a as the intrinsic
directing group, both secondary and primary alkylamines could
be introduced to the [RhCp*Cl2]2/CsOAc system. To the best
of our knowledge, transition-metal-catalyzed C−H activation/
amination directed by a pyrazol-5(4H)-one moiety (as in 1a)
has not been reported yet. Meanwhile, compound 1a itself is a
neuroprotective drug marked as Edaravone11,12 in 2001 in
Japan for neurological recovery following acute brain ischemia
and subsequent cerebral infarction. Therefore, our current C−
H activation/amination study on compound 1a not only
provides a novel example of intermolecular C−H amination on
arenes bearing an intrinsic directing group, but also offers a new
strategy to generate new analogues of the existing drug 1a for
immediate drug screening.
With 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a) as the
arene substrate and [Cp*RhCl2]2 as the catalyst, we first
Received: October 14, 2013
© XXXX American Chemical Society
A
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Letter
Scheme 1. Reported C−H Aminations and Our Proposal
Scheme 2. Scope of the N-Aryl Pyrazol-5-ones and N-
a
Benzoate Secondary Alkylamines
screened various C−H amination conditions using either
morpholine benzoate 2a13 or N-chloromorpholine 414 as the
coupling partner. Meanwhile, various silver salts, additives,
oxidants, and solvents were also tested (see Supporting
Information (SI)).8,9 It was found that the optimal amination
conditions included using [Cp*RhCl2]2 (2.5 mol %) as the
catalyst, PivOH (0.5 equiv) and CsOAc (2.0 equiv) as the
additives, and morpholine N-benzoate as the coupling reagent
in MeOH at 50 °C, forming product 3aa in 72% yield.
With the optimized conditions in hand, we then explored the
scope and generality of the reaction with a series of N-aryl
pyrazol-5-one substrates (Scheme 2). It was found that N-aryl
pyrazol-5-ones (1a−h), bearing electron-neutral or -donating
groups in the phenyl ring, were well tolerated, and products
3aa−3ha were obtained in 46−81% yields with exclusive ortho-
selectivity. In the cases of 1b−f where two ortho-positions were
available, the amination occurred only on the less steric site
(3ba, 3ea, 3fa). Similarly, N-naphthalenyl pyrazolone was
aminated in the less sterically hindered position in good yield
(62%, 3ea). Substrate 1i15 bearing a 4-methyl group on the
pyrazol-5-one ring also participated in the amination reaction,
although product 3ia was obtained in a relatively lower yield
(33%). The result seems reasonable since the 1H-pyrazol-
5(4H)-one in 1i was tautomerized to 1H-pyrazol-3(2H)-one in
the product during the reaction and the existence of a 4-methyl
hampered this conversion.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), [Cp*RhCl2]2
b
(2.5 mol %), CsOAc (2 equiv), PivOH (0.5 equiv), 50 °C, 12 h.
Reaction time was 24 h. The reaction was performed at rt for 4 h.
c
were well tolerated (3ab, 3ad, 3ag). A bulky amination reagent
derived from 2,6-dimethylmorpholine was also tolerated to
afford product 3ag in 62% yield. However, it was not clear why
the nonsubstituted piperidine benzoate gave a lower yield (3ac,
31%).
Encouraged by the C−H amination with both secondary and
primary N-chloroalkylamines reported by Yu,9 we then tested
whether this is also the case in our study. Accordingly, a small
series of N-benzoate primary alkylamines were prepared and
subjected to the amination of N-aryl pyrazol-5-one substrates
under the optimized conditions (Scheme 3). To our delight, all
the N-benzoate primary amines showed superior activities in
terms of both reaction efficiency and yield. With 1a as the
model substrate, amination with benzoate derived from
cyclohexanamine proceeded very well leading to corresponding
primary amino substituted pyrazol-5-one 7b in 93% yield.
Compounds 7a and 7c bearing acyclic primary amino groups
were obtained as well in 82% and 78% yields, respectively. High
Meanwhile, a small series of benzoates 2b−g derived from
various secondary alkylamines were employed as the coupling
partners to react with 1a under the optimized amination
conditions. As shown in Scheme 2, all the tested benzoates
derived from piperidine/piperazine/morpholine took part in
the amination reaction smoothly and gave corresponding
products 3ab−3ag in 31−78% yields. Both electron-donating
(−OMe) and electron-withdrawing (−COOMe) substituents
B
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Letter
a
Scheme 3. C−H Amination with Primary Amines
Scheme 4. Control Experiments
a
Reaction conditions: 1 (0.5 mmol), 6 (0.75 mmol), [Cp*RhCl2]2
(2.5 mol %), CsOAc (2 equiv), PivOH (0.5 equiv), 50 °C, 1 h.
yields (>80%) were obtained from tetrahydro-2H-pyran-4-
amine and (N-Boc-piperidinyl)-4-amine (7d, 7e). Meanwhile,
with the N-benzoate primary amine as the coupling partner,
various N-aryl pyrazol-5-ones were also investigated. As shown
in Scheme 3, amination reagents with an electron-withdrawing
group (Cl or CF3) or with an electron-donating group (OMe)
reacted smoothly giving the corresponding products 7f−h in
66−82% yields. Notably, the substrate bearing an ester group in
the pyrazol-5-one ring also participated in the reaction readily
and offered product 7i in 86% yield.
All the structures of the products were fully characterized and
secured by the X-ray single crystal analysis of 7d (see SI).
Notably, the structure of 1H-pyrazol-5(4H)-one as in 1
tautomerizes to 1H-pyrazol-3(2H)-one as in product 3. Since
it has been reported that 1H-pyrazol-5(4H)-one 1a is stable in
CDCl3 and readily tautomerizes to 1H-pyrazol-3(2H)-one 1a′
in DMSO-d6,12 we conducted an NMR analysis of substrate 1a
in CD3OD and found that it was indeed tautomerized
completely to 1a′. Meanwhile, aminations of dimethyl- and
dichloro-substituted pyrazol-5(4H)-ones 8a and 8b were
conducted under the same conditions and no reaction was
observed (Scheme 4) suggesting that the reactive carbonyl α-H
is critical for the amination reactions.
Figure 1. Proposed mechanism.
to give the complexes C which then converts to product 3aa
under the acidic conditions (path b).
In summary, a new rhodium(III)-catalyzed intermolecular
C−H amination of arenes directed by a pyrazolone moiety was
developed. This protocol is characterized by the following
features: (1) it is the first example of rhodium(III)-catalyzed
intermolecular C−H aromatic amination directed by an
intrinsic functionality of the substrate/product; (2) both
primary and secondary alkylamines can be introduced; (3)
Since substrate 1a itself is a marketed neuroprotective drug
(Edaravone), new amino analogues will directly generate
pharmaceutically useful products for biological screening.
Besides, the relatively mild reaction conditions, low catalyst
loading, and broad scope of aminating reagents make this
reaction valuable for practical use.
ASSOCIATED CONTENT
* Supporting Information
■
S
Based on the above results, a tentative mechanism was
proposed. As shown in Figure 1, substrate 1a converts to its
tautomer 1a′ in MeOH and then undergoes a C−H activation
with the active catalyst RhCp*(OAc)2 to give a RhIII species A.
As proposed by Yu9 and Glorius,8b species A might go through
two possible paths to form aminated product 3aa. In path a,
oxidative addition of benzoate 2a to rhodacycle A leads to a
RhV species B, which then undergoes a reductive elimination
followed by acidification to afford final product 3aa.
Alternatively, the rhodacycle A can directly react with
morpholine benzoate 2a through an electrophilic amination8a,13
Experimental details and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: aozhang@simm.ac.cn.
*E-mail: qz_yao@yahoo.com.cn.
Notes
The authors declare no competing financial interest.
C
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Letter
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ACKNOWLEDGMENTS
■
This work was supported by grants from the Chinese NSF
(81125021, 81373277) and from the State Key Laboratory of
Drug Research (SIMM1302KF-08), Shanghai Institute of
Materia Medica.
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