Copper-catalyzed sequential cyclization/migration of alkynyl hydrazides for construction of ring-expanded N-N fused pyrazolones

Article abstract of DOI:10.1021/acs.orglett.0c02378

A copper-catalyzed sequential cyclization/migration reaction of alkynyl hydrazides for the synthesis of ring-expanded N-N fused pyrazolones was developed. Control experiments indicate that the copper-ligand complex plays an essential role in the reaction. This approach features a broad scope including some functional group tolerance as well as a nucleophilic addition/1,3-migration/formal 1,2-migration sequence. This protocol provides simple manipulation and less waste due to high yield and atom economy. The synthetic utility of N-N fused pyrazolones was also demonstrated by further transformations.

Full text of DOI:10.1021/acs.orglett.0c02378

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Sequential Cyclization/Migration of Alkynyl
Hydrazides for Construction of Ring-Expanded N−N Fused
Pyrazolones
Keiji Konishi, Motohiro Yasui, Hitomi Okuhira, Norihiko Takeda, and Masafumi Ueda*
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ABSTRACT: A copper-catalyzed sequential cyclization/migration
reaction of alkynyl hydrazides for the synthesis of ring-expanded N−
N fused pyrazolones was developed. Control experiments indicate
that the copper−ligand complex plays an essential role in the
reaction. This approach features a broad scope including some
functional group tolerance as well as a nucleophilic addition/1,3-
migration/formal 1,2-migration sequence. This protocol provides
simple manipulation and less waste due to high yield and atom
economy. The synthetic utility of N−N fused pyrazolones was also
demonstrated by further transformations.
Scheme 1. Transition-Metal-Catalyzed Sequential
Cyclization−Migration Reaction
itrogen-containing heterocycles are included in various
Nuseful compounds, such as natural products, pharma-
ceuticals, agrochemicals, dyes, and polymeric materials.1
Therefore, the development of a new synthetic methodology
for N-containing heterocycles is an important problem in
organic synthetic chemistry, and consequently, various
methodologies have been reported.2 One of the most powerful
methods for the synthesis of N-containing heterocycles is the
intramolecular nucleophilic addition of a nitrogen atom into an
activated alkyne by a π-Lewis acidic transition metal catalyst.3
Generally, such reactions proceed in a highly atom-economical
manner under mild conditions. In contrast, sequential (i.e.,
domino or tandem) reactions, which enable transformation
from a simple starting material to a complex molecule by
combining two or more different reactions during single
manipulation, are powerful strategies for short-step synthesis.4
Based on these methodologies, the synthesis of heterocycles
via a sequential cyclization−migration reaction has been
developed. This strategy offers not only the construction of
heterocycles but also the viability of various substituents that
are difficult to introduce.5 For most examples of sequential
nucleophilic addition−migration reaction for synthesis of N-
containing heterocycles, transition-metal-catalyzed cyclization
of alkynes bearing N−Y functional groups (Y = migratory
group) followed by 1,3-migration has been reported (Scheme
1, eq 1).6 Moreover, Iwasawa7a and Zhang7b established
cyclization/1,2-migration sequences to generate N-fused
tricyclic indoles using cyclic amines or amides, respectively
(eq 2). Although these are pioneering examples of the
synthesis of heterocycles via cyclization/1,2-migration, 1,2-
migration accompanied by C−N bond formation has not been
reported yet. Therefore, we have devised the intramolecular
cyclization of hydrazide involved in 1,2-migration while
forming a C−N bond. Herein, we report the copper-catalyzed
sequential cyclization/1,3-migration/formal 1,2-migration of
alkynyl hydrazides to generate ring-expanded N−N fused
Received: July 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02378
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
pyrazolones (eq 3). Moreover, N−N fused pyrazolones are
known to exhibit a wide range of biological activities for TNF-
α inhibition,8a antibiotics,8b and herbicides.8c Although various
synthetic methods for constructing N−N fused pyrazolone
skeletons have been reported because of their interesting
structure,9 alkynyl hydrazides, which are easily prepared via the
condensation of propiolic acid with hydrazine, have not been
employed as substrates.10
temperature, the yields decreased (entries 14 and 15).
Therefore, the optimum reaction conditions were determined
to include 10 mol % of CuBr2 and bathocuproine in PhCl
under reflux (entry 13). It is noted that the reaction could also
be carried out in 1.6 mmol scale without any problem (86%
yield, entry 16).
A variety of substrates were then screened under the
optimized sequential reaction conditions (Scheme 2). First,
We began our research using phenylalkynyl hydrazide 1aa as
the model substrate. First, hydrazide 1aa was treated with 10
mol % of Cu(OTf)2 and CuCl2 as a catalyst in dichloroethane
(DCE) under reflux, but the desired N−N fused pyrazolone
2aa was not obtained (Table 1, entries 1 and 2). In contrast,
a
Scheme 2. Substrate Scope
a
Table 1. Optimization of Cyclization/Migration Reaction
entry
catalyst
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
Cu(OTf)2
CuCl2
CuBr2
CuBr
DCE
DCE
DCE
DCE
DCE
MeCN
EtOH
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
0
0
21
5
AuBr3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
25
20
25
42
28
68
64
70
93
71
76
86
9
bipyridyl
phenanthroline
neocuproine
bathophenanthroline
bathocuproine
bathocuproine
bathocuproine
bathocuproine
10
11
12
13
14
15
b
PhCl
PhCl
PhCl
c
CuBr2
d
16
CuBr2
a
Substrate 1aa (0.13−0.56 mmol) was treated with a catalyst (0.13−
0.056 mmol) and ligand (0.013−0.056 mmol) in a solvent and stirred
b
under reflux for 30 min. The reaction was carried out at 100 °C.
c
d
The reaction was carried out using 5 mol % CuBr2. 1aa (1.6 mmol)
was employed.
the expected sequential cyclization/migration reaction using
CuBr2 gave 2aa in 21% yield (entry 3). It is noted that a
brominated product was not observed.11 CuBr was not
effective for this sequential reaction, although AuBr3 was
comparable to CuBr2 (entries 4 and 5). Next, the solvent effect
on the reaction was investigated using MeCN and EtOH,
which have similar boiling points (b.p.). As a result, almost
similar yields as in the case of DCE were observed for such
solvents, while the reaction using PhCl was conducted at 132
°C to afford 2aa in higher yield (entries 6−8). This result
suggests that this reaction strongly depends on the reaction
temperature. Moreover, various ligands on the copper catalyst
were investigated. The addition of bipyridyl noticeably
decreased the yield, while phenanthroline increased the yield
up to 68%, which indicates that this sequential reaction is
affected by the choice of ligand (entries 9 and 10). Further
investigation of the ligands led to a 93% yield when
bathocuproine was employed (entry 13). When the reaction
was carried out with a decreased catalyst loading or at a lower
a
Standard reaction conditions: 1ab−1fa (0.15−0.43 mmol), CuBr2
(0.015−0.043 mmol), and bathocuproine (0.015−0.043 mmol) in
PhCl under reflux for 30 min. The reaction was carried out for 24 h.
b
alkynyl hydrazides 1ab−1an bearing a variety of substituents
on the benzene ring for the construction of N−N fused
pyrazolone were investigated. The desired pyrazolones 2ab−
2ak were obtained in high yield, and reactions with both
electron-donating and electron-withdrawing groups at the
para-position were feasible and functional-group-tolerant (2ab,
Me; 2ac, OMe; 2ad, Ph; 2ae, F; 2af, Br; 2ag, CO2Me; 2ah,
CN; 2ai, NO2; 2aj, CF3; 2ak, MOM; 68%−96%). The
structure of 2af was confirmed by X-ray crystallography, as
B
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a
shown in Scheme 2. In addition, pyrazolones 2al−2an having
methyl groups at the ortho- or meta-position on the benzene
ring were also obtained in high yields (2al, 2-Me; 2am, 3-Me;
2an, 3,5-Me2; 71%−94%). Even reactions with alkynyl
hydrazides 1ao and 1ap bearing a 1-naphthyl group or a 1,3-
benzodioxole unit, respectively, proceeded smoothly (2ao−
2ap; 76%−79%). Next, alkynyl hydrazides bearing an alkyl
group at the alkyne terminus were investigated. n-Butyl and
cyclohexyl, as well as bulky substituents such as a tert-butyl
group, were applicable to afford the corresponding pyrazolones
(2aq−2as; 72%−96%). Isopropenylalkynyl hydrazide 1at,
which might be labile to transition metal catalysts, was also
transformed to pyrazolone 2at in 76% yield. Furthermore, the
cyclic amine moiety was investigated. Alkynyl hydrazides with
octahydrocyclopenta[c]pyrrole or indoline gave corresponding
tricyclic fused compounds 2ba and 2ca in 89% and 63% yields,
respectively. Hydrazide 1da, derived from 2,5-dihydropyrrole,
was also tolerant in this sequential reaction. Subsequently, the
corresponding pyrazolone 2ea was regioselectively obtained
from the hydrazide with the NHBoc group at the 3-position on
the pyrrolidine ring, which was likely due to the 1,2-migration
proceeding while the N atom of the amide prevented the steric
repulsion from the bulky NHBoc moiety. Finally, when N-
piperidino-alkynylhydrazide 1fa was used, the desired ring
expansion proceeded in moderate yield.
Scheme 4. Control Experiments
To demonstrate the synthetic utility of this methodology,
further chemical transformations were carried out (Scheme 3).
a
Scheme 3. Product Transformation
Standard reaction conditions: 9, 10, or 1ga (0.066−0.32 mmol),
CuBr2 (0.0066−0.032 mmol), and bathocuproine (0.0066−0.032
mmol) in PhCl under reflux for 30 min.
into product 2aa in 81% yield under standard conditions, while
decomposition occurred without the catalyst and ligand (eq
2).9d This result suggests that not only does the spiro
ammonium intermediate exist as a reaction intermediate, but
also the catalyst promotes migration. To investigate the effect
on a bromide ion, tetrabutyl ammonium bromide (TBAB) was
employed as a catalyst to afford 2aa in 31% yield, which
indicates a bromide ion contributes to the reaction, especially,
ring expansion (eq 3). Furthermore, the reaction using N-
methyl hydrazide 10 as a substrate showed no reaction, which
shows that the amide proton is involved in the reaction (eq 4).
Finally, when acyclic hydrazide 1ga was used as a substrate,
pyrazolone 11 was obtained in 71% yield but not 2ga, probably
because the ethyl group of 1ga was removed during the
reaction (eq 5). This result suggests that the ring expansion
reaction would be involved in the intramolecular nucleophilic
substitution of alkyl bromide.
First, with PtO2 under a hydrogen atmosphere, the double
bond of pyrazolone 2aa could be reduced to generate 3-
pyrazolidinone 3 in high yield. Moreover, it was possible to
introduce various substituents at the 2-position of pyrazolones
under oxidative conditions. Nitration,12a iodination, thiola-
tion,12b and alkynylation12c reactions proceeded smoothly to
afford the corresponding products 4−7 in good to high yields.
With Lawesson’s reagent under heating conditions, pyrazolone
2aq was converted to thiopyrazolone 8 in good yield.
Some control experiments were carried out to gain in-depth
insight into the reaction mechanism (Scheme 4). First, starting
material 1aa and aminimide 9 were obtained when the catalyst
and ligand were not employed in the reaction (eq 1). This
result indicates that the copper catalyst promotes cyclization
but to minimal effect. Next, spiro aminimide 9 was converted
Inspired by the aforementioned results and recent reports,6,7
a plausible reaction mechanism is proposed in Scheme 5. First,
alkynylhydrazide 1aa is coordinated to the copper catalyst−
ligand complex A13 to activate the alkyne moiety, followed by
5-endo-dig cyclization proceeding to form spiro ammonium
intermediate C.14,15 Subsequently, copper aminimide D is
generated via 1,3-migration of the amide proton.16 Next, the
bromide ion of copper aminimide D undergoes intramolecular
nucleophilic attack of an electrophilic carbon of neighboring
pyrrolidinium to produce alkyl bromide E. Finally, copper
amide reacts with intramolecular alkyl bromide to form N−N
fused pyrazolone 2aa, while regenerating copper complex A.17
In conclusion, we have introduced a copper-catalyzed
sequential migration reaction of readily available alkynylhy-
C
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02378
Scheme 5. Proposed Mechanism
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for JSPS
KAKENHI (JP18K06590, M.U.; JP19K23815, M.Y.;
JP19K05467, N.T.), the Hoansha Foundation (M.U.), and
Nagai Memorial Research Scholarship from the Pharmaceut-
ical Society of Japan (N-195302, K.K.). We also thank Rimi
Konishi from the Division of Material Science, Advanced
Research Support Center (ADRES), Ehime University for her
technical assistance with the X-ray crystallographic analysis.
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also demonstrated by further transformations.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02378.
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CCDC 1993619 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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AUTHOR INFORMATION
Corresponding Author
■
Masafumi Ueda − Kobe Pharmaceutical University, Kobe 658-
8558, Japan; orcid.org/0000-0002-8003-2971;
Email: masa-u@kobepharma-u.ac.jp
Authors
Keiji Konishi − Kobe Pharmaceutical University, Kobe 658-
8558, Japan
Motohiro Yasui − Kobe Pharmaceutical University, Kobe 658-
8558, Japan; orcid.org/0000-0001-9324-3463
Hitomi Okuhira − Kobe Pharmaceutical University, Kobe 658-
8558, Japan
Norihiko Takeda − Kobe Pharmaceutical University, Kobe 658-
8558, Japan
D
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