Synthesis of Triazolo- and Oxadiazolopiperazines by Gold(I)-Catalyzed Domino Cyclization: Application to the Design of a Mitogen Activated Protein (MAP) Kinase Inhibitor

Article abstract of DOI:10.1021/acs.orglett.8b03500

An efficient method for the synthesis of [1,2,4]triazolo[4,3-a]piperazine derivatives was established based on a gold(I)-catalyzed domino cyclization of an amidrazone substrate with a terminal alkyne. The amidoxime congeners were converted into [1,2,4]oxadiazolo[4,5-a]piperazine derivatives in the presence of a gold catalyst. The oxadiazolopiperazine is a promising scaffold for the design of novel inhibitors against p38 mitogen activated protein kinase (MAP kinase).

Full text of DOI:10.1021/acs.orglett.8b03500

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Triazolo- and Oxadiazolopiperazines by Gold(I)-
Catalyzed Domino Cyclization: Application to the Design of a
Mitogen Activated Protein (MAP) Kinase Inhibitor
Koki Yamamoto,† Yasushi Yoshikawa,‡ Masahito Ohue,‡ Shinsuke Inuki,† Hiroaki Ohno,†
and Shinya Oishi*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
‡Department of Computer Science, School of Computing, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8550, Japan
S
* Supporting Information
ABSTRACT: An efficient method for the synthesis of [1,2,4]triazolo-
[4,3-a]piperazine derivatives was established based on a gold(I)-catalyzed
domino cyclization of an amidrazone substrate with a terminal alkyne.
The amidoxime congeners were converted into [1,2,4]oxadiazolo[4,5-
a]piperazine derivatives in the presence of a gold catalyst. The
oxadiazolopiperazine is a promising scaffold for the design of novel
inhibitors against p38 mitogen activated protein kinase (MAP kinase).
used piperazines are versatile building blocks for the
development of bioactive substances. One representative
example is the dipeptidyl peptidase IV inhibitor, sitagliptin,
which is currently used in clinics for treatment of diabetes
(Figure 1).1 Fezolinetant is a neurokinin-3 (NK3) receptor
would be provided by a gold-catalyzed intramolecular cascade
reaction of open-chain precursors bearing an alkyne moiety.
That is, the gold-catalyzed reaction of amidrazone 1 would
lead to the formation of piperazine B1 and tetrahydro-1,4-
diazepine B2 through a 6-exo-dig type and 7-endo-dig type
hydroamination of A, respectively (Scheme 1). The piperazine
F
Scheme 1. Possible Reaction Pathways for Gold(I)-
Catalyzed Domino Cyclization of Hydrazonamide
Figure 1. Structures of bioactive [1,2,4]triazolo[4,3-a]piperazine
derivatives.
antagonist, which is expected to be a therapeutic agent
candidate in clinical trials for hot flashes in menopausal
women.2 These agents share a characteristic [1,2,4]triazolo-
[4,3-a]piperazine scaffold. There have also been a number of
applications of fused piperazine scaffolds3 as enzyme inhibitors
and receptor ligands including a p38α kinase inhibitor,4
poly(ADP-ribose) polymerase (PARP) inhibitors,5 and histone
deacetylase (HDAC) inhibitors.6 For these medicinal chem-
istry investigations, a variety of synthetic approaches for
obtaining fused piperazine scaffolds have been developed.7
During the past decade, gold(I) catalysts have attracted
considerable attention as effective π-acids for the activation of
alkynes.8 The gold-catalyzed hydroalkoxylation and hydro-
amination of alkynes and alkenes have been used extensively to
synthesize a broad range of heterocycles.9−11 We envisaged
that [1,2,4]triazolo[4,3-a]piperazine or related heterocycles
(B1) and 1,4-diazepine (B2) intermediates could be converted
into 1,2,4-triazole scaffolds (2 and 3, respectively) by the
subsequent 5-exo-trig type hydroamination (aminal forma-
tion).12 Herein, we report a novel synthetic approach for
[1,2,4]triazolo[4,3-a]piperazine derivatives 2 and their 1,2,4-
oxadiazole congeners by a gold-catalyzed intramolecular
cascade reaction. The applications of the [1,2,4]oxadiazolo-
Received: November 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03500
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
[4,5-a]piperazine scaffold to medicinal chemistry approaches
are also presented.
For our initial experiments, we investigated the optimization
of the reaction conditions for the cascade cyclization of
amidrazone 1a (Table 1). The substrate amidrazone 1a was
entries 2−6], we found that use of Ph3PAuCl and LAuCl
provided 2a in 64% and 73% yields, respectively (entries 4 and
6). No transformation was observed by treatment with Tf2NH
or (Ph3C)B(C6F5)4 (entries 7 and 8).14 The higher temper-
ature (80 °C) in the presence of Ph3PAuCl improved the
reaction efficiency (entries 9). Among three silver salts
(AgNTf2, AgOTf, and AgSbF6) tested for the reactions
(entries 9, 11, and 12), use of AgOTf led to a decrease in
the yield (38%, entry 11). Screening of the reaction solvent
(entries 13−16) revealed that toluene afforded the best result
in terms of the reaction time and yield (entry 16). Decreasing
the loading of catalyst to 5 mol % led to a decrease in the yield
of 2a even after a prolonged reaction time (entry 17). The
optimal reaction conditions were obtained in the presence of
LAuCl/AgNTf2 as a catalyst in toluene (entry 18).
Table 1. Optimization of Reaction Conditions
Next, we examined the substituent effect at the phenyl group
of amidrazone 1 on the intramolecular cyclizations (Table 2).
yield
a
b
entry
catalyst
solvent
DCE
DCE
conditions
(%)
1
2
3
4
5
6
7
8
IPrAuCl/AgNTf2
JohnPhosAuCl/AgNTf2
BrettPhosAuCl/AgNTf2 DCE
Ph3PAuCl/AgNTf2
(t-Bu)3PAuCl/AgNTf2
LAuCl/AgNTf2
50 °C, 21 h
50 °C, 21 h
50 °C, 21 h
50 °C, 21 h
50 °C, 21 h
50 °C, 21 h
50 °C, 21 h
50 °C, 21 h
80 °C, 3 h
100 °C, 2 h
80 °C, 98 h
80 °C, 9.5 h
80 °C, 2 h
80 °C, 5 h
80 °C, 5 h
80 °C, 2.5 h
80 °C, 9 h
80 °C, 2.5 h
19
45
38
64
21
73
0
Table 2. Investigation of the Substituent Effect at the
Substrate Phenyl Group
DCE
DCE
DCE
DCE
DCE
DCE
TCE
DCE
DCE
CH3CN
i-PrOH
Tf2NH
(Ph3C)B(C6F5)4
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgOTf
Ph3PAuCl/AgSbF6
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
Ph3PAuCl/AgNTf2
0
9
74
57
38
72
53
63
72
73
60
78
10
11
12
13
14
15
16
17
18
a
entry
substrate
R1
R2
R3
yield (%)
b
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
74 (78 )
69
Me
OMe
NO2
F
Cl
Br
I
H
H
1,4-dioxane
toluene
b
62 (86 )
c
69
Ph3PAuCl/AgNTf2
LAuCl/AgNTf2
toluene
toluene
b
63 (71 )
58
58
52
78
83
a
b
DCE: 1,2-dichloroethane. TCE: 1,1,2,2-tetrachloroethane. Isolated
c
yield. 5 mol % of the catalyst was used.
1j
a
b
Isolated yield. LAuCl was used instead of Ph3PAuCl.
Ph3PAuCl/AgNTf2-mediated reaction of amidrazones 1b and
1c bearing an electron-donating methyl and methoxy group at
the ortho position (R1) proceeded smoothly to give the desired
products 2b and 2c in 69% and 62% yields, respectively
(entries 2 and 3). Amidrazones 1d−h bearing an electron-
withdrawing nitro and halogen group at the same position were
well tolerated (entries 4−8). Use of LAuCl instead of
Ph3PAuCl led to improvement in the product yields (entries
1, 3, and 5). The positions of the substituent in the reaction
were investigated by using amidrazones 1i and 1j bearing a
methyl group at the meta position (R2) or para position (R3).
Both substrates reacted more efficiently to give the
corresponding triazolopiperazines 2i and 2j in 78% and 83%
yields, respectively (entries 9 and 10). These results implied
that the substituents at the phenyl group were unlikely to
significantly affect the cyclization mode and yield.
obtained by the reaction of the corresponding benzamide with
trifluoromethanesulfonic anhydride (Tf2O) followed by
conjugation with N-tosylhyrdazine13 as an inseparable mixture
of hydrazonamide form 1aX and imidohydrazine form 1aY
(see the Supporting Information). The reaction of 1a with 10
mol % of IPrAuCl/AgNTf2 in 1,2-dichloroethane (DCE) at 50
°C gave [1,2,4]triazolo[4,3-a]piperazine 2a as the isolable
isomer, albeit in a low yield of 19% (entry 1). After screening
several other phosphine ligands [JohnPhos, BrettPhos, Ph3P,
(t-Bu)3P, and tris(4-trifluoromethylphenyl)phosphine (L);
We further investigated the scope of the reaction using a
variety of substrates (Table 3). Amidrazone 1k bearing a
cyclohexyl group at the R1 position reacted less efficiently to
give the corresponding triazole 2k in 48% yield (entry 1). In
contrast, amidrazone 1l bearing a n-propyl group was well
B
DOI: 10.1021/acs.orglett.8b03500
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Letter
Table 3. Substrate Scopes
Scheme 2. Reaction Scope of Amidoximes
a
entry
substrate
R1
R2
R3
yield (%)
1
2
3
4
5
6
7
8
1k
1l
cyclohexyl
n-Pr
2-thienyl
2-pyridyl
Ph
Ph
Ph
Ph
Ts
Ts
Ts
Ts
Ns
Ts
Ts
Ts
H
H
H
H
48
68
81
75
65 (68 )
30
0
0
1m
1n
1o
1p
1q
b
H
Br
Me
Ph
1r
a
b
Isolated yield. LAuCl was used instead of Ph3PAuCl.
tolerated and gave 3-propyltriazole 2l in 68% yield (entry 2).
Thiophene 1m and pyridine 1n also reacted smoothly to
provide the triazoles 2m and 2n, respectively (entries 3 and 4).
The reaction of the substrate having an easily removable nosyl
(Ns) group at the R2 position also afforded an N-Ns protected
piperazine derivative 2o (entry 5). Amidrazone 1p incorporat-
ing a bromoalkynyl group was also converted to the desired
product 2p, but in a lower yield (entry 6). Unfortunately, the
reactions of amidrazone derivatives 1q and 1r bearing a methyl
and phenyl group at the alkynyl terminus (R3 position) did not
proceed at all probably as a result of the lower reactivity of the
internal alkyne for the first step or instability of the possible
product(s) via 7-endo-dig cyclization (entries 7 and 8).
Scheme 3. Synthesis of Oxadiazolopiperazine Derivatives
and Their Biological Activities
To expand the substrate scope, we then moved on to
investigate the reactions of amidoxime derivatives 4, in which
the oxime OH group was expected to work as the second
nucleophilic group of the domino cyclization (Scheme 2). The
reaction under the same conditions using Ph3PAuCl/AgNTf2
for amidoxime 4a provided a [1,2,4]oxadiazolo[4,5-a]-
piperazine 5a in 29% yield. Similarly pyridyl and quinolyl
derivatives (4b and 4c) were converted to the oxadiazolo-
piperazines 5b and 5c, respectively. Amidoxime 4d with a
propylene diamine tether was also subjected to the cyclization
conditions to provide the [1,2,4]oxadiazolo[4,5-a][1,4]-
diazepine 5d via 7-exo-dig/5-exo-trig cyclizations, although in
a lower yield (20%). The o-phenylenediamine derivative 4e
reacted smoothly to produce a unique oxadiazole-fused
quinoxaline derivative 5e in 56% yield. These observations
imply that this reaction would be applicable to the synthesis of
a wide variety of fused triazole and oxadiazole derivatives
including piperidines, diazepines, and quinoxalines. As an
exception, the reaction of imide-derived amidoxime 4f
provided a monocyclic 1,2,4-oxadiazole 5f′ (46%), likely
through the nucleophilic addition of the oxime OH group
onto the intramolecular amide carbonyl group in 4f followed
by dehydration.
mediated phosphorylation of a modified erktide by mobility
shift assay. Compound 6a showed more potent inhibition
against p38α kinase compared with the simple piperazine
derivative 7 [IC50(6a) = 2.1 μM; IC50(7) = 8.0 μM].
Interestingly, oxadiazolopiperazine 6a also exhibited potent
p38β inhibition [IC50(6a) = 5.8 μM], although no inhibition
of piperazine 7 was observed at 30 μM. Of note, no inhibitory
activities of 6a and 7 were observed against p38γ and p38δ
kinases. Alternatively, we designed and synthesized two
The resulting [1,2,4]oxadiazolo[4,5-a]piperazine scaffold
was applied to the development of novel bioactive substances
(Scheme 3). Initially, we designed an oxadiazolopiperazine
derivative 6a, which is a ring-constrained analogue of the p38α
mitogen activated protein kinase (MAP kinase) inhibitor 7.15
It was expected that the 1,2,4-oxadiazole substructure of 6a
could restrict the spatial disposition of the key phenyl group in
7. We assessed the inhibitory activities against p38 kinase-
C
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oxadiazolopiperazine derivatives 6b,c of an NK3 receptor
antagonist, fezolinetant. After removal of the N-Ns group of
5b,c, a fluorobenzoyl group was appended on the piperizine to
provide the expected derivatives 6b,c, respectively. However,
no inhibition of 6b,c against activation of the NK3 receptor
was observed by monitoring intracellular Ca2+ flux (data not
shown).16
To identify the contributing isomer of oxadiazolopiperazine
6a to the bioactivity, two enantiomers (R)-6a and (S)-6a
possessing a quaternary carbon stereocenter were synthesized
via chiral separation using camphorsulfonic acid (see the
Supporting Information). When these two isomers were
independently evaluated for their inhibitory activity against
p38α kinase, the S-isomer (S)-6a exhibited 18-fold more
potent bioactivity compared with the R-isomer [IC50((S)-6a)
= 1.6 μM; IC50((R)-6a) = 29.2 μM]. Similarly, (S)-6a showed
more potent inhibition against p38β kinase [IC50((S)-6a) =
3.6 μM; IC50((R)-6a) = 163 μM].
In order to rationalize the higher potency of the S-isomer
(S)-6a, the possible binding modes of (R)-6a and (S)-6a with
p38α kinase were estimated by docking simulation using Glide
17
̈
in Schrodinger Suite 2018-1. The docking models were
obtained by energy minimization of the complex of each
inhibitor and p38α kinase using MacroModel18 with an
OPLS3 force field.19 For simulation, the crystal structure of the
p38α kinase complexed with an imidazo[1,5-a]piperazine-type
inhibitor 8 was employed (PDB ID: 2QD9; for the structure of
8, see the Supporting Information), because the 3-phenyl-
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine substructure in 8 was
similar to the 3-phenyl-5,6,8,8a-tetrahydro-7H-[1,2,4]-
oxadiazolo[4,5-a]pyrazine part in 6a. In the crystal structure,
a nitrogen atom at the ring junction (position 4 of
imidazo[1,5-a]piperazine) in 8 interacts with the backbone
NH group of Ala34, and the side chains of Lys53 and Asp168
of p38α kinase interact through a water molecule. The binding
mode of the less potent (R)-6a was similar to that of 8, in
which an oxadiazole nitrogen atom interacts with p38α kinase
through a water-mediated interaction. The carbonyl oxygen
makes hydrogen bonds with the NH groups of Met109 and
Gly110 in the hinge region (see the Supporting Information).
Interestingly, the more potent (S)-6a binds with p38α with an
alternative binding mode (Figure 2). The indolylcarbonyl
group of (S)-6a occupied the pocket where the phenyl-
oxadiazole moiety of (R)-6a was bound while the phenyl-
oxadiazole of (S)-6a formed an interaction with the hinge
region of the p38α kinase. In this model, the oxadiazole
nitrogen works as a hydrogen bond acceptor for the backbone
NH groups of Met109 and Gly110. Thus, the more potent
inhibition of (S)-6a is likely attributable to the favorable
interaction between the [1,2,4]oxadiazolo[4,5-a]piperazine
scaffold and p38α kinase.
Figure 2. Structures of MAP kinase inhibitors and the binding mode
of oxadiazolopiperazine (S)-6a with p38α kinase.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03500.
Experimental procedures, characterization data for all
new compounds (PDF)
Accession Codes
CCDC 1872940 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
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: soishi@pharm.kyoto-u.ac.jp.
ORCID
Masahito Ohue: 0000-0002-0120-1643
Hiroaki Ohno: 0000-0002-3246-4809
Shinya Oishi: 0000-0002-2833-2539
Notes
In summary, we developed a facile synthetic process for
triazolopiperazines via a gold-catalyzed cascade cyclization of
amidrazones having a terminal alkyne moiety. We demon-
strated that a variety of fused piperazine derivatives can be
constructed by this reaction. Additionally, the resulting
oxadiazolopiperazine derivative exhibited potent p38α and
p38β kinase inhibition. These types of fused piperazines may
be applicable as a promising scaffold to design novel kinase
inhibitors.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by KAKENHI (15H04654,
15KT0061, 17J10582) from JSPS, Japan; the Basis for
Supporting Innovative Drug Discovery and Life Science
D
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Letter
S.; Tsu, C.; Ringeling, J.; Wager, K.; Xu, H. Bioorg. Med. Chem. Lett.
2014, 24, 5450.
Research (BINDS, JP17am0101092j0001) from AMED, Japan.
We are grateful to Dr. Toru Nakatsu (Kyoto University) for his
generous support of this research. K.Y. is grateful for JSPS
Research Fellowships for Young Scientists.
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DOI: 10.1021/acs.orglett.8b03500
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