Synthesis of 2-Substituted 1,2,3-Triazoles via an Intramolecular N–N Bond Formation

Article abstract of DOI:10.1002/ejoc.201901519

An efficient synthesis of 2-aryl 1,2,3-triazoles based on an intramolecular N–N bond formation is described. Selective activation of bis-hydrazone at the dimethylamino hydrazone group with MeI forms a mono-hydrazonium species. Treatment of the hydrazonium

Full text of DOI:10.1002/ejoc.201901519

DOI: 10.1002/ejoc.201901519
Communication
Heterocycles
Synthesis of 2-Substituted 1,2,3-Triazoles via an Intramolecular
N–N Bond Formation
Cheng-yi Chen,*[a] Xiaowei Lu,[b] Mareike C. Holland,[c] Shichang Lv,[b] Xuebao Ji,[b]
Wei Liu,[b] Jie Liu,[b] Dominique Depre,[c] and Pieter Westerduin[c]
Abstract: An efficient synthesis of 2-aryl 1,2,3-triazoles based to the formation of a wide variety of 2-aryl-1,2,3-triazoles in
on an intramolecular N–N bond formation is described. Selec- good to excellent yields. The reaction likely follows an intra-
tive activation of bis-hydrazone at the dimethylamino hydraz- molecular SN2 displacement mechanism with the trimethyl-
one group with MeI forms a mono-hydrazonium species. Treat- ammonium moiety serving as a good leaving group for the
ment of the hydrazonium species with a base smoothly leads intramolecular N–N bond formation.
arylation using the 1,2,3-triazole in excess to suppress arylation
on the N1-position (Scheme 1, Equ. 1).[6,7] Alternatively, arylation
via SNAr displacement reaction[8a–8c] using 4,5-dibromo 1,2,3-
triazole has also been reported to ensure regioselectivity exclu-
sively at the 2-position of the triazole (Scheme 1, Equ. 2). This
protocol requires preparation of the 4,5-dibromotriazole sub-
strate and subsequent debromination to obtain 3,4-unsubsti-
tuted triazoles. Very recently, a catalyst-free regioselective
N2-arylation of 1,2,3-triazoles using diaryl iodonium salts was
reported (Scheme 1, Equ. 3).[8d] Furthermore, CuSO4-mediated
cyclization of O-acetyl-oximo-hydrazones[11] under basic condi-
tions gives access to 2-aryl-1,2,3-triazole N-oxides which require
subsequent reduction of the oxide moiety using an excess of
zinc dust to deliver 2-aryl-1,2,3-triazoles (Scheme 1, Equ. 4).[9]
Many biologically active compounds contain 1,2,3-triazole
scaffolds as essential structural units even though 1,2,3-triazole
derivatives have not been found in natural products up to
date.[1] The Cu-catalyzed-azide–alkyne-cycloaddition[2] (also re-
ferred to as “click chemistry”) has emerged as a powerful tool
for the construction of 1-substituted triazoles. The protocol,
however, cannot be extended to the synthesis of 2-substituted
1,2,3-triazoles,[3] which also exist in many biologically active
agents. For example, both Suvorexant (MK-4305), a drug for the
treatment of primary insomnia[4] and Seltorexant, a highly selec-
tive OX2R antagonist,[5] contain 2-aryl-substituted 1,2,3-triazole
moieties (Figure 1).
Figure 1. 2-Aryl-1,2,3-triazoles as medicinal agents.
The importance of 2-aryl-substituted 1,2,3-triazoles as medi-
cinal agents has consequently inspired the development of suit-
able synthetic methods towards this class of compounds.[6–10]
As shown in Scheme 1, conventional methods to synthesize
this class of compounds typically relies on a Cu or Pd-catalyzed
[a] Janssen R&D, API Small Molecule Development, Discovery Product
Development & Supply,
Hochstrasse 201, 8205 Schaffhausen, Switzerland
E-mail: cheng88chen@gmail.com
[b] Porton (Shanghai) R&D Center, Zizhu Science Park,
1299 Ziyue Road, Minhang District, Shanghai 200241, China
[c] Janssen R&D, API Small Molecule Development, Discovery Product
Development & Supply,
Turnhoutseweg 30, 2340, Beerse, Belgium
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901519.
Scheme 1. Prior art on the synthesis of 2-substituted 1,2,3-triazoles.
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This process is not environmentally benign as it suffers from yield (entry 11) of the desired product. The reactions appeared
tedious workup to remove copper salts and disposal of excess to be have little dependence on the temperature since similar
zinc waste.[9b] Perhaps the currently most straightforward pro- yields (86–90 %) were obtained at temperatures ranging from
tocol to prepare 2-substituted 1,2,3-triazoles is to use a Cu-cata- 25–85 °C (entries 5, 15 and 16). As expected, the base plays a
lyzed cyclization of bis-hydrazones through an intramolecular crucial role to facilitate the cyclization as no background reac-
N–N bond formation (Scheme 1, Equ. 5).[10] Obviously, aside tion occurred without any base (entry 19) and less than
from the simplicity of this reaction, this protocol is not atom- 2.0 equiv. of K2CO3 (1.0 and 1.2 equiv.) gave lower yields (entries
economical due to the loss of an aniline group, some of which 17 and 18). Based on the reaction condition screening, cycliza-
are expensive.
tion condition using K2CO3 (2.0 equiv.) as base in anhydrous
DMF at 50 °C (entry 15) was chosen and extended to other
substrates.
The N–N bond formation to form 2-aryl-1,2,3-triazoles be-
comes more attractive when one can substitute the aniline
moiety by another less expensive leaving group and run the
reaction under milder conditions. Herein, we report a new and
facile synthesis of 2-aryl-substituted 1,2,3-triazoles via an intra-
molecular SN2 reaction of hydrazonium salts in the presence of
K2CO3 or KHCO3 as base at 25–50 °C in DMF. This method takes
advantage of an easy access to the mixed bis-hydrazones from
commercially available 1,2- or 1,3-dicarbonyl species and highly
efficient SN2 displacement step in the N–N bond formation to-
wards 2-aryl-1,2,3-triazoles.
Table 1. Optimization of reaction conditions.[a]
Entry
Base
Solvent
Temp.
Yield[b]
1
Et3N
DMF
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
50 °C
85 °C
50 °C
50 °C
50 °C
57 %
Trace
29 %
71 %
86 %
76 %
76 %
20 %
60 %
84 %
11 %
Trace
Trace
82 %
90 %
88 %
50 %
72 %
0 %
As shown in Scheme 2, sequential condensation of 1,2-bis-
aldehydes or ketones with ArNHNH2 and dimethylhydrazine in
aqueous media afforded the mono-hydrazone 3. Treatment of
the bishydrazone with methyl iodide gives hydrazonium species
4 in good overall yield. We envisioned that the trimethyl
ammonium moiety in 4 would serve as a good leaving group
for the desired intramolecular N–N bond formation. Initial opti-
mization efforts focused on the cyclization of 4a (Ar = Ph) under
basic conditions. Hence, various bases were employed to test
the feasibility of intramolecular N–N bond formation. As shown
in Table 1, when Et3N was evaluated, the reaction afforded the
desired cyclization product triazole 5a, albeit in moderate yield
(57 %, entry 1). Base screening revealed that organic bases, such
as Et3N, pyridine or DBU, gave low to modest yields (entries 1,
2 and 3), whereas inorganic bases gave much higher yields,
except for tBuOK which only provided 20 % yield (entries 5 to
9). Solvent screening showed that the reaction afforded triazole
5a in much higher yield in polar aprotic solvents such as DMF,
DMAc or acetonitrile (entries 5, 10 and 14, respectively) than in
nonpolar solvents such as toluene (entry 12). Only trace
amounts of the desired triazole 5a were obtained in THF pre-
sumably due to the low solubility of K2CO3 (entry 13) in this
solvent. The reaction in MeOH was ineffective giving only 11 %
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
pyridine
DBU
NaOAc
K2CO3
KHCO3
KOH
tBuOK
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
N/A
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
MeOH
toluene
THF
acetonitrile
DMF
DMF
DMF
DMF
DMF
[a] Reaction conditions: 4a (0.3 mmol), base (0.6 mmol), solvent (2 mL) at
25 °C for 2 h, entry 15 and 16 at 50 and 80 °C, respectively and entry 17 and
18 with 1.0 and 1.2 equiv. of K2CO3, respectively. [b] Yield was calculated with
HPLC against the standard.
As shown in Scheme 3, the cyclization protocol was readily
applied to a wide variety of substrates. Functional groups in-
cluding halide, ether, nitrile, and ester groups were well toler-
ated under the mild reaction conditions. Mono-halo substituted
hydrazonium salts underwent the N–N bond formation reaction
efficiently to give the corresponding triazoles 5b–g in good
yields. We noted that the hydrazonium salts with a fluorine
atom at meta position, 4b, gave the triazole 5b in much higher
yield than those with fluorine at para or ortho position, 5c and
5d, respectively. The cyclization of hydrazonium salts with elec-
tron-donating groups also afforded the expected triazoles 5h–
i in good yields using K2CO3 as base.[12] Surprisingly, the cycliza-
tion of hydrazonium salts with electron-withdrawing groups in
the presence of K2CO3 did not provide the expected triazoles.
However, the weaker base KHCO3 facilitated the cyclization ef-
fectively to give the corresponding triazoles 5j–o in moderate
to good yields. Compound 5p, a key intermediate in the synthe-
sis of Seltorexant, was obtained in 81 % yield. It is worth noting
Scheme 2. Synthetic strategy for 1,2,3-triazoles via intramolecular SN2 reac-
tion.
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that sterically hindered hydrazonium salts also afforded the de-
sired triazoles 5q and 5r in 75 % and 80 % isolated yield, re-
spectively. Furthermore, subjection of the hydrazonium salt de-
rived from the corresponding keto-aldehyde to the reaction
conditions led to triazole 5s in excellent yield. The reaction
could also be applied to a hydrazonium salt derived from a 1,2-
diketone, affording triazole 5t in a respectable yield (58 %). The
practicability of the method was demonstrated by a number of
substrates at >5 mmol scale (5a to 5f, see supporting informa-
tion).
Scheme 4. Triazole preparation from hydrazonium salt 6.
ketone and aldehyde moieties was readily prepared from 1,3-
dicarbonyl derivative 8a[13] in 95 % yield. Subsequent methyl-
ation and cyclization mediated by KHCO3 in DMF at 25 °C af-
forded triazole 10a in 93 % yield. Extension to heterocyclic aro-
matic ketones bearing furan and thiophene groups were also
feasible, leading to compounds 10b and 10c in 96 % and 85 %
yield, respectively. These examples shown in Scheme 4 demon-
strated the versatility of this methodology for the synthesis of
triazoles via an intramolecular N–N bond formation. We envi-
sion a wider scope of the herein described approach since it
can take advantage of readily available 1,3-dicarbonyl species
and aryl diazonium salts.[14]
Scheme 5. Triazole preparation from bishydrazone 10.
We propose that the reaction path likely proceeds via an
SN2 displacement mechanism in which the trimethylammonium
moiety serves as a good leaving group. In this mechanistic pro-
posal (Scheme 6), deprotonation of 4 leads to intermediate 11a
Scheme 3. 2-Aryl-1,2,3-triazoles via intramolecular N–N bond formation.[a]
As shown in Scheme 4, we subsequently demonstrated that
piperidin-1-amine could serve as an alternative reagent to di-
methylhydrazine. Hydrazonium salt 6 was prepared in almost
quantitative yield from 3b in two steps and subsequent cycliza-
tion afforded triazole 5b in 92 % yield, which was higher than
the reaction of the N,N-dimethylhydrazine counterpart (87 %
yield, 5b, Scheme 3).
We next explored alternative synthetic methods to make
mixed hydrazones from an 1,3-dicarbonyl derivative and an aryl
diazonium salt. As shown in Scheme 5, bishydrazone 9a bearing
Scheme 6. Proposed reaction paths for the preparation of 2-aryl-1,2,3-tri-
azoles via an intramolecular N–N bond formation.
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Communication
tion reaction to 2-substituted 1,2,3-triazoles, see: E. Decuypere, S. Ber-
nard, M. Feng, K. Porte, M. Riomet, P. Thuery, D. Audisio, F. Taran, ACS
Catal. 2018, 8, 11882; b) For a recent review on N–N bond formation
see: Q. Guo, Z. Lu, Synthesis 2017, 49, 3835.
a) C. D. Cox, M. J. Breslin, D. B. Whitman, J. D. Schreier, G. B. McGaughey,
M. J. Bogusky, A. J. Roecker, S. P. Mercer, R. A. Bednar, W. Lemaire, J. G.
Bruno, D. R. Reiss, C. M. Harrell, K. L. Murphy, S. L. Garson, S. M. Doran,
T. Prueksaritanont, W. B. Anderson, C. Tang, S. Roller, T. D. Cabalu, D. Cui,
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approval: L. P. H. Yang, Drugs 2014, 74, 1817.
which readily tautomerizes to 11b and subsequent SN2 dis-
placement leads to triazole 5. A preliminary computational DFT
study on the reaction pathway of 4a to 5a proposed that the
intramolecular SN2 reaction of the deprotonated substrate 4a
to give 5a has a transition state of 15.4 kcal/mol and that the
reaction is very exothermic (–56.9 kcal/mol). Opposingly, intra-
molecular SN2 cyclization of non-deprotonated 4a has unfavor-
able reaction energetics and no feasible transition state for an
alternative SN1 pathway could be found (see supporting infor-
mation for more details on the computational study).
In conclusion, we have developed an efficient synthesis of 2-
aryl-1,2,3-triazoles based on an intramolecular N–N bond forma-
tion presumably via SN2 displacement of a hydrazonium species
in the presence of a base. The methodology takes advantage
of the readily available starting materials, milder reaction condi-
tions and complete control of the regioselectivity. The simplicity
of the reaction sequence, wide substrate scope and high effi-
ciency of the N,N-bond formation offer advantages over exist-
ing methods reported in the literature. The method demon-
strated herein provides an expedited and module synthesis of
a wide variety of 2-aryl-1,2,3-triazoles.
[4]
[5]
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[8]
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a) M. Begtrup, J. Molm, J. Chem. Soc., Perkin Trans. 1 1981, 503; b) The
following transformation was scaled up to 2 kg scale to give triazole 5b
in 54 % yield. However, removal of Cu residue and disposal of Zn dust
during work up were capricious.
Supporting Information (see footnote on the first page of this
article): The supporting information is available free of charge.
Copies of 1H and 13C NMR spectra of new compounds are included
in the SI.
[9]
Notes
The authors declare no competing financial interest.
Acknowledgments
We would like to acknowledge Mrs. Huawei Ma and Miss. Huan
Dong at Porton R&D Center (Shanghai, China P. R.) for the ana-
lytical support and Dr Chris Teleha of Janssen R&D (Spring-
house, PA, USA) for helpful discussion during the preparation
of this manuscript.
[10]
[11]
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The cyclization of hydrazonohydrazonium salt 5i in the presence of
KHCO3 was less clean than that with K2CO3, and resulted only in 56 %
isolated yield.
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Keywords: Intramolecular · N–N bond formation · 2-Aryl
1,2,3-triazole · SN2 Displacement · Reaction mechanisms
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[14]
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Received: October 15, 2019
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Heterocycles
C.-y. Chen,* X. Lu, M. C. Holland,
S. Lv, X. Ji, W. Liu, J. Liu,
D. Depre, P. Westerduin .................... 1–5
Synthesis of 2-Substituted 1,2,3-Tri-
azoles via an Intramolecular N–N
Bond Formation
An intramolecular N–N bond forma- molecular SN2 displacement mecha-
tion leads to a wide variety of 2-aryl nism with the trimethylammonium
1,2,3-triazoles based on an intramolec- moiety serving as a good leaving
ular N–N bond formation is described. group for the intramolecular N–N
The reaction likely follows an intra- bond formation.
DOI: 10.1002/ejoc.201901519
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim