Diversity-Oriented Synthesis of 1,2,4-Triazols, 1,3,4-Thiadiazols, and 1,3,4-Selenadiazoles from N-Tosylhydrazones

Article abstract of DOI:10.1021/acs.orglett.1c01379

The diversity-oriented synthesis of 1,2,4-triazols, 1,3,4-thiadiazols, and 1,3,4-selenadiazoles from N-tosylhydrazones was developed, and the reactions were general for a wide range of substrates, in which NH2CN, KOCN, KSCN, and KSeCN were used as odorless sources. Two different pathways were proposed, and N-tosylhydrazonoyl chlorides were formed in situ in the presence of NCS.

Full text of DOI:10.1021/acs.orglett.1c01379

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Diversity-Oriented Synthesis of 1,2,4-Triazols, 1,3,4-Thiadiazols, and
1,3,4-Selenadiazoles from N‑Tosylhydrazones
Zeyang Wei, Qi Zhang, Meng Tang,* Siyu Zhang, and Qian Zhang
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ABSTRACT: The diversity-oriented synthesis of 1,2,4-triazols, 1,3,4-thiadiazols,
and 1,3,4-selenadiazoles from N-tosylhydrazones was developed, and the
reactions were general for a wide range of substrates, in which NH2CN,
KOCN, KSCN, and KSeCN were used as odorless sources. Two different
pathways were proposed, and N-tosylhydrazonoyl chlorides were formed in situ
in the presence of NCS.
tube at higher temperature for 12 h, and aliphatic aldehyde was
itrogen-containing five-membered aromatic heterocycles
Nwith three heteroatoms, such as 1,2,4-triazol, 1,3,4- unsuitable for the transformation.9
In the past decade, we have developed a series of methods
thiadiazole, and 1,3,4-selenadiazole, have been extensively
studied due to their widespread existence in natural products,
materials, and biologically active synthetic compounds.1 Many
drugs containing these nuclei such as alprazolam, trapidil, and
furidiazine are commercially available, and they display a broad
spectrum of pharmaceutical and biological activities. Impres-
sive developments have been achieved, and a variety of
powerful strategies have been developed for their construc-
tion.2−4 However, for some reactions, the starting materials are
not readily commercially available, and most of the sulfur
sources and selenium sources are odorous; meanwhile,
somewhat harsh reaction conditions greatly reduce the
attractiveness of these methods. Therefore, the development
of facile strategies and chemical reactions continues to be a
major challenge for researchers.
for the synthesis of heterocyclic compounds from N-
tosylhydrazones, including pyrazoles,10 indazoles,11 and 1,4-
dihydropyridines.12 Herein, we present a facile diversity-
oriented synthesis of 1,2,4-triazols, 1,3,4-thiadiazols, and
1,3,4-selenadiazoles from N-tosylhydrazones.
The investigation was initiated by a reaction of N-
tosylhydrazone (1a) with cyanamide, and the results were
summarized in Table 1. Initially, we performed the reaction in
DCE without using any additive, and no reaction was detected.
Then, the reaction was conducted in the presence of 0.5 equiv
of BF3·OEt2; after 20 h, 1,2,4-triazol-3-amine 2a could be
isolated in 39% yield (entry 1). To our delight, increasing the
amount of BF3·OEt2 could improve the yields apparently
(entries 2, 3), and 1.5 equiv of BF3·OEt2 resulted in 93% yield
of 2a within 9 h. FeCl3 gave moderate yield (entry 4); other
Lewis acids, such as AlBr3, TiCl4, and Sc(OTf)3, resulted in
lower yields (entries 5−7). Of the solvents screened, CH2Cl2,
CHCl3, CH3CN, CH3NO2, and toluene could give moderate
yields (entries 8−12) (for details, see Supporting Information,
Table S1).
As a readily accessible and useful reagent,5 N-tosylhydra-
zones have been used in the preparation of 1,2,4-triazoles and
1,3,4-thiadiazoles. The synthesis of 1,2,4-triazoles from N-
tosylhydrazones and imines via formal 1,3-dipolar cyclo-
addition reactions has been developed by Maiti et al. and
Kalita et al.;6 the B(C6F5)3-catalyzed dehydrogenative
cyclization of N-tosylhydrazones and anilines to 1,2,4-triazoles
has been disclosed by Koley et al. in 2019;7 Cheng et al. and
Okuma et al. reported the three-component reactions between
two N-tosylhydrazones and different sulfur sources leading to
1,3,4-thiadiazoles, respectively.8 Recently, Yan et al. reported
an I2 promoted synthesis of 1,3,4-thiadiazoles from in situ N-
tosylhydrazones and KSCN, in which KSCN as an odorless
sulfur source was used in the construction of 1,3,4-thiadiazoles
for the first time, but the reactions were conducted in a sealed
Under the above optimized conditions, various N-tosylhy-
drazones 1 were applied to the reaction to test the generality
Received: April 21, 2021
Published: May 14, 2021
https://doi.org/10.1021/acs.orglett.1c01379
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4436−4440
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was tried rigorously and failed many times in a row. For
example, we used KSCN instead of cyanamide in the reaction
under similar conditions to prepare 1,3,4-thiadiazol-2-amine
3a, and different solvents were screened even at higher
temperature, but no reaction could be detected by TLC (Table
2, entries 1, 2). Referring to the results reported in the
Table 1. Screening the Reaction Conditions of 1a with
Cyanamide
a
b
entry
acid (equiv)
solv
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
CHCl3
CH3CN
CH3NO2
toluene
DCE
time (h)
yield (%)
Table 2. Screening the Reaction Conditions of 1a with
1
2
3
4
5
6
7
8
BF3·OEt2 (0.5)
BF3·OEt2 (1.25)
BF3·OEt2 (1.5)
FeCl3 (1.5)
AlBr3 (1.5)
TiCl4 (1.5)
Sc(OTf)3 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
20
20
9
39
75
93
58
31
19
18
68
55
56
37
38
68
a
KSCN
20
20
20
20
20
20
20
20
20
9
b
entry
acid (equiv)
solv
DCE
time/h
yield (%)
c
1
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.25)
BF3·OEt2 (0.5)
BF3·OEt2 (0.25)
BF3·OEt2 (0.5)
AlCl3 (0.5)
TiCl4 (0.5)
H2SO4 (0.5)
HCl (0.5)
BF3·OEt2 (0.5)
BF3·OEt2 (0.5)
BF3·OEt2 (0.5)
BF3·OEt2 (0.5)
5
5
9
9
6
0.5
1
30
0.5
0.5
3
0.5
3
3
N. R.
N. R.
20
c
2
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-AmOH
EtOH
9
d
3
10
11
12
4
5
6
7
29
54
87
64
83
59
73
59
62
37
trace
52
30
c
13
a
Unless noted otherwise, the reactions were conducted with 1a (0.1
e
8
mmol), NH2CN (0.2 mmol), and acid (0.15 mmol) in 2 mL solvent
b
9
at room temperature under an argon atmosphere. Isolated yields.
c
10
11
12
13
14
0.2 mmol NCS was added.
and scope of the method. First, we examined the electronic
effect on the aromatic ring of N-tosylhydrazones. As shown in
Scheme 1, N-tosylhydrazones derived from benzaldehyde
f
15
g
t-BuOH
t-BuOH
0.5
2
16
Scheme 1. Synthesis of 1,2,4-Triazol-3-amines 2
a
Unless noted otherwise, the reactions were conducted with 1a (0.1
mmol), KSCN (0.2 mmol), NCS (0.2 mmol), and acid in 2 mL
b
solvent at reflux temperature under an argon atmosphere. Isolated
c
d
e
yields. Without using NCS. 0.11 mmol NCS was used. The
f
reaction was conducted at room temperature. 0.2 mmol NBS was
used instead of NCS. 0.2 mmol NIS was used instead of NCS.
g
literature, in which in situ N-thiocyanatosuccinimide has better
reactivity in C−S bond formation,13 we added 1.1 equiv of
NCS to the reaction. As we envisaged, product 3a could be
isolated in 20% yield in t-BuOH after 9 h, even though the N-
tosylhydrazone 1a could not be fully consumed (entry 3).
Increasing the amount of NCS could not improve the
transformation (entry 4). Fortunately, we found that
decreasing the amount of BF3·OEt2 resulted in better yields
(entries 5−7), and 0.5 equiv of BF3·OEt2 gave 87% yield
within 0.5 h. Furthermore, the reaction could be performed at
room temperature (entry 8). Then, some acids were screened
(entries 9−12): AlCl3 and TiCl4 gave moderate yields, while
H2SO4 and concentrated HCl could promote the reaction.
Next, a variety of different solvents were also evaluated; t-
AmOH led to lower yields and EtOH gave disappointing
results (entries 13, 14). NBS and NIS could also promote the
reaction, but the yields were lower (entries 15, 16). (For
details, see Supporting Information, Table S2.)
Then, we attempted to synthesize a variety of 1,3,4-
thiadiazol-2-amine derivatives. As shown in Scheme 2, the
electronic effect on the aromatic ring of N-tosylhydrazones had
little influence on the transformation; N-tosylhydrazones
derived from benzaldehyde featuring ortho-, meta-, and para-
substituents as well as electron-donating (3b−3e) or electron-
withdrawing (3f−3k) substituents worked well to furnish the
corresponding products, and the yield was not affected when R
featuring ortho-, meta-, and para- electron-donating substitu-
ents and halogen had little influence on the reaction; products
2b−2j were prepared in good yields. However, lower yields
were observed with nitro (2k, 2l). To our delight, N-
tosylhydrazone derived from cinnamaldehyde, 2-furaldehyde,
and trimethylacetaldehyde was also appropriate in the reaction;
products 2m−2o were given in moderate yields.
Encouraged by the above results, we tried to apply other
cyanates to the reaction. However, to our disappointment, it
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Scheme 2. Synthesis of 1,3,4-Thiadiazol-2-amines 3
Scheme 3. Synthesis of 2-Tosyl-1,2,4-triazol-3-ones 4
Sc(OTf)3 and 1.1 equiv of NCS (for details, see Supporting
Information, Table S4). As shown in Scheme 4, the electronic
contained a nitro (3k). Additionally, N-tosylhydrazones
derived from 2-pyridinecarboxaldehyde, 2-thenaldehyde, and
aliphatic aldehydes were all suitable for the transformation;
products 3l−3o were given in good yields. Furthermore,
product 3p, which has been used widely in the design and
synthesis of biologically active compounds,14 could be
prepared in a 53% yield; and furidiazine, which has
antibacterial activity in animals after oral or intramuscular
administration,15 was obtained in 63% yield. To demonstrate
the synthetic utility of the protocol, we conducted the reaction
with 100 mmol 1a, and 10.8 g of 3a could be isolated in 61%
yield by recrystallization. Furthermore, N-methylsulfonylhy-
drazone and N-phenylsulfonylhydrazone were applicable to the
reaction and gave products 3a in 76% and 72% yields,
respectively, whereas N-phenylhydrazone was unsuitable, and
no product could be confirmed in the current state.
Scheme 4. Synthesis of 1,3,4-Selenadiazol-2-amine 5
Next, we used KOCN in the reaction. By screening the
reaction conditions, we found that 2-tosyl-1,2,4-triazol-3-one
4a could be isolated in 69% yield in CH3CN at room
temperature in the presence of 1.1 equiv of NCS. The structure
of 4a was confirmed by NMR and single-crystal X-ray analysis
(Scheme 3). Acid was not essential, but it could accelerate the
reaction. The reaction could be conducted at reflux temper-
ature. (For details, see Supporting Information, Table S3.)
Meanwhile, we noticed that a small amount of compound 12
(Scheme 5) could be isolated as byproduct. The procedure was
applicable for N-tosylhydrazones with both electron-donating
(4b, 4c) and electron-withdrawing (4d−4f) groups, provided
the desired 2-tosyl-1,2,4-triazol-3-ones in good yields. Addi-
tionally, N-tosylhydrazones derived from cinnamaldehyde, 2-
thenaldehyde, and aliphatic aldehydes were all suitable for the
reaction; products (4g−4j) could be prepared in good yields.
To our delight, KSeCN was also suitable for the reaction.
1,3,4-Selenadiazol-2-amine 5a could be isolated in 58% yield in
CH3CN at room temperature in the presence of 0.5 equiv of
effect on the aromatic ring of N-tosylhydrazones had little
influence on the reaction; products 5b−5f were prepared in
moderate yields. Meanwhile, N-tosylhydrazones derived from
2-furaldehyde, 2-pyridinecarboxaldehyde, 2-thenaldehyde,
ethyl 2-oxoacetate, and aliphatic aldehydes were appropriate
in the reaction, and gave products 5g−5l in moderate yields.
To elucidate the reaction mechanism, some control
experiments were designed with 1a. We found that product
11 (Scheme 5) could be isolated in the presence of NCS in t-
BuOH in about 30% yield. We believed that N-tosylhydrazo-
noyl chloride 8 was formed, although it could not be detected
and isolated in the current. It could be confirmed by the
formation of byproduct 12 in the reaction to prepare 4a. Then,
two different pathways were proposed. In the absence of NCS,
the reaction was initiated by the nucleophilic addition of
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Scheme 5. Proposed Pathway for 1,2,4-Triazols and 1,3,4-thiadiazols Formation
NH2CN to N-tosylhydrazone iminium salt 6 resulting in 7,
which subsequently went through an intramolecular cycliza-
tion, and 1,5-H shift led to 1,2,4-triazol-3-amine 2. In the
presence of NCS, N-tosylhydrazonoyl chloride 8 was formed.
An addition elimination reaction of in situ N-thiocyanatosucci-
nimide and N-tosylhydrazone iminium salt 9 produced
intermediate 10, followed by intramolecular cyclization,
detosylation, and 1,3-H shift resulting in 1,3,4-thiadiazol-2-
amine 3. In certain cases, self-condensation and cyclization of
N-tosylhydrazonoyl chloride 8 gave byproduct 12. 2-Tosyl-
1,2,4-triazol-3-ones 4 and 1,3,4-selenadiazol-2-amine 5 were
formed by the similar process from N-tosylhydrazonoyl
chloride 8. (For details, see Supporting Information, Scheme
S1.)
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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Meng Tang − School of Pharmacy, Lanzhou University,
Lanzhou 730000, P. R. China; orcid.org/0000-0003-
4398-3900; Email: tangmeng@lzu.edu.cn
Authors
Zeyang Wei − School of Pharmacy, Lanzhou University,
Lanzhou 730000, P. R. China
The mechanism explained the inequable dosage of NCS in
different reactions. Due to the formation of N-tosylhydrazo-
noyl chloride 8 and N-thiocyanatosuccinimide, 2 equiv of NCS
was necessary for the preparation of 3. However, in the
preparation of 4 and 5, no compounds similar to N-
thiocyanatosuccinimide were formed, so 1.1 equiv of NCS
was enough. In the preparation of 2, probably due to the better
nucleophilicity of NH2CN, the formation of 8 was
unnecessary; NCS was not required. We also tried to add
NCS in the reaction, but it did not improve the yield; on the
contrary, there were more byproducts like 12, resulting in
lower yield (Table 1, entry 13).
In summary, we have established a neat solution for the
preparation of 1,2,4-triazols, 1,3,4-thiadiazols, and 1,3,4-
selenadiazoles, and it was effective for a wide scope of
substrates. NH2CN, KOCN, KSCN, and KSeCN were used as
odorless sources. N-Tosylhydrazonoyl chlorides were formed
in situ in the presence of NCS, and further studies on their
reactivity are underway in our laboratory.
Qi Zhang − School of Pharmacy, Lanzhou University,
Lanzhou 730000, P. R. China
Siyu Zhang − School of Pharmacy, Lanzhou University,
Lanzhou 730000, P. R. China
Qian Zhang − School of Pharmacy, Lanzhou University,
Lanzhou 730000, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01379
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the NSFC (No. 21772073).
■
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
■
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01379.
Experimental procedures, characterization data, copies of
NMR spectra for all products, and crystal data and
structure refinement for 11 (CCDC 2055756) and 4a
(CCDC 2055757) (PDF)
Accession Codes
CCDC 2055756−2055757 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
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Letter
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