Synthesis of spiro[4.4]thiadiazole derivatives: Via double 1,3-dipolar cycloaddition of hydrazonyl chlorides with carbon disulfide

Article abstract of DOI:10.1039/d1ra03229a

An operationally simple and convenient synthesis method toward a series of diverse spiro[4.4]thiadiazole derivatives via double [3 + 2] 1,3-dipolar cycloaddition of nitrilimines generated in situ from hydrazonyl chlorides with carbon disulfide has been ac

Full text of DOI:10.1039/d1ra03229a

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Synthesis of spiro[4.4]thiadiazole derivatives via
double 1,3-dipolar cycloaddition of hydrazonyl
chlorides with carbon disulfide†
Cite this: RSC Adv., 2021, 11, 18404
a
b
c
b
a
*
*
Yan-Li Li, Dong-Guang Guo, Peng-Tao Pan, Aili Sun
Kai-Kai Wang,
and Rongxiang Chen
a
*
Received 25th April 2021
Accepted 17th May 2021
An operationally simple and convenient synthesis method toward a series of diverse spiro[4.4]thiadiazole
derivatives via double [3 + 2] 1,3-dipolar cycloaddition of nitrilimines generated in situ from hydrazonyl
chlorides with carbon disulfide has been achieved under mild reaction conditions.
DOI: 10.1039/d1ra03229a
rsc.li/rsc-advances
The spirocyclic compounds having cyclic structures connected ve- or six-membered heterocycle in one step in the eld of
through just one carbon atom have attracted much interest organic synthesis.9 In particular, nitrilimines generated in situ
from synthetic chemists and medicinal chemists because of from the corresponding hydrazonyl chloride in the presence of
their ubiquitous presence in the core of a plethora of natural a base are highly active intermediates in organic synthesis and
products and non-natural products, many of which display a broad have been widely used as useful synthons for preparing bioac-
range of pharmacological and biological activities.1 Moreover, tive nitrogen heterocyclic derivatives and spirocyclic
spiro-compounds are unique because of their rigidity and compounds through the [3 + 2],10 [3 + 3]11 and [3 + 4]12 cyclo-
distinctly three-dimensional structure and have proved to be very addition reactions. In addition, the Lu group reported 1,3-
interesting for medicinal chemistry or as ligand and catalyst motifs dipolar cycloaddition of nitrilimines with carbon dioxide (CO2),
in asymmetric synthesis.2 Due to the importance of the spirocyclic providing elegant access to 1,3,4-oxadiazole-2(3H)-ones deriva-
architectures, the methods for synthesis of the spirocyclic moiety tives.13 Meanwhile, carbon disulde (CS2) that it is an analogue
are too many to enumerate. Some common strategies to afford of CO2, has been used for the synthesis of various sulfur-
spirocyclic scaffolds include radical cyclizations,3 Diels–Alder containing heterocyclic compounds for agricultural, medic-
reactions,4 cycloaddition,5 and ring expansion,6 among others. inal, and pharmaceutical applications.14 Based on the above
Many of the known methods for synthesizing spiro structures are literatures and in continuation of our interest in synthesis of
through constructing a new ring of which the substrates include heterocycles, we disclose a novel protocol for the synthesis of
a carbo- or heterocycle structure.7 To the best of our knowledge, spiro[4.4]thiadiazole derivatives double 1,3-dipolar cycloaddi-
a few approaches have offered efficient ways on the formation of tion of nitrilimines generated in situ from hydrazonyl chlorides
two rings through a double 1,3-dipolar cycloaddition in one pot for with carbon disulde under mild conditions.
constructing spirocyclic scaffold.8 Therefore, the design and
In our initial investigation, we chose the hydrazonyl chloride
development of innovative and efficient methodologies via double as the nitrilimine precursor with CS2 as the model reaction to
1,3-dipolar cycloaddition under mild reaction conditions for optimize the reaction conditions. The results of these experi-
synthesizing bioactive content spirocyclic scaffolds from readily ments are summarized in Table 1. No product was observed
available precursors is in great demand in both organic and when the reaction was performed in the absence of base (Table
medicinal chemistry.
1, entry 1). Usually, the active nitrilimine is generated in situ by
On the other hand, the 1,3-dipolar cycloaddition reaction dehydrohalogenation of the corresponding hydrazonyl halide in
(1,3-DCs) has been one of the most prominent reactions to build the presence of an equivalent base. Pleasingly, with the use of
TEA as the base, the double 1,3-dipolar cycloaddition reaction
proceeded very smoothly in CH2Cl2 to give spirothiadiazole
aSchool of Pharmacy, Key Laboratory of Nano-carbon Modied Film Technology product 3a with 60% yield at room temperature (Table 1, entry
Engineering of Henan Province, Xinxiang 453000, P. R. China. E-mail: chenhlmei@
2). The product 3a was obtained with 56% yield in the presence
of DABCO (entry 3). However, the DBU base turned out to be
163.com; sunailiy@126.com; Fax: +86-373-3682674
bMedical College, Xinxiang University, Xinxiang 453000, P. R. China
inactive in the double 1,3-dipolar cycloaddition reaction (entry
cSchool of Life Sciences and Basic Medicine, Xinxiang University, Xinxiang 453000, P.
4). Subsequently, we screened a series of inorganic base to
R. China
improve the yield, such as Na2CO3, K2CO3, Cs2CO3, NaOH and
† Electronic supplementary information (ESI) available: Experimental procedures,
KOH (entries 5–9). In comparison, the product 3a was gave in
structural proof, CIF le of 3h. CCDC 2041891. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/d1ra03229a
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope of the double 1,3-dipolar cycloadditiona
Entry
Base
Solvent
Yield of 3ab (%)
1
2
None
TEA
DABCO
DBU
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
0
60
56
Trace
62
70
92
90
88
80
85
70
61
Trace
Trace
56
62
80
3
4b
5
Na2CO3
K2CO3
Cs2CO3
NaOH
KOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
6
7
8
9
10
11
12
13
14
15
16
17
18c
19d
EtOAc
Toluene
THF
Et2O
Dioxane
MeCN
CH2Cl2
CH2Cl2
92
a
Unless noted otherwise, reactions were performed with hydrazonyl
chloride 1a (0.2 mmol), carbon disulde (0.3 mmol, 1.5 equiv.), base
b
(0.2 mmol, 1 equiv.) in solvent (1.0 mL) at rt for 12 h. Isolated yield
c
by chromatography on silica gel. Reaction was performed with
d
carbon disulde (0.2 mmol, 1 equiv.) for 24 h. Carbon disulde
(1.0 mmol, 5 equiv.).
moderate yields in the presence of TEA, Na2CO3 or K2CO3 (entries
2, 5 and 6). To our delight, the yield of the product 3a was
increased to 92% when used Cs2CO3 as the base (entry 7). Never-
theless, the yield was slightly reduced with the use of NaOH and
KOH as the base (entries 8 and 9). Encouraged by this result, the
reaction was examined with different solvents to improve the yield
of 3a. The reaction can be carried out in CHCl3 and DCE to provide
the expected product in 80% yield and 85% yield, respectively
(entries 10 and 11). Whereas no the desired product formation
take place upon using THF and Et2O as the solvent (entries 14 and
15). The reactions run with either dioxane or MeCN resulted in
moderate conversions (entries 16 and 17). It was found that CH2Cl2
was the best solvent for this transformation compared to CHCl3,
DCE, EtOAc, toluene, THF, Et2O, dioxane and MeCN (entries 10–
17). Moreover, when decreased the amounts of CS2, the reaction
time was prolonged and the yield of the product was lowered (entry
18). Whereas, the yield was not further improved when using 5.0
equiv. of CS2 (entry 19). Therefore, the optimal reaction conditions
have been determined which using Cs2CO3 as the base in CH2Cl2
at room temperature for 12 h (Table 2).
a
Unless noted otherwise, reactions were performed with hydrazonyl
chloride 1 (0.2 mmol), carbon disulde (0.3 mmol, 1.5 equiv.), base
(0.2 mmol, 1 equiv.) in solvent (1.0 mL) at rt for 12 h. Isolated yield by
chromatography on silica gel.
(such as electron-donating or electron-withdrawing) or the
positions of substituents on the benzoyl chloride moiety, to
generate the corresponding products 3 (3a–i) in high yields (92–
96%). In addition, the structure of product 3h (CCDC 2041891)15
was further determined by single-crystal X-ray crystallography
analysis. Furthermore, when using the fused aromatic and
heteroaromatic hydrazonyl chlorides as the substrate reacted
with CS2, the reactions were also found to be compatible and
gave the products (3j–l) in high yields. On the other hand, the
hydrazonyl chlorides containing different substituents (such as
methyl and chloro) on phenylhydrazone moiety also worked
well in the reaction successfully to obtain the desired cyclo-
adducts 3m and 3n in 90% and 93% yield, respectively. Never-
theless, the hydrazonyl chlorides bearing cyano or nitro group
on the benzoyl chloride moiety were not suitable and the ex-
pected cycloadduct 3p and 3q were not formed. Moreover, the
double 1,3-dipolar cycloaddition reaction also didn't work with
aliphatic group (3r) at the hydrazonyl chloride.
With the optimal reaction conditions in hand, we subse-
quently investigated the substrate scope and limitation of the
nitrilimine precursors. The results are shown in Table 1. Under
the optimized conditions, the double 1,3-dipolar cycloaddition
reaction could tolerate a variety of hydrazonyl chlorides bearing
different substituents, regardless of the electronic properties
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Notes and references
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Scheme 1 Scaled-up version of synthesis of 3a.
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To further exhibit the synthetic utility for spirocyclic
compounds, under the optimized conditions, a gram scale
experiment between 4 mmol of hydrazonyl chloride 1a and
6 mmol of CS2 proceeded smoothly to afford the desired
product 3a without a signicant loss of efficiency (1.670 g, in
90% yield) (Scheme 1). The easy scale-up of this process shows
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diversied natural product-like molecules possessing privileged
scaffold for potential application in biomedical research and
other research elds.
As shown in Scheme 2, a plausible mechanism was
proposed. Firstly, the nitrilimine intermediate 4 generated in
situ from the corresponding hydrazonyl halide 1 via eliminating
of HCl in the presence of a base. Then, the nitrilimine 4 reacts
with CS2 through the double 1,3-dipolar cycloaddition reaction
to give the desired product 3.
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Conflicts of interest
The authors declare that they have no known competing
nancial interests or personal relationships that could have
appeared to inuence the work reported in this paper.
Acknowledgements
We are grateful for the nancial support from the National
Natural Science Foundation of China (No. 21801214 and
81702074), Key Scientic Research Project of Colleges and
Universities in Henan Province of China (No. 18A150014,
19A230009 and 20B150019), Key Project of Science and Tech-
nology of Henan Province (No. 202102310298 and
192102110066), the Natural Science Foundation of Henan
Province (No. 202300410016).
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