Multicomponent Coupling Reactions of Two N-Tosyl Hydrazones and Elemental Sulfur: Selective Denitrogenation Pathway toward Unsymmetric 2,5-Disubstituted 1,3,4-Thiadiazoles

Article abstract of DOI:10.1021/acs.orglett.6b02583

A copper-mediated, three-component reaction between two different N-Ts hydrazones and elemental sulfur was developed, leading to a series of unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles in moderate yields with good functional group compatibility. This

Full text of DOI:10.1021/acs.orglett.6b02583

Letter
pubs.acs.org/OrgLett
Multicomponent Coupling Reactions of Two N‑Tosyl Hydrazones and
Elemental Sulfur: Selective Denitrogenation Pathway toward
Unsymmetric 2,5-Disubstituted 1,3,4-Thiadiazoles
Zhen Zhou, Yang Liu, Jiangfei Chen, En Yao, and Jiang Cheng*
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: A copper-mediated, three-component reaction between two different N-Ts hydrazones and elemental sulfur was
developed, leading to a series of unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles in moderate yields with good functional group
compatibility. This procedure features the employment of elemental sulfur and the selective denitrogenation between aryl and
alkyl aldehyde N-tosyl hydrazones, allowing rapid access to unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles frameworks with
chemical diversity and complexity.
denitrogen pathway based on the reactivity discrimination
between aryl and alkyl aldehyde N-tosyl hydrazones.
1,3,4-Thiadiazoles possess a broad spectrum of biological
activities.1 For example, they could serve as antidepressant,2
anxiolytic,3 antimicrobial,4 antituberculosis,5 anti-inflamma-
tory,6 antidiabetic,7 anticancer,8 antihypertensive,9 and anti-
fungal drugs.10 Therefore, numerous versatile and flexible
approaches have been established to access 1,3,4-thiadiazoles,
including the sulfuration of the corresponding 1,4-dicarbonyl
and acyl precursors (in situ formed or not) by P2S5 or
Lawesson’s reagent,11 cyclization of thiohydrazine,12 and
transformation from other heterocycles.13 However, the
sulfuration still suffers from harsh reaction conditions. P2S5
and Lawesson’s reagent are sensitive to moisture have a strong
odor, despite some modifications.14 Moreover, the synthesis of
S-substituted substrate was tedious and, in most cases,
ineffective to access the 2,5-disubstituted analogues with
carbon-centered groups. Therefore, the development of new
methods to access 1,3,4-thiadiazoles via novel pathways and
reaction partners remains an urgent goal for organic chemists.
The multicomponent coupling reactions (MCRs) between
elemental sulfur and two N-tosyl hydrazones as readily available
starting materials show that denitrogenation15 is an ideal
pathway toward such frameworks with chemical diversity and
complexity.16 However, in the case of two N-tosyl hydrazones,
a great challenge arises from the selective denitrogen step
between two N-tosyl hydrazone molecules, which may result in
various distributions of two homoproducts and one cross-
product.17 Herein, we describe a three-component reaction of
elemental sulfur toward unsymmetric 1,3,4-thiadiazoles with
2,5-disubstituted carbon-centered groups via a selective
Initially, we tested the combination of benzaldehyde N-tosyl
hydrazone (1.0 equiv), n-butanal N-tosyl hydrazone (1.2
equiv), and sublimed sulfur in the presence of CuI (20 mol
%) and K2CO3 (2 equiv) in dimethylacetamide (DMAC, 2 mL)
as the model reaction. To our delight, the cross-annulation
product 2-phenyl-5-propyl-1,3,4-thiadiazole 3aa via selective
denitrogenation was isolated in 50% yield, and no homoannu-
lated isomers were detected at 120 °C after 24 h under air
(Table 1, entry 1). Subsequently, other bases such as Na2CO3,
tBuONa, tBuOK, NaOH, Ag2CO3, and NaH2PO4, were
examined. However, they were all inferior to K2CO3, generating
3aa in lower yields (Table 1, entries 2−7). Pleasingly, Cs2CO3
worked well with an acceptable 62% yield (Table 1, entry 8). In
the absence of copper, 3aa was isolated in 44% yield (Table 1,
entry 9). Other tested copper, such as CuCl (39%), and CuBr
(36%), decreased the reaction efficiency (Table 1, entries 10
and 11). The tested solvents, such as DMF, CH3CN, and
dioxane, were inferior to DMAC (24−47%, Table 1, entries
12−14). The reaction efficiency decreased under elevated or
lowered temperature (Table 1, entry 15), as did the procedure
conducted under either N2 or O2, respectively (Table 1, entry
15). Thus, the optimized conditions were established as
follows: benzaldehyde N-tosyl hydrazone (0.1 mmol), n-
butanal N-tosyl hydrazone (0.12 mmol), and sublimed sulfur
Received: August 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02583
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
ethylethyl (3ca, 52%), cyclohexanyl (3ea, 52%), and (2-
methyl)ethyl (3fa, 47%) were facilely introduced to the 5-
position of 2-phenyl-1,3,4-thiadiazoles.
Table 1. Screening of the Optimized Reaction Conditions
Next, the scope of aromatic aldehyde N-tosyl hydrazones in
the reaction with n-butanal N-tosyl hydrazone and sublimed
sulfur was studied (Scheme 2). This procedure was compatible
b
entry
copper
base
solvent
yield (%)
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMF
50
28
39
29
31
<5
24
62
44
39
36
47
34
24
Scheme 2. Substrate Scope of Aryl Aldehyde N-Tosyl
Hydrazones
2
Na2CO3
tBuONa
tBuOK
a
3
4
5
NaOH
6
Ag2CO3
NaH2PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7
8
9
10
11
12
13
14
15
CuCl
CuBr
CuI
CuI
CH3CN
dioxane
DMAC
CuI
c
d
e
f
CuI
44, 28, 52, 25
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), S8 (0.0625
mmol), CuX (20 mol %) in solvent (2 mL) under air at 100 °C.
Isolated yield. 90 °C. 110 °C. Under N2. Under O2.
b
c
d
e
f
(0.0625 mmol) in the presence of CuI (20 mol %) and Cs2CO3
(0.2 mmol) in dimethylacetamide (DMAC, 2 mL).
After the establishment of the optimized reaction conditions,
the substrates scope and limitation of alkyl aldehyde N-tosyl
hydrazones in the reaction with benzaldehyde N-tosyl
hydrazone and sublimed sulfur were tested, as shown in
Scheme 1. As expected, besides n-propyl, this procedure
allowed rapid construction of 2-phenyl-1,3,4-thiadiazoles
substituted with 5-primary carbon groups, such as n-butyl
(3ga, 54%), n-pentyl (3ha, 41%), and ethyl (3ia, 57%) in
moderate yields (3ga−ia). Importantly, the secondary carbon
groups, such as isobutyl (3ba, 51%), isopropyl (3da, 60%), 2-
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), S8 (0.0625
mmol), Cs2CO3 (0.2 mmol), CuI (20 mol %), DMAC (2 mL), air,
100 °C, 12 h.
with some functional groups on the phenyl ring, such as methyl
(3ab, 51%), methoxy (3ac, 53%), trifluoromethyl (3ad, 45%),
fluoro (3ae, 45%), chloro (3af, 48%), and cyano (3ag, 43%),
which provided a facile handle for potentially further
functionalization. 2-Naphthaldehyde N-tosyl hydrazine was
also a good reaction partner, giving the corresponding product
3ai in 52% yield. Notably, 2-thienaldehyde N-tosyl hydrazone
served as a reaction partner, and 3aj was isolated in 55% yield.
Notably, this procedure was also applicable in the synthesis
of symmetric 1,3,4-thiadiazoles (Scheme 3). For example, 2,5-
diphenyl-1,3,4-thiadiazoles 4 and 2,5-dicyclohexyl-1,3,4-thiadia-
zoles 5 were isolated in 67% and 44% yields under the standard
procedure, respectively.
Scheme 1. Substrate Scope of Alkyl Aldehyde N-Tosyl
a
Hydrazones
To gain insight into the mechanism, control experiments
were conducted. No 15N was detected in the 2-phenyl-5-
isopropyl-1,3,4-thiadiazoles by the reaction of isobutanal N-
tosyl hydrazone, 15N-labeled benzaldehyde N-tosyl hydrazone,
and sublimed sulfur under the standard procedure (Scheme 4,
eq 1). However, 15N was totally incorporated in 2-phenyl-5-
a
Scheme 3. Synthesis of Symmetric 1,3,4-Thiadiazoles
a
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), S8 (0.0625
Reaction conditions: N-Ts hydrazone (0.1 mmol), S8 (0.1 mmol),
mmol), Cs2CO3 (0.2 mmol), CuI (20 mol %), DMAC (2 mL), air,
Cs2CO3 (0.2 mmol), CuI (20 mol %), DMAC (2 mL), air, 100 °C, 12
100 °C, 12 h.
h.
B
DOI: 10.1021/acs.orglett.6b02583
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Organic Letters
Letter
Scheme 4. Preliminary Mechanism Study
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02583.
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiangcheng@cczu.edu.cn.
Notes
The authors declare no competing financial interest.
isopropyl-1,3,4-thiadiazoles by the reaction of 15N-labeled
isobutanal N-tosyl hydrazone, benzaldehyde N-tosyl hydrazone,
and sublimed sulfur (Scheme 4, eq 2). This result confirmed
the selective denitrogenation took place in benzaldehyde N-
tosyl hydrazone rather than isobutanal N-tosyl hydrazone.
Moreover, 1,4-diphenylformalazine 6 was subjected to the
standard procedure and no 1,3,4-thiadiazoles was detected,
ruling out the possibility of benzaldehyde 2-butylidenehydra-
zone as the intermediate (Scheme 4, eq 3).
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21272028 and 21572025), “Innovation & Entrepreneur-
ship Talents” Introduction Plan of Jiangsu Province, the Key
University Science Research Project of Jiangsu Province
(15KJA150001), Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology (BM2012110), and Advanced
Catalysis and Green Manufacturing Collaborative Innovation
Center for financial support.
On the basis of these experimental results, a tentative
pathway of this reaction is outlined in Scheme 5. In the case of
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Scheme 5. Tentative Mechanism
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