Annulation Reactions of In-Situ-Generated N-(Het)aroyldiazenes with Isothiocyanates Leading to 2-Imino-1,3,4-oxadiazolines

Article abstract of DOI:10.1021/acs.orglett.8b03663

A novel annulation reaction of N-(het)aroyldiazenes and isothiocyanates has been established. This transformation involves a sequential cyclization and desulfurization/intramolecular rearrangement to produce 2-imino-1,3,4-oxadiazolines. The less-stable N-(het)aroyldiazenes can be conveniently generated in situ by I₂-mediated oxidation of hydrazides, which allows a one-pot synthesis of the products directly from readily accessible hydrazide and isothiocyanate substrates. This operationally simple synthetic process requires no use of malodorous isocyanides and can be conveniently conducted on a gram scale.

Full text of DOI:10.1021/acs.orglett.8b03663

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Annulation Reactions of In-Situ-Generated N‑(Het)aroyldiazenes
with Isothiocyanates Leading to 2‑Imino-1,3,4-oxadiazolines
Qiongli Zhao, Linning Ren, Jiao Hou, Wenquan Yu,* and Junbiao Chang*
College of Chemistry and Molecular Engineering; Collaborative Innovation Center of New Drug Research and Safety Evaluation,
Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
S
* Supporting Information
ABSTRACT: A novel annulation reaction of N-(het)-
aroyldiazenes and isothiocyanates has been established. This
transformation involves a sequential cyclization and desulfuriza-
tion/intramolecular rearrangement to produce 2-imino-1,3,4-
oxadiazolines. The less-stable N-(het)aroyldiazenes can be
conveniently generated in situ by I2-mediated oxidation of
hydrazides, which allows a one-pot synthesis of the products
directly from readily accessible hydrazide and isothiocyanate
substrates. This operationally simple synthetic process requires no use of malodorous isocyanides and can be conveniently
conducted on a gram scale.
n recent years, N-acyldiazenes have attracted considerable
attention as valuable participants in N-heterocyclic carbenes
the synthesis of 2-imino-1,3,4-oxadiazolines under transition-
metal-free conditions.
I
(NHC)-catalyzed annulation reactions including [2 + 3]
cyclizations with α,β-unsaturated aldehydes,1 and [4 + 2]
annulations with enamines,2 ketenes,3 or α-chloroaldehydes.4
The Smith group reported isothiourea-catalyzed asymmetric
functionalization of carboxylic acid derivatives5 or α-aroylox-
yaldehydes6 with N-aryl-N-aroyldiazenes. Subsequently, Meng
and Wang achieved the DMAP-catalyzed cycloaddition of N-
acyldiazenes with allenoates7 or isatin-derived Morita-Baylis-
Hillman adducts.8 In 2017, Zhou and Liu developed an
P(NMe2)3-mediated deoxygenative [4 + 1] cyclization of N-
acyldiazenes and α-dicarbonyl compounds,9 and Koutentis and
co-workers reported an aza-Wittig reaction of N-arylimino-
phosphoranes with N-aryl-N-aroyldiazenes.10 Recently, Mei
and Shi disclosed catalytic asymmetric [3 + 2] cyclo-
annulations of N-acyl azonaphthalenes with azlactones11 or
3-vinylindoles.12 To the best of our knowledge, annulation
reactions of N-acyldiazenes with isothiocyanates have not been
investigated. Herein, we report the construction of novel 2-
imino-1,3,4-oxadiazoline frameworks via this strategy in the
absence of NHCs or other catalysts.
N-Acyldiazenes are commonly prepared from the corre-
sponding hydrazides using oxidizing reagents13 such as
Pb(OAc)4, MnO2, CAN, NaNO2, NBS, or by transition-
metal-catalyzed aerobic oxidation.14 Nevertheless, simple and
efficient protocols are still highly desirable, especially for the
development of one-pot reactions, which makes isolation of
the less-stable N-acyldiazene intermediates unnecessary.
During our studies on I2-promoted reactions, we found that
N-(het)aroyldiazenes could be conveniently generated by
iodine oxidation of the corresponding hydrazides (Table S1
in the Supporting Information). Building on this, we developed
a novel one-pot annulation reaction of hydrazides15 with
isothiocyanates via N-(het)aroyldiazenes generated in situ for
In the presence of K2CO3 or K3PO4 as a base (Table S1), I2-
mediated oxidation of hydrazide 2a efficiently produced N-
acyldiazene 4a in various solvents at room temperature. With
4a in hand, we investigated its annulation with isothiocyanate
3a for the synthesis of 2-imino-1,3,4-oxadiazoline 1a (Table 1).
Solvent screening (Table 1, entries 1−7) indicated that MeCN
is the best solvent for this transformation. Under basic
conditions, the annulation of 3a and 4a at the reflux
temperature gave product 1a in 72% yield (Table 1, entry
6). Using DMSO as the solvent led to a slightly decreased yield
of 1a (Table 1, entry 7). The structure of compound 1a was
confirmed by X-ray crystallography. Screening of a series of
organic and inorganic bases (Table 1, entries 8−12) showed
that K2CO3 is the best base (Table 1, entry 6). Encouraged by
these results, we next probed the feasibility of a one-pot
synthesis of 2-imino-1,3,4-oxadiazoline 1a directly from
hydrazide 2a and isothiocyanate 3a. We found that I2-mediated
one-pot annulation of 2a and 3a provided the desired product
(1a). Consistent with the above results, the reaction in MeCN
gave a higher yield than in DMSO (Table 1, entry 13 vs entry
14), and K2CO3 is better than K3PO4 for this one-pot synthesis
(Table 1, entry 13 vs entry 15). Further optimization of the
reaction conditions suggested that the complete consumption
of substrate 3a requires 1.5 equiv of 2a and 1.5 equiv of I2,
producing the highest yield of 1a (Table 1, entry 17).
Increasing the amount of base failed to improve the yield of the
product (Table 1, entry 18). Under the optimal reaction
conditions, this reaction can be successfully performed on a
gram scale (Table 1, entry 17).
Received: November 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions for the Synthesis of 2-Imino-1,3,4-oxadiazoline 1a
b
entry
4a/2a (equiv)
I2 (equiv)
base (equiv)
solvent
temperature
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
2a (1.0)
2a (1.0)
2a (1.0)
2a (1.2)
2a (1.5)
2a (1.5)
−
−
−
−
−
−
−
−
−
−
−
−
1.2
1.2
1.2
1.2
1.5
1.5
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K3PO4 (2)
Na2CO3 (2)
NaHCO3 (2)
Et3N (2)
toluene
CH2Cl2
DCE
reflux
reflux
reflux
reflux
60 °C
reflux
100 °C
reflux
reflux
reflux
reflux
reflux
reflux
100 °C
reflux
reflux
reflux
reflux
12
12
12
24
12
5
2
2
12
24
12
5
5
2
24
5
5
0
0
0
THF
trace
MeCN
MeCN
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
MeCN
MeCN
MeCN
MeCN
40
72
53
67
62
trace
0
30
60
40
5
72
89 (84)
87
DBU (2)
K2CO3 (3)
K2CO3 (3)
K3PO4 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (4)
c
5
a
BOld font indicates the optimal reaction conditions (entry 17): 2a (0.75 mmol), 3a (0.5 mmol), I2 (0.75 mmol), K2CO3 (3 mmol), MeCN (5
b
c
mL), reflux. Isolated yields. The yield of gram-scale reaction (5 mmol) is given in parentheses.
Having estabished the optimal conditions for a one-pot
reaction, we examined the substrate scope of hydrazides (2).
As shown in Scheme 1, this reaction can tolerate both electron-
donating groups (EDGs) and electron-withdrawing groups
(EWGs) on the phenyl rings at the R1 (1b−1f) and R2 (1k−
1r) positions. Nevertheless, the presence of EWGs in the
group at R2 affected the formation of the products (1l−1r). In
particular, the presence of a halogen at the para- or ortho-
position significantly decreased the yields (1l, 1m, and 1r).
This one-pot protocol is also successful with β-naphthyl-, 2-
furanyl-, and 2-thiophenyl-substituted hydrazides (1g−1i) and
tert-butyl-substituted products (1j and 1s) can be synthesized
in moderate yields from the corresponding hydrazides.
To further explore the reaction scope, a variety of
isothiocyanates (3) were subjected to the above standard
reaction conditions. These substrates were successfully
converted to the expected 2-imino-1,3,4-oxadiazoline products
by the reaction with the hydrazide 2a. This synthesis is
compatible with phenyl isothiocyanates substituted with EDGs
or EWGs (1t−1ab). Replacement of the aryl isothiocyanate
with an aliphatic isothiocyanate significantly decreased the
yield of the product (1ac). The relatively lower yields of the
alkyl-substituted products (1j, 1s, and 1ac) could be due to the
decreased stability of the corresponding diazenes and/or
related intermediates (see Scheme 3, presented later in this
work). The reaction of benzoyl isothiocyanate with 2a under
the optimal annulation conditions produced the corresponding
product (1ad).
corresponding isocyanide (5) was formed in either reaction.
The reaction of isocyanide 5 with N-benzoyldiazene 4a under
the optimal conditions resulted in only 1a, in 15% yield
(Scheme 2B). These observations rule out an isocyanide-based
[4 + 1] mechanism. In addition, no expected product (1a) was
formed in the reactions of 6 (or 7) with 4a under the standard
conditions (Scheme 2C).
On the basis of the experimental results and the previous
studies of annulation reactions involving N-acyldiazenes3,7 or
isothiocyanates,18 a tentative mechanism was proposed for this
one-pot annulation reaction (Scheme 3). Initially, iodine-
mediated oxidation of hydrazide 2 under basic conditions gives
the N-(het)aroyldiazene 4. This in-situ-generated diazo
compound then annulated with isothiocyanate 3 to form a 6-
membered intermediate D. The oxygen atom of the NR2 group
then attacks the exocyclic imine, forming a plausible 5−3
bicycle intermediate E. Finally, the subsequent cleavage of the
strained 3-membered ring affords the 2-imino-1,3,4-oxadiazo-
line framework (1) via S-extrusion.19
In summary, we have developed and reported a novel one-
pot annulation reaction of hydrazides with isothiocyanates for
the synthesis of 2-imino-1,3,4-oxadiazoline under transition-
metal-free conditions. In this reaction, hydrazides are first
oxidized by iodine to form N-(het)aroyldiazenes, which then
undergo a sequential annulation with isothiocyanates, followed
by desulfurization/intramolecular rearrangement to form the
product. This synthetic approach is practically simple and
requires no use of NHC or other organic catalysts. It can also
avoid the need to isolate the less-stable N-(het)aroyldiazene
intermediates and the use of malodorous isocyanides, and it
provides a facile access to 2-imino-1,3,4-oxadiazoline deriva-
tives in a scalable fashion. Further investigation and application
of such reactions is currently ongoing in our laboratory.
Control experiments were performed to investigate if
isothiocyanates act as masked isocyanides15b in this reaction.
Heating isothiocyanate 3a under basic conditions resulted in
thiourea16 6 and urea17 7 (Scheme 2A) and a slow conversion
was observed in the presence of iodine; however, none of the
B
DOI: 10.1021/acs.orglett.8b03663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Substrate Scope
Scheme 2. Control Experiments
Scheme 3. Proposed Mechanism
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wenquan_yu@zzu.edu.cn (W. Yu).
*E-mail: changjunbiao@zzu.edu.cn (J. Chang).
ORCID
Wenquan Yu: 0000-0002-3711-0006
Junbiao Chang: 0000-0001-6236-1256
Notes
The authors declare no competing financial interest.
a
Reaction conditions: 2 (0.75 mmol), 3 (0.5 mmol), I2 (0.75 mmol),
K2CO3 (3 mmol), MeCN (5 mL), reflux (isolated yields are given).
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 81773570 and 81330075), the Outstanding Young
Talent Research Fund of Zhengzhou University (No.
1521316004) for financial support.
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.8b03663.
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DOI: 10.1021/acs.orglett.8b03663
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Org. Lett. XXXX, XXX, XXX−XXX