Pd-catalyzed oxidative annulation of hydrazides with isocyanides: Synthesis of 2-amino-1,3,4-oxadiazoles

Article abstract of DOI:10.1021/ol5006449

An efficient palladium-catalyzed oxidative annulation reaction was developed through sequential isocyanide insertions into N-H and O-H bonds of hydrazides, which provides an efficient access to valuable 2-amino-1,3,4- oxadiazoles and their derivatives.

Full text of DOI:10.1021/ol5006449

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Oxidative Annulation of Hydrazides with Isocyanides:
Synthesis of 2‑Amino-1,3,4-oxadiazoles
Tao Fang,† Qitao Tan,† Zhengwei Ding,† Bingxin Liu,† and Bin Xu*,†,‡,§
†Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
§Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
Shanghai 200062, China
S
* Supporting Information
ABSTRACT: An efficient palladium-catalyzed oxidative an-
nulation reaction was developed through sequential isocyanide
insertions into N−H and O−H bonds of hydrazides, which
provides an efficient access to valuable 2-amino-1,3,4-
oxadiazoles and their derivatives.
he oxadiazole skeleton is one of the most attractive
tolerance, and harsh conditions. Therefore, the development of
Tframeworks with a wide range of biological and novel synthetic methods for 2-aminated oxadiazoles is still in
pharmacological activities and has been generally recognized
as a privileged structure in medicinal chemistry.1 Due to their
favorable metabolic profile and ability to engage in H-bonding,
1,3,4-oxadiazoles have exhibited a broad spectrum of biological
activities such as antimicrobial,2 antimitotic,3 antihypertensive,4
anticonvulsant,5 antiinflammatory,6 and muscle relaxant.7 In
particular, as one of the four isomers of oxadiazoles, the 1,3,4-
oxadiazole nucleus is exemplified as a unique structure in many
therapeutic agents, such as a potent metalloenzyme peptide
deformylase (PDF) inhibitor BB-83698, a nitrofuran anti-
bacterial Furamizole, HIV-integrase inhibitor Raltagravir, and
antihypertensive agents Nesapidil and Tiodazosin. Besides,
oxadiazoles are synthetically versatile substrates, which could be
used as synthetic intermediates for the synthesis of natural
products, for example through a [4 + 2] cycloaddition reaction
to provide the pentacyclic skeleton.8 Therefore, development of
efficient methods for their preparation would be highly
desirable. Generally, pharmacologically interesting 2-amino-
1,3,4-oxadiazoles were prepared by cyclodehydration of acyclic
semicarbazides, which requires functional group activation
reagents such as the Burgess reagent,9a phosphonium
reagents,9b and hypervalent iodine reagents,9c,d or by cyclo-
desulfurization of thiosemicarbazides using several desulfurating
agents such as I2/NaOH,3 carbodiimides,10a,d tosyl chloride,10b
and ethyl bromoacetate.10c Condensation of hydrazides and
aryl isocyanide dichlorides was also reported to give 2-amino-
1,3,4-oxadiazoles.11 Recently, alternative access to 2-amino-
1,3,4-oxadiazoles has been achieved through direct C(2)-
amination of 1,3,4-oxadiazoles using chloroamines,12a o-
benzoylhydroxylamines,12b or DMF12c as novel amination
high demand in terms of synthetic efficiency and starting
material availability.
Isocyanides, which function as both nucleo- and electro-
philes, have proven themselves to be powerful and versatile C1
building blocks for organic synthesis due to their unique
properties.13 In addition to participating in traditional multi-
component reactions,14 Pd-catalyzed reactions involving
isocyanides insertion offer great potential for the synthesis of
various N-containing heterocycles.15,16 As a part of our
continuing efforts to assemble heterocycles through a tandem
strategy,17 herein we report an efficient Pd-catalyzed aerobic
oxidative annulation reaction, whereby a sequential isocyanide
insertion into N−H and O−H bonds of hydrazides is described
to give 2-amino-1,3,4-oxadiazoles in one pot (Scheme 1).
Scheme 1. Pd-Catalyzed Tandem Isocyanide Insertion
Strategy toward 2-Amino-1,3,4-oxadiazoles from Hydrazides
Initially, we started our investigation with the benchmark
reaction between benzohydrazide and tert-butylisocyanide 2a to
afford N-tert-butyl-5-phenyl-1,3,4-oxadiazol-2-amine 3a in 64%
yield in the presence of 5 mol % of Pd(OAc)2 at 80 °C in
toluene (Table 1, entry 1). Intriguingly, a significant improve-
ment of the yield was observed when N-acetyl substituted
12d
−
12e
reagents, or using TEMPO+BF4
or PhI(OAc)2
as an
oxidant in combination with secondary amines. Although these
methods are often effective, some of them suffered from
substrate limitation, lack of diversity, poor functional group
Received: March 2, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Reaction Optimization for Oxadiazole Formation
Scheme 2. Hydrazide Scope in the Synthesis of 2-Amino-
1,3,4-oxadiazoles
a
b
entry
R
Pd source
solvent
atmos. time (h) yield (%)
1
H
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
toluene
toluene
anisole
DME
O2
O2
O2
O2
O2
O2
O2
O2
O2
N2
air
2
64
2
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ts
6
91
3
7
85
4
23
17
23
48
23
23
18
18
11
28
18
24
80
5
t-AmylOH
CH3CN
CH3NO2
DMF
41
6
22
7
trace
trace
trace
trace
33
8
9
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
10
11
12
13
14
15
c
O2
O2
O2
O2
82
d
76
trace
trace
e
Pd(OAc)2
a
All reactions were performed in an oxygen-purged flask on 0.3 mmol
scale, using benzohydrazide 1 (1.0 equiv), tert-butylisonitrile (3.0
equiv), and Pd(OAc)2 (5.0 mol %) in solvent (1.5 mL). t-AmylOH =
b
c
tert-amyl alcohol. DME = 1,2-Dimethoxyethane. Isolated yield. At 70
d
e
°C. Pd(OAc)2 (3.0 mol %) was used as the catalyst. With 51%
conversion of 1.
benzoylhydrazide 1a was used instead of benzohydrazide (entry
2). By switching the solvent from toluene to anisole or DME,
the yield was slightly decreased (entries 3−4); other solvents
provided a limited reaction and gave diminished yields (entries
5−6) or trace amounts of product (entries 7−9). A largely
dropped yield was afforded when the reaction was conducted
under a nitrogen or air atmosphere (entries 10−11), indicating
that oxygen was crucial to this oxidative cyclization reaction.
Further investigation of other parameters revealed that lowering
the temperature or reducing the loading of Pd(OAc)2 resulted
in decreased yields with elongated reaction times (entries 12−
13). No reaction could be observed in the absence of the Pd
catalyst (entry 14). Changing the acetyl substitution of
benzohydrazide to tosyl led to a negative impact on this
reaction (entry 15), which indicates that the leaving group
reactivity (i.e., Ac vs Ts) has an important effect on this
transformation.
With the optimized reaction conditions in hand, we next
investigated the scope of this reaction, as illustrated in Scheme
2. N-Acetyl benzohydrazides bearing various substituents in the
aryl rings, regardless of their electronic properties and
substitution positions, all gave the desired products in good
to excellent yields (3a−3j). It is worth noting that this reaction
was compatible with various functional groups such as halogens
(F, Cl, and Br), which could be subjected to further synthetic
transformations. Hydrazide substrates with disubstitution in the
aryl ring (3k) or containing the substructure of naphthalene
(3l) could also afford the corresponding oxadiazoles in good
yields. To our delight, hydrazides with heterocyclic or alkenyl
subsituents both gave the targeted products (3m, 3n), which
would significantly expand the scope of this reaction. In
addition to tert-butylisocyanide, secondary isocyanide such as
cyclohexyl isocyanide also worked well and gave similar results
(3o−3s). However, no product was observed when phenyl
isocyanide was used, which is presumably due to the quick
a
All reactions were performed in an oxygen-purged flask on 0.3 mmol
scale, using hydrazide (1.0 equiv), isonitrile (3.0 equiv), and Pd(OAc)2
(5.0 mol %) in toluene (1.5 mL). Isolated yield.
b
polymerization of phenyl isocyanide under the reaction
conditions.18
Encouraged by the success of this Pd-catalyzed isocyanide
insertion reaction of hydrazides, to explore the generality and
scope of this practical approach further, the N-acetyl group of
hydrazides was replaced by a variety of N-aryl or alkyl
substitutions (Scheme 3). To our delight, this reaction
predominantly resulted in the formation of novel (imino)-
oxadiazoles (5a−5i), which have shown potent biological
activities19 and are difficult to prepare from easily available
substrates.19,20 The identity of 5a was determined by spectral
analysis and further confirmed by X-ray crystallographic
analysis, and the exo CN bond adopts the Z-configuration
in solid state.21
Benzohydrazides bearing N-aryl or naphthyl substitutions
underwent clean conversion to the desired (imino)oxadiazoles
(5a−5g) in good to excellent yields. Aza analogues with
pyridine substituents could afford the corresponding product
5h smoothly in moderate yield. It is worth noting that
oxadiazole 5i bearing an N-alkyl substituent could be prepared
in moderate yield from N-tert-butyl-benzohydrazide, albeit a
longer reaction time was required, which will further illustrate
the broad substrate scope.
Although a detailed reaction mechanism remains to be
clarified, a plausible mechanism for the formation of 1,3,4-
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Letter
from easily available hydrazides and isocyanides with opera-
tional simplicity. The characteristics of a broad substrate scope,
good functional group tolerance, and synthesis modularity will
provide the described reaction broad utility in organic synthesis.
Further insight into the mechanism, reaction scope, and the
synthetic applications for bioactive compounds are now under
investigation in our group.
Scheme 3. Hydrazide Scope in the Synthesis of 2-Imino-
1,3,4-oxadiazolines
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
compounds, X-ray structure of 5a (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xubin@shu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21272149), Innovation Program of Shanghai Municipal
Education Commission (No. 14ZZ094), and Science and
Technology Commission of Shanghai Municipality (No.
13ZR1416400) for financial support. The authors thank Prof.
Hongmei Deng (Laboratory for Microstructures, SHU) for
NMR spectroscopic measurements.
a
All reactions were performed in an oxygen-purged flask on 0.3 mmol
scale, using hydrazide (1.0 equiv), isonitrile (3.0 equiv) and Pd(OAc)2
b
(5.0 mol %) in toluene (1.5 mL). Isolated yield.
Scheme 4. Plausible Mechanism for Synthesis of 3 and 5
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