Direct Annulation of Hydrazides to 1,3,4-Oxadiazoles via Oxidative C(CO)-C(Methyl) Bond Cleavage of Methyl Ketones

Article abstract of DOI:10.1021/acs.orglett.5b01241

A new strategy for the synthesis of 1,3,4-oxadiazoles was established through direct annulation of hydrazides with methyl ketones. It was found that the use of K₂CO₃ as a base achieves an unexpected and highly efficient C-C bond clea

Full text of DOI:10.1021/acs.orglett.5b01241

Letter
pubs.acs.org/OrgLett
Direct Annulation of Hydrazides to 1,3,4-Oxadiazoles via Oxidative
C(CO)−C(Methyl) Bond Cleavage of Methyl Ketones
Qinghe Gao, Shan Liu, Xia Wu, Jingjing Zhang, and Anxin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: A new strategy for the synthesis of 1,3,4-oxadiazoles was established
through direct annulation of hydrazides with methyl ketones. It was found that the
use of K2CO3 as a base achieves an unexpected and highly efficient C−C bond
3
cleavage. This reaction is proposed to go through oxidative cleavage of Csp −H
bonds, followed by cyclization and deacylation.
leavage of the C−C bond has emerged as a challenging
chemistry7 and material sciences.8 Consequently, much
attention has been paid to the synthesis of the 1,3,4-oxadiazole
skeleton, through either the dehydrative cyclization of 1,2-
diacylhydrazines9 or oxidative cyclization of N-acylhydra-
zones.10 Recently, some pioneering approaches for their
synthesis have been explored.11 In 2014, Xu reported a Pd-
catalyzed oxidative annulation for the synthesis of 2-amino-
1,3,4-oxadiazoles through sequential isocyanide insertions into
N−H and O−H bonds of hydrazides.11a Subsequently,
Lindhardt and Skrydstrup et al. demonstrated a three-
component approach to 1,3,4-oxadiazoles via a Pd-catalyzed
carbonylative assembly of aryl bromides with hydrazides.11b
Most recently, we disclosed Cu-catalyzed decarboxylative
coupling of isatins with hydrazides for the synthesis of 2-
(1,3,4-oxadiazol-2-yl)anilines.11c However, direct annulation of
hydrazides and methyl ketones to construct 1,3,4-oxadiazoles
has not been reported to date, most likely due to the inertia of
ketones.
C
and attractive area which provides new modes of chemical
reactivity to synthetic organic chemistry.1 Traditionally, C−C
bond cleavage can be achieved by oxidative cyclometalation of
three- or four-membered-ring compounds2 and directing a
metal complex to a particular C−C bond using functional
groups.3 Nevertheless, the direct transformation through the
C(CO)−C bond cleavage of ketones is still limited and attracts
the continuous attention of chemists.4 Recently, a few elegant
works on oxidative C(CO)−C bond cleavage of methyl ketones
have been reported (Scheme 1). The group of Bi and Liu
Scheme 1. Oxidative C(CO)−C Bond Cleavage of Methyl
Ketones
Owing to our continuing interest in the construction of
heterocycles, we wished to accomplish this goal by oxidative
3
cleavage of Csp −H bonds of methyl ketones. In the beginning,
p-acetylanisole (1a) and benzohydrazide (2a) were selected as
model substrates. To our delight, the reaction was successful in
3.0 equiv of K2CO3 over 20 h using 2.5 equiv of I2 at 100 °C in
DMSO. The products were a mixture of the 2-phenyl-1,3,4-
oxadiazole (3a, 78%) and the (4-methoxyphenyl)(5-phenyl-
1,3,4-oxadiazol-2-yl)methanone (4a, 21%) (Table 1, entry 1).
Having obtained an initial and promising result, we next
focused on the optimization of the reaction conditions. After
screening a series of bases including K2CO3, KOH, t-BuOK,
K2S2O8, K3PO4, Cs2CO3, NaHCO3, and NaOCH3 and
exploring the reaction temperature and time (Supporting
Information, Table S1), it was found that using 3.0 equiv of
K3PO4 afforded 4a in up to 89% yield (Table 1, entry 5). It was
also found that an increased reaction time or temperature
caused C−C bond cleavage of 4a to form 3a. If the reaction was
described CuI-catalyzed chemoselective oxidation cleavage of
methyl ketones to aldehydes, which proceeded via an
arylglyoxal intermediate without overoxidization.5 Jiao devel-
oped a Cu-catalyzed oxidative C−N and C−O bond formation
through C−C bond cleavage to realize the transformations of
ketones to amides6a and esters.6b,c Despite the significance of
these novel reactions, the direct transformation of ketones
through C(CO)−C bond cleavage is still a fascinating theme.
Herein, we report our progress in the oxidative C(CO)−C
bond cleavage of methyl ketones for the convenient
construction of the 1,3,4-oxadiazole skeleton.
1,3,4-Oxadiazoles are important five-membered aromatic
heterocycles due to their interesting properties in medicinal
Received: April 27, 2015
© XXXX American Chemical Society
A
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Letter
a
However, no products was observed under the standard
conditions when propiophenone was used as a substrate.
The reaction scope was next tested using substrate 1a with
different hydrazines under the optimized conditions to build
diverse 1,3,4-oxadiazoles (Scheme 3). Aryl hydrazines bearing
Table 1. Optimization of the Reaction Conditions
a
Scheme 3. Scope of Hydrazides
a
b
Isolated yield. K2CO3 (4.0 equiv).
electron-neutral (e.g., 4-H, 4-t-Bu, 4-Me), electron-rich (e.g., 4-
OMe, 3-OMe, 2-OMe, 3,4-OCH2O), and electron-deficient
(e.g., 4-NO2, 4-Ph) phenyl rings were converted to the
corresponding products in moderate to good yields (63−
93%; 3a−i). Much to our satisfaction, the optimized conditions
were mild enough to allow a broad range of halogenated (e.g.,
4-Cl, 4-Br) substrates (86−87%; 3j−k) to be reacted, which
allowed for easy further functionalization. 2-Naphthyl hydrazine
also provided the expected product (3l) in 83% yield.
Meanwhile, the optimized conditions could be applied to
various heteroaryl hydrazides, including furanyl, thienyl, and
pyridyl hydrazines, which gave the corresponding products in
moderate to good yields (48−74%; 3m−o). In addition, an
alkyl hydrazide, such as acetohydrazide, was also investigated.
However, the undeacylative product (3p) was isolated and the
desired products was not observed under the standard
conditions.
Recently, α-keto-1,3,4-oxadiazoles have been identified as
inhibitors of cathepsin K,12a human neutrophil elastase
(HNE),12b fatty acid amide hydrolase (FAAH),12c and the
20S proteasome.12d However, to the best of our knowledge,
there is no report about the effective synthesis of α-keto-1,3,4-
oxadiazole derivatives.13 Interestingly, the above C−C bond
cleavage system could be readily switched to produce α-keto-
1,3,4-oxadiazoles through slight modification of the reaction
conditions. Several (het)aryl methyl ketones and hydrazines
were subjected to the procedure, and the corresponding
products were obtained in 61−91% yields (Scheme 4).
With the scope of the method established, the reaction of
acetophenone-β-13C (0.1 mmol) and 2a (0.1 mmol) with I2
(0.25 mmol) in the presence of K2CO3 (0.6 mmol) in DMSO-
d6 was monitored by 13C NMR spectroscopy to probe the
mechanism of this reaction in greater detail (Figure 1). The
results of this study also revealed that phenylglyoxal (1db′), C-
acyl benzoylhydrazone (5d′), and α-keto-1,3,4-oxadiazole (4b′)
were important intermediates in the overall transformation.
A series of control experiments were subsequently carried
out to develop a deeper understanding of the reaction
mechanism (Scheme 5). The hydrated species (1dc) was
subjected to the optimized reaction conditions and gave 3a in
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (2 mL).
Isolated yields. C-Acylhydrazone was isolated.
b
c
carried out using 6.0 equiv of K2CO3 at 110 °C for 16 h, 4a was
fully decarboxylated to form 3a in 89% yield. DMSO/H2O = 3/
1 (v/v) turned out to be more effective solvents for the
deacylation process.
With the optimized conditions in hand, the scope of the
(het)aryl methyl ketones was investigated and compared
(Scheme 2). It was observed that the electronic and substituent
of the aryl ring of (het)aryl methyl ketones had a significant
influence on the efficiency of the C−C bond cleavage.
Obviously, the cleavage of various heteroaryl methyl ketones,
including benzofuran, furan, and thiophene fragments,
proceeded smoothly to generate the desired product 3a.
a
Scheme 2. Scope of Methyl Ketones
a
Isolated yield.
B
DOI: 10.1021/acs.orglett.5b01241
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Letter
a
4b were not observed without K2CO3 (Scheme 5a). When 4b
was used as a substrate in the reaction, the desired product 3a
was formed in 88% yield (Scheme 5b). These results suggested
K2CO3 played an important role in the cyclization/deacylation
process. In addition, in the absence of I2, C-acylhydrazone
(5d)14 was not converted to the target product (Scheme 5c),
indicating that I2 might be useful for cyclization of C-acyl
benzoylhydrazone. When the acetophenone substrate was
replaced with α-iodo acetophenone (1da), which was identified
as a possible precursor of α-ketoaldehyde (1db), the desired
deacylation product was also obtained in 63% yield (Scheme
5d). We also checked the reaction of the acyl hydrazine with
iodoform under the standard conditions in order to eliminate
the possibility of annulation of hydrazides with iodoform
(Scheme 5e).
Scheme 4. Scope of Methyl Ketones and Hydrazides
On the basis of the results in the current study and previous
reports,15 a possible mechanism has been proposed using 1a
and 2a as examples (Scheme 6). The initial reaction of I2 with
a
Isolated yield.
Scheme 6. Possible Mechanism
1a results in the formation of the α-iodo ketone (1aa), which
would be converted to 1ab by a subsequent Kornblum
oxidation. The reaction of benzohydrazide (2a) with the
aldehyde group of 1ab would then give the C-acyl
benzoylhydrazone (5a), which would react with I2 to generate
the iodide intermediate A (path a). This K2CO3-promoted
oxidative iodination may be responsible for the selective
cyclization of 5a. Consequently, the product 4a would then be
smoothly formed via sequential SN2′-type cyclization and
aromatization reactions of A. It is possible that the K2CO3-
promoted isomerization of 5a was followed by intramolecular
cyclization, and then aromatization (path b). Finally, α-keto-
1,3,4-oxadiazole would undergo deacylation to provide the
product 3a in the presence of K2CO3. In addition, the steric
effect of the base might play an important role in the C−C
bond cleavage process.
Figure 1. Progress of the reaction of 1d′ (0.1 mmol) and 2a (0.1
mmol) with I2 (0.25 mmol) in the presence of K2CO3 (0.6 mmol) at
110 °C by 13C NMR (150 MHz, DMSO-d6, 298 0.5 K).
Scheme 5. Control Experiments
In summary, we have developed a new type of C(CO)−
C(methyl) bond cleavage of (het)aryl methyl ketones for the
synthesis of 1,3,4-oxadiazoles via direct annulation of
hydrazides. 13C labeling 13C NMR spectroscopy experiments
demonstrate that the sp3 carbon in (het)aryl methyl ketones
was used as a one carbon synthon to perform the
intermolecular annulation reactions. The generality and high
selectivity of the reaction toward C(sp3)−H bonds together
with employing readily available hydrazides as the substrates
95% yield. This result demonstrated that 1dc was an
intermediate in the current reaction. However, both 3a and
C
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made this method very attractive. Further investigation of the
synthetic applications are ongoing in our laboratory and will be
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ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure and characterization data of
the products. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01241.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
(8) (a) He, G. S.; Tan, L. S.; Zheng, Q.; Prasad, P. N. Chem. Rev.
2008, 108, 1245. (b) Rehmann, N.; Ulbricht, C.; Kohnen, A.;
̈
The authors declare no competing financial interest.
Zacharias, P.; Gather, M. C.; Hertel, D.; Holder, E.; Meerholz, K.;
Schubert, U. S. Adv. Mater. 2008, 20, 129. (c) Zhang, Y.; Zuniga, C.;
Kim, S. J.; Cai, D.; Barlow, S.; Salman, S.; Coropceanu, V.; Bredas, J.
L.; Kippelen, B.; Marder, S. Chem. Mater. 2011, 23, 4002. (d) Kuo, H.
M.; Li, S. Y.; Sheu, H. S.; Lai, C. K. Tetrahedron 2012, 68, 7331.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (Grants 21272085, 21472056).
■
(e) Paraschivescu, C. C.; Matache, M.; Dobrota,
Maxim, C.; Deleanu, C.; Farcasanu, I. C.; Hadade, N. D. J. Org. Chem.
2013, 78, 2670.
̆
C.; Nicolescu, A.;
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