Copper-catalyzed direct synthesis of 1,2,4-oxadiazoles from amides and organic nitriles by oxidative N-O bond formation

Article abstract of DOI:10.1002/ejoc.201501502

Herein, we report the first Cu-catalyzed one-step method for the synthesis of 1,2,4-oxadiazoles from stable, less toxic, and readily available amides and organic nitriles by a rare oxidative N-O bond formation using O₂ as sole oxidant. This met

Full text of DOI:10.1002/ejoc.201501502

DOI: 10.1002/ejoc.201501502
Communication
Copper Catalysis
Copper-Catalyzed Direct Synthesis of 1,2,4-Oxadiazoles from
Amides and Organic Nitriles by Oxidative N–O Bond Formation
Malleswara Rao Kuram,[a,b] Woo Gyum Kim,[a] Kyungjae Myung,[b] and Sung You Hong*[a]
Abstract: Herein, we report the first Cu-catalyzed one-step method has a broad substrate scope and a good tolerance for
method for the synthesis of 1,2,4-oxadiazoles from stable, less diverse functional groups. Moreover, the synthetic utility of this
toxic, and readily available amides and organic nitriles by a rare method is highlighted by the synthesis of biologically active
oxidative N–O bond formation using O2 as sole oxidant. This 3,5-disubstituted derivatives.
Introduction
oped.[1b,1c] One of the classical methods for the synthesis of
1,2,4-Oxadiazole is a privileged scaffold, ubiquitous in various 1,2,4-oxadiazoles (Scheme 1a) widely utilizes amidoximes as the
bioactive molecules, pharmaceuticals, and functional materi- starting precursor, prepared by the addition of carcinogenic
als.[1–4] Furthermore, these five-membered heterocycles have hydroxylamine to a nitrile compound.[6] Then, the amidoximes
been utilized as stable ester or amide bioisosteres in peptide are O-acylated using activated carboxylic acid derivatives
mimetics.[5] Therefore, their synthesis has attracted much atten- followed by intramolecular dehydration to afford 1,2,4-oxadi-
tion; thus, various synthetic methods have been devel- azoles. This often requires high temperatures and long reaction
Scheme 1. Outline of our current approach.
times.[6] Recently, microwave-assisted methods or strong acids
such as pTsOH and ZnCl2 were used to overcome these limita-
tions.[7] Another route for the generation of these heterocycles
involves the 1,3-dipolar cycloaddition of nitrile oxides to nitriles
or azetine derivatives (Scheme 1b).[8] Recently, N-acylamidines
obtained from the condensation of amidines with carboxylic
acids were used as the intermediates; further tandem reaction
with hydroxylamine afforded 1,2,4-oxadiazoles (Scheme 1c).[9a]
Moreover, Jiang and co-workers reported the Cu-catalyzed cas-
cade annulation of amidines with methylarenes using tert-butyl
hydroperoxide as an oxidant.[9b] Despite these diverse meth-
[a] School of Energy and Chemical Engineering, Center for Advanced
Molecular Sciences
Ulsan National Institute of Science and Technology (UNIST)
UNIST-gil 50, Ulsan 689-798, Republic of Korea
E-mail: syhong@unist.ac.kr
http://home.unist.ac.kr/professor/syhong/
[b] Center for Genomic Integrity (CGI), Institute for Basic Science (IBS), School
of Life Sciences, UNIST
UNIST-gil 50, Ulsan 689-798, Republic of Korea
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501502.
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ods,[10] typically multistep processes and harmful reagents are
used for the synthesis of diverse 1,2,4-oxadiazoles.
Table 1. Optimization of the reaction conditions.[a]
Despite the synthetic and medicinal utility of oxa–aza
heterocycles containing N–O bonds, the direct oxidative bond
formation between nitrogen and oxygen atoms are scarce and
typically requires strong oxidants.[11] Among the recently re-
ported transition-metal-catalyzed or transition-metal-free syn-
theses of nitrogen heterocycles involving oxidative N–N cou-
pling,[12] the synthesis of 1,2,4-triazoles by a Cu-catalyzed addi-
tion and oxidative cyclization of amidines with aryl nitriles de-
veloped by Nagasawa and Ueda is noteworthy.[13] However, to
the best of our knowledge, the direct synthesis of 1,2,4-oxadi-
azoles from amides and organic nitriles by direct N–O bond
formation has not been reported. The development of efficient
methods for the synthesis of complex organic molecules from
simple substrates is always demanding and challenging. In this
study, we report a Cu-catalyzed direct method for the synthesis
of 1,2,4-oxadiazoles from readily available and simple starting
precursors, amides, and organic nitriles.
Entry
Catalyst
Ligand
Base
T
[°C]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L2
L2
L1
L3
L4
L5
L4
L4
L4
L4
L4
L4
–
120
120
120
120
120
120
130
150
130
130
130
130
2
22
25
22
36
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2
Results and Discussion
60[c,d]
64[c,d]
68[c,d,e]
92[c,e]
60
First, the reaction conditions were optimized (Table 1) for the
direct synthesis of 1,2,4-oxadiazole using benzamide (1a;
1.2 equiv.) and benzonitrile (2a; 1.0 equiv.). The initial screening
to obtain 1,2,4-oxadiazole using various transition-metal cata-
lysts was unsuccessful (see Supporting Information, Table S2).
To our delight, the desired product was obtained when CuI/
1,10-phenanthroline (L2) and ZnI2 were used in 1,2-dichloro-
benzene at 120 °C under O2, albeit in 2 % GC yield (Table 1,
Entry 1). The addition of a base slightly increased the yield (En-
try 2). Among the bases screened, K2CO3 was the best, resulting
in 22 % yield (see also Table S3). Then, various nitrogen ligands
were screened; bathophenanthroline (L4) increased the yield
up to 36 % compared to other ligands (Entries 3–6). When air
was used instead of O2, 15 % GC yield was obtained; attempts
to use other oxidants including benzoyl peroxide, K2S2O8, and
PhI(OAc)2 were unsuccessful (see Table S4). The reaction did not
proceed in other solvents such as toluene, N,N-dimethylforma-
mide, and dimethyl sulfoxide (Table S5). Interestingly, when the
temperature was increased up to 130 °C without ZnI2, the yield
significantly increased to 60 % (Entry 7). A further increase in
temperature to 150 °C did not affect the yield (Entry 8). The
reaction profile was relatively clean after the addition of MS
(4 Å) in the GC analysis. A further improvement in the yield was
observed when the amounts of benzamide (1a) and benzo-
nitrile (2a) were changed to 1 and 2 equiv., respectively (En-
try 9). Gratifyingly, the addition of ZnI2 increased the isolated
yield up to 92 % (Entry 10). In the presence of a CuII salt, 60 %
yield was obtained (Entry 11). Without a Cu catalyst, no product
formation was observed (Entry 12). Therefore, Entry 10 was se-
lected for the optimal reaction conditions.
10
11
12
CuI
Cu(OTf)2
–
–
[a] Reaction conditions: 1a (1.2 equiv.), 2a (1.0 equiv., 0.2 mmol), catalyst
(10 mol-%), ligand (10 mol-%), base (2.0 equiv.), ZnI2 (10 mol-%) in 1,2-dichlo-
robenzene (1,2-DCB, 1 mL) under O2 (1 atm) for 24 h. [b] GC yield with n-
dodecane as an internal standard. [c] MS (4 Å), isolated yield. [d] Without
ZnI2. [e] 1a (1.0 equiv.) and 2a (2.0 equiv.).
(3) were generally obtained in moderate to excellent yields (up
to 94 %). The reactions of substrates bearing electron-with-
drawing and electron-donating para substituents on the aro-
matic ring of benzonitrile, such as methyl (2b), trifluoromethyl
(2c), fluoro (2d), and phenoxy (2e) groups, afforded the corre-
sponding products in good yields (Scheme 2; 3ab–3ae). In the
case of 4-methoxybenzonitrile (2f), only 33 % yield was ob-
tained (3af), probably because of the reduced electrophilicity
of the cyano group by the strong electron-donating methoxy
group. The detailed reaction mechanism will be discussed fur-
ther below. To our delight, the reactions of ortho-/meta-substi-
tuted benzonitriles afforded the corresponding products in
good to moderate yields (3ag and 3ah). When 1-cyanonaphth-
alene (2i) and naphthalene-2-carbonitrile (2j) were treated with
benzamide (1a), products 3ai and 3aj were obtained in 56 %
and 94 % yields, respectively. The reactions with heterocyclic
nitriles such as isonicotinonitrile (2k), nicotinonitrile (2l), and
imidazo[1,2-a]pyridine-6-carbonitrile (2m) afforded the cor-
responding products (3ak–3am), indicating the broad substrate
scope of the protocol. The reactions of 3-cyanochromone (2n)
Then, the substrate scope and generality of the method un- and benzo[b]thiophene-3-carbonitrile (2o) also afforded the
der the optimized reaction conditions were investigated using corresponding products in moderate yields (3an and 3ao). In-
various organic nitriles containing diverse functional groups terestingly, in the reaction of 1,4-dicyanobenzene, one cyano
(Scheme 2). The results demonstrate broad substrate scope group survived, thus affording 3ap in 65 % yield. Next, the re-
with 1a as a partner, and the corresponding 1,2,4-oxadiazoles activities of different aliphatic nitriles with benzamide (1a) were
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investigated. When nonanenitrile (2q) was used, a good yield
of the product 3aq was obtained. Adamantanecarbonitrile (2r)
and cyclohexanecarbonitrile (2s) were less reactive, resulting in
44 % and 30 % yields, respectively (3ar and 3as). These results
indicate that aromatic nitriles are more reactive. The inductively
donating aliphatic groups may lead to a decrease in the electro-
philicity, resulting in less reactive aliphatic nitriles towards the
nucleophilic attack of amides.
Scheme 3. Synthesis of 1,2,4-oxadizoles from diverse amides under standard
conditions.
complex 4 by coordinating with substrates. The nucleophilic
addition of the amide to the benzonitrile, activated by a Lewis
acidic CuII species, affords CuII complex 5.[14e] The removal of
the proton with a base followed by the rearrangement affords
CuII chelate complex 6. Then, CuIII complex 7 is formed by the
disproportionation of CuII with molecular oxygen, thus reoxidiz-
ing CuI to CuII.[14a,14d] Finally, the reductive elimination affords
the desired product and regenerates the catalytic cycle.
Scheme 2. Synthesis of 1,2,4-oxadizoles from diverse organic nitriles. Stand-
ard conditions: amide 1 (1.0 equiv., 1.0 mmol), organic nitrile 2 (2.0 equiv.,
2.0 mmol), CuI (10 mol-%), L4 (10 mol-%), K2CO3 (2.0 equiv.), ZnI2 (10 mol-
%), MS (4 Å) (300 mg) in 1,2-DCE (2.0 mL) at 130 °C under O2 (1 atm) for
24 h.
Then, the reactivities of various amides with benzonitrile (2a)
were investigated (Scheme 3). The reactions of aryl amides
bearing various para-substituted functional groups such as
methyl (1b), methoxy (1c), nitro (1d), halo (1e and 1f), and
phenyl (1g) proceeded smoothly. The reactions of meta- or or-
tho-substituted aryl amides bearing methoxy (1h), methyl (1i/
1k), nitro (1j), and fluoro (1l) groups afforded the correspond-
ing products in moderate to good yields. The reactions of 3,5-
bis(trifluoromethyl)benzamide (1m) and 3,5-dibromobenz-
amide (1n) with benzonitrile (2a) afforded the corresponding
products 3ma and 3na in good yields. Finally, the heterocyclic
thiophene-2-carboxamide (1o) reacted well with benzonitrile
(2a) to afford 3oa in 53 % yield.
Scheme 4. Proposed reaction mechanism.
To support the proposed reaction mechanism, intermediate
8 was synthesized and subjected to standard reaction condi-
tions; 3aa was obtained in 83 % yield (Scheme 5). This clearly
Based on the previous reports[13,14] and our experimental re-
sults, a reaction mechanism is proposed. The reaction proceeds
by the addition of the amide to the benzonitrile followed by
N–O bond formation to afford the 1,2,4-oxadiazole (Scheme 4).
First, CuI is oxidized to CuII by molecular oxygen and forms
Scheme 5. Mechanistic studies by using intermediate 8.
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Scheme 6. Syntheses of biologically active 1,2,4-oxadiazole derivatives.
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indicates the involvement of intermediate 5 in the proposed
catalytic cycle. When intermediate 8 was subjected to the opti-
mized reaction conditions without ZnI2, the yield of 3aa dra-
matically decreased (45 %), indicating the probable role of ZnI2
during the reductive elimination step or disproportionation of
CuII; yet the role of ZnI2 as a Lewis acid promoting the nucleo-
philic addition cannot be completely ruled out.
To highlight the synthetic utility of this Cu-catalyzed oxida-
tive cyclization, biologically active 1,2,4-oxadiazole derivatives
were synthesized (Scheme 6). The reaction of 2-fluorobenz-
amide (1l) with m-tolunitrile (2g) afforded 3lg in 61 % yield;
this can be converted into ataluren (9),[9a] a drug for the treat-
ment of cystic fibrosis.[15] Recently, Chang and co-workers syn-
thesized and studied the oxadiazole derivative 3pt, a new class
of non-ꢀ-lactam antibiotics that inhibits the penicillin-binding
protein (PBP) 2a.[16] When 4-fluorobenzamide was treated with
2t under optimized reaction conditions, product 3pt was ob-
tained in 54 % yield.
[2]
[3]
[4]
[5]
[6]
[7]
Conclusions
A new method was developed for the synthesis of 1,2,4-oxadi-
azoles by a Cu-catalyzed reaction through a rare oxidative N–O
bond formation, and O2 was used as the sole oxidant, thus
avoiding the synthesis of starting precursors or to use of strong
oxidants, typically required in previous methods. The method
also showed a broad substrate scope and a good tolerance for
diverse functional groups. Considering the ready availability of
stable starting precursors, inexpensive reagents, and the one-
step synthesis, a convenient and highly modular 1,2,4-oxadi-
azole synthesis was developed.
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Acknowledgments
[10]
This research was supported by the Institute for Basic Science
(IBS-R022-D1-2015).
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Keywords: Copper · Heterocycles · 1,2,4-Oxadiazoles ·
Homogeneous catalysis · Cyclization
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