Organocatalytic Oxidative Cyclization of Amidoximes for the Synthesis of 1,2,4-Oxadiazolines

Article abstract of DOI:10.1002/adsc.201800238

Organocatalytic synthesis of bi- and tricyclic fused 1,2,4-oxadiazolines is reported. The reaction proceeds through oxidative cyclization of the corresponding amidoxime using 2,4,6-tris(4-fluorophenyl)pyrylium tetrafluoroborate (T(p-F)PPT) as the organocatalyst, and molecular oxygen as the green oxidant. During the transformation, T(p-F)PPT acts as both the electrophilic catalyst and photocatalyst, and the reaction is promoted by irradiation with visible light. The method introduced herein offers a straightforward route to the preparation of 1,2,4-oxadiazolines with different functionalities, and is highly atom economical. (Figure presented.).

Full text of DOI:10.1002/adsc.201800238

Title: Organocatalytic Oxidative Cyclization of Amidoximes for the
Synthesis of 1,2,4-Oxadiazolines
Authors: Vineet Soni, Jun Kim, and Eun Jin Cho
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800238
Link to VoR: http://dx.doi.org/10.1002/adsc.201800238

10.1002/adsc.201800238
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Oxidative Cyclization of Amidoximes for the
Synthesis of 1,2,4-Oxadiazolines
Vineet Kumar Soni,a Jun Kim,a and Eun Jin Choa*
aDepartment of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of
Korea
E-mail: ejcho@cau.ac.kr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
15]
receptor modulators),[12c,
and type 2 diabetes
Abstract. Organocatalytic synthesis of bi- and
tricyclic fused 1,2,4-oxadiazolines is reported. The
reaction proceeds through oxidative cyclization of
the corresponding amidoxime using 2,4,6-tris(4-
fluorophenyl)pyrylium tetrafluoroborate (T(p-
F)PPT) as the organocatalyst, and molecular oxygen
as the green oxidant. During the transformation,
T(p-F)PPT acts as both the electrophilic catalyst
and photocatalyst, and the reaction is promoted by
irradiation with visible light. The method
introduced herein offers a straightforward route to
the preparation of 1,2,4-oxadiazolines with
different functionalities, and is highly atom
economical with respect to molecular oxygen.
mellitus (TGR5 agonists).[12d]
Keywords: Organocatalysis; Molecular oxygen;
Cyclization; Nitrogen heterocycles
Figure 1. Selected examples of bioactive 1,2,4-
oxadiazolines.
Due to their importance, a variety of methods have
been developed for the synthesis of 1,2,4-
oxadiazolines, which are generally carried out
through the [3+2] cycloaddition of a nitrile oxide
(generated in situ from the corresponding
hydroxamoyl chloride[12d, 16] or nitroalkane[17]) with an
imine [Scheme 1(a)].[18] 1,2,4-Oxadiazolines have
also been produced by the condensation of an
aldehyde with an amidoxime [Scheme 1(b)].[19]
Despite these significant advancements, many of
these methods suffer from one or several drawbacks,
such as difficult substrate preparation, harsh reaction
conditions, or the use of hazardous and/or expensive
transition-metal complexes and additives. Hence the
development of new methodologies for the synthesis
of 1,2,4-oxadiazolines is desirable; in particular,
greener synthetic methods given the importance of,
and intense interest in, green chemistry. Herein, we
present a sustainable methodology for the synthesis
of 1,2,4-oxadiazolines involving the intramolecular
oxidative cyclizations of amidoximes in the presence
The importance of azaheterocycles relates to their
presence as natural products, drugs and biologically
relevant compounds.[1] In particular, 1,2,4-
oxadiazoles are naturally occurring bioactive
molecules,[2] and are also bioisosteres of amides and
esters with enhanced hydrolytic and metabolic
stabilities.[3] 1,2,4-Oxadiazole derivatives possess
diverse biological activities including antimicrobial,[4]
anti-Alzheimer’s
disease,[5]
anticonvulsant,[6]
antithrombotic,[7] and antitumor[8] properties.
Furthermore, this moiety has also been introduced in
polymers,[9] energetic materials,[10] and organic light-
emitting diodes (OLEDs).[11] More specifically, recent
reports illustrate the roles that 1,2,4-oxadiazoline
(4,5-dihydro-1,2,4-oxadiazole) moieties play in a
variety of biologically active molecules (Fig. 1).[12]
These molecules are effective against cognitive
disorders such as Alzheimer’s disease,[12a, 13] cognitive
impairment[14] and schizophrenia,[14] rheumatoid
arthritis (MAPKAPK2 or MK2 inhibitors),[12b] cancer
(selective COX-2 inhibitors and selective androgen
1
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10.1002/adsc.201800238
Advanced Synthesis & Catalysis
of an organocatalyst and molecular oxygen as the sole
oxidant [Scheme 1(c)].
base resulted in reduced or no reactivity (entries 22
and 23). The reaction did not proceed well under air
atmosphere, whereas no product was formed in the
absence of molecular oxygen (entries 24 and 25).
Moreover, the temperature variations showed decline
in product yields (entries 26 and 27). Interestingly,
the use of visible-light irradiation was not necessarily
required as seen in the reaction of 1a with T(p-F)PPT
in the absence of visible light that still provided 2a in
50% yield (entry 28). Nevertheless, the presence of
visible light accelerates the reaction significantly
because the reaction without visible light took much
longer time to reach completion (96 h). The other
organophotocatalysts were also re-evaluated under
dark conditions, but they did not work well besides
TPP derivatives (entry 2 vs. entries 29–31). It is
highly likely that 1a is involved in a non-
photocatalytic nucleophilic pathway with T(p-F)PPT,
where the TPP ion is an electrophilic
organocatalyst.[25]
Scheme 1. Synthetic strategies for 1,2,4-oxadiazolines.
We
began
our
investigation
using
phenyl(pyrrolidin-1-yl)methanone oxime (1a) as a
model substrate for the synthesis of a 1,2,4-
Table 1. Optimization of reaction conditions[a]
oxadiazoline,
3-phenyl-5,6,7,7a-
tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole (2a) at a
concentration of 0.2 M in DMF under an atmosphere
of molecular oxygen (Table 1). The reaction did not
proceed at room temperature (entry 1) and increasing
the temperature to 40 °C or higher[20] did not
sufficiently improve its efficiency to provide a
satisfactory result (entry 2). To improve the efficiency
of the desired cyclization, we planned to utilize
visible-light photocatalysis, a technique that has
recently emerged as a powerful synthetic tool because
of its environmental benignness and mechanistic
versatility in promoting a variety of organic
transformations.[21, 22] We first employed two of the
most popular photocatalysts, namely [Ru(bpy)3]Cl2
and [Ir(dtbbpy)(ppy)2]PF6 (bpy = 2,2'-bipyridine; ppy
= 2-phenylpyridine), with visible-light irradiation
from a compact fluorescent lamp (CFL, 23 W);
however these conditions did not provide the desired
2a, rather they generated N-benzoylpyrrolidine as the
major product (entries 3 and 4). Several other
organophotocatalysts were then explored, including
eosin Y, rhodamine 6G, methylene blue, and
triphenylpyrylium
tetrafluoroborate
(TPPT)
derivatives (entries 5−12). Notably, the use of an
organophotocatalyst minimizes the drawbacks
associated with transition metals, including toxicity
and threshold metal levels in pharmaceutical
products.[23] Among the organophotocatalysts, 2,4,6-
tris(4-fluorophenyl)pyrylium tetrafluoroborate (T(p-
F)PPT) exhibited the highest efficiency, providing 2a
in 93% yield (entry 12).[22h] After further screening of
the solvent system,[24] reaction concentration, source
of light, and the reagent stoichiometry (Table 1,
entries 13−21), we confirmed that the optimum
conditions for the transformation of 1a into 2a
[a]
Reaction conditions: 1a (0.1 mmol) under molecular
involves
2
mol% of T(p-F)PPT at 0.2
M
oxygen atmosphere. [b] Yield was determined by H NMR
spectroscopy using bromoform as the internal standard.
NMR-determined recovery of unreacted 1a in parenthesis.
[d] N-Benzoylpyrrolidine was formed as the major product.
1
concentration in DMF under an atmosphere of
molecular oxygen, and visible-light irradiation using
CFL (entry 12). The presence of organic/inorganic
[c]
2
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10.1002/adsc.201800238
Advanced Synthesis & Catalysis
The substrate scope of the method was investigated
a mixture of oxazolidines 3 and 3′ in various ratios as
side products. To further investigate this outcome, a
solution of 1p in DMF (0.2 M) was stirred at 40 °C
for 12 h in the absence of the catalyst. The
oxazolidines 3 and 3′ were observed, along with
unreacted starting material; however the formation of
2p was not observed which further confirms the
critical role of the catalyst during the formation of the
desired 1,2,4-oxadiazolines.
using the optimized conditions with a variety of
pyrrolidinyl oxime derivatives 1 (Table 2). -
(Pyrrolidin-1-yl)benzaldehyde oxime (1a) derivatives
bearing electron-donating or electron-withdrawing
substituents underwent oxidative cyclization to afford
1,2,4-oxadiazolines in high yields (Table 2, 2a–2g).
The installation of polyaromatic substituents, such as
naphthyl and pyrenyl groups, was realized through
the syntheses of 2h and 2i. Notably, substrates
containing biologically important heteroaromatic
rings, such as pyridyl, indolyl, furyl, and thiophenyl,
also underwent successful oxidative cyclizations to
give the corresponding 1,2,4-oxadiazolines 2j–
2m.[12b, 12d, 16c] Not only were (hetero)aryl amidoximes
suitable substrates for this transformation, but
aliphatic amidoximes also gave 3-alkyloxadiazolines
2n and 2o in good yields. In general, the starting
amidoximes 1 were prepared as mixtures of E/Z
isomers in varying ratios. Irrespective of the ratio, the
Scheme 2. Reaction of cinnamylamidoxime 1p
with/without T(p-F)PPT.
oxidative
cyclizations
proceeded
smoothly,
suggesting that
1
isomerizes under these
photocatalytic conditions.[26] Notably, the synthetic
utility of the method was examined in a gram scale
synthesis in which product 2a was prepared on a 7
mmol scale in a yield similar to that obtained from
the 0.1 mmol scale reaction, despite longer reaction
times.
We explored expanding the substrate scope
through the use of substrates bearing different
amino groups, such as isoindolinyl and
tetrahydroisoquinolinyl (Table 3). Under the
standard conditions, α-(isoindolin-2-yl)benzaldehyde
oxime and α-(isoindolin-2-yl)-2-naphthaldehyde
oxime underwent smooth oxidative cyclization to
give the corresponding tricyclic 1,2,4-oxadiazolines
(Table 3, 5a and 5b). Despite the low yield, a
tetrahydroisoquinoline-fused oxadiazoline 5c was
also obtained; 5c was relatively unstable at room
temperature under atmospheric conditions and
slowly rearranged to 2-{imino(phenyl)methyl}-3,4-
dihydroisoquinolin-1(2H)-one (6) through a ring
opening process.[27] This observation is ascribable to
the presence of the highly acidic hydrogen at the 5-
position of the oxadiazoline ring.
Table 2. Substrate scope in the synthesis of bicyclic
1,2,4-oxadiazolines.[a, b]
Table 3. Synthesis of tricyclic 1,2,4-oxadiazolines.[a, b]
[
a]
Reaction conditions: 1 (0.1 mmol) under molecular
oxygen atmosphere. [b] Yield of isolated product.
The conjugated amidoxime 1p derived from trans-
cinnamaldehyde was also subjected to oxidative
cyclization, but the reaction did not work well for the
desired cyclization, providing product 2p in low yield
[Scheme 2]. The intramolecular addition of the
hydroxyl group to the double bond appears to dictate
the outcome in this case, resulting in the formation of
[a]
Reaction conditions: 4 (0.1 mmol) under molecular
oxygen atmosphere. [b] Yield of isolated product.
The indoline-derived phenylamidoxime 7 was also
examined, but its reaction was relatively inefficient,
3
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10.1002/adsc.201800238
Advanced Synthesis & Catalysis
producing the desired tricyclic 1,2,4-oxadiazoline 8
in only 21% yield, and the indoline 9 as the major
side product through dehydrogenation [Scheme 3(a)].
The piperidinyl oxime derivative 10 reacted in
approximately 10% conversion under the standard
reaction conditions; however this yield could be
increased through the use of DMF/MeCN (1:1 v/v) as
the solvent [Scheme 3(b)]. The reaction of a primary
aliphatic derivative 12 showed less reactivity to give
the desired product 13 only in 13% yield [Scheme
3(c)]. In addition, we attempted to synthesize
triphenylpyrylium (TPP) derivatives were effective
catalysts among the examined photocatalysts, and
that the reaction proceeded even in the absence of
light, albeit less efficiently, suggests that T(p-F)PPT
functions as both an electrophilic catalyst and a
photocatalyst in this transformation. We propose that
the reaction begins by the nucleophilic addition of 1a
to the triphenylpyrylium ion (A) to generate
intermediate B. The dissociation of the C-O bond in
B then produces radicals C and D; this is the step that
is slow and inefficient in the absence of light, but is
promoted by exposure to visible-light (Table 1, entry
12 vs. 23). The oxidation of C by molecular oxygen
regenerates catalyst A. On the other hand, the
iminyloxyl radical D undergoes an intramolecular
1,5-hydrogen atom transfer (HAT)[29] to give the
carbon-centered radical E, which is subsequently
oxidized to the iminium ion F. This oxidation step is
facilitated either by molecular oxygen or more
prominently by excited A* generated from A by
irradiation with visible light. Intramolecular
cyclization of F finally yields the 1,2,4-oxadiazoline
2a.
monocyclic
1,2,4-oxadiazolines
14 and
from
N,N-
dimethylamidoxime
N-benzyl-N-
methylamidoxime 16, but the desired products were
not generated, indicating that the reaction might
require the structural conformation effects in
amidoximes [Scheme 3(d) and (e)].
Scheme 4. Plausible mechanism for the synthesis of 1,2,4-
oxadiazolines.
Scheme 3. Less-efficient and unsuccessful examples.
In conclusion, we have developed a transition-
metal/base-free oxidative cyclization of amidoximes
for the synthesis of fused bicyclic and tricyclic 1,2,4-
oxadiazolines. These reactions proceed in the
presence of the T(p-F)PPT organocatalyst and
molecular oxygen as the oxidant, and are promoted
by irradiation with visible light. During these
transformation, T(p-F)PPT acts as both an
electrophilic catalyst and a photocatalyst. The present
method benefits from advantages associated with the
use of molecular oxygen and visible light. In
addition, the absence of transition metals, ligands,
and bases further adds to the significance of this
strategy. Recent studies on the biological activities of
1,2,4-oxadiazolines reveal exciting opportunities for
their applications to pharmaceuticals.
To propose a mechanism for the oxidative
cyclization, several experiments were further
conducted. First, UV-Visible spectra were recorded
using 1a and T(p-F)PPT. No bathochromic shift for
an equimolar mixture discarded the possibility of
donor-acceptor complex formation (see supporting
information, Figure S1). However, the disappearance
of the O-H peak and chemical shifts of other peaks in
1a were observed during analysis of 1H NMR spectra
when mixing 1a with T(p-F)PPT (1:1 ratio) in the
absence of visible-light and molecular oxygen, which
suggested possible interaction between 1a and T(p-
F)PPT. The mixture was subsequently converted into
2a under molecular oxygen and visible-light
irradiation (see supporting information, Figure S2).[28]
Based on these observations,
a
plausible
mechanism for the oxidative cyclization of
amidoximes is proposed, with 1a as the example
Experimental Section
[Scheme
4]. The
observation
that
only
4
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10.1002/adsc.201800238
Advanced Synthesis & Catalysis
General Experimental Procedure for the Synthesis of
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the 1,2,4-Oxadiazolines 2 and 5
A flame-dried resealable tube equipped with a
magnetic stirrer bar was charged with the
amidoxime 1 or 4 (0.1 mmol), T(p-F)PPT (2 mol%,
0.002 mmol), and DMF (0.5 mL, 0.2 M). Molecular
oxygen was bubbled through the reaction mixture
for 2 min, and the tube was sealed with a silicone
septum screw cap. The test tube was then placed
under a CFL (23 W, 400-800 nm) at 40 °C. The
[6] H.-J. Lankau, K. Unverferth, C. Grunwald, H.
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1
progress of the reaction was monitored by TLC or H
NMR spectroscopy. The reaction mixture was then
diluted with ethyl acetate (EtOAc) and washed with
water and brine. The organic layer was dried over
MgSO4, filtered, concentrated under vacuum, and
purified by flash column chromatography
(hexane/EtOAc = 9:1 v/v) to furnish pure 1,2,4-
oxadiazolines 2 and 5 in 24–87% yields.
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Takata, Chem. Commun. 2012, 48, 10304-10306.
[10]Y. Tang, H. Gao, L. A. Mitchell, D. A. Parrish, J. n.
M. Shreeve, Angew. Chem. Int. Ed. 2016, 55,
3200-3203.
Acknowledgements
We gratefully acknowledge the National Research Foundation of
Korea [NRF-2012M3A7B4049657, NRF-2014-011165, NRF-
2016K1A3A1A19945930, and NRF-2017R1A2B2004082].
[11]Q. Li, L.-S. Cui, C. Zhong, Z.-Q. Jiang, L.-S. Liao,
Org. Lett. 2014, 16, 1622-1625.
[12]a) X. Huang, D. Pissarnitski, H. Li, T. Asberom, H.
Josien, X. Zhu, M. Vicarel, Z. Zhao, M.
Rajagopalan, A. Palani, R. Aslanian, Z. Zhu, W.
Greenlee, A. Buevich, Tetrahedron Lett. 2012, 53,
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[24]The reaction was incomplete and resulted in low
yield of 2a with the formation of N-
benzoylpyrrolidine in higher amount when
performed in other solvents such as MeCN,
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6
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10.1002/adsc.201800238
Advanced Synthesis & Catalysis
COMMUNICATION
Organocatalytic Oxidative Cyclization of
Amidoximes for the Synthesis of 1,2,4-
Oxadiazolines
Adv. Synth. Catal. Year, Volume, Page – Page
Vineet Kumar Soni, Jun Kim, and Eun Jin Cho*
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