A convenient one-pot synthesis of: N -substituted amidoximes and their application toward 1,2,4-oxadiazol-5-ones

Article abstract of DOI:10.1039/c8ra08207c

The first direct one-pot approach for the synthesis of N-substituted amidoximes from secondary amides or the intermediate amides has been developed. Through the Ph₃P-I₂-mediated dehydrative condensation, a variety of N-aryl and N-alkyl amidoximes (R¹(CNOH)NHR², where R¹ or R² = aryl, alkyl, or benzyl) were readily afforded under mild conditions and short reaction times. The synthetic application of the obtained amidoximes has also been demonstrated through the formation of 1,2,4-oxadiazolones via base-mediated carbonylative cyclization with 1,1′-carbonyldiimidazole.

Full text of DOI:10.1039/c8ra08207c

RSC Advances
View Article Online
View Journal | View Issue
PAPER
A convenient one-pot synthesis of N-substituted
amidoximes and their application toward 1,2,4-
oxadiazol-5-ones†
Cite this: RSC Adv., 2018, 8, 38281
ab
Chuthamat Duangkamol,a Nitaya Wiriyaa
*
Wong Phakhodee,
and Mookda Pattarawarapanab
The first direct one-pot approach for the synthesis of N-substituted amidoximes from secondary amides or
the intermediate amides has been developed. Through the Ph3P–I2-mediated dehydrative condensation,
a variety of N-aryl and N-alkyl amidoximes (R1(C]NOH)NHR2, where R1 or R2 ¼ aryl, alkyl, or benzyl)
were readily afforded under mild conditions and short reaction times. The synthetic application of the
obtained amidoximes has also been demonstrated through the formation of 1,2,4-oxadiazolones via
base-mediated carbonylative cyclization with 1,10-carbonyldiimidazole.
Received 4th October 2018
Accepted 1st November 2018
DOI: 10.1039/c8ra08207c
rsc.li/rsc-advances
steps starting from condensation of aldehydes with hydroxyl-
amine hydrochloride, followed by chlorination of the formed
oximes with N-chlorosuccinimide12 or chlorine gas.5c Moreover,
the protocol is ineffective for preparing aliphatic imidoyl chlo-
rides as the starting aldehydes are less reactive. Aliphatic imi-
doyl chlorides are also highly unstable and are oen obtained in
low yields.12,13
Alternatively, N-substituted amidoximes could be synthe-
sized via the addition of hydroxylamine or its analogs to the
activated amide derivatives such as imidoyl chloride (II) derived
from dehydrative chlorination of secondary amide with PCl5 or
P2O5,14 thioamide (III) from treatment of the starting amides
with Lawesson's reagent (p-methoxyphenylthionophosphine
sulphide dimer),15 or imidoylbenzotriazole (IV) from the reac-
tion of an amide with oxalyl chloride and benzotriazole.16 Other
methods include hydrolysis of 1,2,4-oxadiazolones (V),17 or the
reaction of primary nitroalkanes (VI) with amines18 or lithium
amides.19 However, these approaches suffer from various limi-
tations such as the use of highly toxic reagents, multistep
synthesis with tedious work-up and purication, harsh reaction
conditions, long reaction times, low yields, and limit substrate
scope. Therefore, the development of general and practical one-
Introduction
N-Substituted amidoximes are privileged structures that have
been used extensively as versatile building blocks in the
synthesis of various heterocycles such as benzimidazoles,1 4-
aminoquinazolines,2 1-aminoisoquinolines,3 oxadiazoles,4 oxa-
diazolones (thiones),5 and triazoles.1c They also serve as the key
intermediates in the synthesis of amidines as well as metal ion
chelating ligands in coordination chemistry.6 In drug develop-
ment, various N-substituted amidoxime derivatives have been
introduced as prodrug candidates to achieve good cell perme-
ability and oral bioavailability.6a The representative examples
are shown in Fig. 1. Epacadostat (A) is currently being studied in
a phase 3 clinical trial in patients with unresectable or meta-
static melanoma.7 B is a novel inhibitor of indoleamine 2,3-
dioxygenase.8 C and D are potent inhibitors of Escherichia coli
RNA polymerase.9 Oseltamivir prodrug E has been developed as
an anti-inuenza agent with favourable pharmacokinetics.10
Despite their essential applications, only a limited number
of synthetic routes for N-substituted amidoximes has been re-
ported in the literature. Whereas the synthesis of unsubstituted
amidoximes starting from benzonitriles is well-established,6a
the synthesis of N-substituted amidoximes is much less
straightforward requiring laborious multistep procedures.
One of the most commonly used methods involves the
reaction of amines with N-hydroxyimidoyl chloride (I).11
However, I is not readily available and has to be prepared in two
aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai
50200, Thailand. E-mail: wongp2577@gmail.com
bResearch Center on Chemistry for Development of Health Promoting Products from
Northern Resources, Chiang Mai University, Chiang Mai, 50200, Thailand
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra08207c
Fig. 1 Examples of bioactive N-substituted amidoximes.
RSC Adv., 2018, 8, 38281–38288 | 38281
This journal is © The Royal Society of Chemistry 2018

View Article Online
RSC Advances
Paper
Table 1 Optimization of the reaction conditionsa
Entry
Reagent
Base
Yield (%)
1
2
3
4
5
6
7
8
9
I2/Ph3P
I2/Ph3P
I2/Ph3P
I2/Ph3P
I2/Ph3P
I2/Ph3P
NCS/Ph3P
NBS/Ph3P
CBr4/Ph3P
I2
DABCO
DBU
NMM
Imidazole
DIPEA
Et3N
Et3N
Et3N
Et3N
Et3N
nr
Trace
10
20
45
85
nr
nr
nr
Scheme 1 Synthetic approaches toward N-substituted amidoximes.
pot approaches to access a variety of amidoximes derivatives
from readily available precursors is still desirable.
10
nr
In the recent years, iodine-mediated organic synthesis has
attracted considerable attention.20 This could be attributed to
its inexpensiveness, green nature, and high efficiency in
promoting a range of reactions. In particular, the combination
of iodine with triphenylphosphine (Ph3P) provides a highly
effective dehydrating agent leading to rapid and high yielding
synthesis under mild reaction conditions.21 In a continuation of
our interest in developing facile one-pot methods using the
Ph3P–I2 combination,22 we have designed a one-pot approach
for the synthesis of N-substituted amidoximes which enables
the use of inexpensive and commercially available secondary
amides, acid chlorides or carboxylic acids as the key precursors
(Scheme 1). Herein, we wish to report our detailed study in this
aspect.
a
Reaction conditions: N-phenylbenzamide (0.28 mmol), hydroxylamine
hydrochloride (0.42 mmol), Ph3P (0.42 mmol), additive (0.42 mmol),
base (1.4 mmol), CH2Cl2 (2 mL), 0 ꢀC-RT, 2 h. nr ¼ no reaction.
With the optimized reaction conditions in hand, the scope
and generality of the reaction were studied. For this purpose,
the reactions of diverse N-substituted aromatic and aliphatic
amides were investigated, and the results are shown in Scheme
2. N-Aryl substituted secondary amides bearing either an
electron-donating group (EDG), such as methyl or methoxy, or
an electron-withdrawing group (EWG), such as chloro, bromo,
or nitro on the N-phenyl ring underwent smooth conversion to
give 2a–2e in high yields. However, the electronic effect of the 4-
nitro group in the aromatic ring of R1 of amide 1f seems to lower
the yield of 2f. The condition is applicable to substrate bearing
heterocyclic ring although slightly lower yield of the product 2g
was obtained due to the difficulty in the product isolation.
Results and discussion
We started our investigations by optimizing the reaction of N-
phenylbenzamide (1a) with hydroxylamine hydrochloride.
Typically, the reaction was carried out by addition of N-phe-
nylbenzamide (1 equiv.) into a mixture of Ph3P (1.5 equiv.) and
halogenated additive (1.5 equiv.) in freshly dry dichloro-
methane, followed by addition of base (5 equiv.) and hydroxyl-
amine hydrochloride (1.5 equiv.).
As shown in Table 1, among the tested organic bases, only
triethylamine gave rise to the formation of the desired product
2a in high yield (entries 1–6). The reaction in the presence of the
commonly used imidazole gave the product in low yield (entry
4). Using diisopropylethylamine (DIPEA) although led to
increase conversion to the product (entry 5), the reaction was
incomplete even aer 24 h. According to entries 7–9, the reac-
tion did not proceed when replacing iodine with other haloge-
nated additives such as N-chlorosuccinimide (NCS), N-
bromosuccinimide (NBS), or carbon tetrabromide (CBr4). In
addition, no conversion was observed when the reaction was
carried out in the absence of Ph3P (entry 10) indicating that
phosphonium iodide or triphenylphosphoranediiodide are
acting as the key activating species. It should be noted also that
the reaction did not proceed when using oxalyl chloride or
thionyl chloride as the dehydrating agent.
Scheme 2 Synthesis of N-substituted amidoximes 2 starting from
amides.
38282 | RSC Adv., 2018, 8, 38281–38288
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
N-Alkyl substituted amides were also converted into the
RSC Advances
corresponding amidoximes 2h–2i in satisfactory yields. Unlike
other reported procedures which are not suitable for prepara-
tion of amidoximes with R1 ¼ alkyl,12,13 our conditions enable
the synthesis of various acetimidamide derivatives such as 2j–2l
from N-arylacetamide substrates without any difficulty. Other
secondary amides having R1 ¼ ethyl, benzyl, or even long alkyl
chain also provided the products 2m–2o in moderate to high
yields. Additionally, the reaction condition is applicable with
amides bearing a,b-unsaturated moiety. The exclusive forma-
tion of amidoximes 2p and 2q indicated no complication due to
Michael addition to the a,b-unsaturated system. The presence
of steric ortho-substituted methyl group did not affect the
reaction (see compound 2p). It should be noted that primary
amide is also a viable substrate as illustrated in the synthesis of
compound 2r. However, the reactions with tertiary amides such
as N,N-dimethylbenzamide or N-benzoylpiperidine failed to give
the amidoxime products (data not shown).
With the success in the formation of N-substituted amidox-
imes from amide substrates, we thus further investigated
a direct one-pot reaction toward amidoximes using acid chlo-
rides or carboxylic acids as the amide precursors. According to
Scheme 3, condensation of amines with acid chlorides led to an
in situ formation of amides which could then be activated with
Ph3P–I2 before treatment with hydroxylamine hydrochloride.
The reaction using benzoyl chloride gave rise to various ami-
doximes having N-aryl or N-alkyl substituent in moderate to
good yields.
Due to the remarkable difference in the reactivity of
carboxylic acid and amide, it was envisioned that a direct one-
pot synthesis of amidoximes from carboxylic acids via inter-
mediate amides would be possible through a sequential addi-
tion of an amine, then hydroxylamine hydrochloride to
a carboxylic acid in the presence of an excessive amount of
dehydrating agent.
To our delight, the procedure enables the synthesis of
various N-substituted amidoximes in moderate to good yields
(Scheme 3). No complication from the formation of amidine
side-product was observed. This one-pot three-component
coupling led to an improve in the efficiency of the reaction
avoiding laborious separation and purication of the amide
intermediate.
Scheme 4 Proposed mechanism for the Ph3P–I2 mediated synthesis
of N-substituted amidoxime.
triphenylphosphoranediiodide I and triphenylphosphonium
iodide II. Upon additon of an amide and base, phosphorylation
at the oxygen atom of the amide then leads to the formation of
imidinium intermediate III. This species could be converted
into another reactive intermediate, imidoyl iodide IV.
Displacement of III or IV with hydroxylamine hydrochloride
then gives rise to N-substituted amidoxime.
To obtain scientic evidences regarding the mechanism of
the process, 31P{1H} NMR spectroscopy was used to monitor the
progress of the reaction of N-phenylbenzamide. As shown in
Scheme 4 and Fig. S1 (ESI†), addition of Ph3P to the deuterated
chloroform solution of I2 resulted in an appearance of a reso-
nance peak at ꢁ19.8 ppm corresponded to phosphor-
anediiodide species I.23 No signicant change in the 31P{1H}
NMR spectrum was observed aer adding N-phenylbenzamide
except that a small signal appeared at 42.8 ppm. This signal
could be attributed to the presence of phosphonium salt II.
Upon adding Et3N, a signal of Ph3P]O rapidly appeared at
29.16 ppm as a major peak along with some other minor
phosphorus species. Unfortunately, the signal arises from
phosphonium salt intermediate III could not be observed. This
data suggests a rapid conversion of III to IV leading to a release
of Ph3P]O at this stage. Addition of hydroxylamine hydro-
chloride nally led to a complete disappearance of the species I,
while the signal of Ph3P]O appeared in a greater amount.
To our delight, when monitoring the reaction between
benzoyl chloride and aniline, a signal at 65.38 ppm which could
be attributed to the amide phosphonium salt III was detected
upon adding Ph3P and I2 to the preformed N-phenylbenzamide
(Fig. S1, ESI†). This data is consistent with the observed
chemical shi for the nucleoside phosphonium salt (d ¼ 66.2
ppm) in the synthesis of O6-(benzotriazol-1-yl)inosine nucleo-
sides promoted by the same reagent combination.24
Based on the obtained results and our previous experiences
in the Ph3P–I2-mediated synthesis, the mechanism for the
formation of N-substituted amidoximes was proposed as shown
in Scheme 4. The combination of Ph3P with I2 provides
To further demonstrate the synthetic application of the
developed methodology, the conversion of 2 into 1,2,4-oxadia-
zol-5(4H)-one 3 was investigated. These structures are known to
be valuable heterocycles as amidine precursors25 or as bio-
isosteric replacement for the carboxylic acid, amide or ester.26
Additionally, compounds bearing oxadiazolone pharmaco-
phore have been shown to possess a range of pharmacological
and biological activities.14b,27 The reported methods for the
preparation of 1,2,4-oxadiazolones from N-substituted
Scheme 3 Synthesis of N-substituted amidoximes through in situ
formation of amides.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 38281–38288 | 38283

View Article Online
RSC Advances
Paper
MHz for 1H). Chemical shis were reported in parts per million
(ppm, d) downeld from TMS. High resolution mass spectra
(HRMS) were recorded using the LC-DAD-ESI-MS/MS system
consisted of a Waters Alliance 2695 LC-DAD and a Q-TOF 2
(quadrupole mass lter-time-of-ight) mass spectrometer with
a Z-spray ES source.
General procedure for the synthesis of amidoximes from
amides or acid chloride
To a solution of iodine (0.1904 g, 0.75 mmol) and triphenyl-
phosphine (0.1967 g, 0.75 mmol) in dry dichloromethane (4 mL)
was added amide (0.50 mmol), triethylamine (0.35 mL, 2.50
mmol), and hydroxylamine hydrochloride (0.0521 g, 0.75 mmol)
at 0 ꢀC. The reaction mixture was then warm up to room
temperature and stirred until completion of the reaction (typi-
cally within 2 h). The crude mixture was concentrated under
reduced pressure then puried by column chromatography
using 30–70% ethyl acetate in hexane. For the synthesis of
amidoximes from acid chloride, a mixture of acid chloride (0.50
mmol), amine (0.50 mmol), and triethylamine (0.10 mL, 0.75
mmol) in dry dichloromethane (4 mL) was stirred at 0 ꢀC to
room temperature until complete disappearance of the acid
chloride. The in situ generated amide was then subjected to the
reaction with hydroxylamine hydrochloride as described above.
Scheme 5 Synthesis of 1,2,4-oxadiazol-5(4H)-ones 3.
amidoximes oen require multiple steps, harsh reaction
conditions, and long reaction times.5,14b,28
Through a screening for the best reaction conditions, it was
found that, by treatment of amidoximes 2 with 1,10-carbon-
yldiimidazole (CDI) in the presence of nely ground potassium
carbonate, carbonylative cyclization proceeded rapidly to afford
products 3 in good to excellent yields (Scheme 5). The reaction
took place within 10–20 min at room temperature rather than
several hours under the reported reuxing conditions.14b The
method is also applicable with a range of amidoxime substrates
containing N-aryl, N-alkyl, and N-benzyl groups.
General procedure for the synthesis of amidoximes from
carboxylic acids
To a solution of iodine (0.3807 g, 1.5 mmol) and triphenyl-
phosphine (0.3935 g, 1.5 mmol) in dry dichloromethane (5 mL)
was added in one portion with carboxylic acid derivative (0.50
mmol), and amine (0.50 mmol), followed by triethylamine (0.45
mL, 3.25 mmol) at 0 ꢀC. The resulting mixture was continuously
stirred at room temperature for 1 h. Hydroxylamine hydro-
chloride (0.0521 g, 0.75 mmol) was then added and the reaction
mixture was allowed to stir until completion of the reaction
(typically within 2 h). The crude mixture was concentrated
under reduced pressure then puried by column chromatog-
raphy using 30–70% ethyl acetate in hexane.
Conclusions
In summary, we have developed a convenient one-pot approach
for the preparation of N-substituted amidoximes from amides,
or the requisite acid chlorides, or carboxylic acids. The protocol
represents a fast, efficient, and economic alternative to the
earlier reported multistep methods. The mild nature of the
procedure enables a range of starting materials accessible. One
application of amidoximes as building blocks in the synthesis
of 1,2,4-oxadiazol-5(4H)-ones via base-mediated carbonylative
cyclization has been demonstrated. Further utility of these
amidoximes in organic synthesis of other important pharma-
cophores is anticipated.
(Z)-N0-Hydroxy-N-phenylbenzimidamide (2a).29 White solid
(0.0904 g, 85% yield), mp 137–138 ꢀC (lit. 29 mp 136 ꢀC); Rf 0.57
1
(30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) d 7.45 (d, J ¼
7.2 Hz, 2H), 7.37 (t, J ¼ 7.2 Hz, 1H), 7.33 (t, J ¼ 7.2 Hz, 2H), 7.10 (t,
J ¼ 7.6 Hz, 2H), 6.92 (t, J ¼ 7.6 Hz, 1H), 6.67 (d, J ¼ 7.6 Hz, 2H).
(Z)-N0-Hydroxy-N-(p-tolyl)benzimidamide (2b).30 White solid
(0.0864 g, 76% yield), mp 178–179 ꢀC (lit. 30 mp 176–177 ꢀC); Rf
0.30 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.44 (d,
J ¼ 7.6 Hz, 2H), 7.35 (t, J ¼ 7.6 Hz, 1H), 7.31 (t, J ¼ 7.6 Hz, 2H),
6.91 (d, J ¼ 8.0 Hz, 2H), 6.58 (d, J ¼ 8.0 Hz, 2H), 2.22 (s, 3H).
(Z)-N0-Hydroxy-N-(4-methoxyphenyl)benzimidamide (2c).31
Experimental
General information
All reagents were purchased from Sigma-Aldrich Co., USA, and
used without further purication. Dichloromethane was freshly White solid (0.0913 g, 75% yield), mp 139–141 ꢀC (lit. 31 mp
distilled over CaH2 before use. The reaction was monitored by 154.4–157.2 ꢀC); Rf 0.36 (20% EtOAc/hexanes); 1H NMR (400
thin-layer chromatography carried out on silica gel plates MHz, CDCl3) d 7.41 (d, J ¼ 7.6 Hz, 2H), 7.33 (t, J ¼ 7.6 Hz, 1H),
(60F254, MERCK, Germany) and visualized under UV light (254 7.28 (t, J ¼ 7.6 Hz, 2H), 6.66 (s, 4H), 3.71 (s, 3H).
nm). Melting points were determined using Mettler Toledo DSC
(Z)-N-(4-Bromophenyl)-N0-hydroxybenzimidamide (2d).31.
equipment at a heating rate of 6 ꢀC minꢁ1 and are uncorrected. White solid (0.1126 g, 77% yield), mp 193–195 ꢀC (lit. 31 mp
NMR spectra were determined using a Bruker AVANCE™ (400 192–193.5 ꢀC); Rf 0.33 (20% EtOAc/hexanes); 1H NMR (400 MHz,
38284 | RSC Adv., 2018, 8, 38281–38288
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
CDCl3) d 7.37–7.31 (m, 3H), 7.30–7.25 (m, 2H), 7.14 (d, J ¼ 2H); 13C NMR (100 MHz, CDCl3) d 169.6, 159.0, 156.5, 130.9,
8.8 Hz, 2H), 6.47 (d, J ¼ 8.8 Hz, 2H).
130.6, 126.6, 121.8, 114.5, 114.0, 55.5, 55.3, 43.6; HRMS (ESI-
(Z)-N0-Hydroxy-N-(4-nitrophenyl)benzimidamide (2e).32. Yellow TOF) m/z: calcd for C16H19N2O3 [M + H]+ 287.1396, found
solid (0.1032 g, 80% yield), mp 149–151 ꢀC (lit. 32 mp 152 ꢀC); Rf 287.1398.
0.32 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.99 (d,
(Z)-N0-Hydroxy-N,4-diphenylbutanimidamide (2o). Yellow oil
J ¼ 9.2 Hz, 2H), 7.51–7.45 (m, 3H), 7.41 (t, J ¼ 7.6 Hz, 2H), 6.65 (0.0819 g, 64% yield); Rf 0.36 (30% EtOAc/hexanes); 1H NMR
(d, J ¼ 9.2 Hz, 2H).
(400 MHz, CDCl3) d 7.33 (t, J ¼ 7.6 Hz, 2H), 7.26 (t, J ¼ 7.6 Hz,
2H), 7.21–7.17 (m, 2H), 7.11–7.16 (m, 4H), 2.61 (t, J ¼ 7.6 Hz,
(Z)-N0-Hydroxy-N-(4-methoxyphenyl)-4-nitrobenzimꢀidamide
(2f).32 White solid (0.0936 g, 65% yield), mp 160–162 C (lit. 32 2H), 2.45 (t, J ¼ 7.6 Hz, 2H), 1.80 (quin, J ¼ 7.6 Hz, 2H); 13C NMR
1
ꢀ
mp 163 C); Rf 0.60 (40% EtOAc/hexanes); H NMR (400 MHz, (100 MHz, CDCl3) d 153.0, 141.6, 138.9, 129.2, 128.5, 128.3,
CDCl3) d 8.07 (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8.8 Hz, 2H), 6.62 (s, 125.8, 124.7, 124.2, 35.2, 28.5, 27.7; HRMS (ESI-TOF) m/z: calcd
4H), 3.67 (s, 3H).
for C16H19N2O [M + H]+ 255.1497, found 255.1494.
(Z)-N0-Hydroxy-N-(pyridin-4-yl)benzimidamide (2g). White
(Z)-N0-Hydroxy-N-(o-tolyl)cinnamimidamide (2p). White solid
solid (0.0558 g, 52% yield), mp 225–226 ꢀC; Rf 0.35 (60% EtOAc/ (0.0909 g, 72% yield), mp 120–122 ꢀC; Rf 0.50 (30% EtOAc/
hexanes); 1H NMR (400 MHz, CDCl3 + 4 drops of CD3OD) d 8.04 hexanes); H NMR (400 MHz, CDCl3) d 7.40–7.30 (m, 5H), 7.22
1
(d, J ¼ 5.6 Hz, 2H), 7.39–7.30 (m, 5H), 6.40 (d, J ¼ 5.6 Hz, 2H); (d, J ¼ 16.0 Hz, 1H), 7.18–7.05 (m, 4H), 6.48 (d, J ¼ 16.0 Hz, 1H),
13C NMR (100 MHz, CDCl3 + 4 drops of CD3OD) d 159.1, 149.04, 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) d 150.9, 137.7, 136.1,
147.6, 130.70, 130.19, 128.77, 127.87, 113.23; HRMS (ESI-TOF) 134.7, 131.1, 130.8, 128.7, 128.7, 127.1, 126.6, 124.4, 124.0,
m/z: calcd for C12H11N3NaO [M + Na]+ 236.0800, found 236.0807. 117.9, 18.0; HRMS (ESI-TOF) m/z: calcd for C16H17N2O [M + H]+
(Z)-N-Butyl-N0-hydroxy-4-methylbenzimidamide (2h).33. Yellow 253.1341.1916, found 253.1338.
oil (0.0845 g, 82% yield); Rf 0.33 (30% EtOAc/hexanes); 1H NMR
(Z)-N0-Hydroxy-N-(4-methoxybenzyl)cinnamimidamide (2q).
(400 MHz, CDCl3) d 7.37 (d, J ¼ 8.0 Hz, 2H), 7.22 (d, J ¼ 8.0 Hz, Yellow oil (0.1073 g, 76% yield); Rf 0.34 (30% EtOAc/hexanes);
2H), 5.26 (br s, 1H), 3.03 (q, J ¼ 7.2 Hz, 2H), 2.40 (s, 3H), 1.44 1H NMR (400 MHz, CDCl3) d 7.43–7.40 (m, 2H), 7.36–7.24 (m,
(quin, J ¼ 7.2 Hz, 2H), 1.32 (sex, J ¼ 7.2 Hz, 2H), 0.87 (t, J ¼ 5H), 7.20 (d, J ¼ 16.4 Hz, 1H), 6.89 (d, J ¼ 8.8 Hz, 2H), 6.53 (d, J ¼
7.2 Hz, 3H).
16.4 Hz, 1H), 5.61 (br s, 1H), 4.39 (s, 2H), 3.82 (s, 3H); 13C NMR
(Z)-N-Butyl-2-chloro-N0-hydroxybenzimidamide (2i). Color- (100 MHz, CDCl3) d 158.9, 153.9, 136.0, 135.6, 131.4, 128.7,
1
less oil (0.0671 g, 59% yield); Rf 0.45 (30% EtOAc/hexanes); H 128.2, 127.1, 116.9, 114.1, 55.3, 46.4; HRMS (ESI-TOF) m/z: calcd
NMR (400 MHz, CDCl3) d 7.44–7.28 (m, 4H), 5.39 (brs, 1H), 2.87 for C17H19N2O2 [M + H]+ 283.1447, found 283.1454.
(t, J ¼ 7.2 Hz, 2H), 1.88 (d, J ¼ 10.0 Hz, 1H), 1.40 (quin, J ¼
(Z)-N0-Hydroxybenzimidamide (2r).35 Colorless oil (0.0458 g,
7.2 Hz, 2H), 1.26 (sex, J ¼ 7.2 Hz, 2H), 0.82 (t, J ¼ 7.2 Hz, 3H); 13
C
67% yield); Rf 0.70 (40% EtOAc/hexanes); H NMR (400 MHz,
1
NMR (100 MHz, CDCl3) 153.7, 133.9, 131.47, 130.9, 130.6, 129.6, CDCl3) d 7.62 (dd, J ¼ 7.6, 1.6 Hz, 2H), 7.41–7.34 (m, 3H), 4.98 (s,
126.7, 42.56, 33.0, 19.7, 13.7; HRMS (ESI-TOF) m/z: calcd for 2H) 13C NMR (100 MHz, CDCl3) d 152.9, 132.5, 130.0, 128.7,
C
11H15ClN2NaO [M + Na]+ 249.0771, found 249.0774.
(Z)-N-(4-Ethoxyphenyl)-N0-hydroxyacetimidamide (2j). White
126.0.
(Z)-4-(tert-Butyl)-N-cyclohexyl-N0-hydroxybenzimidamide (2s).
solid (0.0775 g, 80% yield), mp 132–134 ꢀC; Rf 0.41 (40% EtOAc/ White solid (0.0715 g, 52% yield), mp 139–140 C; Rf 0.36 (30%
hexanes); 1H NMR (400 MHz, CDCl3) d 7.04 (d, J ¼ 8.8 Hz, 2H), EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.41 (s, 4H), 5.21 (d,
6.86 (d, J ¼ 8.8 Hz, 2H), 4.03 (q, J ¼ 7.2 Hz, 2H), 1.87 (s, 3H), 1.43 J ¼ 10.0 Hz, 1H), 3.15–3.10 (m, 1H), 1.85–1.80 (m, 2H), 1.69–1.67
ꢀ
(t, J ¼ 7.2 Hz, 3H).
(m, 2H), 1.54–1.51 (m, 1H), 1.35 (s, 9H), 1.20–1.13 (m, 5H).
(Z)-N-(4-Chlorophenyl)-N0-hydroxyacetimidamide (2k).34.
White solid (0.0695 g, 75% yield), mp 133–135 ꢀC (lit. 34 mp
1
General procedure for the synthesis of 1,2,4-oxadiazol-5(4H)-
one
ꢀ
132–133 C); Rf 0.40 (30% EtOAc/hexanes); H NMR (400 MHz,
CDCl3) d 7.31 (d, J ¼ 8.4 Hz, 2H), 7.02 (d, J ¼ 8.4 Hz, 2H), 1.97 (s,
3H).
To a solution of N-substituted amidoxime 2 (0.30 mmol) dis-
(Z)-N-(4-Bromophenyl)-N0-hydroxyacetimidamide (2l).18. White solved in acetonitrile (2.0 mL) was added 1,10-carbon-
ꢀ
solid (0.0825 g, 72% yield), mp 86–87 C; Rf 0.51 (30% EtOAc/ yldiimidazole (0.0584 g, 0.36 mmol), followed by nely
hexanes); 1H NMR (400 MHz, CDCl3) d 7.45 (d, J ¼ 8.4 Hz, grounded K2CO3 (0.2073 g, 1.50 mmol). The resulting mixture
2H), 6.96 (d, J ¼ 8.8 Hz, 2H), 1.99 (s, 3H).
was stirred at room temperature for 10–20 min. The crude
(Z)-N0-Hydroxy-N-phenylpropionimidamide (2m).19 Yellow mixture was concentrated under reduced pressure and then
oil (0.0553 g, 67% yield), Rf 0.35 (30% EtOAc/hexanes); 1H NMR puried by short column chromatography using 10–40% ethyl
(400 MHz, CDCl3) d 7.35 (t, J ¼ 8.0 Hz, 2H), 7.17 (t, J ¼ 8.0 Hz, acetate in hexane to give the corresponding product.
1H), 7.11 (d, J ¼ 8.0 Hz, 2H), 2.41 (q, J ¼ 7.6 Hz, 2H), 1.05 (t, J ¼
3,4-Diphenyl-1,2,4-oxadiazol-5(4H)-one (3a).36 White solid
7.6 Hz, 3H).
(0.0707 g, 99% yield), mp 167–168 ꢀC (lit. 36 mp 168–169 ꢀC); Rf
1
(Z)-N0-Hydroxy-N,2-bis(4-methoxyphenyl)acetimidamide (2n). 0.57 (30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) d 7.53–
White solid (0.1158 g, 81% yield), mp 133–134 ꢀC; Rf 0.67 (40% 7.45 (m, 4H), 7.40–7.36 (m, 4H), 7.27–7.22 (m, 2H).
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.38 (s, 1H), 7.34
3-Phenyl-4-(p-tolyl)-1,2,4-oxadiazol-5(4H)-one (3b).37 White
(d, J ¼ 8.4 Hz, 2H), 7.25 (d, J ¼ 8.4 Hz, 2H), 6.92 (d, J ¼ 8.8 Hz, solid (0.0742 g, 98% yield), mp 163–164 ꢀC (lit. 37 mp 163 ꢀC); Rf
1
2H), 6.82 (d, J ¼ 8.8 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.64 (s, 0.51 (30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) d 7.53–
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 38281–38288 | 38285

View Article Online
RSC Advances
Paper
7.47 (m, 1H), 7.39 (s, 2H), 7.38 (s, 2H), 7.26 (d, J ¼ 8.0 Hz, 2H), TOF) m/z: calcd for C11H13N2O3 [M + H]+ 221.0926, found
7.13 (d, J ¼ 8.0 Hz, 2H), 2.41 (s, 3H).
221.0929.
4-(4-Methoxyphenyl)-3-phenyl-1,2,4-oxadiazol-5(4H)-one
4-(4-Chlorophenyl)-3-methyl-1,2,4-oxadiazol-5(4H)-one (3k).
(3c).31. White solid (0.0781 g, 97% yield), mp 161–162 ꢀC (lit. 31 White solid (0.0501 g, 79% yield), mp 137–138 ꢀC; Rf 0.49 (30%
mp 158.1–160.2 ꢀC); Rf 0.52 (30% EtOAc/hexanes); 1H NMR (400 EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.52 (d, J ¼ 8.8 Hz,
MHz, CDCl3) d 7.55–7.46 (m, 1H), 7.40 (s, 2H), 7.39 (s, 2H), 7.17 2H), 7.30 (d, J ¼ 8.8 Hz, 2H), 2.19 (s, 3H); 13C NMR (100 MHz,
(d, J ¼ 8.8 Hz, 2H), 6.96 (d, J ¼ 8.8 Hz, 2H), 3.85 (s, 3H).
CDCl3) d 157.7, 156.0, 136.0, 130.4, 129.6, 128.0, 11.1; HRMS
4-(4-Nitrophenyl)-3-phenyl-1,2,4-oxadiazol-5(4H)-one (3d).32 (ESI-TOF) m/z: calcd for C9H735Cl N2NaO2 [M + Na]+ 233.0094,
Yellow oil (0.0849 g, 100% yield), Rf 0.44 (30% EtOAc/hexanes); found 233.0088, for C9H737ClN2NaO2 [M + Na]+ 235.0064, found
1H NMR (400 MHz, CDCl3) d 8.31 (d, J ¼ 9.2 Hz, 2H), 7.60 (t, J ¼ 235.0061.
7.6 Hz, 1H), 7.45 (t, J ¼ 7.6 Hz, 2H), 7.44 (d, J ¼ 9.2 Hz, 2H), 7.38
(d, J ¼ 7.6 Hz, 2H).
4-(4-Bromophenyl)-3-methyl-1,2,4-oxadiazol-5(4H)-one (3l).
White solid (0.0591 g, 77% yield), mp 160–162 ꢀC; Rf 0.35 (30%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.68 (d, J ¼ 8.4 Hz,
4-(4-Methoxyphenyl)-3-(4-nitrophenyl)-1,2,4-oxadiazol-5(4H)-
one (3e).32. White solid (0.0743 g, 79% yield), mp 173–174 ꢀC; Rf 2H), 7.23 (d, J ¼ 8.4 Hz, 2H), 2.20 (s, 3H); 13C NMR (100 MHz,
0.53 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 8.25 (d, CDCl3) d 157.7, 155.8, 133.4, 130.1, 128.2, 124.1, 11.1; HRMS
J ¼ 8.8 Hz, 2H), 7.62 (d, J ¼ 8.8 Hz, 2H), 7.18 (d, J ¼ 8.8 Hz, 2H), (ESI-TOF) m/z: calcd for C9H779Br N2NaO2 [M + Na]+ 276.9589,
6.99 (d, J ¼ 8.8 Hz, 2H), 3.87 (s, 3H).
found 276.9586, for C9H781BrN2NaO2 [M + Na]+ 278.9569, found
3-Phenyl-4-(pyridin-4-yl)-1,2,4-oxadiazol-5(4H)-one (3f). White 278.9564.
solid (0.0503 g, 70% yield), mp 167–168 ꢀC; Rf 0.30 (40% EtOAc/
4-Phenyl-3-(3-phenylpropyl)-1,2,4-oxadiazol-5(4H)-one (3m).
hexanes); 1H NMR (400 MHz, CDCl3) d 8.71 (dd, J ¼ 4.4, 1.6 Hz, Yellow oil (0.0683 g, 81% yield); Rf 0.37 (30% EtOAc/hexanes);
2H), 7.58 (t, J ¼ 8.0 Hz, 1H), 7.46 (t, J ¼ 8.0 Hz, 2H), 7.38 (d, J ¼ 1H NMR (400 MHz, CDCl3) d 7.55–7.51 (m, 3H), 7.29–7.21 (m,
8.0 Hz, 2H), 7.19 (dd, J ¼ 4.4, 1.6 Hz, 2H); 13C NMR (100 MHz, 5H), 7.22 (d, J ¼ 7.2 Hz, 1H), 7.07 (d, J ¼ 7.2 Hz, 2H), 2.66 (t, J ¼
CDCl3) d 156.8, 151.4, 139.6, 132.5, 129.3, 128.3, 122.4, 120.1; 7.6 Hz, 2H), 2.51 (t, J ¼ 7.6 Hz, 2H), 1.91 (quin, J ¼ 7.6 Hz, 2H);
HRMS (ESI-TOF) m/z: calcd for C13H9N2NaO2 [M + Na]+ 13C NMR (100 MHz, CDCl3) d 158.8, 154.1, 140.2, 131.1, 130.1,
262.0592, found 262.0589.
130.0, 128.5, 128.4, 126.8, 126.3, 34.6, 26.0, 24.4; HRMS (ESI-
3-(4-(tert-Butyl)phenyl)-4-cyclohexyl-1,2,4-oxadiazol-5(4H)-
TOF) m/z: calcd for C17H17N2O2 [M + H]+ 281.1290, found
ꢀ
one (3g). White solid (0.0803 g, 89% yield), mp 172–173 C; Rf 281.1287.
0.36 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.59 (d,
(E)-3-Styryl-4-(o-tolyl)-1,2,4-oxadiazol-5(4H)-one (3n). Color-
1
J ¼ 8.4 Hz, 2H), 7.45 (d, J ¼ 8.4 Hz, 2H), 3.75–3.60 (m, 1H), 2.41– less oil (0.0720 g, 86% yield), Rf 0.60 (30% EtOAc/hexanes); H
2.17 (m, 2H), 1.89–1.85 (m, 2H), 1.82–1.76 (m, 2H), 1.66–1.63 NMR (400 MHz, CDCl3) d 7.51 (t, J ¼ 7.2 Hz, 1H), 7.45–7.33 (m,
(m, 2H), 1.39 (s, 9H), 1.29–1.20 (s, 2H); 13C NMR (100 MHz, 7H), 7.29 (d, J ¼ 7.2 Hz, 1H), 6.28 (d, J ¼ 16.4 Hz, 1H), 2.29 (s,
CDCl3) d 159.2, 158.7, 155.5, 128.4, 126.3, 120.5, 55.4, 35.1, 31.1, 3H); 13C NMR (100 MHz, CDCl3) d 157.9, 156.1, 139.9, 136.7,
29.2, 25.5, 24.5; HRMS (ESI-TOF) m/z: calcd for C18H25N2O2 [M + 134.1, 131.9, 130.8, 130.5, 130.1, 129.0, 128.5, 127.8, 127.6,
H]+ 301.1916, found 301.1923.
4-Butyl-3-(p-tolyl)-1,2,4-oxadiazol-5(4H)-one (3h). Yellow oil 279.1134, found 279.1129.
(0.0621 g, 89% yield), Rf 0.49 (20% EtOAc/hexanes); 1H NMR
(E)-4-(4-Methoxybenzyl)-3-styryl-1,2,4-oxadiazol-5(4H)-one
108.1, 17.6; HRMS (ESI-TOF) m/z: calcd for C17H15N2O2 [M + H]+
ꢀ
(400 MHz, CDCl3) d 7.47 (d, J ¼ 8.0 Hz, 2H), 7.37 (d, J ¼ 8.0 Hz, (3o). White solid (0.0771 g, 83% yield), mp 113–114 C; Rf 0.47
2H), 3.68 (t, J ¼ 7.6 Hz, 2H), 2.47 (s, 3H), 1.60 (quin, J ¼ 4.4 Hz, (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.55 (d, J ¼
2H), 1.27 (sex, J ¼ 7.6 Hz, 2H), 0.87 (t, J ¼ 7.6 Hz, 3H); 13C NMR 16.0 Hz, 1H), 7.47–7.40 (m, 5H), 7.27 (d, J ¼ 8.8 Hz, 2H), 6.93 (d,
(100 MHz, CDCl3) d 158.9, 152.9, 142.6, 130.1, 128.1, 120.6, 42.8, J ¼ 8.8 Hz, 2H), 6.45 (d, J ¼ 16.0 Hz, 1H), 4.84 (s, 2H), 3.82 (s,
30.4, 21.6, 19.5, 13.4; HRMS (ESI-TOF) m/z: calcd for C13H17N2O2 3H); 13C NMR (100 MHz, CDCl3) d 159.9, 156.5, 140.5, 134.2,
[M + H]+ 233.1290, found 233.1286.
130.5, 129.2, 129.1, 128.8, 127.6, 126.3, 114.7, 107.5, 55.4, 45.5;
4-Butyl-3-(2-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (3i). HRMS (ESI-TOF) m/z: calcd for C18H16N2NaO3 [M + Na]+
Colorless oil (0.0654 g, 86% yield), Rf 0.43 (20% EtOAc/hexanes); 331.1059, found 331.1053.
1H NMR (400 MHz, CDCl3) d 7.63–7.57 (m, 2H), 7.51–7.46 (m,
2H), 3.52 (t, J ¼ 7.6 Hz, 2H), 1.50 (quin, J ¼ 7.6 Hz, 2H), 1.20 (sex,
Conflicts of interest
J ¼ 7.6 Hz, 2H), 0.79 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 159.1, 157.3, 134.0, 133.4, 131.7, 130.4, 127.6, 123.1, There are no conicts to declare.
42.8, 30.0, 19.4, 13.3; HRMS (ESI-TOF) m/z: calcd for C12H1335Cl
37-
N2NaO2 [M + Na]+ 275.0563, found 275.0560, for C12H13
Acknowledgements
ClN2NaO2 [M + Na]+ 277.0533, found 277.0536.
4-(4-Ethoxyphenyl)-3-methyl-1,2,4-oxadiazol-5(4H)-one (3j). Financial support from The Thailand Research Fund through
White solid (0.0544 g, 82% yield), mp 83.7–84.2 ꢀC; Rf 0.50 (30% the Royal Golden Jubilee PhD Program to C. D. (Grant No. PHD/
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) d 7.21 (d, J ¼ 8.4 Hz, 0086/2557) and N. W. (Grant No. PHD/0072/2559) are gratefully
2H), 7.01 (d, J ¼ 8.4 Hz, 2H), 4.08 (q, J ¼ 7.2 Hz, 2H), 2.15 (s, 3H), acknowledged. This research work was also partially supported
1.45 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 160.0, by Chiang Mai University. Special appreciation to Chulabhorn
158.4, 156.6, 128.1, 123.3, 115.7, 64.0, 14.7, 11.0; HRMS (ESI- Research Institute (CRI), Thailand for the ESI-MS analysis.
38286 | RSC Adv., 2018, 8, 38281–38288
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
12 F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev,
L. Noodleman, K. B. Sharpless and V. V. Fokin, J. Am.
Chem. Soc., 2005, 127, 210.
Notes and references
1 (a) Y. Yamamoto, T. Tsuritani and T. Mase, Tetrahedron Lett.,
2008, 49, 876; (b) A.-A. Gaber and L. Taib, J. Chem. Sci., 2016,
128, 745; (c) F. Risitano, G. Grassi, F. Foti and F. Caruso, J.
Chem. Res., Synop., 1983, 52.
2 S. S. Patil, P. C. Mhaske, S. V. Patil and V. D. Bobade, J.
Heterocycl. Chem., 2011, 48, 652.
13 D. F. Bushey and F. C. Hoover, J. Org. Chem., 1980, 45, 4198.
14 (a) H. C. Shen, F.-X. Ding, Q. Deng, S. Xu, X. Tong, X. Zhang,
Y. Chen, G. Zhou, L.-Y. Pai, M. Alonso-Galicia, S. Roy,
B. Zhang, J. R. Tata, J. P. Berger and S. L. Colletti, Bioorg.
Med. Chem. Lett., 2009, 19, 5716; (b) J. L. Romine,
S. W. Martin, V. K. Gribkoff, C. G. Boissard,
S. I. Dworetzky, J. Natale, Y. Li, Q. Gao, N. A. Meanwell and
J. E. Starrett Jr, J. Med. Chem., 2002, 45, 2942.
15 (a) B. Ganem, Y. Dong, Y. F. Zheng and G. D. Prestwich, J.
Org. Chem., 1999, 64, 5441; (b) A. Okano, R. C. James,
J. G. Pierce, J. Xie and D. L. Boger, J. Am. Chem. Soc., 2012,
134, 8790.
3 K. Muralirajan, R. Kuppusamy, S. Prakash and C. H. Cheng,
Adv. Synth. Catal., 2016, 358, 774.
4 (a) F.-L. Zhang, Y.-F. Wang and S. Chiba, Org. Biomol. Chem.,
2013, 11, 6003; (b) P. D. Parker and J. G. Pierce, Synthesis,
2016, 48, 1902; (c) S. V. Bhat, D. Robinson, J. E. Moses and
P. Sharma, Org. Lett., 2016, 18, 1100; (d) J. J. Lade,
B. N. Patil, K. S. Vadagaonkar and A. C. Chaskar,
Tetrahedron Lett., 2017, 58, 2103.
5 (a) Y. Durust, C. Altug and F. Kilic, Phosphorus, Sulfur Silicon
Relat. Elem., 2007, 182, 299; (b) T. Gerfaud, H.-L. Wei,
L. Neuville and J. Zhu, Org. Lett., 2011, 13, 6172; (c)
Y. S. Kara, Spectrochim. Acta, Part A, 2015, 149, 920.
6 (a) K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas,
E. A. Varella and D. N. Nicolaides, Curr. Pharm. Des., 2008,
14, 1001; (b) U. S. Mahajan, R. R. Godinde and
P. N. Mandhare, Synth. Commun., 2011, 41, 2195; (c)
J. Oszczapowicz, Basicity, H-bonding, tautomerism and
complex formation of imidic acid derivatives, Wiley, 1991,
vol. 2, p. 623.
7 E. W. Yue, R. Sparks, P. Polam, D. Modi, B. Douty,
B. Wayland, B. Glass, A. Takvorian, J. Glenn, W. Zhu,
M. Bower, X. Liu, L. Leffet, Q. Wang, K. J. Bowman,
M. J. Hansbury, M. Wei, Y. Li, R. Wynn, T. C. Burn,
H. K. Koblish, J. S. Fridman, T. Emm, P. A. Scherle,
B. Metcalf and A. P. Combs, ACS Med. Chem. Lett., 2017, 8,
486.
8 E. W. Yue, B. Douty, B. Wayland, M. Bower, X. Liu, L. Leffet,
Q. Wang, K. J. Bowman, M. J. Hansbury, C. Liu, M. Wei, Y. Li,
R. Wynn, T. C. Burn, H. K. Koblish, J. S. Fridman, B. Metcalf,
P. A. Scherle and A. P. Combs, J. Med. Chem., 2009, 52, 7364.
9 (a) I. Artsimovitch, C. Chu, A. S. Lynch and R. Landick,
Science, 2003, 302, 650; (b) W. Zhu, J. Haupenthal,
M. Groh, M. Fountain and R. W. Hartmann, Antimicrob.
Agents Chemother., 2014, 58, 4242.
16 A. R. Katritzky, N. M. Khashab, N. Kirichenko and A. Singh, J.
Org. Chem., 2006, 71, 9051.
17 (a) G. D'Alo and P. Grunanger, Farmaco, Ed. Sci., 1966, 21,
346; (b) K. Fang, G. Dong, Y. Li, S. He, Y. Wu, S. Wu,
W. Wang and C. Sheng, ACS Med. Chem. Lett., 2018, 9, 312.
18 A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, A. S. Bijieva,
I. V. Aksenova and M. Rubin, Org. Biomol. Chem., 2015, 13,
4289.
19 G. Sanguineti, H. V. Le and B. Ganem, Tetrahedron, 2011, 67,
10208.
20 (a) F. C. Kuepper, M. C. Feiters, B. Olofsson, T. Kaiho,
S. Yanagida, M. B. Zimmermann, L. J. Carpenter,
G. W. Luther, Z. Lu, M. Jonsson and L. Kloo, Angew. Chem.,
Int. Ed., 2011, 50, 11598; (b) S. U. Tekale, S. S. Kauthale,
S. A. Dake, S. R. Sarda and R. P. Pawar, Curr. Org. Chem.,
2012, 16, 1485; (c) H. Togo and S. Iida, Synlett, 2006, 2159.
21 J.-R. Dormoy and B. Castro, Triphenylphosphine-Iodine,
Encyclopedia of Reagents for Organic Synthesis, John Wiley &
Sons, Ltd, 2009, DOI: 10.1002/047084289X.rt376.pub2.
22 (a) W. Phakhodee, S. Wangngae and M. Pattarawarapan, J.
Org. Chem., 2017, 82, 8058; (b) W. Phakhodee,
S. Wangngae, N. Wiriya and M. Pattarawarapan,
Tetrahedron Lett., 2016, 57, 5351; (c) S. Wangngae,
M. Pattarawarapan and W. Phakhodee, Synlett, 2016, 27,
1121; (d) S. Wangngae, M. Pattarawarapan and
W. Phakhodee, J. Org. Chem., 2017, 82, 10331; (e) S. Wet-
osot, W. Phakhodee and M. Pattarawarapan, J. Org. Chem.,
2017, 82, 9923.
10 D. Schade, J. Kotthaus, L. Riebling, J. Kotthaus, H. Mueller-
Fielitz, W. Raasch, O. Koch, N. Seidel, M. Schmidtke and
B. Clement, J. Med. Chem., 2014, 57, 759.
23 S. Wangngae, C. Duangkamol, M. Pattarawarapan and
W. Phakhodee, RSC Adv., 2015, 5, 25789.
24 S. Bae and M. K. Lakshman, J. Org. Chem., 2008, 73, 1311.
25 R. E. Bolton, S. J. Coote, H. Finch, A. Lowdon, N. Pegg and
M. V. Vinader, Tetrahedron Lett., 1995, 36, 4471.
11 (a) F. Fang, J. Zhang, L. Cao, S. Shen, Y. Guo, Z. He and
H. Hu, Tetrahedron, 2016, 72, 2476; (b) J. Hu, Z. Li,
X. Zhang, Y. Han, Y. Liu, Y. Zhao, Y. Liu and P. Gong, Org.
Lett., 2018, 20, 2116; (c) C.-C. Lin, T.-H. Hsieh, P.-Y. Liao,
Z.-Y. Liao, C.-W. Chang, Y.-C. Shih, W.-H. Yeh and
T.-C. Chien, Org. Lett., 2014, 16, 892; (d) D. Gennet,
S. Z. Zard and H. Zhang, Chem. Commun., 2003, 1870; (e)
K. W. J. Baker, K. S. Horner, S. A. Moggach, R. M. Paton
and I. A. S. Smellie, Tetrahedron Lett., 2004, 45, 8913; (f)
S. Zaman, K. Mitsuru and A. D. Abell, Org. Lett., 2005, 7, 609.
26 (a) J. E. Mangette, M. R. Johnson, V.-D. Le, R. A. Shenoy,
H. Roark, M. Stier, T. Belliotti, T. Capiris and P. R. Guzzo,
Tetrahedron, 2009, 65, 9536; (b) D. J. Wustrow,
T. R. Belliotti, T. Capiris, C. O. Kneen, J. S. Bryans,
M. J. Field, D. Williams, A. El-Kattan, L. Buchholz,
J. J. Kinsora, S. M. Lotarski, M. G. Vartanian, C. P. Taylor,
S. D. Donevan, A. J. Thorpe and J. B. Schwarz, Bioorg. Med.
Chem. Lett., 2009, 19, 247; (c) G. D. Diana, D. L. Volkots,
T. J. Nitz, T. R. Bailey, M. A. Long, N. Vescio, S. Aldous,
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 38281–38288 | 38287

View Article Online
RSC Advances
Paper
D. C. Pevear and F. J. Dutko, J. Med. Chem., 1994, 37, 2421; (d) 30 A. E.-A. M. Gaber and H. McNab, J. Anal. Appl. Pyrolysis, 2009,
M. von Wantoch Rekowski, A. Pyriochou, 86, 369.
N. Papapetropoulos, A. Stoessel, A. Papapetropoulos and 31 Y. S. Kara, Spectrochim. Acta, Part A, 2015, 149, 920.
A. Giannis, Bioorg. Med. Chem., 2010, 18, 1288.
27 (a) R. Budriesi, B. Cosimelli, P. Ioan, C. Z. Lanza, D. Spinelli
32 T. Bacchetti and A. Alemagna, Atti Accad. Naz. Lincei, Cl. Sci.
Fis., Mat. Nat., Rend., 1960, 28, 824.
and A. Chiarini, J. Med. Chem., 2002, 45, 3475; (b) E. Carosati, 33 C.-C. Lin, T.-H. Hsieh, P.-Y. Liao, Z.-Y. Liao, C.-W. Chang,
B. Cosimelli, P. Ioan, E. Severi, K. Katneni, F. C. K. Chiu,
S. Saponara, F. Fusi, M. Frosini, R. Matucci, M. Micucci,
Y.-C. Shih, W.-H. Yeh and T.-C. Chien, Org. Lett., 2014, 16,
892.
`
A. Chiarini, D. Spinelli and R. Budriesi, J. Med. Chem., 34 A. Renodon-Corniere, S. Dijols, C. Perollier, D. Lefevre-
2016, 59, 3340; (c) D. N. Nicolaides, K. C. Fylaktakidou,
K. E. Litinas and D. Hadjipavlou-Litina, Eur. J. Med. Chem.,
1998, 33, 715.
Groboillot, J.-L. Boucher, R. Attias, M.-A. Sari, D. Stuehr
and D. Mansuy, J. Med. Chem., 2002, 45, 944.
35 J. K. Augustine, V. Akabote, S. G. Hegde and P. Alagarsamy, J.
Org. Chem., 2009, 74, 5640.
28 (a) T. L. Gilchrist, C. J. Moody and C. W. Rees, J. Chem. Soc.,
Perkin Trans. 1, 1979, 1871; (b) R. Un and D. Sumengen, 36 M. W. Partridge and H. A. Turner, J. Chem. Soc., 1958, 2086.
˘
Chim. Acta Turc., 1976, 4, 131; (c) H. Bartsch, T. Erker and 37 H. Agirba¸s and Y. Kara, Phosphorus, Sulfur Silicon Relat.
G. Neubauer, Monatsh. Chem., 1987, 120, 81.
Elem., 2004, 179, 1435.
29 F. Minisci, R. Galli and A. Quilico, Tetrahedron Lett., 1963, 4,
785.
38288 | RSC Adv., 2018, 8, 38281–38288
This journal is © The Royal Society of Chemistry 2018