Multicomponent Reaction of Z-Chlorooximes, Isocyanides, and Hydroxylamines as Hypernucleophilic Traps. A One-Pot Route to Aminodioximes and Their Transformation into 5-Amino-1,2,4-oxadiazoles by Mitsunobu-Beckmann Rearrangement

Article abstract of DOI:10.1021/acs.joc.5b01676

Synthetically useful aminodioximes are prepared via a novel three-component reaction among Z-chlorooximes, isocyanides, and hydroxylamines by exploiting the preferential attack of isocyanides to nitrile N-oxides via a [3 + 1] cycloaddition reaction. The r

Full text of DOI:10.1021/acs.joc.5b01676

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Article
Multicomponent Reaction of Z-chlorooximes, Isocyanides
and Hydroxylamines as Hyper-nucleophilic Traps. A One-
pot Route to Aminodioximes and Their Transformation into 5-
amino-1,2,4-oxadiazoles by Mitsunobu-Beckmann Rearrangement
Valerntina Mercalli, Alberto Massarotti, Monica Varese, Mariateresa
Giustiniano, Fiorella Meneghetti, Ettore Novellino, and Gian Cesare Tron
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01676 • Publication Date (Web): 11 Sep 2015
Downloaded from http://pubs.acs.org on September 13, 2015
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Multicomponent Reaction of Z-chlorooximes, Isocyanides and Hydroxylamines
as Hyper-nucleophilic Traps. A One-pot Route to Aminodioximes and Their
Transformation into 5-amino-1,2,4-oxadiazoles by Mitsunobu-Beckmann
Rearrangement.
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Valentina Mercalli,a Alberto Massarotti,a Monica Varese,a Mariateresa Giustiniano,*b Fiorella
Meneghetti,c Ettore Novellinob and Gian Cesare Tron*a
a) Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale “A.
Avogadro”, Largo Donegani 2, 28100 Novara, Italy.
b) Dipartimento di Farmacia, Università di Napoli “Federico II”, via D. Montesano 49, 80131
Napoli, Italy.
c) Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L.
Mangiagalli 25, 20133, Milano, Italy.
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TABLE OF CONTENTS
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ABSTRACT
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Synthetically useful aminodioximes are prepared via a novel threeꢀcomponent reaction among Zꢀ
chlorooximes, isocyanides and hydroxylamines by exploiting the preferential attack of isocyanides
to nitrileꢀNꢀoxides via a [3+1] cycloaddition reaction. The results of quantum mechanical studies of
the reaction mechanism are also discussed. Furthermore the oneꢀpot conversion of aminodioximes
to 1,2,3ꢀoxadiazoleꢀ5ꢀamines via MitsunobuꢀBeckmann rearrangement is reported for the first time.
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INTRODUCTION
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Our recent discovery that, at room temperature, nitrileꢀNꢀoxides are excellent electrophilic partners
for isocyanides,1 able to trigger a multicomponent reaction, it opened up a new chapter in the
already rich history of the chemistry of isocyanides.2 The exploitation of this novel reactivity, led to
the discovery of three new multicomponent reaction1,3 and a novel way to synthesize
pharmaceutical relevant ketoamide amides.4 Independently from the strength of the nucleophile
used as third component: carboxylate, phenate and primary and secondary amines (in order of
increasing nucleophilicity), we observed that the reaction between isocyanides and nitrile Nꢀoxides
always overruled the possible attack of the nucleophile to the nitrile Nꢀoxide.5 The unexpected
nitrile Nꢀoxide behavior prompted us to reꢀexamine the reaction mechanism. Indeed, it should be
logic to consider that nitrile Nꢀoxides6 are better electrophilic partners for phenates and amines than
isocyanides which are usually considered as poor nucleophiles.7 It follows that the reaction between
nitrile Nꢀoxides and isocyanides cannot be interpreted as a simple nucleophilic addition. However,
if we consider the isocyanides involved in these transformations in their carbenic nature and not in
their ionic resonance form, a concerted [3+1] cycloaddition reaction between isocyanide and nitrile
Nꢀoxide could take place to give an oxazetidine ring.8 A recent paper corroborates this hypothesis,
demonstrating that isocyanides exist predominantly in the carbenic form.9 Although [3+1]
cycloaddition reactions between isocyanides and azomethine imines, nitrile ylides, and azomethine
ylides10 have already been reported, there are no examples for a [3+1] cycloaddition reaction
between nitrile Nꢀoxides and isocyanides.11 Nitrile Nꢀoxides (1), as well as all the 1,3ꢀdipolar
species, are ambiphilic dipoles characterized by a low energy difference between their HOMO or
LUMO frontier orbitals12 and they can hence react both with electronꢀrich or electronꢀpoor
dipolarophiles, as in this case the isocyanide (2) in its carbenic nature.
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A fourꢀmembered ring should be obtained from this [3+1] cycloaddition (3), which readily opens,
in order to relieve the ring strain, affording the nitrilium intermediate (4) which could now be
attacked by a third nucleophile (5) finally forming the novel product (6) (Scheme 1).
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Scheme 1. Proposed mechanism for the chemoselective addition of isocyanides to nitrile Nꢀoxides
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in the presence of a third stronger nucleophile.
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Stimulated by this hypothesis, we envisaged a novel multicomponent reaction using a hyperꢀ
nucleophile like hydroxylamine as third component even though literature reports on the
isocyanideꢀmediated multiꢀcomponent processes involving hydroxylamine were somehow
discouraging. The reactive nature of hydroxylamine, due to its three nucleophile sites, renders poor
yields and several side products in the Ugi reaction.13 Moreover, hydroxylamines have been shown
to react very fast with the nitrile Nꢀoxides and low temperatures are necessary to give satisfactory
yields.14
RESULTS AND DISCUSSION
In order to verify this hypothesis, ab initio calculations were performed to compare the energies
involved in either the [3+1] cycloaddition or the ionic addition between the isocyanide and the
nitrile Nꢀoxide, and in the reaction between the nucleophile (hydroxylamine) and the nitrile Nꢀ
oxide. The model reaction between phenyl nitrile oxide A, pentyl isocyanide B, and hydroxylamine
C, which generates product P was chosen for this theoretical investigation. The detailed reaction
mechanisms were interpreted using density functional theory (DFT), widely employed to study
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organic reaction mechanisms.15 Two possible reaction pathways were investigated in detail
(Scheme 2).
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Scheme 2. The possible reaction pathways.
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In reaction path 1 the isocyanide carbon atom behaves as a nucleophile attacking the nitrile Nꢀoxide
species to generate intermediate M1. In the second step, the nitrilium ion is attacked by the nitrogen
atom of hydroxylamine. Subsequently, a protrotropic exchange gives the final compound P. We set
the energies of the three reactants (A + B + C) as 0.00 kcal/mol as reference in the energy profile.
The calculated energy barrier for traversing TS1 was 16.88 kcal/mol (depicted in Figure 1A). In
reaction path 2, the isocyanide behaves as carbene giving a [3+1] cycloaddition with the nitrile Nꢀ
oxide species in the first step. Subsequently, the resulting oxatedine ring opens due to ring strain
via the transition state TS4 to generate intermediate M1. The calculated energy barrier for path 2
for traversing TS3 was 11.11 kcal/mol, while the rate limiting step is traversing TS4 that need
23.66 kcal/mol (depicted in Figure 1A).
Figure 1. The energy profile of reactions at the M06ꢀ2X/6ꢀ31G(d, p) level in dichloromethane
(unit: kcal/mol). The energy reference is the sum of the reactant energies computed separately. A)
Pathway 1 and 2 are depicted in red and blue respectively. B) Pathway 3.
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In addition to paths 1 and 2, we also evaluated the direct attack of hydroxylamine C to the phenyl
nitrile oxide A (Pathway 3, Scheme 3). The energy barrier for traversing TS5 was 26.67 kcal/mol
(Figure 1B), which indicates that reactant C cannot compete with the isocyanide B in the reaction
with nitrile Nꢀoxides.
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Scheme 3. The competitive reaction channel investigated (pathway 3).
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Summarizing, the energy barriers of entire pathways 1, 2, and 3 are 16.88, 11.11, and 26.67
kcal/mol, respectively, indicating that path 2 is the most energetically favorable. Moreover, the
energy barrier of path 2 is not too high to be accessible under room temperature reaction conditions.
In order to demonstrate the untamed nature of the reaction between hydroxylamine and nitrile Nꢀ
oxides at room temperature, we carried out a two component reaction between Zꢀphenychlorooxime
and hydroxylamine in dichloromethane in the presence of TEA. The result was a plethora of spots
on TLC and we were able to isolate only trace amounts of the desired compound. After this
preliminary results, we then set up a three component reaction among Zꢀphenylchlorooxime (7),
pentylisocyanide (8) and hydroxylamine as free base16 (9) in dichloromethane using 1 eq of TEA at
1
room temperature. We observed a clean reaction and the smooth formation of two products. H
NMR analysis revealed the formation of the desired aminodioxime 10 in 45 % yield, and the amide
11 in 15 %. (Scheme 4). The success of this novel multicomponent reactions lies in the faster [3+1]
cycloaddition reaction between isocyanides and nitrile Nꢀoxides.
Scheme 4. The novel three component reaction.
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We rationalized the formation of the amide 11 due to the reaction between the nitrilium ion and the
hydroxyl group of hydroxylamine to give an unstable imidate (12) prone to undergo hydrolysis to
the amide (Scheme 5).
Scheme 5. Proposed mechanism for the formation of amide 11.
In order to verify this hypothesis the reaction was run using either Oꢀbenzylhydroxylamine (13) or
Oꢀmethylhydroxylamine (15). The corresponding aminodioxime (14) and (16) were obtained in 82
and 84 % yield respectively without observable formation of the amide byꢀproduct (Scheme 6).
Scheme 6. Multicomponent reaction using Oꢀbenzylhydroxylamine (13) or Oꢀ
methylhydroxylamine (15).
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Motivated by these preliminary results, and with the goal to suppress/reduce the formation of the
undesired amide, and hence decrease the formation of the alcholate of hydroxylamine, we decided
to screen different bases in dichloromethane. The results are shown in Table 1.
Table 1. Optimization of the reaction conditions.
Entry
Base
Equivalents
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Yield (10)
Yield (11)
Nꢀmethyl morpholine
65 %
11 %
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67 %
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Imidazole
NaHCO3
2,6ꢀLutidine
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We observed that the use of the less basic sodium bicarbonate (entry 4) was able to reduce the
formation the amide probably due to the reduced ionization to the corresponding alcoholate and it
increased the yield of aminodioxime to 72 %.
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The H and 13C NMR spectra of the aminodioximes 10, recorded in DMSOꢀd6, revelead the
presence of an equilibrium between the imino and the amino forms, which is shifted prevalently
towards the amino tautomer.17 On the basis of the proposed reaction mechanism (Scheme 3), and
considering that the transition from one oxime geometrical isomer to another requires either high
temperature or acid or base catalysis or ultraviolet light,18 it is reasonable to assume that the first
oxime retains the syn configuration, while the amidoxime moiety can in principle exist as a mixture
of tautomers. As one major isomer is always formed, it is reasonable to think that it is the more
stable amphi form (Z,Z).
With such optimized conditions in hand we explored the scope of this novel multicomponent
reaction using different Zꢀchlorooximes (7, 17-24) and isocyanides (8, 25-27) (Figure 2). The
library of compounds synthesized is shown in Figure 3.
Figure 2. Building blocks used.
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Z-chlorooximes
Isocyanides
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OH
Cl
OH
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NC
NC
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MeO
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Figure 3. Aminodioximes synthesized (Amide byꢀproduct was always isolated in less than 10%).
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OH
N
OH
OH
OH
N
N
N
N
OH
N
N
N
OH
OH
HN
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OH
Cl
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HN
HN
MeO
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43%
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60%
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74%
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OH
OH
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N
N
N
N
OH
OH
OH
OH
NH
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NH
HN
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MeO
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77%
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75%
25%
68%
OH
OH
N
N
OH
OH
N
N
N
N
OH
OH
N
N
OH
OH
HN
HN
HN
HN
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72%
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78%
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33%
34%
OH
OH
OH
N
N
N
N
S
N
S
N
OH
OH
OH
HN
HN
HN
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36%
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57%
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33%
As shown Figure 3, the reaction is quite general: primary, secondary, tertiary isocyanides are all
able to initiate the multicomponent process via [3+1] cycloadditon with nitrile Nꢀoxides, while the
reaction fails with the less reactive aromatic isocyanides. Aromatic, heteroaromatic and aliphatic Zꢀ
chlorooximes were successfully used as precursors of the nitrile Nꢀoxide species. In all the
examples reported a predominant isomer (> 90 %), the amphi form, was obtained. Only when the
tertꢀbutyl isocyanide was used (examples 28, 32, 34, 40) a 1:1 mixture of iminoꢀamino tautomers
was detected (see spectra in the supporting information).
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In order to unambiguously establish the stereochemistry of the aminodioximes synthesized, a
singleꢀcrystal Xꢀray diffraction analysis on derivative 28 was carried out; its crystallographic
structure and the discussion is presented in the supporting information.
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Apart for their undisputed role in analytical chemistry, the obtained aminodioximes (also known as
vicꢀdioximes) are an important class of ligands able to form complexes with several transition
metals. Such complexes have been shown to be useful in different fields of chemistry,19 and some
were also found to exhibit semiconducting properties.20 Their preparation by means of a oneꢀpot
multicomponent reaction constitutes a significant improvement on the previous methods, which
typically require at least 4ꢀ6 reaction/purification steps when starting from acetophenones.21
Aminodioxines are also pivotal reagent for the synthesis of 2ꢀaminofurazans22 under dehydrative
conditions (4 M NaOH). Depending on the substrate functionalization such strong basic conditions
are not always viable, rendering this transformation poor in scope. We recently demonstrated that
for sensitive substrates mild dehydrative conditions using the Mitsunobu reaction on vicinal bisꢀ
oximes can afford furazans.23 We therefore decided to employ the same dehydrative conditions with
the newly formed aminodioximes. In particular, we tried dehydrative Mitsunobu conditions on the
compound 29. Serendipitously, we did not obtain the expected 2ꢀaminofurazan, but the
corresponding 5ꢀaminoꢀ1,2,4ꢀoxadiazole (43) in 74 % yield (Scheme 7). The reaction was
completely chemoselective as no other isomers were detected.24
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Scheme 7. Formation of the 5ꢀaminoꢀ1,2,4ꢀoxadiazole 43 starting from the aminodioxime 29.
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To explain this result, we propose the following mechanistic scenario. The TPPꢀDEAD Morrisonꢀ
BrunnꢀHuisgen betain extracts the proton of the aminooxime. Subsequently, the resulting alcoholate
reacts with the TPPꢀDEAD adduct to give the intermediate 44, which spontaneously undergoes a
Beckmann rearrangement with the concomitant expulsion of TPPO. Finally the hydroxyl group of
hydroxylamine, properly positioned, quenches the carbocationic species affording the 1,2,4ꢀ
oxadiazole nucleus (Scheme 8).25
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Scheme 8. Proposed mechanism for the formation of 5ꢀaminoꢀ1,2,4ꢀoxadiazoles starting from
aminodioxides using Mitsunobu conditions.
OH
OH
N
N
Ph Ph
P
DEAD
TPP
N
N
O
Ph
OH
HN
44
HN
29
TPPO
N
HO
O
N
N
NH
N
H
HN
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43
We applied this novel transformation to synthesize a small library of 5ꢀ aminoꢀ1,2,4ꢀoxadiazoles
(46ꢀ56) (Figure 4).
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Figure 4. 5ꢀaminoꢀ1,2,4ꢀoxadiazoles synthesized.
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O
N
N
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O
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N
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NH
N
NH
NH
N
MeO
Cl
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41%
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66%
46
66%
O
O
N
N
O
N
N
NH
NH
NH
N
N
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62%
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55%
MeO
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68%
O
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O
N
N
O
N
NH
NH
NH
N
N
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47%
N
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49%
F
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73%
O
N
O
N
N
NH
S
N
N
H
S
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68%
55
74%
The reaction appears to be general in scope irrespective of which isomer prevail on the synthesized
amidoximes.
The unprecedented transformation of aminodioximes into 5ꢀaminoꢀ1,2,4ꢀoxadiazoles through a
Beckmann rearrangement was also confirmed by a few reports where 3,5ꢀdiarylꢀ1,2,4ꢀoxadiazoles
were prepared form symmetrical 1,2ꢀaryldioximes of αꢀaryldiketones.26
CONCLUSIONS
In conclusion, we reported a straightforward synthetic route to aminodioximes and 5ꢀ
aminosubstituted 1,2,4ꢀoxadiazoles important class of compounds in several branches of
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chemistry27 which, until now, required long syntheses. The stereochemistry of aminodioximes was
confirmed by singleꢀcrystal Xꢀray diffraction analysis. Quantum mechanical studies supported by
experimental data highlighted a [3+1] cycloaddition mechanism for the reaction of nitrile Nꢀoxides
with isocyanides, further validating the use of such 1,3ꢀdipolar species in isocyanideꢀmediated
multicomponent processes.
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EXPERIMENTAL SECTION
General Methods. Commercially available reagents and solvents were used without further
purification. Dichloromethane was dried by distillation from P2O5 and stored over activated
molecular sieves (4 Å). When necessary the reactions were performed in ovenꢀdried glassware
under a positive pressure of dry nitrogen. Melting points were determined in open glass capillaries
1
and are uncorrected. All the compounds were characterized by IR. H and 13C APT NMR were
recorded on a 300 MHz. Highꢀresolution ESIꢀMS spectra were performed on a LTQ Orbitrap XL
mass spectrometer. The spectra were recorded by infusion into the ESI source using MeOH as the
solvent. Chemical shifts (δ) are reported in part per million (ppm) relative to the residual solvent
peak. Column chromatography was performed on silica gel 70–230 Mesh ASTM or silica gel 230–
400 Mesh ASTM. Thin layer chromatography (TLC) was carried out on 5 x 20 cm plates with a
layer thickness of 0.25 mm (Silica gel 60 F254). When necessary they were developed with KMnO4.
General preparation of hydroxylamine solution.
Hydroxylamine hydrochloride (15 mmol) in methanol (10 mL), was added to a stirred solution of
potassium hydroxide (15 mmol) in methanol (4 mL) at 0 °C. The mixture was stirred for 30 min at
room temperature and the precipitate potassium chloride was removed and the filtrate was used as
such.16
General preparation of aminodioximes (10, 14, 16, 28-42)
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The Zꢀchlorooxime (1 eq.) was dissolved in dry dichloromethane. Isocyanide (1 eq.),
hydroxylamine (solution 1M in methanol, 1.2 eq.) and sodium bicarbonate (1 eq.) were added and
the reaction was stirred at room temperature under a nitrogen atmosphere until all the Zꢀ
chlorooxime was consumed (typically 16 hours as judged by TLC). The reaction mixture was
concentrated under reduced pressure and the crude material was purified by column
chromatography.
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General preparation of 1,2,3-oxadiazole-5-amines (43, 46-56)
To a cooled (0 °C) suspension of aminodioxime (1 eq.) in dry toluene was added
triphenylphosphine (2 eq.). Diethyl azodicarboxylate (DEAD, 2 eq.) was then added dropwise and
the resulting solution was heated at reflux under a nitrogen atmosphere. When reagents was
consumed (typically 16 hours as judged by TLC) the reaction mixture was concentrated under
reduced pressure and the crude material was purified by column chromatography.
(1Z,2Z)-N'-hydroxy-2-(hydroxyimino)-N-pentyl-2-phenylacetimidamide (10)
(Z)ꢀNꢀhydroxybenzimidoyl chloride 100 mg (0.643 mmol), 1ꢀpentil isocyanide 0.081 mL (0.643
mmol), hydroxylamine 0.720 mL (solution 1M in methanol, 0.772 mmol), sodium bicarbonate 54
mg (0.643 mmol), DCM dry 1 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 8:2, 6:4) to give the product as white solid (114 mg, yield 71.6 %).
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Signals are referred to the main isomer: HꢀNMR (300 MHz, DMSOꢀd6) δ 11.67 (s, OH), 9.38 (s,
OH), 7.60 (m, 2H), 7.37 (m, 3H), 5.89 (t, NH, J = 6.4 Hz), 2.77 (br q, 2H) 1.31 (m, 2H), 1.09 (m,
4H), 0.73 (t, 3H, J = 6.7 Hz); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 148.8, 148.4, 135.0, 129.7, 128.9,
126.5, 42.4, 30.6, 28.8, 22.7, 14.3; IR (KBr) 3265, 1653, 1442, 1409, 948, 897, 691 νmax/cmꢀ1; MS
(ESI) m/z (M+Na)+ Calcd for C13H19N3NaO2: 272.1375; Found: 272.1370 [M+Na]+.
(Z)-2-(hydroxyimino)-N-pentyl-2-phenylacetamide (11)
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White solid; yield 11.5 %; HꢀNMR (300 MHz, DMSOꢀd6) δ 11.45 (s, OH), 8.44 (t, NH, J = 5.5
Hz), 7.62 (m, 2H), 7.39 (m, 3H), 3.21 (br q, 2H) 1.46 (m, 2H), 1.30 (m, 4H), 0.87 (t, 3H, J = 6.7
Hz);
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13CꢀNMR (75 MHz, DMSOꢀd6) δ 163.9, 153.5, 133.0, 129.9, 129.2, 126.2, 40.1 (peak overlaps with
DMSOꢀd6), 38.7, 29.1, 22.3, 14.5; IR (KBr) 3330, 2955, 1633, 1560, 1430, 1258, 946
νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C13H19N2O2: 235.1446; Found: 235.1466 [M+H]+.
(1Z,2Z)-N'-(benzyloxy)-2-(hydroxyimino)-N-pentyl-2-phenylacetimidamide (14)
(Z)ꢀNꢀhydroxybenzimidoyl chloride 100 mg (0.643 mmol), 1ꢀpentyl isocyanide 0.081 mL (0.643
mmol), Oꢀbenzylhydroxylamine 0.720 mL (solution 1M in methanol, 0.772 mmol), sodium
bicarbonate 54 mg (0.643 mmol), DCM dry 1 mL. The crude material was purified by column
chromatography (eluents: PE/EtOAc 9:1, 8:2) to give the product as white solid (179 mg, yield
82%).
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Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.78 (s, OH), 7.50ꢀ7.30 (m,
10H), 6.33 (br t, NH), 4.93 (s, 2H), 2.78 (m, 2H), 1.30 (m, 2H), 1.07 (m, 4H), 0.71 (br t, 3H); 13Cꢀ
NMR (75 MHz, DMSOꢀd6) δ 149.1, 148.1, 139.8, 134.6, 129.8, 128.9, 128.6, 128.4, 127.8, 126.4,
74.7, 43.2, 30.6, 28.8, 22.2, 14.3; IR (KBr) 3110, 1630, 1439, 1053, 955, 944, 726 νmax/cmꢀ1; MS
(ESI) m/z (M+H)+ Calcd for C20H26N3O2: 340.2025; Found: 340.2011 [M+H]+.
(1Z,2Z)-2-(hydroxyimino)-N'-methoxy-N-pentyl-2-phenylacetimidamide (16)
(Z)ꢀNꢀhydroxybenzimidoyl chloride 100 mg (0.645 mmol), 1ꢀpentyl isocyanide 0.086 mL (0.645
mmol), methoxyl amine 0.772 mL (solution 1M in methanol, 0.772 mmol), sodium bicarbonate 54
mg (0.645 mmol), DCM dry 1 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 9:1, 8:2) to give the product as white solid (141.8 mg, yield 84%).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.78 (s, OH), 7.61 (m, 2H),
7.40 (m, 3H), 6.18 (br t, NH), 3.65 (s, 3H), 2.78 (m, 2H), 1.30 (m, 2H), 1.09 (m, 4H), 0.75 (br t,
3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 148.5, 148.1, 134.7, 129.8, 129.0, 126.4, 61.0, 43.2, 30.5,
28.8, 22.2, 14.3; IR (KBr) 3137, 1630, 1439, 1414, 1052, 955, 693 νmax/cmꢀ1; MS (ESI) m/z
(M+Na)+ Calcd for C14H21N3NaO2: 286.1531; Found: 286.1518 [M+Na]+.
(1Z,2Z)-N-(tert-butyl)-N'-hydroxy-2-(hydroxyimino)-2-phenylacetimidamide (28)
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(Z)ꢀNꢀhydroxybenzimidoyl chloride 250 mg (1.61 mmol), tertꢀbutyl isocyanide 0.182 mL (1.61
mmol), hydroxylamine 1.8 mL (solution 1M in methanol, 1.93 mmol), sodium bicarbonate 135 mg
(1.61 mmol), DCM dry 3 mL. The crude material was purified by column chromatography (eluents:
PE/EtOAc 7:3, 6:4) to give the product as white solid (162.5 mg, yield 43%).
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Signals are referred to one isomer: HꢀNMR (300 MHz, DMSOꢀd6) δ 11.72 (s, OH), 9.79 (s, OH),
7.65 (br d, 2H), 7.38 (m, 3H), 5.36 (s, NH), 1.08 (s, 9H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 150.3,
146.3, 135.4, 128.8, 128.6, 126.4, 51.3, 31.3; IR (KBr) 3062, 1638, 1404, 1370, 949, 900, 694
νmax/cmꢀ1; MS (ESI) m/z (M+Na)+ Calcd for C12H17N3NaO2: 258.1218; Found: 258.1219 [M+Na]+.
(1Z,2Z)-N-cyclohexyl-N'-hydroxy-2-(hydroxyimino)-2-phenylacetimidamide (29)
(Z)ꢀNꢀhydroxybenzimidoyl chloride 250 mg (1.61 mmol), cyclohexyl isocyanide 0.200 mL (1.61
mmol), hydroxylamine 1.8 mL (solution 1M in methanol, 1.93 mmol), sodium bicarbonate 135 mg
(1.61 mmol), DCM dry 3 mL. The crude material was purified by column chromatography (eluents:
PE/EtOAc 7:3, 6:4) to give the product as white solid (250.5 mg, yield 60%).
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Signals are referred to the main isomer: HꢀNMR (300 MHz, DMSOꢀd6) δ 11.66 (s, OH), 9.40 (s,
OH), 7.65 (m 2H), 7.37 (m, 3H), 5.73 (br d, NH), 2.71 (m, 1H), 1.64 (m, 4H), 1.44 (m, 1H), 1.19
(m, 2H), 1.00 (m, 3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 148.3, 146.9, 134.6, 129.2, 128.5, 125.9,
51.8, 40.1 (peak overlaps with DMSOꢀd6), 34.5, 24.9; IR (KBr) 3263, 1660, 1449, 1412, 950, 903,
694 νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C14H20N3O2: 262.1555; Found: 262.1542 [M+H]+.
(1Z,2Z)-N'-hydroxy-2-(hydroxyimino)-2-(4-methoxyphenyl)-N-pentylacetimidamide (30)
(Z)ꢀNꢀhydroxyꢀ4ꢀmethoxybenzimidoyl chloride 250 mg (1.34 mmol), 1ꢀpentyl isocyanide 0.168 mL
(1.34 mmol), hydroxylamine 1.5 mL (solution 1M in methanol, 1.61 mmol), sodium bicarbonate
113 mg (1.34 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 5:5, 4:6) to give the product as white solid (286 mg, yield 76 %).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.40 (s, OH), 9.34 (s, OH),
7.55 (d, J = 8.8 Hz, 2 H, AA′XX′), 6.97 (d, J = 8.8 Hz, 2 H, AA′XX′), 5.85 (br t, NH), 3.77 (s, 3H),
2.78 (m, 2H), 1.31 (m, 2H), 1.10 (m, 4H), 0.74 (br t, 3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 160.7,
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148.6, 148.4, 129.9, 127.5, 114.4, 55.8, 42.9, 30.7, 28.8, 22.3, 14.3; IR (KBr) 3274, 1652, 1255,
1182, 947, 899, 833 νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C14H22N3O3: 280.1661; Found:
280.1646 [M+H]+.
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(1Z,2Z)-2-(4-chlorophenyl)-N'-hydroxy-2-(hydroxyimino)-N-pentylacetimidamide (31)
(Z)ꢀ4ꢀchloroꢀNꢀhydroxybenzimidoyl chloride 250 mg (1.31 mmol), cyclohexyl isocyanide 0.166
mL (1.31 mmol), hydroxylamine 1.46 mL (solution 1M in methanol, 1.57 mmol), sodium
bicarbonate 110 mg (1.31 mmol), DCM dry 3 mL. The crude material was purified by column
chromatography (eluents: PE/EtOAc 7:3, 6:4) to give the product as white solid (274 mg, yield 74
%).
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Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.86 (br s, OH), 9.48 (br s,
OH), 7.62 (d, J = 8.6 Hz, 2H, AA′XX′), 7.49 (d, J = 8.6 Hz, 2H, AA′XX′), 6.01 (br s, NH), 2.77 (m,
2H), 1.27 (m, 6H), 0.75 (m, 3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 148.1, 147.9, 134.4, 133.9,
129.2, 128.1, 42.9, 30.7, 28.8, 22.2, 14.3; IR (KBr) 3292, 1640, 1493, 1449, 1093, 946, 832
νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C13H19ClN3O2: 284.1165; Found: 284.1142 [M+H]+.
(1Z,2Z)-N-(tert-butyl)-N'-hydroxy-2-(hydroxyimino)-2-(pyridin-3-yl)acetimidamide (32)
(Z)ꢀNꢀhydroxynicotinimidoyl chloride 200 mg (1.28 mmol), tertꢀbutyl isocyanide 0.145 mL (1.28
mmol), hydroxylamine 1.4 mL (solution 1M in methanol, 1.53 mmol), sodium bicarbonate 107.5
mg (1.28 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 6:4, 5:5) to give the product as white solid (75.4 mg, yield 25 %).
Signals referred to one isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.46 (s, OH), 9.95 (s, OH), 8.63
(s, 1H), 8.55 (br d, 1H), 7.84 (br d, 1H), 7.43 (m, 1H), 5.26 (s, NH), 1.32 (s, 9H); 13CꢀNMR (75
MHz, DMSOꢀd6) δ 149.5, 149.1, 147.0, 145.2, 132.9, 129.4, 123.6, 50.8, 28.5; IR (KBr) 3137,
1642, 1504, 1415, 1243, 961, 918 νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C11H17N4O2:
237.1351; Found: 237.1349 [M+H]+.
(1Z,2Z)-N-benzyl-N'-hydroxy-2-(hydroxyimino)-2-phenylacetimidamide (33)
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(Z)ꢀNꢀhydroxybenzimidoyl chloride 250 mg (1.6 mmol), benzyl isocyanide 0.197 mL (1.6 mmol),
hydroxylamine 1.77 mL (solution 1M in methanol, 1.9 mmol), sodium bicarbonate 134 mg (1.6
mmol), DCM dry 3 mL. The crude material was purified by column chromatography (eluents:
PE/EtOAc 9:1, 7:3) to give the product as white solid (331.1 mg, yield 77 %).
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Signals are referred to the main isomer: HꢀNMR (300 MHz, DMSOꢀd6) δ 11.77 (s, OH), 9.55 (s,
OH), 7.53 (m, 2H), 7.32 (m, 4H), 7.17 (m, 4H), 6.41 (t, NH, J = 6.7 Hz), 4.04 (d, 2H, J= 6.7 Hz);
13CꢀNMR (75 MHz, DMSOꢀd6) δ 148.7, 148.3, 140.7, 135.0, 129.6, 128.8, 128.5, 127.6, 127.2,
126.4, 46.8; IR (KBr) 3265, 1658, 1494, 1452, 1093, 944, 902 νmax/cmꢀ1; MS (ESI) m/z (M+H)+
Calcd for C15H16N3O2: 270.1242; Found: 270.1240 [M+H]+.
(1Z,2Z)-N-(tert-butyl)-2-(4-fluorophenyl)-N'-hydroxy-2-(hydroxyimino)acetimidamide (34)
(Z)ꢀ4ꢀfluoroꢀNꢀhydroxybenzimidoyl chloride 250 mg (1.4 mmol), tertꢀbutyl isocyanide 0.158 mL
(1.4 mmol), hydroxylamine 1.6 mL (solution 1M in methanol, 1.7 mmol), sodium bicarbonate 118
mg (1.4 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 8:2, 7:3) to give the product as white solid (248.1 mg, yield 68 %).
Signals referred to one isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.75 (s, OH), 9.84 (s, OH), 7.66
(m, 2H), 7.25 (m, 2H), 5.36 (br s, NH), 1.08 (s, 9H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 163.1 (d, J =
244.5 Hz), 150.2, 146.2, 132.3 (d, J = 2.8 Hz), 128.8 (d, J = 8 Hz), 116.0 (d, J = 21.2 Hz), 51.2,
31.4; F (282 MHz, CDCl3) ꢀ126.02; IR (KBr) 3226, 1643, 1513, 1265, 1224, 953, 834 νmax/cmꢀ1;
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MS (ESI) m/z (M+Na)+ Calcd for C12H16FN3NaO2: 276.1124; Found: 276.1114 [M+Na]+.
(1Z,2Z)-N-cyclohexyl-N'-hydroxy-2-(hydroxyimino)-2-(4-methoxyphenyl)acetimidamide (35)
(Z)ꢀNꢀhydroxyꢀ4ꢀmethoxybenzimidoyl chloride 250 mg (1.3 mmol), cyclohexyl isocyanide 0.161
mL (1.3 mmol), hydroxylamine 1.5 mL (solution 1M in methanol, 1.6 mmol), sodium bicarbonate
109 mg (1.35 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 5:5, 4:6) to give the product as white solid (286.2 mg, yield 75 %).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.39 (s, OH), 9.35 (s, OH),
7.56 (d, J = 8.6 Hz, 2 H, AA′XX′), 6.97 (d, J = 8.6 Hz, 2 H, AA′XX′), 5.67 (br d, NH), 3.81 (s, 3H),
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2.69 (m, 1H), 1.60 (m, 4H), 1.44 (m, 1H), 1.21 (m, 2H), 1.01 (br s, 3H); 13CꢀNMR (75 MHz,
DMSOꢀd6) δ 160.1, 148.0, 147.2, 127.4, 127.2, 114.0, 55.3, 51.8, 40.2 (peak overlaps with DMSOꢀ
d6), 34.6, 25.0; IR (KBr) 3118, 1643, 1514, 1259, 1247, 1178, 944 νmax/cmꢀ1; MS (ESI) m/z (M+H)+
Calcd for C15H22N3O3: 292.1661; Found: 292.1659 [M+H]+.
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(1Z,2Z)-2-cyclohexyl-N'-hydroxy-2-(hydroxyimino)-N-pentylacetimidamide (36)
(Z)ꢀNꢀhydroxycyclohexanecarbimidoyl chloride 350 mg (2.16 mmol), 1ꢀpentyl isocyanide 0.271
mL (2.16 mmol), hydroxylamine 2.4 mL (solution 1M in methanol, 2.59 mmol), sodium
bicarbonate 181 mg (2.16 mmol), DCM dry 3 mL. The crude material was purified by column
chromatography (eluents: PE/EtOAc 7:3) to give the product as white solid (400.1 mg, yield 72%).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 10.83 (s, OH), 9.20 (s, OH),
5.45 (br t, NH), 2.80 (m, 2H), 2.24 (m, 1H), 1.84 (m, 2H), 1.69 (m, 4H), 1.22 (m, 10H), 0.85 (t, 3H,
J = 6.9 Hz); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 153.5, 149.9, 43.2, 43.1, 39.7 (peak overlaps with
DMSOꢀd6), 30.7, 30.5, 29.9, 26.3, 22.5, 14.4; IR (KBr) 3105, 1643, 1467, 1451, 964, 917, 887
νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C13H26N3O2: 256.2025; Found: 256.2019 [M+H]+.
(1Z,2Z)-N-cyclohexyl-N'-hydroxy-2-(hydroxyimino)-3-phenylpropanimidamide (37)
(Z)ꢀNꢀhydroxyꢀ2ꢀphenylacetimidoyl chloride 350 mg (2.1 mmol), cyclohexyl isocyanide 0.261 mL
(2.1 mmol), hydroxylamine 2.3 mL (solution 1M in methanol, 2.5 mmol), sodium bicarbonate 176
mg (2.1 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 7:3, 6:4) to give the product as white solid (194.9 mg, yield 34%).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.06 (s, OH), 9.35 (s, OH),
7.30ꢀ7.18 (m, 5H), 5.22 (br d, NH), 3.57 (2H, peaks overlap with DMSOꢀd6), 2.44 (br s, 1H), 1.45
(br s, 3H), 1.15 (br s, 2H), 0.92 (m, 5H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 149.1, 148.5, 136.5,
129.4, 128.5, 126.7, 52.2, 40.7, 34.5, 25.3, 25.0; IR (KBr) 3064, 1642, 1424, 997, 941, 723, 697
ν
max/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C15H22N3O2: 276.1712; Found: 276.1707 [M+H]+.
(1Z,2Z)-N-benzyl-N'-hydroxy-2-(hydroxyimino)octanimidamide (38)
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(Z)ꢀNꢀhydroxyheptanimidoyl chloride 350 mg (2.14 mmol), benzyl isocyanide 0.261 mL (2.14
mmol), hydroxylamine 2.4 mL (solution 1M in methanol, 2.57 mmol), sodium bicarbonate 180 mg
(2.14 mmol), DCM dry 3 mL. The crude material was purified by column chromatography (eluents:
PE/EtOAc 8:2, 6:4) to give the product as white solid (195.3 mg, yield 33%).
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Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 10.96 (s, OH), 9.42 (s, OH),
7.35ꢀ7.18 (m, 5H), 6.20 (t, NH), 4.07 (d, 2H, J = 4.9 Hz), 1.98 (t, 2H, J = 7.5 Hz), 1.29 (m, 3H),
1.20ꢀ1.09 (m, 5H), 0.81 (br t, 3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 150.0 (2C), 141.4, 128.7,
127.6, 127.2, 46.5, 34.4, 30.1, 28.8, 25.9, 22.5, 14.4; IR (KBr) 3307, 1695, 1461, 1455, 1350, 921,
697 νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C15H24N3O2: 278.1868; Found: 278.1856 [M+H]+.
(1Z,2Z)-N,2-dicyclohexyl-N'-hydroxy-2-(hydroxyimino)acetimidamide (39)
(Z)ꢀNꢀhydroxycyclohexanecarbimidoyl chloride 300 mg (1.86 mmol), cyclohexyl isocyanide 0.231
mL (1.86 mmol), hydroxylamine 2.1 mL (solution 1M in methanol, 2.23 mmol), sodium
bicarbonate 156 mg (1.86 mmol), DCM dry 3 mL. The crude material was purified by column
chromatography (eluents: PE/EtOAc 9:1, 7:3) to give the product as white solid (388.5 mg, yield
78%).
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Signals referred to the main isomer: HꢀNMR (300 MHz, DMSOꢀd6) δ 10.81 (s, OH), 9.19 (s, OH),
5.40 (br d, NH), 2.69 (m, 1H), 2.22 (m, 1H), 1.85ꢀ1.08 (m, 20H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ
153.2, 148.4, 51.9, 42.7, 39.5 (peak overlaps with DMSOꢀd6), 34.8, 30.1, 25.9, 25.7, 25.1; IR (KBr)
3208, 1627, 1449, 1413, 969, 933, 892 νmax/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C14H26N3O2:
268.2025; Found: 268.2013 [M+H]+.
(1Z,2Z)-N-(tert-butyl)-2-cyclohexyl-N'-hydroxy-2-(hydroxyimino)acetimidamide (40)
(Z)ꢀNꢀhydroxycyclohexanecarbimidoyl chloride 300 mg (1.86 mmol), tertꢀbutyl isocyanide 0.210
mL (1.86 mmol), hydroxylamine 2.1 mL (solution 1M in methanol, 2.23 mmol), sodium
bicarbonate 156 mg (1.86 mmol), DCM dry 3 mL. The crude material was purified by column
chromatography (eluents: PE/EtOAc 9:1, 7:3) to give the product as white solid (161.5 mg, yield
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Signals referred to one isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 10.84 (s, OH), 9.69 (s, OH), 5.01
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(s, NH), 2.29 (m, 1H), 1.91 (m, 4H), 1.62 (m, 6H), 1.25 (s, 9H); CꢀNMR (75 MHz, DMSOꢀd6) δ
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155.3, 148.1, 51.2, 40.5, 31.1, 30.1, 29.2, 26.5; IR (KBr) 3276, 1647, 1508, 1449, 1364, 969, 953
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ν
max/cmꢀ1; MS (ESI) m/z (M+Na)+ Calcd for C12H23N3NaO2: 264.1688; Found: 264.1684 [M+Na]+.
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(1Z,2E)-N'-hydroxy-2-(hydroxyimino)-N-pentyl-2-(thiophen-2-yl)acetimidamide, (41)
(Z)ꢀNꢀhydroxythiopheneꢀ2ꢀcarbimidoyl chloride 300 mg (1.8 mmol), 1ꢀpentyl isocyanide 0.226 mL
(1.8 mmol), hydroxylamine 2.0 mL (solution 1M in methanol, 2.16 mmol), sodium bicarbonate 151
mg (1.8 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 9:1, 6:4) to give the product as white solid (157.3 mg, yield 33%).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.63 (s, OH), 9.50 (s, OH),
7.50 (br d, 1H), 7.09 (m, 2H), 5.87 (br t, NH), 2.80 (m, 2H), 1.29 (m, 2H), 1.11 (m, 4H), 0.73 (br t,
3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 148.1, 145.3, 139.2, 128.4, 127.9 (2C), 42.9, 30.7, 28.8,
22.2, 14.3; IR (KBr) 3209, 1546, 1438, 1340, 1231, 912, 701 νmax/cmꢀ1; MS (ESI) m/z (M+H)+
Calcd for C11H18N3O2S: 256.1119; Found: 256.1111 [M+H]+.
(1Z,2E)-N-cyclohexyl-N'-hydroxy-2-(hydroxyimino)-2-(thiophen-2-yl)acetimidamide, (42)
(Z)ꢀNꢀhydroxythiopheneꢀ2ꢀcarbimidoyl chloride 250 mg (1.5 mmol), cyclohexyl isocyanide 0.186
mL (1.5 mmol), hydroxylamine 1.7 mL (solution 1M in methanol, 1.8 mmol), sodium bicarbonate
126 mg (1.5 mmol), DCM dry 3 mL. The crude material was purified by column chromatography
(eluents: PE/EtOAc 9:1, 6:4) to give the product as white solid (238.1 mg, yield 57%).
Signals referred to the main isomer: 1HꢀNMR (300 MHz, DMSOꢀd6) δ 11.63 (s, OH), 9.54 (s, OH),
7.51 (br d, 1H), 7.09 (m, 2H), 5.64 (br d, NH), 2.72 (m, 1H), 1.62 (m, 4H), 1.44 (m, 1H), 1.18 (m,
2H), 1.02 (m, 3H); 13CꢀNMR (75 MHz, DMSOꢀd6) δ 147.2, 145.4, 139.4, 128.3, 128.0, 127.4, 52.4,
40.3 (peak overlaps with DMSOꢀd6), 35.0, 25.4; IR (KBr) 3275, 1658, 1442, 1008, 919, 905, 891
ν
max/cmꢀ1; MS (ESI) m/z (M+H)+ Calcd for C12H18N3O2S: 268.1119; Found: 268.1104 [M+H]+
N-cyclohexyl-3-phenyl-1,2,4-oxadiazol-5-amine, (43)
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Aminodioxime 100 mg (0.383 mmol), triphenylphosphine 200.9 mg (0.766 mmol), diethyl
azodicarboxylate 0.120 mL (0.766 mmol), toluene dry 1 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 95:5, 9:1) to give the product as white solid (69.2 mg,
yield 74%).
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1HꢀNMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.9 Hz, 2H,), 7.43 (m, 3H), 5.63 (br d, NH), 3.66 (m,
1H), 2.08 (m, 2H), 1.71 (m, 2H), 1.63 (m, 1H), 1.36 (m, 5H); 13CꢀNMR (75 MHz, CDCl3) δ 170.7,
168.5, 130.8, 128.7, 127.8, 127.3, 53.0, 33.3, 25.4, 24.7; IR (KBr) 3242, 1647, 1491, 1444, 1390,
1098 νmax/cmꢀ1; m.p. 126.7ꢀ127.7 °C; MS (ESI) m/z (M+H)+ Calcd for C14H18N3O: 244.1449;
Found: 244.1444 [M+H]+.
N-pentyl-3-phenyl-1,2,4-oxadiazol-5-amine (46)
Aminodioxime 70 mg (0.281 mmol), triphenylphosphine 81 mg (0.308 mmol), diethyl
azodicarboxylate 0.048 mL (1.11 mmol), toluene dry 1 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 9:1) to give the product as white solid (43 mg, yield
66%).
1HꢀNMR (300 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 2H), 7.43 (m, 3H), 6.17 (br s, NH), 3.42 (q, 2H,
J = 7.0 Hz), 1.61 (m, 2H), 1.32 (m, 4H), 0.87 (br t, 3H); 13CꢀNMR (75 MHz, CDCl3) δ 171.5,
168.5, 130.9, 128.7, 127.7, 127.3, 43.8, 29.5, 28.8, 22.3, 14.0; IR (KBr) 3244, 1654, 1527, 1462,
1386, 1301 νmax/cmꢀ1; m.p. 68.1ꢀ69.0 °C; MS (ESI) m/z (M+H)+ Calcd for C13H18N3O: 232.1449;
Found: 232.1451 [M+H]+.
N-cyclohexyl-3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-amine (47)
Aminodioxime 150 mg (0.515 mmol), triphenylphosphine 270.2 mg (1.03 mmol), diethyl
azodicarboxylate 0.162 mL (1.03 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 9:1, 85:15) to give the product as yellow solid (93 mg,
yield 66%).
1HꢀNMR (300 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 2 H, AA′XX′), 6.92 (d, J = 8.8 Hz, 2 H,
AA′XX′), 5.82 (br d, NH), 3.81 (s, 3H), 3.62 (m, 1H), 2.02 (m, 2H), 1.68 (m, 2H), 1.45 (m, 1H),
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1.42ꢀ1.10 (m, 5H); 13CꢀNMR (75 MHz, CDCl3) δ 170.5, 168.1, 161.6, 128.8, 120.2, 114.0, 55.4,
52.9, 33.2, 25.3, 24.7; IR (KBr) 3307, 1634, 1390, 1259, 1177, 839 νmax/cmꢀ1; m.p. 110.6ꢀ111.0 °C;
MS (ESI) m/z (M+Na)+ Calcd for C15H19N3NaO2: 296.1375; Found: 296.1360 [M+Na]+.
3-(4-chlorophenyl)-N-pentyl-1,2,4-oxadiazol-5-amine (48)
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Aminodioxime 144 mg (0.507 mmol), triphenylphosphine 266 mg (1.014 mmol), diethyl
azodicarboxylate 0.159 mL (1.014 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography eluents: PE/EtOAc 95:5, 9:1) to give the product as white solid (55 mg,
yield 41%).
1HꢀNMR (300 MHz, CDCl3δ 7.90 (d, J = 8.8 Hz, 2 H, AA′XX′), 7.42 (d, J = 8.8 Hz, 2 H, AA′XX′),
5.82 (br s, NH), 3.44 (q, J = 7.0 Hz, 2H), 1.55 (m, 2H), 1.32 (m, 4H), 0.90 (br t, 3H); 13CꢀNMR (75
MHz, CDCl3) δ 171.4, 167.6, 136.9, 129.0, 128.6, 126.2, 43.9, 29.5, 28.8, 22.3, 14.0; IR (KBr)
3232, 1637, 1413, 1099, 1013, 841 νmax/cmꢀ1; m.p. 105.0ꢀ106.3 °C; MS (ESI) m/z (M+H)+ Calcd for
C13H17ClN3O: 266.1060; Found: 266.1071 [M+H]+.
N-(tert-butyl)-3-phenyl-1,2,4-oxadiazol-5-amine (49)
Aminodioxime 100 mg (0.425 mmol), triphenylphosphine 223 mg (0.850 mmol), diethyl
azodicarboxylate 0.290 mL (0.850 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 95:5, 9:1) to give the product as white solid (62.7 mg,
yield 68%).
1HꢀNMR (300 MHz, CDCl3) δ 8.01 (m, 2H), 7.43 (m, 3H), 5.59 (br s, NH), 1.45 (s, 9H); 13CꢀNMR
(75 MHz, CDCl3) δ 170.5, 168.3, 130.9, 128.8, 128.0, 127.4, 52.9, 29.2; IR (KBr) 3263, 1622,
1379, 1219, 1141, 751 νmax/cmꢀ1; m.p. 87.1ꢀ88.3 °C; MS (ESI) m/z (M+H)+ Calcd for C12H16N3O:
218.1293; Found: 218.1279 [M+H]+.
3-(4-methoxyphenyl)-N-pentyl-1,2,4-oxadiazol-5-amine (50)
Aminodioxime 60 mg (0.215 mmol), triphenylphosphine 112.8 mg (0.430 mmol), diethyl
azodicarboxylate 0.067 mL (0.430 mmol), toluene dry 2 mL. The crude material was purified by
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column chromatography (eluents: PE/EtOAc 95:5, 9:1) to give the product as yellow solid (30.7
mg, yield 55%).
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1HꢀNMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.8 Hz, 2 H, AA′XX′), 6.95 (d, J = 8.8 Hz, 2 H,
AA′XX′), 5.89 (br s, NH), 3.84 (s, 3H), 3.42 (q, J = 6.7 Hz, 2H), 1.62 (m, 2H), 1.33 (m, 4H), 0.90
(br t, 3H); 13CꢀNMR (75 MHz, CDCl3) δ 171.3, 168.2, 161.7, 128.9, 120.2, 114.1, 55.5, 43.9, 29.6,
28.9, 22.4, 14.1; IR (KBr) 3244, 1655, 1393, 1257, 1175, 846 νmax/cmꢀ1; m.p. 72.6ꢀ73.5 °C; MS
(ESI) m/z (M+Na)+ Calcd for C14H19N3NaO2: 284.1375; Found: 284.1355 [M+Na]+.
N-benzyl-3-phenyl-1,2,4-oxadiazol-5-amine (51)
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Aminodioxime 110 mg (0.408 mmol), triphenylphosphine 114.3 mg (0.817 mmol), diethyl
azodicarboxylate 0.128 mL (0.817 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 95:5, 9:1) to give the product as white solid (63.6 mg,
yield 62%).
1HꢀNMR (300 MHz, CDCl3) δ 7.94 (d, J = 6.8 Hz, 2H), 7.43 (m, 3H), 7.34 (m, 5H), 6.71 (br s,
NH), 4.63 (d, J = 6.1 Hz, 2H); 13CꢀNMR (75 MHz, CDCl3) δ 171.4, 168.5, 137.2, 130.9, 128.9,
128.7, 128.1, 127.6, 127.5, 127.3, 47.7; IR (KBr) 3242, 1655, 1494, 1446, 1398, 1350 νmax/cmꢀ1;
m.p. 115.5ꢀ116.0 °C; MS (ESI) m/z (M+H)+ Calcd for C15H14N3O: 252.1136; Found: 252.1135
[M+H]+.
N-(tert-butyl)-3-(4-fluorophenyl)-1,2,4-oxadiazol-5-amine (52)
Aminodioxime 110 mg (0.434 mmol), triphenylphosphine 227.8 mg (0.868 mmol), diethyl
azodicarboxylate 0.136 mL (0.868 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 98:2, 95:5) to give the product as white solid (74.6
mg, yield 73%).
1HꢀNMR (300 MHz, CDCl3) δ 7.98 (m, 2H), 7.10 (m, 2H), 5.58 (br s, NH), 1.44 (s, 9H); 13CꢀNMR
(75 MHz, CDCl3) δ 170.4, 167.5, 164.0 (d, J = 248.5), 129.4 (d, J = 8.6), 124.1, 115.8 (d, J = 21.7),
52.8, 29.0 (3C); 19F (282 MHz, CDCl3) ꢀ109.24; IR (KBr) 3302, 1632, 1410, 1374, 1222, 840
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νmax/cmꢀ1; m.p. 108.1ꢀ109.2 °C; MS (ESI) m/z (M+H)+ Calcd for C12H15FN3O: 236.1199; Found:
236.1185 [M+H]+.
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Aminodioxime 60 mg (0.254 mmol), triphenylphosphine 133 mg (0.508 mmol), diethyl
azodicarboxylate 0.080 mL (0.508 mmol), toluene dry 1 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 9:1, 7:3) to give the product as white solid (27 mg,
yield 49%).
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1HꢀNMR (300 MHz, CDCl3) δ 9.31 (br s, 1H), 8.73 (br s, 1H), 8.40 (br d, 1H), 7.50 (m, 1H), 5.71
(br s, NH), 1.50 (s, 9H); 13CꢀNMR (75 MHz, CDCl3) δ 170.8, 166.4, 151.5, 148.9, 134.7, 124.5,
123.7, 53.0, 29.2; IR (KBr) 3210, 2987, 1750, 1372, 1276, 1226, 1101 νmax/cmꢀ1; m.p. 140.8ꢀ141.7
°C; MS (ESI) m/z (M+H)+ Calcd for C11H15N4O: 219.1245; Found: 219.1246 [M+H]+.
3-benzyl-N-cyclohexyl-1,2,4-oxadiazol-5-amine (54)
Aminodioxime 100 mg (0.383 mmol), triphenylphosphine 200 mg (0.765 mmol), diethyl
azodicarboxylate 0.120 mL (0.765 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 95:5, 9:1) to give the product as white solid (46.6 mg,
yield 47%).
1HꢀNMR (300 MHz, CDCl3) δ 7.31 (m, 3H), 7.30 (m, 2H), 5.65 (br d, NH), 3.87 (s, 2H), 3.52 (m,
1H), 1.98 (m, 2H), 1.74ꢀ1.57 (m, 3H), 1.41ꢀ1.20 (m, 5H); 13CꢀNMR (75 MHz, CDCl3) δ 170.6,
169.7, 136.0, 129.0, 128.7, 127.0, 52.7, 33.3, 32.7, 25.3, 24.7; IR (KBr) 3211, 3088, 1636, 1537,
1397, 718 νmax/cmꢀ1; m.p. 90.9ꢀ91.7 °C; MS (ESI) m/z (M+H)+ Calcd for C15H20N3O: 258.1606;
Found: 258.1601 [M+H]+.
N-pentyl-3-(thiophen-2-yl)-1,2,4-oxadiazol-5-amine (55)
Aminodioxime 110 mg (0.39 mmol), triphenylphosphine 205 mg (0.78 mmol), diethyl
azodicarboxylate 0.122 mL (0.78 mmol), toluene dry 2 mL. The crude material was purified by
column chromatography (eluents: PE/EtOAc 95:5, 9:1) to give the product as yellow solid (68.3
mg, yield 74%).
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