Synthesis of hydroxyethyl methyl morpholinium azide (HEM Morph)N3: A highly efficient new task specific azide-based ionic liquid and its dual application as an azide source and media for synthesis of some novel aromatic O-oxime ethers-1,2,3-triazole conjugates as a potential antihistaminic agents

Article abstract of DOI:10.1016/j.molliq.2019.112245

The synthesis, characterization and application of hydroxyethyl methyl morpholinium azide (HEM Morph)N₃ as a new azide-based ionic liquid (ABIL) has been described. (HEM Morph)N₃ is used as a source of azide and reaction media for three components ‘Click’ Huisgen cycloaddition reaction between O-propargyl oxime ether and alkyl bromide to acquire novel aromatic O-oxime ethers-1,2,3-triazole conjugates as potential antihistaminic agents in good yields. The influence of parameters like temperature, amount of IL, type of azide-based ionic liquids and its reusability is investigated. The (HEM Morph)N₃ is proved to be an efficient, thermally stable, inexpensive and recyclable azide-based ionic liquid which can be easily synthesized and used as both azide's source and reaction media for ‘Click’ Huisgen cycloaddition reaction.

Full text of DOI:10.1016/j.molliq.2019.112245

Journal Pre-proof
Synthesis of hydroxyethyl methyl morpholinium azide (HEM
Morph)N3: A highly efficient new task specific azide-based ionic
liquid and its dual application as an azide source and media for
synthesis of some novel aromatic O-oxime ethers-1,2,3-triazole
conjugates as a potential antihistaminic agents
Mohammad Navid Soltani Rad, Somayeh Behrouz, Hossein
Saremi, Javad Mohammadtaghi-Nezhad
PII:
S0167-7322(19)34619-7
DOI:
https://doi.org/10.1016/j.molliq.2019.112245
MOLLIQ 112245
Reference:
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
17 August 2019
25 November 2019
29 November 2019
Please cite this article as: M.N.S. Rad, S. Behrouz, H. Saremi, et al., Synthesis of
hydroxyethyl methyl morpholinium azide (HEM Morph)N3: A highly efficient new task
specific azide-based ionic liquid and its dual application as an azide source and media for
synthesis of some novel aromatic O-oxime ethers-1,2,3-triazole conjugates as a potential
antihistaminic agents, Journal of Molecular Liquids(2018), https://doi.org/10.1016/
j.molliq.2019.112245
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Synthesis of hydroxyethyl methyl morpholinium azide (HEM Morph)N3: A highly
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efficient new task specific azide-based ionic liquid and its dual application as an
azide source and media for synthesis of some novel aromatic O-oxime ethers-1,2,3-
triazole conjugates as a potential antihistaminic agents
Mohammad Navid Soltani Rad, * Somayeh Behrouz,* Hossein Saremi and Javad Mohammadtaghi-Nezhad
Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology,
Shiraz 71555-313, Iran
*Corresponding authors. Tel.: +98 71 3735 4500; fax: +98 71 3735 4520; e-mail
address: soltani@sutech.ac.ir (M.N. Soltani Rad); behrouz@sutech.ac.ir (S. Behrouz)
1

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Abstract:
The synthesis, characterization and application of hydroxyethyl methyl morpholinium azide (HEM Morph)N3 as a
new azide-based ionic liquid (ABIL) has been described. (HEM Morph)N3 is used as a source of azide and reaction
media for three components ‘Click’ Huisgen cycloaddition reaction between O-propargyl oxime ether and alkyl
bromide to acquire novel aromatic O-oxime ethers-1,2,3-triazole conjugates as potential antihistaminic agents in
good yields. The influence of parameters like temperature, amount of IL, type of azide-based ionic liquids and its
reusability is investigated. The (HEM Morph)N3 is proved to be an efficient, thermally stable, inexpensive and
recyclable azide-based ionic liquid which can be easily synthesized and used as both azide’s source and reaction
media for ‘Click’ Huisgen cycloaddition reaction.
Keywords: ionic liquid, azide-based ionic liquid, (HEM Morph)N3, ‘Click’ Huisgen cycloaddition, aromatic O-oxime
ethers-1,2,3-triazole conjugates, antihistaminic
2

1. Introduction
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Nowadays, there is no doubt that ionic liquids (ILs) have played an indelible role in advancing the
organic synthesis [1,2]. Owing to the widespread perspective of their applications in multifarious field of
chemical sciences in particular organic chemistry, ILs have been the subject of immense interest by
plenty of researchers [3]. Since their well-established unique physiochemical properties comprising
extreme of polarity, negligible vapor pressure and less volatility, non-flammability, high thermal stability,
recyclability, the possibility of fine-tuning and capability to dissolve a wide range of inorganic and
organic materials, they are prevalently used in organic transformations as catalysts [4,5], extractants [6]
and green solvent [7]. Until recently, the vast majority of investigations concerned with established ILs
have focused on imidazolium, pyridinium, piperidinium, pyrrolidium, tetraalkylammonium,
phosphonium and sulphonium-based ILs [8]. Particularly, among the ILs, the imidazolium-based ILs are
the most extensively studied and applied. However, imidazolium-based ILs exhibit few drawbacks
encompassing, instability toward the chemical and electrochemical reactions caused by a possible
alteration at C(2)-carbon of imidazolium cores [9], expensiveness [10], reduced biodegradability [11]
and toxicity [12]. Thus, the discovery of new ILs is still challenging in order to obviate the problems
usually associated with imidazolium-based ILs. In this connection, the morpholinium-based ILs have
gained particular attention regarding to their remarkable properties and advantageous. Morpholinium-
based ILs can be easily synthesized through the short overall reaction and due to the low price of 4-
methylmorpholine, the final price of obtained ILs is low [13]. They are applied as reaction media [14],
catalysts for organic synthesis [15,16], corrosion inhibitors [17], electrolytes [18], gel-electrolytes [19],
media for micellization [20], heat stabilizers or antioxidants for lubricating oil [21], separation of
aromatics from paraffins and cycloalkanes [22], size-controlled synthesis of palladium nanoparticles by
electrochemical method [23], superoxide ion generation [24] and solvent for cellulose [25]. Since the
presence of an oxygen atom in morpholinium moiety, they are able to dissociate mineral salts in
particular Li salts [26]; in addition, they display lower toxicity compare to other used ILs [27].
One of the special features of ionic liquids is their tunability [28]. This simply means that a great deal of
cations and anions can combine together to acquire the plenty of ILs. Despite the incorporation of many
different anions, however very little attention has been paid to azide-based ionic liquids (ABILs). In this
context, very few ABILs have been developed so far. They are including tetrabutylammonium azide
(TBAN3)[29-31], 1-butyl-3-methylimidazolium azide [BMIM][N3] [32-38], 1-butyl-2,3-dimethylimida-
zolium azide [BMMIM][N3] [39], choline azide [40] and aminoalkyl triazolium azide[41] which have been
prepared and utilized as an azide source, media for reaction and electrochemical purposes. In addition,
the incorporation of azide into structure of some ILs also was reported [42, 43]
The classical antihistamines namely first-generation, especially H1 antihistamines are extensively used
for the symptomatic treatment of inflammatory and allergy disorders comprising rhinorrhea, sneezing,
3

hay fever, pollinosis, chronic idiopathic uriticaria, itching of eyes, throat and nose. These agents also
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affect the adrenergic, cholinergic, dopaminergic and serotoninergic receptors. Their ability to relieve of
these symptoms is attributed to antagonize the action of histamine at peripheral H1 receptors [44]. The
major objective of antihistamines research over recent years has focused on developing novel agents
with higher selectivity for H1-receptores and diminishing undesirable CNS effects like sedation,
drowsiness, decreased cognitive ability, somnolence and other peripheral side effects such as dry mouth
urinary retention and so on. The structural activity relationships (SAR) studies of first-generation H1
antihistamines are well indicated that they are very homogeneous in their structure. H1 antihistamines
structurally are represented by a general structure of two aromatic groups (or related heterocyclic cores
and/or isosters) linked to methyne moiety in which attaches to the X group [45]. The X group
traditionally is an oxygen or a nitrogen atom that linked to a spacer usually consist of two or more
carbons. The spacer can be terminated in an amine residue (Figure 1). The structure of some H1
antihistamines drugs (first-generation) is shown in Figure 1 [44].
R
Ar
Spacer
X= O,N
N
X
Ar'
R'
N
N
N
O
N
OH
N
Cl
O
Cl
X
O
Cetrizine
X=H, Diphenhydramine
X=Br, Bromazine
Buclizine
N
N
N
OH
O
Cl
O
NH
O
Cycloheptadine
Hydroxyzine
Ebastine
S
N
N
N
N
N
Cl
N
Prometazine
Meclizine
Cyclizine
Figure 1: General structure of H1-antihistamines (first generation) and structure of some famous H1-
antihistamines
The emerging field of ‘Click’ approach offers a unique strategy for incorporation of 1,2,3-triazolyl
moieties into molecular scaffolds. 1,2,3-Triazole cores are attractive connecting units since the 1H-1,2,3-
triazolyl groups are well-recognized by receptors and enzymes in animal cells and thus involves
remarkable biological activities [47]. The pharmacological importance of 1,2,3-triazoleyl cores are owing
to the fact that they are identified as the non-classical and non-hydrolyzable bioisostere of amide
functionality regarding to their high electronic and topological similarities [48]. Furthermore, they are
4

metabolically stable nucleus with capability of hydrogen bond formation which extensively promote the
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binding of biomolecules to target proteins [49]. Given the tremendous significance of H1-antihistamine
drugs in medicinal chemistry and also in continuation of our ongoing research on incorporation of 1,2,3-
triazolyl cores into bioactive molecules [50-58], hereby we report the synthesis of hydroxyethyl methyl
morpholinium azide (HEM Morph)N3 as a new ABIL and also describe its dual application as both media
and azide source in synthesis of novel aromatic O-oxime ethers-1,2,3-triazole conjugates (I-III) as
potential antihistaminic agents, through three components ‘Click’ Huisgen cycloaddition(Scheme 1). To
the best of our knowledge, this is the first report in which an ABIL has been used as both azide source
and media.
R1
O
O
N
N
R
CuI (cat.)
R2
O
N3
OH
N
N
Br
R1
R2
N
4-8 h, 90 °C
N
(I-III)
R
(HEM Morph)N3
R'
N
N
N
O
O
O
H3C
N
N
N
N
N
N
N
N
N
(I)
(II)
(III)
R
R
R
R= PhCH2, PhCH2CH2,
-naphthoxy-(CH2)3
R'= H, R= Phthalimidyl-(CH2)3,Phthaalimidyl-(CH2)5,
eugenyloxy-(CH2)3,-naphthoxy-(CH2)3
R'= Ph-(CH2)3-O, R= Phthalimidyl-CH2
R= eugenyloxy-CH2,
Phthaalimidyl-(CH2)5
Scheme 1: Three components synthesis of aromatic O-oxime ethers-1,2,3-triazole conjugates (I- III) using (HEM
Morph)N3
2. Experimental section
2.1. General
All chemicals were purchased from Merck. Solvents were purified using standard procedures and stored
over 3Å molecular sieves. Reactions were monitored by TLC using SILG/UV 254 silica-gel plates. Column
1
13
chromatography was performed on silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). H- and C-
NMR spectra were recorded on Brüker Avance-DPX-250 and Brüker Avance-DPX-400 spectrometers
operating at 250/62.5, 300/75 and 400/100 MHz, respectively. Chemical shifts are given in δ relative to
tetramethylsilane (TMS) as an internal standard, coupling constants J are given in Hz. Abbreviations used
for 1H NMR signals are s singlet, d doublet, t triplet, q quartet, m multiplet, b broad, dd doublet of doublet.
GC/MS was performed on a Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel.%). The TGA test was
performed using METTLER TOLEDO instrument. Elemental analyses were performed on a Perkin–Elmer
240-B microanalyzer. IR spectra were obtained using a Shimadzu FT-IR-8300 spectrophotometer.
Melting points were measured using Electrothermal IA 9000 melting point apparatus in open capillary
tubes and are uncorrected.
5

2.2. Synthesis of (HEM Morph)N3.
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In a round bottomed flask (100 mL), it was added 4-Methyl-morpholine (10mmol) and 2-bromoethanol
(10mmol) in anhydrous MeCN (10mL) which refluxed for 24 hours. After the reaction was completed,
the solvent was distilled off to afford (HEM Morph)Br as a white solid (m.p.:150-152 °C). The acquired
(HEM Morph)Br is pure enough to use for the next step; however, if require it can be recrystallized in hot
ethanol. Then, (HEM Morph)Br (10mmol) and NaN3 (10mmol) were charged in a canonical flask in the
presence of anhydrous MeOH (15mL) which vigorously stirred for 24 hours. Afterward, the precipitated
NaBr was separated by a sintered glass and the filtrate was evaporated by a rotary evaporator in vacuo.
The pure (HEM Morph)N3 is obtained as a yellow semi-solid (1.82 g, 97%); m.p. 94-95 °C. IR (KBr): 3300,
1
2964, 1227, 1124 cm-1. H NMR (300 MHz, CDCl3) δppm = 3.25 (s, 3H, CH3), 3.50-3.64 (m, 6H, 3 NCH2),
3.87-3.93 (m, 6H, 3 OCH2), 5.31 (br s, 1H, OH). 13C NMR (75 MHz, CDCl3) δppm = 51.22, 61.29, 61.56, 66.44,
67.03. MS (EI): m/z (%) = 188 (9.4) [M+]. Anal. Calc. for C7H16N4O2: C, 44.67; H, 8.57; N, 29.77; found: C,
44.81; H, 8.74; N, 29.93.
2.3. Synthesis of alkyl bromides (3a-c).
In a round bottomed flask (100 mL), it was added potassium phthalimide (1.85 g, 0.01 mol) and desire
1,n-dibromoalkane (0.02 mol) in the presence of a catalytic amount of TBAI (0.1 g) in anhydrous DMF
(10 mL). The reaction was stirred for 24 h at r.t. After the completion of the reaction (TLC check), the
solvent was evaporated in vacuo and the remaining residue was diluted in CHCl3 (150 mL) and washed
with H2O (3×150 mL). The organic phase was evaporated and the remaining residue was purified by a
short column chromatography on silica and n-hexane as an eluent.
2.4. Synthesis of alkyl bromides (5a-c).
In a round bottomed flask (100 mL), it was added the proper phenol (0.01 mol), desire 1,n-
dibromoalkane (0.02 mol) and K2CO3 (1.38 g, 0.01mol) in the presence of a catalytic amount of TBAB (0.1
g) in anhydrous MeCN (30 mL). The reaction was stirred at reflux for 24 h. After the completion of the
reaction (TLC check), the solvent was evaporated in vacuo and the remaining residue was diluted in
CHCl3 (150 mL) and washed with H2O (3×150 mL). The organic phase was dried (Na2SO4, 10 g),
evaporated and the remaining residue was purified by a short column chromatography on silica and n-
hexane as an eluent.
2.5. Synthesis of oximes 7 and 11.
In a round-bottomed flask (100 mL), a mixture of the appropriate ketone (0.01 mol), NH2OH.HCl (1.39 g,
0.02 mol), NaOH (0.8 g, 0.02 mol), and H2O (2 mL) was dissolved in EtOH (18 mL), and the soln. was
stirred for 24 h at r.t. Then, the mixture was poured into 20 g of ice in H2O (10 mL). The oxime
6

precipitated immediately, and it was filtered, washed with cold H2O (50 mL), and dried in vacuum oven
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(50°C for 2h). Recrystallization from hot MeOH/H2O (1:1) afforded the pure oximes 7 and 11.
2.6. Synthesis of O-propargyl oxime ethers 8 and 12.
In a round-bottomed flask (100 mL), propargyl tosylate (2.73 g, 0.013 mol) was added portionwise to a
soln. of an appropriate oxime (0.01 mol), KOH (0.56 g, 0.01 mol), and 2 mL of H2O in DMSO (18 mL). The
mixture was stirred for 2 h at r.t. (TLC control). Then, the crude product was dissolved in CHCl3 (150 mL)
and washed with H2O (3 × 200 mL). The organic layer was dried (Na2SO4, 10 g) and concentrated to
afford the crude product, which was purified by column chromatography (SiO2, n-hexane/EtOAc 10:1).
2.7. Synthesis of aromatic O-oxime ethers-1,2,3-triazole conjugates 9a-c and 13a-g.
In a round-bottomed flask (100 mL), a mixture containing O-propargyl oxime ethers 8 and/or 12 (0.01
mol), alkyl bromides 3a-c and/or 5a-c (0.012 mol), CuI (0.095 g, 5⨯10-4 mol) and (HEM Morph)N3 (3.8 g,
0.02 mol) was heated at 90 to 95° C on an oil bath for indicated times (Table 4). After the completion of
the reaction (TLC check), the crude product was dissolved in CHCl3 (150 mL), flash filtered through the
sintered glass to remove insoluble solid, and washed with deionized H2O (3 × 100 mL). The organic layer
was dried (Na2SO4, 10 g) and concentrated to afford the crude product, which was purified by column
chromatography (SiO2, n-hexane/EtOAc 1:5).
2.8. Recovery and regeneration of (HEM Morph)N3
After the completion of reaction, primarily, the reaction mixture was diluted in 150 mL pure chloroform
and then the insoluble materials like CuI were filtered by a sintered glass. Next, in a separation funnel,
the chloroform solution was washed with 3⨯ 100 mL deionized water and aquatic phase was separated
and transferred into a 500 mL beaker. Most the volume of aquatic phase is evaporated on a heater stirrer
and when the solution volume was reached to 50 mL, it was evaporated in vacuo by a rotary evaporator.
The obtained viscose oil was kept in a vacuum oven for overnight at 90-100°C. The viscose oil was then
diluted in 50 mL of absolute methanol and sodium azide 0.65 g (0.01 mol) was dispersed and stirred for
overnight. Afterward the precipitation comprising NaBr and unexchanged NaN3 was filtered through a
sintered glass. The remaining filtrate was evaporated in vacuo by a rotary evaporator to obtain almost
pure (HEM Morph)N3 as indicated by FT-IR and NMR spectroscopic methods.
2.9. Characterization
All synthesized compounds are characterized by various spectroscopic methods described as follows.
2.91. 9H-Fluoren-9-one O-(1-phenethyl-1H-1,2,3-triazol-4-yl)methyl oxime (9a)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as yellow
1
solid (319 mg, 84%); m.p. 137-138 °C. IR (KBr): 3100, 2951, 1642, 1509, 1467, 1035 cm-1. H NMR (300
7

MHz, CDCl3) δppm = 3.14 (t, J = 6.0 Hz, 2H, PhCH ), 4.54 (t, J = 6.0, 2H, NCH2), 5.50 (s, 2H, NOCH2), 7.01-
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13
7.72 (complex, 13H, aryl), 8.19 (s, 1H, C(5)-H of triazole). C NMR (75 MHz, CDCl3) δppm = 34.90, 58.11,
68.01, 121.85, 126.18, 128.34, 128.65, 129.59, 130.84, 131.44, 132.07, 132.68, 137.01, 142.90, 144.16,
147.23. MS (EI): m/z (%) = 380 (23.5) [M+]. Anal. Calc. for C24H20N4O: C, 75.77; H, 5.30; N, 14.73; found: C,
75.90; H, 5.38; N, 14.61.
2.9.2. 9H-Fluoren-9-one O-(1-(3-phenylpropyl)-1H-1,2,3-triazol-4-yl)methyl oxime (9b)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as yellow
1
solid (315 mg, 80%); m.p. 83-84 °C. IR (KBr): 3063, 2971, 1620, 1586, 1469, 1035 cm-1. H NMR (300
MHz, CDCl3) δppm = 2.18 (t, J = 6.2 Hz, 2H, PhCH2), 2.57-2.59 (m, 2H, PhCH2CH2), 4.27 (t, J = 6.0 Hz, 2H,
13
NCH2), 5.54 (s, 2H, NOCH2), 7.09-7.76 (complex, 13H, aryl), 8.23 (s, 1H, C(5)-H of triazole). C NMR (75
MHz, CDCl3) δppm = 29.77, 33.74, 52.51, 67.83, 122.07, 126.62, 128.06, 128.86, 129.47, 129.71, 130.28,
130.90, 132.02, 142.52, 142.81, 143.68, 164.98. MS (EI): m/z (%) = 394 (21.8) [M+]. Anal. Calc. for
C25H22N4O: C, 76.12; H, 5.62; N, 14.20; found: C, 76.27; H, 5.50; N, 14.32.
2.9.3. 9H-Fluoren-9-one O-(1-(4-(naphthalen-2-yloxy)butyl)-1H-1,2,3-triazol-4-yl)methyl oxime (9c)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as yellow
1
solid (389 mg, 82%); m.p. 87-88 °C. IR (KBr): 3068, 2982, 1637, 1463, 1390, 1075 cm-1. H NMR (300
MHz, CDCl3) δppm = 1.49-1.59 (m, 2H, OCH2CH2), 2.07-2.17 (m, 2H, NCH2CH2), 4.03 (t, J = 6.0 Hz, 2H,
OCH2), 4.29 (t, J = 6.1 Hz, 2H, NCH2), 5.54 (s, 2H, NOCH2), 7.06-7.74 (complex, 15H, aryl), 8.25 (s,1H, C(5)-
13
H of triazole). C NMR (75 MHz, CDCl3) δppm = 24.95, 27.48, 52.51, 67.83, 68.97, 107.87, 118.67, 121.81,
124.62, 127.19, 127.48, 128.61, 128.86, 129.18, 129.71, 130.02, 130.28, 130.62, 130.90, 131.72, 142.81,
143.68, 155.88, 165.27. MS (EI): m/z (%) = 474 (27.3) [M+]. Anal. Calc. for C30H26N4O2: C, 75.93; H, 5.52;
N, 11.81; found: C, 76.05; H, 5.69; N, 11.97.
2.9.4. (E)-2-(2-(4-((((Phenyl(4-(3-phenylpropoxy)phenyl)methylene)amino) oxy)methyl)-1H-1,2,3-triazol-1-
yl)ethyl)isoindoline-1,3-dione (13a)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as white
solid (450 mg, 77%); m.p. 123-124 °C. IR (KBr): 3061, 2943, 1710, 1621, 1517, 1425, 1036 cm-1. 1H NMR
(300 MHz, CDCl3) δppm = 2.14 (br s, 2H, OCH2CH2), 2.79 (br s, 2H, PhCH2), 3.93 (t, J= 6.0 Hz, 2H,
N(phthalimide)-CH2), 4.1 (t, J = 6.0 Hz, 2H, N(triazole)-CH2), 4.63 (br s, 2H, OCH2CH2), 5.25 (s, 2H,
13
NOCH2), 6.79-7.73 (complex, 19H, aryl, C(5)-H of triazole). C NMR (75 MHz, CDCl3) δppm = 31.10, 32.24,
8

41.99, 48.57, 68.35, 68.91, 114.71, 123.92, 124.76, 126.19, 128.51, 129.03, 129.35, 129.92, 130.22,
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131.09, 131.94, 132.52, 132.78, 133.36, 142.25, 142.52, 150.01, 162.01, 168.34. MS (EI): m/z (%) = 585
(32.9) [M+]. Anal. Calc. for C35H31N5O4: C, 71.78; H, 5.34; N, 11.96; found: C, 71.95; H, 5.50; N, 12.14.
2.9.5. 2-(4-(4-((((Diphenylmethylene)amino)oxy)methyl)-1H-1,2,3-triazol-1-yl)butyl)isoindoline-1,3-dione
(13b)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as white
solid (378 mg, 79%); m.p. 105-106 °C. IR (KBr): 3050, 2987, 1702, 1625, 1449, 1401, 1068 cm-1. 1H NMR
(300 MHz, CDCl3) δppm = 1.68-1.73 (m, 2H, N(phthalimide)-CH2CH2), 1.92-1.96 (m, 2H, N(triazole)-
CH2CH2), 3.68 (t, J = 6.6 Hz, 2H, N(phthalimide)-CH2), 4.36 (t, J = 6.9 Hz, 2H, N(triazole)-CH2), 5.31 (s, 2H,
13
NOCH2), 7.32-7.81 (complex, 15H, aryl, C(5)-H of triazole). C NMR (75 MHz, CDCl3) δppm = 24.53, 26.28,
40.04, 52.94, 67.88, 123.52, 128.48, 128.77, 129.98, 131.45, 132.60, 132.91, 133.75, 142.84, 150.18,
168.03. MS (EI): m/z (%) = 479 (25.1) [M+]. Anal. Calc. for C28H25N5O3: C, 70.13; H, 5.25; N, 14.60; found:
C, 70.29; H, 5.36; N, 14.49.
2.9.6. Benzophenone O-(1-(4-(4-allyl-2-methoxyphenoxy)butyl)-1H-1,2,3-triazol-4-yl)methyl oxime (13C)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as yellow
1
solid (397 mg, 80%); m.p. 48-49 °C. IR (KBr): 3064, 2957, 1692, 1461, 1458, 1060 cm-1. H NMR (300
MHz, CDCl3) δppm = 1.54 (br s, 2H, OCH2CH2), 1.94-2.02 (m, 2H, NCH2CH2), 3.29 (d, J = 6.0 Hz, 2H, PhCH2),
3.47 (s, 3H, OCH3), 4.10 (t, J = 6.0 Hz, 2H, NCH2), 4.31 (t, J = 6.0 Hz, 2H, OCH2), 5.04 (d, J = 6.9 Hz, 2H,
=CH2), 5.32 (s, 2H, NOCH2) , 5.87-5.97 (m, 1H, =CH), 7.26-7.53 (complex, 14H, aryl, C(5)-H of triazole).
13C NMR (75 MHz, CDCl3) δppm = 25.09, 27.39, 40.60, 53.21, 57.24, 68.15, 69.01, 113.23, 114.66, 116.37,
122.12, 128.95, 129.60, 130.14, 131.86, 133.35, 137.04, 143.37, 148.25, 150.50. MS (EI): m/z (%) = 496
(26.8) [M+]. Anal. Calc. for C30H32N4O3: C, 72.56; H, 6.49; N, 11.28; found: C, 72.70; H, 6.65; N, 11.42.
2.9.7. Benzophenone O-(1-(4-(naphthalen-2-yloxy)butyl)-1H-1,2,3-triazol-4-yl)methyl oxime (13d)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as white
1
solid (395 mg, 83%); m.p. 91-92 °C. IR (KBr): 3085, 2968, 1619, 1447, 1402, 1054 cm-1. H NMR (300
MHz, CDCl3) δppm = 1.80-1.87 (m, 2H, OCH2CH2), 2.07-2.17 (m, 2H, NCH2CH2), 4.03 (t, J = 6.2 Hz, 2H,
NCH2), 4.39 (t, J = 6.2 Hz, 2H, OCH2), 5.32 (s, 2H, NOCH2), 7.07-7.75 (complex, 18H, aryl, C(5)-H of
triazole). 13C NMR (75 MHz, CDCl3) δppm = 24.65, 27.78, 52.51, 67.83, 68.97, 107.59, 118.39, 124.35,
126.93, 127.48, 128.32, 129.18, 129.47, 129.71, 130.28, 130.62, 130.90, 131.72, 133.43, 142.81, 150.76,
155.88. MS (EI): m/z (%) = 476 (29.4) [M+]. Anal. Calc. for C30H28N4O2: C, 75.61; H, 5.92; N, 11.76; found:
C, 75.78; H, 6.07; N, 11.89.
9

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2.9.8. 2-(6-(4-((((Diphenylmethylene)amino)oxy)methyl)-1H-1,2,3-triazol-1-yl)hexyl)isoindoline-1,3-dione
(13e)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as white
solid (411 mg, 81%); m.p. 123-124 °C. IR (KBr): 3092, 2983, 1709, 1607, 1439, 1401, 1028 cm-1. 1H NMR
(300 MHz, CDCl3) δppm = 1.36 (br s, 4H, N(triazole)-CH2CH2CH2CH2), 1.65 (br s, 2H, N(phthalimide)-
CH2CH2), 1.89 (br s, 2H, N(triazole)-CH2CH2), 3.62 (t, J = 6.1 Hz, 2H, N(phthalimide)-CH2), 4.29 (t, J = 5.9
13
Hz, 2H, N(triazole)-CH2), 5.32 (s, 2H, NOCH2), 7.27-7.83 (complex, 15H, aryl, C(5)-H of triazole). C NMR
(75 MHz, CDCl3) δppm = 26.55, 27.16, 28.73, 30.58, 40.80, 53.13, 67.70, 124.02, 128.98, 129.27, 129.59,
131.44, 132.39, 132.68, 133.59, 142.60, 150.65, 168.28. MS (EI): m/z (%) = 507 (19.3) [M+]. Anal. Calc.
for C30H29N5O3: C, 70.99; H, 5.76; N, 13.80; found: C, 71.16; H, 5.90; N, 13.67.
2.9.9. (E)-Acetophenone O-(1-(2-(4-allyl-2-methoxyphenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl oxime (13f)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as yellow
1
solid (312 mg, 77%); m.p. 59-60 °C. IR (KBr): 3062, 2946, 1610, 1445, 1380, 1031 cm-1. H NMR (300
MHz, CDCl3) δppm = 2.21 (s, 3H, CH3), 3.29 (d, J = 6.1 Hz, 2H, PhCH2), 3.76 (s, 3H, OCH3), 4.31 (t, J = 6.0 Hz,
2H, NCH2), 4.72 (t, J = 6.0 Hz, 2H, OCH2), 5.04-5.07 (m, 2H, =CH2), 5.35 (s, 2H, NOCH2), 5.88-5.97 (m, 1H,
=CH), 6.63-7.62 (complex, 8H, aryl), 7.99 (s, 1H, C(5)-H of triazole). 13C NMR (75 MHz, CDCl3) δppm
=
12.50, 39.97, 52.36, 56.59, 67.74, 74.38, 112.43, 113.91, 116.32, 122.06, 128.46, 129.60, 130.21, 131.79,
132.94, 136.83, 137.75, 142.59, 148.00, 150.12, 155.87. MS (EI): m/z (%) = 406 (22.9) [M+]. Anal. Calc.
for C23H26N4O3: C, 67.96; H, 6.45; N, 13.78; found: C, 68.12; H, 6.31; N, 13.62.
2.9.10.(E)-2-(6-(4-((((1-Phenylethylidene)amino)oxy)methyl)-1H-1,2,3-triazol-1-yl)hexyl) isoindoline-1,3-
dione (13g)
Column chromatography on silica gel eluted with hexane/EtOAc (1:5) afforded pure product as orange
1
solid (347 mg, 78%); m.p. 90-91 °C. IR (KBr): 3041, 2964, 1715, 1618, 1473, 1406, 1061 cm-1. H NMR
(300 MHz, CDCl3) δppm = 1.37 (br s, 4H, N(triazole)-CH2CH2CH2CH2), 1.65 (br s, 2H, N(phthalimide)-
CH2CH2), 1.91 (br s, 2H, N(triazole)-CH2CH2), 2.22 (s, 3H, CH3), 3.62 (t, J = 6.5 Hz, 2H, N(phthalimide)-
CH2), 4.31 (t, J = 6.1 Hz, 2H, N(triazole)-CH2), 5.34 (s, 2H, NOCH2), 7.33-7.83 (complex, 10H, aryl, C(5)-H
of triazole). 13C NMR (75 MHz, CDCl3) δppm = 12.77, 26.82, 27.10, 28.54, 31.68, 40.60, 52.95, 67.87, 123.84,
128.95, 129.29, 129.60, 131.86, 132.45, 132.73, 137.04, 143.09, 155.99, 167.78. MS (EI): m/z (%) = 445
(24.3) [M+]. Anal. Calc. for C25H27N5O3: C, 67.40; H, 6.11; N, 15.72; found: C, 67.52; H, 6.27; N, 15.85.
10

3. Results and discussion
Journal Pre-proof
The first step of this synthetic approach is initiated by synthesis of (HEM Morph)N3. The procedure for
synthesis of (HEM Morph)N3 is shown in Scheme 2. As can be seen, the commercially available N-methyl
morpholine is N-alkylated via 2-bromoethanol in anhydrous MeCN to acquire (HEM Morph)Br as a white
solid (m.p.:150-152 °C). The obtained (HEM Morph)Br readily undergoes anion exchange with azide ion
using sodium azide in anhydrous methanol at room temperature. Afterward of filtering the precipitated
sodium bromide followed by evaporation of solvent in vacuo a yellow semi-solid (HEM Morph)N3 is
obtained (Figure 2) which melted at 90-95 °C.
O
O
O
N
NaN3
MeCN (anhyd.)
reflux, 24h
Br
N3
OH
NaBr
Br
OH
N
N
OH
MeOH (anhyd.),r.t., 24h
(HEM Morph)N3
(HEM Morph)Br
Scheme 2: Synthetic procedure for (HEM Morph)N3
Figure 2: The semi-solid status of synthesized (HEM Morph)N3
The FT-IR spectrum is a good criterion to indicate whether azide ion has been incorporated into (HEM
Morph)N3 structure or not. IR spectra of (HEM Morph)Br and (HEM Morph)N3 are shown in Figure 3. As
can be easily recognized from comparison of these spectra, an additional sharp peak at 2050 cm-1
1
13
in(HEM Morph)N3 is assigned to azide's stretching frequency. In addition, elemental analysis, H and C
NMR spectra have endorsed the synthesis and purity of (HEM Morph)N3.
11

Journal Pre-proof
Figure 3: The comparison of IR spectra of (HEM Morph)Br and (HEM Morph)N3
Figure 4: The thermogravimetric analysis of (HEM Morph)N3
Thermogravimetric (TGA) analysis for (HEM Morph)N3 conducted at weight of sample in heating rate of
10 °C min−1 in N2 atmosphere within temperature range 26–800 °C. The thermogram of (HEM Morph)N3
is shown in Figure 4. This thermogram indicates the thermal stability of (HEM Morph)N3 up to 150–200
°C with mass loss (≈ 4%) below 100 °C, due to removal of physically adsorbed water from the sample. As
indicated by TGA analysis, the thermal decomposition of (HEM Morph)N3 was initiated at a temperature
above 250°C and the endothermic peaks around 250–400°C correspond to thermal degradation of (HEM
Morph)N3. In general, the (HEM Morph)N3 nearly lost 67% of its overall weight at 800 °C.
12

After the preparation and characterization of (HEM Morph)N , the synthesis of target molecules was
Journal Pre-proof 3
initiated by synthesis of some commercial unavailable alkyl bromides 3a-c and 5a-c. To this end, the
reaction of potassium phthalimde with 1,n-dibromides in the presence of a catalytic amount of
tetrabutylammonium iodide (TBAI) in DMF at room temperature acquired phthalimidyl-functionalized
bromides 3a-c (Scheme 2A). Under the same circumstances, the reaction of phenolic compounds
comprising eugenol and β-naphtol with some 1,n-dibromides in the presence K2CO3 as a base and
tetrabutylammonium bromide (TBAB) in MeCN at reflux, provided phenolic-functionalized bromides 5a-
c(Scheme 2B). Inspired by the general structure of H1-antihistamines (first generation, Figure 1), three
types of symmetrical and unsymmetrical aromatic ketones involving 9-fluorenone, benzophenone and
acetophenone were used to synthesize the title compounds. In this context, the oximation of these
aromatic ketones 6 and 10 (Scheme 2C and 2D) using hydroxylamine hydrochloride in alkali ethanolic
solution at room temperature almost afforded the quantitative yields of the corresponding oximes 7 and
11. Next, the O-propargylation of oximes 7 and 11 by propargyl tosylate in the presence of KOH solution
in wet DMSO at room temperature gave O-propargyl oxime ethers 8 and 12. To our experience, the O-
propargylation of oximes via propargyl tosylate provided better results rather than propargylation using
propargyl chloride and/or bromide. The propargyl tosylate was prepared due to our previously reported
method in a high yield [51]. After obtaining the O-propargyl oxime ethers, the ‘Click’ Huisgen 3CRs
between O-propargyl oxime ethers, (HEM Morph)N3 and desire alkyl bromides were carried out to
obtain the final products (Scheme 2C and 2D). Since the (HEM Morph)N3 is a semisolid IL and displays a
dual role as an azidating agent as well as the reaction media, hence the progress of the reactions is
largely depended on the temperature effect. Since (HEM Morph)N3 is completely melted at 90-95 °C, the
default temperature was set to 90°C for ‘Click’ Huisgen 3CRs, but despite, this reaction was also tested at
diverse temperatures on a sample reaction which results are depicted in Table 1.
Table 1
Effect of temperature on progress of sample reaction
O
N
O
Br
N
CuI (cat.)
O
N3
N
+
+
°
T C
N
OH
N
N
8
9a
Entry a
T °C
r.t.
50
60
70
80
90
100
110
120
Time (h)
Isolated Yield(%)
1
2
3
4
5
6
7
8
9
36
20
15
12
8
4
4
4
4
30
44
51
58
61
84
84
85
84
13

Journal Pre-proof
a Condition: alkyne (1mmol), (HEM Morph)N3 (2 mmol), phenethyl bromide (1.2 mmol), CuI (5⨯10-5 mol)
As can be seen in Table 1, a sample reaction involving the reaction of alkyne 8, (HEM Morph)N3 and
phenethyl bromide in the presence of catalytic amount of CuI was tested at vary temperatures to acquire
compound 9a. The results are well indicating that by gradual increment in temperature, the yield
extensively improves. The highest yield is obtained when the temperature reached to 90 °C and more
(Table 1, entries 6-9). Further elevation in temperature higher than 90 °C has no distinguishable effect in
yield’s promotion.
The amount of this ABIL was also investigated for sample reaction and the results are summarized in
Table 2. As show in Table 3, the optimized amount of used (HEM Morph)N3 was also determined to be 2
equivalents per each reactants’ equivalent (Table 2, entry 3). Using (HEM Morph)N3 less than 2
equivalents defected in completion of reaction (Table 2, entries 1,2) since the lack of homogeneity in
media. However, exploiting the amounts more than 2 equivalents of (HEM Morph)N3 has no
distinguishable effect in progress of reaction (Table 2, entries 4-7).
Table 2
Effect of (HEM Morph)N3 amount on progress of sample reaction
O
N
O
Br
N
CuI (cat.)
O
N3
N
+
+
°
90 C
N
OH
N
N
8
9a
Entry a
mmol (HEM Morph)N3
Time (h)
Isolated Yield (%)
1
2
3
4
5
6
7
1
1.5
2
2.5
3
3.5
4
20
9
4
4
4
48
56
84
84
85
84
85
4.5
4.5
a Condition: alkyne (1mmol), (HEM Morph)N3 (x mmol), phenethyl bromide (1.2 mmol), CuI (5⨯10-5 mol)
To illustrate the efficiency of (HEM Morph)N3, it was studied the capability of (HEM Morph)N3 in
comparison with other yet reported and established ABILs in progress of sample reaction. In this regard,
we carried out the reaction under the influence of TBAN3, [BMIM][N3], [BMMIM[N3] and choline azide
The results are show in Table 3.
Table 3
The efficiency of (HEM Morph)N3 compare to other ABILs in progress of sample reaction
N
O
Br
N
CuI (cat.)
O
+
+
ABIL
°
90 C
N
N
N
14
8
9a

Journal Pre-proof
Entry a
ABIL
Time (h)
Isolated Yield (%)
1
2
3
4
5
(HEM Morph)N3
TBAN3
[BMIM][N3]
[BMMIM[N3]
choline azide
4
11
9
10
6
84
55
61
58
80
a Condition: alkyne ( 1mmol), ABIL ( 2 mmol), phenethyl bromide ( 1.2 mmol), CuI ( 5⨯10-5 mol)
As indicated in Table 3, beside (HEM Morph)N3 (Table 3, entry 1), the choline azide (Table 3, entry 5)
also displayed good yield of 9a, however in a longer reaction time, whereas the other tested ABILs
demonstrated the moderate yields of 9a compare to(HEM Morph)N3 (Table 3, entries 2-4). It is also
worth mentioning that the use of TBAN3, [BMIM][N3] and [BMMIM[N3] are accompanied with side
reactions and products as the result of internal collapse of ionic liquids into butyl azide and subsequent
‘Click’ Huisgen cycloaddition of butyl azide with alkyne 8 which result in synthesis of 9H-fluoren-9-one
O-(1-butyl-1H-1,2,3-triazol-4-yl)methyl oxime as a side product. Thus, performing three components
‘Click’ Huisgen cycloaddition is largely depended on stability of ABIL in which due to TGA analysis
(Figure 4), (HEM Morph)N3 exhibit good stability for ‘Click’ Huisgen cycloaddition.
15

Journal Pre-proof
Table 4
The structure of synthesized compounds
Entry
1
Structure
m.p. °C
137-138
Time (h) a
Isolated Yield(%) a
84
(
)
N
O
2
N
4
4
6
N
N
9a
(
)
N
O
O
3
N
83-84
80
82
N
N
2
3
9b
O
)
4
87-88
N
(
N
N
N
9c
O
O
(
)
123-124
8
77
N
O
O
2
N
N
N
N
N
N
4
O
13a
(
)
Ph 3 O
(
)
N
N
4
N
105-106
48-49
5
6
6
4
6
7
6
7
79
80
83
81
77
78
O
13b
(
)
N
N
O
4
O
N
N
MeO
13c
(
)
4 O
N
O
N
N
N
91-92
7
13d
O
(
)
6
N
O
N
N
N
N
N
123-124
59-60
8
O
(
13e
)
N
O
2
(
O
N
N
9
MeO
13f
O
)
N
N
O
6
N
N
N
90-91
10
O
13g
a These yields correspond to final step of synthesis.
After obtaining the optimized condition, it was screened the applicability of (HEM Morph)N3 in the
synthesis of other aromatic O-oxime ethers-1,2,3-triazole conjugates (Table 4). As shown in Table 4,
diverse symmetrical and unsymmetrical aromatic ketones were converted to their corresponding oximes
and tethered through the O-oxime ether bonds to 1,2,3-triazolyl moieties which are terminated to
aromatic residues comprising phenyl, aryloxy and phethalimidyl groups by different chains of carbon as
spacers. It is also worth mentioning that the oximation of unsymmetrical ketones (Table 4, entries 4, 9
and 10) traditionally generates two stereoisomer (Z) and (E), however the more stable (E)-isomer was
dominantly observed as indicated by NMR analysis. Additionally, very few (Z)-isomer (<4%) was formed
(indicated by HPLC analysis) which hardly detectable and isolable below the scale of 1 mol (%). Good
yields of title compounds were obtained utilizing (HEM Morph)N3 as reaction media and source of azide.
As explained before (see the experimental part), (HEM Morph)N3 can be extracted from the reaction
media. We carried out the recyclability test for (HEM Morph)N3 and studied the efficiency of regenerated
(HEM Morph)N3 on a sample reaction through five consecutive reaction runs. Through the each trial no
16

fresh (HEM Morph)N3 was added and the reused (HEM Morph)N3 was directly employed without further
Journal Pre-proof
purification. The results are recorded in Table 5. According to the results (Table 5), the (HEM Morph)N3
can be regenerated and reused for many sequential trials without significant loss of its activity.
Moreover, the recyclability and reusability of (HEM Morph)N3 is a good criterion for ionic liquid stability.
Table 5
Effect of regenerated (HEM Morph)N3 on progress of sample reaction
OH
N
N
O
O
N
N3
O
Br
+
N
N
°
CuI (cat.), 90 C
N
8
9a
Run
1
2
3
4
Time (h)
Isolated Yield (%)
4
4
4
4
4
84
84
79
79
78
5
a Condition: alkyne ( 1mmol), regenerated (HEM Morph)N3 ( 2 mmol), phenethyl bromide ( 1.2 mmol), CuI ( 5⨯10-
5 mol)
As discussed earlier, (HEM Morph)N3 and choline azide displayed better yields of 9a compare to other
tested ABILs (Table 3). Apart from their thermal stability, there should be another factor which assists
the better progress of the reaction compare to other examined ABILs. It is assumed that the hydroxyl
moiety in (HEM Morph)N3 and choline azide has a role in reaction progress. In this connection, it was
synthesized methyl propyl morpholinium azide (MP Morph)N3 in which the hydroxyl moiety in (HEM
Morph)N3 is replaced by methyl group. The sample reaction was reinvestigated by using (MP Morph)N3
instead of (HEM Morph)N3 under the optimized reaction condition. Unexpectedly, the isolated yield was
diminished to 60% and the reaction time was prolonged to 12 h. Thus, it is presumed that the hydroxyl
moiety has a synergic catalytic activity, potentially through the formation of hydrogen bond with
reactants. Thus in this context, a plausible mechanism is proposed in which hydroxyl ethyl residue in
(HEM Morph)N3 donates hydrogen bond to O-propargyl oxime ether (Scheme 3). Primarily, the alkyl
azide is formed by SN2-type reaction between azide ion and alkyl bromide (step i). The entrance of
cuprous species provides a complex between azide and alkyne (step ii) which converted to a cyclic
intermediate (step iii). This cyclic intermediate is then converted to a cuprous-1,2,3-triazole intermediate
(step iv) and eventually by absorbing a proton and detachment of cuprous, the 1,2,3-triazole adduct is
formed (step v).
17

Journal Pre-proof
O
O
N
O
N
Br-
Br-
Br
R'
N3
N
N
N
N
R'
O
H
O
H
O
H
N
N
N
R'
[Cu]
-H+
(ii)
[Cu]
O
R
O
R
O
R
N
N
N
(i)
R
R
R
(iii)
O
O
N
O
N
Br-
Br-
Br-
N
O
H
O
H
N
N
N
R'
O
H
N
H+
N
N
N R'
N
N
R'
[Cu]
O
R
N
O
R
O
R
(iv)
(v)
N
N
[Cu]
R
R
R
Scheme 3. A Plausible reaction mechanism for the synthesis of O-oxime ethers-1,2,3-triazole conjugates using
(HEM Morph)N3
4. Conclusions
In this work, we have explained the synthesis, characterization and application of hydroxyethyl methyl
morpholinium azide (HEM Morph)N3 as a new azide-based ionic liquid (ABIL). This yellowish semi-solid
ABIL could be melted at 90-95 °C and used as a source of azide as well as reaction media for three
components ‘Click’ Huisgen cycloaddition reaction between O-propargyl oxime ethers and alkyl
bromides to obtain the novel aromatic O-oxime ethers-1,2,3-triazole conjugates which structurally
resemble to first-generation of H1 antihistamines. Good to excellent yields of target products was
obtained utilizing (HEM Morph)N3. The impact of parameters like temperature, amount of IL and types of
ABIL was assessed. The (HEM Morph)N3 was believed to have a synergetic effect on the catalytic
synthesis of target compounds. The(HEM Morph)N3 is proved to be an efficient, thermally stable,
inexpensive, simple, recyclable and with cleaner reaction profile ABIL which can be easily synthesized
and used for ‘Click’ Huisgen cycloaddition and other related reactions.
Acknowledgements
The authors wish to thank Shiraz University of Technology research council for partial support of this
work.
18

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Highlights
 Hydroxyethyl methyl morpholinium azide (HEM Morph)N3 is a new ionic liquid
 The synthesis, characterization and application of (HEM Morph)N3 were described
 (HEM Morph)N3 is an azide source and media used in Click Huisgen cycloaddition
 Compounds similar to H1 antihistamines were synthesized using (HEM Morph)N3
 (HEM Morph)N3 is simple in synthesis, stable, inexpensive and recyclable
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Author Contribution Statement
Prof. Dr. M. N. Soltani Rad as a first corresponding authors was responsible for designing the research project.
Dr. S. Behrouz as a second corresponding author was responsible for data analysis.
Mr H. Saremi was responsible for synthesis of products.
Mr. J. Mohammadtaghi-Nezhad was responsible to synthesize the IL.
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Dear Editor,
There is no conflict of interest exits in the submission of this manuscript, and manuscript is also approved by my co-
author for publication. I would like to declare on behalf of my co-authors that the work described was original research
that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All
the authors listed have approved the manuscript that is enclosed.
Sincerely,
M. N. Soltani Rad
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