Four-component synthesis of disubstituted 1,3,4-oxadiazoles from N-isocyaniminotriphenylphosphorane, phenylacetylenecarboxylic acid, chloroacetone derivatives, and primary amines

Article abstract of DOI:10.1080/00397911.2012.673447

The 1:1 imine intermediate generated by the addition of primary amine to chloroacetone derivatives is trapped by N-isocyaniminotriphenylphosphorane in the presence of phenylacetylenecarboxylic acid, leading to the formation of the corresponding iminophosp

Full text of DOI:10.1080/00397911.2012.673447

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Four-Component Synthesis of
Disubstituted 1,3,4-oxadiazoles From
N-Isocyaniminotriphenylphosphorane,
Phenylacetylenecarboxylic Acid, Chloroacetone
Derivatives and Primary Amines
Ali Ramazani a , Fatemeh Zeinali Nasrabadi a , Zahra Karimi a & Morteza Rouhani b
a Chemistry Department, Zanjan University, Zanjan, Iran
b Young Researchers Club, Zanjan Branch, Islamic Azad University, Zanjan, Iran
Accepted author version posted online: 02 Jan 2013.
To cite this article: Ali Ramazani , Fatemeh Zeinali Nasrabadi , Zahra Karimi & Morteza Rouhani (2013): Four-Component
Synthesis of Disubstituted 1,3,4-oxadiazoles From N-Isocyaniminotriphenylphosphorane, Phenylacetylenecarboxylic Acid,
Chloroacetone Derivatives and Primary Amines, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.673447
To link to this article: http://dx.doi.org/10.1080/00397911.2012.673447
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Four-component Synthesis of Disubstituted 1,3,4-Oxadiazoles from N-
Isocyaniminotriphenylphosphorane, Phenylacetylenecarboxylic Acid,
Chloroacetone Derivatives and Primary Amines
Ali Ramazani1,, Fatemeh Zeinali Nasrabadi1, Zahra Karimi1, Morteza Rouhani2
1Chemistry Department, Zanjan University, Zanjan, Iran, 2Young Researchers Club,
Zanjan Branch, Islamic Azad University, Zanjan, Iran
Corresponding author. Chemistry Department, Zanjan University, P O Box 45195-313,
Zanjan, Iran, Tel.: +98 241 5152572; fax: +98 241 5152477; E-mail:
aliramazani@gmail.com
Abstract
The 1:1 imine intermediate generated by the addition of primary amine to chloroacetone
derivatives is trapped by N-isocyaniminotriphenylphosphorane in the presence of
phenylacetylenecarboxylic acid leading to the formation of the corresponding
iminophosphorane intermediate. Disubstituted 1,3,4-oxadiazole derivatives are formed
via intramolecular aza-Wittig reaction of the iminophosphorane intermediate. The
reactions were completed in neutral conditions at room temperature. The disubstituted
1,3,4-oxadiazole derivatives, were prepared in excellent yields.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
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KEYWORDS: N-Isocyaniminotriphenylphosphorane, chloroacetone derivatives,
Phenylacetylenecarboxylic Acid, 1,3,4-Oxadiazole, Aza-Wittig reaction, Primary Amine
INTRODUCTION
In recent years, multicomponent reactions (MCRs) have become important tools in
modern preparative synthetic chemistry because these reactions increase the efficiency by
combining several operational steps without any isolation of intermediates or changes of
the conditions.1–9 This principle, therefore, is highly efficient in terms of time as well as
resources.10 Among the multicomponent reactions known to date, the most valuable
reactions are those based on isocyanides. Isocyanide-based multicomponent reactions
(abbreviated to IMCRs by Ugi and Dömling) by virtue of their synthetic potential, their
inherent atom efficiency, convergent nature, ease of implementation, and molecular
diversity, have attracted much attention because of the advantages that they offer to the
field of combinatorial chemistry.11-13
The intramolecular version of the aza-Wittig-type reaction has attracted considerable
attention recently because of its high potential for the synthesis of a wide variety of
nitrogen heterocycles, which can be attributed, in good measure, to the rapid progress in
the preparation of functionalized iminophosphoranes. Several interesting hetero-
cyclization reactions involving iminophosphoranes have been reviewed.14 These
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compounds can easily be converted through aza-Wittig reaction with isocyanates, carbon
dioxide, or carbon disulfide into functionalized hetero-cumulenes which exhibit a rich
chemistry of unusual synthetic promise.14-16 The nucleophilicity at the nitrogen is a factor
of essential mechanistic importance in the use of these iminophosphoranes as aza-Wittig
reagents. Iminophosphoranes are important reagents in synthetic organic chemistry,
especially in the synthesis of naturally occurring products, compounds with biological
and pharmacological activity.14-17 In the last years, several preparative procedures have
been reported for the preparations and synthetic applications of iminophosphoranes.17 N-
isocyaniminotriphenylphosphorane 4 is expected to have synthetic potential because it
provides a reaction system in which the iminophosphorane group can react with a
reagent having a carbonyl functionality.17 In recent years, we have established a one-pot
method for the preparation of organophosphorus compounds.18-24
1,3,4-Oxadiazoles have attracted interest in medicinal chemistry as surrogates of
carboxylic acids, esters, and carboxamides.25-27 They are an important class of
heterocyclic compounds that have a wide range of pharmaceutical and biological
activities including antimicrobial, anti-fungal, anti-inflammatory, antihypertensive,
analgesic, antibacterial, hypoglycemic, antimalarial, antitubercular and antidepressant.25-
27 Several methods have been reported in the literature for the synthesis of 1,3,4-
oxadiazoles. These protocols are multi-step in nature.28-30 The most general method
involves the cyclization of diacylhydrazides with a variety of reagents, such as thionyl
chloride, phosphorous oxychloride, or sulfuric acid, usually under harsh reaction
conditions.31 As part of our ongoing program to develop efficient and robust methods for
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the synthesis of heterocyclic compounds,32-42 we wish to report the preparation of a new
class of 1,3,4-oxadiazole derivatives 5a-t by a novel four-component condensation
reaction of chloroacetone derivatives 1, primary amine 2, N-
isocyaniminotriphenylphosphorane 4 and phenylacetylenecarboxylic acid 3 in excellent
yields under neutral conditions (Scheme 1).
RESULTS AND DISCUSSION
The 1:1 imine intermediate generated by the condensation reaction of primary amine 2
with chloroacetone derivatives 1 is trapped by the N-isocyaniminotriphenylphosphorane
4 in the presence of phenylacetylenecarboxylic acid 3 leading to the formation of 1,3,4-
oxadiazole derivatives 5 and triphenylphosphine oxide 6 (Scheme 1 and Table 1). The
reaction proceeds with the high efficiency towards the desired output products under mild
and neutral conditions and no side reactions were observed. The structures of the
products were deduced from their 1H NMR, 13C NMR, IR and Mass spectra.
4a: R1= CH3, R2= H, R= 4-methoxybenzyl; 4b: R1= CH2Cl, R2= H, R= 4-methoxybenzyl;
4c: R1= CH3, R2= H, R= allyl; 4d: R1= CH3, R2= H, R= 4-methylbenzyl; 4e: R1= CH3,
R2= H, R= benzyl 4f: R1= CH2Cl, R2= H, R= benzyl; 4g: R1= CH3, R2= H, R= furfuryl;
4h: R1= CH2Cl, R2= H, R= 4-methylbenzyl; 4i: R1= CH3, R2= H, R= 4-fluorobenzyl; 4j:
R1= CH2Cl, R2= H, R= naphthyl; 4k: R1= CH3, R2= Cl, R= 4-methoxybenzyl; 4l: R1=
CH3, R2= H, R= 2-chlorobenzyl; 4m: R1= CH2Cl, R2= H, R= furfuryl, 4n: R1= CH3,
R2= Cl, R= benzyl; 4o: R1= CH2Cl, R2= H, R= 2-chlorobenzyl; 4p: R1= CH3, R2= H, R=
3,4-dichorobenzyl; 4q: R1= CH3, R2= Cl, R= 4-methylbenzyl; 4r: R1= CH3, R2= H, R=
naphthyl; 4s: R1= CH3, R2= Cl, R= allyl; 4t: R1= CH2Cl, R2= H, R= allyl.
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A mechanistic pathway for the reaction is provided in Scheme 2. On the basis of the
chemistry of isocyanides, it is reasonable to assume that the first step may involve the
formation of imine 7 by the condensation reaction of primary amine 2 with chloroacetone
derivative 1, the next step may involve nucleophilic addition of the N-
isocyaniminotriphenylphosphorane 4 to the imine intermediate 7, which is facilitated by
its protonation with the phenylacetylenecarboxylic acid 3, leading to nitrilium
intermediate 8. This intermediate may be attacked by conjugate base of the carboxylic
acid to form 1:1:1 adduct 9. The intermediate 9 may undergo intramolecular aza-Wittig
reaction32–42 of iminophosphorane moiety with the ester carbonyl to afford the isolated
sterically congested 1,3,4-oxadiazole derivatives 5 by removal of triphenylphosphine
oxide 6 from intermediate 10. It seems that the intramolecular aza-Wittig reaction of
intermediate 9 occurs much faster than its acyl group migration such as in normal Ugi
reaction.12 We try to investigate the presented mechanism in the Scheme 2 by 13P NMR at
room temperature, but the detection of the intermediates at room temperature was fairly
impossible. It seems that the low life time of the intermediates at room temperature is the
reason of this impossibility. We hope to invetigate the mechanism by using dynamic 13P
NMR at low temperature in future studies.
CONCLUSIONS
We think that the reported method offers a mild, simple, and efficient route for the
preparation of sterically congested 1,3,4-oxadiazol derivatives of type 5. Ease of work-
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up, high yields and fairly mild reaction conditions make it a useful addition to modern
synthetic methodologies. Other aspects of this synthetic process are under investigation.
EXPERIMENTAL SECTION
General Procedures
N-Isocyaniminotriphenylphosphorane 4 was prepared based on reported procedures.17
Other starting materials and solvents were obtained from Merck (Germany) and Fluka
(Switzerland) and were used without further purification. The methods used to follow the
reactions are TLC and NMR. TLC and NMR indicated that there is no side product.
Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected.
1H and 13C- NMR spectra (CDCl3) were recorded on a BRUKER DRX-250AVANCE
spectrometer at 250.0 and 62.9 MHz, respectively. IR spectra were measured on a Jasco
6300 FTIR spectrometer. Elemental analyses were performed using a Heraeus CHN-O-
Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430 mass
spectrometer operating at an ionization potential of 70 eV. Preparative layer
chromatography (PLC) plates were prepared from Merck silica gel (F254) powder.
PREPARATION OF N-ISOCYANIMINOTRIPHENYLPOSPHORANE 4
CH2Cl2 (300 mL), PPh3 (52.5 g, 0.2 mol), NEt3 (23 mL) and formylhydrazine (5.1 g, 0.08
mol) were placed in a reaction flask. The slurry was then heated to 50–60 °C, and CCl4
(16.1 mL) was added dropwise over a period of about 30 min. The mixture was kept at
50–60 °C for at least 5–6 h. After cooling to room temperature, 100 mL of a saturated
aqueous Na2CO3 solution was added, the layers were separated, and the aqueous layer
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was washed with two 25 mL portions of CH2Cl2. The combined organic phases were
dried with Na2SO4 and filtered. After evaporation of the solvent, the residue was dried
under high vacuum, pulverised, stirred in 100 mL of ethanol/water (1:1.5) and collected
on a frit. Recrystallisation from hot ethanol yielded 7.0 g (30%) of an orange-brown
crystalline material 4 (m.p. 159–160 °C).17
GENERAL PROCEDURE FOR THE PREPARATION OF COMPOUNDS 5A-T
To a magnetically stirred solution of primary amine derivatives (1 mmol),
chloroacetone derivatives (1 mmol), and N-isocyaniminotriphenylphosphorane (1 mmol)
in CH2Cl2 (5 mL) was added dropwise a solution of phenylacetylenecarboxylic acid (1
mmol) in CH2Cl2 (5 mL) at room temperature over 15 min. The mixture was stirred for
12 h. The solvent was removed under reduced pressure, and the viscous residue was
purified by preparative layer chromatography (PLC) plates (Merck silica gel (F254)
powder; petroleum ether-ethyl acetate (4:1)). The characterization data of the compounds
are given below.
N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(4-METHOXYLBENZYL)AMINE (5A).
Yellow viscose oil; yield: 89%; 1H NMR (CDCl3): δ = 1.73 (s, 3H, CH3), 2.13 (s, 1H,
NH), 3.60 and 3.67 (ABq, J =12.3 Hz , 2H, CH2), 3.77 (s, 3H, OCH3), 3.90 and 3.99
(ABq, J = 11.3 Hz, 2H, CH2 of benzyl), 6.84 (d, J = 8.5 Hz, 2H, CH arom ), 7.23 (d, J =
8.5 Hz, 2H, CH arom), 7.39-7.65 (m, 5H, CHarom). 13C NMR(CDCl3): δ = 22.29 (CH3),
47.16, 50.07 (2CH2), 55.26 (OCH3), 57.73 (C-NH), 113.92, 128.70, 129.44, 130.73,
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132.36 (9CH), 73.41, 97.96, 119.67, 131.26, 154.94, (5C), 158.91, 168.36 (2C=N). IR
(KBr): ν = 3431, 2949, 2847, 2231, 1611, 1509, 1441, 1247, 822, 756, 688 cm-1. MS:
m/z (%); 382 (M+, 4), 345 (52), 211 (68), 136 (92), 121 (100), 91(32), 77 (60), 41(28).
Anal.Calcd.for C21H20ClN3O2 (381.12): C, 66.05; H, 5.28; N, 11.00 %. Found: C, 66.11;
H, 5.22; N, 11.06 %.
N-{2–CHLORO–1–(CHLOROMETHYL)–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(4-METHOXYBENZYL)AMINE (5B).
1
Yellow powder; yield: 92%; m.p. 82-84ºC; H NMR (CDCl3): δ = 2.06 (s, 1H, NH),
3.57 (s, 2H, CH2 of benzyl), 3.76 (s, 3H, OCH3), 4.16 (s, 4H, 2CH2), 6.84 (d, J = 7.5 Hz,
2H, CHarom), 7.19 (d, J = 7.5 Hz, 2H, CHarom), 7.40-7.66 (m, 5H, CHarom). 13C
NMR(CDCl3): δ = 44.34 (2CH2), 46.96 (CH2 of benzyl), 55.26 (OCH3), 61.51 (C-NH),
113.93, 128.73, 129.50, 130.87, 132.41 (9CH), 73.67, 97.24, 119.52, 130.35, 159.07
(5C), 164.92, 165.03 (2C=N). IR (KBr): ν = 3456, 2923, 2851, 2231, 1611, 1512, 1464,
1248, 823, 745 cm-1. MS: m/z (%); 416 (M+), 352 (20), 245 (20), 211 (56), 167 (28), 149
(52), 136 (64), 120 (84), 105 (100), 91 (21), 69(24), 41 (16). Anal.Calcd.for
C21H19Cl2N3O2 (416.30): C, 60.59; H, 4.60; N, 10.09%. Found: C, 60.64; H, 4.65; N,
10.14%.
N-ALLYL-N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL} AMINE (5C).
Yellow viscose oil; yield: 93%; 1H NMR (CDCl3): δ = 1.69 (s, 3H, CH3), 2.10 (s, 1H,
NH), 3.17 (m, 2H, CH2 of allyl), 3.87 and 3.91 (ABq, J = 11.3Hz, 2H, CH2), 5.20 (m,
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2H, =CH2), 5.85 (m, 1H, =CH), 7.41-7.61 (m, 5H, CHarom). 13C NMR(CDCl3): δ = 22.19
(CH3), 46.14, 50.02 (2CH2), 57.92 (C-NH), 128.70, 132.00, 132.35, 135.59 (6CH),
116.80 (=CH2), 73.54, 97.42, 119.72 (3C), 161.28, 168.46 (2C=N). IR (KBr): ν = 3436,
3924, 2852, 2231, 1644, 1538, 1443, 1022, 757, 688 cm-1. MS: m/z (%); 302 (M+, 15),
266 (11), 252 (46), 232 (23), 211 (100),129 (61), 96 (46), 70 (96), 56 (88), 42 (88).
Anal.Calcd.for C16H16ClN3O (301.77): C, 63.68; H, 5.34; N, 13.92%. Found: C, 63.74;
H, 5.40; N, 13.98%.
N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(4-METHYLBENZYL)AMINE (5D).
Yellow viscose oil; Yield: 89%; 1H NMR (CDCl3): δ = 1.74 (s, 3H, CH3), 2.07 (s, 1H,
NH), 2.31 (s, 3H, CH3), 3.64 and 3.69 (ABq, J = 12.5 Hz, 2H, CH2), 3.90 and 3.99 (ABq,
J = 11.3Hz, 2H, CH2 of benzyl), 7.13-7.64 (m, 9H, CHarom). 13C NMR(CDCl3): δ =
21.09, 22.26 (2CH3), 47.48, 50.09 (2CH2), 57.78 (C-NH), 128.18, 128.70, 129.20,
130.72, 132.36 (9CH), 72.81, 97.22, 119.68, 136.13, 137.00 (5C), 151.32, 168.36
(2C=N). IR (KBr): ν = 3440, 2922, 2852, 2231, 1635, 1515, 1446, 1097, 757, 688 cm−1.
MS: m/z (%); 366 (M+, 20), 330 (12), 275 (16), 211 (24), 196(12), 120(60), 105 (100), 77
(9), 42 (8). Anal.Calcd.for C21H20ClN3O (365.86): C, 68.94; H, 5.51; N, 11.49%. Found:
C, 68.99; H, 5.47; N, 11.44%.
N–BENZYL–N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}AMINE (5E).
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Yellow viscose oil; Yield: 90%; 1H NMR (CDCl3): δ = 1.74 (s, 3H, CH3), 2.12 (s,1H,
NH), 3.67 and 3.74 (ABq, J = 12.3 Hz, 2H, CH2), 3.91 and 4.01 (ABq, J = 11.3 Hz, 2H,
13
CH2 of benzyl), 7.27-7.65 (m, 10H, CHarom). C NMR(CDCl3): δ = 22.30 (CH3), 47.74,
50.09 (2CH2), 57.80 (C-NH), 127.36, 128.23, 128.53, 128.71, 130.75, 132.37 (10CH),
73.56, 95.04, 119.65, 139.18 (4C), 151.35, 168.30 (2C=N). IR (KBr): ν = 3441, 2923,
2852, 2231, 1636, 1540, 1496, 758, 737, 689 cm−1. MS: m/z (%); 352 (M+, 40), 316 (56),
261 (36), 211(12), 182 (20), 129 (12), 106 (24), 91 (100), 65 (9), 42 (9). Anal.Calcd.for
C20H18ClN3O (351.83): C, 68.28; H, 5.16; N, 11.94%. Found: C, 68.23; H, 5.21; N,
11.89%.
N–BENZYL–N-{2–CHLORO–1–(CHLOROMETHYL)–1-[5–(2-PHENYL-1-
ETHYNYL)-1,3,4-OXADIAZOL–2–YL]ETHYL}AMINE (5F).
Yellow powder; yield: 85%; m.p. 43-45 ºC; 1H NMR (CDCl3): δ = 2.12 (s, 1H, NH),
3.64 (s, 2H, CH2 of benzyl), 4.17 (s, 4H, 2CH2), 7.30-7.89 (m, 10H, CHarom). 13C
NMR(CDCl3): δ = 44.34 (2CH2), 47.53 (CH2 of benzyl), 61.60 (C-NH), 127.60, 128.26,
128.56, 128.74, 130.88, 132.41 (10CH), 73.55, 100.00, 119.58, 138.25, (4C), 164.87,
169.98 (2C=N). IR (KBr): ν = 3284, 2910, 2827, 2235, 1608, 1437, 1144, 781, 686 cm−1.
Anal.Calcd.for C20H17Cl2N3O (386.27): C, 62.19; H, 4.44; N, 10.88%. Found: C, 62.13;
H, 4.50; N, 10.82%.
N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(2-FURYLMETHYL)AMINE (5G).
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Yellow viscose oil; yield: 90%; 1H NMR (CDCl3): δ = 1.73 (s, 3H, CH3), 2.14 (s, 1H,
NH), 3.74 and 3.82 (ABq, J = 13.7 Hz, 2H, CH2), 3.88 and 3.96 (ABq, J = 11.3 Hz, 2H,
CH2 of benzyl ,), 6.13 (d, J = 2.7 Hz, 1H, CH of furfuryl), 6.27 (m, 1H, CH of furfuryl),
7.33 (m, 1H, CH of furfuryl), 7.39-7.64 (m, 5H, CHarom). 13C NMR(CDCl3): δ = 21.96
(CH3), 40.47, 50.01 (2CH2), 57.34 (C-NH), 107.38, 110.32, 128.71, 130.74, 132.36,
142.16 (8CH), 72.76, 97.27, 119.65, 151.36 (4C), 152.30, 168.02 (2C=N). IR (KBr): ν =
3426, 2923, 2225, 1650, 1539, 1442, 1150, 750, 688 cm−1. Anal.Calcd.for C18H16ClN3O2
(341.79): C, 63.25; H, 4.72; N, 12.29%. Found: C, 63.20; H, 4.77; N, 12.24%.
N-{2–CHLORO–1–(CHLOROMETHYL)–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(4-METHYLBENZYL)AMINE (5H).
Yellow powder; yield: 87%; m.p. 72-74 ºC; 1H NMR (CDCl3): δ = 2.07 (s, 1H, NH),
2.30 (s, 3H, CH3), 3.59 (s, 2H, CH2 of benzyl), 4.15 (s, 4H, 2CH2), 7.12-7.65 (m, 9H,
CHarom). 13C NMR(CDCl3): δ = 21.09 (CH3), 44.34 (2CH2), 47.27 (CH2 of benzyl), 61.55
(C-NH), 128.22, 128.73, 129.21, 130.86, 132.40 (9CH), 73.86, 87.45, 128.80, 135.23,
137.30 (5C), 165.76, 177.03 (2C=N). IR (KBr): ν = 3265, 3976, 2897, 2237, 1551, 1535,
1439, 1109, 805, 773, 685 cm−1. Anal.Calcd.for C21H19Cl2N3O (400.30): C, 63.01; H,
4.78; N, 10.50%. Found: C, 63.07; H, 4.72; N 10.44%.
N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(4-FLUOROBENZYL)AMINE (5I).
Yellow viscose oil; yield: 85%; 1H NMR (CDCl3): δ = 1.72 (s, 3H, CH3), 2.07 (s, 1H,
NH), 3.64 and 3.72 (ABq, J = 12.3 Hz, 2H, CH2), 3.85 and 3.95 (ABq, J = 11.5 Hz, 2H,
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CH2 of benzyl), 6.96-7.65 (m, 9H, CHarom). 13C NMR(CDCl3): δ = 22.34 (CH3), 46.97,
50.07 (2CH2), 57.74 (C-NH), 115.31 (2CH, d, 2JCF = 21.3 Hz), 128.71, 130.78,
132.37(5CH), 129.82 (2CH, d, 3JCF = 7.5 Hz ), 72.71, 97.37, 119.60, 135.00 (4C), 159.25
(1C, d, 1JCF = 220.16 Hz), 168.19, 151.37 (2C=N). IR (KBr): ν = 3456, 3269, 2927, 1608,
1449, 1069 cm−1. Anal.Calcd for C20H17ClFN3O (369.82): C, 64.95; H, 4.63; N, 11.36%.
Found: C, 64.90; H, 4.68; N, 11.41%.
N-{2–CHLORO–1–(CHLOROMETHYL)–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(1-NAPHTHYLMETHYL)AMINE (5J).
Yellow powder; yield: 88%; m.p. 90-92 ºC; 1H NMR (CDCl3): δ = 2.14 (s, 1H, NH),
4.07 (s, 2H, CH2 of benzyl), 4.22 (s, 4H, 2CH2), 7.24-8.07 (m, 12H, CHarom). 13C
NMR(CDCl3): δ = 44.30 (2CH2), 45.98 (CH2 of benzyl), 61.83 (C-NH), 125.39, 126.38,
126.98, 128.59, 128.73, 128.75, 130.92, 132.43, 133.85 (12CH), 72.07, 94.36, 119.85,
123.87, 125.89, 136.28 (6C), 165.32, 166.16 (2C=N). IR (KBr): ν = 3277, 2922, 2850,
2234, 1542, 1436, 1103, 731, 687 cm−1. Anal.Calcd.for C24H19Cl2N3O (436.33): C,
66.06; H, 4.39; N, 9.63%. Found: C, 66.11; H, 4.34; N, 9.58%.
N-{2,2–DICHLORO–1-METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}-N–(4- METHOXYBENZYL)AMINE (5K).
Yellow viscose oil; yield: 84%; 1H NMR (CDCl3): δ = 1.90 (s, 3H, CH3), 2.27 (s, 1H,
NH), 3.62 and 3.76 (ABq, J = 12.3 Hz, 2H, CH2 of benzyl), 3.77(s, 3H, OCH3), 6.21 (s,
1H, CH), 6.85 (d, J = 8.5 Hz, 2H, CHarom), 7.21 (d, J = 8.5 Hz, 2H, CHarom), 7.40- 7.66
(m, 5H, CHarom). 13C NMR(CDCl3): δ = 18.79 (CH3), 47.21 (CH2), 51.08 (C-NH), 56.66
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(OCH3), 63.37 (CH), 113.93, 128.71, 129.37, 130.80, 132.39 (9CH), 78.76, 93.34,
128.55, 130.90, 161.08 (5C), 165.43, 166.37 (2C=N). IR (KBr): ν = 3455, 2924, 2231,
1612, 1512, 1247, 757 cm−1. Anal.Calcd.for C21H19Cl2N3O2 (416.30): C, 60.59; H, 4.60;
N, 10.09%. Found: C, 60.54; H, 4.55; N, 10.04%.
N-(2–CHLOROBENZYL)–N–{2-CHLORO-1-METHYL–1-[5–(2-PHENYL-1-
ETHYNYL)-1,3,4-OXADIAZOL–2–YL]ETHYL}AMINE (5L).
Yellow powder; yield: 94%; m.p. 56-58 ºC; 1H NMR (CDCl3): δ = 1.76 (s, 3H, CH3),
2.29 (s, 1H, NH), 3.79 and 3.86 (ABq, J =13.0 Hz, 2H, CH2), 3.93 and 4.01 (ABq, J =
11.3 Hz, 2H, CH2 of benzyl), 7.16-7.65 (m, 9H, CHarom). 13C NMR(CDCl3): δ = 22.32
(CH3), 45.74, 50.12 (2CH2), 57.82 (C-NH), 127.03, 128.70, 128.85, 129.56, 130.27,
130.73, 132.37 (9CH), 72.56, 97.24, 119.55, 133.69, 136.58 (4C), 168.35, 172.15
(2C=N). IR (KBr): ν = 3286, 2969, 2921, 2224, 1600, 1545, 1459, 1129, 763, 691 cm−1.
Anal.Calcd.for C20H17Cl2N3O (386.27): C, 62.19; H, 4.44; N, 10.88%. Found: C, 62.15;
H, 4.48; N, 10.92%.
N-{2–CHLORO–1–(CHLOROMETHYL)–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(2-FURYLMETHYL)AMINE (5M).
Yellow viscose oil; yield: 88%; 1H NMR (CDCl3): δ = 1.87 (s,1H, NH), 3.73 (s, 2H, CH2
of benzyl), 4.15 (s, 4H, 2CH2), 6.10 (d, J = 2.7 Hz, 1H, CH of furfuryl), 6.26 (m, 1H,
CH of furfuryl), 7.33 (m,1H, CH of furfuryl), 7.40-7.65 (m, 5H, CHarom). 13C
NMR(CDCl3): δ = 40.28 (CH2 of benzyl), 44.19 (2CH2), 61.23 (C-NH), 107.77, 110.40,
128.74, 130.20, 132.40, 142.37 (8CH), 78.32, 93.16, 120.05, 157.27 (4C), 165.42, 166.12
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(2C=N). IR (KBr): ν = 3439, 2924, 2853, 2232, 1633, 1540, 1441, 1147, 740, 688 cm−1.
Anal.Calcd.for C18H15Cl2N3O2 (376.24): C, 57.46; H, 4.02; N, 11.17%. Found: C, 57.40;
H, 4.08; N, 11.11%.
N–BENZYL–N-{2,2–DICHLORO–1-METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-
1,3,4-OXADIAZOL–2–YL]ETHYL}AMINE (5N).
Yellow viscose oil; yield: 82%; 1H NMR (CDCl3): δ = 1.93 (s, 3H, CH3), 2.16 (s, 1H,
NH), 4.50 and 3.54 (ABq, J = 9.5 Hz, 2H, CH2 of benzyl), 6.06 (s, 1H, CH), 7.04-8.45
(m, 10H, CHarom). 13C NMR(CDCl3): δ = 22.20 (CH3), 52.04 (CH2), 58.46 (C-NH), 68.23
(CH), 128.71, 130.81, 132.41, (10CH), 86.52, 93.11, 119.95, 143.48 (4C), 152.88,
163.97 (2C=N). IR (KBr): ν = 3440, 3134, 2907, 2232, 1645, 1507, 1445, 1099, 756, 685
cm−1. Anal.Calcd.for C20H17Cl2N3O (386.27): C, 62.19; H, 4.44; N, 10.88%. Found: C,
62.13; H, 4.50; N, 10.82%.
N-(2–CHLOROBENZYL)–N-{2-CHLORO-1–(CHLOROMETHYL)–1-[5–(2-
PHENYL-1-ETHYNYL)-1,3,4-OXADIAZOL–2–YL]ETHYL}AMINE (5O).
Yellow powder; yield: 94%; m.p. 60-62 ºC; 1H NMR (CDCl3): δ = 2.25 (s, 1H, NH),
3.76 (s, 2H, CH2 of benzyl), 4.18 (s, 4H, 2CH2), 7.21-7.65 (m, 9H, CHarom). 13C
NMR(CDCl3): δ = 44.26 (2CH2), 45.04 (CH2 of benzyl), 61.58 (C-NH), 127.10, 128.74,
129.05, 129.64, 130.43, 132.43, 135.70 (9CH), 73.82, 90.06, 119.49, 130.89, 133.73
(5C), 158.22, 164.70 (2C=N). IR (KBr): ν = 3280, 2983, 2851, 2233, 1541, 1473, 1144,
752, 686 cm−1. Anal.Calcd.for C20H16Cl3N3O (420.72): C, 57.10; H, 3.83; N, 9.99%.
Found: C, 57.16; H, 3.77; N, 9.93%.
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N-{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(3,4-DICHLOROBENZYL)AMINE (5P).
Yellow powder; yield: 86%; m.p. 58-60 ºC; 1H NMR (CDCl3): δ = 1.70 (s, 3H, CH3),
2.06 (s, 1H, NH), 3.64 and 3.75 (ABq, J = 13.0 Hz, 2H, CH2), 3.89 and 4.01 (ABq, J =
11.5 Hz, 2H, CH2 of benzyl), 7.14-7.64 (m, 8H, CHarom). 13C NMR(CDCl3): δ = 22.37
(CH3), 46.52, 50.09 (2CH2), 57.73 (C-NH), 127.46, 128.72, 130.05, 130.36, 130.82,
132.39 (8CH), 72.61, 97.51, 119.55, 131.19, 132.46, 139.71 (6C), 151.40, 167.96
(2C=N). IR (KBr): ν = 3321, 3969, 2887, 2230, 1538, 1467, 1102, 751, 682 cm−1.
Anal.Calcd.for C20H16Cl3N3O (420.72): C, 57.10; H, 3.83; N, 9.99%. Found: C, 57.15; H,
3.88; N, 9.94%.
N-{2,2–DICHLORO–1-METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}-N–(4-METHYLBENZYL)AMINE (5Q).
1
Yellow viscose oil; yield: 83%; H NMR (CDCl3): δ = 1.89 (s, 3H, CH3), 2.31 (s, 3H,
CH3), 2.31 (s,1H, NH), 3.65 and 3.78 (ABq, J = 12.3 Hz, 2H, CH2 of benzyl), 6.21 (s,
1H, CH), 7.10- 7.76 (m, 9H, CHarom). 13C NMR(CDCl3): δ = 21.19, 18.00 (2CH3), 47.56
(CH2), 58.68 (C-NH), 63.46 (CH), 128.10, 128.71, 129.21, 130.92, 132.39 (9CH), 87.76,
95.44, 125.25, 137.03, 146.03 (5C), 162.23, 165.57 (2C=N). IR (KBr): ν = 3440, 2922,
2854, 2223, 1709, 1539, 1443, 1098, 803, 756, 688 cm−1. Anal.Calcd.for C21H19Cl2N3O
(400.30): C, 63.01; H, 4.78; N, 10.50%. Found: C, 63.06; H, 4.73; N, 10.55%.
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N–{2–CHLORO–1–METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-1,3,4-
OXADIAZOL–2–YL]ETHYL}–N-(1-NAPHTHYLMETHYL)AMINE (5R).
Yellow powder; Yield: 86%; m.p. 74-76 ºC; 1H NMR (CDCl3): δ = 1.83 (s, 3H, CH3),
2.14 (s,1H, NH), 3.97 and 4.09 (ABq, J = 11.3 Hz, 2H, CH2), 4.13 and 4.19 (ABq, J =
11.7 Hz, 2H, CH2 of benzyl), 7.39-8.12 (m, 12H, CHarom). 13C NMR(CDCl3): δ = 22.28
(CH3), 45.49, 50.01 (2CH2), 57.96 (C-NH), 123.74, 125.48, 125.79, 126.31, 126.75,
128.32, 128.51, 128.74, 130.78, 132.39 (12CH), 72.77, 92.54, 119.65, 131.72, 133.86,
134.66 (6C), 151.40, 168.32 (2C=N). IR (KBr): ν = 3273, 2962, 2850, 2230, 1540, 1636,
1481, 1093, 755, 702 cm−1. Anal.Calcd.for C24H20ClN3O (401.89): C, 71.73; H, 5.02; N,
10.46%. Found: C, 71.79; H, 5.08; N, 10.40%.
N-ALLYL-N-{2,2–DICHLORO–1-METHYL–1-[5–(2-PHENYL-1-ETHYNYL)-
1,3,4-OXADIAZOL–2–YL]ETHYL}AMINE (5S).
Yellow viscose oil; yield: 82%; 1H NMR (CDCl3): δ = 1.85 (s, 3H, CH3), 2.17 (s,1H,
NH), 3.17 and 3.27 (ABq, J =13.2 Hz, 2H, CH2 of allyl), 5.15 (m, 2H, =CH2), 5.82 (m,
1H, =CH), 6.16 (s, 1H, CH), 7.39- 7.65 (m, 5H, CHarom). 13C NMR(CDCl3): δ = 31.02
(CH3), 47.86 (CH2), 53.32 (C-NH), 71.16 (CH), 128.63, 128.71, 132.39, 135.82 (6CH),
117.56 (CH2), 75.06, 96.35, 117.23 (3C), 165.23, 168.87 (2C=N). IR (KBr): ν = 3456,
3924, 2852, 2232, 1644, 1539, 1443, 1095, 757, 687 cm−1. Anal.Calcd.for C16H15Cl2N3O
(336.22): C, 57.16; H, 4.50; N, 12.50%. Found: C, 57.11; H, 4.55; N, 12.45%.
N-ALLYL-N-{2–CHLORO-1-(CHLOROMETHYL)-1-[5–(2-PHENYL-1-
ETHYNYL)-1,3,4-OXADIAZOL–2–YL]ETHYL}AMINE (5T).
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Yellow viscose oil; yield: 87%; 1H NMR (CDCl3): δ = 1.82 (s, 1H, NH), 3.12 (d, 2H,
CH2 of benzyl), 4.12 (s, 4H, 2CH2), 5.12 (m, 2H, =CH2), 5.80 (m, 1H, =CH), 7.40-7.65
(m, 5H, CHarom). 13C NMR(CDCl3): δ = 44.34 (2CH2), 46.01 (CH2 of benzyl), 61.42 (C-
NH), 128.74, 130.89, 132.41, 134.86 (6CH), 117.24 (CH2), 82.36, 97.89, 119.47 (3C),
162.22, 164.85 (2C=N). IR (KBr): ν = 3440, 2924, 2852, 2232, 1644, 1539, 1440, 1147,
755, 688 cm−1. Anal.Calcd.for C16H15Cl2N3O (336.22): C, 57.16; H, 4.50; N, 12.50%.
Found: C, 57.11; H, 4.55; N, 12.45%.
For complete experimental and spectral details, please see the Supplementary
Information, available online.
ACKNOWLEDGEMENTS
This research was supported by the “Zanjan University” and the “Iran National Science
Foundation: INSF”.
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Scheme 1. Four-component synthesis of sterically congested 2,5-disubstituted 1,3,4-
oxadiazole derivatives 5.
ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
Scheme 2. proposed mechanism for the formation of sterically congested 2,5-
disubstituted 1,3,4- oxadiazole derivatives 5.
ACCEPTED MANUSCRIPT
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