The reaction of N -isocyaniminotriphenylphosphorane (NICITPP) with 2-oxopropyl-1-benzenecarbothioate and a primary amine in the presence of benzoic acid derivatives

Article abstract of DOI:10.1080/10426507.2015.1067213

Reactions of N-isocyaniminotriphenylphosphorane (NICITPP) with 2-oxopropyl-1-benzenecarbothioate in the presence of aromatic carboxylic acids and primary amines proceed smoothly at room temperature (18-26°C) and in neutral conditions to afford sterically

Full text of DOI:10.1080/10426507.2015.1067213

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
The Reaction of N-
Isocyaniminotriphenylphosphorane (Nicitpp)
with 2-Oxopropyl-1-Benzenecarbothioate and A
Primary Amine in the Presence of Benzoic Acid
Derivatives
Ali Ramazani, Fatemeh Zeinali Nasrabadi, Hamideh Ahankar, Pegah
Azimzadeh Asiabi, Fariba Sadri & Sang Woo Joo
To cite this article: Ali Ramazani, Fatemeh Zeinali Nasrabadi, Hamideh Ahankar,
Pegah Azimzadeh Asiabi, Fariba Sadri & Sang Woo Joo (2015): The Reaction of N-
Isocyaniminotriphenylphosphorane (Nicitpp) with 2-Oxopropyl-1-Benzenecarbothioate and A
Primary Amine in the Presence of Benzoic Acid Derivatives, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI: 10.1080/10426507.2015.1067213
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1067213
Accepted author version posted online: 30
Oct 2015.
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ACCEPTED MANUSCRIPT
THE REACTION OF N-ISOCYANIMINOTRIPHENYLPHOSPHORANE
(NICITPP) WITH 2-OXOPROPYL-1-BENZENECARBOTHIOATE AND A
PRIMARY AMINE IN THE PRESENCE OF BENZOIC ACID
DERIVATIVES
Ali Ramazani*,1, Fatemeh Zeinali Nasrabadi2, Hamideh Ahankar3, Pegah Azimzadeh Asiabi1, Fariba
Sadri4 and Sang Woo Joo5
1Department of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran,
2 Department of Chemistry, Islamic Azad University-East Tehran (Ghiam Dasht) of Branch, Tehran
(Iran).
3 Department of Chemistry, Abhar Branch, Islamic Azad University, P O Box 22, Abhar, Iran
4 Department of Chemistry, Payame Noor University, P O BOX 19395-4697 Tehran, Iran
5 School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea, E-
mail: swjoo@yu.ac.kr
*Corresponding Author E-mail: aliramazani@gmail.com
Abstract
Reactions
of
N-isocyaniminotriphenylphosphorane
(NICITPP)
with
2-oxopropyl-1-
benzenecarbothioate in the presence of aromatic carboxylic acids and primary amines proceed smoothly
at room temperature (18-26 °C) and in neutral conditions to afford sterically congested 1,3,4-oxadiazole
derivatives in high yields. The reaction progresses smoothly and clearly under mild conditions and no
side reactions were observed.
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N
N
CH3
H3C
C
R
O
O
Ar
+
CH2Cl2
r.t., 12 h
O
N
N
H
+
+
+
(Ph)3P=O
R
NH2
Ar
OH
N
S
S
P(Ph)3
O
O
Ph
Ph
Keywords
N-isocyaniminotriphenylphosphorane (NICITPP); 2-oxopropyl-1-benzenecarbothioate; aromatic
carboxylic acid; primary amine; 1,3,4-oxadiazole; aza-Wittig reaction
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INTRODUCTION
Multicomponent reactions (MCR) have emerged as an efficient and powerful tool in modern synthetic
organic chemistry due to their valued features such as atom economy, straightforward reaction design,
and the opportunity to construct target compounds by the introduction of several diversity elements in a
single chemical event. Typically, purification of products resulting from MCR is also simple since all the
organic reagents employed are consumed and are incorporated into the target compound.1 MCR, leading
to interesting heterocyclic scaffolds, are particularly useful for the construction of diverse chemical
libraries of „druglike‟ molecules. The isocyanidebased MCR are especially important in this area.2,3
Among the known multicomponent reactions to date, the most valuable reactions are those based on
isocyanides. Isocyanide-based multicomponent reactions (abbreviated to IMCRs by Ugi and Domling) by
virtue of their synthetic potential, their inherent atom efficiency, convergent nature, ease of
implementation, and the generation of molecular diversity, have attracted much attention because of the
advantages that they offer to the field of combinatorial chemistry.4,5
During the past few decades, a great deal of effort has been made to develop methodologies that form
carbonsulfur bonds in the synthesis of molecules with various biological applications. Thioacids have
little reactivity because of their low nucleophilic characteristic. But, the thioesters obtained from thioacids
as nucleophiles are synthetically much valuable due to their widespread application in pharmaceutical
chemistry and also they serve as key intermediates in the synthesis of various bioactive molecules.
Meanwhile, thioesters are used as coupling partners in organometallic reactions, building blocks for the
synthesis of heterocyclic compounds, and acyl transfer reactions.6-16 Also, thioesters are multipurpose
intermediates in natural products synthesis, which have multifarious applications in synthetic chemistry as
precursors to aldehydes, ketones, acids, esters, lactones, amides, lactams, and heterocycles.17,18
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Recently, the intramolecular version of the aza-Wittig-type reaction has attracted much attention
because it has exhibited high potential for the synthesis of a wide variety of nitrogen heterocycles, which
can be attributed to the rapid progress in the preparation of functionalized iminophosphoranes.19 Existence
of the nucleophilicity at the nitrogen is a factor of essential mechanistic importance by applying of these
iminophosphoranes as aza-Wittig reagents. Iminophosphoranes are so important reagents in synthetic
organic chemistry, in
especial in the synthesis of naturally occurring products, compounds with
biological and pharmacological activity.19-21 In recent years, several synthetic methods have been reported
for the preparation of N-isocyaniminotriphenylphosphorane (NICITPP) 6.22 There are several reports
on the use of 6 in the synthesis of metal complexes.22 Nevertheless, the organic chemistry of N-
isocyaniminotriphenylphosphorane
(NICITPP)
6
remains
almost
unexplored.
N-
Isocyaniminotriphenylphosphorane (NICITPP) 6 is expected to have synthetic potential because it
makes a reaction system in which the iminophosphorane group can react with a reagent having a carbonyl
functionality.23 Recently, we have established a one-pot method for the synthesis of organophosphorus
compounds.24-28
In recent years there has been considerable investigation on different classes of oxadiazoles.29-35 In
particular, compounds containing 1,3,4-oxadiazole nucleus have been shown to possess a wide range of
pharmacological and therapeutic activities.29-35 Some 2,5-disubstituted 1,3,4-oxadiazole derivatives have
exhibited analgesic, anti-inflammatory, anticonvulsant, tranquilizing, myorelaxant, antidepressant,
vasodilatatory, diuretic, antiulcer, antiarythmic, antiserotoninic, spasmolytic, hypotensive,
antibronchocontrictive, anticholinergic, and antiemetic activities.29-35 Furthermore, many 2,5-disubstituted
1,3,4-oxadiazole derivatives have been reported as active inhibitors of several enzymes.29-35 As part of our
ongoing program to develop efficient and robust methods for the synthesis of heterocyclic compounds,36-
45
we would like to report the preparation of a new class of 1,3,4-oxadiazole derivatives 7a-f by a novel
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four-component
condensation
reaction
of
2-oxopropyl-1-benzenecarbothioate
3,
N-
isocyaniminotriphenylphosphorane (NICITPP) 6, primary amine 4 and aromatic carboxylic acid 5 in
excellent yields under neutral conditions (Scheme 2).
RESULTS AND DISCUSSION
At first, we prepared the 2-oxopropyl-1-benzenecarbothioate 3 (Scheme 1);46 and then we used it in the
synthesis of 2-(arylamino)-2-(5-aryl-1,3,4-oxadiazol-2-yl)propyl-1-benzenecarbothioate derivatives 7
(Scheme 2). The 1:1 imine intermediate generated by the condensation reaction of primary amine 4 with
2-oxopropyl-1-benzenecarbothioate
3
is trapped by the N-isocyaniminotriphenylphosphorane
(NICITPP) 6 in the presence of aromatic carboxylic acids 5 leads to the formation of 1,3,4-oxadiazole
derivatives 7 and triphenylphosphine oxide 8 (Scheme 2). The reaction proceeds smoothly and cleanly
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. The
¹H NMR spectrum of 7a consisted of a singlet for the CH3 (δ= 1.76 ppm), a singlet for the NH (δ= 2.12
ppm, exchangeable by D2O), a singlet for the CH2 (δ= 3.74 ppm), ABq for the CH2 (δ= 3.76 and δ= 3.84
2
1
13
ppm, JHH = 14.0 Hz), and multiplet for the aromatic protons (δ=7.20-7.96 ppm). The H decoupled C
NMR spectrum of 7a showed 19 distinct resonances, partial assignment of these resonances is given in
1
13
the experimental section. The H and C NMR spectra of compounds 7b–f were similar to those of 7a,
except for the aromatic moieties, which exhibited characteristic signals with appropriate chemical shifts.
A mechanistic pathway for the reaction is provided in Scheme 3. On the basis of the chemistry of
isocyanides, it is reasonable to assume that the first step may involve the formation of imine 9 by the
condensation reaction of primary amine 4 with 2-oxopropyl-1-benzenecarbothioate 3, the next step may
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involve nucleophilic addition of the N-isocyaniminotriphenylphosphorane (NICITPP) 6 to the imine
intermediate 9, which facilitates by its protonation with the carboxylic acid 5, leading to nitrilium
intermediate 10. This intermediate may be attacked by conjugate base of the carboxylic acid to form 1:1:1
adduct 11. The intermediate 11 may undergo intramolecular aza-Wittig reaction36–49 of iminophosphorane
moiety with the ester carbonyl to afford the isolated sterically congested 1,3,4-oxadiazole derivatives 7 by
removal of triphenylphosphine oxide 8 from intermediate 12.
In summary, we think that the reported method offers a mild, simple, and efficient route for the
preparation of sterically congested 1,3,4-oxadiazole derivatives
7
from 2-oxopropyl-1-
benzenecarbothioate, N-isocyaniminotriphenylphosphorane (NICITPP) 6, aromatic carboxylic acids
and primary amines. Its ease of workup, high yields and fairly mild reaction conditions make it a useful
addition to modern synthetic methodologies.
EXPERIMENTAL
General
N-Isocyaniminotriphenylphosphorane (NICITPP) 6 was prepared based on reported
procedures.22 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. IR spectra were measured on a Jasco 6300 FTIR
1
spectrometer. H and 13C NMR spectra (CDCl3) were recorded on a BRUKER DRX-250 AVANCE
6
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spectrometer at 250.0 and 62.5MHz, respectively. Elemental analyses were performed using a Heraeus
CHN-O-Rapid analyzer. Mass spectra were recorded on a Finnigan MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. Preparative layer chromatography (PLC) plates were
prepared from Merck silica gel (F254) powder.
General Procedure for the Preparation of Compounds 7a-f
To a magnetically stirred solution of primary amine derivative (1 mmol; bezylamine, 0.107 g; 4-
methylbenzylamine, 0.121 g; 4-methoxylbenzylamine, 0.137 g), 2-oxopropyl-1-benzenecarbothioate (1
mmol, 0.194 g) and N-isocyaniminotriphenylphosphorane (NICITPP) (1 mmol, 0.302 g) in CH2Cl2 (5
mL) was added dropwise a solution of aromatic carboxylic acid (1 mmol; 4-bromobenzoic acid, 0.201
g; 3-chlorobenzoic acid, 0.157 g; benzoic acid, 0.122 g; 4-chlorobenzoic acid, 0.157 g) in CH2Cl2 (5
mL) at room temperature (18-26 °C) over 15 min. The mixture was stirred at the same temperature (18-
26 °C) for 12 h. The solvent was evaporated 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.
2-(benzylamino)-2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]propyl1-benzenecarbothioate (7a).
White powder (yield 92%), m.p 95-97°C, 1H NMR (CDCl3, 250 MHz): δH (ppm) 1.76 (s, 3H, CH3),
2
2.12 (s, 1H, NH), 3.74 (s, 2H, CH2), 3.76 and 3.84 (ABq, JHH = 14.0 Hz, 2H, CH2), 7.20-7.96 (m,
14H, CHarom,). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 23.21 (CH3), 37.51, 47.98 (2CH2), 56.94 (C-
NH), 127.20, 127.39, 128.17, 128.37, 128.46, 128.64, 132.35, 133.64 (14CH), 122.73, 126.44,
136.54, 139.52 (4C), 164.43, 169.02 (2C=N), 190.52 (C=O). IR (KBr) (õmax, cm−1): 3435, 2926, 2878,
7
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1673, 1603, 1492, 1206, 1074, 909, 832, 731, 688. Ms m/z (%) 508 (4), 358 (64), 278 (20), 132 (24),
105 (96), 91 (100), 77 (68), 65 (20), 51 (28). Anal.Calcd for C25H22BrN3O2S (508.43): C, 59.06; H,
4.36; N, 8.26. Found: C, 59.12; H, 4.30; N, 8.20.
2-(benzylamino)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl1-benzenecarbothioate (7b).
1
Yellow viscous oil (yield 88%), H NMR (CDCl3, 250 MHz): δH (ppm) 1.80 (s, 3H, CH3), 2.48 (s,
2
1H, NH), 3.77 (s, 2H, CH2), 3.79 and 3.87 (ABq, JHH = 13.6 Hz, 2H, CH2), 7.23-8.03 (m, 14H,
CHarom,). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 23.22 (CH3), 37.55, 47.03 (2CH2), 57.01 (C-NH),
125.12, 126.97, 127.27, 127.44, 128.24, 128.52, 128.70, 130.43, 131.83, 132.72 (14CH), 125.42,
135.18, 136.52, 139. 46 (4C), 164.06, 169.16 (2C=N), 190.56 (C=O). IR (KBr) (õmax, cm−1): 3422,
3062, 2923, 1720, 1665, 1551, 1448, 1206, 910, 773, 688. Anal.Calcd for C25H22ClN3O2S (463.11):
C, 64.72; H, 4.78; N, 9.06. Found: C, 64.78; H, 4.85; N, 9.12.
2-(benzylamino)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)propyl1-benzenecarbothioate (7c).
1
Yellow viscous oil (yield 83%), H NMR (CDCl3, 250 MHz): δH (ppm) 1.77 (s, 3H, CH3), 2.80 (s,
2
1H, NH), 3.74 (s, 2H, CH2), 3.77 and 3.86 (ABq, JHH = 13.7 Hz, 2H, CH2), 7.28-8.05 (m, 15H,
CHarom,). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 23.22 (CH3), 37.46, 48.04 (2CH2), 56.99 (C-NH),
127.02, 127.25, 127.44, 128.27, 128.50, 128.67, 129.06, 131.80, 133.65 (15CH), 123.82, 136.61,
139.46 (3C), 165.20, 168.81 (2C=N), 190.64 (C=O). IR (KBr) (õmax, cm−1): 3417, 2923, 2851, 1700,
1663, 1555, 1448, 1205, 909, 698. Anal.Calcd for C25H23N3O2S (429.15): C, 69.91; H, 5.40; N, 9.78.
Found: C, 69.84; H, 5.47; N, 9.71.
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2-(benzylamino)-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl1-benzenecarbothioate (7d).
1
Yellow viscous oil (yield 80%), H NMR (CDCl3, 250 MHz): δH (ppm) 1.81 (s, 3H, CH3), 2.15 (s,
2
1H, NH), 3.77 (s, 2H, CH2), 3.79 and 3.87 (ABq, JHH = 13.6 Hz, 2H, CH2), 7.21-8.01 (m, 14H,
CHarom,). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 23.23 (CH3), 37.52, 48.01 (2CH2), 56.97 (C-NH),
126.68, 127.24, 128.22, 128.50, 128.69, 129.43, 132.01, 133.70 (14CH), 122.28, 136.54, 138.05,
139.54 (4C), 164.38, 169.01 (2C=N), 190.58 (C=O). IR (KBr) (õmax, cm−1): 3398, 3060, 1735, 1665,
1608, 1437, 1206, 910, 722, 691. Anal.Calcd for C25H22ClN3O2S (463.11): C, 64.72; H, 4.78; N,
9.06. Found: C, 64.79; H, 4.71; N, 9.13.
2-[(4-methylbenzyl)amino]-2-(5-phenyl-1,3,4-oxadiazol-2-yl)propyl1-benzenecarbothioate (7e).
1
Yellow viscous oil (yield 75%), H NMR (CDCl3, 250 MHz): δH (ppm) 1.75 (s, 3H, CH3), 2.25 (s,
3H, CH3), 2.32 (s, 1H, NH), 3.69 (s, 2H, CH2), 3.76 and 3.84 (ABq, 2JHH = 13.7 Hz, 2H, CH2), 7.05-
8.03 (m, 14H, CHarom,). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 21.00, 23.20 (2CH3), 37.45, 47.74
(CH2), 56.84 (C-NH), 126.96, 127.39, 128.14, 128.61, 128.97, 129.11, 131.75, 133.64 (14CH),
123.70, 136.61, 136.73, 136.86 (4C), 169.29 (2C=N), 193.65 (C=O). IR (KBr) (õmax, cm−1): 3440,
2921, 2851, 1728, 1663, 1565, 1448, 1205, 910, 773, 688. Anal.Calcd for C26H25N3O2S (443.17): C,
70.40; H, 5.68; N, 9.47. Found: C, 70.33; H, 5.75; N, 9.40.
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2-[(4-methoxybenzyl)amino]-2-(5-phenyl-1,3,4-oxadiazol-2-yl)propyl1-benzenecarbothioate (7f).
1
Yellow viscous oil (yield 72%), H NMR (CDCl3, 250 MHz): δH (ppm) 1.75 (s, 3H, CH3), 2.16 (s,
1H, NH), 3.67 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 3.75 and 3.84 (ABq, 2JHH = 13.7 Hz, 2H, CH2), 6.78-
8.04 (m, 14H, CHarom,). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 23.24 (CH3), 37.44, 47.41 (CH2),
55.20 (OCH3), 56.82 (C-NH), 113.85, 126.96, 127.39, 128.61, 128.99, 129.38, 131.70, 133.56
(14CH), 120.85, 129.90, 136.67, 158.77 (4C), 168.34 (2C=N), 190.30 (C=O). IR (KBr) (õmax, cm−1):
3436, 2926, 2875, 1675, 1604, 1532, 1448, 1240, 1032, 910, 822, 773, 688. Anal.Calcd for
C26H25N3O3S (459.16): C, 67.95; H, 5.48; N, 9.14. Found: C, 67.88; H, 5.41; N, 9.21.
ACKNOWLEDGEMENTS
This research was supported by the “Iran National Science Foundation: INSF”.
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Scheme 1. Synthesis of 2-oxopropyl-1-benzenecarbothioate 3 in water.
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Scheme 2. Four-component synthesis of disubstituted 1,3,4-oxadiazole derivatives 7
7a: R=benzyl, Ar=4-bromophenyl; 7b: R=benzyl, Ar=3-chlorophenyl; 7c: R=benzyl, Ar=phenyl; 7d:
R=benzyl, Ar=4-chlorophenyl; 7e: R=4-methylbenzyl, Ar=phenyl; 7f: R=4-methoxylbenzyl,
Ar=phenyl.
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HO
Ar
5
R
N
O
O
O
- H2O
Ph
S
R
NH2
+
S
CH3
CH3
C
N
N P(Ph)3
CH3
6
O
3
9
4
R
N
O
CH3
HN
S
O
O
Ar
N
CH3
S
O
H3C
H3C
C
N
Ar
P(Ph)3
N
O
NH
O
R
(Ph)3P
11
10
R
HN
N
N
CH3
H3C
R
N
Ar
(Ph)3P=O
+
O
N
P(Ph)3
N
S
H
8
O
H3C
S
O
O
Ar
7
O
Ph
12
Scheme 3. Proposed mechanism for the formation of sterically congested 2,5-disubstituted 1,3,4-
oxadiazole derivatives 4.
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