Solvent-free synthesis of substituted five membered heterocycles: One-pot reaction of primary amine and alkyl propiolate or isothiocyanate in the presence of oxalyl chloride

Article abstract of DOI:10.1016/j.cclet.2013.09.015

A novel, convenient and efficient approach to the synthesis of pyrrole and imidazole derivatives via the reaction between primary amines, alkyl propiolates or isothiocyanate and oxalyl chloride is described. The method offers several advantages including high yields of products and performing reaction under solvent-free conditions.

Full text of DOI:10.1016/j.cclet.2013.09.015

Chinese Chemical Letters 25 (2014) 159–162
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Chinese Chemical Letters
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Original article
Solvent-free synthesis of substituted five membered heterocycles:
One-pot reaction of primary amine and alkyl propiolate or
isothiocyanate in the presence of oxalyl chloride
Zinatossadat Hossaini
Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel, convenient and efficient approach to the synthesis of pyrrole and imidazole derivatives via the
reaction between primary amines, alkyl propiolates or isothiocyanate and oxalyl chloride is described.
The method offers several advantages including high yields of products and performing reaction under
solvent-free conditions.
Received 8 July 2013
Received in revised form 19 August 2013
Accepted 4 September 2013
Available online 5 November 2013
ß 2013 Zinatossadat Hossaini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Solvent-free condition
Primary amines
Pyrroles
Imidazole
Isothiocyanate
Alkyl propiolate
Oxalyl chloride
1. Introduction
muscarinic receptor agonist Pilocarpine [26] and the hypnotic agent
Etomidate [27]. Our research group reported the synthesis of a series
Five membered heterocycles with a nitrogen atom, such as
pyrroles and imidazoles, are important building blocks in a wide
number of biologically active compounds [1–6]. Among them,
pyrroles are heterocycles of great importance because of their
frequent presence in natural products similar to heme, chloro-
phyll, vitamin B12, and various cytochrome enzymes [7]. Some
recently isolated pyrrole-containing marine natural products
have been found to display significant cytotoxicity and function as
multidrug resistance (MDR) reversal agents [8]. Many of these
biologically active compounds function as chemotherapeutic
agents. Also, polysubstituted pyrroles are molecular structures
with immense importance in material science [9]. They have also
been employed as antioxidative [10], antibacterial [11,12],
ionotropic [13,14], antitumor [15], anti-inflammatory [16,17]
and antifungal agents [18]. Also, the imidazole system can be
found in numerous medically relevant compounds, such as the
fungicide Ketoconazole [19] and its family members,
the benzodiazepine antagonist Flumazenil [20], the antineoplas-
tic drug Dacarbazine [21], the antibiotic Metronidazole [22], the
antiulcerative agent Cimetidine [23], the antihyperthyroid
drug Methimazole [24], the prohormone Thyroliberin [25], the
of pyrroles and imidazoles using the reaction of primary amines
with either alkyl propiolates or isothiocyanates in the presence of
oxalyl chloride 3 under solvent-free conditions in good yields.
2. Experimental
All chemicals used in this work were purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were performed
using a Heraeus CHN-O-Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MAT 8430 spectrometer operating at
an ionization potential of 70 eV. IR spectra were measured on a
Shimadzu IR-460 spectrometer. 1H NMR and 13C NMR spectra were
measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1
and 125.8 MHz, respectively, and were obtained for solutions in
CDCl3 using TMS as the internal standard or 85% H3PO4 as the
external standard.
2.1. General procedure for preparation of compounds 4a–e
To a mixture of primary amine 1 (2 mmol) and alkyl propiolate
2 (2 mmol) was added oxalyl chloride 3 (2.5 mmol) at 50 8C. The
reaction mixture was then stirred for 3 h. After completion of
E-mail address: zshossaini@yahoo.com.
1001-8417/$ – see front matter ß 2013 Zinatossadat Hossaini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.09.015

160
Z. Hossaini / Chinese Chemical Letters 25 (2014) 159–162
R'O2C
H
O
Table 1
O
H
Optimization of reaction conditions of compounds 4a and 9a.
Solvent-free
50 oC, 3 h
Cl
+
+
RNH2
Entry Solventa
T (8C) Timeb (h) Yieldc (%) Timed (h) Yielde (%)
Cl
O
N
R
1
2
DMF
90
70
90
70
90
90
120
50
70
90
50
70
8
8
None
30
10
8
25
O
CO2R'
Toluene
Toluene
CH3CN
CH3CN
EtOH
45
1
2
4
3
8
38
8
45
3
4
10
10
10
10
8
50
6
54
R
1,4
Yield (%) of 4
R'
Me
5
50
8
55
6
Trace
Trace
None
None
None
90
24
24
10
10
10
8
Trace
Trace
None
None
None
80
a
90
95
Bn
7
EtOH
Me
b
c
4-MeC6H4CH2
8
H2O
9
H2O
8
n-Bu
95
90
95
Me
Et
10
11
12
H2O
8
Et
d
Solvent-free
Solvent-free
3
t-Bu
3
90
5
85
e
Et
a
The amount of solvent was 5 mL.
Time for synthesis 4a.
Isolated yield for 4a.
Scheme 1. Synthesis of compound 4 using primary amine, alkyl propiolate and
b
c
oxalyl chloride.
d
e
Time for synthesis 9a.
Isolated yield for 9a.
the reaction [TLC (AcOEt/hexane, 1:6, v/v) monitoring], the
reaction mixture was purified by flash column chromatography
on silica gel (Merck 230–400 mesh) using n-hexane–EtOAc as
eluent to afforded pure compounds 4 (Scheme 1).
3. Results and discussion
3.1. Pyrrole derivatives
Synthesis of pyrrole derivatives 4 using the reaction of primary
amines 1 and alkyl propiolate 2 in the presence of oxalyl chloride
3 under solvent-free conditions at 50 8C in good yields was
investigated.
The starting point for our experiments was to optimize the
reaction conditions such as solvent and reactions time for the
production of 1H-pyrrole and 1H-imidazol derivatives (Table 1).
Solvent free condition and 50 8C is suitable for synthesis of
compound 4a and solvent free condition and 70 8C is suitable for
synthesis of compound 9a.
2.2. General procedure for preparation of compounds 9a–e
To a mixture of primary amine 1 (2 mmol) and arylisothio-
cyanate 8 (2 mmol) was added oxalyl chloride 3 (2.5 mmol) at
70 8C. The reaction mixture was then stirred for 5 h. After
completion of the reaction [TLC (AcOEt/hexane, 1:4, v/v) monitor-
ing], the reaction mixture was purified by flash column
chromatography on silica gel (Merck 230–400 mesh) using n-
hexane–EtOAc as eluent to afforded pure compounds 9 (Scheme 2).
R'
N
C
S
S
O
Solvent-free
R
Cl
+
RNH2
N
N
+
Cl
70 oC, 5 h
O
O
O
R'
3
9
1
8
Yield (%) of 9
R
R'
1,8, 9
85
a
b
c
Bn
Me
OMe
Me
4-MeC6H4CH2
80
87
75
75
4-MeOC6H4CH2
NO2
d
e
n-Bu
OMe
Et
Scheme 2. Synthesis of compound 9 using primary amine, isothiocyanate and oxalyl chloride.
H
H
H
+
+
CO2R'
R
R
CO2R'
- HCl
NH
N
3
- HCl
R
CO2R'
H
4
1 + 2
N
H
Cl
-
-HCl
Cl
O
H
O
O
O
5
6
7
Scheme 3. Proposed mechanism for the synthesis of compound 4.

Z. Hossaini / Chinese Chemical Letters 25 (2014) 159–162
161
R'
S
R'
S
O
R'
S
+
R
O
Cl
R
N
N
Cl
R
N
H
O
N
1 + 2
N
H
10
N
H
O
HCl
O
O
HCl
3
Cl
11
9
Scheme 4. Proposed mechanism for the synthesis of compound 9.
Structures of compounds 4a–e were determined on the basis of
their IR, 1H NMR and 13C NMR spectra, and these data were showed
in Supporting information. The mass spectra of these compounds
display molecular ion peaks at the appropriate m/z values. For
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online version, at http://dx.doi.org/10.1016/j.cclet.2013.09.015.

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