Three-component reaction between amines, carbon disulfide and electron-deficient derivatives of chloropyridine or chlorobenzene: Synthesis of 3,6-diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride and dithioylcarbamates derivatives

Article abstract of DOI:10.1007/s13738-013-0300-y

In this study, three-component reaction of some primary and secondary amines with carbon disulfide in the presence of electron-deficient derivatives of chloropyridine or chlorobenzene in the CH₃CN as a solvent is reported. The reaction of prima

Full text of DOI:10.1007/s13738-013-0300-y

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0300-y
ORIGINAL PAPER
Three-component reaction between amines, carbon disulfide
and electron-deficient derivatives of chloropyridine
or chlorobenzene: synthesis of 3,6-diazaspiro[4.5]deca-2,7,9-trien-
6
-ium chloride and dithioylcarbamates derivatives
Reza Ranjbar-Karimi
Mohammad Anary-Abbasinejad
•
Aliyeh Khajeh-Khezri
•
Received: 20 April 2013 / Accepted: 20 June 2013
Ó Iranian Chemical Society 2013
Abstract In this study, three-component reaction of some
primary and secondary amines with carbon disulfide in the
presence of electron-deficient derivatives of chloropyridine
allow the high efficient synthesis of complex molecules
starting from simple substrates in a one-pot manner [2–4].
New strategies for the synthesis of complex molecular
structures from easily available substrates by short and
effective routes have been investigated. As MCRs are one-
pot reactions, they are easier to carry out than multistep
syntheses [5–8]. These reactions are synthetically impor-
tant processes and convergent reactions, in which three or
more starting materials react and basically all or most of
the atoms contribute to the newly formed product [9].
These processes consisting of two or more synthetic steps,
which are carried out without isolation of any intermediate,
allow reducing time and saving money, energy, and raw
materials. Also, the development of simple synthetic routes
for widely used organic compounds from readily available
reagents is one of the major tasks in organic synthesis [10].
This methodology allows molecular complexity and
diversity to be created by the facile formation of several
new covalent bonds in a one-pot transformation. The
method closely approaches the concept of an ideal syn-
thesis, and it is particularly well adapted for combinatorial
synthesis [11]. For all these reasons, the development of
new multicomponent reactions is rapidly becoming one of
the frontiers of organic synthesis. Over the last years, the
preparation and reactions of new spiro-cyclic compounds
have been among our major research interests [12]. Spiro
compounds in which the spiro carbon atom is part of a
heterocyclic ring are of potential interest as biologically
active substances, components of photochromic systems,
and compositions for data recording [13]. Spiro heterocy-
clic compounds are well known to possess varied phar-
macological activities and hence their synthesis has always
been a challenge and an attraction to organic chemists [14].
These compounds, display pronounced antimicrobial [15],
analgesic [16], anti-inflammatory [16], antimycobacterial
or chlorobenzene in the CH CN as a solvent is reported.
3
The reaction of primary amines with carbon disulfide and
electron-deficient compounds of chloropyridine or chloro-
benzene after 6–8 h afforded the three-component addition
product. The reaction of secondary amines with carbon
disulfide and electron-deficient compounds of chloropyri-
dine or chlorobenzene after 3–4 h afforded the two-com-
ponent addition product. The product(s) of reactions were
purified by recrystallization or column chromatography
and their structures were identified by spectroscopy tech-
1
13
niques such as H-NMR, C-NMR, IR, UV and elemental
analysis. The reactions were carried out under mild con-
ditions and without using a catalyst.
Keywords Three-component reaction Á Carbon disulfide Á
Amines Á Electron-deficient Á Chloropyridine Á
Spiro compounds
Introduction
Modern synthetic design demands high efficiency in terms
of minimization of synthetic steps together with maximi-
zation of complexity [1]. One way to fulfill these goals is
the use of multicomponent reactions (MCRs) that consist
of several simultaneous bond-forming reactions which
R. Ranjbar-Karimi (&) Á A. Khajeh-Khezri Á
M. Anary-Abbasinejad
Department of Chemistry, Faculty of Science, Vali-e-Asr
University, 77176 Rafsanjan, Islamic Republic of Iran
e-mail: r.ranjbarkarimi@vru.ac.ir
123

J IRAN CHEM SOC
[
17], antifungal [18], antitumor [19, 20], and antiviral
and possible treatment of AIDS. This property of stabiliz-
ing high oxidation states in metal complexes reflects strong
o-bonding characteristic of these ligands. Although the
sulfur atoms of dithiocarbamate ligands possess o-donor
and n-back-donation characteristics of the same order of
magnitude, these ligands have a special feature in that there
is an additional n-electron flow from nitrogen to sulfur via
a planar delocalised p-orbital system [22]. In this paper, we
report three-component reaction (TCR) of 2-(amino
methyl) pyridine, carbon disulfide, and electron-deficient
derivatives of chloropyridine or chlorobenzene in dry
acetonitrile at room temperature for synthesis of some
spiro-cyclic compounds and also we further develop our
activities [19, 20]. Various approaches to prepare spiro-
cyclics have encountered problems associated with func-
tional group incompatibility at one or more stages and
restricted to a single substitution pattern. In only a few
instances, was the newly generated ring system left with a
useful functionality for further transformations. Therefore,
there is a need to develop new methods for the preparation
of the spiro-linkage under milder reaction conditions with
additional functionality for further synthetic manipulation
[
21]. Dithiocarbamates are a class of metal-chelating,
antioxidant compounds with various applications in medi-
cine for the treatment of bacterial and fungal infections,
Table 1 Reaction of 2-(amino
methyl) pyridine (1), carbon
disulfide (2) with electron-
deficient derivatives of
chloropyridine or
Electron-deficient
Chloropridine or Chlorobenzenye
dry CH CN
NH +
3
2
CS2
+
Product
N
rt
1
2
3
4
chlorobenzene (3) under room
temperature
a
Entry
1
chloropyridine or
Product
Time Yield
Mp (˚C)
178-184
chlorobenzene derivatives
(h)
(%)
NO2
Cl
N
S
S
2
H N
N
C
l
8
73
N
3a
NO
2
4
a
N
Cl
Cl
N
S
S
2
H N
2
N
N
NO2
6
77
67
176-183
125
O2
N
2
3
b
O
2
N
NO
4b
Cl
Cl
N
S
H
2
S
3
4
N
O2
6
8
O2
N
O
2
N
NO
2
3
c
4c
N
Cl
Cl
Cl
NH
2
N
60
200
N
S
(decompose)
3
d
N
S
Cl
H
2
N
N
N
S
S
4
d
N
Cl
S
S
N
N
5
6
N
N
7
8
78
137-145
NH
2
4
e
3
e
Cl
N
S
N
Cl
S
S
Cl
NH
2
N
N
N
S
NH2
N
N
81
140
Cl
S
N
Cl
N
Cl
(decompose)
S
NH
2
3f
4
f
Cl
a
Isolated yield
1
23

J IRAN CHEM SOC
studies to investigation on reaction of other primary and
secondary amines with carbon disulfide in the presence of
electron-deficient derivatives of chloropyridine or chloro-
338 nm which was also consistent with the conjugated
system.
Although we have not established a mechanism for the
formation of compounds 4a–f in an experimental manner, a
reasonable suggestion is shown in Scheme 1. It is reason-
able to assume that compound 4 results from the initial
addition of 2-(amino methyl) pyridine to carbon disulfide
to give zwitterionic active intermediate 9 which reacts with
the electron-deficient derivatives of chloropyridine or
chlorobenzene. Finally, cyclization yields the desired
product.
benzene in CH CN as a solvent.
3
Results and discussion
At the outset of our study, we investigated the three-
component condensation of 2-(amino methyl) pyridine (1)
with carbon disulfide (2) and electron-deficient derivatives
of chloropyridine or chlorobenzene (3) in dry acetonitrile
for 6–8 h at room temperature, after purified by recrystal-
lisation afforded 3,6-diazaspiro[4.5]deca-2,7,9-trien-6-ium
chloride derivatives (4a–f) in good yield (Table 1).
We also examined the similar reaction of the other
primary amines such as benzyl amine (5) with carbon
disulfide (2) and electron-deficient derivatives of chloro-
pyridine or chlorobenzene such as 2,3-dichloroquinoxaline
(3d) but the obtained product was different. The spectro-
scopic data of the product confirmed that these structures
belong to dithioylcarbamates derivatives (Scheme 2).
Finally, we also studied the three-component reaction of
secondary amines with carbon disulfide and electron-defi-
cient derivatives of chloropyridine or chlorobenzene in dry
acetonitrile for 3–4 h at room temperature, after purifica-
tion by recrystallisation, column chromatography on silica
gel afforded two-component product of this reaction (8a–c)
in excellent yield (Table 2).
The structures of compounds 4a–f were confirmed by
1 13
their elemental analyses and IR, H NMR, C NMR. The
IR spectrum of 4a showed a broad absorption band for the
-
1
amine salt group at 2,500–3,100 cm . The nitro stretching
vibrations were observed as strong absorption bands at
-
,556 and 1,397 cm . The H NMR spectra of compound
1
1
1
4
a which taken at 500 MHz, exhibited AB-quartet signal at
2
d = 4.18, 4.21 ppm ( J = -5.69 Hz), which arises
HH
from the CH diastereotopic protons. The protons of the
2
amine pyridine ring, aromatic group observed at
?
d = 7.45–7.96 and d = 8.64–8.75 ppm. The NH2 protons
The structures of compounds 8a–c were deduced from
1 13
their elemental analyses and IR, H NMR, C NMR. The
1
3
appeared as a broad signal at d = 8.58 ppm. The C NMR
spectrum of compound 4a showed 11 signals, in agreement
with the proposed structure. A signal was observed at
IR spectrum of 8a showed a strong absorption band for the
-
1
C=N group at 1,553 cm . The nitro stretching vibrations
were observed as strong absorption bands at 1,580 and
4
1
2.53 for methylene carbon and signals appeared at
20.23–154.26 for alkene and aromatic carbons. The UV
-
1
1
1,336 cm . The H NMR spectra of compound 8a con-
spectrum of the compounds showed strong peaks at 280,
sisted of a 4-H multiplet signal at d = 2.00 ppm
3
(
JHH = 6.5 Hz) for two CH groups of pyrrolidine, a 4-H
2
quartet signal for other two CH groups of pyrrolidine
2
3
(
d = 3.7 ppm, JHH = 7.0 Hz). The aromatic protons
showed characteristic signals between 7.69 and 8.87 ppm.
S
H
N
Cl
N
SH
13
The C NMR spectrum of compound 8a showed nine
NH2
+
S
C
S
H
N
R1
3
distinct resonances in agreement with the proposed
structure.
1
2
9
S
H
N
A suggested mechanism for formation of compounds
8a–c is shown in Scheme 3. It is reasonable to assume that
compound 8a–c results from the initial addition of N-
nucleophile amine 7a–c to carbon disulfide to give inter-
mediate 11 which due to reversible the first stage this
reaction and the higher nucleophilicity of secondary
amines than primary amines, the amine reacts with
R1
H
N
Cl
H
N
H
S
S
S
Cl, H
R1
N
1
0
4
a-f
Scheme 1 The proposed mechanism for the formation of 3,6-
diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride derivatives (4a–f)
Scheme 2 Reaction of benzyl
amine (5) with carbon disulfide
Cl
H
N
H
N
N
Cl
Cl
S
(
(
2) and 2,3-dichloroquinoxaline
3d)
dry CH CN
3
+
CS2
+
NH2
rt, 8h
S
N
N
Cl
5
2
3d
6
123

J IRAN CHEM SOC
Table 2 Reaction of secondary
amines (7), carbon disulfide (2)
with electron-deficient
Electron-deficient
Chloropyridine or Chlorobenzene
dry CH CN
3
Product
NHRR'+ CS2
+
rt
derivatives of chloropyridine or
chlorobenzene (3) under room
temperature
7
2
3
8
a
Entry
NHRR’
chloropyridine or
chlorobenzene
Product
Time Yield
Mp (˚C)
125-127
124-127
102-106
(h)
(%)
derivatives
NO2
NH
N
N
1
7a
N
Cl
3
55
NO2
3a
8a
H
N
NO2
O
N
N
2
3
N
Cl
4
4
70
56
O
7b
3a
NO2
8
b
Me
N
Cl
NO2
Me
HN
N
N
O N
2
7c
O N
NO2
3b
2
8c
a
Isolated yield
component reaction between secondary amines, carbon
disulfide and electron-deficient derivatives of chloropyridine
or chlorobenzene leading to synthesis of two-component
product from these reactions, because the first stage of these
reactions was reversible and the activity nucleophilic of
secondary amines than primary amines is higher, in outcome
the amine reacts with electron-deficient chloropyridine or
chlorobenzene compound. The features of this method
include the good yields of the product, mild reaction con-
dition, simple work-up processes, and also the substance can
be mixed without any activation, which make it a useful
process for the synthesis of these important compounds.
S
NHRR'
+
S C S
R'RN
SH
7a-c
2
11
Addition-Elimination
NHRR' +
Cl
R1
8a-c
R1
a-b
NRR'
3
Scheme 3 Suggested mechanism for formation of compounds 8a–c
electron-deficient chloropyridine or chlorobenzene com-
pound 3 and afforded two-component product.
Experimental section
Conclusion
All materials and solvents were purchased from Sigma-
Aldrich and Merck and were used without any additional
purification. FT-IR spectra of all the final products were
recorded on a Bruker instrument by using the KBr self-
In conclusion, this methodology has been found successful
in the reaction of 2-(aminomethyl) pyridine with carbon
disulfide and electron-deficient derivatives of chloropyridine
or chlorobenzene to achieve 3,6-diazaspiro[4.5]deca-2,7,9-
trien-6-ium chloride derivatives due to activation amino-
pyridine ring nitrogen. In contrast, other primary amines
such as benzyl amine, the major product is most likely
formed from the attack of the S-nucleophile and subsequent
formed dithioylcarbamates derivatives. Also, study three-
1
13
supported pellet technique. H and C NMR spectra were
recorded on a Bruker spectrometer at 500, 250, 125, 100,
62 MHz. NMR spectra were obtained in solution of
DMSO-d and CDCl using tetramethylsilane (TMS) as
6
3
internal standard. The elemental analysis for C, H, N and S
were performed using apparatus model CE-450 analyzer.
UV spectra were taken by UV–Visible Varian, model Cary
1
23

J IRAN CHEM SOC
1
00. The melting points of the products were determined in
mmax = 2,500–3,100 (br), 1,647, 1,587, 1,513, 1,348, 1,335,
-
1 1
open capillary tubes by using BAMSTEAB Electrothermal
apparatus model 9002. Column chromatography was per-
formed using silica (Merck #60). Silica plates (Merck)
were used for TLC analysis.
1,234, 1,111, 1,059, 829, 739 cm ; H-NMR (500 MHz,
DMSO-d ): d = 4.23, 4.25 (2H, AB-quartet,
J = -5.36 Hz, CH H ), 7.54 (1H, t, J = 5.60 Hz, H-8),
6
2
3
A
B
3
7.70 (1H, d, J = 7.80 Hz, H-10), 8.00 (1H, t,
3
3
J = 7.70 Hz, H-7), 8.68 (1H, d, J = 4.70 Hz, H-9), 8.68
?
4
General procedure for preparation of 3,6-
(2H, br, NH ), 9.18 (1H, d, J = 2.20 Hz, Ar–H), 9.45
2
4
13
(1H, d, J = 2.20 Hz, Ar–H) ppm; C-NMR (100 MHz,
diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride system
DMSO-d ): d = 42.25, 123.05, 123.69, 129.71 (2C ),
6
Ar
A solution of the 2-(amino methyl) pyridine 1 (1 mmol,
138.08, 141.76, 142.15, 148.18 (2C ), 148.34, 158.63
Ar
0
.108 g), Carbon disulfide 2 (3 mmol, 0.228 g) in dry
CH CN (5 mL) stirred for 15 min, and then derivatives of
(C=N) ppm; Anal. Calcd for C H ClN O S : C, 37.16; H,
1
2
10
5 4 2
2.60; N, 18.06 %. Found: C, 37.22; H, 2.65; N, 18.15 %;
UV–Vis (CH OH absolute): k = 280, 350 nm.
3
chloropyridine or chlorobenzene 3 (1 mmol) was added
and stirred at room temperature for several hours. After
completion of the reaction (indicated by TLC), the solid
3
max
2-[(2, 4-dinitrophenyl)thio]-1-thia-3,6-
product was filtered off, washed with CH CN and purified
3
diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride (4c)
by recrystallization.
2-(amino methyl) pyridine (1 mmol, 0.108 g), Carbon
2
-[(3-nitropyridine-2-yl) thio]-1-thia-3,6-
disulfide (3 mmol, 0.228 g), 1-chloro-2,4-dinitrobenzene
diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride (4a)
(1 mmol, 0.202 g) and dry CH CN (5 mL) at room tem-
3
perature gave product that was purified by recrystallization
2
-(amino methyl) pyridine (1 mmol, 0.108 g), Carbon
disulfide (3 mmol, 0.228 gr), 2-chloro-3-nitropyridine
1 mmol, 0.159 g) and dry CH CN (5 mL) at room tem-
from CH CN gave 2-[(2, 4-dinitrophenyl)thio]-1-thia-3,6-
3
diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride 4c, 0.26 g
(
(67 %), Green solid, mp: 125 °C; IR (KBr): mmax
2,600–3,100 (br), 1,650, 1,596, 1,520, 1,445, 1,338, 1,044,
=
3
perature gave product that was purified by recrystallization
-
1 1
1,005, 833, 773, 733 cm ; H-NMR (250 MHz, DMSO-
from CH CN gave 2-[(3-nitropyridine-2-yl) thio]-1-thia-
3
3
3
,6-diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride 4a,
.25 g (73 %), Green solid, mp: 178–184 °C; IR (KBr):
d ): d = 4.50 (2H, br, CH H ), 7.46 (1H, t, J = 5.30 Hz,
6
A B
3
H-8), 7.65 (1H, d, J = 8.00 Hz, H-10), 7.80 (1H, d,
0
3
3
J = 8.70 Hz, Ar–H), 7.90 (1H, td, J = 6.20 Hz, J =
4
mmax = 2,500–3,100 (br), 1,640, 1,582, 1,556, 1,494, 1,397,
-
1
1
,335, 1,255, 773, 741 cm ; H-NMR (500 MHz, DMSO-
3
1.50 Hz, H-7), 8.46 (1H, dd, J = 6.40 Hz, J = 2.50 Hz,
4
1
2
3
Ar–H), 8.63 (1H, d, J = 4.50 Hz, H-9), 8.82 (2H, br,
d ): d = 4.18, 4.21 (2H, AB-quartet, J = -5.69 Hz,
6
3
CH H ), 7.47 (1H, t, J = 5.40 Hz, H-8), 7.55 (1H, dd,
?
NH2 ), 8.96 (1H, d, J = 2.20 Hz, Ar–H) ppm; C-NMR
4
13
A
B
3
3
J = 7.00, 4.60 Hz, Ar–H), 7.60 (1H, d, J = 7.80 Hz,
(62 MHz, DMSO-d ): d = 42.93, 121.48, 123.52, 124.06
6
3
H-10), 7.90 (1H, td, J = 6.20 Hz, J = 1.50 Hz, H-7),
4
(2C ), 128.58, 135.82, 137.85, 138.30, 147.38, 148.76 (C–
Ar
?
.58 (2H, br, NH ), 8.64 (1H, d, J = 4.50 Hz, H-9), 8.69
3
8
NO ), 149.15 (C–NO ), 153.45 (C=N) ppm; Anal. Calcd
2
2
2
3
1H, dd, J = 7.00 Hz, J = 1.40 Hz, Ar–H), 8.74 (1H, dd,
4
(
3
for C H ClN O S : C, 40.36; H, 2.87; N, 14.48 %.
13 11 4 4 2
4
J = 3.20 Hz, J = 1.40 Hz, Ar–H) ppm;
13
C-NMR
Found: C, 40.41; H, 2.92; N, 14.50 %; UV–Vis (CH OH
3
(
125 MHz, DMSO-d ): d = 42.53, 120.28 (2C ), 123.50,
absolute): kmax = 290, 344 nm.
6
Ar
1
1
24.09, 135.02, 138.22, 141.78, 142.06, 142.55, 152.85,
54.26 ppm; Anal. Calcd for C H ClN O S : C, 42.04;
Synthesis of compound (4d)
1
2
11
4 2 2
H, 3.23; N, 16.34 %. Found: C, 42.12; H, 3.30; N, 16.43 %;
UV–Vis (CH OH absolute): k = 280, 338 nm.
2-(amino methyl) pyridine (1 mmol, 0.108 g), Carbon
disulfide (3 mmol, 0.228 g), 2,3-dichloroquinoxalin
3
max
2
-[(3, 5-dinitropyridine-2-yl) thio]-1-thia-3,6-
(1 mmol, 0.199 g) and dry CH CN (5 mL) at room tem-
3
diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride (4b)
perature gave product that was purified by recrystallization
from CH CN gave compound 4d, 0.15 g (70 %), Brown
3
2
-(amino methyl) pyridine (1 mmol, 0.108 g), Carbon
disulfide (3 mmol, 0.228 gr), 2-chloro-3,5-dinitropyridine
1 mmol, 0.203 g) and dry CH CN (5 mL) at room tem-
solid, MP: 200 °C (decompose); IR (KBr): mmax
2,500–3,100 (br), 1,641, 1,615, 1,549, 1,467, 1,357, 1,250,
=
-
1,126, 995, 888, 773 cm ; H-NMR (500 MHz, DMSO-
1 1
(
3
2
perature gave product that was purified by recrystallization
d ): d = 4.25, 4.26 [4H, AB-quartet, J = -5.35 Hz,
6
3
4
from CH CN gave 2-[(3, 5-dinitropyridine-2-yl) thio]-1-
3
2(CH H )], 6.90 (1H, td, J = 6.30 Hz, J = 0.80 Hz,
A B
3
Ar–H), 7.46 (1H, m, Ar–H), 7.50 [2H, t, J = 5.80 Hz,
thia-3,6-diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride 4b,
0
3
2(H-Alken)], 7.70 [2H, d, J = 7.80 Hz, 2(H-Alken)], 7.80
.3 g (77 %), Green solid, mp: 176–183 °C; IR (KBr):
123

J IRAN CHEM SOC
3
1H, dd, J = 7.80 Hz, J = 1.20 Hz, Ar–H), 8.05 [2H, td,
4
(
for 15 min, and then 2,3-dichloroquinoxaline (0.5 mmol,
0.099 g) was added, and stirred at room temperature for
several hours, After completion of the reaction (indicated
by TLC), The solid was filtered off and purified by re-
crystallisation from ethyl acetate gave 2-[(benzylcarbamo-
thioyl)thio]-3-chloroquinoxalin-1-ium chloride 6, 0.25 g
(72 %), Yellow solid, mp: 331–339 °C; IR (KBr):
mmax = 3,286, 2,700–3,100 (br), 3,001, 2,938, 2,863, 1,591,
1,526, 1,432, 1,360, 1,338, 1,284, 1,160, 1,129, 1,032, 923,
3
3
3
1
4
J = 6.40 Hz, J = 1.40 Hz, 2(H-Alken)], 8.40 (1H, dd,
4
J = 6.30 Hz, J = 0.80 Hz, Ar–H), 8.69 [2H, d,
?
J = 4.60 Hz, 2(H- Alken)], 8.76 [4H, br, 2(NH )] ppm;
2
3
C-NMR (100 MHz, DMSO-d ): d = 42.43, 119.43,
6
1
1
23.34, 125.52, 126.44, 128.07, 128.89, 135.13, 137.51,
53.35 (C=N), 158.66 (C=N) ppm.
2
-(pyrazin-2-ylthio)-1-thia-3,6- diazaspiro[4.5]
-
1
1
deca-2,7,9-trien-6-ium chloride (4e)
766, 742, 600 cm
3
;
H-NMR (500 MHz, DMSO-d6):
d = 5.00 (2H, d, J = 5.08 Hz, CH –NH), 7.37–7.46 (5H,
2
2
-(amino methyl) pyridine (1 mmol, 0.108 g), Carbon disul-
m, CH-aromatic), 7.52–7.66 (4H, m, CH-aromatic), 12.50
3
?
fide (3 mmol, 0.228 g), 2-chloropyrazin (1 mmol, 0.114 g)
(1H, t, J = 4.55 Hz, NH–CH ), 14.80 (1H, br, NH )
2
1
3
and dry CH CN (5 mL) at room temperature gave product
3
ppm; C-NMR (100 MHz, DMSO-d ): d = 47.93, 115.43,
6
that was purified by recrystallization from ethyl acetate gave
115.49, 125.56 (3C ), 127.14 (2C ), 128.17 (2C ),
Ar
Ar
Ar
2
-(pyrazin-2-ylthio)-1-thia-3,6-diazaspiro[4.5]deca-2,7,9-tri-
128.85 (2C ), 134.73, 137.31, 150.88, 179.28 ppm.
Ar
en-6-ium chloride 4e, 0.23 g (78 %), Green solid, mp:
1
37–145 °C; IR (KBr): mmax = 2,600–3,100 (br), 1,643,
General procedure for preparation of 3-nitro-2-
-
1
1
,498, 1,286, 1,245, 751 cm ; H-NMR (500.13 MHz,
1
(pyrrolidine-1-yl) pyridine (8a)
2
DMSO-d ): d = 4.20, 4.24 (2H, AB-quartet, J = -5.50 Hz,
6
3
CH H ), 6.6 (1H, t, J = 6.30 Hz, H-Alken), 7.65 (1H, d,
A solution of the pyrrolidine (2 mmol, 0.142 g), Carbon
A
B
3
3
J = 8.00 Hz, H-Alken), 7.80 (1H, d, J = 8.70 Hz, Ar–H),
disulfide (3 mmol, 0.228 g) in dry CH CN (5 mL) stirred
3
3
.90 (1H, td, J = 6.20 Hz, J = 1.50 Hz, H-Alken), 8.01
4
7
for 15 min, and then 2-chloro-3-nitropyridine (1 mmol,
0.159 g) was added, and stirred at room temperature for
several hours, After completion of the reaction (indicated
by TLC), the solvent was evaporated to yield the crude
product, which was then purified by column chromatog-
raphy on silica gel (ethyl acetate/n-hexane, 1:4) gave
3-nitro-2-(pyrrolidine-1-yl) pyridine 8a, 0.15 g (55 %),
orange red crystal, mp: 125–127 °C; IR (KBr):
mmax = 3,062, 2,924, 1,580.5, 1,553.4, 1,512, 1,444.8,
4
1H, d, J = 1.80 Hz, Ar–H), 8.46 (1H, dd, J = 6.40 Hz,
3
(
4
?
2
J = 2.50 Hz, Ar–H), 8.39 (2H, br, NH ), 8.63 (1H, d,
3 13
J = 7.50 Hz, H-Alken) ppm; C-NMR (62 MHz, DMSO-
d6): d = 42.33, 120.28, 121.75, 125.02, 131.31, 134.42,
138.65, 147.23, 148.35, 148.72, 155.26 (C=N) ppm; Anal.
Calcd for C H N S Cl: C, 44.21; H, 3.71; N, 18.75 %.
11 11 4 2
Found: C, 44.30; H, 3.75; N, 18.83 %.
-
1 1
Synthesis of compound (4f)
1,391, 1,336, 1,147.7, 1,069, 1,003.5, 748, 741 cm ; H-
NMR (500 MHz, DMSO-d ): d = 2.0 [4H, m, 2(CH )],
6
2
3
3.7 [4H, q, J = 7.0 Hz, 2(CH –N)], 7.7 (1H, dd, J = 8.0,
3
2
-(amino methyl) pyridine (1 mmol, 0.108 g), Carbon
disulfide (3 mmol, 0.228 g), cyanuric chloride (1 mmol,
.184 g) and dry CH CN (5 mL) at room temperature gave
2
3
4.6 Hz, Ar–H), 8.6 (1H, d, J = 8.0 Hz, Ar–H), 8.9 (1H, d,
3
13
0
J = 3.6 Hz, Ar–H) ppm;
C-NMR (125.75 MHz,
3
product that was purified by recrystallization from CH CN
3
CDCl ): d = 24.71 (CH ), 26.17 (CH ), 52.88 (CH –N),
3
2
2
2
gave compound 4f, 0.3 g (81 %), Brown solid, mp: 140 °C
decompose); IR (KBr): mmax = 2,600–3,100 (br), 1,735,
54.96 (CH –N), 122.65 (Ar–C), 133.34 (Ar–C–NO ),
2 2
(
146.15 (Ar–C–NO ), 151.13 (C=N), 153.23 (C=N) ppm;
2
1
,712, 1,641, 1,616, 1,536, 1,491, 1,412, 1,250, 1,127,
-
Anal. Calcd for C H N O : C, 55.95; H, 5.74; N,
11 3 2
9
1 1
72 cm ; H-NMR (500 MHz, DMSO-d ): d = 4.20, 4.22
7
21.75 %. Found: C, 56.01; H, 5.77; N, 21.86 %; UV–Vis
(CH OH absolute): k = 313, 362 nm.
6
2
[
6H, AB-quartet, J = -6.00 Hz, 3(CH H )], 7.4 [3H, t,
A B
3
max
3
3
J = 5.0 Hz, 3(H-Alken)], 7.5 [3H, d, J = 8.0 Hz, 3(H-
3
Alken)], 7.9 [3H, t, J = 8.0 Hz, 3(H-Alken)], 8.4 [6H, br,
4-(3-nitropyridine-2-yl) morpholine (8b)
?
(NH2 )], 8.6 [3H, d, J = 5.0 Hz, 3(H-Alken) ppm; C-
3
13
3
NMR (100 MHz, DMSO-d )]: d = 41.89, 123.52, 124.03,
Morpholine (2 mmol, 0.174 g), Carbon disulfide (3 mmol,
0.228 g), 2-chloro-3-nitropyridine (1 mmol, 0.159 g) in
6
1
38.99, 147.47, 149.88, 152.32, 154.48 ppm.
dry CH CN (5 mL) gave the product that was purified by
3
2
-[(benzylcarbamothioyl)thio]-3-chloroquinoxalin-1-ium
recrystallisation from ethyl acetate gave 4-(3-nitropyridine-
chloride (6)
2-yl) morpholine 8b, 0.2 g (70 %), gold solid, mp:
124–127 °C; IR (KBr): mmax = 2,920, 2,783, 2,719, 1,576,
A solution of the benzyl amine (1 mmol, 0.107 g), Carbon
1,502, 1,450, 1,431, 1,352, 1,308, 1,228, 1,101, 1,048,
-
1 1
872 cm ; H-NMR (500 MHz, CDCl ): d = 3.4 [2H, t,
disulfide (3 mmol, 0.228 g) in dry CH CN (5 mL) stirred
3
3
1
23

J IRAN CHEM SOC
3
J = 4.5 Hz, 2(CH –N)], 3.7 [2H, t, J = 4.5 Hz, 2(CH –
3
References
2
3
2
O)], 6.7 (1H, dd, J = 7.5, 4.5 Hz, Ar–H), 8.1 (1H, d,
3
3
J = 7.5 Hz, Ar–H), 8.3 (1H, d, J = 4.5 Hz, Ar–H) ppm;
1
. B.M. Trost, Science 254, 1471 (1991)
2. H. Bienayme, C. Hulme, G. Oddon, P. Schmidt, Chem. Eur. J. 6,
321 (2000)
1
3
C-NMR (125.75 MHz, CDCl ): d = 48.30 (2CH -N),
3
2
3
6
6.46 (2CH -O), 114.38 (Ar–C), 135.54 (Ar–C), 140.79
2
3. R.V.A. Orru, M. de Greef, Synthesis 1471 (2003)
4. I. Ugi, Pure Appl. Chem. 77, 187 (2001)
(
Ar–C–NO ), 143.34 (C=N), 156.20 (C=N) ppm; Anal.
2
5
6
7
. I. Ugi, B. Werner, A. Domling, Molecules 8, 53 (2003)
. A. Domling, Curr. Opin. Chem. Biol. 4, 318 (2000)
. A. Domling, Chem. Rev. 106, 17 (2006)
Calcd for C H N O : C, 51.67; H, 5.30; N, 20.09 %.
9 11 3 3
Found: C, 51.71; H, 5.32; N, 20.16 %; UV–Vis (CH OH
3
absolute): kmax = 340, 398 nm.
8. L. Weber, Curr. Med. Chem. 9, 1241 (2002)
. A. Domling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
0. R. Ranjbar-Karimi, K. Beiki-Shoraki, A. Amiri, Monatsh Chem.
41, 1101 (2010)
9
1
1
2
-(4-methylpiperidine-1-yl)-3, 5-dinitropyridine (8c)
1
1. A.D. Meijere, H. Nuske, M. Es-Sayed, T. Labahn, M. Schroen, S.
Brase, Angew. Chem. Int. Ed. 38, 3669 (1999)
4
-methylpiperidine (2 mmol, 0.216 g) Carbon disulfide
(
3 mmol, 0.228 gr, 2-chloro-3, 5-dinitropyridine (1 mmol,
.203 g) in dry CH CN (5 mL) gave the product that was
12. J. Frohlich, F. Sauter, C. Hametner, M. Pfalz, Arkivoc vi, 298
2009)
(
0
3
1
1
3. G.A. Shvekhgeimer, Chem. Heterocycl. Compd. 33, 367 (1997)
4. P. Hyeong-Beom, J.N. Hyun, H.J. Hee, C.J. Hoon, C. Jung-
Hyuck, Y.K. Ho, O. Chang-Hyun, Arch. Pharm. 340, 530 (2007)
purified by column chromatography on silica gel (ethyl
acetate/n-hexane, 1: 20) gave 2-(4-methylpiperidine-1-yl)-
3
1
1
, 5-dinitropyridine 8c, 0.15 gr (56 %), yellow crystal, mp:
02–106 °C; IR (KBr): mmax = 3,083, 2,947, 2,843, 1,597,
,571, 1,531, 1,310, 1,244, 1,130, 962, 827, 757 cm ; H-
15. G. Periyasami, R. Raghunathan, G. Surendiran, N. Mathivanan,
Eur. J. Med. Chem. 44, 959 (2009)
16. K.M. Amin, M.M. Kamel, M.M. Anwar, M. Khedr, Y.M. Syamb,
Eur. J. Med. Chem. 45, 2117 (2010)
17. R.R. Kumar, S. Perumal, S.C. Manju, P. Bhatt, P. Yogeeswari, D.
Sriram, Bioorg. Med. Chem. Lett. 19, 3461 (2009)
-
1
1
3
NMR (500 MHz, CDCl ): d = 1.0 (3H, d, J = 6.5 Hz,
3
CH ), 1.3 (2H, m, CH ), 1.6 (1H, m, CH), 1.8 (2H, m,
3
2
3
CH ), 3.1 (2H, t, J = 12.0 Hz, CH –N), 4.0 (2H, t,
1
8. A. Dandia, R. Singh, S. Khaturia, C. Merienne, G. Morgant, A.
Loupy, Bioorg. Med. Chem. 14, 2409 (2006)
9. G. Lang, A. Pinkert, J.W. Blunt, M.H.G. Munro, J. Nat. Prod. 68,
2
2
3
4
J = 11.5 Hz, CH –N), 8.8 (1H, d, J = 5.0 Hz, Ar–H),
2
1
4
.0 (1H, d, J = 5.0 Hz, Ar–H) ppm;
13
9
C-NMR
1
20. C.A. Maier, B. Wuensch, J. Med. Chem. 45, 438 (2002)
796 (2005)
(
125.75 MHz, CDCl ): d = 21.27 (CH ), 30.22 (CH),
3
3
21. S. Kotha, E. Manivannan, Arkivoc iii, 67 (2003)
22. H. Nabipour, S. Ghammamy, S. Ashuri, Z. Shokri, Org. Chem. J.
3
3.63 (2CH ), 48.67 (2CH –N), 128.50 (Ar–C), 131.81
2 2
(
Ar–C-NO ), 133.35 (Ar–C–NO ), 147.36 (C=N), 153.52
2 2
2
, 75 (2010)
(
C=N) ppm; Anal. Calcd for C H N O : C, 49.62; H,
11 14 4 4
5
.30; N, 21.04 %. Found: C, 49.71; H, 5.32; N, 20.96 %;
= 350, 415 nm.
UV–Vis (CH OH absolute): k
3
max
Acknowledgments The authors wish to thank Rafsanjan Vali-e-Asr
University (Rafsanjan, Iran) for the partial support of this work.
123