4-Phenylsulfonyl-2,3,5,6-tetrachloropyridine: synthesis and synthetic utility

Article abstract of DOI:10.1007/s13738-016-1043-3

Abstract: 4-Phenylsulfonyl-2,3,5,6-tetrachloropyridine was synthesized from the reaction of sodium phenylsulfinate with pentachloropyridine in optimized reaction condition. The reaction of some mono- and bidentate N and O nucleophiles with 4-phenylsulfony

Full text of DOI:10.1007/s13738-016-1043-3

J IRAN CHEM SOC
DOI 10.1007/s13738-016-1043-3
ORIGINAL PAPER
4‑Phenylsulfonyl‑2,3,5,6‑tetrachloropyridine: synthesis
and synthetic utility
Reza Ranjbar‑Karimi1 · Alireza Poorfreidoni1
Received: 28 April 2016 / Accepted: 21 December 2016
© Iranian Chemical Society 2016
Abstract 4-Phenylsulfonyl-2,3,5,6-tetrachloropyridine
was synthesized from the reaction of sodium phenylsulfi-
nate with pentachloropyridine in optimized reaction condi-
tion. The reaction of some mono- and bidentate N and O
nucleophiles with 4-phenylsulfonyl-2,3,5,6-tetrachloropyr-
idine was studied in order to assess the impact of electron-
withdrawing functional group (PhSO2−) upon regiochem-
istry of aromatic nucleophilic substitution. Substitution
generally occurs at 4-position of pyridine ring, by less
steric hindrance nucleophiles although mixtures of prod-
ucts (ortho- and para-substituted) are obtained with more
steric hindrance cases. The structures of all the com-
1
pounds were confirmed by IR, H NMR and 13C NMR
spectroscopy as well as elemental analysis and X-ray
crystallography.
Graphical Abstract
4-Phenylsulfonyl-2,3,5,6-tetrachloropyridine: synthesis and synthetic utility
Reza Ranjbar-Karimi,∗ Alireza Poorfreidoni
Department of Chemistry, Faculty of Science, Vali-e-Asr University, Rafsanjan 77176, Islamic
Republic of Iran
Nu
Nu
Ph
SO2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
More hindrance Nu
Less hindrance Nu
N
N
+
N
r.t.
PhSO Na
DMF,
(2 eq.)
2
Ph
Cl
SO2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
Nu
N
* Reza Ranjbar-Karimi
r.ranjbarkarimi@vru.ac.ir
1
Department of Chemistry, Faculty of Science, Vali-e-Asr
University, Rafsanjan 77176, Islamic Republic of Iran
1 3

J IRAN CHEM SOC
Keywords Pentachloropyridine · Tetrachloropyridine ·
Nucleophilic · Substitution · Heterocycle · Synthesis
2,3,5,6-tetrachloro-4-methylsulfonylpyridine reacted at
4-position of ring with less-hindered nucleophiles such as
sodium methoxide and methylamine, while 2-substituted
product formed with larger nucleophiles such as dimethyl-
amine and pyrrolidine [27].
Introduction
In this paper, we would like to report the synthesis of
4-phenylsulfonyl-2,3,5,6-tetrachloropyridine 3 in one-pot
optimized reaction condition and highlight our initial inves-
tigations which demonstrate region-controlled nucleophilic
substitution of 3 with a wide range of nucleophiles.
Pyridines are of great interest as lead compounds in various
natural products [1, 2], pharmaceuticals [3] and functional
materials, such as scaffolds used in supramolecular chem-
istry [4]. A wide range of heterocyclic systems with low
molecular weight have found application in the life science
industries [5–9].
The synthesis of multifunctional heterocyclic core scaf-
folds is increasingly valuable, whereas it may be used as
excellent structures in parallel synthesis [10]. Conse-
quently, there exists a demand for the development of
effective methodology for preparation of appropriate poly-
functional heterocyclic scaffolds for library synthesis and
subsequent biological screening programs [11]. Multisub-
stituted pyridine systems and related bicyclic ring-fused
derivatives with a pyridine substructure have wide rang-
ing bioactivity. But due to the inherent low regioselectivity
and low reactivity of systems such as pyridine in function-
alization processes, it is difficult to access polyfunctional
heteroaromatic compounds from such systems [11]. Poly-
chloroheteroaromatic compounds have great interest in the
industry and showed a wide range of biological activities
such as herbicides and pesticides [12]. Perchloropyridines
such as tetrachloro-4-sulfanylpyridines2,3,5-trichloro-
4,6-bis-sulfanylpyridines and 3,5-dichloro-2,4,6-tris-sul-
fanylpyridines have found interest as bactericides [13], as
pesticides for controlling bacteria, insects, crustaceans,
fungi, nematodes, and weeds, and as host compounds
[14]. Perchloroheterocycles played an important role in the
synthesis of the corresponding perfluoro compounds. For
example, pentachloropyridine is used as intermediates for
the synthesis of other useful material such as pentafluoro-
pyridine [15]. Numerous surveys have been carried out on
nucleophilic substitution reactions of pentachloropyridine
[16–25]. The larger nucleophiles generally react preferen-
tially in the less-hindered 2-position of ring [18, 24, 25]. On
the other, small nucleophiles reacted with pentachloropyri-
dine at 4-position [17, 21, 22, 24]. However, the outcome
of nucleophilic substitution on pentachloropyridine is not
as clear-cut as it seems at the first sight. Therefore, substi-
tution reactions are often solvent dependent. For example,
reaction of pentachloropyridine gave almost exclusively the
2-substituted product with dimethylamine, pyrrolidine or
piperidine in benzene, whereas a mixture of the 2- and the
4-substituted products was formed in ethanol [18, 26].
Iddon and co-workers were synthesized of 2,3,5,6-tet-
Experimental
All solvents and starting materials were purchased com-
mercially (Merck). Solvents were dried using the literature
procedures and distilled before use. The HNMR spectra
1
were recorded at 400 and 300 MHz. The 13CNMR spectra
were recorded at 100 and 75 MHz. The elemental analy-
ses for C, H and N were performed using Heraeus CHN-O
rapid analyzer. TLC analysis was performed on silica gel
TLC plates (Merck).
Synthesis of 2,3,5,6‑tetrachloro‑4‑(phenylsulfonyl)‑
pyridine (3)
Pentachloropyridine 1 (0.251 g, 1 mmol) was added to a
solution of sodium benzenesulfinate 2 (0.328 g, 2 mmol)
in DMF (5 mL). The reaction mixture was stirred at room
temperature for 10 h. The precipitate was isolated by fil-
tration. Recrystallization from ethanol gave 2,3,5,6-tetra-
chloro-4-(phenylsulfonyl)pyridine 3 (0.25 g, 85%) as white
crystals; mp 216–219 °C. (Found: C, 36.8; H, 1.4; N, 3.7
C11H5Cl4NO2S requires: C, 37.0; H, 1.4; N, 3.9). IR (KBr):
νmax 1179.1, 1298.4 (SO2) cm−1 1H NMR (DMSO-d6,
.
300 MHz): δ 8.06 (d, 2H, J = 7.36 Hz, Ar–H), 7.86 (t, 1H,
J = 7.56 Hz, Ar–H), 7.72 (t, 2H, J = 7.48 Hz, Ar–H). 13C
NMR (DMSO-d6, 75 MHz): δ 149 (Ar–C), 146.8 (Ar–C),
139.3 (Ar–C), 135.8 (Ar–CH), 130.2 (Ar–CH), 129.4 (Ar–
C), 128.2 (Ar–CH).
General procedure for reaction of 2,3,5,6‑tetrachloro‑
4‑(phenylsulfonyl)pyridine 3 with bidentate
nucleophiles
Method a 2,3,5,6-Tetrachloro-4-(phenylsulfonyl)pyridine
3 (0.357 g, 1 mmol) was added to a solution of appropriate
nucleophile (1 mmol) and potassium carbonate (0.415 g,
3 mmol) or sodium ethoxide (0.068 g, 1 mmol, for 5c)
in 5 ml CH3CN or EtOH (for 5c). The reaction mixture
was stirred at room temperature or refluxed. The reaction
mixture was poured on water (10 ml) and extracted with
rachloro-4-methylsulfonylpyridine
in
three
steps
from pentachloropyridine [24]. They have shown that
1 3

J IRAN CHEM SOC
ethylacetate (3 × 8 ml), then dried with MgSO4 and solvent
evaporated. The product was obtained after purification
with column chromatography.
NMR (DMSO-d6, 300 MHz): δ 6.83 (1H, NH), 3.85 (2H,
CH2), 3.01 (2H, CH2). 13C NMR (DMSO-d6, 75): δ 150.4
(Ar–C), 145.5 (Ar–C), 114.1 (Ar–C), 59.8 (CH2), 42.6
(CH2).
Method b To a solution of the appropriate nucleophile
(1 mmol) and potassium carbonate (0.415 g, 3 mmol) or
sodium ethoxide (0.068 g, 1 mmol, for 5c) in CH3CN
or EtOH (for 5c) (4 mL) was added 2,3,5,6-tetrachloro-
4-(phenylsulfonyl)-pyridine 3 (0.357 g, 1 mmol). The
reaction mixture was irradiated with ultrasound for
8–60 min, and the progress of the reaction was moni-
tored by TLC. The reaction mixture was poured on water
(10 ml) and extracted with ethylacetate (3 × 8 ml),
then dried with MgSO4 and solvent evaporated. The
product was obtained after purification with column
chromatography.
N1,N3‑Bis(perchloropyridin‑4‑yl)propane‑1,3‑diamine
(5f)
Yield: (65%), yellow solid, mp 164–167 °C. (Found: C,
30.8; H, 1.4; N, 10.9 C13H8Cl8N4 requires: C, 30.9; H, 1.6;
1
N, 11.1). IR (KBr): νmax 3394.9, 3323.1 (NH) cm−1. H
NMR (DMSO-d6, 300 MHz): δ 6.74 (s, 1H, NH), 3.67 (2H,
CH2), 3.32 (NH), 1.83 (2H, CH2). 13C NMR (DMSO-d6,
75 MHz): δ 150.3 (Ar–C), 145.4 (Ar–C), 113.7 (Ar–C), 42
(CH2), 31.8 (CH2).
2‑((Perchloropyridin‑4‑yl)oxy)phenol (5g)
Yield: (45%), white solid, mp 154–157 °C. (Found: C,
40.4; H, 1.5; N, 4.4 C11H5Cl4NO2 requires: C, 40.6; H,
2,3,5,6‑Tetrachloro‑N‑ethylpyridin‑4‑amine (5a)
1
1.5; N, 4.3). IR (KBr): νmax 3422.4 (OH) cm−1. H NMR
Yield: (90%), white solid, mp 66–69 °C. (Found: C, 32.0;
H, 2.1; N, 10.5 C7H6Cl4N2 requires: C, 32.3; H, 2.3; N,
10.8). IR (KBr): νmax 3319.9 (NH) cm−1. 1H NMR (DMSO-
d6, 400 MHz): δ 3.74 (s, NH), 3.70 (q, 2H, J = 7.08 Hz,
CH2), 1.18 (t, 3H, J = 7.08 Hz, CH3). 13C NMR (DMSO-
d6, 100 MHz): δ 150.7 (Ar–C), 145.9 (Ar–C), 113.8 (Ar–
C), 40.4 (CH2), 17.1 (CH3).
(DMSO-d6, 300 MHz): δ 6.97–7.03 (5H, OH and Ar–H).
13C NMR (DMSO-d6, 75 MHz): δ 147.8(Ar–C), 141.9
(Ar–C), 140.4 (Ar–C), 139.7(Ar–C), 126.1 (Ar–CH), 125.5
(Ar–CH), 117.2 (Ar–CH), 117 (Ar–CH), 116.9 (Ar–C).
N1‑(Perchloropyridin‑4‑yl)benzene‑1,2‑diamine (5h)
Yield: (35%), purple solid, mp 213–216 °C. IR (KBr): νmax
1
2,3,5,6‑Tetrachloro‑N‑propylpyridin‑4‑amine (5b)
3318.9 (NH) cm−1. H NMR (DMSO-d6, 300 MHz): δ
9.98 (NH), 6.47–6.89 (4H, Ar–H), 4.98 (NH2). 13C NMR
(DMSO-d6, 75 MHz): δ 145.7 (Ar–C), 141 (Ar–C), 139.3
(Ar–C), 139 (Ar–C), 125.7 (Ar–CH), 125.2 (Ar–CH),
116.2 (Ar–CH), 116 (Ar–CH), 115.7 (Ar–C).
Yield: (85%), brown oil. (Found: C, 34.5; H, 2.5; N, 10.0
1
C8H8Cl4N2 requires: C, 35.1; H, 2.9; N, 10.2). H NMR
(DMSO-d6, 400 MHz): δ 3.61 (t, 2H, J = 7.16 Hz, CH2),
3.36 (s, NH), 1.55 (m, 2H, CH2), 0.856 (t, 3H, J = 7.36 Hz,
CH3). 13C NMR (DMSO-d6, 100 MHz): δ 150.7 (Ar–C),
145.9 (Ar–C), 114 (Ar–C), 47(CH2), 24.4 (CH2), 11.2
(CH3).
4‑(3,5,6‑Trichloro‑4‑(phenylsulfonyl)pyridin‑2‑yl)
morpholine (7a)
Yield (50%), yellow solid, mp 135–138 °C. (Found: C,
44.1; H, 3.0; N, 6.6; C15H13Cl3N2O3S requires: C, 44.2; H,
3.2; N, 6.9). IR (KBr): νmax 1170.8, 1348.4 (SO2) cm−1. 1H
NMR (DMSO-d6, 400 MHz): δ 8.04 (d, 2H, J = 8.4 Hz,
Ar–H), 7.83 (t, 1H, J = 7.56 Hz, Ar–H), 7.70 (t, 2H,
J = 8.32, Hz, Ar–H), 3.72 (t, 4H, J = 3.6 Hz, CH2), 3.32
(t, 4H, J = 4 Hz, CH2). 13C NMR (DMSO-d6, 100 MHz):
δ 157.82 (Ar–C), 147.2 (Ar–C), 146.4 (Ar–C), 140 (Ar–C),
136.4 (Ar–CH), 130.1 (Ar–CH), 128 (Ar–CH), 120.4 (Ar–
C), 119.6 (Ar–C), 66.2 (CH2), 49.9 (CH2).
2‑((Perchloropyridin‑4‑yl)amino)ethan‑1‑ol (5d)
Yield: (65%), yellow solid, mp 129–132 °C. IR (KBr): νmax
1
3547.1 (OH), 3307.2 (NH) cm−1. H NMR (DMSO-d6,
300 MHz): δ 6.45 (t, 1H, J = 5.65 Hz, NH), 4.91 (t, 1H,
J = 5.13 Hz, OH), 3.72 (m, 2H, CH2), 3.54 (m, 2H, CH2).
13C NMR (DMSO-d6, 75): δ 150.8 (Ar–C), 145.3 (Ar–C),
113.9 (Ar–C), 60.4 (CH2), 47.3 (CH2).
N1‑(Perchloropyridin‑4‑yl)ethane‑1,2‑diamine (5e)
4‑(Perchloropyridin‑4‑yl)morpholine (7b)
Yield: (80%), yellow solid, mp 107–110 °C. (Found: C,
30.3; H, 2.3; N, 15.0 C7H7Cl4N3 requires: C, 30.6; H, 2.6;
Yield: (25%), white solid, mp 79–82 °C. 1H NMR (DMSO-
d6, 400 MHz): δ 3.74 (t, 4H, J = 4.76 Hz, CH2), 3.34 (t,
1
N, 15.3). IR (KBr): νmax 3372.9, 3355.1 (NH2) cm−1. H
1 3

J IRAN CHEM SOC
4H, J = 4.48 Hz, CH2). 13C NMR (DMSO-d6, 100 MHz): δ
156.3 (Ar–C), 144.4 (Ar–C), 143.6 (Ar–C), 120.7 (Ar–C),
119.8 (Ar–C), 66.2 (CH2), 49.6 (CH2).
NMR (DMSO-d6, 300 MHz): δ 3.69 (t, 4H, J = 5.6 Hz,
CH2), 2.73 (t, 4H, J = 6 Hz, CH2), 6.6 (s, NH2). 13C NMR
(DMSO-d6, 75): δ 150.6 (Ar–C), 145.4 (Ar–C), 113.4 (Ar–
C), 48.3 (CH2), 44.7 (CH2).
1‑Methyl‑4‑(3,5,6‑trichloro‑4‑(phenylsulfonyl)
pyridin‑2‑yl)piperazine (7c)
X‑ray crystallography
Yield: (40%), yellow solid, mp 119–122 °C. IR (KBr):
Single-crystal X-ray data of the compound were collected
at 293(2) K on STOE IPDS 2T diffractometer with Mo
Kα radiation (λ = 0.71073 Å). The unit cell parameters’
refinement, data reduction and correction for Lp and decay
were performed using X-AREA [28] software. Absorption
corrections were applied using MULABS [29] routine in
PLATON [30]. The structures were solved by direct meth-
ods and refined by the least squares method on F2 using the
SHELXTL program package [31]. All of the calculations
were performed by PLATON. All non-hydrogen atoms
were refined anisotropically. The C-bound hydrogen atoms
were positioned geometrically and refined with a riding
model approximation with their parameters constrained to
the parent atom with Uiso (H) = 1.2 Ueq (C). The N-bound
hydrogen atom was located from the difference Fourier
map and constrained to refine with the parent atoms with
Uiso (H) = 1.2 Ueq (N). Crystallographic data for the struc-
tural analysis have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion no. CCDC 1443770 for the compound. Copy of this
information may be obtained free of charge via http://www.
ccdc.cam.ac.uk/conts/retrieving.html or from The Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
+44-1223-336-033; email: deposit@ccdc.ac.uk).
νmax 1347.7, 1175.6 (SO2) cm−1 1H NMR (DMSO-d6,
.
400 MHz): δ 8.04 (d, 2H, J = 8.28 Hz, Ar–H), 7.82 (t, 1H,
J = 7.64 Hz, Ar–H), 7.70 (t, 2H, J = 8.2 Hz, Ar–H), 3.32
(t, 4H, J = 4.44 Hz, CH2), 2.45 (t, 4H, J = 4.36 Hz, CH2),
2.23 (s, 3H, CH3). 13C NMR (DMSO-d6, 100 MHz): δ
157.9 (Ar–C), 147.1 (Ar–C), 146.4 (Ar–C), 140.1 (Ar–C),
135.4 (Ar–CH), 130.1 (Ar–CH), 128 (Ar–CH), 120.2 (Ar–
C), 119.2 (Ar–C), 54.547 (CH2), 49.3 (CH2), 46.1 (CH3).
6,7‑Dichloro‑1,4‑dimethyl‑8‑(phenylsulfonyl)‑1,2,3,4‑
tetra‑hydropyrido[2,3‑b]pyrazine (7d)
Yield: (80%), yellow solid, mp 99–102 °C. (Found:
C, 47.8; H, 3.0; N, 11.1; C15H15Cl2N3O2S requires: C,
48.4; H, 4.1; N, 11.3). IR (KBr): νmax 1320.1, 1145.6
1
(SO2) cm−1. H NMR (DMSO-d6, 300 MHz): δ 7.72 (d,
2H, J = 8.94 Hz, Ar–H), 7.65 (t, 1H, J = 7.07 Hz, Ar–H),
7.54 (t, 2H, J = 7.56 Hz, Ar–H), 3.4 (2H, CH2), 2.99 (s,
3H, CH3), 2.98 (2H, CH2), 2.93 (s, 3H, CH3). 13C NMR
(DMSO-d6, 75 MHz): δ 150.1 (Ar–C), 143 (Ar–C), 135.9
(Ar–C), 134.6 (Ar–C), 133.6 (Ar–CH), 129.2 (Ar–CH),
128.1 (Ar–C), 127.2 (Ar–CH), 126(Ar–C), 49 (CH2), 47.3
(CH2), 44.9 (CH3), 36.9 (CH3).
N1‑(2‑Aminoethyl)‑N1‑(3,5,6‑trichloro‑4‑
(phenylsulfonyl)‑pyridin‑2‑yl)ethane‑1,2‑diamine (7e)
Results and discussion
Yield: (70%), yellow solid, mp 98–101 °C. (Found: C,
42.0; H, 3.6; N, 12.5; C15H17Cl3N4O2S requires: C, 42.5; H,
4.0; N, 13.2). IR (KBr): νmax 3375.8, 3358.1 (NH2), 1358,
Initially, we optimized the reaction conditions for the one-
pot synthesis of 4-phenylsulfonyl-tetrachloropyridine 3
using pentachloropyridine 1 and sodium benzenesulfinate 2
(Table 1). In the first instance, the effect of solvent on the
yield of the product was evaluated. Among various sol-
vents tested, DMF yielded the best results, whereas DMSO
and CH3CN gave the products in low yields (Table 1, entry
5–8) and solvents such as glycerol and water were ineffec-
tive (Table 2, entry 1–4). The reaction gave moderate yield
in DMF at room temperature, and the yield of reaction
was reduced with enhancement of temperature (entry 10 in
Table 1). Next, we investigated the effect of mole ratio of
reactants on the synthesis of 4-phenylsulfonyl-tetrachloro-
pyridine. We found that the yield improved when the reac-
tion of pentachloropyridine 1 with sodium benzenesulfinate
2 was carried out in mole ratio of 1:2, respectively (entry
12 in Table 1). The yield was highly dependent upon the
reaction temperature, solvent and the mole ratio of starting
1
1151.2 (SO2) cm−1. H NMR (DMSO-d6, 300 MHz): δ
7.86 (2H, d, J = 7.08 Hz, Ar–H), 7.61 (t, 1H, J = 7.68 Hz,
Ar–H), 7.48 (t, 2H, J = 7.59 Hz, Ar–H), 6.64 (2H, NH2),
2.83 (1H, CH2), 2.74, (2H, CH2). 13C NMR (DMSO-d6,
75 MHz): δ 168.2 (Ar–C), 150.7 (Ar–C), 145.4 (Ar–C),
143 (Ar–C), 133.9 (Ar–CH), 129.1 (Ar–CH), 128.5 (Ar–
CH), 127.4 (Ar–CH), 127.9 (Ar–C), 113.9 (Ar–C), 48.3
(CH2), 45.4 (CH2).
N1‑(2‑Aminoethyl)‑N1‑(perchloropyridin‑4‑yl)
ethane‑1,2‑diamine (7f)
Yield: (15%), yellow solid, mp 147–150 °C. (Found:C,
32.9; H, 3.7; N, 16.5; C9H12Cl4N4 requires: C, 33.9; H, 3.8;
1
N, 17.6). IR (KBr): νmax 3391.1, 3347.5 (NH2) cm−1. H
1 3

J IRAN CHEM SOC
Table 1 Optimization of reaction conditions for the formation of 3
at δ = 3.74 ppm for NH, one quartet at δ = 3.70 ppm for
CH2 and one triplet at δ = 1.18 ppm for CH3. There are
no signals for aromatic hydrogens. And13CNMR spectrum
confirmed the presence of CH2 and CH3 at δ = 40.4 and
17.1 ppm, respectively. In IR spectra, NH stretching bond
appeared at 3319.9 cm−1. Similarly, the reaction of pro-
pylamine 4b with 3 gave 2,3,5,6-tetrachloro-N-propylpyri-
din-4-amine 5b in good yield (Table 2, entry 2). Reaction
of sodium ethoxide 4c with 3 gave 2,3,5,6-tetrachloro-
4-ethoxypyridine 5c in moderate yield (Table 2, entry 3)
[32]. Reaction of ethanolamine 4d with 3 gave 2-((perchlo-
ropyridin-4-yl)amino)ethan-1-ol 5d (Table 2, entry 4) aris-
ing from replacement of phenylsufonyl group by nitrogen
atom of ethanolamine. 1HNMR spectrum of compound
5d showed two triplets peak at δ = 6.45 and 4.91 ppm for
NH and OH and two multiplets at δ = 3.72 and 3.54 ppm
for two CH2 groups. Similarly, the reaction of ethylen-
diamine 4e with 3 gave N1-(perchloropyridin-4-yl)ethane-
1,2-diamine 5e (Table 2, entry 5). Also reaction of propane
1,3-diamine 4f with 3 gave N1,N3-bis(perchloropyridin-
Entry Mole ratio
(1:2)
Solvent Temperature Time (h) Yield (%)
(°C)
1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:2
1:2.5
H2O
H2O
r.t.
12
12
12
12
12
10
12
10
48
10
10
10
10
–
2
100
–
3
Glycerol r.t.
Glycerol 100
CH3CN r.t.
CH3CN 60
DMSO r.t.
DMSO 50
–
4
trace
25
20
40
35
50
40
58
85
60
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
r.t.
50
r.t.
r.t.
r.t.
10
11
12
13
1
4-yl)propane-1,3-diamine 5f (Table 2, entry 6). HNMR
of compound 5f showed two singlet peaks at 6.74 and
3.32 ppm for two NH. Chemical shifts of CH2 groups were
located at 3.67 and 1.83 ppm.
Bold values indicate better results than other reaction conditions
materials. The optimum reaction condition for the synthesis
of 4-phenylsulfonyl-tetrachloropyridine 3 was found to be:
pentachloropyridine (1 equiv), sodium benzenesulphinate (2
equiv), at room temperature with DMF (5 mL) as the solvent.
The structure of 3 was confirmed with IR, NMR and ele-
mental analysis. The IR spectrum of 3 showed two absorp-
tion band at 1179.1 and 1298.4 cm−1 for SO2 stretching.
Reaction of primary aromatic N and O nucleophiles, 4g
and 4h with 3 (Table 2 entries 7, 8) led to the 5g and 5h,
respectively, arising from substitution of the most activated
PhSO2 group at the 4-position of the pyridine ring. These
reactions required extended reaction times and refluxed to
proceed to completion.
With these successful and clean reactions in hand, we
then proceeded to investigate other nucleophiles (Table 3
entry 1–4). In each of these cases, mixtures of products
resulting from competing substitution at the positions
ortho and para to the ring nitrogen were obtained, which
could be separated by column chromatography, with sub-
stitution at the position ortho to the ring nitrogen appear-
ing to dominate. Reaction of morpholine 6a with 3 in the
presence of potassium carbonate gave 4-(3,5,6-trichloro-4-
(phenylsulfonyl)pyridin-2-yl)morpholine 7a (50% yield)
and 4-(perchloropyridin-4-yl)morpholine 7b (25% yield).
Similarly the reaction of 1-methylpiperazine 6b with 3 gave
only 1-methyl-4-(3,5,6-trichloro-4-(phenylsulfonyl)pyridin-
2-yl)piperazine 7c. N,N′-dimethylethylenediamine 6c gave
the fused bicyclic compound 7d in high yield by substitu-
tion at the ortho position of the pyridine ring followed by
intermolecular ring closure at the geometrically accessible
meta position. The structure of 7d was confirmed by IR,
NMR and elemental analysis. The IR spectrum 7d showed
two absorption bonds at 1320.1 and 1154.6 cm−1 for SO2
1
The HNMR spectrum of 3 showed a doublet at 8.06 ppm
and two triplets at 7.86 and 7.72 ppm for aromatic H. In
13CNMR spectrum, aromatic carbons were located at 149,
146.8, 139.3, 135.8, 130.2, 129.4 and 128.2 ppm.
The phenylsulfonyl group is strong electron-withdraw-
ing group that helps to maintain the reactivity of pyridine
ring toward further nucleophilic substitution processes.
This allows annelation and further functionalization to pro-
ceed. Annelation processes involving the reaction between
3 and oxygen and primary or secondary N nucleophiles in
the presence of potassium carbonate and also in acetonitrile
were studied (Tables 2, 3).
Our initial investigations centered on the use of primary
amines as nucleophiles. Reactions of 4-phenylsulfonyl-tet-
rachloro-pyridine 3 with ethylamine 4a as a model nucle-
ophile have shown a preference for nucleophilic attack at
the position para to the ring nitrogen and gave 2,3,5,6-tet-
rachloro-N-ethylpyridin-4-amine 5a (Table 2, entry 1) after
1
purification with column chromatography. HNMR analy-
1
sis of product was confirmed compound 5a and indicated
that phenylsulfonyl group replaced by ethylamine. 1HNMR
spectrum of compound 5a showed a broad singlet peak
stretching. HNMR spectrum of 7d showed a doublet at
7.72 ppm and two triplets at 7.65 and 7.54 ppm for aromatic
H. It also indicated a broad peak at 3.40 and 2.98 ppm for
1 3

J IRAN CHEM SOC
Table 2 Reaction of 4-phenylsulfonyl-tetrachloropyridine with primary nucleophiles
Entry Nucleophile
1
Product(s)
%Yield (time/h)a %Yield (time/min)b
90(3)
95(8)
2
3
85(3)
90(8)
55(10)c
60(20)
4
5
6
65(7)
80(7)
65(5)
80(15)
85(15)
70(20)
7
8
45(24)d
35(24)d
45(60)
45(60)
a
b
c
d
CH3CN, K2CO3, r.t
CH3CN, K2CO3, r.t
NaOEt, EtOH, reflux
CH3CN, K2CO3, reflux
1 3

J IRAN CHEM SOC
Table 3 Reaction of 3 with secondary amines
%Yield
(time/h)a
%Yield
(time/min)b
Entry
1
Nucleophile
Product(s)
75(4)
85(12)
2:1(7a:7b)
2:1(7a:7b)
2
40(5)
55(13)
3
80(8)
85(15)
85(6)
90(10)
4
7:1(7e:7f)
7:1(7e:7f)
a
CH3CN, K2CO3, r.t
CH3CN, K2CO3, r.t
b
two methylene groups. Two methyl groups were located at
2.99 and 2.93 ppm. In 13NMR of 7d, chemical shifts of aro-
matics carbons were located in the range of 126–150.1 ppm.
It also showed two methylene groups at 48.96 and
47.28 ppm and two methyl groups at 44.87 and 36.86 ppm.
The reaction of 3 with N-(2-aminoethyl)ethane-1,2-diamine
6d bearing three nucleophilic sites, gave a mixture of 7e and
7f in the ratio of 7:1 arising from the attack of the secondary
amine site at the 2- and 4-positions of the pyridine ring. The
products 7e and 7f were most likely formed from the attack
of the secondary amine site, reflecting the higher nucleophi-
licity of the secondary amines over the primary ones.
The effect of ultrasound on different reactions has been
widely studied during the last two decades [33], and in our
earlier studies, we have reported synthesis of some com-
pounds using ultrasonic irradiation [34, 35]. For conveni-
ence, reactions were performed using ultrasonic irradia-
tion in short reaction time, and the isolated yields compare
favorably with that obtained for the attack of nucleophile
upon 3 under conventional stirring conditions, indicating
that either synthetic mode is applicable.
These results suggest that the regiochemistry of nucleo-
philic attack for system 3 is, in general, governed by the
steric hindrance around the nucleophile whereby less steric
1 3

J IRAN CHEM SOC
hindrance nucleophiles, such as primary amine, prefer-
entially attack at the most activated PhSO2 group at the
4-position of the pyridine ring while more steric hindrance
nucleophiles, such as secondary amine, prefer to attack at
the 2-position of pyridine ring.
packing is further stabilized by the intermolecular π…π
interactions in which the centroid-to-centroid distances are
3.8375(14) and 3.8189(14) Å.
Conclusion
The X‑ray structure of 7a
In conclusion, we have shown that 2,3,5,6-tetrachloro-
4-(phenylsulfonyl)pyridine can be synthesized from reac-
tion of sodium phenylsulfinate with pentachloropyridine in
optimized reaction condition and that can be successfully
reacted with a variety of nucleophiles. The phenylsulfo-
nyl group is strong electron-withdrawing group that helps
to maintain the reactivity of the para position of pyridine
ring toward further nucleophilic substitution processes. Pri-
mary aliphatic and aromatic amine and oxygen nucleophile
occur cleanly at the position para to the ring nitrogen. In
contrast, secondary N nucleophiles gave mostly a mixture
of ortho- and para-substituted products. These results have
been rationalized by using steric hindrance principles.
The asymmetric unit of the title compound comprises
a two independent molecules of 4-(3,5,6-trichloro-4-
(phenylsulfonyl)pyridin-2-yl)morpholine 7a which crys-
tallizes in triclinic system with space group P-1. Two car-
bon and their attached hydrogen atoms and two chlorine
atoms in one of the molecules are found to be disordered
over two positions. The molecular structure of the com-
pound is shown in Fig. 1. The crystal packing of the com-
pound shows weak intermolecular O…Cl [O(2)…Cl(3)
i = 3.4909(11) Å; (i) 1−x, 1−y, −z] interactions which are
slightly shorter than the sum of the van der Waals radii of
Cl atoms [3.50 Å] which is shown in Fig. 2. The crystal
Acknowledgements The authors wish to thank Vali-e-Asr University
of Rafsanjan for partially funding this work.
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