Regiochemistry of nucleophilic substitution of pentachloropyridine with N and O bidentate nucleophiles

Article abstract of DOI:10.1039/c5nj00418g

Site reactivity of some enol-imines derived from N-aryl formamides with pentachloropyridine under basic conditions in dry CH₃CN was investigated. The aromatic nucleophilic substitution of pentachloropyridine with enol-imines occurs at the 4-position of pyridine ring by both oxygen and nitrogen site of enol-imines. Nucleophilic attack by the oxygen of enol-imine gave corresponding oximino compounds as a mixture of E- and Z-isomers. In contrast, nucleophilic attack by the nitrogen of enol-imine gave the unexpected N,N-di-substituted aryl compounds. The structures of all the compounds were confirmed by IR, ¹H NMR, ¹³C NMR and ¹⁹F NMR spectroscopy as well as elemental analysis and X-ray crystallography.

Full text of DOI:10.1039/c5nj00418g

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Regiochemistry of nucleophilic substitution of
pentachloropyridine with N and O bidentate
nucleophiles†
Cite this:DOI: 10.1039/c5nj00418g
Alireza Poorfreidoni,a Reza Ranjbar-Karimi*a and Reza Kiab
Site reactivity of some enol–imines derived from N-aryl formamides with pentachloropyridine under basic
conditions in dry CH3CN was investigated. The aromatic nucleophilic substitution of pentachloropyridine with
enol–imines occurs at the 4-position of pyridine ring by both oxygen and nitrogen site of enol–imines.
Nucleophilic attack by the oxygen of enol–imine gave corresponding oximino compounds as a mixture of
E- and Z-isomers. In contrast, nucleophilic attack by the nitrogen of enol–imine gave the unexpected N,N-
di-substituted aryl compounds. The structures of all the compounds were confirmed by IR, 1H NMR, 13C
NMR and 19F NMR spectroscopy as well as elemental analysis and X-ray crystallography.
Received (in Montpellier, France)
18th February 2015,
Accepted 18th March 2015
DOI: 10.1039/c5nj00418g
www.rsc.org/njc
2-aminothiophenol, is most likely formed from the initial attack
of the S nucleophile and subsequent cyclization.14 In another
Introduction
Perhalogenated aromatic and heteroaromatic compounds are work, we have shown that pentafluoropyridine successfully reacts
important starting materials for the synthesis of other hetero- with some enolates from the oxygen site. The selectivity of
cyclic and macrocyclic compounds.1–3 The great number of nucleophilic substitution in this process was explained on the
review articles and monographs for the synthesis and applica- basis of hard–hard interaction principle.15
tions of pyridines, reflects the important role of substituted
Aromatic nucleophilic substitution reactions proceed via the
pyridines in organic chemistry, biochemistry, and pharmaceutical AE-mechanism;4–6 however, SRN1-,16–18 EA-19–21 and SN (ANRORC)-22
chemistry.4–7 Many researchers are interested in the reactions of mechanisms are also observed. Halogen substituents at 2-, 3-
various N, O, S, C, and P nucleophiles with perhalogenated and 4-positions of pyridines indicate different reactivities to
compounds.8–12 The nature of nucleophile, reaction condition, nucleophiles.4–6
and solvent have a basic role in the regiochemistry of the reactions.
Formamide compounds are widely used as intermediates
Differentiation reactivity of perfluorinated heteroaromatic com- in organic synthesis. N-formyl compounds play a key role in
pounds into hard and soft nucleophiles was achieved by the partial the synthesis of important pharmaceutical compounds such as
replacement of fluorine by bromine in pentafluoropyridine.13 In 1,2-dihydroquinolines,23 cancer chemotherapeutic agents24 and
the last few years, we have been pursuing investigations on the quinolone antibiotics.25 Furthermore, they are also applied
regiochemistry reaction of different nucleophiles with perhalo- as precursors for the synthesis of various compounds such
genated compounds.14 We have shown that 4-substituted tetra- as isocyanide,26 formamidine27 and amination of azoles.28 In
fluoropyridine can successfully react with a variety of unequal 1995, Koppang reported disubstitution on hexafluorobenzene
bidentate nucleophiles. The regioselectivity of nucleophilic with formanilides.29
substitution in this process was explained by the high nucleo-
Continuing our research in this area, we would like to report
philicity of the secondary or primary amino groups and by the the site selectivity of some N and O bidentate nucleophiles in
activating influence of pyridine ring nitrogen that significantly the reaction with pentachloropyridine.
activates the ortho and para sites to itself. In contrast, the major
product of the aromatic unequal bidentate nucleophiles, such as
Results and discussion
a Department of Chemistry, Faculty of Science, Vali-e-Asr University,
Synthesis of precursor formamide compounds
Rafsanjan 77176, Islamic Republic of Iran. E-mail: r.ranjbarkarimi@vru.ac.ir;
Fax: +98-391-322-6800; Tel: +98-913-291-6602
Several papers have reported the preparation of these impor-
tant compounds.30–32 In this paper, we have established a new
method for the synthesis of these compounds in a very short
reaction time with high yields. The reaction of the aromatic
b Chemistry Department, Sharif University of Technology, P.O. Box 11155-3615,
Tehran, Iran
† CCDC 1034368. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5nj00418g
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Table 1 Synthesis of aromatic formamides
Entry
1
Amine
Formamide
Yield (%)
93
Time (min)
1
2
90
3
3
4
5
93
95
94
1
1
4
6
7
90
92
3
4
6
90
90
90
90
4
5
5
5
9
10
11
12
90
5
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amine 1a–l with formic acid 2 without any solvent in the
presence of aminopropyl-silica (APS) 3 as a heterogeneous
catalyst using ultrasonic irradiation gave the corresponding
formamides 4a–l in 1–5 minutes in 90–95% isolated yields
(Table 1). The effect of ultrasound on different reactions has
been widely studied during the last two decades33 and in our
earlier studies, we have reported synthesis of some compounds
using ultrasonic irradiation.34,35
All the formamide compounds were identified by the compar-
ison of their physical and spectral data with those of authentic
samples.30–32
The procedure employs a polymeric catalyst and provides a
simple and effective procedure for the preparation of N-formyl-
amines with good to excellent yield and high purity. This
procedure is characterized by heterogeneous and mild reaction
Scheme 1 General scheme for reaction of formamide with penta-
chloropyridine.
conditions, non-toxic content and an easy reaction work-up, were studied initially because of the relatively high nucleophilicity
making it ideal for both laboratory and large-scale prepara- of such amine species (Scheme 1, path a). Pentachloropyridine
tions. This method also offers advantages such as the clean 5 and N-(2,4-dimethylphenyl)formamide 4a, in the presence of
persistence of reactions at room temperature without using any potassium carbonate and in dry acetonitrile, gave the desired
solvent, utilizing very low amounts of catalyst, generally com- 2,3,5,6-tetrachloropyridin-4-yl (E and Z)-N-(2,4-dimethylphenyl)-
pleting the reaction in 1–5 min, and giving the products in formimidate 6a (Table 3, entry 1) after recrystallization of the
excellent yields. Despite the relative simplicity of this reaction, crude product eluted by ethanol. 1H NMR analysis of the products
the attempted acetylation of amine with acetic acid in aceto- showed the presence of 6a as the major product and as a mixture
nitrile failed. Similarly, the formylation of phenols with formic of E- and Z-isomers. This observation indicated that bidentate
acid in acetonitrile also failed.
nucleophile derived from N-(2,4-dimethylphenyl)formamide 4a
reacted with pentachloropyridine from oxygen site. The electron-
donating effect of methyl group enhanced negative charge density
on oxygen by resonance, therefore making it more nucleophilic
than nitrogen. H NMR spectrum of compound 6a showed one
singlet peak at d = 8.59 ppm and one singlet peak at d = 8.44 ppm
Reaction of formamide with pentachloropyridine
Anions derived from formamides have two nucleophilic sites
(O and N) and it is interesting to know which site is attacked
in the substitution reaction. The reaction conditions were
optimized using the reaction of pentachloropyridine 5 and
N-(4-chlorophenyl)formamide 4e as an example. We investi-
gated the effect of solvent and temperature on the reaction. At
room temperature, the reaction gave moderate yield in aceto-
nitrile whereas the yields were low or trace in other solvents.
Similarly, acetonitrile gave excellent yield at reflux condition
(Table 2). The final product was the same in all solvents and
temperatures. Annelation processes involving reactions between
pentachloropyridine 5 and N-(2,4-dimethylphenyl)formamide 4a
1
0
for alkene hydrogens (Hd, Hd ) of E- and Z-isomers (Scheme 2). It
also indicated two singlet peaks in d = 7.21 and 7.14 ppm for Ha
0
and Ha , two doublet peaks in d = 7.02 and 6.95 ppm for Hb and
0
Hb and two doublet peaks in d = 6.90 and 6.75 ppm for Hc and
0
Hc . Chemical shifts of four methyl groups were located at 2.35,
2.27, 2.26 and 2.20 ppm.
Similarly, the reactions of phenylformamides 4b–d with
pentachloropyridine 5 give 6b–d, respectively, as mixtures of
E- and Z-isomers. With this encouraging result in hand, we
performed the reaction of formamides containing electron-
withdrawing group generated by corresponding aromatic amine
with pentachloropyridine. Pentachloropyridine 5 and N-(3-nitro-
phenyl)formamide 4j, in the presence of potassium carbonate
and in dry acetonitrile, gave the desired 2,3,5,6-tetrachloro-N-(3-
nitrophenyl)pyridin-4-amine 6j (Table 3) in good yield after
recrystallization of the crude product eluted by ethanol.
1H NMR of this compound was quite different from com-
pounds 6a–d. 1H NMR spectrum of compound 6j showed a
broad singlet in 9.4 ppm for NH, two doublets at 7.75 and 7.22
ppm, one triplet in 7.46 ppm and one singlet at 7.71 ppm for
aromatic H. There are no signals for aldehyde or alkene
hydrogen. 13C spectrum was at first slightly puzzling, showing
bands only for the ring carbon atoms. The IR spectrum 6j
showed a broad absorption band at 3335 cmꢀ1 for NH stretch-
ing. The elemental analysis indicated that the product had
the molecular formula C11H5Cl4N3O2. This, together with the
Table 2 Effect of solvent and temperature on the reaction of penta-
chloropyridine and N-(4-chlorophenyl)formamidea
Entry
Solvent
Temperature (1C)
Time (h)
Yield (%)
1
2
THF
THF
r.t.
70
12
15
12
13
12
12
10
12
12
12
12
17
Trace
41
30
3
4
5
6
7
8
9
10
11
12
Acetone
Acetone
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CHCl3
CHCl3
EtOH
r.t.
60
r.t.
43
r.t.
86
r.t.
66
55
N.R
N.R
50
90
N.R
N.R
10
r.t.
83
EtOH
30
a
Reaction conditions: pentachloropyridine (1.0 mmol), potassium
carbonate (1.5 mmol), solvent (5.0 ml).
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Table 3 Reaction of aromatic formamide with pentachloropyridine
Entry
Formamide
Product
Yield (%)
M.P. (1C)
1
31
137–140
2
30
169–172
3
4
35
53
129–132
169–172
5
6
90
40
150–153
180–183
7
75
174–177
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Table 3 (continued)
Entry
8
Formamide
Product
Yield (%)
M.P. (1C)
60
135–138
9
70
65
55
30
271–274
243–247
141–145
108–111
10
11
12
abovementioned NMR data suggested that the compound conditions converted rapidly to the main product B and
was 2,3,5,6-tetrachloro-N-(4-nitrophenyl)pyridin-4-amine 6j. The formyl chloride. Formyl chloride cannot be isolated, because
structure was confirmed by X-ray analysis on a single crystal, as it decomposes to carbon monoxide (CO) and hydrogen
shown in Fig. 1. A similar reaction occurred with other forma- chloride (HCl).
mide 4e–l and 4k,l to yield the corresponding amines 6e–l and
4k,l in moderate to high yields. H NMR spectra of compounds
1
The X-ray structure of 6j
6e–l showed a singlet in the range of 8.5–10 ppm for NH and The asymmetric unit of the title compound comprises a mole-
some signal in the range of 6.8–8.2 ppm for aromatic hydrogen. cule of 2,3,5,6-tetrachloro-N-(3-nitrophenyl)pyridin-4-amine 6j,
In 13C NMR spectra, aromatic carbons were located in the range which crystallizes in monoclinic system with space group P2(1)/n.
of 112–153 ppm. In IR spectra, NH stretching bond appeared in The molecular structure of the compound is shown in Fig. 1.
the range of 3290–3390 cmꢀ1
.
The crystal packing of the compound shows weak intermole-
A
rationalization of these observations is shown in cular Clꢁ ꢁ ꢁCl [Cl(2)ꢁ ꢁ ꢁCl(3)i = 3.4909(11) Å; (i) 1 ꢀ x, 1 ꢀ y, ꢀz]
Scheme 3. We believe the first step in these reactions is the interactions, which are slightly shorter than the sum of the van
expected nucleophilic attack by the nitrogen of formamide, to der Waals radii of Cl atoms [3.50 Å], as shown in Fig. 2. The
give the first formed intermediate A, which under reaction crystal packing is further stabilized by the intermolecular pꢁ ꢁ ꢁp
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interactions in which the centroid to centroid distances are
3.8375(14) and 3.8189(14) Å.
Conclusion
We have demonstrated that pentachloropyridine 5 can success-
fully react with enol–imines from both oxygen and nitrogen
site, depending on the X substituent. When X is an electron-
releasing group, nucleophilic attack is accomplished by oxygen
atom and when X is an electron-withdrawing group attached to
benzene ring, pentachloropyridine is attack to via a nitrogen site.
Scheme 2 E and Z isomers of 6a.
Experimental
All the solvents and starting materials were obtained commer-
cially (Merck). Solvents were dried using the literature recom-
1
mended procedures and distilled before use. H NMR spectra
were recorded at 500 or 300 MHz. 13C NMR spectra were
recorded at 125 or 75 MHz. 19F NMR spectra were recorded at
282 MHz. TLC analysis was performed on silica gel TLC plates
(Merck).
Fig. 1 The molecular structure of 6j.
Preparation of APS
Grafting the silica surface by covalently attached aminopropyl
functional group proceeds via a reaction between silanol
groups and aminopropyl triethoxysilane (APTES) in dry
toluene.36,37 Typically, 5 g of silica sample was dispersed in
50 ml dry toluene and stirred for a few minutes at room
temperature. Then, 5 ml of APTES was slowly added to the
suspension and refluxed for 10 h. After slow cooling, the
resulting solids were filtered, washed with toluene, and dried
under reduced pressure for 24 h. Aminopropyl-grafted sam-
ples were heated at 120 1C for 12 h. The grafted material
obtained afterwards was called APS (aminopropyl-silica).
Finally, we investigated the formylation of amines with formic
acid in the presence of APS as a catalyst.
Scheme 3 Proposed explanation for observed B.
General procedure for the formylation of amines with formic
acid
To a mixture of amine (1 mmol) and formic acid (3 mmol), APS
(0.005 g) was added. The reaction mixture was irradiated with
ultrasound for 1–5 min. The progress of the reaction was
monitored by TLC. After completion, the mixture was diluted
with water (10 ml) and extracted with diethyl ether (2 ꢂ 10 ml).
The combined organic layer was dried over anhydrous MgSO4
and concentrated to afford pure formamide.
General procedure for reactions between pentachloropyridine
and formamidates
Potassium carbonate (1.5 mmol) was added to a solution of
formamide 4 (1 mmol) in dry acetonitrile (5 ml) and the mixture
was stirred at room temperature for 30 min. Then, pentachloro-
pyridine 5 (1 mmol) was added and the resulting solution was
refluxed at 85 1C for 12 h. The reaction mixture was filtered and
Fig. 2 The crystal packing of 6j.
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the solvent was evaporated. The obtained product was recrys- 2,3,5,6-Tetrachloro-N-(2-bromophenyl)pyridin-4-amine (6f)
tallized from EtOH to give the crude product.
Yield: (40%), pale gray solid, mp 180–183 8C. (Found: C, 34.2; H,
1.4; N, 7.3. C11H5BrCl4N2 requires: C, 34.1; H, 1.3; N, 7.2%). IR
2,3,5,6-Tetrachloropyridin-4-yl-N-(2,4-dimethylphenyl)formimidate
(6a)
1
(KBr): 3370 (NH) cmꢀ1. H NMR (300 MHz, DMSO-d6): d 8.75
(1H, s, NH), 7.60 (1H, d, J = 7.9 Hz, Ar–H), 7.31 (1H, t, J = 7.6 Hz,
Yield: (31%), white solid, mp 137–140 8C. (Found: C, 46.1; H,
2.7; N, 7.7. C14H10Cl4N2O requires: C, 46.2; H, 2.7; N, 7.7%).
1H NMR (500 MHz, DMSO-d6): d 8.6 (1H, s, alkene–CH), 8.4 (1H,
s, alkene–CH), 7.21 (1H, s, Ar–H), 7.14 (1H, s, Ar–H), 7.02 (1H,
d, J = 8 Hz, Ar–H), 6.95 (1H, d, J = 9.5 Hz, Ar–H), 6.90 (1H, d, J =
8 Hz, Ar–H), 6.75 (1H, d, J = 8.5 Hz, Ar–H), 2.35 (3H, s, CH3),
2.27 (3H, s, CH3), 2.26 (3H, s, CH3), 2.20 (3H, s, CH3). 13C NMR
(125 MHz, DMSO-d6): d 148 (Ar–C), 146.2 (Ar–C), 137.1 (Ar–C),
135.7 (Ar–C), 133.2 (Ar–C), 133 (Ar–CH), 132 (Ar–CH), 129.3
(Ar–CH), 129.5 (Ar–CH), 124.9 (Ar–CH), 125.1 (Ar–CH), 22 (CH3),
21 (CH3), 19 (CH3), 18 (CH3).
Ar–H), 7.18 (1H, d, J = 8 Hz, Ar–H), 7.10 (1H, t, J = 7.3 Hz, Ar–H):
13C NMR (75 MHz, DMSO-d6): d 148.4 (Ar–C), 145.4 (Ar–C),
139.4 (Ar–C), 132.4 (Ar–CH), 128 (Ar–CH), 126.6 (Ar–CH), 119.2
(Ar–C), 117.5 (Ar–C).
2,3,5,6-Tetrachloro-N-(2,4-dibromophenyl)pyridin-4-amine (6g)
Yield: (75%), pale yellow solid, mp 174–177 8C. (Found: C, 28.3;
H, 1.0; N, 6.1. C11H4Br2Cl5N2 requires: C, 28.4; H, 0.9; N, 6.0%).
IR (KBr): 3364.1 (NH) cmꢀ1 1H NMR (300 MHz, DMSO-d6):
.
d 8.31 (1H, s, NH), 7.73 (1H, d, J = 1.9 Hz, Ar–H), 7.39 (1H, dd, J =
8.5 Hz, J = 2 Hz, Ar–H), 6.93 (1H, d, J = 8.5 Hz, Ar–H). 13C NMR
(75 MHz, DMSO-d6): d 148.7 (Ar–C), 144.9 (Ar–C), 142 (Ar–C),
133.7 (Ar–CH), 130.4 (Ar–CH), 126 (Ar–CH), 118.7 (Ar–C), 117
(Ar–C), 114 (Ar–C).
2,3,5,6-Tetrachloropyridin-4-yl-N-phenylformimidate (6b)
Yield: (30%), white solid, mp 169–172 8C. (Found: C, 42.8; H,
1.7; N, 8.2. C12H6Cl4N2O requires: C, 42.9; H, 1.8; N, 8.3%).
1H NMR (300 MHz, DMSO-d6): d 8.98 (1H, s, alkene–CH), 8.46
(s, alkene–CH), 7.43–7.29 (5H, m, Ar–H). 13C NMR (75 MHz,
DMSO-d6): d 165 (alkene–CH), 161.4 (alkene–CH), 146.3 (Ar–C),
146 (Ar–C), 137.4 (Ar–C), 137 (Ar–CH), 130.1 (Ar–CH), 129.8 (Ar–
CH), 129.1 (Ar–CH), 126.7 (Ar–C), 123.5 (Ar–CH), 121.1 (Ar–CH).
2,3,5,6-Tetrachloro-N-(3-chloro-4-fluorophenyl)pyridin-4-amine
(6h)
Yield: (60%), white solid, mp 135–138 8C. (Found: C, 36.5; H,
1.2; N, 7.6. C11H4Cl4FN2 requires: C, 36.7; H, 1.1; N, 7.8%). IR
(KBr): 3384.8 (NH) cmꢀ1. 1H NMR (300 MHz, DMSO-d6): d 9.07
(1H, s, NH), 7.19 (1H, dd, J = 9 Hz, Ar–H), 7 (1H, dd, J = 2.6 Hz,
J = 6.49, Ar–H), 6.81 (1H, m, Ar–H). 13C NMR (75 MHz, DMSO-
2,3,5,6-Tetrachloropyridin-4-yl-N-(4-methylphenyl)formimidate (6c)
Yield: (35%), white solid, mp 129–132 8C. (Found: C, 43.9; H, d6): d 152.4 (Ar–CF, J = 237.8), 148.2 (Ar–C), 145.2 (Ar–C), 141.2
2.2; N, 8.0. C13H8Cl4N2O requires: C, 44.1; H, 2.3; N, 8.0%). (Ar–C), 121.3 (Ar–CH), 120.3 (Ar–CH, J = 6.8 Hz), 119 (Ar–C),
1H NMR (300 MHz, DMSO-d6): d 8.89 (1H, s, alkene–CH), 8.43 118.8 (Ar–CH, J = 18.5 Hz), 116.2 (Ar–C, J = 21.4 Hz). 19F NMR
(s, alkene–CH), 7.18–7.24 (4H, m, Ar–H), 2.29 (3H, s, CH3). 13C (282 MHz, DMSO-d6): d ꢀ126.1 (1F).
NMR (75 MHz, DMSO-d6): d 161.2 (alkene–CH), 146.3 (Ar–C),
2,3,5,6-Tetrachloro-N-(4-nitrophenyl)pyridin-4-amine (6i)
146.1 (Ar–C), 136.3 (Ar–CH), 136.1 (Ar–CH), 133.9 (Ar–CH),
130.7 (Ar–CH), 130.2 (Ar–CH), 130.1 (Ar–CH), 129.5 (Ar–CH),
128.9 (Ar–CH), 123.5 (Ar–C), 121.3 (Ar–CH), 121 (Ar–CH), 20.5
(CH3), 20.4 (CH3).
Yield: (70%), orange solid, mp 271–274 8C. (Found: C, 37.5; H,
1.5; N, 11.9. C11H5Cl4N3O2 requires: C, 37.4; H, 1.4; N, 11.9%).
IR (KBr): 3290.2 (NH) cmꢀ1 1H NMR (300 MHz, DMSO-d6):
.
d 9.79 (1H, s, NH), 8.11 (2H, d, J = 8.6 Hz, Ar–H), 6.97 (2H, d, J =
8.7 Hz, Ar–H). 13C NMR (75 MHz, DMSO-d6): d 148 (Ar–C), 146.7
(Ar–C), 145.3 (Ar–C), 140.4 (Ar–C), 125.2 (Ar–CH), 125 (Ar–CH),
116 (Ar–C).
2,3,5,6-Tetrachloropyridin-4-yl-N-(4-metoxylphenyl)formimidate (6d)
Yield: (53%), white solid, mp 169–172 8C. (Found: C, 42.6; H,
2.1; N, 7.7. C13H8Cl4N2O2 requires: C, 42.7; H, 2.2; N, 7.6%).
1H NMR (300 MHz, DMSO-d6): d 8.79 (1H, s, alkene–CH), 8.42
(s, alkene–CH), 7.36 (2H, d, J = 5.9 Hz, 8.4 Ar–H), 6.92–7 (2H, m,
Ar–H), 3.75 (3H, s, CH3). 13C NMR (75 MHz, DMSO-d6): d 161.4
(Ar–C), 158.1 (alkene–CH), 157.7 (Ar–C), 147.1 (Ar–C), 146.3 (Ar–C),
130.5 (Ar–CH), 130.2 (Ar–CH), 130 (Ar–CH), 129.1 (Ar–CH), 125.6
(Ar–CH), 123.7 (Ar–CH), 114.9 (Ar–C), 114.2 (Ar–CH), 55.4 (OCH3).
2,3,5,6-Tetrachloro-N-(3-nitrophenyl)pyridin-4-amine (6j)
Yield: (65%), yellow solid, mp 243–247 8C. (Found: C, 37.4; H,
1.5; N, 12.0. C11H5Cl4N3O2 requires: C, 37.4; H, 1.4; N, 11.9%).
IR (KBr): 3355.1 (NH) cmꢀ1 1H NMR (300 MHz, DMSO-d6):
.
d 9.41 (1H, s, NH), 7.75 (1H, d, J = 6.8 Hz, Ar–H), 7.71 (1H, s, Ar–H),
7.46 (1H, t, J = 7.8 Hz, Ar–H), 7.22 (1H, d, J = 7.2 Hz, Ar–H). 13C
NMR (75 MHz, DMSO-d6): d 148.1 (Ar–C), 147.5 (Ar–C), 145.6
(Ar–C), 143.3 (Ar–C), 129.6 (Ar–CH), 124.9 (Ar–CH), 121.5 (Ar–CH),
115.9 (Ar–C), 112.9 (Ar–CH).
2,3,5,6-Tetrachloro-N-(4-chlorophenyl)pyridin-4-amine (6e)
Yield: (90%), white solid, mp 150–153 8C. (Found: C, 38.7; H,
1.4; N, 8.1. C11H5Cl5N2 requires: C, 38.6; H, 1.5; N, 8.2%). IR
(KBr): 3364.1 (NH) cmꢀ1. 1H NMR (300 MHz, DMSO-d6): d 9.05
(1H, s, NH), 7.29 (2H, d, J = 5.9 Hz, Ar–H), 6.95 (2H, d, J = 5.8 Hz,
2,3,5,6-Tetrachloro-N-(3-(trifluoromethyl)phenyl)pyridin-4-amine (6k)
Ar–H). 13C NMR (75 MHz, DMSO-d6): d 147.7 (Ar–C), 145.6 (Ar–C), Yield: (55%), white solid, mp 141–145 8C. (Found: C, 38.2; H,
139.4 (Ar–C), 128.4 (Ar–CH), 126.6 (Ar–C), 121.4 (Ar–CH), 120.8 1.4; N, 7.7. C12H5Cl4F3N2 requires: C, 38.3; H, 1.3; N, 7.6%). IR
(Ar–C).
(KBr): 3390.8 (NH) cmꢀ1. 1H NMR (300 MHz, DMSO-d6): d 9.25
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5 D. Spitzner, in Houben-Weyl, Methoden der Organischen
Chemie, ed. E. Kreher, Thieme, Stuttgart, 1994, vol. E7b,
pp. 286–686.
6 A. Weissberger and E. C. Taylor, The Chemistry of Hetero-
cyclic Compounds, in Pyridine and its Derivatives, ed.
A. Abramovitch, Wiley-Interscience, New York, 1974 and
1975, vol. 14, suppl. 1–4.
(1H, s, NH), 7.43 (1H, t, J = 7.6 Hz, Ar–H), 7.26 (1H, d, J = 8.1 Hz,
Ar–H), 7.25 (1H, s, Ar–H), 7.12 (1H, d, J = 7.5 Hz, Ar–H). 13C
NMR (75 MHz, DMSO-d6): d 147.6 (Ar–C), 145.6 (Ar–C), 142.4
(Ar–C), 130 (Ar–C4), 129.3 (Ar–CH) 124 (CF3), 122.7 (Ar–CH),
121 (Ar–CH), 118.1 (Ar–C), 115.6 (Ar–CH). 19F NMR (282 MHz,
DMSO-d6) d ꢀ61.2 (CF3).
7 L. I. Belen’kii, N. D. Kruchkovskaya and V. N. Gramenitskaya,
Adv. Heterocycl. Chem., 1999, 73, 295.
2,3,5,6-Tetrachloro-N-(2-(trifluoromethyl)phenyl)pyridin-4-
amine (6l)
8 R. E. Banks, J. E. Burgess, W. M. Cheng and R. N. Haszeldine,
J. Chem. Soc., 1965, 575–581.
9 R. E. Banks, R. N. Haszeldine, D. R. Karsa, F. E. Rickett and
I. M. Young, J. Chem. Soc. C, 1969, 1660–1662.
10 R. E. Banks, R. N. Haszeldine, E. Philips and I. M. Young,
J. Chem. Soc. C, 1967, 2091–2095.
Yield: (30%), white solid, mp 108–111 8C. IR (KBr): 3388.6 (NH)
1
cmꢀ1. H NMR (300 MHz, DMSO-d6): d 8.37 (1H, s, NH), 7.66
(1H, d, J = 7.7 Hz, Ar–H), 7.52 (1H, t, J = 7.5 Hz, Ar–H), 7.28 (1H,
t, J = 7.5 Hz, Ar–H), 7.12 (1H, d, J = 7.9 Hz, Ar–H). 13C NMR
(75 MHz, DMSO-d6): d 148.6 (Ar–C), 145.4 (Ar–C), 145.4 (Ar–C),
132.7 (Ar–CH), 129.1 (Ar–CH), 126.3 (Ar–CH), 125.8 (CF3), 117.9
(Ar–CH).
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144–154.
X-ray crystallography
Single crystal X-ray data of the compound was collected at
298(2) K on STOE IPDS 2T diffractometer with Mo Ka radiation
(l = 0.71073 Å). The unit cell parameters refinement, data
reduction and correction for Lp and decay were performed
using X-AREA38 software. Absorption corrections were applied
using MULABS39 routine in PLATON.40 The structures were
solved by direct methods and refined by the least squares
method on F2 using the SHELXTL program package.41 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 con-
strained to refine with the parent atoms with Uiso (H) = 1.2 Ueq
(N). CCDC 1034368.
13 R. D. Chambers, C. W. Hall, J. Hutchinson and R. W. Millar,
J. Chem. Soc., Perkin Trans. 1, 1998, 1705–1714.
14 R. Ranjbar-Karimi and M. Mousavi, J. Fluorine Chem., 2010,
131, 587–591.
15 R. Ranjbar-Karimi and E. Heidari, J. Fluorine Chem., 2013,
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1–79.
17 P. Boy, C. Combellas and A. Thiebault, Synlett, 1991,
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18 R. Beugelmans and J. Chastanet, Tetrahedron, 1993, 49,
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Acknowledgements
The authors wish to thank Vali-e-Asr University of Rafsanjan for
partially funding this work.
24 G. Pettit, M. Kalnins, T. Liu, E. Thomas and K. Parent, J. Org.
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