Iron-Mediated One-Pot Synthesis of 3,5-Diarylpyridines from β-Nitrostyrenes

Article abstract of DOI:10.1021/acs.joc.5b02712

An operationally simple and mild one-pot protocol for the synthesis of a variety of 3,5-diarylpyridines from β-nitrostyrenes was achieved by using elemental iron. This reaction proceeds via reduction of the nitro group, resulting in in situ imine formation followed by trimolecular condensation with concomitant debenzylative aromatization. By employing this method, a series of symmetrical and unsymmetrical 3,5-diarylpyridines were synthesized with good to excellent yields. In addition, this method was also utilized for the synthesis of Sch-21418, an anti-inflammatory agent on gram scale.

Full text of DOI:10.1021/acs.joc.5b02712

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Note
Iron-Mediated One-Pot Synthesis of 3,5-
Diarylpyridines from beta-Nitrostyrenes
Manda Sathish, Jadala Chetna, Namballa Hari Krishna,
Nagula Shankaraiah, Abdullah Alarifi, and Ahmed Kamal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02712 • Publication Date (Web): 01 Feb 2016
Downloaded from http://pubs.acs.org on February 2, 2016
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Iron-Mediated One-Pot Synthesis of 3,5-Diarylpyridines from β-
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Nitrostyrenes
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Manda Sathish,† Jadala Chetna,‡ Namballa Hari Krishna,‡ Nagula Shankaraiah,‡ Abdullah
Alarifi§ and Ahmed Kamal*†
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†Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India
‡Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Hyderabad 500 037, India
§Catalytic Chemistry Research Chair, Chemistry Department, College of Science, King Saud
University, Riyadh 11451, Saudi Arabia.
,†Corresponding author. Tel.: +91-40-27193157; fax: +91-40-27193189;

E-mail: ahmedkamal@iict.res.in.
ABSTRACT: An operationally simple and mild one-pot protocol for the synthesis of a
variety of 3,5-diarylpyridines from β-nitrostyrenes was achieved by using elemental iron.
This reaction proceeds via reduction of nitro group, resulting in in-situ imine formation
followed by trimolecular condensation with concomitant debenzylative aromatization. By
employing this method, a series of symmetrical and unsymmetrical 3,5-diarylpyridines were
synthesized with good to excellent yields. Besides, this method was also utilized for the
synthesis of Sch-21418, an anti-inflammatory agent in gram scale.
KEYWORDS: 3,5-Diarylpyridines; β-nitrostyrenes; iron; reduction; cycloaddition;
aromatization.
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Pyridines are one of the most widely studied class of heterocyclics todate and their
derivatives are found in several natural products which are of great importance in
pharmaceutical and agrochemical research.1,2 Some of the 3,5-disubstituted pyridines also
show significant antimicrobial activity.3 Among the substituted pyridines, Sch-21418, a 3,5-
bis(4-hydroxyphenyl)pyridine shows better inhibitory activity against inflammatory factors
(e.g., interleukin-6).4 Moreover bis-imidiazolyl pyridine was shown to inhibit DNA
topoisomerase II and cause cytotoxicity to Pneumonocystis carinii in an immunosuppressed
rat model along with moderate anti-HIV-1 activity.5 The widespread pharmacological
properties of substituted pyridines have drawn considerable attention of synthetic organic
chemists.6 The synthesis of 3,5-diarylpyridine, however, still greatly depends on the
transition-metal catalyzed cross-coupling reactions at higher temperatures and prolonged
reaction times.7
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Scheme 1. Synthesis of 3,5-disubstituted pyridines.
However, 3,5-disubstituted pyridines have also been constructed through the multi-
component cyclization of small molecules.8-17 In 1953, Eliel and co-workers18 while studying
the synthesis of the alkaloid papaverine, were able to condense homoveratric aldehyde with
ammonia. Instead of papaverine, they isolated a new compound characterized as 3,5-bis(3,4-
dimethoxyphenyl)pyridine. Subsequently, Chuang and co-workers19 synthesized 3,5-
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disubstituted pyridines from acryloyl azides by acetic acid-promoted cycloaddition (Scheme
1a). Recently, Jiao and co-workers20 have synthesized 3,5-diarylpyridines through copper-
catalyzed Chichibabin type cyclization of phenyl acetaldehyde (Scheme 1b). Moreover,
cycloaddition of azadienes with enamines21 and cross-Mannich9a reactions also gave 3,5-
disubstituted pyridines. Most of these methods however, suffer from low yields as well as
multiproduct formation. Therefore, mild and concise approaches to synthesize 3,5-
diarylpyridines from inexpensive and readily available substrates are highly desirable.
At the onset, we attempted a reaction of 3,4,5-trimethoxy-β-nitrostyrene (2e) with
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iron (1 equiv.) in acetic acid at 80 oC for
5
h
to produce 2-(3,4,5-
trimethoxyphenyl)acetaldehyde (5). Interestingly, the isolated product was identified as 3,5-
bis(3,4,5-trimethoxyphenyl)pyridine22 (3e) (20% yield with some of the starting material
13
intact). Comparison of the spectroscopic data (1H and C) of the product with the reported23
data led to the conclusion that 2-(3,4,5-trimethoxyphenyl)acetaldehyde (5) was not formed
1
(Scheme 2). The H NMR spectrum showed two mutually coupled aromatic signals (8.77
doublet with J = 1.2 Hz 2-H and 7.94 triplet with J = 1.9 Hz 1-H) which were assigned to the
two protons of C-2 and C-6 and one proton of C-4 respectively, which indicated a
symmetrical molecule with 3 and 5 substituted pyridine ring. The structure of 3e was further
confirmed by 2D NMR studies (see Supporting Information). To develop new synthetic
protocols for the pharmocologically useful molecules like 3,5-disubstituted pyridines, we
further explored the possibities of a concise one-pot synthesis of 3,5-diarylpyridines from β-
nitrostyrenes under mild conditions.
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Scheme 2. Reaction of 2e with iron in AcOH.
In this note, we intend to report a mild and inexpensive Fe-mediated synthesis of 3,5-
diarylpyridines through nitro reduction followed by condensation of the resultant
enamine/imine in acetic acid at room temperature.
In view of these inspiring results, we further studied the possibility of improving the
yield of 3a. Under similar conditions, increasing the stoichiometry of iron (from 1 equiv. to 2
and 3 equiv.) improved the yield to 50% and 85%, respectively, (entries 2 and 3, Table 1).
However, increasing the stoichiometry of iron (4 equiv.), did not improve the yield further
(entry 4, Table 1), and these studies revealed that three equivalents of iron are optimal for
such a reaction. We also studied the effects of various solvent systems (methanol,
methanol/water (1/1), acetic acid, acetic acid/water (1/1)) and found that acetic acid was the
only suitable solvent for this transformation (Table 1). Additionally, attempts to affect similar
reactivity with other reducing reagents, such as SnCl2∙2H2O in methanol or Zn dust in acetic
acid, were met with limited success (entries 8–10, Table 1). When, the reaction was
performed at room temperature using iron (3 equiv.), complete consumption of nitrostyrene
2e was observed in just 30 min and 3e was formed in 92% yield (entry 11, Table 1). Based on
these observations, we conclude that iron (3 equiv.) in acetic acid at room temperature was
the optimal condition for the synthesis of 3,5-diarylpyridines from β-nitrostyrenes.
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TABLE 1. Optimization of reaction conditions.
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entry
1
reagent
equiv.
solvent
AcOH
temp (oC)
time (h)
yield (%)a
Fe
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2
80
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80
80
70
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rt
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5
20b
50b
85
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-
2
Fe
AcOH
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Fe
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AcOH
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Fe
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AcOH
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Fe
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MeOH
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Fe
3
MeOH:water (1:1)
AcOH:water (1:1)
MeOH
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Fe
3
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SnCl2.2H2O
1.5
3
3
-
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Zn
Zn
Fe
AcOH
5
-
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3
AcOH
80
rt
5
trace
92
3
AcOH
0.5
aIsolated yields, bStarting material recovered.
With these optimized reaction conditions established, several β-nitrostyrenes were
employed for the synthesis of 3,5-diarylpyridine (Scheme 3). Electron-deficient β-
nitrostyrenes gave the corresponding 3,5-diarylpyridines in slightly lower yields (3j and 3o)
when compared to other β-nitrostyrenes. β-Nitrostyrenes with halogen substituents (Cl, Br
and F) provided the corresponding 3,5-diarylpyridines with moderate yields (3f‒i, 3k and 3l);
whereas, electron-rich β-nitrostyrenes yielded the corresponding 3,5-arylpyridines with high
yields (3b‒e), and 3m (Sch-21418) was obtained in very high yields (98%, Scheme 3).
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SCHEME 3. Substrate scope for the construction of symmetric 3,5-diarylpyridines.a
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aReaction conditions: 2 (1 equiv), Fe (3 equiv) in AcOH (5 mL), 30 min at room temperature.
To investigate the synthesis of unsymmetrical 3,5-diarylpyridines using optimal
conditions, a mixture of two different β-nitrostyrenes was reacted with iron (6 equiv. or 3
equiv. for each β-nitrostyrene) in acetic acid and the results are summarized in Scheme 4.
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Although a mixture of products were formed in this reaction, the unsymmetrical products
(4a‒e, Scheme 4) were isolated (separated by column chromatography) with good yields
compared to the symmetrical products (3, Scheme 4).
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SCHEME 4. Substrate scope for the construction of unsymmetrical 3,5-diarylpyridines.a
aReaction conditions: Mixture of two different β-nitrostyrene 2 (each 1 equiv), Fe (6 equiv) in
AcOH (5 mL), 30 min.
The reactivity of β-nitrostyrene (2m, 2 equiv.) with phenyl acetaldehyde (5, 1 equiv.)
was also studied under the optimized conditions. The product 4b was obtained in good yield
(65%, Scheme 5a), however some amount of 3m was found (29%), whereas formation of 3a
was not observed. Furthermore, we carried out a reaction with 2o under optimal conditions
and expected to produce 6 via in-situ nitro reduction and trimolecular condensation. It was
observed that, 6 was not formed however 1-(3,4,5-trimethoxyphenyl)propan-2-one22 (7,
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Scheme 5b) was obtained with 93% yields. The substitution on α-carbon in nitrostyrene
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perhaps interferes with the cyclization step leading to reduction and subsequent hydrolysis.
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SCHEME 5. a) Reaction of 2m and phenyl acetaldehyde (5) using optimal reaction
conditions; b) Reaction of 2o with iron; c) Gram scale reaction of 2m using optimal
conditions.
Based on the bioactivity of Sch-21418 (3m), a gram-scale reaction was performed on
2m (3g) which resulted in higher yields (1.5 g, 98%, Scheme 5c) of 4,4'-(pyridine-3,5-
diyl)diphenol (3m, Sch-21418). The gram scale reaction is highly desirable from a
commercial viewpoint.
CONCLUSION
In conclusion, an operationally simple and mild protocol for the synthesis of 3,5-
diarylpyridines from corresponding β-nitrostyrenes in a one-pot protocol using elemental iron
was developed. This method demonstrates a convenient approach to construct both
symmetrical and unsymmetrical 3,5-diarylpyridines. The reaction proceeds via an in-situ
reduction of nitro to imine functionality followed by trimolecular condensation and tandem
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debenzylative aromatization. An array of both symmetrical and unsymmetrical 3,5-
diarylpyridines were synthesized with good to excellent yields. Thus, we report for the first
time, a spontaneous room temperature synthesis of 3.5-diarylpyridines, which is applicable to
gram scale preparation.
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EXPERIMENTAL SECTION
General Information: The reagents, chemicals and solvents were either purchased from
commercial suppliers or prepared and purified by standard techniques. The thin layer
chromatography (TLC) was performed using pre-coated silica gel 60 F254 MERCK and TLC
plates were visualized by exposure to UV light or iodine vapours. Column chromatography
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was performed using silica gel (60–120 mesh). H, C and F NMR spectra were recorded
with 300, 400 and 500 MHz NMR instruments with tertramethylsilane (TMS) as an internal
standard. Mass spectra were recorded by 45 electro spray ionization mass spectrometry (ESI-
MS). High-resolution mass spectra (ESI-HRMS) were recorded on ESI-QTOF mass
spectrometer. Melting points were determined on an Electro thermal melting point apparatus
and are uncorrected.
General experimental procedure for the synthesis of β-nitrostyrenes (2b-p). Method A:
To a solution of aldehyde (1 equiv) in acetic acid (30 mL) was added ammonium acetate (1.1
equiv), nitromethane (3 equiv) and the reaction mixture was irradiated under Ultrasonic
frequencies (>20 kHz) at ambient temperature for 3 h. After complete consumption of
starting material (monitored by TLC), the solvent was evaporated in vacuo, added water and
extracted with ethyl acetate. The organic phase was washed with water and brine. The
combined organic phases were dried over sodium sulfate, filtered and concentrated under
reduced pressure. The crude products were purified by column chromatography using ethyl
acetate and n-hexane as eluant.
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Method B: To a stirred solution of aldehyde (1 equiv) and nitromethane (2.4 equiv) in
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methanol (25 mL) was added 1M NaOH (10 mL) drop wise at 0 oC. The reaction mixture was
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stirred at 0−10 C for 1 hour. The mixture was slowly added to a solution of 8N HCl (6 mL)
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to maintain the temperature between 0−10 C. The reaction mixture was stirred at room
temperature for 30 min. The resulted solid product was collected by filtration and washed
with water. The crude product was dissolved in ethyl acetate (50 mL), washed with water (50
mL) and the organic layer iswas dried over MgSO4. The solvent was removed and the residue
was recrystallized with hexane/ethyl acetate to get the corresponding pure product.
(E)-1-Methoxy-2-(2-nitrovinyl)benzene (2b).24 Compound 2b was synthesized by method A.
Yellow solid; 197 mg (1.10 mmol), 75% yield; mp: 44−46 oC; 1H NMR (500 MHz, CDCl3) δ
(ppm): 8.13 (d, J = 13.5 Hz, 1H), 7.87 (d, J = 13.5 Hz, 1H), 7.48‒7.42 (m, 2H), 7.04‒6.96
(m, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3)  (ppm): 159.3, 138.0, 135.3, 133.3,
132.2, 120.9, 118.9, 111.2, 55.5; MS (ESI): m/z 180 [M + H]+.
(E)-1-Methoxy-4-(2-nitrovinyl)benzene (2c).25 Compound 2c was synthesized by method A.
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Yellow crystalline solid; 205 mg (1.14 mmol), 78% yield; mp: 83−85 C; H NMR (400
MHz, CDCl3) δ (ppm): 7.98 (d, J = 13.6 Hz, 1H), 7.52 (d, J = 13.6 Hz, 1H), 7.50 (d, J = 8.8
Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3)  (ppm): 162.9,
138.9, 135.0, 131.1, 122.5, 114.8, 55.5; MS (ESI): m/z 180 [M + H]+.
(E)-1,2-Dimethoxy-4-(2-nitrovinyl)benzene (2d).26 Compound 2d was synthesized by method
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A. Yellow solid; 203 mg (0.97 mmol), 81% yield; mp: 135−137 C; H NMR (500 MHz,
CDCl3) δ (ppm): 7.97 (d, J = 13.6 Hz, 1H), 7.53 (d, J = 13.6 Hz, 1H), 7.18 (dd, J = 1.9, 8.2
13
Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H); C
NMR (100 MHz, CDCl3)  (ppm): 152.7, 149.2, 139.3, 135.1, 124.6, 122.7, 111.3, 110.2,
56.0, 55.9; MS (ESI): m/z 210 [M + H]+.
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(E)-1,2,3-Trimethoxy-5-(2-nitrovinyl)benzene (2e).27 Compound 2e was synthesized by
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method A. Yellow crystalline solid; 224 mg (0.93 mmol), 92% yield; mp: 122−124 C; H
NMR (400 MHz, CDCl3) δ (ppm): 7.94 (d, J = 13.6 Hz, 1H), 7.54 (d, J = 13.6 Hz, 1H), 6.76
(s, 2H), 3.92 (s, 3H), 3.91 (s, 6H); 13C NMR (100 MHz, CDCl3)  (ppm): 153.6, 141.7, 139.2,
136.3, 125.2, 106.4, 61.0, 56.2; MS (ESI): m/z 240 [M + H]+.
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(E)-1-Bromo-3-(2-nitrovinyl)benzene (2f).28 Compound 2f was synthesized by method A.
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Light green solid; 155 mg (0.68 mmol), 63% yield; mp: 60−62 C; H NMR (400 MHz,
CDCl3) δ (ppm): 7.93 (d, J = 13.7 Hz, 1H), 7.70 (t, J = 1.7 Hz, 1H), 7.64‒7.61 (m, 1H), 7.56
(d, J = 13.8 Hz, 1H), 7.50−7.46 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3)  (ppm): 138.0, 137.3, 134.8, 132.0, 131.6, 130.8, 127.6, 123.4; MS (ESI): m/z 228
[M + H]+.
(E)-1-Fluoro-3-(2-nitrovinyl)benzene (2g).29 Compound 2g was synthesized by method A.
Yellow solid; 175 mg (1.04 mmol), 65% yield; mp: 42−44 oC; 1H NMR (500 MHz, CDCl3) δ
(ppm): 7.97 (d, J = 13.6 Hz, 1H), 7.56 (d, J = 13.6 Hz, 1H), 7.47‒7.42 (m, 1H), 7.35 (d, J =
13
7.6 Hz, 1H), 7.26−7.18 (m, 2H); C NMR (100 MHz, CDCl3)  (ppm): 162.9 (d, J = 248.7
Hz), 138.0, 137.6, 132.1 (d, J = 8.1 Hz), 131.0 (d, J = 8.1 Hz), 125.1 (d, J = 2.2 Hz), 119.0 (d,
J = 21.3 Hz), 115.3 (d, J = 22.0 Hz); MS (ESI): m/z 168 [M + H]+.
(E)-1-Chloro-4-(2-nitrovinyl)benzene (2h).30 Compound 2h was synthesized by method A.
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Yellow solid; 209 mg (1.14 mmol), 80% yield; mp: 112−114 C; H NMR (400 MHz,
CDCl3) δ (ppm): 7.96 (d, J = 13.7 Hz, 1H), 7.56 (d, J = 13.7 Hz, 1H), 7.49 (d, J = 8.5 Hz,
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2H), 7.43 (d, J = 8.6 Hz, 2H); C NMR (100 MHz, CDCl3)  (ppm): 138.3, 137.6, 137.4,
130.2, 129.7, 128.5; MS (ESI): m/z 184 [M + H]+.
(E)-1-Fluoro-4-(2-nitrovinyl)benzene (2i).25 Compound 2i was synthesized by method A.
Yellow solid; 220 mg (1.32 mmol), 82% yield; mp: 98−100 oC; 1H NMR (400 MHz, CDCl3)
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(100 MHz, CDCl3)  (ppm): 164.8 (d, J = 255.3 Hz), 137.8, 136.8, 131.2 (d, J = 8.8 Hz),
126.3 (d, J = 2.9 Hz), 116.6 (d, J = 22.0 Hz); MS (ESI): m/z 168 [M + H]+.
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(E)-1-(2-Nitrovinyl)-4-(trifluoromethyl)benzene (2j).25 Compound 2j was synthesized by
method B. Light yellow solid; 139 mg (0.64 mmol), 56% yield; mp: 93−95 oC; 1H NMR (500
MHz, CDCl3) δ (ppm): 8.03 (d, J = 13.7 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2
Hz, 2H), 7.62 (d, J = 13.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)  (ppm): 138.8, 137.0,
133.5 (q, J = 32.7 Hz), 133.4, 129.2, 126.3 (q, J = 3.6 Hz), 124.5 (q, J = 272.5 Hz); MS
(ESI): m/z 218 [M + H]+.
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(E)-2-Bromo-1-methoxy-4-(2-nitrovinyl)benzene (2k). Compound 2k was synthesized by
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method B. Yellow solid; 196 mg (0.76 mmol), 82% yield; mp: 132−134 C; H NMR (500
MHz, CDCl3) δ (ppm): 7.91 (d, J = 13.7 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 13.6
Hz, 1H), 7.49 (dd, J = 2.1, 8.5 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 3.97 (s, 3H); 13C NMR (100
MHz, CDCl3)  (ppm): 158.8, 137.4, 135.9, 133.6, 130.4, 123.7, 112.8, 112.1, 56.5; MS
(ESI): m/z 258 [M + H]+.
(E)-1-Fluoro-2-methoxy-4-(2-nitrovinyl)benzene (2l).31 Compound 2l was synthesized by
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method B. Light yellow solid; 194 mg (0.98 mmol), 76% yield; mp: 143−145 C; H NMR
(400 MHz, CDCl3)  (ppm): 7.95 (d, J = 13.7 Hz, 1H), 7.54 (d, J = 13.7 Hz, 1H), 7.16−7.15
(m, 1H), 7.14 (d, J = 1.1 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H); 13C NMR (75 MHz,
CDCl3 + DMSO−d6)  (ppm): 154.0 (d, J = 254.7 Hz), 147.7 (d, J = 11.5 Hz), 137.8, 136.6,
126.2 (d, J = 3.8 Hz), 122.7 (d, J = 7.1 Hz), 116.2 (d, J = 19.2 Hz), 112.8, 55.8; MS (ESI):
m/z 198 [M + H]+.
(E)-4-(2-Nitrovinyl)phenol (2m).32 Compound 2m was synthesized by method A. Yellow
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solid; 3.98 g (24.18 mmol), 59% yield; mp: 163−165 C; H NMR (300 MHz, CDCl3 +
DMSO‒d6) δ (ppm): 9.81 (s, 1H), 7.97 (d, J = 13.3 Hz, 1H), 7.53 (d, J = 13.3 Hz, 1H), 7.44
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(d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H); 13C NMR (125 MHz, DMSO‒d6)  (ppm):
161.4, 139.8, 134.7, 132.2, 121.0, 116.1; MS (ESI): m/z 166 [M + H]+.
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(E)-1-(2-Nitrovinyl)naphthalene (2n).26 Compound 2n was synthesized by method A. Light
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brown solid; 160 mg (0.80 mmol), 63% yield; mp: 81−83 C; 1H NMR (400 MHz, CDCl3) δ
(ppm): 8.83 (d, J = 13.4 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.91 (d, J
= 7.6 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 13.4 Hz, 1H), 7.64‒7.62 (m, 1H), 7.59 (t,
J = 6.9 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)  (ppm): 138.5, 136.1,
133.7, 132.5, 131.5, 129.0, 127.7, 126.9, 126.7, 126.3, 125.3, 122.9; MS (ESI): m/z 200 [M +
H]+.
(E)-4-(2-Nitrovinyl)benzonitrile (2o).26 Compound 2o was synthesized by method B. Light
yellow solid; 138 mg (0.79 mmol), 52% yield; mp: 182−184 oC; 1H NMR (400 MHz, CDCl3)
δ (ppm): 8.00 (d, J = 13.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.62 (d,
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J = 13.8 Hz, 1H); C NMR (100 MHz, CDCl3)  (ppm): 139.4, 136.5, 134.3, 132.9, 129.3,
117.7, 115.2; MS (ESI): m/z 175 [M + H]+.
(E)-1,2,3-trimethoxy-5-(2-nitroprop-1-enyl)benzene (2p).33 Compound 2p was synthesized by
method A. Light yellow solid; 165 mg (0.65 mmol), 64% yield; mp: 82−84 oC; 1H NMR (400
MHz, CDCl3) δ (ppm): 8.04 (s, 1H), 6.65 (s, 2H), 3.91 (s, 3H), 3.89 (s, 6H), 2.49 (s, 3H); 13C
NMR (100 MHz, CDCl3)  (ppm): 153.3, 146.9, 139.4, 133.7, 127.6, 107.4, 60.9, 56.2, 14.1;
MS (ESI): m/z 254 [M + H]+.
General experimental procedure for the synthesis of symmetrical 3,5-diarylpyridines
(3a‒o). To a stirred solution of β-nitrostyrene (2, 1 equiv) in glacial acetic acid (5 mL) was
added iron (3 equiv) and the reaction mixture was stirred for 30 min at room temperature.
After the complete consumption of starting material (monitored by TLC), the solvent was
removed in vacuo. The residue was neutralised with 10% NaOH solution and the aqueous
phase was extracted with ethyl acetate, washed with water and brine. The combined organic
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phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The
resultant crude product was purified by silica gel column chromatography using ethyl acetate
and n-hexane as eluents and the appropriate fractions were collected to yield pure products
(3a‒o).
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3,5-Diphenylpyridine (3a).34 Light brown solid; 139 mg (0.60 mmol), 90% yield; mp:
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132‒134 oC; H NMR (400 MHz, CDCl3) δ (ppm): 8.82 (d, J = 2.1 Hz, 2H), 8.05 (t, J = 2.1
Hz, 1H), 7.65 (d, J = 7.2 Hz, 4H), 7.51 (t, J = 7.2 Hz, 4H), 7.43 (t, J = 7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ (ppm): 146.9, 137.7, 136.6, 132.8, 129.1, 128.2, 127.2; HRMS (ESI):
calcd for C17H14N m/z 232.1121 [M + H]+; found: 232.1124.
3,5-Bis(2-methoxyphenyl)pyridine (3b)19 Yellow solid; 151 mg (0.51 mmol), 93% yield; mp:
1
123‒125 oC; H NMR (400 MHz, CDCl3) δ (ppm): 8.71 (d, J = 1.8 Hz, 2H), 8.02 (t, J = 1.9
Hz, 1H), 7.41‒7.34 (m, 4H), 7.10‒7.00 (m, 4H), 3.84 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm): 156.6, 148.3, 137.6, 133.3, 130.7, 129.4, 127.1, 120.9, 111.2, 55.5; HRMS (ESI):
calcd for C19H18NO2 m/z 292.1332 [M + H]+; found: 292.1337.
3,5-Bis(4-methoxyphenyl)pyridine (3c).19 Yellow crystalline solid; 144 mg (0.49 mmol), 89%
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yield; mp: 234‒236 oC; H NMR (400 MHz, CDCl3) δ (ppm): 8.74 (d, J = 1.8 Hz, 2H), 7.96
(t, J = 2.2 Hz, 1H), 7.58 (d, J = 8.9 Hz, 4H), 7.03 (d, J = 8.8 Hz, 4H), 3.87 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ (ppm): 159.8, 145.9, 136.2, 131.9, 130.2, 128.3, 114.6, 55.4; HRMS
(ESI): calcd for C19H18NO2 m/z 292.1332 [M + H]+; found: 292.1345.
3,5-Bis(3,4-dimethoxyphenyl)pyridine (3d).18 Yellow solid; 156 mg (0.44 mmol), 93% yield;
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173‒175 oC; H NMR (400 MHz, CDCl3) δ (ppm): 8.75 (d, J = 1.9 Hz, 2H), 7.96 (t, J = 2.2
Hz, 1H), 7.20 (dd, J = 2.1, 8.2 Hz, 2H), 7.13 (d, J = 2.1 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H),
3.98 (s, 6H), 3.95 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm): 149.4, 149.3, 146.2, 136.4,
132.2, 130.5, 119.7, 111.6, 110.3, 56.0, 55.9; HRMS (ESI): calcd for C21H22NO4 m/z
352.1543 [M + H]+; found: 352.1545.
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3,5-Bis(3,4,5-trimethoxyphenyl)pyridine (3e).22 Yellow solid; 161 mg (0.39 mmol), 94%
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yield; mp: 227‒229 oC; H NMR (500 MHz, CDCl3) δ (ppm): 8.77 (d, J = 1.2 Hz, 2H), 7.94
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(t, J = 1.9 Hz, 1H), 6.81 (s, 4H), 3.95 (s, 12H), 3.92 (s, 6H); C NMR (125 MHz, CDCl3) δ
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(ppm): 153.7, 146.9, 138.4, 136.8, 133.5, 132.7, 104.6, 60.9, 56.3; HRMS (ESI): calcd for
C23H26NO6 m/z 412.1755 [M + H]+; found: 412.1762.
3,5-Bis(3-bromophenyl)pyridine (3f). Cream color solid; 136 mg (0.35 mmol), 80% yield;
mp: 160−165 oC;1H NMR (500 MHz, CDCl3) δ (ppm): 8.80 (s, 2H), 7.98 (t, J = 2.1 Hz, 1H),
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CDCl3) δ (ppm): 147.3, 139.5, 135.3, 132.8, 131.3, 130.6, 130.2, 125.8, 123.2; HRMS (ESI):
calcd for C17H12Br2N m/z 387.9336 [M (79Br, 79Br) + H]+, 389.9316 [M (79Br, 81Br) + H]+ and
391.9296 [M (81Br, 81Br) + H]+; found: 387.9332, 389.9315 and 391.9295 respectively.
3,5-Bis(3-fluorophenyl)pyridine (3g).20 Cream color solid; 135 mg (0.50 mmol), 85% yield;
mp: 137−140 oC; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.83 (d, J = 1.5 Hz, 2H), 8.01 (t, J =
2.1 Hz, 1H), 7.51–7.45 (m, 2H), 7.44–7.40 (m, 2H), 7.34 (td, J = 1.8, 9.7, 11.5 Hz, 2H), 7.14
(dt, J = 1.5, 8.4, 9.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm): 163.2 (d, J = 247.2 Hz),
147.4, 139.7 (d, J = 7.3 Hz), 135.5, 132.8, 130.7 (d, J = 8.0 Hz), 122.9 (d, J = 2.9 Hz), 115.2
(d, J = 21.2 Hz), 114.2 (d, J = 22.7 Hz); 19F NMR (376 MHz, CDCl3) δ ‒112.09; HRMS
(ESI): calcd for C17H12F2N m/z 268.0932 [M + H]+; found: 268.0936.
3,5-Bis(4-chlorophenyl)pyridine (3h).35 Cream color solid; 134 mg (0.44 mmol), 82% yield;
mp: 172‒1744 oC; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.79 (d, J = 2.1 Hz, 2H), 7.97 (t, J =
2.1 Hz, 1H), 7.57 (d, J = 8.7 Hz, 4H), 7.48 (d, J = 8.7 Hz, 4H); 13C NMR (125 MHz, CDCl3)
δ (ppm): 147.0, 135.9, 135.6, 134.6, 132.5, 129.3, 128.5; HRMS (ESI): calcd for C17H12Cl2N
m/z 300.0341 [M + H]+; found: 300.0346.
3,5-Bis(4-fluorophenyl)pyridine (3i).35 Cream color solid; 135 mg (0.50 mmol), 85% yield;
mp: 171‒172 oC; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.77 (d, J = 1.9 Hz, 2H), 7.95 (t, J =
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2.1 Hz, 1H), 7.60 (q, J = 5.2, 8.7 Hz, 4H), 7.20 (t, J = 8.5 Hz, 4H); C NMR (125 MHz,
CDCl3) δ (ppm): 163.0 (d, J = 247.9 Hz), 146.8, 135.7, 133.7, 132.6, 128.9 (d, J = 8.2 Hz),
116.1 (d, J = 21.8); 19F NMR (376 MHz, CDCl3) δ ‒113.81; HRMS (ESI): calcd for
C17H12F2N m/z 268.0932 [M + H]+; found: 268.0943.
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3,5-Bis(4-(trifluoromethyl)phenyl)pyridine (3j). Yellow solid; 115 mg (0.31 mmol), 68%
yield; mp: 160−163 oC; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.89 (d, J = 2.1 Hz, 2H), 8.07
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(t, J = 2.1 Hz, 1H), 7.77 (q, J = 8.5, 13.4 Hz, 8H); C NMR (100 MHz, CDCl3) δ (ppm):
147.8, 140.9, 135.5, 133.1, 130.7 (q, J = 33.0 Hz), 127.6, 126.1 (q, J = 2.9, 6.6 Hz), 125.3 (q,
J = 272.1 Hz); 19F NMR (376 MHz, CDCl3) δ ‒62.77; HRMS (ESI): calcd for C19H12F6N m/z
368.0868 [M + H]+; found: 368.0875.
3,5-Bis(3-bromo-4-methoxyphenyl)pyridine (3k). Yellow solid; 144 mg (0.32 mmol), 83%
yield; mp: 179−183 oC; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.74 (d, J = 1.6 Hz, 2H), 7.91
(t, J = 2.1 Hz, 1H), 7.83 (d, J = 2.3 Hz, 2H), 7.56 (dd, J = 2.3, 8.5 Hz, 2H), 7.03 (d, J = 8.5
Hz, 2H), 3.97 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm): 156.1, 146.3, 132.0, 131.9,
131.3, 127.2, 112.5, 112.3, 56.4; HRMS (ESI): calcd for C19H16Br2NO2 m/z 447.9548 [M
(79Br, 79Br) + H]+, 449.9527 [M (79Br, 81Br) + H]+ and 451.9507 [M (81Br, 81Br) + H]+; found:
447.9588, 449.9567 and 451.9551 respectively.
3,5-Bis(4-fluoro-3-methoxyphenyl)pyridine (3l). Yellow solid; 142 mg (0.43 mmol), 86%
yield; mp: 187−189 oC ; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.77 (d, J = 1.9 Hz, 2H), 7.93
(t, J = 2.1 Hz, 1H), 7.23−7.17 (m, 4H), 7.16−7.13 (m, 2H), 3.98 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 152.7 (d, J = 247.9 Hz), 148.1 (d, J = 11.0 Hz), 146.9, 136.0, 134.2 (d, J =
3.6 Hz), 132.7, 119.8 (d, J = 7.3 Hz), 116.6 (d, J = 18.3 Hz), 112.6 (d, J = 2.2 Hz), 56.4; 19F
NMR (376 MHz, CDCl3) δ ‒135.53; HRMS (ESI): calcd for C19H16F2NO2 m/z 328.1144 [M
+ H]+; found: 328.1148.
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4,4'-(Pyridine-3,5-diyl)diphenol (3m).7d,36 Light brown solid; 1.56 g (5.9 mmol), 98% yield;
mp: 256‒258 oC; 1H NMR (500 MHz, DMSO–d6) δ (ppm): 9.68 (s, 2H), 8.71 (d, J = 1.5 Hz,
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(125 MHz, DMSO–d6) δ (ppm): 157.6, 144.8, 135.4, 130.3, 128.1, 127.6, 115.8; HRMS
(ESI): calcd for C17H14NO2 m/z 264.1019 [M + H]+; found: 264.1020.
3,5-Di(naphthalen-1-yl)pyridine (3n).20,22 Yellow solid; 118 mg (0.35 mmol), 71% yield; mp:
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173−175 oC; H NMR (500 MHz, CDCl3) δ (ppm): 8.85 (d, J = 1.8 Hz, 2H), 8.01 (t, J = 1.8
Hz, 1H), 7.98–7.92 (m, 6H), 7.58 (d, J = 7.2 Hz, 2H), 7.56–7.50 (m, 6H); 13C NMR (100
MHz, CDCl3) δ (ppm): 149.1, 138.8, 136.0, 135.9, 133.8, 131.4, 128.7, 128.5, 127.6, 126.6,
126.1, 125.4, 125.2; HRMS (ESI): calcd for C25H18N m/z 332.1434 [M + H]+; found:
332.1442.
4,4'-(Pyridine-3,5-diyl)dibenzonitrile (3o).5 Yellow solid; 113 mg (0.40 mmol), 70% yield;
mp: 291‒293 oC; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.90 (s, 2H), 8.05 (s, 1H), 7.82 (d, J
= 8.1 Hz, 4H), 7.76 (d, J = 8.2 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ (ppm): 148.0, 141.6,
135.1, 132.9, 127.9, 118.3, 112.4; HRMS (ESI): calcd for C19H12N3 m/z 282.1026 [M + H]+;
found: 282.1032.
General experimental procedure for the synthesis of unsymmetrical 3,5-diarylpyridines
(4a‒e). To a stirred solution of two different β-nitrostyrenes 2 (1:1, 1 mmol) in glacial acetic
acid (5 mL) was added iron (6 mmol or 3 mmol each β-nitrostyrenes) and the reaction
mixture was stirred for 30 min at room temperature. After the complete consumption of
starting material (monitored by TLC), the solvent was removed in vacuo. The residue was
neutralised with 10% NaOH solution and the aqueous phase was extracted with ethyl acetate,
washed with water and brine. The combined organic phases were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The resultant crude product was purified
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by silica gel column chromatography using ethyl acetate and n-hexane as eluents and the
appropriate fractions were collected to yield pure products (4a‒e).
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3-(3,4-Dimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)pyridine (4a). Yellow solid; 98.8 mg
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(0.25 mmol), 62% yield; mp: 186−189 C; H NMR (400 MHz, CDCl3) δ (ppm): 8.80‒8.73
(m, 2H), 7.98‒7.93 (m, 1H), 7.20 (dd, J = 2.1, 8.3 Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J = 1.9, 8.3
Hz, 1H), 6.80 (s, 2H), 3.97 (s, 3H), 3.95 (s, 9H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
(ppm): 153.8, 149.5, 146.8, 146.6, 143.3, 138.4, 136.9, 133.5, 132.8, 132.6, 130.4, 119.7,
111.7, 110.4, 104.7, 60.9, 56.3, 56.1, 56.0; HRMS (ESI): calcd for C22H24NO5 m/z 382.1649
[M + H]+; found: 382.1654.
4-(5-Phenylpyridin-3-yl)phenol (4b). Yellow solid; 97.3 mg (0.39 mmol), 65% yield; mp:
o
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230−233 C ; H NMR (300 MHz, DMSO‒d6) δ (ppm): 9.71 (s, 1H), 8.80 (dd, J = 1.7, 5.1
Hz, 2H), 8.20 (t, J = 2.1 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.53 (t, J
= 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz,
DMSO‒d6) δ (ppm): 157.7, 145.9, 145.4, 137.0, 135.7, 135.5, 131.1, 129.0, 128.2, 128.1,
127.4, 127.0, 115.8; HRMS (ESI): calcd for C17H14NO m/z 248.1070 [M + H]+; found:
248.1072.
3-Phenyl-5-(4-(trifluoromethyl)phenyl)pyridine (4c). White solid; 64.7 mg (0.21 mmol), 47%
yield; mp: 160−163 C; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92‒8.81 (m, 2H), 8.01‒8.04
o
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(m, 1H), 7.80‒7.74 (m, 4H), 7.67‒7.63 (m, 2H), 7.55‒7.49 (m, 2H), 7.48‒7.41 (m, 1H); C
NMR (125 MHz, CDCl3) δ (ppm): 147.8, 146.9, 141.1 (q, J = 47.2 Hz), 137.6 (q, J = 42.6
Hz), 136.7 (q, J = 26.3 Hz), 135.4 (q, J = 28.1 Hz), 133.1, 133.0, 132.9, 129.1 (q, J = 9.9 Hz),
128.3 (q, J = 25.4 Hz), 127.6, (q, J = 3.6 Hz), 127.2, 126.1 (q, J = 8.1 Hz); HRMS (ESI):
calcd for C18H13F3N m/z 300.0995 [M + H]+; found: 300.1004.
4-(5-(4-Fluorophenyl)pyridin-3-yl)phenol (4d). Light yellow solid; 97.9 mg (0.36 mmol),
61% yield; mp: 226−229 oC; 1H NMR (400 MHz, DMSO‒d6) δ (ppm): 9.72 (s, 1H), 8.79 (dd,
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J = 1.9, 11.3 Hz, 2H), 8.20 (t, J = 2.2 Hz, 1H), 7.89 (q, J = 5.4, 8.8 Hz, 2H), 7.68 (d, J = 8.5
Hz, 2H), 7.35 (t, J = 8.9 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, DMSO‒d6)
δ (ppm): 162.2 (d, J = 245.0 Hz), 157.8, 145.8 (d, J = 8.0 Hz), 145.3 (d, J = 8.8 Hz), 135.5,
134.5, 133.5, 131.2 (d, J = 9.5 Hz), 129.2 (d, J = 8.0 Hz), 128.2, 127.3, 115.8 (t, J = 8.8 Hz);
19F NMR (376 MHz, CDCl3) δ ‒109.62; HRMS (ESI): calcd for C17H13FNO m/z 266.0976
[M + H]+; found: 266.0981.
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3-(4-Chlorophenyl)-5-(3,4-dimethoxyphenyl)pyridine (4e). Yellow solid; 90.1 mg (0.27
o
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mmol), 58% yield; mp: 180−183 C; H NMR (400 MHz, CDCl3) δ (ppm): 8.87‒8.70 (m,
2H), 7.96 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1, 2H), 7.19 (d, J = 7.3 Hz, 1H),
7.13 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 149.5, 149.4, 147.0, 146.2, 136.6, 136.2, 135.5, 134.5, 132.3, 130.3, 129.3,
128.5, 119.7, 111.7, 110.3, 56.1, 56.0; HRMS (ESI): calcd for C19H17ClNO2 m/z 326.0942
[M + H]+; found: 326.0945.
1-(3,4,5-Trimethoxyphenyl)propan-2-one (7).37 Light brown solid; 83.2 mg (0.37 mmol), 94%
yield; mp: 62‒64 oC; 1H NMR (500 MHz, CDCl3) δ (ppm): 6.40 (s, 2H), 3.85 (s, 6H), 3.84 (s,
13
3H), 3.63 (s, 2H), 2.18 (s, 3H); C NMR (125 MHz, CDCl3) δ (ppm): 206.4, 153.4, 137.0,
129.7, 106.3, 60.8, 56.1, 51.2, 29.2; MS (ESI): m/z 225 [M + H]+.
ACKNOWLEDGEMENT
The authors, M.S, J.C and N.H.K acknowledge the Council of Scientific and Industrial
Research (CSIR), New Delhi (India) for the financial support under the 12th Five Year Plan
project “Affordable Cancer Therapeutics (ACT)” (CSC0301). This project was also
supported by King Saud University, Deanship of Scientific Research Chair.
ASSOCIATED CONTENT
Supporting Information
“This material is available free of charge via the Internet at http://pubs.acs.org.” Copies of 2D
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NMR (COSY and NOESY of 3e), 1H, and 13C NMR spectra for the products (PDF).
NOTES
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The authors declare no competing financial interest.
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