One-pot synthesis of 2,4,6-triarylpyridines from β-nitrostyrenes, substituted salicylic aldehydes and ammonium acetate

Abstract

A protocol for the synthesis of 2,4,6-trisubstituted pyridines from the β-nitrostyrenes, available substituted salicylic aldehydes and ammonium acetate was developed. The present strategy features high chemoselectivity and excellent tolerance for a broad range of functional groups, in which the β-nitrostyrenes generated from aldehydes and nitromethane, substituted salicylic aldehydes and ammonium acetate were respectively employed as simple and easily available substrates. This efficient method provides fast access to a variety of structurally diverse pyridine derivatives. The structures of two typical products were confirmed by X-ray crystallography.

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Pyridines are privileged structural motifs and an important class of six-membered nitrogen containing heterocycles which are widely found in numerous natural products,¹ pharmaceuticals,² agrochemicals,³ electrochemicals,⁴ and functional organic materials.⁵ Among them, 2,4,6-triarylpyridines were widely investigated recently because of the broad spectrum of their biological and pharmaceutical properties (Fig. 1) such as anti-cancer, anti-malarial, vasodilator, anti-covulsant, anesthetic, anti-epileptic character and their use as pesticidial, fungicidal and herbicidal agrochemicals.⁶

Fig. 1 Biologically active 2,4,6-triarylpyridines.

Due to their π-stacking ability, 2,4,6-triarylpyridines were also used in supramolecular chemistry as building blocks⁷ or ligands in coordination chemistry and transition metal catalysis.⁸ Additionally, many synthetically symmetrical triarylthio-, triarylseleno- and triaryltelluoropyrylium salt compounds based on 2,4,6-triarylpyridine nucleus with the π-conjugated polyaryl motifs as the photosensitizers have been studied in photodynamic cell-specific cancer therapy.⁹ Given their immense pharmaceutical and material usefulness, the development of efficient syntheses of these functionalized 2,4,6-triarylpyridines has thus attracted many organic and medicinal chemists for decades. Traditionally, there were several methods for the preparation of the 2,4,6-triarylpyridine derivatives,¹⁰ including Chichibabin synthesis,^11–13 and Kröhnke synthesis.^14–16 Apart from ammonium acetate, various containing-nitrogen compounds were used as nitrogen sources in the annulation synthesis of 2,4,6-trisubstituted pyridines. For example, the intermolecular Michael addition reaction and an intramolecular condensation of 1-arylethylamines and ynones through the direct β-C(sp³)–H functionalization of enaminones under metal-free conditions directly constructed 2,4,6-trisubstituted pyridines.¹⁷ Particularly, ketones with amines as simple substrates have a structural advantage to provide, formally, the vinyl amine moiety in the assembly of 2,4,6-trisubstituted pyridines via HOTf-catalyzed and solvent-free system.¹⁸ Very recently, Wu and co-workers reported an iodine-triggered the decarboxylation–deamination of amino acids for the efficient preparation of 2,4,6-trisubstituted pyridines based on the catabolism and reconstruction behaviors of amino acids.¹⁹ Similarly, the combinational employment of iodine and triethylamine promoted effectively to trigger the oxime based synthesis of 2,4,6-trisubstituted pyridines.²⁰ Guan and co-workers also described an iron-catalyzed cyclization of ketoxime carboxylates and N,N-dialkylanilines for the modular synthesis of diverse 2,4,6-trisubstituted pyridines.²¹ Additionally, the functionalization of existing pyridines was another prominent reaction, such as transition-metal catalyzed direct arylation of pyridines via C–H activation.²²

Owing to large spectrum of fascinating applications on pharmaceuticals and materials, the development of methodologies for a direct access to highly substituted and specifically functionalized 2,4,6-triarylpyridines is a continuing challenge in modern synthetic organic chemistry.

Multicomponent reactions received increasing attention because of their efficiency and simplicity, appealing for synthetic and medicinal researchers interested in rapidly accessing new diversity and complexity of targeting moleculars.²³ Recently a large number of reports have indicated that substituted β-nitrostyrenes are important synthetic intermediates and starting materials for the synthesis of a variety of useful building blocks, which widely were employed in the multicomponent reactions as an important component.²⁴ Our previous results also showed that substituted β-nitrostyrenes as essential building blocks were efficiently used to construct heterocyclic cores via multicomponent reactions.²⁵

In this context, nowadays, the multicomponent reactions of β-nitrostyrenes with 2-(iminomethyl)phenols generated from available substituted salicylic aldehydes and ammonium acetate largely leads the way in the synthesis of 2,4,6-triarylpyridines. Notably, this work represents a fascinating approach for the direct construction of two C–N bonds and two C–C bonds via cyclization in a single step to yield diversely asymmetric 2,4,6-triarylpyridines.

We commenced our investigation using 1a, 2a and ammonium acetate (AcONH₄) as the model substrates (Table 1). Initially, in the presence of potassium carbonate (K₂CO₃) as the basic promoter, the reaction was carried out with various solvents, the results indicated that solvents such as EtOH, CH₃CN, toluene and pyridine disfavored the desired transformation (Table 1, entries 1–4) and that polar solvent DMF was the best reaction media (Table 1, entry 5). However, a small improvement in the yield was observed with mixing solvent DMF/EtOH (3 : 1, v/v, mL) (Table 1, entry 6). Further studies on the reaction without basic promoters indicated that the basic promoters should have to be used to stimulate the reaction (Table 1, entry 7). Encouraged by this result, we switched over to optimizing the reaction conditions, and different bases such as the common organic bases triethylamine, piperidine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) and strong inorganic base sodium hydroxide, but none of them was found to be better than K₂CO₃ (Table 1, entries 8–10) despite the complete time was shortened, the strong inorganic base such as sodium hydroxide (NaOH) failed to react under identical conditions (Table 1, entry 11), this maybe because that β-nitrostyrenes afforded the polymerization in the presence of a strong base such as NaOH. Then, we proceeded to investigate the optimum amount of K₂CO₃ required, and it was found that 2 equiv. was sufficient, as upon increasing the amount no change in the yield was observed (Table 1, entries 12 and 14). As shown in Table 1 (entry 6, entries 12–14), K₂CO₃ proved to be the best base among those tested to give the desired product in a maximum yield of 82%. Subsequently, ratio optimization of the mixed solvents showed that the ratio 4 : 1 (DMF/EtOH) was the optimum ratio (Table 1, entry 12, entries 15 and 18). The results indicated that the ratio of DMF/EtOH mixed solvents played an important part in the synthesis of 2,4,6-triarylpyridines via one-pot reaction due to that different ratio of DMF/EtOH mixed solvents should determine the temperature of the reaction system despite under refluxing. From the above results, the reaction conditions were affirmed: 1.0 equivalent of 1a, 2.05 equivalents of 2a, 1.1 equivalents of AcONH₄, and 2.0 equivalents of K₂CO₃ in 5 mL mixed solvents DMF/EtOH (4 : 1, v/v, mL) at 122 °C (reaction system temperature) under refluxing for 5 h.

Table 1 Reactions of 1a and 2a with ammonium acetate under different conditions^a

Entry	Base	Solvent	T (°C)	t (h)	Yield^b (%)
a Reaction conditions: 1 mmol of 1a, 2.05 equiv. of 2a, 1.1 equiv. of AcONH4, appropriate basic reagent, 5 mL solvent, unless otherwise noted.b Isolated yield.
1	K2CO3 (1.0)	EtOH	Reflux	5	0
2	K2CO3 (1.0)	MeCN	Reflux	5	Trace
3	K2CO3 (1.0)	PhMe	Reflux	5	Trace
4	K2CO3 (1.0)	Pyridine	Reflux	5	Trace
5	K2CO3 (1.0)	DMF	Reflux	5	50
6	K2CO3 (1.0)	DMF/EtOH (3 : 1)	118	5	53
7	(—)	DMF/EtOH (3 : 1)	118	24	0
8	Et3N (1.0)	DMF/EtOH (3 : 1)	118	5	31
9	Piperidine (1.0)	DMF/EtOH (3 : 1)	118	4	33
10	DBU (1.0)	DMF/EtOH (3 : 1)	118	3	52
11	NaOH (1.0)	DMF/EtOH (3 : 1)	118	5	Trace
12	K2CO3 (2.0)	DMF/EtOH (3 : 1)	118	5	82
13	K2CO3 (3.0)	DMF/EtOH (3 : 1)	118	5	82
14	K2CO3 (4.0)	DMF/EtOH (3 : 1)	118	5	81
15	K2CO3 (2.0)	DMF/EtOH (2 : 1)	98	8	78
16	K2CO3 (2.0)	DMF/EtOH (4 : 1)	122	5	91
17	K2CO3 (2.0)	DMF/EtOH (5 : 1)	124	5	90
18	K2CO3 (2.0)	DMF/EtOH (8 : 1)	131	5	85

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The scope of this transformation was then investigated under the optimum conditions using different substituted salicylic aldehydes, and available substituted β-nitrostyrenes. The results are summarized in Table 2. Generally, aromatic β-nitroalkenes employed reacted smoothly to give the corresponding pyridines in good to excellent yields (Table 2, 3a–u, 60–91%), regardless of the functional groups at the para-, meta-, or ortho-position. A large range of functional groups on the benzene ring such as methyl, methoxyl, fluoro, chloro, bromo, iodo, nitro, and ethoxyl were all tolerated well. The electronic effects of the substituents on the yield showed the slight difference. Notably, β-nitrostyrenes bearing an electron-donating group on the aromatic ring (Table 2, entries 1–7) worked better than those bearing an electron-withdrawing group. The results also showed that the steric effects of the substituents are apparent, and the β-nitrostyrene with an iodo group afforded relatively low yield. Generally, the β-nitrostyrenes with para-position phenyl groups gave the products in higher yields than those with ortho-, or meta-position phenyl groups (Table 2, entries 8–10). Other β-nitrostyrenes such as 2-(2-nitrovinyl)thiophene, 2-(2-nitrovinyl)furan and 3-(2-nitrovinyl)thiophene also produced the furyl and thienyl products in good yields (Table 2, entries 17–19).

Table 2 Scope with respect to salicylic aldehydes and β-nitrostyrenes^a

Entry	R^1	R	Product	Yield^b (%)
a Salicylic aldehydes 1a–g (1 mmol), β-nitrostyrenes 2a–n (2.05 mmol) and K2CO3 (2.0 equiv.), DMF/EtOH (4 : 1, v/v, mL), reflux (122 °C), 9 h.b Isolated yield.c 2-(2-Nitrovinyl)furan.d 2-(2-Nitrovinyl)thiophene.e 3-(2-Nitrovinyl)thiophene.
1	H	p-OMe	3a	91
2	3-EtO	H	3b	80
3	H	p-Me	3c	83
4	H	H	3d	72
5	5-Cl	p-MeO	3e	70
6	5-Br	p-MeO	3f	72
7	3-Br-5-Cl	p-MeO	3g	62
8	H	o-Cl	3h	61
9	H	m-Cl	3i	67
10	H	p-Cl	3j	86
11	H	p-Br	3k	73
12	H	p-I	3l	60
13	5-F	p-Cl	3m	69
14	5-Cl	p-Cl	3n	76
15	5-Br	p-Cl	3o	77
16	5-NO2	p-Cl	3p	68
17^c	H	Furan-2-	3q	78
18^d	H	Thiophen-2-	3r	73
19^e	H	Thiophen-3-	3s	71
20	H	3,4-OCH2CH2O	3t	64
21	3-Br-5-Cl	m-MeO	3u	66

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Moreover, multisubstituted β-nitrostyrene also reacted under the conditions to afford the corresponding products in moderate yields (Table 2, entry 20). Similarly, substituted salicylic aldehydes bearing an electron-donating group on the aromatic ring were superior for the imine formation/addition reaction than those bearing an electron-withdrawing group (Table 2, entries 2, 5–7, 14–16). Unfortunately, when the salicylic aldehydes were replaced by the common aromatic aldehydes, the reactions were dramatically blocked and the desired products were not yielded. Because the solubility of compound 3p is very low in all organic solvents, just its ¹H NMR was obtained, a clear ¹³C NMR was not gotten. Except compound 3p, other corresponding 2,4,6-trisubstituted pyridines were analyzed by their ¹H NMR, ¹³C NMR and MS. Characteristic ¹H chemical shift of Ar-OH, pyridine C(3)–H and C(5)–H at δ ca. 15.0 (s), 7.90 (s) and 7.70 (s), unequivocally indicated the exclusive chemical environment of hydroxyl and pyridine protons. Product 2,4,6-trisubstituted pyridines 3b and 3d were further characterized by single X-ray crystallography (Fig. 2).²⁶

Fig. 2 Molecular structure of products 3b and 3d.

Moreover, for the products 3b and 3d, an intermolecular hydrogen bond was observed on the basis of its X-ray crystallographic data. See ESI† for the bond length of the intermolecular hydrogen bond of the products 3b and 3d. Additionally, the existence of the intermolecular hydrogen bond was further confirmed by the proton-NMR of the ArOH proton. In CDCl₃ or DMSO-d₆, the OH proton, hydrogen bonded with nitrogen of the pyridine moiety, resonates at ca. 15.0 ppm as a single peak, not as a common broad single peak, this was because the intramolecular hydrogen bond caused difficulties of exchanging the Ar-OH proton with deuterated solvents.

The mechanism proposed for the reaction is illustrated in Scheme 1. Firstly, in the presence of weak basic potassium carbonate, the reaction of salicylic aldehyde and ammonium acetate generated a stable intermediate 2-(iminomethyl)phenol [A], which has an intramolecular hydrogen bond. The formation of the intramolecular hydrogen bond not only stabilizes the structure of imine but also strengthens the basicity and nucleophilicity of imine. Nucleophilic addition of intermediate [A] to β-nitrostyrene afforded 1,4-dipole intermediate [B]. The intermolecular [4 + 2] cyclization of 1,4-dipole intermediate [B] with β-nitrostyrene gave the intermediate hexahydropyridine [C]. Finally, removal of two nitrous acids mediated by potassium carbonate and oxidative aromatization of the intermediate hexahydropyridine [C] produced the 2,4,6-triarylpyridine. Some control experiments were tested for our proposed mechanism. Under the optimized conditions, the model reaction of salicylic aldehyde, 1-chloro-4-(2-nitrovinyl)benzene and ammonium acetate was carried out in the optimized reaction conditions for 3 h aimed at yielding some key intermediates and supporting the mechanistic proposal, but the reaction system was very complicated after workup, the desired intermediates were not isolated by flash chromatography. After workup, the solid mixture was measured by high-resolution ESI mass spectra to afford a stronger ion peak: 392.0604 (m/z), which corresponded to the mass of the molecular ion (M + 1) for the final product 2-(4,6-bis(4-chlorophenyl)pyridin-2-yl)phenol (see ESI†). Additionally, the two mass of the molecular ion (M + 1): 484.4720 and 437.1934, should belong to 2-(4,6-bis(4-chlorophenyl)-3,5-dinitro-1,2-dihydropyridin-2-yl)phenol from the desired inter>mediate 2-(4,6-bis(4-chlorophenyl)-3,5-dinitropiperidin-2-yl)phenol and 2-(4,6-bis(4-chlorophenyl)-3-nitropyridin-2-yl)phenol from the desired intermediate 2-(4,6-bis(4-chlorophenyl)-3-nitro-1,2,3,6-tetrahydropyridin-2-yl)phenol. The results indicated there was a path that leads to the final product, the intermolecular cyclization gave the desired intermediate dinitropiperidines, next, HNO₂ was removed by K₂CO₃ to give the desired intermediate nitrotetrahydropyridines, another HNO₂ was removed by K₂CO₃ to give the desired intermediate dihydropyridines again, the final aromatization yielded the products by air.

Scheme 1 Tentative reaction mechanism.

Conclusions

In summary, we have developed a protocol for the synthesis of polysubstituted pyridines from the β-nitrostyrenes, available substituted salicylic aldehydes and ammonium acetate. The present strategy features high chemoselectivity and excellent tolerance for a broad range of functional groups, in which, the β-nitrostyrenes generated from aldehydes and nitromethane, substituted salicylic aldehydes and ammonium acetate were respectively employed as simple and easily available substrates. Moreover, the method also opens a new entry to β-nitrostyrene based N-heterocycle synthesis based on basic systems.

Experimental section

All melting points were determined in a Yanaco melting point apparatus and are uncorrected. IR spectra were recorded in a Nicolet FT-IR 5DX spectrometer. The ¹H NMR (400 or 600 MHz) and ¹³C NMR (100 or 150 MHz) spectra were recorded in a Bruker AV-400 or 600 spectrometer with TMS as internal reference in CDCl₃ or DMSO-d₆ solutions. The J values are given in hertz. Only discrete or characteristic signals for the ¹H NMR are reported. High-resolution ESI mass spectra were obtained on a UHR-TOF maXis (ESI) mass spectrometer. X-ray crystallographic analysis was performed with a SMART APEX-II diffractometer. Flash chromatography was performed on silica gel (230–400 mesh) eluting with ethyl acetate–hexanes mixture. All reactions were monitored by thin layer chromatography (TLC). All reagents and solvents were purchased from commercial sources and purified commonly before used.

The mixture of substituted salicylic aldehydes (1.0 mmol) and ammonium acetate (85 mg, 1.1 mmol) in the solution of DMF and EtOH (4 : 1, 5 mL) was stirred at room temperature for 30 min. To the mixture was appropriate β-nitrostyrenes (2.05 mmol) and potassium carbonate (138.2 mg, 1.0 mmol) at room temperature. The resultant mixture was stirred at 140 °C for 5–8 h, and the completion of reaction was confirmed by TLC (hexanes/EtOAc, 10/1). Subsequently, the solvents were removed by vacuum, the residues was extracted with dichloromethane (15 mL × 2). The organic phase was washed with water (10 mL) and brine (15 mL), and dried over anhydrate sodium sulfate. After removal of dichloromethane, the crude product was purified by flash chromatography (silica gel, EtOAc/hexanes, 1/20) to give the desirable products 3a–u.

2-(4,6-Bis(4-methoxyphenyl)pyridin-2-yl)phenol (3a)

Yellow solid; mp: 123.2–123.7 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm):14.94 (s, 1H), 7.89–7.86 (m, 4H), 7.67 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.27 (dd, J = 7.8, 7.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 3H), 6.98 (d, J = 8.4 Hz, 2H), 6.88 (dd, J = 7.8, 7.2 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 159.9, 159.8, 159.2, 156.8, 153.8, 149.6, 130.4, 129.9, 129.7, 127.4, 127.3, 125.3, 118.2, 117.7, 117.5, 115.0, 113.6, 113.5, 113.4, 54.4, 54.3; IR (KBr, cm⁻¹) ν: 3435, 2931, 2836, 1748, 1604, 1514, 874, 823; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₂NO₃: 384.1594; found: 384.1610.

2-(4,6-Diphenylpyridin-2-yl)-6-ethoxyphenol (3b)

Yellow solid; mp: 158.3–158.9 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm):15.18 (s, 1H), 7.95 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.75 (s, 1H), 7.64 (d, J = 6.6 Hz, 2H), 7.47–7.37 (m, 7H), 6.67 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 8.4, 7.8 Hz, 1H), 4.09 (q, J = 7.2 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 157.2, 145.1, 150.2, 149.7, 147.7, 137.5, 136.5, 128.6, 128.4, 128.2, 126.2, 126.0, 118.0, 125.4, 117.1, 116.9, 116.1, 115.0, 113.1, 63.3, 13.9; IR (KBr, cm⁻¹) ν: 3447, 2880, 1750, 1606, 1541, 1492, 1428, 869, 817, 765; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₂NO₂: 368.1645; found: 368.1658.

2-(4,6-Di-p-tolylpyridin-2-yl)phenol (3c)

Yellow solid; mp: 160.1–160.8 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm): 14.85 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.25–7.22 (m, 5H), 6.98 (d, J = 8.4 Hz, 1H), 6.85 (dd, J = 7.2, 7.8 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 159.2, 156.9, 154.1, 150.0, 138.7, 138.5, 134.6, 134.3, 130.5, 128.9, 128.8, 126.0, 125.8, 125.3, 118.1, 117.7, 117.5, 115.6, 114.2, 20.3, 20.3; IR (KBr, cm⁻¹) ν: 3444, 2926, 2838, 1750, 1604, 1540, 1509, 1434, 828, 748; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₂NO: 352.1696; found: 352.1710.

2-(4,6-Diphenylpyridin-2-yl)phenol (3d)

Yellow solid; mp: 163.1–163.3 °C (PE/EA); ¹H-NMR (CDCl₃, 400 MHz) δ (ppm):14.71 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.50–7.40 (m, 6H), 7.27 (dd, J = 7.2, 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 7.6, 7.6 Hz, 1H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 159.1, 157.1, 154.3, 150.2, 137.5, 137.1, 130.6, 128.6, 128.4, 128.2, 128.1, 126.2, 125.9, 125.4, 118.0, 117.8, 117.6, 116.2, 114.7; IR (KBr, cm⁻¹) ν: 3451, 1750, 1604, 1540, 1508, 1431, 864, 810, 748; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₈NO: 324.1383; found: 324.1396.

2-(4,6-Bis(4-methoxyphenyl)pyridin-2-yl)-4-chlorophenol (3e)

Yellow solid; mp: 152.3–153.0 °C (PE/EA); ¹H-NMR (DMSO-d₆, 600 MHz) δ (ppm): 14.78 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.37 (dd, J₁ = 9.0 Hz, J₂ = 3.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H); ¹³C-NMR (DMSO-d₆, 100 MHz) δ (ppm): 160.1, 160.0, 157.7, 155.3, 153.8, 150.1, 130.2, 129.4, 129.2, 127.5, 127.3, 124.9, 122.5, 119.0, 119.0, 115.5, 113.7, 113.6, 113.5, 54.5, 54.4; IR (KBr, cm⁻¹) ν: 3442, 2925, 2839, 1746, 1602, 1524, 1477, 1443, 875, 820; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₁ClNO₃: 418.1204; found: 418.1209.

2-(4,6-Bis(4-methoxyphenyl)pyridin-2-yl)-4-bromophenol (3f)

Yellow solid; mp: 168.2–168.6 °C (PE/EA); ¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 14.99 (s, 1H), 7.94 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 10.0 Hz, 2H), 6.98 (d, J = 9.6 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 160.0, 159.9, 158.3, 155.4, 153.9, 149.8, 132.9, 129.4, 129.4, 127.8, 127.4, 127.2, 119.8, 119.4, 115.4, 113.7, 113.5, 113.4, 109.4, 54.4, 54.4; IR (KBr, cm⁻¹) ν: 3435, 2922, 2836, 1747, 1606, 1540, 1450, 1436, 820, 751; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₁BrNO₃: 462.0699; found: 462.0705.

2-(4,6-Bis(4-methoxyphenyl)pyridin-2-yl)-6-bromo-4-chlorophenol (3g)

Yellow solid; mp: 228.7–229.6 °C (PE/EA); ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 16.56 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 8.12 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 3.84 (s, 6H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 160.1, 160.0, 154.9, 154.4, 153.7, 150.1, 132.8, 129.0, 128.6, 127.4, 127.3, 124.1, 122.3, 119.5, 116.8, 114.7, 113.6, 113.5, 111.9, 54.5, 54.4; IR (KBr, cm⁻¹) ν: 3442, 2926, 2866, 1738, 1598, 1544, 1506, 1446, 875, 812, 753; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₀BrClNO₃: 496.0310; found: 496.0303.

2-(4,6-Bis(4-chlorophenyl)pyridin-2-yl)phenol (3h)

Yellow solid; mp: 187.1–187.6 °C (PE/EA); ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.90 (s, 1H), 8.42 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.22 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 7.2, 7.2 Hz, 1H), 6.97–6.74 (m, 2H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 159.0, 157.4, 153.3, 149.2, 135.7, 135.4, 135.0, 134.9, 130.9, 128.5, 128.4, 127.5, 127.2, 125.4, 118.0, 117.8, 117.6, 115.8, 114.8; IR (KBr, cm⁻¹) ν: 3435, 1747, 1603, 1536, 1493, 1434, 819, 747; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₆Cl₂NO: 392.0603; found: 392.0605.

2-(4,6-Bis(2-chlorophenyl)pyridin-2-yl)phenol (3i)

Yellow solid; mp: 154.6–155.2 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm): 14.09 (s, 1H), 7.93 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.61 (dd, J₁ = 7.8, J₂ = 2.4 Hz, 1H), 7.60 (s, 1H), 7.49–7.47 (m, 1H), 7.46 (dd, J₁ = 7.8, J₂ = 2.4 Hz, 1H), 7.39–7.38 (m, 1H), 7.35–7.30 (m, 4H), 7.25 (dd, J = 7.8, 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.86 (dd, J = 7.8, 7.8 Hz, 1H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 160.0, 157.6, 153.6, 148.9, 137.8, 137.7, 132.3, 132.3, 131.7, 131.3, 130.9, 130.5, 130.4, 130.2, 130.1, 127.3, 127.3, 126.5, 123.5, 119.0, 118.9, 118.7, 118.6; IR (KBr, cm⁻¹) ν: 3444, 1747, 1602, 1544, 1490, 860, 784, 741; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₆Cl₂NO: 392.0603; found: 392.0604.

2-(4,6-Bis(3-chlorophenyl)pyridin-2-yl)phenol (3j)

Yellow solid; mp: 189.2–190.2 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm):14.23 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 3.6 Hz, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.41 (d, J = 4.2 Hz, 2H), 7.39 (d, J = 4.2 Hz, 2H), 7.28 (dd, J = 7.8, 7.2 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.89 (dd, J = 7.2, 7.8 Hz, 1H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 158.9, 157.5, 153.2, 149.0, 139.1, 138.8, 134.3, 134.2, 131.0, 129.5, 129.4, 128.8, 128.5, 126.4, 126.1, 125.5, 124.4, 124.2, 118.0, 117.7, 117.6, 116.2, 115.3; IR (KBr, cm⁻¹) ν: 3434, 1748, 1605, 1519, 1448, 821, 726; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₆Cl₂NO: 392.0603; found: 392.0604.

2-(4,6-Bis(4-bromophenyl)pyridin-2-yl)phenol (3k)

Yellow solid; mp: 198.6–199.0 °C (PE/EA); ¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 14.35 (s, 1H), 7.94 (s, 1H), 7.84 (d, J = 7.6 Hz, 3H), 7.68 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.29 (dd, J = 7.2, 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 7.2, 7.6 Hz, 1H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 159.0, 157.4, 153.4, 149.2, 135.8, 135.4, 135.0, 134.9, 130.9, 128.5, 128.4, 127.5, 127.2, 125.4, 118.0, 117.8, 117.6, 115.8, 114.8; IR (KBr, cm⁻¹) ν: 3447, 1743, 1601, 1545, 1443, 875, 830, 767; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₆Br₂NO: 479.9593; found: 479.9593.

2-(4,6-Bis(4-iodophenyl)pyridin-2-yl)phenol (3l)

Yellow solid; mp: 239.1–239.4 °C (PE/EA); ¹H-NMR (DMSO-d₆, 600 MHz) δ (ppm):13.96 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 7.99–7.90 (m, 8H), 7.62 (d, J = 8.8 Hz, 2H), 7.36 (dd, J = 7.8, 7.8 Hz, 1H), 6.99–6.97 (m, 2H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 158.9, 157.4, 153.5, 149.3, 137.4, 137.3, 136.7, 136.4, 130.9, 127.9, 127.6, 125.4, 118.0, 117.7, 117.6, 115.5, 114.8, 95.2, 94.8; IR (KBr, cm⁻¹) ν: 3458, 1741, 1598, 1531, 1426, 819, 752; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₆I₂NO: 575.9317; found: 575.9326.

2-(4,6-Bis(4-chlorophenyl)pyridin-2-yl)-4-fluorophenol (3m)

Yellow solid; mp: 186.8–187.0 °C (PE/EA); ¹H-NMR (DMSO-d₆, 600 MHz) δ (ppm): 13.72 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.21 (dd, J₁ = 10.8 Hz, J₂ = 3.0 Hz, 1H), 8.18–8.16 (m, 4H), 7.68 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 9.0 Hz, 2H), 7.22 (td, J₁ = 9.0 Hz, J₂ = 2.4 Hz, 1H), 6.99 (dd, J₁ = 9.0 Hz, J₂ = 4.8 Hz, 1H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 157.2 (d, J = 2.7 Hz), 155.9 (d, J = 1.5 Hz), 155.8 (d, J = 235 Hz), 154.4, 150.6, 136.3, 136.3, 136.1, 136.0, 129.6, 129.4, 128.5, 128.2, 119.6 (d, J = 30.8 Hz), 119.0, 118.7, 117.2, 115.9, 112.1 (d, J = 52.4 Hz); IR (KBr, cm⁻¹) ν: 3441, 1749, 1606, 1543, 1486, 825, 736; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₅Cl₂FNO: 410.0509; found: 410.0508.

2-(4,6-Bis(4-chlorophenyl)pyridin-2-yl)-4-chlorophenol (3n)

Yellow solid; mp: 185.7–186.2 °C (PE/EA); ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 14.04 (s, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.24 (d, J = 8.0 Hz, 2H), 8.22 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 157.5, 155.9, 153.4, 149.5, 135.2, 135.2, 135.0, 134.9, 130.6, 128.6, 128.4, 127.5, 127.2, 124.9, 122.7, 119.0, 118.6, 116.3, 114.8; IR (KBr, cm⁻¹) ν: 3436, 1746, 1601, 1540, 1487, 1434, 879, 823, 733; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₅Cl₃NO: 426.0214; found: 426.0207.

2-(4,6-Bis(4-chlorophenyl)pyridin-2-yl)-4-bromophenol (3o)

Yellow solid; mp: 195.3–195.7 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm): 14.43 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 158.1, 156.0, 153.5, 149.5, 135.4, 135.2, 135.1, 133.4, 128.6, 128.4, 127.9, 127.8, 127.5, 127.2, 119.5, 119.4, 116.3, 114.8, 109.8; IR (KBr, cm⁻¹) ν: 3433, 1749, 1602, 1539, 1488, 1433, 873, 818, 730; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₁₅BrCl₂NO: 469.9709; found: 469.9710.

2-(4,6-Bis(4-chlorophenyl)pyridin-2-yl)-4-nitrophenol (3p)

Yellow solid; mp: 284.3–284.7 °C (PE/EA); ¹H-NMR (DMSO-d₆, 600 MHz) δ (ppm): 15.02 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 10.2 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 9.0 Hz, 1H); IR (KBr, cm⁻¹) ν: 3441, 1747, 1603, 1540, 1484, 1430, 880, 848, 745; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₁₄NO₃: 437.0454; found: 437.0441.

3′,5′-Di(furan-2-yl)-[1,1′-biphenyl]-2-ol (3q)

Yellow solid; mp: 141.5–141.7 °C (PE/EA); ¹H-NMR (CDCl₃, 600 MHz) δ (ppm): 14.44 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.53 (d, J = 12.6, 2H), 7.26 (dd, J = 8.4, 7.2 Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 6.87 (dd, J = 7.8, 7.2 Hz, 1H), 6.51 (s, 2H); ¹³C-NMR (CDCl₃, 150 MHz) δ (ppm): 159.1, 156.9, 151.0, 150.2, 145.3, 143.2, 142.9, 138.7, 130.6, 125.3, 117.8, 117.6, 111.3, 111.2, 110.1, 109.5, 108.6, 108.5; IR (KBr, cm⁻¹) ν: 3437, 3117, 2689, 1669, 1588, 1447, 1295, 1194, 1081, 1011, 902, 833, 678; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₁₄NO₃: 304.0968; found: 304.0976.

3′,5′-Di(thiophen-2-yl)-[1,1′-biphenyl]-2-ol (3r)

Yellow solid; mp: 180.6–180.9 °C (PE/EA); ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.31 (s, 1H), 8.20 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.33 (dd, J = 7.2, 7.6 Hz, 1H), 7.28–7.25 (m, 2H), 6.96–6.94 (m, 2H); ¹³C-NMR (DMSO-d₆, 100 MHz) δ (ppm): 159.1, 157.6, 150.4, 144.2, 142.7, 140.4, 132.1, 129.7, 129.5, 129.4, 128.4, 128.3, 127.5, 119.6, 119.5, 118.2, 114.7, 113.4; IR (KBr, cm⁻¹) ν: 3441, 1748, 1599, 1541, 831, 753; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₁₄NOS₂: 336.0511; found: 336.0504.

3′,5′-Di(thiophen-3-yl)-[1,1′-biphenyl]-2-ol (3s)

Yellow solid; mp: 176.2–176.8 °C (PE/EA); ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 14.54 (s, 1H), 8.53 (s, 1H), 8.37 (s, 1H), 8.29–8.21 (m, 3H), 7.99 (s, 1H), 7.76 (s, 3H), 7.32 (s, 1H), 6.94–6.93 (m, 2H); ¹³C-NMR (DMSO-d₆, 100 MHz) δ (ppm): 159.8, 157.8, 150.9, 145.4, 140.6, 139.2, 131.9, 128.4, 128.1, 128.0, 127.1, 126.4, 126.2, 125.6, 119.6, 119.2, 118.3, 116.3, 115.0; IR (KBr, cm⁻¹) ν: 3446, 1748, 1604, 1549, 1439, 851, 788, 754; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₁₄NOS₂: 336.0511; found: 336.0507.

2-(4,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-2-yl)phenol (3t)

Yellow solid; mp: 143.8–144.2 °C (PE/EA); ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 14.57 (s, 1H), 8.23 (d, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 7.2, 8.0 Hz, 2H), 7.00 (d, J = 9.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.92–6.90 (m, 2H), 4.29 (s, 8H); ¹³C-NMR (DMSO-d₆, 100 MHz) δ (ppm): 159.7, 157.5, 154.2, 150.2, 145.4, 145.4, 144.3, 144.3, 131.8, 131.3, 130.6, 128.0, 121.0, 120.3, 119.5, 119.2, 118.2, 118.1, 118.0, 116.7, 116.2, 115.9, 115.2, 64.8, 64.2, 64.5; IR (KBr, cm⁻¹) ν: 3442, 2926, 2866, 1738, 1598, 1544, 1506, 1448, 875, 812, 753; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₇H₂₇NO₅: 440.1492; found: 440.1495.

2-(4,6-Bis(3-methoxyphenyl)pyridin-2-yl)-6-bromo-4-chlorophenol (3u)

Yellow solid; mp: 186.9–187.3 °C (PE/EA); ¹H-NMR (DMSO-d₆, 600 MHz) δ (ppm): 16.27 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 7.51 (dd, J = 7.8, 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H); ¹³C-NMR (CDCl₃, 100 MHz) δ (ppm): 159.2, 159.1, 154.8, 154.7, 154.3, 150.8, 138.3, 137.8, 133.1, 129.4, 129.3, 124.2, 122.4, 119.4, 118.6, 118.5, 117.6, 115.1, 114.3, 113.7, 112.2, 111.9, 111.7, 54.5, 54.5; IR (KBr, cm⁻¹) ν: 3433, 2925, 2841, 1750, 1593, 1538, 1455, 821, 724; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₅H₂₀BrClNO₃: 496.0310; found: 496.0311.

Acknowledgements

Financial support of this research by the National Natural Science Foundation of China (NSFC 21173181) is gratefully acknowledged by authors. A Project was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Notes and references

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26. Crystallographic data for 2,4,6-trisubstituted pyridines 3b and 3d have been deposited with the Cambridge Crystallographic Data Centre with the deposition number CCDC 1457745 and 1502300.†.

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Footnote

† Electronic supplementary information (ESI) available: Reactions conditions and spectra. CCDC 1457745 and 1502300. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra18630k

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