Acid-controlled multicomponent selective synthesis of 2,4,6-triaryl pyridines and pyrimidines by using hexamethyldisilazane as a nitrogen source under microwave irradiation

Abstract

An efficient and general protocol for the synthesis of functionalized 2,4,6-triaryl pyridines and pyrimidines was developed from commercially available aromatic ketones, aldehydes and hexamethyldisilazane (HMDS) as a nitrogen source under microwave irradiation. In this multicomponent synthetic route, Lewis acids play an important role in selectively synthesizing six-membered heterocycles, including pyridines (1N) and pyrimidines (2N), by involving [2 + 1 + 2 + 1] or [2 + 1 + 1 + 1 + 1] annulated processes.

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Over the past decade, multicomponent reactions (MCRs) have been recognized as a powerful synthetic tool for the establishment of diverse and complicated skeletons. By definition, these components have been assembled in protocols to form desired compound frameworks without adding any reagents, catalysts, solvents, or substrates.¹ MCRs started from simple and readily available synthons to achieve facile execution, generate high productivities, increase transformation efficiency, and reduce lengthy pathways.² The benefits of these combinatorial approaches are not only the systematic distribution in arrays of reactions to construct iterations but also the utilization of the natural characteristics of the chemical building blocks to connect chemical bonds on the common MCR-product skeletons.³ Some name reactions have been developed by Biginelli,⁴ Hantzsch,⁵ Mannich,⁶ Passerini,⁷ Povarov,⁸ Strecker⁹ and Ugi.¹⁰ These reactions are also broadly applied for synthetic and biological interests.

Nitrogen-containing heterocyclic compounds are identified as one of the privileged structural motifs in organic chemistry.¹¹ Among them, the six-membered heterocyclic compounds such as pyridines and pyrimidines are representative compounds for their broad natural existence in natural products, synthetic intermediates, bioactive compounds, and functional materials.¹² Furthermore, these heterocycles have also been applied in the pharmaceutical industry for their anticancer, antimycobacterial, antibacterial, antimalarial, anti-inflammatory, anticonvulsant, and antimicrobial activities.¹³ Since the first pyrimidine synthesis by Brugnatelli and later on by Kolbe, and the initial discovery of pyridine by Thomas Anderson, the various synthetic approaches of these two families have been an area of continuous active research and innovative methodologies and are frequently reported.¹⁴ As a consequence, providing a facile and efficient protocol for the controllable construction of these two azaaromaric skeletons is highly desired. In a comparison of the reported studies on pyridine synthesis,¹⁵ the synthetic protocols of the pyrimidine motif are relatively rarely developed.

Based on the reported literature, a variety of synthetic routes toward the preparation of substituted pyrimidines have been developed.¹⁶ The nitrogen source on the pyrimidine scaffold is an important issue in these methodologies, as shown in Scheme 1. Numerous commonly used protocols apply a nitrogen-fixed substrate as a starting material, including amidines,¹⁷ nitriles,^18,19 and enamidines (enamidine)²⁰ to construct the pyrimidine skeletons. Among them, substituted amidines are frequently applied as versatile nitrogen-containing blocks to react with various cyclization partners to form a pyrimidine ring to utilize the inherent nitrogen on the substrate.²¹ The MCRs for the preparation of pyrimidines from amidines have also been recognized as an efficient strategy.²² Some other synthetic routes utilized the extrinsic nitrogen-containing reagents, including ammonium acetate,²³ ammonium iodide,²⁴ hydroxylamine,²⁵ and urea²⁶ to generate in situ ammonia surrogate and condensed with carbonyl synthons to construct pyrimidine structures.

Scheme 1 Synthesis of 2,4,6-triarylpyrimidines.

Although many remarkable protocols have been reported for the construction of pyrimidines, the development of a facile synthetic protocol from simple and readily available starting materials under the MCRs strategy is of great interest.²⁷ Recently, Li and Huang developed a concise and efficient protocol by controlling the carbon source to obtain diverse substituted pyridines and pyrimidines with high selectivity. This reaction was conducted from isopropene derivatives and the involvement of NH₄I as the “N” source (Scheme 2A).²⁴ In 2019, Deng and Zhang reported a synthetic route to selectively construct pyridines and pyrimidines by varying “N” sources in ammonium salts (NH₄I and NH₄OAc) under the DMSO/PhCl co-solvent system (Scheme 2B).²² Continuing our investigation of HMDS as a nitrogen source for the synthesis of N-heterocyclic compounds under a MW system,²⁸ herein, we present a synthetic route to construct 1N or 2N six-membered ring pyrimidines 1 and pyridines 2 controlled by Lewis acids (BF₃·OEt₂ and TMSOTf) from commercially available acetophenones 3 and benzaldehydes 4 (Scheme 2C).

Scheme 2 Selective synthesis of pyridines and pyrimidines.

We started our investigation with commercially available acetophenone 3a, benzaldehyde 4a, hexamethyldisilazane (HMDS), and acids under microwave irradiation (MW) to explore the viability of controlling the selective formation of pyrimidine 3 and pyridine 4, as shown in Table 1. Based on our previous report, we first examined TMSOTf as Lewis acid for the synthesis of nitrogen-containing compounds. In entry 1, the reaction of 3a with 4a can provide 2aa in 92% yield in the presence of HMDS and toluene under MW at 150 °C in 0.5 h.²⁸ Various metal triflates conducted the reaction well to obtain compound 2aa in approximate 80% yields (entries 2–6). Other Lewis acids, including AlCl₃ and InCl₃, give good to excellent yields of compound 2aa (entries 7 and 8). Brønsted acids were also investigated in this reaction, TfOH promotes the formation of 2aa in 82% yield but AcOH and p-TsOH did not (entries 9–11). Interestingly, BF₃·OEt₂ catalyzed the reaction of 3a and 4a in the presence of HMDS to obtain corresponding pyrimidine 1aa with 58% yield without the formation of pyridine 2aa (entry 12). When the reaction time was extended from 0.5 to 2 h, the yield of 1aa was increased, that of 2aa did not change (entries 13–14). The reaction proceeded well by changing reaction solvents such as DCM, THF and MeCN with lower isolated yields (entries 15–17). Therefore, an acid-controlled synthesis of pyrimidines and pyridines from commercially available 3a and 4a by using HMDS as a nitrogen source was established.

Table 1 Optimization of the reaction conditions^a

Entry	Acid	Solvent	Yields^b (%)
			1aa	2aa
a Reaction conditions: 3a (4.0 mmol), 4a (4.0 mmol), HMDS (3.0 mL, 14.4 mmol), acid (0.5 mmol), solvent (2 mL), MW (150 °C), 0.5 h.b Isolated yields.c Reaction time: 2 h.
1	TMSOTf	Toluene	0	92
2	In(OTf)3	Toluene	0	80
3	Fe(OTf)3	Toluene	0	80
4	Bi(OTf)3	Toluene	0	81
5	Sc(OTf)3	Toluene	0	82
6	Cu(OTf)2	Toluene	0	76
7	AlCl3	Toluene	0	91
8	InCl3	Toluene	0	80
9	TfOH	Toluene	0	82
10	AcOH	Toluene	N.R.	N.R.
11	p-TsOH	Toluene	N.R.	N.R.
12	BF3·OEt2	Toluene	58	0
13^c	BF3·OEt2	Toluene	68	0
14^c	TMSOTf	Toluene	0	92
15^c	BF3·OEt2	DCM	55	0
16^c	BF3·OEt2	THF	62	0
17^c	BF3·OEt2	MeCN	63	0

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After screening the reaction conditions in Table 1, we examined various acetophenones 3 and benzaldehydes 4 for the synthesis of triaryl-substituted pyrimidines 1 by involving of the conditions mentioned in Table 1, entry 14. As shown in Table 2, the model reaction of 3a with 4a and HMDS in the presence of BF₃·OEt₂ provided 1aa in 78% yield. We first investigated the scope of the reaction with 3a and substituted benzaldehydes 4b–4k (4b, 3FPh; 4c, 4FPh; 4d, 3ClPh; 4e, 4ClPh; 4f, 4CF₃Ph; 4g, 3MePh; 4h, 4MePh; 4i, 4OMePh; 4j, 34OMePh; 4k, 4PhPh, and 4l, furfural), coupling by HMDS/BF₃·OEt₂ system as nitrogen source under MW to provide the corresponding 1ab–1ak, with a yield between 58% and 74%. A lower yield of 1al was obtained when heterocyclic furfural 4l as aldehyde partner. We next screened the functionalized acetophenones 3b–3p (3b, 4FPh; 3c, 4FPh; 3d, 4MePh; 3e, 4OMePh; 3f, 4PhPh; 3g, 3FPh; 3h, 3BrPh; 3i, 3OMePh; 3j, 2FPh; 3j, 2ClPh; 3k, 2BrPh; 3m, 2MePh; 3n, 2OMePh; 3o, 4NO₂Ph and 3p, 4CNPh) with 4a under optimized reaction conditions to afford corresponding pyrimidines 1ba–1pa in modest yields (see Table 3).

Table 2 Synthesis of triaryl-substituted pyrimidines 1^ab

a Reaction conditions: 3 (4.0 mmol), 4 (4.0 mmol), HMDS (3.0 mL, 14.4 mmol), BF₃·OEt₂ (0.5 mmol), toluene (2 mL), MW (150 °C), 0.5 h.b Isolated yields.

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Table 3 Synthesis of triaryl-substituted pyridines 2^a,b

a Reaction conditions: 3 (4.0 mmol), 4 (4.0 mmol), HMDS (3.0 mL, 14.4 mmol), TMSOTf (0.5 mmol), toluene (2 mL), MW (150 °C), 0.5 h.b Isolated yields.

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On the other hand, substituted pyrimidines are recognized as an important scaffold in pharmaceuticals.²⁹ Among them, 2,4,6-triarlpyridines (TAPs) skeleton are also a practical synthon in the synthesis of drugs.³⁰ In our previous work, we conducted the synthesis of TAPs by using HMDS/TMSOTf catalytic system under MW condition.^28f Herein, we also describe a synthetic route to yield TAPs from the easily available acetophenones 3 and benzaldehydes 4 in the optimized reaction condition (Table 1, entry x1x). As shown in Scheme 2, we selected non-substituted 3a with some functionalized benzaldehydes 4c (4-FPh), 4e (4-ClPh), 4g (3-MePh), 4h (4-MePh), 4i (4-OMePh), 4l (2-furan), 4m (3-NO₂Ph), 4n (4-NO₂Ph), 4o (2-OMePh), 4p (3-OMePh), 4q (3,5-OMePh), 4r (3,5-CH₂O₂Ph), 4s (anthracene), 4t (2-naphthalene) and 4r (2-thiophene) under the optimized conditions to give desired pyridines 2ac–2au in 62–93% yields. Further investigation of 4a with diversified acetophenones 3b (4-FPh), 3c (4-ClPh), 3d (4-MePh), 3e (4-OMePh), 3f (4-PhPh), 3g (3-FPh), 3i (3-OMePh), 3l (2-BrPh), 3m (2-MePh), 3n (2-OMePh), 3q (4-CF₃Ph), 3r (3-MePh), 3s (2-furan) and 3t (3-thiophene) in the optimized condition provided corresponding TAPs 2ba–2ta between 70% and 92% yields.

As shown in Scheme 3, non-aromatic benzaldehyde propionaldehyde 4v was also examined with 3a in this transformation to afford the desired pyridine 2av. It is possible that due to the low boiling point of 4v, only a 52% isolated yield of 2av was observed. Acetone 3u was also selected as aliphatic ketone with 4a to investigate this pathway to prepare desired pyridine 2ua in 88% yield.

Scheme 3 Synthesis of compound 2av and 2ua.

On the basis of the above experimental results and the reported literature, a proposed reaction pathway is shown in Scheme 4. Claisen–Schmidt condensation of acetophenone 3 and benzaldehyde 4 occurred to give chalcone synthon I, which further reacts with HMDS to provide intermediate II under acidic conditions.^28f Possibly, benzaldehyde 4 is transformed to intermediate III in BF₃·OEt₂/HMDS system, which then reacted with intermediate II to provide intermediate IV, and further aromatically converted to pyrimidine 1 under MW condition. Differently, TMSOTf acts not only as an acidic catalyst in the formation of II but also as a silylating agent to catalyze the conversion of acetophenone 3 to provide intermediate V. After the condensation of II with V, the intermediate VI was obtained, which further underwent aromatic cyclization to give corresponding pyridine 2. Therefore, we presume that the selective synthesis of skeletons 1 and 2 is based on the alternative pathway by involving BF₃·OEt₂ or TMSOTf.

Scheme 4 Plausible reaction pathway.

Conclusions

In summary, we developed a strategy for the selective synthesis of six-membered heterocyclic compounds pyrimidines, and pyridines from commercially available acetophenones and benzaldehydes. In this protocol, same amounts of acetophenone and benzaldehyde were involved by using HMDS as a nitrogen source and control of Lewis acids under microwave irradiation. Acid catalysts TMSOTf and BF₃·OEt₂ played an important role in this selective transformation of corresponding pyrimidines and pyridines obtained in modest yields in this MCR method.

Experimental section

General information

All reagents and solvents were commercially available and used without further purification. Reactions were routinely performed using the discover SP system (CEM) in the sealed reaction vessels in standard mode with the temperature monitored using a vertically focused IR sensor. All reactions were monitored by thin-layer chromatography on silica gel 60 F254 (Merck) with detection by UV light. Column chromatography was performed using silica gel (200–300 mesh). Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with an MP-2D melting apparatus. ¹H and ¹³C NMR spectra were recorded on a Bruker AVIII 500 spectrometer operating at 500 and 125 MHz, respectively. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constants (Hz) and integration. HRMS were obtained on a Waters LCT Premier XE (Waters Corp., Manchester, UK) instrument equipped with an electrospray source. The X-ray intensity data were measured at a low temperature of 100 K using a Mo Kα radiation diffractometer equipped with a kappa geometry goniometer and corrected for absorption effects using the numerical method (SADABS).

General procedure for the synthesis of skeleton 1

A mixture of acetophenone 3 (4.0 mmol), benzaldehyde 4 (4.0 mmol), HMDS (14.4 mmol), BF₃·OEt₂ (0.5 mmol) and toluene (2 mL) in a dried 35 mL microwave vial at 25 °C. The mixture was subjected to a microwave irradiation instrument and stirred at 150 °C for 0.5 h. The consumption of the starting materials was confirmed by TLC. The reaction was cooled to 25 °C, the mixture of crude product was transferred to a 100 mL round bottom flask, and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1–3/1) afforded compounds 1aa–1pa.

2,4,6-Triphenylpyrimidine (1aa)²². Yield = 78% (481 mg); colorless solid; mp = 191–192 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₇N₂ 309.1386, found 309.1395; ¹H NMR (500 MHz, CDCl₃): δ 8.76 (d, J = 8.0 Hz, 2H), 8.33–8.27 (m, 4H), 8.02 (s, 1H), 7.62–7.51 (m, 9H); ¹³C NMR (125 MHz, CDCl₃): δ 164.70 (2x), 164.46, 138.13, 137.50 (2x), 130.74 (2x), 130.60, 128.87 (4x), 128.45 (2x), 128.41 (2x), 127.25 (4x), 110.25.

2,4-Bis(3-fluorophenyl)-6-phenylpyrimidine (1ab). Yield = 65% (447 mg); colorless solid; mp = 217–218 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₅F₂N₂ 345.1198, found 345.1200; ¹H NMR (500 MHz, CDCl₃): δ 8.49 (d, J = 7.5 Hz, 1H), 8.38 (d, J = 10.0 Hz, 1H), 8.29–8.22 (m, 2H), 8.04–7.97 (m, 2H), 7.95 (s, 1H), 7.59–7.47 (m, 5H), 7.27–7.19 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 165.04, 163.30 (d, J = 244.875 Hz), 163.17 (d, J = 243.125 Hz), 139.92 (d, J = 94.125 Hz), 139.86 (d, J = 93.875 Hz), 136.94, 131.05, 130.43 (d, J = 8.0 Hz), 129.89 (d, J = 7.875 Hz), 128.95 (2x), 127.23 (2x), 124.05 (d, J = 2.25 Hz), 122.74 (d, J = 2.375 Hz), 117.75 (d, J = 21.25 Hz, 2x), 117.58 (d, J = 21.25 Hz, 2x), 115.21 (d, J = 23.0 Hz), 114.19 (d, J = 22.75 Hz), 110.53.

2,4-Bis(4-fluorophenyl)-6-phenylpyrimidine (1ac)^30a. Yield = 70% (482 mg); colorless solid; mp = 212–213 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₅F₂N₂ 345.1198, found 345.1196; ¹H NMR (500 MHz, CDCl₃): δ 8.71 (t, J = 7.5 Hz, 2H), 8.31–8.22 (m, 4H), 7.93 (s, 1H), 7.60–7.53 (m, 3H), 7.28–7.16 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 164.73 (d, J = 248.75 Hz), 164.59 (d, J = 254.875 Hz), 164.85, 163.62, 137.28, 134.18 (d, J = 2.5125 Hz), 133.51 (d, J = 2.875 Hz), 130.89, 130.53 (d, J = 8.625 Hz, 2x), 129.25 (d, J = 8.625 Hz, 2x), 128.92 (2x), 128.70, 127.22 (2x), 115.93 (d, J = 21.625 Hz, 2x), 115.35 (d, J = 21.375 Hz, 2x), 109.72.

2,4-Bis(3-chlorophenyl)-6-phenylpyrimidine (1ad). Yield = 60% (451 mg); white solid; mp = 173–174 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₅Cl₂N₂ 377.0612, found 377.0608; ¹H NMR (500 MHz, CDCl₃): δ 8.66–8.62 (m, 1H), 8.56 (d, J = 7.5 Hz, 1H), 8.26–8.20 (m, 3H), 8.10 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.58–7.53 (m, 3H), 7.52–7.43 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 165.03, 163.31, 163.23, 139.66, 138.97, 136.86, 135.08, 134.57, 131.08, 130.81, 130.68, 130.14, 129.67, 128.94 (2x), 128.44, 127.31, 127.24 (2x), 126.57, 125.31, 110.55.

2,4-Bis(4-chlorophenyl)-6-phenylpyrimidine (1ae)^23c. Yield = 58% (436 mg); white solid; mp = 200–201 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₅Cl₂N₂ 377.0612, found 377.0606; ¹H NMR (500 MHz, CDCl₃): δ 8.64 (d, J = 7.0 Hz, 2H), 8.26 (d, J = 2.5 Hz, 2H), 8.20 (d, J = 7.0 Hz, 2H), 7.97 (s, 1H), 7.57–7.50 (m, 7H); ¹³C NMR (125 MHz, CDCl₃): δ 165.05, 163.62, 163.60, 137.15, 137.12, 136.94, 136.43, 135.73, 131.02, 129.79 (2x), 129.18 (2x), 128.98 (2x), 128.68 (2x), 128.53 (2x), 127.26, (2x) 110.13.

4-Phenyl-2,6-bis(4-(trifluoromethyl)phenyl)pyrimidine (1af)^30a. Yield = 62% (551 mg); white solid; mp = 179–180 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₁₅F₆N₂ 445.1139, found 445.1137; ¹H NMR (500 MHz, CDCl₃): δ 8.80 (d, J = 8.0 Hz, 2H), 8.37 (d, J = 8.0 Hz, 2H), 8.31–8.26 (m, 2H), 8.07 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.62–7.56 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 165.43, 163.48, 163.39, 141.03, 140.51, 136.78, 132.66 (q, J = 30.35 Hz, 2x), 136.42 (q, J = 30.35 Hz, 2x), 131.30, 129.07 (2x), 128.73 (2x), 127.62 (2x), 127.30 (2x), 125.93 (q, J = 3.65 Hz), 125.42 (q, J = 3.65 Hz), 124.17 (d, J = 272.30 Hz), 123.91 (d, J = 272.30 Hz), 111.20.

4-Phenyl-2,6-di-m-tolylpyrimidine (1ag). Yield = 59% (397 mg); white solid; mp = 107–108 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₁N₂ 337.1699, found 337.1703; ¹H NMR (500 MHz, CDCl₃): δ 8.56–8.50 (m, 2H), 8.35 (dd, J = 1.5, 8.0 Hz, 2H), 8.10 (s, 1H), 8.08 (d, J = 7.5 Hz, 1H), 8.00 (s, 1H), 7.60–7.53 (m, 3H), 7.49–7.41 (m, 2H), 7.39–7.32 (m, 2H), 2.52 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 164.97, 164.65 (2x), 138.61, 138.12, 138.02, 137.63, 137.58, 131.51, 131.40, 130.69, 128.97, 128.89 (2x), 128.81, 128.35, 127.89, 127.29 (2x), 125.70, 124.47, 110.40, 21.60 (2x).

4-Phenyl-2,6-di-p-tolylpyrimidine (1ah)²⁵. Yield = 64% (430 mg); colorless solid; mp = 167–168 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₁N₂ 337.1699, found 337.1696; ¹H NMR (500 MHz, CDCl₃): δ 8.63 (d, J = 8.0 Hz, 2H), 8.29 (dd, J = 1.5, 8.5 Hz, 2H), 8.20 (d, J = 8.0 Hz, 2H), 7.96 (s, 1H), 7.59–7.52 (m, 3H), 7.34 (t, J = 8.0 Hz, 4H), 2.47 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 164.58, 164.50 (2x), 141.01, 140.69, 137.76, 135.58, 134.83, 130.58, 129.59 (2x), 129.15 (2x), 128.83 (2x), 128.41 (2x), 127.24 (2x), 127.15 (2x), 109.66, 21.52, 21.45.

2,4-Bis(4-methoxyphenyl)-6-phenylpyrimidine (1ai)²⁵. Yield = 76% (560 mg); yellow solid; mp = 126–127 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₁N₂O₂ 369.1598, found 369.1598; ¹H NMR (500 MHz, CDCl₃): δ 8.68 (d, J = 8.5 Hz, 2H), 8.29–8.23 (m, 4H), 7.89 (s, 1H), 7.59–7.49 (m, 3H), 7.09–7.02 (m, 4H), 3.90 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 164.34, 164.11, 164.06, 161.82, 161.72, 137.84, 131.04, 130.52, 130.09, 130.03 (2x), 128.81 (2x), 128.72 (2x), 127.20 (2x), 114.19 (2x), 113.69 (2x), 108.76, 55.41, 55.35.

2,4-Bis(3,4-dimethoxyphenyl)-6-phenylpyrimidine (1aj). Yield = 72% (617 mg); white solid; mp = 184–185 °C; HRMS (ESI, M⁺ + H) calcd for C₂₆H₂₅N₂O₄ 429.1809, found 429.1811; ¹H NMR (500 MHz, CDCl₃): δ 8.32 (d, J = 8.5 Hz, 1H), 8.26 (s, 1H), 8.25–8.21 (m, 2H), 7.90 (s, 1H), 7.85–7.81 (m, 1H), 7.80–7.75 (m, 1H), 7.57–7.49 (m, 3H), 7.02–6.94 (m, 2H), 4.04 (s, 3H), 4.02 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 164.20, 163.81 (2x), 151.31, 151.19, 149.14, 148.69, 137.61, 131.04, 130.49, 130.16, 128.72 (2x), 127.10 (2x), 121.67, 120.15, 111.03, 110.89, 110.62, 109.91, 108.84, 55.89, 55.84 (2x), 55.78.

2,4-Di([1,1′-biphenyl]-4-yl)-6-phenylpyrimidine (1ak). Yield = 74% (681 mg); white solid; mp = 215–216 °C; HRMS (ESI, M⁺ + H) calcd for C₃₄H₂₅N₂ 461.2012, found 461.2002; ¹H NMR (500 MHz, CDCl₃): δ 8.82 (d, J = 8.0 Hz, 2H), 8.40 (d, J = 8.0 Hz, 2H), 8.33 (d, J = 8.0 Hz, 2H), 8.07 (s, 1H), 7.80 (t, J = 8.0 Hz, 4H), 7.71 (t, J = 8.0 Hz, 4H), 7.63–7.56 (m, 3H), 7.53–7.48 (m, 4H), 7.44–7.37 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 164.78, 164.34, 164.32, 143.57, 143.27, 140.76, 140.33, 137.57, 137.15, 136.37, 130.79, 128.93 (8x), 128.83, 127.85, 127.73, 127.60 (2x), 127.30, 127.20 (4x), 127.18 (4x), 110.12.

2,4-Di(furan-2-yl)-6-phenylpyrimidine (1al). Yield = 56% (323 mg); white solid; mp = 108–109 °C; HRMS (ESI, M⁺ + H) calcd for C₁₈H₁₃N₂O₂ 289.0972, found 289.0966; ¹H NMR (500 MHz, CDCl₃): δ 8.24–8.21 (m, 2H), 7.87 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.55–7.46 (m, 3H), 7.47 (d, J = 3.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 6.65–6.55 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 164.88, 157.93, 156.30, 152.53, 152.05, 144.95 (2x), 136.93, 130.92, 128.87 (2x), 127.24 (2x), 113.63, 112.50, 112.48, 112.05, 107.88.

4-(4-Fluorophenyl)-2,6-diphenylpyrimidine (1ba)²². Yield = 56% (365 mg); white solid; mp = 162–163 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆FN₂ 327.1292, found 327.1294; ¹H NMR (500 MHz, CDCl₃): δ 8.71 (d, J = 7.5 Hz, 2H), 8.31–8.28 (m, 4H), 7.97 (s, 1H), 7.60–7.51 (m, 6H), 7.27–7.23 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 164.86, 164.59 (d, J = 249.475 Hz), 164.51, 163.63, 138.01, 137.43, 133.65 (d, J = 2.75 Hz), 130.84, 130.71, 129.29 (d, J = 8.5 Hz, 2x), 128.93 (2x), 128.46 (2x), 128.44 (2x), 127.26 (2x), 115.93 (d, J = 21.5 Hz, 2x), 109.89.

4-(4-Chlorophenyl)-2,6-diphenylpyrimidine (1ca)²². Yield = 74% (506 mg); white solid; mp = 158–159 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆ClN₂ 343.0997, found 343.0987; ¹H NMR (500 MHz, CDCl₃): δ 8.71 (d, J = 7.5 Hz, 2H), 8.29 (d, J = 7.5 Hz, 2H), 8.25 (d, J = 7.0 Hz, 2H), 7.98 (s, 1H), 7.59–7.53 (m, 8H); ¹³C NMR (125 MHz, CDCl₃): δ 164.98, 164.58, 163.52, 137.95, 137.36, 136.97, 135.95, 130.90, 130.75, 129.14 (2x), 128.94 (2x), 128.55 (2x), 128.47 (2x), 128.45 (2x), 127.28 (2x), 109.98.

2,4-Diphenyl-6-(p-tolyl)pyrimidine (1da)²². Yield = 64% (412 mg); colorless solid; mp = 146–147 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₉N₂ 323.1543, found 323.1534; ¹H NMR (500 MHz, CDCl₃): δ 8.73 (d, J = 6.5 Hz, 2H), 8.29 (d, J = 6.5 Hz, 2H), 8.21 (d, J = 7.0 Hz, 2H), 8.00 (s, 1H), 7.57–7.52 (m, 6H), 7.37 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 164.67, 164.60, 164.42, 141.13, 138.24, 137.64, 134.71, 130.67, 130.54, 129.63 (2x), 128.87 (2x), 128.44 (2x), 128.40 (2x), 127.25 (2x), 127.17 (2x), 109.93, 21.47.

4-(4-Methoxyphenyl)-2,6-diphenylpyrimidine (1ea)²². Yield = 69% (467 mg); colorless solid; mp = 136–137 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₉N₂O 339.1492, found 339.1494; ¹H NMR (500 MHz, CDCl₃): δ 8.72 (d, J = 8.0 Hz, 2H), 8.29 (d, J = 7.5 Hz, 4H), 7.96 (s, 1H), 7.57–7.51 (m, 6H), 7.07 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 164.49, 164.35, 164.21, 161.92, 138.28, 137.71, 130.63, 130.52, 129.96, 128.87 (2x), 128.78 (2x), 128.42 (2x), 128.40 (2x), 127.24 (2x), 114.25 (2x), 109.42, 55.44.

4-([1,1′-Biphenyl]-4-yl)-2,6-diphenylpyrimidine (1fa)²². Yield = 71% (546 mg); colorless solid; mp = 174–175 °C; HRMS (ESI, M⁺ + H) calcd for C₂₈H₂₁N₂ 385.1699, found 385.1705; ¹H NMR (500 MHz, CDCl₃): δ 8.76 (d, J = 8.5 Hz, 2H), 8.39 (d, J = 8.5 Hz, 2H), 8.32 (d, J = 8.0 Hz, 2H), 8.06 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.61–7.53 (m, 6H), 7.52–7.48 (m, 2H), 7.44–7.39 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 164.75, 164.52, 164.31, 143.55, 140.32, 138.16, 137.55, 136.36, 130.76, 130.63, 128.91 (3x), 128.47 (2x), 128.44 (2x), 127.84, 127.71 (2x), 127.58 (2x), 127.28 (2x), 127.17 (2x), 127.12, 110.13.

4-(3-Fluorophenyl)-2,6-diphenylpyrimidine (1ga)²⁷. Yield = 65% (424 mg); white solid; mp = 184–185 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆FN₂ 327.1292, found 327.1293; ¹H NMR (500 MHz, CDCl₃): δ 8.72 (d, J = 7.5 Hz, 2H), 8.30 (d, J = 7.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.99 (s, 1H), 7.59–751 (m, 7H), 7.24–7.22 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 165.06, 164.60, 163.39 (d, J = 2.5 Hz), 163.34 (d, J = 244.75 Hz), 139.88 (d, J = 7.375 Hz), 137.88, 137.30, 130.85 (d, J = 17.875 Hz, 2x), 130.42 (d, J = 8.0 Hz), 128.95 (2x), 128.48 (2x), 128.47 (2x), 127.28 (2x), 122.77 (d, J = 2.375 Hz), 117.62 (d, J = 21.125 Hz), 114.26 (d, J = 22.875 Hz), 110.27.

4-(3-Bromophenyl)-2,6-diphenylpyrimidine (1ha)^30b. Yield = 66% (510 mg); white solid; mp = 128–129 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆BrN₂ 387.0491, found 387.0491; ¹H NMR (500 MHz, CDCl₃): δ 8.72 (d, J = 8.5 Hz, 2H), 8.44 (s, 1H), 8.29 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.61–7.52 (m, 6H), 7.43 (t, J = 8.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 165.04, 164.61, 163.21, 139.60, 137.85, 137.24, 133.61, 130.95, 130.80, 130.40, 130.31, 128.94 (2x), 128.48 (4x), 127.29 (2x), 125.80, 123.20, 110.25.

4-(3-Methoxyphenyl)-2,6-diphenylpyrimidine (1ia)^30c. Yield = 69% (467 mg); white solid; mp = 124–125 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₉N₂O 339.1492, found 339.1489; ¹H NMR (500 MHz, CDCl₃): δ 8.74 (d, J = 6.5 Hz, 2H), 8.30 (d, J = 6.0 Hz, 2H), 8.00 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.60–7.50 (m, 6H), 7.48 (t, J = 8.0 Hz, 1H), 7.09 (dd, J = 1.5, 8.0 Hz, 1H), 3.95 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 164.71, 164.48, 164.41, 160.12, 138.98, 138.08, 137.46, 130.75, 130.61, 129.87, 128.87 (2x), 128.44, (2x) 128.41 (2x), 127.25 (2x), 119.59, 116.29, 112.77, 110.40, 55.43.

4-(2-Fluorophenyl)-2,6-diphenylpyrimidine (1ja)^30d. Yield = 64% (417 mg); white solid; mp = 143–144 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆FN₂ 327.1292, found 327.1293; ¹H NMR (500 MHz, CDCl₃): δ 8.74–8.68 (m, 2H), 8.44–8.38 (m, 1H), 8.32–8.27 (m, 2H), 8.17 (d, J = 1.5 Hz, 1H), 7.60–7.47 (m, 7H), 7.40–7.34 (m, 1H), 7.25–7.22 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 164.54 (d, J = 23.125 Hz), 161.51 (d, J = 250.5 Hz), 160.90, 160.87, 138.04, 137.39, 132.05 (d, J = 8.875 Hz), 131.10 (d, J = 2.0 Hz), 130.82, 130.66, 128.90 (2x), 128.46 (2x), 128.38 (2x), 127.38 (2x), 125.63 (d, J = 10.375 Hz), 124.70 (d, J = 3.25 Hz), 116.54 (d, J = 0.375 Hz), 114.53 (d, J = 0.375 Hz).

4-(2-Chlorophenyl)-2,6-diphenylpyrimidine (1ka)²². Yield = 61% (417 mg); white solid; mp = 118–119 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆ClN₂ 343.0997, found 343.0996; ¹H NMR (500 MHz, CDCl₃): δ 8.69–8.66 (m, 2H), 8.30–8.27 (m, 2H), 8.03 (s, 1H), 7.89–7.82 (m, 1H), 7.59–7.50 (m, 7H), 7.49–7.41 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 164.69, 164.64, 163.89, 137.95, 137.58, 137.27, 132.44, 131.70, 130.89, 130.69, 130.66, 130.50, 128.94 (2x), 128.47 (4x), 127.38 (2x), 127.22, 115.16.

4-(2-Bromophenyl)-2,6-diphenylpyrimidine (1la)²². Yield = 56% (432 mg); white solid; mp = 130–131 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆ClN₂ 387.0491, found 387.0498; ¹H NMR (500 MHz, CDCl₃): δ 8.68 (d, J = 7.5 Hz, 2H), 8.29 (d, J = 7.0 Hz, 2H), 7.97 (s, 1H), 7.80–7.73 (m, 2H), 7.60–7.47 (m, 7H), 7.35 (t, J = 8.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 166.09, 164.55, 163.82, 139.59, 137.91, 137.22, 133.75, 131.57, 130.90, 130.72, 130.70, 128.94 (2x), 128.49 (2x), 128.47 (2x), 127.76, 127.36 (2x), 121.65, 115.07.

2,4-Diphenyl-6-(o-tolyl)pyrimidine (1ma)²². Yield = 54% (348 mg); white solid; mp = 59–60 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₉N₂ 323.1543, found 323.1551; ¹H NMR (500 MHz, CDCl₃): δ 8.73–8.66 (m, 2H), 8.32–8.30 (m, 2H), 7.77 (s, 1H), 7.66–7.50 (m, 7H), 7.46–7.35 (m, 3H), 2.61 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.19, 164.16, 164.04, 138.65, 138.12, 137.37, 136.50, 131.27, 130.81, 130.61, 129.63, 129.41, 128.93 (2x), 128.46 (4x), 127.26 (2x), 126.15, 114.36, 20.71.

4-(2-Methoxyphenyl)-2,6-diphenylpyrimidine (1na)²⁷. Yield = 58% (392 mg); white solid; mp = 67–68 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₉N₂O 339.1492, found 339.1500; ¹H NMR (500 MHz, CDCl₃): δ 8.70 (d, J = 7.0 Hz, 2H), 8.30 (s, 1H), 8.29–8.24 (m, 3H), 7.56–7.49 (m, 7H), 7.18 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 164.20, 163.60, 163.40, 158.06, 138.39, 137.91, 131.49, 131.33, 130.46, 130.36, 128.81 (2x), 128.36 (2x), 128.33 (2x), 127.34, 126.98 (2x), 121.17, 115.39, 111.60, 55.76.

4-(4-Nitrophenyl)-2,6-diphenylpyrimidine (1oa)²². Yield = 71% (501 mg); yellow solid; mp = 216–217 °C; HRMS (ESI, M⁺ + H) calcd for C₂₂H₁₆ClN₂ 354.1237, found 354.1231; ¹H NMR (500 MHz, CDCl₃): δ 8.71 (d, J = 5.0 Hz, 2H), 8.46 (d, J = 8.5 Hz, 2H), 8.41 (d, J = 9.0 Hz, 2H), 8.30 (d, J = 3.5 Hz, 2H), 8.06 (s, 1H), 7.59–7.56 (m, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 165.49, 164.86, 162.30, 149.17, 143.42, 137.53, 136.92, 131.24, 131.07, 129.05 (2x), 128.58 (2x), 128.48 (2x), 128.20 (2x), 127.32 (2x), 124.10 (2x), 110.84.

4-(2,6-Diphenylpyrimidin-4-yl)benzonitrile (1pa)²². Yield = 65% (433 mg); yellow solid; mp = 185–186 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₆N₃ 334.1339, found 334.1334; ¹H NMR (500 MHz, CDCl₃): δ 8.71–8.64 (m, 2H), 8.33 (d, J = 8.5 Hz, 2H), 8.28–8.22 (m, 2H), 7.94 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.60–7.51 (m, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 165.18, 164.59, 162.40, 141.46, 137.48, 136.82, 132.55 (2x), 131.12, 130.95, 128.94 (2x), 128.48 (2x), 128.37 (2x), 127.69 (2x), 127.20 (2x), 1218.47, 113.98, 110.40.

General procedure for the synthesis of skeleton 2

A mixture of acetophenone 3 (4.0 mmol), benzaldehyde 4 (4.0 mmol), HMDS (14.4 mmol), TMSOTf (0.5 mmol) and toluene (2 mL) in a dried 35 mL microwave vial at 25 °C. The mixture was subjected to a microwave irradiation instrument and stirred at 150 °C for 0.5 h. The consumption of the starting materials was confirmed by TLC. The reaction was cooled to 25 °C, the mixture of crude product was transferred to a 100 mL round bottom flask, and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1–3/1) afforded compounds 2aa–2av.

2,4,6-Triphenylpyridine (2aa)²². Yield = 92% (565 mg); colorless solid; mp = 138–139 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₈N 308.1439, found 308.1447; ¹H NMR (500 MHz, CDCl₃): δ 8.35–8.31 (m, 4H), 7.96 (s, 2H), 7.82–7.80 (m, 2H), 7.66–7.57 (m, 6H), 7.57–7.51 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 157.32 (2x), 149.99, 139.45 (2x), 138.87, 128.96 (2x), 128.93 (2x), 128.83, 128.58 (4x), 127.03 (6x), 116.93 (2x).

4-(4-Fluorophenyl)-2,6-diphenylpyridine (2ac)^28f. Yield = 76% (535 mg); colorless solid; mp = 141–142 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₇FN 326.1340, found 326.1337; ¹H NMR (500 MHz, CDCl₃): δ 8.22 (d, J = 8.0 Hz, 4H), 7.84 (s, 2H), 7.74–7.71 (m, 2H), 7.54 (t, J = 8.0 Hz, 4H), 7.49–7.46 (m, 2H), 7.23 (t, J = 8.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 163.31 (d, J = 247.25 Hz), 157.49 (2x), 149.04, 139.36 (2x), 135.03 (d, J = 3.0 Hz), 129.08 (2x), 128.87 (d, J = 8.25 Hz, 2x), 128.68 (4x), 127.06 (4x), 116.83 (2x), 116.06 (d, J = 21.375 Hz, 2x).

4-(4-Chlorophenyl)-2,6-diphenylpyridine (2ae)^28f. Yield = 83% (566 mg); yellow solid; mp = 119–120 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₇ClN 342.1044, found 342.1048; ¹H NMR (500 MHz, CDCl₃): δ 8.20 (d, J = 8.0 Hz, 4H), 7.84 (s, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.56–7.49 (m, 6H), 7.48–7.44 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.66 (2x), 148.92, 139.38 (2x), 137.46, 135.17, 139.31 (2x), 129.15 (2x), 128.72 (4x), 128.43 (2x), 127.10 (4x), 116.79 (2x).

2,6-Diphenyl-4-(m-tolyl)pyridine (2ag)^28f. Yield = 80% (514 mg); yellow solid; mp = 84–85 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₀N 322.1590, found 322.1588; ¹H NMR (500 MHz, CDCl₃): δ 8.26–8.20 (m, 4H), 7.90 (s, 2H), 7.5–7.51 (m, 6H), 7.49–7.41 (m, 3H), 7.31 (d, J = 7.5 Hz, 1H), 2.49 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 157.42, 150.30, 139.61, 139.02, 138.80, 129.70, 128.99, 128.67, 127.86, 127.11, 124.27, 117.13, 21.52.

2,6-Diphenyl-4-(p-tolyl)pyridine (2ah)^28f. Yield = 93% (597 mg); white solid; mp = 117–118 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₀N 322.1590, found 322.1588; ¹H NMR (500 MHz, CDCl₃): δ 8.23 (d, J = 8.5 Hz, 4H), 7.90 (s, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.54 (t, J = 8.0 Hz, 4H), 7.47 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 157.42 (2x), 150.00, 139.64 (2x), 139.03, 136.03, 129.79 (2x), 128.95 (2x), 128.65 (4x), 127.10 (4x), 126.96 (2x), 116.85 (2x), 21.22.

4-(4-Methoxyphenyl)-2,6-diphenylpyridine (2ai)^28f. Yield = 81% (546 mg); white solid; mp = 101–102 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₀NO 338.1545, found 338.1541; ¹H NMR (500 MHz, CDCl₃): δ 8.22 (d, J = 7.5 Hz, 4H), 7.87 (s, 2H), 7.72 (d, J = 9.0 Hz, 2H), 7.57–7.50 (m, 4H), 7.49–7.43 (m, 2H), 7.06 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 160.43, 157.41 (2x), 149.59, 139.68 (2x), 131.24, 128.93 (2x), 128.64 (4x), 128.28 (2x), 127.09 (4x), 116.57 (2x), 114.49 (2x), 55.38.

4-(Furan-2-yl)-2,6-diphenylpyridine (2al)^28f. Yield = 81% (481 mg); brown solid; mp = 154–155 °C; HRMS (ESI, M⁺ + H) calcd for C₂₁H₁₆NO 298.1226, found 298.1236; ¹H NMR (500 MHz, CDCl₃): δ 8.26–8.18 (m, 4H), 7.95 (s, 2H), 7.61–7.46 (m, 7H), 6.99 (d, J = 3.0 Hz, 1H), 6.62–6.54 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 157.48 (2x), 151.95, 143.58, 139.44 (2x), 139.03, 129.05 (2x), 128.64 (4x), 127.04 (4x), 112.97 (2x), 112.08, 108.45.

4-(3-Nitrophenyl)-2,6-diphenylpyridine (2am)^30e. Yield = 81% (570 mg); colorless solid; mp = 140–141 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₇N₂O₂ 353.1285, found 353.1280; ¹H NMR (500 MHz, CDCl₃): δ 8.59 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 4H), 8.05 (d, J = 7.5 Hz, 1H), 7.88 (s, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.57–7.51 (m, 4H), 7.50–7.44 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.92 (2x), 148.81, 147.60, 140.72, 138.98 (2x), 133.06, 130.14, 129.37 (2x), 128.77 (4x), 127.09 (4x), 123.61, 122.07, 116.70 (2x).

4-(4-Nitrophenyl)-2,6-diphenylpyridine (2an)^28f. Yield = 87% (612 mg); white solid; mp = 174–175 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₇N₂O₂ 353.1290, found 353.1290; ¹H NMR (500 MHz, CDCl₃): δ 8.39 (d, J = 8.5 Hz, 2H), 8.24–8.18 (m, 4H), 7.90 (d, J = 8.5 Hz, 2H), 7.88 (s, 2H), 7.56–7.51 (m, 4H), 7.51–7.45 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.96 (2x), 148.14, 147.83, 145.44, 139.00 (2x), 129.42 (2x), 128.81 (4x), 128.16 (2x), 127.11 (4x), 124.35 (2x), 116.93 (2x).

4-(2-Methoxyphenyl)-2,6-diphenylpyridine (2ao)^28f. Yield = 83% (560 mg); yellow gum; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₀NO 338.1545, found 338.1541; ¹H NMR (500 MHz, CDCl₃): δ 8.20 (d, J = 7.5 Hz, 4H), 7.88 (s, 2H), 7.55–7.49 (m, 4H), 7.48–7.41 (m, 4H), 7.14–7.09 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 156.74, 156.60, 147.87, 139.85, 130.50, 130.02, 128.78, 128.60, 128.46, 127.13, 121.06, 119.70, 111.44, 55.67.

4-(3-Methoxyphenyl)-2,6-diphenylpyridine (2ap)^28f. Yield = 89% (600 mg); white solid; mp = 124–125 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₂₀NO 338.1539, found 338.1538; ¹H NMR (500 MHz, CDCl₃): δ 8.23 (d, J = 7.5 Hz, 4H), 7.90 (s, 2H), 7.54 (t, J = 7.5 Hz, 4H), 7.50–7.43 (m, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.28 (t, J = 2.0 Hz, 1H), 7.03 (dd, J = 2.0, 8.0 Hz, 1H), 3.92 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 160.14 157.46 (2x), 150.06, 140.53, 139.53 (2x), 130.14, 129.02 (2x), 128.67 (4x), 127.10 (4x), 119.57, 117.13 (2x), 114.17, 112.99, 55.40.

4-(3,5-Dimethoxyphenyl)-2,6-diphenylpyridine (2aq). Yield = 79% (580 mg); colorless solid; mp = 101–102 °C; HRMS (ESI, M⁺ + H) calcd for C₂₅H₂₂NO₂ 368.1645, found 368.1644; ¹H NMR (500 MHz, CDCl₃): δ 8.26 (d, J = 7.0 Hz, 4H), 7.89 (s, 2H), 7.56 (t, J = 7.0 Hz, 4H), 7.49 (t, J = 7.0 Hz, 2H), 6.91 (s, 2H), 6.61 (s, 1H), 3.90 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 161.42 (2x), 157.51 (2x), 150.28, 141.32, 139.61 (2x), 129.14 (2x), 128.78 (4x), 127.21 (4x), 117.21 (2x), 105.57 (2x), 100.67, 55.57 (2x).

4-(Benzo[d][1,3]dioxol-5-yl)-2,6-diphenylpyridine (2ar)^28f. Yield = 87% (611 mg); white solid; mp = 152–153 °C; HRMS (ESI, M⁺ + H) calcd for C₂₄H₁₈NO₂ 352.1332, found 352.1333; ¹H NMR (500 MHz, CDCl₃): δ 8.20–8.18 (m, 4H), 7.82 (s, 2H), 7.55–7.48 (m, 4H), 7.47–7.42 (m, 2H), 7.28–7.21 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.06 (s, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.46 (2x), 149.71, 148.47, 148.44, 139.55 (2x), 133.12, 129.02 (2x), 128.69 (4x), 127.09 (4x), 121.06, 116.76 (2x), 108.86, 107.45, 101.49. Single-crystal X-ray diagram: crystal of 2q was grown by slow diffusion of EtOAc into a solution of 2q in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P2₁/n, a = 6.4058(2) Å, b = 12.1092(3) Å, c = 21.6453(7) Å, V = 1677.71(9) ų, Z = 4, d_calcd = 1.391 mg m⁻³, F(000) = 736, 2θ range 1.927–27.102, R indices (all data) R1 = 0.0412, wR2 = 0.0956. CCDC number is 2085356.†

4-(Anthracen-9-yl)-2,6-diphenylpyridine (2as)^28f. Yield = 62% (505 mg); yellow solid; mp = 222–223 °C; HRMS (ESI, M⁺ + H) calcd for C₃₁H₂₂N 408.1747, found 408.1745; ¹H NMR (500 MHz, CDCl₃): δ 8.58 (s, 1H), 8.28–8.22 (m, 4H), 8.10 (d, J = 8.5 Hz, 2H), 7.84 (s, 2H), 7.75 (d, J = 9.0 Hz, 2H), 7.54–7.48 (m, 6H), 7.47–7.43 (m, 2H), 7.42–7.37 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.03 (2x), 148.90, 139.23 (2x), 134.30, 131.29 (2x), 129.53 (2x), 129.20 (2x), 128.74 (4x), 128.53 (2x), 127.48, 127.13 (4x), 126.15 (2x), 126.07 (2x), 125.35 (2x), 121.39 (2x).

4-(Naphthalen-2-yl)-2,6-diphenylpyridine (2at)^28f. Yield = 83% (593 mg); white solid; mp = 128–129 °C; HRMS (ESI, M⁺ + H) calcd for C₂₇H₂₀N 358.1590, found 358.1590; ¹H NMR (500 MHz, CDCl₃): δ 8.30–8.21 (m, 5H), 8.05–7.96 (m, 4H), 7.95–7.90 (m, 1H), 7.87 (dd, J = 1.5, 8.0 Hz, 1H), 7.60–7.52 (m, 6H), 7.51–7.45 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.56 (2x), 150.07, 139.59 (2x), 136.27, 133.49, 133.40, 129.05 (2x), 128.91, 128.70 (4x), 128.42, 127.74, 127.15 (4x), 126.74, 126.68, 126.45, 124.81, 117.28 (2x).

2,6-Diphenyl-4-(thiophen-2-yl)pyridine (2au)^30e. Yield = 84% (526 mg); white solid; mp = 161–162 °C; HRMS (ESI, M⁺ + H) calcd for C₂₁H₁₆NS 314.0998, found 314.1006; ¹H NMR (500 MHz, CDCl₃): δ 8.25–8.19 (m, 4H), 7.89 (s, 2H), 7.64–7.61 (m, 1H), 7.55 (t, J = 7.5 Hz, 4H), 7.51–7.46 (m, 2H), 7.45 (dd, J = 1.0, 5.0 Hz, 1H), 7.19 (dd, J = 3.5, 5.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 157.64 (2x), 142.92, 141.88, 139.33 (2x), 129.09 (2x), 128.65 (4x), 128.32, 127.06 (4x), 126.85, 125.19, 115.25 (2x).

4-Ethyl-2,6-diphenylpyridine (2av)^30h. Yield = 52% (270 mg); yellow gum; HRMS (ESI, M⁺ + H) calcd for C₁₉H₁₈N 260.1434, found 260.1430; ¹H NMR (500 MHz, CDCl₃): δ 8.06 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.55–7.38 (m, 6H), 7.32 (s, 1H), 2.97 (q, J = 8.0 Hz, 2H), 1.43 (t, J = 8.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 163.94, 157.47, 149.57, 139.96, 139.08, 129.01 (2x), 128.78, 128.73, 128.67 (2x), 127.12 (4x), 118.58, 116.23, 31.66, 13.98.

2,6-Bis(4-fluorophenyl)-4-phenylpyridine (2ba)^28f. Yield = 89% (611 mg); white solid; mp = 175–176 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₆F₂N 344.1245, found 344.1242; ¹H NMR (500 MHz, CDCl₃): δ 8.20–8.16 (m, 4H), 7.82 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.57–7.52 (m, 2H), 7.51–7.47 (m, 1H), 7.20 (t, J = 8.5 Hz, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 163.64 (d, J = 247.125 Hz, 2x), 156.46 (2x), 150.44, 138.84 (2x), 135.57 (d, J = 2.75 Hz, 2x), 129.15 (2x), 129.11, 128.89 (d, J = 8.2 Hz, 4x), 127.14 (2x), 116.67, 115.62 (d, J = 21.3625 Hz, 4x).

2,6-Bis(4-chlorophenyl)-4-phenylpyridine (2ca)^28f. Yield = 91% (683 mg); colorless solid; mp = 186–187 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₆Cl₂N 376.0654, found 376.0654; ¹H NMR (500 MHz, CDCl₃): δ 8.12 (d, J = 8.5 Hz, 4H), 7.84 (s, 2H), 7.73–7.71 (m, 2H), 7.56–7.49 (m, 7H); ¹³C NMR (125 MHz, CDCl₃): δ 156.31 (2x), 150.54, 138.67, 137.75 (2x), 135.27 (2x), 129.17 (2x), 128.90 (4x), 128.33 (4x), 127.14 (2x), 117.06 (2x).

4-Phenyl-2,6-di-p-tolylpyridine (2da)^28f. Yield = 88% (590 mg); colorless solid; mp = 159–160 °C; HRMS (ESI, M⁺ + H) calcd for C₂₅H₂₂N 336.1747, found 336.1744; ¹H NMR (500 MHz, CDCl₃): δ 8.12 (d, J = 8.0 Hz, 4H), 7.85 (s, 2H), 7.76–7.74 (m, 2H), 7.55–7.52 (m, 2H), 7.49–7.47 (m, 1H), 7.33 (d, J = 8.0 Hz, 4H), 2.45 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 157.38 (2x), 149.99, 139.26, 138.93 (2x), 136.88 (2x), 129.38 (4x), 129.04 (2x), 128.83, 127.16 (2x), 126.97 (4x), 116.49 (2x), 21.30 (2x).

2,6-Bis(4-methoxyphenyl)-4-phenylpyridine (2ea)^28f. Yield = 92% (676 mg); white solid; mp = 131–132 °C; HRMS (ESI, M⁺ + H) calcd for C₂₅H₂₂NO₂ 368.1645, found 368.1645; ¹H NMR (500 MHz, CDCl₃): δ 8.20 (d, J = 9.0 Hz, 4H), 7.79 (s, 2H), 7.75 (d, J = 7.5 Hz, 2H), 7.58.7.52 (m, 2H), 7.51–7.46 (m, 1H), 7.07 (d, J = 8.0 Hz, 4H), 3.89 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 160.40 (2x), 156.81 (2x), 149.84, 139.21, 132.23 (2x), 128.94 (2x), 128.72, 128.27 (4x), 127.05 (2x), 115.53 (2x), 113.93 (4x), 55.24 (2x)

2,6-Di([1,1′-biphenyl]-4-yl)-4-phenylpyridine (2fa)^28f. Yield = 72% (661 mg); white solid; mp = 180–181 °C; HRMS (ESI, M⁺ + H) calcd for C₃₅H₂₆N 460.2060, found 460.2058; ¹H NMR (500 MHz, CDCl₃): δ 8.32 (d, J = 8.0 Hz, 4H), 7.95 (s, 2H), 7.82–7.75 (m, 6H), 7.70 (d, J = 8.0 Hz, 4H), 7.59–7.53 (m, 2H), 7.53–7.46 (m, 5H), 7.43–7.37 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 157.12 (2x), 150.23 (2x), 141.81 (2x), 140.68 (2x), 139.06, 138.47 (2x), 129.13 (2x), 129.00 (2x), 128.83 (4x), 127.52 (4x), 127.43 (4x), 127.20 (2x), 127.12 (4x), 117.04 (2x).

2,6-Bis(3-fluorophenyl)-4-phenylpyridine (2ga)^28f. Yield = 92% (631 mg); white solid; mp = 147–148 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₆F₂N 344.1245, found 344.1254; ¹H NMR (500 MHz, CDCl₃): δ 7.98–7.92 (m, 4H), 7.89 (s, 2H), 7.77–7.72 (m, 2H), 7.58–7.53 (m, 2H), 7.52–7.45 (m, 3H), 7.18–7.13 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 163.35 (d, J = 243.75 Hz, 2x), 156.19 (d, J = 2.25 Hz, 2x), 150.62, 141.62 (d, J = 7.375 Hz, 2x), 138.59, 130.20 (d, J = 8.125 Hz, 2x), 129.22, 129.20 (2x), 127.15 (2x), 122.56 (d, J = 2.375 Hz, 2x), 117.62 (2x), 116.00 (d, J = 21.125 Hz, 2x), 114.06 (d, J = 22.75 Hz, 2x).

2,6-Bis(3-methoxyphenyl)-4-phenylpyridine (2ia)^30f. Yield = 82% (602 mg); colorless gum; HRMS (ESI, M⁺ + H) calcd for C₂₅H₂₂NO₂ 368.1645, found 368.1640; ¹H NMR (500 MHz, CDCl₃): δ 7.89 (s, 2H), 7.82–7.81 (m, 2H), 7.79–7.73 (m, 4H), 7.57–7.52 (m, 2H), 7.51–7.46 (m, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.01 (dd, J = 2.5, 8.0 Hz, 2H), 3.93 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 160.03 (2x), 157.18 (2x), 150.17, 141.03 (2x), 138.98, 129.66 (2x), 129.10 (2x), 128.98, 127.16 (2x), 119.53 (2x), 117.39 (2x), 114.71 (2x), 112.66 (2x), 55.38, 55.36.

2,6-Bis(2-bromophenyl)-4-phenylpyridine (2la)^28f. Yield = 61% (565 mg); white solid; mp = 150–151 °C; HRMS (ESI, M⁺ + H) calcd for C₂₃H₁₆Br₂N 463.9644, found 463.9644; ¹H NMR (500 MHz, CDCl₃): δ 7.85 (s, 2H), 7.78–7.75 (m, 2H), 7.74–7.70 (m, 4H), 7.55–7.50 (m, 2H), 7.49–7.46 (m, 1H), 7.45–7.41 (m, 2H), 7.27 (td, J = 2.0, 8.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 158.39 (2x), 148.20, 141.18 (2x), 138.11 (2x), 133.29 (2x), 131.75 (2x), 129.76 (2x), 129.13 (2x), 127.58 (2x), 127.21 (2x), 121.94 (2x), 121.41 (2x).

4-Phenyl-2,6-di-o-tolylpyridine (2ma)^28f. Yield = 81% (543 mg); white solid; mp = 133–134 °C; HRMS (ESI, M⁺ + H) calcd for C₂₅H₂₂N 336.1747, found 336.1747; ¹H NMR (500 MHz, CDCl₃): δ 7.74–7.72 (m, 2H), 7.60 (s, 2H), 7.54–7.49 (m, 4H), 7.48–7.43 (m, 1H), 7.34–7.27 (m, 6H), 2.49 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 160.09 (2x), 148.79, 140.72 (2x), 138.49, 135.90 (2x), 130.68 (2x), 129.83 (2x), 129.13 (2x), 129.02, 128.24 (2x), 127.12 (2x), 125.83 (2x), 120.11 (2x), 20.62 (2x).

2,6-Bis(2-methoxyphenyl)-4-phenylpyridine (2na)^28f. Yield = 77% (565 mg); white solid; mp = 133–134 °C; HRMS (ESI, M⁺ + H) calcd for C₂₅H₂₂NO₂ 368.1651, found 368.1642; ¹H NMR (500 MHz, CDCl₃): δ 8.00 (s, 2H), 7.96 (dd, J = 1.5, 7.5 Hz, 2H), 7.76–7.72 (m, 2H), 7.54–7.49 (m, 2H), 7.47–7.42 (m, 1H), 7.42–7.36 (m, 2H), 7.14–7.09 (m, 2H), 7.04 (d, J = 8.5 Hz, 2H), 3.90 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 157.08 (2x), 155.97 (2x), 147.66 (2x), 139.48, 131.56 (2x), 129.72 (2x), 129.62, 128.91 (2x), 128.51, 127.34 (2x), 121.41 (2x), 121.05 (2x), 111.41 (2x), 55.72 (2x).

4-Phenyl-2,6-bis(4-(trifluoromethyl)phenyl)pyridine (2qa)^30f. Yield = 85% (753 mg); white solid; mp = 156–157 °C; HRMS (ESI, M⁺ + H) calcd for C₂₅H₁₆F₆N 444.1182, found 444.1180; ¹H NMR (500 MHz, CDCl₃): δ 8.30 (d, J = 8.0 Hz, 4H), 7.99–7.92 (m, 2H), 7.78 (d, J = 8.0 Hz, 4H), 7.75 (d, J = 7.0 Hz, 2H), 7.60–7.50 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 156.24, 150.87, 142.50 (2x), 138.34, 131.07 (q, J = 32.7 Hz, 2x), 129.40 (2x), 129.28 (2x), 127.38 (4x), 127.16 (2x), 125.71 (d, J = 3.5 Hz, 4x), 124.23 (q, J = 273.62 Hz, 2x), 118.18 (2x).

4-Phenyl-2,6-di-m-tolylpyridine (2ra)^30g. Yield = 70% (469 mg); yellow solid; mp = 162–163 °C; (ESI, M⁺ + H) calcd for C₂₅H₂₂N 336.1747, found 336.1742; ¹H NMR (500 MHz, CDCl₃): δ 8.04 (s, 2H), 8.00 (d, J = 7.5 Hz, 2H), 7.89 (s, 2H), 7.77 (d, J = 7.5 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 2.51 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 151.71 (2x), 150.02, 139.64 (2x), 139.11, 138.27 (2x), 129.75 (2x), 129.06 (2x), 128.89, 128.58 (2x), 127.83 (2x), 127.17 (2x), 124.30 (2x), 117.15 (2x), 21.59 (2x).

2,6-Di(furan-2-yl)-4-phenylpyridine (2sa)^28f. Yield = 76% (436 mg); bown solid; mp = 118–119 °C; HRMS (ESI, M⁺ + H) calcd for C₁₉H₁₄NO₂ 288.1025, found 288.1033; ¹H NMR (500 MHz, CDCl₃): δ 7.81 (s, 2H), 7.78–7.74 (m, 2H), 7.58–7.55 (m, 2H), 7.54–7.50 (m, 2H), 7.49–7.44 (m, 1H), 7.20 (dd, J = 1.0, 3.0 Hz, 2H), 6.58–6.55 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 153.77 (2x), 149.77, 149.69 (2x), 143.28 (2x), 138.38, 129.11, 129.04 (2x), 127.03 (2x), 114.80 (2x), 112.05 (2x), 109.09 (2x).

4-Phenyl-2,6-di(thiophen-3-yl)pyridine (2ta)^28f. Yield = 80% (510 mg); yellow solid; mp = 135–136 °C; HRMS (ESI, M⁺ + H) calcd for C₁₉H₁₄NS₂ 320.0562, found 320.0561; ¹H NMR (500 MHz, CDCl₃): δ 8.08 (dd, J = 1.5, 3.0 Hz, 2H), 7.84 (dd, J = 1.5, 5.0 Hz, 2H), 7.76–7.72 (m, 4H), 7.59–7.54 (m, 2H), 7.52–7.48 (m, 1H), 7.45 (dd, J = 3.0, 5.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 153.64 (2x), 150.15, 142.44 (2x), 138.90, 129.09 (2x), 128.98, 127.10 (2x), 126.45 (2x), 126.14 (2x), 123.78 (2x), 116.60 (2x).

2,6-Dimethyl-4-phenylpyridine (2ua)³¹. Yield = 88% (322 mg); white solid; mp = 58–59 °C; HRMS (FAB, M⁺ + H) calcd for C₁₃H₁₄N 184.1126, found 184.1126; ¹H NMR (500 MHz, CDCl₃): δ 7.73–7.54 (m, 2H), 7.51–7.39 (m, 3H), 7.19 (s, 2H), 2.60 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 158.01, 149.35, 138.61, 128.99 (2x), 128.85 (2x), 127.05 (2x), 118.53 (2x), 24.41 (2x).

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

The authors thank Ping-Yu Lin (IOC, Academia Sinica) for mass measurement, Ministry of Science and Technology (MOST 110-2811-M-001-644; MOST 111-2811-M-001-089 and 111-2113-M-001-043) and the Thematic Research Project, Academia Sinica Taiwan (AS-TP-111-M01) for financial support. Chieh-Kai Chan acknowledges Postdoctoral Scholar Program from Academia Sinica.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterisation data, copies of ¹H and ¹³C NMR spectra data. See https://doi.org/10.1039/d2ra04739j

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