Synthesis method of 2,3,5,6-tetrasubstituted pyridine compounds

Abstract

The present invention provides a method for synthesizing 2,3,5,6-tetrasubstituted pyridine compounds, and describes an effective and practical method for synthesizing tetrasubstituted pyridines by promoting the reaction of enaminones with DMSO by imidazole hydrochloride. The present invention shows good functional group tolerance and synthesizes a series of pyridines with moderate to good yields in the absence of metal catalysts.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, relates to tetrasubstituted pyridine compounds, and specifically relates to a method for synthesizing 2,3,5,6-tetrasubstituted pyridine compounds. Background Art

[0002] Pyridine is a class of nitrogen-containing heterocyclic compounds that are very important in natural products, functional materials and medicinal chemistry. Among them, multi-substituted symmetrical pyridines can be used as fungicides and herbicides. In addition, symmetrical pyridines can also be used as nitrogen ligands in transition metal-catalyzed organic reactions. The traditional method for synthesizing 2,3,5,6-tetrasubstituted pyridine compounds is mainly synthesized by condensation and oxidative aromatization of 1,3-dicarbonyl compounds, formaldehyde and inorganic ammonium salts, but the yield is generally low and the substrate range is narrow. In 2014, Guan et al. used ketoximine acetate and N,N-dimethylformamide as raw materials and synthesized 2,3,5,6-tetrasubstituted symmetrical pyridine under ruthenium catalysis, but expensive metal ruthenium was used in the reaction. Comprehensively reviewing previous synthetic methods, it is found that these methods generally have the disadvantages of difficult raw materials, narrow substrate range, and lack of economic and greenness. Summary of the invention

[0003] In order to solve the problems in the prior art, the object of the present invention is to provide a method for synthesizing 2,3,5,6-tetrasubstituted pyridine compounds.

[0004] Unless otherwise specified, the parts described in the present invention are all parts by weight and the percentages described are all mass percentages.

[0005] To achieve the above object, the technical solution of the present invention is:

[0006] A method for synthesizing a 2,3,5,6-tetrasubstituted pyridine compound adopts the following synthetic route:

[0007]

[0008] Where R1 is

[0009] R2 is selected from hydrogen, one or more substituted C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, one or more halogen-substituted C 1-6 Alkyl, nitro;

[0010] R3 is

[0011] R4 is selected from hydrogen, one or more substituted C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, one or more halogen-substituted C1-6 Alkyl, nitro,

[0012] The catalyst is selected from one or more of imidazole hydrochloride, trifluoromethanesulfonic acid, ferric chloride, acetic acid, p-toluenesulfonic acid, hydrochloric acid, and sulfuric acid; preferably imidazole hydrochloride. Further, the amount of imidazole hydrochloride is 1-4 equivalents, preferably 2-4 equivalents. The reaction temperature is 90-130°C, preferably 110-130°C.

[0013] The term "C 1-6 The term "alkyl" refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl, more preferably methyl, ethyl, propyl or isopropyl.

[0014] The above-mentioned "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0015] The above-mentioned "-OC 1-6 The term "alkyl" refers to a saturated straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, etc., preferably methoxy and ethoxy.

[0016] The compound of formula II is selected from the following compounds:

[0017] 2,6-Dimethylpyridine-3,5-diylbis(phenyl ketone) (2a):

[0018] 2,6-Dimethylpyridine-3,5-diylbis(p-tolylmethanone) (2b):

[0019] 2,6-Dimethylpyridine-3,5-diylbis(4-methoxyphenyl)methanone) (2c):

[0020] 2,6-Dimethylpyridine-3,5-diylbis(4-ethylphenyl)methanone (2d):

[0021] 2,6-Dimethylpyridine-3,5-diylbis(4-chlorophenyl)methanone) (2e):

[0022] 2,6-Dimethylpyridine-3,5-diylbis(4-bromophenyl)methanone) (2f):

[0023] 2,6-Dimethylpyridine-3,5-diylbis(4-fluorophenyl)methanone) (2g):

[0024] 2,6-Dimethylpyridine-3,5-diyl di-o-tolyl ketone (2h):

[0025] 2,6-Dimethylpyridine-3,5-diylbis(2-bromophenyl)methanone) (2i):

[0026] 2,6-Dimethylpyridine-3,5-diylbis(2-chlorophenyl)methanone) (2j):

[0027] 2,6-Dimethylpyridine-3,5-diylbis(m-tolyl ketone) (2k):

[0028] 2,6-Dimethylpyridine-3,5-diylbis(3-methoxyphenyl)methanone) (21):

[0029] 2,6-Dimethylpyridine-3,5-diylbis(3-bromophenyl)methanone) (2m):

[0030] 2,6-Dimethylpyridine-3,5-diylbis(3-chlorophenyl)methanone) (2n):

[0031] 2,6-Dimethylpyridine-3,5-diylbis(3,4-dichlorophenyl)methanone)(2o):

[0032] 2,6-Diphenylpyridine-3,5-diylbis(phenylmethanone) (4a):

[0033] 2,6-Di-p-tolylpyridine-3,5-diylbis(phenyl ketone) (4b):

[0034] 2,6-Di-p-tolylpyridine-3,5-diylbis(phenyl ketone) (4c):

[0035] 2,6-Bis(4-chlorophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4d):

[0036] 2,6-Bis(4-bromophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4e):

[0037] 2,6-Bis(4-(trifluoromethyl)phenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4f):

[0038] 2,6-Bis(3-methoxyphenyl)pyridine-3,5-diyl)bis(phenyl ketone) (4g):

[0039] 2,6-Bis(3-chlorophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4h):

[0040] 2,6-Bis(3-fluorophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4i):

[0041] 2,6-Bis(3,4-dimethylphenyl)pyridine-3,5-diyl)bis(phenyl ketone) (4j):

[0042] 2,6-Di(furan-2-yl)pyridine-3,5-diyl)bis(phenyl ketone) (4k):

[0043] 2,6-Di(thiophen-2-yl)pyridine-3,5-diyl)bis(phenylmethanone) (4l): 2,6-Di(naphthalen-2-yl)pyridine-3,5-diyl)bis(phenylmethanone) (4m).

[0044] Beneficial Effects

[0045] The present invention provides a method for synthesizing 2,3,5,6-tetrasubstituted pyridine compounds, and describes an effective and practical method for synthesizing tetrasubstituted pyridines by promoting the reaction of enaminones with DMSO by imidazole hydrochloride. The present invention shows good functional group tolerance and synthesizes a series of pyridines in moderate to good yields without metal catalysts. DETAILED DESCRIPTION

[0046] The present invention is described in detail below by specific examples. It is pointed out that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above invention content. The raw materials and reagents used in the present invention are all commercially available products.

[0047] Example 1

[0048] Materials and Methods

[0049] Commercial reagents were purchased from Meyer Reagent Co., Ltd. (Shanghai, China), McLean Reagent Co., Ltd. (Shanghai, China), Chongqing Chuandong Chemical Co., Ltd. (Chongqing, China), etc., and used as received without further purification. 1H and 13C NMR spectra were recorded on a Bruker Avance-III spectrometer (600 MHz and 151 MHz) using TMS as an internal standard. Chemical shifts are reported in ppm and coupling constants (J) are in Hz. Multiplicities are reported as follows: singlet (s), doublet (d), doublet doublet (dd), multiple (m), triplet (t), and broad singlet (brs). TLC plates were visualized by exposure to ultraviolet light or iodine. Purification of crude compounds and separation of reaction mixtures were performed using silica gel (200-300 mesh, Shanghai, China) column chromatography.

[0050] General procedure for the synthesis of pyridine:

[0051] Enaminone (0.6 mmol), imidazole hydrochloride (0.9 mmol) and DMSO (3 mL) were added to a round-bottom flask. The mixture was stirred at 120 °C for 8 hours. The reaction was monitored by TLC. When the reaction was complete, a saturated solution of NaCl (40 mL) was added. After the aqueous phase was extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo, and silica gel was added. The residue was separated by chromatography (petroleum ether / ethyl acetate 20:1) to obtain the desired product.

[0052] The study started with the optimization of conditions for the model reaction of primary enamine ketone 1a and DMSO. The reaction of 1a (0.6 mmol) and DMSO with imidazole hydrochloride (0.3 mmol) can provide the desired product 2a with an acceptable yield of 46% at 90 °C (Table 1, entry 1). Encouraged by the results, when the reaction was carried out in the presence of various Brnsted and Lewis acids, the reaction was shown to be able to produce 2a, with imidazole hydrochloride showing some of the best effects (Table 1, entries 1-7). On the other hand, the model reaction was carried out in the range of 1.0 equivalent to 4.0 equivalents of imidazole chloride loading. The results showed that 3 equivalents of imidazolium chloride can effectively promote the reaction to completion within 8 hours, giving 65% of the product 2a (Table 1, entries 8-9). Next, different temperatures were scanned to improve the yield, and 120 °C was determined to be the optimal temperature for the reaction (Table 1, entries 11-13). The optimized conditions were determined to be 1a (0.6 mmol) in DMSO at 120 °C in the presence of imidazole hydrochloride (0.9 mmol) to afford the desired product 2a in 88% yield (Table 1, entry 12).

[0053] Table 1. Optimization of reaction conditionsa

[0054]

[0055]

[0056]

[0057] a Reaction conditions: 1a (0.6 mmol, 2.0 eq.) was heated in 3 mL DMSO for 8 h.

[0058] b Isolated yield

[0059] Under the optimized reaction conditions, the inventors next studied the compatibility of the method. Scheme 2 summarizes the results. Satisfactorily, enaminones (1a-1o) with different functional groups were successfully applied to react with DMSO, and the corresponding products were obtained in moderate to good yields (67-88%). The electron-donating (4-Me, 4-OMe, 4-Et, 3-Me, 3-OMe, 2-Me) groups attached to the benzene ring of enaminones showed excellent reactivity (67%-83%, 2b-2d, 2k, 2l and 2h). In addition, the presence of electron-withdrawing substituents (4-Cl, 4-Br, 4-F, 3-Br, 3-Cl, 2-Br, 2-Cl, 3,4-Cl) in the benzene ring of enaminones was also beneficial, and the yields of the corresponding pyridines were 73-85% (2e-2g, 2m, 2n, 2i, 2j and 2o).

[0060] Scheme 2. Synthesis of tetrasubstituted pyridines a,b

[0061]

[0062]

[0063] a Reaction conditions: 1a (0.6 mmol) and imidazolium chloride (0.9 mmol) were reacted in DMSO (3 mL) at 120 °C for 8 hours. b Isolated yield.

[0064] To further explore the generality of this approach, structural variations of enaminones (R3) were examined according to Scheme 3. Probing R3 showed that a wide range of structures were tolerant to this protocol. A series of para-substituted enaminones (3a–3f), including some with electron-donating groups (Me, CH(CH3)2) and some with electron-withdrawing groups (Cl, Br), were converted to the corresponding pyridines in good to excellent yields (80–94%, 4a–4e). However, the presence of strong electron-withdrawing substituents in the C4 aryl ring of the enaminones was found to be detrimental, and the corresponding pyridines were obtained in slightly reduced yields 4f. In addition, meta- and poly-substituted enaminones were able to afford the desired products in moderate to good yields (4g–4j). This protocol also showed high compatibility with a variety of heterocycles, including thiophene 4l and furan 4k, affording the desired products in 75% and 69% yields, respectively. Meanwhile, high aryl naphthyl 3m smoothly provided the desired product in 86% yield.

[0065] Scheme 3. Synthesis of tetrasubstituted pyridines a,b

[0066]

[0067]

[0068] Reaction conditions: 1a (0.6 mmol) and imidazolium chloride (0.9 mmol) were reacted in DMSO (3 mL) at 120 °C for 8 hours. b Isolated yield.

[0069] In summary, the present invention provides an efficient and practical protocol for the preparation of tetrasubstituted pyridines from enaminones with DMSO under the promotion of imidazolium chloride. In addition, control experimental results show that dimethyl sulfoxide is used as a single carbon surrogate. It is worth noting that the main advantages of this protocol are the tolerance to a wide range of functional groups and the avoidance of metal catalysts. Multi-gram scale reactions were also performed to ensure the scalability of the reaction.

[0070] NMR data of the target compound: 2,6-dimethylpyridine-3,5-diylbis(phenyl ketone) (2a): yellow oily liquid (83.2 mg, yield 88%); 1 H NMR (600MHz, CDCl3) δ7.79 (dd, J=8.3, 1.2Hz, 4H), 7.62–7.58 (m, 3H), 7.47 (t, J=7.8Hz, 4H), 2.61 (s, 6H). 13 C NMR (151MHz, CDCl3) δ196.20,158.11,136.87,136.57,133.82,130.59,129.99,128.80,23.53.

[0071] 2,6-Dimethylpyridine-3,5-diylbis(p-tolylmethanone) (2b): yellow oily liquid (84.5 mg, yield 82%); 1 H NMR (600MHz, CDCl3) δ7.69 (d, J = 8.1 Hz, 4H), 7.57 (s, 1H), 7.26 (d, J = 8.3 Hz, 4H), 2.59 (s, 6H), 2.42 (s, 6H). 13 C NMR (151MHz, CDCl3) δ195.92,157.66,144.94,136.22,134.35,130.88,130.17,129.49,23.41,21.74.

[0072] 2,6-Dimethylpyridine-3,5-diylbis(4-methoxyphenyl)methanone) (2c): pale yellow oily liquid (90.1 mg, yield 80%); 1H NMR (600MHz, CDCl3) δ7.80–7.75(m,4H),7.56(s,1H),6.96–6.92(m,4H),3.89–3.86(m,6H),2.60–2.57(m,6H). 13 C NMR (151MHz, CDCl3) δ194.87,164.21,157.20,135.71,132.44,131.09,129.74,114.04,55.58,23.27.

[0073] 2,6-Dimethylpyridine-3,5-diylbis(4-ethylphenyl)methanone: yellow oily liquid (85.8 mg, yield 77%)

[0074] ); 1 H NMR (600MHz, CDCl3) δ7.71 (d, J = 8.3Hz, 4H), 7.58 (s, 1H), 7.29 (d, J = 8.5Hz, 4H), 2.71 (q, J = 7.6Hz, 4H), 2.60 (s, 6H), 1.26 (t, J = 7.6Hz, 6H). 13 C NMR (151MHz, CDCl3) δ195.94,157.70,151.07,136.26,134.54,130.86,130.31,128.32,29.02,23.40,15.10.

[0075] 2,6-Dimethylpyridine-3,5-diylbis(4-chlorophenyl)methanone) (2e): yellow solid (85.3 mg, yield 74%); mp 106-108°C; 1 HNMR (600MHz, CDCl3) δ7.72 (d, J = 8.6 Hz, 4H), 7.56 (s, 1H), 7.45 (d, J = 8.6 Hz, 4H), 2.59 (s, 6H). 13 CNMR (151MHz, CDCl3) δ194.84,158.26,140.59,136.26,135.11,131.28,130.30,129.23,23.56.

[0076] 2,6-Dimethylpyridine-3,5-diylbis(4-bromophenyl)methanone) (2f): yellow oily liquid (110.7 mg, yield 78%); 1 H NMR (600MHz, CDCl3) δ7.66–7.61(m,8H),7.56(s,1H),2.59(s,6H). 13C NMR (151MHz, CDCl3) δ195.02,158.32,136.31,135.52,132.23,131.34,130.24,129.37,23.57.

[0077] 2,6-Dimethylpyridine-3,5-diylbis(4-fluorophenyl)methanone) (2 g): yellow oily liquid (76.9 mg, yield 73%); 1 H NMR (600MHz, CDCl3) δ7.82(dd,J=8.9,5.3Hz,4H),7.57(s,1H),7.16(t,J=8.6Hz,4H),2.59(s,6H). 13 C NMR (151MHz, CDCl3) δ194.56,167.07,165.37,157.99,136.07,133.20,133.18,132.70,132.64,130.52,116.19,116.04,23.46.

[0078] 2,6-Dimethylpyridine-3,5-diyldi-o-tolylmethanone (2h): yellow oily liquid (69 mg, yield 67%); 1 H NMR (600MHz, CDCl3) δ7.58(s,1H),7.38(td,J=7.5,1.3Hz,2H),7.29–7.25(m,4H),7.19(t,J=7.5Hz,2H),2.62(s,6H),2.47(s,6H). 13 C NMR (151MHz, CDCl3) δ198.21,159.24,138.78,137.39,131.90,131.75,130.49,125.67,23.93,20.82.

[0079] 2,6-Dimethylpyridine-3,5-diylbis(2-bromophenyl)methanone) (2i): yellow oily liquid (120.7 mg, yield 85%); 1 H NMR (600MHz, CDCl3) δ7.55–7.52(m,2H),7.51(s,1H),7.35–7.31(m,4H),7.29(ddd,J=7.9,6.3,2.8Hz,2H),2.77(s,6H). 13 C NMR (151MHz, CDCl3) δ195.67,161.65,141.55,140.16,133.52,132.02,129.83,129.44,127.48,119.96,24.61.

[0080] 2,6-Dimethylpyridine-3,5-diylbis(2-chlorophenyl)methanone) (2j): yellow oily liquid (92.2 mg, yield 80%); 1 H NMR (600MHz, CDCl3) δ7.55 (s, 1H), 7.42–7.38 (m, 4H), 7.37–7.35 (m, 2H), 7.31 (ddd, J = 7.8, 7.2, 1.3Hz, 2H), 2.75 (s, 6H). 13 C NMR (151MHz, CDCl3) δ195.12,161.14,140.83,138.03,132.26,131.87,130.42,130.08,127.03,24.47.

[0081] 2,6-Dimethylpyridine-3,5-diylbis(m-tolylmethanone) (2k): yellow oily liquid (77.3 mg, yield 75%); 1 H NMR (600MHz, CDCl3) δ7.62(s,2H),7.59(s,1H),7.55(d,J=7.7Hz,2H),7.41(d,J=7.6Hz,2H),7.35(t,J=7.6Hz,2H),2.61(s,6H),2.40(s,6H). 13 C NMR (151MHz, CDCl3) δ196.45,157.98,138.77,136.93,136.47,134.64,130.74,130.31,128.63,127.40,23.49,21.31.

[0082] 2,6-Dimethylpyridine-3,5-diylbis(3-methoxyphenyl)methanone) (2l): yellow oily liquid (94.5 mg, yield 83%); 1 H NMR (600MHz, CDCl3) δ7.61 (s, 1H), 7.40–7.38 (m, 2H), 7.35 (t, J = 7.9Hz, 2H), 7.26(t,J=6.9Hz,2H),7.14(dd,J=8.2,2.6Hz,2H),3.85(s,6H),2.61(s,6H). 13 C NMR (151MHz, CDCl3) δ195.97,160.00,158.10,138.21,136.59,130.58,129.73,123.05,120.44,113.65,55.51,23.48.

[0083] 2,6-Dimethylpyridine-3,5-diylbis(3-bromophenyl)methanone) (2m): yellow oily liquid (106.5 mg, yield 75%); 1 H NMR (600MHz, CDCl3) δ7.94(t,J=1.7Hz,2H),7.75–7.72(m,2H),7.66(d,J=7.8Hz,2H),7.59(s,1H),7.37(t,J=7.9Hz,2H),2.63(s,6H). 13 C NMR (151MHz, CDCl3) δ194.49,158.84,138.64,136.77,136.69,132.62,130.39,129.85,128.54,123.25,23.63

[0084] 2,6-Dimethylpyridine-3,5-diylbis(3-chlorophenyl)methanone) (2n): yellow oily liquid (93.4 mg, yield 81%); 1 H NMR (600MHz, CDCl3) δ7.78(t,J=1.8Hz,2H),7.63–7.61(m,2H),7.60–7.57(m,3H),7.43(t,J=7.9Hz,2H),2.63(s,6H). 13 C NMR (151MHz, CDCl3) δ194.61,158.82,138.46,136.75,135.28,133.77,130.15,129.87,129.69,128.09,23.63.

[0085] 2,6-Dimethylpyridine-3,5-diylbis(3,4-dichlorophenyl)methanone) (2o): yellow oily liquid (108.8 mg, yield 80%); 1 H NMR (600MHz, CDCl3) δ7.88–7.86 (m, 2H), 7.57 (t, J = 2.9Hz, 5H), 2.61 (s, 6H). 13 C NMR (151MHz, CDCl3) δ193.52,158.88,138.72,136.41,136.37,133.79,131.54,131.00,129.65,128.79,23.62.

[0086] 2,6-Diphenylpyridine-3,5-diylbis(phenylmethanone) (4a): white solid (123.9 mg, yield 94%); mp 193-196°C; 1H NMR (600MHz, CDCl3) δ8.07 (s, 1H), 7.75 (d, J = 6.4Hz, 4H), 7.69 (s, 4H), 7.48 (t, J = 7.0Hz, 2H), 7.34 (t, J = 6.6Hz, 4H), 7.29 (s, 6H). 13 C NMR (151MHz, CDCl3) δ196.65,158.05,138.84,138.62,136.42,133.55,131.91,129.94,129.58,129.44,128.49,128.41.

[0087] 2,6-Di-p-tolylpyridine-3,5-diylbis(phenyl ketone) (4b) 5 : White solid (117.8 mg, yield 84%); mp 140-142°C; 1 HNMR (600MHz, CDCl3) δ7.99 (s, 1H), 7.77–7.73 (m, 4H), 7.59 (d, J = 8.1Hz, 4H), 7 .46(t,J=7.4Hz,2H),7.33(t,J=7.8Hz,4H),7.08(d,J=7.9Hz,4H),2.28(s,6H). 13 C NMR (151MHz, CDCl3) δ196.83,157.93,139.51,138.70,136.58,135.95,133.43,131.36,129.97,129.53,129.13,128.48,21.25.

[0088] 2,6-Di-p-tolylpyridine-3,5-diylbis(phenyl ketone) (4c): white solid (125.7 mg, yield 80%); mp 101-103°C; 1 HNMR (600MHz, CDCl3) δ8.02(s,1H),7.73(d,J=7.3Hz,4H),7.61(d,J=8.2Hz,4H),7.44(t,J=7.4Hz,2H ),7.31(t,J=7.8Hz,4H),7.12(d,J=8.1Hz,4H),2.83(dt,J=13.8,6.9Hz,2H),1.17(d,J=6.9Hz,12H). 13 C NMR (151MHz, CDCl3) δ196.84,158.14,150.33,138.79,136.68,136.24,133.26,131.34,129.91,129.66,128.38,126.45,33.87,23.68.

[0089] 2,6-Bis(4-chlorophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4d): white solid (131.2 mg, yield 86%); mp 160-162°C; 1 H NMR(600MHz, CDCl3)δ8.01(d,J=3.5Hz,1H),7.73(d,J=7.8Hz,4H),7.63–7.59( m,4H),7.52–7.47(m,2H),7.35(dd,J=11.3,4.3Hz,4H),7.26(d,J=8.5Hz,4H). 13 C NMR (151MHz, CDCl3) δ196.15,156.74,138.81,136.90,136.20,135.88,133.89,132.08,130.77,129.93,128.71,128.69.

[0090] 2,6-Bis(4-bromophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4e): white solid (146.9 mg, yield 82%); mp 149-152°C; 1 H NMR (600MHz, CDCl3) δ8.00(s,1H),7.73(dd,J=8.2,1.0Hz,4H),7.56–7.53(m,4H),7.51(t,J=7.4Hz,2H),7.44–7.40(m,4H),7.35(t,J=7.8Hz,4H). 13 CNMR(151MHz, CDCl3)δ196.11,156.81,138.78,137.33,136.18,133.91,132.08,131.67,131.00,129.93,128.70,124.28.

[0091] 2,6-Bis(4-(trifluoromethyl)phenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4f): white solid (120.9 mg, yield 70%); mp 100-102°C; 1 H NMR (600MHz, CDCl3) δ8.05(s,1H),7.78(d,J=8.1Hz,4H),7.77–7.73(m,4H),7.56(d,J=8.2Hz,4H),7.52(t,J=7.4Hz,2H),7.37(t,J=7.8Hz,4H). 13C NMR (151MHz, CDCl3) δ195.70,156.76,141.68,138.62,136.08,134.08,132.89,129.94,129.80,128.79,125.42,125.40.

[0092] 2,6-Bis(3-methoxyphenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4 g): light yellow oily liquid (115.4 mg, yield 77%); 1 H NMR(600MHz, CDCl3)δ8.02(s,1H),7.74(dd,J=8.3,1.1Hz,4H),7.48–7.44(m,2H),7.32(t,J=7.8Hz,4H),7 .27–7.26(m,2H),7.24–7.22(m,2H),7.17(t,J=7.9Hz,2H),6.82(ddd,J=8.2,2.5,0.8Hz,2H),3.72(s,6H). 13 C NMR (151MHz, CDCl3) δ196.55,159.57,157.66,139.95,136.47,133.52,132.16,129.82,129.43,128.48,122.19,115.74,114.60,55.27.

[0093] 2,6-Bis(3-chlorophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4h): yellow oily liquid (106.8 mg, yield 70%); 1 H NMR (600MHz, CDCl3) δ8.07 (s, 1H), 7.74–7.72 (m, 4H), 7.71 (d, J = 1.3Hz, 2H), 7.52–7.48 (m, 2H), 7.48–7. 45(m,2H),7.36(q,J=7.7Hz,4H),7.27(dd,J=2.0,1.0Hz,1H),7.26–7.25(m,1H),7.19(t,J=7.9Hz,2H). 13 C NMR (151MHz, CDCl3) δ196.06,156.66,140.02,139.00,136.18,134.59,133.88,132.56,129.83,129.62,129.58,129.55,128.67,127.63.

[0094] 2,6-Bis(3-fluorophenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4i): yellow oily liquid (107 mg, yield 75%);1 H NMR (600MHz, CDCl3) δ8.05 (s, 1H), 7.74 (dd, J = 8.3, 1.1Hz, 4H), 7.52–7.45 (m, 4H ),7.37(dt,J=15.7,4.2Hz,6H),7.23(td,J=8.0,5.8Hz,2H),7.01–6.96(m,2H). 13 C NMR (151MHz, CDCl3) δ196.09,163.52,161.88,156.64,140.48,138.88,136.16,133.88,132.51,129.98,129.89,128.68,125.29,116.45.

[0095] 2,6-Bis(3,4-dimethylphenyl)pyridine-3,5-diyl)bis(phenylmethanone) (4j): white solid (117.5 mg, yield 79%); mp 160-162°C; 1 H NMR (600MHz, CDCl3) δ7.98 (s, 1H), 7.74 (d, J = 7.5Hz, 4H), 7.49 (s, 2H), 7.45 (t, J = 7.4Hz, 2H) ,7.36(d,J=7.6Hz,2H),7.32(t,J=7.7Hz,4H),7.01(d,J=7.7Hz,2H),2.18(d,J=2.7Hz,12H). 13 C NMR (151MHz, CDCl3) δ196.97,158.17,138.67,138.15,136.65,136.26,133.34,131.28,130.78,129.88,129.66,128.42,127.06,19.67,19.59.

[0096] 2,6-Di(furan-2-yl)pyridine-3,5-diyl)bis(phenylmethanone) (4k): white solid (86.8 mg, yield 69%); mp 135-137°C; 1 H NMR (600MHz, CDCl3) δ7.81(dd,J=8.3,1.2Hz,4H),7.77(s,1H),7.53(t,J=7.4Hz,2H),7.39(dd, J=8.1,7.6Hz,4H),7.27–7.25(m,2H),7.19(dd,J=3.4,0.6Hz,2H),6.41(dd,J=3.4,1.8Hz,2H). 13C NMR (151MHz, CDCl3) δ195.40,151.81,146.66,144.60,137.52,136.80,133.54,129.51,129.20,128.63,112.81,112.15

[0097] 2,6-Di(thiophen-2-yl)pyridine-3,5-diyl)bis(phenyl ketone)(4l) 5 : White solid (101.6 mg, yield 75%); mp 118-120°C; 1 H NMR (600MHz, CDCl3) δ7.87–7.84(m,4H),7.74(s,1H),7.55(t,J=7.4Hz,2H),7.42–7.39(m,6H),7.20(d,J=3.7Hz,2H),6.89(dd,J=4.9,3.9Hz,2H). 13 CNMR (151MHz, CDCl3) δ196.26,149.93,142.14,137.68,136.05,134.10,129.99,129.91,129.39,129.28,128.84,128.17.

[0098] 2,6-Di(naphthalene-2-yl)pyridine-3,5-diyl)bis(phenyl ketone) (4m): white solid (139.2 mg, yield 86%); mp 178-180°C; 1 H NMR(600MHz, CDCl3)δ8.17(s,2H),8.15(s,1H),7.88(dd,J=8.5,1.4Hz,2H),7.80–7 .74(m,10H),7.47–7.42(m,4H),7.37(t,J=7.4Hz,2H),7.25(dd,J=10.2,5.3Hz,4H). 13 C NMR (151MHz, CDCl3) δ196.83,157.97,139.06,136.50,136.06,133.54,132.94,1 32.17,129.95,129.80,128.68,128.50,128.30,127.61,126.98,126.55,126.34.

Claims

1. A method for synthesizing a 2,3,5,6-tetrasubstituted pyridine compound of formula II, using the following synthetic route: The compound of formula II is selected from the following specific compounds: (2,6-dimethylpyridine-3,5-diyl)bis(phenyl ketone); (2,6-dimethylpyridine-3,5-diyl)bis(p-tolyl ketone); (2,6-dimethylpyridine-3,5-diyl)bis(4-methoxyphenyl ketone); (2,6-dimethylpyridine-3,5-diyl)bis(4-ethylphenyl ketone); (2,6-dimethylpyridine-3,5-diyl)bis((4-chlorophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis((4-bromophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis((4-fluorophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis(o-tolylmethanone); (2,6-dimethylpyridine-3,5-diyl)bis((2-bromophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis((2-chlorophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis(m-tolyl ketone); (2,6-dimethylpyridine-3,5-diyl)bis((3-methoxyphenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis((3-bromophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis((3-chlorophenyl)methanone); (2,6-dimethylpyridine-3,5-diyl)bis((3,4-dichlorophenyl)methanone); (2,6-diphenylpyridine-3,5-diyl)bis(phenylmethanone); (2,6-di-p-tolylpyridine-3,5-diyl)bis(phenyl ketone); (2,6-di-p-tolylpyridine-3,5-diyl)bis(phenyl ketone); (2,6-bis(4-chlorophenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-bis(4-bromophenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-bis(4-(trifluoromethyl)phenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-bis(3-methoxyphenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-bis(3-chlorophenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-bis(3-fluorophenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-bis(3,4-dimethylphenyl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-di(furan-2-yl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-di(thiophen-2-yl)pyridine-3,5-diyl)bis(phenylmethanone); (2,6-di(naphthalen-2-yl)pyridine-3,5-diyl)bis(phenyl ketone); The catalyst is imidazole hydrochloride; the dosage of the imidazole hydrochloride is 2-4 equivalents; and the reaction temperature is 110-130°C.

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