CN115894345A - Method for photocatalytic synthesis of chiral aza-arene functionalized cyclobutane compound - Google Patents

Method for photocatalytic synthesis of chiral aza-arene functionalized cyclobutane compound Download PDF

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CN115894345A
CN115894345A CN202111106518.XA CN202111106518A CN115894345A CN 115894345 A CN115894345 A CN 115894345A CN 202111106518 A CN202111106518 A CN 202111106518A CN 115894345 A CN115894345 A CN 115894345A
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azaarene
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尹艳丽
江智勇
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Henan University of Technology
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Abstract

The invention relates to a method for photocatalytic synthesis of chiral aza-arene functionalized cyclobutane compounds, belonging to the technical field of organic synthesis. DPZ is used as a visible light catalyst, any two of an ketene compound 1, a vinyl aza-arene 2 and a (E) -alkenyl aza-arene 3 react in an organic solvent under the irradiation of visible light in the presence of chiral phosphonic acid CPA under the atmosphere of argon to obtain a chiral aza-arene functionalized cyclobutane compound 4-6. The method has the advantages of simple reaction substrate, mild reaction conditions, no heavy metal participation, high yield, high enantioselectivity and good diastereoselectivity.

Description

Method for photocatalytic synthesis of chiral aza-arene functionalized cyclobutane compounds
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing chiral aza-arene functionalized cyclobutane compounds through photocatalysis.
Background
The nitrogen heterocyclic aromatic hydrocarbon compound widely exists in natural products, pharmaceutically active molecules and functional materials, and can be used as a carbonyl analogue to drive related prochiral nitrogen heterocyclic aromatic hydrocarbon to participate in asymmetric reaction by utilizing the electron deficiency characteristic of an embedded imine group (C = N) in the substances.
As is known, sunlight is a green, pollution-free and abundant clean energy, and solar light-induced chemical conversion can efficiently convert light energy into chemical energy, thereby realizing green and environment-friendly synthesis of compounds. Based on the fact that visible light (390-750 nm) occupies 43% of the solar spectrum, visible light-driven photocatalytic reactions have become an important means of molecular synthesis in recent years. In recent years, photo-redox and hydrogen-bond concerted catalysis have been widely applied to provide enantiomerically enriched imine-containing azaarene derivatives. The high reactivity of the free radicals can overcome the low activation capability of the azaarene, and as an effective strategy, various azaarene derivatives can be obtained by directly using a substrate based on the azaarene.
The types of asymmetric catalytic reactions via the ground-state ionic pathway are still very limited due to the weak electron withdrawing properties of nitrogen-containing aromatic heterocycles. Thus, there is a need to develop a process for obtaining chiral azaarene-functionalized cyclobutanes via the free radical route.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for synthesizing chiral aza-arene functionalized cyclobutane compounds through photocatalysis. The method has the advantages of simple reaction substrate, mild reaction conditions, no heavy metal participation, high yield, high enantioselectivity and good diastereoselectivity. The chromophore (DPZ) derived from dicyanopyrazine is used as a photosensitizer, the ketene compound 1 generates a diradical through energy transfer under the excitation of visible light, and the Chiral Phosphoric Acid (CPA) catalyst can perform enantioselective cycloaddition with the vinyl azaarene 2 through H bond induction. A wide variety of chiral azaarene-functionalized cyclobutanes, including cyclobutanes either all-carbon quaternary stereocenters or four adjacent stereocenters, are obtained in high yields, high enantioselectivities, and high diastereoselectivities. (E) The alkenylazaarenes 3 can also be used as reactants for vinylazaarenes 2, resulting in important but difficult to obtain enantiomerically enriched 1, 2-azaarenes substituted cyclobutanes, in which the azaarene group can be flexibly adjusted.
The invention discloses a method for photocatalytic synthesis of chiral aza-arene functionalized cyclobutane compounds, which comprises the following steps: DPZ is used as a visible light catalyst, any two of an ketene compound 1, a vinyl aza-arene 2 and a (E) -alkenyl aza-arene 3 react in an organic solvent under the irradiation of visible light in the presence of chiral phosphonic acid CPA under the atmosphere of argon to obtain a chiral aza-arene functionalized cyclobutane compound 4-6;
Figure BDA0003272618020000021
wherein Ar is 1 And Ar 2 Are all selected from nitrogen-containing heterocyclic aromatic compounds; r is 1 、R 2 、R 3 And R 4 Are all selected from C1-C8 alkyl, C1-C8 cycloalkyl, thiophene or substituted thienyl, pyridine or substituted pyridyl, quinoline or substituted quinolyl, phenyl or substituted phenyl; the substituent is halogen, C1-C4 alkyl and C1-C4 alkoxy.
Further, in the above technical scheme, the mol ratio of the ketene compound 1 to the vinyl aza-arene 2 is 2; the mol ratio of the ketene compound 1 to the (E) -alkenyl azaarene 3 is 2; the molar ratio of vinylazaarene 2 to (E) -alkenylazaarene 3 is 1.
Further, in the above technical solution, the molar ratio of the organic photocatalyst DPZ to the nitrogen heteroaromatic compound is 0.001 to 0.005.
Further, in the above technical solution, the molar ratio of the chiral phosphonic acid CPA to the nitrogen heteroaromatic compound is 0.05-0.1.
Further, in the above technical solution, the organic solvent is chloroform.
Further, in the above technical scheme, the reaction temperature is-35 ℃ to-20 ℃.
Furthermore, in the technical scheme, the organic photocatalyst DPZ has small relative molecular mass, is easy to synthesize and has high catalytic efficiency. Under the preferable conditions, the addition amount of the chiral phosphonic acid CPA is preferably 10% of the molar amount of the chiral phosphonic acid CPA per mmol of the azaaromatic hydrocarbon compound; chloroform solvent is adopted, and the reaction temperature is-35 ℃.
Further, in the above technical solution, the visible light wavelength is 450 to 455nm.
The invention has the beneficial effects that:
1. the method adopts a metal-free DPZ photocatalyst and a chiral hydrogen bond catalyst for concerted catalysis, opens double bonds of an internal double bond compound (ketene or (E) -alkenyl azaarene) by energy transfer to form high-activity diradicals, and then synthesizes chiral azaarene functionalized cyclobutane compounds with high yield, high enantioselectivity and high diastereoselectivity by [2+2] cycloaddition reaction with alkenyl azaarene compounds, wherein the chiral azaarene functionalized cyclobutane compounds comprise cyclobutane substituted by all-carbon quaternary stereocenter or four adjacent stereocenters or 1, 2-azaarene.
2. The photocatalyst prepared by the method is free of metal, low in dosage, high in catalytic efficiency, mild in reaction condition, stable and efficient, simple to operate, environment-friendly, wide in substrate range, green and environment-friendly, and has great popularization and application values.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following examples, but the scope of the present invention is not limited thereto.
In the following examples, the organic photocatalyst DPZ was prepared according to the literature (Yu Zhao, chenhao Zhang, kek Foo chi, old \711richpytela, guo Wei, hongjun Liu, filip Bures, zhiyong jiang. Chiral phosphonic acid CPA precursors were purchased from cellosolve.
Condition optimization experiment a
Figure BDA0003272618020000031
Figure BDA0003272618020000032
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Figure BDA0003272618020000041
a 0.01 mmol scale in 0.5mL solvent.Irradiation distance＝3cm. b Determined by TLC analysis of the UV(254nm)and KMnO 4 solution-staining signals between 1a and 4a. c Determined by HPLC analysis on a chiral stationary phase. d Determined by crude 1 HNMR. e 0.1mmol scale,with irradiation by 3x 3W blue LEDs,after 36h,adduct 3was obtained in 84％yield with 91％ee and 7:1:1dr.N.A.＝not available.N.D.＝not determined.
Example 1
The synthesis of ((1R, 2R, 3R) -2-phenyl-3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone, reaction formula:
Figure BDA0003272618020000042
1mg of DPZ as the organic photocatalyst was dissolved in 200. Mu.L of toluene, 35.5. Mu.L (0.0005mmol, 0.005eq) of the solution was taken up in a 25mL Schlenk tube, and the toluene was blown dry with an air pump. Then 41.6mg (0.2 mmol) of (E) -chalcone, 10.5mg (0.1 mmol) of vinylpyridine and 1.7mg (0.01 mmol) of chiral phosphonic acid C are added, 5mL of dry chloroform is added, and after three times of vacuum-liquid nitrogen freezing-room temperature-argon protection, the reaction flask is placed in a-35 ℃ incubator and stirred for 36 hours under the irradiation of 3 cm/three 3W blue LED lamps. After the reaction was completed, the chloroform was distilled off by a rotary evaporator, and column chromatography (n-hexane/ethyl acetate 100 to 5) was performed to obtain phenyl ((1r, 2r, 3r) -2-phenyl-3- (pyridin-2-yl) cyclobutyl) methanone 26.3mg, a white solid, yield 84%, diastereoselectivity dr = 7. The melting point is 98.7-101.1 ℃, 1 H NMR(300MHz,CDCl 3 )δ8.53(d,J＝4.1Hz,1H),8.06-7.94(m,2H),7.54(t,J＝7.3Hz,1H),7.43(t,J＝7.5Hz,2H),7.35(td,J＝7.7,1.9Hz,1H),7.09-6.99(m,3H),6.99-6.90(m,3H),6.79(d,J＝7.9Hz,1H),4.72(q,J＝9.5Hz,1H),4.48(t,J＝9.2Hz,1H),4.06(td,J＝9.3,4.2Hz)； 13 C NMR(75MHz,CDCl 3 )δ200.4,160.3,148.7,139.7,135.7,135.5,133.0,128.5,127.8,127.7,126.0,124.1,121.0,46.2,44.8,43.4,26.8；HRMS(ESI)m/z 314.1534(M+H + ),calc.for C 22 H 20 NO 314.1539.
example 2
The synthesis of ((1R, 2R, 3R) -2- (4-methoxyphenyl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone, reaction formula:
Figure BDA0003272618020000051
in this example, (E) -chalcone in example 1 was replaced with (E) -3- (4-methoxyphenyl) -1-phenyl-2-propenyl-1-one, and the other steps were the same as in example 1, to give ((1 r,2r, 3r) -2- (4-methoxyphenyl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone 25.8mg, yellow oil, yield 75%, diastereoselectivity dr =12.6, optical purity 90 ee. 1 H NMR(300MHz,CDCl 3 )δ8.55(d,J＝4.2Hz,1H),7.96(d,J＝7.2Hz,2H),7.52(t,J＝7.3Hz,1H),7.43(d,J＝7.8Hz,2H),7.37(dd,J＝7.3,5.5Hz,1H),7.04-6.96(m,1H),6.85(d,J＝8.6Hz,2H),6.78(d,J＝7.8Hz,1H),6.59(d,J＝8.6Hz,2H),4.63(q,J＝8.8Hz,1H),4.39(t,J＝9.2Hz,1H),4.02(td,J＝9.3,4.3Hz,1H),3.67(s,3H),3.21-3.09(m,1H),2.74(dt,J＝11.3,8.5Hz,1H)； 13 C NMR(75MHz,CDCl 3 )δ200.5,160.3,157.8,148.5,135.8,135.7,133.0,131.8,129.0,128.5,124.2,121.1,113.1,55.0,45.9,45.3,43.4,26.3；HRMS(ESI)m/z 344.1639(M+H + ),calc.for C 23 H 22 NO 2 344.1645.
Example 3
The synthesis of ((1R, 2R, 3R) -2- (3-chlorophenyl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone, reaction formula:
Figure BDA0003272618020000061
in this example, (E) -chalcone of example 1 was replaced with (E) -3- (3-chlorophenyl) -1-phenyl-2-propenyl-1-one, and the other steps were the same as in example 1 to obtain ((1R, 2R, 3R) -2- (3-chlorophenyl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methylKetone 30.9mg, yellow oil, yield 89%, diastereoselectivity dr =8.8, optical purity 87% ee. 1 H NMR(300MHz,CDCl 3 )δ8.55(d,J＝3.9Hz,1H),8.00(d,J＝7.0Hz,2H),7.63-7.53(m,1H),7.46(t,J＝7.5Hz,2H),7.40(td,J＝7.7,1.8Hz,1H),7.01(dd,J＝6.5,4.8Hz,1H),6.99-6.94(m,2H),6.91(s,1H),6.82(d,J＝7.6Hz,2H),4.73(q,J＝8.8Hz,1H),4.48(t,J＝9.3Hz,1H),4.01(td,J＝9.1,3.8Hz,1H),3.15(td,J＝10.6,3.8Hz,1H),2.69(dt,J＝11.3,8.6Hz,1H)； 13 C NMR(75MHz,CDCl 3 )δ200.1,148.9,141.9,135.7,135.5,133.6,133.2,128.9,128.6,128.6,127.9,126.2,126.0,124.1,121.3,45.1,44.8,43.3,27.5；HRMS(ESI)m/z 348.1145(M+H + ),calc.for C 22 H 19 ClNO 348.1150.
Example 4
((1R, 2R, 3R) -2- (2-methylphenyl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone was synthesized according to the following reaction scheme:
Figure BDA0003272618020000062
in this example, (E) -chalcone in example 1 was replaced with (E) -3- (2-methylphenyl) -1-phenyl-2-propenyl-1-one, and the other steps were the same as in example 1, to give ((1r, 2r, 3r) -2- (2-methylphenyl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone 22.9mg, yellow solid, yield 70%, diastereoselectivity dr =11.4, 1.8, optical purity 88 ee. The melting point is 76.6-78.0 ℃. 1 H NMR(300MHz,CDCl 3 )δ8.49(d,J＝4.9Hz,1H),8.06(d,J＝7.0Hz,2H),7.60-7.53(m,1H),7.47(t,J＝7.4Hz,2H),7.30(td,J＝7.7,1.9Hz,1H),6.97-6.85(m,5H),6.77(d,J＝7.8Hz,1H),4.97(q,J＝9.2Hz,1H),4.68(t,J＝9.4Hz,1H),4.06(td,J＝9.0,3.4Hz,1H),3.08(td,J＝10.5,3.4Hz,1H),2.71(dt,J＝11.0,8.6Hz,1H),2.32(s,3H)； 13 C NMR(75MHz,CDCl 3 )δ200.4,160.3,148.5,139.5,137.2,135.7,133.0,128.7,128.6,128.5,127.6,126.8,124.9,124.2,121.0,46.1,44.9,43.3,26.7,21.2；HRMS(ESI)m/z 328.1693(M+H + ),calc.for C 23 H 22 NO 328.1696.
Example 5
((1R, 2R, 3R) -2- (thiophen-3-yl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone was synthesized according to the following reaction scheme:
Figure BDA0003272618020000071
in this example, (E) -chalcone in example 1 was replaced with (E) -1-phenyl-3- (thiophen-3-yl) -2-propenyl-1-one, and the other steps were the same as in example 1, to give ((1r, 2r, 3r) -2- (thiophen-3-yl) -3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone 21.7mg, yellow oil, yield 68%, diastereoselectivity dr =6.6, 1, optical purity 91 ee. 1 H NMR(300MHz,CDCl 3 )δ8.58(d,J＝3.5Hz,1H),7.99-7.91(m,2H),7.54(t,J＝7.3Hz,1H),7.42(t,J＝7.6Hz,3H),7.05(dd,J＝7.0,5.5Hz,1H),6.97(dd,J＝5.0,2.9Hz,1H),6.86(d,J＝7.8Hz,1H),6.71(d,J＝2.5Hz,1H),6.57(dd,J＝5.0,1.3Hz,1H),4.52(dt,J＝23.0,8.6Hz,2H),4.01(td,J＝9.0,4.4Hz,1H),3.16(ddd,J＝11.4,9.2,4.4Hz,1H),2.73(dt,J＝11.4,8.1Hz,1H)； 13 C NMR(75MHz,CDCl 3 )δ200.22,160.37,148.66,141.03,135.80,135.64,133.05,128.53,127.48,124.75,123.98,121.40,121.23,46.46,43.18,42.01,26.40；HRMS(ESI)m/z 320.1100(M+H + ),calc.for C 20 H 18 NOS 320.1104.
Example 6
Synthesis of (4-fluorophenyl) ((1R, 2R, 3R) -2-phenyl-3- (pyridin-2-yl) cyclobutyl) methanone, of the formula:
Figure BDA0003272618020000072
in this example, (E) -chalcone from example 1 was replaced with (E) -1- (4-fluorophenyl) -3-phenyl-2-propenyl-1-one, and the other steps were the same as in example 1 to give 25.8mg of (4-fluorophenyl) ((1R, 2R, 3R) -2-phenyl-3- (pyridin-2-yl) cyclobutyl) methanone as a yellow solid in 78% yield and diastereoselective dr>20, optical purity 88% ee. The melting point is 99.1-101.4 ℃. 1 H NMR(300MHz,CDCl 3 )δ8.54(d,J＝4.3Hz,1H),8.15-7.90(m,2H),7.34(td,J＝7.7,1.9Hz,1H),7.13-7.04(m,3H),7.04-6.95(m,3H),6.94-6.87(m,2H),6.77(d,J＝7.8Hz,1H),4.68(q,J＝8.4Hz,1H),4.44(t,J＝9.2Hz,1H),4.04(td,J＝9.2,4.1Hz,1H),3.15(ddd,J＝11.1,9.5,4.1Hz,1H),2.74(dt,J＝11.3,8.5Hz,1H)； 19 F NMR(376MHz,CDCl 3 )δ-105.30； 13 C NMR(75MHz,CDCl 3 )δ198.89,167.38,164.00,160.15,148.74,139.51,135.56,132.09(d,J F-C ＝3.0Hz),131.15(d,J F-C ＝9.4Hz),127.79(d,J F-C ＝3.0Hz),126.14,124.19,121.05,115.64(d,J F-C ＝21.8Hz),46.28,44.82,43.36,26.61；HRMS(ESI)m/z 332.1440(M+H + ),calc.for C 22 H 19 FNO 332.1445.
Example 7
((1R, 2R, 3R) -3- (4-methylpyridin-2-yl) -2-phenylcyclobutyl) (phenyl) methanone was synthesized according to the following reaction scheme:
Figure BDA0003272618020000081
in this example, the vinylpyridine in example 1 was replaced with 2-methyl-2-vinylpyridine, and the other steps were the same as in example 1 to give ((1r, 2r, 3r) -3- (4-methylpyridin-2-yl) -2-phenylcyclobutyl) (phenyl) methanone 25.8mg, white solid in 79% yield, diastereoselectivity dr =12.4, and optical purity 95% ee. The melting point is 99.8-101.5 ℃. 1 H NMR(300MHz,CDCl 3 )δ8.37(d,J＝5.0Hz,1H),8.01-7.92(m,2H),7.58-7.50(m,1H),7.43(t,J＝7.4Hz,2H),7.12-6.99(m,3H),6.97-6.91(m,2H),6.80(d,J＝5.1Hz,1H),6.61(s,1H),4.71(q,J＝9.5Hz,1H),4.46(t,J＝9.2Hz,1H),4.00(td,J＝9.3,4.3Hz,1H),3.20-3.07(m,1H),2.73(dt,J＝11.4,8.5Hz,1H),2.12(s,3H)； 13 C NMR(75MHz,CDCl 3 )δ200.5,159.9,148.2,139.7,135.7,133.0,128.6,128.5,127.9,127.7,126.0,125.1,122.1,46.2,44.8,43.1,26.8,20.8.HRMS(ESI)m/z 328.1691(M+H + ),calc.for C 23 H 22 NO 328.1696.
Example 8
(1R, 2R, 3R) -3- (1-methyl-1H-benzimidazol-2-yl) -2-phenylcyclobutyl) (phenyl) methanone was synthesized according to the following reaction scheme:
Figure BDA0003272618020000082
in this example, the vinylpyridine of example 1 was replaced with 1-methyl-2-vinyl-1H-benzimidazole and the other steps were the same as in example 1 to give ((1r, 2r, 3r) -3- (1-methyl-1H-benzimidazol-2-yl) -2-phenylcyclobutyl) (phenyl) methanone 21.2mg, yellow solid, yield 58%, diastereoselectivity dr =5.7, 1, optical purity 91 ee. The melting point is 98.8-100.6 ℃. 1 H NMR(300MHz,CDCl 3 )δ7.92(d,J＝7.0Hz,2H),7.85(d,J＝7.5Hz,1H),7.55-7.47(m,1H),7.39(t,J＝7.6Hz,2H),7.26(td,J＝7.4,1.4Hz,1H),7.19(td,J＝7.6,1.3Hz,1H),7.05(d,J＝7.3Hz,2H),7.01(dd,J＝4.4,2.0Hz,1H),6.98(s,1H),6.96(s,2H),4.69(q,J＝9.1Hz,1H),4.41(t,J＝9.2Hz,1H),4.11(td,J＝9.2,3.6Hz,1H),3.54(ddd,J＝12.7,9.6,3.6Hz,1H),3.01(s,3H),2.88(dt,J＝11.6,8.9Hz,1H)； 13 C NMR(75MHz,CDCl 3 )δ199.9,153.9,142.1,138.8,136.1,135.4,133.2,128.6,128.5,128.2,127.9,127.3,122.1,121.7,119.1,108.7,46.4,46.2,35.1,29.1,25.5；HRMS(ESI)m/z 367.1800(M+H + ),calc.for C 25 H 23 N 2 O 367.1805.
Example 9
(1R, 2R, 3R) -3-methyl-2-phenyl-3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone was synthesized with the following reaction scheme:
Figure BDA0003272618020000091
in this example, vinylpyridine obtained in example 1 was replaced with 2- (propyl-1-en-2-yl) pyridine, and the other steps were carried out in the same manner as in example 1 to obtain ((1R, 2R, 3R) -3-methyl-2-phenyl-3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone 26.2mg as a white solid in 80% yield and diastereoselective dr>20, optical purity 95% ee. The melting point is 53.9-56.0 ℃. 1 H NMR(300MHz,CDCl 3 )δ8.56(d,J＝3.9Hz,1H),8.05-7.92(m,2H),7.57-7.48(m,1H),7.41(t,J＝7.5Hz,2H),7.32-7.24(m,1H),7.08-6.95(m,4H),6.86-6.78(m,2H),6.73-6.64(m,1H),4.47(q,J＝9.3Hz,1H),4.05(d,J＝9.3Hz,1H),3.71-3.51(m,1H),2.33(dd,J＝10.9,8.8Hz,1H),1.68(s,3H)； 13 C NMR(75MHz,CDCl 3 )δ200.6,163.1,147.9,139.6,135.9,135.4,133.0,128.6,128.5,127.8,126.3,122.5,120.9,53.8,47.3,41.9,34.8,29.3；HRMS(ESI)m/z 328.1691(M+H + ),calc.for C 23 H 22 NO 328.1696.
Example 10
(1R, 2R, 3R) -3- (1-methyl-1H-benzimidazol-2-yl) -2, 3-diphenylcyclobutyl) (phenyl) methanone was synthesized according to the following reaction scheme:
Figure BDA0003272618020000101
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in this example, the vinylpyridine of example 1 was replaced with 1-methyl-2- (1-phenylvinyl) -1H-benzimidazole and the other steps were carried out in the same manner as in example 1 to give ((1R, 2R, 3R) -3- (1-methyl-1H-benzimidazol-2-yl) -2, 3-diphenylcyclobutyl) (phenyl) methanone 33.6mg as a yellow oil in a yield of 76% as a diastereoselective dr>20, optical purity 92% ee. 1 H NMR(300MHz,CDCl 3 )δ7.99(d,J＝8.1Hz,3H),7.56-7.49(m,1H),7.42(d,J＝7.8Hz,2H),7.37(d,J＝1.4Hz,3H),7.33(d,J＝7.5Hz,2H),7.28-7.20(m,2H),7.16-7.09(m,1H),7.07-6.96(m,3H),6.92(d,J＝6.9Hz,2H),5.08(d,J＝10.0Hz,1H),4.75-4.52(m,1H),4.26(dd,J＝10.6,8.8Hz,1H),2.50(t,J＝10.3Hz,1H),2.23(s,3H)； 13 C NMR(75MHz,CDCl 3 )δ199.8,155.0,144.4,141.5,138.3,137.0,135.6,133.2,128.9,128.6,128.5,128.3,127.6,126.9,125.9,122.4,121.9,119.5,109.0,51.0,48.1,43.6,38.8,30.0；HRMS(ESI)m/z 443.2112(M+H + ),calc.for C 31 H 27 N 2 O 443.2118.
Example 11
(1R, 2R, 3R) -2, 3-diphenyl-3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone was synthesized with the following reaction scheme:
Figure BDA0003272618020000102
in this example, the vinylpyridine in example 1 was replaced with (E) -2-styrylpyridine, and the other steps were the same as in example 1 to give 31.1mg of ((1r, 2r, 3r) -2, 3-diphenyl-3- (pyridin-2-yl) cyclobutyl) (phenyl) methanone as a yellow oily substance in 80% yield, diastereoselectivity dr =2, and optical purities of 91% ee and 98% ee, respectively. 1 H NMR(300MHz,CDCl 3 )δ8.54(dd,J＝43.7,3.8Hz,1H),8.00-7.84(m,2H),7.56-7.45(m,2H),7.45-7.33(m,3H),7.27(d,J＝4.3Hz,3H),7.25-7.10(m,7H),7.08-6.96(m,1H),5.31-4.95(m,2H),4.84(ddt,J＝16.4,9.6,4.3Hz,2H),4.47(dd,J＝10.3,5.6Hz,0H)； 13 C NMR(75MHz,CDCl 3 )δ199.5,199.1,159.7,159.3,148.9,148.8,139.9,139.9,139.7,137.0,136.8,136.2,135.6,132.6,132.6,128.3,28.2,128.2,128.1,128.1,127.9,127.9,127.8,127.7,126.6,126.1,126.1,125.9,124.1,122.2,121.6,121.1,50.0,49.7,49.2,48.3,46.3,46.0,43.7,42.4；HRMS(ESI)m/z 390.1847(M+H + ),calc.for C 28 H 24 NO 390.1852.
Example 12
(1R, 2R,3R, 4R) -3- (isoquinolin-1-yl) -2-methyl-4-phenylcyclobutyl) (phenyl) methanone was synthesized according to the following reaction scheme:
Figure BDA0003272618020000111
in this example, the vinylpyridine in example 1 was replaced with (E) -1- (prop-1-en-1-yl) isoquinoline and the other steps were carried out in the same manner as in example 1 to give ((1R, 2R,3R, 4R) -3- (isoquinolin-1-yl) -2-methyl-4-phenylcyclobutyl) (phenyl) methanone 22.6mg as a yellow oil in 60% yield and diastereoselective dr>20, optical purity 70% ee. 1 H NMR(300MHz,CDCl 3 )δ8.48(d,J＝5.7Hz,1H),8.10(d,J＝6.8Hz,2H),7.95(d,J＝8.3Hz,1H),7.64-7.56(m,2H),7.51(td,J＝7.2,6.8,5.2Hz,3H),7.45-7.34(m,2H),6.91(dd,J＝7.8,1.8Hz,2H),6.86-6.71(m,3H),4.89(dd,J＝10.0,7.5Hz,1H),4.73(dd,J＝10.1,7.5Hz,1H),4.44(dd,J＝10.0,5.6Hz,1H),4.33(dt,J＝10.0,6.3Hz,1H),1.21(d,J＝7.1Hz,3H)； 13 C NMR(75MHz,CDCl 3 )δ200.0,159.4,141.2,139.7,137.1,135.6,133.1,129.5,128.7,128.3,128.0,127.5,127.3,126.8,126.5,125.9,125.2,119.2,48.7,48.1,42.5,33.8,16.6；HRMS(ESI)m/z 378.1848(M+H + ),calc.for C 27 H 24 NO 378.1852.
Example 13
Synthesis of 1-methyl-2- ((1R, 2S, 3R) -3-phenyl-2- (pyridin-2-yl) cyclobutyl) -1H-benzimidazole of the formula:
Figure BDA0003272618020000112
in this example, (E) -chalcone was replaced with (E) -2-styrylpyridine, vinylpyridine was replaced with 1-methyl-2-ethen-1H-benzimidazole, the substrate equivalence ratio was 1, and the chiral phosphonic acid C1 was replaced with C15, and the other steps were the same as in example 1, to give 25.1mg of 1-methyl-2- ((1r, 2s, 3r) -3-phenyl-2- (pyridin-2-yl) cyclobutyl) -1H-benzimidazole as a yellow oil in 74% yield, 1 diastereoselectivity dr =9, and optical purity was 88 ee. 1 H NMR(300MHz,CDCl 3 )δ8.36(d,J＝4.9Hz,1H),7.82(d,J＝7.3Hz,1H),7.30(d,J＝4.4Hz,4H),7.25-7.12(m,4H),7.08-7.01(m,1H),6.93(dd,J＝7.0,5.4Hz,1H),6.86(d,J＝7.9Hz,1H),4.59(q,J＝9.8Hz,1H),4.40(t,J＝9.9Hz,1H),4.21(td,J＝8.9,2.3Hz,1H),3.44(ddd,J＝11.1,8.7,2.3Hz,1H),3.18(s,3H),2.72(dd,J＝19.7,10.0Hz,1H)； 13 C NMR(75MHz,CDCl 3 )δ159.3,154.3,148.7,143.6,142.0,136.2,135.8,128.3,126.5,126.3,121.9,121.8,121.6,121.3,119.1,108.6,53.0,42.2,34.5,29.3,29.2；HRMS(ESI)m/z 340.1805(M+H + ),calc.for C 23 H 22 N 3 340.1808.
Example 14
Synthesis of 2- ((1R, 2S, 3R) -1-ethyl-3-phenyl-2- (pyridin-2-yl) cyclobutyl) -4-methylquinoline, of the formula:
Figure BDA0003272618020000121
in this example, (E) -chalcone was replaced with (E) -2-styrylpyridine, vinylpyridine with 2- (but-1-en-2-yl) -4-methylquinoline, substrate equivalence ratio was 1, chiral phosphonic acid C1 was replaced with C21, and the other steps were the same as in example 1 to give 27.2mg of 2- ((1r, 2s, 3r) -1-ethyl-3-phenyl-2- (pyridin-2-yl) cyclobutyl) -4-methylquinoline, as a yellow oil, in 72% yield, diastereoselectivity dr =17, and optical purity 91 ee. 1 H NMR(300MHz,CDCl 3 )δ8.40(d,J＝3.9Hz,1H),8.07(d,J＝8.3Hz,1H),7.80(d,J＝6.9Hz,1H),7.62(ddd,J＝8.4,6.8,1.5Hz,1H),7.44(ddd,J＝8.2,6.8,1.3Hz,1H),7.30-7.23(m,4H),7.22(d,J＝2.0Hz,1H),7.14(ddd,J＝8.5,5.4,2.7Hz,1H),6.91(ddd,J＝7.5,4.9,1.1Hz,1H),6.68(d,J＝7.9Hz,1H),6.44(s,1H),4.10-3.96(m,2H),3.96-3.86(m,1H),2.48(dq,J＝14.6,7.4Hz,1H),2.29(d,J＝0.9Hz,3H),2.20-2.03(m,2H),0.65(t,J＝7.4Hz,3H)； 13 C NMR(75MHz,CDCl 3 )δ161.4,160.0,148.6,147.0,144.6,142.3,135.7,130.0,128.4,128.2,126.7,126.5,125.9,125.5,123.3,122.3,121.6,121.1,60.6,53.4,37.4,36.2,33.7,18.4,8.9；HRMS(ESI)m/z 379.2165(M+H + ),calc.for C 27 H 27 N 2 379.2169.
Example 15
Synthesis of 4-methyl-2- ((1R, 2S, 3R) -3-phenyl-2- (quinolin-2-yl) cyclobutyl) quinoline, of the formula:
Figure BDA0003272618020000131
in this example, the procedure of example 1 was repeated except that (E) -chalcone was replaced with (E) -2-styrylpyridine, vinylpyridine was replaced with 4-methyl-2-styrylquinoline, the substrate equivalent ratio was 1>20, optical purity 94% ee. 1 H NMR(300MHz,CDCl 3 )δ8.04(d,J＝8.5Hz,1H),7.97(d,J＝8.5Hz,1H),7.74(d,J＝8.3Hz,1H),7.68-7.52(m,4H),7.45-7.38(m,3H),7.38-7.27(m,3H),7.21(q,J＝7.3,6.3Hz,1H),7.04(d,J＝8.5Hz,1H),6.88(s,1H),4.89(q,J＝9.5Hz,1H),4.58(t,J＝9.9Hz,1H),4.41(td,J＝9.3,3.0Hz,1H),3.31(ddd,J＝11.8,9.2,3.1Hz,1H),2.76(dt,J＝11.0,9.0Hz,1H),2.27(s,3H)； 13 C NMR(75MHz,CDCl 3 )δ161.0,160.6,147.4,147.3,144.9,143.0,135.2,129.6,128.9,128.8,128.6,128.3,127.2,126.6,126.6,126.5,126.0,125.5,125.3,123.4,122.9,120.6,54.0,44.4,40.8,29.5,18.2；HRMS(ESI)m/z 401.2006(M+H + ),calc.for C 29 H 25 N 2 401.2012.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.

Claims (7)

1. A method for photocatalytic synthesis of chiral azaarene functionalized cyclobutane compounds is characterized by comprising the following steps: DPZ is used as a visible light catalyst, any two of an ketene compound 1, a vinyl aza-arene 2 and a (E) -alkenyl aza-arene 3 react in an organic solvent under the irradiation of visible light in the presence of chiral phosphonic acid CPA under the atmosphere of argon to obtain chiral aza-arene functionalized cyclobutane compounds 4-6;
Figure FDA0003272618010000011
wherein Ar is 1 And Ar 2 Are all selected from nitrogen-containing heterocyclic aromatic compounds; r 1 、R 2 、R 3 And R 4 Are all selected from C1-C8 alkyl, C1-C8 cycloalkyl, thiophene or substituted thienyl, pyridine or substituted pyridyl, quinoline or substitutedQuinolinyl, phenyl or substituted phenyl; the substituent is halogen, C1-C4 alkyl and C1-C4 alkoxy.
2. The process for the photocatalytic synthesis of chiral azaarene-functionalized cyclobutanes according to claim 1, wherein: the mol ratio of the ketene compound 1 to the vinyl aza-arene 2 is 2; the mol ratio of the ketene compound 1 to the (E) -alkenyl azaarene 3 is 2; the molar ratio of vinylazaarene 2 to (E) -alkenylazaarene 3 is 1.
3. The process for the photocatalytic synthesis of chiral azaarene-functionalized cyclobutanes according to claim 1, wherein: the molar ratio of the organic photocatalyst DPZ to the nitrogen heteroaromatic compound is 0.001-0.005.
4. The photocatalytic synthesis of chiral azaarene-functionalized cyclobutanes as in claim 1, wherein: the molar ratio of the chiral phosphonic acid CPA to the nitrogen heteroaromatic compound is 0.05-0.1.
5. The photocatalytic synthesis of chiral azaarene-functionalized cyclobutanes according to any one of claims 1 to 4, wherein: the organic solvent is chloroform.
6. The process for the photocatalytic synthesis of chiral azaarene-functionalized cyclobutanes according to any one of claims 1 to 4, wherein: the reaction temperature is-35 ℃ to-20 ℃.
7. The photocatalytic synthesis of chiral azaarene-functionalized cyclobutanes according to any one of claims 1 to 4, wherein: the visible light wavelength is 450-455nm.
CN202111106518.XA 2021-09-22 2021-09-22 Method for photocatalytic synthesis of chiral aza-arene functionalized cyclobutane compound Pending CN115894345A (en)

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