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1、底物合成路线汇报之前硝基生成叠氮的反应经过仔细查询，CA以及文献上全部都需要邻位醛基，不可取：Angewandte Chemie, International Edition, 50(7), 1702-1706; 20111目标产物2 合成路线一2.1步骤1 Org. Lett.,2010,12(12), pp 28842887To a cold (0 C) solution of substituted 2-aminobenzophenone (1.97 g, 10.0 mmol, 1 equiv) in 50 mL of acetic acid and 50 mL of water was
2、 added sodium nitrite (1.04 g, 15.0 mmol, 1.5 equiv). After stirring for 1 hour,sodium azide (0.975 g, 15.0 mmol, 1.5 equiv) was added slowly into the stirring mixture, and the mixture was allowed to warm to ambient temperature. After an additional hour of stirring, the resulting mixture was neutral
3、ized with a saturated aqueous solution of Na2CO3 and extracted with 3 20 mL of CH2Cl2. The resulting organic phase was dried over Na2SO4 and decanted. The filtrate was concentrated in vacuo to afford a yellow oil. Purification by MPLC (1:99 EtOAc:hexanes) afforded the product.2.2 步骤2 J. Org. Chem. 2
4、011, 76, 47154720To a suspension of methyltriphenylphosphonium bromide (72 mmol, 25.7 g) in THF (50 mL) was added dropwise NaHMDS (1.0 M THF, 72 mL) at -78C. The resulting solution was stirred at this temperature for 15 min, and then a solution of 2-nitrobenzaldehyde (60 mmol, 9.06 g) in THF (20 mL)
5、 was added, and the resulting reaction mixture was further stirred at rt for 14 h. The reaction was quenched using saturated NH4Cl (aq), and the crude product was extracted twice with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purifie
6、d by silica gel column chromatography with n-hexane/diethyl ether (90/10) as the eluant to obtain the product (9.28 g, 95%) Angewandte Chemie, International Edition, 52(5), 1556-1559; 2013 2.3 步骤3Chem. Commun., 2013, 49, 2989-2991 A mixture of -methylstyrene (3.00 g, 25.4 mmol, 1 eq) and NBS (5.42 g
7、, 30.5 mmol, 1.2 eq) were suspended in CCl4 (60 mL) and heated under reflux for six hours. After that time, the mixture was cooled and the precipitated succinimide was separated by filtration and the solvent and the excess of -methylstyrene removed under reduced pressure. Of the 4.21 g of the clear
8、yellow oil obtained, GC-MS analysis indicated a ca. 3:1 ratio of product to 1-bromo-2-phenyl-1-propene. This product (S4) was used without further purification (3.50 g, 70%).2.4 步骤4Chem. Commun., 2013, 49, 29892991Potassium phthalimide (2.58 g, 13.9 mmol, 1.1 eq) was added to a solution of S4 (2.5 g
9、, 12.7 mmol, 1 eq) in DMF (35 mL) at room temperature. The resulting mixture was stirred for 18 hours, after whichtime a dark brown colour was formed and a white precipitate observed. Dichloromethane (30 mL) was added and the mixture poured onto water (100 mL). The aqueous phase was separated and ex
10、tracted with dichloromethane (3x). The combined organic extract was then washed with NaOH aq (0.2 M) and dried with anhydrous sodium sulfate. The dichloromethane was removed in vacuo and the residue purified by column chromatography (pentane:EtOAc 7:3) to afford the protected product S5 as white nee
11、dles (2.39 g, 72%).2.5 步骤5Chem. Commun., 2013, 49, 29892991Hydrazine hydrate (1.64 mL, 33.8 mmol, 5 eq) was added to a suspension of S5 (1.78 g, 6.77 mmol, 1 eq) in ethanol (120 mL). The resulting mixture was heated under reflux for one hour. Then HCl aq. (2.0 M) (12 mL) was added and the reaction h
12、eated for a further one hour. The reaction mixture was then cooled to 4 C and the phthalyl hydrazide removed by filtration. The ethanol was removed in vacuum and the solid residue was redissolved in 20 mL NaOH aq. (2.0 M). The solution was extracted with diethyl ether (5x) and the organic extract wa
13、s dried (Na2SO4), filtered and the solvent removed to give the product 5c as a colourless oil (819 mg, 91%).2.6 步骤6Angewandte Chemie, International Edition, 53(34), 9068-9071; 2014A solution of benzoyl chloride (11.6 mL, 14.06 g, 100.0 mmol) in THF (20 mL) was slowly added at 0C to an orange solutio
14、n of aniline (9.6 mL, 9.81 g, 105.3 mmol) and triethylamine (15.3 mL, 11.13 g, 110.0 mmol) in THF (250 mL), which resulted in a colorless precipitate. After the reaction mixture was stirred for 2.5 hours at room temperature, the formed triethylammonium chloride was removed by filtration and washed w
15、ith THF (50 mL). All volatiles were removed in vacuo from the filtrate to give an orange solid, which was washed with pentane to afford N-phenylbenzamide as a colorless solid. Yield: 19.63 g (99.5 mmol, 99.5%).3问题此路线先上叠氮基的话，后期步骤需要加热回流，叠氮基遇热稳定性降低，所以又考虑了下个路线：3.1新增步骤Angewandte Chemie, International Edi
16、tion, 50(7), 1702-1706; 2011To a solution of aniline (3 mmol) in 5 mL of CH2Cl2 was added subsequently 24 mg of CuSO4, 1.2 mL of Et3N,freshly prepared triflyl azide (9 mmol) in 15 mL of CH2Cl2, 1 mL of water and 2 mL of MeOH. The resulting mixture was allowed to react at room temperature overnight. Then, the reaction mixture was taken up by 15 mLdichloromethane,
