Method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction

Abstract

The present invention provides a method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction, belonging to the technical field of compound preparation method. The method is to use olefin and oxidative amination reagent as reaction substrates, fluorine reagent as nucleophilic fluorine source, divalent iron salt Fe (II) as catalyst, react in air to obtain unprotected β-amino fluoride. This method uses olefin as reaction substrate, introduces nitrogen atom and fluorine atom simultaneously by one-step reaction, greatly shortens the synthesis step of β-amino fluoride, improves preparation efficiency, and shortens time.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation methods, and particularly relates to a method for preparing unprotected beta-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction. Background Art

[0002] Currently, the preparation of β-amino fluorides is mainly through the nucleophilic ring-opening reaction of aziridine, the reduction reaction of amides, cyano groups or azides with fluorine atoms, and the deprotection reaction of secondary or tertiary β-amino fluorides. The substrates of these reactions need to be pre-functionalized, the preparation is complicated, and they need to go through multiple steps to obtain them, which greatly reduces the efficiency of the atoms and steps of the reaction. The ammonia fluorination reaction of olefins can introduce nitrogen atoms and fluorine sources at the same time. At present, the ammonia sources containing electron-withdrawing groups are more studied, followed by dialkyl ammonia sources, while unprotected ammonia sources have not yet been studied. (a) L. Mu,; R.Slavik,; A. Müller, et al. Pharmaceuticals 2014, 7 , 339. (b) N. Turkman, A. Shavrin, RA Ivanov, et al. Bioorganic&Medicinal Chemistry 2011, 19 , 5698. (c)TK Venkatachalam, FM Uckun, Synthetic Communications, 2004, 34 , 2463. (d)Chen, P.; Liu, G. Eur. J. Org. Chem. 2015, 4295. (e) Kong, W.; Merino, E.;Nevado, C. Chimia 2014, 68 , 430. (f) Chemler, SR; Bovino, MT Catalyticaminohalogenation of alkenes and alkynes. ACS Catal. 2013, 3 , 1076. (g)Serguchev, YA; Ponomarenko, MV; Ignat'ev, NV J. Fluorine Chem. 2016, 185 , 1. ) Summary of the invention

[0003] The purpose of the present invention is to provide a method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction. The method uses olefins with wide sources and low prices as reaction substrates, and simultaneously introduces nitrogen atoms and fluorine atoms through a one-step reaction, thereby greatly shortening the synthesis steps of the reaction and improving the atomic efficiency and time efficiency.

[0004] In order to achieve the above object, the present invention adopts the following technical solution:

[0005] A method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction, comprising:

[0006] Olefins and oxidative amination reagents are used as reaction substrates, fluorine reagents are used as nucleophilic fluorine sources, and divalent iron salts Fe(II) are used as catalysts. The reaction is carried out in air to obtain unprotected β-amino fluorides.

[0007] Preferably, the olefin is an aryl olefin, a heteroaryl olefin or an alkyl olefin.

[0008] Preferably, the aromatic olefin is an aromatic olefin of styrene, α-methylstyrene, β-methylstyrene, naphthylene with hydrogen, alkyl, phenyl, methoxy, benzoyl ester, halogen, or azide functional group on the benzene ring, or an olefinic derivative with galactose, estrone, or lithocholic acid, and the alkyl olefin is a 1,1-disubstituted olefin with a carbon chain length of 1-7.

[0009] Preferably, the olefin is 4-phenylstyrene, 4-vinylphenylbenzoate, 4-benzoylstyrene, 4-methoxystyrene, 4-fluorostyrene, 2,4,5-trimethylstyrene, 2-alkenylbenzothiophene, 6-bromo-3,4-methylenedioxystyrene, 1-azidomethyl-4-vinylbenzene, 4-heptynylstyrene, 4-vinylphenylethanol, α-methylstyrene, benzocyclopropene, 2-methyl-5-phenyl-1-pentene or 2-methyl-4-benzyloxy-1-pentene.

[0010] Preferably, the oxidative amination reagent is 4-nitrobenzamide trifluoromethanesulfonate, benzoylhydroxylamine trifluoromethanesulfonate, methanesulfonylhydroxylamine trifluoromethanesulfonate, p-toluenesulfonylhydroxylamine trifluoromethanesulfonate, acetylhydroxylamine trifluoromethanesulfonate or pivaloylhydroxylamine trifluoromethanesulfonate.

[0011] Preferably, the fluorine reagent is triethylamine trihydrofluoride.

[0012] Preferably, the reaction temperature is room temperature to 80° C., and the reaction time is 15-60 min.

[0013] Preferably, the catalyst is iron phthalocyanine.

[0014] Preferably, the solvent added during the reaction is dichloromethane, 1,1-dichloroethane or chloroform.

[0015] Preferably, the molar ratio of the olefin, the oxidative amination reagent, the fluorine reagent and the divalent iron salt is 1:2.5:4:0.1.

[0016] Beneficial effects of the present invention

[0017] The present invention provides a method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction, wherein the method uses olefin and oxidative amination reagent as reaction substrates, fluorine reagent as nucleophilic fluorine source, and divalent iron salt Fe(II) as catalyst, and reacts in air to obtain unprotected β-amino fluoride. Compared with the prior art, the raw material olefin used in the present invention is a basic chemical in the petrochemical industry, which has a wide source and is inexpensive. The method uses olefin as a reaction substrate and simultaneously introduces nitrogen atoms and fluorine atoms through a one-step reaction. The synthesis steps of β-amino fluoride are greatly shortened, the preparation efficiency is improved, and the time is shortened. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The β-amino fluoride prepared in Example 1 of the present invention 1 H NMR spectra;

[0019] Figure 2 The β-amino fluoride prepared in Example 1 of the present invention 13 C NMR spectra;

[0020] Figure 3 The β-amino fluoride prepared in Example 1 of the present invention 19 F NMR spectra;

[0021] Figure 4 The β-amino fluoride prepared in Example 2 of the present invention 1 H NMR spectra;

[0022] Figure 5 The β-amino fluoride prepared in Example 2 of the present invention 13 C NMR spectra;

[0023] Figure 6 The β-amino fluoride prepared in Example 2 of the present invention 19 F NMR spectra;

[0024] Figure 7 The β-amino fluoride prepared in Example 3 of the present invention 1 H NMR spectra;

[0025] Figure 8The β-amino fluoride prepared in Example 3 of the present invention 13 C NMR spectra;

[0026] Fig. 9 The β-amino fluoride prepared in Example 3 of the present invention 19 F NMR spectra;

[0027] Fig.10 The β-amino fluoride prepared in Example 4 of the present invention 1 H NMR spectra;

[0028] Fig.11 The β-amino fluoride prepared in Example 4 of the present invention 13 C NMR spectra;

[0029] Fig.12 The β-amino fluoride prepared in Example 4 of the present invention 19 F NMR spectra;

[0030] Fig.13 The β-amino fluoride prepared in Example 5 of the present invention 1 H NMR spectra;

[0031] Fig.14 The β-amino fluoride prepared in Example 5 of the present invention 13 C NMR spectra;

[0032] Fig.15 The β-amino fluoride prepared in Example 5 of the present invention 19 F NMR spectra;

[0033] Fig.16 The β-amino fluoride prepared in Example 6 of the present invention 1 H NMR spectra;

[0034] Fig.17 The β-amino fluoride prepared in Example 6 of the present invention 13 C NMR spectra;

[0035] Fig.18 The β-amino fluoride prepared in Example 6 of the present invention 19 F NMR spectra;

[0036] Fig.19 The β-amino fluoride prepared in Example 7 of the present invention 1 H NMR spectra;

[0037] Fig. 20 The β-amino fluoride prepared in Example 7 of the present invention 13 C NMR spectra;

[0038] Fig.21 The β-amino fluoride prepared in Example 7 of the present invention 19 F NMR spectra;

[0039] Fig. 22 The β-amino fluoride prepared in Example 8 of the present invention 1 H NMR spectra;

[0040] Fig.23 The β-amino fluoride prepared in Example 8 of the present invention 13 C NMR spectra;

[0041] Fig.24 The β-amino fluoride prepared in Example 8 of the present invention 19 F NMR spectra;

[0042] Fig.25 The β-amino fluoride prepared in Example 9 of the present invention 1 H NMR spectra;

[0043] Fig.26 The β-amino fluoride prepared in Example 9 of the present invention 13 C NMR spectra;

[0044] Fig. 27 The β-amino fluoride prepared in Example 9 of the present invention 19 F NMR spectrum.

[0045] Fig.28 The β-amino fluoride prepared in Example 10 of the present invention 1 H NMR spectra;

[0046] Fig.29 The β-amino fluoride prepared in Example 10 of the present invention 13 C NMR spectra;

[0047] Fig.30 The β-amino fluoride prepared in Example 10 of the present invention 19 F NMR spectrum.

[0048] Fig.31 The β-amino fluoride prepared in Example 11 of the present invention 1 H NMR spectra;

[0049] Fig.32 The β-amino fluoride prepared in Example 11 of the present invention 13 C NMR spectra;

[0050] Fig.33The β-amino fluoride prepared in Example 11 of the present invention 19 F NMR spectra;

[0051] Fig.34 The β-amino fluoride prepared in Example 12 of the present invention 1 H NMR spectra;

[0052] Fig.35 The β-amino fluoride prepared in Example 12 of the present invention 13 C NMR spectra;

[0053] Fig.36 The β-amino fluoride prepared in Example 12 of the present invention 19 F NMR spectra;

[0054] Fig.37 This is the Noesy diagram of the β-amino fluoride prepared in Example 12 of the present invention;

[0055] Fig.38 The β-amino fluoride prepared in Example 13 of the present invention 1 H NMR spectra;

[0056] Fig.39 The β-amino fluoride prepared in Example 13 of the present invention 13 C NMR spectra;

[0057] Fig.40 The β-amino fluoride prepared in Example 13 of the present invention 19 F NMR spectra;

[0058] Fig.41 The β-amino fluoride prepared in Example 14 of the present invention 1 H NMR spectra;

[0059] Fig.42 The β-amino fluoride prepared in Example 14 of the present invention 13 C NMR spectra;

[0060] Fig.43 The β-amino fluoride prepared in Example 14 of the present invention 19 F NMR spectrum. DETAILED DESCRIPTION

[0061] The present invention discloses a method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction. In the method, the Fe(II) catalyst is firstly reacted with an oxidative amination reagent [RO-NH3] + [OTf] -Coordination and single electron transfer reactions occur to form a nitrogen radical cation intermediate I, which reacts with an olefin to form a carbon radical intermediate II, and intermediate II undergoes an intramolecular electron transfer reaction to form intermediate III, and releases divalent iron Fe(II). Under the action of a fluorine nucleophile, intermediate III undergoes a nucleophilic ring-opening reaction to obtain the final target product. Taking Example 1 as an example, the reaction process is as follows:

[0062]

[0063] The present invention is further described in detail below with reference to specific examples. The raw materials involved in the examples are all commercially available or known compounds.

[0064] Example 1

[0065]

[0066] Experimental conditions A: Taking 4-phenylstyrene as an example, the specific reaction steps are: 4-nitrobenzylhydroxylamine trifluoromethanesulfonate ([4-NO2-BzONH3] + [OTf] - , 249 mg, 0.75 mmol, 2.5 equiv) was added to a mixture of olefin 4-phenylstyrene (54.1 mg, 0.30 mmol, 1.0 equiv), iron phthalocyanine (17.0 mg, 0.03 mmol, 0.1 equiv), triethylamine trihydrofluoride (196 μL, 1.2 mmol, 4.0 equiv) and anhydrous dichloromethane (DCM, 2.0 mL) and reacted at 30 °C in air for 30 min to obtain unprotected β-amino fluoride.

[0067] Workup step A: After the reaction was completed, Et3N (0.5 mL) was added at 0 °C to quench the reaction, and then directly separated by column chromatography (PE / EA = 1:3 as eluent) to obtain the unprotected β-amino fluoride 2a in 73% yield: 1 H NMR(600 MHz, CDCl3) δ 7.65 – 7.56 (m, 4H), 7.47 – 7.42 (m, 2H), 7.41 (d, J = 8.4Hz, 2H), 7.39 – 7.34 (m, 1H), 5.58 (ddd, J = 48.0, 7.2, 3.6 Hz, 1H), 3.22 –3.06 (m, 2H), 1.44 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 141.6, 140.7, 137.1 (d, J = 19.8 Hz), 129.0, 127.6, 127.4, 127.3, 126.1 (d, J = 7.2 Hz), 95.8 (d, J = 170.6Hz), 48.3 (d, J = 24.8 Hz). 19 F NMR (565 MHz, CDCl3) δ -184.62 – -185.28 (m). IRν max (film): 3714, 3609, 3432, 3344, 2933, 2844, 2586, 1749, 1643, 1507 cm -1 .HRMS (ESI) m / z calcd for C 14 H 14 FNNa [M+Na] + : 238.1002; found: 238.1003. Figure 1-3 shown.

[0068] Example 2

[0069] The experimental conditions are the same as those in Example 1, except that the olefin 4-phenylstyrene in Example 1 is replaced by 4-vinylphenylbenzoate. The post-treatment steps B are as follows.

[0070] Post-treatment step B: After the reaction was completed, 0.5 mL of triethylamine was added at 0 °C to quench the reaction, and then Boc2O (138 μL, 0.60 mmol, 2.0 equiv) was added and stirred for 2 hours. After the reaction was completed, yellow oily liquid 2b' (60.6 mg, 0.23 mmol, 75%) was directly separated by column chromatography. 1 H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 6.6 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 5.50 (dd, J= 48.0, 8.4 Hz, 1H), 4.90 (s, 1H), 3.71 – 3.48 (m, 1H), 3.37 – 3.20 (m, 1H), 1.39 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ 165.2, 155.9, 151.3, 135.1 (d, J = 20.0 Hz), 133.9, 130.3, 129.5,128.7, 126.9 (d, J = 7.1 Hz), 122.1, 92.9 (d, J = 173.1 Hz), 80.0, 46.5 (d, J =24.0 Hz), 28.5. 19 F NMR (565 MHz, CDCl3) δ -183.40 (ddd, J = 48.5, 31.4, 17.1Hz). IR ν max (film): 3249, 3005, 2945, 1734, 1685, 1667, 1523, 1169, 965, 876,701 cm -1 . HRMS (ESI) m / z calcd for C 20 H 22 FNO4Na [M+Na] + : 382.1425; found:382.1420. Figure 4-6 shown.

[0071] Example 3

[0072] The experimental conditions and post-treatment steps were the same as those in Example 2, except that the reaction time was reduced from 30 minutes to 15 minutes, and the olefin 4-vinylphenyl benzoate in Example 2 was replaced by 4-methoxystyrene.

[0073] According to experimental conditions A and post-treatment steps B: Yellow oily liquid 2c' (60.6 mg, 0.23 mmol, 75%) was obtained by column chromatography. 1 H NMR (600 MHz, CDCl3) δ 7.22 – 7.18 (m, 2H),6.84 (d, J = 8.4 Hz, 2H), 5.39 (dd, J= 48.0, 8.4 Hz, 1H), 4.87 (s, 1H), 3.74 (s,3H), 3.62 – 3.45 (m, 1H), 3.39 – 3.24 (m, 1H), 1.37 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ 160.1, 155.9, 129.5 (d, J = 20.0 Hz), 127.3 (d, J = 6.3 Hz), 114.1, 93.2(d, J = 171.0 Hz), 79.8, 55.4, 46.4 (d, J = 24.6 Hz), 28.5. 19 F NMR (565 MHz, CDCl3) δ -179.10 (ddd, J = 48.2, 31.5, 16.3 Hz). IR ν max (film): 3416, 2933,2844, 1641, 1515, 1411, 1168, 899, 769, 703 cm -1 . HRMS (ESI) m / z calcd for C 14 H 20 FNO3Na [M+Na] + : 292.1319; found: 292.1320. Figure 7-9 shown.

[0074] Example 4

[0075] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenyl benzoate in Example 2 is replaced by 4-fluorostyrene.

[0076] According to the operation steps A and post-treatment steps B, yellow oily liquid 2d' was obtained by column chromatography (51.7 mg, 0.20 mmol, 67%). 1 H NMR (600 MHz, CDCl3) δ 7.37 – 7.30 (m, 2H), 7.07 (t, J =8.4 Hz, 2H), 5.51 (dd, J= 48.6, 8.4 Hz, 1H), 4.94 (s, 1H), 3.79 – 3.52 (m,1H), 3.45 – 3.22 (m, 1H), 1.44 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ 163.0 (d, J = 247.4 Hz), 155.9, 133.3 (d, J = 22.9 Hz), 128.0 – 127.1 (m), 115.7 (d, J =21.7 Hz), 92.8 (d, J = 172.4 Hz), 80.0, 46.5 (d, J = 23.9 Hz), 28.5. 19 F NMR (565 MHz, CDCl3) δ -113.06 (s,1H), -182.2 (ddd, J = 48.8, 31.1, 17.6 Hz,1H).IR ν max (film): 3435, 3011, 2939, 1680, 1555, 1513, 1429, 1368, 1157, 968,871, 780 cm -1 . HRMS (ESI) m / z calcd for C 13 H 18 F2NO2 [M+H] + : 258.1300; found:258.1300. Figure 10-12 shown.

[0077] Example 5

[0078] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenyl benzoate in Example 2 is replaced by 2,4,5-trimethylstyrene.

[0079] According to the operation steps A and post-treatment steps B, yellow oily liquid 2e' (64.1 mg, 0.23 mmol, 76%) was obtained by column chromatography. 1 H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 6.86 (s, 1H), 5.59 (dd, J= 48.0, 8.4 Hz, 1H), 4.91 (s, 1H), 3.63 – 3.43 (m, 1H), 3.33 – 3.13(m, 1H), 2.22 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 1.37 (s, 9H). 13 C NMR (150MHz, CDCl3) δ 155.9, 137.0, 134.4, 132.9 (d, J = 18.5 Hz), 132.1, 132.0, 126.6(d, J = 8.7 Hz), 91.2 (d, J = 170.1 Hz), 79.7, 45.8 (d, J = 24.5 Hz), 28.5, 27.5,19.4 (d, J = 2.3 Hz), 18.4. 19 F NMR (565 MHz, CDCl3) δ -184.41 (ddd, J = 48.6,33.0, 16.4 Hz). IR ν max (film): 3448, 2917, 2836, 1688, 1552, 1539, 1411,1168, 1040, 825 cm -1 . HRMS (ESI) m / z calcd for C 16 H 24 FNO2Na [M+Na] + : 304.1683;found: 304.1683. Figure 13-15 shown.

[0080] Example 6

[0081] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenyl benzoate in Example 2 is replaced by 2-vinylbenzothiophene.

[0082] According to the operation steps A and post-treatment steps B, yellow oily liquid 2f '(51.3mg, 0.17mmol, 58%) was obtained by column chromatography. 1H NMR (600 MHz, CDCl3) δ 7.79 – 7.74 (m, 1H), 7.72 – 7.68(m, 1H), 7.33 – 7.27 (m, 2H), 7.27 – 7.24 (m, 1H), 5.75 (dd, J = 48.0, 4.8 Hz,1H), 4.90 (s, 1H), 3.80 – 3.65 (m, 1H), 3.59 – 3.49 (m, 1H), 1.38 (s, 9H). 13 CNMR (150 MHz, CDCl3) δ 155.9, 139.9 (d, J = 21.4 Hz), 139.1, 125.1, 124.7,124.2, 123.0 (d, J = 6.8 Hz), 122.6, 89.6 (d, J = 172.3 Hz), 80.1, 46.0 (d, J =24.8 Hz), 28.5. 19 F NMR (565 MHz, CDCl3) δ -170.14 (ddd, J = 46.4, 28.0, 16.8Hz). IR ν max (film): 3440, 3363, 2918, 2841, 1691, 1507, 1459, 1367, 1265,1161, 1053, 740 cm -1 . HRMS (ESI) m / z calcd for C 15 H 19 FSNO2 [M+H] + : 296.1115;found: 296.1116. Figure 16-18 shown.

[0083] Example 7

[0084] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenylbenzoate in Example 2 is replaced by 6-bromo-3,4-methylenedioxystyrene.

[0085] According to the operation steps A and post-treatment steps B, a yellow oily liquid 2g '(70.4mg, 0.20 mmol, 65%) was obtained by column chromatography. 1H NMR (500 MHz, CDCl3) δ 6.98 (s, 1H), 6.91 (s, 1H), 5.98(dd, J = 15.5, 1.5 Hz, 2H), 5.73 (dd, J = 48.0, 6.0 Hz, 1H), 4.86 (s, 1H), 3.75 –3.55 (m, 1H), 3.49 – 3.24 (m, 1H), 1.42 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ155.7, 148.3, 147.3, 130.0 (d, J = 21.6 Hz), 112.9, 111.9, 107.2, 102.1, 92.4(d, J = 174.1 Hz), 79.8, 44.9 (d, J = 24.2 Hz), 28.4. 19 F NMR (565 MHz, CDCl3) δ -185.3 (ddd, J = 47.9, 28.7, 19.8 Hz). IR ν max (film): 3378, 3056, 2964, 1689,1529, 1407, 1254, 1171, 1114, 867, 638 cm -1 . HRMS (ESI) m / z calcd for C 14 H 18 FBrNO4 [M+H] + : 362.0398; found: 362.0396. Figure 19-21 shown.

[0086] Example 8

[0087] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenyl benzoate in Example 2 is replaced by 1-azidomethyl-4-vinylbenzene.

[0088] According to the operation steps A and post-treatment steps B, yellow oily liquid 2h '(61.8mg, 0.21 mmol, 70%) was obtained by column chromatography. 1H NMR (600 MHz, CDCl3) δ 7.32 – 7.29 (m, 2H), 7.29 – 7.25(m, 2H), 5.48 (dd, J = 48.6, 8.4 Hz, 1H), 4.88 (s, 1H), 4.28 (s, 2H), 3.67 –3.50 (m, 1H), 3.37 – 3.19 (m, 1H), 1.37 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ155.9, 137.6 (d, J = 19.7 Hz), 136.1, 128.5, 126.1 (d, J = 7.1 Hz), 93.1 (d, J =172.6 Hz), 80.0, 54.5, 46.5 (d, J = 24.0 Hz), 28.5. 19 F NMR (565 MHz, CDCl3) δ -184.6 (ddd, J = 48.9, 31.8, 17.8 Hz). IR ν max (film): 3332, 3021, 2912, 2100,1688, 1509, 1407, 1364, 1161, 1059, 963, 809, 710 cm -1 . HRMS (ESI) m / z calcdfor C 14 H 19 FN4O2Na [M+Na] + : 317.1384; found: 317.1379. Figure 22-24 shown.

[0089] Example 9

[0090] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenylbenzoate in Example 2 is replaced by 4-heptynylstyrene.

[0091] According to the operation steps A and post-treatment steps B, yellow oily liquid 2i '(60.0mg, 0.18 mmol, 60%) was obtained by column chromatography. 1 H NMR (600 MHz, CDCl3) δ 7.33 (d, J= 7.8 Hz, 2H), 7.21 –7.16 (m, 2H), 5.44 (dd, J = 48.6, 8.4 Hz, 1H), 4.85 (s, 1H), 3.74 – 3.44 (m,1H), 3.36 – 3.16 (m, 1H), 2.32 (t, J = 7.2 Hz, 2H), 1.56 – 1.51 (m, 2H), 1.37(s, 9H), 1.36 – 1.32 (m, 2H), 1.32 – 1.26 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13 CNMR (150 MHz, CDCl3) δ 155.9, 136.6 (d, J = 19.7 Hz), 131.9, 125.5 (d, J = 7.2Hz), 124.8, 93.1 (d, J = 172.3 Hz), 91.4, 80.2, 79.9, 46.4 (d, J = 23.1 Hz),31.3, 28.5, 28.5, 22.4, 19.5, 14.1. 19 F NMR (565 MHz, CDCl3) δ -184.5 (ddd, J =48.6, 31.3, 17.5 Hz). IR ν max (film): 3363, 2949, 2841, 2223, 1674, 1521,1470, 1267, 1168, 1159, 964, 833, 734 cm -1 . HRMS (ESI) m / z calcd for C 20 H 28 FNO2Na [M+Na] + : 356.1996; found: 356.1991. Figure 25-27 shown.

[0092] Example 10

[0093] The experimental conditions and post-treatment steps are the same as those in Example 2, except that the olefin 4-vinylphenyl benzoate in Example 2 is replaced by 4-vinylphenyl ethanol.

[0094] According to the operation step A and the work-up step B, yellow oily liquid 2j' (51.3 mg, 0.17 mmol, 58%) was obtained by column chromatography. 1 H NMR (500 MHz, CDCl3) δ 7.31 – 7.26 (m, 2H), 7.26 – 7.22(m, 2H), 5.49 (dd, J = 49.0, 8.5 Hz, 1H), 4.97 (s, 1H), 3.84 (t, J = 6.5 Hz, 2H),3.71 – 3.55 (m, 1H), 3.45 – 3.27 (m, 1H), 2.86 (t, J = 6.5 Hz, 2H), 1.43 (s,9H). 13 C NMR (150 MHz, CDCl3) δ 155.9, 139.4, 135.6 (d, J = 19.8 Hz), 129.4,125.9 (d, J = 6.9 Hz), 93.2 (d, J = 172.2 Hz), 79.9, 63.6, 46.5 (d, J = 24.3 Hz),39.0, 28.5. 19 F NMR (565 MHz, CDCl3) δ -183.0 (ddd, J = 48.4, 31.3, 17.4 Hz). IRν max (film): 3455, 3332, 2918, 2821, 1705, 1689, 1516, 1464, 1367, 1267, 1162,1050, 911, 848, 738 cm -1 . HRMS (ESI) m / z calcd for C 15 H 22 FNO3Na [M+Na] + :306.1476; found: 306.1475. Figure 28-30 shown.

[0095] Embodiment 11

[0096] The experimental conditions and post-treatment steps are the same as those in Example 3, except that the olefin 4-methoxystyrene in Example 3 is replaced by α-methylstyrene.

[0097] According to the operation steps A and post-treatment steps B, yellow oily liquid 2k '(53.2mg, 0.21mmol, 70%) was obtained by column chromatography. 1 H NMR (500 MHz, CDCl3) δ 7.40 – 7.33 (m, 4H), 7.33 – 7.25(m, 1H), 4.85 (s, 1H), 3.72 – 3.59 (m, 1H), 3.53 – 3.45 (m, 1H), 1.65 (d, J =22.0 Hz, 3H), 1.40 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ 156.1, 142.2 (d, J = 21.5Hz), 128.5, 127.8, 124.4 (d, J = 9.3 Hz), 97.6 (d, J = 173.2 Hz), 79.6, 49.7 (d, J = 22.9 Hz), 28.4, 24.6 (d, J = 24.7 Hz). 19 F NMR (565 MHz, CDCl3) δ -152.9 –153.1 (m). IR ν max (film): 3442, 3335, 2988, 1721, 1675, 1509, 1447, 1393,1367, 1250, 1163, 766, 698 cm -1 . HRMS (ESI) m / z calcd for C 14 H 21 FNO2 [M+H] + :254.1551; found: 254.1552. Figure 31-33 shown.

[0098] Example 12

[0099] The experimental conditions and post-treatment steps are the same as those of Example 2, except that the olefin 4-vinylphenylbenzoate in Example 2 is replaced by benzocyclopropene.

[0100] According to the operation steps A and post-processing steps B, a yellow oily liquid 21' ( dr= 7:1, 46.7 mg, 0.19 mmol, 62%). Major syn -isomer (2ac'-I): 1 H NMR (600 MHz, CDCl3)δ 7.45 – 7.39 (m, 1H), 7.34 – 7.29 (m, 1H), 7.24 – 7.19 (m, 2H), 5.60 (dd, J =58.2, 4.8 Hz, 1H), 5.09 (d, J = 9.6 Hz, 1H), 4.58 – 4.24 (m, 1H), 3.22 (dd, J =15.0, 7.2 Hz, 1H), 2.89– 2.79 (m, 1H), 1.42 (s, 9H). 13 C NMR (150 MHz, CDCl3) δ155.7, 143.1, 137.8 (d, J = 15.3 Hz), 131.0 (d, J = 4.5 Hz), 127.5 (d, J = 3.7 Hz),126.6 (d, J = 2.7 Hz), 125.3 (d, J = 2.9 Hz), 94.6 (d, J = 176.8 Hz), 79.9, 53.7(d, J = 19.1 Hz), 36.8, 28.5. 19 F NMR (565 MHz, CDCl3) δ -179.2 (dd, J = 58.3, 25.7Hz). IR ν max (film): 3440, 3332, 2979, 1705, 1688, 1508, 1303, 1252, 1165,1054, 753 cm -1 . HRMS (ESI) m / z calcd for C 14 H 18 FNO2Na [M+Na] + : 274.1214; found:274.1210. As Figure 34-36 shown. Fig.37Noesy diagram of the β-amino fluoride prepared in Example 12 of the present invention; the diagram shows that the fluorine atom and the nitrogen atom are on the same side in space.

[0101] Embodiment 13

[0102]

[0103] Experimental conditions A: 4-nitrobenzoylhydroxylamine trifluoromethanesulfonate ([4-NO2-BzONH3] + [OTf] - , 249 mg, 0.75 mmol, 2.5 equiv) was added to a mixture of 1 g (48.1 mg, 0.30 mmol, 1.0 equiv) of 2-methyl-5-phenyl-1-pentene, ferric phthalocyanine (FePc, 17.0 mg, 0.03 mmol, 0.1 equiv), triethylamine trihydrofluoride (196 μL, 1.2 mmol, 4.0 equiv) and anhydrous 1,2-dichloroethane (2.0 mL), and the reaction was carried out at 80 °C in air for 1 hour.

[0104] According to the post-treatment step B, after the reaction was completed, 0.5 mL of triethylamine was added at 0 °C to quench the reaction, and then Boc2O (138 μL, 0.60 mmol, 2.0 equiv) was added and stirred at room temperature for 2 hours to obtain a yellow oily liquid 2g' (46.1 mg, 0.16 mmol, 52%). 1 H NMR (500 MHz, CDCl3) δ 7.30 – 7.24 (m, 2H), 7.23 –7.09 (m, 3H), 4.79 (t, J = 6.5 Hz, 1H), 3.28 (dd, J = 22.0, 6.5 Hz, 2H), 2.61 (d, J = 7.0 Hz, 2H), 1.76 – 1.65 (m, 3H), 1.64 – 1.54 (m, 1H), 1.45 (s, 9H), 1.28(d, J = 22.0 Hz, 3H). 13 C NMR (150 MHz, CDCl3) δ 156.3, 142.0, 128.52, 128.50,126.0, 97.3 (d, J = 167.7 Hz), 79.6, 48.1 (d, J = 22.1 Hz), 37.0 (d,J = 21.9 Hz),36.2, 28.5, 25.4 (d, J = 5.9 Hz), 21.7 (d, J = 24.2 Hz). 19 F NMR (565 MHz, CDCl3) δ-149.90 – -150.80 (m). IR ν max (film): 3443, 3378, 3045, 2917, 2852, 1716,1619, 1515, 1458, 1370, 1241, 1168, 742 cm -1 . HRMS (ESI) m / z calcd for C 17 H 26 FNO2 [M+Na] + : 318.1840; found: 318.1847. Figure 38-40 shown.

[0105] Embodiment 14

[0106] The experimental conditions and post-treatment steps were the same as those of Example 7, except that the olefin 2-methyl-5-phenyl-1-pentene in Example 13 was replaced by 2-methyl-4-benzyloxy-1-pentene.

[0107] According to experimental conditions B and post-treatment step B, yellow oily liquid 2h' (54.1 mg, 0.17 mmol, 58%) was obtained by column chromatography. 1 H NMR (600 MHz, CDCl3) δ 7.29 – 7.16 (m, 5H), 4.92 – 4.86(m, 1H), 4.42 (s, 2H), 3.58 – 3.48 (m, 2H), 3.25 (dd, J = 19.8, 6.6 Hz, 2H),1.98 – 1.81 (m, 2H), 1.37 (s, 9H), 1.27 (d, J = 22.2 Hz, 3H). 13 C NMR (150 MHz, CDCl3) δ 156.2, 138.2, 128.5, 127.8, 127.7, 96.4 (d, J = 169.2 Hz), 79.5, 73.3,65.6 (d, J = 7.0 Hz), 48.0 (d, J= 24.2 Hz), 37.4 (d, J = 22.4 Hz), 28.5, 22.7 (d, J = 23.8 Hz). 19 19F NMR (565 MHz, CDCl3) δ -149.48 – -149.83 (m). IR ν max (film): 3245, 3030, 2981, 2784, 1749, 1690, 1507, 1403, 1377, 1366, 1163, 927, 854, 742, 701 cm -1 . HRMS (ESI) m / z calcd for C 17 H 26 19FNNaO3 [M+Na] + : 334.1789; found: 334.1791. As Figures 41-43 shown.

Claims

1. A method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination reaction, characterized in that: include: Using olefins and oxidative amination reagents as reaction substrates, fluorine reagents as nucleophilic fluorine sources, and divalent iron salts Fe(II) as catalysts, the reaction is carried out in air to obtain unprotected β-amino fluorides; The oxidative amination reagent is 4-nitrobenzamide trifluoromethanesulfonate, benzoylhydroxylamine trifluoromethanesulfonate, methanesulfonylhydroxylamine trifluoromethanesulfonate, p-toluenesulfonylhydroxylamine trifluoromethanesulfonate, acetylhydroxylamine trifluoromethanesulfonate or pivaloylhydroxylamine trifluoromethanesulfonate; The fluorine reagent is triethylamine trihydrofluoride; The catalyst is iron phthalocyanine.

2. The method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination according to claim 1, characterized in that: The olefin is an aryl olefin, a heteroaryl olefin or an alkyl olefin.

3. The method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination according to claim 2, characterized in that: The aromatic olefins are styrene, naphthylene vinyl with hydrogen, alkyl, phenyl, methoxy, benzoyl ester, halogen, azide functional groups on the benzene ring, or olefinic derivatives with galactose, estrone, and lithocholic acid. The alkyl olefins are 1,1-disubstituted olefins with a carbon chain length of 1-7.

4. The method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination according to claim 1, characterized in that: The olefin is 4-phenylstyrene, 4-vinylphenylbenzoate, 4-benzoylstyrene, 4-methoxystyrene, 4-fluorostyrene, 2,4,5-trimethylstyrene, 2-alkenylbenzothiophene, 6-bromo-3,4-methylenedioxystyrene, 1-azidomethyl-4-vinylbenzene, 4-heptynylstyrene, 4-vinylphenylethanol, α-methylstyrene, benzocyclopropene, 2-methyl-5-phenyl-1-pentene or 2-methyl-4-benzyloxy-1-pentene.

5. The method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination according to claim 1, characterized in that: The reaction temperature is from room temperature to 80°C, and the reaction time is 15-60 minutes.

6. The method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination according to claim 1, characterized in that: The solvent added during the reaction is dichloromethane, 1,1-dichloroethane or chloroform.

7. The method for preparing unprotected β-amino fluoride by iron-catalyzed olefin ammonia fluorination according to claim 1, characterized in that: The molar ratio of the olefin, the oxidative amination reagent, the fluorine reagent and the divalent iron salt is 1:2.5:4:0.1.

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