A method for asymmetric synthesis of ortho-halogenated alcohol compounds

Abstract

The application belongs to the technical field of chemical synthesis, and particularly relates to a method for asymmetrically synthesizing adjacent halogenated alcohol compounds. The cis adjacent halogenated alcohol compound is prepared through catalytic hydrogenation of asymmetric dynamic kinetic resolution of alpha halogenated ketone. The method has mild reaction conditions, excellent enantiomer and diastereomer selectivity, high efficiency and good yield, and has good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for asymmetric synthesis of adjacent halohydrin compounds. Background Art

[0002] Many halohydrin compounds have been found in natural products. The structural formulas of some of these compounds are shown below. Due to their pharmacological and biological activities, they can be used as key core structures to derive anticancer active compounds.

[0003]

[0004] Therefore, identifying economical routes to such compounds is highly desirable. Although chemists have developed numerous methods for the asymmetric reduction of α-haloketones, only three examples of such reductions have been reported. As for the asymmetric hydrogenation of cyclic α-haloketones, no examples have been reported to date. Summary of the Invention

[0005] The present invention provides a method for asymmetric synthesis of vicinal halohydrin compounds, comprising:

[0006]

[0007] Using compound (1) as a substrate, in the presence of H2, [Ir(COD)Cl]2 as a metal precursor, ligands (L1-L6), a base and a solvent, an asymmetric synthesis is carried out to generate cis-vicinal halohydrin (2);

[0008]

[0009] The alkyl group includes C 1-8 The alkyl groups specifically include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl;

[0010] The alkoxy group includes C 1-8 Alkoxy groups including methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy;

[0011] The halogen includes: fluorine, chlorine, bromine, and iodine;

[0012] The Ar group in the ligand is an aryl group, which is selected from at least one of phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl and 3,5-di-tert-butyl-4-methoxyphenyl.

[0013] As a preferred technical solution of the present invention, the solvent is selected from: i PrOH, EtOH, MeOH, TFE, DCM, hexane, THF, toluene.

[0014] As a preferred technical solution of the present invention, the base is selected from: t BuOK, t BuONa, t BuOLi, KOMe, LiOMe, NaOH, KOH, more preferably KOH.

[0015] As a preferred technical solution of the present invention, the reaction temperature is 20-40°C.

[0016] As a preferred technical solution of the present invention, 5-30 atmospheres of H2 are selected.

[0017] As a preferred technical solution of the present invention, the reaction time is 12-36 hours.

[0018] As a preferred technical solution of the present invention, 0.05 mol% [Ir(COD)Cl]2 / L1 is used as a catalyst, KOH (0.1 equivalent) is used as a base, compound 1 / [Ir / L1] complex catalyst = 100 / 1, toluene (0.25 M) is used as a solvent, and the reaction is carried out at 25°C for 24 hours.

[0019] As a preferred technical solution of the present invention, compound 2 is selected from the following compounds 2a-2x:

[0020]

[0021] The beneficial effects of the present invention compared to the prior art include:

[0022] We have demonstrated the high catalytic efficiency of the developed [Ir / L1] complex in the operationally simple and practical asymmetric hydrogenation of cyclic halogenated ketones with dynamic kinetic resolution.

[0023] The reaction conditions of the present invention are applicable to a series of differently substituted 3-fluorobenzophenone derivatives, 2-fluorotetralone derivatives, 2-chlorotetralone derivatives and 3-chlorobenzophenone derivatives.

[0024] This reaction, through asymmetric catalytic hydrogenation with dynamic kinetic resolution, can directly afford the corresponding enantiomerically enriched cis-vicinal halohydrin with excellent diastereo- and enantioselectivity (>99% de, up to 99% ee). The reaction proceeds under mild indoor conditions and has promising applications. DETAILED DESCRIPTION

[0025] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited thereto.

[0026] General Example 1

[0027] The following routes were used to investigate different ligands, and the results are as follows:

[0028]

[0029] Example ligand Conversion rate (%) Dr Ee(%) 1-1 L1 full 97:3 86 1-2 L2 full 90:10 84 1-3 L3 full 92:8 85 1-4 L4 full 96:4 57 1-5 L5 full 91:9 72 1-6 L6 full 95:5 85 1-7 L1 full >99:1 93

[0030] Examples 1-1 to 1-6: Compound 1a was used as a template substrate. Under an inert gas atmosphere, 0.4 mmol of compound 1a was dissolved in 1.0 ml of solvent. A [Ir(COD)Cl]2 / ligand complex solution was prepared. The molar ratio of 1a to the catalyst was 200 / 1. t BuOK (10 mol%, 0.04 mmol) was reacted at 25°C under 50 atm of H₂ for 16 hours. The reaction solution was analyzed by H₄NMR to determine conversion and dr value, and its optical purity was determined by chiral HPLC. In Examples 1-7, all other conditions remained unchanged, except that the molar ratio of 1a to catalyst was 1000, and the hydrogen pressure was reduced to 5 atm.

[0031] The above results show that for all ligands L1-L6, complete conversion was obtained with good diastereoselectivity (dr) reaching 90:10 to >99:1 and enantioselectivity (ee) of 57-93%; among them, L1 ligand had the best diastereoselectivity and enantioselectivity.

[0032] With L1 ligand, when the catalyst loading was reduced to 0.1% and the H2 pressure was reduced to 5 atm, both the diastereoselectivity and enantioselectivity were found to be much better (>99:1dr, 93%ee).

[0033] General Example 2

[0034] Based on Example 1, ligand L1 was selected, a catalyst loading of 0.1%, and H2 at 5 atmospheres. Different bases and solvents were screened for reaction. The results are as follows:

[0035]

[0036] Example alkali solvent <![CDATA[Conversion rate (%) b > <![CDATA[Dr b ]]> <![CDATA[Ee(%) c ]]> 2-1 <![CDATA[ t Full]]> <![CDATA[ i PrOH]]> full >99:1 93 2-2 <![CDATA[ t Full]]> EtOH 56 >99:1 82 2-3 <![CDATA[ t Full]]> MeOH 0 -- -- 2-4 <![CDATA[ t Full]]> TFE 0 -- -- 2-5 <![CDATA[ t Full]]> DCM 93 >99:1 93 2-6 <![CDATA[ t Full]]> hexane 77 >99:1 96 2-7 <![CDATA[ t Full]]> THF full >99:1 85 2-8 <![CDATA[ t Full]]> toluene full >99:1 97 2-9 <![CDATA[ t Good]]> toluene full >99:1 92 2-10 <![CDATA[ t BuOLi]]> toluene 64 >99:1 93 2-11 KOMe toluene full >99:1 94 2-12 LiOMe toluene 5 >99:1 92 2-13 NaOH toluene full >99:1 96 2-14 KOH toluene full >99:1 99

[0037] From the results, we found that:

[0038] (1) The conversion rates in different solvents vary greatly: i In PrOH, full conversion was obtained, but the conversion of EtOH was 56%, MeOH and trifluoroethanol were basically unreactive, dichloromethane and hexane had good conversion rates at 93% and 77%, respectively, especially the ee value of hexane (96% ee) was better than i PrOH (93% ee), THF and toluene were all fully converted, with toluene having the best ee value (97% ee).

[0039] (2) The conversion rates in different bases vary greatly: From the results, it was found that KOMe also provided a complete conversion of 94% ee, but LiOMe only provided a conversion of 5%, t BuONa and t BuOLi gave complete conversion and >99:1 diastereoselectivity, but lower enantioselectivity at 92% ee and 93% ee. The best results were obtained with KOH as the base, with complete conversion, >99:1 diastereoselectivity, and an optical purity of 99% ee.

[0040] General Example 3

[0041] Based on the above screening conditions, the optimized conditions were set as follows: 0.05 mol% [Ir(COD)Cl]2 / L1 as catalyst, KOH (0.1 equivalent) as base, and toluene (0.25 M) as solvent at 25°C. Under these optimized conditions, the substrate scope of the reaction was explored using a series of cyclic α-haloketones. The results are as follows:

[0042]

[0043] Compounds 1b-1h with various electron-withdrawing groups on the aryl groups, such as fluorine, chlorine, bromine, and nitro substituents at various positions on the phenyl ring, produced the desired cis-vicinal fluoropropanes 2b-2h in 93%-98% yields with excellent diastereoselectivities (>99% de) and high levels of enantioselectivities (up to 99% ee). Additionally, substrates 1i-1j containing electron-donating groups on the phenyl ring, such as methyl and methoxy substituents, were also investigated and exhibited good yields (98%) with excellent diastereoselectivities (>99% de) and good enantioselectivities (91%-94% ee).

[0044] Subsequently, a series of 2-fluorotetralones and 2-fluoroindan-1-ones (1k-1q) substituted with different electron-donating or electron-withdrawing groups were studied, which were converted to the corresponding cis-vicinal fluoropropanes 2k-2q in excellent yields (98%-99%) as well as excellent diastereoselectivities (>99% de) and enantioselectivities (96%-99% ee).

[0045] The fluorine substituent was converted to a chlorine substituent at the α-position of the ketone. 3,6-Dichlorochromen-4-one (1r) was subsequently subjected to standard conditions to afford cis-3,6-dichlorochromen-4-ol 2r in 95% yield with >99% desulfurization and 99% ee.

[0046] To further expand the substrate scope, a series of differently substituted 2-chlorotetralone derivatives and 5H-benzocyclohepten-5-one (1s-1x) were subjected to optimized conditions, which gave the corresponding vicinal chloropropanes 2s-2k in good yields (96%-98%) with excellent diastereoselectivities (>99% de) and enantioselectivities (97%-99% ee).

[0047] The data of the compound are as follows:

[0048] (3S,4R)-3-Fluorobenzopyran-4-ol (2a)

[0049]

[0050] Colorless crystals, 67 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =42.7(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.47(d,J=7.6Hz,1H),7.23(dddd,J=8.0,7.3,1.7,0.6H z,1H),6.99(td,J=7.5,1.2Hz,1H),6.85(dd,J=8.2,0.9Hz,1H),5.00(dddd,J= 48.3,5.6,3.6,2.0Hz,1H),4.90(dd,J=20.0,4.0Hz,1H),4.48(ddd,J=12.2,7. 8,5.6Hz,1H),4.21(dddd,J=28.5,12.2,2.0,1.2Hz,1H),2.37(d,J=7.8Hz,1H). 19 F NMR (376MHz, CDCl3): δ-209.40 (dddd, J=48.1, 28.4, 20.0, 7.9Hz).

[0051] (3S,4R)-3,7-Difluorobenzopyran-4-ol (2b)

[0052]

[0053] Colorless crystals, 72 mg, 97% yield, dr (cis / trans)>99:1, ee cis =96%,[α] D 23 =46.8(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.42(dd,J=8.6,6.4Hz,1H),6.71(td,J=8.4,2.5Hz,1H),6.57(dd,J=10.0,2.5Hz,1H),4.99(dddd,J=48.1,5.6,3.6,2.0H z,1H),4.86(ddd,J=19.6,8.9,3.5Hz,1H),4.48(ddd,J=12.3,7.9,5.6Hz,1H),4.22(ddt,J=28.2,12.2,1.6Hz,1H),2.34(dd,J=8.9,2.3Hz,1H). 19 F NMR (376MHz, CDCl3): δ-111.52 (q, J=8.2Hz), -209.63 (dddd, J=48.0, 28.1, 19.5, 8.1Hz).

[0054] (3S,4R)-3,8-Difluorobenzopyran-4-ol (2c)

[0055]

[0056] Colorless crystals, 73 mg, 98% yield, dr (cis / trans)>99:1, ee cis =93%,[α] D 23 =33.6(c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ7.25(d,J=8.4Hz,1H),7.03(ddd,J=10.5,8.2,1.6Hz,1H),6.91(td,J=8.0,4.7Hz,1H),5.02(dddd,J=48.0,5.4 ,3.6,1.9Hz,1H),4.90(dd,J=20.6,3.6Hz,1H),4.57(ddd,J=12.4,8.3,5.2Hz,1H),4.28(ddt,J=29.9,12.5,1.5Hz,1H),2.45(br,1H). 13 C NMR (100MHz, CDCl3): δ150.9 (d, J = 246.1Hz), 141.8 (d, J = 11.6Hz), 124.3, 123.7 (d, J = 3.6Hz), 121. 2(d,J=7.1Hz), 116.4(d,J=17.6Hz), 85.9(d,J=178.2Hz), 65.1(d,J=22.3Hz), 64.9(dd,J=19.7Hz). 19 F NMR (376MHz, CDCl3): δ-136.26 (dd, J=10.7, 4.5Hz), -209.43 (dddd, J=48.7, 29.5, 20.8, 8.3Hz).

[0057] HRMS(ESI / ion trap):m / z[M+H-H2O] + calcd for C9H7F2O 169.0465,found169.0456.

[0058] (3S,4R)-6-Chloro-3-fluorobenzopyran-4-ol (2d)

[0059]

[0060] Colorless crystals, 80 mg, 99% yield, dr (cis / trans)>99:1, ee cis =96%,[α] D 23 =58.3(c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ7.46 (s, 1H), 7.17 (dd, J = 8.6, 2.4Hz, 1H), 6.78 (d, J = 8.6Hz, 1H), 4.99 (d, J = 48.3Hz, 1H), 4.84(dd,J=21.4,3.5Hz,1H), 4.49(ddd,J=13.1,8.6,4.8Hz,1H), 4.20(dd,J=31.6,12.6Hz,1H), 2.40(br,1H). 13 C NMR (100MHz, CDCl3): δ152.0, 129.9, 128.4, 126.5, 123.5, 117.9, 85.8 (d, J = 178.1Hz), 65.1 (d, J = 21.7Hz), 65.0 (d, J = 19.8Hz). 19 F NMR (376MHz, CDCl3): δ-209.50 (dddd, J=48.5, 30.7, 21.3, 8.5Hz).

[0061] HRMS(ESI / ion trap):m / z[M+H-H2O] + calcd for C9H7ClFO 185.0169,found185.0161.

[0062] (3S,4R)-7-Chloro-3-fluorobenzopyran-4-ol (2e)

[0063]

[0064] Colorless crystals, 80 mg, 99% yield, dr (cis / trans)>99:1, ee cis =93%,[α] D 23 =45.9(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.40 (d, J=8.3Hz, 1H), 6.97 (dd, J=8.3, 2.1Hz, 1H), 6.87 (d, J=2.1Hz, 1H), 4.99 (dddd, J=48.2, 5.4, 3. 6,1.9Hz,1H),4.85(d,J=20.3Hz,1H),4.49(ddd,J=12.4,8.3,5.3Hz,1H),4.21(ddt,J=29.8,12.4,1.5Hz,1H),2.34(br,1H). 13C NMR (100MHz, CDCl3): δ154.0, 135.2, 129.8, 121.9, 120.4, 116.6, 86.0 (d, J = 178.6Hz), 65.0 (d, J = 22.3Hz), 64.9 (d, J = 19.8Hz). 19 FNMR (376MHz, CDCl3): δ-209.56 (dddd, J=56.4, 30.1, 21.0, 7.5Hz).

[0065] HRMS(ESI / ion trap):m / z[M+H-H2O] + calcd for C9H7ClFO 185.0169,found185.0161.

[0066] (3S,4R)-7-Bromo-3-fluorobenzopyran-4-ol (2f)

[0067]

[0068] Colorless crystals, 96 mg, 98% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =38.6(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.33(d,J=8.2Hz,1H),7.11(dd,J=8.2,1.6Hz,1H),7.03(d,J=1.6Hz,1H),4.99(d,J=48.4 Hz,1H),4.83(d,J=20.5Hz,1H),4.48(ddd,J=13.1,8.3,5.1Hz,1H),4.21(dd,J=30.1,12.4Hz,1H),2.41(br,1H). 19 F NMR (376MHz, CDCl3): δ-209.50 (dddd, J=49.8, 30.0, 20.7, 8.3Hz).

[0069] (3S,4R)-6-Bromo-3-fluorobenzopyran-4-ol (2g)

[0070]

[0071] Colorless crystals, 96 mg, 98% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23=27.3(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.61(d,J=2.5Hz,1H),7.30(dd,J=8.7,2.4Hz,1H),6.73(d,J=8.7Hz,1H),4.99(d,J=48.3 Hz,1H),4.85(d,J=21.1Hz,1H),4.49(ddd,J=13.1,8.6,4.8Hz,1H),4.20(dd,J=31.6,12.6Hz,1H),2.43(br,1H). 13 C NMR (100MHz, CDCl3): δ152.5, 132.8, 131.3, 124.0, 118.3, 113.7, 85.8 (d, J = 178.5Hz), 65.1 (d, J = 21.8Hz), 65.0 (d, J = 19.8Hz). 19 F NMR (376MHz, CDCl3): δ-209.61 (dddd, J=47.6, 30.6, 21.4, 8.5Hz).

[0072] HRMS(ESI / ion trap):m / z[M+H-H2O] + calcd for C9H7BrFO 228.9664,found228.9654.

[0073] (3S,4R)-3-Fluoro-6-nitrobenzopyran-4-ol (2h)

[0074]

[0075] Colorless crystals, 79 mg, 93% yield, dr (cis / trans)>99:1, ee cis =%[α] D 23 =195.5(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ8.46 (d, J = 2.7Hz, 1H), 8.10 (dd, J = 9.1, 2.7Hz, 1H), 6.93 (d, J = 9.1Hz, 1H), 5.09 (dt, J = 48.3, 3.9Hz, 1 H), 4.93 (dd, J = 23.0, 6.9Hz, 1H), 4.63 (ddd, J = 13.5, 9.5, 4.3Hz, 1H), 4.34 (dd, J = 33.7, 13.0Hz, 1H), 2.62 (d, J = 9.2Hz, 1H). 19F NMR (376MHz, CDCl3): δ-209.30 (dddd, J=48.3, 33.1, 23.1, 9.6Hz).

[0076] (3S,4R)-3-Fluoro-6-methylbenzopyran-4-ol (2i)

[0077]

[0078] Colorless crystals, 71 mg, 98% yield, dr (cis / trans)>99:1, ee cis =94%,[α] D 23 =31.0(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.26(br,1H),7.03(dd,J=8.4,2.2Hz,1H),6.75(d,J=8.3Hz,1H),4.99(dddd,J=48.2,5.8,3.6,2.1Hz, 1H), 4.87 (d, J = 18.8, 1H), 4.44 (ddd, J = 12.1, 7.6, 5.8Hz, 1H), 4.16 (ddt, J = 27.7, 12.1, 1.5Hz, 1H), 2.32 (br, 1H), 2.29 (s, 3H). 19 F NMR(376MHz, CDCl3): δ-209.72(m).

[0079] (3S,4R)-3-Fluoro-6-methoxybenzopyran-4-ol (2j)

[0080]

[0081] Colorless crystals, 78 mg, 99% yield, dr (cis / trans)>99:1, ee cis =91%,[α] D 23 =44.3(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.01 (d, J=2.3Hz, 1H), 6.86-6.73 (m, 2H), 4.99 (dddd, J=48.3, 5.3, 3.7, 1.8Hz, 1H), 4.87 (dd, J= 20.8,3.7Hz,1H),4.45(ddd,J=12.4,8.1,5.2Hz,1H),4.16(ddt,J=30.3,12.4,1.5Hz,1H),3.77(s,3H),2.38(br,1H). 19F NMR (376MHz, CDCl3): δ-209.44 (dddd, J=48.7, 29.7, 20.8, 8.3Hz).

[0082] (1R,2S)-2-Fluoro-1,2,3,4-tetrahydronaphthalen-1-ol (2k)

[0083]

[0084] Colorless crystals, 66 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =21.2(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.52(dd,J=5.5,3.7Hz,1H),7.30-.21(m,2H),7.17-7.09(m,1H),5.00(ddt,J=49.7,8.7,3.0Hz,1H),4.81(ddd,J=17.8, 7.2,3.3Hz,1H),3.04(ddd,J=15.9,9.7,3.8Hz,1H),2.80(dt,J=17.1,6.7Hz,1H),2.49-2.29(m,2H),2.02(ddtd,J=27.1,13.6,6.9,2.6Hz,1H). 19 F NMR (376MHz, CDCl3): δ-197.58 (dddd, J=50.1, 25.1, 17.6, 5.9Hz).

[0085] (1R,2S)-2-Fluoro-2,3-dihydro-1H-inden-1-ol (2l)

[0086]

[0087] Colorless crystals, 60 mg, 99% yield, dr (cis / trans)>99:1, ee cis =96%,[α] D 23 =53(c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ7.48 (dd, J=5.1, 3.6Hz, 1H), 7.34-7.22 (m, 3H), 5.32 (dtd, J=53.8, 4.3, 1 .5Hz,1H),5.13(ddd,J=18.2,10.4,4.2Hz,1H),3.33-3.02(m,2H),2.39(dd,J=10.4,4.4Hz,1H). 19 F NMR (376MHz, CDCl3): δ-201.51 (m).

[0088] (1R,2S)-7-Bromo-2-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol (2m)

[0089]

[0090] Colorless crystals, 96 mg, 98% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =43.4(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.68 (d, J=2.1Hz, 1H), 7.34 (dd, J=8.2, 2.2Hz, 1H), 6.99 (d, J=8.2Hz, 1H), 5.00 (ddt, J=49.9, 7.8, 2.7Hz, 1H), 4.72 (ddd, J=2 0.1,8.3,3.3Hz,1H),2.97(dt,J=17.4,7.2Hz,1H),2.72(dt,J=17.2,6.2H z,1H),2.45(dd,J=8.2,2.6Hz,1H),2.44-2.29(m,1H),2.10-1.85(m,1H). 13 C NMR (100MHz, CDCl3): δ138.0 (d, J = 3.6Hz), 134.6, 131.8, 131.2, 130.1, 120.2, 9 0.6(d,J=173.6Hz), 68.8(d,J=19.6Hz), 24.8(d,J=6.6Hz), 24.7(d,J=18.8Hz). 19 FNMR (376MHz, CDCl3): δ-200.28 (dddd, J=50.2, 30.3, 20.4, 6.4Hz).

[0091] HRMS (ESI / ion trap): m / z [M+Na] + calcd for C10 H 10 BrFNaO 266.9797,found266.9786.

[0092] (1R,2S)-6-Chloro-2-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol (2n)

[0093]

[0094] Colorless crystals, 79 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =58.4(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.44(d,J=8.3Hz,1H),7.21(dd,J=8.3,2.1Hz,1H),7.11(d,J=2.1Hz,1H),4.98(ddt,J=49.8,8.2,2.9Hz,1H),4.73(ddd,J=1 8.9,7.7,3.3Hz,1H),3.00(dt,J=15.5,7.1Hz,1H),2.75(dt,J=17.3,6.4H z,1H),2.45(dd,J=7.7,2.7Hz,1H),2.41-2.30(m,1H),2.07-1.90(m,1H). 13 C NMR (100MHz, CDCl3): δ137.6, 134.2 (d, J = 4.2Hz), 133.9, 130.6, 128.2, 127.0, 9 0.8(d,J=173.7Hz), 68.7(d,J=19.5Hz), 25.4(d,J=8.7Hz), 24.5(d,J=20.2Hz). 19 FNMR(376MHz, CDCl3): δ-199.05(m).

[0095] HRMS (ESI / ion trap): m / z [M+Na] + calcd for C 10 H 10 ClFNaO 223.0302,found223.0292.

[0096] (1R,2S)-2-Fluoro-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol(2o)

[0097]

[0098] Colorless crystals, 78 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =43.6(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.06(d,J=2.8Hz,1H),7.04(d,J=8.4Hz,1H),6.81(dd,J=8.4,2.8Hz,1H),4.99(ddt,J=49.9,8.3,2.9Hz,1H),4.75(dd,J =18.9,3.3Hz,1H),3.80(s,3H),2.96(dt,J=15.3,7.0Hz,1H),2.72(dt, J=16.7,7.0Hz,1H),2.42-2.30(m,1H),2.27(br,1H),2.09-1.89(m,1H). 19 F NMR (376MHz, CDCl3): δ-198.97 (dddd, J=48.5, 28.0, 18.6, 6.0Hz).

[0099] (1R,2S)-2-Fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol(2p)

[0100]

[0101] Colorless crystals, 78 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =18.3(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.40 (d, J=8.5Hz, 1H), 6.81 (dd, J=8.6, 2.7Hz, 1H), 6.64 (d, J=2.7Hz, 1H), 4.94 (ddt, J=49.4, 9.2, 3.1Hz, 1H), 4.78 (ddd, J=16 .1,6.7,3.4Hz,1H),3.79(s,3H),3.08-2.91(m,1H),2.78(dt,J=17.1,7.1 Hz,1H),2.43-2.33(m,1H),2.31(dd,J=6.6,2.8Hz,1H),2.10-1.91(m,1H). 13C NMR (100MHz, CDCl3): δ159.6, 137.2, 130.9, 127.9 (d, J = 4.9Hz), 113.1, 113.0, 91. 4(d,J=174.3Hz), 68.7(d,J=19.0Hz), 55.4, 26.4(d,J=9.5Hz), 24.2(d,J=19.7Hz). 19 F NMR (376MHz, CDCl3): δ-195.87 (m).

[0102] HRMS (ESI / ion trap): m / z [M+Na] + calcd for C 11 H 13 FNaO2219.0797,found219.0787.

[0103] (1R,2S)-2-Fluoro-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (2q)

[0104]

[0105] Colorless crystals, 78 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =10.4(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.24(t,J=8.4Hz,1H),7.12(d,J=7.7Hz,1H),6.79(d,J=8.1Hz,1H),4.96(ddt,J=49.7,8.9,3.0Hz,1H),4.79(ddd,J=17.3,7.1,3 .3Hz,1H),3.83(s,3H),2.91(dtd,J=18.0,6.6,2.1Hz,1H),2.68(dt,J=18. 0,6.9Hz,1H),2.49-2.23(m,2H),1.99(ddtd,J=26.9,13.6,6.8,2.6Hz,1H). 13 CNMR (100MHz, CDCl3): δ156.8, 136.8 (d, J = 4.3Hz), 127.3, 124.9, 121.1, 109.3, 91.2 (d, J = 173.6Hz), 69.0 (d, J = 19.1Hz), 55.50, 23.69 (d, J = 19.7Hz), 20.24 (d, J = 8.8Hz). 19F NMR (376MHz, CDCl3): δ-197.72(m).

[0106] HRMS (ESI / ion trap): m / z [M+Na] + calcd for C 11 H 13 FNaO2219.0797,found219.0787.

[0107] (3S,4R)-3,6-Dichlorobenzopyran-4-ol (2r)

[0108]

[0109] Colorless crystals, 83 mg, 95% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =45.9(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.38(d,J=2.5Hz,1H),7.19(dd,J=8.8,2.6Hz,1H),6.80(d,J=8.8Hz,1H),4 .88(dd,J=7.2,3.7Hz,1H),4.46(dt,J=6.9,3.4Hz,1H),4.41-4.26(m,2H),2.49(d,J=7.2Hz,1H). 13 C NMR (100MHz, CDCl3): δ151.8,130.3,129.2,126.4,123.3,118.2,66.1,66.0,57.3.

[0110] HRMS(ESI / ion trap):m / z[M+H-H2O] + calcd for C9H7ClO2200.9874,found200.9865.

[0111] (1R,2S)-2-Chloro-1,2,3,4-tetrahydronaphthalen-1-ol(2s)

[0112]

[0113] Colorless crystals, 70 mg, 96% yield, dr (cis / trans)>99:1, ee cis =97%,[α] D 23 =22.2(c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ7.55-7.44(m,1H),7.30-7.19(m,2H),7.17-7.06(m,1H),4.86(dd,J=7.5,3.4Hz,1H),4.55(dt ,J=8.7,3.1Hz,1H),3.12(dt,J=17.3,6.5Hz,1H),2.85(dt,J=17.3,6.6Hz,1H),2.56-2.33(m,2H),2.26-2.14(m,1H).

[0114] (5R,6S)-6-Chloro-6,7,8,9-tetrahydrobenzo[7]cyclo-5-ol (2t)

[0115]

[0116] Colorless crystals, 78 mg, 99% yield, dr (cis / trans)>99:1, ee cis =%[α] D 23 =-170.0(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.33-7.27(m,1H),7.25-7.17(m,2H),7.13-7.07(m,1H),5.08(s,1H),4.40(dd,J=9.2,3.0Hz,1H),3.27-3.0 0(m,1H),2.64(dd,J=14.2,8.6Hz,1H),2.57-2.43(m,2H),2.25(ddt,J=14.2,7.3,3.4Hz,1H),1.97-1.83(m,1H),1.71-1.54(m,1H).

[0117] (1R,2S)-2,6-dichloro-1,2,3,4-tetrahydronaphthalen-1-ol (2u)

[0118]

[0119] Colorless crystals, 85 mg, 98% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =14.6(c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ7.43 (d, J=8.3Hz, 1H), 7.20 (dd, J=8.4, 2.2Hz, 1H), 7.1 1(d,J=2.2Hz,1H),4.81(dd,J=8.0,3.4Hz,1H),4.53(dt,J=8.2,3.0Hz,1H),3. 09(dt,J=17.4,6.9Hz,1H),2.80(dt,J=17.4,6.3Hz,1H),2.49(d,J=8.0Hz,1H) ,2.39(ddt,J=14.2,8.1,6.1Hz,1H),2.19(dddd,J=13.9,8.3,6.4,2.7Hz,1H).

[0120] (1R,2S)-7-Bromo-2-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (2v)

[0121]

[0122] Colorless crystals, 103 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =21.2(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.67(d,J=2.1Hz,1H),7.35(dd,J=8.2,2.1Hz,1H),6.99(d,J=8.2Hz,1H),4.81(dd,J=8.6,3.5Hz,1H),4.56(dt,J=7.6,3.0Hz,1H ),3.14-2.98(m,1H),2.76(dt,J=17.4,6.0Hz,1H),2.48(d,J=8.5Hz,1H),2. 39(ddt,J=13.52,7.4,5.8Hz,1H),2.20(dddd,J=14.3,8.6,6.3,2.6Hz,1H).

[0123] (1R,2S)-2-Chloro-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol

[0124]

[0125] Colorless crystals, 83 mg, 98% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =31.4(c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ7.07-6.98(m,2H),6.82(dd,J=8.5,2.8Hz,1H),4.82(dd,J=8.2,3.4Hz,1H),4.56(dt,J=8.1,3.0Hz,1H),3.80(s,3H),3 .02(dt,J=17.0,6.9Hz,1H),2.76(dt,J=16.9,6.2Hz,1H),2.44(d,J=8.1Hz,1H),2.46-2.33(m,1H),2.18(dddd,J=13.9,8.4,6.3,2.6Hz,1H).

[0126] (1R,2S)-2-Chloro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (2x)

[0127]

[0128] Colorless crystals, 84 mg, 99% yield, dr (cis / trans)>99:1, ee cis =99%,[α] D 23 =21.5(c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ7.38(d,J=8.5Hz,1H),6.80(dd,J=8.5,2.6Hz,1H),6.64(d,J=2.6Hz,1H),4.80(dd,J=7.0,3.3Hz,1H),4.49(dt,J=9.1,3.1Hz,1H ),3.79(s,3H),3.07(dt,J=17.3,6.3Hz,1H),2.81(dt,J=17.3,6.9Hz,1H),2 .45(d,J=6.9Hz,1H),2.43-2.36(m,1H),2.16(dtd,J=13.3,6.4,2.8Hz,1H).

[0129] General Example 4

[0130] The general route for preparing the compound substrate is shown below:

[0131] 1) Synthesis of Compounds 1a-1q:

[0132]

[0133] According to the general route, a 50 mL round-bottom flask equipped with a stirrer and a condenser was charged with the ketone compound (4.0 mmol, 1.0 equiv), SelectFluor (1.70 g, 4.8 mmol, 1.2 equiv), MeOH (7 mL), and H2SO4 (20 μL, 0.4 mmol, 0.1 equiv). The resulting suspension was heated at 50°C (oil bath) for 24-72 hours (reaction completion monitored by TLC, petroleum ether / ethyl acetate 80:20). After the reaction mixture was cooled, the slurry was diluted with 3 mL of methanol and filtered. The resulting solid was washed with MeOH (2×3 mL), and the filtrate was concentrated under reduced pressure.

[0134] The resulting mixture was dissolved in CH2Cl2 (20 mL), washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate, 95:5 to 85:15) to give 1a-1q as a white crystalline solid.

[0135] 3-Fluorobenzan-4-one (1a)

[0136]

[0137] White solid, 7.5 g, 90% yield. 1 H NMR (400MHz, CDCl3): δ7.91 (dd, J=7.9, 1.8Hz, 1H), 7.53 (ddd, J=8.7, 7.2, 1.8Hz, 1H), 7.08 (t ,J=7.5Hz,1H),7.00(d,J=8.4Hz,1H),5.16(ddd,J=47.0,9.2,4.7Hz,1H),4.70-4.47(m,2H). 19 F NMR (376MHz, CDCl3): δ-204.05 (ddd, J=47.0, 15.9, 7.5Hz).

[0138] 3,7-Difluorobenzopyran-4-one (1b)

[0139]

[0140] White solid, 200 mg, 72% yield. 1 H NMR (400MHz, CDCl3): δ7.95 (dd, J=8.8, 6.5Hz, 1H), 6.82 (ddd, J=8.8, 8.0, 2.4Hz, 1H) ,6.71(dd,J=9.6,2.4Hz,1H),5.13(ddd,J=46.9,8.5,4.7Hz,1H),4.75-4.40(m,2H). 19F NMR (376MHz, CDCl3): δ-98.49 (m), -203.59 (ddd, J=46.9, 17.3, 8.5Hz).

[0141] 3,8-Difluorobenzopyran-4-one (1c)

[0142]

[0143] White solid, 193 mg, 70% yield. 1 H NMR (400MHz, CDCl3): δ7.71 (dt, J=8.0, 1.5Hz, 1H), 7.35 (ddd, J=10.5, 8.0, 1.6Hz, 1H ),7.04(td,J=8.0,4.3Hz,1H),5.19(ddd,J=46.8,8.9,4.6Hz,1H),4.93-4.45(m,2H). 19 F NMR (376MHz, CDCl3): δ-134.31 (dd, J=10.1, 4.5Hz), -203.63 (ddd, J=47.2, 17.1, 7.9Hz).

[0144] 6-Chloro-3-fluorobenzopyran-4-one (1d)

[0145]

[0146] White solid, 480 mg, 80% yield. 1 H NMR (400MHz, CDCl3): δ7.87 (d, J=2.7Hz, 1H), 7.47 (dd, J=8.9, 2.7Hz, 1H), 6.98 (d, J=8.9Hz, 1H), 5.14 (ddd, J=46.9, 8.8, 4.7Hz, 1H), 4.77-4.48 (m, 2H). 19 F NMR (376MHz, CDCl3): δ-203.73 (ddd, J=47.2, 17.4, 8.4Hz).

[0147] 7-Chloro-3-fluorobenzopyran-4-one (1e)

[0148]

[0149] White solid, 213 mg, 76% yield. 1H NMR (400MHz, CDCl3): δ7.84 (d, J=8.4Hz, 1H), 7.10-6.93 (m, 2H), 5.13 (ddd, J=46.9, 8.7, 4.6Hz, 1H), 4.70-4.42 (m, 2H). 19 F NMR (376MHz, CDCl3): -203.50 (ddd, J=46.6, 16.9, 8.3Hz).

[0150] 7-Bromo-3-fluorobenzopyran-4-one (1f)

[0151]

[0152] White solid, 200 mg, 75% yield. 1 H NMR (400MHz, CDCl3): δ7.77 (d, J=8.9Hz, 1H), 7.25-7.20 (m, 2H), 5.13 (ddd, J=46.9, 8.7, 4.7Hz, 1H), 4.75-4.47 (m, 2H). 19 F NMR (376MHz, CDCl3): δ-203.50 (ddd, J=46.4, 17.5, 7.9Hz).

[0153] 6-Bromo-3-fluorobenzopyran-4-one (1g)

[0154]

[0155] White solid, 430 mg, 68% yield. 1 H NMR (400MHz, CDCl3): δ8.20-7.89(m,1H),7.70-7.46(m,1H),6.99-6.85(m,1H),5.26-4.92(m,1H),4.76-4.44(m,2H). 19 FNMR(376MHz, CDCl3): δ-203.71(m).

[0156] 3-Fluoro-7-nitrobenzopyran-4-one (1h)

[0157]

[0158] White solid, 430 mg, 78% yield. 1H NMR (400MHz, CDCl3): δ8.80(d,J=2.8Hz,1H),8.39(dd,J=9.2,2.8Hz,1H),7.18(d,J=9.2Hz,1H),5.30-5.03(m,1H),4.80-4.71(m,2H). 19 FNMR (376MHz, CDCl3): δ-202.73 (ddd, J=46.0, 16.4, 11.9Hz).

[0159] 3-Fluoro-6-methylbenzopyran-4-one (1i)

[0160]

[0161] White solid, 405 mg, 75% yield. 1 H NMR (400MHz, CDCl3): δ7.70(s,1H),7.34(d,J=8.5Hz,1H),6.91(d,J=8.5Hz,1 H),5.14(dddd,J=47.1,9.3,4.7,2.5Hz,1H),4.72-4.34(m,2H),2.32(s,3H). 19 F NMR (376MHz, CDCl3): δ-204.07 (ddd, J=47.2, 16.5, 7.4Hz).

[0162] 3-Fluoro-6-methoxybenzopyran-4-one (1j)

[0163]

[0164] White solid, 178 mg, 65% yield. 1 H NMR (400MHz, CDCl3): δ7.31 (d, J=3.2Hz, 1H), 7.14 (dd, J=9.1, 3.2Hz, 1H), 6.95 (d, J=9.1Hz,1H),5.14(ddd,J=47.0,9.1,4.7Hz,1H),4.74-4.41(m,2H),3.81(s,3H). 19 F NMR (376MHz, CDCl3): δ-203.86 (ddd, J=47.2, 16.8, 8.1Hz).

[0165] 2-Fluoro-3,4-dihydronaphthalen-1(2H)one (1k)

[0166]

[0167] Colorless crystals, 697 mg, 85% yield.1 H NMR (400MHz, CDCl3): δ8.07(dd,J=7.8,1.4Hz,1H),7.53(td,J=7.5,1.5Hz,1H),7.36(t,J=7.5Hz,1H),7.27(d,J=7.7Hz,1H),5.15(ddd,J =47.9,12.7,5.1Hz,1H),3.13(dd,J=9.5,4.1Hz,2H),2.58(dddt,J=12.5,10.3,5.1,4.2Hz,1H),2.36(tddd,J=12.6,9.3,7.8,6.7Hz,1H). 19 FNMR (376MHz, CDCl3): δ-190.32 (dt, J=48.1, 9.1Hz).

[0168] 2-Fluoro-2,3-dihydro-1H-inden-1-one (1l)

[0169]

[0170] Colorless crystals, 2.8 g, 92% yield. 1 H NMR (400MHz, CDCl3): δ7.80(d,J=7.7Hz,1H),7.67(t,J=7.5Hz,1H),7.46(d,J=7.7Hz,1H),7.44(t,J=7.5Hz ,1H),5.27(ddd,J=51.1,7.8,4.4Hz,1H),3.63(dt,J=16.9,7.5Hz,1H),3.23(ddd,J=22.2,16.9,4.4Hz,1H). 19 F NMR (376MHz, CDCl3): δ-193.99 (ddd, J=51.1, 23.9, 7.2Hz).

[0171] 7-Bromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (1m)

[0172]

[0173] Colorless crystals, 968 mg, 80% yield. 1H NMR (400MHz, CDCl3): δ8.18 (dt, J=5.5, 2.3Hz, 1H), 7.63 (ddd, J=8.2, 3.0, 1.7Hz, 1H), 7.16 (d, J=8.2Hz, 1H),5.14(dddt,J=47.7,12.6,5.1,1.2Hz,1H),3.21-3.03(m,2H),2.67-2.49(m,1H),2.42-2.22(m,1H). 19 F NMR (376MHz, CDCl3): δ-190.70 (ddd, J=48.3, 11.2, 6.9Hz).

[0174] 6-Chloro-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (1n)

[0175]

[0176] Colorless crystals, 842 mg, 85% yield. 1 H NMR (400MHz, CDCl3): δ8.00(d,J=8.4Hz,1H),7.33(dd,J=8.4,2.0Hz,1H),7.28(br,1H),5. 12(ddd,J=47.7,12.5,5.1Hz,1H),3.21-2.99(m,2H),2.66-2.49(m,1H),2.44-2.24(m,1H). 19 F NMR (376MHz, CDCl3): δ-190.70 (ddd, J=48.3, 11.2, 6.9Hz).

[0177] 2-Fluoro-7-methoxy-3,4-dihydronaphthalen-1(2H)one(1o)

[0178]

[0179] Colorless crystals, 737 mg, 76% yield. 1 H NMR (400MHz, CDCl3): δ7.52(d,J=2.8Hz,1H),7.18(d,J=8.5Hz,1H),7.10(dd,J=8.5,2.8Hz,1H),5.13(ddd ,J=47.9,12.8,5.1Hz,1H),3.85(s,3H),3.06(dd,J=9.4,4.2Hz,2H),2.63-2.49(m,1H),2.43-2.26(m,1H). 19 F NMR (376MHz, CDCl3): δ-190.41 (m).

[0180] 2-Fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)one(1p)

[0181]

[0182] Colorless crystals, 819 mg, 84% yield. 1 H NMR (400MHz, CDCl3): δ8.04(d,J=8.8Hz,1H),6.87(dd,J=8.8,2.5Hz,1H),6.70(d,J=2.5Hz,1H),5.09(ddd ,J=48.0,12.4,5.1Hz,1H),3.86(s,3H),3.08(dd,J=9.2,4.2Hz,2H),2.61-2.47(m,1H),2.41-2.24(m,1H). 19 F NMR (376MHz, CDCl3): δ-190.37 (ddd, J=47.7, 10.2, 6.7Hz).

[0183] 2-Fluoro-5-methoxy-3,4-dihydronaphthalen-1(2H)one (1q)

[0184]

[0185] Colorless crystals, 719 mg, 74% yield. 1 H NMR (400MHz, CDCl3): δ7.65(dd,J=7.9,1.1Hz,1H),7.32(t,J=8.0Hz,1H),7.05(dd,J=8.1,1.0Hz,1H),5.15(ddd,J=48.3,1 3.1,5.2Hz,1H),3.87(s,3H),3.27(dtd,J=18.0,4.9,3.3Hz,1H),2.95-2.70(m,1H),2.65-2.50(m,1H),2.39-2.18(m,1H). 19 F NMR (376MHz, CDCl3): δ-191.03 (ddt, J=47.3, 10.2, 5.4Hz).

[0186] 2) Synthesis of compounds 1r-1x

[0187]

[0188] A MeOH solution (100 mL) containing ketone (10 mmol), thiourea (15 mg, 0.2 mmol) and N-chlorosuccinimide (1.60 g, 12 mmol) was heated in an oil bath at 35°C under an N atmosphere for 3 h. The solution was concentrated under reduced pressure, then AcOEt (50 mL) and H2O (20 mL) were added and stirred for 10 minutes. The organic layer was separated and the aqueous phase was extracted with AcOEt (2 x 50 mL). The combined organic fractions were dried over MgSO4 and concentrated to give the crude product. Purification by silica gel column chromatography (eluent: hexane / AcOEt = 5 / 1) gave the product 1r-1x.

[0189] 3,6-Dichlorobenzopyran-4-one (1r)

[0190]

[0191] White solid, 480 mg, 45% yield. 1 H NMR (400MHz, CDCl3): δ7.89 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 8.9, 2.7 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.67 (dd, J = 11.4, 3.1 Hz, 1H), 4.61-4.50 (m, 2H). 13 C NMR (100MHz, CDCl3): δ184.5,159.4,136.8,128.0,127.4,119.9,119.8,71.2,54.8.

[0192] HRMS (ESI / ion trap): m / z [M+H] + = Calculated value for C9H7Cl2O2 216.9823, found 216.9814.

[0193] 2-Chloro-3,4-dihydronaphthalen-1(2H)one(1s)

[0194]

[0195] Light yellow liquid, 5.8 g, 95% yield. 1H NMR (400MHz, CDCl3): δ8.07 (dd, J=7.9, 1.4Hz, 1H), 7.51 (td, J=7.5, 1.5Hz, 1H), 7.33 (td, J=7.6, 1.1Hz, 1H), 7.26 (d, J=7.7Hz, 1H), 4.6 2(dd,J=7.8,3.9Hz,1H),3.27(ddd,J=17.1,8.0,4.6Hz,1H),2.98(ddd,J=17.1,7.0,4.7Hz,1H),2.63-2.51(m,1H),2.50-2.39(m,1H).

[0196] 6-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]cyclo-5-one (1t)

[0197]

[0198] Light yellow liquid, 834 g, 86% yield. 1 H NMR (400MHz, CDCl3): δ7.64 (dd, J=7.7, 1.5Hz, 1H), 7.41 (td, J=7.5, 1.5Hz, 1H), 7.3 0(td,J=7.6,1.2Hz,1H),7.20(dd,J=7.5,1.1Hz,1H),4.80(dd,J=8.7,4.7Hz,1H),3 .02(ddd,J=15.8,7.7,3.4Hz,1H),2.92(ddd,J=15.8,9.6,3.4Hz,1H),2.39(dddd,J =14.3,9.7,6.1,4.7Hz,1H),2.20(ddt,J=14.0,8.7,5.3Hz,1H),2.11-1.87(m,2H).

[0199] 2,6-Dichloro-3,4-dihydronaphthalen-1(2H)one (1u)

[0200]

[0201] White solid, 952 mg, 89% yield. 1 H NMR (400MHz, CDCl3): δ8.02(d,J=8.4Hz,1H),7.51-7.09(m,2H),4.61(dd,J=7.3,3.8Hz,1H),3.27(dd d,J=17.3,8.4,4.6Hz,1H),2.95(ddd,J=17.0,6.6,5.0Hz,1H),2.63-2.50(m,1H),2.52-2.39(m,1H).

[0202] 7-Bromo-2-chloro-3,4-dihydronaphthalen-1(2H)-one (1v)

[0203]

[0204] White solid, 908 mg, 88% yield. 1 H NMR (400MHz, CDCl3): δ8.19(d,J=2.2Hz,1H),7.62(dd,J=8.2,2.2Hz,1H),7.17(d,J=8.2Hz,1H),4.61(dd,J=7.3,3.8 Hz,1H),3.24(ddd,J=17.3,8.3,4.6Hz,1H),2.94(ddd,J=17.3,6.5,4.7Hz,1H),2.63-2.50(m,1H),2.52-2.39(m,1H).

[0205] 2-Chloro-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (1w)

[0206]

[0207] White solid, 1.5 g, 90% yield. 1 H NMR (400MHz, CDCl3): δ7.53(d,J=2.8Hz,1H),7.17(d,J=8.4Hz,1H),7.09(dd,J=8.5,2.8Hz,1H),4.61(dd,J=7.6,3.8Hz,1H) ,3.83(s,3H),3.20(ddd,J=16.9,8.0,4.5Hz,1H),2.92(ddd,J=16.9,6.8,4.6Hz,1H),2.63-2.49(m,1H),2.49-2.32(m,1H).

[0208] 2-Chloro-6-methoxy-3,4-dihydronaphthalen-1(2H)one (1x)

[0209]

[0210] White solid, 952 mg, 89% yield. 1H NMR (400MHz, CDCl3): δ8.05 (d, J=8.8Hz, 1H), 6.86 (dd, J=8.8, 2.5Hz, 1H), 6.70 (dd, J=2.4, 1.1Hz, 1H), 4.58 (dd, J=7.4, 3.9Hz, 1H),3.86(s,3H),3.25(ddd,J=17.1,8.4,4.5Hz,1H),2.93(ddd,J=17.0,6.7,4.6Hz,1H),2.61-2.48(m,1H),2.49-2.33(m,1H).

[0211] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for asymmetric synthesis of vicinal halohydrin compounds, characterized in that: include: Using compound (1) as substrate, in the presence of H2, [Ir(COD)Cl]2 as metal precursor, ligands (L1-L6), base and solvent, an asymmetric synthesis is carried out to generate cis-vicinal halohydrin (2). The Ar group in the ligand is an aryl group, which is selected from at least one of phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl and 3,5-di-tert-butyl-4-methoxyphenyl.

2. The method for asymmetric synthesis of a vicinal halohydrin compound according to claim 1, wherein The solvent is selected from: i PrOH, EtOH, MeOH, TFE, DCM, hexane, THF or toluene.

3. The method for asymmetric synthesis of a vicinal halohydrin compound according to claim 1, wherein The base is selected from: t BuOK, t BuONa, t BuOLi, KOMe, LiOMe, NaOH or KOH.

4. The method for asymmetric synthesis of vicinal halohydrin compounds according to claim 1, wherein Select 5-30 atmospheres of H2.

5. The method for asymmetric synthesis of vicinal halohydrin compounds according to claim 1, wherein The reaction time is 12-36 hours.

6. The method for asymmetric synthesis of vicinal halohydrin compounds according to claim 1, wherein The reaction was carried out at 25° C. for 24 hours using 0.05 mol% [Ir(COD)Cl] 2 / L1 as catalyst, KOH as base, compound 1 / catalyst = 100 / 1 and toluene as solvent.

7. The method for asymmetric synthesis of vicinal halohydrin compounds according to claim 1, wherein Compound 2 is selected from the following compounds 2a-2x:

Images