CN104692987B - Cheap and efficient synthesis method of halogenated alcohols and derivatives thereof - Google Patents

Abstract

The invention discloses a cheap and high-efficiency synthesis method of haloalcohols. In an organic solvent, the alkene compound represented by the formula I is mixed with a halide, a sulfoxide and an additive, and the alkene compound can be prepared with high selectivity through the hydroxyhalogenation reaction of the alkene. The halogenated alcohol shown in formula II is obtained, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are respectively selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy, ester, acyl , amide group, dialkylamino group, aryl group, substituted aryl group, heterocyclic aryl group or substituted heterocyclic aryl group, when R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each independently exist Can be the same or different; or R ¹ and R ² , R ¹ and R ³ , R ² and R ⁴ , R ³ and R ⁴ , R ⁵ and R ⁶ are combined to form a cycloalkyl group or a substituted cycloalkyl group , benzocycloalkyl or substituted benzocycloalkyl, aromatic heterocycle or substituted aromatic heterocycle; M is selected from hydrogen, lithium, sodium, potassium, cesium, beryllium, magnesium, calcium, strontium, barium, Zinc, copper, iron, ammonium or tetraalkylammonium; X is selected from chlorine, bromine or iodine.

Description

A Cheap and Efficient Synthesis Method of Halohydrin and Its Derivatives

technical field

The invention relates to a method for synthesizing a compound, in particular to a method for synthesizing a halogenated alcohol, and belongs to the field of chemical synthesis.

Background technique

Halohydrins are important organic synthons in drug synthesis. Many intermediates widely used in drug synthesis, such as amino alcohols, hydroxy acids, epoxy compounds, and aziridines, can be conveniently synthesized through halohydrins. Therefore, the development of efficient halohydrin synthesis methods is currently an important topic in academia and industry. (Dagani, M.J.; Barda, H.J.; Benya, T.J.; Sanders, D.C. Eds. Ulmann's Encyclopedia of Industrial Chemistry: Bromine Compounds, Wiley-VCH, Weinheim, 2002). Among the many methods for synthesizing halohydrins, the synthesis of halohydrins through the hydroxyhalogenation reaction of alkenes has aroused great interest of researchers due to the convenience and easy availability of alkenes. In the traditional synthesis method, N-bromosuccinimide (NBS), a relatively expensive reagent, is needed, and the method has poor atom economy. Inspired by oxidative halogenation reactions in nature (Villancourt, F.H.; Yeh, E.; Vosburg, D.A.; Garneau-Tsodikova, S.; Walsh, C.T. Chem. Rev. 2006, 106, 3364), chemists developed the oxidative hydroxyhalogenation The reaction method is used to synthesize halohydrins, that is, the method of synthesizing halohydrins by using halides as halogen sources and adding oxidizing agents to realize the hydroxyhalogenation reaction of alkenes. But so far, the conditions of this type of oxidative hydroxyhalogenation reaction are all relatively complicated. Usually, it is necessary to add halides, reagents for providing oxygen sources, oxidizing agents, additives, solvents, etc. in the reaction system, and sometimes it is necessary to add catalysts (Pandit, P.; Gayen, K.S.; Khamarui, S.; Chatterjee, N.; Maiti, D.K. Chem. Commun. 2011, 47, 6933 and Dewkar, G.K.; Narina, S.V.; Sudalai, A. Org. Lett. 2003, 5, 4501), These reactions lead to difficult operation, low atom economy rate and high cost. In view of the importance of halohydrins, it is necessary to develop new oxidative halogenation strategies to realize the hydroxyhalogenation of alkenes and provide a cheap and efficient method for the synthesis of halohydrins.

Contents of the invention

The object of the present invention is to provide a cheap and high-efficiency synthesis method of halohydrins, which can obtain halohydrins with high selectivity through the hydroxyhalogenation reaction of olefins.

In order to achieve the above object, the technical means adopted in the present invention are:

A method for synthesizing haloalcohols, characterized in that: in an organic solvent, the alkene compound shown in formula I is mixed with halides, sulfoxides and additives, and the halohydrin compound shown in formula II is prepared by the hydroxyhalogenation reaction of alkene alcohol,

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are respectively selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy, ester, acyl, amido, dialkylamino, aromatic A group, a substituted aryl group, a heterocyclic aryl group or a substituted heterocyclic aryl group, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different when they exist independently; or R ¹ and R ² , R ¹ and R ³ , R ² and R ⁴ , R ³ and R ⁴ , R ⁵ and R ⁶ combine to form cycloalkyl or substituted cycloalkyl, benzocycloalkyl or substituted Benzocycloalkyl, aromatic heterocycle or substituted aromatic heterocycle;

M is selected from hydrogen, lithium, sodium, potassium, cesium, beryllium, magnesium, calcium, strontium, barium, zinc, copper, iron, ammonium or tetraalkylammonium;

X is selected from chlorine, bromine or iodine;

The additive is selected from sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrogen at least one of phenylsulfonic acid or p-bromobenzenesulfonic acid;

The organic solvent is 1,2-dichloroethane, 1,2-dibromoethane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, butyl acetate, acetone, nitro Methane, acetonitrile, toluene, benzene, chlorobenzene, n-hexane, tetrahydrofuran, 1,4-dioxane, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, or substituted alcohols; or not Add the above-mentioned solvent, and directly use sulfoxide as the solvent.

In the present invention, preferably, R ¹ , R ² , R ³ and R ⁴ are each selected from one of the following groups: (1) hydrogen; (2) C _1-6 alkyl, hydroxyalkane C _1-3 group; (3) phenyl, naphthyl, biphenyl, benzothienyl, benzofuryl; (3) straight chain/branched C _1-4 alkyl, C _1-3 hydroxy Alkyl, C _1-3 alkoxy or halogen substituted phenyl; (4) And (5) R ¹ and R ² , R ¹ and R ³ , R ² and R ⁴ , R ³ and R ⁴ combine to form indanyl, tetrahydro-1-naphthyl, benzocycloheptyl, chromo Full base or cyclohexyl.

In the present invention, preferably, R ¹ , R ² , R ³ and R ⁴ are respectively selected from hydrogen, methyl, n-pentyl, n-hexyl, hydroxymethyl, 1-phenyl, 2-phenyl, 1-naphthalene Base, 2-naphthyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, phenethyl, p-tert-butylphenyl, p-bromophenyl, p-iodophenyl, p-hydroxymethyl Phenyl, p-methoxyphenyl, biphenyl, benzothienyl, benzofuryl, Or R ¹ and R ² , R ¹ and R ³ , R ² and R ⁴ , R ³ and R ⁴ are combined to form indanyl, tetrahydro-1-naphthyl, benzocycloheptyl, chromanyl or cyclohexyl.

In the present invention, preferably, R ⁵ and R ⁶ are independently selected from C _1-10 alkyl, phenyl, C _1-3 alkyl substituted phenyl; or R ⁵ and R ⁶ are combined to form a cycloalkyl group Or a substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl.

In the present invention, preferably, R ⁵ and R ⁶ are both methyl groups.

In the present invention, preferably, the reaction temperature is 0-150°C, more preferably 60°C.

In the present invention, preferably, the molar ratio of olefin compound (I) to halide is 1:1～1:50, more preferably 1:1.2; the molar ratio of olefin compound (I) to sulfoxide is 1:0.5～ 1:1000, more preferably 1:56.

In the present invention, preferably, the halide is hydrogen bromide or sodium iodide; the additive is sulfuric acid or hydrobromic acid; and the organic solvent is dimethyl sulfoxide.

In the present invention, preferably, the molar ratio of the olefin compound (I) to the additive is 1:0.5˜1:50, more preferably 1:1.2.

Further, the present invention provides a synthetic method of hydroxy azide compound (III) and epoxy compound (IV), characterized in that: the haloalcohol is prepared according to the above-mentioned synthetic method, and the haloalcohol is prepared through a one-pot Converted to hydroxyl azide compound (III) and epoxy compound (IV) by method:

The method of the present invention has wide applicability and can provide several known halohydrins and derivatives thereof. Specifically, the preparation method of the compound in Table 1 is provided in detail in the specific examples of the present invention:

Target compound: Table 1

detailed description

The present invention will be further described below in conjunction with specific embodiments, and the advantages and characteristics of the present invention will become clearer along with the description. However, the examples are merely exemplary and do not limit the scope of the present invention in any way. Those skilled in the art should understand that the details and forms of the technical solutions of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the protection scope of the present invention.

Example 1 Synthesis of 2-bromo-1-(2-naphthyl)-ethanol

a): Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Naphthyl)-ethanol 105 mg, yield 84%.

b): Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 70°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Naphthyl)-ethanol 100 mg, yield 80%.

c): Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 62mg of sodium bromide, 60mg of sulfuric acid, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Naphthyl)-ethanol 94 mg, yield 75%.

d): Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 243mg of 20% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Naphthyl)-ethanol 105 mg, yield 84%.

e): Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 169mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Naphthyl)-ethanol 102 mg, yield 82%.

f): Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 245mg of 33% hydrobromic acetic acid solution, 2mL of dimethyl sulfoxide, and stir at 70°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Naphthyl)-ethanol 100 mg, yield 80%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.84–7.81 (m, 4H), 7.51–7.43 (m, 3H), 5.07 (dd, J=8.9, 3.3Hz, 1H), 3.70 (dd, J=10.5 ,3.4Hz,1H),3.60(dd,J＝10.5,8.9Hz,1H),2.78(brs,1H); ¹³ CNMR(100MHz,CDCl ₃ )δ137.6,133.3,133.2,128.5,128.0,127.7,126.4, 126.3, 125.2, 123.5, 73.9, 40.0.

Example 2 Synthesis of 2-bromo-1-phenyl-ethanol

Take a 25mL Schlenk reaction tube, add 52mg of styrene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-phenyl- Ethanol 72 mg, yield 71%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.38–7.31 (m, 5H), 4.92 (dt, J=8.9, 3.1Hz, 1H), 3.63 (dd, J=10.5, 3.3Hz, 1H), 3.56– 3.51 (m, 1H), 2.68 (d, J=3.2Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 140.2, 128.7, 128.4, 125.9, 73.8, 40.2.

Example 3 Synthesis of 2-bromo-1-(4-methyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add p-methylstyrene 59mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- Methyl-phenyl)-ethanol 97 mg, yield 90%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.25 (d, J=8.3Hz, 2H), 7.18 (d, J=7.9Hz, 2H), 4.88–4.86 (m, 1H), 3.60 (dd, J= 10.4, 3.4Hz, 1H), 3.52(dd, J＝10.4, 3.4Hz, 1H), 2.64(d, J＝3.0Hz, 1H), 2.35(s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ138.2, 137.3, 129.3, 125.9, 73.6, 40.2, 21.1.

Example 4 Synthesis of 2-bromo-1-(3-methyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add m-methylstyrene 59mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(3- Methyl-phenyl)-ethanol 87 mg, yield 81%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.25(t, J=6.5Hz, 1H), 7.19(s, 1H), 7.16–7.12(m, 2H), 4.87(dt, J=8.8, 3.0Hz, 1H), 3.61(dd, J＝10.4, 3.3Hz, 1H), 3.54–3.50(m, 1H), 2.68(d, J＝3.2Hz, 1H), 2.36(s, 3H); ¹³ C NMR (100MHz , CDCl ₃ ) δ140.2, 138.4, 129.2, 128.5, 126.6, 123.0, 73.8, 40.2, 21.4.

Example 5 Synthesis of 2-bromo-1-(2-methyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add o-methylstyrene 59mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-(2- Methyl-phenyl)-ethanol 97 mg, yield 90%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.52–7.50(m,1H),7.26–7.20(m,2H),7.16–7.14(m,1H),5.12(d,J=9.4Hz,1H), 3.57(dd, J=10.6,3.0Hz,1H),3.47(dd,J= ^10.6,3.0Hz ,1H),2.68(d,J=2.1Hz,1H),2.33(s,3H); (100MHz, CDCl ₃ ): δ138.3, 134.7, 130.6, 128.2, 126.5, 125.3, 70.7, 39.0, 19.0.

Example 6 Synthesis of 2-bromo-1-(4-tert-butyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add 80mg of p-tert-butylstyrene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- tert-butyl-phenyl)-ethanol 110 mg, yield 86%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.40 (d, J=8.4Hz, 2H), 7.31 (d, J=8.3Hz, 2H), 4.89 (dt, J=9.0, 3.0Hz, 1H), 3.62 (dd, J=10.4, 3.3Hz, 1H), 3.56–3.52(m, 1H), 2.65(d, J=3.0Hz, 1H), 1.31(s, 9H); ¹³ C NMR (100MHz, CDCl ₃ ) δ151.5, 137.2, 125.7, 125.6, 73.6, 40.2, 34.6, 31.3.

Example 7 Synthesis of 2-bromo-1-(4-phenyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add 90mg p-phenylstyrene, 101mg 48% hydrobromic acid aqueous solution, 2mL dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- Phenyl-phenyl)-ethanol 126 mg, yield 91%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.63–7.60 (m, 4H), 7.49–7.45 (m, 4H), 7.38 (t, J=7.3Hz, 1H), 4.98 (dd, J=8.9, 3.3 Hz, 1H), 3.69(dd, J=10.5, 3.4Hz, 1H), 3.62–3.57(m, 1H), 2.77(s, 1H); ¹³ C NMR(100MHz, CDCl ₃ ) δ141.3, 140.5, 139.2, 128.8, 127.4, 127.3, 127.0, 126.4, 73.5, 40.0. HRMS (ESI) Calcd for [C ₁₄ H ₁₃ BrNaO, M+Na] ⁺ : 299.0042, Found: 299.0046.

Example 8 Synthesis of 2-bromo-1-(4-methoxy-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add 67mg of p-methoxystyrene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- Methoxy-phenyl)-ethanol 107 mg, yield 93%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.27 (d, J=8.7Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 4.84 (dd, J=8.7, 3.6Hz, 1H), 3.78 (s, 3H), 3.56 (dd, J = 10.4, 3.7Hz, 1H), 3.50 (dd, J = 10.4, 8.8Hz, 1H), 2.77 (s, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ159.5, 132.4, 127.2, 114.0, 73.3, 55.2, 40.0.

Example 9 Synthesis of 2-bromo-1-(4-bromo-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add p-bromostyrene 92mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- Bromo-phenyl)-ethanol 86 mg, yield 61%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.49 (d, J=8.6Hz, 2H), 7.25 (d, J=8.6Hz, 2H), 4.87 (dt, J=8.8, 3.2Hz, 1H), 3.59 (dd, J=10.6, 3.2Hz, 1H), 3.48(dd, J=10.6, 8.8Hz, 1H), 2.76(d, J=3.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ139. 2, 131.7, 127.6, 122.3, 73.0, 39.7.

Example 10 Synthesis of 2-bromo-1-(4-iodo-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add p-iodostyrene 115mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- Iodo-phenyl)-ethanol 164 mg, yield 50%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.71(d, J=8.3Hz, 2H), 7.13(d, J=8.3Hz, 2H), 4.87(d, J=8.6Hz, 1H), 3.60(dd ,J=10.5,3.4Hz,1H),3.49(dd,J=10.4,8.9Hz,1H),2.67(s,1H); ¹³ CNMR(100MHz,CDCl ₃ )δ139.9,137.8,127.9,94.0,73.1, 39.8. HRMS (ESI) Calcd for [C ₈ H ₈ BrINaO,M+Na] ⁺ : 348.8695, Found: 348.8711.

Example 11 Synthesis of 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add 67mg of p-hydroxymethylstyrene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- Hydroxymethyl-phenyl)-ethanol 96 mg, yield 83%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.37–7.32 (m, 4H), 4.88 (dd, J = 8.6, 3.4 Hz, 1H), 4.62 (s, 2H), 3.58 (dd, J = 10.4, 3.4 Hz, 1H), 3.50 (dd, J=10.3, 8.6Hz, 1H), 3.03 (brs, 1H), 2.37 (brs, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ141.0, 139.7, 127.2, 126.1, 73.5, 64.7, 39.9. HRMS (ESI) Calcd for [C ₉ H ₁₁ BrNaO ₂ ,M+Na] ⁺ : 252.9835, Found: 252.9842.

Example 12 Synthesis of 2-bromo-1-(4-(phthalimide-methyl)-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add p-(phthalimide-methyl)styrene 132mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(4- (phthalimido-methyl)-phenyl)-ethanol 132 mg, yield 73%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.83 (dd, J=5.4, 3.1Hz, 2H), 7.70 (dd, J=5.5, 3.0Hz, 2H), 7.43 (d, J=8.2Hz, 2H) ,7.33(d,J=8.1Hz,2H),4.88(dd,J=8.8,3.4Hz,1H),4.83(s,2H),3.58(dd,J=10.5,3.4Hz,1H),3.48( dd, J=10.5, 8.8Hz, 1H), 2.75 (brs, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ168.0, 140.0, 136.5, 134.0, 132.0, 128.9, 126.3, 123.3, 73.4, 41.2, 39.9. HRMS (ESI) Calcd for [C ₁₇ H ₁₄ BrNNaO ₃ ,M+Na] ⁺ : 382.0049, Found: 382.0053.

Example 13 Synthesis of 2-bromo-1-(1-naphthyl)-ethanol

Take a 25 mL Schlenk reaction tube, add 77 mg of 1-naphthalene ethylene, 101 mg of 48% hydrobromic acid aqueous solution, and 2 mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-(1- Naphthyl)-ethanol 100 mg, yield 80%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.96(d, J=8.3Hz, 1H), 7.89–7.86(m, 1H), 7.81(d, J=8.2Hz, 1H), 7.73(d, J= 7.2Hz, 1H), 7.56–7.46(m, 3H), 5.68(dd, J=9.4, 2.3Hz, 1H), 3.82(dd, J=10.7, 2.7Hz, 1H), 3.61(dd, J=10.7 ,9.4Hz,1H),2.86(s,1H); ¹³ C NMR(100MHz,CDCl ₃ )δ135.7,133.7,130.0,129.1,128.9,126.5,125.7,125.5,123.5,122.3,71.0,39.7.HRMS(ESI ) Calcd for [C ₁₂ H ₁₁ BrONa,M+Na] ⁺ : 272.9886, Found: 272.9896.

Example 14 Synthesis of 2-bromo-1-benzothienyl-ethanol

Take a 25mL Schlenk reaction tube, add 80mg of benzothienylethylene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction, add 15 mL of ethyl acetate to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate three times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-benzothiophene Base-ethanol 100mg, yield 78%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.81(d, J=7.3Hz, 1H), 7.74–7.71(m, 1H), 7.37–7.30(m, 2H), 7.25(s, 1H), 5.22( dt,J=7.8,3.9Hz,1H),3.75(dd,J=10.5,3.8Hz,1H),3.68(dd,J=10.5,8.0Hz,1H),2.93(d,J=4.3Hz,1H ); ¹³ C NMR (101MHz, CDCl ₃ ) δ144.2, 139.2, 124.6, 124.5, 123.7, 122.5, 121.3, 70.3, 39.1. HRMS (ESI) Calcdfor[C ₁₀ H ₉ BrNaOS, M+Na] ⁺ :278.9450, Found :278.9447.

Example 15 Synthesis of 2-bromo-1-benzofuryl-ethanol

Take a 25mL Schlenk reaction tube, add 72mg of benzofurylethylene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction, add 15 mL of ethyl acetate to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate three times, combine the organic phases, and separate by column chromatography to obtain 2-bromo-1-benzofuran Base-ethanol 98mg, yield 81%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.54(d, J=7.5Hz, 1H), 7.44(d, J=8.1Hz, 1H), 7.27(t, J=7.4Hz, 1H), 7.22(dd ,J=9.0,5.7Hz,1H),6.72(s,1H),5.05(dd,J=10.8,5.6Hz,1H),3.81(dd,J=10.5,4.4Hz,1H),3.75(dd, J=10.5,6.8Hz,1H),2.98(d,J=5.8Hz,1H); ¹³ CNMR(100MHz,CDCl ₃ )δ155.4,154.7,127.7,124.5,123.0,121.2,111.2,104.2,68.0,36.3. HRMS (ESI) Calcd for [C ₁₀ H ₉ BrNaO ₂ ,M+Na] ⁺ : 262.9678, Found: 262.9678.

Example 16 Synthesis of 1-bromo-2-phenyl-2-propanol

Take a 25mL Schlenk reaction tube, add 59mg of methyl styrene, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-bromo-2-phenyl- 2-propanol 45 mg, yield 42%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.47–7.45(m,2H),7.37(t,J=7.6Hz,2H),7.31–7.27(m,1H),3.76(d,J=10.6Hz, 1H), 3.70(d, J=10.6Hz, 1H), 2.59(s, 1H), 1.67(s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ144.1, 128.4, 127.5, 124.8, 73.1, 46.3, 28.0.

Example 17 Synthesis of 2-bromo-1-phenyl-1-propanol

Take a 25mL Schlenk reaction tube, add 59mg of methyl styrene, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-phenyl- 1-propanol 68 mg, yield 63%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.36–7.29(m, 5H), 4.99(t, J=3.4Hz, 1H), 4.41(qd, J=6.8, 3.6Hz, 1H), 2.57(d, J=3.3Hz, 1H), 1.54 (t, J=6.7Hz, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 139.5, 128.3, 128.0, 126.3, 77.2, 56.1, 18.8.

Example 18 Synthesis of 2-bromo-1-phenyl-1-heptanol

Take a 25mL Schlenk reaction tube, add 87mg of phenylheptene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-phenyl- 1-heptanol 68 mg, yield 50%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.38–7.28 (m, 5H), 5.01 (t, J=3.7Hz, 1H), 4.33–4.28 (m, 1H), 2.57 (d, J=3.5Hz, 1H),1.80–1.54(m,3H),1.32–1.13(m,5H),0.84(t,J＝7.2Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ139.9,128.5,128.3,128.0, 126.5, 77.2, 63.7, 31.5, 31.0, 27.5, 22.4, 13.9. HRMS (ESI) Calcd for [C ₁₃ H ₁₉ BrONa, M+Na] ⁺ : 293.0512, Found: 293.0517.

Example 19 Synthesis of 2-bromo-1-phenyl-1,3-propanediol

Take a 25mL Schlenk reaction tube, add 67mg of cinnamyl alcohol, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-bromo-1-phenyl- 1,3-propanediol 61 mg, yield 53%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.37–7.30 (m, 5H), 5.01 (dd, J=6.1, 4.0Hz, 1H), 4.26 (dd, J=10.9, 4.9Hz, 1H), 3.99 ( dt, J＝11.4, 5.6Hz, 1H), 3.88–3.82(m, 1H), 3.40(d, J＝4.1Hz, 1H), 2.83(t, J＝6.4Hz, 1H); ¹³ C NMR (100MHz , CDCl ₃ ) δ140.2, 128.5, 128.4, 126.5, 76.8, 64.1, 59.4.

Example 20 Synthesis of trans-2-bromo-1-indanol

Take a 25mL Schlenk reaction tube, add indene 58mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain trans-2-bromo-1- Indenol 74mg, yield 69%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.45–7.39(m,1H),7.32–7.21(m,3H),5.30(d,J=3.8Hz,1H),4.26(dd,J=13.2,7.3 Hz, 1H), 3.56(dd, J＝16.2, 7.2Hz, 1H), 3.21(dd, J＝16.2, 7.4Hz, 1H), 2.56(s, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ141 .6, 139.7, 129.0, 127.6, 124.5, 124.1, 83.4, 54.5, 40.4, 40.2.

Example 21 Synthesis of trans-2-bromo-1,2,3,4-tetrahydro-1-naphthol

Take a 25mL Schlenk reaction tube, add 65mg of dihydronaphthalene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Add 15 mL of ethyl acetate after the reaction to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain trans-2-bromo-1, 2,3,4-tetrahydro-1-naphthol 92 mg, yield 81%.

¹ H NMR (400MHz, CDCl ₃ )δ7.51–7.49(m,1H),7.26–7.21(m,2H),7.11–7.09(m,1H),4.88(d,J=6.7Hz,1H), 4.34(ddd,J=9.8,7.0,3.2Hz,1H),3.00–2.86(m,2H),2.64(s,1H),2.53–2.46(m,1H),2.31–2.21(m,1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 135.4, 134.9, 128.5, 128.3, 128.0, 126.6, 74.0, 56.1, 29.6, 28.0.

Example 22 Synthesis of trans-2-bromo-benzocycloheptanol

Take a 25mL Schlenk reaction tube, add 72mg of benzocycloheptene, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain trans-2-bromo-benzo Cycloheptanol 72 mg, yield 60%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.53(d, J=3.8Hz, 1H), 7.25–7.18(m, 2H), 7.11–7.09(m, 1H), 4.96(d, J=8.3Hz, 1H),4.37–4.34(m,1H),2.94–2.89(m,1H),2.79–2.72(m,1H),2.69(s,1H),2.51–2.45(m,1H),2.25–2.16( m,1H),2.00–1.91(m,1H),1.61–1.54(m,1H); ¹³ C NMR(100MHz,CDCl ₃ )δ140.2,138.3,129.3,128.1,127.0,126.3,76.3,60.4,36.6, 33.9, 24.5. HRMS (ESI) Calcd for [C ₁₁ H ₁₃ BrONa,M+Na] ⁺ : 263.0042, Found: 263.0040.

Example 23 Synthesis of trans-3-bromo-4-hydroxychroman

Take a 25mL Schlenk reaction tube, add 66mg of 2-H-chromene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain trans-3-bromo-4- Hydroxychroman 97mg, yield 85%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.37(d, J=7.7Hz, 1H), 7.28–7.24(m, 1H), 7.00(td, J=7.6, 1.0Hz, 1H), 6.89(dd, J＝8.3Hz, 0.4Hz, 1H), 4.89(t, J＝4.6Hz, 1H), 4.52–4.47(m, 1H), 4.32–4.27(m, 2H), 2.52(d, J＝4.8Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ153.1, 130.2, 129.3, 121.6, 121.3, 116.9, 69.8, 66.2, 48.1. HRMS (ESI) Calcd for [C ₉ H ₉ BrNaO ₂ , M+Na] ⁺ : 250.9678, Found: 250.9674.

Example 24 Synthesis of 3-(bromoethanol)-estrone

Take a 25mL Schlenk reaction tube, add vinylestrone 140mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 3 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 142 mg of 3-bromoethanol-estrone. Yield 75%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.30(d, J=8.2Hz, 1H), 7.15(d, J=8.2Hz, 1H), 7.13(s, 1H), 4.87(d, J=8.8Hz ,1H),3.63(dd,J=10.4,3.2Hz,1H),3.54(dd,J=10.0,9.2Hz,1H),2.93(dd,J=8.4,4.4Hz,1H),2.69(s, 1H), 2.54–2.41(m,2H), 2.29–2.26(m,1H), 2.19–1.95(m,4H), 1.68–1.42(m,6H), 0.91(s,3H); ¹³ C NMR ( 100MHz, CDCl ₃ )δ220.8,140.1,137.8,136.9,126.50(126.48),125.7,123.39(123.37),73.6(73.5),50.4,47.9,44.3,40.1,38.0,35.8,31.5,29.358)(29 , 25.6, 21.5, 13.8. HRMS (ESI) Calcd for [C ₂₀ H ₂₆ BrO ₂ ,M+H] ⁺ : 377.1111, Found: 377.1112.

Example 25 Synthesis of 3-bromoethanol-vitamin E

Take a 25mL Schlenk reaction tube, add 206mg of vinyl vitamin E, 101mg of 48% hydrobromic acid aqueous solution, 2mL of dimethyl sulfoxide, and stir at 60°C for 5 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 172 mg of 3-bromoethanol-estrone. Yield 86%.

¹ H NMR (400MHz, CDCl ₃ )δ6.95(s,1H),6.92(s,1H),4.79(dd,J=9.1,3.3Hz,1H),3.60(dd,J=10.4,3.5Hz, 1H), 3.54(dd, J＝10.4, 8.8Hz, 1H), 2.75(t, J＝7.1Hz, 2H), 2.55(brs, 1H), 2.17(s, 2H), 1.82–1.73(m, 2H ),1.60–1.04(m,24H),0.89–0.84(m,12H); ¹³ C NMR(100MHz,CDCl ₃ )δ152.4,130.3,126.6,126.00(125.98),124.57(124.53),120.6,73.9,40.4 ,40.2,40.1,39.4,37.43,37.41,32.8,32.7,31.1,28.0,24.8,24.3,24.2,22.7,22.6,22.3,21.0,19.7,19.6,16.1. HRMS(ESI) Calcd for [C ₂₉ H ₄₉ BrNaO ₂ , M+Na] ⁺ :531.2808, Found: 531.2817.

Example 26 Synthesis of 2-iodo-1-(2-naphthyl)-ethanol

Take a 25mL Schlenk reaction tube, add 77mg of naphthalene ethylene, 90mg of sodium iodide, 100mg of concentrated sulfuric acid, 1mL of dimethyl sulfoxide and 1mL of 1,2-dichloroethane, and stir at 60°C for 10 hours. After the reaction, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 2-iodo-1-(2- Naphthyl)-ethanol 100 mg, yield 67%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.84–7.82 (m, 4H), 7.50–7.43 (m, 3H), 4.98 (dd, J=8.6, 3.6Hz, 1H), 3.56 (dd, J=10.4 ,3.6Hz,1H),3.47(dd,J＝10.4,8.6Hz,1H),2.64(brs,1H); ¹³ CNMR(100MHz,CDCl ₃ )δ138.4,133.2,133.1,128.6,128.0,127.8,126.4, 126.2, 124.9, 123.4, 74.1, 15.2.

Example 27 Synthesis of 2-iodo-1-(4-methoxy-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add 67mg of p-methoxystyrene, 90mg of sodium iodide, 100mg of concentrated sulfuric acid, 1mL of dimethyl sulfoxide and 1mL of 1,2-dichloroethane, and stir at 60°C for 10 hours. After the reaction, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-iodo-1-(4- Methoxy-phenyl)-ethanol 103 mg, yield 74%.

¹ H NMR (400MHz, CDCl ₃ )δ7.30–7.23(m,2H),6.92–6.83(m,2H),4.76(dd,J＝8.6,3.9Hz,1H),3.79(s,3H), 3.42 (dd, J=10.2, 3.9Hz, 1H), 3.36 (dd, J=10.3, 8.6Hz, 1H); ¹³ CNMR (100MHz, CDCl ₃ ) δ 159.4, 133.2, 126.9, 113.9, 73.6, 55.2, 15.4.

Example 28 Synthesis of 2-iodo-1-(4-bromo-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add p-bromostyrene 92mg, sodium iodide 90mg, concentrated sulfuric acid 100mg, dimethyl sulfoxide 1mL and 1,2-dichloroethane 1mL, and stir at 60°C for 10 hours. After the reaction, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 2-iodo-1-(4- Bromo-phenyl)-ethanol 121 mg, yield 74%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.52–7.45 (m, 2H), 7.30–7.21 (m, 2H), 4.77 (dd, J=8.5, 3.7Hz, 1H), 3.45 (dd, J=10.3 , 3.7Hz, 1H), 3.34 (dd, J=10.3, 8.5Hz, 1H), 2.59 (s, 1H); ¹³ CNMR (100MHz, CDCl ₃ ) δ 140.0, 131.7, 127.4, 122.2, 73.2, 14.9.

Example 29 Synthesis of 2-iodo-1-phenyl-ethanol

Take a 25mL Schlenk reaction tube, add 52mg of styrene, 90mg of sodium iodide, 100mg of concentrated sulfuric acid, 1mL of dimethyl sulfoxide and 1mL of 1,2-dichloroethane, and stir at 60°C for 10 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 2-iodo-1-phenyl- Ethanol 91 mg, yield 73%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.34(s, 3H), 7.40–7.26(m, 2H), 4.79(dt, J=8.8, 3.1Hz, 1H), 3.45(dd, J=10.3, 3.7 Hz, 1H), 3.36 (dd, J=10.3, 8.7Hz, 1H), 2.68 (d, J=3.1Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ141.1, 128.6, 128.3, 125.7, 73.9, 15.2.

Example 30 Synthesis of 1-iodo-2-phenyl-2-propanol

Take a 25mL Schlenk reaction tube, add 59mg of methylstyrene, 90mg of sodium iodide, 100mg of concentrated sulfuric acid, 1mL of dimethyl sulfoxide and 1mL of 1,2-dichloroethane, and stir at 60°C for 10 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-iodo-2-phenyl- 2-propanol 88mg, yield 67%.

¹ H NMR (400MHz, CDCl ₃ )δ7.49–7.40(m,2H),7.31(m,3H),3.67–3.56(m,2H),2.40(s,1H),1.71(s,3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.1, 128.3, 127.4, 124.6, 72.6, 28.9, 24.2.

Example 31 Synthesis of 1-iodo-4-phenyl-2-butanol

Take a 25mL Schlenk reaction tube, add 66mg of 1-phenylbutene, 90mg of sodium iodide, 100mg of concentrated sulfuric acid, 1mL of dimethyl sulfoxide and 1mL of 1,2-dichloroethane, and stir at 60°C for 10 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-iodo-4-phenyl- 2-butanol 98 mg, yield 71%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.28(t, J=7.5Hz, 2H), 7.19(d, J=2.6Hz, 3H), 3.52(dq, J=11.8, 6.4Hz, 1H), 3.35 (dd, J=10.2,3.6Hz,1H),3.23(dd,J=10.2,6.7Hz,1H),2.79(dt,J=14.7,7.4Hz,1H),2.69(dt,J=13.7,8.0 Hz, 1H), 2.15 (s, 1H), 1.93–1.82 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 141.2, 128.4, 128.3, 126.0, 70.1, 38.1, 31.8, 16.4.

Example 32 Synthesis of 1-iodo-2-octanol

Take a 25mL Schlenk reaction tube, add 56mg of 1-octene, 90mg of sodium iodide, 100mg of concentrated sulfuric acid, 1mL of dimethyl sulfoxide and 1mL of 1,2-dichloroethane, and stir at 60°C for 10 hours. After the reaction, add 15 mL of ethyl acetate to quench the reaction, add 5 mL of brine to wash, separate the organic phase, extract the water phase with ethyl acetate three times, combine the organic phases, and separate by column chromatography to obtain 59 mg of 1-iodo-2-octanol , yield 46%.

¹ H NMR (400MHz, CDCl ₃ ) δ3.52 (dq, J=7.4, 4.3Hz, 1H), 3.39 (dd, J=10.1, 3.5Hz, 1H), 3.24 (dd, J=10.2, 6.8Hz, 1H), 2.08(d, J＝4.3Hz, 1H), 1.55(td, J＝7.5, 6.9Hz, 2H), 1.49–1.29(m, 8H), 0.95–0.84(m, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 70.9, 36.6, 31.6, 29.1, 25.6, 22.5, 16.8, 14.0.

Example 33 Synthesis of 2-iodo-cyclohexanol

Take a 25mL Schlenk reaction tube, add cyclohexene 41mg, sodium iodide 90mg, concentrated sulfuric acid 100mg, dimethyl sulfoxide 1mL and 1,2-dichloroethane 1mL, and stir at 60°C for 10 hours. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, and 5 mL of brine was added for washing. The organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 26 mg of 2-iodo-cyclohexanol. Yield 23%.

¹ H NMR (400MHz, CDCl ₃ ) δ4.04 (ddd, J = 12.3, 9.7, 4.3 Hz, 1H), 3.66 (td, J = 10.0, 4.4 Hz, 1H), 2.48 (dqd, J = 13.4, 3.6 ,1.9Hz,1H),2.38(s,1H),2.17–2.07(m,1H),2.11–1.97(m,1H),1.85(ddt,J＝12.3,5.3,3.1Hz,1H),1.59– 1.18 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 75.9, 43.4, 38.6, 33.6, 27.9, 24.4.

Example 34 Synthesis of 2-azido-1-(4-methyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add p-methylstyrene 59mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. Then 65 mg of sodium azide was added, and the reaction was continued for 12 hours. Add 15 mL of ethyl acetate to quench the reaction after the reaction is over, add 5 mL of brine to wash, separate the organic phase, and extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-azido-1-( 4-methyl-phenyl)-ethanol 68 mg, yield 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.22 (d, J=8.0Hz, 2H), 7.16 (d, J=8.0Hz, 2H), 4.78 (dd, J=8.1, 3.9Hz, 1H), 3.42 (dd, J = 12.6, 8.2Hz, 1H), 3.35 (dd, J = 12.6, 3.9Hz, 1H), 2.62 (brs, 1H), 2.34 (s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ138.0, 137.6, 129.3, 125.8, 73.1, 57.9, 21.0.

Example 35 Synthesis of 2-azido-1-(2-naphthyl)-ethanol

Take a 25mL Schlenk reaction tube, add 77mg of p-2-naphthaleneethylene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Then 65 mg of sodium azide was added, and the reaction was continued for 12 hours. Add 15 mL of ethyl acetate to quench the reaction after the reaction is over, add 5 mL of brine to wash, separate the organic phase, and extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-azido-1-( 2-naphthyl)-ethanol 79 mg, yield 74%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.87–7.83 (m, 4H), 7.52–7.45 (m, 3H), 5.05 (dd, J=7.8, 4.1Hz, 1H), 3.57 (dd, J=12.4 ,8.0Hz,1H),3.52(dd,J＝12.4,4.8Hz,1H),2.48(s,1H); ¹³ CNMR(100MHz,CDCl ₃ )δ137.8,133.2,133.1,128.5,127.9,127.7,126.4, 126.2, 124.9, 123.5, 73.5, 57.9.

Example 36 Synthesis of 2-azido-1-(4-phenyl-phenyl)-ethanol

Take a 25mL Schlenk reaction tube, add 90mg of p-4-phenyl-styrene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Then 65 mg of sodium azide was added, and the reaction was continued for 12 hours. Add 15 mL of ethyl acetate to quench the reaction after the reaction is over, add 5 mL of brine to wash, separate the organic phase, and extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-azido-1-( 4-phenyl-phenyl)-ethanol 96 mg, yield 80%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.61–7.57(m,4H),7.46–7.42(m,4H),7.38–7.33(m,1H),4.91(dt,J＝7.5,3.6Hz,1H ), 3.52 (dd, J=12.6, 7.9Hz, 1H), 3.47 (dd, J=12.6, 4.1Hz, 1H), 2.45 (d, J=3.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 141.3, 140.5, 139.5, 128.8, 127.5, 127.4, 127.1, 126.3, 73.2, 58.0.

Example 37 Synthesis of 2-azido-1-(1-naphthyl)-ethanol

Take a 25mL Schlenk reaction tube, add 77mg of p-1-naphthaleneethylene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Then 65 mg of sodium azide was added, and the reaction was continued for 12 hours. Add 15 mL of ethyl acetate to quench the reaction after the reaction is over, add 5 mL of brine to wash, separate the organic phase, and extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases, and separate by column chromatography to obtain 2-azido-1-( 1-naphthyl)-ethanol 79 mg, yield 74%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.90–7.87(m,1H),7.83–7.80(m,1H),7.75(d,J=8.2Hz,1H),7.62(d,J=7.1Hz, 1H), 7.49–7.39(m,3H), 5.54–5.51(m,1H), 3.51–3.44(m,2H), 2.82(d, J=3.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 135.9, 133.6, 129.9, 129.0, 128.6, 126.4, 125.7, 125.3, 123.4, 122.2, 70.3, 57.2.

Example 38 Synthesis of 1-(4-methyl-phenyl)-oxirane

Take a 25mL Schlenk reaction tube, add p-methylstyrene 59mg, 48% hydrobromic acid aqueous solution 101mg, dimethyl sulfoxide 2mL, and stir at 60°C for 12 hours. Then, under cooling with ice water, 1 mL of tetrahydrofuran was added, and 0.5 mL of 10% aqueous sodium hydroxide solution was added dropwise, and the reaction was continued for 0.5 hours after the addition was completed. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-(4-methyl-benzene Base)-oxirane 54mg, yield 80%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.18–7.12 (m, 4H), 3.82 (dd, J=3.9, 2.7Hz, 1H), 3.11 (dd, J=5.4, 4.1Hz, 1H), 2.78( dd, J=5.5, 2.6 Hz, 1H), 2.33 (s, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.9, 134.5, 129.1, 125.4, 52.3, 51.0, 21.1.

Example 39 Synthesis of 1-(2-naphthyl)-oxirane

Take a 25mL Schlenk reaction tube, add 77mg of 2-naphthylethene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Then, under cooling with ice water, 1 mL of tetrahydrofuran was added, and 0.5 mL of 10% aqueous sodium hydroxide solution was added dropwise, and the reaction was continued for 0.5 hours after the addition was completed. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-(2-naphthyl)- Ethylene oxide 65mg, yield 76%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.84–7.80 (m, 4H), 7.51–7.45 (m, 2H), 7.32 (dd, J=8.5, 1.7Hz, 1H), 4.03 (dd, J=3.9 ,2.6Hz,1H),3.22(dd,J=5.4,4.1Hz,1H),2.90(dd,J=5.4,2.6Hz,1H); ¹³ C NMR(100MHz,CDCl ₃ )δ135.0,133.2,133.1, 128.3, 127.7, 126.3, 126.0, 125.1, 122.6, 52.5, 51.2.

Example 40 Synthesis of 1-(4-phenyl-phenyl)-oxirane

Take a 25mL Schlenk reaction tube, add 90mg of 4-phenyl-styrene, 101mg of 48% hydrobromic acid aqueous solution, and 2mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Then, under cooling with ice water, 1 mL of tetrahydrofuran was added, and 0.5 mL of 10% aqueous sodium hydroxide solution was added dropwise, and the reaction was continued for 0.5 hours after the addition was complete. After the reaction, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-(4-phenyl-benzene Base)-oxirane 82mg, yield 84%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.58–7.56 (m, 4H), 7.44–7.41 (m, 2H), 7.35–7.31 (m, 3H), 3.89 (dd, J＝3.9, 2.6Hz, 1H ),3.16(dd,J＝5.4,4.1Hz,1H),2.83(dd,J＝5.4,2.6Hz,1H); ¹³ CNMR(100MHz,CDCl ₃ )δ141.1,140.6,136.6,128.7,127.4,127.2, 127.0, 125.9, 52.2, 51.2.

Example 41 Synthesis of 1-(1-naphthyl)-oxirane

Take a 25 mL Schlenk reaction tube, add 77 mg of 1-naphthalene ethylene, 101 mg of 48% hydrobromic acid aqueous solution, and 2 mL of dimethyl sulfoxide, and stir at 60°C for 12 hours. Then, under cooling with ice water, 1 mL of tetrahydrofuran was added, and 0.5 mL of 10% aqueous sodium hydroxide solution was added dropwise, and the reaction was continued for 0.5 hours after the addition was completed. After the reaction was completed, 15 mL of ethyl acetate was added to quench the reaction, washed with 5 mL of brine, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and separated by column chromatography to obtain 1-(2-naphthyl)- Ethylene oxide 67mg, yield 78%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.11 (dd, J=8.0, 0.9Hz, 1H), 7.87–7.84 (m, 1H), 7.77 (d, J=8.0Hz, 1H), 7.55–7.40 ( m, 4H), 4.46–4.45 (m, 1H), 3.25 (dd, J=5.8, 4.1Hz, 1H), 2.77 (dd, J=5.8, 2.7Hz, 1H); ¹³ C NMR (101MHz, CDCl ₃ ) δ 133.6, 133.2, 131.4, 128.7, 128.1, 126.3, 125.8, 125.5, 122.8, 122.2, 50.7, 50.6.

Claims (9)

1. a kind of synthetic method of halohydrin, it is characterised in that：In organic solvent by the olefin(e) compound shown in Formulas I and halogenation The mixing of thing, sulfoxide and additive, is obtained the halohydrin shown in Formula II by the hydroxyl halogenation of alkene,

Wherein R¹、R²、R³、R⁴The one kind being respectively selected from the constituted group of following group：(1) hydrogen；(2)C_1-6Alkane Base, C_1-3Hydroxyalkyl；(3) phenyl, naphthyl, xenyl, benzothienyl, benzofuranyl；(3) Jing straight chains/side chain C_1-4Alkane Base, hydroxyalkyl C_1-3、C_1-3The phenyl that alkoxy or halogen replaces；(4) And (5) R¹With R²、R¹With R³、R²With R⁴、R³With R⁴Combine It is collectively forming indanyl, tetrahydrochysene -1- naphthyls, benzo ring heptyl, Chromanyl or cyclohexyl；

R⁵And R⁶It is methyl；

MX is hydrogen bromide or sodium iodide；

The additive is sulphuric acid or hydrobromic acid；

The organic solvent is dimethyl sulfoxide.

2. the synthetic method according to right 1, it is characterised in that：R¹、R²、R³And R⁴It is respectively selected from hydrogen, methyl, n-pentyl, just Hexyl, methylol, 1- phenyl, 2- phenyl, 1- naphthyls, 2- naphthyls, p-methylphenyl, an aminomethyl phenyl, o-methyl-phenyl-, benzene second Base, to tert-butyl-phenyl, p-bromophenyl, to iodophenyl, to hydroxymethyl phenyl, p-methoxyphenyl, xenyl, benzothiophene Base, benzofuranyl, Or R¹With R²、R¹With R³、R²With R⁴、R³With R⁴Combine and be collectively forming indanyl, tetrahydrochysene -1- naphthyls, benzo ring heptyl, chromane Base or cyclohexyl.

3. synthetic method according to claim 1, it is characterised in that：The reaction temperature is 0~150 DEG C.

4. synthetic method according to claim 1, it is characterised in that：The reaction temperature is 60 DEG C.

5. synthetic method according to claim 1, it is characterised in that：Olefin(e) compound (I) with the mol ratio of halogenide is 1:1~1:50；Olefin(e) compound (I) is 1 with the mol ratio of sulfoxide:0.5~1:1000.

6. synthetic method according to claim 1, it is characterised in that：Olefin(e) compound (I) with the mol ratio of halogenide is 1:1.2；Olefin(e) compound (I) is 1 with the mol ratio of sulfoxide:56.

7. synthetic method according to claim 1, it is characterised in that：Olefin(e) compound (I) with the mol ratio of additive is 1:0.5~1:50.

8. synthetic method according to claim 1, it is characterised in that：Olefin(e) compound (I) with the mol ratio of additive is 1:1.2。

9. the synthetic method of a kind of hydroxyl azido compound (III) and epoxide (IV), it is characterised in that：Will according to right Ask the synthetic method described in any one of 1-8 that halohydrin is obtained, the halohydrin is converted into hydroxyl azido compound through one kettle way And epoxide (IV) (III)：