A preparation method of o-dibromide or allyl dibromide

Abstract

The present invention discloses a method for preparing an ortho-dibromide or an allyl dibromide. The method uses a conjugated diene as a raw material and, through substrate induction, a double bromination addition reaction to achieve the preparation of the ortho-dibromide or the allyl dibromide. Ortho-dibromides or allyl bromides are widely present in many natural products and drug molecules and are often used as intermediates in synthetic processes in many fields.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of ortho-dihalides or allyl halides in the direction of organic synthesis, and particularly relates to a preparation method of ortho-dibromide or allyl dibromide. Background Art

[0002] Organic compounds containing bromine atoms are abundant in pharmaceuticals and natural products. They are not only chemical raw materials but are also often used as important synthons in the synthesis of drug intermediates (Butler, A.; Walker, JV Chem. Rev., 1993, 93, 1937). Many bromine-containing natural products have pharmacological value, and such natural products often contain ortho-dibromide or allylic bromide fragments (Burreson, BJ; Woolard, FX; Moore, RE Chem. Lett., 1975, 4, 1111-1114). Due to the lack of methods for the selective dibromination of conjugated olefins, the synthesis of ortho-dibromides or allylic bromides still relies on multistep pathways. Therefore, the development of a method for the efficient and selective formation of ortho-dibromides or allylic bromides has become a focus of chemists.

[0003] Common natural products containing o-dibromide or allyl bromide are as follows:

[0004]

[0005] The dibromination of 1,3-dienes is an attractive and efficient one-step route to rapidly construct ortho-dibromides or allylic bromides. However, dibromination can occur at multiple different sites on the 1,3-dienes, resulting in poor selectivity, numerous byproducts, and low yields of ortho-dibromides or allylic bromides (Chiappe, C.; Capraro, D.; Conte, V.; Pieraccini, D. Org. Lett., 2001, 3, 1061).

[0006] The selectivity of the dibromination of 1,3-dienes is as follows:

[0007]

[0008] Chemists have developed methods for preparing ortho-dibromides or allylic bromides via the dibromination of 1,3-dienes. While these methods generally offer good selectivity, they are often demanding, have poor substrate compatibility, and often require the pre-synthesis of starting materials substituted with various electron-withdrawing groups (Kobelevskaya, VA; Popov, AV; Zinchenko, SV; Rulev, AY Eur. J. Org. Chem., 2020, 5544-5550), leading to cumbersome synthesis steps.

[0009] In addition, chemists have also developed methods to synthesize allyl bromides through substitution (Singh, K.; Staig, SJ; Weaver, JD J Am. Chem. Soc., 2014, 136, 5275-5278.) and elimination reactions (Zhang, H.; Collins, J.; Nyamwihura, R.; Ware, S.; Kaiser, M.; Ogungbe, IV, Bioorg. Med. Chem. Lett. 2018, 28, 1647-1651.). However, it is impossible to obtain ortho-dibromide or allyl dibromide at the same time; and the substrates are relatively limited, and by-products are often generated.

[0010] Therefore, it is very necessary to develop a simple and efficient method to dibrominate different 1,3-dienes to obtain various o-dibromides or allylic bromides with regioselectivity. Summary of the Invention

[0011] The present invention addresses the problems of the prior art and provides a method for preparing an ortho-dibromide or an allyl dibromide. The present invention uses a conjugated diene as a raw material and, through substrate induction, a double bromination addition reaction to prepare the ortho-dibromide or the allyl dibromide, thereby overcoming the above-mentioned shortcomings of the prior art.

[0012] The preparation method of the ortho-dibromide or allyl dibromide of the present invention adopts a one-step method to obtain the target product, which specifically comprises the following steps:

[0013] Take a dry and clean 15mL sealed tube, add a magnetic rod of appropriate size, add the corresponding 1,3-diene (0.2mmol, 1.0equiv), add an organic solvent (1mL) at room temperature, and then add TMSBr solution (0.3mmol, 1.0M dissolved in CH2Cl2) and NBS (0.3mmol, 0.5M dissolved in THF) solution dropwise in sequence. The reaction mixture is stirred at room temperature for ten seconds; then, 4mL of saturated Na2S2O3 aqueous solution is immediately added to quench the reaction mixture, dilute with an appropriate amount of water, extract with CH2Cl2, and dry the obtained organic layer with an appropriate amount of anhydrous Na2SO4 and concentrate under reduced pressure. Purify our crude product using preparative high performance liquid chromatography to obtain the target product o-dibromide or allyl dibromide.

[0014] The reaction route is as follows:

[0015]

[0016] Wherein the substituent R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from alkyl, phenyl or bromine atoms. The alkyl group includes alkyl and substituted alkyl groups, the phenyl group includes phenyl and substituted phenyl groups, and the substituents may be substituents containing halogen, Si, S, N and other elements, such as OTBS, OTf, OTs and the like.

[0017] The organic solvent is ultra-dry tetrahydrofuran.

[0018] The present invention presents a new substrate-induced strategy to dibrominate different 1,3-dienes to obtain various ortho-dibromides or allylic bromides, which are specifically related to the structure of the reaction substrate. 2 When it is phenyl or alkyl, it tends to generate 1,2-addition products; R 3 When the phenyl or alkyl group is present, 1,4-addition products are favored. Ortho-dibromides or allylic bromides are widely present in many natural products and pharmaceutical molecules and are often used as synthetic intermediates in various fields. Furthermore, a series of product transformation studies have been conducted to demonstrate their potential applications in organic synthesis. DETAILED DESCRIPTION

[0019] The first substrate synthesis route:

[0020]

[0021] Prepare a round-bottom flask of appropriate volume, add a magnetic particle of appropriate size, dry it, and add 1.2 equivalents of C 19 H 18 BrP (methyltriphenylphosphonium bromide), after evacuating the flask three times on the operating table, THF was added under the protection of N2, and then the flask was placed at 0°C and n-butyllithium (1.2 equiv) was added dropwise. The resulting suspension was continued to react at 0°C. After 30 minutes, the corresponding cinnamaldehyde (1.0 equiv) was added dropwise to the above solution. After 1 hour, the solution was allowed to react at room temperature. During the reaction, a TLC plate was continuously used to monitor whether the reaction was complete. After the reaction was completed, the resulting mixed solution was returned to room temperature, extracted, dried, concentrated, and purified by column chromatography to obtain the corresponding conjugated diene substrate.

[0022] The second substrate synthesis route:

[0023]

[0024] Method a) (R = aryl): First, prepare a dry flask. After evacuating the flask three times on the bench, slowly add 3-S0 (1.0 equiv) and ultra-dry THF (0.2 M) under magnetic stirring and argon protection. The flask is then placed at -78°C and KHMDS (1.3 equiv, 1.0 M in THF) or LiHMDS (1.3 equiv, 1.0 M in THF) is slowly added dropwise. After the addition is completed, stirring is continued for 30 minutes. Then, diphenyl chlorophosphate (1.5 equiv) is slowly added dropwise. The resulting mixed solution is stirred at -78°C for 2 hours. After the reaction is completed, the solution is allowed to return to room temperature and quenched with an appropriate amount of water. The resulting solution is extracted, dried, and concentrated under reduced pressure to obtain the desired crude product. The crude product is then purified to obtain 3-S1.

[0025] Method b) (R = alkyl): First, prepare a dry flask. After evacuating the laboratory bench three times, slowly add 3-S0 (1.0 equiv) and ultra-dry THF (0.2 M) under magnetic stirring and argon protection. The flask is then placed at -78°C and LDA (1.1 equiv, 2.0 M in THF) is slowly added dropwise. After the addition is completed, stirring is continued for 30 minutes. Then, diphenyl chlorophosphate (1.5 equiv) is slowly added dropwise. The resulting mixed solution is stirred and reacted for one hour. After the reaction is completed, the reaction solution is allowed to return to room temperature and quenched with water. The resulting solution is extracted, dried, and concentrated under reduced pressure to obtain the desired crude product. The crude product is then purified to obtain 3-S1.

[0026] A dry round-bottom flask was prepared and the catalyst (dppe) NiCl2 (2.5 mol%) was first added. After three evacuations on the bench, ultra-dry THF (0.25 M) was slowly added under magnetic stirring and argon protection. The flask was placed in a 0°C ice-water bath, and C2H3BrMg (vinyl magnesium bromide) (1.05 equiv, 1.0 M in THF) was added dropwise. The resulting mixture was stirred and reacted at 0°C. The reaction was monitored using a TLC plate. After the reaction was completed, the solution was allowed to return to room temperature and quenched with an appropriate amount of ammonium chloride solution (saturated). The resulting solution was extracted, dried, and concentrated under reduced pressure to obtain the desired crude product, which was then purified by column chromatography to obtain the corresponding conjugated diene 3.

[0027] Example 1: (E)-(3,4-dibromobut-1-en-1-yl)benzene (2a)

[0028]

[0029] To a dry, clean 15 mL sealed tube, add a magnetic rod of appropriate size, 1a (0.2 mmol, 1.0 equiv), and ultra-dry THF (1 mL) at room temperature. TMSBr (0.3 mmol, 1.0 M in CHCl) and NBS (0.3 mmol, 0.5 M in THF) were then added dropwise. The reaction mixture was stirred at room temperature for ten seconds. The reaction mixture was immediately quenched with 4 mL of saturated aqueous NaSO, diluted with water, and extracted with CHCl. ​​The resulting organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield the desired product 2a as a light yellow oil in a 99% yield.

[0030] By nuclear magnetic resonance spectroscopy ( 1 HNMR) and carbon nuclear magnetic resonance spectroscopy ( 13 C NMR) chemical shift and fragmentation analysis of the light yellow oily liquid and high resolution mass spectrometry (HRMS) molecular weight determination confirmed that the light yellow oily liquid product obtained in the above reaction was 2a.

[0031] 1H NMR (400MHz, CDCl3) δ7.46–7.40(m,2H),7.38–7.28(m,3H),6.69(d,J=15.6Hz,1H),6.24(dd,J=15.6,9.7Hz ,1H),4.90(dddd,J=10.5,9.7,4.5,0.7Hz,1H),3.92(dd,J=10.2,4.5Hz,1H),3.76(dd,J=10.2,9.8Hz,1H).

[0032] 13 C NMR(101MHz, CDCl3)δ135.45,135.18,128.86,128.84,127.33,127.11,51.62,35.20.HRMS(ESI):m / z calculated for[C 10 H 10 Br2-Br] + :208.9966,found:208.9974.

[0033] Example 2: (E)-1-(3,4-dibromobut-1-en-1-yl)-4-methylbenzene (2b)

[0034]

[0035] 1b was used as the starting substrate to prepare the target product 2b in the same manner as in Example 1. The product was a yellow oily liquid with a yield of 88%.

[0036] 1 H NMR (400MHz, CDCl3) δ7.25–7.20(m,3H),7.14–7.20(m,1H),6.22(dd,J=15.6,9.7Hz,1H),4.89(dddd, J=10.5,9.7,4.5,0.7Hz,1H),3.92(dd,J=10.1,4.5Hz,1H),3.76(dd,J=10.1,9.8Hz,1H),2.35(s,3H).

[0037] 13 C NMR (101MHz, CDCl3) δ138.46,135.36,135.30,129.64,128.74,127.70,127.10,124.34,51.79,35.24,21.50.

[0038] HRMS(ESI):m / z calculated for[C11 H 12 Br-Br] + :223.0123,found:223.0131.

[0039] Example 3: (E)-1-bromo-4-(3,4-dibromobut-1-en-1-yl)benzene (2c)

[0040]

[0041] 1c was used as the starting substrate to prepare the target product 3c by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 75%.

[0042] 1 H NMR (400MHz, CDCl3) δ7.49–7.44(m,2H),7.29–7.25(m,2H),6.62(d,J=15.6Hz,1H),6.23(dd,J=15.6,9.6H z,1H),4.87(dddd,J=10.4,9.5,4.4,0.6Hz,1H),3.91(dd,J=10.2,4.5Hz,1H),3.74(dd,J=10.2,9.5,1H).

[0043] 13 C NMR(101MHz, CDCl3)δ134.36,133.90,132.00,128.56,128.05,122.77,51.05,34.99HRMS(ESI):m / z calculated for[C10H9Br3-Br] + :286.9071,found:286.9078.

[0044] Example 4: (E)-1-(3,4-dibromobut-1-en-1-yl)-4-fluorobenzene (2d)

[0045]

[0046] 1d was used as the starting substrate to prepare the target product 2d by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 99%.

[0047] 1H NMR (400MHz, CDCl3) δ7.50–7.30(m,2H),7.07–6.99(m,2H),6.65(d,J=15.6Hz,1H),6.16(ddd,J=15.7,9.7,0. 6Hz, 1H), 4.88 (dddd, J=10.5, 9.6, 4.5, 0.7Hz, 1H), 3.92 (dd, J=10.1, 4.5Hz, 1H), 3.75 (dd, J=10.1, 9.8Hz, 1H).

[0048] 13 C NMR (101MHz, CDCl3) δ 163.09 (d, J = 248.7Hz), 133.96, 131.63 (d, J = 3.5Hz), 128.76 (d, J = 8.3Hz), 127.12, 115.87 (d, J = 21.9Hz), 51.40, 35.14.

[0049] 19 FNMR (376MHz,CDCl3)δ-112.46.

[0050] HRMS(ESI):m / z calculated for[C 10 H9Br2F-Br] + :226.9872,found:226.9850.

[0051] Example 5: (E)-1-chloro-2-(3,4-dibromobut-1-en-1-yl)benzene (2e)

[0052]

[0053] 1e was used as the starting substrate to prepare the target product 2e by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 91%.

[0054] 1 H NMR (400MHz, CDCl3) δ7.61–7.53(m,1H),7.40–7.33(m,1H),7.28–7.20(m,2H),7.09(d,J=15.6Hz,1H), 6.23(dd,J=15.6,9.7Hz,1H),4.92(m,1H),3.92(dd,J=10.2,4.5Hz,1H),3.76(dd,J=10.2,10.0Hz,1H).

[0055] 13C NMR (101MHz, CDCl3) δ133.76,133.63,131.06,130.02,129.89,129.74,127.27,127.09,50.87,34.98.

[0056] HRMS(ESI):m / z calculated for[C 10 H9Br2Cl-Br] + :242.9577,found:242.9573.

[0057] Example 6: (E)-1-(3,4-dibromobut-1-en-1-yl)-3-fluorobenzene(2f)

[0058]

[0059] 1f was used as the starting substrate to prepare the target product 2f by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 86%.

[0060] 1 H NMR (400MHz, CDCl3) δ7.31(td,J=8.0,5.9Hz,1H),7.21–7.09(m,2H),6.99(tdd,J=8.4,2.6,1.0Hz,1H),6.65(d,J=15.6Hz,1H),6 .24(dd,J=15.6,9.6Hz,1H), 4.87(dddd,J=10.5,9.7,4.5,0.7Hz,1H), 3.92(dd,J=10.2,4.5Hz,1H), 3.75(dd,J=10.2,9.9Hz,1H).

[0061] 13 C NMR (101MHz, CDCl3) δ163.18 (d, J = 246.1Hz), 137.73 (d, J = 7.7Hz), 133.90 (d, J = 2.6Hz), 130.34 (d, J=8.4Hz), 128.68, 123.03 (d, J=2.7Hz), 115.66 (d, J=21.3Hz), 113.52 (d, J=22.0Hz), 50.78, 34.93.

[0062] 19 FNMR (376MHz,CDCl3)δ-112.64.

[0063] HRMS(ESI):m / z calculated for[C 10H9Br2F-Br] + :226.9872,found:226.9851.

[0064] Example 7: (E)-(3,4-dibromopent-1-en-1-yl)benzene (2 g)

[0065]

[0066] 1 g of the target product was prepared as the starting substrate using the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 80% (dr = 1:1).

[0067] 1 H NMR (400MHz, CDCl3) δ7.46–7.40(m,2H),7.38–7.32(m,2H),7.32–7.27(m,1H),6.75–6. 60(m,1H),6.45–6.30(m,1H),5.08–4.71(m,1H),4.53–4.29(m,1H),1.94–1.86(m,3H). 13 C NMR (101MHz, CDCl3) δ135.62,135.41,134.06,128.84,128.75,128.69,12 8.16,127.12,127.06,124.70,59.75,58.69,52.02,51.29,25.09,21.56.

[0068] HRMS(ESI):m / z calculated for[C 11 H 12 Br2-Br] + :223.0123,found:223.0140.

[0069] Since the product is a mixture of diastereomers, not all 1 HNMR and 13 C NMR signals can be resolved.

[0070] Example 8: (E)-tert-butyl((2,3-dibromo-5-phenylpent-4-en-1-yl)oxy)dimethylsilane(2h)

[0071]

[0072] 1h was used as the starting substrate to prepare the target product 2h, and the preparation method was the same as that in Example 1. The product was a light yellow oily liquid with a yield of 85% (dr = 1:1).

[0073] 1 H NMR (400MHz, CDCl3) δ7.43–7.40(m,2H),7.36–7.32(m,2H),7.31–7.28(m,1H),6.65(d,J=15.6,9.0Hz,1H),6.46(dd,J=53.4,15.6,9. 7Hz,1H),5.15(dd,J=16.8,9.8,4.8Hz,1H),4.34(td,J=6.3,4.2Hz,1H),4.17–4.03(m,2H),0.93(d,J=1.5Hz,9H),0.14–0.08(m,6H). 13 C NMR (101MHz, CDCl3) δ134.34,133.59,128.82,128.66,128.64,127.67,127.26,127.10,12 7.07,65.61,65.55,58.33,57.47,55.78,53.81,25.97,18.46,-5.16,-5.19,-5.22,-5.24.

[0074] HRMS(ESI):m / z calculated for[C 17 H 26 Br2OSi-Br] + :353.0937,found:353.0901.

[0075] Since the product is a mixture of diastereomers, not all 1 HNMR and 13 C NMR signals can be resolved.

[0076] Example 9: (E)-(3,4-dibromooct-1-en-1-yl)benzene (2i)

[0077]

[0078] 1i was used as the starting substrate to prepare the target product 2i by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 61% (dr = 1:1).

[0079] 1H NMR (400MHz, CDCl3) δ7.44–7.40(m,2H),7.37–7.32(m,2H),7.31–7.27(m,1H),6.71–6.55(m,1H),6.45–6.32(m,1H) ,5.08–4.82(m,1H),4.30–4.22(m,1H),2.30–1.80(m,2H),1.50–1.70(m,2H),1.50–1.30(m,2H),1.00–0.85(m,3H).

[0080] 13 C NMR (101MHz, CDCl3) δ135.64,134.90,133.91,128.83,128.71,128.65,128.18,127.11,127.06,12 5.67,59.41,58.80,58.59,58.09,36.67,34.41,29.99,29.29,22.14,22.09,14.07.HRMS(ESI):m / z calculated for[C 14 H 18 Br2-Br] + :265.0592,found:265.0607.

[0081] Since the product is a mixture of diastereomers, not all 1 HNMR and 13 C NMR signals can be resolved.

[0082] Example 10: (E)-(3,4-dibromobut-1-ene-1,2-diyl)dibenzene(2j)

[0083]

[0084] 1j was used as the starting substrate to prepare the target product 2j in the same manner as in Example 1. The product was a light yellow oily liquid with a yield of 64%.

[0085] 1 H NMR (400MHz, CDCl3) δ7.46–7.38(m,5H),7.13–7.07(m,3H),6.93–6.87(m,2H),6.82(s,1H) ,5.16(dd,J=11.6,4.4Hz,1H), 3.83(dd,J=10.2,4.3Hz,1H), 3.57(dd,J=11.6,10.1Hz,1H).

[0086] 13 C NMR (101MHz, CDCl3) δ137.53,135.70,135.38,134.31,130.25,129.75,128.85,128.42,128.22,128.07,57.46,33.09.

[0087] HRMS(ESI):m / z calculated for[C 16 H 14 Br2-Br] + :285.0279,found:285.0281.

[0088] Example 11: (E)-(1,4-dibromobut-2-en-1-yl)cyclohexane (2k)

[0089]

[0090] 1k was used as the starting substrate to prepare the target product 2k. The preparation method was the same as in Example 1. Pale yellow oily liquid, product yield 92% (2k+2k') (2k:2k'=71:29, the regioisomer ratio is 1 The crude product was determined by HNMR analysis). 2k: 1 H NMR (400MHz, CDCl3) δ7.76–7.30(m,5H),7.17(s,1H),5.00(dd,J=11.1,4.5Hz,1H),4.02(t,J=10.7Hz,1H),3.83(dd,J=10.3,4.5Hz,1H).

[0091] 13 C NMR (101MHz, CDCl3) δ134.31,133.77,129.51,129.21,128.92,128.44,55.93,33.59.2k': 1 H NMR (400MHz, CDCl3) δ7.77–7.31(m,1.7H),7.25(s,0.34H),6.76–6.58(m,0.34H),4.10(d,J=7.9Hz,0.68H).

[0092] 13 C NMR (101MHz, CDCl3) δ138.03,130.62,129.31,129.09,128.40,123.92,56.35,29.26.

[0093] HRMS(ESI):m / z calculated for[C 10 H9Br3-Br] + :286.9071,found:286.9076.

[0094] Example 12: (E)-(3,4-dibromo-3-methylbut-1-en-1-yl)benzene (21)

[0095]

[0096] 1l was used as the starting substrate to prepare the target product 2l by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 47%.

[0097] 1 H NMR (400MHz, CDCl3) δ7.42–7.37(m,2H),7.35–7.30(m,2H),7.28–7.24(m,1H),6.73(d,J=16 .0Hz,1H),6.25(d,J=15.9,1H),3.58(d,J=10.4Hz,1H),3.54(d,J=10.3Hz,1H),1.53(s,3H).

[0098] 13 C NMR (101MHz, CDCl3) δ136.45,132.59,129.96,128.78,128.04,126.74,71.95,45.24,26.59.

[0099] HRMS(ESI):m / z calculated for[C 11 H 12 Br2-Br] + :223.0123,found:226.0116.

[0100] Example 13: (E)-(2-(3,4-dibromobut-1-en-1-yl)propane-1,3-diyl)dibenzene(2m)

[0101]

[0102] 1m was used as the starting substrate to prepare the target product 2m by the same preparation method as in Example 1. A pale yellow solid was obtained with a product yield of 70%.

[0103] 1H NMR (400MHz, CDCl3) δ7.35–7.27(m,5H),7.25–7.18(m,3H),7.15–7.12(m,2H),5.58(dd,J=10.5,1.1Hz,1H),5.15( td,J=10.8,4.3Hz,1H),3.90(dd,J=9.8,4.3Hz,1H),3.71(dd,J=10.9,9.7Hz,1H),3.53–3.32(m,2H),3.28(s,2H).

[0104] 13 C NMR (101MHz, CDCl3) δ145.02,138.62,138.23,129.32,129.13,128.73,128.61,127.66,126.61,126.59,46.72,42.80,35.97,35.75.

[0105] HRMS(ESI):m / z calculated for[C 18 H 18 Br2-Br] + :313.0592,found:313.0614.

[0106] Example 14: (E)-(5,6-dibromohex-3-en-1-yl)benzene (2n)

[0107]

[0108] 1n was used as the starting substrate to prepare the target product 2n. The preparation method was the same as that in Example 1. Pale yellow oily liquid, the product yield was 81% (1.2:1.4=40:60, the regioisomer ratio was 1 The crude product was determined by HNMR analysis).

[0109] 1H NMR(400MHz, CDCl3)δ7.36–7.26(m,2.74H)(2n+2n'),7.24–7.16(m,3.98H)(2n+2n'),6.05–5.78(m,2.45 H)(2n+2n'),5.56(dd,J=15.0,9.5Hz,0.28H)(2n),4.66(td,J=10.0,4.6Hz,0.27H)(2n),4.43(td,J=8.3 ,6.1Hz,1H)(2n'),3.93(d,J=7.2Hz,2H)(2n').3.81(dd,J=10.1,4.6Hz,0.28H)(2n),3.61(dd,J=10.7,1 0.3Hz,0.28H)(2n),2.90–2.65(m,2.74H)(2n+2n'),2.47–2.38(m,0.57H)(2n),2.33–2.09(m,2H)(2n').

[0110] 13 C NMR (101MHz, CDCl3)2n: δ141.29,136.33,129.33,128.62,128.53,126.15,51.46,35.40,35.23,33.85.

[0111] 2n': δ140.39,135.84,128.71,128.68,128.48,126.42,52.64,40.20,31.16.

[0112] HRMS(ESI):m / z calculated for[C 12 H 14 Br2-Br] + :237.0313,found:237.0296.

[0113] Since the product is a mixture of isomers and 1.2:1.4=40:60, not all 1 H NMR and 13 C NMR signals can be resolved.

[0114] Example 15: methyl(E)-4-(3,4-dibromobut-1-en-1-yl)benzoate(2o)

[0115]

[0116] 1o was used as the starting substrate to prepare the target product 2o. The preparation method was the same as that in Example 1. The product was a light yellow oily liquid with a yield of 92% (1.2:1.4=63:27, with a regioisomer ratio of 1 The crude product was analyzed by HNMR to confirm that the 1,4-addition product was completely converted to the 1,2-addition product after 20 h at 25°C).

[0117] 1 H NMR (400MHz, CDCl3) δ8.01(d,J=8.4Hz,2H),7.48(d,J=8.3Hz,2H),6.72(d,J=15.6Hz,1H),6.3 5(dd,J=15.6,9.6Hz,1H),4.99–4.74(m,1H),3.97–3.89(m,4H),3.76(dd,J=10.5,10.4Hz,1H).

[0118] 13 C NMR (101MHz, CDCl3) δ166.79,139.81,134.01,130.14,129.80,126.98,52.32,50.63,34.83.

[0119] HRMS(ESI):m / z calculated for[C 12 H 12 Br2O2-Br] + :267.0021,found:267.0029.

[0120] Example 16: (E)-1-(3,4-dibromobut-1-en-1-yl)-4-nitrobenzene (2p)

[0121]

[0122] 1p was used as the starting substrate to prepare the target product 3p. The preparation method was the same as that in Example 1. Pale yellow oily liquid, the product yield was 91% (1.2:1.4=48:52, the regioisomer ratio was 1 The crude product was analyzed by HNMR to confirm that the 1,4-addition product was completely converted to the 1,2-addition product after 60 h at 25°C).

[0123] 1H NMR (400MHz, CDCl3) δ8.34–8.10(m,2H),7.70–7.42(m,2H),6.75(d,J=15.6Hz,1H),6.41(dd,J=15.6,9.5Hz ,1H),4.88(dddd,J=10.5,9.6,4.3,0.7Hz,1H),3.94(dd,J=10.2,4.4Hz,1H),3.76(dd,J=10.5,10.4Hz,1H).

[0124] 13 C NMR(101MHz, CDCl3)δ147.71,141.77,132.68,131.82,127.68,124.22,49.68,34.51.HRMS(ESI):m / z calculated for[C 10 H9Br2NO2-Br] + :253.9817,found:253.9819.

[0125] Example 17: (Z)-(1,4-dibromobut-2-en-2-yl)benzene (4a)

[0126]

[0127] 3a was used as the starting substrate to prepare the target product 4a by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 88% (Z / E = 64:36, Z / E was obtained from previously reported spectral data).

[0128] 1 H NMR (400MHz, CDCl3) δ7.49–7.45(m,2H),7.43–7.33(m,3H),6.22(t,J=8.6Hz,1H),4.40(s,2H),4.22(d,J=8.7Hz,2H).

[0129] 13 C NMR(101MHz, CDCl3)δ141.18,138.98,128.81,128.75,128.32,126.33,26.90,26.73.HRMS(ESI):m / z calculated for C 10 H 10 Br2[M+Na] + :310.9047,found:310.9059.

[0130] Example 18: (Z)-1-(1,4-dibromobut-2-en-2-yl)-2-methylbenzene (4b)

[0131]

[0132] 3b was used as the starting substrate to prepare the target product 4b by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 95% (Z / E=62:38).

[0133] 1 H NMR (400MHz, CDCl3) δ7.27–7.16(m,3H),7.13–7.08(m,1H),6.30–6.16(t,1H),4.27(s,2H),4.19(d,J=8.6Hz,2H),2.26(s,3H).

[0134] 13 C NMR (101MHz, CDCl3) δ141.24,135.79,135.39,130.54,129.40,128.56,128.51,125.94,37.20,28.79,19.61.

[0135] HRMS(ESI):m / z calculated for[C 11 H 12 Br2-Br] + :223.0123,found:223.0128.

[0136] Example 19: (Z)-1-(1,4-dibromobut-2-en-2-yl)-3,5-dimethylbenzene (4c)

[0137]

[0138] 3c was used as the starting substrate to prepare the target product 4c by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 74% (Z / E=67:33).

[0139] 1 H NMR (400MHz, CDCl3)7.11–6.97(m,1H),7.03–6.97(m,1H),6.91–6.85(m,1H),6.19(t,J=8.7Hz,1H),4.39(s,2H),3.88(d,J=8.3Hz,2H),2.34(s,6H).

[0140] 13 C NMR (101MHz, CDCl3) δ141.48,138.97,138.33,130.43,127.74,124.19,27.11,26.95,21.51.

[0141] HRMS(ESI):m / z calculated for[C 12 H 14 Br2-Br] + :237.0279,found:237.0281.

[0142] Example 20: (Z)-1-(tert-butyl)-4-(1,4-dibromobut-2-en-2-yl)benzene (4d)

[0143]

[0144] 3d was used as the starting substrate to prepare the target product 4d, and the preparation method was the same as Example 1. The product was a light yellow oily liquid with a yield of 74% (Z / E=68:32).

[0145] 1 H NMR (400MHz, CDCl3) δ7.45–7.38(m,4H),6.23(t,J=8.7Hz,1H),4.40(s,2H),4.23(d,J=8.7Hz,2H),1.33(s,9H).

[0146] 13 C NMR (101MHz, CDCl3) δ151.94,140.92,135.84,127.96,125.93,125.76,34.77,31.38,27.18,26.67.

[0147] HRMS(ESI):m / z calculated for[C 14 H 18 Br2-Br] + :265.0592,found:265.0587.

[0148] Example 21: (Z)-1-chloro-3-(1,4-dibromobut-2-en-2-yl)benzene (4e)

[0149]

[0150] 3e was used as the starting substrate to prepare the target product 4e by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 83% (Z / E = 70:30).

[0151] 1 H NMR (400MHz, CDCl3) δ7.45(dt,J=1.8,1.1Hz,1H),7.38–7.28(m,3H),6.22(t,J=8.6Hz,1H),4.35(s,2H),4.20(d,J=8.6Hz,2H).

[0152] 13 C NMR (101MHz, CDCl3) δ140.87,139.95,134.78,130.05,129.14,128.74,126.59,124.54,26.36,26.31.

[0153] HRMS(ESI):m / z calculated for[C 10 H9Br2Cl-Br] + :242.9577,found:242.9595.

[0154] Example 22: (Z)-1-(1,4-dibromobut-2-en-2-yl)-4-fluorobenzene(4f)

[0155]

[0156] 3f was used as the starting substrate to prepare the target product 4f, and the preparation method was the same as Example 1. The product was a light yellow oily liquid with a yield of 75% (Z / E=67:33).

[0157] 1 H NMR (400MHz, CDCl3) δ7.48–7.41(m,2H),7.16–7.03(m,2H),6.17(t,J=8.6Hz,1H),4.37(s,2H),4.20(d,J=8.6Hz,2H).

[0158] 13 C NMR (101MHz, CDCl3) δ163.04 (d, J = 248.2Hz), 140.21, 135.07 (d, J = 3.9Hz), 12 8.15(d,J=8.1Hz),127.99(d,J=1.4Hz),115.78(d,J=21.6Hz),26.73,26.70.

[0159] 19 FNMR(376MHz, CDCl3)δ-112.92,-113.03.

[0160] HRMS(ESI):m / z calculated for C 10 H9Br2F[M+H] + :306.9133,found:306.9126.

[0161] Example 23: (Z)-1-bromo-4-(1,4-dibromobut-2-en-2-yl)benzene (4 g)

[0162]

[0163] 3g of the starting substrate was used to prepare 4g of the target product by the same preparation method as in Example 1. The product was a light yellow oily liquid with a yield of 67% (Z / E=73:27).

[0164] 1 H NMR (400MHz, CDCl3) δ7.53–7.48(m,2H),7.37–7.32(m,2H),6.19(dt,J=14.0,8.5Hz,1H),4.35(s,2H),4.19(d,J=8.6Hz,2H).

[0165] 13 C NMR(101MHz, CDCl3)δ140.12,137.87,131.96,128.48,127.96,122.88,26.53,26.32.HRMS(ESI):m / z calculated for[C 10 H9Br3-Br] + :286.9071,found:286.9085.

[0166] Example 24: (Z)-1-chloro-4-(1,4-dibromobut-2-en-2-yl)benzene (4h)

[0167]

[0168] 3h was used as the starting substrate for the reaction to prepare the target product 4h, and the preparation method was the same as that in Example 1. The product was a light yellow oily liquid with a yield of 82% (Z / E=70:30).

[0169] 1H NMR (400MHz, CDCl3) δ7.43–7.41(m,1H),7.41–7.38(m,1H),7.38–7.35(m,1H),6.21(t,J=8.7Hz,1H),4.36(s,2H),4.20(d,J=8.7Hz,2H).

[0170] 13 C NMR(101MHz, CDCl3)δ140.07,137.39,134.68,129.00,128.43,127.67,26.56,26.40.HRMS(ESI):m / z calculated for[C 10 H9Br2Cl-Br] + :242.9577,found:242.9577.

[0171] Example 25: (Z)-4-(1,4-dibromobut-2-en-2-yl)-1,1'-biphenyl(4i)

[0172]

[0173] 3i was used as the starting substrate to prepare the target product 4i by the same preparation method as in Example 1. The product was a pale yellow solid with a yield of 76% (Z / E = 69:31).

[0174] 1 H NMR (400MHz, CDCl3) δ7.64–7.58(m,5H),7.48–7.42(m,2H),7.41–7.33(m,2H),6.29(t,J=8.7Hz,1H),4.43(s,2H),4.24(d,J=8.7Hz,2H).

[0175] 13 C NMR (101MHz, CDCl3) δ141.54,140.71,140.42,137.67,128.99,127.73,127.48,127.16,126.70,26.97,26.56.

[0176] HRMS(ESI):m / z calculated for[C 16 H 14 Br2-Br] + :285.0279,found:285.0276.

[0177] Example 26: (Z)-4-(1,4-dibromobut-2-en-2-yl)phenyltrifluoromethanesulfonate (4j)

[0178]

[0179] 3j was used as the starting substrate to prepare the target product 4j, and the preparation method was the same as that in Example 1. The product was a light yellow solid with a yield of 90% (Z / E=68:32).

[0180] 1 H NMR (400MHz, CDCl3) δ7.59–7.53(m,2H),7.32–7.27(m,2H),6.23(t,J=8.6Hz,1H),4.36(s,2H),4.20(d,J=8.6Hz,2H).

[0181] 13 C NMR (101MHz, CDCl3) δ149.67, 139.61, 139.48, 129.84, 128.39, 121.88, 118.96 (d, J = 320.8Hz), 36.81, 26.31.

[0182] 19 FNMR(376MHz, CDCl3)δ-72.74,-72.80.

[0183] HRMS(ESI):m / z calculated for[C 11 H9Br2F3O3S-Br] + :356.9408,found:356.9393.

[0184] Example 27: (Z)-4-(1,4-dibromobut-2-en-2-yl)phenyl 4-methylbenzenesulfonate(4k)

[0185]

[0186] 3k was used as the starting substrate to prepare the target product 4k, and the preparation method was the same as in Example 1. The product was a light yellow solid with a yield of 80% (Z / E = 72:28).

[0187] 1H NMR (400MHz, CDCl3) δ7.75–7.69(m,2H),7.42–7.37(m,2H),7.35–7.30(m,2H),7. 01–6.97(m,2H),6.21–6.16(m,1H),4.33(s,2H),4.18(d,J=8.6,2H),2.46(s,3H).

[0188] 13 C NMR (101MHz, CDCl3) δ149.74,145.65,139.79,137.91,132.36,129.96,128.87,128.63,127.60,122.73,26.50,26.39,21.88.

[0189] HRMS(ESI):m / z calculated for[C 17 H 16 Br2O3S-Br] + :379.0004,found:379.0008.

[0190] Example 28: (Z)-1-(1,4-dibromobut-2-en-2-yl)-4-(trifluoromethyl)benzene (41)

[0191]

[0192] 31 was used as the starting substrate to prepare the target product 41, and the preparation method was the same as in Example 1. The product was a light yellow oily liquid with a yield of 81% (Z / E = 79:21).

[0193] 1 H NMR (400MHz, CDCl3) δ7.67–7.62(m,2H),7.61–7.56(m,2H),6.27(t,J=8.6Hz,1H),4.39(s,2H),4.21(d,J=8.7Hz,2H).

[0194] 13 C NMR (101MHz, CDCl3) δ142.57, 139.94, 129.88, 128.83, 126.75, 125.80 (q, J = 3.8Hz), 124.05 (d, J = 272.6Hz), 26.17, 26.14.

[0195] 19 FNMR (376MHz,CDCl3)δ-62.70.

[0196] HRMS(ESI):m / z calculated for[C 11 H9Br2F3-Br] + :276.9840,found:276.9840.

[0197] Example 29: (Z)-1-(benzyloxy)-4-(1,4-dibromobut-2-en-2-yl)benzene (4m)

[0198]

[0199] 3m was used as the starting substrate to prepare the target product 4m by the same preparation method as in Example 1. The product was a pale yellow solid with a yield of 74% (Z / E = 79:21).

[0200] 1 H NMR (400MHz, CDCl3) δ7.47–7.32(m,5H),7.02(d,J=8.6Hz,2H),6.97(d,J=8. 7Hz,2H),6.19–6.14(m,1H),5.08(s,2H),4.37(s,2H),4.20(d,J=5.1Hz,2H).

[0201] 13 C NMR (101MHz, CDCl3) δ158.96,141.58,136.83,129.57,128.77,128.22,127.66,127.59,127.54,115.00,70.16,37.68,29.48.

[0202] HRMS(ESI):m / z calculated for[C 17 H 16 Br2O-Br] + :315.0385,found:315.0390.

[0203] Example 30: (Z)-2-(1,4-dibromobut-2-en-2-yl)naphthalene(4n)

[0204]

[0205] 3n was used as the starting substrate to prepare the target product 4n by the same preparation method as in Example 1. The product was a pale yellow solid with a yield of 58% (Z / E = 71:29).

[0206] 1H NMR (400MHz, CDCl3) δ7.96–7.77(m,4H),7.60–7.56(m,1H),7.55–7.48(m,2H),6.37(t,J=8.7Hz,1H),4.51(s,2H),4.27(d,J=8.7Hz,2H).

[0207] 13 C NMR (101MHz, CDCl3) δ141.14,136.11,133.35,133.33,128.54,128.50,128.39,127.90,127.75,126.68,125.64,124.01,27.00,26.69.

[0208] HRMS(ESI):m / z calculated for C 14 H 12 Br2[M+H] + :338.9384,found:338.9383.

[0209] Example 31: (Z)-2-(1,4-dibromobut-2-en-2-yl)-9H-fluorene(4o)

[0210]

[0211] 3o was used as the starting substrate to prepare the target product 4o by the same preparation method as in Example 1. The product was a pale yellow solid with a yield of 34% (Z / E = 79:21).

[0212] 1 H NMR (400MHz, CDCl3) δ7.87–7.74(m,2H),7.66(s,1H),7.57–7.53(m,1H),7.47–7.32(m,1H),7.42–7. 36(m,1H),7.35–7.29(m,1H),6.29(t,J=8.7Hz,1H),4.46(s,2H),4.26(d,J=8.7Hz,2H),3.93(s,2H).

[0213] 13 C NMR (101MHz, CDCl3) δ143.83,143.70,142.41,141.54,141.19,137.45,127.63, 127.23,127.03,125.24,125.19,122.98,120.27,120.11,37.09,27.21,26.99.

[0214] HRMS(ESI):m / z calculated for[C 17 H 14 Br2-Br] + :279.0279,found:297.0284.

[0215] Example 32: (Z)-((4-(1,4-dibromobut-2-en-2-yl)phenyl)ethynyl)trimethylsilane(4p)

[0216]

[0217] 3p was used as the starting substrate to prepare the target product 4p, and the preparation method was the same as in Example 1. The product was a light yellow oily liquid with a yield of 65% (Z / E=71:29).

[0218] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 8.3Hz, 2H), 7.41 (d, J = 8.2Hz, 2H), 6.23 (dd, J = 8. 6,0.7Hz,1H),4.36(d,J=0.7Hz,2H),4.19(d,J=0.7Hz,2H),0.25(d,J=0.9Hz,9H).

[0219] 13 C NMR (101MHz, CDCl3) δ140.46,138.82,132.37,128.54,126.11,123.53,104.67,95.83,26.66,26.25,0.08.

[0220] HRMS(ESI):m / z calculated for[C 15 H 18 Br2Si-Br] + :305.0362,found:305.0372.

[0221] Example 33: (E)-(1,4-dibromo-3-methylbut-2-en-2-yl)benzene(4q)

[0222]

[0223] 3q was used as the starting substrate to prepare the target product 4p using the same preparation method as in Example 1. The product was a pale yellow oily liquid with an 86% yield (E / Z = 95:5, confirmed to be the E-isomer according to reported literature; the configurational inversion may be due to steric hindrance, making the E-isomer more stable).

[0224] 1 H NMR (400MHz, CDCl3) δ7.42–7.29(m,5H),4.22(s,2H),3.84(s,2H),2.06(s,3H).

[0225] 13 C NMR (101MHz, CDCl3) δ139.51,137.33,135.13,128.68,128.25,127.96,36.80,34.13,17.26.

[0226] HRMS(ESI):m / z calculated for[C 11 H 12 Br2-Br] + :223.0123,found:223.0128.

[0227] Example 34: (E)-(1,4-dibromobut-2-ene-2,3-diyl)dibenzene(4r)

[0228]

[0229] 3r was used as the starting substrate to prepare the target product 4r, and the preparation method was the same as Example 1. The product was a light yellow solid with a yield of 82% (determined to be the E-isomer according to reported literature, the reason for the configuration flip may be due to steric hindrance, and the E-isomer is more stable).

[0230] 1 H NMR (400MHz, CDCl3) δ7.49–7.38 (m, 10H), 4.05 (s, 4H).

[0231] 13 C NMR (101MHz, CDCl3) δ139.36,138.24,128.74,128.48,128.35.

[0232] HRMS(ESI):m / z calculated for[C 16 H 14 Br2-Br] + :285.0279,found:285.0278.

[0233] Example 35: (E)-4,4'-(1,4-dibromobut-2-ene-2,3-diyl)bis(fluorobenzene)(4s)

[0234]

[0235] 3s was used as the starting substrate to prepare the target product 4s, and the preparation method was the same as Example 1. The product was a pale yellow solid with a yield of 66% (determined to be the E-isomer according to reported literature; the configuration flip may be due to steric hindrance, and the E-isomer is more stable).

[0236] 1 H NMR (400MHz, CDCl3) δ7.49–7.39(m,4H),7.21–7.11(m,4H),3.99(s,4H).

[0237] 13 C NMR (101MHz, CDCl3) δ162.71 (d, J = 247.9Hz), 138.90, 133.91 (d, J = 3.5Hz), 132.24 (d, J=10.2Hz), 130.22 (d, J=8.1Hz), 128.65 (d, J=12.1Hz), 115.87 (d, J=21.5Hz), 35.51.

[0238] 19 FNMR (376MHz,CDCl3)δ-113.09.

[0239] HRMS(ESI):m / z calculated for[C 16 H 12 Br2F2-Br] + :321.0091,found:321.0060.

[0240] Example 36: (Z)-(1,4-dibromo-6-methylhept-2-en-3-yl)benzene (4t)

[0241]

[0242] 3t was used as the starting substrate to prepare the target product 4t, and the preparation method was the same as in Example 1. The product was a light yellow oily liquid with a yield of 80% (Z / E=63:37).

[0243] 1H NMR (400MHz, CDCl3) δ7.44–7.30(m,5H),6.14(t,J=8.3Hz,1H),4.99(dd,J=11.7,4.3Hz,1H),3.81–3. 74(m,2H),1.87–1.74(m,2H),1.72–1.62(m,1H),0.92(dd,J=12.0,6.3Hz,3H),0.84(t,J=6.2Hz,3H).

[0244] 13 C NMR (101MHz, CDCl3) δ 146.06, 136.13, 130.26, 129.17, 128.42, 128.15, 56.50, 38.15, 33.42, 28.61, 22.53, 22.46.

[0245] HRMS(ESI):m / z calculated for[C 14 H 18 Br2-Br] + :265.0592,found:265.0625.

[0246] Example 37: (Z)-(5-bromo-3-(bromomethyl)pent-3-en-1-yl)benzene (4u)

[0247]

[0248] 3u was used as the starting substrate to prepare the target product 4u, and the preparation method was the same as in Example 1. The product was a light yellow oily liquid with a yield of 80% (Z / E = 70:30).

[0249] 1 H NMR (400MHz, CDCl3) δ7.24–7.14(m,5H),5.91(t,J=8.4Hz,1H),3.93(s,2H),3 .81(d,J=8.4Hz,2H),2.80(dt,J=8.5,6.2Hz,2H),2.60(dd,J=9.0,6.7Hz,2H).

[0250] 13 C NMR (101MHz, CDCl3) δ140.98,140.91,128.70,128.56,127.32,126.48,37.43,34.19,30.51,27.20.

[0251] HRMS(ESI):m / z calculated for[C12 H 14 Br2-Br] + :237.0279,found:237.0296。

Claims

1. A method for preparing an ortho-dibromide or allyl dibromide, wherein the target product is prepared by a one-step method, characterized in that The steps include: The reaction substrate, 1,3-diene, is added to a sealed tube. An organic solvent is then added at room temperature. Then, a TMSBr solution and an NBS solution are added dropwise in sequence. The reaction mixture is stirred at room temperature for ten seconds. Next, a saturated aqueous Na2S2O3 solution is immediately added to quench the reaction mixture. The mixture is diluted with water and extracted with CH2Cl2. The resulting organic layer is dried over anhydrous Na2SO4, concentrated under reduced pressure, and then separated and purified to obtain the target product, o-dibromide or allyl dibromide. The reaction route is as follows: ； Wherein the substituent R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from an alkyl group, a phenyl group or a bromine atom; The organic solvent is ultra-dry tetrahydrofuran.

2. The preparation method according to claim 1, wherein: The molar ratio of 1,3-diene, TMSBr and NBS is 2:3:3.

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