CN115490621A - Preparation method of iodobicyclo [1.1.1] pentane derivative - Google Patents
Preparation method of iodobicyclo [1.1.1] pentane derivative Download PDFInfo
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- CN115490621A CN115490621A CN202211262985.6A CN202211262985A CN115490621A CN 115490621 A CN115490621 A CN 115490621A CN 202211262985 A CN202211262985 A CN 202211262985A CN 115490621 A CN115490621 A CN 115490621A
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- reaction
- pentane
- iodobicyclo
- ethyl acetate
- iodoform
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- JQBKEUBPDXVQKD-UHFFFAOYSA-N 3-iodobicyclo[1.1.1]pentane Chemical class C1C2CC1(I)C2 JQBKEUBPDXVQKD-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- OKJPEAGHQZHRQV-UHFFFAOYSA-N iodoform Chemical compound IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims abstract description 42
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 21
- 239000011630 iodine Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- -1 sulfinic acid sodium salt Chemical class 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 11
- ZTXSPLGEGCABFL-UHFFFAOYSA-N 1.1.1-propellane Chemical compound C1C23CC31C2 ZTXSPLGEGCABFL-UHFFFAOYSA-N 0.000 claims abstract description 8
- NZZFYRREKKOMAT-OUBTZVSYSA-N diiodomethane Chemical group I[13CH2]I NZZFYRREKKOMAT-OUBTZVSYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 138
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 16
- 239000012300 argon atmosphere Substances 0.000 claims description 15
- INLFWQCRAJUDCR-LYLBMTSKSA-N spirostane Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 INLFWQCRAJUDCR-LYLBMTSKSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000003153 propellanes Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 abstract description 12
- 230000006103 sulfonylation Effects 0.000 abstract description 3
- 238000005694 sulfonylation reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000005286 illumination Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 150000001335 aliphatic alkanes Chemical class 0.000 description 8
- KFZUDNZQQCWGKF-UHFFFAOYSA-M sodium;4-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=C(S([O-])=O)C=C1 KFZUDNZQQCWGKF-UHFFFAOYSA-M 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000010523 cascade reaction Methods 0.000 description 3
- 230000026045 iodination Effects 0.000 description 3
- 238000006192 iodination reaction Methods 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000002083 iodinating effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000011941 photocatalyst Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- PCCKONVRKJWSDK-UHFFFAOYSA-M sodium 2,3-dihydro-1-benzofuran-5-sulfinate Chemical compound [Na+].[O-]S(=O)c1ccc2OCCc2c1 PCCKONVRKJWSDK-UHFFFAOYSA-M 0.000 description 1
- ZBKKIKXRUXGSDO-UHFFFAOYSA-M sodium;4-fluorobenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=C(F)C=C1 ZBKKIKXRUXGSDO-UHFFFAOYSA-M 0.000 description 1
- JZEDOEPVMYKFAB-UHFFFAOYSA-M sodium;4-methoxybenzenesulfinate Chemical compound [Na+].COC1=CC=C(S([O-])=O)C=C1 JZEDOEPVMYKFAB-UHFFFAOYSA-M 0.000 description 1
- YAHKQSVGVMFKMR-UHFFFAOYSA-M sodium;4-nitrobenzenesulfinate Chemical compound [Na+].[O-][N+](=O)C1=CC=C(S([O-])=O)C=C1 YAHKQSVGVMFKMR-UHFFFAOYSA-M 0.000 description 1
- CHLCPTJLUJHDBO-UHFFFAOYSA-M sodium;benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=CC=C1 CHLCPTJLUJHDBO-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/38—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing five carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an iodobicyclo [1.1.1] pentane derivative, which comprises the following steps: the sulfinic acid sodium salt, [1.1.1] propellane and iodine source are taken as raw materials, added into a solvent, reacted under the irradiation of a light source, and after the reaction is finished, the iodine source is diiodomethane or iodoform, and the iodinated sulfonylation product of the [1.1.1] propellane is obtained through post-treatment. The invention adopts cheap diiodomethane or iodoform as an iodine source to replace other expensive iodine sources, and adopts illumination reaction to obtain the product, and the method has the advantages of mild reaction conditions, convenient operation, wide substrate universality, high product yield, low preparation cost and wide application value.
Description
Technical Field
The invention relates to a preparation method of iodobicyclo [1.1.1] pentane derivatives, in particular to a method for efficiently preparing [1.1.1] spirostane iodination sulfonylation by generating sulfonyl free radicals by sodium sulfinate and diiodomethane or iodoform through a Single Electron Transfer (SET) process under the action of visible light and further initiating a free radical cascade reaction.
Background
In recent years, bicyclo [1.1.1] pentane (BCPs) has wide application value in the fields of medicines, materials and the like by virtue of unique structure and property, and bicyclo [1.1.1] pentane (BCPs) can be used as a biological isostere of benzene ring, tert-butyl and internal alkyne, and has pharmacokinetic properties of improving solubility, improving membrane permeability, increasing metabolic stability and the like. Therefore, different functional groups are introduced into the [1.1.1] propellane, and the method has important significance for drug development.
iodo-BCP compounds present certain challenges in the synthesis process due to the structural specificity. The Anderson group of subjects first reported iodinated alkylation and iodinated heteroaromatic cyclization of [1.1.1] spiroalkanes using photoredox (ACCCATAL. 2019,9, 9568-9574). They then reported iodination of [1.1.1] propeller alkanes using triethylboron as a radical initiator (j.am. Chem. Soc.2021, 143, 9729-9736). On the basis, the patent reports that the iodobicyclo [1.1.1] pentane derivative is efficiently prepared by iodinating and sulfonylating [1.1.1] pyrrolidine by utilizing sulfinic acid sodium salt and diiodomethane or iodoform to generate sulfonyl radicals through a Single Electron Transfer (SET) process under the action of visible light without using an external photocatalyst and further initiating a radical cascade reaction.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a simple, efficient and low-cost method for preparing iodobicyclo [1.1.1] pentane derivatives. The invention defines a preparation method of iodobicyclo [1.1.1] pentane derivatives, which specifically comprises the steps of taking sodium sulfinate shown in a formula (I), 1.1.1] propellane shown in a formula (II) and an iodine source as raw materials, adding the raw materials into a solvent, reacting under the irradiation of a light source, and carrying out post-treatment after the reaction is finished to obtain a [1.1.1] propellane iodinated and sulfonylated product shown in a formula (III), wherein the iodine source is diiodomethane or iodoform, and the reaction equation is shown as follows:
in the formula, R is an electron-withdrawing group or an electron-donating group, the electron-withdrawing group is halogen, trifluoromethyl, nitro or cyano, and the electron-donating group is alkyl, alkoxy, phenyl or substituted phenyl.
Further, the invention also defines that the heteroaromatic ring is a five-membered aromatic ring containing nitrogen, oxygen and sulfur atoms or a six-membered aromatic ring containing nitrogen atoms.
Furthermore, the invention also limits the light source to be an ultraviolet lamp, a blue lamp and a green lamp, and the wattage range is 10W-90W, and the preferred range is 40W blue lamp.
Furthermore, the invention also limits the solvent for reaction to be one or more of acetonitrile, N-dimethylformamide, dimethyl sulfoxide, methanol, nitromethane and water.
Further, the invention also defines that the reaction is carried out under the argon atmosphere or the air atmosphere.
Further, the present invention also defines the reaction temperature to be 20 ℃ to 40 ℃, preferably 30 ℃.
Further, the invention also limits the reaction time to 3-24h, preferably 8-12 h.
Further, the present invention also defines that, when the iodine source is diiodomethane, the ratio of the amounts of the sulfinic acid sodium salt, [1.1.1] propellane and iodine source is 1: (1-3): (1 to 3), preferably 1:2:1.5.
further, the invention also defines that when the iodine source is iodoform, the charging ratio of the sulfinic acid sodium salt to the [1.1.1] propellane to the iodoform is (1-3): (1-3): 1, preferably 1.5:2:1.
furthermore, the invention also defines the specific operation of the synthesis method as follows: in a reaction tube, sodium sulfinate, 1.1.1 propeller alkane and iodine source are added according to the feeding molar ratio, solvent is added, reaction is carried out for 12h under the irradiation of 40W blue light lamp, and the 1.1.1 propeller alkane iodination sulfonylation product is obtained after post treatment
Further, the invention also defines that when the iodine source is diiodomethane, the solvent is a mixed solvent of acetonitrile and water with the volume ratio of 4. When the iodine source is iodoform, the solvent is a mixed solvent of acetonitrile and water with the volume ratio of 10.
Further, the invention also limits the post-reaction treatment process to be as follows: after the reaction is completed, adding saturated sodium thiosulfate into the reaction liquid to quench the reaction, then adding ethyl acetate and water to dilute the reaction liquid, extracting the reaction liquid for three times by using ethyl acetate, collecting an organic phase, distilling the organic phase under reduced pressure, and separating the organic phase by using a column to obtain a [1.1.1] propeller alkyl iodinated sulfonylated product.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
under the irradiation of visible light, the invention generates sulfonyl free radicals by the reaction of sodium sulfinate and diiodomethane or iodoform, and further initiates the cascade reaction of the free radicals, thereby realizing the efficient preparation of the iodisulfonylation of the [1.1.1] spirostane. The reaction does not need to add a catalyst and an oxidant, adopts cheap diiodomethane or iodoform as an iodine source, has the advantages of simple and convenient operation, mild conditions, good substrate universality, low cost, high reaction yield and the like, and has wide pharmaceutical chemistry and industrial synthesis values.
Detailed Description
The synthesis scheme of the present invention is illustrated below with reference to specific examples, but the scope of the present invention is not limited thereto.
EXAMPLE 1 Synthesis of 1-iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (35.7mg, 0.2mmol), diiodomethane (80.3mg, 0.3mmol), acetonitrile (1.6 mL), water (0.4 mL) were added to a reaction tube under an argon atmosphere, and [1.1.L ] was added finally]The reaction was carried out for 12h under the irradiation of a blue-light lamp (40W, fourth grade, 427nm kessil bulb LED) with spirostane (0.68mL, 0.59M,0.4 mmol), the reaction was detected by TLC, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by chromatography on silica gel with stoneOil ether: ethyl acetate (volume ratio 30]Pentane (56.5 mg) in 81% yield. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝8.2Hz,2H),7.36(d,J＝8.0Hz,2H),2.49(s,6H),2.45(s,3H). 13 C NMR(100MHz,Chloroform-d)δ145.25,133.66,130.00,128.55,59.19,57.81,21.68,2.47.HRMS(ESI)m/z:calcd for C 12 H 14 IO 2 S[M+H] + 348.9754,found:348.9767.
EXAMPLE 21 Synthesis of iodo-3-tosylbicyclo [1.1.1] pentane.
Sodium p-toluenesulfinate (35.8mg, 0.2mmol), diiodomethane (80.3mg, 0.3mmol), acetonitrile (1.6 mL), water (0.4 mL) were added to the reaction tube under an argon atmosphere, and finally [1.1.L ] propeller alkane (0.68mL, 0.59M,0.4 mmol) was added, and stirred under 395-mpurple LED for 12h, and the reaction was checked by TLC, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate (30 vol..
EXAMPLE synthesis of 31-iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (35.7 mg,0.2 mmol), diiodomethane (80.4 mg,0.3 mmol), acetonitrile (1.6 mL), water (0.4 mL) were added to the reaction tube under an argon atmosphere, and finally [1.1.L ] propeller alkane (0.68mL, 0.59M,0.4 mmol) was added, and stirred under 530nm green LED for 12h, and the reaction was checked by TLC, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate (30 vol.).
EXAMPLE synthesis of 41-iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (35.9mg, 0.2mmol), diiodomethane (80.4mg, 0.3mmol), acetonitrile (1.6 mL), water (0.4 mL) were added to the reaction tube under argon atmosphere, and finally [1.1.l ] propeller (0.68mL, 0.59M,0.4 mmol) was added, and the reaction was performed for 3h under the irradiation of a blue light lamp (40W, fourth gear, 427nm kessil bulb LED), followed by TLC detection, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate (30 vol..
EXAMPLE Synthesis of 51-iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (35.9mg, 0.2mmol), diiodomethane (80.4mg, 0.3mmol) and dimethyl sulfoxide (2 mL) are added into a reaction tube under the argon atmosphere, and finally [1.1.l ] propeller alkane (0.68mL, 0.59M and 0.4 mmol) is added, the reaction is carried out for 12h under the irradiation of a blue light lamp (40W, fourth grade, 427nm kessil bulb LED), TLC detection reaction is carried out, and after the reaction is completed, saturated sodium thiosulfate is used for quenching reaction. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate (30 vol..
EXAMPLE 61 Synthesis of iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (35.2 mg,0.2 mmol), iodoform (78.1mg, 0.2 mmol), acetonitrile (2 mL), water (0.2 mL) were added to a reaction tube under an argon atmosphere, and finally [1.1.L ] propeller alkane (0.83mL, 0.48M,0.4 mmol) was added, and the reaction was carried out under the irradiation of a blue lamp (40W, fourth, 427nm kessil bulb LED) for 12h, followed by TLC detection, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 30: 1), to give 56.4mg of 1-iodo-3-tosylbicyclo [1.1.1] pentane as a white solid in a yield of 82%.
EXAMPLE 71 Synthesis of iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (35.6mg, 0.2mmol), iodoform (79.0mg, 0.2mmol), acetonitrile (2 mL), and water (0.2 mL) were added to the reaction tube, and [1.1.l ] propeller (0.9mL, 0.44M, 0.4mmol) was finally added thereto, and the reaction was carried out under irradiation of a blue light lamp (40W, fourth, 427nm kessilbele LED) for 12h, followed by TLC detection, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate (30 vol..
EXAMPLE 81 Synthesis of iodo-3-tosylbicyclo [1.1.1] pentane
Sodium p-toluenesulfinate (53.3mg, 0.3mmol), iodoform (78.7mg, 0.2mmol), acetonitrile (2 mL), water (0.2 mL) were added to a reaction tube under an argon atmosphere, and finally [1.1.l ] propeller alkane (0.62mL, 0.65M,0.4 mmol) was added thereto, and the reaction was carried out under irradiation of a blue light lamp (40W, fourth, 427nm kessil bulb LED) for 12h, followed by TLC detection, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate (30 vol.).
EXAMPLE Synthesis of 91- ((4-fluorophenyl) sulfonyl) -3-iodobicyclo [1.1.1] pentane
Sodium p-fluorobenzenesulfonate (36.8mg, 0.2mmol), diiodomethane (80.5mg, 0.3mmol), acetonitrile (1.6 mL), water (0.4 mL) were added to a dry pressure-resistant tube under an argon atmosphere, and [1.1.l ] was finally added]The reaction was carried out for 12 hours under the irradiation of a blue light lamp (40W, fourth grade, 427nm kessil bulb LED) with rotaxane (0.68mL, 0.59M,0.4 mmol), and after the reaction was completed, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate (30 vol.]Pentane 50.6mg, yield 71%. 1 H NMR(400MHz,Chloroform-d)δ7.91–7.81(m,2H),7.31–7.18(m,2H),2.51(s,6H). 13 C NMR(100MHz,Chloroform-d)δ167.40,164.84,132.73,132.70,131.45,131.36,116.90,116.68,59.14,57.80,1.94. 19 F NMR(376MHz,Chloroform-d)δ-102.43.HRMS(ESI)m/z:calcd for C 11 H 11 FIO 2 S[M+H] + 352.9503,found:352.9484.
EXAMPLE 10 Synthesis of (1- ((4-tert-butylphenyl) sulfonyl) -3-iodobicyclo [1.1.1] pentane
To a reaction tube were added sodium p-tert-butylsulfinate (44.0mg, 0.2mmol), diiodomethane (80.3mg, 0.3mmol), acetonitrile (1.6 mL), water (0.4 mL) under an argon atmosphere, and finally [1.1.L ]]The reaction was carried out for 12h under the irradiation of a blue-light lamp (40W, fourth grade, 427nm kessil bulb LED) with spirostane (0.68mL, 0.59M,0.4 mmol), the reaction was detected by TLC, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate (30 vol.]Pentane 53.0mg, yield 68%. 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),2.40(s,6H),1.34(s,9H). 13 C NMR(100MHz,Chloroform-d)δ158.13,133.64,128.31,126.31,56.99,49.66,48.46,35.30,31.00.HRMS(ESI)m/z:calcd for C 15 H 19 IO 2 S[M+H] + 391.0223,found:391.0231.
EXAMPLE Synthesis of 111-iodo-3-tosylbicyclo [1.1.1] pentane
To a reaction tube, sodium benzenesulfinate (49.4 mg,0.3 mmol), iodoform (78.3 mg,0.2 mmol), acetonitrile (2 mL), water (0.2 mL) were added under argon atmosphere, and [1.1.L ] was added]Propalane (0.8mL, 0.5M, 0.4mmol) in a blue lamp (40W, fourth gear, 42W)7nm kessilbule LED) for 12h, detecting the reaction by TLC, and quenching the reaction by saturated sodium thiosulfate after the reaction is completed. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate (30 vol.]Pentane 66.1mg, yield 99%. 1 H NMR(400MHz,Chloroform-d)δ7.89–7.79(m,2H),7.72–7.63(m,1H),7.62–7.52(m,2H),2.50(s,6H). 13 C NMR(100MHz,Chloroform-d)δ136.66,134.10,129.35,128.52,59.18,57.75,2.24.HRMS(ESI)m/z:calcd for C 11 H 12 IO 2 [M+H] + 334.9597,found:334.9593.
Example Synthesis of 121-iodo-3- ((4-methoxyphenyl) sulfonyl) bicyclo [1.1.1] pentane
To a dry pressure-resistant tube under argon atmosphere were added sodium p-methoxybenzenesulfinate (58.2mg, 0.3mmol), iodoform (78.5mg, 0.2mmol), acetonitrile (2 mL), water (0.2 mL), and finally [1.1.l]The reaction was carried out for 12h under the irradiation of a blue light lamp (40W, fourth grade, 427nm kessil bulb LED) with spirostane (0.8mL, 0.5M, 0.4mmol), the reaction was monitored by TLC, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate (volume ratio 30]Pentane 71.1mg, yield 98%. 1 H NMR(400MHz,Chloroform-d)δ7.79–7.68(m,2H),7.06–6.95(m,2H),3.87(s,3H),2.48(s,6H). 13 C NMR(100MHz,Chloroform-d)δ164.07,130.62,128.04,114.56,59.16,57.94,55.68,2.49.HRMS(ESI)m/z:calcd for C 12 H 14 IO 3 S[M+H] + 364.9703,found:364.9709.
Example Synthesis of 131-iodo-3- ((4-nitrophenyl) sulfonyl) bicyclo [1.1.1] pentane
To a reaction tube under an argon atmosphere were added sodium 4-nitrobenzenesulfinate (41.3mg, 0.2mmol), iodoform (78.6 mg, 0.2mmol), acetonitrile (2 mL), water (0.2 mL), and finally [1.1.l]Propolane (0.9mL, 0.45M and 0.4mmol) reacts for 12h under the irradiation of a blue light lamp (40W, fourth grade, 427nm kessilbule LED), the reaction is detected by TLC, and after the reaction is completed, the reaction is quenched by saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate (volume ratio 15]Pentane 51.1mg, yield 68%. 1 H NMR(400MHz,Chloroform-d)δ8.48–8.37(m,2H),8.11–8.00(m,2H),2.54(s,6H). 13 C NMR(100MHz,Chloroform-d)δ151.19,142.49,130.04,124.52,59.19,57.62,1.12.HRMS(ESI)m/z:calcd for C 11 H 11 INO 4 S[M+H] + 379.9448,found:379.9442.
Example Synthesis of 145- ((3-iodobicyclo [1.1.1] pent-1-yl) sulfonyl) -2, 3-dihydrobenzofuran
Under an argon atmosphere, sodium 2, 3-dihydrobenzofuran-5-sulfinate (41.0mg, 0.2mmol), iodoform (78.2mg, 0.2mmol), acetonitrile (2 mL), water (0.2 mL) were added to a reaction tube, and finally [1.1.L ] was added]The reaction was carried out for 12h under the irradiation of a blue light lamp (40W, fourth grade, 427nm kessil bulb LED) with spirostane (0.8mL, 0.5M, 0.4mmol), the reaction was monitored by TLC, and after completion of the reaction, the reaction was quenched with saturated sodium thiosulfate. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by silica gel chromatographyCrude product, petroleum ether: ethyl acetate (volume ratio 10]Pent-1-yl) sulfonyl) -2, 3-dihydrobenzofuran-61.5 mg with a yield of 82%. 1 H NMR(400MHz,Chloroform-d)δ7.64–7.55(m,2H),6.86(d,J＝8.2Hz,1H),4.69(t,J＝8.8Hz,2H),3.27(t,J＝8.8Hz,2H),2.49(s,6H). 13 C NMR(100MHz,Chloroform-d)δ165.06,130.27,128.73,128.00,125.54,109.85,72.44,59.19,57.95,28.90,2.58.HRMS(ESI)m/z:calcd for C 13 H 14 IO 3 S[M+H] + 376.9703,found:376.9713.
Claims (10)
1. A preparation method of iodobicyclo [1.1.1] pentane derivatives is characterized in that sulfinic acid sodium salt shown in formula (I), 1.1.1] propellane shown in formula (II) and an iodine source are used as raw materials, added into a solvent, reacted under the irradiation of a light source, and after the reaction is finished, a [1.1.1] propellane iodinated and sulfonylated product shown in formula (III) is obtained through post-treatment, wherein the iodine source is diiodomethane or iodoform, and the reaction equation is shown as follows:
in the formula, R is an electron-withdrawing group or an electron-donating group, the electron-withdrawing group is halogen, trifluoromethyl, nitro or cyano, and the electron-donating group is alkyl, alkoxy, phenyl or substituted phenyl.
2. The method for preparing iodobicyclo [1.1.1] pentane derivatives according to claim 1, wherein the heteroaromatic ring is a five-membered aromatic ring containing nitrogen, oxygen or sulfur atoms or a six-membered aromatic ring containing nitrogen atoms.
3. The method for preparing iodobicyclo [1.1.1] pentane derivative according to claim 1, wherein the light source is an ultraviolet lamp, a blue lamp, or a green lamp, and the wattage range is 10W-90W, preferably 40W blue lamp.
4. The method of claim 1, wherein the solvent is one or more of acetonitrile, N-dimethylformamide, dimethylsulfoxide, methanol, nitromethane, and water.
5. The method for preparing an iodobicyclo [1.1.1] pentane derivative according to claim 1, wherein the reaction is carried out in an argon atmosphere or an air atmosphere.
6. A process for the preparation of an iodobicyclo [1.1.1] pentane derivative according to claim 1, wherein the reaction temperature is 20 ℃ to 40 ℃, preferably 30 ℃.
7. The process for the preparation of iodobicyclo [1.1.1] pentane derivatives according to claim 1, wherein the reaction time is 3-24h, preferably 8-12 h.
8. The method for preparing an iodobicyclo [1.1.1] pentane derivative according to claim 1, wherein when the iodine source is diiodomethane, the ratio of the amounts of the sulfinic acid sodium salt, [1.1.1] propeller and the iodine source is 1: (1-3): (1 to 3), preferably 1:2:1.5; when the iodine source is iodoform, the feeding ratio of the sulfinic acid sodium salt to the [1.1.1] propellane to the iodoform is (1-3): (1-3): 1, preferably 1.5:2:1.
9. the method for preparing an iodobicyclo [1.1.1] pentane derivative according to claim 8, wherein when the iodine source is diiodomethane, the solvent is a mixed solvent of acetonitrile and water in a volume ratio of 4; when the iodine source is iodoform, the solvent is a mixed solvent of acetonitrile and water with the volume ratio of 10.
10. The method for preparing iodo-bicyclo [1.1.1] pentane derivatives according to claim 1, wherein the method comprises the following steps: adding sodium sulfinate, 1.1.1 spirostane and an iodine source into a reaction tube according to the feeding molar ratio, adding a solvent, reacting for 12 hours under the irradiation of a 40W blue light lamp, adding saturated sodium thiosulfate into a reaction liquid after the reaction is completed to quench the reaction, then adding ethyl acetate and water to dilute, extracting for three times with ethyl acetate, collecting an organic phase, distilling under reduced pressure, and separating by a column to obtain a 1.1.1 spirostane iodinated and sulfonylated product.
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| CN114349774A (en) * | 2021-12-23 | 2022-04-15 | 凯美克(上海)医药科技有限公司 | Preparation method of bicyclo [1.1.1] pentyl angular position borate compound |
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| CN114349774A (en) * | 2021-12-23 | 2022-04-15 | 凯美克(上海)医药科技有限公司 | Preparation method of bicyclo [1.1.1] pentyl angular position borate compound |
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| PICKFORD, HELENA D. 等: "Rapid and Scalable Halosulfonylation of Strain-Release Reagents", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》, pages 202213508 * |
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