CN117903027A - Method for synthesizing asymmetric disulfide compound by photoinduction catalysis - Google Patents
Method for synthesizing asymmetric disulfide compound by photoinduction catalysis Download PDFInfo
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- CN117903027A CN117903027A CN202410062754.3A CN202410062754A CN117903027A CN 117903027 A CN117903027 A CN 117903027A CN 202410062754 A CN202410062754 A CN 202410062754A CN 117903027 A CN117903027 A CN 117903027A
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- 238000000034 method Methods 0.000 title claims abstract description 34
- -1 disulfide compound Chemical class 0.000 title claims abstract description 32
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 239000000758 substrate Substances 0.000 claims abstract description 21
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 20
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims abstract description 10
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 44
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 claims description 16
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 4
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-UHFFFAOYSA-N 0.000 claims description 2
- 239000007836 KH2PO4 Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 2
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 claims 1
- IBTGEEMBZJBBSH-UHFFFAOYSA-N 2,6-dimethoxypyridine Chemical compound COC1=CC=CC(OC)=N1 IBTGEEMBZJBBSH-UHFFFAOYSA-N 0.000 claims 1
- 239000001154 2-(methoxymethyl)pyrazine Substances 0.000 claims 1
- MYDVJLOKNIAHPH-UHFFFAOYSA-N 2-Methoxy-6-methylpyrazine Chemical compound COC1=CN=CC(C)=N1 MYDVJLOKNIAHPH-UHFFFAOYSA-N 0.000 claims 1
- XQABVLBGNWBWIV-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1 XQABVLBGNWBWIV-UHFFFAOYSA-N 0.000 claims 1
- YSHMQTRICHYLGF-UHFFFAOYSA-N 4-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=NC=C1 YSHMQTRICHYLGF-UHFFFAOYSA-N 0.000 claims 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 50
- 150000002019 disulfides Chemical class 0.000 abstract description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 abstract description 9
- 239000011593 sulfur Substances 0.000 abstract description 9
- 238000007306 functionalization reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 239000007800 oxidant agent Substances 0.000 abstract description 2
- 238000007789 sealing Methods 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- 150000003573 thiols Chemical class 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- 238000010257 thawing Methods 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 150000003568 thioethers Chemical group 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 3
- 125000002228 disulfide group Chemical group 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000005691 oxidative coupling reaction Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 description 1
- HUEXNHSMABCRTH-UHFFFAOYSA-N 1h-imidazole Chemical compound C1=CNC=N1.C1=CNC=N1 HUEXNHSMABCRTH-UHFFFAOYSA-N 0.000 description 1
- VCDNEJSJJUVVJY-UHFFFAOYSA-N 2,4,6-trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1.CC1=CC(C)=NC(C)=C1 VCDNEJSJJUVVJY-UHFFFAOYSA-N 0.000 description 1
- NXRGKFVQYZGDIY-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1.CC1=CC=CC(C)=N1 NXRGKFVQYZGDIY-UHFFFAOYSA-N 0.000 description 1
- NMWDYLYNWRFEMR-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1.CC1=CC=CC=N1 NMWDYLYNWRFEMR-UHFFFAOYSA-N 0.000 description 1
- KIDLUFAKISHFQQ-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1(=CC=CC=C1)C1=NC=CC=C1.C1(=CC=CC=C1)C1=NC=CC=C1 KIDLUFAKISHFQQ-UHFFFAOYSA-N 0.000 description 1
- XZEIEWPMMMPSFY-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1.COC1=CC=NC=C1 XZEIEWPMMMPSFY-UHFFFAOYSA-N 0.000 description 1
- TXWBZNOXADEHRQ-UHFFFAOYSA-N 4-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=NC=C1.CC(C)(C)C1=CC=NC=C1 TXWBZNOXADEHRQ-UHFFFAOYSA-N 0.000 description 1
- RXAFXHRAUBYNMP-UHFFFAOYSA-N C(C)(C)(C)C1=NC(=CC=C1)C(C)(C)C.C(C)(C)(C)C1=NC(=CC=C1)C(C)(C)C Chemical compound C(C)(C)(C)C1=NC(=CC=C1)C(C)(C)C.C(C)(C)(C)C1=NC(=CC=C1)C(C)(C)C RXAFXHRAUBYNMP-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 1
- 150000002192 fatty aldehydes Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical group O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing an asymmetric disulfide compound by photoinduction catalysis, which takes benzaldehyde or non-activated fatty alkane as a substrate, takes sulfone disulfide reagent as a sulfur source, takes 390 nm LED as a light source to induce hydrogen atom transfer catalysis, and can realize simple and direct synthesis of disulfide products. The method does not need substrate functionalization, has mild reaction conditions, avoids the use of metal catalysts and oxidants, can obtain asymmetric disulfide compounds with a medium or higher yield, greatly reduces the difficulty and cost of the reaction, and has great significance for realizing accurate functionalization of the medicament in the later stage.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing an asymmetric disulfide compound by photoinduction catalysis.
Background
Disulfide-based compounds have unique reaction characteristics and pharmaceutical chemistry, are widely present in natural products, and play a unique role as a critical structural basis in numerous disciplines such as life sciences, pharmaceutical sciences, food chemistry, material sciences, and the like. Most of the common disulfide bond-containing compounds belong to the asymmetric disulfide group derivatives. The synthesis of asymmetric dithioderivatives is also more difficult than symmetric dithioderivatives due to the problems related to chemical selectivity. The existing methods for preparing the disulfide derivatives mainly comprise methods such as oxidative coupling of different thiols, a thioether exchange method, a nucleophilic substitution method, a nickel-catalyzed reduction thio reaction of tetrasulfide and the like.
Oxidative coupling of (a) different thiols
The synthesis of asymmetric disulfide bonds by oxidation of thiols is one of the simple and convenient methods, but it is difficult to avoid the formation of symmetric disulfide derivatives and other by-products.
Obtaining asymmetric disulfide compounds by oxidative coupling of different thiols
(Di) thioether exchange process
In 2004 Tanaka et al reported a highly efficient disulfide exchange reaction of symmetrical disulfide bonds and asymmetrical disulfide bonds catalyzed by [ Rh (cod) 2]BF4 under argon shield. No other additives or ligands are required for this reaction. This reaction is applicable to different alkyl, aryl and heteroaryl dithio groups in good to excellent yields (74% -95%).
Obtaining asymmetric disulfide compounds by thioether exchange process
Tanaka et al have conducted intensive studies on the mechanism of this reaction, suggesting a possible mechanism in which the process is reversible, which results in that an excessive amount of disulfide is required for the reaction in order to promote the equilibrium of the reaction.
(III) nucleophilic substitution method
In 2011, hahn et al, who studied all mechanochemical laboratories in korea, reported a novel method for synthesizing asymmetric disulfide compounds by reacting sulfonyl chloride with thiol. In the reaction mechanism they propose, sulfonyl chloride reacts with thiol or symmetrical disulfide groups to form chlorinated thioethers, which are key intermediates for the reaction. And reacting with another molecule of mercaptan under the action of alkali to obtain the asymmetric disulfide compound. The method is suitable for aliphatic mercaptan and aromatic mercaptan, and the yield is in the range of 50-96%.
Obtaining asymmetric disulfide compounds by nucleophilic substitution
(IV), nickel-catalyzed reduction of tetrasulfide
Inspired by Pratt work, wang devised a method for successfully exploiting the cross-coupling reaction of unactivated alkyl bromides with symmetrical tetrasulfide using a nickel catalyzed reduction coupling strategy to construct asymmetric alkyl-alkyl disulfides and alkyl-aryl disulfides, the asymmetric disulfides being prepared from halogenated hydrocarbons by nickel catalyzed tetrasulfide cross-electroreagent coupling. The reaction is carried out under mild conditions, has good chemoselectivity and can effectively assemble disulfide with different modifications.
Asymmetric disulfide based compounds obtained by nickel catalysis of tetrasulfide
In the reported studies, many reactions require a large number of functionalization modifications on the reaction substrate, which makes the range of the reaction substrate limited and increases the difficulty and cost of the reaction to some extent, which makes the asymmetric disulfide-based compounds of great value in practical use. For this reason, it is necessary and interesting to develop a new method for synthesizing asymmetric disulfide compounds which is simple to operate, mild in reaction conditions and applicable to C-H substrates without prior functionalization.
The invention comprises the following steps:
The invention aims to provide a method for synthesizing an asymmetric disulfide compound by photoinduced catalysis.
The invention adopts the following technical scheme:
a method for synthesizing an asymmetric disulfide compound by photoinduction catalysis comprises the steps of taking cyclohexane, cyclohexanone, benzaldehyde, p-methoxybenzaldehyde or 3-phenylpropionaldehyde as a substrate, taking phenylsulfonyl tertiary butyl disulfide as a disulfide bond donor, taking tetrabutylammonium decatungstate (TBADT) as a catalyst, and synthesizing the asymmetric disulfide compound by photoinduction catalysis under an alkaline condition; the asymmetric disulfide-based compound has a structure shown in 3a-3 e;
According to one embodiment of the invention, the base is selected from one or several combinations of sodium bicarbonate, pyridine (pyridine), 2,6-lutidine (2, 6-Lutidine), quinuclidine (quinuclidine), triethylenediamine (DABCO), 2,4, 6-collidine (2, 4, 6-TRIMETHYLPYRIDINE), isoquinoline (isoquinoline), 4-methoxypyridine (4-methoxypyridine), 4-tert-butylpyridine (4- (tert-butyl) pyridine), 2,6-dimethoxypyridine (2, 6-dimethoxypyridine), 2-methylbenzimidazole (2-methyl-1H-benzod imidazole), 1H-imidazole (1H-imidazole), 2-methylpyridine (2-METHYLPYRIDINE), quinoline (quinline), 2-methoxy-6-methylpyridine (2-methoxy-6-METHYLPYRIDINE), 2,6-di-tert-butylpyridine (2, 6-di-tert-butylpyridine), 2-phenylpyridine (2-phenylpyridine)、NaHCO3、KHCO3、Na2CO3、K2HPO4、K3PO4、K2CO3、NaHSO3、KH2PO4.
According to one embodiment of the invention, when the starting material is cyclohexane or cyclohexanone and the corresponding asymmetric disulfide compound is 3a or 3c, the base is sodium bicarbonate.
According to one embodiment of the invention, when the starting material is benzaldehyde, p-methoxybenzaldehyde or 3-phenylpropionaldehyde, the corresponding asymmetric disulfide compound is 3b, 3d or 3e, the base is sodium bisulphite or 2, 6-lutidine.
According to one embodiment of the invention, the light is LED light with a wavelength of 390nm.
According to one embodiment of the invention, when the starting material is cyclohexane or cyclohexanone, the corresponding asymmetric disulfide compound is 3a or 3c, the disulfide donor is used in an amount of 0.2 to 3 equivalents.
According to one embodiment of the invention, when the starting material is benzaldehyde, p-methoxybenzaldehyde or 3-phenylpropionaldehyde, the corresponding asymmetric disulfide compound is 3b, 3d or 3e, the disulfide bond donor is used in an amount of 0.2 to 5.0 equivalents.
According to one embodiment of the invention, the solvent is one or a combination of several of acetonitrile, water, acetone and chlorodichloroethane. Preferably, the solvent comprises acetonitrile; further, the solvent is a mixed solvent of acetonitrile and water, wherein the dosage ratio of acetonitrile to water is 1-9:1, a step of; still further, the ratio of acetonitrile to water was 1:1.
Advantageous effects
The invention discloses a method for synthesizing an asymmetric disulfide compound by photoinduction catalysis, which takes benzaldehyde or non-activated fatty alkane as a substrate, takes sulfone disulfide reagent as a sulfur source, takes a 390nm LED as a light source to induce hydrogen atom transfer catalysis, and can realize simple and direct synthesis of disulfide products. This is a new method which has not been mentioned at all in the previous studies. The method does not need substrate functionalization, has mild reaction conditions, avoids the use of metal catalysts and oxidants, can obtain asymmetric disulfide compounds with a medium or higher yield, greatly reduces the difficulty and cost of the reaction, and has great significance for realizing accurate functionalization of the medicament in the later period.
Detailed Description
In order to further illustrate the present invention and its advantages, the following description of the embodiments of the invention further illustrates the technical solution of the present invention, it should be understood that these examples only help to understand the present invention and should not be construed as limiting the invention in any way.
Except for special descriptions, the parts are parts by weight, and the percentages are mass percentages.
EXAMPLE 1 preparation of Compounds from 3a
The synthetic route is as follows:
The operation steps are as follows:
1) Aliphatic hydrocarbon substrate (5.0 eq) (cyclohexane, cyclohexanone, etc.), phenylsulfonyl tertiary butyl disulfide (1.0 eq), tetrabutylammonium decatungstate (TBADT) (4 mol%) and sodium bicarbonate (1.5 eq) were mixed in acetonitrile solution (0.1M) in a sealed tube with magnetic stirrer;
2) Sealing the sealing tube and placing the sealing tube in a Dewar bottle filled with liquid nitrogen, opening the sealing tube after the mixed liquid is frozen and connecting the sealing tube on the double calandria for pumping air for 1 to 2 minutes, then sealing the sealing tube again and thawing the sealing tube in water, and repeating the operation for 3 to 4 times;
3) Switching the double-row pipes to a state of filling argon, opening the sealing pipe, and sealing the sealing pipe again after filling argon;
4) The sealed tube is placed on a magnetic stirrer and is modulated and stirred, 390 nm fixed wavelength LED lamp (40W) is used for irradiating the reaction liquid, the reaction liquid is about 1 to 2 cm away from the light source and is free from shielding, a small fan is erected to ensure that the reaction temperature is about 25 ℃, and the reaction time is about 1 to 2 hours.
And (3) purification:
the product reaction can be obtained through chromatographic column separation, the polarity of the separating eluent is between the polarity of pure petroleum ether and the polarity of petroleum ether: diethyl ether=50:1 according to different aliphatic hydrocarbon substrates, the separating result can be observed through TLC plate oxidation color development, and the color developing agent is phosphomolybdic acid ethanol solution or potassium permanganate solution.
The effect of different bases on the reaction was examined with reference to example 1 above.
a Standard conditions 1a (1.0 mmol), 2a (0.2 mmol), TBADT (4 mol%), and MeCN (2 mL) were irradiated under a schlenk tube (20 mL) with a 390nm fixed wavelength LED (40W) light source. The schlenk tube was placed in a dewar and cycled 3 times with liquid nitrogen freezing, pumping, thawing operations, and then replaced with argon for air.
b Using dibromomethane as an internal standard, estimated by crude 1 H-NMR analysis.
According to the experimental results, when Na 2CO3 is selected as a reaction additive base, the conversion rate of the reaction substrate 2a reaches 100%, and the target product is the optimal yield.
The effect of the amount of different sulfur sources on the reaction was examined with reference to example 1 above.
a Standard conditions 1a (1.0 mmol), 2a, TBADT (4 mol%), and MeCN (2 mL) were irradiated with a 390nm fixed wavelength LED (40W) light source under a schlenk tube (20 mL). The schlenk tube was placed in a dewar and cycled 3 times with liquid nitrogen freezing, pumping, thawing operations, and then replaced with argon for air.
b Using dibromomethane as an internal standard, estimated by crude 1 H-NMR analysis.
According to the experimental result, when an excessive sulfur source is selected to participate in the reaction, the yield of the target product can be greatly improved; however, the reaction is still preferred for the excess of C-H substrate, considering that the unactivated alkane substrate is more accessible, the sulfur source is more costly than the one, and that the reaction gives the desired product in moderate or higher yields when the alkane substrate is in excess.
The effect of different solvents on the reaction was examined with reference to example 1 above.
a Standard conditions 1a (1.0 mmol), 2a (0.2 mmol), TBADT (4 mol%) and the corresponding solvents (2 mL) were irradiated under a schlenk tube (20 mL) with a 390nm fixed wavelength LED (40W) light source. The schlenk tube was placed in a dewar and cycled 3 times with liquid nitrogen freezing, pumping, thawing operations, and then replaced with argon for air.
b Using dibromomethane as an internal standard, estimated by crude 1 H-NMR analysis.
According to the experimental results, when acetonitrile or acetone is selected for the reaction: when water (1:1) is used as a solvent, the conversion rate of the reaction substrate 2a reaches 100%, and the yield of the target product is optimal; consider the use of the single reagent acetonitrile as a solvent versus acetone: water (1:1) is more convenient and therefore it is the optimal reaction condition.
Example 2 preparation of Compound 3b
The synthetic route is as follows:
The method comprises the following steps:
1) Benzaldehyde or fatty aldehyde substrate (5.0 eq) (benzaldehyde, p-methoxybenzaldehyde, 3-phenylpropionaldehyde, etc.), phenylsulfonyl tertiary butyl disulfide (1.0 eq), tetrabutylammonium decatungstate (TBADT) (4 mol%) and sodium bicarbonate (1.5 eq) are mixed and dissolved in acetonitrile solution (0.1M) in a sealed tube with a magnetic stirrer;
2) Sealing the sealing tube and placing the sealing tube in a Dewar bottle filled with liquid nitrogen, opening the sealing tube after the mixed liquid is frozen and connecting the sealing tube on the double calandria for pumping air for 1 to 2 minutes, then sealing the sealing tube again and thawing the sealing tube in water, and repeating the operation for 3 to 4 times;
3) Switching the double-row pipes to a state of filling argon, opening the sealing pipe, and sealing the sealing pipe again after filling argon;
4) The sealed tube is placed on a magnetic stirrer and is modulated and stirred, 390 nm fixed wavelength LED lamp (40W) is used for irradiating the reaction liquid, the reaction liquid is about 1 cm to 2 cm away from the light source and is free from shielding, a small fan is erected to ensure that the reaction temperature is about 25 ℃, and the reaction time is about 2 hours to 4 hours.
Purifying:
The product reaction can be obtained by chromatographic column separation, the polarity of the separating eluent is about petroleum ether/diethyl ether=100:1 according to different aliphatic hydrocarbon substrates, and the separation result can be observed by TLC plate.
The effect of different organic bases on the reaction was examined with reference to examples 1 and 2 above.
According to the above reaction results, when the organic base 2, 6-lutidine is selected as an additive for the reaction, the yield of the reaction target product 3b is optimal, and the byproducts 4a, 5a are relatively few.
The effect of different inorganic bases on the reaction was examined with reference to examples 1 and 2 above.
According to the reaction result, when inorganic alkali sodium bisulphite is selected as an additive in the reaction, the yield of a reaction target product 3b is optimal, and byproducts 4a are relatively fewer; although the by-product 4a is less and the yield of the target product 3b is not much different when the organic base 2, 6-lutidine is selected, sodium sulfite is selected as the reaction additive under optimal conditions in view of the fact that the use of an inorganic base is relatively more environmentally friendly.
The effect of the reaction of the sulfur source at different dosages was examined with reference to examples 1 and 2 above.
According to the above experimental results, when an excessive amount of sulfur source is selected as the reaction condition, the yield of the target product is not significantly improved, and the reaction by-product 5a is significantly increased when the sulfur source substrate 2a is 3-fold equivalent; in addition, the C-H substrate is more available relative to the sulfur source substrate, so the reaction is still optimized for a 1b excess.
Referring to example 1, a 3c compound was prepared using cyclohexanone as a starting material. Referring to example 2, 3d compounds were synthesized starting from p-methoxybenzaldehyde. Referring to example 2, 3e compounds were synthesized starting from 3-phenylpropionaldehyde.
The structural formula and nuclear magnetic data of the compound are as follows:
1-(tert-butyl)-2-cyclohexyldisulfane:1H NMR(600MHZ,CDCl3)δ2.72-2.65(m,1H),2.07(dd,J＝8.6,4.5,2H),1.79–1.76(m,2H),1.62–1.58(m,1H),1.31(s,9H),1.29-1.16(m,5H).13C NMR(151MHz,CDCl3)δ50.42,49.10,47.21,32.96,30.21,30.02,26.01,25.76(3C).
3-(tert-butyldisulfaneyl)cyclohexan-1-one:1H NMR(600MHz,CDCl3)δ3.06(tt,J＝10.4,4.2Hz,1H),2.79(ddt,J＝14.3,4.3,1.8Hz,1H),2.39–2.33(m,2H),2.32–2.23(m,2H),2.18–2.09(m,1H),1.78–1.62(m,2H),1.32(s,9H).13C NMR(151MHz,CDCl3)δ208.49,49.05,47.72,47.33,40.85,31.17,30.01,24.14(3C).
SS-(tert-butyl)benzo(dithioperoxoate):1H NMR(600MHz,CDCl3)δ8.04(dd,J＝7.1Hz,2H),7.62(t,J＝7.5Hz,1H),7.49(dd,J＝8.3,7.4Hz,2H),1.36(s,9H).13C NMR(151MHz,CDCl3)δ190.42,135.94,133.91,128.84(2C),127.79(2C),49.09,29.83(3C).
SS-(tert-butyl)4-methoxybenzo(dithioperoxoate):1H NMR(600 MHz,CDCl3)δ8.02(d,J＝8.9Hz,1H),6.95(d,J＝8.9Hz,1H),3.88(s,2H),1.35(s,6H).13C NMR(151MHz,CDCl3)δ188.54,164.24,130.05(2C),128.70,114.04(2C),55.55,48.83,29.81(3C).
SS-(tert-butyl)3-phenylpropane(dithioperoxoate):1H NMR(600 MHz,CDCl3)δ7.36–7.27(m,2H),7.21(tt,J＝7.9,1.3Hz,3H),3.02(s,4H),1.28(s,9H).13C NMR(151MHz,CDCl3)δ197.60,139.71,128.58(2C),128.35(2C),48.74,43.80,31.41,29.71(3C).
Claims (10)
1. A method for synthesizing an asymmetric disulfide compound by photoinduction catalysis comprises the steps of taking cyclohexane, cyclohexanone, benzaldehyde, p-methoxybenzaldehyde or 3-phenylpropionaldehyde as a substrate, taking phenylsulfonyl tertiary butyl disulfide as a disulfide bond donor, taking tetrabutylammonium decatungstate (TBADT) as a catalyst, and synthesizing the asymmetric disulfide compound by photoinduction catalysis under an alkaline condition; the asymmetric disulfide-based compound has a structure shown in 3a-3 e;
2. The method of claim 1, wherein the base is selected from one or a combination of sodium bicarbonate, pyridine, 2, 6-lutidine, quinuclidine, triethylenediamine, 2,4, 6-collidine, isoquinoline, 4-methoxypyridine, 4-t-butylpyridine, 2, 6-dimethoxypyridine, 2-methylbenzimidazole, 1H-imidazole, 2-picoline, quinoline, 2-methoxy-6-methylpyrazine, 2, 6-di-t-butylpyridine, 2-phenylpyridine 、NaHCO3、KHCO3、Na2CO3、K2HPO4、K3PO4、K2CO3、NaHSO3、KH2PO4.
3. The process according to claim 1, wherein when the starting material is cyclohexane or cyclohexanone and the corresponding asymmetric disulfide compound is 3a or 3c, the base is sodium bicarbonate.
4. The process of claim 1, wherein when the starting material is benzaldehyde, p-methoxybenzaldehyde or 3-phenylpropionaldehyde and the corresponding asymmetric disulfide compound is 3b, 3d or 3e, the base is sodium bisulphite or 2, 6-lutidine.
5. The method of any one of claims 1-4, wherein the light is LED light having a wavelength of 390nm.
6. The process according to claim 5, wherein the disulfide bond donor is used in an amount of 0.2 to 3 equivalents when the starting material is cyclohexane or cyclohexanone and the corresponding asymmetric disulfide compound is 3a or 3 c.
7. The method according to claim 5, wherein the disulfide bond donor is used in an amount of 0.2 to 5.0 equivalents when the starting material is benzaldehyde, p-methoxybenzaldehyde or 3-phenylpropionaldehyde and the corresponding asymmetric disulfide compound is 3b, 3d or 3 e.
8. The method of claim 5 or 6, wherein the solvent is one or a combination of acetonitrile, water, acetone, and chlorodichloroethane.
9. The method of claim 8, wherein the solvent comprises acetonitrile, and the solvent is a mixed solvent of acetonitrile and water, wherein the ratio of acetonitrile to water is 1-9:1.
10. The method of claim 9, wherein the ratio of acetonitrile to water is 1:1.
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