CN109956960B - Synthetic method of isothiourea catalyst - Google Patents

Synthetic method of isothiourea catalyst Download PDF

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CN109956960B
CN109956960B CN201711434362.1A CN201711434362A CN109956960B CN 109956960 B CN109956960 B CN 109956960B CN 201711434362 A CN201711434362 A CN 201711434362A CN 109956960 B CN109956960 B CN 109956960B
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isothiourea
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孙智华
吴圣峰
戴伊如
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Shanghai University of Engineering Science
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The invention relates to the field of organic chemistry, in particular to a synthetic method of an isothiourea catalyst. The method comprises the following steps: (1) synthesizing o-nitrobenzene tert-butyl thioether from o-fluoronitrobenzene serving as a starting material and tert-butyl mercaptan under the alkali catalysis condition; (2) hydrogenating the o-nitrobenzene tert-butyl thioether to generate o-aminophenyl tert-butyl thioether; (3) oxidizing the o-aminophenyl tert-butyl thioether to obtain o-aminophenyl tert-butyl sulfoxide; (4) the o-aminobenzene tert-butyl sulfoxide reacts with an isocyano-p-toluene propyl sulfonate compound to prepare the isothiourea organic catalyst. The method of the invention utilizes multi-component reaction, and three functional groups are converted into a new functional group without metal and efficiently; each step has high yield, low atom cost, less pollution, simple operation, low cost and mild reaction condition, is suitable for batch industrial production, and has wide application prospect.

Description

Synthetic method of isothiourea catalyst
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a method for synthesizing an organic catalyst, in particular to a method for synthesizing an isothiourea catalyst.
Background
The organic catalyst is used for catalyzing organic reaction, and has the advantages of mild reaction conditions, high yield, high reaction speed and the like, so the development of the high-efficiency organic catalyst is very important, and particularly the organic catalyst with wide application is used. The isothiourea organic catalyst plays a relatively good catalytic role in chiral synthesis, esterification, carbon acylation, heterocyclic ring synthesis and the like, and plays a very important role in catalytic synthesis of active medicines and pesticides.
org.Lett.,2006,10,1351-1354 found that BTM (CAS:885051-07-0) is highly effective in the kinetic resolution of secondary benzyl alcohol, and can enantioselectively catalyze the acylation reaction of the silane acetal carbon with the selectivity as high as 355.
Figure BDA0001525547390000011
A.J.Wagner, J.G.David and S.D.Rychnovsky, (org.Lett.,2011,13, 4470-4473.) found that HBTs with different configurations had different reaction rates during the hydroxyl esterification process, thereby enabling kinetic resolution.
Figure BDA0001525547390000021
Smith et al found that (2S,3R) -HyperBTM (CAS:1203507-02-1) catalyzes the intermolecular Michael addition of an aryl acetic acid and an α -keto- β, γ -unsaturated ester to form a chiral lactone with an ee value of up to 99% (J.Am.chem.Soc.2011,133, 2714-2720).
Figure BDA0001525547390000022
The document j.am.chem.soc.2010,132, 11629-11641 states that (S) -2- (naphthalen-1-yl) -2, 3-dihydrobenzo [ d ] imidazo [2,1-b ] thiazole ((S) -Np-BTM) as an acyl transfer catalyst gives very stereoselective acid esters in kinetic resolution of racemic r-arylalkanoic acids.
Figure BDA0001525547390000023
DHPB is a catalyst with wide application, has more catalytic reaction types, has better application in the aspects of esterification, carbon acylation and synthesis of heterocyclic ring and substituted heterocyclic ring, and compared with DBU,
the DHPB is obviously improved by amine catalysts such as DMAP. The structure of the compound is as follows:
Figure BDA0001525547390000031
org, lett, 2014,16, 964-one-pot 967, using DHPB as catalyst, to synthesize trifluoromethyl-substituted pyrones.
Figure BDA0001525547390000032
Org, Lett.,2014,16, 6496-. The tetra-substituted pyridine has great effects on pesticides, medicines and materials.
Figure BDA0001525547390000033
Org, Lett.,2010,12,2660-2663, utilizes DHPB as a catalyst to catalyze the acylation reaction of the carbon silanolate with a yield of over 90%, preferably 99/1.
Figure BDA0001525547390000034
In the conventional method for synthesizing the isothiourea organic catalyst, a compound 7 as a key intermediate is basically required to be prepared, and in the following conventional preparation method, 3-aminopropanol and the compound 7 are basically reacted and then subjected to a photocyclization reaction to obtain a target product DHPB.
Med. chem.,2016,59, 2612-one-step 2632 describes a preparation method of isothiourea compounds, which comprises the steps of preparing a compound 7 from 6 serving as a raw material under the conditions of tert-butyl nitrite and cuprous chloride, reacting with 3-aminopropanol at 130 ℃ for 3 hours under an alkaline condition to obtain 8, and continuously reacting after hydroxyl is sulfonylated by p-methylbenzene under the alkaline condition to obtain a target product, wherein the target total yield is less than 50%, and the reaction temperature is higher.
Figure BDA0001525547390000041
The title of Shijiazhuang academy, 2013,15,22-24, describes the use of compound 9 as the starting material, chlorinated with oxalyl chloride, refluxed for 5 hours to give intermediate compound 7.
Figure BDA0001525547390000042
J.org.chem.,2009,74, 8309-containing 8313 uses benzothiazole as a raw material, reacts with carbon tetrachloride as a chlorine source and DMF as a solvent under the condition of lithium tert-butoxide to generate a compound 7, and the poisonous substance carbon tetrachloride is used in the reaction, and the yield is not high as the multi-step synthesis.
In view of the fact that isothiourea organic catalysts are organic catalysts with great application value prospects, it is very meaningful to find a convenient and low-cost synthesis method.
Disclosure of Invention
In order to solve the problems, the method provides a novel method which utilizes multi-component reaction, does not have metal, can efficiently convert three functional groups into a new functional group, has simple operation, lower cost, higher yield, atom economy and less pollution and is suitable for industrial production.
A new method for synthesizing isothiourea organic catalyst is disclosed, the isothiourea organic catalyst is shown in formula A and B, the steps are as follows:
Figure BDA0001525547390000051
wherein R is1Is composed of
Figure BDA0001525547390000052
R2Is H or
Figure BDA0001525547390000053
R3Is a compound of formula (I) in the formula (H),
Figure BDA0001525547390000054
preferably, R is1Is composed of
Figure BDA0001525547390000055
Or, R2Is H, and R3H or
Figure BDA0001525547390000056
Alternatively, the first and second electrodes may be,
Figure BDA0001525547390000057
and is
Figure BDA0001525547390000058
(1) Synthesizing o-nitrobenzene tert-butyl thioether (compound 2) by taking o-fluoronitrobenzene (compound 1) as a starting material and tert-butyl mercaptan under the base catalysis condition;
(2) hydrogenating the o-nitrobenzene tert-butyl thioether (compound 2) to generate o-aminophenyl tert-butyl thioether (compound 3);
(3) oxidizing the o-aminophenyl tert-butyl thioether (compound 3) to obtain o-aminophenyl tert-butyl sulfoxide (compound 4);
(4) the o-aminobenzene tert-butyl sulfoxide (compound 4) reacts with an isocyano-p-toluene propyl sulfonate compound to prepare an isothiourea organic catalyst (compound A or B);
the structure of the isocyano-p-toluenesulfonic acid propyl ester compound (compound 5) is shown as (5A,5B,5C,5D and 5E) below, and isothiourea organic catalysts of formula A or formula B are respectively obtained;
Figure BDA0001525547390000061
5A and 5D respectively obtain isothiourea organic catalysts shown in the formula A; 5B,5C and 5E respectively to obtain the isothiourea organic catalyst shown in the formula B.
In the step (1), the solvent is one or more of the following substances: toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or methanol, preferably N, N-dimethylformamide; the alkali is 1, 8-diazabicycloundecen-7-ene, sodium carbonate, triethylamine, sodium hydroxide or sodium tert-butoxide, and sodium carbonate is preferred; the reaction time is 2-12h, preferably 8 h.
In the step (2), the catalyst for hydrogenation reaction is Raney nickel or palladium carbon, the dosage is 1wt% -10 wt%, and the preferred catalyst is Raney nickel, the dosage is 5 wt% -10 wt%; the solvent for hydrogenation reaction is at least one of toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or methanol, preferably ethanol or methanol. The hydrogenation reaction conditions are as follows: reacting for 2-6 hours at normal temperature and normal pressure.
In the step (3), the oxidizing agent used in the oxidation reaction is hydrogen peroxide, m-chloroperoxybenzoic acid or potassium permanganate, preferably m-chloroperoxybenzoic acid; the solvent for the oxidation reaction is one or more of the following substances: toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dichloromethane, dimethyl sulfoxide or methanol, preferably dichloromethane. The reaction conditions are as follows: adding an oxidant at the temperature of minus 20-25 ℃, and reacting for 20-60 minutes; preferably: adding an oxidant at the temperature of minus 20-10 ℃, and reacting for 20-40 minutes; more preferably, the reaction temperature is from-20 to-5 ℃.
And washing the oxidation reaction product, drying and concentrating the organic phase, and separating by using a silica gel column to obtain the o-aminophenyl tert-butyl sulfoxide. The silica gel column separation conditions were: the volume ratio is 3-6: 1, preferably under conditions such that the elution is carried out with a petroleum ether/ethyl acetate ratio of 1: 4 petroleum ether/ethyl acetate.
In the step (4), the molar ratio of the o-aminobenzene tert-butyl sulfoxide (compound 4) to the isocyanato-p-toluenesulfonyl propyl ester compound is 1: 1-2, preferably 1: 1.0 to 1.1, more preferably 1: 1.1; the reaction conditions are as follows: reacting for 2-12 hours at the temperature of 40-120 ℃, preferably reacting for 3-10 hours at the temperature of 80-115 ℃, and more preferably reacting for 3-8 hours at the temperature of 95-105 ℃; the solvent for the reaction is one or more of the following: dioxane, toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dichloromethane, dimethyl sulfoxide or methanol, preferably toluene or dioxane. And washing the reaction solution, separating, drying and concentrating the organic phase, and separating by a silica gel column to obtain the isothiourea organic catalyst.
Preferably, in the step (4), the solvent for the reaction is dioxane or toluene, and the molar ratio of the o-aminobenzene tert-butyl sulfoxide to the isocyanato-p-toluenesulfonyl propyl ester compound is 1:1 to 1.1, and reacting for 3 to 8 hours at the temperature of 95 to 105 ℃ under the protection of nitrogen or inert gas; and washing the reaction solution, separating, drying and concentrating the organic phase, and separating by a silica gel column to obtain the isothiourea organic catalyst. The silica gel column separation conditions were: mixing the components in a volume ratio of 1: eluting with 8-10 parts of methanol/dichloromethane; more preferably, the ratio of 1: methanol/dichloromethane elution of 10.
Preferably, the prepared isothiourea organic catalyst is a compound DHPB (3, 4-dihydro-2H-benzol [4,5]]thiazolo[3,2-a]pyrimidine), i.e., a structure of formula B, and R2＝H、R3When ═ H, the reaction solvent of step (4) is toluene or dioxane, more preferably toluene; the prepared isothiourea organic catalyst is HBTM or (2S,3R) -HyperBTM, namely a structure shown as a formula B, and R is2＝H、
Figure BDA0001525547390000071
Or
Figure BDA0001525547390000072
In this case, the reaction solvent in the step (4) is dioxane. When the prepared isothiourea organic catalyst is of a structure shown in a formula A (namely BTM or (S) -Np-BTM), the reaction solvent in the step (4) is dioxane.
Preferably, the isocyanato-propyl p-toluenesulfonate compound 5 in the step (4) is (R) -2-isocyano-2-phenethyl 4-methylbenzenesulfonate (5A), and the obtained isothiourea organic catalyst is (R) -2-phenyl-2, 3-dihydrobenzo [ d ] imidazo [2,1-b ] thiazole, (R) -2-phenyl-2,3-
dihydrobenzol [ d ] imidozole [2,1-b ] thiazole (BTM, CAS:885051-07-0), having the following structure:
Figure BDA0001525547390000081
preferably, the isopropyl p-toluenesulfonate propyl ester compound 5 in the step (4) is (R) -3-isocyano-3-phenylpropyl 4-methylbenzenesulfonate (5B), and the obtained isothiourea organic catalyst is (R) -2-phenyl-3,4-dihydro-2H-benzo [4,5] thiazolo [3,2-a ] pyrimidine, (S) -2-phenyl-3, 4-dihydro-2H-benzoo [4,5] thiazolo [3,2-a ] pyrimidine (HBTM) (CAS:1316861-19-4) has the following structure:
Figure BDA0001525547390000082
preferably, the isopropyl p-toluenesulfonate propyl isocyanate compound 5 in the step (4) is (S) -2- ((S) -isocyano (phenyl) methyl) -3-methylbutyl 4-methylbenzenesulfonate (5C), and the obtained isothiourea organic catalyst is (2S,3R) -3-isopropyl-2-phenyl-3,4-dihydro-2H-benzo [4,5] thiazolo [3,2-a ] pyrimidine, (2S,3R) -3-isoproxyl-2-phenyl-3, 4-dihydo-2H-benzol [4,5] thiazolo [3,2-a ] pyrimidi ((2S,3R) -perbtm) (CAS:1203507-02-1) has the following structure:
Figure BDA0001525547390000083
preferably, the isocyanato-propyl p-toluenesulfonate compound 5 in the step (4) is (R) -3-isocyano-3- (naphthalene-1-yl) propyl 4-methylbenzenesulfonate (5D), and the obtained isothiourea organic catalyst is (S) -2- (naphthalene-1-yl) -2, 3-dihydrobenzo [ D ] imidazo [2,1-b ] thiazole ((S) -Np-BTM) and has the following structure:
Figure BDA0001525547390000084
preferably, the isocyanato-propyl-p-toluenesulfonate compound 5 in the step (4) is 3-isocyano propyl-1-p-methylbenzenesulfonate (5E), and the obtained isothiourea organic catalyst is 3, 4-dihydro-2H-benzol [4,5] thiazolo [3,2-a ] pyrimidine (dhpb), and has the following structure:
Figure BDA0001525547390000091
the method has the beneficial effects that o-fluoronitrobenzene is used as a raw material to synthesize a compound 3-o-aminobenzene tert-butyl sulfoxide to react with an isocyano-p-toluenesulfonate propyl compound, and a multi-component reaction is adopted in the last key step, so that the isothiourea organic catalyst is obtained. The method of the invention utilizes multi-component reaction to efficiently convert three functional groups into a new functional group; each step has high yield, low atom cost, less pollution, simple operation, low cost and mild reaction condition, is suitable for batch industrial production, and has wide application prospect.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
Figure BDA0001525547390000092
EXAMPLE 1 Synthesis of Compound 2 (o-nitrophenyl tert-butyl sulfide)
2.8g (0.02mol) o-fluoronitrobenzene (Compound 1) was dissolved in 40ml DMF solvent, 4.3g (0.03mol) potassium carbonate solid was added, the temperature was raised to 80 ℃ and 2.0g (0.022mol) t-butylmercaptan was added dropwise and the reaction was continued for 2 h. After the reaction, 100ml of water and 100ml of dichloromethane were added for extraction, and the organic phase was washed twice with 100ml of water. The organic phase was concentrated to give 4.2g (0.0199mol) of Compound 2 (o-nitrophenyl tert-butyl sulfide) in 99% yield. (1H NMR(400MHz,CDCl3)δ7.71(dd,J＝7.6,1.5Hz,1H),7.66(dd,J＝7.7,1.6Hz,1H),7.49(dqd,J＝15.0,7.5,1.6Hz,2H),1.31(s,9H)).
EXAMPLE 2 Synthesis of Compound 3 (o-aminophenyl tert-butyl sulfide)
Dissolving 4.2g (0.0199mol) of the compound 2 (o-nitrophenyl tert-butyl sulfide) in methanol, adding 400mg of Raney nickel under the protection of nitrogen, reacting for 4 hours at normal temperature and pressure under the condition of hydrogen, performing suction filtration, and concentrating the filtrate to obtain 3.4g (0.0188mol) of the compound 3 (o-aminophenyl tert-butyl sulfide) with the yield of 94%.
EXAMPLE 3 Synthesis of Compound 4 (o-aminophenyl tert-butyl sulfoxide)
1.8g (0.01mol) of the compound 3 (o-aminophenyl tert-butyl thioether) is dissolved in 20ml of dichloromethane solution, the temperature is reduced to-10 ℃, m-CPBA solution (2.1g (0.012mol) is dissolved in 20ml of dichloromethane) is dripped, after the dripping is finished, the reaction is carried out for half an hour, the filtration is carried out, the filtrate is washed twice by 40ml of saturated sodium sulfite and once by 40ml of saturated sodium carbonate. The organic phase was dried over sodium sulfate, concentrated and separated with silica gel column (petroleum ether: ethyl acetate 4:1) to obtain 1.8g (0.009mol) of compound 4 (o-aminobenzene tert-butyl sulfoxide) in 90% yield. (1H NMR(400MHz,CDCl3)δ7.24–7.17(m,1H),7.10(d,J＝7.0Hz,1H),6.71(t,J＝7.5Hz,1H),6.63(d,J＝8.2Hz,1H),5.15(s,2H),1.31(s,9H).13C NMR(100MHz,CDCl3)δ149.4,131.8,128.8,117.9,117.5,116.4,58.8,23.5.HRMS(ESI)m/z calcd for C10H15NOS[M+H]+198.0947,found 198.0927).
EXAMPLE 4 Synthesis of Compound 4 (o-aminophenyl tert-butyl sulfoxide)
1.8g (0.01mol) of the compound 3 are dissolved in 20ml of dichloromethane solution, the temperature is reduced to 10 ℃, m-CPBA solution (2.1g (0.012mol) is dissolved in 20ml of dichloromethane) is added dropwise, after the dropwise addition is finished, the reaction is carried out for half an hour, the filtration is carried out, the filtrate is washed twice by 40ml of saturated sodium sulfite and once by 40ml of saturated sodium carbonate. The organic phase was dried over sodium sulfate, concentrated and separated with silica gel column (petroleum ether: ethyl acetate 4:1) to obtain 1.5g (0.0076mol) of compound 4 (o-aminobenzene tert-butyl sulfoxide) (yield 76%).
Example 5 Synthesis of DHPB
1.97g (0.01mol) of Compound 4 and 2.63g (0.011mol) of 3-isocyanopropyl-1-p-methylbenzenesulfonate (5E) are dissolved in 40mL of toluene, the mixture is reacted for 4 hours at 100 ℃ under nitrogen protection, 50mL of saturated aqueous sodium carbonate solution is added after the reaction is completed for liquid separation, the organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the mixture is purified by methanol: dichloromethane: 1:10 column chromatography on silica gel afforded 1.6g (86% yield) of the product DHPB. ESIMS: C10H10N2S (M + H +)191.06 (C10H 2H +) to (C10H 2H + 191.06)1H NMR(400MHz,CDCl3)δ7.35–7.24(m,2H),7.20(td,J＝7.9,1.1Hz,1H),7.00(td,J＝7.6,1.0Hz,1H),6.75(d,J＝8.0Hz,1H),3.81–3.71(m,2H),3.62–3.53(m,2H),2.09–1.96(m,2H)).
Example 6 Synthesis of DHPB
1.97g (0.01mol) of Compound 4 and 2.63g (0.011mol) of 3-isocyanopropyl-1-p-methylbenzenesulfonate (5E) are dissolved in 40mL of toluene, the mixture is reacted for 4 hours at 80 ℃ under nitrogen protection, 50mL of saturated aqueous sodium carbonate solution is added after the reaction is completed for liquid separation, the organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the mixture is purified by methanol: dichloromethane: silica gel column separation with 1:10 eluent gave 0.5g of DHPB (yield 26%).
Example 7 Synthesis of Compound DHPB
1.97g (0.01mol) of Compound 4 and 2.63g (0.011mol) of 3-isocyanopropyl-1-p-methylbenzenesulfonate (5E) were dissolved in 40mL of dioxane, the mixture was heated to 100 ℃ under nitrogen protection to react for 4 hours, 50mL of saturated aqueous sodium carbonate solution was added after the reaction was completed for liquid separation, the organic phase was dried over sodium sulfate and then concentrated under reduced pressure, and the mixture was purified by methanol: dichloromethane: 1:10 eluent silica gel column separation gave 1.1g of the product DHPB (58% yield).
EXAMPLE 8 Synthesis of Compound BTM
1.97g (0.01mol) of Compound 4 and 3.01g (0.01mol) of (R) -2-isocyano-2-phenethyl 4-methylbenzenesulfonate (5A) were dissolved in 40mL of dioxane, the temperature was raised to 100 ℃ under nitrogen protection to react for 6 hours, 50mL of a saturated aqueous sodium carbonate solution was added after the reaction was completed for liquid separation, the organic phase was dried over sodium sulfate and concentrated under reduced pressure, and the mixture was purified with methanol: dichloromethane: 1:10 eluent silica gel column separation gave 1.53g of BTM as a product (yield 61%). (1H NMR(400MHz,CDCl3)δ7.45–7.36(m,4H),7.45–7.36(m,4H),7.32(dd,J＝7.5,5.2Hz,2H),7.21(td,J＝7.7,1.0Hz,1H),7.00(td,J＝7.7,0.9Hz,1H),6.69(d,J＝7.5Hz,1H),5.69(dd,J＝10.2,8.1Hz,1H),4.30(dd,J＝10.2,9.0Hz,1H),3.74(t,J＝8.5Hz,1H)).
EXAMPLE 9 Synthesis of HBTM Compound
1.97g (0.01mol) of Compound 4 and 3.15g (0.01mol) of (S) -3-isocyano-3-phenylpropyl 4-methylbenzenesulfonate (5B) were dissolved in 40mL of dioxane, the temperature was raised to 100 ℃ under nitrogen protection to react for 6 hours, 50mL of a saturated aqueous sodium carbonate solution was added after the reaction was completed for liquid separation, the organic phase was dried over sodium sulfate and then concentrated under reduced pressure, followed by reaction with methanol: dichloromethane: 1:10 eluentSilica gel column separation gave HBT M2.20g (yield 83%). (1H NMR(400MHz,CDCl3)δ7.38(d,J＝4.4Hz,4H),7.34(dd,J＝7.7,0.8Hz,1H),7.28(dd,J＝7.7,5.1Hz,1H),7.23(td,J＝7.9,1.1Hz,1H),7.04(td,J＝7.6,0.9Hz,1H),6.77(d,J＝7.9Hz,1H),4.75(dd,J＝8.0,4.0Hz,1H),3.85(ddd,J＝11.5,8.6,4.8Hz,1H),3.78–3.66(m,1H),2.33(ddd,J＝13.7,9.7,5.0Hz,1H),2.10–1.95(m,1H))。
EXAMPLE 10 Synthesis of (2S,3R) -HyperBTM Compound
1.97g (0.01mol) of Compound 4 and 3.57g (0.01mol) of (S) -2- ((S) -isocyano (phenyl) methyl) -3-methylbutyl 4-methylbenzenesulfonate (5C) were dissolved in 40mL dioxane, reacted for 6 hours at 100 ℃ under nitrogen protection, 50mL of a saturated aqueous sodium carbonate solution was added after the reaction was completed for liquid separation, the organic phase was dried over sodium sulfate and concentrated under reduced pressure, washed with methanol: dichloromethane: 1:10 eluent silica gel column separation gave 1.26g (yield 41%) of the product (2S,3R) -HyperBTM. (1H NMR(400MHz,CDCl3):#＝7.35-7.20(m,7H；),7.04(dt,J＝7.6,1.2Hz,1H；),6.81(d,J＝8.0Hz,1H),4.93(dd,J＝4.4,1.6Hz,1H),3.88(ddd,J＝11.6,5.2,1.6Hz,1H),3.35(app.t,J＝11.6Hz,1H),1.96(ddt,J＝11.2,9.2,4.8Hz,1H),1.38-1.23(m,1H),1.14(d,J＝6.4Hz,3H3),0.85(d,J＝6.8Hz,3H))。
EXAMPLE 11 Synthesis of (S) -Np-BTM Compound
1.97g (0.01mol) of Compound 4 and 3.65g (0.01mol) of (R) -3-isocyano-3- (naphthalen-1-yl) propyl 4-methylbenzenesulfonate (5D) were dissolved in 40mL of dioxane, the temperature was raised to 100 ℃ under nitrogen protection to react for 6 hours, 50mL of a saturated aqueous sodium carbonate solution was added after the reaction was completed for liquid separation, the organic phase was dried over sodium sulfate and concentrated under reduced pressure, and the mixture was purified by methanol: dichloromethane: 1:10 eluent silica gel column separation gave 1.90g (yield 63%) of product (S) -Np-BTM. (1H NMR(CDCl3):d 7.98-7.89(m,2H),7.80(d,J＝8.1Hz,1H),7.70(d,J＝7.2Hz,1H),7.62-7.45(m,3H),7.32(dd,J＝7.5,1.0Hz,1H),7.16(td,J＝7.8,1.0Hz,1H),6.97(ddd,J＝7.8,7.5,0.9Hz,1H),6.62(dd,J＝7.8,0.9Hz,1H),6.42(dd,J＝10.5,7.8Hz,1H),4.53(dd,J＝10.5,8.7Hz,1H),3.71(dd,J＝8.7,7.8Hz,1H)；HRMS:C19H15N2S(M+H+)303.0950).

Claims (10)

1. A synthetic method of isothiourea organic catalyst is characterized by comprising the following steps:
(1) synthesizing o-nitrobenzene tert-butyl thioether from o-fluoronitrobenzene serving as a starting material and tert-butyl mercaptan under the alkali catalysis condition;
(2) hydrogenating the o-nitrobenzene tert-butyl thioether to generate o-aminophenyl tert-butyl thioether;
(3) oxidizing the o-aminophenyl tert-butyl thioether to obtain o-aminophenyl tert-butyl sulfoxide;
(4) reacting o-aminobenzene tert-butyl sulfoxide with a compound 5A to prepare an isothiourea organic catalyst BTM; alternatively, the first and second electrodes may be,
reacting o-aminobenzene tert-butyl sulfoxide with a compound 5B to prepare an isothiourea organic catalyst HBTM; alternatively, the first and second electrodes may be,
the o-aminobenzene tert-butyl sulfoxide reacts with a compound 5C to prepare an isothiourea organic catalyst (2S,3R) -HyperBTM; alternatively, the first and second electrodes may be,
the o-aminobenzene tert-butyl sulfoxide reacts with the compound 5D to prepare an isothiourea organic catalyst (S) -Np-BTM; alternatively, the first and second electrodes may be,
reacting o-aminobenzene tert-butyl sulfoxide with a compound 5E to prepare an isothiourea organic catalyst DHPB;
the isothiourea organic catalyst has the following structure:
Figure DEST_PATH_IMAGE001
Figure 219402DEST_PATH_IMAGE002
Figure DEST_PATH_IMAGE003
Figure 866371DEST_PATH_IMAGE004
Figure DEST_PATH_IMAGE005
the 5A is (R) -2-isocyano-2-phenethyl 4-methylbenzenesulfonate, the 5B is (R) -3-isocyano-3-phenylpropyl 4-methylbenzenesulfonate, the 5C is (S) -2- ((S) -isocyano (phenyl) methyl) -3-methylbutyl 4-methylbenzenesulfonate, the 5D is (R) -3-isocyano-3- (naphthalene-1-yl) propyl 4-methylbenzenesulfonate, and the 5E is 3-isocyanopropyl-1-p-methylbenzenesulfonate.
2. The method for synthesizing isothiourea organic catalyst as claimed in claim 1, wherein in step (1), the solvent is one or more of the following substances: toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or methanol; the alkali is 1, 8-diazabicycloundecen-7-ene, sodium carbonate, triethylamine, sodium hydroxide or sodium tert-butoxide; the reaction temperature is 70-90 ℃, and the reaction time is 2-12 h.
3. The method for synthesizing isothiourea organic catalyst according to claim 1, wherein the catalyst for hydrogenation in step (2) is raney nickel or palladium carbon, and the solvent for hydrogenation is at least one of toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or methanol.
4. The method for synthesizing isothiourea organic catalyst as claimed in claim 1, wherein in step (3), the oxidizing agent used in the oxidation reaction is hydrogen peroxide, m-chloroperoxybenzoic acid or potassium permanganate; the solvent for the oxidation reaction is one or more of the following substances: toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dichloromethane, dimethyl sulfoxide or methanol; adding an oxidant at the temperature of-20-25 ℃, and reacting for 20-60 minutes.
5. The method for synthesizing isothiourea organic catalyst as claimed in claim 1, wherein in step (4), the molar ratio of o-aminobenzene tert-butyl sulfoxide to one of compounds 5A-5E is 1: 1-2; the reaction conditions are as follows: reacting for 2-12 hours at the temperature of 40-120 ℃; the solvent for the reaction is one or more of the following: dioxane, toluene, tetrahydrofuran, 1, 2-dichloroethane, ethanol, acetonitrile, N-dimethylformamide, dichloromethane, dimethyl sulfoxide or methanol.
6. The method for synthesizing the isothiourea organic catalyst as claimed in claim 1 or 5, wherein in the step (4), the solvent for reaction is toluene or dioxane, and the o-aminobenzene tert-butyl sulfoxide and any one of the compounds 5A-5E react for 3-10 hours at 80-115 ℃ under the protection of nitrogen or inert gas; and washing the reaction solution, separating, drying and concentrating the organic phase, and separating by a silica gel column to obtain the isothiourea organic catalyst.
7. The method for synthesizing an isothiourea organic catalyst as claimed in claim 1 or 5, wherein in the step (4), when reacting with the compound 5A,5B,5C or 5D, the reaction solvent is dioxane; when reacting with compound 5E, the reaction solvent is toluene.
8. The method for synthesizing isothiourea organic catalyst as claimed in claim 6, wherein the silica gel column separation conditions are: mixing the components in a volume ratio of 1: 8-10% methanol/dichloromethane.
9. The method for synthesizing isothiourea organic catalyst as claimed in claim 4, wherein in step (3), the oxidation reaction product is washed, the organic phase is dried and concentrated, and the ortho-aminobenzene tert-butyl sulfoxide is obtained by silica gel column separation; the silica gel column separation conditions were: the volume ratio is 3-6: 1, petroleum ether/ethyl acetate.
10. The method for synthesizing isothiourea organic catalyst as claimed in claim 4, wherein the amount of catalyst used in step (2) is 1wt% to 10wt%, the solvent for hydrogenation reaction is ethanol or methanol, and the reaction is carried out at normal temperature and pressure for 2 to 6 hours.
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* Cited by examiner, † Cited by third party
Title
Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain;Margherita Brindisi,等;《Journal of Medicinal Chemistry》;20160218;第59卷(第6期);第2612-2632页 *
Photoinduced Intramolecular Cyclization of o-Ethenylaryl Isocyanides with Organic Disulfides Mediated by Diphenyl Ditelluride;Takenori Mitamura，等;《The Journal of Organic Chemistry》;20110404;第76卷(第10期);第3880-3887页 *
The reactions of heterocyclic isothiocyanates bearing an ortho ester group with N-nucleophiles. The scope and some limitations of the reaction;Urleb, Uros;《Journal of Heterocyclic Chemistry》;19950228;第32卷(第1期);第69-71页 *

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