CN102786532B - Sulfur heterocyclic compound and preparation process thereof - Google Patents
Sulfur heterocyclic compound and preparation process thereof Download PDFInfo
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- CN102786532B CN102786532B CN201210320016.1A CN201210320016A CN102786532B CN 102786532 B CN102786532 B CN 102786532B CN 201210320016 A CN201210320016 A CN 201210320016A CN 102786532 B CN102786532 B CN 102786532B
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- 0 C*C[C@](C(Cc1c(C)cc(*c(c-2c3)ccc3I)c-2c1)=*)O Chemical compound C*C[C@](C(Cc1c(C)cc(*c(c-2c3)ccc3I)c-2c1)=*)O 0.000 description 3
- RVEDEVKTBFKYCN-QYPLGUKPSA-N CC(C1)[C@@]1(C(C(C1)C2=Cc3c1c(cc(cc1)Br)c1[s]3)=O)C2=O Chemical compound CC(C1)[C@@]1(C(C(C1)C2=Cc3c1c(cc(cc1)Br)c1[s]3)=O)C2=O RVEDEVKTBFKYCN-QYPLGUKPSA-N 0.000 description 1
- BKYFGZVFPQXICI-UHFFFAOYSA-N CCC(C(C)C1O)C(C2)C1=CC(SC1=CC3)=C2C1=CC3Br Chemical compound CCC(C(C)C1O)C(C2)C1=CC(SC1=CC3)=C2C1=CC3Br BKYFGZVFPQXICI-UHFFFAOYSA-N 0.000 description 1
- ILUIOZPNEYDTMX-RXMQYKEDSA-N CC[C@@H](C(c(cc1N)c2cc1Br)=O)C2=O Chemical compound CC[C@@H](C(c(cc1N)c2cc1Br)=O)C2=O ILUIOZPNEYDTMX-RXMQYKEDSA-N 0.000 description 1
- SDGOBUGTTUTDTA-UHFFFAOYSA-N CN(C(c(c1c2)cc3c2Sc(cc(cc2)I)c2N3)=O)C1=O Chemical compound CN(C(c(c1c2)cc3c2Sc(cc(cc2)I)c2N3)=O)C1=O SDGOBUGTTUTDTA-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a sulfur heterocyclic compound and a preparation process thereof. The structural formula of the compound is represented as follows. In the formula, an R group represents CH3, OCH3, Br, I, NO2, NH2 and SnBu3. The sulfur heterocyclic compound is high in pharmacological activity and biological activity, good in photoinduction transfer reaction characteristic and capable of being widely used in industries such as polymerization inhibitors, antioxidants of lubricating agents, biological medicines and dyes.
Description
Technical field
The present invention relates to class sulfur heterocyclic ring compound and preparation method thereof, the especially preparation method of dibenzothiophen and phenothiazine derivative.
Technical background
Heterogeneous ring compound has multiple excellent biological activity at medicine and pesticide field, is widely used in the industries such as pharmacy, polymkeric substance, agricultural chemicals and weedicide.Its synthetic method be current medicine and pesticide research hot fields it
Dibenzothiophen, also known as dibenzothiophene, has benzene and diphenyl sulfide structure.Dibenzothiophen structure is comparatively stable, is present in the carbolineum cut of coal tar, the electrophilic substitution reactions such as nitrated, sulfonation, halogenation, acylations can occur, main attack 2-position or 8-position.Generally speaking, the preparation of dibenzothiophen derivative is reacted for raw material enforcement is further with dibenzothiophen and comparatively simple dibenzothiophen derivative often.Such as: 2,8-formyl radical dibenzothiophene (J.Am.Chem.Soc., 1973,95:956-957) be exactly by dibenzothiophen carry out respectively 2,8-halogen substiuted then acidylate product; 1-methyl 2-nitro dibenzothiophene is prepared from by 2-nitro dibenzothiophene and methylmagnesium-chloride.But because the complex structure degree of dibenzothiophen derivative is different, a kind of method may can only have ideal route of synthesis to some specific structures, but for the indefinite structures higher relative to complexity, can only look for another way.
Thiodiphenylamine, also known as phenothiazine, is the important triatomic ring organic compound containing N, S element.Thiodiphenylamine and derivative thereof have very high pharmacologically active, biological activity and good photoinduction shift reaction characteristic, are widely used in stopper, the oxidation inhibitor of lubricant, the industry such as biological medicine and dyestuff.In recent years, along with the exploitation of electroluminescent organic material, phenothiazine compound also receives attention in photochromics preparation.But the synthesis gimmick for thiodiphenylamine and derivative thereof is then comparatively single.Such as: as schizophrenia medicine ground Torazina be exactly utilize elemental sulfur and intermediate N-phenyl-3-chloroaniline at high temperature to generate six-ring to prepare product further.
The present invention be directed to the dibenzothiophen and phenothiazine derivative with complex construction, a kind of new preparation method is provided.
Summary of the invention
The object of the invention is for sulfur heterocyclic compound in prior art especially have the dibenzothiophen of complex construction, thiodiphenylamine derivative preparation method single, the technical problem that preparation technology is numerous and diverse, productive rate is low, provides simple sulfur heterocyclic compound of a kind of preparation technology and preparation method thereof.The inventive method efficiency of pcr product is high, and by product is low.
For realizing object of the present invention, one aspect of the present invention provides a kind of sulfur heterocyclic compound, and general structure is as follows:
Wherein, R group selects CH
3, OCH
3, Br, I, NO
2, NH
2, SnBu
3.
Wherein, the preparation method of the compound of described general structure (I), comprises the following steps:
1) nucleophilic substitution reaction
By the general structure of equimolar amount be
compd A, general structure are
compd B and K
2cO
3be dissolved in DMF and stir, carry out nucleophilic substitution reaction, obtained structural formula is
compound C;
2) reduction reaction
Compound C is dissolved in ethanol, then adds A hydrochloric acid soln, after mixing, add SnCl
22H
2o, stir, carry out reduction reaction, obtained general structure is
compound D;
3) diazotization reaction
Compound D is joined in B hydrochloric acid soln, reduce the temperature of reactant and remain 0-5 DEG C, then adding NaNO
2, stir, carry out diazotization reaction, obtained structural formula is
diazonium salt E;
4) ring closure reaction
Diazonium salt E is joined CuSO
4-CH
3cOOH-H
2in O solution, be carry out ring closure reaction under the condition of 90-100 DEG C in temperature, obtain final product.
Particularly, in the compound of described general structure (I), R group selects CH
3, OCH
3, Br, NO
2, NH
2; In step 1), R group selects CH
3, OCH
3, Br, NO
2, NH
2; The temperature of reaction of described nucleophilic substitution reaction is 15-30 DEG C, and the reaction times is 16-20h; The compd A of 2mmol is added in the DMF of every 20ml.
Especially, also comprise the reaction system after by nucleophilic substitution reaction and carry out water washing, extraction into ethyl acetate aqueous phase, then use anhydrous MgSO
4or Na
2sO
4dry ethyl acetate phase, then carry out distillation removal ethyl acetate.
Wherein, structural formula described in step 1) is
compd B is prepared from accordance with the following steps:
A) first 4-bromine phthalic imidine is dissolved in DMF, adds the NaH of equimolar amount, when system does not have bubble to produce, add CH
3i carries out nitrogen and methylates.DMF is removed, solid water repetitive scrubbing, MeOH recrystallization, obtained N-methyl-4-bromine phthalic imidine after reaction 1-3h
B) will under stirring
join dense H
2sO
4in, drip HNO of being fuming
3, at temperature is 15-30 DEG C, carry out nitration reaction.Reaction solution is placed in frozen water, and the water repetitive scrubbing of the solid after suction filtration, to obtain final product.
Particularly, steps A) in every 100ml DMF in add 4-bromine phthalic imidine 0.1mol; The CH of 0.11mol is added in the DMF of every 100ml
3i; N-formyl sarcolysine glycosylation reaction temperature is 15-30 DEG C, and the reaction times is 1-3h.
Particularly, step B) in every dense H of 100ml
2sO
4in add the N-methyl 4-bromine phthalic imidine of 0.08mol; Described N-methyl-4-bromine phthalic imidine divides and joins described dense H for 2-3 time
2sO
4in; The dense H of every 100ml
2sO
4to be fuming described in middle dropping 20ml HNO
3; The nitration reaction time is 8-10h.
Particularly, step 2) described in Compound C and SnCl
22H
2the mol ratio of O is 1:5; The temperature of reaction of described reduction reaction is 15-30 DEG C, and the reaction times is 6-8h; The mass percent concentration of described A hydrochloric acid soln is 35%; Described ethanol is 1:1-5 with the ratio of the volume of hydrochloric acid soln, is preferably 1:1.
Especially, the Compound C of 1mmol is dissolved in every 10ml ethanol.
Especially, also comprise the reaction system after by reduction reaction and carry out suction filtration, CH after solids washed with water
3oH recrystallization.
Particularly, the mass percent concentration of the hydrochloric acid soln of B described in step 3) is 17.5%; The diazotization reaction time is 1-1.5h, is preferably 1h; Described NaNO
2the volumetric molar concentration of solution is 0.2mol/L, is namely dissolved with the NaNO of 1mmol in every 5ml water
2.
Particularly, CuSO described in every 100ml in step 4)
4-CH
3cOOH-H
2cuSO in O solution
4quality be 2.5g, CH
3the volume of COOH is 25ml; The temperature of reaction of described ring closure reaction is 15-30 DEG C, and the reaction times is 2-3h.
Wherein, general structure is
the preparation method of compound, comprises the following steps:
1) nucleophilic substitution reaction
By the 4-bromo thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF and stir, carry out nucleophilic substitution reaction, obtained compound
2) reduction reaction
By compound
be dissolved in ethanol, then add A hydrochloric acid soln, after mixing, add SnCl
22H
2o, stirs, carries out reduction reaction, obtained compound
3) diazotization reaction
By compound
join in B hydrochloric acid soln, reduce temperature of charge and remain 0-5 DEG C, then adding NaNO
2, stir, carry out diazotization reaction, obtained diazonium salt
4) ring closure reaction
By diazonium salt
join CuSO
4-CH
3cOOH-H
2in O solution, under temperature is 90-100 DEG C of condition, carry out ring closure reaction, obtained compound
5) tributyl tin electrophilic substitution reaction
By compound
be dissolved in Isosorbide-5-Nitrae-dioxane with two tributyl tins, then add triphenylphosphine palladium, reflux, carry out electrophilic substitution reaction, to obtain final product.
Particularly, the temperature of reaction of nucleophilic substitution reaction described in step 1) is 15-30 DEG C, and the reaction times is 16-20h; The 4-bromo thiophenol of 2mmol is added in the DMF of every 20ml.
Wherein, structural formula described in step 1) is
compd B is prepared from accordance with the following steps:
A) first 4-bromine phthalic imidine is dissolved in DMF, then adds the NaH of equimolar amount, when system does not have bubble to produce, add CH
3after I carries out n-formyl sarcolysine glycosylation reaction 1-3h, remove DMF, MeOH recrystallization after solid use water repetitive scrubbing, obtained N-methyl-4-bromine phthalic imidine
B) will under stirring
join dense H
2sO
4in, then drip HNO of being fuming
3, then at temperature is 15-30 DEG C, carry out nitration reaction, reaction solution is placed in frozen water, and the water repetitive scrubbing of the solid after suction filtration, to obtain final product.
Particularly, steps A) in every 100ml DMF in add 4-bromine phthalic imidine 0.1mol; The CH of 0.11mol is added in the DMF of every 100ml
3i; N-formyl sarcolysine glycosylation reaction temperature is 15-30 DEG C, and the reaction times is 1-3h.
Particularly, step B) in every dense H of 100ml
2sO
4in add the N-methyl-4-bromine phthalic imidine of 0.08mol; Described N-methyl-4-bromine phthalic imidine divides and joins described dense H for 2-3 time
2sO
4in; The dense H of every 100ml
2sO
4to be fuming described in middle dropping 20ml HNO
3; The nitration reaction time is 8-10h.
Particularly, step 2) described in compound
with SnCl
22H
2the mol ratio of O is 1:5; The temperature of reaction of described reduction reaction is 15-30 DEG C, and the reaction times is 6-8h; The mass percent concentration of described A hydrochloric acid soln is 35%; Described ethanol is 1:1-5 with the ratio of the volume of hydrochloric acid soln, is preferably 1:1.
Especially, the compound of 1mmol is dissolved in every 10ml ethanol
Particularly, the mass percent concentration of the hydrochloric acid soln of B described in step 3) is 17.5%; The diazotization reaction time is 1-1.5h, is preferably 1h; Described NaNO
2the volumetric molar concentration of solution is 0.2mol/L, is namely dissolved with the NaNO of 1mmol in every 5ml water
2.
Particularly, CuSO described in every 100ml in step 4)
4-CH
3cOOH-H
2cuSO in O solution
4quality be 2.5g, CH
3the volume of COOH is 25ml; The temperature of reaction of described ring closure reaction is 15-30 DEG C, and the reaction times is 2-3h.
Particularly, in step 5) every 30ml Isosorbide-5-Nitrae-dioxane in add the compound of 0.15mmol
the triphenylphosphine palladium of 1mmol bis-tributyl tin and 0.05mmol.
Especially, in step 5), the reflux time is 5-6h, namely carries out tributyl tin electrophilic substitution reaction 5-6h.
Particularly, also comprise and reacted mixture is carried out suction filtration removal triphenylphosphine palladium; Isosorbide-5-Nitrae-dioxane is removed in underpressure distillation.
Wherein, general structure is
the preparation method of compound, comprises the following steps:
1) nucleophilic substitution reaction
By the 4-bromo thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF, stir, carry out nucleophilic substitution reaction, obtained compound
2) reduction reaction
By compound
be dissolved in ethanol, then add A hydrochloric acid soln, after mixing, add SnCl
22H
2o, stirs, carries out reduction reaction, obtained compound
3) diazotization reaction
By compound
join in B hydrochloric acid soln, reduce temperature of charge and remain 0-5 DEG C, then adding NaNO
2, stir, carry out diazotization reaction, obtained diazonium salt
4) ring closure reaction
By diazonium salt
join CuSO
4-CH
3cOOH-H
2in O solution, be carry out ring closure reaction under the condition of 90-100 DEG C in temperature, obtained compound
5) tributyl tin electrophilic substitution reaction
By compound
be dissolved in Isosorbide-5-Nitrae-dioxane with two tributyl tins, then add triphenylphosphine palladium, heating, carries out electrophilic substitution reaction, obtained compound
6) iodine electrophilic substitution reaction
By compound
be dissolved in ethanol, then add H
2o
2solution, NaI and hydrochloric acid soln, carry out electrophilic substitution reaction, adds saturated NaHSO after reaction 50-60min
3solution cancellation is reacted, and adds ethyl acetate and extract after then adding NaOH solution regulator solution pH to 7.2, and ethyl acetate is removed in distillation, to obtain final product.
Particularly, the compound of 0.1mmol is added in step 6) in every 50ml ethanol
described H
2o
2the mass percent concentration of solution is 3%; Described H is added in every 50ml ethanol
2o
2solution 25ml; Compound described in step 6)
be 1:1 with the mol ratio of NaI; The volumetric molar concentration of described hydrochloric acid soln is 1M; Hydrochloric acid soln described in the 50ml added in every 50ml ethanol; Described saturated NaHSO
3the consumption of solution is the compound of every 0.1mmol
add NaHSO saturated described in 50ml
3solution carries out described cancellation reaction; The volumetric molar concentration of described NaOH solution is 1M.
Particularly, also comprise ethyl acetate is added anhydrous MgSO with after water repetitive scrubbing mutually
4, dry ethyl acetate phase, is then carrying out underpressure distillation removal ethyl acetate.
Wherein, the preparation method of the compound of described general structure (II), comprises the following steps: by the general structure of equimolar amount be
compound F 17-hydroxy-corticosterone, general structure are
compd B and K
2cO
3be dissolved in DMF and stir, carry out ring closure reaction, to obtain final product.
Particularly, the temperature of reaction of described ring closure reaction is 10-30 DEG C, and the reaction times is 8-25h; Described R group selects CH
3, OCH
3, Br, I, NO
2, NH
2, SnBu
3.
Especially, the compound F 17-hydroxy-corticosterone of 2mmol is added in the DMF of every 15ml.
Particularly, also comprise distillation and remove DMF, residue is washed, extraction into ethyl acetate, and the mutually dried solid ethanol of ethyl acetate carries out recrystallization.
Wherein, structure is
the preparation method of compound, comprise the following steps:
1) by the 2-amino-5-nitro thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF and stir, carry out ring closure reaction, obtained compound
2) by compound
be dissolved in ethanol, add A hydrochloric acid soln, then add SnCl
22H
2o stirs, and carries out reduction reaction, to obtain final product.
Wherein, the temperature of reaction of ring closure reaction described in step 1) is 15-30 DEG C, and the reaction times is 8-25h; 2-amino-5-the nitro thiophenol of 2mmol is added in the DMF of every 15ml.
Particularly, also comprise distillation and remove DMF, residue is washed, extraction into ethyl acetate, and the mutually dried solid ethanol of ethyl acetate carries out recrystallization and obtains mixture
Wherein, step 2) described in A hydrochloric acid soln mass percent concentration be 35%; Described mixture
with SnCl
22H
2the mol ratio of O is 1:5; The temperature of reaction of described reduction reaction is 15-30 DEG C, and the reaction times is 6-8h; Described ethanol is 10:5-7 with the ratio of the volume of A hydrochloric acid soln, is preferably 10:6.
Particularly, the compound of 1mmol is dissolved in every 10ml ethanol
Wherein, structure is
the preparation method of compound, comprises the following steps:
1) by the 2-amino-5-bromo thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF and stir, carry out ring closure reaction, obtained compound
2) by compound
be dissolved in Isosorbide-5-Nitrae-dioxane with two tributyl tins, then add triphenylphosphine palladium, reflux, carry out tributyl tin electrophilic substitution reaction, to obtain final product.
Wherein, the temperature of reaction of ring closure reaction described in step 1) is 15-30 DEG C, and the reaction times is 8-25h; 2-amino-5-the bromo thiophenol of 2mmol is added in the DMF of every 15ml.
Particularly, also comprise underpressure distillation and remove DMF, residue is washed, extraction into ethyl acetate, and the mutually dried solid ethanol of ethyl acetate carries out recrystallization and obtains mixture
Wherein, step 2) described in every 15ml Isosorbide-5-Nitrae-dioxane in add the compound of 0.1mmol
the triphenylphosphine palladium of 0.5mmol bis-tributyl tin and 0.03mmol.
Especially, step 2) in the reflux time be 3-4h, namely carry out tributyl tin electrophilic substitution reaction 3-4h.
Particularly, also comprise and reacted mixture is carried out suction filtration removal triphenylphosphine palladium; Isosorbide-5-Nitrae-dioxane is removed in underpressure distillation.
The present invention compared with prior art tool has the following advantages and effect:
1, provide a kind of sulfur-bearing five-membered ring of comparatively wide spectrum and the preparation method of hexa-member heterocycle, because this reaction method is not by substituent restriction on phenyl ring, therefore there is wider practicality.
2, provide a kind of synthetic route of simple and effective sulfur heterocyclic compound, raw material mix is simple, easily obtains, is conducive to scale production and preparation.
3, the reaction conditions of sulfur heterocyclic compound preparation method of the present invention gentle, be easier in laboratory implementation.
Specific embodiment
Embodiment 1 prepares N-methyl-4-nitro-5-bromine phthalic imidine
4-bromine phthalic imidine (22.6g 0.1mol) is dissolved in 100ml DMF, adds NaH (4.0g, 0.1mol), when system does not have bubble to produce again, start to drip CH
3i(15.6g, 0.11mol) carry out n-formyl sarcolysine glycosylation reaction, temperature of reaction is 15-30 DEG C, is preferably 20 DEG C.1-3h(is preferably 2h) after, rotate and evaporate DMF, solid water repetitive scrubbing, uses MeOH recrystallization, obtains crystal N-methyl-4-bromine phthalic imidine
20g, productive rate 83%.
The n-methyl-4-bromine phthalic imidine (20g, 0.08mol) of drying point 3 times (or 2 times) is added the dense H of 100ml
2sO
4(98%), in, slowly drip 20ml and to be fuming HNO
3, wait to dropwise, room temperature (20 DEG C) stir, carry out nitration reaction after 8 hours by liquid pouring in frozen water, suction filtration, solid water repetitive scrubbing, obtains N-methyl-4-nitro-5-bromine phthalic imidine
16g, productive rate 70%.
N-methyl-4-nitro-5-bromine phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,ppm):8.65(1H,s),8.55(H,s),3.24(3H,s)。
Embodiment 2 prepares N-methyl-4-nitro-5-(4-bromobenzene sulfydryl) phthalic imidine
The 4-bromo thiophenol (0.38g, 2mmol) of equimolar amount and N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) are dissolved in 20ml DMF, add K
2cO
3(0.28g, 2mmol), room temperature (15-25 DEG C) stirs, and carries out nucleophilic substitution reaction.
After reaction 20h, reaction system washes with water, is then extracted with ethyl acetate aqueous phase, and uses anhydrous Na
2sO
4dry ethyl acetate phase.Rotary evaporation is removed ethyl acetate and is obtained orange solids
(i.e. N-methyl-4-nitro-5-(4-bromobenzene sulfydryl) phthalic imidine) 0.42g, productive rate 53%.
N-methyl-4-nitro-5-(4-bromobenzene sulfydryl) phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.63(1H,s),7.68(2H,d,J=10.5Hz),7.45(2H,d,J=10.5Hz),7.34(1H,s),3.18(3H,s)。
Embodiment 3 prepares N-methyl-4-amino-5-(4-bromobenzene sulfydryl) phthalic imidine
By N-methyl-4-nitro-5-(4-bromobenzene sulfydryl) phthalic imidine (0.39g, 1mmol) is dissolved in 10ml ethanol, and add 10ml concentrated hydrochloric acid (concentration is 35%) under stirring, then add SnCl
22H
2o(1.13g, 5mmol), room temperature (15-30 DEG C) stirs 6 hours.Suction filtration, after solid use water repetitive scrubbing, uses CH
3oH recrystallization obtains needle-like crystal
(i.e. N-methyl-4-amino-5-(4-bromobenzene sulfydryl) phthalic imidine) 0.28g, productive rate 77%.
N-methyl-4-amino-5-(4-bromobenzene sulfydryl) phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):7.65(2H,d,J=10.5Hz),7.43(2H,d,J=10.5Hz),7.53(1H,s),7.34(1H,s),3.18(3H,s)。
Embodiment 4 prepares bromo-2, the 3-dicarboximide base dibenzothiophene of N-methyl-8-
By 0.36g(1mmol) N-methyl-4-amino-5-(4-bromobenzene sulfydryl) phthalic imidine puts into 10ml (35%HCl/H
2o=1:1), in hydrochloric acid soln, adopt ice bath the temperature of reaction system reduced and remain 0-5 DEG C, then instill NaNO
2solution, carry out diazotization reaction, reaction system becomes scarlet.After reaction 1h, obtained
wherein said NaNO
2the volumetric molar concentration of solution is 0.2mol/L, is namely dissolved with the NaNO of 1mmol in every 5ml water
2;
Will
be added drop-wise to CuSO
4-CH
3cOOH-H
2carry out ring closure reaction in O solution, liquid color becomes green from blueness, and after reaction 2-3h, cooling, suction filtration, solid Isosorbide-5-Nitrae-dioxane recrystallization, obtains white crystal
(i.e. bromo-2, the 3-dicarboximide base dibenzothiophene of N-methyl-8-) 0.23g, productive rate 66.4%, wherein, CuSO described in every 100ml
4-CH
3cOOH-H
2cuSO containing 2.5g in O solution
4, 25ml CH
3cOOH; Described CuSO
4-CH
3cOOH-H
2the temperature of O solution is 90-100 DEG C.
Bromo-2, the 3-dicarboximide base dibenzothiophene of N-methyl-8-
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.56(1H,s),8.42(1H,s),8.32(1H,s),7.79(1H,d,J=10.6Hz),7.69(1H,d,J=10.5Hz),3.25(3H,s)。
Embodiment 5 prepares N-methyl-4-nitro-5-(4-methylbenzene sulfydryl) phthalic imidine
The 4-methylbenzene phenyl-sulfhydrate (0.25g, 2mmol) of equimolar amount and N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) are dissolved in 20ml DMF, add K
2cO
3(0.28g, 2mmol), room temperature (15-30 DEG C) stirs, and carries out nucleophilic substitution reaction.
After nucleophilic substitution reaction 20h, reaction system washes with water, is then extracted with ethyl acetate aqueous phase, uses anhydrous Na
2sO
4dry ethyl acetate phase, decompression is removed ethyl acetate and is obtained orange solids
(i.e. N-methyl-4-nitro-5-(4-methylbenzene sulfydryl) phthalic imidine) 0.26g, productive rate 39.6%.
N-methyl-4-nitro-5-(4-methylbenzene sulfydryl) phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.51(1H,s),7.62(1H,s),7.49(2H,d,J=10.6Hz),7.09(2H,d,J=10.5Hz),3.28(3H,s)2.52(1H,s)。
Embodiment 6 prepares N-methyl-4-amino-5-(4-methylbenzene sulfydryl) phthalic imidine
By N-methyl-4-nitro-5-(4-methylbenzene sulfydryl) phthalic imidine (0.32g, 1mmol) is dissolved in 10ml ethanol, and add 10ml concentrated hydrochloric acid (concentration is 35%) under stirring, then add SnCl
22H
2o(1.13g, 5mmol), room temperature (15-30 DEG C) stirs 6 hours.Suction filtration, solid use water repetitive scrubbing, CH
3oH recrystallization obtains needle-like crystal
(i.e. N-methyl-4-amino-5-(4-methylbenzene sulfydryl) phthalic imidine) 0.21g, productive rate 70.4%.
N-methyl-4-amino-5-(4-methylbenzene sulfydryl) phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):7.45(2H,d,J=10.5Hz),7.43(1H,s),7.38(2H,d,J=10.5Hz),7.33(1H,s),3.28(3H,s),2.58(3H,s)。
Embodiment 7 prepares N, 8-dimethyl-2,3-dicarboximide base dibenzothiophene
By 0.30g(1mmol) N-methyl-4-amino-5-(4-methylbenzene sulfydryl) phthalic imidine puts into 10ml (35%HCl/H
2o=1:1), in hydrochloric acid soln, adopt ice bath method the temperature of reaction system reduced and remain 0-5 DEG C, then instill NaNO
2solution, carry out diazotization reaction, reaction system becomes scarlet, after reaction 1h, obtained
wherein said NaNO
2the volumetric molar concentration of solution is 0.2mol/L, is namely dissolved with the NaNO of 1mmol in every 5ml water
2;
Will
be added drop-wise to CuSO
4-CH
3cOOH-H
2in O solution, liquid color becomes green from blueness, and after reaction 2-3h, cooling, suction filtration, solid Isosorbide-5-Nitrae-dioxane recrystallization, obtains white crystal
(i.e. N, 8-dimethyl-2,3-dicarboximide base dibenzothiophene) 0.19g, productive rate 67.5%, wherein, CuSO described in every 100ml
4-CH
3cOOH-H
2cuSO containing 2.5g in O solution
4, 25ml CH
3cOOH; Described CuSO
4-CH
3cOOH-H
2the temperature of O solution is 90-100 DEG C.
N, 8-dimethyl-2,3-dicarboximide base dibenzothiophene
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.56(1H,s),8.28(1H,s),8.07(1H,s),7.79(1H,d,J=10.3Hz),7.69(1H,d,J=10.4Hz),3.23(3H,s),2.57(3H,s)。
Embodiment 8 prepares N-methyl-4-nitro-5-(4-anisole sulfydryl) phthalic imidine
The 4-methoxybenzenethiol (0.28g, 2mmol) of equimolar amount and N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) are dissolved in 20ml DMF, add K
2cO
3(0.28g, 2mmol), room temperature (15-30 DEG C) stirs, and carries out nucleophilic substitution reaction.
Nucleophilic substitution reaction is after 16 hours, and reaction system washes with water, is then extracted with ethyl acetate aqueous phase, and uses anhydrous Na
2sO
4dry ethyl acetate phase.Rotary evaporation is removed ethyl acetate and is obtained orange solids
(i.e. N-methyl-4-nitro-5-(4-anisole sulfydryl) phthalic imidine) 0.28g, productive rate 40.7%.
N-methyl-4-nitro-5-(4-anisole sulfydryl) phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.56(1H,s),7.60(1H,s),7.45(2H,d,J=10.6Hz),7.38(2H,d,J=10.5Hz),3.98(3H,s),3.20(3H,s)。
Embodiment 9 prepares N-methyl-4-amino-5-(4-anisole sulfydryl) phthalic imidine
By N-methyl-4-nitro-5-(4-anisole sulfydryl) phthalic imidine (0.34g, 1mmol) is dissolved in 10ml ethanol, and add 10ml concentrated hydrochloric acid (concentration is 35%) under stirring, then add SnCl
22H
2o(1.13g, 5mmol), room temperature (15-30 DEG C) stirs 6 hours.Suction filtration, solid use water repetitive scrubbing, CH
3oH recrystallization obtains needle-like crystal
(i.e. N-methyl 4-amino-5-(4-anisole sulfydryl) phthalic imidine) 0.25g, productive rate 79.5%.
N-methyl-4-amino-5-(4-anisole sulfydryl) phthalic imidine
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):7.45(1H,s),7.35(2H,d,J=10.5Hz),7.32(2H,d,J=10.5Hz),7.31(1H,s),3.98(3H,s),3.20(3H,s)。
Embodiment 10 prepares N-methyl-8-methoxyl group-2,3-dicarboximide base dibenzothiophene
By 0.31g(1mmol) N-methyl-4-amino-5-(4-anisole sulfydryl) phthalic imidine input 10ml (35%HCl/H
2o=1:1), in hydrochloric acid soln, adopt ice bath the temperature of reaction system reduced and remain 0-5 DEG C, then instill NaNO
2solution, carry out diazotization reaction, reaction system becomes scarlet, after reaction 1h, obtained
wherein said NaNO
2the volumetric molar concentration of solution is 0.2mol/L, is namely dissolved with the NaNO of 1mmol in every 5ml water
2;
Will
be added drop-wise to CuSO
4-CH
3cOOH-H
2carry out ring closure reaction in O solution, liquid color becomes green from blueness, and after reaction 2h, cooling, suction filtration, solid Isosorbide-5-Nitrae-dioxane recrystallization, obtains white crystal
(i.e. N-methyl-8-methoxyl group-2,3-dicarboximide base dibenzothiophene) 0.22g, productive rate 74.0%, wherein, CuSO described in every 100ml
4-CH
3cOOH-H
2cuSO containing 2.5g in O solution
4, 25ml CH
3cOOH; Described CuSO
4-CH
3cOOHH
2the temperature of O solution is 90-100 DEG C.
N-methyl-8-methoxyl group-2,3-dicarboximide base dibenzothiophene
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.53(1H,s),8.27(1H,s),7.78(1H,d,J=11.0Hz),7.69(1H,s),7.21(1H,d,J=11.0Hz),3.97(3H,s),3.24(3H,s)。
Embodiment 11 prepares N-methyl-8-tributyl tin-2,3-dicarboximide base dibenzothiophene
By N-methyl-8-bromo-2,3-dicarboximide base dibenzothiophene 51.9mg(0.15mmol) and two tributyl tin 580mg(1.0mmol) be dissolved in 1 of 30mL, in 4-dioxane, then add 58mg (0.05mmol) triphenylphosphine palladium, reflux 6 hours, carry out tributyl tin electrophilic substitution reaction, then suction filtration removes triphenylphosphine palladium successively, and Isosorbide-5-Nitrae-dioxane is removed in underpressure distillation, residual solids carries out silica gel column chromatography separating purification, obtains 23.5mg white solid
(i.e. N-methyl-8-tributyl tin-2,3-dicarboximide base dibenzothiophene).
N-methyl-8-tributyl tin-2,3-dicarboximide base dibenzothiophene
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.62(1H,s),8.37(1H,s),7.88(1H,d,J=9.8Hz),7.65(1H,d,J=9.8Hz),3.25(3H,s),1.63(6H,m),1.35(12H,m),0.92(9H,m)。
Embodiment 12 prepares iodo-2, the 3-dicarboximide base dibenzothiophene of N-methyl-8-
Under room temperature (10-30 DEG C), the 55.6mg(0.1mmol to being dissolved in 50mL ethanol) add 25ml H in N-methyl-8-tributyl tin-2,3-dicarboximide base dibenzothiophene
2o
2(3%), 15mg (0.1mmol) NaI and 50ml volumetric molar concentration is the hydrochloric acid soln of 1M, stirs, carries out iodine substitution reaction and add the saturated NaHSO of 50ml after 50 minutes
3the substitution reaction of solution cancellation iodine; Then add the NaOH solution regulator solution pH extremely neutral (pH=7.2) that volumetric molar concentration is 1M, then add ethyl acetate and repeatedly extract, and ethyl acetate is washed with water 2-3 time mutually, and then add anhydrous MgSO
4dry ethyl acetate phase, underpressure distillation removing ethyl acetate, obtains faint yellow bulk crystalline after solid residue recrystallizing methanol
(i.e. iodo-2, the 3-dicarboximide base dibenzothiophene of N-methyl-8-) 25mg, productive rate 63.6%.
Iodo-2, the 3-dicarboximide base dibenzothiophene of N-methyl-8-
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.63(1H,s),8.56(1H,s),8.31(1H,s),7.85(1H,d,J=11.4Hz),7.67(1H,d,J=10.5Hz),3.25(3H,s)。
Embodiment 13 prepares N-methyl-7-bromo-10H-thiodiphenylamine-2,3-dicarboximide
By 2-amino-5-bromo thiophenol (0.41g, 2mmol) and N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) and K
2cO
3(0.28g, 2mmol) is dissolved in 15mlDMF according to mol ratio 1:1:1, stirring at room temperature.After ring closure reaction 25h, DMF is removed in underpressure distillation, and residue washes with water, extraction into ethyl acetate, and ethyl acetate uses Na mutually
2sO
4drying, solid ethanol carries out recrystallization, obtains light yellow crystal
(i.e. N-methyl-7-bromo-10H-thiodiphenylamine-2,3-dicarboximide) 0.31g, productive rate 42.9%.
N-methyl-7-bromo-10H-thiodiphenylamine-2,3-dicarboximide
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.67(1H,s),7.56(1H,s),7.47(1H,d,J=11.4Hz),7.31(1H,s),6.78(1H,d,J=10.8Hz),3.18(3H,s)。
Embodiment 14 prepares N-methyl-7-methyl isophthalic acid 0H-thiodiphenylamine-2,3-dicarboximide
By 2-amino-5-methylbenzene phenyl-sulfhydrate (0.28g, 2mmol) and N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) and K
2cO
3(0.28g, 2mmol) is dissolved in 15mlDMF according to mol ratio 1:1:1, stirring at room temperature.Ring closure reaction is after 18 hours, and DMF is removed in underpressure distillation, and residue washes with water, extraction into ethyl acetate, and ethyl acetate uses Na mutually
2sO
4drying, solid ethyl alcohol recrystallization, obtains light yellow crystal
(i.e. N-methyl-7-methyl isophthalic acid 0H-thiodiphenylamine-2,3-dicarboximide) 0.21g, productive rate 35.4%.
N-methyl-7-methyl isophthalic acid 0H-thiodiphenylamine-2,3-dicarboximide
1hNMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.65(1H,s),7.33(1H,s),7.05(1H,d,J=11.4Hz),6.81(1H,s),6.58(1H,d,J=10.8Hz),3.38(3H,s),2.58(3H,s)。
Embodiment 15 prepares N-methyl-7-methoxyl group-10H-thiodiphenylamine-2,3-dicarboximide
By 2-amino-5-methoxybenzenethiol (0.32g, 2mmol), N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) and K
2cO
3(0.28g, 2mmol) is dissolved in 15mlDMF according to mol ratio 1:1:1, stirring at room temperature.After ring closure reaction 9h, DMF is removed in underpressure distillation, and residue washes with water, extraction into ethyl acetate, and ethyl acetate uses Na mutually
2sO
4drying, solid ethanol carries out recrystallization, obtains light yellow crystal
(i.e. N-methyl-7-methoxyl group-10H-thiodiphenylamine-2,3-dicarboximide) 0.30g, productive rate 48.0%.
N-methyl-7-methoxyl group-10H-thiodiphenylamine-2,3-dicarboximide
1hNMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.65(1H,s),7.76(1H,s),7.27(1H,d,J=11.4Hz),7.11(1H,s),6.88(1H,d,J=10.8Hz),3.98(3H,s),3.24(3H,s)。
Embodiment 16 prepares N-methyl-7-iodo-10H-thiodiphenylamine-2,3-dicarboximide
By 2-amino-5-iodobenzene thiophenol (0.50g, 2mmol), N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) and K
2cO
3(0.28g, 2mmol) is dissolved in 15mlDMF according to mol ratio 1:1:1, stirring at room temperature.After ring closure reaction 18h, DMF is removed in underpressure distillation, and residue washes with water, extraction into ethyl acetate, and ethyl acetate uses Na mutually
2sO
4drying, solid ethanol carries out recrystallization, obtains light yellow crystal
(i.e. N-methyl-7-methoxyl group-10H-thiodiphenylamine-2,3-dicarboximide) 0.41g, productive rate 50.2%.
N-methyl-7-methoxyl group-10H-thiodiphenylamine-2,3-dicarboximide
1h NMR's is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.66(1H,s),7.73(1H,s),7.63(1H,d,J=10.8Hz),7.31(1H,s),6.66(1H,d,J=10.8Hz),3.18(3H,s)。
Embodiment 17 prepares N-methyl-7-amino-10H-thiodiphenylamine-2,3-dicarboximide
By 2-amino-5-nitro thiophenol (0.34g, 2mmol), N-methyl-4-nitro-5-bromine phthalic imidine (0.57g, 2mmol) and K
2cO
3(0.14g, 1mmol) is dissolved in 15mlDMF according to mol ratio 1:1:0.5, stirring at room temperature, and after ring closure reaction 8h, DMF is removed in underpressure distillation, and residue washes with water, extraction into ethyl acetate, and ethyl acetate uses Na mutually
2sO
4drying, solid ethanol carries out recrystallization, obtains dark brown crystals
(i.e. N-methyl-7-nitro-10H-thiodiphenylamine-2,3-dicarboximide) 0.28g.
N-methyl-7-nitro-10H-thiodiphenylamine-2,3-dicarboximide
1h NMR is as follows:
1H NMR(500MHz,CDCl
3,ppm):8.66(1H,s),8.48(1H,s),8.03(1H,d,J=10.8Hz),7.71(1H,s),7.41(1H,s),6.96(1H,d,J=10.8Hz),3.18(3H,s)。
N-methyl-7-nitro-10H-thiodiphenylamine-2,3-dicarboximide (0.33g, 1mmol) is dissolved in 10ml ethanol, adds 6ml concentrated hydrochloric acid (35%) under stirring, then add SnCl
22H
2o(1.13g, 5mmol), room temperature (15-25 DEG C) stirs 6 hours.Decompress filter, solid washes with water repeatedly, obtains needle-like crystal with ethyl alcohol recrystallization
(i.e. N-methyl-7-amino-10H-thiodiphenylamine-2,3-dicarboximide) 0.15g.
N-methyl-7-amino-10H-thiodiphenylamine-2,3-dicarboximide
1hNMR is as follows:
1H NMR(500MHz,CDCl
3,δppm):8.56(1H,s),7.55(1H,s),7.43(1H,d,J=10.8Hz),7.23(1H,d,J=10.8Hz),6.73(1H,s),3.18(3H,s)。
Embodiment 18 prepares N-methyl-7-tributyl tin-10H-thiodiphenylamine-2,3-dicarboximide
By bromo-for N-methyl-7-10H-thiodiphenylamine-2,3-dicarboximide 36.1mg(0.1mmol) and two tributyl tin 290mg(0.5mmol) be dissolved in 1 of 15mL, in 4-dioxane, then add 35mg (0.03mmol) triphenylphosphine palladium, reflux carries out substitution reaction in 3 hours, and then suction filtration removes triphenylphosphine palladium successively, underpressure distillation removes 1,4-dioxane, residual solids carries out silica gel column chromatography separating purification, obtains 8.5mg greenish yellow solid
(i.e. N-methyl-7-tributyl tin-10H-thiodiphenylamine-2,3-dicarboximide).
1H NMR(500MHz,CDCl
3,δppm):8.56(1H,s),8.13(1H,s),7.67(1H,d,J=10.0Hz),7.19(1H,d,J=10.1Hz),3.22(3H,s),1.65(6H,m),1.36(12H,m),1.31(9H,m)。
Claims (7)
1. a preparation method for sulfur heterocyclic compound, comprises the following steps, and the general structure of wherein said sulfur-bearing hybrid compounds is as shown in formula I
wherein R group selects CH
3, OCH
3, Br, NO
2, NH
2:
1) nucleophilic substitution reaction
By the general structure of equimolar amount be
compd A, structural formula are
compd B and K
2cO
3be dissolved in DMF and stir, carry out nucleophilic substitution reaction, obtained structural formula is
compound C, the temperature of reaction of wherein said nucleophilic substitution reaction is 15-30 DEG C, and the reaction times is 16-20h;
2) reduction reaction
Compound C is dissolved in ethanol, adds the hydrochloric acid soln that mass percent concentration is 35%, after mixing, add SnCl
22H
2o, carries out reduction reaction under stirring, and obtained structural formula is
compound D;
3) diazotization reaction
Compound D being joined mass percent concentration is in the hydrochloric acid soln of 17.5%, reduces the temperature of reactant and remains 0-5 DEG C, then adding NaNO
2, carry out diazotization reaction under stirring, obtained structural formula is
diazonium salt E;
4) ring closure reaction
Diazonium salt E is joined CuSO
4-CH
3cOOH-H
2in O solution, under temperature is 90-100 DEG C of condition, carries out ring closure reaction, obtains final product.
2. preparation method as claimed in claim 1, is characterized in that step 4) in CuSO described in every 100ml
4-CH
3cOOH-H
2cuSO in O solution
4quality be 2.5g, CH
3the volume of COOH is 25ml.
3. a preparation method for sulfur heterocyclic compound, comprises the following steps, and the general structure of wherein said sulfur-bearing hybrid compounds is
1) nucleophilic substitution reaction
By the 4-bromo thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF and stir, carry out nucleophilic substitution reaction, obtained compound
the temperature of reaction of wherein said nucleophilic substitution reaction is 15-30 DEG C, and the reaction times is 16-20h;
2) reduction reaction
By compound
be dissolved in ethanol, add the hydrochloric acid soln that mass percent concentration is 35%, after mixing, add SnCl
22H
2o, stirs, carries out reduction reaction, obtained compound
3) diazotization reaction
By compound
joining mass percent concentration is in the hydrochloric acid soln of 17.5%, reduces the temperature of reactant and remains 0-5 DEG C, then adding NaNO
2, stir, carry out diazotization reaction, obtained diazonium salt
4) ring closure reaction
By diazonium salt
join CuSO
4-CH
3cOOH-H
2in O solution, be carry out ring closure reaction under the condition of 90-100 DEG C in temperature, question response system cools to obtain compound
5) tributyl tin electrophilic substitution reaction
By compound
be dissolved in Isosorbide-5-Nitrae-dioxane with two tributyl tins, then add triphenylphosphine palladium, reflux, carry out electrophilic substitution reaction, to obtain final product.
4. a preparation method for sulfur-bearing hybrid compounds, comprises the following steps, and the general structure of wherein said sulfur-bearing hybrid compounds is
1) nucleophilic substitution reaction
By the 4-bromo thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF and stir, carry out nucleophilic substitution reaction, obtained compound
the temperature of reaction of wherein said nucleophilic substitution reaction is 15-30 DEG C, and the reaction times is 16-20h;
2) reduction reaction
By compound
be dissolved in ethanol, add the hydrochloric acid soln that mass percent concentration is 35%, after mixing, add SnCl
22H
2o, stirs, carries out reduction reaction, obtained compound
3) diazotization reaction
By compound
joining mass percent concentration is in the hydrochloric acid soln of 17.5%, reduces the temperature of reactant and remains 0-5 DEG C, then adding NaNO
2, stir, carry out diazotization reaction, obtained diazonium salt
4) ring closure reaction
By diazonium salt
join CuSO
4-CH
3cOOH-H
2in O solution, be carry out ring closure reaction under the condition of 90-100 DEG C in temperature, obtained compound
5) tributyl tin electrophilic substitution reaction
By compound
be dissolved in Isosorbide-5-Nitrae-dioxane with two tributyl tins, then add triphenylphosphine palladium, reflux, carry out tributyl tin electrophilic substitution reaction, then obtained compound
6) iodine electrophilic substitution reaction
By compound
be dissolved in ethanol, then add H
2o
2solution, NaI and hydrochloric acid soln, carry out electrophilic substitution reaction, adds saturated NaHSO after reaction 50-60min
3solution carries out cancellation reaction, adds ethyl acetate and extract after then adding NaOH solution regulator solution pH to 7.2, and ethyl acetate is removed in underpressure distillation, to obtain final product.
5. a general structure is
the preparation method of sulfur heterocyclic compound, comprise the following steps, wherein R group selects CH
3, OCH
3, Br, I, NO
2, NH
2, SnBu
3:
By the general structure of equimolar amount be
compound F 17-hydroxy-corticosterone, general structure are
compd B and K
2cO
3be dissolved in DMF and stir, carry out ring closure reaction, to obtain final product, wherein, ring closure reaction temperature of reaction is 10-30 DEG C, and the reaction times is 8-25h.
6. a structure is
the preparation method of sulfur-bearing hybrid compounds, comprise the following steps:
1) by the 2-amino-5-nitro thiophenol of equimolar amount, general structure be
compd B and K
2cO
3be dissolved in DMF and stir, carry out ring closure reaction, obtained compound
wherein, ring closure reaction temperature of reaction is 10-30 DEG C, and the reaction times is 8-25h;
2) by compound
be dissolved in ethanol, then add the hydrochloric acid soln that mass percent concentration is 35%, then add SnCl
22H
2o, stirs, carries out reduction reaction, to obtain final product.
7. a structure is
the preparation method of sulfur-bearing hybrid compounds, comprise the following steps:
1) by the 2-amino-5-bromo thiophenol of equimolar amount, structural formula be
compd B and K
2cO
3be dissolved in DMF and stir, carry out ring closure reaction, obtained compound
wherein, ring closure reaction temperature of reaction is 10-30 DEG C, and the reaction times is 8-25h;
2) by compound
be dissolved in Isosorbide-5-Nitrae-dioxane with two tributyl tins, then add triphenylphosphine palladium, reflux, carry out tributyl tin electrophilic substitution reaction, to obtain final product.
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Anilines Made Easily: From Aldehydes to Tri-,Tetra-, and Pentasubstituted Anilines in Two Steps;Helfried Neumann,等;《Angew. Chem. Int. Ed.》;20031231(第42期);第4503-4507页, 尤其Table 2 * |
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