CN106146364B - A kind of synthetic method of sulfenamide compound - Google Patents
A kind of synthetic method of sulfenamide compound Download PDFInfo
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- CN106146364B CN106146364B CN201610512893.7A CN201610512893A CN106146364B CN 106146364 B CN106146364 B CN 106146364B CN 201610512893 A CN201610512893 A CN 201610512893A CN 106146364 B CN106146364 B CN 106146364B
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- 0 Cc(cc1)ccc1SN(*)C=[U] Chemical compound Cc(cc1)ccc1SN(*)C=[U] 0.000 description 2
- WLHCBQAPPJAULW-UHFFFAOYSA-N Cc(cc1)ccc1S Chemical compound Cc(cc1)ccc1S WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/08—Sulfenic acids; Derivatives thereof
- C07C313/18—Sulfenamides
- C07C313/26—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C313/28—Y being a hydrogen or a carbon atom
Abstract
The present invention relates to a kind of synthetic method of sulfenamide compound shown in lower formula (III), the method includes：In organic solvent, in the presence of catalyst, alkali and auxiliary agent, lower formula (I) compound and lower formula (II) compound react, post-treated after reaction, to obtain the formula (III) compound,Wherein, R1Selected from methyl or ethyl；R2Selected from H, C1‑C6Alkyl, C1‑C6Alkoxy or halogen.The method uses specific compound of reaction, and by the comprehensive selection of catalyst, alkali, auxiliary agent and organic solvent, purpose product is obtained so as to high yield, and completely new path is provided for the synthesis of such compound, has extensive actual application value.
Description
Technical field
The present invention relates to a kind of synthetic method of sulfur-containing compound, relate more particularly to a kind of sulfenamide compound
Synthetic method belongs to organic chemical synthesis field.
Background technology
The sulfenamide compound of electron deficient usually has good bioactivity, prodrug activity, and can be used as drug
Common intermediate in synthesis.For example, following compounds shows excellent antibacterial activity,
Therefore, the synthetic method of exploitation sulfenamide compound will be to the production of organic synthesis, such as medicine intermediate
Etc. generate active influence, while for numerous scientific research personnel be also a long-term and challenging job.
So far, it is anti-that a variety of catalysis for synthesizing electron deficient sulfenamide compound have been developed in the prior art
Induction method.Such as：
(" Exploration of the " Traceless " the Reductive Ligation of S- such as Zhang Jiming
Nitrosothiols ", Organic Letters, 2009,11,477-480) one kind is reported with S-nitrosothiol class chemical combination
The method that object reacts structure sulfenamide compound for raw material, reaction equation are as follows：
In addition, (" the Selective and Scalable Synthesis of such as Roman Pluta
Trifluoromethanesulfenamides and Fluorinated Unsymmetrical Disulfides using a
Shelf-Stable Electrophilic SCF3Reagent ", Chem.Eur.J., 2004,20,17315-17318) report
A kind of synthetic method of sulfenamide compound, reaction equation are as follows：
However, the reaction process condition of these existing methods is more harsh, and yield is to be improved, substrate source need into
The problems such as one step extends.
Thinking based on these problems, the present invention provides a kind of synthetic method of sulfenamide compound, this kind of sides
Method uses N- alkyl amine compounds and thio-ether type compounds for starting material, real under the action of specific catalyst system and catalyzing
The high yield synthesis for having showed sulfenamide compound, has very extensive actual application value.
Invention content
In order to overcome many defects as indicated above, present inventor has performed in-depth studies and exploration, are paying
After enough creative works, so as to complete the present invention.
Specifically, technical scheme of the present invention and content are related to sulfenamide compound shown in a kind of lower formula (III)
Synthetic method, the method includes：In organic solvent, in the presence of catalyst, alkali and auxiliary agent, lower formula (I) compound
It reacts with lower formula (II) compound, it is post-treated after reaction, to obtain the formula (III) compound,
Wherein, R1Selected from methyl or ethyl；
R2Selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen.
In the synthetic method of the present invention, the C1-C6The meaning of alkyl refers to the straight chain for having 1-6 carbon atom
Or branched alkyl, it may be, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6Alkoxy refers to then " C defined above1-C6Alkyl " and O
Group after atom is connected, such as methoxyl group, ethyoxyl, positive propoxy, n-butoxy.
In the synthetic method of the present invention, halogen is fluorine, chlorine, bromine or iodine atom.
In the synthetic method of the present invention, the R1Most preferably methyl.
In the synthetic method of the present invention, the catalyst is bis- (cyclopentadienyl group) zirconium dichlorides, two cyclopentadienyl of dichloro
Any one in zirconium, bis- (n-butyl cyclopentadienyl) zirconium dichlorides or hexafluoroacetylacetone zirconium, most preferably bis- (normal-butyls
Cyclopentadienyl group) zirconium dichloride.
In the synthetic method of the present invention, the alkali is 1,8- diazabicylos, 11 carbon -7- alkene (DBU), Isosorbide-5-Nitrae -
Diazabicylo [2.2.2] octane (DABCO), tri- azabicyclics of 1,5,7- [4.4.0] decyl- 5- alkene (TBD), NaOH, the tert-butyl alcohol
Any one in potassium or dimethylamino naphthyridine (DMPA), most preferably Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO).
In the synthetic method of the present invention, the auxiliary agent is tetraphenylporphyrin and copper trifluoromethanesulfcomposite (Cu (OTf)2)
Mixture, wherein tetraphenylporphyrin and copper trifluoromethanesulfcomposite (Cu (OTf)2) molar ratio be 1:3-4 may be, for example, 1:3、1:
3.5 or 1:4.
In the synthetic method of the present invention, the organic solvent is n,N-Dimethylformamide (DMF), dimethyl Asia
In sulfone (DMSO), toluene, benzene, acetonitrile, 1,4- dioxane or polyethylene glycol 200 (PEG-200) any one or it is arbitrary more
The mixture of kind, most preferably volume ratio 1:The mixture of 2 1,4- dioxane and polyethylene glycol 200 (PEG-200).
Wherein, the dosage of the organic solvent there is no stringent restrictions, those skilled in the art can be according to actual conditions
It carries out suitably selection and determines, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post-processing
Thin description.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and formula (II) compound is 1:
1.2-1.8 may be, for example, 1:1.2、1:1.5 or 1:1.8.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and catalyst is 1:0.04-
0.08, it may be, for example, 1:0.04、1:0.06 or 1:0.08.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and alkali is 1:0.1-0.2, such as
Can be 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and auxiliary agent is 1:0.08-0.15,
The mole dosage of i.e. described formula (I) compound and the tetraphenylporphyrin and copper trifluoromethanesulfcomposite (Cu (OTf) for constituting the auxiliary agent2)
Integral molar quantity ratio be 1:0.08-0.15 may be, for example, 1:0.08、1:0.1、1:0.12、1:0.14 or 1:0.15.
In the synthetic method of the present invention, reaction temperature is 70-90 DEG C, may be, for example, 70 DEG C, 80 DEG C or 90 DEG C.
In the synthetic method of the present invention, the reaction time is 7-10 hours, be may be, for example, 7 hours, 8 hours, 9 hours
Or 10 hours.
In the synthetic method of the present invention, post-processing after reaction can be specific as follows：It after reaction, will be anti-
It answers liquid to filter while hot, adjusts the pH value of filtrate to neutrality, then fully vibrated with deionized water, add petroleum ether extraction 2-3
It is secondary, merge organic phase, is concentrated under reduced pressure, gained residue crosses silica gel flash column chromatography, with volume ratio 1:3 acetone and chloroform it is mixed
It closes liquid to be rinsed, to obtain the formula (III) compound.
In conclusion the present invention provides a kind of synthetic method of sulfenamide compound, the method is using specific
Compound of reaction, and by the comprehensive selection of catalyst, alkali, auxiliary agent and organic solvent, purpose is obtained so as to high yield
Product provides completely new path for the synthesis of such compound, has extensive actual application value.
Specific implementation mode
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
At room temperature, to appropriate organic solvent (for volume ratio 1:2 1,4- dioxane and polyethylene glycol 200 (PEG-200)
Mixture) in, be added 100mmol on formula (I) compound, the upper formula (II) compounds of 120mmol, bis- (the positive fourths of 8mmol catalyst
Cyclopentadienyl group) zirconium dichloride, 10mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO) and 15mmol auxiliary agents (for
3.75mmol tetraphenylporphyrins and 11.25mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture), then stir under be warming up to
70 DEG C, and be stirred to react at such a temperature 10 hours；
After reaction, reaction solution is filtered while hot, adjusts the pH value of filtrate to neutrality, is then fully shaken with deionized water
It swings, adds petroleum ether extraction 2-3 times, merge organic phase, be concentrated under reduced pressure, gained residue crosses silica gel flash column chromatography, with body
Product ratio 1:3 acetone and the mixed liquor of chloroform are rinsed, to obtain upper formula (III) compound, yield 97.5%.
1H NMR(CDCl3,400MHz):δ 8.43 (s, 1H), 7.35 (d, J=8.6Hz, 2H), 7.17 (d, J=7.0Hz,
2H),3.15(s,3H)。
Embodiment 2
At room temperature, to appropriate organic solvent (for volume ratio 1:2 1,4- dioxane and polyethylene glycol 200 (PEG-200)
Mixture) in, be added 100mmol on formula (I) compound, the upper formula (II) compounds of 180mmol, bis- (the positive fourths of 4mmol catalyst
Cyclopentadienyl group) zirconium dichloride, 20mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO) and 8mmol auxiliary agents (for
1.6mmol tetraphenylporphyrins and 6.4mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture), then stir under be warming up to 90
DEG C, and be stirred to react at such a temperature 7 hours；
After reaction, reaction solution is filtered while hot, adjusts the pH value of filtrate to neutrality, is then fully shaken with deionized water
It swings, adds petroleum ether extraction 2-3 times, merge organic phase, be concentrated under reduced pressure, gained residue crosses silica gel flash column chromatography, with body
Product ratio 1:3 acetone and the mixed liquor of chloroform are rinsed, to obtain upper formula (III) compound, yield 97.2%.
1H NMR(CDCl3,400MHz):δ8.46(s,1H),7.18(s,4H),3.12(s,3H),2.36(s,3H)。
Embodiment 3
At room temperature, to appropriate organic solvent (for volume ratio 1:2 1,4- dioxane and polyethylene glycol 200 (PEG-200)
Mixture) in, be added 100mmol on formula (I) compound, the upper formula (II) compounds of 150mmol, bis- (the positive fourths of 6mmol catalyst
Cyclopentadienyl group) zirconium dichloride, 15mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO) and 12mmol auxiliary agents (for
2.7mmol tetraphenylporphyrins and 9.3mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture), then stir under be warming up to 80
DEG C, and be stirred to react at such a temperature 9 hours；
After reaction, reaction solution is filtered while hot, adjusts the pH value of filtrate to neutrality, is then fully shaken with deionized water
It swings, adds petroleum ether extraction 2-3 times, merge organic phase, be concentrated under reduced pressure, gained residue crosses silica gel flash column chromatography, with body
Product ratio 1:3 acetone and the mixed liquor of chloroform are rinsed, to obtain upper formula (III) compound, yield 97.6%.
1H NMR(CDCl3,400MHz):δ 8.52 (s, 1H), 7.37 (d, J=8.8Hz, 2H), 6.91 (d, J=8.8Hz,
2H),3.80(s,3H),3.08(s,3H)。
Embodiment 4
At room temperature, to appropriate organic solvent (for volume ratio 1:2 1,4- dioxane and polyethylene glycol 200 (PEG-200)
Mixture) in, be added 100mmol on formula (I) compound, the upper formula (II) compounds of 150mmol, bis- (the positive fourths of 6mmol catalyst
Cyclopentadienyl group) zirconium dichloride, 15mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO) and 12mmol auxiliary agents (for
2.7mmol tetraphenylporphyrins and 9.3mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture), then stir under be warming up to 80
DEG C, and be stirred to react at such a temperature 9 hours；
After reaction, reaction solution is filtered while hot, adjusts the pH value of filtrate to neutrality, is then fully shaken with deionized water
It swings, adds petroleum ether extraction 2-3 times, merge organic phase, be concentrated under reduced pressure, gained residue crosses silica gel flash column chromatography, with body
Product ratio 1:3 acetone and the mixed liquor of chloroform are rinsed, to obtain upper formula (III) compound, yield 78.1%.
1H NMR(CDCl3,400MHz):δ8.44(s,1H),7.32(m,2H),7.24(m,3H),3.58(m,2H),1.17
(t, J=7.2Hz, 3H).
By above-described embodiment 1-3 as it can be seen that when synthetic method using the present invention, purpose can be obtained with good yield
Product.But it was unexpectedly determined that working as R therein1For ethyl when, yield is only 78.1% (see embodiment 4), significantly it is low
Yield when for methyl.This may be to be increased since the length of ethyl chain will be longer than methyl so that reacting steric hindrance, to
Result in the significant decrease of yield.For the deficiency, inventor has carried out further further investigation, and specific by being added
Activator and solve the problems, such as this, which is disclosed in the another piece patent application applied on the same day.
Embodiment 1-3 is carried out as follows to repeat experiment, to investigate influence of the different factors for end reaction effect.
Embodiment 4-12
Embodiment 4-6：Except bis- (n-butyl cyclopentadienyl) zirconium dichlorides of catalyst are replaced with bis- (cyclopentadienyl groups)
Outside zirconium dichloride, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain embodiment 4-6.
Embodiment 7-9：In addition to by catalyst, bis- (n-butyl cyclopentadienyl) zirconium dichlorides replace with bis cyclopentadienyl zirconium dichloride,
Its operation is constant, to repeat to implement embodiment 1-4, sequentially obtains embodiment 7-9.
Embodiment 10-12：Except bis- (n-butyl cyclopentadienyl) zirconium dichlorides of catalyst are replaced with hexafluoroacetylacetone
Outside zirconium, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain embodiment 10-12.
As a result it see the table below 1.
Table 1
It can be seen that bis- (n-butyl cyclopentadienyl) zirconium dichlorides have best catalytic effect, other catalyst
Effect is significantly reduced, bis- (cyclopentadienyl group) zirconium dichlorides even very similar with its structure.
Embodiment 13-27
Embodiment 13-15：Except alkali DABCO is replaced with 1,8- diazabicylos, 11 carbon -7- alkene (DBU) outside, Qi Tacao
Work is constant, to repeat to implement embodiment 1-3, sequentially obtains embodiment 13-15.
Embodiment 16-18：Except alkali DABCO is replaced with 1,5,7- tri- azabicyclic [4.4.0] decyl- 5- alkene (TBD) outside,
Its operation is constant, to repeat to implement embodiment 1-3, sequentially obtains embodiment 16-18.
Embodiment 19-21：In addition to alkali DABCO is replaced with NaOH, other operations are constant, to repeat to implement implementation
Example 1-3, sequentially obtains embodiment 19-21.
Embodiment 22-24：In addition to alkali DABCO is replaced with potassium tert-butoxide, other operations are constant, to repeat to implement
Embodiment 1-3 sequentially obtains embodiment 22-24.
Embodiment 25-27：In addition to alkali DABCO is replaced with dimethylamino naphthyridine (DMPA), other operations are constant, to
Repetition implements embodiment 1-3, sequentially obtains embodiment 25-27.
As a result 2 be see the table below.
Table 2
It can be seen that in all alkali, DABCO has the effect of best, and other alkali cause yield to have significant drop
Low, especially DMPA and TBD, this proves that the type selection of alkali is unpredictable.
Embodiment 28-36
Embodiment 28-30：In addition to the one-component tetraphenylporphyrin that auxiliary agent is replaced with to the total dosage of original two kinds of components,
Its operation is constant, to repeat to implement embodiment 1-3, sequentially obtains embodiment 28-30.
Embodiment 31-33：Except the one-component copper trifluoromethanesulfcomposite (Cu that auxiliary agent is replaced with to the total dosage of original two kinds of components
(OTf)2) outside, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain embodiment 31-33.
Embodiment 34-36：In addition to being omitted auxiliary agent, other operations are constant, to repeat to implement embodiment 1-
3, sequentially obtain embodiment 34-36.
As a result 3 be see the table below.
Table 3
It can be seen that when using any type one-component as auxiliary agent, yield is significantly reduced, especially only
It uses Cu (OTf)2When, yield is reduced to 69% or so.And more, it is surprising that when without using auxiliary agent, yield has instead
72.2-73.4% is higher than embodiment 31-33 and Cu (OTf) is only used only2When yield, this prove Cu (OTf)2It does not rise and takes office
What improvement.And work as Cu (OTf)2When being applied in combination with tetraphenylporphyrin, then the excellent yield of embodiment 1-3 is achieved, this
Proof has played unexpected synergy and mutual promoting action between the two.
Embodiment 37-43
In addition to organic solvent is replaced with following one-component, other operations are constant, to repeat to implement implementation
Example 1-3, obtains embodiment 37-43, used organic solvent, embodiment correspondence and products collection efficiency see the table below 4.
Table 4
It can be seen that when using single organic solvent, yield is significantly lower than and uses Isosorbide-5-Nitrae-dioxane and PEG-
Yield when 200 mixture, this proves that the type of organic solvent has a certain impact for reaction process.
In conclusion the present invention provides a kind of synthetic method of sulfenamide compound, the method is using specific
Compound of reaction, and by the comprehensive selection of catalyst, alkali, auxiliary agent and organic solvent, purpose is obtained so as to high yield
Product provides completely new path for the synthesis of such compound, has extensive actual application value.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention
It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within and are protected defined by the application the appended claims
Within the scope of shield.
Claims (6)
1. the synthetic method of sulfenamide compound shown in a kind of lower formula (III), the method includes：In organic solvent,
In the presence of catalyst, alkali and auxiliary agent, lower formula (I) compound and lower formula (II) compound react, and pass through after reaction
Post-processing, to obtain the formula (III) compound,
Wherein, R1Selected from methyl or ethyl；
R2Selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
The catalyst is bis- (n-butyl cyclopentadienyl) zirconium dichlorides；
The alkali is 1,4- diazabicylos [2.2.2] octane；
The auxiliary agent is the mixture of tetraphenylporphyrin and copper trifluoromethanesulfcomposite, wherein tetraphenylporphyrin and copper trifluoromethanesulfcomposite
Molar ratio is 1:3-4；
The organic solvent is volume ratio 1:2 1,4- dioxane and the mixture of polyethylene glycol 200.
2. synthetic method as described in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1.2-1.8.
3. synthetic method as described in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of catalyst are
1:0.04-0.08。
4. synthetic method as described in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of alkali are 1:
0.1-0.2。
5. synthetic method as described in claim 1, it is characterised in that：The mole dosage of formula (I) compound and composition institute
The ratio for stating the tetraphenylporphyrin of auxiliary agent and the integral molar quantity of copper trifluoromethanesulfcomposite is 1:0.08-0.15.
6. synthetic method as described in any one in claim 1-5, it is characterised in that：Reaction temperature is 70-90 DEG C；Reaction time
It is 7-10 hours.
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| CN101602752A (en) * | 2008-06-10 | 2009-12-16 | 南开大学 | N-sulfenamide groups-N '-tertiary butyl-N, the fragrant hydrazide compound of N '-two and preparation and application |
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