CN106045887B - A kind of synthetic method of N- ethyls sulfenamide compound - Google Patents
A kind of synthetic method of N- ethyls sulfenamide compound Download PDFInfo
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- CN106045887B CN106045887B CN201610496568.6A CN201610496568A CN106045887B CN 106045887 B CN106045887 B CN 106045887B CN 201610496568 A CN201610496568 A CN 201610496568A CN 106045887 B CN106045887 B CN 106045887B
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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 N ethyls sulfenamide compound shown in lower formula (III), the method includes：In organic solvent, in the presence of catalyst, alkali, auxiliary agent and activator, lower formula (I) compound and lower formula (II) compound react, post-treated after reaction, to obtain the formula (III) compound,Wherein, R1Selected from H, C1‑C6Alkyl, C1‑C6Alkoxy or halogen.The method uses specific compound of reaction, and pass through the comprehensive selection of catalyst, alkali, auxiliary agent, organic solvent and activator, purpose product is obtained so as to high yield, completely new path is provided for the synthesis of such compound, there is extensive actual application value.
Description
Technical field
The present invention relates to a kind of synthetic methods of sulfur-containing compound, relate more particularly to a kind of N- second sulfenamide chemical combination
The synthetic method of object, 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 Trifl such as Roman Pluta
uoromethanesulfenamides 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 N- ethyls sulfenamide compound,
This kind of method uses N- ethyl-formamide class compounds and thio-ether type compounds for starting material, in the effect of specific catalyst system and catalyzing
Under, the high yield synthesis of N- ethyl formoxyl sulfenamide compounds is realized, there is very extensive actual application value.
It should be noted that：The present invention is the improvement for the another piece patent application applied on the same day, and the another piece patent application is logical
It crosses reference and is fully incorporated into.
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 N- ethyl sulfenamides shown in a kind of lower formula (III)
The synthetic method of compound, the method includes：In organic solvent, in the presence of catalyst, alkali, auxiliary agent and activator,
Lower formula (I) compound and lower formula (II) compound react, post-treated after reaction, to obtain the formula (III)
Compound,
Wherein, R1Selected 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 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 activator is N- sulfonic acid butyl-pyridinium tosilate.
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, the molar ratio of formula (I) compound and activator is 1:0.05-0.1,
It may be, for example, 1:0.05、1:0.07、1:0.09 or 1:0.1.
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, activator and organic solvent, obtained so as to high yield
To purpose product, completely new path is provided for the synthesis of such compound, there is 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 150mmol, bis- (the positive fourths of 6mmol catalyst
Cyclopentadienyl group) zirconium dichloride, 15mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO), 12mmol auxiliary agents (for
2.7mmol tetraphenylporphyrins and 9.3mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture) and 7.5mmol activator N- sulphurs
Acid butyl pyridinium p-toluenesulfonate is warming up to 80 DEG C under then stirring, and is 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 92.8%.
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).
Embodiment 2
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate organic solvent (for volume ratio 1:2 1,4- dioxane and polyethylene glycol 200 (PEG-200)
Mixture) in, it is double that formula (I) compound, formula (II) compound described in 120mmol, 8mmol catalyst described in 100mmol is added
(n-butyl cyclopentadienyl) zirconium dichloride, 10mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO), 15mmol are helped
Agent is (for 3mmol tetraphenylporphyrins and 12mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture) and 5mmol activator N- sulphurs
Acid butyl pyridinium p-toluenesulfonate is warming up to 70 DEG C under then stirring, and is 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 the formula (III) compound, yield 92.4%.
Characterize data is the same as embodiment 1.
Embodiment 3
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate organic solvent (for volume ratio 1:2 1,4- dioxane and polyethylene glycol 200 (PEG-200)
Mixture) in, it is double that formula (I) compound, formula (II) compound described in 180mmol, 4mmol catalyst described in 100mmol is added
(n-butyl cyclopentadienyl) zirconium dichloride, 20mmol alkali 1,4- diazabicylos [2.2.2] octane (DABCO), 8mmol auxiliary agents
(for 2mmol tetraphenylporphyrins and 6mmol copper trifluoromethanesulfcomposites (Cu (OTf)2) mixture) and 10mmol activator N- sulfonic acid
Butyl-pyridinium tosilate is warming up to 90 DEG C under then stirring, and is 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 the formula (III) compound, yield 92.9%.
Characterize data is the same as embodiment 1.
By above-described embodiment 1-3 as it can be seen that especially compared with the another piece patent application applied on the same day, when the synthesis of the present invention
When activator being added in method, the yield of product can be significantly increased.
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 63.3-64.2%.And more, it is surprising that when without using auxiliary agent, yield is instead
There is 70.5-71.4%, is higher than embodiment 31-33 and Cu (OTf) is only used only2When yield, this prove Cu (OTf)2Do not play
Any 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.
Embodiment 44-46
In addition to being omitted activator N- sulfonic acid butyl-pyridinium tosilate therein, other operations are constant,
To repeat to implement embodiment 1-3, embodiment 44-46 is sequentially obtained, as a result see the table below 5.
Table 5
It can be seen that when without using the activator, the yield of product has significant reduction, this proves N- sulfonic acid butyl
The use of pyridinium p-toluenesulfonate can significantly improve reactivity, and reaction forward is promoted to carry out, excellent to achieve
Technique effect.
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, organic solvent and activator, obtained so as to high yield
To purpose product, completely new path is provided for the synthesis of such compound, there is 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, auxiliary agent and activator, lower formula (I) compound and lower formula (II) compound react, reaction knot
Shu Houjing is post-processed, to obtain the formula (III) compound,
R1Selected 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 activator is N- sulfonic acid butyl-pyridinium tosilate；
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：Formula (I) compound and activator
Molar ratio is 1:0.05-0.1.
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Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2520400A (en) * | 1947-11-03 | 1950-08-29 | Phillips Petroleum Co | Production of sulfenamides |
| US2671804A (en) * | 1948-12-28 | 1954-03-09 | Phillips Petroleum Co | Preparation and use of alkylene polyamine sulfenamides and thiosulefnamides |
| US3412144A (en) * | 1965-10-04 | 1968-11-19 | Dow Chemical Co | Process for producing sulfenamides |
| CA1133922A (en) * | 1979-03-07 | 1982-10-19 | Mohamed A. H. Fahmy | N-sulfinyl carbamates |
| US4350699A (en) * | 1981-03-30 | 1982-09-21 | The Regents Of The University Of California | Pyridylalkoxysulfinyl derivatives of carbamate esters |
| JP3448635B2 (en) * | 1998-09-18 | 2003-09-22 | 独立行政法人産業技術総合研究所 | Sulfenamide compound and method for producing the same |
| CN102307889A (en) * | 2008-12-23 | 2012-01-04 | 集润德斯股份公司 | Sulfurizing reagents and their use for oligonucleotides synthesis |
| CN105348159B (en) * | 2015-11-16 | 2017-03-29 | 河南理工大学 | A kind of thio Methomyl of lead compound and its synthetic method |
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