CN101514171A - One-step method for synthesizing N-methyl-N-methoxyamide - Google Patents
One-step method for synthesizing N-methyl-N-methoxyamide Download PDFInfo
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- CN101514171A CN101514171A CNA2009100216791A CN200910021679A CN101514171A CN 101514171 A CN101514171 A CN 101514171A CN A2009100216791 A CNA2009100216791 A CN A2009100216791A CN 200910021679 A CN200910021679 A CN 200910021679A CN 101514171 A CN101514171 A CN 101514171A
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- methoxyamide
- methoxyl group
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Abstract
The invention provides a one-step method for synthesizing N-methyl-N-methoxyamide, comprising the steps of: taking methylene dichloride or tetrahydrofuran as a solvent, reacting carboxylic acid with triphenylphosphine, N-bromosuccimide and N-methyl-N-methoxyamine to generate relevant N-methyl-N-methoxyamide. The invention is simple in reaction procedure, easily-available in raw materials, mild in reaction conditions, environmentally-friendly, low in synthesis cost, high in efficiency and yield and easy in after treatment as well as can efficiently synthesize various chiral or achiral N-methyl-N-methoxyamide.
Description
Technical field
The invention belongs to technical field of organic synthesis, the synthetic method that relates to a kind of N-methyl-N-methoxyamide, relating in particular to a kind of is solvent with methylene dichloride or tetrahydrofuran (THF), with carboxylic acid and triphenylphosphine, N-bromo-succinimide and N-methyl-N-methoxyl group amine effect, the method for one-step synthesis corresponding N-methyl-N-methoxyamide.
Background technology
N-methyl-N-methoxyamide (hereinafter to be referred as the Weinreb acid amides) is the crucial acylting agent of a class, has been widely used in the synthetic of natural product active substance at present.This class acid amides is different with other acid amides, does the time spent with organometallic reagent (as Grignard reagent), generates ketone rather than alcohol.It is aldehyde that the Weinreb acid amides also is easy to by metal hydride reduction.What be worth emphasizing is, has optically active Weinreb acid amides and organometallic reagent or metal hydride and does the time spent, and its configuration can not change.Since Bahm in 1981 and Weinreb report Weinreb acid amides synthetic, the research of relevant this compounds becomes the big focus in the organic chemical reactions research in recent years, has obtained using widely and paying close attention to, and has developed many novel synthesis.
Directly from carboxylic acid, one-step synthesis Weinreb acid amides is a perfect method.But carbonyl activation earlier just can generate acid amides with the HNMeOMe reaction.Activator N, N '-dicyclohexyl carbodiimide (DCC), diethyl cyano group phosphoric acid ester (DEPC), 1,1 '-carbonyl dimidazoles (CDI) etc. is the most frequently used activator.Giampaolo Giacomelli etc. adopt comparatively cheap 2-chloro-4, and 6-dimethoxy-[1,3,5] triazine (CDMT) is a carboxyl activator, and it is effective that this method is compared, but CDMT has pungency.In recent years, many reports about synthetic Weinreb acid amides novel method: Gunda has appearred, Georg etc. respectively with reported a kind of easy single stage method (one kettle way) synthesis of chiral or the novel method of achirality Weinreb acid amides in 2000 and 2004, they are at N, the N-diisopropylethylamine exists down, carboxylic acid has generated the acyl fluorides intermediate product with deoxofluorination agent ([bis (2-methoxyethyl) amino] sulfur trifluoride) effect earlier, and acyl fluorides produces the Weinreb acid amides with N-methyl-N-methoxyl group amine (HNMeOMe) reaction again.The shortcoming of this method is that employed deoxofluorination agent is comparatively expensive, and reacted residuum or by product be difficult to remove from mixture, causes wastage of material and productive rate low.
Summary of the invention
The method that the purpose of this invention is to provide one-step synthesis N-methyl-N-methoxyamide that a kind of technology is simple, cost is low, productive rate is high.
The present invention synthesizes the method for N-methyl-N-methoxyamide, is to be solvent with methylene dichloride or tetrahydrofuran (THF), with carboxylic acid and triphenylphosphine, N-bromo-succinimide and N-methyl-N-methoxyl group amine effect, and generation corresponding N-methyl-N-methoxyamide.Its concrete technology is as follows:
With carboxylic acid, triphenylphosphine, N-bromo-succinimide, N-methyl-N-methoxyl group amine 1)～(1: 1.2: 1.2: mol ratio 2) was dissolved in methylene dichloride or the tetrahydrofuran (THF), under-25 ℃～room temperature, reacted 1～2 hour with (1: 1: 1:; After TLC detection raw material reaction is intact, use saturated NaHCO
3Dichloromethane extraction is used in aqueous solution cancellation, and drying promptly gets N-methyl-N-methoxyamide.Its reaction formula is as follows:
In order to improve productive rate as much as possible, after the present invention can make carboxylic acid and triphenylphosphine and the effect of N-bromo-succinimide earlier, again with N-methyl-N-methoxyl group amine effect, synthetic N-methyl-N-methoxyamide.
The carboxylic acid that the present invention adopts can be any carboxylic acid, and promptly R is phenyl, alkyl, amino etc.
Synthetic N-methyl of the present invention-N-methoxyamide product, through IR,
1HNMR,
13CNMR detects, and is pure product.
The present invention can synthesize various chiralitys or achiral N-methyl-N-methoxyamide (Weinreb) acid amides effectively.
The present invention is by a large amount of experiments, from material ratio, and temperature of reaction, aspects such as productive rate compare, and reaction conditions is optimized, and found that: about 0 ℃, material ratio is with carboxylic acid (RCOOH): triphenylphosphine (PPh
3): N-bromo-succinimide (NBS): N-methyl-N-methoxyl group amine (HNMeOMe)=1: 1: 1.1: during 1.7 molar ratio ingredient, productive rate is the highest.
The present invention compared with prior art has the following advantages:
1, the present invention adopts carboxylic acid, triphenylphosphine, N-bromo-succinimide, N-methyl-N-methoxyl group amine to be raw material, and is cheap and easy to get, and synthetic cost is low;
2, the present invention adopts single stage method to synthesize N-methyl-N-methoxyamide, and reaction process is simple, reaction times section, combined coefficient height (generally just can synthesize target product at 1～2 hour); Pure product productive rate height (80～99%);
3, reaction conditions gentleness of the present invention is generally carried out under 0 ℃～room temperature; Adopting hypotoxic methylene dichloride or tetrahydrofuran (THF) is solvent and extraction agent, environmental friendliness, and aftertreatment is easy.
Embodiment
Below by specific embodiment synthetic method of the present invention is further described.
Synthesizing of embodiment 1, N-methyl-N-methoxy benzamide
In the two-mouth bottle of 50mL, add the 4mL methylene dichloride, be cooled to about 0 ℃, under agitation 1mmol phenylformic acid, 1mmol triphenylphosphine and 1.1mmol N-bromo-succinimide are added wherein; Stir the N-methyl-N-methoxyl group amine that adds 1.7mmol after 10 minutes, behind the reaction 30min, add NaHCO
3Saturated solution cancellation reaction 30min tells organic phase; The water dichloromethane extraction is used anhydrous MgSO
4Drying, column chromatography gets target compound---N-methyl-N-methoxy benzamide.Productive rate is 81%.
Its reaction formula is as follows:
Target compound N-methyl-N-methoxy benzamide is through IR,
1HNMR,
13CNMR detects, and its product is pure target compound, and data are as follows:
IRv(neat)/cm
-1?3061，2968，2933，2819，1644，1576，1451，1416，1377，1213，982，787，707；
1H?NMR(400MHz，CDCl
3，ppm)：δ＝7.67(d，J＝8Hz，2H)，7.46-7.38(m，3H)，3.56(s，3H)，3.36(s，3H)；
13C?NMR(100MHz，CDCl
3)：169.9，134.1，130.5，128.1，127.9，60.1，33.7。
Synthesizing of embodiment 2, N-methyl-N-methoxyl group-2-(N-is to the Methyl benzenesulfonyl base) hydrocinnamamide
In the two-mouth bottle of 50mL, add the 4mL tetrahydrofuran (THF), be cooled to about 0 ℃, under agitation 1mmol (N-is to the Methyl benzenesulfonyl base) phenylpropionic acid, 1mmol triphenylphosphine and 1.1mmol N-bromo-succinimide are added wherein; Stir the N-methyl-N-methoxyl group amine that adds 1.7mmol after 10 minutes, reaction 1h adds NaHCO
3Saturated solution cancellation reaction 30min; Tell organic phase, water dichloromethane extraction, anhydrous MgSO
4Drying, column chromatography gets target compound---N-methyl-N-methoxyl group-2-(N-is to the Methyl benzenesulfonyl base) hydrocinnamamide.Productive rate is 88%.
Its reaction formula is as follows:
Target compound N-methyl-N-methoxyl group-2-(N-is to the Methyl benzenesulfonyl base) hydrocinnamamide is through IR,
1HNMR
13CNMR detects, and its product is pure product, and data are as follows:
IRv(neat)/cm
-13066，2931，1672，1600，1457，1424，1391，1325，1159，1086，993，946，812，748，700，675；
1H?NMR(400MHz，CDCl
3)：δ＝7.58(d，J＝8.4Hz，2H)，7.23-7.18(m，5H)，7.09(t，J＝7.6Hz，3.8Hz?2H)，5.39(d，J＝10Hz，1H)，4.52(t，J＝9.2Hz，4.6Hz?1H)，3.42(s，3H)，2.94(s，3H)，2.86-2.81(m，2H)，2.38(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ＝171.0，143.3，136.9，135.8，129.5，129.5，128.4，127.2，126.9，61.2，54.0，39.7，32.0，21.5。
Embodiment 3:N-methyl-N-methoxyl group-3,5,5-trimethyl acetyl amine synthetic
Step: in the two-mouth bottle of 50mL, add the 4mL tetrahydrofuran (THF), be cooled to about 0 ℃, under agitation 1mmol 3,5,5 Trimethylhexanoic acid, 1mmol triphenylphosphine are mixed 1.1mmol N-bromo-succinimide and add wherein; Stir the N-methyl-N-methoxyl group amine that adds 1.7mmol after 10 minutes, behind the reaction 3h, add NaHCO
3Saturated solution cancellation reaction 30min tells organic phase, water dichloromethane extraction, anhydrous MgSO
4Drying, column chromatography gets target compound---N-methyl-N-methoxyl group-3,5,5-trimethyl acetyl amine.Productive rate is 99%.Its reaction formula is as follows:
Target compound N-methyl-N-methoxyl group-3,5,5-trimethyl acetyl amine be through IR,
1HNMR,
13CNMR detects, and its product is pure product, and data are as follows:
IR?v(neat)/cm
-13319，2955，2934，1668，1465，1412，1379，1247，1177，1116，1004，940；
1H?NMR(400MHz，CDCl
3)：δ＝3.68(s，3H)，3.21(s，3H)，2.41-2.36(m，1H)，2.30-2.24(m，1H)，2.15-2.12(m，1H)，1.29-1.25(m，1H)，1.15-1.10(m，1H)，1.018-0.015(d，J＝5.2Hz，3H)，0.92(s，9H)；
13C?NMR(100MHz，CDCl
3)：δ＝174.1，61.1，50.9，41.4，32.0，31.1，29.9，26.4，22.9。
Synthesizing of embodiment 4, N-methyl-N-methoxyl group-3-chlorine propionic acid amide
In the two-mouth bottle of 50mL, add the 4mL tetrahydrofuran (THF), be cooled to about 0 ℃, under agitation 1mmol 3-chloropropionic acid, 1mmol triphenylphosphine and 1.1mmol N-bromo-succinimide are added wherein; Stir the N-methyl-N-methoxyl group amine that adds 1.7mmol after 10 minutes, behind the reaction 30min, add NaHCO
3Saturated solution cancellation reaction 30min tells organic phase, water dichloromethane extraction, anhydrous MgSO
4Drying, column chromatography gets target compound---N-methyl-N-methoxyl group-3-chlorine propionic acid amide. productive rate is 84%.
Its reaction formula is as follows:
Target compound N-methyl-N-methoxyl group-3-chlorine propionic acid amide is through IR,
1HNMR,
13CNMR detects, and its product is pure product, and data are as follows:
IR?v(neat)/cm
-12970，2938，1665，1427，1389，1319，1298，1180，1106，992；
1H?NMR(400MHz，CDCl
3)：δ＝3.85-3.79(t，J＝7.2，6.4，2H)3.71(s，3H)，3.21(s，3H)，2.94-2.93(t，J＝2.68，2H)；
13C?NMR(100MHz，CDCl
3)：δ＝170.8，61.3，39.2，34.9，32.0。
Claims (5)
1, the method for the synthetic N-methyl of single stage method-N-methoxyamide, it is characterized in that: with methylene dichloride or tetrahydrofuran (THF) is solvent, with carboxylic acid and triphenylphosphine, N-bromo-succinimide and N-methyl-N-methoxyl group amine effect, generate corresponding N-methyl-N-methoxyamide.
2, the method for the synthetic N-methyl of single stage method-N-methoxyamide according to claim 1, it is characterized in that: after described carboxylic acid elder generation and triphenylphosphine and the effect of N-bromo-succinimide, with N-methyl-N-methoxyl group amine effect, synthesize N-methyl-N-methoxyamide again.
3, the method for the synthetic N-methyl of single stage method-N-methoxyamide as claimed in claim 1 or 2, it is characterized in that: described carboxylic acid, triphenylphosphine, N-bromo-succinimide, N-methyl-N-methoxyl group amine with (1: 1: 1: 1)～(1: 1.2: 1.2: mol ratio 2), in-25 ℃～room temperature reaction 1～2 hour; Use saturated NaHCO
3After the aqueous solution cancellation, use dichloromethane extraction again, drying promptly gets N-methyl-N-methoxyamide.
4, the method for the synthetic N-methyl of single stage method-N-methoxyamide as claimed in claim 1 or 2, it is characterized in that: described carboxylic acid, triphenylphosphine, N-bromo-succinimide, N-methyl-N-methoxyl group amine were with 1: 1: 1.1: 1.7 molar ratio ingredient.
5, the method for the synthetic N-methyl of single stage method-N-methoxyamide as claimed in claim 1 or 2, it is characterized in that: temperature of reaction is 0 a ℃～room temperature.
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| CNA2009100216791A CN101514171A (en) | 2009-03-12 | 2009-03-12 | One-step method for synthesizing N-methyl-N-methoxyamide |
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| CNA2009100216791A CN101514171A (en) | 2009-03-12 | 2009-03-12 | One-step method for synthesizing N-methyl-N-methoxyamide |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102942464A (en) * | 2012-12-06 | 2013-02-27 | 西北师范大学 | Synthesis method of compound 1-(2-halogenophenyl)-3-methyl-butanone-1 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102942464A (en) * | 2012-12-06 | 2013-02-27 | 西北师范大学 | Synthesis method of compound 1-(2-halogenophenyl)-3-methyl-butanone-1 |
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Open date: 20090826 |