CN102432487B - Catalysis-based amino acetylation method - Google Patents

Catalysis-based amino acetylation method Download PDF

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CN102432487B
CN102432487B CN201110280249.9A CN201110280249A CN102432487B CN 102432487 B CN102432487 B CN 102432487B CN 201110280249 A CN201110280249 A CN 201110280249A CN 102432487 B CN102432487 B CN 102432487B
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hdbu
oac
substrate
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陈新志
计立
钱超
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Zhejiang University ZJU
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Abstract

The invention discloses a catalysis-based amino acetylation method. The catalysis-based amino acetylation method utilizes Lewis alkali ionic liquid [HDBU]OAc as a catalyst, acetic anhydride as an acetylation agent, and an alicyclic amine or an aromatic amine as a substrate. The catalysis-based amino acetylation method comprises the following steps that 1, the substrate undergoes an acetylation reaction in the dis-presence of a solvent at a temperature of 40 to 80 DEG C for 0.3 to 1.5 hours, wherein a mole ratio of acetic anhydride to the substrate is (1.0 to 2.0): 1 and a mole ratio of Lewis alkali ionic liquid [HDBU]OAc to the substrate is in a range of 10 to 30%; 2, after the acetylation reaction, ether is added into the products; 3, the mixture obtained by the step 2 is filtered and separated; 4, the supernatant extract obtained by the step 3 is washed orderly through a saturated NaHCO3 solution and water; 5, the washed supernatant extract is added with waterless Na2SO4 for drying; and 6, the ether is removed by reduced pressure rotary distillation so that a finished product is obtained. The catalysis-based amino acetylation method has the characteristics of wild reaction conditions, high yield, low cost, environmental benefits and high safety.

Description

The acetylizad method of catalytic amino
Technical field
The present invention relates to a kind of methodology of organic synthesis, the particularly glycylization of Lewis basic ion liquid [HDBU] OAc catalysis reaction.
Background technology
Acetylization reaction is one of modal reaction in organic synthesis, and ethanoyl is also the conventional protecting group in complicated building-up reactions.According to bibliographical information; the acetylize of hydroxyl protection in alcohols and phenolic compound molecule; normal Acetyl Chloride 98Min. or the diacetyl oxide of adopting carries out under acid or base catalysis, and wherein pyridine, DMAP (DMAP) and 4-pyrroles's pyridine (PPY) etc. are all the basic catalysts of excellent property.In addition, protonic acid (as tosic acid), Lewis acid (as transition metal halide, fluoroform sulphonate, Yttria-zirconia) and solid acid are (as polynite, HBF 4siO 2, HClO 4siO 2deng) etc. an acidic catalyst also can catalytic amino acetylization reaction.Although above-described catalyzer is even applied in suitability for industrialized production in laboratory scale, still there is the defects such as and poisonous and harmful expensive such as long reaction time, severe reaction conditions, required reagent.
1,8-diazabicyclo (5.4.0) 11-7-alkene (1,8-diazabicyclo (5.4.0) undec-7-ene, be called for short DBU) be a kind of organic alkali, structure is as shown in S-1, and sterling is colourless or light yellow transparent liquid, main application is the good organic bases de-acidying agent in synthesizing as medicine, can replace such as triethylamine, N, N-xylidene(s), pyridine and quinoline etc., be widely used in organic synthesis.DBU with common organic acid generation neutralization reactions such as acetic acid after can obtain ionic liquid at room temperature, general structure is as shown in S-2, such ionic liquid can catalysis Michael addition and a series of organic reactions (reference: (a) Tetrahedron Lett.2009 such as Knoevenagel condensation, 50,1653; (b) Arkivoc, 2009, XI, 288; (c) Chem.Res.Chinese Universities, 2009,25,876; (d) J.Chem.Res.2010,30.).
Figure BDA0000092512330000011
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of reaction conditions gentleness, yield is high, cost is low, the acetylizad method of the catalytic amino of green safety.
In order to solve the problems of the technologies described above, the invention provides a kind of acetylizad method of catalytic amino, take Lewis basic ion liquid [HDBU] OAc as catalyzer, diacetyl oxide is acetylation reagent, take aliphatic amide or aromatic amine as substrate; Substrate carries out acetylization reaction under condition of no solvent; Temperature of reaction is 40～80 ℃, and the reaction times is 0.3～1.5h;
The mol ratio of diacetyl oxide and substrate is 1.0～2.0: the mol ratio of 1, Lewis basic ion liquid [HDBU] OAc and substrate is 10%～30%;
After reaction finishes, add ether, filter, separate, upper layer of extraction liquid is used saturated NaHCO successively 3after solution and water washing, add anhydrous Na 2sO 4dry, vacuum rotary steam is removed ether, obtains product.
As the improvement of the acetylizad method of catalytic amino of the present invention: the preparation method of Lewis basic ion liquid [HDBU] OAc is as follows:
In reactor, add 1,8-diazabicyclo (5.4.0) 11-7-alkene (DBU), under ice-water bath condition, drip the Glacial acetic acid of (slowly dripping) equimolar amount, keeping during this time temperature is 0～5 ℃, after dropwising, remove ice-water bath, at room temperature react 22～26h, gains are dry 22～26h (drying temperature is 50～70 ℃) under vacuum condition, obtain faint yellow full-bodied Lewis basic ion liquid [HDBU] OAc, its structural formula is as follows:
Figure BDA0000092512330000021
As the acetylizad further improvements in methods of catalytic amino of the present invention: adopt TLC and GC monitoring reaction process.
As the acetylizad further improvements in methods of catalytic amino of the present invention: aliphatic amide can be selected benzylamine, n-Butyl Amine 99, hexahydroaniline, quadrol etc.; Aromatic amine can be selected aniline, para-totuidine, Ortho Toluidine, p-Nitroaniline, o-Nitraniline, m-anisidine, o-trifluoromethyl aniline, Ortho-Chloro aniline, p-Chlorobenzoic acid amide, para-fluoroaniline etc.
Its English name of Lewis basic ion liquid of the present invention is Lewis basic ionic liquid.Room temperature refers generally to 10～30 ℃.In the present invention, the substrate of every 10mmol is used in conjunction with the ether of 10～30ml.
The reaction formula of Lewis basic ion liquid [HDBU] OAc is as follows:
Figure BDA0000092512330000022
The reaction formula of acetylization reaction of the present invention is as follows:
Figure BDA0000092512330000031
R＝aryl，alkyl。
Adopt method of the present invention, the purity of products therefrom is generally 96%～99%.If needed, can be according to routine techniques column chromatography separating-purifying.
The glycylization reaction of Lewis basic ion liquid of the present invention [HDBU] OAc catalysis, tool has the following advantages:
1, catalyzer raw material DBU price is relatively cheap, makes to have solved it after ionic liquid at room temperature and have the problem of unhappy smell, and is convenient to preserve;
2, in contrast to the acetylation catalysts such as pyridine, DMAP, 4-pyrroles's pyridine (PPY), significantly reduced catalyst levels, reaction conditions is gentleer, and the reaction times is short, and yield is high, has simplified post-reaction treatment, reacts more green close friend;
3, in contrast to transition metal salt catalyzer, [HDBU] OAc is all insensitive to water and air, and there is no the residual problem of heavy metal ion, little to equipment corrosion;
4, catalyst preparation process is simple, convenient operation.
Embodiment
Ionic liquid described in following examples [HDBU] OAc is Lewis basic ion liquid [HDBU] OAc above informing.
Embodiment 1, ionic liquid [HDBU] OAc preparation, carry out successively following steps:
In 50mL there-necked flask, add 7.6g (50mmol) DBU, add ice-water bath, open magnetic agitation.Measure Glacial acetic acid 3.0g (50mmol), proceed to constant pressure funnel, slowly splash in flask, keep during this time temperature of reaction lower than 5 ℃.Treat that Glacial acetic acid dropwises, remove ice-water bath, stirring reaction 24h under room temperature.Gained oily reactant obtains light yellow viscous liquid after vacuum-drying 24h at 60 ℃, is ionic liquid [HDBU] OAc, is placed in moisture eliminator and preserves.Its structural formula is as follows:
Figure BDA0000092512330000032
A kind of glycyl method of embodiment 2, Lewis basic ion liquid catalyst, take ionic liquid [HDBU] OAc as catalyzer, carry out successively following steps:
In the 25mL flask of being furnished with spherical condensation tube, add benzylamine (1.07g, diacetyl oxide (1.03g 10mmol) and newly steaming, 10.1mmol), add again catalyzer [HDBU] OAc (0.42g,, 20% mol ratio), open magnetic agitation, be slowly warming up to 50 ℃.TLC (developping agent: EtOAc/hexanes=1: 4, V/V) and GC monitoring reaction process.After 30min benzylamine transform complete, add 20mL ether dilute reaction solution, filter, can isolate upper strata product, the organic phase (containing the upper layer of extraction liquid of product) of gained is used the saturated NaHCO of 10mL successively 3after solution and 10mL water washing, add 0.5g anhydrous Na 2sO 4dry, decompression (O.02MPa) is revolved to steam and is removed ether, obtains white solid 1.37g (yield 92%,, purity is 97.3%), melting range 60.3-62.2 ℃. 1h NMR (400MHz, CDCl 3, TMS): 7.33-7.24 (m, 5H), 6.15 (br s, 1H), 4.38 (d, J=5.70Hz, 2H), 1.99 (s, 3H). 13c NMR (100MHz, CDCl 3): 169.95,138.16,128.57,127.46,127.28,43.50,23.19. product is confirmed as N-acetobenzylamide.
A kind of glycyl method of embodiment 3, Lewis basic ion liquid catalyst, take ionic liquid [HDBU] OAc as catalyzer, carry out successively following steps:
In the 25mL flask of being furnished with spherical condensation tube, add aniline (0.93g, diacetyl oxide (1.03g 10mmol) and newly steaming, 10.1mmol), add again catalyzer [HDBU] OAc (0.42g,, 20% mol ratio), open magnetic agitation, be slowly warming up to 50 ℃.TLC (developping agent: EtOAc/hexanes=1: 4, V/V) and GC monitoring reaction process.After 45min aniline transform complete, add 20mL ether dilute reaction solution, filter, can isolate upper strata product, gained organic phase (containing the upper layer of extraction liquid of product) is used the saturated NaHCO of 10mL successively 3after solution and 10mL water washing, add 0.5g anhydrous Na 2sO 4dry, vacuum rotary steam is removed ether, obtains white solid 1.28g (yield 95%, purity is 96.8%), melting range 113.4-114.9 ℃. 1h NMR (400MHz, CDCl 3, TMS): 7.88 (br s, 1H), 7.50 (d, J=7.6Hz, 2H), 7.29 (t, J=7.5Hz, 2H), 7.09 (t, J=7.4Hz, 1H), 2.14 (s, 3H). 13c NMR (100MHz, CDCl 3): 168.93,138.01,128.87,124.26,120.13,24.39. product is confirmed as monoacetylaniline.
A kind of glycyl method of embodiment 4, Lewis basic ion liquid catalyst, take ionic liquid [HDBU] OAc as catalyzer, carry out successively following steps:
In the 25mL flask of being furnished with spherical condensation tube, add para-totuidine (1.07g, diacetyl oxide (1.03g 10mmol) and newly steaming, 10.1mmol), add again catalyzer [HDBU] OAc (0.42g,, 20% mol ratio), open magnetic agitation, be slowly warming up to 50 ℃.TLC (developping agent: EtOAc/hexanes=1: 4, V/V) and GC monitoring reaction process.After 45min para-totuidine transform complete, add 20mL ether dilute reaction solution, filter, isolate upper strata product, gained organic phase (containing the upper layer of extraction liquid of product) is used the saturated NaHCO of 10mL successively 3after solution and 10mL water washing, add 0.5g anhydrous Na 2sO 4dry, vacuum rotary steam is removed ether, obtains white solid 1.40g (yield 94%, purity is 97.5%), melting range 144.3-145.5 ℃. 1h NMR (400MHz, CDCl 3, TMS): 7.36 (d, J=8.4Hz, 2H), 7.28 (br s, 1H), 7.11 (d, J=8.2Hz, 2H), 2.31 (s, 3H), 2.15 (s, 3H). 13c NMR (100MHz, CDCl 3): 169.04,135.60,133.53,129.40,120.36,24.38,20.95. product is confirmed as N-acetyl-p-toluidine.
A kind of glycyl method of embodiment 5, Lewis basic ion liquid catalyst, take ionic liquid [HDBU] OAc as catalyzer, carry out successively following steps:
In the 25mL flask of being furnished with spherical condensation tube, add Ortho Toluidine (1.07g, diacetyl oxide (1.03g 10mmol) and newly steaming, 10.1mmol), add again catalyzer [HDBU] OAc (0.42g,, 20% mol ratio), open magnetic agitation, be slowly warming up to 50 ℃.TLC (developping agent: EtOAc/hexanes=1: 4, V/V) and GC monitoring reaction process.After 45min para-totuidine transform complete, add 20mL ether dilute reaction solution, filter, isolate upper strata product, gained organic phase (containing the upper layer of extraction liquid of product) is used the saturated NaHCO of 10mL successively 3after solution and 10mL water washing, add 0.5g anhydrous Na 2sO 4dry, vacuum rotary steam is removed ether, obtains white solid 1.39g (yield 93%, purity is 97.2%), melting range 102.1-103.8 ℃. 1h NMR (400MHz, CDCl 3, TMS): 7.62 (d, J=8.0Hz, 1H), 7.30 (br s, 1H), 7.14 (d, J=7.1Hz, 1H), 7.06 (d, J=7.3Hz, 1H), 2.20 (s, 3H), 2.13 (s, 3H). 13c NMR (100MHz, CDCl 3): 168.72,135.60,130.44,130.09,126.54,125.46,123.96,24.00,17.76. product is confirmed as N-acetyl Ortho Toluidine.
Embodiment 6～11 is basic identical with the operation steps of embodiment 2～5, adopts different substrates, and the reaction times changes to some extent according to the difference of substrate, therefore classifies the result of embodiment 6～11 as table 1, so that contrast.
Table 1
Figure BDA0000092512330000051
Figure BDA0000092512330000061
Finally, it is also to be noted that, what more than enumerate is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.

Claims (3)

1. the acetylizad method of catalytic amino, is characterized in that: take Lewis basic ion liquid [HDBU] OAc as catalyzer, diacetyl oxide is acetylation reagent, take aliphatic amide or aromatic amine as substrate; Substrate carries out acetylization reaction under condition of no solvent; Temperature of reaction is 40～80 ℃, and the reaction times is 0.3～1.5h;
The mol ratio of described diacetyl oxide and substrate is 1.0～2.0:1, and the mol ratio of Lewis basic ion liquid [HDBU] OAc and substrate is 10%～30%;
After reaction finishes, add ether, filter, separate, upper layer of extraction liquid is used saturated NaHCO successively 3after solution and water washing, add anhydrous Na 2sO 4dry, vacuum rotary steam is removed ether, obtains product;
Described aliphatic amide is benzylamine, n-Butyl Amine 99, hexahydroaniline or quadrol;
Described aromatic amine is aniline, para-totuidine, Ortho Toluidine, p-Nitroaniline, o-Nitraniline, m-anisidine, o-trifluoromethyl aniline, Ortho-Chloro aniline, p-Chlorobenzoic acid amide or para-fluoroaniline.
2. the acetylizad method of catalytic amino according to claim 1, is characterized in that: the preparation method of described Lewis basic ion liquid [HDBU] OAc is as follows:
In reactor, add 1,8-diazabicyclo (5.4.0) 11-7-alkene, under ice-water bath condition, drip the Glacial acetic acid of equimolar amount, keeping during this time temperature is 0～5 ℃, after dropwising, remove ice-water bath, at room temperature react 22～26h, gains are dry 22～26h under vacuum condition, obtain Lewis basic ion liquid [HDBU] OAc, its structural formula is as follows:
Figure FDA0000435979540000011
3. the acetylizad method of catalytic amino according to claim 2, is characterized in that: adopt TLC and GC monitoring reaction process.
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