CN114437040B - N-axis chiral pyrrole amide tertiary amine catalyst and preparation method and application thereof - Google Patents
N-axis chiral pyrrole amide tertiary amine catalyst and preparation method and application thereof Download PDFInfo
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Abstract
An N-N axis chiral pyrrole amide tertiary amine catalyst and a preparation method and application thereof, wherein the chemical structure is shown as formula 4a, formula 4b and formula 7; the preparation method comprises the following steps: taking a compound shown in a formula 1 or a formula 5 and KOH as raw materials, adding methanol and water, stirring to react at 60 ℃, tracking the reaction by TLC until the reaction is finished, adjusting the PH to 1, extracting and concentrating to obtain a compound shown in a formula 3 or a formula 6; adding the compound of formula 3 or formula 6, EDCI and HOBT into dichloromethane, adding the compound of formula 2 and triethylamine under stirring, stirring for reaction at 25 ℃, tracking the reaction by TLC until the reaction is finished, adjusting the pH of an organic phase to 1 after the reaction liquid is extracted, discarding the organic phase, adjusting the pH of a water phase to 9-10, extracting by dichloromethane, concentrating and purifying to obtain the compound of formula 4 or formula 7. The catalyst prepared by the invention has better stereoselectivity control and better catalytic effect, and can be applied to asymmetry [4+2]]In a cyclization reaction; the method has simple steps and reduces the cost.
Description
Technical Field
The invention relates to the field of organic synthetic chemistry, in particular to an N-N axis chiral pyrrole amide tertiary amine catalyst and a preparation method and application thereof.
Background
The chiral amide tertiary amine catalyst is a catalyst with wide application and can be used for catalyzing various organic chemical reactions, however, most of the chiral amide tertiary amine catalysts are carbon chiral center amide tertiary amine catalysts, and almost no axial chiral amide tertiary amine catalysts exist, and the existing amide tertiary amine catalysts have poor control on stereoselectivity of some reactions and poor catalytic effect.
Disclosure of Invention
In order to solve the problems, the invention aims to provide an N-N axis chiral pyrrole amide tertiary amine catalyst which has better control on stereoselectivity and better catalytic effect.
The second purpose of the invention is to provide a preparation method of the N-N axis chiral pyrrole amide tertiary amine catalyst, which has mild reaction conditions, low cost and high enantioselectivity.
The invention also aims to provide an application of the N-N axis chiral pyrrole amide tertiary amine catalyst, and the catalyst can be applied to asymmetric [4+2] cyclization reaction.
In order to achieve the purpose, the invention adopts the technical scheme that: an N-axis chiral pyrrole amide tertiary amine catalyst comprises N-axis chiral indole-pyrrole amide tertiary amine and N-axis chiral pyrrole-pyrrole amide tertiary amine, and the chemical structures of the N-axis chiral indole-pyrrole amide tertiary amine catalyst are shown in formula 4 and formula 7:
in the formula 4, R 1 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl; r is 2 One selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; r is 3 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl; r 5 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl;
in the formula 7, R is selected from one of hydrogen, C1-C5 alkyl, aryl and substituted aryl; r is 1 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl; r is 3 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl; r 5 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl;
in the formulae 4 and 7, R 6 One selected from hydrogen, phenyl, substituted phenyl and C1-C6 alkyl; r is 7 One selected from hydrogen, phenyl, substituted phenyl and C1-C6 alkyl; r is 8 Selected from C1-C6 alkyl.
The invention also provides a preparation method of the N-N axis chiral pyrrole amide tertiary amine catalyst, which comprises the following steps:
(1) Taking a compound of a formula 1 or a compound of a formula 5 and potassium hydroxide as raw materials, adding methanol and water, stirring for reaction at 60 ℃, tracking the reaction by TLC until the reaction is finished, adjusting the pH to 1 by using 6N hydrochloric acid solution, extracting by using dichloromethane, and then concentrating to obtain a compound of a formula 3 or a compound of a formula 6;
wherein the dosage ratio of the compound shown in the formula 1, potassium hydroxide, methanol and water is 1.0mmol:20mmol:7.0mL:2.3mL; the dosage ratio of the compound of the formula 5, potassium hydroxide, methanol and water is 1.0mmol:20mmol:7.5mL:2.5mL;
the structural formula of the compound of the formula 1 is
Wherein R is selected from C1-C6 alkyl; r is 1 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl; r 2 One selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; r 3 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl; r is 4 One selected from C1-C6 alkyl; r 5 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl;
the structural formula of the compound of the formula 3 is
In the formula R 1 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl; r is 2 One selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; r 3 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl; r 5 One selected from hydrogen, C1-C4 alkyl, aryl and substituted aryl;
the structural formula of the compound shown in the formula 5 is
The formula R is selected from one of hydrogen, C1-C5 alkyl, aryl and substituted aryl; r 1 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl; r is 2 Selected from C1-C6 alkyl; r 3 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl; r is 4 Selected from C1-C6 alkyl; r is 5 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl;
the structural formula of the compound shown in the formula 6 is
The formula R is selected from one of hydrogen, C1-C5 alkyl, aryl and substituted aryl; r 1 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl; r is 3 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl; r 5 One selected from hydrogen, C1-C5 alkyl, aryl and substituted aryl;
(2) Adding a compound of a formula 3 or a compound of a formula 6, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole into dichloromethane, adding a compound of a formula 2 and triethylamine under stirring, reacting under stirring at 25 ℃, and tracking the reaction by TLC until the reaction is finished; extracting the reaction liquid by using dichloromethane, adjusting the pH of an organic phase to 1 by using 2N hydrochloric acid solution, discarding the organic phase, adjusting the pH of an aqueous phase to 9-10 by using saturated sodium carbonate solution, extracting by using dichloromethane, drying, concentrating and purifying to obtain a compound of a formula 4 or a formula 7;
wherein the dosage ratio of the compound shown in the formula 3, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, the compound shown in the formula 2, triethylamine and dichloromethane is 1.0mmol: (0.2-3.0) mmol: (0.2-3.0) mmol: (0.3-4.0) mmol:3.0mmol:10mL; wherein the dosage ratio of the compound shown in the formula 6, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, the compound shown in the formula 2, triethylamine and dichloromethane is 1.0mmol:3.0mmol:3.0mmol:4.0mmol:3.0mmol:10mL;
the structural formula of the compound of the formula 2 is
In the formula R 6 One selected from hydrogen, phenyl, substituted phenyl and C1-C6 alkyl; r is 7 One selected from hydrogen, phenyl, substituted phenyl and C1-C6 alkyl; r is 8 Selected from C1-C6 alkyl.
The invention also provides application of the N-N axis chiral pyrrole amide tertiary amine catalyst in asymmetric [4+2] cyclization reaction.
Compared with the prior art, the invention adopts N-N axis chiral pyrrole compounds as raw materials to synthesize the amide tertiary amine catalyst, and the catalyst has two amide tertiary amine fragments and also has N-N axis chiral fragments, so that the stereoselectivity of the reaction can be better controlled, and a better catalytic effect is shown. The preparation method has simple steps, cheap and easily-obtained raw materials, and reduces the cost; the reaction conditions of all the steps of the method are conventional conditions, mild reaction conditions are realized, the enantioselectivity is improved, the method is more suitable for industrial mass production, and the application range of the method is widened. The N-N axial chiral pyrrole amide tertiary amine catalyst prepared by the invention is applied to asymmetric [4+2] cyclization reaction, and the catalytic effect is superior to that of a common catalyst in the prior art.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
The synthetic route of this example is as follows:
compound 1 (167mg, 0.43mmol), potassium hydroxide (482mg, 8.6 mmol) were added to 3mL of methanol, 1mL of water was further added, the reaction was stirred at 60 ℃ and followed by TLC until completion, pH was adjusted to 1 with 6N hydrochloric acid solution, extraction was performed with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated to give compound 3 (150mg, 97% yield).
The structural characterization data for product 3 is as follows:
m.p.141.9-143.0℃；[α] D 20 ＝-42.9(c 0.70,Acetone)； 1 H NMR(400MHz,DMSO-d 6 ):δ7.78(d,J＝8.0Hz,1H),7.44(s,1H),7.38–7.32(m,1H),7.26–7.20(m,1H),7.12–7.08(m,3H),6.99–6.94(m,2H),6.89(d,J＝8.3Hz,1H),6.79(s,1H),2.00(s,3H)； 13 C NMR(100MHz,DMSO-d 6 ):δ166.1,160.9,138.8,138.1,133.2,130.5,129.0,128.9,127.9,127.7,126.5,123.7,123.5,123.0,111.9,111.1,109.7,108.1,10.1；IR(KBr):1699,1652,1558,1533,1472,1456,1418,1395,1338,1259,517cm -1 ；ESI FTMS exact mass calcd for(C 21 H 16 N 2 O 4 -H) - requires m/z 359.1037,found m/z 359.1044；The enantiomeric excess:94％,determined by HPLC(AD-H,hexane/isopropanol＝70/30,flow rate 1.0mL/min,I＝254nm)t R ＝14.393min(major),t R ＝39.750min(minor).
example 2
The synthetic route of this example is as follows:
compound 3 (72.0mg, 0.2mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (115mg, 0.6mmol) and 1-Hydroxybenzotriazole (HOBT) (81.0mg, 0.6mmol) were added to 2mL of methylene chloride, and compound 2a (70.4mg, 0.8mmol) and triethylamine (NEt) were added with stirring 3 ) (60.7mg, 0.6 mmol), stirring the reaction at 25 ℃ and TLC tracing the reaction to completion; extracting the reaction solution by using dichloromethane, adjusting the pH of an organic phase to 1 by using 2N hydrochloric acid solution, discarding the organic phase, adjusting the pH of an aqueous phase to 9-10 by using saturated sodium carbonate solution, extracting by using dichloromethane, drying, concentrating, and purifying by column chromatography to obtain the compound 4a (57.2mg, 57% yield).
The structural characterization data for product 4a is as follows:
m.p.67.4-68.2℃；[α] D 20 ＝-24.0(c 0.48,Acetone)； 1 H NMR(400MHz,CDCl 3 ):δ7.66(d,J＝7.8Hz,1H),7.34–7.27(m,1H),7.23–7.19(m,1H),7.14(s,1H),7.12–7.06(m,3H),7.05–7.00(m,2H),6.95(d,J＝8.2Hz,1H),6.64(s,1H),6.63–6.57(m,1H),6.51–6.45(m,1H),3.54–3.49(m,2H),3.37–3.30(m,2H),2.55–2.50(m,2H),2.35–2.30(m,2H),2.29(s,6H),2.21(s,3H),2.13(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ164.9,159.4,138.5,136.2,133.3,132.0,130.2,128.4,127.5,126.7,126.2,123.9,122.5,122.4,114.7,109.7,106.8,105.5,58.0,57.2,45.2,44.9,36.7,36.5,9.9；IR(KBr):1636,1588,1544,1401,1266,1225,1188,1157,1040,746cm -1 ；ESI FTMS exact mass calcd for(C 29 H 36 N 6 O 2 +H) + requires m/z 501.2973,found m/z 501.2985；The enantiomeric excess:94％,determined by HPLC(OD-H,hexane/isopropanol＝70/30,flow rate 1.0mL/min,I＝254nm)t R ＝3.933min(minor),t R ＝5.680min(major).
example 3
The synthetic route of this example is as follows:
compound 3 (36.0mg, 0.1mmol), EDCI (47.9mg, 0.25mmol) and HOBT (29.7mg, 0.22mmol) were added to 1mL of methylene chloride, and compound 2b (42.7mg, 0.3mmol) and NEt were added with stirring 3 (30.4 mg,0.3 mmol), stirring at 25 ℃ for reaction, tracking the reaction by TLC until the reaction is finished, extracting the reaction solution by dichloromethane, adjusting the pH of an organic phase to 1 by using a 2N hydrochloric acid solution, discarding the organic phase, adjusting the pH of an aqueous phase to 9-10 by using a saturated sodium carbonate solution, extracting by dichloromethane, drying, concentrating, and purifying by column chromatography to obtain the compound 4a (46.7 mg,77% yield).
The structural characterization data for product 4b is as follows:
m.p.108.7-109.6℃；>95:5dr； 1 H NMR(400MHz,CDCl 3 ):δ7.66(d,J＝7.9Hz,1H),7.33–7.27(m,1H),7.23–7.18(m,2H),7.10–7.04(m,3H),7.03–6.98(m,2H),6.94(d,J＝8.2Hz,1H),6.78–6.73(m,1H),6.66(s,1H),6.50–6.44(m,1H),3.68–3.59(m,1H),3.49–3.40(m,1H),2.69–2.62(m,1H),2.52–2.47(m,1H),2.46–2.40(m,1H),2.28(s,6H),2.22(s,3H),2.05(s,6H),1.92–1.82(m,2H),1.80–1.74(m,2H),1.72–1.59(m,2H),1.47–1.29(m,2H),1.29–1.26(m,1H),1.25–1.17(m,2H),1.17–1.13(m,1H),1.13–1.04(m,2H),0.96–0.87(m,1H)； 13 C NMR(100MHz,CDCl 3 ):δ165.2,159.5,138.6,136.1,133.2,132.4,130.0,128.4,127.5,126.7,126.1,123.9,122.4,122.2,115.5,109.7,107.8,105.9,66.5,66.2,51.5,51.3,40.0,39.6,32.9,32.1,25.4,25.2,24.7,24.5,21.3,20.9,9.8；IR(KBr):1640,1588,1543,1439,1268,1241,1188,1031,745cm -1 ；ESI FTMS exact mass calcd for(C 37 H 48 N 6 O 2 +H) + requires m/z 609.3912,found m/z 609.3930.
example 4
The synthetic route of this example is as follows:
compound 5 (95.6mg, 0.2mmol) and potassium hydroxide (224mg, 4.0mmol) were added to 1.5mL of methanol, 0.5mL of water was further added, the reaction was stirred at 60 ℃ and followed by completion of the reaction by TLC, pH was adjusted to 1 with 6N hydrochloric acid solution, extraction was performed with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated to give compound 6.
The obtained compound 6 (0.2 mmol), EDCI (115mg, 0.6 mmol) and HOBT (81.0 mg,0.6 mmol) were added to 2mL of methylene chloride, and compound 2a (70.4 mg,0.8 mmol) and NEt were added thereto under stirring 3 (60.7mg, 0.6 mmol), stirring at 25 ℃ for reaction, TLC tracing the reaction until the reaction is finished, extracting the reaction solution with dichloromethane, adjusting the pH of an organic phase to 1 with 2N hydrochloric acid solution, discarding the organic phase, adjusting the pH of an aqueous phase to 9-10 with saturated sodium carbonate solution, extracting with dichloromethane, drying, concentrating, and purifying by column chromatography to obtain the compound 7 (59.1mg, 50% yield).
The structural characterization data for product 7 is as follows:
m.p.113.3-114.6℃；[α] D 20 ＝+42.2(c 0.54,Acetone)； 1 H NMR(400MHz,CDCl 3 ):δ7.71(d,J＝8.0Hz,1H),7.67(d,J＝8.6Hz,1H),7.57–7.52(m,1H),7.42–7.35(m,2H),7.30–7.26(m,1H),7.23(s,1H),7.18–7.15(m,3H),7.08(s,1H),7.06–6.99(m,3H),6.96(s,1H),6.86(s,1H),3.66–3.49(m,4H),2.79–2.66(m,4H),2.46(s,6H),2.44(s,6H),2.23(s,3H),2.19(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ165.0,164.9,136.0,135.5,133.4,132.5,132.3,129.9,128.8,128.5,128.4,127.5,127.4,127.2,126.2,126.1,126.0,124.4,124.3,114.5,114.4,106.0,105.6,58.4,58.3,44.9,36.0,10.3,10.2；IR(KBr):1628,1587,1559,1458,1405,1267,1187,1039,756cm -1 ；ESI FTMS exact mass calcd for(C 36 H 42 N 6 O 2 +H) + requires m/z 591.3442,found m/z 591.3459；The enantiomeric excess:97％,determined by HPLC(AD-H,hexane/isopropanol＝90/10,flow rate 1.0mL/min,I＝254nm)t R ＝11.427min(major),t R ＝23.103min(minor).
example 5
The synthetic route of this example is as follows:
compound 8 (23.8mg, 0.1mmol), compound 9 (17.8mg, 0.11mmol), and catalyst 4b (12.2mg, 0.02mmol) obtained in example 3 were dissolved in acetone, the reaction was stirred at-50 ℃ for 12h, and after completion of the reaction was monitored by TLC, trimethylsilazomethane (TMSCHN) was added 2 ) (0.1 mL), methanol (0.1 mL), stirred at-50 ℃ for 10min, spin-dried, and purified by column chromatography to give compound 10 (22.3mg, 54% yield).
The structural characterization data for product 10 is as follows:
m.p.209.1-209.7℃；>95:5dr；[α] D 20 ＝-99.1(c 0.33,Acetone)； 1 HNMR(400MHz,CDCl 3 ):δ8.32(d,J＝6.9Hz,1H),7.86–7.78(m,2H),7.55–7.46(m,2H),7.41–7.37(m,1H),7.32–7.27(m,2H),7.26(s,1H),7.22–7.12(m,5H),4.31(s,1H),3.67(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ170.6,163.1,158.4,148.3,138.2,133.8,133.0,129.4,129.1,129.0,128.7,128.0,127.9,126.1,125.8,123.9,121.8,121.0,59.8,53.1,50.5；IR(KBr):1734,1668,1540,1497,1458,1440,1266,1166,757cm -1 ；ESI FTMS exact mass calcd for(C 24 H 18 N 2 O 3 S+H) + requires m/z 415.1111,found m/z 415.1110；The enantiomeric excess:92％,determined by HPLC(AD-H,hexane/isopropanol＝70/30,flow rate 1.0mL/min,I＝254nm)t R ＝11.423min(major),t R ＝20.370min(minor).
the experimental procedures for examples 6-8 were the same as in example 5, except that different catalysts, different temperatures were used, with examples 6-7 using catalyst 4a prepared in example 2 and catalyst 7 prepared in example 4 of the present invention; example 8 uses a commercial chiral tertiary amine catalyst of the same type having the formula 11, shown below.
The catalysts, temperatures, yields and enantioselectivities (ee) of the products (formula 10) obtained in examples 5 to 8 are shown in Table 1.
TABLE 1 catalysts of examples 5-8, yield and enantioselectivity (ee) of the obtained product (formula 10)
As can be seen from Table 1, catalyst 4b is significantly better controlling the stereoselectivity of the reaction than commercial catalyst 11, and catalysts 4a and 7 are controlling the yield of the reaction to approach or exceed commercial catalyst 11.
Claims (3)
1. An N-N axis chiral pyrrole amide tertiary amine catalyst is characterized by comprising N-N axis chiral indole-pyrrole amide tertiary amine and N-N axis chiral pyrrole-pyrrole amide tertiary amine, and the chemical structures of the N-N axis chiral indole-pyrrole amide tertiary amine and the N-N axis chiral pyrrole-pyrrole amide tertiary amine are shown as formula 4a, formula 4b and formula 7:
2. a method for preparing the N-N axis chiral pyrrole amide tertiary amine catalyst according to claim 1, which comprises the following steps:
(1) Taking a compound of a formula 1 or a compound of a formula 5 and potassium hydroxide as raw materials, adding methanol and water, stirring for reaction at 60 ℃, tracking the reaction by TLC until the reaction is finished, adjusting the pH to 1 by using 6N hydrochloric acid solution, extracting by using dichloromethane, and then concentrating to obtain a compound of a formula 3 or a compound of a formula 6;
wherein the dosage ratio of the compound shown in the formula 1, potassium hydroxide, methanol and water is 1.0mmol:20mmol: 70 mL:2.3mL; the dosage ratio of the compound shown in the formula 5, the potassium hydroxide, the methanol and the water is 1.0 mmol/20 mmol/7.5 mL/2.5 mL;
the structural formula of the compound of the formula 1 is
The structural formula of the compound of the formula 3 is
The structural formula of the compound shown in the formula 5 is
The structural formula of the compound of formula 6 is
(2) Adding a compound of a formula 3 or a compound of a formula 6, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole into dichloromethane, adding a compound of a formula 2 and triethylamine under stirring, reacting under stirring at 25 ℃, and tracking the reaction by TLC until the reaction is finished; extracting the reaction liquid by using dichloromethane, adjusting the pH of an organic phase to 1 by using 2N hydrochloric acid solution, discarding the organic phase, adjusting the pH of an aqueous phase to 9-10 by using saturated sodium carbonate solution, extracting by using dichloromethane, drying, concentrating and purifying to obtain a compound of a formula 4a, a formula 4b or a formula 7;
wherein the dosage ratio of the compound shown in the formula 3, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, the compound shown in the formula 2, triethylamine and dichloromethane is 1.0mmol, (0.2-3.0) mmol, (0.3-4.0) mmol:3.0mmol:10mL; wherein the dosage ratio of the compound shown in the formula 6, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, the compound shown in the formula 2, triethylamine and dichloromethane is 1.0mmol:3.0mmol: 4.0mmol:3.0mmol:10mL;
the compound of formula 2Has the structural formula
3. The application of N-N axis chiral pyrrole amide tertiary amine catalyst in asymmetric [4+2] cyclization reaction as claimed in claim 1, wherein the reaction formula of the asymmetric [4+2] cyclization reaction is as follows:
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