CN118027038A - Hydrogen-bond-assisted chiral dicycloimidazole organic micromolecular catalyst and synthesis method thereof - Google Patents

Abstract

The invention relates to a hydrogen bond-assisted chiral dicyclic imidazole catalyst and a synthesis method thereof, and the structure of the catalyst is shown as a chemical formula (I)

Description

Hydrogen-bond-assisted chiral dicycloimidazole organic micromolecular catalyst and synthesis method thereof

Technical Field

The invention relates to a chiral dicycloimidazole catalyst, in particular to a hydrogen bond-assisted chiral dicycloimidazole small organic molecule compound and a synthesis method thereof.

Background

Chiral micromolecular catalysts have been developed fully in over 20 years, including chiral primary amine catalysts, chiral secondary amine catalysts, chiral tertiary amine catalysts, chiral phosphoric acid catalysts, phase transfer micromolecular catalysts and the like play an important role in the field of asymmetric catalysis, and have become the third-class efficient catalysts at present. The small molecular catalyst has the advantages of high activity, easy structure transformation and the like, is simpler to prepare, has lower manufacturing cost, and can be applied to industry on a large scale. Therefore, small molecule catalysts have become a research hotspot in the field of asymmetric catalysis in the chemical world for the last decades.

In the field of organic micromolecule catalysis, the chiral tertiary amine catalyst is widely applied to the field of asymmetric catalytic synthesis because of high activity, stable structure and easy transformation. At present, chiral tertiary amine catalysts with various structures, in particular chiral organic small molecule catalysts using tertiary amine as Lewis base, are developed, and more scientific researchers are concerned. The tertiary amine organic catalysts which are researched more at present mainly comprise quinuclidine, dimethylaminopyridine (DMAP), N-methylimidazole (NMI), amidines and the like, and the chiral organic catalysts with Lewis base characteristics also provide a new method and thinking for various asymmetric synthesis. However, the catalyst has the advantages of complex structure, high synthesis difficulty, high synthesis cost, low catalytic efficiency, difficult chiral control and difficulty in industrial application. Therefore, it is a great challenge to develop new chiral tertiary amine catalysts with higher activity and selectivity.

The Zhang Mo subject group develops a series of oxygen group substituted chiral dicycloimidazole catalysts (J.Am.chem.Soc.2010, 132, 15939) based on a molecular skeleton' bond angle regulation strategy from 2010, and has good catalytic effect in asymmetric phosphorylation and carboylation reactions. On the basis, the invention provides a series of novel chiral dicycloimidazole compounds with nitrogen group substitution, especially with urea, thiourea and squaric amide groups. The invention discovers that the introduction of the hydrogen bond auxiliary group at the position shown in the formula (I) can obviously improve the reaction activity promotion effect and the stereoselectivity control effect of the dicyclic imidazole catalyst. The structure type of the chiral dicycloimidazole catalyst is expanded, and the development of research in the field of small organic molecule catalysts is promoted.

Disclosure of Invention

The invention aims to provide a chiral dicycloimidazole organic small molecule compound assisted by hydrogen bonds and a synthesis method thereof, aiming at the defects of the prior art.

The invention aims at realizing the following technical scheme:

The invention relates to a hydrogen bond-assisted chiral dicyclic imidazole chiral small organic molecule compound, which has a structural formula shown in a formula (I):

Wherein n=1, 2,

The chiral configuration of carbon is R or S,

RR 'N is one of C1-C10 alkyl or aryl substituted amido, sulfonamide, phosphoryl, fang Xian amino, ureido and thiourea, and R' can be the same or different.

As one embodiment, R is H; r' is one of C1-C10 alkyl or aryl substituted ureido, thiourea and amino, and comprises tert-butyl ureido, 4- (trifluoromethyl) phenylureido, tert-butyl thioureido, adamantyl thioureido, phenylthioureido, 4- (tert-butyl) phenylthioureido, 4- (methoxy) phenylthioureido, 3, 5-bis (methoxy) phenylthioureido, 4- (nitro) phenylthioureido, fluorophenyl thioureido, 2,4, 6-trifluorophenylureido, 4- (trifluoromethyl) phenylthioureido, 3, 5-bis (trifluoromethyl) phenylthioureido,

The invention also relates to an intermediate for preparing the hydrogen bond-assisted chiral dicyclic imidazole chiral small organic molecule compound, wherein the structural formula of the intermediate is shown as the formula (II) or (III):

Wherein the chiral configuration of the carbon is R or S.

The invention also relates to a synthesis method of the hydrogen bond assisted chiral dicycloimidazole organic small molecule compound (III)Derivatization to give the compound (I)/>

As one embodiment, the method comprises:

1) Optically pure Compound (III) Reacting with isocyanate or isothiocyanate to obtain a chiral dicyclic imidazole organic small molecule compound (I) with urea/thiourea groups, wherein the RR' N group is urea or thiourea groups substituted by C1-C10 alkyl or aryl;

Or, 2) optically pure compound (III) Reacting with anhydride to obtain a chiral dicycloimidazole organic small molecule compound (I) with an amide group, wherein the RR' N group is an amide group substituted by C1-C10 alkyl or aryl;

or, 3) the optically pure compound (III) And 3, 4-dimethoxy-3-cyclobutene-1, 2-diketone to obtain a chiral dicycloimidazole organic small molecule compound (I) with square amide groups, wherein RR' N groups are square amide groups substituted by C1-C10 alkyl or aryl.

Wherein in step 1), the molar ratio of the optically pure compound (III) to isocyanate or isothiocyanate is 1:1.2; the reaction condition is 20-30 ℃ for 24 hours. In step 2), the molar ratio of the optically pure compound (III) to the anhydride is 1:1.2; the reaction condition is 20-30 ℃ for 24 hours. In step 3), the molar ratio of the optically pure compound (III) to the 3, 4-dimethoxy-3-cyclobutene-1, 2-dione is 1:1; the reaction condition is that the reaction is carried out for 48 hours at 20-30 ℃.

As one embodiment, the compound of formula (III) is prepared by a process comprising the steps of: optically pure compound (II)Obtaining the compound (III)/>, through reduction reactionThe reduction reaction takes palladium carbon as a reducing agent; the reaction conditions are as follows: the reaction is carried out for 18 hours at 20-30 ℃ under the condition of hydrogen pressure of 30 bar.

As a specific embodiment, optically pure compound (II)(1.49 G,10mmol,1.0 eq.) with 10% palladium on carbon (0.149 g,10mmol%,0.1 eq.) under hydrogen pressure 30bar at room temperature for 18 hours to give compound (III)/>

As one embodiment, the compound of formula (II) is prepared by a process comprising the steps of:

S1, compound (IV) The racemization compound (V) is obtained through synthesis of azide substitution reaction

S2, resolution of the racemic compound (V) by CSP-HPLC to obtain optically pure compound (II)

In the step S1, the azide substitution reaction is to react the compound (IV) with diphenyl azide phosphate in the presence of alkali 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) at 20-30 ℃ for 18 hours. Wherein, the mol ratio of the compound (IV), the diphenyl azide phosphate (DPPA) and the DBU is 1:1.2:1.2.

As a specific embodiment, in step S1, compound (IV)(1.24 G,10mmol,1.0 eq) with diphenyl azide phosphate (2.6 mL,12mmol,1.2 eq) under the condition of alkali DBU (1.79 mL,12mmol,1.2 eq) at room temperature for 18 hours to obtain racemic compound (V)/>

The invention also relates to an application of the chiral dicycloimidazole organic small molecule compound assisted by hydrogen bonds in asymmetric acylation reaction.

As one embodiment, the asymmetric acylation reaction is a reaction in which asymmetric acylation is performed to build up a phosphorus chirality.

The synthesis route of the hydrogen bond assisted chiral dicyclic imidazole chiral small organic molecule compound is shown as follows:

as one embodiment, the chiral dicycloimidazole small organic molecule compound with hydrogen bond auxiliary function is prepared by the following method:

Imidazole is taken as a raw material, acrolein with different substituents is added and cyclized to obtain (IV), then Mitsunobu reaction is carried out to obtain (V), and the following three steps are carried out to obtain the target compound (I) (wherein n=1).

Or chloroacetaldehyde is used as a raw material to react with 2-amino-3-benzyloxy pyridine with different substituents, palladium-carbon reduction is carried out to obtain (IV), mitsunobu reaction is carried out to obtain (V), and the following three steps are carried out to obtain the target compound (I) (n=2).

(1) Resolution of (V) by CSP-HPLC to obtain optically pure (II);

(2) And then palladium carbon reduction is carried out to obtain (III)

(3) Finally, the derivatization reaction is carried out to obtain (I) (RR' N groups are various amido, sulfonamide, phosphoryl amino, fang Xian amino, ureido, thiourea groups and the like which are substituted by C1-C10 alkyl or aryl).

The specific synthetic route is as follows:

The invention has the following beneficial effects:

The synthesized chiral dicyclic imidazole catalyst assisted by hydrogen bond can be applied to various reactions such as asymmetric phosphorylation, asymmetric sulfinylation, asymmetric carbocylation and the like, for example, has high catalytic activity and stereoselectivity, and has better application prospect; wherein the phosphorus chiral product can be obtained in greater than 99% yield and greater than 99% enantioselectivity by an asymmetric acylation de-symmetrization reaction.

Detailed Description

The present invention will be described in detail with reference to examples. The following examples will assist those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any way. It should be noted that several modifications and improvements can be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention.

Example 1

Preparation of 7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (V)

Firstly, 200mL of two-port bottles are baked three times under the condition of vacuumizing by a heating gun, cooled to room temperature, then, racemate 7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (1.24 g,10mmol,1.0 eq) is added into the dried two-port bottles, vacuumizing is carried out for three times, nitrogen is replaced by vacuumizing, the reaction system is ensured to be anhydrous and anaerobic, then tetrahydrofuran (20 mL) and alkali DBU (1.79 mL,12mmol,1.2 eq) are added into the reaction system under the nitrogen atmosphere, stirring is carried out for 30 minutes under the ice bath until the raw materials are completely dissolved, then, an azide reagent diphenyl azide phosphate (DPPA, 2.6mL,12mmol,1.2 eq) is slowly added into the ice bath for reaction for 30 minutes under the temperature of 0 ℃ and then, the reaction is transferred to the room temperature for 18 hours. After the reaction of the raw materials was completed, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was stirred with silica gel directly, followed by column chromatography (petroleum ether/ethyl acetate=1:3) to give the pure product (1.1 g), 75% yield, as a pale yellow oily liquid.

¹H NMR(CDCl₃,400MHz):δ7.17(d,J＝1.2Hz,1H),6.94(d,J＝1.2Hz,1H),4.91(dd,J＝7.6,2.8Hz,1H),4.12(m,1H),3.97(m,1H),2.93(m,1H),2.52(m,1H).

Example 2

Preparation of (R or S) -7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole and (-) -7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (II)

CSP-HPLC method: the (R) -7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole and (S) -7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole can be obtained by using a separation type chiral IG chromatographic column, and the ee is more than 99 percent, and the yield is 95 percent.

Example 3

Preparation of (R or S) -7-amino-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (III)

First, a chiral-split catalyst (R) -7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole or (S) -7-azido-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (1.49 g,10mmol,1.0 eq) and 10% palladium on carbon (0.149 g,10mmol, 0.1 eq) were added to a single-mouth bottle, methanol (20 mL) was added, and then the single-mouth bottle was placed in a hydrogenation reactor, and sealed. Three substitutions with hydrogen were made, and after completion of the substitution, the hydrogen pressure was increased to 30bar and stirred at room temperature for 18 hours. After the reaction is completed, slowly opening a release valve of the hydrogenation kettle, releasing hydrogen, adding diatomite, filtering to remove palladium carbon, spin-drying mother liquor, directly stirring the mother liquor with silica gel, and separating by column chromatography (ethyl acetate/methanol=10/1) to obtain (R or S) -7-amino-6, 7-dihydro-5H-pyrrole [1,2-a ] imidazole (1.17 g) as light yellow oily liquid with the yield of 95%.

¹H NMR(CDCl₃,400MHz):δ7.08(d,J＝1.2Hz,1H),6.85(d,J＝1.2Hz,1H),4.36(dd,J＝8.0,5.6Hz,1H),4.06–4.11(m,1H),3.85–3.92(m,1H),2.91–2.99(m,1H),2.33–2.24(m,1H).

Example 4

Preparation of (R or S) -1- (tert-butyl) -3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-7-yl) urea (Compound (I))

Firstly, baking 200mL two-port bottles for three times by using a heating gun under the condition of vacuumizing, cooling to room temperature, adding (R or S) -7-amino-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (1.23 g,10mmol,1.0 eq) into the dried two-port bottles, vacuumizing and replacing nitrogen for three times to ensure the anhydrous and anaerobic state of a reaction system, then adding a solvent methylene dichloride (30 mL) under the nitrogen atmosphere, adding isocyanate (12 mmol,1.2 eq) at room temperature, reacting for 24 hours at room temperature, monitoring by Thin Layer Chromatography (TLC), removing the solvent by reduced pressure rotary evaporation after the raw materials are reacted completely, directly stirring a silica gel, and separating (methylene dichloride/methanol/ammonia=30/1/0.03) by column chromatography to obtain (R or S) -7- (3, 5-bis (trifluoromethyl) phenyl) urea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole, yield of 95 percent, and the enantioselectivity is kept to be 99 percent.

¹H NMR(CDCl₃,400MHz):δ7.05(d,J＝1.2Hz,1H),6.88(d,J＝1.2Hz,1H),6.15(d,J＝4.0Hz,1H),5.79(br,1H),5.23(m,1H),4.06–4.11(m,1H),3.89–3.95(m,1H),3.07–3.15(m,1H),2.40–2.46(m,1H),1.30(s,9H).

Example 5

Preparation of (R or S) -7- (4- (trifluoromethyl) phenyl) urea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The experimental procedure was as in example 4 with a yield of 89%.

¹H NMR(CDCl₃,400MHz):δ9.37(br,1H),7.39-7.45(m,4H),7.19(d,J＝8.0Hz,1H),7.12(d,J＝1.2Hz,1H),6.80(d,J＝4.0Hz,1H),5.35 -5.41(m,1H),3.92–3.95(m,2H),3.09–3.17(m,1H),2.44–2.53(m,1H).¹⁹F NMR(CDCl₃,376MHz):δ-61.72ppm.

Example 6

Preparation of (R or S) -7-tert-butylthiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

Firstly, baking 200mL two-port bottles for three times by using a heating gun under the condition of vacuumizing, cooling to room temperature, adding (R or S) -7-amino-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (1.23 g,10mmol,1.0 eq) into the dried two-port bottles, vacuumizing and replacing nitrogen for three times to ensure the anhydrous and anaerobic state of a reaction system, adding a solvent dichloromethane (30 mL) under the nitrogen atmosphere, adding isothiocyanate (12 mmol,1.2 eq) at room temperature, reacting for 24 hours at room temperature, monitoring by Thin Layer Chromatography (TLC), removing the solvent by reduced pressure rotary evaporation after the raw materials are reacted completely, directly stirring a sample by silica gel, and separating (dichloromethane/methanol/ammonia=30/1/0.03) by column chromatography to obtain (R or S) -7-tert-butylthiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole, wherein the yield is 81%, and the enantioselectivity is kept at 99%.

¹H NMR(CDCl₃,400MHz):δ7.12(s,1H),6.91(d,J＝1.2Hz,1H),5.93(m,1H),4.09–4.15(m,1H),3.94–4.01(m,1H),3.26–3.33(m,1H),2.43–2.52(m,1H),1.47(s,9H).

Example 7

Preparation of (R or S) -7-adamantylthiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a 75% yield.

¹H NMR(CDCl₃,400MHz):δ7.12(s,1H),6.94(s,1H),5.98(m,1H),4.11–4.17(m,1H),3.96–4.03(m,1H),3.26–3.31(m,1H),2.48–2.58(m,1H),2.08(m,3H).1.86(m,6H).1.66(m,6H).

Example 8

Preparation of (R or S) -7-phenylthiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 88%.

¹H NMR(CDCl₃,400MHz):δ7.33–7.47(m,5H),7.20(s,1H),6.85(s,1H),6.11(m,1H),3.90–4.13(m,2H),3.24–3.33(m,1H),2.47–2.59(m,1H).

Example 9

Preparation of (R or S) -7- (4- (tert-butyl) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The experimental procedure was as in example 6 with a yield of 89%.

¹H NMR(CDCl₃,400MHz):δ7.35(m,4H),7.21(s,1H),6.85(s,1H),6.21(m,1H),4.03–4.09(m,1H),3.93–4.00(m,1H),3.22–3.31(m,1H),2.53–2.63(m,1H),1.30(s,9H).

Example 10

Preparation of (R or S) -7- (4- (methoxy) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 88%.

¹H NMR(CDCl₃,400MHz):δ7.26–7.29(m,2H),7.14(s,1H),6.87–6.89(m,3H),6.01(m 1H),4.04–4.09(m,1H),3.93–3.99(m,1H),3.79(s,3H),3.28–3.36(m,1H),2.48–2.57(m,1H).

Example 11

Preparation of (R or S) -7- (3, 5-bis (methoxy) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 91%.

¹H NMR(CDCl₃,400MHz):δ7.12(s,1H),6.86(s,1H),6.59(m,2H),6.29(m,1H),6.00(m,1H),4.03–4.08(m,1H),3.92–3.99(m,1H),3.77(s,6H),3.26–3.33(m,1H),2.49–2.58(m,1H).

Example 12

Preparation of (R or S) -7- (4- (nitro) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 82%.

¹H NMR(CDCl₃,400MHz):δ10.32(br,1H),9.06(br,1H),7.93–8.17(m,4H),7.21(s,1H),6.84(s,1H),6.36(m,1H),4.02–4.06(m,2H),3.28–3.36(m,1H),2.53–2.63(m,1H).

Example 13

Preparation of (R or S) -7- (4-fluorophenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I)) the experimental procedure was followed in example 6 with a yield of 85%.

¹H NMR(CDCl₃,400MHz):δ9.10(br,1H),8.09(br,1H),7.41–7.45(m,2H),7.11(s,1H),7.00–7.04(m,2H),6.87(s,1H),6.07(m,1H),4.05–4.11(m,1H),3.94–4.00(m,1H),3.28–3.35(m,1H),2.48–2.57(m,1H).

Example 14

Preparation of (R or S) -7- (2, 4, 6-trifluorophenyl) urea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 83%.

¹H NMR(CDCl₃,400MHz):δ8.01(br,1H),7.59(br,1H),7.12(s,1H),6.88(s,1H),6.63–6.67(m,2H),5.55 -5.61(m,1H),4.23–4.29(m,1H),4.00–4.07(m,1H),3.15–3.21(m,1H),2.64–2.74(m,1H).¹⁹F NMR(CDCl₃,376MHz):δ-111.54ppm,-111.70ppm.

Example 15

Preparation of (R or S) -7- (4- (trifluoromethyl) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 84%.

¹H NMR(CDCl₃,400MHz):δ9.93(br,1H),8.66(br,1H),7.53–7.76(m,4H),7.13(s,1H),6.86(s,1H),6.17(m,1H),4.00–4.06(m,2H),3.29–3.34(m,1H),2.49–2.59(m,1H).¹⁹F NMR(CDCl₃,376MHz):δ-62.12ppm.

Example 16

Preparation of (R or S) -7- (3, 5-bis (trifluoromethyl) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (Compound (I))

The procedure was as in example 6 with a yield of 88%.

¹H NMR(CDCl₃,400MHz):δ10.27(br,1H),9.00(br,1H),8.09(s,2H),7.59(s,1H),7.17(s,1H),6.88(s,1H),6.32(m,1H),4.08–4.14(m,1H),4.00–4.05(m,1H),3.27–3.32(m,1H),2.51–2.61(m,1H).¹⁹F NMR(CDCl₃,376MHz):δ-62.85ppm.

Example 17

Preparation of (R or S) -3- ((3, 5-bis (trifluoromethyl) phenyl) amino) -4- ((6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound (I))

Intermediate 3- (3, 5-bis (trifluoromethyl) phenylamino) -4-methoxycyclobut-3-ene-1, 2-dione (0.399 g,1mmol,1.0 eq) was added to a two-necked flask, solvent was added to restillate dichloromethane (30 mL), and (+) -7-amino-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (0.123 g,1mmol,1.0 eq) was added to the reaction system, stirred at room temperature for 48 hours, monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by direct silica gel column chromatography (dichloromethane/methanol/ammonia=10/1/0.03) to give (+) 3- ((3, 5-bis (trifluoromethyl) phenyl) amino) -4- ((6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-7-yl) amino) cyclobut-3-ene-1, 2-dione in 85% yield (0.36 g).

¹H NMR(CDCl₃,400MHz):δ8.03(s,2H),7.52(s,1H),7.17(s,1H),6.99(s,1H),5.96(m,1H),3.93–4.06(m,2H),3.19–3.29(m,1H),2.43–2.66(m,1H).

Example 18

Preparation of tert-butyl (R or S) - (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-7-yl) carbamate (Compound (I))

Firstly, 200mL of two-port bottles are baked three times under the condition of vacuumizing by a heating gun, after the two-port bottles are cooled to room temperature, the (R or S) -7-amino-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (1.23 g,10mmol,1.0 eq) is added into the two-port bottles which are dried, vacuumizing is carried out for three times, the anaerobic state of the reaction system is ensured, then the solvent dichloromethane (30 mL) is added under the nitrogen atmosphere, di-tert-butyl dicarbonate (2.62 g,12mmol,1.2 eq) is added at room temperature, the reaction is carried out for 24 hours at room temperature, the reaction is monitored by Thin Layer Chromatography (TLC), after the reaction of the raw materials is completed, the solvent is removed by rotary evaporation under reduced pressure, the mixture is directly stirred into silica gel, and the (dichloromethane/methanol/ammonia=30/1/0.03) is separated by column chromatography, so that the (R or S) - (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-7-yl) carbamic tert-butyl ester can be obtained, the yield of 95%, and the enantioselectivity is kept 99%.

¹H NMR(CDCl₃,400MHz):δ7.12(s,1H),6.91(s,1H),5.23(m,1H),5.02(m,1H),4.09–4.15(m,1H),3.91–3.98(m,1H),3.06–3.11(m,1H),2.46–2.55(m,1H),1.44(s.9H).

Examples of the foregoing catalyst applications are provided below:

In addition to designing and synthesizing the chiral dicycloimidazole organic small molecular compound assisted by hydrogen bonds, the catalyst is also applied to asymmetric carbonylation reaction, and a catalytic product is obtained at most with a conversion rate of more than 99% and an enantioselectivity of more than 99%, the effect of the chiral dicycloimidazole catalyst assisted by hydrogen bonds is obviously better than that of the chiral dicycloimidazole catalyst substituted by oxygen groups reported in the prior patent, and the specific experimental steps are shown in example 19.

Example 19

The step of constructing phosphorus chiral experiment by implementing asymmetric acylation and desymmetrization by using hydrogen bond-assisted chiral dicyclic imidazole catalyst

Firstly, a 10mL Schlenk bottle is baked three times under the condition of vacuumizing by a heating gun, and after the bottle is cooled to room temperature, vacuumizing is performed for three times, and nitrogen is replaced. Bisphenol phosphate substrate 2a (53 mg,0.2mmol,1.0 eq), chiral dicycloimidazole catalyst (7- (3, 5-bis (trifluoromethyl) phenyl) thiourea-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole, 8mg,0.02mmol,0.1 eq) were then added to a Schlenk flask, the flask was again evacuated to replace nitrogen three times, and base 2, 6-lutidine (23.4. Mu.L, 0.2mmol,1.0 eq) and solvent toluene (6 mL) were added under nitrogen atmosphere, and the flask was sealed with a sealing film. 1-naphthoyl chloride 1a (31. Mu.L, 0.206mmol,1.03 eq) was dissolved in 2mL of toluene, and acid chloride 1 was added to the reaction system by a continuous injection pump over 1.5 hours and reacted at room temperature for 5 hours. After the reaction was completed, 0.1mL of water was added to quench the reaction, the organic solvent was removed by rotary evaporation under reduced pressure, followed by extraction with dichloromethane three times, the organic phases were combined and dried over anhydrous sodium sulfate, the anhydrous sodium sulfate was removed by suction filtration, the organic phase was rotary dried under reduced pressure and then directly stirred with silica gel, and column chromatography was carried out (dichloromethane/ethyl acetate=30:1) to give the catalytic product 3aa (81.7 mg,98% yield,98% ee) as a white solid. The product is a useful chiral intermediate.

¹H NMR(CDCl₃,400MHz):δ10.65(s,1H),8.89(d,J＝8.4Hz,1H),8.45(dd,J＝7.6,1.2Hz,1H),8.10(d,J＝8.4Hz,1H),7.98(ddd,J＝13.2,7.6,1.6Hz,1H),7.94–7.86(m,1H),7.72–7.63(m,1H),7.61–7.51(m,3H),7.41(tdd,J＝8.0,2.8,1.2Hz,1H),7.36(dd,J＝8.0,5.6Hz,1H),7.17–7.00(m,2H),6.77–6.64(m,1H),6.53–6.44(m,1H),3.66(d,J＝11.6Hz,3H);³¹P NMR(CDCl₃,162MHz):δ38.5.

In this reaction, the catalysts of examples 4-18 correspond to the following conversions and enantioselectivities, respectively:

the foregoing describes specific embodiments of the present invention. It is to be understood that the invention is not limited to the particular embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the claims without affecting the spirit of the invention.

Claims (7)

1. The chiral dicycloimidazole chiral small organic molecule compound assisted by hydrogen bonds is characterized by having a structural formula shown in a formula (I):

Wherein the chiral configuration of the carbon is R or S,

RR 'N is one of C1-C10 alkyl or aryl substituted amido, sulfonamide, phosphoryl, fang Xian amino, ureido and thiourea, and R' can be the same or different.

2. An intermediate for preparing the hydrogen bond assisted chiral bicyclic imidazole chiral small organic molecule compound of claim 1, wherein the intermediate has a structural formula shown as formula (ii) or (iii):

Wherein the chiral configuration of the carbon is R or S.

3. A method for synthesizing a hydrogen bond-assisted chiral bicycloimidazole small organic molecule compound according to claim 1, wherein the compound (III)Derivatization to give the compound (I)/>

4. A method for synthesizing a hydrogen bond assisted chiral bicyclic imidazole small organic molecule compound according to claim 3, wherein the method comprises:

Optically pure Compound (III) Reacting with isocyanate or isothiocyanate to obtain a chiral dicyclic imidazole organic small molecule compound (I) with urea/thiourea groups, wherein the RR' N group is urea or thiourea groups substituted by C1-C10 alkyl or aryl;

or, an optically pure compound (III) Reacting with anhydride to obtain a chiral dicycloimidazole organic small molecule compound (I) with an amide group, wherein the RR' N group is an amide group substituted by C1-C10 alkyl or aryl;

or, an optically pure compound (III) And 3- (3, 5-bis (trifluoromethyl) phenylamino) -3, 4-dimethoxy-3-cyclobutene-1, 2-dione to obtain a chiral dicycloimidazole organic small molecule compound (I) with a square amide group, wherein RR' N group is C1-C10 alkyl or aryl substituted square amide group.

5. The method for synthesizing a hydrogen bond-assisted chiral bicyclic imidazole small organic molecule compound according to claim 3, wherein the compound represented by formula (III) is prepared by a method comprising the steps of: optically pure compound (II)Obtaining the compound (III)/>, through reduction reaction

6. The method for synthesizing a hydrogen bond assisted chiral bicyclic imidazole small organic molecule compound according to claim 5, wherein the compound represented by formula (II) is prepared by a method comprising the steps of:

S1, compound (IV) The racemization compound (V) is obtained through synthesis of azide substitution reaction

S2, resolution of the racemic compound (V) by CSP-HPLC to obtain optically pure compound (II)

7. Use of a hydrogen bond assisted chiral bicyclic imidazole small organic molecule compound according to claim 1 in an asymmetric acylation reaction.