CHIRAL AMINE-SQUARAMIDE COMPOUND BASED ON SPIROBIINDANE SKELETON, PREPARATION METHOD AND USE THEREOF

Abstract

A chiral amine-squaramide compound based on a spirobiindane skeleton, a preparation method and use thereof provided. The chiral amine-squaramide is an enantiomeric compound having the general formula (I) and is useful for asymmetric catalytic organic reactions with good catalytic activity and enantioselectivity. The chiral amine-squaramide compound is obtained by preparation of compound of formula (I) through addition of a compound of formula (II) with squaric acid ester. The synthetic reaction route is simple, and it is easy for large-scale application. The novel chiral amine-squaramide organocatalyst has economic utility and promising industrial applications.

##STR00001##

Claims

1. A chiral amine-squaramide compound of formula (I) based on a spirobiindane skeleton: ##STR00023## wherein, X is H, CH.sub.3; R.sup.1, R.sup.6, R.sup.3, R.sup.4 are H; R.sup.2, R.sup.5 are H or CH.sub.3; a moiety ##STR00024## R.sup.9 phenyl, substituted phenyl, phenylmethylene or phenylethylidene, the substituted phenyl is 1-5 membered replaced with substituents selected from F, CI, Br, I, NO.sub.2, CN, C.sub.1-4 alkyl, C.sub.1-4 perfluoroalkyl, C.sub.1-4 alkoxy, C.sub.1-4 perfluoroalkoxy, an enantiomer thereof, a racemate thereof or a diastereomer thereof.

2. The chiral amine-squaramide compound of formula (I), an enantiomer thereof, a racemate thereof or a diastereomer thereof according to claim 1, wherein the chiral amine-squaramide of formula (I) is: ##STR00025##

3. A method for preparing the chiral amine-squaramide compound of formula (I) according to claim 1, comprising the following step: allowing a compound of formula (II) and a compound of formula (II-e) to have an addition reaction in an organic solvent to obtain a compound of formula (I): ##STR00026## wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as defined in claim 1.

4. Use of the chiral amine-squaramide compound of formula (I) based on a spirobiindane skeleton, an enantiomer thereof, a racemate thereof or a diastereomer thereof according to claim 1, wherein the chiral amine-squaramide compound of formula (I) based on a spirobiindane skeleton, an enantiomer thereof, a racemate thereof is used in an asymmetrically catalyzed addition reaction.

5. The use according to claim 4, wherein the asymmetrically catalyzed addition reaction is an asymmetrically catalyzed conjugate addition reaction of a 3-trifluoroethylidene indolinone derivative and a pyrazol-3-one.

Description

DESCRIPTION OF EMBODIMENTS

[0037] The present application will now be described in detail by way of examples, which are intended to be illustrative of the present application and are not intended to be limiting. The compound of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combinations thereof with other compound synthesis methods, and equivalents thereof well known to those skilled in the art, and are also commercially available. Preferred embodiments include, but are not limited to, the examples of the present application. It will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the application without departing from the spirit and scope of the application.

[0038] Example 1 Synthesis of (R.sub.a,R,R)-II-1.

##STR00010##

[0039] (R)-II-c1 (1.56 g, 3.2 mmol) and (R,R)-II-d1 (12.8 mmol, (R,R)-1,2-diaminocyclohexane) and K.sub.2CO.sub.3 (1.33 g, 9.6 mmol) were dissolved in 70 mL of acetonitrile and heated at reflux under nitrogen for 12 h, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was added to 50 mL of diethyl ether and washed with water. The organic phase was dried and concentrated and subjected to column chromatography (EtOAc/PE=? additional 5% triethylamine was added) to give (R.sub.a,R,R)-II-1l (737 mg, with a yield of 52%) as a white solid.

[0040] M.p. 84-86? C.; [?].sub.D.sup.20=+183.9 (c=1.00, CH.sub.2Cl.sub.2). .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 6.87 (d, J=8.4 Hz, 4H), 3.85 (d, J=12.9 Hz, 2H), 3.26 (d, J=13.1 Hz, 5H), 2.97-2.85 (m, 1H), 2.49 (t, J=9.8 Hz, 1H), 2.36 (d, J=15.9 Hz, 2H), 2.34 (s, 6H), 2.12 (d, J=9.6 Hz, 1H), 1.90 (d, J=12.5 Hz, 2H), 1.66 (s, 2H), 1.49 (s, 6H), 1.24 (s, 6H), 1.19-1.12 (m, 2H) ppm; HRMS (ESI.sup.+) calcd for [C.sub.31H.sub.43N.sub.2].sup.+, m/z 443.3421, found 443.3421.

Example 2 Synthesis of (R.SUB.a.,S,S)-II-2.

[0041] ##STR00011##

[0042] Referring to the procedure of Example 1, (R,R)-II-d1 was replaced with (S,S)-II-d2 (12.8 mmol, (R,R)-1,2-diaminocyclohexane) to give (R.sub.a,S,S)-II-2 (790 mg, with a yield of 56%).

[0043] M.p. 88-90? C.; [?].sub.D.sup.20=+201.2(c=1.00, CH.sub.2Cl.sub.2); HRMS (ESI.sup.+) calcd for C.sub.31H.sub.42N.sub.2, m/z 443.3421, found 443.3422.

Example 3 Synthesis of (R.SUB.a.,R,R)-II-3.

[0044] ##STR00012##

[0045] Referring to the procedure of Example 1, (R,R)-II-d1 was replaced with (R,R)-II-d3 (12.8 mmol, (R,R)-1,2-diamino-1, 2-diphenylethane) to give (R.sub.a,R,R)-II-3 (886 mg, with a yield of 51%).

[0046] M.p. 96-99? C.; [?].sub.D.sup.20=+58.2(c=1.00, CH.sub.2Cl.sub.2); HRMS (ESI.sup.+) calcd for [C.sub.39H.sub.44N.sub.2+H].sup.+, m/z 541.3512, found 541.3573.

Example 4 Synthesis of (R.SUB.a.,S,S)-II-4.

[0047] ##STR00013##

[0048] Referring to the procedure of Example 1, (R,R)-II-d1 was replaced with (S,S)-II-d4 (12.8 mmol, (S,S)-1,2-diamino-1,2-diphenylethane) to give (R.sub.a,S,S)-II-4 (743 mg, with a yield of 43%).

[0049] M.p. 98-102? C.; [?].sub.D.sup.20=+17.4 (c=1.00, CH.sub.2Cl.sub.2); HRMS (ESI.sup.+) calcd for [C.sub.39H.sub.44N.sub.2+H].sup.+, m/z 541.3512, found 541.3577.

Example 5 Synthesis of (R.SUB.a.,R,R)-I-1.

[0050] ##STR00014##

[0051] (R.sub.a,R,R)-II-1(0.2mmol) was dissolved in 5 mL of dichloromethane and 3-((3, 5-bis (trifluoromethyl) phenyl) amino)-4-methoxycyclobut-3-ene-1, 2-dione (67.8 mg, 0.2 mmol) was added. The mixture was stirred for reaction at room temperature for 48 h, and then filtered and washed with acetonitrile to give the product (R.sub.a,R,R)-I-1 (139 mg, with a yield of 93%).

[0052] M.p. 234-236? C.; [?].sub.D.sup.20=62.5(c=1.00, CH.sub.2Cl.sub.2); .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?10.09 (s, 1H), 8.02 (s, 2H), 7.67 (s, 1H), 7.63 (s, 1H), 6.81 (d, J=10.6 Hz, 3H), 4.23 (s, 1H), 3.59 (d, J=13.0 Hz, 2H), 3.29 (d, J=13.0 Hz, 2H), 2.72-2.65 (m, 1H), 2.50 (d, J=1.5 Hz, 6H), 2.31-2.23 (m, 2H), 2.19 (s, 4H), 2.03 (d, J=12.8 Hz, 1H), 1.67 (dd, J=36.9, 12.7 Hz, 3H), 1.57 (d, J=7.9 Hz, 1H), 1.40 (s, 6H), 1.34-1.22 (m, 2H), 1.14 (s, 6H) ppm; HRMS (ESI.sup.+) calcd for [C.sub.43H.sub.46F.sub.6N.sub.3O.sub.2].sup.+, m/z 750.3489, found 750.3489.

Example 6 Synthesis of (R.SUB.a.,S,S)-I-2.

[0053] ##STR00015##

[0054] Following the procedure of Example 5, (R.sub.a,R,R)-II-1(0.2 mmol) was replaced with (R.sub.a,S,S)-II-2 to give (R.sub.a,S,S)-I-2 (133 mg, with a yield of 89%).

[0055] HRMS (ESI.sup.+) calcd for [C.sub.43H.sub.46F.sub.6N.sub.3O.sub.2].sup.+, m/z 750.3489, found 750.3487.

Example 7 Synthesis of (R.SUB.a.,R,R)-I-3.

[0056] ##STR00016##

[0057] Following the procedure of Example 5, (R.sub.a,R,R)-II-1(0.2 mmol) was replaced with (R.sub.a, R,R)-II-3 to give (R.sub.a, R,R)-I-3 (737 mg, with a yield of 87%).

[0058] HRMS (ESI.sup.+) calcd for [C.sub.51H.sub.47F.sub.6N.sub.3O.sub.2+H].sup.+, m/z 848.3606, found 848.3605.

Example 8 Synthesis of (R.SUB.a.,S,S)-I-4.

[0059] ##STR00017##

[0060] Following the procedure of Example 5, (R.sub.a,S,S)-II-1(0.2 mmol) was replaced with (R.sub.a,S,S)-II-4 to give (R.sub.a,S,S)-I-4 (770 mg, with a yield of 91%).

[0061] HRMS (ESI+) calcd for [C51H47F6N302+H] +, m/z 848.3606, found 848.3608.

Application Example 1

[0062] ##STR00018##

[0063] Tert-butyl (E)-2-oxo-3-(2,2,2-trifluoroethylidene) indoline-1-carboxylate (37.6 mg, 0.12 mmol, 1.2 eq) and 2, 5-diphenyl-2, 4-dihydro-3H-pyrazol-3-one (0.1 mmol, 1 eq) were dissolved in 1 mL of 1, 2-dichloroethane, and the organocatalyst (R.sub.a,R,R)-I-1 (0.01 mmol, 0.1 eq) was added; then the mixture was stirred and reacted at room temperature for 16 h until the reaction was completed, after which trifluoroacetic acid (1 mmol, 10 eq) was added and reacted for 2 hours, followed by isolation and purification of the resulting asymmetric addition product (R,R)-12a (with a yield of 91%, 95% ee, 94:6 d.r.) by using a preparative chromatography plate (ethyl acetate: n-hexane=1:4).

[0064] .sup.1H NMR (600 MHZ, CDCl.sub.3) ?12.20 (s, 1H), 8.49 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.61 (d, J=7.3 Hz, 2H), 7.53 (t, J=7.4 Hz, 2H), 7.50-7.42 (m, 3H), 7.29 (dd, J=14.7, 7.4 Hz, 2H), 7.12 (t, J=7.4 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.91 (d, J=7.7 Hz, 1H), 4.32 (q, J=9.3 Hz, 1H), 4.05 (s, 1H) ppm.

[0065] HPLC conditions: chiral chromatographic column IC-3 (hexane/i-PrOH=95/5, flow rate 1.5 mL/min, ?=210 nm), t.sub.R((R,R)-12a)=8.28 min, t.sub.R((S,S)-12a)=6.60 min.

Comparative Example

[0066] Referring to the procedure of Application Example 1, (R.sub.a,R,R)-I-1 was replaced with the quinine amine-based chiral ammonia-squaramide catalyst (compound 2, configuration (R)) of the literature Mechanochemically Activated Asymmetric Organocatalytic Domino Mannich Reaction-Fluorination. ACS Sustain. Chem. Eng.2020, 8, 14417., to give an asymmetric addition product (S,S)-12a (with a yield of 63%, 88% ee, 97:3 d.r.).

[0067] Wherein the structure of compound 2 is as follows:

##STR00019##

Application Example 2

[0068] Starting materials were charged according to the procedure of Application Example 1, but the amount of the catalyst was reduced, i.e., an organic catalyst (R.sub.a,R,R)-I-1 (0.001 mmol, 0.01 eq) was used; then after reaction under stirring at room temperature for 16 h, trifluoroacetic acid (1 mmol, 10eq) was added to react for 2 h, followed by isolation and purification of the resulting asymmetric addition product (R,R)-12a (with a yield of 67%, 88% ee, 96:4 d.r.) by directly using a preparative chromatography plate (ethyl acetate: n-hexane=1:4).

[0069] Conclusion: the activity of the catalyst far surpasses the effect of known catalysts, i.e., with 1% of the catalyst, the asymmetric conjugate addition can still be catalyzed, obtaining a high yield and a high enantioselectivity.

Application Example 3

[0070] ##STR00020##

[0071] Referring to the procedure of Application Example 1, 2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one was replaced with 2-phenyl-5-(p-tolyl)-2,4-dihydro-3H-pyrazol-3-one to give an asymmetric addition product (R,R)-12b (with a yield of 74%, 93% ee,>99:1 d.r.).

[0072] .sup.1H NMR (400 MHz, CDCl.sub.3) ?12.12 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.47 (dd, J=17.6, 8.0 Hz, 4H), 7.32 (dd, J =18.3, 7.7 Hz, 4H), 7.19-7.10 (m, 2H), 6.96 (d, J=7.7 Hz, 1H), 4.33 (q, J=9.7 Hz, 1H), 4.06 (s, 1H), 2.46 (s, 3H) ppm.

[0073] HPLC conditions: chiral chromatographic column IC-3 (hexane/i-PrOH= 90/10, flow rate 1 mL/min, ?=254 nm), t.sub.R ((R,R)-12b)=7.91 min, t.sub.R ((S,S)-12b)=6.56 min.

Application Example 4

[0074] ##STR00021##

[0075] Referring to the procedure of Application Example 1, 2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one was replaced with 2-(4-chlorophenyl)-5-phenyl-2, 4-dihydro-3H-pyrazol-3-one to give an asymmetric addition product (R,R)-12c (with a yield of 66%, 90% ee, 96:4 d.r.).

[0076] 1H NMR (400 MHZ, CDCI3) 8 8.34 (s, 1 H), 7.77 (d, J=8.8 Hz, 2H), 7.60-7.52 (m, 5H), 7.45 (d, J=8.8 Hz, 2H), 7.32 (t, J=7.7 Hz, 2H), 7.16 (t, J=7.5 Hz, 1 H), 7.06 (d, J=7.5 Hz, 1 H), 6.97 (d, J=7.8 Hz, 1 H), 4.28 (q, J=8.8 Hz, 1 H), 4.06 (s, 1 H) ppm.

[0077] HPLC conditions: chiral chromatographic column IC-3 (hexane/i-PrOH= 95/5, flow rate 1 mL/min, ?=254 nm), t.sub.R ((R,R)?12c)=7.09 min, t.sub.R((S,S)-12c)=6.02 min.

Application Example 5

[0078] ##STR00022##

[0079] Referring to the procedure of Application Example 1, tert-butyl (E)-2-oxo-3-(2, 2, 2-trifluoroethylidene) indoline-1-carboxylate was replaced with tert-butyl (E)-4-methyl-2-oxo-3-(2,2,2-trifluoroethylidene) indoline-1-carboxylate to give an asymmetric addition product (R,R)-12d (with a yield of 52%,>99% ee, 94:6 d.r.).

[0080] .sup.1H NMR (400 MHZ, CDCl.sub.3) ?8.13 (s, 1H), 7.84 (d, J=7.9 Hz, 2H), 7.63-7.44 (m, 7H), 7.34 (t, J=7.4 Hz, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 4.27 (dd, J=18.4, 9.0 Hz, 1H), 4.03 (s, 1H), 2.36 (s, 3H) ppm.

[0081] HPLC conditions: chiral chromatographic column IC-3 (hexane/i-PrOH= 90/10, flow rate 1 mL/min, ?=254 nm), t.sub.R((R,R)-12d)=4.12 min, t.sub.R((S,S)-12d)=6.18 min.