Chiral sulfinamide carboxylic acid compound as well as synthesis method and application thereof

Abstract

The invention relates to a chiral sulfinamide carboxylic acid compound and a synthesis method and application thereof, the chiral sulfinamide carboxylic acid compound is a compound with a structure shown in a formula (1), and the chiral sulfinamide carboxylic acid compound is mainly structurally characterized in that carboxylic acid and chiral sulfinamide substituent groups exist at the ortho-position of a heteroaromatic ring at the same time, and the heteroaromatic ring can be a mono-or multi-substituted benzene ring, a mono-or multi-substituted naphthalene ring, a thiophene or furan ring and a pyridine ring. The synthesis steps of the chiral sulfinamide are simple, the raw materials are cheap and easy to obtain, the reaction conditions are mild, and the operation is simple and convenient. The chiral carboxylic acid is a novel protonic acid chiral catalyst. The catalyst is especially suitable for asymmetric reaction catalyzed by transition metal, and the product has high yield and enantioselectivity. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a novel chiral sulfenamide carboxylic acid, a synthesis method thereof and application thereof in a palladium-catalyzed oxime ether-directed asymmetric synthesis of diaryl carbinol derivatives. Background Art

[0002] The transition metal-catalyzed asymmetric carbon-hydrogen bond activation reaction is of great significance. It can make the carbon-hydrogen bonds widely present in organic matter undergo a one-step functionalization reaction to construct a variety of chiral skeletons. Compared with traditional asymmetric synthesis, this method is simpler and more efficient, and has great potential application value. It has now become a frontier hotspot in asymmetric catalysis research. Among transition metal catalysts, palladium has attracted much attention because it is not only suitable for a variety of directing groups, but also can construct different types of bonds, such as CO, CN, CX and CC bonds. In 2008, Yu Jinquan's research group used mononitrogen protected amino acids (MPAAs) as chiral ligands to achieve palladium-catalyzed enantioselective CH activation for the first time (Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882-4886). Since then, a variety of single nitrogen protected amino acid derivatives, chiral phosphoric acid derivatives and chiral binaphthol derivatives have been developed as chiral ligands, and have shown good reactivity in palladium-catalyzed asymmetric carbon-hydrogen bond activation reactions (Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.; Yu, J.-Q. Acc. Chem. Res. 2020, 53, 833-851; Yan, S.-B; Zhang, S.; Duan, W.-L. Org. Lett., 2015, 17, 2458–2461; Han, Y.-Q.; Ding, Y.; Zhou, T.; Yan, S.-Y.; Song, H.; Shi, B.-FJ Am. Chem. Soc., 2019, 141, 4558–4563). The development of chiral ligands plays an important role in asymmetric reactions. However, in the current field of palladium-catalyzed asymmetric carbon-hydrogen bond activation, the types of chiral ligands are relatively limited. Among them, palladium-catalyzed oxime-oriented asymmetric carbon-hydrogen bond activation has not been fully explored. The main reason is that the chiral ligands are not well adapted to this type of reaction system, making it difficult to achieve effective chiral regulation.

[0003] The invention uses optically active chiral sulfenamide as a starting material to synthesize a novel chiral sulfenamide carboxylic acid, and uses the synthesized chiral sulfenamide carboxylic acid as a chiral ligand for palladium-catalyzed oxime ether-directed asymmetric reaction of diaryl carbinol derivatives and alkynyl bromide to prepare chiral 2-alkynyl diaryl carbinol derivatives. Summary of the invention

[0004] One of the purposes of the present invention is to provide a carboxylic acid having a chiral sulfenamide structure.

[0005] The second object of the present invention is to provide a method for preparing the chiral sulfenamide carboxylic acid.

[0006] The third object of the present invention is to provide the use of the chiral sulfenamide carboxylic acid in the palladium-catalyzed oxime ether-directed reaction of a diarylcarbinol derivative with an acetylene bromide derivative to prepare a chiral diarylcarbinol derivative.

[0007] The chiral sulfenamide carboxylic acid compound of the present invention is an optically active compound having structural formula (I), (II), (III) or (IV):

[0008]

[0009] In formula (I), (II), (III) or (IV): R is independently selected from aryl or substituted aryl or alkyl, and the substituent on the aryl is selected from alkyl or alkoxy. 1 R is selected from one or more of H, alkyl, alkoxy, alkanoyloxy, alkoxycarbonyl, cyano, nitro and halogen. 2 is independently selected from H, alkyl, halogen, alkoxy, cyano, nitro, alkanoyloxy, alkoxycarbonyl, aryl or substituted aryl, and the substituent on the aryl is selected from alkyl or alkoxy. In (III), X is independently selected from S and O, wherein the carboxylic acid substituent (-COOH) and the sulfenamide substituent [RS(O)NH-] can be located at the 2,3-position or 3,4-position of the heterocyclic ring. In (IV), the carboxylic acid substituent and the sulfenamide substituent can be located at the 2,3-position or 3,4-position of the pyridine ring.

[0010] Preferably, R is independently selected from C1-C4 alkyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is selected from one or more C1-C4 alkyl;

[0011] R 1 One or more selected from H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkoxycarbonyl, cyano, nitro and halogen (when more than one, R 1 represents multiple substituents);

[0012] R 2is independently selected from H, C1-C4 alkyl, halogen, C1-C4 alkoxy, cyano, nitro, C1-C4 alkanoyloxy, C1-C4 alkoxycarbonyl, substituted silicon, phenyl or substituted phenyl, the substituent on the phenyl is selected from C1-C4 alkyl (III) X is independently selected from S and O, wherein the carboxylic acid substituent and the sulfenamide substituent can be located at the 2,3-position or 3,4-position of the heterocyclic ring. The carboxylic acid substituent and the sulfenamide substituent in (IV) can be located at the 2,3-position or 3,4-position of the pyridine ring.

[0013] As further preferred, R is independently selected from phenyl, 4-methyl substituted phenyl, 2,4,6-trimethyl substituted phenyl or tert-butyl;

[0014] R 1 One or more selected from H, methyl, tert-butyl, methoxy, formyloxy, methoxycarbonyl, cyano, nitro, F or Cl;

[0015] R 2 Independently selected from H, methyl, tert-butyl, halogen, methoxy, cyano, nitro, formyloxy, methoxycarbonyl, phenyl or substituted phenyl, the substituent on the phenyl being selected from methyl.

[0016] As a further preference, the chiral sulfenamide carboxylic acid compound is one of the following compounds:

[0017]

[0018] The chiral sulfenamide carboxylic acid may be a levorotatory isomer or a dextrorotatory isomer having the same general chemical formula.

[0019] The present invention further provides a method for preparing the chiral sulfenamide carboxylic acid, and the synthesis steps are as follows:

[0020] In the first step, palladium acetate (0.01-0.06 equivalents), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (0.02-0.12 equivalents), chiral sulfenamide (1.1-1.6 equivalents) and cesium carbonate (1.3-2.6 equivalents) are placed in a 50 ml Shrek tube. The Shrek tube is evacuated and then filled with nitrogen, and repeated 2-3 times. Under nitrogen protection, methyl or ethyl ester (or ethyl ester) of o-bromo or o-iodoaryl (naphthyl or heteroaryl) formate (1.0 equivalents) and 10-20 ml of dioxane are added, and then the reaction mixture is stirred at 80-120°C (oil bath) until the raw material is consumed. After cooling to room temperature, water is added and the reaction mixture is extracted with ethyl acetate. The combined organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. Purification is performed by column chromatography to obtain the corresponding compound A.

[0021] In the second step, the product A obtained in the first step is dissolved in a tetrahydrofuran / water (1:1-3:1) mixed solvent at 0-20°C, and lithium hydroxide (2-6 equivalents) is added in batches. After the reaction is completed, ethyl acetate and 1.0M hydrochloric acid aqueous solution are added to the system. The aqueous layer is then extracted twice with ethyl acetate. The combined organic layer is washed with water and brine in turn, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue is recrystallized with ethyl acetate to obtain the corresponding chiral sulfenamide carboxylic acid compound B.

[0022] The preparation process of chiral sulfenamide carboxylic acid, the general reaction formula is as follows:

[0023]

[0024] Where: R, R' and R 1 is defined as above.

[0025] The present invention further provides an application of the chiral sulfenamide carboxylic acid B, wherein the chiral sulfenamide carboxylic acid compound is used as a chiral ligand for palladium-catalyzed oxime ether-directed asymmetric reaction of a diarylcarbinol derivative 1 and an alkynyl bromide 2 to prepare a chiral 2-alkynyl diarylcarbinol derivative 3, and the reaction formula is:

[0026]

[0027] Where: R 3 Methyl or two R 3 Connect two R 3 The carbon atoms of R are cyclized together to form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, 4,4-dimethylcyclohexane, 3,3-5,5-tetramethylcyclohexane or adamantyl. 4 R is one or more of methyl, ethyl, isopropyl, tert-butyl, phenyl, tert-butyldimethylsilyloxy, triisopropylsilyloxy, hydroxymethyl, methoxy, benzyloxy, hydroxyl, acetyl, F, Cl, and Br. 5 It is tert-butyldimethylsilyl, triethylsilyl, and triisopropylsilyl.

[0028] The chiral sulfenamide carboxylic acid B is used in an asymmetric catalytic reaction process as follows: the diaryl carbinol derivative 1 is mixed with acetylene bromide 2, a palladium catalyst, silver carbonate, and chiral sulfenamide carboxylic acid B in a molar equivalent of 1:1.0-3.0:0.05-0.15:1.0-3.0:0.1-0.2 in a mixed solvent of tetrahydrofuran and chloroform, reacted at 25-40°C for 24-72 hours, filtered after the reaction is completed, and purified by column chromatography to obtain a chiral 2-alkynyl diaryl carbinol derivative 3.

[0029] The invention provides a method for synthesizing a novel chiral carboxylic acid with a sulfenamide substituent. The chiral sulfenamide carboxylic acid is a novel proton acid chiral catalyst. When a diaryl carbinol derivative is used for palladium catalysis and reacted with acetylene bromide to prepare a chiral 2-alkynyl diaryl carbinol derivative, the product has high yield and enantioselectivity. DETAILED DESCRIPTION

[0030] The following examples will help to understand the present invention, but are not intended to limit the scope of protection of the present invention.

[0031] Example 1 Preparation of (R)-2-((tert-butylsulfinyl)amino)benzoic acid:

[0032]

[0033] In the first step, 0.09 mmol of palladium acetate, 0.18 mmol of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene, 3.6 mmol of 2-methylpropane-2-sulfenamide and 6.0 mmol of cesium carbonate are placed in a 50 ml Shrek tube. The Shrek tube is evacuated and then filled with nitrogen, and repeated 2 to 3 times. 3.0 mmol of methyl o-bromobenzoate and 15 ml of dioxane are added under nitrogen protection, and then the reaction mixture is placed at 100 ° C (oil bath) and stirred until the raw material is consumed. After cooling to room temperature, water is added and the reaction mixture is extracted with ethyl acetate. The combined organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. Purification is performed by column chromatography to obtain the corresponding compound A.

[0034] In the second step, the product obtained in the first step (1.0 mmol A) was dissolved in 4 ml of tetrahydrofuran / water (1:1) mixed solvent at 0 degrees, and 2.0 mmol lithium hydroxide was added in batches. After the reaction was completed, ethyl acetate and 1.0M hydrochloric acid aqueous solution were added to the system. Then the water layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine in turn, then dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate to obtain 314 mg of the corresponding chiral sulfenamide carboxylic acid compound. MP: 135.2-137.0℃; 1 H NMR (400MHz, CDCl3) δ10.03 (s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.51–7.45 (m, 2H), 7.00–6.94 (m, 1H), 1.46 (s, 9H); 13 C NMR(101MHz, CDCl3)δ170.8,146.1,134.8,132.3,120.9,115.8,114.9,57.2,22.9; HRMS(ESI)m / z:[M+Na]+ Calcd for C 11 H 15 NNaO3S264.0665; found:264.0663.

[0035] Example 2 Preparation of various other chiral sulfenamide carboxylic acids

[0036] The preparation process is the same as that of Example 1, but the ortho-bromo (or iodo) aryl formate added in the first step is replaced by other corresponding substituted aryl groups or the chiral sulfenamide R substituents are different, and the corresponding chiral sulfenamide carboxylic acid data are as follows:

[0037] (R)-2-((Mesitylenesulfinyl)amino)benzoic acid

[0038]

[0039] MP: 206.8-208.5℃; 1 H NMR (400MHz, CDCl3) δ8.42 (d, J = 7.9Hz,

[0040] 1H),8.05(d,J=7.6Hz,1H),7.79(t,J=7.3Hz,1H),7.57(t,J=7.1Hz,1H),6.74(s,2H),2.27(s,6H),2.19(s,3H); 13 C NMR(101MHz, CDCl3)δ168.2,146.7,141.8,140.2,137.2,132.9,131.8,130.8,130.0,128.4,127.8,21.2,20.0; HRMS(ESI)m / z:[M+Na] + Calcdfor C 16 H 17 NNaO3S 326.0824; found:326.0826.

[0041] (R)-3-((tert-Butylsulfinyl)amino)-2-naphthoic acid

[0042]

[0043] MP: 165.1-167.0℃; 1 H NMR (400MHz, CDCl3) δ9.93(s,1H),8.43(s,1H),7.72–7.67(m,3H),7.50(t,J=7.5Hz,1H),7.31(t,J=7.6Hz,1H),1.50(s,9H); 13C NMR(101MHz, CDCl3)δ170.0,141.1,136.7,134.4,129.4,129.4,128.1,126.5,124.8,116.6,111.9,57.2,23.0; HRMS(ESI)m / z:[M+Na] + Calcd for C 15 H 17 NNaO3S 314.0821; found:314.0823.

[0044] (R)-3-((tert-Butylsulfinyl)amino)thiophene-2-carboxylic acid

[0045]

[0046] MP: 154.1-155.8℃; 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 7.48 (d, J = 5.4Hz, 1H), 7.11 (d, J = 5.4Hz, 1H), 1.37 (s, 9H); 13 C NMR(101MHz, CDCl3)δ167.9,150.1,133.5,118.4,107.6,57.5,22.6; HRMS(ESI)m / z:[M+Na] + Calcd for C9H 13 NO3S2Na 270.0229; found:270.0228.

[0047] (R)-2-((tert-Butylsulfinyl)amino)-6-methylbenzoic acid

[0048]

[0049] 1 H NMR (400MHz, CDCl3) δ9.22(s,1H),7.30–7.25(m,1H),7.19(d,J=8.2Hz,1H),6.86(d,J=7.4Hz,1H),2.47(s,3H),1.42(s,9H); 13 C NMR(101MHz, CDCl3)δ171.7,144.1,141.2,132.0,125.4,119.8,115.3,57.1,23.1,22.8; HRMS(ESI)m / z:[M+Na] + Calcd for C 12 H 17NNaO3S278.0821; found:278.0819.

[0050] (R)-2-((tert-Butylsulfinyl)amino)-5-methylbenzoic acid

[0051]

[0052] MP: 126.4-128.1℃; 1 H NMR (400MHz, CDCl3) δ9.75 (s, 1H), 7.63 (s, 1H), 7.25 (d, J = 8.5Hz, 1H), 7.20–7.18 (m, 1H), 2.18 (s, 3H), 1.33 (s, 9H); 13 C NMR(101MHz, CDCl3)δ170.8,143.7,135.7,132.2,130.4,116.1,114.9,57.1,22.8,20.5; HRMS(ESI)m / z:[M+Na] + Calcdfor C 12 H 17 NNaO3S278.0821; found:278.0823.

[0053] (R)-2-((tert-Butylsulfinyl)amino)-4-methylbenzoic acid

[0054]

[0055] MP: 134.2-136.0℃; 1 H NMR (400MHz, CDCl3) δ9.89 (s, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.26 (s, 1H), 6.75 (dd, J = 8.2, 1.6Hz, 1H), 2.36 (s, 3H), 1.42 (s, 9H); 13 C NMR(101MHz, CDCl3)δ171.2,146.3,146.2,132.3,122.1,116.2,112.0,57.0,22.9,22.1; HRMS(ESI)m / z:[M+Na] + Calcd for C 12 H 17 NNaO3S278.0821; found:278.0822.

[0056] (R)-2-((tert-Butylsulfinyl)amino)-3-fluorobenzoic acid

[0057]

[0058] MP: 143.3-145.1℃; 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),7.79(d,J=7.9Hz,1H),7.56–7.51(m,1H),7.14–7.08(m,1H),1.27(s,9H); 13 C NMR(101MHz,DMSO-d6)δ169.2(d,J C-F =3.7Hz),153.4(d,J C-F =245.0Hz),133.6(d,J C-F =11.0Hz),127.2(d,J C-F =3.3Hz),122.2(d,J C-F =7.7Hz),121.3(d,J C-F =19.6Hz),120.2,56.6,21.7; 19 F NMR(376MHz,DMSO-d6)δ-134.58; HRMS(ESI)m / z:[M+Na] + Calcd for C 11 H 14 FNNaO3S282.0571; found:282.0575.

[0059] (R)-2-(tert-Butylsulfinyl)amino)-6-fluorobenzoic acid

[0060]

[0061] MP: 115.5-116.8℃; 1 H NMR (400MHz, CDCl3) δ9.90(s,1H),7.35(td,J=8.4,5.8Hz,1H),7.16(d,J=8.4Hz,1H),6.67(td,J=9.4,7.9,2.5Hz,1H),1.42(s,9H); 13 C NMR(101MHz,CDCl3)δ168.4,163.2(d,J C-F =259.6Hz),146.9(d,J C-F =3.8Hz),134.4(d,J C-F =11.8Hz),111.7(d,J C-F =3.5Hz),109.3(d,J C-F=24.0Hz),106.1(d,J C-F =14.4Hz),57.6,22.8; 19 FNMR (376MHz, CDCl3) δ-103.70; HRMS (ESI) m / z: [M+Na] + Calcd for C 11 H 14 FNNaO3S282.0571; found:282.0570.

[0062] (R)-6-((tert-Butylsulfinyl)amino)-2-fluoro-3-methylbenzoic acid

[0063]

[0064] MP: 123.7-125.2℃; 1 H NMR (400MHz, CDCl3) δ9.66 (s, 1H), 7.25 (d, J = 8.1Hz, 1H), 7.10 (d, J = 8.4Hz, 1H), 2.22 (s, 3H), 1.44 (s, 9H); 13 CNMR (101MHz,CDCl3)δ168.4(d,J C-F =2.3Hz),161.0(d,J C-F =257.9Hz),144.6(d,J C-F =3.3Hz),136.0(d,J C-F =8.1Hz),118.5(d,J C-F =19.2Hz),111.7(d,J C-F =3.7Hz),106.2(d,J C-F =14.8Hz),57.4,22.8,14.2; 19 FNMR (376MHz, CDCl3) δ-107.68; HRMS (ESI) m / z: [M+Na] + Calcd for C 12 H 16 FNNaO3S296.0727; found:296.0726.

[0065] (R)-6-((tert-Butylsulfinyl)amino)-3-chloro-2-fluorobenzoic acid

[0066]

[0067] MP: 183.5-185.1℃; 1H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 7.42 (dd, J = 9.0, 7.6Hz, 1H), 7.13 (dd, J = 9.1, 1.6Hz, 1H), 1.42 (s, 9H); 13 CNMR (101MHz,CDCl3)δ167.5(d,J C-F =3.4Hz),158.4(d,J C-F =261.9Hz),145.3(d,J C-F =3.1Hz),134.7(d,J C-F =2.2Hz),114.5(d,J C-F =20.2Hz),112.2(d,J C-F =4.3Hz),107.5(d,J C-F =14.4Hz),57.8,22.8; 19 F NMR (376MHz, CDCl3) δ-104.56; HRMS (ESI) m / z: [M+Na] + Calcd for C 11 H 13 ClFNNaO3S 316.0181; found:316.0181.

[0068] (S)-6-((tert-Butylsulfinyl)amino)-2,3-difluorobenzoic acid

[0069]

[0070] MP: 131.2-132.8℃; 1 H NMR (400MHz, CDCl3) δ9.62(s,1H),7.29–7.22(m,1H),7.09–7.05(m,1H),1.43(s,9H); 13 C NMR(101MHz,CDCl3)δ167.2(d,J C-F =3.2Hz),150.9(dd,J C-F =262.1,14.0Hz),145.9(dd,J C-F =243.7,14.0Hz),141.7,121.8(dd,J C-F =18.6,2.5Hz),111.7(t,J C-F =5.1Hz),108.5(d,J C-F =10.9Hz),57.6,22.8; 19F NMR(376MHz,CDCl3)δ-129.34(d,J F-F =21.6Hz),-144.91(d,J F-F =21.6Hz); HRMS(ESI)m / z:[M+Na] + Calcdfor C 11 H 13 F2NNaO3S 300.0476; found:300.0475.

[0071] Example 3 Chiral sulfenamide carboxylic acid compounds as chiral ligands for palladium-catalyzed oxime ether-directed asymmetric reaction of diarylcarbinol derivatives 1a with alkynyl bromide 2 to prepare chiral 2-alkynyl diarylcarbinol derivatives 3a

[0072] 0.1 mmol of diarylmethanol derivative 1a, 0.01 mmol of dichloro(acetonitrile)palladium(II), 0.1 mmol of silver carbonate and 0.02 mmol of (R)-6-((tert-butylsulfinyl)amino)-3-chloro-2-fluorobenzoic acid were placed in a 10 ml Shrek tube. The Shrek tube was evacuated and then filled with nitrogen, and this was repeated three times. Under a nitrogen atmosphere, 4 ml of tetrahydrofuran / chloroform mixed solvent (v / v=3 / 1) and 0.3 mmol of alkynyl bromide 2 were added by syringe, and the reaction mixture was then stirred at 30°C (aluminum heat transfer module) for 48 h. Next, the mixture was diluted with dichloromethane and filtered through diatomaceous earth. After concentration, the residue was chromatographed on a thin layer silica gel plate to obtain the target product 3a.

[0073]

[0074] Characterization of typical product 3a:

[0075] (S)-Cyclopentanone O-(phenyl(2-((triisopropylsilyl)ethynyl)phenyl)methyl)oxime

[0076]

[0077] The yield was 79%, and the ee value was 92%. HPLC [AD-H] (n-hexane / isopropanol = 98 / 2, 0.6 ml / min) λ = 254 nm, tr = 10.4 min (main product), 11.5 min (minor product). 1HNMR (400MHz, CDCl3) δ7.55(d,J=7.6Hz,1H),7.46(d,J=7.8Hz,3H),7.35(q,J=8.1,7.7Hz,3H),7.30–7 .20(m,2H),6.77(s,1H),2.61(t,J=7.0Hz,2H),2.39(t,J=6.9Hz,2H),1.85–1.74(m,4H),1.17(s,21H); 13 CNMR (100MHz, CDCl3) δ167.1,144.0,141.3,133.3,128.5,128.1,127.6,127.4,127.0,1 26.8,122.5,105.2,95.9,83.5,31.1,28.3,25.3,24.8,18.8,11.4; HRMS(ESI)m / z:[M+H] + Calcd for C 29 H 40 NOSi 446.2874; found:446.2874.

[0078] Example 4 The reaction results of other diarylmethanol derivatives 1 and alkyne bromide 2 in the presence of chiral sulfenamide carboxylic acids (R)-6-((tert-butylsulfinyl)amino)-3-chloro-2-fluorobenzoic acid and (S)-6-((tert-butylsulfinyl)amino)-2,3-difluorobenzoic acid:

[0079]

Claims

1. A chiral sulfenamide carboxylic acid compound, characterized in that: An optically active compound having a structure as shown in formula (I), (II), (III) or (IV): In formula (I), (II), (III) or (IV): R is independently selected from aryl or substituted aryl or alkyl, and the substituent on the aryl is selected from alkyl or alkoxy; R 1 One or more selected from H, alkyl, alkoxy, alkanoyloxy, alkoxycarbonyl, cyano, nitro and halogen; R 2 independently selected from H, alkyl, halogen, alkoxy, cyano, nitro, alkanoyloxy, alkoxycarbonyl, aryl or substituted aryl, wherein the substituent on the aryl is selected from alkyl or alkoxy; (III) wherein X is independently selected from S and O, wherein the carboxylic acid substituent and the sulfenamide substituent may be located at the 2, 3-position or the 3, 4-position of the heterocyclic ring; The positions of the carboxylic acid substituent and the sulfenamide substituent in (IV) can be at the 2, 3-position or the 3, 4-position of the pyridine ring.

2. The chiral sulfenamide carboxylic acid compound according to claim 1, characterized in that R is independently selected from C1-C4 alkyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is selected from one or more C1-C4 alkyl; R 1 One or more selected from H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkoxycarbonyl, cyano, nitro and halogen; R 2 Independently selected from H, C1-C4 alkyl, halogen, C1-C4 alkoxy, cyano, nitro, C1-C4 alkanoyloxy, C1-C4 alkoxycarbonyl, phenyl or substituted phenyl, and the substituent on the phenyl is selected from C1-C4 alkyl.

3. The chiral sulfenamide carboxylic acid compound according to claim 1, characterized in that R is independently selected from phenyl, 4-methyl substituted phenyl, 2,4,6-trimethyl substituted phenyl or tert-butyl; R 1 One or more selected from H, methyl, tert-butyl, methoxy, formyloxy, methoxycarbonyl, cyano, nitro, F or Cl; R 2 Independently selected from H, methyl, tert-butyl, halogen, methoxy, cyano, nitro, formyloxy, methoxycarbonyl, phenyl or substituted phenyl, the substituent on the phenyl being selected from methyl.

4. The chiral sulfenamide carboxylic acid compound according to claim 1, characterized in that One of the following compounds:

5. A method for synthesizing a chiral sulfenamide carboxylic acid compound according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) palladium acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, chiral sulfenamide and cesium carbonate are placed in a reactor, the reactor is evacuated, and then filled with nitrogen, and the process is repeated 2 to 3 times, and methyl or ethyl o-bromo or o-iodoaryl formate and dioxane are added under nitrogen protection, and then the reaction mixture is stirred at 80 to 120° C. until the raw materials are consumed, and then the corresponding compound A is obtained through post-treatment; (2) Compound A obtained in the first step is dissolved in a mixed solvent of tetrahydrofuran and water at 0-20° C., and lithium hydroxide is added in batches. After the reaction is completed, ethyl acetate and aqueous hydrochloric acid are added to the system for quenching, and then post-treatment is performed to obtain the corresponding chiral sulfenamide carboxylic acid compound B.

6. A use of a chiral sulfenamide carboxylic acid compound as claimed in any one of claims 1 to 4, characterized in that: The chiral sulfenamide carboxylic acid compound is used as a chiral ligand for palladium-catalyzed oxime ether-directed asymmetric reaction of diarylcarbinol derivative 1 and alkynyl bromide 2 to prepare chiral 2-alkynyl diarylcarbinol derivative 3: Where: R 3 Independently selected from C1-C3 alkyl or two R 3 Connect two R 3 The carbon atoms of 10 Cycloalkyl or substituted C3-C 10 Cycloalkyl, the C3-C 10 The substituent on the cycloalkyl group is a C1-C4 alkyl group; R 4 is one or more of C1-C4 alkyl, aryl, silanoxy, hydroxymethyl, alkoxy, hydroxyl, acetyl, F, Cl, and Br; R 5 It is a sterically hindered silane group.

7. The use of the chiral sulfenamide carboxylic acid compound according to claim 6, characterized in that: R 3 Methyl or two R 3 Connect two R 3 The carbon atoms of the cyclopropane radical are cyclized together to form a cyclopropane radical, cyclobutane radical, cyclopentane radical, cyclohexane radical, cycloheptane radical, cyclooctane radical, 4,4-dimethylcyclohexane radical, 3,3-5,5-tetramethylcyclohexane radical or adamantyl radical.

8. The use of the chiral sulfenamide carboxylic acid compound according to claim 6, characterized in that: R 4 It is one or more of methyl, ethyl, isopropyl, tert-butyl, phenyl, tert-butyldimethylsilyloxy, triisopropylsilyloxy, hydroxymethyl, methoxy, benzyloxy, hydroxyl, acetyl, F, Cl, and Br.

9. The use of the chiral sulfenamide carboxylic acid compound according to claim 6, characterized in that: R 5 It is tert-butyldimethylsilyl, triethylsilyl, and triisopropylsilyl.

10. The use of the chiral sulfenamide carboxylic acid compound according to claim 6, characterized in that: The reaction process is: the diaryl carbinol derivative 1 is mixed with alkynyl bromide 2, palladium catalyst, silver carbonate, and chiral sulfenamide carboxylic acid compound in a molar equivalent of 1:1.0-3.0:0.05-0.15:1.0-3.0:0.1-0.2 in a mixed solvent of tetrahydrofuran and chloroform, reacted at 25-40°C for 24-72 hours, and after the reaction is completed, filtered, and purified by column chromatography to obtain a chiral 2-alkynyl diaryl carbinol derivative 3.

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