Chiral sulfoxide compounds and methods for their preparation

Abstract

The application relates to a chiral sulfoxide compound and a preparation method thereof. The chiral copper catalyst used in the method is generated in-situ from a copper salt and a chiral P, N, N-tridentate ligand in a reaction medium, a series of chiral sulfoxide compounds are synthesized in high yield and high enantioselectivity through an asymmetric propargyl substitution reaction. The application has the characteristics of simple operation, easily available raw materials, wide substrate application range and high enantioselectivity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a chiral sulfoxide compound and its preparation method. Background Technology

[0002] Chiral sulfoxides are widely found in natural products and drug molecules with important biological activities. For example, chiral drugs containing sulfoxide structures can also be used to treat proton pump inhibitors (such as esomeprazole) for gastric ulcers [(a) Bentley, R. Chem. Soc. Rev. 2005, 34, 609-624; (b) Legros, J.; Dehli, JR; Bolm, C. Adv. Synth. Catal. 2005, 347, 19-31; (c) Lindberg, P.; Braendstroem, A.; Wallmark, B.; Mat [tsson, H.; Rikner, L.; Hoffmann, KJ Med. Res. Rev. 1990, 10, 1-54; (d) Maguire, AR; Papot, S.; Ford, A.; Touhey, S.; O'Connor, R.; Clynes, M. Synlett 2001, 2001, 0041-0044. (e) Osorio-Lozada, A.; Prisinzano, T.; Oliva, HFT etrahedron: Asymmetry 2004, 15, 3811-3815.]. These compounds can be used as chiral auxiliaries and intermediates for the synthesis of complex chiral natural products, as well as as chiral ligands or chiral catalysts for various asymmetric catalytic reactions. [(a)Carmen Carreno, M.; Hernandez Torres, G.; Ribagorda, M.; Urbano, A. Chem. Commun. 2009, 6129-6144; (b) Sipos, G.; Drinkel, EE; Dorta, R .Chem.Soc.Rev.2015,44,3834-386; (c)Trost,BM;Rao,M.Angew.Chem.Int.Ed.2015,54,5026-5043;(d)Otocka,S.Kwiatkowska, Madalinska, L.; [P.Chem.Rev.2017,117,4147-4181; (e)Jia,T.;Wang,M.;Liao,J.Top.Curr.Chem.2019,377,1-29; (f)Bunno,Y.;Tsukimawashi,Y.;Kojima,M.;Yoshino,T.;Matsunaga,S.ACS Catal.2021,11,2663-2668]. Therefore, the synthesis of these compounds has always attracted widespread attention from researchers and is one of the hot topics in the field of organic synthesis. The synthetic methods for chiral sulfoxides include biological and chemical methods. Biological sulfoxide methods can be divided into: (1) enzymes, such as cytochrome P-450 enzymes, cyclohexane monooxygenase, chloroperoxidase, and bromoperoxidase; (2) microorganisms, such as bacteria (Corynebacterium equi ATCC21107, Pseudomonas putidaUV4) and fungi (Helminthosporium, Mortierella isabellina); (3) antibodies. This method has the advantages of green process, high substrate / enzyme ratio and high optical purity for some substrates, but it also has problems such as high cost of enzymes or microorganisms, low substrate concentration and narrow substrate applicability (a slight change in substituents leads to a sharp decrease in enantioselectivity) [Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651-3706.]. Chemical methods are divided into four types: chiral co-induction, chiral oxidant, resolution and asymmetric catalysis. The first three methods all require stoichiometric chiral starting materials to participate in the reaction, which does not meet the requirements of green chemistry and atom economy [Wojaczynska, E.; Wojaczynski, J. Chem. Rev. 2010, 110, 4303-4356.]. Asymmetric catalysis is the inevitable trend for the future development of chiral sulfoxide compounds.[(a) Zhu, Y.-C.; Li, Y.; Zhang, B.-C.; Zhang, F.-X.; Yang, Y.-N.; Wang, Catal.2019,9,9164-9177; (c) Liu, W.-T.; Wu, Y.; Zhu, J.-F.; Guo, Y.-H.; Wang, N.; Ke, J.; Yu, P.-Y.; He, C.ACS Catal. 2020, 10, 7207-7215; (d) Zhou, T.; Jiang, M.-X.; Qian, P.-F.; Yao, Q.-J.; Xu, X.-T.; Zhang, K.; Shi, B.-F. Org. Lett. 2021, 23, 7910-7915.]. Existing reports mainly focus on the construction of chiral sulfoxides via catalytic oxidation and asymmetric CH bond functionalization, with relatively limited catalytic strategies [(a) Qian, P.-F.;Li, J.-Y.;Zhou, T.;Shi.B.-F.Synthesis2022,54,4784-4794;(b) Zhang, Q.;Wu, L.-S.;Shi.B.-F.Chem 2022,8,384-413;(c) Zhu, H.-M.;Wang, C.;Zong.L.-L.Chin.J.Org.Chem.2021,41,3431-3447.]. Therefore, developing new asymmetric catalytic strategies for the simple and efficient construction of chiral sulfoxides is of great significance. Summary of the Invention

[0003] The purpose of this invention is to provide a chiral sulfoxide compound and its synthetic method, which synthesizes the chiral sulfoxide compound through a copper-catalyzed asymmetric propargyl substitution reaction between a 2,2'-sulfinyl diphenol compound and a propargyl compound. This invention features readily available starting materials, simple operation, mild reaction conditions, and high enantioselectivity.

[0004] The specific steps are as follows:

[0005] (1) Preparation of chiral copper catalyst: Under nitrogen protection, copper salt and P,N,N-ligands were stirred in a reaction medium at a molar ratio of 1:1 to 10 for 1 to 2 hours to obtain chiral copper catalyst;

[0006] (2) Sulfoxide compounds and their preparation: Prolyl compounds, 4-hydroxycoumarin compounds and base additives were dissolved in the reaction medium, and then the solution was added to the above-mentioned chiral copper catalyst solution under nitrogen protection. The mixture was stirred at 0-10°C for 0.1-24 hours. After the reaction was completed, the mixture was concentrated under reduced pressure until there was basically no solvent. The product was separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to obtain the target product.

[0007] The molar ratio of the chiral copper catalyst to the 2,2'-sulfinyl diphenol compound is 0.01 to 1:1;

[0008] The molar ratio of the alkali additive to the 2,2'-sulfinyl diphenol compound is 1 to 10:1;

[0009] The molar ratio of the 2,2'-sulfinyl diphenol compound to the propargyl compound is 1:1 to 3.

[0010] The chiral sulfoxide compound has one of the following structures:

[0011]

[0012] I and II are enantiomers, wherein: R is H, a C1-C10 alkyl or alkoxy group, a C3-C10 cycloalkyl group, a phenyl or substituted phenyl group, a benzyl or substituted benzyl group, a naphthyl or substituted naphthyl group, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen group, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5.

[0013] The 2,2'-sulfinyl diphenol compound has the following structure:

[0014]

[0015] In the formula: R is H, a C1-C10 alkyl or alkoxy group, a C3-C10 cycloalkyl group, a phenyl or substituted phenyl group, a benzyl or substituted benzyl group, a naphthyl or substituted naphthyl group, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen group, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5.

[0016] The propargyl compounds have the following structures:

[0017]

[0018] In the formula: the leaving group X is one of fluorine, chlorine, bromine, iodine, C1-C10 alkyl carboxylate, C1-C10 alkyl carbonate, C1-C10 alkyl sulfonate, C1-C10 alkyl phosphate, phenyl carboxylate and substituted phenyl carboxylate, phenyl carbonate and substituted phenyl carbonate, phenyl sulfonate and substituted phenyl sulfonate or phenyl phosphate and substituted phenyl phosphate; the substituents on the substituted phenyl group are one or more of C1-C10 alkyl, C1-C10 alkoxy, halogen, nitro, ester or cyano, and the number of substituents is 1 to 5.

[0019] The copper salt is one or more of Cu(OAc)2·H2O, CuSO4·H2O, Cu(OAc)2, CuSO4, Cu(OTf)2, CuCl2, CuOAc, CuCl, CuI, CuClO4, CuOTf·0.5C6H6, Cu(CH3CN)4BF4, or Cu(CH3CN)4ClO4.

[0020] The chiral P,N,N-ligands have the following structural features:

[0021]

[0022] In the formula: R 1 R 5 It is a C1-C10 alkyl or alkoxy group, a C3-C10 cycloalkyl group, a phenyl or substituted phenyl group, a benzyl or substituted benzyl group, a naphthyl or substituted naphthyl group, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen group, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5.

[0023] R 2 R 3 R 4 The substituent is H, halogen, acyl, nitro, C1-C10 alkyl and alkoxy, cycloalkyl with C3-C10 carbon atoms, phenyl and substituted phenyl, benzyl and substituted benzyl, naphthyl and substituted naphthyl, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are one or more of C1-C10 alkyl, C1-C10 alkoxy, halogen, nitro, ester, or cyano groups, and the number of substituents is 1 to 5.

[0024] The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydropyran, dimethyl sulfoxide, or N,N-dimethylformamide.

[0025] The alkaline additive is i Pr2NEt, NET3, DBU t BuOK, KOH, NaOH, Na2CO3, NaHCO3, t One or more of BuOK, K2CO3, Cs2CO3 or K3PO4.

[0026] The preferred catalytic reaction conditions are: temperature -10℃, reaction medium methanol, pressure atmospheric pressure, and time 12 hours.

[0027] The reaction equation for this invention is:

[0028]

[0029] The present invention has the following advantages:

[0030] 1. It exhibits high reactivity, good stereoselectivity, and mild reaction conditions.

[0031] 2. The starting materials are cheap and readily available.

[0032] 3. Chiral ligands are easy to synthesize, and the catalysts are inexpensive, readily available, and used in small quantities.

[0033] 4. This method can conveniently synthesize various chiral sulfoxide compounds.

[0034] This method utilizes a chiral copper catalyst generated in situ in a reaction medium from a copper salt and a chiral P,N,N-tridentate ligand. Following an asymmetric propargyl substitution reaction, a series of chiral sulfoxide compounds are synthesized in high yield and with high enantioselectivity. This invention features simple operation, readily available raw materials, a wide range of applicable substrates, and high enantioselectivity. Attached Figure Description

[0035] Figure 1 The proton NMR spectrum prepared in Example 1;

[0036] Figure 2 The carbon NMR spectrum prepared in Example 1. Detailed Implementation

[0037] The following examples will further illustrate the invention, but are not intended to limit the invention. Nuclear magnetic resonance (NMR) measurements were performed using a Bruker NMR spectrometer, and high-performance liquid chromatography (HPLC) measurements were performed using an Agilent 1100 series HPLC system.

[0038] Example 1

[0039] Cu(CH3CN)4BF4 and L-2-1 complex to act as a chiral catalyst, and the reaction produces a chiral sulfoxide compound II-1.

[0040] In a reaction flask, the metal precursor Cu(CH3CN)4BF4 (0.0075 mmol, 2.4 mg) and the chiral ligand L-2-1 (0.00825 mmol, 3.9 mg) were added. Under nitrogen protection, 1.0 mL of anhydrous methanol was added, and the mixture was stirred at room temperature for 1 hour. Then, the reaction tube was transferred to a -10°C constant-temperature freezer, and propargyl ester IV-1 (0.18 mmol, 45.0 mg), 2,2'-sulfinyl diphenol compound III-1 (0.15 mmol, 39.3 mg), and... i Pr₂NEt (0.18 mmol, 32 μL) was dissolved in 2.0 mL of anhydrous methanol. This solution was then added to the stirred catalyst solution under nitrogen protection, and the reaction was carried out at -10 °C for 12 h. After the reaction was complete, the solution was concentrated under reduced pressure until almost solvent-free, separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to give a white solid, 91% yield, 93% ee. The 1H and 1C NMR spectra of product II-1 are shown below. Figure 1 , Figure 2 As shown: 1 H NMR(400MHz,DMSO-d6)δ10.08(s,1H),7.34-7.28(m,2H),7.20-7.19(m,1H),7.13-7.07(m,2H),6. 79-6.77(d,J=8.2Hz,1H),4.79(t,J=2.6Hz,2H),3.55(t,J=2.4Hz,1H),2.27(s,3H),2.21(s,3H); 13 C NMR (101MHz, DMSO-d6) δ153.5,152.7,133.4,133.2,132.9,131.5,129.2,128.8,126.6,126.6,116.5,114. 0,79.2,79.0,56.8,20.6,20.6. HPLC (Chiralpak AD-H, n-hexane / i-PrOH=85 / 15, 0.8mL / min, 254nm, 40℃): t R (major) = 13.6 min, t R (minor) = 15.6 min.

[0041] The structural formulas of Ⅲ-1, Ⅳ-1, Ⅱ-1, and L-1-1 are as follows:

[0042]

[0043] Example 2

[0044] L-1-1 reacts with ligands to form product II-1.

[0045] In Example 1, ligand L-2-1 was replaced with ligand L-1-1, and the rest remained the same as in Example 1. The reaction yielded compound II-1 in 94% yield and 90% ee.

[0046] The structural formula of L-1-1 is as follows:

[0047]

[0048] Example 3

[0049] L-2-2 reacts as a ligand to form product II-1.

[0050] In Example 1, ligand L-2-1 was replaced with ligand L-2-2, and the rest remained the same as in Example 1. The reaction yielded compound II-1 in 87% yield and 89% ee.

[0051] The structural formula of L-2-2 is as follows:

[0052]

[0053] Example 4

[0054] The reaction of Cu(CH3CN)4ClO4 and L-2-1 catalyzes the formation of product II-1.

[0055] In Example 1, Cu(CH3CN)4BF4 was replaced with Cu(CH3CN)4ClO4, and the rest was the same as in Example 1. Compound II-1 was obtained in 90% yield and 93% ee.

[0056] Example 5

[0057] The catalytic reaction of Cu(OTf)2 and L-2-1 produces product II-1.

[0058] Replacing Cu(CH3CN)4BF4 in Example 1 with Cu(OTf)2, and otherwise the same as in Example 1, yielded compound II-1, 85% yield, 88% ee.

[0059] Example 6

[0060] NEt3, as an alkaline additive, reacts to produce product II-1.

[0061] In Example 1 i Pr2NEt was replaced with NEt3, and the rest was the same as in Example 1. Compound II-1 was obtained in 93% yield and 92% ee.

[0062] Example 7

[0063] DBU, as an alkaline additive, reacts to form product II-1.

[0064] In Example 1 i Pr2NEt was replaced with DBU, and the rest was the same as in Example 1. Compound II-1 was obtained in 87% yield and 90% ee.

[0065] Example 8

[0066] Anhydrous ethanol was used as the reaction solvent to generate product II-1.

[0067] In Example 1, anhydrous methanol was replaced with anhydrous ethanol, and the rest was the same as in Example 1, to obtain compound II-1 with a yield of 91% and an ee of 87%.

[0068] Example 9

[0069] IV-2 was used as a reaction solvent to generate product II-1.

[0070] Replacing compound IV-1 of propargyl in Example 1 with IV-2, and otherwise the same as in Example 1, compound II-1 was obtained with a yield of 92% and an ee of 91%.

[0071]

[0072] The above-described embodiments are merely examples of implementation methods of the present invention, but should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements are all within the scope of protection of the present invention.

Claims

1. A method for preparing a chiral sulfoxide compound, characterized in that: In the presence of a base additive, a chiral copper catalyst catalyzes the synthesis of chiral sulfoxide compounds from 2,2'-sulfinyl diphenols and propargyl compounds via asymmetric propargyl substitution reactions. The chiral sulfoxide compound has one or two of the following structures: ； I and II are enantiomers of each other, wherein: R is H, a C1~C10 alkyl group and a C1~C10 alkoxy group, a C3~C10 cycloalkyl group, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group, a naphthyl group and a substituted naphthyl group, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl group, the substituted benzyl group, and the substituted naphthyl group are one or more of a C1~C10 alkyl group, a C1~C10 alkoxy group, a halogen group, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5 respectively; The 2,2'-sulfinyl diphenol compound has the following structure: ； In the formula: R is H, a C1~C10 alkyl group and a C1~C10 alkoxy group, a C3~C10 cycloalkyl group, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group, a naphthyl group and a substituted naphthyl group, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl group, the substituted benzyl group, and the substituted naphthyl group are one or more of a C1~C10 alkyl group, a C1~C10 alkoxy group, a halogen group, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5; The propargyl compounds have the following structures: ； In the formula: the leaving group X is one of fluorine, chlorine, bromine, iodine, C1~C10 alkyl carboxylic acid ester, C1~C10 alkyl carbonate, C1~C10 alkyl sulfonate, C1~C10 alkyl phosphate, phenyl carboxylic acid ester and substituted phenyl carboxylic acid ester, phenyl carbonate and substituted phenyl carbonate, phenyl sulfonate and substituted phenyl sulfonate or phenyl phosphate and substituted phenyl phosphate; the substituents on the substituted phenyl group are one or more of C1-C10 alkyl, C1-C10 alkoxy, halogen, nitro, ester or cyano, and the number of substituents is 1 to 5; Preparation of chiral copper catalyst: Under nitrogen protection, copper salt and chiral P,N,N-ligands were stirred in a reaction medium at a molar ratio of 1:1~10 for 1~2 hours to obtain chiral copper catalyst; The chiral P, N, N-ligands have the following structural features: ； In the formula: R 1 R 5 It is a C1-C10 alkyl group and a C1-C10 alkoxy group, a C3-C10 cycloalkyl group, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group, a naphthyl group and a substituted naphthyl group, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen group, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5; R 2 R 3 R 4 The substituent is H, halogen, acyl, nitro, C1-C10 alkyl and C1-C10 alkoxy, cycloalkyl with C3-C10 carbon atoms, phenyl and substituted phenyl, benzyl and substituted benzyl, naphthyl and substituted naphthyl, or a five- or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are one or more of C1-C10 alkyl, C1-C10 alkoxy, halogen, nitro, ester, or cyano groups, and the number of substituents is 1 to 5; The copper salt is one or more of Cu(OAc)2·H2O, CuSO4·H2O, Cu(OAc)2, CuSO4, Cu(OTf)2, CuCl2, CuOAc, CuCl, CuI, CuClO4, CuOTf·0.5C6H6, Cu(CH3CN)4BF4, or Cu(CH3CN)4ClO4.

2. The preparation method according to claim 1, characterized in that: The specific steps of this method are as follows: Propylene compounds, 2,2'-sulfinyl diphenol compounds, and a base additive were dissolved in a reaction medium. This solution was then added to the stirred solution of the chiral copper catalyst under nitrogen protection. The reaction temperature was -10 to 0°C. o Stir at C for 5-24 hours; after the reaction is complete, concentrate under reduced pressure until almost no solvent remains, separate by silica gel column chromatography, concentrate under reduced pressure, and dry under vacuum to obtain the target product.

3. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the chiral copper catalyst to the 2,2'-sulfinyl diphenol compound is 0.01~1:1; The molar ratio of the alkali additive to the 2,2'-sulfinyl diphenol compound is 1~10:1; The molar ratio of the 2,2'-sulfinyl diphenol compound to the propargyl compound is 1:1~3.

4. The preparation method according to claim 1 or 2, characterized in that: The alkaline additive is i Pr2NEt, NET3, DBU t BuOK, KOH, NaOH, Na2CO3, NaHCO3, t One or more of BuOK, K2CO3, Cs2CO3 or K3PO4; The reaction medium is methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydropyran, dimethyl sulfoxide, or... N , N - At least one or more of dimethylformamides.

5. The preparation method according to claim 1 or 2, characterized in that: The catalytic reaction conditions are as follows: temperature -10°C. o C to -8 o C, the reaction medium is methanol, the pressure is atmospheric pressure, and the time is 12-16 hours.

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