A chiral diacetylene compound and preparation method thereof

Abstract

The invention discloses a chiral diacetylene compound and a preparation method thereof. The copper catalyst used in the method is in situ generated by a metal copper precursor and a chiral pyridine oxazoline ligand in a reaction medium, and the chiral diacetylene compound is obtained with high yield and high selectivity through an asymmetric propargyl amination reaction. The invention has the characteristics of cheap catalyst, simple ligand preparation, high activity, high selectivity, mild reaction conditions, simple operation, etc.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a chiral diacetylene compound and a preparation method thereof. Background Art

[0002] Alkyne is one of the basic structural units of many important organic compounds and a commonly used synthetic building block in synthetic chemistry. It is widely used in fine chemicals, medicinal chemistry, materials chemistry and other fields. Compared with single alkynes, diacetylene compounds can provide two alkyne groups and several carbon atoms to participate in the reaction at the same time, with higher structural flexibility and a wider range of applications. Transition metal-catalyzed tandem cycloisomerization reactions of diacetylene compounds have become an important way to construct complex heterocyclic and carbon ring framework molecules. This tandem reaction has significant atom economy and ecological advantages, and this type of method is easy, simple and safe to operate.[(a) Huang, H.; Zhu, g.Lett.2007,9,3953;(c)González-Rodríguez,C.;Varela,JA;Castedo,L.;Saá,CJAm.Chem.Soc.2007,129,12916;(d)B arluenga, J.; Riesgo, L.; Vicente, R.; López, LA; Tomás, MJ Am. Chem. Soc. 2008, 130, 13528; (e) Zhang, C.; Cui, D.; Yao, L .;Wang,B.;Hu,Y.;Hayashi,TJOrg.Chem.2008,73,7811;(f)Zhang,D.;Yao,L.;Wei,Y.;Shi,M.Angew.Chem.Int.Ed.2011 ,50,2583; (g)Zheng,H.;Adduci,LL;Felix,RJ;Gagné,MRAngew.Chem.Int.Ed.2014,53,7904;(h)Naoe,S.;Saito,T.;Uc Hiyama, M.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2015, 17, 1774; (i) Corma, A.; García, H. Chem. Rev. 2003, 103, 4307; (i) j) Michelet, V.; Toullec, PY; Genet, J. Angew. Chem. Int. Ed. 2008, 47, 4268; (k) Strom, KR; Impastato, AC; Moy, KJ; Landreth, AJ; Snyder, JK Org. Lett. 2015, 17, 2126; (l) Ning, Y.; Wu, N; Yu, H.; Liao, P.; Li, X.; Bi, X. Org. Lett. 2015, 17, 2198.]. The above methods have unique advantages in the construction of furan, pyridine, morpholine, condensed ring indole and other skeletons. In view of the important role of chiral diyne compounds in organic synthesis, the simple and efficient construction of chiral diyne compounds has important value and research significance.

[0003] Alkyne compounds are widely present in nature and are commonly used chemical raw materials. In recent years, transition metal-catalyzed asymmetric propargyl amination reactions have been widely developed [(a) Detz, RJ; Delville, MMEH; Hiemstra, H.; van Maarseveen, JH Angew.Chem.Int.Ed.2008,47,3777; (b) Hattori, G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew.Chem.Int.Ed.2008, 47, 3781; (c) Zhang, C.; Wang, Y.-H.; Hu, Zheng,Z.;Xu,J.;Hu,X.-P.Adv.Synth.Catal.2012,354,2854;(d)Shibata,M.;Nakajima,K.; Nishibayashi, Y. Chem. Commun. 2014, 50, 7874; (e) Zhang, D.-Y.; Shao, L.; Xu, J.; Hu, X.-P.ACS Catal.2015,5,5026; (f) Liu, Z.-T.; Wang, Y.-H.; Zhu, F.-L.; Hu, X.-P. Org. Lett.2016,18,1190.], the method can directly and efficiently construct chiral diyne compounds. The inventor's research group has been committed to the design and development of chiral ligands and their application research in asymmetric catalytic reactions for many years. The present invention uses a chiral catalyst formed by a chiral pyridine oxazoline ligand and transition metal copper to successfully realize an asymmetric propargyl amination reaction, and obtains chiral diyne compounds with high yield and high selectivity. Summary of the invention

[0004] The purpose of the present invention is to provide a simple and efficient synthesis method for preparing chiral diacetylene compounds in view of the shortcomings of the prior art.

[0005] The specific steps of the technical solution of the present invention are as follows:

[0006] (1) Preparation of chiral copper catalyst: Under nitrogen protection, copper salt and chiral pyridine oxazoline ligand are stirred in a reaction medium at 40° C. for 0.5 to 2 hours to prepare a chiral copper catalyst by in-situ coordination;

[0007] (2) Preparation method of chiral diacetylene compounds: The chiral copper catalyst solution obtained in step (1) is brought to room temperature, and an amine compound (II), a 1,3-dipropargyl compound (III) and a base additive are added in sequence, and the reaction is continued for 12 to 24 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, separated by silica gel column chromatography, concentrated under reduced pressure, and dried in vacuo to obtain a chiral diacetylene compound (I).

[0008] The chiral diacetylene compound (I) of the present invention has the following structure:

[0009]

[0010] Where: R 1 , R 2 , R 3 It is H, C1-C10 alkyl, C1-C10 cycloalkyl, phenyl and substituted phenyl, benzyl and substituted benzyl, naphthyl and substituted naphthyl, a five-membered or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur or nitrogen atoms; the substituent is one or more of C1-C3 alkyl, C1-C3 alkoxy, halogen, nitro, ester or cyano, and the number of substituents is 1 to 5.

[0011] The amine compound (II) of the present invention has the following structure:

[0012]

[0013] Where: R 1 , R 2 is the same as R in the structural formula I 1 , R 2 Same group;

[0014] The 1,3-dipropargyl compound (III) of the present invention has the following structure:

[0015]

[0016] Where: R 3 is the same as R in the structural formula I 3 The same group; wherein the leaving group X is fluorine, chlorine, bromine, iodine, alkyl carboxylate, alkyl carbonate, alkyl sulfonate, alkyl phosphate, phenyl and substituted phenyl carboxylate, phenyl and substituted phenyl carbonate, phenyl and substituted phenyl sulfonate or phenyl and substituted phenyl phosphate; the substituent on the substituted phenyl is one or more of C1-C10 alkyl, C3-C6 alkoxy, halogen, nitro, ester or cyano, and the number of substituents is 1 to 5.

[0017] The copper salt is at least one of Cu(OAc)2·H2O, CuSO4·H2O, Cu(OAc)2, CuSO4, Cu(OTf)2, CuCl2, CuOAc, CuCl, CuI, Cu(ClO4)2, CuOTf·0.5C6H6, Cu(CH3CN)4BF4 or Cu(CH3CN)4ClO4, preferably CuOTf·0.5C6H6.

[0018] The alkaline additive is i Pr2NEt、NEt3、 t BuOK, KOH, NaOH, Na2CO3, NaHCO3, t At least one of BuOK, K2CO3, Cs2CO3 or K3PO4, preferably i Pr2NEt.

[0019] The pyridine bisoxazoline ligand has the following structure:

[0020]

[0021] Where: R 4 , R 5 It is one or more of H, C1-C10 chain alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl with substituents, phenyl and substituted phenyl, naphthyl and substituted naphthyl, benzyl and substituted benzyl, and five-membered or six-membered heterocyclic aromatic groups containing one or more oxygen, sulfur, and nitrogen atoms; the substituents on the C3-C6 cycloalkyl, the phenyl, the naphthyl, and the benzyl are one or more of C1-C10 alkyl, C3-C6 alkoxy, halogen, nitro, ester, or cyano, and the number of substituents is 1 to 5;

[0022] The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide, preferably methanol.

[0023] The molar ratio of the chiral pyridine bisoxazoline ligand to the copper salt is 1 to 5:1;

[0024] The molar ratio of the copper catalyst to the 1,3-dipropargyl compound (III) is 0.01 to 1:1

[0025] The molar ratio of the amine compound (II) to the 1,3-dipropargyl compound (III) is 2 to 4:1;

[0026] The molar ratio of the base additive to the amine compound (II) is 2 to 4:1.

[0027] The reaction temperature is room temperature;

[0028] The reaction time is 12 to 24 hours.

[0029] To achieve the above object, the technical solution of the present invention is as follows:

[0030]

[0031] Beneficial effects of the present invention:

[0032] 1. The starting materials are cheap and readily available.

[0033] 2. Chiral catalysts are cheap and readily available and are used in small amounts.

[0034] 3. Good reaction activity, high stereoselectivity, and easy-to-achieve reaction conditions; BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. The embodiments of the present invention are described in detail below in conjunction with the accompanying drawings, wherein:

[0036] Figure 1 The chiral N,N prepared in Example 1 ’ -H NMR spectrum of [1,3-phenylbis(2-propyne)]-bis(N-methylaniline);

[0037] Figure 2 The chiral N,N prepared in Example 1 ’ -[1,3-phenylbis(2-propyne)]-bis(N-methylaniline) carbon NMR spectrum;

[0038] Figure 3 The chiral N,N prepared in Example 10 ’ -H NMR spectrum of [1,3-phenylbis(2-propyne)]-bis(N-ethylaniline);

[0039] Figure 4 The chiral N,N prepared in Example 10 ’ Carbon NMR spectrum of -[1,3-phenylbis(2-propyne)]-bis(N-ethylaniline). DETAILED DESCRIPTION

[0040] The following examples will further illustrate the present invention, but are not intended to limit the present invention. Nuclear magnetic resonance was measured by a Bruker nuclear magnetic resonance instrument, and high performance liquid chromatography (HPLC) was measured by an Agilent 1100 series high performance liquid chromatograph. The chiral ligands used in the reaction were prepared in the laboratory or purchased commercially.

[0041] Example 1

[0042] Preparation method of chiral diacetylene compounds: Under nitrogen protection, place the metallic copper precursor CuOTf·1 / 2C6H6 (0.01mmol, 2.5mg) and the chiral pyridine oxazoline ligand L-1-1 (0.02mmol, 7.9mg) in a 25mL Hullon tube, add 1mL of anhydrous methanol, stir at 40℃ for 1 hour, and prepare the chiral copper catalyst by in-situ coordination. Then cool the above reaction solution to room temperature, dissolve the substrate 1,3-phenyldipropargyl alcohol acetate II-1 (0.2mmol, 54.0mg), N-methylaniline III-1 (0.44mmol, 47.1mg), N,N-diisopropylethylamine (0.44mmol, 73μL) in 2mL of anhydrous methanol, add to the above stirred chiral copper catalyst solution, and continue to react for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure until there was almost no solvent, separated by silica gel column chromatography (volume ratio, petroleum ether / ethyl acetate = 20:1), concentrated under reduced pressure, and dried in vacuo to obtain the chiral diyne product I-1 with a yield of 90%, dr = 95:5, and 93% ee.

[0043] The product H-NMR and C-NMR spectra are as follows: Figure 1 , 2 As shown: 1 H NMR(400MHz, CDCl3)δ7.78(s,1H),7.54-7.52(m,2H),7.39-7.35(m,1H),7.30–7.26(m,4H), 6.99-6.97(m,4H),6.87-6.83(m,2H),5.79–5.78(m,2H),2.68(s,6H),2.50(d,J=2.3Hz,2H). 13 C NMR (101MHz, CDCl3) δ150.1,138.2,129.2,128.5,127.2,127.1,126.9,119.1,115.6,115.6,79 .8,75.1,56.6,33.8.HPLC(ChiralcelOD-H,n-hexane / i-PrOH=85 / 15,0.8mL / min,254nm,40℃):t R (minor)=8.1min,t R (major) = 20.4min.

[0044] The structural formulas of I-1, II-1, III-1, and L-1-1 are as follows:

[0045]

[0046] Example 2

[0047] L-1-2 acts as a ligand to generate product I-1

[0048] The ligand L-1-1 in Example 1 was replaced by the ligand L-1-2, and the rest was the same as Example 1. The reaction gave compound I-1 with a yield of 83%, dr=94:6, and 90% ee.

[0049] The structural formula of L-1-2 is as follows:

[0050]

[0051] Example 3

[0052] L-1-3 acts as a ligand to generate product I-1

[0053] The ligand L-1-1 in Example 1 was replaced by the ligand L-1-3, and the rest was the same as Example 1. The reaction gave compound I-1 with a yield of 85%, dr=93:7, and 92% ee.

[0054] The structural formula of L-1-3 is as follows:

[0055]

[0056] Example 4

[0057] L-1-4 acts as a ligand to generate product I-1

[0058] The ligand L-1-1 in Example 1 was replaced by the ligand L-1-4, and the rest was the same as Example 1. The reaction gave compound I-1 with a yield of 88%, dr=93.5:6.5, and 93% ee.

[0059] The structural formula of L-1-4 is as follows:

[0060]

[0061] Example 5

[0062] Cu(CH3CN)4BF4 and L-1-1 catalyze the reaction to produce product I-1

[0063] The copper salt Cu(OTf)2 in Example 1 was replaced by Cu(CH3CN)4BF4, and the rest was the same as Example 1. The reaction gave compound I-1 with a yield of 89%, dr=95:5, and 90% ee.

[0064] Example 6

[0065] CuCl and L-1-1 catalyze the reaction to produce product I-1

[0066] The copper salt CuOTf·0.5C6H6 in Example 1 was replaced by CuCl, and the rest was the same as Example 1. The reaction gave compound I-1 with a yield of 89%, dr=92:8, and 83% ee.

[0067] Example 7

[0068] Triethylamine acts as a base additive to participate in the reaction to generate product I-1

[0069] The base additive N,N-diisopropylethylamine in Example 1 was replaced by triethylamine, and the rest was the same as Example 1. The reaction afforded compound I-1 with a yield of 89%, dr=95:5, and 92% ee.

[0070] Example 8

[0071] Li2CO3 acts as a base additive to participate in the reaction to generate product I-1

[0072] The base additive N,N-diisopropylethylamine in Example 1 was replaced by an inorganic base Li2CO3, and the rest was the same as Example 1. The reaction gave compound I-1 with a yield of 93%, dr=97:3, and 93% ee.

[0073] Example 9

[0074] Anhydrous ethanol is used as a reaction medium to participate in the reaction to generate product I-1

[0075] The reaction medium anhydrous methanol in Example 1 was replaced by anhydrous ethanol, and the rest was the same as Example 1. The reaction afforded compound I-1 with a yield of 84%, dr=94:6, and 91% ee.

[0076] Example 10

[0077] II-2 acts as a substrate to generate product I-2

[0078] The N-methylaniline II-1 in Example 1 was replaced by N-ethylaniline II-2, and the rest was the same as in Example 1 to obtain compound I-2 with a yield of 91%, dr=97 / 3, and 95% ee. The product H NMR and C NMR spectra are shown in Figure 3 , 4 As shown: 1 H NMR (400MHz, CDCl3) δ7.81-7.79(m,1H),7.54–7.50(m,2H),7.36-7.32(m,1H),7.26–7.22(m,4H),6.93-6. 91(m,4H),6.83-6.80(m,2H),5.67-5.66(m,2H),3.33–3.16(m,4H),2.50-2.49(m,2H),1.06-1.02(m,6H). 13C NMR (101MHz, CDCl3) δ148.1,138.6,129.0,128.5,127.1,127.0,118.8,118.8,116.2,116.1,81.1 ,74.6,56.2,42.4,13.6.HPLC(ChiralcelOD-H,n-hexane / i-PrOH=95 / 5,0.8mL / min,254nm,40℃):t R (minor)=6.5min,t R (major) = 16.3min.

[0079] The structural formula of I-2 and II-2 is as follows:

[0080]

[0081] The chiral diacetylene compounds of the present invention can undergo polymerization reaction with carbon dioxide and halogenated hydrocarbons under the catalysis of silver tungstate at normal pressure, and high molecular weight polyacetylene esters can be obtained with high yield under mild conditions. In addition, tetraphenylethylene (TPE), tetraphenylpyrazine (TPP) and silole moieties with aggregation-induced emission (AIE) characteristics can be introduced into the polymer backbone to obtain polyacetylene esters with the same AIE characteristics, and this material also has good degradation performance (Macromolecules, 2018, 51, 42-48).

Claims

1. A method for preparing a chiral diacetylene compound, characterized in that: In the reaction medium, in the presence of a base additive, under the catalysis of a copper / chiral pyridine oxazoline ligand catalyst, an amine compound (II) and a 1,3-dipropargyl compound (III) undergo an asymmetric propargyl substitution reaction to obtain a chiral diacetylene compound (I); The chiral diacetylene compound (I) has the following structure: ， Where: R 1 , R 2 , R 3 R is H, a C1-C10 alkyl 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-membered or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; 3 The number is 1~4; The substituents on the substituted phenyl, substituted benzyl and substituted naphthyl are one or more of C1~C3 alkyl, C1~C3 alkoxy, halogen, nitro, ester or cyano, and the number of substituents on the phenyl, benzyl and naphthyl is 1 to 5 respectively; The amine compound (II) has the following structure: ， Where: R 1 , R 2 is the same as R in the structural formula I 1 , R 2 Same group; The 1,3-dipropargyl compound (III) has the following structure: ， Where: R 3 is the same as R in the structural formula I 3 The same group; wherein the leaving group X is fluorine, chlorine, bromine, iodine, C3-C6 alkyl carboxylate, C3-C6 alkyl carbonate, C3-C6 alkyl sulfonate, C3-C6 alkyl phosphate, phenyl and substituted phenyl carboxylate, phenyl and substituted phenyl carbonate, phenyl and substituted phenyl sulfonate or phenyl and substituted phenyl phosphate; the substituent on the substituted phenyl is one or more of C1-C10 alkyl, C3-C6 alkoxy, halogen, nitro, ester or cyano, and the number of substituents is 1 to 5; The alkaline additive is i Pr2NEt、NEt3、 t BuOK, KOH, NaOH, Na2CO3, NaHCO3, t At least one or more of BuOK, K2CO3, Cs2CO3 or K3PO4; The preparation method of the copper / chiral pyridine oxazoline ligand catalyst is as follows: under nitrogen protection, copper salt and chiral pyridine oxazoline ligand are stirred in a reaction medium at 25-40° C. for 0.5-2 hours for in-situ coordination to obtain the copper / chiral pyridine oxazoline ligand catalyst; The copper salt is at least one of Cu(OAc)2·H2O, CuSO4·H2O, Cu(OAc)2, CuSO4, Cu(OTf)2, CuCl2, CuOAc, CuCl, CuI, Cu(ClO4)2, CuOTf·0.5C6H6, Cu(CH3CN)4BF4 or Cu(CH3CN)4ClO4; The pyridine bisoxazoline ligand has the following structure: ， Where: R 4 , R 5 They are one or more of H, C1~C10 chain alkyl, C3~C6 cycloalkyl or C3~C6 cycloalkyl with substituents, phenyl and substituted phenyl, naphthyl and substituted naphthyl, benzyl and substituted benzyl, and five-membered or six-membered heterocyclic aromatic groups containing one or more oxygen, sulfur or nitrogen atoms; the substituents on the C3~C6 cycloalkyl, the substituents on the phenyl, the substituents on the naphthyl and the substituents on the benzyl are one or more of C1~C10 alkyl, C3~C6 alkoxy, halogen, nitro, ester or cyano, and the number of substituents is 1 to 5.

2. The preparation method according to claim 1, characterized in that: Preparation method of chiral diyne compounds: The prepared copper / chiral pyridine oxazoline ligand catalyst solution is cooled to room temperature, and an amine compound (II), a 1,3-dipropargyl compound (III) and a base additive dissolved in a reaction medium are added, and the reaction is continued for 12 to 24 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, separated by silica gel column chromatography, concentrated under reduced pressure, and dried in vacuo to obtain a chiral diyne compound (I).

3. The preparation method according to claim 1 or 2, characterized in that: The reaction medium is at least one or more of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide; The alkaline additive is NEt3.

4. The preparation method according to claim 3, characterized in that: The reaction medium is methanol.

5. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the chiral pyridine bisoxazoline ligand to the copper salt is 1 to 10:1; The molar ratio of the copper / chiral pyridine oxazoline ligand catalyst to the 1,3-dipropargyl compound (III) is 0.001-1:1 in terms of copper; The molar ratio of the amine compound (II) to the 1,3-dipropargyl compound (III) is 2 to 10:1; The molar ratio of the base additive to the 1,3-dipropargyl compound (II) is 2-10:

1.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the chiral pyridine bis-oxazoline ligand to the copper salt is 1-5:1; the molar ratio of the copper / chiral pyridine oxazoline ligand catalyst to the 1,3-dipropargyl compound (III) is 0.01-1:1 in terms of copper; The molar ratio of the amine compound (II) to the 1,3-dipropargyl compound (III) is 2-8:1; The molar ratio of the base additive to the 1,3-dipropargyl compound (II) is 2-8:

1.

7. The preparation method according to claim 5, characterized in that: The molar ratio of the chiral pyridine bis-oxazoline ligand to the copper salt is 1-3:1; the molar ratio of the copper / chiral pyridine oxazoline ligand catalyst to the 1,3-dipropargyl compound (III) is 0.03-1:1 in terms of copper; The molar ratio of the amine compound (II) to the 1,3-dipropargyl compound (III) is 2-5:1; The molar ratio of the base additive to the 1,3-dipropargyl compound (II) is 2-5:

1.

8. The method according to claim 1, characterized in that: The concentration range of the substrate 1,3-dipropargyl compound in the reaction medium is 0.001-0.01 mol / L.

9. A chiral diacetylene compound characterized by: The chiral diacetylene compound (I) has the following structure: ， Where: R 1 , R 2 , R 3 R is H, a C1-C10 alkyl 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-membered or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; 3 The number is 1~4; The substituents on the substituted phenyl, substituted benzyl and substituted naphthyl are one or more of C1~C3 alkyl, C1~C3 alkoxy, halogen, nitro, ester or cyano, and the number of substituents on the phenyl, benzyl and naphthyl is 1 to 5 respectively.

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