阅读说明：本技术 一种e/z混合或单一构型的三取代烯烃的不对称催化氢化制备手性烷基化合物的方法 (Method for preparing chiral alkyl compound by asymmetric catalytic hydrogenation of E/Z mixed or single-configuration tri-substituted olefin ) 是由 陆展 陆鹏 于 2019-09-16 设计创作，主要内容包括：本发明公开了一种E/Z混合或单一构型的三取代烯烃的不对称催化氢化制备手性烷基化合物的方法：以式I所示的三取代烯烃为原料,以常压氢气作为氢源,CoBr<Sub>2</Sub>-IIP络合物为催化剂,硅烷类化合物为助催化剂,在还原剂的作用下,反应24～48小时制得式II所示的手性烷基化合物。本发明的原料为E/Z混合三取代烯烃或单一E或Z构型的三取代烯烃；使用E/Z混合三取代烯烃时,不限制其中E、Z构型比例,原料来源易得,节省成本。本发明方法反应条件温和,操作简便,原子经济性高,且反应的转化率也较好,一般均可达到>99％,对映体选择性也较高,一般为70％～98％。<Image he="256" wi="693" file="DDA0002202754080000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a method for preparing chiral alkyl compounds by asymmetric catalytic hydrogenation of E/Z mixed or single-configuration tri-substituted olefin, which comprises the following steps: using tri-substituted olefin shown in formula I as raw material, using normal pressure hydrogen as hydrogen source, and using CoBr 2 And (3) reacting the-IIP complex serving as a catalyst and the silane compound serving as a cocatalyst for 24-48 hours under the action of a reducing agent to obtain the chiral alkyl compound shown in the formula II. The raw material of the invention is E/Z mixed tri-substituted olefin or single E or Z configuration tri-substituted olefin; when the E/Z mixed tri-substituted olefin is used, the configuration proportion of E, Z is not limited, the raw material source is easy to obtain, and the cost is saved. The method has the advantages of mild reaction conditions, simple and convenient operation, high atom economy and better reaction conversion rate, and can generally achieve the aim of>99 percent and higher enantioselectivity, which is generally 70 to 98 percent.)

1. A method for preparing chiral alkyl compounds by asymmetric catalytic hydrogenation of E/Z mixed or single configuration tri-substituted olefins, which comprises the following steps: using tri-substituted olefin shown in formula I as raw material, using normal pressure hydrogen as hydrogen source, and using CoBr₂the-IIP complex is used as a catalyst, the silane compound is used as a cocatalyst, and the chiral alkyl compound shown in the formula II is prepared by reacting for 24-48 hours under the action of a reducing agent;

in formula II, wherein represents a chiral carbon atom;

in the formula I or formula II, R¹Is optionally selected from C₂-C₈Alkyl, naphthyl, a radical of the formula III or C₄～C₁₀N, O, S-containing heterocyclic aryl groups;

the R is¹In (A), the C₂-C₈H on the alkyl group of (a) is unsubstituted or substituted with 1 or more substituents a, which are phenyl, naphthyl, heterocyclic aryl or substituted phenyl; the heterocyclic aryl is indolyl, pyridyl, pyrrolyl, thienyl or furyl; the substituted phenyl refers to phenyl with H on the phenyl substituted by more than 1 substituent B, and the substituent B is C₁-C₃Alkyl of (C)₁-C₃Alkoxy, benzyloxy or C₁-C₃Alkylthio groups of (a);

the R is¹In (A), the C₄～C₁₀The N, O, S-containing heterocyclic aryl group is pyridyl, pyrrolyl, thienyl, indolyl or furyl;

the R is¹In (1), the naphthyl and C₄～C₁₀H of the N, O, S-containing heterocyclic aryl group of (a) is unsubstituted or substituted with 1 or more substituents C, said substituents C being C₁-C₃Alkyl or C₁-C₃Alkoxy group of (a);

the R is¹In the group of the formula III, R⁴、R⁵、R⁶、R⁷、R⁸Optionally selected from H, halogen, C₁-C₂Alkyl of (C)₁-C₃Alkoxy, benzyloxy, C₁-C₃Any one of alkylthio, ester group of C1-C3, tert-butyldimethylsilyloxy, trifluoromethyl, trifluoromethoxy, dimethylamino, pinacolboroesterethyl, menthol oxy and estradiol protected estrone oxy, R⁴、R⁵、R⁶、R⁷、R⁸When all are H, the compound shown in the formula III is phenyl; the halogen is F, Cl, Br or I;

in the formula I or formula II, R²Is optionally selected from C₁-C₄Alkyl groups of (a);

in the formula I or formula II, R³Is optionally selected from C₁-C₃Alkyl, phenyl or benzyl of (a); said C is₁-C₃H of the alkyl group of (A) is unsubstituted or substituted by 1 or more substituents D, wherein the substituents D are phenyl and C₁-C₃Or 1, 3-dioxolanyl;

when R is²And R³When both are unsubstituted alkyl, R²The number of carbon chains is not equal to R³Carbon chain number + 1.

2. The method of claim 1, wherein R is¹Is C₂-C₈Alkyl, naphthyl, 6-methoxy naphthyl, pyridyl, 2-methoxy pyridyl, indolyl, N-methyl indolyl or the group of formula III;

the R is¹In (A), the C₂-C₈H on the alkyl group of (A) is substituted by a substituent A, R¹Is represented by R^A—(CH₂)_nN is an integer of 2 to 8, R^AIs a substituent A, R on a carbon chain^AIs phenyl, naphthyl or p-methoxyphenyl;

the R is¹Wherein the group shown in the formula III is phenyl or substituted phenyl with 1-2 substituents, and the substituents on the substituted phenyl are halogen and C₁-C₂Alkyl of (C)₁-C₃Alkoxy, benzyloxy, C₁-C₃Alkylthio group of C1-C3, ester group of C1-C3, tert-butyldimethylsilyloxy group, trifluoromethyl group, trifluoromethoxy group, dimethylamino group, pinacolboronic ester ethyl group, menthol oxy group or estradiol protected estrone oxy group;

R₃is C₁-C₃Alkyl, phenyl or benzyl of (a); said C is₁-C₃H on the alkyl group of (a) is unsubstituted or substituted by a substituent D, when substituted by a substituent D，R₃Is represented by R^D—(CH₂)_mM is an integer of 1-3, and the substituent D is phenyl, an ester group of C1-C3 or 1, 3-dioxolane.

3. The method of claim 1, wherein the tri-substituted olefin of formula I is an E/Z mixed tri-substituted olefin or a tri-substituted olefin of a single E or Z configuration; when the tri-substituted olefin is mixed in the E/Z, the configuration ratio of E, Z is not limited.

4. The method of claim 1, wherein the silane compound is a polysiloxane or a diphenylsilane.

5. The method of claim 1, wherein the catalyst CoX is₂The IIP complex is optically pure compound shown as formula IV or enantiomer or racemate thereof, wherein R in the formula IV⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹Optionally selected from H, C₁-C₁₆Alkyl of (C)₁-C₁₆Alkoxy, phenyl, naphthyl or benzyl:

h on the alkyl and the alkoxy is not substituted or substituted by more than 1 substituent E, and the substituent E is nitro, halogen, phenyl, methoxycarbonyl, trifluoromethyl, hydroxyl or C₁～C₃Aldehyde group of (A), C₁～C₃Carboxyl group, amino group, C₁～C₃An ester group or an amide group of (a);

h on the phenyl, benzyl and naphthyl is not substituted or is substituted by more than 1 substituent F, and the substituent F comprises C₁～C₃Alkyl of (C)₁～C₃Alkoxy, nitro, halogen, phenyl, methoxycarbonyl, trifluoromethyl, hydroxy, C₁～C₃Aldehyde group of (A), C₁～C₃Carboxyl group, amino group, C₁～C₃Ester or amide groups of；

X is F, Cl, Br, I, OAc, CF₃SO₃Any one of them.

6. The method of claim 5, wherein the catalyst CoX is₂the-IIP complex is a compound of formula IV wherein R¹⁶、R¹⁷、R¹⁸、R²⁰、R²¹Are all H; r¹⁰、R¹⁴Each independently is C₁-C₄Alkyl or diphenylmethine of (a); r¹¹、R¹²、R¹³Are all H; r¹⁵Is H or C₁-C₄Alkyl groups of (a); r⁹Is C₁-C₄Alkyl, benzyl or phenyl of (a); r¹⁹Is C₁-C₄Alkyl, benzyl or phenyl of (a); and X is Cl or Br.

7. The method of claim 6, wherein the chiral CoX is₂The IIP complex is of formula IV-1 or IV-2:

8. the method of claim 7, wherein the catalyst is chiral CoX₂When the compound represented by the formula IV-1 is used as the IIP complex, polysiloxane is used as the silane compound; catalyst chiral CoX₂When the compound represented by the formula IV-2 is used as the IIP complex, diphenylsilane is used as the silane compound.

9. The method of claim 1Process characterized by the trisubstituted olefin, CoX₂-IIP complex, silane compound, reducing agent in a ratio of mass of 1: 0.02-0.1: 0.1: 0.06-0.3.

10. The method according to claim 1, wherein an organic solvent is added in the synthesis method, wherein the organic solvent is any one of benzene, carbon tetrachloride, toluene, tetrahydrofuran, diethyl ether, dichloromethane, acetonitrile, dioxane, petroleum ether, cyclohexane, N-hexane, ethyl acetate, chloroform, and N, N-dimethylamide;

the reducing agent is any one of sodium triethylborohydride, sodium tri-sec-butylborohydride, lithium triethylborohydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amylate, sodium ethoxide, sodium methoxide and potassium methoxide.

Technical Field

The method relates to a method for preparing chiral alkyl compounds by hydrogenation of E/Z mixed or single-configuration tri-substituted olefin, in particular to a method for preparing chiral drug molecular intermediates with optical activity by simple reaction.

Background

Chirality is a fundamental property of nature, and the "thalidomide event" has led to the growing recognition of the importance of chirality. The asymmetric catalytic hydrogenation reaction has the advantages of atom economy, simple operation, high reaction activity, environmental friendliness and the like, is one of the most effective methods for obtaining chiral compounds, and has wide application in the synthesis of chiral drugs and natural products and the industrial production of pesticide molecules. Knowles and Noyori et al therefore shared the nobel chemical prize in 2001. [ a) Knowles, W.S.Angew.chem.int.Ed.2002, 41,1998; b) noyori, R.Angew.chem.int.Ed.2002,41,2008.)

The core of the asymmetric hydrogenation reaction of olefin is metal and chiral ligand, wherein the metal is dominated by noble metal such as rhodium, ruthenium and iridium, and the chiral ligand is mainly bidentate phosphine-containing ligands such as DIPAMA diphosphine ligand, BINAP diphosphine ligand, Duphos diphosphine ligand, chiral spiro nitrogen phosphorus ligand and phosphine oxygen oxazoline ligand [ a) Knowles, W.S.; sabacaky, m.j.; et.j.am.chem.soc.1975, 97,2567; b) miyashita, a.; yasuda, a.; takaya, a.; et.J.am.chem.Soc.1980, 102, 7932; c) noyori, r.; ohta, m., Hsiao, y.; et al.J.am.chem.Soc.1986,108, 7117; d) burk, m.j.acc.chem.res.2000, 33,363; e) xie, j.h.; wang, l.x.; fu, y.; et al.j.am.chem.soc.2003, 125,4404; f) tolstoy, p.; engman, m.; paptchikhine, a.; bergquist, j.; church, t.l.; leung, a.w. -m.; andersson, p.g.; j.am.chem.soc.2009,131, 8855; g) kaiser, s.; smidt, s.p.; pfaltz, a.angelw.chem.int.ed.2006, 45,5194.; h) biosca, m.; magre, m.; p-pues, o.; di guez, M.; ACS catal.2018,8,10316; i) perry, m.c.; cui, x.h.; powell, m.t.; hou, D. -R.; reibenspies, j.h.; burgess, K.J.Am.chem.Soc.2003, 125,113.

However, in the reported asymmetric catalytic hydrogenation of non-functionalized tri-substituted olefins, the starting materials used are all single configuration olefins of E or Z formula [ a) Margarita, c; andersson, p.g.j.am. chem.soc.2017,139, 1346; b) bell, s.; wustenberg, b.; kaiser, s.; menges, f.; netscher, t.; pfaltz; science 2006,311,642. The synthesis of the tri-substituted olefin with a single configuration usually requires a multi-step synthesis route, and the separation from the (E/Z) mixed tri-substituted olefin also requires higher cost, so that the method is not in accordance with the sustainable development concept of green economy. In 1993, Stephen L. Buchwald, the academy of sciences, USA, first reported the asymmetric hydrogenation of non-functionalized tri-substituted olefins catalyzed by titanium metal, of which only one example is (E/Z) mixed tri-substituted olefins. But with low conversion and enantioselectivity (E/Z. 64/36, 80% yield, 31% ee) (Broene, R.D.; Buchwald, S.L.J.Am.chem. Soc.1993,115,12567.)

To date, a great deal of attempts have been made to screen conventional noble metals and chiral ligands against this problem, but no successful examples have been reported. In addition, the precious metal reserves are rare, are often strategic resources and have certain toxicity. Therefore, the method has important significance in developing cheap metal catalytic systems with abundant reserves and environmental friendliness, and particularly has wide application prospects in the fields of medicines and chiral materials.

In 2016, the terrestrially developed group of subjects at Zhejiang university successfully achieved asymmetric hydrogenation of 1, 1-diarylolefins using imidazopyridine oxazoline chiral ligands (OIP) with inexpensive metallic cobalt, but this system failed to catalyze the asymmetric hydrogenation of non-functionalized tri-substituted olefins, especially (E/Z) mixed tri-substituted olefins (Chen, J. -H.; Chen, C. -H.; Ji, C. -L.; Lu, Z.Org.Lett.2016,18,1594.). Therefore, the development of an asymmetric hydrogenation catalytic system of cheap metal and the realization of the asymmetric catalytic hydrogenation reaction of the non-functionalized mixed tri-substituted olefin with high enantioselectivity have important research value and significance.

Disclosure of Invention

The invention catalyzes the asymmetric hydrogenation reaction of (E/Z) mixed trisubstituted olefin by the catalyst formed by matching the imine pyridine imidazoline nitrogen-containing tridentate ligand (IIP) and cheap metal cobalt, which is constructed by the subject group, can obtain good conversion rate and enantiomer selectivity.

The invention is realized by the following technical scheme:

a method for preparing chiral alkyl compounds by asymmetric catalytic hydrogenation of E/Z mixed or single configuration tri-substituted olefins, which comprises the following steps: using tri-substituted olefin shown in formula I as raw material, using normal pressure hydrogen as hydrogen source, and using CoBr₂the-IIP complex is used as a catalyst, the silane compound is used as a cocatalyst, and the chiral alkyl compound shown in the formula II is prepared by reacting for 24-48 hours under the action of a reducing agent;

in formula II, wherein represents a chiral carbon atom.

The reaction formula of the present invention can be represented by the following formula:

in the formula I or formula II, R¹Is optionally selected from C₂-C₈Alkyl, naphthyl, a radical of the formula III or C₄～C₁₀N, O, S-containing heterocyclic aryl groups;

the R is¹In (A), the C₂-C₈H on the alkyl group of (a) is unsubstituted or substituted with 1 or more substituents a, which are phenyl, naphthyl, heterocyclic aryl or substituted phenyl; said heterocyclic aryl isIndolyl, pyridyl, pyrrolyl, thienyl or furanyl; the substituted phenyl refers to phenyl with H on the phenyl substituted by more than 1 substituent B, and the substituent B is C₁-C₃Alkyl of (C)₁-C₃Alkoxy, benzyloxy or C₁-C₃Alkylthio groups of (a);

the R is¹In (A), the C₄～C₁₀The N, O, S-containing heterocyclic aryl group of (a) is pyridyl, pyrrolyl, thienyl, indolyl or furyl, preferably pyridyl, indolyl or pyrrolyl;

the R is¹In (1), the naphthyl and C₄～C₁₀H of the N, O, S-containing heterocyclic aryl group of (a) is unsubstituted or substituted with 1 or more substituents C, said substituents C being C₁-C₃Alkyl or C₁-C₃Alkoxy group of (a);

the R is¹In the group of the formula III, R⁴、R⁵、R⁶、R⁷、R⁸Optionally selected from H, halogen, C₁-C₂Alkyl of (C)₁-C₃Alkoxy, benzyloxy, C₁-C₃R is any one of alkylthio, ester group of C1-C3, tert-butyldimethylsilyloxy, trifluoromethyl, trifluoromethoxy, dimethylamino, pinacolboroester ethyl, menthol oxy and estradiol protected estrone oxy, R is⁴、R⁵、R⁶、R⁷、R⁸When all are H, the compound shown in the formula III is phenyl. The halogen is F, Cl, Br or I.

In the formula I or formula II, R²Is optionally selected from C₁-C₄Alkyl group of (1).

In the formula I or formula II, R³Is optionally selected from C₁-C₃Alkyl, phenyl or benzyl of (a); said C is₁-C₃H of the alkyl group of (A) is unsubstituted or substituted by 1 or more substituents D, wherein the substituents D are phenyl and C₁-C₃Or 1, 3-dioxolanyl.

When R is²And R³When both are unsubstituted alkyl, R²The number of carbon chains is not equal to R³Carbon chain number + 1.

Further, R is¹Preferably C₂-C₈Alkyl, naphthyl, 6-methoxy naphthyl, pyridyl, 2-methoxy pyridyl, indolyl, N-methyl indolyl or the group of formula III;

the R is¹In (A), the C₂-C₈H on the alkyl group of (A) is substituted by a substituent A, R¹Can be represented as R^A—(CH₂)_nN is an integer of 2 to 8, R^AIs a substituent A, R on a carbon chain^APreferably phenyl, naphthyl or p-methoxyphenyl;

the R is¹Wherein the group shown in the formula III is phenyl or substituted phenyl with 1-2 substituents, and the substituent on the substituted phenyl is preferably halogen or C₁-C₂Alkyl of (C)₁-C₃Alkoxy, benzyloxy, C₁-C₃Alkylthio of, C₁-C₃Ester group of (a), tert-butyldimethylsilyloxy group, trifluoromethyl group, trifluoromethoxy group, dimethylamino group, pinacolboronic ester group ethyl group, menthol oxy group or glycol-protected estrone oxy group.

R₃Preferably C₁-C₃Alkyl, phenyl or benzyl of (a); said C is₁-C₃When H on the alkyl group of (A) is unsubstituted or substituted by a substituent D, and R is substituted by a substituent D₃Can be represented as R^D—(CH₂)_mM is an integer of 1-3, and the substituent D is phenyl or C₁-C₃Or 1, 3-dioxolanyl.

The tri-substituted olefin shown in the formula I as the raw material used in the invention can be (E/Z) mixed tri-substituted olefin or olefin with single E or Z configuration, the configuration ratio of E, Z is not limited, mixed olefin with any E/Z configuration or olefin with single E configuration or olefin with Z configuration can be used in the method, and the chiral characteristics of chiral alkyl compound products prepared from raw materials with different configuration ratios are the same.

Drawings

FIG. 1 is a single crystal structural diagram of a compound of formula IV-1 as a catalyst.

Detailed Description

The technical solution of the present invention is further specifically described below by specific examples, but the scope of the present invention is not limited thereto.