CN115850120A - Preparation method of alcohol alpha-carbon hydrogen bond alkylated compound - Google Patents
Preparation method of alcohol alpha-carbon hydrogen bond alkylated compound Download PDFInfo
- Publication number
- CN115850120A CN115850120A CN202211645598.0A CN202211645598A CN115850120A CN 115850120 A CN115850120 A CN 115850120A CN 202211645598 A CN202211645598 A CN 202211645598A CN 115850120 A CN115850120 A CN 115850120A
- Authority
- CN
- China
- Prior art keywords
- tert
- bis
- benzyl
- preparation
- carbon hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses a preparation method of an alcohol alpha-carbon hydrogen bond alkylated compound, which mainly comprises the following steps: mixing an alcohol compound, a Michael acceptor, a co-catalyst, a photocatalyst, a hydrogen atom transfer reagent and an organic solvent, and irradiating the reaction system under a protective atmosphere by taking visible light as a driving force; after the reaction is finished, the alcohol alpha-carbon hydrogen bond alkylated compound is prepared by post-treatment. The synthetic method has the advantages of greenness, high efficiency, high atom economy, high selectivity, few byproducts, wide range of reaction substrates and low cost, and the compound provided by the invention can be popularized and applied in the fields of organic synthesis, medicines, pesticides, materials, dyes, detergents and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an alcohol alpha-carbon hydrogen bond alkylated compound, the alcohol alpha-carbon hydrogen bond alkylated compound prepared by the synthesis method, and application of the alcohol alpha-carbon hydrogen bond alkylated compound.
Background
Alcohols, which are a large class of organic compounds, are compounds in which a hydrogen atom in a side chain of an aliphatic hydrocarbon, an alicyclic hydrocarbon, or an aromatic hydrocarbon is substituted with a hydroxyl group. In general, the alcohols are alcohols in which the hydroxy group is connected to a saturated sp 3 The hybridized carbon atoms are connected. The carbon atom directly attached to the hydroxyl group of the functional group in the alcohol compound is referred to as an α carbon atom. It has been shown that it has a higher sp 3 The compounds with carbon atom ratio can improve the drug property of the compounds, so the alpha-carbon hydrogen bond functionalization of the alcohols, especially the alpha-carbon hydrogen bond alkylation of the natural alcohols, has important significance for developing more effective alcohol drugs.
At present, in order to realize the alkylation of the alcohol alpha-carbon hydrogen bond, the following schemes mainly exist: for example, the alpha-carbon hydrogen bond alkylation of various alcohol compounds can be realized by using tetra-n-butyl ammonium phosphate as a cocatalyst; however, the method involves only two examples of alcohol substrates of natural products, and the types of substrates that can be used are few. In addition, alpha-carbon hydrogen bond alkylation of primary alcohols can be accelerated by the use of bulky spirosilanes and borates as co-catalysts. However, the substrate range of the current methods is mainly limited to primary alcohol, and the universality is poor.
The present invention aims at clarifying a process for producing an alpha-carbon hydrogen bond alkylated alcohol compound which can use structurally various alcohols (especially secondary alcohol, hindered alcohol, etc.) as substrates.
Disclosure of Invention
In view of the above, the present invention needs to provide a method for preparing an alcohol α -carbon hydrogen bond alkylated compound, which has the advantages of greenness, high efficiency, high atom economy, high selectivity, less byproducts, wide range of reaction substrates, good universality, and low cost.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of an alcohol alpha-carbon hydrogen bond alkylated compound, which comprises the following steps:
mixing an alcohol compound shown in a formula (I), a Michael acceptor shown in a formula (II), a co-catalyst, a photocatalyst and a hydrogen atom transfer reagent, adding into an organic solvent, irradiating for 2-48 hours (preferably, blue light with the wavelength of 390-470nm and 30 ℃ and 24 hours) at-20-80 ℃ under a protective atmosphere (nitrogen in the embodiment of the invention), and carrying out post-treatment on the obtained reaction liquid to obtain an alcohol alpha-carbon hydrogen bond alkylated compound shown in a formula (III);
in the formula (I), R1 is selected from one of C1-6 alkoxy, phenyl substituted by C1-C5 alkyl, C1-C5 haloalkyl, C1-C6 alkyl or cycloalkyl, and N- (tert-butyloxycarbonyl) aminoethyl;
the Michael acceptor shown in the formula (II) is selected from one of benzyl 2- (bis (tert-butoxycarbonyl) amino) acrylate, methyl acrylate, benzyl acrylate, methyl methacrylate, 2-methoxyethyl 2-acrylate, trifluoroethyl acrylate, 1, 3-hexafluoroisopropyl acrylate, N-methyl-N-phenylacrylamide, N-methyl-N-benzylacrylamide, ethyl 2-phenylacrylate and parthenolide;
the quantity ratio of the alcohol compound shown in the formula (I), the Michael acceptor shown in the formula (II), the cocatalyst, the photocatalyst and the hydrogen atom transfer reagent substance is 1-3: 1: 0.04-0.4: 0.002-0.4: 0.05 to 1 (preferably 2.05;
the cocatalyst is a boron catalyst;
the photocatalyst is selected from bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine][2-2' -bis (4-tert-butylpyridine)]Iridium bis (hexafluorophosphate) salt ([ Ir { dF (CF)) 3 )ppy} 2 (dtbbpy)]PF 6 )、[Ir(ppy)2(dtbbpy)]PF6, 2,4, 6-triphenyl boron tetrafluoride pyran salt, 10-methyl-9-mesitylacridine perchlorate, 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN), acid red and rhodamine(preferably bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine)][2-2' -bis (4-tert-butylpyridine)]Iridium bis (hexafluorophosphate) salt);
the hydrogen atom transfer agent is one selected from the group consisting of quinuclidine, 3-quinuclidinone, 3-quinuclidinyl acetate, benzoglidine, 3-quinuclidinyl benzamide, 4-methyl-N- { 1-azabicyclo [2.2.2] octan-3-yl } benzene-1-sulfonamide, (S) -N- ((S) -quinuclidin-3-yl) -1,2,3, 4-tetrahydronaphthalene-1-carboxamide, 4-cyanoquinuclidine, and ethylquinuclidine-4-carboxylate (preferably quinuclidine).
Further, R1 is preferably cyclohexyl, methyl, N- (t-butoxycarbonyl) aminoethyl, ethyl, isopropyl, t-butyl, isopentyl, 3-fluoropropyl, 3-trifluoropropyl, 2-methoxyethyl, phenylpropyl.
Further, the boron catalyst is selected from one of Criboborol, bortezomib, 2- (hydroxymethyl) phenylboronic acid cyclic monoester, tavaborol, 3-dimethylbenzo [ C ] [1,2] oxapentan-1 (3H) -ol, phenylboronic acid, 4-fluorobenzeneboronic acid, 4-trifluoromethylphenylboronic acid, diphenylboronic acid, and 10H-dibenzo [ B, E ] [1,4] oxaboron-10-ol; tavaborole is preferred.
Further, the organic solvent is selected from one of acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and 1, 2-dichloroethane, preferably 1, 2-dichloroethane.
The volume of the organic solvent is 2-8mL/mmol based on the amount of the substance of the Michael acceptor shown in the formula (II);
the post-treatment comprises the following steps: extracting the reaction liquid by using ethyl acetate, distilling an organic phase to remove a solvent, performing column chromatography separation on the residue by using 200-300-mesh silica gel, eluting by using a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1-1.
The invention further provides the application of the alcohol alpha-carbon hydrogen bond alkylation product in organic synthesis, medicines, pesticides, materials, dyes or detergents.
The method is adopted, and the parthenolide derivative is obtained through one-step synthesis.
The parthenolide derivative belongs to a sesquiterpene lactone natural product, and is NF- K The B inhibitor can reduce histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1, has various important pharmacological activities such as antitumor, antiviral, anti-inflammatory and antiatherosclerotic activities, and can be used for preparing antitumor drugs, antiviral drugs, anti-inflammatory drugs and antiatherotic drugs.
The invention adopts the method and obtains the homoserine derivative by one-step synthesis.
The compounds of the invention are homoserine derivatives, L-homoserine is a non-protein amino acid, the derivatives can be converted into other important chemical intermediates through enzymatic reaction, and L-homoserine is also an important intermediate for synthesizing chiral herbicide glufosinate; and has rich biological activity, such as effective inhibition of sickle red blood cells and antifungal activity, and can be used for preparing medicaments for inhibiting sickle red blood cells and antifungal medicaments.
The invention has the following beneficial effects:
the synthesis method disclosed by the invention develops that an alcohol compound without modification and a Michael acceptor are used as reaction substrates on the basis of a boron catalyst and a visible light co-catalyzed free radical coupling reaction, and an alcohol alpha-carbon hydrogen bond alkylation product is directly obtained by one-step reaction under mild conditions, so that the method can be used for preparing various complex alcohol compounds, the reaction substrates are cheap and wide in range, and the synthesis method is simple to operate, high in yield, good in selectivity, few in byproducts, economical and efficient; the synthetic method is not only suitable for primary alcohol, but also suitable for secondary alcohol, large-position hindered alcohol and the like, and has excellent universality.
The synthesis method is beneficial to industrial production, has wide application prospect, and can be popularized and applied in the fields of organic synthesis, medicines, pesticides, materials, dyes, detergents and the like.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative, and is not to be construed as limiting the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The present invention is illustrated below by specific examples, which are provided for illustrative purposes only and do not limit the scope of the present invention in any way, and in addition, unless otherwise specified, conditions or steps are not described in detail and the methods are conventional, and reagents and materials used are commercially available.
Example 1
Benzyl 2- (bis (tert-butoxycarbonyl) amino) acrylate (188mg, 0.5 mmol) and cyclohexanol (100mg, 1mmol) were placed in 2mL of 1, 2-dichloroethane, followed by addition of the photocatalyst [ Ir { dF (CF { dF) 3 )ppy} 2 (dtbbpy)]PF 6 (2.8mg, 0.0025mmol), tacorol as a cocatalyst (3.8mg, 0.025mmol) and quinuclidine as a hydrogen atom transfer reagent (11mg, 0.1mmol), and the reaction apparatus was charged with nitrogen gas to replace the air in the apparatus;
reacting for 24 hours at 30 ℃ by taking blue light with the wavelength of 390-470nm as a driving force; after the reaction is finished, extracting an organic phase of the obtained reaction liquid by using ethyl acetate, distilling to remove the solvent, carrying out column chromatography separation on the residue by using 200-300-mesh silica gel, and carrying out column chromatography separation by using a solvent with a volume ratio of 1: a mixture of 10 ethyl acetate and petroleum ether was used as an eluent to elute, and the eluent containing the objective product was collected, evaporated in vacuo and dried to obtain benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate in a yield of 205mg and a yield of 86%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was: 1 H NMR(500MHz,CDCl 3 )δ7.35–7.27(m,5H),5.19–5.09(m,3H),2.51–2.47(m,1H),2.46(br,1H),1.86(dd,J＝15.2,5.9Hz,1H),1.65–1.56(m,4H),1.47–1.40(m,20H),1.37–1.22(m,2H). 13 C NMR(125MHz,CDCl 3 )δ172.05,152.23,135.47,128.38,128.07,127.88,83.27,70.07,67.08,54.57,38.67,36.95,27.87,25.70,22.15,22.09.HRMS(ESI)m/z:[M+H] + Calcd.for C 26 H 40 NO 7 478.2799,found 478.2807。
example 2
The present example uses the same embodiment as example 1, except that: the photocatalyst adopted is [ Ir (ppy) 2 (dtbbpy)]PF 6 (2.3mg, 0.0025mmol), the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 134mg, 56%.
Example 3
The present example uses the same embodiment as example 1, except that: the photocatalyst used was 2,4, 6-triphenylpyrane boron tetrafluoride salt (1mg, 0.0025mmol), and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 102mg, 43% yield.
Example 4
The present example uses the same embodiment as example 1, except that: the photocatalyst used was 10-methyl-9-mesitylacridine perchlorate (1.2mg, 0.0025mmol), and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 86mg, which was 36%.
Example 5
The present example uses the same embodiment as example 1, except that: the photocatalyst used was 4CzIPN (1.9mg, 0.0025mmol) and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 112mg, 47% yield.
Example 6
The present example uses the same embodiment as example 1, except that: the photocatalyst used was acid red (1.2mg, 0.0025mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 129mg, 54% yield.
Example 7
The present example uses the same embodiment as example 1, except that: the photocatalyst used was rhodamine (0.9mg, 0.0025mmol), and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 107mg, which was 45%.
Example 8
The present example uses the same embodiment as example 1, except that: the amount of the photocatalyst used was (1.2mg, 0.001mmol), and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 112mg, that was 47%.
Example 9
The present example uses the same embodiment as example 1, except that: the amount of the photocatalyst used was 11mg,0.01mmol, and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 126mg, 53%.
Example 10
The present example uses the same embodiment as example 1, except that: the amount of the photocatalyst used was (16.8mg, 0.015mmol), and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 133mg, which was 56%.
Example 11
The present example uses the same embodiment as example 1, except that: the amount of the photocatalyst used was (22.4mg, 0.02mmol), and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 140mg, which was 59%.
Example 12
The present example uses the same embodiment as example 1, except that: the amount of the photocatalyst used was (224mg, 0.2mmol), and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 143mg and 60%.
Example 13
The present example uses the same embodiment as example 1, except that: the cocatalyst used was krebs (6.3mg, 0.025mmol) and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 145mg and 61% yield.
Example 14
The present example uses the same embodiment as example 1, except that: the co-catalyst used was bortezomib (9.6mg, 0.025mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 145mg, 61% yield.
Example 15
The present example uses the same embodiment as example 1, except that: the cocatalyst used was 2- (hydroxymethyl) phenylboronic acid cyclic monoester (3.3mg, 0.025mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 124mg, 52% yield.
Example 16
The present example uses the same embodiment as example 1, except that: the co-catalyst used was 3, 3-dimethylbenzo [ C ] [1,2] oxapentaborane-1 (3H) -ol (4.0mg, 0.025mmol), and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 169mg, with a yield of 71%.
Example 17
The present example uses the same embodiment as example 1, except that: the co-catalyst used was phenylboronic acid (3.0 mg,0.025 mmol) and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 78mg, 31% yield.
Example 18
The present example uses the same embodiment as example 1, except that: the co-catalyst employed was 4-fluorobenzeneboronic acid (3.5mg, 0.025mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 88mg at 37% yield.
Example 19
The present example uses the same embodiment as example 1, except that: the co-catalyst used was 4-trifluoromethylphenylboronic acid (4.7mg, 0.025mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in a yield of 90mg and 38%.
Example 20
The present example uses the same embodiment as example 1, except that: the co-catalyst employed was diphenylboronic acid (4.5mg, 0.025mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 81mg at 34% yield.
Example 21
The present example uses the same embodiment as example 1, except that: the co-catalyst used was 10H-dibenzo [ B, E ] [1,4] oxaboron-10-ol (4.9mg, 0.025mmol), and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 72mg, 30% yield.
Example 22
The present example uses the same embodiment as example 1, except that: the amount of cocatalyst used was 3.0mg,0.02mmol and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 171mg at 72%.
Example 23
The present example uses the same embodiment as example 1, except that: the amount of the co-catalyst used was (7.6 mg, 0.05mmol), and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in a yield of 164mg and 69%.
Example 24
The present example uses the same embodiment as example 1, except that: the amount of cocatalyst employed was (15mg, 0.1mmol) and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 119mg, 50% yield.
Example 25
The present example uses the same embodiment as example 1, except that: the amount of co-catalyst used was 30.2mg,0.2mmol and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 102mg at 43% yield.
Example 26
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was 3-quinuclidinyl acetate (16.9mg, 0.1mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 174mg, 73% yield.
Example 27
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was benzogliadine (23.1mg, 0.1mmol) and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 169mg, 71% yield.
Example 28
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was 3-quinuclidinylbenzamide (23mg, 0.1mmol), and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 168mg, 68% yield.
Example 29
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was 4-methyl-N- { 1-azabicyclo [2.2.2] oct-3-yl } benzene-1-sulfonamide (28mg, 0.1mmol), and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 74mg in 31% yield.
Example 30
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was (S) -N- ((S) -quinuclidin-3-yl) -1,2,3, 4-tetrahydronaphthalene-1-carboxamide (28.4mg, 0.1mmol) and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in a yield of 150mg and 63%.
Example 31
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was 3-quinuclidinone (12.5mg, 0.1mmol), and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 24mg, 10% yield.
Example 32
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was ethyl quinuclidine-4-carboxylate (18.3mg, 0.1mmol) and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 174mg, 73% yield.
Example 33
The present example uses the same embodiment as example 1, except that: the hydrogen atom transfer reagent used was 4-cyanoquinuclidine (13.6 mg, 0.1mmol), and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was produced in 88mg, 37% yield.
Example 34
The present example uses the same embodiment as example 1, except that: the amount of the hydrogen atom transfer agent used was (2.8mg, 0.025mmol), and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 160mg, which was 67%.
Example 35
The present example uses the same embodiment as example 1, except that: the amount of the hydrogen atom transfer reagent used was 5.5mg,0.05mmol, and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 165mg in yield and 69%.
Example 36
The present example uses the same embodiment as example 1, except that: the amount of the hydrogen atom transfer reagent used was (8.3mg, 0.075mmol), and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 167mg, which was 70%.
Example 37
The present example uses the same embodiment as example 1, except that: the amount of the hydrogen atom transfer reagent used was (16.7 mg, 0.15mmol), and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 162mg, 68%.
Example 38
The present example uses the same embodiment as example 1, except that: the amount of the hydrogen atom transfer reagent used was 33.3mg,0.3mmol, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 129mg, 54%.
Example 39
The present example uses the same embodiment as example 1, except that: the amount of the hydrogen atom transfer reagent used was 55.6mg,0.5mmol, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 114mg and 48%.
Example 40
The present example uses the same embodiment as example 1, except that: the organic solvent used was 2ml acetonitrile, and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 176mg, 74%.
EXAMPLE 41
The present example uses the same embodiment as example 1, except that: the organic solvent used was 2mL of dichloromethane, and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 200mg, 84% yield.
Example 42
The present example uses the same embodiment as example 1, except that: the organic solvent used was 2ml of ethyl acetate, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 191mg, 80%.
Example 43
The present example uses the same embodiment as example 1, except that: the organic solvent used was 2mL of N, N-dimethylformamide and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in a yield of 114mg and 48%.
Example 44
The present example uses the same embodiment as example 1, except that: the organic solvent used was 2mL of dimethyl sulfoxide, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 169mg, which was 71%.
Example 45
The present example uses the same embodiment as example 1, except that: the organic solvent used was 2mL of N, N-dimethylacetamide, and the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was produced in 105mg and 44% yield.
Example 46
The present example uses the same embodiment as example 1, except that: the amount of the organic solvent used was 4mL, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 176mg, which was 74%.
Example 47
The present example uses the same embodiment as example 1, except that: the amount of the organic solvent used was 1mL, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 188mg, which was 79%.
Example 48
The present example uses the same embodiment as example 1, except that: the amount of the alcohol compound used was 50mg,0.5mmol, and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 174mg, 73%.
Example 49
The present example uses the same embodiment as example 1, except that: the amount of the alcohol compound used was 75mg,0.75mmol, and the yield of the product, benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate, was 191mg, 80%.
Example 50
The present example uses the same embodiment as example 1, except that: the amount of the alcohol compound used was 125mg,1.25mmol, and the yield of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 207mg, which was 87%.
Example 51
The present example uses the same embodiment as example 1, except that: the amount of the alcohol compound used was 150mg,1.5mmol, and the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -3- (1-hydroxycyclohexyl) propionate was 212mg in a yield of 89%.
Example 52
The present example uses the same embodiment as example 1, except that: the alcohol compound used was methanol (32mg, 1mmol), and the product obtained was benzylbis (tert-butoxycarbonyl) homoserine, with a yield of 153mg and a yield of 75%.
The nuclear magnetic resonance result of the product benzylbis (tert-butoxycarbonyl) homoserine is as follows: 1 H NMR(500MHz,CDCl 3 )δ7.38-7.27(m,5H),5.20-5.13(m,2H),5.03(dd,J＝9.8,4.7Hz,1H),3.79-3.69(m,1H),3.64-3.57(m,1H),2.52-2.47(m,1H),2.46-2.39(m,1H),2.09-2.01(m,1H),1.46(s,18H). 13 CNMR(125MHz,CDCl 3 )δ170.65,152.59,135.54,128.44,128.15,127.97,83.61,66.91,59.00,55.66,32.62,27.89.HRMS(ESI)m/z:[M+H] + Calcd.for C 21 H 32 NO 7 410.2173,found 410.2179。
example 53
The present example uses the same embodiment as example 1, except that: the alcohol compound used was ethanol (32mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxyvalerate in 158mg, 74% yield.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butyloxycarbonyl) amino) -4-hydroxyvalerate is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.37-7.30(m,5H),5.21-4.99(m,3H),4.06-3.98(3.82-3.69)(m,1H),3.04(br,1H),2.47(2.15)(ddd,J＝14.6,6.2,4.3Hz,1H),2.08-2.01(1.86-1.76)(m,1H),1.45(1.44)(s,18H),1.24(1.23)(s,3H). 13 C NMR(100MHz,CDCl 3 )δ170.94(170.69),152.72(152.24),135.53,128.42,128.12,127.94,83.66(83.32),66.89,66.11,63.96,56.05(55.85),39.69,38.85,27.88(27.86),23.47(23.00).HRMS(ESI)m/z:[M+H] + Calcd.for C 22 H 34 NO 7 424.2330,found424.2333。
example 54
The present example uses the same embodiment as example 1, except that: the alcohol compound used was isopropanol (60mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxy-4-methylpentanoate in a yield of 164mg in a yield of 75%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butyloxycarbonyl) amino) -4-hydroxy-4-methyl valerate is as follows: 1 H NMR(500MHz,CDCl 3 )δ7.39-7.28(m,5H),5.21-5.10(m,3H),2.55(dd,J＝15.2,5.1Hz,1H),2.53(br,1H),1.86(dd,J＝15.1,6.2Hz,1H),1.44(s,18H),1.28(s,3H),1.25(s,3H). 13 C NMR(125MHz,CDCl 3 )δ171.91,152.28,135.48,128.43,128.14,127.93,83.39,69.50,67.17,55.32,43.44,30.53,28.74,27.92.HRMS(ESI)m/z:[M+H] + Calcd.for C 23 H 36 NO 7 438.2486,found438.2496。
example 55
The present example uses the same embodiment as example 1, except that: the alcohol compound used was n-butanol (74mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxyheptanoate at a yield of 185mg, which was 82%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxyheptanoate is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.39-7.28(m,5H),5.23-5.01(m,3H),3.88-3.79(3.59-3.50)(m,1H),2.88(br,1H),2.55-2.48(1.79-1.70)(m,1H),2.13-2.06(m,1H),1.52-1.40(m,22H),0.96-0.87(m,3H). 13 C NMR(100MHz,CDCl 3 )δ171.00(170.80),152.69(152.21),135.54,128.40,128.09,127.93,83.58(83.26),69.68,67.54,66.86,55.98(55.80),39.57,39.19,38.23,37.01,29.65,27.89(27.85),18.92(18.79),13.96.HRMS(ESI)m/z:[M+H] + Calcd.for C 24 H 38 NO 7 452.2643,found452.2645。
example 56
The present example uses the same embodiment as example 1, except that: the alcohol compound used was isoamyl alcohol (88mg, 1mmol), and the product obtained was methyl benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxy-6-heptanoate at a yield of 162mg in 70% yield.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxy-6-heptanoic acid methyl ester is: 1 H NMR(500MHz,CDCl 3 )δ7.37-7.28(m,5H),5.23-4.99(m,3H),3.96-3.86(3.74-3.53)(m,1H),2.55-2.46(2.11-2.04)(m,1H),1.82-1.67(m,2H),1.46-1.43(m,18H),0.96-0.83(m,6H). 13 CNMR(100MHz,CDCl 3 )δ171.01(170.78),152.74(152.25),135.56,128.42,128.12,127.95,83.60(83.27),68.04,66.89,65.84,55.98(55.78),46.65(46.16),38.72(37.38),29.67,27.92(27.87),24.62(24.59),23.28(22.98),22.29(22.05).HRMS(ESI)m/z:[M+H] + Calcd.for C 25 H 40 NO 7 466.2799,found 466.2807。
example 57
The present example uses the same embodiment as example 1, except that: the alcohol compound used was 3-fluoropropanol (78mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -6-fluoro-4-hydroxyhexanoate in 118mg yield of 52%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -6-fluoro-4-hydroxyhexanoate is: 1 H NMR(400MHz,CDCl 3 )δ7.38-7.29(m,5H),5.21-5.00(m,3H),4.76-4.46(m,2H),4.11-4.02(3.81-3.72)(m,1H),3.25(2.38)(d,J＝3.1Hz,1H),2.59-2.51(2.23-2.14)(m,1H),2.13-2.05(1.70-1.59)(s,1H),1.93-1.76(m,2H),1.46(1.45)(s,18H). 13 C NMR(100MHz,CDCl 3 )δ170.82(170.58),152.84(152.29),135.51,135.47,128.44,128.16,127.98(127.97),83.86(83.47),82.38(82.00),80.75(80.38),67.00(66.97),64.05(64.00),55.92(55.81),38.30,37.71(37.62),37.52(37.43),37.29,27.91(27.87).HRMS(ESI)m/z:[M+H] + Calcd.for C 23 H 35 FNO 7 456.2392,found 456.2398。
example 58
The present example uses the same embodiment as example 1, except that: the alcohol compound used was 3, 3-trifluoropropanol (114mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -6, 6-trifluoro-4-hydroxyhexanoate in a yield of 86mg, which was 35%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -6, 6-trifluoro-4-hydroxyhexanoate was: 1 H NMR(400MHz,CDCl 3 )δ7.39-7.28(m,5H),5.22-5.10(m,2H),5.07-4.95(m,1H),3.90-3.82(3.61-3.52)(m,1H),3.32(2.35)(d,J＝3.8Hz,1H),2.59-2.51(2.34-2.27)(m,1H),2.20-2.12(2.09-2.02)(m,1H),1.84-1.66(m,2H),1.46(1.45)(s,18H). 13 C NMR(100MHz,CDCl 3 )δ170.72(170.48),152.86(152.36),135.43(135.40),128.47,128.23,128.02(128.01),83.99(83.67),68.72,67.11(67.07),66.38,55.96(55.83),38.22(37.27),30.44(30.15),,29.68(29.50),27.90(27.87).HRMS(ESI)m/z:[M+H] + Calcd.for C 23 H 33 F 3 NO 7 492.2204,found 492.2208。
example 59
The present example uses the same embodiment as example 1, except that: the alcohol compound used was N- (tert-butoxycarbonyl) ethanolamine (161mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -5- ((tert-butoxycarbonyl) amino) -4-hydroxyvalerate in 172mg yield and 64% yield.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -5- ((tert-butoxycarbonyl) amino) -4-hydroxyvalerate is: 1 H NMR(400MHz,CDCl 3 )δ7.38-7.28(m,5H),5.21-4.93(m,4H),3.92(3.79)(br,1H),3.63(3.56)(br,1H),3.38-3.27(3.71-3.65)(m,1H),3.18-2.99(m,1H),2.57-2.40(2.22-2.12)(m,1H),2.06-1.98(1.80-1.75)(m,1H),1.51-1.38(m,27H). 13 C NMR(100MHz,CDCl 3 )δ170.96(170.59),170.71,156.94(156.26),152.69,152.18,152.12,152.03,135.45,135.42,135.38,128.43,128.16,127.98,83.87(83.43),67.42,67.09,67.05,67.01,66.93,55.78(55.55),35.41(34.60),28.32(28.30),27.88(27.86).HRMS(ESI)m/z:[M+H] + Calcd.for C 27 H 43 N 2 O 9 539.2963,found 539.2969。
example 60
The present example uses the same embodiment as example 1, except that: the alcohol compound used was phenylpropanol (136mg, 1mmol), and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxy-6-phenylhexanoate in a yield of 200mg and a yield of 78%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxy-6-phenylhexanoate is: 1 H NMR(400MHz,CDCl 3 )δ7.36-7.30(m,5H),7.29-7.23(m,2H),7.22-7.14(m,3H),5.22-5.01(m,3H),3.93-3.82(3.58-3.39)(m,1H),3.08(br,1H),2.86-2.75(m,1H),2.74-2.63(m,1H),2.60-2.52(2.12-2.04)(m,1H),2.24-2.01(m,2H),1.89-1.74(m,2H),1.44(1.43)(s,18H). 13 CNMR(100MHz,CDCl 3 )δ170.97(170.73),152.77(152.30),142.04(141.93),135.53(135.51),128.44,128.39,128.37,128.31,128.15,127.98,125.79(125.72),83.71(83.41),69.60,66.94,55.99,55.90,39.09,38.62,38.22,37.21,32.07(32.02),29.68,27.91(27.86).HRMS(ESI)m/z:[M+H] + Calcd.for C 29 H 40 NO 7 514.2799,found 514.2801。
example 61
The present example uses the same embodiment as example 1, except that: the alcohol compound used was ethylene glycol methyl ether (76mg, 1mmol) and the product obtained was benzyl 2- (bis (tert-butoxycarbonyl) amino) -4-hydroxy-5-methoxyvalerate in 147mg yield at 65%.
The nuclear magnetic resonance result of the product benzyl 2- (bis (tert-butyloxycarbonyl) amino) -4-hydroxy-5-methoxy valerate is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.39-7.29(m,5H),5.22-5.06(m,3H),4.05-3.97(3.82-3.73)(m,1H),3.44(3.30)(dd,J＝9.5,3.4Hz,1H),3.38(3.37)(s,3H),3.03(2.45)(d,J＝3.1Hz,1H),2.48-2.39(2.24-2.16)(m,1H),2.10-1.96(1.88-1.81)(m,1H),1.65-1.59(m,1H),1.45(1.44)(s,18H). 13 C NMR(100MHz,CDCl 3 )δ170.81(177.73),152.54(152.12),135.58,128.43,127.98(127.95),83.52(83.21),68.23,67.02,66.92(66.86),59.13(59.02),55.66(55.39),34.28(33.44),27.93(27.89).HRMS(ESI)m/z:[M+H] + Calcd.for C 23 H 36 NO 8 454.2435,found 454.2439。
example 62
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was methyl acrylate (43mg, 0.5 mmol) and the product obtained was methyl 3- (1-hydroxycyclohexyl) propionate at a yield of 66mg and 71%.
The nuclear magnetic resonance result of the product methyl 3- (1-hydroxycyclohexyl) propionate is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.64(s,3H),2.41(t,J＝7.6Hz,2H),1.76(t,J＝7.6Hz,2H),1.69(br,1H),1.61-1.24(m,10H). 13 CNMR(100MHz,CDCl 3 )δ175.12,70.57,51.62,37.29,36.62,28.02,25.67,22.07.HRMS(ESI)m/z:[M+H] + Calcd.for C 10 H 19 O 3 187.1329,found 187.1333。
example 63
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was benzyl acrylate (81mg, 0.5 mmol) and the product obtained was benzyl 3- (1-hydroxycyclohexyl) propionate at a yield of 103mg in 79%.
The nuclear magnetic resonance result of the product benzyl 3- (1-hydroxycyclohexyl) propionate is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.40-7.28(m,5H),5.12(s,2H),2.49(t,J＝7.6Hz,2H),1.81(t,J＝7.6Hz,2H),1.71(br,1H),1.60-1.45(m,6H),1.44-1.33(m,2H),1.28-1.24(m,2H). 13 C NMR(100MHz,CDCl 3 )δ174.45,135.93,128.51,128.20,128.17,70.65,66.31,37.36,29.67,28.32,25.70,22.11.HRMS(ESI)m/z:[M+H] + Calcd.for C 16 H 23 O 3 263.1642,found 263.1646。
example 64
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was methyl methacrylate (50mg, 0.5 mmol) and the product obtained was methyl 3- (1-hydroxycyclohexyl) -2-methylpropionate in 56mg yield at 56%.
The nuclear magnetic resonance result of the product methyl 3- (1-hydroxycyclohexyl) -2-methylpropionate is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.66(s,3H),2.81-2.74(2.38-2.28)(m,1H),2.74-2.64(m,1H),2.00(dd,J＝14.2,10.3Hz,1H),1.80-1.30(m,10H),1.18(1.16)(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.60(178.16),70.97(70.95),51.79,46.17(40.15),38.69,38.39,36.63,34.71,34.49,25.74,25.01,22.65,22.13,19.60.HRMS(ESI)m/z:[M+H] + Calcd.for C 11 H 21 O 3 201.1485,found 201.1489。
example 65
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was 2-methoxyethyl 2-acrylate (65mg, 0.5 mmol), and the product obtained was 2-methoxyethyl 3- (1-hydroxycyclohexyl) propionate at a yield of 76mg, which was 66%.
The nuclear magnetic resonance result of the product 2-methoxyethyl 3- (1-hydroxycyclohexyl) propionate is as follows: 1 H NMR(400MHz,CDCl 3 )δ4.26-4.21(m,2H),3.62-3.57(m,2H),3.38(s,3H),2.47(t,J＝7.1Hz,2H),1.80(t,J＝7.0Hz,2H),1.61-1.49(m,6H),1.43-1.35(m,2H),1.31-1.26(m,2H). 13 C NMR(100MHz,CDCl 3 )δ174.61,70.64,70.40,63.44,58.94,37.38,29.68,28.28,25.74,22.13.HRMS(ESI)m/z:[M+H] + Calcd.for C 12 H 23 O 4 231.1591,found 231.1597。
example 66
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was trifluoroethyl acrylate (77mg, 0.5 mmol), and the product obtained was 2, 2-trifluoroethyl 3- (1-hydroxycyclohexyl) propionate at a yield of 100mg in 79%.
The nuclear magnetic resonance results of the product 2, 2-trifluoroethyl 3- (1-hydroxycyclohexyl) propionate were: 1 H NMR(400MHz,CDCl 3 )δ4.55-4.39(m,2H),2.82-2.44(m,2H),2.36-1.82(m,2H),1.80-1.42(m,10H). 13 CNMR(100MHz,CDCl 3 )δ177.68,171.22,84.14,60.83,60.47,60.10,59.75,39.51,38.74,38.28,35.92,31.10,29.68,25.79,24.91,22.59.HRMS(ESI)m/z:[M+H] + Calcd.for C 11 H 18 F 3 O 3 255.1203,found 255.1210。
example 67
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was 1,1,1,3,3,3-hexafluoroisopropyl acrylate (111mg, 0.5 mmol), and the product obtained was 1,1,1,3,3, 3-hexafluoropropan-2-yl 3- (1-hydroxycyclohexyl) propionate in 108mg yield at 67%.
The nuclear magnetic resonance results of the product 1, 3-hexafluoropropan-2-yl 3- (1-hydroxycyclohexyl) propanoate were: 1 H NMR(400MHz,CDCl 3 )δ5.86-5.69(m,1H),2.86-2.47(m,2H),2.39-1.91(m,2H),1.91-1.29(m,10H). 13 C NMR(100MHz,CDCl 3 )δ177.40,169.68,84.20,66.84,66.50,66.16,65.89,38.64,38.29,35.90,30.82,25.61,24.91,22.59,22.56.HRMS(ESI)m/z:[M+H] + Calcd.for C 12 H 17 F 6 O 3 323.1076,found 323.1079。
example 68
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was N-methyl-N-phenylacrylamide (81mg, 0.5 mmol) and the product obtained was 3- (1-hydroxycyclohexyl) -N-methyl-N-phenylacrylamide in a yield of 69mg with a yield of 53%.
The nuclear magnetic resonance result of the product 3- (1-hydroxycyclohexyl) -N-methyl-N-phenylacrylamide is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝6.7Hz,2H),7.35(d,J＝5.8Hz,1H),7.19(d,J＝7.1Hz,2H),3.25(s,3H),2.67(br,1H),2.25-2.15(m,2H),1.77-1.68(m,2H),1.57-1.32(m,8H),1.29-1.25(m,2H). 13 C NMR(100MHz,CDCl 3 )δ174.25,143.97,129.77,127.84,127.19,70.17,37.61,29.64,28.18,25.81,22.19.HRMS(ESI)m/z:[M+H] + Calcd.for C 16 H 24 NO 2 262.1802,found 262.1809.
example 69
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was N-methyl-N-benzylacrylamide (98mg, 0.5 mmol) and the product obtained was N-benzyl-3- (1-hydroxycyclohexyl) -N-methylpropanamide in 62mg yield at 45%.
The nuclear magnetic resonance result of the product N-benzyl-3- (1-hydroxycyclohexyl) -N-methylpropanamide is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.42-7.13(m,5H),4.60(4.57)(s,2H),2.94(2.96)(s,3H),2.72(br,1H),2.52(t,J＝6.9Hz,2H),1.93-1.80(m,2H),1.66-1.38(m,10H). 13 C NMR(100MHz,CDCl 3 )δ174.61(174.20),137.29(136.46),128.93,128.58,128.02,127.61,127.34,126.29,70.34(70.28),51.05(53.45),37.88(37.79),34.87(34.22),29.69(s),27.38(26.97),25.87(25.85),22.68,22.32(22.27).HRMS(ESI)m/z:[M+H] + Calcd.for C 17 H 26 NO 2 276.1958,found 276.1967。
example 70
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was ethyl 2-phenylacrylate (88mg, 0.5 mmol) and the product obtained was ethyl 3- (1-hydroxycyclohexyl) -2-phenylpropionate at a yield of 70mg, 51%.
The nuclear magnetic resonance result of the product 3- (1-hydroxycyclohexyl) -2-phenylpropionic acid ethyl ester is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.37-7.21(m,5H),4.20-4.01(m,2H),3.85(dd,J＝10.0,2.7Hz,1H),2.49(dd,J＝14.2,10.4Hz,1H),1.79(dd,J＝14.4,2.6Hz,1H),1.59-1.39(m,8H),1.30-1.22(m,3H),1.19(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ175.10,140.54,128.66,127.74,127.03,104.99,71.10,60.91,46.41,38.71,36.77,25.70,22.13,22.09,14.00.HRMS(ESI)m/z:[M+H] + Calcd.for C 17 H 25 O 3 277.1798,found 277.1805。
example 71
The present example uses the same embodiment as example 1, except that: the Michael acceptor used was parthenolide (124mg, 0.5 mmol) and the product obtained was (Z) -8- ((1-hydroxycyclohexyl) methyl) -1a, 5-dimethyl-2, 3,6,7,7a,8,10a, 10b-octahydroxyepinephrine [2',3':9,10] cyclododecane [1,2-b ] furan-9 (1 aH) -one in a yield of 111mg, 64%.
The product (Z) -8- ((1-hydroxycyclohexyl) methyl) -1a, 5-dimethyl-2,3,6,7,7a, 8,10a, 10b-octahydroepinephrine [2',3':9,10]Cyclo ten carbon [1,2-b ]]The nuclear magnetic resonance result of furan-9 (1 aH) -ketone is as follows: 1 H NMR(400MHz,CDCl 3 )δ5.34(br,1H),5.16(d,J＝11.8Hz,1H),3.91(t,J＝9.1Hz,1H),3.50(s,1H),2.71(d,J＝9.0Hz,1H),2.59(t,J＝11.0Hz,1H),2.46-2.25(m,2H),2.25-2.10(m,2H),2.05-1.85(m,3H),1.74-1.56(m,8H),1.54-1.38(m,3H),1.35-1.20(m,8H). 13 C NMR(100MHz,CDCl 3 )δ179.47,134.35,125.16,83.38,69.76,66.12,61.53,50.64,43.43,41.13,39.65,36.69,36.57,29.67,29.42,25.76,24.05,22.24,17.14,16.87.HRMS(ESI)m/z:[M+H] + Calcd.for C 21 H 33 O 4 349.2373,found 349.2380。
the above examples show that the synthesis method of the present invention can realize the alkylation of the alpha-carbon hydrogen bond of various alcohol compounds, and is also suitable for the structure modification of steroid drugs and natural products. The synthesis method is simple to operate, mild in reaction conditions and wide in application range, can be used for preparing various complex alcohol compounds, and has the advantages of high selectivity, few byproducts, wide range of reaction substrates, good universality and low cost.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of an alcohol alpha-carbon hydrogen bond alkylated compound is characterized by comprising the following steps:
mixing an alcohol compound shown in a formula (I), a Michael acceptor shown in a formula (II), a co-catalyst, a photocatalyst and a hydrogen atom transfer reagent, adding the mixture into an organic solvent, irradiating the mixture for 2 to 48 hours at-20 to 80 ℃ under a protective atmosphere by visible light, and carrying out aftertreatment on the obtained reaction liquid to obtain an alcohol alpha-carbon hydrogen bond alkylated compound shown in a formula (III);
R 1 -OH (I)
in the formula (I), R1 is selected from one of C1-6 alkoxy, phenyl substituted by C1-C5 alkyl, C1-C5 haloalkyl, C1-C6 alkyl or cycloalkyl, and N- (tert-butyloxycarbonyl) aminoethyl;
the Michael acceptor shown in the formula (II) is selected from one of benzyl 2- (bis (tert-butoxycarbonyl) amino) acrylate, methyl acrylate, benzyl acrylate, methyl methacrylate, 2-methoxyethyl 2-acrylate, trifluoroethyl acrylate, 1, 3-hexafluoroisopropyl acrylate, N-methyl-N-phenylacrylamide, N-methyl-N-benzylacrylamide, ethyl 2-phenylacrylate and parthenolide;
the mass ratio of the alcohol compound shown in the formula (I), the Michael acceptor shown in the formula (II), the cocatalyst, the photocatalyst and the hydrogen atom transfer reagent substance is 1-3: 1: 0.04-0.4: 0.002-0.4: 0.05 to 1;
the cocatalyst is a boron catalyst;
the photocatalyst is selected from bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine][2-2' -bis (4-tert-butylpyridine)]Iridium bis (hexafluorophosphoric acid)Salt, [ Ir (ppy) 2 (dtbbpy)]PF 6 One of 2,4, 6-triphenyl pyran boron tetrafluoride salt, 10-methyl-9-mesitylacridine perchlorate, 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile, acid red and rhodamine;
the hydrogen atom transfer agent is selected from one of quinuclidine, 3-quinuclidinone, 3-quinuclidinyl acetate, benzozolidine, 3-quinuclidinyl benzamide, 4-methyl-N- { 1-azabicyclo [2.2.2] octane-3-yl } benzene-1-sulfonamide, (S) -N- ((S) -quinuclidin-3-yl) -1,2,3, 4-tetrahydronaphthalene-1-carboxamide, 4-cyano quinuclidine and ethyl quinuclidine-4-carboxylate.
2. The method of claim 1 for the preparation of an alcoholic alpha-carbon hydrogen bond alkylated compound, characterized in that: the protective atmosphere is nitrogen.
3. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: the photocatalyst is bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bi (4-tert-butylpyridine) ] iridium bis (hexafluorophosphate) salt.
4. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: the hydrogen atom transfer agent is quinuclidine.
5. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: r1 is cyclohexyl, methyl, N- (tert-butyloxycarbonyl) aminoethyl, ethyl, isopropyl, tert-butyl, isoamyl, 3-fluoropropyl, 3-trifluoropropyl, 2-methoxyethyl or phenylpropyl.
6. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: the boron catalyst is selected from one of Cliborol, bortezomib, 2- (hydroxymethyl) phenylboronic acid cyclic monoester, tavaborol, 3-dimethylbenzo [ C ] [1,2] oxapentoborane-1 (3H) -alcohol, phenylboronic acid, 4-fluorobenzeneboronic acid, 4-trifluoromethylphenylboronic acid, diphenylboronic acid and 10H-dibenzo [ B, E ] [1,4] oxaborol-10-alcohol.
7. The method of claim 6 for the preparation of an alcoholic alpha-carbon hydrogen bond alkylated compound, characterized in that: the boron catalyst is tavabororo.
8. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: the organic solvent is selected from one of acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and 1, 2-dichloroethane; the volume of the organic solvent is 2-8mL/mmol based on the amount of the substance of the Michael acceptor represented by the formula (II).
9. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: the visible light is blue light with the wavelength of 390-470 nm.
10. The process for the preparation of alcoholic α -carbon hydrogen bonding alkylated compounds according to claim 1, characterized in that: the post-treatment comprises the following steps: extracting the reaction liquid by using ethyl acetate, distilling an organic phase to remove a solvent, performing column chromatography separation on the residue by using 200-300-mesh silica gel, eluting by using a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1-1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211645598.0A CN115850120A (en) | 2022-12-20 | 2022-12-20 | Preparation method of alcohol alpha-carbon hydrogen bond alkylated compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211645598.0A CN115850120A (en) | 2022-12-20 | 2022-12-20 | Preparation method of alcohol alpha-carbon hydrogen bond alkylated compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115850120A true CN115850120A (en) | 2023-03-28 |
Family
ID=85674737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211645598.0A Pending CN115850120A (en) | 2022-12-20 | 2022-12-20 | Preparation method of alcohol alpha-carbon hydrogen bond alkylated compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115850120A (en) |
-
2022
- 2022-12-20 CN CN202211645598.0A patent/CN115850120A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| SUN TIANYI等: ""Direct α-C-H Alkylation of Structurally Diverse Alcohols via Combined Tavaborole and Photoredox Catalysis"", ORG. LETT., vol. 24, pages 1 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2534140B1 (en) | Efficient methods for z- or cis-selective cross-metathesis | |
| Overman et al. | A convenient method for obtaining trans-2-aminocyclohexanol and trans-2-aminocyclopentanol in enantiomerically pure form | |
| US20100184998A1 (en) | Organic compounds | |
| CA2692636A1 (en) | Process for producing cisatracurium and associated intermediates | |
| US9206090B2 (en) | Tricyclic chiral compounds and their use in asymmetric catalysis | |
| JP2001508446A (en) | Asymmetric synthesis and catalysis by chiral heterocyclic compounds | |
| Bando et al. | Regio-and stereoselective synthesis of 1, 3-hydroxyl amines via palladium-catalyzed carbonate-carbamate transformation with unique stereoselectivity: synthesis of 3-amino-4-penten-1-ols | |
| Bravo et al. | Asymmetric synthesis of α-arylglycinols via additions of lithium methyl p-tolyl sulfoxide to N-(PMP) arylaldimines followed by “non oxidative” Pummerer reaction | |
| DE60102825T2 (en) | KINETIC RACEMATING OF CHIRALER 2 AND 3 SUBSTITUTED CARBOXYLIC ACIDS | |
| KR101130818B1 (en) | Method for preparing chiral amino acid from azlactones using bifunctional bis-cinchona alkaloid thiourea organo catalysts | |
| CN115850120A (en) | Preparation method of alcohol alpha-carbon hydrogen bond alkylated compound | |
| JP4948172B2 (en) | Catalytic asymmetric desymmetrization of prochiral cyclic and meso cyclic anhydrides | |
| EP0692538A2 (en) | Process for producing optically active L-amino acids, novel optically active L-aminoacids with bulky side-chains and their use | |
| US11708320B2 (en) | Environmentally-friendly hydroazidation of olefins | |
| JP2007531704A5 (en) | ||
| US9079824B2 (en) | Method for the synthesis of an amino acetal | |
| JP3987944B2 (en) | Process for producing polysubstituted cyclobutane and polysubstituted cyclobutene compound | |
| Gheewala | Enantioselective Brønsted Acid Catalysis with Chiral Pentacarboxycyclopentadienes | |
| Ng | Zwitterion-Catalyzed Organic Transformations and Ammonium Fluoride-Catalyzed Dibromination of Alkenes | |
| Caplan | Total Synthesis of Divergolides E and H and an Investigation into the Oxidative Rearrangement to Divergolides C and D | |
| Pop | Towards the total synthesis of (-)-sparteine and other lupin alkaloids & new chiral catalysts for asymmetric epoxidations | |
| WO2010094029A2 (en) | Asymmetric cyclopropanation with succinimidyl diazoacetate | |
| CN118005533A (en) | Preparation method of chiral cyano amine derivative | |
| US9328061B2 (en) | Simple organic molecules as catalysts for practical and efficient enantioselective synthesis of amines and alcohols | |
| JP2004075609A (en) | Optically active amino acid derivative and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |