CN115160123A - Method for preparing carboxylic acid compound by oxidizing alcohol with oxygen as oxidant under catalysis of copper - Google Patents

Method for preparing carboxylic acid compound by oxidizing alcohol with oxygen as oxidant under catalysis of copper Download PDF

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CN115160123A
CN115160123A CN202110354940.0A CN202110354940A CN115160123A CN 115160123 A CN115160123 A CN 115160123A CN 202110354940 A CN202110354940 A CN 202110354940A CN 115160123 A CN115160123 A CN 115160123A
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nmr
reaction
oxygen
tempo
hours
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麻生明
于一博
钱辉
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Fudan University
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Fudan University
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Priority to PCT/CN2022/081399 priority patent/WO2022206399A1/en
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    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
    • C07C51/23—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups
    • C07C51/235—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of —CHO groups or primary alcohol groups
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Abstract

The invention discloses a method for preparing carboxylic acid compound by oxidizing alcohol with oxygen as oxidant under the catalysis of copper, which is specifically to use copper nitrate (Cu (NO) in organic solvent at the temperature of 25-50 DEG C 3 ) 2 ·3H 2 O), 2,2,6,6-tetramethylpiperidine oxynitride (TEMPO) and acidic inorganic salt as catalysts, and oxygen or air as an oxidizing agent, and oxidizing the alcohol to produce a carboxylic acid compound. The method has the advantages of simple operation, easily obtained raw materials and reagents, mild reaction conditions, high yield, wide substrate functional group compatibility, enlargeable reaction scale, environment-friendly whole reaction process, no pollution and the like, and is suitable for industrialization.

Description

Method for preparing carboxylic acid compound by oxidizing alcohol with oxygen as oxidant under catalysis of copper
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a method for preparing a carboxylic acid compound by oxidizing alcohol with oxygen as an oxidant under the catalysis of copper.
Background
Carboxylic acid compounds are a very useful class of chemicals that are widely used in laboratory research, industrial production, and daily life, and carboxylic acids are also widely found in drug molecules, such as ibuprofen, naproxen, and indomethacin. One of the most straightforward methods for synthesizing such compounds is the one-step oxidation of a primary alcohol to a carboxylic acid. Therefore, the development of a catalytic system which is economical, mild in condition, environment-friendly and wide in functional group compatibility has very important application prospect. Conventional oxidation processes tend to require an equivalent or excess amount of oxidizing agent to oxidize the corresponding alcohol and can generate equivalent amounts of industrial waste, such as KMnO 4 Oxidation, jone's oxidation, and the like. Such processes have the disadvantage that the oxidizing agents contain heavy metals, are expensive, are harsh, produce waste materials which pollute the environment and are not suitable for large-scale industrial production (mahMOod, a.; robinson, g.e.; powell, l.org.process res.dev.1999,3,363 sharp, s.; faisal, m.; safe, a.; ghumro, s.a..(ii) a El-seed, h.r.; rasheed, s.; abbas, n.; larik, f.a.; channar, p.a.; abdul fantah, t.; ashraf, z.; solargi, z.a.curr.org.synth.2018,15,1091; wendlandt, a.e.; stahl, s.s.angelw.chem., int.ed.2015,54,14638; uyanik, m.; ishihara, k. Chem. Commun.2009, 2086). Oxygen is a cheap, readily available, abundant, environmentally friendly oxidant, and so there is currently a wide interest in using oxygen as an oxidant (i.w.c.e.arends, r.a.sheldon, modern Oxidation Methods, wiley-VCH, weinheim,2004, pp.83-118, t.mallat, a.baiker, chem.rev.2004,104,3037-3058, i.e. mark, p.r.giles, m.tsukazaki, i.chell-Regnaut, gautier, r.dumeuier, f.philippipart, k.doda, j.l.mutonkole, s.m.brown, c.j.urch, adv.inorg.chem.2004,56,211-240, b.z.zhan, a.thompson, tetrahedron 2004,60,2917-2935, m.j.schultz, m.s.sigman, tetrahedron 2006,62,8227-8241, t.matsumoto, m.ueno, n.wang, s.kobayashi, chem.asian j.2008,3,196-214 c.parmeggnia, f.cardona, grem.chem.14, 547-564). However, in the current oxygen-containing oxidation systems for copper-catalyzed alcohols, the reaction mostly remains with aldehydes. TEMPO as a class of stable, inexpensive nitroxide radicals plays an important role in oxidation systems with iron or copper salts as catalysts (Gamez, p.; arends, i.w.c.e.; reedijk, j.; sheldon, r.a.chem.comm.2003, 2414; ma, s.; liu, j.; li, s.; chen, b.; chen, j.; kuang, j.; liu y, y.; wan, b.; wang, y.; ye, j.; yu q.; yuan, w.; yu, s.adv.synth.cat.2011, hoover, j.m.; stahl 2012, s.s.j.; am.chem.soc.2011, 901, 353, j.; syn j.78, mag r.t.; s.22, r.t, mag j.; s.42, r.t.11, r.t.; s.11, r.r.r.t.t, mag r.t.11, r.; s.r.t, s.11, r.r.t.r.r.t.11. However, the oxygen oxidation of alcohols directly to carboxylic acids has not been reported in the current copper and TEMPO system reports.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a method for preparing a carboxylic acid compound by oxidizing alcohol by using oxygen as an oxidizing agent, which has the advantages of mild reaction, high efficiency, low cost, suitability for industrial production and green copper catalysis.
The invention overcomes the defects that equivalent or excessive oxidant or noble metal is used as a catalyst, the reaction condition is harsh, the substrate compatibility range is limited, the reaction needs high temperature and high pressure and the like in the prior oxidation technology, provides a method for oxidizing alcohol to generate carboxylic acid compound by using more clean, cheap and rich oxygen under the atmospheric pressure condition, and the reaction takes copper nitrate, TEMPO and acid inorganic salt which are easily obtained in industry as the catalyst and oxygen as the oxidant. The method has the advantages of low required cost, wide raw material source, less pollutants generated in the reaction process, mild reaction, high efficiency, low cost, environmental friendliness, suitability for large-scale production and the like.
The invention provides a method for preparing carboxylic acid compound by oxidizing alcohol with oxygen as an oxidant under the catalysis of copper, which takes alcohol as a raw material, copper nitrate trihydrate, 2,2,6,6-tetramethylpiperidine oxynitride and acidic inorganic salt as catalysts and oxygen as the oxidant in an organic solvent at the temperature of 25-50 ℃, and the alcohol is oxidized to generate the carboxylic acid compound, wherein the reaction process is shown as a reaction formula (1):
Figure BDA0003003253570000021
wherein the content of the first and second substances,
R 1 including alkyl, alkyl with functional group, cycloalkyl, heterocyclic radical, aryl, alkynyl with functional group, terpenes and steroid structure.
The heterocyclic group is a heterocyclic ring with carbon, nitrogen, oxygen or sulfur atoms as ring atoms;
the aryl is phenyl, nitro substituted phenyl, halogen substituted phenyl, ester group substituted phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, thienyl, furyl or naphthyl;
the alkynyl is a terminal alkynyl with the chain length of C3-C16;
the functional group in the alkyl with the functional group is halogen, ether bond, ester group, heteroaryl, aryl, alkynyl, amino and carbon-carbon double bond;
the functional group in the alkynyl with the functional group is alkyl silicon base, alkyl, alkenyl, alkynyl and propargyl substituted by alkyl silicon base.
Preferably, said R is 1 Comprises C1-C16 alkyl, C3-C10 cycloalkyl, C3-C8 heterocyclic radical, alkyl with functional group, terpenes and steroid structure.
The functional group in the alkyl with the functional group is fluorine, chlorine, bromine, iodine, ether bond, ester group, thienyl, indolyl, furyl, benzofuryl, benzothienyl, benzopyranyl, phenyl, halogenated phenyl, alkylphenyl, alkoxy naphthyl, biphenyl, nitrophenyl, ester group-substituted phenyl, alkynyl or amino;
the amino is a protecting group-containing amino; the protecting group is p-toluenesulfonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, acetyl and trifluoroacetyl.
The heterocyclic group of C3-C8 is furan ring or thiophene ring.
Further preferably, R 1 Including C3-C16 alkyl, C6-C10 cycloalkyl, sulfur-containing and oxygen-containing alicyclic rings.
Specifically, the raw material alcohol is fatty alcohol, benzyl alcohol, alkynyl alcohol, amino alcohol, prodrug (alkyl alcohol with functional group), complex molecule (terpenes, steroid structure).
The aliphatic alcohol is hexadecanol, undecanol, octanol, 4,4,4-trifluorobutanol, 9-bromo-1-nonanol, 9-iodo-1-nonanol, 8- (toluene-4-sulfonyloxy) -octanol, methyl 6-hydroxyhexanoate, 2-hexyloxyethanol, phenylpropanol, 2-bromophenylethanol, thiophene-2-ethanol, tetrahydrofuran-2-methanol, (S) -tetrahydrofuran-2-methanol, 2-phenylpropanol, (S) -2-phenylpropanol, 2-methylbutanol, (S) -2-methylbutanol, cyclohexanemethanol, adamantanemethanol, cyclohex-3-ene-1-methanol.
The benzyl alcohol is 4-nitrobenzyl alcohol, 4- (trifluoromethyl) benzyl alcohol, 4- (methoxycarbonyl) benzyl alcohol, 4-iodobenzyl alcohol, 3-iodobenzyl alcohol, 2-iodobenzyl alcohol, 4-methylbenzyl alcohol or 3-methoxybenzyl alcohol.
The alkynyl alcohol is 10-undecenyl-1-alcohol, 6-heptyne-1-alcohol, 4-pentyne-1-alcohol, 3-methylsilyl propinol, 6-octyne-1-alcohol, 6,9-decanediyne-1-alcohol, 10-trimethylsilyl-6,9-decanediyne-1-alcohol and 7-allyl-6-heptyne-1-alcohol.
The amino alcohol is (R) -or (S) - (N-p-toluenesulfonyl) valinol, (R) -or (S) - (N-p-toluenesulfonyl) phenylalaninol, (R) -or (S) - (N-tert-butoxycarbonyl) phenylalaninol, (R) -or (S) - (N-benzyloxycarbonyl) phenylalaninol, (N-p-toluenesulfonyl) alaninol, (S) - (N-p-toluenesulfonyl) alaninol, or (R) - (N-p-toluenesulfonyl) -prolinol.
The prodrug is 2- (6-methoxy-2-naphthyl) -1-propanol, (S) -2- (6-methoxy-2-naphthyl) -1-propanol, 2- (3-fluoro-4-phenyl) phenyl-1-propanol, (R) -2- (3-fluoro-4-phenyl) phenyl-1-propanol, 2- (4-isobutyl) phenyl-1-propanol, (S) -2- (4-isobutyl) phenyl-1-propanol, 4-hydroxyethylbiphenyl, 2- ((4- (1-hydroxy-2-propyl) -benzyl) -1-cyclopentanol, indomethacin precursor.
The complex molecule is (3 alpha, 5 beta) -3,24-cholediol, sclareol (3R, 5S) -6-hydroxy-3,5-isopropyl diene dioxyhexanoic acid tert-butyl ester.
In the method, the molar ratio of the alcohol, the copper nitrate trihydrate, 2,2,6,6-tetramethylpiperidine oxynitride and the acidic inorganic salt is 100 (1-20) to (1-30) to (1-20); preferably, the molar ratio of the alcohol, the copper nitrate trihydrate, 2,2,6,6-tetramethylpiperidine oxynitride and the acidic inorganic salt is 100 (1-10): 1-10; further preferably, is 100.
In the method, the organic solvent is one or a mixture of more of toluene, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,1-dichloroethane, trichloromethane, ethyl acetate, 1,3-dichloropropane, 1,2-dichloropropane, nitromethane, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran and the like; preferably, the organic solvent is 1,2-dichloroethane.
In the method, the acidic inorganic salt is a bronsted acidic inorganic salt or a lewis acidic inorganic salt, and comprises potassium dihydrogen phosphate, sodium hydrogen sulfate, potassium sulfate, tin chloride, indium chloride, copper fluoride, aluminum chloride, zinc chloride, bismuth chloride, ytterbium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate and scandium trifluoromethanesulfonate; preferably, sodium bisulfate, potassium bisulfate; further preferably, it is potassium hydrogen sulfate.
In the present invention, the source of the oxygen is pure oxygen or oxygen in air.
In the present invention, the reaction is preferably carried out at room temperature or 50 ℃.
In the present invention, the reaction time is 12 to 96 hours.
In the method of the present invention, when oxygen is used as the oxidant and the reaction temperature is room temperature, the reaction time is preferably 36 hours; when the reaction is carried out at 50 ℃ using oxygen as the oxidant, the reaction time is preferably 12 hours;
when air is used as the oxidizing agent and the reaction temperature is room temperature, the reaction time is preferably 72 hours.
Furthermore, the method of the invention can utilize oxygen in the air as an oxidant and amplify the reaction, and the specific operation is as follows: firstly, an air bag is used as an oxygen source, and an oxygen ball is added for supplement after 12 hours of reaction. The method effectively avoids the danger possibly brought by the operation of pure oxygen in industry, reduces the requirement of equipment and is convenient for industrial application.
There are two possible mechanisms for the reaction of the present invention: in route A, cu 2+ Combining with TEMPO to obtain int.1, reacting with alcohol to obtain int.2, and eliminating with beta-H and reducing to obtain aldehyde, TEMPOH and Cu + . In route B, TEMPO is first disproportionated under acidic conditions to TEMPO + And TEMPOH, the alcohol may be TEMPO + Oxidation to aldehyde simultaneously yields TEMPOH. Subsequently, water attacks the protonated aldehyde int.3, forming int.4, which can be further oxidized to carboxylic acid. Cu + Can be substituted by NO 2 Oxidative regeneration of Cu 2 + While NO 2 Is reduced to NO. NO 2 From NO and O 2 And (4) reaction regeneration. TEMPOH and Cu 2+ The reaction can be converted to TEMPO, completing the reaction cycle, as shown below.
Figure BDA0003003253570000041
The invention also provides the application of the method in preparing carboxylic acid compounds through alcohol.
The beneficial effects of the invention include: the invention discloses a method for preparing carboxylic acid compound by using alcohol as raw material, copper nitrate trihydrate, 2,2,6,6-tetramethyl piperidine nitrogen oxide and acidic inorganic salt as catalyst, and oxygen or air as oxidant, wherein the alcohol is oxidized to generate carboxylic acid compound at room temperature or 50 deg.C in organic solvent. The method of the invention uses pure oxygen or air as an oxidant, and can selectively oxidize primary alcohol containing multiple functional groups such as carbon-carbon double bond, carbon-carbon triple bond, halogen, ester group and the like to obtain carboxylic acid compounds. The method has quite wide substrate universality, almost covers various types of primary alcohols, the yield of aliphatic primary alcohol is up to 99 percent, and cheap green catalytic amounts of copper nitrate, TEMPO, potassium hydrogen sulfate and oxygen are used, so that the defects of narrow substrate range, low yield of aliphatic primary alcohol and requirement of equivalent amount of noble metal or toxic oxidant in the traditional method are overcome. The method has the advantages of mild reaction, high efficiency, simple operation, low cost, wide substrate functional group compatibility, high practicability, environmental friendliness, suitability for large-scale production and the like.
The invention has the advantage of wide compatibility of substrate functional groups, can be used for oxidizing common fatty alcohol and catalyzing the oxidation of alcohol with complex structure, such as alcohol containing halogen, ether bond, ester group, heteroaryl, aryl, alkynyl and amino functional groups, and in addition, terpenoid and steroid structures are compatible under the condition of the invention. The invention is also suitable for the oxidation of the drug molecule precursor to prepare the drug molecule, and provides a path for the synthesis of the drug molecule. The method has the advantages of mild reaction conditions, simple operation, high yield, convenient separation and purification and the like. The invention overcomes the defects that equivalent oxidant or noble metal is still needed as catalyst in the prior art, the reaction condition is harsh, the substrate range is narrow, and the like. The method is not only suitable for small-scale laboratory synthesis, but also can be amplified to large-scale industrial production.
The method utilizes the clean energy oxygen or air which is green, cheap and widely available to replace the chemical oxidant required in the traditional oxidation method as the oxidant, the byproduct is water, the whole reaction process hardly produces any pollution to the environment, and the method meets the requirement of green chemistry. The copper nitrate trihydrate, TEMPO and acidic additive used in the process of the invention are all commercially available reagents and are inexpensive. The invention has mild reaction condition and simple post-treatment, thereby being convenient to operate and easy to control. The invention has high reaction yield and can effectively reduce the production cost.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Note: mol in the reaction formulae of the following examples represents mol; cu (NO) 3 ) 2 ·3H 2 O represents copper (II) nitrate trihydrate; TEMPO means 2,2,6,6-tetramethylpiperidine oxide; KHSO 4 Represents potassium hydrogen sulfate; DCE represents 1,2-dichloroethane; et (Et) 2 O represents diethyl ether; DCM represents dichloromethane; rt represents room temperature; o is 2 balloon means that the reaction is carried out under an oxygen atmosphere provided by an oxygen balloon; airball means that the reaction is carried out under an oxygen atmosphere provided by an air ball; air bag means that the reaction is carried out under an air atmosphere provided by an air bag; o is 2 bag means that the reaction is carried out in an air atmosphere with oxygen supplemented by an oxygen bag; h represents an hour; the boiling range of petroleum ether is 60-90 ℃; nuclear magnetic yield of 1 H NMR confirmed that the internal standard is dibromomethane, and the mesh number of the silica gel is 300-400.
Example 1
Figure BDA0003003253570000061
Step I: inserting balloon on Schlenk tube, changing oxygen for 3 times, sequentially addingInto Cu (NO) 3 ) 2 ·3H 2 O(24.6mg,0.1mmol),TEMPO(16.1mg,0.1mmol),KHSO 4 (14.1mg, 0.1mmol), 1a (243.0 mg,1.0 mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours until TLC monitoring the reaction completion. The reaction mixture was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), the solvent was removed by rotary evaporation, and the crude product was isolated and purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate =10/1 to 1/1) to give the product 2a as a pale yellow solid (252.3 mg, 98%).
Step II: inserting balloon on Schlenk tube, changing oxygen for 3 times, sequentially adding Cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol),TEMPO(15.8mg,0.1mmol),KHSO 4 (14.1mg, 0.1mmol), 1a (243.0 mg,1.0 mmol) and DCE (2 mL). The reaction was stirred under 50 ℃ oil bath for 12 hours until completion of the reaction was monitored by TLC. The reaction solution was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), the solvent was removed by rotary evaporation, and the crude product was isolated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =10/1 to 1/1) to give the product, 2a, as a pale yellow solid (247.4 mg, 96%).
2a: 1 H NMR(400MHz,CDCl 3 ):δ＝2.34(t,J＝7.4Hz,2H,CH 2 ),1.63(quintet,J＝7.3Hz,2H,CH 2 ),1.39-1.13(m,24H,12 x CH 2 ),0.88(t,J＝6.6Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.5,34.1,31.9,29.66,29.62,29.61,29.56,29.49,29.40,29.3,29.2,29.0,24.6,22.6,14.0.
Example 2
Figure BDA0003003253570000062
The operation was identical to that of example 1, step I,1b (175.0 mg,99% pure, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(23.8mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.5mg, 0.1mmol), DCE (4 mL), reacted for 36 hours to give 2b (182.6 mg, 97%) as a pale yellow solid (first elution: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 1/1 (. About.100 mL); second elution: 10/1 (. About.220 mL) to 1/1 (. About.100 mL)).
The same procedure as in example 1, step II,1b (173.9mg, 99% pure, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.0mg,0.1mmol)，TEMPO(15.8mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) was reacted for 12 hours to give 2b (168.6mg, 91%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =20/1 (. About.210 mL) to 1/1 (. About.100 mL).
2b (low boiling point solid, melting point cannot be determined by recrystallization); 1 H NMR(400MHz,CDCl 3 )δ＝11.63(brs,1H,COOH),2.34(t,J＝7.6Hz,2H,CH 2 ),1.63(quintet,J＝7.2Hz,2H,CH 2 ),1.38-1.12(m,14H,7 x CH 2 ),0.88(t,J＝6.8Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.6,34.1,31.8,29.5,29.3,29.21,29.16,29.0,24.6,22.6,14.0；IR(neat,cm -1 ):3300-2500,1707,1465,1411,1379,1242,1066,1057；MS(70eV,EI)m/z(％):186(M + ,17.75),73(100).
example 3
Figure BDA0003003253570000071
The procedure is as in example 1, step I,1c (130.0 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol)，TEMPO(16.3mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give a light yellow liquid 2c (139.0 mg, 96%) (eluent: petroleum ether/ethyl acetate =20/1 (-210 mL) to 5/1 (-60 mL), then 1/1 (-100 mL)).
The procedure is as in example 1, step II,1c (130.9mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (14.0 mg, 0.1mmol), DCE (2 mL) for 12 hours to give a light yellow liquid 2c (131.4 mg, 91%) (eluent: petroleum ether/Ethyl acetate =10/1 (-220 mL) to 1/1 (-100 mL)).
2c: 1 H NMR(400MHz,CDCl 3 ):δ＝11.45(brs,1H,COOH),2.35(t,J＝7.6Hz,2H,CH 2 ),1.64(quintet,J＝7.3Hz,2H,CH 2 ),1.42-1.18(m,8H,4 x CH 2 ),0.88(t,J＝6.8Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.5,34.1,31.5,28.9,28.8,24.6,22.5,13.9.
Example 4
Figure BDA0003003253570000072
The procedure was as in example 1, step I,1d (131.2mg, 98% by weight, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give a yellow solid 2d (104.2mg, 73%) (eluent: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 3/1 (. About.200 mL)).
The operation was identical to that of example 1, step II,1d (130.0 mg,98% by weight, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.7mg,0.1mmol)，TEMPO(15.7mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol) and DCE (2 mL) for 12 h gave a yellow solid 2d (100.8mg, 70%) (eluent: petroleum ether/Ethyl acetate =10/1 (. About.220 mL) to 4/1 (. About.250 mL)).
2d (low boiling point solid, unable to recrystallize to measure melting point); 1 H NMR(400MHz,CDCl 3 )δ＝10.57(brs,1H,COOH),2.66(t,J＝7.8Hz,2H,CH 2 ),2.56-2.37(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝177.3,126.3(q,J＝274.4Hz),29.0(q,J＝30.0Hz),26.9(q,J＝3.1Hz)； 19 F NMR(376MHz,CDCl 3 ):δ＝–67.6；IR(neat,cm -1 ):3250-2250,1716,1446,1427,1384,1254,1228,1138,1107；MS(70eV,EI)m/z(％):142(M + ,0.8),125((M-OH) + ,21.16),77(100).
example 5
Figure BDA0003003253570000081
The procedure was as in example 1, step I,1e (229.2mg, 97% pure, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.6mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give 2e (226.5mg, 96%) as a white solid (eluent: petroleum ether/ethyl acetate =10/1 (-270 mL) to 1/1 (-150 mL)).
The procedure is as in example 1, step II,1e (229.2mg, 97% purity,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.0mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) for 12 hours to give 2e (227.9mg, 96%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =10/1 (. About.380 mL) to 1/1 (. About.200 mL)).
2e: 1 H NMR(400MHz,CDCl 3 )δ＝3.40(t,J＝6.8Hz,2H,CH 2 ),2.35(t,J＝7.4Hz,2H,CH 2 ),1.85(quintet,J＝7.1Hz,2H,CH 2 ),1.73-1.53(m,2H,CH 2 ),1.52-1.38(m,2H,CH 2 ),1.38-1.02(m,6H,3 x CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.5,34.0,33.8,32.7,28.9,28.8,28.4,28.0,24.5.
Example 6
Figure BDA0003003253570000082
The procedure is as in example 1, step I,1f (262.6mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give 2f (268.1mg, 97%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =10/1 (. About.160 mL) to 2/1 (. About.240 mL)).
The procedure is as in example 1, step II,1f (262.5mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.8mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (14.0 mg,0.1 mmol), DCE (2 mL) was reacted for 12 hours to give 2f (267.3 mg, 97%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =15/1 (. About.160 mL) to 10/1 (. About.160 mL) and then 2/1 (. About.300 mL)).
2f.p.60.2-60.9 ℃ (petroleum ether/dichloromethane); 1 H NMR(400MHz,CDCl 3 )δ＝10.42(brs,1H,COOH),3.18(t,J＝6.8Hz,2H,CH 2 ),2.35(t,J＝7.4Hz,2H,CH 2 ),1.82(quintet,J＝7.1Hz,2H,CH 2 ),1.71-1.53(m,2H,CH 2 ),1.46-1.21(m,8H,4 x CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.3,34.0,33.4,30.3,28.9,28.8,28.2,24.5,7.1；IR(neat,cm -1 ):3200-2350,1689,1463,1428,1301,1271,1234,1195；MS(70eV,EI)m/z(％):157((M-I) + ,34.7)；55(100).
example 7
Figure BDA0003003253570000091
The procedure is as in step I of example 1, 1g (303.7mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.0mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (14.0 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give 2g (309.3 mg, 97%) of a pale yellow solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.180 mL) to 1/1 (. About.300 mL)).
The procedure is as in example 1, step II,1g (302.2mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol)，TEMPO(16.3mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) was reacted for 12 hours to give 2g (295.4mg, 93%) of a pale yellow solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 2/1 (. About.150 mL), then 1/1 (. About.300 mL)).
2g, m.p.60.3-61.5 ℃ (petroleum ether/dichloromethane); 1 H NMR(400MHz,CDCl 3 )δ＝11.48(brs,1H,COOH),7.78(d,J＝8.4Hz,2H,Ar-H),7.35(d,J＝8.0Hz,2H,Ar-H),4.02(t,J＝6.4Hz,2H,CH 2 ),2.44(s,3H,CH 3 ),2.32(t,J＝7.6Hz,2H,CH 2 ),1.72-1.49(m,4H,2 x CH 2 ),1.38-1.14(m,6H,3 x CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.0,144.6,133.0,129.7,127.7,70.4,33.8,28.6,28.5,28.3,24.9,24.3,21.4；IR(neat,cm -1 ):3100-2800,1694,1597,1467,1352,1236,1189,1096；MS(ESI)m/z:315(M+H) + ,332(M+NH 4 ) + ,337(M+Na) + ；Anal.Calcd.For C 15 H 22 O 5 S:C 57.31,H 7.05；found C 57.31,H 6.81.
example 8
Figure BDA0003003253570000101
The procedure is as in example 1, step I,1h (146.8mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(15.7mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol) and DCE (4 mL) for 36 h to give a pale red liquid for 2h (125.8mg, 78%) (eluent: petroleum ether/ethyl acetate =10/1 (-220 mL) to 5/1 (-240 mL) and then 1/1 (-100 mL)).
The procedure is as in example 1, step II,1h (146.1mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (2 mL) was reacted for 12 hours to give a pale red liquid for 2h (116.0 mg, 72%) (eluent: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 5/1 (. About.240 mL), and then 2/1 (. About.220 mL) to 1/1 (. About.100 mL)).
2h: 1 H NMR(400MHz,CDCl 3 )δ＝10.89(brs,1H,COOH),3.68(s,3H,CH 3 ),2.49-2.20(m,4H,2 x CH 2 ),1.77-1.56(m,4H,2 x CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝179.4,173.8,51.5,33.5,24.1,23.9.
Example 9
Figure BDA0003003253570000102
The procedure is as in example 1, step I,1I (146.3 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol)，TEMPO(15.8mg,0.1mmol)，KHSO 4 (14.0 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give a pale yellow liquid 2i (126.5 mg, 79%) (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 1/1 (. About.200 mL)).
The procedure is as in example 1, step II,1i (146.9mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.6mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (14.1mg,0.1 mmol), DCE (2 mL) was reacted for 12 hours to give 2i (119.3mg, 74%) as a pale yellow liquid (eluent: petroleum ether/ethyl acetate =10/1 (-330 mL) to 5/1 (-120 mL), then 1/1 (-160 mL)).
2i: 1 H NMR(400MHz,CDCl 3 )δ＝11.15(brs,1H,COOH),4.13(s,2H,CH 2 ),3.56(t,J＝6.6Hz,2H,CH 2 ),1.63(quintet,J＝7.0Hz,2H,CH 2 ),1.45-1.17(m,6H,3 x CH 2 ),0.89(t,J＝6.8Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝175.7,72.0,67.6,31.4,29.2,25.4,22.4,13.8.
Example 10
Figure BDA0003003253570000111
The procedure is as in example 1, step I,1j (0.14mL, d =1.001g/mL,98% throughput, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol), DCE (4 mL) for 36 h afforded 2j (146.9mg, 97%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 2/1 (. About.150 mL)).
The procedure is as in example 1, step II,1j (0.14mL, d =1.001g/mL,98% throughput, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.5mg, 0.1mmol), DCE (2 mL) for 12 hours gave a pale yellow solid 2j (150.1mg, 99%) (eluent: petroleum ether/ethyl acetate =20/1 (. About.100 mL) to 10/1 (. About.220 mL), then 5/1 (. About.120 mL)).
2j: 1 H NMR(400MHz,CDCl 3 )δ＝11.86(brs,1H,COOH),7.33-7.22(m,2H,Ar-H),7.22-7.07(m,3H,Ar-H),2.93(t,J＝7.8Hz,2H,CH 2 ),2.65(t,J＝8.0Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝179.6,140.0,128.4,128.1,126.3,35.5,30.4.
Example 11
Figure BDA0003003253570000112
The same procedure as in 1, step I,1k (206.6mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give 2k (193.4mg, 89%) as a pale yellow solid (9% aldehyde in the crude product as monitored by nuclear magnetic monitoring) (eluent: petroleum ether/ethyl acetate =10/1 (-160 mL) to 2/1 (-300 mL)).
2k m.p.105.2-106.1 ℃ (petroleum ether/dichloromethane); 1 H NMR(400MHz,CDCl 3 )δ＝11.02(brs,1H,COOH),7.56(d,J＝8.0Hz,1H,Ar-H),7.32-7.22(m,2H,Ar-H),7.18-7.08(m,1H,Ar-H),3.82(s,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝177.0,133.5,132.8,131.5,129.1,127.6,125.0,41.3；IR(neat,cm -1 ):3250-2400,1698,1474,1444,1345,1298,1239,1197,1165；MS(70eV,EI)m/z(％):216(M + ( 81 Br),8.01),214(M + ( 79 Br),6.99),135(100).
example 12
Figure BDA0003003253570000121
The procedure is as in example 1, step I,1l (128.8mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give 2l (137.7 mg, 97%) of a pale yellow solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 1/1 (. About.200 mL)).
The procedure is as in example 1, step II,1l (128.3 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.6mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (14.0 mg,0.1 mmol), DCE (2 mL) was reacted for 12 hours to give 2l (107.4 mg,71%,94% by volume purity) of a light brown solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 1/1 (. About.120 mL)).
2l: 1 H NMR(400MHz,CDCl 3 ):δ＝11.73(brs,1H,COOH),7.21(dd,J 1 ＝4.4Hz,J 2 ＝2.0Hz,1H,Thiophene-H),6.99-6.87(m,2H,Thiophene-H),3.86(s,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝177.1,134.0,127.2,126.9,125.3,35.0.
Example 13
Figure BDA0003003253570000122
The procedure is as in example 1, step I,1m (102.7mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to obtain a pale yellow liquid 2m (83.0 mg,69%,97% by volume purity) (eluent: petroleum ether/ethyl acetate =3/1 (. About.160 mL) to 1/2 (. About.150 mL)).
The procedure is as in example 1, step II,1m (102.3 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol), DCE (2 mL) for 12 hours gave a pale yellow liquid 2m (65.3 mg, 56%) (eluent: petroleum ether/ethyl acetate =10/1 (. About.160 mL) to 5/1 (. About.120 mL), then 2/1 (. About.180 mL) to 1/1 (. About.200 mL)).
2m: 1 H NMR(400MHz,CDCl 3 ):δ＝10.30(brs,1H,COOH),4.51(dd,J 1 ＝8.4Hz,J 2 ＝5.6Hz,1H,CH),4.04(q,J＝7.3Hz,1H,one proton of CH 2 ),3.95(q,J＝7.2Hz,1H,one proton of CH 2 ),2.41-2.21(m,1H,one proton of CH 2 ),2.18-2.04(m,1H,one proton of CH 2 ),2.02-1.82(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝177.8,76.2,69.5,30.1,25.2.
Example 14
Figure BDA0003003253570000131
The procedure is as in example 1, step I, (S) -1m (104.3mg, 97% punity, 1.0mmol,99% ee), cu (NO) 3 ) 2 ·3H 2 O(24.0mg,0.1mmol)，TEMPO(15.8mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol), DCE (4 mL) for 36 hours gave (S) -2m (87.6 mg, 76%) as a pale yellow liquid (eluent: petroleum ether/ethyl acetate =3/1 (. About.200 mL) to 1/1 (. About.200 mL)).
(S)-2m:[α] D 24 ＝-36.02(c＝1.035,CHCl 3 ) (literature report value: [ alpha ]] D ＝-36.0(c＝1.21,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 ):δ＝10.12(brs,1H,COOH),4.51(dd,J 1 ＝8.4Hz,J 2 ＝5.6Hz,1H,CH),4.11-3.99(m,1H,one proton of CH 2 ),3.99-3.86(m,1H,one proton of CH 2 ),2.43-2.23(m,1H,one proton of CH 2 ),2.19-2.03(m,1H,one proton of CH 2 ),2.04-1.86(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝177.8,76.3,69.5,30.1,25.2；IR(neat,cm -1 ):3400-2400,1722,1449,1352,1277,1198,1175,1071；MS(70eV,EI)m/z(％):71((M-COOH) + ,100).
The ee value of (S) -2m was determined by HPLC by conversion to (S) -2 m'.
NaHCO is added into the flask once 3 (37.9mg, 0.45mmol), (S) -2m (17.6mg, 0.15mmol), bnBr (40.5mg, 98% pure, 0.23mmol), DMF (2.0 mL). After stirring at room temperature for 3 hours, the reaction was quenched with water (5 mL). The mixture was extracted with ether (10mL. Times.3), and the organic phases were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation and the crude product was subjected to silica gel column chromatography to give a yellow liquid (S) -2m "(10.6 mg,34%,99% ee) (eluent: petroleum ether/ethyl acetate =5/1 (-180 mL)).
(S)-2m”： 1 H NMR(400MHz,CDCl 3 )δ＝7.51-7.28(m,5H,Ar-H),5.27-5.03(m,2H,OCH 2 ),4.51(dd,J 1 ＝8.4Hz,J 2 ＝5.2Hz,1H,CH),4.10-3.97(m,1H,one proton of CH 2 ),3.96-3.78(m,1H,one proton of CH 2 ),2.35-2.15(m,1H,one proton of CH 2 ),2.08-1.80(m,3H,one proton of CH 2 and CH 2 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝14.8min,t R (minor)＝17.4min.
Example 15
Figure BDA0003003253570000132
The procedure was as in example 1, step I,1n (138.1mg, 98% by weight, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.7mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give 2n (147.5 mg, 99%) as a pale yellow liquid (eluent: petroleum ether/ethyl acetate =15/1 (. About.160 mL) to 4/1 (. About.250 mL)).
The procedure is as in example 1, step II,1n (139.3mg, 98% pure, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(23.9mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) was reacted for 13 hours to give 2n (140.3mg, 93%) as a pale yellow liquid (4% aldehyde in the crude product as monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =15/1 (. About.160 mL) to 10/1 (. About.270 mL) and then 4/1 (. About.120 mL)).
2n: 1 H NMR(400MHz,CDCl 3 )δ＝11.60(brs,1H,COOH),7.37-7.20(m,5H,Ar-H),3.72(q,J＝7.2Hz,1H,CH),1.49(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝181.1,139.6,128.6,127.5,127.3,45.3,18.0；IR(neat,cm -1 ):3250-2300,1699,1497,1453,1413,1378,1264,1229,1064；MS(70eV,EI)m/z(％):150(M + ,25.84),105(100).
Example 16
Figure BDA0003003253570000141
The procedure was as in example 1, step I, (S) -1n (137.0 mg,1.0mmol,99% ee), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 40 hours to give (S) -2n (143.1mg, 95%,99% ee) as a pale yellow liquid (eluent: petroleum ether/ethyl acetate =15/1 (. About.160 mL) to 4/1 (. About.250 mL)).
(S)-2n:HPLC conditions:AD-H column,hexane/i-PrOH＝95/5,1.0mL/min,λ＝214nm,t R (major)＝9.1min,t R (minor)＝8.1min；[α] D 25 ＝+75.64(c＝0.94,CHCl 3 ) (literature report value: [ alpha ]] D 20 ＝+69.2(c＝1.0,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 )δ＝10.63(brs,1H,COOH),7.38-7.17(m,5H,Ar-H),3.71(q,J＝7.2Hz,1H,CH),1.49(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝181.0,139.7,128.6,127.5,127.3,45.3,18.0；IR(neat,cm -1 ):3300-2300,1699,1497,1453,1413,1378,1261,1228,1064；MS(70eV,EI)m/z(％):150(M + ,25.05),105(100).
Example 17
Figure BDA0003003253570000142
The procedure is as in example 1, step I,1o (89.2mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(15.8mg,0.1mmol)，KHSO 4 (14.0 mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give 2o (99% yield with dibromomethane as an internal standard, NMR).
Example 18
Figure BDA0003003253570000151
The procedure is as in example 1, step I,1p (113.8mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(23.9mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give 2p (120.4mg, 94%) (eluent: petroleum ether/ethyl acetate =20/1 (. About.310 mL) to 1/1 (. About.200 mL)) as a pale yellow liquid.
The procedure is as in example 1, step II,1p (114.9mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.7mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) for 12 hours to give 2p (121.4mg, 94%) as a pale yellow liquid (eluent: petroleum ether/ethyl acetate)Ester =20/1 (-310 mL) to 2/1 (-180 mL)).
2p: 1 H NMR(400MHz,CDCl 3 )δ＝11.43(brs,1H,COOH),2.33(tt,J 1 ＝11.2Hz,J 2 ＝3.7Hz,1H,CH),1.99-1.85(m,2H,CH 2 ),1.82-1.68(m,2H,CH 2 ),1.68-1.55(m,1H,one proton of CH 2 ),1.54-1.37(m,2H,CH 2 ),1.36-1.15(m,3H,CH 2 and one proton of CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝182.8,42.9,28.7,25.6,25.3.
Example 19
Figure BDA0003003253570000152
The procedure is as in example 1, step I,1q (167.4 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) reacted for 72 hours to give 2q (161.1mg, 89%) of a white solid (6% aldehyde in the crude product as monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =20/1 (. About.210 mL) to 10/1 (. About.110 mL) and then 5/1 (. About.120 mL)).
The procedure is as in example 1, step II,1q (167.5 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (2 mL) was reacted for 12 hours to give 2q (147.9mg, 81%) of a white solid (11% aldehyde in the crude product as monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =20/1 (-210 mL) to 10/1 (-220 mL), then 5/1 (-120 mL), ethyl acetate (150 mL).
2q, m.p.172.0-175.4 ℃ (melting point is directly measured without recrystallization in all solvents); 1 H NMR(400MHz,CDCl 3 )δ＝11.85(brs,1H,COOH),2.09-1.97(m,3H,3 x CH),1.96-1.82(m,6H,3 x CH 2 ),1.78-1.59(m,6H,3 x CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝184.6,40.5,38.5,36.4,27.8；IR(neat,cm -1 ):3250-2400,1687,1450,1409,1324,1281,1252,1183,1084；MS(70eV,EI)m/z(％):180(M + ,10.28),135(100).
example 20
Figure BDA0003003253570000161
The procedure is as in example 1, step I,3a (154.3 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 36 h to give 4a as a pale yellow solid (145.4 mg, 87%) (eluent: petroleum ether/ethyl acetate =5/1 (. About.120 mL), ethyl acetate (200 mL)). 4a: 1 H NMR(400MHz,CD 3 OD)δ＝8.32(d,J＝8.4Hz,2H,Ar-H),8.23(d,J＝8.8Hz,2H,Ar-H)； 13 C NMR(100MHz,CD 3 OD):δ＝167.6,152.0,137.6,131.9,124.5.
example 21
Figure BDA0003003253570000162
The procedure is as in example 1, step I,3b (176.1mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 37 hours to give 4b (153.5mg, 81%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.120 mL) to 1/1 (. About.300 mL)).
4b: 1 H NMR(400MHz,DMSO-d 6 )δ＝13.49(brs,1H,COOH),8.18(d,J＝8.0Hz,2H,Ar-H),7.88(d,J＝8.4Hz,2H,Ar-H)； 13 C NMR(100MHz,DMSO-d 6 ):δ＝166.3,134.7,132.6(q,J＝31.9Hz),130.1,125.6(q,J＝3.7Hz),123.8(q,J＝271.0Hz)； 19 F NMR(376MHz,DMSO-d 6 ):δ＝–61.5.
Example 22
Figure BDA0003003253570000163
The procedure was as in example 1, step I,3c (170.0 mg,98% to purity,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(25.4mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol) and DCE (4 mL) were reacted for 60 hours to give 4c (154.3 mg,85%) as a white solid (6% aldehyde in the crude product monitored by nuclear magnetism) (eluent: petroleum ether/Ethyl acetate =10/1 (-160 mL) to 5/1 (-120 mL) and then 1/1 (-400 mL)).
4c: 1 H NMR(400MHz,DMSO-d 6 )δ＝13.36(brs,1H,COOH),8.18-7.86(m,4H,Ar-H),3.90(s,3H,OCH 3 )； 13 C NMR(100MHz,DMSO-d 6 ):δ＝166.6,165.6,134.8,133.2,129.6,129.4,52.4.
Example 23
Figure BDA0003003253570000171
The procedure was as in example 1, step I,3d (242.0 mg,97% by weight, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(26.5mg,0.1mmol)，TEMPO(16.4mg,0.1mmol)，KHSO 4 (14.0 mg,0.1 mmol), DCE (4 mL) was reacted for 96 hours to give 4d (216.9 mg, 87%) as a pale yellow solid (4% aldehyde in the crude product monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =10/1 (-160 mL) to 5/1 (-120 mL), then 2/1 (-450 mL)).
4d: 1 H NMR(400MHz,DMSO-d 6 )δ＝13.13(brs,1H,COOH),7.90(d,J＝8.0Hz,2H,Ar-H),7.21(d,J＝8.0Hz,2H,Ar-H)； 13 C NMR(100MHz,DMSO-d 6 ):δ＝166.9,137.6,131.1,130.3,101.1.
Example 24
Figure BDA0003003253570000172
The procedure was as in example 1, step I,3e (236.0 mg,98% by weight, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 96 hours to give 4e (181.9mg, 74%) as a white solid (16% aldehyde in the crude product as monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =15/1 (. About.1) (. Sup.60 mL) to 5/1 (. About.120 mL), then 1/1 (. About.200 mL)).
4e, m.p.185.8-186.4 ℃ (petroleum ether/ethyl acetate) (reported in literature values: m.p.184-185 ℃ (isopropanol)); 1 H NMR(400MHz,CD 3 OD)δ＝8.34(s,1H,Ar-H),8.00(d,J＝8.0Hz,1H,Ar-H),7.92(d,J＝8.0Hz,1H,Ar-H),7.24(t,J＝7.8Hz,1H,Ar-H)； 13 C NMR(100MHz,CD 3 OD):δ＝168.0,142.8,139.6,133.9,131.3,129.9,94.4；IR(neat,cm -1 ):3100-2250,1677,1587,1561,1428,1411,1295,1260,1170,1058；MS(70eV,EI)m/z(％):248(M + ,100).
example 25
Figure BDA0003003253570000181
The procedure was as in example 1, step I,3f (238.5 mg,98% by weight, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.5mg, 0.1mmol), DCE (4 mL) was reacted for 96 hours to give 4f (99.9mg, 40%) as a white solid (32% aldehyde in the crude product as monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =20/1 (. About.100 mL) to 4/1 (. About.250 mL) and then 2/1 (. About.150 mL)).
4f, m.p.161.0-162.2 ℃ (petroleum ether/ethyl acetate); 1 H NMR(400MHz,CD 3 OD)δ＝8.00(d,J＝7.6Hz,1H,Ar-H),7.79(dd,J 1 ＝7.8Hz,J 2 ＝1.4Hz,1H,Ar-H),7.44(td,J 1 ＝7.6Hz,J 2 ＝0.5Hz,1H,Ar-H),7.18(td,J 1 ＝7.6Hz,J 2 ＝1.6Hz,1H,Ar-H)； 13 C NMR(100MHz,CD 3 OD):δ＝170.0,142.3,137.7,133.5,131.6,129.0,94.2；IR(neat,cm -1 ):3200-2300,1670,1579,1560,1464,1401,1293,1250,1145,1012；MS(70eV,EI)m/z(％):248(M + ,100).
example 26
Figure BDA0003003253570000182
The procedure was as in step I of example 1,3g(125.1mg,1.0mmol)，Cu(NO 3 ) 2 ·3H 2 O(24.6mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 96 hours to give 4g (89.8 mg, 66%) of a pale yellow solid (32% aldehyde in the crude product monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =10/1 (. About.160 mL) to 1/1 (. About.200 mL)).
4g: 1 H NMR(400MHz,CDCl 3 )δ＝11.42(brs,1H,COOH),8.01(d,J＝8.0Hz,2H,Ar-H),7.27(d,J＝8.0Hz,2H,Ar-H),2.43(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝172.5,144.6,130.2,129.2,126.6,21.7.
Example 27
Figure BDA0003003253570000183
The procedure was as in example 1, step I,3h (140.7mg, 98% purity, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 96 h to give a white solid (85.1 mg, 56%) (43% aldehyde was monitored by nuclear magnetism in the crude product) (eluent: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 2/1 (. About.300 mL)).
4h: 1 H NMR(400MHz,CDCl 3 )δ＝12.32(brs,1H,COOH),7.73(d,J＝7.6Hz,1H,Ar-H),7.63(s,1H,Ar-H),7.38(t,J＝8.0Hz,1H,Ar-H),7.16(dd,J 1 ＝8.0Hz,J 2 ＝2.0Hz,1H,Ar-H),3.86(s,3H,OCH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝172.4,159.6,130.5,129.5,122.7,120.5,114.4,55.4.
Example 28
Figure BDA0003003253570000191
The procedure is as in example 1, step I,5a (168.7mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，
TEMPO(16.2mg,0.1mmol)，KHSO 4 (14.0mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give white solid 6a (167.4 mg, 92%) (eluent: petroleum ether/ethyl acetate =10/1 (-160 mL) to 1/1 (-200 mL)).
6a: 1 H NMR(400MHz,CDCl 3 )δ＝11.68(brs,1H,COOH),2.35(t,J＝7.6Hz,2H,CH 2 ),2.18(td,J 1 ＝7.0Hz,J 2 ＝2.7Hz,2H,CH 2 ),1.94(t,J＝2.6Hz,1H,CH),1.63(quintet,J＝7.3Hz,2H,CH 2 ),1.52(quintet,J＝7.2Hz,2H,CH 2 ),1.47-1.11(m,8H,4 x CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.5,84.6,68.1,34.0,29.0,28.9,28.8,28.5,28.3,24.5,18.3.
Example 29
Figure BDA0003003253570000192
The procedure was as in example 1, step I,5b (114.4 mg,97% pure, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give a pale yellow liquid 6b (117.0mg, 94%) (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 2/1 (. About.150 mL)). 6b: 1 H NMR(400MHz,CDCl 3 )δ＝11.67(brs,1H,COOH),2.40(t,J＝7.4Hz,2H,CH 2 ),2.51(td,J 1 ＝6.9Hz,J 2 ＝2.5Hz,2H,CH 2 ),1.97(t,J＝2.6Hz,1H,CH),2.40(quintet,J＝7.6Hz,2H,CH 2 ),2.40(quintetq,J＝7.4Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.1,83.7,68.7,33.4,27.6,23.6,18.0；IR(neat,cm -1 ):3296,3200-2250,2117,1702,1456,1412,1332,1289,1233,1147；MS(ESI)m/z:127(M+H) + .
example 30
Figure BDA0003003253570000201
The procedure is as in example 1, step I,5c (84.2mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give 6c (74.0mg, 75%) as a white solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 1/1 (. About.120 mL)).
6c: 1 H NMR(400MHz,CDCl 3 )δ＝11.60(brs,1H,COOH),2.62(t,J＝7.2Hz,2H,CH 2 ),2.57-2.38(m,2H,CH 2 ),2.01(s,1H,CH)； 13 C NMR(100MHz,CDCl 3 ):δ＝178.3,82.0,69.2,33.1,14.0.
Example 31
Figure BDA0003003253570000202
The procedure is as in example 1, step I,5d (127.8mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(19.0mg,0.12mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 36 hours to give yellow liquid 6d (117.5mg, 83%) (eluent: petroleum ether/diethyl ether =4/1 (. About.250 mL) to 1/1 (. About.200 mL)).
6d: 1 H NMR(400MHz,CDCl 3 )δ＝10.90(brs,1H,COOH),0.26(s,9H,3 x CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝157.6,97.2,93.9,-1.1.
Example 32
Figure BDA0003003253570000203
The operation was identical to that of example 1, step I,5e (127.8mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 42 hours to give 6e (134.9mg, 94%) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 2/1 (. About.150 mL)).
6e, m.p.42.4-43.2 ℃ (petroleum ether); 1 H NMR(400MHz,CDCl 3 )δ＝11.40(brs,1H,COOH),2.38(t,J＝7.4Hz,2H,CH 2 ),2.26-2.07(m,2H,CH 2 ),1.86-1.65(m,5H,CH 3 and CH 2 ),1.53(quintet,J＝7.2Hz,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.2,78.4,75.9,33.6,28.2,23.8,18.3,3.4；IR(neat,cm -1 ):3250-2400,1689,1457,1438,1413,1316,1295,1245,1147；MS(ESI)m/z:141(M+H) + .
example 33
Figure BDA0003003253570000211
The procedure is as in example 1, step I,5f (75.4 mg,0.5 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(20.1mg,0.125mmol)，KHSO 4 (13.7mg, 0.1mmol) and DCE (2 mL) for 29 h to give yellow liquid 6f (70.8mg, 86%) (eluent: petroleum ether/ethyl acetate =5/1 (-300 mL) to 2/1 (-210 mL)).
6f: 1 H NMR(400MHz,CDCl 3 )δ＝10.45(brs,1H,COOH),3.15(q,J＝2.4Hz,2H,CH 2 ),2.38(t,J＝7.4Hz,2H,CH 2 ),2.20(tt,J 1 ＝6.9Hz,J 2 ＝2.4Hz,2H,CH 2 ),2.07(t,J＝2.6Hz,1H,CH),1.82-1.67(m,2H,CH 2 ),1.64-1.47(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝179.9,80.4,78.7,73.6,68.4,33.5,27.8,23.7,18.3,9.5；IR(neat,cm -1 ):3293,3300-2800,1703,1458,1413,1311,1289,1233,1148；MS(ESI)m/z:163(M-H) - .
Example 34
Figure BDA0003003253570000212
The procedure is as in example 1, step I,5g (111.1mg, 0.5mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(24.1mg,0.15mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) was reacted for 49 hours to give 6g (92.6mg, 78%) of a yellow liquid (eluent: petroleum ether/ethyl acetate =5/1 (. About.240 mL) to 3/1 (. About.200 mL)).
6g: 1 H NMR(400MHz,CDCl 3 )δ＝3.18(t,J＝2.4Hz,2H,CH 2 ),2.38(t,J＝7.6Hz,2H,CH 2 ),2.20(tt,J 1 ＝6.9Hz,J 2 ＝2.4Hz,2H,CH 2 ),1.79-1.68(m,2H,CH 2 ),1.62-1.51(m,2H,CH 2 ),0.16(s,9H,3 x CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.0,100.6,84.7,80.2,73.9,33.5,27.8,23.7,18.4,10.8,-0.1；IR(neat,cm -1 ):3150-2750,2182,1707,1412,1308,1291,1249,1149；MS(ESI)m/z:235(M-H) - ；HRMS calcd m/z for C 13 H 21 O 2 Si[M+H] + :237.1305,found 237.1302.
Example 35
Figure BDA0003003253570000213
The procedure is as in example 1, step I,5h (76.0 mg,0.5 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(23.8mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (2 mL) was reacted for 49 hours to give 6h (yield 67% with dibromomethane as an internal standard and nuclear magnetic monitoring). The crude product was placed in a flask for 6h, and THF/MeOH (6.0 mL, 3. Then add TMSCHN to the flask 2 (0.4mL, 2.0M in hexane, 0.8mmol). The reaction was stirred at room temperature for 1 hour with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After rotary evaporation of the solvent, a pale yellow liquid was isolated by silica gel column chromatography for 6h "(48.7 mg, 54%) (13% aldehyde was detected in the crude product by nuclear magnetic monitoring) (eluent: petroleum ether/ethyl acetate =60/1 (. About.300 mL)).
6h”: 1 H NMR(400MHz,CDCl 3 )δ＝5.88-5.75(m,1H,＝CH),5.30(dq,J 1 ＝16.9Hz,J 2 ＝1.8Hz,1H,one proton of＝CH 2 ),5.09(dq,J 1 ＝9.9Hz,J 2 ＝1.7Hz,1H,one proton of＝CH 2 ),3.67(s,3H,OCH 3 ),3.00-2.85(m,2H,CH 2 ),2.34(t,J＝7.6Hz,2H,CH 2 ),2.22(tt,J 1 ＝7.0Hz,J 2 ＝2.3Hz,2H,CH 2 ),1.82-1.66(m,2H,CH 2 ),1.62-1.48(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝173.9,133.2,115.6,82.0,76.9,51.4,33.5,28.3,24.1,23.0,18.4；IR(neat,cm -1 ):2949,2866,1737,1642,1436,1363,1172,1149；MS(ESI)m/z:181(M+H) + ,203(M+Na) + ；HRMS calcd m/z for C 11 H 17 O 2 [M+H] + :181.1223,found 181.1221.
Example 36
Figure BDA0003003253570000221
The procedure was as in example 1, step I, (R) -7a (257.9mg, 1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) for 24 h to give (R) -8a (250.9mg, 92%) as a white solid (eluent: petroleum ether/acetone =3/1 (-200 mL) to 1/1 (-250 mL)). (R) -8a [ m.p.146.7-147.5 ℃ (petroleum ether/acetone); [ alpha ] to] D 26 ＝-4.49(c＝0.99,CHCl 3 )； 1 H NMR(400MHz,CD 3 OD)δ＝7.72(d,J＝8.4Hz,2H,Ar-H),7.32(d,J＝8.0Hz,2H,Ar-H),3.62(d,J＝5.6Hz,1H,CH),2.40(s,3H,CH 3 ),2.01(sextet,J＝6.6Hz,1H,CH),0.94(d,J＝6.4Hz,3H,CH 3 ),0.88(d,J＝6.8Hz,3H,CH 3 )； 13 C NMR(100MHz,CD 3 OD):δ＝174.3,144.5,139.1,130.5,128.2,62.7,32.4,21.4,19.6,18.1；IR(neat,cm -1 ):3291,3200-2400,1705,1597,1464,1331,1288,1159,1088；MS(70eV,EI)m/z(％):226((M-COOH) + ,80.18),91(100).
The ee value of (R) -8a was determined by HPLC by conversion to (R) -8 a'.
The crude product (R) -8a (54.5mg, 0.2mmol) was placed in a flask, and THF/MeOH (4.0 mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL) and then with saturated sodium carbonate solutionAnd saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, white solid (R) -8a "(42.9mg, 75%,>99% ee) (eluent: petroleum ether/ethyl acetate =4/1 (250 mL)).
(R)-8a”: 1 H NMR(400MHz,CDCl 3 )δ＝7.71(d,J＝8.0Hz,2H,Ar-H),7.28(d,J＝8.0Hz,2H,Ar-H),5.10(d,J＝10.0Hz,1H,NH),3.73(q,J＝5.1Hz,1H,CH),3.44(s,3H,OCH 3 ),2.41(s,3H,CH 3 ),2.02(sextet,J＝6.5Hz,1H,CH),0.95(d,J＝6.8Hz,3H,CH 3 ),0.87(d,J＝6.8Hz,3H,CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝95/5,0.5mL/min,λ＝214nm,t R (major)＝43.8min.
Example 37
Figure BDA0003003253570000231
The procedure was as in example 1, step I, (S) -7a (258.4 mg,1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(23.9mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 24 hours to give (S) -8a (239.3mg, 92%) as a white solid (eluent: petroleum ether/acetone =3/1 (. About.200 mL) to 1/1 (. About.200 mL)). (S) -8a (m.p.146.8-147.5 ℃ (petroleum ether/acetone) (literature report: m.p.146.4-147.7 ℃ (water)); [ alpha ] to] D 27 ＝+4.14(c＝1.00,CHCl 3 ) (literature report value: [ alpha ]] D 25 ＝+17.1(c＝2.23,CHCl 3 ))； 1 H NMR(400MHz,CD 3 OD)δ＝7.72(d,J＝8.0Hz,2H,Ar-H),7.32(d,J＝8.0Hz,2H,Ar-H),3.62(d,J＝5.6Hz,1H,CH),2.39(s,3H,CH 3 ),2.01(sextet,J＝6.6Hz,1H,CH),0.94(d,J＝6.8Hz,3H,CH 3 ),0.88(d,J＝6.8Hz,3H,CH 3 )； 13 C NMR(100MHz,CD 3 OD):δ＝174.3,144.5,139.1,130.5,128.2,62.7,32.4,21.4,19.6,18.1；IR(neat,cm -1 ):3291,3150-2350,1703,1597,1464,1331,1288,1159,1088；MS(70eV,EI)m/z(％):226((M-COOH) + ,87.14),91(100).
The ee value of (S) -8a was determined by HPLC by conversion to (S) -8 a'.
The crude product (S) -8a (54.2mg, 0.2mmol) was placed in a flask and THF/MeOH (4.0 mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, white solid (S) -8a "(40.3mg, 71%,>99% ee) (eluent: petroleum ether/ethyl acetate =4/1 (250 mL)).
(S)-8a”: 1 H NMR(400MHz,CDCl 3 )δ＝7.71(d,J＝8.0Hz,2H,Ar-H),7.28(d,J＝8.4Hz,2H,Ar-H),5.13(d,J＝10.0Hz,1H,NH),3.73(q,J＝5.1Hz,1H,CH),3.44(s,3H,OCH 3 ),2.41(s,3H,CH 3 ),2.02(sextet,J＝6.5Hz,1H,CH),0.95(d,J＝6.8Hz,3H,CH 3 ),0.87(d,J＝6.8Hz,3H,CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝95/5,0.5mL/min,λ＝214nm,t R (major)＝46.5min.
Example 38
Figure BDA0003003253570000241
The procedure was as in example 1, step I, (R) -7b (311.6 mg,1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(24.7mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol), DCE (4 mL) for 24 hours to give (R) -8b (313.7 mg,96%) (eluent: petroleum ether/ethyl acetate =3/1 (-200 mL) to 1/1 (-300 mL)).
(R) -8b; [ alpha ] to] D 27 ＝+9.28(c＝1.00,CHCl 3 ) (literature report value: [ alpha ]] D 27 ＝+12.3,(c＝1.00,acetone))； 1 H NMR(400MHz,CD 3 OD)δ＝7.54(d,J＝7.6Hz,2H,Ar-H),7.28-7.00(m,7H,Ar-H),4.00(t,J＝6.8Hz,1H,CH),3.02(dd,J 1 ＝13.6Hz,J 2 ＝5.6Hz,1H,one proton of CH 2 ),2.83(dd,J 1 ＝13.4Hz,J 2 ＝8.2Hz,1H,one proton of CH 2 ),2.38(s,3H,CH 3 )； 13 C NMR(100MHz,CD 3 OD):δ＝174.3,144.4,139.0,137.7,130.5,130.4,129.3,128.0,127.7,58.7,39.8,21.4；IR(neat,cm -1 ):3318,3200-2800,1709,1597,1388,1328,1273,1159,1088；MS(70eV,EI)m/z(％):274((M-COOH) + ,228((M-Bn) + ,11.45),5.60),91(100).
The ee value of (R) -8b was determined by HPLC by conversion to (R) -8 b'.
The crude (R) -8b (64.5mg, 0.2mmol) was placed in a flask and THF/MeOH (4.0 mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, white solid (R) -8b "(52.1mg, 77%,>99% ee) (eluent: petroleum ether/ethyl acetate =4/1 (250 mL)).
(R)-8b”: 1 H NMR(400MHz,CDCl 3 )δ＝7.63(d,J＝8.0Hz,2H,Ar-H),7.33-7.14(m,5H,Ar-H),7.12-6.97(m,2H,Ar-H),5.17(s,1H,NH),4.20(t,J＝6.0Hz,1H,CH),3.48(s,3H,OCH 3 ),3.09-2.91(m,2H,CH 2 ),2.39(s,3H,CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝80/20,1.0mL/min,λ＝214nm,t R (major)＝18.4min.
Example 39
Figure BDA0003003253570000242
The procedure was as in example 1, step I, (S) -7b (305.4mg, 1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(23.9mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.7mg, 0.1mmol) and DCE (4 mL) for 24 h to give (S) -8b (294.7mg, 96%) as a white solid (eluent: petroleum ether/Ethyl acetate)And (c) =3/1 (-200 mL) to 1/1 (-200 mL)).
(S) -8b (m.p.150.8-151.5 ℃ (petroleum ether/ethyl acetate) (reported in the literature: m.p.150.4-152.9 ℃ (water)); [ alpha ] to] D 27 ＝-10.75(c＝1.02,CHCl 3 ) (literature report value: [ alpha ]] D 27 ＝-11.8,(c＝1.00,acetone))； 1 H NMR(400MHz,CD 3 OD)δ＝7.54(d,J＝8.0Hz,2H,Ar-H),7.30-7.00(m,7H,Ar-H),4.02(t,J＝6.8Hz,1H,CH),3.02(dd,J 1 ＝14.0Hz,J 2 ＝5.6Hz,1H,one proton of CH 2 ),2.84(dd,J 1 ＝13.8Hz,J 2 ＝8.2Hz,1H,one proton of CH 2 ),2.37(s,3H,CH 3 )； 13 C NMR(100MHz,CD 3 OD):δ＝174.3,144.4,139.1,137.8,130.5,130.4,129.4,128.0,127.7,58.7,39.9,21.4；IR(neat,cm -1 ):3319,3200-2800,1709,1694,1597,1388,1328,1274,1159,1088；MS(70eV,EI)m/z(％):274((M-COOH) + ,5.97),228((M-Bn) + ,11.95),91(100).
The ee value of (S) -8b was determined by HPLC by conversion to (S) -8 b'.
The crude product (S) -8b (63.8mg, 0.2mmol) was placed in a flask and THF/MeOH (4.0 mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, white solid (S) -8b "(57.5mg, 86%,>99% ee) (eluent: petroleum ether/ethyl acetate =4/1 (250 mL)).
(S)-8b”: 1 H NMR(400MHz,CDCl 3 )δ＝7.63(d,J＝8.4Hz,2H,Ar-H),7.30-7.14(m,5H,Ar-H),7.13-6.97(m,2H,Ar-H),5.17(d,J＝9.2Hz,1H,NH),4.20(dt,J 1 ＝11.1Hz,J 2 ＝4.6Hz,1H,CH),3.48(s,3H,OCH 3 ),3.10-2.94(m,2H,CH 2 ),2.39(s,3H,CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝80/20,1.0mL/min,λ＝214nm,t R (major)＝37.1min.
Example 40
Figure BDA0003003253570000251
The procedure is as in example 1, step I, (R) -7c (251.4mg, 1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.7 mg,0.1 mmol), DCE (4 mL) was reacted for 17 hours to give (R) -8c (257.4 mg, 97%) as a yellow liquid (eluent: petroleum ether/ethyl acetate =3/1 (. About.200 mL) to 1/1 (. About.300 mL)).
(R)-8c:[α] D 25 ＝-21.75(c＝1.21,CHCl 3 ) (literature report value: [ alpha ]] D 25 ＝-24.8(c＝1.00,EtOH))； 1 H NMR(400MHz,CD 3 Cl,rotamers present)δ＝11.44(brs,1H,COOH),7.38-7.07(m,5H,Ar-H),[6.65(d,J＝7.2Hz,0.40H),5.10(d,J＝8.0Hz,0.54H),1H,NH],[4.70-4.56(m,0.55H),4.57-4.30(m,0.41H),1H,CH],3.28-3.11(m,1H,one proton of CH 2 ),[3.07(dd,J 1 ＝13.6Hz,J 2 ＝6.0Hz,0.58H),2.95-2.80(m,0.41H),1H,one proton of CH 2 ],[1.41(s,5H),1.29(s,4H),9H,3 x CH 3 ]； 13 C NMR(100MHz,CD 3 Cl,rotamers present):δ＝176.1,175.8,156.6,155.3,136.4,135.8,129.34,129.29,128.4,126.9,126.8,81.5,80.1,56.0,54.1,38.9,37.7,28.1,27.8；IR(neat,cm -1 ):2980,3200-2800,1713,1663,1497,1395,1368,1159,1052；MS(70eV,EI)m/z(％):265(M + ,0.36),164((M-Boc) + ,9.64),57(100).
The ee value of (R) -8c was determined by HPLC by conversion to (R) -8 c'.
The crude product (R) -8c (57.2mg, 0.2mmol) was placed in a flask and THF/MeOH (4.0 mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, a pale yellow liquid (R) -8c "(42.3mg, 70%,>99％ee) (eluent: petroleum ether/ethyl acetate =4/1 (120 mL)).
(R)-8c”: 1 H NMR(400MHz,CD 3 Cl,rotamers present)δ＝7.37-7.19(m,3H,Ar-H),7.18-7.07(m,2H,Ar-H),[5.13-4.86(m,0.85H),4.84-4.68(m,0.14H),1H,NH],[4.65-4.47(m,0.85H),4.46-4.32(m,0.14H),1H,CH],3.81-3.60(m,3H,OCH 3 ),3.19-2.88(m,2H,CH 2 ),1.41(s,9H,3 x CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝5.6min.
Example 41
Figure BDA0003003253570000261
The procedure was as in example 1, step I, (S) -7c (252.4mg, 1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 17 hours to give (S) -8c (246.4mg, 93%) as a yellow liquid (eluent: petroleum ether/ethyl acetate =3/1 (. About.200 mL) to 1/1 (. About.300 mL)).
(S)-8c:[α] D 26 ＝+21.98(c＝1.06,CHCl 3 ) (literature report value: [ alpha ]] D 25 ＝+24.9(c＝1.20,EtOH))； 1 H NMR(400MHz,CD 3 Cl,rotamers present)δ＝11.39(brs,1H,COOH),7.42-7.03(m,5H,Ar-H),[6.63(d,J＝7.2Hz,0.38H),5.06(d,J＝8.0Hz,0.53H),1H,NH],[4.70-4.57(m,0.55H),4.48-4.32(m,0.39H),1H,CH],3.28-3.12(m,1H,one proton of CH 2 ),[3.07(dd,J 1 ＝13.8Hz,J 2 ＝6.2Hz,0.58H),2.95-2.80(m,0.38H),1H,one proton of CH 2 ],[1.41(s,5H),1.29(s,4H),9H,3 x CH 3 ]； 13 C NMR(100MHz,CD 3 Cl,rotamers present):δ＝176.3,176.0,156.6,155.3,136.4,135.8,129.4,129.3,128.5,126.9,126.9,81.6,80.2,56.1,54.2,39.0,37.7,28.2,27.9；IR(neat,cm -1 ):2979,3200-2800,1713,1662,1497,1395,1368,1159,1052；MS(70eV,EI)m/z(％):265(M + ,0.57),164((M-Boc) + ,10.47),57(100).
The ee value of (S) -8c was determined by HPLC by conversion to (S) -8 c'.
The crude product (S) -8c (42.3mg, 0.16mmol) was placed in a flask and THF/MeOH (4.0 mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, a pale yellow liquid (S) -8c "(36.9mg, 83%,>99% ee) (eluent: petroleum ether/ethyl acetate =4/1 (120 mL)).
(S)-8c”: 1 H NMR(400MHz,CD 3 Cl,rotamers present)δ＝7.40-7.19(m,3H,Ar-H),7.18-7.04(m,2H,Ar-H),[5.13-4.87(m,0.84H),4.82-4.68(m,0.14H),1H,NH],[4.68-4.20(m,0.83H),4.45-4.29(m,0.13H),1H,CH],3.71(s,3H,OCH 3 ),3.26-2.75(m,2H,CH 2 ),1.41(s,9H,3 x CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝6.1min.
Example 42
Figure BDA0003003253570000271
The procedure was as in example 1, step I, (R) -7d (285.2mg, 1.0mmol,99% ee), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) for 22 hours to give (R) -8d as a pale yellow liquid (269.7mg, 90%,>99% ee) (eluent: petroleum ether/ethyl acetate =3/1 (-200 mL) to 1/1 (-300 mL)).
(R)-8d:HPLC conditions:AD-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝18.1min；[α] D 31 ＝-31.24(c＝0.895,CHCl 3 )； 1 H NMR(400MHz,CD 3 Cl,rotamers present)δ＝10.59(brs,1H,COOH),7.60-7.18(m,8H,Ar-H),7.13(d,J＝6.8Hz,2H,Ar-H),[6.33(d,J＝6.8Hz,0.21H),5.27(d,J＝8.0Hz,0.77H),1H,NH],5.15-4.91(m,2H,CH 2 ),[4.77-4.61(m,0.75H),4.57-4.45(m,0.22H),1H,CH],3.28-2.87(m,2H,CH 2 )； 13 C NMR(100MHz,CD 3 Cl,rotamers present):δ＝176.3,176.0,156.6,155.9,136.0,135.7,135.4,129.3,128.6,128.5,128.2,128.1,127.9,127.2,67.6,67.1,55.6,54.6,38.5,37.7；IR(neat,cm -1 ):2960,3200-2800,1713,1515,1497,1375,1345,1213,1049；MS(ESI)m/z:298(M-H) - .
Example 43
Figure BDA0003003253570000281
The procedure was as in example 1, step I, (S) -7d (285.7mg, 1.0mmol; 99% ee), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol) and DCE (4 mL) were reacted for 22 hours to give (S) -8d (277.7mg, 93%,>99% ee) (eluent: petroleum ether/ethyl acetate =3/1 (-200 mL) to 1/1 (-300 mL)).
(S)-8d:HPLC conditions:AD-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝22.7min；[α] D 31 ＝+33.76(c＝0.85,CHCl 3 )； 1 H NMR(400MHz,CD 3 Cl,rotamers present)δ＝11.14(brs,1H,COOH),7.40-7.15(m,8H,Ar-H),7.12(d,J＝7.2Hz,2H,Ar-H),[6.45(d,J＝7.2Hz,0.23H),5.34(d,J＝8.0Hz,0.75H),1H,NH],5.16-4.90(m,2H,CH 2 ),[4.75-4.60(m,0.74H),4.58-4.40(m,0.25H),1H,CH],3.27-2.84(m,2H,CH 2 )； 13 C NMR(100MHz,CD 3 Cl,rotamers present):δ＝176.1,175.9,156.7,155.9,136.0,135.7,135.5,129.3,128.5,128.4,128.1,128.0,127.9,127.1,67.6,67.1,55.6,54.6,38.4,37.6；IR(neat,cm -1 ):2945,3200-2800,1712,1515,1497,1375,1345,1157,1048；MS(ESI)m/z:298(M-H) - .
Example 44
Figure BDA0003003253570000282
The procedure is as in example 1, step I,7e (229.3 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.7mg, 0.1mmol), DCE (4 mL) for 16 h to give 8e (211.0 mg, 87%) as a white solid (eluent: petroleum ether/Ethyl acetate =5/1 (-180 mL) to 1/1 (-200 mL)).
8e, m.p.138.3-139.4 ℃ (petroleum ether/acetone) (literature report value: m.p.138-139 ℃ (water)); 1 H NMR(400MHz,CD 3 OD)δ＝7.73(d,J＝8.4Hz,2H,Ar-H),7.34(d,J＝8.0Hz,2H,Ar-H),3.88(q,J＝7.1Hz,1H,CH),2.40(s,3H,CH 3 ),1.29(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CD 3 OD):δ＝
175.4,144.7,139.2,130.6,128.1,52.6,21.4,19.5；IR(neat,cm -1 ):3273,2434,1709,1495,1339,1289,1243,1168,1090；MS(70eV,EI)m/z(％):198((M-COOH) + ,10.28),91(100).
example 45
Figure BDA0003003253570000291
The procedure was as in example 1, step I, (S) -7e (229.9mg, 1.0mmol,>99％ee)，Cu(NO 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 12 hours to give (S) -8e (205.7mg, 84%) as a white solid (eluent: petroleum ether/acetone =5/1 (. About.180 mL) to 1/1 (. About.300 mL)). (S) -8e: [ alpha ]] D 26 ＝+0.90(c＝1.005,CHCl 3 ) (ii) a m.p.132.3-133.2 deg.C (petroleum ether/acetone) (reported in literature values: m.p.129-131 deg.C (ethyl acetate)); 1 H NMR(400MHz,CD 3 OD)δ＝7.73(d,J＝8.0Hz,2H,Ar-H),7.34(d,J＝8.0Hz,2H,Ar-H),3.87(q,J＝7.1Hz,1H,CH),2.40(s,3H,CH 3 ),1.28(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CD 3 OD):δ＝175.4,144.7,139.2,130.6,128.1,52.7,21.4,19.5；IR(neat,cm -1 ):3269,3300-2800,1710,1653,1379,1290,1230,1149,1090；MS(70eV,EI)m/z(％):198((M-COOH) + ,10.28),91(100).
the ee values of (S) -8e were determined by HPLC by conversion to (S) -8 e'.
The crude product (S) -8e (49.0 mg, 0.2mmol) was placed in a flask and THF/MeOH (4.0 mL, 3. TMSCHN was then added to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, a pale yellow liquid (S) -8e "(37.0mg, 71%,>99% ee) (eluent: petroleum ether/ethyl acetate =4/1 (250 mL)).
(S)-8e”: 1 H NMR(400MHz,CDCl 3 )δ＝7.73(d,J＝8.4Hz,2H,Ar-H),7.30(d,J＝8.0Hz,2H,Ar-H),5.37(d,J＝8.4Hz,1H,NH),3.99(quintet,J＝7.4Hz,1H,CH),3.54(s,3H,OCH 3 ),2.42(s,3H,CH 3 ),1.38(d,J＝7.2Hz,3H,CH 3 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝24.1min.
Example 46
Figure BDA0003003253570000292
The procedure was as in step I of example 1, (R) -7f (254.9mg, 1.0mmol,99% ee), cu (NO) 3 ) 2 ·3H 2 O(24.5mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol) and DCE (4 mL) were reacted for 25 hours to give (R) -8f (245.7mg, 91%) as a pale yellow liquid (eluent: ethyl acetate (150 mL)).
(R)-8f:[α] D 24 ＝+90.60(c＝1.13,CHCl 3 ) (literature report value: [ alpha ]] D ＝+92.3(c＝1.0,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 )δ＝9.97(brs,1H,COOH),7.76(d,J＝8.0Hz,2H,Ar-H),7.34(d,J＝8.0Hz,2H,Ar-H),4.46-4.21(m,1H,CH),3.60-3.41(m,1H,one proton of CH 2 ),3.35-3.19(m,1H,one proton of CH 2 ),2.43(s,3H,CH 3 ),2.18-1.89(m,3H,one proton of CH 2 and CH 2 ),1.81-1.62(m,1H,one proton of CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝176.9,143.9,134.3,129.7,127.3,60.2,48.5,30.6,24.4,21.3；IR(neat,cm -1 ):3563,3200-2750,1743,1706,1334,1282,1233,1154,1091；MS(70eV,EI)m/z(％):224((M-COOH) + ,97.75),91(100).
The ee of(R)-8fwas determinedby HPLC analysis after being converted to(R)-8f”.
The ee values of (R) -8f were determined by HPLC by conversion to (R) -8f ″.
The crude product (R) -8f (54.4mg, 0.2mmol) was placed in a flask and THF/MeOH (4.0mL, 3. Then add TMSCHN to the flask 2 (0.12mL, 2.0M in hexane, 0.24mmol). The reaction was stirred at room temperature for 4 hours with CH 2 Cl 2 The reaction was quenched (20 mL), washed with saturated sodium carbonate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, a pale yellow liquid (R) -8f "(36.3mg, 63%,>99% ee) (eluent: petroleum ether/ethyl acetate =3/1 (200 mL)).
(R)-8f”: 1 H NMR(400MHz,CDCl 3 )δ＝7.75(d,J＝8.0Hz,2H,Ar-H),7.32(d,J＝8.0Hz,2H,Ar-H),4.34-4.25(m,1H,CH),3.72(s,3H,OCH 3 ),3.54-3.45(m,1H,one proton of CH 2 ),3.37-3.25(m,1H,one proton of CH 2 ),2.43(s,3H,CH 3 ),2.08-1.89(m,3H,one proton of CH 2 and CH 2 ),1.82-1.68(m,1H,one proton of CH 2 )；HPLC conditions:OJ-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R (major)＝36.8min.
Example 47
Figure BDA0003003253570000301
The procedure is as in example 1, step I,9a (217.1mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.3mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) for 41 hours to give 10a as a pale yellow solid (225.6mg, 98%) (eluent: petroleum ether/ethyl acetate =8/1 (-180 mL) to 1/1 (-200 mL)).
10a, m.p.154.4-156.2 ℃ (petroleum ether/dichloromethane); 1 H NMR(400MHz,CDCl 3 )δ＝7.81-7.65(m,3H,Ar-H),7.41(d,J＝8.4Hz,1H,Ar-H),7.18-6.98(m,2H,Ar-H),4.00-3.76(m,4H,CH and OCH 3 ),1.58(d,J＝6.8Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.7,157.7,134.9,133.8,129.3,128.9,127.2,126.2,126.1,119.0,105.6,55.3,45.2,18.1；IR(neat,cm -1 ):3200-2700,1706,1603,1458,1391,1264,1230,1029；MS(70eV,EI)m/z(％):230(M + ,48.9),185(100).
example 48
Figure BDA0003003253570000311
The procedure was as in example 1, step I, (S) -9a (215.2mg, 1.0mmol,98% ee), cu (NO) 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol) and DCE (4 mL) were reacted for 47 hours to give (S) -10a (215.5mg, 94%,99% ee) as a white solid (eluent: petroleum ether/ethyl acetate =5/1 (. About.180 mL) to 1/1 (. About.200 mL)).
(S) -10a, m.p.152.0-153.1 deg.C (petroleum ether/dichloromethane) (literature reported values: m.p.152-154 deg.C (n-hexane/dichloromethane)); HPLC conditions AD-H columns, hexane/i-PrOH =95/5,1.0mL/min, lambda =214nm, t R (major)＝22.2min,t R (minor)＝20.4min；[α] D 25 ＝+66.52(c＝1.08,CHCl 3 ) (literature report value: [ alpha ]] D 26 ＝+64.9(c＝1.8,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 )δ＝7.80-7.60(m,3H,Ar-H),7.40(d,J＝8.4Hz,1H,Ar-H),7.18-7.03(m,2H,Ar-H),4.02-3.78(m,4H,CH and OCH 3 ),1.58(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.8,157.7,134.8,133.8,129.3,128.9,127.2,126.2,126.1,119.0,105.6,55.3,45.2,18.1；IR(neat,cm -1 ):3300-2700,1725,1681,1453,1393,1263,1174,1156；MS(70eV,EI)m/z(％):230(M + ,47.23),185(100).
Example 49
Figure BDA0003003253570000312
The procedure is as in example 1, step I,9b (230.4mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(25.0mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (4 mL) was reacted for 40 hours to give white solid 10b (240.2mg, 98%) (eluent: petroleum ether/ethyl acetate =15/1 (-160 mL) to 4/1 (-250 mL), then 2/1 (-150 mL)).
10b, m.p.112.6-113.7 ℃ (petroleum ether/dichloromethane); 1 H NMR(400MHz,CDCl 3 )δ＝7.60-7.48(m,2H,Ar-H),7.47-7.27(m,4H,Ar-H),7.21-7.04(m,2H,Ar-H),3.78(q,J＝7.1Hz,1H,CH),1.55(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.2,159.7(d,J＝247.3Hz),140.9(d,J＝7.2Hz),135.4,130.9(d,J＝4.0Hz),128.9(d,J＝2.3Hz),128.4,128.1(d,J＝13.5Hz),127.7,123.7(d,J＝4.0Hz),115.4(d,J＝23.7Hz),44.8,18.0； 19 F NMR(376MHz,CDCl 3 ):δ＝-117.9；IR(neat,cm -1 ):3100-2400,1695,1460,1415,1296,1216,1074；MS(70eV,EI)m/z(％):244(M + ,55.23),199(100).
example 50
Figure BDA0003003253570000321
The procedure was as in example 1, step I, (R) -9b (229.4 mg,1.0mmol,98% ee), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.5mg, 0.1mmol), DCE (4 mL) was reacted for 38 hours to give (R) -10b (238.8mg, 98%,99% ee) as a pale yellow solid (eluent: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 3/1 (. About.200 mL), and then 2/1 (. About.150 mL)).
(R) -10b; HPLC conditions AD-H column, hexane/i-PrOH =95/5,1.0mL/min, λ =214nm, t R (major)＝9.2min,t R (minor)＝12.6min；[α] D 27 ＝-45.57(c＝0.98,CHCl 3 ) (literature report value: [ alpha ]] D 25 ＝-46.0(c＝0.90,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 )δ＝10.73(brs,1H,COOH),7.52(d,J＝7.6Hz,2H,Ar-H),7.47-7.26(m,4H,Ar-H),7.20-7.04(m,2H,Ar-H),3.77(q,J＝7.1Hz,1H,CH),1.55(d,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.4,159.7(d,J＝247.3Hz),140.9(d,J＝7.9Hz),135.4,130.9(d,J＝4.0Hz),128.9(d,J＝3.1Hz),128.4,128.1(d,J＝14.2Hz),127.7,123.7(d,J＝3.2Hz),115.4(d,J＝23.7Hz),44.8,17.9； 19 F NMR(376MHz,CDCl 3 ):δ＝-117.9；IR(neat,cm -1 ):3400-2800,1728,1692,1482,1417,1390,1174,1141；MS(70eV,EI)m/z(％):244(M + ,51.67),199(100).
Example 51
Figure BDA0003003253570000322
The procedure is as in example 1, step I,9c (192.7mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.8mg, 0.1mmol), DCE (4 mL) was reacted for 40 hours to give a pale yellow liquid 10c (201.6mg, 98%) (eluent: petroleum ether/ethyl acetate =10/1 (. About.220 mL) to 4/1 (. About.250 mL)).
10c: 1 H NMR(400MHz,CDCl 3 )δ＝10.82(brs,1H,COOH),7.21(d,J＝7.6Hz,2H,Ar-H),7.09(d,J＝7.6Hz,2H,Ar-H),3.69(q,J＝6.9Hz,1H,CH),2.44(d,J＝6.8Hz,2H,CH 2 ),1.84(hept,J＝6.6Hz,1H,CH),1.48(d,J＝6.8Hz,3H,CH 3 ),0.89(d,J＝6.8Hz,6H,2 x CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝181.2,140.7,136.9,129.3,127.2,45.0,30.1,22.3,18.0；IR(neat,cm -1 ):3300-2350,1710,1458,1419,1229,1183,1070；MS(70eV,EI)m/z(％):206(M + ,50.21),161(100).
Example 52
Figure BDA0003003253570000331
The procedure was as in EXAMPLE 1, step I, (S) -9c (193.9mg, 1.0mmol,98% ee), cu (NO) 3 ) 2 ·3H 2 O(24.6mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol) and DCE (4 mL) were reacted for 42 hours to give (S) -10c (201.1mg, 97%,98% ee) (eluent: petroleum ether/Ethyl acetate =15/1 (. About.160 mL) to 4/1 (. About.250 mL)) as a pale yellow liquid.
(S)-10c:HPLC conditions:OJ-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R (major)＝10.2min,t R (minor)＝9.5min；[α] D 25 ＝+55.07(c＝1.14,CHCl 3 ) (literature report value: [ alpha ]] D 20 ＝+54.7(c＝0.68,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 )δ＝11.36(brs,1H,COOH),7.21(d,J＝8.0Hz,2H,Ar-H),7.09(d,J＝8.0Hz,2H,Ar-H),3.69(q,J＝7.1Hz,1H,CH),2.44(d,J＝7.2Hz,2H,CH 2 ),1.84(hept,J＝6.7Hz,1H,CH),1.49(d,J＝7.2Hz,3H,CH 3 ),0.89(d,J＝6.8Hz,6H,2 x CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝181.2,140.8,136.9,129.3,127.2,44.96,44.94,30.1,22.3,18.0；IR(neat,cm -1 ):3250-2350,1702,1450,1418,1282,1229,1184,1070；MS(70eV,EI)m/z(％):206(M + ,49.01),161(100).
Example 53
Figure BDA0003003253570000332
The procedure is as in example 1, step I,9d (199.2mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(16.3mg,0.1mmol)，KHSO 4 (13.5mg, 0.1mmol) and DCE (4 mL) were reacted for 47 hours to give a white solid 10d (185.7mg, 87%) (eluent: petroleum ether/Ethyl acetate = 3)1 (. About.200 mL) to 1/1 (. About.200 mL)).
10d; 1 H NMR(400MHz,DMSO-d 6 )δ＝12.38(brs,1H,COOH),7.65(d,J＝7.6Hz,2H,Ar-H),7.61(d,J＝8.0Hz,2H,Ar-H),7.46(t,J＝7.6Hz,2H,Ar-H),7.40-7.30(m,3H,Ar-H),2.62(s,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 ):δ＝172.7,140.0,138.6,134.3,130.0,129.0,127.4,126.62,126.60,40.3；IR(neat,cm -1 ):3250-2300,1683,1487,1412,1345,1249,1204,1036；MS(70eV,EI)m/z(％):212(M + ,44.47),167(100).
example 54
Figure BDA0003003253570000341
The procedure is as in example 1, step I,9e (236.0 mg,1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.0mg,0.1mmol)，TEMPO(16.2mg,0.1mmol)，KHSO 4 (13.5mg, 0.1mmol), DCE (4 mL) was reacted for 84 hours to give a pale yellow liquid 10e (236.9mg, 96%) (eluent: petroleum ether/ethyl acetate =5/1 (. About.180 mL) to 2/1 (. About.300 mL)).
10e: 1 H NMR(400MHz,CDCl 3 )δ＝10.12(brs,1H,COOH),7.22(d,J＝7.2Hz,2H,Ar-H),7.11(d,J＝7.6Hz,2H,Ar-H),3.70(q,J＝7.1Hz,1H,CH),3.11(dd,J 1 ＝14.0Hz,J 2 ＝4.0Hz,1H,one proton of CH 2 ),2.50(dd,J 1 ＝13.6Hz,J 2 ＝9.6Hz,1H,one proton of CH 2 ),2.42-2.25(m,2H,CH 2 ),2.19-2.00(m,2H,CH and one proton of CH 2 ),2.00-1.87(m,1H,one proton of CH 2 ),1.80-1.63(m,1H,one proton of CH 2 ),1.61-1.41(m,4H,CH 3 and one proton of CH 2 )； 13 C NMR(100MHz,CDCl 3 ):δ＝220.5,180.3,139.0,137.6,129.0,127.5,50.8,44.8,38.0,35.0,29.0,20.4,18.0；IR(neat,cm -1 ):3400-2250,1734,1703,1512,1454,1378,1156,1072；MS(70eV,EI)m/z(％):246(M + ,86.3),201(100).
Example 55
Figure BDA0003003253570000342
The operation is as in example 1, step I,9f (171.8mg, 0.5mmol), cu (NO) 3 ) 2 ·3H 2 O(12.4mg,0.05mmol)，TEMPO(8.1mg,0.05mmol)，KHSO 4 (7.1 mg, 0.05mmol), DCE (2 mL) was reacted for 90 hours to give 10f (116.6 mg, 65%) as a yellow solid (4% aldehyde in the crude product as monitored by nuclear magnetism) (eluent: petroleum ether/ethyl acetate =5/1 (-600 mL) to 3/1 (-200 mL), then 1/1 (-200 mL) to give an impure product (141.9 mg). The impure product was washed with sodium carbonate solution at pH 9-10, the aqueous phase was separated, then acidified to pH 6-7 with 3M HCl (aq.), EA (10mL x 3) was extracted three times, and the solvent was removed under reduced pressure).
10f, m.p.149.0-149.9 deg.C (petroleum ether/dichloromethane) (literature reported values: m.p.159-161 deg.C (ethyl acetate)); 1 H NMR(400MHz,CDCl 3 )δ＝7.66(d,J＝8.0Hz,2H,Ar-H),7.46(d,J＝8.4Hz,2H,Ar-H),6.95(d,J＝2.0Hz,1H,Ar-H),6.85(d,J＝9.2Hz,1H,Ar-H),6.67(dd,J 1 ＝9.0Hz,J 2 ＝2.2Hz,1H,Ar-H),3.82(s,3H,OCH 3 ),3.69(s,2H,CH 2 ),2.38(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝176.6,168.3,156.1,139.3,136.2,133.8,131.2,130.8,130.5,129.1,115.0,111.8,111.7,101.2,55.7,30.0,13.3；IR(neat,cm -1 ):3200-2250,1695,1676,1607,1474,1354,1326,1218,1150；MS(70eV,EI)m/z(％):359(M( 37 Cl) + ,2.74),357(M( 35 Cl) + ,6.87),84(100).
example 56
Figure BDA0003003253570000351
The procedure is as in example 1, step I,11a (254.1mg, 1.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(24.1mg,0.1mmol)，TEMPO(16.0mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol) and DCE (4 mL) were reacted for 24 hours to give 12 (244.2mg, 98%) as a white solid (eluent: petroleum ether/Ethyl acetate =25/1 (-260 mL) to 10/1 (-220 mL)).
12: 1 H NMR(400MHz,CDCl 3 ):δ＝2.41(t,J＝15.4Hz,1H,one proton of CH 2 ),2.23(dd,J 1 ＝16.2Hz,J 2 ＝6.2Hz,1H,one proton of CH 2 ),2.08(d,J＝11.6Hz,1H),1.97(dd,J 1 ＝14.8Hz,J 2 ＝6.0Hz,1H),1.88(d,J＝14.0Hz,1H),1.77-1.56(m,2H),1.54-1.26(m,7H),1.26-1.12(m,1H),1.12-0.96(m,2H),0.92(s,3H,CH 3 ),0.89(s,3H,CH 3 ),0.84(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝176.7,86.2,59.0,56.5,42.0,39.4,38.6,35.9,33.04,32.98,28.6,21.4,20.8,20.4,17.9,14.9.
Example 57
Figure BDA0003003253570000352
The procedure is as in example 1, step II,11b (362.7mg, 1.0mmol), cu (NO) 3 ) 2 ·3H 2 O(24.4mg,0.1mmol)，TEMPO(16.1mg,0.1mmol)，KHSO 4 (13.9mg, 0.1mmol), DCE (2 mL) for 23 h gave a white solid 13 (267.7mg, 71%) (eluent: petroleum ether/ethyl acetate =4/1 (. About.250 mL) to 1/1 (. About.200 mL)).
13: 1 H NMR(400MHz,CDCl 3 )δ＝10.15(brs,1H,COOH),2.70(t,J＝14.2Hz,1H,one proton of CH 2 ),2.50-2.21(m,3H),2.21-2.10(m,1H),2.09-1.96(m,3H),1.95-1.74(m,4H),1.69-1.55(m,1H),1.55-1.05(m,15H),1.02(s,3H,CH 3 ),0.94(d,J＝6.0Hz,3H,CH 3 ),0.69(s,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝213.7,180.1,56.3,55.8,44.2,42.6,42.2,40.6,39.9,37.0,36.9,35.4,35.1,34.7,30.9,30.6,28.0,26.5,25.6,24.0,22.5,21.1,18.1,11.9.
Example 58
Figure BDA0003003253570000361
The procedure is as in example 1, step I,11c (259.5mgmmol)，Cu(NO 3 ) 2 ·3H 2 O(24.2mg,0.1mmol)，TEMPO(15.9mg,0.1mmol)，KHSO 4 (13.6 mg,0.1 mmol), DCE (4 mL) was reacted for 36 hours to give 14 as a white solid (163.6 mg, 76%) (eluent: petroleum ether/ethyl acetate =2/1 (. About.300 mL) to 1/1 (. About.200 mL)).
14:[α] D 23 ＝-59.06(c＝1.00,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ＝5.12-4.90(m,1H,CH),4.60(t,J＝7.6Hz,1H,CH),4.40(s,1H,OH),2.67(dd,J 1 ＝16.0Hz,J 2 ＝6.8Hz,1H,one proton of CH 2 ),2.58(dd,J 1 ＝16.0Hz,J 2 ＝6.4Hz,1H,one proton of CH 2 ),2.48-2.27(m,2H,CH 2 ),1.46(s,9H,C(CH 3 ) 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝177.3,168.7,81.7,74.5,67.0,40.9,35.1,27.8；IR(neat,cm -1 ):3433,2979,2932,1777,1723,1368,1256,1147,1120；MS(ESI)m/z:234(M+NH 4 ) + ,239(M+Na) + ；HRMS calcd m/z for C 10 H 16 O 5 Na[M+Na] + :239.0890,found 239.0884.
Example 59
Figure BDA0003003253570000362
The procedure is as in example 1, step II,1a (2.4349g, 10.0 mmol), cu (NO) 3 ) 2 ·3H 2 O(241.5mg,1.0mmol)，TEMPO(160.1mg,1.0mmol)，KHSO 4 (137.0mg, 1.0mmol), DCE (20 mL) was reacted for 13 hours to obtain a white solid 2a (2.3126g, 90%) (recrystallization: 1.6826g (petroleum ether/chloroform = 10/1) was obtained for the first time, 0.5185g (petroleum ether/chloroform = 20/1) was obtained for the second time, and 0.1115g (petroleum ether/chloroform = 20/1) was obtained for the third time).
2a: 1 H NMR(400MHz,CDCl 3 ):δ＝11.48(brs,1H,COOH),2.34(t,J＝7.6Hz,2H,CH 2 ),1.63(quintet,J＝7.3Hz,2H,CH 2 ),1.47-1.16(m,24H,12 x CH 2 ),0.88(t,J＝6.6Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝180.6,34.1,31.9,29.68,29.66,29.6,29.43,29.36,29.2,29.1,24.7,22.7,14.1.
Example 60
Figure BDA0003003253570000363
The procedure is as in step I of example 1, and Cu (NO) is added to a 500mL three-necked flask in that order 3 ) 2 ·3H 2 O(1.2102g,5.0mmol)，TEMPO(796.9mg,5.0mmol)，KHSO 4 (679.3mg, 5.0 mmol), (S) -1o (5.5mL, d =0.811g/mL,98% pure, 50.0 mmol), DCE (100 mL). The reaction was carried out at room temperature until completion of the nuclear magnetic detection reaction (36 hours). The reaction mixture was passed through a short column of silica gel (3 cm), eluted with diethyl ether (200 mL), the solvent was removed by rotary evaporation, and distilled under reduced pressure with a water pump to give (S) -2o (3.6269g, 72%,98% ee) (the fraction (0.013MPa, 90-110 ℃ C.) was collected to give (S) -2o (2.6172 g), the residue was transferred to a 25mL bottle and distilled again to collect the fraction (0.013MPa, 86-102 ℃ C.) to give (S) -2o (1.0097 g)). (S) -2o R (major)＝16.7min,t R (minor)＝15.8min；[α] D 25 ＝+18.36(c＝1.205,CHCl 3 )(reported:[α] D 23 ＝+19.2(c＝1.15,CHCl 3 ))； 1 H NMR(400MHz,CDCl 3 )δ＝10.70(brs,1H,COOH),2.40(sextet,J＝7.0Hz,1H,CH),1.72(hept,J＝7.2Hz,1H,one proton of CH 2 ),1.50(hept,J＝7.1Hz,1H,one proton of CH 2 ),1.18(d,J＝7.2Hz,3H,CH 3 ),0.95(t,J＝7.4Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝183.3,40.7,26.3,16.1,11.3；IR(neat,cm -1 ):3300-2450,1702,1464,1417,1383,1227,1157,1089；MS(ESI)m/z:101(M-H) - .
Example 61
Figure BDA0003003253570000371
Cu (NO) was added to a 500mL three-necked flask in sequence 3 ) 2 ·3H 2 O(1.2033g,5.0mmol)，TEMPO(798.8mg,5.0mmol)，KHSO 4 (682.1mg, 5.0 mmol), (S) -1o (5.5mL, d =0.811g/mL,98% punity, 50.0 mmol), DCE (100 mL). The three-necked flask was then connected to a 70L air bag via an air extraction valve. After stirring at room temperature for 12 hours, the other port was connected to a 2L oxygen balloon through an air extraction valve to supplement oxygen. The reaction was stirred at room temperature until completion of the nmr detection reaction (24 hours). The reaction solution was passed through a short column of silica gel (3 cm), eluted with diethyl ether (200 mL), rotary evaporated to remove the solvent, and distilled under reduced pressure with a water pump to give a yellow liquid (S) -2o (4.1961g, 81%,98% purity,98% ee) (fraction (0.032MPa, 112-134 ℃ C.)))).
(S)-2o:HPLC conditions:OJ-H column,hexane/i-PrOH＝99/1,0.5mL/min,λ＝214nm,t R (major)＝16.5min,t R (minor)＝15.7min； 1 H NMR(400MHz,CDCl 3 )δ＝10.73(brs,1H,COOH),2.40(sextet,J＝6.9Hz,1H,CH),1.72(hept,J＝7.2Hz,1H,one proton of CH 2 ),1.50(hept,J＝7.1Hz,1H,one proton of CH 2 ),1.18(d,J＝7.2Hz,3H,CH 3 ),0.95(t,J＝7.4Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 ):δ＝183.1,40.5,26.1,15.9,11.0.
Example 62
Figure BDA0003003253570000372
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.3mg,0.1mmol),TEMPO(32.1mg,0.2mmol),KHSO 4 (14.0 mg,0.1 mmol), 1r (112.1 mg,1.0 mmol) and DCE (4 mL). The reaction was stirred at room temperature for 72 hours. The reaction solution was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), and the solvent was removed by rotary evaporation to give 2r, a crude spectrum showed a nuclear magnetic yield of 52% and the corresponding aldehyde nuclear magnetic 2r' yield of 13%.
Example 63
Figure BDA0003003253570000381
Sequentially adding Cu (NO) into Schlenk tube under air atmosphere 3 ) 2 ·3H 2 O(24.7mg,0.1mmol),TEMPO(15.8mg,0.1mmol),KHSO 4 (13.6mg, 0.1mmol), 1a (243.3mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 72 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 88% and the corresponding aldehyde nuclear magnetic 2a' yield of 10%.
Example 64
Figure BDA0003003253570000382
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.2mg,0.1mmol),TEMPO(16.0mg,0.1mmol),SnCl 4 (0.1mL, 0.1mmol,1.0M in DCM), 1a (242.5mg, 1.0 mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, crude spectrum showing nuclear magnetic yield of 13% and corresponding aldehyde nuclear magnetic 2a' yield of 80%.
Example 65
Figure BDA0003003253570000383
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.1mg,0.1mmol),TEMPO(15.8mg,0.1mmol),InCl 3 (21.5mg, 0.1mmol), 1a (242.6mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 67% and the corresponding aldehyde nuclear magnetic 2a' yield of 14%.
Example 66
Figure BDA0003003253570000391
Under oxygen atmosphere, shi LaiSequentially adding Cu (NO) into the gram tube 3 ) 2 ·3H 2 O(24.4mg,0.1mmol),TEMPO(16.2mg,0.1mmol),CuF 2 ·2H 2 O (13.7mg, 0.1mmol), 1a (243.4mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 71% and the corresponding aldehyde nuclear magnetic 2a' yield of 5%.
Example 67
Figure BDA0003003253570000392
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.2mg,0.1mmol),TEMPO(15.8mg,0.1mmol),AlCl 3 (14.5mg, 0.1mmol), 1a (242.5mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 90% and the corresponding aldehyde nuclear magnetic 2a' yield of 6%.
Example 68
Figure BDA0003003253570000393
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.1mg,0.1mmol),TEMPO(16.1mg,0.1mmol),ZnCl 2 (13.5mg, 0.1mmol), 1a (242.7mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 92% and the corresponding aldehyde nuclear magnetic 2a' yield of 4%.
Example 69
Figure BDA0003003253570000394
Adding C into Schlenk tube under oxygen atmosphereu(NO 3 ) 2 ·3H 2 O(24.2mg,0.1mmol),TEMPO(15.8mg,0.1mmol),BiCl 3 (31.6 mg, 0.1mmol), 1a (241.5 mg,1.0 mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, crude spectrum showed 96% nuclear magnetic yield and 1% corresponding aldehyde nuclear magnetic 2 a'.
Example 70
Figure BDA0003003253570000401
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.7mg,0.1mmol),TEMPO(16.0mg,0.1mmol),KH 2 PO 4 (13.7mg, 0.1mmol), 1a (243.3mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 87% and the corresponding aldehyde nuclear magnetic 2a' yield of 12%.
Example 71
Figure BDA0003003253570000402
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.5mg,0.1mmol),TEMPO(15.9mg,0.1mmol),NaH 2 PO 4 (12.1mg, 0.1mmol), 1a (242.9mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction solution was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), and the solvent was removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 98%.
Example 72
Figure BDA0003003253570000403
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.6mg,0.1mmol),TEMPO(16.0mg,0.1mmol),NaHSO 4 ·H 2 O (13.8mg, 0.1mmol), 1a (242.6mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction solution was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), and the solvent was removed by rotary evaporation to give 2a, a crude spectrum showing 99% nuclear magnetic yield.
Example 73
Figure BDA0003003253570000411
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O (24.2 mg, 0.1mmol), TEMPO (15.9mg, 0.1mmol), KCl (7.5mg, 0.1mmol), 1a (243.9mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a in crude spectrum 76% nuclear magnetic yield and 18% corresponding aldehyde nuclear magnetic 2 a'.
Example 74
Figure BDA0003003253570000412
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O (24.1mg, 0.1mmol), TEMPO (15.8mg, 0.1mmol), KBr (11.9mg, 0.1mmol), 1a (242.3mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 30% and the corresponding aldehyde nuclear magnetic 2a' yield of 61%.
Example 75
Figure BDA0003003253570000413
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.2mg,0.1mmol),TEMPO(16.0mg,0.1mmol),KNO 3 (10.3mg,0.1mmol),1a(243.4mg,1.0mmol)And DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 69% and the corresponding aldehyde nuclear magnetic 2a' yield of 20%.
Example 76
Figure BDA0003003253570000414
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.1mg,0.1mmol),TEMPO(16.2mg,0.1mmol),K 2 S 2 O 8 (27.3mg, 0.1mmol), 1a (243.6mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction solution was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), and the solvent was removed by rotary evaporation to give 2a, crude spectrum showing nuclear magnetic yield 95%.
Example 77
Figure BDA0003003253570000421
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.1mg,0.1mmol),TEMPO(15.9mg,0.1mmol),KHSO 4 (13.6mg, 0.1mmol), 1a (244.0 mg,1.0 mmol) and CHCl 3 (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 91% and the corresponding aldehyde nuclear magnetic 2a' yield of 9%.
Example 78
Figure BDA0003003253570000422
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.5mg,0.1mmol),4-OH-TEMPO(17.3mg,0.1mmol),KHSO 4 (14.0mg, 0.1mmol), 1a (242.7mg, 1.0mmol) and DCE (4 mL). The reaction is stirred at room temperatureStirring for 36 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation to give 2a, a crude spectrum showing a nuclear magnetic yield of 29% and the corresponding aldehyde nuclear magnetic 2a' yield of 66%.
Example 79
Figure BDA0003003253570000423
TEMPO (16.0 mg, 0.1mmol), KHSO were added to Schlenk's tube in this order under an oxygen atmosphere 4 (13.7mg, 0.1mmol), 1a (242.3mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction solution passes through a silica gel short column (3 cm), ether elution (3 x25 mL) is carried out, the solvent is removed by rotary evaporation, the crude spectrum shows that the nuclear magnetic yield of 2a is 0, and the corresponding nuclear magnetic yield of 1a for alcohol recovery is 100%.
Example 80
Figure BDA0003003253570000431
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(24.3mg,0.1mmol),KHSO 4 (14.1mg, 0.1mmol), 1a (243.8mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction solution is passed through a silica gel short column (3 cm), ether elution (3X 25 mL) is carried out, the solvent is removed by rotary evaporation, and a crude spectrum shows that the nuclear magnetic yield of 2a is 0, and the corresponding nuclear magnetic yield of 1a after alcohol recovery is 100%.
Example 81
Figure BDA0003003253570000432
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O (24.5mg, 0.1mmol), TEMPO (16.1mg, 0.1mmol), 1a (243.5mg, 1.0mmol) and DCE (4 mL). The reaction was stirred at room temperature for 36 hours. The reaction was filtered through a short column of silica gel (3 cm), eluted with ether (3X 25 mL), the solvent removed by rotary evaporation and the crude spectrum showed a nuclear magnetic yield of 0 for 2a (same as 2a in example 80) and the corresponding aldehyde nuclear magnetic 2The yield of a' was 61%, and the yield of the corresponding nuclear magnetism for alcohol recovery 1a was 21%.
Example 82
Figure BDA0003003253570000433
Sequentially adding Cu (NO) into Schlenk tube under oxygen atmosphere 3 ) 2 ·3H 2 O(25.1mg,0.1mmol),TEMPO(15.9mg,0.1mmol),KHSO 4 (14.1mg, 0.1mmol), 1s (177.4mg, 1.0mmol,96% purity), and DCE (4 mL). The reaction was stirred at room temperature for 10 hours. The reaction was passed through a short column of silica gel (3 cm), eluted with ether (3X 25 mL) and the solvent removed by rotary evaporation, the crude spectrum showed a 2s (2 s 'corresponding acid) nuclear magnetic yield of 0, the corresponding aldehyde nuclear magnetic 2s' yield of 54% and the corresponding alcohol recovery nuclear magnetic 1s yield of 46%.
The protection content of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art are intended to be included within the present invention without departing from the spirit and scope of the inventive concept and are intended to be protected by the following claims.

Claims (9)

1. A method for preparing carboxylic acid compound by oxidizing alcohol with oxygen as an oxidant under the catalysis of copper is characterized in that the method takes alcohol as a raw material, takes copper nitrate trihydrate, 2,2,6,6-tetramethylpiperidine nitrogen oxide and acidic inorganic salt as catalysts, and takes oxygen as an oxidant to oxidize the alcohol to generate the carboxylic acid compound in an organic solvent at the temperature of 25-50 ℃; the reaction process is shown as a reaction formula (1):
Figure FDA0003003253560000011
wherein the content of the first and second substances,
the R is 1 Including alkyl, alkyl with functional group, cycloalkyl, heterocyclic group, aryl, alkynyl with functional group, terpenes and steroid structure;
the heterocyclic group is a heterocyclic ring with carbon, nitrogen, oxygen or sulfur atoms as ring atoms;
the aryl is phenyl, nitro substituted phenyl, halogen substituted phenyl, ester group substituted phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, thienyl, furyl or naphthyl;
the alkynyl is a terminal alkynyl with the chain length of C3-C16;
the functional group in the alkyl with the functional group is halogen, ether bond, ester group, heteroaryl, aryl, alkynyl, carbon-carbon double bond and amino;
the functional group in the alkynyl with the functional group is alkyl silicon base, alkyl, alkenyl, alkynyl and propargyl substituted by alkyl silicon base.
2. The method of claim 1, wherein R is 1 Comprises C1-C16 alkyl, C3-C10 cycloalkyl, C3-C8 heterocyclic radical, alkyl with functional group, terpenes and steroid structure;
the functional group in the alkyl with the functional group is fluorine, chlorine, bromine, iodine, ether bond, ester group, thienyl, indolyl, furyl, benzofuryl, benzothienyl, benzopyranyl, phenyl, halogenated phenyl, alkylphenyl, alkoxy naphthyl, biphenyl, nitrophenyl, ester group-substituted phenyl, alkynyl or amino; the amino is amino containing a protecting group, and the protecting group is p-toluenesulfonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, acetyl and trifluoroacetyl;
the heterocyclic group of C3-C8 is furan ring or thiophene ring.
3. The method of claim 1, wherein the acidic inorganic salt is a bronsted or lewis acidic inorganic salt comprising potassium bisulfate, sodium dihydrogen phosphate, potassium sulfate, tin chloride, indium chloride, copper fluoride, aluminum chloride, zinc chloride, bismuth chloride, ytterbium triflate, lanthanum triflate, scandium triflate.
4. The method of claim 1, wherein the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, chloroform, toluene, acetonitrile, chloroform, ethyl acetate, 1,3-dichloropropane, 1,2-dichloropropane, nitromethane, ethylene glycol dimethyl ether, dioxane, and tetrahydrofuran.
5. The method of claim 1 wherein the molar ratio of the starting alcohol, copper nitrate trihydrate, 2,2,6,6-tetramethylpiperidine nitroxide, acidic inorganic salt is 100 (1-20) to (1-30) to (1-20).
6. The method of claim 1, wherein the reaction time is 12 to 96 hours.
7. The method of claim 1, wherein the source of oxygen is pure oxygen or oxygen in air.
8. The method of claim 7, wherein if the oxygen in the air is used as the oxidant, the air bag is used as the source of the oxygen, and after 12 hours of reaction, the oxygen balloon is added as supplement.
9. Use of a process according to any one of claims 1 to 8 for the preparation of carboxylic acid compounds via alcohols.
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