CN114874119B - Method for synthesizing 3, 4-dialkylated-4-pyrroline-2-one derivative by photocatalysis - Google Patents
Method for synthesizing 3, 4-dialkylated-4-pyrroline-2-one derivative by photocatalysis Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a method for synthesizing 3, 4-double alkylation-4-pyrroline-2-ketone derivative by photocatalysis, which is induced by visible lightNRegioselective tandem enamides beta-C (sp) 2 ) Preparation of 3, 4-dialkylated-4-pyrrolin-2-one derivatives by H alkylation/acrylamide alkylation/alkenylation cyclization. The invention has mild reaction condition, high efficiency, wide substrate range and high regioselectivity, and provides a convenient method for synthesizing 3, 4-dialkylated 4-pyrroline-2-ketone.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a 3, 4-dialkylated-4-pyrroline-2-one derivative by photocatalysis.
Background
4-pyrrolin-2-one (also known as 1, 3-dihydropyrrol-2-one or α, β -unsaturated γ -lactam) derivatives are widely found in natural alkaloids or clinical drug molecules such as cyanogramide, violacein, diaorthothasin, sagassumlactam, cestulactam K, denicrin D, and At-2 HM-iso-DNCC-431.
Traditionally, 4-pyrrolin-2-one can be found in Ru 3 (CO) 12 Catalytic and high temperature and pressure synthesis from alpha, beta-unsaturated imines, CO and olefins. In 2004, the Sames topic group developed [ Ir (coe) 2 Cl] 2 Catalytic oxidative cyclization of 2, 2-dimethyl-1- (pyrrolidin-1-yl) -3-butenone, which requires the use of 4 equivalents of norbornene and 2 equivalents of ligand, but only synthesis gives 3 4-pyrrolin-2-one products (B.DeBoef, S.J.Pastine, D.Sames, J.Am.Chem.Soc.2004,126,6556-6557). 2017, lv YunCopper catalyzed aminated bis-fluoroalkyl reactions of alkynes and α -difluorobromoacetamides were developed before and greetings and 3, 3-difluoro-4-pyrrolin-2-one (Y.Lv, W.Pu, Q.Chen, Q.Wang, J.Niu, Q.Zhang, J.Org.Chem.2017,82, 8282-8289.) the Novikov group achieved some progress in the synthesis of 3-alkoxy-4-pyrrolin-2-one derivatives by Rh catalyzed denitrification cyclization of triazoles with diazo esters (A.N.Koronatov, N.V.Rostovskii, A.F.Khlebnikov, M.S.Novikov, org.Lett.2020,22, 7958-7963.) recently, the Su Weiping group achieved the synthesis of 3, 3-diaryl-4-pyrrolin-2-one starting from alkylaryl ketones and primary amines, which required the use of copper catalysts and 3 equivalents of 2, 6-tetramethylpiperidine oxide (TEMPO) as the oxidant (R.Hu, Y.Tao, X.Zhang, W.Su, angew.Chem.Int.Ed.2021,60,8425-8430; angew. Chem.2021,133, 8506-8511.) although the synthesis of 4-pyrrolin-2-one derivatives had progressed, the above reactions required vigorous reaction conditions and the use of transition metal catalysts which were mild or expensive, and the development of a very mild, economical, but expensive, 4-pyrrolin-2-one derivatives.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for synthesizing 3, 4-dialkylated-4-pyrroline-2-one derivatives by photocatalysis. The reaction is mild, clean, efficient, wide in substrate range, free of transition metal catalyst, easy to scale up to gram scale, and meanwhile has the characteristics of simplicity and convenience in operation, environment friendliness and the like.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a method for synthesizing 3, 4-double alkylation-4-pyrroline-2-ketone derivative by photocatalysis is characterized by adopting the following route:
wherein the method comprises the steps of
R 1 Is that
R 5 Is H, one or more C 1-6 Alkyl or cycloalkyl, one or more OC 1-6 Alkoxy, one or more halogens or one or more halogen-substituted halocs 1-6 An alkyl group;
R 2 is that
C 1-6 Alkyl or cycloalkyl, -CH 2 CH＝CH 2 or-CH 2 C.ident.CH wherein R 6 Is H or one or more halogens; r is R 7 Is C 1-6 Alkyl or cycloalkyl, OC 1-6 Alkoxy-or halogen-substituted halo C 1-6 An alkyl group; r is R 3 Is H or C 1-6 An alkyl group; r is R 4 H, C of a shape of H, C 1-6 Alkyl or COR 8 X is halogen; y is cyano, COR 8 Or halogen; r is R 8 For OC 1-6 Alkoxy, phenyl or NR 9 R 10 ；R 9 And R is 10 Each independently is C 1-6 An alkyl group.
In the above method, when R of the starting compound 1 3 In case of H, the prepared product is compound 3; when R of the starting compound 1 3 Is C 1-6 In the case of alkyl, the product prepared is compound 4.
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. The term "C" as used herein 1-6 Alkyl or cycloalkyl "means a saturated straight or branched hydrocarbon or cycloalkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like, preferably methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclopentyl or cyclohexyl. The term "-O-C" as used in the present invention 1-6 Alkyl "refers to saturated, straight or branched chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, t-butoxy, and the like. The term "halogen-substituted C" as used herein 1-6 Alkyl "refers to one or more halogen substituted saturated straight or branched hydrocarbon radicals having 1 to 6 carbon atoms, such as difluoromethylTrifluoromethyl, and the like.
In the compounds herein, R 5 The two can be ortho, meta or para, can be substituted simultaneously with ortho, meta or/and para, and can be substituted independently. R is R 6 The two can be ortho, meta or para, can be substituted simultaneously with ortho, meta or/and para, and can be substituted independently.
Preferably, in the above method, R 1 Is that
Wherein R is 5 Is H, 4-tBu, 4-MeO, 4-I, 4-Br, 4-Cl, 4-F, 4-CF 3 、3-Br、2-F、3,5-(CF 3 ) 2 ；R 2 Is->
iPr or Cy, where R 6 H, cl and F; r is R 6 Is t-Bu and OMe; r is R 3 H, me, et or Pr; r is R 4 Is H, me, COR 8 The method comprises the steps of carrying out a first treatment on the surface of the X is Br; y is cyano, COR 8 Halogen; r is R 8 Either OMe or OEt. />
The photocatalyst of the present invention is selected from Ir (ppy) 3 、[Ir(dtbbpy)(ppy) 2 ]PF 6 、Ru(bpy) 3 Cl 2 Eosin Y is preferably used in an amount of 1 to 5mol%. The solvent of the invention is selected from CH 3 CN, DCE, DMSO or acetone. The light of the invention is blue light or solar natural light. The compounds of formula 2 according to the invention are used in amounts of 1 to 2.5 equivalents. The photocatalytic reaction of the present invention requires the addition of a base selected from the group consisting of K 2 CO 3 、Na 2 CO 3 、Na 2 HPO 4 Or 2, 6-lutidine. The alkali of the invention is preferably Na 2 CO 3 ，Na 2 CO 3 The amount of (2) is 1-2 equivalents.
In the above method, the 3, 4-dialkylated-4-pyrrolin-2-one derivative is selected from the group consisting of:
3- (1-benzyl-4-cyanomethyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionitrile (3 a),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 1),
3- (1-benzyl-5- (4-tert-butylphenyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 2),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-methoxyphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 3),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-iodophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 4),
3- (1-benzyl-5- (4-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 5),
3- (1-benzyl-5- (4-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 6),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 7),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5- (4-trifluoromethylphenyl) -2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 8),
3- (1-benzyl-5- (3-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 9),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (2-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 10),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 c),
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 d 1),
3- (1-benzyl-5- (3, 5-bistrifluoromethylphenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 d 2),
3- (1-benzyl-4-ethyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 e 1),
3- (1-benzyl-3-methyl-2-oxo-5-phenyl-4-propyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 e 2),
3- (1- (4-chlorobenzyl) -4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 f 1),
3- (4- (2-ethoxy-2-oxoethyl) -1- (4-fluorobenzyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 f 2),
3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -1-isopropyl-3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 g 1),
3- (1-cyclohexyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 g 2),
3- (1-allyl-3, 4-dimethyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4H 1),
3- (1-allyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4H 2),
ethyl 3- (5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-1- (2-propyn-1-yl) -2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 i),
3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-1-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 j 1),
3- (1- (4-tert-butylphenyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 j 2),
3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -1- (4-methoxyphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 j 3),
methyl 3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 k 1),
phenyl 3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 k 2),
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) -N, N-dimethylpropionamide (4 k 3),
1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-3- (3-oxo-3-phenylpropyl) -1, 3-dihydro-2H-pyrrol-2-one (4 k 4),
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) -2-methylpropanoic acid methyl ester (4 l),
diethyl 2- ((1-benzyl-4- (2-ethoxy-2-oxo-1-propionyloxyethyl) -3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) methyl) malonate (3 m),
1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-3- (2, 2-trichloroethyl) -1, 3-dihydro-2H-pyrrol-2-one (4 n).
The 3, 4-double alkylation-4-pyrroline-2-ketone derivative prepared by the invention can be used as a raw material or an intermediate to synthesize natural alkaloids or clinical drug molecules such as cyanogamide, violacein, diacetorthothasin, sagassumlactam, terstulactam K, denicorin D, at-2HM-iso-DNCC-431 and the like; can also be used as impurity reference substances of the natural alkaloids or clinical drug molecules.
The beneficial effects are that:
the invention provides a method for synthesizing 3, 4-double alkylation-4-pyrroline-2-ketone derivative by photocatalysis, which is characterized in that N-alkenyl acrylamide induced by visible light and activated alkyl bromide are connected in series with enamide beta-C (sp 2 ) Preparation of 3, 4-dialkylated-4-pyrrolin-2-one derivatives by H alkylation/acrylamide alkylation/alkenylation cyclization. The invention has mild reaction condition, high efficiency, wide substrate range and high regioselectivity, and provides a convenient method for synthesizing 3, 4-dialkylated 4-pyrroline-2-ketone.
Detailed Description
The present invention is described in detail below by way of specific examples, which are given herein for the purpose of further illustration only and are not to be construed as limiting the scope of the present invention, as many insubstantial modifications and variations of the present invention will become apparent to those skilled in the art in light of the foregoing disclosure. The raw materials and the reagents are all commercial products.
The product synthesis step:
general procedure for 4-pyrrolin-2-one synthesis:
n-alkenyl acrylamide 1 (0.3 mmol), fac-Ir (ppy) (1 mol%,0.003mmol,2 mg), na were sequentially added to a 25mL Schlenk reaction tube equipped with a magnetic stirrer under an argon atmosphere 2 CO 3 (1.5 eq., 0.45mmol,48 mg), oxygen scavenging MeCN (3.0 mL) and alkyl bromide 2 (0.66 or 0.33 mmol). The mixture was stirred for 2 hours at room temperature under blue LED irradiation in an anaerobic environment. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (petroleum ether-ethyl acetate) to give 4-pyrrolin-2-one 3 or 4 as a product.
Substrate N-alkenyl acrylamide 1 synthesis
Synthesis of substrate 1 according to the literature (M.Kobayashi, T.Suda, K.Noguchi, K.Tanaka, angew.Chem., int.Ed.2011,50, 1664-1667)
Primary amines (13.9 mmol) of toluene (14 mL), ketones (13.9 mmol) and
a mixed solution of molecular sieves (4.5 g) was reacted at 120℃for 6 hours to give a mixed solution of crude imine. After cooling, the molecular sieve was filtered off and washed with toluene (3 mL). Triethylamine (2 equivalents, 27.8 mmol) and methacryloyl chloride (1.2 equivalents, 16.7 mmol) were added to the filtrate with cooling in an ice water bath, then naturally brought to room temperature and stirring was continued at room temperature for 12 hours. Quench the reaction with water (50 mL) and use CH 2 Cl 2 (25 mL. Times.4) extraction. The residue obtained by evaporating the solvent was purified by column chromatography on silica gel (petroleum ether-ethyl acetate) to give N-alkenyl acrylamide 1.
N-benzyl-N- (1-styryl) methacrylamide 1a and 2-bromoacetonitrile 2a were used as reaction starting materials, ir (ppy) 3 As a Photocatalyst (PC), 2 equivalents of Na 2 CO 3 In acetonitrile solvent and simultaneously irradiated with blue LED, the reaction results are shown in table 1). After 12h, the bis-alkylated/cyclized product 4-pyrrolin-2-one was produced in 56% yield3a (SEQ ID NO: 1). Acetonitrile is the optimal reaction solvent, and the reaction results performed in other solvents are not as good as those in acetonitrile solvents (SEQ ID Nos. 2 to 4). No Na is added 2 CO 3 When the reaction system is decomposed, the use effect of other alkali (inorganic alkali or organic alkali) is not as good as Na 2 CO 3 (sequence numbers 6-8). Ir (ppy) is used 3 As photocatalysts are crucial for the reaction, other photocatalysts (e.g. [ Ir (dtbbpy) (ppy) ] 2 ]PF 6 、Ru(bpy) 3 Cl 2 And Eosin Y) are catalyzed, no bis-alkylation/cyclization product 3a is produced (SEQ ID Nos. 9-11). The reaction has high reaction speed and high efficiency, and can reduce Na by only irradiating with blue light for 2 hours 2 CO 3 The yield of 4-pyrrolin-2-one 3a can still reach 56% (SEQ ID NO: 12) when the amount is 1.5 equivalent.
TABLE 1 optimization of reaction conditions
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.66 mmol), fac-Ir (ppy) 3 (0.003mmol),Na 2 CO 3 (0.6mmol),CH 3 CN (3.0 mL), 6W blue LED (455 nm), ar, room temperature, 12h.
Referring to the above method, the inventors studied the applicable range of the reaction under optimal reaction conditions (table 2). Reaction of ethyl bromoacetate 2b with N-vinyl acrylamide 1a produced 3, 4-bis-alkylated 4-pyrrolin-2-one 3b1 in 65% yield. Both para-or meta-substituted electron-rich (3 b2-3b 3) and electron-poor enamine 1-position aryl groups (3 b4 and 3b 9) can be compatible by this reaction, yielding a series of bis-alkylated 4-pyrrolin-2-one products. The compatibility of the reaction with activated aryl halides (3 b4-3b6 and 3b 9) reserves a reaction site for further metal catalyzed coupling reactions. The reaction may be more sensitive to steric hindrance and the substrate ortho to the enamine 1-aryl group substituted with a fluorine atom may be required to be reactedWith 2mol% Ir (ppy) 3 The yield of the corresponding dialkylated product 3b10 after 12h was also only 44%. Notably, the α - (pyridin-2-yl) enamide substrate can also be reacted with 2b to yield the corresponding bis-alkylated γ -lactam 3c in 57% yield. When the enamine 2-position of the diene substrate is occupied by a methyl, ethyl or propyl group, etc., then the monoalkylated 4-pyrrolin-2-one product (4 d and 4 e) is formed. The test results of substituents on enamine nitrogen atoms show that N-vinyl acrylamide with nitrogen atoms protected by alkyl groups (3 f and 3 g) or aryl groups (3 j1-3j 3) are high-activity substrates, and can successfully react with ethyl bromoacetate 2b to generate corresponding gamma-lactam. Surprisingly, both diene and triene substrates bearing non-activated alkenyl or non-activated alkynyl groups are compatible with this reaction. Although the yields of the corresponding N-allyl products 4h1 and 4h2 were lower, the yields of the corresponding N-propargyl product 4i were comparable to the other reactions. These results again demonstrate the surprising regioselectivity and chemoselectivity of the reaction. The inventors have subsequently studied the applicability of alpha-activated alkyl bromides, including methyl bromoacetate (4 k 1), phenyl bromoacetate (4 k 2), 2-bromo-N, N-dimethylacetamide (4 k 3) and alpha-bromoacetophenone (4 k 4), with the corresponding 4-pyrrolin-2-one products being smoothly formed. Both methyl 2-bromopropionate and diethyl 2-bromopropionate smoothly react to generate corresponding 4l and 3m 4-pyrrolin-2-one products. Interestingly, CCl under enhanced conditions 4 Can also be used as halohydrocarbon of the cyclization reaction and correspondingly contains CCl 3 The yield of 4-pyrrolin-2-one 4n was 55%.
TABLE 2 substrate ranges [a]
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.66 mmol), fac-Ir (ppy) 3 (0.003mmol),Na 2 CO 3 (0.45mmol),CH 3 CN (3.0 mL), 6W blue LED (455 nm), ar, room temperature, 2h. [b] Ir(ppy) 3 (0.006mmol),12h。 [c] 1.1 equivalents 2 are used.
The inventors performed a 13-fold amplification experiment to demonstrate the industrial scale-up capability of the reaction (3 a). The reaction of 3-aza-1, 5-diene 1b7 with ethyl bromoacetate 2b on a 4mmol scale gave 4-pyrrolin-2-one 3b7 with only a slight decrease in yield (63%, 1.17 g). The inventors then tried to induce the reaction of dienes 1d1 and 2b using natural sunlight and found that the yield of the corresponding 4-pyrrolin-2-one 4d1 was somewhat higher than under standard conditions (3 b).
In summary, the method for synthesizing the 3, 4-dialkylated-4-pyrrolin-2-one derivative by photocatalysis provided by the invention is characterized in that the N-alkenyl acrylamide and the activated alkyl bromide are subjected to regioselective tandem enamide beta-C (sp 2 ) Preparation of 3, 4-dialkylated-4-pyrrolin-2-one derivatives by H alkylation/acrylamide alkylation/alkenylation cyclization. The invention has mild reaction condition, high efficiency, wide substrate range and high regioselectivity, and provides a convenient method for synthesizing 3, 4-dialkylated 4-pyrroline-2-ketone.
Characterization of product spectra
3- (1-benzyl-4-cyanomethyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionitrile (3 a), flash column chromatography (petroleum ether/ethyl acetate=12:1, v/v), 56% yield (60 mg), yellowish oil. R f (Petroleum ether/EtOAc=4:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.50–7.41(m,3H),7.21–7.15(m,5H),6.84–6.82(m,2H),4.58(d,J＝15.2Hz,1H),4.53(d,J＝15.2Hz,1H),3.20(d,J＝18.0Hz,1H),3.10(d,J＝18.0Hz,1H),2.31–2.22(m,2H),2.19–2.05(m,2H),1.48(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ180.2,143.9,136.7,130.1,129.3,129.1,128.6,128.0,127.7,127.5,118.9,117.1,109.4,50.6,44.5,31.1,22.3,13.4,12.9.HRMS(ESI-TOF)Calcd for C 23 H 22 N 3 O + ([M+H] + )356.1757.Found 356.1751.
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 1), flash column chromatography (petroleum ether/ethyl acetate=20:1, v/v), 65% yield (88 mg), yellowish oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.39–7.30(m,3H),7.19–7.14(m,5H),6.89–6.84(m,2H),4.60(d,J＝15.4Hz,1H),4.49(d,J＝15.3Hz,1H),4.15–4.03(m,4H),2.99(d,J＝16.0Hz,1H),2.95(d,J＝16.0Hz,1H),2.23–2.07(m,3H),1.94(ddd,J＝13.0,10.1,5.4Hz,1H),1.31(s,3H),1.24(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.5,173.0,171.2,141.9,137.4,129.8,129.5,129.1,128.4,128.3,127.4,127.1,115.0,61.0,60.4,50.8,44.3,30.9,30.4,29.4,22.1,14.2,14.0.HRMS(ESI-TOF)Calcd for C 27 H 32 NO 5 + ([M+H] + )450.2275.Found 450.2271.
Ethyl 3- (1-benzyl-5- (4-tert-butylphenyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 2), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 53% yield (81 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.34–7.31(m,2H),7.17–7.13(m,3H),7.12–7.09(m,2H),6.87–6.84(m,2H),4.59(d,J＝15.3Hz,1H),4.49(d,J＝15.3Hz,1H),4.15–4.03(m,4H),3.02(d,J＝15.9Hz,1H),2.96(d,J＝15.9Hz,1H),2.23–2.06(m,3H),1.93(ddd,J＝13.0,10.5,5.1Hz,1H),1.32(s,9H),1.30(s,3H),1.24(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.6,173.1,171.4,152.3,142.0,137.5,129.4,128.2,127.5,127.1,126.4,125.3,114.7,61.0,60.4,50.8,44.3,34.7,31.3,30.9,30.5,29.4,22.1,14.2,14.1.HRMS(ESI-TOF)Calcd for C 31 H 40 NO 5 + ([M+H] + )506.2901.Found 506.2903.
Ethyl 3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-methoxyphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 3), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 45% yield (65 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.23–7.18(m,3H),7.14–7.10(m,2H),6.92(dd,J＝7.1,2.4Hz,2H),6.88–6.84(m,2H),4.61(d,J＝15.3Hz,1H),4.49(d,J＝15.3Hz,1H),4.16–4.04(m,4H),3.84(s,3H),3.00(d,J＝15.9Hz,1H),2.96(d,J＝15.9Hz,1H),2.24–2.07(m,3H),1.95(ddd,J＝13.0,10.2,5.3Hz,1H),1.31(s,3H),1.25(t,J＝7.0Hz,3H),1.24(t,J＝7.0Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.6,173.0,171.4,160.1,141.8,137.6,131.2,128.3,127.4,127.1,121.6,114.8,113.8,61.0,60.4,55.3,50.8,44.3,30.9,30.5,29.4,22.1,14.2,14.1.HRMS(ESI-TOF)Calcd for C 28 H 34 NO 6 + ([M+H] + )480.2381.Found 480.2388.
Ethyl 3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-iodophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 4), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 57% yield (99 mg), colorless oil, R f (Petroleum ether/EtOAc=8:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.67–7.64(m,2H),7.20–7.17(m,3H),6.92–6.87(m,4H),4.59(d,J＝15.4Hz,1H),4.47(d,J＝15.4Hz,1H),4.14–4.02(m,4H),2.94(s,2H),2.18–2.06(m,3H),2.00–1.90(m,1H),1.30(s,3H),1.23(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,172.9,171.1,141.0,137.6,137.2,131.5,129.0,128.4,127.32,127.31,115.7,95.4,61.1,60.5,50.9,44.4,30.9,30.3,29.4,22.1,14.2,14.1.HRMS(ESI-TOF)Calcd for C 27 H 31 INO 5 + ([M+H] + )576.1241.Found 576.1249.
Ethyl 3- (1-benzyl-5- (4-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 5), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 57% yield (91 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.47–7.43(m,2H),7.20–7.17(m,3H),7.06–7.03(m,2H),6.88(dd,J＝6.8,2.7Hz,2H),4.60(d,J＝15.4Hz,1H),4.47(d,J＝15.4Hz,1H),4.14–4.02(m,4H),2.94(s,2H),2.23–2.07(m,3H),2.01–1.91(m,1H),1.30(s,3H),1.24(t,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,172.9,171.1,140.9,137.2,131.6,131.4,128.42,128.40,127.3,123.6,115.7,61.1,60.4,50.9,44.3,30.9,30.3,29.4,22.1,14.2,14.0.HRMS(ESI-TOF)Calcd for C 27 H 31 BrNO 5 + ([M+H] + )528.1380.Found 528.1383.
Ethyl 3- (1-benzyl-5- (4-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 6), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 54% yield (81 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.31–7.28(m,2H),7.20–7.16(m,3H),7.12–7.09(m,2H),6.89–6.86(m,2H),4.60(d,J＝15.4Hz,1H),4.47(d,J＝15.4Hz,1H),4.15–4.03(m,4H),2.94(s,2H),2.19–2.07(m,3H),1.97–1.91(m,1H),1.30(s,3H),1.24(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,172.9,171.1,140.8,137.2,135.3,131.1,128.7,128.4,127.9,127.32,127.30,115.7,61.1,60.4,50.9,44.3,30.9,30.3,29.4,22.1,14.2,14.0.HRMS(ESI-TOF)Calcd for C 27 H 31 ClNO 5 + ([M+H] + )484.1885.Found 484.1881.
Ethyl 3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 7), flash column chromatography (petroleum ether/ethyl acetate=25:1, v/v), 70% yield (99 mg), colorless oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.18–7.12(m,5H),7.03–6.97(m,2H),6.86(dd,J＝6.7,2.9Hz,2H),4.60(d,J＝15.4Hz,1H),4.46(d,J＝15.4Hz,1H),4.15–4.03(m,4H),2.94(s,2H),2.33–2.07(m,3H),2.01–1.91(m,1H),1.31(s,3H),1.24(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,172.9,171.1,163.1(d,J＝249.5Hz),141.0,137.3,131.8(d,J＝8.3Hz),128.4,127.32,127.26,125.5(d,J＝3.4Hz),115.6,115.5(d,J＝21.7Hz),61.1,60.4,50.9,44.3,30.9,30.3,29.4,22.1,14.2,14.0. 19 F NMR(376MHz,CDCl 3 )δ-111.34(ddd,J＝13.7,8.7,5.6Hz,1F).HRMS(ESI-TOF)Calcd for C 27 H 31 FNO 5 + ([M+H] + )468.2181.Found 468.2182.
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5- (4-trifluoromethylphenyl) -2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 8), flash column chromatography separation (Petroleum ether/Ethyl acetate)Ester=25:1, v/v), 49% yield (76 mg), colorless oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝8.1Hz,2H),7.30(d,J＝8.0Hz,2H),7.18–7.13(m,3H),6.85–6.82(m,2H),4.62(d,J＝15.4Hz,1H),4.48(d,J＝15.4Hz,1H),4.15–4.03(m,4H),2.95(s,2H),2.25–2.09(m,3H),2.03–1.93(m,1H),1.33(s,3H),1.24(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.3,172.8,170.9,140.6,137.0,133.3(q,J＝1.5Hz),131.2(q,J＝32.7Hz),130.2,128.5,127.4,127.3,125.3(q,J＝3.8Hz),123.8(q,J＝272.4Hz),116.3,61.2,60.5,51.0,44.4,30.9,30.3,29.4,22.1,14.2,14.0. 19 F NMR(376MHz,CDCl 3 )δ-62.86(s,3F).HRMS(ESI-TOF)Calcd for C 28 H 31 F 3 NO 5 + ([M+H] + )518.2149.Found 518.2146.
Ethyl 3- (1-benzyl-5- (3-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 9), flash column chromatography (petroleum ether/ethyl acetate=25:1, v/v), 54% yield (86 mg), colorless oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.50(ddd,J＝8.0,2.0,1.2Hz,1H),7.26(dd,J＝1.8,1.8Hz,1H),7.21–7.17(m,4H),7.11(ddd,J＝7.7,1.4,1.4Hz,1H),6.87(dd,J＝6.7,2.9Hz,2H),4.59(d,J＝15.4Hz,1H),4.48(d,J＝15.3Hz,1H),4.15–4.03(m,4H),2.95(s,2H),2.19–2.08(m,3H),2.02–1.92(m,1H),1.31(s,3H),1.24(t,J＝7.2Hz,3H),1.22(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.3,172.9,170.9,140.5,137.1,132.7,132.3,131.5,129.9,128.4,127.44,127.36,122.3,116.0,61.1,60.5,51.0,44.4,30.8,30.4,29.4,22.0,14.2,14.1.HRMS(ESI-TOF)Calcd for C 27 H 31 BrNO 5 + ([M+H] + )528.1380.Found 528.1396.
Ethyl 3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (2-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 b 10), 2:3 diastereomeric mixture, flash column chromatography (petroleum ether/ethyl acetate=30:1, v/v), 44% yield (62 mg), yellowish oil. R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.42–7.34(stack,1H major and 1H minor),7.14–7.00(stack,6H major and 6H minor),6.83–6.79(stack,2H major and 2H minor),4.89–4.81(stack,1H major and 1H minor),4.25–4.17(stack,1H major and 1H minor),4.16–3.93(stack,4H major and 4H minor),3.00–2.91(stack,2H major and 2H minor),2.25–1.88(stack,4H major and 4H minor),1.34(s,3H minor),1.31(s,3H major),1.24(t,J＝7.1Hz,3H major and 3H minor),1.18(t,J＝7.1,3H major),1.17(t,J＝7.1,3H minor). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ180.89(major),180.86(minor),173.05(major),172.98(minor),170.75(major),170.69(minor),160.0(d,J＝248.3Hz,minor),160.1(d,J＝248.8Hz,major),137.2(major),137.1(minor),136.2(minor),135.9(major),132.39(d,J＝11.4Hz,major),132.36(d,J＝11.3Hz,minor),131.52(d,J＝8.0Hz,minor),131.46(d,J＝8.0Hz,major),128.3(major),128.2(minor),127.6,127.24(major),127.21(minor),127.1,124.18(d,J＝2.7Hz),124.15(d,J＝3.3Hz),117.6(d,J＝15.8Hz,minor),117.5(d,J＝16.0Hz,major),117.25(minor),117.19(major),115.7(d,J＝21.3Hz,minor),115.6(d,J＝21.3Hz,major),61.03(minor),60.96(major),60.42(major),60.35(minor),51.2(major),51.1(minor),44.3(d,J＝2.0Hz,minor),44.1(d,J＝1.8Hz,major),30.84(minor),30.75(major),30.4(minor),30.3(major),29.4(minor),29.1(major),22.2(minor),21.9(major),14.2(major and minor),14.0(major),13.9(minor). 19 F NMR(376MHz,CDCl 3 )δ-112.16to-112.27(stack,1F major and 1F minor).HRMS(ESI-TOF)Calcd for C 27 H 31 FNO 5 + ([M+H] + )468.2181.Found 468.2180.
Ethyl 3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 c), flash column chromatography (petroleum ether/ethyl acetate=8:1, v/v), 57% yield (77 mg), yellowish oil, R f (Petroleum ether/EtOAc=4:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ8.69(ddd,J＝4.9,1.9,0.9Hz,1H),7.59(ddd,J＝7.7,7.7,1.8Hz,1H),7.37(ddd,J＝7.7,1.1,1.1Hz,1H),7.28–7.24(m,1H),7.09(q,J＝3.6Hz,3H),6.82–6.80(m,2H),4.90(d,J＝15.2Hz,1H),4.85(d,J＝15.2Hz,1H),4.14–4.02(m,4H),3.11(d,J＝15.9Hz,1H),3.06(d,J＝15.9Hz,1H),2.20–2.08(m,3H),1.95(ddd,J＝12.7,9.2,5.6Hz,1H),1.32(s,3H),1.22(t,J＝7.1Hz,6H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.1,173.0,171.1,149.5,149.2,140.3,137.5,136.5,128.2,127.4,127.0,125.3,123.5,116.9,61.2,60.4,51.1,43.9,30.9,30.4,29.4,22.0,14.2,14.0.HRMS(ESI-TOF)Calcd for C 26 H 31 N 2 O 5 + ([M+H] + )451.2227.Found 451.2217.
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 d 1), flash column chromatography separation (petroleum ether/ethyl acetate=24:1, v/v), 61% yield (72 mg), yellowish oil. R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.18–7.14(m,3H),7.01(d,J＝7.0Hz,4H),6.85(dd,J＝6.4,3.1Hz,2H),4.61(d,J＝15.3Hz,1H),4.43(d,J＝15.3Hz,1H),4.10(qd,J＝7.2,3.9Hz,2H),2.21–2.02(m,3H),1.98–1.91(m,1H),1.57(s,3H),1.30(s,3H),1.24(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.8,173.0,162.7(d,J＝248.8Hz),137.6,136.2,131.7(d,J＝8.2Hz),128.3,127.4,127.2,126.3(d,J＝3.6Hz),119.2,115.4(d,J＝21.6Hz),60.5,50.7,44.1,30.6,29.6,21.9,14.2,8.7. 19 F NMR(376MHz,CDCl 3 )δ-112.19(p,J＝7.3Hz,1F).HRMS(ESI-TOF)Calcd for C 24 H 27 FNO 3 + ([M+H] + )396.1969.Found 396.1966.
Ethyl 3- (1-benzyl-5- (3, 5-bistrifluoromethylphenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 d 2), flash column chromatography (petroleum ether/ethyl acetate=25:1, v/v), 64% yield (98 mg), yellowish oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.39(s,2H),7.19–7.12(m,3H),6.77(dd,J＝7.4,2.2Hz,2H),4.65(d,J＝15.5Hz,1H),4.41(d,J＝15.6Hz,1H),4.18–4.06(m,2H),2.33–2.07(m,3H),2.05–1.94(m,1H),1.60(s,3H),1.35(s,3H),1.26(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.5,172.8,136.8,134.6,132.7,131.8(q,J＝33.7Hz),129.9(q,J＝3.9Hz),128.6,127.6,127.2,122.9(q,J＝273.0Hz),122.4(hept,J＝3.8Hz),121.6,60.6,51.1,44.5,30.6,29.7,22.0,14.2,8.8. 19 F NMR(376MHz,CDCl 3 )δ-62.96(s,6F).HRMS(ESI-TOF)Calcd for C 26 H 26 F 6 NO 3 + ([M+H] + )514.1811.Found 514.1808.
Ethyl 3- (1-benzyl-4-ethyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 e 1), flash column chromatography (petroleum ether/ethyl acetate=50:1, v/v), 73% yield (86 mg), yellowish oil, R f (Petroleum ether/EtOAc=10:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,3H),7.16–7.13(m,3H),7.07–7.04(m,2H),6.85–6.81(m,2H),4.56(d,J＝15.2Hz,1H),4.42(d,J＝15.2Hz,1H),4.16–4.04(m,2H),2.20–1.93(m,6H),1.35(s,3H),1.25(t,J＝7.1Hz,3H),0.92(t,J＝7.6Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.6,173.1,138.2,137.7,130.6,129.9,128.7,128.3,128.2,127.6,127.0,124.1,60.4,51.2,44.1,31.2,29.6,22.9,17.5,15.1,14.2.HRMS(ESI-TOF)Calcd for C 25 H 30 NO 3 + ([M+H] + )392.2220.Found 392.2222.
3- (1-benzyl-3-methyl-2-oxo-5-phenyl-4-propyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 e 2), flash column chromatography (petroleum ether/ethyl acetate=50:1, v/v), 77% yield (93 mg), colorless oil, R f (Petroleum ether/EtOAc=10:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,3H),7.16–7.13(m,3H),7.05–7.02(m,2H),6.85–6.80(m,2H),4.55(d,J＝15.2Hz,1H),4.42(d,J＝15.2Hz,1H),4.11(qd,J＝7.1,5.2Hz,2H),2.19–1.88(m,6H),1.41–1.23(m,8H),0.75(t,J＝7.3Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.6,173.1,138.5,137.7,130.7,129.9,128.6,128.3,128.2,127.5,127.0,122.7,60.4,51.1,44.1,31.2,29.6,26.8,23.5,22.8,14.5,14.2.HRMS(ESI-TOF)Calcd for C 26 H 32 NO 3 + ([M+H] + )406.2377.Found 406.2376.
Ethyl 3- (1- (4-chlorobenzyl) -4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 f 1), flash column chromatography (petroleum ether/ethyl acetate=25:1, v/v), 51% yield (76 mg), colorless oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.19–7.14(m,4H),7.07–7.01(m,2H),6.80(d,J＝8.5Hz,2H),4.55(d,J＝15.4Hz,1H),4.44(d,J＝15.4Hz,1H),4.08(dtd,J＝14.2,7.1,3.8Hz,4H),2.94(s,2H),2.23–2.04(m,3H),2.00–1.89(m,1H),1.29(s,3H),1.24(t,J＝7.1Hz,3H),1.22(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,172.8,171.1,163.1(d,J＝249.9Hz),140.6,135.8,133.2,131.7(d,J＝8.4Hz),128.8,128.6,125.3(d,J＝3.6Hz),115.8,115.7(d,J＝21.6Hz),61.1,60.5,50.9,43.6,30.8,30.2,29.4,22.0,14.2,14.0. 19 F NMR(376MHz,CDCl 3 )δ-62.96(s,1F).HRMS(ESI-TOF)Calcd for C 27 H 30 ClFNO 5 + ([M+H] + )502.1791.Found 502.1799.
Ethyl 3- (4- (2-ethoxy-2-oxoethyl) -1- (4-fluorobenzyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 f 2), flash column chromatography (petroleum ether/ethyl acetate=25:1, v/v), 64% yield (94 mg), yellowish oil. R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.16(ddd,J＝8.3,5.3,2.5Hz,2H),7.07–7.01(m,2H),6.90–6.80(m,4H),4.55(d,J＝15.3Hz,1H),4.45(d,J＝15.3Hz,1H),4.14–4.02(m,4H),2.94(s,2H),2.19–2.04(m,3H),2.00–1.89(m,1H),1.29(s,3H),1.24(t,J＝7.1Hz,3H),1.22(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,172.8,171.1,163.1(d,J＝249.8Hz),162.0(d,J＝245.8Hz),140.7,133.1(d,J＝3.3Hz),131.7(d,J＝8.3Hz),129.2(d,J＝8.2Hz),125.5(d,J＝3.5Hz),115.8,115.6(d,J＝21.7Hz),115.3(d,J＝21.6Hz),61.1,60.5,50.9,43.6,30.9,30.3,29.4,22.0,14.2,14.0. 19 F NMR(376MHz,CDCl 3 )δ-111.03(ddd,J＝13.8,8.7,5.5Hz,1F),-115.00(p,J＝8.1,7.7Hz,1F).HRMS(ESI-TOF)Calcd for C 27 H 30 F 2 NO 5 + ([M+H] + )486.2087.Found 486.2093.
3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -1-isopropyl)Ethyl-3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl-propionate (3 g 1), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 63% yield (79 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.39–7.34(m,2H),7.14(dd,J＝8.7,8.7Hz,2H),4.12–4.04(m,4H),3.63(hept,J＝6.9Hz,1H),2.88(s,2H),2.17–2.13(m,2H),2.03(ddd,J＝13.6,9.4,6.8Hz,1H),1.92–1.85(m,1H),1.32(s,3H),1.30(s,3H),1.26–1.21(m,9H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.5,173.0,171.3,163.1(d,J＝249.6Hz),141.8,131.8(d,J＝8.3Hz),126.3(d,J＝3.5Hz),115.8(d,J＝21.6Hz),115.2,61.0,60.4,50.9,46.3,31.0,30.6,29.3,21.9,20.2,20.1,14.2,14.1. 19 F NMR(376MHz,CDCl 3 )δ-111.36(ddd,J＝13.8,8.7,5.5Hz,1F).HRMS(ESI-TOF)Calcd for C 23 H 31 FNO 5 + ([M+H] + )420.2181.Found 420.2190.
Ethyl 3- (1-cyclohexyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 g 2), flash column chromatography (petroleum ether/ethyl acetate=40:1, v/v), 65% yield (89 mg), colorless oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.37–7.32(m,2H),7.17–7.11(m,2H),4.12–4.04(m,4H),3.15(tt,J＝12.1,3.8Hz,1H),2.87(s,2H),2.16–2.08(m,3H),2.02(ddd,J＝13.6,9.6,6.8Hz,1H),1.91–1.84(m,1H),1.73–1.50(m,6H),1.26–1.21(m,9H),1.10–0.97(m,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.5,173.0,171.3,163.1(d,J＝249.3Hz),142.0,131.7(d,J＝8.5Hz),126.4(d,J＝3.5Hz),115.8(d,J＝21.5Hz),115.1,61.0,60.4,54.6,50.9,31.0,30.6,29.9,29.8,29.3,26.03,26.01,25.0,21.9,14.2,14.1. 19 F NMR(376MHz,CDCl 3 )δ-111.36(tt,J＝9.2,5.5Hz,1F).HRMS(ESI-TOF)Calcd for C 26 H 35 FNO 5 + ([M+H] + )460.2494.Found 460.2493.
Ethyl 3- (1-allyl-3, 4-dimethyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4H 1), flash column chromatography (petroleum ether/ethyl acetate=50:1, v/v), 34% yield (33 mg), yellowish oil. R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.44–7.37(m,3H),7.28–7.24(m,2H),5.60(ddt,J＝17.2,10.5,5.3Hz,1H),4.99(dq,J＝10.3,1.5Hz,1H),4.86(dq,J＝17.2,1.6Hz,1H),4.10(qd,J＝7.2,2.6Hz,2H),4.00–3.89(m,2H),2.25–2.05(m,3H),1.99–1.87(m,1H),1.63(s,3H),1.27–1.22(m,6H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.6,173.1,137.3,133.2,130.3,129.7,128.7,128.4,118.5,116.5,60.5,50.6,42.7,30.6,29.7,21.9,14.2,8.8.HRMS(ESI-TOF)Calcd for C 20 H 26 NO 3 + ([M+H] + )328.1907.Found 328.1909.
3- (1-allyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4H 2), flash column chromatography (petroleum ether/ethyl acetate=25:1, v/v), 37% yield (38 mg), yellowish oil. R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.28–7.22(m,2H),7.14–7.08(m,2H),5.61(ddt,J＝17.1,10.4,5.3Hz,1H),5.01(dq,J＝10.3,1.4Hz,1H),4.86(dq,J＝17.1,1.6Hz,1H),4.10(qd,J＝7.1,2.1Hz,2H),3.99–3.87(m,2H),2.24–2.02(m,3H),1.98–1.86(m,1H),1.61(s,3H),1.27(s,3H),1.24(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.5,173.0,162.8(d,J＝248.7Hz),136.3,133.1,131.6(d,J＝8.2Hz),126.2(d,J＝3.5Hz),119.0,116.5,115.5(d,J＝21.6Hz),60.5,50.6,42.7,30.6,29.7,21.9,14.2,8.8. 19 F NMR(376MHz,CDCl 3 )δ-112.12(td,J＝8.6,4.5Hz,1F).HRMS(ESI-TOF)Calcd for C 20 H 25 FNO 3 + ([M+H] + )346.1813.Found 346.1811.
Ethyl 3- (5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-1- (2-propyn-1-yl) -2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 i), flash column chromatography separation (petroleum ether/ethyl acetate=25:1, v/v), 56% yield (59 mg), yellowish oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.39–7.34(m,2H),7.18–7.13(m,2H),4.15–4.04(m,3H),4.00(dd,J＝17.6,2.5Hz,1H),2.24–2.02(m,4H),1.98–1.88(m,1H),1.63(s,3H),1.26(s,3H),1.24(t,J＝7.1Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,173.0,162.9(d,J＝249.1Hz),135.5,131.7(d,J＝8.3Hz),125.7(d,J＝3.4Hz),119.4,115.8(d,J＝21.7Hz),78.8,71.2,60.5,50.6,30.8,30.2,29.5,21.5,14.2,8.8. 19 F NMR(376MHz,CDCl 3 )δ-111.77(tt,J＝8.9,5.3Hz,1F).HRMS(ESI-TOF)Calcd for C 20 H 23 FNO 3 + ([M+H] + )344.1656.Found 344.1654.
Ethyl 3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-1-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 j 1), flash column chromatography separation (petroleum ether/ethyl acetate=25:1, v/v), 56% yield (77 mg), yellowish oil. R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.26–7.21(m,4H),7.19–7.14(m,1H),7.00–6.91(m,4H),4.19–4.03(m,4H),3.14(d,J＝15.9Hz,1H),3.10(d,J＝15.9Hz,1H),2.36–2.12(m,3H),2.02(ddd,J＝13.7,10.7,5.3Hz,1H),1.38(s,3H),1.29(t,J＝7.1Hz,3H),1.22(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ180.4,172.8,171.4,162.7(d,J＝249.5Hz),140.9,135.0,131.3(d,J＝8.3Hz),128.7,126.9,126.8,125.6(d,J＝3.5Hz),115.9,115.4(d,J＝21.7Hz),61.3,60.5,51.3,31.4,30.7,29.4,22.1,14.2,14.1. 19 F NMR(376MHz,CDCl 3 )δ-111.55(tt,J＝8.8,5.4Hz,1F).HRMS(ESI-TOF)Calcd for C 26 H 29 FNO 5 + ([M+H] + )454.2024.Found 454.2029.
Ethyl 3- (1- (4-tert-butylphenyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 j 2), flash column chromatography separation (petroleum ether/ethyl acetate=40:1, v/v), 50% yield (76 mg), yellowish oil. R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.26–7.22(m,4H),6.97–6.92(m,2H),6.91–6.87(m,2H),4.19–4.03(m,4H),3.14(d,J＝15.9Hz,1H),3.09(d,J＝15.8Hz,1H),2.35–2.11(m,3H),2.00(ddd,J＝13.6,10.8,5.2Hz,1H),1.37(s,3H),1.29(t,J＝7.1Hz,3H),1.25(s,9H),1.22(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ180.5,172.9,171.5,162.7(d,J＝249.1Hz),149.8,141.0,132.2,131.3(d,J＝8.3Hz),126.2,125.7(d,J＝3.3Hz),125.6,115.7,115.4(d,J＝21.7Hz),61.3,60.5,51.2,34.5,31.4,31.3,30.8,29.4,22.1,14.2,14.1. 19 F NMR(376MHz,CDCl 3 )δ-111.73(ddd,J＝13.8,8.8,5.5Hz,1F).HRMS(ESI-TOF)Calcd for C 30 H 37 FNO 5 + ([M+H] + )510.2650.Found 510.2635.
Ethyl 3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -1- (4-methoxyphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 j 3), flash column chromatography (petroleum ether/ethyl acetate=30:1, v/v), 60% yield (87 mg), colorless oil, R f (Petroleum ether/EtOAc =6:1,v/v)0.33. 1 H NMR(400MHz,CDCl 3 )δ7.26–7.21(m,2H),6.97–6.88(m,4H),6.78–6.74(m,2H),4.15(q,J＝7.1Hz,2H),4.09(qd,J＝7.1,3.0Hz,2H),3.74(s,3H),3.11(d,J＝2.4Hz,2H),2.35–2.11(m,3H),2.00(ddd,J＝13.7,10.7,5.4Hz,1H),1.37(s,3H),1.28(t,J＝7.2Hz,3H),1.23(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ180.6,172.9,171.4,162.7(d,J＝249.3Hz),158.2,141.1,131.4(d,J＝8.2Hz),128.2,127.9,125.6(d,J＝3.5Hz),115.5,115.4(d,J＝21.5Hz),114.0,61.3,60.5,55.4,51.1,31.4,30.7,29.4,22.0,14.2,14.1. 19 F NMR(376MHz,CDCl 3 )δ-111.67(dt,J＝8.9,5.1Hz,1F).HRMS(ESI-TOF)Calcd for C 27 H 31 FNO 6 + ([M+H] + )484.2130.Found 484.2135.
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid methyl ester (4 k 1), flash column chromatography (petroleum ether/ethyl acetate=24:1, v/v), 63% yield (73 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.18–7.14(m,3H),7.00(d,J＝7.0Hz,4H),6.85(dd,J＝5.6,4.1Hz,2H),4.60(d,J＝15.4Hz,1H),4.44(d,J＝15.3Hz,1H),3.64(s,3H),2.26–2.04(m,3H),1.99–1.89(m,1H),1.57(s,3H),1.30(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.7,173.4,162.7(d,J＝248.8Hz),137.6,136.3,131.7(d,J＝8.2Hz),128.3,127.4,127.2,126.3(d,J＝3.4Hz),119.2,115.4(d,J＝21.6Hz),51.6,50.7,44.1,30.6,29.4,21.9,8.7. 19 F NMR(376MHz,CDCl 3 )δ-112.18(p,J＝6.9Hz,1F).HRMS(ESI-TOF)Calcd for C 23 H 25 FNO 3 + ([M+H] + )382.1813.Found 382.1812.
Phenyl 3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 k 2), flash column chromatography separation (petroleum ether/ethyl acetate=24:1, v/v), 64% yield (85 mg), colorless oil, R f (Petroleum ether/EtOAc=6:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.36(tt,J＝7.9,2.2Hz,2H),7.24–7.15(m,4H),7.06–6.99(m,6H),6.90–6.85(m,2H),4.64(d,J＝15.3Hz,1H),4.46(d,J＝15.3Hz,1H),2.48–2.22(m,3H),2.06(ddd,J＝13.5,10.6,5.1Hz,1H),1.62(s,3H),1.34(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.8,171.5,162.8(d,J＝249.0Hz),150.6,137.5,136.4,131.7(d,J＝8.2Hz),129.4,128.4,127.4,127.2,126.2(d,J＝3.6Hz),125.8,121.5,119.2,115.5(d,J＝21.6Hz),50.7,44.2,30.5,29.7,21.9,8.8. 19 F NMR(376MHz,CDCl 3 )δ-112.06(p,J＝7.0Hz,1F).HRMS(ESI-TOF)Calcd for C 28 H 27 FNO 3 + ([M+H] + )444.1969.Found 444.1958.
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) -N, N-dimethylpropionamide (4 k 3), flash column chromatography separation (petroleum ether/ethyl acetate=1:1, v/v), 50% yield (59 mg), pale yellow oil, R f (Petroleum ether/EtOAc=2:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.17–7.13(m,3H),7.06–7.00(m,4H),6.89–6.85(m,2H),4.63(d,J＝15.2Hz,1H),4.44(d,J＝15.2Hz,1H),2.91(s,3H),2.87(s,3H),2.23–1.94(m,4H),1.59(s,3H),1.30(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ182.1,172.3,162.7(d,J＝248.8Hz),137.7,135.7,131.7(d,J＝8.2Hz),128.3,127.6,127.2,126.4(d,J＝3.5Hz),120.0,115.5(d,J＝21.6Hz),50.7,44.0,37.2,35.4,31.0,28.4,21.7,8.7. 19 F NMR(376MHz,CDCl 3 )δ-112.13(p,J＝6.9Hz,1F).HRMS(ESI-TOF)Calcd for C 24 H 28 FN 2 O 2 + ([M+H] + )395.2129.Found 395.2129.
1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-3- (3-oxo-3-phenylpropyl) -1, 3-dihydro-2H-pyrrol-2-one (4 k 4), flash column chromatography separation (petroleum ether/ethyl acetate=50:1, v/v), 69% yield (89 mg), colorless oil, R f (Petroleum ether/EtOAc=10:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.80–7.78(m,2H),7.58–7.53(m,1H),7.44–7.40(m,2H),7.23–7.16(m,3H),7.04–6.99(m,2H),6.97–6.90(m,4H),4.69(d,J＝15.1Hz,1H),4.44(d,J＝15.1Hz,1H),2.84(ddd,J＝16.9,10.3,5.8Hz,1H),2.62(ddd,J＝16.9,9.9,5.4Hz,1H),2.15(qdd,J＝13.9,10.0,5.5Hz,2H),1.56(s,3H),1.33(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ199.3,182.1,162.7(d,J＝248.8Hz),137.8,136.7,136.1,133.0,131.7(d,J＝8.2Hz),128.6,128.4,128.0,127.8,127.3,126.3(d,J＝3.6Hz),119.7,115.5(d,J＝21.6Hz),50.7,44.1,33.5,30.0,21.8,8.7. 19 F NMR(376MHz,CDCl 3 )δ-112.10(ddd,J＝13.7,8.8,5.6Hz,1F).HRMS(ESI-TOF)Calcd for C 28 H 27 FNO 2 + ([M+H] + )428.2020.Found 428.2032.
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) -2-methylpropanoic acid methyl ester (4 l), 3:2 diastereomeric mixture, flash column chromatography separation (petroleum ether/ethyl acetate=40:1, v/v). R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. Major isomer 32% yield (38 mg), colorless oil. 1 H NMR(400MHz,CDCl 3 )δ7.17–7.14(m,3H),7.03–6.97(m,4H),6.87(dd,J＝6.5,3.1Hz,2H),4.67(d,J＝15.3Hz,1H),4.41(d,J＝15.4Hz,1H),3.51(s,3H),2.28(dtd,J＝13.5,6.8,3.2Hz,1H),2.19(dd,J＝13.7,9.2Hz,1H),1.84(dd,J＝13.7,3.4Hz,1H),1.52(s,3H),1.26(s,3H),1.14(d,J＝6.9Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ182.0,176.7,162.6(d,J＝248.6Hz),137.5,136.2,131.6(d,J＝8.2Hz),128.2,127.4,127.1,126.4(d,J＝3.4Hz),119.2,115.3(d,J＝21.5Hz),51.6,51.3,44.2,39.6,36.6,22.9,19.6,8.8. 19 F NMR(376MHz,CDCl 3 )δ-112.38(p,J＝7.2Hz,1F).HRMS(ESI-TOF)Calcd for C 24 H 27 FNO 3 + ([M+H] + ) 396.1969.Found 396.1960 minor isomer 23% yield (27 mg), colorless oil. 1 H NMR(400MHz,CDCl 3 )δ7.16–7.13(m,3H),7.04–6.97(m,4H),6.85–6.81(m,2H),4.76(d,J＝15.4Hz,1H),4.22(d,J＝15.4Hz,1H),3.67(s,3H),2.47(dtd,J＝13.8,6.9,4.7Hz,1H),2.37(dd,J＝14.0,8.2Hz,1H),1.61(dd,J＝14.0,4.8Hz,1H),1.58(s,3H),1.27(s,3H),1.13(d,J＝7.0Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ181.4,176.6,162.7(d,J＝248.4Hz),137.7,136.0,131.6(d,J＝8.3Hz),128.2,127.3,127.0,126.5(d,J＝3.4Hz),119.6,115.3(d,J＝21.6Hz),51.7,50.6,43.9,39.2,36.6,22.9,18.6,9.0. 19 F NMR(376MHz,CDCl 3 )δ-112.43(p,J＝7.0Hz,1F).HRMS(ESI-TOF)Calcd for C 24 H 27 FNO 3 + ([M+H] + )396.1969.Found 396.1963.
Diethyl 2- ((1-benzyl-4- (2-ethoxy-2-oxo-1-propionyloxyethyl) -3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) methyl) malonate (3 m), flash column chromatography (petroleum ether/ethyl acetate=20:1, v/v), 73% yield (129 mg), colorless oil, R f (Petroleum ether/EtOAc=5:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.34–7.15(m,5H),7.14–7.11(m,3H),6.81–6.77(m,2H),4.77(d,J＝15.4Hz,1H),4.26–4.03(m,8H),3.70–3.54(m,3H),2.50(dd,J＝14.7,9.4Hz,1H),2.35(dd,J＝14.7,3.2Hz,1H),1.30(t,J＝7.1Hz,3H),1.29(s,3H),1.25(t,J＝7.1Hz,3H),1.19(t,J＝7.1Hz,3H),1.05(t,J＝7.2Hz,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ179.9,169.4,169.1,167.8,167.3,143.4,137.2,130.3(br),129.2,129.0,128.2,127.8,127.2,127.0,113.3,61.8,61.604,61.597,61.5,50.3,49.0,48.0,43.9,34.1,21.8,14.02,14.00,13.9,13.5.HRMS(ESI-TOF)Calcd for C 33 H 40 NO 9 + ([M+H] + )594.2698.Found 594.2705.
1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-3- (2, 2-trichloroethyl) -1, 3-dihydro-2H-pyrrol-2-one (4 n), flash column chromatography separation (petroleum ether/ethyl acetate=60:1, v/v), 55% yield (71 mg), colorless oil, R f (Petroleum ether/EtOAc=10:1, v/v) 0.33. 1 H NMR(400MHz,CDCl 3 )δ7.19–7.15(m,3H),7.07–7.00(m,4H),6.92–6.87(m,2H),4.70(d,J＝15.3Hz,1H),4.33(d,J＝15.3Hz,1H),3.51(d,J＝15.2Hz,1H),3.11(d,J＝15.2Hz,1H),1.73(s,3H),1.32(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ180.1,162.8(d,J＝248.9Hz),137.4,137.1,131.7(d,J＝8.2Hz),128.3,127.8,127.2,126.4(d,J＝3.3Hz),116.8,115.5(d,J＝21.6Hz),96.3,59.1,51.0,44.6,24.3,10.6. 19 F NMR(376MHz,CDCl 3 )δ-111.92(p,J＝6.9Hz,1F).HRMS(ESI-TOF)Calcd for C 21 H 20 Cl 3 FNO + ([M+H] + )426.0589.Found 426.0588.
Claims (9)
1. A method for synthesizing 3, 4-double alkylation-4-pyrroline-2-ketone derivative by photocatalysis is characterized by adopting the following route:
wherein the method comprises the steps of
R 1 Is that
R 5 H, C of a shape of H, C 1-6 Alkyl, C 1-6 Alkoxy, halogen or halogen substituted C 1-6 An alkyl group;
R 2 is that
C 1-6 Alkyl or cycloalkyl, -CH 2 CH＝CH 2 or-CH 2 C.ident.CH wherein R 6 Is H or halogen; r is R 7 H, C of a shape of H, C 1-6 Alkyl, C 1-6 An alkoxy group; r is R 3 Is H or C 1-6 An alkyl group; r is R 4 H, C of a shape of H, C 1-6 Alkyl or COR 8 X is halogen; y is cyano, COR 8 Or halogen; r is R 8 Is C 1-6 Alkoxy, phenyl or NR 9 R 10 ；R 9 And R is 10 Each independently is C 1-6 An alkyl group; when R of the starting compound 1 3 In case of H, the prepared product is compound 3; when R of the starting compound 1 3 Is C 1-6 In the case of alkyl, the product prepared is compound 4;
the light is blue light or solar natural light; the photocatalytic catalyst is selected from Ir (ppy) 3 Or [ Ir (dtbbpy) (ppy) ] 2 ]PF 6 ；
The photocatalytic reaction requires the addition of a base selected from the group consisting of K 2 CO 3 、Na 2 CO 3 、Na 2 HPO 4 Or 2, 6-lutidine.
2. The method of claim 1, wherein: the halogen is fluorine, chlorine, bromine or iodine; the C is 1-6 Alkyl or cycloalkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl; the C is 1-6 Alkoxy is methoxy, ethoxy or tert-butoxy; the halogen substituted C 1-6 Alkyl is difluoromethyl or trifluoromethyl.
3. The method of claim 1, wherein: r is R 1 Is that
Wherein R is 5 Is H, 4-tBu, 4-MeO, 4-I, 4-Br, 4-Cl, 4-F, 4-CF 3 、3-Br、2-F、3,5-(CF 3 ) 2 ；R 2 Is->
iPr or Cy, where R 6 H, cl and F; r is R 7 H, t-Bu and OMe; r is R 3 H, me, et or Pr; r is R 4 Is H, me, COR 8 The method comprises the steps of carrying out a first treatment on the surface of the X is Br; y is cyano, COR 8 Halogen; r is R 8 Either OMe or OEt.
4. A method according to any one of claims 1-3, wherein: the amount of the photocatalytic catalyst is 1 to 5mol%.
5. The method of claim 4, wherein: the solvent is selected from CH 3 CN, DCE, DMSO or acetone.
6. The method of claim 4, wherein: the compound of formula 2 is used in an amount of 1 to 2.5 equivalents.
7. The method of claim 1, wherein: the alkali is Na 2 CO 3 。
8. The method of claim 1, wherein: the light is blue light or solar natural light; the photocatalytic catalyst is Ir (ppy) 3 The dosage is 1-5mol%; the solvent is CH 3 A CN; the amount of the compound of formula 2 is 1 to 2.5 equivalents; the base added in the photocatalysis reaction is Na 2 CO 3 ，Na 2 CO 3 The amount of (2) is 1-2 equivalents.
9. The method of claim 1, wherein: the 3, 4-dialkylated-4-pyrrolin-2-one derivative is selected from 3a-4n compounds:
3- (1-benzyl-4-cyanomethyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionitrile (3 a),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 1),
3- (1-benzyl-5- (4-tert-butylphenyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 2),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-methoxyphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 3),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-iodophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 4),
3- (1-benzyl-5- (4-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 5),
3- (1-benzyl-5- (4-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 6),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 7),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5- (4-trifluoromethylphenyl) -2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 8),
3- (1-benzyl-5- (3-chlorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 9),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -5- (2-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 b 10),
3- (1-benzyl-4- (2-ethoxy-2-oxoethyl) -3-methyl-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 c),
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 d 1),
3- (1-benzyl-5- (3, 5-bistrifluoromethylphenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 d 2),
3- (1-benzyl-4-ethyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 e 1),
3- (1-benzyl-3-methyl-2-oxo-5-phenyl-4-propyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4 e 2),
3- (1- (4-chlorobenzyl) -4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 f 1),
3- (4- (2-ethoxy-2-oxoethyl) -1- (4-fluorobenzyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 f 2),
3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -1-isopropyl-3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 g 1),
3- (1-cyclohexyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 g 2),
3- (1-allyl-3, 4-dimethyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4H 1),
3- (1-allyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (4H 2),
ethyl 3- (5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-1- (2-propyn-1-yl) -2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 i), ethyl 3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-1-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) propionate (3 j 1),
3- (1- (4-tert-butylphenyl-4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 j 2),
3- (4- (2-ethoxy-2-oxoethyl) -5- (4-fluorophenyl) -1- (4-methoxyphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionic acid ethyl ester (3 j 3),
methyl 3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 k 1),
phenyl 3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) propionate (4 k 2), 3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) -N, N-dimethylpropionamide (4 k 3),
1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-3- (3-oxo-3-phenylpropyl) -1, 3-dihydro-2H-pyrrol-2-one (4 k 4),
3- (1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl) -2-methylpropanoic acid methyl ester (4 l), 2- ((1-benzyl-4- (2-ethoxy-2-oxo-1-propionyloxyethyl) -3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl) methyl) malonic acid diethyl ester (3 m),
1-benzyl-5- (4-fluorophenyl) -3, 4-dimethyl-3- (2, 2-trichloroethyl) -1, 3-dihydro-2H-pyrrol-2-one (4 n).
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| 可见光催化膦酰基自由基介导的吡咯啉合成反应研究;张敏;中国优秀硕士学位论文全文数据库医药卫生科技辑(第01期);第E079-5页 * |
| 基于自由基迁移/[4~++2]极性环加成策略的烯烃官能化反应研究;陈洪磊;中国博士学位论文全文数据库工程科技Ⅰ辑(第09期);第B014-13页 * |
| 无金属催化非活化烯烃的多氯甲基化/芳基化自由基反应合成含多氯甲基吲哚啉;李文兰,等;有机化学;第39卷(第06期);第1727-1734页 * |
| 金属催化不饱和烃的官能化应用于吡咯烷和吡咯啉类化合物的合成;张金刚;等;有机化学;都38卷(第06期);第1319-1326页 * |
| 铜催化N-烯基丙烯酰胺氰异丙基化/烯基化反应合成1,3-二氢吡咯-2-酮;戴恩睿,等;有机化学;第39卷(第12期);第3524-3531页 * |
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