CN102153477A - Novel method for synthesizing chiral 4-nitryl-3, 5-diaryl cyclohexanone - Google Patents
Novel method for synthesizing chiral 4-nitryl-3, 5-diaryl cyclohexanone Download PDFInfo
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Abstract
The invention belongs to the field of asymmetric synthesis, and particularly relates to a novel method for catalyzing and synthesizing a chiral 4-nitryl-3, 5-diaryl cyclohexanone compound by chiral thiocarbamide as a catalyst. The method comprises the following steps of: (1) reacting by taking diketene and nitromethane as a reaction substrate, quinine-derived thiocarbamide as a chiral catalyst and methylbenzene as solvent at the temperature of between 20 and 25 DEG C for 24 to 72 hours to generate a Michael addition product; and (2) reacting by taking the Michael addition product obtained in the step (1) as a reactant, potassium hydroxide as a catalyst and ethanol as solvent at the temperature of between 0 and 10 DEG C for 0.5 to 2 hours to obtain a chiral 4-nitryl-3, 5-diaryl cyclohexanone derivative. The novel method for synthesizing the chiral 4-nitryl-3, 5-diaryl cyclohexanone compound has the advantages of readily available materials and mild reaction conditions and is easy and convenient to operate, and a reaction system is insensitive to air, aqueous vapor and the like and aftertreatment is convenient, so the chiral 4-nitryl-3, 5-diaryl cyclohexanone compound is suitable for industrial production. Simultaneously, the synthetic method has the characteristics of high yield and excellent diastereoselectivity and enantioselectivity.
Description
Technical field
The invention belongs to asymmetric catalysis field, being specifically related to a kind of is that catalyst prepares chirality 4-nitro-3 with the chirality thiocarbamide, the method for 5-diaryl pimelinketone compound.
Background technology
The chirality cyclohexanone derivative of functionalization is the compound that a class has biological and physiologically active, has considerable application in the synthesizing of many natural products.We find by literature survey, all contain the fragment of chirality cyclohexanone derivative in the molecular structure of a lot of natural products and medicine, (referring to: [T. Bui, C. F. Barbas III,
Tetrahedron Lett., 2000,41,6951], [J. Jiang, J. L. Bunda, G. A. Doss, G. G. Chicchi, M.M. Kurtz, K. L.Tsao, C. X. Tong, S. Zheng, A. Upthagrove, K. Samuel, K. Tschirret-Guth, R. Kumar, S. Wheeldon, A. Carlson, E. J. Hargreaves, R. Burns, D. Hamill, T. Ryan, C. Krause, S. M. Eng, W. DeVita, R. J. Mills, S. G.
J. Med. Chem., 2009,52,3039], [J. Barluenga, F. Aznar, C. Ribas, C. Vald é], [Y. Hoashi, T. Yabuta, P. Yuan, H. Miyabe, Y. Takemoto,
Tetrahedron., 2006,62,365], [A. C. Silvanus, B. J. Groombridge, B. I. Andrews, D. R. Carbery,
J. Org. Chem., 2010,75,7491]).
In the prior art, the method for synthesis of chiral cyclohexanone derivative has:
(1) this compounds is synthesized in classical Diels-Alder reaction, but these class methods much all will be used metal catalyst, and to air, steam etc. are relatively more responsive.(referring to: [and R. Thayumanavan, B. Dhevalapally, K. Sakthivel, F. Tanaka, C. F. Barbas III,
Tetrahedron Lett., 2002,43,3817], [D. B.Ramachary, N. S. Chowdari, C. F. Barbas III,
Tetrahedron Lett., 2002,43,6743], [F. Aznar, A. B. Garc ì a, M. A. Cabal,
Adv. Synth. Catal., 2006,348,2443], [D. B.Ramachary, N. S. Chowdari, C. F. Barbas III,
Angew. Chem., 2003,115,4365;
Angew. Chem. Int. Ed., 2003,42,4233], [J. Long, J. Hu, X. Shen, B. Ji, K. Ding,
J. Am. Chem. Soc., 2002,124,10]);
(2) 2004 years, people such as the Yue Gensen of Denmark have reported with Chiral Amine as catalyst α, the placed in-line Michael-aldol reaction of beta unsaturated ketone and 'beta '-ketoester obtains the chirality cyclohexanone derivative high enantioselectivity, and the enantioselectivity value is up to 99%.(referring to: [and N. Halland, P. S. Aburel,
Angew. Chem. Int. Ed. 2004,43,1272], [J. Pulkkinen, P. S. Aburel, N. Halland,
Adv. Synth. Catal. 2004,346,1077]), the reaction process of this method is as follows:
(3) 2004 years, Takemoto group reported the catalytic g of chirality cyclohexanediamine deutero-chirality thiourea catalyst, the method for unsaturated b-ketone ester of d-and nitro alkene reaction synthesis of chiral cyclohexanone derivative.(referring to: [and Y. Hoashi, T. Yabuta, Y. Takemoto,
Tetrahedron Letters. 2004,45,9185], [Y. Hoashi, T. Yabuta, P. Yuan, H. Miyabe, Y. Takemoto,
Tetrahedron.2006,62,365]), the reaction process of this method is as follows:
(4) 2009 years, gondola Melchiorre seminar has reported the α of quinine deutero-chiral primary amine as catalyst, two Michael addition cascade reactions take place in β insatiable hunger and ketone and nitro alkene, (Z)-3-cyano group-α-Jia Jirouguisuan ethyl ester or N-benzyl maleimide, obtain the chirality cyclohexanone derivative of functionalization highly-solid selectively.(referring to: [and L. Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli, P. Melchiorre,
Angew. Chem. Int. Ed., 2009,48,7196]), the reaction process of this method is as follows:
。
After nineteen twenty-four Kohler and Helmkamp form cyclohexanone derivative with sodium alkoxide as base catalysis diketene and dimethyl malonate [E. P Kohler, R. W. Helmkamp,
J. Am. Chem. Soc. 1924,46,1267], increasing achirality catalyzer, as: KF/ alkalescence Al
2O
3, phase-transfer catalyst (PTC), diazabicylo dodecane (DBU) or the like, be used to be used for synthetic achiral cyclohexanone derivative.(referring to: [and J. Li, W. Xu, G. Chen, T. Li,
Ultraso. Sonochem. 2005,12,473], [D. Zhang, X. Xu, J. Tan; Q. Liu,
Synlett., 2010,917], [A. C. Silvanus, B. J. Groombridge, B. I. Andrews, D. R. Carbery,
J. Org. Chem., 2010,75,7491]).
But the raw material that technique scheme relates to is difficult to obtain and costs an arm and a leg.
Summary of the invention
Goal of the invention of the present invention provides a kind of preparation method of chirality cyclohexanone derivative.
To achieve the above object of the invention, the technical scheme of this employing may further comprise the steps:
(1) with diketene R
1CH=CHCOCH=CHR
2With Nitromethane 99Min. be reaction substrate, be chiral catalyst with quinine deutero-thiocarbamide, be solvent with toluene, in 20～25 ℃ of down reactions 24～72 hours, generate single Michael addition adducts;
(2) the single Michael addition adducts with step (1) is a reactant, and with potassium hydroxide catalyst, ethanol is solvent, reacts 0.5～2 hour under 0～10 ℃ of condition, obtains 4-nitro-3,5-diaryl cyclohexanone derivative; Described 4-nitro-3, the chemical structural formula of 5-diaryl cyclohexanone derivative is as follows:
Wherein, R
1And R
2Be selected from respectively: phenyl, 3,5-Dimethoxyphenyl, p-methylphenyl, p-isopropyl phenyl, to fluorophenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, o-bromophenyl, a kind of in bromophenyl, p-trifluoromethyl phenyl, 2,4 dichlorophenyls, furyl, the thienyl;
In the technique scheme, in the step (1), described catalyst consumption is preferably 15～25% of diketene amount of substance, and most preferred amount is that 20%(result is best), the molecular formula of described quinine deutero-thiocarbamide is a kind of in the compound shown in the following chemical structural formula:
In the optimized technical scheme, in the step (1), R
1And R
2Identical.
In the technique scheme, in the step (2), catalyst consumption is 8～12% of a diketene amount of substance, more preferably 10%.
In the technique scheme, catalyst I and II according to known references [B. Vakulya, S. Varga, A. Cs á mpai, T. So ó s,
Org. Lett., 2005,7,1967] in method prepare, starting raw material is business-like quinine (Quinine) or quinidine (Quinidine), concrete reactions steps is as follows:
Wherein, reagent a is selected from: triphenyl phosphorus, diisopropyl azodiformate, diphenyl phosphate azide and tetrahydrofuran (THF); Reagent b is selected from: 3, and 5-two trifluoromethyl lsothiocyanates and tetrahydrofuran (THF)s.
In the technique scheme, it is opposite using catalyst I and the resulting product configuration of II.
In the technique scheme, what step (1) obtained is the product of Nitromethane 99Min. to single Michael addition of diketene, and do not become ring this moment, with R
1And R
2The diketene that all is phenyl is an example, and the described reaction process of step (1) is as follows:
After column chromatography for separation obtains the product of above-mentioned single Michael addition, be dissolved in the ethanolic soln of potassium hydroxide, carry out the Michael reaction second time, obtain 4-nitro-3,5-diaryl cyclohexanone derivative, described reaction process is as follows:
In the optimized technical scheme, as substrate diketene R
1CH=CHCOCH=CHR
2In R
1And R
2In aromatic ring on when electron-donating group (as methyl, sec.-propyl, methoxyl group) is arranged, the reaction times extends to 72 hours; When being other group, the reaction times is 24～48 hours.
In the further technical scheme, after reaction finishes, reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, and (eluent is an ethyl acetate to crude product: sherwood oil=1: 10) can obtain target product by simple column chromatography.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. the present invention has realized that first diketene and Nitromethane 99Min. are with synthetic 4-nitro-3 under quinine deutero-chirality thiocarbamide and the potassium hydroxide catalysed condition, the novel method for synthesizing of 5-diaryl cyclohexanone derivative, this method has raw material and is simple and easy to, and is easy and simple to handle, the reaction conditions gentleness, to air, water etc. are all insensitive, and post-processing operation is convenient, the productive rate height, advantages such as cis-selectivity is outstanding, and enantioselectivity is good.
2. when the present invention is than the Diels-Alder of classics reaction and above-mentioned additive method, these class methods be simple and easy to and the diketene of cheapness and the Nitromethane 99Min. that commercialization can get be starting raw material, very big advantage is arranged from cost.
Description of drawings
Accompanying drawing 1 is the crystalline structure synoptic diagram of compound 3n among the embodiment 15.
Embodiment
Below in conjunction with drawings and Examples the present invention is further described:
Embodiment one:
1a (58.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3a(63.5mg), yield is 86% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3): δ 7.34 – 7.27 (m, 2H), 7.27 – 7.22 (m, 3H), 7.23 – 7.15 (m, 3H), 6.98 (dd,
J=13.7,8.6 Hz, 2H), 5.22 (dd,
J=6.9,4.8 Hz, 1H), 3.87 (dd,
J=14.0,7.1 Hz, 1H), 3.81 – 3.61 (m, 1H), 3.26 (dd,
J=15.8,9.4 Hz, 1H), 3.00 (dd,
J=16.2,6.4 Hz, 1H), 2.93 – 2.67 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 42.0,42.4,42.6,43.5,91.7,127.4,127.8,128.3,128.6,129.2,129.5,137.0,139.6,207.9 ppm. HRMS:calcd.for C
18H
13NO
3295.1208, found:295.1207. [α]
Rt D=+44.6 (c=0.50, CHCl
3, 90.2% ee), above digital proof purpose product prepares successfully.
Embodiment two:
1a (58.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3a ' (28.1mg), yield are 38% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3): δ 7.34 – 7.27 (m, 2H), 7.27 – 7.22 (m, 3H), 7.23 – 7.15 (m, 3H), 6.98 (dd,
J=13.7,8.6 Hz, 2H), 5.22 (dd,
J=6.9,4.8 Hz, 1H), 3.87 (dd,
J=14.0,7.1 Hz, 1H), 3.81 – 3.61 (m, 1H), 3.26 (dd,
J=15.8,9.4 Hz, 1H), 3.00 (dd,
J=16.2,6.4 Hz, 1H), 2.93 – 2.67 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 42.0,42.4,42.6,43.5,91.7,127.4,127.8,128.3,128.6,129.2,129.5,137.0,139.6,207.9 ppm. HRMS:calcd.for C
18H
13NO
3295.1208, found:295.1210. [α]
Rt D=-45.8 (c=0.50, CHCl
3, 93.2% ee), above digital proof purpose product prepares successfully.
Embodiment three:
1b (88.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3b(79.8mg), yield is 77% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (300 MHz, CDCl
3): δ 6.37 (s, 3H), 6.20 (d,
J=1.8 Hz, 3H), 5.27 (dd,
J=6.8,5.1 Hz, 1H), 4.12 (d,
J=7.1 Hz, 1H), 3.98 – 3.80 (m, 1H), 3.75 (d,
J=7.2 Hz, 12H), 3.25 (dd,
J=16.1,9.3 Hz, 1H), 3.01 (dd,
J=16.3,5.9 Hz, 1H), 2.80 (dd,
J=15.4,5.9 Hz, 2H).
13C NMR (75MHz, CDCl
3): δ 42.0,42.5,42.9,43.4,55.5,91.4,99.6,99.7,139.3,142.0,161.2,161.6,207.8 ppm. HRMS:calcd.for C
18H
13NO
3415.1631, found:415.1633.[α]
Rt D=+26.3 (c=1.00, CHCl
3, 92.0% ee)., above digital proof purpose product prepares successfully.
Embodiment four:
1c (65.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3c(43.6mg), yield is 54% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.05 (d,
J=13.4 Hz, 6H), 6.86 (d,
J=7.6 Hz, 2H), 5.26 – 5.04 (m, 1H), 3.80 (d,
J=6.9 Hz, 1H), 3.75 – 3.51 (m, 1H), 3.20 (dd,
J=15.9,9.2 Hz, 1H), 3.05 – 2.86 (m, 1H), 2.83 – 2.63 (m, 2H), 2.24 (d,
J=5.9 Hz, 6H).
13(100MHz, CDCl3): δ 21.0,41.8,41.9,42.0,43.3,91.6,127.1,127.4,129.6,129.9,133.8,136.3,137.8,138.1,207.9 ppm. HRMS:calcd.for C for C NMR
18H
13NO
3323.1521, found:323.1525. [α]
Rt D=+90.6 (c=0.50, CHCl
3, 90.4% ee)., above digital proof purpose product prepares successfully.
Embodiment five:
1d (79.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3d(63.4mg), yield is 67% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.18 (dd,
J=17.6,8.1 Hz, 6H), 6.98 (d,
J=7.9 Hz, 2H), 5.27 (s, 1H), 3.90 (d,
J=6.8 Hz, 1H), 3.79 – 3.69 (m, 1H), 3.43 – 3.21 (m, 1H), 3.01 (d,
J=5.8 Hz, 1H), 2.93 – 2.71 (m, 4H), 1.22 (t,
J=6.8 Hz, 12H).
13C NMR (100MHz, CDCl
3): δ 23.7,23.9,33.6,41.7,41.9,42.2,43.2,91.5,126.9,127.1,127.3,127.4,134.1,136.7,148.6,148.8,207.9 ppm. HRMS:calcd.for C
18H
13NO
3379.2147, found:.379.2154. [α]
Rt D=+66.0 (c=1.00, CHCl
3, 90.0% ee)., above digital proof purpose product prepares successfully.
Embodiment six:
1e (67.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3e(60.4mg), yield is 73% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.22 (d,
J=2.9 Hz, 2H), 7.13 – 6.88 (m, 6H), 5.23 (dd,
J=6.7,4.8 Hz, 1H), 3.96 – 3.60 (m, 2H), 3.25 (dd,
J=15.6,8.5 Hz, 1H), 3.00 (d,
J=5.1 Hz, 1H), 2.93 – 2.63 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 41.4,41.6,42.0,43.5,91.3,115.8,116.0,116.1,116.3,128.6,128.8,129.2,129.3,132.4,134.8,206.9 ppm. HRMS:calcd.for C
18H
13NO
3331.1020, found:331.1014. [α]
Rt D=+33.5 (c=1.00, CHCl
3, 92.8% ee)., above digital proof purpose product prepares successfully.
Embodiment seven:
1f (75.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3f(58.9mg), yield is 65% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.58 – 7.35 (m, 1H), 7.21 (dd,
J=18.7,8.1 Hz, 6H), 7.06 (d,
J=7.0 Hz, 1H), 5.32 (s, 1H), 4.44 (d,
J=2.8 Hz, 1H), 3.94 (d,
J=14.2 Hz, 1H), 3.40 (t,
J=15.0 Hz, 1H), 3.22 (dd,
J=16.5,7.0 Hz, 1H), 2.88 (d,
J=14.3 Hz, 1H), 2.55 (dd,
J=15.5,3.0 Hz, 1H).
13C NMR (100MHz, CDCl
3): δ 36.8,39.7,40.8,41.0,86.2,127.5,127.7,127.8,128.7,129.4,129.5,129.9,130.4,130.5,133.4,134.1,136.6,208.0 ppm. HRMS:calcd.for C
18H
13NO
3, 363.0429, found:363.0426. [α]
Rt D=-88.0 (c=1.00, CHCl
3, 90.4% ee), above digital proof purpose product prepares successfully.
Embodiment eight:
1g (75.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3g(61.7mg), yield is 68% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.28 (d,
J=13.3 Hz, 5H), 7.14 (s, 1H), 7.05 (s, 1H), 6.96 (d,
J=6.8 Hz, 1H), 5.27 (s, 1H), 3.90 (d,
J=6.8 Hz, 1H), 3.78 (s, 1H), 3.27 (dd,
J=15.8,8.9 Hz, 1H), 3.03 (dd,
J=16.2,5.0 Hz, 1H), 2.92 – 2.70 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 41.6,41.8,42.0,43.1,90.7,114.5,125.4,127.4,128.5,130.3,135.2,138.5,141.0,206.3 ppm. HRMS:calcd.for C
18H
13NO
3363.0429, found:363.0431. [α]
Rt D=+40.4 (c=0.50, CHCl
3, 84.4% ee), above digital proof purpose product prepares successfully.
Embodiment nine:
1h (75.5mg successively packs in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3h(74.4mg), yield is 82% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.32 (dd,
J=15.2,7.6 Hz, 4H), 7.19 (d,
J=7.1 Hz, 2H), 6.99 (d,
J=7.1 Hz, 2H), 5.22 (d,
J=5.0 Hz, 1H), 3.84 (dd,
J=22.2,15.6 Hz, 2H), 3.25 (dd,
J=15.5,7.9 Hz, 1H), 3.02 (dd,
J=15.9,5.7 Hz, 1H), 2.82 (ddd,
J=24.7,15.6,7.0 Hz, 2H).
13C NMR (100MHz, CDCl
3): δ 41.5,41.7,41.8,43.3,90.9,128.5,128.9,129.1,129.5,134.0,134.4,135.0,137.4 ppm. HRMS:calcd.for C
18H
13NO
3363.0429, found:363.0427. [α]
Rt D=+75.2 (c=1.00, CHCl
3, 91.6% ee), above digital proof purpose product prepares successfully.
Embodiment ten:
1i (98.0 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3i(90.6mg), yield is 80% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.57 (d,
J=7.9 Hz, 1H), 7.43 (d,
J=7.8 Hz, 1H), 7.29 (d,
J=7.4 Hz, 1H), 7.22 (t,
J=7.7 Hz, 2H), 7.15 (d,
J=7.6 Hz, 1H), 7.06 (dd,
J=21.4,7.5 Hz, 2H), 5.28 (s, 1H), 4.42 (d,
J=3.4 Hz, 1H), 3.88 (d,
J=14.2 Hz, 1H), 3.52 – 3.18 (m, 2H), 3.04 – 2.69 (m, 1H), 2.55 (d,
J=15.3 Hz, 1H).
13C NMR (100MHz, CDCl
3): δ 39.1,39.9,40.8,43.2,86.3,124.1,127.3,127.8,128.0,128.4,129.7,130.2,132.3,133.3,133.8,135.7,144.0,208.0 ppm. HRMS:calcd.for C
18H
13NO
3452.9398, found:452.9434. [α]
Rt D=-112.6 (c=0.50, CHCl
3, 90.0% ee), above digital proof purpose product prepares successfully.
Embodiment 11:
1j (98.0 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3j(74.4mg), yield is 66% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.54 – 7.32 (m, 4H), 7.05 (d,
J=7.7 Hz, 2H), 6.86 (d,
J=7.9 Hz, 2H), 5.16 (s, 1H), 3.87 – 3.64 (m, 2H), 3.27 – 3.03 (m, 1H), 2.93 (dd,
J=16.0,4.6 Hz, 1H), 2.73 (ddd,
J=25.0,15.8,6.4 Hz, 2H).
13C NMR (100MHz, CDCl
3): δ 29.7,41.7,41.8,43.3,90.8,122.2,122.7,128.9,129.2,132.2,132.5,135.5,138.0,206.5. ppm. HRMS:calcd.for C
18H
13NO
3450.9419, found:450.9417. [α]
Rt D=+85.6 (c=0.50, CHCl
3, 92.0% ee), above digital proof purpose product prepares successfully.
Embodiment 12:
1k (92.7 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3k(84.2mg), yield is 78% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.62 (dd,
J=14.8,7.8 Hz, 4H), 7.40 (d,
J=7.6 Hz, 2H), 7.20 (d,
J=7.6 Hz, 2H), 5.40 – 5.31 (m, 1H), 3.95 (dd,
J=18.3,6.4 Hz, 2H), 3.29 (dd,
J=15.9,7.9 Hz, 1H), 3.12 – 2.98 (m, 1H), 2.93 (dd,
J=16.0,5.1 Hz, 1H), 2.84 (dd,
J=16.1,9.5 Hz, 1H).
13C NMR (100MHz, CDCl
3): δ 41.8,41.9,42.2,43.4,90.1,122.3,125.0,125.7,125.8,125.9,126.0,126.3,126.4,128.1,138.0,140.3,142.7,206.0. ppm. HRMS:calcd.for C
18H
13NO
3431.0956, found:432.1037. [α]
Rt D=+42.7 (c=1.00, CHCl
3, 94.0% ee), above digital proof purpose product prepares successfully.
Embodiment 13:
1l (53.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3l(39.8mg), yield is 58% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.43 – 7.12 (m, 3H), 6.25 (s, 2H), 6.10 (d,
J=25.4 Hz, 1H), 5.39 (d,
J=4.6 Hz, 1H), 4.11 – 3.88 (m, 1H), 3.74 (d,
J=4.0 Hz, 1H), 3.12 – 2.83 (m, 2H), 2.83 – 2.59 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 37.1,37.2,40.8,40.9,86.0,108.1,108.3,110.5,110.6,142.7,142.9,150.3,151.2,204.7. ppm. HRMS:calcd.for C
18H
13NO
3275.0794, found:275.0794. [α]
Rt D=+19.2 (c=0.25, CHCl
3, 85.0% ee), above digital proof purpose product prepares successfully.
Embodiment 14:
1m (61.5 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3m(56.8mg), yield is 74% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.28 – 7.09 (m, 2H), 6.89 (s, 3H), 6.78 (s, 1H), 5.24 (d,
J=4.2 Hz, 1H), 4.22 (d,
J=6.0 Hz, 1H), 3.97 (d,
J=4.6 Hz, 1H), 3.24 (dd,
J=15.5,9.5 Hz, 1H), 3.08 (dd,
J=15.7,5.8 Hz, 1H), 2.95 – 2.68 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 38.0,38.8,43.2,43.3,91.3,125.4,125.5,126.0,126.2,127.2,127.4,139.3,141.9,205.3. ppm. HRMS:calcd.for C
18H
13NO
3307.0337, found:307.0335. [α]
Rt D=+11.6 (dark sample c=0.50, CHCl
3, 91.8% ee), above digital proof purpose product prepares successfully.
Embodiment 15:
1n (93.0 mg successively pack in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3n(76.8mg), yield is 71% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.50 (s, 1H), 7.44 – 7.16 (m, 4H), 7.07 (d,
J=8.2 Hz, 1H), 5.33 (s, 1H), 4.46 (s, 1H), 3.92 (d,
J=13.9 Hz, 1H), 3.43 (t,
J=14.8 Hz, 1H), 3.27 (dd,
J=16.1,6.0 Hz, 1H), 2.91 (d,
J=16.2 Hz, 1H), 2.61 (d,
J=15.3 Hz, 1H).
13C NMR (75MHz, CDCl
3): δ 37.1,40.2,41.1,41.2,86.2,128.4,128.6,129.3,130.1,130.2,130.3,130.9,133.1,134.5,135.0,135.4,135.5,207.6. ppm. HRMS:calcd.for C
18H
13NO
3432.9620, found:432.9606. [α]
Rt D=-44.4 (c=0.50, CHCl
3, 90.6% ee), above digital proof purpose product prepares successfully.
A small amount of 3n is placed the 10m bottle, and the mixed solvent that adds proper amount of acetone and normal hexane makes it dissolving, and room temperature is placed a couple of days, separates out white needle-like crystals.This crystal detects through Rigaku Mercury CCD/AFC diffractomrter diffractometer and obtains molecular structure as shown in Figure 1.Molecular formula: C
18H
13C
L4NO
3, molecular weight: 433.11, spacer is
P21, unit cell parameters is: a=11.575 (3)
, b=7.6295 (19)
, c=21.699 (6)
, V=1899.1 (8)
3,
Z=2,
Dc=1.515 g/cm
3,
F(000)=880, final discrepancy factor be R [
I2
s]=0.0991,0.2007, R
w=0.2010,0.1687, above digital proof purpose product prepares successfully.
Embodiment 16:
1o (67.0mg successively packs in the reaction flask, 0.25 mmol), Nitromethane 99Min. (263.2 uL, 5.0 mmol) and thiourea catalyst (29.7 mg, 0.05 mmol), add 1mL toluene, at room temperature reacted 24-72 hour, (eluent is an ethyl acetate to column chromatography: after sherwood oil=1:5-1:10) separates raw material and catalyzer, resistates is dissolved in potassium hydroxide (1.1 mg, 0.020 in ethanol mmol) (2mL) solution, reaction is 2 hours under 0 ° of C, obtains crude product;
Reaction system saturated ammonium chloride cancellation, ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying removes and desolvates, (eluent is an ethyl acetate: sherwood oil=1:10) can obtain target product 3o(69.1mg), yield is 84% to crude product by simple column chromatography.
Product is analyzed, and the result is as follows:
1H NMR (400 MHz, CDCl
3) δ 7.34 – 7.07 (m, 7H), 7.02 – 6.87 (m, 2H), 5.17 (dd,
J=20.0,14.6 Hz, 1H), 3.90 – 3.53 (m, 2H), 3.19 (dd,
J=15.9,8.7 Hz, 1H), 3.04 – 2.88 (m, 1H), 2.86 – 2.61 (m, 2H).
13C NMR (100MHz, CDCl
3): δ 41.4,41.5, and 41.6,42.0,42.3,42.4,43.1,43.5,91.0,91.1,127.1,127.5,128.4,128.5,128.9,128.9,129.4,133.9,135.2,136.5,137.7,139.0,207.0,207.1. ppm. HRMS:calcd.for C
18H
13NO
3329.0819, found:329.0817.[α]
Rt D=+54.0 (c=0.50, CHCl
3,64% ee on the major disteroisomer and, 91% ee on the minor), above digital proof purpose product prepares successfully.
Claims (4)
1. the preparation method of a chirality cyclohexanone derivative is characterized in that, may further comprise the steps:
(1) with diketene R
1CH=CHCOCH=CHR
2With Nitromethane 99Min. be reaction substrate, be chiral catalyst with quinine deutero-thiocarbamide, be solvent with toluene, in 20～25 ℃ of down reactions 24～72 hours, generate single Michael addition adducts;
(2) the single Michael addition adducts with step (1) is a reactant, and with potassium hydroxide catalyst, ethanol is solvent, reacts 0.5～2 hour under 0～10 ℃ of condition, obtains 4-nitro-3,5-diaryl cyclohexanone derivative, and structural formula is as shown below:
In the formula, R
1And R
2Be selected from respectively: phenyl, 3,5-Dimethoxyphenyl, p-methylphenyl, p-isopropyl phenyl, to fluorophenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, o-bromophenyl, a kind of in bromophenyl, p-trifluoromethyl phenyl, 2,4 dichlorophenyls, furyl, the thienyl;
The molecular formula of described quinine deutero-thiocarbamide is a kind of in the compound shown in the following chemical structural formula:
2. according to the preparation method of the described chirality cyclohexanone derivative of claim 1, it is characterized in that R
1And R
2Identical.
3. according to the preparation method of the described chirality cyclohexanone derivative of claim 1, it is characterized in that in the step (1), described catalyst consumption is 15～25% of a diketene amount of substance.
4. according to the preparation method of the described chirality cyclohexanone derivative of claim 1, it is characterized in that in the step (2), described catalyst consumption is 8～12% of a diketene amount of substance.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103508826A (en) * | 2013-10-12 | 2014-01-15 | 苏州大学张家港工业技术研究院 | Preparation method of chiral trisubstituted indane compound |
| CN103910737A (en) * | 2014-03-25 | 2014-07-09 | 浙江师范大学 | Chiral 1, 4-dihydropyran (2, 3-c) pyrazole derivative as well as synthesis method and application of chiral 1, 4-dihydropyran (2, 3-c) pyrazole derivative |
| CN106188078A (en) * | 2016-07-15 | 2016-12-07 | 苏州大学 | A kind of chiral spiro hydroxyindole benzopyrone the synthetic method of 3,4 dihydropyrane compounds |
| CN110372514A (en) * | 2019-07-24 | 2019-10-25 | 常州大学 | A kind of method and its catalyst being catalyzed asymmetric Michael addition reaction |
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2011
- 2011-02-25 CN CN 201110046184 patent/CN102153477A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 《Chem.Commun》 20110217 Bin Wu et al. Efficient synthesis of optically active 4-nitro-cyclohexanones via bifunctional thiourea-base catalyzed double-Michael addition of nitromethane to dienones 第3992-3994页 1-4 第47卷, * |
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| CN103508826A (en) * | 2013-10-12 | 2014-01-15 | 苏州大学张家港工业技术研究院 | Preparation method of chiral trisubstituted indane compound |
| CN103508826B (en) * | 2013-10-12 | 2015-04-08 | 苏州大学张家港工业技术研究院 | Preparation method of chiral trisubstituted indane compound |
| CN103910737A (en) * | 2014-03-25 | 2014-07-09 | 浙江师范大学 | Chiral 1, 4-dihydropyran (2, 3-c) pyrazole derivative as well as synthesis method and application of chiral 1, 4-dihydropyran (2, 3-c) pyrazole derivative |
| CN103910737B (en) * | 2014-03-25 | 2016-08-17 | 浙江师范大学 | 1,4-dihydropyran (2,3-c) pyrazole derivatives of chirality and synthetic method thereof and application |
| CN106188078A (en) * | 2016-07-15 | 2016-12-07 | 苏州大学 | A kind of chiral spiro hydroxyindole benzopyrone the synthetic method of 3,4 dihydropyrane compounds |
| CN106188078B (en) * | 2016-07-15 | 2018-04-03 | 苏州大学 | A kind of synthetic method of chiral spiro hydroxyindole benzopyrone and 3,4 dihydropyrane compounds |
| CN110372514A (en) * | 2019-07-24 | 2019-10-25 | 常州大学 | A kind of method and its catalyst being catalyzed asymmetric Michael addition reaction |
| CN110372514B (en) * | 2019-07-24 | 2022-09-27 | 常州大学 | Method for catalyzing asymmetric Michael addition reaction and catalyst thereof |
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