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Structure of 15484-46-5 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 10, p. 1610 - 1614
[2] Tetrahedron Asymmetry, 2009, vol. 20, # 2, p. 210 - 213
[3] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2533 - 2543
[4] Chemistry - A European Journal, 2010, vol. 16, # 22, p. 6509 - 6517
[5] Chemistry - A European Journal, 2010, vol. 16, # 22, p. 6495 - 6508
[6] Organometallics, 2011, vol. 30, # 24, p. 6718 - 6725
[7] Advanced Synthesis and Catalysis, 2012, vol. 354, # 16, p. 3025 - 3035
[8] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1775 - 1786
[9] ChemBioChem, 2017, vol. 18, # 7, p. 685 - 691
2
[ 15484-46-5 ]
[ 80657-57-4 ]
[ 72657-23-9 ]
Yield
Reaction Conditions
Operation in experiment
58 % ee
With (cycloocta-1,5-diene)-[(S,S)-2,2'-bis(ferrocenyl-phenylphosphino)-1,1'-biphenyl] rhodium tetrafluoroborate; hydrogen In dichloromethane at 20℃; for 16 h; Autoclave
K.3. Asymmetric catalyzed hydrogenationTypical procedure A solution of [Rh(COD)L*]BF4 (0.005 mmol, 1 molpercent) and substrate (0.5 mmol) in dry solvent (7.5 mL) was introduced in a stainless steel autoclave. The autoclave was closed, purged with hydrogen and then pressurized with hydrogen. After 16h of stirring at room temperature, the pressure was released to atmospheric pressure and the solution was transferred to a round bottom flask. The solvent was removed on a rotary evaporator to give a residue which was purified by column chromatography on silica gel to afford the hydrogenated product. The enantiomeric excess was determined by HPLC on chiral column.Results of aymmetric catalyzed hydrogenations by rhodium complexes of ligands (1-48) or (1-49) are presented in table 9 and 10. Table 9. Asymmetric catalyzed hydrogenation by rhodium complexes of ligands (1-48)Substrate Diphosphine 48 Cond. (RT 16h) ProductR R2 R R8 Solvant P Conv ee(¾) (percent) (percent)63 48a Ph oAn Ph Ph MeOH 4 64 93 61 (R)10 100 63 (R)20 100 60 (R)THF 10 6 ndCH2C12 7 nd Table 10. Asymmetric catalyzed hydrogenation by rhodium complex of ligand (I'-49c)
Reference：
[1] Advanced Synthesis and Catalysis, 2003, vol. 345, # 1-2, p. 185 - 189
[2] Advanced Synthesis and Catalysis, 2007, vol. 349, # 10, p. 1592 - 1596
[3] Advanced Synthesis and Catalysis, 2007, vol. 349, # 10, p. 1592 - 1596
[4] Tetrahedron Asymmetry, 2009, vol. 20, # 2, p. 210 - 213
[5] Advanced Synthesis and Catalysis, 2008, vol. 350, # 10, p. 1610 - 1614
[6] Angewandte Chemie - International Edition, 2009, vol. 48, # 12, p. 2162 - 2165
[7] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2525 - 2532
[8] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2525 - 2532
[9] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2533 - 2543
[10] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2533 - 2543
[11] Chemistry - A European Journal, 2009, vol. 15, # 39, p. 10272 - 10279
[12] Advanced Synthesis and Catalysis, 2010, vol. 352, # 14-15, p. 2663 - 2666
[13] Tetrahedron Asymmetry, 2010, vol. 21, # 21-22, p. 2671 - 2674
[14] Organometallics, 2011, vol. 30, # 24, p. 6718 - 6725
[15] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
[16] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
[17] Advanced Synthesis and Catalysis, 2012, vol. 354, # 1, p. 59 - 64
[18] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 1949 - 1960
[19] Chemistry - A European Journal, 2012, vol. 18, # 33, p. 10368 - 10381
[20] Chemistry - A European Journal, 2012, vol. 18, # 33, p. 10368 - 10381
[21] European Journal of Organic Chemistry, 2012, # 26, p. 4963 - 4968
[22] European Journal of Inorganic Chemistry, 2012, # 29, p. 4684 - 4693
[23] Patent: WO2013/7724, 2013, A1, . Location in patent: Page/Page column 88; 89; 90
[24] Advanced Synthesis and Catalysis, 2014, vol. 356, # 4, p. 795 - 804
[25] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1775 - 1786
[26] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1775 - 1786
[27] ChemBioChem, 2017, vol. 18, # 7, p. 685 - 691
3
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]
Yield
Reaction Conditions
Operation in experiment
44%
With potassium carbonate In water at 20℃; for 2 h;
Example 106: methyl 2-(hydroxymethyl)acrylate44percentA saturated aqueous solution (10 mL) of K2CO3 (3.5 g, 117 mmol, 1.6 eq.) was slowly added to a rapidly stirred solution of trimethylphosphonoacetate (5.46 g, 30 mmol, 1.0 eq.) and paraformaldehyde (6.63 g, 48 mmol, 4.0 eq.) at r.t.. After the addition the mixture was stirred for 2 h. Then the mixture was extracted with DCM. The organic layer was concentrated to give the compound (1.5 g, 44percent) as a yellow oil. 1U NMR (400 MHz, CD3OD) δ: 6.29 (s, IH), 5.83 (s, IH), 3.75 (s, 3H), 3.72 (s, 2H).
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 6, p. 1929 - 1932[2] Angew. Chem., 2015, vol. 127, # 6, p. 1949 - 1952,4
[3] Tetrahedron, 2008, vol. 64, # 17, p. 3701 - 3712
[4] Patent: WO2011/17561, 2011, A1, . Location in patent: Page/Page column 72
[5] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3539 - 3545
4
[ 50-00-0 ]
[ 1779-58-4 ]
[ 15484-46-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate In water at 10 - 20℃; for 6 h;
Three bottle adding 119.2 g methoxy carbonyl methylene triphenyl bromination phosphorus, 300 ml water and 58 g 30percent formaldehyde aqueous solution, control 10 - 15 °C slowly dropping 30percent potassium carbonate aqueous solution to 266.8 g, then completing 15 - 20 °C lower heat insulating 6 hours, filtering to remove the insoluble matter (triphenyl phosphate). The filtrate by adding dichloromethane 500 ml extraction, the organic phase is concentrated, after removing the solvent control 70 - 90 °C, vacuum degree 0.098 mpa under reduced pressure distillation, to obtain 2 - hydroxy methyl methacrylate 25.7 g (yield 85percent).
Reference：
[1] Patent: CN106336357, 2017, A, . Location in patent: Paragraph 0031; 0034; 0035
5
[ 50-00-0 ]
[ 292638-85-8 ]
[ 15484-46-5 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 45 - 55℃; for 15 h; Large scale
In a 200 liter clean reactor, 65 kg of methyl acrylate, 2.52 kg of sodium bicarbonate, 2.8 kg of DABCO (anhydrous), 0.5 kg of hydroquinone, 7.5 kg of paraformaldehyde,Reflux heating steam heated to between 45-55 degrees incubated for 15 hours,Cool to room temperature, add 15 kg of saturated salt water, add about 6 kg of concentrated hydrochloric acid, adjustPH3-4.The layers were separated, the organic phase was washed with 10 kg of saturated brine, dried over 10 kg of sodium sulfate, filtered and concentrated to remove acrylic acidMethyl esters gave a colorless liquid 28 kg, high vacuum distillation product 24 kg, GC purity of 95percent, the yield of 83percentFurther high vacuum distillation can be 97percent purity products.
68%
With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In tetrahydrofuran at 20℃; for 5 h;
3.0 g of paraformaldehyde, 15 ml of methyl acrylate were dissolved in 25 ml of dioxane, and then 3.2 g of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was added. The reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated to dryness, a small amount of a polymerization inhibitor was added, and distilled under reduced pressure to obtain 10.2 g of methyl 2-hydroxymethyl acrylate,n a yield of 68percent.
19%
at 25℃; Inert atmosphere
General procedure: Into a round bottom flask charged with a stirbar was added 1.0 equiv. aldehyde, followed by 2.0 equiv. methyl acrylate and 0.5 equiv. DABCO. The reaction mixture was stirred until judged complete by TLC, then was partitioned between 1.0 M acetic acid and CH2Cl2. The organic layer was set aside, and the residual product was extracted from the aqueous layer with an additional portion of CH2Cl2. The combined organic layers were washed with deionized water then brine, then concentrated and purified via column chromatography.
87 %Chromat.
With 4-methoxy-phenol; lithium chloride In N,N-dimethyl acetamide; water at 50℃; for 4 h;
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
87 %Chromat.
With 4-methoxy-phenol In 1-methyl-pyrrolidin-2-one; water at 50℃; for 4 h;
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
82 %Chromat.
With potassium chloride; 4-methoxy-phenol In water; acetonitrile at 50℃; for 6 h;
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
85 %Chromat.
With 4-methoxy-phenol; lithium chloride In methanol; N,N-dimethyl acetamide; water at 50℃; for 6.5 h;
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
83 %Chromat.
With 4-methoxy-phenol; calcium chloride In water; acetonitrile at 50℃; for 6.5 h;
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
3.3 kg
at 70℃; for 8 h; Industrial scale
17.3 kg of methyl acrylate (hereinafter also referred to as AM), 1.54 kg of paraformaldehyde 1.54 Kg, and 0.99 kg of 30percent trimethylamine (hereinafter also referred to as TMA) aqueous solution were placed in a 20 L reaction vessel and stirred at 70 ° C. for 8 hours to continue the reaction. The α-hydroxymethylacrylic acid ester obtained by the reaction was 4.49 kg. After the reaction, it was separated into an AM phase and an aqueous phase by standing, and the aqueous phase was removed. Thereafter, the AM layer was washed with 1000 g of water, and the obtained AM layer was subjected to simple distillation (while blowing a mixed gas (7percent O 2 / N 2) for 6 hours It was distilled off. The obtained bottom liquid contained 3.67 kg of α-hydroxymethylacrylic acid ester, and precision distillation (at a column top temperature of 86 to 87 ° C / 13 hPa while blowing a mix gas (7percent O 2 / N 2) Precision distillation) to obtain 3.30 kg of α-hydroxymethylacrylic acid ester. The dimer content of trimethylamine and α-hydroxymethylacrylic acid ester was measured by the above method.
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 16, p. 5413 - 5418
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1539 - 1553
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 2, p. 555 - 559[4] Angew. Chem., 2018, vol. 130, # 2, p. 564 - 568,5
[5] Patent: CN107417531, 2017, A, . Location in patent: Paragraph 0028; 0029; 0030; 0031
[6] Tetrahedron Letters, 2005, vol. 46, # 17, p. 3071 - 3072
[7] Organic Letters, 2011, vol. 13, # 15, p. 3864 - 3867
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5757 - 5762
[9] Tetrahedron, 2002, vol. 58, # 37, p. 7437 - 7447
[10] Tetrahedron Letters, 2008, vol. 49, # 23, p. 3744 - 3748
[11] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2533 - 2543
[12] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2525 - 2532
[13] Patent: CN107915668, 2018, A, . Location in patent: Paragraph 0017
[14] Organic Letters, 2009, vol. 11, # 3, p. 575 - 578
[15] Chemical Communications, 2012, vol. 48, # 91, p. 11232 - 11234
[16] Organic Preparations and Procedures International, 2005, vol. 37, # 3, p. 231 - 237
[17] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6143 - 6148
[18] Advanced Synthesis and Catalysis, 2018, vol. 360, # 13, p. 2566 - 2570
[19] Synthetic Communications, 2000, vol. 30, # 11, p. 2061 - 2069
[20] Tetrahedron Asymmetry, 2013, vol. 24, # 7, p. 395 - 401
[21] Chemical Communications, 2006, # 26, p. 2756 - 2758
[22] Tetrahedron, 2010, vol. 66, # 51, p. 9733 - 9737
[23] Journal of Organic Chemistry, 1994, vol. 59, # 12, p. 3408 - 3412
[24] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 380 - 385
[25] Tetrahedron, 1992, vol. 48, # 38, p. 8317 - 8328
[26] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2075 - 2077
[27] Chemical Communications, 2014, vol. 50, # 96, p. 15216 - 15219
[28] Advanced Synthesis and Catalysis, 2010, vol. 352, # 14-15, p. 2663 - 2666
[29] Organic Letters, 2006, vol. 8, # 15, p. 3359 - 3362
[30] Patent: EP1832571, 2007, A1, . Location in patent: Page/Page column 7; 8
[31] Patent: EP1832571, 2007, A1, . Location in patent: Page/Page column 7; 9
[32] Patent: EP1832571, 2007, A1, . Location in patent: Page/Page column 7; 9
[33] Patent: EP1832571, 2007, A1, . Location in patent: Page/Page column 7; 8
[34] Patent: EP1832571, 2007, A1, . Location in patent: Page/Page column 7; 9
[35] Journal of the American Chemical Society, 2009, vol. 131, # 35, p. 12562 - 12563
[36] Tetrahedron Letters, 2010, vol. 51, # 34, p. 4482 - 4485
[37] Chemical Communications, 2011, vol. 47, # 11, p. 3219 - 3221
[38] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 4, p. 814 - 820
[39] Journal of the American Chemical Society, 2014, vol. 136, # 1, p. 119 - 121
[40] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[41] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1775 - 1786
[42] Organic Letters, 2015, vol. 17, # 18, p. 4432 - 4435
[43] Organic Letters, 2016, vol. 18, # 10, p. 2355 - 2358
[44] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5777 - 5780
[45] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5504 - 5507
[46] Journal of the American Chemical Society, 2016, vol. 138, # 24, p. 7698 - 7704
[47] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5359 - 5362
[48] Patent: JP2017/43555, 2017, A, . Location in patent: Paragraph 0051
[49] Organic Letters, 2018, vol. 20, # 17, p. 5380 - 5383
6
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]
[ 292638-85-8 ]
Yield
Reaction Conditions
Operation in experiment
56%
With potassium carbonate In water at 23℃;
Acrylate 20. Synthesized by a method adapted from Villieras and Rambaud.2 To around-bottom flask equipped with a stir bar were added trimethyl phosphonoacetate (S1,9.1 mL, 63 mmol, 1.00 equiv) and formaldehyde (S2, 20.5g, 37percent in water, 252 mmol,4.00 equiv). The flask was lowered into a ambient-temperature water bath. To themixture was added a saturated solution of potassium carbonate in water (15.3 g, 110mmol, 1.75 equiv) dropwise via addition funnel over the course of one hour, and stirringwas continued for an additional hour. The reaction mixture was quenched by addition ofsaturated aqueous ammonium chloride (30 mL), then extracted three times with diethylether. The combined organics were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Methyl acrylate, produced as a side-product,was removed by azeotropic distillation with methanol. The residue was purified byvacuum distillation (~0.5 torr, 44 °C) to afford acrylate 20 as a clear oil (4.07 g, 56percentyield) with minor impurities which were carried forward to the next reaction. Thecharacterization data matched those reported in the literature.3
With formaldehyd; paraformaldehyde In diethyl ether; nitrogen
Preparation of Methyl 3-hydroxy-2-methylidene-propanoate To a mixture containing 27 ml (25.83 g, 0.30 mmoles of methyl acrylate and 2.5 g (22.29 mmoles) of 1,4-diazabicyclo[2,2,2]-octane (DABCO), formaldehyde was added (generated by pyrolysis of paraformaldehyde at 200° C.) in a nitrogen current for 1 h. The mixture was then left to react for 7 days at room temperature. At the end of that time an extraction was performed with diethyl ether (2*100 ml) and the result was washed with water (2*400 ml). The ether extracts were dried over anhydrous sodium sulphate, filtered and vacuum concentrated, giving 19.5 g (77percent yield) of methyl 3-hydroxy-2-methylidene-propanoate in oil form.
Reference：
[1] Journal of the Chemical Society, 1950, p. 236,240
17
[ 67-56-1 ]
[ 107-19-7 ]
[ 13463-39-3 ]
[ 15484-46-5 ]
Reference：
[1] Journal of Organic Chemistry, 1963, vol. 28, p. 2835 - 2838
18
[ 15484-46-5 ]
[ 4224-69-5 ]
Yield
Reaction Conditions
Operation in experiment
86%
With phosphorus tribromide In acetonitrile at 20℃; for 4 h;
10.2 g of 2-hydroxymethyl methacrylate obtained in the previous step was dissolved in 150 ml of acetonitrile, and then 4 ml of phosphorus tribromide was carefully added thereto.After the addition was completed, the reaction was continued at room temperature for 4 hours.Carefully quenched with water and desolvated to remove acetonitrile.The residue was added with 100 ml of water, extracted twice with ethyl acetate, and desolvated to obtain 13.5 g of a colorless liquid in a yield of 86percent.
79%
at 25℃; Inert atmosphere
General procedure: Into a round bottom flask charged with a magnetic stirbar was added 1 equiv. MBH adduct, followed by 3 equiv. 33wt percent HBr (in HOAc). The solution was vigorously stirred until judged complete by TLC, then was poured into a 1 : 1 (volumetric) mixture of deionized water and CH2Cl2. The organic layer was separated, then the residual product was extracted from the aqueous layer with an additional portion of CH2Cl2. The combined organic layers were washed with deionized water then brine, then were dried with Na2SO4, filtered, concentrated, and purified via column chromatography.
72%
With phosphorus tribromide In dichloromethane at 0℃; for 2.25 h; Inert atmosphere
Methyl(2-bromomethyl)acrylate, Method B: The desiredMBH adduct (1.5715g, 13.53 mmol, 1.00 eq.) was weighed into a round-bottomflask that had been dried and flushed with N2. Dry CH2Cl2 (45 mL, 0.3M)was added and the mixture was cooled to 0 °C in an ice bath. PBr3(0.64 mL, 6.77 mmol, 0.50 eq.) was added slowly and the ice bath was removedshortly after complete addition. Thereaction as stirred and monitored by TLC analysis and determined to be completeafter approximately 2h and 15 min. The reactionwas quenched by opening to air and adding ice. It was extracted with CH2Cl2(2 x 50 mL) and the combined organic layers were washed with brine and driedover sodium sulfate. Solvent was removeden vacuo and the residue purified viachromatography. The product was notdried on vacuum for very long due to volatility. The product was isolated as alight yellow oil in 72percent yield (1.7284g, 9.66 mmol).
Reference：
[1] Tetrahedron Asymmetry, 2013, vol. 24, # 7, p. 395 - 401
[2] Patent: CN107915668, 2018, A, . Location in patent: Paragraph 0018
[3] Organic Letters, 2011, vol. 13, # 15, p. 3864 - 3867
[4] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2075 - 2077
[5] Chemical Communications, 2014, vol. 50, # 96, p. 15216 - 15219
[6] Synthetic Communications, 1987, vol. 17, # 3, p. 291 - 298
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 19, p. 4270 - 4273
[8] Journal of Organometallic Chemistry, 2006, vol. 691, # 24-25, p. 5406 - 5422
[9] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5757 - 5762
[10] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3539 - 3545
[11] Synthetic Communications, 1987, vol. 17, # 3, p. 291 - 298
[12] Chemical Communications, 2006, # 26, p. 2756 - 2758
[13] Tetrahedron Letters, 2010, vol. 51, # 34, p. 4482 - 4485
[14] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 4, p. 814 - 820
[15] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2796 - 2803
[16] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[17] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5777 - 5780
19
[ 75-18-3 ]
[ 15484-46-5 ]
[ 4224-69-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
With N-Bromosuccinimide; sodium chloride In diethyl ether; dichloromethane
Preparation of Methyl 2-bromomethyl-2-propenoate To a solution of N-bromosuccinimide (5.17 g, 26.8 mmoles) in dry dichloromethane (40 ml) were added dimethyl sulphide (4 ml) in dichloromethane (50 ml), drop by drop with stirring at 0° C. for 10 min. To the resulting mixture was added methyl 3-hydroxy-2-metylidene-propanoate (3.15 g, 31.50 mmoles) dissolved in dichloromethane (40 ml), leaving it for 24 hours at room temperature. At the end of that time, it was poured into an aqueous solution of sodium chloride and ice. An extraction was performed with diethyl ether (3*100 ml), and the result was washed with water and dried over anhydrous sodium sulphate. Following vacuum concentration, 4.33 g of a yellow oil was obtained (89percent yield) of methyl 2-bromomethyl-2-propenoate.
Reference：
[1] Patent: US2003/199575, 2003, A1,
20
[ 15484-46-5 ]
[ 108-24-7 ]
[ 30982-08-2 ]
Reference：
[1] Tetrahedron, 1992, vol. 48, # 38, p. 8317 - 8328
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1539 - 1553
[3] Patent: EP2415751, 2012, A1, . Location in patent: Page/Page column 63
[4] Chemistry - A European Journal, 2018, vol. 24, # 19, p. 4810 - 4814
[5] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8076 - 8080
21
[ 15484-46-5 ]
[ 75-36-5 ]
[ 30982-08-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 13, p. 2566 - 2570
[2] Advanced Synthesis and Catalysis, 2008, vol. 350, # 10, p. 1610 - 1614
[3] Organic Letters, 2006, vol. 8, # 15, p. 3359 - 3362
22
[ 15484-46-5 ]
[ 72657-23-9 ]
Yield
Reaction Conditions
Operation in experiment
> 90 % ee
With flavin mononucleotide; alpha-D-glucopyranose; glucose dehydrogenase from Thermoplasma acidophilum; old yellow enzyme 1 from Saccharomyces pastorianus; nicotinamide adenine dinucleotide phosphate In aq. buffer at 20℃; for 24 h; Enzymatic reaction
General procedure: Ene-reductase activity assays were performed at ambient temperature under anaerobic conditions (Coy Laboratory, Grass Lake, MI). For preparing reaction stock solution, individual substrates (see below) were dissolved in 50mM Tris–HCl (pH 7.5), supplemented with 200μM NADP+, 100mM glucose, and glucose dehydrogenase (GDH) from Thermoplasma acidophilum (2 units for IVTT reactions, 5 units for purified enzyme reactions). Individual substrate concentrations were chosen to ensure vmax conditions or maximum solubility. At these substrate levels, reaction times were adjusted for 10–50percent substrate conversion. To assay OYE activity in IVTT experiments, 20μL of the reaction stock solution was mixed with 2–10μL IVTT reaction mixture and the total assay volume was adjusted to 30μl with 50mM Tris–HCl (pH 7.5). To assay purified OYE1 variants, the enzyme (final concentration: 250nM) was added to 500μl reaction stock solution. Reaction progress was monitored by removing 30-μl aliquots from the assay solution and quenching them by mixing thoroughly with 30μL of ethyl acetate containing 1mM cyclohexanone as internal standard. A sample of the organic phase was collected and analyzed by GC (protocols: see below). The enantio/diasteriomeric excess were calculated by integration of product and substrate peak areas. Relative rates of conversion for individual substrates were calculated by dividing the measured rate of conversion for OYE1 variant over the corresponding rate for wild type OYE1.
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1775 - 1786
[2] Tetrahedron Asymmetry, 2009, vol. 20, # 2, p. 210 - 213
[3] Angewandte Chemie - International Edition, 2009, vol. 48, # 12, p. 2162 - 2165
[4] Advanced Synthesis and Catalysis, 2008, vol. 350, # 16, p. 2533 - 2543
[5] Advanced Synthesis and Catalysis, 2010, vol. 352, # 14-15, p. 2663 - 2666
[6] Tetrahedron Asymmetry, 2010, vol. 21, # 21-22, p. 2671 - 2674
[7] Tetrahedron, 2016, vol. 72, # 46, p. 7282 - 7287
[8] ChemBioChem, 2017, vol. 18, # 7, p. 685 - 691
23
[ 15484-46-5 ]
[ 80657-57-4 ]
[ 72657-23-9 ]
Yield
Reaction Conditions
Operation in experiment
58 % ee
With (cycloocta-1,5-diene)-[(S,S)-2,2'-bis(ferrocenyl-phenylphosphino)-1,1'-biphenyl] rhodium tetrafluoroborate; hydrogen In dichloromethane at 20℃; for 16 h; Autoclave
K.3. Asymmetric catalyzed hydrogenationTypical procedure A solution of [Rh(COD)L*]BF4 (0.005 mmol, 1 molpercent) and substrate (0.5 mmol) in dry solvent (7.5 mL) was introduced in a stainless steel autoclave. The autoclave was closed, purged with hydrogen and then pressurized with hydrogen. After 16h of stirring at room temperature, the pressure was released to atmospheric pressure and the solution was transferred to a round bottom flask. The solvent was removed on a rotary evaporator to give a residue which was purified by column chromatography on silica gel to afford the hydrogenated product. The enantiomeric excess was determined by HPLC on chiral column.Results of aymmetric catalyzed hydrogenations by rhodium complexes of ligands (1-48) or (1-49) are presented in table 9 and 10. Table 9. Asymmetric catalyzed hydrogenation by rhodium complexes of ligands (1-48)Substrate Diphosphine 48 Cond. (RT 16h) ProductR R2 R R8 Solvant P Conv ee(¾) (percent) (percent)63 48a Ph oAn Ph Ph MeOH 4 64 93 61 (R)10 100 63 (R)20 100 60 (R)THF 10 6 ndCH2C12 7 nd Table 10. Asymmetric catalyzed hydrogenation by rhodium complex of ligand (I'-49c)
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With palladium dichloride In 1,2-dimethoxyethane at 50℃;
With 1,4-diaza-bicyclo[2.2.2]octane; tempol; 4-methoxy-phenol at 76℃; for 14h; oxygen-nitrogen atmosphere;
52
Example 52; A 500 mL four-neck flask equipped with a stirrer, condenser, thermometer, gas inlet and pressure reducing device was charged with 232.2 g of methyl α-(hydroxymethyl) acrylate, 11.22 g of 1,4-diazabicyclo[2.2.2]octane as the catalyst, and 0.12 g of hydroquinone monomethyl ether and 0.12 g of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl as the polymerization inhibitors. Next, while blowing a mixed gas composed of 7 vol% oxygen and 93 vol% nitrogen into the reaction mixture, the reaction mixture was raised to a temperature of 90°C; 1.5 hours after reaching 90°C, the reaction mixture was to 76°C and a solution of 22.4 g of 1,4-diazabicyclo[2.2.2]octane dissolved in 103.6 g of methanol was added dropwise over 2 hours, after which the reaction was continued for another 14 hours at 76°C. Following the reaction, measurement was carried out by gas chromatography, whereupon the yield of methyl α-(methoxymethyl) acrylate was 72 mol% with respect to methyl α-(hydroxymethyl) acrylate, and the conversion of methyl α-(hydroxymethyl) acrylate was 87 mol%. The resulting reaction mixture had a weight of 369.4 g and contained 50.8 wt% (187.6 g, 1.44 mol) of methyl α-(methoxymethyl) acrylate and 8.1 wt% (29.9 g, 0.26 mol) of methyl α-(hydroxymethyl) acrylate. The ratio of methyl α-(hydroxymethyl) acrylate to methyl α-(methoxymethyl) acrylate was 13.7 wt%. Next, 176 g of a 10 wt% aqueous sodium hydroxide solution (sodium hydroxide: 17.6 g, 0.44 mol) was added to this reaction mixture and stirring was carried out at room temperature for 30 minutes, after which oil-water separation was carried out by leaving the mixture at rest for 30 minutes, thereby giving 253.0 g of the organic phase. The number of moles of the sodium hydroxide added per mole of the methyl α-(hydroxymethyl) acrylate was 1.7 moles. The amount of methyl α-(allyloxymethyl) acrylate in the resulting organic phase was 178.4 g (1.37 mol), representing 95.1 wt% recovery, and the amount of methyl α-(hydroxymethyl) acrylate was 3.3 g (0.03 mol), representing a percent decrease of 89.0 wt%. The ratio of methyl α-(hydroxymethyl) acrylate to methyl α-(methoxymethyl) acrylate was as low as 1.8 wt%.
With phosphorus tribromide; In acetonitrile; at 20℃; for 4h;
10.2 g of 2-hydroxymethyl methacrylate obtained in the previous step was dissolved in 150 ml of acetonitrile, and then 4 ml of phosphorus tribromide was carefully added thereto.After the addition was completed, the reaction was continued at room temperature for 4 hours.Carefully quenched with water and desolvated to remove acetonitrile.The residue was added with 100 ml of water, extracted twice with ethyl acetate, and desolvated to obtain 13.5 g of a colorless liquid in a yield of 86%.
82%
With phosphorus tribromide; In dichloromethane; at 0 - 20℃;
Briefly, compound la (2.0 g, 17.23 mmol) was dissolved in 20 mL of dry DCM and cooled to 0 C in ice bath. PBr3 (2.332 g, 8.615 mmol) was added slowly to the solution. Then the reaction mixture was stirred at room temperature. The completion of reaction was monitored by TLC. The reaction was then quenched by the addition of ice. The reaction solution was neutralized by sodium bicarbonate solution and then extracted with DCM three times. Organic layers were collected and dried over anhydrous sodium sulfate, then concentrated. Compound lb was obtained by flash chromatography. Yield: 2.52 g, 82%. -NMR (400 MHz, CDCl3): d 6.34 (s, 1H), 5.96 (s, 1H), 4.18 (s, 2H), 3.82(s, 3H).
79%
With hydrogen bromide; acetic acid; at 25℃;Inert atmosphere;
General procedure: Into a round bottom flask charged with a magnetic stirbar was added 1 equiv. MBH adduct, followed by 3 equiv. 33wt % HBr (in HOAc). The solution was vigorously stirred until judged complete by TLC, then was poured into a 1 : 1 (volumetric) mixture of deionized water and CH2Cl2. The organic layer was separated, then the residual product was extracted from the aqueous layer with an additional portion of CH2Cl2. The combined organic layers were washed with deionized water then brine, then were dried with Na2SO4, filtered, concentrated, and purified via column chromatography.
72%
With phosphorus tribromide; In dichloromethane; at 0℃; for 2.25h;Inert atmosphere;
Methyl(2-bromomethyl)acrylate, Method B: The desiredMBH adduct (1.5715g, 13.53 mmol, 1.00 eq.) was weighed into a round-bottomflask that had been dried and flushed with N2. Dry CH2Cl2 (45 mL, 0.3M)was added and the mixture was cooled to 0 C in an ice bath. PBr3(0.64 mL, 6.77 mmol, 0.50 eq.) was added slowly and the ice bath was removedshortly after complete addition. Thereaction as stirred and monitored by TLC analysis and determined to be completeafter approximately 2h and 15 min. The reactionwas quenched by opening to air and adding ice. It was extracted with CH2Cl2(2 x 50 mL) and the combined organic layers were washed with brine and driedover sodium sulfate. Solvent was removeden vacuo and the residue purified viachromatography. The product was notdried on vacuum for very long due to volatility. The product was isolated as alight yellow oil in 72% yield (1.7284g, 9.66 mmol).
With 1,4-diaza-bicyclo[2.2.2]octane; 2-allyloxymethyl-acrylic acid methyl ester; at 50℃; for 2h;
Example 54; Acetic anhydride (87 g) as a derivatizing agent was added dropwise over a period of 1 hour to 371 g of the reaction mixture obtained in Example 53, and the mixture was stirred for 2 hours at 50C. The amount of methyl α-(hydroxyethyl) acrylate in 458 g of this reaction mixture was 2 g. The reaction mixture was then washed with water to remove the catalyst, following which purification was carried out by distillation using a distillation apparatus (theoretical number of plates, 13) and under reduced pressure (operating pressure, 2 kPa). The amount of reaction mixture prior to distillation was 450 g, and included 256 g of methyl α-(allyloxymethyl) acrylate, 1 g of methyl α-(hydroxymethyl) acrylate and 30 g of methyl α-(acetoxymethyl) acrylate. Following distillation, 192 g of product containing 99.3 wt% of methyl α-(allyloxymethyl) acrylate and 0.2 wt% of methyl α-(hydroxymethyl) acrylate was obtained.
With 1H-imidazole In N,N-dimethyl-formamide at 0℃; Inert atmosphere;
81%
With dmap; triethylamine In dichloromethane at 0 - 20℃; Sealed tube; Inert atmosphere;
Silyl ether 21. To a flame-dried round-bottom flask equipped with a stir bar were addedtert-butyl dimethyl silyl chloride (5.34 g, 35.4 mmol, 1.01 equiv) and 4-(N,Ndimethylamino)pyridine (430 mg, 3.5 mmol, 0.10 equiv), and the flask was sealed with arubber septum and placed under an inert atmosphere. Dichloromethane (75 mL, 0.48 M)was added and the solution was cooled in an ice-water bath. Acrylate 20 (4.07 g, 35.0mmol, 1.00 equiv) was added to the solution, followed by a dropwise addition oftriethylamine (15 mL, 105.2 mmol, 3.00 equiv) to give a cloudy suspension. Thereaction mixture was allowed to warm slowly to 20 °C and TLC analysis showedcomplete conversion after 11 hours. The reaction mixture was vacuum filtered through afritted funnel to remove ammonium salts, and washed with cold, aqueous hydrochloricacid (1 N, 75 mL). The aqueous layer was back-extracted with dichloromethane (3 x 10mL, 1 x 20 mL). The combined organics were washed with saturated aqueous sodiumbicarbonate (70 mL) and the aqueous layer was back-extracted with dichloromethane (3 x10 mL). The combined organics were washed with brine (40 mL) and the aqueous layerwas back-extracted with dichloromethane (2 x 10 mL). The combined organics weredried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography on SiO2 (30:1 hexanes:EtOAc) to affordsilyl ether 21 (6.53 g, 81% yield) as a clear oil. The characterization data matched thosereported in the literature.4
78%
With dmap; triethylamine In dichloromethane for 2h; Ambient temperature;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 9h;
90%
With 1,4-diaza-bicyclo[2.2.2]octane In methanol at 20℃; for 9h;
90%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 12h;
89.2%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 12h;
1 Example 1:
To 3.0g (100mmol)Paraformaldehyde (100mmol) and 27.0ml (300mmol) methyl acrylate (300mmol) are starting materials,11.2g (100mmol) of triethylenediamine was added and reacted in 25ml of 1,4-dioxane and 25ml of distilled water at room temperature for 12h. After the reaction, it was extracted with ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 10.351 g of methyl 2-(hydroxymethyl)acrylate, with a yield of 89.2%. Take 9.284g (80mmol) of methyl 2-(hydroxymethyl)acrylate and stir in 100ml of anhydrous ether. Add 3.8mL (40mmol) of phosphorus tribromide slowly at 0°C, warm the mixture to room temperature, and stir for 2h. Then the reaction was stopped, cooled to 0°C, 15 mL of cooling water was added dropwise, the mixture was extracted with anhydrous ether, the extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 12.443g of methyl 2-(bromomethyl)acrylate. The yield: 87.4%.
83%
With 1,4-diaza-bicyclo[2.2.2]octane; sodium hydrogencarbonate; hydroquinone at 45 - 55℃; for 15h; Large scale;
2 Example 2: Synthesis of methyl 2-hydroxymethyl acrylate
In a 200 liter clean reactor, 65 kg of methyl acrylate, 2.52 kg of sodium bicarbonate, 2.8 kg of DABCO (anhydrous), 0.5 kg of hydroquinone, 7.5 kg of paraformaldehyde,Reflux heating steam heated to between 45-55 degrees incubated for 15 hours,Cool to room temperature, add 15 kg of saturated salt water, add about 6 kg of concentrated hydrochloric acid, adjustPH3-4.The layers were separated, the organic phase was washed with 10 kg of saturated brine, dried over 10 kg of sodium sulfate, filtered and concentrated to remove acrylic acidMethyl esters gave a colorless liquid 28 kg, high vacuum distillation product 24 kg, GC purity of 95%, the yield of 83%Further high vacuum distillation can be 97% purity products.
81%
In 1,4-dioxane; water for 10h; Heating;
80%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 12h;
78%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water for 6h; ultrasonic bath;
74%
With 1,4-diaza-bicyclo[2.2.2]octane at 30 - 40℃; for 120h; ultrasound;
70%
With 1,4-diaza-bicyclo[2.2.2]octane sonification;
69%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; Inert atmosphere;
68%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃;
68%
With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In tetrahydrofuran at 20℃; for 5h;
1.1 Synthesis of 2-methyl hydroxymethyl methacrylate
3.0 g of paraformaldehyde, 15 ml of methyl acrylate were dissolved in 25 ml of dioxane, and then 3.2 g of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was added. The reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated to dryness, a small amount of a polymerization inhibitor was added, and distilled under reduced pressure to obtain 10.2 g of methyl 2-hydroxymethyl acrylate,n a yield of 68%.
66%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃;
65%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃;
62%
With hexamethylenetetramine In 1,4-dioxane; water at 20℃; for 52h;
62%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water for 14h;
55%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water Inert atmosphere;
52%
With trimethylamine In water at 60℃; for 6h;
43%
Inert atmosphere;
42%
With triethylamine In water at 60℃; for 6h;
38%
With 1,4-diaza-bicyclo[2.2.2]octane; water In 1,4-dioxane at 20℃; for 48h;
30%
With 1,4-diaza-bicyclo[2.2.2]octane In water at 158 - 164℃; for 0.025h; Irradiation;
30%
Stage #1: formaldehyd With hydrogenchloride In water at 90℃; for 3h; Inert atmosphere;
Stage #2: acrylic acid methyl ester With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 12h; Inert atmosphere;
24%
With 1,4-diaza-bicyclo[2.2.2]octane for 72h;
19%
With 1,4-diaza-bicyclo[2.2.2]octane at 25℃; Inert atmosphere;
General Procedure for Morita-Baylis-Hillman Reactions
General procedure: Into a round bottom flask charged with a stirbar was added 1.0 equiv. aldehyde, followed by 2.0 equiv. methyl acrylate and 0.5 equiv. DABCO. The reaction mixture was stirred until judged complete by TLC, then was partitioned between 1.0 M acetic acid and CH2Cl2. The organic layer was set aside, and the residual product was extracted from the aqueous layer with an additional portion of CH2Cl2. The combined organic layers were washed with deionized water then brine, then concentrated and purified via column chromatography.
19%
With 1,4-diaza-bicyclo[2.2.2]octane at 20℃; Inert atmosphere;
11%
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 24h;
Stage #1: formaldehyd With phosphoric acid In water at 90℃; for 1.5h;
Stage #2: acrylic acid methyl ester With 1,4-diaza-bicyclo[2.2.2]octane In tetrahydrofuran; water at 20℃; for 36h;
87 %Chromat.
With 4-methoxy-phenol; lithium chloride In N,N-dimethyl acetamide; water at 50℃; for 4h;
2
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
87 %Chromat.
With 4-methoxy-phenol In 1-methyl-pyrrolidin-2-one; water at 50℃; for 4h;
11
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
82 %Chromat.
With potassium chloride; 4-methoxy-phenol In water; acetonitrile at 50℃; for 6h;
16
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
85 %Chromat.
With 4-methoxy-phenol; lithium chloride In methanol; N,N-dimethyl acetamide; water at 50℃; for 6.5h;
10
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
83 %Chromat.
With 4-methoxy-phenol; calcium chloride In water; acetonitrile at 50℃; for 6.5h;
14
[Examples 2 to 16] ; The process was performed under the same conditions except for changing the starting acrylate compound, solvent added (aprotic polar solvent), tertiary amine compound catalyst, inorganic salt and reaction time in Example 1. The yields of the objective compounds are shown together with the reaction conditions in Table 1.
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water for 72h;
With 1,4-diaza-bicyclo[2.2.2]octane
With 1,4-diaza-bicyclo[2.2.2]octane
With methylated nitrogen-substituted porous silica SBA-15 In 1,4-dioxane at 149.84℃;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 95℃;
In water
With 1,4-diaza-bicyclo[2.2.2]octane at 0℃;
With 1,4-diaza-bicyclo[2.2.2]octane at 20℃; for 168h;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 24h;
Methyl 17-((triisopropylsilyloxy)methyl)acrylate (5):
A solution of paraformaldehyde (901.3 mg, 29.1 mmol, 5.0 equiv) in 1,4-dioxane/H2O (1:1, 10 mL) was stirred for 30 min at room temperature. To the mixture, methyl acrylate 3 (520 μL, 5.81 mmol, 1.0 equiv) and DABCO (3.26 g, 29.1 mmol, 5.0 equiv) were added. After stirring for 24 h, the mixture was diluted with ether and quenched with a saturated NaCl solution. The aqueous layer was then extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product 4 was used in the next reaction, without further purification.To a solution of 4 (101.0 mg, 0.86 mmol, 1.0 equiv) and imidazole (349.5 g, 5.16 mmol, 6.0 equiv) in CH2Cl2, TIPSCl (400.4 μL, 1.89 mmol, 2.2 equiv) was added at room temperature. After stirring for 18 h, the mixture was diluted with CH2Cl2 and quenched with a saturated NH4Cl solution. The aqueous layer was then extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc=40:1) afforded 5 as a yellow oil (123.3 mg, 0.45 mmol, 52%, over two steps). Rf 0.30 (hexane/EtOAc=40:1); 1H NMR (300 MHz, CDCl3) δ 6.28 (1H, dd, J=4.1, 2.1 Hz, H18), 6.00 (1H, dd, J=4.5, 2.1 Hz, H18), 4.45 (2H, t, J=2.0 Hz, H19), 3.75 (3H, s, Me), 1.21-1.05 (21H, m, TIPS).
With 1,4-diaza-bicyclo[2.2.2]octane; water In 1,4-dioxane Inert atmosphere; Schlenk technique;
3.3 kg
With trimethylamine at 70℃; for 8h; Industrial scale;
1
17.3 kg of methyl acrylate (hereinafter also referred to as AM), 1.54 kg of paraformaldehyde 1.54 Kg, and 0.99 kg of 30% trimethylamine (hereinafter also referred to as TMA) aqueous solution were placed in a 20 L reaction vessel and stirred at 70 ° C. for 8 hours to continue the reaction. The α-hydroxymethylacrylic acid ester obtained by the reaction was 4.49 kg. After the reaction, it was separated into an AM phase and an aqueous phase by standing, and the aqueous phase was removed. Thereafter, the AM layer was washed with 1000 g of water, and the obtained AM layer was subjected to simple distillation (while blowing a mixed gas (7% O 2 / N 2) for 6 hours It was distilled off. The obtained bottom liquid contained 3.67 kg of α-hydroxymethylacrylic acid ester, and precision distillation (at a column top temperature of 86 to 87 ° C / 13 hPa while blowing a mix gas (7% O 2 / N 2) Precision distillation) to obtain 3.30 kg of α-hydroxymethylacrylic acid ester. The dimer content of trimethylamine and α-hydroxymethylacrylic acid ester was measured by the above method.
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water Inert atmosphere;
With 1,4-diaza-bicyclo[2.2.2]octane at 20℃; Inert atmosphere; Schlenk technique;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃; for 12h;
3.3 kg
With trimethylamine In water at 70℃; for 8h; Large scale;
1-4; 1-2; 5-8; 3 Example 1
Methyl acrylate (hereinafter also referred to as AM) 17.3 kg,Paraformaldehyde 1.54kg, 30% trimethylamine0.99 kg of an aqueous solution (hereinafter, also referred to as TMA) was placed in a 20 L reaction vessel, and stirred at 70° C. for 8 hours to continue the reaction.The amount of α-hydroxymethyl acrylic acid ester obtained by the reaction was 4.49 kg.After the reaction, the mixture was allowed to stand to separate into an AM phase and an aqueous phase, and the aqueous phase was removed.After that, the AM layer was washed with 1000 g of water, and the obtained AM layer was subjected to simple distillation (mix gas (7% O2/N2) while being blown,While adjusting the internal temperature so that it does not exceed 100°C,AM was distilled off at a pressure of 330 to 67 hPa) over 6 hours.The obtained bottom liquid contained 3.67 kg of α-hydroxymethylacrylic acid ester,Precision distillation (while blowing mixed gas (7% O2/N2),Perform precision distillation at a column top temperature of 86 to 87° C./13 hPa),3.30 kg of α-hydroxymethyl acrylic acid ester was obtained.The measurement of the dimer content of trimethylamine and α-hydroxymethylacrylic acid ester was performed byThe procedure was as described above.
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water at 20℃;
With 1,4-diaza-bicyclo[2.2.2]octane In 1,4-dioxane; water Inert atmosphere;
Synthetic procedure for allyl sulfones.
General procedure: 1) To a solution of paraformaldehyde (1.3 equiv) and acrylate (1.0 equiv) in dioxanewa ter (1:1, v/v) was added DABCO (1.3 equiv) and thereaction progress was monitored by TLC. Upon completion, the reaction mixture was partitioned with EtOAc and water. The organ ic layerwas separated and washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product waspurified by column chromatography on silica gel to afford corresponding alcohols.
With 1,4-diaza-bicyclo[2.2.2]octane at 25℃; for 24h; Inert atmosphere;
Stage #1: formaldehyd With phosphoric acid In water at 90℃; for 5h;
Stage #2: trimethyl phosphonoacetate With potassium carbonate In water at 35 - 40℃; for 0.9h;
55%
With potassium carbonate In water at 20℃; for 1h;
44%
With potassium carbonate In water at 20℃; for 2h;
106
Example 106: methyl 2-(hydroxymethyl)acrylate44%A saturated aqueous solution (10 mL) of K2CO3 (3.5 g, 117 mmol, 1.6 eq.) was slowly added to a rapidly stirred solution of trimethylphosphonoacetate (5.46 g, 30 mmol, 1.0 eq.) and paraformaldehyde (6.63 g, 48 mmol, 4.0 eq.) at r.t.. After the addition the mixture was stirred for 2 h. Then the mixture was extracted with DCM. The organic layer was concentrated to give the compound (1.5 g, 44%) as a yellow oil. 1U NMR (400 MHz, CD3OD) δ: 6.29 (s, IH), 5.83 (s, IH), 3.75 (s, 3H), 3.72 (s, 2H).
With hydrogen In methanol at 50℃; for 23h; Title compound not separated from byproducts.;
With hydrogen; p-benzoquinone In methanol at 15℃; for 23h; Title compound not separated from byproducts.;
With di[(η-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate; (Rc,Ra)-THNAPhos; hydrogen In dichloromethane at 20℃; for 24h; optical yield given as %ee;
With bis(norbornadiene)rhodium(l)tetrafluoroborate; dicyclohexyl{1-[(S)-3,5-dioxa-4-phospha-cyclohepta(2,1-a;3,4-a')dinaphtalen-4-yl]-3-methyl-2-indolyl}phosphine; hydrogen In dichloromethane at 20℃; for 20h; Inert atmosphere; optical yield given as %ee;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; (2S)-methyl (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthalen-4-ylamino)-2-isobutylethanoate; hydrogen In dichloromethane at 24.84℃; for 16h; optical yield given as %ee;
With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); hydrogen bromide; hydrogen; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) In methanol at 50℃; for 23h; optical yield given as %ee;
With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); tetrafluoroboric acid; hydrogen; (S)-[(5,6),(5’,6’)-bis(ethylenedioxy)biphenyl-2,2’ diyl]bis(diphenylphosphine) In methanol at 15℃; for 23h; optical yield given as %ee;
With BF4(1-)*C8H10Rh(1+)*C17H27NO2P2; hydrogen In tetrahydrofuran at 25℃; for 1.5h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With BF4(1-)*C8H10Rh(1+)*C21H35NO2P2; hydrogen In tetrahydrofuran at 25℃; for 1.5h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With bis(norbornadiene)rhodium(l)tetrafluoroborate; C36H29N2O4P; hydrogen In dichloromethane at 20℃; for 12h;
With NADH In water at 30℃; for 24h; aq. buffer; Enzymatic reaction; optical yield given as %ee;
With bis(norbornadiene)rhodium(l)tetrafluoroborate; 6-(2-diphenylphosphanyl-6-isopropylphenoxy)-2,2-dimethyl-4,4,8,8-tetranaphthalen-2-yltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine; hydrogen In dichloromethane at 20℃; for 12h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With BF4(1-)*C49H54O4P2Rh(1+); hydrogen In tetrahydrofuran at 20℃; for 18h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N(1)-(3,5-bis(trifluoromethyl)phenyl)-N(2)-(3-(((11bS)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yloxy)methyl)benzyl)phthalamide; hydrogen In dichloromethane at 20℃; for 20h; Autoclave; optical yield given as %ee;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N(1)-(4-butylphenyl)-N(2)-(7-((11bS)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yloxy)naphthalen-1-yl)phthalamide; hydrogen In dichloromethane at 20℃; for 20h; Autoclave; optical yield given as %ee;
With chlorobis(cyclooctene)rhodium(I) dimer; C6H15N*C42H55N2O5PS2; hydrogen In dichloromethane at 25℃; for 18h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With D-glucose; pichia stipitis CBS 6054 old yellow enzyme 2.6 (OYE 2.6) at 20℃; for 6h; aq. buffer; Enzymatic reaction; optical yield given as %ee; stereoselective reaction;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N-(4-(((11bS)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yloxy)methyl)phenyl)benzamide; hydrogen In dichloromethane at 20℃; for 20h; Inert atmosphere; optical yield given as %ee;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N-(3-(((11bS)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yloxy)methyl)benzyl)-4-methoxybenzamide; hydrogen In dichloromethane at 20℃; for 20h; Inert atmosphere; optical yield given as %ee;
28 % ee
With leukotriene B<SUB>4</SUB> 12-hydroxydehydrogenase from Rattus norvegicus, rat; NADPH In aq. buffer at 30℃; for 24h; Enzymatic reaction; stereoselective reaction;
55 % ee
With bis(norbornadiene)rhodium(l)tetrafluoroborate; (N,N'-phenylenebis(3,5-di-tert-butylsalicylideneiminato))zinc(II); C50H44N3O2P; hydrogen In dichloromethane at 25℃; for 16h;
58 % ee
With (cycloocta-1,5-diene)-[(S,S)-2,2'-bis(ferrocenyl-phenylphosphino)-1,1'-biphenyl] rhodium tetrafluoroborate; hydrogen In dichloromethane at 20℃; for 16h; Autoclave;
K.3 K.3. Asymmetric catalyzed hydrogenation
K.3. Asymmetric catalyzed hydrogenationTypical procedure A solution of [Rh(COD)L*]BF4 (0.005 mmol, 1 mol%) and substrate (0.5 mmol) in dry solvent (7.5 mL) was introduced in a stainless steel autoclave. The autoclave was closed, purged with hydrogen and then pressurized with hydrogen. After 16h of stirring at room temperature, the pressure was released to atmospheric pressure and the solution was transferred to a round bottom flask. The solvent was removed on a rotary evaporator to give a residue which was purified by column chromatography on silica gel to afford the hydrogenated product. The enantiomeric excess was determined by HPLC on chiral column.Results of aymmetric catalyzed hydrogenations by rhodium complexes of ligands (1-48) or (1-49) are presented in table 9 and 10. Table 9. Asymmetric catalyzed hydrogenation by rhodium complexes of ligands (1-48)Substrate Diphosphine 48 Cond. (RT 16h) ProductR R2 R R8 Solvant P Conv ee(¾) (%) (%)63 48a Ph oAn Ph Ph MeOH 4 64 93 61 (R)10 100 63 (R)20 100 60 (R)THF 10 6 ndCH2C12 7 nd Table 10. Asymmetric catalyzed hydrogenation by rhodium complex of ligand (I'-49c)
87 % ee
With [((R)-tert-butylmethylphosphino)(ditert-butylphosphino)amine](1,5-cyclooctadiene)rhodium(I) monotetrafluoroborate; hydrogen In methanol at 0℃; Glovebox; Sealed tube; Inert atmosphere;
76 % ee
With glucose dehydrogenase; potassium phosphate; D-glucose; ene reductase YqjM wild type enzyme C26H; NADPH In 2-methyltetrahydrofuran; aq. phosphate buffer at 30℃; Inert atmosphere; Enzymatic reaction; enantioselective reaction;
85 % ee
With glucose dehydrogenase; potassium phosphate; D-glucose; ene reductase YqjM wild type enzyme C26N/I69A; NADPH In 2-methyltetrahydrofuran; aq. phosphate buffer at 30℃; for 24h; Inert atmosphere; Enzymatic reaction; Overall yield = 44 %; Overall yield = 52 mg; enantioselective reaction;
79 % ee
With TsER C25G/I67T for 24h; Enzymatic reaction; stereoselective reaction;
76 % ee
With D-glucose; Bacillus subtilis 168 glucose dehydrogenase E170K/Q252L; Thermus scotoductus SA-01 ene-reductase; β-nicotinamide adenine dinucleotide phosphate sodium salt; cobalt(II) chloride In aq. phosphate buffer; ethanol at 30℃; for 24h; Enzymatic reaction; enantioselective reaction;
2.3. Biotransformations: screening scale
General procedure: All reactants were mixed in 1.5 mL reaction tubes containing (final concentrations) 100 mM glucose, 10 μM enzyme, 0.1 mM CoCl2, 0.25 mM NADP+, GDH-60 (2.2 U mL 1) and 10 mM substrate (from 1 M stock in EtOH). The reactions were performed at least in triplicates in total reaction volume of 200 μL at 30 C and 700 rpm in a Thermomixer (Eppendorf). To stop the reaction, the aqueous solution was extracted with 200 μL ethyl acetate. Conversion and enantiomeric excess was determined by GC or HPLC. Peaks were assigned based on available authentic standards, by mass analysis or full characterisation. Precise ee determination for low conversion levels was performed as previously described [24]. The optical rotation of 2-methylcyclopentan-1-one (13b) was determined to assign chirality. All reactants were mixed in a 50 mL reaction containing 45 mL KPi buffer (100 mM, pH 7.4), glucose (87.5 mM), NADP+ (0.25 mM), BsGDH (2.2 U mL 1) and TsER C25G/I69T (20 μM). Reaction started upon addition of 50 mM 2-methylcyclopenten-1-one (13a) with 5 mL n-pentane and was performed at 30 C and 200 rpm. After completion the whole reaction mixture was extracted with n-pentane and the solvent was carefully evaporated under vacuum. The optical rotation was measured with a 20 mg mL 1 solution in chloroform in a 50 mm cuvette with a polarimeter P800-T, KRÜSS with λ =589 nm at 25 C and result in [∝]D25 -81 indicating that 2R-methylcyclopentanone is formed according to Shimoda et al.[35].
Stage #1: methyl 2-hydroxymethylacrylate With magnesium iodide In dichloromethane Cooling with acetone-dry ice; Inert atmosphere;
Stage #2: 2-iodo-propane With triethyl borane; tri-n-butyl-tin hydride In hexane; dichloromethane at -78℃; for 2.5h; Inert atmosphere;
78%
Stage #1: methyl 2-hydroxymethylacrylate With magnesium iodide In dichloromethane at -78℃; for 30h;
Stage #2: 2-iodo-propane With triethyl borane; tri-n-butyl-tin hydride In hexane; dichloromethane for 2.5h;
1 Preparation of methyl 2-(hydroxymethyl)-4-methyl pentanoate
MgI2 (683 mg, 2.45 mmol) was added to anhydrous CH2Cl2 (6 mL), and the mixture was stirred at normal temperature for 45 min. The mixture was cooled to -78° C., and then methyl 2-(hydroxymethyl)acrylate dissolved in anhydrous CH2Cl2 (8 mL) was added thereto. The mixture was further stirred at -78° C. for 30 min, and then isopropyl iodide (417 mg, 24.5 mmol), Bu3SnH (2.57 mg, 8.84 mmol) and Et3B (8.84 mL, 8.84 mmol, 1.0 M/hexane solution) in sequence were slowly added thereto. Immediately after all were added thereto, air (20 mL) was slowly added thereto through a syringe. After the mixture was stirred for 2 hr and 30 min, the reactant was diluted in diethyl ether (120 mL). Silica gel (10 g) was added thereto, and then the resulting mixture was evaporated under reduced pressure. The powder obtained was washed with hexane (500 mL) and extracted with diethyl ether (300 mL), evaporation was performed under reduced pressure, and then column chromatography was used to obtain 150 mg (yield 78%) of the title compound. 1H NMR (300 MHz, CDCl3) d 0.87 (d, J=6.0 Hz, 3H), 0.88 (d, J=5.4 Hz, 3H), 1.32-1.38 (m, 1H), 1.41-1.76 (m, 2H), 2.34 (s, 1H), 2.45-2.86 (m, 1H), 3.68-3.70 (m, 2H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3) d 22.16, 22.43, 25.78, 37.86, 45.45, 51.89, 63.38, 162.18, 176.11.
52%
Stage #1: methyl 2-hydroxymethylacrylate With magnesium iodide In dichloromethane at -78℃; for 0.5h;
Stage #2: 2-iodo-propane With triethyl borane; oxygen; tri-n-butyl-tin hydride In hexane; dichloromethane at -78℃; for 3h;
3-cyclohexyl-2-hydroxymethyl-propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: methyl 2-hydroxymethylacrylate With magnesium iodide In dichloromethane at -78℃; for 0.5h;
Stage #2: Cyclohexyl iodide With triethyl borane; oxygen; tri-n-butyl-tin hydride In hexane; dichloromethane at -78℃; for 3h;
Stage #1: methyl 2-hydroxymethylacrylate With magnesium iodide In dichloromethane at -78℃; for 0.5h;
Stage #2: ethyl iodide With triethyl borane; oxygen; tri-n-butyl-tin hydride In hexane; dichloromethane at -78℃; for 3h;
2-hydroxymethyl-4,4-dimethylpentanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: methyl 2-hydroxymethylacrylate With magnesium iodide In dichloromethane at -78℃; for 0.5h;
Stage #2: tert-Butyl iodide With triethyl borane; oxygen; tri-n-butyl-tin hydride In hexane; dichloromethane at -78℃; for 3h;
With triethylamine; In dichloromethane; at 0 - 20℃;
Compound lb (232 mg, 2 mmol) was dissolved in 5 mL of DCM with TEA (220 mg, 2 mmol) and cooled to 0 C. To the solution, acetyl chloride (157 mg, 2 mmol) was added dropwise. The reaction mixture was stirred at room temperature after addition. After reaction, the reaction solution was collected by filtration and extracted with water for three times. The organic layers were collected and dried over anhydrous sodium sulfate. The solution was further filtered and concentrated to afford crude product which was subjected to flash chromatography to obtain pure compound 6. Yield: 224.4 mg, 71%. -NMR (400 MHz, CDCh): d 6.36 (s, 1H), 5.85 (s, 2H), 4.81 (s, 2H), 3.79 (s, 3H), 2.10 (s, 3H). 13C-NMR (100 MHz, CDCh): 5(ppm) 170.41, 165.68, 135.21, 127.60, 62.47, 52.06, 20.88.
With N-Bromosuccinimide; sodium chloride; In diethyl ether; dichloromethane;
Preparation of Methyl 2-bromomethyl-2-propenoate To a solution of N-bromosuccinimide (5.17 g, 26.8 mmoles) in dry dichloromethane (40 ml) were added dimethyl sulphide (4 ml) in dichloromethane (50 ml), drop by drop with stirring at 0 C. for 10 min. To the resulting mixture was added methyl 3-hydroxy-2-metylidene-propanoate (3.15 g, 31.50 mmoles) dissolved in dichloromethane (40 ml), leaving it for 24 hours at room temperature. At the end of that time, it was poured into an aqueous solution of sodium chloride and ice. An extraction was performed with diethyl ether (3*100 ml), and the result was washed with water and dried over anhydrous sodium sulphate. Following vacuum concentration, 4.33 g of a yellow oil was obtained (89% yield) of methyl 2-bromomethyl-2-propenoate.
With formaldehyd; paraformaldehyde In diethyl ether; nitrogen
Preparation of Methyl 3-hydroxy-2-methylidene-propanoate
Preparation of Methyl 3-hydroxy-2-methylidene-propanoate To a mixture containing 27 ml (25.83 g, 0.30 mmoles of methyl acrylate and 2.5 g (22.29 mmoles) of 1,4-diazabicyclo[2,2,2]-octane (DABCO), formaldehyde was added (generated by pyrolysis of paraformaldehyde at 200° C.) in a nitrogen current for 1 h. The mixture was then left to react for 7 days at room temperature. At the end of that time an extraction was performed with diethyl ether (2*100 ml) and the result was washed with water (2*400 ml). The ether extracts were dried over anhydrous sodium sulphate, filtered and vacuum concentrated, giving 19.5 g (77% yield) of methyl 3-hydroxy-2-methylidene-propanoate in oil form.
9 EXAMPLE 9
EXAMPLE 9 When 130 g (1 mole) of cyclohexanol formaldehyde hemiacetal in 100 g of cyclohexanol and 86 g (1 mole) of methyl acrylate are reacted, 8 g (71.4 millimoles) of 1,4-diazabicyclo [2.2.2]octane are added and the mixture is stirred for 70 hours at 25° C., methyl 2-(hydroxymethyl)-acrylate is obtained in a yield of 45% (according to HPLC).
With diisopropyl{1-[(S)-3,5-dioxa-4-phospha-cyclohepta(2,1-a;3,4-a')dinaphthalen-4-yl]-3-methyl-2-indolyl}phosphine; bis(norbornadiene)rhodium(l)tetrafluoroborate; hydrogen In dichloromethane at -40℃; for 15h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With N-methyl-N-{(S)-1-[2-(diphenylphosphino)phenyl]ethyl}-(S)-1,10-bi-2-naphthylphosphoramidite; bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; hydrogen In dichloromethane at 20℃; for 24h; optical yield given as %ee;
With BF4(1-)*C8H10Rh(1+)*C17H27NO2P2; hydrogen In dichloromethane at 25℃; for 1.5h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With diisopropyl{1-[(S)-3,5-dioxa-4-phospha-cyclohepta(2,1-a;3,4-a')dinaphthalen-4-yl]-3-methyl-2-indolyl}phosphine; bis(norbornadiene)rhodium(l)tetrafluoroborate; hydrogen In dichloromethane at -40℃; for 16h; optical yield given as %ee; enantioselective reaction;
With bis(norbornadiene)rhodium(l)tetrafluoroborate; (11bM)-4-((1R,2S)-1-(diphenylphosphino)-3-methoxy-1-phenylprop-2-yloxy)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine; hydrogen In tetrahydrofuran at 20℃; for 12h; Autoclave; optical yield given as %ee;
With BF4(1-)*C49H54O4P2Rh(1+); hydrogen at 20℃; for 18h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
97% ee
With bis(norbornadiene)rhodium(l)tetrafluoroborate; C60H46O4P2; hydrogen In tetrahydrofuran at 0℃; for 18h; Inert atmosphere;
93 % ee
With glucose dehydrogenase; potassium phosphate; D-glucose; ene reductase YqjM wild type enzyme C26N/I69A; NADPH In 2-methyltetrahydrofuran; aq. phosphate buffer at 30℃; Inert atmosphere; Enzymatic reaction; enantioselective reaction;
> 99 % ee
With NCR W100I for 24h; Enzymatic reaction; stereoselective reaction;
>99 % ee
With D-glucose; Bacillus subtilis 168 glucose dehydrogenase E170K/Q252L; Thermus scotoductus SA-01 ene-reductase C25D/I67C; β-nicotinamide adenine dinucleotide phosphate sodium salt; cobalt(II) chloride In aq. phosphate buffer; ethanol at 30℃; for 24h; Enzymatic reaction; enantioselective reaction;
2.3. Biotransformations: screening scale
General procedure: All reactants were mixed in 1.5 mL reaction tubes containing (final concentrations) 100 mM glucose, 10 μM enzyme, 0.1 mM CoCl2, 0.25 mM NADP+, GDH-60 (2.2 U mL 1) and 10 mM substrate (from 1 M stock in EtOH). The reactions were performed at least in triplicates in total reaction volume of 200 μL at 30 C and 700 rpm in a Thermomixer (Eppendorf). To stop the reaction, the aqueous solution was extracted with 200 μL ethyl acetate. Conversion and enantiomeric excess was determined by GC or HPLC. Peaks were assigned based on available authentic standards, by mass analysis or full characterisation. Precise ee determination for low conversion levels was performed as previously described [24]. The optical rotation of 2-methylcyclopentan-1-one (13b) was determined to assign chirality. All reactants were mixed in a 50 mL reaction containing 45 mL KPi buffer (100 mM, pH 7.4), glucose (87.5 mM), NADP+ (0.25 mM), BsGDH (2.2 U mL 1) and TsER C25G/I69T (20 μM). Reaction started upon addition of 50 mM 2-methylcyclopenten-1-one (13a) with 5 mL n-pentane and was performed at 30 C and 200 rpm. After completion the whole reaction mixture was extracted with n-pentane and the solvent was carefully evaporated under vacuum. The optical rotation was measured with a 20 mg mL 1 solution in chloroform in a 50 mm cuvette with a polarimeter P800-T, KRÜSS with λ =589 nm at 25 C and result in [∝]D25 -81 indicating that 2R-methylcyclopentanone is formed according to Shimoda et al.[35].
With glucose dehydrogenase; potassium phosphate; D-glucose; ene reductase YqjM wild type enzyme; NADPH In 2-methyltetrahydrofuran; aq. phosphate buffer at 30℃; Inert atmosphere; Enzymatic reaction; enantioselective reaction;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; (Rc,Ra)-THNAPhos; hydrogen In dichloromethane at 20℃; for 24h; optical yield given as %ee;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; 1-(3-(diphenylphosphanyl)phenyl)urea; (2S)-methyl (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthalen-4-ylamino)-2-isobutylethanoate; hydrogen In dichloromethane at 24.84℃; for 16h;
With BF4(1-)*C8H10Rh(1+)*C21H35NO2P2; hydrogen In dichloromethane at 25℃; for 1.5h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With NADH In water at 30℃; for 24h; aq. buffer; Enzymatic reaction; optical yield given as %ee;
With bis(norbornadiene)rhodium(l)tetrafluoroborate; C39H28O3P2; hydrogen In dichloromethane at 20℃; for 12h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
> 90 % ee
With reduced flavin mononucleotide; alpha-D-glucopyranose; glucose dehydrogenase from Thermoplasma acidophilum; old yellow enzyme 1 from Saccharomyces pastorianus; nicotinamide adenine dinucleotide phosphate In aq. buffer at 20℃; for 24h; Enzymatic reaction; enantioselective reaction;
4.5 Enzymatic activity assay for OYE1 variants
General procedure: Ene-reductase activity assays were performed at ambient temperature under anaerobic conditions (Coy Laboratory, Grass Lake, MI). For preparing reaction stock solution, individual substrates (see below) were dissolved in 50mM Tris-HCl (pH 7.5), supplemented with 200μM NADP+, 100mM glucose, and glucose dehydrogenase (GDH) from Thermoplasma acidophilum (2 units for IVTT reactions, 5 units for purified enzyme reactions). Individual substrate concentrations were chosen to ensure vmax conditions or maximum solubility. At these substrate levels, reaction times were adjusted for 10-50% substrate conversion. To assay OYE activity in IVTT experiments, 20μL of the reaction stock solution was mixed with 2-10μL IVTT reaction mixture and the total assay volume was adjusted to 30μl with 50mM Tris-HCl (pH 7.5). To assay purified OYE1 variants, the enzyme (final concentration: 250nM) was added to 500μl reaction stock solution. Reaction progress was monitored by removing 30-μl aliquots from the assay solution and quenching them by mixing thoroughly with 30μL of ethyl acetate containing 1mM cyclohexanone as internal standard. A sample of the organic phase was collected and analyzed by GC (protocols: see below). The enantio/diasteriomeric excess were calculated by integration of product and substrate peak areas. Relative rates of conversion for individual substrates were calculated by dividing the measured rate of conversion for OYE1 variant over the corresponding rate for wild type OYE1.
With DrER for 24h; Enzymatic reaction; stereoselective reaction;
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N(1)-(4-butylphenyl)-N(2)-(4-((11bS)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yloxy)phenyl)phthalamide; hydrogen In dichloromethane at 20℃; for 20h; Autoclave;
With bis(norbornadiene)rhodium(l)tetrafluoroborate; C50H44N3O2P; C112H112N8O8Zn; hydrogen In dichloromethane at 25℃; for 16h;
83 % ee
With bis(norbornadiene)rhodium(l)tetrafluoroborate; C6H15N*C27H29F3NO4PSSi2; C27H26NO4P; hydrogen In dichloromethane for 18h; enantioselective reaction;
With palladium 10% on activated carbon; hydrogen; potassium carbonate In methanol at 20℃; for 7h;
With 1,4-diaza-bicyclo[2.2.2]octane; tempol; 4-methoxy-phenol at 100℃; for 14h; Air blowing;
15
Example 15; A 200 mL four-neck flask equipped with a stirrer, condenser, thermometer, gas inlet and oil bath was charged with 40.6 g of methyl α-(hydroxymethyl) acrylate, 1.96 g of 1,4-diazabicycio[2.2.2]octane as the catalyst, and 0.02 g of hydroquinone monomethyl ether and 0.02 g of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl as the polymerization inhibitors. While blowing air into the reaction mixture, the mixture was then raised to a temperature of 100°C and the reaction was carried out for 2 hours. Next, 37.9 g of crotyl alcohol (a cis-trans mixture available from Tokyo Chemical Industry Co., Ltd.) and 1.96 g of the catalyst 1,4-diazabicyclo[2.2.2]octane were added dropwise over a period of 2 hours at normal pressure, and the reaction was continued for another 12 hours. Following the reaction, measurement was carried out by gas chromatography, whereupon the yield of methyl α-(crotyloxymethyl) acrylate with respect to the methyl α-(hydroxymethyl) acrylate was 60 mol%, the conversion of methyl α-(hydroxymethyl) acrylate was 90 mol%, and the yield of crotyl ester as the unsaturated alkyl ester was 1.9 mol% with respect to the methyl α-(hydroxymethyl) acrylate. Next, the remaining crotyl alcohol was distilled off under a reduced pressure (operating pressure, 7 kPa) by simple distillation, following which 18.4 g of an 8 wt% sodium hydroxide solution was added to the resulting reaction mixture. Stirring was then carried out for 30 minutes at room temperature, after which the mixture at left at rest for 30 minutes to effect oil-water separation. Next, 4.6 g of an 8 wt% sodium hydroxide solution was added to this organic phase and stirring was carried out at room temperature for 30 minutes, after which the mixture was left at rest for 30 minutes to effect oil-water separation, thereby giving an organic phase. The resulting organic phase was then washed with a 5 wt% aqueous solution of Glauber's salt, and oil-water separation was carried out. This operation was carried out one more time, after which 53.9 g of an organic phase was obtained. No methyl α-(hydroxymethyl) acrylate starting material was present in the resulting organic phase. Next, 0.05 g of hydroquinone methyl ether, 0.05 g of 2-t-butyl hydroquinone and 0.05 g of triphenyl phosphite were added to the above organic phase, and simple distillation was carried out under a reduced pressure. Pure methyl α-(crotyloxymethyl) acrylate was obtained at 13 kPa and a column head temperature of 93°C. The methyl α-(crotyloxymethyl) acrylate content was 97.1 wt%, the nitrogen content was below the limit of detection, the amount of peroxide was 2 ppm, and the content of crotyl ester as the unsaturated alkyl ester was 0.8 wt%. Next, 500 ppm of 2-t-butyl hydroquinone was added as an antioxidant to the resulting purified methyl α-(crotyloxymethyl) acrylate, thereby giving a methyl α-(crotyloxymethyl) acrylate composition. The Hazen color number for this composition was below 10.
With dmap In dichloromethane at 20℃; for 2h; Inert atmosphere;
With dmap In dichloromethane at 20℃;
With dmap In dichloromethane
With dmap In dichloromethane at 20℃; for 5h; Inert atmosphere; Schlenk technique;
With dmap In dichloromethane at 20℃;
Stage #1: methyl 2-hydroxymethylacrylate With dmap In dichloromethane at 0℃; for 0.166667h;
Stage #2: di-<i>tert</i>-butyl dicarbonate In dichloromethane at 0 - 20℃;
With dmap In dichloromethane at 0℃; for 5h; Inert atmosphere;
Stage #1: methyl 2-hydroxymethylacrylate; acetonitrile With methanesulfonic acid at 60 - 110℃; for 6.25h; Inert atmosphere;
Stage #2: With water; potassium carbonate In acetonitrile Inert atmosphere; Cooling with ice;
4.3. Synthesis of methyl (2-acetamidomethyl)acrylate 2a
Applying the procedure for the formation of methyl 3-aryl-(2-acetamidomethyl)acrylates,35,36 acrylate 1a (7.00g, 60.3mmol) was dissolved in acetonitrile (250mL) and the solution was heated to 60°C. Next methanesulfonic acid (162mL, 2.5mol) was dropped (within 15min) into the solution. The reaction mixture was heated to 110°C and stirred for 6h. The reaction mixture was cooled (ice bath) and diluted with water. By adding K2CO3, the pH-value was adjusted to 7-8. After extraction with ether, the organic phase was washed with brine and dried (Na2SO4). After evaporation of the solvents, the residue was purified by flash chromatography (cyclohexane/AcOEt=4:1 to 2:1) to yield 2a (4.5g, 47%). 1H NMR (CDCl3): δ=6.22 (1H, m, =CH), 6.16 (1H, br s, NH), 5.78 (1H, m, =CH), 4.04 (2H, br d, J=6.1Hz, CH2N), 3.74 (3H, s, OCH3); 1.95 (3H, s, CH3); 13C NMR (CDCl3): δ=169.9 (C=O), 166.7 (C=O), 136.4 (=C), 127.1 (=CH2), 51.9 (OCH3), 40.5 (CH2N), 23.2 (CH3). Anal. Calcd for C7H11NO3 (157.167): C, 53.49; H, 7.05; N, 8.91. Found: C, 53.73; H, 6.97; N, 8.99.
With dodecacarbonyl-triangulo-triruthenium; 1-Adamantanecarboxylic acid; 1,3-bis-(diphenylphosphino)propane In m-xylene at 140℃; for 20h; Inert atmosphere; Sealed tube;
4-methylene-3',4'-dihydro-1'H,3H-spiro[furan-2,2'-naphthalene]-1',5(4H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With dodecacarbonyl-triangulo-triruthenium; 1-Adamantanecarboxylic acid; 1,3-bis-(diphenylphosphino)propane In m-xylene at 140℃; for 20h; Inert atmosphere; Sealed tube;
With triphenylphosphine; In dichloromethane; at 0 - 20℃; for 0.216667h;Inert atmosphere; Schlenk technique;
General procedure: Under N2 atmosphere and at 0 C, to a stirred solution of MBHalcohols 1 (0.3 mmol) and PPh3 (0.6 mmol) in EtOAc orCH2Cl2 (2 mL) in a Schlenk tube (25 mL) was slowly addedazodicarboxylates 2 (0.6 mmol) over 5 minutes by the means ofa microsyringe. The resulting reaction mixture was allowed towarm up to room temperature and stirred until the MBH alcohols1 were completely consumed, as monitored by TLC. Thesolvent was removed under reduced pressure and the residuewas purified by column chromatography on silica gel (gradienteluant: petroleum ether/ethyl acetate 9:1-3:1) to afford thehydrazines 3.
methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 1h;
89%
In N,N-dimethyl-formamide at 0 - 20℃; for 19h;
89%
With 1H-imidazole In dichloromethane at 0 - 25℃; for 1h;
87%
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
55.1 Step 1. Methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)acrylate (compound 262)
Imidazole (1.29 g, 19.0 mmol) and tert-butylchlorodiphenylsilane (4.95 mL, 19.0 mmol) were added to a stirred solution of methyl 2-(hydroxymethyl)acrylate 261 (1.77 mL, 17.2 mmol) in DMF (20 mL) at 0 °C. The reaction was allowed to warm to RT and was stirred for ~16 h. The reaction mixture was diluted with EtOAc (30 mL) and NaHCO3 (30 mL, Sat Aq) was added. The organic phase was separated and the aqueous phase was extracted again with EtOAc (3 × 30 mL). The combined organic fractions were washed with water (3 × 50 mL) and brine (2 × 50 mL), dried using MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-50% EtOAc/isohexane) to give the desired product 262 as colourless oil (5.34 g, 87%). Rt3.16 min (Method 1a) m/z 377 [M + Na]+(ES+).1H NMR (500 MHz, DMSO-d6): d, ppm 7.66-7.59 (m, 4H), 7.52-7.41 (m, 6H), 6.25 (q, J = 1.8 Hz, 1H), 6.03 (q, J = 2.0 Hz, 1H), 4.36 (s, 2H), 3.64 (s, 3H), 1.01 (s, 9H).
66%
With 1H-imidazole In tetrahydrofuran at 0 - 20℃;
Synthesis of compound 8a
Compound la (3.48 g, 30 mmol) was dissolved in 50 mL of dry THF with imidazole (2.250 g, 33 mmol). TBDPSCI (9.070 g, 33 mmol) was added to the solution dropwise at 0 °C. The reaction was stirred overnight at room temperature. Then, precipitate was removed by filtration to achieve clear solution which was further extracted with saturated sodium bicarbonate solution, water and brine. The organic layers were combined and dried over anhydrous sodium sulfate. The solution was collected, concentrated and subjected to flash chromatography to afford compound 8a. Yield, 6.99 g, 66%. -NMR (400 MHz, CDCl3): 5(ppm) 7.64-7.69 (m, 4H), 7.34-7.47 (m, 6H), 6.33(q, J= 1.9 Hz, 1H), 6.1 l(q, J=l.9 Hz, 1H), 4.42 (t, J=2. l Hz, 2H), 3.70 (s, 3H), 1.08 (s, 9H). 13C-NMR (100 MHz, CDCb): 5(ppm) 166.25, 139.33, 135.46, 133.24, 129.78, 127.77, 124.09, 62.21, 51.63, 26.82, 19.30. MS (m/z): [M]+ calcd. for C2, H2(,(LSI. 354.17; found, 377.1 for [M+Na]+.
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 25℃; for 12h;
With 1H-imidazole In dichloromethane at 0 - 20℃; for 1h;
Acrylate 20. Synthesized by a method adapted from Villieras and Rambaud.2 To around-bottom flask equipped with a stir bar were added trimethyl phosphonoacetate (S1,9.1 mL, 63 mmol, 1.00 equiv) and formaldehyde (S2, 20.5g, 37% in water, 252 mmol,4.00 equiv). The flask was lowered into a ambient-temperature water bath. To themixture was added a saturated solution of potassium carbonate in water (15.3 g, 110mmol, 1.75 equiv) dropwise via addition funnel over the course of one hour, and stirringwas continued for an additional hour. The reaction mixture was quenched by addition ofsaturated aqueous ammonium chloride (30 mL), then extracted three times with diethylether. The combined organics were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Methyl acrylate, produced as a side-product,was removed by azeotropic distillation with methanol. The residue was purified byvacuum distillation (~0.5 torr, 44 °C) to afford acrylate 20 as a clear oil (4.07 g, 56%yield) with minor impurities which were carried forward to the next reaction. Thecharacterization data matched those reported in the literature.3
With 1H-imidazole In dichloromethane at 0 - 20℃; for 1h;
123.3 mg
With 1H-imidazole; dmap In dichloromethane at 20℃; for 18h; Inert atmosphere;
Methyl 17-((triisopropylsilyloxy)methyl)acrylate (5):
A solution of paraformaldehyde (901.3 mg, 29.1 mmol, 5.0 equiv) in 1,4-dioxane/H2O (1:1, 10 mL) was stirred for 30 min at room temperature. To the mixture, methyl acrylate 3 (520 μL, 5.81 mmol, 1.0 equiv) and DABCO (3.26 g, 29.1 mmol, 5.0 equiv) were added. After stirring for 24 h, the mixture was diluted with ether and quenched with a saturated NaCl solution. The aqueous layer was then extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product 4 was used in the next reaction, without further purification.To a solution of 4 (101.0 mg, 0.86 mmol, 1.0 equiv) and imidazole (349.5 g, 5.16 mmol, 6.0 equiv) in CH2Cl2, TIPSCl (400.4 μL, 1.89 mmol, 2.2 equiv) was added at room temperature. After stirring for 18 h, the mixture was diluted with CH2Cl2 and quenched with a saturated NH4Cl solution. The aqueous layer was then extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc=40:1) afforded 5 as a yellow oil (123.3 mg, 0.45 mmol, 52%, over two steps). Rf 0.30 (hexane/EtOAc=40:1); 1H NMR (300 MHz, CDCl3) δ 6.28 (1H, dd, J=4.1, 2.1 Hz, H18), 6.00 (1H, dd, J=4.5, 2.1 Hz, H18), 4.45 (2H, t, J=2.0 Hz, H19), 3.75 (3H, s, Me), 1.21-1.05 (21H, m, TIPS).
With 1H-imidazole In dichloromethane Inert atmosphere;
With potassium carbonate; In water; at 10 - 20℃; for 6h;
Three bottle adding 119.2 g methoxy carbonyl methylene triphenyl bromination phosphorus, 300 ml water and 58 g 30percent formaldehyde aqueous solution, control 10 - 15 °C slowly dropping 30percent potassium carbonate aqueous solution to 266.8 g, then completing 15 - 20 °C lower heat insulating 6 hours, filtering to remove the insoluble matter (triphenyl phosphate). The filtrate by adding dichloromethane 500 ml extraction, the organic phase is concentrated, after removing the solvent control 70 - 90 °C, vacuum degree 0.098 mpa under reduced pressure distillation, to obtain 2 - hydroxy methyl methacrylate 25.7 g (yield 85percent).
7-fluoro-3-methyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
7-chloro-3-methyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
With 1,1,1,3',3',3'-hexafluoro-propanol for 12h; Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
7-iodo-3-methyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
3,9-dimethyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
3,8-dimethyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
3,7-dimethyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
2-hydroxymethyl-4-methyl-4-nitropentanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 20 - 80℃;
9.A Step A: 2-Hydroxymethyl-4-methyl-4-nitro-pentanoic acid methyl ester
l,8-Diazabicyclo[5.4.0]undec-7-ene (3.6 mL, 24 mmol) was added to 2-mtropropane (26.5 mL, 292 mmol). This mixture was heated to 65 °C and the heat was turned off and methyl 2-(hydroxymethyl)acrylate (25 mL, 243 mmol) was added dropwise. The heat was then turned back on at 80 °C. After heating for lh the heat was turned off and the reaction was stirred at room temperature overnight before heating at 80 °C for another 2h. The reaction was diluted with ethyl acetate (250 mL) and washed with 1M hydrogen chloride (2 x 125 mL), aqueous bicarbonate (125 mL) and brine (125 mL). The reaction product mixture was chromatographed on a 330g column of silica gel in 0-60% hexanes: ether eluting at 55-60% to give 2-hydroxymethyl-4-methyl-4-nitro- pentanoic acid methyl ester (29.68g, 60%) as a light green oil. ESI-MS m/z calc. 205.21, found 206.1 (M+l)+. Retention time: 1.67 minutes. 1H NMR (250 MHz, CDC13) ppm 1.50 - 1.59 (m, 6 H) 1.85 - 1.98 (m, 1 H) 2.10 - 2.23 (m, 1 H) 2.36 - 2.50 (m, 1 H) 2.60 (d, J=5.71 Hz, 1 H) 3.66 - 3.77 (s, 3 H)
60%
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 20 - 80℃;
1 Step 1: 2-Hydroxymethyl-4-methyl-4-nitro-pentanoic acid methyl ester
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.6 mL, 24 mmol) was added to 2-nitropropane (26.5 mL, 292 mmol). This mixture was heated to 65 °C and the heat was turned off and methyl 2-(hydroxymethyl)acrylate (25 mL, 243 mmol) was added dropwise. The heat was then turned back on at 80 °C. After heating for 1h the heat was turned off and the reaction was stirred at room temperature overnight before heating at 80 °C for another 2h. The reaction was diluted with ethyl acetate (250 mL) and washed with 1M hydrogen chloride (2 x 125 mL), aqueous bicarbonate (125 mL) and brine (125 mL). The reaction product mixture was chromatographed on a 330g column of silica gel in 0-60% hexanes:ether eluting at 55-60% to give 2-hydroxymethyl-4-methyl-4-nitro-pentanoic acid methyl ester (29.68g, 60%) as a light green oil. ESI-MS m/z calc.205.21, found 206.1 (M+1)+. Retention time: 1.67 minutes
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
With trifluoromethylsulfonic anhydride; trimethylamine In dichloromethane at 0 - 20℃; for 12h;
2 First Process
Trifluoromethanesulfonic anhydride (25.0 g) and dichloromethane (80.0 ml) were put into a reaction vessel and cooled to 0° C. Compound (T-8) (10.3 g) and a dichloromethane (160 ml) solution containing trimethylamine (8.97 g) were slowly added dropwise thereto. The obtained solution was poured into 1,6-hexanediol (314 g) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and an aqueous layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with anhydrous magnesium sulfate. This solution was concentrated under a reduced pressure, and the residue was purified through silica gel chromatography (volume ratio, heptane:ethyl acetate=3:2), and thereby Compound (T-9) (11.3 g; 59%) was obtained.
With 2,6-di-tert-butyl-4-methyl-phenol In tetrahydrofuran at 60℃; Inert atmosphere;
Synthesis of compound 7
Compound lb (116 mg, 1 mmol) was dissolved in 5 mL of THF with 4-nitrophenyl isocyanate (164.1 mg, 1 mmol) and 2,6-Di-tert-butyl-4-methylphenol (2.2 mg, 0.01 mmol). The reaction mixture was heated at 60 °C under argon atmosphere. The completion of reaction was followed by TLC. Compound 7 was obtained by flash chromatography. Yield: 134 mg, 48%. ' H- NMR (400 MHz, MeOH-d4): 5(ppm) 8.19 (d, 2H), 7.67 (d, 2H), 6.37(d, 1H), 5.98(d, 1H), 4.91 (s, 2H), 3.79 (s, 3H). 13C-NMR (100 MHz, MeOH-d4): 5(ppm) 165.71, 153.21, 145.29, 142.54, 135.75, 126.75, 124.45, 117.50, 62.88, 51.13. MS (m/z): [M]+ calcd. for Ci2Hi2N206, 280.07; found, 303.1 for [M+Na]+.
Synthesis of compound 30
Solution of compound la (116.1 mg, 1 mmol) in 2 mL of dry DCM was cooled to 0 °C. p-Toluenesulfonyl isocyanate (205 mg, 1.05 mmol) was added to the solution. Completion of reaction was monitored by TLC. The residue was subjected to flash chromatography after removing the solvent to afford compound 30. Yield, 285 mg, 91%. ' H-NMR (400 MHz, MeOH-d4): 5(ppm) 7.85 (m, 2H),7.39 (m, 2H), 6.28(s, 1H), 5.81 (s, 1H), 4.75 (s, 2H), 3.7l(s, 3H), 2.44 (s, 3H). 13C- NMR (100 MHz, CDCft): 5(ppm) 165.38, 144.71, 136.50, 135.00, 129.19, 127.67, 127.34, 125.76, 63.62, 51.10, 20.13. MS (m/z): [M]+ calcd. for CI3HI5N06S, 313.06; found, 336.0 for [M+Na]+.
methyl 3-acetoxy-2-bromo-2-(bromomethyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.92 g
Stage #1: methyl 2-hydroxymethylacrylate; acetyl chloride In dichloromethane at 0 - 20℃; for 12h;
Stage #2: With bromine In dichloromethane at 0℃; for 2h;
dimethyl 2-chloro-4-methylenepentanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With acetic acid In toluene at 130℃; for 24h;
Synthesis of Dimethyl 2-chloro-4-methylenepentanedioate (9):
Methyl 2-(hydroxymethyl)acrylate (5.0 g, 43.06 mmol), d = 1.13 g/mL) and 2-Chloro-1,1,1-ethoxyethane (8.0 mL, 51.67 mmol, d = 1.15 g/mL)were added together in 200 mL round bottom flask with 100 mL tolueneand catalytic amount acetic acid (1 mL, 4.31 mmol). The reactionmixture was refluxed for 24 h at 130 C. The completion of reaction wasmonitored by TLC. The reaction mixture was subjected to azeotropicdistillation with toluene under reduced pressure (3x50 mL) to providethe desired compound obtained as a yellow oil and used as such withoutfurther purification, yield 85%. 1H NMR (500 MHz, Chloroform-d) δ6.32 (s, 1H), 5.74 (s, 1H), 4.54 (dd, J = 8.2, 6.4 Hz, 1H), 3.76 (s, 6H),3.06 (dd, J = 14.3, 6.3 Hz, 1H), 2.82 (dd, J = 14.2, 8.3 Hz, 1H). 13C NMR(126 MHz, CDCl3) δ 169.7, 166.6, 134.7, 130.1, 54.9, 53.0, 52.2, 37.9.HRMS (ESI-): m/z 207.0414 [M + H]+; calculated for C8H11ClO4 [M +H]+ 207.0419
dimethyl (2S,4S,5S)-4-(hydroxymethyl)-5-(4-methoxyphenyl)pyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
[(4-methyl-benzylidene)-amino]-acetic acid methyl ester[ No CAS ]
dimethyl (2S,4S,5S)-4-(hydroxymethyl)-5-(4-tolyl)pyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
dimethyl (2S,4S,5S)-5-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
N-(4-bromobenzylidene)glycine methyl ester[ No CAS ]
dimethyl (2S,4S,5S)-5-(4-bromophenyl)-4-(hydroxymethyl)pyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
dimethyl (2S,4S,5S)-4-(hydroxymethyl)-5-(4-(trifluoromethyl)phenyl)pyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
dimethyl (2S,4S,5S)-4-(hydroxymethyl)-5-phenylpyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
dimethyl (2S,4S,5S)-5-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
dimethyl (2S,4S,5S)-5-(4-chlorophenyl)-4-(hydroxymethyl)-2-methylpyrrolidine-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With C36H36FeN3PS; silver(I) acetate; triethylamine In tetrahydrofuran at 20℃; for 16h; Schlenk technique; Inert atmosphere; enantioselective reaction;
With glucose dehydrogenase; D-glucose; NADP+ bound ketoreductase from Lactobacillus kefirF147L/ L153Q/ Y190P M206F/L199A/M205F mutant; magnesium(II) sulfate; NADPH In dimethyl sulfoxide at 32℃; for 16h; Inert atmosphere; Irradiation; Enzymatic reaction; Overall yield = 54 percentChromat.;
General procedure for photoenzymatic reactions.
General procedure: Taking 1a + 2a → 3a as anexample, in a Coy vinyl anaerobic chamber (O2 concentration <10 ppm), to a4-ml vial containing a magnetic stir bar, solutions of NADP+ (10 mM stock inTris buffer, 15 mol%), glucose (500 mM stock in Tris buffer, 2.5 equiv.), GDH(GDH-105 (Codexis, Inc.), 1,000-U stock in Tris buffer, 2.5 U), P2-D12 mutant K3(0.75 mol%), redox-active ester 1a (10 μl of 1,200 mM DMSO stock, 0.012 mmol)and acceptor-substituted alkene 2a (10 μl of 400 mM stock in DMSO, 0.004 mmol)were added to a solvent mixture containing Tris buffer (50 mM, 1 mM MgSO4,pH 7.6), DMSO and glycerol. The total volume of the reaction mixture was1,500 μl, with final concentrations for DMSO and glycerol around 15% and 10%,respectively. The vial was sealed with a screwcap, removed from the anaerobicchamber, illuminated with blue LEDs and stirred for 16 h at ~32 °C with twocooling fans (see Supplementary Fig. 1 for reaction set-up).For the reaction work-up, EtOAc (1.5 ml) and 20.0 μl of an internal standardstock (2% v/v of n-dodecane in EtOAc) were added and mixed thoroughly. Theorganic phase was separated and then analysed by gas chromatography-massspectrometry (GC-MS) and chiral high-performance liquid chromatography(HPLC). Product formation was confirmed by comparison of retention times inGC/HPLC, mass spectra of the crude material and the reference. GC-MS yield wasdetermined relative to the n-dodecane internal standard according to a calibrationcurve. Enantioselectivity was determined by chiral HPLC
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