* 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] Chemische Berichte, 1982, vol. 115, # 7, p. 2592 - 2605
[2] Journal of Organic Chemistry, 1947, vol. 12, p. 435[3] Journal of Organic Chemistry, 1948, vol. 13, p. 937
4
[ 7726-95-6 ]
[ 7553-56-2 ]
[ 64-19-7 ]
[ 122-59-8 ]
[ 1878-91-7 ]
Reference：
[1] Journal of Organic Chemistry, 1947, vol. 12, p. 435[2] Journal of Organic Chemistry, 1948, vol. 13, p. 937
5
[ 281-23-2 ]
[ 122-59-8 ]
[ 700-57-2 ]
[ 52804-26-9 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 9, p. 1672 - 1675[2] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 9, p. 1882 - 1886
6
[ 122-59-8 ]
[ 14316-61-1 ]
Reference：
[1] Synthesis, 1981, # 8, p. 616 - 620
[2] Synthetic Communications, 2007, vol. 37, # 18, p. 3219 - 3223
[3] Bulletin of the Polish Academy of Sciences, Chemistry, 1984, vol. 32, # 3-6, p. 129 - 134
[4] Journal of the American Chemical Society, 2005, vol. 127, # 44, p. 15521 - 15527
[5] Journal of the American Chemical Society, 2002, vol. 124, # 15, p. 3905 - 3913
[6] Tetrahedron, 2009, vol. 65, # 50, p. 10430 - 10435
7
[ 122-59-8 ]
[ 594-09-2 ]
[ 2065-23-8 ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1,3-diazido-propane In neat (no solvent) at 20℃; for 0.333333 h;
General procedure: To a mixture oftrimethylphosphite/triethylphosphite (1.0mmol) and carboxylic acid (1.0mmol),1,3-diazidopropane (0.5mmol) was added slowly in a drop wise manner (to avoidaccumulation of azide) and the mixture was stirred at room temperature for10-20 minutes. (Caution As azides arepotentially explosive, all the reactions should be carried out behind a blastshield with personal protective equipment. In particular, the sequence of addition of thereactants should be strictly followed to avoid the accumulation of organicazides. This has been achieved in thepresent investigation by the slow drop wise addition of the bis azide to thereaction mixture containing trialkylphosphite during which the azide group isinstantaneously converted to iminophosphorane and hence no difficulty wasencountered). After the completion ofthe reaction (as monitored by TLC), the mixture was poured onto crushedice. Then the reaction mixture wasextracted with dichloromethane and the organic layer was dried over anhydrousNa2SO4. Thesolvent was removed and the residue was purified by column chromatography usingsilica gel as the adsorbent and petroleum ether: ethyl acetate (98:2) as themobile phase to afford the corresponding carboxylic esters (3a-v) as colourless oily liquids. Yield (71-80percent)
With hydrogenchloride; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In 1,4-dioxane; water at 20℃; for 2h;
4.2. General procedure for the synthesis of xanthine analogues (4-9)
General procedure: Synthesis of intermediary 1,3-dialkyl-7H-xanthine analogues (14):1,3-Dimethyl- (10a) or 1,3-diethyl-5,6-diaminouracil (10b)(10 mmol) was dissolved in a minimum amount of dioxane/H2O(1:1). EDAC (13.4 mmol) and the appropriate carboxylic acid(10 mmol) was added and the pH was adjusted to 5 with 4 NHCl. The reaction was stirred for 2 h at room temperature. Exceptfor the synthesis of compounds 8c, 8d and 9b-d, the reactionwas subsequently neutralized (pH 7) with the addition of 1 NNaOH. The precipitate was collected via filtration and suspendedin 100 mL of dioxane/H2O (1:1). The reaction was then heated atreflux for 2 h at room temperature. After cooling to 0 C, the precipitatethat formed was collected by filtration and washed with50 mL H2O. In the case of compounds 8c and 8d, H2O (30 mL)was added to the reaction and the reaction was subsequently extractedto CHCl3 (9 25 mL). The combined organic phases werewashed with H2O (4 80 mL) followed with brine (4 80 mL),dried over anhydrous MgSO4 and finally concentrated under reducedpressure. The crude residue was dissolved in a mixture of30 mL aqueous NaOH (1 M)/dioxane (1:1) and heated under refluxfor 45 min. After cooling to 0 C, the reaction was acidified with 4 N HCl and the resulting precipitate was collected by filtration andwashed with 50 mL water. For the synthesis of 9b-d, 1 g of sodiumhydroxide was dissolved in H2O (1 mL) and added to the reaction.The reaction was heated under reflux for 2 h, cooled to 0 C andacidified with 4 N HCl. The resulting precipitate, the 7H-xanthineanalogues (yields 29-75%), were collected via filtration andwashed with 50 mL H2O.
With lithium hydroxide monohydrate; water at 0 - 20℃; for 12h;
2-Phenoxyacetic acid:
To a solution of ethyl 2-phenoxyacetate (2 g, 11.1 mmol) in 1:1:1 mixture of THF/MeOH/ H20 (40 mL) was added lithium hydroxide monohydrate at 0 °C. The reaction was stirred atroom temperature for 12 h. After completion, the volatiles were removed under reduced pressure, diluted with water, neutralized with iN HC1 and the volatiles were removed under pressure. The residue was dissolved in EtOH (15 mL) and the solids were filtered. The filtrate was concentrated under reduced pressure to afford 1.6 g of 2-phenoxyacetic acid (Yield =95%).
94%
Stage #1: phenoxyacetic acid ethyl ester With sodium hydroxide In tetrahydrofuran at 20℃; for 24h;
Stage #2: With acetic acid In tetrahydrofuran; water
82%
With sodium hydroxide In ethanol; water for 8h; Reflux;
4.1.1.2. General synthetic procedure for phenoxy acetic acid derivatives4(a-e).
General procedure: The mixture of compounds ( 3a-e , 0.02 mol) was dissolvedin ethanol (15 ml), and sodium hydroxide (0.035 mmol) in water(5 ml) was added. The mixture was refluxed for eight h, and thereaction mixture was cooled and acidified with 3 N hydrochloricacids. The precipitate was filtered, washed with ice water, and finally recrystallized from ethanol to afford the compounds 4(a-e) .2-phenoxy acetic acid (4a)°Yield 82%; M.P: 125-127C. IR (KBr) max (cm-1): 1640==( CO ), 1730 (acid, CO ), 3430-3510 (acid OH). 1HNMR(400 MHz, DMSO-d6) (ppm): 4.62 (s, 2H, OCH2), 6.86-7.24(m, 5H, Ar-H), 13.05 (s, 1H, COOH). 13C NMR (100 MHz, DMSO-d6) (ppm): 170.65, 158.1, 129.8, 121.4, 114.8, 64.8, 40.4, 40.4,+40.2, 40.0, 39.8, 39.6, 39.4, 39.2. LC-MS m/z 152 [ M]. Anal. Calcd for C8H8O3(152): C, 63.15; H, 5.30. Found: C, 63.10; H,5.20%.
81%
With sodium hydroxide In ethanol Reflux;
81%
With sodium hydroxide In ethanol; water Reflux;
1 4.1.2.1 General synthetic procedure for phenoxyacetic acid analogues (4a-j)
General procedure: Compounds (3a-j,0.02mol) were dissolved in ethanol (15mL), sodium hydroxide (0.035mol) in water (5mL) was added, and the mixture was refluxed for 5-9h. The reaction mixture was cooled and acidified with 2N hydrochloric acid. The precipitate was filtered, washed with water, and finally recrystallized from methanol to afford desired compounds (4a-j). Compound (4a) is takenas a representative example to explain physical and characterization data.
With potassium hydroxide
With lithium hydroxide In tetrahydrofuran
With lithium hydroxide In tetrahydrofuran; water at 20℃;
With water; lithium hydroxide In tetrahydrofuran
With water
With water Alkaline conditions;
With lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;
With sodium hydroxide In tetrahydrofuran at 20℃; for 24h;
2-Phenoxyacetic acid (36).
000191] 2-Phenoxyacetic acid (36). Compound 34 (2 g, 0.011 mol) was dissolved in 100ml of THF, and 1 M NaOH (110 ml, 0.11 mol) was added. The reaction mixture was stirred atRT for 24 h. The solution was then acidified by the addition of 40 ml of acetic acid. The reactionmixture was diluted with 150 ml of H20 and the product was extracted with ethyl acetate. Theorganic extracts were dried over magnesium sulfate and concentrated. The crude product waswashed several times with hexane:ethylacetate (9:1) to give a pale white solid (1.58 g, 94 %). 1HNMR (300 MHz, CD2Cb) 8 4.69 (s, 2H), 6.92 (d, J = 8.2 Hz, 2H), 7.03 (t, J = 7.0 Hz, 1H), 7.32 (t, J =7.6 Hz, 2H).
Alkaline conditions;
With water; sodium hydroxide In ethanol
5
Scheme 10 Reagents and conditions: a) BrCH2COOEt, 2C03, acetone; b) IN aq. NaOH, EtOH; c) HCl.HN(OMe)Me, NMM, DMA P. WSCI.HC1, CH2C12; d) thiazole, n-BuLi, Et20.
With ethanol; sodium hydroxide In water
Stage #1: phenoxyacetic acid ethyl ester With sodium hydroxide In methanol; water for 1h;
Stage #2: With hydrogenchloride In water
With potassium hydroxide In ethanol; water at 20℃; for 1.5h;
General procedure for the synthesis of 5a-f
General procedure: A mixture of phenols (0.3 mmol), acetone (10 ml), dimethylformamide(10 ml), ethyl chloroacetate (2.5 ml, 0.26 mmol), potassiumcarbonate (2 g) and potassium iodide (0.15 g) was heated at75 C for 12 h. Afterwards, the solid was filtered and the solventof the filtrate was removed in vacuo. The colorless liquid (4a-f)obtained was dissolved in ethanol (20 ml). A solution of potassiumhydroxide (7.2%, 5 ml) was added and stirred at room temperaturefor 1.5 h. The mixture was poured into hydrochloric acid (1 mol/L)and a white precipitate was formed. Purification by recrystallizationfrom methanol afforded the corresponding aryloxyl acid (5a-f)
With sodium hydroxide In methanol at 20℃; for 1h;
Synthesis of 2-(3,4-dichlorophenoxy)acetic acid (5j).
General procedure: To a stirred solution of 4j (2.5 g, 9.8 mmol) in MeOH (30 mL) was added 3N NaOH solution (13.1 mL, 39.3 mmol). After being stirred at room temperature for 1 h, the mixture was diluted with water (100 mL), acidified with 3N HCl, and extracted with dichloromethane (100 mL × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.12 g, 97% yield) . 1H NMR (300MHz, DMSO-d6) δ 7.49(d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H),4.73 (s, 2H).
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 1h;
5.1.19. General procedure for the synthesis of 22a-g
General procedure: 1MNaOH was added dropwise to a solution of 21a-g in dioxaneat 0 C. After stirring at r.t. for 1 h, the dioxane was evaporated andthe residue was washed with ethyl acetate. Then the water layerwas acidified with 1M HCl to pH 3 and extracted with ethyl acetate.The combined organic layer was washed with brine (50 mL),dried over anhydrous Na2SO4, and concentrated or directly filteredthe solid to give 22a-g as a white solid.5.1.20. 2-Phenoxyacetic acid (22a)Compound 22a (635 mg, 73.4% yield for two steps) was preparedfrom phenol (532 mg, 5.7 mmol) and ethyl 2-bromoacetate(967 mg, 5.9 mmol) following the general procedure. 1H NMR(400 MHz, DMSO-d6) d 12.95 (br. s, 1H), 7.27e7.31 (m, 2H),6.89e6.97 (m, 3H), 4.66 (s, 2H).
In water at 110℃; Alkaline conditions;
With sodium hydroxide In ethanol; water Reflux;
General procedure for the synthesis of phenoxy acetic acidanalogs (4a-g)
General procedure: Compounds (4a-g) were synthesized as per the earlierreported method from our group [19]. To a solution of phenoxyester Compounds (3a-g, 0.05 mol) in ethanol (15 ml),sodium hydroxide (0.04 mol) was added. The mixture wasthen refluxed for 7-10 h using heating mental. After thecompletion of the hydrolysis reaction [monitored by TLCusing the solvent system hexane:ethyl acetate:methanol(6:3:1)], the mixture was cooled to room temperature andthen acidified with 2 N hydrochloric acid. The precipitatewas filtered out, washed with distilled water and finallyrecrystallized from methanol to afford desired phenoxy aceticacid analogs (4a-g).
With ethanol; sodium hydroxide Reflux;
General procedure for the synthesis of phenoxyacetic acid analogs (4a-h)
General procedure: To the solution of compounds (3a-h, 0.05 mol) in ethanol (15 ml), alcoholic sodium hydroxide solution (3 ml, 0.04 mol) was added. The reaction mixture was allowed to reflux for 8-10 h, and the completion of the reaction was monitored using TLC hexane: ethyl acetate: methanol system (6:3:1). The mixture was cooled and acidified with 2 N hydrochloric acid. The precipitate was filtered, washed with distilled water, and finally recrystallized from methanol to afford desired compounds (4a-h) [15].
With 18-crown-6 ether; trimethyldodecylammonium chloride; tetra-n-butylphosphonium chloride; sodium hydroxide In water for 3h; Reflux;
2 Example 2
In a 250 mL four-necked flask, 5 g of phenol, 5.5 g of chloroacetic acid and 10 g of water were added, adjusted to pH 12 by adding a caustic soda, 0.5 kg of catalyst (polyethylene glycol 800, dodecyltrimethylammonium chloride , 18 crown ether 6, tetrabutylphosphine chloride molar ratio: 40: 10: 5: 3), using the program temperature, 3.5min from the normal temperature rose to reflux, reflux reaction 3hr; Cooling to room temperature, Hydrochloric acid to adjust the pH value of 2, cooled to 10 ° C, crystallization 3 hours, filtration, washing, drying at 90 ° C for 2 hours, the appearance of white solid 7.53g, phenoxyacetic acid content of 99.1%; filtrate 13.4 G, and the content of phenoxyacetic acid was 3.50%. The solid yield of phenoxyacetic acid was 93.27% and the total yield was 99.2% (both based on phenol).
98.5%
With sodium hydroxide In water at 60 - 80℃; for 2h;
Preparation of phenoxy acetic acid (C8H8O3)
To 11.47 mmol of sodium hydroxide 5 mmol of phenol was added and diluted. 6 mmol of chloroacetic acid was dissolved in warm water and added to the above mixture and stirred constantly for 2 h at 60 to 80 °C. 35 % Hydrochloric acid was added and vacum fractionated using benzene as solvent. The white coloured solid obtained (Scheme-II) was recrystallized using water and ethanol mixture (m.p. 98.2 to 98.9 °C)
97%
With sodium hydroxide Irradiation;
96%
Stage #1: chloroacetic acid With sodium hydroxide
Stage #2: phenol With sodium hydrogencarbonate at 100℃; for 0.666667h;
1 Example 1: Preparation of phenoxyacetic acid
1Kg of chloroacetic acid was added to the reactor, 1Kg of sodium hydroxide solution with a concentration of 10%Stir for 15 ~ 20 minutes,Then add 800g of 0.6mmol of phenol, with sodium bicarbonate to adjust the PH value of 11; then heated at 100 ° C for 40 minutes;Then add hydrochloric acidThe pH was adjusted to 4; finally, the mixture was cooled in an ice water bath and the resulting solid was washed and dried to give phenoxyacetic acid in an amount of 96%.
78%
Stage #1: chloroacetic acid With sodium hydroxide In water
Stage #2: phenol With sodium hydroxide In ethanol; water at 105℃; for 5.33333h;
76%
Stage #1: chloroacetic acid With sodium hydroxide In water Cooling with ice;
Stage #2: phenol In ethanol; water for 0.333333h;
Stage #3: In ethanol; water at 105℃; for 5h;
Synthesis of Phenoxyacetic Acid Derivatives (B1-7)
General procedure: Compounds B1-7 were prepared by similar procedures. In atypical synthesis of B1, monochloroacetic acid (0.04 mol,3.78 g) was dissolved in deionized water (15 mL) under thecondition of stirring and an ice bath. Then NaOH (25 %) wasadded dropwise until the pH value was adjusted to 9-10, thena solution of sodium chloroacetate was obtained. To a solutionof NaOH (0.03 mol, 1.20 g), deionized water (15 mL) andethanol (5 mL), phenol (0.04 mol, 3.76 g) was slowly addedunder stirring. After addition, the mixture was stirred for20 min, then the above sodium chloroacetate was addeddropwise, and heated to 105 °C and refluxed for 5 h. Thereaction mixture was cooled to room temperature. The pHvalue of the mixture was acidified to 1-2 with diluted hydrochloricacid. The precipitate was filtered, washed with dilutedhydrochloric acid many times, and recrystallized and dried invacuum, resulting in a white solid product of thephenoxyacetic acid (B1)
75%
With iron(III) hydroxide; sodium carbonate; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h; Sealed tube;
74%
Stage #1: chloroacetic acid With sodium hydroxide In water
Stage #2: phenol With sodium hydroxide In ethanol; water for 5h; Reflux;
72%
With potassium hydroxide In water Reflux;
4.1.3. Synthesis of Phenoxy Acetic Acid Derivatives (PAA1-PAA5)
General procedure: The phenol derivative (19.2 mmol) was mixed with a solutionof potassium hydroxide (71.4 mmol, 4 g) in 8mL ofwater in a two necked round bottom flask until homogeneoussolution was produced. As the mixture began to boil, 6mL of50% w/v solution (g/ml) of chloroacetic acid was addeddrop-wise using dropping funnel placed in the side arm ofthe flask. The reaction mixture was refluxed until reactionwas completed (monitored by TLC). The solution was transferredto a beaker, cooled to room temperature and acidifiedby drop-wise addition of HCl (monitor using pH paper). Theresultant mixture was cooled in an ice bath, the crude productwas filtered and re-crystallized from boiling water.
70%
With sodium hydroxide for 0.00833333h; microwave irradiation;
67%
Stage #1: chloroacetic acid With sodium hydroxide In water Cooling with ice;
Stage #2: phenol With sodium hydroxide In ethanol; water at 105℃; for 5h;
Synthesis of phenoxyacetic acid derivatives (4a-h)
General procedure: A mixture of NaOH (0.04 mol, 1.60 g), deionized water (20 mL) and ethanol (20 mL) were poured into a 150 mL three-necked flask, then phenol (0.04 mol, 3.76 g) was slowly added under stirring. Twenty minutes later, the above sodium chloroacetate was added dropwise. The reaction solution was heated to 105 °C and refluxed for 5 h. After cooling down, the pH value of the mixture was acidified to 1-2 with diluted hydrochloric acid. The precipitate was collected by filtration and washed with diluted hydrochloric acid many times. Recrystallized and dried under a vacuum, resulting in a white solid product of the phenoxyacetic acid (4a).
66%
With sodium hydroxide; bentonite In water for 0.0833333h; microwave irradiation;
29%
With sodium hydroxide In water at 100℃; for 2h; Inert atmosphere;
With sodium hydroxide Zerlegen des ausgeschiedenen phenoxyessigsauren Natriums mit verd. Salzsaeure;
With alkali
With sodium hydroxide In water Heating;
With sodium hydroxide for 1h; Heating;
With sodium hydroxide Heating;
With sodium hydroxide In water for 2h;
With sodium hydroxide for 4h; Heating;
With sodium hydroxide
With sodium hydroxide
With sodium hydroxide
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h;
Alkaline conditions;
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;
Stage #1: chloroacetic acid; phenol With sodium hydroxide In water for 2h;
Stage #2: With hydrogenchloride In water
4.1. General procedure for the synthesis of aryloxy acetic acids (7k-s)
General procedure: Equimolar quantities of chloroacetic acid (0.05 mol) and appropriate phenol (6k-s) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH (0.12 mol in 25 mL water) was slowly added with constant stirring. The solution was stirred for 2 h until the solution turned clear, brown or yellow and then the reaction mixture was evaporated in an evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified by adding con. HCl. The precipitated aryloxy acetic acid was filtered and recrystallized from water or ethanol.
With sodium hydroxide at 100 - 110℃;
With sodium hydroxide In water
General procedure for the synthesis of aryloxy acetic/propionicacids (2a-q and 3a-q)
General procedure: Equimolar quantities of 2-chloro acetic acid/3-chloro propionicacid (0.05 mol) and appropriate phenol (1a-q) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH(0.12 mol in 25 mL water) was slowly added with constant stirring.The solution was stirred for 2 h until the solution turned clear,brown or yellow and then the reaction mixture was evaporatedin a evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified byadding con. HCl. The precipitated aryloxy acetic/propionic acidwas filtered and recrystallized from water or ethanol
With sodium hydroxide
With sodium hydroxide In water at 100 - 110℃;
With sodium hydroxide In water at 85 - 90℃; for 2h;
Synthesis of phenoxyacetic acids
General procedure: Overall the phenoxyacetic acids were commercially available, except for 4-methylphenoxyacetic acid and 4-methoxyphenoxyacetic acid. The latter phenoxyacetic acids were synthesized via a general synthetic route as described elsewhere [1,2,3]. In short, the appropriate substituted phenol (20 mmol) was added to anaqueous solution of NaOH (10 mL). Chloroacetic acid (34 mmol) was added and the reaction was heated (85-90 °C) under reflux for 2 h and subsequently cooled to room temperature to yield a thick precipitation with a pH of 12. The reaction was acidified with concentrated HCl to a pH of 2 and extracted to diethyl ether (100 mL). The organic phase was extracted thrice with 100 mL of sodium carbonate solution (5%). The pooled aqueous phases were acidified to a pH of 2 with HCl to yield a precipitate. The desired phenoxyacetic acid was collected by filtration and left to dry overnight in the fume hood. Analytical pure samples were obtained after recrystallization from methanol.
With sodium hydroxide In water at 100℃;
1
0.3mol of chloroacetic acid dissolved in 60ml water, adjusted to pH 9 with sodium hydroxide, then add 0.2mol phenol, 100 ° C reflux,To give compound T1,Followed by addition of thionyl chloride for chlorination reaction to obtain compound T2,The thionyl chloride solvent was evaporated to give a brown liquid,And then with anthranilic acid condensation reaction,Get T3, PPA and then preheated to 130 ° C by adding T3 to compound, to obtain compound T4,The T4 was reacted with thionyl chloride at 80 ° C under reflux to give compound T5,The purified T5 was then added to a single-necked flask and phenol was added at 60 ° C overnight, followed by addition of 1,4-butanediamine at 120 ° C for 12 h,Finally, the product was purified by silica gel column to give compound 2T6.
With sodium hydroxide In water for 15h; Reflux;
2.2.1. Preparation of substituted phenoxyacetic acid
General procedure: Solution (A) of substituted phenol (0.25 M) with sodiumhydroxide (NaOH) in water as a solvent medium is preparedand heated up to boiling. In another round bottom flask,solution (B) of chloro-acetic acid in sodium hydroxide is prepared.The solution (B) is dropwise added to the boiling solution(A). The resulting reaction mixture was then refluxed for15 h by keeping the mixture alkaline, throughout the reactionprocess. Dilute hydrochloric acid was added to thisrefluxed solution while warm. Precipitates of substituted phenoxyaceticacid began to separate out by pouring it into theice bath. Residues were collected and recrystallized with hotwater (Takeda et al., 1998).
With tris(2-methoxyphenyl)bismuthine In benzene for 12h; Heating;
75%
With tris(2-methoxyphenyl)bismuthine In benzene for 12h; Heating;
75%
With acetyl chloride at 80℃; for 24h; Cooling with ice;
With sulfuric acid; benzene unter Entfernen des entstehenden Wassers;
With pyridine; O-phenyl phosphorodichloridate
With toluene-4-sulfonic acid for 5h; Heating;
With sulfuric acid
With sulfuric acid for 3h;
With sulfuric acid for 3h; Heating;
With sulfuric acid In ethanol
With sulfuric acid
With sulfuric acid
With sulfuric acid Reflux;
With sulfuric acid for 8h; Reflux;
General method for the synthesis of hydrazides
General procedure: Substituted aromatic acid (0.01 mol) was dissolved in 20 ml absolute ethanol added 1 ml conc. H2SO4 and refluxed for 8 h. The two third volume of reaction mixture was removed under reduced pressure and then poured into crushed ice and neutralized with sodium bicarbonate to obtain esters. In the subsequent step equimolar quantity of substituted ester (0.005 mol) and hydrazine hydrate (0.25 ml, 0.005 mol) in ethanol was refluxed for 24 h with stirring. The two third volume of alcohol was removed under reduced pressure and the reaction mixture was poured into the crushed ice. The resultant precipitate was filtered, washed with water and dried. The solid was recrystallized from 25 ml of 90 % ethanol. The purity of the compounds was checked by TLC using toluene-ethyl acetate-formic acid (5:4:1) as mobile phase.
With sulfuric acid Reflux;
With toluene-4-sulfonic acid for 3h; Reflux;
With hydrogenchloride Reflux;
4.2. General procedure for the synthesis of ethyl aromatic esters (8a-s)
General procedure: Each substituted benzoic acid or aroyloxy acetic acid (7a-s) 0.088 mol was refluxed for 2-12 h in 2.4 mol of HCl gas saturated anhydrous ethanol. Then a hot solution was poured into 300 mL of water (no hydrochloride separates) to which solid Na2CO3 was added until the solution turns neutral. Precipitated ester was filtered by suction, dried and recrystallized from ethanol or methanol. In case of liquid esters, the neutralized solution was extracted with chloroform (25 mL x 3), the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear liquid.
With sulfuric acid for 6h; Reflux;
Synthesis of Substituted Aryloxy hydrazide 5(a-g)
General procedure: The substituted acid (0.1 mole) and ethanol (50 ml) were taken with a few drops of concentrated sulfuric acid and it was refluxed for 6 hours.The reaction mixture was concentrated bydistilling of the excess of ethanol under reduced pressure and treated with a saturated solution of sodium bicarbonate. The ester obtained used for the preparation of hydrazide directly. The ester(0.1 mole) was dissolved in appropriate quantity of ethanol and to this hydrazine hydrate (0.1 mole) was added. The reaction mixture was taken in a round bottomed flask and refluxed for a period of 12-18 hours. Excess of ethanol was distilled off under reduced pressure. It was then poured into ice cold water and the solid obtained was filtered. It was crystallized from ethanol.
at 80℃; Acidic conditions;
With acetyl chloride for 24h; Cooling with ice; Reflux;
Synthesis of Phenoxyacetohydrazide Derivatives (D1-7)
General procedure: Compounds D1-7 were prepared by similar procedures. In atypical synthesis of D1, a mixture of phenoxyacetate(10 mmol, 1.80 g), hydrazine hydrate (80 %, 5 mL) and absoluteethanol (30 mL) was added to a 150 mL three-neckflask, then the reaction mixture was refluxed for 5 h. Themixture was cooled to room temperature. The crude productwas collected by filtration and washed several times with ethanol.After drying, white needle crystal was recrystallizedfrom ethanol and dried in vacuum
Stage #1: 2-phenoxyacetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran
Stage #2: ethanol In tetrahydrofuran at 20℃; for 16h;
Stage #1: 2-phenoxyacetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.5h;
Stage #2: ethanol In tetrahydrofuran at 20℃; for 16h;
Ethyl 2-phenoxyacetate (17)
Ethyl 2-phenoxyacetate (17): To a slurry of N,N’- carbonyldimidazole in anhydrousTHF was added a solution of phenoxyacetic acid 16 in anhydrous. Upon addition, rapid effervescence was observed. This solution was allowed to stir for 30 mm past the end ofeffervescence. At this time absolute ethanol was added and the mixture allowed to stir at room temperature for 16 hours. The mixture was then concentrated down and the residue taken up indichioromethane. The organic layer was washed three times with half the volume of saturated NaHCO3. The organic layer was then washed with brine dried over MgSO4 and concentrated togive the desired product as a colorless oil. ‘H NMR (400 MHz, CDC13, 30 °C) ö 7.28 (2H, dd J = 3.0 and 1.8 Hz), 6.97 (1H, t, J = 3.1 Hz), 6.89 (2H, d, J 2.00 Hz), 4.61 (2H, s), 4.26 (2H, q, J =7.15), 1.29 (3H, t, J = 7.13 Hz); ‘3C NMR (CDC13, 100 MHz): ö = 168.9, 157.8, 129.6, 121.7,114.7, 65.4, 61.3, 14.2.
With sodium hypochlorite; sodium bromide; at 5 - 36℃; for 0.00666667h;
1), configure three solutions of A, B, C with 95% alcohol to configure 500mL 1mol / L phenoxyacetic acid solution,The B solution is a 1 mol/L sodium bromide solution.The C solution is a 1.03 mol/L sodium hypochlorite solution;2) In the Corning G1 microchannel first-stage reactor,Pumping B and C solutions at a weight ratio of 1:2 at 5 C.The retention time is 6 seconds.Obtaining a B+C solution;3), in the Corning G1 microchannel secondary reactor simultaneously pumping A solution and B + C solution in a molar ratio of A solution: B + C solution = 1: 1.03 mol / L,The reaction was carried out at 5 C for 18 seconds;4) In the Corning G1 microchannel three-stage reactor,Aged at 36 C for 6 seconds;5) The aged reaction liquid enters the vacuum receiver.Desolvation and collectionP-bromophenoxyacetic acidThe reaction solution;6) Adjust the pH to 2~3 with dilute hydrochloric acid.And cooling to 0 ~ 5 C, crystallization of p-bromophenoxyacetic acid,Centrifugation,Ice wash,Vacuum drying,Got the finished bromophenoxyacetic acid,221 g of bromophenoxyacetic acid having a content of 98.6% was obtained.The yield was 94.3%.
With (phthalocyaninato)iron(II); chlorine; acetic acid In water at 75℃; for 0.5h;
2 Example 2: Preparation of 2,4-dichlorophenoxyacetic acid
In the reaction flask, 10 mol of phenoxyacetic acid raw powder of Example 1,700 g of acetic acid and 175 g of water,0.1 mol of phthalocyanine iron; after stirring,Start to access 22mol chlorine for chlorination, stirring heated to 75 ° C,Continue stirring for half an hour;After the reaction product was cooled directly to 18 ° C, hold for about 0.6 hours,Suction filtration,The resulting cake was dried directly 60 ° C,2,4-dichlorophenoxyacetic acid, 99.7% content,Yield (relative to phenoxy acetic acid) 98%.
99%
With dihydrogen peroxide; chlorine In benzene at 100℃; for 1h;
3 Example 7 Synthesis of 2-methyl-4-chlorophenol
In a 2000 ml reaction flask,Add 1000g benzene solution of phenoxyacetic acid [containing phenoxyacetic acid 152g (1 mole)]Heated to 100 °C, began to pass chlorine, chlorine gas to 45g (0.58 moles),At the same time adding hydrogen peroxide (content 30%),To 90 g (1.15 moles) of chlorine, 42 g (0.6 moles) of hydrogen peroxide was added.Chlorine gas and hydrogen peroxide were added to stop the reaction, and the reaction was continued for 1 hour to stop the reaction. The reaction was allowed to stand for stratification, and the organic phase was concentrated to recover the solvent.The product was 2,4-dichlorophenoxyacetic acid (223 g). The mass content was 98% by HPLC and the yield was 99%. The aqueous phase was used in the wastewater treatment station.
99.4%
With iron(III) chloride; dimethylsulfide; chlorine In chloroform at 70℃; for 5h;
1 Example 1
200 g of ethanol, 95 g (1 mol) of chloroacetic acid and 0.1 g of concentrated sulfuric acid were mixed and stirred at 70 ° C, and dehydrated and dehydrated for 5 hours to obtain ethyl chloroacetate.125 g (1 mol) of 94.3 g (1 mol) of phenol and a 32% by mass aqueous sodium hydroxide solution were mixed and stirred, and the temperature was raised to about 70 ° C to obtain a sodium phenolate solution.The prepared ethyl chloroacetate was added to the sodium phenolate solution in one portion, stirred for 0.5 h, and then layered, and the upper oil phase was transferred to the hydrolysis reactor.125 g (1 mol) of a 32% aqueous sodium hydroxide solution was added and refluxed for 0.5 h, 30 g of 30% hydrochloric acid was added, and the mixture was crystallized at 10 ° C for 1 h, filtered, and the filter cake was dried to obtain phenoxyacetic acid.body.Put phenoxyacetic acid into the chlorination reactor, add 100g of chloroform, add 0.5g of ferric chloride and 0.3g of dimethyl disulfide, then pass chlorine at 70 °C for 5h to obtain 2,4-dichlorophenoxy Acetic acid reaction solution.The solution was desolvated and crystallized at 10 ° C for 1 h, filtered, and the filter cake was dried to obtain 2,4-dichlorophenoxyacetic acid solid 221 g, purity 99.4%, yield 99.4%.
95.2%
With hydrogenchloride; dihydrogen hexachloroplatinate; aluminum (III) chloride; bismuth(III) chloride; iron(III) chloride; rhodium(III) oxide; phosphotungstic acid; bismuth phosphotungstate; dihydrogen peroxide; titanium tetrachloride; tin(IV) chloride; magnesium chloride; zinc(II) chloride at 40℃; for 6h; Large scale;
9 Exaple 9
To the filtrate was added 10 kg of 30% hydrochloric acid, 9.1 kg 30% Hydrogen peroxide, The molar ratio between the components is: FeCl 3: MgCl 2: ZnCl 2: SnCl 4: AlCl 3: TiCl 4: BiCl 3: phosphotungstic acid: bismuth phosphotungstate: H2PtCl 6: Rh2O3 = 10: 5: 15: 10: 10: 12: 5: 10: 0.1: 0.2) at 40 °C for 6 hr, cooled to room temperature, filtered for 20 min, washed with methanol at 130° C Drying for 2 hours, white crystals 5.62kg, 2,4-D content of 98.6%. The product yield was 95.2% (in terms of phenol).
With sulfuryl dichloride; acetic acid
With N,N'-dichloro-urea
With chlorine at 150℃;
With chlorine; iron; acetic acid at 20 - 60℃;
With hydrogenchloride; sodium chlorate; acetic acid
With sodium hypochlorite; sodium iodide; In methanol; water; at 25 - 36℃;
1), 152 g of phenyloxyacetic acid and 154 g of sodium iodide were dissolved in 600 mL of methanol aqueous solution,Stirring, maintaining the temperature at 25 ~ 30 C; 2), adding 770 g of a 10% sodium hypochlorite aqueous solution at 25 to 30 C with stirring; 3) After the completion of the dropwise addition, the temperature is raised to 30 to 36 C, and the reaction is stirred for 1 to 2 hours; 4), heating and distilling off methanol, cooling to room temperature, adding 5% hydrochloric acid solution, adjusting the pH to 2 to 3, and precipitating 4-iodophenoxyacetic acid; 5), cooled to 10 C, allowed to stand for 0.5 ~ 1h, filtered, washed with cold water and dried to obtain 263 g of 4-iodophenoxyacetic acid, the purity was 99.2%, the yield was 94.6%.
With 2-Picolinic acid; ferrous(II) sulfate heptahydrate; sodium bromate In water; dimethyl sulfoxide at 20℃; for 8h; Inert atmosphere; Irradiation;
71%
With <di(4-tert-butylcyclohexyl) peroxydicarbonate> In acetonitrile
68%
With trifluorormethanesulfonic acid; 1 wt% Pt on TiO2 In acetonitrile at 25℃; for 6h; Inert atmosphere; Sealed tube; Irradiation;
46 Example 46
In the quartz reaction tube, add 1.2 mL of acetonitrile, 4-methylquinoline 0.15mmol (concentration of 0.125mol/L), phenoxyacetic acid 0.3mmol, 0.06mmol of trifluoromethanesulfonic acid and 10mg of Pt/TiO2 (1wt%), Replace the atmosphere in the reaction tube with an argon inert atmosphere, seal, stir, and the reaction temperature is 25°C. After 6.0 hours of reaction under UV LED irradiation, it was separated and purified by silica gel column chromatography. The yield of the product 4-methyl-2-(phenoxymethyl)quinoline was 68%.
61%
With bis-[(trifluoroacetoxy)iodo]benzene In benzene for 9h; Heating;
With bis-(trifluoroacetoxy)-iodo-benzene In benzene for 2.5h; Heating; Yield given;
Stage #1: sodium monochloroacetic acid; sodium phenoxide In water at 90℃; for 2h;
Stage #2: With hydrogenchloride In water at 30℃;
1 Example 1
In a 1000 ml four-port bottle equipped with a stirrer, a thermometer, a reflux condenser, and a dropping funnel,400 g of a sodium phenoxide aqueous solution (containing 95 g of phenol, 1 mol, 40 g of sodium hydroxide, 1 mol) was added,The mixture was heated to 90°C with stirring, and 460 g of a sodium chloroacetate solution dropwise(containing 125 g of chloroacetic acid, 1.32 mol, 53 g of sodium hydroxide, 1.33 mol), heated to reflux, reaction for 2 hours, cooled to 30°C, started dropping hydrochloric acid, adjusting the pH to 0, stirring and cooling to 10°C, suction filtration, washing and drying,147 g of product was obtained with a content of more than 98% and a yield of 95%.
With Amberlite IRA 400 1.) water, 2.) water, 100 deg C, 1 h; Yield given. Multistep reaction;
(±)-cis-3-phenoxy-1,4-diphenyl-2-azetindione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine; N-tosylimidazole In dichloromethane at 20℃; Green chemistry;
Synthesis of 2-azetidinones (3-13); general procedure
General procedure: A mixture of Schiff base (1.0 mmol), triethylamine (5.0 mmol),carboxylic acid (1.3 mmol) and tosylimidazole (1.3 mmol) in dry CH2Cl2 (20 mL) was stirred at room temperature overnight. The mixture was washed successively with saturated NaHCO3 (20 mL) and brine (15 mL). The organic layer wasdried and the solvent was removed to give the crude product,which was purified by crystallisation from EtOH to give pure2-azetidinones 3-13. 3-Phenoxy-1,4-diphenyl-2-azetindione (3): M.p. 190-192 °C (lit.24191-193 °C).
59%
With bis-(2,2,2-trichloroethyl)phosphorochloridate; triethylamine In dichloromethane for 48h; Ambient temperature;
With trimethylsilyl polyphosphate ester at 100℃; for 2.5h;
94%
With hydrogenchloride In lithium hydroxide monohydrate for 2.5h; Reflux;
A mixture of phenoxyacetic acid (10 mmol) and o-phenylenediamine (10 mmol) was boiled under reflux with stirring for 2.5 h in 15 ml 6 N HCl. At the end of the reaction period, the mixture was neutralized with excess of NaHCO3. The collected precipitate washed with water, dried in vacuum, purified by flash chromatography, eluting with CHCl3 and re-crystallized by using EtOH-H2O. mp: 159-161 °C, yield 94%, reaction temperature 100 161 °C. Elemental analysis: C% 75.00 (calculated), 74.76 (found); H% 5.35 (calculated), 5.31 (found); N% 12.50 (calculated), 12.58 (found).
90%
for 0.25h; microwave irradiation;
90%
With hydrogenchloride In lithium hydroxide monohydrate at 130℃; for 18h;
2-(Phenoxymethyl)-1 H-benzimidazole (61).
2-(Phenoxymethyl)-1 H-benzimidazole (61). A 100 mL flask fitted with a stir-bar and condenser was charged with 1 ,2-phenylenediamine (9.94 g, 92.1 mmol), phenoxyacetic acid (14.0 g, 92.1 mmol), and 4M HCI (140 mL). The suspension was heated in a 130 °C bath forming a green solution. After 18 hr, the reaction had gone to completion as monitored by HPLC. The mixture was cooled in an ice bath forming a solid. The solid was filtered, pressed with rubber dam, and rinsed with H2O (2 x 15 mL). The residue was partitioned with EtOAc (300 mL) and saturated NaHCO3 (125 mL). The organic phase was washed with brine (100 mL), filtered through phase separation paper, and concentrated in vacuo to give 18.5 g of 61 as an off-white solid (90%). 1 H NMR (300 MHz, CDCI3): δ 10.08 (bs, 1 H), 7.82-7.40 (bm, 2H), 7.35- 7.26 (m, 4H), 7.08-6.95 (m, 3H), 5.40 (s, 2H) ppm. HPLC analysis (15:10:75 H2O:A1 :MeOH) showed a purity of greater than 99% with a retention time of 4.2 min
80%
With hydrogenchloride In lithium hydroxide monohydrate for 4h; Reflux;
Synthesis of phenoxy/2-naphthalen-1-yl/naphthoxy-methyl-1H-benzimidazole (4a-c)
General procedure: A mixture of o-phenylenediamine 3 (0.05 mol; 0.54 g) and phenoxyacetic acid/naphthylacetic acid/naphthoxyacetic acid (0.05 mol) was refluxed in 4 N HCl for 4 h on a heating mantle. After completion of reaction, solution was poured onto crushed ice; ammonia solution was added dropwise to neutralize, and the resulting solid was filtered, washed with cold water, dried and recrystallized with ethanol.
With hydrogenchloride Heating;
With hydrogenchloride In lithium hydroxide monohydrate Heating;
With hydrogenchloride Microwave irradiation;
With hydrogenchloride In lithium hydroxide monohydrate for 0.25h; Microwave irradiation;
With hydrogenchloride
With hydrogenchloride In lithium hydroxide monohydrate
General procedure for the synthesis of targetcompounds (21-35, 41-55, 61-75)
General procedure: Compounds 21-35, 41-55, and 61-75 have been prepared following reported procedures. A mixture of 1,2-phenylenediamine derivatives (1 eq) and the corresponding carboxylic acid derivaties (1.1 eq) was refluxed for a periodof 15-27 h in 5M hydrochloric acid. The reaction mixture was poured onto ice water and neutralized by mixing with NaHCO3 till slightly basic pH (8-9) to get the precipitate.The resulting precipitate was filtered off and washed with cold water. Recrystallized with a suitable solvent. The resulting crystalline compounds were filtered and the vacuumed product was dried
With hydrogenchloride In lithium hydroxide monohydrate
General procedure for the synthesis of targetcompounds (21-35, 41-55, 61-75)
General procedure: Compounds 21-35, 41-55, and 61-75 have been prepared following reported procedures. A mixture of 1,2-phenylenediamine derivatives (1 eq) and the corresponding carboxylic acid derivaties (1.1 eq) was refluxed for a periodof 15-27 h in 5M hydrochloric acid. The reaction mixture was poured onto ice water and neutralized by mixing with NaHCO3 till slightly basic pH (8-9) to get the precipitate.The resulting precipitate was filtered off and washed with cold water. Recrystallized with a suitable solvent. The resulting crystalline compounds were filtered and the vacuumed product was dried
With [ReOCl2(1,2-bis(diphenylphosphino)ethane)]; hydrogen; potassium tetraphenylborate; In tetrahydrofuran; at 160℃; under 30003 Torr; for 24h;Autoclave; Inert atmosphere;
General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98% and 1%, respectively. In the above Examples 6-1,Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure),Except that to adopt the conditions described in Table 7-9,It has been reduced (hydrogenated) in the same manner as in Example 6-1.However,The entry 19-26 in Table 9,Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9.
94%
With strain of the zygomycete fungus S. racemosum MUT 770; In dimethyl sulfoxide; for 72h;Enzymatic reaction;
2.3. Biotransformation experimentsFungal strains were pre-grown in Petri dishes containing maltextract solid medium (MEA: 20 g L-1 glucose, 20 g L-1 malt extract,20 g L-1 agar, 2 g L-1 peptone) from which the inoculum for liquidcultures was set up. The fungus was inoculated as conidia suspen-sion (1 106 conidia/mL) in 50 mL asks containing 40 mL of maltextract liquid medium. Flasks were incubated at 25 C and weremaintained under agitation (110 rpm).After 2 days of pre-growth, a 500 mM solution of the substratein DMSO was added, to a starting substrate concentration (c0) of1-5 mM. For each substrate, three biological replicates were run.The experiment was run for 3 days after the addition of the sub-strates, during which time 1 mL samples were taken, at speciedintervals (usually 24, 48, and 72 h). Each sample was extractedwith EtOAc (500 L), the organic phase was dried over anhydrousNa2SO4 and analysed by means of GC/MS. In some cases (see Section2.4) the isolation of the reduced product has been carried out.For each set of biotransformations, one ask was used to mea-sure the initial biomass and pH before the addition of the substrate.These parameters were also evaluated at the end of the experimentfor all the asks. The liquid media was separated from the biomassby ltration and was used for pH measurement while the myceliawere dried at 60 C for 24 h to measure the biomass dry weight. 2-Phenoxyethanol: from phenoxyacetic acid (25.9 mg, 94%) andfrom methyl phenoxyacetate (26.4 mg, 96%). 1H NMR (400 MHz,CDCl3, TMS): = 7.28 (m, 2H, aromatic hydrogens), 6.93 (3H, m,aromatic hydrogens), 4.08 (m, 2H, PhOCH2CH2OH), 3.94 (m, 2H,PhOCH2CH2OH). 13C NMR (100 MHz, CDCl3, TMS): = 158.6, 129.4,121.0, 114.6, 69.2, 61.2. GC/MS: tR = 11.82 min, m/z 138 (M+, 27), 94(100), 77 (32).
88%
With 1,1,3,3-Tetramethyldisiloxane; copper(II) bis(trifluoromethanesulfonate); In toluene; at 80℃; for 16h;sealed tube;
General procedure: In a sealed tube, 29 mg Cu(OTf)2 (0.08 mmol, 8 mol %) and 0.7 mL TMDS (537 mg, 4 mmol, 8 Si-H mol/mol substrate) were introduced to a solution of aliphatic carboxylic acid (1 mmol) in 1.5 mL toluene. After stirring 16 h at 80 C, the reaction mixture was cooled to room temperature and quenched with 4 mL H2O. The organic layer was extracted with CH2Cl2, dried with anhydrous MgSO4, and evaporated under reduced pressure. The crude was purified by silica gel column chromatography to obtain the alcohol.
75%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 4h;
Plus lithium tetrahydrate(0.35 g, 9.15 mmol),Anhydrous tetrahydrofuran (THF, 10 mL),Stir,A solution of phenoxyacetic acid (4 c, 6.1 mmol) in THF (10 mL) was slowly added dropwise. After completion of the drop, room temperature reaction 4h. The reaction was terminated, the remaining LiAlH4 was extracted with a small amount of water, and the appropriate amount of ethyl acetate was added. The mixture was filtered and the solid was filtered off. The solution was concentrated to dryness under reduced pressure to give a colorless transparent liquid in 75%
99.6%Chromat.
With cobalt(II) oxide; hydrogen; In 1,4-dioxane; at 179.84℃; under 15001.5 Torr; for 7h;Autoclave;
General procedure: The hydrogenation of carboxylic acids or other substrates was performed in a high-pressure stainless-steel autoclave (Xinyuan Chemical Machinery, Series CJK, 300 mL) with a maximum stirring rate of 1500 r/min. In a typical experiment, 0.2 g of catalyst (or without catalyst for the control experiment), 3 mmol of the substrate, and 100 mL alkane solvent (n-hexane, n-heptane, i-octane, or n-dodecane) were well mixed in the autoclave and purged with pure nitrogen at room temperature. The gas supply and discharge were carried out manually through needle valves. The autoclave was rapidly heated to the desired temperature and hydrogen was introduced at 2 MPa to initiate the reaction. The reaction pressure was kept at 2 MPa with a small negative deviation (?0.2 MPa) owing to the consumption of hydrogen. Samples of the liquid phase were continuously taken through a sampling tube with a filter at certain intervals. The stirring rate was kept at 750 r/min during the reaction.
With diphosphorus tetraiodide; triethylamine; In dichloromethane; at 20℃;
General procedure: Diphosphorus tetraiodide (0.5 mmol) was added to a solution of substituted acetic acids (1.5 mmol), imines (1.0 mmol) and triethylamine (5.0 mmol) in dry CH2Cl2 (20 ml) at room temperature and the mixture was stirred overnight. The reaction mixture was washed successively with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product, which was purified by crystallization from EtOAc to give pure beta-lactams 3a-j and 5a-b.
88%
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine; In dichloromethane; at 20℃;
General procedure: EEDQ (1.3 mmol) was added to a solution of the substituted acetic acid (1.3 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature, and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4) and filtered, and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from 95% EtOH.
With potassium hydrogensulfate; water In methanol at 100℃; for 48h;
Typical alcoholysis procedure.
General procedure: A mixture of the amide (1, 1 mmol), alcohol (15 mL), and pulverized potassium bisulfate (1.1 g, 8 mmol) was refluxed for the specified time. The alcohol was removed in vacuo and the residue was triturated with hexanes (or other appropriate solvent such as DCM or ethyl acetate to dissolve the product). Removal of hexanes in vacuo provided the following pure products
79%
With benzene-1,2-dicarboxylic acid at 250℃; for 0.5h; microwave irradiation;
With hydrazine monohydrate; N-(chloromethylene)-N-methylmethanaminium chloride; triethylamine In dichloromethane at 20℃; for 7h;
General procedure for synthesis of acylhydrazines 2-5
General procedure: A solution of carboxylic acid (1.0 mmol), Vilsmeier reagent (1.0 mmol) and Et3N (3.0 mmol) in dry CH2Cl2 (10 mL) at room temperature was added to a solution of hydrazine hydrate (4.0 mmol) in dry CH2Cl2 (5 mL) and the mixture was stirred 7 h. The mixture was washed successively with saturated NaHCO3 (15 mL) andbrine (15 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from ethanol 95 %. Spectral data for 2-5 have been previously reported.
With hydrazine hydrate monohydrate In methanol for 25h; Heating;
With hydrazine hydrate monohydrate at 90℃; for 4h;
Multi-step reaction with 2 steps
1: H2SO4 / 3 h / Heating
2: hydrazine hydrate / ethanol / 14 h / Heating
Multi-step reaction with 2 steps
1: H2SO4 / 3 h
2: hydrazine hydrate / ethanol / 14 h / Heating
Multi-step reaction with 2 steps
1: H2SO4
2: NH2NH2*H2O
Multi-step reaction with 2 steps
1: p-toluenesulfonic acid / 5 h / Heating
2: hydrazine hydrate / ethanol / 3 h / Heating
Multi-step reaction with 2 steps
1: sulfuric acid / 8 h / Reflux
2: hydrazine hydrate monohydrate / ethanol / 24 h / Reflux
With sulfuric acid; hydrazine hydrate monohydrate In ethanol for 6h; Reflux;
General procedure for the preparation of acid hydrazides(10a-i)
General procedure: The appropriate aromatic acids 9a-i (0.01 mol) were dissolved in absolute ethanol (10 ml). Hydrazine hydrate (0.02 mol, 1 ml) and few drops of conc. sulphuric acid were added. The reaction mixture was refluxed for 6 h. The resulting solid obtained was filtered, dried and crystallized from methanol. The completion of reaction was monitored by thin-layer chromatography and infrared spectrophotometer (Jha et al., 2010). (10a: naphthoxy acetic acidhydrazide; 10b: phenylacetic acid hydrazide; 10c: p-nitrobenzoic acid hydrazide; 10d: o-chlorobenzoic acid hydrazide; 10e: p-chlorobenzoic acid hydrazide; 10f: nicotinic acid hydrazide; 10g: phenoxyacetic acid hydrazide; 10h: 3,5-dinitrobenzoic acid hydrazide; 10i: salicylic acid hydrazide.)
Multi-step reaction with 2 steps
1: acetyl chloride / 20 h / 80 °C
2: hydrazine hydrate monohydrate / ethanol / 6 h / 85 °C
With hydrazine monohydrate; Vilsmeier reagent; triethylamine In dichloromethane at 20℃;
With hydrazine hydrate monohydrate
Multi-step reaction with 2 steps
1: acetyl chloride / 24 h / 80 °C / Cooling with ice
2: hydrazine hydrate monohydrate / ethanol / 85 °C
2-phenoxy-N-(3-(trifluoromethyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72h;
General Procedure for the Preparation of Compounds
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N’-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
With Vilsmeier reagent; hydrazine hydrate; triethylamine In acetonitrile at 20℃;
General Procedure for One-pot Synthesis of Symmetrical 1,3,4-oxadiazoles 5a-k(Method B)
General procedure: Hydrazine hydrate (0.3 mmol) was added to a solution of carboxylic acid (1.0 mmol),Vilsmeier reagent (1.0 mmol) and Et3N (2.0 mmol) in dry CH3CN (20 mL) at room temperature.After 2 hours Vilsmeier reagent (0.4 mmol) and Et3N (1.0 mmol) were addedand the mixture was stirred at room temperature for 8 hours. Saturated NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3 £ 20 mL). The organic layerwas washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removedunder reduced pressure to give the crude products. The crude residues were purified bycrystallization from 95% ethanol. Spectral data for 5a-b, 5d, 5f-h and 5j have been previouslyreported,26-32 and were matched by the products of this work.
88%
With aluminum oxide; hydrazine hydrate In ethanol for 0.0416667h; microwave irradiation;
Multi-step reaction with 3 steps
1: H2SO4 / 3 h / Heating
2: hydrazine hydrate / ethanol / 14 h / Heating
3: 90 percent / POCl3 / Heating
With poly(ethylene glycol) supported dichlorophosphate at 120℃; for 0.133333h; microwave irradiation;
84%
With poly(ethylene glycol)-supported dichlorophosphate at 120℃; microwave irradiation;
66%
Stage #1: thiosemicarbazide; 2-phenoxyacetic acid With trichlorophosphate for 0.5h; Reflux;
Stage #2: With water for 4h; Reflux;
44.4%
Stage #1: thiosemicarbazide; 2-phenoxyacetic acid In chloroform at 60℃; for 10h; Reflux;
Stage #2: With hydrogenchloride In water for 5h; Reflux;
Synthesis of compounds 1a-e (General method).
General procedure: To a hot (60 °C) solution of 5-mmol carboxylic acid (2.5 mmol for dicarboxylic acid) in a mixture of polyphosphate ester (20g), chloroform (30 mL) and 5 mmol of thiosemicarbazide was added. The reaction mixture was refluxed for 10 h, then 15 mL of distilled water was added to the mixture and the residual PPE was neutralized by NaHCO3.
With trichlorophosphate at 100℃; for 4h;
Stage #1: thiosemicarbazide; 2-phenoxyacetic acid With trichlorophosphate at 75℃; for 0.5h;
Stage #2: In water for 4h; Reflux;
General procedure for the preparation of 2-((phenoxy orsubstituted phenoxy)methyl/ethyl)-1,3,4-thiadiazol-5-amines (4a-qand 5a-q)
General procedure: A mixture of benzoic acid (50 mmol), N-aminothiourea(50 mmol) and POCl3 (13 mL) was heated at 75 C for 0.5 h. Themixture was cooled to which water (10 mL) was added and thereaction mixture was refluxed for 4 h. The mixture was cooled and pH was adjusted to 8.0 by adding 50% sodium hydroxide solution.The separated solid was filtered and recrystallized from ethanolto give desired compounds.
In trichlorophosphate for 4h; Reflux;
Synthesis of 5-((3,4-dichlorophenoxy)methyl)-1,3,4-thiadiazol-2-amine (6j).
General procedure: A solution of 5j (2.4 g, 11.0 mmol) and thiosemicarbazide (2.0 g, 22.0 mmol) in phosphorus oxychloride (30 mL) was stirred at reflux for 4 h. After cooling,water (50 mL) was added. After being stirred at reflux for 12 h, the mixture was cooled to room temperature and neutralized with 5N NaOH. The resulting solid was separated by filtration, washed with water, and dried in vacuo to give the titlec ompound (2.9 g, 95% yield). 1H NMR (300 MHz, DMSOd6)δ 7.52 (d, J = 9.0 Hz, 1H), 7.36 (s, 1H), 7.03 (d, J = 9.0Hz, 1H), 5.31 (s, 2H).
With [2-(dicyclohexylphosphino)ethyl]trimethylammonium chloride; phenylsilane; In tetrahydrofuran; water; at 20.0℃; for 2.0h;Inert atmosphere;
General procedure: A suspension of PdEnCat 30 (Aldrich; 0.4 mmol/g loading, 0.05 equiv) inTHF-H2O (9:1, 5 mL) was bubbled with argon for 10 min.After this time, DCHT (0.15 equiv) and the correspondingallyl ester 1 (1.0 equiv, 70 mg) were added under positivepressure. Finally, PhSiH3 was injected (2.0 equiv), and themixture was allowed to react for 2 h at r.t. under an argonatmosphere. After this time, the reaction was filtered throughCelite and the filtrate was evaporated under reducedpressure. The remaining solid was dissolved with EtOAc (20mL) and washed with H2O (3 × 10 mL) and brine (3 × 10mL). The organic layer was dried (MgSO4) and evaporatedunder vacuum. Purification by solid-phase extraction (C18reverse-phase chromatography, H2O/MeOH) gave purecarboxylic acids 2 (yields shown in Table 1). Purity wasdetermined by HPLC, 1H NMR and 13C NMR analyses. Allthe carboxylic acids are commercially available. Therecorded 1H and 13C NMR spectra of the synthesizedcompounds were consistent with those registered forcommercial samples.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
<Exaraple 29> 3-(2-phenoxy-aceryl-amino)-benzamideTo a solution of phenoxy-acetic acid (100 mg, 0.65 mmol), 3-amino benzamide (178.9 mg, 1.31 mmol), HOBt (177.7 mg, 1.31 mmol) and DIPEA (170 mg, 1.31 mmol) in DMF (6 ml) was added EDC (252 mg, 1.31 mmol) at room temperature and'the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH : MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH : MC = 1:9 ~ 2:8) to afford of 3-(2-phenoxy- aceryl-amino)-benzamide as a colorless solid (146 mg, 82% yield).. 1H NMR (DMSO-d6, 300 MHz) 10.19(1H, s, CONH), 8.09(1H, s, aromatic), 7.93(1H, s, aromatic), 7.80(1H, d, J=9.0 Hz, aromatic), 7.56(1H, d, J = 7.5 Hz, aromatic), 7.35(4H, m, CONH2, aromatic), 6.98(3H, m, aromatic), 4.70(2H, s, OCH2).
82%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of phenoxy-acetic acid (100 mg, 0.65 mmol), 3-amino benzamide (178.9 mg, 1.31 mmol), HOBt (177.7 mg, 1.31 mmol) and DIPEA (170 mg, 1.31 mmol) in DMF (6 ml) was added EDC (252 mg, 1.31 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH: MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH:MC=1:9~2:8) to afford of 3-(2-phenoxy-acetyl-amino)-benzamide as a colorless solid (146 mg, 82% yield). 1H NMR (DMSO-d6, 300 MHz) 10.19 (1H, s, CONH), 8.09 (1H, s, aromatic), 7.93 (1H, s, aromatic), 7.80 (1H, d, J=9.0 Hz, aromatic), 7.56 (1H, d, J=7.5 Hz, aromatic), 7.35 (4H, m, CONH2, aromatic), 6.98 (3H, m, aromatic), 4.70 (2H, s, OCH2).
4-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With Vilsmeier reagent; triethylamine In dichloromethane at 20℃;
93%
With Benzoyloxymethylene-dimethyl-ammonium; chloride; triethylamine In dichloromethane at 20℃;
93%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
General procedure
General procedure: Ac2O (1.5 mmol) was added to a solution of substitutedacetic acid (1.5 mmol), Schiff base (1.0 mmol), DMSO (1.5 mmol), and Et3N(5.0 mmol) in dry CH2Cl2 (10 mL) at room temperature, and the mixture wasstirred overnight. The mixture was washed successively with saturatedNaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4),filtered and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from EtOAc.
93%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
92%
With 1-methyl-2-fluoropyridinium p-toluenesulfonate; triethylamine In dichloromethane at 20℃; stereoselective reaction;
86%
With Vilsmeier reagent; triethylamine In dichloromethane at 20℃;
86%
With Vilsmeier reagent; triethylamine In dichloromethane at 0 - 20℃;
Stage #1: Thiosalicylic acid With sulfuric acid for 0.0833333h;
Stage #2: 2-phenoxyacetic acid at 80℃; for 2h;
3.1 2.3.1 Synthesis of 2-(carboxymethoxy)thioxanthone (TX-OCH2COOH)
Thiosalicylic acid (1.6 g, 10.3 mmol) was slowly added to concentrated sulfuric acid (15 mL) and tihe mixture was stirred for 5 min to ensure through mixing. Phenoxyacetic acid (6.7 g, 44 mmol) was added slowly to the stirred mixture over a period of 30 min. After the addition, the reaction mixture was stirred at room temperature for 1 h, then at 80 °C for 2 h, after which it was left to stand at room temperature overnight. The resulting mixture was poured carefully with stirring into a 10-fold excess of boiling water ant it was then further boiled for 5 min. The solution was cooled and filtered. The residue was recrystallized from dioxane/water. Yield: 80%; mp: 200 °C; IR (ATR): ν = 3480, 2927, 1753, 1637, 1603, 758; 1H NMR (250 MHz, DMSO-d6, δ): 8.46-7.42 (m, 7H, Ar H), 4.84 (s, 2H, CH2); C15H10O4S (286 g mol-1): Calcd. C 62.94, H 3.50, S 11.19; Found C 63.59, H 4.36, S 10.95.
47%
With sulfuric acid at 5 - 60℃; for 2h;
2 Example 2; Preparation of 2-carboxymethoxythioxanthone from mercaptobenzoic acid
Concentrated sulphuric acid (250g) and mercaptobenzoic acid (15.4g) were charged to a reactor and phenoxyacetic acid (25.8g) was added over 1 hour keeping the temperature at 5-25°C. The temperature was raised to 50-60°C for 1 hour then water (270mls) was added. The solid product was filtered and washed with water (2x50mls). The solid was stirred in 120mls 50% aqueous acetone and brought to reflux for 0.5 hours. After cooling to 15°C, the solid was filtered, washed with water and dried. 2-Carboxymethoxythioxanthone (13.5g) was obtained in 47% yield. This was pale yellow solid, melting point 210-215°C. Again, a single isomer of the product was produced. The present invention enables a substituted thioxanthone compound to be provided that is substantially free of impurities and can be isolated in yields of up to, and possibly in excess of, 80% and as a single isomer. This invention displays a yield from a single stage process that greatly exceeds that from alternative multi-stage conventional synthetic routes and provides material which is essentially free of impurities. The thioxanthone compounds so produced are useful as reactive intermediates in the pharmaceutical and photochemical industries
Stage #1: Thiosalicylic acid With sulfuric acid In water
Stage #2: 2-phenoxyacetic acid In water at 20 - 80℃; for 3.5h;
2.2.b
Example 2b: 2-Carboxymethyloxy thioxanthone2-Carboxymethyloxy thioxanthone can be synthesized by a one-step reaction: Thiosalycylic acid (O.lmol) was slowly added to 150ml of concentrated sulfuric acid, and the mixture was stirred for 5min to ensure thorough mixing. Phenoxyl acetic acid (0.5mol) were added slowly to the stirred mixture over a period of 30 min. After the addition, the reaction mixture was stirred at room temperature for Ih and then at 800C for 2h, after which it was left to stand at room temperature overnight. The resulting mixture was poured carefully with stirring into a 10-fold excess of boiling water, and was further boiled for lOmin. The solution was cooled and filtered. The residue was recrystallized from di- oxane-water .
1 Example 1; Preparation of 2-carboxymethoxythioxanthone from dithiobisbenzoic acid
Concentrated sulphuric acid (500g) and dithiobisbenzoic acid (30.6g) were charged to a reactor and phenoxyacetic acid (60.8g) was added over 1 hour keeping the temperature at 0-25°C. After stirring for 1 hour, water (470mls) was added. The solid product was filtered and washed with water (2x50mls). The solid was then stirred in 50% aqueous acetone (200mls) and heated to reflux for 0.5 hours. After cooling to ambient temperature the solid was filtered, washed with water and dried. 2-Carboxymethoxythioxanthone (43.4g) was obtained in 76% yield. This was a dull yellow solid, melting point 207 - 212°C. Assay by HPLC >97%. A single isomer was obtained.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; water;
Step A Preparation of 6-(2-chlorophenoxy)-8-methyl-2-(methylthio) pyrido[2,3-d]pyrimidin-7(8H)-one To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (5.5 g, 30 mmol) and <strong>[6956-85-0]methyl 2-chlorophenoxyacetate</strong> (prepared as in Example 4 using 2-chlorophenol, 7.0 g, 35 mmol) in 80 mL of 1-methyl-2-pyrrolidinone was added potassium carbonate (9.0 g, 65.2 mmol). The reaction mixture was heated to 120 C. and after 12 hours, additional phenoxyacetate (2*, 0.5 g, 2.5 mmol) and potassium carbonate (2*, 2.0 g, 15 mmol) was added. After 6 hours of stirring at 120 C., the reaction was cooled to room temperature and water (100 mL) was added. The solution was stirred for 45 minutes and filtered. The resultant solid was filtered and washed with water (2*) and ether (2*). Drying of the product via vacuum oven yielded 9.0 g of the sulfide (mass spec. M+1=334).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one;
Step A Preparation of 6-(4-chlorophenoxy)-8-methyl-2-(methylthio) pyrido[2,3-d]pyrimidin-7(8H)-one To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 3.0 mmol) and <strong>[4841-22-9]methyl 4-chlorophenoxyacetate</strong> (prepared as in Example 4 using 4-chlorophenol, 0.66 g, 3.3 mmol) in 5 mL of 1-methyl-2-pyrrolidinone was added potassium carbonate (0.5 g, 3.6 mmol). The reaction mixture was heated to 120 C. and after 12 hours, additional phenoxyacetate (0.3 g, 1.5 mmol) and potassium carbonate (0.4 g, 2.9 mmol) was added. After 6 hours of stirring at 120 C., the reaction was cooled to room temperature and poured into water (100 mL). The reaction mixture was extracted with ethyl acetate (2*, 75 mL) and the resultant organic solution was washed with water (5*, 50 mL) then dried (brine, MgSO4). Evaporation of the solution yielded a solid which was recrystallized (EtOAc/Hexane) yielding 0.55 g of the sulfide (mass spec. M+1=334).
With chlorosulfonic acid In chloroform at 0℃; for 0.333333h;
Intermediate 71 - 2-(4-(chlorosulfonyl)phenoxy)acetic acid
Phenoxyacetic acid (1 g, 6.58 mmol) was dissolved in 20 ml of chloroform and cooled in an ice bath, then 4 ml of chlorosulfonic acid was added dropwise. After the completion of the dropwise addition, the reaction was carried out at 0 ° C for 20 minutes. The reaction was quenched with ice water at room temperature for 30 minutes. Direct filtration and drying Intermediate 71 (white solid, 1 g), The yield was 61%.
With chlorosulfonic acid In chloroform
II Synthesis of 4-Chlorosulfonyl Phenoxyacetic Acid
EXAMPLE II Synthesis of 4-Chlorosulfonyl Phenoxyacetic Acid 50 mM (7, 6 g) phenoxyacetic acid was dissolved in 75 ml chloroform, cooled in ice-bath and stirred. 16.5 ml chlorosulfonic acid in 25 ml chloroform was added dropwise during a period of 10-15 minutes. The temperature was kept at 0° for 20 minutes then allowed to remain at room temperature for an additional 30 minutes. The two-phase liquid was poured into a beaker containing about 300 g. of crushed ice. The separated aqueous phase was extracted twice with 50 ml ether, then the combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the remaining material was recrystallized from ether-hexane mixture. Yield 9.75 g. (77.8%, Melting point: 155-157° (uncorrected). TLC: Sigma F254 anal. plate. Detection: UV 254 nm, 355 nm. Eluent A) Ethyl Acetate - Acetic acid 9:1 v/v
With chlorosulfonic acid In chloroform
II Synthesis of 4-Chlorosulfonyl Phenoxyacetic Acid
EXAMPLE II Synthesis of 4-Chlorosulfonyl Phenoxyacetic Acid 50 mM (7, 6 g) phenoxyacetic acid was dissolved in 75 ml chloroform, cooled in ice-bath and stirred 16.5 ml chlorosulfonic acid in 25 ml chloroform was added dropwise during a period of 10-15 minutes. The temperature was kept at 0° for 20 minutes then allowed to remain at room temperature for an additional 30 minutes. The two-phase liquid was poured into a beaker containing about 300 g. of crushed ice. The separated aqueous phase was extracted twice with 50 ml ether, then the combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the remaining material was recrystallized from ether-hexane mixture. Yield 9.75 g. (77.8%, Melting point 155°-157° (uncorrected). TLC: Sigma F254 anal. plate. Detection: UV 254 nm, 355 10 nm. Eluent (A) Ethyl Acetate-Acetic acid 9:1 v/v
13.B EXAMPLE 13
B. ethyl p-ethylphenoxyacetate. A mixture of 30 g. of phenoxyacetic acid, 100 ml. of ethanol and 10 ml. of sulfuric acid is refluxed for 22 hours, cooled, poured into ice water and extracted with methylene chloride. The organic extract is washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under vacuum, to yield ethyl phenoxyacetate, b.p. 123°/17 mm.Hg.
Stage #1: 2-phenoxyacetic acid With 1,1'-carbonyldiimidazole In dichloromethane; water at 0 - 20℃; for 0.5h; Inert atmosphere;
Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane; water at 0 - 20℃; Inert atmosphere;
N-Methoxy-N-methyl-2-phenoxyacetamide (7f).
According to a reported procedure with some modifications, a solution of phenoxyacetic acid (6f, 1.00 g, 6.57 mmol) in anhydrous CH2C12 (10 mL) was treated portionwise with Ι,Γ-carbonyldiimidazole (1.39 g, 8.57 mmol) at 0 °C under argon. The ice bath was removed, and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was treated with triethylamine (1.3 mL, 9.3 mmol) and N, O-dimethylhydroxylamine hydrochloride (0.90 g, 9.2 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature under argon. 1 M HC1 (10 mL) was added. The organic phase was washed (water), dried (Na2S04) and concentrated to a transparent oil. Column chromatography [silica, hexanes/ EtOAc (1 : 1)] afforded a transparent oil (1.18 g, 91%). The characterization values (.H NMR) were consistent with those in the literature
86%
Stage #1: 2-phenoxyacetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 5℃; for 1h;
Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; for 20h;
A.A2.a-1
Example A2; a-1. Preparation of intermediate 4; 1,1'-carbonyldiimidazole (24 g, 0.148 mol) was added portionwise to a mixture of phenoxyacetic acid (15 g, 0.0985 mol; CAS [122-59-8]) in CH2Cl2 (150 ml) while cooled on a ice-bath at 5°C. The mixture was stirred for 1 hour at 5°C and N,O-dimethylhydroxylamine hydrochloride (14.4 g, 0.148 mol) was added and the suspension was stirred at room temperature for 20 hours. The mixture was poured out into HCl 1 N and extracted with CH2Cl2. The organic layer was washed with K3CO3 10 %, dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and the solvent was evaporated. Yielding: 16.6 g of intermediate 4 (86 %).
69%
Stage #1: 2-phenoxyacetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 23℃;
Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane at 0 - 10℃;
With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
5
Scheme 10 Reagents and conditions: a) BrCH2COOEt, 2C03, acetone; b) IN aq. NaOH, EtOH; c) HCl.HN(OMe)Me, NMM, DMA P. WSCI.HC1, CH2C12; d) thiazole, n-BuLi, Et20.
With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
To phenoxyacetic acid (50.0 g, 0.33 mol) dissolved in tetrahydrofuran (210 mL) was slowly added 1,1'-carbonyldiimidazole (56.0 g, 0.35 mol) with additional tetrahydrofuran (30 mL). After stirring for 1.5 hr at room temperature, triethylamine (92 mL, 0.66 mol) was added all at once and methyl 6-aminohexanoate hydrochloride (66.0 g, 0.36 mol) was added in portions over 20 min. The reaction mixture was stirred at room temperature overnight, heated at 50 C. for 20 min, and then stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, added to 1 N hydrochloric acid (750 mL) and extracted with ethyl acetate (2*250 mL). The combined organic layers were washed with 1 N hydrochloric acid (1*100 mL), water (1*100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil. NMR analysis indicated presence of phenoxyacetic acid. The concentrate was dissolved in toluene (450 mL) and stirred 15 min with 25% sodium bicarbonate (200 mL). The organic layer was filtered through 1 PS paper, concentrated under reduced pressure, diluted with hexanes, and concentrated again, to give 76.89 g (84%) of the title compound, amide, as a yellow oil.
cis-N-(4-methoxy-phenyl)-3-phenoxy-4-(4-methoxy-phenyl)-azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
General procedure
General procedure: Ac2O (1.5 mmol) was added to a solution of substitutedacetic acid (1.5 mmol), Schiff base (1.0 mmol), DMSO (1.5 mmol), and Et3N(5.0 mmol) in dry CH2Cl2 (10 mL) at room temperature, and the mixture wasstirred overnight. The mixture was washed successively with saturatedNaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4),filtered and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from EtOAc.
91%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
89%
With Benzoyloxymethylene-dimethyl-ammonium; chloride; triethylamine In dichloromethane at 20℃;
88%
With (methoxymethylidene)dimethylammonium methyl sulfate; triethylamine In dichloromethane at 20℃;
Stage #1: phenol With sodium hydroxide In ethanol; water at 20℃; for 0.333333h;
Stage #2: sodium monochloroacetic acid In ethanol; water at 102℃; for 5h;
Synthesis of phenoxyacetic acid derivative (b1-7)
General procedure: 55mmol monochloroacetic acid was dissolved in 15mL deionized water under the condition of ice water bath, then 30% NaOH solution was used to adjust pH 8-9, sodium chloroacetate solution was obtained. 45mmol NaOH was dissolved in mixed solvent of 15mL deionized water and 5mL ethanol at room temperature with constant stirring, 45mmol phenol was subsequent slowly added. After stirring for another 20min, sodium chloroacetate solution was added. Subsequently, the mixture was refluxed at 102°C for 5h. After the mixture was cooled to room temperature, pH was adjusted to 1-2 with 2.0mol·L-1 HCl, amounts of white precipitations were gained. The precipitations were filtered and washed 3 times with dilute hydrochloric acid, dried at 60°C. White crude product was dispersed in 100mL heated deionized water, pH was adjusted to 8.0 using saturated potassium carbonate solution, then mixture solution was filtered, and filtrate was collected. White precipitated was obtained by adjusting pH of filtrate to 1-2 with 2.0mol·L-1 HCl. After cooled down to room temperature naturally, the mixture was filtered, washed with dilute hydrochloric acid, dried overnight in vacuum, then target product (b1) was obtained. The synthetic procedures of phenoxyacetic acid derivative (b2-7) were similar to that of phenoxyacetic acid (b1). Phenoxyacetic acid (b1), white powder, yield 75%. 1H NMR (400MHz, CDCl3) δ/ppm: 8.83 (dd, J=5.0, 1.5Hz, 2H), 8.03 (dd, J=7.5, 1.5Hz, 2H), 7.39 (dd, J=7.5, 5.1Hz, 2H). MS (EI) m/z (%): 153 (M+1, 8), 152 (M, 86), 108 (8), 107 (100), 94 (26), 79 (24), 77 (87), 65 (14).
70.2%
With sodium hydroxide In ethanol; water for 1h; Reflux;
67%
With sodium hydroxide In ethanol; water at 105℃; for 5h;
General procedure: To 10 mL of a 0.2 M solution of a SET reagent 2 or 3 (2 mmol), cooled to 0 C, was added a solution of the appropriate aryloxyalkanoic acid 1 (for the relative molar ratios, see Table 1), dissolved in dry THF (5 mL). Reactions with Li or Na metal were run under closely related reaction conditions, by adding solutions of the appropriate aryloxyalkanoic acid 1 to suspension of the freshly cut metal in dry THF.Each mixture was vigorously stirred and allowed to reach rt for 12 h, after which time it was quenched by slow dropwise addition of H2O (15 mL). The organic solvent was evaporated in vacuo and the resulting mixture was extracted with CH2Cl2 (3×10 mL). The aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2 (3×10 mL), and the organic phases were collected, washed with H2O (1×10 mL), brine (10 mL) and dried (Na2SO4). After evaporation of the solvent, the resulting mixture was analyzed by 1H NMR spectroscopy.
General procedure: To 10 mL of a 0.2 M solution of a SET reagent 2 or 3 (2 mmol), cooled to 0 C, was added a solution of the appropriate aryloxyalkanoic acid 1 (for the relative molar ratios, see Table 1), dissolved in dry THF (5 mL). Reactions with Li or Na metal were run under closely related reaction conditions, by adding solutions of the appropriate aryloxyalkanoic acid 1 to suspension of the freshly cut metal in dry THF.Each mixture was vigorously stirred and allowed to reach rt for 12 h, after which time it was quenched by slow dropwise addition of H2O (15 mL). The organic solvent was evaporated in vacuo and the resulting mixture was extracted with CH2Cl2 (3×10 mL). The aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2 (3×10 mL), and the organic phases were collected, washed with H2O (1×10 mL), brine (10 mL) and dried (Na2SO4). After evaporation of the solvent, the resulting mixture was analyzed by 1H NMR spectroscopy.
General procedure: To 10 mL of a 0.2 M solution of a SET reagent 2 or 3 (2 mmol), cooled to 0 C, was added a solution of the appropriate aryloxyalkanoic acid 1 (for the relative molar ratios, see Table 1), dissolved in dry THF (5 mL). Reactions with Li or Na metal were run under closely related reaction conditions, by adding solutions of the appropriate aryloxyalkanoic acid 1 to suspension of the freshly cut metal in dry THF.Each mixture was vigorously stirred and allowed to reach rt for 12 h, after which time it was quenched by slow dropwise addition of H2O (15 mL). The organic solvent was evaporated in vacuo and the resulting mixture was extracted with CH2Cl2 (3×10 mL). The aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2 (3×10 mL), and the organic phases were collected, washed with H2O (1×10 mL), brine (10 mL) and dried (Na2SO4). After evaporation of the solvent, the resulting mixture was analyzed by 1H NMR spectroscopy.
N-(4-Methoxyphenyl)-3-phenylpropenaldimine[ No CAS ]
[ 122-59-8 ]
cis-1-(4-methoxyphenyl)-3-phenoxy-4-styrylazetidin-2-one-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: N-(4-Methoxyphenyl)-3-phenylpropenaldimine; 2-phenoxyacetic acid With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In dichloromethane at 20℃;
Stage #2:
General Procedure for the Synthesis of 2-azetidinones
General procedure: To a stirred solution of CDMT (1.5 mmol) in dry CH2Cl2(15 mL), N-methylmorpholine (NMM) (6.0 mmol) was added dropwise and allowed to stir for 10 min. To the white suspension containing DMTMM salt, the Schiff base (1.0mmol) and the carboxylic acid (1.5 mmol) were added and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15mL), dried with Na2SO4 and concentrated in vacuo. 2-azetidinones 3a-k, 3n-o were purified by crystallizationfrom EtOAc and 2-azetidinones 3l-m by short column chromatographyon silica gel
With diethyl chlorophosphate; triethylamine at 20℃;
cis-1-(4-methoxynaphthalen-1-yl)-3-phenoxy-4-p-tolyl-azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With Benzoyloxymethylene-dimethyl-ammonium; chloride; triethylamine In dichloromethane at 20℃;
92%
With trifluoro-[1,3,5]triazine; triethylamine In dichloromethane at 20℃;
90%
With triethylamine; 3,5-dinitrobenoyl chloride In dichloromethane at 20℃;
General Procedure for the Synthesis of 2-azetidinones 3a-p
General procedure: A 3,5-dinitrobenzoyl chloride (1.3 mmol) was added to asolution of the substituted acetic acid (1.3 mmol), the imine(1.0 mmol) and Et3N (4.0 mmol) in dry CH2Cl2 (12 mL) atroom temperature and the mixture was stirred overnight. Themixture was washed successively with saturated NaHCO3(12 mL) and brine (12 mL). The organic layer was dried(Na2SO4), filtered and the solvent was removed under reducedpressure to give the crude products. 2-azetidinones 3apwere purified by crystallization from 95% ethanol.
1-methyl-4-(4-nitrophenyl)-3-phenoxyazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With Benzoyloxymethylene-dimethyl-ammonium; chloride; triethylamine In dichloromethane at 20℃;
78%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
General procedure
General procedure: Ac2O (1.5 mmol) was added to a solution of substitutedacetic acid (1.5 mmol), Schiff base (1.0 mmol), DMSO (1.5 mmol), and Et3N(5.0 mmol) in dry CH2Cl2 (10 mL) at room temperature, and the mixture wasstirred overnight. The mixture was washed successively with saturatedNaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4),filtered and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from EtOAc.
78%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; triethylamine In dichloromethane at 20℃;
1 General procedure for the synthesis of 2-azetidinones
General procedure: 4.2. A phosphonitrilic chloride (0.5 mmol) was added to a solution of the substituted acetic acid (1.5 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15mL) at room temperature and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, and the solvent was removed under reduced pressure to give the crude products. β-Lactams 5a-u, 7a-d, 11a-c, 17a-d were purified by crystallization from ethyl acetate, β-lactams 9a-c were purified by crystallization from 96% ethanol, β-lactams 13a-c by short column chromatography (hexane/EtOAc 7:3), and β-lactams 15a-c by short column chromatography (hexane/EtOAc 9:1).
90%
With 3,6-dichloro-1,2,4,5-tetrazine; triethylamine In dichloromethane at 20℃;
Synthesis of 2-azetidinones (4a-l and 6a-b); general procedure
General procedure: 3,6-Dichlorotetrazine (1.5 mmol) was added to solutions of substitutedacetic acids (1.5 mmol), imines (1.0 mmol) and triethylamine(5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature and the mixturewas stirred overnight. The reaction mixture was washed successivelywith saturated NaHCO3 (15 mL) and brine (15 mL). The organic layerwas dried (Na2SO4), filtered and the solvent was removed to give thecrude product, which was purified by crystallisation from EtOAc togive pure β-lactams 4a-l and 6a-b.
N-(4'-phenethyl)-4-phenyl-1-aza-1,3-butadiene[ No CAS ]
[ 122-59-8 ]
1-(4-ethoxyphenyl)-3-phenoxy-4-styrylazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;
88%
With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; triethylamine In dichloromethane at 20℃;
1 General procedure for the synthesis of 2-azetidinones
General procedure: 4.2. A phosphonitrilic chloride (0.5 mmol) was added to a solution of the substituted acetic acid (1.5 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15mL) at room temperature and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, and the solvent was removed under reduced pressure to give the crude products. β-Lactams 5a-u, 7a-d, 11a-c, 17a-d were purified by crystallization from ethyl acetate, β-lactams 9a-c were purified by crystallization from 96% ethanol, β-lactams 13a-c by short column chromatography (hexane/EtOAc 7:3), and β-lactams 15a-c by short column chromatography (hexane/EtOAc 9:1).
General procedure: The mixture of 0.1mol of phenoxy acetic acid derivative(PAA1-PAA5) and 0.1mol of dicyclohexyl carbodiimide in10 mL dichloromethane was stirred at room temperature.After 30 minutes, a solution of AB or APB in 20 ml of dichloromethaneand 5 ml of pyridine was added. The reactionmixture was stirred initially at 0C for 2 h followed by stirring at room temperature for 12 h. The precipitated dicyclohexylureawas removed by filtration and the solvent wasdistilled at reduced pressure on rotary vacuum evaporator.The dried product was dissolved in ethyl acetate (10 mL) andthe solution was washed with 10% aqueous solution of sodiumbicarbonate followed by distilled water to remove thetraces of residual dicyclohexylurea. The ethyl acetate layerwas dried with anhydrous magnesium sulphate and then solventwas distilled off to obtain the crude product which wasrecrystallized from ethanol-water mixture.
1-(4-methoxynaphthalen-1-yl)-4-(4-methoxyphenyl)-3-phenoxy-azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
General procedure
General procedure: Ac2O (1.5 mmol) was added to a solution of substitutedacetic acid (1.5 mmol), Schiff base (1.0 mmol), DMSO (1.5 mmol), and Et3N(5.0 mmol) in dry CH2Cl2 (10 mL) at room temperature, and the mixture wasstirred overnight. The mixture was washed successively with saturatedNaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4),filtered and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from EtOAc.
91%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
1-(4-methoxynaphthalen-1-yl)-4-(4-chlorophenyl)-3-phenoxyazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
General procedure
General procedure: Ac2O (1.5 mmol) was added to a solution of substitutedacetic acid (1.5 mmol), Schiff base (1.0 mmol), DMSO (1.5 mmol), and Et3N(5.0 mmol) in dry CH2Cl2 (10 mL) at room temperature, and the mixture wasstirred overnight. The mixture was washed successively with saturatedNaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4),filtered and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from EtOAc.
89%
With acetic anhydride; dimethyl sulfoxide; triethylamine In dichloromethane at 20℃;
With 0.5% Pd/Sibunit carbon material; hydrogen; In water; at 30℃; under 760.051 Torr; for 100h;
General procedure: Two replicates of each hydrodechlorination run were carriedout in a continuous basket stirred tank reactor (Carberry SpinningCatalyst Basket) from Autoclave Engineers, provided with tem-perature, pressure and gas flow control. The aqueous solution ofeach organochlorinated reactant was fed to the reactor at 4 mL/minand H2was continuously passed at 50 N mL/min. A catalyst load-ing of 2.95 g/L was always used, so that the space-time was fixedat 2.95 kgcath/molCl.All the experiments were performed at 30C,atmospheric pressure and 600 rpm stirring velocity. The progressof the reaction was followed by analyzing periodically samplesof the exit liquid stream taken with a fraction collector (FC203B-Gilson) along the 100 h on stream of the experiments. The datareproducibility was better than ±5%. The existence of internal andexternal mass transfer limitations is discarded in our experimentalconditions, as demonstrated in previous studies [30,31]. The organic compounds in the effluent from HDC of 2,4-DCPwere analyzed by GC with a flame ionization detector (GC 3900 Var-ian) using a 30 m long × 0.25 mm i.d. capillary column (CP-Wax 52CB). 2,4-D, MCPA and the aromatic reaction byproducts were quan-tified by HPLC (Varian Prostar 325) with a UV detector using a C18as stationary phase (Valco Microsorb-MW 100-5 C18) at 280 nmand a mixture of acetonitrile and acid water (acetic acid 0.1%) asmobile phase at 0.5 mL/min. Analysis of chloride was performedby ionic chromatography (Metrohm 790 Personal IC). The pH wasmeasured with a pH meter (CRISON) Ecotoxicity measurements were carried out by a bioassay fol-lowing the standard Microtox test procedure (ISO 11348-3, 1998),based on the decrease of light emission by the marine bacteria Vib-rio fischeri (Photobacterium phosphoreum), using a Microtox M500Analyzer (Azur Environmental), in order to determine of EC50val-ues of the reaction compounds.
With hydrogen; In water; at 30℃; under 760.051 Torr;
Two replicates of each hydrodechlorination run were carried out in a continuous basket stirred tank reactor (Carberry SpinningCatalyst Basket) from Autoclave Engineers, provided with temperature, pressure and gas flow control. The aqueous solution of each organochlorinated reactant was fed to the reactor at 4 mL/minand H2 was continuously passed at 50 N mL/min. A catalyst loading of 2.95 g/L was always used, so that the space-time was fixedat 2.95 kgcath/molCl. All the experiments were performed at 30C, atmospheric pressure and 600 rpm stirring velocity. The progress of the reaction was followed by analyzing periodically samples of the exit liquid stream taken with a fraction collector (FC203B-Gilson) along the 100 h on stream of the experiments. The data reproducibility was better than ±5%.
3) The sodium phenate solution and sodium chloroacetate aqueous solution at a molar ratio of 1.0: 1.0 while dropping with a heating jacket The tube of constant pressure funnel, at about 95 reaction, the retention time was maintained at 15min,The reaction solution was then overflowed into a three-necked flask equipped with dilute hydrochloric acid at 15 C,With dilute hydrochloric acid adjusted pH = 5, and then stirred at 25 C for 1 hour,Filtered by suction to give 73.8 g of white crystalline powder, HPLC = 98.3%, yield 96.2%.
With hydrogenchloride; In water;pH 1;
General procedure: General procedure: To a solution of phenol or ring-substituted phenol (20 mmol) in water (20 mL) was added sodium chloroacetate (22 mmol) at rt. The mixture was heated and stirred at reflux for 8 h. The reaction mixture was cooled and the pH was adjusted to a value of 1.0 with 5 N HCl. The solution was filtered and the obtained solid was recrystallized from dehydrated ethanol to afford the pure product. 2-Phenoxyacetic acid (1a) Following the general procedure the compound 1a was obtained in 79 % yield as a white solid. m.p. 100-101 C. 1H NMR (400 MHz, CDCl3) delta 10.40 (s,1H), 7.31(t, J = 8.0 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 8.1 Hz, 2H), 4.68 (s,2H). MS (ESI) m/z: 151 [M-H]-. (S1)
With 1,3-diazido-propane In neat (no solvent) at 20℃; for 0.333333h;
General procedure forthe synthesis of alkyl esters from trialkylphosphite (3a-v)
General procedure: To a mixture oftrimethylphosphite/triethylphosphite (1.0mmol) and carboxylic acid (1.0mmol),1,3-diazidopropane (0.5mmol) was added slowly in a drop wise manner (to avoidaccumulation of azide) and the mixture was stirred at room temperature for10-20 minutes. (Caution As azides arepotentially explosive, all the reactions should be carried out behind a blastshield with personal protective equipment. In particular, the sequence of addition of thereactants should be strictly followed to avoid the accumulation of organicazides. This has been achieved in thepresent investigation by the slow drop wise addition of the bis azide to thereaction mixture containing trialkylphosphite during which the azide group isinstantaneously converted to iminophosphorane and hence no difficulty wasencountered). After the completion ofthe reaction (as monitored by TLC), the mixture was poured onto crushedice. Then the reaction mixture wasextracted with dichloromethane and the organic layer was dried over anhydrousNa2SO4. Thesolvent was removed and the residue was purified by column chromatography usingsilica gel as the adsorbent and petroleum ether: ethyl acetate (98:2) as themobile phase to afford the corresponding carboxylic esters (3a-v) as colourless oily liquids. Yield (71-80%)
N-(4-chloro-2-fluorophenyl)-2-phenoxyacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
N-(4-(N-(4-methylpyrimidin-2-yl)sulfamoyl)phenyl)-2-phenoxyacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
[1-(2,4-Dichloro-phenyl)-meth-(E)-ylidene]-(4-methoxy-phenyl)-amine[ No CAS ]
[ 122-59-8 ]
4-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine In dichloromethane at 20℃;
General procedure for the synthesis of 2-azetidinones (5a-m)
EEDQ (1.3 mmol) was added to a solution of the substituted acetic acid (1.3 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature, and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4) and filtered, and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from 95% EtOH. 4-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one (5b) White solid, mp 132-135 °C; IR (KBr) cm 1: 1755 (CO, β-lactam); 1H NMR (CDCl3) δ: 3.69 (s, 3H, OMe), 5.52 (d, 1H, J 4.9, H-4), 5.71 (d, 1H, J 4.9, H-3), 6.75-7.29 (m, 12H, ArH); 13C NMR (CDCl3) δ: 54.4 (OMe), 57.0 (C-4), 80.3 (C-3), 113.5, 114.8, 117.6, 121.5, 124.8, 126.3, 127.7,128.2, 128.7, 128.9, 133.2, 133.9, 155.7, 155.9 (aromatic carbons), 161.3 (CO, β-lactam). Anal. calcd. for C22H17Cl2NO3: C, 63.78; H, 4.14; N, 3.38. Found: C, 63.87; H, 4.28; N, 3.43.
94%
With triethylamine; N-tosylimidazole In dichloromethane at 20℃; Green chemistry;
Synthesis of 2-azetidinones (3-13); general procedure
General procedure: A mixture of Schiff base (1.0 mmol), triethylamine (5.0 mmol),carboxylic acid (1.3 mmol) and tosylimidazole (1.3 mmol) in dry CH2Cl2 (20 mL) was stirred at room temperature overnight. The mixture was washed successively with saturated NaHCO3 (20 mL) and brine (15 mL). The organic layer wasdried and the solvent was removed to give the crude product,which was purified by crystallisation from EtOH to give pure2-azetidinones 3-13.
88%
With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In dichloromethane at 20℃;
General Procedure for the Synthesis of 2-azetidinones
General procedure: 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT) (1.3 mmol) was added to a solution of corresponding carboxylic acid (1.3 mmol), corresponding imine (1.0 mmol) and triethylamine (5.0 mmol) in 20 mL dry CH2Cl2 at room temperature and the mixture was stirred overnight at room temperature. Then the organic solution was washed successively with saturated NaHCO3 (20 mL)and brine (20 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products which were purified by crystallization from 95% ethanol. Spectral data for 3a-k and 3n-o have been previously reported.
4-(2,4-dichlorophenyl)-1-(4-ethylphenyl)-3-phenoxyazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In dichloromethane at 20℃;
General Procedure for the Synthesis of 2-azetidinones
General procedure: 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT) (1.3 mmol) was added to a solution of corresponding carboxylic acid (1.3 mmol), corresponding imine (1.0 mmol) and triethylamine (5.0 mmol) in 20 mL dry CH2Cl2 at room temperature and the mixture was stirred overnight at room temperature. Then the organic solution was washed successively with saturated NaHCO3 (20 mL)and brine (20 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products which were purified by crystallization from 95% ethanol. Spectral data for 3a-k and 3n-o have been previously reported.
85%
With triethylamine; N-tosylimidazole In dichloromethane at 20℃; Green chemistry;
Synthesis of 2-azetidinones (3-13); general procedure
General procedure: A mixture of Schiff base (1.0 mmol), triethylamine (5.0 mmol),carboxylic acid (1.3 mmol) and tosylimidazole (1.3 mmol) in dry CH2Cl2 (20 mL) was stirred at room temperature overnight. The mixture was washed successively with saturated NaHCO3 (20 mL) and brine (15 mL). The organic layer wasdried and the solvent was removed to give the crude product,which was purified by crystallisation from EtOH to give pure2-azetidinones 3-13.
83%
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine In dichloromethane at 20℃;
General procedure for the synthesis of 2-azetidinones (5a-m)
General procedure: EEDQ (1.3 mmol) was added to a solution of the substituted acetic acid (1.3 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature, and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4) and filtered, and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from 95% EtOH.
With semicarbazide hydrochloride; In dichloromethane; at -45 - 20℃;
General procedure: An ozone-oxygen mixture (1 mol O3 per 1 mol of a double bond) was bubbled at a temperature specified in Table 1 through a solution of an olefin (10.0 mmol) in a mixture of CH2Cl2 (20 mL) and (5.7 mL). The reaction mixture was purged with argon. NH2C(O)NHNH2HCl (3.90 g (35.0mmol) per one double bond) was added at the same temperature. The reaction mixture was stirred at room temperature until peroxides disappeared (monitoring by means of the starch-iodine test), then CH2Cl2 and were distilled off. The residue was dissolved in CHCl3 (150 mL), washed with water (4 x 15 mL), dried with Na2SO4 and concentrated by evaporation.
2-(naphthalen-2-yloxy)-N'-(2-phenoxyacetyl)acetohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With Vilsmeier reagent; triethylamine In acetonitrile at 20℃; for 6h;
General procedure for synthesis of asymmetrical diacylhydrazines 17-26
General procedure: Acylhydrazines 2-5 (1.0 mmol) was added to a solution of carboxylic acid (1.5 mmol), Vilsmeier reagent (1.5 mmol) and Et3N (5.0 mmol) in dry CH3CN(15 mL) at room temperature and the mixture was stirred 6 h. Saturated NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3 9 15 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from ethanol 95 %. The data for 19 hasbeen previously reported [35].
With N-(1-chloroethylidene)-N-methylmethanaminium chloride; triethylamine In acetonitrile
N-(2-chloropyridin-3-yl)-1-(4-nitrophenyl)methanimine[ No CAS ]
[ 122-59-8 ]
1-(2-chloropyridin-3-yl)-4-(4-nitrophenyl)-3-phenoxyazetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With Vilsmeier reagent; triethylamine In dichloromethane at 20℃;
81%
With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In dichloromethane at 20℃;
General Procedure for the Synthesis of 2-azetidinones
General procedure: 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT) (1.3 mmol) was added to a solution of corresponding carboxylic acid (1.3 mmol), corresponding imine (1.0 mmol) and triethylamine (5.0 mmol) in 20 mL dry CH2Cl2 at room temperature and the mixture was stirred overnight at room temperature. Then the organic solution was washed successively with saturated NaHCO3 (20 mL)and brine (20 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products which were purified by crystallization from 95% ethanol. Spectral data for 3a-k and 3n-o have been previously reported.
80%
With Vilsmeier reagent; triethylamine In dichloromethane at 20℃;
N-(4-(4-bromophenyl) thiazol-2-yl)-2-phenoxyacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-(4-bromophenyl)-1,3-thiazol-2-amine; 2-phenoxyacetic acid With 2,6-dimethylpyridine In dichloromethane at 25 - 30℃; for 0.5h;
Stage #2: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 0 - 5℃;
11 4.1.2.3 General synthetic procedure for 4-Phenyl-2-Phenoxyacetamide Thiazoles analogues (8a-ab)
General procedure: Phenoxyacetic acids (4a-j, 2mmol) in dry DCM (20ml) was stirred at 25-30°C, and then lutidine (3mmol) was added, followed by the addition of substituted amino-4-phenyl-1,3-thiazoles (2mmol). The reaction mixture was stirred at the same temperature for 30min, then cooled to 0-5°C and TBTU (2mmol) was added over a period of 30min maintaining the temperature below 5°C. The reaction mass was stirred overnight and monitored by TLC using chloroform: methanol (9:1) as the mobile phase. The purity of the compounds was determined using high performance liquid chromatography (HPLC) by reversed phase agilent zorbax SB-C18 column method, with methanol (50%): acetonitrile (30%): water (20%) as mobile phase. The solvent was evaporated at reduced pressure, quenched by the addition of crushed ice and the obtained solid was filtered, dried and recrystallized from ethanol to afford compounds 8a-ab in good yield [supplementary files].
With ATP; 2-amino-2-hydroxymethyl-1,3-propanediol; coenzyme A; In water; at 21.0℃;Enzymatic reaction;
General procedure: Biotransformations were performed in vitro using CoA ligases (phi, PhCL, CBL and ipfF) in combination with N-acyltransferases (CASHT and HolE) as purified proteins. The enzyme activity was evaluated towards a small panel of acids and amines (figure 2 & 6). Reactions were prepared in 1.5 ml Eppendorf tubes according to table 9 and incubated overnight at 21 C with shaking 700 rpm in an Eppendorf thermomixer. Reactions containing no N-acyltransferase served as a negative control. A summary of the reactions evaluated is presented in table 10, the associated LC-MS traces for successful reactions which yielded amide product are shown in figure 9. There was a background chemical reaction between the CoA ester corresponding to acid 7 with amines 23, 30 and 32, which was observed in the negative control. There was no detectable increase over the background in the corresponding N-acyltransferase (HolE) reactions; therefore amines 23, 30 and 32 are not substrates for HolE. Nonetheless, sixteen of the reactions screened were successful and yielded structurally diverse amide products in good yields.
With ATP; 2-amino-2-hydroxymethyl-1,3-propanediol; coenzyme A; In water; at 21℃;Enzymatic reaction;
General procedure: Biotransformations were performed in vitro using CoA ligases (phi, PhCL, CBL and ipfF) in combination with N-acyltransferases (CASHT and HolE) as purified proteins. The enzyme activity was evaluated towards a small panel of acids and amines (figure 2 & 6). Reactions were prepared in 1.5 ml Eppendorf tubes according to table 9 and incubated overnight at 21 C with shaking 700 rpm in an Eppendorf thermomixer. Reactions containing no N-acyltransferase served as a negative control. A summary of the reactions evaluated is presented in table 10, the associated LC-MS traces for successful reactions which yielded amide product are shown in figure 9. There was a background chemical reaction between the CoA ester corresponding to acid 7 with amines 23, 30 and 32, which was observed in the negative control. There was no detectable increase over the background in the corresponding N-acyltransferase (HolE) reactions; therefore amines 23, 30 and 32 are not substrates for HolE. Nonetheless, sixteen of the reactions screened were successful and yielded structurally diverse amide products in good yields.
Stage #1: 2-phenoxyacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile for 0.5h;
Stage #2: 7-(diethylamino)-4-(hydroxymethyl)-2H-chromen-2-one In acetonitrile at 20℃; for 48h;
4.3 (3) Synthesis of CM-0-PEA
Into a 50mL round bottom flask, added the phenoxyacetic acid (PEA, 91.3mg, 0.60mmol), EDC• HC1 (90.0mg, 0.47mmol), acetonitrile (25mL) in proper order, after stirring for 10 minutes add 7-diethylamino-4-hydroxymethylcoumarin (CM-OH, 100mg, 0.40mmol), the reaction was carried out at room temperature for 48 hours, and after the reaction was completed, it was dried, obtained yellow solid was separated by column chromatography, and then obtained 44.0mg of light yellow product, yield is 28.0%.
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