* 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：
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[9] Asian Journal of Chemistry, 2012, vol. 24, # 6, p. 2739 - 2743
[10] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 599 - 613
[11] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 1873 - 1885
6
[ 50-84-0 ]
[ 5292-39-7 ]
[ 652-12-0 ]
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7
[ 50-84-0 ]
[ 201230-82-2 ]
[ 89-20-3 ]
[ 100-21-0 ]
[ 528-44-9 ]
[ 1967-31-3 ]
[ 74-11-3 ]
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8
[ 50-84-0 ]
[ 19719-28-9 ]
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[ 50-84-0 ]
[ 6306-60-1 ]
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[ 57479-70-6 ]
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[ 12775-96-1 ]
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[ 2736-23-4 ]
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13
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[ 74-11-3 ]
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[ 5106-98-9 ]
[ 56363-84-9 ]
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With dicobalt octacarbonyl; tert-butylisonitrile In acetonitrile at 80℃; for 4 h;
0.5 mmol (0.0955 g) of 2,5-dichlorobenzoic acid, 0.75 mmol (0.2011 g) of 2-bromothiophenesulfonyl azide and 0.025 mmol (0.0086 g) of octacarbyldicobalt were weighed, respectively.Add to a 25 mL reaction tube;Then, 4 mL of acetonitrile solvent, 100 μl of t-butyl isocyanide measured by a micro syringe was sequentially added to the above reactor, and the whole reaction system was stirred at 80 ° C for 4 hours;After the completion of the reaction, the mixture was concentrated by rotary evaporation, and the mixture was applied and separated by column chromatography (column separation conditions: 200-300 mesh silica gel powder, mobile phase ethyl acetate: petroleum ether = 1:4, yielding 0.1583 g The object product was obtained as a white solid in a yield of 76percent.
Reference：
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[2] Chemistry - A European Journal, 2012, vol. 18, # 45, p. 14444 - 14453
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[4] Patent: CN108558822, 2018, A, . Location in patent: Paragraph 0035; 0036; 0037; 0040; 0043
18
[ 53595-65-6 ]
[ 50-84-0 ]
[ 519055-62-0 ]
Yield
Reaction Conditions
Operation in experiment
65%
With dmap; 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 20℃; for 1 h;
DCM (2.0 mL) was added to a 20 mL vial containing DMAP (3.81 mg, 0.031 mmol), 2-chloro-1-methylpyridin-1-ium iodide (0.191 g, 0.748 mmol), 2,4-dichlorobenzoic acid (0.119 g, 0.623 mmol), 5-bromothiophene-2-sulfonamide (0.302 g, 1.25 mmol) at rt. After stirring for 5 min, TEA (0.261 ml, 1.869 mmol) was slowly added to the reaction mixture. The reaction was stirred at rt for 1 h. The reaction solvent was concentrated under vacuum and the crude residue was taken up in ethyl acetate, washed with 1N HCl (1 mL), water, and brine. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel flash column chromatography eluting with ethyl acetate in hexane from 0 to 30percent to give the desired product (0.168 g, 65percent) as colorless crystals: 1H NMR (499 MHz, CDCl3) δ 7.73 (d, J = 4.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.14 (d, J = 4.1 Hz, 1H).
With pyridine; water; potassium carbonate for 0.25h; sonication;
88%
With pyridine; copper; potassium carbonate In water for 2h; Heating;
With copper(l) iodide; copper; potassium carbonate at 180℃;
With barium dihydroxide; water; copper at 160 - 170℃;
Stage #1: 2,4 dichlorobenzoic acid With sodium carbonate In water at 50 - 75℃;
Stage #2: at 100℃; for 4h;
Stage #3: With hydrogenchloride In water at 20℃;
15
Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicated in Table 6 was stirred with a solution of 3 mmol Na2CO3 at 50-75° C. until all of the halogen-substituted benzoic acid was dissolved. Subsequently, 0.02 mmol CuSO4 and 0.04 mmol rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1 mL deionized water were added and the reaction mixture was heated at 80-100° C. for 4 h. After cooling to ambient temperature the reaction mixtures were carefully acidified with 35% aqueous HCl.In isolation method A, the products were extracted from the aqueous layer twice with ethyl acetate, the ethyl acetate fractions were combined and the crude reaction product was isolated by evaporation of ethyl acetate under vacuum. In isolation method B, the products were isolated by filtration, washed with water and dried under vacuum. The crude reaction product was analyzed by 1H NMR (d6-dmso). The results are summarized in Table 6. TABLE 6 Examples 8~23 Starting material Halogenated Benzoic Acid Isolation CONV SEL Example Benzoic Acid Product T (° C.) Method (%) (%) 8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro- 2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100 A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl- 12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo- 4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 15 2,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro- 2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A 74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99 dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro- 20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5- 2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5- 80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B 73 >99 bromo-
With dihydrogen peroxide for 0.0361111h; Microwave irradiation;
94%
With selenium(IV) oxide; dihydrogen peroxide In tetrahydrofuran for 18h; Heating;
93%
With polysterene-bound phenylseleninic acid; dihydrogen peroxide In tetrahydrofuran for 12h; Heating;
93%
With tert.-butylhydroperoxide In water at 70℃; for 3h; Green chemistry;
91%
With dihydrogen peroxide; toluene-4-sulfonic acid; β‐cyclodextrin In water at 50℃; for 15h;
General Procedure.
General procedure: To a solution of 30% hydrogen peroxide(5.0 mmol) was added aldehyde (1.0 mmol), PTSA(1.0 mmol) and β-cyclodextrin (0.1 mmol). The reactionmixture was stirred for 15 h at 50 oC. After cooling to roomtemperature, the reaction mixture was dissolved in the solutionof 10% aqueous sodium bicarbonate, extracted intodiethyl ether (2 × 25 mL), and washed with water. The aqueouslayer was acidified to pH 3 with 2 M hydrochloric acid.The product was extracted with dichloromethane (2 × 25mL) and dried over magnesium sulfate. Evaporation of organiclayer under reduced pressure gave the desired carboxylicacid.
87%
With sodium perborate In acetic acid at 45 - 50℃;
87%
Stage #1: 2,4-dichlorobenzaldeyhde With tin(II) oxide; dihydrogen peroxide In water; acetonitrile at 60℃; for 2h;
Stage #2: With hydrogenchloride In water
84%
With {methyl-2-[N-2-(acetonate)ethylidynenitrilo]ethyl}aminato(-1)-1-cyclopentene dithiocarboxylate nickel(II); dihydrogen peroxide In water; acetonitrile at 60℃; for 4h;
80%
With oxygen for 0.133333h; microwave irradiation;
79%
With dihydrogen peroxide In acetic acid at 90℃; for 7h;
71%
With sodium hydroxide In water at 20 - 75℃; for 24h;
2.4. Oxidation of aldehydes catalyzed by CuO(at)HPS
General procedure: In a two-necked round bottom flask equipped with a condenser, the aldehyde (1 mmol), was dropped into the mixture of catalyst (4 mol%) and NaOH (1.5 mmol) in deionized water (3 mL). The resulting mixture was stirred at room temperature under air atmosphere for 15 min and then the temperature reached 75 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered off and the catalyst rinsed with deionized water and ethanol. The filtrate was treated with H2SO4 (30 wt.%). The precipitated carboxylic acid was filtered, washed with water and dried in vacuum. (For liquid products after addition of H2SO4, the product was extracted using diethyl ether (4 × 5 mL).
With potassium permanganate; water; sodium carbonate
With potassium permanganate; magnesium sulfate
Multi-step reaction with 2 steps
1: hydrazine hydrate; hydrogenchloride / ethanol; water / 1 h / Reflux
2: [bis(acetoxy)iodo]benzene / tetrahydrofuran / 4 h / 20 °C / Green chemistry
42 mg
With oxygen In acetonitrile at 80℃; for 24h; Green chemistry;
1 Example 1
A solution of sulfuric acid (9.8 g, 0.1 mol) was added dropwise to a 100 mL round bottom flask and 2,4-dichlorobenzonitrile (17.2 g, 0.1 mol) was added dropwise. After completion of the dropwise addition, the reaction was carried out at 125 to 130 ° C for 2 hours,The reaction is finished, cooled to below 100 ° C, diluted with water, cooled to below 50 ° C, and the raw materials are removed by layering. The resulting solution is concentrated to about half by decompression,To obtain 17.38 g of 2,4-dichlorobenzoic acid in 91% yield.
With sodium bis(2-methoxyethoxy)aluminium dihydride; In diethyl ether; at 20℃; for 1h;
To a 100 mL round bottom flask was added 2,4-dichlorobenzoic acid (19.1 g, 0.1 mol) and ether (30 mL), followed byRed-Al (20.2 g, 0.1 mol),The reaction was stirred at room temperature for 1 h, filtered, and the residue was run three times with ether (5 mL x 3) The resulting organic phase was distilled to give 17.17 g of 2,4-dichlorobenzyl alcohol in 97% yield.
General procedure: To a mixture of the appropriate substituted benzoic acid (8.6 mmol) in methanol (10 mL) was added sulfuric acid (0.5 mL),and the mixture was heated overnight at 60 C. The reaction was then allowed to cool to room temperature, the solvent was reduced by evaporation, and the residue was diluted in cold water and neutralized with sodium hydrogen carbonate solution. The aqueous solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the title compound as oil.
With glycerol-based sulfonic acid functionalized carbon catalyst; for 6h;Reflux; Green chemistry;
General procedure: To a stirred solution of substituted aryl carboxylic acid 1 (0.15 mol) in methanol (0.75 mol) glycerol-based solid acid catalyst (28 wt% of aryl carboxylic acid) was added and heated to reflux for 6 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature. The catalyst was separated by filtration and was washed with methanol for recycle. Methanol was then distilled off under reduced pressure to get the pure methyl ester 2.
22.7 g
With sulfuric acid; for 18h;Reflux;
To a stirred solution of 2,4-dichlorobenzoic acid (20 g, 105 mmol) in methanol (200 mL) was drop-wise added concentrated sulfuric acid (2.0 mL) and the mixture was refluxed for 18 h. The solvent was evaporated under the reduced pressure. The residue was diluted with ice cold water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL), aqueous saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 22.7 g of the titled product. 1H NMR (300 MHz, DMSO-i delta 3.32 (s, 3H), 8.10 (d, J = 7.8 Hz, 2H), 8.30 (s, 1H); APCI-MS (m/z) 205 (M+H)+.
With aluminum oxide; aminosulfonic acid; urea for 0.1h; Irradiation;
Multi-step reaction with 3 steps
1: N,N-dimethyl-formamide; thionyl chloride / tetrahydrofuran / 5 h / Reflux
2: ammonium hydroxide / 1.5 h / -10 - 20 °C
3: trichlorophosphate / N,N-dimethyl-formamide / 5.5 h / -15 - 20 °C
Multi-step reaction with 2 steps
1.1: thionyl chloride / tetrahydrofuran / 1 h / 50 °C
1.2: 0.08 h / 0 °C
2.1: palladium diacetate; Selectfluor; acetonitrile / 18 h / 20 °C
In a round-bottom flask under N2 were introduced respectively 2,4-dichlorobenzoic acid (270 mg, 1.4 mmol), anhydrous THF (30 mL),DMF (4 drops) and oxalyl chloride (470 L, 5.6 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. In a round-bottom flask under N2 were introduced respectively 5-bromothiophene-2-sulfonamide (300mg, 1.2 mmol), EtOAc (10 mL), Et3N (300 L, 3.2 mmol) and DMAP (2mg, 0.02 mmol). A solution of 2,4-dichlorobenzoyl chloride, previously prepared in dried toluene (10 mL), was added via a syringe over 15min. The mixture was stirred for 5 h at 55 C under N2, cooled to room temperature and quenched with 0.5 M aqueous HCl solution (40 mL).The resulting mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were dried over anhydrous MgSO4, filteredand concentrated under reduced pressure. The crude residue was purifiedby silica gel chromatography using DCM as eluent to afford 1k.Yield: 300 mg (59%); yellow solid; mp 114-116 C.1H NMR (400 MHz, CDCl3): = 9.07 (br s, 1 H), 7.74 (d, J = 6.0 Hz, 1 H),7.73 (d, J = 1.6 Hz, 1 H), 7.45 (d, J = 1.9 Hz, 1 H), 7.36 (dd, J = 8.4, 2.0 Hz,1 H), 7.13 (d, J = 4.1 Hz, 1 H).13C NMR (100 MHz, CDCl3): = 162.2, 139.5, 138.6, 136.0, 132.5,131.9, 130.7, 130.5, 129.3, 128.2, 123.3.
N-[2,4-dichlorobenzoyl]-naphthalene-2-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
With dmap In dichloromethane
32 Example 32; N-[2,4-dichlorobenzoyl]-naphthalene-2-sulfonamide
An 8 mL reaction vial is charged with 0.39 mmol (1.5 eq) of 2,4-dichlorobenzoic acid. 2.0 mL of CH2Cl2 is then added to the acid.A stock solution of naphthalene-2-sulfonamide and DMAP in CH2Cl2 is made so that 0.26 mmol (1 eq) of the sulfonamide and 48 mg (0.39 mmol, 1.5 eq) of DMAP can be delivered to each reaction vial in 4.0 mL of stock solution.The 4.0 mL of stock solution is then added to the reaction vials containing the benzoic acid. The vials are capped and shook. At least 0.261 g (loading= 2.0 mmol/g, 0.52 mmol, 2.0 eq) of carbodiimide polystyrene resin is added to the reaction vials. The vials are rotated over the weekend. Thin layer chromatography is then conducted with 10% MeOH:CH2Cl2 as the eluant to access reaction mixtures.At least 0.77 g (4.5 eq, loading=1.53 mmol/g, 1.17 mmol)of MP-TsOH (sulphonated polystyrene resin that is the resin-bound equivalent to p-toluenesulfonic acid) is added to each reaction vial. The vials are rotated overnight. The resins are then filtered off and the reaction mixtures collected. The reaction mixtures are purified using reverse phase HPLC. ES(-)MS m/z 378, (M-H)- consistent with 2 Cl.
General procedure: A mixture of substituted benzoic acids (11a-g) (0.001M, 2.12g) and ethanol (20mL) were heated under reflux until the benzoic acid was dissolved in ethanol then few drops of concentrated H2SO4 was added to the mixture and reflux for 8h. The resulting mixture was cooled to room temperature and a saturated solution of sodium bicarbonate was added to the mixture to neutralise the benzoic acid. The precipitated product was filtered and washed with water and dried. The dried product was recrystallized with ethanol.
With sulfuric acid;Reflux;
General procedure: To a stirred solution of different benzoic acids (6.42 mmol) in ethanol (3 mL) was added H2SO4 (0.1mL) and heated to reflux for 6-10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain the respective ethyl benzoate derivatives.
With sulfuric acid;Reflux;
General procedure: We added dense H2SO4 (0.098g, 1mmol) to a solution of substituted benzoic acid (5mmol) in dry ethyl alcohol (10mL). The mixture was heated under reflux until completion (as monitored via TLC), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with 0.1M Na2CO3, brine, dried and concentrated, respectively. The crude products (intermediate 3) were used directly for the next step.
With sulfuric acid;Reflux;
General procedure: The different organic acid (0.02 mol; 1a-o) was taken in 200 mL roundbottom flask. 20 mL absolute ethanol (99%) was added to the flask andstirred for ten minutes to homogenize the reaction contents. Later on, 2.5 mLconcentrated sulphuric acid, an activator, was added and reaction contents wererefluxed for 3-4 hours. Thin layer chromatography was the technique used tomonitor the completion of reaction by using 1:4 ratio of n-hexane and ethylacetate as mobile phase. After maximum completion, reaction mixture wastreated with 10% aqueous Na2CO3 (pH 9-10) to neutralize the reaction mixtureand to remove unreacted free acid. To get the pure esters, solvent extraction ofneutralized reaction mixture was performed by 50 mL of CHCl3 in a separatingfunnel for 3-4 times. After that CHCl3 layer was separated from the lowerdensity aqueous layer and was distilled by using rotary evaporator to acquireethyl esters.
With sulfuric acid;Reflux;
General procedure: Aryl/aralkyl carboxylic acids (Ia-n) (0.032 mol)were homogenized in ethanol (99%, 30 mL) in a 250mL round bottom flask. Concentrated sulfuric acid(2.5 mL) was added in the mixture and set to reflux for3-5 h. TLC was developed for monitoring reactioncompletion. At maximum completion, the 10% aqueoussodium carbonate solution was poured to neutralizethe mixture up to pH of 9-10 after addition of 150mL distilled water. This step converted untreatedorganic acid and sulfuric acid into salts washed awayby aqueous layer. The esters were filtered or extractedby solvent extraction technique using 50 mL chloroformor diethyl ether from a separating funnel. Chloroform wasdistilled off to collect esters (IIa-n) [18, 19].
With sulfuric acid;Reflux;
General procedure: (Un)Substituted benzoic acid (IVa-n) (0.02 mol) was refluxed with 60 mL EtOH for 4-5 h in the presence of conc. H2SO4 (1.25 mL) in around-bottom flask (250 mL). TLC plates were used to monitor the reaction. Excess distilled water (150 mL) was added after reaction completion and pH was adjusted to 8-10 by 20% aq. Na2CO3 solution. The product was collected through sequential extraction with CHCl3 (20 mL × 3). Chloroform was distilled off to collect the product. In some cases, the product was collected through filtration. Esters (Va-n) were used in further synthesis [18, 19].
With sulfuric acid; at 80℃; for 7h;
General procedure: Taking 6a as an example, a mixture of benzoic acid (2.5 g,20.0 mmol), 4 mL sulfuric acid, and 50 mL ethanol was heated under reflux for 7 h (hour, h). After finishing the reaction, it was poured into water and extracted by ethylacetate, dried with anhydrous Na2SO4, and then the solventof the organic phase was evaporated under vacuum to give colorless liquid 4a. Then excess 80% N2H4·H2O and 15 mLof ethanol were added into the flask containing 4a, which was heated under reflux about 5 h. After the reaction was completed, it should be cooled into room temperature overnight and the white solid 5a was given after being filtered, washed with ethanol and dried in open air. Finally, 5a (1.4 g,8.0 mmol) was then subjected to substitution reaction with KOH (0.9 g, 15.6 mmol) and CS2(1.2 g, 15.0 mmol) togenerate intermediate 6a. At the same time, 6b-6m was synthesized by the methods described in the literature (Shi et al.2015; Du et al. 2013).
EXAMPLE 4 Using 2,4-dichloro benzoic acid and sodium cyanate A mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 430 gms of 2,4-dichlorobenzoic acid and 370 gms of sodium cyanate were heated to reflux and refluxed for 6 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was then washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-80 C. for a period of 2 hours under good agitation. It was then cooled to 0-5 C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane:methanol mixture to furnish 40 gms of pure oxcarbazepine.
With hydrogenchloride; dimethyl amine;copper(I) chloride; In methanol; ice-water; water;
EXAMPLE 2 Synthesis of 4-chloro-2-methoxybenzoic acid from 2,4-dichlorobenzoic acid Except for using 2.8 g of 2,4-dichlorobenzoic acid (14.6 mM), 0.75 g of cuprous chloride (7.5 mM) and 100 ml of methanol containing 20% dimethylamine (77 g), the same apparatus, reagents and procedures were employed for reaction as in Example 1. The reaction was followed by reversed-phase HPLC as in Example 1, and as a result, completion of the methanol reaction within two hours was confirmed. After the methanol was removed, 50 ml of water was added and heated in a bath temperature of 80 C., to turn the solution into a uniform mixture solution of green. The green solution was cooled in ice-water to a room temperature. Then, 1.2 ml of conc. HCl was added to consequently deposit needle-liuke crystal.
EXAMPLE 11 Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, and 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7- hexafluoro-1-[3H]-isobenzofuranone, 59.3 g (0.31 mol) of 2,4-dichlorobenzoic acid and 100 ml of xylene were charged, and the mixture was reacted at 150 C. for 12 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 32.8 g of tetrafluorophthalic anhydride. The yield was 72.05%.
(1) Methyl 2,4-dichlorobenzoate The synthesis was carried out according to the method of Example 7-(1). 2,4-Dichlorobenzoic acid (25.0 g), 1,2-dichloroethane (50 ml), methanol (40 ml), concentrated sulfuric acid (2.0 ml) were used as reagents to give 24.5 g of a colorless transparent liquid (yield 91%). IR (KBr): 3080, 2910, 1720, 1580, 1545 cm-1 1 H-NMR (CDCl3) delta: 3.87(3H, s), 7.57(1H, dd, J=8.4, 2.0 Hz), 7.78(1H, d, J=2.0 Hz), 7.86(1H, d, J=8.4 Hz)
The mother liquor, concentrated as in Example 2 to 700 g of water-free solution, and having a bromide and chloride content of 0.25 and 0.09 wt-%, respectively, was treated with 5.1 g of 50% hydrobromic acid, 73 g of water and 300 g of dichlorotoluene, and subjected to another oxidation reaction under the same conditions, resulting in 337 g of 2,4-dichlorobenzoic acid (95.1% of the theory).
(1) A mixture of 2,4-dichlorobenzoic acid (67.4 g), absolute methanol (135 ml), and copper powder (3.37 g) is refluxed for 6-7 hours while introducing gaseous dimethylamine. The reaction mixture is mixed with a large amount of water, acidified with hydrochloric acid, and shaken with ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is washed with isopropyl ether and filtered to give 2-methoxy-4-chlorobenzoic acid (43.6 g) as crystals melting at 139.5 to 141 C.
(i) Methyl 2,4-Dichlorobenzoate 2,4-Dichlorobenzoic acid (50g: Aldrich) was refluxed with thionyl chloride (250ml) for 1 hour. The solution was filtered and evaporated to drynesn under reduced pressure. The resulting oil was added dropwise to dry methanol (200ml) with stirring at room temperature. After 1 hour the resulting solution was evaporated to dryness under reduced pressure and the residue taken up in ether. The organic phase was washed twice with water, charcoaled filtered and dried over magnesium sulphate. Yield 40g of a yellow oil.
6-Chloro-pyridine-S-sulfonic acid 2,4-dichloro-benzoyl amide; l.l'-Carbonyl-diimidzole (4.22 g, 26 mmol) was added to a solution of 2,4- dichlorobenzoic acid (4.73 g, 24.8 mmol) in 100 ml dichloromethane the mixture was stirred for 30 minutes at room temperature and subsequently refluxed for 30 minutes. Then -chloro-pyridine-S-sulfonic acid amide (5.00 g, 26 mmol) and 1,8- diazabicylo[5.4.0]undec-7-en (3.96 g, 26 mmol) were added and the mixture was <n="18"/>stirred at room temperature overnight. After evaporation to dryness the residue was taken up with 100 ml ethyl acetate and washed with 1 M HCl and 1 M NaOH and the organic phase was dried over sodium sulphate and concentrated in vacuo. Flash chromatography (SiO2, heptane - ethyl acetate gradient) yielded 6.72 g of the title compound as a white solid, m/z = 365 (ES+), 363 (ES-).
Stage #1: 1-(2,4-dichlorophenyl)ethan-1-one With tert.-butylhydroperoxide; sodium hydroxide; tungsten(VI) oxide In water at 80℃; for 8h;
Stage #2: With hydrogenchloride In water
87%
With hydroxylamine hydrochloride; iodine In dimethyl sulfoxide at 100℃; for 5h;
80%
With Oxone; trifluoroacetic acid In 1,4-dioxane for 10h; Reflux; Green chemistry;
Benzoic Acid (3a); Typical Procedure from Acetophenone or Phenylacetylene
General procedure: To a mixture of acetophenone (100 mg, 1 equiv) or phenylacetylene (1 equiv) in dioxane (5 mL), Oxone (2 equiv) and TFA (2 equiv) were added. The mixture was then heated to reflux for 10 h and then cooled to r.t. H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were treated with sat. NaHCO3 solution and the aqueous layer was poured onto crushed ice and treated with 2 M HCl; a colorless solid precipitated out. The precipitate was filtered off and dried in vacuo to give benzoic acid (3a) after column chromatography (silica gel; EtOAc-hexane, 1:9) as a white crystalline solid; yield: 0.096 g (95%) from 1a; mp 122-123 °C.
60%
With copper(l) iodide; hydroxylamine hydrochloride; oxygen In dimethyl sulfoxide at 100℃; for 12h;
With dihydrogen peroxide In water at 22 - 25℃; for 11688h;
To 2, 4-dichlorobenzoic acid (2.76 g) in dry THF (100 ml) was added slowly via syringe with vigorous stirring at-78 C sec-butyllithium (1.4 M in cyclohexane, 23.7 ml). After 1 h at-78 C methyl iodide (1.17 ML) was added in one portion with vigorous stirring. The mixture was allowed to warm to 25 C over 4 h and water was added. After 5 min it was partitioned between aqueous HCI (1 M) and EtOAc. The organic layer was washed (brine), dried (MGS04), filtered and concentrated in vacuo to give a yellow oil (3 g) that was treated as described in procedure G3 (assuming 14.4 mmol substituted benzoic acid content). Column chromatography gave a yellow oil (3.0 g) which consisted of a mixture of compounds as judged by NMR. This material (using 3 g N-bromosuccinimide) was treated as described in procedure G2 to give, besides 3-BROMOMETHYL-2, 4-DICHLORO benzoic acid methyl ester (1.1 g) a colourless oil (1. 9 g) consisting of a mixture of compounds as judged by NMR, containing 2-bromomethyl-4, 6-dichlorobenzoic acid methyl ester. This material (estimated from NMR to contain 2.9 mmol substituted benzyl bromide) and 5- amino-2-methoxy phenol (0.48 g) in dry DMF (2 ml) were heated in a microwave reactor to 150 C for 12 min. The mixture was concentrated in vacuo, triturated with CH2CI- 2: EtOAc: petroleum ether 1: 1: 5 (ca. 15 ML), and then ca. 2 ML each of CH2CI2 and MeOH to give the title compound as an off-white solid (0.61 g). Additional material 0.06 g) was obtained from chromatography of the organic extracts: NMR ('H, d6-DMSO): 8 9.16 (s, 1H), 7.76-83 (m, 2H), 7.37 (s, 1H), 7.12 (d, 1H), 6.95 (d, 1H), 4.88 (s, 2H), 3.75 (s, 3H). MS (m/z) : 322 [M-H]- (2CI). Example 6: 5, 7-DICHLORO-2- 4-METHOXY-3- [2- (4-METHYL-PIPERIDIN-1-YL)-ETHOXY] PHENYL}- 2, 3-DIHYDROISOINDOL-1-ONE hydrochloride To 2, 4-dichlorobenzoic acid (0.96 g) in dry THF (30 mi) was added slowly via syringe with vigorous stirring at-78 C sec-butyllithium (1.3 M in cyclohexane, 9.2 ML). After 1 h at-78 C methyl iodide (0.44 ml) was added in one portion with vigorous stirring. The mixture was allowed to warm to 25 C over 4 h and water was added. After 5 min it was partitioned between aqueous HCI (1 M) and EtOAc. The organic layer was washed (brine), dried (MGS04), filtered and concentrated in vacuo to give a yellow oil that was treated as described in procedure G3 (assuming 5 mmol substituted benzoic acid content). Column chromatography gave a yellow oil (0.81 g) which consisted of a mixture of compounds as judged by NMR. This material (assuming 3.7 mmol content of the of substituted toluene) was treated as described in procedure G2 to give a colourless oil (0.59 g) consisting of a mixture of compounds as judged by NMR. Half of this material and 4-METHOXY-3- [2- (4- METHYL-PIPERIDIN-1-YL)-ETHOXY]-PHENYLAMINE HYDROCHLORIDE (P5,0. 65 MMOL) in dry DMF (1.3 ML) were heated in a microwave reactor to 150 C for 15 min. The mixture was concentrated in vacuo, and the residue submitted to column chromatography, follwed by conversion to the hydrochloride salt (G1) to give the title compound as a faint yellow solid (0.11 g): NMR ('H, d4-MeOH): 8 7.76 (d, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.24 (dd, 1H), 7.11 (d, 1H), 4.91 (s, 2H), 4.40 (t, 2H), 3.90 (s, 3H), 3.72-3. 79 (m, 2H), 3.57 (t, 2H), 3.11 (t, 2H), 1.90-2. 04 (m, 2H), 1.65-1. 82 (m, 1H), 1.44-1. 57 (m, 2H), 1.04 (d, 3H) (only data for major protonation isomer given). MS (M/Z) : 449 [MH] + (2CI).
General procedure: Substituted-5-phenyl-1, 3, 4-thiadiazol-2-amine (5)was synthesized by according to reportedliterature 2 Equimolar mixture of substituted benzoicacid and semicarbazide in 100ml round bottom flask,POCl3(13 ml) were added to it and heated at 75 0Cfor half an hour. After cooling down to roomtemperature then add water. The reaction mixturewas reflux for 4 hr, after cooling the mixture wasbasified to PH-8 by drop wise addition of 50 %NaOH solution under the stirring. The precipitatewas filtered and recrystallized from ethanol toobtained pure yield of compounds. 5-phenyl-1,3,4-thiadiazol-2-amine
4.1.3. General method for the preparation of compounds 4a-d
General procedure: An equimolar mixture (0.01 mol) of 4-amino-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (2) and the appropriate aromatic acid in POCl3 (10 mL) was refluxed for 8-10 h. The reaction mixture was cooled to room temperature and gradually poured onto ice cold water with stirring. The mixture was allowed to stand overnight and the solid separated out was filtered, treated with dilute NaOH solution and washed thoroughly with cold water. The solid obtained was filtered, dried and crystallized from ethanol.
With Au NCs/TiO2; oxygen; sodium hydroxide; In water; at 120℃; under 7500.75 Torr; for 6h;Autoclave; Green chemistry;
General procedure: The oxidation of alcohols was performed in an autoclave reactor equipped with a magnetic stirrer, thermocouple, automatic temperature controller and a pressure gauge. After the addition of desired amount of reactant, catalyst, water and NaOH, the autoclave was sealed. The atmosphere over the mixture was replaced with O2 for three times. Then the reactor was heated to the desired temperature with stirring. Subsequently, the pressure of O2 was charged to 1.0 MPa and kept constant during the reaction through feeding O2. When the reaction was finished, the reactor was cooled down to the ambient temperature. The reaction mixture was diluted with acetone to dissolve the products. After the catalyst was separated, the filtrate was acidified to pH of 2.0 by hydrochloric acid. The oxidation products were analyzed by gas chromatography equipped with a flame ionization detector. The isolated yield of carboxyl acid was obtained with the following procedure. The solvent of the mixture after acidification was removed through rotary evaporation. The pH of the residual was adjusted to 10.0 with NaOH (2.0 M), and then it was extracted with ethyl acetate for three times. The aqueous layer was acidified to pH 2.0 using HCl (6.0 M) and extracted with ethyl acetate. The organic layer was removed ethyl acetate through rotary evaporation to get the carboxylic acid. The carboxylic acid was dried overnight for calculation of the isolated yield.
70%
With tetra-N-butylammonium tribromide; In acetonitrile; at 20℃; for 24h;Irradiation;
General procedure: In a 50ml Pyrex round-bottom flask, a mixture of alcohol (1mmol), TBATB (10-20mg, 0.02-0.04mmol) in 10ml of CH3CN was exposed to blue or violet light LED irradiation at room temperature under an air atmosphere with stirring. The progress of the photocatalytic oxidation reaction was monitored by TLC on silica gel plates. The reaction mixture externally irradiated until the alcohol was completely consumed.
With tert.-butylhydroperoxide; In neat (no solvent); at 80℃; for 6h;Green chemistry;
General procedure: To a mixture of alcohol (1mmol) and electrospun PVA/Fe2O3/MoSB nanocomposite (0.005g), 0.6mmol t-BuOOH (57muL) was added under solvent free conditions and the reaction mixture was stirred at 80C for 6h.
With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃;
3.1.General procedure for compounds 3a-e.
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid 1a or its derivatives 1b-e (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 °C overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give yellow solid.
91.5%
Stage #1: 2,4 dichlorobenzoic acid; 3-methylantranilic acid With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide
1.1 1. Preparation of 2-((2-oxo-5-chlorophenyl)amino)-3-methylbenzoic acid
2,4-dichlorobenzoic acid (4.05 mmol) in dimethylformamide (50ml), and 2-amino-3-methylbenzoic acid (5.26mmol), potassium carbonate (8.10 mmol) and copper powder (2.03 mmol), then stirred overnight at 130°C , then the reaction mixture was cooled to 200ml of water was added, the mixture was adjusted with hydrochloric acid to give a pH of about 3, and the resulting precipitate was suction filtered and dried to give a pale yellow solid, 2-((2-oxo-5-chlorophenyl)amino)-3-methylbenzoic acid, yield 91.5%.
91.5%
With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃;
1.1 1. Preparation of 2 - ((2-carboxy-5-chlorophenyl) amino) benzoic acid methyl -3
2,4-dichlorobenzoic acid (0.618,4.05 dirty 1) in dimethylformamide (01 ^, 50.001111), and 2-amino-3-methylbenzoic acid (0. 79g, 5 . 26mmol), potassium carbonate (I. 12g, 8. lOmmol) and copper powder (0. 13g, 2. 03mmol), and then stirred at 130 ° C overnight, then the reaction mixture was cooled to 200ml of water was added , hydrochloric acid and the mixture was adjusted to give a pH of about 3, and the resulting precipitate was suction filtered and dried, to give a pale yellow solid, i.e., 2 - ((2-carboxy-5-chlorophenyl) amino) -3-methyl- benzoic acid.Yield 91.5%.
91.5%
With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃;
4.1. General procedure for compounds 3a-d.
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid derivatives 1a-d (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give solid powder.
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid 1a or its derivatives 1b-e (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 C overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give yellow solid.
98.9%
2,4-dichlorobenzoic acid (4.05 mmol) in dimethylformamide (50ml), and <strong>[3177-80-8]2-amino-3-methoxybenzoic acid</strong> (5.26mmol), potassium carbonate (8.10 mmol) and copper powder ( 2.03mmol), then stirred overnight at 130C , then the reaction mixture was cooled to 200ml of water was added, the mixture was adjusted with hydrochloric acid to give a pH of about 3, and the resulting precipitate was suction filtered and dried to give a pale as a yellow solid, 2-((2-oxo-5-chlorophenyl)amino)-3-methoxybenzoic acid, yield 98.9%
98.9%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
2,4-dichlorobenzoic acid (0.61g, 4.05mmol) in dimethylformamide (DMF, 50.00ml), and 2- Amino-3-methoxybenzoic acid (0.88g, 5.26mmol), potassium carbonate (1.12g, 8.10mmol) and copper powder (0.13g, 2.03 mmol), then stirred at 130 C overnight, then the resulting reaction mixture was cooled and added to 200ml Water, hydrochloric acid and the resulting mixture was adjusted to about pH 3, and the resulting precipitate was suction filtered and dried to give a pale yellow The solid, i.e., 2 - ((2-oxo-5-chlorophenyl) amino) -3-methyl-benzoic acid. Yield 98.9%.
98.9%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid derivatives 1a-d (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give solid powder.
2-((2-carboxy-5-chlorophenyl)amino)-3-(trifluoromethyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.1%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid 1a or its derivatives 1b-e (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 °C overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give yellow solid.
67.1%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
2,4-dichlorobenzoic acid (0.61g, 4.05mmol) in dimethylformamide (DMF, 50.00ml), and 2- Amino-3-trifluoromethylbenzoic acid (1.08g, 5.26mmol), potassium carbonate (1.12g, 8.10mmol) and copper powder (0.13g, 2.03mmol), Then at 130 ° C under stirring overnight, then the reaction mixture thus obtained was added to a 200 ml of water, hydrochloric acid and the resulting mixture was adjusted to about pH 3, and the resulting precipitate was suction filtered and dried to give a pale As a yellow solid, i.e., 2 - ((2-oxo-5-chlorophenyl) amino) -3-trifluoromethylbenzoic acid, yield-67.1percent .
2-((2-carboxy-5-chlorophenyl)amino)-3,5-dichlorobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45.6%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid 1a or its derivatives 1b-e (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 C overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give yellow solid.
45.6%
2,4-dichlorobenzoic acid in dimethylformamide (50ml) in(04.05mmol), <strong>[2789-92-6]2-amino-3,5-dichlorobenzoic acid</strong> (5.26mmol), potassium carbonate (8.10 mmol) and copper powder (2.03mmol), then stirred overnight at 130C , followed by reaction of the resulting after cooling the mixture was added to 200ml of water, hydrochloric acid and the mixture was adjusted to a pH of about 3 is obtained, and the resulting precipitate was suction filtered and dried, to give a pale yellow solid, 2-((2-oxo-5-chlorophenyl)amino)-3,5-dichlorobenzoic acid, a yield of 45.6%.
45.6%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
2,4-dichlorobenzoic acid (0.61g, 4.05mmol) in dimethylformamide (DMF, 50.00ml), and 2- Amino-3,5-dichlorobenzoic acid (1.08g, 5.26mmol), potassium carbonate (1.12g, 8.10mmol) and copper powder (0.13g, 2.03 mmol), then stirred at 130 C overnight, then the resulting reaction mixture was cooled and added to 200ml Water, hydrochloric acid and the resulting mixture was adjusted to about pH 3, and the resulting precipitate was suction filtered and dried to give a pale yellow The solid, i.e., 2 - ((2-oxo-5-chlorophenyl) amino) -3,5-dichlorobenzoic acid, 45.6% yield.
45.6%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid derivatives 1a-d (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give solid powder. 4.1.1. 2-((2-carboxy-5-chlorophenyl)amino)-3,5-dichlorobenzoic acid (3a) Yield 45.6%; 1H NMR (400 MHz, DMSO-d6) delta 13.36 (s, 2H), 10.10 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.5, 1.9 Hz, 1H), 6.34 (d, J = 1.8 Hz, 1H).
(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl 2,4-dichlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: The vacuum dried intermediate 3 (0.002 mol) was then reacted with mono- and di-substituted benzoic acids (0.003 mol) separately in presence of anhydrous potassium carbonate (0.003 mol) in DMF (10 mL). The reaction mixture was stirred at room temperature for about 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and allowed stir for 10 min. The solid obtained was filtered and washed successively with distilled water and recrystallized from ethanol to obtain4(a?n).
General procedure: 5.1.5 1-[3-(Trifluoromethyl)benzoyl]piperazine (8a) A solution of 3-(trifluoromethyl)benzoic acid (9.5 g, 0.05 mol) and CDI (8.90 g, 0.055 mol) was stirred in 30 ml anhydrous THF at room temperature for 30 min. In a separate round bottom flask added piperazine (10.76 g, 0.125 mol) and <strong>[142-64-3]piperazine dihydrochloride</strong> (20 g, 0.125 mol) in 60 ml of water. The reaction mixture was stirred for 5 min and added 14 g NaCl. Then add the brine solution to the round bottom flask containing acyl imidazole and stir the reaction mixture for 5 h. The mixture was filtered and the filtrate distilled by rotary evaporation to remove THF. The aqueous layer was washed with ethyl acetate (3 * 10 ml) to remove diacylated product. The pH of the aqueous layer was adjusted to about 9 using saturated solution of NaOH and washed with ethyl acetate (4 * 30 ml). The organic layer was washed with water (4 * 25 ml), dried over anhydrous Na2SO4 for overnight, concentrated by rotary evaporation and purified by flash chromatography to afford 1-[3-(trifluoromethyl) benzoyl]piperazine as colorless solid (6.5 g, 50%). The intermediate compounds 1-(3-fluorobenzoyl)piperazine (8b), 1-(3-methoxybenzoyl)piperazine (8c), 1-(4-tert-butylbenzoyl)piperazine (8d), N,N-dimethyl-3-(piperazin-1-ylcarbonyl)aniline (8e), 1-(4-bromobenzoyl) piperazine (8f) and 1-(2,4-dichlorobenzoyl) piperazine (8g) were prepared by commercially available materials 3-fluorobenzoic acid, 3-methoxybenzoic acid, 4-tert-butylbenzoic acid, 3-(dimethylamino) benzoic acid, 4-bromobenzoic acid and 2,4-dichlorobenzoic acid respectively using the similar procedure of 1-[3-(trifluoromethyl)benzoyl]piperazine (8a) described above.
2,4-dichloro-N-(3,5-di-tert-butyl-4-hydroxyphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 6h;
General procedure: 5.1.23 2,4-Dichloro-N-(3,5-di-tert-butyl-4-hydroxyphenyl)benzamide (3b) Compound 3b was prepared in a similar manner to that described in the synthesis of compound 2a with <strong>[950-58-3]4-amino-2,6-di-tert-butylphenol</strong> 12b instead of 2-(tert-butyl)benzene-1,4-diol 7 as starting material with a 92% yield as a white solid. ESI(+)-MS (m/z): 394.2 [M+H]+; 1H NMR (400 MHz, CDCl3): delta 7.76 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.45 (s, 2H), 7.38 (dd, J = 8.3, 1.9 Hz, 1H), 5.18 (s, 1H), 1.48 (s, 18H).; 5.1.2 3-(tert-Butyl)-4-hydroxyphenyl cinnamate (2a) Compound 2a was prepared in a similar manner to that described in the synthesis of compound 1 with the cinnamic acid instead of 2,4-dichlorobenzoic acid with a 85% yield as a white solid.; 5.1.1 3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) 2,4-Dichlorobenzoic acid 6a (190 mg, 1 mmol) and 2-(tert-butyl)benzene-1,4-diol 7 (166 mg, 1 mmol) were dissolved in DCM (5 mL) with stirring. Then EDCI (210 mg, 1.1 mmol), DIEPA (400 mg, 3 mmol), and DMAP (12 mg, 0.1 mmol) were added in the system. After stirring 6 h, the mixture was diluted with DCM (15 mL), washed with water (10 mL) and brine, and dried to yield the crude product. The crude product was purified with column chromatography (petroleum ether (60-90 C)/acetone) on silica gel to afford the desired products 1 (200 mg, 63%).
2,4-dichloro-N-(4-hydroxy-3-isopropylphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 6.0h;
General procedure: 5.1.24 2,4-Dichloro-N-(4-hydroxy-3-isopropylphenyl)benzamide (3c) Compound 3c was prepared in a similar manner to that described in the synthesis of compound 2a with <strong>[16750-66-6]4-amino-2-isopropylphenol</strong> 12c instead of 2-(tert-butyl)benzene-1,4-diol 7 as starting material with a 88% yield as a white solid. ESI(+)-MS (m/z): 324.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta 10.22 (s, 1H), 9.47 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.64-7.49 (m, 2H), 7.43 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.6, 2.1 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 3.21 (m, 1H), 1.15 (d, J = 6.9 Hz, 6H).; 5.1.2 3-(tert-Butyl)-4-hydroxyphenyl cinnamate (2a) Compound 2a was prepared in a similar manner to that described in the synthesis of compound 1 with the cinnamic acid instead of 2,4-dichlorobenzoic acid with a 85% yield as a white solid.; 5.1.1 3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) 2,4-Dichlorobenzoic acid 6a (190 mg, 1 mmol) and 2-(tert-butyl)benzene-1,4-diol 7 (166 mg, 1 mmol) were dissolved in DCM (5 mL) with stirring. Then EDCI (210 mg, 1.1 mmol), DIEPA (400 mg, 3 mmol), and DMAP (12 mg, 0.1 mmol) were added in the system. After stirring 6 h, the mixture was diluted with DCM (15 mL), washed with water (10 mL) and brine, and dried to yield the crude product. The crude product was purified with column chromatography (petroleum ether (60-90 C)/acetone) on silica gel to afford the desired products 1 (200 mg, 63%).
2,4-dichloro-N-(4-hydroxy-3-methylphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 6h;
General procedure: 5.1.26 2,4-Dichloro-N-(4-hydroxy-3-methylphenyl)benzamide (3e) Compound 3e was prepared in a similar manner to that described in the synthesis of compound 2a with 4-amino-2-ethylphenol 12e instead of 2-(tert-butyl)benzene-1,4-diol 7 as starting material with a 91percent yield as a white solid. ESI(+)-MS (m/z): 310.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta 10.20 (s, 1H), 9.19 (s, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.61-7.49 (m, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 2.11 (s, 3H).; 5.1.2 3-(tert-Butyl)-4-hydroxyphenyl cinnamate (2a) Compound 2a was prepared in a similar manner to that described in the synthesis of compound 1 with the cinnamic acid instead of 2,4-dichlorobenzoic acid with a 85percent yield as a white solid.; 5.1.1 3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) 2,4-Dichlorobenzoic acid 6a (190 mg, 1 mmol) and 2-(tert-butyl)benzene-1,4-diol 7 (166 mg, 1 mmol) were dissolved in DCM (5 mL) with stirring. Then EDCI (210 mg, 1.1 mmol), DIEPA (400 mg, 3 mmol), and DMAP (12 mg, 0.1 mmol) were added in the system. After stirring 6 h, the mixture was diluted with DCM (15 mL), washed with water (10 mL) and brine, and dried to yield the crude product. The crude product was purified with column chromatography (petroleum ether (60-90 °C)/acetone) on silica gel to afford the desired products 1 (200 mg, 63percent).
N-(3-(tert-butyl)-4-hydroxyphenyl)-2,4-dichlorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 6.0h;
General procedure: 5.1.22 N-(3-(tert-Butyl)-4-hydroxyphenyl)-2,4-dichlorobenzamide (3a) Compound 3a was prepared in a similar manner to that described in the synthesis of compound 2a with <strong>[4151-62-6]4-amino-2-(tert-butyl)phenol</strong> 12a instead of 2-(tert-butyl)benzene-1,4-diol 7 as starting material with a 87% yield as a white solid. ESI(+)-MS (m/z): 338.5 [M+H]+; 1H NMR (400 MHz, CDCl3): delta 7.70 (d, J = 8.4 Hz,1H), 7.68 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.4, 2.6 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 6.66 (d, J = 8.4 Hz,1H), 4.82 (s, 1H), 1.39 (s, 9H).; 5.1.2 3-(tert-Butyl)-4-hydroxyphenyl cinnamate (2a) Compound 2a was prepared in a similar manner to that described in the synthesis of compound 1 with the cinnamic acid instead of 2,4-dichlorobenzoic acid with a 85% yield as a white solid.; 5.1.1 3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) 2,4-Dichlorobenzoic acid 6a (190 mg, 1 mmol) and 2-(tert-butyl)benzene-1,4-diol 7 (166 mg, 1 mmol) were dissolved in DCM (5 mL) with stirring. Then EDCI (210 mg, 1.1 mmol), DIEPA (400 mg, 3 mmol), and DMAP (12 mg, 0.1 mmol) were added in the system. After stirring 6 h, the mixture was diluted with DCM (15 mL), washed with water (10 mL) and brine, and dried to yield the crude product. The crude product was purified with column chromatography (petroleum ether (60-90 C)/acetone) on silica gel to afford the desired products 1 (200 mg, 63%).
General procedure: To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 percent yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 % yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
8-chloro-3-(2,4-dichlorophenyl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With trichlorophosphate; In ethanol; at 140℃; for 0.25h;Microwave irradiation;
A CEM-designed 10-mL pressure-rated vial was charged with POCl3(2 mL), <strong>[89570-82-1]3-chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine</strong> (211 mg,1mmol), 4-methoxylbenzoic acid or analogous acid (1mmol). The mixture was irradiated in a CEM Discover Focused Synthesiser (150 W, 140C, 200 psi, 15min). The mixture was cooled to room temperature by passing compressed air through the microwave cavity for 2 min. It was poured into cold ice (40 mL) and the formed precipitate filtered. The crude solid was recrystallised from EtOH to give the title compound 2a and others. All the other compounds were synthesised according to the same procedure.
2-((2-carboxy-5-chlorophenyl)amino)-3-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.6%
Stage #1: 2,4 dichlorobenzoic acid; 3-nitroanthranilic acid With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide
11.1 1. Preparation of 2-((2-oxo-5-chlorophenyl)amino)-3-nitrobenzoic acid
2,4-dichlorobenzoic acid (4.05 mmol) in dimethylformamide (50ml), and 2-amino-3-nitrobenzoic acid (5.26mmol), potassium carbonate (8.10 mmol) and copper powder (2.03 mmol), then stirred overnight at 130°C , then the reaction mixture was cooled to 200ml of water was added, the mixture was adjusted with hydrochloric acid to give a pH of about 3, and the resulting precipitate was suction filtered and dried to give a pale yellow solid, 2-((2-oxo-5-chlorophenyl)amino)-3-nitrobenzoic acid, 59.6% yield
59.6%
With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃;
4.1. General procedure for compounds 3a-d.
General procedure: 2,4-dichlorobenzoic acid 2 (0.61 g, 4.05 mmol), anthranilic acid derivatives 1a-d (5.26 mmol), potassium carbonate (1.12 g, 8.10 mmol) and copper powder (0.13 g, 2.03 mmol) was stirred in DMF (30 mL) and heated at 130 overnight. The suspension was cooled to room temperature and water (40 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with water and the resulting solution was acidified with concentrated hydrochloric acid to a pH of 3-4. The resulting suspension was stirred for 30 minutes, and the precipitate was filtered and washed with water and then dried to give solid powder.
With water; palladium diacetate; triethylamine; triphenylphosphine In 1,4-dioxane at 110℃; for 2h; Flow reactor;
Ortho-substituted carbonylation in flow using a “tube-in-tube” reactor
General procedure: For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set at 0.125 mL/min, temperature of the reactor at 110 °C, pressure of CO at 15 bar with a back pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady state after which time the flow streams were switched to pass from the loops where the substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of 1,4-dioxane while the second loop (5 mL) was filled with a solution made from the ortho-substituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) in 5.8 mL of 1,4-dioxane. An Omnifit column filled with 1.71 cm3 (r = 0.33 cm, h = 5.00 cm) of cotton was positioned just before the back pressure regulator to trap any particulate matter formed to avoid blocking of the back pressure regulator. After the substrates were passed through the system, the outlet of the flow stream was directed into a receptacle where the excess carbon monoxide gas was vented off in the fume cupboard. The reaction mixture was then evaporated to dryness, ethyl acetate (25 mL) and sodium carbonate solution (2 M, 10 mL) were added and transferred to a separating funnel. After collecting the aqueous layer, the organic layer was extracted with sodium carbonate solution (2 M, 2 × 10 mL). The combined aqueous layers were acidified by the addition of 2 M HCl solution which was then extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over sodium sulfate, and the solvent evaporated under vacuum to give the crude product as a solid. The crude product was then recrystallised from the appropriate solvent.
With dmap; 2-chloro-1-methyl-pyridinium iodide; triethylamine; In dichloromethane; at 20℃; for 1h;
DCM (2.0 mL) was added to a 20 mL vial containing DMAP (3.81 mg, 0.031 mmol), 2-chloro-1-methylpyridin-1-ium iodide (0.191 g, 0.748 mmol), 2,4-dichlorobenzoic acid (0.119 g, 0.623 mmol), 5-bromothiophene-2-sulfonamide (0.302 g, 1.25 mmol) at rt. After stirring for 5 min, TEA (0.261 ml, 1.869 mmol) was slowly added to the reaction mixture. The reaction was stirred at rt for 1 h. The reaction solvent was concentrated under vacuum and the crude residue was taken up in ethyl acetate, washed with 1N HCl (1 mL), water, and brine. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel flash column chromatography eluting with ethyl acetate in hexane from 0 to 30% to give the desired product (0.168 g, 65%) as colorless crystals: 1H NMR (499 MHz, CDCl3) δ 7.73 (d, J = 4.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.14 (d, J = 4.1 Hz, 1H).
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃; for 12h;
4.1.2. General procedure for the synthesis of 4a-4u
General procedure: Trifluoroacetic acid anhydride (TFAA, 2 mmol) was added to a solution of 1-methoxynaphthalene 2 (1.5 mmol) and various commercial available aromatic carboxylic acid (1 mmol) in Trifluoroacetic acid (TFA, 1 mL) and stirred at room temperature for 12 h. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by chromatography to give the desired products 4a-4u. Spectral data of all title compounds (4a-4u) were provided in Supplementary Material.
[Cd(isonicotinamide)2(2,4-dichlorobenzoate)2(H2O)2][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.42%
In methanol; ethanol at 20℃; for 2h;
2.3.2. Synthesis of [Cd(inic)2(L2)2(H2O)2] (2)
A solution of Cd(CH3COO)2 2H2O (27.0 mg, 0.100 mmol)in 6mL of MeOH was added to an EtOH solution (12 mL)containing 2,4-dichlorobenzoic acid (HL2) (38.2 mg,0.200 mmol) and isonicotinamide (24.4 mg, 0.200 mmol),under continuous stirring. The solution was stirred forabout 2 h at room temperature, the solution became turbid,then a few drops of conc. ammonia was added till the solution became clear completely. The clear solution was filteredinto the test tube, after several days colorless crystalsformed, which was filtered off, washed with EtOH and driedunder vacuum to afford 66.0 mg of the product. Yield:85.42% (Based on isonicotinamide). Elem. Anal.: Calc. forC26H22CdCl4N4O8 (772.68): C, 40.38; H, 2.85; N, 7.25%.Found: C, 40.34; H, 2.79; N, 7.21%. Infrared spectrum (KBrdisk, cm1): 3760w(OH), 3349w(as(NH)), 3230w(s(NH)),3148m, 3070m, 2934m, 2881m, 1682s, 1606s(as(CO2)), 1562m, 1519m, 1487m, 1447m, 1403s(s(CO2)), 1351m,1308m, 1266m, 1225m, 1181m, 1137m, 1092m, 1048m,1005m, 963m, 920m, 876m, 833m, 789m, 748m, 707m,664m, 629m, 607m.
(2,3,3-trimethylbutan-2-ylcarbamoyl)(2-(prop-2-ynyloxy)phenyl)methyl 2,4-dichlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 2,4‐dichlorobenzoic acid; o-(prop-2-ynoxy)-benzaldehyde With tetrabutylammonium bromide In ethanol at 20℃; for 1h; Inert atmosphere;
Stage #2: 1,1,3,3-tetramethylbutyl isocyanide In ethanol at 5 - 20℃; for 12h; Inert atmosphere;
3.2.1. General Procedure for the Synthesis of (2,3,3-trimethylbutan-2-ylcarbamoyl)(2-(prop-2-ynyloxy)phenyl)methyl substituted benzoate (Novel passeriniadducts) (4a-j)
General procedure: In a 100 ml RBF equipped with a hot magnetic stirrerwith the septum, the mixture of aromatic acid (1) (0.01 mol),2-(prop-2-ynyloxy)benzaldehyde (2) (0.01 mol) and tetrabutyl ammonium bromide (TBAB) (10 mol%) was added inethanol as the solvent; the mixture was stirred at RT (roomtemperature) under nitrogen atmosphere for 1.0 h. The reactionmixture was cooled to 5-10 oC temperature and 2-isocyano-2,3,3-trimethylbutane (3) (0.012 mol) was addedhastily under the same reaction conditions. The reaction wasoptimized with or without PTC and is well discussed in theresults and discussion part (Table 1). It was stirred for a further12 h at RT conditions under TLC monitoring [hexane(4): ethyl acetate (6)]. After completion of the reaction, thesolvent was distilled off under vacuum and column chromatography(30% Ethyl acetate and 70% Hexane) was performedfor the purification of the product.A similar procedure was followed to obtain other diverse adducts (4a-j) (Reaction Scheme 1). All the synthesized molecules were confirmed by MS, IR, PMR, CMR, and elemental analysis.
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