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Chemical Structure| 100-83-4
Chemical Structure| 100-83-4
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Product Details of [ 100-83-4 ]

CAS No. :100-83-4 MDL No. :MFCD00003368
Formula : C7H6O2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :122.12 Pubchem ID :-
Synonyms :
3-Hydroxybenzaldehyde

Calculated chemistry of [ 100-83-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 33.85
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.02
Log Po/w (XLOGP3) : 1.29
Log Po/w (WLOGP) : 1.2
Log Po/w (MLOGP) : 0.79
Log Po/w (SILICOS-IT) : 1.52
Consensus Log Po/w : 1.17

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.84
Solubility : 1.78 mg/ml ; 0.0145 mol/l
Class : Very soluble
Log S (Ali) : -1.67
Solubility : 2.59 mg/ml ; 0.0212 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.72
Solubility : 2.31 mg/ml ; 0.0189 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 100-83-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 100-83-4 ]

* 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.

  • Upstream synthesis route of [ 100-83-4 ]
  • Downstream synthetic route of [ 100-83-4 ]

[ 100-83-4 ] Synthesis Path-Upstream   1~95

  • 1
  • [ 110-89-4 ]
  • [ 100-83-4 ]
  • [ 73279-04-6 ]
YieldReaction ConditionsOperation in experiment
78% at 60 - 110℃; for 2 h; In a reaction flask equipped with a stirrer, a condenser and a thermometer, 2.4 g of 3-hydroxybenzaldehyde was added,It was dissolved in 40 mL of formic acid, stirred,4.2 g of piperidine was added at less than 60 ° C and heated to 110 ° C for 2 h after completion of the addition (TLC showed complete reaction).Cooled to 15 ° C after dilution with 150mL water, add 0.1g activated carbon decolorization, filtration,The solution was adjusted to pH 8.5 with a 12percent ammonia solution and crystallized at 10 ° C. The crystals were filtered off, washed with water and dried to give intermediate III-1 and yellow crystals 3.0 g in 78percent yield.
70% With sodium hydroxide; formic acid In <i>N</i>-methyl-acetamide; water; isopropyl alcohol Preparation 1
1-Piperidinomethyl-3-phenol
Piperidine (50 mL, 0.50 mole) was added dropwise to a stirred solution of 3-hydroxybenzaldehyde (30.0 g, 0.246 mole) in dimethylformamide (40 mL) with cooling to maintain the temperature below 45° C.
The solution was heated at 50° C. for 15 minutes then cooled to 40° C. A solution of formic acid (97percent, 25 mL. 0.64 mole) and water (2 mL) was added dropwise with stirring while the temperature was maintained at 40° C. with cooling.
The resulting stirred solution was heated slowly (vigorous gas evolution commenced at about 60° C.) to 110°-115° C. and maintained at that temperature for 1.5 hours.
The solution was cooled to 40° C. and was added to 300 mL of water at 0° C. with vigorous stirring.
Aqueous 25percent sodium hydroxide was added until the reaction mixture was at pH 9.4 and stirring was continued for 1.5 hours at ambient temperature.
The mixture was cooled to 0° C. over 1 hour and the solid was collected by filtration, washed thoroughly with water (0° C., 300 mL)), and dried in vacuo to give 43.7 g of the desired product.
The product was dissolved in 2-propanol (115 mL) by heating to reflux, filtered (washed through with 15 mL hot 2-propanol), and cooled slowly to 0° C. with stirring.
The solid was collected by filtration, washed with 2-propanol (0° C., 40 mL)) and dried in vacuo to give 32.96 g (70.0percent yield) of the title compound; m.p.=135°-137° C.
55% With sodium borohydrid; sodium carbonate In ethanol REFERENCE EXAMPLE 1
Synthesis of 3-(1-piperidinomethyl)phenol
In 800 ml of ethanol was dissolved 122 g of 3-hydroxybenzaldehyde and thereto was gradually added 210 g of piperidine.
To the mixture was added 38 g of sodium borohydride under cooling with ice and the mixture was stirred for 8 hours at room temperature.
The resulting mixture was concentrated at a reduced pressure.
To a residue were added ice-cold water and hydrochloric acid to render a solution acidic.
The solution was washed with diethyl ether.
An aqueous layer was made alkaline with addition of sodium carbonate and then extracted with ethyl acetate.
After removing the solvent, 106 g (yield 55percent) of 3-(1-piperidinomethyl)phenol was obtained in the form of white crystal.
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[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 4, p. 989 - 994
[3] ChemMedChem, 2015, vol. 10, # 1, p. 83 - 93
[4] Patent: CN103626722, 2016, B, . Location in patent: Paragraph 0049-0052
[5] Synthetic Communications, 1999, vol. 29, # 1, p. 15 - 20
[6] Patent: US4927970, 1990, A,
[7] Patent: US5401739, 1995, A,
[8] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3834 - 3837
[9] Journal of Pharmacology and Experimental Therapeutics, 1997, vol. 283, # 3, p. 1534 - 1543
[10] Patent: US4927970, 1990, A,
[11] Patent: US4767769, 1988, A,
[12] Patent: US4293557, 1981, A,
[13] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 3886 - 3890
[14] Patent: CN106883197, 2017, A, . Location in patent: Paragraph 0009
  • 2
  • [ 110-89-4 ]
  • [ 100-83-4 ]
  • [ 73279-04-6 ]
YieldReaction ConditionsOperation in experiment
84.7% With ammonia In hydrogenchloride; methanol; ethyl acetate (1)
Synthesis of 3-pyridinomethylphenol STR6
3-Hydroxybenzaldehyde (III) (0.246 mol, 30 g) was dissolved into 150 ml of methanol.
Piperidine (IV) (0.6 mol, 52 g) was added to the solution and the mixture was stirred at room temperature to dissolution.
To the solution was added under ice cooling sodium hydrogen borate (0.247 mol, 9.4 g) while stirring over 1 hour, followed by continued stirring for 1 hour at room temperature.
The reaction mixture was concentrated under vacuum.
The residue was dissolved in 200 ml of 3N hydrochloric acid and washed twice with 50 ml of ethyl acetate.
The water layer was alkalinized (pH 10) with about 50 ml of concentrated aqueous ammonia to deposit crystals.
The crystals were collected by filtration, washed with water, dried under vacuum, and recrystallized from a mixed solvent of acetone and n-hexane, to obtain 40 g of 3-piperidinomethylphenol (V) (yield: 84.7percent).
m.p. 135°-138° C.
Reference: [1] Patent: US5317026, 1994, A,
  • 3
  • [ 110-89-4 ]
  • [ 100-83-4 ]
  • [ 73279-04-6 ]
Reference: [1] Patent: US4318913, 1982, A,
  • 4
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  • [ 54881-49-1 ]
Reference: [1] Australian Journal of Chemistry, 2005, vol. 58, # 8, p. 565 - 571
[2] Patent: WO2017/127371, 2017, A1,
[3] Organic Letters, 2018, vol. 20, # 5, p. 1388 - 1391
  • 5
  • [ 100-83-4 ]
  • [ 824-98-6 ]
Reference: [1] Journal of the Chemical Society, 1935, p. 1533,1543
[2] Journal of the Chemical Society, 1935, p. 1533,1543
  • 6
  • [ 100-83-4 ]
  • [ 77-78-1 ]
  • [ 824-98-6 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1965, vol. 1, p. 1847 - 1857[2] Zhurnal Organicheskoi Khimii, 1965, vol. 1, # 10, p. 1815 - 1827
  • 7
  • [ 100-83-4 ]
  • [ 6705-03-9 ]
Reference: [1] Journal of the Chemical Society, 1925, vol. 127, p. 2171
  • 8
  • [ 72915-12-9 ]
  • [ 25561-30-2 ]
  • [ 100-83-4 ]
  • [ 354-38-1 ]
  • [ 55982-15-5 ]
Reference: [1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
  • 9
  • [ 100-83-4 ]
  • [ 618-49-5 ]
YieldReaction ConditionsOperation in experiment
50% With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 125℃; for 48 h; General procedure: Aldehyde (0.5mmol), NH2OH·HCl (0.6mmol) and Cs2CO3 (0.6mmol) were stirred at 125°C for 48h in a 3:1 mixture of DMSO–H2O (2mL) under air. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and treated with water (1mL). The resulting mixture was extracted with ethyl acetate (3×5mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate and hexane. The purified products were identified by 1H NMR spectra and the melting points comparison with the literature data.
Reference: [1] Tetrahedron, 2002, vol. 58, # 52, p. 10323 - 10328
[2] RSC Advances, 2014, vol. 4, # 27, p. 13782 - 13787
[3] RSC Advances, 2016, vol. 6, # 43, p. 37093 - 37098
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[5] Journal of Chemical Research - Part S, 2003, # 3, p. 176 - 178
[6] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7590 - 7593
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[8] Applied Organometallic Chemistry, 2018, vol. 32, # 6,
  • 10
  • [ 100-83-4 ]
  • [ 618-49-5 ]
  • [ 873-62-1 ]
Reference: [1] Synthesis, 2003, # 2, p. 243 - 246
  • 11
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  • [ 5020-41-7 ]
Reference: [1] Journal of the Chemical Society, 1935, p. 1533,1543
[2] Journal of the Chemical Society, 1935, p. 1533,1543
  • 12
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  • [ 10516-71-9 ]
Reference: [1] Tetrahedron Asymmetry, 2014, vol. 25, # 6-7, p. 578 - 582
  • 13
  • [ 100-83-4 ]
  • [ 1882-69-5 ]
Reference: [1] Journal of the Chemical Society, 1925, vol. 127, p. 2171
  • 14
  • [ 100-83-4 ]
  • [ 42454-06-8 ]
YieldReaction ConditionsOperation in experiment
25% With nitric acid In benzene The starting compound has formula V wherein R5 is H in this particular example.
3 g of 3-hydroxy benzaldehyde (formula V) are slowly added to 30 ml of nitric acid (d=1.17, 28percent solution).
The temperature of the solution is maintained between 35° C. and 45° C.
At the end of the addition, hydrolysis is performed and the reaction mixture is then allowed to stand at room temperature.
A yellow precipitate is so obtained; it is filtered and then refluxed in benzene (20 ml) during 15 to 20 minutes.
The insoluble part is taken off and recrystallized in water.
The 3-hydroxy 6-nitro benzaldehyde (formula VI) is recovered with a final yield of 25percent.
M.P. =167° C. (C7 H5 N O4, M=167).
25% Inert atmosphere 4.1.1
5-Hydroxy-2-nitrobenzaldehyde (5)
3-Hydroxybenzaldehyde (21 g, 0.17 mol) were slowly added to 200 ml of 28percent nitric acid.
Subsequently the mixture was neutralized with aqueous sodium hydroxide solution and stirred for 1 h at room temperature.
The resulting yellow precipitate was filtered and then dissolved in 150 ml of benzene.
This mixture was heated to reflux for 30 min and then cooled down to room temperature.
The insoluble material was recovered by filtration and recrystallized from water to deliver (5, 7.0 g, 42 mmol, 25percent) as yellow crystals.
Mp, 167-168 °C. 1H NMR (CDCl3): δ = 6.16 (br s, 1H), 7.13 (dd, 1H), 7.29 (d, 1H), 8.16 (d, 1H), 10.48 (s, 1H). LC-MS: Rt = 1.33 min; MS: m/z = 168 [M+1]+.
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[2] Patent: US5139707, 1992, A,
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 444 - 452
[4] Journal of the Chemical Society, 1925, vol. 127, p. 2171
[5] Journal of the Chemical Society, 1925, vol. 127, p. 876,877[6] Journal of the Chemical Society, 1926, p. 150
[7] Journal of the American Chemical Society, 1952, vol. 74, p. 4572,4575
[8] Chemische Berichte, 1914, vol. 47, p. 3048
[9] Justus Liebigs Annalen der Chemie, 1912, vol. 391, p. 44
[10] Chemische Berichte, 1901, vol. 34, p. 4000
[11] Chemische Berichte, 1901, vol. 34, p. 4001
[12] Tetrahedron Letters, 2002, vol. 43, # 18, p. 3449 - 3451
[13] Journal of Organic Chemistry, 1979, vol. 44, # 3, p. 409 - 412
[14] Journal of the American Chemical Society, 2012, vol. 134, # 31, p. 13103 - 13107
[15] Tetrahedron, 2010, vol. 66, # 38, p. 7544 - 7561
[16] Angewandte Chemie - International Edition, 2017, vol. 56, # 7, p. 1885 - 1889[17] Angew. Chem., 2017, vol. 129, # 7, p. 1911 - 1915,5
  • 15
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  • [ 42454-06-8 ]
  • [ 42123-33-1 ]
Reference: [1] Synthetic Communications, 2003, vol. 33, # 14, p. 2497 - 2503
  • 16
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  • [ 42454-06-8 ]
  • [ 704-13-2 ]
Reference: [1] Patent: DE20116, , ,
[2] Chemische Berichte, 1889, vol. 22, p. 2341
[3] Chemische Berichte, 1882, vol. 15, p. 2053,3052
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 1, p. 586,587
  • 17
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  • [ 20357-24-8 ]
Reference: [1] Chemische Berichte, 1882, vol. 15, p. 2055
[2] Journal of the Chemical Society, 1925, vol. 127, p. 2171
[3] Tetrahedron, 2010, vol. 66, # 38, p. 7544 - 7561
  • 18
  • [ 100-83-4 ]
  • [ 7310-94-3 ]
  • [ 56962-12-0 ]
YieldReaction ConditionsOperation in experiment
21.7%
Stage #1: With toluene-4-sulfonic acid In acetonitrile at 20℃; for 0.0833333 h;
Stage #2: With N-chloro-succinimide In acetonitrile at 20℃; for 2 h;
Intermediate 28a and 28b 2-chloro-5-hydroxybenzaldehyde (28a) and 4-chloro-3- hydroxybenzaldehyde ( To a solution of 3-hydroxybenzaldehyde (1 g, 10 mmol) in acetonitrile (50 mL) was added p- toluenesulfonic acid (3.4 g, 20 mmol) portionwise. The mixture was stirred at room temperature for 5 min, and NCS (1.33 g, 10 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The mixture was quenched with aqueous sodium thiosulfate, and diluted with ethyl acetate and brine. The organic layer was separated, dried, and concentrated to give the crude products which were purified by silica gel chromatography eluting with petroleum ether /ethyl acetate (10: 1 to 5: 1) to give 2-chloro-5-hydroxybenzaldehyde (340 mg, 21.7percent yield intermediate 28a) as yellow solid; 'H-NMR (CDC13) δ 10.43 (s, 1H), 7.54-7.56 (d, 1H), 7.30- 7.37 (m, 2H) and 4-chloro-3-hydroxybenzaldehyde (310 mg, 19.7percent yield, intermediate 28b) as yellow solid. ^- MR (CDC13) δ 10.43 (s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.06-7.09 (dd, 1H).
21.7% With N-chloro-succinimide; toluene-4-sulfonic acid In acetonitrile at 20℃; for 2 h; To a solution of 3-hydroxybenzaldehyde (1 g, 10 mmol) in acetonitrile (50 mL) was added p-toluenesulfonic acid (3.4 g, 20 mmol) portionwise.
The mixture was stirred at room temperature for 5 min, and NCS (1.33 g, 10 mmol) was added and the resulting mixture was stirred at room temperature for 2 h.
The mixture was quenched with aqueous sodium thiosulfate, and diluted with ethyl acetate and brine.
The organic layer was separated, dried, and concentrated to give the crude products which were purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (10:1 to 5:1) to give 2-chloro-5-hydroxybenzaldehyde (340 mg, 21.7percent yield intermediate 28a) as yellow solid; 1H-NMR 1H-NMR (CDCl3) δ 10.43 (s, 1H), 7.54-7.56 (d, 1H), 7.30-7.37 (m, 2H) and then 4-chloro-3-hydroxybenzaldehyde (310 mg, 19.7percent yield, intermediate 28b) as yellow solid. 1H-NMR 1H-NMR (CDCl3) δ 10.43 (s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.06-7.09 (dd, 1H).
Reference: [1] Patent: WO2014/143799, 2014, A2, . Location in patent: Page/Page column 391
[2] Patent: US2014/275528, 2014, A1, . Location in patent: Paragraph 0322; 0323
  • 19
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  • [ 7310-94-3 ]
  • [ 56962-10-8 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
  • 20
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  • [ 26066-16-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 21, p. 4812 - 4819
  • 21
  • [ 100-39-0 ]
  • [ 100-83-4 ]
  • [ 1700-37-4 ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; 3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). Benzyl bromide (3.21 mL, 27.1 mmol) was added to this suspension, and stirred for 14 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (5.16 g, 99percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 5.13 (2H, s), 7.24-7.25 (1H, m), 7.35-7.49 (8H, m), 9.98 (1H, s).
98% With potassium carbonate In acetonitrile for 3 h; Reflux [0284] In acetonitrile (50 mE) solvent, benzyl bromide (4.6 mE, 38.68 mmol) was added to a solution including 3-hy- droxybenzaldehyde (5.0 g, 40.94 mmol) and potassium carbonate (8.49 g, 61.43 mmol), and the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was distributed between methylene chloride and watet An organic layer was dried by using Mg504 and filtered. The filtrate was evaporated, and water was added to the resultant solid. The solid was filtered and washed with water to obtain Compound 123a (8.53 g, 98percent).[0285] ‘H NMR (500 MHz, DMSO-d5) ö 9.97 (s, 1H),7.54-7.5 1 (m, 3H), 7.47 (d, 2H, J=7.5 Hz), 7.40 (t, 2H, J=7.0 Hz), 7.37-7.32 (m, 2H), 5.19 (s, 2H); ‘3C NMR (100 MHz, DMSO-d5) ö 193.6, 159.5, 138.3, 137.3, 131.1, 129.1, 128.6, 128.4, 123.4, 122.4, 114.6, 70.1.
98% With potassium carbonate In acetonitrile for 3 h; Reflux In acetonitrile (50 mL) solvent, benzyl bromide (4.6 mL, 38.68 mmol) was added to a solution including 3-hydroxybenzaldehyde (5.0 g, 40.94 mmol) and potassium carbonate (8.49 g, 61.43 mmol), and the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was distributed between methylene chloride and water. An organic layer was dried by using MgSO4 and filtered. The filtrate was evaporated, and water was added to the resultant solid. The solid was filtered and washed with water to obtain Compound 123a (8.53 g, 98percent).
96% With potassium carbonate In acetonitrile at 20℃; [0043] In a 500 mL round-bottomed flask was added 3-hydroxybenzaldehyde (3.00 g, 24.57 mmol), potassium carbonate (6.80 g, 49.2 mmol), and benzyl bromide (2.92 mL, 24.57 mmol) in acetonitrile (150 mL) to give a brown suspension that was left stirring overnight at room temperature. The solvent was then evaporated, and the beige residue was diluted with water and extracted with ethyl acetate (3 x 75 mL). The organic layer was dried with magnesium sulfate and concentrated on a rotary evaporator. Purification by column chromatography (5percent ethyl acetate in hexanes) gave compound 1 as a white crystalline solid (5.0215 g, 23.66 mmol, 96percent). 1H NMR (400 MHz, CDC13) δ ppm 5.11 (s, 2 H) 7.32 - 7.52 (m, 9 H) 9.96 (s, 1 H). m/z 213 [M+H]+.
89% With potassium carbonate In acetonitrile at 20℃; for 14 h; To the solution of the 3-hydroxybenzaldehyde (1.43 g, 11.69 mmol) in acetonitrile were added benzyl bromide (2.0 g, 11.69 mmol) and potassium carbonate (3.23 g, 23.38 mmol) and stirred for 14 h at room temperature. After the completion of reaction, as indicated by TLC, solvent was removed in vacuo, the residue was diluted with water and extracted with ethyl acetate (3 × 20 mL). The separated organic layers were dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residual oil was purified by flash chromatography (n-hexane/ethyl acetate 95:5) to yield compound 14 (2.2 g, 89percent) as white solid; Rf = 0.54 (n-hexane/ethyl acetate 95:5); 1H NMR (400 MHz; CDCl3; TMS) δ 9.97 (1H, s), 7.32–7.48 (8H, m), 7.23–7.26 (1H, m), 5.12 (2H, s).
81.1% With potassium carbonate In ethanol REFERENTIAL EXAMPLE 2
Production of N-methyl-3-benzyloxybenzylamine hydrochloride
15.0 g of m-hydroxybenzaldehyde was dissolved in 200 ml of ethanol, and 25.0 g of potassium carbonate and 32 g of benzyl bromide were added.
With stirring, the mixture was heated under reflux for 6 hours.
After the reaction, the insoluble inorganic salts were removed by filtration.
The filtrate was evaporated under reduced pressure, and purified by silica gel column chromatography [Wakogel C-200, 150 g; hexane/chloroform=1/1] and then recrystallized from hexane to give 21.1 g (yield 81.1percent) of 3-benzyloxybenzaldehyde having a melting point of 56° to 57° C.
76% With caesium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere A mixture of benzyl bromide (1.4 g; 8.2 mmol), 3-hydroxybenzaldehyde (1 .0 g; 8.2 mmol) and Cs2CO3 (2.67 g; 8.2 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature under N2. After evaporation of solvent in vacuo, the residue was diluted to 20 ml with CH2CI2 , washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (1 .33 g; 76percent) as creamy foam. 1H-NMR (CDCI3 ) 5.1 1 (s, 2H); 7.2 - 7.48 (m, 9H); 9.96 (s, 1 H)
8.59 g With caesium carbonate In acetonitrile for 16 h; Reflux; Inert atmosphere 3-Hydroxybenzaldehyde (5.00 g, 0.041 mol) was dissolved in anhydrous acetonitrile (130 mL) under argon atmosphere. Cesium carbonate (20.01 g, 0.061 mol) was added and the suspension stirred for 5 min. Benzyl bromide (11.69 mL, 0.102 mol) was then added and the solution heated at reflux for 16 h. The solution was concentrated on rotary evaporator, water was added and the mixture was extracted with EtOAc. The organic phase was washed twice with water, once with brine, dried over MgSO4, filtered and concentrated. Water was added and the mixture was extracted with CH2Cl2. The crude product was purified by flash chromatography on silica gel with hexanes/EtOAc (80/20) to yield 3a as a white solid (8.59 g). 1H NMR δ (CDCl3) 5.13 (s, 2H, PhCH2O), 5.33 (s, 2H, COOCH2Ph), 7.35-7.50 (m, 9H, 2-CH, 4-CH, 5-CH, 6-CH and PhCH2O), 10.00 (s, 1H, PhCHO).

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  • 22
  • [ 100-44-7 ]
  • [ 100-83-4 ]
  • [ 1700-37-4 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate In ethanol for 6 h; Reflux A mixture of 3-hydroxybenzaldehyde (3 g, 24.59 mmol), benzyl chloride (4.1 mL, 35.79 mmol) and anhydrous K2CO3 (2.4 g, 17.39 mmol) in absolute EtOH (30 mL) was refluxed for 6 h. Then the reaction mixture was concentrated to dryness, redissolved in 10 mL of CH2Cl2 and washed with 5percent aqueous NaOH (3 × 10 mL). The organic layer was dried with anhydrous Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (hexane/EtOAc, 8:2) to afford 5.1 g of 3-benzyloxy-benzaldehyde (98percent) as a white solid. Mp: 54–56 °C; 1H NMR (300 MHz, CDCl3): δ = 9.85 (s, 1H, CHO), 7.32 (m, 9H, H-2, H-4, H-5, H-6, Ph), 5.11 (s, 2H, OCH2Ph); 13C NMR (75 MHz, CDCl3) δ 192.5 (CHO), 159.7 (C-3), 138.2 (C-1), 136.7 (C-1′), 130.5 (CH-5), 129.1 (CH-3′, CH-5′), 128.6 (CH-4′), 127.9 (CH-2′, CH-6′), 124.1 (CH-6), 122.6 (CH-4), 113.6 (CH-2), 70.6 (OCH2Ph); ESMS m/z (percent): 213 (100) [M+1]+.
84% With sodium carbonate In acetone Step 1
Preparation of 3-Benzyloxybenzaldehyde
24.2 g (0.2 mol) of 3-hydroxybenzaldehyde and 25.32 g (0.2 mol) of benzyl chloride were placed in 500 ml of acetone and 21.2 g (0.2 mol) of sodium carbonate was added thereto.
The resulting solution was stirred for 12 to 24 hours with heating, cooled to room temperature.
The solvent was removed under a reduced pressure and the residue thus obtained was washed with water and the extracted with ethyl acetate twice.
The organic layer was dried and the solvent was removed under a reduced pressure to obtain a residue.
The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9:1) as an eluent to obtain 35.6 g (yield 84percent) of the title compound as a colorless liquid.
1H-NMR (CDCl3, TMS) δ (ppm) 10.01 (s, 1H), 7.67-7.18 (m, 9H), 5.14 (s, 2H); MS (m/e): 212 (MW, 32), 121 (73), 91 (100).
79% With potassium carbonate; potassium iodide In ethanol for 4.5 h; Reflux A suspension of 3-hydroxy benzaldehyde 11, benzyl chloride 12, K2CO3 and KI in 50mL of EtOH was refluxed for 4.5h. After cooling the solid thus obtained was filtered and washed several times with H2O. The crude product was purified by column chromatography. Yield, 79percent; dull white solid; m. p. 77–78°C; Rf=0.61.
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YieldReaction ConditionsOperation in experiment
74% With palladium diacetate; potassium hydrogencarbonate; DL-Pro-NHMe In tert-Amyl alcohol at 120℃; for 24 h; Inert atmosphere General procedure: A mixture of arylaldehyde (0.1 g, 1 mmol), dihaloarene (0.565 g, 2 mmol), Pd(OAc)2 (0.022 g, 10.0 molpercent), N-phenylpicolinamide (L7, 0.019 g, 15.0 molpercent) and potassium hydrogen carbonate (0.5 g, 5 mmol) in tert-amyl alcohol (5.0 ml) was taken in 100.0 ml round bottom flask under N2 atmosphere and stirred for 120°C for 24 h. Progress of the reaction was monitored continuously by TLC with ethyl acetate: hexane (2:3) eluent system. After completion of reaction, crude was poured into crushed ice and then filter the reaction mixture. Filtrate then extracted with ethyl acetate (3 times). Organic layer was separated, dried (over anhydrous Na2SO4) and evaporated under reduced pressure and purified by column chromatography to obtain desired product. Characterization data of compounds 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3v and 3x were found exactly similar as reported in the literature (References of above compound are mentioned in Supplementary data).
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YieldReaction ConditionsOperation in experiment
91% With acetic acid; hydroxylamine-O-sulfonic acid In water at 50℃; for 6 h; General procedure: In a 10 mL round bottom flask at 0 °C, aldehyde (1.0 mmol, 1.0 equiv) and NH2OSO3H (1.1 mmol, 1.1 equiv) were dissolved in 4 mL of H2O with acetic acid (1.0 mmol, 1 equiv). The reaction was stirred at 50 °C for 6 h or until complete conversion by TLC. The reaction was quenched with aqueous 10percent NaHCO3 (1 mL) and the resulting mixture was extracted with EtOAc (3*10 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to afford the crude product. The product was directly characterized unless traces of impurities required purification by automated silica gel flash chromatography (three examples).
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YieldReaction ConditionsOperation in experiment
63% With bromine In dichloromethane at 35 - 40℃; 3-Hydroxybenzaldehyde (120g, 0.98 moles) was suspended in 2400 ML OF CH2CL2 in a 5L 4-neck round bottom flask equipped with overhead stirrer, temperature probe, addition funnel, and condenser. The mixture was heated to 35-40° C in order to dissolve the starting material. Bromine (52 mL, 1.0 moles, 1.02 eq. ) was added dropwise through the addition funnel at a rate which maintained the reaction temperature between 35-38° C. The mixture was then allowed to stir overnight at 35 C. THE mixture was slowly cooled to-5-0° C over two hours and then allowed to stir at that temperature for lh more. The solid which formed was then collected by filtration through a Buchner funnel and the filter cake washed with 400mL of a cold 1 : 1 CHZCHEPTANE solution. The gray solid was then dried in vacuo (0.2mm Hg) at room temperature. Yield = 124.3g (63percent).
55% at 15 - 22℃; Example 1; 2-bromo-5-hydroxybenzaldehyde (3) 3-hydroxybenzaldehyde (10 g, 81.9 mmol) was dissolved in glacial acetic acid (50 mL) and cooled at 15° C. To the stirred solution, bromine (15.7 g, 98.2 mmol) was added dropwise while keeping the temperature below 22° C. After overnight stirring at room temperature, the volatiles were removed under vacuum without heating; the residue was co-evaporated three times with hexane (15 mL) and taken up in warm chloroform. Upon cooling, 9.05 g of 2-bromo-5-hydroxybenzaldehyde 3 were obtained as a white solid in two crops. Yield 55percent.1H NMR (300 MHz, CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.10 (dd, J1=8.7 Hz, J2=3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5BrO2: 199.9472, found: 199.9463; mp: 132-134° C.
55% at 20℃; To a stirred solution of 1.5 g (12.3 mmol) of 3-hydroxybenzaldehyde in 10 mL of glacialacetic acid at 22C was added 2.35 g (14.7 mmol) of bromine so as to keep the temperatureat or below 22. After stirring overnight at r.t., the volatiles were removed underreduced pressure. The residue was washed with hexane (3 £ 15 mL) and then taken up inwarm chloroform. After cooling, a total of 1.35 g (55percent) of 2-bromo-5-hydroxybenzaldehyde2 was obtained in two crops. Mp: 132–134C, lit. mp 134 C.27 1H RMN(300 MHz, CD3COCD3) d ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J D 8.7 Hz, 1H),7.34 (d, J D 3.1 Hz, 1H), 7.10 (dd, J1 D 8.7 Hz, J2 D 3.1 Hz, 1H); 13C RMN (75 MHz,CD3COCD3) d ppm: 192.8 (CHO), 159.3 (C-5), 136.7 (C-6), 136.2 (C-1), 125.1 (C-4),117.3 (C-3), 117.2 (C-2); HRMS (EI) m/z: Calcd for C7H5BrO2: 199.9472. Found:199.9463.
55% With bromine In chloroform; acetonitrile at 20℃; for 4 h; Cooling with ice A suspension of 3-hydroxybenzaldehyde (48.85 g, 400 mmol) in a 10:1 mixture of chloroformlacetonitril (330 mL) was cooled with an ice bath. Then, bromine (63.9 g, 1 equiv) was added dropwise and the bath was removed to stir the mixture at room temperature. After 4 h, the reaction was quenched with a saturated NaHCO3 solution (150 mL). The phases were separated and the organic layer was washed with water (150 mL). The concentrated organic phase was filtered through a thin pad of Celite and eluted with a 4:1 mixture of dichloromethane/ethyl acetate. Solvent was removed in vacuo and the remaining solid was crystallized several times from ethyl acetate/hexane to give 44.15 g of 2-bromo-5- hydroxybenzaldehyde as light brown needles. Yield 55percent; mp: 132-134 °C. ‘H NMR (300 MHz, CD3COCD3) ö ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J= 8.7 Hz, 1H), 7.34 (d, J= 3.1 Hz, 1H), 7.10 (dd, J, = 8.7 Hz, J2 = 3.1 Hz, 1H); ‘3C NMR (75 MHz, CD3COCD3) ö ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI)mlz: calcd for C7H5BrO2: 199.9472, found: 199.9463.
50% With bromine; sodium carbonate In chloroform Preparation of 2-bromo-5-hydroxybenzaldehyde:
A solution of 4.2 ml of bromine (82 mmol) in 30 ml of chloroform is slowly added to a solution of 10 g of 3-hydroxybenzaldehyde (82 mmol) in 100 ml of chloroform.
The reaction solution is then combined with 50 ml of 6percent sodium carbonate solution and vigorously stirred.
Once neutralisation is complete, the phases are separated and the solvent removed from the organic phase.
The crude product is recrystallized with dilute acetic acid, whereupon 8.24 g of the product (7) are obtained as white needles at a yield of 50percent.

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YieldReaction ConditionsOperation in experiment
22% With tetrafluoroboric acid diethyl ether; [bis(pyridine)iodine]+ tetrafluoroborate In dichloromethane at 20℃; for 0.0833333 h; To a solution of 1.0 g (8.18 mmol) of 3-hydroxybenzaldehyde in 100 mL of dichloromethane,was slowly added 1.078 g (12.28 mmol) of HBF4¢OEt2 at r.t., followed by theaddition of 3.045 g (8.18 mmol) of IPy2BF4 bis(pyridyl)iodonium(I) tetrafluoroborate.The solution was stirred for 5 min at r.t., after which a solution of 15 mL of 1M HClwere added in 15 mL of water. The aqueous layer was extracted with dichloromethane (3£ 10 mL) and the combined organic layers were washed with 10 mL water and 25 mL5percent sodium thiosulfate aqueous solution and dried over Na2SO4. Removal of the volatilesunder reduced pressure afforded a brownish solid, which was recrystallized from chloroformto afford 443 mg (22percent) of 5-hydroxy-2-iodobenzaldehyde 4 as a brownish solid,mp. 130–132C, lit. mp. 125–126C.24 1H NMR (300 MHz, CD3COCD3): d 9.96 (s, 1H),9.15 (s, 1H), 7.85 (d, J D 8.6 Hz, 1H), 7.34 (d, J D 3.1 Hz, 1H), 6.98 (dd, J1 D 8.5 Hz, J2D 3.1 Hz, 1H); 1H RMN (300 MHz, CDCl3): d 9.99 (s, 1H), 7.79 (d, J D 8.4 Hz, 1H),7.45 (d, J D 3.0 Hz, 1H), 6.91 (dd, J1 D 8.4 Hz, J2 D 3.0 Hz, 1H), 6.18 (br s, 1H); 13CRMN (75 MHz, CD3COCD3): d 196.6 (CHO), 160.1 (C-5), 143.3 (C-3), 137.9 (C-1),125.4 (C-4), 118.1 (C-6), 88.5 (C-2); 13C RMN (75 MHz, CDCl3) d ppm: 196.3 (CHO),156.7 (C-5), 141.4 (C-3), 135.7 (C-1), 123.9 (C-4), 116.5 (C-6), 89.4 (C-2); HRMS (EI)m/z: Calcd for C7H5IO2: 247.9334. Found: 247.9292.
15.0 g With ammonium hydroxide; iodine; potassium iodide In water at 22 - 26℃; To a solution of 3-hydroxybenzaldehyde (16.0 g, 0.13 mmol) in aq. NH4OH (150 mL) wasslowly added a solution of ‘2 (37.2 g, 0.14 mmol) and 28percent Aq.KI (250 mL). The reactionmixture was stirred at rt for 3-4 h. The reaction mass was acidified with dil.HC1. The precipitated solid was filtered and dissolved in diethyl ether again filtered off insoluble part and concentrated the organic layer to afford 15.0 g of title product. ‘H NMR (300 MHz,DMSO-d6): 10.60 (br br s, 1H), 9.87 (s, 1H), 7.94-7.92 (d, J = 7.2 Hz, 1H), 7.30 (s, 1H),7.12-7.10 (d, J= 7.5 Hz, 1H); MS [M+Hj: 247.
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  • 53
  • [ 100-83-4 ]
  • [ 7310-94-3 ]
  • [ 56962-12-0 ]
YieldReaction ConditionsOperation in experiment
21.7%
Stage #1: With toluene-4-sulfonic acid In acetonitrile at 20℃; for 0.0833333 h;
Stage #2: With N-chloro-succinimide In acetonitrile at 20℃; for 2 h;
Intermediate 28a and 28b 2-chloro-5-hydroxybenzaldehyde (28a) and 4-chloro-3- hydroxybenzaldehyde ( To a solution of 3-hydroxybenzaldehyde (1 g, 10 mmol) in acetonitrile (50 mL) was added p- toluenesulfonic acid (3.4 g, 20 mmol) portionwise. The mixture was stirred at room temperature for 5 min, and NCS (1.33 g, 10 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The mixture was quenched with aqueous sodium thiosulfate, and diluted with ethyl acetate and brine. The organic layer was separated, dried, and concentrated to give the crude products which were purified by silica gel chromatography eluting with petroleum ether /ethyl acetate (10: 1 to 5: 1) to give 2-chloro-5-hydroxybenzaldehyde (340 mg, 21.7percent yield intermediate 28a) as yellow solid; 'H-NMR (CDC13) δ 10.43 (s, 1H), 7.54-7.56 (d, 1H), 7.30- 7.37 (m, 2H) and 4-chloro-3-hydroxybenzaldehyde (310 mg, 19.7percent yield, intermediate 28b) as yellow solid. ^- MR (CDC13) δ 10.43 (s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.06-7.09 (dd, 1H).
21.7% With N-chloro-succinimide; toluene-4-sulfonic acid In acetonitrile at 20℃; for 2 h; To a solution of 3-hydroxybenzaldehyde (1 g, 10 mmol) in acetonitrile (50 mL) was added p-toluenesulfonic acid (3.4 g, 20 mmol) portionwise.
The mixture was stirred at room temperature for 5 min, and NCS (1.33 g, 10 mmol) was added and the resulting mixture was stirred at room temperature for 2 h.
The mixture was quenched with aqueous sodium thiosulfate, and diluted with ethyl acetate and brine.
The organic layer was separated, dried, and concentrated to give the crude products which were purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (10:1 to 5:1) to give 2-chloro-5-hydroxybenzaldehyde (340 mg, 21.7percent yield intermediate 28a) as yellow solid; 1H-NMR 1H-NMR (CDCl3) δ 10.43 (s, 1H), 7.54-7.56 (d, 1H), 7.30-7.37 (m, 2H) and then 4-chloro-3-hydroxybenzaldehyde (310 mg, 19.7percent yield, intermediate 28b) as yellow solid. 1H-NMR 1H-NMR (CDCl3) δ 10.43 (s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.06-7.09 (dd, 1H).
Reference: [1] Patent: WO2014/143799, 2014, A2, . Location in patent: Page/Page column 391
[2] Patent: US2014/275528, 2014, A1, . Location in patent: Paragraph 0322; 0323
  • 54
  • [ 100-83-4 ]
  • [ 7310-94-3 ]
  • [ 56962-12-0 ]
  • [ 56962-10-8 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
  • 55
  • [ 100-83-4 ]
  • [ 100-58-3 ]
  • [ 22272-48-6 ]
Reference: [1] Patent: US2003/8882, 2003, A1,
  • 56
  • [ 100-83-4 ]
  • [ 42123-33-1 ]
  • [ 704-13-2 ]
YieldReaction ConditionsOperation in experiment
47% With isopropyl nitrate; sulfuric acid; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane at 20℃; for 0.25 h; To a stirring solution of 3- hydroxybenzaldehyde 23 (618 mg, 5.0 mmol) in dichloromethane (10 mL) was added tetrabutylammoniumhydrogen sulfate (85.0 mg, 0.25 mmol) and isopropyl nitrate (1.27 mL, 12.5 mmol). Concentrated sulfuric acid (610 μ) was added dropwise and the resulting reaction mixture was allowed to stir at room temperature for 15 minutes. The reaction contents were then transferred to a separatory funnel containing 50 mL of an aqueous saturated sodium bicarbonate solution. Dichloromethane was then used to extract the crude product. The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was adsorbed onto silica gel and purified via flash column chromatography eluting with 99: 1 to 4: 1 hexanes:ethyl acetate to give isomer 30 (R = 0.44 in 3: 1 hexanes:ethyl acetate) as a yellow solid (201 mg, 24percent yield) followed by the desired product 28 (R/= 0.19 in 3: 1 hexanes:ethyl acetate) as a pale yellow solid (411 mg, 47percent yield). This is a known procedure (D. A. Learmonth (Portela & C.A., S.A., Port.), GB- 2377934, 2003). We were able to obtain 28 (CAS number: 42123-33-1) in 63percent yield during the course of these investigations. Characterization Data for Compound 28: 1H NMR (400 MHz, CDC13): δ 10.40 (s, 1H), 10.30 (s, 1H), 7.67 (ddd, J = 8.3, 7.4, 0.7 Hz, 1H), 7.37 (dd, = 8.3, 1.4 Hz, 1H), 7.31 (dd, J = 7.4, 1.4 Hz, 1H). HRMS (DART): calc. for C7H9N204 (0511) [M+NH4]+: 185.0557, found: 185.0559. MP: 155-158 °C, lit. 157 °C (W. S. Saari, S. W. King, J. Med. Chem. 1974, 17, 1086-1090). Characterization Data for 30: 1H NMR (400 MHz, CDCI3): δ 10.58 (s, 1H), 10.06 (d, J = 0.6 Hz, 1H), 8.28 (d, = 8.7 Hz, 1H), 7.66 (d, = 1.7 Hz, 1H), 7.51 (dd, = 8.7, 1.7 Hz, 1H). Spectral values for 30 identical to previously reported 1H NMR data (A. Tsoukala, L. Liguori, G. Occhipinti, H.R. Bjorsvik, Tet. Lett. 2009, 50, 831-833). MP: 129-131 °C, lit. 127°C (J. Cologne, F. Pierre, Bull. Soc. Chim. Fr. 1964, 12, 3090-3096).
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[2] Patent: WO2016/154051, 2016, A1, . Location in patent: Paragraph 00245
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  • [ 3111-51-1 ]
  • [ 20035-32-9 ]
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  • 67
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  • [ 73604-31-6 ]
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  • [ 100-83-4 ]
  • [ 60760-04-5 ]
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  • 69
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  • [ 57772-57-3 ]
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  • [ 100-83-4 ]
  • [ 68208-19-5 ]
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  • 71
  • [ 1895-39-2 ]
  • [ 100-83-4 ]
  • [ 85684-61-3 ]
YieldReaction ConditionsOperation in experiment
36% With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 5 h; [0471j A solution of sodium chlorodifluoroacetate (12.48 g, 82 mmol) and 3-hydroxybenzaldehyde (5.00 g, 40.9 mmol) in DMF (75 ml) was added over 3 hours to a solution of DMF (25 ml) containing potassium carbonate (8.49 g, 61.4 mmol) at 95 °C. The reaction was allowed to age for an additional 2 hours and then cooled. The reaction mixyure was diluted with water (100 ml) and extracted with ethyl acetate (4 x50 ml). The organic extract was washed with 10percent (mlv) aqueous LiC1 solution (3 x 25 ml), dried over sodium sulfate, filtered and evaporated to give a residue that was flash chromatographed (15percent EtOAc/hexane) to give 3-(difluoromethoxy)benzaldehyde (2.50 g, 14.52 mmol, 36percent) as a yellow oil. The NMR was consistent with the proposed structre.
Reference: [1] Patent: WO2014/127042, 2014, A1, . Location in patent: Paragraph 0471
  • 72
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[2] Patent: US4579848, 1986, A,
  • 73
  • [ 100-83-4 ]
  • [ 56962-10-8 ]
YieldReaction ConditionsOperation in experiment
55% for 16 h; To a suspension of 3-hydroxybenzaldehyde (20.12 g, 160 mmol) in HOAC (40 mL) was added carefully tBuOCl (20 mL, 176 mmol) with stirring. The reaction became a clear solution and strongly exothermic. It was allowed to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with H20 and dried to give 2-chloro-3-hydroxybenzaldehyde (13.77 g, 55 percent), GCMS (EI) mlz 156, 158 (M+). To a solution OF 2-CHLORO-3-HYDROXYBENZALDEHYDE (4.55 g, 29 mmol) in DMF (30 mL) was added K2CO3 (4.8 g, 34.9 mmol) followed by MeI (2.7 mL, 43.6 mmol), and the mixture was stirred at room temperature for 16 hours. Following concentration IN VACUO, the residual was taken up in ethyl acetate, washed with H2O, brine, dried over NA2S04, and concentrated. Purification by column chromatography on silica gel with ethyl ACETATE/HEXANES 1/5 afforded 2-chloro-3-methoxybenzaldehyde 3a (4.68 g, 94 percent) as a colorless oil, which solidified upon standing. GCMS (EI) M/Z 170, 172 (M+).
55% for 16 h; To a suspension of 3-hydroxybenzaldehyde (20.12 g, 160 mmol) in HOAC (40 mL) was added carefully tBuOCI (20 mL, 176 mmol) with stirring. The reaction became a clear solution and strongly exothermic. It was allowed to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with H20 and dried to give 2-chloro-3-hydroxybenzaldehyde (13.77 g, 55 percent), GCMS (EI) M/Z 156,158 (M+).
55% With tert-butylhypochlorite In acetic acid for 16 h; To a suspension of 3-HYDROXYBENZALDEHYDE (20.12 g, 160 mmol) in HOAC (40 mL) was added carefully tBuOCl (20 mL, 176 mmol) with stirring. The reaction became a clear solution and strongly exothermic. It was allowed to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with HZ0 and dried to give 2-chloro-3-hydroxybenzaldehyde (13.77 g, 55 percent), GCMS (EI) m/z 156,158 (M+).
46.9% at 20℃; for 16 h; Cooling To a suspension of 3-hydroxybenzaldehyde (5 g, 40.98 mmol) in AcOH (10 mL) was added carefully t-BuOC1 (5 mL, 45.08 mmol) with stirring. It was allowed to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with H20 and dried to give the title product (3 g, 46.9percent). ‘H-NMR (400 MHz, CDC13): ö 10.66 (br, 1H),10.33 (s, 1H), 7.31-7.25 (m, 3H).
40% With chlorine In acetic acid at 15 - 20℃; for 12 h; lntermediate 12; 2-Chloro-3-hydroxybenzaldehyde. Chlorine was bubbled through a solution of m- hydroxybenzaidehyde (CAS 100-83-4) (100 g, 820 mmol) in glacial acetic acid (440 g) at 15 0C until the increase in weight was 56 g. The mixture was stirred at room temperature for 12 h. Then the colorless crystals (~70 g) were separated by filtration, dryed in vacuo and recrystallized from Et2O/hexane mixture (1:1) to give the title compound (51.5 g, 40percent, 330 mmol) as colorless crystals. GC/MS data: 155 (M-H)+ (calculated for C7H5CIO2 156.6); 1H NMR data (DMSO-d6): 10.63 (s, 1H, COH); 10.34 (s, 1H, OH); 7.25-7.33 (m, 3H, Ph).

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[3] Patent: WO2005/7164, 2005, A1, . Location in patent: Page 30-31
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[7] Patent: WO2017/127371, 2017, A1, . Location in patent: Page/Page column 17
[8] Patent: WO2006/136924, 2006, A1, . Location in patent: Page/Page column 58
[9] Chemistry - A European Journal, 2014, vol. 20, # 28, p. 8594 - 8598
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  • [ 7310-94-3 ]
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  • [ 56962-10-8 ]
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  • 76
  • [ 100-83-4 ]
  • [ 196081-71-7 ]
YieldReaction ConditionsOperation in experiment
28% With bromine; sodium acetate In acetic acid at 20℃; for 2.25 h; The suspension of 3-hydroxybenzaldehyde (5 g, 0.04 mol), iron powder (172 mg, 3 mmol) and sodium acetate (6.72 g, 0.08 mol) in acetic acid (40 mL) was warmed until a clear solution was obtained and then cooled to room temperature. To this mixture was dropwise added a solution of bromine in glacial acetic acid (10 mL) over 15 min. After the addition, the reaction mixture was stirred for 2 h and then poured into ice-water. The resulting mixture was extracted with dichloromethane (3x50 mL). The combined extracts were dried over anhydrous Na2S04 and concentrated. The residue was re-crystallized from dichloromethane to afford the product (2.3 g, yield 28percent). 1H NMR (400 MHz, DMSO-<3/4 δ 10.30 (s, 1 H), 7.54- 7.51 (m, 1H), 7.39-7.35 (m, 1H), 7.31-7.27 (m, 1H), 5.90 (s, 1H).
28%
Stage #1: at 20℃; Heating
Stage #2: for 2 h;
A suspension of 3-hydroxybenzaldehyde (5 g, 40 mmol), iron powder (172 mg, 3 mmol) and sodium acetate (6.72 g, 80 mmol) in acetic acid (40 mL) was warmed until a clear solution was obtained and then cooled to room temperature. To this mixture was added dropwise a solution of bromine (7.2 g, 45 mmol) in glacial acetic acid (10 mL) over 15 min. After the addition, the reaction mixture was stirred for 2 h and then poured into ice- water. The resulting mixture was extracted with dichloromethane (3x50 mL). The combined extracts were dried over anhydrous Na2S04 and concentrated. The residue was re- crystallized from dichloromethane to afford the product (2.3 g, 28percent). 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1 H), 10.26 (s, 1 H), 7.38-7.24 (m, 3H).
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[2] Patent: WO2012/33858, 2012, A2, . Location in patent: Page/Page column 76
[3] Patent: WO2015/21396, 2015, A2, . Location in patent: Paragraph 00121-00122
[4] Organic Letters, 2016, vol. 18, # 21, p. 5656 - 5659
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[3] Patent: WO2012/9818, 2012, A1,
[4] Patent: US2013/331593, 2013, A1,
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[6] Patent: WO2017/130109, 2017, A1,
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[2] Patent: WO2006/123725, 2006, A1, . Location in patent: Page/Page column 46
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  • [ 91523-50-1 ]
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YieldReaction ConditionsOperation in experiment
96% With sodium hydrogensulfate monohydrate In hexane; acetonitrile for 0.5 h; Reflux; Sonication; Green chemistry General procedure: To a solution of an aldehyde (1 mmol), ethyl/methyl acetoacetate or acetylacetone(1 mmol) and urea/thiourea (1.2 mmol) in n-hexane/CH3CN (2.5:0.5 mL), NaHSO4·H2O(3 mmol) was added. The reaction mixture was then heated to reflux and synchronously irradiated by ultrasound (240 W) via a micro-tip probe for an appropriate time. Progress of the reactions was monitored by TLC (n-hexane/EtOAc: 5/3). After completion of the reaction, the solution was cooled to room temperature and H2O (5 mL) was then added followed by stirring for 5 min. The mixture was extracted with EtOAc (3 × 8 mL) anddried over anhydrous Na2SO4. Evaporation of the solvent and recrystallization of the crude product in hot MeOH affords the pure DHPM (4–69) in 91–98percent yield (Tables 2 and 3).
96% With alumina In neat (no solvent) at 100℃; for 0.15 h; Microwave irradiation; Green chemistry General procedure: A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol), the corresponding urea derivative 3(3 mmol) and the 3D printed Al2O3 structure (0.350 g) was submitted to microwave irradiation (100 °C) in coated vial. After completion of the reaction, as indicated by TLC, the mixture was cooled and the desired compound solidified. For those 1,2,3,4-tetrahydropyrimidine-5-carboxylates that not solidified, the reaction mixture was poured onto crushed ice and stirred for 5-10 min. The solid obtained was filtered under suction, washed with ice-cold water (20 mL) and then purified by column chro-matography or recrystallization from the appropriate solvent.
94% With Graphite In neat (no solvent) at 120℃; for 0.166667 h; Green chemistry General procedure: A mixture of benzaldehyde (106mg, 1mmol), urea (60mg, 1mmol), ethylacetoacetate (130mg, 1mmol) and (10mg, 10percentw/w) graphite was heated at 70°C (120°C in case of thiourea). The heterogenous mixture slowly became clear and a solid product started to seperate out. After completion of the reaction (1h, TLC) the entire mass solidified. The solid mass was crushed, washed with 5mL of cold water to remove unreacted urea and filtered.The solid was then dissolved in hot ethanol, and the catalyst was separated by filtration. On cooling the filtrate pure crystals of the product (1a) was obtained, yield 97percent (237mg). In all the cases, the product obtained was characterized by comparing spectral data and melting points with literature data.
90% With o-phthalimide-N-sulfonic acid In neat (no solvent) at 120℃; for 3 h; General procedure: To a mixture of aryl aldehyde 4 (1 mmol), β-dicarbonyl 5 (1 mmol), and urea or thiourea 6 (1.2 mmol) was added 10 mol percent of phthalimide-N-sulfonic acid (PISA). The reaction mixture was heated to 120 °C on a heating mantle for the appropriate time. After completion of the reaction, as indicated by TLC analysis, the system was cooled to room temperature. Ethanol (5 mL) was added to the reaction mixture, and the mixture was heated until a homogeneous solution was obtained. Next, ethyl acetate was added to the resulting mixture and then cooled to RT, and the catalyst was recovered by filtration and washed thoroughly with ethyl acetate and then diethyl ether. The recovered catalyst was then reused under the same conditions as above for at least five reactions. After this, the organic phase was concentrated by evaporation, distilled water was added to the residue, and the solid thus obtained.The resulting solid product was filtered off, washed with cold water, and then thereaction mixture was subjected to isolation with preparative TLC using a mixture of ethyl acetate and n-hexane (3:10) as eluent.
90% at 120℃; for 3 h; Green chemistry General procedure: A mixture of aryl aldehyde 1 (1 mmol), b-dicarbonyl 2 (1 mmol), urea or thiourea 3 (1.2 mmol), and 10 mol percent of PPI was added and the reaction mixture was heated at 120 C for 1–3 h. During the heating, the progress of the reaction mixture was monitored by TLC analysis. After completion of the reaction, the reaction was cooled to room temperature. The solid product was dissolved in ethanol and water, filtered by simple filtration, and washed with water (5 mL), and the residue was recrystallized from ethanol to give the desired compounds in high yields. The filtrate was evaporated to remove water and leave the catalyst. The same catalyst was employed to synthesize further derivatives. The products are known and their identity was confirmed by comparison of their physical and spectroscopic data with those available in the literature.
88% With tris(pentafluorophenyl)borate In ethanol for 3 h; Reflux; Green chemistry General procedure: A mixture of benzaldehyde 1a (106 mg, 1 mmol), ethyl acetoacetate 2a (130 mg, 1 mmol) and urea 3a (90 mg,1.5 mmol) in EtOH (10 mL) was refluxed in the presence of B(C6F5)3 (18.1 mg, 1 molpercent). After completion of reaction, as indicated by TLC analysis, the solvent was evaporated. The resulting mass was treated with ice-cold water and the solid obtained was filtered, washed with cold water, dried and re-crystallized from ethanol to give pure product (4a).
87% With molybdophosphoric acid supported on Y zeolite In acetonitrile for 7 h; Reflux Method A. A mixture of 1 (122 mg, 1.0 mmol), ethylacetoacetate (130 mg, 1.0 mmol), and thiourea (190 mg,2.5 mmol) in MeCN (15 ml) was mixed with HPA supportedon Y zeolite (8 wtpercent NaY + 0.5 mM HPA) and refluxed for7 h. After cooling, the heteropoly acid (HPA) supported onHY filtered off and washed with hot water and ethanol toremove thiourea from the surface of the catalyst. Then, thecatalyst dried and was maintained for new runs. The filtratewas evaporated to dryness and the residue was recrystallized from EtOH to afford 2 (254 mg, 87 percent), m.p. 181–185 °C (Lit.[6, 7] 184–186 °C), Rf = 0.71. 1H NMR (DMSO-d6): δ 10.29(s, 1 H, NH), 9.60 (s, 1 H, NH), 9.44 (s, 1 H, OH), 7.10 (t,J = 7.8 Hz, H-5), 6.65 (d, 1 H, J2’,4′ = 2.4Hz, Harom.-2′), 6.64(m, 2 H, Harom.-4 + Harom.-6), 5.09 (d, 1 H, JNH,4 = 5.5 Hz,H-4), 4.02 (q, 2 H, J = 7.8Hz, CH2CH3), 2.28 (s, 3 H, C6-Me),1.12 (t, 3 H, J = 7.8 Hz, CH2CH3). 13C NMR (DMSO-d6): δ174.6 (C = S), 165.7 (CO2Et), 157.9 (C-6), 145.3 (C3’-OH + Carom.-1′), 130.0 (Carom.-5′), 117.7 (Carom.-2′ +Carom.-6′), 133.6 Carom.-4′), 101.2 (C-5), 60.1 (CH2CH3),54.5 (C-4), 17.7, 17.6 (C6-Me), 14.5 (CH2CH3). EI-MS:m/z (percent) = 292 [M]+. Anal. Calcd. for C14H16N2O3S(292.35): C, 57.52; H, 5.52; N, 9.58. Found: C, 57.32;H, 5.39; N, 9.32 percent. Method B. A mixture of 1 (244 mg, 2.0 mmol), ethylacetoacetate (300 mg, 2.30 mmol), and thiourea (380 mg,5.0 mmol) in EtOH (15 ml) in the presence conc. Hydrochloricacid (1 ml) was heated under reflux for 3 h. After cooling,the mixture was poured onto ice (20 g). The precipitate wasfiltered and dried and recrystallized from EtOH to give 2(292 mg, 50 percent), TheNMR spectra, m.p. and mixed m.p. werealmost similar for those of 2 prepared in method A.
86% for 4 h; Reflux General procedure: A mixture of 0.025 mol of urea or thiourea, 0.025 mol of an arylaldehyde, 0.025 mol of ethyl acetoacetate or acetylacetone, 10 mL ethanol and 3 drops of a liquid or 2-3 mg of solid phenol was heated under reflux for 6-24 h and the reaction mixture was then cooled to 0 °C and the product was filtered, washed with water, dried and recrystallized from a suitable solvent. The progress of the reaction was monitored by TLC using ethyl acetate and n-hexane (1:2) as eluent.
85% With chloro-trimethyl-silane In acetonitrile for 24 h; Inert atmosphere; Reflux General procedure: A 10 mmol mixture of the corresponding benzaldehyde (4),15 mmol of methyl or ethyl acetoacetate (5), 761 mg (10 mmol,1.0 equiv) of thiourea (6), 1.27 mL (10 mmol, 1.0 equiv) oftrimethylsilylchloride (TMSCl) and 7.0 mL of anhydrous acetonitrileunder nitrogen atmosphere was formulated in a 50 mL roundbottom flask, equipped with a magnetic stirring bar. The watercondenser was set at the neck of round bottom flask then the mixturewas stirred for 1 min at room temperature to allow homogenization,followed by reflux for 24 h at oil bath. After cooling thereaction mixture, solvent was evaporated under reduced pressurethrough rotary evaporator. Thereafter, 500 mL of ice water waspoured into reaction mixture and allowed to stir for 1 h in orderto obtain maximum precipitation. Filtration delivered the pureDHPMs. Where needed, the product was recrystallized or directlypurified by gradient dry flash chromatography using appropriatesolvents. The physical and spectroscopic data of DHPM 7–12 werefound in good agreement with the literature [11,13,20]. 4.2.1.1.
83% With psychortria douarrei catalyst dispersed on montmorillonite K10 In neat (no solvent) at 80℃; for 1.2 h; A mixture of ethyl acetoacetate (781 mg, 6.Ommol),3-hydrobenzaldehyde (488 mg, 4.0 mmol), thiourea (457 mg,6.0 mmol) and P douarrei crude catalyst (265 mg, amount corresponding to 1.0 mmol of nickel following previous dosing), supported on montmorillonite K10 (265 mg) was placed in a 10 mE sealed tube. The tube was heated to 80° C. in oil bath, under magnetic stirring for 1.2 h. The mixture was then extracted with hot ethanol (10 mE, 70° C.) and filtered in order to remove the catalyst, which was reactivated by heating (150°C.). The solutionwas poured into crushed ice (20 g) and stirred for 20 mm. The solid separated was filtered under suction, washed with cold water (30 mE) and recrystallized from hot ethanol, affording pure product, as colorless crystals (973 mg, 83percent). The same procedure was followed with G. pruinosa catalyst and commercial NiCl2. Mp 185-186° C. (184-186°C.);IR 3298,3181,3115,2982, 1663, 1617, 1573 cm’; ‘H NMR (DMSO-d5, 300 MHz) ö: 1.14 (t, J=7.4 Hz, 3H), 2.29 (s, 3H), 4.04 (q, J=7.4 Hz, 2H), 5.11 (d, J=3.5 Hz, 1H), 6.60-6.71 (m, 3H), 7.06-7.15 (m, 1H), 9.42 (brs, 1H),9.62 (brs, 1H), 10.29 (brs, 1H); ‘3C NMR (DMSO-d5, 75 MHz) ö: 14.0, 17.1, 54.2, 59.6, 100.8, 113.0, 114.4, 117.0, 129.3, 144.8, 144.9, 157.4, 165.4, 174.2. MS (EI+) calculated for C,4H,6N2035 [M]292.1. found 293.1 [M+H].
80% With bis(p-sulfoanilino)triazine-functionalized silica-coated magnetite nanoparticles In neat (no solvent) at 100℃; for 1.16667 h; General procedure: A mixture of aromatic aldehyde (1 mmol), b-keto ester or dimedone (1 mmol) and urea or thiourea (1.2 mmol) was stirred in presence MNPs-BSAT (20 mg) at 100 °C under solvent-free condition for the appropriate time (Scheme 1). After completion of the reaction as indicated by TLC (using n-hexane-ethyl acetate as eluent), the resulting mixture was diluted with hot ethanol (15 mL) and the catalyst separated by an external magnet and washed with hot ethanol (5 mL) two times. The filtrate was cooled to room temperature and the crude products which precipitated were collected and recrystallized from ethanol if necessary.
79% With tin(II) chloride dihdyrate In acetonitrile at 70 - 75℃; Sonication General procedure: A mixture of an aldehyde (10 mmol), a diamino compound (12 mmol), a dicarbonyl compound (10 mmol, mL), SnCl2·2H2O (10 molpercent) and acetonitrile (10 mL) was mixed in a pyrex tube. The mixture was then irradiated in ultrasonic bath at 70–75 °C. The reaction was monitored by TLC. After the completion of the reaction, the resulting precipitate was filtered and crude product was recrystallized from an appropriate solvent or purified through columnchromatography.
75% With ytterbium(III) triflate In acetonitrile at 120℃; for 1 h; Microwave irradiation General procedure: The appropriate β-keto ester (0.75–3.0mmol, 1.5 equiv.), the appropriate aldehyde (0.5–2.0mmol, 1 equiv.), the appropriate urea or thiourea (0.5–2.0mmol, 1 equiv.) and Yb(OTf)3 (0.05–0.20mmol, 0.10 equiv.) were placed in a microwave oven vial (0.5–2.0mL) with a magnetic stirring bar and dissolved in THF or MeCN (0.5–1.0mL). The resulting mixture is heated to 120°C for 30–60min using microwave irradiation. The resulting mixture is poured onto an ice-water mixture and left for precipitation. The resulting crude solids were purified by recrystallization, DCVC or flash chromatography.
74% With copper dichloride In ethanol at 80℃; for 4 h; General procedure: To a stirred mixture of thiourea (1.00 mmol), substituted benzaldehydes E–G (Scheme 1)(1.00 mmol), ethyl acetoacetate (130 mg, 1.00 mmol), and anhydrous cupric chloride(10 molpercent) were added. The mixture was heated at 80°C for 4 h under stirring. After thereaction was completed (checked by TLC), a mixture of H2O:EtOH 8:5 (13 mL) was added andthe resulting slurry was stirred at 80°C until total dissolution. After being cooled to roomtemperature, the reaction mixture was poured onto crushed ice (30 g) and stirred for5–10 min. The separated solid was filtered under suction (water aspirator), washed withice-cold water (50 mL), and then recrystallized from hot ethanol to afford the pureproduct.2.3. Ethyl-4-(3-hydroxyphenyl)-6-methyl-2-thioxo-pyrimidine-5-carboxylate(monastrol) L1))From 3-hydroxybenzaldehyde (E) (122 mg). Yield: 216 mg (74percent); mp 185–186°C (Lit. [23, 25]184–186°C).
72% With 1-butyl-1,2,4-triazolium triflate In ethanol at 80℃; for 1 h; Green chemistry General procedure: Catalyst 1a-c (10 molpercent) was added to a solution of aldehyde (1.0 mmol), β-ketoester (1.5 mmol) and urea or thiourea (2.0 mmol) in ethanol (0.5 mL). The reaction mixture was heated at 80 °C using oil bath for the specified time (0–5 h). The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and subsequently quenched with a mixture of water:ethanol (5:0.5 mL). The solid product was filtered and washed with n-hexane (5mL ×2), which afforded pure 3,4-dihydropyrimidin-2(1H)-ones or 3,4-dihydropyrimidin-2(1H)-thiones in pure form.
71% at 100℃; for 3 h; General procedure: Aldehyde (3 mmol), ethyl acetoacetate (0.586 g, 4.5 mmol), urea (0.270 g, 4.5 mmol) or thiourea (0.343 g, 4.5 mmol), and β-cyclodextrin (17 mg, 0.5 molpercent) were mixed in a 25 mL round bottom flask for 3h at a temperature of 100 °C. The reaction mixture was cooled and the solid was solubilized in ethanol and the addition of few drops of cold water to precipitate the product. The precipitated solid was filtered on sintered funnel. The crude product was further purified by recrystallization from ethanol to afford pure 3,4-dihydropyrimidin-2(1H)-ones. After separation of the product by filtration, the filtrate was washed with ethyl acetate and the aqueous phase was concentrated on rotary evaporator obtaining the catalyst.
64% With 1-ethyl-1,2,4-triazolium phenylsulfonate In ethanol at 70 - 80℃; for 2.5 h; General procedure: Catalyst 1-ethyl-1,2,4-triazolium phenylsulfonate (TrHEtPS) (10 mol) was added to a solution of urea or thiourea (2.0 mmol), β-ketoester (1.5 mmol) and aldehyde (1.0 mmol) in ethanol (0.5 mL). The reaction mixture was heated at 70 to 80 °C for the specified time (0-5 h) (Scheme-II). The completion of the reaction was monitored by thin layer chromatography (ethyl acetate:hexane: :4:1) and then the reaction mixture was cooled to room temperature. Then, quenched with mixture of water: ethanol (5:0.5 mL). The obtained solid product was filtered, and washed with n-hexane (5mL) and afforded 3,4-dihydropyrimidin-2(1H)-ones or 3,4-dihydropyrimidin-2(1H)-thiones.
52% With 25,26,27,28-terahydroxycalix[4]arene-5,11,7,23-tetrasulfonic acid In ethanol for 8 h; Reflux General procedure: Aldehydes (3 mmol), ethyl acetoacetate (4.5 mmol) and (thio)urea (4.5 mmol) were dissolved in 3 mL of ethanol containing p-sulfonic acid calix[4]arene (0.5 mol percent). The mixture was heated under reflux and stirred for 8 h.20 All DHPMs were characterized by NMR (1H and 13C), infrared, melting point and elemental analysis. Characterization data for compounds BA9, BA11-BA14, BA16-BA21, BA24-BA28, BA30 and BA32 were recently reported by da Silva et al.20 Data for compounds BA2, BA10, BA15, BA22, BA29, BA31 and BA33 are listed as Supplementary data.

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