* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Green Chemistry, 2009, vol. 11, # 11, p. 1881 - 1888
2
[ 88-67-5 ]
[ 108-46-3 ]
[ 1139-83-9 ]
Yield
Reaction Conditions
Operation in experiment
80.1%
Stage #1: With sodium hydroxide In water for 0.5 h; Reflux Stage #2: With copper(II) sulfate In water for 0.166667 h; Reflux
Example 2: 3-hydroxy-6H-benzo[c]chromen-6-one A mixture of 2-lodobenzoic acid (30 gram, 0.12 mol), resorcinol (40 gram, 0.36 mol), and NaOH (17.4 g, 0.44 mol) in water (150 mL) is heated under reflux for 30 min. After the addition of aqueous CuS04 (28percent, 25 mL) the mixture is refluxed for additional 10 min, during which time the product (0.62 g) precipitates as a white powder. The precipitate is filtered and washed with cold water. Yield obtained: 80.1 percent, 1H NMR (DMSO) δ 6.71 (d, 1 H), 6.80 (dd, 1H), 7.51 (t, 1 H), 7.83 (t, 1 H), 8.08-8.22 (m, 3H ), 10.32 (s, 1 H).
80.1%
With sodium hydroxide In water for 0.5 h; Reflux
A mixture of 2-iodobenzoic acid (30 g, 0.12 mol), resorcinol(40 g, 0.36 mol), and NaOH (17.4 g, 0.44 mol) in water (150 mL)was heated under reflux for 30 min. After the addition of aqueousCuSO4 (28percent, 25 mL) the mixture was refluxed for additional10 min, during which time the product (0.62 g) precipitated as awhite powder. The precipitate was filtered and washed with coldwater. Yield obtained: 80.1percent, 1H NMR (DMSO-d6) d 6.71 (d, 1H),6.80 (dd, 1H, Ar-H), 7.51 (t, 1H, Ar-H), 7.83 (t, 1H, Ar-H), 8.08–8.22 (m, 3H, Ar-H), 10.32 (s, 1H, AOAH).
76%
Stage #1: With sodium hydroxide In water for 1 h; Reflux Stage #2: With copper(II) sulfate In water for 0.166667 h; Reflux
A mixture of 2-iodobenzoic acid (6 mmol), resorcinol(18 mmol), and NaOH solution (22 mmol) in water (20 mL)was refluxed for 1 h. After the addition of aqueous CuSO4(15percent, 10 mL) to the mixture, refluxing was continued foradditional 10 min. The product was filtered, and washed withice-water and obtained as a white powder. 1H NMR (DMSOd6,400 MHz): δ = 10.30 (s, 1H, OH), 8.15–8.12 (m, 3H),7.86–7.83 (m, 1H), 7.50 (s, 1H), 6.77–6.74 (m, 2H). 13CNMR (DMSO-d6, 125 MHz) δ (ppm) major rotamer:160.5 ppm for lactone carbonyl. Yield obtained: 76percent.
72%
Stage #1: With sodium hydroxide In water for 1 h; Reflux Stage #2: With copper(II) sulfate In water for 0.166667 h; Reflux
A mixture of 2-iodobenzoic acid (120 mmol), resorcinol(360 mmol), and NaOH solution (440 mmol) in water(50 mL) was refluxed for 1 h. After the addition of aqueousCuSO4 (28percent, 25 mL) to the mixture, refluxing was continuedfor 10 min. The product was filtered, and washed withice-water and obtained as a white powder. Yield obtained:72percent. 1H NMR (DMSO-d6, 400 MHz): δ = 10.30 (s, 1H,OH), 8.17 (m, 3H, Ar-H), 7.87 (t, 1H, Ar-H), 7.50 (t, 1H, Ar-H), 6.76 (m, 2H, Ar-H).
Reference：
[1] Patent: WO2014/129989, 2014, A1, . Location in patent: Page/Page column 13
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 19, p. 5141 - 5154
[3] Journal of Fluorescence, 2018, vol. 28, # 5, p. 1255 - 1259
[4] Letters in Drug Design and Discovery, 2018, vol. 15, # 11, p. 1131 - 1140
3
[ 88-67-5 ]
[ 86-39-5 ]
Reference：
[1] Journal of Pharmaceutical Sciences, 1981, vol. 70, # 7, p. 812 - 813
4
[ 88-67-5 ]
[ 40274-67-7 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 24, p. 7647 - 7657
CAUTION IBX is explosive under impact or heating to >200 C. IBX was prepared following the procedure described by Sputore and co-workers. 16 In a 500 mL round-bottom flask fitted with a mechanical stirrer, 2-iodobenzoic acid (12.5 g, 50.4 mmol) was added to a solution of Oxone (40.281 g,65.5 mmol) in deionized water (163 mL). The mixture was heated to 73 °C and stirred vigorously for 3 h, after, which time the reaction was cooled to 0 °C and slowly stirred for 1.5 h. The mixture was filtered through a fritted glass funnel and the resulting white solid washed with water (730 mL), acetone (235 mL), and dried under high vacuum for 2 days to produce the title compound as a white solid in 84percent yield (11.848 g, 42.3 mmol).
70%
at 55 - 68℃; for 4.5 h;
Compound 104 was prepared from compound 103. Potassium bromate (16.6 g, 0.1 mol) was added over 0.5 h to a vigorously stirred mixture of 2-iodobenzoic acid (20 g, 0.08 mmol) and 180 mL 0.73 M H2SO4 (0.13 mol) in a 55° C. bath. The mixture was stirred for 4 h at 68° C., and the Br2 formed was removed by reduced pressure in the reaction process. The reaction was cooled to room temperature with an ice bath. Filtration and washing of the solid with ice water and iced ethanol gave the desired compound IBX (16 g, 70percent yield).
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[1] Journal of the Chemical Society, 1948, p. 32,33[2] Journal of the Chemical Society, 1946, p. 116
[3] Journal of Organic Chemistry, 2014, vol. 79, # 16, p. 7451 - 7458
13
[ 88-67-5 ]
[ 609-67-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
for 2 h; Reflux
General procedure: A mixture of various carboxylic acids (1.0mmol), an excess of thionyl chrolide (5mL) was refluxed for 2h and concentrated in vacuo to give corresponding acyl chloride (quant).
99.9%
at 100℃;
[12451 Step 1: Synthesis of 2-iodobenzoyl chloride[12461 2-Iodobenzoic acid (4.000 g, 16. 128 mmol) and 50C12(23.399 mL, 322.555 mmol) were stirred overnight at 100 °C, and then the reaction mixture was concentrated under reduced pressure. The product was used without additional purification (4.295 g, 99.9 percent, brown oil).
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14
[ 79-37-8 ]
[ 75-09-2 ]
[ 88-67-5 ]
[ 609-67-6 ]
Reference：
[1] Patent: US5498630, 1996, A,
15
[ 88-67-5 ]
[ 5159-41-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 15 h;
To a THF solution (16 mL) of commercially available o-iodobenzoicacid (4.15 g, 16.8 mmol) was added boran–dimethylsulfide complex (1.90 mL, 20.0 mmol) at 0°C. After stirring for 15 h at room temperature, phosphate buffer (pH 7) was added. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, o-iodobenzylalcohol (3.84 g, 98 percent) was obtained as a white solid and used for the next step without further purification. To a DCM suspension (33 mL) of manganese(IV) oxide (14.0 g, 161 mmol) was added the crude o-iodobenzylalcohol (3.77 g, 16.1 mmol). After stirring for 30 h at room temperature, the resulting suspension was filtrated through a small pad of celite using DCM as an eluent. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to give o-iodobenzaldehyde (3.36 g,90percent) as pale yellow crystals.
94%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 16 h; Inert atmosphere
To a solution of 2-iodobenzoic acid (5.3 g, 21 mmol) in tetrahydrofuran (43 mL) at 0 °C, was addedborane-dimethyl sulfide (2.2 mL, 24 mmol) dropwise over 20 minutes. The reaction mixture wasstirred vigorously at room temperature for 16 hours then quenched with methanol (1 mL) followed bya saturated aqueous solution of potassium carbonate (5 mL). The layers were separated and theaqueous layer extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washedwith water (10 mL) and saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The crude product was recrystallised from hexanes affording(2-iodophenyl)methanol S1 (4.7 g, 94percent) as long white crystals; mp 90–92 °C (lit.,1 90–95 °C); Rf =0.82 (1:1 hexanes-ethyl acetate); δH (400 MHz; CDCl3) 7.82 (1H, d, J = 7.6 Hz, ArH), 7.46 (1H, dd, J= 7.6, 1.5 Hz, ArH), 7.40 (1H, t, J = 7.6 Hz, ArH), 7.00 (1H, dt, J = 7.6, 1.5 Hz, ArH), 4.68 (2H, d,J = 6.2 Hz, CH2), 2.00 (1H, t, J = 6.2 Hz, OH); The spectroscopic data were in agreement with thatreported in the literature.
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16
[ 26260-02-6 ]
[ 88-67-5 ]
[ 5159-41-1 ]
Reference：
[1] Chemische Berichte, 1930, vol. 63, p. 855,865[2] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2>138, p. 51,54
[3] Chemische Berichte, 1930, vol. 63, p. 855,865[4] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2>138, p. 51,54
[5] Chemische Berichte, 1930, vol. 63, p. 855,865[6] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2>138, p. 51,54
17
[ 88-67-5 ]
[ 40400-13-3 ]
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[3] Organic Letters, 2018, vol. 20, # 24, p. 7898 - 7901
18
[ 64-17-5 ]
[ 88-67-5 ]
[ 1829-28-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 78℃; for 5 h;
General procedure: Iodobenzoic acid (10 g) was added to 60 mL of alcohol derivatives (methanol, ethanol, n-butanol, iso-butanol and sec-butanol) in 5 mL conc. H2SO4, separately. The reaction mixtures were stirred electromagnetically in oil bath at 65, 78, 100, 105 and 95°C for 24, 5, 2, 4 and 4 hrs, respectively. Then excess alcohol derivatives were removed under vacuum rotary evaporator. Then water and ethyl acetate was added to final residues and organic layer was separated and washed three times with water and with saturated bicarbonate solution. Finally, the mixtures were dried over Na2SO4 and excess solvent was removed by distillation that resulted 97percent yield of methyl-2-iodobenzoate, 99percent yield of ethyl 2-iodobenzoate, 95percent yield of n-butyl 2-iodobenzoate, 96percent yield of 2-methylpropyl-2-iodobenzoate and 98percent yield of butan-2-yl- 2-iodobenzoate, respectively. (Scheme 1, Table 1).
88%
at 78℃; for 2.5 h;
Ethanol (50.0 mL), H2SO4 (0.5 mL) and 2-iodobenzoic acid (2.00 mg, 8.06mmole) were added into an oven-dried 100 mL round-bottomed flask. Thereaction was run at 78 °C for 2.5 hours. After the reaction was complete, thesolvent was removed in vacuo by rotary-evaporatory. The resulting residue was diluted withethyl acetate (30 mL) and then washed with saturated sodium bicarbonate solution (40 mL). Theaqueous phase was then extracted with ethyl acetate (30 mL). The combined organic layers werewashed with water (30 mL) followed by drying over MgSO4 and concentration in vacuo usingrotary-evaporator. The desired product (1.94 g, 88 percent) was obtained as light yellow oil withoutfurther purification: IR (ZnSe) ν (cm-1): 3062 (w), 2980 (m), 1719 (s), 1101 (s), 1561 (s), 1042(s), 737 (s), 686 (s); 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2, 3H), 4.41 (q, J = 7.2, 2H), 7.15 (dt, J = 7.2, 1.5, 1H), 7.41 (dt, J = 7.5, 1.2, 1H), 7.99 (dd, J = 7.8, 0.9, 1H), 7.80 (dd, J =7.5, 1.5, 1H); 13C NMR (300 MHz, CDCl3) δ 13.6, 60.5, 93.9, 127.0, 130.7, 131.1, 136.1, 143.2,167.0.
85%
for 24 h; Acidic conditions; Reflux
Ethyl 2-iodobenzoate 4d was prepared from esterification of corresponding halo-acid by refluxing in ethanol for 24 h. Pure product was obtained in 85percent yield by column chromatography using dichloromethane as eluent.
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[10] Asian Journal of Chemistry, 2015, vol. 27, # 10, p. 3605 - 3608
[11] Tetrahedron Letters, 2017, vol. 58, # 6, p. 574 - 577
[12] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 2, p. 207 - 212
[13] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
[14] Patent: CN108586364, 2018, A, . Location in patent: Paragraph 0058; 0059; 0060
19
[ 88-67-5 ]
[ 109-63-7 ]
[ 1829-28-3 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 120℃; for 4 h;
General procedure: In a 50 mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser and a calcium chloride drying tube was placed nicotinic acid (1 g, 8.1 mmol) suspended in boron trifluoride etherate (10 mL). The reaction mixture was stirred and heated to 120 °C overnight during which the creamy reaction mixture changed into a brownish solution. Thin layer chromatography (hexane/ethyl acetate 3:1) revealed complete reaction. The cooled reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extract was washed to the end of effervescence with a saturated solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo giving a crude yield of 1.11 g (92percent).
Reference：
[1] Bulletin of the Chemical Society of Ethiopia, 2018, vol. 32, # 2, p. 387 - 392
20
[ 88-67-5 ]
[ 75-03-6 ]
[ 1829-28-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 26, p. 5886 - 5892
21
[ 88-67-5 ]
[ 1829-28-3 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 24, p. 9517 - 9520
To a solution of 2-iodobenzoic acid (46) (15g/60mmol) in 200mL of methanol were added 8.8mL of sulfuric acid dropwise. The solution was refluxed for 16h. The mixture was allowed to cool to room temperature and most of the methanol was evaporated by rotary evaporator until approximately 20mL of solution. The product was then partitioned between water and dichloromethane. The aqueous phase was extracted 2×150mL of dichloromethane. The organic layer was then washed with 3×100mL of saturated solution of bicarbonate, 3×100mL of water, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. Compound 47 was isolated as light yellow oil (15.4g/98percent).Methyl 2-iodobenzoate (47). IR νmax (cm−1) (KBr): 3444, 3057, 2994, 2946, 2894, 2836, 1728, 1579, 1459, 1428, 1290, 1249, 1127, 1100, 1013, 738.
97%
at 65℃; for 24 h;
General procedure: Iodobenzoic acid (10 g) was added to 60 mL of alcohol derivatives (methanol, ethanol, n-butanol, iso-butanol and sec-butanol) in 5 mL conc. H2SO4, separately. The reaction mixtures were stirred electromagnetically in oil bath at 65, 78, 100, 105 and 95°C for 24, 5, 2, 4 and 4 hrs, respectively. Then excess alcohol derivatives were removed under vacuum rotary evaporator. Then water and ethyl acetate was added to final residues and organic layer was separated and washed three times with water and with saturated bicarbonate solution. Finally, the mixtures were dried over Na2SO4 and excess solvent was removed by distillation that resulted 97percent yield of methyl-2-iodobenzoate, 99percent yield of ethyl 2-iodobenzoate, 95percent yield of n-butyl 2-iodobenzoate, 96percent yield of 2-methylpropyl-2-iodobenzoate and 98percent yield of butan-2-yl- 2-iodobenzoate, respectively. (Scheme 1, Table 1).
96%
for 3 h; Reflux
2-Iodobenzoic acid (7.50 g, 30.2 mmol, 1 equiv) was dissolved in MeOH (150 mL), then concentrated sulfuric acid (20 mL) was added slowly. The mixture was stirred and heated at reflux for 3 h. After cooling to r.t., the reaction mixture was diluted with Et2O (150 mL),the layers were separated, and the organic phase was washed with H2O (2 × 150 mL), sat. aq NaHCO3(200 mL) and sat. aq NaCl (200 mL). After drying over MgSO4, the solvent was removed in vacuo to give the product. Yield: 7.59 g (29.0 mmol, 96percent); colorless oil. 1H NMR (400 MHz, CDCl3): δ= 3.93 (s, 3 H), 7.14 (ddd, J= 8.0, 7.5,1.7 Hz, 1 H), 7.39 (ddd, J= 7.7, 7.5, 1.2 Hz, 1 H), 7.79 (dd, J= 7.7,1.7 Hz, 1 H), 7.99 (dd, J= 8.0, 1.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ= 52.5, 94.0, 127.9, 130.9, 132.6, 135.1,141.3, 166.9. HRMS (EI): m/z [M – H]·+calcd for C8H6IO2: 260.9412; found:260.9407.
92%
at 50℃; for 0.333333 h; Sonication
General procedure: The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol), PS-Ph3P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na2CO3 (0.057 g, 0.542 mmol) were added to MeOH (0.5 mL). Then the mixture was sonicated in an ultrasonic bath (Elmasonic S 30H) at 50°C for the specified time. After completion, the crude mixture was filtered through a short pad of silica to obtain the product after solvent evaporation. Whenever necessary, the product was further purified by flash chromatography.
85%
at 0 - 90℃; for 8 h;
To a stirred solution of 2-iodobenzoic acid (10.0 g, 40.32 mmol, 1 equiv) in MeOH (100 ml_) was added H2S04 (10 ml_) drop wise at 0°C. The reaction mixture was warmed to 90°C and stirred for 8 hours. The reaction mixture was cooled and concentrated. The residue was basified with saturated sodium bicarbonate at 0°C and extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with water and brine solution then dried over sodium sulphate and evaporated to obtain methyl 2-iodobenzoate as colour less liquid (9.0 g, 85percent). (0698) 1H NMR (400 MHz, CDCI3) δ ppm 3.93 (s, 3 H), 7.15 (t, J=8.0 Hz, 1 H), 7.40 (t, J=7.2 Hz, 1 H), 7.80 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H).
55%
at 70℃; for 20 h;
General procedure: The mixture of carboxylic acid, alcohol and N-bromosuccinimide was stirred in a 25 mL reactortube at 70 °C for 2–40 h. After the completion of the reaction, the mixture was cooled to roomtemperature and alcohol was evaporated under reduced pressure. The isolation procedure was as follows, except where noted differently in Section 3.2.6. The residue was dissolved in ethyl acetate andconsecutively washed with 10 mL of 10percent Na2S2O3 (aq), 5 mL of saturated NaHCO3 (aq) and 10 mL ofdistilled water. The water phase was extracted with ethyl acetate (3Χ5 mL). The organic layers were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure.
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[3] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 798 - 816
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[9] Journal of Organic Chemistry, 2015, vol. 80, # 8, p. 3891 - 3901
[10] Synlett, 2015, vol. 26, # 14, p. 2006 - 2008
[11] Advanced Synthesis and Catalysis, 2018, vol. 360, # 20, p. 3889 - 3893
[12] Tetrahedron, 2003, vol. 59, # 33, p. 6251 - 6259
[13] Journal of Organic Chemistry, 2012, vol. 77, # 7, p. 3197 - 3214
[14] Organic Letters, 2017, vol. 19, # 9, p. 2274 - 2277
[15] Tetrahedron Letters, 2004, vol. 45, # 52, p. 9599 - 9602
[16] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 10, p. 3060 - 3073
[17] Patent: WO2018/15879, 2018, A1, . Location in patent: Page/Page column 80-81
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[19] Journal of the American Chemical Society, 1984, vol. 106, # 15, p. 4218 - 4227
[20] Organic Letters, 2016, vol. 18, # 17, p. 4166 - 4169
[21] Organic and Biomolecular Chemistry, 2018, vol. 16, # 48, p. 9472 - 9476
[22] Molecules, 2018, vol. 23, # 9,
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[28] Organic Letters, 2009, vol. 11, # 22, p. 5350 - 5353
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[32] Organic Letters, 2014, vol. 16, # 17, p. 4424 - 4427
[33] Synlett, 2016, vol. 27, # 1, p. 25 - 28
[34] European Journal of Organic Chemistry, 2016, vol. 2016, # 5, p. 1043 - 1049
[35] Tetrahedron, 2016, vol. 72, # 24, p. 3454 - 3467
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[37] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1971 - 1985
26
[ 88-67-5 ]
[ 74-88-4 ]
[ 610-97-9 ]
Reference：
[1] Angewandte Chemie, International Edition, 2014, vol. 53, # 37, p. 9860 - 9864,5[2] Angewandte Chemie, 2014, vol. 126, # 37, p. 10018 - 10022,5
[3] European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 550 - 556
[4] Organic and Biomolecular Chemistry, 2011, vol. 9, # 3, p. 656 - 658
[5] Journal of Organic Chemistry, 2008, vol. 73, # 17, p. 6642 - 6646
[6] Journal of the American Chemical Society, 2012, vol. 134, # 29, p. 12002 - 12009
[7] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3623 - 3625
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11606 - 11611
29
[ 88-67-5 ]
[ 3240-34-4 ]
[ 610-97-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 10, p. 2027 - 2031
30
[ 88-67-5 ]
[ 610-97-9 ]
Reference：
[1] Journal of the American Chemical Society, 1930, vol. 52, p. 5263,5264
[2] RSC Advances, 2013, vol. 3, # 38, p. 17271 - 17280
[3] Patent: WO2017/40693, 2017, A1,
31
[ 1634-04-4 ]
[ 88-67-5 ]
[ 610-97-9 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 7, p. 1444 - 1447
32
[ 88-67-5 ]
[ 87-59-2 ]
[ 61-68-7 ]
Reference：
[1] Journal of Chemical Research, 2006, # 5, p. 342 - 344
33
[ 88-67-5 ]
[ 61-68-7 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 11, p. 2127 - 2131
34
[ 88-67-5 ]
[ 19230-50-3 ]
Yield
Reaction Conditions
Operation in experiment
42%
at 135℃; for 1 h;
During this preparation up to 25 mmol I2 are formed. Therefore, the synthesis has to be conducted in a well-ventilated fume cupboard. Prepared according to literature procedure [10]. 2-Iodobenzoic acid (4, 10 g, 40.3 mmol, 1 equiv) was added to a mixture of HNO3 (35 mL, 65percent) and H2SO4 (85 mL, 95percent). The solution was heated to 135 °C and stirred for 1 h. Subsequently, the resulting brown slurry was poured onto ice and the grey precipitate was filtered off and washed with copious amounts of water. Then, the filtrate was suspended in water (100 mL), heated to 100 °C and treated with a solution of KI (8.5 g, 51.2 mmol, 1.3 equiv) and H2SO4 (5 drops) in water (10 mL) over the course of 1 h. Finally, the brown suspension was filtered hot and washed with water to afford the pure product (5 g, 42percent) as a brown solid. If impure product is obtained, boiling with water followed by hot filtration can be applied.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 12, p. 4778 - 4783
[2] Synlett, 2013, vol. 24, # 13, p. 1707 - 1711
[3] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 1 - 6
[4] Organic Letters, 2011, vol. 13, # 3, p. 518 - 521
[5] Helvetica Chimica Acta, 1930, vol. 13, p. 310,311[6] Helvetica Chimica Acta, 1932, vol. 15, p. 1102
[7] Chemische Berichte, 1893, vol. 26, p. 2473
[8] Patent: US6225323, 2001, B1,
35
[ 88-67-5 ]
[ 19230-50-3 ]
[ 5398-69-6 ]
Reference：
[1] Dalton Transactions, 2013, vol. 42, # 2, p. 355 - 358
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 45, p. 9680 - 9684
36
[ 88-67-5 ]
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 19230-50-3 ]
Reference：
[1] Helvetica Chimica Acta, 1930, vol. 13, p. 310,311[2] Helvetica Chimica Acta, 1932, vol. 15, p. 1102
37
[ 88-67-5 ]
[ 2142-70-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 16, p. 5863 - 5870
38
[ 88-67-5 ]
[ 19230-50-3 ]
[ 5398-69-6 ]
Reference：
[1] Dalton Transactions, 2013, vol. 42, # 2, p. 355 - 358
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 45, p. 9680 - 9684
39
[ 88-67-5 ]
[ 5398-69-6 ]
Reference：
[1] Journal of Organic Chemistry, 1970, vol. 35, # 4, p. 1196 - 1198
40
[ 88-67-5 ]
[ 25563-04-6 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1969, vol. 34, # 8, p. 2258 - 2277
41
[ 88-67-5 ]
[ 591-19-5 ]
[ 13278-39-2 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 16, p. 7451 - 7458
42
[ 88-67-5 ]
[ 74-88-4 ]
[ 181765-86-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 550 - 556
43
[ 88-67-5 ]
[ 181765-86-6 ]
Reference：
[1] Patent: WO2018/15879, 2018, A1,
44
[ 88-67-5 ]
[ 21740-00-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 5, p. 640 - 647
[2] Chemische Berichte, 1896, vol. 29, p. 1410
[3] Tetrahedron Letters, 2011, vol. 52, # 29, p. 3726 - 3728
45
[ 88-67-5 ]
[ 108-24-7 ]
[ 87413-09-0 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 3, p. 1014 - 1022
[2] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 28, p. 7428 - 7440
46
[ 88-67-5 ]
[ 128796-39-4 ]
[ 84392-17-6 ]
Yield
Reaction Conditions
Operation in experiment
74.55%
With 20% palladium hydroxide-activated charcoal; sodium carbonate In water at 80 - 90℃; for 6 h;
2-Iodobenzoic acid (100 gm, 0.4032 moles) , 4-(Trifluoromethyl)phenyl boronic acid (99.55 gm, 0.524 moles), sodium carbonate (164 gm, 1.55 moles) and 20 percent palladium hydroxide on carbon (15 gm) in water (3.0 L) was heated to 80-90°C for 6 hrs. The progress of the reaction was monitored by HPLC. After completion of the reaction the reaction mass was cooled 70-80°C and filtered through hyflow bed. The filtrate was cooled to room temperature and the pH was adjusted to 1-2 with hydrochloric acid. The precipitated solid was filtered and washed with 1.0 L water. The solid was dissolved in 376 ml ethanol at 60-70°C and charcolised. The solution was filtered through hyflow bed at 60°C and washed with 180 mL hot ethanol. Water (1.086 L ) was added to the filtrate at 50 -60°C and the precipitated solid was cooled to room temperature. The solid was filtered and dried in air oven for 12 hrs at 60°C to afford 80 gm of 4'- (Trifluoromethyl)biphenyl-2-carboxylic acid as a white solid (Yield 74.55 percent, HPLC purity 99.98 percent).
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 6, p. 2662 - 2668
[2] Organic Letters, 2015, vol. 17, # 23, p. 5832 - 5835
[3] Organic and Biomolecular Chemistry, 2018, vol. 16, # 11, p. 1971 - 1975
48
[ 88-67-5 ]
[ 199786-58-8 ]
Reference：
[1] Patent: WO2018/15879, 2018, A1,
49
[ 88-67-5 ]
[ 887144-97-0 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 29, p. 12002 - 12009
50
[ 88-67-5 ]
[ 81290-20-2 ]
[ 887144-94-7 ]
Reference：
[1] Chemical Communications, 2018, vol. 54, # 18, p. 2240 - 2243
51
[ 88-67-5 ]
[ 887144-94-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 39, p. 9120 - 9123
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2947 - 2950
[3] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6763 - 6768
[4] Angewandte Chemie - International Edition, 2014, vol. 53, # 52, p. 14559 - 14563[5] Angew. Chem., 2014, vol. 126, # 52, p. 14787 - 14791,5
[6] Patent: WO2016/57931, 2016, A1,
[7] European Journal of Organic Chemistry, 2017, vol. 2017, # 2, p. 271 - 277
[8] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1452 - 1458
[9] Advanced Synthesis and Catalysis, 2018, vol. 360, # 18, p. 3553 - 3562
52
[ 88-67-5 ]
[ 689291-89-2 ]
Reference：
[1] Patent: WO2018/15879, 2018, A1,
53
[ 88-67-5 ]
[ 288-36-8 ]
[ 1001401-62-2 ]
Yield
Reaction Conditions
Operation in experiment
67%
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere
1,2,3-triazole(0.7 ), 2-iodo-benzoic acid (1.0 ), cesium carbonate (2.36 g, 7.20 mmol)Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.10 g, 0.75 mmol), cuprous iodide (0.08 g, 0.40 mmo 1), N, N-dimethyl Amide (18 mL)Were successively added to a 100 mL single-necked round bottom flask and gradually warmed to 100 ° C for 4 hours under nitrogen protection.The reaction was quenched, cooled, diluted with tap water and extracted with ethyl acetate (200 mL X).The aqueous layer was acidified with concentrated hydrochloric acid (ρH- = 1 ~ 2) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure and purified by column chromatography. (Dichloromethane / methanol (v / v) = 30/1) gave the title compound (yellow solid, 0.511 g, 67percent)
With trichloroisocyanuric acid; In acetonitrile; at 75℃; for 0.166667h;
The compound was prepared according to the literature procedure (Matousek, V. et al. J. Org. Chem. 2013, 78, 6763-6768) . A suspension of 2-iodobenzoic acid (30.0 g, 0.121 mmol, 1.00 equiv) in MeCN (225 mL) was heated to 75C. A solution of trichloroisocyanuric acid (9.46 g, 0.0407 mol, 1.01 Cl+ equiv) in MeCN (45mL) was added in one portion and the reaction mixture was heated at 75 C for 10 min. The reaction mixture was diluted with MeCN (150 mL) and vacuum-filtered over an oven-preheated, sintered-glass funnel and the filter cake was rinsed with additional hot MeCN (150 mL) . The filtrate was concentrated in vacuo to near dryness and the resulting yellow solid was collected by filtration and washed with cold MeCN. The mother liquor from filtration was partially concentrated in vacuo, giving a second crop of crystals. The combined crops were dried under vacuum overnight to afford the title compound as a slightly yellow crystalline solid (28.0 g, 0.0991 mol, 82%). NMR Spectroscopy: XH NMR (400 MHz, CDC13, 25C, δ) : 8.27 (dd, J= 7.5, 1.5 Hz, 1H) , 8.22 (dd, J = 8.0, 0.5 Hz, 1H), 8.00 (ddd, J= 8.5, 7.2, 1.6 Hz, 1H) , 7.80 (td, J= 7.4, 0.8 Hz, 1H) . 13C NMR (125 MHz, CDC13, 25C, 5): 167.2, 136.8, 133.6, 132.0, 128.8, 127.0, 117.2. These spectroscopic data correspond to previously reported data.
During this preparation up to 25 mmol I2 are formed. Therefore, the synthesis has to be conducted in a well-ventilated fume cupboard. Prepared according to literature procedure [10]. 2-Iodobenzoic acid (4, 10 g, 40.3 mmol, 1 equiv) was added to a mixture of HNO3 (35 mL, 65%) and H2SO4 (85 mL, 95%). The solution was heated to 135 C and stirred for 1 h. Subsequently, the resulting brown slurry was poured onto ice and the grey precipitate was filtered off and washed with copious amounts of water. Then, the filtrate was suspended in water (100 mL), heated to 100 C and treated with a solution of KI (8.5 g, 51.2 mmol, 1.3 equiv) and H2SO4 (5 drops) in water (10 mL) over the course of 1 h. Finally, the brown suspension was filtered hot and washed with water to afford the pure product (5 g, 42%) as a brown solid. If impure product is obtained, boiling with water followed by hot filtration can be applied.
With nitric acid; In sulfuric acid;
EXAMPLE 1 2-Iodo-5-Nitrobenzoic Acid 2-Iodobenzoic acid (100 g) was dissolved in 400 mL of concentrated sulphuric acid and placed in a 2 liter 3 necked flask. The flask was fitted with reflux condenser, a thermometer and an addition funnel. Fuming nitric acid (400 ml) was added drop by drop. The addition was adjusted in such a way that the temperature was allowed to raise to 80 C. over a period of 2 hours. During the addition, the reaction mixture was stirred vigorously and maintained the temperature at 80 C. for an additional 2 hours. After the completion of the reaction, the reaction mixture was poured slowly into crushed ice (3 Kg). The contents were allowed to settle and were filtered. The yellow precipitate was collected and dried at 30 C. The yield was 90 grams.
With sulfuric acid; nitric acid; at 0 - 130℃; for 1.75h;
Prepared according to literature procedure. The 2-iodobenzoic acid (1,000 mg, 4.03 mmol) was pre-cooled at 0 C and then a solution of Conc. HNO3 (1.50 mL) and Conc. H2SO4 (4.50 mL) was added slowly. The mixture was allowed to stir at 0 C for 15 minutes, ice bath was moved, stirred at room temperature for 30 minutes, and followed by to stir the mixture at 130 C for 1 hour. The mixture was yellow, cooled with ice bath, then filtered with suction flask and Buchner funnel. The light yellow solid was obtain. 1H NMR (300 MHz, CDCl3) delta 8.12 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 2.3 Hz, 1H). Other data was identical to the literature values.
(1) A suspension of o-iodo benzoic acid (1 g, 4.03 mmol) , <strong>[696-63-9]4-methoxythiophenol</strong> (565 mg, 4.03 mmol) , KOH (451 mg, 8.1 mmol) and copper powder (25.6 mg, 0.403 mmol) in deionized water (2 mL) , undertook two cycles of microwaves of 6 min each at the power of 180 Watt (Tmax=100C, Pmax=100 psi) , cooling the sample during the radiation with a flow of compressed air. The obtained suspension was dissolved in an aqueous solution of KOH 2N and filtered. The filtrate was acidified with HCl IN and the formed precipitate filtrated and dried under reduced pressure (T=50C). The obtained solid was purified through trituration with acetone obtaining the product 1 (850 mg, 81%, white solid) . H1-NMR (d6-DMSO 200MHz): delta 3.82 (s, 3H), 6.63 (d, IH), 7.06- 7,20 (m, 3H), 7.30-7.40 (m, IH), 7.45-7.49 (d, 2H), 7.91(dd, IH) .
81%
With copper; potassium hydroxide; In water; at 100℃; under 5171.62 Torr;Irradiation with microwave;
(1) A suspension of o-iodo benzoic acid (1 g, 4.03 mmol), <strong>[696-63-9]4-methoxythiophenol</strong> (565 mg, 4.03 mmol), KOH (451 mg, 8.1 mmol) and copper powder (25.6 mg, 0.403 mmol) in deionized water (2 mL), undertook two cycles of microwaves of 6 min each at the power of 180 Watt (Tmax=100 C., Pmax=100 psi), cooling the sample during the radiation with a flow of compressed air. The obtained suspension was dissolved in an aqueous solution of KOH 2N and filtered. The filtrate was acidified with HCl 1N and the formed precipitate filtrated and dried under reduced pressure (T=50 C.). The obtained solid was purified through trituration with acetone obtaining the product 1 (850 mg, 81%, white solid). H1-NMR (d6-DMSO 200 MHz): delta 3.82 (s, 3H), 6.63 (d, 1H), 7.06-7.20 (m, 3H), 7.30-7.40 (m, 1H), 7.45-7.49 (d, 2H), 7.91 (dd, 1H).
With copper(l) iodide; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation;
SC-1-39 Acid [0023] A microwave reactor tube was charged with ortho-iodo benzoic acid (496 mg, 2 mmol), aniline (0.45 mL, 4 mmol), K2CO3 (832 mg, 6 mmol), CuI (400 mg, 2.08 mmol) and 10 mL DMF/H2O (9:1). The reaction was subjected to 300 Watt microwave irradiation with the internal temperature maintained at 100 C. for 1 h. After completion of the reaction was observed by TLC, 1 N HCl (9 mL) was added to the reaction mixture to obtain a final pH of 6.0. The solvent was then removed under reduced pressure and water chased with toluene. The crude compound was isolated on SiO2 using hexane/EA and recrystallised from toluene to give 267 mg (63%) of white solid; mp: 176.6-177.0
72%
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 8h;
To a mixture of 2-iodobenzoic acid (5.00 g, 20.00 mmol), Aniline (1.86 g, 20.00 mmol)and Potassium carbonate (5.50 g, 40.00 mmol) in 20 mL DMF wereadded CuI (0.76 g, 4.00 mmol).The reaction mixture was stirred at105 C for 8 h. After cooling to room temperature the mixture waspoured into 60 mL water and the pH was adjusted to 4-5 using 1 NHCl.The formed precipitates were filtrated and dried to obtained yellowsolid. Yield: 72%, m.p. 180-182 C.1H NMR (300 MHz, CDCl3) delta (ppm):9.31 (brs, 1H, COOH), 8.05 (d, J = 8.10 Hz, 1H, ArH), 7.40-7.33 (m,3H, ArH), 7.29-7.21 (m, 3H, ArH), 7.16-7.11 (m, 1H, ArH), 6.78-6.73(m, 1H, ArH).
63%
With copper(l) iodide; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Sealed tube; Microwave irradiation;
A microwave reactor tube was charged with ortho-iodo benzoic acid (496 mg, 2 mmol), aniline (24) (0.45 mL, 4 mmol), K2C03 (832 mg, 6 mmol), Cul (400 mg, 2.08 mmol) and 10 mL DMF/H20 (9: 1). The reaction was subjected to 300 Watt microwave irradiation with the internal temperature maintained at 100 C for 1 h. After completion of the reaction was observed by TLC, 1 N HCl (~ 9 mL) was added to the reaction mixture to obtain a final pH of 6.0. The solvent was then removed under reduced pressure and water was azeotropically removed with 3 X 10 mL of toluene. The crude compound was isolated on Si02 using hexane/EA and recrystallised from toluene to give 267 mg (63%) of white solid; MP = 176.6 - 177.0 C. 1H NMR (400 MHz, CDC13): delta 6.76 (t, 1 H, J = 7.5 Hz, Ar), 7.13 (t, 1 H, J = 7.3 Hz, Ar), 7.23 (d, 1 H, J = 8.7 Hz, Ar), 7.26-7.28 (m, 2 H, Ar), 7.33-7.39 (m, 3 H, Ar), 8.04 (dd, 1 H, J = 1.6 Hz and J = 8.1 Hz, Ar), 9.33 (s, 1 H, C02H).
63%
With copper(l) iodide; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation;
A microwave reactor tube was charged with ortho-iodo benzoic acid (29) (496 mg, 2 mmol), aniline (31) (0.45 mL, 4 mmol), K2CO3 (832 mg, 6 mmol), CuI (400 mg, 2.08 mmol) and 10 mL DMF/H2O (9:1). The reaction was subjected to 300 Watt microwave irradiation with the internal temperature maintained at 100 oC for 1 h. After completion of the reaction was observed by TLC, 1 N HCl (~ 9 mL) was added to the reaction mixture to obtain a final pH of 6.0. The solvent was then removed under reduced pressure and water was azeotropically removed with 3 X 10 mL of toluene. The crude compound was isolated on SiO2 using hexane/EA and recrystallised from toluene to give 267 mg (63%) of white solid; MP = 176.6 - 177.0 oC. (MP Lit ADDIN EN.CITE Scherrer1980143414314317Scherrer, Robert A.Beatty, Helga R.Preparation of o-substituted benzoic acids by the copper(II)-catalyzed reaction of diphenyliodonium-2-carboxylate with anilines and other nucleophilesJ. Org. Chem.J. Org. Chem.2127-314511iodonium carboxyphenyl aniline condensationanthranilic acid phenylbenzoic acid phenoxybenzothiazinone phenylcopper catalyst carboxyphenyliodonium condensation1980//0022-326310.1021/jo01299a02010.1021/jo01299a0204: 180 oC) 1H NMR(matches Lit ADDIN EN.CITE Mei2006875878717Mei, XuefengAugust, Adam T.Wolf, ChristianRegioselective Copper-Catalyzed Amination of Chlorobenzoic Acids: Synthesis and Solid-State Structures of N-Aryl Anthranilic Acid DerivativesJ. Org. Chem.J. Org. Chem.142-149711regioselective copper catalyzed amination chlorobenzoic acidprepn solid structure arylanthranilic derivcrystallog e arylanthranilic deriv hydrogen bond2006//American Chemical Society0022-326310.1021/jo051880910.1021/jo05188095) (400 MHz, CDCl3): delta 6.76 (t, 1 H, J = 7.5 Hz, Ar), 7.13 (t, 1 H, J = 7.3 Hz, Ar), 7.23 (d, 1 H, J = 8.7 Hz, Ar), 7.26-7.28 (m, 2 H, Ar), 7.33-7.39 (m, 3 H, Ar), 8.04 (dd, 1 H, J = 1.6 Hz and J = 8.1 Hz, Ar), 9.33 (s, 1 H, CO2H).
With 20% palladium hydroxide-activated charcoal; sodium carbonate; In water; at 80 - 90℃; for 6h;
2-Iodobenzoic acid (100 gm, 0.4032 moles) , 4-(Trifluoromethyl)phenyl boronic acid (99.55 gm, 0.524 moles), sodium carbonate (164 gm, 1.55 moles) and 20 % palladium hydroxide on carbon (15 gm) in water (3.0 L) was heated to 80-90C for 6 hrs. The progress of the reaction was monitored by HPLC. After completion of the reaction the reaction mass was cooled 70-80C and filtered through hyflow bed. The filtrate was cooled to room temperature and the pH was adjusted to 1-2 with hydrochloric acid. The precipitated solid was filtered and washed with 1.0 L water. The solid was dissolved in 376 ml ethanol at 60-70C and charcolised. The solution was filtered through hyflow bed at 60C and washed with 180 mL hot ethanol. Water (1.086 L ) was added to the filtrate at 50 -60C and the precipitated solid was cooled to room temperature. The solid was filtered and dried in air oven for 12 hrs at 60C to afford 80 gm of 4'- (Trifluoromethyl)biphenyl-2-carboxylic acid as a white solid (Yield 74.55 %, HPLC purity 99.98 %).
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;
1,2,3-triazole(0.7 ), 2-iodo-benzoic acid (1.0 ), cesium carbonate (2.36 g, 7.20 mmol)Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.10 g, 0.75 mmol), cuprous iodide (0.08 g, 0.40 mmo 1), N, N-dimethyl Amide (18 mL)Were successively added to a 100 mL single-necked round bottom flask and gradually warmed to 100 C for 4 hours under nitrogen protection.The reaction was quenched, cooled, diluted with tap water and extracted with ethyl acetate (200 mL X).The aqueous layer was acidified with concentrated hydrochloric acid (rhoH- = 1 ~ 2) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure and purified by column chromatography. (Dichloromethane / methanol (v / v) = 30/1) gave the title compound (yellow solid, 0.511 g, 67%)
2-iodobenzoic acid (1 g, 4.03 mmol), 2H-l,2,3-triazole (0.334 g, 4.84 mmol), copper(I) iodide (0.768 g, 4.03 mmol), cesium carbonate (2.63 g, 8.06 mmol) were reacted in DMF at 120 C under microwave irradiation for 20 minutes. Then the reaction was monitored confirming the presence of the required product. Large amount of starting material resulted left. The reaction was further irradiated for 20 minutes at 120 C. Solvent was then removed under vacuum, poured into water (100 ml) and neutralised with 37% HC1. Aqueous phase was extracted with Et20 (3x100 ml), and the collected organic phases were concentrated to give 1 g of crude material. This was purified with Biotage SP1 (over a 340g C18 column) eluting with a gradient of ACN and water (modified with 0.5% HCOOH). Fractions were collected and concentrated under vacuum to give the title compound D43 as colourless solid (140 mg). UPLC (GEN QC Basic): rt = 0.29 minutes, peak observed: 188 (M-l) C9H7N302 requires: 189. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 6.47 (br. s., 1 H) 7.47 - 7.59 (m, 1 H) 7.66 (t, 1 H) 7.75 - 7.87 (m, 3 H) 7.91 (d, 1 H)
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF (1.0 mL) was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), copper(I) iodide (0.25 g, 1.2 mmol), Cs2CO3 (7.08 g, 21.7 mmol), and trans-N,N?-dimethylcyclohexane-l ,2-diamine (0.31 g, 2.17 mmol). The mixture was heated at 120 CC for 12h. The reaction was cooled to ii, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on Si02 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the title compound.?HNMR (500 MHz, DMSO-d6) 3 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. LRMS m/z (M+H) 190.2 found, 190.2.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
To a solution of 2-iodobenzoic acid (3.0 g, 12.1 mmol) in DMF was added 1,2,3- triazole (1.5 g, 21.7 mmol), Cs2C03(7.1 g, 21.7 mmol), Cul (114 mg, 0.6 mmol), and trans-N,K- dimethylc)rclohexane-l,2-diamine (310 mg, 2.2 mmol). After heating at 120 C for 10 min in a microwave reactor, the mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (MeOH in DCM with 0.1% AcOH) to give Intermediate H as the faster eluting isomer. 1H NMR (DMSO-d6 , 500MHz) delta 13.05 (brs, 1 H), 8.12 (s, 2H), 7.81-7.52 (m, 4H).
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
Intermediate A 2-(2H-l .2.3-Triazol-2-yl)benzoyl acid A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF (1.0 mL) was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), copper(I) iodide (0.25 g, 1.2 mmol), Cs2C03 (7.08 g, 21.7 mmol), and fras-N,N'-dimethylcyclohexane-l ,2-diamine (0.31 g, 2.17 mmol). The mixture was heated at 120 C for 12h. The reaction was cooled to rt, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on Si02 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the title compound.1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. LRMS m/z (M+H) 190.2 found, 190.2.
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
To a solution of 2-iodobenzoic acid (3.0 g, 12.1 mmol) in DMF was added 1,2,3- triazole (1.5 g, 21.7 mmol), Cs2CO3 (7.1 g, 21.7 mmol), Cul (114 mg, 0.6 mmol), and trans-N,N?dimethylcyclohexane- 1 ,2-diamine (310 mg, 2.2 mmol). After heating at 120 C for 10 mm in amicrowave reactor, the mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (MeOH in DCM with 0.1% AcOH) to give Intermediate N as the faster eluting isomer. ?H NMR (DMSO-d6, 500MHz) oe 13.05 (brs, 1 H), 8.12 (s, 2H), 7.8 1-7.52 (m, 4H).
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 10h;Microwave irradiation;
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF (1.0 mL) was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), CsCO3 (7.08 g, 21.7 mmol), and trans-N,N'- dimethylcyclohexane-l52-diamine (0.31 g, 2.17 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc5 and filtered through Celite. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-l52,3-triazol-2-yl)benzoyl acid. Data for 2-triazolyl isomer: 1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s , IH)5 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired l-(2H-l,2,3-triazol-2-yl)benzoic acid eluted second. A portion of the desired acid (0.10 g, 0.53 mmol) was treated with thionyl chloride (0.59 g, 5.3 mmol) in dichloromethane (5.0 mL) at rt. After stirring at RT for 1 h, the mixture was concentrated, azeotroping with benzene to yield acid chloride A-3.
With copper(l) iodide; caesium carbonate; N,N?-trans-dimethyl cyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
2-(2H-l,2.3-triazol-2-vDbenzoic acid B-3A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with (1.5 g, 21.7 mmol) 1,2,3-triazole, 7.08 g (21.7 mmol) CsCO3, 114 mg (0.60 mmol) CuI and 310 mg (2.17 mmol) trans-N,N'-dimethylcyclohexane-l,2-diamine. The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc, and <n="35"/>filtered through CeIi te. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-l,2,3-triazol-2-yl)benzoyl acid, B-3. Data for B-3: 1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s , IH), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired l-(2H-l,2,3-triazol-2-yl)benzoic acid eluted second.
2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate; acetic acid; In N,N-dimethyl-formamide;
Reference Example 2-5 2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (5.23 g, 30 mmol), o-iodobenzoic acid (8.93 g, 36 mmol), copper acetate (II) (0.654 g, 3.6 mmol) and potassium carbonate (4.98 g, 36 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux for 1 hour under an argon atmosphere. After the solution was cooled to room temperature, the mixture was poured into water. The solution was made weakly acidic by the addition of acetic acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give the title compound (8.64 g, 98% yield).
With potassium carbonate; In N,N-dimethyl-formamide;
(a) To a solution of 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) is added potassium carbonate (33.4 g, 0.242 mol), followed by 5-amino-1-ethylpyrazole (24.2 g, 0.218 mol) and finally Cu(OAc)2.H2 O (0.9 g, 0.0045 mol). The reaction mixture is refluxed overnight, cooled and then poured into ice water. Acetic acid and HCl are added until a pH of about 4 is obtained. A precipitate forms which is collected by filtration, washed with water and dried to afford 21.4 g of N-(1-ethylpyrazol-5-yl) anthranilic acid.
With potassium carbonate; In N,N-dimethyl-formamide;
(a) To a solution of 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) was added potassium carbonate (33.4 g, 0.242 mol), followed by 5-amino-1-ethylpyrazole (24.2 g, 0.218 mol) and finally Cu(OAc)2.H2 O (0.9 g, 0.0045 mol). The reaction mixture was refluxed overnight, cooled and then poured into ice-water. Acetic acid and HCl were added until a pH of about 4 was obtained. A precipitate formed which was collected by filtration, washed with water and dried to afford 21.4 g of N-(1-ethylpyrazol-5-yl) anthranilic acid.
EXAMPLE 4 Dibenz[b,f][1,4]Thiazepin-11(10H)-One A mixture of 1.4 grams of 2-aminothiophenol, 2.5 grams of 2-iodobenzoic acid, 0.5 grams of copper bronze, 2.6 grams of potassium hydroxide and 15 ml of water were refluxed under nitrogen for 51/2 hours. The mixture was then filtered and the filtrate acidified with concentrated hydrochloric acid, stirred for 1 hour and the solid collected by suction filtration. After washing with ethanol and diethyl ether, the solid was dried in vacuo to give 2.1 grams (75% of theory) of 2-[(2'-aminophenyl)thiol]benzoic acid as an off white powder, m.p. 220 C. (dec.) suitable for use in the next reaction. The amino acid described above was heated neat to 200-230 C. for 4 hours. Crystallization from ethyl acetate provided 0.22 grams (23% of theory) of dibenz[b,f][1,4]thiazepin-11(10H)-one as a light beige crystalline power, m.p. 258-259 C.
1-(2-carboxyphenyl)-3-methyl-6-nitroindazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.6 g (69.4%)
With potassium carbonate;
EXAMPLE 11 5-Amino-2-methyl-6H-pyrazolo[4,5,1-d,e]acridin-6-one (Compound 11): 3-Methyl-6-nitroindazole (64.5 g), 46.0 g of 2-iodobenzoic acid, 40.8 g of potassium carbonate and 1.89 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 53.6 g (69.4percent) of 1-(2-carboxyphenyl)-<strong>[6494-19-5]3-methyl-6-nitroindazole</strong>.
With hydrogenchloride; potassium hydroxide; hydrogen sulfide; copper; magnesium; In sodium hydroxide; water; benzene;
Reaction of <strong>[60811-18-9]2-chloro-5-bromofluorobenzene</strong> (84.6 g) with magnesium (10.7 g) in ether (200 ml) yields a solution of Grignard reagent. This is cooled to 20-25 C. and powdered sulfur (10 g) is added portionwise during 80 minutes while stirring. The mixture is diluted with ether (100 ml), stirred for one hour at room temperature and then set aside overnight. Next day, the mixture is decomposed by dropwise addition of dilute (1:1) hydrochloric acid (200 ml) while stirring. On addition of ether, the ethereal layer is separated and the product is taken up in an excess of 10% sodium hydroxide solution. The aqueous layer, containing the sodium salt of the product, is separated, acidified by addition of hydrochloric acid and the liberated 3-fluoro-4-chlorothiophenol is taken up in benzene, b.p. 97-98 C./Torr, yield 35.7 g (54%). The thiol from the preceding experiment (72.3 g), followed by o-iodobenzoic acid (98 g) and molecular copper (2.7 g), is added to a solution of potassium hydroxide (75 g) in water (800 ml). The mixture is stirred and refluxed for 7 hours, filtered while warm and the filtrate acidified by addition of concentrated hydrochloric acid (80 ml). After standing overnight, the product is filtered, washed with water, boiled with ethanol (800 ml), cooled, again filtered and dried, yielding 106 g (85%) of 2-(3-fluoro-4-chlorophenylthio)benzoic acid. A sample of the product is crystallized from a large volume of ethanol; m.p. 231-232 C.
With sodium iodate; sulfuric acid; iodine; In chloroform; at 25 - 30℃; for 1h;
General procedure: In a four-necked flask equipped with a thermometer and a stirrer, after dissolving 13.9 g of o-fluorobenzoic acid in 69.5 g of sulfuric acid and 55.6 g of DCM, 4.5 g of sodium iodate and 13.0 g of iodine were added to the reaction solution, and stirring was started to control the reaction. The temperature is 25-30 C, the reaction is kept for 1 h, and a purple solid is precipitated in the reaction liquid. After the reaction of the raw material is completed, the reaction solution is poured into a cold aqueous solution of sodium thiosulfate to be quenched, the reaction solution is spun and filtered, and 41.7 ml is used. Recrystallization of methanol gave 20 g of 2-fluoro-5-iodobenzoic acid. The yield was 75.8% and the purity was 99.0%.
With (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;In a microwave reactor;
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with (1.5 g, 21.7 mmol) 1,2,3-triazole, 7.08 g (21.7 mmol) CsCO3, 114 mg (0.60 mmol) CuI and 310 mg (2.17 mmol) trans-N,N'-dimethylcyclohexane-1,2-diamine. The mixture was heated at 120 C. for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on SiO2 (MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-1,2,3-triazol-2-yl)benzoyl acid, A-1. Data for A-1: 1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired 2-(1H-1,2,3-triazol-2-yl)benzoic acid eluted second.
With copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
Intermediate E: 2-(2H-l,2,3-triazol-2-yl)benzoic acid Int E Step 1 : 2-(2H-l,2,3-triazol-2-yl)benzoic acid (Int E) To a solution of 2-iodobenzoic acid (3.0 g, 12.1 mmol) in DMF was added 1,2,3-triazole (1.5 g, 21.7 mmol), Cs2C03 (7.1 g, 21.7 mmol), Cul (114 mg, 0.6 mmol), and trans-N,N'-dimethylcyclohexane- 1,2-diamine (310 mg, 2.2 mmol). After heating at 120 C for 10 min in a microwave reactor, the mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (MeOH in DCM with 0.1% AcOH) to give Int E as the faster eluting isomer. 1H NMR (DMSO-d6, 500MHz) delta 13.05 (brs, 1 H), 8.12 (s, 2H), 7.81-7.52 (m, 4H).
Example 9; N-[5-(l .1 -dimethylethvO- 1.3.4-thiadiazol-2-yl1-5-r(ethylamino)sulfonyl1-2- iodobenzamide; Intermediate 14; lambda/-r5-(lJ-dimethylethyl)-l,3,4-thiadiazol-2-yll-2-iodobenzamide; 2-Iodobenzoic acid (2 mmol), EDC (2 mmol), and HOBt (4 mmol) were added to 6ml DCM and stirred at rt for 1 hour. 5-(l,l-dimethylethyl)-l,3,4- thiadiazol-2-amine (2 mmol) was added as a solution in 4ml DMF. The reaction was stirred at rt for 1 hour and then diluted with ethyl acetate. The solution was washed with IN HCl, sat. sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and then evaporated to give iV-[5-(l,l-dimethylethyl)- l,3,4-thiadiazol-2-yl]-2-iodobenzamide (750 mg) pure by LCMS.MS (ESI): 388 [M+H]+.
With copper(l) iodide; TPGS-450-M; caesium carbonate; In water; at 20℃; for 12h;Inert atmosphere; Green chemistry;
General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt % TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product.
With copper(l) iodide; TPGS-450-M; caesium carbonate; In water; at 20℃; for 12h;Inert atmosphere; Green chemistry;
General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt percent TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product.
BEAD LOADING Rink Amide MBHA resin (87 mg, 0.06 mmol, 0.69 mmol/g loading) was pre-swelled in a 5 mL disposable syringe equipped with a frit by rotating with DCM (3 mL) for 1 h. The resin was then washed with DMF (5 X 4 mL). The Fmoc protecting group on the bead was removed by treatment with 5 bed volumes (ca. 4 mL) of a 20% piperidine solution in DMF for 20 min. Meanwhile, Fmoc-Phe-OH (116 mg, 0.3 mmol, 5 equiv) was dissolved in DMF (3 mL) along with HOBt (41 mg, 0.3 mmol, 5 equiv). Diisopropyl carbodiimide (DIC) (50 muL, 0.3 mmol, 5 equiv) was then added and the resulting mixture was stirred at room temperature for 20 min. After 20 minutes, the resin was washed with DMF (5 X 4 mL). To the thoroughly washed resin bed, was added the coupling solution (Fmoc-Phe-OH,HOBt, and DIC), and the resulting mixture was rotated for 12 h. The loaded resin was then washed with DMF (5 X 4 mL) and used in subsequent Fmoc solid phase peptide synthesis as described below. FMOC REMOVAL The Fmoc group of the terminal amino acid of the growing peptide chain was deprotected by treating the resin beads (0.69 mmol/g loading) with a 20% solution of piperidine in DMF (ca. 4 mL) with rotation for three minutes. The deprotection cocktail was then discharged from the syringe and the resin beads were treated with a fresh portion of 20% piperidine in DMF for three minutes.This protocol is repeated until the resin beads have been treated with four aliquots of 20% piperidine in DMF. The final portion is then discharged from the syringe and the deprotected beads are washed with DMF (5 X 4 mL). The washed, deprotected resin beads were then immediately coupled with the next amino acid in the sequence. HOBT-MEDIATED COUPLING The next amino acid in a desired sequence was activated as the HOBt ester by dissolving the desired amino acid (0.3 mmol, 5 equivalents relative to the 0.69 mmol/g resin loading) along with HOBt (41 mg, 0.3 mmol, 5 equiv) in DMF/DCM (1:1) (3 mL). To the resulting solution was added DIC (50 muL, 0.3mmol, 5 equiv) and the resulting solution was stirred at room temperature for twenty minutes (usually while the terminal amino acid of the resin bound sequence is deprotected).The resulting solution of HOBt ester was added to the N-terminal deprotected, resin-bound, peptide sequence and the mixture was rotated for one hour. The resin beads were then thoroughly washed with DMF (5 X 4 mL). The resulting N-terminal, Fmoc-protected, resin-bound peptide sequence was then resubjected to the Fmoc removal protocol and subsequent HOBt couplings until the desired sequence had been assembled. N-TERMINAL O-IODOBENZOATE CAPPING The N-terminus of the peptide was capped with the o-iodoarylamido active site by the HOBt active ester methodology. The o-iodobenzoic acid (0.3 mmol, 5 equivalents relative to the 0.69 mmol/g resin loading) was dissolved along with HOBt (41 mg, 0.3 mmol, 5 equiv) in DMF/DCM (1:1) (3 mL). To the resulting solution was added DIC (50 muL, 0.3 mmol, 5 equiv) and the resulting solution was stirred at room temperature for twenty minutes (usually while the terminal aminoacid of the resin bound sequence is deprotected).The resulting solution of HOBt ester was added to the N-terminal deprotected, resin-bound, peptide sequence and the mixture was rotated for one hour. The resin beads were then thoroughly washed with DMF (5 X 4 mL). TFA CLEAVAGE/GLOBAL SIDE-CHAIN DEPROTECTION OF PEPTIDES Peptides were cleaved from the resin beads by employing the following protocol: The fully assembled, resin-bound peptides were prepared for cleavage by washing the beads with DMF (5 X 4 mL), DCM (5 X 4 mL), and methanol (5 X 4mL). The syringe plunger was removed from the barrel and the resin beads were dried overnight in the vacuum oven at 25 C. The following day, the resin was treated with a cleavage cocktail comprised of a mixture of TFA/H2O/TIS(95:2.5:2.5) (3 mL) for 2.5 h with minimal, intermittent agitation. The cleavage cocktail, containing the solvated, resin-free peptide was then ejected into a 5 mL pear-shaped flask and the solvent was removed under a stream of nitrogen to give a thick oil. The crude peptide was then precipitated by the addition of ice-cold diethyl ether. The solid peptide was then isolated by vacuum filtration and washed with copious amounts (ca. 15-20 mL) of cold ethyl ether. The solid peptide was then dried in vacuo. The identity of the desired sequence was verified by MALDI-TOF mass spectrometry.
BEAD LOADING Rink Amide MBHA resin (87 mg, 0.06 mmol, 0.69 mmol/g loading) was pre-swelled in a 5 mL disposable syringe equipped with a frit by rotating with DCM (3 mL) for 1 h. The resin was then washed with DMF (5 X 4 mL). The Fmoc protecting group on the bead was removed by treatment with 5 bed volumes (ca. 4 mL) of a 20% piperidine solution in DMF for 20 min. Meanwhile, Fmoc-Phe-OH (116 mg, 0.3 mmol, 5 equiv) was dissolved in DMF (3 mL) along with HOBt (41 mg, 0.3 mmol, 5 equiv). Diisopropyl carbodiimide (DIC) (50 muL, 0.3 mmol, 5 equiv) was then added and the resulting mixture was stirred at room temperature for 20 min. After 20 minutes, the resin was washed with DMF (5 X 4 mL). To the thoroughly washed resin bed, was added the coupling solution (Fmoc-Phe-OH,HOBt, and DIC), and the resulting mixture was rotated for 12 h. The loaded resin was then washed with DMF (5 X 4 mL) and used in subsequent Fmoc solid phase peptide synthesis as described below. FMOC REMOVAL The Fmoc group of the terminal amino acid of the growing peptide chain was deprotected by treating the resin beads (0.69 mmol/g loading) with a 20% solution of piperidine in DMF (ca. 4 mL) with rotation for three minutes. The deprotection cocktail was then discharged from the syringe and the resin beads were treated with a fresh portion of 20% piperidine in DMF for three minutes.This protocol is repeated until the resin beads have been treated with four aliquots of 20% piperidine in DMF. The final portion is then discharged from the syringe and the deprotected beads are washed with DMF (5 X 4 mL). The washed, deprotected resin beads were then immediately coupled with the next amino acid in the sequence. HOBT-MEDIATED COUPLING The next amino acid in a desired sequence was activated as the HOBt ester by dissolving the desired amino acid (0.3 mmol, 5 equivalents relative to the 0.69 mmol/g resin loading) along with HOBt (41 mg, 0.3 mmol, 5 equiv) in DMF/DCM (1:1) (3 mL). To the resulting solution was added DIC (50 muL, 0.3mmol, 5 equiv) and the resulting solution was stirred at room temperature for twenty minutes (usually while the terminal amino acid of the resin bound sequence is deprotected).The resulting solution of HOBt ester was added to the N-terminal deprotected, resin-bound, peptide sequence and the mixture was rotated for one hour. The resin beads were then thoroughly washed with DMF (5 X 4 mL). The resulting N-terminal, Fmoc-protected, resin-bound peptide sequence was then resubjected to the Fmoc removal protocol and subsequent HOBt couplings until the desired sequence had been assembled. N-TERMINAL O-IODOBENZOATE CAPPING The N-terminus of the peptide was capped with the o-iodoarylamido active site by the HOBt active ester methodology. The o-iodobenzoic acid (0.3 mmol, 5 equivalents relative to the 0.69 mmol/g resin loading) was dissolved along with HOBt (41 mg, 0.3 mmol, 5 equiv) in DMF/DCM (1:1) (3 mL). To the resulting solution was added DIC (50 muL, 0.3 mmol, 5 equiv) and the resulting solution was stirred at room temperature for twenty minutes (usually while the terminal aminoacid of the resin bound sequence is deprotected).The resulting solution of HOBt ester was added to the N-terminal deprotected, resin-bound, peptide sequence and the mixture was rotated for one hour. The resin beads were then thoroughly washed with DMF (5 X 4 mL). TFA CLEAVAGE/GLOBAL SIDE-CHAIN DEPROTECTION OF PEPTIDES Peptides were cleaved from the resin beads by employing the following protocol: The fully assembled, resin-bound peptides were prepared for cleavage by washing the beads with DMF (5 X 4 mL), DCM (5 X 4 mL), and methanol (5 X 4mL). The syringe plunger was removed from the barrel and the resin beads were dried overnight in the vacuum oven at 25 C. The following day, the resin was treated with a cleavage cocktail comprised of a mixture of TFA/H2O/TIS(95:2.5:2.5) (3 mL) for 2.5 h with minimal, intermittent agitation. The cleavage cocktail, containing the solvated, resin-free peptide was then ejected into a 5 mL pear-shaped flask and the solvent was removed under a stream of nitrogen to give a thick oil. The crude peptide was then precipitated by the addition of ice-cold diethyl ether. The solid peptide was then isolated by vacuum filtration and washed with copious amounts (ca. 15-20 mL) of cold ethyl ether. The solid peptide was then dried in vacuo. The identity of the desired sequence was verified by MALDI-TOF mass spectrometry.
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 24h;
General procedure: CuI (0.05 equiv), 1,10-phenanthroline (0.1 equiv) and K2CO3 (2 equiv) were placed in an oven-dried screw-capped test tube with Teflon-lined septum that was filled with nitrogen. About 2.5 mL of dry DMF was then added at room temperature. Now the corresponding aryl iodide (1.0 mmol) was added followed by MBI or FMBI (1.0 equiv) and the tube was placed in the preheated oil bath at 140 C and the reaction mixture was magnetically stirred for 22 h. After complete disappearance of iodobenzene (the progress of the reaction was followed by TLC), the reaction mixture was allowed to cool to room temperature. Then water was added and the reaction mixture was extracted with ethyl acetate. After removal of the solvent in vacuum, the crude residue was purified by column chromatography.5- (or 6-) (Difluoromethoxy)-2-(phenylsulfanyl)-1H-benzimidazole (1).
With triethylamine; In toluene; at 100℃; under 760.051 Torr; for 4h;Autoclave;
General procedure: To a 100 mL stainless steel autoclave, 2-iodobenzoic acid(1 mmol), aryl amine (2 mmol), ImmPd-IL (2 mol%), toluene (10 mL)and Et3N (2.5 mmol) were added. The autoclave was closed, purgedthree times with nitrogen followed with carbon monoxide andthen pressurized with 1 atm of CO and heated at 100C for 4 h.After completion of reaction the reactor was cooled to room tem-perature, the remaining CO gas was carefully vented, and thereactor was opened. The reactor vessel was thoroughly washedwith ethyl acetate (10-15 mL) to remove any traces of productand catalyst if present. The catalyst was filtered and the reac-tion mixture was evaporated under vacuum. The residue obtainedwas purified by column chromatography (silica gel, 60-120 mesh;petroleum ether/ethyl acetate, 95:05) to afford the desired prod-uct. The products were confirmed by GC, GC-MS,1H NMR and13C NMR spectroscopic techniques. The purity of compounds wasdetermined by GC-MS analysis.
With caesium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
EXAMPLE B2-(2H-l,2.3-triazol-2-v0benzoic acid (B- 1)A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with (1.5 g, 21.7 mmol) 1,2,3-triazole, 7.08 g (21.7 mmol) CsCO3, 1 14 mg (0.60 mmol) CuI and 310 mg (2.17 mmol) trans-N,N'-dimethylcyclohexane-l,2-diamine. The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-l,2,3-triazol-2-yl)benzoyl acid, B-I . Data for IM : 1HNMR (500 MHz, DMSO-(I6) delta 13.05 (br s , IH), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired 2-(lH-l,2,3-triazol-2-yl)benzoic acid (B-2) eluted second.
Synthesized according to a slight modification of two previously reported procedures.18 Neat2-iodobenzoic acid (3.00 g, 12.1 mmol) was cooled down to 0 C, to which was added a mixture offuming HNO3 (3.0 mL) and concentrated H2SO4 (13.5 mL). This mixture was then stirred at 0 C for 1 h,then at rt for 30 min, and finally at 135 C for 2 h, before being cooled back down to rt. The resultingsolution was poured into plenty of ice water and filtered. The solid was transferred to an Erlenmeyer flaskand suspended in water (300 mL), then heated to a boil. A solution of KI (2.41 g, 14.5 mmol) in water (15mL) acidified to pH 3 with a few drops of concentrated H2SO4 was added portion-wise to this boiling suspension (I2 vapors were generated with each portion). Omitting this step as in Subramanian?s reportyields the iodoso analog. The solution was filtered while still boiling, then the filtrate was stored at 4 Cfor 18 h after which time the desired compound precipitated. 2-Iodo-5-nitrobenzoic acid was thencollected by filtration while still cold to afford 1.73 g (49%) as a 13:2 mixture with the undesired2-iodo-3-nitrobenzoic acid isomer. The inseparable mixture was used as is in the next step.Characterization matches the data previously reported in the literature
General procedure: Equimolar quantities of compound 2 (1 mmol) and a substituted carboxylic acid were dissolved in phosphoryl chloride (5 mL) and heated at 80C for 3-6 h, the progress of reaction being monitored by TLC. The reaction mixture was then heated under reduced pressure to allow excess phosphoryl chloride to distill off, and the residue was subjected to flash chromatography on silica gel using 15-25% acetone in petroleum ether as eluent to give the target compounds 3a-m (Table 1).
With sodium sulfate; In methanol; at 20℃;Sealed tube;
General procedure: To a solution of imidazole carbaldehyde (1a-d) (100 mg, 1 equiv) in methanol (3 mL) were added successively Na2SO4 (0.2 g), amine 2a-d (1.2 equiv), alkynoic acid 3a-c (1.2 equiv) and isonitrile 4a-c (1.2 equiv) in a screw capped vial equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 24-48 h in closed vial. After completion of the reaction, the mixture was diluted with dichloromethane (100 mL) and was extracted with water (50 mL). Organic layer was washed with brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtained residue which was subjected to silica gel column chromatography (1-5 % methanol in dichloromethane) to afford the desired product 5a-r as solid.
With sodium sulfate; In methanol; at 20℃;Sealed tube;
General procedure: To a solution of imidazole carbaldehyde (1a-d) (100 mg, 1 equiv) in methanol (3 mL) were added successively Na2SO4 (0.2 g), amine 2a-d (1.2 equiv), alkynoic acid 3a-c (1.2 equiv) and isonitrile 4a-c (1.2 equiv) in a screw capped vial equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 24-48 h in closed vial. After completion of the reaction, the mixture was diluted with dichloromethane (100 mL) and was extracted with water (50 mL). Organic layer was washed with brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtained residue which was subjected to silica gel column chromatography (1-5 % methanol in dichloromethane) to afford the desired product 5a-r as solid.
With sodium sulfate; In methanol; at 20℃;Sealed tube;
General procedure: To a solution of imidazole carbaldehyde (1a-d) (100 mg, 1 equiv) in methanol (3 mL) were added successively Na2SO4 (0.2 g), amine 2a-d (1.2 equiv), alkynoic acid 3a-c (1.2 equiv) and isonitrile 4a-c (1.2 equiv) in a screw capped vial equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 24-48 h in closed vial. After completion of the reaction, the mixture was diluted with dichloromethane (100 mL) and was extracted with water (50 mL). Organic layer was washed with brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtained residue which was subjected to silica gel column chromatography (1-5 % methanol in dichloromethane) to afford the desired product 5a-r as solid.
Example 2: 3-hydroxy-6H-benzo[c]chromen-6-one A mixture of 2-lodobenzoic acid (30 gram, 0.12 mol), resorcinol (40 gram, 0.36 mol), and NaOH (17.4 g, 0.44 mol) in water (150 mL) is heated under reflux for 30 min. After the addition of aqueous CuS04 (28%, 25 mL) the mixture is refluxed for additional 10 min, during which time the product (0.62 g) precipitates as a white powder. The precipitate is filtered and washed with cold water. Yield obtained: 80.1 %, 1H NMR (DMSO) delta 6.71 (d, 1 H), 6.80 (dd, 1H), 7.51 (t, 1 H), 7.83 (t, 1 H), 8.08-8.22 (m, 3H ), 10.32 (s, 1 H).
80.1%
With sodium hydroxide; In water; for 0.5h;Reflux;
A mixture of 2-iodobenzoic acid (30 g, 0.12 mol), resorcinol(40 g, 0.36 mol), and NaOH (17.4 g, 0.44 mol) in water (150 mL)was heated under reflux for 30 min. After the addition of aqueousCuSO4 (28%, 25 mL) the mixture was refluxed for additional10 min, during which time the product (0.62 g) precipitated as awhite powder. The precipitate was filtered and washed with coldwater. Yield obtained: 80.1%, 1H NMR (DMSO-d6) d 6.71 (d, 1H),6.80 (dd, 1H, Ar-H), 7.51 (t, 1H, Ar-H), 7.83 (t, 1H, Ar-H), 8.08-8.22 (m, 3H, Ar-H), 10.32 (s, 1H, AOAH).
76%
A mixture of 2-iodobenzoic acid (6 mmol), resorcinol(18 mmol), and NaOH solution (22 mmol) in water (20 mL)was refluxed for 1 h. After the addition of aqueous CuSO4(15%, 10 mL) to the mixture, refluxing was continued foradditional 10 min. The product was filtered, and washed withice-water and obtained as a white powder. 1H NMR (DMSOd6,400 MHz): delta = 10.30 (s, 1H, OH), 8.15-8.12 (m, 3H),7.86-7.83 (m, 1H), 7.50 (s, 1H), 6.77-6.74 (m, 2H). 13CNMR (DMSO-d6, 125 MHz) delta (ppm) major rotamer:160.5 ppm for lactone carbonyl. Yield obtained: 76%.
72%
A mixture of 2-iodobenzoic acid (120 mmol), resorcinol(360 mmol), and NaOH solution (440 mmol) in water(50 mL) was refluxed for 1 h. After the addition of aqueousCuSO4 (28%, 25 mL) to the mixture, refluxing was continuedfor 10 min. The product was filtered, and washed withice-water and obtained as a white powder. Yield obtained:72%. 1H NMR (DMSO-d6, 400 MHz): delta = 10.30 (s, 1H,OH), 8.17 (m, 3H, Ar-H), 7.87 (t, 1H, Ar-H), 7.50 (t, 1H, Ar-H), 6.76 (m, 2H, Ar-H).
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 90℃; for 12h;Inert atmosphere;
General procedure: To an oven dried three neck RB containing 2-Iodobenzoic acid (1) (2mmol), benzyl amine (2) (4mmol) and CuI(0.4mmol) in DMSO(3ml) was added 0.55g of K2CO3. Then, the reaction mixture was allowed to stir at 90C under air atmosphere for 12h.The completion of the reaction was monitored by TLC. After being cooled at room temperature the reaction mixture was poured in to ice cooled water and extracted with ethyl acetate two times. The combined organic layer was washed with brine and then dried over anhydrous Na2SO4. The solvent was evaporated and the crude product was purified by column chromatography (hexane(80)/ ethyl acetate (20)) on silica gel to afford 2-phenyl-4H-benzo[d][1,3]oxazine-4-one.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;
General procedure: Preparation of Intermediates 4 To a mixture of 2-iodine benzoic acids 1 (4 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (4.8 mmol)and N-hydroxybenzotrizole (0.48 mmol) were added amines(4.8 mmol) at room temperature. The reaction mixture wasstirred overnight and washed with water successively. Theorganic layer was dried over anhydrous sodium sulfate. Then,the solvent was removed under vacuum to afford crude com-pounds 2. 2-Iodine benzamides 2 (3.00 mmol) were added to30 mL triethylamine in a round-bottom flask, then the solutionwas degassed with nitrogen for 10 min. CuI (0.306 mmol) andPdCl2(PPh3)2 (0.1044 mmol) were added and the system wasplaced under nitrogen atmosphere. Trimethylsilylacetylene(6 mmol) was added dropwise over 3 min. And the mixture washeated with stirring at 608C overnight. The reaction was allowedto cool to room temperature and then filtered over Celite. Thefiltrate was concentrated and purified by column chromatogra-phy on silica gel with petroleum ether and ethyl acetate as sol-vents to give the intermediates 3. Then, compounds 3(1.73 mmol) were added to 15mL MeOH in a flask and mixedwith K2CO3 (1.73 mmol). The flask was placed under nitrogenatmosphere and the system was stirred for 15 min, after whichH2O was added to the flask. The organic layer was extractedwith ethyl acetate, dried over Na2SO4, and concentrated undervacuum. The crude oil was then purified by column chroma-tography on silica gel to get structures 4.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;
General procedure: Preparation of Intermediates 4 To a mixture of 2-iodine benzoic acids 1 (4 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (4.8 mmol)and N-hydroxybenzotrizole (0.48 mmol) were added amines(4.8 mmol) at room temperature. The reaction mixture wasstirred overnight and washed with water successively. Theorganic layer was dried over anhydrous sodium sulfate. Then,the solvent was removed under vacuum to afford crude com-pounds 2. 2-Iodine benzamides 2 (3.00 mmol) were added to30 mL triethylamine in a round-bottom flask, then the solutionwas degassed with nitrogen for 10 min. CuI (0.306 mmol) andPdCl2(PPh3)2 (0.1044 mmol) were added and the system wasplaced under nitrogen atmosphere. Trimethylsilylacetylene(6 mmol) was added dropwise over 3 min. And the mixture washeated with stirring at 608C overnight. The reaction was allowedto cool to room temperature and then filtered over Celite. Thefiltrate was concentrated and purified by column chromatogra-phy on silica gel with petroleum ether and ethyl acetate as sol-vents to give the intermediates 3. Then, compounds 3(1.73 mmol) were added to 15mL MeOH in a flask and mixedwith K2CO3 (1.73 mmol). The flask was placed under nitrogenatmosphere and the system was stirred for 15 min, after whichH2O was added to the flask. The organic layer was extractedwith ethyl acetate, dried over Na2SO4, and concentrated undervacuum. The crude oil was then purified by column chroma-tography on silica gel to get structures 4.
2-[3-(ethoxycarbonyl)-1H-indazol-1-yl]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere;
The potassium carbonate (218 mg, 1 . 58mmol) and 2-iodo benzoic acid (313 mg, 1 . 26mmol) adding <strong>[4498-68-4]1H-indazole-3-carboxylic acid ethyl ester</strong> (200 mg, 1 . 05mmol) in N, N-dimethylformamide (20 ml) in solution. Solution with nitrogen-degassing, then adding destannylation copper (I) (20 mg, 0 . 11mmol), and then the whole in 100 C heating sleepovers. The reaction mixture in accordance with its solubility in ethyl acetate and 2MHCl distribution between, then the organic phase salt water washing, the magnesium sulfate drying, filtration, evaporation, to secure oil, methanol through the pre-washing column purification PE-AX. The compound containing several drops of triethylamine is the most a small amount of methanol. Post washing with methanol, the product of formic acid (10%)/ dichloromethane mixture to elute, to secure oil, the used directly without further purification.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere;
Potassium carbonate (218 mg, 1.58 mmol) and 2-iodobenzoic acid (313 mg, 1.26 mmol) are added to a solution of <strong>[4498-68-4]ethyl 1H-indazole-3-carboxylate</strong> (200 mg, 1.05 mmol) in N,N-dimethylformamide (20 ml). The solution is degassed with nitrogen and then copper(I) iodide (20 mg, 0.11 mmol) is added, before the whole is heated at 100 C. overnight. The reaction mixture is distributed according to its solubility between ethyl acetate and 2M HCl and then the organic phases are washed with brine, dried over magnesium sulphate, filtered and evaporated to provide an oil, which is purified by a PE-AX column pre-washed with methanol. The compound is applied in the minimal amount of methanol with several drops of triethylamine. The column is washed with methanol and the product is eluted with a formic acid (10%)/dichloromethane mixture to provide an oil, which is used directly without being purified further. (0353) LC/MS (C17H14N2O4) 311 [M+H]+; RT 2.22 (Method A)
To a reactor, 5 part of the compound represented by formula (I0-4-a) and 8 parts of potassium persulfate were added and stirred at 5 C. for 30 minutes, and then 29.45 part of sulfonic acid were added thereto and stirred at 23 C. for 30 minutes. (0614) To the obtained mixture, 5.49 parts of the compound represented by formula (I0-6-b) and 25 parts of chloroform were added and stirred at 23 C. for 2 hours. To the obtained reaction mixture, 60 parts of chloroform and 20 parts of saturated aqueous sodium hydrogen carbonate solution were added and stirred at 23 C. for 30 minutes, followed by being left for separation. To the separated organic layer, 20 parts of ion exchanged water was added and then stirred at 23 C. for 30 minutes, followed by being separated for collecting an organic layer. (0615) Then the washed one was concentrated and, 2.72 parts of the compound represented by formula (I0-6) were separated from the collected concentrated residue by silica gel column chromatography [silica gel 60N, manufactured by KANTO CHEMICAL, Co., Inc.; spherical shape, neutral, 100-210 mum, eluent: chloroform/methanol=1/1]. (0616) MASS (Mass Spectrum): 406.0 (molecular ion peak)
(E)-1-(2-cyclohexylvinyl)-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
Following a reported procedure,19 trifluoromethanesulfonic acid (TfOH, 0.533 mL, 6.00 mmol, 1.00equiv.) was added dropwise to a stirred solution of 2-iodobenzoic acid (60) (1.49 g, 6.00 mmol, 1.00equiv.) and meta-chloroperoxybenzoic acid (mCPBA-77%, 1.48 g, 6.60 mmol, 1.10 equiv.) indichloromethane (37.5 mL) at 0 C. After 15 minutes stirring at room temperature, <strong>[57002-01-4](E)-(2-cyclohexylvinyl)boronic acid</strong> (70) (1.85 g, 12.0 mmol, 2.00 equiv.) was added in one portion at 0 C. Thereaction mixture was stirred for an additional 1 hour at room temperature, then the resulting mixture wasconcentrated in vacuo. Diethyl ether (300 mL) was added and the resulting mixture was vigorouslystirred over 30 minutes. The solid was filtered off and washed with portions of diethyl ether (5 x 50 mL).The resulting solid was dissolved in dichloromethane (50 mL) and treated with a solution of saturatedaqueous sodium bicarbonate (50 mL). The mixture was vigorously stirred for 1 hour, then the organiclayer was diluted with dichloromethane (100 mL) and the two layers were separated. The aqueous layerwas extracted with additional portions of dichloromethane (3 x 50 mL) and the combined organic layerswere washed with water (50 mL) and brine (50 mL), then dried over magnesium sulfate and filtered. Thevolatiles were removed to afford pure (E)-1-(2-cyclohexylvinyl)-1,2-benziodoxol-3(1H)-one (1n) (0.654g, 1.84 mmol, 31% yield) as a beige solid.
With copper 8-hydroxyquinolinate; sodium hydroxide; In water; at 100℃; for 0.5h;Microwave irradiation;
To a reaction vessel was added 1 mmol of 2-iodobenzoic acid, <strong>[6313-33-3]formamidine hydrochloride</strong> (also called <strong>[6313-33-3]formamidine hydrochloride</strong>, CH4N2HCDI mmol, 8-quinolinato copper (B) 0.05 mmol, 1 mmol of sodium hydroxide and 3 mL of water were placed in a microwave reactor and heated in a microwave reactor at 150 W for 100 C to 30 minutes, and then cooled to room temperature, extracted with ethyl acetate The product was concentrated under reduced pressure and the product was purified by column chromatography to give a white solid in 94% yield.
With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
With sodium azide; poly[(μ3-3,5-dinitrobenzoato-κ3O1:O1':O3)(μ2-hydroxido-κ2O:O)copper(II)]; ammonium acetate; In dimethyl sulfoxide; at 140℃; for 8h;Catalytic behavior;
General procedure: A mixture of substituted vic-diketone/α-hydroxy ketone (1 mmol), 2-iodobenzoic acid (1 mmol), organo Cu (II)-catalyst (10 mol %), NH4OH (1 mol%) and NaN3 (1 mmol) in DMSO (3 mL) was taken in a 50 mL round bottom flask and refluxed for specified time. The progress of reaction was monitored by TLC. After the completion of the reaction the product was extracted with Ethyl acetate and further purified by Column Chromatography using silica gel 60-120 mesh.
With ammonium hydroxide; sodium azide; poly[(μ3-3,5-dinitrobenzoato-κ3O1:O1':O3)(μ2-hydroxido-κ2O:O)copper(II)]; In dimethyl sulfoxide; for 6h;Reflux;
General procedure: A mixture of substituted vic-diketone/α-hydroxy ketone (1 mmol), 2-iodobenzoic acid (1 mmol), organo Cu (II)-catalyst (10 mol %), NH4OH (1 mol%) and NaN3 (1 mmol) in DMSO (3 mL) was taken in a 50 mL round bottom flask and refluxed for specified time. The progress of reaction was monitored by TLC. After the completion of the reaction the product was extracted with Ethyl acetate and further purified by Column Chromatography using silica gel 60-120 mesh.
With potassium acetate; copper diacetate; copper; at 120℃;Inert atmosphere;
A mixture of a (7.9 g, 38 mmol, 1.2 eq), h (8.0 g, 32 mmol, 1.0 eq), Cu powder (0.61 g, 9.6 mmol, 0.3 eq), Cu(OAc)2 (1.7 g, 9.6 mmol, 0.3 eq), and KOAc (9.4 g, 96 mmol, 3.0 eq) in 2-pentanol (200 mL) was stirred at 120 C overnight under N2 atmosphere, and cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo Tire residue was dissolved in H2O (100 mL), acidified to pi 1 5 with 1 N HC1, and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine, dried over anhydrous NacSQy and concentrated to afford the crude which was triturated with acetonitrile (30 mL), filtered to afford c (4.2 g, 40%) as a yellow solid. LC/MS: 326.0 [M+H]+.
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