* 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.
With indium; acetic acid In ethyl acetate for 5 h; Reflux; Inert atmosphere
General procedure: 2-Nitroaniline derivative (1 mmol) was added to a mixture of indium powder (574 mg, 5.0 mmol for 2-nitroaniline, 918 mg 8.0 mmol for 1,2-dinitroarene), and acetic acid (0.572 mL, 10 mmol) in ethyl acetate (2 mL), followed by the addition of trimethyl orthoester (2.0 mmol) in ethyl acetate (3 mL for 2-nitroaniline; 8 mL for 1,2-dinitroarene). The reaction mixture was stirred at reflux under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, poured into 10percent NaHCO3 (30 mL), and then extracted with ethyl acetate (30 mL.x.3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted with ethyl acetate/hexane (v/v=10/90) for 2-phenylbenzimidazole derivatives or methanol/dichloromethane (v/v=1/99) for 2-methylbenzimidazole derivatives through a silica gel column to give the corresponding benzimidazoles. The structures of the benzimidazoles were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS, and were mostly known compounds. HRMS data were reported in addition for unknown compounds.
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 10194 - 10202
3
[ 64-18-6 ]
[ 20691-72-9 ]
[ 78597-27-0 ]
Yield
Reaction Conditions
Operation in experiment
68%
at 90℃; for 12 h;
Intermediate Example 12.5-((Trimethylsilyl)ethynyl)- 1H-benzo[d]imidazolea) 5-lodo- 1H-benzo[djimidazoleTo a solution 4-ioclo-2-nitroaniline (1 g, 3.7mmol) in formic acid (10 ml), iron(2.1 g, 37 mmol) was added and heated at 90°C for 12 h. The formic acid was distilledoff and the crude was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sQdiurn sulphate. The solvent was distilled off to afford the title product in 68 percent. yield (0.85 g)..LC-MS (ES]): Calculated mass: 243.95; Observed mass: 244.8 [M+H} + (rt: 0.173 mm).
With sodium periodate; sulfuric acid; iodine; potassium iodide; sodium sulfite In water; acetic acid at 25℃; for 4 h;
General procedure: Iodination of phenol (1d) in the presence of Na2SO3 (typical procedure). A 100-mL round-bottom flask was charged with a solution of 3 mmol of phenol in 10 mL of acetic acid, and a solution of KI3 and Na2SO3 (prepared preliminarily by addition of 3 mmol of iodine and 3 mmol of Na2SO3 to a solution of 3 mmol of potassium iodide in 3 mL of water) was added rapidly. At the same time, a solution of 3 mmol of NaIO4 in 5 mL of water was added, and 0.5 mL of sulfuric acid was rapidly added using a pressure-equalizing dropping funnel. The mixture was stirred at 25°C, the progress of the reaction being monitored by TLC. When the reaction was complete, the mixture was poured into ice-cold water, and the solid product was separated by vacuum filtration, washed twice with deionized water, and dried.
95%
With Iodine monochloride In acetic acid at 20 - 50℃; for 1.5 h;
Referring to Scheme 5-1, to a stirred solution of 1 (18.8 g, 137 mmol) and NaOAc (12.7 g, 155 mmol) in AcOH (70 mL) was added IC1 (25.0 g, 155 mmol) in AcOH (40 mL) slowly over 30 min. The mixture was heated at 50 °C for 30 min and stirred at rt for additional 30 min. The reaction mixture was poured slowly into 3/40 (150 mL) while vigorous stirring and the stirring was continued for 17 h. The resulting precipitate was collected by filtration, washed with water (100 mL), dried under vacuum to give 2 (35 g, 95percent yield) as a red powder. LC-MS (ESI) m/z 264.9 (M + H)+.
95%
at 20 - 50℃; for 1.5 h;
EXAMPLE 5 - Synthesis of Compounds of Formula IVb[0327] Step a. Referring to Scheme 5-1, to a stirred solution of 1 (18.8 g, 137 mmol) and NaOAc (12.7 g, 155 mmol) in AcOH (70 mL) was added ICl (25.0 g, 155 mmol) in AcOH (40 mL) slowly over 30 min. The mixture was heated at 50 °C for 30 min and stirred at rt for additional 30 min. The reaction mixture was poured slowly into H2O (150 mL) while vigorous stirring and the stirring was continued for 17 h. The resulting precipitate was collected by filtration, washed with water (100 mL), dried under vacuum to give 2 (35 g, 95percent yield) as a red powder. LC-MS (ESI) m/z 264.9 (M + H)+.
48%
With 1,4-dibenzyl-1,4-diazoniabicyclo[2.2.2]octane dichloroiodate In neat (no solvent) at 20℃; for 0.75 h;
General procedure: General procedure for the iodination of aryl amines under solvent-free conditions.DBDABCODCI (0.5 mmol) and aryl amine (1 mmol) were triturated together in a porcelainmortar at room temperature. After completing reaction which monitored by TLC, the ethylacetate added to mixture and filtered, the organic layer washed with 5percent aqueous sodiumthiosulfate, and dried over MgSO4. The solvent was removed in vacuum and the crude mixturewas purified by column chromatography using ethyl acetate and hexane mixture and analyzedby m.p. and 1H NMR spectroscopy.
Reference：
[1] Monatshefte fur Chemie, 2002, vol. 133, # 10, p. 1325 - 1330
[2] Tetrahedron Letters, 2006, vol. 47, # 28, p. 4793 - 4796
[3] Russian Journal of Organic Chemistry, 2016, vol. 52, # 3, p. 433 - 436[4] Zh. Org. Khim., 2016, vol. 52, # 3, p. 433 - 436,4
[5] Tetrahedron, 2003, vol. 59, # 14, p. 2497 - 2518
[6] Tetrahedron, 2003, vol. 59, # 17, p. 3131 - 3156
[7] Patent: WO2011/150243, 2011, A1, . Location in patent: Page/Page column 115; 116
[8] Patent: WO2010/65668, 2010, A1, . Location in patent: Page/Page column 115-116
[9] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 23, p. 6324 - 6335
[10] Tetrahedron, 2004, vol. 60, # 1, p. 81 - 92
[11] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 10194 - 10202
[12] MedChemComm, 2013, vol. 4, # 7, p. 1118 - 1123
[13] Synthetic Communications, 1992, vol. 22, # 22, p. 3215 - 3219
[14] Synthetic Communications, 2010, vol. 40, # 23, p. 3506 - 3513
[15] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2058 - 2060
[16] Synthetic Communications, 2008, vol. 38, # 11, p. 1792 - 1798
[17] Australian Journal of Chemistry, 1983, vol. 36, # 11, p. 2317 - 2325
[18] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2445 - 2454
[19] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
[20] RSC Advances, 2014, vol. 4, # 12, p. 6267 - 6274
[21] Bulletin of the Chemical Society of Ethiopia, 2015, vol. 29, # 1, p. 157 - 162
[22] Canadian Journal of Chemistry, 2005, vol. 83, # 10, p. 1808 - 1811
[23] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1902, vol. 135, p. 179[24] Bulletin de la Societe Chimique de France, 1902, vol. <3> 27, p. 965
[25] Journal of the Chemical Society, 1928, p. 783
[26] Zhurnal Obshchei Khimii, 1934, vol. 4, p. 557,559[27] Chem. Zentralbl., 1935, vol. 106, # II, p. 505
[28] Acta Crystallographica Section B: Structural Science, 2002, vol. 58, # 4, p. 701 - 709
[29] Synthetic Communications, 2008, vol. 38, # 22, p. 3894 - 3902
5
[ 88-74-4 ]
[ 20691-72-9 ]
Yield
Reaction Conditions
Operation in experiment
68%
With iodine In ethanol; dichloromethane; water
A. Synthesis of 4-Iodo-2-nitroaniline: The procedure of Sy, W. W. (Synthetic Communications 22(22):3215-19 (1992)) was adapted. To a solution of 2-nitroaniline (1.38 g, 10.0 mMol, Aldrich, used as received) in EtOH (100 mL) was added iodine (2.54 g, 10.0 mMol, used as received) and Ag2 SO4 (3.11 g, 10.0 mMol, used as received). The mixture was stirred at room temperature for 1 h (monitored by TLC). The yellow precipitate that formed was removed by filtration and the filtrate was evaporated to dryness under reduced pressure giving 2.74 g of crude product. The sample was dissolved in dichloromethane and washed with 5percent sodium hydroxide solution (40 mL), followed by water. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was chromatographed over silica gel and eluted with chloroform. Preparative TLC (elution with chloroform) gave pure 4-iodo-2-nitroaniline (1.8 g, 68.0percent) as a yellow powder. NMR (1 H, CDCl3): δ4.832 (s, 2H); 6.658 (d, J=8.7 Hz, 1H); 7.595 (dd, J1 =1.5 Hz, J2 =8.7 Hz, 1H); 8.442 (d, J=1.5 Hz, 1H).
Reference：
[1] Patent: US5514680, 1996, A,
6
[ 364-75-0 ]
[ 20691-72-9 ]
Reference：
[1] Tetrahedron, 2010, vol. 66, # 38, p. 7642 - 7650
[2] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1926, vol. <5>12, p. 829[3] Bulletin des Societes Chimiques Belges, 1927, vol. 36, p. 372[4] Chem. Zentralbl., 1927, vol. 98, # I, p. 885
7
[ 88-74-4 ]
[ 20691-72-9 ]
[ 100704-34-5 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
8
[ 552-32-9 ]
[ 20691-72-9 ]
Reference：
[1] Journal of Chemical Research - Part S, 1998, # 4, p. 204 - 205
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 2934 - 2935
11
[ 89942-26-7 ]
[ 20691-72-9 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1913, vol. 157, p. 1156,1157[2] Bulletin de la Societe Chimique de France, 1914, vol. <4>15, p. 90,92
12
[ 89488-56-2 ]
[ 20691-72-9 ]
Reference：
[1] Journal of the Indian Chemical Society, 1962, vol. 39, # 8, p. 534 - 536
13
[ 622-50-4 ]
[ 20691-72-9 ]
Reference：
[1] Chemische Berichte, 1878, vol. 11, p. 109
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1913, vol. 157, p. 1156,1157[3] Bulletin de la Societe Chimique de France, 1914, vol. <4>15, p. 90,92
14
[ 103-84-4 ]
[ 20691-72-9 ]
Reference：
[1] Chemische Berichte, 1878, vol. 11, p. 109
15
[ 7664-93-9 ]
[ 20691-72-9 ]
[ 116529-49-8 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1914, vol. 158, p. 719[2] Bulletin de la Societe Chimique de France, 1914, vol. <4> 15, p. 382
[3] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 II, p. 579
16
[ 364-75-0 ]
[ 7664-41-7 ]
[ 20691-72-9 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1927, vol. 36, p. 375,376[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 886
17
[ 7790-99-0 ]
[ 64-19-7 ]
[ 88-74-4 ]
[ 20691-72-9 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1902, vol. 135, p. 179[2] Bulletin de la Societe Chimique de France, 1902, vol. <3> 27, p. 965
18
[ 20691-72-9 ]
[ 21304-38-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
With tin(II) chloride dihdyrate In ethanol at 75℃; for 2 h;
Commercial 4-iodo-2-nitroaniline was reduced with 5 eq tin dichloride dihydrate in ethanol solution (75°C, 2 h) to give 92percent 4- iodo-l,2-phenylenediamine as light red solid.
92%
With tin(II) chloride dihdyrate In ethanol at 75℃; for 2 h;
Commercial 4-iodo-2-nitroaniline was reduced with 5 eq tin dichloride dihydrate in ethanol solution (75° C., 2 h) to give 92percent 4-iodo-1,2-phenylenediamine as light red solid.
89.1%
With hydrogenchloride; iron In ethanol; water for 6 h; Reflux
4-iodo-2-nitroaniline (2.64 g, 10.0 mmol)Was dissolved in 80percent ethanol (60 mL)Concentrated hydrochloric acid (2.5 mL) was added.Iron powder (2.23 g, 40.0 mmol) was added,And the mixture was heated under reflux for 6 hours under stirring.After returning to room temperature,The precipitate was filtered,The solvent was distilled off under reduced pressure.After extraction with ethyl acetate (100 mL × 2) and saturated aqueous sodium hydrogen carbonate solution,The organic layer was washed with saturated brine.After dehydration with anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure,The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/1 (volume ratio)) as an elution solvent,Compound 9 was obtained in a yield of 1.98 g (89.1percent).
81%
With hydrogenchloride; tin(ll) chloride In water at 0 - 70℃;
To a stirred solution of SnC3/4 (78.0 g, 346 mmol) in concentrated HC1 (150 mL) was added 2 (25.4 g, 92.0 mmol) in three portions over 30 min at rt. The reaction mixture was heated at 70 °C for 1 h and then stirred at 0 °C overnight. The mixture was treated with 3/40 (150 mL) and stirred for 2 h. The precipitate was collected by filtration and dried under vacuum to afford 3 (17 g, 81percent yield) as a grey solid. LC-MS (ESI) m/z 235.0 (M + H)+.
81%
at 0 - 70℃;
Step b. To a stirred solution of SnCl2 (78.0 g, 346 mmol) in concentrated HCl (150 mL) was added 2 (25.4 g, 92.0 mmol) in three portions over 30 min at rt. The reaction mixture was heated at 70 °C for 1 h and then stirred at 0 °C overnight. The mixture was treated with H2O (150 mL) and stirred for 2 h. The precipitate was collected by filtration and dried under vacuum to afford 3 (17 g, 81percent yield) as a grey solid. LC-MS (ESI) m/z 235.0 (M + H)+.
Reference：
[1] Patent: WO2010/43711, 2010, A1, . Location in patent: Page/Page column 56
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6714 - 6723
[3] Patent: US2012/46307, 2012, A1, . Location in patent: Page/Page column 27
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7241 - 7257
[5] Patent: JP2016/79108, 2016, A, . Location in patent: Paragraph 0051
[6] Patent: WO2011/150243, 2011, A1, . Location in patent: Page/Page column 115; 116
[7] Patent: WO2010/65668, 2010, A1, . Location in patent: Page/Page column 116
[8] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 10194 - 10202
[9] Australian Journal of Chemistry, 1983, vol. 36, # 11, p. 2317 - 2325
[10] Patent: WO2010/17401, 2010, A1, . Location in patent: Page/Page column 75-76
[11] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4193 - 4196
[12] Angewandte Chemie - International Edition, 2012, vol. 51, # 21, p. 5226 - 5229
[13] Patent: US2013/136782, 2013, A1, . Location in patent: Paragraph 0212
[14] Journal of the Serbian Chemical Society, 2014, vol. 79, # 3, p. 277 - 282
[15] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 255 - 267
19
[ 20691-72-9 ]
[ 21304-38-1 ]
Reference：
[1] Patent: US2010/215616, 2010, A1,
20
[ 645-00-1 ]
[ 20691-72-9 ]
[ 6293-83-0 ]
[ 100704-34-5 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 2934 - 2935
21
[ 20691-72-9 ]
[ 89488-57-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With sulfuric acid; acetic acid; sodium nitrite In water at -5 - 0℃; for 0.5 h; Stage #2: With sodium iodide In water at 60℃; for 1 h;
Synthesis of (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol, (R)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol and (S)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol 1,4-Diiodo-2-nitrobenzene 4-Iodo-2-nitroaniline (6.60 g, 0.025 mol) was suspended in water (19 mL) and glacial acetic acid (17.5 mL) (Sapountzis et al., 2005, which is incorporated herein by reference). The mixture was cooled to 0° C. Sulfuric acid (17.5 mL, 0.328 mol) was added cautiously. The mixture was cooled to minus 5° C., and a solution of NaNO2 (1.90 g, 0.028 mol) in water (7.5 mL) was added dropwise at a rate that the temperature would not exceed 0° C. Upon completion of the addition the mixture was stirred for 30 minutes and was added in small portions to a boiling solution of sodium iodide (22.33 g, 0.149 mol) in water (7.5 mL) (CAUTION: vigorous nitrogen evolution). The resulting mixture was kept at 60° C. for one hour, then cooled down to room temperature, followed by addition of diethyl ether (500 mL). The ether solution was separated, washed twice with water (150 mL) and once saturated NaHCO3 (150 mL). The solution was dried over Na2SO4 and concentrated in vacuo to a solid, which was recrystallized from ethanol to yield 1,4-diiodo-2-nitrobenzene (9.30 g, 99percent). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H, J=2.0 Hz), 7.75 (d, 1 H, J=8.3 Hz), 7.56 (dd, 1 H, J=8.3 and 2.0 Hz).
Reference：
[1] Patent: US9200319, 2015, B2, . Location in patent: Page/Page column 61; 62
[2] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2445 - 2454
[3] Tetrahedron, 2004, vol. 60, # 1, p. 81 - 92
22
[ 473-34-7 ]
[ 20691-72-9 ]
[ 873386-86-8 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 783
23
[ 7647-01-0 ]
[ 473-34-7 ]
[ 20691-72-9 ]
[ 873386-86-8 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 783
With tin(II) chloride dihdyrate; In ethanol; at 75℃; for 2h;
Commercial <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> was reduced with 5 eq tin dichloride dihydrate in ethanol solution (75C, 2 h) to give 92% 4- iodo-l,2-phenylenediamine as light red solid.
92%
With tin(II) chloride dihdyrate; In ethanol; at 75℃; for 2h;
Commercial <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> was reduced with 5 eq tin dichloride dihydrate in ethanol solution (75 C., 2 h) to give 92% 4-iodo-1,2-phenylenediamine as light red solid.
89.1%
With hydrogenchloride; iron; In ethanol; water; for 6h;Reflux;
<strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (2.64 g, 10.0 mmol)Was dissolved in 80% ethanol (60 mL)Concentrated hydrochloric acid (2.5 mL) was added.Iron powder (2.23 g, 40.0 mmol) was added,And the mixture was heated under reflux for 6 hours under stirring.After returning to room temperature,The precipitate was filtered,The solvent was distilled off under reduced pressure.After extraction with ethyl acetate (100 mL × 2) and saturated aqueous sodium hydrogen carbonate solution,The organic layer was washed with saturated brine.After dehydration with anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure,The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/1 (volume ratio)) as an elution solvent,Compound 9 was obtained in a yield of 1.98 g (89.1%).
81%
With hydrogenchloride; tin(ll) chloride; In water; at 0 - 70℃;
To a stirred solution of SnC¾ (78.0 g, 346 mmol) in concentrated HC1 (150 mL) was added 2 (25.4 g, 92.0 mmol) in three portions over 30 min at rt. The reaction mixture was heated at 70 C for 1 h and then stirred at 0 C overnight. The mixture was treated with ¾0 (150 mL) and stirred for 2 h. The precipitate was collected by filtration and dried under vacuum to afford 3 (17 g, 81% yield) as a grey solid. LC-MS (ESI) m/z 235.0 (M + H)+.
81%
With hydrogenchloride; tin(ll) chloride; at 0 - 70℃;
Step b. To a stirred solution of SnCl2 (78.0 g, 346 mmol) in concentrated HCl (150 mL) was added 2 (25.4 g, 92.0 mmol) in three portions over 30 min at rt. The reaction mixture was heated at 70 C for 1 h and then stirred at 0 C overnight. The mixture was treated with H2O (150 mL) and stirred for 2 h. The precipitate was collected by filtration and dried under vacuum to afford 3 (17 g, 81% yield) as a grey solid. LC-MS (ESI) m/z 235.0 (M + H)+.
With hydrogenchloride; tin(II) chloride dihdyrate; In water; at 20 - 65℃; for 2.41667h;
4-Iodo-2-nitroaniline (35.2 g, 0.133 mol) was added in batches via an open funnel over 25 mm to a heated (65 0C) mixture of SnCl2JH2O (106.86 g, 0.465 mol) and 12 N HCl (200 ml). An additional 12N HCl (30 ml) was added and the reaction mixture was heated at 65 0C for an additional 1 h, and stirred at room temperature for 1 h. It was placed in a refrigerator for 15 h, and the precipitate was filtered. The resultant solid was transferred into a flask containing water (210 ml), cooled (ice/water), and a solution of NaOH (aq) (35 g in 70 ml of water) was added to it over 10 min with stirring. The cooling bath was removed, and vigorous stirring was continued for 45 min. The mixture was filtered and the solid was washed with water and dried in vacuo to provide iodide M47a as a tan solid (25.4 g). The product was used in the next step without further purification. 1H NMR (DMSO-dg, delta - 2.5 ppm, 500 MHz): 6.79 (d, J - 2,1H), 6.63 (dd, J = 1.9, 8.1, IH), 6.31 (d, J = 8.1, IH), 4.65 (br s, 2H), 4.59 (br s, 2H). LC/MS: Anal. Calcd. for [M+H]+ C6H8IN2: 234.97; found: 234.9.
With hydrogenchloride; tin(ll) chloride; In ethanol; water; for 1h;Reflux;
General procedure: A mixture of 10 (188 mg, 0.5 mmol) and SnCl2 (190 mg, 1.0 mmol) dissolved in 50 mL of ethanol containing 2 mL of concentrated hydrochloric acid was stirred under reflux for 1 h. After the mixture had cooled to room temperature, 2 M NaOH (100 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4. The filtrate was concentrated to give 151 mg of 11 (87.0 %). 1H NMR (400 MHz, CDCL3) delta 9.25 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.91 (dd, J = 8.8, 1.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 4.02 (s, 2H). MS (APCI): m/z calcd for C14H10IN3 346.99; found 348.00 (M+H+).
With tin(II) chloride dihdyrate; In ethyl acetate; at 20℃; for 12h;Reflux;
4-Iodo-2-nitroaniline (440 mg, 1.67 mmol, 1.0 eq.) was dissolved in EtOAc (50 mL) in a 100 mL round bottom flask at room temperature, and SnCl2.2H2O (1.88 g, 8.33 mmol, 5.0 eq.) was added. The reaction mixture was stirred at reflux for 12 h and extracted upon cooling to room temperature with saturated aq. NaHCO3 (3×30 mL). The combined aqueous layers were washed with EtOAc (2×30 mL). The resulting organic layers were combined and dried over MgSO4, and the solvent was removed in vacuo.
With hydrazine hydrate; In ethanol; 1,2-dichloro-ethane; at 30 - 50℃; for 1h;
General procedure: Ra/Ni (0.4-0.5 g) was added in small portions to a stirred solution of 6.5 mmol of the required nitro compound (4-11) in 12 mL EtOH, 12 mL 1,2-dichloroethane and 2 mL (20 mmol) hydrazine hydrate at 30 C. After completion of the Ra/Ni addition, the mixture was heated in a water bath (50 C, 60 min) and filtered through celite. The filtrate was evaporated in vacuo and crude product used for further syntheses.
With caesium carbonate; In methanol; hexane; water; butanone;
Method b: To a mixture of the <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (142 mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 mL) was dropwise added a solution of Boc2O (37.8 g, 173 mmol) in 2-butanone (170 mL) and the resulting mixture was stirred at 52 C. for 26 h. The solvent was removed in vacuum, the residue was treated with a mixture of H2O (240 mL) and MeOH (240 mL) and extracted with hexane (3*500 mL). The combined hexane layer was washed with brine (200 mL) and all aqueous layers were reextracted with hexane (300 mL). All combined hexane layers were dried over MgSO4, filtered and the solvent was removed in vacuum to give an orange solid, which was purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
With dmap; trifluoroacetic acid; In tetrahydrofuran; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Method c: To a solution of the <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23 C. was dropwise added within 70 min a solution of Boc2O (246 g, 1128 mmol) in THF (500 mL) and stirring was continued at 23 C. for 75 min. The entire mixture was evaporated to dryness and dried at HV to leave a dark brown solid (253.59 g). This material was dissolved in DCM (1100 mL), cooled to 0 C. and TFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0 C. for 2 h, poured into icecold sat. NaHCO3-sol., extracted with DCM, washed with brine and dried over MgSO4. Removal of the solvent in vacuum left a dark brown solid (199.71 g) which was coated on silica gel and purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
With caesium carbonate; In methanol; hexane; water; butanone;
Method b To a mixture of the <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (142 mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 mL) was dropwise added a solution of Boc2O (37.8 g, 173 mmol) in 2-butanone (170 mL) and the resulting mixture was stirred at 52 C. for 26 h. The solvent was removed in vacuum, the residue was treated with a mixture of H2O (240 mL) and MeOH (240 mL) and extracted with hexane (3*500 mL). The combined hexane layer was washed with brine (200 mL) and all aqueous layers were reextracted with hexane (300 mL). All combined hexane layers were dried over MgSO4, filtered and the solvent was removed in vacuum to give an orange solid, which was purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
With dmap; trifluoroacetic acid; In tetrahydrofuran; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Method c To a solution of the <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23 C. was dropwise added within 70 min a solution of Boc2O (246 g, 1128 mmol) in THF (500 mL) and stirring was continued at 23 C. for 75 min. The entire mixture was evaporated to dryness and dried at HV to leave a dark brown solid (253.59 g). This material was dissolved in DCM (1100 mL), cooled to 0 C. and TFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0 C. for 2 h, poured into icecold sat. NaHCO3-sol., extracted with DCM, washed with brine and dried over MgSO4. Removal of the solvent in vacuum left a dark brown solid (199.71 g) which was coated on silica gel and purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Preparation of (2-nitro-phenyl)-carbamic acid tert.-butyl esters from 2-nitroanilines Method a: To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0 C. was added a solution of the <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 4-iodo-2-nitrophenylisocyanate as a yellow solid.
In ethyl acetate;
Method a To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0 C. was added a solution of the <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 4-iodo-2-nitrophenylisocyanate as a yellow solid.
Example A1 (4-Iodo-2-nitro-phenyl)-carbamic Acid tert.-Butyl Ester Prepared the isocyanate from <strong>[20691-72-9]4-iodo-2-nitroaniline</strong> (12.0 g, 45.5 mmol; prepared from 2-nitroaniline according to Wilson, J. Gerald; Hunt, Frederick C. Aust. J. Chem. 1983, 36, 2317-25; CAS-No. [20691-72-9]) with diphosgene (4.1 mL, 34.1 mmol) in EtOAc (250 mL), followed by treatment with tert.-BuOH (12 mL) in CH2Cl2 (60 mL) according to the general procedure A (method a). Obtained as a yellow solid (8.23 g, 82%). MS (EI) 390 (M+); mp 92-94 C.
A. Synthesis of 4-Iodo-2-nitroaniline: The procedure of Sy, W. W. (Synthetic Communications 22(22):3215-19 (1992)) was adapted. To a solution of 2-nitroaniline (1.38 g, 10.0 mMol, Aldrich, used as received) in EtOH (100 mL) was added iodine (2.54 g, 10.0 mMol, used as received) and Ag2 SO4 (3.11 g, 10.0 mMol, used as received). The mixture was stirred at room temperature for 1 h (monitored by TLC). The yellow precipitate that formed was removed by filtration and the filtrate was evaporated to dryness under reduced pressure giving 2.74 g of crude product. The sample was dissolved in dichloromethane and washed with 5% sodium hydroxide solution (40 mL), followed by water. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was chromatographed over silica gel and eluted with chloroform. Preparative TLC (elution with chloroform) gave pure 4-iodo-2-nitroaniline (1.8 g, 68.0%) as a yellow powder. NMR (1 H, CDCl3): delta4.832 (s, 2H); 6.658 (d, J=8.7 Hz, 1H); 7.595 (dd, J1 =1.5 Hz, J2 =8.7 Hz, 1H); 8.442 (d, J=1.5 Hz, 1H).
4-Iodo-2-nitroaniline (35.2 g, 0.133 mol) was added in batches via an open funnel over 25 mM to a heated (65 C.) mixture of SnCl2.2H2O (106.86 g, 0.465 mol) and 12N HCl (200 ml). An additional 12N HCl (30 ml) was added and the reaction mixture was heated at 65 C. for an additional 1 H, and stirred at room temperature for 1 h. It was placed in a refrigerator for 15 H, and the precipitate was filtered. The resultant solid was transferred into a flask containing water (210 ml), cooled (ice/water), and a solution of NaOH (aq) (35 g in 70 ml of water) was added to it over 10 min with stirring. The cooling bath was removed, and vigorous stirring was continued for 45 min. The mixture was filtered and the solid was washed with water and dried in vacuo to provide 4-iodobenzene-1,2-diamine as a tan solid (25.4 g). The product was used in the next step without further purification. 1H NMR (DMSO-d6, =2.5 ppm, 500 MHz): 6.79 (d, J=2,1H), 6.63 (dd, J=1.9, 8.1, 1H), 6.31 (d, J=8.1, 1H), 4.65 (br s, 2H), 4.59 (br s, 2H). LC/MS: Anal. Calcd. for [M+H]+ C6R8IN2: 234.97; found: 234.9.
Intermediate Example 12.5-((Trimethylsilyl)ethynyl)- 1H-benzo[d]imidazolea) 5-lodo- 1H-benzo[djimidazoleTo a solution 4-ioclo-2-nitroaniline (1 g, 3.7mmol) in formic acid (10 ml), iron(2.1 g, 37 mmol) was added and heated at 90C for 12 h. The formic acid was distilledoff and the crude was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sQdiurn sulphate. The solvent was distilled off to afford the title product in 68 %. yield (0.85 g)..LC-MS (ES]): Calculated mass: 243.95; Observed mass: 244.8 [M+H} + (rt: 0.173 mm).
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent.
With indium; acetic acid; In ethyl acetate; for 5h;Reflux; Inert atmosphere;
General procedure: 2-Nitroaniline derivative (1 mmol) was added to a mixture of indium powder (574 mg, 5.0 mmol for 2-nitroaniline, 918 mg 8.0 mmol for 1,2-dinitroarene), and acetic acid (0.572 mL, 10 mmol) in ethyl acetate (2 mL), followed by the addition of trimethyl orthoester (2.0 mmol) in ethyl acetate (3 mL for 2-nitroaniline; 8 mL for 1,2-dinitroarene). The reaction mixture was stirred at reflux under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, poured into 10% NaHCO3 (30 mL), and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted with ethyl acetate/hexane (v/v=10/90) for 2-phenylbenzimidazole derivatives or methanol/dichloromethane (v/v=1/99) for 2-methylbenzimidazole derivatives through a silica gel column to give the corresponding benzimidazoles. The structures of the benzimidazoles were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS, and were mostly known compounds. HRMS data were reported in addition for unknown compounds.
With indium; acetic acid; In ethyl acetate; for 3h;Reflux; Inert atmosphere;
General procedure: 2-Nitroaniline derivative (1 mmol) was added to a mixture of indium powder (574 mg, 5.0 mmol for 2-nitroaniline, 918 mg 8.0 mmol for 1,2-dinitroarene), and acetic acid (0.572 mL, 10 mmol) in ethyl acetate (2 mL), followed by the addition of trimethyl orthoester (2.0 mmol) in ethyl acetate (3 mL for 2-nitroaniline; 8 mL for 1,2-dinitroarene). The reaction mixture was stirred at reflux under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, poured into 10% NaHCO3 (30 mL), and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted with ethyl acetate/hexane (v/v=10/90) for 2-phenylbenzimidazole derivatives or methanol/dichloromethane (v/v=1/99) for 2-methylbenzimidazole derivatives through a silica gel column to give the corresponding benzimidazoles. The structures of the benzimidazoles were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS, and were mostly known compounds. HRMS data were reported in addition for unknown compounds.
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