Structure of 89642-49-9
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| CAS No. : | 89642-49-9 |
| Formula : | C7H3BrN2O2 |
| M.W : | 227.02 |
| SMILES Code : | N#CC1=CC=C(Br)C([N+]([O-])=O)=C1 |
| English Name : | 4-Bromo-3-nitrobenzonitrile |
| MDL No. : | MFCD00982006 |
| InChI Key : | FXRMUJPWDOLCLX-UHFFFAOYSA-N |
| Pubchem ID : | 3926861 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 47.68 |
| TPSA ? Topological Polar Surface Area: Calculated from |
69.61 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.39 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.16 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.23 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.02 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.33 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.43 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.91 |
| Solubility | 0.278 mg/ml ; 0.00122 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.25 |
| Solubility | 0.126 mg/ml ; 0.000557 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.72 |
| Solubility | 0.429 mg/ml ; 0.00189 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.15 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.97 |
* 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.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With ethanol; sodium acetate |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56% | With sulfuric acid; nitric acid at 0 - 20℃; for 3h; | 1 4-Bromo-3-nitrobenzonitrile To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H2SO4 (10 mL) was added dropwise at 0° C. nitric acid (6 mL). The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2.5 h. The resulting solution was poured into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral. The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100% CH3CN, 5 min gradient; ESI-MS 227.1 Ink (MH+). |
| With nitric acid | ||
| With sulfuric acid; potassium nitrate Eingiessen in Wasser; |
| With nitric acid In sulfuric acid | 1 4-Bromo-3-nitrobenzonitrile Example 1 4-Bromo-3-nitrobenzonitrile To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H2SO4 (10 mL) was added dropwise at 0° C. nitric acid (6 mL). The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2.5 h. The resulting solution was poured into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral. The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100% CH3CN, 5 min gradient; ESI-MS 227.1 m/z (MH+). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 84% | With iron; ammonium chloride In methanol; water at 60℃; | 5.11. General Procedure A: nitroaryl reduction General procedure: The appropriate nitroaryl (1 eq), iron powder (4 eq), and ammoniumchloride (6 eq) were combined in 2:1 methanol/water (0.2 M) andstirred at 60 C for 18-24 h. Once cooled to r.t., the reaction mixture waspassed through a plug of Celite. The filtrate was extracted with DCM (3x)and the combined organic portions were washed with brine (1x), driedover sodium sulfate, filtered, and concentrated in vacuo to afford theproduct. The product was purified by column chromatography ifrequired. |
| With hydrogenchloride; tin(ll) chloride | ||
| With ethanol; tin(ll) chloride Reflux; | 10 3-amino-4-bromobenzonitrile (SC9a). 4-Bromo-3 -nitrobenzonitrile (1g, 4.4 mmol) in EtOH (10 ml) was treated with SnCl2(4.17 g, 22 mmol) and heated under reflux for 90 min. The mixture was cooled down, diluted with EtOAc poured to crushed ice, basified with sat. NaHCCE and the thick precipitate was filtered off and washed with EtOAc. The filtrate was washed with brine, dried over MgSO4and evaporated. The crude product was used without further purification. White solid (0.74g, 85%). |
| With ethanol; tin(ll) chloride Reflux; | 10 3-amino-4-bromobenzonitrile (SC9a). 4-Bromo-3 -nitrobenzonitrile (1g, 4.4 mmol) in EtOH (10 ml) was treated with SnCl2(4.17 g, 22 mmol) and heated under reflux for 90 min. The mixture was cooled down, diluted with EtOAc poured to crushed ice, basified with sat. NaHCCE and the thick precipitate was filtered off and washed with EtOAc. The filtrate was washed with brine, dried over MgSO4and evaporated. The crude product was used without further purification. White solid (0.74g, 85%). | |
| > 99 %Spectr. | With hydrogen In ethanol at 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 66% | With triethylamine at 60℃; for 3h; | |
| 66% | With copper(l) iodide; triethylamine at 60℃; for 3h; | 3; 3.g General Procedure for Silyl Acetylenes (61 b,e,f). Cul (2 mol %) was added to a stirred mixture of an aryl halide 60, (trimethylsilyl)acetylene (min. 1.3 equiv), and PdCl2(PPh3)2 (2 mol %) in triethylamine. See . The mixture was heated at 60 °C until the reaction was complete (ca. 3 h). Salts were filtered off and washed with EtOAc. Combined filtrates were evaporated under reduced pressure, and the residue was purified by column chromatography eluding with hexane/EtOAc. The recovered material was recrystallized as necessary. 3-nitro-4-[2-(trimethylsilyl)ethynyl]benzonitrile (61 b) was prepared from aryl bromide 60b as an off-white solid (1.61 g, 66%): mp 81-82 °C (toluene/hexane); 1H NMR δ 8.69 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 8.0 and 1.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 0.27 (s, 9H); HPLC (Method B) tR 8.39 min (100 area % at 254 nm). Anal. (C12H12N2O2Si) C, H, N. A second general method is depicted in Scheme 2 immediately hereinabove and comprises the cycloaddition of cyanophenylacetylenes 51 and benzaldehyde chlorooximes 52 in the presence of bis(tributyltin) oxide, see Moriya, O., et al., J. Chem. Soc., Perkin Trans., 1, 413-417 (1994); Moriya, O., et al., J. Chem. Soc., Chem. Commun., 17-18 (1991), or triethylamine, see Thomsen, l., et al., Acta Chem. Scand. (B), 319-313 (1988), in nonpolar solvents to give isoxazole dinitriles 53a-h,k-s and bromonitrile 53i. The latter was treated with copper(I) cyanide to give dinitrile 53j. See Friedman. L., et al., J. Org. Chem., 26, 2522-2524 (1961). This method also afforded alternate routes to dinitriles 50a,b,g, k prepared by the first method as provided in Scheme 1. The phenylacetylene synthons 51a-g were prepared as shown in Scheme 3 below. Starting materials 60a,e,g were commercially available. Nitration of 60a gave 60b. See Borsche, W., L., et al., Chem. Ber., 49, 2222-2243 (1916). The latter was reduced to aniline 56, see Blanksma, J. J., et al., Recl. Trav. Chim. Pays-Bas, 66, 365-373 (1947), which underwent diazotization followed by treatment with copper(l) chloride to give chlorobenzene 60c. Triflate 60d was prepared by treatment of 4-bromo-3-hydroxybenzonitrile with triflic anhydride. The preparation of aryl iodide 60f began with the known transformation of aldehyde 57 to iodo derivative 58. See Lulinski, P., et al., Bull. Chem. Soc. Jpn., 73(4), 951-956 (2000). Treatment of 58 with hydroxylamine hydrochloride gave aldoxime 59, which was dehydrated to give nitrile 60f using acetic anhydride. The aryl halides or triflates 60a-g were treated with (trimethylsilyl)acetylene, see Roesch. K. R., et al., J. Org. Chem., 66, 412-420 (2001), or with 2-methyl-3-butyn-2-ol, see Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998), to give intermediates 61a-f or 62a-f, respectively, of which 61a,d and 62a have been reported previously. See Dirk. S. M., et al., Tetrahedron, 59(3), 287-293 (2003); Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The acetylenes 51 (of which 51a,e were known previously), see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997); Dulog, L., et al., Liebigs Ann. Chem., 9, 1663-1671 (1995), were obtained by the treatment of intermediates 61 or 62 with cesium carbonate in acetonitrile or sodium hydride in toluene, respectively. See Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The use of cesium carbonate in acetonitrile was introduced for the deprotection of intermediates 61 after the treatment of compound 61b with potassium carbonate in methanol, see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997), failed to give product 51b. The pathway using 2-methyl-3-butyn-2-ol provided more economical preparations of all phenylacetylenes 51 except nitro analog 51b. ; Reagents and conditions: (a) fuming HNO3, H2SO4; (b) Fe, AcOH, EtOH; (c) NaNO2, aq. HCl, then CuCl; (d) NalO4, l2, AcOH, AC2O, H2SO4; (e) NH2OH HCl, Py, EtOH (f) Ac2O; (g) TMSA, Pd2Cl2(PPh3)2, Cul, Et3N; (h) TMSA, PPh3, Pd(PPh3)4, Cul, piperidine; (j) 2-methyl-3-butyn-2-ol, Pd2Cl2(PPh3)2, Cul, Et3N; (k) 2-methyl-3-butyn-2-ol, 10% Pd/C, PPh3, Cul, aq. K2CO3/DME; (I) Cs2CO3, aq. CH3CN or MeOH; (m) NaH, toluene. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3: 67 percent / bis(tributyltin) oxide / CH2Cl2 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3: 83 percent / bis(tributyltin) oxide / benzene |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2.1: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3.1: 67 percent / bis(tributyltin) oxide / CH2Cl2 4.1: HCl / ethanol; dioxane / 0 - 20 °C 4.2: 32 percent / NH3 / ethanol |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2.1: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3.1: 83 percent / bis(tributyltin) oxide / benzene 4.1: HCl / ethanol; dioxane / 0 - 20 °C 4.2: 21 percent / NH3 / ethanol |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 4-bromo-3-nitrobenzonitrile; Trimethylenediamine Stage #2: With hydrogenchloride In ethanol | 2 [0126] N i-(4-cyano-2-nitro-phenyl)-propane-l ,3-diamine monohydrochloride. mp >230°C;FTIR (KBr) cm"1: 3364.13, 2929.80, 2222.94, 1625.89, 1561.22, 1524.98, 1410.25, 1364.46, 1261.01, 1176.10, 921.75, 819.69; 1H NMR (D2O, 4.79) δ: 8.58 (IH, d, J=I.54Hz, 3-Ar-H), 7.73 (IH, dd, J=1.70, 9.13Hz, 5-Ar-H), 7.12 (IH, d, J=9.15Hz, 6-Ar-H), 3.58 (2H, t, J=6.91Hz, 3- CH2), 3.13 (2H, t, J=8.01Hz, 1-CH2), 2.08 (2H, m, 2-CH2); 13C NMR (DMSO-d6) δ: 146.68, 137.58, 131.90, 131.01, 118.22, 115.90, 96.29, 36.06, 29.78, 25.77; HRMS(CI) calculated for C10H12N4O2: (M+l) 221.1039, found 221.1040. |

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