CERTIFICATE
Scheme 2.32: Synthetic path for the formation of 2-substituted benzimidazoles
2.5 Experimental Section
2.5.1 General methods and material
All manipulations were carried out under purified argon using a standard double manifold.
Tetrahydrofuran (THF), 1,4-dioxane, p-xylene were dried via double distillation over Na/Benzophenone prior to the experiment,165-166 methanol & ethanol were dried and distilled under argon according to literature procedure.165-166 The CDCl3 and DMSO-d6 were purchased either from MERCK or Sigma-Aldrich and used as such.
1H, 13C, 19F and 31P NMR spectra were recorded either on Bruker ASCEND 600 operating at 600 MHz for 1H, 150 MHz for 13C, 565 MHz for 19F & 242 MHz for 31P or on Bruker AVANCE 400 operating at 400 MHz for 1H, 100 MHz for 13C, 376 MHz for 19F & 162 MHz for 31P.
HRMS measurements were done using an Agilent Accurate-Mass Q-TOF ESI–MS 6520. GC measurements were performed on an Agilent 7820-GC instrument fitted with Agilent Front SS7 inlet N2 HP5 column (30 m length x 0.32 mm ID). X–ray crystallographic data were collected either on a Bruker Nonius Smart Apex II X−ray diffractometer or on an Oxford SuperNova microfocus X–ray diffractometer with graphite–monochromatized Mo–K
radiation. The data refinement and cell reductions were carried out either by Bruker SAINT167 program or by CrysAlisPro.168 Structures were solved by direct methods using SHELXS–14.169 The solved structures were further refined by the full matrix least–squares method using SHELXL–14.169 GC analyses (TCD detection) were performed on a Agilent 7820-GC instrument fitted with Agilent Front SS7 inlet N2 HP5 column (30 m length ´ 0.32 mm ID) using the following method: Agilent 7820-GC Detector, Oven temperature 70 C, Time at
TH-3049_166122006
Kanu Das, Ph.D Thesis, IIT Guwahati 80 starting temp: 0 min, Hold time = 10 min, Flow rate (carrier): 5 mL/min (N2), Split ration: 50, Inlet temperature: 70 C, Detector temperature: 250 C.
Synthesis of dimethyl pyridine-2,6-dicarboxylate (2.44): To a single neck round bottom flask containing pyridine-2,6-dicarboxylic acid (2.43) (4.08 g, 24.41 mmol), SOCl2 (30 mL, 413.72 mmol) was added dropwise at 0 °C. The reaction mixture was refluxed for 6 h followed by slow addition of methanol (30 mL) at 0 °C. The resulting mixture was refluxed for an additional 12 h. Subsequently, excess SOCl2
and MeOH were distilled off. Saturated NaHCO3 solution was added to the residue and stirred for 30 minutes. The product was extracted from the aqueous phase using dichloromethane. The organic fraction was dried over anhydrous Na2SO4 and the solvent was evacuated from the organic portion to yield 4.2 g (90%) of pyridine-2,6-dicarboxylate (2.44) as a white solid. 1H NMR (600 MHz, CDCl3): δ = 8.32 (d, J = 7.8 Hz, 2H, Ar), 8.03 (t, J = 7.8 Hz, 1H, Ar), 4.03 (s, 6H, CO2CH3). 13C NMR (150 MHz, CDCl3): δ = 165.18 (CO2CH3), 148.29, 138.55, 128.21 (Ar), 53.38 (CO2CH3). HRMS (ESI): m/z calculated for [C9H9NO4+H]+: 196.0610, found:
196.0612.
Synthesis of pyridine-2,6-diyldimethanol (2.45): Pyridine-2,6-dicarboxylate (2.44) (1.00 g, 5.15 mmol) was dissolved in absolute ethanol (20 mL) under an argon atmosphere. Subsequently, NaBH4 (1.21 g, 31.98 mmol) was slowly added into the above solution at 0 °C. The reaction mixture was then stirred for 2 h at room temperature followed by reflux for 6 h. The reaction mixture was concentrated under vacuum followed by addition of saturated solution of K2CO3 (40 mL). The mixture was stirred for additional 2 h at 60 °C. The product was extracted into dichloromethane (20 mL x 3) and the organic fraction was dried over anhydrous Na2SO4. Removal of volatiles under reduced pressure resulted in pyridine-2,6-diyldimethanol (2.45) as a white solid. Yield: 0.626 g (87%).
1H NMR (600 MHz, CDCl3): δ = 7.70 (t, J = 7.7 Hz, 1H, Ar), 7.19 (d, J = 7.7 Hz, 2H, Ar), 4.78 (s, 4H, CH2), 3.32 (bs, 2H, CH2OH). 13C NMR (150 MHz, CDCl3): δ = 158.51, 137.62, 119.32 (Ar), 64.51 (CH2OH). HRMS (ESI): m/z calculated for [C7H9NO2+H]+: 140.0712, found:
140.0701.
Synthesis of pyridine-2,6-dicarbaldehyde (2.46): A mixture of pyridine-2,6- diyldimethanol (2.45) (0.25 g, 1.79 mmol) and SeO2 (0.19 g 1.79 mmol) in 1,4- dioxane (10 mL) was refluxed for 12 h and then passed through a celite pad. The solvent was evaporated under vacuum to obtain a reddish type solid. Pyridine-2,6-
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Kanu Das, Ph.D Thesis, IIT Guwahati 81 dicarbaldehyde (2.46) was obtained as a white solid after purification by silica column chromatography using hexane and ethyl acetate (80:20) as eluent. Yield 0.201 g (82%). 1H NMR (600 MHz, CDCl3): δ = 10.17 (s, 2H, CH=O), 8.19 (d, J = 7.5 Hz, 2H, Ar), 8.15 – 8.03 (m, 1H, Ar). 13C NMR (150 MHz, CDCl3): δ = 192.44 (CH=O), 153.06, 138.51, 125.44 (Ar).
HRMS (ESI): m/z calculated for [C7H5NO2+H]+: 136.0399 , found: 136.0392.
Synthesis of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N- cyclohexylmethanimine) (2.47a): To 10 mL of toluene, containing pyridine-2,6-dicarbaldehyde (2.46) (0.21 g, 1.55 mmol) and cyclohexyl amine (0.32 mL, 3.31 mmol), catalytic amounts of p-toluenesulfonyl chloride (1 mg, 5 mol) was added and refluxed for 30 minutes. The solution was filtered, solvent was evaporated from filtrate and the resulting residue was extracted with hexane. The product (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N-cyclohexylmethanimine) (2.47a) was obtained as a yellow gel (0.41 g, 88%) after removal of hexane. 1H NMR (600 MHz, CDCl3): δ = 8.43 (s, 2H, N=CH), 8.00 (d, J = 7.7 Hz, 2H, Ar), 7.76 (t, J = 7.8 Hz, 1H, Ar), 3.30 (ddd, J = 10.7, 6.5, 4.1 Hz, 2H, NCH(CH2)5), 1.83 (dt, J = 13.2, 3.7 Hz, 4H, NCH(CH2)5), 1.76 (dd, J = 12.5, 3.8 Hz, 4H), 1.72 – 1.64 (m, 2H, NCH(CH2)5), 1.59 (tdd, J = 12.9, 10.8, 3.7 Hz, 4H, NCH(CH2)5), 1.44 – 1.31 (m, 4H, NCH(CH2)5), 1.31 – 1.18 (m, 2H, NCH(CH2)5). 13C NMR (150 MHz, CDCl3): δ = 159.51 (N=CH), 154.71, 137.13, 122.25 (Ar), 69.78 (NCH(CH2)5), 34.26, 25.71, 24.82 (NCH(CH2)5). HRMS (ESI): m/z calculated for [C19H27N3+H]+: 298.2283, found: 298.2304
Synthesis of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N- phenylmethanimine) (2.47b): To 25 mL of toluene, containing pyridine-2,6-dicarbaldehyde (2.46) (1.0 g, 7.4 mmol) and aniline (1.5 mL, 16.4 mmol) catalytic amounts of p-toluenesulfonyl chloride (5 mg, 25 mol) was added and refluxed for 30 minutes. The solution was filtered, solvent was evaporated from filtrate and the resulting residue was extracted with hexane. The product (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N-phenylmethanimine) (2.47b) was obtained as a reddish yellow solid (1.71 g, 81%) after removal of hexane. 1H NMR (600 MHz, CDCl3): δ = 8.69 (s, 2H, N=CH), 8.30 (d, J = 7.7 Hz, 2H, Ar), 7.95 (t, J = 7.7 Hz, 1H, Ar), 7.47 – 7.41 (m, 4H, Ar), 7.37 – 7.28 (m, 6H, Ar). 13C NMR (150 MHz, CDCl3): δ = 160.29 (N=CH), 154.76, 150.94, 137.49, 129.41, 127.07, 123.42, 121.33 (Ar). HRMS (ESI): m/z calculated for [C19H15N3+H]+: 286.1344, Found 286.1407.
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Kanu Das, Ph.D Thesis, IIT Guwahati 82 Synthesis of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N- isopropylmethanimine) (2.47c): To 10 mL of ethanol, containing pyridine-2,6-dicarbaldehyde (2.46) (0.21 g, 1.55 mmol) and isopropyl amine (0.32 mL, 3.91 mmol) catalytic amounts of p-toluenesulfonyl chloride (1 mg, 5 mol) was added and refluxed for 30 minutes. The solution was filtered, solvent was evaporated from filtrate and the resulting residue was extracted with hexane. The product (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N-isopropylmethanimine) (2.47c) was obtained as a reddish yellow oil (0.30 g, 90%) after removal of hexane. 1H NMR (400 MHz, CDCl3): δ = 8.42 (s, 2H, N=CH), 8.02 (d, J = 7.8 Hz, 2H, Ar), 7.77 (t, J = 7.7 Hz, 1H, Ar), 3.65 (septet, J = 6.4 Hz, 2H, NCH(CH3)2), 1.28 (d, J = 6.4 Hz, 12H, NCH(CH3)2). 13C NMR (100 MHz, CDCl3):
δ = 159.23 (N=CH), 154.72, 137.17, 122.29 (Ar), 61.51 (NCH(CH3)2), 24.08 (NCH(CH3)2).
HRMS (ESI): m/z calculated for [C13H19N3+H]+ 246.1970 , found: 246.1954.
Synthesis of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N- tertbutylmethanimine) (2.47d): To 10 mL of ethanol, containing pyridine-2,6-dicarbaldehyde (2.46) (0.23 g, 1.70 mmol) and tert-butyl amine (0.5 mL, 4.7 mmol), catalytic amounts of p-toluenesulfonyl chloride (1 mg, 5 mol) was added and refluxed for 30 minutes. The solution was filtered, solvent was evaporated from filtrate and the resulting residue was extracted with hexane. The product (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N-tertbutylmethanimine) (2.47d) was obtained as a reddish yellow oil (0.32 g, 94%) after removal of hexane. 1H NMR (600 MHz, CDCl3): δ = 8.40 (s, 2H, N=CH), 8.05 (d, J = 7.7 Hz, 2H, Ar), 7.77 (t, J = 7.5 Hz 1H, Ar), 1.32 (s, 18H, NC(CH3)3). 13C NMR (150 MHz, CDCl3): δ = 156.39 (N=CH), 155.25, 137.22, 121.82 (Ar), 58.10 (NC(CH3)3), 29.75 (NC(CH3)3). HRMS (ESI): m/z calculated for [C15H23N3+H]+: 246.1970 , found: 246.1954.
Synthesis of dichloro[N,N-(2,6-pyridinediyl-
N)dimethylidyne]bis[cyclohexanamine-
N](triphenylphosphine)ruthenium (2.48a): A mixture of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N-cyclohexylmethanimine) (2.47a) (0.043 g, 0.15 mmol) and RuCl2(PPh3)3 (0.143 g, 0.15 mmol) were dissolved in dry tetrahydrofuran (5 mL) under an argon atmosphere and refluxed for 12 h. During the course of the reaction the colour changed from violet to reddish brown. The solvent was evacuated and the residue was washed with diethyl ether (3 x 5 mL) followed by pentane (2 x 5mL). Upon
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Kanu Das, Ph.D Thesis, IIT Guwahati 83 vacuum drying of the washed residue, 0.085 g (81%) of 2.48a was obtained as a reddish-brown solid. Crystals suitable for X–ray analysis were obtained by a slow diffusion of pentane (1 mL) into a dichloromethane solution (1 mL) of 2.48a (10 mg). 1H NMR (400 MHz, CDCl3): = 7.94 (s, 2H, N=CH), 7.71 – 7.61 (m, 6H, Ar), 7.25 – 7.07 (m, 12H, Ar), 4.41 – 4.35 (m, 2H, NCH(CH2)5), 3.11 – 3.08 (m, 2H, NCH(CH2)5), 1.81 – 1.77 (m, 2H, NCH(CH2)5), 1.68 – 1.36 (m, 8H, NCH(CH2)5), 1.26 – 0.97 (m, 6H, NCH(CH2)5), 0.85 – 0.83 (m, 2H, NCH(CH2)5). 13C NMR (100 MHz, CDCl3): = 162.41, 160.81 (N=CH), 132.75, 132.66, 132.59, 132.17, 129.20, 129.18, 128.18, 128.06, 127.97, 122.91, 67.47 (NCH(CH2)5), 36.64, 32.07, 25.99, 25.97, 25.66 (NCH(CH2)5). 31P NMR (162 MHz, CDCl3): = 29.42. HRMS (ESI): m/z calculated for [C37H42ClN3PRu]+: 696.1848, found: 696.1835.
Synthesis of dichloro[N,N-(2,6-pyridinediyl-
N)dimethylidyne]bis[benzenamine-
N](triphenylphosphine)ruthenium (2.48b): A mixture of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N-phenylmethanimine) (2.47b) (0.030 g, 0.10 mmol) and RuCl2(PPh3)3 (0.096 g, 0.10 mmol) were dissolved in dry tetrahydrofuran (5 mL) under an argon atmosphere and refluxed for 12 h. During the course of the reaction the colour changed from violet to reddish brown. The solvent was evacuated and the residue was washed with diethyl ether (3 x 5 mL) followed by pentane (2 x 5mL). Upon vacuum drying of the washed residue, 2.48b was obtained as a reddish-brown solid in quantitative yield. Crystals suitable for X–ray analysis were obtained by a slow diffusion of pentane (1 mL) into a dichloromethane solution (1 mL) of 2.48b (10 mg). 1H NMR (400 MHz, CDCl3): = 7.97 (s, 2H, N=CH), 7.58 (d, 4H, J = 7.2 Hz, Ar), 7.36 – 7.26 (m, 8H, Ar), 7.18 – 7.03 (m, 10H, Ar), 6.84 – 6.76 (m, 6H, Ar). 13C NMR (100 MHz, CDCl3): = 164.34, 161.86, 150.98, 133.00, 132.91, 130.99, 130.54, 129.08, 129.06, 128.54, 128.46, 128.13, 127.68, 127.58, 125.21, 125.06 (Ar). 31P NMR (162 MHz, CDCl3): = 32.27. HRMS (ESI): m/z calculated for [C37H30ClN3PRu]+: 684.0909, found: 684.0908.
Synthesis of drichloro[N,N-(2,6-pyridinediyl-
N)dimethylidyne]bis[2-propanamine-
N](triphenylphosphine)ruthenium (2.48c): A mixture of (1E,1E)- 1,1-(pyridine-2,6-diyl)bis(N-isopropylmethanimine) (2.47c) (0.036 g, 0.16 mmol) and RuCl2(PPh3)3 (0.152 g, 0.16 mmol) were dissolved in dry tetrahydrofuran (5 mL) under an argon atmosphere and refluxed for 12 h. During the course of the reaction the
TH-3049_166122006
Kanu Das, Ph.D Thesis, IIT Guwahati 84 colour changed from violet to reddish brown. The solvent was evacuated and the residue was washed with diethyl ether (3 x 5 mL) followed by pentane (2 x 5mL). Upon vacuum drying of the washed residue, 0.098 g (85%) of 2.48c was obtained as a reddish-brown solid. Crystals suitable for X–ray analysis were obtained by a slow diffusion of pentane (1 mL) into a dichloromethane solution (1 mL) of 2.48c (10 mg). 1H NMR (400 MHz, CDCl3): = 7.98 (s, 2H, N=CH), 7.71 – 7.47 (m, 6H, Ar), 7.25 – 7.10 (m, 12H, Ar), 4.81 (septet, J =6.4 Hz, 2H, NCH(CH3)2), 1.57 (d, J = 6.5 Hz, 6H, NCH(CH3)2), 0.86 (d, J = 6.6 Hz, 6H, NCH(CH3)2). 13C NMR (100 MHz, CDCl3): = 162.37, 160.63 (N=CH), 132.73, 132.64, 132.56, 132.14, 129.34, 129.32, 128.34, 128.17, 128.07, 123.09 (Ar), 59.33 (NCH(CH3)2), 25.56, 21.67 (NCH(CH3)2).
31P NMR (162 MHz, CDCl3): =29.16. HRMS (ESI): m/z calculated for [C31H34ClN3PRu]+: 616.1222, found: 616.1204.
Synthesis of dichloro[N,N-(2,6-pyridinediyl-N)dimethylidyne]bis[2- methyl-2-propanamine-N](triphenylphosphine)ruthenium (1.48d):
A mixture of (1E,1E)-1,1-(pyridine-2,6-diyl)bis(N- tertbutylmethanimine) (2.47d) (0.050 g, 0.20 mmol) and RuCl2(PPh3)3
(0.196 g, 0.20 mmol) were dissolved in dry tetrahydrofuran (5 mL) under an argon atmosphere and refluxed for 12 h. During the course of the reaction the colour changed from violet to reddish brown. The solvent was evacuated and the residue was washed with diethyl ether (3 x 5 mL) followed by pentane (2 x 5mL). Upon vacuum drying of the washed residue, 0.119 g (86%) of 2.48d was obtained as a reddish-brown solid. Crystals suitable for X–ray analysis were obtained by a slow diffusion of pentane (1 mL) into a dichloromethane solution (1 mL) of 2.48d (10 mg). HRMS (ESI): m/z calculated for [C33H38ClN3PRu]+: 644.1535, found:
644.1531.