72016-31-0

Basic information

• Product Name: Orellanine II
• Synonyms: (2,2'-Bipyridine)-3,3',4,4'-tetrol;3,3'-dihydroxy-1H,1'H-[2,2']bipyridinyl-4,4'-dione
• CAS NO: 72016-31-0
• Molecular Formula: C₁₀H₈N₂O₄
• Molecular Weight: 220.185
• Mol File: 72016-31-0.mol

Chemical Properties

• Boiling Point: 257.4°Cat760mmHg
• Flash Point: 109.5°C
• Density: 1.684g/cm³
• CAS DataBase Reference: Orellanine II(CAS DataBase Reference)
• NIST Chemistry Reference: Orellanine II(72016-31-0)
• EPA Substance Registry System: Orellanine II(72016-31-0)

Safety Data

• Hazardous Substances Data: 72016-31-0(Hazardous Substances Data)

Synthetic route

3,3',4,4'-tetramethoxy-2,2'-bipyridine (101664-55-5) → orelline (72016-31-0)

Conditions	Yield
With hydrogen bromide In acetic acid for 5h; Heating;	77%
With hydrogen bromide at 150℃; sealed tube, overnight;	60%
With hydrogen bromide at 120℃;	60%

3,3'-Bis<<2-(trimethylsilyl)ethoxy>methoxy>-2,2'-bipyridin-4,4'-diol (119767-30-5) → orelline (72016-31-0)

Conditions	Yield
With hydrogenchloride In methanol for 1h; Heating;	75%

4,4'-dihydroxy-3,3'-dimethoxy-2,2'-bipyridine (405137-22-6) → orelline (72016-31-0)

Conditions	Yield
With hydrogen bromide In acetic acid for 5h; Heating;	71%

3,3'-dihyroxy-4,4'-dimethoxy-2,2'-bipyridyl (104819-53-6) → orelline (72016-31-0)

Conditions	Yield
With hydrogen bromide In acetic acid for 5h; Heating;	70%

3,3',4,4'-tetrahydroxy-2,2'-bipyridine-1,1'-dioxide (37338-80-0) → orelline (72016-31-0)

Conditions	Yield
at 220℃; under 0.01 Torr; sublimation;	50%
for 336h; Irradiation;

3,3'-Dihydroxy-2,2'-bipyridin-4,4'-dicarbaldehyd (119767-37-2) → orelline (72016-31-0)

Conditions	Yield
With dihydrogen peroxide In potassium hydroxide at 60 - 70℃; for 1h;	36%

C22H34Li2N2O4Si2 → orelline (72016-31-0)

Conditions	Yield
With bis-trimethylsilanyl peroxide In diethyl ether for 0.5h; Ambient temperature;	11%
Multi-step reaction with 3 steps 1: 45 percent / 0.5 h / -20 - -15 °C 2: 75 percent / conc. HCl / H2O / 30 h / Heating 3: 36 percent / 30percent H2O2 / aq. KOH / 1 h / 60 - 70 °C View Scheme
Multi-step reaction with 2 steps 1: 10 percent / 0.5 h / -5 °C 2: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 10 percent / bis(trimethylsilyl)-peroxide / 0.5 h / -5 °C 2: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme

2-iodo-3-hydroxypyridine (40263-57-8) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 70 percent / NaH / dimethylsulfoxide / 15 h / 0 - 20 °C 2.1: 2,2,6,6-tetramethylpiperidine; BuLi / tetrahydrofuran; hexane / 1 h / -50 °C 2.2: B(OMe)3 / tetrahydrofuran; hexane / 2 h / -75 °C 2.3: 78 percent / aq. AcOH; AcOOH / tetrahydrofuran; hexane / -75 - 20 °C 3.1: 71 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 4.1: [Pd(PPh3)4]; CuBr / dioxane / 15 h / Heating 5.1: aq. HCl / diethyl ether / 15 h / 20 °C 6.1: 70 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme
Multi-step reaction with 6 steps 1.1: 85 percent / MeONa / dimethylformamide / 15 h / 0 - 20 °C 2.1: 2,2,6,6-tetramethylpiperidine; BuLi / tetrahydrofuran; hexane / 1 h / -50 °C 2.2: B(OMe)3 / tetrahydrofuran; hexane / 2 h / -75 °C 2.3: 63 percent / aq. AcOH; AcOOH / tetrahydrofuran; hexane / -75 - 20 °C 3.1: 69 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 4.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 4.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 4.3: [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 5.1: aq. HCl / tetrahydrofuran / 7 h / 50 °C 6.1: 71 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme
Multi-step reaction with 5 steps 1.1: 85 percent / MeONa / dimethylformamide / 15 h / 0 - 20 °C 2.1: 2,2,6,6-tetramethylpiperidine; BuLi / tetrahydrofuran; hexane / 1 h / -50 °C 2.2: B(OMe)3 / tetrahydrofuran; hexane / 2 h / -75 °C 2.3: 63 percent / aq. AcOH; AcOOH / tetrahydrofuran; hexane / -75 - 20 °C 3.1: 71 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 4.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 4.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 4.3: 59 percent / [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 5.1: 77 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-3-methoxy-pyridine (93560-55-5) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 2,2,6,6-tetramethylpiperidine; BuLi / tetrahydrofuran; hexane / 1 h / -50 °C 1.2: B(OMe)3 / tetrahydrofuran; hexane / 2 h / -75 °C 1.3: 63 percent / aq. AcOH; AcOOH / tetrahydrofuran; hexane / -75 - 20 °C 2.1: 69 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 3.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 3.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 3.3: [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 4.1: aq. HCl / tetrahydrofuran / 7 h / 50 °C 5.1: 71 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme
Multi-step reaction with 4 steps 1.1: 2,2,6,6-tetramethylpiperidine; BuLi / tetrahydrofuran; hexane / 1 h / -50 °C 1.2: B(OMe)3 / tetrahydrofuran; hexane / 2 h / -75 °C 1.3: 63 percent / aq. AcOH; AcOOH / tetrahydrofuran; hexane / -75 - 20 °C 2.1: 71 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 3.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 3.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 3.3: 59 percent / [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 4.1: 77 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-3-(methoxymethoxy)pyridine (87905-88-2) → orelline (72016-31-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 2,2,6,6-tetramethylpiperidine; BuLi / tetrahydrofuran; hexane / 1 h / -50 °C 1.2: B(OMe)3 / tetrahydrofuran; hexane / 2 h / -75 °C 1.3: 78 percent / aq. AcOH; AcOOH / tetrahydrofuran; hexane / -75 - 20 °C 2.1: 71 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 3.1: [Pd(PPh3)4]; CuBr / dioxane / 15 h / Heating 4.1: aq. HCl / diethyl ether / 15 h / 20 °C 5.1: 70 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-3,4-dimethoxypyridine (153199-59-8) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 1.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 1.3: 59 percent / [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 2.1: 77 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-3-methoxypyridin-4-ol (405137-17-9) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 69 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 2.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 2.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 2.3: [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 3.1: aq. HCl / tetrahydrofuran / 7 h / 50 °C 4.1: 71 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: 71 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 2.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 2.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 2.3: 59 percent / [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 3.1: 77 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-3-methoxy-4-(methoxymethoxy)pyridine (405137-19-1) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -75 °C 1.2: ZnCl2 / tetrahydrofuran; hexane / -75 - 20 °C 1.3: [Pd(PPh3)4] / tetrahydrofuran; hexane / 20 h / Heating 2.1: aq. HCl / tetrahydrofuran / 7 h / 50 °C 3.1: 71 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-4-methoxy-3-(methoxymethoxy)pyridine (405137-18-0) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: [Pd(PPh3)4]; CuBr / dioxane / 15 h / Heating 2: aq. HCl / diethyl ether / 15 h / 20 °C 3: 70 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

2-iodo-3-(methoxymethoxy)pyridin-4-ol (405137-24-8) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 71 percent / Ag2CO3 / tetrahydrofuran / 15 h / 20 °C 2: [Pd(PPh3)4]; CuBr / dioxane / 15 h / Heating 3: aq. HCl / diethyl ether / 15 h / 20 °C 4: 70 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

3,3'-dimethoxy-4,4'-bis-methoxymethoxy-[2,2']bipyridinyl → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. HCl / tetrahydrofuran / 7 h / 50 °C 2: 71 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

4,4'-dimethoxy-3,3'-bis(methoxymethoxy)-2,2'-bipyridine → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. HCl / diethyl ether / 15 h / 20 °C 2: 70 percent / aq. HBr / acetic acid / 5 h / Heating View Scheme

3-HYDROXYPYRIDINE (109-00-2) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 52 percent / Br2, HCl / aq. NaOH / 20 °C 2: 1.) NaH / 1.) DMF, 25 deg C, 1 h; 2.) 1.5 h 3: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 4: 22 percent / 1.) 1.5 M BuLi; 2.) 2-(phenylsulfonyl)-3-phenyloxaziridine / 1.) Et2O, -50 deg C, hexan, 2h; 2.) -20 deg C, THF, 75 min 5: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 7 steps 1: 52 percent / Br2, HCl / aq. NaOH / 20 °C 2: 1.) NaH / 1.) DMF, 25 deg C, 1 h; 2.) 1.5 h 3: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 4: 1.5 M BuLi / diethyl ether / -50 - -20 °C 5: 45 percent / 0.5 h / -20 - -15 °C 6: 75 percent / conc. HCl / H2O / 30 h / Heating 7: 36 percent / 30percent H2O2 / aq. KOH / 1 h / 60 - 70 °C View Scheme
Multi-step reaction with 6 steps 1: 52 percent / Br2, HCl / aq. NaOH / 20 °C 2: 1.) NaH / 1.) DMF, 25 deg C, 1 h; 2.) 1.5 h 3: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 4: 1.5 M BuLi / diethyl ether / -50 - -20 °C 5: 10 percent / 0.5 h / -5 °C 6: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme

2-bromo-pyridin-3-ol (6602-32-0) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaH / 1.) DMF, 25 deg C, 1 h; 2.) 1.5 h 2: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 3: 22 percent / 1.) 1.5 M BuLi; 2.) 2-(phenylsulfonyl)-3-phenyloxaziridine / 1.) Et2O, -50 deg C, hexan, 2h; 2.) -20 deg C, THF, 75 min 4: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 6 steps 1: 1.) NaH / 1.) DMF, 25 deg C, 1 h; 2.) 1.5 h 2: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 3: 1.5 M BuLi / diethyl ether / -50 - -20 °C 4: 45 percent / 0.5 h / -20 - -15 °C 5: 75 percent / conc. HCl / H2O / 30 h / Heating 6: 36 percent / 30percent H2O2 / aq. KOH / 1 h / 60 - 70 °C View Scheme
Multi-step reaction with 5 steps 1: 1.) NaH / 1.) DMF, 25 deg C, 1 h; 2.) 1.5 h 2: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 3: 1.5 M BuLi / diethyl ether / -50 - -20 °C 4: 10 percent / 0.5 h / -5 °C 5: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme

2-bromo-3-(β-trimethylsilyl ethoxymethoxy)pyridine (118399-88-5) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 2: 22 percent / 1.) 1.5 M BuLi; 2.) 2-(phenylsulfonyl)-3-phenyloxaziridine / 1.) Et2O, -50 deg C, hexan, 2h; 2.) -20 deg C, THF, 75 min 3: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 2: 1.5 M BuLi / diethyl ether / -50 - -20 °C 3: 45 percent / 0.5 h / -20 - -15 °C 4: 75 percent / conc. HCl / H2O / 30 h / Heating 5: 36 percent / 30percent H2O2 / aq. KOH / 1 h / 60 - 70 °C View Scheme
Multi-step reaction with 4 steps 1: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 2: 1.5 M BuLi / diethyl ether / -50 - -20 °C 3: 10 percent / 0.5 h / -5 °C 4: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 2: 1.5 M BuLi / diethyl ether / -50 - -20 °C 3: 10 percent / bis(trimethylsilyl)-peroxide / 0.5 h / -5 °C 4: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 79 percent / NiCl2*6H2O, triphenylphosphine, Zn / dimethylformamide / 0.42 h / 60 °C 2: 1.5 M BuLi / diethyl ether / -50 - -20 °C 3: 11 percent / bis(trimethylsilyl)-peroxide / diethyl ether / 0.5 h / Ambient temperature View Scheme

3,3'-Bis<<2-(trimethylsilyl)ethoxy>methoxy>-2,2'-bipyridin (119767-27-0) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 22 percent / 1.) 1.5 M BuLi; 2.) 2-(phenylsulfonyl)-3-phenyloxaziridine / 1.) Et2O, -50 deg C, hexan, 2h; 2.) -20 deg C, THF, 75 min 2: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 1.5 M BuLi / diethyl ether / -50 - -20 °C 2: 45 percent / 0.5 h / -20 - -15 °C 3: 75 percent / conc. HCl / H2O / 30 h / Heating 4: 36 percent / 30percent H2O2 / aq. KOH / 1 h / 60 - 70 °C View Scheme
Multi-step reaction with 3 steps 1: 1.5 M BuLi / diethyl ether / -50 - -20 °C 2: 10 percent / 0.5 h / -5 °C 3: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 1.5 M BuLi / diethyl ether / -50 - -20 °C 2: 10 percent / bis(trimethylsilyl)-peroxide / 0.5 h / -5 °C 3: 75 percent / 2N HCl / methanol / 1 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 1.5 M BuLi / diethyl ether / -50 - -20 °C 2: 11 percent / bis(trimethylsilyl)-peroxide / diethyl ether / 0.5 h / Ambient temperature View Scheme

3,3'-Bis<<2-(trimethylsilyl)ethoxy>methoxy>-2,2'-bipyridin-4,4'-dicarbaldehyd (119767-36-1) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / conc. HCl / H2O / 30 h / Heating 2: 36 percent / 30percent H2O2 / aq. KOH / 1 h / 60 - 70 °C View Scheme

2-bromo-3,4-dimethoxy pyridine (104819-52-5) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / NiCl2, P(Ph)3, Zn / dimethylformamide / 50 °C 2: 60 percent / 48percent HBr / 120 °C View Scheme
Multi-step reaction with 4 steps 1: 1.) NiCl2*6H2O, Ph3P, Zn powder / 1.) DMF, 50 deg C, 1 h; 2.) DMF, 50 deg C, 2 h; other cond.: Cu, KI, DMF or Pd/C, phase transfer conditions 2: 85 percent / m-chloroperbenzoic acid / CHCl3 / 8 h / Ambient temperature 3: 60 percent / 48percent aq. HBr / 5 h / 120 °C 4: 50 percent / 220 °C / 0.01 Torr / sublimation View Scheme
Multi-step reaction with 2 steps 1: 1.) NiCl2*6H2O, Ph3P, Zn powder / 1.) DMF, 50 deg C, 1 h; 2.) DMF, 50 deg C, 2 h; other cond.: Cu, KI, DMF or Pd/C, phase transfer conditions 2: 60 percent / 48percent aq. HBr / 150 °C / sealed tube, overnight View Scheme

2-bromo-3,4-dimethoxy pyridine-N-oxide (105011-83-4) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus tribromide 2: 87 percent / NiCl2, P(Ph)3, Zn / dimethylformamide / 50 °C 3: 60 percent / 48percent HBr / 120 °C View Scheme
Multi-step reaction with 5 steps 1: 85 percent / PBr3 / CHCl3 / 0.5 h / 60 °C 2: 1.) NiCl2*6H2O, Ph3P, Zn powder / 1.) DMF, 50 deg C, 1 h; 2.) DMF, 50 deg C, 2 h; other cond.: Cu, KI, DMF or Pd/C, phase transfer conditions 3: 85 percent / m-chloroperbenzoic acid / CHCl3 / 8 h / Ambient temperature 4: 60 percent / 48percent aq. HBr / 5 h / 120 °C 5: 50 percent / 220 °C / 0.01 Torr / sublimation View Scheme
Multi-step reaction with 3 steps 1: 85 percent / PBr3 / CHCl3 / 0.5 h / 60 °C 2: 1.) NiCl2*6H2O, Ph3P, Zn powder / 1.) DMF, 50 deg C, 1 h; 2.) DMF, 50 deg C, 2 h; other cond.: Cu, KI, DMF or Pd/C, phase transfer conditions 3: 60 percent / 48percent aq. HBr / 150 °C / sealed tube, overnight View Scheme

4-methoxypyridin-3-amine (33631-09-3) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: 80 percent / Br2, conc. HCl / 1 h 3: 42 percent / NiCl2*6H2O/(C6H5)3P, Zn / 4 h / 50 °C 4: 27 percent / 30percent H2O2, (CH3CO)2O / 14 h / 100 °C 5: 92 percent / Na / 0.25 h / Heating 6: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 7: 336 h / Irradiation View Scheme

2-chloro-3-fluoropyridine (17282-04-1) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: 64 percent / (CH3CO)2O, 30percent H2O2 / 12 h / 80 °C 2: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 3: 1.) Na, 2.) PCl3 / 1.) MeOH, 24 h, room temp. 2.) chloroform, 2 h, reflux 4: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 5: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 6: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 7: 336 h / Irradiation View Scheme
Multi-step reaction with 5 steps 1: 64 percent / (CH3CO)2O, 30percent H2O2 / 12 h / 80 °C 2: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 3: 1.) Na, 2.) PCl3 / 1.) MeOH, 24 h, room temp. 2.) chloroform, 2 h, reflux 4: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 5: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 8 steps 1: 64 percent / (CH3CO)2O, 30percent H2O2 / 12 h / 80 °C 2: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 3: 83 percent / Na / methanol / 72 h / Ambient temperature 4: 80 percent / PCl3 / CHCl3 / 2 h / Heating 5: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 6: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 7: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 8: 336 h / Irradiation View Scheme
Multi-step reaction with 6 steps 1: 64 percent / (CH3CO)2O, 30percent H2O2 / 12 h / 80 °C 2: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 3: 83 percent / Na / methanol / 72 h / Ambient temperature 4: 80 percent / PCl3 / CHCl3 / 2 h / Heating 5: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 6: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 6 steps 1: 54 percent / acetic anhydride, 30percent H2O2 2: 42 percent / 100percent HNO3/ 100percent H2SO4 containing 10percent SO3 3: Ambient temperature 4: PCl3 5: 25 percent / dimethylformamide / 4 h / 50 °C 6: 46 percent / 33percent HBr / acetic acid / 4 h View Scheme

2-Chlor-3-fluorpyridin-1-oxid (85386-94-3) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 2: 1.) Na, 2.) PCl3 / 1.) MeOH, 24 h, room temp. 2.) chloroform, 2 h, reflux 3: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 4: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 5: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 6: 336 h / Irradiation View Scheme
Multi-step reaction with 4 steps 1: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 2: 1.) Na, 2.) PCl3 / 1.) MeOH, 24 h, room temp. 2.) chloroform, 2 h, reflux 3: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 4: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 7 steps 1: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 2: 83 percent / Na / methanol / 72 h / Ambient temperature 3: 80 percent / PCl3 / CHCl3 / 2 h / Heating 4: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 5: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 6: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 7: 336 h / Irradiation View Scheme
Multi-step reaction with 5 steps 1: 44 percent / conc. H2SO4/H2SO4 (20percent SO3) (1:1); H2SO4 (20percent SO3)/100percent HNO3 / 1 h / Heating 2: 83 percent / Na / methanol / 72 h / Ambient temperature 3: 80 percent / PCl3 / CHCl3 / 2 h / Heating 4: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 5: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 42 percent / 100percent HNO3/ 100percent H2SO4 containing 10percent SO3 2: Ambient temperature 3: PCl3 4: 25 percent / dimethylformamide / 4 h / 50 °C 5: 46 percent / 33percent HBr / acetic acid / 4 h View Scheme

2-chloro-3,4-dimethoxypyridine (101664-59-9) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 2: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 3: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 4: 336 h / Irradiation View Scheme
Multi-step reaction with 2 steps 1: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 2: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 25 percent / dimethylformamide / 4 h / 50 °C 2: 46 percent / 33percent HBr / acetic acid / 4 h View Scheme

2-Chlor-3,4-dimethoxypyridin-1-oxid (101664-58-8) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 80 percent / PCl3 / CHCl3 / 2 h / Heating 2: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 3: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 4: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 5: 336 h / Irradiation View Scheme
Multi-step reaction with 3 steps 1: 80 percent / PCl3 / CHCl3 / 2 h / Heating 2: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 3: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 3 steps 1: PCl3 2: 25 percent / dimethylformamide / 4 h / 50 °C 3: 46 percent / 33percent HBr / acetic acid / 4 h View Scheme

2-Chlor-3-fluor-4-nitropyridin-1-oxid (101664-56-6) → orelline (72016-31-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) Na, 2.) PCl3 / 1.) MeOH, 24 h, room temp. 2.) chloroform, 2 h, reflux 2: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 3: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 4: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 5: 336 h / Irradiation View Scheme
Multi-step reaction with 3 steps 1: 1.) Na, 2.) PCl3 / 1.) MeOH, 24 h, room temp. 2.) chloroform, 2 h, reflux 2: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 3: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 6 steps 1: 83 percent / Na / methanol / 72 h / Ambient temperature 2: 80 percent / PCl3 / CHCl3 / 2 h / Heating 3: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 4: 53 percent / 30percent H2O2, (CH3CO)2O, / 14 h / 100 °C 5: 77 percent / 33percent HBr/CH3COOH / 5 h / Heating 6: 336 h / Irradiation View Scheme
Multi-step reaction with 4 steps 1: 83 percent / Na / methanol / 72 h / Ambient temperature 2: 80 percent / PCl3 / CHCl3 / 2 h / Heating 3: 52 percent / NiCl2*6H2O/(C6H5)3P, Zn, KI / dimethylformamide / 12 h / 50 °C 4: 46 percent / 33percent HBr/CH3COOH / 5 h / Heating View Scheme
Multi-step reaction with 4 steps 1: Ambient temperature 2: PCl3 3: 25 percent / dimethylformamide / 4 h / 50 °C 4: 46 percent / 33percent HBr / acetic acid / 4 h View Scheme

orelline (72016-31-0) → 3,3',4,4'-tetrahydroxy-2,2'-bipyridine-1,1'-dioxide (37338-80-0)

Conditions	Yield
With dihydrogen peroxide for 8h; Ambient temperature;	87%
for 336h; Irradiation; isomerisation also without irradiation;

diazomethane (186581-53-3, 908094-01-9) + orelline (72016-31-0) → 3,3'-dihyroxy-4,4'-dimethoxy-2,2'-bipyridyl (104819-53-6)

Conditions	Yield
In diethyl ether Ambient temperature;

Upstream product

• 101664-55-5 3,3',4,4'-tetramethoxy-2,2'-bipyridine 
• 119767-37-2 3,3'-Dihydroxy-2,2'-bipyridin-4,4'-dicarbaldehyd 
• 119767-30-5 3,3'-Bis<<2-(trimethylsilyl)ethoxy>methoxy>-2,2'-bipyridin-4,4'-diol 
• 37338-80-0 3,3',4,4'-tetrahydroxy-2,2'-bipyridine-1,1'-dioxide 
• 104819-53-6 3,3'-dihyroxy-4,4'-dimethoxy-2,2'-bipyridyl 
• 405137-22-6 4,4'-dihydroxy-3,3'-dimethoxy-2,2'-bipyridine 
• 87905-88-2 2-iodo-3-(methoxymethoxy)pyridine 
• 153199-59-8 3,4-dimethoxy-2-iodopyridine 
• 405137-17-9 2-iodo-3-methoxypyridin-4-ol 
• 405137-19-1 2-iodo-3-methoxy-4-(methoxymethoxy)pyridine 
• 405137-18-0 2-iodo-4-methoxy-3-(methoxymethoxy)pyridine 
• 6602-32-0 2-bromo-pyridin-3-ol 
• 118399-88-5 2-bromo-3-(β-trimethylsilyl ethoxymethoxy)pyridine 
• 33631-09-3 4-methoxypyridin-3-amine 

Downstream Products

• 37338-80-0 3,3',4,4'-tetrahydroxy-2,2'-bipyridine-1,1'-dioxide 

Relevant articles and documents

New syntheses of orelline and analogues via metalation and cross-coupling reactions

New total syntheses of orelline and some analogues are reported. The methodology involves metalation of 3-alkoxy-2-iodopyridines to afford 3,4-dialkoxy-2-iodopyridines, on which cross-coupling reactions are performed to reach the 2,2′-bipyridine skeleton of the alkaloid.

Synthesis of Orelline

Orelline (1), a metabolite of the toadstool Cortinarius Orellanus Fries with 2,2'-bipyridine structure, has been synthesized by the following method.The easily accessible 2-bromo-3-hydroxypyridine (3) was converted into the corresponding methyl (SEM) ether 4 and coupled with Zn and NiCl2/Ph3P to form the bipyridine derivative 5 in 79percent yield.Due to the chelating effect of the two SEM-ether groups in 5, it was possible to form selectively the dilithium compound 6 by an exchange reaction with BuLi at -50 deg C in Et2O.Reaction of 6 with electrophiles at -20 deg C afforded the 4- and 4,4'-substituted bipyridines 7-14 in excellent-to-reasonable yield.Oxidations of 6 with 2-(phenylsulfonyl)-3-phenyloxaziridin and with bis(trimethylsilyl)peroxide gave the 4,4'-diol 9 in 22 and 10percent yield, respectively.Methanolysis of 9 directly afforded crystalline 1 in high yield, with properties identical with those of natural orelline.Formylation of 6 with N-formylmorpholine gave 45percent of the dicarbaldehyde 13.Removal of the SEM groups in 13 by hydrolysis afforded the dihydroxydicarbaldehyde 15 that could be oxidized to 1 with alkaline H2O2.Attempts to oxidize 1 to orellanine (2) with 35percent H2O2 according to a known procedure were unsuccessful (cf.Exper.Part).Compound 7 with two Me3Si groups in 4,4'-position gave after methanolysis the fluorescence dye 16 with an appreciable Stokes shift in cyclohexane.

Syntheses of Hydroxylated Bipyridines, I. - Orellanine, the Poison of a Toadstool

Two syntheses of orellanine, -3,3',4,4'-tetrol-1,1'-dioxide (5b), are developed which comprise 10 or 11 steps, respectively.The chemical reactions of 5b with diazomethane and on UV irradiation are described.

NEW REACTIONS OF PYRIDINES AND TOTAL SYNTHESIS OF THE FUNGAL TOXIN ORELLANINE

Dihalogenated pyridines react easily with sulphur nucleophiles, in dipolar aprotic solvents (DMF), to afford the products of mono- or of bis-substitution depending on the experimental conditions.On the contrary, with oxygen nucleophiles the bis-substituted products can be obtained only with some particular substrates.A new and efficient procedure to effect the homo-coupling of halogenoarenes will be presented.This reaction, wich occurs under the influence of low-valent nickel complexes, allowed us to effect the total synthesis of Orellanine, the lethal toxin of Cortinarius orellanus mushroom, as well as the syntheses of its decompositionproducts Orellinine and Orelline.The chemical properties of these three products and their behaviour towards UV irradiation will be presented and discussed.

SYNTHESIS OF ORELLANINE, THE LETHAL POISON OF A TOADSTOOL

A ten step synthesis of the structure of orellanine, 3,3',4,4'- hydroxy-2,2'-bipyridyl-bis-N-oxide (1a), is described which proves the identity of the natural product.