The synthetic process of 5-Methyl-2,2'-bipyridine (CAS NO. ) contains 3 steps. And the process needs tert-Butylithium, which is extremely pyrophoric and must not be allowed to come into contact with the atmosphere. This reagent should only be handled by individuals trained in its proper and safe use. It is recommended that transfers be carried out by using a 20 mL or smaller glass syringe filled to no more than 2/3 capacity, or by cannula. The synthetic route is as follows:

A. Synthesis of . A 500-mL, two-necked, round-bottomed flask equipped with an internal thermometer and egg-shaped, -coated magnetic stirrer is charged with 150 mL of water (H₂O) and 40 g of concentrated sulfuric acid (H₂SO₄). This aqueous solution is cooled below 0°C by immersion in an acetone/ice bath, and 2-amino-5-methylpyridine (18.2 g, 168 mmol) is added. The reaction mixture is treated with an aqueous solution of sodium nitrite (NaNO₂) (15.4 g, 223 mmol in 30 mL of H₂O) at a rate sufficient to maintain a reaction temperature of 0-5°C. After addition of the NaNO₂ solution is complete, the resulting mixture is stirred at 0°C for 45 min, and then heated to 95°C for 15 min. The reaction mixture is allowed to cool to room temperature and a 50% w/w aqueous sodium hydroxide (NaOH) solution is added until a pH of 6.5-7.0 is achieved (≈30 mL). After the reaction mixture is heated to 60°C, the hot solution is extracted with ethyl acetate (EtOAc) (4 × 100 mL). The combined organic fractions are dried over anhydrous sodium sulfate (Na₂SO₄), filtered, and concentrated on a rotary evaporator to yield a pale-yellow solid. Purification by recrystallization from hot/cold ethyl acetate (EtOAc) (≈300 mL) gives 2-hydroxy-5-methylpyridine (11.2 g, 61%) as white crystalline needles.

B. Synthesis of 5-Methyl-2-(trifluoromethanesulfonyl)oxypyridine. The following procedure for the preparation of the 5-methyl-2-pyridyl triflate may also be used to synthesize the 4- and 6-methyl derivatives. A 200-mL Schlenk flask containing a Teflon-coated, magnetic stirring bar and capped with a rubber septum is flushed with nitrogen. The flask is charged with 2-hydroxy-5-methylpyridine (4.85 g, 44.4 mmol) and dry pyridine (140 mL). After the reactant dissolves, the flask is cooled to -12°C by immersion in an acetone/ice bath. (15.1 g, 53.5 mmol) is added rapidly to the flask via syringe through the rubber septum. The solution is stirred at 0°C for 30 min and poured into a separatory funnel containing H₂O (150 mL). The mixture is extracted with dichloromethane (CH₂Cl₂) (3 × 100 mL) and the combined organic fractions are dried over anhydrous Na₂SO₄. Filtration and concentration on a rotary evaporator, followed by flash chromatography on 375 g of deactivated silica gel with 20% EtOAc: 80% hexanes, gives 9.89 g (92%) of 5-methyl-2-(trifluoromethanesulfonyl)oxypyridine as a clear, colorless oil.

C. Synthesis of 5-Methyl-2,2'-bipyridine. The 4- and 6-methyl-2,2'-bipyridines may also be prepared using the following procedure. A 500-mL, two-necked, round-bottomed flask with a Teflon-coated magnetic stirrer is placed in a dry ice/acetone bath (-78°C), then 80 mL of tetrahydrofuran (THF) and tert-butyllithium (tert-BuLi) (1.75 M in pentane, 52 mL, 91.0 mmol) are added to it, followed by dropwise addition of 2-bromopyridine (7.13 g, 4.3 mL, 45.1 mmol). The canary yellow THF solution becomes reddish-brown upon addition of the pyridyl bromide. After the solution is stirred at -78°C for 30 min, anhydrous zinc chloride (ZnCl₂) (13.3 g, 97.4 mmol) is added, and the reaction is stirred at 25°C for 2 hr. The 5-methylpyridyl triflate (8.95 g, 37.1 mmol) , lithium choride (LiCl) (3.18 g, 75.2 mmol), and tetrakis(triphenylphosphine) palladium (Pd(PPh₃)₄) (1.75 g, 1.5 mmol) are then added. The brownish-yellow reaction mixture is heated at reflux for 18 hr. After the solution is cooled, an aqueous solution of ethylenediaminetetraacetic acid () (55 g, 148 mmol in 400 mL) is added and the pH is adjusted to ≈8 with saturated aqueous sodium bicarbonate (NaHCO₃). The solution is stirred for 15 min then poured into a separatory funnel. The product is extracted with CH₂Cl₂ (3 × 200 mL). The combined organic fractions are dried over anhydrous Na₂SO₄ , filtered, and concentrated using a rotary evaporator. Flash chromatography on 275 g of deactivated silica gel ( 20% EtOAc: 80% hexanes) affords 5.94 g (94%) of 5-methyl-2,2'-bipyridine as a very pale yellow oil.