芳基和烯基卤化物在温和条件下的钯催化插羰反应是合成羧酸及其衍生物的非常有用的合成方法。反应机理是芳基和烯基卤化物先和Pd(0)发生氧化加成反应生成芳基或烯基钯配合物，然后CO插入到钯--碳键之间，还原消除，最后在醇或水等试剂的亲和进攻下就形成了相应的酯或羧酸。芳香的或α,β—不饱和的羧酸或酯就是芳基或烯基卤化物在水或醇中通过插羰反应制得的。

反应实例

羧酸

A 200-mL glass pressure bottle equipped with two valves and a pressure gaugewas charged with 8 mg of Pd(PPh₃)(Cl)₂, 40 mg of triphenylphosphme, and 2.0 g of 2-(acetylamino)-5-(1-methylethyl)phenylbromide. The bottle was then evacuated, refilled with argon three times, andcharged further with 2.2 mL of deoxygenated tri-n-butylamine and 0.5 mL of deoxygenatedwater. The apparatus was then pressurized with 3 atm of carbon monoxide,sealed, heated 18 h with stirring at a bath temperature of 120-125 °C, and then allowed to cool. The finalpressure was 1.1 atm at 23 °C. Hydrochloric acid (2.4 M) was added to the viscousorange-brown reaction mixture in four 2-mL portions with constant agitation. The crude yield of 2-11which separated (95% pure by NMR) was 1.63 g (94%). Recrystallization fromethanol-water gave 1.35 g (78%) of a light yellow solid.

羧酸酯

A mixture of the iodobenzene 2-1 (0.46 mmol), w-indo alcohol 2-2(0.83 mmol), K₂CO₃ (1.38 mmol), and PdCl₂(0.04 mmol) in dry benzene (6 mL) was heated at 120℃ with stirring in anautoclave under carbon monoxide (12 atm) for 16 h. The reaction mixture wasfiltered and the easter 3 was isolated by column chromatography in 70% yield.

（2R,4S）-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-bromopyrimidin-2-yl)}-amino-2-ethyl-6-methoxy-3,4-dihyfro-2H-[1,5]naphthridine-1-carboxylicacid ethyl ester (18 g) is dissolved in N,N-dimethylformamide (60 mL), andthereto are added palladium acetate (611 mg), 1,1’-bis(diphenylphosphino)-ferrocene(3.02 g), ethane (31.7 mL) and triethylamine (37.9 mL). The mixture is purgedby carbon monoxide at room temperature for 10 minutes, then is heated at 90 ^oCand stirred overnight under 40 psi of carbon monoxide. The reaction solution iscooled to room temperature, and thereto is added saturated brine and extractedwith ethyl acetate. The organic layer is washed with saturated brine, driedover magnesium sulfate, and concentrated under reduced pressure. The resultingresidue is purified by column chromatography (silica gel; hexane:ethyl acetate= 8:1) to give(2R.4S)-4-{[3,5-bis(triflouromethyl)benzyl]-(5-ethoxycarbonylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylicacid ethyl ester (12.4 g).

To a stirred solution of 3-(aminocarbonyl)-4-{[3-(methyloxay)penyl]amino}-6-iodoquinoline(1 g) in ethanol (50 mL) was added triethylamine (0.63 mL) anddichlorobis(triphenylphosphine)palladium (II) (0.08 g). The flask was evacuatedand refilled with nitrogen three times and then evacuated and refilled withcarbon monoxide two times. The mixture was heated at 80^oC under anatmosphere of carbon monoxide for 16 h. the mixture was cooled to 20^oCand the solvent removed in vacuo. Purificationby column chromatography on silica gel, eluting with 9:1 ethyl acetate:cyclohexane, gave the title compound as a pale yellow solid (0.8 g).

6-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-B]pyrazol-3-yl]-quinoline(22.7 g, 45 mmol) is added to a mixture of sodium acetate (19 g, 230 mmol) andthe palladium catalyst [1,1’-bis (diphenylphosphimo) ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (850 mg, 1.04 mmol)in 130 mL methanol. Place the mixture under 50 psi carbon monoxide atmosphereand stir while warming to 90^oC over 1 hour and with constantcharging with additional carbon monoxide. Allow the mixture to cool over 8hours, recharge again with carbon monoxide and heat to 90^oC. Thepressure may rise to about 75 psi. The reaction is complete in about an hourwhen the pressure is stable and TLC (1:1 toluene/acetaone) shows no remainingbromide. Partition the mixture between methylene chloride (600 mL) and water (1L). Extract the aqueous portion with an additional portion of methylene chloride(400 mL). Filter the organic solution through a 300 mL silica plug and washwith 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone. Discardthe acetone portion. Combine appropriate fractions and concentrate to yield18.8 g (87.4%) of the desired subtitled intermediate as a pink powder.

A solution ofN-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (30.0 g), Et₃N(19.1 mL), MeOH (110.6 mL), Pd(OAc)₂ (431 mg), and1,3-bis(diphenylphosphino)propane (791.9 mg) in 375 mL anhydrous DMF is stirredat room temperature until everything dissolves. CO (g) is slowly bubbledthrough for 2 days and the reaction is maintained at 70^oC. Thereaction is cooled to room temperature. The product is precipitated by adding160 mL 1 N HCl into the reaction mixture. An orange solid precipitates iscollected. The solid is triturated with EtOAc, filtered, and washed with CH₂Cl₂to afford 23.8 g (93 % yield) of the title compound as an off-white solid.

A mixture of 2-(3-iodo-2-methyl-phenyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (26 g, 0.067 mol), Pd(PPh₃)₄(2.4 g, 0.002 mol), Et₃N (14.3 mL, 0.1 mol), 110 mL of acetonitrileand 50 mL of methanol was stirred under 50 Psi of carbon monoxide at 50 °C for 8 h. Thereaction mixture was filtered and concentrated in vacuo. The residue wasdissolved in 250 mL of ethyl acetate, then washed with water and brine, driedover anhydrous sodium sulfate and concentrated in vacuo to give crude product,which was purified by column chromatography (petroleum ether: ethyl acetate30:1 to 10:1) to afford the title product (20 g, 93%) as a gray solid.

PdCl₂ (18.4 g, 0.104 mol) and BINAP (27.6g, 0.044 mol) were added to a solution of 5-(2-bromo-phenyl)-oxazole (331.0 g,0.44 mol) and Et₃N (242.2 g, 2.22 mol) in 6 L CH₃OH/CH₃CN(2:1) in steel bomb. The mixture was stirred at 100 °C under CO (1 atm) for 48 h. The mixture was filtered and the filtratewas evaporated. The residue was purified by column chromatography(EtOAc/petroleum = 1:10) to give 2-oxazol-5-yl-benzoicacid methyl ester (210.0 g, 70 %)as brown oil.

酰胺

A mixture of 2-52-A (6.3 mg, 11 rmnol), Pd(PPh₃)₄(1.27 g, 1.1 mmol) and n-Bu₃N (4.47 g, 24.2 mmol) in toluene (20 mL)was heated under carbon monoxide(10 atm) at 110^oC for 24 h. Ethylacetate was added to the reaction mixture and the organic layer was washed with5% HCl, 5% Na₂S₂O₃, sat. NaHCO₃ andthen brine, dried over Na₂SO₄ and evaporated. The residuewas purified by column chromatography [ethy1 acetate-CH2Cl2 (1:l)]. The secondfraction was 2-52 (3.93 g, 69 %).

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