Flow carbonylation of sterically hindered ortho-substituted iodoarenes

The flow synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced via a reverse “tube-in-tube” flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions.


Ortho-substituted carbonylation in flow using a "tube-in-tube" reactor.
For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set at 0.125 mL/min, temperature of the reactor at 110 °C, pressure of CO at 15 bar with a back pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady state after which time the flow streams were switched to pass from the loops where the substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of 1,4-dioxane while the second loop (5 mL) was filled with a solution made from the orthosubstituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) in 5.8 mL of 1,4-dioxane.
An Omnifit ® column filled with 1.71 cm 3 (r = 0.33 cm, h = 5.00 cm) of cotton was positioned just before the back pressure regulator to trap any particulate matter formed to avoid blocking of the back pressure regulator. After the substrates were passed through the system, the outlet of the flow stream was directed into a receptacle where the excess carbon monoxide gas was vented off in the fume cupboard. The reaction mixture was then evaporated to dryness, ethyl acetate (25 mL) and sodium carbonate solution (2 M, 10 mL) were added and transferred to a separating funnel. After collecting the aqueous layer, the organic layer was extracted with sodium carbonate solution (2 M, 2 × 10 mL). The combined aqueous layers were acidified by the addition of 2 M HCl solution which was then extracted with ethyl acetate (3 x 25 mL).
The organic layer was dried over sodium sulfate, and the solvent evaporated under vacuum to give the crude product as a solid. The crude product was then recrystallised from the appropriate solvent.

Heck-carbonylation in flow using the plug flow reactor.
For the Heck-carbonylation of iodobenzene and ethanol, a mixture of 1.64 mL DBU (11.0 mmol) and 5 mL of ethanol was made to which palladium acetate (5 mg, 0.022 mmol) was added and left stirring for 15 minutes to obtain a pale orange solution. Iodo benzene (2.05 g, 10.0 mmol) was then added to this solution and left stirring for 5 minutes. This solution was then injected in the flow reactor (Uniqsis FlowSyn), at the following conditions: coil temperature of 120 °C, carbon monoxide rate of 2 mL/min at 8 bar of pressure (supplied using EL-Flow Select Bronkhorst flow meter), solvent flow rate of 0.3 mL/min, 100 psi BPR S4 and a residence time of 2 hours. The crude was purified on a silica column (9:1, hexane: ethyl acetate) to obtain 0.6 g (41% isolated yield) as a pale yellow oil.
Note: The flow reactor was equilibrated at the appropriate conditions for 2 h prior to the addition of the substrates. Additionally, by using a flow of 2 mL/min of carbon monoxide it was ensured that equal size plugs (~0.5 cm long) of gas/liquid were obtained allowing for large interfacial areas, which should ensure carbon monoxide saturation in the liquid plug over the 2 h residence time.

Ortho-substituted carbonylation in batch (Conventional Lab).
A solution of palladium acetate (20 mg, 0.08 mmol) and triphenylphosphine (48 mg, 0.168 mmol) in 11.8 mL of 1,4-dioxane was prepared, to which 2-chloro-iodobenzene (0.401g, 1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) were added in a N 2 filled 25 mL flask. A balloon (made from two balloons inside each other) of carbon monoxide was attached to the flask and the flask was emptied through an empty needed. This process was repeated once and then the third time the carbon monoxide in the balloon was not emptied by removing the empty needle. The reaction was heated to reflux, cooled after 2 h or 24 h, solvent evaporated and the same extraction/purification for the flow protocol was repeated using acetonitrile to recrystallise the product.

Ortho-substituted carbonylation in batch (High-Pressure Lab).
A solution of palladium acetate (80 mg, 0.32 mmol) and triphenylphosphine (192 mg, 0.672 mmol) in 24 mL of 1,4-dioxane was prepared and stirred for 15 min, to which a solution of 2chloro-iodobenzene (1.602 g, 6.72 mmol), triethylamine (1.088 g, 1.50 mL, 10.76 mmol) and water (2.02 g, 112 mmol) in 24 mL of 1,4-dioxane was added in the Parr autoclave (stainless steel, 100 mL capacity, 200 bar maximum pressure). The autoclave was tightly sealed and placed in the heating rig. The autoclave was then purged with nitrogen (3 × 10 bar) and with carbon monoxide (3 × 10 bar), keeping 10 bar of carbon monoxide in the autoclave at which point it was heated to 110 °C over 15 minutes. The carbon monoxide pressure was adjusted to 15 bar and the reaction was left stirring for 2 h and was then cooled down to 30 °C over 2 h.
The autoclave was then purged with nitrogen (4 × 10 bar) and the reaction mixture removed from the autoclave. The same extraction/purification sequence as for the flow protocol was

(4-Bromo-3-iodophenyl)methanol, 30:
To a suspension of 4-bromo-3-iodobenzaldehyde (1.24 g, 4.0 mmol) in methanol (6 mL) at 0 ºC, NaBH 4 (0.08 g, 2.0 mmol) was added in small portions over 10 minutes. The reaction mixture was allowed to warm to room temperature and left stirring for 1 h. The solvent of the reaction mixture was then evaporated under vacuum and the residue was dissolved in ethyl acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic layer was dried over sodium sulphate and the solvent evaporated under vacuum to give the desired product as white solid which was used without further purification.

1-Bromo-4-(ethoxymethyl)-2-iodobenzene, 31:
To a solution of (4-bromo-3-iodophenyl)methanol (30) (1.15 g, 3.67 mmol) in THF (4 mL), NaH (60% in hexane, 0.224 g, 5.5 mmol) was added in small portions over 5 minutes while keeping the reaction mixture at 0 ºC. Iodoethane (0.860 g, 0.44 mL, 5.5 mmol) was then added to the reaction mixture which was then allowed to warm up to room temperature and left stirring for 2 h. The solvent of the reaction mixture was then evaporated under vacuum and the residue was dissolved in ethyl acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic layer was dried over sodium sulphate and the solvent evaporated under vacuum to give the desired product as yellow oil which was purified using flash silica chromatography 0.5:9.5 -2:3 EtOAc/hexane gradient to give the product as a colourless liquid.  To a suspension of 4-bromo-3-iodobenzaldehyde (1.24 g, 4.0 mmol) and glycine hydrochloride (0.838 g, 6.0 mmol) in acetonitrile (6 mL), triethylamine (0.836 g, 6.0 mmol) S14 was added and reaction mixture was left stirring at room temperature for 4 h. The solvent of the reaction mixture was then evaporated under vacuum and the residue was dissolved in ethyl acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic layer was dried over sodium sulphate and the solvent evaporated under vacuum to give the desired imine intermediate which was used in the next step without further purification. The imine intermediate was dissolved in THF (6 mL) and tert-butyl methacrylate (1.138 g, 8.0 mmol) was added followed by lithium bromide (0.694 g, 8.0 mmol) and triethylamine (1.11 g, 8.0 mmol). The reaction mixture was left stirring at room temperature for 2 h after which the solvent of the reaction mixture was then evaporated under vacuum and the residue was dissolved in ethyl acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic layer was dried over sodium sulphate and the solvent evaporated under vacuum to give the desired crude product as a yellow oil which was purified using flash silica chromatography 1:9 EtOAc/hexane.  To a solution 32 (2.0 g, 3.72 mmol) in dichloromethane (4 mL), pivolyl chloride (0.580 g, 0.594 mL, 4.83 mmol) was added followed by triethylamine (0.489 g, 0.674 mL, 4.83 mmol) and reaction was left stirring at room temperature for 2 h. The reaction mixture was then washed with brine solution (3 x 25 mL) and the organic layer dried over sodium sulphate and the solvent evaporated under vacuum to give the desired product as a yellow oil which was purified using flash silica chromatography 1:9 EtOAc/hexane.