Learning Objectives

The direct α-C(sp3) heteroarylation of ketones can be performed using this efficient microwave-assisted protocol. Selected examples of heteroaryl ketones synthesized in this study are shown in Figure 1. Specifically, compound 1a was synthesized and isolated as a pale-yellow oil (0.49 mmol, 192 mg, 98 %). Its ¹H and ¹³C NMR spectra are shown in Figure 2 to confirm the structure and purity. The presence of a two-proton singlet signal δ 4.26 ppm in the ¹H spectrum confirmed the successful C-C coupling between the ketone α carbon and the heteroaryl halide. The structures of all the synthesized heteroaryl compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS¹⁸.

For microwave-assisted organic reactions using non-polar or weakly polar solvents, the biggest challenge is to raise the reaction temperature to the desired range. The microwave reactor used in our study has a few unique features to achieve this purpose. First, it is equipped with four silica carbide (SiC) plates (Figure 3A) which have excellent microwave absorption ability that help to conduct the heat to reaction vials¹⁹. Second, the controlled microwave heating in sealed reaction vessels (Figure 3B) can achieve high temperature and high pressure and thus dramatically reduce reaction times. Third, it has two standard magnetrons of 850 W that can deliver up to 1500 W microwave power over the full power range. The microwave irradiation is continuously controlled by sophisticated software and wireless sensors to achieve homogeneous heating. The maximum available power for an experiment depends mainly on the solvent and number of vessels used.

The most frequently used solvent in our heteroarylation is toluene, a non-polar weak microwave absorber. Thus, the microwave power in our experiments was set to 1300 W, the highest recommended power. The high microwave power and silica carbide (SiC) plates are extremely important to help toluene achieve the desired reaction temperature. As seen in Figure 4, the reaction progress graph, the reaction mixture achieved the desired temperature of 130 °C in less than 10 min. This is important for efficient and successful heteroarylation reactions since the temperature has great impact on reaction yields, especially when the reaction time is only a few minutes.

As mentioned above, extreme caution is necessary if the experiment is performed in volatile solvents under microwave irradiation. Among the several solvents we tested for the heteroarylation, tetrahydrofuran (THF) has a boiling point of 66 °C and is used as an example of a volatile solvent to explain the total pressure calculation. Three components need to be considered for total pressure calculation: the solvent vapor, the inert gas introduced during the reaction set up, and any possible gas evolved during the reaction. First, under the current reaction temperature of 130 °C, THF will have a vapor pressure of 4121.5 mmHg or 5.49 bar. This can be estimated from the Antoine Equation:

log₁₀(P) = A – [B / (T + C)]

where P is the calculated vapor pressure in mmHg and T is the temperature in Celsius (°C). The coefficients A, B and C for THF in the temperature range of 121 to 265 °C are 7.42725, 1532.81 and 272.081, respectively²⁰.

Second, the pressure of the inert nitrogen will increase as the reaction temperature increases. The volume of the nitrogen is estimated to be 1 mL, which is the difference between the vial volume (4 mL) and the reaction solution volume (3 mL). Using the approximation that nitrogen volume does not change throughout the reaction, the final nitrogen pressure under the reaction temperature can be found to be 1.39 bar using the equation below:

P₁/T₁ = P₂/T₂

where P₁ is 1 atm or 1.01325 bar, T₁ is room temperature (293 K) and T₂ is reaction temperature in Kelvin (130 °C; 403 K).

Finally, there is no gas evolved during the heteroarylation reaction, so product gas pressure is not needed for total pressure consideration. For those reactions that evolves gas (H₂, NH₃, CO₂, etc), the following formula can be used to calculate the pressure increase caused by the evolved gas:

PV = nRT

where V is the volume above the solution in the reaction vial, n is the molar amount of gas evolved, R is the gas constant (8.314 x 10^-2 L·bar·K^-1·mol^-1), and T is the reaction temperature in Kelvin.

Overall, the total pressure in a sealed vial at the reaction temperature when the volatile solvent THF is utilized for this heteroarylation is estimated to be:

P(total) = P(THF vapor pressure) + P(N₂) + P(evolved gas) = 5.49 bar + 1.39 bar + 0 = 6.88 bar

This number is well below the microwave vial pressure limit of 20 bar, therefore, THF is a safe solvent to use in the reported direct heteroarylation reaction.

Besides the reaction conditions, the purification is also crucial for the successful preparation of heteroaryl compounds. The purification of heteroaryl compounds is often laborious and difficult due to the lone pair electrons on the heteroatom and the aromatic ring. Recrystallization is not ideal for small-scale reactions, so flash chromatography is the main technique we rely on. We struggled with several different modifications to improve the separation, such as adding 1% Et₃N or toluene to the solvents. Eventually we settled on a slight modification of the EtOAc/hexanes solvent system by adding additional time at 100% EtOAc gradient at the end of the elution. This allowed us to isolate the compounds with one nitrogen very well (Figure 5A) as these compounds tend to elute around 70% – 100% EtOAc gradient. However, when this method was utilized for compounds with two or more nitrogen atoms, it took an additional 5 to 10 min to elute the column at the 100% EtOAc gradient to obtain the product. The CH₃OH/CH₂Cl₂ solvent system was employed alternatively to purify compounds with two or more nitrogen atoms to get faster elution (Figure 5B).

Figure 1: Reaction scheme and selected examples for the microwave-assisted Pd-catalyzed heteroarylation of ketones. Reaction conditions are as follows unless otherwise noted: 1.0 equiv. heteroaryl halide, 1.1 equiv. ketone, 1 mol % XPhos Pd G4 catalyst, 2.4 equiv. ^tBuONa, toluene, microwave irradiation at 130 °C for 10 min.
^a Reaction was conducted under traditional thermal conditions at 100 °C for 4 h.
^b Reaction was conducted at room temperature for 3 days.
^c Pd₂(dba)₃ was used as the catalyst and XPhos was used as the ligand. The catalyst and ligand were premixed in toluene for 30 min under Ar before the addition of the rest of the reagents. Reactions were conducted under microwave irradiation at 120 °C for 20 min.
^d Reaction was conducted under microwave irradiation at 130 °C for 20 min due to the less reactive secondary α-carbon in cyclohexanone.
^e This figure has been modified from Quillen, A., et al.¹⁸. Adapted with permission from Quillen, A., et al. Palladium-Catalyzed Direct α-C(sp3) Heteroarylation of Ketones under Microwave Irradiation. The Journal of Organic Chemistry. 84 (12), 7652-7663 (2019). Copyright 2019 American Chemical Society. Please click here to view a larger version of this figure.

Figure 2: ¹H and ¹³C NMR Spectra for compound 1a. ¹H NMR (CDCl₃, 500 MHz, ppm): δ 8.53 (1H, s), 8.49 (1H, d, J = 5.05 Hz), 8.00 (2H, d, J = 7.6 Hz), 7.58 (1H, d, J = 6.85 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.46 (2H, t, J = 7.8 Hz), 7.24 (1H, dd, J = 7.8,4.6 Hz), 4.26 (2H, s). ¹³C NMR (CDCl₃, 125MHz, ppm): δ196.5, 150.7, 148.4, 137.3, 136.3, 133.6, 130.3, 128.9, 128.5, 123.5, 42.4. Please click here to view a larger version of this figure.

Figure 3: Silicon carbide (SiC) plates and microwave reaction vial assembly. (A) Four SiC plates are placed on the rotor inside the microwave reactor. Each plate can hold up to 24 reaction vials and up to 96 reactions can be set up for each experiment. (B) A close-up view of the microwave reaction vial, seal and cap. The microwave vial and seal are disposable, and the microwave cap is made of polyether ether ketone (PEEK) and it is reusable. Please click here to view a larger version of this figure.

Figure 4: Representative reaction progress graph: microwave power (blue) and IR sensor temperature (orange) versus reaction time. The IR sensor temperature reached 113 °C at 8 min during the ramp step, indicating the reaction solution temperature reached 130 °C. The microwave power was held at between 300 W and 500 W during the hold step. Please click here to view a larger version of this figure.

Figure 5: Representative flash chromatography purification plot. (A) Compound 6 eluted with EtOAc/hexanes (0% to 100% over 12 min) with an extension of 100% EtOAc for 3 min. (B) Compound 3 eluted with CH₃OH/CH₂Cl₂ (0% to 30% over 12 min) with an extension of 30% CH₃OH for 2 min. Please click here to view a larger version of this figure.