A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Summary

Heteroaryl compounds are important molecules utilized in organic synthesis, medicinal and biological chemistry. A microwave-assisted heteroarylation using palladium catalysis provides a rapid and efficient method to attach heteroaryl moieties directly to ketone substrates.

Abstract

Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal catalysis, the literature on direct heteroarylation is scarce. The presence of heteroatoms such as nitrogen, sulfur and oxygen often make heteroarylation a challenging research field due to catalyst poisoning, product decomposition and the rest. This protocol details a highly efficient direct α-C(sp3) heteroarylation of ketones under microwave irradiation. Key factors for successful heteroarylation include the use of XPhos Palladacycle Gen. 4 Catalyst, excess base to suppress side reactions and the high temperature and pressure achieved in a sealed reaction vial under microwave irradiation. The heteroarylation compounds prepared by this method were fully characterized by proton nuclear magnetic resonance spectroscopy (¹H NMR), carbon nuclear magnetic resonance spectroscopy (¹³C NMR) and high-resolution mass spectrometry (HRMS). This methodology has several advantages over literature precedents including broad substrate scope, rapid reaction time, greener procedure and operational simplicity by eliminating the preparation of intermediates such as silyl enol ether. Possible applications for this protocol include, but are not limited to, diversity-oriented synthesis for the discovery of biologically active small molecules, domino synthesis for the preparation of natural products and ligand development for new transition metal catalytic systems.

Introduction

Microwaves interact with materials through ionic conduction or dipolar polarization to provide rapid and homogeneous heating. Microwave-assisted organic reactions have gained increasing popularity in research laboratories after the first report for rapid organic synthesis in 1986¹. Though the exact nature of microwave heating is not clear and the existence of a "nonthermal" microwave effect is still under debate, significant rate enhancements for microwave-assisted organic reactions have been observed and reported². Sluggish reactions that normally take hours or days to finish have been reported to be completed within minutes under microwave irradiation^3,4,5,6. Difficult organic reactions that require high activation energy such as cyclizations and construction of sterically hindered sites were reported to be successful under microwave irradiation with improved reaction yields and purity⁷. Combined with other features such as solvent-free reactions and domino reactions, microwave-assisted organic synthesis offers unparalleled advantages in the design of eco-friendly reactions.

Unlike its arylation equivalent, which has been widely studied, heteroarylation, especially on the α-C(sp3) of carbonyl compounds, has been rarely reported in the literature^8,9,10. The few literature reports of α-heteroarylation of carbonyl compounds had great limitations such as a stoichiometric amount of catalysts, narrow substrate scope, and isolation of reaction intermediates^11,12,13. There are several challenges for the direct α-heteroarylation of ketones that remain to be solved in order to make it a general approach. First, heteroatoms tend to coordinate to the transition metal catalyst and cause catalyst poisoning^14,15. Second, the α-H in the mono(hetero)arylation product is more acidic than those in the starting material. Thus, it tends to react further to make the undesired (bishetero)arylation or (multihetero)arylation products. Third, carbonyl compounds often have a lower cost than heteroaryl compounds, so it is practical to use excess carbonyl compounds to drive the reaction to completion. However, excess carbonyl compounds would often cause self-condensation, a frequently encountered problem in the transition metal-catalyzed α-heteroarylation of carbonyl compounds.

In this report, we describe our recent study on the direct α-C(sp3) heteroarylation of ketones using a microwave-assisted reaction protocol. To address the first challenge, catalyst poisoning discussed above, strongly coordinating and sterically hindered ligands were utilized to minimize the catalyst poisoning by heteroatoms. Bulky ligands were also expected to slow down the side reactions such as (bishetero)arylation or (multihetero)arylation^16,17, the second challenge mentioned above. To minimize the effect of the third challenge, the formation of the ketone self-condensation side products, more than 2 equivalents of base was employed to convert ketones to their corresponding enolates. The long reaction time and high reaction temperature, together with the challenges specifically associated with the direct α-C(sp3) heteroarylation of ketones, render it a suitable candidate for microwave-assisted organic synthesis research.

Protocol

CAUTION:

• Microwave reaction vials should be operated under 20 bar for the microwave reactor equipped with a 4 x 24MG5 rotor. If the reaction uses very volatile solvents, generates gas, or if solvents decompose, it is necessary to calculate the pressure at certain reaction temperatures to make sure the total pressure in the vial is less than 20 bar.
• Standard techniques in organic synthesis for glove box, flash chromatography and nuclear magnetic resonance (NMR) are utilized in this protocol.
• Appropriate Personal Protective Equipment (PPE) should be used during the experiment. These include safety goggles, a lab coat, nitrile gloves, long pants and closed-toe shoes.
• Consult all Safety Data Sheets (SDS) prior to the use of the chemicals in this procedure, as some of the chemicals are hazardous, corrosive, toxic or flammable.
• All chemical waste should be disposed of properly in designated waste containers.

1. Reaction set up

1. Use the following amounts of reagents for the example reaction in Figure 1 - the formation of 1-phenyl-2-(pyridin-3-yl)ethanone (compound 1a) from acetophenone and 3-iodopyridine.
2. Oven-dry microwave reaction vials equipped with stirring bars overnight. Purge argon vigorously into toluene for 30 min to degas the solvent prior to use.
3. Preparation of reagents and supplies for glove box usage
   1. Gather two 100 µL syringes, four small spatulas, two glass pipets, two microwave seals, two microwave caps, two microwave stirring bars, at least four pieces of pre-folded weighing paper, four Kimwipes, four rubber bands, and two 100 mL beakers along with all the necessary reactants/solvents.
   2. Put the microwave vials, seals, and caps in one of the 100 mL beakers, then cover the beaker with a Kimwipe and wrap a rubber band around the beaker to keep the Kimwipe in place.
   3. Place the beaker and the rest of the items from step 1.3.1 into the transport box and take it into the glove box workstation.
4. Transport the reagents and supplies in step 1.3 into the glove box.
   1. Inside the purged glove box, weigh 115 mg of NaO^tBu (molecular weight (MW) 96.1, 1.2 mmol, 2.4 eq.) directly into the microwave reaction vial.
   2. Use a glass pipet to add half of the degassed toluene (1 mL) into microwave reaction vial.
   3. Weigh 9 mg of precatalyst XPhos Pd G4 (MW 860.5, 0.01 mmol, 2 mol%) and add it into the microwave vial. Dip a spatula into the solution in the vial and swirl to ensure the complete transfer of the catalyst.
   4. Use a suitable microliter syringe to add 64.4 µL of acetophenone (MW 120.15, 66.1 mg, 0.55 mmol, 1.1 eq.) into the microwave vial.
   5. Weigh 103 mg of 3-iodopyridine (MW 205.0, 0.5 mmol, 1.0 eq.) and add it into the microwave vial.
   6. Add the remaining half of degassed toluene so that the total reaction mixture is about 3 mL.
      NOTE: The reaction solution volume should not exceed ¾ of the total volume capacity of the microwave reaction vial. For the standard glass vials used in this protocol, the vial volume is 4 mL and the recommended reaction volume is 0.3 mL – 3 mL.
   7. Line up the seal and the cap carefully and put them on the microwave reaction vial. The cap should be finger tight.
   8. Take the chemicals, supplies and trash out of the glove box.

2. Microwave irradiation

1. Take the assembled reaction vial to the microwave reactor and place it on the silicon carbide (SiC) plate on the rotor. For multiple reaction vials, space them evenly across the four silicon carbide (SiC) plates on the rotor.
2. Parameter set-up
   NOTE: The most important parameters are the IR sensor temperature limit, microwave power and time.
   1. Set the Infrared (IR) sensor temperature limit to 113 °C.
      NOTE: IR sensor-measured temperatures tend to be lower than reaction solution temperatures due to a non-preventable temperature gradient between the sample and the outside of the vessel. There is a linear relationship between these two temperatures: IR T (°C) = Reaction T (°C)/1.152. When the IR sensor temperature is 113 °C, the actual reaction temperature will be 130 °C using the equation given above.
   2. Program the microwave power and time for each step:
      Step 1: Power ramp = 1300 W, 10 min, Fan Level = 1, Stirrer = High
      Step 2: Power hold = 1300 W, 10 min, Fan Level = 1, Stirrer = High
      Step 3: Cooling = 60 °C, Fan Level = 3
      NOTE: The microwave power will adjust automatically when the actual reaction temperature reaches the target temperature.
3. Run the reaction under microwave irradiation. Record the actual reaction time and temperature.

3. Product isolation

1. After the microwave reaction vial cools to ambient temperature, transfer the reaction mixture into a separatory funnel using a minimal amount of ethyl acetate (EtOAc).
2. Use acid-base extraction to isolate the crude product.
   1. Add 2 mL of saturated NH₄Cl to the separatory funnel.
   2. Add 10 mL of EtOAc to the separatory funnel and extract the product. Separate the organic layer and save it in a clean, dry beaker. Repeat the extraction two more times, and combine the organic layers.
   3. Dry the combined organic layer with anhydrous Na₂SO₄ for 20 min.
   4. Decant the clear solution into a round bottom flask and evaporate the solvent by rotatory evaporation under reduced pressure to yield the crude product.
   5. Record the shape, color and mass of the crude product.
3. Take ¹H and ¹³C NMR spectra for the crude product to confirm the presence of the characteristic peaks for the expected product.
4. Combine the crude product from the NMR sample with the rest of the crude product for flash chromatography purification below.
5. Use automated flash chromatography to purify the final product.
   1. Sample loading: Dissolve the crude product in 1-2 mL of acetone, followed by the addition of 1.5 g of silica gel to make a slurry. Use rotatory evaporation to remove acetone very carefully so that the product is loaded on the silica gel. Transfer the resulting silica gel to an empty flash chromatography loading cartridge.
   2. Assemble the loading cartridge, prepacked column, test tube rack and solvent lines for the automated medium pressure liquid chromatography (MPLC) system.
   3. Set up the solvent gradient and other parameters for the MPLC system and run the flash chromatography.
      NOTE: The automated flash chromatography solvent gradients are suggested based on the heteroaryl product structural features:
      1) If the product has one or zero nitrogen atoms (N) or hydroxyl groups (OH), use EtOAc/hexanes (0% to 100% over 12 min) with an extension at 100% EtOAc gradient for 2-6 min.
      2) If the product has two or more nitrogen atoms (N) or hydroxyl groups (OH), use CH₃OH/CH₂Cl₂ (0% to 30% over 12 min) with an extension at 30% CH₃OH gradient for 1-3 min.
   4. Combine the desired MPLC fractions and evaporate the solvent to collect the pure product. Dry the purified product under high vacuum for at least 1 h to remove residual solvent.

4. Product characterization

1. Weigh 5 - 10 mg of the final purified product, dissolve it in deuterated chloroform (CDCl₃) (or other appropriate deuterated solvent), and take a ¹H NMR spectrum.
2. Weigh 10 - 30 mg of the final purified product, dissolve it in CDCl₃ (or other appropriate deuterated solvent), and take a ¹³C NMR spectrum.
3. Analyze the NMR spectra to confirm the product structure.
4. Recover the NMR sample in a 1 dram vial by evaporating the solvent.
5. Once the NMR spectra support the correct structure, submit a 1 mg sample for HRMS testing to confirm the molecular formula.

Results

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 single...

Discussion

The methodology described herein was developed to access valuable synthesis building blocks – heteroaryl compounds. Compared to precedent literature reports on heteroarylation, the choice of this current catalytic system showed several significant advantages. First, it avoids the use of protecting groups, the isolation of reactive intermediates, the stoichiometry requirement of catalysts, and the extended reaction times^11,17. Second, the SiC plates offer a ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Chloroform-d (99.8+% atome D)	Acros Organics	AC209561000	contains 0.03 v/v% TMS
CombiFlash Rf Flash Chromatography system	Teledyne Isco		automated flash chromatography system
CombiFlash Solid load catridges (5 gram)	Teledyne Isco	69-3873-235	disposable
CombiFlash prepacked column (4g)	Teledyne Isco	69-2203-304	RediSep Rf silica 40-60 um, disposable
Microwave Reactor - Multiwave Pro	Anton Paar	108041	Microwave Reactor
Microwave Reactor Rotor 4X24 MG5	Anton Paar	79114	for parallel organic synthesis with with 4 SiC Well Plate 24
Microwave reaction vials	Wheaton® glass	224882	disposible, 13-425, 15x46 mm, reaction solution 0.3 - 3.0 mL, working pressure 20 bar
Microwave reaction vial seals, set	Anton Paar	41186	made of Teflon; disposable
Microwave reaction vial screw cap	Anton Paar	41188	made of PEEK; forever reusable
Microwave reaction vial stirring bar	CTechGlass	S00001-0000	Magnetic, PTFE, Length 9mm. Diameter: 3mm. (Package of 5)
NaOtBu	Sigma-Aldrich	703788	stored in a glovebox under nitrogen atmosphere
Nuclear Magnetic Resonance Spectrometer	Joel		500 MHz spectrometer
Silica gel	Teledyne Isco	605394478	40-60 microns, 60 angstroms
Toluene	Sigma-Aldrich	244511	vigorously purged with argon for 2 h before use
XPhos Palladacycle Gen. 4 Catalyst	STREM	46-0327	stored in a glovebox under nitrogen atmosphere
various ketones	Sigma-Aldrich or Fisher or Ark Pharm.		substrates for heteroarylation
various heteroaryl halides	Sigma-Aldrich or Fisher or Ark Pharm.		substrates for heteroarylation