A protocol for the gram-scale synthesis of polyfluoroaryl sulfides via an SNAr step

Summary Polyfluoroaryl sulfide is one of the prevalent motifs ubiquitous in materials and pharmaceutical chemistry. We herein describe a simple yet efficient procedure for their synthesis from readily available thiols and polyfluoroarenes via an SNAr step. We detail specific steps for a gram-scale preparation of 2-((perfluoropyridin-4-yl)thio)benzo[d]thiazole 3 from mercaptobenzothiazole 1 and pentafluoropyridine 2. For complete details on the use and execution of this protocol, please refer to Liao et al. (2022).1


SUMMARY
Polyfluoroaryl sulfide is one of the prevalent motifs ubiquitous in materials and pharmaceutical chemistry. We herein describe a simple yet efficient procedure for their synthesis from readily available thiols and polyfluoroarenes via an S N Ar step. We detail specific steps for a gram-scale preparation of 2-((perfluoropyridin-4-yl)thio)benzo[d]thiazole 3 from mercaptobenzothiazole 1 and pentafluoropyridine 2.
For complete details on the use and execution of this protocol, please refer to Liao et al. (2022). 1

BEFORE YOU BEGIN
Aromatic thioethers are attractive targets for the development of new efficient synthesis protocols being a recurring motif in bioactive compounds, 2,3 pharmaceuticals, 4,5 and materials science. 6,7 This predilection is further amplified with the limitations purported from reported literature methods such as poor regioselectivity and the necessity of transition metals. 8,9 Other protocols for the synthesis of polyfluoroaryl sulfides are also rather complex; requiring hetarenium salts that act as an activated substrate for thiolation 10,11 or are comported into focused settings such as in the preparation of polymers 12 and in peptide stapling. 13,14 We further reckoned that a straightforward, metal-free approach for the synthesis of polyfluoroaryl sulfides could provide a solution to the previously mentioned challenges. With S N Ar as a viable pathway, a general protocol that is regioselective, cheap, and simple is disclosed to provide para-thiolated polyfluoroarenes in a wider substrate scope, lower overall cost, and good to excellent yields. Additionally, this protocol is amenable to late-stage functionalization of natural product derivatives and is commutable to solvent-free mechanical ball milling 15,16 and flow reaction, 17 please refer to Liao et al. 1 We have also previously applied this protocol for the installation of pentafluoropyridines in benzyl mercaptans and mercaptoacetates, which activates the latter two for the desulfurative nickel-catalyzed reductive LiebeskindÀSrogl type cross-coupling with aryl halides. 18 In this step, the purification of triethylamine is described. Triethylamine stored for a long time may contain excessive impurities and/or moisture. This step can be skipped if using brand new bottle of triethylamine. According to our test, the quality of triethylamine will affect the yield by about 10%-15% in this substrate.

Preprocessing.
a. Carefully weigh 1084.4 mg CaH 2 in a 100 mL oven-dried single-neck round bottom flask equipped with 6 mm* 24 mm teflon stir-bar. b. Add 60 mL of triethylamine. Troubleshooting 1. c. Seal the round bottom flask with a rubber septum and lock the system by inserting a nitrogen balloon through an inlet needle. d. Stir the mixture at room temperature overnight (14 h) ( Figure 1B).

Distillation.
a. Set-up the distillation apparatus and connect the condenser to the source of cold water, keep the distillation system under nitrogen through the Schlenk line. b. Turn on the condenser. Confirm that there is no water leakage. c. Connect the CaH 2 -pretreated triethylamine flask to the distillation apparatus and fix with a joint clip. d. Wrap the condenser with cloth or tissue paper to prevent the condensed water from dripping into the oil bath ( Figure 1C).
Alternatives: Oil bath can be replaced with heating mantle or aluminum heating blocks.
e. Cover the distilling flask with aluminum paper to maintain uniform heating ( Figure 1C). f. Slowly increase the temperature to 80 C and collect the triethylamine distillate in three (3) separate round-bottom flasks connected through a cow-type receiver.
CRITICAL: Do not distill all the triethylamine. Keep about 10-15 mL to avoid any danger from the residual CaH 2 . The residual CaH 2 should be gradually quenched with alcohols (such as methanol) to ice water in an ice bath.
g. Use H-NMR to identify whether it contains impurities. Troubleshooting 2.  appropriate treatment (e.g., adding molecular sieves, using freeze-pump-thaw technique or sparging with nitrogen/argon to remove water and/or air) and storing it under an inert atmosphere.
f. Add 0.836 mL of distilled triethylamine into the reaction flask with a 1 mL plastic syringe. g. Inject 0.439 mL (4.0 mmol) pentafluoropyridine into the reaction flask with a 1 mL plastic syringe ( Figure 2B). h. Power on the stirring plate and set the stirring speed to 600 rpm ( Figure 2C).
Note: Pentafluoropyridine has a low boiling point, seal reaction flask to avoid spillage.

Tracking reactions and purification
Timing: 2 h This step describes how to determine if the reaction is completed, and how to obtain the final product 3 by purification. b. Use a capillary to dip the organic layer solution (generally, EtOAc will be in the upper layer), spot on thin-layer chromatography plate with the perfluoroarene starting material and thiol. c. Use hexane as the mobile phase and place the TLC plate in the sealed camber ( Figure 3B).
Take the TLC plate out when the R f value is around 0.8. d. Confirm whether the reaction is complete by 254 nm UV lamp ( Figure 3C). If perfluoroarene starting material remains, extend the reaction time until it is well-consumed.
3. Extraction. a. After confirming the termination of the reaction (it takes 1 h in this example reaction), rinse the vial with 20 mL EtOAc and transfer the reaction mixture into a 125 mL separatory funnel. b. Add 20 mL of saturated NH 4 Cl (aq) into the separatory funnel and close it with a Teflon stopper.
Shaking the funnel until layering is separated ( Figure 4A). Troubleshooting 4. c. The aqueous layer was collected in a 100 mL beaker, then repeating the step 3b for three times. The well-extracted organic layer was placed in a 100 mL beaker. d. Pour the beaker containing the aqueous layer into a separatory funnel, extract with 20 mL EtOAc and combine the organic layers in the same beaker. e. Add 2 g of anhydrous magnesium sulfate to the beaker containing the organic layer, stir well with a glass rod until no suspended particles float in the solution ( Figure 4B).
Note: If no suspension of anhydrous magnesium sulfate is observed, add 1 g at a time. Excessive addition may result in decreased yield.
f. The magnesium sulfate was removed by suction filtration with 70 mm filter paper and Bü chner funnel, further rinsed twice with 15 mL EtOAc ( Figure 4C).    ll

OPEN ACCESS
f. Collet the sample with 11 mL test tube. Confirm presence of 2-((perfluoropyridin-4-yl)thio) benzo[d]thiazole 3, as in steps 2b-2d (step-by-step method details) ( Figure 5B). g. Pour the test tubes in which the desired product was detected into a 250 mL round bottom flask, remove the solvent with a rotary evaporator under 300 mbar and 40 C for 30 min. h. Further remove the remaining solvent by using a high vacuum for 15 min. i. The final product was obtained as white solid (1084.0 mg, 0.3428 mmol, 85.7% isolated yield) ( Figure 5C). Troubleshooting 6. TLC: R f = 0.67 (Hexane/ethyl acetate 10:1).

LIMITATIONS
The protocol is limited to aryl fluorides. Complete results on functional group compatibility can be found in our previously published article (Liao et al. 1 ).

TROUBLESHOOTING Problem 1
Step 1b (before you begin): Triethylamine has an unbearable stench.

Potential solution
The boiling point of triethylamine is only 89 C (192 F), it is easy to volatilize at room temperature and produce an unpleasant odor. Therefore, all operations should be performed in a well-ventilated fume hood, and the used syringes or glassware should be cleaned immediately after use.

Problem 2
Step 2g (before you begin): The H-NMR spectrum indicates that the distilled triethylamine still contains impurities.

Potential solution
Carefully confirm the following precautions to ensure the purity of the distilled reagents.
Heating the mixture gradually and stirring smoothly with a magnet stirrer to avoid bumping. Collecting the samples in sections with several flasks ( Figure 1C). If the above steps have been strictly followed but there are still impurities, try the other fresh bottle of triethylamine.

Potential solution
All operations should be performed in a well-ventilated fume hood. If the balance is not in a fume hood, use a beaker instead of the weighing paper and cover it by a lid to reduce odor emissions. Glassware with mercaptan (thiol) residues can be cleaned by soaking in bleach.

Problem 4
Step 2a and 3b (step-by-step method details): Solvent spills during shaking, and the layering is not obvious after shaking.

Potential solution
Due to the volatility of organic solvents, part of the solvent will turn into gas after shaking. Try to shake the vial lightly for five times and open the cap to release the gas pressure in the vial.
If the layer does not separate well, add some brine can resolve the emulsion.

Problem 5
Step 4 (step-by-step method details): After column chromatography the final product is still not pure.

Potential solution
The following fine-tuning can improve the performance of column chromatography in separating products.
Increase the amount of silica gel in the column during packing (step 4c, step-by-step method details). Reduce the proportion of polar solvent, which is ethyl acetate in this case in the mobile phase.

Problem 6
Step 4i (step-by-step method details): Yield is lower than expected.

Potential solution
This reaction has good reproducibility, if the yield is much lower than we report here, try to inspect the following notes.
When filtering anhydrous magnesium sulfate, rinse several times with solvent to avoid product residue.
In step 4d (step-by-step method details), if there is still residue in the bottle, rinse with eluent to ensure that all compounds have entered the column.

RESOURCE AVAILABILITY
Lead contact Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Shao-Chi Lee (shaochi.lee@kaust.edu.sa).

Materials availability
This study did not generate new unique reagents.
Data and code availability d This study did not generate code. d Original data for substrate scope and the detail of ball milling/flow techniques please refer to our previous article (Liao et al. 1 ).
d Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.