Mechanochemical Difluoromethylations of Alcohols

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY-NC 3.0 https://creativecommons.org/licenses/by-nc/3.0/ Mechanochemical Difluoromethylations of Alcohols © Authors Published version van Bonn, Pit; Ke, Jinbo; Weike, Christopher; Ward, Jas S.; Rissanen, Kari; Bolm, Carsten van Bonn, P., Ke, J., Weike, C., Ward, J. S., Rissanen, K., & Bolm, C. (2023). Mechanochemical Difluoromethylations of Alcohols. CCS chemistry, 5(8), 1737-1744. https://doi.org/10.31635/ccschem.023.202302783 2023 Mechanochemical Difluoromethylations of Alcohols Pit van Bonn1, Jinbo Ke1, Christopher Weike1, Jas S. Ward2, Kari Rissanen2& Carsten Bolm1* 1Institute of Organic Chemistry, RWTH Aachen University, 52074 Aachen, 2Department of Chemistry, University of Jyvaskyla, 40014 Jyväskylä *Corresponding author: [email protected] Cite this: CCS Chem.2023, 5, 1737–1744 DOI: 10.31635/ccschem.023.202302783 Difluoromethyl ethers are formed through mechanochemical reactions of alcohols with difluorocarbene in a mixer mill. The protocol could be applied to primary, secondary, and tertiary alcohols, yielding the corresponding products in excellent yields (up to 99%) after 1 h reaction time at room temperature. The transformations proceeded under solvent-free reaction conditions, followed by product purification by filtration, which drastically reduced the amount of waste generated during the process. OHR 1 R 3 R 2 OR 1 R 3 R 2 CF 2 H KFHF, CsCl + TMSCF 2 Br Solvent-free reaction Pure product after filtration rt, 1 h 1°, 2°, and 3° alcohols Mild reaction conditions Operationally simple Difluorocarbene pathway Keywords: mechanochemistry, ball milling, solventfree reaction, difluorocarbene, difluoromethyl ether Introduction Due to its unique physiochemical properties, the difluoromethoxy group is an emerging structural motif in pharmaceutical and agrochemical research. Compared with a methoxy group, it induces a higher metabolic stability and lipophilicity, in contrast to a trifluoromethoxy moiety, it reveals hydrogen bond donor capabilities. As a result, the difluoromethoxy group has become a valuable structural component, allowing the fine-tuning of important properties.1,2Notable examples of marketed difluoromethyl ethers include the proton pump inhibitor Pantoprazole and the insecticide Flucythrinate.3,4In light of this background, the development of strategies to synthesize aryl and alkyl difluoromethyl ethers is of great interest.5–7 Although recent approaches toward aryl difluoromethyl ethers involve C–H bond functionalizations of suitable arenes,8–11 most methods start from phenols.8,12–19 Deprotonations with bases lead to phenoxides which react with electrophilic difluorocarbene. For alcohols, this strategy is less effective due to their higherpK a values. Initial attempts to apply difluorocarbene precursors in reactions with alcohols (HCF 2 Cl,20,21 BrCF 2 P(O)(EtO) 2 ,22 TMSCF 2 Br,16 CF 2 N 2 ,23 ZnBrCF 3 ·2CH 3 CN,24 HFPO,25 and FSO 2 CF 2 CO 2 H17) showed the formation of the desired difluoromethyl ethers, but the protocols suffered from the requirement of an excess of alcohol, a poor reactivity, or a narrow substrate scope. Of particular interest is the study by Levchenko et al.,26 who used FSO 2 CF 2 CO 2 H and copper catalyst to difluoromethylate primary and secondary alcohols. However, tertiary alcohols were not suitable and the air pollutant SO 2 is formed as a side product of the reaction (Scheme 1a). Shen and coworkers27 reported a Lewis acid-activated difluoromethylated sulfonium ylide, which reacted by nucleophilic substitution of CF 2 H+with various primary and secondary alcohols in dichloromethane (DCM). Due to increased steric hindrance, tertiary alcohols showed low conversions. Finally, Hu and coworkers28 presented difluoromethylation of alcohols with TMSCF 2 Br as a difluorocarbene precursor (Scheme 1a). As mild activators, potassium acetate (KOAc) and potassium bifluoride (KFHF) were used. An extensive optimization revealed that the key to this transformation was a high concentration in a two-phase solvent system of DCM/water. Difluoromethyl ethers of primary, secondary, and tertiary alcohols were obtained after extraction of the reaction mixture with DCM and subsequent column chromatography. Secondary and COMMUNICATION Received: Feb. 3, 2023 | Accepted: May 4, 2023 | Published: June 2, 2023 DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1737 tertiary alcohols required more equivalents of both difluorocarbene precursor and activator. Recently, the same group reported an optimized protocol with water as a solvent.29 Here also, DCM was used to extract the product from the reaction mixture, and modified conditions for secondary and tertiary alcohols were still required. Melting at elevated temperatures or solubilization with the addition of DCM was necessary to give satisfying yields for solid alcohols. In 2019, Liu and coworkers30 developed difluoromethylations of alcohols with an S-(difluoro-methyl)sulfonium salt as a difluorocarbene precursor (Scheme 1a). Again, a two-phase solvent system and optimized conditions for secondary alcohols were required. Besides the synthesis of alkyl difluoromethyl ethers through the reaction of alcohol with difluorocarbene or CF 2 H+, stepwise approaches from alcohols via thioformates (Scheme 1b)31,32 or more recently, difluorocarbene-induced ring-openings of cyclic ethers with various nucleophiles have been developed (Scheme 1c).33–35 In general, however, the stepwise methods suffer from a rather small substrate scope and the requirement of multiple purifications, along with product structures of difluoromethyl ethers obtained by ring-opening of cyclic ethers being limited by ring size and nucleophile. In the search for more environmentally benign reactions, ball milling has made a successful entry into various fields of chemistry.36–54 Following a mechanochemical approach has often superseded the use of solvents, which are a major hazard and contribute greatly to the waste produced in a reaction. Furthermore, compared to analogous solvent-based syntheses the same or better results in yields and catalyst loadings have been achieved. Also, altered product selectivities, possible conversions of insoluble substrates, and shorter reaction times can be beneficial attributes of mechanochemical reactions.48,55 In ball milling, the reactants, and reagents are simply added to a milling jar loaded with milling balls, the jar is sealed and placed inside a milling machine. When the machine is started, the jar is shaken or rotated, and the mixing of the reaction mixture, as well as energy transfer from the movement of the ball by shear and impact forces, can facilitate the reaction. In addition to batch processes in planetary and mixer mills, the use of (a) (b) (c) (d) Scheme 1 | Available strategies for synthesizing O-difluoromethylated alcohols. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1738 continuously operated twin screw extruders56–58 or resonant acoustic mixers59–62 has recently shown promise for the scale-up in sustainable organic chemistry. Herein, we report mechanochemical difluoromethylations of primary, secondary, and tertiary alcohols yielding the corresponding difluoromethyl ethers after 1 h reaction time at room temperature (Scheme 1d). The reactions were carried out under solvent-free reaction conditions, allowing the isolation of the products by simple filtration, thereby reducing the amount of waste generated. Results and Discussion At the starting point of the investigation, various difluorocarbene precursors were screened in the reaction with a model substrate [1,1′-biphenyl]-4-ylmethanol (1a, see Supporting Information Table S1). Choices about activator and stoichiometry were made based on previously published solution-based protocols. The reactions were carried out for 1 h at room temperature in stainless steel (SS) milling equipment. Either difluoromethyl ether 2a was either not formed at all or formed in a yield of up to 18% with a combination of BrCF 2 P(O)(OEt) 2 and K 3 PO 4 . To our delight, the difluorocarbene precursor TMSCF 2 Br (3) developed by Hu and coworkers with KFHF as an activator yielded 2a in 65% yield.5,63,64 The high substrate density under mechanochemical conditions and the mild difluorocarbene generation with activator KFHF appeared to be beneficial in the direct reaction of alcohol as a nucleophile with difluorocarbene.28 Furthermore, the identity of 2a was confirmed by a singlecrystal X-ray diffraction study (Scheme 2), which was solved in the P2 1 /nspace group with six crystallographically independent molecules present in the asymmetric unit cell. Optimization of the difluoromethylation reaction conditions Based on the initial success with TMSCF 2 Br (3)asa difluorocarbene precursor, the reaction conditions were optimized. Varying the activator from KFHF to KF, CsF, NaI, KOAc, or TBAF), as well as liquid-assisted grinding (LAG) did not improve the yield of 2a (see Supporting Information Table S2). Changing the milling equipment from SS to zirconium dioxide (ZrO 2 ) and polytetrafluoroethylene (PTFE) resulted in an increase in yield of 2a from 65% to 70% and to 81%, respectively (Figure 1a). Since the weight of the balls was kept constant in the three performed reactions, we assumed that the increased yield was due to the high chemical inertness, a low surface adhesion, and likely, a more efficient mixing in the PTFE jars (for further details, see Supporting Information Table S3). Reducing the amount of KFHF in the PTFE jars lowered the yield of 2a (Figure 1b, entry 2). To our delight, the use of alkali chloride salts as grinding auxiliaries in combination with 4 equiv of KFHF gave very positive results. Hence, the addition of either NaCl or CsCl to the reaction mixture led to 2a in quantitative yield (entries 3–6). Lowering the amount of TMSCF 2 Br or KFHF resulted in a decreased yield of 2a (entries 7 and 8). The same was observed when the milling frequency in the reaction with CsCl was reduced (entry 9). No product formation was observed with CsCl in the absence of KFHF or for a reaction under optimized conditions without milling (entries 10 and 11). To our surprise, this very positive result was highly substrate specific. Thus, when the optimized conditions for solid alcohol 1a (m.p. 100 °C) were transferred to liquid alcohol 1b (m.p. –16 °C), difluoromethyl ether 2b was obtained in only 22% yield (Figure 1b, entry 12). Further optimization of the amount of grinding auxiliary, as well as the type of ball, revealed that 12 equiv of CsCl with Scheme 2 | Optimized procedure for the mechanochemical difluoromethylation of alcohols. A crystallographic technique was used to determine the molecular structure, with anisotropic displacement parameters at a 50% probability level. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1739 one PTFE ball (d= 10 mm) was superior to all other combinations in this case, yielding 2b in 89% yield (entries 13–16). We attributed the requirement of a larger amount of CsCl, compared to the reaction with solid alcohol 1a to an insufficient mixing as the combination of the liquid alcohol with the 4 equiv of CsCl led to a rather sticky reaction mixture (see Supporting Information Figure S1 and Table S4). A yield increase was also observed when toluene was used as a LAG additive (entry 17). Substitution of CsCl with NaCl was not possible, but cheaper KCl could replace CsCl (entries 18 and 19). Until this stage, the product isolation involved extraction of the product from the jar with dichloromethane, followed by purification through a combination of aqueous work-up and column chromatography. In this manner, product 2a was obtained in 94% yield (Figure 1b, entry 6). Considering the negative environmental impact of dichloromethane, this part of the process had to be changed. Pleasingly, less harmful ethyl acetate proved to be a suitable alternative for the extraction of the jar,65 and the salts were removed by filtration over cotton. Following the new protocol, 2a was obtained in 93% yield after solvent evaporation (Scheme 2). Substrate scope With the optimal conditions in hand, the applicability of the developed difluoromethylation procedure toward primary, secondary, and tertiary alcohols was explored (Scheme 3). 2-Phenyl benzyl alcohol (1c) and 1-naphthale- nemethanol (1d) gave pure products 2c and 2d after filtration in yields of 85% and 91%, respectively. In the reaction with pyrene, purification by column chromatography was required due to an insufficient conversion and the formation of side products, obtaining 2e in 44% yield. Benzyl alcohols 1f–jwith both electron-withdrawing and electron-donating substituents in the para position were smoothly converted to their difluoromethylated analogs 2f–j; and in general, the yields were high (up to 99%). Changing the position of the methoxy substituent on benzyl alcohol from para (1j)tometa (1k) and ortho (1l) did not affect the reaction outcome. Starting from 3,4,5- trimethoxybenzyl alcohol, the yield of difluoromethyl ether 2m was only 64%, and an additional purification to separate an undesired formate side product was required. 2-Phenyl ethanols bearing either a bromo (1n) or a methoxy (1o) substituent gave the corresponding products in excellent yields. Difluoromethylated glycol ether 2p was obtained in 68% yield. Allyl and 3-thienyl alcohols 1q and 1r reacted well to provide the corresponding difluoromethyl ethers 2q and 2r in very good yields. Applying lignin model compound 1s bearing a central carbonyl group and several ether moieties was less successful leading to difluoromethylated 2s in only 19% yield after purification. Secondary alcohols with benzylic hydroxy groups gave [1-(difluoromethoxy)ethyl]arenes 2t,2u, and 2v in yields ranging from 96% to 99%. (–)-8-Phenylmenthol was successfully difluoromethylated to give pure 2w in 47% yield. Difluoromethyl ether 2x was obtained in 85% yield, Figure 1 | Standard conditions used in optimization of the reaction conditions: alcohol (0.2 mmol), activator, and TMSCF 2 Br (0.4 mmol, 2 equiv) in a PTFE milling jar (25 mL) with one PTFE milling ball (d = 12 mm; m = 3.45 g) at 25 Hz for 1 h. aDetermined by 1Hor 19F NMR spectroscopy; in parenthesis: yield after column chromatography. bWith 1.5 equiv of TMSCF 2 Br. cMilling at 20 Hz. dWithout milling. eWith another PTFE ball (d = 10 mm; m = 1.8 g). fWith PhMe as LAG additive (0.25 μL·mg−1). gThe volume of the alkali chloride salt was equal to the volume of 12.0 equiv of CsCl. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1740 OHR1 R3 R2 OR1 R3 R2CF2H KFHF (4 equiv), CsCl (4 or 12 equiv) rt, 1 h + 3 (2 equiv) TMSCF2Br OCF2H R 2a, R = Ph, 99% (93%)a 2b, R = H, 89%b OCF2H 2c, 99% (85%)a2d, 96% (91%)a OCF2H 2e,55%(44%) a,c OCF2H 2f, 2g, 2h, OCF2H X 2i, X = Me, 81% (67%)a 2j,X = MeO,74% b OCF2H MeO 2k, 2l, 2m, O R CF2H 2n, R = 2-Br, 96% (75%)b 2o, R = 3,4-MeO, quant. (99%)b 2p, 69% (68%)a,c2r, quant.b S CF2H O OCF2H 2q, 90% (88%)a O OMe O O OMe OMe CF2H 2s, 22% (19%)a,c OCF2H Me 2t, 99% (99%)a OCF2H Me Me 2u, 95% (61%)b O Me CF2H 2v, 96% (26%)b2w, 49% (47%)b O Me MeMe CF2H OCF2HMe 5 Me CF2H O 2x, 85%b2y, 90%b CF2H O 2z, 98% (87%)a2aa, 91% (86%)a,c CF2H H H H Me Me Me O MeMe 2ab, 90%b Me O 2ad, 28%b Me O Me 2ac, 99% (97%)b O MeCF2H 2ae, 47% (42%)b,c 3 O O CF2H Ph Primary alcohols Secondary alcohols Tertiary alcohols OCF2HCF2HCF2H Me 1 2 X = CO2Me, 99% (99%)a X = F, 94%b X = CN, 81% (39%)a 3-MeO, 99% (80%)b 2-MeO, 96%b 3,4,5-(MeO)3, 64% (65%)b,c Me Me Scheme 3 | Reaction conditions used to assess the scope of the alcohols: A mixture of alcohol (0.2 mmol), TMSCF 2 Br (0.4 mmol, 2 equiv), KFHF (0.8 mmol, 4 equiv), and CsCl (a0.8 mmol, 4 equiv or b2.4 mmol, 12 equiv) was milled at 25 Hz for 1 h. The yield was determined by 1H NMR spectroscopy using dichloroethane as the internal standard. In parentheses: yield after filtration. cPurified by column chromatography. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1741 demonstrating compatibility of the developed protocol with terminal alkynes. Octan-2-ol (1y) and indan-2-ol (1z) were smoothly converted leading to difluoromethyl ethers 2y and 2z in 90% and 98% yields, respectively. Furthermore, a derivative of the natural product pregnenolone was applied to this protocol affording the corresponding difluoromethyl ether 2aa in 92% yield. For completion, the applicability of tertiary alcohols was investigated. Commonly, such compounds require optimized reaction conditions with an excess of the difluorocarbene precursor and prolonged reaction times. However, the standard reaction conditions worked well providing difluoromethyl ether 2ab and 2ac in 90% and 99% yields, respectively. Sterically, more hindered alcohol 1ad gave product 2ad in 28% yield. Difluoromethyl ether 2ae was obtained in 47% yield from 1,2-diphenyl- propane-2-ol (1ae). Attempts to difluoromethylated phenols, thiols, and imidazoles remained unsuccessful. N-Difluoromethylating 5-phenyltetrazole gave two regioisomers in 34% and 26% yields (for details, see Supporting Information Scheme S1). To confirm the hypothesis that difluorocarbenes were involved under these solvent-free reactions with alcohols, the difluoromethylation of 1a was performed under optimized conditions (Figure 1b, entry 6) in the presence of α-methyl styrene (for details, see Supporting Information Table S5). As suspected, the yield of 2a dropped from quantitative to 43%, and with 1 equiv of α-methyl styrene, the corresponding difluorocyclopropane was formed in 61% yield. This trend was even more pronounced when 2 equiv of the olefine were added. Conclusion We have developed mechanochemical difluoromethylation reactions of primary, secondary, and tertiary alcohols. The mild, solvent-free reaction conditions tolerated various functional groups, and the products were obtained after milling for 1 h at room temperature in a mixer mill. TMSCF 2 Br served as a precursor of difluorocarbene, formed in situ, and smoothly reacted with the alcohol. The simplicity of the process and the possibility to purify the products by filtration highlights that these milling events offer opportunities for more environmentally benign reaction control. The Cambridge Crystallographic Data Centre (CCDC) 2239503 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,or by sending an email to [email protected], or by contacting the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. Supporting Information Supporting Information is available and includes additional optimizations of reaction conditions, detailed experimental procedures, and analytic data of the synthesized compounds. Conflict of Interest There is no conflict of interest to report. Funding Information This research was made possible by the generous support of the Rhine-Westphalia Technical University of Aachen (RWTH Aachen University). We also acknowledge the Alexander von Humboldt Foundation for support of K. R. (AvH research award). References 1. Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor”Concept. J. Med. Chem. 2017,60, 797–804. 2. Zafrani, Y.; Sod-Moriah, G.; Yeffet, D.; Berliner, A.; Amir, D.; Marciano, D.; Elias, S.; Katalan, S.; Ashkenazi, N.; Madmon, M.; Gershonov, E.; Saphier, S. CF 2 H, a Functional Group- Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH 3 ?J. Med. Chem. 2019,62, 5628–5637. 3. Metcalf, R. L.; Horowitz, A. R. Insect Control, 2. Individual Insecticides. In Ley, C., Ed.; Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2014. 4. Cheer, S. M.; Prakash, A.; Faulds, D.; Lamb, H. M. Pantoprazole. Drugs 2003,63, 101–133. 5. Hu, J.; Ni, C. Recent Advances in the Synthetic Application of Difluorocarbene. Synthesis 2014,46, 842–863. 6. Loison, A.; Toulgoat, F.; Billard, T.; Hanquet, G.; Panossian, A.; Leroux, F. R. Recent Synthetic Methods Towards the –OCHF 2 Moiety. Tetrahedron 2021,99,132458. 7. Sap, J. B. I.; Meyer, C. F.; Straathof, N. J. W.; Iwumene, N.; Am Ende, C. W.; Trabanco, A. A.; Gouverneur, V. Late-Stage Difluoromethylation: Concepts, Developments and Perspective. Chem. Soc. Rev. 2021,50, 8214–8247. 8. Fier, P. S.; Hartwig, J. F. Synthesis of Difluoromethyl Ethers with Difluoromethyltriflate. Angew. Chem. Int. Ed. 2013,52, 2092–2095. 9. Lee, J. W.; Zheng, W.; Morales-Rivera, C. A.; Liu, P.; Ngai, M.-Y. Catalytic Radical Difluoromethoxylation of Arenes and Heteroarenes. Chem. Sci. 2019,10, 3217–3222. 10. Lee, J. W.; Lim, S.; Maienshein, D. N.; Liu, P.; Ngai, M. Y. Redox-Neutral TEMPO Catalysis: Direct Radical (Hetero)Aryl C−H Di- and Trifluoromethoxylation. Angew. Chem. Int. Ed. 2020,59, 21475–21480. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1742 11. Lin, D.; Prakash, G. K. S. Visible-Light Photoredox- Catalyzed C(sp2)–HDifluoromethoxylation of (Hetero)arenes Utilizing a Shelf-Stable Pyridinium Reagent. Org. Lett. 2022,24, 7707–7711. 12. Zhang, L.; Zheng, J.; Hu, J. 2-Chloro-2,2-difluoroaceto- phenone: A Non-ODS-Based Difluorocarbene Precursor and Its Use in the Difluoromethylation of Phenol Derivatives. J. Org. Chem. 2006,71, 9845–9848. 13. Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H.-J. Chlorodifluoromethyl Phenyl Sulfone: A Novel Non-Ozone-Depleting Substance-Based Difluorocarbene Reagent for O- and N-Difluoromethylations. Chem. Commun. 2007, 5149–5151. 14. Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Diethyl Bromodifluoromethylphosphonate: A Highly Efficient and Environmentally Benign Difluorocarbene Precursor. Tetrahedron 2009,65, 5278–5283. 15. Sperry, J. B.; Sutherland, K. A Safe and Practical Procedure for the Difluoromethylation of Methyl 4-Hydroxy-3- iodobenzoate. Org. Process Res. Dev. 2011,15, 721–725. 16. Li, L.; Wang, F.; Ni, C.; Hu, J. Synthesis of gem-Difluor- ocyclopropa(e)nes and O-, S-, N-, and P-Difluoromethylated Compounds with TMSCF 2 Br. Angew. Chem. Int. Ed. 2013,52, 12390–12394. 17. Chen, Q.-Y.; Wu, S.-W. A Simple Convenient Method for Preparation of Difluoromethyl Ethers Using Fluorosulfonyldifluoroacetic Acid as a Difluorocarbene Precursor. J. Fluor. Chem. 1989,44, 433–440. 18. Wang, F.; Huang, W.; Hu, J. Difluoromethylation of O-, S-, N-, C-Nucleophiles Using Difluoromethyltri(n-butyl)ammonium Chloride as a New Difluorocarbene Source. Chin. J. Chem. 2011,29, 2717–2721. 19. Liu, G.-K.; Qin, W.-B.; Li, X.; Lin, L.-T.; Wong, H. N. C. Difluoromethylation of Phenols and Thiophenols with the S- (Difluo-romethyl)sulfonium Salt: Reaction, Scope, and Mechanistic Study. J. Org. Chem. 2019,84, 15948–15957. 20. Hine, J.; Tanabe, K. Isopropoxyfluoromethylene. J. Am. Chem. Soc. 1957,79, 2654–2655. 21. Mizukado, J.; Matsukawa, Y.; Quan, H.-d.; Tamura, M.; Sekiya, A. Reactions of Aliphatic Fluoro-Alcohols with CHClF 2 at Atmospheric Pressure. J. Fluorine Chem. 2006, 127, 400–404. 22. Flynn, R. M.; Burton, D. J. Synthetic and Mechanistic Aspects of Halo-F-Methylphosphonates. J. Fluor. Chem. 2011,132, 815–828. 23. Mitsch, R. A.; Robertson, J. E. Difluorodiazirine. V. Difluoromethyl Esters and Ethers. J. Heterocycl. Chem. 1965,2, 152–156. 24. Miethchen, R.; Hein, M.; Naumann, D.; Tyrra, W. Organofluorine Compounds and Fluorinating Agents, 15. O– Difluoromethylations of Monosaccharides by Trifluoromethylzinc Bromide. Liebigs Ann. 1995,9,1717–1719. 25. Mizukado, J.; Matsukawa, Y.; Quan, H.-d.; Tamura, M.; Sekiya, A. Insertion Reactions of Difluorocarbene Generated by Pyrolysis of Hexafluoropropene Oxide to OH Bond. J. Fluor. Chem. 2005,126, 365–369. 26. Levchenko, K.; Datsenko, O. P.; Serhiichuk, O.; Tolmachev, A.; Iaroshenko, V. O.; Mykhailiuk, P. K. Copper- Catalyzed O-Difluoromethylation of Functionalized Aliphatic Alcohols: Access to Complex Organic Molecules with an OCF 2 H Group. J. Org. Chem. 2016,81, 5803–5813. 27. Zhu, J.; Liu, Y.; Shen, Q. Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide. Angew. Chem. Int. Ed. 2016,55, 9050–9054. 28. Xie, Q.; Ni, C.; Zhang, R.; Li, L.; Rong, J.; Hu, J. Efficient Difluoromethylation of Alcohols Using TMSCF 2 Br as a Unique and Practical Difluorocarbene Reagent Under Mild Conditions. Angew. Chem. Int. Ed. 2017,56, 3206–3210. 29. Zhang, R.; Ni, C.; Xie, Q.; Hu, J. Difluoromethylation of Alcohols with TMSCF 2 Br in Water: A New Insight into the Generation and Reactions of Difluorocarbene in a Two-Phase System. Tetrahedron 2020,50, 131676. 30. Liu, G.-K.; Li, X.; Qin, W.-B.; Peng, X.-S.; Wong, H. N. C.; Zhang, L.; Zhang, X. Facile Difluoromethylation of Aliphatic Alcohols with an S-(Difluoro-methyl)sulfonium Salt: Reaction, Scope and Mechanistic Study. Chem. Commun. 2019, 55, 7446–7449. 31. Hagooly, Y.; Cohen, O.; Rozen, S. A General Route for Constructing Difluoromethyl Ethers. Tetrahedron Lett. 2009, 392–394. 32. Dolbier, W. R., Jr.; Wang, F.; Tang, X.; Thomoson, C. S.; Wang, L. Three Step Procedure for the Preparation of Aromatic and Aliphatic Difluoromethyl Ethers from Phenols and Alcohols Using a Chlorine/Fluorine Exchange Methodology. J. Fluor. Chem. 2014,160,72–76. 33. Zhang, R.; Li, Q.; Xie, Q.; Ni, C.; Hu, J. Difluorocarbene- Induced Ring-Opening Difluoromethylation-Halogenation of Cyclic (Thio)Ethers with TMSCF 2 X (X=Br, Cl). Chem. Eur. J. 2021,71, 17773–17779. 34. Sheng, H.; Su, J.; Li, X.; Song, Q. Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers. CCS Chem. 2022,4, 3820–3831. 35. Zhu, X.; Wei, J.; Hu, C.; Xiao, Q.; Cai, L.; Wang, H.; Xie, Y.; Sheng, R. Difluorocarbene-Induced Ring Opening of Tetrahydrofuran with TMSCF 2 Br for Difluoromethoxybutylation of N-Aryl-N-hydroxylamines. Eur. J. Org. Chem. 2022, e202200629. 36. James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Frišči´c, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Mechanochemistry: Opportunities for New and Cleaner Synthesis. Chem. Soc. Rev. 2012,41, 413–447. 37. Wang, G.-W. Mechanochemical Organic Synthesis. Chem. Soc. Rev. 2013,42, 7668–7700. 38. Andersen, J.; Mack, J. Mechanochemistry and Organic Synthesis: From Mystical to Practical. Green Chem. 2018,20, 1435–1443. 39. Stolle, A.; Szuppa, T.; Leonhardt, S. E. S.; Ondruschka, B. Ball Milling in Organic Synthesis: Solutions and Challenges. Chem. Soc. Rev. 2011,40, 2317–2329. 40. Howard, J. L.; Cao, Q.; Browne, D. L. Mechanochemistry as an Emerging Tool for Molecular Synthesis: What Can It Offer? Chem. Sci. 2018,9, 3080–3094. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1743 41. Do, J.-L.; Frišči´c, T. Mechanochemistry: A Force of Synthesis. ACS Cent. Sci. 2017,3,13–19. 42. Frišči´c, T.; Mottillo, C.; Titi, H. M. Mechanochemistry for Synthesis. Angew. Chem. Int. Ed. 2020,59, 1018–1029. 43. Rightmire, N. R.; Hanusa, T. P. Advances in Organometallic Synthesis with Mechanochemical Methods. Dalton Trans. 2016,45, 2352–2362. 44. Bolm, C.; Hernández, J. G. Mechanochemistry of Gaseous Reactants. Angew. Chem. Int. Ed. 2019,58, 3285–3299. 45. Krusenbaum, A.; Grätz, S.; Tigineh, G. T.; Borchardt, L.; Kim, J. G. The Mechanochemical Synthesis of Polymers. Chem. Soc. Rev. 2022,51, 2873–2905. 46. Jones, A. C.; Leitch, J. A.; Raby-Buck, S. E.; Browne, D. L. Mechanochemical Techniques for the Activation and Use ofZero-ValentMetalsinSynthesis.Nat. Synth. 2022,1,763–775. 47. Ardila-Fierro, K. J.; Hernández, J. G. Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry. ChemSusChem 2021,14, 2145–2162. 48. Cuccu, F.; De Luca, L.; Delogu, F.; Colacino, E.; Solin, N.; Mocci, R.; Porcheddu, A. Mechanochemistry: New Tools to Navigate the Uncharted Territory of “Impossible”Reactions. ChemSusChem 2022,15, e202200362. 49. Fantozzi, N.; Volle, J.-N.; Porcheddu, A.; Virieux, D.; Garcia, F.; Colacino, E. Green Metrics in Mechanochemistry. ChemRxiv 2022. doi: https://doi.org/10.26434/chemrxiv- 2022-b370p 50. Tan, D.; Garcia, F. Main Group Mechanochemistry: From Curiosity to Established Protocols. Chem. Soc. Rev. 2019,48, 2274–2292. 51. Auvray, T.; Frišči´c, T. Shaking Things from the Ground- Up: A Systematic Overview of the Mechanochemistry of Hard and High-Melting Inorganic Materials. Molecules 2023,28, 897. 52. Pérez-Venegas, J. E. Mechanochemical and Mechanoenzymatic Synthesis of Pharmacologically Active Compounds: A Green Perspective. ACS Sustainable Chem. Eng. 2020,8, 8881–8893. 53. Ying, P.; Yu, J.; Su, W. Liquid-Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals. Adv. Synth. Catal. 2021,363, 1246–1271. 54. Yang, X.; Wu, C.; Su, W.; Yu, J. Mechanochemical C–X/ C–H Functionalization: An Alternative Strategic Access to Pharmaceuticals. Eur. J. Org. Chem. 2022, e202101440. 55. Hernández, J. G.; Bolm, C. Altering Product Selectivity by Mechanochemistry. J. Org. Chem. 2017,82, 4007–4019. 56. Crawford, D. E.; Miskimmin, C. K. G.; Albadarin, A. B.; Walker, G.; James, S. L. Organic Synthesis by Twin Screw Extrusion (TSE): Continuous, Scalable and Solvent-Free. Green Chem. 2017,19, 1507–1518. 57. Colacino, E.; Isoni, V.; Crawford, D.; García, F. Upscaling Mechanochemistry: Challenges and Opportunities for Sustainable Industry. Trends Chem. 2021,3, 335–339. 58. Bolt, R. R. A.; Leitch, J. A.; Jones, A. C.; Nicholson, W. I.; Browne, D. L. Continuous Flow Mechanochemistry: Reactive Extrusion as an Enabling Technology in Organic Synthesis. Chem. Soc. Rev. 2022,51, 4243–4260. 59. Am Ende, D. J.; Anderson, S. R.; Salan, J. S. Development and Scale-Up of Cocrystals Using Resonant Acoustic Mixing. Org. Process Res. Dev. 2014,18, 331–341. 60. Nagapudi, K.; Umanzor, E. Y.; Masui, C. High- Throughput Screening and Scale-Up of Cocrystals Using Resonant Acoustic Mixing. Int. J. Pharm. Sci. 2017,521, 337–345. 61. Titi, H. M.; Do, J.-L.; Howarth, A. J.; Nagapudi, K.; Frišči´c, T. Simple, Scalable Mechanosynthesis of Metal–Organic Frameworks Using Liquid-Assisted Resonant Acoustic Mixing (LA-RAM). Chem. Sci. 2020,11, 7578–7584. 62. Gonnet, L.; Lennox, C. B.; Do, J. L.; Malvestiti, I.; Koenig, S. G.; Nagapudi, K.; Frišči´c, T. Metal-Catalyzed Organic Reactions by Resonant Acoustic Mixing. Angew. Chem. Int. Ed. 2022,61, e2021150. 63. Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. Preparation of and Fluoroalkylation with (Chlorodifluoromethyl)trimethylsilane, Difluorobis(trimethylsilyl)methane, and 1,1,2,2-Tetrafluoro-1,2-bis(trimethylsilyl) ethane. J. Am. Chem. Soc. 1997,119,1572–1581. 64. Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang, K.-W.; Hu, J. Chloride Ion-Catalyzed Generation of Difluorocarbene for Efficient Preparation of gem-Difluorinated Cyclopropenes and Cyclopropanes. Chem. Commun. 2011,47, 2411–2413. 65. Prat, D.; Pardigon, O.; Flemming, H.-W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Sanofi’s Solvent Selection Guide: A Step Toward More Sustainable Processes. Org. Process Res. Dev. 2013,17, 1517–1525. COMMUNICATION DOI: 10.31635/ccschem.023.202302783 Citation: CCS Chem. 2023, 5, 1737–1744 Link to VoR: https://doi.org/10.31635/ccschem.023.202302783 1744