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Fluorination Chemistry Fluorination Chemistry 2 Let Sigma-Aldrich Assist You With All of Your Fluorination Needs Fluorine has a profound ability to alter the biological properties of a compound due to its electronegativity and small size. In pharmaceutical research, fluorine is often introduced into the target compound to improve bioavailability and enhance the metabolic stability profile. However, the general and practical fluorination of functionalized molecules continues to be a highly researched area. We are pleased to feature an ever-expanding portfolio of fluorination reagents and fluorinated building blocks to assist fluorination, difluoromethylation and trifluoromethylation. Did you know? At least 8 out of the 39 FDA approved drugs in 2012 were small molecules containing fluorine? …. and that Sigma-Aldrich is your trusted resource for reagents and building blocks to incorporate fluorine to assist in obtaining your next hit? To learn more, visit Aldrich.com/fluoro O Cl F3C O O N H N H NHMe N Order 800-325-3010 O MeHN F Stivarga® Bayer Healthcare Aldrich.com F Technical Service 800-325-5832 Me O Me N N CN S Xtandi® Astellas Pharma CF3 Fluorination Chemistry Fluorination The high toxicity/corrosivity of HF renders any fluorination technology that precludes its use or generation highly valuable to synthetic chemists. With this in mind, Aldrich Chemistry provides a versatile toolbox of fluorine reagents for both nucleophilic and electrophilic methods. Classically, the source of electrophilic fluorine has been fluorine gas, which is highly toxic and a strong oxidizer. The Aldrich catalog has a growing portfolio of milder, safer and highly stable alternatives for electrophilic fluorination. These reagents have shown excellent utility in several applications, ranging from electrophilic aromatic substitution to formation of α-fluoro-keto species. In the mode of nucleophilic fluorination, we provide fluoride sources for direct displacement of alcohols, additions to aldehydes, ketones and carboxylic acids in highly chemoselective fashions for small molecule synthesis as well as poly-fluorination for materials synthesis. O F "F " R H3C N CH3 SF3 CH3 SF3 N H3CO SF3 OCH3 F R t-Bu F F S N BF4 H3C F CH3 N S CH3 F BF4 O DAST Deoxo-Fluor® FluoleadTM XtalFluor-M® XtalFluor-E® 235253 774642 494119 94327 94324 734039 719447 719439 (1.0 M in dichloromethane) Figure 1. Nucleophilic Fluorination "F " X F Cl N N 2BF4 N F XFn 2BF4 N H3C Selectfluor® 439479 Figure 2. Electrophilic Fluorination Selectfluor® II 716219 OTf N F OTf 323659 Cl N F Cl 738123 PhO2S F N SO2Ph NFSI 392715 3 4 Aldrich Chemistry now features an innovative fluorinating reagent, PhenoFluor™ (SFL00001), which is capable of producing a wide range of aryl fluorides directly from the corresponding phenol (tolerant of several aryl functional group), without requiring functionalization of the free alcohol through common approaches, e.g. sulfonylation.1 OH Phenofluor was also shown to accomplish late-stage fluorination of highly functionalized free alcohols. This unprecedented display of regioselectivity further demonstrates the value of this reagent in late-stage derivatization. R i-Pr i-Pr N Me HO Me Me Me Me i-Pr F OH OH O OH O O Me HO Me Me F i-Pr Me Me OH PhenoFluor SFL00001 Me OH O OH O Me O Me Late-Stage O O N TM O Me Et F No Preactivation R Derivatization O Et O Me OH O Me F Me Me Me Me References: (1) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482. (2) Sladojevich, F.; Arlow, S. L.; Tang, P.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 2470. Additional Fluorinated Building Blocks: 755028 755036 755206 755303 756849 757047 758205 758485 759333 759392 759996 763616 Aldrich.com Order 800-325-3010 Technical Service 800-325-5832 Fluorination Chemistry Difluoromethylation The difluoromethyl group (R-CF2H) has recently garnered much attention in drug, agrochemical and material research since it is isoteric to a carbinol group (CH2OH). The Aldrich catalog has innovative sources for installing the difluoromethyl group through nucleophilic addition and radical functionalization of C-H bonds. Nucleophlic difluoromethylation of carbonyls and imines using (Difluoromethyl)trimethylsilane (744050) and Difluoromethyl phenyl sulfone (742600) was developed by Jinbo Hu and coworkers. O O S CF2H Zinc difluoromethanesulfinate (DFMS, 767840), developed in the Baran lab, can directly add CF2H to heterocycles under open flask conditions making it very operationally simple to carry out difluoromethylation. A wide range of heteroaromatic substrates are compatible (namely nitrogen-containing heterocycles) and several functional groups are tolerated in presence of DFMS. Me Me Si CF2H Me 742600 X "CF2H " R X = O, N RX CF2H R 744050 Figure 3. Nucleophilic Difluoromethylation References: (1) Shen, X.; Ni, C.; Hu, J. Helv. Chim. Acta 2012, 95, 6606-6610. (2) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13, 5342-5345. R H HF2C X O S O Zn O O S CF2H CF2H R X Baran DFMS 767840 Reference: Fujiwara, Y.; Dixon, J. A.; O'Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95-100. Additional Difluoromethyl Building Blocks: 722472 729973 730475 733261 733962 733997 734934 759341 5 6 Trifluoromethylation Trifluoromethylation has been a rapidly growing field in chemical research, one that has interfaced elegantly with catalysis in crafting new chemical methodologies for placing trifluoromethyl groups onto molecules. In the arena of stoichiometric reagents, Aldrich offers three classes of reagents amendable to trifluoromethylation. For nucleophilic trifluoromethylation, the Ruppert-Prakash reagent (488712, 819062) has long been a staple for adding CF3 to carbonyls and imines. This reagent has also been featured in several publications in tandem with transition metal catalysis to install CF3 to several motifs. More recently, trifluoromethylation by a radical process has been developed in the Baran (771406) and Hartwig (777692) groups. The Baran TFMS reagent, like the DFMS reagent, can be used to convert aryl and heteroaryl C-H bonds directly into C-CF3 bonds under mild conditions. Trifluoromethylator® is one of the more robust reagents used to form C-CF3 bonds from aryl and vinylogous iodides. "CF3 " R X = O, N SH Me Me Si CF3 Me Ruppert-Prakash 488712 91862 (~2.0 M in THF) RX O S Zn O O O S N CF3 Baran TFMS 771406 CF3 N Cu CF3 Trifluoromethylator® 777692 Figure 5. Radical Trifluoromethylation S CF3 X = O, N N HO O F3C F3C R "CF3 " CF3 X = H, I A new nucleophilic trifluoromethylation source was developed by the Colby group. The Colby Trifluoromethylation Reagent (L511315) is an air-stable solid that adds CF3 to ketones and thiols under mildly basic conditions. The major by-products from this reaction are DBU and trifluoroacetate, which are both considered benign. X " CF3 " X CF3 N H Colby Trifluoromethylation Reagent L511315 The Aldrich portfolio also offers electrophilic sources of trifluoromethyl groups. Notably, the Togni I (696641, 754218) and Togni II (771147) reagents can provide highly selective trifluoromethylation of a wide range of substrates. The Togni II reagent is offered as a safer alternative for shipping and storage, available as a mixdown formulation with Celatom® that can either be easily isolated by washing away Trifluoromethylation the adsorbent or even used directly. Electrophilic Figure 4. Nucleophilic Fluorination X F3C I O Me "CF3 " F3C I O O Me Togni Reagent 696641 754218 X CF3 Togni II Reagent 771147 S X CF3 483869 (R = BF4 ) 483877 (R = OTf ) Figure 6. Electrophilic Trifluoromethylation Reference: Fiederling, N.; Hallar, J.; Schramm, H. Org. Process Res. Dev., 2013, 17, 318. For a complete listing of the Baran Reagents, which promote innate C-H functionalization of aryl and heteroaryl motifs, visit Aldrich.com/baranreagents Aldrich.com Order 800-325-3010 Technical Service 800-325-5832 Fluorination Chemistry Additional Trifluoromethyl Building Blocks: 725838 725846 725854 725870 725889 728470 728616 728683 728748 729957 729981 730009 730025 730173 730181 730467 730483 733237 733989 734004 737232 737240 754994 755001 755230 For our complete portfolio of fluorinated reagents and building blocks, visit Aldrich.com/fluoro 7 Invest in Your Synthesis! Sigma-Aldrich Has the Tools for Fluorination! Ace all-PTFE filter reactor assembly These PTFE filter reactors can be used for fluorine chemistry and with strong alkaline compounds that can etch glass. The head, head joints, body, stirrer-bearing, bottom filter assembly with valve, and stirring shaft with agitator are all PTFE. Even the O-Rings are PTFE encapsulated. The filter supports are polypropylene. The bottom filter assembly is either #50 or #80 Ace-Thred™ and threads in/out for easy capture of filtrate, or for cleaning. A Halar® coated stainless steel internal coil is included (in the 1 L size) for heating or cooling the contents. IKA RW 20 over head stirrer recommended. Capacity 250 mL 500 mL Joints 24/40 24/40 Cat. No. Z690368 Z690473 1L 24/40 Z690503 IKA® RW 20 Digital Overhead Stirrer • With digital display (LED) •Robust, slim line, ergonomic design •With constant power-drive •Two speed ranges for universal use from 60 - 2,000 rpm •Push-through agitator shafts (only when stationary) Volts 110 230 IKA 9011601 901160X Cat. No. Z645087 Z645095 For product pricing and ordering information, visit Aldrich.com/labware Enabling Science to Improve the Quality of Life Order/Customer Service (800) 325-3010 • Fax (800) 325-5052 Technical Service (800) 325-5832 • sigma-aldrich.com/techservice Development/Custom Manufacturing Inquiries (800) 244-1173 Safety-related Information sigma-aldrich.com/safetycenter ©2013 Sigma-Aldrich Co. LLC. All rights reserved. SAFC, SIGMA-ALDRICH, and ALDRICH are trademarks of Sigma-Aldrich Co. LLC, registered in the US and other countries. Add Aldrich is a trademark of Sigma-Aldrich Co. LLC. Celatom is a registered trademark of EP Minerals, LLC. IKA is a registered trademark of IKA-Werke GmbH & Co. KG Trifluoromethylator is a registered trademark of Catylix, Inc. Halar is a registered trademark of Solvay Group. Ace-Thred is a trademark of Ace Glass, Inc. PhenoFluor is a trademark of Scifluor Life Sciences, LLC. Aldrich brand products are sold through Sigma-Aldrich, Inc. 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