Recent Developments in Nucleophilic Fluorination

Transcription

1 ecent Developments in ucleophilic luorination + K + S K + 13 ipr ipr ipr ipr S Vlad Bacauanu MacMillan esearch Group Group eting March 13th, 2018

2 Importance of ovel luorination Technologies Improved membrane permeance Enhanced metabolic stability C bond Present in 20 30% new approved drugs 2 C S fleroxacin 2 ezetimibe Cl fluticasone clofarabine ustero, S.; Soloshonok, V. A.; Liu,. et al. Chem. ev. 2014, 114, Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu,. et al. Chem. ev. 2016, 116, 422.

3 Importance of Developing ucleophilic luorination Strategies + K + S K B Cl 2 B ipr ipr ipr ipr S + 2 S S 2 nucleophilic fluorination electrophilic fluorination Why would you choose to do nucleophilic fluorination? Generally cheaper reagents vs. electrophilic 18 2 Potentially better G tolerance ( + is oxidizing) Significantly more desirable for 18 PET imaging 2 ( 18 + reagents are inconveniently made from 18 2 ) Campbell, M. G.; itter, T. Chem. ev. 2015, 115, 612. Liang, T.; eumann, C..; itter, T. Angew. Chem., Int. Ed. 2013, 52, 8214.

4 ecent Developments in ucleophilic luorination nstruction of Alkyl C Bonds ucleophilic substitution promoted by hydrogen bonding Deoxyfluorination of aliphatic alcohols Transition metal-catalyzed allylic fluorination Direct hydrofluorination of alkenes tal-mediated aminofluorination of alkenes Asymmetric hydrofluorination of epoxides Manganese-catalyzed C fluorination see YYL group meeting Ac nstruction of Aromatic C Bonds tal-mediated fluorination of arenes see JT group meeting ucleophilic aromatic substitution of (pseudo)halides itter s S Ar deoxyfluorination of phenols

5 Aliphatic ucleophilic Substitution eactions with luoride X alkyl (pseudo)halide substitution elimination Why is an S 2 reaction using a fluoride source not as straightforward as it looks? water / protic solvents hydrogen bonding polar aprotic solvents no hydrogen bonding solubility nucleophilicity basicity good poor (no S 2) weak counterion dependent good strong (competitive E2) Lee, S.; Chi, D. Y. et al. Chem. Soc. ev. 2016, 45, 4638.

6 Unexpected S 2 eactions with luoride in Alcohol Solvents Ms Bu 4 + solvent, 80 ºC, 1 h alkyl mesylate in C: 33% 61% in tbu: 87% 9% TBA 4(tBu), in C: 71% 29% S controllable fluoride diminished basicity decent nucleophilicity enhanced leaving group ability Lee, S.; Chi, D. Y. et al. Chem. Soc. ev. 2016, 45, 4638.

7 Scope of ydrogen Bond-Promoted ucleophilic lourination X Cs + t-bu or t-amyl alcohol, 90 ºC Tf Ts I 2 C Boc 93% yield (2 h) 69% yield (1.5 h, 25 ºC) 90% yield (24 h) Applications in radio-labelling % CY 70% CY 66% CY Lee, S.; Chi, D. Y. et al. J. Am. Chem. Soc. 2006, 128,

8 Application of ydrogen Bond-Promoted ucleophilic lourination Ms C C 2 I C 3 C, 90 ºC I Desired fluorinated producted obtained in 1% yield PET imaging of dopamine transporters Lee, S.; Chi, D. Y. et al. J. Am. Chem. Soc. 2006, 128,

9 Application of ydrogen Bond-Promoted ucleophilic lourination Ms C C 2 C 2 I C 3 C, 90 ºC I I competitive -alkylation major product Ms C C 2 I tbu, 100 ºC I amine inhibited via -bonding 36% CC Lee, S.; Chi, D. Y. et al. J. Am. Chem. Soc. 2006, 128,

10 General Deoxyfluorination of Aliphatic Alcohols direct Ubiquitous functional group deoxyfluorination Circumvent prefunctionalization Deoxyfluorination reagents S 3 S 3 B 4 S 2 + ipr ipr S ipr ipr DAST Deoxo-luor Xtalluor-E enoluor Pyluor (1975) (1999) (2009) (2011) (2015) Et S Et + Example of mechanism S Et 2 S Et 2 + Middleton, W. J. J. rg. Chem. 1975, 40, 574. Doyle, A. G. et al. J. Am. Chem. Soc. 2015, 137, uturier, M. et al. J. rg. Chem. 2010, 75, itter, T. et al. J. Am. Chem. Soc. 2013, 135, Liang, T.; eumann, C..; itter, T. Angew. Chem., Int. Ed. 2013, 52, 8214.

11 Selected Examples of Alcohol Deoxyfluorination Bn Bn Bn Bn protected glucose S 18 MTBD, C 80 ºC, 20 min Bn Bn Bn 15% CC 18 Bn 71% yield (rt to ºC, DCM) 2 C 82% yield (80 ºC, in toluene) ipr ipr ipr ipr 2.0 equiv. DIPEA 2.0 equiv. K 2 20 h ielsen, M. K.; Ugaz, C..; Li, W.; Doyle, A. G. J. Am. Chem. Soc. 2015, 137, Sladojevich,.; Arlow, S. I.; Tang, P.; itter, T. J. Am. Chem. Soc. 2013, 135, 2470.

12 tal-catalyzed ucleophilic sp 3 luorination via π-allyl Chemistry branched allylic fluorides challenging to prepare via deoxyfluorination + racemization (competing S 1) regioselectivity elimination X [M] cat. [M] allylic (pseudo)halide π-allyl approach branched linear catalyst-controlled regioselectivity Application of established π-allyl chemistry towards nucleophilic fluorination Potential control over regioselectivity by modulating nature of catalytic species pportunities for asymmetric construction of fluorinated products

13 π-allyl thodologies for ucleophilic sp 3 luorination CCl 3 Et 3 3 cat. [Ir(cod)Cl] 2 Et 2, 23 ºC, 1 2 h Topczeswki, J. J.; Tweson, T. J.; guyen,. M. J. Am. Chem. Soc. 2011, 133, (tbu) 4 Bu mol% [Pd(dba) 2 ], 15 mol% P 3 T, 23 ºC, 1 h = p- 2 -C 6 4 Brown, J. M.; Gouverneur, V. et al. Angew. Chem., Int. Ed. 2011, 123, racemic Cl Ag cat. [Pd], chiral ligand enantio- material X 23 ºC, h X enriched Katcher, M..; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, Katcher, M..; Sha, A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

14 Doyle s Palladium-Catalyzed Asymmetric Allylic luorination X Cl or Cl Ag cat. [Pd], chiral ligand or T, 23 ºC, h X or racemic mixture enantioenriched products chiral ligand chiral ligand P 2 2 P P 2 2 P Ts C 2 Boc Bn TBS 4 85% yield 88% ee 74% yield 96% ee 68% yield 14:1 dr, 90% ee 85% yield 10:1 b:l, 93% ee 50% yield 16:1 b:l, 90% ee 84% yield >20:1 b:l, 58% ee Katcher, M..; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, Katcher, M..; Sha, A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

15 Doyle s Palladium-Catalyzed Asymmetric Allylic luorination Cl 1.1 equiv. Ag cat. [Pd], cat. P 3 Et 2 C > 20:1 dr T, 23 ºC, 6 h Et 2 C stereoretention Katcher, M..; orrby, P..; Doyle, A. G. rganometallics 2014, 33, 2121.

16 Doyle s Palladium-Catalyzed Asymmetric Allylic luorination Et 2 C > 20:1 dr Cl 3 P Cl Pd Et 2 C outer sphere attack Et 2 C stereoretention 2 C 3 P Pd Cl 2.0 equiv. Ag d 8 -T, 23 ºC, 24 h 2 C 49% yield 3 P Pd TBS Et 2 C expected for hard nucleophile 56% yield silyl ethers are tolerated no product typical π-allyl substrates incompatible Typical π-allyl mechanism involving naked as nucleophile unlikely Katcher, M..; orrby, P..; Doyle, A. G. rganometallics 2014, 33, 2121.

17 Proposed chanism for Palladium-Catalyzed Allylic luorination Cl L n Pd 0 L n Pd 0 + Pd II P 3 + L n Pd 0 Cl Pd δ+ P 3 Pd II P 3 Cl Pd II P 3 3 P Pd δ+ P 3 outer sphere attack by soft Pd nucleophile P 3 3 P Pd II + P 3 + P 3 AgCl Ag chloride LG necessary for ion exchange with Ag cationic electrophile Katcher, M..; orrby, P..; Doyle, A. G. rganometallics 2014, 33, 2121.

18 Palladium-Catalyzed Allylic C luorination allylic C substrate 15 mol% Pd(TA) 2 ligand 10 mol% (,)-(salen)crcl Et 3 3 (6 eq.), BQ (2 eq.) DCE, 23 ºC, 72 h branched product Bn S S Pd Bn 3 CC CC 3 tbu Cr tbu tbu tbu Pd(TA) 2 ligand (,)-(salen)crcl Lewis acid benzoquinone (BQ) oxidant + ligand Potential reaction pathway L n Pd(C 3 C 2 ) 2 BQ C 3 C 2 3 CC Pd II 3 CC Pd II BQ Braun, M. G.; Doyle, A. G. J. Am. Chem. Soc. 2013, 135,

19 Palladium-Catalyzed Allylic C luorination allylic C substrate 15 mol% Pd(Ac) 2 (SC 2 ) 2 10 mol% co-catalyst source (6 eq.), BQ (2 eq.) DCE, 23 ºC, 72 h branched product source co-catalyst yield Ag 0% K 0% Et 3 3 Et 3 3 (salen)mncl 33% 14% tbu M tbu Et 3 3 Et 3 3 (salen)crcl (salen)cr 51% 28% tbu tbu (salen)m (salen)cr potentially generated in situ unlikely nucleophile Pd II 3 CC BQ [Cr] Lewis acid increases [Pd] electrophilicity Braun, M. G.; Doyle, A. G. J. Am. Chem. Soc. 2013, 135,

20 Palladium-Catalyzed Allylic C luorination allylic C substrate 15 mol% Pd(TA) 2 ligand 10 mol% (,)-(salen)crcl Et 3 3 (6 eq.), BQ (2 eq.) DCE, 23 ºC, 72 h branched product 5 Cl 6 Bn S ligand S Bn 53% yield 7.0:1 b:l 54% yield 7.8:1 b:l Br % yield 7.0:1 b:l 47% yield 7.5:1 b:l 33% yield 2.0:1 b:l 43% yield 6.8:1 b:l Braun, M. G.; Doyle, A. G. J. Am. Chem. Soc. 2013, 135,

21 ecent Advances in Direct ydrofluorination of Alkenes 15 mol% Pd(TA) 2 ligand direct hydrofluorination DCE, 23 ºC, 72 h hydrofluoric acid pk a = 3.2 toxic and corossive gas difficult alkene protonation S K + 13 pk a (KS 4 ) = 1.9 liquid reagent enhanced acidity S 9 Et Et Et 3 convenient liquid source acidity further diminished large excess required improved nucleophilicity strong -bond acceptor Lu, Z.; Zeng, X.; ammond, G. B.; Xu, B. J. Am. Chem. Soc. 2017, 139,

22 Direct ydrofluorination of Alkenes Using a KS 4 mplex 2 15 mol% Pd(TA) 2 ligand complex (1.0 eq.) 2 solvent, 0 ºC to rt DCE, 23 ºC, 72 h solvent complex time alkene SM product DCM Py h 100% 0% DCM K 2 S h 84% 16% DCM KS h 57% 43% DCE KS h 29% 71% DCE KS h 3% 83% DCE K 2 P h 100% 0% Lu, Z.; Zeng, X.; ammond, G. B.; Xu, B. J. Am. Chem. Soc. 2017, 139,

23 Direct ydrofluorination of Alkenes Using a KS 4 mplex mol% Pd(TA) 2 ligand KS 4 13 (0.5 eq.) 3 DCE, 0 ºC to rt, 1 2 h DCE, 23 ºC, 72 h Br S 79% yield 72% yield 61% yield C Bz Et 53% yield 62% yield 45% yield 61% yield Lu, Z.; Zeng, X.; ammond, G. B.; Xu, B. J. Am. Chem. Soc. 2017, 139,

24 Palladium-Catalyzed Aminofluorination of Alkenes alkene Pd II amino-palladation Pd II, oxidant fluorination ucleophilic amino-fluorination of alkenes containing tosyl-protected amines Ts Ts 80% Ts Ts Ts Ts 80% alkene conditions fluoroamine Ts Ts 87% 4:1 dr 10 mol% Pd(Ac) 2 2 eq. I(Piv) 2 MgS 4 5 eq. Ag C 3 C, rt Ts Ts 82% 5:1 dr Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131,

25 chanism for Palladium-Catalyzed Aminofluorination of Alkenes Pd II D Ts trans-amino palladation Pd II D Ts Pd II coordination D Ts D Pd IV Ts direct E 72% D Ts Pd II D Ts trans Pd-species eductive elimination I(Piv) 2 Ag Pd IV D Ts S 2 28% D trans Ts cis competes with S 2 for formation of C bond Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131,

26 ther Examples of tal-catalyzed Alkene Aminofluorination S PdCl 2 (C 3 C) 2 (10 mol%) I(Piv) 2 (2 eq.) Ag (3 eq.) C 3 C, 0 35 ºC, 8 h (10 equiv.) sulfonamide β-fluoro amine derivative S CAr e(b 4 ) 6 2 (10 mol%) ligand (10 mol%) Et 3 3, Xtalluor-E C 2 Cl 2, rt, MS, 1 4 h Boc Ar = 3,5-(C 3 ) 2 -C 6 3 fluorinated aminoalcohol Zhu,.; Liu, G. Acta. Chim. Sinica 2012, 70, u, D.-.; Liu, G.-S.; Zhu, C.-L.; Yuan, B.; Xu,. rg. Lett. 2014, 16, Chen, P.; Liu, G. Eur. J. rg. Chem. 2015, 4295.

27 chanistic Insight for Iron-Catalyzed Aminofluorination of Alkenes CAr e II, L* source e II, L* source CAr Iron involved in bond-forming step 3.2:1 dr, 81% ee Ablation of alkene stereochemistry XeL n el n el n fast stereoconvergent anti product XeL n el n el n u, D.-.; Liu, G.-S.; Zhu, C.-L.; Yuan, B.; Xu,. rg. Lett. 2014, 16, 2912.

28 pportunities for Asymmetric ydrofluorination of Epoxides py () n Precedented emarkable reactivity racemic mixture of fluoroalcohols py () n chiral LA enantioenriched product? ast background rxn Catalyst inhibition aufe the first asymmetric hydrofluorination of epoxides K 2 / 18-crown mol% (salen)crcl tbu Cr Cl tbu DM, 60 ºC, 80 h tbu tbu 55% ee (salen)crcl Bruns, S.; aufe, G. J. luor. Chem. 2000, 104, 247. ollingworth, C.; Gouverneur, V. Chem. mmun. 2012, 48, 2929.

29 Doyle s Lewis Acid-Catalyzed Asymmetric ydrofluorination of Epoxides Doyle s Catalytic Asymmetric Epoxide ydrofluorination (,-salen) (cat.) organocatalyst (cat.) C, IP Et 2 or TBME, rt, h tbu tbu tbu tbu Key design element: slow generation of active (,-salen) 3 C C 3 IP slow C 3 C 2 C 3 DB or S ( )-tetramisole Desymmetrization Kinetic resolution 2 C n-bu 88% yield 86% ee 65% yield 93% ee 75% yield 90% ee 82% yield 90% ee 47% yield (GC) 99% ee 44% yield 99% ee Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268.

30 chanistic Investigation for Asymmetric ydrofluorination of Epoxides rds Expected reaction pathway X vs non-linear effects with (salen) (2) consistent with bimetallic rds buildup of negative charge on substrate consistent with epoxide opening in rds Discrepancy: kinetic studies show first order in (salen) catalyst! Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

31 chanistic Investigation for Asymmetric ydrofluorination of Epoxides tethered dimeric (salen) (8) tbu tbu tbu tbu 3 tbu tbu (!!!) rate data show half-order dependence on 8 (!!!) rate ehhancement relative to monomer absence of non-linear effects consistent with bimetallic mechanism Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

32 chanistic Investigation for Asymmetric ydrofluorination of Epoxides X u u X two units in resting state association preferred X one unit in rds u bimetallic rds 1 / 2 = 0.5 th order in catalyst product X X u two units in resting state association preferred u two units in rds bimetallic rds 2 / 2 = 1 st order in catalyst product Bimetallic rate-determining step + dimeric resting state = first order kinetics Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

33 chanistic Investigation for Asymmetric ydrofluorination of Epoxides Simplified mechanistic picture C, IP (matched epoxide) organocatalyst dissociates dimer and increases rds 2 nucleophilicity Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

34 Aliphatic C ucleophilic luorination with Manganese mplexes C substrate Ag cat. Mn(TMP)Cl I, TBA 3 2 C / DCM, 50 ºC sp 3 C product s s Cl Mn s s Mn V Mn IV via AT via rebound S 2 3 C Ac 3 C 18 Ac Ac 18 Boc 44% yield 8:1 dr, 4:1 rr 51% yield 1.5:1 dr 57% yield 23% CC 51% CC Liu, W.; uang, X.; Cheng, M.-J.; ielsen,. J.; Goddard, W. A.; Groves, J. T. Science 2012, 337, uang, X.; Liu, W.; en,.; eelamegam,.; ooker, J. M.; Groves, J. T. J. Am. Chem. Soc. 2014, 136, 6842.

35 Aliphatic C ucleophilic luorination with Manganese mplexes Ag cat. Mn(TMP)Cl Cl s C substrate I, TBA 32 C / DCM, 50 ºC s s MnV MnIV via AT Mn sp3 C product s via rebound or more details, see Yong s group meeting on manganese catalysis Liu, W.; uang, X.; Cheng, M.-J.; ielsen,. J.; Goddard, W. A.; Groves, J. T. Science 2012, 337, uang, X.; Liu, W.; en,.; eelamegam,.; ooker, J. M.; Groves, J. T. J. Am. Chem. Soc. 2014, 136, 6842.

36 ecent Developments in ucleophilic luorination nstruction of Alkyl C Bonds ucleophilic substitution promoted by hydrogen bonding Deoxyfluorination of aliphatic alcohols Transition metal-catalyzed allylic fluorination Direct hydrofluorination of alkenes tal-mediated aminofluorination of alkenes Asymmetric hydrofluorination of epoxides Manganese-catalyzed C fluorination see YYL group meeting Ac nstruction of Aromatic C Bonds tal-mediated fluorination of arenes see JT group meeting ucleophilic aromatic substitution of (pseudo)halides itter s S Ar deoxyfluorination of phenols

37 Transition tal-diated ucleophilic lourination of Arenes Tf Cs [Pd] catalyst C 2 Et, 110 ºC C 2 Et Buchwald, S. L. et al. Science 2008, 325, B 3 K K Cu(Tf 2 ) (stoich.) C C 3 C, 60 ºC C Ye, Y.; Schimler, S. D.; anley, P. S.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, C Ag 2 C C 3 C, rt, 1 h ier, P. S.; artwig, J.. Science 2013, 342, 956.

38 Transition tal-diated ucleophilic lourination of Arenes

39 ucleophilic Aromatic Substitution of aloarenes with aked luoride X source X = Cl, Br, 2 nucleophilic substitution fluoroarene Cs + K + Pr Pr + Pr Pr + low solubility in organics requires high temperatures good solubility offmann elimination when drying good solubility easy preparation and drying Schimler, S. D.; yan. S. J.; Bland, D. C.; Anderson, J. E.; Sanford, M. S. J. rg. Chem. 2015, 80,

40 Sanford s ucleophilic Aromatic Substitution of aloarenes with 4 Cl 4 + (2 equiv.) aryl chloride DM, 25 ºC, 24 h fluoroarene 3 C Cl 3 C C 2 ipr C 2 ipr 98% yield 92% yield 79% yield equiv. 2 yield 0 99% C C 1 76% 2 1% 90% yield 80% yield (at 80 ºC) 7% yield (at 80 ºC) aked fluoride S Ar very sensitive to presence of water Schimler, S. D.; yan. S. J.; Bland, D. C.; Anderson, J. E.; Sanford, M. S. J. rg. Chem. 2015, 80,

41 itter s Deoxyfluorination of enols ipr ipr ipr ipr 3 equiv. Cs, ºC phenol enoluor fluoroarene Adaptable towards fluorination with nucleophilic 18 mpatible with wide range of electronically distinct arenes Unique S Ar approach for deoxyfluorination of phenols Tang, P.; Wang, W.; itter, T. J. Am. Chem. Soc. 2011, 133, eumann, C..; ooker, J. M.; itter, T. ature 2016, 534, 369.

42 A ncerted ucleophilic Aromatic Substitution Approach Traditional S Ar ncerted S Ar u LG u LG u δ LG δ u LG LG u LG u Well-established stepwise substitution Stabilization of TS charge by ring igh sensitivity to arene substituents Underexplored concerted pathway Charge distributed among ring, u and LG Good tolerance of arene electronics LG LG LG LG C C eumann, C..; ooker, J. M.; itter, T. ature 2016, 534, 369.

43 A ncerted ucleophilic Aromatic Substitution Approach Ar Ar Cs deoxyfluorination Ar Ar + Ar Ar 2 Cs Cs 2 Ar Ar Ar Ar characterized by X-ray isolable concerted TS 18 TMS enoluor dioxane, 50 ºC k( 16 ) / k( 18 ) = ± egative charge buildup on ring in rds (ρ = 1.8 vs ρ = 3 8 for step-wise S Ar) C bond cleavage occurs in rds eumann, C..; ooker, J. M.; itter, T. ature 2016, 534, 369.

44 A ncerted ucleophilic Aromatic Substitution Approach 18 TMS enoluor dioxane, 50 ºC k( 16 ) / k( 18 ) = ± egative charge buildup on ring in rds (ρ = 1.8 vs ρ = 3 8 for step-wise S Ar) C bond cleavage occurs in rds eumann, C..; ooker, J. M.; itter, T. ature 2016, 534, 369.

45 Substrate Scope for itter s Deoxyfluorination of enols ipr ipr ipr ipr 3 equiv. Cs, ºC phenol enoluor fluoroarene 2 3 C 75% yield 92% yield 87% yield 90% yield 92% yield Et Ac 88% yield 95% yield 90% yield Tang, P.; Wang, W.; itter, T. J. Am. Chem. Soc. 2011, 133,

46 Adaption of Deoxyfluorination or 18 Labelling Ar Cl + Ag 2 C 3 Ar CCl 3, 60 ºC Cl CCl 3, 60 ºC + Ar Ar Cl 18 butanone / Et 130 ºC, 20 min S 2 18 Br Cl % CC 87% CC 90% CC 98% CC 27% isolated CY Et 2 C S 18 Et % CC 61% CC 86% CC 18 eumann, C..; ooker, J. M.; itter, T. ature 2016, 534, 369.

47 Problems with 18 Labelling of More Electron-ich Substrates Limitation in 18 labelling: electron-rich/-neutral substrates PA 18 limiting + Ar Ar 18 unfavorable Ar Ar PA (phenol activation reagent) Ar Cl + Ar Cl More electron-rich substrates do not react sufficiently fast ordination with Cpu + restores a favorable enough equilibrium Solution: coordination with Cpu + increases electrophilicity u + PA 18 limiting u + Ar 18 + Ar less unfavorable Ar 18 u + Ar u + 18 ooker, J. M.; itter, T. et al. ACS Cent. Sci. 2017, 3, 944.

48 Scope of Improved 18 Labelling of enols (cod)ucpcl Et 85 ºC, 30 min u + + Ar Cl + Ar Cl 18 C / DMS 125 ºC, 30 min Ac 2 Br 89% CC 99% CC 30% CC 43% CC Boc 2 18 Ac 18 98% CC 18 80% CC 24% isolated CY ooker, J. M.; itter, T. et al. ACS Cent. Sci. 2017, 3, 944.

49 ecent Developments in ucleophilic luorination nstruction of Alkyl C Bonds ucleophilic substitution promoted by hydrogen bonding Deoxyfluorination of aliphatic alcohols Transition metal-catalyzed allylic fluorination Direct hydrofluorination of alkenes tal-mediated aminofluorination of alkenes Asymmetric hydrofluorination of epoxides Manganese-catalyzed C fluorination nstruction of Aromatic C Bonds tal-mediated fluorination of arenes ucleophilic aromatic substitution of (pseudo)halides itter s S Ar deoxyfluorination of phenols