Unique Reactivity of Fluorinated Molecules with Transition Metals

382 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

doi:10.2533/chimia.2014.382 Chimia 68 (2014) 382–409 © Schweizerische Chemische Gesellschaft Unique Reactivity of Fluorinated Molecules with Transition Metals

Silvia Catalánab, Sócrates B. Munozc, and Santos Fustero*ab

Abstract: Organofluorine and organometallic chemistry by themselves constitute two potent areas in organic synthesis. Thus, the combination of both offers many chemical possibilities and represents a powerful tool for the design and development of new synthetic methodologies leading to diverse molecular structures in an efficient manner. Given the importance of the selective introduction of fluorine atoms into organic molecules and the effectiveness of transition metals in C–C and C–heteroatom bond formation, this review represents an interesting read for this aim. Keywords: Catalysis · Copper · Cross coupling · Fluorine · Gold · Metathesis · Pauson–Khand reaction · Silver · Transition metal

1. Introduction drug-like molecules. In this way, the pres- appeared over the last few years about ence of fluorine in drugs has an extraor- transition metal-mediated fluorination, The use of transition metals in organic dinary impact on a variety of medical ap- difluoromethylation, and trifluoromethyl- synthesis has been immense throughout plications, including anti-inflammatory, ation methods,[1d,5] we have also sought to history and it is experiencing continuous antibacterial, antitumor and antiviral compile some examples which display a development and increasing application. agents, CNS-modulator compounds, or significantly different reactivity of fluori- Over the past decades, transition metal- drugs for lowering blood cholesterol lev- nated molecules than their non-fluorinated catalyzed/mediated reactions have become els such as atorvastatin (Lipitor®), devel- analogs. one of the most efficient methods for C–C oped by Pfizer and one of the best selling and C–heteroatom bond formation, in drugs in the world. Furthermore, the use particular for the construction of hetero- of 18F-radiolabelled compounds employed 2. Transition Metal-mediated cyclic molecules. Indeed, the most im- in Positron Emission Tomography (PET) Reactions portant organic reactions, such as Suzuki, experiments has exponentially grown in Sonogashira, Heck, olefin and alkyne the last few years. Therefore, the impor- 2.1 Cobalt-mediated Pauson– metathesis and so forth, are catalyzed by tant role of the fluorine atom in medicinal Khand Reaction transition metal complexes. Owing to the chemistry is obvious,[1b,3] and it can be af- The Pauson-Khand reaction (PKR) is ongoing innovation in this area, transition firmed that fluorine chemistry will contrib- one of the key methods for the construc- metals have been successfully incorporat- ute significantly to the future progress in tion of cyclopentenone derivatives, which ed in the ever-growing field of organofluo- medicine.[4] can in turn undergo diverse chemical trans- rine chemistry with remarkable and often In this review, we provide an overview formations.[6] Nevertheless, the control of unexpected results. of recent advances in the field of fluo- the regiochemical outcome of the PKR It is well-known that the selective in- rine chemistry combined with transition is an important setback. Whereas the introduction of fluorine atoms into organic metal catalysis that have been reported in termolecular PKR of terminal alkynes is molecules has become one of the most the last five years (Fig. 1). Given the sig- completely regioselective, always provid- efficient methods for modulation of their nificant number of reviews, which have ing α-substituted cyclopentenones, the less biological properties[1] and a common frequently used internal nonsymmetric al- strategy in new drug discovery process- kynes can afford two regioisomers. That es,[2] either by modifying known natural is not the case for fluorinated alkynes, in products or by searching for more active which the electron-withdrawing effect of Ru the fluorinated substituents determines the regioselectivity (Scheme 1). Ag In contrast to the intramolecular ver- Pd sion, no report on intermolecular PKR of C F fluorinated alkynes had been described *Correspondence: Prof. S. Fusteroab until Riera, Fustero and coworkers re- Tel.: +34 963 54 42 79 ported the first example with norborna- E-mail: [email protected] C RF aDepartamento de Química Orgánica Au diene in the presence of a stoichiometric Universidad de Valencia Cu amount of dicobalt hexacarbonyl complex E-46100 Burjassot, Spain [Co (CO) ] under standard thermal condi- b 2 8 Laboratorio de Moléculas Orgánicas [7] Centro de Investigación Príncipe Felipe Co tions (Scheme 2). E-46012, Valencia, Spain Surprisingly, in all examples, the fluori- cLoker Hydrocarbon Research Institute nated moiety was α to the carbonyl group, Department of Chemistry as opposed to the standard selectivity. The University of Southern California, Los Angeles CA 90089, USA Fig. 1. Fluorine and transition metals. authors suggested that the regioselectivity Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 383

Scheme 1. General served, bearing a CF group at the α posi- O O 3 R2=H trends of the regiose- tion to the enone.[8] R1 R1 + lectivity of intermo- Furthermore, this methodology was R1 lecular PKR. extended to the removal of the trifluoro- not observed Co0 methyl group by treatment with DBU in R2 O O nitromethane/water, affording the unex- R1=EDG EDG + EWG pected β-substituted PK adducts (Scheme R2=EWG EWG EDG 5). The mechanism proposed consisted of (no steric effects) major minor a Michael addition of nitromethane which EDG= electron-donating group EWG= electron-withdrawing group would entail a loss of fluoride giving gem- difluoroenone 3. Then, a conjugative addition of water would take place, followed by a retro-aldol reaction, which would afford O 1. Co2(CO)8 H intermediate 4. The final cyclopentenone Toluene, rt R1 R 5 would be formed by retro-Michael reac- F RF tion on enol 4 (Scheme 5). This method 1 2. H R1 constituted a novel procedure to obtain Toluene, 70 ˚C 2 PK substrates from terminal alkynes with inverse regiochemistry employing the tri- H O H O H O H O fluoromethyl group as a steering group. F F F F F F In contrast, Konno et al. reported the CF 3 synthesis of 2-fluoralkyl-2-cyclopente- CONHBn CONHpMeOC6H4 NH H H H H H Ph Ph O Ph CO2Et nones via Co-mediated PKR of several tri- Me fluoromethyl alkynes with 2-norbornene 2a 40% 2b 48% 2c 62% 2d 92% dr 1:1 instead of norbornadiene (Scheme 6, part A).[9] Scheme 2. Intermolecular PKR of fluorinated alkynes. In this process, the regioselectivity was not complete and the PK adducts were ob- Scheme 3. Catalytic tained as isomeric mixtures, despite apply- PKR of 1 with norbor- ing the same strategy but different reaction nadiene. conditions. Additionally, the influence of H O alkyne substitution was studied, support- CO (2 bar) ing the idea that the steric hindrance is a EtO C CF 2 3 CF3 determining factor in the regiochemical 10 mol% cat. outcome of the reaction (Scheme 6, part 1 Toluene H CO2Et B). Recently, Riera and coworkers have 2d confirmed these results by expanding their CO R previous work to norbornene and also eth- OC Co Co CO ylene (Scheme 7).[10] As Konno et al., they OC CO A,R=CO90˚C, 18 h, 57% yield obtained mixtures of regioisomers with F C CO Et B,R=PPh3 70 ˚C,24h,73% yield norbornene under established reaction 3 2 conditions, identifying α-fluorinated cy- catalyst clopentenone as the major isomer, whereas

B O O O O [Co (CO) ] (OC) Co Co(CO) H H F H 2 8 3 3 CH NO R1 H 3 2 R CF CF CF R H 3 2 2 Base + - Standard PKR H H R BH F H R 1. CF -Cu(Phen) R 3 2 3 NO2 NO2 2. [Co2(CO)8]

2e R= Ph, 77% H H O H O H O H O 2f R= p-MeC6H4,95% (OC)3Co Co(CO)3 H O O 2g R= o-MeOC6H4,74% 2 CF CF2 3 2h R= p-(C5H11)C6H4,99% R CF3 2i R= p-CF3C6H4,70% F CO CH NO H R 2 H R 3 2 H R R 2j R= p-FC6H4,81% CF -directed PKR 2 NO 4 NO 5 3 2k R= C11H23,79% 2 2

Scheme 4. Standard intermolecular PKR for internal alkynes and the Scheme 5. Postulated mechanism for the CF elimination. 3 sequence for internal CF -substituted alkynes. 3 of PK adducts was not determined by elec- Subsequently, the scope of this pro- the minor one was the regioisomer with the tronic but by steric effects mainly. In addi- cess was studied employing a wide variety CF at the β-position. Nevertheless, only 3 tion, a catalytic version of this process was of internal CF -substituted alkynes con- one PK adduct, α-trifluoromethyl cyclo- 3 also developed successfully by Riera and taining aromatic, aliphatic, and olefinic pentenone, was observed when using eth- coworkers, using 10 mol% of the cobalt- substituents (Scheme 4). In all cases, the ylene as the alkene, although the chemical alkyne complex formed in situ (Scheme 3). formation of a single regioisomer was ob- yields were moderate. 384 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

yield), diastereoselectivity was excellent A) B) O O O O (dr >20:1). 1. Co2(CO)8 (1.2 equiv) CF3 + R R F RF + R 2.2 Gold-catalyzed Reactions OMe 2. CF3 1 1 OMe 3equiv R RF Arguably, gold chemistry attracts suf- 2 6 (CH2)2Cl2,reflux 9examples ficient attention by itself owing to the ex- up to 92% yield ceptional properties of gold complexes to 2:6 from 22:78 to 100:0 p-MeOC6H4 71 :29(90%) R= CO2Et, p-ClC6H4, o-MeOC6H4,etc. m-MeOC6H4 69 :31(86%) activate multiple bonds such as alkenes, RF=CF3,CHF2 o-MeOC6H4 22 :78(72%) alkynes, allenes or enynes, and promote surprising transformations in a single syn- Scheme 6. PKR of CF -substituted alkynes 1 with 2-norbornene and influence of alkyne substitu- 3 thetic operation. By adding the unique re- tion in the regiochemical outcome. activity of fluorinated substrates to this, an Au–F bond results in a great combination Likewise, only a few examples of the O which offers many chemical possibilities. H2CCH2 intramolecular PKR of fluorinated enynes (OC)3Co Co(CO)3 In the last few years, important ad- (6 bar) CF3 have been reported thus far. In this context, vances in this chemistry have been made Ichikawa and Nadano described an attrac- R CF3 Toluene and many reports have appeared in the lit- R tive route to synthesize steroid and alkaloid 80-85 ˚C erature involving the study of the influence 4examples analogs containing fluorine groupings in of fluorine in gold-catalyzed processes. 23-58% yield their structures.[11] In particular, pyrrolidine Based upon the pioneering studies report- ring-fused fluorinated cyclopentenone de- Scheme 7. Intermolecular PKR of 1 with ed by Zhang and others[13] about the evi- rivatives 11 were synthesized through a ethylene. dence for the existence of an Au(i)/Au(iii) catalytic cycle, Hammond and coworkers Scheme 8. Co- Ts developed a direct route to α-substituted N NHTs mediated intramo- α-fluoroketones from alkynes by a gold- CF3 sec-BuLi CF3 R1 8 lecular PKR in the R1 catalyzed one-pot cascade reaction Br Li synthesis of 11. Et O -105 ˚C [14] 2 CF3 (Scheme 10). Only the combination of 7 -105 ˚C to -50 ˚C 9 the pre-catalyst Ph PAuCl and Selectfluor 3 as an external oxidant promoted the for- 1 Br R1 PKR R CF3 mation of the catalytically active gold(iii) R2 Co2(CO)8 N TsN O complex, which was able to trigger a hy- 2 Ts NaH, DMF R CF3 CH2Cl2 rt, 30 min dration/oxidative arylation/electrophilic R 2 10 then, CH3CN 60 ˚C 11 fluorination sequence under mild condi- 84-92% 11a R1=Ph; R2=H;81% dr 94:6 tions in good yields and moderate regio- 11b R1=Ph; R2=Et; 85% dr 83:17 selectivities. 11c R1= n-Pr; R2=H;71% dr 86:14 Thus, Hammond proposed that Selectfluor was in fact the activator of the cationic gold complex. This hypothesis of O O Co-mediated intramolecular PKR from S S an oxidation of gold(i) to gold(iii) by ‘F+’ HN tBu HN tBu N-propargyl-N-[2-(trifluoromethyl)allyl] 1. Co2(CO)8 was also supported by the studies of Toste CH2Cl2,rt amides 10, which were in turn prepared by H and coworkers.[15] They isolated, for first R1 2. NMO, rt a sequence of (trifluoromethyl)vinylation time, a gold(iii) fluoride complex as a di- 1 2 R2 R =H, R =CF3 of imines 8, followed by propargylation of (36%) dr >20:1 mer which was successfully characterized 12 F3C O amides 9 (Scheme 8). 13 by X-ray crystallography. The gold(iii) flu- More recently, Fustero et al. described, oride species showed a unique reactivity in Scheme 9. Intramolecular PKR in the synthesis for the first time, an intramolecular PKR of tricyclic amines 13. cross-coupling reactions with arylboronic acids (Scheme 11). Scheme 10. Gold- In this context, a tandem gold-catalyzed I Ph3PAu Cl catalyzed one-pot process starting from propargyl acetates Selectfluor cascade reaction. was reported by Nevado and de Haro.[16] Selectfluor was used again as an oxidant for the synthesis of α-fluoroenones 14 PhB(OH)2 O F through a tandem [3,3]-sigmatropic rear- Selectfluor Ph III + R Alkyl Alkyl rangement-fluorination process (Scheme Ph3PAu Cl CH3CN/H2O F R 12). In contrast to previous statements, (20:1) the cationic gold(i) complex was the catalytically active species which promoted a F F of a CF -alkyne tethered to a chiral aryl- 1,3-migration of the acyloxy moiety by ac- XeF2,CDCl3 3 (NHC)AuI Me AuIII homoallylic sulfonamide skeleton in the tivation of the alkyne. The resulting vinyl- rt, 20 min (NHC) Me asymmetric synthesis of tricyclic amines Au(i) intermediate A was then oxidized 13 (Scheme 9).[12] Building on the prin- to gold(iii) (B) by Selectfluor. Reductive Ar yield (%) ciples of diversity-oriented synthesis, dif- elimination was considered the last step to ArB(OH)2 C H 45 Ar Me 6 5 2 4-MeOC6H4 25 ferent aryl, alkyl or terminal alkyne deriva- transform the Csp –Au(iii) bond into the (NHC)AuAr 4-O2NC6H4 51 Csp2–F bond, giving rise to α-fluoroenone C F 49 tives were subjected to this protocol with 6 5 CF -alkyne being of particular interest. derivatives 14 in good yields. 3 Scheme 11. Au(iii)-catalyzed cross-coupling Although the isolated yield of the result- Nevertheless, Gouverneur and co- with arylboronic acids. ing CF -PK adduct was moderate (36% workers reported a similar methodology 3 Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 385

Scheme 12. Tandem tion metal-catalyzed reactions involving O IPrAuNTf2 O gold-catalyzed fluorinated building blocks have gained R2 Selectfluor F [3,3]-sigmatropic importance in the last decade, especially 1 O 3 R R rearrangement-fluori- gold-catalyzed processes. Among them, NaHCO3 nation process. IPr Au(I)+ CH CN/H O R2 R1 gold-catalyzed stereoselective tandem 3 3 2 R 14 hydroamination-formal aza-Diels-Alder reaction of fluorinated α-substituted [3,3]-sigmatropic reductive rearrangement elimination propargylic amino esters is a representa- IPr tive example.[20] Au+ F R2 O O The starting α-amino esters 22 were R3 1 [AuI]+IPr [AuIII]+IPr synthesized by adding propargyl zinc to R R3 R3 O O the corresponding fluorinated imino esters -AcOH R2 R1 Selectfluor R2 R1 21 in DMF as solvent under Barbier-type H O 2 AB conditions (Scheme 17). The reactivity of 22 was then explored in the presence to obtain α-fluoroenones.[17] In this case, the proposed mechanism did not involve L R2 2 O 1 2 a gold-catalyzed electrophilic fluorination R Au 2 + R F R O [LAu]+ R +[LAu] Selectfluor 1 R3 • step but gold promoted the isomerization R 1 R 3 R3 R1 + R O of the propargylic ester to give allenyl ac- [3,3]-sigmatropic O O −[LAu] −Ac rearrangement O O etate, which then reacted with Selectfluor R3 (Scheme 13). 29-85% yield Based upon these observations, up to 12.5:1 E/Z Hammond and coworkers employed alle- Scheme 13. Alternative proposal for the formation of α-fluoroenones catalyzed by gold. nyl carbinol esters 15 in the stereoselective synthesis of fluoroalkyl α,β-unsaturated Scheme 14. Gold- [18] R3 O ketones 17 (Scheme 14). First, isomeri- O catalyzed isomeriza- + zation of the allene substrate in the presence O O [LAu(I)] O R3 Selectfluor F tion-fluorination of R1 of gold produced a diene intermediate (16), • R2 allenes 15. R1 CDCl ,rt R1 R2 3 CH3CN, rt 17 which quickly reacted with Selectfluor to R2 exclusively give the E isomer of the cor- 15 16 70-96% responding fluorinated ketone 17 in high up to 99:1 E/Z yield. More recently, a gold-catalyzed tandem 1. NaAuCl H O 1. NaAuCl H O aminocyclization/electrophilic fluorina- F 4.2 2 Ar 4.2 2 F F (5 mol%) (5 mol%) tion sequence has been reported by Arcadi EtOH, rt CH3CN, 0˚C et al. for the synthesis of 3,3-difluoro- R Ar R R Ar N 2. Selectfluor 2. Selectfluor (1 equiv) N NH2 and 3-fluoroindole derivatives 19 and 20 (3 equiv) DMSO, 0˚Ctort H (Scheme 15).[19] Starting from o-alkynyl 19 18 20 anilines (18) and by using an excess of 12 examples 6examples Selectfluor in EtOH at room temperature, 40-85% yield 20-85% yield necessarily in the presence of a gold(i) or gold(iii) catalyst (e.g. Ph PAuNTf , AuCl, Scheme 15. Gold-catalyzed tandem aminocyclization/electrophilic fluorination of 18. 3 2 AuCl or NaAuCl ·2H O), an assorted li- 3 4 2 brary of C(3) difluorinated indoles 19 was Scheme 16. F Proposed mechanism prepared in good yields (Scheme 15). III I [Au L] [Au L] H pathways for Au- By slightly modifying the reaction (a)(b) catalyzed cyclization- conditions, the selective formation of C(3) Ar Ar Ar N N N fluorination process. monofluorinated derivatives 20 was fea- H Selectfluor H H+ [AuL]+ H sible (Scheme 15 and 16). Considering that Selectfluor is able to oxidize gold(i) Scheme 17. Gold- to gold(iii) and the latter also catalyzed the catalyzed stereo- Br PMP cyclization/fluorination process, two pos- PMP HN selective tandem N Zn, hydroamination-for- sible mechanism pathways were proposed: F3C mal aza-Diels-Alder the one (a) involving an Au(i)/Au(iii) cata- F3C CO2Et DMF,2h EtO2C 0˚Ctort reaction of fluorinated lytic cycle and a second (b) involving a 21 22 protodeauration followed by a non-cata- α-substituted propar- lyzed fluorination step on the indole inter- gylic amino esters 22. CO Et mediate (Scheme 16). H 2 On the other hand, one of the most F C 3 N CF3 commonly used methods to generate fluo- Ph PAuCl (5 mol%) H 3 EtO C AgOTf (5 mol%) 2 N CO2Et rinated compounds consists of using fluo- H + rinated building blocks for assembling the N CF3 new molecule. The presence of fluorine in Toluene, rt, 5h PMP OMe these small fragments confers a particular reactivity upon them. Therefore, transi- MeO 23 24 386 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

of gold salts. Unexpectedly, the isolated product was identified as a tetracycle 23 Ph + Ph Ph TfO- Ph [Ph3PAu] H whose formation involved four new bonds N H TfO- F C F C -TfOH F C F3C 3 N 3 N 3 N and five stereocenters, as a single diaste- RO2C RO2C RO2C reoisomer. A gold(i)-catalyzed intramolec- RO2C AuPPh AuPPh ular hydroamination followed by a formal 22 II3 I3 24 aza-Diels-Alder reaction was the sequence proposed for the final outcome, which was Scheme 18. Proposed mechanistic explanation. further extended to non-fluorinated substrates. Moreover, when the aromatic group ating blocks, new selective fluorination tached to the nitrogen atom was less acti- methods are continuously emerging in RF vated, the process evolved to the hydroam- the literature. Herein, we focus on those RF R N Boc Boc ination product, fluorinated pyrroline 24, catalyzed by palladium, among others. In N R H 1 [Au(I)]+ 26 R as a major product (Scheme 18). this sense, the groups of Gouverneur and er up to 99:1 and/or 1 It is well known that the transition Brown described a palladium-catalyzed al- 25 R RF Boc N metal-catalyzed intramolecular hydroami- lylic fluorination reaction of properly func- RF=CF3,C2F5,CHF2,CH2F R nation reaction has become one of the tionalized substrates under mild conditions R=H, F, CF3,OMe, OCH2O R1 most significant methods to access nitro- (Scheme 22).[23] The allylic leaving group 27 gen-containing heterocycles. In particular, resulted determining to yield 2-substituted gold complexes have emerged as power- propenyl fluorides 31 in high yields, as the Scheme 19. Gold-catalyzed hydroamination of ful catalysts for this purpose. As a general traditionally used leaving groups in palla- fluorinated o-alkynylaryl carbamates 25. rule, most gold-catalyzed hydroaminations lead to the formation of the isoquinoline framework via 6-endo-dig cyclization, the CH3 CH2F CHF2 CF3 CF2CF3 Boc Boc Boc Boc Boc Boc corresponding 5-exo-dig product being un- N N N N N N stable. H H H H H H

As reported by Fustero and cowork- Ph Ph Ph Ph Ph Ph ers, the hydroamination of fluorinated o- A 0:100 B 40 :60 C 40 :60 D 85 :15 E 80 :20 F 80 :20 (58%) alkynylaryl carbamates 25 catalyzed by a (83%) (60%) (90%) (>99%) (>99%) cationic gold(i) complex evolved prefera- 6-endo-dig5>>> >>>>>>>-exo-dig bly to the isoindoline skeleton 26,[21] as opposed to the standard statements (Scheme Scheme 20. α-Substituent effect on the gold(i)-catalyzed cycloisomerization reaction. 19). Moreover, the regioselectivity could be controlled and directed toward one ma- Scheme 21. jor product by tuning the electronic prop- O OBn Preparation of the key O Ph PAuNTf erty of the alkyne moiety. 3steps OH O 3 2 O intermediate 29 in the Br (1 mol%) Also, an electronic effect of the fluori- OEt BnO F synthesis of racemic OBn CH Cl ,rt nated group was observed since the grad- F F F F 2 2 24 h F fluorinated carbohy- ual introduction of fluorine atoms at the MgBr O drates. 28 87% α-position A-F to the nitrogen promoted (±)-29 a 5-exo-dig mechanism, leading to isoindoline derivative 26 as the major product, OBn OBn OBn OBn in contrast to the published results with F F F F F O F O F O F O non-fluorinated substrates (Scheme 20). O O O O O OMe O F H F In some cases, 1,2-dihydroisoquinolines H O H OMe H H 27 arising from a 6-endo-dig mechanism were also detected. Gouverneur and coworkers reported a de novo synthesis of a variety of racemic fluorinated carbohydrates using syn-glycal Pd(dba)2 (5 mol%) 1 PPh (15 mol%) 1 1 (±)-cis-29 as the key intermediate, which R NO2 3 R R TBAF•(t-BuOH)4 (2.5 equiv) was in turn prepared by a gold-catalyzed O F OH [22] R2 R2 R2 cyclization as the key step (Scheme 21). THF,rt, 1-4h O 31 32 Difluorinated ynone 28 was used as build- 30 ing block for this purpose, which underwent a selective 6-endo-dig cyclization in the presence of Gagosz’ catalyst F F F MeO F F (Ph PAuNTf ), leading to the desired inter- 3 2 tBu Ph MeO MeO Br mediate in good yield. An in-depth NMR investigation was carried out on the re- >95% 95% 85% 84% 66% sulting gem-difluorinated hexose analogs to study the existence of intramolecular F F F F

C–F···H–O hydrogen bonds. MeO F3C 39% 65% 35% >95% 2.3 Palladium-catalyzed Reactions Despite widely-used fluorinated build- Scheme 22. Pd-catalyzed allylic fluorination reaction of 30. Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 387

dium-catalyzed allylic alkylations, such as Also, Doyle and coworkers described as chiral ligand (Scheme 26).[25] As stated carbonates or acetates, led to the recovery an asymmetric version, the enantioselec- before, a Pd(ii) π-allyl intermediate was in- of the starting material or form the allylic tive synthesis of cyclic allylic fluorides volved in the catalytic cycle based on a nu- alcohol 32 under the reaction conditions. 35 in just one step from the correspond- cleophilic attack of fluoride on this system. Thus, p-nitrobenzoate was unexpectedly ing allylic chlorides 34 in the presence of Despite the tolerance with many func- employed as the leaving group of choice. a chiral biphosphine-ligated palladium(ii) tional groups, low enantioselectivities (ee Fluorination was then carried out in the complex with AgF (Scheme 24).[24] 21–71%) were observed for those less ste- presence of 5 mol% of Pd(dba) and 15 Experimental results supported a dis- rically hindered and no fluorination reac- 2 mol% of PPh at room temperature, using tinct mechanism for the C–F bond formation occurred with secondary alkyl amines. 3 tetra-n-butylammonium tetra(tert-butyl tion based on a S 2-type nucleophilic at- By contrast, α-branched allylic chlorides N alcohol)-coordinated fluoride [TBAF·(t- tack of fluoride on a Pd(ii) π-allyl inter- and bromides generated the corresponding BuOH) ] as a ‘F-’ source. mediate with an overall retention of the fluorides with excellent regio- and enanti- 4 This methodology was also applied, configuration (Scheme 25). oselectivity. Additionally, in the context of for the first time, to the synthesis of [18F]- Its wide substrate scope, including si- diversity-oriented synthesis, several trans- radiolabeled compounds, which are widely lyl ethers and alcohols, makes this method formations were carried out on the allylic employed in positron emission tomogra- very useful to prepare allylic fluorides fluoride 37 achieving access to a variety phy (PET) experiments, and in oncology, with excellent enantioselectivities, having of optically pure fluorinated molecules despite their somewhat short half-life. become an essential alternative to the de- whose synthesis would be unfeasible or Hence, as a first example of transition met- hydroxyfluorination with (diethylamino) comprise several steps (Scheme 27). al-mediated 18F-fluorination, a palladium- sulfur trifluoride (DAST). Thus far, several examples of fluorina- catalyzed allylic fluorination reaction of Later on, Doyle et al. extended this tion reactions requiring a prefunctionaliza- propenyl esters 33 was carried out using, protocol to branched acyclic systems, de- tion of the substrate have been displayed. in this case, [18F]TBAF as a fluorinating veloping a highly regio- and enantioselec- Nevertheless, the direct functionalization reagent in acetonitrile at room temperature tive synthesis of branched allylic fluorides of C–H bonds has recently emerged as (Scheme 23). 37 from allyl chlorides 36 and using L2 a powerful tool in organic synthesis.[26] Synthetic methods for assembling C–F Scheme 23. Pd- bonds under mild conditions, even more Pd(dba)2,PPh3 catalyzed allylic fluo- so, at the final stage of the synthetic route, [18F]TBAF rination reaction of 33 18 are of particular value. While C–H fluori- OR F 18 by using [ F]TBAF. nations using electrophilic fluorinating re- 33 CH3CN, rt agents have been slightly more explored, 5min RCY= 9-42% (n=12) those using nucleophilic fluoride are R= COC6H4p-NO2 scarce. In this sense, Sanford and cowork- RYC=radio chemical yield ers described a palladium-catalyzed benzylic fluorination reaction by C–H bond activation of 8-methylquinoline deriva- Scheme 24. tives 38 to obtain 39 in moderate to good Pd2(dba)3 (5 mol%) Enantioselective syn- Cl F O O [27] (R,R)-L1 (10 mol%) yields (Scheme 28). NH HN thesis of cyclic allylic fluorides 35. Z AgF,THF,rt, 24 h Z PPh2 Ph2P 34 35 L1 F F F F F L FAg+ F Cl PdII F O N SN2nucleophilic attack Ts OH CO2Me CH2OTBS 85% 62% 74% ee 88% ee 90% 68% 56% 59% ee 96% ee 90%, dr 14:1 ee 93%, dr 7:1 ee 87%, dr 20:1 AgCl +[PdIIL]

Scheme 25. Proposed mechanistic explanation.

Pd2(dba)3 (5 mol%) O O (R,R)-L2 (10 mol%) F NH HN R R Cl F F AgF,toluene PPh2 Ph2P R' R' CH 36 rt, 48 h 37 L2 3 OH CbzN O CbzN OH F F F F 67% yield, 93% ee 76% yield, 93% ee a d BnO F 6:1 dr F BnO TBSO Br 4 4 OH b F e OH 83%, ee 21% 50%, ee 90% 84%, ee 58% 66%, ee nd b:l >20:1 b:l 16:1 b:l >20:1 b:l >20:1 CbzN CbzN 94% yield, 93% ee 98% yield, 93% ee CbzN F F F F F c f F CH 37 93% ee 3 OAc O CbzN BocN CbzN CbzN diversity-oriented synthesis 97% yield, 93% ee 73% yield, 64% ee,10:1 E/Z 84%, ee 90% 62%, ee 97% 88%, ee 93% 85%, ee 93%, b:l 10:1 b:l >20:1 b:l >20:1 b:l 10:1 awith DAST ee 49%, b:l 2:1 a) Wacker oxidation; b) ozonolysis/reduction; c) hydrogenation; [b:l]=branched:linear selectivity; nd=non-determined d) dihydroxylation; e) hydroboration/oxidation; f) cross-metathesis aStarting from >99% ee branched allylic alcohol Scheme 27. Access to optically pure fluorinated molecules from allylic Scheme 26. Selective synthesis of branched allylic fluorides 37. fluoride 37. 388 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

R1 R1 in the presence of a phosphine-based li- prepared in situ from arylboronic acid de- Pd(OAc)2 (10 mol%) gand should be mentioned (Scheme 31).[29] rivatives 43' by treatment with NaF and + - PhI(OPiv)2,Ag F Apparently, the phosphine ligand played KHF , giving the corresponding aryl fluo- 2 N R2 N R2 MgSO4,CH2Cl2 an important role in the process as a Lewis rides 44 in excellent yields (Scheme 33). H 60 ˚C,16h F base promoter as it seems that it cleaved The mild reaction conditions used in this 38 30-70% 39 the H–CF bond to provide the Pd–CF case were well tolerated by a wide range 11 examples 3 3 complex 42 which could participate further of functionalized aryl substrates apart from Scheme 28. Pd-catalyzed benzylic fluorination in aromatic trifluoromethylations. heterocycles. Furthermore, arene fluorina- by C–H bond activation of 38. In the field of arene fluorination, Ritter tion was highly regioselective, except for and coworkers have recently reported a those compounds containing electron- In general, fluorination took place in similar reaction with aryl trifluoroborates withdrawing groups (e.g. amide), which the presence of different substituents in- catalyzed by an air- and moisture-stable gave constitutional isomers. The authors cluding halogens (e.g. Br, F or I), although terpyridyl palladium(ii) complex (Scheme proposed a single-electron-transfer (SET) chemical yields were not as good as desir- 32).[30] This metal complex acted as a prec- pathway as a plausible mechanism, involv- able owing to the C–H oxygenation side atalyst since a rare palladium(iii) species, ing a Pd(iii) intermediate and radical spe- reaction. Sanford proposed an F–Pd(iv) which was further isolated and character- cies. complex as the key intermediate in the ized by X-ray analysis, was in fact the cata- In line with this issue, a Pd-catalyzed catalytic process but, neither the role of lyst in the fluorination reaction. difluoroalkylation of aryl boronic acids 45 Ag+ ion, whose presence was a requisite, The trifluoroborates 43 could also be has been reported very recently by Zhang and coworkers.[31] To attach the difluoromethylene group (CF ) to the arene ring, 2 O O S . S (15 mol%) they employed readily available bromodi- Bn Pd Bn (TFA) fluoromethylated phosphonate, acetate 2 F and amides as fluorinated building blocks Cr(salen)Cl (10 mol%) + R R R F (Scheme 34). Et N.3HF, BQ 40 3 41 branched 41' linear ClCH2CH2Cl 23 ˚C,72h up to 7.8 :1

F F F O F O O O O Me BnO Cl N O O 5 4 6 2 Me Me OAc 3 OAc 3 56% 59% 54% OH 68% Me 2 Me 2 H H F F F F F Me Me F Ph Br [Pd]/Cr(salen)Cl 4 3 4 H H Ph AcO AcO 54% 64% 47% 16% 33% H Et3Nξ3HF, BQ H

Scheme 29. Pd-catalyzed allylic C–H fluorination. Scheme 30. Direct allylic fluorination of steroid derivatives.

nor the identity of the active fluorinating Ph Ph HCF3 Ph Ph [(Ph P)Pd(Ph)(µ-OH)] reagent could be elucidated. 3 2 P Ph n-Bu3P(10 mol%) P Ph 2 Pd 2 Pd P OH In this context, Doyle et al. developed +dppp (2 equiv) -2PPh DMF,rt P CF3 3 Ph Ph distinct reaction conditions for their palla- Ph Ph 42 dium-catalyzed allylic C–H fluorination using a Pd(ii)-sulfoxide complex as cata- Scheme 31. Selective H–CF activation by palladium. lyst, Et N·3HF as fluoride source and ben- 3 3 zoquinone (BQ) as an external oxidant.[28] precatalyst Scheme 32. Catalytic The conversion of the allylic substrate 40 fluorination of aryl + into 41 was markedly improved when a 2 trifluoroborates. 3+ Cr(salen)Cl complex was used as catalytic N 2BF - 4 N N II N - additive. It should be noted that the addi- Pd N 3BF4 III N tion of the fluorine atom was highly che- CNCH3 NPd 1mol% N 2mol% terpy moselective for allylic position over other N sensitive positions such as the propargylic or benzylic ones (Scheme 29). BF K Moreover, the authors applied this 3 NaF,Selectfluor F methodology to transform a polyfunction- R R alized steroid into its fluorinated analog, DMF or CH3CN providing the desired molecule in good 4-40 ˚C,15h 43 44 15 examples yield and regioselectivity (Scheme 30). This process highlights the ready ac- up to 99% yield cess to a wide range of fluorinated derivatives, for instance, from natural products, Scheme 33. II [Pd ]2mol% Fluorination of trifluo- in a single operation under mild conditions B(OR)2 F without anhydrous requirements. CN terpy 4mol% CN roborates prepared in Selectfluor In the context of C–H activation, the re- EtO C EtO C situ from arylboronic 2 2 acid 43'. cent work by Grushin and Takemoto on the NaF,KHF2 43' CH CN, 40 ˚C selective H–CF activation with palladium 3 44 (86-95%) 3 Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 389

and monocyclic fluorides 50, compatible F F O B(OH) Pd(PPh ) with different nucleophiles to obtain 51. 2 3 4 R2 1 Xantphos 1 R 2 R H H The selective benzylic fluoride displace- + BrCF2R CuI, K2CO3 ment over other functional groups tethered 45 dioxane, 80 ˚C 46 H to the molecule is particularly noteworthy EtO CF C 2 38 examples 2 2 R =PO(OEt)2,CO2Et, (Scheme 38). CONR'R'' up to 98% yield fluorinated estrone analog Furthermore, the authors adapted the previous reaction conditions to Suzuki– Scheme 34. Pd-catalyzed difluoroalkylation of aryl boronic acids 45. Miyaura cross-coupling of selected benzylic fluorides with phenylboronic acid. Interestingly, only the Xantphos-Pd interesting from a synthetic point of view. In that case, the regioselectivity of the complex formed in the reaction media In this sense, Gouverneur and Brown ex- process could be controlled by employing catalyzed the process efficiently, provid- plored the reactivity of benzylic fluorides an appropriate phosphine ligand (Scheme ing aryldifluoromethyl derivatives 46 in 50 in palladium-catalyzed substitution and 39). good to excellent yields. Moreover, this ap- cross-coupling reactions in detail.[34] In It is well-known that the inclusion of proach has been successfully applied to the that paper, the ability of fluoride as leaving fluorinated fragments, such as the trifluo- late-stage synthesis of interesting bioactive group was disclosed even in the presence romethyl group, in organic molecules has compounds for drug discovery (Scheme of other leaving groups such as acetate or contributed significantly to the develop- 34). Although the mechanism has not been carbonate. Based on their previous mecha- ment of new pharmaceuticals.[36] In this elucidated so far, the authors proposed the nistic experiments with allylic fluorides,[35] respect, the Ruppert–Prakash reagent (TMSCF ) and its difluoromethyl variant formation of difluoromethylene radicals Gouverneur and coworkers established 3 (TMSCF H), as ‘CF ’ and ‘CF H’ anion through a Pd-promoted SET pathway as suitable conditions for a palladium(0)-cat- 2 3 2 the initial step. This radical species would alyzed nucleophilic substitution of bicyclic source respectively, have led to a substan-

Scheme 36. SET O F L Pd0 +BrCF R2 L Pd+ ·- BrCF R2 F O Intramolecular hydro- n 2 n 2 F Pd(OAc) F O F R2 2 2 amination reaction of ArB(OH) N R TBAF N (10 mol%) I 2 2 II 2 F difluoroamides 47. LnPd Br + ·CF2R R CF2Pd LnBr H N THF,rt Et N, THF 2 R1 3 1 R 0.5-3 h rt, 16 h R Scheme 35. Proposed radical-based mecha- 47 48 (60-78%) R1 49 (33-63%) nism. react with L Pd(i)Br generated in situ to n provide the active catalyst which would be Favored 4-exo-dig Cyclization involved in the subsequent cross-coupling O L reaction (Scheme 35). F F F R2 L O O Pd + F Leaving aside fluorination reactions, N δ - F F F H δ L fluorine-containing compounds behave in F 2 N 1 N R a particular manner in the presence of pal- L4Pd R Pd R2 R2 N O L H 1 R1 ladium. That is the case of difluoropropar- R1 H R gyl amides 47 synthesized for the first time AB(Z)-49 major by Hammond and coworkers[32] and further used in the synthesis of difluoro β- and Scheme 37. Formation of four-membered ring lactam 49. γ-lactams by Fustero and coworkers.[33] These small heterocycles constitute attrac- Scheme 38. Pd- tive scaffolds in total synthesis as well as [Pd(0)], Ligand catalyzed nucleophilic new molecular entities in drug discovery. Ar F Ar Nu substitution of ben- As mentioned before, Fustero, Hammond 50 NuH (1.5−2equiv) 51 zylic fluorides. et al. reported a regioselective synthesis of Et3N, EtOH four- and five-membered ring lactams via an intramolecular hydroamination reaction SO2Ph OPh NHPh N O of difluoroamides 47 (Scheme 36). Ph Ph Ph Cl The formation of γ-lactam 48 could 66% 22% 87% 88% be explained by a base-promoted nucleo- O O N philic addition of the amidic nitrogen to the SO Ph N 2 N electron-deficient triple bond in the pres- O O N ence of TBAF. In contrast, the formation of 2 O 95% 84% N β-lactam 49 was observed in the presence 95% of palladium acetate and Et N favoring a 87% 3 4-exo-dig over 5-endo-dig mechanism as a result of the gem-difluoro moiety (Scheme Scheme 39. Suzuki– 37). F Ph Miyaura cross- Given the high number of methods for .BF (5 mol%) Pd(allyl)COD.BF (5 mol%) Pd(allyl)COD 4 4 coupling of benzylic selective fluorination recently reported XPhos (20 mol%) F DPEPhos (10 mol%) fluorides with phenyl- [5] PhB(OH) (2 equiv) Cl PhB(OH) (2 equiv) in the literature, the use of the result- 2 2 boronic acid. Ph K3PO4 (2 equiv), THF K3PO4 (2 equiv), nPrOH Cl ing fluorides as appropriate substrates in 60 ˚C, 48 h 95 ˚C, 16 h subsequent transformations would be very 78% 64% 390 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

tial improvement in organic synthesis. Scheme 40. Allylation 3 R of trifluoroethyl sul- However, the efficient incorporation of SO Ph 2 3 Pd2(dba)3/L R OCO2Et fones 52. the trifluoroethyl moiety ‘CF CH ’ had re- + 2 3 2 1 2 R mained a challenge until recently. In 2012, R CF3 R THF,40˚C, 1h 52 Shibata and coworkers employed trifluo- 2 3 F C SO2Ph 53a R =R =H 3 R1 roethyl phenyl sulfones 52 and allyl car- 53b R2=H, R3=Ph 1 2 3 bonates 53 to provide trifluorohomoallylic R =H, Ar,alkyl 53c R =CH3,R =H 54 18 examples sulfones 54 in excellent yields under mild up to 99% yield conditions (Scheme 40).[37] This approach constitutes an advantage Scheme 41. + over typical base-mediated allylation and [Pd] 2 Proposed mecha- [Pd] OEt CF3 R 3 52 R1 involved a Pd(0)-catalyzed decarboxyla- R OCO2Et 3 nism of Pd-catalyzed R3 R tive allylation of 52 via a cationic π-allyl R2 PhO2S decarboxylative al- R2 palladium complex intermediate. The eth- 53 CO2 EtOH 54 lylation. oxy anion resulting from decarboxylation [Pd] of allyl carbonate acts as a base deproton- ating sulfone 52 and reacts further with Scheme 42. the π-allyl palladium complex, regenerat- 10% Pd/C 1. Mg, MeOH/THF Reductive desulfonyl- H2 5h,0˚C ing the catalyst and leading to the desired Ph Ph ation reaction. product 54 (Scheme 41). F3C SO2Ph MeOH 2. 10% Pd/C, H2 CF2H 93% MeOH, overnight Furthermore, Shibata and coworkers 54 55 explored the utility of these products which rt, 96% gave rise to the corresponding difluoromethyl derivatives 55 in high yields when they were subjected to reductive desulfo- owing to its ability to act as both π and σ to-separate proto-demetalated product ob- nylation reaction (Scheme 42). Lewis acid, as well as the availability of its tained with the use of aryl stannanes. In The difluoromethylene ‘CF ’ grouping the presence of a base, aryl boronic acids 2 f orbitals, utilization of silver(i) in organic is also an interesting structural moiety as it synthesis has gained significant popularity and esters were shown to transmetalate to confers particular biological properties to in the past several years.[40a–e] silver in a methanolic solution; subsequent organic molecules.[38] Generally, the con- reaction with Selectfluor (61) in acetone version of the carbonyl group with DAST 2.4.1 Csp2–F Bonds afforded aryl fluorides 59 in a one-pot or deoxofluor has been the method of Due in part to their unique physico- fashion in good yields (Scheme 44, part I). choice to introduce the difluoromethylene chemical and biological properties, aryl Unlike the metal-free fluorination of alke- group into organic molecules. However, a fluorides have found increased applications nylboronic acids and trifluoroborates,[43] drawback of this method is its incompat- in fields of pharmaceutical, agrochemical which usually gives a 1:1 ratio of E/Z iso- ibility with many functional groups. As and material sciences.[41] The direct for- mers,[44] transmetalation from boron 62 to an alternative, gem-difluoroallylation of mation of C(Ar)–F bonds has remained an silver occurs in a stereospecific way, thus boron-containing compounds 56 such as important challenge for chemists and new providing complete control of the stereo- aryl and vinyl boronic acids, borates and and mild methods for direct incorporation chemistry in the preparation of vinyl fluo- trifluoroborates salts, has been described of fluorine allowing a broader functional rides 63 (Scheme 44, part II). recently by Zhang and coworkers, involv- group tolerance are still ardently sought- Following the initial discovery of ing a cross-coupling reaction catalyzed by after. silver-mediated fluorinations, a catalytic palladium (Scheme 43).[39] A simple pro- In recent years silver-mediated/cata- fluorination of aryl stanannes 58a was tocol, wide functional group compatibility, lyzed transformations have emerged as developed.[42c] Unproductive protodestan- very low catalyst loading (0.4–0.01 mol%) powerful tools for the construction of such nylation products were suppressed by ad- and high regioselectivity (α/γ up to >37:1) dition of NaHCO (2 equiv) and NaOTf an important functionality. As outlined by 3 are the advantages of this process. Ritter and coworkers,[42] aryl fluorides 59 (1 equiv), thereby making the use of 5 mol% of Ag O and 1.5 equiv of 60 pos- can be prepared in good yields starting from 2 2.4 Silver-catalyzed Reactions functionalized aryl tri-n-butyl stannanes sible (Scheme 45, part A). Mechanistic Although silver has been known since 58a and the fluorinating reagent F-TEDA- investigations suggested a Ag(i)-Ag(ii) re- antiquity, its use had mainly been limited PF (60), a derivative of Selectfluor. The dox cycle. Oxidation of a species (ArAg). 6 to ornament manufacture and minting, in authors later expanded their methodology (AgOTf) with reagent 60 led to a bimetallic spite of its outstanding electrical conductiv- to the less toxic arylboronic acids 58b[42b] Ag(ii) intermediate which is responsible ity and unique redox chemistry. However, with complete suppression of the difficult- for the carbon–fluorine bond formation,

Scheme 44. Silver- R1 Silver-mediated fluorination α mediated fluorination R2 F BrF2C γ F 60 or 61 F of aryl nucleophiles Ar M Pd (dba) ,base 1.05 -1.2 equiv R 2 3 [I] R and vinylboronic Ar B 2.0-3.0 equiv AgOTf Cl dioxane, 80 ˚C 1 2 N acids. R R Conditionsa 59 56 N 24-36 h 58a M=Sn(nBu)3 Isolated yields 2X 57 F 58b M=B(OH) ,Bpin, Bnepa 63-86% 35 examples 2 X=PF6 (60) Up to 93% yield 1.0 equiv NaOH X=BF4 (61),Selectfluor [II] M F B =B(OH) ,BF K, pinacol ester Up to 10 gscale R 1.05 equiv 61 R 2 3 2.0 equiv AgOTf R' R' a 63 pin= pinacolate, 62 M=B(OH) , nep=neopentylglycolate Scheme 43. gem-Difluoroallylation of boron 2 Isolated yields 65-74% derivatives 56. Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 391

Scheme 45. Silver- a mechanism that differs from traditional Silver-catalyzed fluorination cross-coupling mechanisms with other catalyzed fluorination transition metals (Scheme 45, part B). M 1.5 equiv of 60 F of aryl stannanes and 5mol% Ag O Hitherto, silver-catalyzed fluorinations of (A) R 2 R mechanistic hypothesis. 2.0 equiv NaHCO3 boron nucleophiles have not been reported. 1.0 equiv NaOTf 59 58a M=Sn(n-Bu)3 acetone, 65 ˚C Isolated yields 2.4.2 Csp3–F bonds 63-86% A substantial achievement in the construction of Csp3–F bonds not restricted to Mechanistic hypothesis the synthesis of α-fluoro carbonyl com- L AgOTf 60 reductive [45] (B) Ar-M (ArAgI).(AgIOTf) Ar AgII AgII Ar-F pounds, was reported by Li and cowork- 2equiv elimination ers in 2012.[46] Catalytic amounts ofAgNO F 3 were shown to promote decarboxylative fluorination of aliphatic carboxylic acids Scheme 46. + 64 by Selectfluor (Scheme 46). It was sug- AgI F Decarboxylative fluo- gested, that an Ag(iii)–F species I formed rination of aliphatic AgNO3 (cat) in situ from F+ and the Ag(i) catalyst was Selectfluor (2 equiv) carboxylic acids. II RCO H R-F F Ag F AgIII reduced to an Ag(ii)–F species II after a 2 acetone/H O 2 II SET by a carboxylate anion, thus releasing 64 reflux, 3h 65 R I CO and the alkyl radical R., which was lat- 2 3o >2o>1o>>> aromatic er trapped by the Ag(ii)–F species, regen- Reactivity CO RCOO- erating the Ag(i) catalyst and forming the 2 alkyl fluoride 65, thus closing the catalytic R cycle.A metal-free radical decarboxylative F fluorination had been known from the corresponding t-Bu peresters by NFSI,[47] but F H the required extra step for their preparation HO2C 66a 70 % was avoided in Li’s protocol. Furthermore, H H 3 Chemoselective the method made site-selective Csp –F O bond formation in aqueous media and decarboxylation H 66b R= H(dr 1:1), 77 % with excellent chemoselectivity towards R= Me, 80 % aliphatic carboxylic acids possible. Under these conditions, the reactivity of the substrates was in the order of 3°>2°>1°, while AgOTf (4 equiv) aromatic carboxylic acids were inert, thus, CF3 KF (4 equiv) TiO2 allowing the preparation of substrate 66a R + TMSCF3 R R + CF3CO2Ag in good yield. The authors demonstrated DCE, 85 ºC, hν (1 equiv) 24 h the scope of the process in the preparation (5-20 equiv) 67 of two biologically relevant fluorinated steroids 66b (Scheme 46). Scheme 47. C–H trifluoromethylation of arenes.

2.4.3 Synthesis of CF -(Hetero)aro- 3 regioisomers were obtained and that the erated in situ from TMS-R and AgF using F matic Compounds reaction was suppressed in the presence perfluorohexane as solvent. Notably, other Direct C–H trifluoromethylation of of TEMPO, lent further support to the in- donor solvents commonly used in trifluo- aromatics can be achieved by means of a termediacy of a •CF radical, possibly from romethylations such as DMF led to a num- 3 reaction of arenes and heteroarenes with AgCF . ber of by-products and/or decreased yields. [48] 3 silver trifluoroacetate in the presence of Very recently, Bräse and coworkers[50] In some cases, the di-ortho R -substituted TiO as a photocatalyst. In this transforma- F 2 disclosed a procedure for the ortho-selec- products 70 where observed, albeit in low- tion, the photochemical decarboxylation of tive C–H functionalization of aromatics. er yields. Salient features of this process CF CO Ag on the surface of excited TiO 3 2 2 By means of a triazene-directing group 68, include: a remarkably high site-selectivity generated •CF radicals, which underwent 3 they were able to achieve direct trifluoro- towards ortho-trifluoromethylated prod- radical addition to the aromatic substrates, methylation, perfluoroethylations, hepta- ucts as well as the possibility to further thus affording trifluoromethyl aromatics fluoropropylation and ethoxycarbonyldi- transform the triazene moiety, thus making 67 as a mixture of regioisomers (Scheme fluoromethylation of aromatics 69. In this this a highly attractive method for direct 47). transformation, the AgR species was gen- C–H trifluoromethylation (Scheme 48). A silver-mediated direct C–H trifluo- F romethylation has also been accomplished by means of a AgOTf/TMSCF /KF sys- Scheme 48. Triazene- 3 directed ortho- tem. In this fashion, Sandford and cowork- AgF,TMSRF ers[49] were able to afford trifluoromethyl- N N N trifluoromethylation of N N N aromatics. ated products by using an excess (20 equiv) N N N AgRF + of the arene, 4 equiv of AgOTf, 4 equiv of R R R KF and TMSCF (1 equiv) (Scheme 47). F F F 3 R R R Noticeably, iodobenzene afforded a non- ipso-substituted product, thus contrasting 68 R =CF,C F ,C F , 69 Major 70 Minor with the Cu-catalyzed/mediated proce- F 3 2 5 3 7 CF2CO2Et dures (vide infra). Moreover, the fact that ortho-selective 392 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

A novel approach for the synthesis of benzotrifluorides 71 was recently intro- TMSCF3 +AgF duced by Wang and coworkers.[51] Starting t-BuONO (1.1 equiv) from AgCF and readily available aromatic Cl 3 NH2 HCl (aq) (2.0 equiv) N2 AgCF3 (3.5 equiv) CF3 amines, trifluoromethyl arenes were ob- R R R tained after the one-pot diazotization reac- EtCN, 0ºC, 15 min -78 ºC, 3h tion with the t-BuONO/HCl(aq) system. then rt, 1h 71 After the generation of the corresponding 48 examples diazonium chloride in an EtCN solution, up to 93% yield 3.5 equiv of previously prepared AgCF 3 Scheme 49. Sandmeyer-type trifluoromethylation with AgCF . were added at low temperature (–78 ºC). 3 Interestingly, the more stable and isolable tetrafluoroborate salts were less reactive Silver-catalyzed aminofluorination of allene and alkynes under their optimized reaction conditions. This transformation tolerates a variety of functional groups, from electron-donor, Ag(cat) Nu Nu • or R R' electron-withdrawing, alkynyl, vinyl and Nu-,F+ or even to boron pinacolates (Scheme 49). F Furthermore, a number of benzofurans and F indoles were smoothly converted into the Nu=NRR' corresponding CF -substituted products. 3 However, 3-aminopyridine afforded only a 10% yield. Notably, ortho-substituted Silver-catalyzed aminofluorination of allenes starting materials were also suitable substrates, thus, the corresponding products R' were obtained in high yields. Similar re- R R' R' ports that use the CuCF species have re- TsHN R R 3 AgNO NFSI cently emerged (vide infra). • 3 TsN TsN I. I II. II Ag (Ag )m Ag (Ag )m R'' R'' R'' 2.4.4 Electrophilic/Radical 72 I II F Fluorination/Fluoroalkylation of C–C Multiple Bonds 2.4.4.1 Reactions with Allenes and R' R' R R Alkynes Aromatization In recent years, transition metal-cat- TsN HN alyzed cyclization reactions have gained F F R'' R'' popularity for the fast and efficient syn- 73 74 thesis of a number of biologically relevant 28-92% heterocycles[40b] starting from readily 60-89% 21 examples 8examples available starting materials.[52] In a series of reports, Liu’s group[53] Scheme 50. Silver-catalyzed synthesis of pyrrol derivatives. disclosed a novel tandem approach for the synthesis of fluorine-containing heterocycles. With the use of 20 mol% 51, path 1). In the presence of 3 equiv of 4-fluoro-1,2-dihydroisoquinolines 79. The AgNO and the electrophilic fluorinating Li CO 5 equiv of NFSI, suitably substi- 3 2 3, success of the reaction with an N-alkyl reagent N-fluoro-bis(benzenesulfonyl) tuted o-alkynyl benzaldimines were shown substituent as opposed to the t-butyl sub- amine (NFSI), fluorinated dihydropyr- to provide 1,3 dipolar intermediates of type stituent was explained in terms of the roles 73 (Scheme 50), and isoquinolines III, which were later trapped with dimethyl thermal stability of the resulting isoquino- 76 (Scheme 51) were assembled, start- acetylene dicarboxylate 77a in a [3+2] di- linium species. In this report, a bidentate ing from N-tosyl-protected allenes 72 and polar cycloaddition reaction. In this trans- nitrogen ligand L2 (Scheme 51) promoted N-substituted-o-alkynyl benzaldimines 75, formation an oxazolidine-based bidentate the trifluoromethylation with the Ruppert- respectively. ligand L1 (Scheme 51) was proved to be Prakash reagent TMSCF to afford 79 in 3, Intramolecular aminofluorination of essential to promote product formation. good yields (Scheme 51, path 3). the starting materials led to vinyl-Ag in- The pyrrolo(α)isoquinolines generated Recently, You and coworkers[54] com- termediate I, which was further oxidized from this double tandem process were bined a tandem cyclization approach and by NFSI to afford the bimetallic Ag(ii) achieved in good yields. Furthermore, the electrophilic fluorination for the synthesis fluoride intermediate II and a vinyl fluo- presence of a CF group in the dipolaro- 3 of 3,3-difluoro-3H-indoles 81, 3-fluoro- ride upon reductive elimination of the C–F phile 77b afforded 78 in good yields and indoles 82 and 2-subtituted-3,3-difluoroin- fragment. The obtained dihydropyrroles with excellent regioselectivity, thus dem- dolines 83 starting from readily available 73 were successfully aromatized to afford onstrating the usefulness of the CF group 3 o-alkynylanilines. The combination of a the fluoro-pyrrol derivatives 74 in good as a tool to dictate the stereochemical out- silver-catalyzed cyclization and electro- yields (Scheme 50). come of these transformations (Scheme philic fluorination with NFSI or Selectfluor Fluorinated isoquinolines 76 were 51, path 2). provided fluorinated indole derivatives in readily obtained from the aminofluorina- In a related report, the N-alkylated a single operation efficiently and in good tion of N-t-Bu-o-alkynyl benzaldimines isoquinolinium species IV derived from yields (Scheme 52). These tandem and 75 with 1.5 equiv of NFSI with concomi- the fluorination protocol was trifluoro- one-pot procedures are regarded as highly tant elimination of isobutylene (Scheme methylated to afford 1-(trifluoromethyl)- efficient, avoiding the need for purification Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 393

of the corresponding intermediates. In this Silver-catalyzed aminofluorination of alkynes transformation, the 3-fluoro-indole derivatives 82 were isolated in modest yields, Path 1 possibly due to the over-oxidation by the R' N NFSI (1.5 equiv), + Li CO (1 equiv), N F source. 2 3 16 examples up to 87% yield A related silver-mediated process dis- DMA, 60 ºC R 75 closed by Hammond and coworkers[55] R R'=t-Bu (-isobutylene) F AgNO 3 76 involves the cyclization-triggered addition 20 mol% of the Ruppert-Prakash reagent to amino- alkynes under microwave irradiation. The F F Path 2 R [3+2] R presence of 1.5 equiv of AgF enabled the NFSI (5 equiv), Dipolar R' N one-pot preparation of α-trifluoromethyl N Li2CO3 (3 equiv), N CO2Me EWG amines 85 of varying ring sizes in short Cycloaddition R (±) L1 (20 mol%) III reaction times. Most likely, the real nu- + MeO2C X cleophilic species is the in situ generated Ag DMA, 60 ºC 78 R'=CH CO Me MeO2C X 2 2 12 examples AgCF . Deuterium labeling experiments 77a X=CO Me, 3 2 up to 85% yield suggested that this species underwent nu- 77b X= CF3 cleophilic addition to a reversibly formed CF Path 3 3 enamine intermediate I. Accordingly, in R' R' NFSI (1.5 equiv), N N the absence of a second nucleophile, in- Me4NF (2 equiv), termediate I, generated after the initial al- R R L2 (20 mol%), TMSCF3 (5 equiv) F kyne hydroamination of 84, was detected R'= Alkyl IV F 79 15 examples but could not be isolated. The role of sil- up to 70% yield ver in this transformation, apart from the generation of AgCF , was likely to be the 3 O PhO S SO Ph O N alkyne activation for the intramolecular 2 N 2 N N hydroamination step and the importance F N of a second nucleophilic species for the NFSI (±) L1 L2 reaction was highlighted (Scheme 53). Noticeably, the reaction worked well not only with CF as nucleophile, but excellent Scheme 51. Silver-catalyzed synthesis of isoquinolines, pyrrolo(α)isoquinolines and trifluorometh- 3 yields were also obtained when TMSCN yl-substituted dihydroisoquinolines. was used under copper catalysis affording Scheme 52. Silver- α-cyano-amines, thus, the broad nature of Tandem catalyzed synthesis this alkyne double addition concept was N NHR of fluoro-indol deriva- showcased. Ag2CO3 10 mol%, NFSI (2.0 equiv) R' tives. R=H F F 2.4.4.2 Reactions with Alkenes 80 81 In recent years, radical fluoro-func- R' 14 examples tionalization of alkenes has emerged as a up to 81% powerful strategy for the efficient preparation of fluorine-containing molecules. AgNO3 10 mol%, MeCN, 60 ºC, R Hydrofluorination, carbofluorination, oxy- 8-16 h One pot N R' fluorination are among the methods of par- Selectfluor (1.2 equiv), rt, 2-5 h ticular interest, and more recently, methods for the aminofluorination and phos- R R=H, Me, Bn 82 F phonofluorination have appeared in the N 6examples R' literature (Schemes 54–58). Noteworthy, 30-57% One pot R silver catalysis has been a crucial compo- H Selectfluor (2 equiv), N Nu nent in many of these transformations, in NuH (3-5 equiv) which other transition metals were unable R' F to bring about product formation. 0ºC, 0.5-2.0 h 83 F R=Me Nu= HO-,RO- A significant achievement for the syn- 15 examples thesis of α-CF -ketones from olefin start- up to 91% 3 ing materials and radical CF sources was 3 [56] reported independently by Xiao and Scheme 53. [57] Maiti. In Xiao’s report, styrene de- Synthesis of R' TMSCF , rivatives were transformed into the cor- 3 n n α-trifluoromethyl R N R N responding α-trifluoromethyl ketones 87 amines. RHN n AgF 1.5 equiv CF under metal-free conditions, albeit in low R' R' 3 84 85 yields. In Maiti’s methodology, yields and I functional group tolerance were substan- 9examples tially improved with the aid of silver ca- 87-95% talysis. Accordingly, α-trifluoromethyl ketones were obtained not only from styrenes use of the inexpensive Langlois reagent attractive. Catalytic amounts of potassium but also from heteroaromatics, as well as CF SO Na, room temperature and open-air persulfate K S O as an external oxidant in 3 2 2 2 8 vinyl cycloalkane starting materials. The conditions makes this method particularly conjunction with 20 mol%AgNO under air 3 394 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

afforded the corresponding products 87 in excellent yields (Scheme 54). Mechanistic Silver catalyzed-mediated fluoro-functionalization of alkenes investigations suggested the involvement O O of an α-trifluoromethyl benzylic radical O Ar P OEt species I, generated by the reaction of a Nu= R N OEt R' +/⋅ -/⋅ Nu R' E R' CF radical with the olefin, which was F or CF3./ Nu 3 or - + later trapped by persulfate or dioxygen (as R or F /E R F R F Ph CF3 18 E= H, determined by O-labeling experiments). (CF3) Owing to the exceptionally mild reaction conditions, functional groups such as ester, keto, aldehyde, nitro and cyano were toler- H 18O ated as well as the easily oxidized chloro- CF3SO2Na, CF3 33 examples methyl group (Scheme 54). R R up to 95 % A similar fluoro-functionalization of 86 R' AgNO3/K2S2O4 (cat) R' olefins was reported in 2013 by Li and air,rt 87 coworkers,[58] in which silver catalysis CF3 CF3 18 played an essential role in the radical ami- R O2 nofluorination of unactivated alkenes in R' aqueous media. Through the reaction of I the corresponding substituted enamides 88 with 2 equiv of Selectfluor as the flu- Scheme 54. Oxytrifluoromethylation of alkenes. orine atom source and 10 mol% of Ag(i) salts, a range of fluorinated N-substituted Scheme 55. pyrrolidin-2-ones, oxazolidin-2-ones and O Aminofluorination of AgNO [cat] O N,N-disubstituted imidazolidin-2-ones Ar 3 alkenes. (89, X=C, O and N, respectively) was pre- X N Selectfluor (2 equiv) H X N Ar pared (Scheme 55). The authors surmised H O/CH Cl ,reflux that a radical intermediate II generated R 2 2 2 R F upon reaction of an amidyl radical and the 88 32 examples 89 double bond, was quenched by a fluorine up to 91% atom from a Ag(ii)–F generating the ami- O Ar X=C, O, N nofluorination product 89 and regenerat- N ing the Ag(i) catalyst. A number of Ag(i) X salts such as AgNO , AgOTf and AgOAc 3 R in a 10 mol% loading could efficiently II catalyze this transformation and the best yields were observed with the use of a CH Cl /H O (2:1) biphasic solvent system. tion was shown to exhibit a broad substrate are prone to dimerize to give alkyl dimers. 2 2 2 Noticeably, formation of the product was scope. Additionally, stereoselective phos- This is in sharp contrast with the thermal not observed when NFSI was used instead phonofluorination of a steroid derivative stability exhibited by their perfluorinated of Selectfluor, this observation being in ac- afforded 91a in 89% yield with high diaste- counterparts, which are relatively stable at cordance with the notion that Selectfluor reoselectivity. Nevertheless, electron-poor room temperature, thus, capable of engag- is responsible for the oxidation of Ag(i) alkenes and easily oxidized functionalities ing in various chemical transformations catalyst to Ag(iii)–F, a transformation that were not tolerated under the optimized with other reactive species.[40e] In this would be less favorable with the less pow- conditions (Scheme 56). transformation, only β,β-difluorostyrene erful oxidant NFSI (Scheme 55). Recent efforts to prepare an elusive derivatives were shown to homocouple, Expanding the above-mentioned meth- α-CF -benzyl silver species, from the re- while other alkyl-substituted gem-difluo- 3 odology, the same team developed the action of AgF and gem-difluoroalkenes 92 roalkenes afforded only the hydrofluorina- analogous phosphonofluorination of al- led to the discovery by Hu and cowork- tion products. The hexafluorobutanes 93 kenes.[59] In this instance, simple unactivat- ers,[60] of a process for the preparation of were generally obtained as a 1:1 mixture ed alkenes 90 were reacted with Selectfluor symmetric 2,3-bis-(aryl)-1,1,1,4,4,4-hexa- of syn/anti diastereoisomers. Notably, the and catalytic amounts of AgNO in the fluorobutanes 93 that proceeds through a products could also be obtained if a mix- 3 presence of a number of phosphites to give proposed CF -substituted benzyl radical ture of CsF and AgBF was used instead 3 4 91. As in the radical aminofluorination, the species IV. These unanticipated results of AgF (Scheme 57). Further applications presence of water was found to be crucial were explained by the thermal instability of of this novel α-CF -benzyl silver species 3 for product formation. While the presence in situ generated alkylsilver species, which remain to be developed and challenges as- of a base led to complete suppression of the reaction, a mixed solvent system consisting Scheme 56. AgNO [cat] of CH Cl :H O:AcOH (1:2:1) was found to H 3 F O Phosphono- 2 2 2 (EtO)2P(O)H (2 equiv) give the best results. The beneficial effect P OEt fluorination. R Selectfluor (2 equiv) R 33 examples OEt O of such a particular system was rationalized H2O/CH2Cl2 up to 95% 90 R' 40 ºC 12-48 h R' P(OEt) on the basis that a biphasic system prevents 91 2 H F the product from further oxidation. Even O H though the role of the acid remains to be P OEt R clarified, the authors surmised that stabil- OEt H H R' ity of Ag(iii)–F and Ag(ii)–F is enhanced AcO 91a 89% yield under acidic conditions. This transforma- III dr 8:1 Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 395

sociated with its thermal instability still Scheme 57. AgF (3 equiv), 4Å MS CF3 Fluorinative homo- need to be overcome. pyridine/THF 12 examples F Ar coupling of gem- In recent years, the reactivity of silver Ar syn:anti mixtures Ar difluorostyrenes. towards carbene and carbenoid species F dark, 80 ºC,6h up to 78% has been recognized as substantially dif- 92 CF3 ferent from other transition metals.[61] For 93 instance, it has been shown that silver vi- Ar CF3 nyl carbenes show electrophilic reactivity IV at the vinylogous position rather than the carbene site. Exploiting this property and as continuation of their work on silver vi- Scheme 58. O AgOAc [cat] O H O nyl carbene species, Davies and cowork- 95a Vinylogous fluorina- R3 Et3N.3HF F [62] R1 R1 tion of diazoesters. ers reported a vinylogous fluorination R3 H 2 CH Cl reflux 2 of silver vinyl carbenes to afford γ-fluoro- N2 R 2 2 H R 95 H H 94 28 examples α,β-unsaturated esters 95. In this transfor- O 60% O up to 96 % mation, the silver carbene species V was F dr >20/1 R3 suggested to form in situ from the corre- R1 sponding vinyl diazoester compounds 94. Ag R2 Nucleophilic fluorination by Et N.3HF V 3 led to the corresponding products in good yields. Using this methodology, the au- iodo-trifluoromethyl arenes 98 were con- cycles (100a–c). A thermal hexadehydro- thors were able to prepare a fluorinated de- veniently obtained in good yields with this Diels-Alder reaction of a tetrayne scaffold rivative of farnesol. Furthermore, in spite trifluoromethylation-iodination protocol. 99 served as a novel access to benzyne of the absence of a chiral ancillary ligand, The nucleophilic AgCF species was gen- intermediate I, which upon complexation 3 the fluorinated steroid derivative 95a was erated in situ by the reaction of TMSCF with silver was functionalized by addition 3 successfully synthesized with good dia- and AgF in a 1:1 ratio. In this transforma- of fluoride (from AgBF ), AgCF (gener- 4 3 stereoselectivity. The origin of this diaste- tion, the use of 1-iodophenylacetylene (97) ated in situ from AgF and TMSCF ) and 3 reoselectivity was explained in terms of was found crucial for the success of the di- AgSCF nucleophiles. As in Hu’s method, 3 stereoelectronic effects arising from the functionalization, while other X+ sources the authors were able to perform a double conformation adopted by the substrate such as the N-halosuccinimides NCS, NBS functionalization by trapping the aryl- (Scheme 58). and NIS mainly provided the trifluoro- silver species with suitable electrophiles methyl arene arising from the protonoly- such as N-halosuccinimides. Although the 2.4.4.3 Reactions with Arynes sis of the arylsilver species. Likewise, a strict necessity of a fourth alkyne moiety Arynes are widely recognized as an sterically demanding secondary amine, in order to promote the Diels-Alder re- important class of reactive intermediates 2,2,6,6-tetramethyl-piperidine (L, Scheme action for aryne formation represents a in synthetic organic chemistry.[63] Since 59) was found to be of utmost importance drawback of this method, the mechanistic their discovery, they have found numer- to achieve best results. The role of the li- novelty and the possibility of assembling a ous applications; however, it was only gand was surmised to facilitate the trifluo- number of biologically relevant fluorine- recently that they have successfully been romethylation step, as well as decreasing containing heterocycles such as indolines, used within the context of organofluorine the barrier for the second iodination step isoindolines and dehydrobenzofurans in a chemistry. In an unprecedented transfor- by the formation of a 6-membered ring single operational step, overrides such lim- mation, Hu and coworkers[64] disclosed transition state (TS) assisted by hydrogen itation. To illustrate its scope, the method a protocol for the silver-mediated vicinal and halogen bonding (Scheme 59). was applied to substrates containing a di- difunctionalization of in situ-generated In a related report, Lee and cowork- hydrocholesterol moiety, thus affording benzyne intermediates I, obtained from ers,[65] as continuation of their work on fluorinated, trifluoromethylated and tri- o-trimethylsilyl aryl triflates 96. In this aryne chemistry,[66] successfully prepared fluoromethylthiolated derivatives 100a–c, fashion, the otherwise difficult to obtain o- a series of fluorine-containing hetero- respectively (Scheme 60).

CsF (4 equiv) R' R' OTf CF AgCF3 (3 equiv) 3 R Ph I R 10 examples up to 86% TMS L (1 equiv), MeCN I R R' R 35 examples 97 50 ºC,5h AgI [Ag] /E+ 96 98 Y up to 93% (3 equiv) Y Y Z R Z Z X E= H, I, Br,Cl Ag F- 99 I E

AgCF3 [Ag]= AgBF 100a (X=F) N Y=NTs, O, CH2 4 R R AgSCF H Z=NTs, CH 3 100b (X=CF3) 2 AgCF CF3 L 3 100c (X=SCF3) I Ag

L H O H H

H 100a X=F,80% Ar Ag N n-Bu H 100b X=CF3,67% H 100c X=SCF3,83% N X Ts Ph I N H Proposed TS

Scheme 59. Iodo-trifluoromethylation of arynes. Scheme 60. Fluorine-containing heterocycles. 396 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

2.4.5 Direct Functionalization with Scheme 61. Silver- Trifluoromethyl-chalcogen (CF E) AgPF6 (2 equiv) mediated synthesis of 3 103 (2 equiv) Fragments Sn(n-Bu)3 OCF3 trifluoromethyl ethers Due to their special properties, trifluo- R 104 (1.2 equiv) R from aryl stannanes and boronic acids. romethyl ethers, thioethers and seleno- NaHCO3 (2 equiv) 102 ethers occupy a privileged position in the 101a THF:acetone 1:3 12 examples -30 ºC,2-4 h agrochemical and pharmaceutical fields. up to 88% In recent years, the synthesis of Csp2– ECF compounds (E = group 6 element O, One Pot 3 S or Se) has received considerable interest. 1) NaOH (1 equiv), rt, MeOH 15 min then AgPF Numerous methodologies[67,68] for the in- B(OH)2 6 OCF3 (2 equiv), 0ºC30min corporation of CF E moieties based on hal- R R 3 ogen exchange, radical, electrophilic and 2) 103 (2 equiv), 104 (1.2 equiv) 102 6examples nucleophilic approaches have been report- 101b NaHCO3 (2 equiv), ed in the literature since the 1930s, how- THF:acetone 1:3 up to 72% ever, they often rely on indirect approaches -30 ºC,2-4 h or require hazardous reagents/conditions. On the other hand, more efficient ways to NMe 2 Cl introduce the CF E functionality, namely, S N 3 Me N NMe the direct cross-coupling of a suitable cou- 2 2 N 2PF6 OCF3 pling partner with a pregenerated or in situ F 104 F-TEDA-PF formed CF E fragment have long been 103 TAS-OCF3 6 3 recognized as a superior strategy, mainly dominated by Cu- and Ag-mediated transformations. Accordingly, there has been a flurry of activity in the field and new chemistry is highly restricted to the cop- benzaldoximes 107 and catalytic amounts reagents and methods have recently ap- per species CuSCF (vide infra), a number of AgOTf as a π-activator. In this fashion, 3 peared in the chemical literature and previ- of silver-mediated transformations have trifluoromethylthiol-substituted isoquino- ous methodologies have been improved. In recently emerged. It is noteworthy that tri- lines 108 were obtained in good yields. this review, such advances will be briefly fluoromethylthiosilver (AgSCF ) was first The presence of 4-MeO-benzenesulfonyl 3 mentioned; comprehensive reviews are reported by Emeleus[71] in the 1960s, while chloride as activator for the N-oxide gener- available elsewhere.[68] the more widely used CuSCF species ated upon addition of AgSCF was critical 3 3 Recently, a major breakthrough in the was prepared from the former via a meta- for the success of the process (Scheme 62). synthesis of trifluoromethyl ethers was thetical reaction with copper(i) halides by achieved by Ritter and coworkers.[69] The Yagupolskii in 1975.[72] 2.5 Copper-catalyzed Reactions team was able to perform, for the first time, A recent development in the field of tri- Historically, fluoroalkyl and perfluo- a direct C(aryl)–OCF bond formation via fluoromethylthiolation chemistry was re- roalkyl compounds of copper have re- 3 a silver-mediated oxidative coupling of ported by Wang and coworkers.[73] In their ceived more attention than perhaps any aryl-stannanes 101a and arylboronic ac- report, a series of oxindoles 106 were pre- other metal. Since the pioneering work ids 101b with a trifluoromethoxide source pared by the reaction of alkenes 105 and by McLoughling and Thrower[74] on the TAS-OCF (103). As originally reported AgSCF as a novel source of SCF radicals preparation of perfluoroalkylcoppers back 3 3 3 by Kolomeitsev,[70] in Ritter’s report, 103 under oxidative conditions. Noteworthy, in 1969, increasing attention has been paid was conveniently generated in situ from radical SCF chemistry was largely lim- to this species for the construction of bio- 3 trifluoromethyltriflate (CF SO OCF ) and ited to the gaseous CF SH, CF SCl or logically relevant molecules possessing 3 2 3 3 3 tris(dimethylamino)-sulfonium difluo- CF S-SCF developed 50 years ago.[67g,h] the CF , CF H, SCF and SeCF function- 3 3 3 2 3 3 rotrimethylsilicate (TAS-F). Mediated by Noticeably, CuSCF afforded no product alities and numerous copper-mediated as 3 stoichiometric amounts of AgPF in the under the optimized conditions, thus, high- well as -catalyzed procedures have been 6 presence of F-TEDA-PF (104) as an oxi- lighting the role of silver in the generation reported in the literature. Although older 6 dant, a series of aryl nucleophiles 101 af- of •SCF radicals (Scheme 62). works may be commented where neces- 3 forded aryl trifluoromethyl ethers 102 in In a related report, SCF -containing sary, this work focuses on the develop- 3 good yields (Scheme 61). heterocycles were successfully synthe- ments in the field since 2012. In cases for It is important to note that, due to the sized starting from AgSCF , o-alkynyl which some reviews on particular related 3 thermal instability of CF O–, which de- 3 composes to fluoride and difluorophos- Scheme 62. R' R' gene, to date, similar approaches for the Synthesis of SCF - N O N 3 direct construction of Ar–OCF bonds substituted oxindoles 3 R R O 26 examples with other transition metals remain un- and isoquinolines. R'' R'' up to 91% available, which is likely to be associated 105 F3CS with the usually elevated temperatures (3 equiv) S O8 that are generally employed to promote K2 2 106 AgSCF3 such a demanding reductive elimination. AgOTf Furthermore, catalytic versions of this pro- 10 mol% SCF3 cess are currently unavailable. OH N In contrast to their oxygen counter- R N 13 examples parts, direct incorporation of the SCF R up to 90% 3 R' R' functionality via organometallic species 107 has long been known. Even though SCF 108 3 Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 397

topics have been published more recently, Scheme 63. Aromatic R R CuI (10mol%) R R trifluoromethylation only the literature published thereafter will I I Diamine ligand (10 mol %) CF3 CF3 be considered. or Het or Het catalytic using copper TESCF3/KF salts. DMF/NMP,60˚C, 24 h 109 2.5.1 Aromatic Trifluoromethylation Up to 95% yield Since the pioneering work by Kobayashi and coworkers,[75] who reported the first trifluoromethylation of aryl, vinyl, N N alkyl, and even heterocyclic halides with in Diamine ligand situ generated CuCF from CF I and cop- 3 3 per powder, a number of other methodologies[76] employing stoichiometric amounts trifluoromethyl arenes starting from ani- reaction of the corresponding anilines. The of Cu were reported. A catalytic transfor- lines via their aryldiazonium salts prepared isolated salts were then reacted with CuCF 3 mation with fluorosulfonyl difluoroacetate in situ or separately (Scheme 64, part C). formed in situ from the Ruppert-Prakash was developed by Chen[77] and coworkers; Fu and coworkers utilized an electro- reagent (I) and CuSCN to obtain Ar-CF 3 however, a major step forward was re- philic CF reagent (XV, Fig. 2) for the motifs in good yields. This transforma- 3 ported by Amii’s group.[78] Their protocol synthesis of CF -substituted arenes. In tion tolerated a range of electron-poor and 3 enabled the aromatic trifluoromethylation their report, the aryl diazonium salts were electron-rich functional groups such as of (hetero)aryl iodides 109 with the use prepared in situ by means of isoamyl ni- keto, cyano, ester and amino. Remarkably, of TESCF /KF and 10 mol% CuI in the trite, thus, avoiding the need for purifica- iodo substituents were not affected under 3 presence of a bidentate chelating ligand tion. These protocols tolerate functional the reaction conditions, thus dramatically 1,10-phenantroline (Scheme 63). groups such as ether, thioethers, amide, al- expanding the possibilities for further In recent years, there has been a flurry kynyl and notably, bromide and hydroxyl. functionalization.[85] of activity in the field of copper-catalyzed Heteroaromatic amines are also suitable Of particular significance is the suc- or -mediated aromatic trifluoromethyl- substrates for this Sandmeyer trifluoro- cessful utilization of fluoroform (CF H) as 3 ations and a number of procedures have methylation reaction. Based on mechanis- a direct source of the CF motif. The im- 3 been developed which rely on an array of tic studies, the authors surmised that this portance is centered on the fact that fluo- common CF transfer reagents. Sources of process involves a radical pathway. Thus, roform (a by-product of Teflon® manufac- 3 CF moiety can be categorized as nucleo- a series of trifluoromethylated bicyclic turing) is produced in amounts exceeding 3 philic, electrophilic and radical (Fig. 2). structures was accessed in this fashion.[84] 20,000 tons annually. Furthermore, it is a Important developments in the area In a similar work, Gooβen’s group potent green house gas with an estimated include the use of aryl bromides as elec- achieved a copper-mediated trifluorometh- global warming potential 11,700 times trophilic coupling partners,[79] arylboronic ylation of a series of aryldiazonium tetra- greater than that of CO .[86] Thus, its effi- 2 acids[79b,80] with CF + sources, as well as fluoroborates prepared by a diazotization cient utilization for the synthesis of valu- 3 with nucleophilic CF sources under oxi- able chemicals and building blocks is of 3 dative conditions. Recently, a rapid syn- remarkable importance. Accordingly, the thesis of trifluoromethyl arenes was re- Common nucleophilicCF3sources: groups of Grushin[87] and Prakash[88] inde- [81] ported under flow chemistry conditions. TMSCF3 (I), TESCF3 (II), CF3COOM (M=Na, K) (III), pendently developed conditions for its di- Furthermore, room temperature[80f] trifluo- CF3H(IV), K[CF3B(OMe)3](V), FSO2CF2CO2Me (VI) rect utilization in several important chemi- romethylations have also been enabled un- cal transformations (Scheme 65). O O OH O OTMS der ligand-free conditions[82] as well as by The direct cupration of fluoroform (IV) S P [83] Ph CF3 HO CF EtO R N CF NHC ligand frameworks (Scheme 64, 3 EtO CF3 2 3 was first reported by Grushin and cowork- part A and B). (VII)(VIII)(IX)(X) ers by means of a novel dialkoxycuprate

Until recently, copper-catalyzed or Common electrophilic or radical CF sources: 110, obtained through the reaction of CuCl -mediated aromatic trifluoromethylations 3 and 2 equiv of t-BuOK in DMF (Scheme CF I CF SO Na (CF SO ) Zn O NMe2 3 3 2 3 2 2 - had relied on aryl halides or arylboronic (XI) (XII) (XIII) S X 65). This process enabled the copper-me- Ph CF3 acids as starting materials for such trans- (XIV) diated trifluoromethylation of arylboronic CF X- formations (Scheme 64, part A and B). 3 F3C I O acids,[87b] aryl iodides, aryl bromides and S X However, a major development for the even some aryl chlorides.[87d] In Grushin’s construction of Ar-CF motifs, came in- X= C(Me)2 (XVI) report, arylboronic acids were smoothly 3 (XV) X= CO (XVII) dependently from the groups of Fu[84] and trifluoromethylated at room temperature Gooβen,[85] when they were able to prepare Fig. 2. Sources of CF functionality. employing 2 equiv of fluoroform-derived 3

DMF R X CuCl + K(DMF)[Cu(Ot-Bu)2] Cu, CF - (A) 3 2 t-BuOK 110 Refs 79, 81-83 X= I, Br CF 3 1) Diazotization R NH (A) CF3H 2) Cu, CF - or CF + 2 R R (B) Previous works R 3 3 B(OH)2 X (C) R R CF3 CF3 R M + - Recent developments (2013) Cu, CF3 or CF3 /[O] CuCF3 (B) Air,rt Refs 84, 85. X= I,Br,Cl Refs 79, 80 DMF 57 examples 24 examples M= B(OH) ,Bpin 0.4-7h 2 up to 99% yield up to 96% isolated yield

Scheme 64. Aromatic trifluoromethylation of aryl halides, arylboron spe- Scheme 65. Trifluoromethylation of aromatics by fluoroform-derived cies and anilines. CuCF . 3 398 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

CuCF . In some cases, reactions were romethyl analog of the Ruppert-Prakash any direction with the use of appropriate 3 performed at 0 ºC in order to minimize reagent TMSCF H and stoichiometric halide salts. Remarkably, even defluori- 2 the proto-deborylation by-product. This amounts of CuI. In this transformation nation was possible at room temperature. method is particularly attractive due to the electron-rich and electron-neutral iodo- These outstanding results however, are low cost of CF H and the use of air as the arenes are suitable substrates, however, limited to the very specific macrocyclic 3 oxidant. Furthermore, no ligand or exter- electron-withdrawing functionalities af- ligand framework and their application to nal additive was necessary to promote the forded only the protodehalogenated prod- more general substrates was not reported. transformation. Arguably, the cost-effec- ucts and a competitive difluoromethyl- Nevertheless, Ribas’ seminal work paved tiveness of this transformation overcomes ation of carbonyl moieties was observed the way for the discovery and development the issue of using super-stoichiometric (Scheme 66, part B). of more general Cu mediated fluorination quantities of Cu (Scheme 65, part A). In a related report, Prakash and co- reactions. For the case of aryl halides, most aryl workers[93] introduced a novel reagent for Soon after Ribas’ report, Hartwig and and heteroaryl iodides were smoothly tri- the direct incorporation of the CF H func- coworkers disclosed a Cu-mediated proto- 2 fluoromethylated at temperatures from 25 tionality, namely, tributyl(difluoromethyl) col for the fluorination of aryl iodides us- ºC to 60 ºC with 1.2 to 2.0 equiv of CuCF . stannane n-Bu SnCF H. This non-volatile ing AgF as the fluoride source. As noted 3 3 2 On the other hand, only electron-poor aryl reagent was conveniently accessed from by previous authors, the success in the bromides and 2-bromopyridines afforded the reaction of TMSCF and n-Bu Sn- transformation relies heavily on weakly 3 3 the corresponding products in practical H via difluorocarbene insertion[94] into coordinating counterions and ligands on yields at elevated temperature (ca. 60 ºC) the Sn–H bond. In this fashion, difluo- Cu, thus, after screening a series of nitrile- (Scheme 65, part B). The isomeric 3-bro- romethylations of aryl and heteroaryl io- ligated copper(i) species, it was found that mopyridines are much less reactive and can dides proceed smoothly with 2–3 equiv the best results were obtained with the use only be obtained in yields of up to 17%. In of n-Bu SnCF H in DMA at 100–120 ºC. of 3 equiv of (t-BuCN) CuOTf in DMF 3 2 2 this transformation, an interesting ortho ef- Contrary to Hartwig’s protocol, electron- at 140 ºC. In this manner, electron-poor fect was observed, i.e. substrates with elec- withdrawing groups are tolerated affording as well as electron-rich iodoarenes were tron-withdrawing substituents in the ortho the corresponding difluoromethyl arenes smoothly converted into the corresponding position were particularly reactive, thus, in good yields. Remarkably, owing to the aryl fluorides (Scheme 68, part A). providing high yielding products. As ex- reduced oxophilicity of tin vs silicon, al- Next, the same group reported an al- pected only highly electrophilic heteroaryl dehyde, keto and even ester moieties are ternative approach starting from arylboro- chlorides with ortho electron-withdrawing unaffected, thus, carbonyl difluoromethyl- nate esters and the electrophilic fluoride moieties were reactive enough to afford the ation was not observed (Scheme 66, part reagent 114. In this transformation, the corresponding products, albeit in lower 19F C). choice of the base proved to be of criti- NMR yields and requiring higher reaction cal importance. Not only transmetallation temperature (80 ºC). 2.5.3 Ar–F Bond Formation must be promoted, but also base-induced The generation of C(aryl)–F bonds decomposition of the F+ source must be 2.5.2 Aromatic Difluoromethylation catalyzed by copper was recently reported avoided. To that end, only AgF successful- Amongst fluoroalkyl moieties, the by Ribas and coworkers (Scheme 67).[95] ly afforded the corresponding products in difluoromethyl (CF H) group has attracted A macrocyclic arylcopper(iii) complex good yields, whereas other alkoxide bases 2 increasing attention due to its potential 112 generated after oxidative addition were less effective. The authors surmised application in the pharmaceutical arena. of an aryl halide 111 to a Cu(i) catalyst, that the success of AgF as a base was due The difluoromethyl group is bioisosteric was shown for the first time, to undergo to its lower solubility and nucleophilicity, with the carbinol (OH) group, yet reason- facile C–F reductive elimination at room thus, preventing an unproductive trans- ably lipophilic. Additionally, it can act as temperature in acetonitrile, a transfor- metallation of the arylboronate to a Cu(i) a hydrogen bond donor. For these proper- mation previously limited to Pd species. species. Furthermore, 19F NMR spectros- ties, the CF H motif has been used in the Noteworthy, the same protocol could be copy studies, made the identification of an 2 preparation of numerous biologically ac- used to perform the halogen exchange in Cu(iii)-fluoride species, analogous to the tive compounds such as sugars,[89] enzyme [90] inhibitors and agrochemicals. In sharp Scheme 66. (A) contrast to its perfluoro counterpart, di- I 1. CuI, TMSCF CO Et 2 2 CF2H Difluoromethyl arenes 2. H+ rect incorporation of this functionality is R R R=EWG by three-step se- extremely rare. Most of the methods avail- 3. Decarboxylation quence (A), direct able rely on indirect methods such as de- (B) cross-coupling with I I CF H CF H TMSCF H (B) and oxofluorination of aromatic aldehydes. TMSCF2H(5equiv) 2 2 2 R or R or from n-Bu SnCF H Recently, a multistep procedure in- CuI, CsF,NMP 3 2 120ºC,24hrs (C). volving a copper-catalyzed cross-coupling R=EDG of aryl iodides with TMSCF CO Et, hy- 2 2 (C) drolysis and decarboxylation sequence n-Bu SnCF H(2-3 equiv) I I 3 2 CF H CF H [91] CuI, KF 2 2 was reported by Amii’s group. In this R or R or sequence, the last decarboxylation step DMA 100-120 ºC was successful only for electron-poor sub- R=EWG, EDG strates, thus limiting the reaction scope Tolerates CHO, CO, CO2R (Scheme 66, partA). To date, there are only two reports on the direct and regiospecific Scheme 67. First difluoromethylation of aromatics; both re- copper-catalyzed C–F (MeCN)4CuOTf X (10 mol%) lying on copper-mediated transformations. H III H H bond formation. N X N N Cu N N F N [92] H AgF (2 equiv) H H Fier and Hartwig disclosed a method N N N for the direct difluoromethylation of aryl Me Me Me and vinyl iodides with 5 equiv of a difluo- 111 (X= Cl, Br,I) 112 113 Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 399

Scheme 68. Copper- XVII (Fig. 2), •CF radicals can be gener- 3equiv [CuI], 2equiv [CuI], M 3 I mediated aromatic 2equiv AgF 2equiv 115 ated in situ after an initial SET from the R R DMF,140 ºC,22h EtOAc, 25-80 ºC fluorination of aryl Cu(i) catalyst. The ensuing CF addition to F 3 (A) (C) 12 h iodides (A), arylboron M=BF3K, SnBu3 the olefinic double bond and subsequent pinacolates (B), aryl- deprotonation afforded the corresponding trifluoroborates (C), Bpin 2equiv[CuI], (B) (D) 4equiv [CuII ], products in good yields. In this fashion, R 3equiv 114 BF K stannanes and oxida- 4equiv KF 3 quinones and naphtoquinones possessing 2equiv AgF tive fluorination of ar- MeCN, 60 ºC,20h R DMF,140ºC, 22 h yltrifluoroborates (D). either electron-rich or -deficient aryl sub-

X- stituents 117 were successfully prepared. 114 X= PF6 115 X= OTf Notably, halogen substituents were unaf- N F fected under the reaction conditions, thus, enabling further chemical transformations (Scheme 70, path A). Alternatively, Szabo’s procedure em- one described by Ribas (vide supra), pos- tion. In all of the above-mentioned reports ployed 1.5 equiv of XVII, stoichiometric sible. Subsequent rate-limiting transmeta- (Scheme 68), products are often contami- amounts of a Cu(i) salt as well as cata- lation afforded an arylcopper(iii) fluoride nated by the virtually inseparable arenes, lytic amounts of bis(pinacolato)diboron (5 which underwent rapid reductive elimina- originated from the protodehalogena- mol%) as a radical activator. Nevertheless, tion (Scheme 68, part B). tion or protodeborylation side reactions. contrasting with Wang’s procedure, the A very similar approach is the utiliza- Furthermore, catalytic versions of such stoichiometric version of this transformation of aryl trifluoroborates and aryl stan- transformations are currently unavailable, tion enabled the bis(trifluoromethylation) nanes as nucleophilic coupling partners.As the only examples being possible via Ag or of substrates by employing 2 equiv of outlined by Sandford,[96] such arylboron Pd catalysis (vide supra). Togni’s reagent. In this fashion, a series and aryltin species can be fluorinated with of CF -functionalized quinones and naph- 3 the use of 115 as an electrophilic fluorine 2.5.4 Trifluoromethylation of Olefinic toquinones bearing Me, MeO and chloro source and 2 equiv of (t-BuCN) CuOTf, substituents were prepared in good yields 2 C–H Bonds under mild conditions. Interestingly, and In recent years, a number of copper- (Scheme 70, path B). contrasting with Hartwig’s report, aryl- catalyzed procedures that enable the direct Copper catalysis has enabled ole- boron pinacolates afforded only traces of trifluoromethylation of C–H bonds have finic trifluoromethylations of a series of the desired product under these conditions. been published. These protocols include: enamides at room temperature to obtain In the case of aryl stannanes, fluorinations 119. As outlined by Feng and Loh,[100] a) methods in which a Csp2–CF motif can 3 occurred at room temperature, while aryl- be accessed and b) methods for the con- N-vinyl acetamides 118 were reacted with trifluoroborates required heating at 80 ºC. 1.1 equiv of Togni’s reagent XVII in THF struction of Csp3–CF motifs via olefin 3 Both electron-poor and electron-rich sub- difunctionalization reactions (Scheme 69). at room temperature in the presence of strates were suitable substrates for this The most recent protocols are commented 10 mol% of the cationic copper species transformation, achieving the correspond- (MeCN) CuPF . Interestingly, single crys- on below. 4 6 ing products in practical yields (Scheme tal X-ray diffraction analysis of the product 68, part C). revealed a trans configuration with respect 2.5.4.1 Construction of Csp2–CF A considerable improvement was later 3 to the nitrogen atom. In this transforma- disclosed by Sanford’s group,[97] who pub- Bonds tion, functionalities such as acetyl, cyano, lished a procedure for the fluorination of Recently, the groups of Szabo[98] and sulfonyl and chloro were tolerated, thus aryltrifluoroborates from the inexpensive Wang[99] disclosed a protocol for the direct enabling further functionalizations. A KF mediated by Cu(OTf) . The use of an C–H trifluoromethylation of quinones 116. single heterocyclic enamide was also a 2 inexpensive fluorine source, as well as the In Wang’s report, the transformation was suitable substrate albeit affording the de- operational simplicity and mild reaction performed with catalytic amounts of CuI sired product in only 50% yield even with conditions, make this method particularly (ca. 20 mol%). Owing to the dichotomous a higher catalyst loading (ca. 20 mol%) attractive for large-scale industrial applica- nature of the hypervalent iodine reagent (Scheme 71). tions. The role of Cu(OTf) is believed to 2 be twofold: as the promoter for the C–F bond formation and as an oxidant. This Scheme 69. R Path A Path B R hypothesis is in agreement with the ob- Pathways for olefin servation that >2 equiv of Cu(OTf) are R trifluoromethylation. 2 CF3 Nu CF3 required in order to achieve good yields. Olefinic Double In this fashion, substrates bearing elec- Trifluoromethylation Functionalization tron-donor, electron-withdrawing, as well as carbonyl groups is successfully fluorinated. Heteroaromatic substrates are also Path B Path A fluorinated, albeit in a modest yield (20%). O O O Togni's (XVII)(1.5 equiv) Togni's (XVII)(2equiv) As in previous reports, a high valent Cu(iii) R CuCN (1 equiv) R CuI (20 mol%) R intermediate is surmised to be responsible Bpin2 (5 mol%) t-BuOH-DCM (1:1) for the C–F bond formation event (Scheme CF3 H CF3 CHCl3,rt, 18 h 55 ºC,12h O O O 68, part D). Ref. 98 Ref. 99 In spite of such developments, all these 117 116 117 methods for the construction of C(aryl)–F R=Me, MeO, Cl, H R=Ar,Alk, Br,Cl, H bonds suffer several drawbacks that are 15 examples 15examples up to 89% up to 83% mainly associated with the contamination by side products and product purifica- Scheme 70. Direct quinone C–H trifluoromethylation. 400 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

Building upon this transformation, Scheme 71. Room CF the same team reported a procedure for Togni's (XVII)(1.1 equiv) 3 temperature an olefinic C–H trifluoromethylation of (MeCN) CuPF (10 mol%) 19 examples preparation of (E)- 4 6 up to 92% alkenes.[101] This time, by employing a AcHN R THF,rt, 20 h AcHN R β-trifluoromethyl enamides. series of N-tosyl-protected acrylamides 118 119 120, 1.2 equiv of Togni’s reagent and 10 trans-Olefin mol% CuCl, the authors were able to obtain β-trifluoromethyl enamides 121 in Scheme 72. good yields and with a Z-configuration O O Synthesis of (Z)-α,β- exclusively. Importantly, the success of R Togni's (XVII)(1.2 equiv) R NHTs NHTs unsaturated trifluoro- this transformation greatly relies on the CuCl(10 mol%) 18 examples methyl amides. DMSO, 80 ºC,N ,20h up to 96% presence of the N-tosyl group, since other 2 CF directing groups such as NHBn, NHPh, 3 120 121 OH and OMe all failed to afford the de- Z-Isomers sired product. The authors surmised that R= Ar,Alk, the increased acidity of the NH moiety was likely to be associated with that obser- Scheme 73. vation. In this manner, electron-donating O O O Synthesis of as well as electron-withdrawing α-aryl F3C XVII (1.5 equiv) F C NH α-trifluoromethyl α,β- acrylamides were smoothly converted into Z CuI (10 mol%) 3 Z DMF,80ºC, N N O unsaturated carbonyl products. Notably, the thioether moiety 2 HO R R compounds. was compatible with this reaction and no 122 O 123 catalyst poisoning was observed in that Z= (Het)Ar,Alk, OPh, OBn,SPh NR2,NHPh, NHBn, NH2 E-isomers OH case. Furthermore, α-alkyl acrylamides 28 examples Trifluridine (76%) were also suitable substrates. In that case, up to 92% the products were obtained as mixtures of allylic-CF and the desired olefinic-CF 3 3 acyclic α-oxoketene dithioacetals 124 the latter afforded products as a mixture of products; nevertheless, the desired product with the Ruppert-Prakash reagent under E/Z isomers. In that work, one example of was the major one in all cases (Scheme oxidative conditions in the presence of trifluoromethylation of an internal olefin 72). A short time later, a very similar pro- 10–20 mol% of a Cu(ii) salt. Addition of was reported in 68% yield (127). Although tocol employing Umemoto’s reagent XV the bidentate ligand 1,10-phenantroline, 3 an isolated case, this result clearly dem- and N,N-diethyl acrylamides was also re- equiv of KF as a base and 2 equiv Ag CO onstrates the possibility to circumvent the [102] 2 3 ported. as an external oxidant was found to be limitations involved with the incorpora- [103] Very recently, Bi and coworkers critical for achieving good yields, while tion of dithioacetal activating groups. To disclosed a synthetic protocol for the oxidants such as PhI(OAc) or ligand-free further illustrate the synthetic applicabil- 2 α-trifluoromethylation of α,β-unsaturated conditions failed to provide the desired ity of the method, the authors prepared a carbonyl compounds. In their report, the products 125. In this transformation, ben- series of trifluoromethyl-pyrimidines 129 olefinic trifluoromethylation was possible zoyl substrates bearing methyl, methoxy, via a condensation of 128 with guanidine through the reaction of 1.5 equiv of Togni’s chloro and fluoro substituents were tol- (Scheme 74). reagent and a series of enones, enamides erated. Additionally, cinnamoyl ketene as well as α,β-unsaturated esters, thioes- dithioacetals were also trifluoromethyl- ters and amides 122 in the presence of ated, albeit in a substantially lower yield. 2.5.4.2 Alkene Double 10 mol% CuI. Mechanistic investigations Notably, heteroaroyl (furoyl and thienoyl) Functionalization: Construction of suggest that a •CF radical generated by 3 Csp3–CF Bonds as well as an ester ketene dithioacetal were 3 a SET from CuI is likely to be involved. found to be suitable substrates, affording As previously mentioned, electrophilic In this process, the products 123 were re- CF sources can also enable the double the corresponding products in good yields. 3 gioselectively trifluoromethylated at the Furthermore, not only dithioacetals 124, functionalization of olefins if coupled with α-position. Furthermore, the geometry but also monomethylthio acetals 126 were external nucleophiles. Alternatively, the around the double bond was determined found to be suitable substrates. However, nucleophilic fragment can arise from the to be of an E configuration. Although the authors did not comment on the origin of the regio- and stereoselectivity, this none- O O theless, certainly represents an important Cu(OH)2 (10-20 mol% H CF R 1,10-phen (10-20%) 3 synthetic procedure that complements the TMSCF R 37 examples + 3 up to 92% (3 equiv) Ag CO (2 equiv) one previously described by Loh (vide su- S S 2 3 124 KF (3 equiv) S S pra). To further illustrate the synthetic ap- DCE, 100 ºC 125 R=Me, (Het)Ar,OEt, Cinnamoyl plicability of their procedure, the team suc- Cyclic or acyclic dithioacetals cessfully prepared a series of biologically active trifluoromethylated compounds in- O O cluding the antiviral agent trifluridine with CF NH NH 126 3 CF R 2 R 127 R 3 HNO3 a 76% yield (Scheme 73). CF O 3 H2N NH2 NN An alternative approach for the prepa- SMe K CO ration of α-trifluoromethyl carbonyl com- MeS SMe 2 3 R SMe R Me Me MeCN 100 ºC pounds was reported by Yu’s group.[104] 128 CF3 129 R=H, E/Z 4.5:1, 70% 68% 3examples In this process, the authors were able to R=Me E/Z 3.6:1, 65% Synthetic Utility 71-75 % perform a copper-catalyzed trifluoromethylation reaction of a series of cyclic and Scheme 74. Trifluoromethylation of α-oxoketene dithioacetals. Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 401

same electrophilic reagent, as in the case Scheme 75. OCOAr' X Togni's (XVII) Trifluoromethyl- of the carboxylate fragment from Togni’s or CF or CF Ar Y Ar 3 Y 3 benzoyloxylation and reagent (vide infra). CuI (10 mol% to 1equiv) Along these lines, Szabo[105] and 130 131 conditions 132 133 trifluoromethyl-halo- Ar =2-iodo-phenyl Y= R3Si, RS genation of alkenes. Sodeoka[106] independently disclosed a X= I, Br method for the trifluoromethyl-benzoyloxylation of alkenes by means of Togni’s reagent XVII and olefin derivatives 130, in Scheme 76. Togni's (XVII)(1.1 equiv) Oxytrifluoro- the presence of catalytic or stoichiometric (MeCN) CuPF (10 mol %) OH 4 6 O methylation of unacti- Cu(i) salts. In this fashion, a series of sty- N N L1 (20 mol%) CF3 L1 vated alkenes. rene derivatives were trifluoromethylated MeCN, 55 ºC, 16 h at the β position with subsequent addition 134 O of the carboxylate moiety at the α position O O Me CF O O O 3 O CF3 O of 132. Intriguingly, when performed in CF3 O CF3 the presence of stoichiometric amounts of CF3 Ph Ph CF CuX (X = I, Br) and vinyl silanes or sulfides 94% 71% 64% 3 73% 35% 50% 131 as substrates, an α-addition of halide dr 2.2:1 94% ee ion was observed instead of the expected carboxylate fragment 133. Although these methods are limited to the incorporation of tion was shown to be very clean, thus prod- However, it is noteworthy that a current halide or carboxylate as nucleophiles, they ucts were obtained in pure form simply by limitation of this protocol is that an excess a NaHCO wash, thus avoiding column of alkene was necessary in order to achieve certainly showcase the possibilities of Cu 3 catalyzed/mediated alkene double func- chromatography (Scheme 77). good yields (Scheme 78). tionalization chemistry and in some ways, Very recently, Qing[108] reported a Building upon the above method- complement the silver chemistry reported variant of the above mentioned reaction. ologies, efforts have focused on the de- in this area (vide supra) (Scheme 75). In that work, the team was able to utilize velopment of double functionalization an alternative CF source, namely, the of alkenes in which nucleophiles other Recently, a significant improvement 3 Langlois reagent NaSO CF as a source than O-nucleophiles could be employed. in terms of the scope of O-nucleophiles 2 3 of •CF radicals. Additionally, with the Accordingly, owing to the important prop- that can be employed in oxytrifluoro- 3 methylation reactions was disclosed by use of N-hydroxy-carbamate 137 as the erties of organoazides in pharmaceutical and agricultural sectors, Liu and cowork- Buchwald’s group.[107] In their report, the O-nucleophile, they were able to perform a [109] team was able to employ a series of nucleo- copper-catalyzed oxytrifluoromethylation ers recently disclosed an efficient cop- philes other than the 2-iodo-phenyl carbox- of alkenes in a three-component fashion. per-catalyzed trifluoromethylazidation of ylate fragment using Togni’s reagent. In Styrene derivatives bearing electron-do- alkenes. In that work, a series of olefin de- this fashion, upon addition of the CF mo- nating and electron-withdrawing groups rivatives 139 were trifluoromethylazidated 3 tif from the electrophilic Togni’s reagent, were suitable substrates. Noticeably, even with the aid of Togni II reagent (XVII) simple carboxylates, primary alcohols, unactivated alkenes were shown to un- and catalytic amounts of Cu(i) salt at phenols and even allylic alcohols were able dergo double functionalization under the room temperature. In this transformation, reaction conditions. Furthermore, α,β- 2 equiv of TMSN served as the source to trap the thus-generated intermediate in 3 unsaturated esters, ketones and amides of the N motif. The substrate scope of an intramolecular fashion. Consequently, 3 by varying the chain size, a series of tri- were also efficiently transformed. In order the present transformation is remarkably fluoromethyl substituted lactones and vari- to illustrate the scalability of the process, broad. For example, not only styrene de- ous heterocycles were accessed (Scheme the authors prepared 1.2 g of substrate 138a rivatives were transformed but also cyclic 76). Remarkably, enantiopure allylic al- in 71% yield. In addition, this product was and acyclic internal olefins delivered the cohols gave rise to the corresponding tri- efficiently reduced to the corresponding corresponding trifluoromethyl azides in fluoromethyl epoxides without a drop in β-trifluoromethyl alcohol in 90% yield. good yields. Moreover, monosubstituted enantiomeric excess. Keys to the success of this protocol include the use of the cat- Scheme 77. ionic copper complex (MeCN) CuPF as 4 6 NHAc Oxytrifluoro- Togni's (XVII)(1.1 equiv) OMe S NHAc well as a quinoline-based bidentate ligand AcHN methylation of en- CF OMe L1 (Scheme 76). R CuCl (10 mol%) 3 amides. R CF3 MeOH, rt, 20 h A similar approach for the oxytrifluoro- 135 136 96% yield methylation of enamides 135 was reported R= Ar or Het(Ar) by Loh.[100] In that work, quantitative yields of a series of trifluoromethyl aminals 136 were obtained simply by the reaction of a Scheme 78. CO Me series of enamides with Togni II reagent 2 Oxytrifluoro- CO Me NaSO2CF3 (4 equiv), N 2 CuSO /5H O(10 mol%) O Ph methylation of (XVII) in the presence of 10 mol% CuCl N + R 4 2 22 examples HO Ph t-BuOOH, rt CF alkenes with in methanol at room temperature (Scheme R 3 up to 87% 3equiv 137 138 N-hydroxy- 77). In this fashion, substrates possessing carbamate. electron-withdrawing as well as electron- R= Aryl, het(aryl), alkyl, COMe, CO2Me, CO2NH2 releasing substituents in the aromatic ring CO2Me were smoothly transformed. Furthermore, N O Ph substrates bearing heteroaromatic substitu- Mo(CO)6 OH CF MeCN/H O CF ents were also efficiently transformed into Ph 3 2 Ph 3 138a 1.2 g 90% products in excellent yields. It must be 71% further emphasized that this transforma- 402 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

and 1,1-disubstituted alkenes were also R' smoothly transformed. Of particular sig- Togni II (XVII) N3 R' 60 examples nificance is the fact that α,β-unsaturated Terminal and (MeCN)4CuPF6 (5 mol%) CF R R 3 up to 94% carbonyl compounds were also suitable cyclic olefins R'' TMSN3 (2 equiv), R'' substrates. In this fashion, with the aid of 139 DMA, rt R= (het)aryl, alkyl, CO H, CO Me, a chiral auxiliary, they were able to syn- 2 2 140 thesize precursors of type 140b, which CONMe2,PO(OEt)2 R'= H, alkyl could be further transformed into the cor- R''= H, alkyl responding β-CF -α-amino acids 141b. To O 3 NH further illustrate the synthetic applicabil- N3 2 F3C F3C ity, the same group synthesized a series CONR* CO2H of complex olefins including a steroidal H O 140b 59% dr 9:1 141b 72% er 13:1 derivative, which successfully delivered H H compound 140a in good yield and good NR*= O O diastereoselectivity (Scheme 79). N S 3CF 3 N 140a 2.5.5 Trifluoromethylthiolation 68% dr >20:1 (S)-camphorsultam Reactions: Direct Introduction of SCF Fragments 3 Scheme 79. Trifluoromethylazidation of alkenes. As previously mentioned, the SCF 3 motifs have attracted a great deal of attention for a very long time. Since the prepara- Nucleophilic SCF3 sources tion of CuSCF by Yagupolskii,[72] a great 3 amount of work has been focused on the PPh Ph + Ph3P 3 N CF3S[Q] TMSCF /S Cu field. Recently, milder and more efficient 3 8 N N CuSCF3 methods and reagents that allow the direct SCF3 + SCF3 Q= XXa NMe4, Cu trifluoromethyl-chalcogenation have been XVIII XXb NBu4, XIX XXI XXII SCF3 reported.[67,68] The current methods for such XXc S(NMe2)3 transformation could be categorized in: a) XXIII nucleophilic, where a CF S- anion is the Radical or electrophilicSCF3 sources 3 putative active species and b) electrophilic, O F CS I O SCF3 in which a ‘SCF +’ source is involved in 3 I O 3 CF SCl F CS SCF the bond formation. Some common sourc- 3 3 3 N SCF3 es of SCF moiety are shown in Fig. 3. 3 XXIV XXV XXVIIa XXVIIb XXVI O 2.5.5.1 Nucleophilic Originally reported Confirmed structure Trifluoromethylthiolation Fig. 3. Nucleophilic, radical or electrophilic SCF sources. Themostrecentadvancesinnucleophil- 3 ic trifluoromethylthiolation are based in transition metal-catalyzed cross-coupling XXI protocols, in which copper-catalyzed/me- CuSCN (10 mol%) XXVI (1.15 equiv) B(OH)2 B(OH)2 diated protocols represent the vast major- 1,10-phen (20 mol%) CuCl (10 mol%) R R ity of available methods. Nevertheless, re- K3PO4 (3 equiv) bpy (20 mol%) ports utilizing other transition metals such Ag CO (2 equiv) A D K2CO3 (2 equiv) 2 3 DME, 45 ºC as Pd[110] and Ag have also been published 4Å,DMF,rt (vide supra). Only the most recent works ref 111 ref 117 SCF3 will be discussed here. For a more compre- R hensive treatment, the reader is encouraged to consult other specialized reviews.[67,68] X Br [111] R XXIII ref 114 Recently Qing and coworkers uti- I XXIII B C refs 113 or lized a strategy previously reported by Y. or R or or L. Yagupolskii,[112] in which the –SCF an- R=(het)Ar XXII ref 115 3 X= Br,I XVIII or XXb/CuI Br ion is prepared in situ from elemental sul- ref 116 fur and TMSCF . In his report, a series of 3 arylboronic acids were converted into the Scheme 80. Some nucleophilic and electrophilic trifluoromethylthiolation reactions. corresponding trifluoromethylthioethers in good to excellent yields. A current limitation of such method is the employment of aryl iodides as well as aryl bromides were of allylic bromides[115] (Scheme 80, path expensive Ag CO as an oxidant (Scheme C). Although the main drawback of such a 2 3 successfully transformed (Scheme 80, 80, path A). path B). Remarkably, benzyl bromides[114] method involves the use of stoichiometric An alternative approach was reported were also suitable substrates and the corre- amounts of copper, the enhanced reactivity by Weng and Huang.[113] Recently the team sponding products were delivered in good and such well-defined systems is greatly developed an air-stable CuSCF reagent showcased by their ability to transform 3 to excellent yields. Furthermore, expand- XXIII possessing a bidentate chelating ni- ing upon the above methodology, the same such challenging substrates. trogen ligand which was efficiently used team prepared a complex bearing triphe- Alternatively, Rueping and cowork- to perform trifluoromethylthiolation of nyl phosphine as ligand and efficiently uti- ers[116] disclosed a procedure for the syn- aryl electrophiles. In such transformation lized it to effect trifluoromethylthiolation thesis of vinyl-trifluoromethylthioethers Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 403

through the reaction of XVIII and the corresponding vinyl iodides as the electro- B(OH)2 F CS I O philic coupling partner in pyridine as sol- 3 R (2 equiv) SCF3 vent. In this report, the team also applied (MeCN)4CuPF6 (10 mol%) CuBr(SMe)2 (20 mol%) R SCF3 catalytic quantities of CuI (ca. 10 mol%) bpy (20 mol%) bpy (20 mol% Originally and reagent XXb, albeit with longer reac- K2CO3 (2 equiv) XXVIIa K2CO3 (2 equiv) proposed tion times (Scheme 80, path B). Very recently, the same team[117] disclosed a new synthetic procedure to access I OSCF3 the previously reported reagent XXVI, which avoids the use of the gaseous and toxic XXIV. In this report, XXVI was con- Revised XXVIIb veniently prepared by a metathetical reac- Structure tion of N-chlorophtalimide and CuSCF . 3 Next, reagent XXVI was successfully Scheme 81. Electrophilic trifluoromethylthiolation and revised structure of reagents. employed to perform a copper-catalyzed trifluoromethylthiolation of arylboronic acids in good yields (Scheme 80, path D). to prepare a range of interesting synthetic Then, RCM in the presence of Grubbs It should be mentioned that the team also and natural products including amino ac- catalyst [Ru-I] was carried out under mild utilized XXVI to perform the same trans- ids, carbo- and heterocycles, etc. Moreover, conditions leading to fluorinated piperi- formation to alkynes. it is common to find in the literature ma- dines 144 in excellent yields. Interestingly, In recent years, owing to their syn- ny examples of metathesis, in particular when two enyne isomers, homopropargyl thetic potential, several benziodioxole and enyne metathesis (EYM), in combination allyl amine 146 and homoallyl propargyl benziodioxolone-based hypervalent iodine with Diels-Alder or Pauson-Khand reac- amine 145, were subjected to the opti- compounds have received great atten- tions, for instance. However, examples that mized reaction conditions, only the latter tion from the research community.[118,119] involve fluorinated substrates are lacking. underwent cyclization, providing the cor- Along these lines, the group of Shen[120] On these premises, Bonnet-Delpon responding 1,3-diene 147 (Scheme 82). recently disclosed a protocol in which an and coworkers reported the synthesis of In 2012, Portella and coworkers devel- CF -substituted piperidine derivatives 144 oped a similar strategy for the synthesis electrophilic SCF transfer reagent was 3 3 by Ru-catalyzed RCM from doubly un- of CF -containing cyclopentenecarboxylic successfully utilized to perform trifluoro- 3 methylthiolations of several nucleophiles. saturated trifluoromethylated amines 143 acid derivatives 148 as promising building In this fashion, several enolates, alkynes (Scheme 82).[124] The starting fluorinated blocks.[125] The derivatization of the final and arylboronic acids were successfully amines 143 were readily prepared through products would be a special feature of this transformed into the corresponding tri- a one-pot, Zn-mediated C-allylation/N- work (Scheme 83). fluoromethyl thioethers in good yields allylation sequence in moderate to good On the other hand, Osipov and Dixneuf (Scheme 81). yields. described the behavior of N-tethered Originally, the electrophilic reagent used in this work was proposed to consist Scheme 82. Ru- of a sulfur-bound hypervalent iodine motif, one-pot R1 R1 Allyl R1 R4 N AllylBr,Zn* N N catalyzed RCM of such as the one depicted in XXVIIa (Fig. doubly unsaturated 3). However, as outlined by Buchwald and CF3 F3C F3C R2 R3 R2 R3 trifluoromethylated [121] RCM PCy coworkers, thanks to a recently intro- Cl 3 amines 143. 143 144 Ru duced crystalline sponge method for X-ray 54-86 % 7examples Cl Ph [Ru-I] up to 96 % PCy3 [122] diffraction analysis, the structure of CH Cl ,rt [Ru-I] XXVIIa was unambiguously determined. 2 2 Bn Bn The analysis demonstrated that the reagent N N RCEYM Bn Bn possesses a thioperoxy framework such as N N F3C F3C the one depicted in XXVIIb, rather than F3C F3C 145 146 147 (not observed) the previously reported benziodoxole unit. 95% In this report, the authors provide significant evidence by NMR analysis, which Scheme 83. suggests that such a structure is still the O 5 Synthesis and de- prevalent one not only in the solid state, but AllylOCO Et Grubbs I F3C CO2R 2 F3C OR5 rivatization of cyclo- also in solution. However, it must be fur- [Pd], dppe [Ru-I] CF CH CO R5 pentenecarboxylic ther emphasized, that such findings do not 3 2 2 THF reflux CH2Cl2,rt acid derivatives 148. in any form, affect the previously reported 148 reactivity of the reagent (Scheme 81). R5=H,88% R5=Bn, 99% 2.6 Ruthenium-catalyzed Reactions F3C CO2Bn F3C CO2H Among the different processes catalyzed by ruthenium, metathesis reactions surely belong to the most important ones. O O Particularly, cross (CM) and ring-closing metathesis (RCM) have turned into some F3C CO2H F3C CO2CH3 of the most efficient tools for the creation of C–C bonds.[123] As a result, Ru-based metathesis catalysts have widely been used OH NHBn 404 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

trifluoromethyl enynes towards ruthe- R nium-based metathesis catalysts.[126] PG PG R N2 PG The addition of vinyl- or allylmagne- N MgBr N N 1. R= TMS, CO2Et sium bromide to imines 149 followed by n F C CO CH F3C F3C 3 2 3 2. a) NaH, DMF,0ºC n n N-propargylation afforded closely related H CO C [Cp*(Cl)Ru(cod)] H CO C 149 b) 3 2 (5 mol%) 3 2 1,6- and 1,7-enynes 150 (Scheme 84).[126b,c] CH2Br 151 150 However, these intermediates were not PG= Boc, Cbz, Ts Et2Oordioxane n= 0, 1 51-72% rt to 100 ºC 12 examples used in ‘normal’ RCEYM. Instead, they up to 80% were treated with the ruthenium pre-cat- TMS alyst [Cp*(Cl)Ru(cod)], in the presence Cl PG of a diazocompound, affording the first N Ru F3C trifluoromethylated bicyclic proline and n pipecolic acid derivatives 151, respec- H3CO2C tively. The only difference between this A tandem carbene addition–cyclopropana- Scheme 84. Carbene insertion/cyclopropanation tandem reaction. tion reaction and an RCEYM, besides the initial carbene insertion step, was the last step of the catalytic cycle based on inter- H3C H3C RCOCl H C N N 3 N mediate A (Scheme 84). The authors sug- ArI, [Pd]/CuI [Pd]/CuI 1 F C Ar F C COR gested that the Cp*(Cl)Ru moiety favors 3 3 F3C H CO C H CO C reductive elimination with respect to the 3 2 piperidine/DMF 3 2 Et3N, THF H3CO2C 79-93% 64-83% (IMes)Cl Ru moiety, finally leading to 153 152 155 2 metathesis. [Ru-III] (5 mol%) By using 1,7-enyne analogs with the [Ru-II] (5 mol%) Mes NN Mes Mes NN Mes ethylene (1 atm) aforementioned substrates 150, the same Toluene, 80ºC Cl Cl Ru Ru Cl Toluene, 80 ºC authors investigated their reactivity un- Ph Cl O der RCEYM conditions. After observing PCy3 that the RCEYM on terminal enyne 152 CH3 [Ru-II] [Ru-III] CH3 F C F C invariably led to the self-cross-metathesis 3 N R2 3 N H CO C H CO C O of the RCEYM product in a significant ra- 3 2 3 2 tio, the authors performed a Pd-catalyzed R1 67-74% yield 48-75% yield Sonogashira cross-coupling with differ- 154 4examples 5examples 156 ent aryl iodides for the substitution on the triple bond (Scheme 85). Treatment of the Scheme 85. RCEYM on substituted fluorinated 1,7-enynes. new substituted enynes 153 with Grubbs catalyst [Ru-II] in toluene at 80 ºC afforded RCEYM products 154 in good yields rise to fluorinated carbo- and heterocyclic ticomponent protocol in which 1,7-octadi- (Scheme 85). derivatives in moderate to good yields ene was used as an in situ source of ethyl- Interestingly, enynes derived from (Scheme 86, pathway A).[128b] The one-pot ene gas (Scheme 86, pathway B).[128c] In ortho-substituted aryl iodides were com- protocol began with the ethylene-mediated this case, the ethylene released from the pletely inert to RCEYM under different CEYM on alkynes 157 in the presence of RCM of 1,7-octadiene activated the ru- reaction conditions. The authors attrib- Hoveyda-Grubbs catalyst [Ru-III] leading thenium precatalyst, which in turn reacted uted this observation to a steric effect that to a full conversion into the diene interme- with the alkyne 157 triggering the tandem would shield the triple bond, thus prevent- diate 158. Then, dienophile was added at CEYM/Diels-Alder reaction sequence. ing coordination to the ruthenium center. room temperature to initiate the subse- A different tandem process involving Furthermore, terminal enyne 152 was quent Diels-Alder reaction. cross metathesis but, this time, in com- cross-coupled with different acid chlo- As an alternative to Mori’s conditions, bination with aza-Michael addition, was rides affording enynones 155, which were the same authors reported a complemen- reported by Fustero et al. Based upon in turn cyclized using Hoveyda-Grubbs tary methodology based on a tandem mul- previous work using carbamates[129a] or catalyst [Ru-III], under an ethylene atmo- sphere to obtain 156 (Scheme 85). Scheme 86. In contrast to RCEYM, the intermo- Mori's conditions Sequential CEYM/ lecular version, i.e. the cross-enyne me- pathwayA ethylene F Diels-Alder reaction. tathesis (CEYM) reaction, has been much F less applied in synthesis probably due to Toluene 90 ºC R1 O the difficulty of controlling E/Z selectiv- dienophile ity in its final products. Nevertheless, the F 158 beneficial effect of ethylene gas discovered F by Mori et al.[127] revolutionized this issue, [Ru-III] providing 1,3-dienes efficiently. To the best R1 O R2 of our knowledge, only a few examples of 157 F CEYM involving fluorinated alkynes have F R2 been reported so far.[128] 4 1 Fustero et al. disclosed a tandem one- R O 159 pot CEYM/Diels-Alder reaction of difluo- pathwayB dienophile 15 examples ropropargylic alkynes with different di- Toluene, 90ºCtort up to 87% enophiles under Mori’s conditions, giving Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 405

N-sulfinyl amines[129b] as nucleophilic Scheme 87. O O Tandem CM-IMAMR nitrogen sources, a tandem CM/intramo- F 1 F R O n R2 sequence. lecular aza-Michael reaction (IMAMR) F N F H + [Ru-III](5 mol%) was performed on α,α-difluorinated am- n R2 O N ides 160, leading to interesting scaffolds Ti(Oi-Pr)4 (10 mol%) R1 161a R2=CH 162 such as fluorinated γ- and δ-lactams 162 3 CH2Cl2 heat 160 161b R2=OEt [130] 1 Tandem up to 61% (Scheme 87). R =PMP,OCH3 In a tandem fashion, fluorinated amides 160 reacted with methyl vinyl ketone [Ru-III] t-BuOK 1 161a in the presence of Hoveyda-Grubbs R2=OEt O NHR THF O rt to reflux catalyst [Ru-III] and titanium(iv) tetraiso- F OEt propoxide as a co-catalyst, leading to the F n corresponding lactams 162 by IMAMR in 163 (71-90%) good yields. In contrast to ketones, esters derived from ethyl acrylate 161b stopped Scheme 88. at the CM step (163) and the addition of O OH Asymmetric reduction potassium tert-butoxide was required to Cl of fluorinated ketones RF R promote cyclization (Scheme 87). R1 [Ru] (I) 2 F Ru using Ru-based cata- R Ts H One of the best ways of revealing the NN lysts. HCO2H/Et3N distinct reactivity of fluorine-containing 164 165 Ph Ph molecules is to compare them with their (I) non-fluorinated analogs. Thus, Hoff and coworkers exposed these differences be- OH OH OH OH tween aryl fluorinated and non-fluorinated CH CH F CHF CF ketones in Ru-catalyzed asymmetric trans- 3 2 2 3 fer hydrogenation (ATH).[131] A range of aryl fluoromethyl ketones 164 were Conversion (%) 98 (24h) >99 (2h) >99 (6h) >99 (6h) subjected to reduction with complex I, ee (%) 97 97 90 44.5 observing that the gradual introduction >> >>>>>lower enantioselectivity of fluorine atoms into the α-methyl substituent of the ketone accelerated the H2 (10 atm), NaOCH3 H C F reaction significantly and improved con- F F F F F F 3 CH3OH, 40 ºC OH version into 165 (>99%) in most cases. OR2 OH + OR2 H C R1 R1 R1 3 However, a sharp decrease of enantiose- H X OH 167a 98% yield, 84% sel. O N PPh2 167 10 examples lectivity was observed for trifluoroketones Ru 166 168 F P CO up to >99% yield (Scheme 88). Ph X up to >99% selectivity no reaction 2 OH The authors attributed the lower se- 169a X=H, Cl C2H5O2C lectivity mainly to a size effect, i.e. an in- CH3CO2CH3 169b X=H, H 167b 91% yield, 74% sel. 169c X=Cl, Cl crease in the size of the fluoroalkyl group. CF3CH2CO2CH3 Also, an additional electronic effect caused by the aromatic group was suggested by Scheme 89. Selective hydrogenation of α-fluorinated esters catalyzed by Ru(ii) catalysts 169. calculations; this effect would play an im- nBuLi, (CH O) Br portant role in the π–π interaction between 2 n OMs the catalyst and the substrate. THF,-78 ºC LiBr Ar CF 3 then Zn Another example was recently reported Br Br then MsCl, Et3N O 172 • by Ikariya and coworkers in the synthesis CBr4,PPh3 Ar CF Ar CF of α-fluorinated alcohols 167 and hemiac- 3 Toluene reflux 3 1. n-BuLi, CH I Ar CF 3 Br 3 etals 168 from fluorinated esters 166 via 170 171 THF,-78 ºC Br Zn 174 ruthenium-catalyzed selective hydroge- 2. NBS, AIBN Ar CF [132] DCE 100 ºC 3 nation (Scheme 89). It is noteworthy 173 that the hydrogenation of β-fluorinated esters or non-fluorinated methyl acetate Scheme 90. Synthesis of CF -substituted allenes 174. 3 were unsuccessful. Moreover, aliphatic α-monofluoro esters were hydrogenated of 1-aryl-1-trifluoromethylallenes 174 was to give CF -containing homoallylic alco- 3 in good yields but decreasing selectivity performed starting from trifluoromethyl hols 175 (Scheme 91), involving the for- probably due to the epoxidation of the re- ketones 170 (Scheme 90), which under- mation of a new quaternary stereocenter. sulting monofluorinated alcohol. Although went olefination to give the corresponding The authors proposed a mechanism based the reaction proceeded under mild condi- methylene dibromides 171. Through two on allylruthenium species Ia-Ib as the key tions, the process exhibited a strong de- equivalent pathways, the latter was trans- intermediates in the catalytic cycle. To pendence on the reaction conditions as any formed into the allylic bromide 172 and/ complement this study, the final synthon change in temperature, amount of base, or 173 and subsequent treatment with zinc 175 was employed as building block for catalyst or hydrogen pressure modified the dust led to the expected allenes 174. the synthesis of different substrates such as product ratio of 167/168. The optimized combination of the fluorinated nitrile 176 and the methyl The behavior of CF -substituted al- RuHCl(CO)(PPh ) as a precatalyst and ester 177 (Scheme 91). 3 3 3 lenes in the presence of a ruthenium com- DPPM as a ligand catalyzed efficiently the On the other hand, an efficient, regi- plex were studied by Krische and cowork- reductive coupling of 1-aryl-1-trifluoro- oselective cyclotrimerization of trifluoro- ers.[133] Furthermore, an effective synthesis methylallenes 174 with paraformaldehyde methylated internal alkynes 178 catalyzed 406 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

by a Ru (CO) /2-DPPBN [2-(diphenyl 3 12 phosphine)benzonitrile] catalytic sys- RuHCl(CO)(PPh3) (5 mol%) CN • tem was described by Kawatsura et al. DPPM (5 mol%) F3C Ph (Scheme 92). Although this reaction had + (CH O) OH 2 n F C Ar 176 already been reported previously using Ar CF3 i-PrOH/Toluene 3 O nickel[134a] and rhodium[134b] catalysis, this 174 105-120 ºC 175 example was the first one catalyzed by a OCH3 ruthenium complex. Ar Ar F3C Ph Optimization revealed that Ru (CO) 3 12 177 CF as a precatalyst with 2-DPPBN phosphine LnClRu 3 LnClRu CF3 in a 2:1 specific ratio was the perfect combination for providing unsymmetri- Ia Ib cal fluorinated benzene derivatives 179 in Scheme 91. Ru-catalyzed reductive coupling of CF -containing allenes to paraformaldehyde. high yields and excellent regioselectivities. 3 The ruthenacyclopentadiene species A was identified as the active catalyst-intermedi- PPh2 ate (Scheme 92). In general, this method (5 mol%) CF3 CF3 tolerated different substituents at the aro- Ru3(CO)12 CN Ar Ar Ar Ar matic moiety of the alkyne; however, elec- (3.3 mol%) 2-DPPBN (L) tron-withdrawing groups slightly favored Ar CF3 Ar CF3 F3C CF3 178 CH3CN, 80 ºC the formation of symmetrical products CF Ar 180. A steric effect of an ortho-substituted 3 179 aromatic group was also observed, inhibit- CF3 180 minor isomer ing the process. Ar up to 92% yield symmetric Ru(CO) L up to >98% regioselectivity Up to now, we have reviewed the most 3 Ar= 4-ClC6H4 Ar 4-CF3C6H4 recent advances in transition metal-cata- 4-EtO CC H lyzed trifluoromethylations. Besides pal- CF3 2 6 4 ladium, silver or copper, ruthenium is also A able to participate in such a reaction. In general, the ruthenium complex catalyzes Scheme 92. Ru-catalyzed regioselective cyclotrimerization of trifluoromethylated alkynes. the redox formation of the electrophilic trifluoromethyl radical (•CF ), which is in- 3 Cl4 deed the active species in the addition to Zr 183 CF I [Ru(II)] the substrate. O O 3 O O ZrCl or HfCl O O In this context, Zakarian and coworkers 4 4 O N redox SET R Et N, R I(182) R N 3 F N 184 described the diastereoselective addition O O • CF3 • [Ru(III)] of CF to N-acyl oxazolidinones 181 via RuCl (PPh ) RF Ph 3 2 3 3 [135] CH Cl ,45˚C in situ generated zirconium enolates. Ph 181 2 2 Ph 183 Cl4 Cl4 Zr Zr In contrast to previously reported 19 examples O O O O α-trichloromethylation of titanium eno- RF=CF3,C3F7,C4F9, up to 88% yield C F ,CF Ar O N O N lates,[136] TiCl was not effective for fluo- 8 13 2 F up to >98:2 dr 4 CF3 CF3 roalkylation and other metal halides were screened. The optimized reaction condi- Ph IIPh I tions established ZrCl and HfCl as the 4 4 Scheme 93. Asymmetric trifluoromethylation of N-acyl oxazolidinones. metal halides of choice for enolization of 181, Ru(PPh ) Cl as the best catalyst and 3 3 2 trifluoromethyl or perfluoroalkyl/benzyl of allylsilanes 185 was developed under CF radical source.[137a] The photoredox 3 iodides (R I) 182 as the fluoroalkyl radical mild conditions, employing Togni reagent catalyst of choice was Ru(bpy) Cl ·6H O F 3 2 2 source (Scheme 93). XVII or Umemoto reagent XV (Fig. 2) as which, under visible-light irradiation, re- Additionally, Zakarian and coworkers demonstrated by NMR experiments the formation in situ of zirconium enolates Scheme 94. 184 by reaction of 181 with ZrCl and Et N O Photoredox-based 4 3 trifluoromethylation of at room temperature. The freshly formed O or •CF allylsilanes 185. enolate was then trapped by •CF species, 3 I S 3 OTf which were in turn generated from iodo- XVII CF3 XV CF3 trifluoromethane 182 by a Ru(ii)-catalyzed 3+ 2+ redox process (Scheme 93). A final single Ru(bpy)3 *Ru(bpy)3 electron transfer from intermediate II, in equilibrium with I, to Ru(iii) complex led • visible CF3 to the final CF -substituted oxazolidinone light 3 2+ 183, initiating a new catalytic cycle. SiCH3 Ru(bpy)3 CF3 The group of Gouverneur have perfect- 1 2 1 2 ly combined this kind of process with the R R Photoredox-based R R effect of visible-light on ruthenium cata- (E)-185 trifluoromethylation (E/Z)-186 [137] lysts, i.e. photoredox catalysis. Thus, er >99:1 er up to 88:12 the photoredox-based trifluoromethylation Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 407

sulted in excited-state [Ru*]-species in- Ag and Cu. More specifically, the unique, Lundgren, M. Stradiotto, Angew. Chem. Int. Ed. volved in •CF generation (Scheme 94). differential reactivity of these transition 2010, 49, 9322. 3 [6] R. Ríos Torres, in ‘The Pauson–Khand Arguably, the silyl group in the starting metals towards organofluorine compounds Reaction’, Ed. R. Ríos Torres, Wiley-VCH, substrate would be the steering group since have received the most attention. Because Weinheim, 2012. it was crucial to get good regio- and stereo- of the tremendous advances achieved in [7] J. Kizirian, N. Aiguabella, A. Pesquer, S. selectivity. Additionally to this effect, the this field over the last few years, this re- Fustero, P. Bello, X. Verdaguer, A. Riera, Org. CF source was found to be determining view may provide valuable complemen- Lett. 2010, 12, 5620. 3 [8] N. Aiguabella, C. del Pozo, X. Verdaguer, S. on reactivity as well as stereoselectivity. In tary information on this issue, including Fustero, A. Riera, Angew. Chem. Int. Ed. 2013, general, this method allowed the synthesis preferably those examples reported in the 52, 5355. of allylic CF products 186 as the E iso- last three years. Indeed, this promising [9] T. Konno, T. Kida, A. Tani, T. Ishihara, J. 3 mer as the major product by using Togni field is significantly growing, as much in Fluorine Chem. 2012, 144, 147. [10] N. Aiguabella, E. M. Arce, C. del Pozo, X. reagent XVII (Fig. 2). However, Umemoto academy as in industry and, as a result, a Verdaguer, A. Riera, Molecules 2014, 19, 1763. reagent XV provided higher E-selectivity future review about the further develop- [11] R. Nadano, J. Ichikawa, Chem. Lett. 2007, 36, to the detriment of the chemical yield. ments in this area should be considered in 22. Furthermore, trifluoromethylation as a short time. [12] S. Fustero, R. Lázaro, N. Aiguabella, A. Riera, well as addition of other fluorine group- A. Simón-Fuentes, P. Barrio, Org. Lett. 2014, 16, 1224. ing (e.g. CF CF group) were successfully 2 3 Acknowledgments [13] a) G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. performed on enantioenriched substrates, We thank the Spanish Ministerio de Chem. Soc. 2010, 132, 1474; b) G. Zhang, Y. although a loss of the optical purity was Ciencia e Innovación (CTQ2010-19774- Peng, L. Cui, L. Zhang, Angew. Chem. Int. Ed. observed for the E-isomer. C02-01) and the Generalitat Valenciana 2009, 48, 3112; c) Y. Peng, L. Cui, G. Zhang, L. Zhang, J. Am. Chem. Soc. 2009, 131, 5062; d) The same authors also worked onthenet (PROMETEO/2010/061) for their financial W. E. Brenzovich, Jr. D. Benitez, A. D. Lackner, fluoroform (CF H) addition to alkenes and support. S.C. thanks the Spanish government 3 H. P. Shunatona, E. Tkatchouk, W. A. Goddard alkynes employing separately CF radical for a Juan de la Cierva contract. III, F. D. Toste, Angew. Chem. Int. Ed. 2010, 3 and hydrogen atom sources, i.e. Umemoto 49, 5519; e) A. D. Melhado, W. E. Brenzovich, reagent XV and methanol respectively.[137b] Received: March 27, 2014 A. D. Lackner, F. D. Toste, J. Am. Chem. Soc. 2010, 132, 8885. Besides being the solvent of the reaction, [14] W. Wang, J. Jasinski, G. B. Hammond, B. Xu, the role of methanol as a hydrogen donor [1] a) J.-P. Bègué, D., Bonnet-Delpon, ‘Bioorganic Angew. Chem. Int. Ed. 2010, 49, 7247. should be particularly highlighted since an and Medicinal Chemistry of Fluorine’, Wiley, [15] N. P. Mankad, F. D. Toste, J. Am. Chem. Soc. external hydrogen source such as Hantzsch Hoboken, NJ, 2008; b) K. Müller, C. Faeh, 2010, 132, 12859. ester was not required. Thus, the hydrotri- F. Diederich, Science 2007, 317, 1881; c) S. [16] T. de Haro, C. Nevado, Chem. Commun. 2011, Purser, P. R. Moore, S. Swallow, V. Gouverneur, 47, 248. fluoromethylation would be based on a Chem. Soc. Rev. 2008, 37, 320; d) T. Liang, C. [17] M. N. Hopkinson, G. T. Giuffredi, A. D. Gee, V. similar mechanism to the aforementioned N. Neumann, T. Ritter, Angew. Chem. Int. Ed. Gouverneur, Synlett 2010, 18, 2737. (Scheme 95) in which a Ru-based photore- 2013, 52, 8214 and references therein. [18] Z. Jin, R. S. Hidinger, B. Xu, G. B. Hammond, dox process generated •CF species to be [2] D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308. J. Am. Chem. Soc. 2012, 77, 7725. 3 [19] a) A. Arcadi, E. Pietropaolo, A. Alvino, V. added regioselectively to the alkene/alkyne [3] a) D. J. O’Hagan, J. Fluorine Chem. 2010, 131, 1071; b) S. R. Pattan, N. S. Dighe, H. V. Michelet, Beilstein J. Org. Chem. 2014, 10, 187/188. Final oxidation of methanol by Shinde, M. B. Hole, V. M. Gavare, Asian J. Res. 449; b) A. Arcadi, E. Pietropaolo, A. Alvino, V. the strong oxidant Ru(bpy) 3+ regenerated Michelet, Org. Lett. 2013, 15, 2766. 3 Chem. 2009, 2, 376; c) I. Ojima, ‘Fluorine in the catalyst on one hand and, on the other medicinal chemistry and chemical biology’, [20] S. Fustero, P. Bello, J. Miró, M. Sánchez- hand, it transferred a hydrogen atom to Wiley-Blackwell, Chichester, 2009; d) W. K. Roselló, M. A. Maestro, J. González, C. del Hagmann, J. Med. Chem. 2008, 51, 4359; e) K. Pozo, Chem. Comm. 2013, 49, 1336. the radical intermediate 189 leading to the L. Kirk, Org. Proc. Res. Devel. 2008, 12, 305. [21] S. Fustero, I. Ibáñez, P. Barrio, M. A. Maestro, expected terminal CF -substituted com- S. Catalán, Org. Lett. 2013, 15, 832. 3 [4] R. Filler, R. Saha, Future Med. Chem. 2009, 1, pounds 190 and/or 191. 777. [22] G. T. Giuffredi, B. Bernet, V. Gouverneur, Eur. [5] a) Z. Jin, G. B. Hammond, B. Xu, Aldrichimia J. Org. Chem. 2011, 20-21, 3825. Acta 2013, 45, 67; b) T. Besset, C. Schneider, [23] C. Hollingworth, A. Hazari, M. N. Hopkinson, D. Cahard, Angew. Chem. Int. Ed. 2012, 51, M. Tredwell, E. Benedetto, M. Huiban, A. D. 3. Conclusions 5048; c) C. Hollingworth, V. Gouverneur, Gee, J. M. Brown, V. Gouverneur, Angew. Chem. Commun. 2012, 48, 2929; d) T. Furuya, Chem. Int. 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