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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 in- troduction 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 addi- tion 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.
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