Recent progress in direct introduction of fluorinated groups on alkenes and alkynes by means of C-H bond functionalization.

DOI: 10.1002/chem.201404537

Minireview

& Fluorine Chemistry

Recent Progress in Direct Introduction of Fluorinated Groups on Alkenes and Alkynes by means of C H Bond Functionalization Tatiana Besset,* Thomas Poisson,* and Xavier Pannecoucke[a]

Chem. Eur. J. 2014, 20, 1 – 17

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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Minireview mations, base-promoted processes, and transition metal-catalyzed functionalization of alkenes and alkynes. Special attention will be paid to explanations of the reaction mechanisms.

Abstract: The direct introduction of fluorine and fluorinated building blocks has recently attracted a lot of attention and particularly the direct functionalization of alkenes and alkynes. This review will highlight the major progress recently made in that field, with a focus on photocatalyzed transfor-

Introduction

a halogenated fluorinated species and, quite recently, 3) the direct introduction of fluorinated moieties on non-prefunctionalized substrates with a fluorinated reagent. Furthermore, direct C H bond functionalization has recently appeared as a very appealing and atom economical strategy,[6] as it does not require pre-functionalization of the substrates through a prior halogen atom introduction step or the stoichiometric formation of an organometallic species.[7] Hence, recent efforts from the scientific community have resulted in the design of several elegant and efficient methods to directly introduce fluorine atoms or fluorinated building blocks on C H bonds.[5e, 8] To date, these approaches have mainly dealt with the direct C H functionalization of aromatic and heteroaromatic compounds. In contrast, the direct introduction of fluorine atoms or fluorinated building blocks to alkenes and alkynes remains scarce. Herein, we would like to highlight the recent progress achieved in the field of the direct introduction of fluorine or fluorinated building blocks to access to either fluorinated alkenes or fluorinated alkynes over the last decade. Indeed, despite their potent applications in medicinal chemistry, as agrochemicals or as versatile building blocks, the development of modern and straightforward methods to obtain those targets remains underexplored. Although radical chemistry has been widely used, this review will only report the most recent results using radical processes and particularly those by means of photocatalysis. We would like to focus on transition metal-catalyzed reactions and base-assisted processes. The first part of this review will discuss the introduction of fluorinated groups on alkenes, whereas the second part will focus on the synthesis of fluorinated alkynes.

Nowadays, scientific advances in organic chemistry are driven by social demand, which results from our contemporary concerns. Among them, the quest for new therapeutics is an important field of research. For example, the resurgence of drugresistant strains of several diseases, such as tuberculosis, has pressured pharmaceutical companies to renew their drugs portfolio in order to continue to offer active pharmaceuticals. As part of this research field, organic chemists are involved in the development of new synthetic methods to reach elaborate targets with potential biological activities.[1] Quite recently, organofluorine chemistry has attracted renewed interest. Indeed, fluorine is a very intriguing atom; owing to its unique properties, such as its electronegativity, its size, and the high stability of the C F bond, its presence has a significant tendency to modify the physical and biological properties of a molecule.[2] As a result, the introduction of fluorine atoms or fluorinated groups to bioactive molecules has become a privileged approach toward the design of new pharmaceuticals. As a result, more than 25 % of drugs contain fluorine atom(s) and, in 2011, three of the top ten selling drugs in the United States incorporated at least one fluorine atom within their structures.[3] Taking these observations into account, it is obvious that the design of new and efficient methodologies to obtain fluorinated targets constitutes an important challenge for the organic chemistry community. Moreover, the only way to access to fluorinated molecules relies on the introduction of fluorine atoms or fluorinated building blocks by means of chemical engineering. Indeed, despite its abundance in the Earth’s crust (13th most abundant element), natural fluorinated molecules are scarce (fewer than 15) and, in contrast to chlorine and bromine atoms, no fluoroperoxidase enzyme has been evidenced, thus excluding possible chemoenzymatic pathways.[4] Commonly, fluorinated molecules are synthesized either by fluorination reactions using fluorinating reagents, such as Selectfluor, DAST [(diethylamino)sulphur trifluoride], Fluolead, or PhenoFluor, or through the introduction of simple fluorinated moieties, such as CF3.[5] This last approach is a privileged way to access to fluorinated molecules. It has been widely explored using 1) radical chemistry, 2) transition metal-catalyzed crosscoupling reactions with a fluorinated organometallic species or

Fluorinated alkenes Fluorinated alkenes from alkenes Photocatalyzed transformations In the 1980s, several reports dealt with the introduction of fluorinated building blocks by means of single electron transfer (SET).[9] With the recent expansion of photoredox catalysis,[10] there is renewed interest in the introduction of fluorinated building blocks on alkenes by means of SET. Indeed, photoredox processes represent a convenient alternative to the traditional SET process and allow for the design of new chemical transformations.[11] In 2012, Yu and co-workers took advantage of the SOMOphilic character of enamides and ene-carbamates to carry out the reaction with fluorinated electron-deficient bromides.[12]

[a] Dr. T. Besset, Dr. T. Poisson, Prof. X. Pannecoucke COBRA UMR CNRS 6014, Btiment IRCOF, 1 rue Tesnire 76821 Mont Saint Aignan Cedex (France) E-mail: [email protected] [email protected]

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Minireview products.[14] The radical pathway of the reaction was assessed; the reaction performed with b-pinene 5 afforded the rearranged product 6, resulting from ring opening subsequent to the CF3 radical addition to the double bond (Scheme 2). Cho and co-workers proposed the following mechanism to explain the reaction outcome. First, the visible-light-excited Ru2 + (Ru2 + *) reacted with 1 equivalent of base to give the reactive species Ru + (Scheme 3). Reaction with CF3I then formed the CF3 radical and regenerated the Ru photocatalyst. The CF3 radical performed an addition on the alkenes 3, forming a new

Using the iridium photocatalyst [Ir(ppy)2(dtbbpy)]PF6 (ppy = 2phenylpyridine, dtbbpy = 4,4’-di-tert-butyl bipyridine) and Na2HPO4 as a base in MeCN, the CF2CO2Et moiety was readily introduced on enamides and ene-carbamates in excellent yields. Notably, this process was extended to the trifluoromethylation reaction using trifluoromethanesulfonyl chloride (CF3SO2Cl) as a CF3 radical source. The enamides 2 a–e were isolated in fairly decent yields (Scheme 1). To explain the reac-

Dr. Tatiana Besset was educated in chemistry at the University of Grenoble (France) in the group of Dr. Andrew E. Greene, where she obtained her doctoral degree in 2009. She then moved to the Westflische Wilhelms Universitt Mnster (Germany) as a postdoctoral fellow in the group of Prof. Frank Glorius (Rh C H bond activation). In 2011, she joined the group of Prof. Joost N. H. Reek at the University of Amsterdam (the Netherlands), as a postdoctoral fellow in collaboration with the company Eastman where she was working on supramolecular encapsulated rhodium catalysts for branched selective hydroformylation of alkenes. Since October 2012, she is working as a CNRS Researcher (CR2, Charge de Recherche CNRS) in the “Fluorinated Biomolecules Synthesis” team at INSA Rouen, France. Prof. Xavier Pannecoucke was born in Lille (France) in 1967. He got his Ph.D. in BioOrganic Chemistry in 1993 from the University Louis Pasteur of Strasbourg (France), under the supervision of Professors Guy Ourisson and Bang Luu. He then moved to Japan for one year to carry out his first postdoctoral studies in the laboratory of Prof. Koichi Narasaka at the University of Tokyo. He moved again to Great Britain for fourteen months to carry out his second postdoctoral studies in the laboratory of Prof. Steven V. Ley at the University of Cambridge. He then went back to France as a Matre de Confrences at the University of Rouen in the group of Prof. J.-C. Quirion. In 2003, he took a position of Professor at the INSA of Rouen, leading the group of “Fluorinated Biomolecules Synthesis” and heading from 2011 COBRA laboratory (UMR 6014). His main research interests are dealing with development of new methodologies to access fluorinated biomolecules (peptidomimetics, carbohydrates, nucleosides, heterocycles).

Scheme 1. Photoredox Ir-catalyzed difluoromethylation and trifluoromethylation of enamides and ene-carbamates.

tion outcome, the authors proposed the following reaction pathways: Ir3 + * generated from the excitation of Ir3 + by visible light is quenched by RFX (BrCF2CO2Et or CF3SO2Cl) to provide the corresponding fluorinated radical I and the Ir4 + species. The radical I reacts with the SOMOphilic enamides 1 to form a new amido radical II. Then, Ir4 + oxidizes the amido radical II into the N-acyl iminium cation III. Notably, this oxidation might also result from a propagation step (path B). Finally, deprotonation of III by the base releases the enamide 2 (Scheme 1). In the same year, Cho and co-workers reported the trifluoromethylation of alkenes 3 a–k by means of visible-light photoredox catalysis (Scheme 2).[13] The authors used CF3I as a CF3 radical precursor in the presence of 0.1 mol % of the ruthenium catalyst [Ru(phen)3Cl2] along with 2 equivalents of the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction was applied to a wide range of alkenes and proved to be highly functional-group tolerant. Products 4 a–k were obtained in very good yields and the reaction turned out to be selective toward the formation of the E isomer along with traces of allyl–CF3 Chem. Eur. J. 2014, 20, 1 – 17

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Dr. Thomas Poisson received his Ph.D. in 2008 from the University of Rouen under the supervision of Dr. Vincent Levacher working on the development of new enantioselective protonation reactions. Then, he moved to the University of Tokyo as a JSPS postdoctoral fellow within the group of Prof. Shu¯ Kobayashi working on new asymmetric process using alkaline earth metal complexes. In 2010, he moved to the RWTH Aachen where he was working with Prof. Magnus Rueping as a postdoctoral research associate. In 2011, he joined the “Fluorinated Biomolecules Synthesis” team at INSA Rouen as an Assistant Professor.

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Scheme 2. Photocatalyzed trifluoromethylation of alkenes.

Scheme 4. Photocatalyzed trifluoromethylation of diarylethenes.

yields with moderate E/Z selectivities (Scheme 4). Interestingly, the reaction proceeded smoothly with tri-substituted alkenes furnishing the products 9 f and 9 g in good yields.[15] The authors suggested the following mechanism to explain the reaction pathway. The photoactivated Ru2 + * species generated the trifluoromethyl radical I from a one-electron reduction of Umemoto’s reagent 7. This radical reacted with alkene 8 to afford the more stabilized benzyl radical II. A subsequent oxidation mediated by the Ru3 + species gave the carbocation III, which underwent an elimination of the acidic a-CF3 proton to release the product 9. Note that Akita and co-workers did not propose a propagation mechanism since the reaction required continuous irradiation of the reaction media (Scheme 4). In 2013, Carreira and Martin reported the photocatalyzed introduction of the 2,2,2-trifluoroethyl moiety on styrene derivatives 11 a–i (Scheme 5).[16] This methodology, using cobalt catalyst 10 and 2,2,2-trifluoroethyliodide under blue LED irradiation, gave the corresponding fluorinated styrenes 12 a–i in good to excellent yields. It is worthy to mention that this process was applied under continuous mode. The flow process proved to be also highly efficient giving the allylic trifluoromethane 12 a–c, h in good to excellent yield (Scheme 5). Although the introduction of fluorinated moieties by means of SET pathways has been widely explored and has been recently updated by using photocatalysis, the rapid expansion of transition metal-catalyzed processes has opened new avenues, such as C H bond functionalization. Indeed, this field enabled the design of new and efficient processes. It is therefore not surprising that much attention has recently been devoted to

Scheme 3. Proposed mechanism of the photocatalyzed trifluoromethylation of alkenes.

radical intermediate I. Subsequently, either a propagation step (path A) or an oxidation reaction can occur (paths B and C). In path A, the propagation would furnish the iodinated alkane II, which would undergo an E2 elimination to provide the desired trifluoromethylated alkenes 4. Alternative pathways (B and C), involving an oxidation of the radical I would afford the carbocation III. The latter might either be trapped by iodide to form II and then eliminate HI to give 4 (path B) or a proton abstraction on the carbocation III would directly afford the desired trifluoromethylated alkene 4. However, the authors ruled out this last hypothesis, since the product 4 should arise from an E2 elimination of HI to form the E isomer (Scheme 3). Akita and Koike developed a Ru-catalyzed photoredox process using Umemoto’s reagent 7 and blue LED as the light source. The reaction was applied to several a,a-diarylethenes. Trifluoromethylated products 9 a–g were obtained in good &

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Scheme 5. Photocatalyzed 2,2,2-trifluoroethylation of styrenes. Yields of products obtained under continuous mode are given into parentheses.

Scheme 7. Direct copper-catalyzed trifluoromethylation of alkenes.

the elaboration of transition metal-mediated transformations for the introduction of fluorinated moieties on alkenes.

In early 2012, Loh and co-workers reported an elegant and straightforward access to b-trifluoromethylated enamides.[19] By using a copper catalyst and the Togni’s reagent 17 as a CF3 source in THF, Loh applied this methodology to a broad range of acyclic and cyclic enamides 20 a–m (Scheme 8). The resulting trifluoromethylated enamides 21 a–m were isolated in good to excellent yields with a complete E selectivity. Then, to gain insight into the reaction pathway, mechanistic studies were carried out. When the reaction was monitored by EPR (electron paramagnetic resonance) spectroscopy, no radical

Transition metal-promoted introduction of CF3 In 2011, Fu and Liu developed an allylic trifluoromethylation reaction and, during their study, they reported a single example of Cu-catalyzed trifluoromethylation of alkenes (Scheme 6).[17] The product 15 was obtained in 38 % yield along with a signifi-

Scheme 6. First example of copper-catalyzed trifluoromethylation of terminal alkene. Tc = thiophene-2-carboxylate.

cant amount of allylic-CF3 product 16 (32 %). Notably, this first example constituted a proof of concept for such a scenario. To date, no explanation for this result has been forthcoming, since theoretical calculations suggested the favorable formation of the allylic-CF3 substituted substrate 16 (Scheme 6). In the course of the development of a new copper-catalyzed oxytrifluoromethylation reaction of alkenes, Sodeoka and coworkers discovered that the addition of a Brønsted acid (TsOH) led to the exclusive direct trifluoromethylation of alkenes. The reaction was trans selective. The authors presumed a plausible elimination of the benzoate moiety on the oxytrifluoromethylation product I through an E1 mechanism to explain the formation of the thermodynamically more stable trifluoromethylated E alkene 19 (Scheme 7).[18] Chem. Eur. J. 2014, 20, 1 – 17

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Scheme 8. Loh’s trifluoromethylation of enamides.

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Minireview was tolerant to a-alkylsubstituted acrylamides 23 k–n, which afford predominantly the b-trifluoromethylated acrylamides along with a small amount of the trifluoromethylated products at the allylic position. Regarding the reaction mechanism, authors proposed the involvement of a radical species since the addition of radical scavengers had a deleterious effect on the yield of the reaction. Moreover, an intermolecular KIE experiment revealed that the olefinic C H bond cleavage was not the rate-determining step (KIE = 1). According to these observations, the following mechanism was suggested: first a ligand exchange afforded the new copper species I, which underwent an oxidation step with the Togni’s reagent 17 giving the CuIII species II. Then, an intramolecular SET gave the radical cation III in equilibrium with the cationic intermediate IV. Finally, a proton abstraction followed by a reductive elimination produced the trifluoromethylated Z-olefin 23 along with the regeneration of the catalyst (Scheme 9). Concomitantly to this report, our group reported a similar transformation using a stoichiometric amount of CuI and Umemoto’s reagent 13 as electrophilic CF3 source (Scheme 10).[22]

species were detected. This observation has been further confirmed since the presence of 2,6-di-tert-butyl-p-cresol (BHT), a radical scavenger, did not have a deleterious effect on the reaction yield. However, the addition of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to the reaction mixture suppressed the reaction. The authors proposed that the inhibition of the reaction with TEMPO arose either from a decomposition of the Togni’s reagent 17 or from an oxidation of the CuI catalyst into a CuII species. Hence, the authors proposed a cationic reaction mechanism whereby the CuI catalyst reacted with the Togni’s reagent 17 to form the highly electrophilic iodinated species I.[20] This key intermediate would then react with the enamide 20 to form the new cyclic iodinated species II in equilibrium with the a-l3-iodane imine III. Then, reductive elimination provided the a-trifluoromethylated imines IV, which underwent a proton elimination or transfer to deliver the product 21 along with the regeneration of the copper catalyst (Scheme 8). Later in 2013, Loh and co-workers extended the scope of their trifluoromethylation process to electron-deficient alkenes.[21] They found that a-substituted N-Ts-acrylamides were suitable substrates to perform the b-introduction of the CF3 moiety using Cu catalyst and the Togni’s reagent 17 (Scheme 9). This process was applied to a broad range of aaryl-substituted acrylamides 22 a–n in good to excellent yields with a total selectivity for the Z isomer. Notably, the reaction

Scheme 10. Trifluoromethylation of various acrylamides.

This process was applied to different a-phenyl-substituted acrylamides 24 a–d with various amide-type directing groups and several a-aryl and alkyl substituted N,N-diethyl acrylamides 24 e–i. The resulting products were obtained in moderate to good yields with complete Z selectivity. Notably, the reaction proved to be also compatible with b- and a,b-disubstituted N,N-diethylacrylamides, leading to difficult-to-prepare tri- and tetrasubstituted alkenes 25 j and 25 k. In 2014, Bi and co-workers reported the copper-catalyzed atrifluoromethylation of a,b-unsaturated ketone, ester, thioester and amide species 26 a–j using Togni’s reagent 17 (Scheme 11). The reaction proved to be functional-group tolerant and the corresponding trifluoromethylated products 27 a–j

Scheme 9. Trifluoromethylation of electron-deficient alkenes. [a] Global yields of 23 and the allylic trifluoromethylated product; ratios are given in parenthesis.

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Scheme 12. Pd-catalyzed Heck reaction with BrCF2SO2Ph 28.

yields. Cyclic and acyclic enol ethers and a thioenol ether were suitable substrates for this transformation. The corresponding products 30 g and 30 i–j were isolated in somewhat better yield than with the styrene derivatives. Rudimental mechanistic studies were performed in the presence of radical scavengers and no deleterious effect was observed on the reaction yield. These observations prompted the authors to rule out a plausible SET-initiated radical reaction as previously proposed by Chen[25] and Burton[26] with Pd0 as a catalyst. Thus, Reutrakul and co-workers proposed a classical Heck pathway to explain the reaction outcome (Scheme 12). In 2013, our group reported a copper-catalyzed difluoromethylation reaction of dihydropyrans 31 a–c (Scheme 13).[27] This process was also successfully applied to several types of glycals

Scheme 11. Copper-catalyzed a-trifluoromethylation of a,b-unsaturated carbonyl compounds.

were obtained in good to high yields as a single E isomer. Rudimental mechanistic studies supported a radical pathway to explain the regio- and stereochemical outcome of the reaction. The CF3 radical generated from the reduction of the Togni’s reagent 17 by CuI reacted at the a-position of 26. Then a SET process involving a CuII species released a carbocation II which provided the E-a,b-unsaturated product after proton abstraction.[23] Although the direct introduction of the CF3 group has been widely investigated due to its relevance in pharmaceutical design, the introduction of other functionalized fluorinated moieties has been less explored, despite the possibility of post-functionalization. The introduction of these original fluorinated groups could therefore become a powerful tool toward the design and discovery of new pharmaceuticals or agrochemical substances. To our knowledge, no radical-free direct introduction of functionalized fluorinated building blocks was reported prior to 2012. Transition metal-promoted introduction of CF2R

Scheme 13. Difluoromethylation reaction of enol ethers and glycals.

Reutrakul and co-workers reported in 2012 an elegant Heck reaction using (bromodifluoromethyl)sulfonyl benzene 28 as a fluorinated building block to access to the vinyldifluoromethylated products (Scheme 12).[24] This approach represented the first transition metal-catalyzed introduction of functionalized fluorinated building blocks (CF2R) on non-pre-functionalized substrates. After an extensive investigation, authors found that the reaction proceeded smoothly in the presence of [Pd(PPh3)4] as a catalyst, in combination with K2CO3 as a base in toluene at 100 8C. This catalytic system was applied to a broad range of styrene derivatives 29 a–j in low to moderate Chem. Eur. J. 2014, 20, 1 – 17

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(glucals 31 d–h, galactals 31 i–k, rhamnals 31 l–m, and arabinals 31 o–p). The corresponding difluoromethylated glycals 32 were obtained in good yields with a complete C2 regioselectivity. Later in 2014, the same authors extended this reaction to enamide-type substrates 33 a–m (Scheme 14).[28] Under slightly modified conditions, the difluoromethylation of various N-protected enamides was achieved. The process was functionalgroup tolerant since even an allylic acetate substituent (compound 34 d) was compatible under these reaction conditions. 7


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Minireview Fluorinated Alkynes The selective and direct introduction of fluorine containing moieties constitutes an area of high current interest, owing to the pivotal role of these functional groups in privileged molecules. Among the important fluorinated building blocks, we would like to focus on alkynes, key versatile scaffolds used in the synthesis of several complex molecules. Indeed, despite their high potential, very limited efficient synthetic routes to build up such backbones have, to date, been reported. Notably, in most cases, several synthetic steps or costly functionalized fluorinated precursors are required. Recently, significant synthetic breakthroughs have been reported in the literature, which partially address the aforementioned shortcomings. This section will showcase the recent advances relying on base-promoted and transition-metal mediated transformations. Base-promoted introduction of fluorinated groups on alkynes Transition metal-free system appeared as a straightforward way to introduce fluorinated groups onto molecules especially on terminal alkynes as it has been showcased by the recent reports in this research field. Indeed, by using a stoichiometric or a catalytic amount of base and electrophilic fluorinating reagents, new synthetic routes toward valuable building blocks containing fluorinated motifs have been elaborated. Introduction of CF3 The first example of CF3 introduction to alkynes was disclosed by Umemoto and Ishihara in the early 1990s, during their studies towards the design and synthesis of electrophilic trifluoromethylating reagents (Scheme 15).[29] They showed that different S-(trifluoromethyl)dibenzothiophenium salts 13, 36 b, and related selenium derivative 36 a turned out to be efficient in the trifluoromethylation of lithium phenyl acetylide 37, affording the corresponding trifluoromethylated alkynes 38 in good yields (58–89 %). Although only one example was reported, this pioneering work demonstrated the potential of such basepromoted approaches.

Scheme 14. Copper-catalyzed difluoromethylation of enamides.

Notably, endo and vinylogous enamides 33 e and 33 f were also suitable substrates. This methodology was also extended to the acyclic enamides 33 g–k with good yields. Remarkably, this difluoromethylation reaction was applied to the uridine derivative 33 m thus highlighting the potential late stage introduction of the CF2CO2Et moiety on functionalized substrates. In the course of the development of this process, further mechanistic investigations were performed. As a result, the copper species 35 has been characterized as an intermediate of the reaction thanks to a MS analysis of the reaction media. Moreover, the cyclic voltammetry study of the reaction revealed a reversible coordination of the copper complex to the double bond of the enamides (intermediate I) before the formation of the metalated enamide II. Then an oxidative addition occurred at the C Br bond of BrCF2CO2Et giving intermediate III. Finally, a reductive elimination furnished the desired product 34 (Scheme 14). This catalytic cycle might explain the chemical transformation depicted in Scheme 13.

Introduction of fluorine atom About 20 years later, Ma and co-workers applied a similar strategy to introduce a fluorine atom onto terminal alkynes 39 a–m (Scheme 16).[30] They reported ready access to fluorinated al-

Scheme 15. Pioneering examples of Umemoto and Ishihara.

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Scheme 16. Synthesis of fluorinated alkynes.

kynes 40 a–m by means of the reaction of an acetylide anion with an electrophilic fluorine source, N-fluorobenzenesulfonimide (NFSI). 20 fluorinated aromatic-substituted alkynes and dialkynes were synthesized in 48–90 % yield. Remarkably, this method was tolerant to a number of functional groups including halogens such as Br. Such base-promoted strategy has since been further extended to the introduction of other fluorine containing groups, such as CF2R, SCF3, and SO2R (see below). Introduction of CF2R Due to the importance of the difluoromethyl group (CF2H), significant efforts have been devoted to the development of new transformations and to the design of new difluoromethylated reagents (CF2R source; Scheme 17). A first report by Kitazume showed that the CF2 carbene generated from chlorodifluoromethane reacted smoothly with functionalized lithium acetylides (Scheme 17 a).[31] The following mechanism was proposed: After abstraction of the proton of chlorodifluoromethane with lithium acetylide (or nBuLi), the corresponding chlorodifluoromethyl anion I furnished the difluorocarbene II that might react with lithium acetylide. The resulting difluoromethylated acetylide III released the product 42 and the chlorodifluoromethyl anion I after a proton abstraction of CF2HCl. Recently, Hu and co-workers used difluoromethyltri(n-butyl)ammonium chloride as a versatile and nontoxic difluorocarbene source (Scheme 17 b).[32] The treatment of aryl-substituted alkynes with nBuLi and nBu3N(CF2H)Cl (1.2 equiv) in THF allowed the formation of the desired products. However, only two examples, 42 d and e, were obtained with moderate yields (42 % and 53 %, respectively), which hampered the widespread application of such an approach. Another pathway to prepare difluoromethylated derivatives relied on the use of direct “HCF2 + ”-transferring reagents. In 2009, Hu and co-workers reported the synthesis of a-difluoromethyl sulfoximine 43 and its application as an electrophilic CF2H source in reaction with various nucleophiles, including lithium acetylides (Scheme 18).[33] Indeed, the difluoromethylation of aryl-substituted acetylenes 44 in the presence of 43 and nBuLi proceeded well with good yields (46–87 %). The authors suggested that this electrophilic difluoromethylation might involve the in situ formation of a difluorocarbene, probChem. Eur. J. 2014, 20, 1 – 17

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Scheme 17. Difluoromethylation reaction using difluorocarbene sources.

Scheme 18. Hu’s difluoromethylation of alkynes using sulfoximine 43.

ably resulting from the deprotonation of 43 by lithium acetylides. The subsequent difluorocarbene intermediate underwent the nucleophilic attack of lithium acetylides, generating I. A final protonation step by the sulfoximine 43 or 44 would furnish the desired product 45 and would release the difluorocarbene species. In the same vein, Magnier and co-workers synthesized the dichlorofluoro-, bromodifluoro- and trifluoromethyl alkynes 50 9


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Minireview (Scheme 19). For this purpose, they used electrophilic fluoroalkylating agents based on a sulfoximine skeleton (46, 47 and 48) to afford the corresponding products 50 in poor to moderate yields.[34]

Scheme 19. Application of electrophilic fluoroalkylating reagents. Scheme 21. Electrophilic fluoroalkylation of alkynes.

In addition, two complementary synthetic routes aiming at the introduction of “CF2Br” groups on alkynes have been designed. In 2006, the group of Hammond reported the synthesis of g-substituted difluoropropargyl bromides 52 a–f from terminal alkynes 51 a–f (Scheme 20).[35] The treatment of g-substitut-

Qing and co-workers described a metal-free oxidative trifluoromethylthiolation of terminal alkynes (Scheme 22).[38] Under mild conditions in DMF, alkynyl trifluoromethylated sulfides 58 a–l were obtained in moderate to good yields in the presence of TMSCF3 and S8. The elemental sulfur had a crucial role in achieving high yields. Notably, an excess of TMSCF3 (5 equiv) was required for the efficiency of the transformation. Importantly, the scope of the reaction was not restricted to aryl-substituted alkynes since two aliphatic-substituted substrates 57 k–l were converted albeit in low to moderate yields (21–57 %). To gain some insights into the reaction mechanism, the authors performed additional experiments. As a result, it turned out that a radical pathway might be ruled out for this transformation and authors assumed that the SCF3 anion might be the active species and elemental sulfur the oxidant. Based on these observations, the following mechanism was proposed: 1) Conversion of TMSCF3 into the active trifluoromethylsulfenyl anion species I in the presence of KF, S8, and DMF,

Scheme 20. Synthesis of difluoropropargyl bromides by using CF2Br2.

ed lithium acetylide with CF2Br2 at very low temperature allowed the synthesis of g-alkyl-, g-silyl-, and g-aryl-substituted difluoropropargyl bromides 52 a–f in high yields (up to 92 %). However, it is noteworthy that the use of CF2Br2, an ozone-depleting reagent forbidden by the Montreal protocol,[36] seriously hampered the synthetic utility of this transformation. More recently, Xiao and co-worker reported the synthesis of new electrophilic bromodifluoromethylation and pentafluoroethylation reagents 53 and 54, respectively (Scheme 21).[37] The authors demonstrated that the electrophilic (bromodifluoromethyl)diphenylsulfonium salt 53 could efficiently react with arylsubstituted alkynyl lithium. This method was applied to both aryl- and alkyl-substituted alkynes 55 a–e in moderate yields (45–57 %). Introduction of SCF3 Over the past few years, introduction of the SCF3 moiety on molecules has been of growing interest, mainly due to its intrinsic properties such as its high lipophilicity and strong electron-withdrawing effect. Therefore, several methods for the trifluoromethylthiolation of alkynes have been developed. &

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Scheme 22. Metal-free oxidative trifluoromethylthiolation of terminal alkynes.

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Minireview 2) reaction of the resulting KSCF3 I with the alkyne 57 in the presence of the oxidant (S8) to furnish the desired product 58. The fact that this direct route to alkynyl trifluoromethylated sulfides demonstrated a large functional group tolerance and required the use of readily available reagents showcased the high synthetic potential of this approach. In addition, a complementary approach employing trifluoromethanesulfenamide 60 as a stable and easy-to-handle electrophilic SCF3 source, was reported by Billard and co-workers [Scheme 23, Eq. (1)].[39] When engaged with an organolithium reagent, in situ prepared by deprotonation of terminal alkynes 59 with nBuLi, the corresponding trifluoromethylthioethers 61 were obtained. The reaction proceeded well with alkyl-and aromatic substrates, while alkyl derivatives gave poorer yield due to their volatility. The same authors hypothesized that this process might be performed with a catalytic amount of base to extend the scope of the reaction to base-sensitive substrates [Scheme 23, Eq. (1)].[40] Indeed, during the trifluoromethylthiolation process, lithium amide I was formed. This latter could abstract the proton of the terminal alkynes thus regenerating the lithium acetylide that would react with 60. This very fast transformation (only 1 min) allowed a total conversion of aro-

matic, aliphatic, and silylated alkynes bearing various functional groups in good to high yields using 10–20 mol % of base (LiHMDS or nBuLi). This methodology was further extended to pentafluoroethylthiolation [Scheme 23, Eq. (2)].

Introduction of SO2RF A similar strategy to access to acetylenic triflones and nonaflones was reported by the groups of Hanack and Fuchs, successively (Scheme 24). Initial lithiation of terminal alkynes 65 with nBuLi followed by an addition of Tf2O or Nf2O afforded the functionalized acetylenic triflones and nonaflones 66.[41]

Scheme 24. Synthesis of acetylenic triflones and nonaflones.

Transition metal-mediated introduction of fluorinated groups on alkynes Introduction of CF3 Recently, interest has grown within the scientific community for the direct introduction of fluorinated groups by means of transition metal. Especially, the application of such approach toward the functionalization of terminal alkynes appeared as a complementary alternative to the base-promoted fluorofunctionalization of unsaturated molecules. One strategy to introduce the trifluoromethyl group relied on the use of a photoredox process. In the course of the development of the hydrotrifluoromethylation of alkynes through photoredox catalysis,[42] Cho and co-workers reported the conversion of terminal alkynes 67 into the corresponding fluorinated derivatives 68. In that case, the use of tBuOK as a base in the presence of fac-[Ir(ppy)3] as photocatalyst and CF3I under blue LED irradiation furnished the trifluoromethylated alkynes in 60–68 % yields (Scheme 25).

Scheme 25. Photocatalyzed trifluoromethylation of alkynes.

In 2010, Qing reported a direct copper-mediated oxidative trifluoromethylation of terminal alkynes with TMSCF3.[43] This transformation represented the first example of an oxidative cross-coupling reaction between a nucleophilic trifluoromethylating reagent and a nucleophilic substrate (Scheme 26, conditions A). This copper-promoted reaction constituted the first method toward the C(sp) CF3 bond formation. The reaction turned out to be particularly efficient and tolerant to various

Scheme 23. Stoichiometric and catalytic electrophilic trifluoromethanesulfanylation of alkynes. [a] Yields of isolated product; numbers in parenthesis are crude yields determined by 19F NMR spectroscopy using PhOCF3 as an internal standard. Chem. Eur. J. 2014, 20, 1 – 17

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Scheme 26. Copper-mediated oxidative trifluoromethylation of terminal alkynes.

functional groups furnishing a panel of trifluoromethylated alkynes 70 a–d, h–i in moderate to high yields. The key to success of this process was 1) the in situ pre-generation of a CuCF3 species stabilized by 1,10-phenanthroline and 2) the use of an excess of TMSCF3 to offset the decomposition of CuCF3. Remarkably, the formation of the trifluoromethylated alkynes 70 a–d, h–i was predominant over the formation of the Glaser–Hay homocoupling product. Two years later, to overcome the need for an excess of TMSCF3 and rather harsh conditions (100 8C), Qing and coworkers reported milder conditions to access to these scaffolds (Scheme 26, conditions B).[44] Their improved procedure required the initial formation of [(phen)Cu(CF3)] from CuCl and tBuOK with one equivalent of TMSCF3. Then, the following addition of the terminal alkynes afforded the corresponding products at room temperature with similar yields to those reported in their first communication. Note that this method to prepare trifluoromethylated alkynes was applied by Riera and co-workers in their study toward the synthesis of b-substituted Pauson–Khand adducts.[45] Despite the effectiveness of these both aforementioned methods, a stoichiometric amount of copper was still required to complete the transformation. It is therefore unsurprising that Qing and co-workers proceeded to develop a catalytic process (Scheme 27).[46] For that purpose, special attention was paid to get insights into the reaction mechanism. Two main features were drawn from that study: 1) A potential fast decomposition of the CF3 anion in the reaction mixture, which might be limited by a slow addition of TMSCF3 and 2) the necessity to slowly introduce the alkyne to the preformed active species CuCF3, thus minimizing the Glaser–Hay homocoupling side-reaction. The following mechanism was proposed to explain this transformation: In the presence of a Lewis base (KF) the CuCF3 species was formed from CuCl and TMSCF3. Subsequent reaction with alkyne 71 led to the complex II that was then oxidized into the CuIII intermediate. Finally, a reductive elimination furnished the expected product 72 and regenerated the copper catalyst (Scheme 27).[47] Notably, this catalytic &

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Scheme 27. Copper-catalyzed trifluoromethylation of terminal alkynes.

process was as efficient as the previous stoichiometric processes and, under these conditions, challenging substrates could be easily converted into the desired fluorinated alkynes, such as 71 d. Quite recently, Evano and Blanchard reported a practical procedure to access to this key building block using either the preformed copper acetylide or a one-pot procedure under oxidative conditions.[48] In the course of the development of a practical synthetic method to prepare CuCF3 from a low-cost CF3 source, Mikami and co-workers reported a one-pot CuCF3-formation/trifluoromethylation of alkynes (Scheme 28).[49] CuCF3 was prepared starting from 2,2,2-trifluoroacetophenone and K[Cu(OtBu)2]. With two equivalents of CuCF3 and tetramethylethylenediamine (TMEDA) as a ligand, the oxidative trifluoromethylation of terminal alkynes 73 a–f was achieved under milder conditions to others methods, since the reaction proceeded at RT under

Scheme 28. Mikami’s trifluoromethylation process.

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Minireview 82, as an electrophilic CF3 source (Scheme 29 c).[52] At room temperature, a wide range of terminal alkynes 80 were efficiently converted into the corresponding trifluoromethylated products 81 in high yields (70–98 %). This approach proved to be functional-group tolerant, showcasing the synthetic utility of this method. Once again, the slow addition of the substrate to the reaction mixture was required to limit the formation of diynes resulting from a homocoupling reaction.

air. As previously observed, slow addition of the alkyne derivatives proved to be crucial for high yields (88–95 %). Furthermore, Xiao and co-workers showed that an electrophilic CF3 source, such as the Umemoto salt 76, was also efficient in the copper-mediated trifluoromethylation of terminal alkynes 75 (Scheme 29 a).[50] Note that a catalytic approach

Introduction of CF2P(O)(OR’)2 The direct introduction of a functionalized difluorophosphonate moiety on terminal alkynes 83 was studied by the group of Qing (Scheme 30).[53] Indeed, not only restricted to the CF3 moiety, the copper-mediated oxidative cross-coupling between non-prefunctionalized alkynes and the readily available (R’O)2P(O)CF2SiMe3 allowed the preparation of a,a-difluoropropargylphosphonates 84 in moderate yields. The mode of addition of reagents was critical for the success of the reaction, highlighting that the {(R’O)2P(O)CF2Cu} species might be involved in this process.

Scheme 30. Introduction of difluorophosphonates on alkynes by Qing.

Introduction of SCF3 Recently, Shen and co-workers developed a bench-stable trifluoromethylthiolated hypervalent iodine reagent 86.[54] In the presence of an excess of alkynes 85, the corresponding alkynyl trifluoromethylsulfides 87 were obtained in good yields by a copper-catalyzed process (Scheme 31). Scheme 29. Electrophilic trifluoromethylation of alkynes.

under milder conditions (30 8C) has been already reported in 2012 using 20 mol % of CuCl, Umemoto’s reagent 13 and 2,4,6collidine as a ligand (Scheme 29 b).[51] Aromatic alkynes and aliphatic substrates were isolated in moderate to good yields (26–79 %). The authors proposed the following mechanism: The treatment of CuCl in dimethylacetamide (DMAc) in the presence of 2,4,6-collidine and alkyne 78 led to the copper acetylide I after coordination/deprotonation of the alkyne. Then, two plausible pathways might be involved: 1) an oxidative addition of CF3 + furnished the corresponding CuIII complex II, which underwent a reductive elimination to give the product or alternatively 2) the copper acetylide might be involved in a SN2-type reaction at the CF3 center to provide the expected product (intermediate III). In the last step, the catalyst is regenerated. In a similar way, a copper-catalyzed trifluoromethylation of terminal alkynes was developed using Togni’s reagent Chem. Eur. J. 2014, 20, 1 – 17

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Scheme 31. Shen’s trifluoromethylsulfenylation of alkynes.

Very recently, Qing and co-workers described a convenient method that does not require the use of an excess of TMSCF3 or a pre-prepared electrophilic reagent (Scheme 32). Indeed, when a nucleophilic trifluoromethylation reagent (AgSCF3) was mixed with an oxidant (NCS), an electrophilic trifluoromethylthiolated reagent was generated in situ, allowing the reaction with a C-nucleophile. As a result, aryl-and alkyl-substituted al13


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Scheme 32. Trifluoromethylthiolation of alkynes by Qing.

kynyl trifluoromethyl sulfides 89 were prepared in moderate to excellent yields (61–93 %).[55]

Introduction of perfluoroalkyl groups It is worth mentioning that, in the course of their study on the cupration of C2F5H, Grushin and Lishchynskyi reported a single example of the C2F5 transfer from CuC2F5 onto phenylacetylene under oxidative conditions (Scheme 33).[56]

Scheme 33. Grushin’s perfluoroalkylation of alkynes.

Finally, Ma and co-workers demonstrated the possibility to introduce a 2,2,2-trifluoroethyl group onto non-prefunctionalized alkynes (Scheme 34). In 2012, they described a copper-catalyzed access to 2,2,2-trifluorethyl-substituted alkynes using gaseous 2,2,2-trifluorodiazoethane generated from CF3CH2NH2·HCl.[57] A series of 2,2,2-trifluoroethylated alkynes 92 a–l were synthesized in 80–96 % yields using only 3 equivalents of CF3CH2NH2.HCl. One year later, Xu and co-workers reported an alternative to the previous method employing the easy-to-handle and readily available 1,1,1-trifluoro-2-iodoethane (Scheme 34).[58] The authors proposed the following mechanism: The complex I, prepared from [Pd2(dba)3] (dba = dibenzylideneacetone) and bis-[2-(diphenylphosphino)phenyl]ether (DPEPhos), underwent an oxidative addition with CF3CH2I. Ligand exchange followed by coordination to the alkyne 93 led to the complex III. Deprotonation of the ligated alkyne by 1,4-diazabicyclo[2.2.2]octane (DABCO) afforded a square-planar Pd complex IV that would furnish the desired product 94 after reductive elimination along with the regeneration of the complex I.

Scheme 34. Trifluoroethyl group insertion into alkynes.

new and innovative methodologies, which have given access to versatile fluorinated building blocks. Even though much progress has been achieved within the last five years, this area of research remains in its infancy, since crucial milestones are yet to be reached. Indeed, the development of general, mild, and functional-group-tolerant methodologies still represent a major goal to perform efficient transformations able to be applied in late-stage functionalization of molecules. We do believe that this Minireview will be a real asset to afford further insight in this field and will inspire the organic chemistry community for the development of new, innovative, and efficient methods for the introduction of fluorine atoms and fluorinated building blocks onto alkenes and alkynes.

Summary and Outlook The direct introduction of fluorine atoms and fluorinated building blocks has become a real challenge in organic synthesis, due to the impact of fluorine on the properties of molecules. In this Minireview we reported the recent efforts devoted to the fluoro-functionalization of alkenes and alkynes by radical processes, base-promoted transformations, or transition metal catalysis. These efforts have culminated in the development of &

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Acknowledgements This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029) and Rgion Haute-Normandie (CRUNCh network). 14



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Received: July 23, 2014 Published online on && &&, 0000

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Minireview

MINIREVIEW & Fluorine Chemistry

The direct introduction of fluorine and fluorinated building blocks has recently attracted lot of attention and particularly the direct functionalization of alkenes and alkynes. This Minireview highlights the major progress recently made in this field, with particular focus on modern radical reactions, base-promoted processes and transition metal-catalyzed functionalization of alkenes and alkynes. Special attention will be paid to explanation of the reaction mechanisms.

T. Besset,* T. Poisson,* X. Pannecoucke && – && Recent Progress in Direct Introduction of Fluorinated Groups on Alkenes and Alkynes by means of C H Bond Functionalization

Fluorine Chemistry The direct introduction of fluorine and fluorinated building blocks has recently attracted a lot of attention and particularly the direct functionalization of alkenes and alkynes. The Minireview on page && ff., T. Besset, T. Poisson, and X. Pannecouke highlights the major progress recently made in that field, with a focus on photocatalyzed transformations, base-promoted processes, and transition metal-catalyzed functionalization of alkenes and alkynes and special attention paid to the explaining the mechanisms of such reactions.

Chem. Eur. J. 2014, 20, 1 – 17

www.chemeurj.org


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Trifluoromethylation of alkenes with concomitant introduction of additional functional groups.

Functionalization of fluorinated molecules by transition-metal-mediated C-F bond activation to access fluorinated building blocks.

Synthesis of triazine-based materials by functionalization with alkynes.

Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes.

Neutral CH and cationic CH donor groups as anion receptors.

Photocatalytic arylation of alkenes, alkynes and enones with diazonium salts.

Intramolecular aminocyanation of alkenes by N-CN bond cleavage.

Effect of ionic charge on the CH···π hydrogen bond.

C-H Bond Functionalization by Mechanochemistry.

Syntheses of sulfides and selenides through direct oxidative functionalization of C(sp3)-H bond.

Recent progress in surgery for the victims of disaster, terrorism, and war--Introduction.

The Mechanism of N-O Bond Cleavage in Rhodium-Catalyzed C-H Bond Functionalization of Quinoline N-oxides with Alkynes: A Computational Study.

Rhodium-catalyzed dehydrogenative coupling of phenylheteroarenes with alkynes or alkenes.

Straightforward measurement of individual (1)J(CH) and (2)J(HH) in diastereotopic CH(2) groups.

Cascade multicomponent synthesis of indoles, pyrazoles, and pyridazinones by functionalization of alkenes.

Selective CH functionalization of methane, ethane, and propane by a perfluoroarene iodine(III) complex.

A radical anti-Markovnikov addition of alkyl nitriles to simple alkenes via selective sp(3) C-H bond functionalization.

Recent advances in C(sp(3))-H bond functionalization via metal-carbene insertions.

Ligand-based carbon-nitrogen bond forming reactions of metal dinitrosyl complexes with alkenes and their application to C-H bond functionalization.

Redox-Neutral Dual Functionalization of Electron-Deficient Alkenes.

Access to Six- and Seven-Membered 1,7-Fused Indolines via Rh(III)-Catalyzed Redox-Neutral C7-Selective C-H Functionalization of Indolines with Alkynes and Alkenes.

Functionalization of medical cotton by direct incorporation of silver nanoparticles.

Introduction of ribonucleic acids into cells by means of liposomes.

Metal Catalysis in Thiolation and Selenation Reactions of Alkynes Leading to Chalcogen-Substituted Alkenes and Dienes.