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INTRODUCTION

Although organofluorine compounds are very scarce in the biosphere, fluorine has become the kingpin of drug discovery ( 1). To date, 20-25 percent of drugs contain

at least one fluorine atom. Due to its steric resemblance to hydrogen and extreme electronegativity (a small atom with a big ego), fluorine has been extensively employed to modulate the biological properties of drug molecules, such as acidity, basicity, protein binding affinity, and lipophilicity (Figure 1). The introduction of fluorine can enhance the metabolic stability (bioavailability) of organic molecules due to the unfavourable energetic cost of breaking a C-F bond to form a C-O bond. Owing to the large dipole moment of the C-F bond, fluorine substitution can also lead to substantial conformational changes through various stereoelectronic interactions, therefore altering the bioactivity of organic molecules (2). Moreover, the applications of 19F nuclear magnetic resonance imaging (MRI) and 18F radiolabeling (for Positron Emission Tomography, PET) have become the most promising strategies in in vivo and ex vivo biological studies.Historically, attempts to utilize fluorinated compounds in clinical medicine date back to the 1940s, when Robbins evaluated fluorohalocarbons as nonflammable anesthetics (1b).

The benefi t of introducing fl uorine into pharmaceuticals has been widely recognized. This thus leads to an urgent demand of capable protocols that enable fl uorination and fl uoroalkylations with high effi cacy and selectivity. Although challenges remain, signifi cant progress has been made over the past three decades, thereby allowing effi cient incorporation of fl uorine into complex organic molecules. Covering a brief history of fl uorine chemistry and its association with pharmaceutical chemistry, this article reviews what the authors consider the state of the art in the fi eld of synthetic organofl uorine chemistry.

ABSTRACT

Organofl uorine chemistry; fl uorinated pharmaceuticals; fl uorination; trifl uoromethylation; difl uoromethylation; monofl uoromethylation.

KEYWORDS

G.K. SURYA PRAKASH*, FANG WANG*Corresponding authorUniversity of Southern California, Loker Hydrocarbon Research Institute, 837 Bloom Walk, Los Angeles, CA 90089, USA

Fluorine: the new kingpin of drug discovery

Surya Prakash

Figure 1. A. Properties involving fl uorine, trifl uoromethyl group and others; B. selected fl uorine stereoelectronic effects; C. fl uorine effects on acidity and basicity;D. fl uorine effects on lipophilicity.

In 1957, the advent of potent tumour-inhibiting 5-fluorouracil marked the new era of intertwining organofluorine and medicinal chemistry (3). Afterwards, particularly during the past three decades, the fluorine substitution strategy expanded exponentially in drug design and discovery (Blue bars, Figure 2A), as reflected by the diversity of fluorinated drugs (Figure 2B and 2C). Without doubt, the boom in fluorinated pharmaceuticals is closely associated with the advances of synthetic organofluorine chemistry (Red bars, Figure 2A). In fact, the majority of fundamental fluorinated motifs employed in the pharmaceutical arena had been obtained prior to the 1960s (Figure 2D) (4). The first fluorinated organic compound, methyl fluoride, was prepared by Dumas and Peligot in 1835 through the treatment of methyl sulfate with potassium fluoride (KF). Aryl fluorides were originally obtained by Schmitt et al. in 1870 through dediazonative fluorination. The method was later improved by Balz and Schiemann, and is now known as the Balz-Schiemann reaction. Pioneered by Swarts, the preparation of trifluorotoluene was achieved a century ago via halogen exchange of benzotrichloride with hydrogen fluoride and antimony trifluoride.

Figure 2. A. Publications relevant to organofl uorine chemistry and fl uorine-containing drugs (based on a SciFinder search in April 2012); B. fl uorinated drugs among 10 best-selling drugs in 2011; C. selected fl uorine-containing drugs and drug candidates; D. milestones in synthetic organofl uorine chemistry prior to 1960s.

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with satisfactory chemo-, regio-, and/or stereoselectivity. To fulfil such demands, many remarkable achievements have been made in recent years. Herein, we would like to briefly review the state of the art in the field of synthetic organofluorine chemistry.

Notably, although many of these conventional protocols are still extensively employed, their synthetic utility is largely limited to rather simple molecules because of the harsh reaction conditions. Therefore, amenable methods and reagents are ardently sought for the construction of complex molecules

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Figure 4. Various trifluoromethylating reagents and CAr-CF3 bond forming reactions. A. Nucleophilic trifluoromethylating reagents; B. electrophilic trifluoromethylating reagents; C. radical trifluoromethylating reagents; D. selected C-CF3 bond forming reactions.

Figure 3. C-F bond forming reactions. A. Direct nucleophilic fluorination; B. deoxofluorination (nucleophilic); C. electrophilic fluorination.

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However, for the sake of brevity, stereoselective fluorination and fluoroalkylations are not included in the manuscript and can be referred to elegant reviews in Ref. 13.

FLUORINATING AGENTS AND C-F BOND FORMING REACTIONS

Undoubtedly, C-F bond formation is the fundamental theme in organofluorine chemistry. Compared with other carbon-halogen bond forming reactions, C-F bond formation is hampered by the notorious nature of fluorine, such as the exceedingly high reactivity of fluorine gas (F2), the low nucleophilicity of fluoride, and the relatively lower availability of “F+” sources, among others. To overcome these challenges, a series of reagents has been developed for various synthetic targets. As depicted in Figure 3A, hydrogen fluoride (HF), inorganic fluoride salts, and pyridine-(HF)n complex (Olah’s reagent) are amongst the most common fluorinating agents. To enhance the nucleophilicity of fluoride, weakly coordinating quaternary ammonium cations have been introduced as counterions into nucleophilic fluorinating agents. By means of nucleophilic fluorination, a wide spectrum of fluorinated compounds can be prepared, including alkenyl fluorides, allylic fluorides, benzylic fluorides, alkyl fluorides, fluorohydrins, and many important 18F-radiotracers for PET (5). Among these transformations, the recent achievement by Buchwald and co-workers is noteworthy, they demonstrated the first palladium(0)-catalyzed cross-coupling reaction between aryl triflates and CsF. An alternative C-F bond forming strategy is deoxofluorination (Figure 3B). This is primarily facilitated by sulfur tetrafluoride and its derivatives, such as N,N-diethylaminosulfur trifluoride (DAST), FluoleadTM, and XtalFluor-M®. This method allows formation of C-F bonds from various oxygenated substrates (such as aliphatic alcohols, carbonyl compounds, carboxylic acid derivatives) via an SN2-like mechanism (6). Apart from these conventional protocols, Ritter and co-workers have recently shown that phenols can also participate in deoxofluorination in the presence of an imidazole-based reagent (7). Even though free “F+” species remains unknown in the condensed phase, several versatile reagents have been exploited in formal electrophilic fluorination reactions, such as construction of stereogenic fluorinated carbon centres, fluorination of potassium vinyltrifluoroborates, desilylative fluorination reactions, and fluorination of aryl Grignard reagents

(Figure 3C) (8). Metal-mediated/catalyzed electrophilic aromatic fluorination has also received increasing attention (9). Sanford et al. demonstrated the first palladium-catalyzed electrophilic aromatic fluorination by means of C-H bond activation (10). Ritter’s group reported that aryl-fluorine bonds could be formed by treating aryl stannanes or boronic acids with “F+” reagents in the presence of stoichiometric or catalytic amounts of silver triflate (11, 12). More recently, the same research group

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established a remarkable aromatic fluorination protocol utilizing Pd(IV) (18F)fluoride generated from the corresponding Pd(IV) complex and K18F (5). It should also be mentioned that a metal-free oxidative fluorination of phenols was also reported by Gouverneur and co-workers recently (13).

FLUOROMETHYLATING REAGENTS AND CFX-C BOND FORMING REACTIONS

In principle, fluoroalkylated organic compounds can be prepared via both fluorination and fluoroalkylations. However, the latter can be superior in efficacy and functional group compatibility under many conditions, particularly when fluoroalkyl groups contain multiple fluorine atoms. Amongst various fluoroalkyl functionalities, the trifluoromethyl group is of special interest due to its frequent appearance in medicinal chemistry. Owing to the inherent instability of the trifluoromethyl carbanion, nucleophilic trifluoromethylation usually necessitates unique reagents (Figure 4A). For example, nucleophilic trifluoromethylation of carbonyl compounds primarily relies on the utilization of trifluoromethyltrimethylsilane (TMSCF3, the Ruppert-Prakash reagent) (14). On the other hand, electrophilic trifluoromethylation was underdeveloped for decades due to the dearth of electrophilic trifluoromethylating reagents. Over the past twenty years, significant progress has been made in this field, which has led to many amenable reagents , such as trifluoromethyl chalcogenium salts (15), hypervalent iodine-based trifluoromethylating compounds (Togni’s reagents) (16), and trifluoromethylated Johnson-type reagents (Figure 4B) (17). Facilitated by these reagents, many trifluoromethylated organic compounds otherwise difficult to achieve can thus be prepared. Moreover, radical trifluoromethylation protocols based on sodium trifluoromethanesulfinate-tBuOOH and trifluoromethanesulfonyl chloride-photocatalyst systems have also been employed (Figure 4C) (18). Recently, many chemists have realized the bonanza in the field of synthetic organofluorine chemistry, leading to a burst of transition metal-catalyzed/mediated trifluoromethylation methodologies (Figure 4D) (9, 19, 20). Cu-catalyzed aromatic trifluoromethylation was pioneered by Chen and co-wokers in1989 (21).

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Such chemistry was revisited by Amii et al., who exploited the viable CuI-phen-TESCF3 system to achieve various trifluoromethylated arenes (22). Similar trifluoromethylation of aryl chlorides was later achieved by Buchwald’s group through Pd(0)-Pd(II) catalysis (23a). By means of C-H activation, Yu et al. also accomplished a Pd(II)-

catalyzed ortho-trifluoromethylation of arenes utilizing Umemoto’s reagent (23b). Similar to Langlois et al. who employed fluoroform (CF3H) in DMF as a CF3 source (24), Grushin et al. prepared CF3Cu in DMF solution from CF3H, which readily reacted with various aryl halides (25a) and aryl boroinc acids (25b). In addition, the oxidative trifluoromethylation of aryl boronic acids was recently demonstrated by Qing et al. Based on Langlois’ protocol (26), MacMillan’s group (18a) and Baran’s group

Figure 7. Recent Developments in Difluoromethylation and Monofluoromethylation. A. Fluorinated Johnson-type reagents; B. various sulfur-CF2X difluoromethylating reagents; C. sulfur-CFXY based monofluoromethylating reagents; D. selected difluoromethylation reactions.

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Figure 5. Various C-CF3 bond forming reactions.

Figure 6. Incorporation of CF3-X Motifs Into Organic Molecules. A. Trifluoromethoxylation; B. trifluoromethanethiolation; C. incorporation of terminal CF3-alkyl and alkenyl groups.

(18b) have independently reported methods for the radical trifluoromethylation of arenes, affording various positional isomers. According to MacMillan and co-workers, the divergent regioselectivity of the present radical trifluoromethylation can be beneficial for the development of new medicinal agents (18a). Apart from these aromatic trifluoromethylation reactions, various other CF3-C bond forming reactions have also been achieved by means of transition metal catalysis/mediation. Based on their previous methodology, Qing et al. attained catalytic trifluoromethylation of terminal alkynes through an oxidative cross coupling reaction (27). Demonstrated by Buchwald (28) and Hu (29), respectively, both potassium vinyltrifluoroborates and α,β-unsaturated carboxylic acids could undergo trifluoromethylation to afford the corresponding trifluoromethyl vinyl compounds. Significantly improved from the original protocol by McLoughlin, Cu-mediated/catalyzed Csp3-CF3 bond constructions were also achieved by Vicic (30), Shibata (31), and more recently by Sodeoka (32) and Gouverneur (33),using different trifluoromethylating reagents. In particular, Buchwald and co-workers have revealed a Cu-catalyzed allylic trifluoromethylation of terminal olefins using Togni’s reagent (34).

OTHER IMPORTANT REAGENTS AND PROTOCOLS

In addition to the above mentioned trifluoromethylation reactions, there has been an increasing interest in furnishing pharmaceuticals with diverse fluorinated motifs, such as the trifluoromethoxy group, the trifluoromethanesulfanyl group, and the α,α,α-trifluoroethyl group, to name a few. Although conventional methods (such as deoxofluorination of phenyl fluoroformate) allow the preparation of structurally simple trifluoromethyl ethers and sulfides, these approaches are considerably limited by their harsh reaction conditions, operational difficulties, and the employment of highly toxic reagents. A handful of novel methods and reagents have thus been developed for the direct introduction of hetero-CF3 groups (Figure 6A and 6B) (35). Moreover, due to the vast potential of terminal trifluoromethylated alkyl and alkenyl-containing compounds in medicinal chemistry, much synthetic effort has been directed toward the relevant chemistry (Figure 6C). Carreira et al. have achieved a rather practical protocol for the in situ generation of trifluoromethyl diazomethane, which can be exploited as a “CF3CH” equivalent in many reactions (36). Hu group has reported a Pd-catalyzed 2,2,2-trifluoromethylation of organoboronic acids and esters using CF3CH2I as the CF3CH2 source (37). Furthermore, Prakash and co-workers also showed the synthesis of β-trifluoromethylstyrenes via a domino Heck coupling reaction (38). Despite the dynamic research in trifluoromethyl-related chemistry, analogous difluoromethylation and monofluoromethylation chemistry has received less attention. Primarily promoted by Prakash, Hu, and Shibata, a series of robust reagents, advanced by various S-CFn bond moieties, has been achieved in the past decade. In addition to the delicate modulation of the fluoromethyl reactivity, the sulfur-containing activating groups can also undergo facile removal upon the completion of fluoroalkylations, thus allowing the preparation of CF2H and CFH2-containing compounds (Figure 7A-7C) (39). Recently demonstrated by Prakash and Hu, difluoromethyl 2-pyridyl sulfone was utilized as a nucleophilic difluoro(sulfonato)methylating agent (Figure 7D) (40). Intriguingly, Prakash and Hu have demonstrated that TMSCF3 can also serve as a versatile difluorocarbene equivalent in [2+1] cycloaddition reactions of alkenes and alkynes (Figure 7D) (41). Furthermore, utilizations of TMSCF2H as a viable agent in nucleophilic and aromatic difluoromethylation reactions have also been shown recently by Hu (42) and Hartwig (43).

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CONCLUSION

The introduction of fluorine into organic molecules is not a new business. The major concern of contemporary synthetic fluorine chemistry is efficacy, selectivity, functional group compatibility, among others. Over the past three decades, organofluorine chemistry has been notably advanced by many amenable protocols and reagents, thereby enabling the efficient incorporation of fluorine and fluorinated motifs are enabled under rather mild reaction conditions. A spectrum of fluorinated molecules is thus available for small molecule-based drug discovery. The development of potent medicines and potential drug candidates containing fluorine has ranked fluorine as a kingpin of drug discovery, which inadvertently becomes a driving force for synthetic organofluorine chemistry. As we have seen, there is already a synergism in the interface of fluorine and pharmaceutical chemistry. We believe such vibrant integration will usher a flourishing future for both fields.

ACKNOWLEDGMENT

Support of our work by the Loker Hydrocarbon Research Institute is gratefully acknowledged. Respectfully, dedicated to Professor George A. Olah, a doyen of fluorine chemistry, on the occasion of his eighty fifth birthday.

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Readers interested in a complete list of references are kindly invited to write to the author at gprakash@usc.edu

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