Fluorine: the New Kingpin of Drug Discovery

FINE CHEMICALS Peer reviewed article

Surya Prakash Fluorine: the new kingpin of drug discovery

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

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

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 30 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.

INTRODUCTION

lthough 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 A 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 Figure 1. A. Properties involving fl uorine, trifl uoromethyl strategies in in vivo and ex vivo biological studies. group and others; B. selected fl uorine stereoelectronic Historically, attempts to utilize fluorinated compounds in clinical effects; C. fl uorine effects on acidity and basicity; medicine date back to the 1940s, when Robbins evaluated D. fl uorine effects on lipophilicity. fluorohalocarbons as nonflammable anesthetics (1b).

chimica oggi/Chemistry Today - vol. 30 n. 5 September/October 2012 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.

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. FINE CHEMICALS

Notably, although many of these conventional protocols are with satisfactory chemo-, regio-, and/or stereoselectivity. still extensively employed, their synthetic utility is largely limited To fulfil such demands, many remarkable achievements to rather simple molecules because of the harsh reaction have been made in recent years. Herein, we would like to conditions. Therefore, amenable methods and reagents are briefly review the state of the art in the field of synthetic ardently sought for the construction of complex molecules organofluorine chemistry.

Figure 4. Various trifluoromethylating reagents and CAr-CF3 bond forming reactions. A. Nucleophilic trifluoromethylating reagents; B. electrophilic Figure 3. C-F bond forming reactions. A. Direct nucleophilic trifluoromethylating reagents; C. radical fluorination; B. deoxofluorination (nucleophilic); C. trifluoromethylating reagents; D. selected C-CF3 bond electrophilic fluorination. forming reactions.

chimica oggi/Chemistry Today - vol. 30 n. 5 September/October 2012 FINE CHEMICALS

However, for the sake of brevity, stereoselective fluorination and established a remarkable aromatic fluorination protocol utilizing fluoroalkylations are not included in the manuscript and can be Pd(IV) (18F)fluoride generated from the corresponding Pd(IV) referred to elegant reviews in Ref. 13. complex and K18F (5). It should also be mentioned that a metal-free oxidative fluorination of phenols was also reported by Gouverneur and FLUORINATING AGENTS AND C-F BOND FORMING co-workers recently (13). REACTIONS

Undoubtedly, C-F bond formation is the fundamental theme in FLUOROMETHYLATING REAGENTS AND CFX-C BOND organofluorine chemistry. Compared with other carbon-halogen FORMING REACTIONS bond forming reactions, C-F bond formation is hampered by the notorious nature of fluorine, such as the exceedingly In principle, fluoroalkylated organic compounds can be high reactivity of fluorine gas (F2), the low nucleophilicity of prepared via both fluorination and fluoroalkylations. However, fluoride, and the relatively lower availability+ of“F ” sources, the latter can be superior in efficacy and functional group among others. To overcome these challenges, a series of compatibility under many conditions, particularly when reagents has been developed for various synthetic targets. fluoroalkyl groups contain multiple fluorine atoms. Amongst As depicted in Figure 3A, hydrogen fluoride (HF), inorganic various fluoroalkyl functionalities, the trifluoromethyl group is of fluoride salts, and pyridine-(HF)n complex (Olah’s reagent) are special interest due to its frequent appearance in medicinal amongst the most common fluorinating agents. To enhance chemistry. the nucleophilicity of fluoride, weakly coordinating quaternary Owing to the inherent instability of the trifluoromethyl ammonium cations have been introduced as counterions carbanion, nucleophilic trifluoromethylation usually necessitates into nucleophilic fluorinating agents. By means of nucleophilic unique reagents (Figure 4A). For example, nucleophilic fluorination, a wide spectrum of fluorinated compounds can be trifluoromethylation of carbonyl compounds primarily relies prepared, including alkenyl fluorides, allylic fluorides, benzylic on the utilization of trifluoromethyltrimethylsilane (TMSCF3, the fluorides, alkyl fluorides, fluorohydrins, and many important Ruppert-Prakash reagent) (14). 18F-radiotracers for PET (5). Among these transformations, the On the other hand, electrophilic trifluoromethylation was recent achievement by Buchwald and co-workers is noteworthy, underdeveloped for decades due to the dearth of electrophilic they demonstrated the first palladium(0)-catalyzed cross- trifluoromethylating reagents. Over the past twenty years, coupling reaction between aryl triflates and CsF. An alternative significant progress has been made in this field, which has led to C-F bond forming strategy is deoxofluorination (Figure 3B). This many amenable reagents , such as trifluoromethyl chalcogenium is primarily facilitated by sulfur tetrafluoride and its derivatives, salts (15), hypervalent iodine-based trifluoromethylating such as N,N-diethylaminosulfur trifluoride (DAST), FluoleadTM, compounds (Togni’s reagents) (16), and trifluoromethylated and XtalFluor-M®. This method allows formation of C-F bonds Johnson-type reagents (Figure 4B) (17). Facilitated by these from various oxygenated substrates (such as aliphatic alcohols, reagents, many trifluoromethylated organic compounds carbonyl compounds, carboxylic acid derivatives) via an SN2- otherwise difficult to achieve can thus be prepared. Moreover, 33 like mechanism (6). Apart from these conventional protocols, radical trifluoromethylation protocols based on sodium Ritter and co-workers have recently shown that phenols can trifluoromethanesulfinate-tBuOOH and trifluoromethanesulfonyl also participate in deoxofluorination in the presence of an chloride-photocatalyst systems have also been employed imidazole-based reagent (7). Even though free “F+” species (Figure 4C) (18). Recently, many chemists have realized the remains unknown in the condensed phase, several versatile bonanza in the field of synthetic organofluorine chemistry, reagents have been exploited in formal electrophilic fluorination leading to a burst of transition metal-catalyzed/mediated reactions, such as construction of stereogenic fluorinated trifluoromethylation methodologies (Figure 4D) (9, 19, 20). carbon centres, fluorination of potassium vinyltrifluoroborates, Cu-catalyzed aromatic trifluoromethylation was pioneered by desilylative fluorination reactions, and fluorination of Chen and co-wokers in1989 (21). 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 FINE CHEMICALS

Such chemistry was revisited by Amii et al., who exploited catalyzed ortho-trifluoromethylation of arenes utilizing

the viable CuI-phen-TESCF3 system to achieve various Umemoto’s reagent (23b). Similar to Langlois et al. who trifluoromethylated arenes (22). Similar trifluoromethylation employed fluoroform (CF3H) in DMF as a CF3 source of aryl chlorides was later achieved by Buchwald’s (24), Grushin et al. prepared CF3Cu in DMF solution from group through Pd(0)-Pd(II) catalysis (23a). By means of CF3H, which readily reacted with various aryl halides C-H activation, Yu et al. also accomplished a Pd(II)- (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 5. Various C-CF3 bond forming reactions. 34

Figure 7. Recent Developments in Difluoromethylation and Monofluoromethylation. A. Fluorinated Johnson- Figure 6. Incorporation of CF3-X Motifs Into Organic Molecules. type reagents; B. various sulfur-CF2X difluoromethylating A. Trifluoromethoxylation; B. trifluoromethanethiolation; C. reagents; C. sulfur-CFXY based monofluoromethylating incorporation of terminal CF3-alkyl and alkenyl groups. reagents; D. selected difluoromethylation reactions.

chimica oggi/Chemistry Today - vol. 30 n. 5 September/October 2012 (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). FINE CHEMICALS

CONCLUSION 2. a) D. O’Hagan, Chem. Soc. Rev., 37, pp. 308-319 (2008); b) L. Hunter, Beilstein J. Org. Chem., 6, No. 38 (2010), doi:10.3762/bjoc.6.38. 3. R. Duschinsky, E. Pleven et al., J. Am. Chem. Soc., 79, pp. 4559-4559 The introduction of fluorine into organic molecules is not a (1957). new business. The major concern of contemporary synthetic 4. T. Okazoe, Proc. Jpn. Acad., Ser. B, 85, pp. 276-289 (2009). fluorine chemistry is efficacy, selectivity, functional group 5. For a review paper on recent developments of fluorination reactions, compatibility, among others. Over the past three decades, see: C. Hollingworth, V. Gouerneur, Chem. Commun., 48, pp. 2929- organofluorine chemistry has been notably advanced by 2942 (2012). many amenable protocols and reagents, thereby enabling 6. P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, the efficient incorporation of fluorine and fluorinated motifs Applications, Wiley-VCH: Weinheim, pp. 57-72 (2004). are enabled under rather mild reaction conditions. 7. P. Tang, W. Wang et al., J. Am. Chem. Soc., 133, pp. 11482-11484 A spectrum of fluorinated molecules is thus available for (2011). small molecule-based drug discovery. The development of 8. a) P.T. Nyffeler, S.G. Durón et al., Angew. Chem. Int. Ed., 44, pp. 192- 212 (2005); b) D. Cahard, X. Xu et al., Chem. Soc. Rev., 39, pp. 558-568 potent medicines and potential drug candidates containing (2010). fluorine has ranked fluorine as a kingpin of drug discovery, 9. For a recent review paper regarding metal-mediated/catalyzed which inadvertently becomes a driving force for synthetic electrophilic fluorination, see: T Furuya, A.S. Kamlet et al.,Nature , 473, organofluorine chemistry. As we have seen, there is already pp. 470-477 (2011). a synergism in the interface of fluorine and pharmaceutical 10. K.L. Hull, W.Q. Anani et al., J. Am. Chem. Soc., 128, pp. 7134-7135 chemistry. We believe such vibrant integration will usher a (2006). flourishing future for both fields. 11. a) T. Furuya, A.E. Strom et al., J. Am. Chem. Soc., 131, pp. 1662-1663 (2009); b) T. Furuya, T. Ritter, Org. Lett., 11, pp. 2860-2863 (2009); c) P. Tang, T. Furuya et al., J. Am. Chem. Soc., 132, pp. 12150-12154 (2010). ACKNOWLEDGMENT 12. Pioneering work on electrophilic fluorination of vinyl stannanes D.P. Matthews, S.C. Miller et al., Tetrahedron Lett., 34, pp. 3057-3060 (1993); b) pioneering work on electrophilic fluorination of alkenyl boronic Support of our work by the Loker Hydrocarbon Research acids and trifluoroborates, N.A. Petasis, A.K. Yudin et al., Synlett, pp. Institute is gratefully acknowledged. Respectfully, dedicated 606-608 (1997). to Professor George A. 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