Fluorinated Heterocycles - ACS Publications - American Chemical

Chapter 1

Fluorinated Heterocycles 1

Downloaded by UNIV OF ALABAMA BIRMINGHAM on January 11, 2013 | http://pubs.acs.org Publication Date: January 1, 2009 | doi: 10.1021/bk-2009-1003.ch001

Andrei A. Gakh and Kenneth L. Kirk

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O a k Ridge National Laboratory, Oak Ridge, T N 37831-6242 Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

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This introductory chapter is a quick overview of almost 100 years of fluoroheterocyclic chemistry, with particular attention to modern synthetic methods and applications presented in this book. Critical discussions regarding various synthetic procedures including nucleophilic and electrophilic fluorination, metal-catalyzed heterocyclization, cine- and tele- substitution in N-fluoroheterocycles, fluorodenitration, water-based chemistry, as well as applications of fluorinated heterocycles in medicine and agriculture are presented along with the examples of fluorohetrocyclic compounds of particular interests.

© 2009 American Chemical Society

In Fluorinated Heterocycles; Gakh, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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Historical Perspective The history of ring-fluorinated heterocycles can be traced back to the seminal work of Chichibabin who carried out the synthesis of 2-fluoropyridine (1) over 90 years ago (/). However, real progress in this field did not gain momentum until about four decades later, in the 1950s, with the development of new synthetic methods and more readily handled fluorinating agents. It was in this period that 5-fluorouracil (2) was prepared in a rational approach to new anti-cancer agents (2). The effectiveness of this drug heralded the development of many related anti-cancer agents that still have important clinical applications 50 years after the original discovery (3). Another major success story followed shortly thereafter with the discovery of the fluoroquinolone family of antibiotics in the early 1970s (4). A particularly important member of this group, ciprofloxacine (3), was approved for human use in the U S in late 1980s. There continues to be extensive work being done in the development of new fluoroquinolones (4,5). In addition to these examples, there is an ever-growing inventory of important clinical agents derived from fluorinated heterocyclic compounds. These and other applications will be discussed briefly in this introductory chapter. Ο

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Ν 2-Fluoropyridine 1

5-Fluorouracil 2

Ciprofloxacine 3

The Status of the Field Despite these and other important early breakthroughs, not limited to biomedical applications, the status of development of the field of fluorinated heterocyclic chemistry as a whole can be characterized as "evolving." This is particularly true when this specialized field is compared to the more mature areas of related chemistry, such as the chemistry of fluoroaromatic compounds or the chemistry of non-fluorinated heterocycles. There are many contributing factors for this relatively under-developed status of fluorinated heterocyclic chemistry.


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Synthetic Challenges One factor which clearly amplifies synthetic problems associated with preparation of certain classes of fluorinated heterocycles is the combination of special properties of a heteroatom and special properties of the fluorine atom. The failure of the thermal Schiemann reaction to produce ring-fluorinated imidazoles is one example (6). Many other examples exist. Three major approaches can be highlighted in an attempt to provide a general overview of existing synthetic methodology for the preparation fluorinated heterocycles: (i) synthesis from fluorinated building blocks, (ii) chemical modification of fluorinated heterocycles with the retention of fluorine atom, and (iii) introduction of fluorine (or fluorine-bearing fragments) into an already formed heterocyclic moiety. A l l three methods have their advantages and disadvantages, so modern synthetic methodology is best contemplated with the consideration of all approaches, even though the first method is far more widely used than the last two combined. The ready availability of a wide variety of fluorine-containing building blocks, many on an industrial scale, is one major reason for the popularity of the fluorinated synthon approach to the synthesis of fluorinated heterocycles. The relative ease of carbon-heteroatom bond formation as the key step of the heterocyclization process, and the plurality of excellent, well-developed heterocyclization procedures suitable for fluorinated components also are important factors. It is not a coincidence that this synthetic methodology is being used exclusively or in combination with other approaches in a preponderance of the papers presented in this book (7-/2). Due to inherit predilections of this synthetic method, it is most suitable for the synthesis of fluoroalkyl- and fluoroaryl-substituted heterocycles (including annulated benzazole(azine) fluorinated heterocyces), and, to a lesser degree, ring-fluorinated heterocycles. Among these, fluoroalkyl and fluoroaryl fragments, trifluoromethyl and mono-fluorinated o-, m- and p-fluorophenyl fragments are the most popular ones (availability of appropriate building blocks being an obvious driving factor). Lately, some other fluorinated groups, such as trifluoromethoxy (//) and pentafluorosulphanyl (12) groups, have begun to occupy a permanent place in the pool of available fluorinated sub-fragments. Some examples of heterocyclic compounds prepared via this methodology are presented below (Figure 1) (7-12). One of the notable variants of the above methodology employs carbocyclization instead of heterocyclization. This synthetic approach typically entails transition metal mediated carbon-carbon bond formation (via Diels-Alder reactions or intramolecular methathesis-type transformations). One of the clear advantages of this method is easy access to ring-fluorinated annulated fluoroheterocycles that are difficult to prepare by other means. Examples of fluorinated heterocycles prepared by this method are presented below (Figure 2) (8J3).



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Figure 2, Examples of fluorinated heterocyclic compounds prepared by carbocyclization reactions.



7 Another popular synthetic strategy involves modification of fluorinated heterocycles with at least partial retention of fluorine to produce a new fluorinated heterocyclic compound. (A special case is represented by fluorine migration reactions, notably exemplified by the reactions of N-fluoropyridinium salts with strong bases discussed below.) This widely used approach to fluorinated heterocycles can also be found in almost all previously mentioned chapters of this book (7-/5). Although transformations of fluorinated heterocycles can be achieved by many modem synthetic methods, lithiation and subsequent reactions of lithiated fluoroheterocycles deserves special attention since the reaction is both facilitated and directed by the presence of the strongly electron-withdrawing fluorine atom (14). Finally, introduction of fluorine (or fluorine-bearing fragments) into an already formed heterocyclic moiety is a third widely used synthetic method. Two complimentary approaches are used routinely to accomplish this transformation - electrophilic replacement of a hydrogen atom with "electrophilic" fluorine (including an addition-elimination pathway similar to the one used for the synthesis of 5-fluorouracil 2), and nucleophilic replacement of a good leaving group using a source of fluoride anion. (Installation of the trifluoromethyl group also can be carried out by either electrophilic or neucleophilic procedures.) A less common synthetic methodology entails substitution of a hydrogen atom via transient formation and subsequent rearrangement of halogen-heteroatom compounds (such as //-fluorinated heterocycles), but these examples are rare. The presence of heteroatoms amplifies problems associated with direct fluorination, and has hindered widespread use of this approach for the preparation of C-fluorinated heterocycles. With respect to electrophilic substitution, there is generally reduced reactivity of heterocycles compared to carbocycles due to the electron-withdrawing properties of two ubiquitous heteroatoms (N and/or O). Combined with low regioselectivity of elemental fluorine, a commonly used electrophilic fluorinating agent in earlier studies, these factors often resulted in poor regioselectivity in the C-fluorination process. In the preponderance of cases a mixture of fluorinated isomers is produced accompanied by unreacted non-fluorinated substrate. Separation and purification is difficult because of the small differences in physical properties (boiling points) of fluorinated heterocycles and their non-fluorinated hydrogen-bearing analogues. The situation improved somewhat with the advent of modem electrophilic fluorinating agents including commercially available JV-fluorinated reagents such as N*-F D A B C O derivatives and N - F sulfonimides, as well as industrially important fluoroxysulfate salts M "OS0 OF and more exotic ones such as fluorinated fullerenes C F 8 (15), fluorine nitrate F O N 0 (16), or even noble gas reagents such as F X e O S 0 C F (17). However, an adequate resolution of problems associated with electrophilic fluorination of heterocycles has not been realized. So far the best results have been achieved in cases where a +

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8 heterocycle (for example - N-methylpyrazole) possesses only one strongly preferred reactive site in the specific reaction conditions (18). In the case of nucleophilic substitution, regioselectivity is usually not an issue because this is usually determined by the position of a leaving group (notwithstanding rare cases of cine/tele substitution), but other challenges exist. For example, desolvation of fluoride and/or inhibition of coordination are required to expose the latent nucleophilicity of fluoride, but "naked" fluoride is a relatively strong base. This can be particularly problematic with base-sensitive heterocycles or with heterocycles bearing, for example, an acidic N - H functionality. In addition, in comparison to other common nucleophiles, even under such conditions fluoride is not impressively nucleophilic. A variety of new sources of fluoride anion and reaction conditions designed to address these issues have been developed (including systems containing weakly coordinated fluoride ion such as anhydrous tetrabutylammonium fluoride (19) in aprotic solvents), but it did not solve all the problems completely. For example, a supposedly textbook reaction between 2-chloropyridine and K F proceeds only in harsh conditions (200 °C, dimethylsulfone, 21 days) with only moderate yield (ca. 50%) of expected 2-fluoropyridine (20). A variety of additional workaround approaches have been employed to improve kinetic characteristics of these reactions by using less-common leaving groups, such as a nitro group "fluorodenitration" (21,22), and other groups (23). A very promising approach entails the use of positively charged leaving groups, such as trimethylammonium and dimethylsulfonium. These leaving groups allow syntheses of fluorinated heterocycles by nucleophilic displacement using hydrated fluoride ion and fluorination reactions can be performed even in water-based mixed solvents. Nucleophilic fluorination in water can be considered as the Holy Grail of not only the chemistry of fluoroheterocyclic compounds, but also general organic fluorine chemistry as well (see also the discussion on "Nucleophilic Fluorination in Water" below). Perhaps the only class of fluoroheteroycles where direct fluorination appears to be a relatively reliable process providing adequate regioselectivity in the preponderance of cases is the unique class of N-fluoroheterocycles (24). Some examples of fluoroheterocycles prepared by electrophilic and nucleophilic fluorination are presented below (Figure 3) (18,19,21,23,24,25). It appears that these and other problems associated with fluorination of heterocyclic systems can be cited as reasons for the presence of gaps in the family of fluoroheterocycles. For example, while almost all possible isomers of fluoropyridines are known and many of them are available from commercial sources, a search of available literature revealed no simple, reliable synthetic procedures for the synthesis of such simple fluoroheterocycles as 5fluorotetrazole and 3-fluorothiophene, even though both compounds are registered in the C A S database, and synthetic procedures for preparation of the isomeric 2-fluorothiophene and derivatives of 5-fluorotetrazole are known. The



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Fluorinated Heterocycles - ACS Publications - American Chemical

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