Fluorination

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Fluorination of Aryl-Alkenyl-Iodonium Salts for Preparing Alkenyl Fluorides

  • Wenchao QuEmail author
  • Ximin Li
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-1855-8_13-1

Brief Introduction

Alkenyl fluorides are important building blocks for constructing fluoroalkene moiety containing complex organic molecules, which may possess interesting biological activities and thus are particularly attractive to the pharmaceutical and agrochemical industries [1, 2, 3]. In addition, they can be used as monomers for polymerization and copolymerization to form fluoropolymers with certain special properties [4, 5, 6]. Numerous synthetic approaches have been developed to obtain selectively functionalized alkenyl fluorides which can be classified into five major categories based upon the organic reactions: (1) Horner-Wadsworth-Emmons, Horner-Wittig, Julia, Peterson, and Reformatsky-type olefination reactions, (2) hydrofluorination of alkynes, (3) electronic fluorination of alkenyl metals, (4) reductive elimination reaction of multi-halo compounds, and (5) various metal catalyzed cross-coupling reactions using fluoroalkenyl moiety containing synthons, etc. These synthetic methods have been summarized in several reviews and book chapters from different perspectives [1, 2, 3, 7, 8, 9, 10, 11, 12].

In recent years, the development of hypervalent iodonium salts has played an important role in organofluorination and radiofluorination, especially in the development of new radiopharmaceutical and molecular imaging agents [13, 14, 15]. The synthetic methods for multifunctionalized alkenyl fluorides using aryl-alkenyl-iodonium salts as intermediates have been established over the last two decades. A summary of these synthetic methods, which offer several advantages, including mild reaction conditions, good reaction yields, access to a variety of functional groups, as well as high stereoselectivity, is given in the following paragraphs.

Synthesis of Multifunctionalized Fluoroalkenes Via Aryl-Alkenyl-Iodonium Salt Intermediates

The synthesis of fluoroalkenes via fluorination of aryl-alkenyl-iodonium salts was first published by Ochiai et al. in 1994. In their report, (Z)-1-iodo-2-fluoro-1-decene was synthesized by the reaction of (Z)-(β-iodovinyl)phenyliodonium iodide with n-Bu4I (Fig. 1) [16].
Fig 1

Synthesis of (Z)-1-iodo-2-fluoro-1-alkenes reported by Ochiai group

Four years later, Hara and Yoneda et al. reported the synthesis of E-isomers of 1-iodo-2-fluoro-1-alkenes through an (E)-(2-fluoroalk-1-enyl)-(4-methylphenyl)iodonium fluoride intermediate, which was synthesized by reacting a terminal alkyne with p-iodotoluene difluoride in Et3N-5HF (Fig. 2) [17]. The advantage of this method is that various functional groups, such as ketone, ester, protected aldehyde, chloride, and even hydroxy groups, are compatible with it.
Fig. 2

Synthesis of (E)-1-iodo-2-fluoro-1-alkenes reported by Hara and Yoneda et al.

Follow-up reports by the same research group between 1999 and 2001 demonstrated the versatility of these iodonium fluoride salts in other organic reactions, such as palladium-catalyzed carbonylation [18], Heck-type reaction [19], Stille-type reaction [20], and Sonogashira-type reaction after being converted to (E)-1-iodo-2-fluoro-1-alkenes [21]. Those palladium-catalyzed cross-coupling methods provided various α,β-unsaturated compounds with high stereoselectivity and good yields under mild reaction conditions (Fig. 3).
Fig. 3

Synthesis of α,β-unsaturated compounds using (E)-(2-fluoroalk-1-enyl)-(4-methylphenyl)iodonium fluorides

In order to make an easier access to these important organic synthons, Hara’s group further improved the synthetic methods to obtain both (Z)- and (E)-2-fluoro-alkenyliodonium salts in 2003 and 2004, respectively. Both approaches featured milder reaction conditions, higher reaction yields, and high stereoselectivity (Fig. 4) [22, 23]. For (Z-) isomers, the use of 20% aqueous HF in CHCl3 with mild heating provided the desired iodonium salts bearing a carbonyl group, a halide group, or an ester group with good yields. For E-isomers, replacing Et3N-5HF with a stoichiometric amount of HBF4-Et2O promoted the reaction between terminal alkynes containing different C-2 position alkyl groups with para-iodotoluene difluoride in CH2Cl2 at −78 °C in only 5 minutes with good yields and high stereoselectivity.
Fig. 4

Two modified methods for synthesizing (Z)- and (E)-2-fluoro-1-alkenyl-iodonium salts

In 2004, Hara and his colleagues reported that (Z)-3-fluoro-2,3-unsaturated esters could be synthesized stereoselectively using palladium-catalyzed methoxy-carbonylation from (Z)-2-fluoro-alkenyliodonium salts (Fig. 5, A) [24]. Later, they reported that the use of (Z)-2-fluoro-1-iodo-1-alkenes instead of (Z)-2-fluoro-alkenyliodonium salts gave better results for palladium-catalyzed cross-coupling reactions, such as carbonylation, Suzuki, Heck, Sonogashira, and Stille reactions. A variety of fluoroalkenyl compounds were synthesized by this modified method in excellent yields and stereoselectivity (Fig. 5, B) [25].
Fig. 5

(Z)-2-fluoro-1-alkenyl-iodonium salts for palladium-catalyzed cross-coupling reaction

In 2005, Guan, Hara, and their coworkers reported a convergent and stereoselective synthesis of fluorinated analogs of insect sex pheromones using (E)- and (Z)-2-fluoro-alkenyliodonium salts as the intermediates (Fig. 6) [26]. The simplicity, good reaction yields, and the high stereoselectivity of these synthetic pathways illustrated the advantages of this methodology in utilizing 2-fluoro-alkenyliodonium salts to introduce a fluoroalkenyl moiety into the skeleton of organic molecules.
Fig. 6

Synthesis of fluorinated analogs of insect sex pheromones

Hara and his coworkers later reported another new methodology using either (Z)- or (E)-2-fluoro-1-alkenyliodonium salts. After treating (Z)-2-fluoro-1-alkenyliodonium salts with LDA at −78 °C, the in-situ formed 2-fluoroalkylideneiodonium ylide further reacted with trialkylboranes to yield (E)-(fluoroalkenyl)borane. Reactions of this borane intermediate under different conditions afforded various fluoroalkenes or α-fluoroketone products stereoselectively. After switching Z-iodonium salts to E-isomers, the corresponding products were also obtained with good yields and high stereoselectivity under slightly modified conditions (Fig. 7, A) [27]. This methodology was further extended by reacting 2-fluoroalkylideneiodonium ylides with various alkylboranes followed by transesterification and gave pinacol esters. These pinacol ester intermediates proved to be good substrates for Suzuki-type cross-coupling reactions for assembling trisubstituted fluoroalkenes with a variety of functional groups (Fig. 7, B) [28].
Fig. 7

Synthesis of trisubstituted fluoroalkenes using 2-fluoro-alkenyliodonium salts and organoborane reagents combined methodology

In 2007, Hara and his colleagues reported a stereoselective synthesis of polyenes taking advantage of the higher reactivity of 2-fluoro-alkenyliodonium salts compared to 2-fluoro-1-iodoalkenes (Fig. 8) [29]. The Heck-type cross-coupling reaction between 2-fluoro-alkenyliodonium salts and vinyldioxaborolanes proceeded under mild conditions (ambient temperature), which dramatically reduced side reactions and provided fluorodienylboronate intermediates with high stereoselectivity and generally good yields. These fluorodienylboronates can be used for synthesizing complex fluoropolyenes with decent reaction yields and high stereoselectivity.
Fig. 8

Heck reaction using 2-fluoro-alkenyliodonium salts

In 2008, Yoshida and Hara et al. reported an interesting ring-closing method to synthesize fluoroalkenyl containing cyclopentenes using (Z)-2-fluoroalkenyliodonium salts (Fig. 9) [30]. Treating these iodonium salts with a strong base, such as potassium tert-butoxide, yielded (α-fluoroalkylidene)carbene, and a subsequent 1,5-C-H insertion reaction provided fluorocyclopentenes in good yields.
Fig. 9

Synthesis of fluorocyclopentenes from (Z)-fluoroalkenyliodonium salts

In 2011, Nguyen, Emond, and their collaborators reported an optimized method for the synthesis of (Z)-2-fluoroalkenyliodonium salts using CsF as the fluorine source (Fig. 10) [31]. Additionally, they developed a one-pot-two-reaction method to give vinyl fluoride compounds with good yields by introducing NaBH4 as a reducing agent to remove the iodonium group.
Fig. 10

Improved synthesis of (Z)-fluoroalkenyliodonium salts and their use in vinyl fluorides synthesis

In 2012, Shimobaba et al. investigated a method using deprotonation and an aldehyde quench to synthesize trisubstituted (Z)-2-fluoroalkenyliodonium salts stereoselectively (Fig. 11) [32]. Under a lower reaction temperature (−90 °C versus −78 °C), the (E)-isomer of trisubstituted 2-fluoroalkenyliodonium salt was selectively synthesized in good yields. These multifunctionalized fluoroalkenyl compounds can serve as promising intermediates for synthesizing various fluoroalkene derivatives.
Fig. 11

Synthesis of trisubstituted 2-fluoroalkenyliodonium salts

Conclusion

After exploration over two decades, fluoroalkenyliodonium salts have developed into sophisticated synthons for synthesizing complex organic molecules containing an alkenyl fluoride moiety. The related synthetic methods demonstrate many advantages, such as mild reaction conditions, good reaction yields, high stereoselectivity, as well as the flexibility of combination with various metal-catalyzed cross-coupling reactions to synthesize multifunctionalized polyenes. There is no doubt that more applications will be found in pharmaceutical, agrochemical, and material science research.

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Citigroup of Biomedical Imaging CenterWeill Cornell MedicineNew YorkUSA
  2. 2.Avid Radiopharmaceuticals, IncPhiladelphiaUSA