Owing to the presence of two C=C bonds in allenes, the reactivities of allenes are very different from those of alkenes and alkynes. The unique structure of allenes allows a great number of useful transformations [1, 2, 3, 4]. During the past several decades, tremendous progress has been made in fluorination of alkenes and alkynes with different fluorination reagents [5, 6, 7]. Alkene fluorination is an efficient way to alkyl fluorides, whereas the same reaction of alkynes provides the alkenyl fluorides . Fluorination of allenes provides another potential pathway to afford the alkenyl, 1,3-alkadienyl, allylic, propargylic, and alkynylic fluorides. However, due to the lack of efficient control of the regio- or stereoselectivity, the fluorination of allene compounds has not yet received extensive investigation. So far only limited examples of fluorination of allenes have been reported. From the mechanistic aspect, most of these reactions can be classified into three types: electrophilic fluorination, nucleophilic fluorination, and transition metal-catalyzed fluorination. In this chapter, we summarize the recent progress of fluorination of allenes for preparing alkenyl fluorides with emphasis on the reaction mechanisms and the control of the regio- or stereoselectivity.
Electrophilic additions of allenes have been demonstrated to be very powerful reactions in organic synthesis since two functionalities are introduced with one of the two carbon–carbon double bonds remaining intact. The electrophilic fluorination of allene compounds could provide many potentially useful fluoro compounds. Among the variety of electrophilic fluorination reagents, Selectfluor® (1-chloromethyl-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octanebis(tetrafluoro- borate), also called F-TEDA-BF4) has been demonstrated to be one of the most reliable, mild, inexpensive, yet effective electrophilic fluorination reagents [8, 9, 10].
In 2005, Gouverneur and coworkers developed the electrophilic fluorodesilylation reactions of 2,3-allenyltrimethylsilanes 1 with Selectfluor®, affording various 3-fluoro-1,3-dienes 2 with different substitutions as mixtures of E/Z isomers of a 2/1 ratio in yields ranging from 11% to 99% depending on the substitutions of the starting allenylsilanes (Scheme 1) . The authors proposed an SE2’ electrophilic fluorination mechanism for this transformation: regiocontrolled electrophilic addition of Selectfluor to allenyltrimethylsilanes leads to the generation of an intermediate 3 with the positive charge α to the trimethylsilyl group. Subsequent desilylation process affords the final 3-fluoro-1,3-dienes (2). The approach of the electrophile to the central carbon of the allenylmethylsilane preferentially from the less steric sides leads to the production of the major E isomer.
In the following year, Gouverneur and coworkers reported electrophilic fluorodesilylation reaction of 1,2-allenylsilanes 4 with Selectfluor® at room temperature in acetonitrile, which led to the formation of various terminal and nonterminal secondary propargylic monofluorides 5 with isolated yields ranging from 40% to 78% (Scheme 2) . The reaction tolerates alkyl, alkenyl, and silyloxy groups. Mechanistically, electrophilic addition of Selectfluor® at C3 in 1,2-allenylsilanes provides a fluorinated vinyl cation (7) stabilized by the C–Si bond. The desired propargylic fluorides are afforded by the subsequent desilylation process. The fluorinated allenylsilane 6 generating from a 1,2-silyl shift as a side product confirms the presence of a fluorinated vinyl cationic intermediate 7.
Later, the same authors achieved the electrophilic fluorodesilylation of enantioenriched allenylsilanes with efficient transfer of chirality, which occurs via a highly stereospecific anti-SE2’ process to afford both propargylic fluoride (R)-9 and (S)-9 (Scheme 3) .
In 2008, Hammond and coworkers reported that the deprotonation of allenoates 11 with lithium diisopropylamide (LDA) provides alkynyl enolates 13 in situ, which would be trapped with NFSI to afford the observed products (12) in moderate to good yields (Scheme 4) .
Other than functionalized allenes, simple allenes can also be applied to the electrophilic fluorination reaction in the presence of electrophilic reagents. In 2008, Ma and coworkers reported highly regioselective fluorohydroxylation reactions of simple allenes (Scheme 5) . By using Selectfluor® as the electrophilic reagent, the internal C=C double bond in 3-aryl substituted 1,2-allenes 14 could be highly regioselectively fluorohydroxylated to produce 2-fluoroalken-3-ols 15 in 37–88% yields. However, the geminal bisalkyl-substituted allenes failed to afford any fluorinated products, which indicated the necessity of the aryl group in this transformation.
Later, Ma and coworkers applied this strategy to the fluorohydroxylation of 1,2-allenyl phosphine oxides 16 with Selectfluor® for the synthesis of 2-fluoro-3-hydroxy-1(E)-alkenyl diphenyl phosphine oxides 17 with very high regio- and stereoselectivities (Scheme 6) . Similarly, the existence of an aryl group at 3-position in the starting materials is also necessary. A plausible mechanism was proposed as follows: the interaction of the relatively electron-rich carbon–carbon double bond in allene with F+ forms the intermediate 18; a five-membered cyclic intermediate 19 is subsequently generated via neighboring group participation of the oxygen atom in the diphenyl phosphine oxide; the final product 17 is afforded by the attack of water molecule to the positively charged phosphorous atom to cleave the P–O bond. The perfect E-stereoselectivity of this transformation results from the neighboring group participation of the diphenyl phosphine oxide functionality forming cyclic intermediates 19.
The electrophilic fluorocyclization reaction of 2,3-allenoic acids 20 with Selectfluor® in MeCN in the presence of 10 equiv. of H2O or even in pure water affords β-fluorobutenolides 21 in moderate to high yields (Scheme 7) . The electrophilic fluorocyclization may be facilitated by the hydrogen bonding between Selectfluor® and H2O.
Further studies of Ma and coworkers extend this strategy to the reaction of 2,3-allenoates with Selectfluor®, which are more readily available as compared to 2,3-allenoic acids. Under different conditions, 4-fluoro-2(5H)-furanones 23 and (E)-3-fluoro-4-oxo-2-alkenoates 24 were produced, respectively, from 2,4-disubstituted 2,3-allenoates 22 in moderate yields with a high selectivity (Scheme 8) . The reaction of fully substituted 2,3-allenoates afforded the corresponding 4-fluoro-2(5H)-furanones 23 highly selectively with up to 95% yield. Mechanistically, interaction of Selectfluor® with the allene moiety and the subsequent intramolecular attack of the carbonyl oxygen give the five-membered intermediate 25, which may isomerize to 26; subsequent hydroxylation at the 5-position would afford fluorohydroxylation product 27; ketone 24 would be generated by the subsequent oxidation with Selectfluor® (R3 = H, Path I, Scheme 8); and deethylation of intermediate 26 may lead to lactone products 23 (Path II, Scheme 8).
Subsequetly, Zhu, Zhao, and coworkers observed that fluorovinylic γ-lactones 29 and pyrrolidine 31 could be obtained by the electrophilic fluorocyclization of 4,5-allenoic acids 28 and tosylamides 30 with Selectfluor®, respectively, in moderate to good yields (Scheme 9) . From the mechanistic aspect, two different types of products might be formed, γ-lactone 29 and seven-membered lactone 32, but γ-lactone 29 was isolated as the only product.
Inorganic fluoride such as calcium fluoride (CaF2) is the main form of fluorine in nature, so it should be more economical and practical to use inorganic fluorides as fluorine sources. Direct nucleophilic addition of F− was accomplished with perfluoropenta-1,2-diene 33 early in the 1960s (Scheme 10) . The reaction of perfluoropenta-1,2-diene 33 with cesium fluoride in foramide led to the formation of nonafluoropent-2-ene 34; with anhydrous CsF the reaction in the vapor phase provides perfluoro-3-pentyne 35. Attack of the nucleophilic F− at the terminal carbon atom of 33 affords an intermediate carbanion 36 with a trans-configuration. Protonation gave the trans-pentene derivative 34. Alternatively, elimination of fluoride forms perfluoro-3-pentyne 35.
Nucleophilic addition of F− with electron-deficient 1,2-allenyl ketones using TBAF · 3H2O in water as a nucleophilic fluorination agent afforded a series of β-fluoroenones 38, as a mixture of E/Z isomers with the E isomer being major in moderate to good yields (Scheme 11) . Mechanistically, nucleophilic addition of F− at the central allenyl carbon atom of 1,2-allenyl ketones affords two resonance contributors, 39 and 40. Subsequent protonation of 40 affords enol 41, from which β-fluoro-α,β-unsaturated ketone 38 is obtained as the final product. Simultaneously, protonation of anion 39 may also produce β-fluoro-β,γ-enone (42), which may readily isomerize to the thermodynamically more stable β-fluoro-α, β-unsaturated enone 38.
In 2013, Ma and coworkers developed a highly regioselective iodofluorination reaction of simple allenes 43 for the convenient synthesis of 2-iodoallylic fluorides. Et3N · 3HF and NIS are used as the fluorine source and the iodine source for iodofluorination, respectively. A series of 2-iodoallylic fluorides were synthesized in moderate to good yields with excellent branched/linear regioselectivity, in which the branched isomer 44 was major (Scheme 12) . Notably, ester and ether could survive under the standard reaction conditions. The iodofluorination reactions of geminally disubstituted allenes 43a and 43b may also proceed smoothly with a nice branched/linear selectivity.
(Difluoroiodo)toluene (TolIF2), possessing two fluorines on the iodine atom, can serve as a source of both electrophilic and nucleophilic fluorine atoms. Recently, Murphy and coworkers reported TolIF2-mediated fluorination reaction of phenylallenes 46, which provided an efficient synthesis of 1,1-difluoroalkyl-substituted styrenes 47 (Scheme 13) . A plausible mechanism was proposed as follows: BF3 · Et2O is used as a promoter to activate TolIF2, increasing its electrophilicity, thereby facilitating the electrophilic attack on the weakly nucleophilic allene, forming benzylic cation 48, which may isomerize to iodocyclopropylium cation 49. Subsequent fluorination of intermediate 48 or 49 builds the first C–F bond to provide intermediate 50 (path a). On the other hand, iodofluorination might be achieved through ligand metathesis between phenylallene and TolIF2 to produce intermediate 50 (path b). Phenonium ion 51 will be afforded by the intramolecular substitution reaction. The second C–F bond is formed by the exclusive nucleophilic attack of fluoride at the fluorinated carbon atom in 51 to open the three-membered ring to afford the final product, fluorinated styrene 47.
Loh and coworkers achieved Prins cyclization for the preparation of fluorinated 2,6-trans dihydropyrans 54 in moderate to good yields with excellent diastereoselectivities, by using 2-hydroxy-3-(trimethylsilyl)penta-3,4-dienoate 52 and various aldehydes 53 as substrates (Scheme 14) . Higher yields were observed for this transformation when aliphatic aldehydes were used as compared to benzaldehyde derivatives. Mechanistically, the Prins cyclization occurs through a distorted chair transition state (Scheme 14). BF3 · Et2O was used both as the promoter and as the fluorine source. The stabilization of the lone pairs of the ester group on the positive charge of oxocarbonium carbon compels the carbonyl group to present an axial orientation in the chair transition state, which offers stereoelectronic control to provide the desired intermediate 55. Thus, the final fluorinated 2,6-trans dihydropyran is afforded selectively from intermediate 55.
Transition Metal-Catalyzed Fluorination
Transition metal-catalyzed tandem cyclization and fluorination of unsaturated carbon–carbon bonds are efficient pathways to construct fluorinated heterocycles. In 2011, Liu and coworkers applied this strategy to the fluorination of allenes, developing an novel silver-catalyzed intramolecular aminofluorination of allenes for the synthesis of 4-fluoro-2,5-dihydropyrroles 58 (Scheme 15) . In this transformation, NFSI was used as the oxidant and the fluorine source. Mechanistically, the C–F bond formation may proceed via oxidative fluorination of the vinyl C–Ag bond via a bimetallic oxidative addition-reductive elimination. The final aminofluorination products 58 could be efficiently converted into 4-fluoropyrroles 59 in a one-pot fashion with good yields.
In 2012, a gold-catalyzed three-component tandem reaction between 2-benzyl-2,3-allenoates 60, Selectfluor®, and water was reported by Liu and coworkers to afford a variety of fluoroindenes 61 in moderate to good yields (Scheme 16) . A possible mechanism was proposed: Nucleophilic addition of H2O on the gold-coordinated allenoate 62 provides an organogold (I) intermediate 63, which is subsequently oxidized into an organogold (III) species 64 in the presence of Selectfluor® (path a). Hydroxyauration reaction of allene 60 with H2O and a cationic gold (III) species 65 is an alternative pathway for affording intermediate 64 (path b). Subsequent cycloauration followed by reductive elimination provides the product 67. Finally, the fluoroindene 61 is provided from 67 by a consecutive process of 1,3-H shift of the indene ring and oxidation of hydroxy to carbonyl group followed by fluorination of the resulting ketone.
Doyle and coworkers reported the tandem C–C and C–F bond formation within the palladium-catalyzed intramolecular cyclic carbofluorination of allenes, producing monofluoromethylated benzocycloalkenes 69 in moderate to good yields (Scheme 17) . P[3,5-(CF3)2-C6H3]3 was used for indole formation as the ligand, while XPhos was used for benzofuran or benzothiene synthesis. Such intermolecular carbofluorination of the three-component reaction of allenes 70, aryl iodides 71, and AgF was also reported. It is worth noting that the regioselectivity largely depends on the structure of the allene substrate. For the allenes with ester substituent, the linear isomer 72 was provided due to the preferential conjugation with the ester. On the other hand, products with a slight excess of the branched isomer 73d and 73e were obtained from allenes with phenyl or BzOCH2CH2 substituents.
Similar reaction of palladium-catalyzed three-component tandem carbofluorination of allenes 74 with ArI 75 and AgF was also reported by Liu and coworkers (Scheme 18) . The substrates scope studies indicate that the branched/linear regioselectivity was mainly determined by the electronic properties of the aryl iodides. The aryl iodides with electron-withdrawing substituents lead to a higher branched/linear selectivity.
Conclusion and Perspectives
In this chapter, we summarize the progress achieved in allene fluorinations, which constitute challenging and synthetically useful transformations for constructing different fluorinated compounds. However, control of the regio- or stereoselectivity especially enantioselectivity for the C–F bond formation is still in its early stage. Thus, new strategies and concepts are highly desirable for such fluorinations of allenes. The transition metal catalysis is supposed to be a good option in this topic due to their mild conditions and the potential of controlling the enantioselectivity by applying chiral ligands.