1,1-Difluoroallenes have two fluorine substituents, which are located on the cumulated diene substructure to decisively affect their reactivities. In addition to the reactions compiled in our previous review,² synthetic reactions of 1,1-difluoroallenes have been continuously investigated since the authors' publication in Org. Synth. that described difluoroallene production by difluorovinylidenation of aldehydes and ketones.³ As a result, the fluorine substituents allow bond-forming reactions of 1,1-difluoroallenes to proceed in α-, β-, or γ-selective fashions, all of which are illustrated below.

As discussed in the original article,³ an In(III) catalyst facilitates the domino Friedel-Crafts-type cyclization/ring expansion sequence of 1,1-difluoroallenes 1. Subsequent one-pot dehydrogenation leads to pinpoint-fluorinated polycyclic aromatic hydrocarbons 2 (F-PAHs, Scheme 1).⁴ The domino reaction allows two carbon-carbon bond formations, first at the position α to the fluorine substituents and subsequently at the γ-position.

Three applications were developed using the above domino reaction to construct extended π systems, namely, (i) tandem benzene ring construction,⁵ (ii) π-extended aryne generation,⁶ and (iii) benzene ring extension.⁷ These applications resulted in the successful generation of difluorinated, monofluorinated, and fluorine-free π-extended molecular systems.

The first application of the domino cyclization/ring expansion sequence involves tandem benzene ring construction (Figure 1).⁵ Bis(1,1-difluoroallene) 3 (a) and 4 (b), prepared from m- and p-xylenes via the corresponding dialdehydes, underwent the domino reaction in a tandem fashion to afford pinpoint-difluorinated dibenzoanthracene 5 and picene 6 in 76% and 75% yields, respectively. The physicochemical features of the synthesized F-PAHs were examined, specifically their solubility in organic solvents⁸ and their potential as materials for electronic devices.⁵

Secondly, the synthesis of "half HBCs" was facilitated by π-extended aryne generation from 1,1-difluoroallenes (Scheme 2).⁶ The structure of half HBCs is a half section of HBCs (hexabenzocoronenes), which are promising as materials for photovoltaic cells. o-Bromo- or o-iodofluoroarenes 7 were prepared by the In(III)-catalyzed domino reaction of 1,1-difluoroallenes involving halogenation of the C-In bond with N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS).^4a Compounds 7 served as precursors for π-extended arynes 8 upon treatment with butyllithium, while 6-fluoro[4]helicene (not shown) also served as an aryne precursor via dehydrofluorination upon treatment with Me₂ (TMP)ZnLi (TMP, tetramethylpiperidino).⁹ The produced arynes were subjected to the Diels-Alder reaction with diarylated isobenzofurans,¹⁰ yielding cycloadducts (81-89% yields, not shown), which were easily transformed to half HBCs 9 by deoxygenative aromatization followed by aryl-aryl coupling in 78-96% yields (2 steps).

Third, benzene ring extension was accomplished through the attachment of a fluorobenzo moiety to existing fluoroarenes.⁷ Under microwave (MW) irradiation, commercially available 1-fluoronaphthalene was effectively cyanoethylated by aromatic nucleophilic substitution for fluorine (Figure 2). The half reduction of the nitrile gave aldehyde 10, whose difluorovinylidenation afforded the corresponding 1,1-difluoroallene 11. Next, 11 underwent Friedel-Crafts-type cyclization followed by dehydrofluorination to provide the benzene ring-extended fluorophenanthrene 12 in 94% yield (the first cycle). Application of second and third cycles similarly extended the π system until it eventually afforded pinpoint-fluorinated [5]phenacene (picene) 13 (Scheme 3). In addition to phenacenes with zig-zag benzene rings, such as 13, triphenylene 14 with a trigonal structure was produced by applying the benzene ring extension cycle to internally fluorinated arenes (Scheme 4).

Apart from cyclizations, 1,1-difluoroallenes also undergo α-selective addition of oxygen nucleophiles, such as phenols, carboxylic acids, and sulfonic acids, in the presence of an Au(I) or an Au(III) catalyst (Scheme 5).¹¹ Thus, using the aurated allylic CF₂ cations, the hard O-nucleophiles were regioselectively introduced to 1,1-difluoroallenes, yielding 1,1-difluoroallylic ethers and esters 15 in 74%-92% yields. In contrast, soft sulfur and nitrogen nucleophiles underwent γ-selective addition (vide infra: Scheme 9).

Bond-forming reactions at the position β to the fluorine substituents were facilitated by a palladium catalyst involving π-allylpalladium(II) formation.¹² Difluoroallene 16 with a bromophenyl moiety was intramolecularly carbopalladated to form the π-allylpalladium(II) species with a six-membered ring structure, which in turn underwent β-hydrogen elimination, followed by isomerization to yield difluoromethylated naphthalene 17 in 60% yield (Scheme 6). The difluoromethyl group is a bioisostere of a hydroxy group and is attracting attention in the field of pharmaceuticals and agrochemicals as a hydrogen donor for hydrogen bonding while simultaneously exhibiting hydrophobicity.

The intramolecular β-selective carbometallation was followed by intermolecular fluorometallation (cat. Pd(0)/PhI/AgF, Scheme 7),¹³ where the generation of vinylsilver(I) was proposed to participate in Pd(0)-catalyzed coupling, leading to (trifluoromethyl)alkene 18 in 65% yield. A rhodium(I) catalyst bearing a nitrogen ligand facilitated C-S bond formation in a β-selective fashion (Scheme 8), while Rh(I) with a phosphine ligand promoted γ-addition (vide infra: Scheme 10).¹⁴

Organocopper(I) reagents promote γ-selective bond-forming reactions in almost all cases.¹⁵ 3-Monosubstituted 1,1-difluoroallene 19 reacted with ethylcopper(I) to afford the corresponding addition product, γ-branched 1,1-difluoro-1-alkene 20 (E = H), in 95% yield via protonolysis of the 2,2-difluorovinylcopper(I) intermediate (Figure 3).¹⁶ When quenched by electrophiles, such as halogenating agents and halostannanes, β-functionalized 1,1-difluoro-1-alkenes 21 and 22, respectively (66%-84% yields). The 2,2-difluorovinylcopper(I) intermediates enabled Pd(0)-catalyzed coupling with iodobenzene, yielding a three-component coupling product 23 in 90% yield.

B₂pin₂ and PhMe₂SiBpin with a Cu(I)-catalyst promoted γ-selective borylation and silylation of 1,1-difluoroallenes, which afforded 3,3-difluoroallylboronate 24 and silane 25 in 86% yields, respectively (Figure 4).¹⁷ The formed difluoroallylboronates reacted with aldehydes to provide 2,2-difluorohomoallylic alcohols (not shown).

As well as undergoing alkylation, borylation, and silylation reactions, 1,1-difluoroallenes underwent the γ-selective addition of benzamide and thiophenol in the presence of an Au(I) [or an Au(III)] catalyst through cationic intermediates (Scheme 9, see also: Scheme 5).¹¹ 3,3-Difluoroallylic amine 26 and thioether 27 were synthesized in 81% and 72% yields, respectively. The use of a Rh(I) catalyst with a chiral phosphine ligand aided in the synthesis of chiral 3,3-difluoroallylic thioether 28 via γ-selective C-S bond formation (Scheme 10, see also: Scheme 8).¹⁴

The related monofluoroallenes underwent γ-selective intramolecular C-O and C-N bond formations in the presence of an Ag(I) catalyst (Scheme 11). Ring-fluorinated heterocycles, dihydropyran 29, and tetrahydropyridine 30, were obtained in 54% and 52% yields, respectively.¹⁸

In summary, since our report on the synthesis of 1,1-difluoroallenes by carbonyl difluorovinylidenation, the reactions of 1,1-difluoroallenes have been steadily investigated and their unique reactivities have been revealed. Now, regioselective bond-forming reactions in 1,1-difluoroallenes can be successfully effected at each of the three, α-, β-, and γ-positions with the aid of metals, such as In(III), Au(I), Au(III), Pd(0), Cu(I), and Ag(I), which enables the synthesis of fluorinated and fluorine-free cyclic and acyclic molecules. As a result, 1,1-difluoroallenes are extremely adaptable synthetic building blocks. Despite these advances in ionic reactions, further research on their behavior under radical conditions and in electrocyclization processes is still required.¹⁹