Fuchibe Kohei

Ichikawa Junji

Organic Syntheses

English

Tsukuba Repository  (Tulips-R)

   Org. Synth. 2022, 99, 113-124                    Published on the Web 06/06/2022   Ó 2022 Organic Syntheses, Inc. DOI: 10.15227/orgsyn.99.0113    113  Discussion Addendum for: Preparation of 1,1-Difluoroallenes by Difluorovinylidenation of Carbonyl Compounds  Kohei Fuchibe*1 and Junji Ichikawa*1  Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan  Original Article: Fuchibe, K.; Abe, M.; Oh, K.; Ichikawa, J. Org. Synth. 2016, 93, 352–366.      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 OHCF3CH2I (1.1 equiv)then Ac2O (1.5 equiv)–50 °C to 0 °C, 15 minAcODMF, –30 °C to RT, 3.5 h12FFA.B.Zn (2.2 equiv) HIFFAcOIFFTHF, –93 °C, 20 minLiNi-Pr2 (2.2 equiv)CF2=C(I)Li, THF–93 °C to –50 °C, 25 min  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 114 substituents allow bond-forming reactions of 1,1-difluoroallenes to proceed in a-, b-, or g-selective fashions, all of which are illustrated below.   Bond Forming Reactions on the a-Carbon  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 a to the fluorine substituents and subsequently at the g-position.  Scheme 1. In(III)-catalyzed synthesis of F-PAHs Three applications were developed using the above domino reaction to construct extended p systems, namely, (i) tandem benzene ring construction,5 (ii) p-extended aryne generation,6 and (iii) benzene ring extension.7 These applications resulted in the successful generation of difluorinated, monofluorinated, and fluorine-free p-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 cat. InBr3CH2Cl2, rtFF F F+α– H+ then – H2ODifluorovinylidenation1 2CH3Org. Synth. 2016, 93, 352.DDQRef. 3γ  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 115 synthesized F-PAHs were examined, specifically their solubility in organic solvents8 and their potential as materials for electronic devices.5  Figure 1. Synthesis of pinpoint-difluorinated PAHs (F-PAHs) Secondly, the synthesis of “half HBCs” was facilitated by p-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  p-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).    FF FFα α’F F31) 4 mol% InBr3    ClCH2CH2Cl, rt, 1 h2) DDQ (2.5 equiv)    ClCH2CH2Cl, reflux    1.5 h (one-pot)5  76% (2 steps)F4 6  75% (2 steps)as aboveF FF Fαα’F(a)(b)γ γ’γγ’  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 116  Scheme 2. Synthesis of half HBCs  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 p 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).  FF Fα1X2 mol% InBr3NBS or NIS (1.2 equiv)ClCH2CH2Cl, rt, 30 minthe  CF3CO2H (1 equiv)Ref. 4aR R1)97  X = Br, quant;     X = I, 94%81) n-BuLi (1.2 equiv), diarylated isobenzofuran, Et2O–THF (4:1), rt, 2 h (X = Br), 81–89%2) SnCl2, HBr, THF, 60 °C, 5 h to overnight then FeCl3 (30 equiv), ClCH2CH2Cl/MeNO2 (5:1)    0 °C,  0.5 to 1 h, 78–96%2)γR = H, n-Hex, t-Bu  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 117   Figure 2. Benzene ring extension cycle   Scheme 3. Synthesis of fluorinated phenacenes  Benzene RingExtension Difluorovinylidenation     3)Domino Friedel–Crafts-typeCyclization / Ring ExpansionFormylalkylationF FOF121011αF1), 2)4)1) CH3CH2CN (4 equiv), KHMDS (4 equiv), THF, 80 °C    MW, 1.5 h, 82%2) DIBAL (1.2 equiv), Toluene, –78 °C, 2 h, 81%3) A. CF2=C(I)Li (1.2 equiv) THF, –95 °C then Ac2O (1.5 equiv);    B. Zn (2.0 equiv), DMF, rt, 2 h 73% (2 steps)4) 2 mol% InBr3, ClCH2CH2Cl, rt, 1 h, 94%1F 2nd Cycle 3rd Cycle131st cycleF13 2  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 118  Scheme 4. Synthesis of fluorinated triphenylenes Apart from cyclizations, 1,1-difluoroallenes also undergo a-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 g-selective addition (vide infra: Scheme 9).   Scheme 5. Synthesis of 1,1-difluoroallylic ethers and esters   Bond Forming Reactions on the b-Carbon  Bond-forming reactions at the position b to the fluorine substituents were facilitated by a palladium catalyst involving p-allylpalladium(II) formation.12 Difluoroallene 16 with a bromophenyl moiety was intramolecularly carbopalladated to form the p-allylpalladium(II) species with a six-membered ring structure, which in turn underwent b-hydrogen elimination, FFF Fα1) CH3CH2CN (4 equiv), KHMDS (4 equiv), THF, 80 °C, MW, 76%2) DIBAL (1.2 equiv), toluene, –78 °C, 80 °C3) A. CF2=C(I)Li (1.2 equiv), THF, –95 °C then Ac2O (1.5 equiv);     B. Zn (2.0 equiv), DMF, rt, 61% (2 steps)4) 2 mol% InBr3, ClCH2CH2Cl, rt, 98%1) – 3) 4)14F FαPh(CH2)2 Ph(CH2)2ORF F3 mol% AuCl(PPh3)3 mol% AgSbF6or4 mol% AuCl3ClCH2CH2Cl, MS 4A70 °C, 3 h 15 R = Ph, 80%      R = Ac, 74%     R = SO2CH3, 92%Ph(CH2)2Au CF2+ROH (1.2 equiv)(19F NMR Yd.)  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 119 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.  Scheme 6. Synthesis of difluoromethylated naphthalenes The intramolecular b-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 b-selective fashion (Scheme 8), while Rh(I) with a phosphine ligand promoted g-addition (vide infra: Scheme 10).14  Scheme 7. Synthesis of arylated (trifluoromethyl)alkenes CF2BrPdCHF2β16Br3 mol% Pd2(dba)3·CHCl36 mol% P(C6H4m-CH3)3EtOH (50 equiv)K2CO3 (5 equiv)DMF, 120 °C, 2 h17  60%F Fβ10 mol% PdCl2(PPh3)220 mol% DPEPhosAgF (3 equiv)PhI (2 equiv)CH2Cl2/MeCN (10:1)60 °C, 12 hPhF3C(CH2)2Ph(CH2)2Ph18  65%OPPh2Ph2PDPEPhosF F  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 120  Scheme 8. Synthesis of sulfanylated (difluoromethyl)alkenes   Bond Forming Reactions on the g-Carbon  Organocopper(I) reagents promote g-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, g-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, b-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.  Figure 3. Synthesis of g-branched 1,1-difluoro-1-alkenes βSCHF2(CH2)2Ar(CH2)2ArF FAr = C6H4p-OCH2Ph4 mol% [Rh(cod)]BF45 mol% LHSC6H4p-OMe (2 equiv)toluene/MeCN, 60 °C, 12 hL =N NOMe80%, β/γ = > 20:119  Ar = 1-naphthylEtMgBr (1.7 equiv)CuBr (1.7 equiv)SMe2 (1.7 equiv)THF, –60 °C, 1 hF FγAr(CH2)2 Ar(CH2)2CuCF2EtAr(CH2)2HCF2Et Ar(CH2)2XCF2Et Ar(CH2)2SnBu3CF2Et Ar(CH2)2PhCF2EtNCS, NBS, or NIS (1.7–5.1 equiv)– 60 °C, 2 hH3O+, –60 °C, 1 h n-Bu3SnCl (1.7 equiv)–60 °C, 3 h5 mol% [Pd2(dba)3]·CHCl310 mol% PPh3PhI (1.0 equiv), rt, 20 h20  95%21  X = Cl, 76%      X = Br, 75%      X = I, 84%22  66% (19F NMR Yd.) 23  90%Ar(CH2)2ECF2EtE+20–23β  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 121 B2pin2 and PhMe2SiBpin with a Cu(I)-catalyst promoted g-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).  Figure 4. Synthesis of 3,3-difluoroallylic boronates and silanes As well as undergoing alkylation, borylation, and silylation reactions, 1,1-difluoroallenes underwent the g-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 g-selective C–S bond formation (Scheme 10, see also: Scheme 8).14  Scheme 9. Synthesis of 3,3-difluoroallylic amines and thioethers 5 mol% CuIB2pin2 (1.2 equiv)11 mol% t-BuOKt-BuOH (2 equiv)THF, 50 °C, 24 hF FγPh(CH2)2 Ph(CH2)2HCF2Bpin24  86%(a)5 mol% CuIPhMe2SiBpin (1.5 equiv)11 mol% t-BuOKt-BuOH (1 equiv)THF, 28 °C, 12 hF FγPh(CH2)2 Ph(CH2)2HCF2SiMe2Ph25  86%(b)F FγPh(CH2)2 Ph(CH2)2HCF2NHCOPh3 mol% AuCl(PPh3)3 mol% AgSbF6PhCONH2 or PhSH (1.2 equiv)ClCH2CH2Cl, 70 °Cw/ or w/o MS 4A26  81% (19F NMR Yd.)3 h, w/ MS 4A27  72%2 h, w/o MS 4AorPh(CH2)2HCF2SPh  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 122  Scheme 10. Synthesis of chiral 3,3-difluoroallylic thioethers  The related monofluoroallenes underwent g-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  Scheme 11. Synthesis of heterocyclic fluoroalkenes 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, a-, b-, and g-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     CF2SAr(CH2)2*γF FAr = C6H4p-OCH2Ph2 mol% [Rh(cod)Cl]25 mol% LHSC6H4p-OMe (2 equiv)EtOH, rt, 36 hL =Ph2P PPh228  91%, γ/β = 16:1, 92% eeOMeAr(CH2)2FγPh(CH2)2 10 mol% AgNO3acetone(/H2O), rt, 48 h29  XH = OH  54%30  XH = NHBn  52%XHXFPh(CH2)2  Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 123 References  1. Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305–8571, Japan. E-mail: kfuchibe@chem.tsukuba.ac.jp (ORCID: 0000-0002-6759-7003); junji@chem.tsukuba.ac.jp. (ORCID: 0000-0001-6498-326X). This work was partially supported by TOSOH FINECHEM CORPORATION.  2. Fuchibe, K.; Ichikawa, J. in Science of Synthesis Knowledge Updates 2014, Vol. 2 (Eds.: Nielsen, B. M.; Krause, N.; Marek, I.; Schaumann, E.; Wirth, T.), Georg Thieme, Stuttgart, 2014, pp. 217–231. 3. Fuchibe, K.; Abe, M.; Oh, K.; Ichikawa, J. Org. Synth. 2016, 93, 352–366. 4. (a) Fuchibe, K.; Mayumi, Y.; Zhao, N.; Watanabe, S.; Yokota, M.; Ichikawa, J. Angew. Chem. Int. Ed. 2013, 52, 7825–7828; (b) Fuchibe, K.; Mayumi, Y.; Yokota, M.; Aihara, H.; Ichikawa, J. Bull. Chem. Soc. Jpn. 2014, 87, 942–949. 5. Fuchibe, K.; Shigeno, K.; Zhao, N.; Aihara, H.; Akisaka, R.; Morikawa, T.; Fujita, T.; Yamakawa, K.; Shimada, T.; Ichikawa, J. J. Fluorine Chem. 2017, 203, 173–184. 6. Fuchibe, K.; Abe, M.; Idate, H.; Ichikawa, J. Chem. Asian J. 2020, 15, 1384–1392. 7. Fuchibe, K.; Imaoka, H.; Ichikawa, J. Chem. Asian J. 2017, 12, 2359–2363. 8. Printed Organic and Molecular Electronics (Eds.: Gamota, D.; Brazis, P.; Kalyanasundaram, K.; Zhang J.), Springer, Berlin, 2005. 9. Uchiyama, M.; Kobayashi, Y.; Furuyama, T.; Nakamura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto, TY. Kondo, Y.; Morokuma, K. J. Am. Chem. Soc. 2008, 130, 472–480. 10. Hamura, T.; Nakayama, R. Chem. Lett. 2013, 42, 1013–1015. 11. Fuchibe, K.; Abe, M.; Sasaki, M.; Ichikawa, J. J. Fluorine Chem. 2020, 232, 109452. 12. Fuchibe, K.; Watanabe, S.; Takao, G.; Ichikawa, J. Org. Biomol. Chem. 2019, 17, 5047–5054. 13. Luo, H.; Zhao, Y.; Wang, D.; Wang, M.; Shi, Z. Green Synth. Catal. 2020, 1, 134–142. 14. Han, X.; Wang, M.; Liang, Y.; Zhao, Y.; Shi, Z. Nat. Synth. 2022, 1, 227–234. 15. As an exceptional case, Hammond reported substitution reaction of 1,1-difluoroallenes with organocopper(I) reagents at the position a to the   Org. Synth. 2022, 99, 113-124  DOI: 10.15227/orgsyn.99.0113 124 fluorine substituents. See: Mae, M.; Hong, J. A.; Xu, B.; Hammond, G. B. Org. Lett. 2006, 8, 479–482. 16. Fuchibe, K.; Ueda, M.; Yokota, M.; Ichikawa, J. Chem. Lett. 2012, 41, 1619–1621. 17. Shan, C.-C.; Dai, K.-Y.; Zhao, M.; Xu, Y.-H. Eur. J. Org. Chem. 2021, 2021, 4054–4058. 18. You, Y.; Wu, J.; Yang, L.; Wu, T. Chem. Commun. 2022, 58, 1970–1973. 19. In the early stages of fluoroallene chemistry, Dolbier reported electrocyclization of 1,1-difluoroallenes with reaction partners, such as diazoalkanes and nitrile oxides. See: (a) Dolbier, W. R.,  Jr.; Burkholder, C. R.; Piedrahita, C. A. J. Fluorine Chem. 1982, 20, 637–647; (b) Dolbier, W. R., Jr.; Burkholder, C. R.; Winchester, W. R. J. Org. Chem. 1984, 49, 1518–1522.    Kohei Fuchibe was born in Fukui, Japan in 1974. He received his B.Sc. in 1999 and Ph.D. in 2002 from the University of Tokyo (Prof. K. Narasaka). He joined Gakushuin University as a research associate in 2002 and was promoted to an Assistant Professor in 2007. He moved to University of Tsukuba as a Lecturer in 2007 and was promoted to an Associate Professor in 2011. His research interests involve synthetic reactions catalyzed by transition metals or organic small molecules.   Junji Ichikawa was born in Tokyo, Japan in 1958. He received his B.Sc. in 1981 and Ph.D. in 1986 from the University of Tokyo (Prof. T. Mukaiyama). He joined Kyushu University as an Assistant Professor in 1985. In 1989, he was a research associate at Harvard University (Prof. E. J. Corey) and then worked at Kyushu Institute of Technology as a Lecturer and an Associate Professor. In 1999, he moved to the University of Tokyo as an Associate Professor. He was appointed as a Professor at University of Tsukuba in 2007. His research interests lie in the area of synthetic methodology based on the properties of metals and fluorine.  

Preparation of 1,1-Difluoroallenes by Difluorovinylidenation of Carbonyl Compounds

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Preparation of 1,1-Difluoroallenes by Difluorovinylidenation of Carbonyl Compounds

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