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Angewandte Chemie International Edition:DOI:10.1002/anie.201500229 Phosphorus Heterocycles German Edition:DOI:10.1002/ange.201500229 Environment-SensitiveFluorescent Probe:ABenzophosphole Oxide with an Electron-Donating Substituent** Eriko Yamaguchi, Chenguang Wang,Aiko Fukazawa,* Masayasu Taki, Yoshikatsu Sato, Taeko Sasaki, Minako Ueda, Narie Sasaki, Tetsuya Higashiyama,* and Shigehiro Yamaguchi* Abstract: Electron-donating aryl groups were attached to phosphine oxide and sulfide derivatives exhibit desirably high electron-accepting benzophosphole skeletons.Among several thermal and chemical stability.Taking advantage of these derivatives thus prepared, one benzophosphole oxide was features,phosphole-based materials have been widely applied particularly interesting,asitretained high fluorescence quan- in organic electronics,[1g,h] including organic light-emitting tum yields even in polar and protic solvents.This phosphole- diodes[3,4] and photovoltaics.[5] However,biological applica- based compound exhibited adrastic color change of its tions have not yet been explored exhaustively.Inthis context, fluorescence spectrum as afunction of the solvent polarity, we would like to disclose here the successful development of while the absorption spectra remained virtually unchanged. highly fluorescent phosphole derivatives,and demonstrate Capitalizing on these features,this phosphole-based compound their potential as fluorescent bioimaging probes. was used to stain adipocytes,inwhich the polarity of Thecombination of an electron-accepting p-skeleton with subcellular compartments could then be discriminated on the an electron-donating moiety represents arational design basis of the color change of the fluorescence emission. approach for producing environment-sensitive fluorescent molecules.[6] Following this avenue,wehave now designed the Phosphole,aheavier phosphorus analogue of pyrrole,isan attractive building block for p-conjugated materials.[1] Whereas pyrrole is aromatic and has electron-donating properties,phosphole is nonaromatic and exhibits an elec- tron-accepting character.[1b, 2] Relative to pyrrole, the lone- pair electrons of the pyramidalized phosphorus atom in the phosphole conjugate to alesser extent with the p-system. Instead, effective orbital interaction occurs between the p*orbital of abutadiene moiety and the s*orbital of an exocyclic s bond on the phosphorus atom, thus resulting in adecreased LUMO level. Theelectron-accepting properties of phosphole can be further increased by facile transforma- tions into phosphine oxides,phosphine sulfides,phosphonium salts,and metal complexes.Among these,especially the [*] E. Yamaguchi,Prof. Dr.A.Fukazawa, Prof. Dr.S.Yamaguchi Department of Chemistry,Graduate School of Science Nagoya University Furo, Chikusa, Nagoya 464-8602 (Japan) E-mail:[email protected] [email protected] T. Sasaki, Prof. Dr.N.Sasaki, Prof. Dr.T.Higashiyama DivisionofBiological Science, Graduate School of Science Nagoya University,Furo, Chikusa, Nagoya 464-8602 (Japan) C. Wang, Prof. Dr.M.Taki, Dr.Y.Sato, Dr.M.Ueda, Prof. Dr.T.Higashiyama, Prof. Dr.S.Yamaguchi Institute of Transformative Bio-Molecules (WPI-ITbM) Nagoya University,Furo, Chikusa, Nagoya 464-8602 (Japan) E-mail:[email protected] [**] This work was supported by JST,CREST (S.Y.), aGrant-in-Aid for Scientific Research on Innovative Areas “Organic Synthesis based on Reaction Integration” (no. 2105) from MEXT (Japan) (A.F.), and Figure 1. a) Chemical structures of the benzophosphole derivatives 1– the Japan Advanced Plant Science Network. E.Y.thanks the JSPS for 4 and benzothiophene dioxide congener 5.b)Comparison of represen- aResearch Fellowship for Young Scientists. ITbM is supported by tative environment-sensitive fluorescent probes, whereby circles and the World Premier International Research Center (WPI) Initiative, squares represent the maxima of absorptionand emission, respec- Japan. tively.Empty and filled symbols denote wavelengthsinnonpolar and Supporting information for this article is available on the WWW polar solvents, respectively.[a] Reference [8b];[b] Reference [9b,c]; under http://dx.doi.org/10.1002/anie.201500229. [c] Reference[10];[d] Reference [11b]. Angew.Chem. Int.Ed. 2015, 54,4539 –4543 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 4539 Angewandte. Communications environment-sensitive fluorescent molecule 1 by combining position, in moderate to good yields.Anensuing Suzuki– an electron-accepting benzophosphole oxide with an elec- Miyaura cross-coupling reaction of 7 with phenylboronic acid tron-donating triphenylamine substituent (Figure 1a). Envi- under standard reaction conditions afforded the derivatives ronment-sensitive fluorescent probes are particularly impor- 1 and 2 in good yields.The compound 1 was further tant for the visualization of polarity changes associated with transformed into the corresponding phosphole sulfide 3 by cellular events,[7] and the general requirements for such treatment with Lawessons reagent. An analogous phospho- probes are:1)high fluorescence quantum yields (FF)irre- nium derivative 4 was also prepared by the reduction of 1 with spective of the solvent polarity,2)large Stokes shifts to avoid HSiCl3,and subsequent treatment with methyl triflate.The autofluorescence interference,and 3) drastic color change of structures of these compounds were assigned unequivocally the fluorescence emission as afunction of the solvent polarity. based on the results from NMR spectroscopy and mass Several previously reported fluorophores,such as prodan,[8] spectrometry measurements. 1,8-ANS,[9] dapoxyl,[10] and Nile red,[11] are known to satisfy The p-(diphenylamino)phenyl-substituted benzophos- these requisites.However,incomparison to these, 1 offers the phole oxide 1 exhibited excellent fluorescent properties following additional advantages:1)compatibility with (Table 1). In toluene,the absorption maximum of 1 was 405 nm light-emitting diode lasers,which are frequently used for excitation in fluorescence microscopy,and 2) bath- Table 1: Photophysical properties of 1–5 in various solvents. ochromically shifted reddish fluorescence emission as aresult [b] of excitation with such a405 nm laser (Figure 1b). Herein, we Cmpd Solvents labs e lem FF e FF [a] 4 1 1 4 1 1 discuss the key structural requisites necessary for our new [nm] [10 mÀ cmÀ ] [nm] [10 mÀ cmÀ ] fluorophore to exhibit its characteristic fluorescence proper- 1 toluene 415 1.87 528 0.94 1.8 ties,and we also demonstrate its application in cell imaging. CHCl3 420 1.74 553 0.94 1.6 An important advantage of benzophosphole oxide as an CH2Cl2 415 1.73 565 0.90 1.6 acetone 403 1.73 575 0.84 1.5 electron-accepting building block is the facile synthetic access ethanol 417 1.60 593 0.58 0.9 to its skeleton. Recently,several new reactions have been DMSO 412 1.66 601 0.64 1.1 [12] developed for the synthesis of benzophospholes. Our 2 toluene 364 1.03 471 0.74 0.8 contributions to this area include aversatile synthesis DMSO 364 0.94 490 0.69 0.7 for benzophospholes based on the intramolecular trans- 3 toluene 412 1.58 526 0.87 1.4 halophosphanylation of o-phosphanylphenylacetylenes,[13,14] DMSO 411 1.28 608 0.61 0.8 which afforded aseries of donor–acceptor-type benzophos- 4 toluene 448 1.34 672 0.20 0.3 DMSO 440 1.23 702 0.02 0.02 pholes.Thus,starting from the (o-bromophenyl)(p-substi- 5 toluene 419 2.56 507 0.92 2.4 tuted phenyl)acetylene precursors 6,alithiation with two DMSO 418 2.29 628 0.06 0.1 equivalents of tBuLi, followed by treatment with PhP- [a] Longest wavelength absorption maximum. [b] Absolute fluorescence (NEt )Cl generated the corresponding o-aminophosphanyl- 2 quantum yields determined with acalibrated integrating sphere system substituted intermediates (Scheme 1). Without isolation, (errors < 3%). asubsequent treatment with PBr3 resulted in the halogen- ation of the phosphorus moiety,followed by an intramolec- ular cyclization by trans-halophosphanylation. This conven- observed at labs = 415 nm, while an intense fluorescence band ient one-pot procedure furnished the 3-bromobenzo[b]phos- with afluorescence quantum yield (FF)of0.94 was recorded phole oxides 7,bearing electron-donating aryl groups at the 2- at lem = 528 nm. With increasing solvent polarity,the absorp- tion spectra showed only subtle changes (labs = 403–420 nm), whereas the fluorescence bands were shifted significantly in abathochromic direction (DMSO:601 nm;EtOH:593 nm). Most notably, 1 preserves high fluorescence quantum yields in polar (DMSO: FF = 0.64) and protic solvents (EtOH: FF = 0.58) despite the corresponding large Stokes shifts (DMSO: 1 1 7630 cmÀ ;EtOH:7120 cmÀ ). Thefact that abrightness of the fluorescence,denoted by the product of molar extinction [15] 4 coefficient (e)and FF, of about 10 was attained even in ethanol, thus suggests potential applications for this com- pound as afluorescent probe. Acomparison of 1 with related compounds,including the anisyl-substituted 2,containing aweaker electron-donating substituent, as well as with the electron-accepting benzo- phosphole sulfide 3,phosphonium salt 4,and thiophene dioxide congener 5,demonstrates that the well-balanced combination of the electron-accepting phosphole oxide and the electron-donating diphenylamino group in 1 is,inmore Scheme 1. Synthesis of the donor-substituted benzophosphole deriva- than one way,crucial for the presence of the observed tives 1–4.Tf=trifluoromethanesulfonyl. outstanding photophysical properties (Table 1; for exhaustive 4540 www.angewandte.org 2015

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