ORGANIC CHEMISTRYFRONTIERS

RESEARCH ARTICLE

Cite this: Org. Chem. Front., 2019, 6,3961

Received 27th September 2019,Accepted 23rd October 2019

DOI: 10.1039/c9qo01190k

rsc.li/frontiers-organic

Non-symmetric thieno[3,2-b]thiophene-fusedBODIPYs: synthesis, spectroscopic properties andproviding a functional strategy for NIR probes†

Yijuan Sun,a Hao Yuan,b Linting Di,a Zhikuan Zhou,a Lizhi Gai, *a,b

Xuqiong Xiao, a Weijiang He b and Hua Lu *a

Aromatic conjugation at the [β] position is an efficient strategy to construct NIR BODIPY dyes; functionali-

zation of such BODIPYs is difficult because of fewer modifiable positions. The methyl group at the 3,5-

position can be versatilely functionalized by the Knoevenagel condensation reaction. In this paper, a small

series of non-symmetric thieno[3,2-b]thiophene-fused BODIPYs have been prepared via the conden-

sation of 7H-thieno[2’,3’:4,5]thieno[3,2-b]pyrrole-6-carbaldehydes and various pyrroles, followed by

coordination with BF2. The resulting BODIPY dyes exhibited red absorption and emission with extremely

high absorption coefficients (2 × 105 M−1 cm−1) and fluorescence quantum yields up to 1.00. Importantly,

the remaining methyl group at the 3-position can be further functionalized to achieve NIR probes; we

then synthesized an organosilicon-based probe for F− and evaluated its imaging in living cells. The struc-

ture–property relationships were interpreted on the basis of X-ray crystallography, optical spectroscopy

and theoretical calculations.

Introduction

In recent years, numerous research attempts have been madeon the exploration of novel red and near-infrared (NIR) dyefluorophores utilized as agents for fluorescence imaging andas efficient photosensitizers in photodynamic therapy.1 Amongthe various types of fluorophores, BODIPY derivatives haveattracted remarkable attention due to their excellent photo-physical properties and structural versatility.2 In contrast totheir outstanding photophysical characteristics, the maximumabsorption of classical BODIPYs occurs at around 500 nm,2

which significantly limits the application scope of BODIPYs.In order to obtain BODIPYs absorbed in the red/NIR region,various modification methods of BODIPYs have been investi-gated: (i) rigidification of rotatable moieties, (ii) replacementof the meso carbon atom with a nitrogen atom to prepare aza-BODIPY dyes, (iii) extension of π conjugation by the introduc-

tion of aryl, vinyl, styryl and arylethynyl moieties and (iv) theextension of the π conjugation by the fusion of aryl units withthe pyrrole unit.3 Fusion of π-sufficient heteroaryl moietieswith the BODIPY skeleton is a powerful protocol to prepare theBODIPY derivatives with intrinsic red or NIR photophysicalfeatures.4

Thieno[3,2-b]thiophene is an electron-rich molecule,5

which possesses strong electron-donating ability and enablesefficient extension of the π system. We noticed that symmetricthieno[3,2-b]thiophene fused BODIPYs display NIR absorptionand emission with excellent spectroscopic properties;6 however,their further functionalization is very difficult due to fewer mod-ifiable positions. We envisioned that the fusion of thieno[3,2-b]thiophene on one side of the BODIPY core to form non-sym-metric BODIPY derivatives could extend the π-conjugationefficiently; more importantly, the methyl group on the 3-posi-tion of the as-prepared BODIPYs could be further functionalized(Scheme 1). Taking advantage of the extraordinary affinitybetween fluoride and silicon,7 a NIR fluoride probe wasdesigned via the Knoevenagel condensation reaction.

Results and discussionSynthetic procedures

Ethyl 7H-thieno[2′,3′:4,5]thieno[3,2-b]pyrrole-6-carboxylate 1was prepared in 75% yield according to literature procedures.6

Precursor 3, which was synthesized in a good yield via the

†Electronic supplementary information (ESI) available: HR-MS spectra, 1H and13C-NMR spectra, and additional experimental and calculated optical spectra.CCDC 1879308, 1941926, 1935458 and 1941928. For ESI and crystallographicdata in CIF or other electronic format see DOI: 10.1039/c9qo01190k

aKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of

Education, and Key Laboratory of Organosilicon Material Technology of Zhejiang

Province, Hangzhou Normal University, No. 2318, Yuhangtang Road, Hangzhou

311121, P. R. China. E-mail: lizhigai@hznu.edu.cn, hualu@hznu.edu.cnbState Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of

Microstructures, Nanjing University, Nanjing, 210093, P. R China

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reduction and oxidation of 1, was used for the condensationreactions with different pyrrole derivatives in the presence ofPOCl3 as a catalyst. On subsequent treatment with BF3OEt2under basic conditions, the desired thieno[3,2-b]thiophene-fused BODIPYs 4–7 were obtained in 30–64% yields(Scheme 2). All targeted complexes were fully characterized by1H NMR, 13C NMR, high resolution mass spectrometry(HR-MS) and X-ray single crystal analysis.

The single crystals of 4–7 were obtained by slowly evaporat-ing hexane into their dichloromethane solution. As shown inFig. 1, the boron atom of 4–7 was coordinated in a tetrahedralgeometry by two nitrogen and two fluorine atoms. TheBODIPY π-conjugated core shows an almost planar confor-mation. In the molecular packing diagrams, head-to-tail orhead-to-head π–π stacking interactions are observed with aninterplanar distance of approximately 3.41 Å for 4 and 3.99 Åfor 5. However, the head-to-head π–π stacking interaction isobserved in the molecular packing diagrams with interplanarseparations of approximately 2.80 Å for 6, indicating the exist-ence of strong interaction. In the case of 7, the dihedral anglebetween the α-position of the phenyl group and the BODIPYcore structure is 46.33°.

Optical properties

The photophysical properties of the desired thieno[3,2-b]thio-phene-fused BODIPYs 4–7 were investigated in six differentsolvents and summarized in Fig. 2, S1, S2† and Table 1. InDCM, the intense and broader absorption of dyes 4–7 areobserved in the range of 560–620 nm, indicating that more

than one optical transition contributes to the intense band (seethe DFT section).8 With respect to the absorption of BDP inTHF, the absorption maxima of non-symmetric thieno[3,2-b]thiophene fused BODIPYs are redshifted by 77 nm for 4, 80 nmfor 5, 78 nm for 6, and 105 nm for 7, suggesting that the fusionof thieno[3,2-b]thiophene is an efficient approach to obtain ared character. Dye 7 has a molar extinction coefficient of around97 700 M−1 cm−1, which is lower than those of 4–6, due to thetwisted phenyl group,9 which was supported by X-ray analysis.

The fluorescence spectra showed a typical mirror–imagerelationship of the lowest energy absorption spectra. The stron-gest absorption slightly depended on the polarity of thesolvent, with a blue shift at around 10–13 nm when the solventpolarity changes on moving from hexane to acetonitrile. Asimilar trend can be observed in the emission maxima. Allthese features suggest that the emission occurs from theweakly polar, relaxed Franck–Condon excited state. LargeStokes shifts were observed for 4–7 and they generallyincreased from hexane to acetonitrile, due to a large difference

Scheme 2 Synthesis and structures of non-symmetric thieno[3,2-b]thiophene-fused BODIPYs 4–7.

Fig. 1 Front (left) and packing diagram (right) views of the molecularstructures of 4 (a), 5 (b), 6 (c) and 7 (d) with the thermal ellipsoids set at50% probability. Green represents F atoms, red represents S atoms, bluerepresents N atoms, grey represents C atoms, and orange represents Batoms. Hydrogen atoms are omitted for clarity.

Fig. 2 (a) UV/Vis absorption spectra and (b) fluorescence spectra of4–7 in CH2Cl2. λex = 530 nm.

Scheme 1 Designed structures of NIR non-symmetric thieno[3,2-b]thiophene-fused BODIPYs.

Research Article Organic Chemistry Frontiers

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in the permanent dipole moments between the ground stateand the excited state. The fluorescence decay profiles of dyes4–7 could be described by a single-exponential fit with afluorescence lifetime in the range of nanoseconds in all thesolvents investigated, similar to the lifetime data of thereported BODIPY systems. The photostability of thieno[3,2-b]thiophene-fused BODIPYs 4–7 in DCM was evaluated bycontinuous irradiation with a laser (525 nm or 635 nm).Compared with the well-known commercial dye, rhodamine6G or methylene blue, 4–7 showed much better photostability(Fig. S3 and S4†).

DFT calculations

In order to investigate the electronic structures and observedphotophysical properties, DFT and TD-DFT calculations wereperformed using the B3LYP functional and 6-31G(d) basis setsof the Gaussian09 software package (Fig. 3).10 Table 2 lists therelevant lowest energy transitions. For 4–7, the calculatedabsorption spectra were blue-shifted compared with the experi-mental values, similar to the reported BODIPY systems,and their sequences match rather well with the measuredabsorption spectra in solution.11 According to Table 2, the twolowest transitions S1 and S2 consist of the HOMO → LUMO andHOMO−1 → LUMO transitions. It is also apparent that the twolowest transitions are rather close-lying in energy/wavelength.

Both optical transitions contribute to the main band in the560–620 nm regions in the absorption spectra. The HOMOand LUMO are almost effectively spread over the entire mole-cule (Fig. 3), while the HOMO−1 orbitals are almost localized onthe 7H-thieno[2′,3′:4,5]thieno[3,2-b]pyrrole unit exhibiting a

marked significant overlap between the occupied and virtualorbitals, indicating that a weak ICT transition occurs from thedonor thieno[3,2-b]thiophene moiety unit to the BODIPY πsystem. In addition, the incorporation of a benzene ring at theα-position of BODIPY stabilizes the LUMO relative to 4, but thereis no effect on the HOMO. It narrows the HOMO–LUMO gap(Fig. 3 and Table 2), and causes a bathochromic shift of the mainabsorption band in both the calculated and observed spectra.

F− recognition

The excellent optical properties of non-symmetric thieno[3,2-b]thiophene fused BODIPY derivatives inspired us to explore

Table 1 Spectroscopic and photophysical properties of 4–7 in various solvents at 298 K

Dye Solvent λabsa [nm] FWHMabs [nm] lg ε b λem

c [nm] FWHMem [nm] SSd [cm−1] τe [ns] ΦFf kr

g [108 s−1] knrh [108 s−1]

4 Hexane 571 26 5.43 577 63 182 5.28 0.35 0.66 1.23Toluene 573 27 5.41 584 61 329 4.79 0.38 0.79 1.29CH2Cl2 568 32 5.36 581 65 394 4.37 0.33 0.76 1.53THF 565 34 5.38 579 67 428 4.16 0.29 0.71 1.71MeOH 561 36 5.32 575 68 434 3.54 0.26 0.73 2.09MeCN 559 41 5.33 576 70 528 3.30 0.23 0.70 2.33

5 Hexane 579 25 5.41 586 73 206 5.63 0.34 0.61 1.17Toluene 580 29 5.37 592 64 349 4.95 0.47 0.95 1.07CH2Cl2 575 38 5.29 589 68 413 5.58 0.42 0.75 1.04THF 573 36 5.23 587 65 416 5.26 0.44 0.84 1.06MeOH 569 43 5.31 584 63 451 5.56 0.43 0.77 1.03MeCN 566 49 5.25 583 66 515 5.24 0.39 0.74 1.16

6 Hexane 580 29 5.42 587 71 206 5.21 0.36 0.69 1.23Toluene 582 32 5.40 593 61 319 4.68 0.48 1.03 1.11CH2Cl2 577 41 5.35 589 60 353 5.21 0.52 1.00 0.92THF 574 36 5.35 587 60 386 5.11 0.51 1.00 0.96MeOH 571 41 5.34 585 64 419 5.68 0.44 0.77 0.99MeCN 569 47 5.22 585 67 481 5.15 0.36 0.69 1.24

7 Hexane 603 33 4.99 615 27 324 5.57 1.00 1.80 n.a.i

Toluene 607 37 4.97 622 30 397 4.38 1.00 2.28 n.a.i

CH2Cl2 603 39 4.96 618 31 403 4.53 0.86 1.90 0.31THF 601 38 4.95 617 32 431 4.60 0.86 1.87 0.30MeOH 595 39 4.88 612 33 467 4.20 0.66 1.57 0.81MeCN 593 42 4.87 611 34 497 3.98 0.63 1.58 0.93

a Absorption maximum in different solvents. b Extinction coefficients for the most intense absorption band. c Fluorescent bands in different sol-vents. d Stokes shift. e Fluorescence lifetime. f Fluorescence quantum yield, the standard errors are less than 5%. g Radiative rate constants werecalculated using kr = ΦF/τ.

hNonradiative rate constants were calculated using knr = (1 − ΦF)/τ.iNot available.

Fig. 3 The energy level diagram from left to right for the frontier MOsof the dyes 4–7 using the B3LYP functional with 6-31G(d) basis sets.

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their applications as sensors. F− is directly associated withmany human diseases.12 Fluoride is a strong hydrogen-bondacceptor, and has a high affinity for silicon. Based on this strat-egy, we designed probe 9 via the Knoevenagel condensationreaction13 between 4-hydroxybenzaldehyde and BODIPY 4, fol-lowed by the reaction with chlorotriisopropylsilane in the pres-ence of 4-dimethylaminopyridine (DMAP) and triethylamine(Scheme 3). The intermediate product 8 showed red absorption(λmax = 631 nm) and emission (λmax = 659 nm) in acetonitrile. Infact, probe 9 is highly soluble in common solvents and can beused in acetonitrile to evaluate its sensing capability.

The sensing properties of compound 9 were investigated bymonitoring the changes in fluorescence and UV-vis absorptionspectra. There were no obvious changes in the absorption andfluorescence peaks of probe 9 upon addition of other commonanions such as Cl−, Br−, I−, CO3

2−, HCO3−, CH3COO

−, SO42−,

NO2−, PO4

3−, SCN−, HPO42− and H2PO4

− (1 mM). Only F− trig-gered a red shift of the absorption band of 9 from 631 to738 nm, resulting in a color change from navy blue to light cyanwhich is visible to the naked eye (Fig. 4). It also leads to a sig-nificant decrease in the peak fluorescence intensity at 651 nmin the presence of F−, as a result of cleavage of the Si–O bond,inducing ICT from the phenyl to the BODIPY moiety along withsignificant changes in the photophysical properties (Fig. 5). Thelimitation for the detection of F− is evaluated to be 1.66 μM.Therefore, probe 9 is a highly selective and sensitive ratiometricchemodosimeter for F− in acetonitrile solution. In the case ofcompound 8, the responses for OH− and F− were also investi-gated, and it showed similar spectroscopic changes due to theformation of BODIPY-O− (Fig. S5†).

In order to demonstrate the practicality of probe 9 inbiology, we performed laser confocal fluorescence imaging offluoride in MCF-7 cells with fluorescent probe 9. The MCF-7

cells were pretreated with 20 µM of 9 for 40 min at 37 °C, and dis-played strong intracellular fluorescence (Fig. 6). And then treat-ment with F− for 30 min in the culture medium followed bywashing with phosphate buffered saline to remove extracellularF− resulted in the disappearance of the bright red fluorescence inthese cells. Bright field measurements confirm that the cells aftertreatment with both F− and 9 were viable throughout theimaging experiments. These phenomena indicated that probe 9can be used for the detection of intracellular F− in living cells.

Table 2 Selected transition energies and wave functions of 4–7 calcu-lated using the DT-DFT method with the B3LYP functional and 6-31G(d)basis set

StateaEnergy[eV] λ [nm] fb Orbitals (coefficient)c

4 S1 2.61 475 0.13 H−1 → L (77%), H → L (22%)S2 2.71 457 0.65 H−1 → L (22%), H → L (79%)

5 S1 2.60 478 0.32 H−1 → L (52%), H → L (48%)S2 2.71 458 0.50 H−1 → L (48%), H → L (52%)

6 S1 2.61 476 0.37 H−1 → L (49%), H → L (50%)S2 2.70 459 0.49 H−1 → L (50%), H → L (50%)

7 S1 2.48 500 0.59 H−1 → L (17%), H → L (84%)S2 2.60 477 0.19 H−1 → L (83%), H → L (17%)

a Excited state. bOscillator strength. cMOs involved in the transitions.

Fig. 5 Left: Fluorescence spectra of 9 (10−5 M) in CH3CN after theaddition of F− (1 mM). Inset: Plot of emission intensity versus TBAF con-centration. Right: Fluorescence spectra of 9 (10−5 M) in CH3CN after theaddition of 200 equiv. of various anions. The insert shows the colorchanges under light (above) and UV light (365 nm, below).

Fig. 4 Left: Absorption spectra of 9 (10−5 M) in CH3CN after theaddition of F−. Right: Absorption spectra of 9 (10−5 M) in CH3CN afterthe addition of 200 equiv. of various anions.

Scheme 3 Synthesis of probe 9.

Fig. 6 Confocal fluorescence images of F− in MCF-7 cells. (a) MCF-7cells loaded with 20 µM probe for 10 min at 37 °C. (b) Probe 9-loadedcells incubated with 40 µM F− for 30 min at 37 °C. (c) and (d) The brightfield images of (a) and (b) respectively. (e) and (f) Merge the image of thecorresponding fluorescence and bright field images. Scale bars: 20 µm.

Research Article Organic Chemistry Frontiers

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Conclusions

In summary, we have prepared and characterized a series ofthieno[3,2-b]thiophene-fused non-symmetric BODIPY dyes. Byfurther modifying the non-symmetrical BODIPY dye 4, a colori-metric and fluorescence chemodosimeter sensor for the reco-gnition of fluoride ions based on Si–O bond cleavage is obtained.MCF-7 cells imaging experiments demonstrate that probe 9 is ableto perform in living cell. The synthesis and functional modifi-cation of the non-symmetric near-infrared BODIPY dye provides aneffective way for the development of red or NIR fluorescent dyes.

Procedure and characterizationSpectroscopic measurements

UV-Vis spectra were obtained by using a Shimadzu UV-1800spectrophotometer. The fluorescence spectra and the fluo-rescence lifetimes of the samples were recorded on a HoribaJobinYvon Fluorolog-3 spectrofluorimeter. All solvents were ofUV spectroscopic grade for spectrometry.

Samples for absorption and emission measurements wereplaced in 1 cm × 1 cm quartz cuvettes. For all measurements,the temperature was kept constant at (298 ± 2) K. A dilute solu-tion with an absorbance of less than 0.05 at the excited wave-length was used for the measurement of fluorescencequantum yields. The luminescence quantum yields in solutionwere measured by using fluorescein with excited wavelengthrhodamine 6G (Φ = 0.88, in ethanol) as a reference.14 Thequantum yield Φ as a function of solvent polarity is calculatedusing the following equation.15

Φsample ¼ ΦstdIsample

Istd

� �Astd

Asample

� �nsample

nstd

� �2ð1Þ

where subscripts sample and std denote the sample and stan-dard, respectively, Φ is the quantum yield, I is the integratedemission intensity, A stands for the absorbance, and n is therefractive index.

The fluorescence lifetimes of the samples were determinedwith a Horiba JobinYvon Fluorolog-3 spectrofluorimeter.Absorption and emission measurements were carried out in1 × 1 cm quartz cuvettes. The goodness of fit of the singledecays as evaluated by the reduced chi-squared (χ2R) and auto-correlation function C( j ) of the residuals was below χ2R < 1.2.

When the fluorescence decays were monoexponential, the rateconstants of radiative (kr) and nonradiative (knr) deactivation werecalculated from the measured fluorescence quantum yield (ΦF)and fluorescence lifetime (τ) according to eqn (2) and (3):

kr ¼ ΦF=τ ð2Þknr ¼ ð1� ΦFÞ=τ ð3Þ

Computational details

The ground state structures of compounds 4–7 are optimizedusing the density functional theory (DFT) method with the

B3LYP functional and 6-31G(d) basis set. The absorption pro-perties were predicted by the time-dependent (TD-DFT)method with the same basis set. All of the calculations wereperformed with the Gaussian09 program package.10

Cell culture and confocal imaging

MCF-7 cells were maintained following the protocols provided bythe American Type Culture Collection (ATCC). MCF-7 cells werecultured in Dulbecco’s modified Eagle’s medium (DMEM) andsupplemented with 10% fetal bovine serum (FBS), NaHCO3

(2 g L−1), and 1% antibiotics (penicillin/streptomycin, 100 U ml−1)for 24 h. Cultures were maintained at 37 °C under a humidifiedatmosphere containing 5% CO2 and 95% air. Confocal fluo-rescence imaging studies were performed on an LSM 710 confocallaser-scanning microscope (Carl Zeiss Co., Ltd). Prior to imaging,the medium was removed. Cell imaging was carried out afterwashing the cells with phosphate buffered saline three times.

X-ray structure determination

The X-ray diffraction data were collected on a Bruker SmartApex CCD diffractometer with graphite monochromated Mo Kαradiation (λ = 0.71073 Å) using the ω–2θ scan mode. The struc-ture was solved by direct methods and refined on F2 by full-matrix least-squares methods using SHELX-2000.16 All calcu-lations and molecular graphics were carried out on a computerusing the SHELX-1997 program package and ORTEP2 v2.‡

Experimental sectionSynthesis of (7H-thieno[2′,3′:4,5]thieno[3,2-b]pyrrol-6-yl)methanol (2)

To a stirred solution of 1 (1.0 g, 4 mmol) in anhydrous THF(80 mL) was added LiAlH4 (304 mg, 8 mmol) slowly at 0 °C.

‡Crystal data: Compound 4: A brown block-like crystal of the approximatedimensions was measured. Triclinic, space group P1̄, a = 8.2395(4) Å, b =8.3633(4) Å, c = 21.5671(10) Å, α = 87.1040(10)°, β = 82.8260(10)°, γ =79.6960(10)°, V = 1458.72(12) Å3, Z = 4, F(000) = 680.0, ρ = 1.513 Mg m−3,R1 [I > 2σ(I)] = 0.0433, wR2 [all data] = 0.1352, GOF = 1.032. CCDC no. 1879308†for 4 containing the supplementary crystallographic data for this paper.Compound 5: A brown block-like crystal of the approximate dimensions was

measured. Monoclinic, space group P21/c, a = 14.9084(8) Å, b = 14.6028(8) Å, c =20.2000(8) Å, α = 90.00°, β = 130.628(2)°, γ = 90.00°, V = 3337.6(3) Å3, Z = 1,F(000) = 1488.0, ρ = 1.434 Mg m−3, R1 [I > 2σ(I)] = 0.0406, wR2 [all data] = 0.1149,GOF = 1.029. CCDC no. 1941926† for 5 containing the supplementary crystallo-graphic data for this paper.Compound 6: A brown block-like crystal of the approximate dimensions was

measured.Monoclinic, Space group P21/c, a = 10.326(2) Å, b = 7.2969(15) Å, c = 24.541(5) Å,

α = 90.00°, β = 100.637(5)°, γ = 90.00°, V = 1817.4(7) Å3, Z = 4, F(000) = 808.0, ρ =1.419 Mg m−3, R1 [I > 2σ(I)] = 0.0515, wR2 [all data] = 0.1369, GOF = 0.997. CCDC no.1935458† for 6 containing the supplementary crystallographic data for this paper.Compound 7: A brown block-like crystal of the approximate dimensions was

measured.Orthorhombic, space group P212121, a = 10.5714(19) Å, b = 12.149(2) Å, c = 13.188

(2) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V = 1693.8(5) Å3, Z = 4, F(000) = 776.0, ρ =1.491 Mg m−3, R1 [I > 2σ(I)] = 0.0456, wR2 [all data] = 0.0986, GOF = 1.045. CCDC no.1941928† for 7 containing the supplementary crystallographic data for this paper.

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The mixture was stirred at room temperature for 24 h and thencooled to 0 °C. The mixture was diluted with Et2O (50 mL) andquenched with 15% aqueous sodium hydroxide (0.3 mL). Theorganic layer was washed with brine, and dried over anhydrousNa2SO4. After removing the solvents by evaporation, the result-ing residue 2 was obtained as a grey solid (470 mg, 57%),which was used for the next step without further purification.

Synthesis of 7H-thieno[2′,3′:4,5]thieno[3,2-b]pyrrole-6-carbaldehyde (3)

Activated manganese dioxide (1.97 g, 22.7 mmol) was added toa stirred solution of 2 (470 mg, 2.27 mmol) in CH2Cl2 (20 mL).The reaction mixture was kept for 24 h at room temperature.The resulting solution was diluted with CH2Cl2 (100 mL), andfiltered over Celite. The filtrate was evaporated to drynessunder vacuum, and the crude product was purified using achromatography column to afford 3 as a white solid (329 mg,70%). 1H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 7.76 (d, J =4 Hz, 1H), 7.50 (d, J = 4 Hz, 1H), 7.42 (s, 1H).

Synthesis of 4

Under a nitrogen atmosphere, POCl3 (0.04 mL, 0.44 mmol)was added to a stirred solution of 3 (78 mg, 0.38 mmol) and2,4-dimethylpyrrole (0.04 mL, 0.38 mmol) in CH2Cl2 (20 mL) at0 °C. When the reaction was complete, as shown by TLC ana-lysis, Et3N (0.53 mL, 3.8 mmol) was added at 0 °C and stirredfor 10 min, and then BF3·OEt2 (0.56 mL, 4.4 mmol) was addedto the mixture. The reaction mixture was stirred for 12 h atroom temperature, quenched by the addition of saturatedaqueous NaHCO3, and then extracted with CH2Cl2. Theorganic layer was dried over Na2SO4, and evaporated todryness under reduced pressure. The residue was purifiedusing a chromatography column to afford 4 as a red solid(80 mg, 64%). 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 4 Hz,1H), 7.22 (d, J = 4 Hz, 1H), 7.15 (s, 1H), 6.99 (s, 1H), 6.15 (s,1H), 2.65 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ:161.59, 148.99, 147.67, 144.59, 137.08, 133.93, 132.80, 124,123.47, 121.50, 121.10, 118.33, 46.29, 15.33, 11.48. HRMS-ESI:m/z: calcd for [C15H11BF2N2S2 + Na]+: 355.0320, found:355.0316.

The synthesis of 5 is similar to that of 4 with a yield of 56%1H NMR (400 MHz, CDCl3) δ: 7.57 (d, J = 4 Hz, 1H), 7.22 (d, J =4 Hz, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 2.62 (s, 3H), 2.42 (dd, J1 =J2 = 8 Hz, 2H), 2.15 (s, 3H), 1.1 (t, J = 8.0 Hz, 3H). 13C NMR(101 MHz, CDCl3) δ: 161.99, 148.08, 146.62, 140.26, 136.84,134.78, 133.18, 131.93, 124.17, 122.41, 121.42, 117.26, 47.04,17.43, 14.37, 13.45, 9.6. HRMS-ESI: m/z: calcd for[C17H15BF2N2S2]

+: 360.0735, found: 360.0749.

The synthesis of 6 is similar to that of 4 with a yield of 52%1H NMR (400 MHz, CDCl3) δ: 7.56 (d, J = 4 Hz, 1H), 7.21 (d, J =4 Hz, 1H), 7.10 (s, 1H), 6.92 (s, 1H), 2.82 (s, 3H), 2.31 (s, 3H),1.40 (s, 9H). 13C NMR (101 MHz, CDCl3) δ: 162.70, 148.15,146.68, 139.35, 139.13, 137.17, 136.71, 133.31, 132.03, 124.16,122.11, 121.42, 117.24, 33.62, 31.49, 17.55, 17.52, 17.50, 12.95.

HRMS-ESI: m/z: calcd for [C19H19BF2N2S2]+: 388.1049, found:

388.1052.

The synthesis of 7 is similar to that of 4 with a yield of 30%1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 7.6 Hz, 2H), 7.45 (m,4H), 7.31 (s, 1H), 7.26 (s, 1H), 7.14 (d, J = 4.4 Hz, 1H), 6.99 (s,1H), 6.66 (d, J = 4.2 Hz, 1H). HRMS-ESI: m/z: calcd for[C19H11BF2N2S2 + Na]+: 403.0321, found: 403.0325.

Synthesis of 8

A solution of 4 (80 mg, 0.24 mmol), 4-hydroxybenzaldehyde(35 mg, 0.29 mmol) and a few crystals of p-TsOH in a mixtureof toluene (20 mL) and piperidine (1.0 mL) was placed in around bottom flask equipped with a Dean Stark trap. Themixture was heated until it evaporated to dryness. Aftercooling to room temperature, the resulting mixture was dis-solved in DCM and washed with water three times. Theorganic phase was dried over Na2SO4 and the solvent was evap-orated under reduced pressure. The resulting crude residuewas purified by silica gel flash column chromatography toyield 8 as a dark green solid (40 mg, 38%). 1H NMR (400 MHz,THF-d8) δ: 8.88 (s, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 9.2Hz, 4H), 7.38 (s, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.07 (s, 1H), 6.91(s, 1H), 6.83 (d, J = 8.2 Hz, 2H), 2.30 (s, 3H). 13C NMR(101 MHz, THF-d8) δ: 160.72, 159.49, 148.49, 146.97, 144.32,140.94, 139.56, 138.31, 133.96, 132.71, 130.40, 128.58, 124.97,121.90, 121.81, 117.90, 117.19, 116.62, 116.27, 11.15.HRMS-ESI: m/z: calcd for [C22H15BF2N2OS2 + Na]+: 459.0583,found: 459.0585.

Synthesis of 9

Under a nitrogen atmosphere, chlorotriisopropylsilane(0.05 mL, 0.25 mmol) was slowly added to a solution of 8(20 mg, 0.05 mmol), 4-dimethylaminopyridine (3 mg,0.03 mmol) and Et3N (4 drops) in CH2Cl2 (20 mL). The reac-tion mixture was stirred for 4 h at room temperature andquenched with distilled water. The resulting mixture wasextracted with CH2Cl2, washed with brine, and dried overNa2SO4. After removing the solvent under reduced pressure,the residue was purified using a chromatography column togive 9 as a navy blue solid (16 mg, 54%). 1H NMR (400 MHz,CDCl3) δ: 7.61 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 6.4 Hz, 3H), 7.33(d, J = 16.2 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.02 (s, 1H), 6.93(t, J = 8.0 Hz, 3H), 6.68 (s, 1H), 2.20 (s, 3H), 1.32 (m, 3H), 1.20(m, 18H). 13C NMR (101 MHz, CDCl3) δ: 158.38, 158.24,158.11, 148.28, 146.70, 143.51, 139.85, 138.76, 137.53, 133.82,132.22, 129.83, 129.31, 129.25, 124.25, 121.48, 120.92, 120.55,117.32, 117.02, 116.66, 31.72, 22.79, 18.78, 18.04, 17.68, 17.02,14.22, 13.17, 12.84, 11.52. HRMS-ESI: m/z: calcd for[C31H35BF2N2OS2Si + Na]+: 615.1919, found: 615.1925.

Conflicts of interest

There are no conflicts to declare.

Research Article Organic Chemistry Frontiers

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Acknowledgements

We thank the National Natural Science Foundation of China(No. 21801057, 21871072), the Program for High-LevelInnovation Team in Universities of Zhejiang Province, theresearch funding project of Hangzhou Normal University(2018PYXML009, 2018QDL002, 2018YLXK16), and the OpenFunds of Nanjing University State Key Laboratory ofCoordination Chemistry (SKLCC1813) for financial support.Theoretical calculations were carried out at the ComputationalCentre for Molecular Design of Organosilicon Compounds,Hangzhou Normal University.

Notes and references

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