# Synthesis of indazole-based fluorophores

Thibault Gallavardin, Xavier Franck

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Thibault Gallavardin, Xavier Franck. Synthesis of indazole-based fluorophores. Organic & Biomolecular Chemistry, In press, 10.1039/D5OB01732G. hal-05419511

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# Synthesis of indazole-based fluorophores

Thibault Gallavardin*ª and Xavier Franck*ª

Indazoles are commonly used in medicinal chemistry as indole surrogates, nonetheless, their unique electronic scaffold involving two tautomeric forms make them promising for optical applications. This review summarizes synthetic routes to indazole-based fluorophores and other photoactive compounds, including photosensitizers and photochromic molecules. They include N1-, N2-substituted derivatives as well as fused indazoles and detail their various applications as bioprobes, metal ligands, and photoswitches

## 1. Introduction

Heterocyclic compounds are the basis for synthetic innovations in chemistry and are frequently used in medicinal chemistry or incorporated in the scaffold of fluorescent molecules. Unlike indoles, however, indazoles are rare heterocycles, hardly found in nature but of significant pharmacological interest.¹⁻⁶ Indazole is an aromatic heterocycle composed of fused benzene and pyrazole rings, also known as benzpyrazole or isoindazone. Its five-membered ring contains two nitrogen atoms and exhibits ring tautomerism, existing mainly in the form of the thermodynamically favoured 1H-indazole tautomer in the solid, liquid, and gaseous phases. The 2H-indazole form is less stable,⁷ and the 3H- even less since it only exists if two substituents are present at the C3 position (Scheme 1). The planar nature of the indazole ring allows for extensive derivatisation through positional functionalization and side chain modifications. As 1H- or 2H-indazoles have different electronic repartitions that can be fixed by functionalizing either one or the other position, different delocalized π-conjugated systems driving unique fluorescence properties can be obtained, notably solvatochromism, viscosity-dependence, aggregation-induced emission (AIE), and, in some cases, even phosphorescence at low temperature. Substitution at key positions (e.g., position 3) enables extension of the π-conjugated system and modulation of donor-acceptor character, thereby affecting orbital energies (HOMO/LUMO) and excited-state charge-transfer properties. The pKa of the N-H of the indole is 13.86, preventing deprotonation in the biological environment.

However, it decreases to pKa*=10.10 in the excited state⁷ and can be further decreased by the presence of electron-withdrawing groups, increasing its sensitivity to its environment.

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Tautomerism of indazole ring.</figcaption></figure>

The examples presented in this review will highlight the structural sensitivity of indazole-based fluorophores and reveal their potential as tuneable luminescent platforms for use in sensing, imaging, and materials science. Emphasis will be drawn on the synthetic routes toward indazole-based fluorophores according to their substitution, and in the last section, different applications, notably cell-staining, will be reported.

## 2. NH-indazoles

N-Unsubstituted 1H-indazoles have been poorly studied for their photophysical properties. Because of the tautomerism between 1H- and 2H- forms, these molecules have different fluorescence properties, complicating their studies. 3-ketoindazoles 2 have been reported to exhibit phosphorescence at 80 K in solution with a lifetime up to 1.5 seconds or at room temperature in the solid state; they were prepared by cyclization of alkynyl substituted 2-triazenes 1 in the presence of TMSCl (Scheme 2).⁸
<figure><img src="image_3.png" /><figcaption>**Scheme 2.** Synthesis of 3-ketoindazoles and phosphorescence in 2-MeTHF at 80 K (Ar=Ph). Reproduced from ref. 8 with permission from the Royal Society of Chemistry.</figcaption></figure>

Styryl-indazoles **4** prepared by Knoevenagel reaction from 7-formyl-indazoles **3** are efficient photochromic dyes that can isomerize then cyclize on a judiciously placed electrophilic moiety. In this case, the molecule can release a proton after the isomerization/cyclisation sequence under light activation (470 nm) and is named a photoacid. The reverse reaction can be achieved by exposure to light at another wavelength e.g. 365 nm. (Scheme 3).⁹,¹⁰ A stationary state can be reached and an isobestic point is obtained at 351nm from the two irradiations (470 and 365 nm) (Scheme 3b). The photoswitching of **4** can be obtained without fatigue upon alternatingly irradiating at 470 nm and 365 nm light for 11 cycles (Scheme 3c).

<figure><img src="image_4.png" /><figcaption>b) stationary state</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 3.** Synthesis and photoswitching of Indazole photoacid **4**. Adapted with permission from ref. 9.</figcaption></figure>

Indazole derivative containing salicylaldimine **5** do not show fluorescence in solution but is strongly emissive in the solid state, although with lower wavelength than indole analogues, it is easily prepared by condensation of salicylaldehyde on 3-amino indazole (Scheme 4).¹¹

<figure><img src="image_6.png" /><figcaption>**Scheme 4.** Salicylaldimine-containing indazole and solid-state fluorescence. Reproduced from ref. 11 with permission from the Royal Society of Chemistry.</figcaption></figure>

### 3. 1N-substituted indazoles
N-substituted 1H-fluorescent indazoles can be prepared by two main strategies: 1) 1N-functionalization of the free indazole by eg. alkylation or arylation and 2) construction of the indazole ring from hydrazone. When considering functionalization of the free indazole, a mixture of 1N and 2N-alkylation/arylation can be obtained due to tautomerism, 1N-substitution being, however, the predominant reaction.

5- or 6-aminoidazoles can be tris-arylated under Ullman coupling conditions to give the tri-arylated derivatives with low yields, which show absorption up to 400 nm and emission maxima up to 441 nm. 5-amino derivatives 6 show red-shifted absorption compared to the 6-amino derivatives 7 (Scheme 5).¹²

<figure><img src="image_7.png" /><figcaption>**Scheme 5.** Fluorescent aminoindazoles.¹²</figcaption></figure>

5-Aminoindazole can also be converted into diazo compound 8 by nitrosation followed by the addition of dimethylaniline. The remaining free 1H-indazole can be deprotonated and reacted with CS₂ before the addition of an alkylating agent. The so-obtained indazole 9 can be incorporated in a polymer via RAFT polymerization technique, leading to a terminal azobenzene functionalized polystyrene. This polymer can self-assemble into stable spherical aggregates upon UV irradiation, leading to a significant fluorescence enhancement (Scheme 6).¹³

<figure><img src="image_8.png" /><figcaption>**Scheme 6.** Fluorescent polymer incorporating 5-diazo-indazole.¹³</figcaption></figure>

Similarly, 3-carboxymethylindazole 10 can be regioselectively arylated at N-1 position by o-chloro-nitroaryl(heteroaryl) derivatives followed by reduction of the nitro moiety to give the corresponding amine 11 (Scheme 7). These compounds exhibit solid-state fluorescence up to 540 nm.¹⁴

<figure><img src="image_9.png" /><figcaption>**Scheme 7.** Fluorescent 3-carboxymethylindazoles.¹⁴</figcaption></figure>

1N-substituted indazoles can be incorporated in an acridine scaffold by condensation of 5-nitro-indazole 12 with various aryl-acetonitrile derivatives 13 under basic conditions, leading to pyrazoloacridines 14. These compounds exhibit a broad absorption band with a maximum at 375 nm along with emission up to 450 nm when substituted by electron-donating moieties (scheme 8).¹⁵⁻¹⁷
<figure><img src="image_10.png" /><figcaption>**Scheme 8.** Synthesis and spectroscopic data of some pyrazoloacridines in CHCl<sub>3</sub>, adapted from ref. 17 Creative Common CC BY.</figcaption></figure>

As for NH indazoles, 1N-Me indazoles can be part of photochromes **17** that are built by the addition of 6-bromoindazole **15** on a functionalized perfluorocyclopentene **16** after lithium-halogen exchange (Scheme 9). Photochromism is observed after irradiation at 297 nm, as shown by the appearance of a new visible absorption band (566 nm) due to the formation of the closed-ring isomer. The cyclization can be reversed upon irradiation at λ > 500 nm.<sup>18</sup>

<figure><img src="image_11.png" /><figcaption>**Scheme 9.** Indazole-based photochrom and appearance/disappearance of new absorption bands (R=H) in hexane, adapted from ref. 18 with permission.</figcaption></figure>

Benzothiadiazole derivatives can also be prepared by Wittig reaction on protected 3-indazolecarboxaldehydes **18**. These resulting compounds are very fluorescent in dichloromethane (QY: **19a**: 0.92, **19b**: 0.96, and **19c**: 0.77), and present large Stokes' shifts. They also exhibited noticeable fluorescence in the solid state, with a quantum yield of 0.31 for 1N-Me indazole **19b** (Scheme 10).<sup>19</sup>
<figure><img src="image_12.png" /><figcaption>**Scheme 10.** Synthesis and solid-state fluorescence of benzothiadiazole-derived indazoles **19a-c**. Adapted from ref 19 Creative Common CC BY.</figcaption></figure>

N-1 functionalized indazoles can also be prepared regioselectively from hydrazine or hydrazone derivatives. Addition of various hydrazones **20** on *p*-benzoquinone in the presence of Pd(OAc)₂ and TFA provided the corresponding 6-hydroxyindazoles **21** via an Aza-Nenitzescu reaction mechanism (Scheme 11).²⁰,²¹ The introduction of electron-withdrawing groups (R²) on the skeleton generates a red-shift in both absorption and emission. These compounds are either emissive in solid state (absorption up to 440nm and emission up to 570 nm) or in solution (absorption up to 412nm and emission up to 578 nm in THF). The same reaction performed in the presence of 3 equivalents of *p*-benzoquinone resulted in a double addition of the benzoquinone moiety, providing hydroxbenzofuran-fused indazoles **22**.

<figure><img src="image_13.png" /><figcaption>**Scheme 11.** Aza-Nenitzescu synthesis of indazoles and solid-state fluorescence adapted from refs. 20 and 21 with permission.</figcaption></figure>

Similarly, aromatic or aliphatic hydrazine derivatives can add onto *p*-quinone methides **23** in the presence of a palladium catalyst to give the N-1 functionalized indazole **24** (Scheme 12). One limitation is that *p*-quinone methide must be sterically hindered to be stable. The resulting indazoles show absorption bands ranging from 316 to 338 nm and emission bands ranging from 386 to 420 nm in CH₃CN. They show a weak bathochromic shift (18 nm) from toluene to DMSO, while quantum yields range from 31 to 85% with higher values when the indazole is substituted by electron-donating moieties.²²
<figure><img src="image_14.png" /><figcaption>**Scheme 12.** Synthesis of indazoles from hydrazine and *p*-quinone methide.²²</figcaption></figure>

Hydrazine derivatives can also add onto arylhalides or 2-halogenopyridines substituted by 3-acylpyrrole 25 to give indazoles or aza-indazoles 26 (Scheme 13). The obtained products exhibit absorbance wavelength ranging from 311 and 377 nm, while emission ranges from 390 to 454 nm and a Stokes' shift up to 121 nm in dichloromethane. Notably, the substituent on the 1N of the indazole (Me, Bn, or even H) has little or no effect on the absorption and emission wavelengths. The presence of a heteroaromatic ring (azaindazole) results in red-shifted absorption (25 nm) and emission (50 nm) compared to the corresponding aromatic ring (indazole).²³

<figure><img src="image_15.png" /><figcaption>**Scheme 13.** Synthesis of indazoles from hydrazine and (het)aryl halide.²³</figcaption></figure>

Benzannulation of pyrazoles 27a-b with alkynes yields N-1-functionalized indazoles 28a-b, where the aromatic ring is fully substituted by the same residue coming from the lateral chain of the alkyne (Scheme 14). Two different conditions can be used, depending on the nature of the substitution at position 4 of the pyrazole (either H or Br). These indazoles exhibit solid-state fluorescence with absorption at 315 nm and deep blue emission at

416 nm in the case of 4-OMePh substituents on the aromatic ring (emission in a CH₃CN solution being at 395 nm).²⁴

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /><figcaption>**Scheme 14.** Synthesis of indazoles by benzannulation of pyrazoles, adapted from ref. 24 with permission.</figcaption></figure>

Oxabicyclic alkenes 28 prepared by reaction of furan on *in situ* generated benzyne 27 are useful intermediates for the preparation of β-extended indazoles. Indeed, they can react with nitrile imines 29 dipoles by 1,3-dipolar cycloaddition and, after deoxygenation followed by aromatization, oxadisilole-fused 1H-benzo[f]indazoles 30 and 1H-naphtho[2,3-f]indazoles 31, were obtained (Scheme 15).²⁵ Both series exhibit fluorescence with oxadisilole-fused 1H-benzo[f]indazoles series absorbing between 386 and 400 nm and emitting between 446 and 523 nm, and the 1H-naphtho[2,3-f]indazoles absorbing between 484 and 487 and emitting between 499 and 502 nm in CH₂Cl₂. Introduction of R = NO₂ group resulted in a
red-shifted absorption and emission (400/523) compared to R=H (386/446), although the quantum yield dropped from 0.80 to 0.16. In addition, it has also been reported that the intermediate oxabicyclic alkene, although not fully conjugated, displayed fluorescence properties.²⁶

<figure><img src="image_19.png" /><figcaption>**Scheme 15.** Synthesis of oxadisilole-fused 1H-benzo[f]indazoles and 1H-naphtho[2,3-f]indazoles.²⁵</figcaption></figure>

## 4. 2N-substituted indazoles

Few methods for the regioselective formation of 2N-substituted indazoles have been described, and alkylation/arylation of the NH of the free indazole mostly occurs at the N-1 position. In particular conditions, such as Al or Ga/Al catalysis, allylation or alkylation occurs only at the N-2 position.²⁷ These conditions have been employed to prepare

fluorescent indazoles after reaction of indazole **32** with α-bromocarbonyl compounds, which, after reduction of the carbonyl followed by chlorination and β-elimination, yield 2-alkeny-2H indazoles **33** (Scheme 16).²⁸ Coumarin-containing indazole **35** can also be prepared by Knoevenagel condensation. These two compounds fluoresce around 400 nm while absorbing around 330 nm in THF, they both display high quantum yield.

<figure><img src="image_20.png" /><figcaption>**Scheme 16.** Synthesis 2N-substituted indazole by regioselective alkylation.²⁸</figcaption></figure>

The Rhodium (II) catalyzed reaction of diazo compounds with aromatic aldehydes proved to be very effective for the preparation of 2N-arylated indazoles **36**.²⁹ In the case of unsymmetrical diazo compounds, the steric and electronic effects on both aromatic rings play an important role on the regioselectivity of the indazole substitution, although 2N substituted ones were always obtained **37a** and **37b** can be formed. (Scheme 17). Depending on their substitution pattern, the indazoles so obtained exhibit absorptions ranging from 303 to 351 nm, whereas their emission ranges from 398 to 438 nm with quantum yield values ranging from <1 to 26% in 10 mM HEPES at pH 7.3.
<figure><img src="image_21.png" /><figcaption>**Scheme 17.** Synthesis of 2N-substituted indazoles **36** and **37** via Rhodium catalyzed reaction of diazo compounds, and absorption and fluorescence data in 10 mM HEPES at pH 7.3. Adapted from ref. 29 with permission.</figcaption></figure>

BOSHPYs are BODIPYs analogues with an indazole core are easily prepared by condensation of 1,3-diiminoisoindoline or 3-iminoisoindolinone with 3-aminoindazole in EtOH. The intermediates **38** and **39** were treated with BF₃.Et₂O in the presence of a base to give the corresponding borylated products **40** and **41** as crystalline solids (Scheme 18).³⁰ The compounds exhibit strong fluorescence and aggregate with either hypochromic or bathochromic shift in absorbance or fluorescence, and have high quantum yields. Unlike Bodipys, these compounds have large Stokes' shifts from 95 to 114 nm.

<figure><img src="image_22.png" /><figcaption>**Scheme 18.** Synthesis of BOSHPY derivatives adapted from ref. 30 with permission.</figcaption></figure>

### 5. Fused substituted indazoles

Fused substituted indazoles result generally in highly fluorescent scaffolds with large Stokes' shifts because of extended conjugation and rigidification of the skeleton that diminishes non-radiative deexcitation pathways. The fused polycyclic molecules incorporate the indazole moiety mostly at its N-2 and C-3 position and can be prepared from either an already built indazole skeleton (either NH or 2N-substituted) or from diazo compounds.

3-amino indazoles react with carbonyl compounds under various conditions to form fused pyrimidoindazoles **42**. One or two equivalents of electrophilic compounds are necessary, either as aldehyde and ketone functions or by using an
alkyne that could be activated by a metal. (Scheme 19).³¹⁻³³ The pyrimidazoles so obtained exhibit weak quantum yields but large Stokes' shift (usually >200 nm) with absorption wavelengths around 300 nm and emission above 500 nm, depending on the nature of the substituents and the solvent. The incorporation of a selenium residue in **43** lowers its absorption to 286 nm, and leads to a strong solvatochromism with emission ranging from 339 to 427 nm.

<figure><img src="image_23.png" /><figcaption>**Scheme 19.** Synthesis of fused pyrimidoindazoles.³¹⁻³³</figcaption></figure>

Pyrimidazoles can also be prepared by condensation of 3-aminoindazole with a methylketone and a β-cetoamide in the presence of I₂. In this case, an extra pyrrolidone ring is formed which is fused with the pyrimido[1,2-**b**]indazole skeleton (Scheme 20).³⁴ The first reactive intermediate of the reaction sequence is generated by condensation of the methylketone

on the β-cetoamide to give **44** bearing a highly activated double bond, which then reacts with 3-amino indazole in a Michael fashion. The so obtained compound **45** shows aggregation induced emission (AIE) as the fluorescence (λem 360 nm, λem ≈ 525 nm) first decreased as the water content increased up to 70% then fluorescence intensity increased as the water fraction increased from 80 to 95%.

<figure><img src="image_24.png" /><figcaption>**Scheme 20.** Synthesis of pyrrolidone-fused pyrimido[1,2-**b**]indazoles, and their aggregation induced emission adapted from ref. 34 with permission from the Royal Society of Chemistry.</figcaption></figure>

When a similar condensation of 3-amino indazoles is done with two equivalents of a methylketone and in the presence of catalytic amount of CuOTf, MnCl₂ and I₂, aromatization is prevented and 3-oxo-pyrimido[1,2-**b**]indazoles **46** are obtained. (Scheme 21).³⁵ The obtained fused indazole exhibit very strong fluorescence intensity as the unsubstituted molecule (R = H) shows absorption and emission wavelengths at 475 nm and 576 nm, respectively, in DMSO with 62% quantum yield. There is little solvatochromism however, but intensity of the signal is strongly dependent of the solvent.
<figure><img src="image_25.png" /><figcaption>**Scheme 21.** Synthesis of fused 3-oxo-pyrimido[1,2-**b**]indazoles, and spectroscopic data for R=H adapted from ref. 35 with permission.</figcaption></figure>

Free NH indazoles can react at either N-1 or N-2 positions to generate fused polycyclic fluorophores. 1*H*-indazole-7-carbaldehyde reacts with trans-cinnamaldehyde in the presence of an organocatalyst that catalyses the reaction via an iminium–enamine cascade process. This enables the synthesis of chiral fused tricyclic indazole derivatives **47** (e.e. up to 88%) through an aza-Michael addition/intramolecular cyclization. Photophysical properties show absorption and emission maxima at 396 and 474 nm in chloroform, respectively for Ar = 4-ClPh (Scheme 22).³⁶

<figure><img src="image_26.png" /></figure>

Ar = Ph, ClPh, OMePh, NO₂Ph, 2-naphthyl, 2-thienyl

<caption>**Scheme 22.** Synthesis of fused chiral tricyclic 1-N substituted indazoles.³⁶</caption>

Other electrophilic moieties can be used, such as sulfoxonium ylids,³⁷ iodinium ylids,³⁸,³⁹ cyclopropenones,⁴⁰ and alkynes⁴¹ that give rise to N2-functionalized fused indazoles **48-50** (Scheme 23). In the case of Rhodium-catalyzed oxidative annulation of 1*H*-indazoles with alkynes, the obtained indazolo[3,2-*a*]isoquinolines **50** show strong solvatochromism with absorption/emission shifting from 404/458 nm in MeOH to 410/583 nm in MeCN in the case of the nitro-substituted derivative.
<figure><img src="image_27.png" /></figure>

48a

TFE, 100 °C, 12 h
17-89%

R = Ph, OMePh, MePh, FPh, ClPh, BrPh, CF₃Ph...

<figure><img src="image_28.png" /></figure>

48b

AgOAc (10%), PivOH (1 equiv.)

TFE, 100 °C, 3 h; 6-99%

OR

(RhCp\*Cl₂)₂ (2%), AgSbF₆ (4%),

AcOH (2 equiv.) MeOH, 38 °C, 12 h; 0-99%

<figure><img src="image_29.png" /></figure>

49

AdCOOH

HFIP 100 °C, air, 24 h

26-72%

Ar = Ph, MePh, tBuPh, FPh, CF₃Ph...

<figure><img src="image_30.png" /></figure>

50

dioxane, 80°C, 12h, air

0-95%

R¹ = Me, Br, Cl, F...

R² = PhMe, PhBr, PhCl, PhF, PhCF₃, Me, Et, Pr...

<figure><img src="image_31.png" /></figure>

R¹ = pNO₂

R² = Ph

**Scheme 23.** Synthesis of fused 2N-substituted indazoles from refs 37-41. Fluorescence spectra of **50** (R¹ = pNO₂, R² = Ph) adapted from ref. 41 with permission from the Royal Society of Chemistry.

**6. Indazoles as ligands in metal complexes**

Nitrogen atoms on the indazole ring make this heterocycle suitable to be used as a ligand in metal complexes. In this way, indazole ruthenium(III) complexes KP1019 and KP1339 were developed as an anti-cancer drug to kill cisplatin-resistant tumors (Scheme 24). However, there are only a few examples of indazole-containing transition metal complexes with reported luminescence. For example, the incorporation of indazole into copper complex **51** increased its fluorescence,⁴² while the opposite effect was observed in complex **52**.⁴³ This ON/OFF effect was used to perform selective titration of Cu²⁺ in water. Indazoles can be coupled via both nitrogen atoms with pyridine to form tridendate indazolylpyridines. These ligands have been used to prepare iron complexes such as **53**; unfortunately, in this case, only intraligand (IL) emission was observed.⁴⁴

<figure><img src="image_32.png" /></figure>

51

X⁺ = H⁺ KP1019

X⁺ = Na⁺ KP1339

<figure><img src="image_33.png" /></figure>

52

<figure><img src="image_34.png" /></figure>

**Scheme 24.** Metal complexes bearing indazole ligands.⁴²⁻⁴⁴

Indazoles can also serve as antennas in lanthanide complexes, absorbing light and transferring the energy to the lanthanide-centred orbitals. Their incorporation in these complexes also helps to shield the lanthanides from the outer environment, which increases the luminescence lifetime and intensity of the lanthanide ion. In this way, indazole can sensitize dysprosium, terbium, and europium in diketonate complexes **54** and **55**, thanks to its high-lying triplet state energy (Scheme 25).⁴⁵
<figure><img src="image_35.png" /><figcaption>**Scheme 25.** Indazole as a ligand in lanthanide complexes.<sup>45</sup></figcaption></figure>

The presence of two nitrogen atoms enables the coupling of indazole to larger structures, allowing for the construction of cages that increase the stability of the complexes and better shield the lanthanide ions from external interactions. In this way, indazolylpyridine ligands can be modified to incorporate more chelating functions, such as carboxylates, leading to luminescent terbium complexes with an emission quantum yield of up to 0.35 for complex **56** in water (Scheme 26). However, the replacement of indazole by diazole provided stronger luminescence in terbium complexes.<sup>46,47</sup> The sensitization of europium turned out to be less efficient, with a maximum of 0.16 with ligand **57**; this was attributed to a higher quenching by water caused by O-H vibrations.

<figure><img src="image_36.png" /><figcaption>**Scheme 26.** Terbium and europium, indazolylpyridine complexes **56-61**, and their luminescence quantum yields.<sup>46,47</sup></figcaption></figure>

The central pyridine can be replaced by triazine, which yields better two-photon absorbing (TPA) ligands (Scheme 27). The increase in TPA is due to the more electron-withdrawing nature of the triazine and the introduction of an aniline moiety. These two elements promote internal charge transfer (ICT) and electron delocalization, resulting in a TPA cross-section of 98 GM for the indazole containing **62** and 320 GM for the pyrazole **63**. Remarkably, these lanthanide complexes can internalize into living cells, enabling TPA microscopy.<sup>48</sup> However, as energy of the lowest

excited state of the ligand is very close to the europium <sup>5</sup>D<sub>0</sub> orbital energy, a back transfer occurs, causing the quenching of the luminescence as the temperature increases. This effect is even more pronounced with such push-pull ligands in polar environments, as they stabilize ICT states. This complex was used as a temperature probe in a range from 0°C to 50°C.<sup>49</sup>

<figure><img src="image_37.png" /><figcaption>**Scheme 27.** Two-photon absorbing europium(III) complexes **62** and **63**.<sup>48,49</sup></figcaption></figure>

Indazole can also be coupled with cyclen to give the ligand **64** (Scheme 28). The complexation with lanthanide provided monohydrated complexes with low luminescence in the case of europium and ytterbium, and 0.17 quantum yield with Tb.<sup>50</sup> These quenching were attributed to the presence of a water molecule in the vicinity of the lanthanide. When fluoride is added, dimerization occurs, leading to the formation of a dinuclear lanthanide complex. At the same time, the water molecule is expelled, leading to a 22-fold increase in luminescence.

<figure><img src="image_38.png" /><figcaption>**Scheme 28.** Indazole as antenna in cyclen-based lanthanide complexes and dimerization upon fluoride addition. Adapted from ref. 50 with permission.</figcaption></figure>
## 7. Photoactive indazoles in biological applications

Indazole is widely used in medicinal chemistry, with many selective receptor inhibitors based on this structure, as this heterocycle contains two nitrogen atoms that can act as H-bond acceptors and donors, respectively.³,⁵,⁶ This selectivity, combined with its optical properties, should promote the development of selective fluorescent markers for live-cells imaging. The VEGFR tyrosine kinase inhibitor, axitinib,⁵¹ has demonstrated photoactive properties, as it exhibits photochromic behavior (Scheme 29).⁵² Under light illumination, photoisomerization occurs from the *E* stereoisomer to the *Z*, resulting in a change in the absorption profile and a change in the molecule's affinity for VEGFR. Indeed, the activity of the *Z* isomer is 43 times lower than that of the *E* isomer in the *in vitro* VEGFR2 kinase assay, which makes it attractive in photopharmacy. However, the photochromism of axitinib is only reversible in DMSO and not in water, in which the *E* to *Z* transformation is blocked due to the formation of a dimer **65** by [2+2] photocycloaddition, which limits its photocontrol in biological media. In order to solve this problem, the diazo derivative **66** was synthesized, but this modification resulted in a decrease in the affinity of this molecule and a fast thermal isomerization from *Z* to *E*, rendering it unsuitable for this application.⁵³ The introduction of a benzene ring between the diazo bridge and the indazole in compound **67** prevented this fast thermal isomerization, but unfortunately, the *E* and *Z* isomers showed no significant difference in affinity. Therefore diazocine **68** was synthesized; the photoswitching of this compound proved satisfactory, while the difference in affinity between the *E* and the *Z* isomers was promising. The use of this compound in HUVEC cell lysates enabled modulation of the phosphorylation.

<figure><img src="image_39.png" /><figcaption>**Scheme 29.** Axitinib photoswitching and photochromic derivatives.⁵¹⁻⁵³</figcaption></figure>

Unfortunately, the application of axitinib as a fluorophore is limited by its absorption and emission in the UV range. In order to shift its spectral properties to the visible range, pyridine can be replaced by more electron-withdrawing groups. The easy access to 3-carboxaldehyde indazoles **69** by nitrosation⁵⁴ of indole allows the synthesis of axitinib derivatives bearing strong electron-deficient groups by Knoevenagel reaction. In this way, hemicyanine **70** was synthesized (Scheme 30); the presence of a strong electron-withdrawing group shifted the pKa of indazole from 13.9⁷ to 9.0.⁵⁵ The fluorescence quantum yield of this molecule is very low in non-viscous solvents but increases with viscosity, allowing it to be used as a viscosity probe. As a cationic fluorophore, they accumulated preferentially in mitochondria, where their emissions undergo a redshift; this phenomenon has been attributed to aggregation caused by the membrane potential of mitochondria.⁵⁵
<figure><img src="image_40.png" /></figure>

69

<figure><img src="image_41.png" /></figure>

Viscosity effect on fluorescence

Co-localization
70 (red) - Mitotracker (green)

<caption>**Scheme 30.** Preparation of **70**, fluorescence increase depending on the viscosity, and colocalization in live cells with Mitotracker green. Adapted from ref. 55 with permission.</caption>

A cationic nature is not mandatory for
mitochondria targeting as several neutral indazole
compounds have been found to stain
mitochondria. Among them, compound **71** bearing
the strong electron-withdrawing group
dicyanoisophorone is a viscosity-sensitive
fluorophore. It was used to monitor the increase in
viscosity inside mitochondria upon the addition of
ionophores. This molecule was then used in a
Parkinson's disease model based on PC-12 cells
incubated with glutamic acid (Scheme 31).⁵⁶

<figure><img src="image_42.png" /><figcaption>**Scheme 31.** Synthesis of **71** and live cell imaging before and after the addition of glutamic acid, leading to a viscosity increase inside mitochondria, triggering the *in cellulo* fluorescence of **71**. Adapted from ref. 56 with permission.</figcaption></figure>

The introduction of an indazole group in a
fluorophore can improve the selectivity of dyes for
mitochondria (Scheme 32). Starting from
quinoxaline derivatives of coumarin, lucifer yellow,
and Nile blue, which localize in both mitochondria
and liposomes, replacing the quinoxaline ring **72**
with indazole, aza-indazole, and aza-indole to give
**73-75** decreased their lipophilicity, thereby
enabling selective targeting of mitochondria.⁵⁷

<figure><img src="image_43.png" /><figcaption>**Scheme 32.** Replacement of quinoxaline to increase the selectivity to mitochondria.⁵⁷</figcaption></figure>

Fused indazoles have also been proposed as
mitochondria probes for cell imaging. The family of
compound **78** was synthesized through a one-pot
reaction combining Pd-catalysis and cyclisation
with an aryne (Scheme 33).⁵⁸ First, a Pd-catalysed
abstraction of dinitrogen from the azide group
leads to the formation of the carbodiimide **76**. This
latter is then trapped by hydrazine to give the
azomethine **77**, which reacts with *in situ* generated
arynes to give the final compounds with yields
ranging from 63% to 82%.

<figure><img src="image_44.png" /><figcaption>**Scheme 33.** One-pot synthesis of fused indazoles through Pd-catalysis and cyclisation with aryne.⁵⁸</figcaption></figure>
Indazole can be an efficient π-conjugated core to design fluorophores with a wide range of emissions. In this way, N2-methylated indazoles 79 substituted in position 3 by a furan or thiophene moiety can be prepared by C-H activation, leading to fluorophores emitting from 398 nm to 632 nm depending on the nature of their electron-withdrawing or donating groups (Scheme 34).⁵⁹ Knoevenagel reaction of aldehyde 80 with malonitrile yields the vinyl dicyano derivative 81 and shifts the fluorescence from 584 nm to the near-infrared region (709 nm) in dichloromethane, but lowers the quantum yield (Scheme 34). 81 is efficient at staining mitochondria with a better photostability than Mitotracker green and red.

<figure><img src="image_45.png" /></figure>

**Scheme 34.** Synthesis of fluorescent indazole by C-H activation and Knoevenagel coupling and their fluorescence emission wavelengths and quantum yields.⁵⁹

Similar indazoles, functionalized in position 2, can be directly synthesized by photochemistry. Reactive nitroso compounds **82a**, generated by the 395 nm irradiation of the *o*-nitrobenzyl alcohol **82**, react with primary amines, giving **82b**, which cyclize to provide compounds **83** (Scheme 35).⁶⁰ Exploiting this methodology, numerous modified drugs were synthesized, as well as the G-quadruplex probe **84**. This molecule selectively targets Pu22 G-quadruplex present in *c-MYC* oncogene. However, *in cellulo*, this compound localizes in mitochondria.

<figure><img src="image_46.png" /></figure>

**Scheme 35.** Direct synthesis of 2N-substituted indazoles by *o*-nitrobenzyl alcohol irradiation and application for the development of G-quadruplex probe 85.⁶⁰

Based on an analogous structure, the N-acetyltransferase (NAT) probe **88** was designed featuring an extended electron-withdrawing group and an amino group as an acetyl acceptor (Scheme 36).⁶¹ This molecule is similar to the DCM derivative **86**, bearing an aniline group, and whose fluorescence is quenched when its amino group is acetylated. Indazole **88** has an opposite behavior since its fluorescence is triggered by acetylation. Indeed, the luminescence of the amino compound **88** is low due to the rotation of the indazole furan bond at the excited state, leading to a dark conformer. After acetylation, the excited state adopts a planar conformation, resulting in the appearance of a fluorescence signal at 700 nm. This phenomenon was exploited in hepatic cells HepG2 expressing N-acetyltransferase; after 1h incubation, a fluorescence signal can be measured, which was not present when quercetin, a NAT quencher, was added.
<figure><img src="image_47.png" /><figcaption>**Scheme 36.** A, B) Fluorescent turn-OFF or ON induced by N-Acetyl Transferase (NAT), C) Fluorescence live cells image of HepG2 cells in the absence or presence of quercetin, a NAT inhibitor. Adapted from ref. 61Creative Common CC BY.</figcaption></figure>

Other indazole compounds substituted in position 3 by an electron-withdrawing group were found to target the nucleus in live cell imaging (Scheme 37). In this family, benzimidazole **90** stains selectively the nuclear membrane of live HeLa cells.⁶² A small structural modification can induce a big change in cellular distribution, for instance, introducing two chlorine atoms such as in **92**, or replacing the indazole with an indole, such as in **91** makes the compounds target mitochondria. The regioisomer **93** where the lateral benzyloxy group is shifted from position 6 to position 5 also stains the nuclear membrane, but it also targets biomolecules inside the nucleus, which might be either nucleic acids or intranuclear proteins. Docking studies have been carried out, suggesting that the specificity of **90** is due to specific interactions with nuclear membrane lipids.

<figure><img src="image_48.png" /><figcaption>**Scheme 37.** Live cell imaging showing the high variability in the biodistribution of a family of benzimidazole compounds. Adapted from ref. 62 with permission.</figcaption></figure>

The indazole compound **90** was applied for the detection of mercury in the cellular environment (Scheme 38). Upon binding with mercury, this non-π-conjugated compound **94** evolves to give the fluorescent rhodamine-like compound **95** with absorption at 500 nm and emission at 600 nm.⁶³

<figure><img src="image_49.png" /><figcaption>**Scheme 38.** Synthesis of **94** and reaction with mercury ion leading to fluorescence signal at 600 nm and detection of mercury *in cellulo*. Adapted from ref. 63 with permission.</figcaption></figure>

Photoactive indazoles can be directly photochemically generated in a biological medium. The reaction of sydnones with activated alkynes, such as arynes, produces indazoles by cycloaddition and decarboxylation,⁶⁴ that can be
accelerated by light illumination.⁶⁵ This approach was used in a bio-orthogonal theranostic approach in which a disysdnone **96** is illuminated at 405 nm in the presence of 1,4-Naphthoquinone **97** bearing a leaving group.⁶⁶ The induced cycloaddition led to the release of **99** in an aqueous environment or inside mitochondria and produced **98**, a photosensitizer, generating singlet oxygen under illumination (Scheme 39).

<figure><img src="image_50.png" /><figcaption>**Scheme 39.** Top) Reaction of disydnones with naphthoquinone leading to the release of the fluorescent **95** and the photosensitizer **94**.⁶⁶</figcaption></figure>

## Conclusions

Indazole is mostly found in medicinal chemistry but is an emerging core for the design of fluorophores and photoactive compounds and some functionalized indazoles are now used in biological imaging. Indeed, as this scaffold is widely approved for the development of drugs that interact with biomolecules, it should be further exploited for the development of selective biosensors. In addition, it can help modulate the lipophilicity of the compounds to reduce liposome staining. It should be noted that many indazole fluorophores target mitochondria whether cationic or neutral. The application of indazole as a photoactive ligand is still rare, although its two

nitrogen atoms can interact with metal or lanthanide and could facilitate its functionalization. Taken together, these data suggest that the indazole nucleus constitutes a promising platform for the development of tunable fluorescent probes: by carefully selecting substituents, extension of conjugation, and by employing strategies to control aggregation or rigidify the structure, one can design dyes with tailored absorption/emission wavelengths, possibly even dual-state emission (fluorescence and phosphorescence), and favorable brightness or AIE properties.

Nevertheless, the photophysical behaviors remain highly dependent on substitution pattern, environment and molecular conformation. This highlights the need for systematic studies combining synthesis, photophysical characterization (absorption, fluorescence, phosphorescence, quantum yield, lifetimes), and theoretical modeling (e.g., DFT / TD-DFT) to map structure-property relationships in indazole-based fluorophores.

## Author contributions

Thibault Gallavardin Writing – original draft, review and editing (equal). Xavier Franck Writing – original draft review and editing (equal).

## Conflicts of interest

There are no conflicts to declare.

## Acknowledgements

This work was partially supported by Normandie Université, the Région Normandie, the Centre National de la Recherche Scientifique, Université de Rouen Normandie, INSA Rouen Normandie, Université Caen Normandie, ENSICAEN, Labex SynOrg (ANR-11-LABX-0029), the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM) and Innovation Chimie Carnot (I2C).

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