# Synthesis of polynitrogen-containing [6-5-6] tricyclic derivatives by N–N bond formation and their fluorescent properties

Moussa Ndiaye, Frédéric Robert, Marie-Aude Hiebel, Franck Suzenet

► To cite this version:

Moussa Ndiaye, Frédéric Robert, Marie-Aude Hiebel, Franck Suzenet. Synthesis of polynitrogen-containing [6-5-6] tricyclic derivatives by N–N bond formation and their fluorescent properties. Journal of Organic Chemistry, 2025, 90 (20), pp.6692-6701. 10.1021/acs.joc.5c00081. hal-05343545

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# Synthesis of Polynitrogen-Containing [6-5-6] Tricyclic Derivatives by N–N Bond Formation and Their Fluorescent Properties

Moussa Ndiaye, Frédéric Robert, Marie-Aude Hiebel,* and Franck Suzenet*

<figure><img src="image_2.png" /></figure>

**ABSTRACT:** Polynitrogen-containing scaffolds are of major interest for many applications. To optimize and improve the potential of these scaffolds, it is important to be able to easily introduce and modulate the substituents, regardless of the number and position of the nitrogen atoms in the structure. Therefore, the synthetic approach ideally requires mild experimental conditions and an expanded scope of application. To this end, a versatile and efficient synthesis of [6-5-6] tricyclic derivatives of pyridopyrazolopyrazine, dipyridopyrazole, and pyridopyrazolopyrimidine types was undertaken at room temperature. Against all odds, the key oxidative cyclization step was successfully applied to two electron-poor heteroaromatic partners, and theoretical calculations were performed to rationalize the proposed mechanism for the N–N bond formation. Measurements of the fluorescence properties showed the strong impact of the number and position of nitrogen in the tricyclic scaffold. Among the seven families studied, pyridopyrazolopyrazine offers the best fluorescence properties in terms of brightness.

## INTRODUCTION

Present in countless organic molecules, nitrogen is an indispensable heteroatom to confer or improve molecular properties in the fields of medicinal chemistry, materials chemistry, and many others.¹,² In this context and in addition to N–C bonds, various N-heteroatom bonds, including the N–N bond, are widely found in natural or synthetic compounds. Among them, [6-5-6]-polyazaheterocycles 2 (Figure 1) have been closely investigated for their wide spectrum of biological activities such as antiparkinsonian agents,³ pantothenate kinase inhibitors,⁴ or negative allosteric modulators of mGlu₁/₅ or to a lesser extent for their potent fluorescent properties.⁶,⁷

The synthesis of this polynitrogen-containing [6-5-6] tricycles relied mostly on the formation of a third heterocycle. For that, two main strategies are followed: (1) the modification of the pyrazolopyridine ring through either multicomponent⁸⁻¹⁰ or condensation reactions¹¹⁻¹⁵ and (2) an annulation reaction from pyridinium N-amidine derivatives (Figure 1a).¹⁶,¹⁷

Additionally, a direct and more challenging N–N coupling reaction could be an efficient convergent alternative with more retrosynthetic flexibility.¹⁸ Several intramolecular mild strategies have recently been developed for the formation of the central aromatic five-membered heterocycle such as

pyrazoles, fused or not, with other aromatic rings.¹⁹⁻²² However, regarding the formation of fused polyazaheterocyclic compounds with pyrazoles as central rings, fewer conditions are available and are mainly based on the generation of nitrene through harsh experimental conditions from azido or nitro derivatives (Figure 1b).²³⁻²⁶

Recently, heteroaromatic amines in the presence of hypervalent iodine provided a mild alternative to trigger N–N cyclization at room temperature.²⁷ Restricted to heteroarylfused 1,3a,6a-triazapentalenes, this oxidative cyclization was highly efficient due to the electron-deficient character of the starting heteroaromatic amine and the electron-rich character of the pyrazole moiety (Figure 1c). This pattern was confirmed and emphasized by the additional electronic effects of the substituents introduced on the pyrazine or pyrazole parts.

This strategy is now investigated further for the synthesis of [6-5-6]-polyazaheterocycles 2 where, in an innovative way, both partners for the oxidative cyclization are electrondeficient (Figure 1d). The key starting heteroaromatic amines 1 can be straightforwardly synthetized via a Stille cross-coupling reaction. Moreover, the cyclization step was studied by DFT to corroborate the proposed mechanism. The spectroscopic characterization of these compact [6-5-6]azaheterocycles completes the study.
<figure><img src="image_3.png" /><figcaption>**Figure 1.** (a–d) Formation of [6-5-6]-azaheterocycles from N–N bond cyclization.</figcaption></figure>

## RESULTS AND DISCUSSION

First, the required amine intermediates were synthetized via a Stille cross-coupling reaction with the commercially available 2-pyridinylstannane (Scheme 1). In the presence of palladium catalyst in toluene and/or DMF at 110 °C, starting either from

<figure><img src="image_4.png" /><figcaption>**Scheme 1.** Synthesis of the Aminated Intermediates</figcaption></figure>

chlorinated, brominated, or iodinated amino-pyrazines, - pyridines, and -pyrimidines, the cross-coupled products 1a,

1f, 1j, and 1l were successfully isolated in moderate to good yields.²⁸ Electron-withdrawing groups such as cyano- or trifluoromethyl substituents on the starting azine or diazine (left-side heterocycle, Scheme 1) material were well tolerated (1b, 1g, 1k, 1i, and 1m). A loss of reactivity was nonetheless observed when a nitro group was present (1h) or for the 6-trifluoromethylpyrimidin-4-amine (1o) due to significant degradation and steric hindrance, respectively. The presence of an electron-donating group was also considered starting from 5-chloro-2-methoxypyrimidin-4-amine. The expected coupled product 1n was obtained with difficulty due to the formation of numerous side products.

To investigate the electronic and steric effects of substituents (in green) present on the nucleophilic nitrogen-containing heterocycle (bold heterocycle, Schemes 1 and 2) on the cyclization step, bicycles 1c–e were also synthesized. For this purpose, 2-pyridylstannane precursors bearing a 6-methoxy-, 4methoxy-, or 4-trifluoromethyl substituent were synthetized either by halogen-metal exchange or by Pd cross-coupling reaction³³,³⁴ (see Supporting Information for experimental details). These organometallics were then used as coupling partners to yield products 1c, 1d, and 1e (conditions A and B, Scheme 1).²⁹ In addition to the pyridine ring, 2-pyrimidinyl and 2-pyrazinyl moieties were introduced under modified experimental conditions (condition C, Scheme 1) to offer compounds 1p and 1q, respectively.²³ All of the expected heteroaromatic amines were isolated as stable solid compounds.

With these bicyclic aromatic amines in hand, oxidative cyclization was performed using phenyliodine(III) diacetate (PIDA) in the presence of sodium hydride in DMF at room temperature. Despite having an electron-poor partner (azine vs. pyrazole, Figure 1c,d), the formation of the N–N bond proceeded smoothly (Figure 2). Interestingly, in contrast to what was observed with the heteroaryl-fused 1,3a,6atriazapentalene series,²⁷ the reaction occurred on a broader scope of substrates with the same trend of reactivity. The nature of the starting heteroaryl amine (pyridyl-, pyrazyl-, and pyrimidyl-) had almost no influence on the efficiency of the cyclization reaction; only a drift of the yield was noticed for pyrazolo[1,5-a:4,3-b']dipyridines 2j

<footnote>a Reaction performed on 900 mg (5.20 mmol)</footnote>

<footnote>b Stille reaction performed on NO₂ derivative followed by a reduction with Sn in aqueous HClconc</footnote>
and 2k, probably due to a minor withdrawing influence of the nitrogen toward the amine function in this series. A general trend underlined that the introduction of an electron-withdrawing group, either CF₃ or CN, moderately facilitated the formation of the expected product (2a vs. 2b; 2f vs. 2g; 2j vs. 2k; and 2l vs. 2m and 2o). The methoxy group in compound 2n unexpectedly improved the cyclization yield, probably due to its -I effect. A control reaction with aniline was unsuccessful.

<figure><img src="image_5.png" /><figcaption>**Scheme 2.** Formation of [6-5-6] Fused (Aza)Indazoles</figcaption></figure>

Regarding the nucleophilic nitrogen-containing heterocycle (in bold, Scheme 2), a similar enhancement of reactivity was noticed when an electron-donating group (OMe) was introduced (2a vs. 2c or 2d). A reduction of the yield occurred with a CF₃ group (2d vs. 2e), but surprisingly, the cyclization performed better than the unsubstituted pyridopyrazolopyrazine (2a vs. 2e). Finally, nitrogen atoms included in the pyrazine and pyrimidine rings (bold part) were also eligible, giving access to 2p and 2q in 58% and 83% yields, respectively. It is worth noting that, unlike anilines, no azo compound was observed under these experimental procedures³⁵ and all compounds synthetized were bench-stable.

Several possible pathways may be envisaged for the formation of an N–N bond. After deprotonation of the amine 1a, substitution of an acetate in PIDA by the amine

anion is most likely (Figure 2). At this stage, the newly formed intermediate I can then evolve along different routes. A second deprotonation would give rise to compound II (pathway A), which, with the loss of an acetate, could give rise to imidoiodinane III, ready for the cyclization step (via TS1). The direct attack of pyridine on compound I would form IV (pathway B), the protonated form of 2a, via the transition state TS2. Substitution of the iodine(III) on I with an acetate (via TS3) could form V (pathway C), which could cyclize from VII either by the loss of an acetate or by an intramolecular rearrangement as in TS4.

DFT calculations (MN15/def2tzvp//SMD(DMF)) helped us identify the most likely pathway. First of all, nitrene VI and nitrenium VII were ruled out because of their very high energies. For pathway B, the search for a transition state, such as TS2, was unsuccessful. Pathway A, via an iminoiodinane intermediate such as III, seemed more realistic via a reasonable transition state TS1, and the need for a second deprotonation would explain the necessary use of more than two equivalents of base. The better reactivity with aromatics containing electron-withdrawing groups can then be explained by a decreased electron density of the charged nitrogen, offering a better stabilization of the amine anion (either after deprotonation of 1a and in II). From the calculations, it seemed that pathway C could eventually compete with TS4 being only slightly higher than TS1, but the transition state TS3 between I and V could not be found.

Thanks to the wide variety of polynitrogen-containing scaffolds bearing various substituents in hand, we endeavored to produce a global overview of their fluorescence properties. The λ<sub>Abs</sub>, λ<sub>em</sub>, and λ<sub>exc</sub> as well as the quantum yield and molar extinction coefficients were systematically measured for all compounds in DCM (Table 1). The main observation shows that the nature of both azines affects the excitation and emission wavelengths as well as their brightness (ε × φ<sub>r</sub>). A bathochromic effect can be underlined for the pyridopyrazolopyrazine series (2a–e), which also exhibits higher fluorescence quantum yields and molar extinction coefficients than the dipyridopyrazole (2f–k) and pyridopyrazolopyrimidine (2l–o) systems. In this best series, the best performance was observed with electron-donating groups on the pyridyl part (bold side, 2c and 2d). On the other hand, derivatives bearing a trifluoromethyl group (2b and 2e) gave rise to no improvement compared to the unsubstituted pyridopyrazolopyrazine (2a) and showed moderate performance. Finally, the introduction of an additional nitrogen atom (2p and 2q) induces a significant decay of the fluorescent properties, both on the quantum yields and on the molar absorption coefficients along with a hypochromic shift.
<figure><img src="image_6.png" /><figcaption>**Figure 2.** Possible mechanisms for the N-N bond cyclization and results of the DFT calculations.</figcaption></figure>

<table><caption>**Table 1:** Spectroscopic characterization of 2a-q in DCM</caption><thead><tr><th>Product</th><th></th><th>λ<sub>ex</sub><sup>[a]</sup> [nm]</th><th>λ<sub>em</sub><sup>[a]</sup> [nm]</th><th>Δ<sup>[c]</sup> [nm]</th><th>ε<sub>max</sub><sup>[d]</sup></th><th>Φ<sub>F</sub><sup>[e]</sup></th></tr></thead><tbody><tr><td rowspan="5">R<sub>1</sub>-N=N-N=N-R<sub>2</sub></td><td>2a</td><td>394</td><td>448</td><td>54</td><td>7596</td><td>0.30</td></tr><tr><td>2b</td><td>405</td><td>460</td><td>55</td><td>7538</td><td>0.32</td></tr><tr><td>2c</td><td>408</td><td>460</td><td>52</td><td>11931</td><td>0.74</td></tr><tr><td>2d</td><td>415</td><td>471</td><td>56</td><td>10497</td><td>0.46</td></tr><tr><td>2e</td><td>382</td><td>436</td><td>54</td><td>11203</td><td>0.22</td></tr><tr><td rowspan="2">R<sub>1</sub>-N=N-N=N-R<sub>2</sub></td><td>2p</td><td>390</td><td>442</td><td>52</td><td>5450</td><td>0.07</td></tr><tr><td>2q</td><td>369</td><td>416</td><td>47</td><td>6901</td><td>0.06</td></tr><tr><td rowspan="3">R<sub>1</sub>-N=N-N=N-R<sub>2</sub></td><td>2f</td><td>369</td><td>413</td><td>44</td><td>3092</td><td>0.09</td></tr><tr><td>2g</td><td>379</td><td>433</td><td>54</td><td>6502</td><td>0.13</td></tr><tr><td>2i</td><td>370</td><td>419</td><td>49</td><td>4025</td><td>0.05</td></tr><tr><td rowspan="2">R<sub>1</sub>-N=N-N=N-R<sub>2</sub></td><td>2j</td><td>369</td><td>415</td><td>46</td><td>2845</td><td>0.07</td></tr><tr><td>2k</td><td>372</td><td>423</td><td>51</td><td>3751</td><td>0.06</td></tr><tr><td rowspan="4">R<sub>1</sub>-N=N-N=N-R<sub>2</sub></td><td>2l</td><td>356</td><td>403</td><td>47</td><td>2758</td><td>0.06</td></tr><tr><td>2m</td><td>364</td><td>417</td><td>53</td><td>3956</td><td>0.10</td></tr><tr><td>2n</td><td>375</td><td>434</td><td>59</td><td>4506</td><td>0.08</td></tr><tr><td>2o</td><td>342</td><td>400</td><td>58</td><td>4603</td><td>0.02</td></tr></tbody></table>

<footnote>[a] Apparent maxima of absorption bands. [b] Apparent maxima of emission bands. [c] Stokes Shift values. [d] Units: L.mol⁻¹.cm⁻¹. [e] φ is the fluorescence quantum yield determined using Coumarin 153 (φ=0.38 in EtOH) as a reference standard.</footnote>
## CONCLUSIONS

Fused polyazaheterocyclic compounds with pyrazole as the central ring are known to be an important class of compounds, mainly due to their biological applications. Herein, their concise synthesis was facilitated through an innovative approach relying on N–N vs. C–N bond formation thanks to a mild oxidative cyclization. The successful use of PIDA in the oxidative cyclization with heteroaromatic amines was extended to electron-poor partners like (di)azines giving access to 17 compounds in good to excellent yields. For all of these small molecules, the fluorescent properties were recorded and the best performance was observed for the pyridopyrazolopyrazine series.

## EXPERIMENTAL SECTION

**General Remarks.** Unless otherwise noted, all reagent-grade chemicals and commercially available solvents were used without further purification. Reactions were monitored by thin-layer chromatography (TLC) using aluminum sheets coated with silica gel 60 F254. Flash column chromatography was carried out using silica gel 60 (0.04–0.06 mm). Solvents mentioned as being dry were purified with a dry station GT S100 immediately prior to their use. NMR spectra were recorded with a 250 MHz (¹H: 250 and ¹³C: 63 MHz), 300 MHz (¹H: 300 and ¹³C: 75 MHz), or 400 MHz (¹H: 400 and ¹³C: 100.7 MHz) Bruker spectrometer. Chemical shifts are given in parts per million (ppm) from tetramethylsilane (TMS), calibrated to the residual solvent peak. Coupling constants "J" are expressed in hertz (multiplicity: s = singlet, bs = broad singlet, d = doublet, dd = double doublet, dt = double triplet, t = triplet, q = quartet, m = multiplet...). High-resolution accurate mass (HRAM) measurements were performed on a Bruker maXis mass spectrometer (Q-TOF) by the "Fedé ratio'n de Recherche" ICOA/CBM (FR2708) platform. Melting points were measured in open capillary tubes without prior recrystallization.

**General Procedure A of Synthesis of Biaryls 1a–1d, 1f–1o (Condition A).**²⁸ General procedure for the title compounds taking 1a as an example: In a dry flask and under argon, 2-amino-3chloropyrazine (500 mg, 3.89 mmol, 1 equiv) was solubilized in toluene (36 mL, 0.15 M), and then, 2-tributylstannylpyridine (1.58 g, 4.28 mmol, 1.1 equiv) and Pd(PPh₃)₄ (45 mg, 10 mol%) were added. The resulting mixture was heated at 110 °C using a heating mantle until complete consumption of the starting material by TLC. Upon cooling to room temperature, a saturated solution of KF was added to the reaction, and the resulting mixture was stirred for 30 min and then passed through a short celite. The celite was washed with Et₂O, and the filtrate was concentrated and then purified by column chromatography to give the expected biaryls.

**General Procedure B of Synthesis of Biaryl 1e (Condition B).**²⁹ The mixture of 2-amino-3-chloropyrazine (200 mg, 1.67 mmol, 1 equiv), 2-(tributylstannyl)-4-(trifluoromethyl)pyridine³⁰ (1.09 g, 2.51 mmol, 1.5 equiv), Pd₂(dba)₃ (46 mg, 0.05 mmol, 3 mol%), and tri(2-furyl)phosphine (35 mg, 0.15 mmol, 9 mol%) was refluxed in toluene (10 mL) using a heating mantle for 48 h. The solvent was removed in vacuo and to give after purification with column chromatography (eluent 7:3, ethyl acetate/ether petroleum) 80 mg (22%) of 1e as a white solid.

**General Procedure C of Synthesis of Biaryls 1p–1q (Condition C).**²³,³¹ General procedure for the title compounds taking 1p as an example: In a dry flask and under argon, 2-amino-3chloropyrazine³⁶ (130 mg, 0.98 mmol, 1 equiv) was solubilized in DMF (2.6 mL, 0.38 M), and 2-tributylstannylpyrimidine (398 mg, 1.08 mmol, 1.1 equiv), PdCl₂(PPh₃)₂ (34 mg, 0.05 mmol, 5 mol%), and Cul (2 mg, 0.01 mmol, 1 mol%) were added. The resulting mixture was heated at 115 °C using a heating mantle until the total disappearance of the starting material. After returning to room temperature, a saturated solution of KF (5 mL) was added to the reaction medium, and the resulting mixture was stirred for 30 min and then passed through a short celite. The celite was washed with Et₂O, and the filtrate was concentrated and then purified by column chromatography to give the expected biaryls.

**General Procedure D of the Cyclization: Synthesis of Tricycles [6-5-6].** General procedure for the title compounds taking 2a as an example: In a dry flask under argon, 2-amino-3-(pyridin-2yl)pyrazine 1a (52 mg, 0.3 mmol, 1 equiv) was dissolved in anhydrous dimethylformamide (2 mL, 0.15 M) and added portionwise NaH 60% dispersion in mineral oil (30 mg, 0.75 mmol, 2.5 equiv). The resulting mixture was stirred for 15 min, followed by the addition of Phl(OAc)₂ (193 mg, 0.6 mmol, 2.0 equiv), and the mixture was left at room temperature until the total consumption of the starting material (1–2 h). The solution was slowly hydrolyzed with cold water (3 mL), and ethyl acetate (10 mL) was added. The organic phase was washed with water (2 × 5 mL) and brine (5 mL) and then dried over MgSO₄. After concentration under reduced pressure, the product was purified by flash chromatography on silica gel.

**Optical Spectroscopy.** The absorption spectra were recorded on a Shimadzu UV-1800 spectrophotometer. The fluorescence measurements were performed using a Horiba Scientific FluoroMax spectrofluorometer. Sample solutions were completely degassed by purging them with argon. All compounds' solutions were prepared just before spectroscopic analysis. The fluorescence quantum yields (φ) were calculated by using a standard Coumarin 153 in ethanol (φ = 0.38),³² where λₐbs: absorption wavelengths; λₐexc and λₐem: maxima of excitation and emission bands; and ε (L·mol⁻¹·cm⁻¹): molar extinction coefficient. Fluorescence quantum yields (φF) were determined in various solvents (1,4-dioxane, DCM, ethanol, and water) at room temperature, using Coumarin 153 as the standard, upon selection of λₐexc and λₐem (maximum of emission) as the excitation and emission wavelengths.

**Quantum Yield Measurement.** The quantum yield of the compounds in organic solvents was calculated according to the following equation:

$$ \varphi_{F[\text{sample}]} = \varphi_{F[\text{standard}]} \times (I_{\text{sample}} / I_{\text{standard}}) \times (A_{\text{standard}} / A_{\text{sample}}) \times (n_{\text{sample}} / n_{\text{standard}})^2 $$

φ denotes the quantum yield; I denotes the area under the fluorescence band; A denotes the absorbance (in the range 0.01–0.1 AU); and n denotes the refractive index of the solvent (at 25 °C). All compound solutions were freshly prepared before each spectroscopic analysis, degassed with argon (during 30–40 min), and protected from direct light throughout the analysis.

**2-Amino-3-(pyridin-2-yl)pyrazine (1a).** The general procedure A was applied from 2-amino-3-chloropyrazine³⁶ (500 mg, 3.89 mmol) and 2-tributylstannylpyridine for 24 h to give after purification with column chromatography (eluent 7:3, ethyl acetate/ether petroleum) 301 mg (1.75 mmol, 45%) of 1a as a yellow solid. mp:
124–125 °C; IR $\bar{\nu}$ (cm⁻¹) 3316, 3243, 3129, 3047, 2645, 2350, 2325, 2160, 2056, 1609, 1559, 1530, 1492, 1448, 1429, 1216, 1096, 1059; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.60 (1H, dd, J = 4.9, 2.0, 0.9 Hz), 8.54 (1H, dt, J = 8.2, 0.9 Hz), 8.03 (1H, d, J = 2.4 Hz), 7.96 (1H, d, J = 2.5 Hz), 7.83 (1H, ddd, J = 8.2, 7.5, 1.8 Hz), 7.29 (1H, ddd, J = 7.4, 5.1, 1.1 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 157.1 (C), 154.4 (C), 147.2 (CH), 147.2 (CH), 143.2 (CH), 136.7 (CH), 133.7 (C), 132.7 (CH), 122.9 (CH), 122.5 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₉H₉N₄ 173.0827; Found 173.0823.

**2-Amino-3-(pyridin-2-yl)-5-(trifluoromethyl)pyrazine (1b).** The general procedure A in a mixture of toluene/DMF (3:1) was applied from 2-amino-3-chloro-5-(trifluoromethyl)pyrazine²⁷ (200 mg, 0.83 mmol) and 2-tributylstannylpyridine for 18 h to give after purification with column chromatography (eluent 3:7, ethyl acetate/ether petroleum) 102 mg (0.43 mmol, 51%) of 1b as a yellow solid. mp = 156–157 °C; IR $\bar{\nu}$ (cm⁻¹) 3300, 3157, 3072, 1625, 1587, 1562, 1406, 1368, 1330, 1267, 1169, 1118, 1096, 1033; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.64–8.61 (2H, m), 8.35 (1H, s), 7.87 (1H, td, J = 7.8, 1.8 Hz), 7.39–7.31 (1H, m); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 155.7 (C), 155.4 (C), 147.2 (CH), 140.4 (CH, q, J = 3.3 Hz), 137.2 (CH), 132.6 (C), 131.4 (C, q, J = 35.2 Hz), 123.7 (CH), 123.1 (CH), 122.3 (C, q, J = 272.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) $\delta$ -66.42; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈F₃N₄ 241.0701; Found 241.0698.

**2-Amino-3-(6-methoxypyridin-2-yl)pyrazine (1c).** The general procedure A was applied from 2-amino-3-chloropyrazine (100 mg, 0.77 mmol)⁶ and 2-methoxy-6-tributylstannylpyridine³³ for 18 h to give after purification with column chromatography (eluent 1:1, ethyl acetate/ether petroleum) 106 mg (0.52 mmol, 68%) of 1c as a yellow solid. mp = 115–116 °C; IR $\bar{\nu}$ (cm⁻¹) 3336, 3137, 3039, 1607, 1577, 1456, 1425, 1260, 1226, 1016; ¹H NMR (250 MHz, CDCl₃) $\delta$ 8.10 (1H, dd, J = 7.7, 0.8 Hz), 8.02 (1H, d, J = 2.5 Hz), 7.96 (1H, d, J = 2.5 Hz), 7.74 (1H, dd, J = 8.2, 7.7 Hz), 6.78 (1H, dd, J = 8.2, 0.8 Hz), 4.00 (3H, s). ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 162.5 (C), 154.4 (C), 153.9 (C), 142.9 (CH), 139.5 (CH), 134.0 (C), 133.0 (CH), 115.6 (CH), 110.1 (CH), 53.6 (CH₃); HRMS (ESI-TOF) *m/z*: [M + H]⁺ Calcd. for C₁₀H₁₁N₄O 203.0933; Found 203.0932.

**2-Amino-3-(4-methoxypyridin-2-yl)pyrazine (1d).** The general procedure A was applied from 2-amino-3-chloropyrazine³⁶ (500 mg, 3.62 mmol) and 4-methoxy-2-(tributylstannyl)pyridine³³,³⁷ for 18 h to give after purification with column chromatography (eluent 7:3, ethyl acetate/ether petroleum) 95 mg (0.147 mmol, 13%) of 1d as a yellow solid. mp = 149–150 °C; IR $\bar{\nu}$ (cm⁻¹) 3327, 3260, 3144, 2954, 2840, 1591, 1556, 1486, 1425, 1402, 1296, 1200, 1089, 1019; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.40 (1H, d, J = 5.8 Hz), 8.07 (1H, d, J = 2.6 Hz), 8.02 (1H, d, J = 2.5 Hz), 7.94 (1H, d, J = 2.5 Hz), 6.83 (1H, dd, J = 5.8, 2.6 Hz), 3.95 (3H, s). ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 166.3 (C), 158.9 (C), 154.4 (C), 148.3 (CH), 143.1 (CH), 133.5 (C), 132.3 (CH), 110.9 (CH), 106.3 (CH), 55.3 (CH₃); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₁₁N₄O 203.0933; Found 203.0927.

**2-Amino-3-(4-(trifluoromethyl)pyridin-2-yl)pyrazine (1e).** The mixture of 2-amino-3-chloropyrazine (200 mg, 1.67 mmol),³⁶ 2(tributylstannyl)-4-(trifluoromethyl)pyridine³⁰ (1.5 equiv), Pd₂(dba)₃ (3 mol%), and tri(2-furyl)phosphine (9 mol%) was refluxed in toluene (10 mL) for 48 h.²⁹ The solvent was removed in vacuo and to give after purification with column chromatography (eluent 7:3, ethyl acetate/ether petroleum) 80 mg (0.33 mmol, 22%) of 1e as a white solid. mp = 150–151 °C; IR $\bar{\nu}$ (cm⁻¹) 3347, 3266, 3159, 1604, 1563, 1526, 1433, 1408, 1212, 1139; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.83 (1H, s), 8.78 (1H, d, J = 5.2 Hz), 8.09 (1H, d,

J = 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz), 7.49 (1H, d, J = 5.3 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 158.6 (C), 154.3 (C), 148.3 (CH), 144.2 (CH), 139.1 (C, q, J = 35.3 Hz), 133.0 (CH), 132.0 (C), 122.9 (C, q, J = 272.6 Hz), 118.5 (CH, q, J = 3.8 Hz), 118.0 (CH, q, J = 3.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) $\delta$ -64.85; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈F₃N₄ 241.0701; Found 241.0698.

**2-Amino-3-(pyridin-2-yl)pyridine (1f).** The general procedure A was applied from commercially available 2-amino-3-bromopyridine (300 mg, 1.73 mmol) and 2-tributylstannylpyridine for 24 h to give after purification with column chromatography (eluent 6:4, ethyl acetate/ether petroleum) 201 mg (0.18 mmol, 68%) of 1f as a yellow solid. mp = 126–127 °C; IR $\bar{\nu}$ (cm⁻¹) 3305, 3076, 1613, 1589, 1583, 1552, 1483, 1453, 1431, 1421, 1186, 1113, 1092, 1072; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.61 (1H, ddd, J = 4.9, 1.9, 1.0 Hz), 8.10 (1H, dd, J = 4.9, 1.8 Hz), 7.82 (1H, dd, J = 7.6, 1.8 Hz), 7.76 (1H, td, J = 8.0, 1.9 Hz), 7.67 (1H, d, J = 8.1 Hz), 7.20 (1H, ddd, J = 7.4, 4.9, 1.2 Hz), 6.75 (2H, s), 6.70 (1H, dd, J = 7.6, 4.8 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 157.5 (C), 157.3 (C), 149.0 (CH), 148.0 (CH), 137.0 (CH), 136.6 (CH), 121.6 (CH), 121.5 (CH), 116.3 (CH), 113.3 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₁₀N₃ 172.0869; Found 172.0870.

**2-Amino-3-(pyridin-2-yl)-5-cyanopyridine (1g).** The general procedure A was applied from 2-amino-3-iodo-5-cyanopyridine²⁷ (300 mg, 1.22 mmol) and 2-tributylstannylpyridine for 24 h to give after purification with column chromatography (eluent 4:6, ethyl acetate/ether petroleum) 165 mg (0.84 mmol, 69%) of 1g as an orange solid. mp = 150–151 °C; IR $\bar{\nu}$ (cm⁻¹) 3463, 3370, 3215, 2917, 2649, 2224, 1905, 1607, 1591, 1481, 1436, 1334, 1251, 1140, 1091, 1074, 998, 894, 829, 802; ¹H NMR (250 MHz, CDCl₃) $\delta$ 8.63–8.50 (2H, m), 7.91–7.77 (1H, m), 7.41 (1H, d, J = 8.4 Hz), 7.35–7.25 (1H, m), 7.14 (2H, s), 6.99 (1H, d, J = 8.5 Hz); ¹³C{1H} NMR (63 MHz, CDCl₃) $\delta$ 157.7 (C), 146.8 (CH), 146.8 (C), 137.8 (C), 137.1 (CH), 129.1 (CH), 123.0 (CH), 123.0 (CH), 122.8 (CH), 119.7 (C), 118.8 (C); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₁H₉N₄ 197.0822; Found 197.0823.

**2-Amino-3-(pyridin-2-yl)-5-nitropyridine (1h).** The general procedure A was applied from 2-amino-3-iodo-5-nitropyridine⁷ (300 mg, 1.12 mmol) and 2-tributylstannylpyridine for 24 h to give after purification with column chromatography (eluent 4:6, ethyl acetate/ether petroleum) 80 mg (0.37 mmol, 33%) of 1h as an orange solid. mp = 154–155 °C; IR $\bar{\nu}$ (cm⁻¹) 3234, 3076, 2922, 1617, 1585, 1504, 1473, 1417, 1360, 1314, 1289, 1275, 1240, 1165, 1137; ¹H NMR (250 MHz, CDCl₃) $\delta$ 9.03 (1H, d, J = 2.5 Hz), 8.74 (1H, d, J = 2.6 Hz), 8.65 (1H, d, J = 4.9 Hz), 7.94–7.84 (2H, m), 7.40–7.27 (1H, m). ¹³C{1H} NMR (63 MHz, CDCl₃) C (NO₂) not visible $\delta$ 160.9 (C), 154.9 (C), 148.0 (CH), 146.9 (CH), 137.7 (CH), 131.4 (CH), 122.8 (CH), 121.7 (CH), 114.1 (C); HRMS (ESI-TOF) *m/z*: [M + H]⁺ Calcd. for C₁₀H₉N₄O₂ 217.0720; Found 217.0723.

**2-Amino-3-(pyridin-2-yl)-5-(trifluoromethyl)pyridine (1i).** The general procedure A was applied from 2-amino-3-iodo-5(trifluoromethyl)pyridine²⁷ (300 mg, 1.05 mmol) and 2-tributylstannylpyridine for 18 h to give after purification with column chromatography (eluent 4:6, ethyl acetate/ether petroleum) 180 mg (0.75 mmol, 72%) of 1i as a white crystal solid. mp = 121–122 °C; IR $\bar{\nu}$ (cm⁻¹) 3295, 3136, 2959, 2927, 2851, 1626, 1588, 1556, 1426, 1339, 1273, 1243, 1145, 1087, 1021; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.63 (1H, d, J = 4.5 Hz), 8.34 (1H, d, J = 1.2 Hz), 8.03 (1H, d, J = 2.3 Hz), 7.82 (1H, td, J = 7.8, 1.9 Hz), 7.76 (1H, d, J = 8.1 Hz), 7.29–7.27 (1H, m); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 159.6 (C), 156.0 (C), 148.1 (CH), 146.5 (CH, q, J = 4.2 Hz), 137.4 (CH), 133.3 (C,
(CH, q, J = 3.3 Hz), 124.6 (C, q, J = 268.5 Hz), 122.3 (CH), 121.7 (CH), 116.0 (C, q, J = 33.0 Hz), 115.1 (C); ¹⁹F NMR (376 MHz, CDCl₃) δ -60.99; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₁H₉F₃N₃ 240.0743; Found 240.0745.

**3-Nitro-2-(pyridin-2-yl)pyridine (1j')**. The general procedure C was applied from commercial 2-chloro-3-nitropyridine (300 mg, 1.12 mmol) and 2-tributylstannylpyridine for 18 h to give after purification with column chromatography (eluent 6:4, ethyl acetate/ether petroleum) 195 mg (0.97 mmol, 87%) of 1j' as a white solid. mp = 135-136 °C; IR ν (cm⁻¹) 3063, 2958, 2928, 1597, 1585, 1533, 1445, 1420, 1371; ¹H NMR (400 MHz, CDCl₃) δ 8.83 (1H, dd, *J* = 4.8, 1.5 Hz), 8.61 (1H, *ddd*, *J* = 4.8, 1.8, 1.0 Hz), 8.08 (2H, *dt*, *J* = 8.1, 1.3 Hz), 7.88 (1H, *td*, *J* = 7.8, 1.8 Hz), 7.49 (1H, *dd*, *J* = 8.1, 4.7 Hz), 7.37 (1H, *ddd*, *J* = 7.7, 4.8, 1.2 Hz). ¹³C{1H} NMR (101 MHz, CDCl₃) C (NO₂) no visible δ 154.1 (C), 151.4 (CH), 150.8 (C), 149.2 (CH), 137.2 (CH), 132.3 (CH), 124.6 (CH), 123.6 (CH), 123.2 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈N₃O₂ 202.0611; Found 202.0616.

**3-Amino-2-(pyridin-2-yl)pyridine (1j).** In a bottom flask were added 3-nitro-2-(pyridin-2-yl)pyridine 1j' (200 mg, 1 mmol) and a mixture of HCl (37%)/MeOH (1:1; 12 mL). After total dissolution, powdered Sn was added and the suspension was heated at 40 °C for 1 h. Afterward, the mixture was filtrated on celite and a solution of NaOH (6M) was added to the filtrate until the appearance of a white precipitate. The precipitate was filtered, and the filtrate was added in the mixture of AcOEt/H₂O (1:1; 20 mL). The organic phase was washed with water (10 mL) and a saturated NaCl solution (10 mL), dried over MgSO₄, and concentrated on a rotary evaporator. The residue was purified by column chromatography on silica gel (eluent 1:1, ethyl acetate/ether petroleum) to yield compound 1j as a white solid (118 mg, 0.69 mmol, 69%). mp = 131-132 °C; IR ν (cm⁻¹) 3381, 3255, 3061, 3044, 2999, 2957, 2921, 2305, 1918, 1600, 1585, 1445, 1420, 1313, 1258, 1223, 1141, 1064, 1036; ¹H NMR (250 MHz, CDCl₃) δ 8.59-8.52 (1H, m), 8.48 (1H, d, *J* = 8.2 Hz), 8.04 (1H, *dd*, *J* = 4.1, 1.7 Hz), 7.78 (1H, *ddd*, *J* = 8.4, 7.4, 1.8 Hz), 7.22-7.15 (1H, m), 7.11-6.98 (2H, m), 6.33 (2H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 159.5 (C), 147.0 (CH), 144.0 (C), 138.2 (CH), 137.2 (C), 136.7 (CH), 124.6 (CH), 124.5 (CH), 122.4 (CH), 122.0 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₁₀N₃ 172.0869; Found 172.0870.

**3-Amino-2-(pyridin-2-yl)-6-(trifluoromethyl)pyridine (1k).** The general procedure A was applied from commercially available 3-amino-2-chloro-6-(trifluoromethyl)pyridine (300 mg, 1.52 mmol) and 2-tributylstannylpyridine for 20 h to give after purification with column chromatography (eluent 4:6, ethyl acetate/ether petroleum) 215 mg (0.90 mmol, 59%) of 1k as a brown solid. mp = 138-139 °C; IR ν (cm⁻¹) 3313, 3103, 3047, 2993, 1625, 1587, 1562, 1416, 1346, 1271, 1245, 1144, 1103, 1061; ¹H NMR (400 MHz, CDCl₃) δ 8.62 (1H, d, *J* = 8.2 Hz), 8.57 (1H, d, *J* = 5.1 Hz), 7.87-7.79 (1H, m), 7.42 (1H, d, *J* = 8.5 Hz), 7.30-7.23 (1H, m), 7.06 (1H, d, *J* = 8.4 Hz), 6.84 (2H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 158.3 (C), 146.9 (CH), 146.0 (C), 136.9 (CH), 136.1 (C), 135.8 (C, q, *J* = 35.7 Hz), 123.9 (CH), 122.8 (CH), 122.7 (CH), 122.3 (C, q, *J* = 272.5 Hz), 121.3 (CH, q, *J* = 2.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ -66.56; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₁H₉F₃N₃ 240.0743; Found 240.0745.

**4-Amino-5-(pyridin-2-yl)pyrimidine (1l).** The general procedure A in a mixture of toluene/DMF (3:1) was applied from commercially available 4-amino-5-iodopyrimidine (305 mg, 1.39 mmol) and 2-tributylstannylpyridine (1.1 equiv) for 48 h to give after purification with column chromatography (eluent 95:5,

dichloromethane/ MeOH) 124 mg (0.72 mmol, 52%) of 1l as a white solid. mp = 179-180 °C; IR ν (cm⁻¹) 3310, 3094, 3037, 2993, 1622, 1584, 1562, 1416, 1362, 1245, 1150, 1061; ¹H NMR (250 MHz, CDCl₃) δ 8.70 (1H, s), 8.60 (1H, *td*, *J* = 5.0, 1.5 Hz), 8.52 (1H, s), 7.79 (2H, *dd*, *J* = 6.2, 1.8 Hz), 7.30-7.23 (1H, m); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 161.3 (C), 158.4 (CH), 154.7 (C), 154.1 (CH), 148.1 (CH), 137.2 (CH), 122.1 (CH), 120.5 (CH), 113.4 (C); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₉H₉N₄ 173.0822; Found 173.0826.

**4-Amino-5-(pyridin-2-yl)-2-(trifluoromethyl)pyrimidine (1m).** The general procedure A in a mixture of toluene/DMF (3:1) was applied from 4-amino-5-iodo-2-(trifluoromethyl)pyrimidine²⁷ (250 mg, 0.87 mmol) and 2-tributylstannylpyridine for 48 h to give after purification with column chromatography (eluent 95:5, dichloromethane/MeOH) 102 mg (0.43 mmol, 49%) of 1m as a colorless solid. mp = 204-205 °C; IR ν (cm⁻¹) 3325, 3167, 2328, 2287, 2049, 1976, 1628, 1590, 1543, 1353, 1299, 1197, 1134, 1071; ¹H NMR (400 MHz, CDCl₃) δ 9.66 (1H, s), 8.84 (1H, s), 8.69 (1H, d, *J* = 5.0, 1.4 Hz), 7.92-7.84 (2H, m), 7.39-7.33 (1H, m), 6.09 (1H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 161.9 (C), 155.9 (C, q, *J* = 36.0 Hz), 154.2 (CH), 153.4 (C), 148.2 (CH), 137.5 (CH), 122.9 (CH), 121.0 (CH), 119.5 (C, q, *J* = 276.2 Hz), 114.6 (C); ¹⁹F NMR (376 MHz, CDCl₃) δ -71.24; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈F₃N₄ 241.0696; Found 241.0700.

**4-Amino-2-methoxy-5-(pyridin-2-yl)pyrimidine (1n).** The general procedure A in a mixture of toluene/DMF (3:1) was applied from 4-amino-2-methoxy-5-iodopyrimidine² (900 mg, 3.50 mmol) and 2-tributylstannylpyridine for 48 h to give after purification with column chromatography (eluent 7:3, ethyl acetate/ether petroleum) 99 mg (0.49 mmol, 14%) of 1n as a white solid. mp = 153-154 °C; IR ν (cm⁻¹) 3313, 3142, 2959, 2919, 2848, 1606, 1538, 1462, 1270, 1162, 1140, 1094, 1009; ¹H NMR (400 MHz, CDCl₃) δ 8.65-8.52 (2H, m), 7.82-7.68 (2H, m), 7.21 (1H, *t*, *J* = 6.5 Hz), 3.99 (3H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 165.2 (C), 163.35 (C), 156.5 (CH), 155.0 (C), 147.8 (CH), 137.1 (CH), 121.2 (CH), 119.6 (CH), 108.3 (C), 54.5 (CH₃); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₁₁N₄O 203.0927; Found 203.0928.

**4-Amino-5-(pyridin-2-yl)-6-(trifluoromethyl)pyrimidine (1o).** The general procedure A in a mixture of toluene/DMF (3:1) was applied from 4-amino-5-bromo-6-(trifluoromethyl)pyrimidine²⁷ (1.1 g, 4.55 mmol) and 2-tributylstannylpyridine for 48 h to give after purification with column chromatography (eluent 95:5, dichloromethane/ MeOH) 153 mg (0.64 mmol, 14%) of 1o as a white solid. mp = 159-160 °C; IR ν (cm⁻¹) 3401, 3312, 3154, 3053, 2654, 2654, 2328, 2163, 2055, 1979, 1650, 15558, 1486, 1337, 1179, 1144, 1020; ¹H NMR (400 MHz, CDCl₃) δ 8.75 (1H, d, *J* = 4.8 Hz), 8.66 (1H, s), 7.86 (1H, *td*, *J* = 7.8, 1.8 Hz), 7.45-7.36 (2H, m), 5.82 (2H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 163.0 (C), 157.9 (CH), 151.9 (C), 150.8 (C, q, *J* = 35.6 Hz), 150.0 (CH), 137.6 (CH), 126.0 (CH, q, *J* = 3.1 Hz), 123.8 (CH), 121.3 (C, q, *J* = 274.4 Hz), 115.2 (C); ¹⁹F NMR (376 MHz, CDCl₃) δ -62.97; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈F₃N₄, 241.0696; Found 241.0700.

**2-Amino-2-(pyrimidin-2-yl)pyrazine (1p).** The general procedure C was applied from 2-amino-3-chloropyrazine³⁶ (130 mg, 0.98 mmol) and 2-tributylstannylpyrimidine for 24 h to give after purification with column chromatography (eluent 98:2, dichloromethane/MeOH) 85 mg (0.49 mmol, 50%) of 1p as a white solid. mp = 174-175 °C; IR ν (cm⁻¹) 3412, 3259, 3181, 3144, 3059, 3034, 2967, 1596, 1569, 1522, 1475, 1338, 1211, 1179, 1123, 1091, 1053; ¹H NMR (400 MHz, CDCl₃) δ 8.91 (2H, *d*, *J* = 4.8 Hz), 8.14 (2H,
dd, *J* = 8.6, 2.0 Hz), 7.29 (1H, *t*, *J* = 4.8 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 163.7 (C), 157.1 (CH), 155.2 (C), 144.7 (CH), 134.1 (CH), 131.8 (C), 119.5 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₈H₈N₅ 174.0774; Found 174.0776.

**2-Amino-2-(pyrazin-2-yl)pyrazine (1q).** The general procedure C was applied from 2-amino-3-chloropyrazine³⁶ (100 mg, 0.77 mmol) and 2-tributylstannylpyrazine for 7 h to give after purification with column chromatography (eluent 9:1, toluene/acetone) 72 mg (0.42 mmol, 54%) of 1q as a yellow solid. mp = 203–204 °C; IR ν̄ (cm⁻¹) 3375, 3254, 3143, 3042, 1913, 1607, 1529, 1516, 1433, 1403, 1339, 1206, 1166, 107, 1043, 1009; ¹H NMR (250 MHz, CDCl₃) δ 9.79 (1H, d, *J* = 1.5 Hz), 8.58–8.47 (2H, m), 8.09 (1H, d, *J* = 2.4 Hz), 8.02 (1H, d, *J* = 2.4 Hz), 7.01 (2H, s); ¹³C{1H} NMR (63 MHz, CDCl₃) δ 154.4 (C), 152.0 (C), 145.3 (CH), 144.2 (CH), 143.0 (CH), 141.2 (CH), 133.3 (CH), 131.6 (C); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₈H₈N₅ 174.0774; Found 174.0776.

**Pyrido[1',2':1,5]pyrazolo[3,4-b]pyrazine (2a).** The general procedure D was applied from 1a (50 mg, 0.29 mmol) for 2 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 31 mg (0.18 mmol, 63%) of 2a as a yellow powder. mp = 146–147 °C; IR ν̄ (cm⁻¹) 3094, 3079, 3044, 1638, 1556, 1533, 1426, 1388, 1274, 1226, 1197, 1147, 1121, 1046, 1007; ¹H NMR (400 MHz, CDCl₃) δ 8.91 (1H, d, *J* = 6.9 Hz), 8.82 (1H, d, *J* = 2.0 Hz), 8.60 (1H, d, *J* = 2.0 Hz), 8.46 (1H, d, *J* = 8.6 Hz), 7.68–7.56 (1H, m), 7.43 (1H, td, *J* = 7.0, 1.4 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 153.3 (C), 147.3 (CH), 139.6 (CH), 135.0 (C), 129.4 (CH), 126.3 (C), 125.0 (CH), 119.2 (CH), 119.1 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₉H₇N₄ 171.0671; Found 171.0666.

**2-(Trifluoromethyl)pyrido[1',2':1,5]pyrazolo[3,4-b]pyrazine (2b).** The general procedure D was applied from 1b (65 mg, 0.27 mmol) for 45 min to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 52 mg (0.22 mmol, 81%) of 2b as a yellow powder; mp = 203–204 °C; IR ν̄ (cm⁻¹) 3110, 3046, 2921, 1856, 1642, 1556, 1438, 1393, 1343, 1304, 1280, 1249, 1197, 1133, 1085, 1048, 1012; ¹H NMR (400 MHz, CDCl₃) δ 9.14 (1H, s), 9.00 (1H, d, *J* = 6.8 Hz), 8.58 (1H, d, *J* = 8.6 Hz), 7.82–7.73 (1H, m), 7.63–7.54 (1H, m); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 153.5 (C), 143.7 (CH, q, *J* = 3.3 Hz), 137.5 (C, q, *J* = 35.8 Hz), 135.4 (C), 130.1 (CH), 126.8 (CH), 125.2 (C), 122.2 (C, q, *J* = 275.0 Hz), 120.8 (CH), 119.9 (CH); ¹⁹F NMR (376 MHz, CDCl₃) δ –65.07; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₆F₃N₄ 239.0536; Found 239.0535.

**7-Methoxypyrido[1',2':1,5]pyrazolo[3,4-b]pyrazine (2c).** The general procedure D was applied from 1c (60 mg, 0.30 mmol) for 2 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 55 mg (0.27 mmol, 92%) of 2c as a yellow powder. mp = 178–179 °C; IR ν̄ (cm⁻¹) 3341, 3056, 1633, 1549, 1397, 1263, 1151, 1114, 1036, 1010; ¹H NMR (250 MHz, CDCl₃) δ 8.84 (1H, d, *J* = 2.1 Hz), 8.57 (1H, d, *J* = 2.1 Hz), 8.13 (1H, dd, *J* = 8.5, 1.2 Hz), 7.65 (1H, dd, *J* = 8.5, 7.8 Hz), 6.83 (1H, dd, *J* = 7.8, 1.2 Hz), 4.32 (3H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 153.5 (C), 151.2 (C), 147.7 (CH), 139.4 (CH), 136.6 (C), 126.7 (CH), 126.3 (C), 110.8 (CH), 97.2 (CH), 57.5 (CH₃); HRMS (ESITOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₉N₄O 201.0776; Found 201.0774.

**9-Methoxypyrido[1',2':1,5]pyrazolo[3,4-b]pyrazine (2d).** The general procedure D was applied from 1d (50 mg, 0.25 mmol) for 2 h to provide after purification with column chromatography (eluent 9:1; ethyl acetate/ether petroleum) 45 mg (0.22 mmol, 90%) of 2d as a yellow powder. mp = 192–193 °C; IR ν̄ (cm⁻¹) 3459, 3117, 3045, 3018, 2957, 1907, 1641, 1539, 1463, 1419, 1311, 1236,

1197, 1162, 1043; ¹H NMR (400 MHz, CDCl₃) δ 8.79 (1H, d, *J* = 2.0 Hz), 8.75 (1H, d, *J* = 7.5 Hz), 8.50 (1H, d, *J* = 2.0 Hz), 7.76 (1H, d, *J* = 2.8 Hz), 7.10 (1H, dd, *J* = 7.5, 2.8 Hz), 4.04 (3H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 158.0 (C), 154.2 (C), 147.5 (CH), 138.4 (CH), 136.3 (C), 130.4 (CH), 126.0 (C), 112.5 (CH), 97.6 (CH), 56.4 (CH₃); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₉N₄O 201.0776; Found 201.0774.

**9-(Trifluoromethyl)pyrido[1',2':1,5]pyrazolo[3,4-b]pyrazine (2e).** The general procedure D was applied from 1e (50 mg, 0.21 mmol) for 2 h to provide, after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 37 mg (0.15 mmol, 74%) of 2e as a yellow powder. mp = 196–197 °C; IR ν̄ (cm⁻¹) 3338, 3126, 3078, 3036, 1565, 1459, 1327, 1268, 1117, 1047; ¹H NMR (400 MHz, CDCl₃) δ 9.01 (1H, d, *J* = 7.3 Hz), 8.91 (1H, d, *J* = 2.0 Hz), 8.79–8.75 (1H, m), 8.72 (1H, d, *J* = 2.0 Hz), 7.59 (1H, dd, *J* = 7.2, 2.1 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 153.7 (C), 148.1 (CH), 141.5 (CH), 133.7 (C), 129.9 (CH), 127.1 (C), 126.8 (C, q, *J* = 34.0 Hz), 123.0 (C, q, *J* = 273.0 Hz), 116.8 (CH, q, *J* = 4.9 Hz), 114.8 (CH, q, *J* = 3.5 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –63.02; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₆F₃N₄ 239.0545; Found 239.0541.

**Pyrazolo[1,5-a:3,4-b']dipyridine (2f).** The general procedure D was applied from 1f (90 mg, 0.53 mmol) for 2 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 55 mg (0.33 mmol, 62%) of 2f as a colorless solid. mp = 137–138 °C; IR ν̄ (cm⁻¹) 3118, 3051, 2324, 2185, 2076, 1644, 1589, 1548, 1459, 1278, 1255, 1141, 1077; ¹H NMR (400 MHz, CDCl₃) δ 8.98–8.88 (2H, m), 8.46 (1H, dd, *J* = 8.1, 1.6 Hz), 8.17 (1H, d, *J* = 8.6 Hz), 7.52 (1H, *t*, *J* = 7.8 Hz), 7.33 (1H, *t*, *J* = 6.9 Hz), 7.21 (1H, dd, *J* = 8.1, 4.4 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 159.8 (C), 153.2 (CH), 136.1 (C), 129.4 (CH), 130.0 (CH), 123.7 (CH), 118.6 (CH), 117.5 (CH), 115.8 (CH), 108.0 (C); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈N₃ 170.0713; Found 170.0712.

**Pyrazolo[1,5-a:3,4-b']dipyridine-3-carbonitrile (2g).** The general procedure D was applied from 1g (100 mg, 0.51 mmol) for 2 h to provide 72 mg (0.37 mmol, 73%) of 2g after purification with column chromatography (eluent 6:4; ethyl acetate/ether petroleum) as a yellow powder. mp = 270–271 °C; IR ν̄ (cm⁻¹) 3120, 3050, 2999, 2227, 1577, 1501, 1432, 1391, 1312, 1280, 1197, 1134, 1109, 1042, 1004; ¹H NMR (400 MHz, CDCl₃) δ 8.88 (1H, d, *J* = 7.0 Hz), 8.54 (1H, d, *J* = 8.5 Hz), 8.20 (1H, d, *J* = 8.9 Hz), 7.77 (1H, d, *J* = 8.9 Hz), 7.72–7.63 (1H, m), 7.54–7.45 (1H, m); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 142.9 (C), 135.9 (C), 134.1 (C), 129.1 (CH), 126.7 (C), 126.4 (CH), 125.8 (CH), 123.9 (CH), 119.9 (CH), 119.2 (CH), 118.46 (C); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₁H₇N₄ 195.0665; Found 195.0663.

**3-(Trifluoromethyl)pyrazolo[1,5-a:3,4-b']dipyridine (2i).** The general procedure D was applied from 1i (80 mg, 0.33 mmol) for 1 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 55 mg (0.23 mmol, 70%) of 2i as a yellow powder. mp = 232–233 °C; IR ν̄ (cm⁻¹) 3067, 2980, 2901, 2645, 2325, 2157, 1979, 1653, 1609, 1537, 1429, 1369, 1340, 1305, 1296, 1285, 1153, 1131, 1096, 1058; ¹H NMR (400 MHz, CDCl₃) δ 9.09 (1H, s), 8.96 (1H, d, *J* = 6.9 Hz), 8.72 (1H, s), 8.23 (1H, d, *J* = 8.6 Hz), 7.64 (1H, *t*, *J* = 7.9 Hz), 7.43 (1H, *t*, *J* = 7.1 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) δ 160.4 (C), 149.7 (CH, q, *J* = 3.6 Hz), 135.9 (C), 129.7 (CH), 127.8 (CH, q, *J* = 4.1 Hz), 125.5 (CH), 124.6 (C, q, *J* = 272.3 Hz), 118.9 (CH), 118.7 (CH), 118.2 (C, q, *J* = 33.2 Hz), 106.5 (C); ¹⁹F NMR (376 MHz, CDCl₃) δ –60.15; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd for C₁₁H₇F₃N₃ 238.0587; Found 238.0589.
**Pyrazolo[1,5-a:4,3-b']dipyridine (2j).** The general procedure D was applied from 1j (100 mg, 0.58 mmol) for 2 h to provide after purification with column chromatography (eluent 6:4; ethyl acetate/ ether petroleum) 43 mg (0.25 mmol, 43%) of 2j as a colorless powder. mp = 112–113 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3041, 1545, 1518, 1437, 1390, 1330, 1267, 1208, 1142, 1119, 1010; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.80 (1H, d, *J* = 6.9 Hz), 8.67 (1H, d, *J* = 4.1 Hz), 8.46 (1H, d, *J* = 8.6 Hz), 8.17 (1H, d, *J* = 8.7 Hz), 7.56–7.44 (2H, m), 7.31 (1H, t, *J* = 6.9 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 144.9 (CH), 143.1 (C), 135.4 (C), 133.0 (C), 128.4 (CH), 123.6 (CH), 123.4 (CH), 123.3 (CH), 118.5 (CH), 117.9 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₈N₃ 170.0713; Found 170.0714.

**3-(Trifluoromethyl)pyrazolo[1,5-a:4,3-b']dipyridine (2k).** The general procedure D was applied from 1k (100 mg, 0.42 mmol) for 1 h to provide after purification with column chromatography (eluent 6:4; ethyl acetate/ether petroleum) 54 mg (0.23 mmol, 55%) of 2k as a brown powder. mp = 139–140 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3110, 3051, 2931, 2846, 1635, 1587, 1443, 1360, 1283, 1221, 1170, 1119, 1072; ¹H NMR (400 MHz, CDCl₃) $\delta$ 8.85 (1H, d, *J* = 6.8 Hz), 8.54 (1H, d, *J* = 8.6 Hz), 8.26 (1H, d, *J* = 8.9 Hz), 7.81 (1H, d, *J* = 9.0 Hz), 7.62–7.55 (1H, m), 7.41 (1H, td, *J* = 6.9, 1.5 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 143.3 (C), 142.3 (C, q, *J* = 35.4 Hz), 135.9 (C), 132.4 (C), 128.9 (CH), 124.7 (CH), 124.5 (CH), 122.3 (C, q, *J* = 274.1 Hz), 119.6 (CH, q, *J* = 2.6 Hz), 119.2 (CH), 119.2 (CH); ¹⁹F NMR (376 MHz, CDCl₃) $\delta$ –65.72; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₁H₇F₃N₃ 238.0587; Found 238.0589.

**Pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidine (2l).** The general procedure D was applied from 1l (100 mg, 0.58 mmol) for 2 h to provide after purification with column chromatography (eluent 98:2; dichloromethane/MeOH) 43 mg (0.26 mmol, 44%) of 2l as a yellow powder. mp = 201–202 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3087, 3040, 2919, 2850, 2160, 1641, 1590, 1543, 1435, 1278, 1241, 1189, 1117, 1095, 1021; ¹H NMR (400 MHz, CDCl₃) $\delta$ 9.55 (1H, s), 9.25 (1H, s), 8.97 (1H, d, *J* = 6.8 Hz), 8.28 (1H, d, *J* = 8.6 Hz), 7.72 (1H, t, *J* = 7.9 Hz), 7.48 (1H, t, *J* = 7.0 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 161.0 (C), 158.2 (CH), 152.8 (CH), 135.3 (C), 130.0 (CH), 127.1 (CH), 119.2 (CH), 119.0 (CH), 107.5 (C); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₉H₇N₄ 171.0665; Found 171.0668.

**2-(Trifluoromethyl)pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidine (2m).** The general procedure D was applied from 1m (60 mg, 0.25 mmol) for 1 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 45 mg (0.19 mmol, 75%) of 2m as a yellow powder. mp = 231–232 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3113, 3082, 3052, 2679, 2513, 1982, 1953, 1897, 1834, 1733, 1642, 1587, 1526, 1482, 1427, 1368, 1314, 1285, 1258, 1208, 1184, 1107, 1003; ¹H NMR (400 MHz, CDCl₃) $\delta$ 9.66 (1H, s), 9.09–9.04 (1H, m), 8.43–8.36 (1H, m), 7.89–7.81 (1H, m), 7.64–7.56 (1H, m); ¹³C{1H} NMR (101 MHz, Acetone-d₆) $\delta$ 161.3 (C), 155.5 (C, q, *J* = 35.6 Hz), 154.6 (CH), 136.5 (C), 131.3 (CH), 129.6 (CH), 121.7 (CH), 121.4 (C, q, *J* = 275.0 Hz), 121.1 (CH), 109.4 (C); ¹⁹F NMR (376 MHz, Acetone-d₆) $\delta$ –69.81; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₆F₃N₄ 239.0539; Found 239.0541.

**2-Methoxypyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidine (2n).** The general procedure D was applied from 1n (50 mg, 0.25 mmol) for 1 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 35 mg (0.18 mmol, 71%) of 2n as a colorless powder. mp = 213–214 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3085, 3048, 3021, 3002, 2953, 2850, 1962, 1726, 1654, 1596, 1528, 1439, 1392, 1368, 1244, 1202, 1143, 1047; ¹H NMR (400 MHz, CDCl₃) $\delta$ 9.33 (1H, s), 8.86–8.80 (1H, m), 8.13–8.08 (1H, m),

7.67–7.60 (1H, m), 7.36–7.30 (1H, m), 4.15 (3H, s); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 166.1 (C), 163.6 (C), 155.3 (CH), 136.1 (C), 130.0 (CH), 127.3 (CH), 117.9 (CH), 117.7 (CH), 103.4 (C), 55.2 (CH₃); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₉N₄O 201.0774; Found 201.0771.

**4-(Trifluoromethyl)pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidine (2o).** The general procedure D was applied from 1o (50 mg, 0.21 mmol) for 1 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 42 mg (0.18 mmol, 85%) of 2o as a colorless powder. mp = 197–198 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3049, 1636, 1583, 1543, 1447, 1422, 1347, 1312, 1286, 1132, 1111; ¹H NMR (400 MHz, CDCl₃) $\delta$ 9.33 (1H, s), 9.05 (1H, d, *J* = 6.8 Hz), 8.45 (1H, d, *J* = 8.7 Hz), 7.88–7.79 (1H, m), 7.63–7.57 (1H, m); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 162.2 (C), 157.1 (CH), 150.8 (C, q, *J* = 39.1 Hz), 133.8 (C), 130.3 (CH), 128.4 (CH), 121.5 (CH, q, *J* = 4.6 Hz), 121.1 (C, q, *J* = 276.5 Hz), 120.3 (CH), 102.5 (C); ¹⁹F NMR (376 MHz, CDCl₃) $\delta$ –68.29; HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₁₀H₆F₃N₄ 239.0539; Found 239.0542.

**Pyrazino[2',3':3,4]pyrazolo[1,5-a]pyrimidine (2p).** The general procedure D was applied from 1p (60 mg, 0.35 mmol) for 1 h to provide after purification with column chromatography (eluent 7:3; ethyl acetate/ether petroleum) 34 mg (0.20 mmol, 58%) of 2p as a yellow powder. mp = 230–231 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3066, 3003, 2077, 1935, 1626, 1611, 1558, 1540, 1526, 1388, 1340, 1265, 1244, 1206, 1155, 1117, 1074; ¹H NMR (400 MHz, CDCl₃) $\delta$ 9.13 (1H, dd, *J* = 7.0, 1.5 Hz), 8.90 (2H, dd, *J* = 3.7, 1.6 Hz), 8.78 (1H, d, *J* = 1.8 Hz), 7.47 (1H, dd, *J* = 7.0, 4.2 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 154.3 (C), 148.6 (CH), 148.5 (CH), 142.7 (C), 141.9 (CH), 135.4 (CH), 123.5 (C), 114.1 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₈H₆N₅ 172.0618; Found 172.0619.

**Pyrazolo[1,5-a:3,4-b']dipyrazine (2q).** The general procedure D was applied from 1q (60 mg, 0.35 mmol) for 1 h to provide after purification with column chromatography (eluent 8:2; ethyl acetate/ether petroleum) 49 mg (0.29 mmol, 83%) of 2q as a yellow powder. mp = 239–240 °C; IR $\bar{\nu}$ (cm$^{-1}$) 3093, 3070, 3044, 3021, 2954, 2506, 1943, 1899, 1769, 1722, 1666, 1554, 1541, 1517, 1441, 1375, 1304, 1251, 1190, 1158, 1000; ¹H NMR (400 MHz, CDCl₃) $\delta$ 9.87 (1H, s), 8.96 (1H, d, *J* = 2.0 Hz), 8.84 (2H, d, *J* = 2.5 Hz), 8.54 (1H, d, *J* = 4.7 Hz); ¹³C{1H} NMR (101 MHz, CDCl₃) $\delta$ 152.6 (C), 147.8 (CH), 144.4 (CH), 142.6 (CH), 136.9 (CH), 129.6 (C), 125.8 (C), 122.2 (CH); HRMS (ESI-TOF) *m/z*: [M+H]⁺ Calcd. for C₈H₆N₅ 172.0618; Found 172.0619.

# AUTHOR INFORMATION

## Corresponding Authors

Marie-Aude Hiebel – Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans 45067, France; 
[orcid.org/00000001-9476-9176](https://orcid.org/00000001-9476-9176); Phone: (+33)-2-3849-4575;
Email: [marie-aude.hiebel@univ-orleans.fr](mailto:marie-aude.hiebel@univ-orleans.fr)

Franck Suzenet – Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans 45067, France; [orcid.org/0000-0003-1394-1603](https://orcid.org/0000-0003-1394-1603); Phone: (+33)-2-3849-4580;
Email: [franck.suzenet@univ-orleans.fr](mailto:franck.suzenet@univ-orleans.fr)

## Authors

Moussa Ndiaye – Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans 45067, France
Author Contributions

M.N.: investigation, methodology, synthesis and formal analysis. F.R.: DFT calculations and writing. M.-A.H.: formal analysis, conceptualization, supervision, funding acquisition, writing – original draft, and writing – review and editing. F.S.: formal analysis, conceptualization, supervision, writing – review and editing.

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

The authors gratefully acknowledge major financial support
from the French Agence Nationale de la Recherche - ANR
(ANR-18-CE07-0009-01), which made this study possible, as
well as the projects CHemBio (FEDER-FSE 2014-
2020EX003677), Tech-Sab (FEDER-FSE 2014-2020-
EX011313), the RTR MotivHealth (2019-00131403), and the
LabEx programs SYNORG (ANR-11-LABX-0029) and IRON
(ANR-11-LABX-0018-01) for their financial support to ICOA,
UMR 7311, University of Orléans, CNRS. The authors also
gratefully acknowledge Sophie Front from the synthesis
platform of ICOA for the scale-up reactions performed on 1f
and 2f.

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